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.

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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 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 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 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. 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 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)

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)

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 (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 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 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

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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 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 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.,