NCRP report no 150 extrapolation of radiation induced cancer risks from nonhuman experimental systems to humans

NCRP REPORT No 150 EXTRAPOLATION OF RADIATION-INDUCED CANCER RISKS FROM NONHUMAN EXPERIMENTAL SYSTEMS TO HUMANS N C R P National Council on Radiation Protection and Measurements NCRP REPORT No 150 Extrapolation of RadiationInduced Cancer Risks from Nonhuman Experimental Systems to Humans Recommendations of the NATIONAL COUNCIL ON RADIATION PROTECTION AND MEASUREMENTS Issued November 18, 2005 National Council on Radiation Protection and Measurements 7910 Woodmont Avenue, Suite 400/Bethesda, MD 20814-3095 LEGAL NOTICE This Report was prepared by the National Council on Radiation Protection and Measurements (NCRP) The Council strives to provide accurate, complete and useful information in its documents However, neither NCRP, the members of NCRP, other persons contributing to or assisting in the preparation of this Report, nor any person acting on the behalf of any of these parties: (a) makes any warranty or representation, express or implied, with respect to the accuracy, completeness or usefulness of the information contained in this Report, or that the use of any information, method or process disclosed in this Report may not infringe on privately owned rights; or (b) assumes any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this Report, under the Civil Rights Act of 1964, Section 701 et seq as amended 42 U.S.C Section 2000e et seq (Title VII) or any other statutory or common law theory governing liability Disclaimer Any mention of commercial products within NCRP publications is for information only; it does not imply recommendation or endorsement by NCRP Library of Congress Cataloging-in-Publication Data Extrapolation of radiation-induced cancer risks from nonhuman experiment systems to humans p cm — (NCRP report ; no 150) “Issued November 2005,” Includes bibliographical references and index ISBN 0-929600-86-X Radiation carcinogenesis Radiation—Toxicology Animal models in research I National Council on Radiation Protection and Measurements II Series RC268.55.E97 2005 616.99’4071—dc22 2005031014 Copyright © National Council on Radiation Protection and Measurements 2005 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 251.] Preface This Report reviews the scientific issues associated with the extrapolation of radiation-induced cancer risks from nonhuman experimental systems to humans The basic principles of radiation effects at the molecular and cellular level are examined with emphasis on comparisons among various species including humans These comparisons among species are then continued for cancers of similar cell types in the same organ system Risk estimates are made from an observed level of effect as a function of organ dose The major organ systems are individually considered Extrapolation models are reviewed and include external and internal radiation exposures At the beginning of the nuclear age there was no idea what risks workers would face in the handling of such substances as plutonium The only option was to rely on experimental animal data and extrapolation This effort, together with good health physics practices and medical surveillance resulted in, by and large, a wellprotected workforce Many experimental animal studies were undertaken shortly after World War II One aim was to understand the biological effects of radiation, and, hopefully, the mechanisms of the effects Another aim was to determine the influence of such factors as dose rate, radiation quality, gender, and age at exposure Much has been learned and the general information has been incorporated into efforts associated with risk estimations More specifically, the experimental data have been the basis for selecting dose and dose-rate effectiveness factors (DDREF) and radiation quality factors These factors are used to moderate risk estimates either for patterns of irradiation or types of radiation for which there are inadequate data The risk estimates used in radiation protection throughout the world come almost entirely from the atomic-bomb survivors, who were acutely exposed to high-dose-rate gamma rays, not at all like the industrial (e.g., uranium miners’) exposures Hence, the concern for the influence of dose rate and fractionation An additional concern is the lack of appropriate data for estimating risk to people exposed in space missions Again, we must rely on experimental studies iii iv / PREFACE Much remains to be done It is believed that if more relevant data could be obtained to develop acceptable methods of extrapolation across species, risk estimates could be improved With an understanding of what information is necessary to undertake extrapolation, it would be possible to make better use of the considerable body of data on cancer induction by radiation This Report includes a discussion of nontargeted radiation effects that potentially influence dose-response characteristics of cells and tissues at low absorbed doses These nontargeted effects include bystander effects, genomic instability, and adaptive radiation responses, all of which are subjects of presently active research It is anticipated that future NCRP reports will analyze the influence of these factors on radiation dose-response characteristics and variations in radiation response(s) among species This Report gives an account of the steps by which a group of researchers has advanced the pragmatic and theoretical approaches to extrapolation of estimates of risk from radionuclides and external radiation The Report identifies the problems in extrapolating the current data from, for example, mice to humans It provides examples of using Bayesian statistics to successfully estimate DDREF values for humans from data for mice, and also provides a measure of uncertainty for this estimate The Report also shows how a defensible quantitative estimate of radiation injury can be determined for humans even when the exposure data of interest are either lacking or of poor quality, and how mortality data for laboratory animals can be used to predict age-specific radiation-induced risks for humans for general endpoints like life shortening, all cancers, and selected subsets of cancers involving homologous tissues Every example of an interspecies prediction of radiationinduced mortality contained within this Report was made in the absence of an extensive understanding of cellular and molecular genetic effects of radiation These latter types of effects are important for providing a degree of confidence to use of the so-called biological models, but they were not critical, as stated above, for the empirical models, which take into account a great deal of what is presently known Perhaps the most encouraging aspect of the Report is the account of how the effect of life span can be extrapolated across species, and examples of doing so from mice to dogs to humans are given The differences of life span among species has long been studied, and the possibility of using life shortening not only as an integrated index of radiation effects, but also for deriving a single value of relative biological effectiveness and DDREF for radiation PREFACE / v protection purposes seemed worth examining Lastly, the Report recommends research that is required to advance this important field This Report was prepared by Scientific Committee 1-4 on the Extrapolation of Risks from Nonhuman Experimental Systems to Man Serving on Scientific Committee 1-4 were: David G Hoel, Chairman Medical University of South Carolina Charleston, South Carolina Members Bruce A Carnes University of Oklahoma Oklahoma City, Oklahoma William C Griffith University of Washington Seattle, Washington Robert L Dedrick National Institutes of Health Bethesda, Maryland Peter G Groer University of Tennessee Knoxville, Tennessee R.J Michael Fry Indianapolis, Indiana R Julian Preston U.S Environmental Protection Agency Research Triangle Park, North Carolina Douglas Grahn Madison, Indiana Consultants Kelly H Clifton University of Wisconsin Madison, Wisconsin Hildegard M Schuller University of Tennessee Knoxville, Tennessee Scott C Miller University of Utah Salt Lake City, Utah Thomas M Seed Catholic University of America Washington, D.C NCRP Secretariat Morton W Miller, Consultant (2004–2005) Bruce B Boecker, Consultant (2004–2005) William M Beckner, Senior Staff Scientist (1992–1997, 2000–2004) Thomas M Koval, Senior Staff Scientist (1997–2000) Cindy L O’Brien, Managing Editor David A Schauer, Executive Director vi / PREFACE The Council wishes to express its appreciation to the Committee members for the time and effort devoted to the preparation of this Report NCRP gratefully acknowledges the financial support provided by the U.S Department of Energy, Office of Biological and Environmental Research Thomas S Tenforde President Contents Preface iii Executive Summary and Recommendations 1.1 Why Is Extrapolation Still Required? 1.2 Summary of Findings 1.2.1 Historical Aspects 1.2.2 Neoplastic Disease 1.2.2.1 Hematopoietic System 1.2.2.2 Lung 1.2.2.3 Breast 1.2.2.4 Thyroid 1.2.2.5 Skin 1.2.2.6 Gastrointestinal Track 1.2.2.7 Bone 1.2.3 Somatic Genetic Damage at Molecular and Cellular Levels 1.2.4 Extrapolation Models and Methods 1.2.4.1 Toxicity of Chemotherapeutic Drugs 1.2.4.2 Life Shortening 1.2.4.3 Interspecies Prediction of Life Shortening and Cancer from External Irradiation 1.2.4.4 Extrapolation of Dose-Rate Effectiveness Factors 10 1.2.4.5 Interspecies Prediction of Injury from Internally-Deposited Radionuclides 10 1.3 Conclusions 11 1.4 Recommendations 13 Introduction 15 History of Extrapolation: Nonhuman Experimental Systems to Humans 17 3.1 Introduction 17 3.2 Lessons Learned from Genetic Risks 21 vii viii / CONTENTS 3.2.1 Methods of Estimation 22 3.2.1.1 Doubling-Dose Method 22 3.2.1.2 Direct Method 23 3.2.1.3 Gene-Number Method 23 3.2.2 Discussion of Methods of Estimating Genetic Risk 23 3.2.3 Role of Genetics in the Estimation of Somatic Risks 25 3.3 Somatic Risks 26 Tissue and Organ Differences Among Species with Emphasis on the Cells of Origin of Cancers 38 4.1 Introduction 38 4.2 Hematopoietic System 40 4.2.1 Introduction: Leukemias and Lymphomas 40 4.2.2 Comparison of Radiation-Induced Leukemias Among Species 42 4.2.3 Pathology and Dose-Response Relationships 43 4.2.4 Comparison of Hematopoietic Systems 44 4.2.5 Target Cells 45 4.2.6 Comparison of Cytogenetic Processes: Common or Species-Specific Patterns 47 4.2.7 Leukemogenesis Resulting from Gene Rearrangements 49 4.2.8 Secondary Cytogenetic Lesions Associated with Leukemia Promotion and Progression 50 4.2.9 Hematopoietic Cell Origins of the Putative “Critical” Genic Lesions and the Nature of Induced Genic Dysfunctions 51 4.2.10 Cooperating Oncogenes in Lymphoid Neoplasias 52 4.2.11 Cooperating Oncogenes in Myeloid Neoplasias 53 4.2.12 Hematopoeitic Microenvironment 54 4.2.13 Summary 55 4.3 Lung 56 4.3.1 Introduction 56 4.3.2 Adenocarcinoma 57 4.3.3 Squamous-Cell Carcinoma 58 4.3.4 Small-Cell Lung Carcinoma 59 CONTENTS 4.4 4.5 4.6 4.7 4.8 / ix 4.3.5 Large-Cell Carcinoma 62 4.3.6 Summary 62 Breast 63 4.4.1 Histogenesis of Mammary Glands and Mammary Cancer 63 4.4.2 Hormones and Mammary Carcinogenesis 65 4.4.3 Cellular Origins of Mammary Cancer 66 4.4.4 Summary 68 Thyroid 68 4.5.1 General Background 68 4.5.2 Histogenesis of the Thyroid Gland and Thyroid Cancer 69 4.5.3 Thyroid Function and its Control 70 4.5.4 Cellular Economy of the Thyroid Gland and the Origin of Cancer 71 4.5.5 Summary 72 Skin 72 4.6.1 Introduction 72 4.6.2 Epidermal Cancers 73 4.6.3 Melanoma 74 4.6.4 Tumors of the Dermis 74 4.6.5 Mechanisms of Epidermal Carcinogenesis 74 4.6.6 Importance of Interactions 75 4.6.7 Summary 75 Gastrointestinal Tract 75 4.7.1 Introduction 75 4.7.2 Stomach 75 4.7.3 Small Intestine 76 4.7.4 Colorectal Tumors 76 4.7.5 Summary 77 Bone 77 4.8.1 Humans 77 4.8.2 Mice 78 4.8.3 Rats 79 4.8.4 Dogs 80 4.8.5 Summary 80 Radiation Effects at the Molecular and Cellular Levels 84 5.1 Introduction 84 5.2 Effects of Ionizing Radiations at the Molecular Level 85 NCRP PUBLICATIONS / 253 77 Exposures from the Uranium Series with Emphasis on Radon and Its Daughters (1984) 78 Evaluation of Occupational and Environmental Exposures to Radon and Radon Daughters in the United States (1984) 79 Neutron Contamination from Medical Electron Accelerators (1984) 80 Induction of Thyroid Cancer by Ionizing Radiation (1985) 81 Carbon-14 in the Environment (1985) 82 SI Units in Radiation Protection and Measurements (1985) 83 The Experimental Basis for Absorbed-Dose Calculations in Medical Uses of Radionuclides (1985) 84 General Concepts for the Dosimetry of Internally Deposited Radionuclides (1985) 86 Biological Effects and Exposure Criteria for Radiofrequency Electromagnetic Fields (1986) 87 Use of Bioassay Procedures for Assessment of Internal Radionuclide Deposition (1987) 88 Radiation Alarms and Access Control Systems (1986) 89 Genetic Effects from Internally Deposited Radionuclides (1987) 90 Neptunium: Radiation Protection Guidelines (1988) 92 Public Radiation Exposure from Nuclear Power Generation in the United States (1987) 93 Ionizing Radiation Exposure of the Population of the United States (1987) 94 Exposure of the Population in the United States and Canada from Natural Background Radiation (1987) 95 Radiation Exposure of the U.S Population from Consumer Products and Miscellaneous Sources (1987) 96 Comparative Carcinogenicity of Ionizing Radiation and Chemicals (1989) 97 Measurement of Radon and Radon Daughters in Air (1988) 99 Quality Assurance for Diagnostic Imaging (1988) 100 Exposure of the U.S Population from Diagnostic Medical Radiation (1989) 101 Exposure of the U.S Population from Occupational Radiation (1989) 102 Medical X-Ray, Electron Beam and Gamma-Ray Protection for Energies Up to 50 MeV (Equipment Design, Performance and Use) (1989) 103 Control of Radon in Houses (1989) 104 The Relative Biological Effectiveness of Radiations of Different Quality (1990) 105 Radiation Protection for Medical and Allied Health Personnel (1989) 106 Limit for Exposure to “Hot Particles” on the Skin (1989) 107 Implementation of the Principle of As Low As Reasonably Achievable (ALARA) for Medical and Dental Personnel (1990) 254 / NCRP PUBLICATIONS 108 Conceptual Basis for Calculations of Absorbed-Dose Distributions (1991) 109 Effects of Ionizing Radiation on Aquatic Organisms (1991) 110 Some Aspects of Strontium Radiobiology (1991) 111 Developing Radiation Emergency Plans for Academic, Medical or Industrial Facilities (1991) 112 Calibration of Survey Instruments Used in Radiation Protection for the Assessment of Ionizing Radiation Fields and Radioactive Surface Contamination (1991) 113 Exposure Criteria for Medical Diagnostic Ultrasound: I Criteria Based on Thermal Mechanisms (1992) 114 Maintaining Radiation Protection Records (1992) 115 Risk Estimates for Radiation Protection (1993) 116 Limitation of Exposure to Ionizing Radiation (1993) 117 Research Needs for Radiation Protection (1993) 118 Radiation Protection in the Mineral Extraction Industry (1993) 119 A Practical Guide to the Determination of Human Exposure to Radiofrequency Fields (1993) 120 Dose Control at Nuclear Power Plants (1994) 121 Principles and Application of Collective Dose in Radiation Protection (1995) 122 Use of Personal Monitors to Estimate Effective Dose Equivalent and Effective Dose to Workers for External Exposure to Low-LET Radiation (1995) 123 Screening Models for Releases of Radionuclides to Atmosphere, Surface Water, and Ground (1996) 124 Sources and Magnitude of Occupational and Public Exposures from Nuclear Medicine Procedures (1996) 125 Deposition, Retention and Dosimetry of Inhaled Radioactive Substances (1997) 126 Uncertainties in Fatal Cancer Risk Estimates Used in Radiation Protection (1997) 127 Operational Radiation Safety Program (1998) 128 Radionuclide Exposure of the Embryo/Fetus (1998) 129 Recommended Screening Limits for Contaminated Surface Soil and Review of Factors Relevant to Site-Specific Studies (1999) 130 Biological Effects and Exposure Limits for “Hot Particles” (1999) 131 Scientific Basis for Evaluating the Risks to Populations from Space Applications of Plutonium (2001) 132 Radiation Protection Guidance for Activities in Low-Earth Orbit (2000) 133 Radiation Protection for Procedures Performed Outside the Radiology Department (2000) 134 Operational Radiation Safety Training (2000) 135 Liver Cancer Risk from Internally-Deposited Radionuclides (2001) 136 Evaluation of the Linear-Nonthreshold Dose-Response Model for Ionizing Radiation (2001) NCRP PUBLICATIONS / 255 137 Fluence-Based and Microdosimetric Event-Based Methods for Radiation Protection in Space (2001) 138 Management of Terrorist Events Involving Radioactive Material (2001) 139 Risk-Based Classification of Radioactive and Hazardous Chemical Wastes (2002) 140 Exposure Criteria for Medical Diagnostic Ultrasound: II Criteria Based on all Known Mechanisms (2002) 141 Managing Potentially Radioactive Scrap Metal (2002) 142 Operational Radiation Safety Program for Astronauts in Low-Earth Orbit: A Basic Framework (2002) 143 Management Techniques for Laboratories and Other Small Institutional Generators to Minimize Off-Site Disposal of Low-Level Radioactive Waste (2003) 144 Radiation Protection for Particle Accelerator Facilities (2003) 145 Radiation Protection in Dentistry (2003) 146 Approaches to Risk Management in Remediation of Radioactively Contaminated Sites (2004) 147 Structural Shielding Design for Medical X-Ray Imaging Facilities (2004) 148 Radiation Protection in Veterinary Medicine (2004) 149 A Guide to Mammography and Other Breast Imaging Procedures (2004) 150 Extrapolation of Radiation-Induced Cancer Risks from Nonhuman Experimental Systems to Humans (2005) Binders for NCRP reports are available Two sizes make it possible to collect into small binders the “old series” of reports (NCRP Reports Nos 8–30) and into large binders the more recent publications (NCRP Reports Nos 32–150) Each binder will accommodate from five to seven reports The binders carry the identification “NCRP Reports” and come with label holders which permit the user to attach labels showing the reports contained in each binder The following bound sets of NCRP reports are also available: Volume I NCRP Reports Nos 8, 22 Volume II NCRP Reports Nos 23, 25, 27, 30 Volume III NCRP Reports Nos 32, 35, 36, 37 Volume IV NCRP Reports Nos 38, 40, 41 Volume V NCRP Reports Nos 42, 44, 46 Volume VI NCRP Reports Nos 47, 49, 50, 51 Volume VII NCRP Reports Nos 52, 53, 54, 55, 57 Volume VIII NCRP Report No 58 Volume IX NCRP Reports Nos 59, 60, 61, 62, 63 Volume X NCRP Reports Nos 64, 65, 66, 67 Volume XI NCRP Reports Nos 68, 69, 70, 71, 72 Volume XII NCRP Reports Nos 73, 74, 75, 76 Volume XIII NCRP Reports Nos 77, 78, 79, 80 Volume XIV NCRP Reports Nos 81, 82, 83, 84, 85 256 / NCRP PUBLICATIONS Volume XV NCRP Reports Nos 86, 87, 88, 89 Volume XVI NCRP Reports Nos 90, 91, 92, 93 Volume XVII NCRP Reports Nos 94, 95, 96, 97 Volume XVIII NCRP Reports Nos 98, 99, 100 Volume XIX NCRP Reports Nos 101, 102, 103, 104 Volume XX NCRP Reports Nos 105, 106, 107, 108 Volume XXI NCRP Reports Nos 109, 110, 111 Volume XXII NCRP Reports Nos 112, 113, 114 Volume XXIII NCRP Reports Nos 115, 116, 117, 118 Volume XXIV NCRP Reports Nos 119, 120, 121, 122 Volume XXV NCRP Report No 123I and 123II Volume XXVI NCRP Reports Nos 124, 125, 126, 127 Volume XXVII NCRP Reports Nos 128, 129, 130 Volume XXVIII NCRP Reports Nos 131, 132, 133 Volume XXIX NCRP Reports Nos 134, 135, 136, 137 Volume XXX NCRP Reports Nos 138, 139 Volume XXXI NCRP Report No 140 (Titles of the individual reports contained in each volume are given previously.) NCRP Commentaries No 10 11 12 13 Title Krypton-85 in the Atmosphere—With Specific Reference to the Public Health Significance of the Proposed Controlled Release at Three Mile Island (1980) Guidelines for the Release of Waste Water from Nuclear Facilities with Special Reference to the Public Health Significance of the Proposed Release of Treated Waste Waters at Three Mile Island (1987) Review of the Publication, Living Without Landfills (1989) Radon Exposure of the U.S Population—Status of the Problem (1991) Misadministration of Radioactive Material in Medicine—Scientific Background (1991) Uncertainty in NCRP Screening Models Relating to Atmospheric Transport, Deposition and Uptake by Humans (1993) Considerations Regarding the Unintended Radiation Exposure of the Embryo, Fetus or Nursing Child (1994) Advising the Public about Radiation Emergencies: A Document for Public Comment (1994) Dose Limits for Individuals Who Receive Exposure from Radionuclide Therapy Patients (1995) Radiation Exposure and High-Altitude Flight (1995) An Introduction to Efficacy in Diagnostic Radiology and Nuclear Medicine (Justification of Medical Radiation Exposure) (1995) NCRP PUBLICATIONS 14 15 16 17 18 / 257 A Guide for Uncertainty Analysis in Dose and Risk Assessments Related to Environmental Contamination (1996) Evaluating the Reliability of Biokinetic and Dosimetric Models and Parameters Used to Assess Individual Doses for Risk Assessment Purposes (1998) Screening of Humans for Security Purposes Using Ionizing Radiation Scanning Systems (2003) Pulsed Fast Neutron Analysis System Used in Security Surveillance (2003) Biological Effects of Modulated Radiofrequency Fields (2003) Proceedings of the Annual Meeting No 10 11 12 Title Perceptions of Risk, Proceedings of the Fifteenth Annual Meeting held on March 14-15, 1979 (including Taylor Lecture No 3) (1980) Critical Issues in Setting Radiation Dose Limits, Proceedings of the Seventeenth Annual Meeting held on April 8-9, 1981 (including Taylor Lecture No 5) (1982) Radiation Protection and New Medical Diagnostic Approaches, Proceedings of the Eighteenth Annual Meeting held on April 6-7, 1982 (including Taylor Lecture No 6) (1983) Environmental Radioactivity, Proceedings of the Nineteenth Annual Meeting held on April 6-7, 1983 (including Taylor Lecture No 7) (1983) Some Issues Important in Developing Basic Radiation Protection Recommendations, Proceedings of the Twentieth Annual Meeting held on April 4-5, 1984 (including Taylor Lecture No 8) (1985) Radioactive Waste, Proceedings of the Twenty-first Annual Meeting held on April 3-4, 1985 (including Taylor Lecture No 9)(1986) Nonionizing Electromagnetic Radiations and Ultrasound, Proceedings of the Twenty-second Annual Meeting held on April 2-3, 1986 (including Taylor Lecture No 10) (1988) New Dosimetry at Hiroshima and Nagasaki and Its Implications for Risk Estimates, Proceedings of the Twenty-third Annual Meeting held on April 8-9, 1987 (including Taylor Lecture No 11) (1988) Radon, Proceedings of the Twenty-fourth Annual Meeting held on March 30-31, 1988 (including Taylor Lecture No 12) (1989) Radiation Protection Today—The NCRP at Sixty Years, Proceedings of the Twenty-fifth Annual Meeting held on April 5-6, 1989 (including Taylor Lecture No 13) (1990) Health and Ecological Implications of Radioactively Contaminated Environments, Proceedings of the Twenty-sixth 258 / NCRP PUBLICATIONS 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Annual Meeting held on April 4-5, 1990 (including Taylor Lecture No 14) (1991) Genes, Cancer and Radiation Protection, Proceedings of the Twenty-seventh Annual Meeting held on April 3-4, 1991 (including Taylor Lecture No 15) (1992) Radiation Protection in Medicine, Proceedings of the Twenty-eighth Annual Meeting held on April 1-2, 1992 (including Taylor Lecture No 16) (1993) Radiation Science and Societal Decision Making, Proceedings of the Twenty-ninth Annual Meeting held on April 7-8, 1993 (including Taylor Lecture No 17) (1994) Extremely-Low-Frequency Electromagnetic Fields: Issues in Biological Effects and Public Health, Proceedings of the Thirtieth Annual Meeting held on April 6-7, 1994 (not published) Environmental Dose Reconstruction and Risk Implications, Proceedings of the Thirty-first Annual Meeting held on April 12-13, 1995 (including Taylor Lecture No 19) (1996) Implications of New Data on Radiation Cancer Risk, Proceedings of the Thirty-second Annual Meeting held on April 3-4, 1996 (including Taylor Lecture No 20) (1997) The Effects of Pre- and Postconception Exposure to Radiation, Proceedings of the Thirty-third Annual Meeting held on April 2-3, 1997, Teratology 59, 181–317 (1999) Cosmic Radiation Exposure of Airline Crews, Passengers and Astronauts, Proceedings of the Thirty-fourth Annual Meeting held on April 1-2, 1998, Health Phys 79, 466–613 (2000) Radiation Protection in Medicine: Contemporary Issues, Proceedings of the Thirty-fifth Annual Meeting held on April 7-8, 1999 (including Taylor Lecture No 23) (1999) Ionizing Radiation Science and Protection in the 21st Century, Proceedings of the Thirty-sixth Annual Meeting held on April 5-6, 2000, Health Phys 80, 317–402 (2001) Fallout from Atmospheric Nuclear Tests—Impact on Science and Society, Proceedings of the Thirty-seventh Annual Meeting held on April 4-5, 2001, Health Phys 82, 573–748 (2002) Where the New Biology Meets Epidemiology: Impact on Radiation Risk Estimates, Proceedings of the Thirty-eighth Annual Meeting held on April 10-11, 2002, Health Phys 85, 1–108 (2003) Radiation Protection at the Beginning of the 21st Century–A Look Forward, Proceedings of the Thirty-ninth Annual Meeting held on April 9–10, 2003, Health Phys 87, 237–319 (2004) Advances in Consequence Management for Radiological Terrorism Events, Proceedings of the Fortieth Annual Meeting held on April 14–15, 2004, Health Phys 89, 415–588 (2005) NCRP PUBLICATIONS / 259 Lauriston S Taylor Lectures No 10 11 12 13 14 15 Title The Squares of the Natural Numbers in Radiation Protection by Herbert M Parker (1977) Why be Quantitative about Radiation Risk Estimates? by Sir Edward Pochin (1978) Radiation Protection—Concepts and Trade Offs by Hymer L Friedell (1979) [available also in Perceptions of Risk, see above] From “Quantity of Radiation” and “Dose” to “Exposure” and “Absorbed Dose”—An Historical Review by Harold O Wyckoff (1980) How Well Can We Assess Genetic Risk? Not Very by James F Crow (1981) [available also in Critical Issues in Setting Radiation Dose Limits, see above] Ethics, Trade-offs and Medical Radiation by Eugene L Saenger (1982) [available also in Radiation Protection and New Medical Diagnostic Approaches, see above] The Human Environment—Past, Present and Future by Merril Eisenbud (1983) [available also in Environmental Radioactivity, see above] Limitation and Assessment in Radiation Protection by Harald H Rossi (1984) [available also in Some Issues Important in Developing Basic Radiation Protection Recommendations, see above] Truth (and Beauty) in Radiation Measurement by John H Harley (1985) [available also in Radioactive Waste, see above] Biological Effects of Non-ionizing Radiations: Cellular Properties and Interactions by Herman P Schwan (1987) [available also in Nonionizing Electromagnetic Radiations and Ultrasound, see above] How to be Quantitative about Radiation Risk Estimates by Seymour Jablon (1988) [available also in New Dosimetry at Hiroshima and Nagasaki and its Implications for Risk Estimates, see above] How Safe is Safe Enough? by Bo Lindell (1988) [available also in Radon, see above] Radiobiology and Radiation Protection: The Past Century and Prospects for the Future by Arthur C Upton (1989) [available also in Radiation Protection Today, see above] Radiation Protection and the Internal Emitter Saga by J Newell Stannard (1990) [available also in Health and Ecological Implications of Radioactively Contaminated Environments, see above] When is a Dose Not a Dose? by Victor P Bond (1992) [available also in Genes, Cancer and Radiation Protection, see above] 260 / NCRP PUBLICATIONS 16 17 18 19 20 21 22 23 24 25 26 27 28 Dose and Risk in Diagnostic Radiology: How Big? How Little? by Edward W Webster (1992) [available also in Radiation Protection in Medicine, see above] Science, Radiation Protection and the NCRP by Warren K Sinclair (1993) [available also in Radiation Science and Societal Decision Making, see above] Mice, Myths and Men by R.J Michael Fry (1995) Certainty and Uncertainty in Radiation Research by Albrecht M Kellerer Health Phys 69, 446–453 (1995) 70 Years of Radiation Genetics: Fruit Flies, Mice and Humans by Seymour Abrahamson Health Phys 71, 624–633 (1996) Radionuclides in the Body: Meeting the Challenge by William J Bair Health Phys 73, 423–432 (1997) From Chimney Sweeps to Astronauts: Cancer Risks in the Work Place by Eric J Hall Health Phys 75, 357–366 (1998) Back to Background: Natural Radiation and Radioactivity Exposed by Naomi H Harley Health Phys 79, 121–128 (2000) Administered Radioactivity: Unde Venimus Quoque Imus by S James Adelstein Health Phys 80, 317–324 (2001) Assuring the Safety of Medical Diagnostic Ultrasound by Wesley L Nyborg Health Phys 82, 578–587 (2002) Developing Mechanistic Data for Incorporation into Cancer and Genetic Risk Assessments: Old Problems and New Approaches by R Julian Preston Health Phys 85, 4–12 (2003) The Evolution of Radiation Protection–From Erythema to Genetic Risks to Risks of Cancer to ? by Charles B Meinhold, Health Phys 87, 240–248 (2004) Radiation Protection in the Aftermath of a Terrorist Attack Involving Exposure to Ionizing Radiation by Abel J Gonzalez, Health Phys 89, 418–446 (2005) Symposium Proceedings No Title The Control of Exposure of the Public to Ionizing Radiation in the Event of Accident or Attack, Proceedings of a Symposium held April 27-29, 1981 (1982) Radioactive and Mixed Waste—Risk as a Basis for Waste Classification, Proceedings of a Symposium held November 9, 1994 (1995) Acceptability of Risk from Radiation—Application to Human Space Flight, Proceedings of a Symposium held May 29, 1996 (1997) 21st Century Biodosimetry: Quantifying the Past and Predicting the Future, Proceedings of a Symposium held February 22, 2001, Radiat Prot Dosim 97(1), (2001) NCRP PUBLICATIONS / 261 National Conference on Dose Reduction in CT, with an Emphasis on Pediatric Patients, Summary of a Symposium held November 6-7, 2002, Am J Roentgenol 181(2), 321–339 (2003) NCRP Statements No 10 Title “Blood Counts, Statement of the National Committee on Radiation Protection,” Radiology 63, 428 (1954) “Statements on Maximum Permissible Dose from Television Receivers and Maximum Permissible Dose to the Skin of the Whole Body,” Am J Roentgenol., Radium Ther and Nucl Med 84, 152 (1960) and Radiology 75, 122 (1960) X-Ray Protection Standards for Home Television Receivers, Interim Statement of the National Council on Radiation Protection and Measurements (1968) Specification of Units of Natural Uranium and Natural Thorium, Statement of the National Council on Radiation Protection and Measurements (1973) NCRP Statement on Dose Limit for Neutrons (1980) Control of Air Emissions of Radionuclides (1984) The Probability That a Particular Malignancy May Have Been Caused by a Specified Irradiation (1992) The Application of ALARA for Occupational Exposures (1999) Extension of the Skin Dose Limit for Hot Particles to Other External Sources of Skin Irradiation (2001) Recent Applications of the NCRP Public Dose Limit Recommendation for Ionizing Radiation (2004) Other Documents The following documents were published outside of the NCRP report, commentary and statement series: Somatic Radiation Dose for the General Population, Report of the Ad Hoc Committee of the National Council on Radiation Protection and Measurements, May 1959, Science 131 (3399), February 19, 482–486 (1960) Dose Effect Modifying Factors in Radiation Protection, Report of Subcommittee M-4 (Relative Biological Effectiveness) of the National Council on Radiation Protection and Measurements, Report BNL 50073 (T-471) (1967) Brookhaven National Laboratory (National Technical Information Service, Springfield, Virginia) Residential Radon Exposure and Lung Cancer Risk: Commentary on Cohen's County-Based Study, Health Phys 87(6), 656–658 (2004) Index totipotent stem cells and progeny 66 Types 1–3 64 Bystander effects 104, 106, 109–110 Actuarial life tables 184 Age-specific death rates Age-specific mortality risks 37 Aging, theories of 32 Argonne National Laboratory (ANL) 18 Atomic Bomb Casualty Commission 143 Atomic-bomb survivors 2, 4, 19, 48, 153, 172 Autocrine function 54 Cancer pathology 43 Carcinogenesis 35 Carcinogenic process 39 progression 39 promotion 39 Chernobyl 164 Chromosomal aberrations 16, 42, 47–48, 50 deletions 47–48 Philadelphia (Ph1) 48, 50 Chromosome 42 Committee on the Biological Effects of Atomic Radiation 22 Conclusions 11–13 Cumulative survivorship curves 140–149 Bayesian 10–11, 16, 149, 177 Beagle(s) 18, 42, 80, 162, 167, 176 animal of choice 80 internally-deposited radionuclides 80 osteosarcomas 80 Biodosimetry 13 Body burden 239Pu 19 Bone, tumors or cancer, in 7, 77–83, 166–169, 175–181 beagles 80 external radiation 79 humans 77–78 induced by chemical carcinogens 79 internally-deposited radionuclides 79 mice 78–79 oncogenes 79 rats 79 viruses 79 Breast cancer 6, 63–68, 153–156 hormonal promotion 66 ovariectomy 65 sensitivity to carcinogens 64 terminal end buds (TEB) 63 Deoxyribonucleic acid (DNA) 3, 12, 16, 24, 35 damage 3, 12, 16 microarray testing 24 radiation-induced lesions 35 repair 16, 35 Dog 18, 42, 80 Dose and dose-rate effectiveness factor (DDREF) 1, 13–14, 19 Dose, permissible 28 Dose-rate effectiveness factor (DREF) 1, 2, 4, 10, 12–13, 15, 19, 37, 149, 183 Dose-rate effects 16 Drosophila 26 262 INDEX Effects 1, 3, 25 genetic somatic stochastic 1, 25 Effects of radiation 35 increased when LET increased 35 increase in dose increase 35 reduced when dose rate reduced 35 Empirical methods 35 Erz Mountains 164 Exposures, radiation 15 acute 15 fractionated 15 gamma rays 15 homes 15 mining population 15 patients 15 occupationally exposed 15 x rays 15 Extracellular matrix 16 Extrapolation (history, radiation effects) 1, 8, 17–37 across species, to humans 1, 17–37 age-specific death rates 37 insufficient data (present) 19 life-shortening 37 neoplastic 37 Extrapolation models 122–182 absolute/relative risk 138 acute 122–125 age-specific mortality 138 anticancer drugs 122 body surface 123 chemical toxicities 122–127 chronic 125–127 maximal tolerated dose (MTD) 123 pharmacokinetics 123 Phase trials (animals) 124 Phase trials (humans) 123 Extrapolations, of radiationinduced 140–156 breast cancer 149–156 mice to dogs 140–143 / 263 mice to dogs and humans 143–149 mice to humans 149–156 mortality 140–149 Gastrointestinal (GI) tract (cancer) 6, 75–77 colon/colorectal 75–77 esophagus 75 rectum 75 small intestine 75–76 stomach 75–76 Gene 7, 16, 50 alterations expression 16 nomenclature (see Glossary) protooncogenes 50 tumor specific 16 tumor-suppressor 50 Genes, conservation of, for 35 cell differentiation 35 cell proliferation control 35 DNA repair 35 Gene expression profiling 24 Genes (human) 24, 49–55, 72, 75, 77, 79, 94–96, 98, 101, 113–115 ABL 51 ADRA1 51 ADRB2 51 APC 77 ATM 95, 98 BCR/ABL (hybrid) 49, 51, 52, 55 BRCA1 24, 94 BRCA2 24, 94 CD14 51 CSF2 51 FGF1 51 GMF1 51 HPRT 101 IL3 51 IL4 51 IL5 51 MYC 50 NR3C1 51 PBX 54 RAS 113, 114 RET 72 264 / INDEX SPARC 51 TCF7 51 TLX1 54 TP53 50, 96 XPA 75 Genes (mice) 42, 52–53, 75, 77, 79, 94, 97, 114, 115, 116 Abl 53 Apc 77 Bmi1 53 Fos 79 Hoxb8 53 Hoxd3 53 HRas 114 Il1b 53 Il3 53 Myc 52–53, 115–116 Nbs1 94 NRas 53, 114–115 Pax5 42 Pbbcp2 53 Pim1 53 Pla2q2a 77 Ptch+/– 75 Ras 97, 114 Tgfbr1 42 Trp53 97 Genes (oncogenes) 49, 111–116 Abl 49 ABL1 116 Myc 115–116 Ras 111–115 Genes (tumor-suppressor) 117–120 APC 118 BRCA1 118 BRCA2 118 NF1 118 NF2 118 RB1 118 TP53 117, 118, 119, 120 Trp53 117 Tsc2 119 WT1 118 Gompertz 8, 27, 29–33, 130–138, 141, 145, 184 distribution/function 29–33, 130–138, 141, 145 equation 27 intercept 32 slope(s) 32, 33 Hematopoietic system (cancers) 5, 40–56 atomic-bomb survivors 41 cytogenetic processes 47 Hodgkin’s disease 41 leukemias/lymphomas 40–42 non-Hodgkin’s lymphoma 41 target cells 45–46 trisomy, chromosome 21 41 Hematopoietic unit 44–45 hematopoietics 44–45 progenitor cells 44–45 stroma 44–45 Hepatitis 39 confounded by 39 Heritable diseases radiation-induced Hogs 68 Homeostatic state 29 departure from 29 Host factor(s) 5, 10, 36, 38, 40 cell-cell communication 40 cytokines 40 differences 10, 36 microenvironment 40 stroma 40 Inhalation Toxicology Research Institute (ITRI) 168 Internal emitters 4, 11, 18–19, 78, 156, 160–164, 166, 168–169, 174–175, 177–178, 180–181 Americium-241 164, 168 Cerium-144 174 Iodine-131 156 Plutonium-238 168, 174–175, 178, 180–181 Plutonium-239 11, 18–19, 156, 164, 168, 174–175, 177, 181 Radon-222 156 INDEX Radium-224 19, 78, 156, 161–162, 166, 168–169, 177–178, 181 Radium-226 11, 18, 168–169 Radium-226,228 156, 160–162, 164, 168 Strontium-90 168, 174, 177–178 Strontium-90-Yttrium-90 181 Thorium-228 161, 164, 168 Thorium-230 163–164 Thorium-232 156, 161, 163 Yttrium-90 174 Yttrium-91 174 International Agency for Research on Cancer (IARC) 38 International Commission on Radiation Protection (ICRP) 19 Ions, heavy Kaplan-Meier survival curves 142 Langerhan’s cells 73 Lawrence Livermore National Laboratory 74 workers 74 Lethality function 29 Life 8–9, 20, 27, 33–34 mean duration of 27 shortening 8–9, 20, 33–34 span differences 34 Linear-energy transfer (LET) 2, 8, 12, 15, 17, 86, 106, 157, 159, 168 high-LET 12, 15, 86, 106 low-LET 8, 15, 17, 86, 106 Liver (cancer) 39 Lung (cancer) 4, 5, 56–63, 171–175, 181–182 alveologenic 57 adenocarcinoma 56 atomic-bomb survivors 59–60 bronchiolar 57 genes RAS and TP53 59, 61 hamsters 61 human 56–62 K-Ras 58 large-cell carcinoma 56 mice 57 / 265 squamous-cell carcinoma 59 radon induction 59 rats 58 Trp53 gene 58 uranium miners 60 Manhattan Project 21 Mayak 168–169, 172 Mean after-survival (MAS) 33 Medical Research Council (MRC) 22 Messenger RNAs 24 Molecular/cellular radiation effects 84–91, 94–100, 102–104, 106, 109–120 adaptive responses 110 breakage first hypothesis 104 bystander effects 109–110 cell-cycle aspects 95–96 chromosome aberrations 84, 102 confounders 109–110 double strand breaks 86–87 DNA damage 85–86 excision 91 fluorescence in situ hybridization techniques 103 genomic instability 110 genes, DNA repair 94–100 genes XRCC2 and Nbs1 90 high-LET 86, 106 homologous recombination 88 interchromosomal 90 intrachromosomal 90 low-LET 86, 106 mutations 84 non-homologous end joining (NHEJ) 88–89 oncogenes 111–116 recombination 90 repair 86–91, 95–96, 109–116 single-strand breaks 87 tumor suppressor genes 117–120 Mortality 8, 26, 28, 32–33 extrinsic 28 intrinsic 8, 28 laws of 26 ratio 33 theories about 32 266 / INDEX Mutation(s) 16, 30–31 life expectancy reduction 31 rate(s) 31 somatic 30 Neutrons 2, 12 fission Nontargeted radiation effects 106, 109–110 adaptive 110 bystander 106, 109–110 genomic instability 110 Nuclear weapons 21 radionuclide fallout 21 testing 21 Oncogene activation 111–116 Oncogenesis 15 human prediction 15 Opossum (Monodelphis domestica) 74 Patients 2, 15, 21 radiotherapy Plutonium 15, 21 (see internal emitters) Probability density function 10 Proportional hazard models (PHMs) 8, 11, 145, 150, 177, 181 Radiation 2, 4, 17 external general population 17 internal limits 17 protection working population 17 Radiation Effects Research Foundation 143 Radiation weighting factors 1, 13, 15 Radionuclides 156 (see internal emitters) Radium dial painters 18, 160 Radon 11, 18 (see lung cancer) lung cancer 18 uranium miners 18 Rat (strain) 64 Sprague-Dawley 64 Recommendations 13–14 Relative biological effectiveness (RBE) 4, 12–13, 19, 37, 156 Risk 2, 10, 12, 21–26 genetic 2, 21–26 mortality 10 relative 12 Risk estimates, of cancer induction 3, 22–37 cell type direct method 23 doubling-dose method 22–23 gene number method 23 history of somatic 26–37 somatic 22–37 Rotifer (Proales) 26 Saint Bernard (dog) 80 Scaling factors 145 Sheep 68 Skin (epidermal) cancer 6, 73–76 atomic-bomb survivors 74 basal-cell carcinoma 6, 73 guinea pigs 74 humans 6, 73–75 melanoma 6, 74 mice 74 opossum 74 squamous-cell carcinoma 73 tinea capitis patients 74 ultraviolet radiation 75 U.S Department of Energy workers 74 Smokers 57 Stochastic effects 1, 157 Somatic genetic repair DNA DNA repair DNA replication DNA content Stroma 44–45, 54 Strontium 11 (see internal emitters) Summary 183–187 Summary of findings 3–11 INDEX Survival times, mean 29 Survivorship curves 26 Drosophila 26 humans 26 Theories of 32 aging 32 mortality 32 Thorium 11 (see internal emitters) Thorotrast® 169 (see internal emitters) Thyroid cancer 6, 68–72 adults 68 cellular origin: clonal 71 children 68 goitrogenesis 71 histogenesis 69 humans 68–69, 71–72 RET (protooncogene) 72 RET/PTC1 72 thyroid stimulating hormone (TSH) 70 Toxicity ratio, method/approach 4, 18–19, 168, 175–176 plutonium-239/radium-224 19 relative 18 / 267 Toxicology chemical radionuclide Transuranics 11 (see internal emitters) United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 22 Ultraviolet (UV) exposures Uranium 21 (see internal emitters) Uranium miners 18, 172 lung cancer 18 radon exposure 18 U.S Atomic Energy Commission 18 U.S Department of Energy 74 workers 74 U.S National Academy of Sciences/National Research Council (NAS/NRC) 22 Weibull distribution 150 World Health Organization (WHO) 60 .. .NCRP REPORT No 150 Extrapolation of RadiationInduced Cancer Risks from Nonhuman Experimental Systems to Humans Recommendations of the NATIONAL COUNCIL ON RADIATION PROTECTION... by NCRP Library of Congress Cataloging-in-Publication Data Extrapolation of radiation- induced cancer risks from nonhuman experiment systems to humans p cm — (NCRP report ; no 150) “Issued November... radionuclides in laboratory animals to humans 3 History of Extrapolation: Nonhuman Experimental Systems to Humans 3.1 Introduction The study of the mechanisms of biological effects of radiation have