Risk to the Thyroid from Ionizing Radiation

NCRP REPORT No. 159

Risk to the Thyroid from Ionizing Radiation

Recommendations of the NATIONAL COUNCIL ON RADIATION PROTECTION AND MEASUREMENTS

December 1, 2008

National Council on Radiation Protection and Measurements 7910 Woodmont Avenue, Suite 400 / Bethesda, MD 20814-3095

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Library of Congress Cataloging-in-Publication Data National Council on Radiation Protection and Measurements. Scientific Committee 1-8 on Risk to the Thyroid from Ionizing Radiation. Risk to the thyroid from ionizing radiation. p. ; cm. -- (NCRP report ; no. 159) Extensive update and expansion of: Induction of thyroid cancer by ionizing radiation. c1985. Includes bibliographical references and index. ISBN 978-0-929600-97-0 1. Thyroid gland--Cancer--Etiology. 2. Ionizing radiation--Toxicology. 3. Ionizing radiation--Dose-response relationship. I. National Council on Radiation Protection and Measurements. Induction of thyroid cancer by ionizing radiation. II. Title. III. Series: NCRP report ; no. 159. [DNLM: 1. Thyroid Neoplasms--etiology. 2. Parathyroid Diseases--etiology. 3. Parathyroid Glands--radiation effects. 4. Radiation Dosage. 5. Thyroid Diseases-etiology. 6. Thyroid Gland--radiation effects. WK 270 N27782r 2009] RC280.T6N38 2009 362.196'9897--dc22 2008052979

Copyright © National Council on Radiation Protection and Measurements 2008 All rights reserved. This publication is protected by copyright. No part of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotation in critical articles or reviews.

[For detailed information on the availability of NCRP publications see page 521.]

Preface This Report provides an extensive update and expansion of the earlier National Council on Radiation Protection and Measurements (NCRP) Report No. 80, Induction of Thyroid Cancer by Ionizing Radiation. Reviews were performed of pertinent additional and new observations reported over the past two decades on radiation dosimetry from: • epidemiological studies of radiogenic thyroid disease; • dose-response relationships; • risk estimates and models for internal and external exposures of humans to ionizing radiations; • genetic alterations associated with cellular and organ damage; and • thyroid and parathyroid diseases. This Report uses updated observations and analytic procedures to assess the risk of carcinogenic and benign diseases of the thyroid gland from ionizing radiation, and it also includes the risk of diseases of the parathyroid gland following ionizing radiation exposure. Two different mathematical models are generally used in this Report to summarize the dose-response relationships observed in epidemiological studies. The use of an excess absolute risk (EAR) or excess relative risk (ERR) model does not imply any biological relationship between the risk due to radiation and the baseline risk. The EAR model expresses the excess cancer risk as being simply added to the baseline (or background) risk, and is regarded as “additive.” The ERR model expresses the excess cancer risk due to an exposure as being proportional to the baseline risk and is regarded as “multiplicative.” There are advantages and disadvantages to both models. The collective results of these analyses are that radiation, whether from external or internal sources, can increase the risk of thyroid cancer, with age at the time of exposure the most critical modifying factor (i.e., children are much more sensitive than adults). The risk of thyroid and parathyroid disease following external radiation exposure has been better quantified since the last NCRP iii

iv / PREFACE report on this topic. However, there remains much to be learned about the risk of thyroid disease following radioiodine exposure. In the interval between the last NCRP report on this topic and the present Report there has been an enormous effort to further quantify the risk, especially of thyroid cancer, following exposure to 131I. The nuclear reactor accident at Chernobyl (April 1986) exposed millions of individuals of all age groups (including those in utero) to substantial doses of 131I. Other populations exposed to radioiodine such as the population living downwind from the Semipalatinsk Nuclear Test Site are only now being studied. Scrutiny at all levels has been high and ongoing. There appears to be a clear association between radioiodine exposure and thyroid cancer, mainly in children, but risk estimates are still associated with more uncertainty than is desirable. Reliable age- and sex-specific risk estimates require good information on dosimetry and the influence of other factors such as the amount of stable iodine in the diet. The study of radiation-induced cancers is a long-term project. Further study will be needed to define better the risk due to radioiodine exposure and to determine the effects of time since exposure. Considerably more research needs to be done to understand better the relative biological effectiveness of internal dose from the different radioactive iodines when compared to external dose. The present Report draws 30 conclusions and makes five recommendations for future endeavors in this important area of human health and safety. This Report was prepared by NCRP Scientific Committee 1-8 on Risk to the Thyroid from Ionizing Radiation. Serving on this Scientific Committee were: Henry D. Royal, Chairman Mallinckrodt Institute of Radiology St. Louis, Missouri Members David V. Becker New York Hospital Cornell Medical Center New York, New York

A. Bertrand Brill Vanderbilt University Nashville, Tennessee

Roy E. Shore Radiation Effects Research Foundation Hiroshima, Japan

R. Michael Tuttle Memorial Sloan Kettering Cancer Center New York, New York

PREFACE

Bruce W. Wachholz Gaithersburg, Maryland

/ v

David A. Weber Victor, New York

Pasquale D. Zanzonico Memorial Sloan-Kettering Cancer Center New York, New York

Advisors Elaine Ron National Cancer Institute Bethesda, Maryland

Consultants Jay H. Lubin National Cancer Institute Bethesda, Maryland

Xiaonan Xue Albert Einstein College of Medicine New York, New York

NCRP Secretariat Morton W. Miller, Staff Consultant (2006–2008) William M. Beckner, Staff Consultant (1996–2005) Cindy L. O’Brien, Managing Editor David A. Schauer, Executive Director

The Council expresses its appreciation to the Committee members and consultants for their time and efforts devoted to the preparation of this Report. NCRP gratefully acknowledges the financial support provided by the U.S. Environmental Protection Agency (EPA), the National Aeronautics and Space Administration (NASA), and the National Cancer Institute (NCI) under Grant Number R24 CA074206-10. The contents of this Report are the sole responsibility of NCRP, and do not necessarily represent the official views of EPA, NASA or NCI, National Institutes of Health.

Thomas S. Tenforde President

Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17 1.1 Historic Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18 1.1.1 Radioiodine Production and Use in the Study of Thyroid Physiology . . . . . . . . . . . . . . . . . . . . . . . .18 1.1.2 Use of Radioiodine in Medical Treatment . . . . . .19 1.1.3 Radiation Effects on the Thyroid Observed in Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20 1.1.4 Radioiodine in the Environment . . . . . . . . . . . . . .23 1.2 Overview of this Report . . . . . . . . . . . . . . . . . . . . . . . . . . .27 1.2.1 Thyroid and Parathyroid Glands . . . . . . . . . . . . .27 1.2.2 Radiation Dosimetry and Dose Reconstruction . .27 1.2.3 Radiation Effects . . . . . . . . . . . . . . . . . . . . . . . . . .29 1.2.4 Radiation Risk for Thyroid Neoplasms . . . . . . . .29 1.2.5 Screening for Thyroid Disease Following Radiation Exposure . . . . . . . . . . . . . . . . . . . . . . . .29 1.2.6 Conclusions and Recommendations . . . . . . . . . . .30 1.2.7 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30 2. Thyroid and Parathyroid Glands . . . . . . . . . . . . . . . . . . . . . .31 2.1 Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . .31 2.1.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31 2.1.2 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34 2.1.2.1 Iodine Metabolism . . . . . . . . . . . . . . . . .35 2.1.2.2 Thyroid Hormone Metabolism. . . . . . . .38 2.1.2.3 Regulatory Effects of Stable Iodine . . . .40 2.1.2.4 Parathyroid Hormone Metabolism and Regulation . . . . . . . . . . . . . . . . . . . .42 2.2 Diseases of the Thyroid and Parathyroid Glands . . . . . . .42 2.2.1 Benign Thyroid Nodules . . . . . . . . . . . . . . . . . . . .43 2.2.2 Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . .44 2.2.2.1 Thyroid Cancers in Adults . . . . . . . . . . .45 2.2.2.2 Thyroid Cancers in Children . . . . . . . . .48 2.2.3 Functional Diseases . . . . . . . . . . . . . . . . . . . . . . . .49

vii

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2.3

2.4

2.2.3.1 Hyperthyroidism . . . . . . . . . . . . . . . . . . 2.2.3.2 Hypothyroidism. . . . . . . . . . . . . . . . . . . 2.2.3.3 Hyperparathyroidism . . . . . . . . . . . . . . Medical Uses of Radiation . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1 External Beam Radiation Therapy Exposures of the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2 Diagnostic Use of Radioactive Tracers in the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3 Radioactive Iodine Therapy . . . . . . . . . . . . . . . . . 2.3.4 Thyroid Dose from Radioactive Iodine . . . . . . . . Thyroid Genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1 DNA Damage and Cellular Response . . . . . . . . . 2.4.2 Molecular Biology Techniques . . . . . . . . . . . . . . . 2.4.2.1 Functional Significance of DNA Alteration. . . . . . . . . . . . . . . . . . . . . . . . 2.4.2.2 Technical Requirements . . . . . . . . . . . . 2.4.2.3 Oncogenesis, Mitotic Rate, and Growth Potential . . . . . . . . . . . . . . . . . .

49 50 51 51 52 52 53 55 56 57 60 60 60 61

3. Radiation Dosimetry and Dose Reconstruction . . . . . . . . 63 3.1 Specification of Dose in Principle and in Practice . . . . . . 63 3.1.1 Specification of Dose: Ideal . . . . . . . . . . . . . . . . . 64 3.1.2 Specification of Dose: Practical . . . . . . . . . . . . . . 64 3.1.2.1 Physical Dosimetry . . . . . . . . . . . . . . . . 65 3.1.2.2 Biological Dosimetry . . . . . . . . . . . . . . . 66 3.2 External Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.2.1 Medical External Radiation Exposure . . . . . . . . 67 3.2.2 External Radiation Exposure Associated with the Atomic Bombings of Hiroshima and Nagasaki . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 3.3 Internal Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 3.3.1 Radioisotopes of Iodine . . . . . . . . . . . . . . . . . . . . . 72 3.3.2 Age-Dependent Thyroid Absorbed Doses from Radioisotopes of Iodine . . . . . . . . . . . . . . . . . . . . . 79 3.3.3 Environmental Dispersion of Radioiodine . . . . . 87 3.3.4 Potassium Iodide Blockade of Radioiodine Uptake in the Thyroid . . . . . . . . . . . . . . . . . . . . . 92 3.3.5 Limitations of the Radiobiological Significance of Iodine-129 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 3.3.6 Spatial and Temporal Inhomogeneities in Intrathyroidal Radioiodine Distribution and Absorbed Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 3.3.7 Dose Assessment of Major Environmental Releases of Radioiodines . . . . . . . . . . . . . . . . . . 102

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3.3.7.1

Nevada Test Site Cohort Exposed to Fallout . . . . . . . . . .104 3.3.7.2 Marshall Islanders . . . . . . . . . . . . . . . .107 3.3.7.3 Hanford Site . . . . . . . . . . . . . . . . . . . . .111 3.3.7.4 Chernobyl Nuclear Reactor Accident .114 Radiation Dosimetry in Specific Epidemiological Studies of Radiogenic Thyroid Disease . . . . . . . . . . . . . .119 131I-Contaminated

3.4

4. Radiation Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .143 4.1 Animal Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .144 4.1.1 Experiments with Rodents . . . . . . . . . . . . . . . . .144 4.1.2 Experiments in Larger Animals . . . . . . . . . . . . .146 4.1.3 Experiments to Determine Relative Biological Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 4.2 Types of Epidemiologic Studies . . . . . . . . . . . . . . . . . . . .149 4.2.1 Cohort Studies . . . . . . . . . . . . . . . . . . . . . . . . . . .153 4.2.2 Case-Control Studies . . . . . . . . . . . . . . . . . . . . . .154 4.2.3 Clinical Screening Studies . . . . . . . . . . . . . . . . .155 4.2.4 Ecological (Aggregate) Studies . . . . . . . . . . . . . .156 4.3 Methodological Issues Regarding Studies of Radiation and Thyroid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .157 4.3.1 Sources of Uncertainty in Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158 4.3.2 Incidence Versus Mortality Data . . . . . . . . . . . .159 4.3.3 Micro-Carcinomas and Screening for Thyroid Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161 4.4 Human Thyroid Cancer Following External Irradiation 163 4.4.1 Atomic-Bomb Survivors Study . . . . . . . . . . . . . .164 4.4.2 Rochester Thymus Study . . . . . . . . . . . . . . . . . .174 4.4.3 Israeli Tinea Capitis Study . . . . . . . . . . . . . . . . .175 4.4.4 Chicago Head and Neck Irradiation Study . . . .176 4.4.5 Boston Lymphoid Hyperplasia Study . . . . . . . . .178 4.4.6 Childhood Cancer Survivor Study . . . . . . . . . . .179 4.4.7 Swedish Skin Hemangioma Studies (Gothenburg and Stockholm) . . . . . . . . . . . . . . .181 4.5 Human Thyroid Cancer Following Internal Irradiation .182 4.5.1 Diagnostic Iodine-131 Studies . . . . . . . . . . . . . .183 4.5.1.1 Swedish Diagnostic 131I Study . . . . . . .183 4.5.1.2 FDA Childhood Diagnostic 131I Study .189 4.5.1.3 German Diagnostic 131I Study in Children . . . . . . . . . . . . . . . . . . . . . . . .190 4.5.1.4 Summary of Thyroid Cancers Following Diagnostic Internal Irradiation with 131I . . . . . . . . . . . . . . .190 4.5.2 Therapeutic Iodine-131 Studies . . . . . . . . . . . . .191

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4.6

4.7

Swedish Hyperthyroid Study . . . . . . . U.S. Cooperative Thyrotoxicosis Therapy Follow-Up Study. . . . . . . . . . 4.5.2.3 British Hyperthyroid Study . . . . . . . . 4.5.3 Environmental Iodine-131 Studies . . . . . . . . . . 4.5.3.1 Nevada Test Site . . . . . . . . . . . . . . . . . 4.5.3.2 Fallout from Nuclear Weapons Testing . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3.3 Marshall Islanders . . . . . . . . . . . . . . . 4.5.3.4 Semipalatinsk Nuclear Test Site . . . . 4.5.3.5 Hanford Site . . . . . . . . . . . . . . . . . . . . 4.5.3.6 Chernobyl Environmental Exposure . 4.5.3.7 Mayak Nuclear Weapons Production Facility . . . . . . . . . . . . . . . . . . . . . . . . . 4.5.3.8 Chernobyl Occupational Exposure. . . Benign Thyroid Nodules Following Radiation Exposure 4.6.1 Medical Exposures: External . . . . . . . . . . . . . . . 4.6.1.1 Robert Packer Hospital Head and Neck Study . . . . . . . . . . . . . . . . . . . . . 4.6.1.2 French Hemangiomas Study . . . . . . . 4.6.1.3 Massachusetts Fluoroscopy Study . . . 4.6.1.4 Chicago Head and Neck Irradiation Study . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.1.5 Tinea Capitis Study . . . . . . . . . . . . . . 4.6.2 Stockholm Medical Diagnostic Iodine-131 Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6.3 Atomic-Bomb Survivors . . . . . . . . . . . . . . . . . . . 4.6.3.1 Nagasaki Thyroid Disease Study . . . . 4.6.3.2 Hiroshima Autopsy Study . . . . . . . . . 4.6.3.3 Noncancer Disease Incidence . . . . . . . 4.6.3.4 Thyroid Disease Prevalence . . . . . . . . 4.6.4 Environmental Exposures . . . . . . . . . . . . . . . . . 4.6.4.1 Chernobyl Cleanup Workers Study . . 4.6.4.2 Chinese High Background Study . . . . 4.6.4.3 India High Background Study . . . . . . Functional Thyroid Disease . . . . . . . . . . . . . . . . . . . . . . . 4.7.1 Thyroid Function Following External Beam Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . 4.7.2 Thyroid Function Following Radioiodine Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7.3 Thyroid Function Following Environmental Exposure to Radioiodine . . . . . . . . . . . . . . . . . . 4.7.3.1 Marshall Islands Fallout. . . . . . . . . . . 4.7.3.2 Nevada Test Site . . . . . . . . . . . . . . . . . 4.7.3.3 Hanford Thyroid Disease Study . . . . .

191 192 193 194 195 196 197 200 201 203 217 217 220 220 220 221 228 228 229 229 230 230 230 231 231 232 232 233 234 235 235 237 238 238 239 241

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4.7.3.4

Evidence from Atomic-Bomb Survivors in Nagasaki and Hiroshima. . . . . . . . .241 4.7.3.5 Chernobyl Nuclear Reactor Accident .244 4.7.4 Summary of Major Points of the Medical Literature Review . . . . . . . . . . . . . . . . . . . . . . . .247 4.8 Molecular Effects of Ionizing Radiation to the Thyroid .248 4.8.1 Generalized, Less Specific Nuclear Damage . . .248 4.8.1.1 Quantitative Abnormalities in Nuclear DNA . . . . . . . . . . . . . . . . . . . .248 4.8.1.2 Chromosome Banding Studies. . . . . . .249 4.8.1.3 Fluorescent Chromosome Specific Analysis . . . . . . . . . . . . . . . . . . . . . . . .250 4.8.1.4 Micro- and Minisatellite DNA Patterns . . . . . . . . . . . . . . . . . . . . . . . .251 4.8.1.5 Gene Expression Analysis . . . . . . . . . .251 4.8.2 Specific Oncogene Activation . . . . . . . . . . . . . . .251 4.8.2.1 RET Proto-oncogene Activation. . . . . .252 4.8.2.2 Other Specific Mutations . . . . . . . . . . .253 4.8.2.3 Bystander Effects of Ionizing Radiation . . . . . . . . . . . . . . . . . . . . . . .253 4.8.2.4 Search for a Molecular Signature . . . .254 4.9 Parathyroid Function . . . . . . . . . . . . . . . . . . . . . . . . . . . .254 4.9.1 Swedish Tuberculous Adenitis Study . . . . . . . . .255 4.9.2 Minnesota Hyperparathyroidism Study . . . . . . .256 4.9.3 Atomic-Bomb Survivors Study . . . . . . . . . . . . . .256 4.9.4 Chicago Head and Neck Irradiation Study . . . .256 4.10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .257 5. Radiation Risk for Thyroid Neoplasms . . . . . . . . . . . . . . .259 5.1 Dose-Response Relationships . . . . . . . . . . . . . . . . . . . . . .260 5.1.1 Excess Absolute Risk Model. . . . . . . . . . . . . . . . .261 5.1.2 Excess Relative Risk Model . . . . . . . . . . . . . . . . .264 5.2 Past Risk Estimates and Models . . . . . . . . . . . . . . . . . . .267 5.3 Factors that Affect Thyroid Cancer Risk Estimates . . . .270 5.3.1 Analyses of External Radiation Data on Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .270 5.3.1.1 Shape of the Dose-Response Curve . . .273 5.3.1.2 Effect of Dose Uncertainty on the Risk Estimates . . . . . . . . . . . . . . . . . . .275 5.3.1.3 Effects of Fractionation or Protraction of Dose. . . . . . . . . . . . . . . . . . . . . . . . . .278 5.3.2 Modifiers of Thyroid Cancer Radiation Risk . . .278 5.3.2.1 Variation in Risk by Age at Exposure .278 5.3.2.2 Variation in Risk by Time Since Exposure or Attained Age . . . . . . . . . .279

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5.4

5.5

Variation in Thyroid Cancer Risk by Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 5.3.2.4 Variation in Thyroid Cancer Risk by Ethnicity . . . . . . . . . . . . . . . . . . . . . . . 283 5.3.2.5 Impact of Thyroid Cancer Screening on Risk Estimates . . . . . . . . . . . . . . . . 285 5.3.2.6 Hereditary Factors and Radiation-Induced Thyroid Cancer . . 285 5.3.2.7 Other Possible Modifiers of Thyroid Cancer Risk from Radiation . . . . . . . . 286 5.3.3 Possible Models of Thyroid Cancer Risk from Ionizing Radiation . . . . . . . . . . . . . . . . . . . . . . . 286 5.3.3.1 Estimated EAR (104 PY Gy)–1 for External, Low-LET Radiation . . . . . . 286 5.3.3.2 Estimated ERR Gy –1 for External, Low-LET Radiation. . . . . . . . . . . . . . . 287 5.3.3.3 Temporal Aspects of Risk Models for Thyroid Cancer . . . . . . . . . . . . . . . . . . 288 5.3.3.4 Comparison of Risk Models for Thyroid Cancer . . . . . . . . . . . . . . . . . . . . . . . . . 290 5.3.4 Estimates of Lifetime Risks of Thyroid Cancer from External Exposure: Results and Comparison of Models 1 through 6 . . . . . . . . . . 294 5.3.5 Estimation of Lifetime Thyroid Cancer Mortality Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 5.3.6 Internal-Exposure Risk Estimates for Thyroid Cancer: Relative Biological Effectiveness . . . . . 306 Estimation of Radiation Risk for Thyroid Nodules . . . . 313 5.4.1 Acute External Exposure in Childhood or Adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 5.4.2 Protracted Exposures and Adult Exposures . . . 314 5.4.3 Discussion and Conclusions Regarding Radiation Risk of Thyroid Nodules . . . . . . . . . . . . . . . . . . . 314 Summary of Radiation Risk of Thyroid Disease . . . . . . 315

6. Screening for Thyroid Disease Following Radiation Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1 National Cancer Institute Workshop . . . . . . . . 6.1.2 Follow-Up of Patients Treated with External Beam Radiation Therapy for Malignant Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3 National Academy of Sciences Report . . . . . . . . 6.2 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

318 318 319

320 320 322

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7. Conclusions and Recommendations . . . . . . . . . . . . . . . . . .323 7.1 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .323 7.2 Research Recommendations . . . . . . . . . . . . . . . . . . . . . . .330 Appendix A. Radiation Dosimetry Quantities and Units and Related Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .332 A.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .332 A.2 Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .332 A.3 Absorbed Dose and Specific Energy . . . . . . . . . . . . . . . . .336 A.4 Kerma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .338 A.5 Linear Energy Transfer and Lineal Energy . . . . . . . . . .338 A.6 Relative Biological Effectiveness . . . . . . . . . . . . . . . . . . .339 A.7 Quality Factor, Radiation Weighting Factor, Dose Equivalent, and Equivalent Dose . . . . . . . . . . . . . . . . . . .340 A.8 Dose-Rate Effect and Dose and Dose-Rate Effectiveness Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .341 Appendix B. Radiation Dosimetry for External Beam Radiation Therapy and Brachytherapy . . . . . . . . . . . . . . .343 B.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .343 B.1.1 External Beam Radiation Therapy . . . . . . . . . . .343 B.1.2 Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . .345 B.2 Specification of Dose and Dose Distribution . . . . . . . . . .347 B.3 Estimation of Medical External Dose . . . . . . . . . . . . . . .348 B.3.1 External Beam Radiation Therapy . . . . . . . . . . .348 B.3.2 Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . .352 Appendix C. Technical Aspects of Radiation Dosimetry for the Atomic-Bomb Survivors: The Dosimetry System 1986 and the Dosimetry System 2002 . . . . . . . . . . . . . . . . . . . . . .356 Appendix D. Technical Aspects of Thyroid Radiation Dosimetry of Radioisotopes of Iodine . . . . . . . . . . . . . . . .362 D.1 Radioiodide Pharmacokinetics . . . . . . . . . . . . . . . . . . . . .362 D.2 Calculation of Internal Dose . . . . . . . . . . . . . . . . . . . . . . .363 D.3 Dietary Iodine Levels and Potassium Iodide Blockade . .367 Appendix E. Animal Experiments . . . . . . . . . . . . . . . . . . . . . . .370 E.1 Experiments in Rodents . . . . . . . . . . . . . . . . . . . . . . . . . .370 E.1.1 University of California Berkeley . . . . . . . . . . . .370 E.1.2 Post-Graduate Medical School of London . . . . . .374 E.2 Experiments in Larger Animals . . . . . . . . . . . . . . . . . . . .376 E.3 Experiments to Determine Relative Biological Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .378

xiv / CONTENTS Appendix F. Additional Epidemiological Studies on Exposure to External Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382 F.1 Medical Therapy in Childhood . . . . . . . . . . . . . . . . . . . . 382 F.1.1 Childhood Treatment Studies Published Prior to 1965 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382 F.1.2 University of Rochester Thymic Enlargement Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 F.1.3 Cincinnati Benign Childhood Disease Study . . . 387 F.1.4 University of Chicago Thyroid Unit Study . . . . 388 F.1.5 New York Tinea Capitis Study . . . . . . . . . . . . . . 389 F.2 Medical Therapy in Adulthood . . . . . . . . . . . . . . . . . . . . 390 F.2.1 New York Tuberculous Adenitis Study . . . . . . . 390 F.2.2 Leiden, Netherlands Study of Irradiation for Benign Head/Neck Conditions . . . . . . . . . . . . . . 391 F.2.3 Thyroid Cancer and Prior Radiation Therapy . . 392 F.2.4 Gothenburg, Sweden Cervical Tuberculous Adenitis Study . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 F.2.5 Connecticut Case-Control Study . . . . . . . . . . . . 393 F.2.6 Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 393 F.2.7 Radium-226 or X-Ray Therapy for Metropathia 394 F.2.8 Radiotherapy for Peptic Ulcer . . . . . . . . . . . . . . 395 F.2.9 Stockholm, Sweden Study of Irradiation for Benign Breast Disease . . . . . . . . . . . . . . . . . . . . 395 F.2.10 French Study of Skin Angioma Patients . . . . . . 396 F.2.11 Swedish Study Following X-Ray Treatment of Cervical Spine in Adults . . . . . . . . . . . . . . . . . . . 397 F.3 Occupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . 397 F.3.1 Radium Dial Workers . . . . . . . . . . . . . . . . . . . . . 398 F.3.2 Chinese Medical X-Ray Workers . . . . . . . . . . . . 398 F.3.3 U.S. Hanford Site and U.K. Sellafield Site Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 F.4 Medical Diagnostic Studies . . . . . . . . . . . . . . . . . . . . . . . 399 F.4.1 Multiple Fluoroscopic Exams for Tuberculosis Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 F.4.2 Case-Control Studies. . . . . . . . . . . . . . . . . . . . . . 400 Appendix G. Previous Risk Estimates and Models . . . . . . . . G.1 BEIR I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G.2 BEIR III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G.3 NCRP Report No. 80 . . . . . . . . . . . . . . . . . . . . . . . . . . . . G.4 BEIR V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G.5 UNSCEAR Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G.6 BEIR VII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

402 402 403 405 408 409 410

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Appendix H. Supplemental Information on Model Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .411 H.1 Excess Relative and Absolute Risk Estimates for Pooled Analysis of Thyroid Cancer Following Exposure to External Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . .411 H.2 Supplemental Risk Estimates for Pooled Analysis of Thyroid Cancer Following Exposure to External Radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .427 Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .431 Abbreviations and Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . .442 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .444 The NCRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .512 NCRP Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .521 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .532

Executive Summary Purpose and Rationale The primary purpose of this Report is to update the National Council on Radiation Protection and Measurements (NCRP) Report No. 80, Induction of Thyroid Cancer by Ionizing Radiation, first published in 1985, and reprinted in 1987. NCRP Report No. 80 (NCRP, 1985a) entailed an initial analysis of the risk of thyroid cancer from: (1) external radiation from a variety of sources, including studies undertaken in Israel, Japan, and the United States; and (2) internal radiation (notably 131I) from fallout, and diagnostic and therapeutic medical procedures. The modifying effect of ethnic background was also analyzed. The literature surveyed in NCRP Report No. 80 included 147 references, spanning the period from 1949 to 1984. That report was comprised of 11 sections and four appendices, a total of 94 pages. The general conclusions of NCRP Report No. 80 (NCRP, 1985a) were as follows: • Women appear to have at least twice the risk of men for clinically apparent (thyroid) cancers at a given exposure. • Data suggesting that children are more susceptible than adults warrant a 50 % reduction in risk coefficients when estimates derived for people less than or equal to 18 y at exposure are applied to a population of adults. • Human experience and much animal data suggest that 131I is less carcinogenic to the thyroid, per 0.01 Gy absorbed dose, than external radiation. Iodine-131 is considered to be no more than one-third as effective as external radiation in the induction of thyroid cancer in the general population. • For the calculation of risks of fatal (thyroid) cancer, current levels of medical diagnosis and care are assumed, and a maximum of 10 % of the clinically evident radiation-induced thyroid cancers are expected to be lethal. • After exposure to external irradiation, the projected overall lifetime incidence of fatal thyroid cancer would be 7.5 cases per 0.01 Gy absorbed dose to the thyroid in a general population of one million persons. This estimate is consistent 1

2 / EXECUTIVE SUMMARY with earlier lifetime estimates from the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR, 1977) report (5 to 15 cases), the ICRP (1977) report (five cases), and the National Academy of Sciences/ National Research Council (NAS/NRC, 1980) report (6 to 18 cases) for similar exposures. • Ethnic background was found to influence the risk of radiation-induced thyroid cancer [e.g., the relative risk for Jews compared to non-Jews was about 3.5 after adjusting for gender, time since exposure (TSE), and dose]. NCRP Report No. 80 acknowledged that “large gaps in the existing data, the low incidence of thyroid cancer, and the small size of populations available for study make risk derivations uncertain.” The report also indicated a need for further data from laboratory animals on the comparative aspects (x rays versus 131I) of radiationinduced thyroid carcinogenesis at low doses, including other rodent strains and species exposed early and late in life and with testing for whether or not “latency is dose related.” Information on the carcinogenicity of 123I and 99mTc, both used for medical imaging of the thyroid gland because they yield superior image quality and lower doses to the thyroid, were deemed needed. Twenty-three years have passed since NCRP Report No. 80 was published. The Three-Mile Island nuclear reactor accident occurred in 1979 [but with no significant release of radioactive material (0.74 TBq of 131I] or radiation exposures to the general surrounding population) and increased public concern about the release of fission products as a result of a nuclear reactor accident. In 1986, the Chernobyl nuclear reactor accident in Ukraine released large amounts of radioactive materials (including 1.8 EBq of 131I) to the surrounding areas and also exposed large numbers of civilians of all age groups, including fetuses, and cleanup workers to external and/or internal radiation. Concern for the populations in and surrounding the Hanford Nuclear Reactors in Washington State arose when information about releases of radioactive materials, particularly 131I [27 PBq (Napier, 2002)], which occurred largely between 1944 and 1947, was made public in the mid-1980s. The incidence of thyroid cancer in the United States has increased in recent years, likely due to an increased ability to detect thyroid cancer with the use of diagnostic ultrasound (Davies and Welch, 2006). Improved follow-up of patients and populations exposed (and controls) has facilitated further elucidation of short- and longterm consequences for radiation-induced thyroid cancers and increased the overall database for risk assessment. Improved risk

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models, surveillance procedures, and statistical approaches have been developed and employed. These collective factors provided the rationale for the present Report. This Report is intended to be comprehensive and to serve as an authoritative reference on risks to the thyroid from ionizing radiation and other relevant topics. This Executive Summary describes NCRP’s key findings and conclusions and also provides a road map for the interested reader to the balance of this Report. Goals The present NCRP Report has five goals: • Review all major epidemiological studies published in the English language through December 2006 that deal with thyroid and parathyroid disease related to exposure to ionizing radiations, with emphasis on the induction of thyroid cancer. • Review the conclusions of earlier evaluations by NAS/NRC and UNSCEAR on the induction of thyroid disease related to exposure to ionizing radiation. • Review the physics and biology associated with dose to the thyroid. • Provide recommendations on the magnitude of radiation risks with doses for induction of thyroid disease, especially thyroid cancer, with emphasis on the importance of gender, age at time of exposure, TSE, exposure rate, and ethnicity. • Provide recommendations on the relative biological effectiveness (RBE) of different radiations with emphasis on RBE of internal exposure of the thyroid from 131I as compared to external exposure of the thyroid from kilovoltage x rays. These goals are addressed in seven sections and eight related appendices. The literature covered by this Report includes more than 750 references that were published from 1896 to 2008. Synopsis of this Report Section 1 provides a brief sequential outline of the contents of this Report: • provision of an overview of the anatomy, physiology, and pathophysiology of the thyroid and parathyroid glands;

4 / EXECUTIVE SUMMARY • critical review of radiation dosimetry among human cohorts exposed to medical and nonmedical radiation and subsequently evaluated for radiation-associated disease of the thyroid or parathyroid glands; • derivation of absolute and relative risk factors for radiationassociated thyroid cancer; and • recommendations for medical follow-up of individuals receiving significant radiation exposure to the thyroid and who have excess risk for thyroid disease, especially cancer. Of note is the fact that the reported incidence in the United States of thyroid cancer has risen from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002, a statistically-significant 2.4-fold increase. This increase is attributed to improved detection procedures of small papillary thyroid cancers. The mortality rate from thyroid cancers (all ages, all races, and both genders) has, however, remained low and stable, at 0.5 deaths per 100,000 persons. Section 2 presents an analysis of the anatomy and physiology, including embryological and neonatal development, of the thyroid gland. This latter aspect is particularly relevant since children (exposed in utero or during the first years of life) are shown later (Sections 4 and 5) to be particularly sensitive to radiation-induced thyroid cancer compared with exposures later in life. The thyroid gland is unique in that it concentrates iodine 500-fold and produces thyroid hormones whose molecules each can have three or four iodine atoms; this fact explains why, on the one hand, there is a daily need for iodine in the diet to maintain a healthy, functioning thyroid gland and why, on the other hand, radioactive iodines (e.g., 131 I from reactor loss of containment accidents or atomic-bomb fallout) that enter the food chain predominantly through the pasturecow-milk human pathway (cows eating 131I-contaminated foliage; the radioiodine is concentrated in the cow’s milk, which is consumed by humans, with the radioiodine concentrating in the thyroid glands) can lead to large thyroid doses and the subsequent development of thyroid cancers. The introduction of diagnostic ultrasound has greatly increased the sensitivity of medical evaluation in detecting abnormal thyroid anatomy. Thyroid cancer occurs in all age groups. Women are more prone than men to this disease. In 2006, there was a prediction of 30,180 new cases of thyroid cancer in the United States, and in this period it was expected that 1,500 people would die from this disease. There are few thyroid fatalities under the age of 40 y and there are some ethnic differences for incidence and mortality with thyroid cancer. Children are a special group of individuals whose thyroid cancers present in a

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manner different from that of adults; children generally have more advanced disease at the time of diagnosis (i.e., higher rates of local invasion and distant metastasis) than adults. In the past, external beam radiation therapy (EBRT) has been used in treating certain benign medical abnormalities. In addition, low doses of radioactive iodine have been used to evaluate thyroid function, and high doses of radioactive iodine have been used to treat hyper-functioning thyroid tissue and thyroid cancer. Our knowledge of genetic alterations in the thyroid in the etiology of thyroid cancers is increasing. Section 3 deals with radiation dosimetry and dose reconstruction as related to thyroid exposures. The issue is complicated for several reasons: • The dose from external exposures to atomic-bomb detonations or nuclear reactor accidents has to be estimated from a number of indirect measurements and assumptions. Such considerations involve but are not limited to estimates of the radiation exposures, distance from the hypocenter of the emission site, presence or absence of shielding, and approximations of the various types of radiation emissions. • The dose from internal exposures (e.g., absorbed 131I) involves uncertainties related to the amount of radioiodine ingested or inhaled, the distribution of the internalized radioiodine in the body and biological half-lives. • The fact that most of the dose from 131I is from beta particles requires consideration of the anatomy and physiology of the thyroid gland. Most of the iodine localizes in the thyroid follicles, making estimates of the dose to the target cells more complex, especially in abnormal thyroid glands that can have follicles of varying sizes and function. In the normal thyroid gland, the distribution of radioactive iodine is reasonably homogeneous within the thyroid, thus facilitating dose estimations. The fact that 131I concentrates in the colloid thereby reduces the dose to follicular cells at risk for cancer induction (NAS/NRC, 1996). • The environmental dispersion of radioiodine is also complex, as two individuals, each equally distant but in opposite direction from the release site, may subsequently demonstrate vastly different uptakes of the radioiodine. Meteorological conditions greatly affect dispersion direction and food-chain aspects of dietary contamination from inadvertent or accidental releases of radionuclides to the environment.

6 / EXECUTIVE SUMMARY • Potassium iodide, if orally administered just before or just after such accidental release of radioactive iodine can nearly completely block thyroidal uptake of radioiodine. • The dietary sufficiency/insufficiency for iodine of each individual needs to be understood but often can only be estimated in terms of uptake of radioactive iodine. Dietary sufficiency can partly mitigate 131I uptake, but dietary insufficiency would allow enhanced 131I uptake. The four major cohorts exposed to internal radiation from environmental releases of radioiodine are discussed: • • • •

Nevada Test Site (NTS) Marshall Islands Hanford Site Chernobyl nuclear reactor accident

Each cohort presented with different exposure conditions, including releases of radionuclides over widely ranging time frames. The various approaches to these four different cohorts are thorough, from dosimetry determinations (including reconstructions) to medical follow-up and analyses. Section 3 closes with commentary and tabulated analyses of dose estimates from other epidemiological reports of thyroid cancer from external exposure during childhood, from internal (131I) exposures in adults, and of thyroid nodules in relation to external or internal irradiation of thyroids in adults and children. Section 4 provides an overview of the types of studies used to determine the effects of radiation on the thyroid. This section is divided into two major parts, animal data and epidemiologic studies. Data from experiments with animals have relevance to humans because, as discussed in NCRP Report No. 150 (NCRP, 2005), thyroid carcinogenesis is essentially similar among mammalian species. This fact allows for extrapolation from animal studies (e.g., rats, mice, dogs) to humans and for design of experiments, including control of all experimental variables, which is not possible with humans. An initial observation with animal studies was that high doses yielded few thyroid cancers, but low doses yielded significant numbers of thyroid cancers. The lack of a neoplastic effect with the high doses was attributed to radiation-induced cell death, which was not observed with low doses. Thus, the lower doses were more carcinogenic than the higher doses. Irradiation of neonatal and juvenile dogs resulted in significantly more thyroid neoplasms than in mature dogs. RBE of comparable radiation exposures of

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mice and rats, from earlier studies of external (x-ray) radiation and internal 131I radiation, was much higher for the external than the internal radiation, RBEs ranging from 2 to 10 (external/internal), respectively, depending on the study. However, the most recent rodent study suggests RBE of x rays and 131I may be similar, but interpretation is not straightforward. Follicular cancers, and not papillary cancers, were the predominant cancers increased. The Long-Evans rat has a high natural rate of developing medullary carcinoma of the thyroid (>27 %), suggesting a peculiar genetic constitution. Thyroid adenomas had a different response, with 131I being much less effective. The small size of the rat gland would result in a more uniform dose distribution. Methodologically sound epidemiological studies optimally possess: • enrollment of exposed and unexposed individuals (a cohort study), or diseased and nondiseased individuals (casecontrol study); • long-term (decades) follow-up; • comparable study groups except for the variable of interest; • precise dose estimates; • range of doses; • large number of participants; • large range of ages of exposed individuals; and • statistical control of confounding variables. The data from epidemiological studies provide the most valuable information on health effects from various radiation exposures in humans. Such studies, however, are not without uncertainties. For example, dose reconstruction involves assumptions that can include substantial uncertainties in the estimates of dose to individuals. In addition, measuring the effect is often difficult, especially when studying a disease like thyroid cancer where the incidence is very dependent on how exhaustively the population is examined or screened. Often, the most unambiguous endpoint is mortality but this endpoint is not as useful for thyroid cancer since most persons who develop thyroid cancer do not die from this disease. The most informative data for risk estimation are obtained from studies of children exposed to external radiation. These include: • the Atomic-Bomb Survivors Study • Rochester Thymus Study • Israel Tinea Capitis Study

8 / EXECUTIVE SUMMARY • Chicago Head and Neck Irradiation Study • Boston Lymphoid Hyperplasia Study • Childhood Cancer Survivor Study (United States, United Kingdom, and Canada) • the Swedish Skin Hemangioma Studies (Stockholm and Gothenburg) The collective results indicate that external radiation can increase the risk of thyroid cancer; with age at the time of exposure being the most important modifying factor (i.e., children, especially under age 5 y, and adolescents are much more sensitive than adults). The effects of modifying factors (e.g., gender, ethnicity, and attained age) are less certain. Most epidemiological studies of thyroid cancer incidence following internal radiation exposure (primarily 131I) have been less informative due to the small numbers of exposed children and adolescents. These studies are grouped within one of three types: 1. 2. 3.

medical use of 131I for diagnostic purposes; medical use of 131I for therapeutic purposes; and environmental 131I contamination studies.

Within the first group are the: • Swedish and German Diagnostic 131I Studies; and • U.S. Food and Drug Administration (FDA) Childhood Diagnostic Study. The number of thyroid cancers is small within this group despite the substantial doses received. Nearly all patients were administered 131I during the second decade of their lives (i.e., ages 10 to 19 y), by which age the risk of radiation exposure is smaller. Within the second group are: • Swedish Hyperthyroid Study; • U.S. Cooperative Thyrotoxicosis Therapy Follow-Up Study; and • British Hyperthyroid Study. Each of these studies has attending complications and limited utility for assessing risk. Most patients were treated as adults and for much of the collective data it appears that therapeutic application of 131I is a safe therapy for hyperthyroidism.

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Within the third group are studies of: • children in Nevada and Arizona who were exposed to fallout from NTS; • population in the United States and Scandinavia exposed to fallout from atmospheric nuclear weapons testing; • Marshall Islanders; • population living downwind from the Semipalatinsk Nuclear Test Site; • population living around the Hanford Site; • civilian population living around Chernobyl; and • cleanup workers mitigating the effects of the Chernobyl nuclear reactor accident. Unlike medical exposures, these populations were exposed to a mixture of fission products, including radioiodines with a short half-life (e.g., 133I) as well as 131I. For the first five groups, there were only marginal suggestions of an association between dose and thyroid cancers. For example, for the children in Nevada and Arizona who were exposed to fallout from NTS there was no statistically-significant increase in thyroid cancers, but with an analysis of combined benign and malignant thyroid tumors, a significantly increased risk was observed. For the U.S. population exposed to radioactive fallout from the atmospheric nuclear weapons testing, the only group that had a slightly increased risk was children who were 0 to 1 y at the beginning of the period of exposure (1951 to 1961). Due to small numbers and complex dosimetry, studies of the Marshall Islanders have not been very informative about the risk of thyroid cancers following exposure to 131I. The Semipalatinsk Nuclear Test Site was used for 118 atmospheric nuclear tests between 1949 and 1963. Within the local surrounding population the prevalence of thyroid cancers was greater in women than in men, but the prevalence of thyroid cancer in the exposed group was not increased relative to that of the unexposed group. No increases in any thyroid diseases were found in studies of children exposed due to releases of 131I at the Hanford Site. The Chernobyl nuclear reactor accident (April 1986) released a large amount (1.8 EBq) of 131I, which resulted in the exposure of a large population (in utero fetuses to neonates, adolescents and adults) primarily through the pasture-cow-milk-human pathway. In addition, there was widespread contamination from other radionuclides, principally 137Cs. The first reports of increases in thyroid cancer risk in children were published in 1992, only 6 y after the

10 / EXECUTIVE SUMMARY accident. These first reports were initially greeted with skepticism because of the short latency period and the widely held belief that 131 I was considerably less effective than external radiation exposure for causing thyroid cancer. Since these early reports, there have been comprehensive ongoing efforts to improve individual thyroid dose estimates and to follow the exposed population to determine the effects of the exposure. Twenty years after the accident, there is convincing evidence for an association between radioactive iodine exposure following childhood exposures and thyroid cancer, but risk estimates remain uncertain and the effects of modifying factors such as the amount of stable iodine in the diet need to be better understood. Birth cohort studies revealed a large increase in thyroid cancer incidence after the accident in young Ukrainian children exposed to the fallout from Chernobyl. In Belarus, 1,342 adult and seven childhood thyroid cancers were reported in the 10 y period before the Chernobyl nuclear reactor accident, whereas 4,006 adult and 508 childhood thyroid cancers were reported during the 9 y period after the accident. Long-term follow-up is needed to determine how thyroid cancer risk changes as a function of TSE. In addition to the civilian population exposures to the fallout from the Chernobyl nuclear reactor accident, analyses are under way on occupational exposures associated with its cleanup. Hundreds of thousands of civilian workers, military servicemen, scientists, and medical staff from the former Soviet Union were involved in entombing the damaged reactor and cleaning up the contaminated environment. Surveillance has included thyroid cancer incidence and mortality among this cohort of workers. In contrast to the civilian population exposures, where the major source of radiation was ingested 131I, the cleanup workforce was mainly exposed to external radiation from gamma-ray-emitting radionuclides. There is large uncertainty with regard to individual dosimetry, but some attempt was made to control the dose limit to workers, which decreased with time (years) after the accident. The present findings, through 2006, suggest a nonsignificant trend toward increased thyroid cancers within this adult cohort of workers. It is presently unclear to what extent internal 131I exposure contributed to the findings. Additional follow-up may clarify this complicated issue. Section 5 deals with radiation risk for thyroid neoplasms. This section begins with elaboration on the various ways risk can be measured, with emphasis on two approaches, the excess relative risk (ERR) model and the excess absolute risk (EAR) model. Both models are empirically based. The ERR model expresses excess

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cancer risk as being proportional to the underlying baseline rate, and is sometimes called the “multiplicative” model. The EAR model expresses excess cancer risk as being independent of the baseline cancer rate and that the excess cancers are simply added to the baseline cancers. The EAR model is sometimes called the “additive” model. Both models can have variations to account for gender, age at exposure, attained age, and TSE. The number of thyroid cancers predicted by various models is compared. Section 5 closes with a discussion of the risk of developing benign thyroid nodules following radiation exposure. Due to methodological differences, it is not possible to combine the results of different studies so tabulations of the main studies of radiation and benign thyroid nodule incidence or prevalence are presented. These 10 different studies, derived from radiation treatment of different disorders not associated with the thyroid but for which the thyroid might be expected to have had some inadvertent radiation exposure (e.g., tinea capitis, lymphoid hyperplasia), collectively show an association between radiation (dose) and risk of thyroid nodules, either as ERR or EAR. In a few instances, the 95 % confidence intervals (CIs) do not exclude one (which means the effect is not statistically significant and chance cannot be excluded as an explanation) but the overall results suggest increased risk with radiation exposure. Section 6 concerns medical follow-up of persons exposed to ionizing radiation and deals with the subsequent detection and treatment of nodular thyroid disease, both benign or malignant. These outcomes are the primary long-term sequelae of ionizing radiation of the thyroid. This section reviews briefly the significant changes that have occurred over the past 30 y, from the 1975 National Cancer Institute (NCI) workshop on “Late Effects of Irradiation to the Head and Neck in Infancy and Childhood” to the 1999 Institute of Medicine (NAS/IOM, 1999) report dealing with fallout and its potential consequences for thyroid disease. An evidence-based approach was used by the IOM committee. The major recommendation was that there should not be any public program or clinical policies promoting or encouraging routine screening for thyroid cancer in asymptomatic people possibly exposed to radioactive iodine from fallout of the much earlier NTS tests (1950s). The IOM committee recognized that thyroid cancer was rare in the general population, that exposure to 131I during childhood appears to increase the risk of thyroid cancer, that it would be difficult (but not impossible) to estimate individual levels of internal 131I body burdens, and that there was no evidence that early detection of thyroid cancer through screening programs (as opposed to routine clinical

12 / EXECUTIVE SUMMARY practice) improves health outcomes or has benefits that significantly outweigh risks. An informative pamphlet is available from NCI (2008).

Synopsis of this Report’s Conclusions and Recommendations Conclusions The conclusions of this NCRP Report differ significantly from those of the earlier NCRP (1985a) report. Major sources of new data have been published since 1985 that have resulted in a reevaluation of the risk models for thyroid cancer following radiation exposure. A pooled analysis (Ron et al., 1995) of studies of thyroid cancer following external radiation exposure was published in 1995. This analysis demonstrated a strong inverse relationship between the risk of thyroid cancer and increasing age at the time of radiation exposure and also suggested that a relative risk model was preferred over an absolute risk model. In addition, studies of the large population who were exposed when they were children and adolescents to radioiodines released as a result of the Chernobyl nuclear reactor accident have begun to provide further insight into the effectiveness of radioiodines in causing thyroid cancer. The major differences in conclusions of the NCRP (1985a) report, the current Report, and the NAS/NRC (2006) report are summarized in Table ES.1. For the population at greatest risk (ages 0 to 14 y), the current Report’s preferred model predicts a lifetime risk that is up to 1.5 times greater than that in NCRP Report No. 80. For the entire population, the risk is less for the current Report than for the NCRP (1985a) report (Table 5.10). Compared to many other cancers, thyroid cancer is usually treated by surgery (thyroidectomy) and in some cases with the additional use of large doses of 131I. The mortality from thyroid cancers is low, especially before age 40 y. Screening asymptomatic patients for thyroid cancer is not recommended for two major reasons. First, the prognosis of patients with thyroid cancer is very good with conventional medical monitoring; it is unlikely that much benefit would be derived from a screening program. Second, the prevalence of thyroid nodules is very high and the tests to distinguish thyroid cancer from benign nodules are suboptimal. Because of this, unnecessary surgery (removal of the thyroid gland) will be performed in many patients without thyroid cancer.

SYNOPSIS OF THIS REPORT’S CONCLUSIONS

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Recommendations The recommendations of this NCRP Report are as follows: 1. There remains a need for better information on the relative biological effectiveness (RBE) of 131I relative to other types of radiation (e.g., x ray, 60Co) for induction of thyroid cancer. Animal model systems can be used for this effort since the cells of origin of thyroid cancer in humans and animals are the same, doses to the animals can be carefully controlled, as can a variety of other variables such as age, gender, diet, and genomics. There should be consideration given to the fact that high doses of ionizing radiation can kill cells and, thus, result in an underestimation of the carcinogenic effects of the exposure at lower doses. 2. Thyroid genomics is a relatively young but rapidly emerging, important field. Studies are needed of individuals with and without thyroid disease, and who had or did not have a significant thyroid radiation dose. Certain geneticallyengineered strains of mice for thyroid cancer may be useful in pursuit of Recommendation No. 1. 3. The extensive analyses underway of the Chernobyl nuclear reactor accident should continue since there is a large cohort of individuals of all ages exposed to large internal doses of 131I. This population provides an opportunity to study life-time risks for radiation-induced thyroid cancer from such exposures. 4. The oncogenesis of thyroid cancer needs further elucidation. The generally accepted assumption is that tissue with high cell turnover (i.e., proliferating) is more susceptible to radiation-induced effects than cells with low to no cell turnover rates. Although this assumption offers an explanation for why children are more susceptible to radiationinduced thyroid cancer than adults, the pathophysiologic mechanisms need further investigation. 5. There is a need for a better understanding of modifying factors associated with radiation-induced thyroid cancer. Age at the time of exposure, and the amount of dietary iodine have been clearly identified as important factors in the etiology of thyroid cancer. Additional information is needed about other factors that could influence the development of radiation-induced thyroid cancer, including diet, genomics, attained age, gender, and ethnicity. The effect of intensity of screening also requires further study. There is also a need to investigate the effects of varying degrees of

NCRP Report No. 80 (NCRP, 1985a)

This Report

BEIR VII (NAS/NRC, 2006)

Preferred Model Absolute risk

ERR

ERR

• Strong inverse relationship between the risk of thyroid cancer and the age at the time of radiation exposure for ages <20 y. • Small risk over the age of 20 y. • Little if any risk over the age of 40 y.

• Strong inverse relationship between the risk of thyroid cancer and the age at the time of radiation exposure for ages <20 y. • Small risk over the age of 20 y. • Little if any risk over the age of 30 y.

ERR decreases considerably (40 % by 40 y)

Constant ERR

ERR for women is equal to the relative risk for men.

Relative risk for women is twice the relative risk for men.

Effect of Age at Time of Exposure Risk for children (<18 y) is twice the risk of adults.

Effect of TSE Constant absolute risk Gender Absolute risk for women is twice the absolute risk for men.

14 / EXECUTIVE SUMMARY

TABLE ES.1—Tabulated comparative conclusions of NCRP Report No. 80 (NCRP, 1985a), the current NCRP Report, and the NAS/NRC (2006) report.

Internal Exposure • 131I and 125I are no more than one-third as effective as external radiation in causing thyroid cancer. • 135I, 133I, 132I, 123I, and 99mTc are as effective as external radiation in causing thyroid cancer.

• Quantitative relationship between dose from 131I and the development of thyroid neoplasia remains uncertain.

SYNOPSIS OF THIS REPORT’S CONCLUSIONS

• All radioiodines are likely to be between 60 to 100 % as effective as external radiation in causing thyroid cancer. • The absolute risk for women is about twice that for men because of the former’s higher normal incidence level (i.e., EAR for women is about twice that for men, but they share a common ERR). • The amount of stable iodine in the diet may be an important modifier of risk (in addition to its important effect on thyroid dose).

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16 / EXECUTIVE SUMMARY bias in the reconstructed doses on the analysis of statistical power and the slope and confidence intervals of the dose-response relationship in an epidemiological study. This Report’s specific and detailed conclusions and recommendations are presented in Section 7.

1. Introduction The overall objective of this Report is to update NCRP Report No. 80, Induction of Thyroid Cancer by Ionizing Radiation (NCRP, 1985a). Coverage of the effects of ionizing radiation has been expanded to include benign diseases of the thyroid and diseases of the parathyroid. The specific objectives of this Report include the following: • provision of a brief summary of the anatomy, physiology, and pathophysiology of the thyroid and parathyroid glands; • critical review of radiation dosimetry among human cohorts exposed to medical or nonmedical radiation and subsequently evaluated for radiation-associated disease of the thyroid or parathyroid glands; • summary of radiation effects on the thyroid and parathyroid glands, primarily from studies of exposed human cohorts and secondarily from experimentally exposed animals; • derivation of absolute and relative risk estimates for radiation-associated thyroid cancer, with estimation of confidence intervals, and with adjustments for important modifying factors such as gender, ethnicity and age effects; and • recommendations for medical follow-up of individuals receiving significant radiation exposure to the thyroid and having some excess risk for thyroid and parathyroid disease, particularly thyroid cancer. The first part of this section (Section 1.1) briefly reviews the history of our knowledge about the thyroid, the early use of radioiodine in the study of thyroid physiology (Section 1.1.1) and for the treatment of thyroid disease (Section 1.1.2), radiation effects on the thyroid (Section 1.1.3), and the environmental fate of radioiodines (Section 1.1.4). The second section (Section 1.2) provides a summary of the material presented in this Report on the anatomy and physiology of the thyroid and parathyroid glands, dose, dose effects, risk estimation using dose-response models, and medical follow-up of persons exposed to ionizing radiation. 17

18 / 1. INTRODUCTION 1.1 Historic Overview The function of the thyroid gland was not known until the end of the 19th century (Werner, 1991). In 1895, Baumann discovered that the thyroid gland contained a high concentration of iodine (Baumann, 1896). A year later, Vassale and Generali (1896) distinguished the clinical syndromes of myxedema (caused by the lack of thyroid hormone) and tetany (caused by the lack of parathormone produced by the adjacent parathyroid glands). Rapid advances in our understanding of thyroid physiology began in 1936 when Hertz et al. (1938) began using radioactive iodine to study iodine metabolism. With the advent of the nuclear age, radioiodine became available, making treatment of some thyroid diseases with radioiodine a practical option. The importance of 131I as an environmental contaminant was first recognized by Herbert Parker at Hanford in 1945 (Parker, 1945), followed by early attempts to model the pasture-cow-milk pathway (Chamberlain and Chadwick, 1952). Concerns about the carcinogenic effects of radiation on the human thyroid were first raised by Duffy and Fitzgerald (1950a; 1950b) who noted the association of childhood thyroid irradiation and the subsequent development of thyroid cancer. A decade later, it was recognized that radioiodine was an important component of radioactive fallout due to the atmospheric testing of nuclear weapons and other environmental releases (Conard et al., 1966; Eisenbud and Harley, 1955; 1956; FRC, 1960; Perkins, 1963; Till, 1997). Concerns about the potential health effects of fallout led to studies on the fate of radioiodine in the environment (Simon and Robison, 1997; Simon et al., 1990; Van Middlesworth, 1954). After the 1986 Chernobyl nuclear reactor accident, an increase in thyroid cancer in children locally exposed to radioiodine was observed, further increasing the interest in the effects of radiation exposure on the thyroid (Baverstock et al., 1992; Beral and Reeves, 1992; Kazakov et al., 1992). The first assessment of thyroid doses received at large distances from the Nevada Nuclear Test Site was published by Tamplin and Fisher (1966). 1.1.1

Radioiodine Production and Use in the Study of Thyroid Physiology

In 1934, Frederic and Irene Joliot-Curie first made the discovery that bombarding stable isotopes with neutrons could create artificial radionuclides (Becker and Sawin, 1996; Sawin and Becker, 1997). In late 1936, experiments in rabbits using radioiodine to

1.1 HISTORIC OVERVIEW

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study iodine metabolism were commenced in a cooperative effort involving the Massachusetts General Hospital (Adelstein, 2001) and the Massachusetts Institute of Technology (MIT) (Evans, 1975). Iodine-128 was produced using a radium-beryllium neutron source (Hertz et al., 1938). Despite the short half-life (25 min), the small amount of activity available, and the large amount of stable iodine present, Hertz et al. (1938) were able to demonstrate increased iodine uptake with thyroid stimulation and decreased uptake as the amount of stable iodine increased. Evans made the discouraging calculation that ~27.8 GBq of 128I would be needed to deliver a radiation absorbed dose of 1 Gy to the thyroid (Sawin and Becker, 1997). In comparison, a typical absorbed dose to the thyroid from 131I treatment of hyperthyroidism today is ~80 to 100 Gy and usually requires administration of ~370 MBq of 131I. The initial work with 128I was so successful that the investigators at MIT were quickly able to obtain funding for the first cyclotron that was to be used exclusively for biomedical research. The cyclotron was operating by November 1, 1940 and was first used to produce 130I (half-life 12.36 h) from the deuteron bombardment of tellurium targets. This method of production also resulted in a “contaminant,” namely 131I. 1.1.2

Use of Radioiodine in Medical Treatment

In 1938, Glenn Seaborg was the first to correctly identify 131I (Livingood and Seaborg, 1938). Although cyclotron-produced 131I could be chemically separated from the tellurium target, a mixture of radioiodines was obtained. Iodine-131 could be primarily obtained if the product were stored for a few days to allow decay of the shorter half-life radioiodines. Purer 131I would not become available until 1946 when it was separated as a byproduct from fission products and made available to the medical community by the U.S. Atomic Energy Commission. In March 1941, Hertz and Roberts used 130I to treat their first patient for hyperthyroidism. The 130I was produced in the MIT cyclotron and thus was contaminated with 131I. They reported the results of their treatment of 10 hyperthyroid patients at a meeting in Atlantic City in May 1942 (Hertz and Roberts, 1942). At this same meeting, Joseph Hamilton and John Lawrence presented the results of three patients that had been treated for hyperthyroidism with predominantly 131I (Hamilton and Lawrence, 1942). Their first patient had been treated in October 1941. Although Hamilton reported the administered activity to be <37 MBq of 131I, the therapeutic effect was consistent with thyroid doses that would be the

20 / 1. INTRODUCTION result of administration of 5 to 10 times that activity. Hamilton’s cyclotron-produced 131I was contaminated with the yet-to-be discovered 125I. Errors in radioassay that plagued early physicists probably led to substantial underestimations of thyroid dose. The results of two different series of hyperthyroid patients from the Thyroid Clinic of the Massachusetts General Hospital treated with 130I and 131I produced by the MIT cyclotron were published in the May 11, 1946 issue of the Journal of the American Medical Association. In one series (Hertz and Roberts, 1946), 185 to 925 MBq of 130I were administered and the calculated thyroid doses were 5 to 25 Gy, respectively, and in the other 0.56 to 3 GBq of 130I were administered, with calculated thyroid doses of ~35 to 200 Gy, respectively (Chapman and Evans, 1946; Chapman and Maloof, 1955). The optimal dose for the treatment with 130I was never resolved because in June 1946 the U.S. Atomic Energy Commission announced the availability of fission-produced radionuclides, including large quantities of highly purified 131I (ACHRE, 1996). Initial studies of the treatment of thyroid cancer were begun in 1941 by investigators from Columbia University in New York City (Keston et al., 1942). They discovered that a large percentage of administered 130I localized in the thyroid cancer metastasis of one of their patients. About the same time, another patient with thyroid cancer at Montefiore Hospital in New York was treated with 3.77 GBq 130I (Seidlin et al., 1946). The availability of large quantities of purified 131I made the treatment of thyroid cancer with this radionuclide practical. The results of this treatment were so impressive that it produced a major public impact when it was reported. Newspapers reported that as a result of the war effort, a remarkable “cancer cure” had been found at Oak Ridge (Brucer, 1978). 1.1.3

Radiation Effects on the Thyroid Observed in Patients

For many years, external radiation was used to treat many benign diseases, including diseases in children (Jacobs et al., 1999). In their seminal paper, Duffy and Fitzgerald (1950b) described 28 cases of thyroid cancer in children between age 4 and 18 y. Ten of these children had a history of thymic irradiation. At the time, childhood thyroid cancer was thought to be extremely rare with only ~40 cases having been reported in the English-language literature from 1920 to 1940. Some contemporary authors (McClellan and Francis, 1996) stated that Duffy and Fitzgerald were the first to show that ionizing radiation caused thyroid cancer. In fact, what Duffy and Fitzgerald stated in their 1950 paper was much less definitive and worth quoting:

1.1 HISTORIC OVERVIEW

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“To propose a cause-and-effect relationship between thymic irradiation and the development of cancer would be quite unjustified on the basis of data at hand when one considers the large number of children who had irradiation to an ‘enlarged thymus.’ However, the potential carcinogenic effects of irradiation are becoming increasingly apparent and such relationships as those of thymic irradiation in early life and subsequent development of thyroid or thymic tumors might be profitably explored.” Interest in thyroid cancer following childhood radiation exposure grew rapidly in the 1950s. In 1951, Winship reviewed his own cases and the world’s literature and was able to identify a total of 192 cases of childhood thyroid cancer (Winship, 1952). Prior to 1950, physicians caring for these patients did not systematically ask about prior radiation exposure and at least 10 y would pass before a relationship between radiation exposure and the risk of childhood thyroid cancer was definitively established. For almost two decades, Winship periodically updated his reviews of his own experience and the world’s literature. His 1970 paper summarizes the findings in 856 cases (under the age of 15 y) from 35 countries (Winship and Rosvoll, 1970). Eighty percent of the cases were from the United States. Seventy-three percent of cases had a history of prior radiation therapy for a benign condition such as an “enlarged thymus gland,” chronic tonsillitis, acne, cervical adenitis and angiomas, or nevi of the neck. A graph of the reported number of cases of childhood thyroid cancer by year leads to some interesting speculation (Figure 1.1). Winship writes that the graph shows a rapid rise in the number of reported cases of childhood thyroid cancer beginning in 1945, and that the number of cases peaked in 1958 and then rapidly declined. He attributed this temporal pattern to the use and subsequent abandonment of external radiation therapy of children for benign conditions. Unfortunately, critical interpretation of the meaning of the graph is not possible because the number of cases reported can be greatly affected by factors other than disease incidence. For example, the rarity of childhood cancer may have initially motivated physicians to report their cases. As more cases were reported, the motivation to report additional cases may have lessened. It seems unlikely that this graph truly represents the incidence of childhood thyroid cancer. For such a large effect to be due to radiation exposure, the thyroid dose when averaged over all children in the population would have to be in the range of 0.5 Gy. Winship’s study included no data about thyroid dose. However, it would be

22 / 1. INTRODUCTION

Fig. 1.1. Worldwide reported cases of childhood thyroid cancer (Winship and Rosvoll, 1970). See text for Winship’s explanation of the temporal tends.

highly unlikely that the average per capita dose due to external radiation would be even a small fraction of the 0.5 Gy that would be needed to account for this effect. Winship’s data [as well as early data from Chernobyl (Sections 4.5.3.6 and 4.5.3.7)] highlight the importance of rigorously collecting unbiased incidence data. In addition, accurate data about dosimetry would be necessary to make any defensible inferences about the cause of any change in incidence data. The first large systematic studies were conducted by Simpson and coworkers (Simpson and Hempelmann, 1957; Simpson et al., 1955). Questionnaires were mailed to 1,722 patients who had been treated with radiation therapy as children for “thymic enlargement” between 1925 and 1951 and 1,795 untreated siblings. Six thyroid cancers were observed in the treated group (0.08 expected) and zero thyroid cancers were observed in the untreated siblings (0.08 expected). The authors concluded that “radiation must be suspected as a possible factor in the etiology.” Comprehensive incidence and mortality data on thyroid cancer in the United States have only been available since 1973 (Ries et al., 2006) for all ages, all races, and both genders. The reported incidence of thyroid cancer in the United States has increased from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2002, a 2.4-fold increase (95 % CI 2.2 to 2.6, p < 0.001 for trend) (Davies and Welch,

1.1 HISTORIC OVERVIEW

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2006) (Figure 1.2). There has been no significant change in the incidence of the less common histological types of thyroid cancer: follicular, medullary, or anaplastic. This increase has been due to the detection by ultrasound of small (<2 cm) papillary thyroid cancers (Figure 1.3). In contrast, the mortality rate from thyroid cancer (all ages, all races, and both genders) has been stable between 1973 and 2002 (~0.5 deaths per 100,000 persons). Even from this extensive database, it is difficult to identify a meaningful trend in childhood thyroid cancer in the United States due to a very low baseline incidence of thyroid disease and the resulting poor precision of the data collected. Another important source of data for the effects of radiation on the thyroid has been the follow-up studies of the survivors at Hiroshima and Nagasaki. An increase in the incidence of thyroid carcinoma in this population was reported in the early 1960s (Hollingswogth et al., 1963; Socolow et al., 1963). Thyroid carcinoma was the first solid cancer whose incidence was noted to be increased in this population. 1.1.4

Radioiodine in the Environment

To accelerate the development of nuclear weapons in the 1950s, the U.S. government conducted tests of nuclear weapons at NTS from 1951 to 1968 (NCI, 1997). Atmospheric testing ended on

Fig. 1.2. Thyroid cancer incidence and mortality in the United States, 1973 to 2002 (Davies and Welch, 2006).

24 / 1. INTRODUCTION

Fig. 1.3. Trends in incidence of (top) thyroid cancer (1973 to 2002) and (bottom) papillary tumors by size (1988 to 2002) in the United States (Davies and Welch, 2006).

August 5, 1963 when the United States and the Soviet Union signed the Limited Test Ban Treaty, which banned testing in the atmosphere, outer space, and underwater. Underground testing was still permitted. The detonation of a nuclear weapon and controlled nuclear fission results in the production of hundreds of radioactive fission fragments. As these radionuclides decay, additional decay products

1.1 HISTORIC OVERVIEW

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are produced. One of the most biologically significant decay products is 131I (Campbell et al., 1959; Comar et al., 1957; Eisenbud and Wrenn, 1963; Garner, 1966). Only ~2 % of 131I is produced directly as a fission product (Table 1.1). Most of the 131I results from the decay of shorter half-life precursor radionuclides. Selenium-131, 131Sb, and 131Te are produced directly as fission products and account for ~97 % (27, 47 and 23 %, respectively) of the 131I that is ultimately produced. The exact fission yield depends on the type of fissionable material and specific design of the nuclear weapon (Turkevich and Niday, 1951). Iodine-131 is potentially the most biologically significant of the fission products because of the pasture-cow-milk-human pathway. This pathway provides a means by which 131I that has been dispersed and diluted in the environment can be efficiently concentrated in a major human food source. The importance of this pathway was not initially recognized. However, by the early 1960s, this pathway had been extensively studied (Bruner, 1963).

TABLE 1.1—Sources of 131I from fission products and from short half-life fission precursor radionuclides. Radionuclide

Half-Lifea

Relative Contribution to 131 I in Falloutb (%)

In-131

28 s

1

Sn-131

56 s

27

23 min

47

Sb-131 22 % 78 %

Te-131m

Te-131 I-131 Xe-131 a b

Browne et al. (1978). Crouch (1977) and Hicks (1981).

30 h

0.002

25 min

23

8d

2 0

26 / 1. INTRODUCTION Beck and Bennett (2002) estimated that 675 EBq of 131I were released worldwide as the result of atmospheric testing of nuclear weapons. NCI (1997) estimated that ~5.55 EBq of 131I was released as a consequence of atmospheric testing in the continental United States. The average per capita dose to the thyroid from 131I was estimated to be 20 mGy (10 to 40 mGy, 95 % CI) to the 160 million people living in the United States at the time of testing. In some counties, the average per capita dose to the thyroid from 131I was estimated to be 0.12 to 0.16 Gy. Thyroid doses to children were estimated to be three to seven times greater than the average per capita doses. Children whose main source of milk was from a “backyard cow” may have received thyroid doses that were three to four times greater than average childhood doses because the short time between milk production and consumption allowed little time for 131I and other radioiodines, such as 133I, to decay. Children who drank milk from goats may have received thyroid doses that were three to four times greater than the average childhood doses from the milk of a backyard cow because goats concentrate 131I to a greater degree than cows (NCI, 1997). Iodine-131 was also released to the environment by nuclear weapons production facilities such as those in Hanford, Washington. A comprehensive dose reconstruction has estimated that the thyroid doses to children living in the Hanford area ranged from 0.02 to 2.4 Gy. The 95 % confidence interval was approximately a factor of three to five times above and below the 174 mGy median (Davis et al., 2002; 2004a). A health effects study of the most highly-exposed children was also completed (Davis et al., 2004a) and noted that the “disease incidence among participants is comparable to incidence in nonexposed populations.” Iodine-131 has also been released into the environment as the result of nuclear reactor accidents. The first major accident occurred at the Windscale Reactor (now Sellafield) in England in October 1957. Approximately 740 TBq of 131I were released (Clarke, 1974; Dunster et al., 1958; Eisenbud, 1987). There were no increases in thyroid cancer or other adverse health outcomes observed in subsequent follow-up studies of those exposed due to the Windscale accident (Crick and Linsley, 1984; McGeoghegan and Binks, 2000; Robertson and Falconer, 1959). Maximum doses to local individuals close to the site were estimated to be on the order of 10 mGy to the thyroids of adults and, 100 mGy to thyroids of children. The worst nuclear reactor accident in history occurred at the Chernobyl nuclear reactor in Ukraine in April of 1986. Approximately 1.8 EBq of 131I were released over a 10 d period (Apostoaei

1.2 OVERVIEW OF THIS REPORT

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and Miller, 2004; UNSCEAR, 2000a). Follow-up of children exposed to radiation following the Chernobyl nuclear reactor accident revealed an association between radiation exposure and the incidence of thyroid cancer, prompting many scientists who had thought that 131I was less effective than external radiation in causing thyroid cancer, to reevaluate the carcinogenicity of 131I (Thomas et al., 2000). 1.2 Overview of this Report This Report consists of a total of seven sections plus eight appendices. 1.2.1

Thyroid and Parathyroid Glands

Section 2 of this Report reviews pertinent basic anatomy and physiology of the thyroid and parathyroid glands. In addition, an introductory review of clinical diseases of the thyroid is provided. To evaluate epidemiological studies of radiation effects on the thyroid, some understanding of the meaning and reliability of disease endpoints is needed. The endpoints that are of greatest importance are those which have an impact on patient health (morbidity) and/ or life expectancy (mortality). Some endpoints can be measured accurately using blood tests of thyroid function (e.g., hypothyroidism) (Helfand and Redfern, 1998). Unfortunately, the results of blood tests are rarely available in environmental epidemiological studies that attempt to retrospectively assess disease endpoints. Determination of the incidence of thyroid cancer is also difficult since the incidence is dependent on the intensity of the diagnostic work-up. In all adult populations, there is a large reservoir of undiagnosed thyroid cancer (Tan and Gharib, 1997). Under these circumstances, the more intensively one looks for thyroid cancer, the more thyroid cancer is found. 1.2.2

Radiation Dosimetry and Dose Reconstruction

The dose and the effect need to be estimated to determine dose-effect relationships for radiation effects on the thyroid. In the past, reviews of epidemiological studies of radiation effects on the thyroid have emphasized problems related to evaluation of the effects. However, there has been little discussion related to estimation of the doses and associated uncertainties. Section 3 defines and discusses these uncertainties. The uncertainties may

28 / 1. INTRODUCTION be considerable but are generally smaller in studies that involve external radiation sources and brief exposure periods (Davis et al., 2002; 2004a; Hoffman et al., 2002; Kopecky et al., 2004; Land et al., 2003; Moore et al., 2006; NCI, 1997; Simon et al., 2006a; 2006b; 2006c; Stram and Kopecky, 2003). Under these circumstances, estimates of dose are based on consideration of well-known physical factors. The dose to the atomic-bomb survivors has been studied most extensively, yet there continues to be uncertainty in estimates of individual dose. Recent estimates of this uncertainty have been in the range of ±30 to 40 % (Gilbert, 1984; Kellerer, 1999; Pierce et al., 1990; Ruhm et al., 1998). The recent comprehensive reevaluation of the dosimetry known as the 2002 Dosimetry System (DS02) (Young and Kerr, 2005) includes a formal uncertainty analysis, which finds the uncertainty of estimates of individual doses at ~29 %. Less well-studied are the uncertainties associated with estimates of reconstructed thyroid doses in other controlled settings, such as radiation therapy in a medical environment. Small changes in assumed geometry, in the physical characteristics of the radiation, and in positioning of the patient can result in substantial changes in estimates of dose in the thyroid. Determination of the thyroid dose from exposure to radioiodines either intentionally or accidentally released into the environment is complicated by many factors, including estimates of how much radioiodine is transported in the environment and how much iodine is ingested or inhaled; the fraction of radioiodine that accumulates in the thyroid, the size of the thyroid, and the biological half-life of iodine in the thyroid gland. For these reasons, estimates of thyroid dose from radioiodines in the environment are generally associated with much more uncertainty than are thyroid doses from acute radiation exposures from well-characterized external sources. Epidemiological studies of populations exposed to radioiodine are severely hampered by these uncertainties. Direct measurement of thyroid activity, as was the case in large numbers of people in the settlements around Chernobyl, diminishes the uncertainty of thyroid dose estimates. However, even with direct measurement of thyroid activity, considerable uncertainty remains due to uncertainty related to the standardization of the radioassay equipment and procedures, the time-course of the activity in the gland (due to continued ingestion and a variable biological half-life), and the size of the thyroid gland (Gavrilin et al., 1999). Because of the difficulties described above, epidemiological studies of populations exposed to radioiodine are hampered by the large and complex uncertainties in retrospectively reconstructing an individual’s thyroid dose.

1.2 OVERVIEW OF THIS REPORT

1.2.3

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Radiation Effects

Thyroid and parathyroid diseases caused by radiation are indistinguishable from thyroid and parathyroid diseases caused by other factors. One of the most valuable tools available to the epidemiologist to help distinguish radiation-associated diseases from other diseases is to determine the dose-response relationship. In the first portion of Section 4, the types of experimental designs used for epidemiological studies are reviewed. In the remainder of Section 4, the results of major relevant animal studies and numerous human epidemiological studies are summarized. The strengths and weaknesses of major studies are highlighted. 1.2.4

Radiation Risk for Thyroid Neoplasms

Because of the limited quality and quantity of the dose-response data, relatively simple dose-response models have been used. Choices must be made between an absolute and a relative-risk model and, ideally, the model should be adjusted for important factors such as age at the time of exposure, gender, and TSE or attained age. The first portion of Section 5 reviews basic doseresponse models; models that best represent the data summarized in Sections 3 and 4 are also presented. 1.2.5

Screening for Thyroid Disease Following Radiation Exposure

Section 6 describes the usefulness of medical follow-up of persons exposed to ionizing radiation, which has been a controversial topic. In the past, recommendations have often been based on expert opinion and have come from the radiation protection community. In the last 15 to 20 y, there has been a dramatic change in medicine from recommendations that are based on expert opinion to recommendations that are based on direct scientific evidence. This change is particularly relevant to recommendations for screening populations that have been exposed to ionizing radiation for thyroid cancer. In 1975, when concerns about radiation-induced thyroid cancer from therapeutic medical exposures were high, NCI sponsored a workshop entitled “Late Effects of Irradiation to the Head and Neck in Infancy and Childhood.” As a result of this workshop, an informational pamphlet for physicians was published (NCI, 1977) that recommended that any individuals who thought they had head and neck irradiation as an infant or child should see their physician for a thyroid exam (NCI, 1977). Consideration of surgical

30 / 1. INTRODUCTION exploration was recommended for all palpable nodules. This 1975 expert opinion-based recommendation was modified in an NAS/ IOM (1999) report. The main reason for this modification was that there is no scientific evidence to suggest that screening asymptomatic individuals would result in more benefit than harm. 1.2.6

Conclusions and Recommendations

In Section 7 of this Report, the major conclusions are summarized and the implications of the updated risk estimates are discussed. Gaps in relevant knowledge are reviewed, as are recommendations for research that is likely to yield important and needed new information. 1.2.7

Appendices

To make the body of this Report more readable for persons with a general interest in this topic, some of the detailed text that provides more comprehensive coverage of a particular topic is presented in appendices, and many technical terms are explained in the Glossary. The topics covered by the eight appendices include: • Radiation Dosimetry Quantities and Units and Related Concepts (Appendix A); • Radiation Dosimetry for External Beam Radiation Therapy and Brachytherapy (Appendix B); • Technical Aspects of Radiation Dosimetry for the AtomicBomb Survivors: The Dosimetry System 1986 and the Dosimetry System 2002 (Appendix C); • Technical Aspects of Thyroid Radiation Dosimetry of Radioisotopes of Iodine (Appendix D); • Animal Experiments (Appendix E); • Additional Epidemiological Studies (Appendix F); • Past Risk Estimates and Models (Appendix G); and • Supplemental Information on Model Development (Appendix H).

2. Thyroid and Parathyroid Glands A primary objective of this Report is to describe the adverse effects of radiation on the thyroid and parathyroid glands. To study and/or understand these effects, one must be knowledgeable about the normal anatomy and function of these glands as well as the spontaneously-occurring pathology. In this section, the normal anatomy and physiology of the thyroid gland and the parathyroid glands are reviewed and common clinically important diseases of the thyroid and parathyroid glands are discussed. Current and past medical procedures that expose the thyroid and parathyroid glands to radiation are described. The final portion of the section summarizes what is known about genetic alterations that are associated with different thyroid and parathyroid diseases. 2.1 Anatomy and Physiology Anatomy is generally defined as the study of biological structures and physiology as the study of biological functionality. 2.1.1

Anatomy

Important elements of anatomy include: • embryology (how organs and structures in the organism develop); • gross anatomy (biological structures that can be seen with the unaided eye); and • microscopic anatomy (biological structures that can be seen with a microscope). The thyroid gland is the earliest endocrine glandular structure to appear in fetal development. Arising from a thickening in the anterior pharyngeal floor at gestational day 16, the thyroid descends into a normal position in the base of the neck by the second month of gestation. Synthesis of thyroglobulin has been detected as early as the fifth gestational week, but iodine trapping with subsequent thyroid hormone production does not begin until 31

32 / 2. THYROID AND PARATHYROID GLANDS after the 10th gestational week. By week 11, the gland is often functional with thyroid hormone detectable in fetal serum; Table 2.1 lists the mass of the fetal thyroid at various gestational ages. The parathyroid glands develop from the third and fourth branchial pouches. The third branchial pouches give rise to the two inferior parathyroid glands while the fourth branchial pouches give rise to the two superior parathyroid glands. The thyroid is a butterfly-shaped ductless gland composed of a right and left lobe connected by a narrow isthmus (Figure 2.1). Normally, the thyroid is located in the anterior neck at approximately the level of the third cartilage ring of the trachea. The thyroid gland increases in size during childhood and adolescence (Figure 2.2) (Zimmermann et al., 2004), eventually reaching a normal adult size of 15 to 20 g (Figure 2.3). Although the normal thyroid gland is generally palpable by trained examiners, it can be difficult to palpate in individuals with short stocky necks. Most adults have four parathyroid glands, but up to 20 % of adults can have either more or less than four glands (ranging from 1 to 12 parathyroid glands). The anatomic location of the four parathyroid glands is quite variable. In general, the superior parathyroid glands are found in close proximity to the posterior surface of the upper poles of the thyroid. The inferior parathyroid glands are usually found near the posterior surface of the lower poles of the thyroid, but can be located in the lower neck, the mediastinum, or in the thymus. Each parathyroid gland is shaped like a kidney bean and ranges from 2 to 7 mm in length, 2 to 4 mm in width, and 0.5 to 2 mm in thickness. The basic unit of cellular organization within the thyroid is the follicle (Figure 2.4). Thyroid follicles are spherical structures ranging from 20 to 500 Pm in diameter composed of a single layer of follicular epithelial cells bound by a basement membrane enclosing a lumen filled with colloid. Colloid is a proteinaceous substance largely composed of thyroglobulin secreted by the follicular thyroid epithelium. Thyroglobulin, a 600,000 kD protein, is the intrathyroidal storage form of thyroid hormones that is produced by the follicular cells. The parafollicular clear cells (C-cells) produce calcitonin (i.e., a hormone that plays a role in the regulation of serum calcium). The parathyroid glands are surrounded by a thick connective tissue capsule that extends into the gland as fibrous septa dividing the gland into lobules. Parathyroid hormone, the primary hormone product of the parathyroid glands, is synthesized and released by the chief cells, which are round C-cells with a centrally located nucleus that make up the major cell type of the parathyroid glands.

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TABLE 2.1—Reference values for the mass of the fetal thyroid at various ages (ICRP, 2002). Fetal Age (weeks)

Mass (g)

8 10 15 20 25 30 35 38

0.011 0.022 0.077 0.18 0.36 0.63 1.0 1.3

Fig. 2.1. The thyroid gland is a bi-lobed structure that is normally located anterior to the trachea just below the larynx. The portion of the thyroid gland that connects the two lobes is called the isthmus. The four parathyroid glands are much smaller than the thyroid. For simplicity, the locations of the four parathyroid glands are shown as clear ovals. The parathyroid glands would not be visible in this view since they are located behind the thyroid gland.

34 / 2. THYROID AND PARATHYROID GLANDS

Fig. 2.2. Ultrasound-determined thyroid volume as a function of age for boys and girls from age 6 to 12 y for several countries. The 50th percentile (P50) and the 97th percentile (P97) are also plotted (Zimmermann et al., 2004).

In contrast to calcitonin, increases in parathyroid hormone cause increases in serum calcium levels. 2.1.2

Physiology

The thyroid gland is unique in that it concentrates iodine and produces thyroid hormones that have three or four iodine atoms.

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Fig. 2.3. Mass of apparently normal thyroid glands for males and females as a function of age (ICRP, 2002).

This section reviews the metabolism of iodine, thyroid hormone metabolism, the regulatory effects of stable iodine, and parathyroid hormone metabolism. 2.1.2.1 Iodine Metabolism. Stable iodine and its radioisotopes are rapidly absorbed from the gastrointestinal (GI) tract and the lungs. Hamilton observed that 80 % or more of orally administered radioiodine was absorbed in the first hour (Hamilton, 1938) and was almost completely absorbed by 2 h. The initial rate of absorption of radioiodine is ~1 to 5 % min–1 in normal subjects (Keating and Albert, 1949), although food in the GI tract slows the rate of absorption (Stanley and Astwood, 1947). One of the initial steps in thyroid hormone synthesis involves active accumulation of iodine by the thyroid. Thyroid epithelial

36 / 2. THYROID AND PARATHYROID GLANDS

Fig. 2.4. Depiction of the microscopic anatomy of the thyroid gland.

cells have a polarity in which iodine is trapped by a specific energy-dependent sodium-iodine symporter (transporter) at the blood stream side of the cell, and transported to the luminal aspect of the cell where it is incorporated into thyroid hormone at the cell membrane. This mechanism allows the thyroid to concentrate high levels of iodine, often with thyroid-to-serum concentration ratios of 25:1 or higher. Sodium-iodine symporters are not unique to the thyroid. They are also present in smaller quantities in gastric mucosa, salivary glands, mammary glands, choroid plexus, ovaries, placenta and skin. Because of this very efficient iodine-trapping mechanism, as well as the intrathyroidal recirculation of iodine, normal thyroid function can be maintained with as little as 150 Pg of iodine intake per day. Total body iodine stores are only 15 to 20 mg of iodine, most of which is stored in the thyroid gland. Since fecal loss of iodine is negligible (10 Pg d–1), dietary iodine intake can be closely approximated from the amount excreted in the urine. Since studies of iodine deficiency are usually based on urine samples, rather than 24 h urine collections, the adequacy of iodine in the diet is usually expressed as the concentration of iodine in micrograms per liter of urine (Delange et al., 2001). The World Health Organization classifies insufficient iodine intake as <10 Pg of iodine per deciliter of urine, adequate iodine intake as 10 to 19.9 Pg of iodine per deciliter of urine, and more than adequate iodine uptake as t20 Pg of iodine

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per deciliter of urine (De Benoist et al., 2004). Figure 2.5 shows the relationship between urinary iodine and the prevalence of goiter (NAS/IOM, 2000). In adults, a safe range of iodine intake appears to be from 150 to 1,500 Pg d–1 of iodine. Recommendations from the Food and Nutrition Board of IOM for the daily intake of iodine for different ages and genders are shown in Table 2.2 (NAS/IOM, 2000). The primary dietary sources of iodine are fish, with lesser amounts in milk, eggs and meats. Vegetables and fruits generally have very low iodine content. One vegetable with considerable iodine is spinach. In many countries, iodized salt and bread products are used to supplement dietary iodine. In the United States, the median intake of iodine per day is ~240 to 300 Pg d–1 for men and 190 to 210 Pg d–1 for women. Recent studies have shown that

Fig. 2.5. Relationship between the prevalence of goiter and urinary iodine concentration. Populations in which the prevalence of goiter is above the dotted horizontal line are defined as endemic for goiters (NAS/IOM, 2000).

38 / 2. THYROID AND PARATHYROID GLANDS TABLE 2.2—Daily intake of iodine for different ages and genders (NAS/IOM, 2000). Adequate Intakea (Pg d–1)

Infants 0 – 6 months 7 – 12 months

Estimated Average Requirementb (Pg d–1)

Recommended Dietary Allowancec (Pg d–1)

110 130

Children 1–8y 9 – 13 y 14 – 18 y

65 73 95

90 120 150

Adults

95

100

160

220

Pregnant women

aThe recommended average daily intake based on observed or experimentally determined approximations, or estimates of nutrient intake by a group(s) of apparently healthy people that are assumed to be adequate; used when recommended daily allowance cannot be determined. bThe average daily nutrient intake estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group. cThe average daily dietary nutrient intake sufficient to meet the nutrient requirement of nearly all (97 to 98 %) healthy individuals in a particular life stage and gender group.

the amount of iodine in the American diet is decreasing due to a lower intake of salt and replacement of iodine containing food additives with noniodine containing additives (Hollowell et al., 1998; Soldin et al., 2003). 2.1.2.2 Thyroid Hormone Metabolism. Once iodine has been accumulated in the follicular cell, it is incorporated into tyrosine molecules that form part of the thyroglobulin protein. The biological half-life of iodine incorporated into thyroglobulin within the normal thyroid is usually 80 to 120 d. Release of thyroid hormone requires enzymatic degradation of the thyroglobulin molecule at the follicular cell border. This degradation results in release of two primary forms of thyroid hormone from the gland: tetraiodothyronine (thyroxine, T4) and triiodothyronine (T3). T4, the primary thyroid hormone

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secreted by the thyroid, contains four iodine atoms and has a circulating half-life in the blood of ~7 d (Figure 2.6). T3, which is secreted from the thyroid gland in smaller quantities than T4, contains three iodine atoms, and has a circulating half-life in the blood of ~12 h. Most T3 present in the serum results from conversion of T4 to T3 by a specific regulated enzymatic process in peripheral tissues. Since T3 is several times more potent in producing the classic effects of thyroid hormone than T4, this peripheral conversion is an important step in the action of thyroid hormone. Thyroid hormones are very insoluble in water and are, therefore, transported through the blood stream in conjunction with protein carriers (primarily thyroid binding globulin). The liver inactivates thyroid hormone by breaking it down into biologically inert components that are then excreted by the kidneys. Thyroid hormone production is closely regulated by the hypothalamic-pituitary-thyroid axis (Figure 2.7). Thyroid releasing hormone (TRH) is produced by the hypothalamus. TRH causes the anterior pituitary to produce thyroid stimulating hormone (TSH). TSH stimulates cyclic adenosine monophosphate production and the adenylate cyclase cascade by interaction with a specific TSH transmembrane receptor. Stimulation of the thyroid by TSH results in increased iodine accumulation and increased thyroid hormone synthesis and secretion within minutes of administration. A number of feedback loops are used to modulate the production of thyroid hormone. In an otherwise normal person, when there is excess thyroid hormone in the blood (hyperthyroidism), the anterior pituitary decreases the production of TSH and the TSH levels in the blood decreases. When TSH is absent, the normal thyroid gland stops

Fig. 2.6. Molecular structure of T4. The structure of T3 is identical to T4 except that the iodine in the 5c position (indicated by the arrow) is absent.

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Fig. 2.7. Hypothalamus-pituitary-thyroid axis.

producing thyroid hormone. In some disease states (e.g., hyperthyroidism) that will be discussed later, the thyroid functions autonomously (i.e., continues to produce thyroid hormone despite the absence of TSH). In an otherwise normal person, when there is too little thyroid hormone in the blood (hypothyroidism), the anterior pituitary produces more TSH and the TSH levels in the blood are elevated. A common cause for patients becoming hypothyroid is that the thyroid gland can no longer make adequate amounts of thyroid hormone. The parafollicular C-cells in the thyroid gland synthesize and secrete calcitonin. C-cells do not have the ability to concentrate iodine and do not synthesize thyroid hormones. Malignant transformation of C-cells results in medullary thyroid cancer, which has a much different biological behavior and genetic profile than the more common papillary and follicular thyroid cancers that derive from the thyroid follicular cells. 2.1.2.3 Regulatory Effects of Stable Iodine. While TSH is the predominant regulator of iodine transport within the thyroid gland, there is evidence that the iodine transport system is also

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autoregulated by one or more forms of inorganic iodine. The main regulatory effects of iodine on the thyroid include a decrease in the response of the thyroid to TSH stimulation, an acute inhibition of thyroid hormone synthesis [i.e., the Wolff-Chaikoff effect (Markou et al., 2001)], and an inhibition of thyroid hormone secretion. After several days, the thyroid gland often adapts to a higher circulating iodine level and resumes function. This autoregulatory system is thought to be the primary mechanism for the adaptation in iodine transport seen in response to chronic iodine administration. In patients with hyperthyroidism, iodine administration may result in a transient decrease in thyroid function which can be followed by a marked overproduction of thyroid hormone and clinical thyrotoxicosis. Stable iodine in milligram quantities can be used to markedly decrease the uptake of radioactive iodine, particularly if it is given a few hours before or after the exposure occurs (Saxena et al., 1962; Zanzonico and Becker, 2000). The use of potassium iodide to decrease the uptake of radioactive iodine is discussed in detail in Section 3.3.4. Stable iodine administration to emergency personnel and workers has been previously endorsed by NCRP (1977). Administration of stable iodine prior to exposure to radioiodine is very effective in reducing thyroid dose. Two main pathways for exposure to radioiodine exist: inhalation and ingestion. The inhalation pathway is of greatest concern within minutes to hours after the atmospheric release of radioiodine. If stable iodine can be distributed and administered within 1 to 2 h to the population at highest risk following the accidental release of radioactive iodine, the dose to the thyroid from inhalation can be reduced. Rapidly identifying the population at highest risk will be difficult due to rapid changes in meteorological conditions (e.g., wind patterns, precipitation) and other complex factors affecting the inhalation pathway. Other interventions to reduce the thyroid dose from inhalation of radioiodines include sheltering and/or evacuation and/or administration of T4 in doses large enough to suppress thyroid function. Which interventions would be most cost-effective in decreasing the thyroid dose from inhalation, and under what conditions, continues to be debated. Several European countries have distributed stable iodine to populations living near nuclear power plants so that it will be readily available in the event of an accident. Stable iodine has not been widely distributed in the United States, although some medical associations (e.g., American Thyroid Association) have recommended this precaution (Becker and Zanzonico, 1997). The U.S. Nuclear Regulatory Commission has provided funding for stockpiling potassium iodide near nuclear power plants and has

42 / 2. THYROID AND PARATHYROID GLANDS left the decision on whether to stockpile stable iodine to the individual states. The effectiveness of various strategies for distributing stable iodine to reduce the thyroid dose from the accidental release of radioiodine to members of the general population was the subject of an NAS/NRC (2004) report. The report concluded that the optimum strategy was dependent on local factors and no one strategy could be recommended for all situations. A major pathway for exposure of the general population to radioiodine is the ingestion of contaminated food (particularly fresh milk and some dairy products). The most effective measure to prevent unintended exposure from this pathway is to monitor sources of food and to prevent the intake of contaminated feed by cows and contaminated milk by humans. Since it will take a few days for radioiodine to be transported through the pasture-cowmilk pathway, the time scale over which this intervention can be implemented is days to weeks. Contaminated food can be diverted to time-consuming processes that allow for radioactive decay (e.g., cheese making, powdered milk, etc.). Use of potassium iodide may be considered a supplementary measure in cases where effective control over the food supply is not possible. 2.1.2.4 Parathyroid Hormone Metabolism and Regulation. Parathyroid hormone, produced by the chief cells of the parathyroid gland, is the primary regulator of serum calcium concentration. Parathyroid hormone stimulates absorption of calcium in the GI tract and the kidney, as well as release of calcium from skeletal stores. The chief cells have a unique calcium sensor that continuously assesses serum calcium concentrations and regulates parathyroid hormone release. Precise regulation of the release of parathyroid hormone by the parathyroid glands, and calcitonin by the parafollicular C-cells of the thyroid, results in very tight control of serum calcium concentrations despite wide variations in oral calcium intake. 2.2 Diseases of the Thyroid and Parathyroid Glands Diseases of the thyroid are generally classified as anatomical and/or functional abnormalities. Anatomical abnormalities are usually diagnosed because there is a change in the size and shape of the thyroid gland, whereas functional abnormalities of the thyroid are usually diagnosed as a result of blood tests that show that there is too much or too little circulating thyroid hormone. There is often overlap in these disease-classification systems in that functional disease (e.g., an overactive thyroid gland) can be associated

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with anatomical abnormalities (e.g., thyroid enlargement). Because the normal parathyroid glands are much smaller than the thyroid, anatomical changes in the parathyroid are rarely clinically apparent (i.e., palpable). Diseases of the parathyroid usually present as a functional abnormality detected by abnormal results from a blood or urine test. Common structural abnormalities of the thyroid include nodules (solitary or multiple), enlargement of the thyroid (goiter), enlargement with multiple nodules (multinodular goiter), or atrophy (decrease in size) of the gland. Most thyroid nodules are benign and have a limited growth capacity that will not spread to other tissues and, usually, do not affect the function of the thyroid gland. The percentage of thyroid nodules that are cancerous is small.

2.2.1

Benign Thyroid Nodules

Several epidemiologic studies have demonstrated that thyroid nodules can be detected by physical examination in ~5 % of all women and ~1 % of all men over age 50 y (Ezzat et al., 1994; Vander et al., 1968). The prevalence of ultrasound-detected abnormalities within the thyroid is as much as 10-fold higher than physical examination estimates and approaches 50 % in adults >60 y (Frates et al., 2005). Most often, ultrasound detected abnormalities are too small (<1 cm) to be detected by physical examination. Most of the ultrasound detected abnormalities will never cause the patient symptoms or shorten the patient’s lifespan (Tan and Gharib, 1997). These ultrasonic findings are consistent with Woolner’s autopsy study in which 49 % of asymptomatic adults were shown to have thyroid nodules (Woolner et al., 1960). However, undue concern about these abnormalities can lead to further diagnostic tests and may ultimately lead to unnecessary surgery. Nodular thyroid disease is most commonly detected on a routine physical examination of the neck (Hegedus, 2004). The likelihood that the nodule is benign is dependent on the size of the nodule, its rate of growth, the presence of other similar abnormalities in the thyroid, and the age and gender of the patient. Approximately 90 % of nodules detected on physical examination will be benign in average-risk patients. The most efficient, cost-effective way to determine if an easily palpable solitary thyroid nodule is benign or malignant is to examine a small tissue sample that is obtained by aspirating the thyroid nodule with a small needle (Gharib and Goellner, 1993). This procedure is called a fine-needle aspiration (FNA) biopsy.

44 / 2. THYROID AND PARATHYROID GLANDS Sometimes the presence of one or more nodules on a physical examination will be uncertain depending on the clinical circumstances. An ultrasound examination of the thyroid may be performed to confirm the presence of a thyroid nodule, and to determine if multiple thyroid nodules are present. Ultrasound can also be used to guide the FNA biopsy when the nodule is difficult to feel on physical exam (Frates et al., 2005). 2.2.2

Thyroid Cancer

According to predictions prepared by the American Cancer Society, 30,180 new cases of thyroid cancer were estimated to be diagnosed in 2006 in the United States. During this same period, an estimated 1,500 people would die of thyroid cancer (Jemal et al., 2006). Thyroid cancer occurs in all age groups (Figure 2.8) (Ries et al., 2006). The incidence varies with gender and age and is about threefold higher in women between the ages of 15 and 50 y old than in men in that age group, reaching a peak incidence in women between the ages of 30 and 70 y. A gradually increasing incidence in thyroid cancer is seen in men as they age. For females, thyroid cancer incidence plateaus at approximately age 35 y and begins to decline at about age 60 y. In contrast, the incidence of thyroid cancer in men continues to rise until the age of 74 y. Until the age of ~60 y, the case-fatality rate (mortality/ incidence) for women is ~50 % less than the case fatality rate for men. There are very few thyroid cancer fatalities under the age of 40 y. In the United States, the incidence and mortality rates of thyroid cancer also vary among racial/ethnic groups (Table 2.3). The Surveillance Epidemiology and End Results (SEER) database (Ries et al., 2006) does not report 95 % confidence interval for different incidence and mortality rates, so it is difficult to know when these values are significantly different. In women, the highest incidence rates of thyroid cancer occur in Asian/Pacific Islander women (11.1 per 100,000) and the lowest rates occur in black women (6.2 per 100,000). In men, the highest incidence rates are seen in white non-Hispanic men (4.2 per 100,000) with the lowest rates seen in Hispanic men (3.2 per 100,000). Within each racial/ethnic group, the incidence of thyroid cancer in women is approximately threefold higher than in men. In women, thyroid cancer mortality is highest in Asian/Pacific Islander women (0.7 per 100,000) and lowest in white women (0.5 per 100,000). In men, ethnicity has very little effect on mortality rates (0.4 to 0.5 per 100,000).

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Fig. 2.8. Thyroid cancer incidence and mortality for all races in the United States (Ries et al., 2006). Open symbols represent thyroid cancer incidence, closed symbols represent thyroid cancer mortality rates.

The average lifetime risk of being diagnosed with some form of thyroid cancer is 0.64 % (6.4 per 1,000) for white women and 0.31 % (3.1 per 1,000) for white men. The lifetime risk of dying from some form of thyroid cancer is 0.06 % for white women and 0.04 % for white men. By comparison, the lifetime risk of women developing invasive breast cancer is 14.21 % with a lifetime risk of dying from that disease of 2.99 % (Ries et al., 2006). The majority of clinically significant thyroid cancers are detected as an asymptomatic palpable nodule. Most retrospective reviews have reported that the mean size of thyroid cancer nodules to be between 2 and 3 cm at the time of diagnosis. 2.2.2.1 Thyroid Cancers in Adults. Thyroid cancers are classified based on the cell of origin and histologic characteristics of the tumor (Figge et al., 2006). Thyroid cancers of follicular epithelial cell origin include papillary, follicular and anaplastic tumors; medullary thyroid cancer arises from the calcitonin secreting parafollicular C-cells. Papillary thyroid cancer is the most common form of thyroid cancer and accounts for >80 % of nonradiation-associated spontaneous

46 / 2. THYROID AND PARATHYROID GLANDS TABLE 2.3—SEER incidence and U.S. mortality age-adjusted rates of thyroid cancer by race/ethnicity and sex (Ries et al., 2006).

Race/Ethnicity

Rate per 100,000 Persons (1998 – 2002) Total

Males

Females

7.6

4.0

11.1

White

4.2

11.7

Black

2.2

6.2

Asian/Pacific Islander

4.0

12.4

American Indian/Native Alaskan

—

6.7

Hispanic

3.2

10.3

0.4

0.5

White

0.5

0.5

Black

0.4

0.5

Asian/Pacific Islander

0.4

0.7

American Indian/Native Alaskan

—

—

Hispanic

0.5

0.7

Incidence All races

Mortality All races

0.5

thyroid cancers in the United States. On microscopic examination, papillary thyroid cancer has a complex papillae-type structure with distinctive nuclear features of optically clear overlapping nuclei, pseudo-inclusions, and nuclear grooves. At least 20 % of papillary cancers have multiple microscopic foci throughout the thyroid gland. Local invasion through the thyroid capsule and into local structures is seen in 5 to 10 % of cases. Local cervical lymph node metastasis is present in ~40 % of cases. Distant metastasis at diagnosis is present in 5 % of patients (usually involving the lung). In the two largest series of patients with treated papillary thyroid cancers, primary tumor size of <1.5 cm in diameter at diagnosis was rarely associated with mortality and was infrequently

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associated with cervical lymph node or distant metastasis (Hay et al., 2002a; 2002b; Mazzaferri and Kloos, 2001). Autopsy studies in persons not known to have thyroid disease during their lifetime have demonstrated a prevalence of occult thyroid cancer in as many as 5 to 13 % of individuals in the United States, and 6 to 36 % of individuals in Asia and Europe (Martinez-Tello et al., 1993; Miller et al., 1996). These occult cancers occur in all age groups, but the incidence increases after age 40 y. They occur in similar rates in both genders. These occult cancers are usually <1 cm and are often only 3 to 4 mm in size. Furthermore, there are few data that demonstrate that aggressive surgical intervention or radioactive iodine therapy has a measurable impact on either morbidity or mortality in papillary thyroid cancers <1.5 cm. It seems unlikely that these unsuspected occult carcinomas represent clinically significant disease in the majority of patients. In general, papillary cancer has a very good prognosis with 20 y survival rates >95 % in treated patients (Sherman, 2003). Cancerspecific mortality rates are higher in patients older than age 40 y who present with more widespread disease. Papillary thyroid cancer arising in patients with a known history of irradiation appears to follow a clinical course similar to that of thyroid cancer developing in patients with no history of radiation exposure (Rubino et al., 2002; Schneider et al., 1986). Follicular thyroid cancer also arises from the thyroid follicular cells. Like papillary thyroid cancer, follicular cancer usually presents as a solitary, asymptomatic thyroid nodule. The mean age at diagnosis is, however, usually ~10 y older than that normally seen in papillary thyroid cancer. Follicular cancers often have no histologically distinguishing nuclear features. Therefore, histological diagnosis of follicular cancer relies on the documentation of either capsular or vascular invasion by the thyroid follicular cells. In contrast to papillary thyroid cancer that often spreads to cervical lymph nodes, follicular thyroid cancers have a higher risk of distant metastasis to the lungs or bone. Overall, the prognosis in follicular thyroid cancer is slightly worse than that for papillary thyroid cancer in terms of likelihood of recurrence and disease-specific death (Sherman, 2003). Anaplastic thyroid cancer is a highly malignant tumor characterized by local invasion of neck structures surrounding the thyroid and results in a >95 % mortality rate within 1 y of diagnosis. Anaplastic thyroid cancer arises from thyroid follicular cells, but the thyroid is so poorly differentiated that it no longer concentrates radioactive iodine. Unfortunately, neither chemotherapy nor EBRT is very effective at controlling this disease (Pasieka, 2003).

48 / 2. THYROID AND PARATHYROID GLANDS Medullary thyroid cancer arises from the parafollicular C-cells that synthesize and secrete calcitonin. While ~70 % of medullary cancer cases are sporadic, the remaining 30 % develop as part of one of several well-defined autosomal dominant hereditary syndromes. For many of these syndromes, the specific, causative genetic mutation in the RET proto-oncogene is well established. Evaluation of the RET proto-oncogene is a commercially available test and is widely used in clinical practice in the evaluation of these patients. Radiation exposure is not thought to be a significant risk factor for the development of medullary thyroid cancer. 2.2.2.2 Thyroid Cancers in Children. Spontaneously-occurring thyroid cancer in children typically presents in a manner different than that for adult thyroid cancers. Even in the absence of prior radiation exposure, children tend to have more advanced disease staging, higher rates of local invasion, cervical (neck) lymph node metastasis, and distant metastasis at the time of diagnosis than do adults (Ceccarelli et al., 1988; De Keyser and Van Herle, 1985; Goepfert et al., 1984; Harness et al., 1971; 1992; Jereb and Lowhagen, 1972; Jocham et al., 1994; Lamberg et al., 1989; La Quaglia et al., 2000; Massimino et al., 1995; McHenry et al., 1988; Segal et al., 1998; Tallroth et al., 1986; Welch Dinauer et al., 1999; Zimmerman, 1997; Zimmerman et al., 1988; Zohar et al., 1986). Furthermore, the rate of developing local cervical recurrence or distant metastasis appears to be higher in children than in adults of similar stages at diagnosis. Despite these more aggressive clinical features, the short-term mortality (20 y) in childhood cancer is much lower than in adults with similarly aggressive disease. As with thyroid cancer diagnosed in adults, survival rates of over 95 % are demonstrated in most large series of treated childhood thyroid cancers. It is important to note that the median follow-up of these childhood thyroid cancer series is only 10 to 15 y. Unlike adult thyroid cancer, there is a paucity of data on long-term (20 to 40 y) morbidity or mortality of differentiated thyroid cancer diagnosed and treated in childhood (Grigsby et al., 2002). Thyroid cancer patients who were children or adolescents (<19 y old) at the time of the Chernobyl nuclear reactor accident appears to have higher rates of both local cervical and distant metastasis than that reported for a large series of spontaneously-occurring adult thyroid cancers (Pacini et al., 1997; 1999). While it has been suggested that these Chernobyl-associated childhood thyroid cancers behave aggressively (Pacini et al., 1997; 1999), it remains unclear whether the clinical presentation and course are significantly different than spontaneously-occurring childhood thyroid

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cancers (UNSCEAR, 2000a). Studies of populations of children exposed to external radiation have suggested that the prognosis with radiation-induced thyroid cancer is no worse and may be better than spontaneously-occurring thyroid cancer (Viswanathan et al., 1994). 2.2.3

Functional Diseases

Functional abnormalities of the thyroid are characterized as either hyperthyroidism or hypothyroidism. Although structural abnormalities (e.g., thyroid enlargement) often accompany these functional abnormalities, diagnosis is usually based on detection of abnormal levels of thyroid hormone in the blood, and treatment is directed at returning these thyroid hormone levels to the normal range. The residual structural abnormalities rarely cause clinicallysignificant symptoms. The most common cause for functional thyroid abnormalities is a group of diseases referred to as autoimmune thyroid disease. Autoimmune thyroid diseases are associated with circulating antibodies that react specifically with thyroid antigens or receptor sites. The precipitating factors for the development of these antibodies have not been well defined, but there seems to be a genetic predisposition to these disorders since autoimmune thyroid disease frequently occurs in families. 2.2.3.1 Hyperthyroidism. The symptoms of thyrotoxicosis (excessive quantities of thyroid hormone) include nervousness, emotional lability, inability to sleep, tremors, frequent bowel movements, excessive sweating, and heat intolerance (Wartofsky, 1994). The diagnosis of thyrotoxicosis is made by measuring the amount of thyroid hormone in the blood. Typically, the amount of thyroxine is elevated and the amount of TSH is decreased. Free thyroxine measurements are more predictive than measurement of total thyroxine since only unbound thyroxine is metabolically active. TSH, which is produced by the anterior pituitary, should not be confused with thyroid stimulating immunoglobulin (TSI) (discussed below). Some patients have subclinical hyperthyroidism (McDermott et al., 2003). Typically these patients are asymptomatic, have normal free T4 and free T3 levels but have a decreased TSH. These patients are at increased risk for developing overt thyrotoxicosis, cardiac arrhythmias, and osteoporosis (Fatourechi, 2001; Toft, 2001). Some forms of thyrotoxicosis are caused by the thyroid producing an excessive amount of thyroid hormone (hyperthyroidism).

50 / 2. THYROID AND PARATHYROID GLANDS Other forms of thyrotoxicosis are caused by the release of preformed thyroid hormone (thyroiditis) or by the ingestion of excessive amounts of thyroid hormone (e.g., thyrotoxicosis factitia). Measurement of a 24 h radioactive iodine uptake (RAIU) (Section 2.3.2) is sometimes necessary to distinguish thyrotoxicosis due to hyperthyroidism (elevated 24 h RAIU) from thyrotoxicosis due to the release of preformed thyroid hormone, or the ingestion of excessive amounts of thyroid hormone (low 24 h RAIU). Graves’ disease is the most common cause of hyperthyroidism; its treatment and management are discussed by Boger and Perrier (2004), Pearce and Braverman (2004), and Topliss and Eastman (2004). In this autoimmune disease, an abnormal antibody, TSI, stimulates the thyroid to produce thyroid hormone. Continuous stimulation of the thyroid gland results in enlargement of the gland, as well as increased secretion of thyroid hormone. TSI also causes proliferation of tissue behind the eyes causing some patients with Graves’ disease to have bulging eyes (exophthalmos). The factors that initiate the production of TSI are not well understood. It is possible to measure TSI in serum, but this assay is not routinely obtained. Hyperthyroidism can also be caused by focal areas of hyperfunctioning thyroid tissue (toxic nodular goiter). Although the etiology of toxic nodular goiter (Plummer’s disease) is not clear, it is not associated with anti-thyroid antibodies. Hyperfunctioning nodules are usually and easily palpated by experienced examiners. Clinical treatment and management of Plummer’s disease are discussed by Kang et al. (2002) and Meller et al. (2000). 2.2.3.2 Hypothyroidism. The symptoms of hypothyroidism (too little thyroid hormone) are nonspecific and their onset is often insidious. Symptoms include fatigue, lethargy, constipation, cold intolerance, stiffness and cramping of muscles, carpal tunnel syndrome, and menorrhagia (Wartofsky, 1994). The diagnosis of hypothyroidism is made by measuring the amounts of thyroid hormones in the blood. Typically, the amount of thyroxine is decreased and the amount of TSH is increased. As with the diagnosis of hyperthyroidism, free thyroxine measurements are more reliable than measurement of total thyroxine. Hypothyroidism is usually related to the inability of the thyroid to produce enough thyroid hormone. Much less common causes of hypothyroidism include pituitary dysfunction (decreased TSH production) or peripheral insensitivity to the effects of thyroid hormone. Hypothyroidism is much more common than hyperthyroidism. The prevalence of subclinical hypothyroidism (normal serum T3 and T4; elevated TSH)

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(Cooper, 2001; Lindsay and Toft, 1997) is sufficiently high in women (1 in 71) that screening for hypothyroidism in women over the age of 50 y has been recommended by some experts (Helfand, 2004). Clinical treatment and management of hypothyroidism are discussed by Topliss and Eastman (2004). The presence of anti-thyroid antibodies does not necessarily result in overstimulation of the thyroid gland. Some types of antibodies (anti-thyroperoxidase) are associated with a chronic destructive process within the thyroid gland known as “chronic lymphocytic thyroiditis” or “Hashimoto’s thyroiditis” (Orgiazzi, 1999; Slatosky et al., 2000; Walfish, 1997). Chronic lymphocytic thyroiditis is the leading cause of spontaneously-occurring hypothyroidism in iodine-sufficient regions of the world. Many anti-thyroid antibodies can now be measured. The significance of these antibodies in the absence of clinically apparent disease is unclear. The detection of an antibody in the serum is not necessarily diagnostic for a specific disease process, but may indicate that a patient is at increased risk for clinically apparent hypothyroidism in the future. 2.2.3.3 Hyperparathyroidism. Excess production of parathyroid hormone by parathyroid glands results in hyperparathyroidism (Marx, 2000). Abnormally elevated levels of parathyroid hormone result in elevated levels of serum calcium. Chronic elevations in serum calcium have been associated with lethargy, emotional lability, dyspepsia, and kidney stones. Prolonged hyperparathyroidism can result in osteoporosis. In general, surgical resection of the overfunctioning parathyroid gland(s) is curative with postoperative normalization of parathyroid hormone levels and serum calcium. External radiation has been reported as a risk factor for development of hyperparathyroidism (Fujiwara et al., 1992; Schneider et al., 1995). 2.3 Medical Uses of Radiation A number of medical applications expose the thyroid and parathyroid glands to radiation. EBRT has been used for benign and malignant conditions of the head and neck. Internal exposures, predominately from radioiodines, have resulted from diagnostic studies as well as from therapy for benign and malignant disorders of the thyroid. Newer diagnostic studies (e.g., helical computed tomography) may result in organ doses that have been associated with an increased risk of cancer (Brenner et al., 2001).

52 / 2. THYROID AND PARATHYROID GLANDS 2.3.1

External Beam Radiation Therapy Exposures of the Thyroid

For many years, external beam radiation therapy (EBRT) was used in the treatment of many benign medical conditions including thymus enlargement, hemangiomas, tinea capitis, acne, and lymphoid and tonsillar hypertrophy (Jacobs et al., 1999). After an elucidation of an association between EBRT and thyroid cancer, these practices have been abandoned. However, EBRT continues to be a mainstay of therapy for many patients with lymphoma and other cancers after which benign and malignant thyroid disease and hypothyroidism may result (Hancock et al., 1991). External irradiation is also associated with an increased risk of acoustic neuromas (Preston et al., 2002; Shore et al., 2003; Shore-Freedman et al., 1983) as well as tumors of the parathyroid (Fujiwara et al., 1992; 1994a; 1994b; Schneider et al., 1995) and salivary glands (Saku et al., 1997; Schneider et al., 1998; Shore-Freedman et al., 1983; Zheng et al., 2004). 2.3.2

Diagnostic Use of Radioactive Tracers in the Thyroid

The 24 h RAIU continues to be used clinically to obtain an overall measurement of thyroid function. As mentioned earlier, the 24 h RAIU is sometimes useful to differentiate thyrotoxicosis from an overactive thyroid gland (high 24 h RAIU) from thyrotoxicosis due to inflammation of the thyroid gland and the subsequent release of preformed thyroid hormone (low 24 h RAIU). In addition, the 24 h RAIU is used at many medical centers to determine the amount of radioiodine to administer for therapy of hyperthyroidism. The standard measurement for radioiodine uptake is accomplished using a sodium iodide probe to measure the percent of administered radioactive iodine that localizes in the thyroid gland 24 h after the administration (Becker et al., 1996a). An identical amount of radioactive iodine, as was administered to the patient, is put in a small cylindrical container. The container is placed in a neck phantom. The phantom, typically made of some sort of plastic, is designed to simulate the geometry of the neck. The phantom permits calculation of the conversion factor from a known quantity of radioiodine in the phantom to a count rate measured by the sodium iodide probe (Hine and Williams, 1967). The same neck phantom is typically used for all patients regardless of their neck size. The percentage 24 h RAIU is equal to the ratio of the background corrected count rate measured from the patient to the background corrected count rate measured from the phantom.

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The normal percentage uptake of radioiodine at 24 h in adults is 10 to 30 %. Measurements at other time-points are sometimes used. Uptake measurements can generally be made with much less administered activity than required for imaging studies of the thyroid (Table 2.4). Uptake studies are most commonly done with 131I although 123I can be used. Iodine-123 is more expensive than 131I and is less available due to its short half-life (13 h). The increased dose (~10 times greater) from 131I, as compared to 123I, is rarely an issue since uptake studies are most commonly performed in patients with suspected hyperthyroidism. If hyperthyroidism is confirmed, these patients are treated with much larger amounts of 131I, typically 370 MBq. Sodium 99mTc pertechnetate can also be used to measure thyroid uptake. However, unlike iodine, the thyroid traps but does not organify pertechnetate. Because iodine is both trapped and organified by the thyroid, the uptake measured using radioiodine at 24 h is much higher (10 to 30 % of the administered activity) than the uptake measured by 99mTc pertechnetate 20 to 30 min after injection (a few percent of the administered activity). Thyroid imaging (scintigraphy) can be used to determine the distribution of radioactive iodine or pertechnetate within the thyroid gland (Becker et al., 1996b). This evaluation is sometimes useful to: (1) differentiate hyperthyroidism due to a hyperfunctioning thyroid nodule (toxic nodular goiter) from hyperthyroidism due to a diffusely hyperfunctioning thyroid gland (Graves’ disease) or (2) determine if a thyroid nodule functions normally. If a thyroid nodule functions normally, the chance that the nodule is thyroid cancer decreases significantly. Unfortunately, only ~10 % of thyroid nodules have normal function. Lack of function increases the chances that the nodule is due to thyroid cancer, but most poorly functioning nodules are still benign. As discussed below, more definitive differentiation of thyroid cancer from benign nodules of the thyroid requires the examination of tissue samples obtained from FNA or surgical biopsy. Estimated effective dose equivalents and thyroid doses from the commonly administered radiopharmaceuticals used for uptake and for thyroid imaging studies are given in Table 2.4. 2.3.3

Radioactive Iodine Therapy

Larger amounts of radioactive iodine can be used to deliver a sufficient dose to the thyroid to destroy normal tissue, hyperfunctioning thyroid tissue, as well as differentiated thyroid cancer. For the treatment of hyperfunctioning thyroid tissue (e.g., Graves’ disease) 260 to 550 MBq of 131I is usually administered; this activity will typically deliver doses of ~70 to 100 Gy to the thyroid. Larger doses are used to treat patients with hyperfunctioning nodules.

Radiopharmaceutical

Type of Test

Administered Activity (MBq)a

Thyroid Dose (mGy)

Effective Dose Equivalent (mSv)

Na131I iodide

Uptake

0.15 – 0.37 po

50 – 130

1.6 – 4

Na123I iodide

Uptake

1.5 – 3.7 po

5 – 12

0.17 – 0.41

99m

Tc pertechnetate

Uptake

74 – 370 iv

1.7 – 8.5

1–5

131I

iodide

Thyroid imaging

1.8 – 3.7 po

600 – 1,300

19 – 40

I iodide

Thyroid imaging

3.7 – 7.4 po

12 – 24

0.41 – 0.81

Thyroid imaging

74 – 370 iv

1.7 – 8.5

1–5

Na

123

Na

99m

Tc pertechnetate

a po

= by mouth iv = intravenous injection

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TABLE 2.4—Dose to the adult thyroid and effective dose equivalent from common diagnostic studies [normal (25 %) thyroid uptake is assumed] (ICRP, 1988).

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For the treatment of thyroid cancer, 131I is given in much larger amounts, up to 9.25 GBq per treatment, than those used in the treatment of hyperthyroidism. One reason for the larger amounts is that the percent of the administered activity that accumulates per gram of tissue is usually much less in thyroid cancer than occurs in normal or hyperfunctioning thyroid tissue. In patients with extensive disease, tumoricidal doses are limited by the need to limit the dose to the bone marrow to <2 Gy to minimize hematopoietic toxicity. Serial measurements of the amount of 131I in the blood at multiple time-points after administration of a tracer dose could be used to better estimate the dose to the bone marrow. In practice, such measurements are cumbersome and are rarely done. The dose to the thyroid tumor is, unfortunately, rarely known with precision as important factors such as the size of the tumor, the percent of the administered activity that localizes in the tumor, and the biological half-life of activity in the tumor are rarely known. Only a few medical centers base their selection of treatment doses on patientspecific biodistribution data. 2.3.4

Thyroid Dose from Radioactive Iodine

The thyroid dose from radioactive iodine is dependent on three major subject-specific factors: • percent of the administered activity that accumulates in the thyroid; • size of the thyroid; and • biological half-life of the radioactive iodine in the thyroid gland. The percent of the administered activity that accumulates in the thyroid depends on: • amount of stable iodine in the diet, • age of the patient (younger children have higher thyroid uptakes than adults), and • level of function of the thyroid gland (hyperfunctioning thyroid glands will accumulate more iodine than will hypofunctioning glands). The level of function of the thyroid gland also affects the biological half-life of iodine. Iodine has a shorter biological half-life in hyperfunctioning thyroid glands than in hypofunctioning thyroid glands.

56 / 2. THYROID AND PARATHYROID GLANDS The relatively constant or increasing uptake with decreasing age and the decreasing thyroid mass with decreasing age mean that for the same ingested activity, younger children have a higher concentration of radioiodine in their thyroid than adults. When the environment is contaminated, the dose to the thyroids of children is further increased by the fact that milk, which is the principal pathway by which radioiodine is concentrated in the human food chain and ingested, makes up a greater proportion of a child’s diet. Patients with an overactive thyroid gland due to Graves’ disease can be treated with medication (e.g., propylthiouracil), surgery, or radioiodine therapy. In the United States, treatment with radioiodine is usually preferred in adults. Three approaches have been used to select the amount of activity used to treat patients. The first approach is to treat most patients with an empirically chosen amount of activity, often ~370 MBq, and to modify the amount of activity based on the severity of the patient’s symptoms (more activity for more severe symptoms) and on gross differences in the size of the thyroid gland (larger amounts of administered activity for larger thyroid glands). The second approach is to calculate the amount of activity that needs to be administered to achieve the desired concentration of radioiodine in the thyroid (e.g., 3.7 MBq g–1). To use this approach, the size of the thyroid needs to be estimated (usually from palpating the neck or less frequently from an ultrasound examination) and the 24 h RAIU needs to be measured. This approach should theoretically result in more uniform results. In practice, there is little evidence that this more rigorous approach results in better patient outcomes. The third approach attempts to adjust the administered activity for an additional factor; variability in biological half-life. This approach is cumbersome for patients since it requires that the patient return to the hospital on several days for additional thyroid measurements. Because of the inconvenience to patients and the lack of evidence that measuring the biological half-life results in a better outcome, few medical centers attempt to measure the biological half-life before treating a patient. A subset of patients who may benefit from this approach are patients who have a short biological half-life of iodine in the thyroid gland. These patients require treatment with larger amounts of radioiodine than do the usual patients. 2.4 Thyroid Genomics Increasing evidence suggests that a small set of regulatory cellular genes appear to be the target for genetic alterations that result in a neoplastic transformation of cells. Alterations in either

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proto-oncogenes or tumor suppressor genes are the most frequently described mutations associated with neoplastic transformation (Fagin, 2002; Nikiforov, 2004; Sarlis, 2000; Sobrinho-Simoes et al., 2005). The discovery of a point mutation in a single base pair in the RET proto-oncogene as the cause of hereditary forms of medullary thyroid cancer has dramatically altered the management of these families (Kebebew and Clark, 2000). In patients with these types of specific RET proto-oncogene mutations, total thyroidectomy is performed early in childhood before medullary thyroid cancer develops within the thyroid (Brandi et al., 2001). In this situation, detection of a specific genetic mutation leads directly to clinical recommendations that can prevent the subsequent development of a potentially lethal malignancy. Proto-oncogenes are genes that are normally expressed at certain times during cell growth and division and encode for proteins that are important in the regulation of cell growth, repair and differentiation (Kim et al., 2003). In general, proto-oncogene activation results in gain-of-function mutations acting in a dominant fashion. The mutationally activated form of a proto-oncogene is known as an oncogene. Proto-oncogenes encode proteins such as growth factors (e.g., sis, PDGF, int-2), growth factor receptors (e.g., erb-b, met, trk, ret), tyrosine kinases (e.g., src, abl), signal transduction regulatory proteins (e.g., ras, gsp), serine/threonine kinases (e.g., mos, raf), and nuclear regulatory proteins (e.g., myc, myb, c-jun). Tumor suppressor genes normally function to regulate or impede progression through the cell cycle (Farid, 2001). Examples of tumor-suppressor genes include TP53, retinoblastoma gene, and PTEN. Inactivation of the tumor-suppressor gene is a loss-offunction mutation that behaves in a recessive fashion. Absence of tumor-suppressor gene activity has been associated with malignant transformation in many types of cancer. 2.4.1

DNA Damage and Cellular Response

Exposure of cells to ionizing radiation results in damage to the deoxyribonucleic acid (DNA) strands and initiates a complex response cascade that is still poorly understood (NCRP, 2001). The basic types of DNA damage include base-pair deletions or substitutions, as well as single- and double-strand DNA breaks. Ordinarily, the cell quickly activates DNA repair mechanisms and enters a cell cycle-specific growth arrest interval that allows time for DNA repair. Possible cellular outcomes include cell death from exposure to ionizing radiation, cell cycle growth arrest with activation of programmed cell death (apoptosis), repair of damage with a

58 / 2. THYROID AND PARATHYROID GLANDS return to normal genomic structure, and misrepair resulting in formation of novel DNA sequences. The results of each of these processes are either the repair or elimination of DNA-damaged cells, and the relation of these processes to radiation-induced thyroid cancers is discussed by Ermak et al. (2003) and Nikiforov (2004). Repair of single-strand DNA breaks is usually efficient since the complementary strand remains intact and can serve as a template for repair of the damaged strand. Repair of double-strand breaks can, however, lead to a variety of aberrant DNA recombination events including chromosomal translocations, deletions, and intrachromosomal rearrangements. Double-strand DNA break rejoining is often accomplished by ligation of two blunt chromosomal ends without the benefit of an intact template. Therefore, it is quite likely that novel DNA sequences will result from the combination of two previously unrelated DNA sequences. These genetic rearrangements are not necessarily detrimental to the cell if the translocation simply moves the genetic location of an entire gene with its regulatory elements to another position on the same or even a different chromosome. These novel chromosomal combinations may result in activation of a proto-oncogene or loss of function of a tumor suppressor gene by alteration of control elements that were previously on adjacent regions of the chromosomes (Ciampi et al., 2005a; 2005b). Misrepair of double-strand breaks can result in activation of proto-oncogenes by combining the regulatory elements from one gene with the functional domain of another gene. The result is unregulated or dysregulated expression of a protein that usually is involved in cellular signaling or cellular regulation. Doublestrand DNA breaks can also result in loss of the coding sequence of important tumor suppressor genes. Loss of these genes greatly enhances the likelihood of malignant transformation (Sarasin et al., 1999). Not all activating mutations require large translocations or deletions of DNA. Often a single base-pair mutation in genomic DNA is capable of activating a specific proto-oncogene. These point mutations occur in specific domains of DNA and alter the function, half-life, or inactivation characteristics of the expressed protein. Small changes in the genomic DNA sequence can have significant effects on the functional characteristics of regulatory proteins. It is now becoming increasingly more apparent that tumor formation is accompanied by both genetic alterations to the DNA sequence described above and also epigenetic alterations to the genome (An, 2007). Epigenetic events are reversible modifications around a gene that can regulate expression of specific genes (normal

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genes, tumor suppressor genes, and oncogenes) without changing the specific nucleotide sequence. Epigenetic modifications of gene expression are particularly important in embryogenesis and are key modulators in the expression of differentiation genes. In malignancy, epigenetic changes have been associated with alterations in cell growth, differentiation status, and angiogenesis promotion. Because of these growth promoting activities, novel therapies that target these epigenetic modifications are actively being explored in preclinical and clinical trials in a wide variety of malignancies (Mai, 2007). Epigenetic modifications usually involve altering either the methylation or acetylation status of DNA, and/or the histone proteins intimately associated with the double-stranded DNA (Furuya et al., 2004; Mitsiades et al., 2005; Puppin et al., 2005). For example, hypermethylation of the promotor regions has been demonstrated to decrease the expression of several tumor suppressor genes in both benign and malignant thyroid nodules, and appears to be linked with activation of BRAF in papillary thyroid cancers and possibly RAS activation in benign nodules and follicular thyroid cancer (Xing, 2007). While regulation of these epigenetic events was initially thought to be mediated through specific enzymes such as DNA methyltransferases, histone methyltransferases, and histone actylases/deacetylase enzymes, more recent data suggest the small, noncoding ribonucleic acid (RNA) may also have an important role in gene transcription or epigenetic regulatory control (Mattick and Makunin, 2006). Since malignant transformation is thought to be a multi-step process, it is possible for genomic DNA damage to cause dysregulation of a gene that is not sufficient to cause a malignant transformation. If the abnormal gene does not significantly affect the ability of the cell to grow and divide, the abnormal gene may be passed onto the cell’s progeny during normal cellular division. Development of additional genomic DNA damage in the progeny may result in malignant transformation at some point in the future. Thus, the ability of ionizing radiation to induce malignant transformation is not limited to the actual cell receiving the direct radiation alterations. It is likely that some genomic DNA damage is passed on to progeny which may contribute to the multiple defects needed to result in a malignant transformation many generations later. A second possible mechanism for radiation-induced malignant transformation has been described that does not involve direct activation of an oncogene by radiation-induced DNA damage or by

60 / 2. THYROID AND PARATHYROID GLANDS the repair attempts of the cell. It has been postulated (Farid, 1996; Little, 2006) that radiation may induce a state of genomic instability that can be transmitted through subsequent cell divisions. The identity and characteristics of this transmissible instability property has not yet been identified. This instability predisposes the cell to multiple errors in DNA replication, thereby increasing the probability of a later occurrence of transforming mutations in the progeny after many generations. 2.4.2

Molecular Biology Techniques

Many techniques have been developed that analyze genomic DNA to determine if there are large-scale alterations in the chromosomes. Such alterations include either an increase or decrease in chromosomal material or normal chromosomal material in abnormal locations, either within the same chromosome or between chromosomes (Ciampl et al., 2005b; Richter et al., 2004; Wreesmann et al., 2002). Other techniques have been developed that look at small-scale changes within specific regions of a chromosome down to even a single base-pair alteration in a specific gene (Ciampi and Nikiforov, 2005; Fukushima and Takenoshita, 2005). 2.4.2.1 Functional Significance of DNA Alteration. Since DNA is the basic blueprint for all cellular proteins, alterations in DNA can result in abnormal function of a wide variety of regulatory proteins required for normal cellular growth and development. As described above, these DNA alterations can result in either an increase or decrease in the function of specific proteins, depending on whether the mutation is activating or inactivating. Therefore, the functional significance of DNA mutations is reflected in changes in the function of the regulatory and structural proteins that are encoded by the specific gene that is mutated. It is the abnormal protein expression that results in the altered structural characteristics and behavioral features that define the transformation of the cell to a malignant phenotype. 2.4.2.2 Technical Requirements. Thyroid cells or thyroid tissue is required for the study of the specific DNA, messenger RNA (mRNA), or protein alterations induced by ionizing radiation in the thyroid (Chadwick, 2000; Thomas and Williams, 2000; Thomas et al., 2000). Many techniques require only very small amounts of fresh thyroid tissue, which can be obtained at the time of a clinically indicated thyroidectomy following pathologic examination of the gland. After adequate samples have been preserved for standard diagnostic histological analysis, there is, generally,

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sufficient tissue of both the thyroid nodule and normal thyroid tissue to allow samples to be frozen for later molecular analysis. Samples as small as 10 to 20 mg are often adequate to perform numerous molecular studies. Fresh frozen tissue samples can be stored in ultra-cold freezers for many months before being used for molecular analysis. Many studies can also be performed on clinical thyroidectomy samples obtained as many as 20 to 30 y previously as part of routine clinical care. These thyroid samples were often preserved as paraffin-embedded tissues, the standard method used by pathologists to prepare tissue samples for histological evaluation. These samples can easily be examined for protein expression using immunohistochemistry staining. Useable DNA and mRNA can often be obtained from these samples (Martin et al., 1994; Mizuno et al., 1998). While there are limitations as to the quantity and quality of nucleic acids recovered from paraffin-embedded histology archives, they offer the unique ability to provide prolonged follow-up information on a specific patient if corresponding clinical data are known. Correlation of clinically important outcomes with specific gene alterations can be accomplished retrospectively by comparing follow-up clinical information with genomic DNA damage or mRNA expression. It is also possible to use the small amount of thyroid cells obtained by standard FNA to perform many molecular biology studies. These thyroid cells can be examined for alterations in genomic DNA, mRNA, and protein expression using modern molecular biology techniques (Werga et al., 2000). Since there is a background spontaneous occurrence of thyroid cancers in all populations, not all thyroid cancers that develop in the aftermath of radiation exposure are caused by radiation. Identification of specific oncogene mutations that are more frequently associated with radiation-induced malignancy than spontaneous malignancy would be helpful in determining the likelihood that a particular cancer was caused by radiation. 2.4.2.3 Oncogenesis, Mitotic Rate, and Growth Potential. Any discussion of the molecular effects of ionizing radiation in the thyroid should attempt to explain why radiation during childhood appears to be more carcinogenic to the thyroid than radiation during adult life. Most authorities agree that malignant transformation is a multi-step process that likely develops over many cell division cycles (Fagin, 2002; 2004). This theory is held by proponents of the multiple-oncogene hit hypothesis, as well as those who support the genomic instability model of malignant transformation. Therefore, it seems likely that cells with the highest mitotic rate and the

62 / 2. THYROID AND PARATHYROID GLANDS highest propensity for replication would have the highest likelihood of developing a malignant transformation after exposure to a carcinogen. In the theoretical construct proposed by Williams (1999) (Figure 2.9), young children have thyroid cells with one or two generations of growth potential remaining, while the adult thyroid is composed almost exclusively of thyroid cells that have essentially no capacity to replicate. Therefore, DNA damage from ionizing radiation is more likely to increase the risk of thyroid cancer in children with a high replication potential as opposed to adults with little or no capacity to divide and replicate normal thyroid cells (Williams, 1999). In summary, ionizing radiation can cause alterations in the genomic DNA of specific cells, which result in abnormal mRNA and subsequent abnormal protein expression. It is the abnormal protein expression that results in the altered structural characteristics and behavioral features that define the transformation of the cell to a malignant phenotype. Recent studies have also demonstrated “nontarget” effects of ionizing radiation that may alter a wide variety of cellular responses apart from direct DNA damage. The relative importance of the targeted and the nontargeted effects of ionizing radiation remain to be defined. Fortunately, a wide variety of modern molecular biology techniques can be used to characterize the abnormalities associated with malignant transformation at the level of alteration in the genomic DNA, mRNA expression, regulatory protein modifications, and final functional protein product.

Fig. 2.9. Follicular cell number with zero, one or two generations of growth remaining as a function of age (adapted from Williams, 1999).

3. Radiation Dosimetry and Dose Reconstruction Section 3 and the associated appendices include radiation dosimetry information relevant to the induction of thyroid cancer and other thyroid diseases by ionizing radiation. External exposures and internal exposures to radioisotopes of iodine as well as medical and nonmedical exposures are considered. A general discussion of the practical limitations of dose estimation in radiation epidemiology studies is presented. Specific considerations for external and internal exposures and a review of the dosimetry are provided for several of the major radiation epidemiology studies. The studies considered are those of the atomic-bomb survivors, NTS “down-winders,” Marshall Islanders, Hanford Cohort, and the Chernobyl Cohort. Additional background material is presented in Appendices A through D (Table 3.1). 3.1 Specification of Dose in Principle and in Practice The quantitative characterization of radiation effects, including the induction of thyroid cancer and other thyroid diseases, requires dose-response analyses. The complex ways in which radiation interacts with matter and the diverse ways in which biological systems respond to radiation require that doses be specified in different ways (ICRP, 1990; NAS/NRC, 1990). Definitions of various

TABLE 3.1—Appendices pertinent to Section 3. Appendix

Title

A

Radiation Dosimetry Quantities and Related Concepts

B

Radiation Dosimetry for External Beam Radiation Therapy and Brachytherapy

C

Chronology of Radiation Dosimetry Development for the Atomic-Bomb Survivors

D

Thyroid Radiation Dosimetry of Radioisotopes of Iodine

63

64 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION quantities used to specify dose and of selected related quantities and concepts with a compilation of Systeme International (SI) quantities and their symbols and units are presented in Appendix A (NCRP, 1985b). 3.1.1

Specification of Dose: Ideal

Ideally, a biologically effective dose (BED) dose-volume histogram for each irradiated individual in an exposed cohort would specify the fraction of cells at risk as a function of BED and include the weighted mean, minimum and maximum BEDs. Among other factors, this would require knowledge of the three-dimensional, spatially-varying dose distribution for each tissue at risk. BED would represent the radiation energy deposited per unit mass of irradiated cell nuclei or other cellular target (i.e., the absorbed dose) scaled by factors related to radiation quality, dose rate, and intrinsic sensitivity to the radiobiological event. 3.1.2

Specification of Dose: Practical

In radiation epidemiology studies, accurate specification of dose among irradiated individuals in an exposed cohort is far from ideal. Dose to an organ or tissue at risk, such as the thyroid, is generally expressed simply as the mean exposure or mean absorbed dose and relies heavily upon the accuracy of calibration factors. For external medical irradiations, only the exposure rate in air at a standard distance from a radiation source may be available. The appropriate exposure-absorbed dose conversion coefficient and depth-dose and/ or isodose curves must be applied to estimate the absorbed doses to the tissue(s) of interest, assuming patient setup and exposure parameters were recorded and are available. Because the type of radiation delivered from a medical procedure is generally well characterized, the appropriate quality factor and dose-rate effectiveness factor may then be used to convert tissue and organ absorbed dose to dose-rate adjusted dose equivalent, although in practice this may be problematic (Straume, 1993). Macroscopic and microscopic heterogeneity, other stochastic aspects of dose, random error, and systematic bias among subgroups of individuals comprising an exposed cohort contribute additional uncertainty to the absorbed dose estimate. Further, uncertainties (errors) in estimated individual doses tend to reduce the slope of dose-response curves. Unless such uncertainties are large, however, their impact on the shape of the dose-response curve is likely to be minimal (Schafer et al., 2001; Stram and Kopecky, 2003).

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3.1.2.1 Physical Dosimetry. Phantom-based measurements of organ doses are generally used only for external medical exposures such as those encountered in EBRT and in brachytherapy. Small ionization chambers or thermoluminescent dosimeters (TLDs) are placed at discrete positions in a uniform water or tissue-equivalent anthropomorphic phantom that approximates the body habitus of average members of the exposed cohort (Attix, 1986; Fowler and Attix, 1966; Kereiakes and Rosenstein, 1980; Lin and Cameron, 1968). More anthropomorphic, heterogeneous phantoms, containing bone, lung and tissue-equivalent materials have also been used in an effort to improve the accuracy and precision of dose estimates. With TLDs or other radiation dosimeters in place, a phantom is exposed to an equivalent (ideally, the same) radiation source, and the same exposure geometry and parameters are used as were used for the exposed population, assuming the exposure geometry and parameters (e.g., source-to-skin distance, exposure time, etc.) are still available. When contemporaneous dosimetry measurements are still available, this is optimum for estimating dose. Even if target-volume doses have been estimated, incidental doses to nearby organs generally are not determined contemporaneously. For example, if the thyroid were well out of the treatment field for EBRT of a brain tumor, the relatively small thyroid dose from scattered radiation generally would not have been addressed in the treatment plan. Moreover, dose estimates for out-of-field organs may be particularly problematic, as such doses vary significantly with changes in position of the patient. For medical internal exposures (e.g., from radioiodine therapy for hyperthyroidism), the activity administered to each patient is carefully documented along with other patient-specific data. In many instances, the percent of the administered activity that localized in the thyroid gland is measured at one time-point, typically 24 h after administration, and the biological half-life of activity in the thyroid gland is assumed based on population reference values. Accurate patient-specific estimates of the size of the thyroid gland may be available from ultrasound imaging, which is more accurate than that based on palpation. When patient-specific data are unavailable, average population doses per unit administered activity (or dose conversion factors) must be applied to individuals in the exposed cohort. The dose conversion coefficients are usually calculated as a function of gender, age, and measured or assumed 24 h RAIU. External dose received by occupationally-exposed workers is recorded by personal dosimeters such as film badges or TLDs (Attix, 1986; Dudley, 1966; Fowler and Attix, 1966; ICRP, 1982;

66 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION Suntharalingam and Cameron, 1966). These dosimeters typically achieve an accuracy of r30 % and a precision of r10 % over an exposure range of 2.58 × 10–6 C kg –1 (the lowest detectable exposure) to 1.56 × 10–1 C kg –1 or more, with constancy (i.e., constant signal per unit exposure) over a wide range of x- and gamma-ray energies. Most radiation workers wear a single dosimeter, typically on the trunk of the body. Since occupational exposures are spatially heterogeneous, the dosimeter-recorded dose cannot accurately reflect the exposures to all organs. Organ dose estimates from environmental radiation exposures are less precise and less accurate than from medical or occupational exposures (NCI, 1997; NCRP, 1977; 1984). Source terms (i.e., the identities and amounts of radionuclides released and the time-course of their release), environmental transport (affected by meteorological and other time-varying environmental conditions), and internalization, metabolism, and excretion (variable among individuals depending on location, age, gender, health, nutritional status, etc.) are all important variables that are seldom accurately known. These variables may be mathematically modeled, and supplemented by activity measurements of environmental samples and/or of individuals among the exposed population. Dose estimates based on individual activity measurements are more reliable than those based exclusively on population modeling analyses. 3.1.2.2 Biological Dosimetry. An increasingly important tool in radiation epidemiology studies is biological dosimetry, an assay of dose-dependent biological markers (such as antigen expression or chromosome abnormalities) as measures of absorbed dose. Although none of the present assays specifically estimate thyroid dose, four of the most prominent whole-body biological dosimetry assays developed to date are the glycophorin A somatic cell mutation assay, the hypoxanthine phosphoribosyltransferase somatic cell mutation assay, fluorescence in situ hybridization for chromosome translocation analysis (known as “chromosome painting”), and electron spin resonance dosimetry from tooth enamel (Durante et al., 1996; Fernandez et al., 1995; Finnon et al., 1995; GarciaSagredo et al., 1996; Gray et al., 1991; Romanyukha et al., 2000; Schmid et al., 1992; Sorokine-Durm et al., 1997; Straume et al., 1997; Streffer et al., 1998; Wiegant et al., 1991). Such assays are restricted to cells that can be obtained by blood or tooth sampling and, therefore, do not directly yield estimates of thyroid or other organ-specific doses. Both the glycophorin A somatic mutation assay and the fluorescence in situ hybridization have been applied to a small cohort of

3.2 EXTERNAL DOSE

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atomic-bomb survivors and to a cohort of Chernobyl cleanup workers (“liquidators”). Samples obtained from atomic-bomb survivors 40 y after the exposure showed a statistically-significant linear relationship between glycophorin A mutation frequency and bonemarrow absorbed dose in the atomic-bomb survivor cohort (Akiyama et al., 1995), although the wide variations in observations preclude individual-specific dose estimation. Blood samples obtained between 1992 and 1999, from 625 Russian cleanup workers exposed at Chernobyl and 182 Russian controls, revealed a statistically-significant change in translocation frequency (increase of 30 % in chromosome translocation frequency over that in nonexposed controls [95 % CI 10 to 53 %, p = 0.002)] with dose (Jones et al., 2002). The estimated average dose for the cleanup workers, based on the average increase in translocations, was 95 mGy. Although these results are of interest, some experts question whether changes in translocation frequencies can be used to reliably measure doses of less than several hundred milligray. 3.2 External Dose 3.2.1

Medical External Radiation Exposure

Important human data related to radiation induction of thyroid cancer have been derived from follow-up of patients who received therapeutic irradiation with incidental radiation to the thyroid; the most common form of such therapy is EBRT, or teletherapy (Appendix B). In contrast, therapy using internally-deposited radionuclides (such as radioisotopes of iodine) is radiobiologically and dosimetrically distinct, in that these radionuclides deliver most of their dose by short-range particulate radiations (i.e., electrons and delta rays) more locally and at a relatively low dose rate, generally with pronounced spatial and temporal variations in dose among different tissues and even within the same tissue. Another form of radiation treatment is brachytherapy, in which sealed sources are used to deliver therapeutic doses to selected sites. Initially, brachytherapy was more common than treatment with EBRT (Quimby, 1931; 1935). With the development of external treatment units, such as 60Co teletherapy and later linear accelerators, the use of brachytherapy declined. Traditional radionuclides such as 226Ra have been replaced by lower-energy gammaray emitters such as 192Ir and 125I. These radionuclides can be handled with lower doses to medical personnel and will deliver less incidental dose to tissues beyond the treatment volume. Brachytherapy delivers a prescribed dose at a relatively high dose rate to

68 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION a well-defined, uniformly irradiated-tissue volume with the dose decreasing rapidly with distance from the sources. The location of the brachytherapy treatment will thus determine whether there is any incidental dose to the thyroid. Treatment at more distant body sites (e.g., the use of sealed sources for the treatment of gynecological cancers) will allow for the calculation of the dose to the thyroid with some precision. The treatment algorithms developed for brachytherapy demonstrate the significant decrease in dose with distance and with the presence of overlying tissue around the sources. Treatment of tumors of the head and neck with sealed sources may involve some incidental dose to the thyroid that can be estimated using modern treatment planning systems. By design, dose in EBRT decreases rapidly at the edge of the treatment field (Hendee and Ibbott, 1996; Johns and Cunningham, 1974; Meredith and Massey, 1977; Mould, 1985; Stanton and Stinson, 1991; Williams and Thwaites, 1993), as illustrated in Figure 3.1 (Hempelmann et al., 1967). For appropriately collimated orthovoltage (200 to 300 kV) x-ray treatment units, the dose decreases by an approximate factor of 10 over a distance from 2 to 3 mm. For situations in which the thyroid may be near or at the edge of the treatment field, even a small error (e.g., <1 cm) in the estimated position of the gland or a small movement by the patient can dramatically alter the estimated thyroid dose. By contrast, consistent with the constancy (or “flatness”) of the depthdose curves in Figure 3.1 and at locations other than the edge of the treatment field, in- and out-of-beam estimates of thyroid dose should be reasonably accurate, assuming that the depth-dose curves are accurately measured. 3.2.2

External Radiation Exposure Associated with the Atomic Bombings of Hiroshima and Nagasaki

The 2002 Dosimetry System (the so-called DS02) (Preston et al., 2004; Young and Kerr, 2005) has superseded the 1986 Dosimetry System (DS86) (Pierce et al., 1996; Preston, 1988; Shimizu et al., 1999; Thompson et al., 1994; Woolson, 1988) and now serves as the basis of risk estimates in the Radiation Effects Research Foundation (RERF) Life Span Study of atomic-bomb survivors. Even at the time of its final approval, there were concerns regarding DS86 and apparent discrepancies between calculated and measured activities of thermal-neutron activation products (Roesch, 1987). These concerns were accentuated by a series of publications on different activation products (Shizuma et al., 1993; 1998; Straume

3.2 EXTERNAL DOSE

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Fig. 3.1. Depth dose curves measured in an anthropomorphic child phantom for orthovoltage x rays of different qualities and a 10 × 10 cm field, illustrating the rapid decrease in thyroid dose as a function of its position relative to the edge of the field (adapted from Hempelmann et al., 1967). TSD is target-to-source distance in centimeters.

et al., 1992), including 60Co, 152Eu, and 154Eu. These publications were interpreted as supporting the possibility that DS86 might have considerably underestimated the neutron dose at distances beyond ~1.5 km from the hypocenter in Hiroshima and overestimated neutron doses at distances within 1 km of the hypocenter, potentially impacting Life Span Study-derived risk estimates. Led by Drs. Hiromi Hasai, George Kerr, and Robert Young, a 5 y effort was therefore undertaken by an international team of over 30 scientists and successfully resolved the foregoing discrepancies and

70 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION quantified their dosimetric effects, culminating in the development of DS02. In the spring of 2003, DS02 was approved by a joint U.S.-Japan senior dosimetry review committee and was formally adopted by RERF later that same year (Cullings and Fujita, 2003; Cullings et al., 2006; Preston et al., 2004). The major changes in DS02 (Cullings and Fujita, 2003; Cullings et al., 2006; Preston et al., 2004; Sinclair et al., 2001; Young and Kerr, 2005) include: • changes in the burst height (580 to 600 m) and yield (15 to 16 kt) for the Hiroshima bomb; • changes in the amount of gamma radiation released by the Nagasaki bomb; • use of newly developed data on neutron scattering and reaction cross sections for oxygen, iron and other elements; • use of a finer energy group structure for computation of free-in-air fluences of neutrons and photons; • use of more detailed information on shielding for people exposed in houses and other wooden structures; • improvements in previous methods used to account for terrain shielding; • introduction of methods to account for terrestrial shielding not considered previously; • use of new weighting factors for the fluence-to-kerma and fluence-to-dose conversions; and • use of new and more refined Monte-Carlo radiation-transport codes. As in various previous analyses (Pierce et al., 1996; Shimizu et al., 1999; Thompson et al., 1994) based on DS86, for the comprehensive incidence analysis based on DS02 (Preston et al., 2007), a quality factor of 10 was assigned to neutrons. Organ doses [expressed as the dose equivalent (units of sievert)] were computed as the gamma-ray dose plus 10 times the neutron dose and are thus sometimes referred to as the “weighted” or “RBE10” doses. RBE for Hiroshima neutrons has been experimentally estimated by irradiating peripheral human lymphocytes in vitro with a source that emits radiation-simulating emissions by the Hiroshima bomb (Dobson et al., 1991; Straume et al., 1991). The neutron RBE was shown to decrease with increasing dose; the maximum RBE was 60 to 80 relative to 60Co gamma rays and 20 to 30 relative to 250 kVp x rays (Dobson et al., 1991). In this instance, maximum RBE is achieved with a very low dose.

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In principle, if RBE for neutrons is too high, it may result in an overestimation of the dose equivalent and, therefore, an underestimation of the radiogenic cancer risk. However, as discussed in detail in Appendix C, neutrons typically accounted for <1 % of the total organ dose and the use of different assumed RBE values would therefore have a minimal impact on risk factors for radiogenic cancer. For example, using a dose-independent value of 20 rather than 10 for the neutron RBE decreases the DS02 derived mean ERR < 5 %, 0.41 to 0.39 Sv–1 (Preston et al., 2004). Of the ~254,000 potentially evaluable atomic-bomb survivors, 93,741 are included in the Life Span Study and were within 10,000 m of the hypocenter at the time of the bombings. DS02 estimates are available for 86,671 of these survivors, 39 more than for DS86 estimates (Cullings et al., 2006). The 7,070 cohort members with unknown DS02 dose estimates were between 100 and 2,600 m (mean: 1,600 m) from the hypocenter at the time of the bombings and potentially received substantial doses. However, their doses could not be reliably estimated because of either the complexity of their shielding or a lack of shielding information. The mean dose among survivors at 1,600 m from the hypocenter at the time of the bombings is ~170 mGy. Despite improvements in dose calculations in general and shielding calculations in particular, uncertainties regarding survivor location and shielding remain a major source of random error. Therefore, the assumed organ dose error, 30 to 40 %, in the latest Life Span Study incidence analysis based on DS02 (Preston et al., 2007) is the same as that assumed in DS86-based analyses (Thompson et al., 1994). Relative to the statistical precision of the derived values, DS02 has not led to any substantial revisions in cancer-risk estimates for cancer mortality among the atomic-bomb survivors (Preston et al., 2004). Specifically, the gender-averaged EAR (at attained age 70 y after exposure at age 30 y) for solid cancers decreased only 7 %, 28.6 (DS86) to 26.9 (DS02) excess cases per 10,000 person-years (PY) sievert (90 % CI of 22 to 34 and 22 to 33 excess cases per 10,000 PY Sv, respectively). For leukemia, the gender-averaged EAR (i.e., the low dose slope in the linear-quadratic dose-response model 25 y after exposure at 20 to 39 y) decreased only 12 %, from 2.1 (DS86) to 1.9 (DS02) excess cases per 10,000 PY Sv (90 % CI of 0.85 to 4.6 and 0.4 to 3.9 excess cases per 10,000 PY Sv, respectively). These revised values are the result of changes in DS02 related to the source terms, improvements in radiation transport models, changes in the burst height and yield of the Hiroshima bomb, and changes in structural and terrestrial shielding terms. Atomic-bomb dosimetry had long been rather uncertain and fraught with unresolved issues, including the yield of the

72 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION Hiroshima bomb, the dose contribution of activation products and fallout, and the neutron dose contribution. However, with the finalization of DS02, these issues, it appears, have been largely resolved. The risk estimates thus derived, while not substantially different from those based on previous dose estimates (i.e., DS86), can now be viewed with substantially more confidence. A chronology of atomic-bomb dosimetry in general and the “neutron discrepancy” in particular is presented in Appendix C. 3.3 Internal Dose The unique physiology of the thyroid results in high, rapid and prolonged selective uptake of iodine, including radioiodines, in thyroidal tissue. Thus, exposure to even relatively low amounts of radioiodines can result in significant thyroid dose. The thyroid also concentrates (but does not organify) technetium in the form of pertechnetate (99mTcO4–), and 99mTc-labeled pertechnetate has been widely used in nuclear medicine for diagnostic studies of the thyroid. The thyroid absorbed dose is 2.3 × 10–5 Gy MBq–1 of 99mTcO4– administered (Stabin et al., 1996). Long-lived 99Tc (physical half-life: 213,000 y) is a component of high-level radioactive waste from nuclear reactors. In view of its long half-life, however, environmentally-dispersed 99Tc is unlikely to contribute significantly to thyroid irradiation in a potentially exposed population (Strom, 2003). 3.3.1

Radioisotopes of Iodine

Twenty-four isotopes of iodine, with mass numbers from 117 to 140 have been identified. All except 127I are radioactive, with physical half-lives ranging from 1 s (140I) to 16 × 106 y (129I). The independent and chain yields of the isotopes of iodine generated by thermal neutron fission of 235U, as tabulated by Holland (1963), are presented in Table 3.2. The low-mass radioisotopes of iodine (117I to 126 I and 130I) are not fission products. Radioisotopes of iodine with mass numbers 129 and 131 through 140 are produced in fission, largely as fission fragment decay products. Iodine-127 is the endproduct of a low-yield fission fragment decay chain and is stable and, therefore, radiobiologically inconsequential. The heavier radioisotopes of iodine, with mass numbers 136 to 140, are produced in abundance during fission but their short physical half-lives (1.5 to 86 s) result in their decay to isotopes of xenon, cesium, barium and lanthanum in the time required for transport to and internalization by an individual.

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TABLE 3.2—Yields of isotopes of iodine from thermal neutron fission of 235U (Holland, 1963).a Isotope Mass Number

Physical Half-Life

Fission Yield (percent of activity produced) Direct

Chain

117

10 min

0

0

118

17 min

0

0

119

17 min

0

0

120

1.4 h

0

0

121

1.5 h

0

0

122

3.5 min

0

0

123

13 h

0

0

124

4.5 d

0

0

125

60 d

0

0

126

13.3 d

0

0

127

Stable

0

0.1

128

25 min

0

0

129

1.6 × 107 y

0

0.8

130

12.5 h

0

0

131

8.05 d

0

2.9

132

2.3 h

0.2

4.4

133

20.8 h

0.6

6.6

134

52.2 min

2.2

7.8

135

6.7 h

2.9

5.5

136

86 s

2.9

3.9

137

22 s

2.2

2.7

138

5.9 s

1.3

1.5

139

2.7 s

0.8

0.8

140

1.5 s

0.3

0.3

aA later, more detailed compilation of fission yields may be found in England and Rider (1994).

74 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION Very short-lived radioiodines, as well as many other very shortlived fission products, contribute to the intense overall radiation flux in the first several minutes after and in the immediate vicinity of the detonation of a nuclear weapon, but they would not contribute significantly to radiation exposures at later times and further distances. Because of its very slow rate of decay, environmentallyreleased 129I becomes a near-permanent component of the biosphere. Iodine-129, -131, -132, -133, -134 and -135 are the radioisotopes of iodine whose environmental release may potentially have some radiobiological significance. However, among the fission-produced radioisotopes of iodine, only 134I (physical half-life: 52.5 min) is short-lived and does not have a long-lived precursor (Table 3.2). Accordingly, there is little opportunity for 134I to be dispersed beyond the fission site. Iodine-134 and its short-lived precursors would completely decay by 1 d post-release (Table 3.3). Only 129I, 131 I, 132I, 133I, 134I, and 135I, therefore, may undergo significant environmental dispersion; 123I, 124I, 125I, 131I, and 132I are used or have been used in medical applications. As a result, the dosimetric analysis in this Report of radioisotopes of iodine is restricted to 123I, 124I, 125I, 129I, 131I, 132I, 133I, 134I, and 135I. Iodine-129 is a special case because of its very long physical half-life (1.57 × 107 y). It has been extensively analyzed in light of the possibility of its long-term accumulation in the environment from prolonged releases associated with nuclear power, particularly from separation and processing of spent fuel rods and storage of waste (Moeller and Ryan, 2004; Moeller et al., 2005; NCRP, 1983). However, the amount of 129I that can actually accumulate in and irradiate the thyroid is limited by its long physical half-life and resulting low specific activity (6.3 MBq g–1). The radiological consequences of 129I, as discussed in Section 3.3.5, are thus relatively minor. A compilation of pertinent physical properties of these radioiodines, excluding 134I, is presented in Table 3.4 (NNDC, 2008). Many years ago, 126I was a significant radionuclide contaminant (up to several percent) of freshly produced 125I, and may still be a contaminant of 125I produced by older methods outside the United States. Iodine-126 (inhaled as iodine vapor) produces almost twice the thyroid dose per unit activity as 125I in adults, and nearly four times in 1 y olds (Eckerman and Sjoreen, 2006). In evaluating and expressing RBE values, the “reference” radiation should be precisely specified, as different values may be obtained depending upon whether megavoltage x and gamma rays (most commonly, 60Co gamma rays) or kilovoltage x rays (most commonly, 250 kV x rays) are used as the reference radiation (Kocher et al., 2005). Brenner (1999), for example, has hypothesized that

TABLE 3.3—Production of potentially radiobiologically-significant radioisotopes of iodine by fission of 235U (adapted from Holland, 1963).a Isotope Mass Number

Activity per Unit Explosive Yield (PBq t–1)

At Equilibrium

With 1 d Decay

Total

Maximum

Time

With 1 d Decay

131

0.96

0.89

0.004

0.004

5h

0.004

132

1.48

1.18

0.518

0.014

8h

0.013

133

2.18

1.00

0.089

0.067

3.5 h

0.033

134

2.59

<3.7 × 10–8

2.479

0.962

46 min

<3.7 × 10–8

135

1.85

0.15

0.229

0.229

2 min

0.019

Original converted from traditional units to SI units.

3.3 INTERNAL DOSE

a

Activity per Unit Steady Power (TBq kW–1)

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123I

124I

125I

126I

129I

13.2 h

4.18 d

60.1 d

13.3 d

1.57 × 107 y

8.04 d

2.3 h

20.3 h

6.7 h

Physical decay constant [p (h–1)]

5.25 × 10–2

6.93 × 10–3

4.81 × 10–4

2.71 × 103

5.04 × 1012

3.59 × 10–3

3.01 × 10–1

3.41 × 10–2

1.03 × 10–1

Decay mode(s)

e– capture E+

e– capture

e– capture

e– capture E+

E–

E–

E–

E–

E–

J ray 159 83

x, J rays 27 – 2, 750 200

x, J rays 3.2 – 22.7 255

x, J rays 27 – 1,420 118

x, J rays 4.1 – 39.6 177

J ray 364 81

J ray 263 – 2,390 294

J ray 530 86

J ray 221 – 2,410 128

Particulate radiation

Auger e–

E+ ray – Auger e

Auger e–

E+ ray – Auger e

E ray

E ray

E ray

E ray

E ray

Mean energy (keV) Abundance (%)

0.70 – 26.6 >100

0.70 – 974 >100

0.70 – 26.6 >100

1.3 – 530 44.2

40.9 100

192 89.4

155 – 842 100

405 99.4

76 – 821 100

2.8 × 10–14

1.7 × 10–13

6.7 × 10–15

6.9 × 10–14

3.9 × 10–15

6.1 × 10–14

3.5 × 10–13

9.6 × 10–14

7.6 × 10–14

4.5 × 10–15

3.1 × 10–14

3.1 × 10–15

1.6 × 10–15

8.6 × 10–15

3.0 × 10–14

7.8 × 10–14

6.6 × 10–14

5.7 × 10–14

Physical half-life

Principal radiationsa Photon radiation Energy (keV) Abundance (%)

Mean energy per nuclear transition Penetrating radiation ['p [Gy-kg (Bq s)–1]b Nonpenetrating radiation ['np [Gy-kg (Bq s)–1]b

131I

132I

133I

135I

76 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.4—Physical properties of radiobiologically-significant radioisotopes of iodine (NNDC, 2008).

Total [' [Gy-kg (Bq s)–1]b

3.2 × 10–14 9.8 × 10–15 1.3 × 10–14 9.1 × 10–14 4.3 × 10–13 1.6 × 10–13 1.3 × 10–13

2.0 × 10–13

9.8 × 10–15

7.1 × 10–14

1.3 × 10–14

9.1 × 10–14

4.3 × 10–13

1.6 × 10–13

1.3 × 10–13

aIncludes b

only x and gamma rays with energies of 10 keV or greater. 'p = mean energy of penetrating radiation released per disintegration 'np = mean energy of nonpenetrating radiation released per disintegration ' = 'p + 'np.

3.3 INTERNAL DOSE

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78 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION beta rays as energetic as those emitted by 131I and certain other radioiodine isotopes as well as megavoltage x and gamma rays (e.g., 60 Co gamma rays), may have a different RBE at low absorbed doses than kilovoltage x rays (e.g., 250 kV x rays) typically encountered in epidemiology studies of thyroid carcinogenesis following medical irradiation. Based on experimental characterization of a variety of radiobiologic endpoints such as chromosomal abnormalities, micronucleus induction, genetic mutations, mouse skin reactions, and oncogenic transformation, 131I beta rays, other fast electrons, and megavoltage x and gamma rays appear to be approximately half as effective as kilovoltage x rays. The difference between these radiations in low-dose biological effectiveness is presumably related to quantitative physical differences in their energy-deposition events. For example, for a lightly filtered 250 kVp x-ray beam, the average x-ray energy is 85 keV and the average energy of photoelectrons and Compton recoil electrons that it produces in soft tissue is 20 keV. Iodine-131 beta rays, however, have an average energy of 192 keV. Based on the difference in linear energy transfer (LET) between 20 and 180 keV electrons, one might have expected the 250 kV x-ray beam to be four, not two, times more biologically effective than 131I. However, a more realistic quantitative characterization of the differences in energy-deposition patterns and, therefore, biological effectiveness with electron energy requires energy-deposition spectra in cellular and subcellular volumes expressed in terms of the stochastic quantity lineal energy ( y) rather than the nonstochastic quantity linear energy transfer (L). For three radiobiological endpoints, exchange-type chromosomal abnormalities, mutation at the hypoxanthine phosphoribosyltransferase locus, and oncogenic transformation in vitro, the low-dose effectiveness of 131I beta rays relative to 250 kV x rays was 0.54, 0.56, and 0.62, respectively, as calculated by Brenner (1999) based on lineal energy ( y) distributions in 1 Pm diameter sites. Brenner concluded, therefore, that the best estimate of RBE of 131I relative specifically to x rays is 0.6 (95 % CI 0.37 to 1.11). Importantly, human data related to radiogenic thyroid cancer are not available specifically for 60Co irradiation. Although atomic-bomb survivors were exposed to high-energy gamma rays similar to 60Co irradiation (as well as neutrons), the pooled analysis (Ron et al., 1995) did not find differences in risk coefficients that could be attributable to the type of radiation exposure. The uncertainty in the risk estimates for individual studies is likely greater than the difference in risk due to the type of radiation exposure. Evaluation of RBE at low dose rates for 131I and other radioiodines with respect to 60Co and other megavoltage radiations therefore remains largely speculative.

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As discussed further in Section 3.3.6, 123I and, in particular, 125I are somewhat unique among the radioisotopes of iodine in that they decay by electron capture with subsequent emission of a cascade of low-energy (<30 keV) Auger electrons (Gillespie et al., 1970; Greig et al., 1970). Such low-energy Auger electrons are characterized by short ranges (of the order of nanometers to microns) and high-LET (of the order of 100 keV Pm–1). As a result, if an Auger electron emitter were incorporated into DNA, the molecular and ensuing biological damage would be pronounced (Humm et al., 1994). Thus, RBE of Auger electron emitters actually incorporated into DNA may be quite high (i.e., of the order of 10 or greater) because they are so densely ionizing (Humm et al., 1994). For 123I and 125I in the form of iodide, however, this is not the case because 123 I and 125I in a chemical form (such as iodide) not incorporated in DNA would result in these nuclei decaying at too far a distance for any significant irradiation by their emitted Auger electrons. The overall biological effectiveness of the various radioisotopes of iodine (e.g., in inducing thyroid neoplasms) is further complicated by the dose-rate effect (Section A.8), with the lower dose rates delivered by longer-lived radionuclides (e.g., 131I with a half-life of 8 d) presumably having a lesser effect per unit dose than the higher dose rates typically delivered by external x and gamma rays. For low-LET radiations, there is evidence from radiobiological studies that the dose and dose-rate effectiveness factor (DDREF), as well as RBE, also depend on energy (Trabalka and Kocher, 2007). This, of course, may complicate evaluation of RBE and DDREF for such radionuclides, as it may be difficult or impossible in practice to distinguish the components of a radioisotope’s overall biological effectiveness in relation to the spatial distribution of energy deposition (i.e., its RBE), versus the rate of energy deposition by its emitted radiations. 3.3.2

Age-Dependent Thyroid Absorbed Doses from Radioisotopes of Iodine

The mean age-dependent thyroid absorbed doses per unit activity of radioiodide inhaled/ingested/injected  D thy for the radiobiologically-significant radioisotopes of iodine are presented in Table 3.5, Appendix D, and Zanzonico (2000a). In the use of the model in Figure 3.2, radioiodine thyroid absorbed dose estimates have generally been derived assuming instantaneous absorption of radioiodine into blood. Except for 125I, the thyroid absorbed dose estimates presented in Table 3.5 (Zanzonico, 2000a) for injected radioiodine are comparable to values

Age

123

I

124

I

125

I

131

I

132

I

133

I

135

I

Newborn Mean residence time Injection

9.30

67.2

319

112

0.880

15.4

4.07

Inhalation

4.96

41.6

202

69.8

0.268

8.44

1.88

Ingestion

8.84

66.8

313

111

0.676

14.9

3.69

Injection

0.133

5.65

3.32

9.68

0.202

2.86

0.586

Inhalation

0.071

3.49

2.11

6.0

0.062

1.57

0.27

Ingestion

0.127

5.59

3.27

9.65

0.155

2.76

0.53

0.140

0.0841

0.0104

0.0868

0.229

0.186

0.144

Injection

3.47

33.7

245

61.7

0.240

6.14

1.35

Inhalation

1.81

20.4

152

37.8

0.0724

3.30

0.612

Ingestion

3.29

21.4

245

61.5

0.185

5.94

1.22

Mean absorbed dose (Gy MBq–1)

Mean absorbed dose rate (Gy h–1 MBq–1) 1y Mean residence time

80 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.5—Age-dependent thyroid residence times, mean absorbed doses, and mean absorbed dose rates per unit activity of radiobiologically-significant radioisotopes of iodine injected, inhaled or ingested as iodide (adapted from Zanzonico, 2000a).a

Mean absorbed dose (Gy MBq–1) Injection

0.037

2.11

1.87

3.89

0.0403

0.83

0.140

Inhalation

0.019

1.28

1.16

2.39

0.0122

0.45

0.064

0.035

2.09

1.87

3.89

0.031

0.80

0.127

0.0105

0.062

0.0076

0.063

0.168

0.135

0.104

Injection

3.49

34.9

313

65.8

0.241

6.19

1.22

Inhalation

1.84

21.4

196

40.7

0.0729

3.36

0.618

3.31

34.7

245

65.5

0.185

5.99

1.26

Injection

0.0195

1.18

1.28

2.17

0.021

0.435

0.066

Inhalation

0.0103

0.722

0.800

1.34

0.0064

0.236

0.033

0.0185

1.17

1.28

2.16

0.0163

0.422

0.068

0.0056

0.034

0.0041

0.033

0.088

0.070

0.054

Injection

3.49

34.9

313

65.8

0.241

6.19

1.22

Inhalation

1.77

20.4

187

38.8

0.0711

3.21

0.597

Ingestion

3.31

34.7

313

65.5

0.185

5.99

1.26

Ingestion –1

–1

Mean absorbed dose rate (Gy h MBq ) 5y Mean residence time

Ingestion –1)

Mean absorbed dose (Gy MBq

–1

Mean absorbed dose rate (Gy h

–1

MBq )

10 y Mean residence time

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123

Age

I

124

I

125

I

131

I

132

I

133

I

135

I

–1

Mean absorbed dose (Gy MBq ) Injection

0.0089

0.538

0.586

0.951

0.0094

0.191

0.029

Inhalation

0.0045

0.314

0.351

0.562

0.0027

0.099

0.014

0.0084

0.532

0.586

0.946

0.0072

0.185

0.030

0.00255

0.0154

0.00187

0.0145

0.0392

0.0308

0.0024

Injection

3.49

35.2

332

66.7

0.241

6.20

1.35

Inhalation

1.81

21.2

204

40.6

0.0722

3.31

0.611

3.36

34.9

332

66.4

0.185

6.00

1.26

Injection

0.00586

0.357

0.408

0.622

0.0061

0.123

0.021

Inhalation

0.00303

0.214

0.251

0.378

0.00184

0.0657

0.009

0.0057

0.351

1.408

0.619

0.0047

0.119

0.020

0.00168

0.0101

0.00123

0.00932

0.0255

0.0198

0.016

Ingestion –1

Mean absorbed dose rate (Gy h

MBq–1)

15 y Mean residence time

Ingestion –1)

Mean absorbed dose (Gy MBq

Ingestion –1

Mean absorbed dose rate (Gy h

MBq–1)

82 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.5—(continued).

Adult Mean residence time Injection

3.49

35.2

332

66.7

0.241

6.20

1.35

Inhalation

1.83

21.4

207

41.0

0.0726

3.34

0.615

3.36

34.9

332

66.4

0.185

6.00

1.26

Injection

0.00365

0.211

0.256

0.376

0.00376

0.0743

0.0123

Inhalation

0.00191

0.135

0.159

0.232

0.00113

0.0040

0.00562

0.0035

0.2190

0.255

0.376

0.00289

0.0719

0.0115

0.00104

0.0063

0.00770

0.00565

0.0156

0.0120

0.0091

Ingestion –1

Mean absorbed dose (Gy MBq )

Ingestion –1

Mean absorbed dose rate (Gy h aSee

–1

MBq )

Appendix D for calculational details.

3.3 INTERNAL DOSE

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84 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

Fig. 3.2. A simplified compartmental model of whole-body and thyroidal pharmacokinetics of radioiodide where k(j,i) = the fractional exchange rate per unit time from compartment i to compartment j (Zanzonico, 2000a). Note that the central compartment (2, Iodide) incorporates but is not limited to blood. Radioiodine, which is either inhaled and/or ingested, is first transferred to this compartment and then to the rest of the body.

Age-dependent exchange rates k(0,1) (h–1)

k(3, 2) (h–1)

k(4, 3) (h–1)

Newborn

0.101

0.140

0.00280

1y

0.107

0.0300

0.000780

5y

0.104

0.0300

0.000480

10 y

0.118

0.0300

0.000480

15 y

0.109

0.0300

0.000420

Adult

0.106

0.0300

0.000420

3.3 INTERNAL DOSE

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86 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION in the literature (Berman et al., 1975; Dunning and Schwarz, 1981; ICRP, 1988; Johnson, 1981; Killough and Eckerman, 1986; Stabin, 1995). The current 125I thyroid absorbed dose estimates are 25 to 50 % greater than the corresponding values in ICRP Publication 53 for 1 to 15 y olds, but only 7 % greater for adults (ICRP, 1988). This reflects the longer biological half-life of radioiodine in the thyroid (Zanzonico, 2000a) used in deriving the dose estimates in Table 3.5 (50, 80, 80, 90, and 90 d) than used in ICRP Publication 53 (ICRP, 1988) (30, 40, 50, 65, and 80 d for 1, 5, 10, 15 y olds, and adults, respectively). Similarly, for adults, the current 125I thyroid absorbed dose estimate based on a biological half-life of 90 d is 20 % greater than that in the Medical Internal Radiation Dose Committee (MIRD) Report 5, where a biological half-life of only 65 d was used (Berman et al., 1975). Note that these differences in biological halflife are dosimetrically significant only for 125I, due to its longer physical half-life (60.1 d). As a result, the effective half-life of 125I in the thyroid is strongly influenced by the assumed biological halflife. For all of the other radioiodines considered, the physical half-lives are much shorter than the biological half-lives and, therefore, the effective half-lives are approximately equal to the respective physical half-lives (Table 3.4). There is considerable variability, 4.1 to 6.8 Gy MBq–1, among previous estimates of the 131I absorbed dose to the newborn thyroid (Berman et al., 1975; Dunning and Schwarz, 1981; ICRP, 1988; Johnson, 1981; Killough and Eckerman, 1986; Stabin, 1995). This appears to largely reflect the variability in estimates of newborn thyroid uptakes at 24 h (25 to 46 %). For the current absorbed dose estimates (Table 3.5), the 24 h thyroid RAIU was assumed to be 60 % in newborns, as specified in the most recent compilation of age-dependent thyroid uptakes (Book et al., 1997). This results in an absorbed dose to the newborn thyroid of 9.7 Gy MBq–1 for intravenously injected 131I. Importantly, the foregoing range of 131I doses per unit intake to the newborn thyroid does not reflect uncertainty in the dose estimates but rather the variations in such estimates resulting from the assumption of different values of pertinent parameters, in this case, the thyroid uptake. (See Section 3.3.3 for a discussion of uncertainty in thyroid dose estimation.) The assumption of complete, instantaneous absorption of radioiodine in the thyroid appears reasonable for ingested radioiodines, except for short-lived 132I. However, because a substantial portion of inhaled radioiodine is exhaled before it is actually absorbed into the blood stream, this assumption results in a substantial overestimation of the actual thyroid absorbed dose for inhalation of all radioiodines. The magnitude of the resulting errors is inversely

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related to the physical half-life of the radionuclide: 48 % for 123I, 35 % for 125I, 38 % for 131I, 70 % for 132I, 46 % for 133I, and 54 % for 135 I. This overestimation of the thyroid absorbed dose for radioiodine ingested or inhaled occurs because a significant fraction of the activity undergoes radioactive decay in situ (in the digestive tract or lungs, respectively) prior to absorption into blood. Except for the lung and gut compartments, the compartmental model (Figure 3.2) used in the current analysis is similar to the three-compartment iodine model in ICRP Publication 56 (ICRP, 1990). This model, in turn, is similar to that in ICRP Publication 30 (ICRP, 1979) and Publication 53 (ICRP, 1988). The ICRP models are based on those developed by Riggs (1952) to describe the pharmacokinetics of iodine in adults after its absorption into blood. In contrast to the current model and those in ICRP Publication 30 (ICRP, 1979) and Publication 56 (ICRP, 1990), the model in ICRP Publication 53 (ICRP, 1988) does not incorporate recycling of iodine into the blood and thyroid. Although the current model as well as the ICRP models (ICRP, 1979; 1988; 1990), are far simpler than the multi-compartment model of Berman et al. (1968) and the more recent model of Berkovski (2002); they appear to be adequate for dosimetric calculations. Harvey has analyzed the uncertainties associated with dose estimates for ingested and inhaled radioiodines (Harvey et al., 2003; 2004). A publication prepared by ICRP [Task Group on Reference Man, basic anatomical and physiological data for use in radiological protection (reference values)] includes updated reference values of anatomical and physiological data for male and female subjects of six different ages: newborn, 1, 5, 10, 15 y, and adult (Boecker, 2003; ICRP, 2002). 3.3.3

Environmental Dispersion of Radioiodine

For at least five decades, large segments of the public in numerous countries have been exposed to varying amounts of 131I and other radioiodines released into the environment. Such environmental releases originated from several sources: atmospheric testing of nuclear weapons, breach-of-containment accidents associated with one or more components of the nuclear fuel cycle, and processing of spent uranium fuel rods. Radiation dosimetry of environmentally-released radionuclides, including radioiodines, is very complex and uncertain because of the many variables that affect their production, dispersion, deposition and internalization (Eisenbud and Wrenn, 1963; Holland, 1963; NCI, 1997). To estimate thyroid dose, the amount of radioiodine

88 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION produced and released into the environment (source term) must be known. How the radioiodine is dispersed and deposited in the environment is greatly affected by its physical state and by meteorological conditions. Internalization is dependent on physiologic factors such as breathing rates and quantities in contaminated foods that are ingested. In addition to the source term, the severity and extent of environmental contamination is dependent on the nature of the release (i.e., weapons testing or breach-of-containment accidents) and the prevailing meteorological conditions at the time of and immediately following the release. The former determines the altitude, the troposphere or stratosphere, to which the released activity rises, while the latter determines the extent of the geographic dispersion of contaminated fallout and is dependent on factors such as wind velocity and direction, altitude-dependent wind shear, humidity, and precipitation patterns [i.e., variables that are unique to each release (NCI, 1997)]. Close to the site of the radioiodine release (the near field) and before the radioiodine is deposited on the ground, radioiodine is internalized primarily by inhalation (Becker, 1987; Becker et al., 1984; NCI, 1997). A smaller fraction of radioiodine is deposited on and absorbed through the skin (Miller et al., 1989). As the radioiodine plume drifts away from the site of the release, the concentration of iodine in the plume decreases due to deposition on the ground and, mainly, due to continued dilution (dispersion) in air. At greater distances, the far field, the primary pathway into the body is ingestion of contaminated food. In Chernobyl, ~90 % of the thyroid dose was due to ingestion of contaminated foodstuffs, primarily milk (Becker et al., 1996c). The environmental dispersion and internalization of radioiodines is erratic and inhomogeneous, depending on meteorological conditions such as wind velocity and direction, temperature, humidity, and precipitation, amount of milk ingested, source of milk (commercial dairy versus backyard cow), iodine nutrition among exposed populations, and interventions such as embargoing of contaminated milk and foodstuffs, and the use of stable iodide (potassium iodide) blockade of the thyroid (NCI, 1997). The major food pathway for radioiodine is the pasture-cow-milkhuman pathway. Radioiodine deposited on pastures is consumed by cows and then concentrated in milk. Radioiodine consumed by humans is then concentrated in the thyroid. The dose to the thyroid from the contaminated pasture-cow-milk-human pathway depends on multiple factors. The amount of radioiodine that is deposited on and retained by pasture vegetation is of critical importance. This,

3.3 INTERNAL DOSE

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in turn, depends on the physical and chemical form of the radioiodine (gaseous versus particulate, organic versus inorganic), the type of deposition (dry or wet) and, if deposited as a result of precipitation, the intensity and duration of rainfall. The extent of radioiodine in contaminated milk also depends on the milk source. For example, there may be a considerable difference in contamination levels of milk between the backyard cow and commercial dairies. In the latter case, locally consumed milk may actually originate at widely dispersed sites affected to very different degrees by the environmental contamination. The physical decay of 131I also must be considered and is dependent on milk collection and processing times, the distance shipped, and shelf-life. The time interval from milking to human consumption may be minimal when the backyard cow (an estimated twofold increase in thyroid absorbed dose relative to that with a commercial milk source) is the milk source. Moreover, the backyard cow is more likely than commercial cows to feed on pasture than on stored fodder, further increasing the radioactive contamination of milk from the backyard cow. Radioactive contamination of milk from the backyard goat is even higher. Radioiodines can appear in a cow’s milk within 5 to 10 h of ingestion of contaminated fodder, with peak concentrations by 36 to 48 h postingestion (NCI, 1997). Exposure to environmental 131I depends on the residential and travel histories, dietary histories, and ages of the individuals at risk during the time periods when fallout occurred. The residential history would include the location and duration of residents at the times of fallout. The dietary history would include the sources, quantities and shelf-lives of contaminated foodstuffs. Although cow’s milk and dairy products are the most important dietary sources of radioiodine exposure, leafy vegetables [in which the time-integrated concentration of 131I is as much as 50 % of that in cow’s milk (NCI, 1997)] must also be considered. Age at the time of fallout is also important because dietary habits change considerably, with babies and children consuming relatively more milk than older individuals and many babies consuming breast milk rather than cow’s milk. In lactating women, radioiodine can appear in rather large amounts, with as much as ~25 % or more of ingested/ inhaled radioiodine excreted in breast milk, and, therefore, delivering significant doses to nursing infants (Ahlgren et al., 1985; Mountford and Coakley, 1989; Mountford et al., 1985; Romney et al., 1986; Rubow et al., 1994; Simon and Bouville, 2002; Weaver et al., 1960). In addition, dietary levels of stable iodine dramatically affect radioiodine uptake by, and irradiation of, the thyroid, with thyroid uptake and dose decreasing sharply with increasing amounts of iodine in the diet (NCI, 1997).

90 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION Most hypothetical reactor accident scenarios propose releases continuing over many hours, providing some time to implement protective actions. Since the initial near-field exposure is primarily through inhalation, protective measures such as air filtration, sheltering, and evacuation are particularly important. Even minimal respiratory protection with a moistened handkerchief can filter out some 1 to 5 Pm particles and significantly reduce inhalation of activity. Sheltering, which includes closing of windows, doors, and ventilation systems, can provide nondisruptive protection when exposure is expected to be of short duration. In high-level releases, evacuation of populations in the immediate vicinity of reactor accidents may be required. Interdiction of contaminated foods, particularly milk and water, can be immediately effective in preventing ingestion of fallout. Finally, potassium iodide blockade can dramatically reduce thyroid uptake of and irradiation by radioiodine, as discussed below in Section 3.3.4 (Becker, 1987; Becker et al., 1984; Zanzonico, 2000b). An error in the estimate of the thyroid 24 h RAIU, biologic half-life, or thyroid mass will result in an error in the calculated radioiodine absorbed dose to the thyroid (Zanzonico, 2000b). This is illustrated graphically in Figure 3.3 for injected/ingested 131I in a euthyroid (i.e., normally functioning thyroid) adult. The thyroid absorbed dose is approximately directly proportional to the 24 h RAIU and inversely proportional to the thyroid mass. Therefore, the relative error in the thyroid absorbed dose is directly proportional to the error in the uptake and the error in the mass. Note that except for long-lived 125I and 129I, any error in the biological half-life has little or no effect, since the biological half-life is generally so long compared to the physical half-life of radioiodine that the effective half-life and, therefore, the absorbed dose is largely determined by the physical half-life of the radioiodine isotope. As noted in Section 1.2.2, the radiation dosimetry of environmental radioiodine is generally less precise and less accurate than those for medical or occupational exposure because of the many physical and biological factors that affect its production, dispersion, deposition, internalization and metabolism (Hoffman, 1999; Hoffman et al., 2004; NCI, 1997; NCRP, 1977; 1984). As further noted, dose estimates based on individual activity measurements are more reliable than those based exclusively on population modeling. Uncertainty in radiation dosimetry and reconstructed dose has long been recognized but only recently have attempts been made to systematically quantify it (Apostoaei and Miller, 2004; Dunning and Schwartz, 1981; Goossens et al., 1998; Hamby and Benke, 1999; Harvey et al., 2003; Hoffman, 1999; Hoffman et al., 2002;

3.3 INTERNAL DOSE

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Fig. 3.3. Absolute error in the calculated thyroid absorbed dose for injected/ingested 131I in a euthyroid adult as a function of the relative error in the thyroid 24 h RAIU biological half-life, or thyroid mass (Zanzonico, 2000b). Note that the biologic half-life curve would not apply to either 125I or 129I, which are long-lived radioisotopes of iodine.

2004; Killough and Eckerman, 1986; Land et al., 2003; Li et al., 2007; NCRP, 1996; 1998; Ng et al., 1990; Schwarz and Dunning, 1982; Simon et al., 2006a). Apostoaei and Miller (2004) found that for 131I the uncertainty in the thyroid dose conversion coefficients [absorbed dose per unit activity internalized (i.e., radioiodine that is inside the body as opposed to on the body or external to the body)] is well represented by a geometric standard deviation (GSD) of 1.7 for both genders and all ages other than infants (for whom a GSD of 1.8 appears more appropriate). The largest contribution to this uncertainty is the thyroid mass, with the contribution of uncertainty in the biokinetic parameters (particularly the blood-to-thyroid exchange rate) almost as large. The uncertainty in the thyroid-to-thyroid absorbed fraction (i.e., the fraction of radiation energy emitted in the thyroid which is deposited in the thyroid) is the smallest contributor to the uncertainty in the dose coefficient. A corollary of these findings is that the potential error in individual thyroid dose estimates can be reduced dramatically if measurements of thyroid mass and radioiodine uptake are available (Hoffman, 1999). The overall uncertainty

92 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION in thyroid dose estimates is, of course, compounded by the uncertainty in the estimate of the amount of radioiodine internalized. Based on critically reviewed data available on thyroid mass and uptake and retention of radioiodine and employing a Monte-Carlo simulation procedure (1,000 iterations), Dunning and Schwartz (1981) found, for each age group [newborns, children (0.5 to 2 y), adolescents (6 to 16 y), and adults (older than 18 y)], a two- to threefold difference between the mean and 99th percentile thyroid mass and biological half-life, and a twofold difference between the mean and 99th percentile uptake. As previously noted (Section 3.3), because of the relatively short physical half-life of 131I (8 d), the precision of estimates of the thyroidal 131I effective half-life and of dose are largely unaffected by the wide variation in this biological half-life. Nonetheless, Dunning and Schwartz (1981) concluded that the ratio of the 99th percentile estimate of dose per unit intake of 131I to the mean estimate is approximately three for each of the age groups. The large uncertainty in the estimated 131I intake would, of course, further increase the overall uncertainty for any individual 131I thyroid dose estimate. In the so-called “NCI Fallout Report” (NCI, 1997) for the NTS Cohort (Section 3.3.7.1), for example, a fivefold overall uncertainty for individual 131I thyroid dose estimates was reported, suggesting a nearly twofold uncertainty in radioiodine intake. Implicit in the foregoing discussion of uncertainty is the assumption that the various factors affecting thyroid dose, the thyroid mass, and uptake and retention of radioiodine, and their uncertainties are independent (Dunning and Schwartz, 1981). However, the covariance of these factors is not well understood, and any nonzero covariance would likely increase the uncertainty of thyroid dose estimates relative to those based on the assumption of zero covariance. 3.3.4

Potassium Iodide Blockade of Radioiodine Uptake in the Thyroid

Potassium iodide, given orally in adequate quantities (65 to 135 mg in adults) and at the appropriate time, can almost completely block thyroidal uptake of radioiodine (Becker, 1987; Becker et al., 1984; Ilin et al., 1972; NCRP, 1977; Robbins, 1983; Rubery and Smales, 1990; Saxena et al., 1962; Stanbury, 1990; Sternthal et al., 1980; Van Middlesworth, 1954; Wolff, 1980; Zanzonico, 2000a; Zanzonico and Becker, 1993). Several mechanisms of action have been proposed including isotope dilution, saturation of the iodide transport mechanism, interference with intrathyroidal

3.3 INTERNAL DOSE

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organification of iodide, and inhibition of hormone release (Dumont et al., 1990; Sternthal et al., 1980; Wolff, 1980). The reduction in thyroid dose achieved with oral potassium iodide blockade can be expressed as the protective effect (PE) (Zanzonico, 2000a; 2000b; Zanzonico and Becker, 1993): D T – D T,B PE = --------------------------, DT where: DT = DT,B =

(3.1)

dose to the thyroid without blocking dose to the thyroid with blocking

The protective effect of potassium iodide blockade is affected by at least two highly variable factors, dietary levels of iodine and the time of potassium iodide administration relative to internalization of 131I. Potassium iodide administration at the time of or shortly before radioiodine internalization provides the greatest protective effect (Blum and Eisenbud, 1967; Ilin et al., 1972; Lengemann and Thompson, 1963; Stanbury, 1990; Zanzonico, 2000a; Zanzonico and Becker, 1993; 2000). Figure 3.4 graphically summarizes the effect of potassium iodide blockade on 131I thyroid uptake (Figure 3.4a), absorbed dose (Figure 3.4b), and protective effect (Figure 3.4c) as a function of the time interval between potassium iodide administration (135 mg of potassium iodide corresponding to 100 mg of iodine) and 131I exposure and the level of dietary iodine (Zanzonico and Becker, 1993). In deriving these data, a dietary iodine intake 100 Pg d–1 less than and greater than the recommended dietary intake of 150 Pg d–1 (NAS/NRC, 1989) was defined as iodine deficiency (50 Pg d–1) and iodine sufficiency (250 Pg d–1), respectively. Further, the data correspond to a single, instantaneous exposure to radioiodine. Administration of 135 mg of potassium iodide before 131I exposure corresponds to negative time intervals (to the left of the ordinate axis) and administration of potassium iodide after 131I exposure corresponds to positive time intervals (to the right of the ordinate axis). Potassium iodide administered up to 48 h before 131I exposure can almost completely block thyroid uptake (Figure 3.4a) and, therefore, greatly reduce the thyroid absorbed dose (Figure 3.4b) regardless of the dietary iodine level. For example, potassium iodide administration 24 and 48 h before 131I exposure yields a protective effect of ~90 and 75 %, respectively, in iodine sufficiency and 95 and 85 %, respectively, in iodine deficiency (Figure 3.4c). Potassium iodide administration 72 h before 131I exposure will

94 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

Fig. 3.4. (a) Decay-corrected 24 h thyroid uptake (percent), (b) thyroid absorbed dose per unit activity inhaled and/or ingested (Gy MBq–1), and (c) potassium iodide protective effect (percent) as a function of time of potassium iodide administration relative to 131I exposure for iodine sufficiency and iodine deficiency. Time “0” represents the time of 131I intake. Negative 24 h thyroid uptakes (percent) between 24 and 0 h represent mathematical artifacts and should be ignored (adapted from Zanzonico and Becker, 2000).

3.3 INTERNAL DOSE

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reduce 24 h RAIU from 26 to 19 % (Figure 3.4a) and yield a protective effect of 32 % in iodine sufficiency (Figure 3.4c). In iodine deficiency, potassium iodide administration at this time will reduce 24 h RAIU from 60 to 25 % (Figure 3.4a) and yield a protective effect of 55 % (Figure 3.4c). However, as indicated in Figure 3.4c, potassium iodide administration 96 h or more before 131I exposure has no significant protective effect (i.e., <10 %). In contrast, potassium iodide administration after exposure to radioiodine yields still significant but less, and rapidly decreasing, blockade. Therefore, even if potassium iodide administration were not initiated early in the course of a breach-of-containment nuclear reactor accident, continued administration over the course of such an accident would be important to block continuing uptake of environmentally-released 131I. Once 131I is incorporated into the thyroid, its slow discharge cannot be accelerated except perhaps with TSH, but further accumulation can be blocked by potassium iodide. Potassium iodide administered up to 2 h after 131I exposure can almost completely block thyroid uptake (Figure 3.4a) and, therefore, greatly reduce the thyroid absorbed dose (Figure 3.4b), yielding protective effects of 80 % and 65 % in iodine sufficiency and iodine deficiency, respectively (Figure 3.4c). However, later potassium iodide administration, even as soon as 8 h after 131I intake, will only modestly reduce uptake (Figure 3.4a) and dose (Figure 3.4b), yielding a protective effect of only 40 % in iodine sufficiency and even less, 15 %, in iodine deficiency (Figure 3.4c). Potassium iodide administration 16 h or later after 131I exposure will have little effect on uptake (Figure 3.4a) and dose (Figure 3.4b) and, therefore, little or no protective effect (Figure 3.4c). In pregnant women, potassium iodide readily crosses the placenta and will block uptake of radioiodine by the fetal as well as the maternal thyroid and effectively reduce the potentially very high doses to the fetal thyroid (Zanzonico and Becker, 1991; 1998). Stable iodine has been reported to have a protective effect in an iodine-deficient population even when given weeks after exposure. This effect is not well studied and is presumably due to decreasing the stimulatory effects of TSH (Cardis et al., 2005). The results of the current model-based analysis (Zanzonico, 2000a) are qualitatively and quantitatively similar to the experimental results of Ilin et al. (1972) in humans. 3.3.5

Limitations of the Radiobiological Significance of Iodine-129

Iodine-129, the longest-lived radioisotope of iodine, has a halflife of 1.57 × 107 y and is produced in nuclear fission. The global

96 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION inventory of naturally-occurring 129I is estimated to be 1.5 TBq; artificially produced 129I could increase this amount by a factor of ~100 (NCRP, 1983). Fortunately, the radiobiological significance of 129I is limited by its low specific activity. For example, based on thyroidal iodine kinetics determined using other, higher-specific activity radioiodines, it has been estimated (Colard et al., 1965) that chronic absorption of 37 kBq h–1 of 129I by individuals having a stable iodine intake of 100 Pg d–1 would result in the deposition of 210,000 kBq in the thyroid. However, because of its low specific activity, 37 kBq of 129I corresponds to 5.7 mg of iodine and 210,000 kBq, therefore, corresponds to 32 g of iodine, which is several thousand times the mean value of 0.012 g of iodine in the thyroid. This intuitively impossible result is resolved by recognizing that sufficiently large amounts of iodine, whether in the form of stable 127I or low specific activity 129I, can dramatically reduce relative iodine uptake by the thyroid, as discussed in Section 3.3.4 in the context of potassium iodide blockade. The quantitative effect of 129I on thyroidal iodine metabolism and dosimetry may be estimated from the data of Blum and Eisenbud (1967), who derived the following functional relationship between the 24 h RAIU of 131I and the simultaneously administered dose of stable iodine [with a stable iodine intake of 150 Pg d–1 (Figure 3.5)]: uptake = 8.64  iodine dose

– 0.59

,

(3.2)

where: uptake

= 24 h RAIU of 131I (in percent of administered activity) iodine dose = dose (milligrams) of stable iodine administered simultaneously with the 131I

Applying Equation 3.2 to a euthyroid adult, the 24 h RAIU of would remain at ~25 % (Figure 3.5), the same as that for other, higher specific-activity radioiodines, for 129I activities of <37 Bq or 6 Pg of 129I. However, in contrast to the other radioiodines, there would be a dramatic reduction in the thyroid uptake at higher 129I activities, to ~2.5 % (a 10-fold reduction) at 37 kBq (or 6 mg), and ~0.25 % (a 100-fold reduction) at 3,700 kBq (or 600 mg). Correspondingly, because of this nonlinear dependence of thyroid uptake of radioiodine on the mass (milligram) “dose” of iodine, the thyroid absorbed dose of injected and/or ingested 129I varies from 0.5 PGy for 1 Bq to 0.15 mGy for 1 kBq to only 150 mGy for 1 MBq. In contrast, for higher specific-activity radioiodines, activities in the 129I

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Fig. 3.5. Radioiodine 24 h RAIU as a function of the mass quantity of stable iodine in the diet per day (Blum and Eisenbud, 1967).

kilobecquerel range represent pharmacokinetically nonperturbing doses of stable iodine, and the relationship between total thyroid absorbed dose per unit activity is essentially constant over all activities. It should be noted that in “aged” fission products (e.g., t6 months old) the only iodine atoms present are those of stable 127I (~25 %) and 129I (~75 %), resulting in an even lower, and continually decreasing specific activity of fission-product 129I than of isotopically pure 129I. As noted in Section 3.3.1, the radiological consequences of 129I have been extensively analyzed because of the possibility of its long-term accumulation in the environment from prolonged releases associated with nuclear power and the reader is referred to the pertinent references (Moeller and Ryan, 2004; Moeller et al., 2005; NCRP, 1983) for further information.

98 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION 3.3.6

Spatial and Temporal Inhomogeneities in Intrathyroidal Radioiodine Distribution and Absorbed Dose

Approximately 90 % of iodine in the thyroid is rapidly localized in the follicular colloid where it remains with a long residence time compared with the physical half-lives of 131I and other radiologically significant radioisotopes of iodine, such as 133I. Thus, the radiation emitted by intrathyroidal radioiodine is emitted almost entirely from that contained within the follicles (Andros and Wollman, 1967; Croft and Pitt-Rivers, 1970; Fujita, 1969; Kayes et al., 1962; Loewenstein and Wollman, 1967; Nunez et al., 1966; Pitt-Rivers et al., 1964; Stein and Gross, 1964). The spatial distribution of absorbed dose delivered by radioiodine within the thyroid may be nonuniform if the average range of nonpenetrating radiations (e.g., electrons and delta rays) is less than the average distance between the centers of adjacent follicles (<300 Pm) or if the iodine radioisotope is sufficiently short-lived (compared to the time required for uniform dispersion throughout the colloid, ~24 h) that a significant portion of decays occur while the radionuclide is still largely in the peripheral colloid and, therefore, adjacent to the follicular cells (Hindie et al., 2001) (see below). For relatively long-lived 131I, its average beta-ray range of 360 Pm (Shleien and Terpilak, 1984) is substantially larger than the average interfollicular distances. Under these conditions, the follicular versus extrafollicular partitioning of thyroidal radioiodine will not be a significant source of inhomogeneity within the thyroid. For example, Hui et al. (1991), modeling the normal human thyroid as an infinite hexagonal closely-packed lattice of spherical follicles having a mean diameter of ~200 Pm and a single layer of 15 Pm high cuboidal follicular cells, found that for a mean 131I thyroid absorbed dose of 1 Gy, the local intrathyroidal absorbed dose varied by only r20 % (i.e., from 0.8 to 1.2 Gy as the intrafollicular radioiodine concentration was varied from 25 to 75 times the extrafollicular concentration and the follicular diameter was varied from 170 to 230 Pm. Thus, for 131I in a uniformly functioning thyroid gland (i.e., for uniform concentrations of radioiodine among follicles), the implicit assumption of uniform activity and cumulated activity distribution and uniform radiation energy deposition is valid. An additional source of inhomogeneity of intrathyroidal absorbed dose is related to differences among follicles in the amounts of radioiodine in the follicle. For example, according to Hui et al. (1991), if only 20 % of the follicles actively concentrate radioiodine, for a mean 131I thyroid absorbed dose of 1 Gy the local intrathyroidal absorbed dose varied by 250 to 300 % [i.e., from

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0.4 to 3 Gy]. In nodular goiters, even larger variations in activity concentrations and doses are encountered among follicles. Another notable source of inhomogeneity of intrathyroidal absorbed dose is related to the kinetics of intrathyroidal distribution of radioiodine (Andros and Wollman, 1967; Croft and PittRivers, 1970; Fujita, 1969; Kayes et al., 1962; Loewenstein and Wollman, 1967; Nunez et al., 1966; Pitt-Rivers et al., 1964; Sinclair et al., 1956; Stein and Gross, 1964). As illustrated in Figure 3.6, following systemic administration of radioiodide, radioiodine appears almost immediately in thyroid follicle cells and in the very periphery of the colloid. By 1 h post-radioiodide administration, radioiodine has penetrated well into the colloid but remains heavily concentrated in the peripheral colloid. Within 24 h post-radioiodide administration, radioiodine has been uniformly dispersed throughout the colloid. Therefore, for relatively long-lived radioiodines such as 131I [physical half-life (T½p) = 8.04 d], the assumption of uniform distribution throughout the thyroid is reasonable. However, for short-lived radioiodines, such as 132I (T½p = 2.3 h), the radioactive disintegrations will occur while the radioiodine is in the follicular cells and the peripheral colloid (Hindie et al., 2001). As illustrated graphically in Figure 3.7, because of the inverse relationship between distance and absorbed dose, this would result in a significant enhancement of the absorbed dose to the follicle cells relative to the mean thyroid absorbed dose. For short-lived 132I localized in or within 15 Pm of follicular cells, the local absorbed dose to the follicular cells may be up to 10 times greater than the mean thyroid absorbed dose resulting from radioiodine uniformly dispersed in the colloid. The several hours or longer time-course for complete dispersion of radioiodine throughout the colloid may result in follicular cell absorbed doses for short-lived radioiodines substantially higher than the mean thyroid absorbed dose. Additionally, depending on the variation of RBE with dose rate, the biological effect on the follicular cells may actually be more than 10-fold greater than that which would correspond to the mean thyroid absorbed dose. Although not quantitatively important in terms of environmental releases of radioiodine (e.g., in a breach-of-containment nuclear reactor accident), 125I is somewhat unique among the radioiodines in that it decays by electron capture with subsequent emission of a cascade of low-energy (<30 keV) Auger electrons (Gillespie et al., 1970; Greig et al., 1970). The short range (<12 Pm) of these low-energy Auger electrons is approximately equal to the height of a thyroid follicular cell. Thus, most of the particulate radiations emitted by 125I uniformly dispersed in the colloid will not irradiate

100 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

Fig. 3.6. Iodine-125 autoradiograms in normal rodent thyroid at 12 s (Andros and Wollman, 1967), 1 h (Loewenstein and Wollman, 1967), and 24 h (Nunez et al., 1966) after administration of radioiodide, illustrating the rapid but not instantaneous uptake by and dispersion throughout the colloid of radioiodine.

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Fig. 3.7. Intrathyroidal distribution of the approximate average absorbed dose rate for different extremes of microscopic distributions of short-lived 132I (range: 1,700 Pm): activity in or within 15 Pm of the follicular cells versus uniformly dispersed in the colloid (adapted from Greig et al., 1970).

the follicular cells or their nuclei. Moreover, particulate radiations emitted by 125I in the peripheral colloid will nonuniformly irradiate the follicular cells, with the absorbed dose sharply decreasing from the apical to the basal portions of these cells. In contrast to longrange beta-ray emitters such as 131I, the average follicular cell dose from intrathyroidal 125I uniformly dispersed in the colloid is, therefore, less than half of the mean thyroid absorbed dose, as illustrated in Figure 3.8. Implicit in the absorbed dose estimates in Table 3.5 are the assumptions that foregoing effects are negligible (i.e., the radioiodine dose to the thyroid is fairly uniform) and that the mean thyroid dose is, therefore, a reliable indicator of radiation risk. In addition to effects related to the possible heterogeneity in the radioiodine distribution within the thyroid, cells at the very periphery of the gland may receive a significantly lower dose than cells within the gland because, on average, half of the beta rays emitted at the periphery reach the gland.

102 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

Fig. 3.8. Inhomogeneity of the absorbed dose contribution from the short-range Auger electrons of intrathyroidal 125I, resulting in a mean follicular-cell dose about twofold lower than the mean gland dose. In comparison, the absorbed dose delivered by the high-energy, long-range beta rays emitted by 131I is essentially uniform over the entire gland (adapted from Greig et al., 1970).

3.3.7

Dose Assessment of Major Environmental Releases of Radioiodines

The following major cohorts exposed to internal radiation from environmental releases of radioiodine are discussed in detail below: • NTS Cohort • Hanford Site Cohort • Chernobyl Nuclear Reactor Accident Cohort The magnitude of notable environmental releases of 131I, including those associated with NTS, the Hanford Site, and the Chernobyl nuclear reactor accident, is summarized in Table 3.6. The environmental release of radioiodines in the Marshall Islands is not included in Table 3.6 but is tabulated separately (Table 3.7) because the activities released of 132I and other short-lived radioiodines were actually considerably greater than that of 131I.

TABLE 3.6—Notable environmental releases of 131I. Event or Purpose

Period of Release

Three Mile Island, Pennsylvania

Nuclear reactor accident

March – April 1979

Idaho National Engineering Laboratory

Nuclear fuel reprocessing

Windscale (Sellafield), United Kingdom

Source

Activity (PBq)

Reference

1957 – 1959

0.12

Apostoaei and Miller (2004), Apostoaei et al. (2005)

Nuclear reactor accident

October 1957

0.74

Apostoaei and Miller (2004)

Oak Ridge National Laboratory, Tennessee

Radioactive lanthanum production

1944 – 1956

0.96

Apostoaei et al. (1999), Apostoaei and Miller (2004)

Savannah River, Georgia

Nuclear fuel reprocessing

1955 – 1962

2.2

Apostoaei and Miller (2004), Till et al. (2001)

Mayak Plant, Russia

Nuclear weapons production

1949 – 1955

14

Mushkacheva et al. (2006)

Hanford, Washington

Plutonium production

1944 – 1956

27

Napier (2002)

Chernobyl, Ukraine

Nuclear reactor accident

April – May 1986

1,800

Apostoaei and Miller (2004)

NTS

Nuclear weapons testing

1952 – 1957

5,600

Apostoaei and Miller (2004)

Worldwide fallout

Nuclear weapons testing

1952 – 1962

675,000

Apostoaei and Miller (2004), Beck and Bennett (2002)

/ 103

Kemeny (1979)

3.3 INTERNAL DOSE

0.00074

104 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION TABLE 3.7—Total intake of radioisotopes of iodine and tellurium by exposed Marshall Islanders according to location (Lessard et al., 1985; Robbins and Adams, 1989). Total Intake of Activitya (MBq)

Physical Half-Life (h)

Ailingnae

Rongelap

Utirik

135I

6.7

25 – 44

70 – 130

2.9 – 5.2

134

I

0.8

16 – 29

2.5 – 4.4

—

133

I

20.8

12 – 21

44 – 78

5.9 – 11

132I

2.3

2.5 – 4.4

12 – 21

2.2 – 4.1

193

0.40 – 0.70

2.0 – 3.6

0.50 – 0.90

78

3.7 – 4.8

11 – 20

2.1– 4.1

0.50 – 0.90

1.6 – 3.0

0.30 – 0.60

Radioisotope

131I 132

Te

131mTe

29.0

aThe intake varied with age; for the range specified, the lower value is for 1 y olds and the higher value is for adults.

3.3.7.1 Nevada Test Site Cohort Exposed to 131I-Contaminated Fallout. Atmospheric testing of nuclear weapons was performed at NTS from 1951 to 1962. Underground testing began in 1961. However, after 1968 only underground testing was allowed and these tests ended in 1992. Ninety tests, conducted mainly in 1952, 1953, 1955, and 1957, released ~5.55 EBq of 131I, 99 % of the total atmospheric 131I released at NTS. Some radioiodine was deposited everywhere in the continental United States, with the highest deposits immediately downwind and the lowest deposits upwind of NTS (the west coast and the southeast). Public Law 97-414 directed the U.S. Secretary of Health and Human Services to “...conduct scientific research and prepare analyses to develop valid and credible methods to estimate the thyroid doses of 131I that are received by individuals from nuclear weapons fallout and to develop valid and credible assessments of the exposure people received from the Nevada atmospheric nuclear bomb tests...” and “to conduct scientific research and prepare analyses necessary to develop valid credible assessments of the risks of thyroid cancer that are associated with thyroid 131I” (NCI, 1997). NCI responded to this directive and prepared a report, published in 1997, entitled, Estimated Exposures and Thyroid Doses Received by the American People from 131I

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in Fallout Following Atmospheric Nuclear Bomb Tests, sometimes known as the “NCI Fallout Report” (NCI, 1997). Estimates of 131I exposures and thyroid doses of the entire U.S. population (160 million people in nearly 3,100 counties) are included in that report, and are summarized below. Human exposure to 131I in fallout from U.S. tests of nuclear weapons resulted mainly from the pasture-cow-milk-human pathway. Because of its short effective half-life (~5 d) on the surface of pasture vegetation, exposure to 131I occurred primarily within the first month following a test. The dose during the second month (from the consumption of fresh milk) would have been <1 % of that in the first 30 d after fallout occurred. If milk were stored, however, and then subsequently consumed, the levels of radioiodine in milk during storage would be reduced with a half-life equivalent to that of the 8.04 d physical half-life of 131I. The NCI dose assessment was performed for each above-ground detonation and was a highly complex, multi-step procedure. The source term was the 131I activity released per detonation, estimated as 5.55 PBq kt–1 of fission yield. Meteorological computer modeling of bi-daily routine weather maps was then performed to determine the geographic dispersion and column content [i.e., the 131I activity in a 1 km2 column of air extending from the ground to the top of the radioactive cloud and the ground deposition of 131I by aerosol impaction (dry deposition) and precipitation (wet deposition)]. Historical radiation monitoring data, including “close-in” survey meter measurements and fallout deposition measurements on gummed film, were reviewed and reanalyzed. The nationwide “gummed-film network” consisted of up to ~100 gummed-film detectors (i.e., 0.3 m by 0.3 m of gummed-film positioned horizontally on a stand 0.9 m above the ground, collected daily, and ashed and counted for beta activity). Note that the total area of the gummed-film network clearly represented a minute sample from which to extrapolate the 131I deposition throughout the continental United States. In a number of geographic areas, declassified independent information was used to compute deposition of specific radionuclides, including 131I, from beta-ray activity on the gummed films. For each test, the gummed-film data were interpolated among counties to derive deposition data for the counties not sampled (the great majority of counties in the nation). For most of the test detonations, dosimetry was based primarily on the gummedfilm network rather than on meteorological modeling, which was mainly used to check the consistency of the gummed-film network. Measurements of deposited activity were not available for three tests conducted in 1951 and for six tests conducted between 1962

106 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION and 1970. For these nine tests (out of a total of 86), atmospheric dispersion and deposition models were used to estimate the amount of 131 I deposited by county (NCI, 1997; Simon and Bouville, 2002). Transfer of 131I from deposition on the ground to fresh cow’s milk was estimated using generally accepted modeling techniques. Pertinent parameters included: the mass interception factor (i.e., the fraction of 131I deposited on the ground that is intercepted by vegetation); the effective half-life of 131I retention by vegetation, ~4.5 d; fresh pasture intake by dairy cows (the product of the total daily dry matter intake and the fraction of total dry matter intake from pasture); and the intake-to-milk transfer coefficient (the quotient of the time-integrated 131I concentration in milk and the 131I activity consumed) experimentally determined to be 140 Bq d L–1 kt–1 (NCI, 1997). Once the time-integrated 131I activity in fresh cow’s milk was determined for each county, production, utilization (drinking versus feeding calves, producing butter, etc.), distribution (consumption on the farm, within the county, or outside the county), and age-, gender- and location-dependent consumption were used to derive the 131I intake by an individual and the resulting thyroid dose (NCI, 1997): D mc  i,k,t e = IMC VW  i,t e u CR  i,k u DCF  k ,

(3.3)

where: Dmc (i, k, te) = median absorbed dose from the milk of a cow (mc) to the thyroid from a given test (te) to an individual of age and gender group (k) living in county (i) IMCVW (i, te) = geometric mean of the volume-weighted1 timeintegrated 131I concentration in milk consumed in county (i) after test (te) CR(i, k) = median consumption rate (CR) of cow’s milk by consumers of age and gender group (k) in county (i) DCF(k) = dose conversion factor (absorbed dose to the thyroid per unit of activity of 131I) for age and gender group (k)

1Volume-weighted concentration indicates the contribution to the geometric mean activity concentration of a given measured activity concentration was weighted by the relative volume of the milk sample assayed.

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= 0 (prior to 10 weeks) to 3.8 (at 25 weeks) in utero, 12 (for 10 month olds) to 15 (for onemonth-olds) among infants, 1.9 (for 17 y olds) to 8.2 (for 2 y olds) among children, 1.3 for men, and 1.8 for women For all NTS tests, the highest per capita thyroid doses, 60 to 160 mGy, occurred in 270 counties (9 %) primarily in western states located east and north of NTS (Utah, Idaho, Montana, Colorado, and Missouri). The highest per capita thyroid doses, 120 to 160 mGy, were restricted to five counties (0.2 %) in Idaho, primarily, and Montana. Because of their greater milk intake as well as smaller gland sizes, the highest thyroid doses occurred in children. The lowest per capita thyroid doses, <20 mGy, occurred in ~1,200 counties (39 %) on the west coast, in the southwest, and the southeast. Intermediate per capita thyroid doses, 20 to 60 mGy, occurred in ~1,600 counties (52 %) in the entire Midwest (from the northern border to eastern Texas) and the northeast (north of Pennsylvania). Nationwide, the mean per capita thyroid doses from all U.S. tests was ~20 mGy (NCI, 1997). The type of milk consumed also is important. It is estimated that at that time ~20,000 individuals in the U.S. population consumed goat’s milk. Thyroid doses to those individuals could have been 10 to 20 times greater than those to other residents of the same county who were the same age and sex and drank the same amount of cow’s milk. Goat’s milk concentrates 131I more than cow’s milk. There are large uncertainties in the estimated county-by-county thyroid doses because it is impossible to know precisely all the information required for such dose estimates. NCI has estimated the resulting uncertainty in the per capita thyroid dose, 20 mGy, to be a factor of two, that is, the per capita thyroid dose may be as small as 10 mGy or as large as 40 mGy. NCI has likewise estimated the uncertainty in an individual’s thyroid dose as a factor of five; if an individual’s estimated thyroid dose is 30 mGy, the actual thyroid dose will likely lie between 6 and 150 mGy (NCI, 1997). Doses from global fallout have also been estimated (Bouville et al., 2002). NCI maintains a website that calculates individual thyroid doses and risks due to 131I fallout from NTS (NCI, 2007a). 3.3.7.2 Marshall Islanders. On March 1, 1954, 253 Marshall Islanders were accidentally exposed to a large amount of radioactive fallout during a high-yield thermonuclear weapons test in the South Pacific (Conard, 1975; 1984; 1991; Conard et al., 1970a; 1975; Cronkite et al., 1997; Howard et al., 1997; Robbins and

108 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION Adams, 1989). Calculated intakes of the relevant radioisotopes of iodine and of tellurium on each island affected are presented in Table 3.7 (James, 1964; Lessard et al., 1985; Robbins and Adams, 1989). The estimated external doses were highest (1.9 Gy) for the 67 inhabitants of Rongelap (Table 3.8). The inhabitants of Ailiginae and Rongelap (19 people with estimated external dose 1.1 Gy) were evacuated by ship on March 4. The 164 inhabitants of Utirik were estimated to have an external dose of 0.1 Gy. A medical team with expertise in radiation effects arrived in Kwajelein on March 8 to examine and care for the Marshallese. In addition, 23 Japanese fishermen on the boat Fukuru Maru (Lucky Dragon) were significantly exposed and experienced nausea and vomiting. Twentyeight U.S. servicemen stationed on Rongerik Atoll were evacuated on March 2. External and internal doses were reconstructed for the 28 American servicemen stationed on Rongerik Atoll Marshall Islands (Goetz et al., 1987). Reconstructed film badge doses were ~0.40 Sv. Internal dose commitments to the thyroid and large intestine provided the only significant increments to the external doses. Total doses are ~2.3 Sv to the thyroid, 1.15 Sv to the lower large intestine, 0.85 Sv to the upper large intestine, and ~0.4 to 0.5 Sv to all other organs. The seriousness of the radiation exposures was quickly understood. The Marshallese evacuated from Rongelap reported snowflake-like fallout that discolored their drinking water (rain water collected from rooftops). About two-thirds of the Rongelapese were nauseous for 2 d; none of the military personnel or the Utirikese had GI symptoms. Hematological changes consistent with the external dose were observed. After several weeks, improvements in the hematology changes were noted and plans were made for the long-term follow-up of this population. The magnitude of the thyroid dose and the subsequent consequences were not initially anticipated. Dose estimates were based on analysis of a pooled 24 h urine sample obtained 17 d after the exposure and back extrapolation from subsequently obtained samples from the deck of the nearby heavily-contaminated Lucky Dragon. Analyses indicated that the only radionuclides that exceeded the maximum permissible levels were 131I and 90Sr. After several thyroid tumors developed and clinical hypothyroidism developed in two children, the thyroid doses were reevaluated. The diagnosis of hypothyroidism in two children with growth retardation was delayed because the Marshallese had a higher normal protein-bound iodine level than U.S. populations. The children responded appropriately to thyroxine once their hypothyroidism was diagnosed and treated.

TABLE 3.8—Mean thyroid dose estimates for exposed Marshall Islanders according to age and location (Lessard et al., 1985; Robbins and Adams, 1989). Atoll

Ailingnae

Distance from Bikini (miles)

95

Total Number Exposed

19

Age at Exposure

Internal

External

a

In utero

4.9

1.1

6

Newborn

—

—

—

1y

13

9y Adult Rongelap

100

67

1.1

6.5

2.8

1.1

3.9

In utero

6.8

1.9

8.7

Newborn

2.5

1.9

4.4

50

1.9

52

9y

20

1.9

22

Adult

10

1.9

12

In uterob

2.6

0.11

2.7

Newborn

0.48

0.11

0.59

1y

6.7

0.11

6.8

9y

3.0

0.11

3.1

Adult

1.5

0.11

1.6

/ 109

Second trimester. bThird trimester.

164

14

5.4

3.3 INTERNAL DOSE

a

300

1.1

Total

b

1y

Utirik

Thyroid Absorbed Dose (Gy)

110 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION NCI has estimated the number of cancers among the Marshallese that are attributable to their radiation exposure from fallout due to nuclear weapons testing in the Marshall Islands (NCI, 2004). The thyroid doses were highest in Rongelap children (Table 3.8). Palpable thyroid nodules were discovered in 12 y old Rongelap females in 1963 and surgically confirmed to be benign in 1964. In 1969, a palpable nodule was found in an Utirikese adult female; the final pathological diagnosis in this case was follicular carcinoma. The numbers of surgically confirmed thyroid tumors diagnosed in the Marshallese from 1964 to 1990 are shown in Table 4.9 (Howard et al., 1997). Thirty-eight benign nodules have been diagnosed in the exposed population and five have been diagnosed in the control group (corresponding to a relative risk of 8.5). Ten palpable thyroid cancers have been diagnosed in the exposed population and two have been diagnosed in the control population [relative risk (RR) = 4.5]. Seven occult thyroid cancers have been diagnosed in the exposed population and two have been diagnosed in the control population (RR = 3.1). It is unclear whether the difference in surveillance accounts for some of the apparent differences in the prevalence of thyroid disease between the exposed population and the unexposed Marshallese comparison group. The dose estimates have a large uncertainty and the degree and consistency of follow-up were not comparable between the exposed and unexposed populations. In addition, thyroid suppressive therapy may have reduced cancer risk in the irradiated group. Cronkite et al. (1997) concluded that, “There are simply not enough cases to draw any conclusion in respect to a dose-effect relationship.” Thyroid ultrasound was first used in the Marshallese population in 1994 (Howard et al., 1997). As expected, ultrasound resulted in the detection of many occult nodules. Surprisingly, the prevalence of nodules in the exposed population was not greater than the prevalence of nodules in the control population, even when Marshallese who had prior thyroid surgery were excluded. Considerable effort has been devoted to reassessing the magnitude of the doses received by inhabitants of the different atolls (Robison et al., 1997; Simon and Graham, 1996). Extensive studies of dose distribution throughout the Marshall Islands downwind of Bikini were conducted by the Nationwide Radiological Study Program. One survey assessed whether there was an association between the prevalence of thyroid nodules on the various Marshall Islands and distance from the Bikini Atoll, where shot BRAVO was detonated (Hamilton et al., 1987). A consistent relationship

3.3 INTERNAL DOSE

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between the geographic distribution of measured long-lived 137Cs contamination and 131I distribution from the different test shots was assumed. Over 7,200 residents on 14 different atolls underwent thyroid screening with neck palpation, and information was collected on their place of residence at the time of the BRAVO shot. A statistically-significant association between distance and thyroid nodule prevalence was found; if the doses received by the inhabitants of Uterik were excluded, however the correlation disappeared. The population of Uterik (164 persons) had an estimated external dose of 0.1 Gy. A multinational 10 y Nationwide Thyroid Disease Study was conducted utilizing the Nationwide Radiological Study dose data. Although a smaller population sample than that of Hamilton et al. (1987) was studied, ascertainment of nodules was based on thyroid ultrasound and neck palpation examination. Using mean 137Cs measurements from the Nationwide Radiological Study, the authors found no significant correlation between thyroid dose and prevalence of thyroid cancer or thyroid nodules among the downwind islanders (Takahashi et al., 2001). Difficulty in reconciling the discrepancy in the findings of Hamilton et al. (1987) and Takahashi et al. (2001) presumably reflects the modest sample size and relatively low statistical power of these two studies. However, the likelihood that a small effect was indeed present is suggested by the reanalysis (Takahashi et al., 2003) of the data of Takahashi et al. (2001), which found some evidence that the prevalence of thyroid cancer did increase with the estimated thyroid dose. Overall, however, since 80 to 90 % of the thyroid dose received by the heavily exposed islanders was from the short-lived radionuclides and gamma radiation, with less well-characterized dose received by the more remote islanders, it seems unlikely that the studies of the Marshall Islanders will provide reliable information on the health risks of 131I (Robbins and Adams, 1989). 3.3.7.3 Hanford Site. In 1943, the U.S. Army Corps of Engineers selected an area of ~560 square miles in southeastern Washington State for a facility to support the Manhattan Project, the U.S. effort during World War II to develop the world’s first atomic bomb. This area, called the Hanford Site, was used for uranium fuel preparation, nuclear reactor operations, fuel reprocessing, plutonium recovery, and radioactive waste management. Nine nuclear reactors for plutonium production were eventually constructed, with reactor operations beginning in 1944 and ending in 1987 (Jenne and Healy, 1950; Napier, 1994; Zorpette, 1996).

112 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION The Hanford Environmental Dose Reconstruction Project, initiated in 1987 by the U.S. Department of Energy and concluded in 1995, was designed to estimate doses to the public from environmental releases of radionuclides from the Hanford Site. The Hanford Environmental Dose Reconstruction Project was the successor to Washington State’s Hanford Health Effects Study and was performed by the Pacific Northwest Laboratory, operated by the Battelle Memorial Institute, and directed by an independent Technical Steering Panel. Based on original records from the time period under study, the environmental source terms were primarily 131I released into the atmosphere and 24Na, 32P, 65Zn, 76As, and 239Np released into the Columbia River. Environmental transport included atmospheric, aquatic and terrestrial as well as commercial milk distribution. Dose estimates derived from the activity released were based on Monte-Carlo calculations for different release scenarios. Individual dose modeling included immersion in, and inhalation of, contaminated air, exposure to contaminated surfaces, immersion in and consumption of contaminated water, and consumption of contaminated fruits and vegetables, fish, game and, most importantly, milk (Napier, 1994). The most important thyroid exposure pathway to the general population was consumption of milk produced by cows grazing on pasture downwind of the Hanford Site. Iodine-131 releases were essentially continuous in the early years of operation, when the greatest activities were being released (1944 to 1947). Thus, infants and young children who drank the radioiodine-contaminated milk from these cows received the highest estimated doses, with median total doses ranging from 0.02 to 2.4 Gy. The uncertainty in these dose estimates is fairly large (i.e., in Ringold, Washington), with a median thyroid dose of 2.4 Gy, the thyroid dose 90 % CI was 0.54 to 8.7 Gy. The projected adult thyroid dose was generally one-tenth of that of children. Thyroid doses >0.085 Gy to infants drinking milk from backyard cows perhaps extended to the Washington-Canada border (Napier, 1994; NAS/NRC, 2000). Importantly, among the Hanford Cohort, dosimetry estimates were based exclusively on dose reconstruction. There were no direct measurements of thyroid activity performed on any members of the cohort. Some measurements of 131I in the environment were used to validate the assumptions in the dose reconstructions. In a noteworthy study by Kopecky et al. (2004), the computer program Calculation of Individual Doses from Environmental Radionuclides (CIDER) developed by the Hanford Environmental Dose Reconstruction Project, was used to estimate the thyroid doses for 3,440 evaluable participants in the Hanford Thyroid Disease

3.3 INTERNAL DOSE

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Study (HTDS). Extensive effort was made to locate and recruit into the study every living cohort member. Participants who completed an in-person interview and physical examination (thyroid palpation) were considered available and were included in subsequent analyses. Whenever possible someone with direct knowledge of the participant’s early life (preferably the participant’s mother) was interviewed about the participant’s residence history; sources and quantities of food, milk and milk products consumed; production and processing techniques for home-grown food and milk products; and other dose-determining characteristics. Default information (e.g., residence, limited dietary information) was used if no interview respondent was available. CIDER provided 100 sets of doses to represent uncertainty of the estimates. These sets were not generated independently for each participant, but reflected the effects of uncertainties in characteristics shared by participants. For this cohort, estimated doses (medians of each participant’s 100 realizations) ranged from 0.0000029 to 2.82 Gy, with mean and median of 1.7 and 0.9 mGy, respectively. Importantly, the authors concluded that the distribution of estimated doses provided HTDS with sufficient statistical power to test for dose-response relationships between 16 different thyroid outcomes and radioiodine exposure. However, according to a number of authors (Carroll et al., 2006; Hofer, 2007; Hoffman et al., 2006; 2007), the uncertainty associated with each of the foregoing median dose estimates was likely underestimated and the statistical power of HTDS compromised due to uncertainty in dose reconstruction that was larger and more complex than recognized by the HTDS investigators.2 These authors further contend that, by ignoring the potential for bias (i.e., overestimation of dose) and sources of uncertainty that were partially composed of classical measurement errors (the HTDS investigators assumed that 100 % of all dose reconstruction uncertainties were Berkson), the statistical power of HTDS was overestimated (Carroll et al., 2006; Hofer, 2007; Hoffman et al., 2006; 2007). Although critics of HTDS raise issues of statistical power and potential bias that broaden the confidence intervals about the estimates of radiation effect on the thyroid gland, the extent to which these potential sources of error apply, and whether they would invalidate the study results (Kopecky et al., 2004; NAS/NRC, 2000; Stram and Kopecky, 2003) is uncertain. None of the 16 measures of 2Information taken from interviews about specific individual diets, and residence histories, is a source of classical error that both compromises the statistical power of an epidemiological study and suppresses the slope of the dose response (Carroll et al., 2006).

114 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION thyroid abnormalities, including those such as autoimmune thyroiditis or ultrasound detected abnormalities, which had large numbers of cases leading to substantial statistical power, increased with estimated thyroid dose (Davis et al., 2004a; Kopecky et al., 2004; 2005). Also none of the laboratory measures of thyroid function evaluated varied with thyroid dose (Davis et al., 2002). Additional analyses based on alternative characterizations of exposure, which were less subject to the potential biases and uncertainties arising from dose reconstruction, also revealed no increased risk of thyroid disease or abnormality (Davis et al., 2002). Although the largest environmental releases of 131I and other radionuclides associated with processing of spent uranium fuel rods occurred at the Hanford Site, substantial cumulative releases also occurred at the Savannah River Site (Till et al., 2001), the Oak Ridge X-10 Facility (Apostoaei et al., 1999), and, to a lesser extent, the Idaho National Engineering Laboratory (Apostoaei et al., 2005). Comparable releases to those at the Hanford Site also occurred at the Mayak Facility in the Ural Mountains of the former Soviet Union (Apostoaei and Miller, 2004; Mushkacheva et al., 2006). 3.3.7.4 Chernobyl Nuclear Reactor Accident. Shortly after 1:00 am local Ukraine time on April 26, 1986, the core of Reactor No. 4 at the Chernobyl Nuclear Power Plant (near the town of Pripyat in Ukraine) suffered a prompt criticality excursion resulting in a steam explosion, initiating what became, by far, the world’s worst nuclear reactor accident (Gudiksen et al., 1989; IAEA, 1986; UNSCEAR, 2000a; Wilson, 1987). This reactor, a 1,000 MW watercooled, graphite-moderated reactor, differed substantially in design from most reactors in use in the rest of the world. Most reactors use water as the coolant and the moderator. In such reactors, when the coolant is lost, the moderator is also lost so that the rate of the controlled nuclear fission reaction decreases. In Chernobyl-type reactors, the graphite moderator remains even when the coolant is lost, allowing the nuclear reaction to continue. In addition, because graphite burns at sufficiently high temperatures, the resulting fire can be very difficult to extinguish. Importantly, the Chernobyl reactor was not enclosed in a steel-reinforced concrete containment building typical of most reactors. The steam explosion immediately destroyed the reactor building. The reactor fire burned for 10 d. The explosive breach of containment released a large portion of the core inventory (perhaps of the order of 50 %) into the environment. Radioactive fission products were dispersed worldwide (i.e., nearly 10,000 km). It has been estimated that, of the 200 ton core, 5 to 10 tons of particulate

3.3 INTERNAL DOSE

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matter were deposited in the vicinity of the reactor and largely confined to the subsequently established “30 km Exclusion Zone” (from which 115,000 people were permanently evacuated) (Gudiksen et al., 1989; IAEA, 1986; Wilson, 1987). Very large amounts of 131I, shorter-lived radioiodines (such as 132I and 133I), 132Te (the longer-lived parent of 132I), and other radionuclides, including radioisotopes of cesium, xenon, krypton and strontium, were released. The fraction released of specific radionuclides in the core inventory varied widely according to the volatility of the respective chemical elements. Virtually all of the noble gases escaped. Because of the very high temperatures of the reactor fire, radionuclides of volatile elements such as iodine and cesium were readily dispersed as gas and aerosol, which became widely distributed according to prevailing meteorological conditions (Gudiksen et al., 1989; IAEA, 1986; Wilson, 1987). The Chernobyl nuclear reactor accident released 1.5 to 1.9 EBq (4.1 to 5.1 × 107 Ci) of 131I (Gudiksen et al., 1989; IAEA, 1986; Ilyin et al., 1990). In comparison (Nenot, 1990), the Three-Mile Island accident in 1979 in Pennsylvania released ~560 to 740 GBq of 131I (Gerusky, 1981; Kemeny, 1979), the Windscale accident in 1957 in England released ~740 TBq (Nenot, 1990), the Hanford Site in Washington State released ~26 TBq from 1944 to 1947 (Heeb, 1992; 1994; Heeb and Bates, 1994), and a total of ~675 EBq was released worldwide from all nuclear weapons tests between 1945 and 1962 (NCI, 1997) (Table 3.6). Although 89Sr, 141Ce and 144Ce, and 238Pu, 239Pu, and 240Pu constituted most of the activity in particulate form deposited within the 30 km Exclusion Zone, only a relatively small fraction of radioisotopes of more refractory elements was released (Bard et al., 1997; IAEA, 1986; Ilyin et al., 1990; Wilson, 1987). The radioactive plumes from the Chernobyl nuclear reactor accident moved primarily northward over northern Ukraine, southern Belarus, and southern Russia, then westward over parts of Eastern Europe (Poland), and then northwesterly over parts of southern Scandinavia (Finland and Sweden). The most heavily contaminated areas were in northern Ukraine and southern Belarus. In the first day, the plume contained a large proportion of short-lived radioiodines (at least comparable to the amount of 131I), and the areas closest to Chernobyl were more likely exposed to these shorter-lived iodine radioisotopes. Within a week, however, 131I was the predominant radioiodine present. The population in the vicinity of Chernobyl was largely rural, and many residents had backyard cows that supplied milk for family consumption. These cows grazed on highly contaminated pasture, and the milk pathway, the predominant mode of exposure among children, resulted in high

116 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION pediatric thyroid absorbed doses. Consumption of 131I-contaminated leafy vegetables, inhalation of airborne 131I and short-lived 132 I and 133I, and external irradiation from activity deposited on the ground were only minor contributions to the thyroid dose. Thyroid uptake of radioiodine and the resulting thyroid absorbed dose are inversely related to dietary iodine intake, and much of Belarus had areas of moderate iodine deficiency and endemic goiter. As a result, the thyroid dose to Belarusians from radioiodines in the Chernobyl fallout was increased (Gavrilin et al., 1999; Likhtarev et al., 1993; 1994a; 1994b; 1996). Although some effort was made to use potassium iodide for thyroid blockade in the vicinity of Chernobyl, delays (of at least 3 to 5 d) in informing the public about the accident limited the effectiveness of potassium iodide distribution, and optimal administration in terms of time relative to exposure was rarely achieved. Overall, only ~25 % of the population received potassium iodide (Becker et al., 1996c; Mettler et al., 1992a; 1992b). Current thyroid dose estimates in Belarus, Russia and Ukraine were based on ~500,000 measurements of the backgroundcorrected gamma-ray exposure rate against the neck, the so-called “direct thyroid measurements” (Gavrilin et al., 1999; 2004; Goulko et al., 1996; Likhtarev et al., 1993; 1994a; 1994b; 1996; Likhtarov et al., 2005; Mettler et al., 1990; Minenko et al., 2006; O’Hare et al., 2000; Takada et al., 2000). For individuals not undergoing direct thyroid measurements but living in areas where many individuals received such measurements, thyroid doses were assigned on the basis of the mean dose value for those measured individuals of the same age and dietary habits (primarily milk consumption) in the same area. For those individuals who lived in areas with few or no direct thyroid measurements within several weeks of the accident, thyroid doses were assigned on the basis of the mean dose values for those measured individuals of the same age and dietary habits (primarily milk consumption) in other areas having comparable 131I or 137Cs ground deposition levels, 137Cs whole-body burdens, or 131I concentrations in milk. Most of the direct thyroid measurements were made in the field, often by inexperienced, largely untrained personnel. Collimation varied considerably among measurement devices, with some devices having no collimation. Measurement of background count or exposure rate often was not performed or was performed inappropriately. The environment, the individual being counted and any clothing, personnel performing the counting, and perhaps the counting device itself may have been contaminated with radioactive material. Most measurements were performed with devices not

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capable of spectral energy analysis and energy-selective counting. For example, of more than 200,000 direct thyroid measurements performed in Belarus, 80 % were performed with Geiger counters and only 20 % with scintillation detectors. Calibration factors (for converting measured count or exposure rate to 131I activity) may not have been current or may have been otherwise inaccurate. Almost always, only a single measurement was performed for a particular individual and kinetic data, therefore, were not available. As a result, even for individuals with a direct thyroid measurement of activity, the time-activity parameters required for calculation of dose had to be deduced by calculational means. In many locations, however, exposure to radioiodine occurred sporadically over many days. Estimation of thyroid dose depended in many cases on the individual’s personal recollection of their residence history, the source, amount and length of time of any milk consumed, and whether or not and when they received potassium iodide (Gavrilin et al., 2004; Likhtarev et al., 1993; 1994a; 1994b; 1996; Likhtarov et al., 2005; Minenko et al., 2006; Takada et al., 2000). Even though 131I in the thyroid generally accounts for most of the thyroid dose, other exposure pathways may ultimately need to be considered. These include: internal irradiation by short-lived radioiodines (primarily 132I and 133I) and short-lived 132Te (the precursor of 132I) (Balonov et al., 2003; Bleuer et al., 1997; Cardis et al., 2005; Gavrilin et al., 2004; Hindie et al., 2001), internal irradiation by long-lived radionuclides such as 134Cs and 137Cs (Cardis et al., 2005; Minenko et al., 2006), and external irradiation from radionuclides deposited on the ground and from the radioactive plume passing overhead (Minenko et al., 2006; Nedveckaite et al., 2004). The highest thyroid doses were, as expected, delivered to children and were mainly due to consumption of fresh cow’s milk contaminated with 131I. Thyroid absorbed doses derived from measurements among ~30,000 children in Belarus and ~80,000 children in Ukraine ranged from <0.1 to >10 Gy, the principal factors for this wide variability presumably are the origin and amount of milk consumed. The median thyroid dose among these children was ~0.3 Gy in Belarus and Ukraine, with ~1 % of children receiving a thyroid dose in excess of 5 Gy. In Russia, pediatric thyroid doses were approximately twofold less on average (Likhtarev et al., 1993; 1994a; 1994b; 1996; Likhtarov et al., 2005; Mettler et al., 1990; O’Hare et al., 2000; Takada et al., 2000). A frequency histogram of thyroid doses in children living in the Gomel Oblast of Byelorus is shown in Figure 3.9. The uncertainties in the thyroid dose estimates were found to be approximately lognormally distributed, with GSD ranging from 1.6 to 5 (Likhtarev et al., 2003). The

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Fig. 3.9. Frequency distribution of thyroid absorbed dose stratified according to age at exposure among children living in the Gomel Oblast of Byelorus at the time of the Chernobyl nuclear reactor accident (UNSCEAR, 2000a).

medians of GSD were 1.7 and 2.1 for the Ukrainian and Belarusian individuals, respectively. The major sources of uncertainty were related to the estimation of the thyroid mass of each individual and of the thyroidal content of 131I at the time of the direct thyroid measurement. In a case-control study of Chernobyl-related thyroid cancer among children in Belarus (Gavrilin et al., 2004), the range of the 131 I thyroid doses among the 107 cases and the 214 controls was 0.00002 to 4.3 Gy, with medians of 0.2 Gy for the cases and 0.07 Gy for the controls. The thyroid doses resulting from the intakes of short-lived radioiodines (132I, 133I, and 135I) and radiotelluriums (131mTe and 132Te) were also estimated and compared to the doses from 131I. The thyroid doses from the short-lived radionuclides for the cases and the controls ranged from 0.3 to 10 % of the 131I thyroid doses, with median values of 2 % for both cases and controls. In a larger case-control study (276 cases and 1,300 controls) of thyroid cancer among children in Belarus and the Russian Federation (Cardis et al., 2005), the median and maximum total thyroid doses were, respectively, 0.37 and 10 Gy in Belarus and 0.04 and 5.3 Gy in the Russian Federation. The median thyroid doses from

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131

I and short-lived radionuclides were, respectively, 0.36 and 0.0016 Gy in Belarus and 0.039 and 0.001 Gy in the Russian Federation. The thyroid dose contributions from long-lived internal radionuclides (principally 134Cs and 137Cs), and external exposure were as small as or smaller than that from the short-lived radionuclides. Based on the foregoing data, therefore, the combined thyroid dose contributions from short- and long-lived internal radionuclides and external exposure were only 1 to 2 % of that from 131I. Implicit in these dose estimates is the assumption that the radioiodine is uniformly distributed throughout the thyroid. For shortlived radioiodines, however, a significant portion of the intrathyroidal decays may occur while the radionuclides are in the peripheral colloid, potentially delivering a substantially higher dose to the follicular cells than that derived assuming a uniform activity distribution (Hindie et al., 2001). 3.4 Radiation Dosimetry in Specific Epidemiological Studies of Radiogenic Thyroid Disease A summary of the radiation dosimetry for the major epidemiological studies of clinical radiogenic thyroid cancer among cohorts exposed to external radiation during childhood or adolescence is presented in Table 3.9. The radiation source for these studies was x rays used for therapy. A summary of the radiation dosimetry in major epidemiological studies of radiogenic thyroid cancer among specific cohorts exposed to internal radiation (i.e., 131I) is presented in tabular form in Table 3.10. A summary of the radiation dosimetry in major epidemiological studies of radiogenic benign thyroid nodules among specific cohorts exposed to external or internal radiation is presented in tabular form in Table 3.11. Epidemiologic details pertinent to inadvertent environmental exposures are presented in Section 4.5.3.

Absorbed Dose (mGy) Study (reference)

Mean

SD and/or Range

—

0 – >4,000

Atomic-bomb survivors (Cullings et al., 2006; Preston, 1988; Preston et al., 2004; 2007; Thompson et al., 1994) Rochester thymus (Shore et al., 1993a)

1,400

3 – 10,000

Dosimetrya

Individual neutron and gamma-ray shielded kerma and organ doses were computed using the latest version of DS02 for studies published after 2002. Organ doses were computed as the gamma-ray dose plus 10 times the neutron dose and expressed in gray rather than sievert. Neutrons (<1 % of the unweighted total organ dose) account for a slightly lower proportion of the total DS02 dose estimates than was the case with the DS86 estimates. To adjust for the impact of bias arising as a result of random errors in individual dose estimates, shielded kerma estimates >4 Gy were truncated to 4 Gy. A 35 % error in individual DS02 dose estimates was assumed. See Appendix C for further details. Information on the x-ray treatments, including number of fields, tube voltage (75, 130, or 250 kVp), filtration (none, 4 mm aluminum, 10 mm aluminum, and 0.5 mm copper), target-to-skin distance (30, 40, or 50 cm), orientation (anterior versus posterior), and field size (3 × 5 to 10 × 10 cm), was extracted from the medical record and by interviews with the treating physicians (Hempelmann, 1967; Hempelmann et al., 1967). Thyroid doses were measured in an anthropomorphic one-week-old infant phantom (with calcium salts for bone, Microvan 1,600“and beeswax for soft tissue, and polystyrene for lung) using an ion chamber placed in the region of the isthmus of the thyroid and a 250 kVp Westinghouse x-ray unit operated to duplicate the actual x-ray treatment conditions. The

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TABLE 3.9—Radiation dosimetry for major epidemiological studies of thyroid cancer: External radiation exposure during childhood or adolescence.

Israeli tinea capitis (Ron et al., 1989; Werner et al., 1968)

93 for all children

45 – 500 for all children

84 for children receiving only one course of therapy

45 – 170 for children receiving only one course of therapy

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Patients received superficial x-ray therapy (70 – 100 kVp, 0.5 mm aluminum filtration, and 1 mm aluminum half-value layer) to five overlapping fields on the scalp (frontal, occipital, right lateral, left lateral, and vertex), with lead shielding on the face and neck. All patients received fractionated radiation therapy consisting of five treatments over 5 d and yielding a total exposure in air of 0.097 C kg –1. The actual prescribed exposure in air ranged from 0.09 to 0.1 C kg –1, and 9 % of patients received more than one course of treatment. The doses to the brain and skull as well as the thyroid were measured using one of the same x-ray units [Zephyr NR-2“ (Picker, Cleveland, Ohio) superficial unit] as used in the treatments; the exposure rates were 0.016 and 0.011 C kg –1 min–1 at target-to-skin distances of 25 and 30 cm, respectively. Using a calibrated ionization chamber, doses were measured in an Alderson child phantom consisting of soft tissue-equivalent material over a skeleton and cut into stackable 2.5 cm thick-transverse sections with a grid of regularly spaced 6 mm diameter holes for the ionization chamber probe. The average thyroid doses for children under 5, 5 to 10, and 10 to 15 y old were 130, 89, and 60 mGy, respectively. The dose was

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

thyroid dose depended on whether the gland was in or out of the treatment field, decreasing over 2 to 3 mm from 100 % depth dose near the edge of the treatment field to 1 % immediately outside of the treatment field. Based on the anatomy of the thymus and thyroid in infants, it was assumed that anterior treatment fields 10 × 10 cm or larger exposed the thyroid to the full depth dose while fields 6 × 8 cm or less exposed it to scattered radiation only. The thyroid dose could be estimated for 91 % of the subjects; for the remaining 9 %, it was uncertain whether the thyroid was in or out of the primary beam and they were excluded from dose-response analyses.

Absorbed Dose (mGy) Study (reference)

Mean

SD and/or Range

Dosimetrya

age-dependent because the thyroids of younger, smaller children were closer to the treatment field and received more scattered as well as primary radiation than the thyroids of older, larger children. Recent reanalyses of these data accounting for uncertainties in the doses (Carroll et al., 2000; Lubin et al., 2004; Schafer et al., 2001) indicate these uncertainties have a minimal impact on dose-response estimation. The authors noted that their doses may be underestimated if children moved during therapy, the therapy was not delivered precisely, or prior radiotherapy was missed. Chicago head and neck irradiation (Ron et al., 1995; Schneider et al., 1993)

570

r270

Pertinent information on radiation therapy, delivered using 200 kVp orthovoltage x rays (0.5 mm copper plus 0.5 mm aluminum added filtration, 1.2 mm copper half-value layer, and 50 cm target-to-skin distance) and consisting of three weekly treatments of 0.034 C kg –1 exposure in air for a total of 0.1 C kg –1 in air to each field, was extracted from the medical record. Usually, right and left lateral treatment fields (8 × 10 cm) were directed at the posterior larynx. Thyroid doses were estimated using a heterogeneous anthropomorphic 6 y old child phantom consisting of an actual skeleton and simulated lung and soft tissue containing calibrated TLDs throughout the thyroid and irradiated with a Philips RT250“ (Philips Electronic Instruments, Mount Vernon, New York) orthovoltage x-ray therapy unit. To estimate the thyroid dose

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TABLE 3.9—(continued).

Boston lymphoid hyperplasia (Pottern et al., 1990; Ron et al., 1995)

240

32 – 550 r66

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The reason for x-ray therapy, age at and dates of treatment, regions irradiated (typically the nasopharynx delivered by right and left lateral opposed fields), treatment field sizes (typically 5 × 7, 6 × 7, or 6 × 8 cm), and exposure (cumulatively ~800 R) were extracted from the medical record of the Children’s Hospital Medical Center, Boston, Massachusetts. Thyroid dose was measured at two beam qualities (3 and 1.2 mm copper half-value layer) for the 6 × 7 cm field produced by a Philips RT250“ orthovoltage x-ray therapy unit, typical of units used in the 1950s, TLDs (r5 %) were distributed in the thyroid of a heterogeneous anthropomorphic 6 y old child phantom containing a skeleton and simulated lung and soft tissue. A correction factor was applied to the measured thyroid dose from the 6 y old child phantom to estimate the thyroid dose for children of other ages. This factor was based on the age-dependent distance from the field edge to the midpoint of the thyroid and on doses measured in a water phantom. Importantly, a 1 cm error in the thyroid position or a 1 cm motion would alter the estimated thyroid dose by at least 30 %. The uncertainty in the thyroid dose was estimated to be 50 %.

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

(r50 %) for children of different ages, a correction factor, based on age-dependent height and weight and related to the distance of the field edge to the midpoint of the thyroid, was used. Substantial uncertainty (>10 %) in the estimated thyroid dose resulted from ambiguity in the medical record regarding whether rectangular treatment fields were vertical (long dimension parallel to the spine resulting in a maximum thyroid dose estimate) or horizontal (long dimension perpendicular to the spine resulting in a minimum thyroid dose estimate).

Absorbed Dose (mGy) Study (reference)

Mean

SD and/or Range

Dosimetrya

Childhood cancer (Ron et al., 1995; Tucker et al., 1991)

13,000

0 – 76,000

Most of the children were treated with orthovoltage x rays, although higher-energy megavoltage radiation was used in more recent years. The thyroid doses were measured using LiF TLDs in an anthropomorphic phantom, with adjustment for age at exposure, height, weight, body surface area, and gland mass. The irradiation conditions were simulated on the basis of machine characteristics, treatment field configurations, and other treatment parameters as extracted from the medical record. Head leakage and scatter were taken into account when possible. Individual thyroid doses were determined for 83 % of the study subjects, but some pertinent treatment information was unavailable for 17 % of the subjects and thyroid doses were estimated on the basis of prevailing radiation therapy practices at the time of treatment of these subjects (Schneider et al., 1993).

Skin hemangioma 226 Ra treatment in Stockholm, Sweden (Lundell et al., 1994)

260

<10 – 2,900

Radiotherapy was given with beta, gamma and/or x rays with radium (226Ra) (flat applicators pre-1935; needles/glass capsules in one or two rows post-1935) and/or contact therapy x rays (<60 kVp, <1 mm aluminum half-value layer, and 15 cm target-to-skin distance). For radium therapy, organ doses were measured using 226Ra needles/capsules placed in the still-available original applicators and the applicators positioned in different locations on a six-month-old baby anthropomorphic phantom, with TLDs placed in holes drilled in the thyroid and other selected organs. For x-ray therapy, organ doses were determined from the original depth-dose and isodose curves.

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TABLE 3.9—(continued).

b

170 – 1,200b

The cohort included 11,807 children treated between 1930 and 1965 only with 226Ra applicators or implants without additional treatment with x rays or other external radionuclides. The application method developed by Ebenius et al. (1952) and introduced for gamma-ray brachytherapy of hemangiomas was used in 81 % of the treatments in this cohort. Two types of 226Ra sources (0.5 to 1.0 mm platinum filtration) were mainly used (83 % of cases), needles (10 or 20 mg of radium) and tubes (7 mg radium). The sources were placed in glass or perspex capsules to achieve fixed distances both to the underlying skin (4.5 mm) and to the next source (4.5 or 5 mm) and one generally fixed parallel to each other in one or two rows. The needles, used in <2 % of the cases, were mainly employed for hemangiomas elevated above the skin and difficult to cover with applicators. The flat applicators (1 to 2 cm2 in area), used in 17 % of the cases, were thin walled to allow transmission of a high percentage of beta rays. To estimate the dose to the different organs (11) at risk, an anthropomorphic phantom of the size of a five- to six-month-old child was constructed and the absorbed dose rate to the organs per unit 226Ra activity in each source region (assuming the activity to be uniformly distributed in the respective source region) was calculated using a treatment-planning system; the calculational results were confirmed by measurements performed during the actual treatment. The actual doses were then calculated using the cumulated activity (226Ra mg h) and the region of the hemangioma. No correction was made for different body sizes, and only the gamma-ray dose, the largest contribution to organ doses, was included.

this table, the term “dose” refers specifically to “absorbed dose.” The interquartile range, 25 to 75th percentile.

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aIn

120

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Skin hemangioma 226Ra treatment in Gothenburg, Sweden (Lindberg et al., 1995)

Study (reference)

Swedish – diagnostic (Hall et al., 1996a)

(Hall et al., 1996b)

Absorbed Dose (mGy) Mean

Dosimetrya

SD and/or Range

All subjects without thyroid mass 1,100

0 – 41,000

with thyroid mass 800

0 – 29,000

Thyroid cancer without thyroid mass 1,200

0 – 26,000

with thyroid mass 1,100

0 – 26,000

Other indication without thyroid mass 900 with thyroid mass 70

0 – 41,000

540

20 – 15,000b

This study includes children and adults (6,821 males and 27,283 females) who received 131I for diagnosis of thyroid disease in Sweden from 1950 to 1969. Thyroid doses for individual patients were determined using the 131I activity administered (2.4 MBq) for suspected thyroid cancer, 1.6 MBq for other indications), the measured 24 h RAIU (average: 40 %; range: 0 to 96 %), and standard dose conversion factors (mGy MBq–1 administered) in ICRP Publication 53 (ICRP, 1988). For 48 % of the patients in the cohort, thyroid mass was estimated based on information in the medical record and on scintigraphic images and the thyroid dose was adjusted based on the estimated thyroid mass. Patients were grouped into four thyroid dose categories: <250, 250 – 500, 510 – 1,000, and >1,000 mGy.

0 – 29,000 This study includes 1,005 girls and women who received 131I for diagnosis of thyroid disease in Sweden from 1952 to 1977. Thyroid doses for individual patients were determined using

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TABLE 3.10—Radiation dosimetry for major epidemiological studies of radiogenic thyroid cancer: Internal (i.e., 131I) radiation in adults and children.

United States – diagnostic (FDA childhood 131I) (Hamilton et al., 1989)

Swedish – therapeutic (Holm et al., 1991)

<100 – >20,000

This study includes 3,503 children and adolescents who received diagnostic administrations of 131I in the United States from 1946 to 1967. The thyroid dose (D) was estimated for each subject using the equation D = 90 UA /M, where U = the percent thyroid uptake, A = the administered 131I activity, and M = the age-dependent thyroid mass. These data were extracted from each subject’s medical record.

>100,000

Not available

This study includes 10,552 adults who received 131I for treatment of hyperthyroidism in Sweden from 1950 to 1975. Thyroid doses of 60 to 100 Gy per treatment for individual patients were determined using the 131I activity administered of 360 MBq for Graves’ disease (51 % of patients) and 700 MBq for toxic nodular goiter (42 %) and other data extracted from

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~800

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

the 131I activity administered of 0.95 MBq, the measured 24 h thyroid uptake, and standard dose conversion factors (mGy MBq–1 administered) in ICRP Publication 53 (ICRP, 1988), with adjustment of the dose for the scintigraphically determined thyroid mass. Patients were grouped into three thyroid dose categories: <250, 250 to 1,000, and >1,000 mGy. This was a study of thyroid nodularity, not specifically thyroid cancer, following diagnostic administration of 131I. Only 2 % of the subjects were referred for suspected thyroid cancer and they received the highest mean dose of 1 Gy; the remaining 98 % were referred for hyperthyroidism and other benign conditions and received substantially lower mean doses of 3.9 to 7 mGy.

Study (reference)

Absorbed Dose (mGy) Mean

Dosimetrya

SD and/or Range

the medical record and dose conversion factors (mGy MBq–1 administered) from ICRP Publication 53 (ICRP, 1988) and from Edmonds and Smith (1986). Among the patients treated, 59, 27, and 14 % received one, two, and three or more treatments, respectively. United States – therapeutic (Ron et al., 1998)

Not available

~50,000 – 70,000

This study (Cooperative Thyrotoxicosis Therapy Follow-Up Study) includes 7,345 men and 28,248 women who received 131I for treatment of hyperthyroidism in the United States and England from 1946 to 1964. As extracted from the medical record, the 131I administered activity per treatment (mean r SD) was 226 r 192 MBq and patients received an mean of 1.8 treatments, yielding an mean cumulative administered activity of 629 MBq, range: 111 to 999 MBq. The mean 24 h RAIU was 62 % among the 20,639 for whom an uptake value was recorded at first examination. Doses to 17 organs excluding the thyroid were estimated by multiplying the administered activity (MBq) by age- and uptake-dependent dose conversion factors (mGy MBq–1) for each organ published in ICRP Publication 53 (ICRP, 1988). Uptakes for those patients for whom an uptake measurement was not performed was based on a subgroup of 3,162 uptake measurements modeled for gender, age, number of treatments, year of treatment, hospital, type of

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TABLE 3.10—(continued).

British – therapeutic (Franklyn et al., 1999)

Not available

Not available

This study includes 1,228 males and 6,189 females who received 131I for treatment of hyperthyroidism in England (West Midlands Region) from 1950 to 1991, yielding 72,073 PY of follow-up. Patients received one (28.9 %), two (12.5 %), or three (2.5 %) 131I administrations and were grouped according to the administered activities: <220 MBq (49.3 %), 221 to 480 MBq (34 %), and >481 MBq (16.6 %). Thyroid absorbed doses were not given.

Former Soviet Union – Semipalatinsk Nuclear Test Site (Simon and Bouville, 2002)

Not available

350 – 3,800

The Semipalatinsk Nuclear Test Site was a nuclear test site of the former Soviet Union. It is located in Kazakhstan in eastern Asia 200 km southwest of the border of the Russian region of Altai. The Soviet Union performed 456 tests (including 86 atmospheric and 30 surface tests) of nuclear devices at the Semipalatinsk Nuclear Test Site from August 1949 to December 1962. The total energy yield of atmospheric nuclear explosions at the Semipalatinsk Nuclear Test Site was ~6.6 Mt. The greatest collective doses were received in the administrative districts (“raions”) of Abay (south of the test site) and Beskaragay (northwest of the test site) with lower doses received in Semipalatinsk City. The total collective dose

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

hyperthyroidism (Graves’ disease versus toxic nodular goiter), and administered activity. The thyroid dose was not estimated because the gland mass, intrathyroidal dose distribution, and effective half-life were generally not known.

/ 129

Study (reference)

Absorbed Dose (mGy) Mean

Dosimetrya

SD and/or Range

from external irradiation was 26,000 person-Sv for the populations living in those regions (Tsyb et al., 1990). Thyroid absorbed doses from both external and internal irradiation have been estimated to represent persons in various villages near the Semipalatinsk Nuclear Test Site at distances from a few tens of kilometers to ~350 km on the basis of measurements of exposure rates above ground, environmental transfer models, and information on typical lifestyle and dietary habits. Doses depended on a variety of factors, including village location, age, and lifestyle attributes which generally depended on ethnicity (Kazak, Russian, German, etc.). Representative whole-body and thyroid doses ranged from 0.2 to 900 mGy and from 0.3 to 3.8 Gy, respectively. In Russia, an estimate of 41,200 person-Sv for the collective effective dose received in the Altai Region of Russia has been reported (Shoikhet et al., 1999). German diagnostic (Hahn et al., 2001)

1.0c

0.5 – 1.6b

This study included 789 children and adolescents who received diagnostic administrations of 131I in the Germany from 1960 to 1979. The thyroid dose (D) in gray was estimated for each subject using the ICRP Publication 53 (ICRP, 1988) model. The administered 131I activity and uptake by the thyroid were

130 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.10—(continued).

a

In this table, the term, “doses,” refers specifically to “absorbed doses.” to 90th percentiles. c Median. b10th

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

obtained from the patients’ records. These values were missing in 1.3 % of participants. The values for age, thyroid weight, and the adjustment factor were interpolated with a third-order polynomial to calculate the dose for any age

/ 131

Study (reference)

Israeli tinea capitis (Ron et al., 1989; 1995)

New York City tinea capitis (Shore et al., 2003)

Absorbed Dose (mGy) Dosimetry Mean

SD and/or Range

For all children 93

45 – 500

For children receiving only one course of therapy 84

45 – 170

60

Not available

See “Dosimetry” column entry in Table 3.9 for “Israeli tinea capitis.”

A cohort of 2,224 children given x-ray treatment (mean age: 7.8 y) and 1,380 children given only topical medications for ringworm of the scalp (tinea capitis) at the New York University/Bellevue Hospital in New York City from 1940 through 1959 were followed (84 to 88 % of the cohort) for a median of 39 y. An epilating dose (unfiltered x rays, 100 kVp, 0.9 mm aluminum half-value layer) was given to five overlapping fields of the scalp over a time interval of 10 to 20 min. The exposure per field ranged from 0.077 to 0.098 C kg –1. The absorbed dose to the thyroid gland averaged ~0.06 Gy, with some variation depending on age at treatment and patient motion (Schulz and Albert, 1968).

132 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.11—Radiation dosimetry for major studies of thyroid nodules in relation to external or internal radiation exposure

1,360

30 – >10,000

/ 133

A cohort of 2,657 infants given x-ray treatment (median age: five weeks, with 95 % <34 weeks) for an “enlarged thymus” at 10 facilities in Rochester, New York between 1926 and 1957, along with 4,833 siblings, were followed (mean: 37 y) by mail survey through 1986. Information on the x-ray treatments (Hempelmann, 1967; Hempelmann et al., 1967; Saenger et al., 1960), including number of fields, tube voltage (75, 130, or 250 kVp), filtration (none, 4 mm aluminum, 1 mm aluminum, and 0.5 mm copper), target-to-skin distance (30, 40, or 50 cm), orientation (anterior versus posterior), and field size (3 × 5 to 10 × 10 cm), was extracted from the medical record and by interviews with the treating physicians. Thyroid doses were measured in an anthropomorphic one-week-old infant phantom (with calcium salts for bone, Microvan 1,600“ and beeswax for soft tissue, and polystyrene for lung) using an ion chamber placed in the region of the isthmus of the thyroid and a 250 kVp Westinghouse x-ray unit operated to duplicate the actual x-ray treatment conditions. The thyroid dose depended on whether the gland was in or out of the treatment field, decreasing over 2 to 3 mm from 100 % depth dose near the edge of the treatment field to 1 % immediately outside of the treatment field. Based on the anatomy of the thymus and thyroid in infants, it was assumed that anterior treatment fields 10 × 10 cm or larger exposed the thyroid to the full depth dose while fields 6 × 8 cm or less exposed it to scattered radiation only. The thyroid dose could be estimated for 91 % of the subjects; for the remaining 9 %, it was uncertain whether

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

Rochester thymus (Shore et al., 1993b)

Study (reference)

Absorbed Dose (mGy) Dosimetry Mean

SD and/or Range

the thyroid was in or out of the primary beam and they were excluded from dose-response analyses. The thyroid dose was markedly affected by whether the gland was inside or outside the primary x-ray beam, which depended on the patient orientation and port size [3 × 5 cm (14 %) or 4 × 5 cm (27 %) to 10 × 10 cm (14 %) or an open port (6 %)]. The thyroid dose distribution was highly skewed, with a dose range of 0.03 to >10 Gy, mean of 1.36 Gy, and median of 0.3 Gy (Saenger et al., 1960). Thymus (Janower and Miettinen, 1971)

400

Not available

A cohort of 511 children given x-ray treatment (mean age: 4.7 y) for an “enlarged thymus” at the Massachusetts Eye and Ear Infirmary in Boston, Massachusetts between 1924 and 1946, along with 506 children with similar illnesses and the siblings of both the irradiated and control subjects, were followed (mean: ~30 y). The x-ray treatment was delivered with a 100 kVp unit, a target-to-skin distance of 20 cm, and a maximum cone diameter of 20 cm; the added filtration was unknown. In 78 % of the cases, the total air exposure was 0.10 C kg –1, delivered in four treatments of 0.025 C kg –1 each at 10 d intervals over a total time of 30 d; 1 % of the patients received <0.10 C kg –1 and 11 % >0.1 C kg –1. An anterior port

134 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.11—(continued).

Chicago tonsils (Ron et al., 1995; Wong et al., 1996)

570

±270

/ 135

A cohort of 4,296 children (age at first treatment: males, 4.2 y; females, 4.7 y) was followed (16,142 PY of follow-up) who received radiation in childhood for benign conditions of the head and neck at Michael Reese Hospital in Chicago, Illinois from 1939 to 1962. Pertinent information on radiation therapy (Ron et al., 1995; Schneider et al., 1993), delivered using 200 kVp orthovoltage x rays (0.5 mm copper plus 0.5 mm aluminum added filtration, 1.2 mm copper half-value layer, and 50 cm target-to-skin distance) and consisting of three weekly treatments of 0.034 C kg –1 exposure in air for a total of 0.01 C kg –1 in air to each field, was extracted from the medical record. Usually, right and left lateral treatment fields (8 × 10 cm) were directed at the posterior larynx. Thyroid doses were estimated using a heterogeneous anthropomorphic 6 y old child phantom consisting of an actual skeleton and simulated lung and soft tissue containing calibrated TLDs throughout the thyroid and irradiated with a Philips RT250“ orthovoltage x-ray therapy unit. To estimate the thyroid dose (r50 %) for children of different ages, a correction factor, based on age-dependent height and weight and related to the distance of the field edge to the midpoint of the thyroid, was used.

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

(with the top of the field at the suprasternal notch) was used in 92 % of the cases and anterior and posterior ports in the remaining 8 %. The “thyroid” dose, of ~0.4 Gy, may be estimated as one-tenth of the exposure (0.10 C kg –1 = 400 R), based on thyroid dose measurements in an “infant” phantom irradiated in a grossly similar manner (Saenger et al., 1960).

Study (reference)

Absorbed Dose (mGy) Dosimetry Mean

SD and/or Range

Substantial uncertainty (greater than ~10 %) in the estimated thyroid dose resulted from ambiguity in the medical record regarding whether rectangular treatment fields were vertical (long dimension parallel to the spine resulting in a maximum thyroid dose estimate) or horizontal (long dimension perpendicular to the spine resulting in a minimum thyroid dose estimate). The thyroid absorbed dose (mean ± SD) was estimated as 0.57 ± 0.27 Gy to males and 0.58 ± 0.27 Gy to females. Boston lymphoid hyperplasia (Pottern et al., 1990; Ron et al., 1995)

240

±66 32 – 550

United States – diagnostic (FDA childhood 131I) (Hamilton et al., 1989)

~800

<100 – >20,000

See “Dosimetry” column entry in Table 3.9 for “Boston lymphoid hyperplasia.”

See “Dosimetry” column entry in Table 3.10 for “United States – diagnostic (FDA childhood 131I).”

136 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.11—(continued).

131

Not available

Not available

In the Cooperative Thyrotoxicosis Therapy Follow-Up Study, the occurrence of malignant and benign thyroid neoplasms was evaluated in 34,684 patients treated (with 131I, thyroidectomy, x rays, or combinations thereof) for hyperthyroidism at 26 facilities (25 in United States and one in England) between 1946 and 1968. In this series, the data on thyroid uptake and retention of 131I were inadequate to determine the thyroid dose. The analysis of the relationship between 131I thyroid dose and the development of thyroid neoplasms was based on the assumption that the clinical result of therapy is related to the dose, with 131I-treated patients stratified from highest to lowest doses as follows: hypothyroid within 1 y of treatment, hypothyroid later than 1 y after treatment, became and remained euthyroid, or required additional therapy to become nonhyperthyroid. No estimates of thyroid doses were presented, however.

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

I– therapeutic (Graves’ disease without preexisting nodules) (Dobyns et al., 1974)

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Study (reference)

Radium dial painters (Polednak, 1986)

Absorbed Dose (mGy) Dosimetry Mean

SD and/or Range

Dose Group 1: 18 mSv

<50 mSv 14 mSv

Dose Group 2: 105 mSv

<50 – 190 mSv 41 mSv

Dose Group 3: 1,140 mSv

t 200 mSv 1,810 mSv

Dose Group 4: 2,330 mSv

t 500 mSv 2,340 mSv

Total 420 mSv

1,160 mSv

The frequency of thyroid diseases (including tumors) was evaluated in 686 female radium dial painters, mostly in Connecticut, New Jersey, and Illinois, who were first employed before 1930 and who had a radium body-burden measurement during their lifetime (1958 to 1976). As noted, “doses” were expressed as dose equivalent (mSv) rather than absorbed dose (mGy). The total thyroid absorbed dose [derived in conventional units to reflect the analysis of Polednak (1986)] was based on numerous assumptions and calculated as the sum of the average internal soft-tissue alpha-ray dose from ingested radium and the external gamma-ray dose emitted by radium in the luminescent paint in the work environment. Internal radiation doses were mainly from 226Ra alpha rays, with gamma rays from daughter products of retained radon measured in exhaled breath by scintillation gamma counting using a thallium-activated sodium iodide [NaI (Tl)] crystal to estimate the individual’s current radium body burden (Stehney, 1955). The initial intake of 226Ra and 228Ra activity (typically of the order of 50 y earlier) was then calculated from this measured body burden using the retention function (Rtissue) of Norris et al. (1955). The average soft-tissue

138 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.11—(continued).

alpha-ray dose rate was DD = CE/M = 0.005 rad d–1 PCi–1 of 226

T

was then DD (T) = D

³

Rtissue dt. Therefore, DD (50 y) = 0.1 rad

0

PCi–1 at 50 y after ingestion of 226Ra. A quality factor of 10 was then applied to convert the alpha-ray doses to dose equivalents. The external gamma-ray dose at a distance d from the radium source was DJ (d) = f X mRa (1 m d–1)2 where f = 0.75 rad R–1 (O’Brien, 1976) and X = the exposure rate at 1 m from 1 g of 226Ra = 0.84 R h–1 g–1. Therefore, D (0.5 m) = 0.03 rad h–1 of J

/ 139

work or 5.9 rad y –1 of employment (assuming 250 8 h work days per year of employment) at a distance of 50 cm = 0.5 m from 1,200 Pg = 0.0012 g of 226Ra. A quality factor of one was applied to convert the gamma-ray doses to dose equivalents. The alpha-ray contribution to the total thyroid dose equivalent ranged from ~40 % in the <5 rem (n = 233) and the 5 to 19 rem (n = 226) groups to nearly 90 % in the t20 rem (n = 227) and the t50 rem (n = 94) groups.

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

Ra ingested, where C = the alpha-ray energy deposited per unit alpha-ray energy emitted per decay = 51.2 g rad MeV–1 d–1 PCi–1, E = the average unit alpha-ray energy emitted per 226Ra decay = 4.77 MeV decay–1, and M = the tissue mass = 50 kg = 50,000 gm for total-body soft tissue. The mean soft-tissue dose, and therefore the thyroid dose, since the time of ingestion T

Study (reference)

Nagasaki thyroid disease (Nagataki et al., 1994)

Hiroshima autopsy (Yoshimoto et al., 1995)

Absorbed Dose (mGy) Dosimetry Mean

SD and/or Range

390 – 600 depending on age and gender

0 – 5,900

The thyroid dose was determined by DS86 and the RBE of neutrons to gamma rays was set at 10. Each atomic-bomb survivor likely received external and internal radiation, and the external radiation could have been from the explosion and/or radioactive fallout. No dosimetric information is available on internal radiation and this dose contribution was ignored. Very little dosimetric information is available on external radiation from fallout and this dose contribution was likewise ignored.

Not available

0 – >500

To assess the radiogenic risk of latent benign and malignant thyroid disease, data were analyzed for 3,821 subjects collected in the course of autopsies of atomic-bomb survivors in Hiroshima from 1951 to 1985 by RERF. The dose estimates used were the DS86 thyroid organ doses, combining neutron and gamma-ray dose estimates into a total organ dose (not dose equivalent). In DS86, organ doses were computed as the gamma-ray dose plus 10 times the neutron dose and expressed in units of sievert, where the weighting factor of 10 is the RBE of atomic-bomb neutrons relative to atomic-bomb gamma rays.

140 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.11—(continued).

Skin hemangioma 226 Ra treatment in Stockholm, Sweden (Lundell et al., 1994) Skin hemangioma 226 Ra treatment in Gothenburg, Sweden (Lindberg et al., 1995)

13,000

0 – 76,000

See “Dosimetry” column entry in Table 3.9 for “Childhood cancer.”

260

<10 – 2,900

See “Dosimetry” column entry in Table 3.9 for “Skin hemangioma 226Ra treatment in Stockholm, Sweden.”

~120

17 – 120

See “Dosimetry” column entry in Table 3.9 for “Skin hemangioma 226Ra treatment in Gothenburg, Sweden.”

3.4 DOSIMETRY IN SPECIFIC EPIDEMIOLOGICAL STUDIES

Childhood cancer (Ron et al., 1995; Tucker et al., 1991)

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Study (reference)

Packer Hospital head and neck irradiation (Royce et al., 1979)

Absorbed Dose (mGy) Dosimetry Mean

SD and/or Range

Scalp 5,340

3,140

Tonsils 7,110

10,400

Neck 4,740

4,470

Chest 7,390

13,000

Combination 20,600

30,900

The occurrence of palpable thyroid abnormalities in 214 individuals with a verified history of EBRT (x-ray) head and neck irradiation at the Robert Packer Hospital in Sayre, Pennsylvania from 1937 to 1970 and in 243 concurrently examined nonirradiated persons (control subjects) was determined based on physical examination by two physicians unaware of the medical history of the examinees. The irradiation sites and site-specific averages and standards deviation were tabulated, but no information was provided on how radiation doses were determined. The overwhelming majority of subjects had received therapeutic irradiation to the tonsils and nasopharynx.

142 / 3. RADIATION DOSIMETRY AND DOSE RECONSTRUCTION

TABLE 3.11—(continued).

4. Radiation Effects This section provides an overview of the types of studies used to determine the effects of radiation on the thyroid. The earliest data are from animal experiments. A selected review of animal experiments is presented in Section 4.1 and in Appendix E. Before reviewing data from studies in humans, the types of epidemiologic studies as well as their strengths and weakness are reviewed in Section 4.2. Methodologic issues especially relevant to studies of thyroid cancer following radiation exposure are discussed in Section 4.3. These two introductory sections are followed by a review of the epidemiological data from human studies. The effects of radiation on human thyroid carcinogenesis will be emphasized since more scientific data are available for carcinogenesis than for other effects. Thyroid carcinogenesis following external exposure to radiation is reviewed in Section 4.4. The major studies that are used in this Report to estimate thyroid cancer risks following external radiation exposure are reviewed in this section. Additional studies of the risk of human thyroid cancer following exposure to external radiation are reviewed in Appendix F. Human studies on the risk of thyroid carcinogenesis following internal exposure to radiation are reviewed in Section 4.5. There are fewer human data available for estimating thyroid cancer risk following internal exposure than data available following external exposure. Studies of benign thyroid nodules following exposure to external and internal radiation are discussed in Section 4.6, and radiation effects on thyroid function are summarized in Section 4.7. Recent studies have described changes in oncogene expression following radiation exposure of the thyroid. These effects have the potential for adding to our basic understanding of the biological processes involved in carcinogenesis. In addition, if some molecular changes occur more frequently as a result of radiation exposure, these changes may be used retrospectively to determine the likely etiology of an individual’s thyroid cancer. Radiation effects on oncogene expression are reviewed in Section 4.8. Finally, radiation effects on the parathyroid glands have been observed. These effects are summarized in Section 4.9. A brief summary of Section 4 is presented in Section 4.10. 143

144 / 4. RADIATION EFFECTS 4.1 Animal Data Numerous animal experiments have been performed to determine the effects of external and internal radiation on the thyroid. A brief description and general conclusions of selected experiments are discussed below. These experiments are discussed in greater detail in Appendix E. The following brief review is divided into three sections. The first section discusses selected early experiments performed in rodents, the second section summarizes studies done in larger animals, and the third section reviews several experiments designed to determine RBE of thyroid doses due to external x rays compared to internal 131I exposure for thyroid carcinogenesis. 4.1.1

Experiments with Rodents

In rodent experiments done in the late 1940s and 1950s, the amount of 131I administered resulted in very large (and uncertain) thyroid doses. Radioactive iodine had then been recently introduced into clinical medicine to perform diagnostic thyroid tests and to treat some benign and malignant thyroid diseases. There was concern about the long-term consequences of the thyroid dose, especially for doses used for therapeutic procedures. This concern helps to explain why such large thyroid doses, 1,500 Gy in some experiments, were used in some early animal experiments. Fifteen hundred gray is ~10 to 20 times the dose used to treat hyperthyroidism (Becker and Hurley, 1996). Although relatively large numbers of animals were used in these experiments, there were few radiation-induced thyroid cancers. Most early experiments did not control for potentially important confounding variables such as the iodine content of the diet and the age and gender of the animal, and there continues to be uncertainty about the best species and strain of rodents to use in experiments designed to mimic the effect of radiation on thyroid carcinogenesis in humans. The results of early experiments on the carcinogenic effects of radiation of the thyroid were inconclusive. Doniach (1950) used the carcinogen acetylaminofluorene alone or in combination with 131I or methylthiouracil (MT) to induce thyroid cancers in rats. The author concluded that radioactive iodine increased the incidence of thyroid adenomas in all groups except for the acetylaminofluorene group. He also discussed the lack of consensus about the criteria that should be used to make the histological diagnosis of thyroid cancer. It was unclear whether the increase in the number of thyroid cancers was due to the dose alone, the increased stimulation of the

4.1 ANIMAL DATA

/ 145

thyroid caused by the radiation-induced hypothyroidism, or a combination of both (Goldberg and Chaikoff, 1951). By using propylthiouracil to induce hypothyroidism, researchers (Goldberg and Chaikoff, 1952) concluded that increased stimulation of the thyroid caused by induced hypothyroidism was not sufficient in itself to cause an increased incidence of thyroid cancer. In further experiments to determine the relative roles of thyroid stimulation versus thyroid radiation exposure in the induction of thyroid cancer these researchers induced hypothyroidism surgically and prevented hypothyroidism with the administration of thyroid hormone (Goldberg et al., 1964). These researchers concluded that it was likely that radiation was an initiating factor and thyrotropin stimulation was a promoting factor for thyroid carcinogenesis. In another experiment designed to determine the relative roles of thyrotropin stimulation and radiation in thyroid carcinogenesis, Doniach (1953) concluded that the combination of radiation and thyrotropin stimulation is more carcinogenic than either factor alone. Because high thyroid doses resulted in cell killing, lower doses resulted in higher incidences of radiation-induced thyroid cancers in rats (Lindsay et al., 1957). The same researchers did experiments on dose fractionation and concluded that dose fractionation did not decrease the carcinogenic effects of 131I; simultaneously they confirmed that lower doses were more carcinogenic (Potter et al., 1960). In an experiment using rats and mice, these researchers concluded that even smaller amounts of 131I such as 0.037 to 0.185 MBq in rats or 0.00925 to 0.0462 MBq in mice caused benign and malignant abnormalities of the thyroid. Researchers performing early studies on the carcinogenic effects of external radiation on the thyroid concluded that thyroid cancers induced by x rays were pathologically similar to those caused by 131I and to those occurring spontaneously in humans (Lindsay et al., 1961). In addition, in some animals, they exposed only one lobe of the thyroid. In these animals, benign abnormalities had a similar incidence in the exposed and unexposed lobes whereas thyroid cancer only occurred in the exposed lobe. The authors concluded that the benign abnormalities were due to the effects of TSH stimulation and that radiation exposure alone or in addition to TSH stimulation was needed for cancer induction. Experiments were performed to determine if gender was an important factor in 131I-induced thyroid cancer (Lindsay et al., 1963). These researchers concluded that the incidence of benign and malignant radioiodine-induced thyroid neoplasms was less in female rats than in male rats.

146 / 4. RADIATION EFFECTS In a 1963 review of his own work and the work of others, Doniach (1963; Doniach et al., 1963) concluded that: • •

131I

is carcinogenic to the rat thyroid; I can produce adenomas after 1 y, which may become malignant after 2 y (two-thirds of the rat’s lifespan); • the optimal carcinogenic dose is ~1 MBq of 131I in the young adult rat; and • an excess of TSH increases the incidence of adenomas and shortens the period before malignancies appear to within 15 months. 131

Doniach (1974) published the results of a study that was designed to confirm that low dose external irradiation of 1, 2.5, and 5 Gy could induce thyroid neoplasms. The author noted that an increase in TSH “may play a permissive role in the development of thyroid tumors following low dose x-radiation to the thyroid.” 4.1.2

Experiments in Larger Animals

Due to practical problems such as space and cost, there are fewer large animal studies than small animal studies of thyroid disease following radiation exposure. Some of these studies are summarized below. For example, 19 sheep were chronically fed daily doses of 131I, resulting in thyroid doses up to 1,000 Gy and increased thyroid neoplasms (15 adenomas and one fibrosarcoma) (Marks et al., 1957a; 1957b). An increase in the number of thyroid neoplasms has also been reported in beagle dogs exposed to varying doses of x rays of 0 to 18.2 Gy and/or 0 to 61.32 Gy of 131I (Lu et al., 1973). In 1997, the incidence of benign and neoplastic thyroid disease in beagles that had received a single whole-body exposure from an external 60Co source in the pre- and postnatal periods was reported (Benjamin et al., 1997). In this lifespan study involving 1,680 beagles, heritable lymphocytic thyroiditis with hypothyroidism was a major contributor to mortality. Throughout most of their lifespan the cumulative incidence of hypothyroidism was greater in the control dogs than in the irradiated dogs (Figure 4.1). Benign and malignant thyroid follicular neoplasms were common in these beagles. Twenty-eight percent of unirradiated dogs had one or more thyroid tumors compared with 26.5 % of irradiated dogs. Only dogs exposed at 70 d postpartum had a significantly increased incidence (41.5 %) of thyroid neoplasia over that in control animals. Interpretation of these results was complicated by the fact that the lifetime incidence of thyroid neoplasia was greater (55 %) in hypothyroid dogs and, that as stated above, more unirradiated dogs

4.1 ANIMAL DATA

/ 147

Fig. 4.1. Cumulative incidence of hypothyroidism in control (circle) and irradiated (square) beagles. All irradiated dogs at all doses and ages at exposure are grouped in this figure (Benjamin et al., 1997).

were hypothyroid. When the analysis was limited to euthyroid dogs, there was a statistically-significant increase in thyroid neoplasia only in dogs irradiated in the neonatal period (day two postpartum) and in the juvenile period (day 70 postpartum) (Figure 4.2). 4.1.3

Experiments to Determine Relative Biological Effectiveness

Studies using very large doses of 131I in rodents of >1.48 MBq are not included in the following review since cell killing predominates with such large doses. Only experiments where the same strain of animals was used to determine RBE of 131I are discussed. Abbatt et al. (1957) used post-radiation impairment of thyroid growth response (goitrogenesis) to compare RBE of 131I and x rays. Propylthiouracil was used to induce thyroid growth in rats three to four months after radiation exposure. The researchers concluded that 131I was 10-fold less effective than x rays in inhibiting goitrogenesis in this animal model. Two studies involving rats that were discussed in Section 4.1.1 have been used to estimate RBE of 131I and x rays (Lindsay et al., 1957; 1961). Based on these two experiments 131I appeared to be five times less effective than x rays in causing thyroid neoplasms. Another study using the incidence of neoplasms in rats compared RBE of 131I and x rays (Doniach, 1957; 1963). Doniach

148 / 4. RADIATION EFFECTS

Fig. 4.2. Lifetime incidence of benign adenomas, thyroid carcinomas, neoplasms (adenomas and carcinomas), or multiple neoplasms in unirradiated beagles compared to beagles exposed to various doses of radiation in the pre- and postnatal periods. Only the results from euthyroid dogs were included in this figure (Benjamin et al., 1997).

estimated 131I was 2 to 20 times less effective than x rays in promoting neoplasms in this animal model. A study comparing the effect of x rays and 131I exposures on the incidence of thyroid neoplasms (adenomas and carcinomas) in adult (age 110 to 130 d) male CBA mice was reported by Walinder (1972a; 1972b). He concluded that external x-ray radiation was 4 to 11 times more effective than 131I in producing adenomas and carcinomas. Walinder and Sjoden (1972) reported the results of a similar experiment using fetal mice and concluded that external x-ray radiation was 5 to 10 times more effective than 131I in producing adenomas and carcinomas. In contrast to the findings in the early studies just discussed, a larger well-designed study published in 1982 found less of a difference in the neoplastic effects of x rays and 131I (Lee et al., 1982). Prior to embarking on their study, they conducted a dosimetric

4.2 TYPES OF EPIDEMIOLOGIC STUDIES

/ 149

study to determine accurately the absorbed thyroid dose from both 131 I and x rays (Lee et al., 1979). The Lee study used 3,000 younger (six week old) rats of the same type (Long-Evans) as Lindsay et al. (1957; 1961; 1963). The thyroid doses used in the study by Lee et al. (1979) were lower than those in the earlier studies and were in the range of doses that is more relevant for environmental and diagnostic exposures. The dose-response curve shown in Figure 4.3a appears to show that x rays were approximately two times more effective than 131I in causing adenomas. The authors concluded: “[t]hough none of these ratios differ from unity, the possibility of x rays being more effective than 131I in thyroid adenoma induction cannot be excluded due to the large variability associated with these observations.” The dose-response curve for thyroid carcinoma was similar for external radiation and for 131I. The carcinogenic risk was approximately proportional to the square root of the dose, and was independent of dose rate (Figure 4.3b). The dose-response curves obtained for adenomas increased more rapidly with dose than predicted by a linear relationship, whereas the dose-response curve for thyroid carcinoma increased less rapidly with dose than predicted by a linear relationship. Critics of this study have pointed out that: • rats developed follicular rather than papillary thyroid cancers; • Long-Evans rats are unusual in that they have a high natural incidence of medullary thyroid cancers; • it is unclear why the dose response for adenomas and carcinomas would be different; and • small size of the rat thyroid would result in a more uniform dose with 131I. No important animal studies of RBE of published since 1982.

131I

and x rays have been

4.2 Types of Epidemiologic Studies Studies of populations exposed to radiation can be divided into four methodologic types: • cohort studies (follow-up of systematically defined groups with/without radiation exposure to determine disease incidence); • case-control studies (a comparison of persons with and without thyroid disease and their radiation exposure history, retrospectively determined);

150 / 4. RADIATION EFFECTS Fig. 4.3. Results from a study of rats by Lee et al. (1982). The solid line is the dose-response curve for 131I; the dashed line is the dose-response curve for x rays. The 95 % confidence interval is also shown. (a) graph of the dose-response curve for adenomas. The 131I curve was best described by the equation P = 2.40 × e0.123D and the x-ray curve was best described by the equation P = 2.45 × e0.0207D where P = the percentage of adenomas, and D = the thyroid dose in gray. (b) graph of the dose-response curve for carcinomas. The 131I curve was best described by the equation P = 7.47 × 10–4 (100 D + 10)0.6838 and the x-ray curve was best described by the equation P = 1.78 × 10–3 (100 D + 10)0.5348 where P = the percentage of carcinomas and D = the thyroid dose in gray (adapted from Lee et al., 1982).

4.2 TYPES OF EPIDEMIOLOGIC STUDIES

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• screening studies of populations exposed to radiation (with no attempt to assess a complete or random sample of a defined population); and • “ecological” studies (comparing rates of disease in various geographic areas where the average exposure levels differed). Some studies are blends of two types (e.g., screening study of persons from a defined exposed cohort, or case-control substudy nested within a cohort study). Occasionally, independent reviewers may also categorize the same study as a different methodological type. A schematic illustration of the fundamental differences between cohort studies and case-control studies is shown in Figure 4.4. Whenever possible, cohort and case-control studies are preferred. In the context of studies of radiation-induced thyroid cancer, cohort studies and case-control studies are viewed as stronger or more informative insofar as they have the following desirable characteristics: • Study groups (exposed and unexposed, or diseased and nondiseased) are enrolled during the same time frame (to avoid biases due to changes in technology and/or diagnostic criteria). The time frame of study should be clearly defined. • Long follow-up (>30 to 40 y) is necessary to determine the effects of attained age on risk estimates. • Study groups should be comparable except for the variable of interest (exposure or disease status). • Dose estimates are precise (i.e., with little uncertainty or misclassification), accurate, and objective (i.e., without systematic bias). • The range of individual doses is broad. The presence of study subjects with high doses substantially increases the statistical power and precision of a study. In general, a study’s power/precision is approximately a function of the meandose squared. A broad range of doses, along with a large study size and extended length of follow-up, is important for examining the shape of the dose-response curve. • The degree of dose fractionation and/or dose protraction is varied so the effects of this variable can be measured. • The number of exposed or diseased subjects is large. The power of a study generally increases as a function of the square root of the number of the study participants. A major limitation in most studies of radiation and thyroid cancer is the relatively small number of thyroid tumors.

152 / 4. RADIATION EFFECTS Fig. 4.4. In a cohort study, subjects are first identified based on their exposure status and then followed (usually prospectively for many years) to determine their disease status. In a case-control study, subjects are first identified based on the disease status and then their exposure history is retrospectively determined.

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Only four extant cohort studies have more than 100 thyroid cancers in the irradiated group (Dickman et al., 2003; Preston et al., 2007; Schneider et al., 1993; Thompson et al., 1994). • The range of ages at the time of exposure is large so the effects of this variable can be measured. Information should be obtained on possible confounding variables (e.g., other risk factors for thyroid disease or other radiation exposures) so that confounding effects can be controlled statistically if needed. Only a few confounding variables (e.g., age at time of exposure and the intensity of screening) have presently been clearly identified. Other variables (e.g., gender and ethnicity) also may be important. 4.2.1

Cohort Studies

A cohort study is one in which an exposed group and an unexposed group are defined (either prospectively at the time of exposure, or retrospectively according to exposure records) before the disease status of each individual is determined. Persons who have the disease(s) in question prior to the exposure or shortly after the exposure are excluded from the study. This group is then followed prospectively to determine disease rates over time; a comparable unexposed group is also generally defined and followed prospectively, although sometimes general population disease rates are used for the unexposed disease rate. A well-designed and well-executed cohort study is generally considered to provide the strongest evidence for defining the risk from an exposure. In such a study, individual doses can be objectively defined prior to disease onset so that there is no potential for bias in imputing exposure. In many cohort studies, there is no true unexposed group but rather varying exposures. A regression analysis of disease incidence or mortality against the amount of exposure can still be used to infer the existence of a risk and to quantify its magnitude. In fact, most of the better cohort studies use dose-response analyses rather than simple comparisons of exposed and unexposed groups. An additional desirable characteristic of a cohort study is that the followup rate is high (85 % or greater is preferable) and is comparable to that in the unexposed group across the dose range in the exposed groups. A cohort study permits complete and accurate disease outcome ascertainment with appropriate medical verification of disease. Because the study is initiated prior to the diagnosis of disease, the

154 / 4. RADIATION EFFECTS investigator has more control over the intensity of the work-up for disease and can establish uniform criteria for disease diagnosis. For thyroid cancer, the issue of comparability of thyroid surveillance across the dose range and in the unexposed group is critical. There are many small slow-growing thyroid cancers that never become clinically apparent (Tan and Gharib, 1997). If exposed patients are examined more comprehensively than nonexposed patients, more thyroid cancers will be diagnosed simply due to differences in work-up intensity (work-up or screening bias). A thyroid screening program (of the exposed and unexposed groups) is highly desirable to ensure that there is comparable surveillance for thyroid disease in all subjects. A less desirable alternative is to acquire information from subjects on the frequency of thyroid examinations to evaluate surveillance comparability between cohorts and across the dose range. The most common limitations of existing cohort studies of radiation and thyroid cancer include: uncertainties in individual dose estimates, small numbers of thyroid cancers, lack of uniform thyroid surveillance, a limited range of age at the time of exposure, small mean dose, and a relatively short (<30 y) duration of follow-up. If the incidence of the disease in question is low, the resources required for a cohort study are large. Under these circumstances, most of the resources are expended collecting information on subjects that never develop the disease of interest. Furthermore, the ideal period of observation is the lifetime of the subjects. Therefore, cohort studies require many years for completion. For these reasons, a case-control study is sometimes more practical to perform. Despite the potential logistic advantages of case-control studies, the most useful information about thyroid cancer and radiation has been derived from cohort studies. 4.2.2

Case-Control Studies

Case-control studies are more susceptible to two important scientific weaknesses, selection and information bias, than are cohort studies. Case-control studies performed using the general or a hospital-based population may have selection biases. The cases may not truly be a random sample of the population with the disease (e.g., cases selected from some hospitals may be underascertained; cases from major academic centers may be more complicated than cases from community hospitals). Likewise, the controls may not truly be a random sample of a population that is identical (with respect to confounding variables) to the case population except for the absence of disease. Selection bias is especially

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likely to occur if the public is aware and concerned about a possible association between an exposure and a disease. Under these circumstances, subjects who have been exposed are more likely to seek medical attention. Physicians are likely to intensify their search for the disease of interest in this self-selected population. If the degree of participation in a case-control study varies between cases and controls, subtle biases may be introduced. To minimize the problem of selection bias, a case-control study can be nested within a cohort. In this type of study, thyroid cancer cases that are detected in a cohort study are compared to several times as many matched noncases (controls) from the cohort, rather than to the entire cohort. This is done so that detailed information can be assembled on the cases and controls that would be too costly to obtain on the entire cohort [e.g., more detailed dosimetry (Boice et al., 1988) or information on possible confounding factors]. This type of case-control study normally has minimal selection biases, except when further information is elicited from case and control subjects so that participation rates become a factor. Information bias occurs when cases are more likely to recall exposures than are controls. Many case-control studies rely on ascertaining a history of exposure by self-reporting (e.g., Hallquist et al., 1994). If there is appreciable misreporting of past radiation exposures (especially under-reporting, but occasionally over-reporting of exposures), this can lead to increasing uncertainty in the analysis and, more importantly, to biased results if the case and control groups have different amounts of under- and overreporting. Several studies have shown substantial inaccuracy in reports of recalled diagnostic radiation exposures (Graham et al., 1963; Preston-Martin et al., 1985), so the potential for bias clearly exists. This potential bias normally causes one to interpret cautiously the results of such studies. However, not all case-control studies are subject to such biases; some investigators have found ways to obtain objective exposure histories for cases and controls (Hallquist et al., 1993a; 1993b; Inskip et al., 1995). 4.2.3

Clinical Screening Studies

A major strength of thyroid screening studies is that all participants have an objective, uniform thyroid examination. The recent adoption of diagnostic ultrasound as a screening procedure has further increased the objectivity and sensitivity of the examination procedures. Nevertheless, most extant thyroid screening studies to evaluate radiation effects have suffered from shortcomings that limit the utility and validity of the findings for purposes of risk estimation:

156 / 4. RADIATION EFFECTS • Many studies have not had clearly defined exposed groups that they seek to screen. Subjects in many screening studies are recruited from publicity campaigns. Without a defined study cohort, there is no way to know what selection biases may have been present. Some screening studies have been designed to minimize selection bias (Fjalling et al., 1986; Kaplan et al., 1988; Maxon et al., 1980; Pottern et al., 1990; Schneider et al., 1993). • Even when there is a defined study cohort, it is very difficult to attain a high participation rate when asymptomatic subjects are asked to come voluntarily for a medical examination. Low participation rates increase the potential for selection biases. It is of even greater concern when participation rates differ between exposed and unexposed groups or across the dose range; in such cases, selection factors may exert a differential effect that could either mask or exaggerate putative dose effects. • Except for a few studies (Maxon et al., 1980; Pottern et al., 1990; Royce et al., 1979; Wang et al., 1990a), published thyroid cancer screening studies have had no unirradiated (control) comparison group with equivalent screening. This limitation would tend to overestimate radiation risk since screening can greatly increase the number of thyroid cancers detected. • Most published thyroid cancer screening studies have been conducted at only one point in time. The effects of inadequate temporal sampling on the estimates of radiation risks are difficult to predict. More cases are usually detected the first time a population is screened. Therefore, lifetime risks may be overestimated if risk is extrapolated from a single screening. Limited temporal sampling provides little information on the temporal course of radiation risk. Only a few thyroid cancer screening studies (Bucci et al., 2001; Kerber et al., 1993; Schneider et al., 1993) have data from more than one point in time. 4.2.4

Ecological (Aggregate) Studies

In contrast to other types of epidemiological studies, an ecological study correlates the rates of disease in various geographic areas with the average dose estimates for those same areas. No information about the disease and exposure status of individuals is collected in an ecological study. Only average doses and average

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disease rates for aggregates of people are used. Because an ecological study does not use data on individuals, it is potentially subject to greater errors than other types of epidemiological studies. The problems of confounding and bias in ecological studies have been described by several authors (Greenland and Morgenstern, 1989; Greenland and Robins, 1994; Lubin, 1998; Piantadosi, 1994). Ecological studies are the weakest of all the epidemiological study designs discussed in this assessment. Until recently, relatively few ecological studies had been conducted regarding radiation exposure and thyroid cancer, so the method was of little importance in this area of research. However, the increase in childhood thyroid cancer following 131I exposure after the Chernobyl nuclear reactor accident in 1986 has spawned a number of ecological studies (Goulko et al., 1998; Ivanov and Tsyb, 1996; Ivanov et al., 1996; 2003; 2005; Jacob et al., 2000; Mahoney et al., 2004; Sobolev et al., 1997; Stsjazhko et al., 1996). Ecological studies can be conducted with relative ease by using cancer registry data and average thyroid dose estimates. Interpretation of the Chernobyl data is complicated by the fact that cancer registry data were collected based on geopolitical boundaries that may have little correlation with thyroid isodose curves. 4.3 Methodological Issues Regarding Studies of Radiation and Thyroid Tumors Two different empiric mathematical models are typically reported to summarize the dose-response relationship observed in epidemiology studies: EAR and ERR. The EAR model expresses the excess risk due to the exposure as being independent of the baseline risk and proportional to the absorbed dose. The simplest equation for EAR is: R = a + bD , where: R a b D

= = = =

(4.1)

total risk baseline risk risk coefficient absorbed dose

Because the risk from the exposure is simply added to the baseline risk, the EAR model is commonly referred to as the “additive” model. The ERR model expresses the excess risk due to the exposure as being proportional to the baseline risk as well as the exposure. The simplest equation for ERR is:

158 / 4. RADIATION EFFECTS R = a  1 + bD .

(4.2)

In this model the risk from the exposure is a product of the baseline risk and the dose. For this reason, this model is often referred to as the “multiplicative” model. These models are discussed in more detail in Section 5.1. In epidemiological studies, investigators often have little control over a variety of factors that may influence the results of their studies. Factors that may affect the quality and/or the results of studies of thyroid cancer and radiation exposure are discussed below. 4.3.1

Sources of Uncertainty in Epidemiological Studies

There are a number of uncertainties in drawing conclusions from epidemiological data regarding radiation and thyroid cancer (NCRP, 1997). As discussed in Section 3.1, the degree of error in thyroid dose estimates varies from study to study and can be appreciable. In some studies of patients treated with external radiation, the thyroid dose is potentially affected by the precise placement and the orientation of the treatment beam; these factors may determine whether the thyroid gland was inside or outside the primary beam. In the Japanese Atomic-Bomb Study, the organ absorbed dose uncertainty is ~30 %, based on DS02 (Preston et al., 2004). In medical studies of 131I exposure, there may be no or limited information on the thyroid uptake, the size of the thyroid gland and retention curves for individuals. In studies of environmental fallout exposures to 131I, the imputed doses have to be reconstructed for most or all the subjects. Dose reconstruction involves numerous assumptions based on varying amounts of data to support the assumed values and the data themselves may have substantial standard deviations. Under these conditions the dose uncertainties tend to be much larger for environmental exposures than for exposures that occur in a much more controlled setting (e.g., radiation therapy). Most risk estimates are derived from studies where the thyroid dose was >10 mGy. Risk observed in studies involving higher doses need to be extrapolated to estimate the risk at lower doses. Several dose-response models have been proposed to perform this extrapolation. Which model is correct is uncertain. When doses are very large, >10 Gy, the dose-response relationship may change due to the effects of cell killing. A major source of uncertainty lies in the small number of thyroid tumors available for analysis in many studies. This source of uncertainty, however, is directly accounted for in the statistical analyses (i.e., it is the basis for the statistical error term). Accounting for other sources of uncertainty is much more difficult.

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Several factors related to measuring the effects of the exposure contribute to uncertainty. No cohort has been studied for their entire lifetime, so estimates of lifetime risk require some extrapolation of the risk during the period of observation to the entire lifetime of the cohort. There is considerable uncertainty about how risk changes with TSE. In the context of thyroid cancer, it is unclear what constitutes complete ascertainment of thyroid cancers since many thyroid cancers will not become clinically apparent during the lifetime of the subject. Problems related to the use of thyroid cancer mortality or thyroid cancer incidence are discussed in more detail in Section 4.3.2. Inaccuracies in the recorded diagnosis also contribute to uncertainty. Further uncertainty is introduced when risk measured in one population is used to predict effects in other populations. The effects of age at exposure and gender have been studied most extensively but considerable uncertainty about how to account fully for these factors remains. Other factors that might affect risk have been less well studied. Some of these factors include ethnicity (Shore et al., 1993a), undocumented genetic variations in thyroid cancer radiation sensitivity (Perkel et al., 1988), dietary intake of stable iodine (Cardis et al., 2005; Shakhtarin et al., 2003), and other dietary factors that may interact with radiation in thyroid carcinogenesis (Shore et al., 1993a). 4.3.2

Incidence Versus Mortality Data

Studies of childhood exposure to radiation are much more informative than studies of adult exposure because the risk of thyroid cancer is much greater following childhood exposure. For thyroid cancers diagnosed during the first four or five decades of life, the case-fatality rates are very low, so that mortality rates are not a good reflection of thyroid cancer incidence. Based on all races and both genders for the United States (Ries et al., 2006), the approximate case-fatality rate was 1.1 % at ages 40 to 44 y and increased to 19.8 % at ages 70 to 74 y, as defined by the ratio of mortality to incidence rates at the respective ages (Figure 4.5). The 10 y relative survival rates for thyroid cancer in the United States are 93 % for papillary cancer and 85 % for follicular cancer across all ages (Hundahl et al., 1998). Five-year survival rates by age based on Ries et al. (2006) are shown in Figure 4.6. The age-specific casefatality rates associated with radiation-induced thyroid cancer are similar to spontaneously-occurring thyroid cancers (Shore et al., 1992). The vast majority of persons who develop thyroid cancer do not die from this disease. Although thyroid cancer mortality rates are a less ambiguous endpoint than incidence rates, studies

160 / 4. RADIATION EFFECTS

Fig. 4.5. Case fatality rate as a function of age and gender. Based on the 1998 to 2002 SEER data (Ries et al., 2006).

Fig. 4.6. Five-year survival rates for thyroid cancer as a function of age at the time of diagnosis (Ries et al., 2006)

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of mortality rates typically lack statistical power due to the small number of deaths. For this reason, studies of thyroid cancer incidence are preferred. 4.3.3

Micro-Carcinomas and Screening for Thyroid Disease

Thyroid cancer incidence depends greatly on the intensity of surveillance and the definition of disease since small thyroid cancers (i.e., microcarcinomas) that would never have become selfevident are very common. Autopsy studies have demonstrated that a substantial proportion (~6 to 13 %) of persons harbor such microcarcinomas of the thyroid [i.e., lesions that histopathologically show malignant changes but did not grow sufficiently to become clinically evident during the individual’s lifetime (Mortensen et al., 1955a; 1955b; Sampson et al., 1974; Solares et al., 2005)]. The proportion of small thyroid cancers found increases with age and is dependent on the comprehensiveness of the pathological examination of the thyroid gland. If the intensity of surveillance for persons with a history of radiation exposure is greater than for persons without a history of exposure, the apparent radiation effect will be overestimated. Thyroid screening, especially with diagnostic ultrasound, has the potential to detect a significant fraction of these medically insignificant micro-carcinomas (Tan and Gharib, 1997). In the Japanese Atomic-Bomb Study, thyroid screening procedures (primarily palpation of the thyroid; diagnostic ultrasound was not used systematically) were episodically used in the Adult Health Study (AHS) subgroup. Even this episodic and not highly sensitive screening yielded thyroid cancer incidence rates ~2.5 times higher than those observed in the non-AHS subgroup (Thompson et al., 1994) (Table 4.1). In the Chicago Head and Neck Irradiation Study (Section 4.4.4), the frequency of thyroid cancer detection before and after a screening program was initiated in an irradiated series using a clinical examination and a 99mTc pertechnetate scan was evaluated (Ron et al., 1992). The investigators found that screening increased the rate of thyroid cancer detection approximately sevenfold and for thyroid nodules the screening effect was ~17-fold above control levels. Such large screening effects can pose problems for epidemiological studies in which only a fraction of the study groups receive screening procedures in the course of normal medical care. This is of particular concern if screening intensity differs in the exposed group when compared to the unexposed controls. It is likewise of concern in ecological studies, such as the Chernobyl studies, in which cancer rates before and after the exposure episode are

Study

Normal Medical Care

Heightened Medical Surveillance

Ratio of Rates (heightened/normal)

Cases

Rate (%)

Cases

Rate (%)

109

15.6

200

109.6

7.0

Males

49

11.8

112

105.6

8.9

Females

60

21.1

88

115.1

5.5

153

1.1

72

2.8

2.5

23

0.4

13

1.4

3.5

130

1.5

59

3.6

2.4

Chicago head and neck irradiation

Atomic bomb Males Females

162 / 4. RADIATION EFFECTS

TABLE 4.1—Thyroid cancer rates by degree of medical surveillance (Ron et al., 1995).

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compared, since thyroid screening programs were greatly increased subsequent to the Chernobyl nuclear reactor accident (Mahoney et al., 2004). Another problem for epidemiological studies arising from thyroid screening is the uncertainty about the histopathology of thyroid nodules detected by diagnostic ultrasound. Only a fraction of these are subjected to FNA biopsy or surgery. Those not biopsied do not receive pathological diagnosis and pose a problem in interpretation of the study results. 4.4 Human Thyroid Cancer Following External Irradiation Several human epidemiological studies convincingly demonstrated that thyroid exposure to external radiation (e.g., x rays of varying energies and dose rates) can cause thyroid cancer. Many questions about the effects of modifying factors on the doseresponse curve remain unanswered. Age at exposure stands out as the most important modifying factor. The modifying effects of gender, attained age, and ethnicity are less certain (Section 5.3.2). There are many studies in the scientific literature reporting an increased incidence of thyroid cancer following external radiation. Due to the many potential problems discussed in Sections 4.2 and 4.3, only relatively few studies can be used to estimate the doseresponse relationship for external radiation and thyroid cancer. The data from seven of the most informative studies have been pooled and reanalyzed (Ron et al., 1995). Due to the large numbers of thyroid cancers (707) and the large range of doses and ages at the time of exposure, this pooled analysis provides the most reliable estimate of thyroid cancer risk following external radiation. This pooled analysis differs from a meta-analysis that only combines the summary statistics from multiple studies. In a pooled analysis, all of the primary data are reanalyzed using common definitions, statistical methods, and assumptions. Six of the seven studies (five cohort studies and one case-control study) used for the pooled analysis are discussed below. The cervical (female genital) cancer study is not discussed in this section because only adults were included in that study. The pooled data from these six studies have been further analyzed and the results of this analysis are presented in Section 5.3.1. In addition, two studies of thyroid cancer following external radiation exposure in children that were published contemporaneously with the pooled analysis are reviewed in this section (Lindberg et al., 1995; Lundell et al., 1994). Other studies of external exposure during childhood and adulthood are described in Appendix F.

164 / 4. RADIATION EFFECTS Except for the study of atomic-bomb survivors, the subjects of all of the studies discussed below were exposed to external radiation as medical treatment. Important methodological features of these six studies are listed in Table 4.2, results of these studies are listed in Table 4.3 and the strengths and limitations are listed in Table 4.4. Unless otherwise noted the values in Tables 4.2 and 4.3 are the values reported in the pooled analysis. These values may differ from the values found in the original paper and in subsequent reviews (Shore, 1992). In the descriptions below, data and results found in the original study will be presented first followed by data and results found in the pooled analysis (when applicable). Table 3.9 lists additional information about the dosimetry for each study. The point estimates and 95 % confidence interval for ERR for the eight studies that included children are shown in Figure 4.7. Two point estimates (with and without a zero intercept) are shown for the Tinea Capitis Study. No point estimate for ERR is shown for the Boston Lymphoid Hyperplasia Study in Figure 4.7 because none was calculated in the pooled analysis, as there were too few thyroid cancers in this study and no thyroid cancers were observed in the control group. The organ absorbed doses due to multidetector computed tomography approach organ absorbed doses for which there is direct epidemiologic evidence for an increase in cancer risk (Brenner and Hall, 2007). Since multidetector computed tomography is new and the dramatic increase in its utilization is recent, there is currently no direct epidemiologic evidence for an increase in risk following those diagnostic x-ray procedures. NAS/NRC (2006) recommended that epidemiologic studies of patients who have had high doses from diagnostic studies, especially children who have had multiple computed tomography studies, be performed. A comprehensive review of follow-up studies of patients treated with external radiation that resulted in high doses to the thyroid is not included here because the dose response in these patients is altered due to cell killing. Many studies have shown an increased risk of thyroid cancer following high doses to the thyroid, but the risk coefficient is less than that observed at lower doses (Bhatia et al., 2003). 4.4.1

Atomic-Bomb Survivors Study

RERF and its predecessor organization, the Atomic Bomb Casualty Commission, have studied the atomic-bomb survivors for more than 50 y. In a 1994 report (Thompson et al., 1994), the results for

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solid cancer incidence were described. A total of 40,795 exposed and 39,213 unexposed subjects was followed for a mean of 24.4 y (1958 to 1987) by using the Hiroshima and Nagasaki tumor registries to ascertain solid-tumor incidence (Ron et al., 1995). The mean dose in the irradiated group was 270 mGy with a range of 10 to 3,990 mGy. The mean age at irradiation was 28 y but ages varied across the entire lifespan. The individual DS86 dose estimates were based on atomic-bomb radiation yields, including distance from the hypocenter and shielding (Preston and Pierce, 1988). A total of 8,613 solid cancers was observed (4,327 in the exposed cohort and 4,286 in the unexposed cohort). The RERF analysis (Thompson et al., 1994) for thyroid cancer incidence differs from that in the pooled analysis in that for the younger age groups Thompson used 10 y age intervals for age at exposure whereas the pooled analysis used 5 y age intervals. In the RERF analysis, ERR at 1 Sv was 1.15 (95 % CI 0.48 to 2.14) for the entire population. Among those under age 20 y at irradiation, there were 59 thyroid cancers in the group receiving t10 mSv, and 25 thyroid cancers among those with <10 mSv. Risk due to radiation was confined mainly to those under age 20 y at the time of exposure; ERR was 9.46 (95 % CI 4.11 to 18.86) for those under age 10 y at the time of exposure and 3.02 (no confidence interval given) for those 10 to 19 y at the time of exposure; there was no significant elevation in risk (ERR = 0.10, 95 % CI <0.23 to 0.75) among those age 20 y or above at the time of exposure. ERR was statistically significant for ages 0 to 9 y and 10 to 19 y at irradiation. EAR was 1.61 [95 % CI 0.78 to 2.52 (104 PY Sv)–1] for the entire cohort. There was a large age at exposure effect on EAR. EARs were 4.37, 2.67 and 0.21 (104 PY Sv)–1 for those <10, 10 to 20, and >20 y old at the time of exposure, respectively. There was no clear evidence of nonlinearity in the dose-response relationship ( p = 0.17) or of a trend in EAR by TSE ( p = 0.46). The background incidence was three to four times as high for females as males and 2.5 times as high among those who received biennial examinations in AHS as those who did not. However, the dose-response slopes were similar by gender ( p > 0.5) and AHS status ( p > 0.4). In the pooled analysis (Ron et al., 1995), there were 225 thyroid cancers (132 in the exposed cohort and 93 in the unexposed cohort) in the atomic-bomb survivors for all ages at the time of exposure. Approximately 13,000 of both the exposed and unexposed cohorts were under the age of 15 y at the time of exposure. Forty of the 132 thyroid cancers in the exposed group occurred in persons under the age of 15 y at the time of exposure. For persons exposed under the age of 15 y, ERR Sv–1 was 4.7 (95 % CI 1.7 to 10.9) and EAR was 2.7 [95 % CI 1.2 to 4.6 (104 PY Sv)–1].

Study (reference)

Type of Study

Method of Cancer Ascertainment

Subjects Exposed/Unexposeda or Cases/Controls (percent female)

Mean Age (y) at Time of Exposure (range)

Follow-Up Duration (y)

Atomic-bomb survivors (<15 y at exposure) (Preston et al., 2007; Ron et al., 1995; Thompson et al., 1994)

Cohort

Tumor registries

~13,000/~13,000 53 %

~7.5 (0 – 14)

30

Rochester thymus (Ron et al., 1995; Shore et al., 1993a)

Cohort

Self-report, medical records

2,475/4,991 42 %

0.1 (0 – 1)

37

Israeli tinea capitis (Lubin et al., 2004; Ron et al., 1989; 1995; Sadetzki et al., 2006)

Cohort

Israel cancer registry, pathology record search

10,834/16,226 51 %

7 (0 – 15)

30

Chicago head and neck irradiation (Ron et al., 1995; Schneider et al., 1993)

Cohort; screening

Multiple screenings, questionnaire, medical records

2,634/0 41 %

4.4 (0 – 15)

33

Boston lymphoid hyperplasia (Pottern et al., 1990; Ron et al., 1995)

Cohort; screening

Palpation, self-report, medical records

1,195/1,063 39 %

6.9 (0.4 – 17.3)

29

166 / 4. RADIATION EFFECTS

TABLE 4.2—Methods and materials for major studies of thyroid cancer in relation to external radiation exposure during childhood or adolescence.

Childhood cancer (Ron et al., 1995; Tucker et al., 1991)

Case control

Clinics, tumor registries

22/82 (45 %)

7 (0 – 20)

5.5

Skin hemangioma 226Ra treatment in Stockholm, Sweden (Lundell et al., 1994)

Cohort

Tumor registry

14,351/0 67 %

0.5 <1.5

39

Skin hemangioma 226Ra treatment in Gothenburg, Sweden (Lindberg et al., 1995)

Cohort

Tumor registry

11,807/0 67 %

0.4 <1.0

31.4

some subjects, unexposed meant exposed to low dose.

4.4 HUMAN THYROID CANCER

aFor

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Thyroid Cancers Observed/Expected (ratio)

Mean Dose (Gy) (range)

ERR Gy –1 (95 % CI)

EAR (104 PY Gy)–1 (95 % CI)

Atomic-bomb survivors (<15 y at exposure) (Preston et al., 2007 ; Ron et al., 1995; Thompson et al., 1994)

40/19.2 (2.1)

0.27 (0.01 – 3.9)

4.7 (1.7 – 10.9)

2.7 (1.2 – 4.6)

Rochester thymus (Ron et al., 1995; Shore et al., 1993a; 1993b)

37/2.7 (13.4)

1.36 (0.03 – 11)

9.1 (3.6 – 28.8)

2.6 (1.7 – 3.6)

Israeli tinea capitis (Lubin et al., 2004; Ron et al., 1989; 1995; Sadetzki et al., 2006)a

44/11.2 (3.9)

0.09 (0.04 – 0.5)

32.5 (14 – 57)

7.6 (2.7 – 13)

Chicago head and neck irradiation (Ron et al., 1995; Schneider et al., 1993)

309/125 (2.5)

0.59 (0.01 – 5.8)

2.5 (0.6 – 26)

3.0 0.5 – 17

Boston lymphoid hyperplasia (Pottern et al., 1990; Ron et al., 1995)

10/0 NAb

0.24 (0.03 – 0.55)

NA NA

12 NA

Childhood cancer (Ron et al., 1995; Tucker et al., 1991)

23/0.4 (53)

12.5 (1 – 76)

1.1 (0.4 – 29)

0.4 (0.1 – 0.6)

Skin hemangioma 226Ra treatment in Stockholm, Sweden (Lundell et al., 1994)

17/7.5 (2.28)

0.26 (<0.01 – 28.5)

4.92 (1.26 – 10.19)

0.90 (0.23 – 1.87)

Study (reference)

168 / 4. RADIATION EFFECTS

TABLE 4.3—Results from major studies of thyroid cancer in relation to external radiation exposure during childhood or adolescence.

Skin hemangioma 226Ra treatment in Gothenburg, Sweden (Lindberg et al., 1995)

15/8 (1.88)

0.116 (0.017 – 0.115)

7.5 (0.4 – 18.1)

1.6 (0.092 – 3.9)

aIn a reanalysis of the Israel Tinea Capitis Study that accounts for dose uncertainties, Lubin et al. (2004) reported that the expected true mean dose (person-year weighted mean = 108 mGy) was larger than the original estimated dose (person-year weighted mean = 94 mGy) and ERR Gy –1 based on the expected true dose was 12 % smaller (ERR Gy –1 = 30.8, 95 % CI 14 to 64) than the original (ERR Gy –1 = 35.1, 95 % CI 16 to 73). The difference between the two ERR Gy –1 estimates was not statistically significant ( p = 0.73) and the patterns of risk did not change. b NA = not available.

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Study (reference)

Strengths

Limitations

Atomic-bomb survivors (<15 y at exposure) (Preston et al., 2007; Ron et al., 1995; Thompson et al., 1994)

• wide range of doses, individually estimated • large study, especially group with low doses • tumor registry follow-up • subjects had no underlying disease • high histological confirmation rate (93 %) • includes all ages • long follow-up

• dose uncertainties of ~30 % • possible selection factors associated with war • no cancer incidence data for first 13 y after bomb • possible selection factors for males of military age not in active service

Rochester thymus (Ron et al., 1995; Shore et al., 1993a; 1993b)

• long follow-up • complete thyroid cancer ascertainment • diagnosis confirmed by review of the medical records and pathology slide review in most cases of thyroid cancer • individual dosimetry; wide range of doses • significant dose response for doses <300 mGy • sibling controls • subjects had no underlying disease; some fractionated exposures • information on other potential risk modifiers • sibling control group

• relatively small number of thyroid cancers especially in the unexposed cohort • narrow age range • publicity concerning radiogenic thyroid cancer may have increased screening for the exposed subjects • ascertainment by mail questionnaire • dose uncertainties

170 / 4. RADIATION EFFECTS

TABLE 4.4—Strengths and limitations of major studies of thyroid cancer in relation to external radiation exposure during childhood or adolescence.

• dose uncertainties • limited range of doses • limited age range at time of exposure • subjects with tinea capitis may differ in some unknown way from subjects without the disease • no systematic screening • publicity concerning radiogenic thyroid cancer may have increased screening for the exposed subjects

Chicago head and neck irradiation (Ron et al., 1995; Schneider et al., 1993)

• large exposed population • multiple screenings • large number of cancers; high prevalence of thyroid disease • individual dosimetry • verification of self-reported thyroid disease • information on benign nodules included

• no nonexposed group • substantial thyroid dose uncertainty since orientation of radiation field was unknown for 70 % of subjects • only 69 % follow-up • incidental thyroid cancers included • possible screening bias

Boston lymphoid hyperplasia (Pottern et al., 1990; Ron et al., 1995)

• comparison group with same disease • individual dosimetry

• reported relative risk for thyroid nodularity, not thyroid cancer because there were few thyroid cancers • dose uncertainties present because orientation of radiation field unknown • ascertainment by self-report, and medical records

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• large exposed and nonexposed groups • two nonexposed groups including a sibling group • low-dose study • individual dosimetry • nearly complete thyroid ascertainment • virtually complete vital status follow-ups

4.4 HUMAN THYROID CANCER

Israeli tinea capitis (Lubin et al., 2004; Ron et al., 1989; 1995; Sadetzki et al., 2006; Schafer et al., 2001)

Study (reference)

Strengths

Limitations

Childhood cancer (Ron et al., 1995; Tucker et al., 1991)

• case-control study nested within a cohort • pathology review • individual dosimetry

• childhood cancer survivors, so chemotherapy etc. treatments • possible referral bias • high doses with possible cell-killing, short average follow-up

Skin hemangioma 226Ra treatment in Stockholm, Sweden (Lundell et al., 1994)

• individual dosimetry • large exposed population • long follow-up, wide range of thyroid doses

• small number of thyroid cancers • narrow range of ages at the time of exposure

Skin hemangioma 226Ra treatment in Gothenburg, Sweden (Lindberg et al., 1995)

• individual dosimetry • low thyroid dose • large exposed population • long follow-up

• small number of thyroid cancers • narrow range of ages at the time of exposure • narrow range of thyroid doses

172 / 4. RADIATION EFFECTS

TABLE 4.4—(continued).

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Fig. 4.7. Point estimates and 95 % confidence intervals of ERR Gy –1 for the pooled analysis and individual studies of childhood (<15 y old) exposure to external radiation. ERR Gy –1 for the Boston Lymphoid Hyperplasia Study was not calculated due to the small number (10) of thyroid cancers but these cases were included in the pooled analysis. For all analyses except for the second tinea capitis analysis, a zero intercept was assumed. The Stockholm and Gothenberg Hemangioma Studies were published contemporaneously with the pooled analysis and, therefore, the data were not included in the pooled analysis.

174 / 4. RADIATION EFFECTS An update of solid cancer incidence in the atomic-bomb survivors from 1958 to 1998 has been published (Preston et al., 2007). There were 206 thyroid cancer cases in the control population (dose <0.005 Gy) and 265 cases in the exposed population. The attributable fraction in the exposed population was 24.5 %. The gender averaged ERR was 0.57 with females having a 30 % higher risk. There was a strong effect of age at exposure with ERR Gy –1 estimated to be 1.21 (95 % CI 0.43 to 2.9), 0.57 (95 % CI 0.24 to 1.1), and 0.27 (95 % CI 0.05 to 0.77) for ages of exposure of 10, 30 and 50 y old, respectively. 4.4.2

Rochester Thymus Study

A total of 2,475 infants who received x-ray treatment for purported enlarged thymus glands and 4,991 sibling controls was followed for an average of 37 y by mail questionnaire, with verification of reported tumors by review of medical records (Shore et al., 1993a; 1993b). Eighteen percent of the exposed subjects were followed for more than 45 y. The median age at the time of exposure was five weeks. Ninety-five percent of the infants were less than age 34 weeks at the time of the x-ray treatment. The thyroid doses were highly skewed with a median dose of 300 mGy, an average dose of 1,360 mGy and a range of 30 to 11,000 mGy. Sixty-two percent of subjects were exposed to thyroid doses of <500 mGy. Doses were related principally to x-ray port size (ranging from 3 × 5 to 10 × 10 inches) and number of dose fractions. There was a modest amount of dose fractionation (54 % received a single exposure whereas 36 % received two treatments, and 11 % received three or more treatments with the fraction interval varying from 1 d to one week or more). Thirty-seven thyroid cancers were observed in the exposed group (1.52 expected) and five thyroid cancers were observed in the nonexposed group (2.85 expected). All of the thyroid cancers in the unexposed group occurred in women. There was a strong dose-response association. A statisticallysignificant dose-response association was found even when the dose range was limited to d 300 mGy but the limited statistical power precluded demonstration of a dose-response association at d 200 mGy. ERR Gy –1 was nine (90 % CI 4.2 to 21.7); EAR was 2.9 [90 % CI 2.1 to 3.9 (104 PY Gy)–1]. In the pooled analysis (Ron et al., 1995), the risk estimates for this population treated with x rays were similar {ERR Gy –1 = 9.1 (95 % CI 3.6 to 28.8) and EAR = 2.6 [95 % CI 1.7 to 3.6 (104 PY Gy)–1)]}. For the ERR model, there was a significant effect of TSE indicating that ERR was decreasing with time although

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thyroid cancer risk continued to be elevated for at least 45 y after exposure. For the EAR risk model there was no significant change relative to TSE. Many factors that might potentially modify risk were evaluated in this study. In the original analysis, statistically-significant increases in risk were associated with Jewish ethnicity (RR = 3.1, 95 % CI 1.5 to 6.2], increased maternal age at first live childbirth (RR = 3.2, 95 % CI 1.2 to 9.3) and education of >13 y (RR = 2.8, 95 % CI 1.2 to 8.4). 4.4.3

Israeli Tinea Capitis Study

A total of 10,834 children who received x-ray therapy for scalp ringworm (tinea capitis) and 16,226 unirradiated siblings or matched subjects was followed for an average of 30 y (Ron et al., 1989). Follow-up was by means of hospital records and the national tumor registry. The children were 0 to 15 y old at the time of x-ray treatment with a mean age of 7 y. The treatment protocol entailed x-irradiation to five fields (frontal, occipital, right lateral, left lateral, and vertex) on the scalp. One field was irradiated each day over five successive days. About 9 % of patients were given a second course of treatment. The mean thyroid dose was 90 mGy, with a range of 40 to 500 mGy depending on age and number of treatment courses (Werner et al., 1968). Two other studies also have essentially confirmed this dose estimate (Harley et al., 1976; Lee and Youmans, 1970). The original dose estimates for this study were increased by 50 % to account for subject movement. The occipital radiation port contributed most of the dose to the thyroid (Lubin et al., 2004; Schafer et al., 2001). There were 44 thyroid cancers within the irradiated group and 16 cases within the larger control group. A linear dose-response was observed. In the original analysis (Ron et al., 1989), ERR Gy –1 for thyroid cancer was calculated to be 27 (95 % CI 15 to 42) and EAR was 12.5 [95 % CI 5.8 to 16 (104 PY Gy)–1]. In the pooled analysis, ERR Gy –1 was 32.5 (95 % CI 14 to 57.1) and EAR was 7.6 [95 % CI 2.7 to 13 (104 PY Gy)–1]. The point estimate for the Tinea Capitis Study was three times higher than the point estimates for the other studies. Because of the high point estimate of the Tinea Capitis Study, supplemental analyses were performed. This study has two comparison groups (siblings and a nonrelated unexposed matched cohort). ERR Gy –1 was essentially the same using either comparison group. When a nonzero intercept was allowed, ERR Gy –1 was 6.6 (95 % CI <0 to 346.8) was much closer to ERR Gy –1 of the pooled analysis but the 95 % confidence

176 / 4. RADIATION EFFECTS intervals were very large. This study provides the strongest evidence for thyroid carcinogenesis at a relatively low dose. The effects of potential risk modifiers were also examined. Using the relative risk model, the authors concluded there was no significant effect of TSE in terms of relative risk for benign and malignant tumors. The relative risk for thyroid cancer for persons born in Asia or North Africa was approximately three times the risk for persons born in Israel. This increase was statistically significant (95 % CI 1 to 20). The relative risk for benign tumors was also three but was not statistically significant (95 % CI 0.67 to 50). There was no statistically-significant effect of gender on relative risk. A statisticallysignificant decrease in risk with increased age at exposure was seen for malignant and benign tumors. There was strong evidence for increasing absolute risk with TSE for malignant and benign tumors. There was a threefold increase in risk for thyroid cancer for persons born in Asia or North Africa compared to the risk for persons born in Israel (95 % CI 1.09 to 17.8). The increased risk for benign tumors was also three but was not statistically significant. The absolute risk for thyroid cancer for males was about one-tenth (95 % CI 0.0 to 0.4) of the risk for females. For benign tumors there was no significant difference due to gender. As with relative risk models, absolute risks for malignant and benign tumors were inversely related to age at exposure. The study was recently updated, adding another 16 y of followup, and now includes 103 thyroid cancers in the exposed group (rate of 211 per 105 PY), and 17 (rate of 70 per 105 PY) in sibling controls and 39 (rate of 79 per 105 PY) in the population controls (Sadetzski et al., 2006). ERR Gy –1 was 20.2 (95 % CI 11.8 to 32.3) and EAR was 9.9 [95 % CI 5.7 to 14.7 (104 PY Gy)–1]. A doseresponse analysis indicated that a linear model provided a reasonably good fit which was not significantly improved by adding a quadratic term. ERR was inversely related to the age at irradiation. ERR decreased significantly (but was still elevated) beyond 40 y after irradiation compared with 20 to 39 y after irradiation. The authors stated that the high risk coefficients observed in this study may be due to increased genetic susceptibility of their study population. 4.4.4

Chicago Head and Neck Irradiation Study

In 1973, a cohort of 5,300 patients who were treated for benign conditions of the head and neck at the Michael Reese Hospital in Chicago, Illinois between 1939 and 1962 was identified (Schneider et al., 1993). Eighty-one percent (4,296 patients) were treated

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before the age of 16 y. Individual dosimetry was calculated for 3,843 patients who were treated before age 16 y. Follow-up was available on 2,634 of these patients. The benign abnormalities of the head and neck that prompted therapy included enlarged tonsils, an enlarged thymus, or enlarged cervical lymph nodes. The mean age at the time of first exposure was 4.4 y (range 0 to 15). There was no unexposed comparison group. The three primary endpoints were: • surgically confirmed thyroid cancer; • surgically confirmed benign thyroid tumors; and • first and second endpoints plus clinically evident thyroid nodules that were not pathologically examined. A combination of clinical examinations and telephone interviews has been used for endpoint ascertainment. The mean length of follow-up was 33 y. For patients treated for enlarged tonsils, radiation treatment consisted of two lateral fields that resulted in exposures in air of 5.72 × 10–2 C kg –1 per field per treatment. The treatments were repeated weekly for three weeks for a total exposure of 17.2 × 10–2 C kg –1 per field. The mean thyroid dose was estimated as 590 mGy, with a range of 10 to 5,800 mGy. Twelve percent of patients had additional treatments. For 70 % of the patients, there was substantial dose uncertainty because the orientation of the rectangular fields used to treat them was unknown. On average, the thyroid dose was 55 % greater if the long axis of the rectangle were parallel to the long axis of the spine than if it were perpendicular to the long axis of the spine. The results of the analyses were similar irrespective of whether the minimum or maximum dose was used. This study was notable for the large number of thyroid cancers, 309 (161 in males and 148 in females). An approximately sevenfold increase in thyroid cancer incidence was attributed to the initiation of a screening program in 1974 (Ron et al., 1992) (Table 4.1). For benign thyroid nodules an even more dramatic (17-fold) screening effect was observed. The malignant cases account for 70.9 % of the thyroid cancer in the exposed subjects in the pooled analysis (Ron et al., 1995). A statistically-significant linear dose-response model was found. For thyroid cancer, ERR Gy –1 was three (95 % CI 1 to 4) and EAR was 1.7 [95 % CI 1.3 to 2.3 (104 PY Gy)–1] [the value of 0.17 10–4 PY rad as reported in the original paper was a misprint and should have been 0.017 10–4 PY rad (Ron et al., 1995)]. In the pooled analysis study, ERR Gy –1 was 2.5 (95 % CI 0.6 to 26) and EAR was 3 [95 % CI 0.5 to 17.1 (104 PY Gy)–1]. Thyroid cancer risk

178 / 4. RADIATION EFFECTS peaked at 25 to 29 y postexposure and remained elevated at least 40 y postexposure. The ERR risk model was preferred by the authors. A large number (549) of benign nodules were also identified. ERR Gy –1 for benign thyroid nodules was 8.2. In their analysis of potential risk modifying factors, there was no effect of gender on ERR Gy –1 for malignant or benign nodules. A statisticallysignificant inverse relationship between age at first exposure and ERR Gy –1 was observed. 4.4.5

Boston Lymphoid Hyperplasia Study

This cohort consisted of patients with lymphoid hyperplasia (97 % of patients had enlarged tonsils or adenoids) who were treated prior to the age of 18 y with external radiation (1,590 patients) or surgery (1,499 patients) at Boston’s Children’s Hospital Medical Center between 1938 and 1969 (Pottern et al., 1990). When the original medical records were reviewed, no specific selection criteria for a particular therapy (radiation or surgery) could be identified. Data were collected using a mailed questionnaire as well as a clinical examination. The primary endpoint was thyroid nodularity (self-reported or by clinical examination). The dose to the thyroid was calculated for each exposed patient. The authors estimated that the error in thyroid dosimetry was approximately r50 % and that a 1 cm movement with the thyroid at the edge of the radiation field would result in a minimum of a 30 % change in thyroid dose. The mean thyroid dose for questionnaire respondents and patients who were examined was 241 mGy, with a range of 32 to 550 mGy and 242 mGy, with a range of 32 to 530 mGy, respectively. The age at the time of exposure was 6.9 y with a range of 0.4 to 17.3 y. The percentage of exposed and unexposed patients who were located and alive was similar, 84 % (1,330/1,590) and 83 % (1,239/ 1,499), respectively. Questionnaires were mailed to 2,569 patients. Fewer unexposed patients returned the questionnaire, 85.8 % (1,063/1,239) compared to exposed patients, 89 % (1,195/1,330). A similar percentage of exposed responders (85.4 %: 1,020/1,195) and unexposed responders (82.7 %: 879/1,063) were eligible for a free clinical examination because they lived in the New England area or planned to visit the area during the study period. A smaller percentage of unexposed subjects (52 %: 457/879) who were eligible for a clinical examination were examined than were eligible exposed subjects (59 %: 602/1,020). The examinations were held between November 1981 and October 1983. The same questionnaire asked about the subject’s gender, race, religion, education, marital status, occupation, and medical history.

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Validation of all self-reported thyroid cancers, goiters, and nodules was attempted by requesting and reviewing the relevant medical records. The clinical examination consisted of an independent head and neck examination performed by two of four collaborating thyroidologists who were unaware of the patients’ exposure status and medical history. The two examiners then compared their results and resolved any discrepancies. Thyroid scintigraphy was only obtained in patients with definitely or equivocally palpable nodules. A blood sample was also obtained for thyroid hormone measurements. The results of this study are summarized in Table 4.5. No results were given for the thyroid hormone measurements. ERR Gy –1 for thyroid nodular disease was similar for males (seven) and females (six). A large ERR Gy –1 (39) for thyroid nodular disease was noted in exposed Jewish patients but this excess was primarily due to an exceptionally low risk among nonexposed Jewish patients. The risk of developing thyroid nodules was greater when the exposure occurred at younger ages (ERR Gy –1 was 27 for <4 y; 10 for 4 to 6 y; 1 for 7 to 18 y). Dose fractionation had no effect on risk. For this study, no individual EAR or ERR for thyroid cancer was calculated in the pooled analysis because of the small number of thyroid cancers. The authors noted that a much higher relative risk for radiation-induced thyroid nodules was estimated from the questionnaire than from the clinical examination data. Therefore, the radiation-induced risk of thyroid nodularity reported from questionnaire studies may overestimate the true risk. 4.4.6

Childhood Cancer Survivor Study

A roster of 9,170 patients who had survived any type of childhood cancer for >2 y was constructed from the records of 13 medical centers in the Canada, United States, and United Kingdom (Tucker et al., 1991). Twenty-three thyroid cancer cases were identified. These cases were matched with 89 control subjects who did not have a subsequent neoplasm. The controls were matched on the basis of histology of the first tumor, duration of follow-up, age at the time of diagnosis of the initial tumor, gender, and race. In the pooled analysis, only 22 cases and 82 controls were included due to insufficient dose information in one case and seven controls. The authors estimated the expected number of thyroid cancers using the Connecticut tumor registry. Twenty-three thyroid cancers were observed and only 0.4 were expected giving a relative risk of 53 (95 % CI 34 to 80). The mean follow-up time was 5.5 y (range 2 to 48 y). None of the chemotherapeutic agents was associated with a statistically-significant increase in thyroid cancer risk.

Relative Risk (95 % CI)

ERR Gy –1 (95 % CI)

0.3 % (3/1060) 0 % (0/3)

15.8 (4.7 – 63.5)

64 (18 – 225)

4.2 % (19/438) 2/19 5/17 2/5 2 0.2 % (2/1060)

2.7 (1.5 – 4.7)

7 (3 – 15)

Exposed

Nonexposed

By questionnaire Thyroid nodules Percent cancer

4.3 % (51/1192) 21.6 % (11/51)

By clinical exam Thyroid nodules Prior surgery Subsequent surgery New cancer diagnosis Total cancers Percent cancer

10.3 % (62/540) 32 % (21/62) 26.8 % (11/41) 2/11 13 1.1 % (13/1192)

180 / 4. RADIATION EFFECTS

TABLE 4.5—Results of the Boston Lymphoid Hyperplasia Study (Pottern et al., 1990).

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Sixty-eight percent of the thyroid cancers arose within the irradiation field; 27 % arose from within 5 to 10 cm of the irradiation field and 5 % arose >10 cm from the irradiation field. All cases received at least 1 Gy to the thyroid; ten controls had no radiation to the thyroid. For the cases, the mean dose to the thyroid was 12.5 Gy with a range of 1 to 76 Gy. Using the cases and controls who had received thyroid doses of <2 Gy as the referent group, the authors determined that the relative risk associated with thyroid doses >2 Gy was 13.1. The relative risk for thyroid doses of 2 to 9.99, 10 to 29.9, and >30 Gy were 14.2 (95 % CI 1.7 to 122), 13.5 (95 % CI 1.4 to 127), and 17.4 (95 % CI 1.4 to 217), respectively. The risk did not decrease in subjects who received >60 Gy to the thyroid. ERR Gy –1 for this case-control study was estimated in the pooled analysis to be 1.1 (0.4 to 29.4). This study had the lowest ERR Gy –1 of all of the studies in the pooled analysis when compared to other studies in which the exposure occurred at less than age 15 y. The lower ERR Gy –1 compared to those of other studies may be due to the effects of cell killing. The original authors had estimated an ERR Gy –1 of 4.24 and an EAR of 0.37 (104 PY Gy)–1. In the pooled analysis, ERR Gy –1 and an EAR were estimated to be 1.1 (95 % CI 0.4 to 29) and 0.4 [95 % CI 0.1 to 0.6 (104 PY Gy)–1], respectively. This study was the only one in the pooled analysis that showed an increase in ERR Gy –1 with age at exposure. 4.4.7

Swedish Skin Hemangioma Studies (Gothenburg and Stockholm)

A cohort of 14,351 infants with skin hemangiomas treated with external radiation involving beta particles, gamma rays and/or x rays were studied by investigators in Stockholm, Sweden (Lundell et al., 1994) to determine their thyroid cancer risk. Treatments were given during the period from 1920 to 1959. The infants, 67 % girls, were <18 months old at treatment with a mean age of six months. About 50 % of the hemangiomas were on the head or neck. About 82 % of the infants received 226Ra therapy and 18 % x-ray therapy (mostly contact therapy). The mean thyroid dose was 260 mGy with a range of <10 to 28,500 mGy. There was an elevated risk of thyroid cancer, with the standardized incidence ratio (SIR) equal to 2.28 (95 % CI 1.3 to 3.7) based on 17 cancers. Baseline cancer rates were assumed to be the same as the rates reported for the population of Stockholm. ERR Gy –1 was estimated to be 4.92 (95 % CI 1.26 to 10.19) and there was a nonsignificant decrease in ERR Gy –1 with increasing TSE. The thyroid cancer excess persisted at least 40 y after exposure. EAR was 0.90 [95 % CI 0.23 to 1.87 (104 PY Gy)–1] and did not

182 / 4. RADIATION EFFECTS demonstrate any trend with time after exposure. The age range of the subjects was too narrow to measure an effect of age at the time of exposure. A cohort of 11,807 infants treated with 226Ra for skin hemangiomas between 1930 and 1965 was studied by investigators in Gothenburg, Sweden (Lindberg et al., 1995), to determine their overall cancer incidence. Thirty-seven percent of treated hemangiomas were located on the head and neck. The median age at the time of treatment was five months; 88 % of infants were treated before the age of 12 months, and only 4.5 % were first treated after the age of 18 months. Absorbed doses to 11 organs were calculated for each infant using a phantom of a five- to six-month-old child. No correction was made for different body sizes according to the age of the infant. The mean dose to the thyroid was 0.12 Gy. The mean length of follow-up was 31 y. A total of 248 cancers was observed and the SIR was 1.21 (95 % CI 1.06 to 1.37). The expected numbers of cancers were determined by using age- and gender-matched cancer incidence for the Swedish population. Statistically-significant increases were found for cancers of the central nervous system (34 cases: SIR = 1.85, 95 % CI 1.28 to 2.59), thyroid (15 cases: SIR = 1.88, 95 % CI 1.05 to 3.09), and other endocrine glands (23 cases: SIR = 2.58, 95 % CI 1.64 to 3.87). Our review of these data provides an estimated ERR Gy –1 for thyroid cancer of 7.3 (95 % CI 0.4 to 18.1). 4.5 Human Thyroid Cancer Following Internal Irradiation The direct epidemiological evidence demonstrating that thyroid exposure to internal irradiation causes thyroid cancer is much sparser than the evidence for external irradiation. Additional data are being accrued from studies of population exposures in countries (Belarus, Kazakhstan, Russia and Ukraine) of the former Soviet Union; the dosimetry in studies of environmental exposures is, however, inherently uncertain. Some epidemiological and experimental data suggest that 131I is not as effective in inducing thyroid malignancies as external radiation (NCRP, 1985a; Shore, 1992; UNSCEAR, 1994), but the early and large increase in thyroid cancer incidence among children living near the Chernobyl nuclear reactor accident has become a catalyst for reevaluating the tumorigenic potential of 131I (UNSCEAR, 2000a). Historically, the biological effectiveness of 131I was thought to be considerably less than x or gamma radiation because of differences in small scale dosimetry (cellular level) and dose rate.

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Prior to the Chernobyl nuclear reactor accident, information on the thyroid cancer risk from 131I exposure was largely from cohort studies of adult patients receiving diagnostic examinations or treatment for hyperthyroidism. From the late 1940s until the early 1970s, over 10 million adults had diagnostic thyroid imaging studies using up to 3.7 MBq of 131I (Becker, 1989). These diagnostic studies resulted in thyroid doses of 1 Gy in adults. Technetium-99m pertechnetate was introduced into clinical practice in the early 1970s and largely replaced 131I for imaging the thyroid because of its lower thyroid dose (~100 times less per study) and better imaging characteristics. In the United States, 131I continues to be the treatment of choice for adult hyperthyroidism (Weetman, 2000a; 2000b). Over two million patients with Graves’ disease have been treated with 131I since the late 1940s (Rivkees et al., 1998). Hyperthyroidism is one of the few nonmalignant diseases still treated by radiation. Due to concerns about radiation-induced malignancies, 131I therapy is less commonly used in pediatric patients (Rivkees et al., 1998). Most epidemiologic studies show that the medical use of 131I in adults is not associated with large increases in thyroid cancer incidence or mortality, but the risk of developing thyroid cancer following childhood 131I diagnostic or therapeutic exposure has not yet been adequately quantified. Important methodological features of these studies are listed in Table 4.6, results of these studies are listed in Table 4.7, and strengths and weaknesses are listed in Table 4.8. In addition to the problem of the limited data currently available on childhood exposure to 131I, the large uncertainties associated with dose estimation for internal exposure increases the difficulties in quantifying the risk per unit absorbed dose. Data from studies of persons exposed to radioiodine contamination of the environment in the Marshall Islands and in states downwind from NTS provided some evidence of an association between 131I exposure and an increased risk of thyroid neoplastic disease. More recently, studies of children exposed to radioiodine as a result of the Chernobyl nuclear reactor accident, leave little doubt that radioiodine exposure can result in thyroid cancer, especially when the exposure occurs in childhood. A report of a descriptive epidemiologic study of cancer mortality among residents of counties near the Hanford Nuclear Facility in Richland, Washington (Boice, 2006) includes a summary of studies related to radiation-induced thyroid cancer, including from exposure to 131I. 4.5.1

Diagnostic Iodine-131 Studies

4.5.1.1 Swedish Diagnostic 131I Study. In 1980, the initial reports of Swedish patients exposed to 131I for diagnostic thyroid imaging

Study (reference)

Type of Study

Method of Cancer Ascertainment

Swedish diagnostic (Dickman et al., 2003; Hall et al., 1996a; 1996b)

Cohort

Tumor registries

FDA diagnostic (Hamilton et al., 1989)

Cohort

Questionnaire, medical records

Swedish therapeutic (Holm et al., 1991)

Cohort

Tumor registries

FDA therapeutic (Franklyn et al., 1998; Ron et al., 1998)

Cohort

Death registry

British hyperthyroid (Franklyn et al., 1999)

Cohort

Tumor registries

German diagnostic (Hahn et al., 2001)

Cohort

Medical records, follow-up

a

NA =

not available. range.

bInter-quartile

Subjects Exposed/Unexposed or Cases/Controls Percent Female

Mean Age ( y) at Time of Exposure (range)

36,792/0 80 %

43 (1 – 75)

24

3,503/NAa NA

10.5 (1 – 20)

27

10,552/0 82 %

57 (13 – 74)

15 (1 – 28)

18,020/10,228 79 %

46.5

21.2

7,417/0 83 %

57

~10

789/1,118 74 %

14.9 (12.5 – 16.6)b

20.9 (12.7 –32.7)b

Follow-Up Duration (y)

184 / 4. RADIATION EFFECTS

TABLE 4.6—Methodologic characteristics of major studies of thyroid cancer in relation to medical exposure to 131I.

TABLE 4.7—Results from major studies of thyroid cancer in relation to medical exposure to 131I. Mean Dose (mGy) (range)

129/—

129/95.6 1.35 (1.05 – 1.71)

1,100 (0 – 40,500)

4/1

4/2.53 2

800 (0 – >20,000)

Swedish therapeutic (Holm et al., 1991)

18/—

18/13.9 1.29 (0.76 – 2.03)

>10,000

U.S. therapeutic (Ron et al., 1998)

24/4

24/6.09 3.94 (2.52 – 5.86)

>50,000 to 70,000a

British hyperthyroid (Franklyn et al., 1999)

9/—

9/2.8 3.25 (1.69 – 6.25)

Used MBq as surrogate for dose

German diagnostic (Hahn et al., 2001)

2/3

2/2.32 0.86 (0.14 – 5.13)

1,000 500 – 1,600b

Observed Thyroid Cancers Exposed/Unexposed

Swedish diagnostic (Dickman et al., 2003; Hall et al., 1996a) FDA diagnostic (Hamilton et al., 1989)

a

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Individual thyroid doses not calculated. range

bInter-quartile

4.5 HUMAN THYROID CANCER

Thyroid Cancers Observed/Expected Ratio (95 % CI)

Study (reference)

Study (reference)

Strengths

Limitations

Swedish diagnostic (Dickman et al., 2003; Hall et al., 1996b)

• unbiased and complete ascertainment of thyroid cancers • known amount of 131I administered • large range of thyroid doses • largest study of thyroid cancer and radiation

• small number of subjects under the age of 20 y • information on thyroid size available only for 50 % of subjects

FDA diagnostic (Hamilton et al., 1989)

• known amount of 131I administered • large range of thyroid doses • largest study of thyroid cancer and diagnostic 131I exposure under the age of 20 y

• small number of subjects • thyroid cancer ascertainment dependent on self-reports • relatively low rates of participation

Swedish therapeutic (Holm et al., 1991)

• known amount of 131I administered • includes incidence and mortality data for all cancers

• short follow-up period • cell killing • small number of subjects under the age of 20 y

U.S. therapeutic (Ron et al., 1998)

• known amount of 131I administered • internal and external control group

• short follow-up period • cell killing • small number of subjects under the age of 20 y • includes only mortality data for all cancers

186 / 4. RADIATION EFFECTS

TABLE 4.8—Strengths and limitations of major studies of thyroid cancer in relation to medical exposure to 131I.

British hyperthyroid (Franklyn et al., 1999)

• known amount of 131I administered • includes cancer incidence and mortality

• short follow-up period • cell killing • small number of subjects under the age of 20 y • very few thyroid cancers (9) • used megabecquerel as surrogate for thyroid and organ dose • focus is on secondary cancers, not thyroid cancers

German diagnostic (Hahn et al., 2001)

• known amount of 131I administered • includes children • internal control group

• low participation rates may introduce bias • few children under the age of 10 y • small number of subjects 4.5 HUMAN THYROID CANCER

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188 / 4. RADIATION EFFECTS studies were published (Holm et al., 1980a; 1980b; 1980c). After the Chernobyl nuclear reactor accident, this initial study was expanded (Holm et al., 1988). Since that time, several updates have been published (Dickman et al., 2003; Hall et al., 1996b; Holm et al., 1989; 1991). This is the largest study of patients who had been exposed to 131I for diagnostic studies of the thyroid. For this present review, the values from the most recent publication (Dickman et al., 2003) are cited and discussed below. The cohort consists of 36,792 Swedish patients from seven university hospitals who were under the age of 75 y when given 131I for diagnostic thyroid imaging in the time period from 1952 to 1969. The most recent study (Dickman et al., 2003) included an additional 1,767 patients who were exposed to external radiation therapy to the neck prior to the administration of 131I. This subset of patients provided an opportunity to study the combined effects of these two types of thyroid exposures. Approximately 32 % of patients were referred for diagnostic imaging because a thyroid tumor was suspected. Other indications for diagnostic imaging included hyperthyroidism (42 %), hypothyroidism (17 %), and hypercalcemia (8 %). Patients with a suspected thyroid tumor were given a larger amount of 131I (i.e., 2.4 versus 1.7 MBq which resulted in a larger thyroid dose of 1.37 versus 0.94 Gy). The mean age at first exam was 43 y and only 7 % of the study population was under age 20 y at the time of first exam; <1 % were under age 10 y. The mean dose to the thyroid gland was 1.1 Gy. Dose estimates were based on the amount of 131I administered and the 24 h thyroid RAIU. Information on thyroid gland size was available for nearly half of the patients. Five or more years after exposure, 129 thyroid cancers (96 papillary or follicular, 27 anaplastic or medullary, one sarcoma, five of uncertain histology) developed with an SIR of 1.35 (95 % CI 1.05 to 1.71). The elevated risk was confined to patients with suspected thyroid tumors with an SIR of 3.5 (95 % CI 2.7 to 4.4); patients who received external radiation therapy had an SIR of 9.8 (95 % CI 6.3 to 14.6). The risk was significantly higher in males, with an SIR of 12.69 (95 % CI 7.25 to 20.60), referred for suspected thyroid tumors, than in females (SIR = 2.86, 95 % CI 2.14 to 3.74). No excess risk or dose response was noted among patients referred for other reasons with an SIR of 0.91 (95 % CI 0.64 to 1.26). Among the 2,367 adolescents and young adults with an average thyroid dose of 1.5 Gy, three thyroid malignancies were observed compared with three expected based on background national rates (SIR = 1.01, 95 % CI 0.21 to 2.96). Two cancers occurred among patients without suspected thyroid tumors (SIR = 0.96, 95 % CI 0.12 to 3.46).

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The authors did not calculate an ERR Gy –1 since no excess risk was observed except in the subset studied because they were suspected of having a thyroid tumor. However, such limited data do not allow for definite statements about childhood exposures to 131I. In a clinical examination of a subgroup of 1,005 adult Swedish women who received 131I diagnostic examinations with a mean dose of 0.54 Gy and 248 nonexposed women, no excess of thyroid nodules or cancer was found (Hall et al., 1996b). The prevalence of thyroid nodules, however, was associated with increasing dose among exposed women (ERR Gy –1 = 0.9, 95 % CI 0.3 to 2.3). These results are suggestive of a small excess of thyroid nodularity, but not cancer, following adult 131I exposure. 4.5.1.2 FDA Childhood Diagnostic 131I Study. A follow-up study of 3,503 U.S. patients who received 131I for diagnostic thyroid procedures before age 20 y has been reported (Hamilton et al., 1989). This cohort was identified by reviewing the records of patients receiving 131I at any of the 21 participating health centers between January 1, 1946 and December 31, 1967. A hospital comparison group (test control group) of patients who had thyroid function tests and did not have 131I exposure was also identified. This comparison group was matched for age, race, gender and date of testing. A second comparison group (diagnostic control group) was made up of siblings of the exposed patients. All study participants were mailed a questionnaire to determine their current health status. Death certificates were obtained for subjects reported to have died during the follow-up period. Pathology reports were requested for all subjects who reported having had thyroid surgery. Approximately 68 % (3,503/5,171) of the eligible exposed subjects returned the questionnaire. The mean and median age at the time of exposure was 10.5 and 10 y, respectively. Thyroid dose calculations were based on the activity administered, the percent uptake, and the estimated weight of the thyroid gland. The mean and median thyroid doses were estimated to be ~0.9 and 0.30 Gy, respectively, but the authors stated that the doses were probably higher because examinations for which some data were lacking were not included in the dosimetry calculations. Nineteen eligible patients reported having had thyroid surgery (15 exposed, three test control, one diagnostic control). Sixteen surgeries confirmed the diagnosis of a thyroid tumor. Six of the thyroid tumors were cancer (four thyroid cancers in the exposed group and one in the test control). The relative risk was 2.96 (95 % CI 0.3 to 70). The expected number of cancers was 3.7 yielding an SIR of only 1.1 relative to SEER data (Ries et al., 2006) as an external comparison group.

190 / 4. RADIATION EFFECTS 4.5.1.3 German Diagnostic 131I Study in Children. To determine the carcinogenic effects of diagnostic amounts of 131I on the juvenile thyroid gland, a multicenter retrospective cohort study was conducted on 4,973 subjects who either had been referred for diagnostic tests using uptake of 131I (2,262) or, had a diagnostic procedure on the thyroid without 131I (2,711) before the age of 18 y (Hahn et al., 2001). The most common reason for the initial referral in both groups was goiter. The median age at the time of initial referral was 14.9 y for the exposed groups and 13.8 y for the unexposed group. Only 147 of the 789 children in the exposed group were under the age of 10 y at the time of exposure. Follow-up examinations were conducted after a mean period of 20 y after the first examination in 35 % of the exposed subjects (789) and in 41 % of the nonexposed subjects (1,118). Iodine-131 dosimetry of the thyroid was carried out according to ICRP Publication No. 53 (ICRP, 1988), and the median thyroid dose was 1 Gy. Younger children received lower thyroid doses (e.g., 0.6 Gy for children 5 y and under). In the exposed group, two thyroid cancers were found during 16,500 PY, compared to three cancers in the nonexposed group during 21,000 PY. The relative risk for the exposed group was 0.86 (95 % CI 0.14 to 5.13). The study did not demonstrate an increased risk for thyroid cancer after administration of 131I in childhood. The authors noted that their study does not contradict the assumption that there is an age group, which is highly sensitive to an increased risk of thyroid carcinoma after 131I exposure. The inability of this study to detect this risk may be due to the small number of children exposed at an early age. 4.5.1.4 Summary of Thyroid Cancers Following Diagnostic Internal Irradiation with 131I. Two factors negatively impact the ability to draw conclusions from published studies of patients following diagnostic internal irradiation with 131I. First, although patients examined before age 20 y with diagnostic 131I received substantial doses to the thyroid, few patients were examined with 131I before age 20 y; therefore the number of subsequent thyroid cancers observed in this population was very small. Second, and more importantly, nearly all of the patients examined before the age of 20 y were examined during the second decade of life (i.e., between ages 10 to 20 y). In accordance with the analyses by Lubin and Ron (1998), the risk from irradiation at ages 10 to 14 y is only ~20 % as great as that at ages 0 to 4 y. Based on the atomic-bomb survivor data, persons exposed at ages 15 to 19 y have even less risk than those exposed between the ages of 10 to 14 y (Thompson et al., 1994).

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Therapeutic Iodine-131 Studies

Hyperthyroidism is uncommon in children. Patients studied after treatment with 131I for hyperthyroidism have almost all been adults. The treatment goal is to deliver 60 to 100 Gy to the thyroid (Becker and Hurley, 1996). For every patient, there is considerable uncertainty about the dose to the thyroid since the dose depends on several important factors in addition to the amount of administered activity. These additional important factors have been discussed in Section 3.3. With thyroid doses in the therapeutic range, ERR Gy –1 for children receiving external radiation begins to level off, probably due to cell killing (Ron et al., 1995). If cell killing is occurring, extrapolation using a linear dose-response model and data from studies of populations exposed to therapeutic amounts of 131I would underestimate thyroid cancer risks at low doses. 4.5.2.1 Swedish Hyperthyroid Study. The thyroid cancer risk in a population of Swedish patients treated with 131I for hyperthyroidism or severe coronary artery disease was first reported in 1980 (Holm et al., 1980a; 1980b; 1980c). Since that time, several updates have been published (Hall and Holm, 1997; Holm, 1984; Holm et al., 1991). The medical records of seven university hospitals in Sweden were reviewed to identify adult patients under the age of 75 y, treated between 1950 to 1975 with 131I for hyperthyroidism (over 40 % of the patients had toxic nodular goiter). This cohort consisted of 10,552 patients (82 % women). The mean age at the time of first exposure was 57 y (range 13 to 74 y). Data were provided about the number of treatments given (one treatment: 59 %; two treatments: 27 %; three or more treatments: 14 %). The mean administered activity was 507 MBq. Larger amounts of 131I were given to patients with toxic nodular goiter, 700 MBq than with Graves’ disease, 359 MBq. The dose to multiple organs was determined. The mean thyroid dose was >100 Gy. Overall cancer incidence was determined by record linkage with the Swedish Cancer Registry for the period from 1958 to 1985. The expected numbers of cancers was determined by using age and gender matched cancer incidence data from the Swedish Cancer Registry. Slightly more total cancers (1,543) were observed than expected 1 y or more after the first treatment with 131I (SIR = 1.06, 95 % CI 1.01 to 1.11). Statistically-increased cancer incidence was observed for the lung, kidney and parathyroid glands. The SIR for thyroid cancer was 1.29 (95 % CI 0.76 to 2.03), based on 18 thyroid cancers. There was no excess risk of thyroid cancer in Graves’ disease patients (SIR = 0.81, 95 % CI 0.30 to 1.76), and although the

192 / 4. RADIATION EFFECTS risk was higher in toxic nodular goiter patients (SIR = 1.7, 95 % CI 0.84 to 3.20), it was not statistically significant. Risk did not vary with TSE (Holm et al., 1991). Cancer mortality was also evaluated in these patients (Hall et al., 1992; 1993). By the end of follow-up in 1986, an increase in thyroid cancer mortality [12; standardized mortality rate (SMR) = 1.95, 95 % CI 1.01 to 3.41] was observed. However, the risk was high within the first year of follow-up and decreased over time. Ten or more years after follow-up began, the SMR was below unity. SMRs were highest among individuals less than age 40 y at the time of treatment and among patients receiving the highest 131I activity. Since the amount of 131I administered activity was related to the severity of the disease, the authors concluded that risk was not associated with the amount of exposure, but rather with the severity of the hyperthyroidism. 4.5.2.2 U.S. Cooperative Thyrotoxicosis Therapy Follow-Up Study. In the United States, the Cooperative Thyrotoxicosis Therapy Follow-Up Study began in 1961 (Saenger et al., 1968). The cohort is comprised of 35,609 hyperthyroid patients treated between 1946 and 1964 at one of 26 study clinics. Approximately 65 % of the study subjects had been treated with 131I; 25 % had received 131I treatment alone, and 39 % had received 131I in addition to surgery and/or anti-thyroid drugs. For the follow-up that ended in 1968, Dobyns and colleagues (Dobyns, 1977; Dobyns et al., 1974) reported that thyroid cancer incidence was not significantly elevated in the 131I treated patients compared to the hyperthyroid patients treated with surgery or anti-thyroid drugs. In this early study, patients who developed thyroid cancer within 5 y of treatment were excluded from the analysis. Williams (1986) has suggested that a slight excess of anaplastic thyroid cancer noted among the 131I treated patients might be due to radiation-induced progression from undetected differentiated carcinomas to undifferentiated carcinomas. Additional follow-up was conducted for two subgroups of the female study population; 3,146 patients at the Mayo Clinic (Hoffman et al., 1982a; 1982b) and 1,762 patients in Boston (Goldman et al., 1988; 1990). Neither thyroid cancer incidence nor mortality was associated with 131I exposure. In the most recent report of this cohort (Ron et al., 1998), there were 35,593 subjects in the final data set. Seventy-nine percent of the subjects were female. Complete follow-up through December 31, 1990 was available for 79 % (28,248) of the patients. In contrast to the Swedish study (Hall et al., 1992), 91 % of patients had Graves’ disease and only 8 % had toxic nodular goiter. The mean

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age at the time of treatment with 131I was 46.5 y; fewer than 500 patients were less than age 15 y; only 37 patients were less than age 10 y. The mean length of follow-up was 21 y; 75 % of the study subjects had follow-up for >10 y. Causes of death were determined from death certificates. Standardized mortality ratios were calculated for the entire follow-up period as well as the first 5 y following therapy and for the period beginning 10 y after treatment. The average amount of 131I administered was 225 MBq per treatment. Patients received 1.8 radioiodine treatments on average, resulting in a cumulative mean total administered activity of 385 MBq. The mean number of treatments and the cumulative administered activity were higher in patients with toxic nodular goiter (2.1 treatments and 629 MBq) than in patients with Graves’ disease (1.7 treatments and 370 MBq). Based on the administered activity, age, and thyroid uptake, when available, doses to 17 organs were calculated for each subject. A total of 2,950 cancer deaths was observed. The SMR (1.03) for all cancers was not elevated. An increased risk of thyroid cancer deaths (24) was observed among the 20,949 patients treated with 131I (SMR = 3.94, 95 % CI 2.52 to 5.86). Much of the risk occurred in the first 5 y (SMR = 12.32, 95 % CI 6.38 to 21.61) of follow-up, but the risk was still significantly elevated 10 y or more after study entry (SMR = 2.78, 95 % CI 1.38 to 4.97). The increased risk was seen primarily among toxic nodular goiter patients. Results of an external (SMR analysis) or an internal (Poisson analysis) comparison indicated that thyroid cancer mortality risk increased with increasing amounts of administered 131I activity, but the trend was not significant in the analysis using the internal comparison when patients having cancer prior to study entry were excluded and the type of hyperthyroidism was taken into account. While the excess deaths due to thyroid cancer might be associated with the 131I exposure, the underlying thyroid pathology also appeared to play a role. It should be noted that for a cancer with extremely good survival, such as thyroid cancer, mortality is clearly not the best endpoint. The increase in thyroid cancer mortality in patients treated with 131I was offset by a statistically-significant decrease in the SMRs for uterine and prostate cancer of 0.63 (0.51 to 0.77) and 0.68 (0.51 to 0.90), respectively. The reasons for this observed decrease in SMRs is unclear. The authors concluded the 131I appears to be a safe therapy for hyperthyroidism. 4.5.2.3 British Hyperthyroid Study. A population-based study of cancer incidence and mortality in 7,417 hyperthyroid patients (83 % female) treated in Birmingham, United Kingdom was conducted

194 / 4. RADIATION EFFECTS (Franklyn et al., 1998; 1999). The mean age at first treatment was 57 y. Patients were treated between 1950 and 1991. Follow-up was restricted to the period from 1971 through 1991, because the nationwide cancer incidence registry was established in 1971. Decreases were observed in overall cancer incidence (SIR = 0.83, 95 % CI 0.77 to 0.90; 634 cancers observed, 761 expected), and the overall cancer mortality also decreased (SMR = 0.90, 95 % CI 0.82 to 0.98; 448 cancer deaths observed, 499 expected). The thyroid cancer incidence (SIR = 3.25, 95 % CI 1.69 to 6.25; 9 cancers observed, 2.8 expected) and mortality (SMR = 2.78, 95 % CI 1.16 to 6.67; 5 cancer deaths observed, 1.8 expected) increased. The number of patients with thyroid cancer was too small for detailed analyses; the thyroid cancer patients did not differ, however, from the rest of the cohort in terms of administered 131I activity or age at exposure. As in the other studies of hyperthyroid patients, few patients were treated before age 30 y. The thyroid pathology among the nine patients was rather unusual: two papillary carcinomas, two follicular carcinomas, two anaplastic carcinomas, and three carcinomas not otherwise specified. Five of the patients died of thyroid cancer and another one died of a carcinoma with unknown primary site. One limitation of this study is that since follow-up only began 21 y after the first patients entered the study, some radiation-associated cancers may have been missed. 4.5.3

Environmental Iodine-131 Studies

A major public health concern is the risk of thyroid cancer following contamination of the environment with radioactive iodine. Radioiodines are fission products and can be released in great quantities following a catastrophic accident at a nuclear power plant or following detonation of a nuclear weapon. Because the physical half-life of 131I is adequately long (8 d), it is of concern. Once dispersed into the environment, it is concentrated by the pasture-cow-milk-human pathway. Once consumed, it is further concentrated in the thyroid gland resulting in thyroid organ doses that are typically 1,000 times the doses to other organs. Epidemiologic studies of several populations living in areas contaminated with radioactive iodine have been conducted. Thyroid dose estimates are much more uncertain following environmental contamination than they are following medical exposures where the amount of radioiodine administered is recorded (Section 3). Recent studies of populations exposed to radioiodines from the Chernobyl nuclear reactor accident have begun to shed some light on the risks from these exposures.

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4.5.3.1 Nevada Test Site. Between 1951 and 1958, more than 100 above-ground nuclear weapons tests were conducted at NTS. The period of maximum fallout was in 1953. Due to concerns about the possible effects of fallout, from 1965 through 1970 the U.S. Public Health Service examined 2,687 children in grades 5 through 12 who were living in Washington County, Utah and Lincoln County, Nevada, and 2,131 children in grades 5 through 12 living in Graham County, Arizona (Rallison et al., 1975). All subjects were born between 1945 and 1956. These examinations consisted of thyroid palpation and measurement of urinary iodide excretion. This early study found only small differences in the incidence of thyroid disease between the Utah-Nevada children and the Arizona children, suggesting no harmful effects from exposure to radioiodines. This cohort was reexamined between 1985 and 1986 by thyroid palpation (Kerber et al., 1993). Due to missing data and subjects moving out of the three counties of interest, 2,473 subjects (92 % of the initial enrollment) were included in the updated analysis. If a thyroid abnormality was detected, blood samples were obtained for thyroid hormone and antibody assays. Based on these tests, a preliminary diagnosis of diffuse enlargement of the thyroid, suspected thyroiditis or nodularity was made. Children with suspected thyroid nodules were further evaluated with a thyroid examination by an endocrinologist, 123I thyroid imaging, and a FNA biopsy. Neither the screeners nor the endocrinologist were blinded to the residence of the subjects. The thyroid dose was determined individually based on information about each subject’s milk and vegetable consumption provided during a telephone interview. If the subject were nursing, information on the mother’s milk and vegetable consumption was also obtained. The dietary history was obtained in 1987, 32 y after the period of maximum fallout. In the prior studies, the thyroid dose was assigned based on group membership rather than on the basis of individual dietary history. Individual thyroid doses included three pathways of exposure (i.e., milk ingestion, vegetable ingestion, and inhalation). An uncertainty value was calculated for each dose. Children living in Utah had the highest mean thyroid dose of 170 ± 270 mGy (1 SD), followed by children living in Nevada and Arizona with mean thyroid doses of 50 ± 94 mGy (1 SD) and 13 ± 37 mGy (1 SD), respectively. Milk ingestion contributed 73 % of the thyroid dose. Ten subjects received thyroid doses of >1 Gy. A total of 56 thyroid nodules was diagnosed from 1965 through 1986. Only benign and malignant nodules were considered to be neoplastic. Dose-response analysis was performed for all thyroid

196 / 4. RADIATION EFFECTS nodules, thyroid neoplasms, and thyroid cancers. Eight prevalent cases of thyroid cancer were detected compared with 5.4 expected. The estimated ERR Gy –1 was 7.9, but was not statistically significant. In an analysis of benign and malignant thyroid tumors combined (19), a significantly increased risk of similar magnitude (ERR Gy –1 = 7) was observed. This screening study was reanalyzed using a careful review of the thyroid diagnoses and an improved algorithm for estimating thyroid doses (Lyon et al., 2006; Simon et al., 2006b). The mean dose for each individual member of the University of Utah Cohort changed from a minimum of 0 to 0.00011 Gy; a mean of 0.11 to 0.12 Gy and a maximum from 4.6 to 1.4 Gy. The variance of individual mean dose changed from 0.036 to 0.028 (Gy2). Although the majority of individuals in the University of Utah Cohort had revised-corrected mean dose that were within a factor of two of what was reported and used in the earlier analysis of Kerber et al. (1993), nearly 20 % of those who resided outside of Washington County, Utah; Graham County, Arizona; and Lincoln County, Nevada, had revised doses that changed by more than a factor of 10. The size of the cohort, the dose ranges, and number of cases of non-neoplastic nodules and all neoplasms detected were corrected and revised in Lyon et al. (2006) from what was reported earlier in Kerber et al. (1993). The number of neoplasms identified by Lyon et al. (2006) changed from 20 to 22, and non-neoplastic nodules changed from 36 to 32. The number of thyroid cancers was unchanged (8). The size of the cohort increased from 2,473 to 2,497. For thyroid cancer, the new estimate of ERR Gy –1 was 0.8 (95 % CI <0 to 14.9, p = 0.74). The change in the risk estimate was due to the changes in the dosimetry, since the number of thyroid cancer cases did not change. In an analysis of benign and malignant thyroid tumors combined (20), a significantly-increased risk [ERR Gy –1 = 13.02 (95 % CI 2.7 to 68.7)] was observed.

4.5.3.2 Fallout from Nuclear Weapons Testing. In a study of the U.S. population, age-calendar, year-gender, and county-specific U.S. thyroid cancer mortality and incidence rates were compared to 131I exposure from the atmospheric bomb tests conducted in the 1950s and 1960s (Gilbert et al., 1998). The thyroid dose estimates were derived from NCI’s assessment, taking geographic location, age at exposure, and birth cohort into account (NCI, 1997). Altogether 4,602 thyroid cancer deaths in 3,053 counties and 12,657 incident thyroid cancers in 194 counties covered by eight SEER cancer registries were included in the analyses. The total average thyroid

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dose from atmospheric testing was estimated to be 24 mGy. Thyroid doses varied by year of exposure and age of exposure. The overall average thyroid doses for the years 1951, 1952, 1953, 1955, 1957, 1958 and 1961 plus were 0, 7, 6, 2, 8, 0 and 1 mGy, respectively. The average U.S. doses for seven age categories (i.e., in utero, 0 to <1, 1 to 4, 5 to 9, 10 to 14, 15 to 19, and 20 y) were 43, 126, 100, 67, 44, 31 and 11 mGy, respectively. Neither cumulative dose nor dose received between 1 and 15 y was associated with thyroid cancer incidence or mortality. An association was suggested for thyroid dose received before age 1 y for thyroid cancer mortality (ERR Gy –1 = 10.6, 95 % CI 1.1 to 29) and thyroid cancer incidence (ERR Gy –1 = 2.4, 95 % CI 0.5 to 5.6). Based on thyroid cancer mortality data alone, an elevated risk was observed for the 1950 through 1959 birth cohort (ERR Gy –1 = 12, 95 % CI 2.8 to 31). The absence of an increased risk from doses received after age 1 y is not consistent with studies of external exposure, but may be due to inherent weaknesses in ecologic studies, as well as the large uncertainties associated with individual county dose estimates. A similar study was done in Scandinavia (Lund and Galanti, 1999) to determine if an increase in thyroid cancer was associated with thyroid exposure due to Soviet testing of nuclear weapons. The Norwegian and Swedish Cancer Registries were used to determine the incidence of thyroid cancer. In addition, doses to the thyroid gland by birth year were estimated from measurements of 131I in milk that were obtained at the time of testing. A maximal cumulative dose of 18 mGy was calculated for subjects born in 1957 and 1958. Children born from 1951 through 1962 were defined as the “high” exposure group. Children born after 1962, when atmospheric testing of nuclear weapons had ended, were used as the control group. Children born between 1947 and 1950 were defined as the “low” exposure group since they would have been older at the time of their exposure. There were 526 thyroid cancers diagnosed between 1958 and 1992 in patients under the age of 25 y. The only group that had a slight increase in risk was the group born from 1951 through 1962 (high exposure) who were diagnosed with cancer between the ages of 7 to 14 y. When compared to the no exposure group, the relative risk was 1.7 (95 % CI 1 to 3). The authors stated that this relative risk is compatible with the risk predicted by NAS/NRC (1990). 4.5.3.3 Marshall Islanders. The external and internal doses to the 253 Marshall Islanders who were accidentally exposed to heavy radioactive fallout during a high-yield nuclear weapons test in the

198 / 4. RADIATION EFFECTS Pacific Ocean (Conard, 1984; Conard et al., 1970a; 1970b; Cronkite et al., 1956; 1997; Howard et al., 1997; Larsen et al., 1978; Robbins and Adams, 1989; Simon, 1997) are discussed in Section 3.3.7.2. Total thyroid doses (internal plus external) was highest in Rongelap children (Table 3.8). Palpable thyroid nodules were discovered in a 12 y old Rongelap female in 1963. These nodules were surgically confirmed to be benign in 1964. In 1969, a palpable nodule was found in an Utirikese adult female, the final pathological diagnosis of which was follicular carcinoma. The numbers of surgically confirmed thyroid tumors diagnosed in the Marshallese from 1964 through 1990 is shown in Table 4.9 (Howard et al., 1997). Thirty-eight benign nodules have been diagnosed in the exposed population and five have been diagnosed in the control group (RR = 8.5). Ten palpable thyroid cancers have been diagnosed in the exposed population and two have been diagnosed in the control population (RR = 4.5). Seven occult thyroid cancers have been diagnosed in the exposed population and two have been diagnosed in the control population (RR = 3.1). It is unclear whether differences in surveillance account for some of the differences between the exposed population and the unexposed Marshallese comparison group. The dose estimates are quite uncertain and the degree and consistency of follow-up were not comparable between the exposed and unexposed groups. In addition, thyroid suppressive therapy may have reduced cancer risk in the irradiated group. The paper of Cronkite et al. (1997) concludes: “There are simply not enough cases to draw any conclusion in respect to a dose effect relationship.” Use of thyroid diagnostic ultrasound was introduced in the Marshallese population in 1994 (Howard et al., 1997). As expected, the ultrasound resulted in the detection of many occult nodules. What was surprising was that the prevalence of nodules in the exposed population was not greater than the prevalence of nodules in the control population even when Marshallese who had prior thyroid surgery were excluded. In contrast to the findings based on palpable nodules, the prevalence of nodules in women was no different than in men. The results did not change when only nodules over 1 cm in size were considered. In addition, there was no apparent dose-response relationship when the number and size of nodules were considered. A survey was undertaken to assess whether there was an association between thyroid nodule prevalence among various Marshall Islanders and distance from the Bikini Atoll where shot BRAVO was detonated (Hamilton et al., 1987). They assumed a consistent relationship between the geographic distribution of long-lived 137Cs contamination (which they measured) and 131I distribution from

TABLE 4.9—Prevalence of thyroid nodules in the Marshallese with surgically confirmed pathology from 1964 through 1990 (adapted from Howard et al., 1997). Adenomas (%)

Papillary Cancers (%)

Follicular Cancers (%)

Occult Cancers (%)

Ailingnae (19)

21.1 (4)

0.0 (0)

0.0 (0)

0.0 (0)

5.3 (1)

Rongelap (67)

25.4 (17)

3.0 (2)

7.5 (5)

0.0 (0)

0.0 (0)

Utirik (167)

6.0 (10)

3.0 (5)

2.4 (4)

0.6 (1)

3.6 (6)

Control (227)

1.8 (4)

0.4 (1)

0.9 (2)

0.0 (0)

0.9 (2)

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200 / 4. RADIATION EFFECTS the different detonations. Over 7,200 residents on 14 atolls, including 2,273 who were born before the BRAVO test, were given a thyroid screening with neck palpation. For residents born before the BRAVO test, information was collected on their residence at the time of the detonation in 1954. A statistically-significant association between distance and thyroid nodule prevalence was found for which the statistical confidence increased with dose from a fallout-cloud that initially went eastward then southward was added. If dose received by persons on Utirik were excluded, the correlation disappeared. Using neck palpation, high resolution diagnostic ultrasound, and FNA biopsy of detected nodules, Takahashi et al. (1997) investigated the prevalence of thyroid nodules and thyroid cancer in 1,322 Marshallese born before 1965. A marginally significant prevalence of thyroid nodules in women and distance from Bikini ( p = 0.06) was found, but there was no information on dose. A multi-national 10 y Nationwide Thyroid Disease Study to determine prevalence of nodules and cancer was conducted with doses based on environmental contamination data collected by the Nationwide Radiological Study (Simon and Graham, 1997; Takahashi et al., 2000). The ascertainment of nodules was based on thyroid diagnostic ultrasound and neck palpation examinations. Using mean 137Cs measurements from Robison et al. (1997), the authors found no significant dose correlation between thyroid cancer or thyroid nodules in the downwind individuals (Takahashi et al., 2003). Difficulty in resolving the discrepancy in the Hamilton et al. (1987) and Takahashi et al. (1997) findings presumably reflects the relatively low-statistical power of both studies due to modest sample sizes. The lack of concordance of the findings from the different surveys called into question the robustness of the Hamilton et al. (1987) findings. A small effect is suggested by the reanalysis of the Takahashi et al. (1997) data, which found suggestive evidence that the prevalence of thyroid cancer did increase with the estimated thyroid dose (Takahashi et al., 2003). A comprehensive assessment of the impact of the Marshall Island tests on cancer risk in the Marshall Islanders is presented in an NCI (2004) report to the Senate Committee on Energy and Natural Resources. 4.5.3.4 Semipalatinsk Nuclear Test Site. Between 1949 and 1963, there were 88 atmospheric and 30 surface tests of Soviet nuclear weapons at the Semipalatinsk Nuclear Test Site in Kazakstan (Gusev et al., 1998). Three tests (1949, 1951 and 1953) contributed to >90 % of the dose to the local population due to fallout (Gusev

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et al., 1997). Populations exposed to fallout have been examined for the presence of thyroid disease (Carr et al., 2002). The prevalence of thyroid nodules and thyroid cancer was determined by diagnostic ultrasound examination and FNA biopsy of nodules in persons who were under the age of 20 y at the time of the fallout exposure. There were 1,989 persons in the exposed group; the estimated dose range was 0.35 to 5 Gy. There were 1,009 persons in the nonexposed group. Sixty percent of the studied population were females. Thyroid nodules (0.2 to 8 cm in diameter) were detected in 31 % (920) of the persons studied. The prevalence of thyroid nodules was significantly greater in females (39 %) than in males (18 %). There was also a statistically-significantly increased risk of thyroid nodules (RR = 1.8, 95 % CI 1.5 to 2.1) in the exposed group (35.2 %) when compared to the unexposed group (21.8 %). There were 25 thyroid cancers (20 papillary, five follicular) in the exposed group and 12 in the unexposed group. The prevalence of thyroid cancer in the exposed group (1.3 %) was not significantly increased when compared to the unexposed group (1.2 %). The trend in thyroid abnormalities with time for residents of the Pavlodar, Semipalatinsk and Ust-Kamenogorsk Regions of Kazakhstan was determined by reviewing thyroid pathology in 7,271 patients (761, 10.5 % men; 6,510, 89.5 % women) (Zhumadilov et al., 2000). No thyroid doses are reported in this descriptive paper. A major goal was to determine if the proportion of patients with thyroid cancer had increased with time; it was found that Hashimoto’s thyroiditis and thyroid cancer had increased over time within the study population. The highest percentage of thyroid cancer occurred in the birth cohort that would have been in early childhood at the time of the testing. The proportion of adenomas decreased with time. 4.5.3.5 Hanford Site. Between 1944 and 1957, the Hanford Site in Washington State released 27 PBq of 131I into the atmosphere (Napier, 2002). The vast bulk of the releases occurred in 1945 and 1946. At that time, the process to extract plutonium from fuel pellets had not been optimized and there was great interest in rapidly increasing the supply of plutonium. In January 1999, the results of the Congressionally-mandated HTDS were released to the public (Davis et al., 2002), a summary of which was published subsequently in a peer-reviewed journal (Davis et al., 2004a). The targeted study population consisted of 5,199 people born between 1940 and 1946 in seven counties in eastern Washington State. This population was selected because they would have been infants or young children at the time of their 131I exposure. Ninety-four percent of the potential study participants were located, 4,350 (84 %) were

202 / 4. RADIATION EFFECTS alive, 3,564 (68.5 %) agreed to participate in the study and 3,440 (66 %) of participants were evaluated. For the 3,191 study participants who had lived near Hanford during the period of atmospheric releases, thyroid doses were estimated based on individual characteristics and dosimetry information from the Hanford Environmental Dose Reconstruction Project (Kopecky et al., 2004; Stram and Kopecky, 2003). The other 249 participants had moved from the Hanford area and were considered to have received no exposure. For 62 % of the exposed participants, it was possible to obtain telephone interviews with mothers or other close relatives. The purpose of the interview was to obtain the person’s childhood history of milk consumption, residence, and other pertinent information concerning the subjects during childhood. A dosimetric model of the source term, environmental transport, deposition, milk distribution, and 131I metabolism was then used to provide dose estimates (including an estimate of dose uncertainty) for each individual. When information on milk consumption was unavailable, default values were assigned in the dosimetric calculation. The estimated thyroid doses from Hanford fallout ranged from ~0.29 to 2,823 mGy, with a median dose of 97 mGy and an arithmetic mean (plus standard deviation) dose of 174 r 224 mGy. Only 24 subjects (0.8 %) had dose estimates >1 Gy; seven (0.2 %) had dose estimates >2 Gy. Two study physicians clinically evaluated each study participant and obtained a medical history (Kopecky et al., 2005). The examination included diagnostic ultrasound, thyroid palpation, and blood tests. Medical records on past thyroid conditions were obtained. Participants were evaluated for 11 categories of thyroid disease, ultrasound-detected abnormalities, and hyperparathyroidism, as well as estimated 131I dose to the thyroid. A total of 19 thyroid cancers was found, including 12 diagnosed through the screening and subsequent work-up (Davis et al., 2004a). A total of 249 benign thyroid nodules was diagnosed by histology or cytology, including 221 diagnosed through the thyroidscreening program. For another 37 presumed benign nodules, no histology or cytology was obtained, making a total of 286 benign thyroid nodules. No association between thyroid dose and either thyroid cancer incidence or benign thyroid nodules incidence was observed (Figure 4.8). For thyroid cancer, the slope of the doseresponse regression curve was 2 × 10–3 Gy –1 (95 % CI –1 × 10–3 to 1.7 × 10–2 Gy –1). For benign thyroid nodules confirmed by histology or cytology, the slope was –8 × 10–3 Gy –1 (95 % CI –2.2 × 10–2 to 4.1 × 10–2 Gy –1). Inclusion of nodules with only a clinical diagnosis gave essentially identical results.

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The investigators reported that the study had 95 % power to detect a 5 % Gy –1 increase in benign thyroid nodules and 96 % power to detect a 2.5 % Gy –1 increase in the incidence of carcinomas. The young ages at the time of exposure would likely increase the magnitude of the expected effects. Failure to detect an effect had there been one is likely due to the fact that the estimated thyroid doses were quite low: the estimated mean dose was ~180 mGy, and <1 % of the study population received doses in excess of 1 Gy. Furthermore, the calculated uncertainties in the dose estimates were fairly large, and not all likely sources of uncertainty were accounted for in the power calculations. The attenuation caused by dose uncertainty plus the low distribution of doses may have led to null results. The authors also studied the cumulative incidence of autoimmune thyroid disease by gender and estimated dose (Figure 4.9). No statistically-significant dose-response relationships were identified. The results of a cancer mortality study among the populations residing in counties near the Hanford Site from 1950 to 2000 have been published (Boice et al., 2006). The authors concluded that living near the Hanford Site has not increased cancer mortality. 4.5.3.6 Chernobyl Environmental Exposure. The literature on the health effects of the Chernobyl nuclear reactor accident is voluminous and varies greatly in quality. The results of the major studies published since 2005 are summarized in Table 4.10. The reasons for differences in risk estimates for the studies listed in this table are not clear but uncertainties in dose estimates and intensity of screening probably account for some of the differences. This selective review concentrates on peer-reviewed English language publications (Cardis et al., 2006). The results of ecological studies will be discussed first followed by a discussion of the more reliable cohort and case-controlled studies. Four years after the Chernobyl Nuclear Power Plant accident in April 1986, thyroid cancer began to appear in children who lived in areas contaminated as a result of the accident, particularly southern Belarus, northern Ukraine, and adjacent areas in western Russia (Baverstock et al., 1992; Kazakov et al., 1992; Stsjazhko et al., 1996; Williams, 1994; Williams et al., 1995). About 1.8 EBq of 131 I were released at the time of the accident. It has been estimated that 131I contributed as much as 90 to 99 % of the internal thyroid dose to the population living in the contaminated areas (Gavrilin et al., 2004; Likhtarev et al., 2003; Minenko et al. 2006; Zvonova and Balonov, 1993). The short-lived radioiodines contributed primarily to the exposures very near the Chernobyl Plant. The short

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Fig. 4.8. Cumulative incidence of thyroid neoplasia outcomes by gender and estimated dose categories from HTDS (Davis et al., 2004a)

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Fig. 4.9. Cumulative incidence of autoimmune disorders by gender and estimated dose categories from HTDS (Davis et al., 2004a).

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Reference

Type of Study

Number of Subjects

Thyroid Cancers

Mean Dose (cGy) (range)

ERR Gy –1 (95 % CI)

EAR (104 PY Gy)–1 (95 % CI)

Cardis et al. (2005)

Case control

Cases: 276 Controls: 1,300

276

Belarus 36.5 (0.7 – 310.9) Russian Federation 4 (0.3 – 169.1

4.5 (2.1 – 8.5)

Not calculated

Ivanov et al. (2006)

Ecological

375,000

199

8 (0 – 20)

Girls 0 – 4 y: 45.3 5 – 9 y: 10.1 10 – 14 y: 1 15 – 17 y: <0 Boys 0 – 9 y: 68.6 10 – 17 y: <0

Not calculated

Jacob et al. (2006)

Ecological

1,620,000

1,089

7 (1.8 – 65)

18.9 (11.1 – 26.7)

2.66 2.19 – 3.13

Kopecky et al. (2006)

Case control

Cases: 66 Controls: 132

66 Not calculated

4.35 (0.014 – 164)

48.7 (4.8 – 1,151)

Not calculated

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TABLE 4.10—Results from major studies of thyroid cancer in relation to exposure due to the Chernobyl nuclear reactor accident.

Likhtarov et al. (2006)

Ecological

301,907

232

35.3 (<2.0 – >200)

8.0 (4.6 – 15)

1.5 (1.2 – 1.9)

Tronko et al. (2006a)

Cohort

13,127

45

200 (0 – >400)

5.25 (1.70 – 27.5)

Not calculated

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210 / 4. RADIATION EFFECTS time between the radiation exposure and the detection of an increased rate of thyroid cancer led to questions about the causal role of radiation (Beral and Reeves, 1992; Ron et al., 1992; Shigematsu and Thiessen, 1992). However, more than 20 y after the accident, the association between radiation and thyroid cancer seems clear, although there still is an appreciable uncertainty in the risk estimates (Astakhova et al., 1998; Cardis et al., 2005; Davis et al., 2004b; Ivanov et al., 2003; 2006; Jacob et al., 1998; 1999; 2000; 2006; Karaoglou and Chadwick, 1998; Kopecky et al., 2006; Likhtarov et al., 2006; Moysich et al., 2002; Sobolev et al., 1997; Tronko et al., 2006a). In Belarus, 1,342 adult and seven childhood thyroid cancers were diagnosed in the 10 y period before the Chernobyl nuclear reactor accident, whereas 4,006 adult and 508 childhood thyroid cancers were reported during the 9 y period after the accident (Demidchik et al., 1996; Pinchera et al., 1996). Birth-cohort analyses have demonstrated a large increase in thyroid cancer incidence after the accident among young Ukrainian children exposed to fallout from Chernobyl (Sobolev et al., 1997; Tronko et al., 1999). In Russia, an increase in thyroid cancer was also observed, but it occurred somewhat later than in either Belarus or Ukraine (Tsyb et al., 1996). In an ecological study that used mean thyroid doses for the contaminated regions of Belarus (0.08 to 0.73 Gy), Russia (0.12 Gy), and Ukraine (0.05 to 0.92 Gy) (Jacob et al., 1998), the slope of the dose-response relation was estimated using relative and absolute risk models. ERR Gy–1 ranged between 22 and 90 in the study area. The authors did not calculate 95 % confidence interval and noted that the relative risk is greatly influenced by the estimate of the very low and uncertain baseline rate in young children. EAR was estimated to be 2.3 (104 PY Gy)–1 (95 % CI 1.4 to 3.8) (Figure 4.10). This estimate is about half as great as the risk for external childhood radiation exposure (Ron et al., 1995), but this difference was not statistically significant. In a subsequent paper (Jacob et al., 2000), these authors estimate that the Chernobyl nuclear reactor accident will result in 15,000 (95 % CI 5,000 to 45,000) excess thyroid cancers in Belarus in the period from 5 to 50 y after the accident. They comment that their estimates of the risk of thyroid cancer from 131I overlap the estimates of the risk from external radiation and, therefore, they cannot conclude that the risk from 131 I exposure is less than the risk from external exposure. The crude nature of the dosimetry by geographic region means that this estimate has substantial uncertainty. An updated analysis of this large ecological study of thyroid cancer incidence as a function of dose and its degree of dependence on

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Fig. 4.10. Excess absolute thyroid cancer risk in the period 1991 to 1995 was among people born between 1971 and 1986. The stars show results for cities with large collective doses. The solid line is the best estimate of EAR per unit dose. Broken and dotted lines indicate 95 % confidence ranges (Jacob et al., 1998).

time after exposure and attained age has been published (Jacob et al., 2006). Data were analyzed for 1,034 settlements in Belarus and Ukraine. The total population of children and adolescents under the age of 18 y in these settlements at the time of the Chernobyl nuclear reactor accident was 1,620,000. Individual thyroid doses were calculated based on measurements of the 131I content in human thyroids performed in May or June 1986. Gender and age specific thyroid doses were assigned for each settlement. The central estimate for the linear coefficient of the EAR dose response was 2.66 [95 % CI 2.19 to 3.13 (104 PY Gy)–1]. EAR was found to be higher for females than for males by a factor of 1.4, which decreased with age at exposure and increased with age attained. The central estimate for the linear coefficient of the ERR Gy –1 dose response was 18.9 (95 % CI 11.1 to 26.7). ERR was found to be smaller for females than for males by a factor of 3.8 and decreased strongly with age at exposure. Both EAR and ERR were higher in the

212 / 4. RADIATION EFFECTS Belarusian settlements than in the Ukrainian settlements. In contrast to ERR, EAR increased with time after exposure in both Belarus and Ukraine. The excess risk estimates were found to be close to those observed in a major pooled analysis of seven studies of childhood thyroid cancer after external exposures (Ron et al., 1995). Shibata et al. (2001) examined three birth cohorts of children with ultrasound and measured serum concentrations of thyroid hormones and antibodies to minimize bias due to screening. FNA biopsies were obtained in subjects with thyroid nodules >5 mm in diameter. A total of 21,601 children was examined. Group I (9,472) consisted of children born after the Chernobyl nuclear reactor accident (born January 1, 1987 to December 31, 1989), Group II (2,409) consisted of children in utero at the time of the Chernobyl nuclear reactor accident (born April 27 to December 31, 1986), and Group III (9,720) consisted of children born before the Chernobyl nuclear reactor accident (born January 1, 1983 to April 26, 1986). A total of 32 thyroid cancers was detected (incidence: 0.15 %). No thyroid cancers were detected in Group I; one thyroid cancer (incidence: 0.04 %) was detected in Group II and 31 thyroid cancers (incidence: 0.32 %) were detected in Group III. The odds ratio (OR) (compared to Group I) were 11 (95 % CI 3 to 176) for Group II and 121 (95 % CI 9 to 31,000) for Group III. No dose-response relationship could be estimated due to the lack of dosimetry data. The authors concluded that the increase in thyroid cancer was due to radiation exposure from the Chernobyl nuclear reactor accident. In a study of adolescents and adults who lived in the Bryansk Region of Russia following the Chernobyl nuclear reactor accident, Ivanov et al. (2003) analyzed thyroid cancer incidence for the period from 1986 through 1998 for residents who were 15 to 69 y old at the time of the accident. A total of 1,051 thyroid cancers was recorded from 1986 through 1998; 769 of these occurred from 1991 through 1998. Relative to the incidence rates of the whole Russian population as controls, SIRs for the Bryansk Region were 1.27 (95 % CI 0.92 to 1.73) for the period 1986 through 1990, and 1.45 (95 % CI 1.20 to 1.73) for the period 1991 through 1998 for males, and 1.94 (95 % CI 1.70 to 2.20) for the period 1986 through 1990 and 1.96 (95 % CI 1.82 to 2.1) for the period 1991 through 1998 for females. No dose-response relationship was observed. The authors attributed the increase in reported thyroid cancer incidence in the Bryansk Region to differences in registration of diseases and regional differences in spontaneous incidence. The time trends of thyroid cancer incidence in Ukrainian children after the Chernobyl nuclear reactor accident have been

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analyzed (Heidenreich et al., 2004). After a minimal latency of 3 y, EAR increased linearly with TSE and was relatively constant for all age groups who were up to 15 y at the time of exposure. For girls who were very young at the time of exposure, EAR was about twice EAR for boys. For girls exposed at age 16 to 18 y, EAR was about five times EAR for boys. Although EAR does not decrease as age at exposure increases, there is an inverse relationship between age and ERR since the risk of spontaneously-occurring thyroid cancer increases with age. Marked increases in thyroid cancer rates following the Chernobyl nuclear reactor accident have also been reported by Mahoney et al. (2004). These authors compared the increase in thyroid cancer incidence in males and females in high and low contamination areas of Belarus. From 1970 to 2001, the relative increase in thyroid cancer was 775 % in males and 1,925 % in females (Figure 4.11). The relative increase in thyroid cancer incidence in high contamination areas was higher (males, 1,020 %; females, 3,286 %) than in low contamination areas (males, 571 %; females, 250 %). The highest relative increase in thyroid cancer incidence occurred in children 0 to 14 y at the time of diagnosis. A study of children living in the most contaminated area of Russia after the Chernobyl nuclear reactor accident (the Bryansk Oblast) was undertaken to determine thyroid cancer risk as a function of dose (Ivanov et al., 2006). This was an ecological study of 375,000 individuals who were exposed as children between the

Fig. 4.11. Annual age-adjusted thyroid cancer incidence rate, by calendar year, gender, and area of exposure, Belarus, 1970 to 2001 (Mahoney et al., 2004).

214 / 4. RADIATION EFFECTS ages of 0 and 17 y. Thyroid doses were determined based on the official methodology approved by the Russian Scientific Commission on Radiation Protection. Between 1991 and 2001, a total of 199 thyroid cancer cases was diagnosed (95 % histologically confirmed) at cancer centers. The performed analysis relied on medical and dosimetric information available from the Russian National Medical and Dosimetric Registry. The analysis revealed statisticallysignificant radiation risk only for those exposed as children at an age of 0 to 9 y. In this group, the SIR (the national incidence rate was used as a reference) in the considered time period is estimated to be 6.7 (95 % CI 5.1 to 8.6) and 14.6 (95 % CI 10.3 to 20.2) for girls and boys, respectively. The risk dependence on age at exposure has also been studied. It has been shown that the lower the age, the higher the risk. For girls whose age at exposure was 0 to 4 y, ERR Gy –1 was 45.3 (95 % CI 5.2 to 9,953; with internal control) and 28.8 (95 % CI 4.3 to 2,238; with external control), respectively. An internal control uses the disease rate in the unexposed members of the study population. An external control uses standardized population rates. For boys whose age at exposure was 0 to 9 y, the corresponding ERR Gy –1 was 68.6 (95 % CI 10 to 4,520) and 177.4 (95 % CI 276 to 106), respectively. ERR Gy –1 for boys >9 y was <0. Dependence of radiation risk on TSE was studied, with the focus on two follow-up periods 1991 through 1996 and 1997 through 2001, respectively. In 1997 through 2001, the radiation risk is shown to decrease among girls and increase among boys. The results of a large ecological study to investigate the relationship between 131I thyroid dose and the diagnosis of thyroid cancer were published in 2006 (Likhtarov et al., 2006). The study population included 301,907 persons who were between the ages of 1 and 18 y at the time of the Chernobyl nuclear reactor accident. Twenty-four percent of the study population had individual thyroid dose estimates and the other 76 % had “individualized” estimates of thyroid dose based on direct thyroid measurements taken from a person of the same age and gender living in the same or nearby settlement. Cases include 232 thyroid cancers diagnosed from January 1990 through December 2001, and all were confirmed histologically. The estimated ERR Gy –1 was eight (95 % CI 4.6 to 15) and EAR (104 PY Gy)–1 was estimated to be 1.5 (95 % CI 1.2 to 1.9). These estimates are compatible with results of other studies from the contaminated areas, as well as studies of external radiation exposure. The ratio of thyroid cancer incidence rates was approximately three when the rates derived from the highest intensity screening area were divided by the rates derived from the lowest intensity screening areas.

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In a case-control study, with 107 cases and 204 controls, conducted in Belarus, a statistically-significant dose-response was demonstrated (Astakhova et al., 1998), but no ERR Gy –1 was calculated due to uncertainties in the thyroid dose. The results of a population-based case-control study of children and adolescents aged 0 to 19 y at the time of the accident who were residing in the more highly contaminated areas of the Bryansk Oblast have been published (Davis et al., 2004b; Stepanenko et al., 2004; Stezhko et al., 2004). Cases were diagnosed with thyroid cancer before October 1, 1997 (26); two controls per case were identified and matched by gender, birth year, and region of residence and type of settlement (urban, town and rural) on April 26, 1986 (52). Individual doses to the thyroid were estimated to range from 3.4 to 2,730 mGy. For the 26 cases, the median dose was 555 mGy (range 4 to 1,640 mGy). For the 52 controls, the median dose was 180 mGy (range 3.4 to 2,730 mGy). The trend of increasing risk with increasing dose was statistically significant (one-sided p = 0.009). No ERR Gy –1 was reported. A population based case-control study of thyroid cancer in Belarus and the Russian Federation evaluated the risk of thyroid cancer after exposure to radioactive iodine in childhood and investigated environmental and host factors that may modify this risk (Cardis et al., 2005). This study included: (1) 276 case patients with thyroid cancer that were diagnosed through 1998 and (2) 1,300 matched control subjects, all younger than 15 y at the time of the accident. Individual doses were estimated for each subject based on their residence history and dietary habits at the time of the accident. Each individual’s likely stable iodine status at the time of the accident and in the following years was also evaluated. A strong dose-response relationship was observed between dose to the thyroid received in childhood and thyroid cancer risk ( p < 0.001). For a dose of 1 Gy, the estimated odds ratio of thyroid cancer varied from 5.5 (95 % CI 3.1 to 9.5) to 8.4 (95 % CI 4.1 to 17.3), depending on the risk model. A linear dose-response relationship was observed up to 1.5 to 2 Gy. The risk of radiation-related thyroid cancer was three times higher in iodine-deficient areas (RR = 3.2, 95 % CI 1.9 to 5.5) than elsewhere. Administration of potassium iodide as a dietary supplement reduced this risk of radiationrelated thyroid cancer by a factor of three (RR = 0.34, 95 % CI 0.1 to 0.9, for consumption of potassium iodide versus no consumption). The authors concluded that exposure to 131I in childhood is associated with an increased risk of thyroid cancer. Iodine deficiency and supplementation appear to modify this risk. In the past, iodine deficiency has been suggested as an important factor

216 / 4. RADIATION EFFECTS (Cardis et al., 2005; Gembicki et al., 1997; Mahoney et al., 2004; Shakhtarin et al., 2003; Tronko et al., 2005) that might modify thyroid cancer risk following exposure to 131I. This report was accompanied by an editorial about what is known and not known about thyroid cancer risk following 131I exposure (Boice, 2005). The results of a cohort study of Ukrainian children and adolescents who were younger than 18 y and lived in the most contaminated parts of Ukraine have been published (Tronko et al., 2006a). All individuals in the cohort had individual estimates of dose to the thyroid based on thyroid radioassays done 10 to 60 d after the accident (Likhtarev et al., 2003; Stezhko et al., 2004). The mean dose was 20 Gy with a range of 0 to >40 Gy. From a cohort of 32,385 subjects, 13,127 individuals were screened with ultrasound and palpation between the years of 1998 and 2000. Forty-five thyroid cancers were detected. ERR Gy –1 was calculated to be 5.5 (95 % CI 1.70 to 27.5). The dose-response relationship was approximately linear. There was a nonsignificant indication that greater age at exposure was associated with decreased radiation-related risk of thyroid cancer. Based on the dose response, it was found that ~75 % (95 % CI 50 to 93) of the thyroid cancers observed were associated with the radiation exposure. This is the only study thus far that provides quantitative risk estimates based on individual measurements of thyroid radiation exposure and minimally confounded by any screening effects. A population-based case-control study was conducted to estimate the radiation-related risk of thyroid cancer in persons who were exposed in childhood to 131I from the Chernobyl nuclear reactor accident (Kopecky et al., 2006). The study included all 66 confirmed cases of primary thyroid cancer diagnosed from April 26, 1986 through September 1998 in residents of Bryansk Oblast, Russia, who were 0 to 19 y old at the time of the accident, along with two individually matched controls for each case. The median thyroid dose was 43.5 mGy with a range of 0.00014 to 2.73 Gy; GSD: 2.2. The ERR Gy –1 associated with radiation exposure, 48.7, was significantly greater than zero ( p = 0.00013), but had an extremely wide 95 % confidence interval (4.8 to 1,151). Adjustment for dose uncertainty nearly tripled ERR Gy –1 to 138, but this was likely an overestimate due to limitations in the modeling of dose uncertainties. The radiation-related excess risk observed in this study is quite large, especially if the uncertainty of dose estimation is taken into account, but is not inconsistent with estimates previously reported for risk after 131I exposure or acute irradiation from external sources. The authors speculate that the differences in their findings for the Chernobyl exposure when compared to their

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studies of the Hanford exposures may be partly explained by differences in iodine in the diet. However, other authors contend that the results of the Hanford Study can be explained by an unrecognized loss of statistical power due to high and complex uncertainty in reconstructed dose, including the presence of undetermined degrees of bias towards dose overestimation (Carroll et al., 2006; Hoffman et al., 2006; 2007). Noncancer thyroid disease in the Bryansk and Kaluga Regions of the Russian Federation among children exposed under the age of 10 y following the Chernobyl nuclear reactor accident was also studied (Ivanov et al., 2005). Individual thyroid doses were estimated for 2,457 subjects whose thyroids were examined by diagnostic ultrasound. Thyroid doses ranged from 0 to 6 Gy, mean 0.132 Gy, SD ± 0.45 Gy. Solid nodules were found in 61 (2.5 %), cysts in 101 (4.1 %), chronic thyroiditis in 27 (1.1 %), and diffuse goiter in 259 (10.5 %) individuals. A statistically-significant dose-response relationship was observed for diffuse goiter in males (OR at 1 Gy = 1.36, 95 % CI 1.05 to 1.99). No statistically-significant doseresponse relationship was observed for the other endpoints. 4.5.3.7 Mayak Nuclear Weapons Production Facility. Between 1948 and 1960, the Mayak Nuclear Weapons Production Plant in the South Ural Mountains of the Russian Federation discharged relatively high levels of radionuclides into the atmosphere (Mushkacheva et al., 2006). The releases, primarily 131I, largely fell on individuals living in the city of Ozyorsk and the surrounding areas. A small clinical screening study was conducted to investigate whether there was an elevated risk of thyroid diseases among individuals living in Ozyorsk during the years of exposure. The study population was comprised of 581 individuals born between 1952 and 1953 and living in Ozyorsk during the years of heaviest exposure (exposed) and 313 individuals of the same age who moved to Ozyorsk after the radioactive releases essentially had stopped (nonexposed). The screening protocol included a patient interview, palpation of the thyroid, cervical lymph nodes and salivary glands, an ultrasound examination, and measurement of free T4, TSH, and anti-thyroperoxidase antibody. The exposed group had a significantly higher prevalence of nodular disease compared with the nonexposed group (RR = 1.4, 95 % CI 1.1 to 1.9). The elevated risk was predominately observed for solitary nodules and nodules 10 mm in diameter. The study is limited by the small number of persons screened and by the lack of individual thyroid doses. 4.5.3.8 Chernobyl Occupational Exposure. Between 1986 and 1990, hundreds of thousands of civilian workers, military servicemen,

218 / 4. RADIATION EFFECTS scientists, and medical staff from the former Soviet Union were involved in entombing the damaged nuclear reactor and cleaning up the contaminated environment (Moore et al., 1997). About 225,000 workers, mostly male, were employed in the 30 km exclusion zone during the first year after the accident. The dose limit for workers was originally set at 0.25 Gy for total service in Chernobyl, but in 1987 it was reduced to 0.1 Gy and in 1988 to 0.05 Gy. In addition to external radiation, workers who were onsite during the first few weeks after the accident also were exposed to radioiodines. Estimated individual external doses have a large degree of uncertainty, and doses from internally-deposited radioiodines are hardly known. Thus, it is unclear how much of a role internal 131I exposure contributes to the findings described below. Thyroid cancer incidence and mortality have been evaluated in a cohort of cleanup workers from Estonia (Rahu et al., 1997; 2006; Tekkel et al., 1997). No thyroid cancers were observed between 1986 and 1993 among 4,742 workers in the cohort. Based on agegender and calendar-specific cancer incidence rates in Estonia, 0.21 cases would have been expected. Among the 1,979 workers participating in a thyroid screening examination, including palpation and diagnostic ultrasound, two thyroid cancers, three benign tumors, and 196 unspecified thyroid nodules were diagnosed (Inskip et al., 1997a). Thyroid nodules were not associated with documented dose, type, time period, or duration of service in Chernobyl, or biological measures of dose. Dosimeter estimates of radiation exposure indicate that the mean external dose to workers participating in this screening study was 0.1 Gy, but no increase in the number of chromosome translocations or insertions were detected based on fluorescence in situ hybridization with whole-chromosome painting probes (Littlefield et al., 1998). The authors of this biodosimetry study concluded that it is likely the recorded doses for these cleanup workers overestimated their average bone-marrow doses, perhaps substantially. An update of the Estonian Cohort and of a Latvian Cohort was published in 2006 (Rahu et al., 2006). Two cohorts of Chernobyl cleanup workers from Estonia (4,786 men) and Latvia (5,546 men) were followed from 1986 to 1998 to investigate cancer incidence among individuals exposed to ionizing radiation from the Chernobyl nuclear reactor accident. Each cohort was identified from various independent sources and followed using nationwide population and mortality registries. Cancers were ascertained by linkage with nationwide cancer registries. Overall, 75 incident cancers were identified in the Estonian Cohort and 80 in the Latvian Cohort. The combined-cohort SIR for all cancers was 1.15 (95 % CI 0.98 to 1.34)

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and for leukemia, 1.53 (95 % CI 0.62 to 3.17, n = 7). Statisticallysignificant excess cases of thyroid (SIR = 7.06, 95 % CI 2.84 to 14.55, n = 7) and brain cancer (SIR = 2.14, 95 % CI 1.07 to 3.83, n = 11) were found, mainly based on Latvian data. However, there was no evidence of a dose response for any of these sites, and the relationship to radiation exposure has not been established. Excess of thyroid cancer cases observed may have been due to screening, the leukemia cases included two unconfirmed diagnoses, and the excess cases of brain tumors may have been a chance finding. There was an indication of increased risk associated with early entry to the Chernobyl area and late follow-up, though not statistically significant. Further follow-up of Chernobyl cleanup workers is warranted to clarify the possible health effects of radiation exposure. In the Russian Federation, 168,000 cleanup workers are being followed through annual medical checkups (Ivanov et al., 1997a; 1997b). Through 1995, 47 thyroid cancers have been diagnosed; 43 % were follicular, 33 % papillary, and 14 % other types of thyroid carcinoma. The estimated ERR Gy –1 was 5.31 (95 % CI 0.04 to 10.58) and EAR was 1.15 [95 % CI 0.08 to 2.22 (104 PY Gy)–1]. This study has been criticized for not using internal comparisons and not accounting for increased medical surveillance among cleanup workers (Boice and Holm, 1997). Boice and Holm also noted that the workers have too short a latency period and that no elevated risk was observed among cleanup workers in Estonia. The investigators contend that they adjusted for a screening effect, discounted the first 4 y after the accident and that the cohort of Estonian cleanup workers was too small to detect an elevated risk of thyroid cancers (Ivanov, 1998). Additional follow-up will be needed to clarify these complicated issues (Ivanov et al., 2004). An overview of the sources of radiation exposure and the doses received by the cleanup workers and a description of the efforts made to estimate individual doses have been published (Bouville et al., 2006). The average dose from external radiation exposure received by the cleanup workers was reported to be about 170 mGy in 1986. This dose decreased from year to year. The radiation exposure was mainly due to external irradiation from gamma-rayemitting radionuclides and was relatively homogeneous over all organs and tissues of the body. These doses were estimated in preparation for two NCI studies of Chernobyl cleanup workers. One study will estimate the cancer incidence and thyroid disease among Estonian, Latvian and Lithuanian workers (Bigbee et al., 1997; Inskip et al., 1997b; Littlefield et al., 1998; Tekkel et al., 1997). The second study will determine the incidence of leukemia and other related blood diseases among Ukrainian workers (Chumak and Krjuchkov, 1998; Chumak et al., 1997; Ilyin et al., 1990).

220 / 4. RADIATION EFFECTS 4.6 Benign Thyroid Nodules Following Radiation Exposure Assessing the harm due to benign thyroid nodules caused by radiation is difficult for several reasons. The incidence will be very dependent on the method of detection (e.g., palpation versus diagnostic ultrasound), the definition of a nodule (e.g., an abnormality greater than an arbitrarily chosen size; typically 1 cm), and the diligence of the search. Because of the large reservoir of clinically unapparent thyroid nodules (Black and Welch, 1993; Tan and Gharib, 1997; Welch and Black, 1997) the more frequent and more comprehensive the examination, the more likely that more nodules will be detected. Benign nodules are rarely symptomatic. The primary complication caused by benign thyroid nodules is that benign thyroid tissue obtained by FNA biopsy may be indistinguishable from thyroid cancer, particularly follicular thyroid cancer (Cai et al., 2006; Cap et al., 1999). Because of the limitations of current diagnostic tests, aggressive evaluation of thyroid nodules will result in more thyroid surgery to definitively differentiate benign thyroid nodules from those that are malignant. It is unlikely that the harm from more surgery will be offset by the benefits of decreased deaths from the earlier diagnosis of thyroid cancer since relatively few patients die from thyroid cancer detected with routine medical surveillance. The potential benefits and harms of screening for thyroid cancer have been addressed in an IOM report (NAS/IOM, 1999), which is reviewed in Section 6. A brief description and evaluation of the main studies of radiation and thyroid nodule incidence or prevalence are given in Tables 4.11, 4.12, and 4.13. 4.6.1

Medical Exposures: External

4.6.1.1 Robert Packer Hospital Head and Neck Study. In this cohort study (Royce et al., 1979; Utiger, 1979), the authors attempted to recall 738 patients who had received therapeutic head and neck irradiation at the Robert Packer Hospital in Sayre, Pennsylvania from 1937 through 1970 (Table 4.12). Of the 265 subjects who responded to public announcements or direct solicitations, a history of head and neck irradiation (mainly tonsils and nasopharynx) could be verified in 214 persons. For the unexposed population (208), each of the irradiated subjects was asked to bring a sibling of the same gender, who was close in age or a nonsibling of the same gender and approximate age; this procedure yielded subjects who, by virtue of not being previously irradiated, served as controls. An additional 35 unexposed persons were selected by age and gender

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from medical center personnel and visitors; the unexposed population included 243 individuals. The thyroid glands of exposed and unexposed subjects were palpated by two endocrinologists who were blinded to each patient’s exposure history. Thyroid abnormalities recorded were an enlarged thyroid gland (>30 g), single or multiple nodules, or a combination of these findings. Persons with thyroid abnormalities were further examined with a 99mTc pertechnetate thyroid scan. Patients with nonfunctioning thyroid nodules or nodules >1.5 cm in size were advised to have surgery. Thyroid nodules were palpable in 6.1 % of the exposed subjects and 4.5 % of the unexposed subjects. This difference was not statistically significant. Six of the 13 irradiated subjects and four of the 11 unexposed subjects with palpable nodules had surgery. One thyroid cancer was found in the irradiated subjects and two thyroid cancers were found in the unexposed subjects at the time of surgery. The authors did not calculate an ERR or EAR. Diffuse thyroid enlargement (with or without nodules) was palpable in 7.9 % of the exposed subjects and 4.9 % of the unexposed subjects. This difference was not statistically significant. The authors concluded “our controlled study did not find an excess of thyroid abnormalities in previously irradiated subjects.” 4.6.1.2 French Hemangiomas Study. A cohort of 5,032 patients who were treated by radiation therapy for skin hemangioma between 1941 and 1973 at the Gustave Roussy Institute in Villejuif, France (Table 4.11) was identified (de Vathaire et al., 1993). Approximately 1,480 of these patients were <14 y old at the time of irradiation and were considered to have thyroid exposure (treated either with 32P, 90Sr, or 90Y for a hemangioma located <5 cm from the thyroid or with 226Ra or x rays at other locations of the hemangioma). A letter was sent to each of the 1,480 patients; 396 responded. Each patient that responded had a physical examination of the thyroid and had serum thyroid hormones measured. The thyroid dose was estimated for each patient. The average thyroid dose was 86 mGy, with a range of 0 to 2,740 mGy. The median time from treatment to screening was 22 y. The thyroid examination consisted of palpation, followed by a scintigraphic scan with 99mTc pertechnetate for most patients. Nine thyroid nodules, including one papillary cancer, were found at the time of the screening examination; five additional nodules had been detected and treated prior to this exam. The authors calculated the absolute risk of thyroid nodules (benign and malignant) to be 1.8 (103 PY Gy)–1. The risk of developing a thyroid nodule was 3.4-fold higher in women than men. Thyroid nodule

Mean Dose (mSv) (range)

Incidence (105 PY)–1 Irradiated (number of nodules)

Incidence (105 PY)–1 Controls (number of nodules)

Israel tinea capitis (Ron et al., 1989)

90 (40 – 500)

12.3 (26)

Israel tinea capitis (Ron et al., 1989)

90 (40 – 500)

NY tinea capitis (Shore et al., 1992)

Study (reference)

Thymus (Shore et al., 1993b) Thymus (Janower and Miettinen, 1971) Chicago, tonsils (Schneider et al., 1993) Boston lymphoid hyperplasia (Pottern et al., 1990)

Relative Risk

ERR Gy –1 (95 % CI)

EAR (104 PY Gy)–1 (95 % CI)

5.4 (17)

2.3

14.4 (2.9 – 35)

7.7 (1.5 – 19)

Adenomas

13.7 (29)

7.6 (24)

1.8

9.0 (0.7 – 23)

6.8 (0.5 – 18)

Other nodules, surgical removal

60

15.9 (11)

2.4 (1)

6.6

93 (1.7 – 647)

22.5 (0.4 – 156)

Adenomas

1,360 (30 – 11,000)

102 (86)

7.3 (11)

14.1

6.3 (3.7 – 11.2)

5.8 (4.5 – 7.3)

Adenomas

~400

64.1 (9)

14.1 (10)

4.6

8.9 (2.3 – 25)

12.5 (3.2 – 35)

Nodules, includes nodular goiter

586 (10 – 5,800)

681 (555)

—

—

8.2 (3 – 37)

—

240 (30 – 550)

127 (44)

9.6 (3)

13.3

64 (18 – 225)

52 (15 – 180)

Endpoint

Benign nodules, multiple screenings Nodules, excludes nodular goiter and cancer

222 / 4. RADIATION EFFECTS

TABLE 4.11—Thyroid nodules: Incidence, number of nodules, and risks in cohort studies.

FDA childhood 131Ia (Hamilton et al., 1989)

~800

7.5 (7)

2.9 (2)

2.6

2.0 (–0.5 – 12.5)

0.6 (–0.1 – 3.6)

Graves’ disease, no palpable nodule at entry; 131Ia (Dobyns et al., 1974)

88,000

17.8 (20)

16.6 (18)

1.1

0.001 (–0.01 – 0.01)

0.001 (–0.01 – 0.02)

Radium dial painters (Polednak, 1986)

630

88 (18)

84 (9)

1.0

0.08 (–0.8 – 2.1)

0.7 (–6.9 – 17)

Adenomas, nodules, nodular goiter

Childhood cancer (Ron et al., 1995; Tucker et al., 1991)

12,500 (1,000 – 76,000)

—

—

53.5

1.1 (0.4 – 29)

0.4 (0.1 – 0.6)

Nodules

Skin hemangioma 226Ra treatment in Gothenburg, Sweden (Lindberg et al., 1995)

116 (17 – 115)b

—

—

1.88

7.5 (0.4 – 18.1)

1.6 (0.092 – 3.9)

Nodules

French hemangiomas (de Vathaire et al., 1993)

86 (0 – 2,740)b

—

—

—

3

18

Nodules

to 75th percentiles. Probably skin dose.

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b

Adenomas

4.6 BENIGN THYROID NODULES

a25th

Nodules, includes nodular goiter

Study (reference)

Dose (Gy)a (range)

Percent Prevalence (number of cases) Irradiated

Control

Relative Risk

ERR Gy –1 (95 % CI)

Endpoints

Multiple fluoroscopy (Kaplan et al., 1988)

0.1 – 1.1

7.7 (6)

4.2 (2)

1.8

2.5 (–0.8 – 16.7)

All nodules

Boston lymphoid hyperplasia (Pottern et al., 1990)

0.24

6.5 (39)

3.7 (15)

2.0

4.3 (0.5 – 11.3)

Nodules, excludes nodular goiter

Nagasaki atomic bomb, all ages (Nagataki et al., 1994)

0.49 (0.01 – 1)

3.2 (53)

1.5 (14)

2.1

2.5 (0.3 – 6.9)

Single solid nodule

Hiroshima-Nagasaki atomic bomb, ages <40 y at exposure (Imaizumi et al., 2006)

0.45

21.6 (325)

10.1 (139)

2.1

2.0 (1.3 – 2.9)b

All solid nodules

0.45

6.9 (104)

3.8 (52)

1.8

1.5 (0.8 – 2.7)b

Benign nodules

2.9

1.3 (15)

0.2 (2)

6.3

1.6 (0.2 – 7.4)

Benign nodular goiter

Thymus/cervical adenitis (Maxon et al., 1980)

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TABLE 4.12—Thyroid nodules: Prevalence and relative risks in screening studies after acute exposures.

0.17

249

Not available

1

0

Robert Packer Hospital (Royce et al., 1979)

~7.2

6.1 (13)

4.5 (11)

1.5

0.08 (–0.05 – 0.37)

Single/multiple nodules

Atomic-bomb autopsy series (Yoshimoto et al., 1995)

0.29

3.6 (97)

2.7 (31)

1.35

0.51 (0.18 – 0.94)

Adenomas

a1 b

Palpable, discrete mass or nonpalpable, focal ultrasound-detected mass of at least 1.5 cm (averaged across three dimensions); histologically or cytologically confirmed as benign by HTDS pathologist

Gy = 100 rad. Dose-response analysis of EOR, adjusted for age at exposure, sex and city; modeled estimate for age 10 y at exposure.

4.6 BENIGN THYROID NODULES

Hanford Thyroid Disease Study (Davis et al., 2004a)

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Study (reference)

Swedish diagnostic 131I (Hall et al., 1996b) Utah fallout (Lyon et al., 2006; Simon, 2006b)d

Dose (Gy)a (range)

Percent Prevalence (number of cases)

Relative Risk

ERR Gy –1 (95 % CI)

Endpoints

Irradiation

Control

0.54 (20 – 1,450)b

10.6 (107)

11.3 (29)

0.9

0.9 (0.3 – 2.3)c

Single and multiple nodules

1 (0.00011 – 1.4)

1.2 (7)

0.49 (13)

2.5

13.02 (2.7 – 68.7)

Benign and malignant nodules, excludes simple goiter

29.1 (37)

3.8 (—)e

7.7

—e

Surgical removal nodules

Marshall Islands, less than age 19 y (Robbins and Adams, 1989) Marshall Islands, age 19+ y (Robbins and Adams, 1989)

4.7

11.1 (14)

8.9 (?)e

1.3

—e

Surgical removal nodules

Marshall Islands survey (Hamilton et al., 1987)

—e

6.1 (110)

2.4 (9)

2.5

—e

Single nodules

Marshall Islands (Takahashi et al., 1997)

—e

22.4 (421)

8.5 (22)

—e

Single nodules

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TABLE 4.13—Thyroid nodules: Prevalence and relative risks in screening studies after protracted exposures.

0.14

7.4 (74)

6.6 (66)

1.1

1.5 (–2.2 – 6.7)

Single nodules

Kerala, India (Pillai et al., 1976)

0.3

0.9 (115)

0.9 (56)

1.0

–0.2 (–1.1 – 1.0)

Single nodules

~0.02 – 0.13

6.5 (13)

4.0 (6)

1.6

9.6 (–5.1 – 48)

Single nodules or adenoma

Chernobyl cleanup workers (Inskip et al., 1997a)

0.11 (0 – 0.61)

10.2 (201)

—

—

–1 (–2 – 1)

All nodules on United States; 165 single, 36 multiple

Medical radiation workers (Antonelli et al., 1996)

Unknown

40.9 (18)

12.5 (11)

3.3

—

Nodules >5 mm per diagnostic ultrasound

Near uranium waste site (Radford et al., 1983)

a

1 Gy = 100 rad. to 90th percentiles. cWithin the irradiated group there was a significant dose-response relation. d For benign neoplasms the percent prevalences (number of nodules) were 0.9 (10) and 0.2 (3) in the irradiated and control groups, respectively. eInformation not given. b10

4.6 BENIGN THYROID NODULES

High radiation area, China (Wang et al., 1990b)

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228 / 4. RADIATION EFFECTS prevalence increased with dose (ERR Gy –1 = 3). Simple diffuse goiter was found in 24 patients and was dose related (ERR Gy –1 = 4). There was a weak indication ( p = 0.08) that treatments administered at a high dose rate (administered within a few minutes) induced nodules more than those at a lower dose rate (from 30 min to several hours). Only four patients had clinical abnormalities in their thyroid function (one hyperthyroid and three hypothyroid). There was no dose response for functional thyroid disorders. 4.6.1.3 Massachusetts Fluoroscopy Study. A cohort of 5,979 women who had been treated for pulmonary tuberculosis (TB) in a Massachusetts sanitarium between 1930 and 1954 (Table 4.12) were identified (Kaplan et al., 1988). A subset of 375 of these women was contacted by telephone survey. One hundred and sixty-three women agreed to participate in this study. Ninety-one women who had received an average of 112 fluoroscopic examinations during their pneumothorax treatment of pulmonary TB over 40 y previously and in 72 women treated for TB by other modalities were included in the study. It could not be determined when or if the thyroid gland was within the primary beam during the fluoroscopic exams, so the average dose may have been as low as 0.1 Gy or as high as 1.1 Gy in the exposed population. Serum thyroid hormone and calcium levels were measured. All thyroid examinations during the pilot study were conducted by one thyroidologist who was unaware of each patient’s exposure history. Thyroid scintigraphy was used to confirm the presence of definite and suspected nodules. Thyroid nodules were diagnosed in 7.7 % of the irradiated group and 4.2 % of the comparison group (prevalence ratio = 1.8, 95 % CI 0.5 to 7.1). Autoimmune thyroid disease was diagnosed in 15 % of the irradiated group and 7 % of the comparison group (prevalence ratio = 2.4, 95 % CI 0.8 to 6.2). Overall, any thyroid abnormality was present in 27 % of the irradiated group and 18 % of the comparison group (prevalence ratio = 1.5, 95 % CI 0.8 to 3). 4.6.1.4 Chicago Head and Neck Irradiation Study. The methodological characteristics (Table 4.2) and the strengths and limitations (Table 4.3) of the Chicago Head and Neck Irradiation Study (Schneider et al., 1993) have been presented. The results for benign nodules are presented here (Table 4.11). Five hundred and fortynine benign nodules were observed. ERR Gy –1 was 8.2 (95 % CI 3 to 37). The authors noted that screening after 1974 increased the age- and gender-adjusted rates for thyroid nodules 17-fold [from 42.3 (104 PY Gy)–1 to 725.2 (104 PY Gy)–1]; screening increased the age- and gender-adjusted rates for thyroid cancer by sevenfold.

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In a follow-up study, 770 subjects were randomly selected to be interviewed by telephone from the 2,985 traced subjects in the Chicago Head and Neck Irradiation Cohort (Wong et al., 1996). The purpose of the structured interview was to gain information on the occurrence of benign and malignant thyroid nodules, socioeconomic factors, religion, height and weight, family history of cancer, and reproductive data in females. In their analysis, the authors sought to determine how these factors might modify the risk for benign thyroid tumors. The authors’ analysis was based on 544 subjects (44 % females) who completed the interviews and had individual thyroid dose estimates. The mean thyroid dose was 570 mGy received at a mean age of 4.5 y. The mean participant age at the time of the telephone survey was 49 y. A total of 131 thyroid nodules was reported by the subjects and confirmed by review of medical records. ERR Gy –1 was 11 (lower 95 % confidence limit of two), which is similar to the risk calculated for the entire cohort. There was a strong effect of age at irradiation ( p = 0.006). Factors that modified the risk included female gender (RR = 2.2, 95 % CI 1.6 to 3.2), Jewish religion (RR = 1.7, 95 % CI 1.1 to 2.5), college graduate (RR = 1.8, 95 % CI 1.2 to 2.8), never married (RR = 1.8, 95 % CI 1 to 3), father with any cancer (RR = 1.3, 95 % CI 1 to 2.1), mother with any cancer (RR = 1.7, 95 % CI 1.2 to 2.5), parent with any cancer (RR = 1.4, 95 % CI 0.97 to 2), and first-degree relative with any cancer (RR = 1.4, 95 % CI 1 to 2). 4.6.1.5 Tinea Capitis Study. The Tinea Capitis Study by Ron et al. (1989) also acquired data on benign tumors of the thyroid (Table 4.11). There were 55 benign tumors (26 adenomas and 29 nodules) in the exposed group and 41 benign tumors (17 adenomas and 24 nodules) in the unexposed group. ERR Gy –1 for benign tumors was eight (95 % CI 7 to 9) and EAR was 14.8 [(104 PY Gy)–1]. 4.6.2

Stockholm Medical Diagnostic Iodine-131 Study

In the Stockholm Medical Cohort Study (Hall et al., 1996b), 1,452 women who had been exposed to 131I for a diagnostic study when under age 45 y between 1952 and 1977 were offered a clinical examination of the neck (Table 4.13). The participation rate in the exposed group was 72 %. The clinical examination was performed on 1,005 women who responded and who met additional eligibility requirements. The examination was performed by two thyroid specialists who were unaware of each subject’s exposure history. The unexposed group consisted of 248 similar-age women recruited from a mammography clinic who met the eligibility criteria. The average age at the time of 131I exposure was 26 y; only 17 % of the women

230 / 4. RADIATION EFFECTS were <20 y at the time of exposure. The mean thyroid dose was 540 mGy. The average length of follow-up was 26 y. The prevalence of palpable thyroid nodules was 10.6 % (107/1,005) among exposed women and 11.3 % (28/248) among unexposed women (RR = 0.9, 95 % CI 0.6 to 1.4). No thyroid cancers were found as a result of this examination. When the low-dose group, <250 mGy was compared to the unexposed group, the relative risk for nodules was 0.6 (95 % CI 0.3 to 1). Within the exposed group there was a dose-response relationship [ERR Gy –1 = 0.9 (95 % CI 0.2 to 2.3)]. ERR was similar for those irradiated before age 20 y and after age 20 y. The authors concluded that their data were the first to show a significant dose response for 131I exposure and thyroid nodules. 4.6.3

Atomic-Bomb Survivors

4.6.3.1 Nagasaki Thyroid Disease Study. To determine the thyroid disease status for the Nagasaki AHS Cohort (Nagataki et al., 1994), thyroid examinations were performed on 2,587 Nagasaki participants (61 % women) 40 y after exposure from the atomicbomb detonation (Table 4.12). The subjects spanned a wide age range at the time of exposure (average age ~19 y). A DS86 thyroid dose estimate was available for 76 % of subjects (1,978). There were 935 participants assigned a thyroid dose of 10 mSv. The average dose assigned to the 1,043 exposed participants with thyroid doses of >10 mSv was ~770 mSv. Thyroid doses could not be estimated for 609 of the participants. The thyroid examination included palpation, diagnostic ultrasound scan with determination of thyroid size, and blood assays for thyroid hormones and antibodies. Thyroid nodules were detected in 190 participants (39 men and 151 women). Solid thyroid nodules were found in 90 patients either at the time of this examination or previously, including 21 thyroid cancers, 16 adenomas, and 3 adenomatous goiters. Statistically-significant dose-response relationships were found for solid nodules (women only), thyroid cancers, thyroid adenomas, and autoimmune thyroid disease. The authors did not calculate an ERR Sv–1 for these findings. 4.6.3.2 Hiroshima Autopsy Study. The autopsy results of 3,821 Hiroshima atomic-bomb survivors (49.6 % women; 1,149 unexposed; 2,672 exposed) were analyzed (Table 4.12) to determine the dose-effect relationship for latent thyroid cancer (greatest dimension 1.5 cm), thyroid adenoma, colloid/adenomatous goiter, and chronic thyroiditis (Yoshimoto et al., 1995). The diagnosis of thyroid disease was histologically based on a routine analysis of a single microscope slide of thyroid tissue.

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The presence of thyroid disease was recorded in 486 autopsies (110 latent thyroid cancers, 128 thyroid adenomas, 128 colloid/ adenomatous goiters, and 80 chronic thyroiditis). The prevalence of thyroid adenomas in the unexposed and exposed cohorts was 2.7 % (31/1,149) and 3.6 % (97/2,672), respectively. The relative risk for thyroid adenoma was ~1.5 at 1 Gy and was similar for both genders. Yoshimoto et al. (1995) stated that their data are the first to show a statistically-significant dose-response relationship for atomic-bomb radiation exposure and thyroid adenomas.

4.6.3.3 Noncancer Disease Incidence. In a study of noncancer disease incidence in atomic-bomb survivors (Yamada et al., 2004), dose-response relationships were found for thyroid disease (Figure 4.12). The relative risk at 1 Gy for thyroid disease was 1.33 (95 % CI 1.19 to 1.49, p < 0.0001). The average number of excess disease cases was 12 (104 PY Gy)–1 and the attributable risk was 18 %. The radiation risk was highest for subjects exposed at younger ages. The relative risk at 1 Gy for subjects exposed at less than age 20 y was 1.54 (95 % CI 1.33 to 1.81, p < 0.0001). For those exposed after age 20 y, the relative risk at 1 Gy was not statistically significant [1.11 (104 PY Gy)–1, 95 % CI 0.96 to 1.30, p < 0.18]. These findings differ from those of HTDS (Davis et al., 2004a). However, the types of exposures differ significantly (acute external versus episodic internal).

4.6.3.4 Thyroid Disease Prevalence. In Hiroshima and Nagasaki, 3,185 members of the AHS Cohort with estimated doses from the atomic bombs were screened for thyroid neoplasia by palpation and ultrasound (Table 4.12), with the examiners blinded as to dose (Imaizumi et al., 2006). The examinations were conducted 55 to 58 y after exposure. The dose-response associations were statistically significant for all solid nodules [excess odds ratio (EOR) Gy –1 = 2.01, 95 % CI 1.33 to 2.94; n = 464], diagnosed malignant tumors (EOR Gy –1 = 1.95, 95 % CI 0.67 to 4.92, n = 70) and diagnosed benign tumors (EOR Gy –1 = 1.53, 95 % CI 0.76 to 2.67, n = 156). The associations were all compatible with linearity, and for all three classifications the risk decreased with increasing age at exposure. The frequency of thyroid nodules was greater among women than men, but the EOR Gy –1 did not differ by gender. Another finding in the study was that autoimmune thyroid diseases were not associated with radiation exposure.

232 / 4. RADIATION EFFECTS

Fig. 4.12. Estimated linear dose response (solid line) for the incidence of six noncancer diseases within the atomic-bomb survivors with significant or suggestive positive or negative associations with radiation exposures, 1958 to 1998. The 95 % confidence intervals are shown as dotted lines. The estimated relative risks and 95 % confidence interval are shown for each dose category (Yamada et al., 2004).

4.6.4

Environmental Exposures

4.6.4.1 Chernobyl Cleanup Workers Study. Thyroid examination, including palpation, diagnostic ultrasound and, selectively, FNA biopsy were conducted on 1,984 of 4,833 Chernobyl cleanup workers from Estonia sent to Chernobyl between 1986 and 1991 (Inskip et al., 1997a); 2,997 of the total workforce were invited for thyroid screening (Table 4.13). The participation rate was 1,984/2,997 or 66 %. Of the screened workers, 63 % (1,247/1,984) were sent to Chernobyl in 1986 and 30 % of them (603/1,984) were sent in April or May of 1986, soon after the incident. Workers at Chernobyl served for an average of three months. The workers were exposed to radiation at a mean age of 32 y and were examined at a mean age of 40 y. Estimates of dose from external sources were obtained from: (1) military or other institutional records, (2) details from a selfadministered questionnaire regarding service dates and types of

4.6 BENIGN THYROID NODULES

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work performed while at Chernobyl, and (3) biodosimetry (chromosomal translocations and glycoporin-A assays). Military and other institutional records were missing for 259 men. Doses to the thyroid glands from radioiodines were unknown. The mean documented dose from external sources was 108 mGy. The maximum recorded dose for any worker was 610 mGy. The primary endpoint was the presence or absence of thyroid nodules as revealed by diagnostic ultrasound. Thyroid nodules were detected by diagnostic ultrasound in 10.2 % (201/1,984) of workers. Single and multiple nodules were found in 8.3 % (165/1984) and 1.8 % (36/1984) of workers, respectively. The mean nodule size was 1 cm (range 0.3 to 5 cm). The nodules detected by ultrasound were palpable in only 22 % (44/201) of workers. In addition, ultrasound did not confirm the presence of a thyroid nodule palpated on physical exam in 95 workers. Among the 77 study participants subjected to FNA biopsy, 2 papillary thyroid cancers, 3 follicular neoplasms, and 10 possible neoplasms were diagnosed. The papillary cancers were confirmed surgically and occurred in workers sent to Chernobyl in May of 1986. The three follicular neoplasms and five of the 10 possible neoplasms were diagnosed as benign nodules following surgery. Five participants with possible neoplasms did not have surgery. For 18 study participants, the FNA biopsy was inadequate for a diagnosis. Among men with nodules, the mean thyroid dose was 102 mGy. Among those without thyroid nodules, the mean thyroid dose was 109 mGy. There was no statistically-significant dose-response relationship for thyroid nodules. The correlation of thyroid nodularity with chromosome translocations in lymphocytes was marginal ( p = 0.10). The authors concluded that these cleanup workers experienced little, if any, increased risk of nodular thyroid disease 9 y after the Chernobyl nuclear reactor accident. 4.6.4.2 Chinese High Background Study. In this study (Table 4.13), thyroid nodularity was evaluated by physical examination in 1,001 women aged 50 to 65 y who lived in a high background-radiation area in China of 0.85 × 10–4 C kg –1 y–1 and 1,005 women from a normal background area of 0.294 × 10–4 C kg –1 y–1 (Wang et al., 1990b). These high background areas have thorium-containing monazite soil. Average cumulative thyroid doses were estimated as 140 mGy in the high background areas and 50 mGy in the normal background areas. The participation rate was 91 %. Each subject responded to a personal interview and had a thyroid examination. The personal interview provided information about medications, medical and reproductive history, symptoms

234 / 4. RADIATION EFFECTS related to thyroid function, thyroid surgery, a family history of thyroid disease, smoking habits, diagnostic and therapeutic x-ray procedures, and diet history. Thyroid examinations consisted of palpation by examiners who were unaware of the subjects’ exposure status. All subjects with positive findings on physical examination of the thyroid and a 10 % random sample of other subjects had a second independent thyroid examination. Blood for thyroid hormone levels and thyroid antibodies was obtained in all subjects with thyroid abnormalities and in 10 % of subjects without thyroid abnormalities. Sixty-five FNA biopsies were also obtained, mostly in subjects with palpable nodules that were 1.5 cm or greater in size. For technical reasons, no results from these FNA biopsies were reported. The prevalence of nodular disease in the high and normal background areas was 9.5 and 9.3 %, respectively, with relative risk of 1.02 (95 % CI 0.76 to 1.35); the respective prevalence for solitary nodules was 7.4 and 6.6 % yielding a prevalence ratio of 1.13 (95 % CI 0.82 to 1.55). No differences were found between the groups in thyroid hormone levels. The authors concluded that continuous exposure to low-level radiation throughout life is unlikely to appreciably increase the risk of thyroid cancer.

4.6.4.3 India High Background Study. In this cohort study (Table 4.13), the prevalence of thyroid nodules was determined for the population living in a high and in a normal background-radiation area on coastal India (Pillai et al., 1976). The high background area was in Kerala, India, where radiation from monazite sands, which contain naturally-occurring radioactive thorium, results in doses of 3.87 to 7.74 × 10–4 C kg –1 y–1, depending on the type of housing. The normal background-radiation area was a similar coastal strip of India. The populations of the high and normal background areas were ~12,000 and 6,000 individuals, respectively. The authors visited each household in the selected areas to collect demographic data and to palpate the thyroid glands of essentially the entire populations in the two defined geographic areas. The age and gender distributions of the two populations were similar. In the two populations, a nearly identical prevalence of single nodules (8.8 versus 9 per 1,000) and of total nodules (11.4 versus 12 per 1,000) were found. Thirty-three persons with nodular lesions of the thyroid from the study area and three from the control area had surgery. None of the nodules was malignant. The authors concluded that there was not a higher than expected incidence of thyroid nodular disease or neoplasms in the area with high background.

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4.7 Functional Thyroid Disease Neoplastic diseases of the thyroid following radiation exposure have been studied more extensively than functional thyroid disease. Functional thyroid diseases include diseases of the thyroid that result in the thyroid gland producing too much (hyperthyroidism) or too little (hypothyroidism) thyroid hormone. These functional diseases may or may not be associated with the presence of thyroid nodules or changes in overall thyroid size (e.g., goiter). 4.7.1

Thyroid Function Following External Beam Radiation Therapy

The first reports of hypothyroidism following EBRT for head and neck cancer appeared in the 1960s (Cannon, 1994; Einhorn and Wilkholm, 1967; Markson and Flatman, 1965). In the Markson study, five patients developed hypothyroidism following EBRT to the neck in fractionated doses between 26.25 and 48.5 Gy (Markson and Flatman, 1965). While the hypothyroidism was initially thought to be related to direct toxicity of radiation to the thyroid cells or the supporting vasculature, several papers in the 1960s and early 1970s noted either a transient or persistent rise in anti-thyroid antibody levels after radioiodine therapy (Einhorn and Wilkholm, 1967; Einhorn et al., 1966; O’Gorman et al., 1964) suggesting a possible autoimmune component to the thyroid dysfunction. More recent studies also noted an increased risk of Graves’ disease in Hodgkin’s patients previously treated with EBRT further strengthening the link between high-dose radiation and development of autoimmune antibodies (Hancock et al., 1991). Over the years, published studies have generally supported the concept that high doses of radiation to the thyroid, either in the form of radioiodine or EBRT, may increase the risk of hypothyroidism. However, differences in radiation treatment volumes, treatment doses, fractionation schemes, techniques, length of follow-up, method of assessment for subsequent thyroid disease, and concurrent treatments or comorbidities between the various studies result in widely differing estimates for specific rates of both early and late hypothyroidism. A recent review (Jereczek-Fossa et al., 2004) noted that primary hypothyroidism was the most common late clinical effect of thyroid radiation (30 to 70 Gy) resulting from high-dose radiation therapy in the cervical region with prevalence rates ranging from 3 to 92 % with a median value of 20 to 30 %. Race was a factor for

236 / 4. RADIATION EFFECTS the development of hyperthyroidism in one study of pediatric patients, with white patients at higher risk than blacks (Metzger et al., 2006). Older patients were at greater risk for developing hyperthyroidism (Tarbell et al., 1990). Furthermore, there does appear to be a dose-response relationship between thyroid irradiation and development of thyroid failure. Hypothyroidism developed in only 4 of 24 (17 %) patients who received mantle doses <26 Gy, but was seen in 74 of 95 (78 %) of those who received doses >26 Gy (Constine and McDougall, 1982; Constine et al., 1984). In the Childhood Cancer Survivor Study, clinical hypothyroidism was diagnosed in 20 % of childhood Hodgkin’s lymphoma survivors who received <35 Gy to the thyroid gland, 30 % in those who received 35 to 44.9 Gy, and 50 % of those who received >45 Gy (Sklar et al., 2000). In a follow-up study this cohort revealed that the risk of thyroid cancer increased with doses up to 20 to 29 Gy [OR = 9.8 (95 % CI 3.2 to 34.8)]. At doses >30 Gy, a reduction in the dose-response was seen (Sigurdson et al., 2005). Using more sensitive techniques to detect mild thyroid dysfunction, nearly all patients receiving thyroid doses in excess of 40 Gy developed a rise in serum TSH consistent with hypothyroidism (Nishiyama et al., 1996a; 1996b). A review by Friedman and Constine (2006) concluded that the highest likelihood of subsequent decreased thyroid function was seen in patients receiving 30 Gy or more to the thyroid (Friedman and Constine, 2006). Due to the long latent period, long-term follow-up of thyroid function is needed for patients exposed to therapeutic radiation (Turner et al., 1995). Very few studies have examined the potential adverse effects to the thyroid from very low-dose ionizing radiation (<1 Gy). Kaplan et al. (1988) noted an increase in autoimmune thyroid disease in a cohort of 91 women exposed to serial fluoroscopic examinations as routine follow-up for pneumothorax therapy for pulmonary TB (Kaplan et al., 1988). The dose to the thyroid was unknown but was estimated to be ~600 mGy on the basis of the number of thyroid nodules found during follow-up. Using a definition of autoimmune thyroid disease that included the presence of anti-microsomal antibodies with at least one additional clinical finding (abnormal thyroid physical examination, elevated serum TSH, or patient history of hypothyroidism, hyperthyroidism or goiter), 15 % of patients exposed to repeated fluoroscopy evaluations were found to have autoimmune thyroid disease versus 7 % of patients followed without routine repeated fluoroscopy (prevalence ratio 2.2, 95 % CI 0.8 to 6.2, not statistically significant). While these results are intriguing, the lack of accurate thyroid dosimetry data and the broad definition of autoimmune thyroid disease make this study difficult to

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interpret, and is an insufficient basis to conclude that the exposures at issue are likely to increase the risk of hypothyroidism. Spitalnik and Straus (1978) found evidence for chronic lymphocytic thyroiditis, benign thyroid nodules, and papillary thyroid cancers in thyroid glands removed for palpable thyroid abnormalities in a cohort of 68 patients who received low-dose EBRT for benign disease during childhood (thymus, tonsillitis, adenoiditis, acne and scalp conditions). While the dose to the thyroid was not known, the authors noted that all received <10 Gy. Given the conditions treated, it is likely that most of the patients received doses between 200 and 1,500 mGy as these were the usual doses received by patients with similar conditions in other studies. Regardless of the dose received, the marked selection bias for cases (all with palpable thyroid disease requiring surgical removal) makes the results not generalizable to patients without palpable thyroid disease. Therefore, no conclusions can be drawn regarding doseresponse relationships from this study. While doses in the 3 to 10 Gy range during childhood for a variety of benign diseases have been linked to the subsequent development of thyroid cancer, there does not appear to be significant increase in clinical hypothyroidism in the years following these therapies (Pincus et al., 1967; Refetoff et al., 1975). In fact, Maxon et al. (1977) concluded that external radiation was associated with clinical hypothyroidism only at doses >10 Gy. In summary, ionizing radiation delivered as EBRT to the head and neck region, with thyroid doses ranging between 25 to 70 Gy, is associated with subsequent clinical hypothyroidism in a dosedependent manner. The mechanism for the subsequent hypothyroidism is not well defined, but is likely a combination of direct toxic effect of radiation on the thyroid cells, toxic effect on the endothelium of the small blood vessels supplying the thyroid, and perhaps a component of autoimmune mediated thyroiditis.

4.7.2

Thyroid Function Following Radioiodine Therapy

Radioactive iodine is used to treat both benign thyroid disease (Graves’ disease and toxic multinodular goiter) (Reid and Wheeler, 2005) and thyroid cancer (Cooper et al., 2006). In both cases, the patients have underlying thyroid disease and receive large therapeutic doses of radioiodine (>80 to 100 Gy). As would be expected, these treatments result in clinical hypothyroidism usually within a few months. These studies have no bearing on the risk of autoimmune thyroid disease from low-dose radiation.

238 / 4. RADIATION EFFECTS 4.7.3

Thyroid Function Following Environmental Exposure to Radioiodine

For many years, the primary endpoint of most studies on environmental radiation exposure was nodular thyroid disease (either benign or malignant). While high-dose irradiation to the thyroid was known to be associated with hypothyroidism (see above), the relatively lower doses of thyroid radiation associated with environmental exposure were not expected to be associated with clinically significant thyroid dysfunction. However, the last few years have seen several publications that have questioned the role of ionizing radiation in the subsequent development of autoimmune thyroid disease (Eheman et al., 2003). The endpoints of these studies vary from development of antithyroid antibodies as an indirect marker of autoimmune thyroiditis, to a rise in serum TSH as a direct marker of hypothyroidism, to autopsy studies of chronic inflammation within thyroid glands examined. To further confound the issue, environmental radiation exposures were often a combination of external radiation and internal ingestion of radioactive substances making them not directly comparable to studies of exposure to radioactive iodine alone or EBRT alone. Eheman et al. (2003) carefully reviewed the studies of environmental exposure to ionizing radiation and subsequent development of autoimmune thyroid disease and concluded that there was some evidence, primarily in the form of ecological studies which indicated that low-dose environmental radiation exposure associated with atomic weapons or nuclear reactor accidents may be associated with a higher than expected prevalence of anti-thyroid antibodies. Low dose is a relative term. A careful review of the dose estimates from the studies examined, and additional studies subsequently published, showed that the definition of “low dose” to the thyroid included in these studies was generally less than several hundred centigray to the thyroid (see detailed review below). 4.7.3.1 Marshall Islands Fallout. The United States conducted above-ground tests of nuclear weapons primarily at NTS and on Bikini and Enewetak Atolls in the Marshall Islands. Weapons testing in the Marshall Islands included more than 65 nuclear detonations over a 12 y period. While the testing resulted in wide-spread deposition of low-level fallout over many of the atolls, the BRAVO accident in March 1954 exposed ~300 inhabitants of Rongelap and Utirik Atolls to thyroid doses ranging from ~1.9 to 20 Gy. The radiation exposure was a combination of external irradiation from fallout deposited on the ground and ingestion of radioactive iodines.

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As would be expected, hypothyroidism developed in two boys exposed as infants to more than 50 Gy thyroidal radiation (Cronkite et al., 1995). Larsen et al. (1982) detected clinical hypothyroidism in eight of the exposed subjects with doses that ranged from 3.9 to 21 Gy. Minimal elevations in serum TSH (none >7 mIU L–1) were noted in six persons exposed to thyroid doses between 1.35 and 14 Gy (Larsen et al., 1982). Despite more than 40 y of follow-up of the BRAVO Cohort, no evidence of an increased prevalence of anti-thyroid antibodies has been detected (Cronkite et al., 1995). In 1993, serum samples were obtained from 3,000 Marshallese alive at the time of the weapons testing program showed only 33 subjects (1.1 %) with elevated levels of anti-thyroid antibodies (Takahashi et al., 1999). Therefore, the data from the Marshall Islands follow-up studies demonstrated that thyroid doses between 3 to 50 Gy can be associated with elevated TSH values and clinical hypothyroidism. However, there is no evidence for the development of anti-thyroid antibodies in this relatively small cohort of subjects followed for >40 y. 4.7.3.2 Nevada Test Site. Between 1951 and 1958, more than 100 above-ground tests of nuclear weapons were conducted at NTS. Radiation exposure was primarily from radioactive iodines with a small component of external irradiation. Rallison et al. (1991) compared the results of thyroid examinations in 2,687 young people living in southwestern Utah and Nevada near NTS with a comparable group of 2,132 young people living in southeastern Arizona (remote from NTS). Initial evaluations were done in 1965 when the subjects were in grades 5 through 12 and then again, ~20 y later, when they were age 30 to 38 y (Rallison et al., 1991). All participants were born between 1945 and 1957, making them age 0 to 7 y during the spring of 1953 (the time of maximum radiation exposure). While specific doses were not known, thyroiditis (defined as diffusely enlarged goiter with or without elevated TSH values and/or anti-thyroid antibodies) was detected in 5.1 % of the entire cohort (6.5 % in the Utah/Nevada Exposed Cohort, 3.4 % in the Arizona Less Exposed Cohort). There was also a suggestion of a slightly higher prevalence rate of hypothyroidism in the Utah/Nevada Cohort (18/1,000 subjects) than in the Arizona Cohort (12/1,000 subjects). Importantly, at the time of last follow-up, 27 % of patients initially diagnosed with thyroiditis had returned to normal thyroid status, 33 % were unchanged, and only 33 % had become hypothyroid during nearly 20 y of follow-up (Rallison et al., 1991).

240 / 4. RADIATION EFFECTS Kerber et al. (1993) published individual dosimetry data for the 4,818 subjects who were initially evaluated by Rallison et al. (1991). The mean (median) thyroid dose for the unexposed Arizona Cohort was 13 mGy (3.6 mGy), for the Nevada Cohort 50 mGy (28 mGy), and for the Utah Cohort 170 mGy (72 mGy). No doseresponse trend was seen for thyroiditis, hypothyroidism or hyperthyroidism when the data were adjusted for age, gender and state of residence. In the most recent analysis of the original Rallison Cohort (Rallison et al., 1991), Lyon et al. (2006) presented an updated analysis that represents modifications of the dosimetry model [based on current understanding of the complex issues involved in estimating thyroid dose from radioiodine fallout in cohort studies (Simon et al., 1990; 2006b)] and updated thyroid disease diagnoses (based on abnormal thyroid blood tests and not physical examination alone). This new analysis demonstrated an increasing risk for thyroiditis (positive anti-thyroid antibodies) with increasing individual dose. Hypothyroidism (elevated TSH) was seen only at the highest dose level >410 mGy (Table 4.14). In order to assess the possible effects of in utero exposure to the NTS fallout, Lloyd et al. (1996) analyzed 403 participants of the original Rallison Cohort who were in utero at the time of highest radiation fallout and who also had individual dosimetry data calculations available and who were reexamined in the 1985 to 1986 evaluations (Lloyd et al., 1996). Only 37/403 had thyroid abnormalities detected nearly 30 y after exposure (17 with thyroiditis based on the original disease definitions, and 4 with hypothyroidism). No dose-response relationship was found for thyroiditis, hypothyroidism, or nodular thyroid disease over a range of estimated thyroid doses ranging from <10 to 2,600 mGy. Therefore, the data from NTS exposures indicate a doseresponse relationship between thyroid irradiation and the development of anti-thyroid antibodies at thyroid doses that extend as low as 75 mGy. It is important to remember that the development of anti-thyroid antibodies is not clinical hypothyroidism. Importantly, despite 30 y of follow-up, no dose relationship was noted for the development of hypothyroidism. Furthermore, an increase in the adjusted relative risk for developing hypothyroidism was seen only at estimated thyroid doses >410 mGy. In part, the discrepancy between the risk of anti-thyroid antibodies and the lack of subsequent development of clinical hypothyroidism is explained by the observations in the initial Rallison et al. (1991) study demonstrating that 27 % of patients diagnosed with thyroiditis actually returned to normal thyroid status with observation alone and an

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TABLE 4.14—Risk of autoimmune thyroid disease relative to thyroid dose (Lyon et al., 2006). Thyroid Dose (mGy)

Thyroiditisa Adjusted Relative Risk (95 % CI)

Hypothyroidb Adjusted Relative Risk (95 % CI)

>0 – 74

1.0

1.0

75 – 215

1.6 (1.1 – 2.5)

1.5 (0.7 – 3.3)

216 – 409

1.9 (1.0 – 3.4)

0.8 (0.2 – 3.4)

>410

5.6 (3.5 – 9.2)

3.3 (1.2 – 9.1)

aTrend b

statistically significant, p = <0.001 for trend. Trend not statistically significant, p = 0.18 for trend.

additional 33 % continued to have thyroiditis without evidence for hypothyroidism. Therefore, while the presence of anti-thyroid antibodies are a risk factor for subsequent development of hypothyroidism, this may or may not happen in an individual patient. In fact, based upon these data, in subjects exposed to NTS fallout, persistent thyroiditis without hypothyroidism or return to normal thyroid function (not clinical hypothyroidism) are the most likely expected outcomes over a 20 to 30 y follow-up period. 4.7.3.3 Hanford Thyroid Disease Study. The Hanford Site in southeastern Washington State was built in the early 1940s to produce plutonium for the Manhattan Project. In 1986, it became public knowledge that 27 PBq of 131I was released from the Hanford Site into the environment between 1944 and 1957. Davis et al. (2004a) identified a cohort of 5,199 individuals who were children at the time of the radiation release, located 4,350 of them, and had complete evaluations on 3,440, which formed the basis of HTDS (Davis et al., 2004a). To date, HTDS is the largest cohort study to specifically examine the effect of environmental exposure to 131I on subsequent development of thyroid disease in a well-defined group of high-risk patients with calculations of individual dosimetry. This study demonstrated no evidence of a statistically-significant relationship between dose to the thyroid (mean 174 mGy, median 97 mGy) during childhood and the subsequent development of hypothyroidism, anti-thyroid antibodies, benign thyroid nodules, or malignant thyroid disease. 4.7.3.4 Evidence from Atomic-Bomb Survivors in Nagasaki and Hiroshima. A large cohort of more than 100,000 Japanese atomicbomb survivors has been extensively studied for a wide variety of

242 / 4. RADIATION EFFECTS potential health effects over the last 60 y (Pearce, 2006; Shimizu et al., 1999). The radiation exposure was primarily external gamma radiation and neutrons, although there was some exposure to a wide range of fallout products as well (Ron et al., 1995). While the increase in thyroid cancer in these subjects is well documented (Thompson et al., 1994), the relationship between radiation exposure and development of autoimmune disease is much less clear. Morimoto et al. (1987) published an evaluation of thyroid function and anti-thyroid antibodies in a subset of the RERF AHS Cohort who were less than age 20 y at the time of the atomic-bomb explosions (Morimoto et al., 1987). There was no difference in TSH values or anti-thyroid anti-body levels determined 30 y after exposure between the exposed cohort (850, thyroid dose >1 Gy) and the unexposed control group (800, thyroid dose = 0 Gy). No subjects were included with thyroid doses <1 Gy. Hypothyroidism was diagnosed in 23 subjects with no correlation between thyroid dose and development of hypothyroidism. Fujiwara et al. (1994a; 1994b) published an evaluation of antithyroid antibodies in a cohort of 2,061 individuals exposed to atomic-bomb radiation in either Hiroshima or Nagasaki. Included in the study were 77 people with no radiation exposure, 683 with 10 to 990 mGy exposure, and 601 people with >1 Gy exposure. Follow-up evaluations were done ~40 y after exposure. No effect of radiation exposure was found on the prevalence of anti-thyroglobulin or anti-microsomal antibody levels. This study did not evaluate TSH levels or clinical evidence of hypothyroidism. Yoshimoto et al. (1995) published the results of thyroid histological examinations at autopsy in 3,821 atomic-bomb survivors in Hiroshima. Most of these subjects were adults at the time of the atomic-bomb explosion with only 197 less than age 19 y at the time of exposure. doses ranged from none (1,149) to 10 to 490 mGy (2,270) to 500 mGy (402). Chronic thyroiditis based on histological examination was detected in 50 subjects. However, unlike the prevalence of latent thyroid cancer and thyroid adenoma, there was no evidence of a relationship between dose and chronic thyroiditis. Histologic changes consistent with thyroiditis were detected in 1.5 % of patients with no radiation exposure, 1 % of patients with 10 to 490 mGy (mean 100 mGy), 3.6 % of patients with 500 to 990 mGy (mean 680 mGy), and 0.5 % of patients with thyroid doses >1 Gy (mean 2.03 Gy). Nagataki et al. (1994) presented results of thyroid function testing and anti-thyroid antibody analysis on a cohort of 2,587 Nagasaki atomic-bomb survivors examined 40 y after exposure. In this cohort, a statistically-significant dose relationship was detected

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between dose to the thyroid and subsequent development of antithyroid antibody positive autoimmune hypothyroidism (TSH > 10 mIU L–1). The dose-response relationship was not linear across estimated thyroid doses that ranged from 0 to 1.5 Sv. The maximum prevalence of autoimmune hypothyroidism was seen at a dose of 0.7 ± 0.2 Sv and then declined back to the levels seen in unirradiated controls at doses above ~1.2 Sv. In order to clarify and expand on the findings of the Nagataki et al. (1994) study of Nagasaki atomic-bomb survivors, Imaizumi et al. (2006) examined thyroid nodules and autoimmune thyroiditis in a larger cohort of atomic-bomb survivors including subjects from both Hiroshima and Nagasaki. Furthermore, because this study was done nearly 10 y after the 1994 Nagataki et al. (1994) study, advances in clinical diagnostics, including more sophisticated ultrasonography and more sensitive anti-thyroid antibody measurements, were included in the updated study (Imaizumi et al., 2006). The updated study consisted of 4,091 subjects (mean age 70 y) examined between 2000 and 2003, more than 50 y after exposure. Unlike the Nagataki study, Imaizumi et al. (2006) found no significant dose relationship for anti-thyroid antibody positive hypothyroidism. On the surface, the results of Nagataki et al. (1994) and Imaizumi et al. (2006) appear to be conflicting. However these apparent conflicts may be explained by significant differences in study design and scope. In addition to examining different patient cohorts, a careful analysis of the manuscripts demonstrates major differences in the definitions used for “anti-thyroid antibody positive hypothyroidism.” In the Nagataki paper, the definition included a TSH > 10 mIU L–1 (quite high by today’s standard where a TSH > 4 to 5 mIU L–1 is considered abnormal) and the older anti-microsomal antibodies were used to determine autoimmunity. The Imaizumi et al. (2006) study used the more precise anti-thyroperoxidase antibody as a determinant of antibody positivity and a more modern TSH value >4 mIU L–1 as the definition of antibody positive hypothyroidism. So in effect, the studies were examining two different endpoints based on differing definitions for the specific endpoints in question. The importance of endpoint definitions and the major impact on results in relation to radiation and thyroid disease has been pointed out previously (Volzke and Hoffman, 2006; Volzke et al., 2005). Without a doubt, the Imaizumi et al. (2006) manuscript most closely approximates current state-of-theart clinical practice (TSH cut off values >4 mIU L–1 and anti-thyroperoxidase antibody determinations) and, therefore, most closely defines the clinical endpoints of interest to patients and clinicians. This study was also accompanied by an editorial (Boice, 2006).

244 / 4. RADIATION EFFECTS In summary, the data from the Japanese atomic-bomb survivors provide no convincing evidence for an association between radiation exposure and subsequent development of autoimmune thyroid disease as long as 40 y after exposure as determined either by elevated TSH values, positive anti-thyroid antibodies, or histologic evidence of chronic lymphocytic thyroiditis at autopsy. It should be noted that most of the studies compared control subjects with no radiation exposure to exposed patients with thyroid doses ranging from 0.5 to 1 Gy. Little information is available for thyroid doses <0.5 Gy. 4.7.3.5 Chernobyl Nuclear Reactor Accident. The Chernobyl nuclear reactor accident in April 1986, resulted in the release of ~1.8 EBq of 131I into the environment, thereby contaminating large regions of Belarus, Ukraine, and southwest Russia (Tuttle and Becker, 2000). Within 5 to 10 y, a dramatic increase in the rate of thyroid cancer was detected in the most highly exposed regions (Cardis et al., 2005; 2006). While there remains controversy regarding the role of 131I versus other shorter-lived radioiodines, most of the radiation exposure to the thyroid to subjects not at the reactor site is probably due primarily to 131I although a smaller component of short-lived radioiodines and external exposure cannot be completely ruled out. One of the earliest studies of thyroid function after the Chernobyl nuclear reactor accident examined 1,214 children living in Kaluga Oblast of southwest Russia in 1992 (Dedov et al., 1993). While the thyroid function tests (including TSH) were all normal, this brief report did describe a relationship between estimated thyroid dose and the presence of anti-thyroid antibodies. Ito et al. (1995) published the results of a massive screening program covering more than 55,000 children exposed to Chernobyl fallout in five regions of Belarus, Russia and Ukraine. The primary endpoint was structural thyroid disease by physical exam and ultrasonographic evaluation. The authors did indirectly estimate the prevalence of chronic thyroiditis presenting as nodular thyroid disease (diagnosed by FNA and ultrasound findings) for each of the five regions using rather broad assumptions. There did appear to be a dose-response relationship for chronic thyroiditis based on thyroid FNA and neck ultrasound that ranged from a prevalence of 0.23 % in the lowest exposed regions to 1.9 % in the highest exposed regions. But as noted above, these estimates cannot be compared with other studies that have based the diagnosis of chronic thyroiditis on more standard blood tests or clinical criteria. In 1991, Sugenoya et al. (1995) compared thyroid examination and thyroid function tests between a cohort of 888 children (ages 10

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to 15 y) living in the heavily contaminated city of Chechelsk, Belarus with a cohort of 521 children (also age 10 to 15 y) from the less contaminated city of Bobruisk, Belarus. While the incidence of diffuse goiter was greater in the less contaminated city, there was no difference in thyroid function tests between the cohorts. Individual doses were not available for the study subjects. Avetisian et al. (1996) reviewed thyroid glands surgically removed in the 4 y prior to the Chernobyl nuclear reactor accident with those removed in the 8 y following. Increased rates of Hashimoto’s thyroiditis, follicular adenoma, and thyroid cancer were found in the thyroid glands removed after the accident (Avetisian et al., 1996). Obviously, the selection bias involved in the decision to proceed with thyroid surgery, screening for thyroid disease, and suspicion of a malignant diagnosis was likely quite different after the accident, than preceding the accident making the data obtained in this study difficult to generalize into meaningful conclusions. Beginning in 1986, the Belarusian government established a disease registry to track changing rates of benign and malignant thyroid disease in children exposed to fallout from Chernobyl. The diagnosis of autoimmune thyroiditis was based on medical record review and lacked standardized diagnostic criteria. However, Lomat et al. (1997) did describe an increase in autoimmune thyroiditis between 1990 and 1995 based on these clinical records. Obviously, the effect of widespread screening and increased awareness of thyroid disease in these areas in the early 1990s could have had a major impact on the reported prevalence of this disease. Therefore, it is difficult to know whether the increase in prevalence in autoimmune thyroid disease reported in this study is a result of radiation exposure or of increased recognition of preexisting thyroid disease. Vykhovanets et al. (1997) reported evaluations of thyroid function tests, anti-thyroid antibodies, and thyroid ultrasonography on a highly selected group of 53 exposed children from northern Ukraine (selected from a study of 1,000 children ages 4 to 15 y at the time of the study). A group of unirradiated children served as the control group. Radiation exposure was associated with higher TSH values and higher rates of anti-thyroid antibody levels, and ultrasonographic abnormalities than seen in the age matched unirradiated control group. The thyroid doses ranged from <1 Gy (mean 0.4 Gy) in 28 patients to 1 to 2 Gy (mean 1.4 Gy) in 18 patients, to >2 Gy (mean 3.2 Gy) in seven patients. A significant correlation between thyroid dose and anti-thyroglobulin antibodies was also found (r = 0.35, p = 0.012). While these data are intriguing, questions regarding selection bias and the small cohort number make it

246 / 4. RADIATION EFFECTS difficult to draw definitive conclusions from the data. However, the data suggest that thyroid doses in the range of 0.4 to 3.2 Gy may be associated with an increase in autoimmune thyroid disease. Similarly, Kasatkina et al. (1997) compared 89 children living in a contaminated region of Russia with 116 children living in a noncontaminated region. While individual thyroid dose estimates are not known, the children living in the contaminated region had higher rates of goiter and anti-thyroid antibodies than children living in the noncontaminated regions, despite relatively higher iodine excretion rates. The incidence of hypothyroidism was not significantly different between the groups. Likewise, Pacini et al. (1998) compared thyroid function tests and anti-thyroid antibodies in a cohort of 287 school children living in a highly-contaminated region of Belarus (Hoiniki), with 208 children living in an area of very low contamination (Braslav). While individual doses are not known, it is quite likely that the doses in Hoiniki were >0.5 Gy based on the high levels of contamination in this region. While there was no difference in TSH levels between the cohorts, the children from the highly contaminated region had a significantly greater prevalence of anti-thyroglobulin and anti-thyroperoxidase antibodies than the noncontaminated control group (19.5 versus 3.8 %, p = 0.0001). Vermiglio et al. (1999) compared thyroid function tests and antithyroid antibodies in a cohort of 143 children from the moderately contaminated region of Tula, Russia with a control group of age 40 y and gender matched children from an uncontaminated nearby region. Anti-thyroperoxidase and antithyroglobulin anti-thyroid antibody levels were significantly higher in the children from the contaminated region than from the noncontaminated region (~13 to 18 % prevalence for exposed children versus 2.5 to 5 % for unexposed children). While individual thyroid doses are not known, based on previous studies, the authors estimated the average thyroid dose to be ~0.35 to 0.49 Gy in the exposed children. No differences in thyroid function tests (TSH, T4 levels) were detected between the groups. Ivanov et al. (2005) reported a careful assessment of individual thyroid dosimetry calculations with thyroid ultrasonographic findings in a cohort of 2,457 children in southwest Russia who were <10 y old at the time of the accident. Thyroid function tests and anti-thyroid antibodies were only done in patients with abnormal thyroid ultrasonography. Median thyroid doses centered around 60 to 120 mGy with a range of 0 to 5,930 mGy. The prevalence of diffuse goiter in males showed a significant dose-response relationship, but there was no evidence of a dose response for ultrasono-

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graphic evidence of thyroiditis. The lack of anti-thyroid antibodies and thyroid function tests makes this study difficult to compare with other studies that have based the diagnosis of thyroiditis on laboratory and clinical findings rather than ultrasonographic criteria alone. While this is the only study to evaluate thyroid doses <400 mGy in Russia, the findings cannot be generalized because the endpoint of thyroiditis was based on ultrasonographic criteria and not the usual thyroid blood tests. Interpretation of these post-Chernobyl studies is hampered because they usually involve small numbers of subjects, often use varying definitions for autoimmune thyroiditis, and in most cases do not have accurate individual thyroid dosimetry data. A recent study by Tronko et al. (2006b) attempted to address these issues by studying a cohort of 12,240 residents of northern Ukraine ~12 to 14 y after exposure who were less than age 18 y at the time of the accident. Individual thyroid doses were available for each subject and precise endpoint definitions were constructed as well. No association with radiation exposure and autoimmune thyroid disease, or antibody positive hypothyroidism was detected across thyroid doses ranging from 0.22 to 4.9 Gy (mean values). However, thyroid radiation exposure was associated with elevated anti-thyroperoxidase antibodies with odds ratios modestly elevated at 1.22 at 0.22, 1.64 at 0.79, and 1.19 at 2 Gy. The lack of antibody positive hypothyroidism, despite elevated anti-thyroperoxidase levels, may reflect either the relatively short time interval between exposure and clinical evaluations (12 to 14 y), or the transient nature of clinically diagnosed autoimmune thyroid disease that can resolve itself without development of hypothyroidism as seen in the NTS followup cohort (Lyon et al., 2006; Rallison et al., 1991). In summary, data from the Chernobyl nuclear reactor accident suggest that people living in highly contaminated regions may be more likely to have anti-thyroid antibodies than people living in less contaminated regions. However, there does not appear to be a significant increase in hypothyroidism at the doses of radiation commonly received in the Chernobyl fallout regions within the range of follow-up years currently evaluable. In the series where thyroid doses could be estimated, the risk of developing anti-thyroid antibodies was usually seen at doses >0.4 to 0.5 Gy. Only the Tronko et al. (2006b) study found an increase in anti-thyroid antibodies (without associated hypothyroidism) at a mean thyroid dose as low as 0.22 Gy. 4.7.4

Summary of Major Points of the Medical Literature Review

• Ionizing radiation delivered as EBRT to the head and neck region, usually for medical therapy reasons, with large

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•

•

•

•

•

thyroid doses ranging between 25 and 70 Gy, is associated with subsequent clinical hypothyroidism in a dose-dependent manner. Data from the Marshall Islands exposures demonstrates that thyroid doses (a combination of external radiation and internal ingestion) between 3 and 50 Gy are a risk factor for hypothyroidism but not for the development of anti-thyroid antibodies. Data from NTS exposures suggest a dose-response relationship between thyroid radiation and the development of anti-thyroid antibodies, without development of hypothyroidism, at thyroid doses that extend as low as 75 mGy (median probably 100 to 120 mGy). Data from HTDS demonstrated no evidence of a relationship between dose to the thyroid from radioactive iodine (median 97 mGy) and the subsequent development of hypothyroidism, anti-thyroid antibodies, benign thyroid nodules or malignant thyroid disease. Data from the Japanese atomic-bomb survivors provide no statistically-significant convincing evidence for an association between radiation exposure and subsequent development of autoimmune thyroid disease as long as 40 y after exposure as determined either by elevated TSH values, positive anti-thyroid antibodies, or histologic evidence of chronic lymphocytic thyroiditis at autopsy. Data from the Chernobyl nuclear reactor accident suggest that people living in highly contaminated regions may be more likely to have anti-thyroid antibodies without hypothyroidism than people living in less contaminated regions. 4.8 Molecular Effects of Ionizing Radiation to the Thyroid

4.8.1

Generalized, Less Specific Nuclear Damage

4.8.1.1 Quantitative Abnormalities in Nuclear DNA. While there were several animal models of radiation-induced thyroid damage described in the 1950s, the first careful examination of the effects of therapeutic 131I on thyroid cell nuclei from human subjects was published by Dobyns and Robison (1968). The amount of DNA contained within each cell was estimated by the absorption of monochromatic light by Feulgen stain within the nucleus. Thyroid samples that had received the higher doses (>100 Gy) of 131I or EBRT had nuclei containing increased nuclear DNA in individual

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cells and more variation in the amounts of nuclear DNA among cells. Furthermore, nuclear volume was increased in the group that received the higher doses of 131I but not in the EBRT group. Socolow et al. (1964) published a cytogenetic analysis of cells cultured from a thyroid adenoma that developed in a patient treated with x rays many years before. Thirteen of 17 metaphases visualized were reported to contain abnormal chromosomes. Doida et al. (1971) reported the results of cytogenetic analyses in four patients treated with x rays in infancy and given preoperative 131I, seven patients were given preoperative 131I but never treated with x-ray therapy, and three patients were never exposed to medical radiation; all patients had nodules thyroid disease. Stable chromosomal aberrations in neoplastic thyroid cells were detected in 22 % of the cells from subjects exposed to EBRT, 1.5 % of the cells from subjects exposed to 131I alone, and 2 % of the cells from subjects without exposure to radiation (control). The interval between exposure to 131I and surgical excision varied from one month to 4 y. This study demonstrated the high prevalence of chromosomal abnormalities induced by EBRT many years before development of the thyroid abnormality. More recently, flow cytometry was used by Komorowski et al. (1988) to measure more precisely the nuclear DNA content of 14 radiation-associated thyroid cancers (11 papillary, 3 follicular). Normal diploid DNA content (the normal chromosome content of a somatic cell) was detected in each sample. While these techniques can provide reasonable estimates of DNA content within individual cells exposed to ionizing radiation, they are too insensitive to identify reliably the small alterations in genes or chromosomes that are often associated with malignancy. The value of these early studies (above) is that they demonstrated that sublethal doses to the thyroid were associated with detectable alterations in nuclear content and cytological structure that persisted for many years after exposure. 4.8.1.2 Chromosome Banding Studies. The development of cell culture techniques and chromosomal staining procedures resulted in remarkable improvements in the ability to characterize normal and abnormal human chromosomes. Each chromosome has a unique banding pattern when stained with specific dyes. This banding pattern can be used reliably to identify each of the normal human chromosomes and the breakpoints in many structural rearrangements. Lehmann et al. (1997) reported a cytogenetic analysis of a single case of papillary thyroid cancer that arose 31 y after exposure to x-ray therapy for thymus enlargement at age 7 y. An abnormal

250 / 4. RADIATION EFFECTS short arm of one homologue of chromosome 2 was the sole abnormality detected in four of the 16 analyzed metaphases. The first comprehensive cytogenetic analysis of pediatric radiation-associated thyroid cancers was published by Zitzelsberger et al. (1999). Detailed karyotyping using Giemsa banding was performed in 56 childhood thyroid cancers developing after the Chernobyl nuclear reactor accident and compared to eight adult thyroid tumors that developed following radioiodine or external radiotherapy. Clonal structural aberrations were found in 13 of 56 (23 %) of the Chernobyl cases and six of eight (75 %) of the radiotherapy cases. To date no series of cytogenetic analyses of spontaneously-developing pediatric thyroid cancers have been published. Therefore, it is difficult to be certain that these specific chromosomal abnormalities are directly related to radiation and not due to differences between adult and childhood thyroid cancers regardless of radiation history. 4.8.1.3 Fluorescent Chromosome Specific Analysis. The development of fluorescent in situ hybridization chromosome specific probes has allowed a more precise study of the presence and location of specific chromosomal regions within the genome. This technique can reliably detect specific chromosomal regions that are duplicated or translocated to another chromosome within the nucleus. Lehmann et al. (1996) used fluorescence in situ hybridization to study chromosomes 1, 4 and 12 in 40 cases of papillary thyroid cancer from Belarusian children exposed to the Chernobyl fallout, and from individuals in Munich (Germany) exposed to EBRT of the thyroid. The highest numbers of translocation events were detected in thyroid cancers that developed after EBRT in childhood. Although the childhood papillary thyroid cancers that developed after the Chernobyl nuclear reactor accident had generally higher chromosomal translocation events than corresponding normal tissue; this difference did not reach statistical significance. These data suggest that, in general, the number of translocation events involving chromosomes 1, 4 and 12 in Belarusian papillary thyroid cancer developing after the Chernobyl nuclear reactor accident is much lower than in EBRT-related thyroid cancers developing during adulthood. Subjects exposed to the highest doses of fallout in Gomel (Belarus) did demonstrate rates of translocations that are within the lower range of values seen in the EBRT-associated thyroid cancers. It is not clear whether the differences in translocation events are due primarily to the different types of radiation exposure, age at exposure, TSE, or to molecular differences in thyroid cancer developing in children and adults.

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4.8.1.4 Micro- and Minisatellite DNA Patterns. Normal chromosomal DNA contains regions in which a specific sequence of nucleotide bases is repeated many times. The repeating patterns can vary from two base pairs to hundreds of base pairs in length. DNA regions containing a repeating sequence pattern of five base pairs or less are generally referred to as microsatellites. Minisatellites are comprised of repeating patterns from 6 to 100 base pairs in length. While the precise function of these satellite DNA regions is still unclear, alterations in the number of repeating sequences within a specific satellite region have been detected in many types of cancer. It has been proposed that alterations in these satellite regions are a reflection of genomic instability and a marker of prior radiation or chemical carcinogen- induced damage. Nikiforov et al. (1998) examined 27 microsatellite, and 3 minisatellite loci in 17 post-Chernobyl childhood papillary thyroid cancer specimens (age range 6 to 18 y). Twenty papillary cancers arising in the United States in subjects with no history of radiation exposure served as an unirradiated control group (age range 16 to 68 y). In the radiation-associated cancers, only one sample (6 %) demonstrated a single microsatellite abnormality. Minisatellite instability was detected in 3/17 (18 %) of radiation-associated cancers and none in the sporadic control cancers (0/20). Without an age and stage matched nonirradiated control group, it is difficult to determine whether these differences are related to radiation exposure or other factors such as age at time of diagnosis, tumor stage, ethnic background, or geographical source. 4.8.1.5 Gene Expression Analysis. Analysis of DNA abnormalities is important in assessing the effect of radiation on thyroid cells. The mRNA and protein products are encoded by the genes and lead to downstream biologic functions/outcomes. With the advent of modern array technology, it is now feasible to examine the expression of thousands of mRNA species produced by malignant cells and to compare this expression profile with that of normal cells and benign nodules. In a study by Detours et al. (2005), the expression profile of 2,400 genes did not differ between a cohort of radiation-induced thyroid cancers and a control group of sporadic thyroid cancers. This result suggests that radiation-induced thyroid cancer is similar to sporadic thyroid cancer in terms of the molecular abnormalities. 4.8.2

Specific Oncogene Activation

An oncogene is a mutated and/or over expressed version of a normal gene (the proto-oncogene). The proto-oncogene is the normal

252 / 4. RADIATION EFFECTS gene, which when mutated or over expressed can lead to malignancy. All identified genes have symbols and names. Thus, for example, RET 3 (the normal gene present in all cells) is the protooncogene and RET/PTC is the mutated form of the RET gene and is therefore best termed an oncogene. RET/PTC is an abbreviation for “rearranged in transformation/papillary thyroid carcinoma.” RET/PTC is the mutated form of the RET proto-oncogene that has frequently been detected in radiation-induced and in sporadic papillary thyroid cancer. RET/PTC1, RET/PTC2, and RET/PTC3 are simple but different variants. 4.8.2.1 RET Proto-oncogene Activation. RET/PTC rearrangements have been identified in spontaneous and radiation-induced papillary thyroid cancers, and have been observed in childhood and adult cases of the disease. RET/PTC appears to occur more frequently in childhood cases, and in radiation-associated rather than spontaneous cases (Nikiforov, 2002; 2004; Tuttle and Becker, 2000). At least eight different RET/PTC activating mutations have been realized. The most commonly described mutations are RET/PTC1 or RET/PTC3, and to a much smaller extent RET/PTC2. The other RET/PTC rearrangements are rare events, often described in single patients (Klugbauer et al., 1998; Salassidis et al., 2000). RET/PTC1 appears to be the most common rearrangement in spontaneous adult and childhood thyroid cancers, whereas RET/ PTC3 rearrangements appear to be more prevalent in radiationinduced thyroid cancers (Nikiforov, 2002; 2004; Tuttle and Becker, 2000). Published clinical studies examining the frequency of RET/ PTC activation following radiation exposure are derived from either subjects treated during childhood with relatively high doses of EBRT, or children exposed to radioactive iodine from the Chernobyl nuclear reactor accident. Higher frequencies of RET/PTC activation are seen in the most heavily contaminated regions of Gomel and Brest; this result suggests that a dose-response relationship may exist (Rabes et al., 2000). Papillary thyroid cancers with a short latency period between radiation exposure and development of clinically-evident thyroid cancer are more likely to harbor RET/PTC3 mutations (Rabes et al., 2000). There is conflicting evidence in the published literature as to which type of RET/PTC mutation is most commonly activated in radiation-induced thyroid cancer. In the Chernobyl experience, 3The glossary entry “genetic nomenclature” briefly elaborates on the distinction between human (e.g., RET) and animal (e.g., Ret) genes having the same genetic function.

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the prevalence of specific types of RET/PTC mutations has changed over the years. In the earliest cases of radiation-induced thyroid cancer in Belarusian children, the predominant reported rearrangements were RET/PTC3 (Elisei et al., 2001; Klugbauer et al., 1995; Nikiforov, 2002; Rabes et al., 2000). Molecular analyses of cases developing after a longer latency period (i.e., 10 y or more after the accident) demonstrated a lower prevalence of RET/PTC3 mutations and a higher prevalence of RET/PTC1 mutations (Rabes et al., 2000). Smida et al. (1999) found near equal frequencies of RET/PTC1 and RET/PTC3 (23.5 and 25.5 %, respectively) among post-Chernobyl children, whereas post-Chernobyl adult patients exhibited only RET/PTC1. It remains uncertain, however, whether the RET/PTC3 mutations seen in the early Chernobyl cases are linked with radiation exposure, the short latency period, or the young age of the patients (Powell et al., 2005; Williams et al., 2004). In summary, activating mutations of the RET/PTC oncogene are common events in spontaneously-developing and radiation-induced papillary thyroid cancer in children. There appears to be a preference for RET/PTC3 mutations in radiation-associated papillary cancers developing shortly after the Chernobyl nuclear reactor accident as opposed to RET/PTC1 in sporadic papillary thyroid cancers. While activating mutations of RET/PTC are common in radiationinduced thyroid cancer arising in children, their presence cannot be used to determine precisely the etiology of a specific case of thyroid cancer since they can also be found in spontaneously-occurring thyroid cancer (Fenton et al., 2000; Williams and Tronko, 1996). 4.8.2.2 Other Specific Mutations. As would be expected, many studies have examined the potential role for essentially all of the major thyroid oncogenes and tumor suppressor genes in radiationinduced thyroid cancer. Unlike the preferential activation of RET/PTC commonly seen in radiation-induced thyroid cancer, no significant increase in BRAF (Collins et al., 2006; Powell et al., 2005), RAS (Challeton et al., 1995; Nikiforov et al., 1996a; 1996b; Suchy et al., 1998; Tuttle et al., 1998; Wright et al., 1991), TP53 (Fogelfeld et al., 1996; Hillebrandt et al., 1996; 1997; Ito et al., 1994; Smida et al., 1999; Suchy et al., 1998), TRK (Beimfohr et al., 1999; Fugazzola et al., 1995), GSP201 (Challeton et al., 1995), or Gs alpha (Waldmann and Rabes, 1997) mutations has been detected in radiation-induced thyroid cancers beyond that seen in nonradiogenic, sporadic thyroid cancers. 4.8.2.3 Bystander Effects of Ionizing Radiation. While most of the focus on radiation-induced oncogenesis has centered on direct

254 / 4. RADIATION EFFECTS damage to the DNA from the ionizing radiation or the water radiolysis products (targeted effects), much data are accumulating on possible nontargeted effects from ionizing radiation (Hamada et al., 2007). A significant body of literature demonstrates that irradiation of either the nucleus or cytoplasm of a target cell is associated with a wide range of changes in neighboring, nonirradiated cells (the “bystander effect”). Presumably, the irradiated cells release signals that result in a wide variety of alterations in adjacent cells, which can include DNA point mutations or DNA breaks. Preliminary data suggest that these bystander effects may be passed on through subsequent cell divisions of the nonirradiated cells. The nature of the signaling molecules, the signaling pathways, and the potential importance of this observation in radiationinduced oncogenesis remain to be defined. 4.8.2.4 Search for a Molecular Signature. For many years, investigators have been searching for a specific molecular signature that would differentiate radiation-induced thyroid cancer from spontaneously-arising thyroid cancer cases. Unfortunately, no specific mutational event or combination of events has been demonstrated to be pathognomonic for radiation-induced thyroid cancer. It appears that the pathogenesis of thyroid cancer, at the molecular level, is very similar for radiation-induced thyroid cancer and for sporadic thyroid cancer developing in either childhood or adult life. This consistent clinical observation suggests that the biologic behavior of radiation-induced thyroid cancer is very similar to that in age- and stage-matched nonirradiated thyroid cancer controls (Schneider and Sarne, 2005). 4.9 Parathyroid Function There are many case series reported in the medical literature describing an association between prior radiation exposure and thyroid and parathyroid disease (Christensson, 1978; De Jong et al., 1991; Hedman and Tisell, 1984; Hedman et al., 1984; Katz and Braunstein, 1983; Netelenbos et al., 1983; Nishiyama et al., 1979; Prinz et al., 1977; 1981; 1982; Rao et al., 1980; Russ et al., 1979; Tamura et al., 1982; Tezelman et al., 1995; Tisell et al., 1976; 1978). In general, it is not possible to estimate the dose-response relationship for radiation exposure and parathyroid disease from these reports due to the inherent limitations of case series. In general, there is no defined cohort, there is no way to control for ascertainment bias, and there is no estimate of dose. The common theme in these papers is that concurrent thyroid and parathyroid abnormalities were common in patients with a history of radiation

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exposure. The clinical course of radiation-associated hyperparathyroidism and spontaneously-occurring hyperparathyroidism is similar (Katz and Braunstein, 1983). One cohort study of parathyroid function in 220 patients treated with radiation therapy (including the neck) for Hodgkin’s disease found no increased incidence of parathyroid disease in the first two decades following exposure (Nader et al., 1984). Data on parathyroid function following radioactive iodine treatment are limited. Decreased as well as increased parathyroid function has been reported (Orme and Conolly, 1971). The first reported cases of increased function were four patients in whom hyperparathyroidism developed after treatment for Graves’ disease (Esselstyn et al., 1982). A cohort study reported no instances of hyperparathyroidism in 125 patients whose hyperthyroidism was treated with radioiodine (Fjalling et al., 1983). A subsequent case series described eight additional patients who developed hyperparathyroidism 4 to 20 y after radioiodine treatment of benign or malignant thyroid disease (Rosen et al., 1984). In a consecutive series of 600 patients treated surgically for primary hyperparathyroidism, review of medical records indicated that 10 patients had prior treatment with 131I (Bondeson et al., 1989). Details of four studies are reviewed below. 4.9.1

Swedish Tuberculous Adenitis Study

A primary report was published in 1977 of a cohort of patients who were treated with EBRT for tuberculous adenitis (Tisell et al., 1977). The results of a larger, more complete study were published in 1985 (Tisell et al., 1985). The prevalence of hyperparathyroidism was determined in a cohort of 444 subjects (281 females, 163 males) who had been treated with EBRT for tuberculous adenitis between 1913 and 1951. Follow-up examinations were performed between 1975 and 1982. The average dose to the parathyroid glands was 7.16 Gy, range 0.4 to 50.9 Gy. The average age at the time of exposure was 19.1 y (range 0 to 44). The average length of follow-up was 43 y. Sixty-three subjects (14.2 %) developed hyperparathyroidism. The average time between exposure and development of hyperparathyroidism was 44 y (range 28 to 62). At or below a dose of 14 Gy, 12.2 % of subjects developed hyperparathyroidism; at higher doses, 28.9 % of subjects developed hyperparathyroidism. The authors plotted the probability of hyperparathyroidism after neck irradiation as a function of parathyroid dose but did not report an ERR or EAR.

256 / 4. RADIATION EFFECTS 4.9.2

Minnesota Hyperparathyroidism Study

A case-control study to assess the effect of prior therapeutic radiation on the incidence of hyperparathyroidism was conducted among the residents of Rochester Minnesota (Beard et al., 1989). Fifty-one cases of surgically confirmed primary hyperparathyroidism were diagnosed between 1975 and 1983, with each case matched by age and gender with two control subjects. A history of radiation exposure was obtained through a review of medical records. The overall odds ratio for any prior therapeutic radiation therapy was 1.9 (95 % CI 0.9 to 4.4) and it was 2.3 (95 % CI 0.9 to 5.7) when limited to patients with a history of prior head and neck exposure. For women, the odds ratios were significantly increased for any prior radiation therapy (2.9, 95 % CI 1.1 to 7.5) and for prior head and neck exposure (3.4, 95 % CI 1.2 to 10.2). 4.9.3

Atomic-Bomb Survivors Study

The prevalence of hyperparathyroidism in a subset of 3,948 atomic-bomb survivors (2,365) and a control population (1,583) has been determined (Fujiwara et al., 1992). The cohort was a subset of the AHS population that was followed with biennial medical examinations. Between August of 1986 and July of 1988, a screening program for hyperparathyroidism was implemented. The diagnosis of hyperparathyroidism was made in 19 subjects (3 males and 16 females). Three cases occurred in the control population. The prevalence of hyperparathyroidism was threefold higher in females than in males. The prevalence rates increased with dose. ERR Gy –1 was estimated to be 3.1 (95 % CI 0.7 to 13). The magnitude of ERR was not affected by gender. The effect appeared to be greater for subjects who were younger at the time of exposure. In a subsequent study (Fujiwara et al., 1994b), levels of calcitonin, parathyroid hormone, and calcium were examined in 1,459 subjects in Hiroshima and Nagasaki. Even after patients with hyperparathyroidism were excluded there was a significant doseresponse relationship for the levels of calcitonin, parathyroid hormone, and calcium. Parathyroid hormone increased initially by 6.8 % Gy –1 but the increase leveled off above a dose of 1 Gy. The dose effect on calcium remained even after adjustments for parathyroid hormone, calcitonin, and confounding factors such as renal function, serum albumin, and medication. The etiologic mechanism of these effects is unclear. 4.9.4

Chicago Head and Neck Irradiation Study

The incidence of hyperparathyroidism in the Chicago Head and Neck Irradiation Cohort of patients who were exposed as children

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has been reported. The relative risk of developing hyperparathyroidism was 2.9 (95 % CI 1.6 to 4.3) under the attained age of 40 and 2.5 (95 % CI 1.1 to 3.9) over the attained age of 40 y. Thirty-one percent of patients who developed hyperparathyroidism also developed thyroid cancer compared to a prevalence of thyroid cancer of 11.2 % for the entire cohort (Cohen et al., 1990). There were 36 cases of hyperparathyroidism (26 parathyroid adenoma, 10 parathyroid hyperplasia) observed in 2,555 subjects who provided information concerning nonthyroid tumors and their general health (Schneider et al., 1995). Parathyroid doses were assumed to be the same as the thyroid dose. The average parathyroid dose to the entire study cohort was 583 mGy. The parathyroid dose was 771 mGy in patients with hyperparathyroidism and 836 mGy in patients with parathyroid adenomas. The mean age of occurrence of hyperparathyroidism was 41.7 y for men and 39.8 y for women. The crude rate of hyperparathyroidism was 3.9 (104 PY Gy)–1. The adjusted rate for persons with an attained age of 35 to 45 y was 9.4 (104 PY Gy)–1. Categorization of subjects with parathyroid doses of <500 mGy as the zero dose group resulted in relative risks of 2.04, 1.36, and 1.40 for the dose categories of 500 to 590, 600 to 690, and t700 mGy, respectively. The authors stated that the dose-response curve does not appear to be monotonic since there appeared to be a plateau >500 mGy. Detailed analysis of the doseresponse curve was limited due to the small number of cases but the slope of the dose-response curve was not affected by gender, age at the time of exposure, or three other measures of time (attained age, years since exposure, and calendar year of diagnosis). The authors could not exclude ascertainment bias as a contributor for the excess cases of hyperparathyroidism observed. 4.10 Conclusions The literature available on radiation effects on the thyroid and parathyroid is extensive, but, as indicated in Section 4.4, only a small fraction of the literature can be used to estimate the dose-response relationship for a few endpoints. To estimate doseresponse relationships, epidemiologists must study large populations for long periods of time. Issues that need to be considered include the effects of factors such as gender, age at the time of exposure, and attained age on the dose-response relationship. Ideally, one would like standardized disease screening and information on interventions that might affect the results. Epidemiologic studies have shown a statistically-significant dose-response relationship between radiation exposure (external

258 / 4. RADIATION EFFECTS and 131I) and thyroid cancer. The strength of this relationship is greatly affected by age at the time of exposure, with young children being at greatest risk. There is also a risk of benign nodules following radiation exposure but the magnitude of the risk is less well known. It is difficult to combine the results of multiple studies of radiation exposure and benign nodule formation because there is variability in how these studies were conducted and the endpoints that were used. It is unlikely that the effects of radiation on thyroid function will be adequately modeled using a linear-nonthreshold dose-response model since functional abnormalities probably do not result from a stochastic process. The role of oncogenes in the pathogenesis of radiation-induced thyroid cancer and benign nodules needs further exploration. There appears to be a dose-response relationship between radiation exposure and parathyroid adenomas but the data available for analysis are limited.

5. Radiation Risk for Thyroid Neoplasms Risk assessment is used in radiation protection to estimate the probability of harm from radiation exposure. Some experts, in the past, have suggested that it is better to overestimate radiation risks rather than to underestimate them [e.g., the report on the Biological Effects of Ionizing Radiation (BEIR) usually referred to as the BEIR V report (NAS/NRC, 1990)]. BEIR V, when discussing the genetic risks from radiation exposure, explicitly stated: “For the purposes of setting radiation standards, it is wiser to estimate risks that might be too large rather than risks that might be too small” (NAS/NRC, 1990). Since the resources available to protect the public’s health are limited, the magnitude of health threats must be quantified as accurately as possible. If certain risks are over- or underestimated, resources to protect the public’s health may be less effective. The risk of thyroid cancer from acute, external irradiation is well documented, better than the risks for a number of other organs, although there is considerable uncertainty about the carcinogenic effects of protracted and internal exposures to the thyroid. Four features of thyroid cancer risk stand out in comparison to many other cancer sites. • most notable is the sizeable inverse association between age at radiation exposure and thyroid cancer risk per unit dose (i.e., risk is very high following exposure in childhood but is small or none following exposure after age 30 or 40 y); • spontaneous thyroid cancer shows a larger difference by sex than most nonhormonal cancers, with women having a risk approximately two to three times as great as men. This same disproportion occurs for radiation-related thyroid cancer.; • thyroid cancer is quite rare, so even though there are large radiation-related relative risks, the number of excess thyroid cancers following whole-body exposure may be less than more common cancer sites such as breast, lung and colon; and 259

260 / 5. RADIATION RISK FOR THYROID NEOPLASMS • mortality from thyroid cancer is low, especially for cancers occurring before age 45 y, so the health detriment from thyroid cancer is proportionally less than that associated with some other types of radiogenic cancers. These features will all figure into the estimation of lifetime risks of thyroid cancer from radiation exposure. There are a number of potentially important modifiers of risk of thyroid cancer such as age at the time of exposure, gender, ethnicity, TSE (or attained age), variations in thyroid surveillance, dose fractionation or protraction, exposure to other carcinogens, the contribution of diet deficient in stable iodine, hereditary factors, and the amount of dietary stable iodine. What is known and not known about the effects of these factors on risk is discussed in Section 5.3. The available data on radiation-related risks of benign thyroid tumors and nodules will also be surveyed. Considerable data have been collected about benign thyroid nodules but these data have larger uncertainties than those for thyroid cancer for several reasons: different investigators have used very different detection methods and definitions of disease, the studies tend to have been less well designed, and the associated doses have been more poorly characterized. In addition, benign thyroid nodules rarely cause the patient any harm except that they may increase the chances that the patient will have unnecessary thyroid surgery. A brief review of past risk estimates and models is given in Appendix G. 5.1 Dose-Response Relationships Accurately modeling the dose-response relationship for thyroid and parathyroid abnormalities following radiation exposure presents numerous challenges. Accurate information on the dose to the thyroid and the epidemiological endpoints is needed to adequately model dose-response relationships. As discussed in Section 3, all epidemiological studies rely on retrospective dose reconstruction to some degree, depending on the type and amount of individual exposure information available. Retrospective calculations of tissue doses may be quite uncertain especially when they are due to unplanned exposures. The uncertainty in dose is rarely fully accounted for in dose-response models. As discussed in Section 4, measurement of biological response is also fraught with many potential errors. Most dose-response models do not account for possible systematic dosimetry errors because such errors are frequently not identified.

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In this section, dose-response relationships will be described first. Although the empirical models used simplify what is a complex biological phenomenon, it would be difficult to justify using more sophisticated biological models due to the limited data, especially at low doses. It should again be noted that much more reliable data currently exist for modeling the risk for thyroid cancer following external radiation than following internal radiation exposure. There is much more uncertainty about the preferred doseresponse model for thyroid disease endpoints other than cancer. What is known about the dose-response relationship for benign thyroid nodules is discussed in Section 5.4. Unlike thyroid cancer, there is no large pooled data set that can be used to more accurately estimate the risk for benign nodules from external radiation. There are few data that can be used to develop a dose-response relationship for autoimmune thyroid disease. These data are briefly summarized in Section 4.6. There are two major hurdles to overcome before a dose-response model for autoimmune thyroid disease can be proposed. First, a better definition of what is meant by this disease is needed. For example, in the absence of thyroid dysfunction, the clinical significance of variations in levels of circulating thyroid antibodies is unclear. Second, little is known about the biological mechanisms that lead to disease. A dose-response relationship can be expected if the mechanisms that lead to disease are stochastic in nature. Autoimmune thyroid disease may primarily be a reflection of whether an individual’s immune system reacts to some thyroid antigen as if it were a foreign protein; if this were the situation, no relatively simple dose-response relationship should be expected. Because of these difficulties, no dose-response relationship is proposed for autoimmune thyroid disease and as summarized in Section 4.6, no excess in hypothyroidism and autoimmune thyroid disease is expected following low doses of radiation to the thyroid gland. Models of epidemiologic data on radiation-induced cancers historically have used EAR or ERR models. These are empirical models rather than biologically-based models, because the relevant biological parameters are ill-defined and the epidemiologic data tend to be too limited to provide adequate information about biological parameters. Brief explanations of the commonly used empirical models follow. 5.1.1

Excess Absolute Risk Model

The excess absolute risk (EAR) (per unit dose) model can be expressed as:

262 / 5. RADIATION RISK FOR THYROID NEOPLASMS observed cancers – expected cancers EAR = ------------------------------------------------------------------------------------------- , PY of observation u mean dose

(5.1)

where the dose is typically expressed in gray or sievert and a multiplier of 10–4 is applied for convenience, so that the expression becomes excess cancers (104 PY Gy)–1 or (104 PY Sv)–1. When there is a range of doses and individual dose estimates are available so that a dose-response analysis can be performed, a Poisson regression analysis is typically used to estimate EAR by the regression slope (Breslow and Day, 1987). In this case, the equation for EAR is similar to the following: R = a i + bD ij ,

(5.2)

where R refers to total risk of disease as a function of the ai baseline rates (for strata such as sex and age at exposure that one might choose to incorporate to control for potential confounding variables) and the radiation effect. The Dij are mean doses for each mathematical unit in the analysis table, where cells are specific to dose category and typically to age at exposure, attained age, sex, and perhaps other factors. The coefficient b is the slope of the regression per unit dose, which is the EAR estimate. The EAR model is also called the “additive” model because the excess cancers due to the exposure are added to the baseline cancers. Equation 5.2 is a linear model, but more complicated dose-response forms could be used. In its simplest form, the constant EAR model predicts that the number of excess cancers will be constant over time and age, and will be comparable for both sexes (Figure 5.1). A more sophisticated EAR model would account for variation in excess rates by sex, age, TSE, etc. Any appropriate model would use a person-years approach to account for the fact that the number of individuals at risk decreases over time due to the occurrence of the disease of interest, deaths due to all causes and losses due to incomplete follow-up. Application of an EAR model to predict lifetime risk without accounting for the fact that with time fewer individuals are at risk may result in an underestimate of thyroid cancer incidence and an overestimate of total excess thyroid cancers. Other modifications to the EAR model are also possible (e.g., a term can be added to the model that increases or decreases the risk with TSE, and with attained age). A more general form of EAR model is described in the BEIR VII report (NAS/NRC, 2006):

O  a,e,d,s,p = O  a,s,p + EAR  a,e,d,s,p .

(5.3)

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Fig. 5.1. Predictions from a simple EAR model. (Top) yearly excess thyroid cancer incidence assuming 0.1 Sv thyroid dose at age 10 y, a 5 y lag period, and EAR of 4.4 (104 PY Sv)–1. Not accounting for deaths from competing causes would result in an underestimate of thyroid cancer incidence and an overestimate of the total number of thyroid cancers. (Bottom) using the same assumptions, the total number of excess thyroid cancers is plotted as a function of years since exposure.

264 / 5. RADIATION RISK FOR THYROID NEOPLASMS Where the incidence rate (O ) is a function of the following variables: a = attained age of an individual e = age at exposure to radiation d = dose of radiation received s = code for sex (one if the individual is a female and zero if male) p = study population specific factors Because incipient cancers caused by an exposure need to undergo further transformation and to increase in size before they become clinically apparent, no excess cancers are expected for some minimum latency period after the radiation exposure. Cancers that appear during the latent period are implicitly assumed to have been preexisting at the time of the radiation exposure. For thyroid cancer, a minimum latent period of 5 y is often assumed. 5.1.2

Excess Relative Risk Model

In contrast to the EAR model, above, the excess relative risk (ERR) model expresses excess risk as being proportional to the underlying baseline rates (usually taking age, gender and race into account). An ERR (per unit dose) model can be expressed as: observed cancers · § ------------------------------------------- –1 © expected cancers ¹ ERR = -------------------------------------------------------------- , mean dose

(5.4)

where dose is expressed in gray or sievert. The ratio (observed cancers/expected cancers) is the relative risk, whose value, if there were no radiation effect, would be one. Therefore, to obtain ERR, one is subtracted from the numerator as shown in Equation 5.4. Put in other terms, ERR can be expressed as the relative risk minus one (RR – 1) divided by the mean dose (D). Again, this is a very simple formulation, and ERRs in epidemiological studies are typically calculated using models that control for age and other effects, but the concept is the same. When there are dose estimates for individuals so that a doseresponse estimate can be calculated, a Poisson regression model (e.g., Ron et al., 1995) is typically used to estimate ERR using a model approximately of this form: R = a i  1 + bD ij ,

(5.5)

where R refers to total risk of disease as a function of the parameters ai and Dij, which are defined the same as for Equation 5.2 and

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the slope b is the ERR estimate of risk per unit dose. Because baseline rates (ai) are multiplied by the risk estimates (bDij) in the second term of Equation 5.5, the ERR model is also known as a “multiplicative” model. To predict lifetime risks using the EAR model, the excess thyroid cancer incidence per unit dose is calculated without any baseline thyroid cancer incidence data. For the ERR model, baseline thyroid cancer rates must be known. Excess thyroid cancer incidence can be calculated using the 1998 through 2000 thyroid cancer incidences for white males and females from the SEER database (Ries et al., 2006) and the ERR model (Figure 5.2). When the constant ERR model does not fit the data adequately, the inclusion of modifying factors to account for attained age, TSE, age at exposure, gender, etc., may improve the model fit. A more general form of ERR model is described in the BEIR VII report (NAS/NRC, 2006):

O  a,e,d,s,p = O  a,s,p > 1 + ERR  a,e,d,s,p @ .

(5.6)

Again, the incidence rate (O ) is a function of the same variables that were defined for the EAR model in Equation 5.3. The principal difference between the EAR and the ERR models is that the EAR model provides an “additive” risk that is independent of the baseline cancer rates, while the ERR model provides the risk in proportion to the baseline rates. Since the baseline rates of most types of cancer increase sharply with age, this difference has important implications in terms of using a model based on childhood irradiation data with a limited follow-up time (e.g., 35 y, to project risk for a lifetime). When the cancer rates are rising with age, the simple ERR model would tend to project a larger lifetime risk than the simple EAR model. In the case of thyroid cancer, the discrepancy between the predicted lifetime number of thyroid cancers using the EAR model and the ERR model would not be as great as many other cancers because the baseline thyroid cancer rate for women is fairly constant after the age of 30 y (Figure 2.8). After radiation exposure to a general population, the majority of excess thyroid cancers occur in women primarily between ages 20 to 60 y (Figure 5.2). As to sex differences in radiation risk estimates, the pooled analysis did not show a statistically-significant difference, an outcome shared by a variety of other studies. In the latest update of the atomic-bomb cancer incidence data (Preston et al., 2007), the gender ratio for radiation effect was not statistically significant (F/M = 1.3, 95 % CI 0.6 to 3).4The other large study by Cardis et al. (2005) reported ERR Gy –1 risks of F/M = 5.3/5.7 = 0.9. Smaller studies

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Fig. 5.2. Predictions from a simple ERR model compared to a simple ERR model.4 (Top) yearly incidence for white males and an assumed 0.1 Sv thyroid dose at age 10 y, a 5 y lag period, and an ERR Sv–1 of 7.7. No adjustment for deaths due to competing causes. (Bottom) yearly excess thyroid cancer incidence for white females and an assumed 0.1 Sv thyroid dose at age 10 y, a 5 y lag period, and an EAR Sv–1 of 7.7. No adjustment for deaths due to competing causes.

4Unlike the absolute risk model, the relative risk model predicts more thyroid cancers among females because the baseline thyroid cancer rate is higher in females than in males. The thyroid cancer incidence for the EAR model is shown for reference.

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(Davis et al., 2004b; Lundell et al., 1994; Tronko et al., 2006a) also did not have gender ratios significantly different from one. While one might make a case that on average ERR is somewhat greater in females than in males, it is not reliably elevated. Figure 5.3 illustrates the BEIR VII (NAS/NRC, 2006) estimate of the change in ERR as a function of age and gender. Figure 5.4 shows the NAS/NRC (2006) estimate of the lifetime attributable risk [the probability that an individual will die from (or develop) thyroid cancer] with exposure to a dose of 0.1 Gy as a function of age at exposure and gender. 5.2 Past Risk Estimates and Models Committees of radiation protection experts have periodically reviewed the literature regarding the risk of thyroid cancer following exposure to ionizing radiation. Summaries of major reviews (BEIR, NCRP, UNSCEAR) are presented briefly below. The major conclusions of the BEIR committees are summarized in Tables 5.1 to 5.4. Four BEIR committee reports: BEIR I (NAS/ NRC, 1972), BEIR III (NAS/NRC, 1980), BEIR V (NAS/NRC, 1990),

Fig. 5.3. ERR of thyroid cancer as a function of age at exposure and gender (NAS/NRC, 2006).

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Fig. 5.4. Lifetime number of excess thyroid cancers expected from a dose of 0.1 Gy as a function of age at time of exposure and gender (NAS/NRC, 2006).

TABLE 5.1—Major conclusions of BEIR I (NAS/NRC, 1972). x

Neoplastic effects of x rays on the thyroid are greater than the effects of 131I.

x

100 % of children exposed to 10 Gy will develop thyroid nodules. Increased nodularity has been observed with doses as low as 0.2 Gy.

x

Thyroid cancer incidence has been reported to increase in atomicbomb survivors exposed under the age of 20 y.

x

Risk coefficients from animal studies are similar to risk coefficients from humans.

x

Risk is age dependent with the highest risk occurring during adolescence.

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TABLE 5.2—Major conclusions of BEIR III (NAS/NRC, 1980). x

Absolute risk for thyroid cancer previously reported in BEIR I of 1.6 to 9.3 cases per 106 PY rad [1.6 to 9.3 (104 PY Gy)–1] had not changed appreciably.

x

For thyroid adenomas, the risk of thyroid nodules was about three times the risk of thyroid cancer, with nodule risk of 12 cases per 106 PY rad [12 (104 PY Gy)–1].

x

The dose-response relationship for thyroid cancer appears to be linear without a threshold for doses between 6.5 to 1,500 rad (0.065 to 15 Gy) from external radiation at high dose rates.

x

The carcinogenic effect seen with external radiation has not been demonstrated in children treated with 131I for hyperthyroidism.

x

Thyroid cancers observed in the Marshallese are difficult to analyze because their radiation exposure was due to a mixture of high dose-rate external and internal radiation.

x

Age may be a weak factor in influencing the effect of radiation on the thyroid. The “apparent” inverse relationship with age is probably mistakenly assumed because therapeutic radiation for benign conditions was primarily used for childhood diseases.

x

Jewish descent may increase the risk of thyroid cancer from external radiation exposure.

x

Most series suggest the peak incidence of thyroid cancers occurs 15 to 25 y after exposure.

x

Effects of fractionation are unclear.

x

The marked difference in risk from external and internal radiation is likely related to dose rate and the markedly heterogeneous dose distribution with internal beta emitters (131I).

x

There is a minimum latent period of 10 y for radiation-induced thyroid cancer.

x

Radiation-induced thyroid cancers are usually associated with a normal life span.

and BEIR VII (NAS/NRC, 2006) have addressed the issue of risks following exposure to low-LET radiation. Each report has had a section on the risk of ionizing radiation to the thyroid. Additional details of the findings of the BEIR reports can be found in Appendix F. This Report updates the findings of NCRP Report No. 80 entitled Induction of Thyroid Cancer by Ionizing Radiation (NCRP,

270 / 5. RADIATION RISK FOR THYROID NEOPLASMS TABLE 5.3—Major conclusions of BEIR V (NAS/NRC, 1990). x

The committee preferred the constant relative risk model for thyroid cancer with a relative risk of 8.3 at 1 Gy (95 % CI 2 to 31).

x

Gender had no effect on the relative risk.

x

The risk in adults was estimated to be one-half the risk in children.

x

The absolute risk of thyroid cancer is two to three times greater in women than in men for radiogenic cancers and spontaneouslyoccurring cancers.

x

Radiogenic cancer is frequently preceded or accompanied by benign thyroid nodules.

x

The frequency of hypothyroidism and simple goiter is increased when exposed to large doses of radiation when young.

x

Radiogenic thyroid cancers are generally papillary.

x

Sustained TSH stimulation increases the risk of thyroid neoplasia.

x

There is no evidence that radiogenic neoplasms develop from parafollicular C cells (medullary thyroid cancer).

1985a). The major conclusions of NCRP Report No. 80 are summarized in Table 5.5. More details about the findings of NCRP Report No. 80 are found in Appendix G. The differences in the findings of this Report with NCRP Report No. 80 are indicated in the Executive Summary. The findings of the three most recent UNSCEAR reports are summarized in Table 5.6. More details of the findings of these reports can be found in Appendix G. 5.3 Factors that Affect Thyroid Cancer Risk Estimates The estimation of thyroid cancer risk from radiation exposure requires consideration of a number of different conditions or issues. Since the pooled analysis of studies on external radiation and thyroid cancer (Ron et al., 1995) is central to many of these considerations, it is described first. This is followed by considerations of the effects of modifiers such as age at exposure, attained age, TSE, sex, ethnicity, hereditary susceptibility factors, and the influence of thyroid screening and surveillance on risk estimates. 5.3.1

Analyses of External Radiation Data on Thyroid Cancer

An analysis by Ron et al. (1995) of seven major studies of thyroid cancer following external exposure to radiation was performed. The

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TABLE 5.4—Major conclusions of the BEIR VII (Land et al., 2003; NAS/NRC, 2006). x

The committee’s preferred model for estimating thyroid cancer risk is based on a pooled analysis of data from seven thyroid cancer incidence studies conducted by Ron et al. (1995), which present ERR or EAR models that do not allow for modification by age at exposure and attained age.

x

The committee utilized data from Land et al. (2003) to account for age at exposure and assumed the excess risk per unit exposure for females was twice that for males in accordance with Ron et al. (1995), even though this difference had not been found to be statistically significant.

x

Based on Land et al. (2003) and Ron et al. (1995), the committee determined that the model for ERR per unit dose should take the form of ERR Gy –1 = 0.79 e–0.083 (e –30) where e is age in years at the time of exposure, and that the BEIR VII model for males and females would then take the form of: - ERR Gy –1 = 0.53 e–0.083 (e –30) for males - ERR Gy –1 = 1.05 e–0.083 (e –30) for females

x

The committee noted that ERR Gy –1 given by Ron et al. (1995) was 7.7 (95 % CI 2.1 to 29) averaged over the two sexes, which in the BEIR VII model would equate to exposure having occurred at age ~2.5 y, which was about the average exposure age in the data analyzed by Ron et al. (1995).

TABLE 5.5—Major conclusions of NCRP Report No. 80 (NCRP, 1985a). x

The absolute risk for thyroid cancer is ~2.5 (104 PY Gy)–1.

x

The absolute risk for thyroid cancer was twice as high in women, 3.3 (104 PY Gy)–1 as in men, 1.7 (104 PY Gy)–1.

x

The risk of thyroid cancer decreases with doses >15 Gy due to cell killing.

x

The mortality from radiation-induced thyroid cancer is similar to the mortality from spontaneously-occurring thyroid cancer.

x

Ninety percent of radiogenic thyroid cancers are papillary type.

x

131

I and 125I are no more than one-third as effective as external radiation in causing thyroid cancer.

x

135I, 133I, 132I, 123I,

x

Approximately 10 % of thyroid cancers are lethal.

and 99mTc are as effective as external radiation in causing thyroid cancer.

272 / 5. RADIATION RISK FOR THYROID NEOPLASMS TABLE 5.6—Major conclusions of the UNSCEAR reports (UNSCEAR, 1972; 1994; 2000b). 1972 UNSCEAR Report x x x x x

The incidence of thyroid cancer in atomic-bomb survivors was inversely related to the distance from the hypocenter. Thyroid cancer occurred more frequently in exposed females than in exposed males Effect of age at time of exposure was unclear. Thyroid cancer risk was 1 to 2 (104 PY Gy)–1. Significance of small occult thyroid cancers was unclear.

1993 UNSCEAR Report x x x x

The absolute risk for thyroid cancer was 7.5 (104 PY Gy)–1 for an age weighted population and 5 (104 PY Gy)–1 for adults. Children were twice as sensitive as adults. Females were two to three times as sensitive as males. 131I is less carcinogenic than external radiation.

2000 UNSCEAR Report x x

There is an increased risk of thyroid cancer in children exposed to radiation from the Chernobyl nuclear reactor accident. Thyroid cancer risk is inversely related to age at exposure.

pooled studies included data on almost 120,000 subjects (58,000 exposed and 61,000 unexposed) and 3 u 106 PY of follow-up. Five of the studies (Pottern et al., 1990; Ron et al., 1989; Schneider et al., 1993; Shore et al., 1993a; 1993b; Thompson et al., 1994) were cohort studies and two (Boice et al., 1988; Tucker et al., 1991) were casecontrol studies. All five cohort studies and one case-control study (Tucker et al., 1991) had data on persons exposed before age 15 y. There was a total of 706 thyroid cancers in the pooled data set. Each study had its own strengths and weaknesses, as described in Section 4.4. As described below the authors used this large data set to assess: • • • •

shape of the dose-response relationship; effect of gender; influence of age at irradiation; temporal patterns of risk in terms of attained age (i.e., ages at observation, and years since exposure); • effects of fractionation; and • influence of screening and clinical surveillance on risk estimates.

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A limitation of the pooled analysis is that potential differences due to variations in the biological effectiveness of the different types of radiation, and to differences in dose rate could not be accounted for. Because of the strong evidence for an inverse association between risk and age at exposure (Section 5.3.2.1), this risk assessment concentrates on data from irradiation before age 15 y. Summary results of the principal studies of thyroid cancer incidence among those irradiated before the age 15 y are given in Section 4.4 (Tables 4.2 to 4.4). Among the cohort studies, there were 436 thyroid cancers among individuals exposed before age 15 y, and 37 thyroid cancers in the unexposed groups. Among those exposed after age 15 y (all in the Japanese Atomic-Bomb Survivors Study), there were 92 thyroid cancers. In the five cohort studies, 71 % (309/436) of the thyroid cancer cases in persons exposed before age 15 y came from the Chicago Head and Neck Irradiation Study conducted at Michael Reese Hospital. For some analyses, it was also possible to include the nested case-control study of thyroid cancer risk following radiotherapy for childhood cancer (Tucker et al., 1991). Only the Cervical Cancer Study and the Atomic-Bomb Survivors Study contributed thyroid cancer cases where the exposure occurred after the age of 15 y. There has also been a marginally significant increase in thyroid cancers (SIR = 1.6, 95 % CI 1 to 2.42) reported in adults after x-ray treatment for benign disorders of the cervical spine (Damber et al., 2002). In order to provide a best estimate of the thyroid cancer risk for those exposed under age 15 y, a pooled analysis was performed (Ron et al., 1995) in which the primary data from each of the studies were combined and reanalyzed using common definitions, statistical methods and assumptions, and uniform categories of dose, sex, age at exposure, and attained age (or TSE). Thyroid cancer rates were elevated in all exposed populations. In addition, the rates were consistently higher in females and the rates increased with attained age. The remaining findings of the pooled study are described under several headings that characterize various aspects of estimating risk. 5.3.1.1 Shape of the Dose-Response Curve. A strong association between dose and thyroid cancer was obtained using a linear model for EAR and ERR (Ron et al., 1995). The linear model fit the data for all studies except for the Childhood Cancer Study where there appeared to be a decrease in the slope of the dose-response curve at high thyroid doses [e.g., >2 Gy]. The authors preferred the relative risk model to the absolute risk model because the relative risk model fit the data somewhat better.

274 / 5. RADIATION RISK FOR THYROID NEOPLASMS Of particular interest are the data in the low-dose range. Three of the five studies analyzed in the pooled analysis (Ron et al., 1995) provided data points under ~0.25 Gy, and in each case the lowest data points were on or above the linear regression slope plotted for the overall dose-response analyses of the pooled data, as shown in Figure 5.5. Thus, these data provide no support for the notion of reduced thyroid cancer risk per unit dose at low doses or of a dose threshold. If anything, the risk per unit dose may be somewhat higher at the lower doses (i.e., the data suggested that a linear fit somewhat underestimated the risk at lower doses and overestimated it at higher doses). One could speculate that this may be due to some cell-inactivation effect at the highest doses which depresses the slope of the overall curve. Alternatively, it is possible that the suggestion of a higher risk per unit dose at lower doses may be partly an artifact. Some studies had no data in the lowest dose range while others were heavily weighted toward low doses. In this situation, if there are variations among studies in the risk estimates

Fig. 5.5. The mean relative risk and 95 % confidence interval for each of the studies in the pooled analysis (Ron, 2002). All three low dose (<0.25 Gy) studies had mean relative risks greater than predicted by the linear fit to the means of all studies.

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for reasons unrelated to the radiation effect, they could present as data points that appear above or below the average curve. However, a linear curve provided a good fit to the entire data; an added quadratic component was not statistically significant, indicating that a linear curve is an adequate description of the data. A factor that could affect risk is the possibility that irradiated subjects receive more thyroid surveillance either because they seek more or because the medical care providers know of their radiation history and screen more frequently and thoroughly. Indirect evidence for this could be seen if the dose-response slope was based only on those who had radiation exposure and had a y-intercept (i.e., zero-dose ERR) greater than zero. Alternatively, if the degree of thyroid surveillance increased approximately in proportion to the thyroid dose for various dose groups, then the y-intercept for the irradiated group would remain approximately zero. If there is a >0 intercept, this would tend to create an artificially steeper slope when the nonirradiated group is included in the dose-response analysis. A test for a nonzero intercept can be conducted by evaluating a term for irradiated versus control in the model, in addition to the dose term. When this was done in the pooled analysis (Ron et al., 1995), a small positive intercept value was obtained, indicating a possible surveillance effect, or other source of irradiatedcontrol noncomparability. Inclusion of this term halved the risk estimate (ERR = 3.8, 95 % CI 1.4 to 10.7), and it also reduced the heterogeneity in risk estimates among the studies so that it was no longer statistically significant ( p = 0.08). Nevertheless, there seems to be insufficient justification to incorporate this ad hoc adjustment, rather than use the simple dose-response estimate. A summary of available dose-response data is shown in Table 5.7. The data for doses under 1 Sv are shown in as much detail as possible from the publications. Several studies suggest that there is increased risk at fairly low doses, although the dose groupings were often wider than would be desirable for an examination of the low-dose region. Nevertheless, the thyroid cancer incidence data for external irradiation in childhood were consistent in showing apparent increased risk at the lowest dose groups in which it was tabulated. 5.3.1.2 Effect of Dose Uncertainty on the Risk Estimates. The possible effects of nondifferential (i.e., approximately random) measurement error in estimated individual doses are to attenuate the slope of the dose-response curve and sometimes to alter the shape of that curve. Attenuation of the dose-response slope is a function of person-to-person inaccuracies/uncertainties in a dose assessment

Dose Groups (mSv)a

Study (reference)

Atomic-bomb survivors (Thompson et al., 1994)

<10 1.0 (93)b

10 – 1,000 (170) 1.38 (115)

>1,000 (1,830) 3.44 (17)

Israeli tinea capitis (Ron et al., 1989)

47 – 80 3.3 (15)

80 – 150 4.2 (24)

150 – 500 6.1 (4)

Rochester thymus (Shore et al., 1993a)

10 – 250 3.85 (2)

250 – 500 13.6 (3)

500 – 2,000 7.1 (1)

2,000 – 4,000 42.3 (11)

20 – 1,000 1.14 (9)

>1,000 10.1 (4)

Diagnostic 131I (Hall et al., 1996a)c

1 – 250 0.55 (5)

260 – 500 0.68 (4)

510 – 1,000 0.47 (5)

>1,000 1.04 (11)

Cervical cancer treatment (Boice et al., 1988)

<50 1.0 (3)b

50 – 100 1.86 (38)

100 – 150 2.39 (10)

150+ 3.42 (21)

Swedish skin hemangioma (Stockholm) (Lundell et al., 1994)

aDose

4,000 – 5,990 78.6 (11)

ranges (mSv) are italicized (with mean doses parenthesized); second line gives relative risk plus observed number of cancers in parentheses. bReference group set to one by definition. cExcluding those referred for suspicion of a thyroid tumor.

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TABLE 5.7—Thyroid cancer among groups with low-dose or fractionated irradiation, according to cumulative dose.

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(so called “classical” measurement error), but some types of errors that are correlated across individuals (e.g., random changes over time in x-ray machine calibration) may have less impact on the slope gradient (Carroll et al., 2006; Schafer et al., 2001; Stram and Kopecky, 2003). It is true that dose uncertainty is not accounted for in the confidence intervals reported in Table 5.7, but no information on dose uncertainty is available for most of the studies. In the case of the Japanese Atomic-Bomb Study, an estimated dose uncertainty is factored into the risk estimates (though RERF statisticians are now working on a more sophisticated and complete version of this). In the case of the Israeli Tinea Capitis Study, factoring in dose uncertainty was found to make little difference in the risk estimates or the confidence intervals (Schafer et al., 2001). The radiation studies in the pooled analysis are subject to both types of measurement error, but the analysis suggests that the impact of measurement error is not large. Lubin et al. (2004) and Schafer et al. (2001) have evaluated the impact of measurement error on the Israeli Tinea Capitis Study and found that correcting for the error changed the thyroid cancer risk coefficient by only ~10 %. The sparseness of the data and limited dose range meant it was not possible to evaluate the degree to which measurement error affected the shape of the dose-response curve in this study. Studies of total solid-tumor incidence or mortality among the atomic-bomb survivors have shown that the dose uncertainties, estimated to be ~30 % (Young and Kerr, 2005), have very little impact on the shape of the dose-response curve (Little and Muirhead, 1996; Preston et al., 2004; Vaeth et al., 1992), and various reports indicate that the degree of attenuation due to measurement error is also relatively small. The Boston Lymphoid Hyperplasia Study estimated the individual dose uncertainties as r50 % (Pottern et al., 1990). A special dosimetry uncertainty occurred in the Chicago Tonsillar Irradiation Study, where for 70 % of the subjects, it was not known whether the orientation of the rectangular port was vertical or horizontal, which could affect the thyroid doses. There has not yet been an analysis of this study that has appropriately taken this uncertainty into account. There are also uncertainties in the Rochester Thymus Irradiation Study for some subjects as to whether the thyroid gland was in or out of the primary beam; the subjects with the most uncertain thyroid doses were not assigned doses and are therefore not included in the analyses. Although the available data suggest that measurement error probably has not seriously biased the estimates of thyroid cancer risk in the pooled analysis, a fuller accounting for uncertainties would be desirable.

278 / 5. RADIATION RISK FOR THYROID NEOPLASMS 5.3.1.3 Effects of Fractionation or Protraction of Dose. In the pooled analysis (Ron et al., 1995), ERR Gy –1 following fractionated exposure was ~30 % less than that after a single exposure. Although not statistically significant, this decrease is suggestive of a small fractionation effect. However, it is difficult to interpret this finding because: (1) the analysis was, in part, a comparison of different studies, so there may have been some noncomparability by interstudy variations in risk; and (2) in some of the studies the dose per fraction was substantial (e.g., 0.5 Gy per fraction), which probably means that the fractionation effect would be underestimated. Because of this, there is too much ambiguity to draw any firm conclusion regarding the effects of dose fractionation from the external radiation studies. The only evidence pertinent to thyroid cancer risk from protracted external radiation will have to come from the studies of occupational or high background area radiation exposures. The extant studies are not informative with regard to childhood exposure and some of them are based on mortality rather than tumor incidence, so there is little useful information regarding gamma- or x-ray dose protraction and the induction of thyroid cancer. 5.3.2

Modifiers of Thyroid Cancer Radiation Risk

Numerous modifiers of thyroid cancer radiation risk have been proposed. In the following sections, possible effects of age at exposure, attained age or TSE, sex, ethnicity, hereditary factors, and thyroid surveillance are discussed. 5.3.2.1 Variation in Risk by Age at Exposure. For the pooled analysis, age at the time of exposure was an important risk modifier (Ron et al., 1995). ERR per unit dose for individuals under age 15 y decreased by about a factor of two for every 5 y increase in age when the ages of 0 to 4 y were used as the referent group. In the Japanese Atomic-Bomb Study of cancer incidence (Thompson et al., 1994), a strong effect of age at exposure was seen, such that ERRs Sv–1 were 9.5, 3, 0.3, and –0.2 at 0 to 9, 10 to 19, 20 to 39, and 40+ y, respectively (Figure 5.6). This provides strong evidence that thyroid cancer risk is inversely related to age at irradiation, such that risk from irradiation in the first decade of life is very high, but there is little risk from irradiation after age 20 y. In fact, those over age 20 y at the time of irradiation did not show a statistically-significant elevation in risk (ERR = 0.10, 90 % CI <–0.23 to 0.75). The studies of radiotherapy for tinea capitis in Israel (Ron et al., 1989), for enlarged tonsils in Chicago (Schneider et al., 1993), for lymphoid

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Fig. 5.6. ERR at 1 Sv by gender and age at exposure of Japanese atomic-bomb survivors (Thompson et al., 1994).

hyperplasia in Boston (Pottern et al., 1990), and for childhood cancer (Tucker et al., 1991) also confirmed the inverse age relationship, although these studies have a more restricted range of ages. One study did not find an age at exposure effect (Fjalling et al., 1986), but methodological weaknesses of the study limit the weight it should be accorded. EAR estimates also varied by age at exposure in the Japanese Atomic-Bomb Study. For those at ages 0 to 9, 10 to 19, and t20 y, EAR estimates were 4.4, 2.7, and 0.2 (104 PY Sv)–1, respectively (Thompson et al., 1994). Only one of the 14 studies of external radiation exposure in adulthood (Table 5.8) showed a statistically-significant excess risk of thyroid cancer (Fjalling et al., 1986), and that study had a mixture of adolescent and adult patients. The results of another study (Damber et al., 2002) were marginally significant. Not surprisingly, most of the studies of 131I exposure in adulthood also showed no statistically-significant excess risk. 5.3.2.2 Variation in Risk by Time Since Exposure or Attained Age. Among the 436 thyroid cancers in the pooled analysis (Ron et al.,

Mean Dose (Sv)

Observed/Expected Thyroid Cancers, RR (95 % CI)

Atomic-bomb survivors (older than age 15 y ATB)a (Ron et al., 1995; Thompson et al., 1994)

0.23

Cervical cancer therapy (Boice et al., 1988)

ERR Sv–1 (95 % CI)

EAR (104 PY Sv)–1 (95 % CI)

92/84.2 = 1.1

0.4 (–0.1 – 1.2)

0.4 (–0.1 – 1.4)

0.11

43/18.3 = 2.35 (0.6 – 8.7)b

1,230 (<0 – 7,700)b

6.87 (–2.04 – 39.2)b

X-ray treatment for cervical adenitis (Fjalling et al., 1986)

7.3

25/4.4 = 5.68 (3.76 – 8.26)c

64 (38 – 100)

1.6 (0.96 – 2.5)

X-ray treatment for tuberculous adenitis (Hanford et al., 1962)

8.2

2/0.4 = 5.0 (0.8 – 17)b

49 (–2 – 190)

0.5 (–0.02 – 2.0)

Benign breast disease (Mattsson et al., 1997)

0.07

4/1.6 = 2.5

2,190 (–320 – 7,400)

4.8 (–0.7 – 16)

226 Ra or x-ray therapy for metropathia (Inskip et al., 1990)

0.01

1/2.0 = 0.5 (0.03 – 2.5)d

–5,000 (–9,800 – 14,700)

11 (–22 – 33)

X-ray therapy for metropathia (Darby et al., 1994)

0.007

3/1.71 = 1.76 (0.36 – 5.13)e

109 (–91 – 590)

–

2/0.74 = 2.70 (0.2 – 32)

1,100 (–530 – 21,000)

2.9 (–1.4 – 54)

Study (reference)

Radiotherapy for peptic ulcer (Griem et al., 1994)

~0.15f

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TABLE 5.8—Thyroid cancer risk estimates from studies of irradiation in adulthood.

X-ray treatment of cervical spine (Damber et al., 2002) Chinese medical x-ray workers (Wang et al., 1990a)

~0.3f

1/0.6 = 1.67 (0.08 – 8.23)e

220 (–310 – 2,400)

0.21 (–0.29 – 2.2)

1.0

22/13.7 = 160 (1.00 – 2.42)

0.6 (0 – 1.42)

—

|1.0g

8/4.80 = 1.67 (0.6 – 4.7)

67 (–40 – 370)

0.10 (–0.06 – 0.54)

U.S. Hanford site (Gilbert et al., 1993)

0.023

3/4.12 = 0.728 (0.19 – 1.98)e

–1,170 (–3,500 – 4,200)

–0.64 (–1.9 – 2.3)

U.K. National Registry for Radiation Workers (Kendall et al., 1992)

0.034

9/4.21 = 2.14e

104.9 (–112.2 – 1,225)b,h

0.11 (–0.12 – 1.3)

U.K. Sellafield (Douglas et al., 1994)

0.124

2/0.83 = 2.41 (0.40 – 8.0)e

1,130 (–480 – 5,600)

0.56 (–0.2 – 2.7)

aATB

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= at the time of bombing. % confidence interval given. c For thyroid screening studies the calculated expected value from population rates was quadrupled to reflect the screening, since studies (Prentice et al., 1982; Ron et al., 1992) have found that thyroid cancer prevalence was increased two to seven times among screenees. dExcludes years zero to nine after irradiation. e Based on mortality only. fEstimated for this tabulation from the indirect information available. gRough estimate given by the authors. h Risk estimate based on the dose-response relationship. b90

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Multiple fluoroscopic exams for TB pneumothorax (Davis et al., 1987)

282 / 5. RADIATION RISK FOR THYROID NEOPLASMS 1995), only two were diagnosed prior to 5 y after irradiation, suggesting that the effective minimum latency period is ~5 y. Reports on the post-Chernobyl data from Belarus and the Ukraine have suggested that some increase in incidence is seen by 3 to 4 y after irradiation. One possibility is that the early excess was attributable to a screening effect, whereby screening leads to earlier detection than would otherwise be the case or to detection of preexisting histologically cancerous nodules that would otherwise have not been detected. Another possibility is that the large collective dose in the children of Belarus and the Ukraine has made it possible to see an early elevation of the cancer rate that cannot be detected in the smaller populations exposed to external radiation. The interpretation of the data on early cancers is unclear at this time, but use of a 5 y minimum latency period is probably a reasonable approximation. The BEIR VII report (NAS/NRC, 2006) preferred risk model for thyroid cancer assumes that ERR is constant as a function of TSE. Reasons for this preference are not discussed in detail. The scientific evidence supporting a decrease in ERR as a function of TSE is accumulating. For example, the authors of the most recent review of the Tinea Capitis Study concluded that 40 y after irradiation, ERR decreases dramatically, although remaining significantly elevated (Sadetzski et al., 2006). In addition, ERR for all solid cancers for the atomic-bomb survivors was reported to decrease at a rate of ~17 % per decade from TSE (Preston et al., 2007). When Lubin and Ron (1998) analyzed the five pooled cohort studies to examine the temporal pattern of thyroid cancer risk following irradiation in childhood, analyses were conducted by TSE and by attained age. They found that ERR peaked ~15 to 19 y after exposure, but was still elevated t40 y after exposure. The corresponding analysis by attained age showed a peak during adolescence and a diminishing, but still elevated, risk to at least age 50 y, the maximum age at observation. The changes in ERR over time were statistically significant ( p < 0.001), indicating it is likely that ERR is not constant over time; nevertheless, the confidence intervals on the temporal pattern of risk were wide, as is often the case when more parameters are added to a model, so the estimates of the temporal pattern of risk have limited precision. Few subjects were observed for more than 45 y in these studies, but it seems prudent to assume that increased risk will continue for a lifetime. 5.3.2.3 Variation in Thyroid Cancer Risk by Sex. Variations in the U.S. “baseline” thyroid cancer rates by age and sex are discussed in

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Section 2.2.2. Female rates are appreciably higher than male rates at nearly all ages; on average, the female rates are two to three times as high as those for males (Figure 2.8). With respect to radiation exposure, ERR was nearly twice as high for females as for males in the pooled analysis (Ron et al., 1995), but this difference was of marginal statistical significance ( p = 0.07). In addition, it was inconsistent across studies, with females showing a higher ERR in some studies, but not others. Other studies have reported that ERRs were similar for males and females (Fjalling et al., 1986; Lundell et al., 1994). Overall, an assumption that ERR is approximately the same for females and males appears compatible with most of the data. However, since the baseline thyroid cancer rates are higher among females than males, having equal ERR for both sexes implies that EAR will be higher in females, and, in fact, a number of studies do show a sex differential in EAR. Among the studies analyzed in the pooled analysis (Ron et al., 1995), the male EAR estimates ranged from ~70 to <20 % of the corresponding female EAR. The BEIR VII (NAS/NRC, 2006) report preferred risk model for thyroid cancer assumes that ERR for females is twice ERR for males. Their reasons for this preference are not discussed in detail. As shown in Table 5.9, the scientific evidence supporting a lower ERR in males than in females is not compelling in that most studies showed no statistically-significant gender radiation interaction effect, and some male/female ratios were greater than unity while others were less. 5.3.2.4 Variation in Thyroid Cancer Risk by Ethnicity. There is substantial variation in “spontaneous” thyroid cancer rates in various geographic areas and ethnic groups. A survey of female thyroid cancer rates (0 to 74 y) in 50 tumor registries or ethnic groups within the registries showed that rates in various countries ranged from three to five times lower than among U.S. white females (Australia, China, England-Wales, India, and Poland) to nearly four times higher than white females (Hawaii, Philippines). Within the United States, various subpopulations have thyroid tumor rates that vary from those among whites. For U.S. females, the ratios of thyroid cancer incidence using white females as the denominator are 0.8 to 1.2 for Hispanics, 0.5 for blacks, 0.6 for New Mexico Native Americans, and 0.8 for California Asians. Other groups of special interest whose ratios, compared to that for U.S. white females have been studied, include: Israeli Jews born in Africa or Asia, 1.4; Japanese (excluding Hiroshima and Nagasaki), 0.5 to 1.5; and Belarus, 0.6.

Commenta

Atomic-bomb survivors (Ron et al., 1995)

Ratio of male/female ERR Gy –1 –2.9 (less than age 15 y ATB) p = 0.39; –0.2 (age 15+ y ATB), p = 0.57

Israeli tinea capitis (Ron et al., 1995)

Ratio of male/female ERR Gy –1 –0.2, p = 0.17

Chicago head and neck irradiation (Ron et al., 1995)

Ratio of male/female ERR Gy –1 –1.8, p = 0.66

Childhood cancer (Ron et al., 1995)

Ratio of male/female ERR Gy –1 –0.6, p = 0.91

Chernobyl and 131I exposure (Cardis et al., 2005)

OR: 5.3 for females (n = 174) and 5.7 for males (n = 102)

Benign disorders of the cervical spine (Damber et al., 2002)

SIR: 1.67 (O/E = 16/9.6) for females and 1.44 for males (6/4.17) with doses of about 1 Gy

Chernobyl and 131I exposure (Davis et al., 2004b)

RR: 2.06 at 1 Gy for females (n = 13) and 1.27 for males (n = 13)

Atomic-bomb survivors (Imaizumi et al., 2006)

There was no interaction of sex with dose in the prevalence of all solid nodules ( p = 0.46), malignant tumors ( p = 0.83), benign nodules ( p = 0.38), other solid nodules ( p = 0.52), and cysts ( p = 0.92)

Chernobyl and 131I exposure (Jacob et al., 2006)

ERR: 3.8 times lower in females than males (ecological study)

Childhood cancer survivors (Ronckers et al., 2006)

ERR: ERR Gy –1 = 1.61 for females (n = 48) and 0.93 for males (n = 22)

Israeli tinea capitis (Sadetzski et al., 2006)

ERR: ERR Gy –1 = 21.1 for females (n = 81) and 17.3 for males (n = 22)

Chernobyl and aATB

131I

exposure (Tronko et al., 2006a)

= at the time of bombing.

ERR: ERR Gy –1 = 16.6 for females (n = 30) and 2.21 for males (n = 15)

284 / 5. RADIATION RISK FOR THYROID NEOPLASMS

TABLE 5.9—Effects of gender on thyroid cancer risk. Study (reference)

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The fact that different populations have different baseline risks for thyroid (and other) cancers raises the problem of how to transfer risk from one population to another. If it is assumed that the risk due to radiation is independent of the baseline risk, then EARs can be transferred from a study population to any other population without adjustment for differences in baseline risks. Or, if it is assumed that the risk due to radiation is proportional to the baseline risk, then ERRs can be transferred without adjustment. The risk-transfer problem has been discussed extensively by others (Land et al., 2003; NCRP, 1997). Very little information is available on ethnic variations in radiation-induced risk of thyroid cancer. One study reported a greater risk of thyroid cancer per unit dose for Jewish subjects than for non-Jewish subjects (RR = 3.3, 95 % CI 1.5 to 7.7) (Shore et al., 2003). Two other studies consisting of all or a large proportion of Jewish subjects have also commented on this possibility (Ron et al., 1989; Schneider et al., 1986), but were not able to make a direct statistical comparison. Pottern et al. (1990) reported a greater risk of thyroid nodules per unit dose in Jewish than in non-Jewish subjects, but were not able to evaluate this for thyroid cancer. With regard to Japanese versus Caucasian radiation risk for thyroid cancer, there has been no study with a direct comparison group, but the thyroid cancer risk estimates for the Japanese Atomic-Bomb Study are intermediate among those from western populations (Table 4.3), suggesting significant ethnic effects have not been observed in multiple studies. 5.3.2.5 Impact of Thyroid Cancer Screening on Risk Estimates. As expected, thyroid cancers are detected more frequently when screening is conducted (Table 4.4). In the Atomic-Bomb Survivors Study, the rate of thyroid cancer was 2.5 times greater in the screened AHS subset than in the remainder of the study subjects (Ron et al., 1992). In the Chicago Head and Neck Irradiation Study, the EAR of thyroid cancer was seven times greater due to screening (Ron et al., 1992). Despite the increase in the thyroid cancer rates, the slope of the dose-response curve was not significantly different when the screened population was compared statistically to the unscreened population. 5.3.2.6 Hereditary Factors and Radiation-Induced Thyroid Cancer. Irradiated and unirradiated populations have shown familial aggregation in ~3 to 6 % of cases (Perkel et al., 1988; Ron et al., 1987; 1989; Schneider et al., 1986; Stoffer et al., 1986). One study attempted to test for a synergism between radiation and hereditary-familial factors, but found no evidence for it (Shore et al.,

286 / 5. RADIATION RISK FOR THYROID NEOPLASMS 1993a). However, the study had limited statistical power for such a comparison. It has been hypothesized that a reason for the high radiation risk of thyroid cancer in the Israeli Tinea Capitis Study is because of a high prevalence of the ataxia-telangiectasia mutation (ATM) germ line mutation among Moroccan Jews who constituted a substantial fraction of that study, but only limited data on this aspect are available. Sadetzki et al. (2006) recently reported that radiation-associated thyroid cancer risk was suggestively greater in North African Jews than in other groups in their cohort, and that the prevalence of an ATM founder mutation was 1.2 % in that group. 5.3.2.7 Other Possible Modifiers of Thyroid Cancer Risk from Radiation. Among women in the Thymus Irradiation Study (Shore et al., 1993a; 1993b), there was evidence that those with a later menarche ( p = 0.04), and possibly those with their first child at a later age ( p = 0.08), had greater radiogenic risk than their counterparts. Oral contraceptive use, hormone replacement therapy, hysterectomy, parity, miscarriage history, smoking history, and obesity were unrelated to radiation risk (McTiernan et al., 1984; Shore et al., 1993a; 1993b). Because of the studies’ limited statistical power and the multiple comparisons performed, the positive and negative findings should be regarded as only suggestive and in need of replication and verification by other independent studies. Dietary stable iodine may also be an important modifier (Cardis et al., 2005). 5.3.3

Possible Models of Thyroid Cancer Risk from Ionizing Radiation

As described in Section 5.1, the two most common dose-response models (EAR and ERR) can be further modified by a number of factors such as TSE. This section describes some possible models of thyroid cancer risks and compares the risk predicted from each model. The methods for calculating the coefficients for the new models in this Report were described in the original pooled analysis (Ron et al., 1995) and in supplemental reports to NAS (Appendix H) (Lubin and Ron, 1998; 2000). 5.3.3.1 Estimated EAR (104 PY Gy)–1 for External, Low-LET Radiation. The pooled analysis of EAR by Ron et al. (1995) was based on those exposed at ages 0 to 14 y in five studies: the Japanese Atomic-Bomb Survivors Study (Thompson et al., 1994), Israeli Tinea Capitis Study (Ron et al., 1989), Rochester Thymus Study

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(Shore et al., 1993a), the Chicago Head and Neck Irradiation Study (Schneider et al., 1993), and the Boston Lymphoid Hyperplasia Study (Pottern et al., 1990). EAR averaged 4.4 [95 % CI 1.9 to 10.1 (104 PY Gy)–1] and the overall EAR was fairly consistent across studies. The estimates of EAR (104 PY Gy)–1 were: Japanese AtomicBomb Study, 2.7; Rochester Thymus Study, 2.6; Chicago Tonsil Study, 3; and Israel Tinea Capitis Study, 7.6; there was considerable overlap among the respective confidence intervals (Table 4.2). Most of the other available studies found an EAR that is similar to these risk estimates as well, as discussed further in Appendix G. For comparison to the present risk estimate of 4.4 (104 PY Gy)–1 (Ron et al., 1995), NCRP (1985a) risk estimate was 2.5 (104 PY Gy)–1. 5.3.3.2 Estimated ERR Gy –1 for External, Low-LET Radiation. In the pooled analysis of five studies of childhood irradiation, the overall estimate of ERR Gy –1 was 7.7 (95 % CI 2.1 to 28.7) (Table 5.10) (Ron et al., 1995). The confidence interval was very wide because of heterogeneity of results among the five studies in their estimates of risk. The conventional 95 % confidence interval, not accounting for heterogeneity, was much narrower: 4.9 to 12. The authors explored the heterogeneity by performing an “influence analysis” (i.e., determining how much the risk estimate changed when individual studies were excluded). When the study with the lowest risk TABLE 5.10—Thyroid cancer ERR Gy –1. Estimates from the pooled analysis of five cohort studies of external, acute radiation exposure (Ron et al., 1995). Dose-Response Analysis Type/Conditionsa

Final model: taking into account heterogeneity in risk estimates among studies Assuming homogeneity of risk estimate among studies

ERR Gy –1 (95 % CI)

7.7 (2.1 – 28.7) 7.7 (4.9 – 12)

Removing the study with the lowest risk estimate

12.2 (3.9 – 37.8)

Removing the study with the highest risk estimate

3.8 (1.4 – 9.9)

Allowing for nonzero dose-response intercept

3.8 (1.4 – 10.7)

a

All models were statistically adjusted for gender, attained age, calendar year interval, and study.

288 / 5. RADIATION RISK FOR THYROID NEOPLASMS estimate, the Chicago Michael Reese Study, was removed, ERR Gy –1 increased to 12.2, while, when the study with the highest risk estimate was removed, the Israeli Tinea Capitis Study, ERR Gy –1 decreased to 3.8 (Table 5.10). Two new studies of infants (see Section 4.4.7 for more details) irradiated for skin hemangiomas have appeared since the pooled analysis was performed, and both have risk estimates compatible with the pooled result [i.e., ERR Gy –1 = 4.9 (95 % CI 1.3 to 10) (Lundell et al., 1994) and 7.5 (95 % CI 0.4 to 18.1) (Lindberg et al., 1995)]. Within this context, heterogeneity means the results of individual studies differ; homogeneity means the results are similar (Table 5.10). In the pooled analysis, the ERR model provided a slightly better statistical fit to the pooled data than did the EAR model, so ERR was chosen preferentially in this study. Nevertheless, since it was not possible to conduct a formal statistical test to compare the two models, this is not a strong conclusion. The ERR model does appear to provide a better fit to the gender data since the radiation risk is approximately proportional to the sex-specific spontaneous rates of thyroid cancer. However, there does not appear to be a compelling reason to prefer one model over the other. Further modeling by Lubin and Ron (1998) showed that neither a constant ERR model nor a constant EAR model provided an optimal fit to the data on the temporal pattern of risk, in that there was variation in the degree of risk by TSE (or, nearly equivalently, by attained age) which is described in more detail in Section 5.3.2.2. The pooled analysis ERR Gy –1 estimate was 7.7; the estimate in the BEIR V report (NAS/NRC, 1990) was 8.3. The BEIR VII report (NAS/NRC, 2006) estimate for how ERR varies with age at exposure is discussed in Section 5.1.2 and shown in Figure 5.3. Two critical features in projecting the lifetime risk of thyroid cancer following radiation exposure are: (1) age at irradiation, and (2) the temporal pattern of the risk beyond the period of observation for which data are currently available.

5.3.3.3 Temporal Aspects of Risk Models for Thyroid Cancer. With respect to the temporal pattern of risk, the pooled analysis of external thyroid irradiation (Ron et al., 1995) included limited data beyond 30 to 35 y after irradiation and virtually none beyond 45 y after irradiation. Therefore, the estimation of a lifetime risk for persons irradiated in childhood requires projecting risk for up to five decades beyond data currently available. The need for data that will contribute to the assessment of a lifetime risk estimate is also a strong justification for the continued follow-up of the major

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irradiated cohorts. Given the observed temporal pattern, it seems reasonable to assume that risk will continue for a lifetime. An ameliorating factor in the uncertainties of projecting risk to longer times after radiation exposure is that, at older ages, an increasing proportion of the population has died from causes unrelated to thyroid irradiation, so that progressively fewer individuals are still at risk of thyroid cancer and the impact of uncertainties in the projection therefore diminishes. The statistical analysis of the temporal pattern of thyroid cancer risk, as a function of TSE (Lubin and Ron, 1998), suggested that models that allow the magnitude of the radiation effect to vary by TSE (i.e., a time-dependent model in which ERR is not constant over time) provided a significantly better fit ( p = 0.001) to the data than did a time-constant ERR model or a time-constant EAR model. The time-dependent statistical analysis showed a pattern of relative risk that peaked at ~15 to 20 y after irradiation and diminished after 30 y, so that the risk for the period 30 to 44 y after irradiation averaged only ~30 to 40 % of that of the earlier time interval. This observation should be tempered by two methodological considerations. First, the Israeli Tinea Capitis Study, which showed the highest risk coefficient of any of the studies, had a mean follow-up time of 30 y and a maximum follow-up time of 37 y; hence, its contribution toward an increased risk disappeared at the longer time periods. Second, the Michael Reese Hospital Study, which had a substantial impact on the risk analysis because of its large number of thyroid cancers, included a strong screening effect of about sevenfold, which was most pronounced at the initial screening at ~25 to 30 y after irradiation, but then diminished at subsequent screenings. Nevertheless, it is thought that these possible temporal artifacts account for only a fraction of the diminished risk at >30 y after irradiation. In support of this viewpoint is the fact that analyses of other data sets in the pooled analysis (i.e., the Rochester thymus data and the Japanese atomic-bomb data) have indicated decreasing risks at longer times after irradiation (Little et al., 1991; 1998; Preston et al., 2007). A diminution in excess risk more than 40 y after exposure is also seen in the updated Israeli Tinea Capitis data (Sadetzki et al., 2006). The original reports (Lubin and Ron, 1998; Ron et al., 1995) of the five pooled studies of radiation exposure and thyroid cancer provided risk coefficients for ages at exposure of 0 to 14 y. Only the Japanese Atomic-Bomb Study had appreciable data beyond age 15 y at exposure; consequently, the estimates for older age groups were based on that study (Thompson et al., 1994).

290 / 5. RADIATION RISK FOR THYROID NEOPLASMS 5.3.3.4 Comparison of Risk Models for Thyroid Cancer. All of the models used to project risk are linear nonthreshold models (i.e., it is assumed that the thyroid cancer risk predicted by a model is proportional to dose to the thyroid). As discussed in Section 5.3.1.3, a linear model provides a good fit to the major data sets of thyroid cancer induction. A clear excess of thyroid cancer has been found at fairly low doses, ~100 mGy, which supports the plausibility of a nonthreshold model. All of the models applied to the data were empirical rather than biologically-based. Biologically-based models will have to wait until the time when the biological mechanisms of induction of thyroid cancer by ionizing radiation are better understood to the point of being quantifiable. Since there is no single best model based on biological or radiobiological considerations, several empirical models were explored to examine the degree of concordance among them. The six models that were selected for examination are briefly described below, and the coefficients applicable to these models are given in Table 5.11. In some cases, the coefficients shown in Table 5.11 are slightly different than those shown in the supplemental analysis (Appendix H) because the age ranges for the calculation of these coefficients were expanded. Model 1: Time-Constant EAR Model. This model was traditionally used in risk assessment (e.g., NAS/NRC, 1972; NCRP, 1985a). It expresses radiation risk as being a constant “additive” amount above the background rates of disease at all ages subsequent to exposure, after some minimum latency period. Lubin and Ron (1998) derived sex-specific risk coefficients for this model based on the pooled analysis of five cohort studies of thyroid cancer and Lubin5 further analyzed the data set to provide modifying coefficients for various ages at irradiation, as shown for Model 1 in Table 5.11. Model 2: Time-Constant ERR Model. This model is now more commonly used than the EAR model in risk assessment, as a number of studies have found that it provides a better fit to the temporal pattern of radiation-induced risk than does the time-constant EAR model. In the case of thyroid cancer, it also provides a better fit in that ERR is comparable for males and females, whereas EAR is not. Furthermore, ERR is affected little or none by screening in the population (provided subjects at all dose levels, including unexposed, 5Lubin,

J.H. (1999). Personal communication (National Cancer Institute, Rockville, Maryland).

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

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have equivalent amounts of screening), while EAR is substantially altered by screening. The time-constant ERR model expresses that (after some minimum latency period) the radiation risk is proportional to the background rates of disease at all ages, rather than a constant “additive” increment. Lubin and Ron (1998) derived a risk coefficient and age modifiers for this model based on the pooled analysis of five thyroid cancer studies (Lubin and Ron, 1998) and Lubin6 provided modifying coefficients for additional ages at irradiation (Model 2, Table 5.11). Model 3: ERR Model Modified by TSE (Upper-Bound Estimate). As already mentioned, the temporal plots shown by Lubin and Ron (1998) indicated that 30 to 44 y after irradiation the risk was only ~30 to 40 % as great, as in the previous 15 y. This categorical model for TSE, which estimated the risk independently for each 5 y age interval, fit the data better than did the time-constant ERR model (Model 2 above). It was thought that a projection of the average risk at 30 to 44 y after irradiation out to all subsequent times/ages would probably represent an upper bound on the estimate of lifetime risk, because the general trend in the temporal curve was downward. The approach of this model was to take the average risk for the interval 30 to 44 y and project that excess risk for the remaining lifetime at that level, rather than projecting a continuing decline in ERR. Table 5.11 gives the risk coefficient modifiers for this model at various ages at exposure and TSE. The 95 % CI for Model 3 (and Model 4) are narrower than the 95 % CIs reported for Model 5 (NAS/NRC, 2006) because use of categorical modeling and the addition of a time since exposure term provided a better fit to the data. Figure 5.7 depicts ERR Gy –1 as a function of TSE following an exposure at age 0 y for Models 2 through 4. Model 4: ERR Model Modified by TSE (Lower Estimate). This model is like Model 3, except it is assumed that ERR continues to decrease at longer times after exposure. To simulate this, the model kept the 30 to 44 y risk out to 50 y, then halved that risk estimate for 50 to 59 y postexposure, and continued halving the estimate for each succeeding decade. Model 5: BEIR VII (ERR) Model. The BEIR VII report (NAS/NRC, 2006) presented an ERR estimate that was based on a reanalysis (Land et al., 2003) of the published pooled data from five major 6Lubin,

J.H. (1999). Personal communication (National Cancer Institute, Rockville, Maryland).

Model Description

Model of Excess Risk [D = thyroid dose (Gy)]

AE = Coefficients for Age at Exposure (ages <5, 5 – 9, 10 – 14, 15 – 19, 20 – 29, t30 y)

TC = Coefficients for Time Since Exposure (5 – 14, 15 – 19, 20 – 24, 25 – 29, 30 – 49, 50 – 59, 60 – 69, 70 – 79, 80 – 89, 90 – 99 y)

Time-constant EAR modela

CM/F u D u AE–M/F where CM/F = 5 (95 % CI 1.9 to 13.5) for males and 8.9 (95 % CI 4.1 to 19.3) for females

AE–M/F = 1, 0.8, 0, 0.1, 0.1, 0.03 for malesb AE–M/F = 1, 0.7, 0.7, 0.3, 0.3, 0.1 for females

1, 1, 1, 1, 1, 1, 1, 1, 1, 1

Time-constant ERR modela

R u 9.0 (95 % CI 2.4 to 24.3) u D u AE c

1, 0.6, 0.2, 0.1, 0.09, 0.03

1, 1, 1, 1, 1, 1, 1, 1, 1, 1

ERR, categorical function of TSEa

R u 11.7 (95 % CI 5.4 to 24.9) u D u A E u TC

1, 0.7, 0.2, 0.2, 0.09, 0.03

1, 1.6, 1, 1.4, 0.394, 0.394, 0.394, 0.394, 0.394, 0.394

ERR, categorical function of TSE (halved)a

R u 11.7 (95 % CI 5.4 to 24.9) u D u A E u TC

1, 0.7, 0.2, 0.2, 0.09, 0.03

1, 1.6, 1, 1.4, 0.394, 0.197, 0.099, 0.049, 0.025, 0.012

BEIR VII ERR model

E , R u CM/F u D u e where CM/F = 0.53 (95 % CI 0.14 to 2) for males and 1.05 (95 % CI 0.28 to 3.9) for females and AE is the age in years

Actual age in years

1, 1, 1, 1, 1, 1, 1, 1, 1, 1

– 0.083  A – 30

292 / 5. RADIATION RISK FOR THYROID NEOPLASMS

TABLE 5.11—Models used to estimate excess thyroid cancer incidence from exposure to low-LET ionizing radiation.

aThe

CM/F u D u AE where CM/F = 1.67 for males and 3.33 for females

1, 1, 1, 0.9d, 0.5, 0.5

1, 1, 1, 1, 1, 1, 1, 1, 1, 1

95 % confidence interval only accounts for standard population sampling variability. The zero coefficient for males exposed at ages 10 to 14 y is a statistical quirk. c R = background age- and sex-specific thyroid cancer rates in the U.S. general population of Caucasians. dFor the NCRP Report No. 80 (NCRP, 1985a) model, there is a dose multiplier of one for external radiation and short-lived radioiodines but 0.33 for 131I and 125I. The age at exposure coefficient of 0.9 given here for ages 15 to 19 y is actually an average of one for ages 15 to 18 y and 0.5 for age 19 y. b

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

NCRP Report No. 80 modeld

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294 / 5. RADIATION RISK FOR THYROID NEOPLASMS

Fig. 5.7. ERR Gy –1 as a function of TSE following an exposure at age 0 y for Models 2 through 4 in Table 5.11. Models 3 and 4 are identical until 50 y since the time of exposure.

cohorts with external irradiation (Ron et al., 1995). Their model incorporated effect modification by: (1) gender, where the risk coefficient was about twice as large for females as males; and (2) age at exposure, using age as a continuous variable. Model 6: NCRP (1985a) (Time-Constant EAR) Model. The previous NCRP report (NCRP Report No. 80) on thyroid cancer induction by ionizing radiation (NCRP, 1985a) used a time-constant EAR model to estimate lifetime risk. Results using this model are presented for comparison with the new models (Models 1 through 4). This model (No. 6) incorporated a twofold difference in thyroid cancer induction by gender (i.e., females have twice as many excess thyroid cancers per unit dose as do males). It also provided a twofold variation in risk by age at the time of exposure, such that those over age 18 y at irradiation were predicted to have only half the risk of those irradiated at younger ages. 5.3.4

Estimates of Lifetime Risks of Thyroid Cancer from External Exposure: Results and Comparison of Models 1 through 6

Based on a pooled analysis of the five studies of external radiation exposure and thyroid cancer risk, Lubin and Ron (1998)

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

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provided risk coefficients for various ages at irradiation (<5, 5 to 9, 10 to 14, 15 to 19, and 20 to 29 y) for Models 1 through 4 (Lubin and Ron, 1998) (Appendix H). For each model, these were of the form of a coefficient for ages 0 to 4 y and a set of multiplicative modifying factors for the other exposure ages (Table 5.11). It is notable that the current risk estimates based on the pooled data analyses and the Japanese Atomic-Bomb Study showed sharply diminishing risk for older ages at irradiation, such that there was no excess thyroid cancer risk for radiation exposure after age 30 y. Nevertheless, the confidence interval included the possibility of some risk, but there is no other study to verify this result. For Models 1 through 4, it was assumed that there was a small risk at all ages >30 y and assigned coefficients are one-third as large as for ages 20 to 29 y. For comparison, NAS/NRC (2006) estimates showed a sharp decrease in risk by age using age as a continuous variable rather than age categories. NCRP Report No. 80 (NCRP, 1985a) assumed that after age 18 y the risk was half as great as for persons irradiated at younger ages. Estimates were developed of lifetime risk to age 100 y using a modified life-table method (Shore and Xue, 1999) to take into account the diminishing population still at risk as age increases because of mortality due to all causes, based on the risk coefficients of Lubin and Ron (1998) (Appendix H). The calculations used the U.S. baseline age-specific thyroid cancer rates (Ries et al., 2006) and all-cause mortality rates for whites in 2001 (NCHS, 2004; Xue and Shore, 2001). Estimates were not made for other racial and ethnic groups in the United States because there is no information on thyroid radiation risk coefficients in other populations. The risk coefficients in Table 5.11, adapted from those reported by Lubin and Ron (1998) for various ages at irradiation were applied for each model. Further calculations were performed to simulate the average lifetime excess thyroid cancer risk for a population of all ages, weighted according to the age distribution of the present U.S. white population (USCB, 2004). A sample of lifetime risk projections for females who received 1 Gy to the thyroid at age 2 y for the EAR model (Model 1) and for three ERR models (Models 2 through 4) is shown for thyroid cancer incidence in Figure 5.8 and for cumulative thyroid cancers in Figure 5.9 and Table 5.12. The statistical uncertainties expressed in the confidence intervals in Table 5.12 take into account the heterogeneity among studies in the derivation of the original risk estimates but not uncertainties in doses or in thyroid cancer ascertainment. Models 1, 2 and 3 (the time-constant EAR, the timeconstant ERR, and ERR changing with TSE projections, respectively) differ modestly in the amount of risk. For the first 20 y after

296 / 5. RADIATION RISK FOR THYROID NEOPLASMS

Fig. 5.8. Predicted yearly incidence of thyroid cancers in 1,000 white females exposed to 1 Gy of radiation at age 2 y for Models 1 through 4.

exposure, the time-constant EAR model (Model 1) predicts the highest thyroid cancer incidence and the time-constant ERR model (Model 2) predicts the lowest cancer incidence (Figure 5.8). From 20 to 35 y after exposure, ERR changing with TSE model predicts the highest cancer incidence and the time-constant EAR model predicts the lowest thyroid cancer incidence. From 35 to 80 y after exposure, the time-constant ERR model predicts the highest cancer incidence and ERR changing with TSE model predicts the lowest thyroid cancer incidence. Note that the major difference in these models is the thyroid cancer incidence that is predicted 40 y or more after exposure. The cumulative number of thyroid cancers predicted by these four models is shown in Figure 5.9. The predictions begin their greatest divergence at ~50 to 60 y after the exposure. Thyroid cancer incidence and the cumulative number of thyroid cancers predicted for females who received 1 Gy to the thyroid at age 2 y were estimated by the two ERR models that incorporate changes with TSE (Models 3 and 4) and are shown in Figures 5.8 and 5.9. As expected, the number of thyroid cancers predicted by Model 4 is less than that predicted by Model 3 since Model 4 has a declining risk more than 50 y after exposure whereas that for Model 3 is constant after that point. Table 5.12 gives the lifetime risk estimates generated by all six models. The lifetime risk estimated from the ERR models that permitted variation by TSE (Models 3 and 4) showed a reduction in risk for all the age at exposure groups compared to the time-constant ERR model (Model 2) of ~20 and 40 %, respectively. With the

Model 2 Time-Constant ERR (95 % CI)

Model 3 ERR, Categorical Function of TSE (95 % CI)

Model 4 ERR, Categorical Function of TSE (halved) (95 % CI)

Model 5 BEIR VII (95 % CI)

Model 6 NCRP Report No. 80c

<5 y

60.6 (28 – 127)

73.5 (20 – 250)

54.0 (25 – 111)

42.9 (20 – 89)

91.0 (24.1 – 283.5)

23.2c

5–9y

39.9 (19 – 84)

44.8 (12 – 159)

43.3 (20 – 90)

37.2 (17 – 77)

60.1 (16.0 – 199.9)

21.6

10 – 14 y

37.0 (17 – 78)

15.0 (4.0 – 56)

13.8 (6.4 – 29)

12.6 (5.8 – 27)

39.7 (10.6 – 136.5)

19.9

15 – 19 y

14.7 (6.8 – 32)

7.3 (2.0 – 28)

14.5d (6.7 – 31)

13.6d (6.3 – 29)

26.0 (6.9 – 91.8)

16.5

20 – 24 y

13.4 (6.2 – 28)

6.2 (1.7 – 23)

6.6 (3.0 – 14)

6.3 (2.9 – 13)

16.7 (4.4 – 59.8)

8.4

25 – 29 y

12.2 (5.6 – 26)

5.6 (1.5 – 21)

6.3 (2.9 – 13)

6.2 (2.9 – 13)

10.3 (2.8 – 37.6)

7.6

30 – 39 y

3.4 (1.6 – 7.3)

1.5 (0.4 – 5.8)

1.9 (0.9 – 3.9)

1.8 (0.9 – 3.9)

4.6 (1.2 – 16.8)

6.4

Gender and Age at Time of Exposure

Female

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Model 1 Time-Constant EAR (95 % CI)

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

TABLE 5.12—Estimates of lifetime thyroid cancer risk (incidence per 1,000 persons irradiated) for various models and ages at the time of acute external exposure to 1 Gy for males and females.a,b

Model 1 Time-Constant EAR (95 % CI)

Model 2 Time-Constant ERR (95 % CI)

Model 3 ERR, Categorical Function of TSE (95 % CI)

Model 4 ERR, Categorical Function of TSE (halved) (95 % CI)

Model 5 BEIR VII (95 % CI)

Model 6 NCRP Report No. 80c

40 – 49 y

2.6 (1.2 – 5.6)

1.1 (0.3 – 4.2)

1.5 (0.7 – 3.1)

1.5 (0.7 – 3.1)

1.5 (0.4 – 5.5)

4.8

50 – 59 y

1.9 (0.8 – 3.9)

0.7 (0.2 – 2.7)

1.0 (0.5 – 2.2)

1.0 (0.5 – 2.2)

0.5 (0.1 – 1.7)

3.3

60 – 69 y

1.1 (0.5 – 2.3)

0.4 (0.1 – 1.5)

0.6 (0.3 – 1.2)

0.6 (0.3 – 1.2)

0.1 (0.03 – 0.5)

2.0

70 – 79 y

0.5 (0.2 – 1.1)

0.2 (0.0 – 0.6)

0.2 (0.1 – 0.5)

0.2 (0.1 – 0.5)

0.03 (0.01 – 0.1)

1.0

80+ y

0.2 (0.1 – 0.4)

0.0 (0.0 – 0.2)

0.06 (0.0 – 0.1)

0.06 (0.0 – 0.1)

0.005 (0.001 – 0.02)

0.3

General female populatione

13.3 (6.2 – 28)

10.8 (2.9 – 38)

10.0 (4.6 – 21)

8.7 (4.1 – 18)

17.4 (4.6 – 58.2)

8.9

Females ages 0 – 14 y

45.5 (21 – 96)

43.8 (12 – 153)

36.7 (17 – 76)

30.6 (14 – 64)

63.0 (4.6 – 58.2)

21.5

Gender and Age at Time of Exposure

298 / 5. RADIATION RISK FOR THYROID NEOPLASMS

TABLE 5.12—(continued).

Male 27.8 (7.5 – 101)

17.8 (8.2 – 37)

12.1 (5.6 – 25)

17.0 (4.5 – 62.0)

10.9

5–9y

24.0 (9.2 – 63)

16.9 (4.5 – 62)

13.7 (6.3 – 29)

10.6 (4.9 – 22)

11.2 (3.0 – 41.4)

10.1

10 – 14 y

0

5.6 (1.5 – 21)

4.3 (2.0 – 9.2)

3.7 (1.7 – 7.9)

7.4 (2.0 – 27.5)

9.3

15 – 19 y

2.6 (1.0 – 6.9)

2.8 (0.7 – 11)

4.7d (2.2 – 9.9)

4.2d (2.0 – 9.0)

4.9 (1.3 – 18.3)

7.6

20 – 24 y

2.3 (0.9 – 6.2)

2.4 (0.6 – 9.2)

2.3 (1.0 – 4.8)

2.1 (1.0 – 4.5)

3.2 (0.8 – 12.0)

3.9

25 – 29 y

2.1 (0.8 – 5.6)

2.3 (0.6 – 8.8)

2.4 (1.1 – 5.0)

2.3 (1.0 – 4.9)

2.0 (0.5 – 7.7)

3.5

30 – 39 y

0.5 (0.2 – 1.4)

0.7 (0.2 – 2.6)

0.8 (0.4 – 1.8)

0.8 (0.4 – 1.7)

1.0 (0.3 – 3.7)

2.9

40 – 49 y

0.4 (0.1 – 1.0)

0.6 (0.1 – 2.1)

0.8 (0.4 – 1.6)

0.8 (0.4 – 1.6)

0.4 (0.1 – 1.4)

2.1

50 – 59 y

0.3 (0.1 – 0.7)

0.4 (0.1 – 1.4)

0.5 (0.3 – 1.2)

0.5 (0.3 – 1.2)

0.1 (0.03 – 0.5)

1.4

60 – 69 y

0.1 (0.0 – 0.4)

0.2 (0.0 – 0.7)

0.3 (0.1 – 0.6)

0.3 (0.1 – 0.6)

0.03 (0.01 – 0.1)

0.8

70 – 79 y

0.1 (0.0 – 0.2)

0.1 (0.0 – 0.3)

0.1 (0.1 – 0.2)

0.1 (0.1 – 0.2)

0.008 (0.002 – 0.03)

0.4

80+ y

0.0 (0.0 – 0.1)

0.0 (0.0 – 0.1)

0.03 (0.0 – 0.1)

0.03 (0.0 – 0.1)

0.001 (0.0004 – 0.006)

0.1

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32.3 (12 – 85)

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

<5 y

Model 1 Time-Constant EAR (95 % CI)

Model 2 Time-Constant ERR (95 % CI)

Model 3 ERR, Categorical Function of TSE (95 % CI)

Model 4 ERR, Categorical Function of TSE (halved) (95 % CI)

Model 5 BEIR VII (95 % CI)

Model 6 NCRP Report No. 80c

General male population

4.8 (1.8 – 13)

4.5 (1.2 – 17)

3.6 (1.7 – 7.7)

2.9 (1.3 – 6.2)

3.6 (0.9 – 13.3)

4.4

Males ages 0 – 14 y

18.5 (7.1 – 49)

16.5 (4.4 – 61)

11.8 (5.5 – 25)

8.7 (4.0 – 18)

11.7 (3.1 – 43.2)

10.0

1.1

1.0

0.8

0.6

1.1

0.5

Gender and Age at Time of Exposure

Females and males 0 – 14 y Average ratio to Model 2

aCalculations were based on the midpoint of the specified age ranges at irradiation. A 5 y minimum latency period was assumed, and modified life-table methods were used to calculate the cumulative incidence out to age 100 y based on U.S. thyroid cancer rates for 1998 to 2000 (Ries et al., 2006), using the 2000 to 2003 age distribution of the U.S. population (USCB, 2004) and accounting for age-specific deaths due to all causes during 2001 (NCHS, 2004). bThese numbers compare to the lifetime baseline (i.e., without radiation exposure) number of thyroid cancers of ~7.7 to 8.5 per 1,000 females starting at various ages <30 y, and 5.7 for a mix of all ages (Footnote e), respectively. For males the respective lifetime baseline thyroid cancers are ~3.0 per 1,000 at all the starting ages 0 to 29 y and 2.5 for a mix of all ages. cNCRP Report No. 80 (NCRP, 1985a) did not give a confidence interval on its estimates of thyroid cancer risk. dThe slight increase in risk predicted for Models 3 and 5 at ages 15 to 19 y when compared to ages 10 to 14 y is an artifact due to the fact that the coefficient for TSE increases to 1.6 at 15 to 19 y after exposure and the baseline thyroid cancer rates are changing. eAll ages, weighted according to the percentage of the sex-specific U.S. white population in each 5 y age interval as of 2003.

300 / 5. RADIATION RISK FOR THYROID NEOPLASMS

TABLE 5.12—(continued).

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

/ 301

Fig. 5.9. Cumulative yearly total number of thyroid cancers in 1,000 white females exposed to 1 Gy of radiation at age 2 y for Model 1 through Model 4.

constant ERR and constant EAR models, the lifetime excess risk following 1 Gy of exposure before age 5 y is ~8 to 10 times as great as the spontaneous lifetime risk (Table 5.11), and, averaged across ages 0 to 14 y at irradiation, the corresponding lifetime excess risks are about five times as great as the spontaneous risk. As a convenient way to compare the findings from the various risk models, the final row in Table 5.12 gives the mean ratio of the lifetime excess cancers, averaged across ages 0 to 14 y at exposure for both sexes for the various models as compared to the timeconstant ERR model (Model 2). These summary values show that the lifetime risk of radiation-induced thyroid cancer predicted by the time-constant EAR model (Model 1) is very similar to that for the time-constant ERR model (Model 2). The models that modify risk according to TSE (Models 3 and 4) yield risk estimates that, on average, are only 60 to 80 % as great as those of Model 2. The results for the BEIR VII model (Model 5) (NAS/NRC, 2006), which used age as a continuous variable and had separate coefficients for males and females, tend to be fairly similar to the results for the present Report’s Model 2, the constant ERR model, except that the BEIR VII values are higher for females at young ages. The result is that the female risks with this model are the highest of any model. The average lifetime risk estimate from NCRP Report No. 80 (NCRP, 1985a) (Model 7) is 54 % as great as that from the time-constant ERR model (Model 2) in this Report.

302 / 5. RADIATION RISK FOR THYROID NEOPLASMS Based on the most recent data and the fit of the models to those data, an ERR model that incorporates adjustment for TSE is preferred. The newest data from the Japanese Life Span Study are continuing to confirm the decrease in ERR at longer follow-up times (Preston et al., 2007), as does the recent update of the Israeli Tinea Capitis Study (Sadetzki et al., 2006). For the two TSE models used here, the overall impact of their use as opposed to the time-constant ERR model is to diminish the lifetime thyroid cancer risk estimate by ~20 to 40 %. There is no clear scientific basis for choosing one over the other. The one yielding a higher risk estimate (Model 3) projects the risk more conservatively to follow-up times where there are no data, although the other one (Model 4) follows more closely what appears to be the trend with respect to TSE. For the two TSE models (Models 3 and 4), the lifetime risk estimates for 1 Gy of radiation exposure to the general population of all ages are ~1 % for females (95 % CI ~0.4 to 2) and 0.3 % for males (95 % CI ~0.1 to 0.7). For the highest risk group, those under age 5 y at irradiation, the estimated lifetime risk of thyroid cancer among U.S. whites using either the constant-ERR (No. 2) model or constant-EAR (No. 1) model is ~6 to 7 % for females and 3 % for males for a 1 Gy thyroid dose, whereas it is estimated to be ~4 to 5 % in females and 1 to 2 % in males with Models 3 and 4 that allow the risk to vary as a function of TSE (Table 5.11). All the models based on the pooled analysis of thyroid cancer (Models 1 through 5) show decreases in the risk estimates according to age at exposure. Below in Table 5.13 is a comparison of the percentage lifetime risk for exposures at different ages for the different models presented in Table 5.12. As can be seen, the risk drops appreciably during the second decade of life for all models, more so for Model 2 than the others. It continues decreasing at ages >20 y, due to the lower risk coefficients and the fewer number of years of life remaining in which cancer might develop. NCRP prefers Models 3 and 4 because they are the most consistent with the data from the five major studies in the pooled analysis (Ron et al., 1995). Of these two models, Model 3 is preferred for radiation protection purposes because it is more conservative (i.e., it does not assume a continued decrease in risk for the longer follow-up times for which we have no data). Longer follow-up of exposed populations will be needed to further evaluate the temporal pattern of ERR with TSE. 5.3.5

Estimation of Lifetime Thyroid Cancer Mortality Risk

Thyroid cancer mortality from radiation exposure has not been well-studied, in part, because the mortality rate is low. A summary

Model 1 (time-constant EAR)

Model 2 (time-constant ERR)

TSE (Model 3) (time-varying ERR: upperbound estimate)

TSE (Model 4) (time-varying ERR: lower estimate)

Model 5 (BEIR VII)

Estimated absolute amount of lifetime risk, age 0 to 4

46.5a

50.7

35.9

27.5

54.0

0 to 4

100 %

100 %

100 %

100 %

100 %

5 to 9

69 %b

61 %

79 %

87 %

66 %

10 to 14

40 %

20 %

25 %

30 %

44 %

15 to 19

19 %

10 %

27 %

32 %

29 %

20 to 29

16 %

8%

12 %

15 %

15 %

30 to 39

4%

2%

4%

5%

5%

40 to 49

3%

2%

3%

4%

2%

50 to 59

2%

1%

2%

3%

1%

60 to 69

1%

1%

1%

2%

<1 %

Age (y)

/ 303

aThe unweighted mean of female and male estimated lifetime thyroid cancers per 1,000 persons per gray irradiated at ages 0 to 4 y, derived from Table 5.12. bThe unweighted mean of the female and male ratios of rates at the designated ages at irradiation divided by the corresponding rate for age 0 to 4 y, expressed as a percent.

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

TABLE 5.13—Comparison of several models as to relative amount of lifetime thyroid cancer risk from exposure at various ages compared to exposure at ages 0 to 4 y.

304 / 5. RADIATION RISK FOR THYROID NEOPLASMS of a number of radiation studies showed a case fatality rate of 4.2 % among 668 largely radiogenic thyroid cancers, but with the limitation that it was not possible to define the average length of observation following thyroid cancer diagnosis for the cases in those studies (Shore, 1992). It is notable that, except for the Japanese Atomic-Bomb Study, the case fatality rate of the remaining studies was only 2 %. Thus far, the case fatality rate in the thyroid cancer cases among children exposed to Chernobyl fallout is also very low. However, too little time has elapsed to have an accurate assessment of the eventual mortality among these cases. The mortality experience in the studies mentioned above is based primarily on thyroid cancers that developed before the age of 45 y. Since there is no evidence to suggest that the mortality experience of radiation-induced thyroid cancer is any worse than that for sporadic cancers (Bucci et al., 2001), the case fatality rates in Section 4.2.2 (Figure 4.6) will be used as a guideline. For persons who were irradiated at ages 0 to 15 y, the risk, as calculated under the TSE models tapers off by about ages 40 to 50 y so that the bulk of the excess thyroid cancers will occur when the case fatality rates are low [estimated as <1 % before age 45 y but 6 to 10 % at ages 55 to 74 y (Figure 4.6)]. Calculating the mortality for radiation-induced thyroid cancer is complicated by the fact that there is considerable uncertainty about the age- and gender-adjusted thyroid cancer mortality rates. Table 5.13 lists the mortality rates predicted by Models 2 and 4. Only two ages of exposure were considered (ages 2 and 12 y). These ages represent the highest and lowest risk childhood risk categories and provide upper and lower bounds for thyroid cancer mortality for childhood exposures. Four simplifying assumptions were made: • the latent period for the clinical diagnosis of thyroid cancer was 5 y; • estimates of 5 y thyroid cancer fatality rates were obtained from Figure 4.6 (Ries et al., 2006); • to account for further mortality more than 5 y after diagnosis, the initial 5 y fatality rate was doubled; and • average thyroid mortality occurs 5 y after diagnosis. In Table 5.14, the cumulative excess thyroid cancer incidence (Table 5.11) are included for comparison to the estimated cumulative lifetime excess thyroid cancer mortality. The values are given as excess number per 1,000 persons, just as in Table 5.11. The mortality is ~10 % of the incidence for Model 2; this is because of the

Age at Time of Exposure

2y

12 y

Incidence/ Mortality

Model 2

Model 4

Male

Female

Male

Female

Incidence

27.8

73.5

12.1

42.9

Mortality

3.0

7.0

0.5

1.4

Incidence

5.6

15.0

3.7

12.6

Mortality

0.6

1.4

0.2

0.5

a Based on age-specific 5 y survival rates for thyroid cancer from the SEER data (Figure 4.6), but the corresponding fatality rates were doubled to approximately account for mortality more than 5 y after diagnosis.

5.3 FACTORS THAT AFFECT THYROID CANCER RISK ESTIMATES

TABLE 5.14—Estimates of lifetime thyroid cancer incidence and mortality (per 1,000 persons irradiated) for various models and ages at time of exposure following a 1 Gy acute external exposure for males and females.a

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306 / 5. RADIATION RISK FOR THYROID NEOPLASMS higher mortality rates at the older ages (Figure 4.6). For Model 4, the mortality is <5 % of the incidence, because with this model the risk declines at longer intervals after exposure (i.e., at older ages). 5.3.6

Internal-Exposure Risk Estimates for Thyroid Cancer: Relative Biological Effectiveness

The primary issue with regard to exposure to 131I is the relative magnitude of risk as compared to external x or gamma radiation; the data regarding this are still sparse but have been augmented by Chernobyl-related studies. In simple biological systems, RBEs can be measured with some precision. In complicated settings such as epidemiologic studies, many of the factors that might affect an estimate of RBE (e.g., type of radiation, DDREF) are unknown and are likely smaller than the uncertainty associated with the measurement of the dose response. Because of this, these factors are usually ignored. For example, the pooled analysis combined the results of studies due to exposures to different types of radiation (e.g., atomic-bomb survivor versus orthovoltage x rays). Several animal studies have attempted to provide information on 131I risk. The early animal studies of thyroid cancer risk from 131I suggested that it was much less effective in inducing thyroid cancer than acute external radiation (Doniach, 1957; Lindsay et al., 1957). However, these and other early studies suffered from some or all of the following limitations: no account was taken of intercurrent mortality in the analyses; the animals were adults when exposed to 131 I; the putative 131I doses were probably underestimated; the 131I thyroid doses were very high, in the cell-killing range. Several decades later, the largest and best rodent study of RBE of 131I (Lee et al., 1982), as compared to external radiation, was conducted using adequate dosimetry and much lower dose levels. It showed that 131I and acute external radiation were about equally effective in inducing thyroid cancer over the dose range of 0.8 to 8.5 Gy, although the confidence interval on the result also would include an RBE of 0.5 or 1.5. The studies of exposure to diagnostic 131I provide very limited information. A Swedish series of 36,792 patients given diagnostic 131 I found no excess risk of subsequent thyroid cancer in the subset who had no external radiotherapy and for whom a suspected thyroid tumor was not the reason for the 131I evaluation (Dickman et al., 2003). The observed and expected numbers of cancers in this group were 36 and 39.5, respectively. Only 1,764 persons younger than 20 y (mostly ages 10 to 19 y) were administered 131I who were not referred because of suspicion of a thyroid tumor (Hall et al.,

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1996b). Their mean thyroid dose was estimated to be ~1.5 Gy. Two thyroid cancers were observed and 2.08 expected among those of ages 0 to 20 y at exposure who had no prior radiotherapy; both cases were 15 to 19 y old at 131I administration. The study lacked statistical power to detect an excess among those less than age 20 y at exposure and was therefore not very informative. Another study of diagnostic 131I administration included 3,503 exposed individuals who had a mean thyroid dose of ~0.9 Gy based on their reported dose distribution, and 2,594 unexposed controls (Chiacchierini, 1990; Hamilton et al., 1989). Four thyroid cancers were detected, but 1.4 were expected based on the internal control group (RR = 2.9, not statistically significant) or 3.7 expected based on SEER general population rates (SIR = 1.1). In a German study (Hahn et al., 2001) of 2,262 children who were exposed to 131I from diagnostic thyroid studies, no significant increase in thyroid cancer risk was observed. Although the diagnostic 131I studies involved substantial thyroid doses, the numbers of thyroid cancers observed among those receiving 131I before age 20 y were very small and very few patients received exposure during the first decade of life. According to the analyses by Lubin and Ron (1998), the risk from irradiation at ages 10 to 14 y is only ~20 % as great as the risk at ages 0 to 4 y, and may be even less at ages 15 to 19 y. A carefully executed study of 3,440 children downwind of the Hanford Facility (Davis et al., 2004a) reported no 131I dose-related excess of thyroid cancer. The principal 131I exposures occurred at roughly ages 0 to 6 y, so late ages at exposure cannot account for the lack of effect. The estimated thyroid doses were quite low; the estimated mean dose was ~180 mGy, and only 0.8 % of the study subjects had doses >1 Gy. The calculated uncertainties in the dose estimates were fairly large and not all likely sources of uncertainty were accounted for in the calculations (Hoffman et al., 2007). The dose uncertainty plus the low distribution of doses may have contributed to the null results. Although the clinical examinations, geographical comparisons, and evaluation of 16 different thyroid endpoints add to the validity of the findings of no effect at the doses of 131I received by the population exposed in utero or as children. The Utah Study of children downwind from NTS recently reported a similar null result for thyroid cancer [estimated ERR Gy –1 = 0.8 (95 % CI <0 to 14.9, p = 0.74, n = 8 cancers)] (Lyon et al., 2006), so the two studies were concordant. However, there was a discrepancy with respect to nonmalignant thyroid nodules, in that the Utah Study reported a strong dose-response association, whereas the Hanford Study did not. The Marshall Islands Study found an excess of thyroid cancers on the most heavily exposed islands of Rongelap and Utirik (Howard

308 / 5. RADIATION RISK FOR THYROID NEOPLASMS et al., 1997). However, the degree and consistency of follow-up were not comparable between the exposed and unexposed groups in the Marshall Islands Study. The dose estimates are uncertain; 80 to 90 % of the dose was from short-lived radionuclides and external radiation. Pacific islanders tend to have very high rates of spontaneous thyroid cancer (Blot et al., 1997) and thyroid suppressive therapy may have reduced the thyroid cancer risk in the irradiated group; these confounding complications make the thyroid cancer results from the Marshall Islands Study difficult to interpret. In the populations downwind from Chernobyl in Belarus and Ukraine, large excesses of thyroid cancers have been reported. Among those who were children at the time of Chernobyl, 2,010 thyroid cancers have been reported in Belarus and 2,344 in the Ukraine between the years 1986 and 2002 (Cardis et al., 2006). In a thyroid screening study, Shibata et al. (2001) estimated the relative risk for thyroid cancer among Gomel school children born before April 26, 1986, as 121 (95 % CI 9 to 31,000) compared with those born after 1986. For those born between the accident time and the end of 1986, the relative risk was 11 (95 % CI 3 to 176). Jacob et al. (2006) reported an excess risk attributable to 131I exposure in an ecologic study (ERR Gy –1 = 18.9, 95 % CI 11 to 27). Astakhova et al. (1998), in a case-control study in Belarus, reported a dose related excess after controlling for detection by screening [OR = 5, 95 % CI 1.5 to 17 to OR = 5.8, 95 % CI 2 to 17 for those with t1 Gy versus <0.3 Gy (Cardis et al., 2006)]. Cardis et al. (2005) had earlier conducted a large case-control study in Belarus and Russia and found an odds ratio of 5.5 (95 % CI 3.1 to 9.5) to 8.4 (95 % CI 4.1 to 17) at 1 Gy. Studies of thyroid cancer following the Chernobyl nuclear reactor accident are described in more detail in Section 4.5.3.6 and the risk coefficients from each study are listed in Table 4.10. The degree to which the elevated thyroid cancer rates may be attributable to intense medical surveillance is uncertain, although it does not account for all of the excess. In the Belarus and Ukraine tabulations of thyroid cancer, after factoring in a correction for screening/surveillance, it still appears that two-thirds or more of the cases are radiation related. In the one analytic study of this issue, Astakhova et al. (1998) in Belarus found suggestively higher relative risks when thyroid cancer cases were compared to population controls rather than to controls with the same type of screening, but the differences were not statistically significant and there were elevated relative risks for those with comparable screening as well. For those with a comparable thyroid screening history, the odds ratio for thyroid doses of 1 Gy in comparison with <0.3 Gy was

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5 (95 % CI 1.5 to 17). A cohort study of Ukrainian children and adolescents has been published (Tronko et al., 2006a). All individuals in the cohort had uniform thyroid surveillance. ERR Gy –1 was calculated to be 5.5 (95 % CI 1.70 to 27.5). A second hypothesis is that the levels of iodine in the diet in some of the affected regions in Belarus and Ukraine are borderline low which may affect the tumor response, as suggested by animal studies. A recent assessment of thyroid cancer risk in children exposed to Chernobyl fallout in Russia has suggested that iodine deficiency increases the radiation risk by about twofold (Shakhtarin et al., 2003). A larger study by Cardis et al. (2005) similarly reported that iodine deficiency increased thyroid radiation risk by about threefold (OR = 3.2, 95 % CI 1.9 to 5.5 for iodine deficiency). Specifically, for those who did not report potassium iodide supplementation, the odds ratio at 1 Gy was 10.8 (95 % CI 5.6 to 21) for those living in areas in the lowest tertile of soil iodine levels, whereas it was 3.5 (95 % CI 1.8 to 7) for those in the highest two tertiles. It should be noted, however, that there was no difference in the radiation odds ratios between the upper two tertiles of soil iodine levels, and that the soil iodine index appeared to be potentially confounded by urban-rural differences because of the way it was calculated. An additional finding of the Cardis et al. (2005) study was that potassium iodide supplementation appeared to reduce thyroid cancer risk by a factor of three (OR = 0.34, 95 % CI 0.1 to 0.9). This was unexpected a priori because the potassium iodide supplements were seldom given at the time of or shortly after the Chernobyl nuclear reactor accident, but rather occurred months to years later. It is possible that the potassium iodide may have reduced risk by inhibiting thyroid growth, but since the numbers of subjects who consumed potassium iodide was relatively small, replication of this finding is needed. Another factor that needs to be considered is the concomitant exposure to both 131I and short-lived radioactive iodines in the Chernobyl fallout (Section 3.7.4). The dose to the thyroid target cells may be larger per unit exposure for short-lived radioiodines than for 131I. Because the short-lived iodines constituted <10 % of the total radioactive radioiodines in the fallout (Gavrilin et al., 2004), except for residents of Pripyat, the short-lived radioiodines would account for only a small fraction of the relevant dose. Even though the doses in Belarus and Ukraine are not known with great precision, the number of children with high doses is substantial, so that an effect is seen in spite of the possible attenuation of the association by the measurement error. In an early study, Jacob et al. (1998) estimated from an ecological epidemiological

310 / 5. RADIATION RISK FOR THYROID NEOPLASMS study that the slope of the dose-response relation for 131I and thyroid cancer was about half as great as the slope for external radiation. However, the crude nature of the dosimetry by geographic region means this estimate has a substantial uncertainty. More recently, the same group has reported another ecological epidemiological study with a larger ERR from 131I (ERR Gy –1 = 18.9, 95 % CI 11 to 27) than the generally accepted risk coefficient for external irradiation of 7.7 (Jacob et al., 2006). An association between individuals 131I exposure levels and thyroid cancer in the Russian Federation was reported by Davis et al. (2004b); the magnitude of the association was compatible with the risk estimates for external radiation, but the confidence interval was wide because there were only 26 cases of thyroid cancer. As mentioned previously, risk estimates ranged from odds ratio of 5 (95 % CI 1.5 to 17) to odds ratio of 5.8 (95 % CI 2 to 17) when those with 1 Gy thyroid exposure were compared with those with <0.3 Gy in the Astakhova et al. (1998) case-control study based on 107 cases. Similarly, the odds ratio ranged from 5.5 (95 % CI 3.1 to 9.5) to 8.4 (95 % CI 4.1 to 17) at 1 Gy based on 276 thyroid cancer cases in the Cardis et al. (2005) study. Although there are large differences in the point estimates that have been published following the Chernobyl nuclear reactor accident (Table 4.10), for the most part, these estimates are consistent with one another given the large 95 % confidence interval; the differences in methodology and the fact that all uncertainties have not been taken into account may explain the large differences in the point estimates. These risk estimates are slightly smaller than, but easily compatible with, the estimated ERR Gy –1 of 7.7 (95 % CI 2.1 to 28.7) in the pooled analysis of thyroid cancer after external irradiation (Ron et al., 1995). The thyroid cancer experience in Belarus, Ukraine, and the Russian Federation renders unlikely a small RBE factor (e.g., 0.1) for 131I. Other assessments of RBE for 131I have been performed. In a review of animal and human data, Laird (1987) used a comparative potency model to determine the relative potency of 131I and of external radiation in causing thyroid cancer. The author used statistical methods to combine different sources of data on the carcinogenic effects on the thyroid. The results of the analysis are shown in Table 5.15. Although in children, the point estimate of EAR for 131I (1.97) was less than the point estimate of EAR for external radiation exposure (3.01), this difference was not statistically significant. The combined data from the several human and rat studies suggested that RBE for 131I compared to external radiation was about two-thirds, but the 95 % confidence interval suggested that

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TABLE 5.15—Estimated EAR for thyroid cancer (104 PY Gy)–1 (Laird, 1987). Group

Exposure

EAR (95 % CI)

Uncertainty (range/risk)

3.01 (1.57 – 5.76)

1.4

1.97 (0.39 – 10.06)

4.9

Children

X ray

Children

131I

Adults

X ray

1.59 (0.29 – 8.77)

5.3

Adults

131

1.04 (0.11 – 9.77)

9.3

I

RBE could be as low as one-seventh or as high as three. Laird (1987) concluded there was no firm evidence to suggest that 131I and external radiation differ in their potency for induction of thyroid cancer; this study was performed at a time when there was much less human data available than now. Based on a combination of biophysical considerations, in vitro data, and animal data, Brenner (1999) concluded that electrons emitted by 131I have a biological effectiveness of “about 0.6” compared to x rays, but there is no convincing evidence that the dose-rate effect differs from unity. RBE for 131I was discussed in a report used to estimate the health effects from releases of radioactive materials from radioactive lanthanum processing at the X-10 site in Oak Ridge, Tennessee (1944 to 1956) (Apostoaei et al., 1999). RBE for 131I was treated as an uncertain variable. The weighted average of the subjective probability distribution for RBE was 0.72. Since the difference in RBE of 131I compared to external radiation exposure may simply be due to dose-rate effects, RBE (and its associated uncertainty) may be equal to the inverse of DDREF. The subjective probabilities for DDREF for breast and thyroid used in the Interactive RadioEpidemiological Program is shown Figure 5.10 (Land et al., 2003). The weighted average of probability distribution for DDREF is ~1.75. This would correspond to an RBE of ~0.57. The BEIR VII committee found a believable range of DDREF values to be 1.1 to 2.3,7 and 7For the purposes of calculating lifetime attributable risk, the BEIR VII committee inflated variance representing the uncertainty in the log DDREF by 50 %.

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Fig. 5.10. Subjective discrete probability distributions for DDREF applied to chronic, low-LET exposures for breast and thyroid (Land et al., 2003).

used a median value of 1.5 to estimate solid cancer risks (NAS/NRC, 2006). This corresponds to an RBE of 0.66. An RBE in the range of 0.6 to 1 is in good agreement with other recent reviews. The UNSCEAR (2000b) report concluded, “In summary, the very limited human data on childhood exposure to 131I and adult exposure to external radiation are insufficient for concluding that there are significant differences between these types of radiation with regard to thyroid cancer induction.” Similarly, IOM recently concluded, “The relative risk for thyroid cancer for a person exposed at that age, compared with an unexposed person of the same age and gender, is calculated using an RBE of 0.66. The committee believes that an RBE of one would be equally acceptable given the scientific information available at this time” (NAS/IOM, 1999). The human data pertinent to RBE of 131I are sparse except for the Chernobyl experience. The Chernobyl data are robust with respect to number of thyroid cancers, but have uncertainties

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associated with the dosimetry and cancer surveillance bias (Section 5.4.1). Therefore, the Chernobyl-associated risks are not precisely quantified. Based on its review of the literature, NCRP concluded that RBE for 131I is likely to be in the range of 0.6 to 1, although some experts believe RBE could be lower than 0.6 or greater than one (Boice et al., 2006; Hoffman et al., 2007). Given the paucity of data on RBE for 131I in humans, the probability distribution of possible values for DDREF (the inverse of RBE) shown in Figure 5.10 is a reasonable representation of the current state of knowledge. 5.4 Estimation of Radiation Risk for Thyroid Nodules 5.4.1

Acute External Exposure in Childhood or Adolescence

Estimates of the risk of thyroid nodules in relation to radiation exposure are shown in Table 4.11 for cohort studies of nodules; Table 4.12 for screening studies of nodule prevalence after acute, external irradiation; and Table 4.13 for studies of nodule prevalence after protracted irradiation. It is notable in Tables 4.11 and 4.12 that essentially all the studies of children exposed to external radiation showed increases in thyroid nodule risk. Several meta-analyses were conducted to obtain rough summary estimates of thyroid nodule risk. In each case, there was heterogeneity among studies in the risk estimates, so this was taken into account in the meta-analysis estimation of confidence intervals. The cohort studies in Table 4.11 showed an average EAR (104 PY Gy)–1 estimate of 6.5 (95 % CI 3 to 13) and an average ERR Gy –1 estimate of 12 (95 % CI 5 to 29). For the screening studies of thyroid nodule prevalence following acute external radiation exposures in Table 4.12, the average ERR Gy –1 estimate was 2 (95 % CI 0.1 to 8). The apparent disparity between the ERR estimates for the cohort studies and the screening studies may not be statistically significant, but if it is real, it may reflect several factors. The cohort studies may have some degree of surveillance bias, wherein irradiated subjects obtain more thyroid screening than unirradiated subjects, thereby heightening the risk estimates of those exposed. Furthermore, the cohort studies tended to have lower mean doses on average than the screening studies. Surveillance biases get magnified more in “risk per unit dose calculations” if the doses are lower than when they are higher, which might account for some of the apparent disparity. Some of the screening studies had poorly defined groups, lower participation rates and other methodological weaknesses. Both types of studies showed clear excesses of thyroid nodules in the irradiated groups.

314 / 5. RADIATION RISK FOR THYROID NEOPLASMS 5.4.2

Protracted Exposures and Adult Exposures

In contrast to the childhood external radiation studies in Tables 5.14 and 4.11, most of the studies of groups with adult 131I exposure or other protracted/fractionated exposures (Table 4.13) did not show a statistically-significant increase in thyroid nodule risk. Two studies have examined thyroid nodules among the Marshall Islanders. Hamilton et al. (1987) examined 2,273 persons who were born before the 1954 BRAVO detonation, which released significant fallout on the Marshall Islands. Hamilton et al. (1987) ascertained each examinee’s residential location for the date of the nuclear test and then determined for each residence its distance from the Bikini Test Site. They found a negative correlation between distance and thyroid nodule prevalence. Similarly, Takahashi et al. (1997) examined 815 Marshall Islanders born before the 1954 detonation, and, according to the island of residence at the time of the BRAVO test, determined the age-adjusted prevalence of all solitary nodules or nodular goiter [i.e., nodules detected by either palpation or diagnostic ultrasound (266) and palpable nodules only (131)] including those that were palpable only after being located by diagnostic ultrasound. The prevalence of all nodular goiter was not significantly correlated with distance from the Bikini Test Site (r = –0.29, p = 0.12). The prevalence of palpable nodules was marginally associated with distance from the test site (r = –0.37, p = 0.06). The Swedish Diagnostic 131I Study showed a statistically significant but small positive slope to the dose-response curve among irradiated subjects, although nodule prevalence was not elevated relative to that of the unirradiated group (Hall et al., 1996a). There also was a statistically-significant dose-response relationship for thyroid nodules in the Utah 131I Fallout Study (Lyon et al., 2006). Most studies of thyroid nodules following irradiation in adulthood do not show a statistically-significant positive effect for either external radiation or 131I. This finding suggests a parallelism between thyroid cancer and thyroid nodule in that for neither is the association with radiation as great with exposure in adulthood as in childhood. 5.4.3

Discussion and Conclusions Regarding Radiation Risk of Thyroid Nodules

Most cohort studies of thyroid nodule risk have the weakness that they rely upon obtaining medical reports of thyroid nodules as they may have come to medical attention, without systematic screenings of the irradiated and unirradiated subjects. Thyroid

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surveillance can greatly increase the prevalence of thyroid nodule detection. For instance, Ron et al. (1992) found that screening increased apparent thyroid nodule incidence 17-fold. This uneven surveillance of subjects in most cohort studies suggests a caveat in using their risk estimates. Screening studies of thyroid nodule prevalence in irradiated groups have generally had only one thyroid screening; the number of cases seen at one point in time may or may not be a valid representation of cumulative incidence, depending, for instance, on how many nodules spontaneously regress. Studies have also varied considerably in other ways. Some have had cytologic or histologic verification for a high proportion of nodules (e.g., Davis et al., 2004a) while others did not. One main difference among studies is whether or not they used diagnostic ultrasound in their screenings, since it is more objective and can detect smaller lesions than can physical examination (Inskip et al., 1997a). Studies have varied in terms of minimum nodule size considered meaningful, with reported minimum sizes ranging from 2 to 10 or 15 mm. Despite the diversity in methods, there is notable consistency among the studies of acute external radiation exposures in childhood, all of which show an elevated risk of thyroid nodules. Studies of protracted or fractionated radiation exposure show mixed results with regard to risk of thyroid nodules. Of the three studies that were positive (the Marshall Islanders, Utah children with fallout exposure, and Swedish children with diagnostic 131I exposure) the Marshall Islands Study should be discounted because most of the dose was from short-lived radioiodines and gamma irradiation rather than 131I (Robbins and Adams, 1989), and in the Swedish Diagnostic 131I Study the modest dose-response trend within the irradiated group was not supported by a comparison with the unirradiated control group. Thus the evidence is insufficient to draw firm conclusions on the effects of protracted or fractionated radiation with thyroid nodule induction. It is difficult to have much confidence in the quantitative risk estimates of thyroid nodules after juvenile acute radiation exposure because the temporal aspects, methods, and potential bias of the surveillance have varied considerably from study to study. Most of the studies in this category show ERRs at least as high as that for thyroid cancer, so the attributable risk is appreciable. 5.5 Summary of Radiation Risk of Thyroid Disease Radiation risks of thyroid cancer are characterized here using the ERR and EAR models based on an analysis of the pooled data from five cohort studies of external radiation and thyroid cancer

316 / 5. RADIATION RISK FOR THYROID NEOPLASMS (Ron et al., 1995). Past thyroid cancer risk estimates are reviewed and two are analyzed for comparison with the present estimates. The pooled data indicate that a linear dose-response curve fits the data well, including indications of excess risk down to ~0.1 Gy. The limited data regarding the possible sparing effect of dose fractionation are indeterminate, but with some suggestion there may be a modest effect. Only three studies, the Atomic-Bomb Survivors Study, the Israeli Tinea Capitis Study, and the University of Utah Study have attempted to adjust for known dose uncertainties; in these studies dose uncertainty corrections had only a small or no effect on risk estimates. Age at exposure is a strong modifier of thyroid cancer risk. The pooled-study risk estimate showed a relative risk at 1 Gy of ~10 when exposure occurred before age 5 y, but the Life Span Study showed no statistically-significant excess risk after age 30 y. TSE, or attained age, is also a modifier of risk among those receiving thyroid irradiation in childhood. The excess risk peaks at ~15 to 20 y after irradiation and diminishes thereafter, but there is still an excess risk 40 y or more after irradiation. The ERR estimates are approximately comparable for males and females. Since the baseline rates of thyroid cancer are higher in females than males at nearly all ages, this means that EAR is greater in females. Little is known about the extent to which other potential modifiers might be important in radiation risk for thyroid cancer; such modifiers include but are not limited to ethnicity, family history of thyroid cancer, iodine deficiency, reproductive factors, or exogenous hormones. Various models of lifetime risk are examined based on the pooled analyses of the available data on external irradiation. For males and females irradiated at ages 0 to 14 y, the several risk models based on the pooled analyses give average lifetime risk estimates ranging from ~1.2 to 2 times as much risk as that projected by NCRP (1985a). For females, the time-constant ERR model projects a lifetime thyroid cancer risk of ~44 per 1,000 following a 1 Gy thyroid dose to a population of mixed ages 0 to 14 y (see Table 5.12 for confidence intervals), while the two models that allow the magnitude of risk to change with TSE project a lifetime thyroid cancer risk of 31 to 37 per 1,000 for the same exposure. The results of the best methodologically sound experimental study of rats suggest an RBE for 131I, as compared with x rays, of close to unity for cancer induction but less than unity for adenoma induction. The human data for juvenile 131I exposure are sparse, except for the Chernobyl data which are much more numerous but also have certain dosimetric and methodological limitations. The collective data suggest an RBE in the range of ~0.6 to 1.

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The data on thyroid nodules are less systematic than those for thyroid cancer owing to variations in the definition and ascertainment of nodules, surveillance biases, etc. The available information suggests an approximate parallelism between the findings for radiation-related thyroid cancer and thyroid nodules with both showing much higher risk when irradiation is in childhood. Radiation-related thyroid cancer and thyroid nodules are more frequent among females, and their excess appears to persist for many years after exposure. Although hypothyroidism in response to very high doses is well established, the data do not permit quantification of a dose response for autoimmune thyroid disease and hypothyroidism at low-tomoderate doses. One problem is that the clinical significance of variations in levels of circulating thyroid antibodies is unclear, and more fundamentally, autoimmune thyroid disease may be largely a reflection of how an individual’s immune system reacts to some thyroid antigen rather than a direct reflection of radiation-induced damage per se, in which case no simple dose-response relationship should be expected. Recent results from atomic-bomb survivors (Imaizumi et al., 2006) and the downwinders at Hanford Site (Davis et al., 2004a) found no dose-related excess of autoimmune thyroid disease, whereas, a recent reanalysis of autoimmune thyroid disease in Utah downwinders reported a statistically-significant doseresponse relationship (Lyon et al., 2006).

6. Screening for Thyroid Disease Following Radiation Exposure Proper medical follow-up of persons exposed to ionizing radiation continues to be a controversial topic. Major concerns are centered on the ability to accurately identify populations at increased risk and on whether screening for disease in the at-risk population is associated with more benefits than harm. Decisions about screening for disease are made in an environment where the public often overestimates the benefits from screening and minimizes the harm. Decisions about screening for disease have important implications for populations such as those exposed to radioiodine from the Chernobyl nuclear reactor accident. This section consists of a brief review of the recommendations of prior scientific bodies and a presentation of conclusions. 6.1 Background Some confusion about screening derives from the lack of a precise definition of screening. The goal is to detect disease in people without symptoms so that they can be treated earlier. The assumption that is often made is that earlier diagnosis will result in reduced mortality and morbidity. The appeal of screening is powerful but recommendations for screening are associated with a special ethical imperative. Before an agency recommends screening, there should be good scientific evidence that indicates that the benefits of screening will outweigh the harms. The IOM report (NAS/IOM, 1999) discussed the pyramid of evidence that is necessary for a national screening policy (Figure 6.1). For screening to be beneficial, an at-risk population needs to be identified, effective treatment of the disease needs to exist, an accurate practical screening test must be available, early detection of disease must improve survival, and the benefits of screening must be greater than the harm. The primary focus of screening following radiation exposure of the thyroid gland has been to detect and appropriately treat nodular thyroid disease, benign and malignant, which is the primary 318

6.1 BACKGROUND

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Fig. 6.1. Pyramid of evidence for national screening policy (NAS/IOM, 1999).

long-term sequela of irradiation of the thyroid by ionizing radiation. A greater appreciation of the possibility of a linkage between thyroid radiation exposure and thyroid dysfunction (overactive and/or under active thyroid) has recently led to additional recommendations regarding assessment of thyroid function by sensitive blood tests as part of follow-up medical care. Over the last 20 y, there has been a dramatic change in the way management guidelines for specific disease conditions are developed. Researchers and clinicians considered to be experts on the issue in question would previously gather together, review the published literature, and write a consensus document based on their review of the data, personal experience, and committee discussions. These types of “expert opinion” guidelines have more recently been supplanted with management guidelines based on a rigorous review of the scientific evidence using very strict criteria to judge the weight of the evidence presented. While these evidence-based medical recommendations still seek the input of experts in the field, the final recommendations are based more on critical review of the existing data than on individual clinician preferences. 6.1.1

National Cancer Institute Workshop

In 1975, when concerns about radiation-induced thyroid cancer from therapeutic medical exposures were high, NCI sponsored a workshop entitled “Late Effects of Irradiation to the Head and Neck in Infancy and Childhood” (Beahrs, 1976). This conference focused almost exclusively on therapeutic uses of EBRT in the treatment of nonmalignant conditions of the head, neck, or upper thorax in infancy and childhood. The conference did not address issues related to exposure of the thyroid to radioactive iodines. Recommendations from this workshop included:

320 / 6. SCREENING FOR THYROID DISEASE • Any individual who thinks he may have had such irradiation, as well as anyone who feels a lump in his thyroid gland, should be encouraged to visit his physician or usual source of medical care for an examination. • In general, surgical exploration should be considered for all palpable thyroid nodules, particularly those that are firm and clearly demarcated and those that are cold on scan (i.e., those that accumulate little radioactive iodine on scan). Medical tests that are considered routine today, such as diagnostic ultrasonography and FNA, were not widely available or commonly used at the time (1975) of the NCI workshop. At that time, evaluation of thyroid nodules relied on physical examination, radioactive iodine scanning, thyroid hormone suppression and surgical exploration for a definitive histological diagnosis. 6.1.2

Follow-Up of Patients Treated with External Beam Radiation Therapy for Malignant Conditions

While the practice of using therapeutic external beam radiation therapy (EBRT) for benign conditions has largely been abandoned, its use as therapy for malignant conditions of the head and neck continues. EBRT is commonly used in the treatment of many young patients with lymphoma and leukemia. Several long-term, followup studies have documented an increase in both nodular thyroid disease and thyroid dysfunction in these patients. Standard medical follow-up in these patients includes yearly physical examination to detect nodular thyroid disease and serum TSH levels to detect thyroid dysfunction. 6.1.3

National Academy of Sciences Report

In August 1997, as NCI was preparing to release a report on exposure to 131I from U.S. continental nuclear weapons testing, the Secretary of the U.S. Department of Health and Human Services asked NAS to evaluate the public health impact and medical implications of this fallout on the American people. Using an evidencebased medicine approach, the IOM committee reviewed the October 1997 two-volume report, analyzed the evidence linking 131I exposure to thyroid disease, reviewed estimates of thyroid cancer cases likely to have been caused by this fallout, and examined possible clinical and public health responses that would be consistent with scientific evidence regarding possible benefits and harms of routine screening for thyroid cancer.

6.1 BACKGROUND

/ 321

With regard to screening for autoimmune thyroid dysfunction, the NAS/IOM (1999) committee noted that data published at that time did not demonstrate a strong relationship between thyroid dysfunction and low-dose radioactive iodine exposure. Since that time, several publications have demonstrated an increased risk of autoimmune thyroid disease in children exposed to radiation from the Chernobyl nuclear reactor accident (Eheman et al., 2003). With regard to screening for thyroid cancer, the primary recommendation of the NAS/IOM (1999) committee was: “The committee recommends against public programs and clinical policies to promote or encourage routine screening for thyroid cancer in asymptomatic people possibly exposed to radioactive iodine from fallout as a consequence of nuclear tests in Nevada during the 1950s.” This recommendation was based on an exhaustive review of the literature, input of experts in many different fields of study, and deliberation by the NAS/IOM committee. The primary factual basis for the recommendation was summarized by the NAS/IOM committee in the following statements. • Thyroid cancer is rare in the general population. • Exposure to 131I during childhood does appear to increase the risk of thyroid cancer. • Most people will not have enough information to accurately identify individual levels of 131I exposure. • Papillary thyroid cancer (including those cases induced by radiation) can effectively be treated with surgery with 20 y disease-specific survival rates >90 % when detected by routine clinical practice without screening programs. • There is no direct evidence that early detection of thyroid cancer through screening programs (as opposed to routine clinical practice) improves health outcomes or has benefits that outweigh harms. • Routine screening programs, especially if diagnostic ultrasound is used as a screening modality, will identify many small thyroid nodules, only a minority of which will be malignant. • FNA biopsies will find cancer in a few nodules, most will be benign. However, 20 to 30 % of FNA attempts will be indeterminant or unsatisfactory and may lead to “unnecessary surgery for many people who do not have cancer or who have very small cancers that would never progress to cause health problems.”

322 / 6. SCREENING FOR THYROID DISEASE The NAS/IOM committee recognized that some people would be concerned about their individual risk for developing thyroid cancer following radiation exposure and encouraged them to discuss their concerns and history with a clinician. Based on estimates of individual dose, patient concern, and individual risk of developing thyroid cancer, clinicians could provide specific recommendations to individual patients. While the NAS/IOM committee did not provide specific recommendations for individual patients, they did “recommend against using ultrasound examination for screening either initially or following a negative result from palpation” of the thyroid for the reason given above. The NAS/IOM committee addressed the recommendations for medical monitoring for thyroid cancer published by the Agency for Toxic Substances and Disease Registry (ATSDR, 1997) for an estimated 14,000 people living around the Hanford Site in Washington State. NCRP does not believe that the circumstances warrant systematic thyroid screening of asymptomatic people living around the Hanford Site, whether or not they had been exposed to 131I. In particular, the Ishida Study (Ishida et al., 1988) cited by ATSDR was seriously flawed and did not provide valid, usable evidence of benefit of such screening. 6.2 Conclusions While widespread screening of the American population potentially exposed to 131I from U.S. continental weapons testing is not advised, it does seem reasonable for individuals with the highest levels of exposure to radioactive iodine fallout who were at a very young age (e.g., neonate to adolescent) at the time of exposure and who drank milk from backyard cows or goats, to discuss their exposure and potential risk of development of thyroid cancer with their health-care provider. Estimates of individual doses to the thyroid and risk of developing thyroid cancer from NTS fallout can be calculated using the NCI individual dose and risk calculation (NCI, 2007a). After discussing the options, many patients in the high-risk subgroups might elect to proceed with palpation of the thyroid and serum TSH measurement every 1 to 2 y in an effort to detect a clinically important disease that may develop in the years following radiation exposure. A series of pamphlets addressing these important clinical issues surrounding 131I fallout developed by the NCI Communications Coordination Program and Office of Communication are available from NCI for clinicians and interested persons (NCI, 2007b; 2002a; 2002b).

7. Conclusions and Recommendations There are three major aspects to this Report’s conclusions and recommendations. First, the conclusions reached in NCRP Report No. 80 (NCRP, 1985a) have changed by the analyses in this Report. This Report’s conclusions were aided by the development of improved analytic techniques, particularly pooled analyses. Ongoing investigations of the population exposed to 131I from the Chernobyl nuclear reactor accident are beginning to shed light on the risk of thyroid cancer. This release of fission products occurred because of a unique design of the reactor. There was no containment structure and the graphite moderator caught fire, resulting in the release of radionuclides over a 10 d period. The thyroid dose resulting from this release was complex since it depended on local meteorological conditions and dietary habits. This unfortunate event has provided a unique opportunity to study the long-term thyroid carcinogenic effects of internal radiation exposure predominantly from 131I on a large population of all age groups. Second, the data on the carcinogenic effects of external radiation are informative, although longer term follow-up studies are needed to quantify better the change in risk with TSE. In contrast, the data on the carcinogenic effects of internal radiation (including 131I) are preliminary. While the data from Chernobyl are voluminous, the present analyses are nonetheless incomplete because of the relatively short time-scale since the accident occurred, and further improvements are needed to better estimate individual thyroid doses. Third, despite the fact that many studies have yet to be completed, certain conclusions and recommendations can be drawn from the present data. These conclusions and recommendations are listed below. 7.1 Conclusions The conclusions of this Report and the relevant section of the Report from which they were derived are listed sequentially below. 323

324 / 7. CONCLUSIONS AND RECOMMENDATIONS 1.

2.

3.

4.

5.

6.

7.

Comprehensive incidence and mortality data on thyroid cancer in the United States have been available since 1973. The incidence of thyroid cancer has increased from 3.6 per 100,000 (1973) to 8.7 per 100,000 (2002), due mainly to improved, more sensitive detection procedures. The overall mortality rate from thyroid cancers (all ages, all races, both genders) is low, 0.5 deaths per 100,000 persons (Section 1). There is difficulty in identifying a meaningful trend in childhood thyroid cancer in the United States because of very low baseline values of thyroid disease and, therefore, the poor precision of data collected (Section 1). Epidemiologic studies of populations exposed to atmospheric fallout of 131I from nuclear weapons testing have generally not shown an association between thyroid dose and an elevation in thyroid cancer. Any effect would be small and difficult to detect, especially because of large uncertainties in reconstructed thyroid doses, even with large numbers of exposed individuals (Section 1). The Chernobyl nuclear reactor accident (April 1986) resulted in a large release and dispersion of radioiodines, particularly 131I, with subsequent evidence of an association between radiation exposure and an increased incidence of thyroid cancer, especially in the population that was exposed as children and adolescents. This result has led to a further analysis of risk of exposure to radioiodines, especially the relative carcinogenicity of radioiodines, including 131I, versus external radiation to the thyroid (Section 1). The thyroid gland requires iodine for normal functioning. Normal thyroid function can be maintained with ~150 µg of iodine intake per day; total iodine stores in the body are 15 to 20 mg of iodine, most of which is stored in the thyroid (Section 2). The thyroid gland concentrates radioactive iodine (e.g., 131I) 1,000-fold so the dose to the thyroid is typically 1,000 times greater than it is to most other organs in the body. The relatively large dose to the thyroid explains why thyroid cancer is the major concern following exposure to radioiodines (Section 2). Administration of stable iodine before exposure or within an hour after exposure to radioiodine is very effective in reducing the carcinogenic effect of radioiodine on the thyroid because it (stable iodine) substantially blocks the

7.1 CONCLUSIONS

8.

9.

10.

11.

12.

13.

/ 325

uptake of radioiodine, thereby reducing the thyroid dose. In addition, stable dietary iodine may have secondary effects, presumably through modulation of TSH levels that modify the risk of thyroid cancer (Section 2). Insufficiency in dietary iodine increases the percentage of radioiodine taken up by the thyroid gland and, therefore, increases the thyroid dose. The increased thyroid dose increases the risk for thyroid cancer (Section 2). Within the adult population there is a large reservoir of undiagnosed thyroid abnormalities, including incidental thyroid cancers that would never become clinically apparent. Thus, the more intensely populations are examined for thyroid cancer the more thyroid cancer will be diagnosed (Section 2). Within the United States, the incidence of thyroid cancer varies with gender and ethnic background. The incidence is generally higher in females than in males, with incidence of thyroid cancer in females ranging from a high of 12.4 per 100,000 individuals per year (for Asian/Pacific Islanders) to a low of 6.2 per 100,000 individuals per year (for African Americans). In the United States, the mortality from thyroid cancer has been steady at ~0.5 deaths per 100,000 individuals per year (Section 2) since the mid1980s although the incidence has been increasing, especially in women. Thyroid cancer in children is unusual in that children usually have more widespread disease at the time of diagnosis than adults. Despite this, the prognosis for children is better than the prognosis in adults. Survival rates for adults and children with thyroid cancer are high (>95 %) although long-term survival data (e.g., 20 to 40 y postexposure) on children are sparse. Papillary thyroid cancer is the most common type in adults and children (Section 2). There are two general types of thyroid dysfunction: hyperthyroidism and hypothyroidism. The former involves excess serum thyroid hormone; the latter decreased serum thyroid hormone. Treatment of these conditions is aimed at returning serum levels of thyroid hormones to the normal range (Section 2). In the past, EBRT was employed for treatment of certain benign medical conditions (e.g., tinea capitis, acne). These treatments were discontinued once an association between radiation exposure and subsequent development of thyroid cancer was established. The use of small amounts of

326 / 7. CONCLUSIONS AND RECOMMENDATIONS

14.

15.

16.

17.

radioactive iodine for assessment of thyroid functional status, and much larger amounts for therapy of hyperthyroidism and thyroid cancer continues because the benefits from these procedures outweigh the risks (Section 2). In epidemiologic investigations involving thyroid radiation exposures, estimates of doses, which can be from sources external or internal to the body, are subject to uncertainty. Nonetheless, such approximations have utility in arriving at risk estimates and outcomes (Section 3). There are presently four major cohorts that were exposed to internal radiation from environmental releases of radioiodine. Each of these cohorts (Chernobyl nuclear reactor accident, Hanford Site, Marshall Islanders, and Nevada Test Site) is unique, and each has its own strengths and/or weaknesses for determining the dose-response relationship for thyroid effects (primarily the induction of thyroid cancer). The Chernobyl nuclear reactor accident is the most recent, involves exposure of the largest population to large amounts of 131I (1.8 EBq of 131I dispersed to the environment), and has provided (and should continue to provide) substantial information on the risk of 131I-induced childhood thyroid cancer (as well as subsequent thyroid cancer in adulthood) (Section 3). The major pathway for environmentally-released 131I to be incorporated into the thyroid is via the pasture-cow-milkhuman pathway (i.e., cows eating foliage contaminated with 131I). The radioiodine is excreted and concentrated in those cows’ milk. The 131I-contaminated milk is then consumed by humans and concentrated in the thyroid gland. The thyroid dose to children is higher because they consume more milk and their thyroid glands concentrate iodine more than adult thyroid glands (Section 3). There are three major groups of epidemiological studies of radiation-induced effects on the thyroid. First, there are eight major epidemiological studies of external radiation exposures of the thyroids of children and adolescents, including the Japanese atomic-bomb survivors, and patients irradiated for diseases such as tinea capitis, thymus disorder, head and neck disorders, certain childhood cancers, and skin hemangiomas. Second, there are also epidemiological data on radiation-induced thyroid cancers in children and adults from diagnostic and therapeutic uses of 131I; this group includes individuals evaluated for thyroid dysfunction and those treated for hyperthyroidism.

7.1 CONCLUSIONS

18.

19.

20.

/ 327

Third, there are epidemiological data on radiationinduced thyroid nodules in children and adults exposed externally or internally to ionizing radiation. Many of the initial conclusions of NCRP Report No. 80 (NCRP, 1985a) were based on initial assessments of some of these cohorts (Section 4). Data on the effect of ionizing radiation on thyroid cancer in laboratory animals has remained sparse. There are reports comparing large and small doses of external and internal radiation, with the result that there is a greater induction of thyroid cancers with the relatively low doses, due to the lesser degree of cell killing. The pathology of radiation-induced thyroid cancers appears to follow the same etiology as in humans; a similar conclusion is discussed in the recently published NCRP Report No. 150 (NCRP, 2005). In general, the composite results of the few animal investigations of RBE of 131I versus x-ray doses continue to indicate that the latter is more effective (per dosage unit) than the former, the factor of effectiveness ranging from 2 to ~10 although the most recent comprehensive rodent study suggests that external radiation and 131 I are equally effective in inducing thyroid cancer and 131I is less effective than external radiation in inducing thyroid adenomas. This Report notes that “no important animal studies of RBE of 131I and x rays have been published since 1982” (Section 4). Two types of studies are most informative when conducting an epidemiology investigation: cohort (exposed and not exposed individuals), and case-control (diseased and disease-free individuals) studies. The resources required to conduct a cohort study are usually greater than for a casecontrol study, especially when the prevalence of the disease of interest is low. The Report notes that “the vast majority of persons who develop thyroid cancer do not die from this disease. Although thyroid cancer mortality rates are a less ambiguous endpoint than incidence rates, studies of mortality rates typically lack statistical power due to the small number of [attributed] deaths” (Section 4). The risks from doses of ionizing radiations have typically been expressed using two empirical mathematical models: the excess relative risk (ERR) and the excess absolute risk (EAR). The ERR model, usually expressed in units of ERR Gy –1 has a term where the baseline cancer risk is multiplied by the dose so the ERR model is sometimes

328 / 7. CONCLUSIONS AND RECOMMENDATIONS referred to as the “multiplicative” model. The EAR model, usually expressed in units of (104 PY Gy)–1 where PY stands for person-years, has a term which is added to the baseline cancer risk, so the EAR model is sometimes referred to as the “additive” model (Section 4). 21.

The quality of epidemiological studies varies considerably, due mainly to the widely differing circumstances facing the investigators. The quality of the study may be impaired due to large uncertainties in dose estimates or to large uncertainties in the measurement of the endpoints used to determine effects. In addition, an epidemiology study may not be informative due to the fact that the dose was too small or the number of people exposed was too small. For example, estimates of doses to the Marshall Islanders are associated with a large amount of uncertainty due to the complexity of the exposure pathways and the lack of contemporaneous radiation measurements. In addition, the number of Islanders exposed to relatively large doses was small. Thus, only a small fraction of this substantial literature can be used to estimate the doseresponse relationships for a few endpoints (Section 4).

22.

There is an inverse association between age at the time of radiation exposure and thyroid cancer risk per unit dose; the risk is very high following exposure in childhood but becomes small to none following exposure after age 30 to 40 y (Section 5).

23.

Spontaneous thyroid cancer shows a greater difference by gender than most cancers, with women having a risk approximating two to three times as great as that for men. This same disproportion is maintained for radiationinduced thyroid cancer (Section 5).

24.

Thyroid cancer is the most common cancer of the endocrine system and is the 12th most common cancer overall although it accounts for only ~30,000 cancers each year (i.e., ~2 % of the yearly total cancer incidence). The prognosis for patients with thyroid cancer is better than the prognosis for most cancers; thyroid cancer results in only ~0.2 % of all cancer deaths each year (the 31st most common cause of cancer deaths). Even though there are large radiation-related relative risks, the absolute numbers of excess thyroid cancers following whole-body radiation exposures are less than those for more common cancer sites such as breast, lung and colon (Section 5).

7.1 CONCLUSIONS

25.

26.

27.

28.

29.

30.

/ 329

The estimates of lifetime thyroid cancer risk per gray of acute external radiation exposure for various models (Table 5.12) vary with age and gender and are internally consistent with each other. These models show that the risk is: (i) highest at the youngest age group (0 to <5 y), (ii) decreases dramatically with increasing age, and (iii) reaches insignificant levels at age ~40 y. For example, the ERR time-constant model for females estimates the lifetime thyroid cancer risk per gray per 1,000 persons irradiated to be 73.5, 6.2, and 0.7 for those exposed at the age of 0 to 5, 20 to 24, and 50 to 59 y, respectively. Because the baseline risk for males is half the risk for females, relative risk models predict the risk for males in a given age group to be about half that of females of the same age group (Section 5). There is more uncertainty for estimates of thyroid cancer risk from radionuclides taken into the body, partly due to large uncertainties concerning RBE. NCRP presently views RBE of 131I to be in the range of 0.6 to 1. Although the population exposed from the Chernobyl nuclear reactor accident is large and has been extensively studied, large uncertainties remain due to uncertainties in individual thyroid doses, methodological issues (e.g., surveillance bias, ecological studies), uncertainties related to possible modifying factors (e.g., dietary iodine), and uncertainties related to projecting risk for the lifetime of the exposed population. The present information suggests a parallelism between the risk estimates for 131I and external radiation (Conclusion No. 25), with the highest risk associated with irradiation occurring in childhood (Section 5). Mortality from thyroid cancer is low, especially for cancers occurring before age 45 y. The health detriment from thyroid cancer is proportionally less than that associated with some other types of radiogenic cancers (Section 5). NCRP agrees with the conclusions of the NAS/IOM committee that recommended against public programs and clinical policies to promote or encourage routine screening for thyroid cancer in asymptomatic people possibly exposed to radioactive iodine from fallout as a consequence of nuclear tests in Nevada during the 1950s. For a variety of reasons, the harms of such follow-up programs are likely to exceed the benefits (Section 6). Individuals concerned about whether a past exposure to ionizing radiation, especially individuals in a high risk

330 / 7. CONCLUSIONS AND RECOMMENDATIONS group (e.g., young at time of exposure, drank milk from backyard cows or goats, lived in an area of high radioiodine fallout) for radiation-induced thyroid cancer, are advised to discuss the matter with their local health-care provider. Selected high-risk subgroups might elect to proceed with thyroid palpation and serum TSH assays every 1 to 2 y (Section 6). 7.2 Research Recommendations 1.

There remains a need for better information on the RBE of relative to other types of radiation (e.g., x rays, 60Co) for induction of thyroid cancer. Animal model systems can be used for this effort since the cells of origin of thyroid cancer in humans and animals are similar, doses to the animals can be carefully controlled, as can a variety of other variables such as age, sex, diet and genomics. There should be consideration given to the fact that high doses of ionizing radiation from 131I can kill cells and, thus result in an underestimation of the carcinogenic effects of the exposure at lower doses. Thyroid genomics is a relatively young but rapidly emerging, important field. Studies are needed of individuals with and without thyroid disease, and who had or did not have a significant thyroid dose. Certain genetically-engineered strains of mice for thyroid cancer may be useful in pursuit of Recommendation No. 1. The extensive studies of the population exposed as a result of the Chernobyl nuclear reactor accident should continue since there is a large cohort of individuals of all ages exposed to large internal doses of 131I. This population provides an opportunity to study lifetime risks for radiation-induced thyroid cancer from radioiodine exposures. The oncogenesis of thyroid cancer needs further elucidation. The generally accepted assumption is that tissue with high-cell turnover (i.e., proliferating) rates is more susceptible to radiation-induced effects than cells with low to no cell turnover rates. Although this assumption offers an explanation for why children are more susceptible to radiation-induced thyroid cancer than adults, the pathophysiologic mechanisms need further investigation. There is a need for a better understanding of modifying factors associated with radiation-induced thyroid cancer. Age at the time of exposure, and the amount of dietary 131I

2.

3.

4.

5.

7.2 RESEARCH RECOMMENDATIONS

/ 331

iodine have been clearly identified as important factors in the etiology of thyroid cancer. Additional information is needed about other factors that could influence the development of radiation-induced thyroid cancer, including diet, genomics, attained age, gender, and ethnicity. The effect of intensity of screening also requires further study. There is also a need to investigate the effects of varying degrees of bias in the reconstructed doses on the analysis of statistical power and the slope and confidence intervals of the dose-response relationship in an epidemiological study.

Appendix A Radiation Dosimetry Quantities and Units and Related Concepts A.1 Introduction Dosimetric quantities may be characterized as stochastic or nonstochastic (ICRU, 1980; 1983; 1998; Rossi, 1968; Zanzonico, 2000b). A quantity subject to statistical fluctuations is termed, stochastic, and the mean, or expectation value, of a large number of determinations of a quantity is termed, nonstochastic. In radiation dosimetry, then, each stochastic quantity has a corresponding nonstochastic quantity. The field of microdosimetry deals with the number, size, and spatial and temporal distributions of individual energy-deposition events, particularly in microscopic structures of the order of molecules, macromolecules and supramolecular complexes in size, characterizing such events in terms of inherently stochastic quantities (Rossi, 1968). A compilation of SI and conventional quantities and their symbols, units, and conversion factors is presented in Table A.1 (NCRP, 1985b; ICRU, 1998). A.2 Exposure Exposure ( X ) is defined as follows: dQX = ---------, dm where: dQ =

dm =

(A.1)

absolute value of the total charge of ions of one sign produced in air when all the electrons and positrons liberated or created by photons (x and gamma rays) in air of mass dm are completely stopped in air mass of air referred to under dQ 332

TABLE A.1—Quantities, symbols, units and conversion factors (NCRP, 1985b). Quantity

Activity Absorbed dose Absorbed dose rate

Symbol for Quantity A D · D

Expression in SI Units 1 per second

Expression in Symbols for SI Units s–1 –1

joule per kilogram

J kg

joule per kilogram second

J kg –1 s–1

Mean energy per ion pair

W

joule

J

Dose equivalent

H

joule per kilogram

J kg –1

joule per kilogram second

J kg –1 s–1

Dose equivalent rate

· H

ampere

A

Electric potential difference

U, V

watts per ampere

WA–1

Exposure

X

coulomb per kilogram

C kg –1

Symbol for Conventional Unit

becquerel

Bq

curie

Ci

3.7 × 1010 Bq

gray

Gy

rad

rad

0.01 Gy

Gy s–1

rad

rad s–1

0.01 Gy s–1

electron volt

eV

1.602 × 10–19 J

Sv

rem

rem

0.01 Sv

Sv s–1

rem per second

rem s–1

0.01 Sv s–1

ampere

A

1.0 A

volt

V

1.0 A

roentgen

R

2.58 × 10–4 C kg –1

sievert

volt

V

Value of Conventional Unit in SI Units

/ 333

I

Conventional Unit

A.2 EXPOSURE

Electric current

Symbols Using Special Name

Special Name for SI Unit

Quantity

Exposure rate

Symbol for Quantity · X

Fluence

)

Fluence rate

· )

Kerma

K

Kerma rate

· K

Expression in SI Units

Expression in Symbols for SI Units

Special Name for SI Unit

Symbols Using Special Name

Conventional Unit

Symbol for Conventional Unit

Value of Conventional Unit in SI Units

coulomb per kilogram second

C kg –1 s–1

roentgen

R s–1

2.58 × 10–4 C kg –1 s–1

1 per meter squared

m–2

1 per centimeter squared

cm–2

1.0 × 104 m–2

1 per meter squared second

m–2 s–1

1 per centimeter squared second

cm–2 s–1

1.0 × 104 m–2 s–1

joule per kilogram

J kg –1

Gy

rad

rad

0.01 Gy

joule per kilogram second

J kg –1 s–1

Gy s–1

rad per second

rad s–1

0.01 Gy s–1

gray

Lineal energy

y

joule per meter

J m–1

kiloelectron volt per micrometer

keV Pm–1

1.602 × 10–10 J m–1

Linear energy transfer

L

joule per meter

J m–1

kiloelectron volt per micrometer

keV Pm–1

1.602 × 10–10 J m–1

334 / APPENDIX A

TABLE A.1—(continued).

P /U

meter squared per kilogram

m2 kg –1

centimeter squared per gram

cm2 g –1

0.1 m2 kg –1

Mass energy transfer coefficient

Ptr /U

meter squared per kilogram

m2 kg –1

centimeter squared per gram

cm2 g –1

0.1 m2 kg –1

Mass energy absorption coefficient

Pen /U

meter squared per kilogram

m2 kg –1

centimeter squared per gram

cm2 g –1

0.1 m2 kg –1

Mass stopping power

S/U

joule meter squared per kilogram

J m2 kg –1

MeV centimeter squared per gram

MeV cm2 g –1

1.602 × 10–14 J m2 kg –1

Power

P

joule per second

J s–1

watt

W

watt

W

1.0 W

Pressure

p

newton per meter squared

N m–2

pascal

Pa

torr

torr

(101,325 / 760) Pa

Radiation chemical yield

G

mole per joule

mol J–1

molecules per 100 electron volts

molecules (100 eV)–1

1.04 × 10–7 mol J–1

Specific energy

z

joule per kilogram

J kg –1

rad

rad

0.01 Gy

gray

Gy

A.2 EXPOSURE

Mass attenuation coefficient

/ 335

336 / APPENDIX A It may often be convenient to refer to a value of exposure at a point inside a material different from air. In such a case, the exposure specified will be that which would be determined for a small quantity of air placed at the point of interest and, therefore, for example, one can speak of the exposure to a point in the thyroid. Exposure is a nonstochastic quantity and thus corresponds to a sufficiently large irradiated volume and/or a sufficiently large amount of radiation to yield insignificant statistical fluctuations in its measured value. A.3 Absorbed Dose and Specific Energy Perhaps the most widely used unit of radiation dose, absorbed dose (D), is defined as follows: dH D = ---------- , dm where dH = dm =

(A.2)

mean energy imparted to matter of mass dm mass of matter referred to under d H

Absorbed dose is a nonstochastic quantity that approaches the expectation value of the stochastic quantity specific energy (z):

H- , z = ------m

(A.3)

where:

H

=

m

=

energy imparted to matter of mass m by one or more energy-deposition events mass of the matter referred to under H

Among clinical studies related to radiogenic effects on the thyroid, and especially among older studies, the dose to the thyroid is often expressed as exposure in roentgen (the SI unit is C kg –1). It is straightforward to relate absorbed dose to exposure for such cases (Johns and Cunningham, 1974). The mean energy required to produce an ion pair in air is nearly constant for all electron energies, corresponding to a value of the mean energy per ion pair (W) of 33.97 eV per ion pair (Boutillon and Perroche-Roux, 1987). Therefore, since the conventional unit of exposure, the roentgen (R), corresponds to 1.61 × 1012 ion pair g –1 of air (i.e., 1 R = 1.61 × 1012 ion pair g –1), 1 eV = 1.602 × 10–12 erg, and 1 Gy = 104 erg g –1, the absorbed dose to air for an exposure of 1 R to air is:

A.3 ABSORBED DOSE AND SPECIFIC ENERGY

u 10

–1

12

ion pair g eV -------------------------------- u 33.97 --------------------- u 1.602 R ion pair

– 12

erg 1 Gy Gy ---------- u ----------- ------------------= 0.00876 ---------- . 4 –1 eV R 10 erg g

1.610 u 10

/ 337

Therefore: D air = 0.00876 X , where: Dair = X =

(A.4)

absorbed dose in air (gray) exposure in air (roentgen)

Under conditions of charged-particle equilibrium for a point in a non-air medium (such as the thyroid), that is, for a volume of nonair medium in air sufficiently small that it does not significantly perturb the photon fluence, Equation A.4 may be modified to yield the absorbed dose in a non-air medium for a given exposure in air (Johns and Cunningham, 1974):

D med

where: Dmed

=

P en · § --------= © U ¹ med P en · § --------© U ¹ air fmed

P en · § --------© U ¹ med = 0.00876 ------------------------ X = f med X . P en · § --------© U ¹ air

(A.5)

absorbed dose (gray) at a point in a non-air medium mass energy absorption coefficient (cm2 g –1) in a non-air medium

=

mass energy absorption coefficient (cm2 g –1) in air

=

exposure to absorbed-dose conversion factor for the non-air medium (Gy R–1) P en · § --------© U ¹ med = 0.00876 ----------------------P en · § --------© U ¹ air

When expressed as a conversion from R in air to 10 mGy (1 rad) in the non-air medium, fmed is very nearly unity (0.87 to 0.968) for a wide range of photon energies (0.01 to 10 MeV) for air, water and

338 / APPENDIX A soft tissues (including thyroid). Therefore, an absorbed dose of 10 mGy in the thyroid may be considered to be approximately numerically equal to an exposure of 1 R to the thyroid. A.4 Kerma Kerma (K ) is defined as follows: dE tr K = ------------, dm where: dEtr =

dm =

(A.6)

sum of the initial kinetic energies of all the charged particles liberated by uncharged particles in matter of mass dm mass of matter referred to under dEtr

In the case in which the matter is air, kerma is referred to as air kerma, with the symbol Ka. A.5 Linear Energy Transfer and Lineal Energy The quality as well as the quantity of radiation are important determinants of the dose-response relationship for radiogenic biological effects. The quality of a radiation is related to the characteristics of the microscopic spatial distribution of energy-deposition events, determined by the mass, charge and energy of the charged particles composing the radiation or, in the case of x rays, gamma rays, and neutrons, the charged particles produced by the radiation. Sparsely ionizing radiations such as x and gamma rays and intermediate- to high-energy electrons and beta particles are characterized as low-quality radiations; densely ionizing radiations such as low-energy electrons (e.g., Auger electrons), protons, neutrons, and alpha particles are typically characterized as high-quality radiations. Importantly, for the same absorbed dose, the doseresponse relationship for radiogenic biological effects are generally less for sparsely ionizing, low-quality radiations than for densely ionizing, high-quality radiations. The quality of radiation is quantitatively characterized by the linear energy transfer (L' ) (also called the restricted linear electronic stopping power) of a material for charged particles: dE ' L ' = § -------------· , © dl ¹ where:

(A.7)

A.6 RELATIVE BIOLOGICAL EFFECTIVENESS

dE' =

dl

=

/ 339

energy lost by a charged particle due to electronic collisions in traversing a distance dl in matter, minus the sum of the kinetic energies of all the electrons released with kinetic energies in excess of ' distance traversed referred to under dE'

The quantity L' requires the specification of a cutoff energy ('), necessitated by primary energy-deposition events resulting in relatively high-energy, relatively long-range secondary electrons (i.e., delta rays), whose energy deposition events may be considered as separate from those along the track of the primary radiation. In radiation protection, this feature is generally disregarded by specification of the unrestricted linear energy transfer (Lf ) [also known simply as LET (L)], where the energy cutoff (') is set equal to infinity (f). Unless stated otherwise, the unrestricted LET (L) is used exclusively in this Report. Although L is actually defined only for charged-particles, it may be specified for noncharged-particles (i.e., neutrons and x and gamma rays) based on the LET of the charged particles produced by the radiation. LET is a nonstochastic quantity similar in concept to the stochastic quantity, lineal energy ( y):

H

s y = -------, l

(A.8)

where:

Hs

=

l

=

energy imparted to the matter in a given volume by a single energy-deposition event mean chord length of the volume referred to under Hs A.6 Relative Biological Effectiveness

As noted above, for the same absorbed dose, the observed level of a particular radiogenic biological effect is generally less for low-LET radiation than for high-LET radiation. The influence of radiation quality on the level of biological effect is quantified by experimental determination of the relative biological effectiveness (RBE). For radiation type “A” (as characterized by its identity and nominal energy): D reference RBE  A = ----------------------, DA where:

(A.9)

340 / APPENDIX A Dreference = absorbed dose of reference radiation (typically a widely available sparsely ionizing radiation such as 60 Co gamma rays) required to produce a specific level of biological effect in an organism or tissue DA = absorbed dose of radiation A required to produce the identical level of biological effect in the organism or tissue with all pertinent parameters, except the radiation itself, maintained as identical as possible. Because RBE represents a ratio of absorbed doses, it is a dimensionless quantity. A.7 Quality Factor, Radiation Weighting Factor, Dose Equivalent, and Equivalent Dose Because the actual value of RBE depends on many factors, such as the experimental subject (e.g., animal, cell), the nature of the biological effect, the absorbed dose, and the absorbed dose rate, a simplified approach to expressing relative biological effectiveness, the quality factor (Q) was devised for purposes of radiation protection (ICRP, 1977; ICRU, 1993). However, because of variations, even for initially monoenergetic radiations, in energy, LET and, therefore, the quality factor along the radiation track, the so-called dose equivalent (H) at a point must be related to the effective quality factor ( Q ), and the absorbed dose at that point such that: H = Q uD,

(A.10)

1 Q = -------- ³ Q  L D L dL D

(A.11)

and L

where: Q = D = Q(L)= DL =

effective quality factor absorbed dose at the point quality factor for particles with LET L at the point spectral distribution in terms of L of the absorbed dose at the point

However, because of the difficulty of determining the energy, LET, and quality factor distributions at a point, a different, more practical quantity, the equivalent dose (HT,R) in tissue or organ T due to radiation R was devised for radiation protection (ICRP, 1991):

A.8 DOSE-RATE EFFECT AND DDREF

H T,R = w R D T,R , where: wR =

DT,R =

/ 341 (A.12)

radiation weighting factor for radiation type R, a dimensionless quantity designed to account for differences in relative biological effectiveness mean absorbed dose to tissue or organ T due to radiation R

When a tissue or organ is irradiated by a combination of different radiations (i.e., radiations of different qualities), the equivalent dose in tissue or organ T (HT) is the summation of the products of the mean tissue or organ dose (DT,R) due to each component radiation R multiplied by the respective radiation weighting factor (wR): HT =

¦ wR DT,R .

(A.13)

R

Like RBE and quality factor, the radiation weighting factor is a dimensionless quantity. The equivalent dose is conceptually different from the dose equivalent. The dose equivalent is based on the absorbed dose at a point in tissue weighted by the LET-dependent distribution of quality factors [Q(L)] at that point. The equivalent dose, in contrast, is based on the mean absorbed dose (DT,R) in the tissue or organ weighted by the radiation weighting factor (wR) for the radiation(s) actually impinging on the body or, in the case of internal radionuclides, as it is actually emitted by the source. In this Report when radiation dose is expressed in terms of the nonstochastic quantity equivalent dose to either the thyroid or to identifiable sub-structures/cell populations within the thyroid, the radiation weighting factors (wR) presented in Table A.2 (ICRP, 2007) were used. The same values for wR are provided in NCRP (1993) with the exception of the approach taken for neutrons. A.8 Dose-Rate Effect and Dose and Dose-Rate Effectiveness Factor According to the dose-rate effect, the probability of a given biological effect at a given dose is directly related to the dose rate (NCRP, 1980). Thus, the biological effectiveness of ionizing radiation is lower at low dose rates than at high dose rates. Quantitative characterization of dose equivalent rates is admittedly arbitrary, with dose rates of the order of 50 mSv y –1 or less

342 / APPENDIX A TABLE A.2—Radiation weighting factors (wR ) for calculation of equivalent dose to tissue or organ T (HT ) (ICRP, 2007; NCRP, 1993).a Radiation Type Photons Electronsb

1 and muons

Protons and charged pions Alpha particles, fission fragments, and heavy ions Neutrons

Radiation Weighting Factor

1 2 20 Continuous function of neutron energyc,d

aAll

values relate to the radiation incident on the body or, for internal radiation sources, emitted from the incorporated radionuclide(s). b The special issue of Auger electrons is discussed in paragraph 116 and in Section B.3.3 of Annex B in ICRP Publication 103 (ICRP, 2007). cSee Figure 1 and Equation 4.3 in ICRP Publication 103 (ICRP, 2007). d The radiation weighting factor approach in NCRP (1993) is based on five neutron energy ranges.

considered low (typical of background and of occupational dose rates, for example) and of the order of 1 Sv min–1 or greater considered high (typical of external radiation therapy). Dose rates between low and high may be characterized as intermediate. Importantly, the dose-rate effect is a general phenomenon applicable to a wide variety of radiogenic biological effects (e.g., carcinogenesis). For radiation protection purposes a dose and dose-rate effectiveness factor (DDREF) has been used to project cancer risk determined at high doses and high dose rates to the risks that would apply to low dose and low dose rates. Conceptually, DDREF is the multiplicative factor by which linear extrapolation of the probability of cancer per unit dose at high dose and high dose rates to low dose and low dose rates overestimates the probability of cancer per unit dose at low doses and low dose rates. Importantly, DDREF increases with increasing dose, that is, the higher the dose at which the high dose-rate probability per unit dose is evaluated, the more it will overestimate the low dose and low dose-rate probability per unit dose.

Appendix B Radiation Dosimetry for External Beam Radiation Therapy and Brachytherapy B.1 Introduction B.1.1

External Beam Radiation Therapy

External beam radiation therapy (EBRT) may be divided into at least three categories, depending on the energy of the radiation: • superficial therapy, 10 to 150 kV; • deep therapy (also known as orthovoltage or kilovoltage therapy), 200 to 300 kV; and • megavoltage therapy (also known as supervoltage therapy), 1 to 20 MeV (Hendee and Ibbott, 1996; Johns and Cunningham, 1974; Meredith and Massey, 1977; Mould, 1985; Stanton and Stinson, 1991; Williams and Thwaites, 1993). Superficial therapy includes the use of very low-energy grenz-ray therapy of 10 to 30 kV x rays and contact therapy of 40 to 50 kV x rays suitable only for treatment of some nonmalignant skin conditions and very superficial lesions, respectively. EBRT machines for superficial and deep therapy have largely been based on the production of bremsstrahlung x rays. For many years, 60Co, or telecobalt units, with a mean gamma-ray energy of 1.25 MeV and a half-life of 5.26 y, were the most widely used instruments in megavoltage therapy. Cesium-137 units, with a mean gamma-ray energy of 0.662 MeV and a half-life of 30 y, have also been used primarily for treatment of more superficial tumors in the head and neck. Particle-accelerating machines that have been used in megavoltage 343

344 / APPENDIX B therapy include the electrostatic Van de Graff generator, which is limited to producing ~2 MeV x rays and the large, rather cumbersome betatron capable of producing x rays and electrons up to 40 MeV in energy. More recently, linear accelerators have emerged as the instrument of choice for megavoltage therapy, producing x rays and electrons with energies of up to ~20 and ~10 MeV, respectively (Hendee and Ibbott, 1996; Johns and Cunningham, 1974; Meredith and Massey, 1977; Mould, 1985; Stanton and Stinson, 1991; Williams and Thwaites, 1993). Specialized accelerators that produce beams of protons, x rays, heavy ions, or mesons are used in specialized applications, mostly at large research laboratories. These sources will not be addressed further in this Report as work with such accelerators contributes little clinical information regarding thyroid radiobiology. Other than radionuclide (60Co, 137Cs) units, teletherapy machines are based on acceleration of electrons to high energies, which then either irradiate a target tissue volume directly or impinge on a high atomic-number target (a metal such as tungsten or copper) to produce a bremsstrahlung photon beam. The raw electron beam is narrow in cross section (~3 mm) and is referred to as a “pencil” beam. For electron therapy, the initially narrow electron beam is broadened into a large, clinically useful beam of ~10 × 10 cm in cross section at the patient’s skin by using one or more thin metal scattering foils that are either uniform in thickness or slightly thicker at the center (Hendee and Ibbott, 1996; Johns and Cunningham, 1974; Meredith and Massey, 1977; Mould, 1985; Stanton and Stinson, 1991; Williams and Thwaites, 1993). For superficial or deep photon therapy, the electrons strike a “reflectance” target and bremsstrahlung x rays are emitted in all directions, with the clinically useful beam corresponding to those photons emitted perpendicular to the direction of travel of the electron beam, as in diagnostic x-ray machines. For megavoltage therapy, higher-energy electrons strike a “transmission” target which absorbs all of the incident electrons and emits bremsstrahlung x rays primarily in the forward direction, that is, the same direction of travel as that of the electron beam. The energy spectrum of unfiltered bremsstrahlung x rays is continuous, with photon energies from zero energy to the maximum kinetic energy of the electrons striking the target. To eliminate the very low-energy nonpenetrating x rays that would simply irradiate skin and not contribute dose to target lesions at depths beyond several millimeters, the x-ray beam is filtered to “harden” the beam. Such filtration is in addition to the inherent filtration provided by, for example, the x-ray tube housing. The added filtration is typically metallic and

B.1 INTRODUCTION

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may be a composite of several metals. For deep therapy units, a composite filter of aluminum, copper and tin, known as a Thoraeus filter, may be used. The penetrability or “quality” of x or gamma rays thus produced is expressed in terms of their half-value layer in a metal such as aluminum or copper, ranging from 1 mm aluminum or 0.030 mm copper for 50 kV x rays to 45 mm aluminum or 14 mm copper for 60Co gamma rays (1.25 MeV). Because the x-ray beam is “forward peaked,” that is, its intensity decreases very rapidly in all directions from its central axis, the beam is very narrow (with a cross section of ~2 × 2 mm). The x-ray beam is, therefore, passed through a metallic flattening filter to broaden it. The uniformity, or “flatness,” of the resulting beam should be <3 %; that is, the x-ray intensity across the beam should be constant to within 3 % (Hendee and Ibbott, 1996; Johns and Cunningham, 1974; Meredith and Massey, 1977; Mould, 1985; Stanton and Stinson, 1991; Williams and Thwaites, 1993). After the narrow beams are broadened using thin scattering foils for electrons or thick flattening filters for photons, the resulting beams are collimated to define precisely the beam cross section. Collimators or diaphragms are typically two orthogonal pairs of lead jaws that can be moved to define the size and rectangular shape of the beam, ranging from 0 × 0 to 40 × 40 cm at a distance of 80 to 100 cm. Additionally, electron beams may be defined using a cone whose aperture is in contact with or at a fixed distance (5 to 10 cm) from the patient’s skin. In older, superficial or deep x-ray units, conical collimators were also used and, therefore, circular fields rather than rectangular fields were defined (Hendee and Ibbott, 1996; Johns and Cunningham, 1974; Meredith and Massey, 1977; Mould, 1985; Stanton and Stinson, 1991; Williams and Thwaites, 1993). Field-shaping attenuating blocks have recently allowed more precise delivery of radiation to target volumes. Three-dimensional conformal therapy or, intensity modulated radiation therapy, employing computer-controlled multi-leaf collimation, is a more recent technological advancement, allowing the therapist to deliver a precise dose to irregular target volumes. B.1.2

Brachytherapy

Brachytherapy is a widely used form of radiation therapy in which sealed sources of activity are mechanically placed close to or within tumors (Hilaris, 1975; Nag, 1994; 1997; Williamson et al., 1995). It utilizes the inverse square law and the sharp distancedependent decrease in radiation intensity to maximize the dose to the tumor volume and to minimize the dose to the surrounding

346 / APPENDIX B normal tissues. In interstitial therapy, radioactive sources in the form of needles or seeds are implanted directly into tumors, such as those of the head and neck, which are accessible from outside the body. In intracavitary therapy, radioactive sources are placed within body cavities (such as the vagina and uterus) adjacent to tumors using gynecological applicators. Interstitial and intracavitary implants are generally temporary and are removed after several days. When a target volume, such as in prostate cancer, does not allow reasonable access for insertion and removal of temporary implants, permanent implants may be used. At surgery, a seed inserter, or “gun,” allows permanent insertion of seeds with sufficiently accurate interseed spacing to deliver the prescribed dose distribution to the treatment volume. Sources may be inserted in a single plane for thin tumors, in two parallel planes for somewhat thicker tumors, or in multiple parallel planes (so-called “volume implants”) for even thicker tumors. In a form of brachytherapy sometimes known as plesiotherapy, radionuclides (most notably, 192Ir) may also be incorporated into plaques, where a planar arrangement of sources in a customized mold is placed directly on the surface of a superficial lesion (Hilaris, 1975; Nag, 1997; Williamson et al., 1995). Because brachytherapy sources constantly emit radiation and, thus pose a potentially significant radiation hazard to medical personnel, one approach to reducing personnel exposure has been the use of afterloading techniques in place of preloading, or “hot source,” techniques (Glasgow and Bourland, 1993; Thomadsen, 1995). In afterloading, empty applicators are first positioned, often with nonradioactive surrogate sources for radiographic verification of the source positions, and the actual radioactive sources are inserted afterwards. More recently, and distinct from conventional or low dose-rate loading with dose rates of ~1 Gy h–1, the high dose-rate remote afterloading technique with dose after rates of ~10 to ~100 Gy h–1 has been introduced into brachytherapy (Kubo et al., 1998; Nag, 1997). After insertion of the afterloading applicators into body cavities in the same manner as in low dose-rate brachytherapy and after radiographic verification of the applicator position, the patient is placed in a shielded room and the applicator(s) connected to the source delivery tubing. Under computer control, high-activity sources are then remotely loaded into position from their shielded storage location and deliver high dose-rate radiation over several minutes, rather than several days. The radioactive sources, in the form of tubes, needles or seeds, are sealed within a double layer of a heavy metal, such as platinum, to enclose and thus prevent the dispersal of the activity, to absorb

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/ 347

particulate radiations such as alpha and beta rays, and to confine the radionuclide’s daughter products. Except for 90Sr/90Y, 106 Ru/ 106 Rh, and 32P, emitting beta rays with ranges of the order of several millimeters in soft tissue, and used in the form of thin metal foils in applicators to treat very superficial lesions of the eye (such as ocular melanoma), only photons accompanying the decay of radionuclides are used therapeutically. B.2 Specification of Dose and Dose Distribution As radiation therapy has evolved, the quantitative characterization of the irradiated tissue and of the dose have been refined (ICRU, 1978a; 1978b; 1999; 2004). The gross tumor volume is the clinically or radiographically demonstrable extent and location of the tumor. The gross tumor volume is surrounded by a region of apparently normal tissue that may be invaded by undetectable microscopic extension of the tumor, and the clinical target volume (CTV) is the anatomic volume of known and suspected tumor. Because CTV is subject to changes over time in size, shape and location, as a result of patient motion or changes in size, shape and location of the tumor and adjacent structures, and because of small day-to-day variations in patient positioning for irradiation over the course of treatment, a margin is placed around CTV to yield the planned target volume (PTV). Further, because of practical limitations in the number and shape of treatment fields, a regularly shaped treatment volume that circumscribes the CTV is specified. In the process of attempting to deliver a uniform dose to PTV, surrounding normal tissues will inevitably be irradiated to a significant dose that is 20 % or greater of the prescribed dose to PTV. For example, using parallel opposed treatment fields to irradiate a deeply seated tumor, superficial tissue overlying the tumor will be in the path of radiation from one or the other of the opposed fields and will be included in the so-called irradiated volume ICRU has recommended that the dose to a reference point at or near the center of PTV as well as the maximum, minimum and, when available, mean doses to PTV be specified (ICRU, 1978b). The reference point often represents the intersection of the beam central axes. “Hot spots,” volumes >15 mm in diameter receiving doses >100 % of the dose to the PTV reference point, should be identified and their doses specified. The so-called dose-volume histogram, a graphical representation of the percentage of PTV receiving a specified dose, is being increasingly used to characterize the PTV dose and the uniformity of irradiation of PTV. The integral dose is the total radiation energy imparted to the patient and represents

348 / APPENDIX B the volume integral of the absorbed dose to the irradiated volume. Since the probability of normal-tissue damage in radiation therapy increases with increasing integral dose, the optimum treatment plan is that which yields the smallest integral dose to the patient for a prescribed dose distribution to PTV. B.3 Estimation of Medical External Dose B.3.1

External Beam Radiation Therapy

References that provide useful background information on the estimation of medical external dose include Hendee and Ibbott (1996), ICRU (1976), Johns and Cunningham (1974), Khan (2003), Meredith and Massey (1977), Mould (1985), Stanton and Stinson (1991), and Williams and Thwaites (1993). The beam geometry used for EBRT is illustrated in Figure B.1a. In this context, there are two basic approaches to specifying distances. The first approach, based on the source-to-skin distance, places the patient’s skin at the axis of rotation, or “isocenter,” of the therapy unit. The source is sometimes referred to as the “focus” or “target,” and the source-to-skin distance is therefore also referred to as the focus-to-skin distance or the target-to-skin distance. The second approach, based on the source-to-axis distance, also known as the focus-to-axis distance, is called the isocentric approach and places the isocenter at a point within the patient such as the center of a specified treatment (or target) volume. For superficial and deep-therapy x rays, the maximum absorbed dose is essentially at the skin surface of the patient, whereas for megavoltage therapy the depth dmax of the maximum-dose point (i.e., the electron equilibrium depth) is at least 0.5 cm below the skin surface. This is known as the “buildup effect” or “skin-sparing effect,” and is one of the important advantages of megavoltage therapy. As shown in Figure B.1b, the beam profile is characterized by its uniformity, or flatness, in the two principal planes over the central 80 % of the beam profile and by its penumbra. The penumbra, or unsharpness, of the beam profile is primarily a geometric effect related to the effective size of the source (or focus): the larger the source, the larger the penumbra. The penumbra is typically ~1 cm for 60Co units and ~0.3 cm for linear accelerators. Depth dose and isodose curves (i.e., lines connecting points of equal dose) are among the most important factors in dosimetry of EBRT. The percent depth dose is the absorbed dose at a specified position in an absorbing medium such as a patient or water-filled phantom expressed as a percentage of the absorbed dose at the maximum dose point. Such curves assume a constant source-to-

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Fig. B.1. (a) Beam geometry and (b) beam profile geometry for EBRT (Stanton and Stinson, 1991) (FAD = focus-to-axis distance, FDD = focusto-diaphragm distance, FSD = focus-to-skin distance, SAD = source-toaxis distance, SDD = source-to-diaphragm distance, SSD = source-to-skin distance, TSD = target-to-skin distance).

350 / APPENDIX B skin distance and incorporate the effects of the inverse-square distance dependence of beam intensity and of attenuation (absorption and scatter). Not only are corresponding depth doses predictably less for kilovoltage than for megavoltage x rays, but the beam edges are less well-defined because of the preponderance of side, rather than forward, scatter at the lower x-ray energies. Depth and field size affect beam flatness: because of the increasing contribution of scatter, the greater the depth and the larger the field size, the more uniform the beam profile. Electrons beams, available from linear accelerators and other particle accelerators, are less widely used than photon beams, and very few, if any, of the follow-up studies of radiogenic thyroid effects involved electron therapy. In contrast to photon therapy, electron beam therapy is typically performed using only a single field. Moreover, electrons are far less penetrating than photons, and electron depth-dose curves are qualitatively and quantitatively different than those for photons. The limited range of electrons is utilized in treating primarily superficial lesions at depths of <10 cm, with almost complete sparing of underlying normal tissues. When using single-field electron beams, the point to which the tumor dose is prescribed, often the 90 % isodose line (~2 cm for 7 MeV electrons to ~5 cm for 18 MeV electrons), is usually the deepest portion of the tumor. Electron beams exhibit considerably less skin sparing than megavoltage photon beams: the skin dose as a percentage of the maximum dose is 30 % for 6 MeV photons and >80 % for 7 to 18 MeV electrons. Electron beam depth-dose curves exhibit “ballooning,” or increasing width of the isodose curves at greater depths (i.e., at lower percentage depth doses). Because two or more adjacent electron beams are often used to irradiate large areas of tissue (e.g., in the treatment of lymphatic chains in lymphoma patients), such ballooning may cause excessive dose to tissue at depth when the beams are made to overlap or abut at the skin surface. If the separation at the skin is too great, tissue at depth may be underdosed. Separation of adjacent fields by ~1 cm, generally corresponding to contiguity of the 50 % isodose lines, is often used. Inhomogeneities, including devices interposed between the source and the patient, have a much greater attenuating effect on electron than on photon beams. Radiation-therapy treatment planning is essentially the process of determining and documenting the optimum method of treating a tumor with radiation, delivering as uniform a prescribed dose as possible throughout the tumor volume, and minimizing the dose to normal tissues (particularly critical normal structures such as the lens of the eye, the spinal cord, and the rectum). Treatment planning includes:

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• direct or radiographic visualization of the location and extent of the tumor and of surrounding normal structures; • radiographic localization or simulation of the treatment fields and their borders, generally performed using a simulator, a radiographic imaging device that simulates the geometry and other properties of the radiation therapy machine; and • field selection and placement, with manual or computerized superposition of isodose contours of one or more beams to determine and document the actual treatment dose distribution and with calculation of the machine “on” time or monitor units per beam. Among the many approaches to EBRT are the use of one or more stationary beams, such as parallel opposed fields, a four-field box, or a four-field diamond and of moving beams, with a complete circular rotation (rotational therapy) or a less-than-complete circular rotation (arc therapy), in which two or more rotational arcs may be used (multiple-arc therapy) or the beam may be turned off for specific segments of the rotation (skip-arc therapy). In contrast to the ideal geometry used in the measurement of standard depth dose curves (radiation impinging perpendicularly on a flat, uniform water-filled phantom), patients have curved surfaces and tissue inhomogeneities such as bone and lung. Most treatment-planning systems correct for such inhomogeneities using calculational algorithms such as tissue-air ratio corrections and effective attenuation corrections. For the “isodose shift” correction for the curvature of the skin surface, isodose lines must be shifted from 0.8 (for up to 1 MeV photons) to 0.4 (for 30 MeV photons) of the length of the tissue deficit or excess relative to the central-axis source-to-skin distance. The direction of the shift is deeper into the body for a tissue deficit and outward towards the skin surface for a tissue excess. Alternative approaches to correction of doses in cases of tissue deficit is the addition of tissue-equivalent bolus material to create a flat surface and, to avoid the loss of skin sparing associated with bolus, the interposition between the source and the patient of metallic custom-shaped compensating filters or noncustomized wedge filters placed at least 15 cm from the patient’s skin. With application of an isodose shift correction to tissue inhomogeneities, isodose lines must be shifted inward 0.6 of any air thickness and 0.4 of any lung thickness and outward 0.5 of any cortical bone thickness. In addition, when several treatment fields are combined, the doses contributed by each field can be varied, or weighted, nonequally by using nonequal machine-on times or numbers of monitor units.

352 / APPENDIX B B.3.2

Brachytherapy

The use of brachytherapy in medicine has been well described (Anderson, 1975; Nag, 1997; Williamson et al., 1995). The physical properties and uses of various brachytherapy sources have been summarized by Williamson8 and are available in Table B.1. Specification of the “strength” of brachytherapy sources (Hanson, 1995; Nath et al., 1987; Williamson et al., 2000) influences the dose-calculation methodology and the dosimetric accuracy achievable. Source strengths have been specified by many different quantities: activity, apparent activity, equivalent mass of radium, mass of radium, and reference exposure rate. Brachytherapy sources are calibrated and specified in terms of the dose rate, specifically, the air-kerma rate, at 1 m from the source center along its transverse bisector. The so-called air-kerma strength (Nath et al., 1987) is defined as the product of the air-kerma rate in free space and the square of the distance and is denoted by the symbol SK. The units of air-kerma strength are PGy m2 h–1 or mGy cm2 h–1, often denoted by the symbol “U.” A larger unit, cGy m2 h–1, is often used for high dose-rate sources; 1 U = 1 PGy m2 h–1 = 10–3 mGy m2 h–1. A number of older quantities remain in use. Cesium-137 tubes, 192Ir seeds, and other radium substitutes are frequently specified in terms of the quantity equivalent mass of radium with units of mg RaEq. The strength of a given source in mg RaEq is the mass (in milligrams) of 226Ra encapsulated by a 0.5 mm thickness of platinum that gives the same transverse-axis dose rate, or air-kerma strength, as the given source. A 1 mg RaEq source of 137Cs or 192Ir has an air-kerma strength (SK) of 72.3 mGy cm2 h–1. Equivalent mass of radium describes the radiation output of a source as a multiple of that of a 1 mg 226Ra needle. Apparent activity is the activity of a point source that yields the same air-kerma strength as that of the actual encapsulated source of the radionuclide. Apparent activity was used to quantify strength of permanent implant sources such as 125I. Brachytherapy dose calculation algorithms have been based upon semiempirical models; the most widely used is the isotropic point source model. The inverse-square law dominates the dose distribution. A one-dimensional model is almost universally used for interstitial seed sources emitting photons with energies >300 keV. Although it accurately models 137Cs source dose distributions, it cannot be assumed to accurately predict dose around lower-energy sources. 8Williamson,

J.F. (1999). Personal communication (Mallinckrodt Institute of Radiology, St. Louis, Missouri).

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Among the older, precalculated dosimetry systems, tables of dose distributions were used to determine the total dose from a standard distribution of sources. In the so-called “Quimby system” (Quimby, 1931; 1935), a uniform distribution of sources was used to achieve a nonuniform dose distribution, with a higher dose in the center than at the periphery of the implanted volume. In the so-called “Paterson-Parker system” (Paterson and Parker, 1934; Paterson et al., 1936), a nonuniform source distribution was used to achieve a uniform dose distribution throughout the implanted volume. The foregoing simple analytic model is not sufficiently accurate for clinical use in the 60 to 100 keV energy range (241Am and 169Yb) or in the 20 to 40 keV permanent-implant energy range (e.g., 125I). Low-energy (e.g., 125I) brachytherapy dosimetry has been based increasingly on TLD and Monte-Carlo photon-transport dosimetry calculations. The former consists of placing small crystalline TLDs, along with the brachytherapy source, into precisely machined slots in a water-equivalent solid phantom and subsequently heating, or annealing, the irradiated TLDs and measuring the resulting light output. A precision of r6 % can be achieved. Comparison of MonteCarlo simulation, a computer-intensive rigorous approach to calculating absorbed dose, and TLD measurements, shows excellent agreement [2 to 3 % (Williamson, 1991)]. The American Association of Physicists in Medicine (AAPM) (Nath et al., 1995), promulgated a dose calculation formalism specifically designed to use a matrix of Monte-Carlo or measured dose rates as its input, in contrast to the classical semiempirical models described above. The formalism uses tables of dosimetric ratios to account for various effects (e.g., radial dose functions are used to account for dose decrease along the transverse axis). The older semi-empirical dose models and AAPM (Nath et al., 1995) calculations are in close agreement for 192Ir and other radium substitutes but differ by as much as 15 % for 125I interstitial seeds. For sources with mean photon energies <300 keV, transverse-axis dosimetry should be based on dose measurements or Monte-Carlo simulations rather than classical models.

Element

Radionuclide

Energy (MeV)

Half-Life

HalfValue Layer Lead (mm)

Exposure Rate Constantb

Source Form

Clinical Application

Obsolete Sealed Sources of Historical Significance Radium

226

Radon

222

Ra

0.83 (mean)

1,626 y

16

8.25c

Tubes and needles

LDRd intracavitary and interstitial

Rn

0.83 (mean)

3.83 d

16

8.25c

Gas encapsulated in gold tubing

Permanent interstitial Temporary molds

0.662

30 y

6.5

3.28

Tubes and needles, seeds in nylon ribbon, metal wires

LDR intracavitary and interstitial

Ir

0.397 (mean)

73.8 d

6

4.69

Encapsulated source on cable

LDR temporary interstitial HDR interstitial and intracavitary

Co

1.25

5.26 y

11

13.07

Encapsulated spheres

HDR intracavitary

0.028

59.6 d

0.025

1.45

Seeds

Permanent interstitial

Currently Used Sealed Sources Cesium

137

Iridium

192

Cobalt

60

Iodine

125

Cs

I

354 / APPENDIX B

TABLE B.1—Physical properties and uses of brachytherapy radionuclides.a

Palladium

103

Gold

198

Ruthenium Strontium

106

0.020

17 d

0.013

1.48

Seeds

Permanent interstitial

Au

0.412

2.7 d

6

2.35

Seeds

Permanent interstitial

3.53 (EE)max

1.01

–

–

Plaque

Treatment of superficial ocular lesions

2.24 (EE)max

28.9 y

–

–

Plaque

Treatment of superficial ocular lesions

0.060

432 y

0.12

0.12

Tubes

LDR intracavitary

0.093

32 d

0.48

1.80

Seeds

LDR temporary interstitial

Cf

2.4 (mean) neutron

2.65 y

–

–

Tubes

High-LET LDR intracavitary

Ru/

90

106

Rh

Sr/90Y

Developmental Sealed Sources Americium

241

Ytterbium

169

Californium

252

Cesium

131

Cs

0.030

9.69 d

0.030

0.64

Seeds

LDR permanent implants

Samarium

145

Sm

0.043

340 d

0.060

0.885

Seeds

LDR temporary interstitial

aWilliamson,

Am Yb

J.F. (1999). Personal communication (Virginia Commonwealth University School of Medicine, Richmond, Virginia). filtration in units of R cm2 mCi–1 h–1. c 0.5 mm platinum filtration; units of R cm2 mg–1 h–1. dLDR = low dose rate HDR = high dose rate bNo

B.3 ESTIMATION OF MEDICAL EXTERNAL DOSE

Pd

/ 355

Appendix C Technical Aspects of Radiation Dosimetry for the Atomic-Bomb Survivors: The Dosimetry System 1986 and the Dosimetry System 2002

Despite initial improvements in the radiation dosimetry for the atomic-bomb survivors, deficiencies persisted, and in the early 1980s a major bi-national U.S.-Japan effort to develop a new dosimetry system was initiated. This led to the development of DS86, which had been used in RERF analyses since 1987 (Dobson et al., 1991; Straume et al., 1991). This initiative included the fabrication at the Los Alamos National Laboratory of a replica of the Hiroshima atomic bomb, the so-called “Little-Boy replica” (LBR); a similar replica of the Nagasaki atomic bomb was not needed because multiple test detonations and dosimetric measurements of Nagasaki-type weapons had previously been performed. LBR was mounted at a height of several meters above ground on a steel support known as the “Comet” stand and the LBR project and the replica itself are, therefore, sometimes referred to as “Comet.” The principal purpose of LBR was to measure angle-dependent neutron fluence and spectra under steady-state conditions and to compare these measurements with calculations. LBR was identical in geometry to the actual Hiroshima weapon and was constructed of materials essentially identical to those used in that weapon. The fissile core had the same 239U enrichment and mass and was fitted with an exact duplicate of the steel casing, stored at the Los Alamos 356

C. TECHNICAL ASPECTS OF RADIATION DOSIMETRY

/ 357

National Laboratory since 1945. DS86 thus incorporated realistic, angle-dependent neutron spectra and other effects of weapon design, as well as pertinent meteorological and topographic factors (Dobson et al., 1991; Kaul, 1988; Straume et al., 1991). DS86 allows the computation of doses to 15 different organs (Kaul et al., 1987). With DS86, neutron doses in Hiroshima were much lower than the corresponding “Tentative 1965 Dose” (T65D) estimates, as indicated in Figure C.1 (i.e., 6- to 10-fold lower at distances of 1,000 and 2,000 m), respectively, from ground zero (Loewe and Mendelsohn, 1981). Conversely, DS86 gamma-ray doses in Hiroshima were generally higher than the corresponding T65D estimates (i.e., two to threefold higher at 2,000 m from ground zero (Figure C.1). In Nagasaki, the situation was reversed (Figure C.1). The T65D gamma-ray doses were higher than those of the DS86 gamma-ray dose, but the differences were small, only 20 to 30 % (Loewe and Mendelsohn, 1981). Overall, according to DS86, <1 to 2 % of tissue doses in Hirsohima were contributed by neutrons and an even smaller proportion in Nagasaki (Loewe and Mendelsohn, 1981). Despite its greater rigor, experimental validation of DS86, particularly of the calculation of neutron dose, was ambiguous at the time of its publication (Preston et al., 2004; Sinclair et al., 2001; Young and Kerr, 2005). There was an apparent discrepancy between 60Co neutron activation measurements in steel samples at distances from 260 to 1,200 m from ground zero in Hiroshima. The measured-to-calculated 60Co activity ratios were always less than one at distances of <500 m and greater than one at distances >500 m (Straume et al., 1992). As a result, many additional neutron-activation measurements, including 60Co, 152Eu, 154Eu, and, more recently, 36 Cl have been made since 1986 on mineral and metal samples from Hiroshima, including a large number of measurements made at distances >1 km. Neutron activation calculations have been performed using the DS86 neutron fluences and spectra and detailed Monte-Carlo modeling of each experimental sample for the reactions 59Co (n, gamma) 60Co, 151Eu (n, gamma) 152Eu, 153Eu (n, gamma) 154Eu, and 35Cl (n, gamma) 36Cl, all of which have been measured in samples from Hiroshima (Shizuma et al., 1993; 1998; Straume et al., 1992). Discrepancies between measurements and calculations are illustrated in Figure C.2 where the ratios of measured (background subtracted)-to-calculated activities are graphed as a function of distance from the Hiroshima hypocenter (Straume et al., 1992). If the measurements and calculations were both correct, the ratio should be unity at all distances. However, the measured-to-calculated activity ratios are very different from unity for

358 / APPENDIX C

Fig. C.1. Neutron and gamma-ray free-in-air doses to tissue in Hiroshima (top) and Nagasaki (bottom) as a function of distance (kilometers) from ground zero calculated using the T65D (dashed line) and DS86 (solid line). Note that, according to T65D, the neutron dose is nearly equal to the gamma-ray dose in Hiroshima. However, according to DS86, the neutron dose is much less than (~1 % or less of) the gamma-ray dose in Hiroshima as well as Nagasaki (adapted from Loewe and Mendelsohn, 1981).

C. TECHNICAL ASPECTS OF RADIATION DOSIMETRY

/ 359

Fig. C.2. Ratios of the measured-to-calculated neutron-activated activities as a function of the distance (meters) from the hypocenter (i.e., the slant range) in samples from Hiroshima for 152Eu, 154Eu, 60Co, and 36Cl. The dashed line is the least-square best fit to all the data points (Straume et al., 1992).

all of the radionuclides, from somewhat less than one near ground zero to much greater than one beyond ~1 km. Because the large number of measurements made for different nuclides by different laboratories using different analytical techniques results in a similar trend, it appeared that the DS86 calculations for thermal neutrons may have been incorrect. In particular, it appeared that at distances beyond ~1 km from ground zero in Hiroshima, the neutron absorbed dose may be 2- to 10-fold higher than that calculated based on DS86 (Straume et al., 1992). The uncertainties associated with the neutron activation measurements were relatively large, however, and the measurements were not considered definitive. Computer transport analyses of DS86 fission neutrons through large distances of air were validated using concrete samples from Nagasaki and chloride detectors placed at selected distances from a bare uranium reactor. Good agreement was observed between accelerator mass spectrometry measurements of 36Cl neutron activation and DS86 calculations for Nagasaki, as well as for the reactor experiment (Straume et al., 1994). The neutron dose from the Hiroshima bomb was almost entirely from fast, not thermal, neutrons. However, thermal neutrons were actually responsible for the production of those radionuclides measured in Hiroshima samples. Since thermal neutrons result from

360 / APPENDIX C the slowing down of fast neutrons, it has been assumed that the thermal-neutron activation is a reasonable indicator of the actual fast-neutron activation. This assumption may not be valid, and Straume and colleagues had suggested that resolution of the foregoing discrepancies in neutron dosimetry may lie in directly measuring fast-neutron activation in Hiroshima samples (Straume, 1993; Straume et al., 1991; 1992; 1994). “Ultra-separation” of nickel from copper and measurement of fast neutron-activated 63Ni by accelerator mass spectrometry were employed to help in resolving this issue. Nickel-63 (half-life: 100 y) is produced in the 63Cu (n, p) 63Ni reaction by neutrons having energies greater than ~1 MeV. In 2003, Straume et al. (2003) reported the detection and measurement of 63Ni produced predominantly by fast neutrons in well-characterized copper samples from Hiroshima. The results (21 samples), expressed as number of 63Ni atoms per gram of copper at distances of 400 to >1,800 m from the hypocenter (the distance range most relevant to survivor data), showed a consistent set of data with 63Ni atoms per gram of copper decreasing sharply with distance and approaching a constant background >1,800 m. This constant background was attributed, in part, to 63Ni production in situ by cosmic radiation. These measurements were in good agreement with those predicted by sample-specific Monte-Carlo computer modeling calculations based on DS86. Thus, the discrepancies appear not to be due to uncertainties in air-transport calculations or in the activation measurements, but rather uncertainties associated with the Hiroshima weapon itself (i.e., the source term). A RERF joint U.S.-Japan working group subsequently initiated a comprehensive effort to definitively identify the source(s) of and to resolve the foregoing “neutron discrepancy” (Cullings and Fujita, 2003). Drs. Hiromi Hasai, George Kerr, and Robert Young led this 5 y effort by an international team of over 30 scientists. This effort culminated in the development of DS02, which successfully resolved the foregoing discrepancy and otherwise refined atomicbomb dosimetry. DS02 was approved by a joint U.S.-Japan senior dosimetry review committee in the Spring of 2003 and was formally adopted by RERF later in 2003 (Cullings and Fujita, 2003; Cullings et al., 2006; Preston et al., 2004). The new dosimetry calculations, which incorporate more detailed modeling and revision of the Hiroshima source term and of terrestrial and structural shielding, agree with both gamma and neutron measurements out to distances from the hypocenter at which sample measurements become indistinguishable from background (RERF, 2003). Importantly, while the yield (21 kt) and burst point (within 2 m of the previous estimate) of the Nagasaki weapon were essentially unchanged from

C. TECHNICAL ASPECTS OF RADIATION DOSIMETRY

/ 361

previous estimates, the estimated yield of the Hiroshima bomb was increased to 16 kt and the hypocenter repositioned 20 m higher and 15 m to the west (RERF, 2003). With the resulting revisions in the source term and revised effects of terrestrial and structural shielding, a possible dramatic upward revision (up to 10-fold) in the neutron dose contribution in Hiroshima at distances relevant to survivors did not materialize in DS02. At ground distances up to 2,500 m from the hypocenter in both Hiroshima and Nagasaki, the gamma-ray air kerma and organ doses were generally ~10 % higher in DS02 than in DS86; the neutron air kerma and organ doses were uniformly lower (but only by 30 % in Nagasaki and by 30 % or less in Hiroshima) in DS02 than in DS86 (Cullings et al., 2006.) The impact of these differences is illustrated by the following. In Hiroshima, the DS02 neutron dose (using a radiation weighting factor of 20) to colon at 1,000 m is ~18 % of the gamma-ray dose (Cullings et al., 2006). The total DS02 colon dose at 1,000 m is therefore only 9 % lower than the DS86 dose {9 % = [(1) × (+1.1) + (0.18) × (–0.05)]} × 100 % where, the factor of –0.05 reflects the fact that the DS02 neutron dose is actually only 5 % lower than the DS86 neutron dose at 1,000 m. The impact on the derived risk factors of the differences in organ doses between DS02 and DS86 was therefore quite minor (Section 3.2.2). With the finalization of DS02, dose estimates and the associated risk estimates among atomic-bomb survivors can now be viewed with substantially more confidence.

Appendix C Technical Aspects of Radiation Dosimetry for the Atomic-Bomb Survivors: The Dosimetry System 1986 and the Dosimetry System 2002

Despite initial improvements in the radiation dosimetry for the atomic-bomb survivors, deficiencies persisted, and in the early 1980s a major bi-national U.S.-Japan effort to develop a new dosimetry system was initiated. This led to the development of DS86, which had been used in RERF analyses since 1987 (Dobson et al., 1991; Straume et al., 1991). This initiative included the fabrication at the Los Alamos National Laboratory of a replica of the Hiroshima atomic bomb, the so-called “Little-Boy replica” (LBR); a similar replica of the Nagasaki atomic bomb was not needed because multiple test detonations and dosimetric measurements of Nagasaki-type weapons had previously been performed. LBR was mounted at a height of several meters above ground on a steel support known as the “Comet” stand and the LBR project and the replica itself are, therefore, sometimes referred to as “Comet.” The principal purpose of LBR was to measure angle-dependent neutron fluence and spectra under steady-state conditions and to compare these measurements with calculations. LBR was identical in geometry to the actual Hiroshima weapon and was constructed of materials essentially identical to those used in that weapon. The fissile core had the same 239U enrichment and mass and was fitted with an exact duplicate of the steel casing, stored at the Los Alamos 356

C. TECHNICAL ASPECTS OF RADIATION DOSIMETRY

/ 357

National Laboratory since 1945. DS86 thus incorporated realistic, angle-dependent neutron spectra and other effects of weapon design, as well as pertinent meteorological and topographic factors (Dobson et al., 1991; Kaul, 1988; Straume et al., 1991). DS86 allows the computation of doses to 15 different organs (Kaul et al., 1987). With DS86, neutron doses in Hiroshima were much lower than the corresponding “Tentative 1965 Dose” (T65D) estimates, as indicated in Figure C.1 (i.e., 6- to 10-fold lower at distances of 1,000 and 2,000 m), respectively, from ground zero (Loewe and Mendelsohn, 1981). Conversely, DS86 gamma-ray doses in Hiroshima were generally higher than the corresponding T65D estimates (i.e., two to threefold higher at 2,000 m from ground zero (Figure C.1). In Nagasaki, the situation was reversed (Figure C.1). The T65D gamma-ray doses were higher than those of the DS86 gamma-ray dose, but the differences were small, only 20 to 30 % (Loewe and Mendelsohn, 1981). Overall, according to DS86, <1 to 2 % of tissue doses in Hirsohima were contributed by neutrons and an even smaller proportion in Nagasaki (Loewe and Mendelsohn, 1981). Despite its greater rigor, experimental validation of DS86, particularly of the calculation of neutron dose, was ambiguous at the time of its publication (Preston et al., 2004; Sinclair et al., 2001; Young and Kerr, 2005). There was an apparent discrepancy between 60Co neutron activation measurements in steel samples at distances from 260 to 1,200 m from ground zero in Hiroshima. The measured-to-calculated 60Co activity ratios were always less than one at distances of <500 m and greater than one at distances >500 m (Straume et al., 1992). As a result, many additional neutron-activation measurements, including 60Co, 152Eu, 154Eu, and, more recently, 36 Cl have been made since 1986 on mineral and metal samples from Hiroshima, including a large number of measurements made at distances >1 km. Neutron activation calculations have been performed using the DS86 neutron fluences and spectra and detailed Monte-Carlo modeling of each experimental sample for the reactions 59Co (n, gamma) 60Co, 151Eu (n, gamma) 152Eu, 153Eu (n, gamma) 154Eu, and 35Cl (n, gamma) 36Cl, all of which have been measured in samples from Hiroshima (Shizuma et al., 1993; 1998; Straume et al., 1992). Discrepancies between measurements and calculations are illustrated in Figure C.2 where the ratios of measured (background subtracted)-to-calculated activities are graphed as a function of distance from the Hiroshima hypocenter (Straume et al., 1992). If the measurements and calculations were both correct, the ratio should be unity at all distances. However, the measured-to-calculated activity ratios are very different from unity for

358 / APPENDIX C

Fig. C.1. Neutron and gamma-ray free-in-air doses to tissue in Hiroshima (top) and Nagasaki (bottom) as a function of distance (kilometers) from ground zero calculated using the T65D (dashed line) and DS86 (solid line). Note that, according to T65D, the neutron dose is nearly equal to the gamma-ray dose in Hiroshima. However, according to DS86, the neutron dose is much less than (~1 % or less of) the gamma-ray dose in Hiroshima as well as Nagasaki (adapted from Loewe and Mendelsohn, 1981).

C. TECHNICAL ASPECTS OF RADIATION DOSIMETRY

/ 359

Fig. C.2. Ratios of the measured-to-calculated neutron-activated activities as a function of the distance (meters) from the hypocenter (i.e., the slant range) in samples from Hiroshima for 152Eu, 154Eu, 60Co, and 36Cl. The dashed line is the least-square best fit to all the data points (Straume et al., 1992).

all of the radionuclides, from somewhat less than one near ground zero to much greater than one beyond ~1 km. Because the large number of measurements made for different nuclides by different laboratories using different analytical techniques results in a similar trend, it appeared that the DS86 calculations for thermal neutrons may have been incorrect. In particular, it appeared that at distances beyond ~1 km from ground zero in Hiroshima, the neutron absorbed dose may be 2- to 10-fold higher than that calculated based on DS86 (Straume et al., 1992). The uncertainties associated with the neutron activation measurements were relatively large, however, and the measurements were not considered definitive. Computer transport analyses of DS86 fission neutrons through large distances of air were validated using concrete samples from Nagasaki and chloride detectors placed at selected distances from a bare uranium reactor. Good agreement was observed between accelerator mass spectrometry measurements of 36Cl neutron activation and DS86 calculations for Nagasaki, as well as for the reactor experiment (Straume et al., 1994). The neutron dose from the Hiroshima bomb was almost entirely from fast, not thermal, neutrons. However, thermal neutrons were actually responsible for the production of those radionuclides measured in Hiroshima samples. Since thermal neutrons result from

360 / APPENDIX C the slowing down of fast neutrons, it has been assumed that the thermal-neutron activation is a reasonable indicator of the actual fast-neutron activation. This assumption may not be valid, and Straume and colleagues had suggested that resolution of the foregoing discrepancies in neutron dosimetry may lie in directly measuring fast-neutron activation in Hiroshima samples (Straume, 1993; Straume et al., 1991; 1992; 1994). “Ultra-separation” of nickel from copper and measurement of fast neutron-activated 63Ni by accelerator mass spectrometry were employed to help in resolving this issue. Nickel-63 (half-life: 100 y) is produced in the 63Cu (n, p) 63Ni reaction by neutrons having energies greater than ~1 MeV. In 2003, Straume et al. (2003) reported the detection and measurement of 63Ni produced predominantly by fast neutrons in well-characterized copper samples from Hiroshima. The results (21 samples), expressed as number of 63Ni atoms per gram of copper at distances of 400 to >1,800 m from the hypocenter (the distance range most relevant to survivor data), showed a consistent set of data with 63Ni atoms per gram of copper decreasing sharply with distance and approaching a constant background >1,800 m. This constant background was attributed, in part, to 63Ni production in situ by cosmic radiation. These measurements were in good agreement with those predicted by sample-specific Monte-Carlo computer modeling calculations based on DS86. Thus, the discrepancies appear not to be due to uncertainties in air-transport calculations or in the activation measurements, but rather uncertainties associated with the Hiroshima weapon itself (i.e., the source term). A RERF joint U.S.-Japan working group subsequently initiated a comprehensive effort to definitively identify the source(s) of and to resolve the foregoing “neutron discrepancy” (Cullings and Fujita, 2003). Drs. Hiromi Hasai, George Kerr, and Robert Young led this 5 y effort by an international team of over 30 scientists. This effort culminated in the development of DS02, which successfully resolved the foregoing discrepancy and otherwise refined atomicbomb dosimetry. DS02 was approved by a joint U.S.-Japan senior dosimetry review committee in the Spring of 2003 and was formally adopted by RERF later in 2003 (Cullings and Fujita, 2003; Cullings et al., 2006; Preston et al., 2004). The new dosimetry calculations, which incorporate more detailed modeling and revision of the Hiroshima source term and of terrestrial and structural shielding, agree with both gamma and neutron measurements out to distances from the hypocenter at which sample measurements become indistinguishable from background (RERF, 2003). Importantly, while the yield (21 kt) and burst point (within 2 m of the previous estimate) of the Nagasaki weapon were essentially unchanged from

C. TECHNICAL ASPECTS OF RADIATION DOSIMETRY

/ 361

previous estimates, the estimated yield of the Hiroshima bomb was increased to 16 kt and the hypocenter repositioned 20 m higher and 15 m to the west (RERF, 2003). With the resulting revisions in the source term and revised effects of terrestrial and structural shielding, a possible dramatic upward revision (up to 10-fold) in the neutron dose contribution in Hiroshima at distances relevant to survivors did not materialize in DS02. At ground distances up to 2,500 m from the hypocenter in both Hiroshima and Nagasaki, the gamma-ray air kerma and organ doses were generally ~10 % higher in DS02 than in DS86; the neutron air kerma and organ doses were uniformly lower (but only by 30 % in Nagasaki and by 30 % or less in Hiroshima) in DS02 than in DS86 (Cullings et al., 2006.) The impact of these differences is illustrated by the following. In Hiroshima, the DS02 neutron dose (using a radiation weighting factor of 20) to colon at 1,000 m is ~18 % of the gamma-ray dose (Cullings et al., 2006). The total DS02 colon dose at 1,000 m is therefore only 9 % lower than the DS86 dose {9 % = [(1) × (+1.1) + (0.18) × (–0.05)]} × 100 % where, the factor of –0.05 reflects the fact that the DS02 neutron dose is actually only 5 % lower than the DS86 neutron dose at 1,000 m. The impact on the derived risk factors of the differences in organ doses between DS02 and DS86 was therefore quite minor (Section 3.2.2). With the finalization of DS02, dose estimates and the associated risk estimates among atomic-bomb survivors can now be viewed with substantially more confidence.

Appendix D Technical Aspects of Thyroid Radiation Dosimetry of Radioisotopes of Iodine D.1 Radioiodide Pharmacokinetics Inhaled or ingested radioiodide is almost completely absorbed into the circulation and a central, or “transfer,” compartment corresponding to the total body extracellular fluid space. From this central compartment, radioiodide is rapidly eliminated with a biological half-life (T½b) of ~6 h, either by excretion (~75 %) or avid localization in the thyroid gland (~25 % in euthryoid adults) (Figure 3.2). Excretion occurs primarily by the urinary route (~90 %), with a small portion (~10 %) via the hepatobiliary route (Berman et al., 1968; ICRP, 1988; Zanzonico, 2000b). (Refer to Section 3.3.3 for a discussion of the uncertainties associated with the thyroid radiation dosimetry of radioisotopes of iodine.) From the thyroid, iodine is then slowly secreted into the total-body plasma space with a T½b of ~90 d in euthyroidism and ~20 d in hyperthyroidism in organified form as protein-bound iodine (i.e., T3 and T4). The thyroid hormones are then either catabolized and deiodinated, with ~90 % of the iodine recycling into the central (transfer) compartment, or eliminated via hepatobiliary excretion (~10 %), yielding a T½b of ~12 d for the thyroid hormones in the hyperthyroid state (Berman et al., 1968; ICRP, 1988; Zanzonico, 2000b). Estimation of the time-dependent radioiodine activity and of the resulting mean residence times in the thyroid was based on the standard compartmental model of iodine pharmacokinetics 362

D.2 CALCULATION OF INTERNAL DOSE

/ 363

presented in Figure 3.2 (Zanzonico, 2000a). A compilation of the pertinent age-dependent biological properties of the thyroid is presented in Table D.1 (Book et al., 1997). Note that this model accounts for both inhalation and ingestion of radioiodine by incorporating lung and gut compartments, Compartments 1 and 1' in Figure 3.2, respectively. The age-dependent absorption fractions from the lung and the absorption fraction from the gut were derived using the ICRP (1979; 1990) estimates. The nondecaycorrected isotope-specific inhalation and ingestion absorption fractions are presented in Table D.2 (Zanzonico, 2000a). The resulting model was adapted to the different radioisotopes of iodine by appending a clearance exchange rate to each compartment i equal to the physical decay constant of the respective radioiodines. Assuming an internalized activity of 37 kBq, the mean residence time of inhaled/ingested radioiodide in the thyroid was determined by dividing the integral of the decayed activity in the thyroid compartment, determined using the area under the curve utility of the SAAM II program (Barrett et al., 1998; Berman et al., 1962; Boston et al., 1981), by the 37 kBq activity internalized. D.2 Calculation of Internal Dose The basis of standard methodologies now used for medical internal radionuclide absorbed dose calculations is the “MIRD formalism,” developed by the Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine. The MIRD formalism, including notation, terminology, mathematical methodology, and reference data, has been disseminated in the form of the collected MIRD pamphlets and associated publications (Loevinger et al., 1991; Zanzonico, 2000b; Zanzonico et al., 1995). Many age- and genderspecific body habitus other than the original 70 kg adult anthropomorphic model (ICRP, 1975), have now been incorporated into the MIRD formalism (Cristy and Eckerman, 1987). These include newborn 1, 5, 10, and 15 y old models (Cristy and Eckerman, 1987). In addition, several computerized versions of the MIRD formalism, including MIRDOSE III (Stabin, 1995), have been developed. For internal radionuclides in general and radioiodine in the thyroid in particular, self-irradiation accounts for nearly the entire absorbed dose to any given target region primarily because of the contribution from particulate radiations (such as beta rays), which are assumed to be completely absorbed in situ since the dimensions of human organs are typically much greater than the ranges in tissue of particulate radiations. Because of the high, rapid uptake and long retention of radioiodine in the thyroid and the rapid excretion

Thyroid Size

Radioiodide in Thyroid 24 h RAIU (decaycorrected) (%)

Biological Half-Lifea,b (d)

Newborn

60

60

1y

25

50

5y

25

10 y

Age

Effective Half-Lifea (d) 123

I

125 c

0.54

34

0.54

3.9

27

80

0.55

4.0

25

80

0.55

15 y

25

90

Adult

25

90

I

20

124

I

131

I

15

132

I

133

I

135

I

Mass (g)

Radiusc of Lobe (cm)

5.7

0.10

0.81

0.28

1.3

6.9

0.10

0.83

0.28

1.8

0.23

34

7.3

0.10

0.84

0.28

3.5

0.29

4.0

34

7.3

0.10

0.84

0.28

7.9

0.38

0.55

4.0

36

7.4

0.10

0.84

0.28

12

0.43

0.55

4.0

36

7.4

0.10

0.84

0.28

21

0.52

aAssuming the time-dependent activity in the thyroid conforms to a monoexponential function. The subscripts “b” and “e” identify the respective half-lives as biological and effective half-lives. bFor 129I, which is very long-lived, the effective half-life equals the biological half-life. cRadius of one sphere of the thyroid, assuming that the thyroid consists of two identical, tangent spheres of unit mass density.

364 / APPENDIX D

TABLE D.1—Age-dependent anatomical and physiological properties of the normal thyroid (Book et al., 1997).

TABLE D.2—Age-dependent absorption fractions of inhaled and ingested radiobiologically-significant radioisotopes of iodine (Zanzonico, 2000b).a,b Age

Ingestion a

I

124

I

125

I, 129Ic

131

I

132

I

133

I

I

Newborn

0.533

0.619

0.632

0.626

0.305

0.550

0.462

1y

0.522

0.605

0.620

0.613

0.302

0.538

0.454

5y

0.527

0.613

0.625

0.619

0.302

0.543

0.507

10 y

0.507

0.585

0.597

0.590

0.295

0.519

0.489

15 y

0.519

0.602

0.615

0.609

0.300

0.534

0.453

Adult

0.524

0.608

0.624

0.615

0.301

0.539

0.456

All ages

0.95

1.0

1.0

1.0

0.77

0.97

0.90

For intravenous injection, the absorption fraction is identically one for all ages and all radioisotopes of iodine. absorption fractions incorporate the effect of radioactive decay of the respective radioisotopes of iodine. cThe respective absorption fractions of 129I, which is very long-lived, essentially equal those of 125I, which is also long-lived. bThese

135

D.2 CALCULATION OF INTERNAL DOSE

Inhalation

123

/ 365

366 / APPENDIX D of extrathyroidal radioiodine, the total thyroid absorbed dose, particularly, that for internal radionuclide may be equated with the self-irradiation absorbed dose (Loevinger et al., 1991; Zanzonico, 2000b): (D.1)

D  thy = D  thy m thy = A˜ thy S  thy m thy , where: D  thy

(D.2)

= mean absorbed dose to the thyroid

D  thy m thy

= mean self-irradiation absorbed dose to the thyroid

A˜ thy S  thy m thy

= cumulated activity in the thyroid = thyroid-to-thyroid S factor A˜ S  thy m thy thy

' i I i  thy m thy { ¦ ------------------------------------------, M thy

(D.3)

i

where: 'i

= equilibrium dose constant for radiation i

Mthy

= mass of the thyroid

M i  thy m thy

= thyroid-to-thyroid absorbed fraction for radiation i

An alternative formulation of Equation D.2 based on the so-called mean residence time (W) is as follows (Loevinger et al., 1991; Zanzonico, 2000b): D  thy = A 0 W thy S  thy m thy , where: A0 = {

Wthy

=

(D.4)

activity inhaled or ingested 1 MBq for the current calculations mean residence time of activity in the thyroid A˜ thy = -----------A0

(D.5)

Through use of the mean residence time thus calculated, the mean absorbed dose rate to the thyroid can be estimated:

D.3 DIETARY IODINE LEVELS AND POTASSIUM IODIDE BLOCKADE

· D  thy D  thy = -------------------W  thy

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(D.6)

where: · D  thy = mean absorbed dose rate to the thyroid The age-dependent thyroid-to-thyroid S factors, S(thymthy), for I, 125I, 129I, 131I, 132I, and 133I were taken from the computer program MIRDOSE III (Stabin, 1995) and are presented in Table D.3. S factors for 135I are not included with this computer program, however. Through use of the physical properties of radioisotopes of iodine presented in Table 3.5, specifically, the equilibrium dose constants and the energies and abundances of the principal radiations (Eckerman and Endo, 2008; Weber et al., 1989), the age (i.e., thyroid mass-dependent) and energy-dependent thyroid-to-thyroid absorbed fractions for penetrating radiations (i.e., photons) (Cristy and Eckerman, 1987), and a thyroid-to-thyroid absorbed fraction of one for nonpenetrating radiations (i.e., electrons and delta rays), the age-dependent thyroid-to-thyroid S factors for 135I were calculated and are also presented in Table D.3 (Zanzonico, 2000a). The age-dependent cumulated activities per unit activity inhaled/ ingested in the thyroid  A˜ thy and residence times (hours) in the thyroid (Wthy) were calculated after incorporating radioactive decay into the compartmental model in Figure 3.2 and integrating the resulting activity in the thyroid compartment (Compartment 3) to infinite time; the residence times are presented in Table 3.5 (Zanzonico, 2000b). By multiplying the age-dependent thyroid-tothyroid S factors, S(thymthy), by the corresponding age-dependent cumulated activities in the thyroid  A˜ thy the mean age-dependent thyroid absorbed doses in Gy MBq–1 of radioiodide inhaled/ ingested) [D(thy)], and absorbed dose rates for each radioisotope of iodine were calculated and are also presented in Table 3.5 (Zanzonico, 2000b). 123

D.3 Dietary Iodine Levels and Potassium Iodide Blockade Computer modeling of iodine metabolism has been used systematically to elucidate the effectiveness of thyroid blockade as a function of dietary iodine status as well as of the time of potassium iodide administration relative to radioiodine intake. Whole-body iodine metabolism was again simulated using the compartmental model in Figure 3.2 and Berman’s SAAM program (Barrett et al., 1998; Berman et al., 1962; Boston et al., 1981).

S(thymthy) (mGy kBq–1 h–1) Age

123

I

124

I

125

I

129

131

I

I

132

I

133

I

135

I

Newborn

0.0143

0.0841

0.0104

0.0289

0.0868

0.229

0.186

0.144

1y

0.0105

0.0624

0.00762

0.0210

0.0632

0.0168

0.135

0.104

5y

0.00559

0.0338

0.00408

0.0109

0.0330

0.0881

0.0703

0.0538

10 y

0.00255

0.0154

0.00187

0.00478

0.0145

0.0392

0.0308

0.0240

15 y

0.00168

0.0101

0.00123

0.00308

0.00932

0.0255

0.0198

0.0159

Adult

0.00104

0.00630

0.000770

0.00186

0.00565

0.0156

0.0120

0.00914

368 / APPENDIX D

TABLE D.3—Age-dependent thyroid-to-thyroid S factors for radioisotopes of iodine (Zanzonico, 2000b).

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Through use of the analytic fit of Blum and Eisenbud (1967) to their measurements of suppression of the 24 h RAIU of 131I as a function of serum concentration of iodide, the following formula relating the iodide-to-thyroid exchange rate to the serum iodide concentration was derived and used in the foregoing compartmental model (Zanzonico and Becker, 1993; 2000): k  thyroid, iodide = 0.37 k  thyroid, iodide 0 > Iodide @

– 0.9

(D.7)

where: k(thyroid, iodide) = iodide-to-thyroid exchange rate (h–1) k(thyroid, iodide)0 = maximum iodide-to-thyroid exchange rate (h–1), that is, the theoretical iodide-to-thyroid exchange rate (h–1) at a serum iodide concentration of zero = 0.0456 h–1 [Iodide] = concentration of iodide in serum [Pg (100 mL)–1] Using Equation D.1, the model is quantitatively adaptable to the entire range of dietary iodine levels, from deficiency that is assumed to correspond to 50 Pg d–1 ingested to sufficiency intake assumed to correspond to 250 Pg d–1 ingested, and to potassium iodide blockade [corresponding to oral administration of 100 mg of potassium iodide (Delange, 1993)]. The pertinent concentrations of iodide in serum were determined using the compartmental model in Figure 3.2 to determine the steady-state amount of iodide in milligrams for a daily intake of 50 or 250 Pg and a Reference Man serum volume of 3,000 mL (ICRP, 1975).

Appendix E Animal Experiments The following review of animal experiments is divided into three sections that parallel the three headings in Section 4.1 and provides additional information about the details of the animal experiments reviewed in Section 4.1. E.1 Experiments in Rodents The literature on radiation-induced thyroid cancer in rodents is extensive. This review is selective and is intended to give the reader an appreciation of the variety and quality of this early scientific work. A limited number of groups of scientists did much of the work. The studies are organized by reporting scientists since studies done by the same scientists had methodological similarities. Within each group, studies are reviewed in chronological order to give the reader an appreciation of the sequential development of insights regarding radiation-induced thyroid cancers in rodents. E.1.1

University of California Berkeley

In the late 1940s, Goldberg and Chaikoff (1951) sacrificed 10 male Long-Evans rats that survived for 18 months after the intraperitoneal injection of 14.8 MBq 131I. The total number of rats that had been injected was not disclosed. All 10 rats had radiation fibrosis and atrophy of the thyroid. Two also had areas of normalappearing thyroid tissue, multiple benign appearing adenomas, and “malignant-like” thyroid tumors, which were pathologically similar to human thyroid cancers. The authors stated that thyroid carcinomas rarely spontaneously occurred in the rat and they proposed two explanations for their observations. They postulated that thyroid tumors might be due to: (1) a direct carcinogenic effect of 131I, or (2) a secondary effect due to excessive thyrotrophic stimulation caused by radioiodine-induced hypothyroidism. The authors did not estimate the thyroid dose but it would have been very large. 370

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Subsequently Doniach (1953) estimated the thyroid dose to be “at least 150,000 reps” (~1,500 Gy) which is ~10 to 20 times the thyroid dose of ~100 Gy used to treat patients with hyperthyroidism. In 1952, Goldberg and Chaikoff reported their findings on the number of thyroid cancers they observed in 25 male LongEvans rats sacrificed 18 to 24 months after receiving 14.8 MBq 131I intraperitoneally when the rats were age 12 weeks (Goldberg and Chaikoff, 1952). The total number of rats initially injected was not stated. Seven of the 25 rats had thyroid carcinomas. Another group of 125, 12 week-old rats were treated with propylthiouracil (which blocked thyroid hormone synthesis) for 3 to 32 months in order to induce excessive thyrotrophic stimulation. These animals developed very large goiters (up to 50 times the normal thyroid size). Although 24 of these rats developed benign thyroid tumors, none of these rats developed malignant lesions. The authors concluded that TSH stimulation alone could be ruled out as the causative agent and that the 131I was responsible for the observed thyroid carcinomas. The results of an experiment using a much larger number (935) of 6 to 12 week-old male and female Long-Evans rats and a range of intraperitoneally administered 131I activity was reported in 1957 (Lindsay et al., 1957). The rats were divided into 10 groups based on their diet, gender and thyroid dose. Five hundred and fifty rats were injected with 0.37, 0.935, 3.7, 7.4, or 14.8 MBq of 131I and 385 rats were used as controls. Male control rats were divided into two groups based on their diet. Only 36 % of the radioiodine exposed rats and 41 % of the nonexposed rats survived long enough (18 to 36 months) to be included in the study’s histological analysis. The remainder of the rats died of “chronic respiratory disease.” Thirty percent of the surviving controls had naturally-occurring “alveolar” thyroid carcinomas, one rat had a benign adenoma, but none had follicular or papillary thyroid carcinomas. In the rats injected with larger amounts of 131I (7.4 or 14.8 MBq), the incidence of spontaneously-occurring alveolar carcinoma decreased and no follicular/ papillary thyroid carcinomas were observed. There were five follicular/papillary thyroid carcinomas observed in rats injected with 0.37 (1), 0.925 (3), and 3.7 (1) MBq, respectively, of 131I. A total of 21 benign thyroid adenomas was observed. Twenty of these adenomas occurred in radioiodine exposed animals with the majority (18) of the adenomas occurring in the animals receiving 0.37 to 3.7 MBq. The authors concluded that: • there was a high spontaneous incidence (30 %) of alveolar thyroid cancer in Long-Evans rats but that these spontaneously-occurring carcinomas could be differentiated from radioiodine-induced follicular/papillary thyroid carcinomas;

372 / APPENDIX E • incidence of both spontaneously-occurring and radioiodineinduced carcinomas decreased with large thyroid doses t7.4 MBq of 131I; • highest incidence of follicular/papillary thyroid carcinomas occurred with administered activities of 0.37, 0.925, and 3.7 MBq; and • highest incidence of benign adenomas occurred with administered activities of 0.37 and 0.925 MBq. The fact that none of 146 rats that received 14.8 MBq developed follicular/papillary thyroid carcinoma raises questions about the validity of the 1951 to 1952 Goldberg and Chaikoff findings. It would appear that the now known high-spontaneous incidence of thyroid tumors in the Long-Evans rat was not fully recognized at the time of the 1951 to 1952 Goldberg and Chaikoff papers and, therefore, that the decreased thyroid tumors was due to radiationinduced cell killing with increasing dose and not a high radiation carcinogenicity at low dose. The effects of dose fractionation were studied in an experiment reported in 1960 (Potter et al., 1960) where 200 male Long-Evans rats were injected intraperitoneally with 131I at age eight weeks. Thyroid tumor incidence 2 y after the 131I injections was determined in 100 male Long-Evans rats receiving 0.925 MBq in a single dose and in 100 male Long-Evans rats receiving a total of 1.48 MBq given in four 0.37 MBq doses at one month intervals. Only 23 % of the 0.925 MBq group survived 2 y; of those, eight (35 %) had spontaneously-occurring alveolar carcinomas, 22 (96 %) had follicular adenomas, three (13 %) had papillary carcinomas, and three (13 %) had follicular carcinomas. Twenty-eight percent of the 1.48 MBq group survived; eight (29 %) had spontaneously-occurring alveolar carcinomas, 27 (96 %) had follicular adenomas, three (11 %) had papillary carcinomas and three (11 %) had follicular carcinomas. No effect from fractionation was seen and the authors emphasized that radiation-induced thyroid cancers were more likely when small amounts (0.37 to 0.925 MBq) of 131I were used. The carcinogenic effects of external thyroid exposure to x rays was reported in 1961 (Lindsay et al., 1961). Four hundred 8 to 12 week-old male Long-Evans rats were evenly divided into four thyroid-dose (1.29 × 10–1, 2.58 × 10–1, 5.6 × 10–1 C kg –1) groups. An additional 50 rats received 2.58 × 10–1 C kg –1 to only the right lobe of the thyroid. The animals were sacrificed 2 y after the exposure to determine the incidence of thyroid abnormalities. Only 27 % (107) of the 450 rats survived 2 y. Papillary or follicular thyroid carcinoma was found in only one of the 22 surviving rats with a

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thyroid dose of 1.29 × 10–1 C kg –1; five of the 22 with a dose of 2.58 × 10–1 C kg –1, and one of the four with a dose of 5.6 × 10–1 C kg –1. Two of the 26 surviving rats with a dose of 2.58 × 10–1 C kg –1 to the right lobe had follicular cancers in the right lobe. None of the unexposed rats (33) had papillary or follicular thyroid carcinoma. The authors concluded that the papillary or follicular thyroid cancers observed in rats following external radiation were pathologically similar to those seen following 131I exposure and similar to human thyroid cancers. In rats with right thyroid lobe irradiation only, the incidence of benign abnormalities was similar in both the right and left lobes but the two follicular thyroid cancers occurred in the irradiated lobe. The authors attributed the increase in benign abnormalities to the effects of TSH stimulation. The authors stated that thyroid cancers may be due to a direct effect of the radiation or due to the combined effects of TSH stimulation and radiation. In order to determine if gender differences were an important factor for radioiodine-induced thyroid cancer, female Long-Evans rats were given intraperitoneal injections of 131I (Lindsay et al., 1963). The control group consisted of 100 rats; the treatment group consisted of 100 rats that were given 0.37 MBq 131I intraperitoneally at monthly intervals for a total of three months. The total administered activity was 1.11 MBq beginning at age two months. The incidence of thyroid abnormalities was determined 2 y after the initiation of the experiment. Thirty-one of the 100 controls survived 2 y compared to 49 of the 100 that had received radioiodine. One of the controls had an adenoma, but none had carcinomas, whereas, in the 131I treated rats, 19 (39 % of the survivors) had adenomas and three had papillary carcinomas. The authors combined the data from this experiment with their data from their 1957 and 1960 reports. Of animals receiving a total of 0.37 to 1.48 MBq 131I in single or divided doses, 4 of 55 (7 %) of the female rats and 15 of 71 (21 %) of the males developed papillary or follicular carcinomas. The authors concluded that the incidence of both benign and malignant radioiodine-induced thyroid neoplasms was less in female rats than in male rats. In another experiment reported in 1964, investigators sought to better determine whether thyroid carcinogenesis was primarily due to thyrotropin stimulation, radiation, or a combination of the two (Goldberg et al., 1964). A total of 876 five to six-week-old female Long-Evans rats was divided into eight groups based on whether the rats did or did not have: • subtotal thyroidectomy; • intraperitoneal injection of 0.037 MBq of 131I; or • exogenous thyroid hormone supplementation.

374 / APPENDIX E The incidence of thyroid neoplasms induced 2 y after the initiation of the study was determined. Only five of the 418 rats that survived 2 y had papillary or follicular carcinomas. Carcinomas occurred in two of the 68 with subtotal thyroidectomy alone, two of the 94 that had received 0.037 MBq 131I, with or without thyroid hormone added to the diet, and one of 110 that had both subtotal thyroidectomy and 0.037 MBq 131I. None of the 105 controls developed papillary or follicular carcinomas. Despite the small numbers of radiation-induced thyroid cancers, the authors concluded that it was likely that radiation was an initiating factor and thyrotropin stimulation was a promoting factor for thyroid carcinogenesis. Later, Lindsay et al. (1968) studied radiation carcinogenesis in 1,076, six-week-old male Long-Evans rats that were sacrificed at 6, 12, and 24 months; and 440, four-week-old male Swiss white mice sacrificed at 3, 6, and 12 months. The rats received 0.037 or 0.185 MBq 131I whereas the mice received 9.25 or 46.2 kBq 131I. The percent of naturally-occurring carcinomas increased progressively with time in each group of rats. Only 653 rats (61 %) and 246 mice (56 %) survived long enough to be examined pathologically. No thyroid adenomas were observed in the control rats, two were observed in the 0.037 MBq group, and 16 were observed in the 0.185 MBq group. One rat that had received 0.037 MBq 131I was found to have a papillary thyroid carcinoma six months after exposure. Only one adenoma was observed in the 9.25 MBq group of mice. No papillary thyroid carcinomas were observed in any mice. There were no pathologic changes to suggest obvious radiation injury or TSH stimulation. The authors concluded both benign and malignant neoplasms may be caused by small “doses” of radiation. E.1.2

Post-Graduate Medical School of London

In 1950, Doniach (1950) conducted an experiment to determine if 131I increased the risk of thyroid cancer in rats. A total of 113 two-month-old hooded Lister rats was assigned to a control group or one of seven treatment groups. The treatments included administration of 131I, MT, and the carcinogen acetylaminofluorene (AAF) alone or in combination with 131I or MT. The rats were sacrificed at age 13 months. Four of the 15 controls developed adenomas versus 10 of 16 treated with 1.184 MBq 131I alone (i.e., 0.592 MBq of 131I at beginning of the study plus 0.592 MBq 131I 5.5 months later), 10 of 16 treated with MT alone, and four of four treated with both 131I and MT. Only two rats (one treated with 131I and MT; one rat treated with 131I, MT and AAF) developed thyroid cancer. The dose from the 131I was estimated at roughly 150 Gy. The author

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concluded that radioactive iodine increased the incidence of thyroid adenomas in all groups except for the AAF group. He also discussed the lack of consensus about the criteria that should be used to make the histological diagnosis of thyroid cancer. Another experiment designed to determine the relative roles of thyrotropin stimulation and radiation in thyroid carcinogenesis was reported by Doniach (1953). A total of 210, 10 week-old (on average) hooded Lister rats was divided into eight groups, one of which was untreated and served as the control. One group received MT only; the other six groups received either 0.185, 1.11 or 3.7 MBq 131I, with or without MT. Only 100 rats survived to be sacrificed 15 months later. With the exception of those receiving 3.7 MBq, all groups, especially those receiving MT, had a high incidence of benign thyroid adenomas. There were five thyroid carcinomas, all of which appeared in the 0.185 MBq plus MT animals. No rat receiving 131I alone or 1.11 to 3.7 MBq plus MT developed a carcinoma. After introducing correction factors for the higher 131I uptake in central versus peripheral follicles and for the dose decrease at the edge of the glands, Doniach estimated that the dose due to 0.185 MBq 131I ranged from 5.7 to 40.5 Gy at the edge and center of the glands. The author concluded that the combination of radiation and thyrotropin stimulation is more carcinogenic than either factor alone. The discussion portion of this paper includes an extensive review of the literature and the following comments. “…it is probable that the present methods of clinical 131I therapy in thyrotoxicosis may eventually prove carcinogenic. We shall have to follow treated patients for 15 to 25 y in order to verify this danger and find out what portion of them develop thyroid cancer.” In the meantime, the author suggested four precautions. “First, …thyrotoxic patients under the age of 45 should only be treated with radioiodine when other methods of treatment are contra-indicated or when the expectation of life is less than 20 y. Secondly, the minimal dose of 131I to produce remission should be administered. Thirdly, thyroxine medication should be instituted and maintained after the thyrotoxic symptoms are relieved. Fourthly, antithyroid drugs are strongly contra-indicated at any time after radioiodine therapy.” These precautions received greater acceptance in Europe than in the United States. Even today, the proportion of patients with

376 / APPENDIX E hyperthyroidism that are treated with radioactive iodine is greater in the United States than in Europe (Weetman 2000a; 2000b). In 1957, Doniach reported the results of a study in which threemonth-old hooded Lister rats received no treatment or 1.11 MBq 131 I or 11 Gy from x ray, with or without MT (Doniach, 1957). The details of this study are discussed in Section 4.3.3. In a review of his own work as well as the literature Doniach (1963), concluded that: (1) 131I is carcinogenic to the rat thyroid; (2) 131I can produce adenomas after 1 y, which may become malignant after 2 y (two-thirds of the rat’s lifespan); (3) the optimal dose for carcinoma induction is ~1.11 MBq 131I in the young adult rat; and (4) an excess of TSH both increases the incidence of adenomas and shortens the carcinogenic period to within 15 months. With regard to adenoma and carcinoma induction, he concluded that an x-ray dose of 10 Gy is approximately equivalent to a “calculated mean dose of ~100 Gy from 131I.” In 1974, Doniach published the results of a study that was designed to confirm that “low dose” external irradiation of 1, 2.5, and 5 Gy could induce thyroid neoplasms (Doniach, 1974). A total of 636, 9 to 12 week old male hooded Lister rats divided into three feeding groups, A-standard diet; B-standard diet plus thyroxine; C-standard diet plus aminotriazole (a goitrogen). These feeding groups were then subdivided into four treatment groups of control and 1, 2.5, and 5 Gy to the thyroid. Two hundred and fifteen animals survived until they were sacrificed and histologically examined 18 to 20 months after the start of the experiment. No thyroid neoplasms were found in the unirradiated rats or the unirradiated rats that received thyroxine. Thyroid adenomas were more common in rats exposed to radiation only (5) than in rats radiation exposed and given thyroxine (1). Only one thyroid cancer occurred in the absence of aminotriazole. All surviving animals receiving aminotriazole had adenomas and many more animals receiving aminotriazole had thyroid carcinomas (12). The author concluded that “TSH may play a permissive role in the development of thyroid tumors following low dose x-radiation to the thyroid.” E.2 Experiments in Larger Animals Due to the logistics, there are many fewer large animal studies than small animal studies of thyroid disease following radiation exposure. A few of these studies are summarized below. Bustad et al. (1957a; 1957b) fed 131I in daily doses of 0.0555 to 5 MBq to sheep for periods up to several years; the calculated cumulative absorbed doses ranged from 70 Gy to >1,000 Gy. Of the 19 sheep, 16 developed adenomas, one a follicular carcinoma, and one a fibrosarcoma.

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Lu et al. (1973) exposed 56 beagle dogs to varying doses of x rays, whole or half body, 0 to 0.47 C kg –1 and/or 131I, 0 to 61.32 Gy in 1 to 13 doses. There were no nonirradiated control dogs. Thirtytwo dogs survived for 3 y or more and were available for analysis; eight developed adenomas and three adenocarcinomas (two follicular and one papillary). Of the three with thyroid carcinomas, one had no x-ray exposure, while the other two had received 0.25 C kg –1 of x-ray exposure; all three had received 131I, given in three to seven doses of 0.629 to 1.92 MBq each, distributed over 3 to 5 y, with calculated thyroid doses of 15.8 to 25.88 Gy. In 1997, the incidence of nonneoplastic and neoplastic thyroid disease in beagles that had been irradiated during the pre- and postnatal periods was reported (Benjamin et al., 1997). A total of 1,680 beagles was in the study. There were an equal number of males and females. Three hundred and sixty beagles were not irradiated and served as controls. Nine hundred and sixty beagles were divided into four groups based on the age at exposure (8 d postcoitus, 28 d postcoitus, 55 d postcoitus, and 2 d postpartum). These four age at exposure groups were further subdivided into two dose groups of ~0.16 and 0.83 Gy giving eight groups of beagles with 120 beagles per group. One hundred and twenty of the remaining 360 beagles were exposed to ~0.82 Gy 70 d postpartum. The final group of 240 beagles was exposed to ~0.82 Gy 365 d postpartum. All irradiated beagles received a single whole-body exposure from an external 60Co source. A subset of 337 dogs was preselected for sacrifice at 5, 8 and 11 y. The remaining 1,343 dogs lived out their lifetime. Direct tests of thyroid function were not done on most dogs. The diagnosis of hypothyroidism was made only when there were classic clinical features accompanied by pathological findings of thyroid atrophy and pituitary thyrotrophic hypertrophy. The thyroids of all dogs were examined with light microscopy. Heritable lymphocytic thyroiditis with hypothyroidism was a major contributor to mortality. In accordance with the experimental protocol, hypothyroid dogs were not given thyroxine replacement therapy. The incidence of hypothyroidism in unirradiated dogs was 16 % (44/231) compared to 11.1 % (117/1,056) in irradiated dogs. Throughout most of their lifespan, the cumulative incidence of hypothyroidism was greater in the control dogs than in the irradiated dogs (Figure 4.1). This finding “was surprising and not easily explained.” A detailed description of the clinical and pathological changes associated with hypothyroidism in this colony of dogs has been published (Benjamin et al., 1996). Benign and malignant thyroid follicular neoplasms were common in these beagles. Twenty-eight percent of unirradiated dogs

378 / APPENDIX E had one or more thyroid tumors compared with 26.5 % of irradiated dogs. Only dogs exposed at 70 d postpartum had a significantly increased incidence (41.5 %) of thyroid neoplasia. Interpretation of these results was complicated by the fact that the lifetime incidence of thyroid neoplasia was greater (55 %) in hypothyroid dogs and, as stated above, more unirradiated dogs were hypothyroid. Further analysis (Figure 4.2) indicated that there was a statistically-significant increase in thyroid neoplasia only in dogs irradiated in the neonatal period (2 d postpartum) and in the juvenile period (70 d postpartum). E.3 Experiments to Determine Relative Biological Effectiveness Rodent studies using very large doses of 131I (>1.48 MBq) are not included in the following review since cell killing predominates with such large doses. Only experiments where the same investigators used the same strain of animals to determine RBE of 131I are discussed. In a study reported by Abbatt et al. (1957), postirradiation impairment of thyroid growth response (goitrogenesis) was used as the endpoint to compare RBE of 131I and x rays. Propylthiouracil was used to induce thyroid growth in rats three to four months after radiation exposure. Forty-two home-bred male albino rats were divided into six equal groups. Group one served as a control. Three groups had thyroids treated with 190 kV x rays (0.5 mm copper, 1 mm aluminum filtration) at doses of 5, 10 and 20 Gy in two fractions, 26 d apart; the dose rate was 1.5 Gy min–1. Two groups were injected intraperitoneally with 0.37 or 1.11 MBq 131I; the dose rate was estimated to be a few 10s of milligray min–1; 1.11 MBq of 131I and 10 Gy x rays produced equivalent near-total inhibition of goitrogenesis. The mean thyroid dose from 1.11 MBq 131I was estimated to be between 100 and 150 Gy, therefore 131I was 10 to 15 times less effective than x rays in inhibiting goitrogenesis in this animal model. The authors speculated that the decreased effectiveness of 131I may be due to two factors (nonuniform dose distribution and decreased dose rate). Two studies that were discussed in Section 4.1.1 have been used to estimate RBE of 131I and x rays (Lindsay et al., 1957; 1961). Based on these two experiments, 131I appeared to be five times less effective than x rays in causing thyroid neoplasms. Another study using the incidence of neoplasms as the endpoint to compare RBE of 131I and x rays has been reported by Doniach (1957; 1963). A total of 160 male and female hooded Lister rats was

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divided into six groups [Group 1: control without MT; Group 2: control with MT; Group 3: 1.11 MBq 131I without MT; Group 4: 1.11 MBq 131I with MT; Group 5: 11 Gy of 190 kV x rays (filtration 0.5 mm copper, 1 mm aluminum) to the thyroid without MT, and Group 6: 11 Gy of x rays to the thyroid with MT]. This amount of 131I and dose to the thyroid from external x-ray irradiation was chosen because they had been previously shown to have similar effects on postradiation impairment of thyroid growth response. One hundred and twelve rats survived until they were sacrificed and their thyroids were histologically examined 15 months after entry into the experiment. Adenomas occurred in all groups. The incidence was particularly high in those receiving MT. After 1.11 MBq 131I alone, 0 of 22 rats developed carcinoma; after 11 Gy x rays, 1 of 13 developed a cancer. The incidence increased to 5 of 24 and 7 of 22, respectively, when MT was also given. With respect to potency to initiate carcinogenesis in rats treated 15 months with MT, 1.11 MBq 131I were approximately equivalent to 11 Gy, external orthovoltage irradiation. Doniach estimated that the thyroid dose from 1.11 MBq 131I (intraperitoneally) ranged from 20 to 240 Gy, therefore 131I was 2 to 20 times less effective than x rays in promoting neoplasms in this animal model. A study comparing the effect of x rays and 131I exposure on the incidence of thyroid neoplasms (adenomas and carcinomas) in adult (age 110 to 130 d) male CBA mice was reported by Walinder (1972a; 1972b). Seven hundred mice were divided into seven equal groups: (1) control; (2) 131I activities of 0.0555, 0.111, or 0.166 MBq injected intraperitoneally; and (3) x-ray thyroid dose of 4.75, 9.5 and 14.3 Gy. The mice were sacrificed at age 680 to 730 d. The 0.111 MBq 131I group (calculated dose 44 Gy to the periphery and 110 Gy to the center of the thyroid) had one carcinoma among the 88 surviving mice. In the 0.166 MBq 131I group with 64 and 160 Gy peripherally and centrally, respectively, there was one carcinoma among 80 mice. Three of 94 mice receiving 15 Gy of external x-ray irradiation developed carcinomas. There were no cancers in the four other groups. The combined incidence of adenomas and carcinomas suggested that: (1) 0.0555 MBq is equivalent to ~4.75 Gy of external x-ray irradiation; (2) 0.111 MBq is equivalent to ~9.5 Gy, and (3) 0.166 MBq is equivalent to ~14.3 Gy. For a given rad dose, external x-ray irradiation was 4 to 11 times more effective than 131I in producing adenomas and carcinomas in adult CBA mice. The same investigators reported the results of a similar experiment using fetal mice (Walinder and Sjoden, 1972). Male and female CBA mice were used. The authors had hoped to use the control mice from the experiment described above as the control for

380 / APPENDIX E this experiment, but they found that the thyroids of the mice exposed in this experiment weighed twice as much as the control thyroids from the prior experiment. At day 18 of gestation (usually 2 d before birth), the mother received either whole-body x-ray irradiation and/or intravenous 131I. In addition to the control group, there were seven experimental groups: 1. 2. 3. 4. 5. 6.

131I

thyroid doses 19 to 21 Gy; 38 Gy; 47 to 49 Gy; 68 to 73 Gy; x-ray thyroid dose 1.8 Gy; 131I thyroid dose 15 to 18 Gy and x-ray thyroid dose of 1.8 Gy; and 7. 131I thyroid dose 26 to 30 Gy and x-ray thyroid dose 1.8 Gy.

It is unclear how many mice were entered into the study, but 552 males and 471 females in the experimental groups were sacrificed at 2 y and their thyroids were examined histologically. Based on the total incidence of neoplasms (adenomas plus carcinomas), the effectiveness of 28 Gy from 131I plus 1.8 Gy from x ray fell between that of 38 and 48 Gy from 131I alone. The addition of 1.8 Gy of x rays appears to have added approximately the same incremental effect as 10 to 20 Gy from 131I (a ratio of ~5 to 10). In contrast to the early studies discussed above, a study published in 1982 is better designed and is, therefore, more defensible scientifically (Lee et al., 1982). Prior to performing their study, a dosimetric study was performed to accurately measure the thyroid dose from both 131I and x rays (Lee et al., 1979). The authors used a new dosimetric model for 131I and they indicated that earlier studies had probably overestimated the dose that was received by the thyroid from 131I by 60 to 70 %. Such an error would have resulted in the underestimation of RBE for 131I. The Lee study used 3,000 younger (six-week old) rats of the same type (Long-Evans) as Lindsay et al. (1957; 1961; 1963). Use of younger rats may have had an important effect on the results of the study given what we now know about the increased sensitivity of children to external radiation. The thyroid doses used in this study were lower than those used in the earlier studies and were in a range that is more relevant for environmental and diagnostic exposures. The rats were evenly divided into 10 experimental groups: two control groups; three groups of thyroid 131I exposures of 0.8, 3.3, and 8.5 Gy; three groups of thyroid x-ray exposures of 0.94, 4.1, and 10.6 Gy, one group of an x-ray pituitary dose of 4.1 Gy; and

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one group of x-ray dose to the pituitary and thyroid of 4.1 Gy. After six months, any rat that appeared moribund was sacrificed. At 2 y, the rats that were still living (62 % of the rats entered into the study) were sacrificed. Histologic examination of the thyroid was performed in a much higher proportion of the animals than in prior studies. In addition, the histologic examination was performed without knowledge of the exposure history of the animal. In recognition of the potential value of the data produced by the experiment, an independent blind review of the thyroid sections was performed and confirmed the findings of the original authors (Capen et al., 1999). The dose-response curve (Figure 4.3a) suggested that 131I was approximately two times less effective than x rays in causing adenomas although the 95 % confidence interval do not exclude the possibility that 131I was as effective as external radiation exposures. The dose-response curves obtained for adenomas were different than the dose-response curves for thyroid carcinomas. The doseresponse curve for thyroid carcinomas was similar for x rays and for 131I. The carcinogenic risk was approximately proportional to the square root of the dose, and the risk was independent of dose rate (Figure 4.3b). This study also demonstrated that, in this experimental model, pituitary radiation had no effect on the occurrence of thyroid cancers. A group of animals given pituitary irradiation was included in this study because when the first reports of the Israeli Tinea Capitus Study were published (Modan et al., 1974; 1977a; 1977b) concern was raised that the combination of thyroid and pituitary irradiation had a synergistic effect on thyroid carcinogenesis. The 95 % CIs of the dose-response curve for thyroid carcinomas, however, did not preclude the possibility that 131I radiation was two to three times less effective than x rays. The risk per rad for the induction of thyroid carcinoma ranged from 0.74 to 2.3 × 10–4; the lowest risk per rad occurred in the highest dose range and the highest risk at the lowest dose, suggesting that cell killing blunted the response at higher doses. The incidence of thyroid carcinoma (papillary and/or follicular) was 2 % for 1.78 kBq (0.48 PCi) 131I and 4 % for 7.1 kBq (1.9 PCi). These figures are only slightly higher than the 1.5 % found by Goldberg et al. (1964) for five- to six-week old female Long-Evans rats given 3.7 kBq (1 PCi) 131I. Dietary iodine in the Lee et al. (1982) study was 1.7 Pg g–1 of rat chow versus 3 Pg g–1 in the Goldberg study. Survival to sacrifice was 50 % in the Goldberg study versus 62 % in the Lee et al. study.

Appendix F Additional Epidemiological Studies on Exposure to External Radiation In addition to the studies reviewed in Section 4.4.1, many other studies of the association between thyroid cancer and external radiation in humans have been published. Some of these additional studies are discussed below. They have been grouped into four major categories (medical therapy in childhood, medical therapy in adulthood, occupational exposure, and medical diagnostic studies) and are briefly reviewed within each category in the order of publication date. If a study includes subjects who were exposed as children as well as those who were exposed as adults, the study is listed in the adult section. F.1 Medical Therapy in Childhood F.1.1

Childhood Treatment Studies Published Prior to 1965

The possible association between childhood thyroid cancer and radiation exposure in childhood was raised by Duffy and Fitzgerald (1950a; 1950b). They reported a case series of 28 children who were diagnosed with thyroid cancer before the age of 18 y at Memorial Hospital in New York in a 16 y period (1932 to 1948). Ten of these children were exposed to external radiation for treatment of an “enlarged thymus” (Jacobs et al., 1999) between the 4th and 16th month of life. Duffy and Fitzgerald’s publications were followed by several others that suggested a causal relationship between early childhood treatment for thymic enlargement and thyroid cancer. Clark 382

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(1955) published a review of the 13 cases of childhood (less than age 15 y) thyroid cancer that he had seen in his practice within the past 6 y. All 13 children had prior radiation treatment for benign conditions. The interval between the time of radiation and the diagnosis of the tumor was 3 to 10 y (average, 6.9 y). The dose in the treatment area ranged from 2 to 7.25 Gy. Clark concluded that his observation “lends strong support to the idea that an association exists between irradiation and the subsequent development of thyroid cancer in late childhood and adolescents.” Eight cases of childhood (<16 y old) thyroid cancer at Children’s Hospital of Philadelphia were reviewed by Fetterman (1956). Two additional cases were uncovered at nearby general hospitals. Eight of these 10 children had prior histories of external radiation therapy. The author concluded, “The problem posed by the frequent association of irradiation in infancy and juvenile thyroid carcinoma is a serious one. So far, a definite relationship has not been proved. Until definite information is available as to whether or not previous irradiation plays a role in the genesis of thyroid carcinoma, the use of ionizing radiation in the treatment of vague or non-neoplastic conditions should be reduced to a minimum.” Fifteen cases of thyroid cancer in children between the ages of 5 and 20 y were reported by Cole et al. (1956). Ten of these patients had a prior history of having received radiation therapy to the head and neck between the ages of two months and 6 y. The doses ranged between 2 to 6.25 Gy. Reports of an association of external radiation therapy and thyroid cancer were greeted with skepticism from some medical practitioners. In his review of the literature, Uhlmann (1956) questioned the findings of prior investigators who had reported this association. He stated, “In animals, cancer of the thyroid has never been produced with x rays.” In addition, he estimated that the maximum amount of radiation to reach the skin over the thyroid during customary treatment of benign hyperplasia of the nasopharynx was 0.18 Gy. “This is much less than the amount of radiation that reaches the thyroid during usual fluoroscopic examination of the chest.” He also reviewed his own experience with 25 patients who were under the age of 21 y at the time when they were referred for treatment of thyroid cancer. Only four of these 25 patients had a history of prior irradiation treatment. In addition, his examination of 480 children who had been treated for hypertrophic lymphoid tissue in the pharynx and for enlarged tonsils did not reveal “a single instance of carcinoma in a follow-up period of 7 y.” The author concluded, “Statistically, the correlation of irradiation and development of cancer of the thyroid is untenable.”

384 / APPENDIX F Snegireff (1959) likewise questioned the relationship of radiation and juvenile thyroid cancer. In 1959, he reviewed the history of the treatment of thymicolymphaticus and published the results of a survey of 148 patients who had been treated with radiation in childhood or infancy for an enlarged thymus gland. He also surveyed 162 patients who were not treated with radiation. None of the irradiated patients had developed a malignant neoplasm. He concluded, “The previously reported high incidence of primary cancer of the thyroid and of leukemia following irradiation for thymic enlargement is not borne out in our sample.” He called for systematic registration of exposed patients so that follow-up studies could be performed. A follow-up study of 958 patients who received radiation therapy for thymic enlargement as children, during the years 1932 to 1951 at the University of Michigan, was reported in 1959 (Latourette and Hodges, 1959). Seven hundred and fifty-four patients (78 %) were <1 y old at the time of their radiation treatment. Only nine patients were >6 y old at the time of their treatment. Five hundred and sixty-seven (59 %) of the patients were male. The largest number of patients were treated in 1937 (157), and there was a rapid decrease in the number treated after 1941. Most patients (661) were treated with a single dose of 2 Gy. The minimum dose was ~0.9 Gy and the maximum dose was 10 Gy. Patients were contacted by sending a general form letter to the patient’s last known address asking about the patient’s health. No mention of radiation was made in the form letter. A second form letter was sent to those who responded to the first letter. If the patient or family indicated any type of tumor, mass, cyst, lump or cancer, additional information was obtained. Complete follow-up information was available for 867 (90.5 %) of the patients. Ninety-nine (11.4 %) of the 867 patients for whom follow-up information was available had died. Thirty-eight of the 99 deaths occurred in children with congenital abnormalities. Six of the 99 deaths were due to neoplasm. The average length of follow-up for the survivors was 19.7 y. A total of 19 patients developed a neoplasm or tumor. Thyroid cancer was only reported in one patient. The authors stated that only three malignant neoplasms (leukemia, lymphosarcoma and thyroid cancer) were possibly related to prior radiation therapy. Wilson et al. (1958) described an additional nine patients that developed thyroid neoplasms following radiation therapy. Seven of the patients developed thyroid cancer and two developed thyroid adenomas. In this series, children were irradiated because of the presence of skin hemangiomas: naevus (5), thyrotoxicosis (2), eczema, and a keloid. The latent period was noted to be under 10 y

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in three cases. The authors stated that, “Exposure in childhood predisposes to the appearances of thyroid neoplasms. The association following radiation in adult life is less certain.” Ten cases of thyroid cancer in children were reported by Rooney and Powell (1959). Seven of these children had received radiation therapy for benign conditions during their infancy or early childhood. According to these authors, these cases raised the total number of reported cases of childhood thyroid cancer worldwide to 357 and approximately one-third of these cases had a prior history of radiation therapy. In 1960, 37 cases of patients with thyroid cancer who were under the age of 25 y when first diagnosed at Johns Hopkins Hospital (Wilson and Asper, 1960) were reported. Sixteen of these patients (43 %) had a history of prior radiation therapy to the head, neck or chest. Thirteen of the 18 (72 %) patients who were under the age of 17 y at the time of diagnosis had a history of prior radiation therapy. The authors concluded that their data “support the concept that x-ray therapy is a causative factor in the development of thyroid cancer in young persons.” Some physicians believed that children who had received radiation treatment for an enlarged thymus subsequently had fewer upper respiratory infections. This belief led to the practice of irradiating children with a normal sized thymus. Conti et al. (1960) did a follow-up study of 1,340 patients born between 1944 and 1946 with a normal sized thymus who had been treated with doses of 1.5 Gy to the anterior mediastinum. The authors hoped to determine whether the increased incidence of cancer that had been reported with patients treated with an enlarged thymus was also observed in treated patients with a normal size thymus. In contrast to several prior studies, no excess in cancer incidence was noted. The authors thought that their negative results might be due to the small numbers of patients, the smaller dose, or the smaller treatment field (4 × 4 cm). F.1.2

University of Rochester Thymic Enlargement Study

The first report of patients treated for thymic enlargement in upper New York State was published by Simpson et al. (1955). Questionnaires were sent to the parents of 1,722 children who had been treated for an enlarged thymus gland. Follow-up was available for 1,400 children. Seventeen had developed a malignant neoplasm including seven cases of leukemia and six cases of thyroid cancer. Nine additional children had developed thyroid adenomas. The incidence of malignant neoplasm was increased when compared to the

386 / APPENDIX F general population and to untreated siblings. A relationship was shown between the type of treatment and thyroid cancers, and between the type of treatment and all malignant tumors. No relationship was observed between the type of treatment and the incidence of leukemia. Simpson and Hempelmann (1957) published a second report of these patients. More detailed information was provided about the treatment protocols. Six different treatment protocols were described. Statements of interest that are from this paper include: • Previous failure to recognize the association between thyroid cancer and radiation exposure may be because children are more susceptible than adults. • Strong circumstantial evidence exists that therapeutic radiation in infants may be an etiological factor in thyroid cancer of childhood and adolescence. Its part in the induction of leukemia and other tumors is less clear and awaits further data. An additional cohort of patients was identified and an extensive report on both cohorts was published in a three papers in 1963 (Pifer et al., 1963; Toyooka et al., 1963a; 1963b). The initial cohort (Series I) was expanded to 1,451 treated patients and 2,073 untreated siblings. The second cohort (Series II) consisted of 1,358 treated patients and 2,256 untreated siblings. The average cumulative dose in air was 3.29 Gy for Series I patients and 1.26 Gy for Series II patients. The port sizes were also larger for Series I patients compared to Series II patients (53 cm2 versus 38 cm2). Twenty malignant neoplasms [leukemia (6), thyroid carcinoma (8), salivary gland tumors (3), other (3)] were identified in treated Series I patients, and two malignant neoplasms [thyroid carcinoma (1), other (1)] were identified in treated Series II patients. Fortytwo benign neoplasms were identified in treated Series I patients and five were identified in treated Series II patients. Excess deaths were observed in treated Series I patients (observed 37; expected 24.5). The authors concluded that the excess deaths and excess benign and malignant neoplasms in treated Series I patients were due to radiation exposure. The lack of findings in the treated Series II patients was attributed to the smaller dose and the smaller size of the treatment port. Subsequent papers described tumor incidence as a function of dose (Hazen et al., 1966) and described the patients with malignant neoplasms in more detail (Pincus et al., 1967).

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Cincinnati Benign Childhood Disease Study

Saenger et al. (1960) reported their results from a telephone survey of parents of children who had received external-radiation therapy for a variety of conditions (thymic enlargement, cervical adenitis, acute and chronic sinusitis, mastoiditis, pneumonitis, enlarged hilar nodes, epilation of the scalp, and other dermatoses) while under the age of 16 y. Treatment was received between 1932 and 1950. Records at four Cincinnati hospitals were used to identify 2,230 children who had been treated. Telephone interviews determined if: (1) the child had been irradiated, (2) any neoplasms had been diagnosed in the child, and (3) any neoplasms had been diagnosed in the unirradiated child. Information was obtained on 1,644 children who had received radiation treatment. The follow-up period was 11 y or greater for 83 % of the subjects. A total of 29 malignant neoplasms was reported (18 in irradiated patients and 11 in siblings). There were 11 cases of thyroid cancer in the irradiated subjects. The authors calculated the expected number of thyroid cancers to be 0.12; therefore the relative risk was ~100. The authors concluded that, “radiation does not appear to be the sole factor responsible for the increased incidence (of thyroid cancer) but rather a contributing factor.” In addition, family health history “is extremely useful in placing in proper perspective possible carcinogenic factors other than radiation.” A subsequent follow-up study of 1,266 of the 2,230 possible subjects was published by Maxon et al. (1980). The irradiated subjects had received x-ray treatment for various benign conditions (enlarged thymus, 37 %; cervical adenitis, 31 %; bronchitis/pneumonia, 11 %; miscellaneous, 21 %). The average age at the time of exposure was 3.6 y. Thyroid doses could be estimated for 312 of the 1,266 exposed children. The mean thyroid dose was estimated as 2.9 Gy. A nonirradiated control group (958) who had received medical or surgical treatment for similar childhood diseases was also identified. Controls were matched for age, gender and race. There were fewer females in the irradiated (43 %) and the control (40 %) groups. The authors attributed this to the fact that it was more difficult to locate females due to a possible change in surname. Irradiated subjects and controls were interviewed by trained nurses who used a detailed questionnaire containing 136 questions related to past and present health status and to family history. Average follow-up was 36.5 y. For the irradiated subjects, there were 16 thyroid cancers and 15 benign thyroid nodules found. The authors emphasized that these tumors were all clinically evident and were not discovered incidentally as part of a screening

388 / APPENDIX F program. For the controls, only one thyroid cancer and two benign thyroid nodules were found. There was also an excess of nonthyroidal cancers found in the irradiated subjects when compared to the controls (15 versus 0). The authors stated that this excess cannot be explained on a familial basis since there was no statisticallysignificant excess of nonthyroid cancer in the family members of the irradiated subjects when compared to the controls (106/5,510 versus 74/4,193). Maxon et al. (1980) calculated EAR for thyroid cancer to be 1.5 (104 PY Gy)–1. In his analysis of these data, Shore (1992) estimated ERR Gy –1 to be 4.5 (95 % CI 2.80 to 6.90) and EAR to be 1.3 [90 % CI 0.8 to 2 (104 PY Gy)–1]. Strengths of this study include its emphasis on “clinically evident” disease, long follow-up, and information on the family histories of the irradiated subjects and the controls. Limitations include small numbers of thyroid cancers; follow-up rate was only 58 % (1,266/2,230) and incomplete information on thyroid dose. F.1.4

University of Chicago Thyroid Unit Study

This study was conducted at the University of Chicago at a time when there was considerable publicity about prior thyroid radiation and the risk of thyroid cancer. DeGroot et al. (1983) reported the results of their examination of 263 patients referred to their thyroid unit solely because of their history of thyroid irradiation and 153 patients referred because they had both a thyroid abnormality and a history of thyroid irradiation over a 10 y period. This summary will be focused primarily on the 263 patients referred solely for their history of thyroid irradiation. For each patient, a complete history including original source data on the type, area and amount of radiation were obtained. When possible, skin and thyroid doses were calculated. Multiple observers confirmed findings related to physical examination of the thyroid. In addition, all patients were evaluated with thyroid function tests, serum thyroglobulin assay, thyroid antibody analysis, chest x ray, and thyroid scintigraphy. All patients with a definite thyroid nodule on physical examination or a well-defined hypofunctioning area on thyroid scintigraphy were advised to have thyroid surgery. All patients who: (1) refused surgery, (2) were thought to have a benign abnormality of the thyroid, or (3) were otherwise normal but were thought to have thyroid doses >0.2 to 0.5 Gy were given thyroid hormone pills to suppress thyroid function. Patients were followed at six months to yearly intervals. Special attention was given to the “value of diagnostic procedures in evaluating such

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patients and to the utility of prophylactic thyroid gland suppressive therapy after initial evaluation.” Patients were treated with external radiation for enlarged tonsils (39 %), thymic enlargement in early infancy (21 %), acne (18 %), and miscellaneous benign diseases (21.6 %). The average thyroid dose was 4.51 ± 9.21 Gy. Individual thyroid doses could not be estimated for many patients. The average age at the time of irradiation was 7.1 ± 8.1 y. The average age at the time of examination was 33.5 ± 11 y. The mean length of follow-up was 26 y. None of the blood tests helped identify patients with nodular thyroid disease. On physical examination thyroid abnormalities were detected in 29.7 % of patients with only a history of thyroid irradiation and in 80.6 % of patients referred for a thyroid abnormality. Surgery was performed in 13.7 % (36/263) of the radiation only group. Physical examination alone detected 10/11 malignancies that were ultimately found. It is unclear if these patients were examined more than once during this period of time. The remaining malignancy (a 6 mm carcinoma) was discovered incidentally when the patient had a parathyroidectomy for hyperparathyroidism. Sixty-eight of the 78 patients with abnormalities on physical exam were found to have benign thyroid lesions. The authors also presented their findings of 153 patients with a history of childhood radiation and a suspected thyroid abnormality. Thirty thyroid cancers were discovered in this referral group. Using average doses, the authors calculated EAR for thyroid cancer to be 8.3 (104 PY Gy)–1. Shore (1992) estimated ERR Gy –1 to be 12 (90 % CI 7 to 19.3), and EAR to be 4.3 [90 % CI 2.5 to 6.9 (104 PY Gy)–1]. One strength of this study is that a careful physical examination by multiple observers and an extensive laboratory examination of all patients was performed. Weaknesses include a large screening bias, inadequate description of dose reconstruction, and individual thyroid doses that were only available in a minority of patients. F.1.5

New York Tinea Capitis Study

Shore et al. (1992) have followed-up, for an average of 39 y, 2,224 children who received x-ray treatment for scalp tinea capitis and 1,380 treated by topical medications for the disease. Follow-up was by means of mail/telephone questionnaires with a follow-up rate of 88 % and with confirmation from medical records of conditions of interest. The children were 0 to 19 y at the time of x-ray treatment with a mean of 8 y. The x-ray treatment to five fields on the scalp was administered in a single session. Fewer than 2 % received a

390 / APPENDIX F second course of x-ray treatment. The mean thyroid dose was estimated as 60 mGy (Harley et al., 1976). Although this study did not find a substantial excess of thyroid cancer (2 observed, 1.3 expected), it is marginally compatible statistically ( p = 0.07 for the difference in risks after adjusting for gender and dose differences) with the Israeli Tinea Capitis Study (Shore et al., 1992). Shore (1992) estimated ERR Gy –1 to be 7.70 (90 % CI 0 to 48.2) and EAR to be 1.5 [90 % CI 0 to 9.4 (104 PY Gy)–1]. F.2 Medical Therapy in Adulthood F.2.1

New York Tuberculous Adenitis Study

Hanford et al. (1962) attempted to obtain follow-up on all 458 patients who had received therapeutic irradiation for nonmalignant disease of the neck [tuberculous adenitis (64.6 %), hyperthyroidism (20.1 %), enlarged thymus (9.4 %), miscellaneous conditions (5.9 %)] at the Presbyterian Hospital in New York City from 1920 to 1950. Follow-up 10 y or more after irradiation was available in 275 patients (60 %). The average length of follow-up was only 25.4 y. Baseline thyroid cancer rates were estimated from the Connecticut Tumor Registry. Eight thyroid cancers were observed and 0.1 were expected. Most (7/8) of the thyroid cancers occurred in the 162 patients treated for tuberculous adenitis, therefore this group was analyzed in more detail. The median age at the time of exposure was ~27 y (range from age 10 to 40 y). Thirty-eight of the 162 subjects were less than age 20 y at the time of their exposure. Five of the seven thyroid cancers occurred in subjects exposed at less than age 20 y. The authors noted, “It does appear that irradiation given during or before adolescence may lead to a larger percentage of thyroid cancer than when it is given later, although the numbers are rather small for such conclusions.” No thyroid cancer occurred earlier than 10 y following exposure. The elapsed time between exposure and thyroid cancer was 17 y. For this subgroup the expected number of thyroid cancers was 0.051 so the relative risk was ~137 (7/0.051). An effort was made to reconstruct individual thyroid doses. Low voltage (100 to 130 kV with a 2 or 3 mm aluminum filter) x rays were employed. Thyroid doses were based on “field size and orientation, total duration of treatment and any other available information.” Based on their tabulation, the average thyroid dose is estimated as ~8.5 Gy (range <1 to >20 Gy). Based on the relative risk and the average thyroid dose, ERR Gy –1 can be crudely estimated to be ~16. With the assumption

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that the duration of follow-up for this subset of patients is similar to that for the entire cohort (25.4 y) and a 5 y lag time, EAR is estimated to be 2.5 (104 PY Gy)–1. For subjects under the age of 20 y at the time of their exposure, Shore (1992) estimated ERR Gy –1 to be 36.5 (90 % CI 17.4 to 69) and EAR to be 9.3 [90 % CI 4.4 to 17 (104 PY Gy)–1]. For subjects over the age of 20 y at the time of their exposure, Shore (1992) estimated ERR Gy –1 to be 1.2 (90 % CI 0.2 to 3.7) and EAR to be 0.9 [90 % CI 0.1 to 2.6 (104 PY Gy)–1.] Because a higher proportion of thyroid cancers occurred in patients treated for tuberculous adenitis, the authors discussed the possibility that patients with tuberculous adenitis are predisposed to develop thyroid cancer. To try to answer this question, they attempted unsuccessfully to identify a suitable cohort of patients who had tuberculous adenitis who were treated with surgery rather than radiation. The authors thought that tuberculous adenitis was unlikely to be a predisposing factor for the development of thyroid cancer. A second issue addressed by the authors was whether smaller doses (hundreds of centigray) of radiation were more carcinogenic than larger doses (thousands of centigray) because of cell killing. They noted that no thyroid cancers were observed in the 65 patients who had been treated with large doses of external radiation for hyperthyroidism. The strengths of this study are that the cohort is well defined, information was obtained about each subject from an examination and/or review of their medical record, and individual thyroid doses were estimated. Weaknesses include low follow-up rate (59 %), small number of thyroid cancers, lack of a control group, and post hoc selection of patients with tuberculous adenitis for a more detailed analysis. F.2.2

Leiden, Netherlands Study of Irradiation for Benign Head/Neck Conditions

Van Daal et al. (1983) randomly selected 605 subjects from a cohort of ~2,400 subjects who had been treated with external radiation for benign diseases of the head and neck. The authors were able to perform clinical examinations on 257 of these 605 subjects (42 % participation rate). An additional 49 subjects responded to a questionnaire. For the 605 subjects, the most common diagnoses were tuberculous lymphadenitis (68 %) and hyperthyroidism (12 %). Individual doses were calculated for all 257 clinically-examined subjects. The mean and median thyroid dose was 10.2 and 7 Gy. The average and median follow-up since exposure for the clinicallyexamined subjects was 39 and 37 y, respectively. The average and

392 / APPENDIX F median age at irradiation was 15 and 14 y. No age ranges were provided. Ten of the 257 subjects were diagnosed with skin cancers and seven were diagnosed with thyroid cancers. The authors noted that the number of thyroid cancers observed was less than the number predicted using the 1977 UNSCEAR risk coefficient of 2 to 10 thyroid carcinomas (104 PY Gy)–1. The authors suggested that the most likely explanation for the lower risk was that the therapy was given in 7 to 10 fractions. Shore (1992) estimated ERR Gy –1 to be 0.5 (90 % CI 0.1 to 1) and EAR to be 0.4 [90 % CI 0.1 to 0.8 (104 PY Gy)–1.] Study strengths include the clinical examination program and long duration of follow-up; weaknesses include the lack of a doseresponse analysis, the potential for selection biases, small numbers of thyroid cancer, inadequate information on age of exposure, and low participation rates. F.2.3

Thyroid Cancer and Prior Radiation Therapy

Cases from the McTiernan et al. (1984) study consisted of 183 females diagnosed with thyroid cancer in western Washington State from 1974 to 1979. Three hundred and ninety-four control cases were matched by place of residence. All subjects answered a telephone interview. The principal purposes of the study were to determine (1) if the relative risk of papillary thyroid cancer following radiation therapy differed from the risk of follicular cancer, and (2) if a history of hypothyroidism (elevated TSH) was associated with the development of thyroid cancer. Forty-four cases reported prior radiation therapy; in 37 instances the therapy involved the head and neck. Twelve controls reported prior radiation therapy; in five instances the therapy involved the head and neck. Therapy was usually for benign diseases. Thyroid doses were not estimated and medical records were not reviewed to confirm the self-reported radiation therapy. The subjects with thyroid cancer were 16.5 times more likely to have a history of radiation exposure than were the controls. This relative risk did not vary with the histological type of thyroid cancer. The relative risk of radiation exposure before the age of 20 y was 42.2. Hypothyroidism was not more common in cases than in controls, but histories of goiter and thyroid nodules were much more common (RR = 6.6 and 12, respectively). Strengths of this study include a large number of thyroid cancers and an assessment of histological type, hypothyroidism, goiter, nodules, and age of exposure as possible confounders. An attempt was also made to measure the possible impact of screening

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for thyroid cancer. Weaknesses include self-reported radiation exposures and no thyroid dosimetry data. F.2.4

Gothenburg, Sweden Cervical Tuberculous Adenitis Study

Fjalling et al. (1986) studied 444 patients (average follow-up of 43 y) who were treated with x rays for cervical tuberculous adenitis. The mean age at irradiation was 19 y (range <5 to >40 y). From their dose tabulation, the average thyroid dose is estimated as ~7.3 Gy. Strengths of the study include a long follow-up time, a fairly high follow-up rate (83 %), a clinical examination of patients, and a review of pathological diagnoses. Weaknesses include the lack of a control group and no attempt to adjust for the effects of screening. The original authors did not estimate ERR or EAR, but these values were subsequently estimated by Shore (1992) to be 3.3 Gy –1 (90 % CI 2.30 to 4.60) for ERR for thyroid cancer, and 1.9 [90 % CI 1.4 to 2.7 (104 PY Gy)–1] for EAR. F.2.5

Connecticut Case-Control Study

Ron et al. (1987) published the results of a population-based case-control interview study of Connecticut subjects who had been diagnosed with thyroid cancer (159). These subjects were identified from the 251 subjects with thyroid cancer that had been reported to the Connecticut Tumor Registry between January 1, 1978 and June 30, 1980. These subjects were matched with 285 controls. Cases and controls were interviewed in their homes by trained interviewers. The questionnaire included questions about suspected risk factors, general environmental factors, source of drinking water, occupation, diet, reproductive history, and medical history. Prior radiation therapy was reported in 12 % (19) of cases and 4 % (11) of controls (RR = 2.8, 95 % CI 1.2 to 6.9). Risk was inversely related to age at exposure. Among females the number of subsequent live births appeared to increase risk, possibly due to increased TSH levels during pregnancy. Other significant risk factors included a history of benign nodules (RR = 33) or goiter (RR = 5.6). No significant associations were identified for a number of suspected risk factors including diagnostic or occupational radiation exposure, medical conditions, or drugs. F.2.6

Cervical Cancer

In this international study of 150,000 women with cervical cancer (Boice et al. 1988), 4,188 women with second cancers were identified as well as 6,880 matched controls. This study and the AtomicBomb Survivors Study are the only two studies in the pooled

394 / APPENDIX F analysis (Ron et al., 1995) that provided information about the risk of radiogenic thyroid cancer when the exposure occurred in adulthood. Cases and controls were obtained from 30 oncology centers and 19 population-based cancer registries in 14 countries. Nineteen types of second cancers were studied. Controls were matched on the basis of: (1) age at the time of diagnosis of invasive cervical carcinoma, (2) race, (3) calendar year at the time of diagnosis of invasive cervical carcinoma, and (4) second cancer-free survival at least as long as the second cancer-free period for the case. The average age at the time of diagnosis of cervical cancer was 52 y; 31 % of women were under the age of 45 y. Most patients with invasive cervical cancer were treated with radiotherapy (93 % of cases; 92 % of controls) in addition to surgery. In the early 1900s, radiotherapy was given using intracavitary radium and orthovoltage x rays (200 to 400 kVp). In the 1940s, higher energy sources such as 60Co gamma rays began to replace lower-energy orthovoltage machines. In the 1950s, megavoltage betatron machines (25 MeV) were introduced. The most recent innovation has been introduction of the use of linear accelerators. Dose reconstruction was performed for all cases and controls. There were 43 thyroid cancer cases and 81 matched controls. For cases, the mean thyroid dose was only ~110 mGy. The relative risk for developing thyroid cancer when the thyroid dose was >50 mGy was 2.35 (95 % CI 0.6 to 8.7), but this finding was not statistically significant. The authors estimated ERR Gy –1 to be 13.3 (95 % CI 0 to 77) and EAR to be 6.87 [95 % CI 2.04 to 39.2 (104 PY Gy)–1]. They noted that their estimates are higher than estimates from most studies of radiogenic thyroid cancer, especially considering the age at the time of exposure. The pooled analysis calculated ERR Gy –1 to be 34.9 (95 % CI 2.2 to infinity), but this risk was not statistically significant due to the large 95 % confidence interval. Shore (1992) estimated ERR Gy –1 to be 3.1 (90 % CI 0.5 to 6.5) and EAR to be 2.9 [90 % CI 0.5 to 6 (104 PY Gy)–1]. Strengths of this study include the large number of cancers; weaknesses include short follow-up. F.2.7

Radium-226 or X-Ray Therapy for Metropathia

Cancer mortality in relation to dose was evaluated in 4,153 women treated with intrauterine-radium treatment for uterine bleeding (Inskip et al., 1990); average follow-up was 26.5 y. Overall mortality was not significantly different from the expected mortality (SMR = 1.03), but cancer mortality was increased (SMR = 1.30). Only one thyroid cancer was observed.

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In another study, Darby et al. (1994) studied 2,067 women who were treated with x-ray therapy for excessive uterine bleeding from 1940 to 1960. Ovarian doses were ~5 Gy. The mean age at the time of exposure was 45 y. The average period of follow-up was 28 y. The mean thyroid dose was 70 mGy (90 % CI 30 to 130 mGy). Three thyroid cancers were observed and 1.71 were expected. The increase in thyroid cancers was not statistically significant. This study is not useful for estimating the risk of thyroid cancer following radiation exposure due to the small thyroid doses and the small number of thyroid cancers observed. F.2.8

Radiotherapy for Peptic Ulcer

Radiotherapy for the treatment of peptic ulcer disease was used from the 1930s until the mid-1960s to decrease excessive gastric-acid secretion. A mortality study of 3,609 patients with peptic ulcer compared cancer mortality in 1,831 patients treated with radiation with 1,778 patients treated by other means (Griem et al., 1994). The mean period of follow-up was 21.5 y. The relative risk for all cancers combined was 1.53 (95 % CI 1.3 to 1.8). Statisticallysignificant increases were noted for cancers of the stomach, pancreas and lung, as well as leukemia. The dose to the thyroid was estimated to be between 100 to 170 mGy. Two thyroid cancers were observed in patients treated with radiation and one thyroid cancer was observed in patients treated with other methods (SMR = 2.70, 95 % CI 0.2 to 32). F.2.9

Stockholm, Sweden Study of Irradiation for Benign Breast Disease

A cohort of 3,090 women who were diagnosed with benign breast disease [fibroadenomatosis (93 %), acute mastitis (4 %), chronic mastitis (3 %)] between 1925 and 1961 was identified (Mattsson et al., 1997). A total 1,216 of these women were treated with x-ray therapy. The median age at the time of exposure was 40 y (range 8 to 74). The mean length of follow-up was 27 y. Doses from scattered radiation were estimated to 14 organs in addition to the breast. The mean thyroid dose was 67 mGy (range 1 to 637 mGy). An additional 1,874 women with benign breast disease who were not treated with radiation served as the unexposed control group. A total of four thyroid cancers was observed in the exposed group and five thyroid cancers occurred in the unexposed group. This difference was not statistically significant. SIRs were also calculated using cancer rates from a tumor registry of women living in Stockholm. The thyroid cancer SIRs were 1.62 (95 % CI 0.44 to

396 / APPENDIX F 4.15) and 1.22 (95 % CI 0.39 to 2.84), respectively, for the exposed and unexposed women. The overall conclusion of the authors was that the relative risk for all solid tumors was increased (RR = 1.83, 95 % CI 1.58 to 2.13) when exposed women with benign diseases of the breast were compared to unexposed women with benign diseases of the breast. Most of the excess was due to breast cancer; a small but statistically-significant increase (RR = 1.22, 95 % CI 1 to 1.49) persisted even when breast, lymphatic and hematological cancers were excluded. SIRs were not elevated in the exposed group once breast cancer was eliminated. Strengths of this study include use of two control groups and few subjects lost to follow-up. The primary weaknesses are the small number of individual cancers observed and the small thyroid dose. F.2.10 French Study of Skin Angioma Patients The results of a French follow-up study of patients whose thyroids had been exposed to radiation during treatment for skin angiomas was published in 1993 (de Vathaire et al., 1993; 1999). The study was conducted between January 1985 and December 1987. Records of a total of 5,032 patients treated for angiomas at the Gustave Roussy Institute were reviewed. Several different treatments had been used. For two of the treatments (90Sr and x rays), the thyroid dose was delivered over a short-time interval (a few seconds to minutes). For the remaining treatments (226Ra, 192Ir, and 32P), the dose was delivered over a long duration (30 min to several hours). The thyroids of 1,650 patients were considered to have been exposed because they were treated either with (192Ir, 32P, or 90Sr/90Y) for an angioma within 5 cm of the thyroid gland or with 226Ra or x rays at any location. There were 1,480 patients who were under the age of 14 y at the time of their treatment. A letter was sent to each of the 1,480 patients asking them to participate in this study. There were 396 patients (305 females/91 males) who agreed to participate. Among of the nonresponders, half of the letters were returned because the person had moved. The mean dose to the thyroid was 0.086 Gy [±0.255 (±1 SD); 0 to 2.74 Gy (minimum to maximum)]. The median length of follow-up was 22 y (range: 11 to 42). Participants had a clinical examination of their thyroid and most had thyroid scintigraphy (341). In addition, serum thyroid hormone and thyroid antibody levels were assayed. The thyroid iodine content was measured by x-ray fluorescence in 197 patients. The major endpoint was the presence of thyroid nodules. There was a total of nine thyroid nodules discovered during the investigators’ clinical evaluation and an additional five nodules

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that were discovered in the past. All nodules were surgically removed. One was a papillary thyroid carcinoma. The frequency of thyroid nodules after 30 y was 6 % (95 % CI 1.5 to 14) and the absolute incidence rate was 1.8 (103 PY Gy)–1. Women were 3.4 times more likely than men to develop a thyroid nodule. Thyroid nodule incidence increased with dose (ERR Gy –1 = 3). ERR Gy –1 was 10 for doses given over a short duration. The incidence of thyroid goiter increased with dose (ERR Gy –1 = 4) but there was no dose-rate effect. Thyroid function was only abnormal in four patients; one hyperthyroidism and three in hypothyroidism. No relationship between thyroid hormones, antibodies or iodine content, and thyroid dose was observed. Weaknesses of this study include a low participation rate, small numbers of subjects, a relatively small average thyroid dose, and screening at only one point in time. F.2.11 Swedish Study Following X-Ray Treatment of Cervical Spine in Adults A cohort of 27,415 persons which in 1950 through 1964 had received x-ray treatment for various benign disorders in the locomotor system (such as painful arthrosis and spondylosis) was selected from three hospitals in Northern Sweden (Damber et al., 2002). A proportion of this cohort consisting of 8,144 individuals (4,075 men and 4,069 women) who received treatment to the cervical spine and, thereby, received an estimated mean dose in the thyroid gland of ~1 Gy. This thyroid dose is considerably lower than radiation given as mantle treatment for Hodgkin’s disease (40 Gy). SIR was calculated by using the Swedish Cancer Register. In the cervical spine cohort, 22 thyroid cancers were found versus 13.77 expected (SIR = 1.60, 95 % CI 1 to 2.42). The corresponding figures for women were 16 observed cases versus 9.60 expected cases (SIR = 1.67, 95 % CI 0.75 to 2.71). Most thyroid cancers (15 out of 22) were diagnosed >15 y after the exposure. In the remaining part of the total cohort (i.e., those without cervical spine exposure), no increased risk of thyroid cancer was found (SIR = 0.98, 95 % CI 0.64 to 1.38). This study is one of the few to suggest that exposure of adults to reasonably high doses (of the order of a few gray) can increase the risk of thyroid cancer but that this increase is much lower than that reported after exposure in childhood. F.3 Occupational Exposure Few occupational radiation exposure studies use thyroid cancer incidence as a primary endpoint.

398 / APPENDIX F F.3.1

Radium Dial Workers

Six hundred and eighty-six female radium dial workers from a cohort of ~1,400 female radium dial workers were included in this study. This subset was chosen because they all had total body radium burdens measured from 1958 to 1976, therefore individual thyroid doses could be calculated (Polednak, 1986). Exposures had occurred between 1913 and 1929. External and internal thyroid doses were estimated. The mean external dose to the thyroid was 98 mGy. The mean internal dose was 32.2 mGy. The author assumed a quality factor of 10 for the internal dose (alpha rays), therefore the dose equivalent to the thyroid was 419 mSv. Only two thyroid cancers were observed (0.67 expected). The author estimated ERR for thyroid cancer to be 46 [95 % CI –19 to 101 (104 PY Sv)–1]. NCRP recalculated ERR and EAR risk estimates as 6 Sv–1 and 1 (104 PY Sv)–1, respectively. Neither of these risk estimates reaches statistical significance since they are based on only two thyroid cancers. In addition, 9 adenomas, 18 nodules or nodular goiters, and 65 goiters (or unspecified thyroid abnormalities) were reported. There was no relationship between the dose and the incidence of benign thyroid abnormalities. Thyroid function tests (T3 resin uptake and free thyroxine index) were also measured in 84 subjects. There was no relationship between the results of the thyroid function tests and the thyroid dose. The strength of this study is that of an extensively studied cohort. Weaknesses include small numbers of thyroid cancers, complex thyroid dosimetry for internal dose, and potential selection biases. F.3.2

Chinese Medical X-Ray Workers

Wang et al. (1990a) followed up 27,011 diagnostic x-ray workers in China and obtained cancer incidence data. The relative risk for thyroid cancer of 1.7 among the x-ray workers was not significantly elevated. The doses to this population are not well characterized, but before about 1960 the doses were high enough that workers sometimes had depressed white cell counts (Wang et al., 1988), and the mean cumulative dose per worker has been estimated as ~0.7 Gy. Most occupational studies of thyroid cancer have only mortality data. In the most recent collaborative 15-country study of over 400,000 nuclear workers, only 17 thyroid cancer deaths were observed (Cardis et al., 2007). As a crude summary, NCRP compared the total observed (O) and expected (E) values for mortality for all occupational studies in this section and found an O/E ratio

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of 32/22.9 = 1.40 (95 % CI 0.97 to 1.9). This is suggestive of a small excess among occupationally-exposed workers, as was the (nonsignificantly) positive dose-response relationship in the largest study, that of the United Kingdom National Registry of Radiation Workers (Kendall et al., 1992). Collectively, these data are compatible with, but do not demonstrate, small risks for thyroid cancer among radiation workers. F.3.3

U.S. Hanford Site and U.K. Sellafield Site Workers

The causes of death of Hanford workers had been studied by Gilbert et al., 1993). Only three thyroid cancer deaths were observed in over 44,000 workers. Cancer mortality and morbidity for 14,282 Sellafield workers were reported by Douglas et al. (1994). Ten thousand two hundred and seventy-six workers (72.3 %) were classified as radiation workers. The mean cumulative dose for the period from 1947 to 1986 was 128.1 mSv. Statistically-significant increases in cancer deaths were noted for only three sites (pleura, thyroid, and ill-defined). Overall SMRs for all cause and cancer deaths were not elevated. Among radiation workers, a statistically-significant increase in thyroid cancer deaths was observed (O = 4, E = 1.12, SMR = 346). A nonsignificant increase in thyroid cancer deaths was also observed in nonradiation workers (O = 2, E = 0.69, SMR = 299). No statistically-significant doseresponse relationship was demonstrated for thyroid cancer mortality. A statistically-significant dose-response relationship was seen for ill-defined sites and leukemia. No analysis of thyroid cancer incidence was undertaken. F.4 Medical Diagnostic Studies F.4.1

Multiple Fluoroscopic Exams for Tuberculosis Pneumothorax

Davis et al. (1987) conducted a retrospective cohort study of 6,910 patients who had been admitted to eight Massachusetts hospitals between 1930 and 1954 for therapy of TB. Two thousand and seventy-four women and 1,277 men were treated with lung collapse therapy, which was monitored with frequent chest fluoroscopy. Women were fluoroscoped an average of 73 times and men an average of 91 times resulting in mean doses to the lungs of 0.81 Gy in women and 1.08 Gy in men. The mean age at the time of exposure was 27.9 y for women and 32.6 y for men. The mean follow-up time was 24.5 y. The remaining TB patients (2,141 women and 1,418 men) were not treated with lung collapse therapy and were not

400 / APPENDIX F exposed to frequent chest fluoroscopy. Cancer mortality rates were determined for the exposed TB patients, the unexposed TB patients, and for an age and gender-matched population. Only two thyroid cancer deaths were observed. Therefore, this study is not useful for estimating the risk of thyroid cancer following radiation exposure. F.4.2

Case-Control Studies

Two case-control studies (Inskip et al., 1995; Wingren et al., 1997) have been performed to determine the effects of medical diagnostic irradiation on thyroid cancer rates. Of these, only one (Inskip et al., 1995) used objective information from the medical records rather than anamnestic (i.e., patient recollection) reports of diagnostic irradiation with their potential for recall bias. In this study, 484 patients with thyroid cancer diagnosed from 1980 to 1992 were matched on the basis of age, gender, and county of residence with an equal number of control subjects. Individual thyroid doses from medical diagnostic x rays were determined by recording the number and types of diagnostic x ray from each case and each control’s medical record. The mean dose was 5.9 mGy in the cases and 5.7 mGy in the controls. This study did not find an association between thyroid cancer and estimated cumulative diagnostic-dose to the thyroid ( p = 0.8), number of x-ray examinations of the headneck-upper spine (trend p = 0.54), or examinations of the chestshoulders-upper GI tract ( p = 0.50). Nor was there an association for diagnostic x-ray examinations before 1960, when doses were probably much higher. Strengths of this study include a large number of thyroid cancers and determination of thyroid doses based on a review of medical records rather than on the memory of subjects. Weaknesses include small thyroid doses and a small percentage of diagnostic exposures when subjects were less than age 20 y. A pooled analysis (Wingren et al., 1997) of two Swedish casecontrol studies (Hallquist et al., 1993b; 1994; Wingren et al., 1993) was performed to estimate the risk for female papillary thyroid cancer from occupational and low-level medical radiation exposure. One hundred and eighty-six thyroid cancer cases were collected from cancer registries. An additional 426 female controls were identified. Cases and controls answered a questionnaire about lifetime residence and occupations, leisure-time exposures, prior diseases, medical treatments and drug use, diseases among relatives, smoking, dietary habits, and reproductive factors. Information about medical and dental x rays was also obtained. The odds ratio (OR) was elevated for only 1 of 19 occupations [OR = 13.1 (95 % CI 2.1 to 389)] for dentists/dental assistants. However,

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this odds ratio was based on small numbers. The odds ratio was also elevated with exposure to radiation from occupational or medical sources, less than age 50 y and more than three pregnancies. The authors reported a statistically-significant positive dose response from diagnostic x rays with the highest of four dose groups being only >1 mGy. In addition, the odds ratio for subjects having 10 or more dental x rays was 3.5 (95 % CI 1.6 to 7.6). Despite these trends, they did not estimate a dose-response coefficient.

Appendix G Previous Risk Estimates and Models Tables summarizing the findings of major periodic reviews of the effects of ionizing radiation on the thyroid (NAS/NRC, 1972; 1980; 1990; 2006; NCRP, 1985a; UNSCEAR, 1972; 1993; 2000b) are given in Section 5.2. Additional details of these reviews are discussed below. G.1 BEIR I The first BEIR report (NAS/NRC, 1972) on the effects of ionizing radiation devoted about five pages to the effects of radiation on the thyroid. The report stated that for the same absorbed dose the neoplastic effects of x rays on the thyroid are greater than the effects of 131I, that nodularity of the thyroid gland approaches 100 % in persons exposed to moderately high doses over 10 Gy during childhood, and increased nodularity of the thyroid gland is observed with doses as low as 0.2 Gy (Hempelmann, 1968). That increased incidence of thyroid cancer in atomic-bomb survivors exposed under the age of 20 y has been reported (Jablon et al., 1971; Wood et al., 1969), and that risk coefficients determined from animal experiments (Lindsay et al., 1957; Vasilenko and Klassovskii, 1967) appear to be the same order of magnitude as the risk coefficients determined in humans (Hempelmann, 1968; Hempelmann et al., 1967; Jablon et al., 1971). The conclusions of the BEIR I committee about the RBE of 131I are ambiguous. The report stated that the observations in the Marshallese children (Conard et al., 1970a) primarily exposed to radioiodines were “consistent with those noted after x-ray exposures, although the number of cases was small (one case of thyroid cancer was found).” The report also stated that “the shorter-lived radioiodine isotopes, which were 10 to 20 times more biologically effective than 131I, were responsible for much of the tissue damage.” 402

G.2 BEIR III

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There is a footnote stating that “Approximately seven-eighths of the total dose due to radioiodine came from decay of 131I and 135I, which irradiated the gland at initial dose rates of 2.8 to 6 mGy per minute, respectively.” The committee also cited studies of chromosomal aberrations in animals that suggested 131I is less effective than external exposure to x rays (Doida et al., 1971; Socolow et al., 1964), but noted that some studies had suggested that 131I and x rays are equivalent (Moore and Colvin, 1966; 1968). The BEIR committee stated that there was “…no clear-cut increase in the number of cases of thyroid cancer …” in the Cooperative Thyrotoxicosis Study. The committee attributed this failure to observe an effect to the fact that the thyroid doses were in excess of the optimal doses for tumor induction. No mention is made of the fact that most patients treated with 131I for hyperthyroidism were adults. The BEIR I committee discussed a few host factors that may affect thyroid cancer risk. They observe that “thyroid stimulating hormone (TSH) is required for induction of thyroid cancer in animals after carcinogenic stimuli.” Cell proliferation kinetics may explain why juveniles are more sensitive to the effects of radiation than adults. The committee estimated that the risk of thyroid cancer following a radiation exposure from birth to 25 to 30 y was 1.6 to 9.3 (104 PY Gy)–1. The committee stated “Since the development of the radiation-induced tumors is age-dependent, the actual risk of tumor induction during childhood is lower than this, and during adolescence is higher. There is a suggestion that cancer induction may decline as the irradiated population enter the third decade, implying a decreased risk at later ages.” The committee cautioned that little is known about the risk of cancer induction at low dose rates of <10 mGy h–1. G.2 BEIR III In 1980, BEIR III was published (NAS/NRC, 1980). This report noted that there had “been a considerable resurgence of interest in radiation-induced thyroid disease” since the NAS/NRC (1972) report. The reason for the increased interest was that the results of several large studies of populations exposed to radiation in childhood were reported in the 1970s (Conard, 1976; Maxon et al., 1977; Modan et al., 1977a; Parker et al., 1974; Schneider et al., 1978). Despite the additional information, BEIR III stated that the absolute risk previously reported in BEIR I of 1.6 to 9.3 (104 PY Gy)–1 had not changed appreciably.

404 / APPENDIX G The BEIR III report cited animal data that implied that external radiation was 10 to 80 times more effective in inducing thyroid cancer than internally administered radionuclides, particularly, those that emit beta radiation (e.g., 131I). It suggested that this difference in effectiveness may be due to micro- and macro-dose inhomogeneities related to the distribution of radioiodine in the thyroid, and that external doses as low as 65 mGy may induce thyroid cancer. BEIR III also discussed other effects such as acute thyroiditis and hypothyroidism. Acute thyroiditis occurred at threshold doses >200 Gy, only practically achievable with radionuclides such as 131I. Primary hypothyroidism was observed after external doses of ~20 Gy and 131I doses in routine clinical use of perhaps as low as 50 Gy. In its discussion of thyroid neoplasms, BEIR III stated that radiation-induced papillary thyroid cancer might have less malignant potential than spontaneously-arising cancers. The mortality for spontaneously-arising papillary thyroid cancer is <5 %. The report stated that “minimal or occult microscopic thyroid cancer” (tumors 1 cm or less in size) have “essentially no malignant potential and should not be considered cancer.” BEIR III also stated that “there is no evidence that benign thyroid neoplasia have malignant potential.” The BEIR III report reviewed studies from the University of Rochester, the University of Chicago, the Michael Reese Hospital, the Israeli Tinea Capitis Study, the New York Tinea Capitis Study, the Co-operative Hyperthyroidism Treatment Study, studies of the Marshall Islanders, studies of the atomic-bomb survivors, and studies of children exposed to fallout. For external doses in the range of 0.065 to 15 Gy, it stated that there appears to be a linear doseresponse relationship for thyroid cancer. From what little evidence that was available, BEIR III stated that there was no evidence that children treated with 131I have the same carcinogenic effect seen with external radiation (Safa et al., 1975). For thyroid adenomas, it stated that in all populations studied, the risk of thyroid nodules was about three times the risk of thyroid cancer or 12 (104 PY Gy)–1. The report discussed the effects of modifying factors. An abbreviated version of its discussion of age follows: “Age may be a weak factor in influencing the effect of radiation on the thyroid, at least with external high dose-rate irradiation. This is particularly true of thyroid neoplasia for both malignant and benign lesions. There may be some increased risk under the age of 20, but this suggestion is based on minimal data… The ‘apparent’ inverse relationship with age is

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probably mistakenly assumed, inasmuch as the nonmalignant conditions for which medical irradiation was used occurred primarily in infants and children.” BEIR III noted that there was a predominance of thyroid neoplasia in females. It stated “there may be as much as a fourfold difference in induction of thyroid neoplasia between genders. This is probably related to the fluctuating hormonal status in females, with significantly greater variations in the pituitary-thyroid axis and in secretion of thyroid-stimulating hormone than in males.” Regarding ethnicity, the report stated that there is an increased risk of radiation-induced thyroid neoplasms in Jewish populations. The effect of attained age on risk was discussed, but no clear trend was identified. The effect of fractionation on risk was unclear and a low dose rate was thought to have accounted for the decreased risk seen with 131I. The BEIR III report estimated that the risk for thyroid cancer incidence was 4 (104 PY Gy)–1 and the absolute risk for benign nodule induction was 12 (104 PY Gy)–1, that a thyroid nodule in an irradiated person is twice as likely to be cancer than it would be in an unirradiated person and that a reasonable estimate of the minimal latent period was 10 y. G.3 NCRP Report No. 80 NCRP Report No. 80, titled Induction of Thyroid Cancer by Ionizing Radiation was published in 1985 (NCRP, 1985a). NCRP derived the report’s risk estimates from studies where the thyroid dose was <15 Gy. Several studies (De Groot et al., 1983; Frohman et al., 1977; Hempelmann et al., 1975; Maxon et al., 1980; Shore et al., 1976) from North America were reviewed. In addition, NCRP reviewed the Israeli Tinea Capitis and Atomic-Bomb Survivor Studies (Prentice et al., 1982; Ron and Modan, 1984; Wakabayashi et al., 1983). Summaries of the Rochester Thymus Study (Hempelmann et al., 1975), Michael Reese Head and Neck Irradiation Study (Frohman et al., 1977), Israeli Tinea Capitis Study (Shore et al., 1976), and Atomic-Bomb Survivor Studies (Prentice et al., 1982; Wakabayashi et al., 1983) are updated in Section 4.4. The New York Tinea Capitis Study (De Groot et al., 1983; Maxon et al., 1980; Shore et al., 1976) is summarized in Appendix D.1. When the results of the North American studies were combined, NCRP Report No. 80 (NCRP, 1985a) calculated the absolute risk for thyroid cancer to be 2.5 (104 PY Gy)–1. This estimate was based on 109 thyroid cancers observed in 7,829 subjects. The mean number

406 / APPENDIX G of years at risk was 21.2; the mean thyroid dose was 2.45 Gy. The total person-years rad at risk was 42,914,880. For the Israeli Study, the absolute risk was 14 (104 PY Gy)–1 and the report noted that the risk was twice as high in subjects of Moroccan or Tunisian descent as those born in Asia, Israel, or North America. Using T65D, the report estimated that the absolute risk for thyroid cancer for women and men in the Atomic-Bomb Survivors Study was 1.9 (104 PY Gy)–1 and 0.65 (104 PY Gy)–1, respectively. No confidence intervals were provided for these estimates. NCRP (1985a) also discussed the effects of possible modifying factors. Based on animal data and data from the Atomic-Bomb Survivor Studies, age at exposure was identified as an important modifying factor. For absolute risk, the risk for females was approximately twice the risk for males. If relative risks were used, the increased risk for males and females was similar. Ethnicity was noted to affect both the baseline risk of thyroid cancer and estimates of absolute risk. The effects of other factors such as species, genetic background, ethnic groups, environment, etc., collectively referred to as heritage were also presented. Considerations of heritage lead NCRP Report No. 80 (NCRP, 1985a) to conclude that the risk estimates it derived from externally irradiated children would appear to be applicable to a non-Jewish, Caucasian population comprised equally of both genders and might overestimate the risk in black Americans while underestimating the risk in Jewish Americans. The human experience following therapeutic 131I exposure (Dobyns et al., 1974; Holm, 1984; Holm et al., 1980c; Safa et al., 1975; Tompkins, 1970) and following diagnostic 131I exposure (Hamilton et al., 1989; Holm et al., 1980a; 1980b; Rallison et al., 1974) was reviewed. NCRP (1985a) concluded that there was no human evidence that therapeutic or diagnostic 131I exposure caused thyroid cancer. Based on the upper 95 % CI of a calculation of zero risk from the therapeutic or diagnostic use of 131I, NCRP Report No. 80 (NCRP, 1985a), Section 4.3, estimated that the maximum risk from 131I to be ~0.6 to 0.7 (104 PY Gy)–1. For children, 131I was no more than one-fourth as effective as external radiation in causing thyroid cancer. In adults, 131I was no more than one-half as effective. An upper limit value of one-third was recommended for the general population until additional data became available. Animal data comparing the effectiveness of 131I to x rays in causing thyroid cancer was also reviewed (Doniach, 1950; 1957; Goldberg and Chaikoff, 1951; 1952; Goldberg et al., 1964; Lee et al., 1982; Lindsay et al., 1957; 1963; Potter et al., 1960; Walinder, 1972a; 1972b; Walinder and Sjoden, 1972). Most researchers used

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Long-Evans or Lister rats. These data are reviewed in Section 4.1. NCRP Report No. 80 (NCRP, 1985a) concluded that the data relevant to comparative risks of 131I and external radiation were relatively limited, data from other rodent strains and species would be desirable, and that extrapolation from animal data to humans remained a difficult process of uncertain validity. The value of onethird, derived from human data, was not convincingly contradicted by the animal data. The effects of 125I (De Ruiter et al., 1976; Gavron and Feige, 1972; Gillespie et al., 1970; Greig et al., 1970; Gross et al., 1967; Lewitus et al., 1971; Malone, 1975; McDougall and Greig, 1976; van Best, 1981; Vickery and Williams, 1971; Weidinger et al., 1974), 129I (Book, 1977; 1983; ICRP, 1990; NCRP, 1983), tellurium, 123I, and 99mTc were also briefly reviewed. Few data were available for use to estimate the carcinogenic risk for 125I. However, based on deterministic effects (hypothyroidism following treatment for hyperthyroidism), 125I had approximately the same effect as 131I. Therefore, NCRP (1985a) recommended using one-third for 125I as well as 131I for their effectiveness compared to external irradiation. NCRP Report No. 80 (NCRP, 1985a) concluded that 129I did not pose a meaningful threat of thyroid carcinogenesis in humans due to its very low-specific activity (Section 3.3.5). It also assumed that 123I, 133I, and 132I resulting from the decay of tellurium would be as effective as external radiation exposure in causing thyroid cancer even though tellurium itself does not concentrate significantly in the thyroid gland. For thyroid cancer mortality risk, NCRP recommended the use of an absolute risk model in the form: specific risk estimate = R u F u S u A u Y u L , where: R = F =

S

=

A Y L

= = =

(G.1)

absolute risk estimate [2.5 (104 PY Gy)–1] dose effectiveness reduction factor (one for external radiation, 132I, 133I, 135I, 99MTc, and 123I; one-third for 131I and 125I) gender factor (four-thirds for women and two-thirds for men) age factor (one for d18 y; one-half for >18 y), years at risk lethality fraction (maximum lifetime lethality of onetenth)

408 / APPENDIX G G.4 BEIR V In 1990, the BEIR V report was published (NAS/NRC, 1990). This BEIR report reanalyzed the data from the Israeli Tinea Capitis Study (Ron and Modan, 1984) and the Rochester Thymus Study (Hempelmann et al., 1975; Shore et al., 1984; 1985). For the absolute risk model, the BEIR V estimate of the risk derived from the Israeli Tinea Capitis Study ranged from 2.3 to 75.7 (104 PY Gy)–1 depending on the duration of latency, gender, age of exposure and ethnicity. For the Rochester Study, EAR varied from 0.6 to 1.8 (10–4 PY Gy)–1 depending on gender and latency. In the Israeli Tinea Capitis Study, EAR for a child over the age of 5 y was nine times greater than the risk from the Rochester Thymus Study. EAR was about three times greater for females than for males, and a pronounced effect was noted for age at exposure in the Israeli Study. EAR was 31 (104 PY Gy)–1 for subjects exposed when they were younger than age 5 y, whereas EAR was 10 (104 PY Gy)–1 for subjects exposed over age 5 y. The Israeli Study also suggested a continual increase in risk with TSE, whereas the Rochester Thymus Study was consistent with a constant EAR with TSE. For the relative risk model, the BEIR V estimate of risk at 1 Gy at age 40 y in the Israeli Tinea Capitis Study varied from 8.3 to 68.7, depending on ethnicity and age at exposure; for the Rochester Thymus Study, the relative risk at 1 Gy at age 40 y varied from 6.7 to 19.2 depending on latency. The relative risk for a child over the age of 5 y in the Israeli Tinea Capitis Study was 2.3 times greater than the risk for the same age group in the Rochester Thymus Study. The relative risk was similar for males and females and it was inversely related to the age at exposure. For the Israeli Study the relative risk was constant with TSE, whereas for the Rochester Thymus Study, the relative risk decreased with TSE. In the Israeli Study, Jews born in Israel had one-third of the thyroid cancer risk of Jews born in Asia or North Africa. BEIR V preferred the constant relative risk model with a relative risk of 8.3 at 1 Gy (95 % CI 2 to 31). It examined a number of risk modifiers (gender, age at exposure, TSE, and ethnic origin). Gender and TSE had no effect on the relative risk. Within the Israeli Cohort, there was some indication that the risk to Israeli born children was one-third of the risk of Asian or North African born children. The risk in adults was estimated to be one-half the risk in children.

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G.5 UNSCEAR Reports The UNSCEAR (1972) report briefly reviewed the findings of the previous UNSCEAR (1964) report that suggested that the incidence of thyroid cancer in atomic-bomb survivors was inversely related to the distance from the hypocenter. UNSCEAR (1972) reviewed the study of the atomic-bomb survivors of Wood et al. (1969) which concluded that “It now seems certain that thyroid cancer has increased among those atomic-bomb survivors who were proximally located to the hypocenter at the time of the bombing.” UNSCEAR (1972) observed that there are indications that thyroid cancer occurred more frequently in exposed females than in exposed males while the effect of age at the time of exposure was unclear. The report estimated the risk of thyroid cancer to 100 to 200 (106 PY Gy)–1 for males and 200 to 400 (106 PY Gy)–1 for females. UNSCEAR (1972) also reviewed autopsy studies of thyroid cancer and discussed the uncertain significance of small occult thyroid cancers. An update of the studies of the Marshall Islanders was included in the report (Conard et al., 1970a) which stated that the only health effect due to their radiation exposure was an increased incidence of thyroid tumors. UNSCEAR (1994) cited EAR estimates for thyroid cancer of 7.5 (104 PY Gy)–1 for an age-weighted population and to be ~5 (104 PY Gy)–1 for adults. The UNSCEAR (1994) risk estimates are based on the summaries of studies reviewed in NCRP Report No. 80 (NCRP, 1985a) and the UNSCEAR (1988) report. The report stated that children are twice as sensitive as adults, and that females are two to three times more sensitive than males. The report concluded that studies suggest that 131I is less carcinogenic than acute exposure to external radiation. However, these studies mostly involved adults who appear to be less sensitive to the induction of thyroid cancer than children. UNSCEAR (2000b) noted that data from most countries suggest that mortality rates from thyroid cancer are falling while incidence is increasing. The report also reviewed in detail the results of the pooled analysis of thyroid cancer after exposure to external radiation (Ron et al., 1995). Studies demonstrating an increased risk for thyroid cancer in children treated with high-dose radiation therapy for Hodgkin’s disease and other childhood cancers also are reviewed. In an attempt to learn more about the effects of fractionation and low dose rates, both studies of children exposed to diagnostic x rays and residents of high background areas were reviewed and reports of thyroid cancer risk in occupationally exposed populations were summarized. In addition, the predominantly negative

410 / APPENDIX G results of follow-up studies of the Chernobyl cleanup workers were presented. The UNSCEAR (2000b) report also discussed the risk of thyroid cancer from internal low-LET exposures. The results from recent studies of populations exposed to 131I for diagnostic and therapeutic purposes are described. Only 7 % of 34,000 patients evaluated by Hall et al. (1996b) were under the age of 20 y at the time of their exposure, and only 1 % were under the age of 10 y. The small excess in thyroid cancer observed in some of these studies appears to be due, at least in part, to underlying thyroid disease. The increased incidence of thyroid cancer in children following the Chernobyl nuclear reactor accident is reviewed. The risk appears to increase with decreasing age at exposure. Most of the thyroid cancers were clinically apparent so screening does not appear to be a major factor in the observed increase. A strong correlation between estimated exposure to radioiodines and thyroid cancer rates has been reported in several Chernobyl studies. G.6 BEIR VII With regard to RBE of internal exposure versus external lowLET exposure, BEIR VII (NAS/NRC, 2006) stated “Although there are no strong reasons to think that the dose-response from internal low-LET exposure would differ from that for external exposure, there is additional uncertainty in applying the BEIR VII risk models to estimate risk from internal exposure.” In addition, BEIR VII brings up the subject of the effectiveness per unit absorbed dose of standard x rays versus high-energy photons and suggests that “the effectiveness per unit absorbed dose of standard x rays may be about twice that from higher-energy photons” and “The effectiveness of lower-energy x rays may be even higher.” BEIR VII concludes this issue by stating “Because of the lack of adequate epidemiological data on this issue, the committee makes no specific recommendation for applying risk estimates in this report to risks from exposure to x rays. However, it may be desirable to increase the risk estimates in this Report by a factor of two or three for the purpose of estimating risk from low dose x-rays exposure.”

Appendix H Supplemental Information on Model Development The methods for calculating the coefficients for the new models in this Report were described in the original pooled analyses (Ron et al., 1995) and in two supplemental documents to NAS. These two documents are reproduced here. In some cases, the coefficients shown in Table 5.11 are slightly different from those shown in the supplemental analysis (Appendix H) because the age ranges for the calculation of these coefficients were expanded.

411

412 / APPENDIX H

H.1 Excess Relative and Absolute Risk Estimates for Pooled Analysis of Thyroid Cancer Following Exposure to External Radiation

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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414 / APPENDIX H

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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416 / APPENDIX H

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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418 / APPENDIX H

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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420 / APPENDIX H

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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422 / APPENDIX H

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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424 / APPENDIX H

H.1 EXCESS RELATIVE AND ABSOLUTE RISK ESTIMATES

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426 / APPENDIX H

H.2 SUPPLEMENTAL RISK ESTIMATES FOR POOLED ANALYSIS

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H.2 Supplemental Risk Estimates for Pooled Analysis of Thyroid Cancer Following Exposure to External Radiation

428 / APPENDIX H

H.2 SUPPLEMENTAL RISK ESTIMATES FOR POOLED ANALYSIS

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430 / APPENDIX H

Glossary absolute risk: Expression of excess risk due to exposure as the arithmetic difference between the risk among those exposed and that obtained in the absence of exposure. The resultant risk coefficient is normalized in this Report to a population base of 10,000 people and is expressed as the number of excess cases per 10,000 persons per gray per year at risk [i.e., (104 PY Gy)–1]. Absolute risk coefficients project can be modeled as a function of time since exposure (or attained age). absorbed dose (D): The energy imparted by ionizing radiation to matter per unit mass at the point of interest. In SI, the unit is joule per kilogram (J kg–1), given the special name gray (Gy) (see rad). adenoma: An ordinary benign neoplasm of epithelial tissue in which the tumor cells form glands or gland-like structures in the stroma, usually well circumscribed, tending to compress rather than infiltrate or invade adjacent tissue. air kerma: Kerma (kinetic energy released per unit mass) is the sum of the initial kinetic energies of all the charged particles liberated by uncharged particles per unit mass of a specified material. The SI unit of kerma is joule per kilogram (J kg–1), with the special name gray (Gy). Kerma can be quoted for any specified material at a point in free space or in an absorbing medium (in this case air). The equation for kerma is given in Section A.4. alpha particles: Energetic nuclei of helium atoms, consisting of two protons and two neutrons emitted spontaneously from nuclei in the decay of some radionuclides (e.g., 226 Ra). Alpha particles have very low penetrating power (e.g., typically stopped by a few centimeters of air or the outer dead layer of skin and underlying basal layer). Alpha particles are generally not a health problem unless the source is taken into the body via inhalation, ingestion or absorption, or through wounds. anaplastic: Growing without form or structure, and refers to aggressive malignant cancers. angioma: A swelling or tumor due to proliferation, with or without dilation, of the blood vessels (hemangioma) or lymphatics (lymphangioma). antibody: An immunoglobulin molecule with a specific amino acid sequence evoked in humans or other animals by an antigen, and characterized by reacting specifically with the antigen in some demonstrable way, antibody and antigen each being defined in terms of the other. ataxia-telangiectasia mutation (ATM): Patients with a mutation in the ATM gene have trouble walking as children (ataxia) and have small red spider-like veins (telangiectasias). They have an increased risk for

431

432 / GLOSSARY cancer and are hypersensitive to the effects of ionizing radiation because of defective DNA repair mechanisms. attained age: The period of time that has lapsed since birth. attributable risk: The probability that an individual will die from (or develop) cancer due to exposure to a causative agent such as radiation. Auger electron: The Auger effect is a phenomenon in physics in which the emission of an electron from an atom causes the emission of a second electron. When an electron is removed from a core level of an atom, leaving a vacancy, an electron from a higher energy level may fall into the vacancy, resulting in a release of energy. Although sometimes this energy is released in the form of an emitted photon, the energy can also be transferred to another electron, which is ejected from the atom. This second ejected electron is called an “Auger electron.” background radiation: The radiation to which a member of the population is exposed from natural sources, such as terrestrial radiation due to naturally-occurring radionuclides in the soil, cosmic radiation originating in outer space, radon, and naturally-occurring radionuclides in the human body. baseline rate of cancer: The annual cancer incidence observed in a population in the absence of the specific agent being studied; the baseline rate includes cancers of all other causes not under study, such as smoking and occupational exposures. becquerel (Bq): The SI special name for the unit [disintegration per second (s–1)] of radioactivity. 1 Bq = 1 disintegration per second; 1 Bq = 0.027 u 10–9 Ci (see radioactivity and curie). activity: conversion from conventional to SI units 1 nCi = 3.7 u 101 disintegrations/s = 37 Bq 1 PCi = 3.7 u 104 disintegrations /s = 3.7 u 104 Bq = 37 kBq 1 mCi = 3.7 u 107 disintegrations /s = 3.7 u 107 Bq = 37 MBq 1 Ci = 3.7 u 1010 transitions/s = 3.7 u 1010 Bq = 37 GBq 1 kCi = 3.7 u 1013 transitions/s = 3.7 u 1013 Bq = 37 TBq 1 MCi = 3.7 u 1016 transitions/s = 3.7 u 1016 Bq = 37 PBq 1 GCi = 3.7 u 1019 transitions/s = 3.7 u 1019 Bq = 37 EBq benign: Denoting the mild character of an illness or the nonmalignant character of a neoplasm. beta particles: Energetic electrons or positrons (i.e., positively charged electrons) emitted spontaneously from nuclei in the decay of some radionuclides (e.g., 90Sr). Beta particles are not highly penetrating (e.g., the lower-energy beta particles are typically stopped by a few millimeters of tissue; the higher-energy beta particles can be stopped by a few centimeters of tissue. biodosimetry: Use of a biological response as an indicator of a dose of an effective agent (e.g., the extent of decline in peripheral blood lymphocytes of humans exposed to ionizing radiation can be used as an indicator of the absorbed dose to the whole body from that exposure).

GLOSSARY

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biological half-life: Time required for the body to eliminate half of an administered dose of any substance by metabolic processes of elimination. brachytherapy: Radiotherapy in which the source of irradiation is placed close to the surface of the body, within a body cavity (e.g., application of radium to the cervix), or directly in tissue (i.e., interstitially). bremsstrahlung: The spectrum of photons produced by the acceleration or deceleration of high-energy electrons, particularly near the coulomb fields of nucei. calcitonin: A peptide hormone, of which eight forms in five species are known; composed of 32 amino acids and produced by the parathyroid, thyroid and thymus glands; its action is opposite to that of parathyroid hormone in that calcitonin increases deposition of calcium and phosphate in bone and lowers the level of calcium in the blood. cancer: A malignant tumor of potentially unlimited growth, capable of invading surrounding tissue or spreading to other parts of the body by metastasis. carcinogen: An agent that is associated with an increase risk of cancer. Ionizing radiation is a physical carcinogen; there are also chemical and biological carcinogens; biological carcinogens may be extrinsic (e.g., viruses) or intrinsic (genetic defects). carcinoma: A malignant tumor (cancer) of epithelial origin. case-control study: An epidemiologic study in which people with disease and a similarly composed control group are compared in terms of exposures to a putative causative agent. cervical adenitis: Inflammation of a lymph node or of a gland in the neck. cohort study: An epidemiologic study in which groups of people (the cohort) are identified with respect to the presence or absence of exposure to a disease-causing agent, and in which the outcomes of disease rates are compared; also called a follow-up study. confidence interval (CI): An interval estimate of an unknown parameter, such as a risk. A 95 % confidence interval, as an example, is constructed from a procedure that is theoretically successful in capturing the parameters of interest in 95 % of its applications. Confidence limits are the endpoints of a confidence interval. curie (Ci): Conventional special name for the unit of radioactivity equal to 3.70 × 1010 Bq (or disintegrations per second) (see becquerel). cyclotron: An accelerator that produces high-speed ions (e.g., protons and deuterons) under the influence of an alternating magnetic field for bombardment and disruption of atomic nuclei. deletions: Type of mutation in which sections of DNA or chromosomes are removed; term can refer to the removal of a single base or many bases. delta ray: Highly energetic electrons produced during inelastic collisions between ionizing radiation and atomic electrons. In a small proportion of collisions, the ejected electron receives a considerable amount of energy (i.e., >1,000 eV), allowing it to travel a long distance and leave

434 / GLOSSARY a trail of secondary ionizations. These secondary ionization events are easily observable in a cloud chamber. deterministic: A description of effects whose severity is a function of dose, for which a threshold may occur. Some examples of somatic effects believed to be deterministic are cataract induction, nonmalignant damage to the skin, hematological deficiencies, and impairment of fertility. deuteron: The nucleus of hydrogen composed of two neutrons and one proton; it thus has the one positive charge characteristic of a hydrogen nucleus. dose: In this Report, used as a generic term when not referring to a specific quantity, such as absorbed dose, equivalent dose, effective dose, and effective equivalent dose. dose and dose-rate effectiveness factor (DDREF): A judged factor by which the radiation effect, per unit of dose, caused by a given high or moderate dose of radiation received at high dose rates is reduced when doses are low or are received at low dose rates. dose-effect (dose-response) model: A mathematical formulation and description of the way the effect (or biological response) depends on dose. dose equivalent: The absorbed dose at a point in tissue, modified by the quality factor at that point. The quality factor takes into account the relative effectiveness of a type of ionizing radiation in inducing stochastic health effects (the quality factor for photons is assigned a value of unity). The SI unit for dose equivalent is the joule per kilogram (J kg–1), with the special name sievert (Sv) (see also equivalent dose). dose rate: The absorbed dose delivered per unit time. effective half-life: The time in which the radionuclide within an organ decreases by one-half as a result of radioactive decay and biological elimination. endemic: Present in a community or among a group of people; said of a disease prevailing continually in a region. epidemiology: The study of the determinants of the frequency of disease in humans. The two main types of epidemiologic studies of disease are cohort (or follow-up) studies and case-control studies. equivalent dose: Absorbed dose multiplied by the quality factor which represents, for the purpose of radiation protection and control, the effectiveness of the radiation relative to sparsely ionizing radiation. The SI unit of equivalent dose is the joule per kilogram (J kg–1), with the special name sievert (Sv) (see also radiation weighting factor and stochastic effects). etiology: The science or description of cause(s) of disease. euthyroid: A normally functioning thyroid. exposure: The condition of having contact with a physical (e.g., ionizing radiation), chemical (e.g., carcinogen), or biological (e.g., virus) agent. follicular: A spherical mass of cells usually containing a cavity. fractionation: The delivery of a given dose of radiation as several smaller doses (fractions) separated by intervals of time.

GLOSSARY

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gamma rays: Electromagnetic radiation (photons) emitted in nuclear transitions (e.g., radioactive decay of 137Cs) with energies particular to the transition. High-energy gamma rays have moderate-to-high penetrating power, are often able to penetrate deep into the body, and require thick shielding, such as up to a meter of concrete. gene nomenclature: The gene nomenclature in this Report conforms to the international standards. Each of the major organisms (e.g., humans, rats, mice) has its own nomenclature. This nomenclature can be accessed through any of several web search engines. In general, human genes are identified with capitalized, italicized letters (e.g., RET), and its expressed protein is identified with all capital letters (e.g., RET). For rats and mice, the genes are identified with an initial capitalized letter plus others in lower case and all letters italicized (e.g., Ret) and its expressed protein identified with all capitalized letters (e.g., RET). geometric mean: The geometric mean of a set of positive numbers is the exponential of the arithmetic mean of their logarithms. The geometric mean of a lognormal distribution is the exponential of the mean of the associated normal distribution. geometric standard deviation (GSD): For a log normal distribution it is the exponential of the standard deviation of the associated normal distribution (always t1). goiter: Enlargement of part or all of the thyroid gland. Graves’ disease: A disease state in which the thyroid gland enlarges and may produce excessive amounts of thyroid hormone. Currently considered to represent an autoimmune disease that is caused by the formation of abnormal immunoglobulin stimulators of the thyroid gland. gray (Gy): The SI special name for the unit (J kg–1) of absorbed dose. 1 Gy = 1 J kg–1 (see absorbed dose and rad). hemangioma: A congenital anomaly in which proliferation of blood vessels leads to a mass that resembles a neoplasm; it can occur anywhere in the body but is most frequently noticed in the skin and subcutaneous tissues. heritage: A term collectively referring to the influence of species, genetic background, ethnic group, and environment on susceptibility to thyroid carcinoma. high-LET radiation: Neutrons or charged particles, such as protons or alpha particles that produce ionizing events densely spaced on a molecular scale (e.g., >10 keV Pm–1). hyperparathyroidism: A condition due to an increase in the secretion of the parathyroids, causing elevated serum calcium, decreased serum phosphorus, and increased excretion of both calcium and phosphorus, calcium stones, and sometimes generalized osteitis fibrosa cystica. hyperthyroidism (thyrotoxicosis): Functional, metabolic state caused by excessive thyroid hormone. hypothalamus: The ventral and medial region of the diencephalons forming the walls of the ventral half of the third ventricle in the brain; it is

436 / GLOSSARY delineated from the thalamus by the hypothalamic sulcus, lying medial to the internal capsule and subthalamus. hypothyroidism: Functional, metabolic state caused by inadequate amounts of thyroid hormone. incidence: The rate at which new cases of a disease develop during some specific time period. The number of new cases of disease found in a population measured over a period of time. inferior: Situated below or directed downward; opposite of superior. in utero: In the womb (i.e., before birth). in vitro: Cell culture conditions in glass, plastic or other material-type containers. in vivo: In the living organism. iodide: The anionic form of iodine such as in potassium iodide. ionizing radiation: Radiation sufficiently energetic to dislodge electrons from an atom, thereby producing an ion pair. Ionizing radiation includes x and gamma radiation, electrons (beta radiation), alpha particles (helium nuclei), and heavier charged atomic nuclei. kilodalton (kD): 1 kD is equal to approximately the weight of 1,000 hydrogen atoms, and is equivalent to 1.66 u 10–21 g. This unit used to express the size of proteins. kiloton energy (kt): Defined strictly as 1012 calories (or 4.2 u 1019 ergs). This is approximately the amount of energy that would be released by the explosion of 1 kt (1,000 tons) of TNT (see TNT equivalent). latent period: The time period between exposure and expression of the disease. For example, after exposure to a dose of radiation, there typically is a delay of several years (the latent period) before any cancer is observed. linear energy transfer (LET): Mean energy lost by charged particles in electronic collisions per unit track length. Unit: keV Pm–1. low-LET radiation: X and gamma rays or light, charged particles such as electrons that produce sparse ionizing events far apart on a molecular scale (e.g., <10 keV Pm–1). malignant: In reference to a neoplasm, having the properties of locally invasive and destructive growth and metastasis. medullary: Relating to the medulla or marrow. megaton energy (Mt): Defined strictly as 1015 calories (or 4.2 u 1022 ergs). This is approximately the amount of energy that would be released by the explosion of 1,000 kt (106 tons) of TNT (see TNT equivalent). meta-analysis: An analysis of epidemiologic data from several studies based on data included in publications. metastasis: The shifting of a disease or its local manifestations, from one part of the body to another, as in the appearance of neoplasms in parts of the body remote from the site of the primary tumor. minimum induction period: The period of time between the exposure to a causative agent and the initial detection of an increased rate of disease.

GLOSSARY

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model: A schematic description of a system, theory or phenomenon that accounts for its known or inferred properties and may be useful for further study of its characteristics. morbidity: A diseased state. The ratio of sick to well in a community, or the frequency of the appearance of complications following a medical procedure or other treatment. mortality (rate): The frequency at which people die from a disease (e.g., a specific cancer), often expressed as the number of such deaths per 100,000 population per year. myxedema: Advanced deficiency of thyroid hormone characterized by a relatively hard edema of the subcutaneous tissue, dryness and loss of hair, subnormal temperature, hoarseness, muscle weakness, and depressed or delayed tendon reflexes; may be associated with drowsiness and slow thought processes. neoplasm: In a more literal sense, any new growth of cells or tissues. The term is customarily used with rather specific reference to a focus of intermittently or constantly progressive comparatively unlimited or uncontrolled new growth that manifests varying degrees of autonomy, and may be benign or malignant. neutrons: Uncharged particles found in the nucleus of every atom except 1H. Energetic neutrons are produced in spontaneous fission of nuclei (e.g., 252Cf), fission induced by absorption of neutrons by nuclei (e.g., 239 Pu), and by absorption of other particles by nuclei (e.g., absorption of alpha particles by 9Be). normal distribution: An unbounded symmatric probability density function. In this distribution, the median and the mode are both equal to the mean. odds ratio (OR): The ratio of the number of people incurring an event to the number of people having non-events. oncogenes: Genes that encode the potential for cancer induction. osteoporosis: A disorder in which bones become increasingly porous, brittle, and subject to fracture due to loss of calcium and other mineral components, sometimes resulting in pain, decreased height, and skeletal deformities. palpable: Perceptible to touch. papillary: Relating to, resembling, or provided with papillae (nipple-like processes). parafollicular: Associated spatially with a follicle. parathyroid gland: Any of usually four small kidney-shaped glands that lie in pairs near or within the posterior surface of the thyroid gland and secrete parathyroid hormone, a hormone necessary for the metabolism of calcium and phosphorus. penumbra: The region of partial illumination or radiation caused by light or x rays not originating from a point source. pertechnetate: Anionic form of technetium used widely in nuclear scanning (99mTcO4). photons: Quanta of electromagnetic radiation, having no charge or mass.

438 / GLOSSARY physical half-life: Time required for a radioactive atom to lost 50 % of its activity due to decay. prefixes for units: Factor 18

Prefix

Symbol

10

exa

E

1015

peta

P

1012

tera

T

10

giga

G

106

mega

M

103

kilo

k

10–1

deci

d

10–2

centi

c

10–3

milli

m

10–6

micro

P

10–9

nano

n

10–12

pico

p

10–15

femto

f

9

prevalence: The number of cases of a disease in existence at a given time per unit of population, usually 100,000 persons. promoter: An agent that is not by itself carcinogenic but can amplify the effect of a true carcinogen by increasing the probability of late-stage cellular changes necessary to complete the carcinogenic process. proportional mortality ratio: The ratio of the percentage of a specific cause of death among all deaths in a population being studied divided by the comparable percentage in a standard population. rad: The previous special unit for absorbed dose. 1 rad = 0.01 J kg–1; 100 rad = 1 Gy (see absorbed dose and gray). radiation: Energy emitted in the form of waves or particles by radioactive atoms as a result of radioactive decay or produced by artificial means, such as x-ray generators. radiation weighting factor (wR): Dimensionless weighting factor developed for purposes of radiation protection and assessing health risks in general terms that accounts for relative biological effectiveness of different types (and, in some cases, energies) of radiations in producing stochastic effects and is used to relate mean absorbed dose in an organ or tissue (T) to equivalent dose. The radiation weighting factor is intended to supersede the mean quality factor  Q and is defined with respect to the type and energy of the radiation incident on the body or, in the case of sources within the body, emitted by the source.

GLOSSARY

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radioactivity: The property of some atomic nuclei of spontaneously-emitting subatomic particles (e.g., alpha and beta particles) and/or gamma rays. radioiodine: A radioisotope of iodine (e.g., 123I). radioisotope: A radioactive atomic species of an element with the same atomic number and usually identical chemical properties. radionuclide: A radioactive element, man-made or from natural sources. radiopharmaceutical: Radioactive substance administered to a patient for diagnostic or therapeutic nuclear-medicine procedures. A radiopharmaceutical contains two parts, the radionuclide and the pharmaceutical (e.g., 99mTc DTPA). In some cases the two are one (e.g., 133Xe gas). radiotherapy: The medical specialty concerned with the use of electromagnetic or particulate radiation in the treatment of disease. relative biological effectiveness (RBE): For a specific radiation, the ratio of absorbed dose of a reference radiation required to produce a specific level of a response in a biological system to absorbed dose of radiation required to produce an equal response. Reference radiation normally is gamma or x rays with an average linear energy transfer of 3.5 keV Pm–1 or less. RBE generally depends on dose, dose per fraction if the dose is fractionated, dose rate, and biological endpoint. relative risk (RR): Expression of risk due to exposure as the ratio of the risk among the exposed to the risk among unexposed. Relative risk coefficients distribute the radiogenic excess in proportion to the natural incidence or mortality over the interval of expression. Relative risk can be modeled as a function of time since exposure (or attained age). rem: The special name for the conventional unit numerically equal to the absorbed dose (D) in rad, modified by a quality factor (Q). 1 rem = 0.01 J kg–1. In the SI system of units, it is replaced by the special name sievert (Sv), which is numerically equal to the absorbed dose (D) in gray modified by a radiation weighting factor (wR). 1 Sv = 100 rem. risk: A chance of injury, loss, or detriment; a measure of the deleterious effects that may be expected as a result of an action or inaction. risk assessment: The process by which the risks associated with an action or inaction are identified and quantified. risk estimate: The increment of the incidence or mortality rate projected to occur in a specified exposed population per unit dose for a specified exposure regimen and expression period. sievert (Sv): The SI special name for the unit (J kg–1) of dose equivalent, equivalent dose, and effective dose. 1 Sv = 1 J kg–1; the unit for weighted dose is also the sievert. SI units: Units of the International System of Units as defined by the General Conference on Weights and Measures in 1960. They are the base units, such as meter (m), kilogram (kg), second (s), and their combinations, which have special names [e.g., the unit of energy (1 J = 1 kg m2 s–2) or absorbed dose (1 Gy = 1 J kg–1)]. somatic cells: Nonreproductive cells.

440 / GLOSSARY specific activity: Activity of a given radioactive nuclide per unit mass of a compound, element, or nuclide. specific risk: A risk model that involves numerous modifications of a risk model to account for factors such as age at exposure, gender, and source of radiation. standardized morbidity rate: The ratio of the morbidity rate from a disease in the population being studied divided by the comparable rate in a standard population. standardized mortality rate (SMR): The ratio of the mortality rate from a disease in the population being studied to the comparable rate in a standard population. stochastic: Health effects, the probability of which, rather than their severity, is assumed to be a function of dose without a threshold. superior: Situated above or directed upward; opposite of inferior. syndrome: The aggregate of signs and symptoms associated with any morbid process. synergistic effect: Increased effectiveness resulting from an interaction between two agents, so that the total effect is greater than the sum of the effects of the two agents acting alone. threshold: The point at which a stimulus first produces an effect (response). thyroglobulin: A thyroid hormone-containing protein, usually stored in the colloid within the thyroid follicles. thyroid: Resembling a shield; denoting a gland (thyroid gland) and a cartilage of the larynx (thyroid cartilage) having such a shape. tinea capitis: A common form of fungus infection of the scalp caused by various species of Microsporum and Trichophyton on or within hair shafts, occurring almost exclusively in children and characterized by irregularly placed and variously sized patches of apparent baldness because of hairs breaking off at the surface of the scalp. TNT equivalent: A measure of the energy released in the detonation of a nuclear (or atomic) weapon, or in the explosion of a given quantity of fissionable material, expressed in terms of the mass of TNT which would release the same amount of energy when exploded. The TNT equivalent is usually stated in kilotons or megatons. The basis of the TNT equivalence is that the explosion of one ton of TNT is assumed to release 109 calories of energy (see kiloton energy, megaton energy, yield). tonsillitis: Inflammation of a tonsil, especially of the palatine tonsil. tumor suppressor gene: A gene that reduces the probability that a normal cell will turn into a tumor cell. A mutation or deletion of a tumor suppressor gene could increase the probability of formation of a tumor. variability: The variation of a quantity among members of a population. Such variation is inherent in nature and is often assumed to be random; it can then be represented by a frequency distribution. weighted dose: The dose, roughly adjusted to account for the increased effectiveness of the small neutron absorbed dose contribution. The

GLOSSARY

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weighted dose equals the gamma-ray dose to a specified organ plus the neutron absorbed dose multiplied by a weighting factor that has usually been set equal to 10 in analyses by the Radiation Effects Research Foundation. Unit: 1 Sv = 1 J kg–1. x ray: Electromagnetic radiation emitted in de-excitation of bound atomic electrons, and frequently occurring in decay of radionuclides, referred to as characteristic x rays, or electromagnetic radiation produced in deceleration of energetic charged particles (e.g., beta radiation) in passing through matter, referred to as continuous x rays or bremsstrahlung. years at risk: The difference between the time that has elapsed between the exposure to the presumed causative agent and the time that the endpoint is observed minus the minimum latent period. yield (or energy yield): The total effective energy released in a nuclear (or atomic) explosion. It is usually expressed in terms of the equivalent tonnage of TNT required to produce the same energy release in an explosion. The total energy yield is manifested as nuclear radiation, thermal radiation, and shock (and blast) energy, the actual distribution being dependent upon the medium in which the explosion occurs (primarily) and also upon the type of weapon and the time after detonation (see TNT equivalent).

Abbreviations and Acronyms AHS BED BEIR CI CIDER

CTV DNA DDREF dL DS02

DS86

EAR EBRT EOR ERR FNA GSD HTDS IOM kD kt LET MIRD MIT mIU L–1 mRNA Mt MT NTS OR PE PTV PY R

Adult Health Study biologically effective dose Biological Effects of Ionizing Radiation (NAS/NRC) confidence interval Calculation of Individual Doses from Environmental Radionuclides computer program developed by the Hanford Environmental Dose Reconstruction Project clinical target volume deoxyribonucleic acid; the genetic material of cells dose and dose-rate effectiveness factor deciliter (100 mL) 2002 Dosimetry System (RERF Reassessment of the Atomic Bomb Radiation Dosimetry for Hiroshima and Nagasaki: Dosimetry System 2002) 1986 Dosimetry System (RERF US-Japan Joint Reassessment of Atomic Bomb Radiation Dosimetry in Hiroshima and Nagasaki) excess absolute risk external beam radiation therapy excess odds ratio excess relative risk fine-needle aspiration geometric standard deviation Hanford Thyroid Disease Study Institute of Medicine kilodalton kiloton linear energy transfer medical internal radiation dose Massachusetts Institute of Technology milli-international units per liter messenger ribonucleic acid megaton methylthiouracil Nevada Test Site odds ratio protective effect planned target volume person-year(s) roentgen

442

ABBREVIATIONS AND ACRONYMS

RaEq RAIU RBE RERF RET/PTC RNA RR SEER SI SIR SMR T3 T4 T65D TB TLD TSE TSH TSI

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radium equivalent activity (expressed in Bq kg–1) radioactive iodine uptake relative biological effectiveness Radiation Effects Research Foundation an oncogene; rearranged in transformation/papillary thyroid carcinoma ribonucleic acid relative risk Surveillance Epidemiology and End Results (NCI) Systeme International d’ Unites (International System of Quantities and Units) standardized incidence ratio standardized mortality ratio triiodothyronine tetraiodothyronine (thyroxine) Tentative 1965 Dose [Atomic Bomb Casualty Commission (RERF) dosimetry system] tuberculosis thermoluminescent dosimeter time since exposure thyroid stimulating hormone thyroid stimulating immunoglobulin

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The NCRP The National Council on Radiation Protection and Measurements is a nonprofit corporation chartered by Congress in 1964 to: 1. Collect, analyze, develop and disseminate in the public interest information and recommendations about (a) protection against radiation and (b) radiation measurements, quantities and units, particularly those concerned with radiation protection. 2. Provide a means by which organizations concerned with the scientific and related aspects of radiation protection and of radiation quantities, units and measurements may cooperate for effective utilization of their combined resources, and to stimulate the work of such organizations. 3. Develop basic concepts about radiation quantities, units and measurements, about the application of these concepts, and about radiation protection. 4. Cooperate with the International Commission on Radiological Protection, the International Commission on Radiation Units and Measurements, and other national and international organizations, governmental and private, concerned with radiation quantities, units and measurements and with radiation protection. The Council is the successor to the unincorporated association of scientists known as the National Committee on Radiation Protection and Measurements and was formed to carry on the work begun by the Committee in 1929. The participants in the Council’s work are the Council members and members of scientific and administrative committees. Council members are selected solely on the basis of their scientific expertise and serve as individuals, not as representatives of any particular organization. The scientific committees, composed of experts having detailed knowledge and competence in the particular area of the committee's interest, draft proposed recommendations. These are then submitted to the full membership of the Council for careful review and approval before being published. The following comprise the current officers and membership of the Council:

Officers President Senior Vice President Secretary and Treasurer

512

Thomas S. Tenforde Kenneth R. Kase David A. Schauer

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Members John F. Ahearne Edward S. Amis, Jr. Sally A. Amundson Kimberly E. Applegate Benjamin R. Archer Stephen Balter Steven M. Becker Joel S. Bedford Eleanor A. Blakely William F. Blakely John D. Boice, Jr. Wesley E. Bolch Thomas B. Borak Andre Bouville Leslie A. Braby David J. Brenner James A. Brink Antone L. Brooks Jerrold T. Bushberg John F. Cardella Stephanie K. Carlson Charles E. Chambers Polly Y. Chang S.Y. Chen Kelly L. Classic Mary E. Clark Michael L. Corradini Allen G. Croff Paul M. DeLuca David A. Eastmond Stephen A. Feig John R. Frazier Donald P. Frush

Ronald E. Goans Robert L. Goldberg Raymond A. Guilmette Roger W. Harms Kathryn Held F. Owen Hoffman Roger W. Howell Timothy J. Jorgensen Kenneth R. Kase Ann R. Kennedy William E. Kennedy, Jr. David C. Kocher Ritsuko Komaki Amy Kronenberg Susan M. Langhorst Edwin M. Leidholdt Howard L. Liber James C. Lin Jill A. Lipoti John B. Little Paul A. Locke Jay H. Lubin C. Douglas Maynard Debra McBaugh Ruth E. McBurney Cynthia H. McCollough Fred A. Mettler, Jr. Charles W. Miller Donald L. Miller William H. Miller William F. Morgan Stephen V. Musolino David S. Myers Bruce A. Napier

Gregory A. Nelson Carl J. Paperiello Terry C. Pellmar R. Julian Preston Jerome C. Puskin Abram Recht Allan C.B. Richardson Michael T. Ryan Thomas M. Seed J. Anthony Seibert Stephen M. Seltzer Edward A. Sickles Steven L. Simon Paul Slovic Christopher G. Soares Daniel J. Strom Thomas S. Tenforde Julie E.K. Timins Richard E. Toohey Lawrence W. Townsend Fong Y. Tsai Richard J. Vetter Chris G. Whipple Robert C. Whitcomb, Jr. Stuart C. White J. Frank Wilson Susan D. Wiltshire Gayle E. Woloschak Shiao Y. Woo Andrew J. Wyrobek X. George Xu R. Craig Yoder Marco A. Zaider

Distinguished Emeritus Members Warren K. Sinclair, President Emeritus; Charles B. Meinhold, President Emeritus S. James Adelstein, Honorary Vice President W. Roger Ney, Executive Director Emeritus William M. Beckner, Executive Director Emeritus A. Alan Moghissi R.J. Michael Fry Seymour Abrahamson Wesley L. Nyborg Thomas F. Gesell Lynn R. Anspaugh John W. Poston, Sr. Ethel S. Gilbert John A. Auxier Andrew K. Poznanski Robert O. Gorson William J. Bair Genevieve S. Roessler Joel E. Gray Harold L. Beck Marvin Rosenstein Arthur W. Guy Bruce B. Boecker Lawrence N. Rothenberg Eric J. Hall Robert L. Brent Henry D. Royal Naomi H. Harley Randall S. Caswell William J. Schull William R. Hendee J. Donald Cossairt Roy E. Shore Donald G. Jacobs James F. Crow John E. Till Bernd Kahn Gerald D. Dodd Robert L. Ullrich Charles E. Land Sarah S. Donaldson Arthur C. Upton Roger O. McClellan William P. Dornsife F. Ward Whicker Barbara J. McNeil Keith F. Eckerman Marvin C. Ziskin Kenneth L. Miller Thomas S. Ely Dade W. Moeller

514 / THE NCRP Lauriston S. Taylor Lecturers Dade W. Moeller (2008) Radiation Standards, Dose/Risk Assessments, Public Interactions, and Yucca Mountain: Thinking Outside the Box Patricia W. Durbin (2007) The Quest for Therapeutic Actinide Chelators Robert L. Brent (2006) Fifty Years of Scientific Research: The Importance of Scholarship and the Influence of Politics and Controversy John B. Little (2005) Nontargeted Effects of Radiation: Implications for Low-Dose Exposures Abel J. Gonzalez (2004) Radiation Protection in the Aftermath of a Terrorist Attack Involving Exposure to Ionizing Radiation Charles B. Meinhold (2003) The Evolution of Radiation Protection: From Erythema to Genetic Risks to Risks of Cancer to ? R. Julian Preston (2002) Developing Mechanistic Data for Incorporation into Cancer Risk Assessment: Old Problems and New Approaches Wesley L. Nyborg (2001) Assuring the Safety of Medical Diagnostic Ultrasound S. James Adelstein (2000) Administered Radioactivity: Unde Venimus Quoque Imus Naomi H. Harley (1999) Back to Background Eric J. Hall (1998) From Chimney Sweeps to Astronauts: Cancer Risks in the Workplace William J. Bair (1997) Radionuclides in the Body: Meeting the Challenge! Seymour Abrahamson (1996) 70 Years of Radiation Genetics: Fruit Flies, Mice and Humans Albrecht Kellerer (1995) Certainty and Uncertainty in Radiation Protection R.J. Michael Fry (1994) Mice, Myths and Men Warren K. Sinclair (1993) Science, Radiation Protection and the NCRP Edward W. Webster (1992) Dose and Risk in Diagnostic Radiology: How Big? How Little? Victor P. Bond (1991) When is a Dose Not a Dose? J. Newell Stannard (1990) Radiation Protection and the Internal Emitter Saga Arthur C. Upton (1989) Radiobiology and Radiation Protection: The Past Century and Prospects for the Future Bo Lindell (1988) How Safe is Safe Enough? Seymour Jablon (1987) How to be Quantitative about Radiation Risk Estimates Herman P. Schwan (1986) Biological Effects of Non-ionizing Radiations: Cellular Properties and Interactions John H. Harley (1985) Truth (and Beauty) in Radiation Measurement Harald H. Rossi (1984) Limitation and Assessment in Radiation Protection Merril Eisenbud (1983) The Human Environment—Past, Present and Future Eugene L. Saenger (1982) Ethics, Trade-Offs and Medical Radiation James F. Crow (1981) How Well Can We Assess Genetic Risk? Not Very Harold O. Wyckoff (1980) From “Quantity of Radiation” and “Dose” to “Exposure” and “Absorbed Dose”—An Historical Review Hymer L. Friedell (1979) Radiation Protection—Concepts and Trade Offs Sir Edward Pochin (1978) Why be Quantitative about Radiation Risk Estimates? Herbert M. Parker (1977) The Squares of the Natural Numbers in Radiation Protection

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Currently, the following committees are actively engaged in formulating recommendations:

Program Area Committee 1: Basic Criteria, Epidemiology, Radiobiology, and Risk SC 1-13 Impact of Individual Susceptibility and Previous Radiation Exposure on Radiation Risk for Astronauts SC 1-15 Radiation Safety in NASA Lunar Missions’ SC 1-16 Uncertainties in the Estimation of Radiation Risks and Probability of Disease Causation SC 1-17 Second Cancers and Cardiopulmonary Effects After Radiotherapy SC 85 Risk of Lung Cancer from Radon

Program Area Committee 2: Operational Radiation Safety SC 2-2 Key Decision Points and Information Needed by Decision Makers in the Aftermath of a Nuclear or Radiological Terrorism Incident SC 2-3 Radiation Safety Issues for Image-Guided Interventional Medical Procedures SC 2-4 Self Assessment of Radiation Safety Programs

Program Area Committee 3: Nuclear and Radiological Security and Safety Program Area Committee 4: Radiation Protection in Medicine SC 4-1 Management of Persons Contaminated with Radionuclides SC 4-2 Population Monitoring and Decontamination Following a Nuclear/ Radiological Incident SC 4-3 Diagnostic Reference Levels in Medical Imaging: Recommendations for Application in the United States SC 4-4 Risks of Ionizing Radiation to the Developing Embryo, Fetus and Nursing Infant

Program Area Committee 5: Environmental Radiation and Radioactive Waste Issues SC 64-22 Design of Effective Effluent and Environmental Monitoring Programs

Program Area Committee 6: Radiation Measurements and Dosimetry SC 6-2 Radiation Exposure of the U.S. Population SC 6-3 Uncertainties in Internal Radiation Dosimetry SC 6-4 Fundamental Principles of Dose Reconstruction In recognition of its responsibility to facilitate and stimulate cooperation among organizations concerned with the scientific and related aspects of radiation protection and measurement, the Council has created a category of NCRP Collaborating Organizations. Organizations or groups of organizations that are national or international in scope and are concerned with scientific problems involving radiation quantities, units, measurements and effects, or radiation protection may be admitted to collaborating status by the Council. Collaborating Organizations provide a means by which NCRP can gain input into its activities from a wider segment of society. At the same time, the relationships with the Collaborating Organizations facilitate wider dissemination of information about the Council's activities, interests and concerns. Collaborating Organizations have the opportunity to comment on draft reports (at the

516 / THE NCRP time that these are submitted to the members of the Council). This is intended to capitalize on the fact that Collaborating Organizations are in an excellent position to both contribute to the identification of what needs to be treated in NCRP reports and to identify problems that might result from proposed recommendations. The present Collaborating Organizations with which NCRP maintains liaison are as follows: American Academy of Dermatology American Academy of Environmental Engineers American Academy of Health Physics American Academy of Orthopaedic Surgeons American Association of Physicists in Medicine American Bracytherapy Society American College of Cardiology American College of Medical Physics American College of Nuclear Physicians American College of Occupational and Environmental Medicine American College of Radiology American Conference of Governmental Industrial Hygienists American Dental Association American Industrial Hygiene Association American Institute of Ultrasound in Medicine American Medical Association American Nuclear Society American Pharmaceutical Association American Podiatric Medical Association American Public Health Association American Radium Society American Roentgen Ray Society American Society for Radiation Oncology American Society of Emergency Radiology American Society of Health-System Pharmacists American Society of Nuclear Cardiology American Society of Radiologic Technologists Association of Educators in Imaging and Radiological Sciences Association of University Radiologists Bioelectromagnetics Society Campus Radiation Safety Officers College of American Pathologists Conference of Radiation Control Program Directors, Inc. Council on Radionuclides and Radiopharmaceuticals Defense Threat Reduction Agency Electric Power Research Institute Federal Aviation Administration Federal Communications Commission Federal Emergency Management Agency Genetics Society of America Health Physics Society Institute of Electrical and Electronics Engineers, Inc. Institute of Nuclear Power Operations

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International Brotherhood of Electrical Workers National Aeronautics and Space Administration National Association of Environmental Professionals National Center for Environmental Health/Agency for Toxic Substances National Electrical Manufacturers Association National Institute for Occupational Safety and Health National Institute of Standards and Technology Nuclear Energy Institute Office of Science and Technology Policy Paper, Allied-Industrial, Chemical and Energy Workers International Union Product Stewardship Institute Radiation Research Society Radiological Society of North America Society for Cardiovascular Angiography and Interventions Society for Pediatric Radiology Society for Risk Analysis Society of Cardiovascular Computed Tomography Society of Chairmen of Academic Radiology Departments Society of Interventional Radiology Society of Nuclear Medicine Society of Radiologists in Ultrasound Society of Skeletal Radiology U.S. Air Force U.S. Army U.S. Coast Guard U.S. Department of Energy U.S. Department of Housing and Urban Development U.S. Department of Labor U.S. Department of Transportation U.S. Environmental Protection Agency U.S. Navy U.S. Nuclear Regulatory Commission U.S. Public Health Service Utility Workers Union of America

NCRP has found its relationships with these organizations to be extremely valuable to continued progress in its program. Another aspect of the cooperative efforts of NCRP relates to the Special Liaison relationships established with various governmental organizations that have an interest in radiation protection and measurements. This liaison relationship provides: (1) an opportunity for participating organizations to designate an individual to provide liaison between the organization and NCRP; (2) that the individual designated will receive copies of draft NCRP reports (at the time that these are submitted to the members of the Council) with an invitation to comment, but not vote; and (3) that new NCRP efforts might be discussed with liaison individuals as appropriate, so that they might have an opportunity to make suggestions on new studies and related matters. The following organizations participate in the Special Liaison Program: Australian Radiation Laboratory

518 / THE NCRP Bundesamt fur Strahlenschutz (Germany) Canadian Nuclear Safety Commission Central Laboratory for Radiological Protection (Poland) China Institute for Radiation Protection Commissariat a l’Energie Atomique (France) Commonwealth Scientific Instrumentation Research Organization (Australia) European Commission Health Council of the Netherlands Health Protection Agency International Commission on Non-ionizing Radiation Protection International Commission on Radiation Units and Measurements Japanese Nuclear Safety Commission Japan Radiation Council Korea Institute of Nuclear Safety Russian Scientific Commission on Radiation Protection South African Forum for Radiation Protection World Association of Nuclear Operators World Health Organization, Radiation and Environmental Health NCRP values highly the participation of these organizations in the Special Liaison Program. The Council also benefits significantly from the relationships established pursuant to the Corporate Sponsor's Program. The program facilitates the interchange of information and ideas and corporate sponsors provide valuable fiscal support for the Council's program. This developing program currently includes the following Corporate Sponsors: Duke Energy Corporation GE Healthcare Global Dosimetry Solutions, Inc. Landauer, Inc. Nuclear Energy Institute The Council's activities have been made possible by the voluntary contribution of time and effort by its members and participants and the generous support of the following organizations: 3M 3M Health Physics Services Agfa Corporation Alfred P. Sloan Foundation Alliance of American Insurers American Academy of Dermatology American Academy of Health Physics American Academy of Oral and Maxillofacial Radiology American Association of Physicists in Medicine American Cancer Society American College of Medical Physics American College of Nuclear Physicians American College of Occupational and Environmental Medicine

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American College of Radiology American College of Radiology Foundation American Dental Association American Healthcare Radiology Administrators American Industrial Hygiene Association American Insurance Services Group American Medical Association American Nuclear Society American Osteopathic College of Radiology American Podiatric Medical Association American Public Health Association American Radium Society American Roentgen Ray Society American Society for Radiation Oncology American Society for Therapeutic Radiology and Oncology American Society of Radiologic Technologists American Veterinary Medical Association American Veterinary Radiology Society Association of Educators in Radiological Sciences, Inc. Association of University Radiologists Battelle Memorial Institute Canberra Industries, Inc. Chem Nuclear Systems Center for Devices and Radiological Health College of American Pathologists Committee on Interagency Radiation Research and Policy Coordination Commonwealth Edison Commonwealth of Pennsylvania Consolidated Edison Consumers Power Company Council on Radionuclides and Radiopharmaceuticals Defense Nuclear Agency Defense Threat Reduction Agency Eastman Kodak Company Edison Electric Institute Edward Mallinckrodt, Jr. Foundation EG&G Idaho, Inc. Electric Power Research Institute Electromagnetic Energy Association Federal Emergency Management Agency Florida Institute of Phosphate Research Florida Power Corporation Fuji Medical Systems, U.S.A., Inc. Genetics Society of America Global Dosimetry Solutions Health Effects Research Foundation (Japan) Health Physics Society ICN Biomedicals, Inc. Institute of Nuclear Power Operations James Picker Foundation

520 / THE NCRP Martin Marietta Corporation Motorola Foundation National Aeronautics and Space Administration National Association of Photographic Manufacturers National Cancer Institute National Electrical Manufacturers Association National Institute of Standards and Technology New York Power Authority Philips Medical Systems Picker International Public Service Electric and Gas Company Radiation Research Society Radiological Society of North America Richard Lounsbery Foundation Sandia National Laboratory Siemens Medical Systems, Inc. Society of Nuclear Medicine Society of Pediatric Radiology Southern California Edison Company U.S. Department of Energy U.S. Department of Labor U.S. Environmental Protection Agency U.S. Navy U.S. Nuclear Regulatory Commission Victoreen, Inc. Westinghouse Electric Corporation Initial funds for publication of NCRP reports were provided by a grant from the James Picker Foundation. NCRP seeks to promulgate information and recommendations based on leading scientific judgment on matters of radiation protection and measurement and to foster cooperation among organizations concerned with these matters. These efforts are intended to serve the public interest and the Council welcomes comments and suggestions on its reports or activities.

NCRP Publications NCRP publications can be obtained online in both hard- and soft-copy (downloadable PDF) formats at http://NCRPpublications.org. Professional societies can arrange for discounts for their members by contacting NCRP. Additional information on NCRP publications may be obtained from the NCRP website (http://NCRPonline.org) or by telephone (800-229-2652, ext. 25) and fax (301-907-8768). The mailing address is: NCRP Publications 7910 Woodmont Avenue Suite 400 Bethesda, MD 20814-3095 Abstracts of NCRP reports published since 1980, abstracts of all NCRP commentaries, and the text of all NCRP statements are available at the NCRP website. Currently available publications are listed below.

NCRP Reports No.

Title 8 22

25 27 30 32 35 36 37 38 40 41 42 44 46

Control and Removal of Radioactive Contamination in Laboratories (1951) Maximum Permissible Body Burdens and Maximum Permissible Concentrations of Radionuclides in Air and in Water for Occupational Exposure (1959) [includes Addendum 1 issued in August 1963] Measurement of Absorbed Dose of Neutrons, and of Mixtures of Neutrons and Gamma Rays (1961) Stopping Powers for Use with Cavity Chambers (1961) Safe Handling of Radioactive Materials (1964) Radiation Protection in Educational Institutions (1966) Dental X-Ray Protection (1970) Radiation Protection in Veterinary Medicine (1970) Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides (1970) Protection Against Neutron Radiation (1971) Protection Against Radiation from Brachytherapy Sources (1972) Specification of Gamma-Ray Brachytherapy Sources (1974) Radiological Factors Affecting Decision-Making in a Nuclear Attack (1974) Krypton-85 in the Atmosphere—Accumulation, Biological Significance, and Control Technology (1975) Alpha-Emitting Particles in Lungs (1975)

521

522 / NCRP PUBLICATIONS 47 49 50 52 54 55 57 58 60 61 62 63 64 65 67 68 69 70 72 73 74 75 76

77 78 79 80 81 82

Tritium Measurement Techniques (1976) Structural Shielding Design and Evaluation for Medical Use of X Rays and Gamma Rays of Energies Up to 10 MeV (1976) Environmental Radiation Measurements (1976) Cesium-137 from the Environment to Man: Metabolism and Dose (1977) Medical Radiation Exposure of Pregnant and Potentially Pregnant Women (1977) Protection of the Thyroid Gland in the Event of Releases of Radioiodine (1977) Instrumentation and Monitoring Methods for Radiation Protection (1978) A Handbook of Radioactivity Measurements Procedures, 2nd ed. (1985) Physical, Chemical, and Biological Properties of Radiocerium Relevant to Radiation Protection Guidelines (1978) Radiation Safety Training Criteria for Industrial Radiography (1978) Tritium in the Environment (1979) Tritium and Other Radionuclide Labeled Organic Compounds Incorporated in Genetic Material (1979) Influence of Dose and Its Distribution in Time on Dose-Response Relationships for Low-LET Radiations (1980) Management of Persons Accidentally Contaminated with Radionuclides (1980) Radiofrequency Electromagnetic Fields—Properties, Quantities and Units, Biophysical Interaction, and Measurements (1981) Radiation Protection in Pediatric Radiology (1981) Dosimetry of X-Ray and Gamma-Ray Beams for Radiation Therapy in the Energy Range 10 keV to 50 MeV (1981) Nuclear Medicine—Factors Influencing the Choice and Use of Radionuclides in Diagnosis and Therapy (1982) Radiation Protection and Measurement for Low-Voltage Neutron Generators (1983) Protection in Nuclear Medicine and Ultrasound Diagnostic Procedures in Children (1983) Biological Effects of Ultrasound: Mechanisms and Clinical Implications (1983) Iodine-129: Evaluation of Releases from Nuclear Power Generation (1983) Radiological Assessment: Predicting the Transport, Bioaccumulation, and Uptake by Man of Radionuclides Released to the Environment (1984) Exposures from the Uranium Series with Emphasis on Radon and Its Daughters (1984) Evaluation of Occupational and Environmental Exposures to Radon and Radon Daughters in the United States (1984) Neutron Contamination from Medical Electron Accelerators (1984) Induction of Thyroid Cancer by Ionizing Radiation (1985) Carbon-14 in the Environment (1985) SI Units in Radiation Protection and Measurements (1985)

NCRP PUBLICATIONS

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83 The Experimental Basis for Absorbed-Dose Calculations in Medical Uses of Radionuclides (1985) 84 General Concepts for the Dosimetry of Internally Deposited Radionuclides (1985) 86 Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Fields (1986) 87 Use of Bioassay Procedures for Assessment of Internal Radionuclide Deposition (1987) 88 Radiation Alarms and Access Control Systems (1986) 89 Genetic Effects from Internally Deposited Radionuclides (1987) 90 Neptunium: Radiation Protection Guidelines (1988) 92 Public Radiation Exposure from Nuclear Power Generation in the United States (1987) 93 Ionizing Radiation Exposure of the Population of the United States (1987) 94 Exposure of the Population in the United States and Canada from Natural Background Radiation (1987) 95 Radiation Exposure of the U.S. Population from Consumer Products and Miscellaneous Sources (1987) 96 Comparative Carcinogenicity of Ionizing Radiation and Chemicals (1989) 97 Measurement of Radon and Radon Daughters in Air (1988) 99 Quality Assurance for Diagnostic Imaging (1988) 100 Exposure of the U.S. Population from Diagnostic Medical Radiation (1989) 101 Exposure of the U.S. Population from Occupational Radiation (1989) 102 Medical X-Ray, Electron Beam and Gamma-Ray Protection for Energies Up to 50 MeV (Equipment Design, Performance and Use) (1989) 103 Control of Radon in Houses (1989) 104 The Relative Biological Effectiveness of Radiations of Different Quality (1990) 105 Radiation Protection for Medical and Allied Health Personnel (1989) 106 Limit for Exposure to “Hot Particles” on the Skin (1989) 107 Implementation of the Principle of As Low As Reasonably Achievable (ALARA) for Medical and Dental Personnel (1990) 108 Conceptual Basis for Calculations of Absorbed-Dose Distributions (1991) 109 Effects of Ionizing Radiation on Aquatic Organisms (1991) 110 Some Aspects of Strontium Radiobiology (1991) 111 Developing Radiation Emergency Plans for Academic, Medical or Industrial Facilities (1991) 112 Calibration of Survey Instruments Used in Radiation Protection for the Assessment of Ionizing Radiation Fields and Radioactive Surface Contamination (1991) 113 Exposure Criteria for Medical Diagnostic Ultrasound: I. Criteria Based on Thermal Mechanisms (1992) 114 Maintaining Radiation Protection Records (1992) 115 Risk Estimates for Radiation Protection (1993) 116 Limitation of Exposure to Ionizing Radiation (1993)

524 / NCRP PUBLICATIONS 117 Research Needs for Radiation Protection (1993) 118 Radiation Protection in the Mineral Extraction Industry (1993) 119 A Practical Guide to the Determination of Human Exposure to Radiofrequency Fields (1993) 120 Dose Control at Nuclear Power Plants (1994) 121 Principles and Application of Collective Dose in Radiation Protection (1995) 122 Use of Personal Monitors to Estimate Effective Dose Equivalent and Effective Dose to Workers for External Exposure to Low-LET Radiation (1995) 123 Screening Models for Releases of Radionuclides to Atmosphere, Surface Water, and Ground (1996) 124 Sources and Magnitude of Occupational and Public Exposures from Nuclear Medicine Procedures (1996) 125 Deposition, Retention and Dosimetry of Inhaled Radioactive Substances (1997) 126 Uncertainties in Fatal Cancer Risk Estimates Used in Radiation Protection (1997) 127 Operational Radiation Safety Program (1998) 128 Radionuclide Exposure of the Embryo/Fetus (1998) 129 Recommended Screening Limits for Contaminated Surface Soil and Review of Factors Relevant to Site-Specific Studies (1999) 130 Biological Effects and Exposure Limits for “Hot Particles” (1999) 131 Scientific Basis for Evaluating the Risks to Populations from Space Applications of Plutonium (2001) 132 Radiation Protection Guidance for Activities in Low-Earth Orbit (2000) 133 Radiation Protection for Procedures Performed Outside the Radiology Department (2000) 134 Operational Radiation Safety Training (2000) 135 Liver Cancer Risk from Internally-Deposited Radionuclides (2001) 136 Evaluation of the Linear-Nonthreshold Dose-Response Model for Ionizing Radiation (2001) 137 Fluence-Based and Microdosimetric Event-Based Methods for Radiation Protection in Space (2001) 138 Management of Terrorist Events Involving Radioactive Material (2001) 139 Risk-Based Classification of Radioactive and Hazardous Chemical Wastes (2002) 140 Exposure Criteria for Medical Diagnostic Ultrasound: II. Criteria Based on all Known Mechanisms (2002) 141 Managing Potentially Radioactive Scrap Metal (2002) 142 Operational Radiation Safety Program for Astronauts in Low-Earth Orbit: A Basic Framework (2002) 143 Management Techniques for Laboratories and Other Small Institutional Generators to Minimize Off-Site Disposal of Low-Level Radioactive Waste (2003) 144 Radiation Protection for Particle Accelerator Facilities (2003) 145 Radiation Protection in Dentistry (2003)

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146 Approaches to Risk Management in Remediation of Radioactively Contaminated Sites (2004) 147 Structural Shielding Design for Medical X-Ray Imaging Facilities (2004) 148 Radiation Protection in Veterinary Medicine (2004) 149 A Guide to Mammography and Other Breast Imaging Procedures (2004) 150 Extrapolation of Radiation-Induced Cancer Risks from Nonhuman Experimental Systems to Humans (2005) 151 Structural Shielding Design and Evaluation for Megavoltage X- and Gamma-Ray Radiotherapy Facilities (2005) 152 Performance Assessment of Near-Surface Facilities for Disposal of Low-Level Radioactive Waste (2005) 153 Information Needed to Make Radiation Protection Recommendations for Space Missions Beyond Low-Earth Orbit (2006) 154 Cesium-137 in the Environment: Radioecology and Approaches to Assessment and Management (2006) 155 Management of Radionuclide Therapy Patients (2006) 156 Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment (2006) 157 Radiation Protection in Educational Institutions (2007) 158 Uncertainties in the Measurement and Dosimetry of External Radiation (2007) 159 Risk to the Thyroid from Ionizing Radiation (2008) Binders for NCRP reports are available. Two sizes make it possible to collect into small binders the “old series” of reports (NCRP Reports Nos. 8–30) and into large binders the more recent publications (NCRP Reports Nos. 32–159). Each binder will accommodate from five to seven reports. The binders carry the identification “NCRP Reports” and come with label holders which permit the user to attach labels showing the reports contained in each binder. The following bound sets of NCRP reports are also available: Volume I. NCRP Reports Nos. 8, 22 Volume II. NCRP Reports Nos. 23, 25, 27, 30 Volume III. NCRP Reports Nos. 32, 35, 36, 37 Volume IV. NCRP Reports Nos. 38, 40, 41 Volume V. NCRP Reports Nos. 42, 44, 46 Volume VI. NCRP Reports Nos. 47, 49, 50, 51 Volume VII. NCRP Reports Nos. 52, 53, 54, 55, 57 Volume VIII. NCRP Report No. 58 Volume IX. NCRP Reports Nos. 59, 60, 61, 62, 63 Volume X. NCRP Reports Nos. 64, 65, 66, 67 Volume XI. NCRP Reports Nos. 68, 69, 70, 71, 72 Volume XII. NCRP Reports Nos. 73, 74, 75, 76 Volume XIII. NCRP Reports Nos. 77, 78, 79, 80 Volume XIV. NCRP Reports Nos. 81, 82, 83, 84, 85 Volume XV. NCRP Reports Nos. 86, 87, 88, 89 Volume XVI. NCRP Reports Nos. 90, 91, 92, 93

526 / NCRP PUBLICATIONS Volume XVII. NCRP Reports Nos. 94, 95, 96, 97 Volume XVIII. NCRP Reports Nos. 98, 99, 100 Volume XIX. NCRP Reports Nos. 101, 102, 103, 104 Volume XX. NCRP Reports Nos. 105, 106, 107, 108 Volume XXI. NCRP Reports Nos. 109, 110, 111 Volume XXII. NCRP Reports Nos. 112, 113, 114 Volume XXIII. NCRP Reports Nos. 115, 116, 117, 118 Volume XXIV. NCRP Reports Nos. 119, 120, 121, 122 Volume XXV. NCRP Report No. 123I and 123II Volume XXVI. NCRP Reports Nos. 124, 125, 126, 127 Volume XXVII. NCRP Reports Nos. 128, 129, 130 Volume XXVIII. NCRP Reports Nos. 131, 132, 133 Volume XXIX. NCRP Reports Nos. 134, 135, 136, 137 Volume XXX. NCRP Reports Nos. 138, 139 Volume XXXI. NCRP Report No. 140 Volume XXXII. NCRP Reports Nos. 141, 142, 143 Volume XXXIII. NCRP Report No. 144 Volume XXXIV. NCRP Reports Nos. 145, 146, 147 Volume XXXV. NCRP Reports Nos. 148, 149 Volume XXXVI. NCRP Reports Nos. 150, 151, 152 Volume XXXVII, NCRP Reports Nos. 153, 154, 155 (Titles of the individual reports contained in each volume are given previously.)

NCRP Commentaries No.

Title 1

4

5 6 7 8 9 10 11 12 13

Krypton-85 in the Atmosphere—With Specific Reference to the Public Health Significance of the Proposed Controlled Release at Three Mile Island (1980) Guidelines for the Release of Waste Water from Nuclear Facilities with Special Reference to the Public Health Significance of the Proposed Release of Treated Waste Waters at Three Mile Island (1987) Review of the Publication, Living Without Landfills (1989) Radon Exposure of the U.S. Population—Status of the Problem (1991) Misadministration of Radioactive Material in Medicine—Scientific Background (1991) Uncertainty in NCRP Screening Models Relating to Atmospheric Transport, Deposition and Uptake by Humans (1993) Considerations Regarding the Unintended Radiation Exposure of the Embryo, Fetus or Nursing Child (1994) Advising the Public about Radiation Emergencies: A Document for Public Comment (1994) Dose Limits for Individuals Who Receive Exposure from Radionuclide Therapy Patients (1995) Radiation Exposure and High-Altitude Flight (1995) An Introduction to Efficacy in Diagnostic Radiology and Nuclear Medicine (Justification of Medical Radiation Exposure) (1995)

NCRP PUBLICATIONS

14 15

16 17 18 19 20

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A Guide for Uncertainty Analysis in Dose and Risk Assessments Related to Environmental Contamination (1996) Evaluating the Reliability of Biokinetic and Dosimetric Models and Parameters Used to Assess Individual Doses for Risk Assessment Purposes (1998) Screening of Humans for Security Purposes Using Ionizing Radiation Scanning Systems (2003) Pulsed Fast Neutron Analysis System Used in Security Surveillance (2003) Biological Effects of Modulated Radiofrequency Fields (2003) Key Elements of Preparing Emergency Responders for Nuclear and Radiological Terrorism (2005) Radiation Protection and Measurement Issues Related to Cargo Scanning with Accelerator-Produced High-Energy X Rays (2007)

Proceedings of the Annual Meeting No.

Title 1 3

4

5

6

7 8

9

10 11

12

Perceptions of Risk, Proceedings of the Fifteenth Annual Meeting held on March 14-15, 1979 (including Taylor Lecture No. 3) (1980) Critical Issues in Setting Radiation Dose Limits, Proceedings of the Seventeenth Annual Meeting held on April 8-9, 1981 (including Taylor Lecture No. 5) (1982) Radiation Protection and New Medical Diagnostic Approaches, Proceedings of the Eighteenth Annual Meeting held on April 6-7, 1982 (including Taylor Lecture No. 6) (1983) Environmental Radioactivity, Proceedings of the Nineteenth Annual Meeting held on April 6-7, 1983 (including Taylor Lecture No. 7) (1983) Some Issues Important in Developing Basic Radiation Protection Recommendations, Proceedings of the Twentieth Annual Meeting held on April 4-5, 1984 (including Taylor Lecture No. 8) (1985) Radioactive Waste, Proceedings of the Twenty-first Annual Meeting held on April 3-4, 1985 (including Taylor Lecture No. 9)(1986) Nonionizing Electromagnetic Radiations and Ultrasound, Proceedings of the Twenty-second Annual Meeting held on April 2-3, 1986 (including Taylor Lecture No. 10) (1988) New Dosimetry at Hiroshima and Nagasaki and Its Implications for Risk Estimates, Proceedings of the Twenty-third Annual Meeting held on April 8-9, 1987 (including Taylor Lecture No. 11) (1988) Radon, Proceedings of the Twenty-fourth Annual Meeting held on March 30-31, 1988 (including Taylor Lecture No. 12) (1989) Radiation Protection Today—The NCRP at Sixty Years, Proceedings of the Twenty-fifth Annual Meeting held on April 5-6, 1989 (including Taylor Lecture No. 13) (1990) Health and Ecological Implications of Radioactively Contaminated Environments, Proceedings of the Twenty-sixth Annual Meeting held on April 4-5, 1990 (including Taylor Lecture No. 14) (1991)

528 / NCRP PUBLICATIONS 13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28 29

Genes, Cancer and Radiation Protection, Proceedings of the Twenty-seventh Annual Meeting held on April 3-4, 1991 (including Taylor Lecture No. 15) (1992) Radiation Protection in Medicine, Proceedings of the Twenty-eighth Annual Meeting held on April 1-2, 1992 (including Taylor Lecture No. 16) (1993) Radiation Science and Societal Decision Making, Proceedings of the Twenty-ninth Annual Meeting held on April 7-8, 1993 (including Taylor Lecture No. 17) (1994) Extremely-Low-Frequency Electromagnetic Fields: Issues in Biological Effects and Public Health, Proceedings of the Thirtieth Annual Meeting held on April 6-7, 1994 (not published). Environmental Dose Reconstruction and Risk Implications, Proceedings of the Thirty-first Annual Meeting held on April 12-13, 1995 (including Taylor Lecture No. 19) (1996) Implications of New Data on Radiation Cancer Risk, Proceedings of the Thirty-second Annual Meeting held on April 3-4, 1996 (including Taylor Lecture No. 20) (1997) The Effects of Pre- and Postconception Exposure to Radiation, Proceedings of the Thirty-third Annual Meeting held on April 2-3, 1997, Teratology 59, 181–317 (1999) Cosmic Radiation Exposure of Airline Crews, Passengers and Astronauts, Proceedings of the Thirty-fourth Annual Meeting held on April 1-2, 1998, Health Phys. 79, 466–613 (2000) Radiation Protection in Medicine: Contemporary Issues, Proceedings of the Thirty-fifth Annual Meeting held on April 7-8, 1999 (including Taylor Lecture No. 23) (1999) Ionizing Radiation Science and Protection in the 21st Century, Proceedings of the Thirty-sixth Annual Meeting held on April 5-6, 2000, Health Phys. 80, 317–402 (2001) Fallout from Atmospheric Nuclear Tests—Impact on Science and Society, Proceedings of the Thirty-seventh Annual Meeting held on April 4-5, 2001, Health Phys. 82, 573–748 (2002) Where the New Biology Meets Epidemiology: Impact on Radiation Risk Estimates, Proceedings of the Thirty-eighth Annual Meeting held on April 10-11, 2002, Health Phys. 85, 1–108 (2003) Radiation Protection at the Beginning of the 21st Century–A Look Forward, Proceedings of the Thirty-ninth Annual Meeting held on April 9–10, 2003, Health Phys. 87, 237–319 (2004) Advances in Consequence Management for Radiological Terrorism Events, Proceedings of the Fortieth Annual Meeting held on April 14–15, 2004, Health Phys. 89, 415–588 (2005) Managing the Disposition of Low-Activity Radioactive Materials, Proceedings of the Forty-first Annual Meeting held on March 30–31, 2005, Health Phys. 91, 413–536 (2006) Chernobyl at Twenty, Proceedings of the Forty-second Annual Meeting held on April 3–4, 2006, Health Phys. 93, 345–595 (2007) Advances in Radiation Protection in Medicine, Proceedings of the Forty-third Annual Meeting held on April 16-17, 2007, Health Phys. 95, 461–686 (2008)

NCRP PUBLICATIONS

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Lauriston S. Taylor Lectures No.

Title 1 2 3 4 5

6

7

8

9 10

11

12 13

14

15 16

17

18 19

The Squares of the Natural Numbers in Radiation Protection by Herbert M. Parker (1977) Why be Quantitative about Radiation Risk Estimates? by Sir Edward Pochin (1978) Radiation Protection—Concepts and Trade Offs by Hymer L. Friedell (1979) [available also in Perceptions of Risk, see above] From “Quantity of Radiation” and “Dose” to “Exposure” and “Absorbed Dose”—An Historical Review by Harold O. Wyckoff (1980) How Well Can We Assess Genetic Risk? Not Very by James F. Crow (1981) [available also in Critical Issues in Setting Radiation Dose Limits, see above] Ethics, Trade-offs and Medical Radiation by Eugene L. Saenger (1982) [available also in Radiation Protection and New Medical Diagnostic Approaches, see above] The Human Environment—Past, Present and Future by Merril Eisenbud (1983) [available also in Environmental Radioactivity, see above] Limitation and Assessment in Radiation Protection by Harald H. Rossi (1984) [available also in Some Issues Important in Developing Basic Radiation Protection Recommendations, see above] Truth (and Beauty) in Radiation Measurement by John H. Harley (1985) [available also in Radioactive Waste, see above] Biological Effects of Non-ionizing Radiations: Cellular Properties and Interactions by Herman P. Schwan (1987) [available also in Nonionizing Electromagnetic Radiations and Ultrasound, see above] How to be Quantitative about Radiation Risk Estimates by Seymour Jablon (1988) [available also in New Dosimetry at Hiroshima and Nagasaki and its Implications for Risk Estimates, see above] How Safe is Safe Enough? by Bo Lindell (1988) [available also in Radon, see above] Radiobiology and Radiation Protection: The Past Century and Prospects for the Future by Arthur C. Upton (1989) [available also in Radiation Protection Today, see above] Radiation Protection and the Internal Emitter Saga by J. Newell Stannard (1990) [available also in Health and Ecological Implications of Radioactively Contaminated Environments, see above] When is a Dose Not a Dose? by Victor P. Bond (1992) [available also in Genes, Cancer and Radiation Protection, see above] Dose and Risk in Diagnostic Radiology: How Big? How Little? by Edward W. Webster (1992) [available also in Radiation Protection in Medicine, see above] Science, Radiation Protection and the NCRP by Warren K. Sinclair (1993) [available also in Radiation Science and Societal Decision Making, see above] Mice, Myths and Men by R.J. Michael Fry (1995) Certainty and Uncertainty in Radiation Research by Albrecht M. Kellerer. Health Phys. 69, 446–453 (1995)

530 / NCRP PUBLICATIONS 20

70 Years of Radiation Genetics: Fruit Flies, Mice and Humans by Seymour Abrahamson. Health Phys. 71, 624–633 (1996)

21

Radionuclides in the Body: Meeting the Challenge by William J. Bair. Health Phys. 73, 423–432 (1997)

22

From Chimney Sweeps to Astronauts: Cancer Risks in the Work Place by Eric J. Hall. Health Phys. 75, 357–366 (1998)

23

Back to Background: Natural Radiation and Radioactivity Exposed by Naomi H. Harley. Health Phys. 79, 121–128 (2000)

24

Administered Radioactivity: Unde Venimus Quoque Imus by S. James Adelstein. Health Phys. 80, 317–324 (2001)

25

Assuring the Safety of Medical Diagnostic Ultrasound by Wesley L. Nyborg. Health Phys. 82, 578–587 (2002)

26

Developing Mechanistic Data for Incorporation into Cancer and Genetic Risk Assessments: Old Problems and New Approaches by R. Julian Preston. Health Phys. 85, 4–12 (2003)

27

The Evolution of Radiation Protection–From Erythema to Genetic Risks to Risks of Cancer to ? by Charles B. Meinhold, Health Phys. 87, 240–248 (2004)

28

Radiation Protection in the Aftermath of a Terrorist Attack Involving Exposure to Ionizing Radiation by Abel J. Gonzalez, Health Phys. 89, 418–446 (2005)

29

Nontargeted Effects of Radiation: Implications for Low Dose Exposures by John B. Little, Health Phys. 91, 416–426 (2006)

30

Fifty Years of Scientific Research: The Importance of Scholarship and the Influence of Politics and Controversy by Robert L. Brent, Health Phys. 93, 348–379 (2007)

31

The Quest for Therapeutic Actinide Chelators by Patricia W. Durbin, Health Phys. 95, 465–492 (2008)

Symposium Proceedings No.

Title 1

The Control of Exposure of the Public to Ionizing Radiation in the Event of Accident or Attack, Proceedings of a Symposium held April 27-29, 1981 (1982)

2

Radioactive and Mixed Waste—Risk as a Basis for Waste Classification, Proceedings of a Symposium held November 9, 1994 (1995)

3

Acceptability of Risk from Radiation—Application to Human Space Flight, Proceedings of a Symposium held May 29, 1996 (1997)

4

21st Century Biodosimetry: Quantifying the Past and Predicting the Future, Proceedings of a Symposium held February 22, 2001, Radiat. Prot. Dosim. 97(1), (2001)

5

National Conference on Dose Reduction in CT, with an Emphasis on Pediatric Patients, Summary of a Symposium held November 6-7, 2002, Am. J. Roentgenol. 181(2), 321–339 (2003)

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NCRP Statements No.

Title 1 2

3

4

5 6 7 8 9 10

“Blood Counts, Statement of the National Committee on Radiation Protection,” Radiology 63, 428 (1954) “Statements on Maximum Permissible Dose from Television Receivers and Maximum Permissible Dose to the Skin of the Whole Body,” Am. J. Roentgenol., Radium Ther. and Nucl. Med. 84, 152 (1960) and Radiology 75, 122 (1960) X-Ray Protection Standards for Home Television Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (1968) Specification of Units of Natural Uranium and Natural Thorium, Statement of the National Council on Radiation Protection and Measurements (1973) NCRP Statement on Dose Limit for Neutrons (1980) Control of Air Emissions of Radionuclides (1984) The Probability That a Particular Malignancy May Have Been Caused by a Specified Irradiation (1992) The Application of ALARA for Occupational Exposures (1999) Extension of the Skin Dose Limit for Hot Particles to Other External Sources of Skin Irradiation (2001) Recent Applications of the NCRP Public Dose Limit Recommendation for Ionizing Radiation (2004)

Other Documents The following documents were published outside of the NCRP report, commentary and statement series: Somatic Radiation Dose for the General Population, Report of the Ad Hoc Committee of the National Council on Radiation Protection and Measurements, 6 May 1959, Science 131 (3399), February 19, 482–486 (1960) Dose Effect Modifying Factors in Radiation Protection, Report of Subcommittee M-4 (Relative Biological Effectiveness) of the National Council on Radiation Protection and Measurements, Report BNL 50073 (T-471) (1967) Brookhaven National Laboratory (National Technical Information Service, Springfield, Virginia) Residential Radon Exposure and Lung Cancer Risk: Commentary on Cohen's County-Based Study, Health Phys. 87(6), 656–658 (2004)

INDEX

Index Terms

Links

A Absolute risk (thyroid cancer)

12

14

176

261

269

271

272

327

403

405

407

411

Absorbed dose (D)

336

Acetylaminofluorene (AAF)

144

374

21

52

237

325

280

387

390

7

144

146

148

195

199

201

220

245

249

269

316

327

370

398

404

161

165

230

231

242

256

285

427

Acne

389 Adenitis

255

Adenoids

178

Adenomas (thyroid)

Adult Health Study (AHS)

Hiroshima AHS Cohort

231

hyperparathyroidism

256

Nagasaki AHS Cohort

230

231

Radiation Effects Research Foundation AHS Cohort

242

This page has been reformatted by Knovel to provide easier navigation.

Index Terms Age

at exposure

attained

Links 3

8

10

13

14

29

151

153

163

165

174

181

192

211

213

250

257

260

270

278

288

291

316

323

331

405

408

3

11

14

29

153

250

262

272

278

297

3

8

10

13

29

151

163

165

174

181

192

211

213

250

257

260

270

279

288

291

316

323

331

405

396

397

408 Agioma

21

Air kerma (Ka)

338

Altai Region

130

Animal studies

144

131

376

carcinogenicity

144

goitrogenesis

378

larger animals

146

malignancy

146

I thyroid carcinogenicity

370

146

376

relative biological effectiveness 378 (131I/x rays) This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Animal studies (Cont.) rodents

144

x-ray thyroid carcinogenicity

372

Anterior pituitary

370

39

TSH production

39

Anti-thyroid antibodies

217

240

246

247

9

195

239

7

28

68

120

158

161

164

230

241

256

272

277

356

285

289

295

273

316

317

393

epidemiology

164

241

256

Life Span Study

316 68

120

356

Auger electrons

79

99

338

Autoimmune thyroiditis

49

235

146

377

Arizona Cohort

242

245

Ataxia-telangiectasia mutation (ATM)

286

Atomic Bomb Casualty Commission Atomic-Bomb Survivors Studies

radiation dosimetry

164

B Beagles euthyroid external irradiation

378

147 146

This page has been reformatted by Knovel to provide easier navigation.

342

Index Terms

Links

Beagles (Cont.) hypothyroidism

146

life span

146

mortality

146

neoplasms

146

thyroiditis

146

BEIR I

268

major conclusions BEIR III

268 269

major conclusions BEIR V

BEIR VII

408

270 271

major conclusions

403

269 270

major conclusions

402

410

270

Belarus (post-Chernobyl reactor accident)

10

115

117

118

182

203

210

211

215

244

282

308

309

310

adult thyroid cancers

210

childhood cancer

210

dietary iodine deficiency

215

dose response relation

215

KI supplementation

215

risk

215

risk modifier

215

thyroid cancers

210

215

215

dose response relations 210 211 215 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Belarus (post-Chernobyl reactor accident) (Cont.) estimated excess thyroid cancers

210

risks (EAR, ERR)

210

thyroid cancer increase

210

Benign thyroid nodules

220

atomic-bomb survivors

230

Chernobyl cleanup workers

232

211

313

Chicago Head and Neck Irradiation

222

228

(civilians)

226

233

environmental exposures

232

French hemangioma

221

223

227

234

224

228

229

Chinese high background

228

India high background (civilians) Massachusetts fluoroscopy medical exposures (external irradiation)

220

Robert Packer Hospital Head and Neck

220

221

226

229

thyroid disease prevalence

224

231

tinea capitis

222

229

218

233

Stockholm medical

I

diagnostic

Biodosimetry

225

131

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Biological Effects of Ionizing Radiation (BEIR) reports

259

265

267

268

269

270

271

282

283

288

291

297

298

299

311

402

402

408 BEIR I

267

268

269

BEIR III

267

269

403

BEIR V

259

267

270

288

265

267

269

271

282

283

288

291

292

293

297

298

299

311

410

362

364

408 BEIR VII

Biological half-life Biologically-effective dose (BED)

64

Boston Lymphoid Hyperplasia Study

8

123

136

164

166

168

171

178

222

277

279

287

Brachytherapy

65

67

68

345

BRAVO (shot)

110

111

200

239

139

184

187

314 British Hyperthyroid Study

8 193

Bryansk Oblast (post-Chernobyl reactor accident)

212

215

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

C Calcitonin

32

40

48

256

42

45

259

371

Calculation of individual dose from environmental radionuclides (CIDER) Carcinomas (thyroid)

112 44

163

372

375

181

271

327

381

Cervical Cancer Study

273

276

280

393

Chechelsk (Belarus Region)

245

Cell killing (radiation-induced) effect on risk estimation

Chemotherapy Chernobyl occupational exposures

47 217

232

6

9

10

12

13

18

19

26

48

67

103

114

161

183

188

194

203

232

244

252

272

308

309

310

318

323

324

326

329

330

19

26

103

115

212

216

217

Chernobyl (post-nuclear reactor accident)

131

I release

childhood thyroid cancer dose response relation

212

risks

216

217

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Chernobyl (post-nuclear reactor accident) (Cont.) childhood thyroid radiation doses cleanup workers

216 9

67

thyroid cancer risk

233

contaminated milk consumption

117

endemic goiter

116

iodine deficiency (civilians)

116

major studies

208

209

risk (EAR, ERR) estimates

208

209

thyroid cancer

208

209

potassium iodide blockade

116

radiation dose

116

232

203

216

203

216

8

122

135

162

166

168

171

176

222

228

256

273

284

287

288

289

8

172

179

236

estimates

116

uncertainties

117

radioactive fallout (atmospheric)

309

radioactive plume

115

RET/PTC mutations (civilians)

252

risk (EAR, ERR) estimates

203

screening (health) programs

161

Chicago Head and Neck Irradiation Study

Childhood Cancer Survivor Study

284 This page has been reformatted by Knovel to provide easier navigation.

Index Terms Childhood thyroid cancer

Links 22

48

Chinese High Background Study benign nodules Chromosome

233 66

banding

249

painting

66

translocations

218

249

218

250

Cincinnati Benign Childhood Disease Study Colloid (thyroid)

387 98

Connecticut Case-Control Study

393

Connecticut Tumor Registry

179

393

8

128

Cooperative Thyrotoxicosis Therapy Follow-Up Study

137

192

306

311

341

403 Cysts (thyroid)

217

284

D Deoxyribonucleic acid (DNA)

57

Dose and dose rate effectiveness factor (DDREF)

79

Dose reconstruction

102

Dose-response models

260

Dose uncertainties

71

275

316

Dosimetry System 1986 (DS86)

68

71

140

230

356

This page has been reformatted by Knovel to provide easier navigation.

165

Index Terms Dosimetry System 2002 (DS02)

Links 28

68

70

120

158

360

71

E Effective dose equivalent

54

Effective half-life

86

90

92

129

364

434

102

194

232

238

244

114

203

232

Hanford Site

111

201

241

Marshall Islanders

107

197

238

195

239

105

Environmental releases of radioiodine

Chernobyl Nuclear Reactor Accident

Mayak Nuclear Weapons Production Facility

217

Nevada Test Site

104

nuclear weapons tests

105

Semipalatinsk Nuclear Test Site

200

Epidemiological studies

149

desirable characteristics

151

study designs

149

uncertainties

158

Epigenetic modifications/ alterations

58

59

This page has been reformatted by Knovel to provide easier navigation.

244

Index Terms Ethnicity

Links 2

3

44

130

175

179

269

285

286

331

10

11

15

157

261

291

412

419

421

424

426

additive

157

262

291

coefficients

412

effect modifiers

419

421

424

426

equations

262

overestimate

263

Poisson regression

262

uncertainty factors

414

underestimate

263

10

11

14

15

157

264

271

411

414

416

422

423

coefficients

411

415

comparison to excess absolute risk

265 14

15

Excess absolute risk (EAR) model

Excess relative risk (ERR) model

defined

equations

10

11

157

264

264

271

females (BEIR VII)

271

males (BEIR VII)

271

multiplicative

158

265

Poisson regression 264 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Excess relative risk (ERR) model (Cont.) relative risk

264

risk modifiers

416

uncertainty

414

422

423

5

47

51

52

65

67

235

247

319

320

325

343

343

348

200

201

212

232

233

234

244

320

50

65

235

External beam radiation therapy (EBRT)

radiation dosimetry

F Fine-needle aspiration (FNA)

321 Fission yields iodine isotopes Fluorescent in situ hybridization Functional (thyroid) diseases

25

72

25

72

250 49

following external beam radiation therapy

235

hyperthyroidism

49

50

65

hypothyroidism

49

50

51

52

3

11

29

46

267

268

G Gender

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Gender (Cont.) excess relative risk thyroid cancer lifetime risk thyroid cancer Genomic stability Goiter

adenomatous

267 268 251 37

129

217

236

392

397

393

137

183

191

192

193

235

237

2

6

9

26

103

111

201

217

317

322

2

26

103

115

230

prevalence

37

relation to iodine concentration

37

toxic nodular

230

129

Gothenburg, Sweden Cervical Tuberculosis Adenitis Study

255

H Hanford

131

I release

autoimmune disorders

203

cancer mortality

203

CIDER

112

dietary iodine

217

dose reconstruction

112

uncertainties

217

217

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Hanford (Cont.) dose-response relationships

203

dose uncertainties

112

114

downwinders

103

111

317

HTDS

112

medical conclusions

114

112

113

201

204

231

241

206

207

categories

204

205

Hashimoto’s thyroiditis

201

245

52

125

181

221

326

384

69

165

243

256

356

357

359

356

357

Hanford Thyroid Disease Study (HTDS)

autoimmune disorders/gender/ dose categories thyroid neoplasia/gender/dose

Hemangiomas

Hiroshima

atomic bomb bomb burst (above ground) height

70

gamma-ray doses

357

hyperparathyroidism

256

hypocenter

69

71

neutron activation analyses

357

359

neutron doses

357

quality factor (neutrons)

70

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Hodgkin’s disease

235

Hyperparathyroidism

254

Hyperthyroidism

255

397

409

8

39

49

50

65

123

128

129

235

240

255

269

325

362

371

Graves’ disease

50

toxic nodular goiter

50

Hypothalamic-pituitary axis

39

40

Hypothyroidism

40

50

51

108

145

235

239

243

246

247

317

325

370

377

378

392

404

I Idaho National Engineering Laboratory

103

131

103

I release

India High Background Study

227

114

234

thyroid nodular disease incidence Institute of Medicine (IOM)

234 312

318

thyroid cancer relative risk conclusions

312

Interactive Radio Epidemiological Program

311

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Intrathyroidal radioiodine distribution

98

follicular cells

98

radiation doses

98

In utero exposures (environmental iodine) Iodine (stable)

240 6

37

38

41

93

215

260

286

6

37

93

215

260

286

309

6

93

215

309 decreases uptake of radioiodines dietary

deficiency/insufficiency sources stable sufficiency supplementation

41

37 260

286

6

93

215

recommended daily dietary intake values 129

Iodine-129 ( I)

38 95

limited radiobiological disease significance

96

longest-lived radioiodine

95

low specific activity

96

131

Iodine-131 ( I)

103

115

103

115

(see radioisotopes) worldwide

This page has been reformatted by Knovel to provide easier navigation.

309

Index Terms

Links

Iodine-131 (131I) (Cont.) disease fallout

103

release

115

131

Iodine-131 ( I) thyroid dose

90

98

Auger electrons

99

101

102

biokinetic factors

91

colloid

98

99

100

dietary

93

99

101

insufficiency

93

sufficiency

93

follicles

98

geometric standard deviation

91

inhomogeneities

98

KI blockade

92

thyroid mass

91

uncertainty

90

Iodine isotopes

73

fission yields

75

mass numbers

73

physical half-life

73

75

Iodine radioisotopes (thyroid radiation dosimetry)

362

biological half-life

364

effective half-life

364

mean absorbed dose rates

366

367

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Iodine radioisotopes (thyroid radiation dosimetry) (Cont.) thyroid age-dependent

364

absorption

365

properties

364

Israeli Tinea Capitis Study

365

7

121

132

166

168

171

175

276

277

284

286

302

316

390

217

244

K Kaluga Oblast childhood thyroid

217

cancer dose response relation

217

radiation doses

217

L Latent period Leukemia

Linear energy transfer (LET)

264

269

304

71

219

320

384

385

386

395

399

78

79

334

338

high-LET

79

low-LET

79

nonstochastic quantity

339

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

M Marshall Islanders

6

9

104

107

183

197

238

307

308

314

confirmed thyroid pathologies

199

Japanese fishermen

108

medical issues

108

nuclear weapon test

107

radioisotope exposures (intake)

104

reconstructed doses

108

Rongelapese

108

thyroid

199

adenomas

199

cancers

199

nodules

199

U.S. servicemen

108

Utirikese

110

111

109

Mayak Nuclear Weapons Production Plant

103

114

131

103

217

increased risk (nodular disease)

217

I release

217

Medical Internal Radiation Dose Committee (MIRD)

363

367

formalism

363

MIRDOSE III

363

367

Medical surveillance

308

318

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Messenger ribonucleic acid (mRNA)

60

61

62

251

Meta-analyses

163

313

Methylthiouracil (MT)

144

374

376

379

144

148

370

378

148

149

adenomas

148

149

carcinomas

148

112

353

357

70

71

165

230

243

256

356

70

356

gamma-ray doses

357

358

hyperparathyroidism

256

carcinogenesis Mice thyroid

379

Monte Carlo (simulations/ modeling)

92 360

N Nagasaki

atomic bomb

hypocenter neutron doses NCRP Report No. 80

71 357

358

1

2

271

323

1

2

271

405

1

2

405

405 conclusions general major

271

This page has been reformatted by Knovel to provide easier navigation.

Index Terms Nevada Test Site (NTS)

absorbed dose (formula) atmospheric testing

Links 6

9

18

23

24

26

102

183

238

239

247

307

314

322

106 23

dose uncertainties

107

fallout (atmospheric)

322

gummed film detector network

105

24

National Cancer Institute website risk calculator

107

weapons testing (131I atmospheric releases) New York Tinea Capitis Study

26

102

389

New York Tuberculosis Adenitis Study Nodules (thyroid)

390 192

217

221

228

233

237

269

313

314

317

398

65

111

113

161

195

200

202

216

217

218

220

221

230

231

234

314

322

330

P Palpation (thyroid)

This page has been reformatted by Knovel to provide easier navigation.

Index Terms Parathyroid

Links 32

42

43

51

4

9

18

25

42

88

105

112

115

194

326

69

120

133

78

163

165

173

177

270

273

274

275

283

286

288

289

294

306

394

capsule

32

chief cells

42

gland anatomy/physiology

32

hormone

32

hormone regulation

32

hyperparathyroidism

51

Parathyroid function studies

254

Atomic-Bomb Survivors

256

Chicago Head and Neck Irradiation

256

conclusions

257

Minnesota Hyperparathyroidism

256

Swedish Tuberculous Adenitis

255

Pasture-cow-milk-human pathway

131

I

Phantom(s)

25 65 135

Pooled analysis

411

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Pooled analysis (Cont.) excess relative risk/excess absolute risk supplemental coefficients

411

linear curve fit

275

low radiation dose effectiveness

274

preference (ERR model)

273

risk estimates

173

graphic illustration

173

supplemental

427

427

strong association (dose/thyroid cancer) Proto-oncogene

273 57

251

5

6

64

67

260

261

275

316

5

67

external

5

67

internal

5

72

major study cohorts

6

119

260

261

R Radiation dose

exposures

radioiodine

104

cow milk

104

goat milk

107

uncertainty

5

64

275

316

This page has been reformatted by Knovel to provide easier navigation.

Index Terms Radiation dose reconstruction

Links 72

biokinetics

72

potassium iodide blockade

92

Radiation dosimetry

64

69

71

74

119

332

356

362

absorbed dose

336

atomic bombs

71

atomic-bomb survivors biological concepts/quantities

74

356 66

67

332

dose and dose rate effectiveness factor

342

defined quantities/units

332

dose equivalent

340

dose-rate factor

341

342

exposure

332

336

internal dose calculations

363

kerma

338

LET

338

phantoms

65

pharmacokinetics

362

physical aspects

65

practical complications

64

quality factor

340

radiation weighting factor

340

69

341

342

radiogenic epidemiologic thyroid disease studies

119

radioiodines 362 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Radiation dosimetry (Cont.) relative biological effectiveness

339

specific energy

336

thyroid blockade

367

Radiation Effects Research Foundation (RERF)

68

69

70

71

140

164

165

277

356

360

361

68

69

71

Radiation effects (thyroid)

143

382

animal studies

144

benign nodules

220

cancer

163

383

external irradiation

163

383

internal irradiation

182

Life Span Study

conclusions

257

epidemiologic studies

149

functional disease

235

molecular effects

248

risk models

157

Radiation risk thyroid cancer

163

259

163

259

conclusions

315

dose response relations

260

factors affecting risk estimates

270

past risk estimates/models

267

thyroid nodules

220

315

313

factors affecting risk estimates 228 314 This page has been reformatted by Knovel to provide easier navigation.

140

Index Terms Radioiodine

Links 25

biokinetics

72

dose reconstruction

87

dosimetry

79

environmental dispersion

87

fission yield

25

KI blockage

92

physical properties

76

Radioiodine therapy

24 h RAIU

Rats

35

72

73

50

52

65

86

90

91

95

96

97

126

128

188

364

369

50

52

53

56

65

86

90

91

95

96

97

126

128

188

364

369

144

145

147

149

150 adenomas

149

150

carcinomas

149

150

dose response curves

149

thyroid cancer

149

follicular

149

papillary

149

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Relative biological effectiveness (RBE)

6

7

13

71

74

78

79

140

147

306

310

316

327

329

330

339

6

7

147

148

149

340 animal data 131

I/x rays (mice) thyroid

adenomas 131

I/x rays (mice) thyroid

carcinomas

148

131

147

I/x rays (rats) goitrogenesis

131

I/x rays (rats) thyroid

neoplasms human data

147 6

7

13

71

74

78

79

140

306

310

316

327

329

330

339

340

313

327

329

232

264

266

270

276

312

131

78

131

7

131

316

131

I/x rays (juveniles)

316

Auger electrons/x rays

79

neutrons/gamma rays

140

I beta rays/x rays I/x rays I/x rays (collective)

reference radiation Relative risk (RR)

74

model (thyroid cancer) 270 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Relative risk (RR) (Cont.) noncancer diseases (95% CIs)

232

RET (proto-oncogene) or “normal form”

252

RET/PTC (mutated form)

252

Risk model comparative outcomes

265

excess absolute risk versus excess relative risk

265

266

267

Risk model comparisons

290

394

BEIR VII

291

297

290

292

293

297

302

303

290

292

296

305

291

294

296

297

291

296

excess absolute risk time constant

296

excess relative risk time constant excess relative risk upper bound excess relative risk model modified by time since exposure (lower bound) external radiation exposures

294

internal radiation exposures (RBEs)

306

NCRP Report No. 80 Model 6

293

thyroid cancer incidence

290

thyroid cancer mortality

302

Risk models

297

10

11

157

327

402

411

additive 11 328 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Risk models (Cont.) excess absolute risk

10

11

157

excess relative risk

10

157

327

327

excess relative risk and excess absolute risk coefficients multiplicative

411 11

previous

402

Risk models, previous

402

BEIR I

402

BEIR III

403

BEIR V

408

BEIR VII

410

NCRP Report No. 80

405

UNSCEAR reports

409

Risk modifying factors

229

328

262

265

266

262

265

266

age

229

ethnicity

229

father with cancer

229

first degree relative with cancer

229

gender (sex)

229

marital status

229

mother with cancer

229

parent with cancer

229

Rochester Thymus Study

7

120

133

166

168

170

276

277

286

287

385

174

182

203

210

213

Russia

214 244 308 This page has been reformatted by Knovel to provide easier navigation.

309

Index Terms

Links

Russia (Cont.) Bryansk Oblast

212

213

childhood cancer risks

211

214

dose response relations

210

increase in thyroid cancer

212

risks (EAR, ERR)

210

thyroid cancer increase

210

Russian Federation

118

211

215

217

219

161

202

275

313

315

317

318

310 childhood dose response relation

215

childhood thyroid cancer risk

215

cleanup workers

219

forthcoming studies

219

individual radiation doses

219

South Ural Mountains

217

S Screening (surveillance)

atomic-bomb survivors

162

benefits

318

biases

313

317

Chicago Head and Neck Irradiation

162

external beam radiation therapy patient follow-up harms

320 318

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Screening (surveillance) (Cont.) males, females

162

National Academy of Sciences report national policy

320 318

National Cancer Institute workshop

319

thyroid benign nodules

202

thyroid cancer rates

161

202

44

160

305

307

8 230

Surveillance (see screening) Surveillance Epidemiology and End Results (SEER)

189

196

183

226

229

314

315

38

39

41

50

246

362

65

124

135

Swedish Diagnostic 131

I Study

Swedish study; X-Ray Treatment of Cervical Spine in Adults

397

SIRs

397

thyroid cancers

397

x-ray exposures

397

T Tetraiodothyronin (thyroxine, T4)

49

Thermoluminescent dosimeter (TLD)

This page has been reformatted by Knovel to provide easier navigation.

353

Index Terms Three Mile Island

Links 2

103

115

131

2

103

115

nuclear reactor accident

2

I release

Thyroglobulin

31

38

388

Thyroid

31

45

48

51

62

146

148

149

161

231

237

364

370

371

372

373

374

376

377

378

381

384

389

392

395

397

adenocarcinomas

377

adenomas

146

148

149

371

372

376

377

379

380

381

age-dependent lobe radius

364

age-dependent mass

364

anatomy/physiology

31

cancer

45

48

237

373

374

376

392

395

397 follicular

47

medullary

48

papillary

45

237

148

370

371

372

373

374

376

379

380

381

389

392

carcinomas

diagnostic radioactive tracers 52 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid (Cont.) external beam radiation therapy

51

fetal age, masses

33

fibrosarcoma

146

follicle cell numbers

62

follicles

32

goitrogenesis hormone

376

378 38

metabolism

38

production regulation

39

hypothalamic-pituitary-thyroid axis

39

iodine metabolism

35

lobe radius

364

mass/gender

364

medical radiation applications

51

microcarcinomas

161

neoplasms

146

373

377

378

137

387

392

396

parafollicular clear cells (C-cells)

32

40

radioactive iodine therapy

53

372

384

384 nodules

thyroiditis

377

thyrotrophic hypertrophy

377

tumors

231

benign

231

malignant

231

370

volume/gender 34 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid absorbed doses (radioiodines)

55

79

age-dependencies

79

362

tabulations

80

85

from radioiodines

55

Thyroid cancer

adults

362

2

4

22

24

44

104

159

197

276

324

325

48

325

22

44

197

22

44

89

22

44

197

208

209

4

children diagnostic ultrasound detection fractionated irradiation incidence

22 2 276 4 324

incidence/mortality ratios

44

incidence/race/gender

45

incidence versus mortality

159

low radiation doses

276

mortality

4 197

adults adults/race/gender racial/ethnic variations relative risk

4 44 44 276

Thyroid cancer; environmental 131

194

Chernobyl

203

I exposures (risk analyses)

occupational exposures 217 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid cancer; environmental (Cont.) Hanford Site

201

Marshall Islanders

197

Mayak Nuclear Weapons Facility

217

Nevada Test Site

195

nuclear weapons testing (fallout)

196

Semipalatinsk Nuclear Test Site

200

Thyroid cancer; epidemiologic studies

119

164

68

120

164

123

178

Irradiation

122

176

Childhood cancer survivor

124

179

Gothenburg skin hemangioma

125

181

Israeli tinea capitis

121

175

Rochester thymus

120

174

Stockholm skin hemangioma

124

181

external exposure Atomic-Bomb Survivors Boston Lymphoid Hyperplasia

68 119

Chicago Head and Neck

internal exposures

126

British therapeutic

129

German diagnostic

130

Semipalatinsk Nuclear Test Site

129

Swedish diagnostic

126

Swedish therapeutic

127

U.S. therapeutic 128 This page has been reformatted by Knovel to provide easier navigation.

175

Index Terms

Links

Thyroid cancer; excess relative risk (ERR)

306

children versus adults x rays versus

131

I exposures

310 306

Thyroid cancer; external radiation (additional studies)

382

adult medical therapy

390

childhood medical therapy

382

medical diagnostic

399

occupational exposures

397

Thyroid cancer; human (external radiation; major studies)

164

166

Atomic-Bomb Survivors

164

166

Boston Lymphoid Hyperplasia

166

178

Irradiation

166

176

childhood cancer

167

179

Israeli Tinea Capitis

166

175

Rochester Thymus

166

174

internal irradiation studies

182

167

Chicago Head and Neck

131

183

131

194

131

191

I diagnostic I environmental I therapeutic

internal medical diagnostic (major studies)

183

British hyperthyroid

184

193

FDA diagnostic

184

189

FDA therapeutic 184 192 This page has been reformatted by Knovel to provide easier navigation.

174

Index Terms

Links

Thyroid cancer; human (external radiation; major studies) (Cont.) German diagnostic

184

190

Swedish diagnostic

184

183

Swedish therapeutic

184

191

Gothenburg

167

181

Stockholm

167

181

skin hemangioma

Thyroid cancer; medical external diagnostic exposure studies

399

case-control studies

400

multiple fluoroscopic exams for tuberculosis

399

Thyroid cancer; occupational external exposures

397

Chinese medical x-ray workers

398

Hanford Site/Sellafield Site workers

399

radium dial workers

398

Thyroid cancer; papillary tumor U.S. incidence

24

Thyroid cancer risk (adult irradiation studies)

280

327

dose

280

excess absolute risk

280

327

excess relative risk

280

327

relative risk

280

390

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid cancer; screening studies (microcarcinomas/thyroid disease)

161

Chicago Head and Neck Irradiation

161

Japanese Atomic-Bomb

161

Thyroid disease (functional) studies

235

atomic-bomb survivors

241

Chernobyl

244

environmental exposures to radioiodine

237

Hanford Thyroid Disease Study

241

Marshall Islands fallout

238

molecular effects

248

Nevada Test Site

239

post-external beam radiation therapy

235

summary

247

thyroid function tests

245

Thyroid diseases

41

anatomical

42

benign nodules

43

cancer

44 adults

44

children

48

physiological Thyroidectomy

42 12

61

373

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid genomics

56

DNA

57 alterations

60

damage

57

epigenetic alterations

58

genomic instability

60

malignant transformation

59

oncogenesis

61

60

Thyroid irradiation (cancer risk modifiers)

270

273

275

286

316

325

328

270

273

278

279

316

328

attained age

270

273

279

331

diet

331

dose

275

278

316

331 age at exposure

fractionation/protraction

278

uncertainty

275

316

ethnicity

270

283

genomics

331

hereditary susceptibility

270

other modifiers

286

screening

270

331

sex (gender)

270 325

surveillance

325

331

273

279

282

328

331

270

thyroid screening 285 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid irradiation (cancer risk modifiers) (Cont.) time since exposure Thyroiditis

270

273

279

217

230

237

239

240

247

127

Thyroid molecular effects of ionizing radiation

248

bystander effects

253

chromosome banding

249

fluorescent chromosome analyses

250

gene expression

251

molecular signature

254

nuclear DNA abnormalities

248

oncogene activation

251

other specific mutations

253

RET proto-oncogene activation

252

satellite DNA patterns

251

Thyroid neoplasms radiation risks

259 259

Thyroid nodules; epidemiologic studies (internal or external exposures)

121

123

124

132

220

313

131

137

Boston Lymphoid Hyperplasia

123

Chicago tonsils

135

I therapeutic

136

Childhood cancer 124 141 This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Thyroid nodules; epidemiologic (Cont.) Hiroshima autopsy

140

Israeli Tinea Capitis

121

Nagasaki thyroid disease

140

New York Tinea Capitis

132

Packer Hospital Head and Neck

142

radium dial painters

138

Rochester thymus

133

skin hemangioma

124

141

Gothenburg

124

141

Stockholm

124

141

132

thymus

134

U.S. diagnostic

127

136

84

87

Thyroid radiation dosimetry (radioiodines) clearance exchange rate compartment model

362

363 84

internal dose calculations

363

mean residence time

363

pharmacokinetics

84

thyroid blockade

367

87

362

Thyroid stimulating hormone (TSH)

40

41

49

50

95

145

146

217

236

238

239

240

242

243

246

322

371

373

374

376

392 393 This page has been reformatted by Knovel to provide easier navigation.

Index Terms Thyroid ultrasound

Links 44

161

200

201

212

217

231

233

245

314

315

320

2

3

10

11

14

29

159

174

192

214

260

262

282

286

288

289

294

296

302

316

323

408

11

52

121

132

164

166

171

173

175

222

229

276

277

278

289

302

316

325

326

389

390

405

408

178

220

389

38

39

49

50

362

398

26

115

182

203

210

211

216

244

247

282

321 Time since exposure (TSE)

Tinea capitis

Tonsils Triiodothyronine (T3)

U Ukraine

dose response relations

210

risks (EAR, ERR)

210

thyroid cancer, children

210

211

This page has been reformatted by Knovel to provide easier navigation.

Index Terms

Links

Uncertainties

260

261

316

preferred dose response models

261

radiation dose

260

261

316

1

2

3

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)

409 reports

409

U.S. Cooperative Thyrotoxicosis Therapy Follow-Up Study

8

192

8

189

26

103

115

26

103

115

U.S. Food and Drug Administration Childhood Diagnostic Study

W Windscale (Sellafield) accident

131

I release

This page has been reformatted by Knovel to provide easier navigation.

272