Health Risks of Ionizing Radiation:

An Overview of Epidemiological Studies

A Report by the Community-Based Hazard Management Program George Perkins Marsh Institute Clark University

March 2006 Health Risks of Ionizing Radiation:

An Overview of Epidemiological Studies

by

Abel Russ, Casey Burns, Seth Tuler, and Octavia Taylor

Community-Based Hazard Management The George Perkins Marsh Institute Clark University Worcester, MA 01610-1477 USA

March 2006 Contents List of Tables ...... vi List of Figures ...... vii Acknowledgments ...... x

1. INTRODUCTION ...... 1 1.1 Goals ...... 1 Ionizing radiation ...... 1 Low dose ...... 1 1.2 A brief history of radiation ...... 1 1.3 Exposure ...... 2 1.4 Standards ...... 3 1.5 Radiation basics ...... 3 1.6 Epidemiological methods ...... 7 Statistical significance ...... 7 Study design ...... 8 1.7 Risk terminology ...... 9 Relative risk ...... 9 Excess relative risk (ERR) ...... 9 Odds ratio (OR) ...... 9 Excessive absolute risk (EAR) ...... 9 Standardized incidence ratio (SIR) ...... 9 Standardized mortality ratio (SMR) ...... 9 P value ...... 10 Confidence interval ...... 10 1.8 Dose-response curves ...... 10 1.9 Overview structure ...... 11

2. BACKGROUND RADIATION ...... 13 2.1 Introduction ...... 13 2.2 Summary of studies ...... 13 External exposure ...... 14 High exposure areas ...... 14 Radon ...... 15 2.3 Discussion ...... 17

3. MEDICAL EXPOSURES ...... 19 3.1 Introduction ...... 19 3.2 Diagnostic exposures ...... 21 Diagnostic x-rays ...... 21 Diagnostic iodine-131 ...... 23

i ii Contents

Thorotrast ...... 24 3.3 Radiotherapy for non-cancer disease ...... 24 Tuberculosis ...... 25 Ankylosingspondylitis ...... 25 Hyperthyroidism ...... 26 Radiotherapy for other non-cancer diseases ...... 26 Radiotherapy for non-cancer disease in children ...... 26 3.4 Radiotherapy for cancer ...... 28 Radiotherapy for childhood cancer ...... 29 3.5 In utero exposures ...... 29 3.6 Parental exposures ...... 30 3.7 Radiologists’ occupational exposures ...... 31 3.8 Conclusions ...... 31

4. ATOMIC BOMB SURVIVORS ...... 43 4.1 Introduction ...... 43 RERF research ...... 43 Doses ...... 44 Uncertainties ...... 45 4.2 Cancer mortality ...... 45 4.3 Noncancer mortality ...... 48 4.4.1 Solid cancer incidence ...... 48 4.4.2 Incidence of leukemia and related cancers ...... 49 4.5 Incidence of noncancer disease ...... 50 4.6 Preconception and prenatal exposures ...... 51 4.7 Discussion ...... 52 Age, time and gender ...... 52 Dose-response curves ...... 52 Applicability to other contexts ...... 53

5. NUCLEAR WEAPONS TESTING ...... 58 5.1 Military personnel ...... 58 5.2 Semipalatinsk Test Site downwinders ...... 59 5.3 Nevada Test Site downwinders ...... 60 Leukemia ...... 60 Thyroid disease ...... 61 5.4 South Pacific testing ...... 63 5.5 Health effects in Scandinavia ...... 63 5.6 Discussion ...... 63

6. RADIATION WORKERS ...... 70 6.1 Introduction ...... 70 Exposure limits ...... 70 Assessing risks ...... 72 6.2 US facilities ...... 73 Hanford ...... 73 Oak Ridge ...... 75 Oak Ridge and age at exposure ...... 76 Rocketdyne ...... 77 Contents iii

Rocky Flats ...... 78 Lawrence Livermore National Laboratory ...... 78 Savannah River Site ...... 79 Los Alamos National Laboratory ...... 80 Portsmouth Uranium Enrichment Plant ...... 80 The Mound Facility ...... 81 Mallinckrodt Chemical Works ...... 81 Linde Air Products Company Ceramics Plant ...... 81 Feed Material Production Center (Fernald site) ...... 82 6.3 UK facilities ...... 82 Sellafield ...... 82 Other UK facilities ...... 83 6.4 Multi-site studies ...... 83 Pooled UK data ...... 83 Pooled Canadian data ...... 84 Pooled US data ...... 85 Pooled international data ...... 86 6.5 Discussion ...... 86 Leukemia and multiple myeloma ...... 87 Solid cancer ...... 88 Female workers ...... 89 Age at exposure ...... 89

7. MAYAK WORKERS ...... 97 7.1 Introduction ...... 97 7.2 Helath effects ...... 97 Lung cancer ...... 97 Bone cancer and liver cancer ...... 98 Leukemia and related cancers ...... 99 Non-cancer disease ...... 99 7.3 Summary ...... 99

8. URANIUM MINERS ...... 103 8.1 Introduction ...... 103 8.2 US studies ...... 104 Navajo miners ...... 106 Pathological observations ...... 106 8.3 Studies of miners in other countries ...... 106 Australia ...... 106 Canada ...... 106 China ...... 107 Czechoslovakia ...... 107 France ...... 107 Germany ...... 107 Sweden ...... 107 8.4 Combined estimates of risk ...... 107 8.5 Discussion ...... 108 Comparisons with residential radon studies ...... 108 iv Contents

9. RADIATION EXPOSURE IN FLIGHT ...... 113 9.1 Epidemiological studies ...... 113 9.2 Cell studies ...... 113 9.3 Discussion ...... 113

10. PRECONCEPTION EXPOSURES ...... 117 10.1 The Seascale leukemia cluster and the Gardner hypothesis ...... 117 10.2 Further studies of the Gardner hypothesis in the UK ...... 118 10.3 Preconception exposure in other settings ...... 119 10.4 Solid cancers in association with preconception expsoures ...... 120 10.5 Adverse birth outcomes in association with preconception exposures ...... 121 10.6 Cell studies ...... 121 10.7 Animal evidence ...... 122 10.8 Discussion ...... 122

11. NUCLEAR POWER ACCIDENTS ...... 130 11.1 Three Mile Island ...... 130 11.2 Chernobyl ...... 131 11.2.1 Dose reconstruction for Chernobyl downwinders ...... 131 11.2.2 Chernobyl emergency workers ...... 132 11.2.3 Childhood thyroid cancer ...... 133 11.2.4 Childhood leukemia ...... 135 11.2.5 Non-cancer effects in children ...... 136 11.2.6 Chernobyl discussion ...... 137

12. COMMUNITIES NEAR NUCLEAR FACILITIES ...... 145 12.1 Introduction ...... 145 Types of studies ...... 146 12.2 US studies ...... 146 Hanford ...... 146 Other US facilities ...... 147 Multi-site studies in the US ...... 148 12.3 UK studies ...... 148 Sellafield ...... 149 Dounreay ...... 149 Other UK facilities and multi-site studies ...... 150 12.4 Nuclear facilities outside the US and UK ...... 151 12.5 Discussion ...... 153

13. DISCUSSION ...... 167 The idea of a threshold dose ...... 167 Positive resluts at low doses ...... 167 Uncertainty and judgement ...... 171 Synthesis of information ...... 171 What if there is a threshold dose? ...... 173 Conclusion ...... 174

Contents v

APPENDIX A ...... 175 Leukemia ...... 175 A.1 About the Disease ...... 175 A.2 Atomic Bomb Survivors ...... 176 A.3 Medical Exposures ...... 176 Adult medical exposures ...... 176 Childhood medical exposures ...... 177 Medical exposure in utero ...... 177 Radiology occupation ...... 177 A.4 Worders ...... 177 A.5 Fallout ...... 178 Nuclear Weapons Testing ...... 178 Chernobyl ...... 178 A.6 Discussion ...... 178

APPENDIX B ...... 181 Thyroid disease ...... 181 B.1 Introduction to the Thyroid ...... 181 B.2 External Radiation and Thyroid Cancer ...... 182 B.3 Internal Radiation and Thyroid Cancer ...... 183 Fallout ...... 183 Chernobyl ...... 183 Medical exposure ...... 184 B.4 Non-cancer Thyroid Disease ...... 184 B.5 Discussion ...... 185

APPENDIX C ...... 187 Analysis of preconception exposure studies ...... 187

APPENDIX D ...... 194 Recent information ...... 194 Fifteen-country worker study ...... 194 Techa River cohort ...... 194 BEIR VII ...... 195

Acronyms & Abbreviations ...... 196

Glossary of Terms for Epidemiology and Radiation ...... 197

Bibliography ...... 211

Index ...... 243

List of Tables

Table 2-1 Studies of background radiation exposure ...... 18 Table 3-1 Studies of diagnostic x-ray exposure (including fluoroscopies and radiologists’ exposures) ...... 33 Table 3-2 Studies of external radiation therapy for benign disease ...... 36 Table 3-3 Studies of internal radiation exposure in diagnosis or treatment of benign disease ...... 39 Table 3-4 Studies of radiation therapy for cancer ...... 41 Table 4-1 ERR estimates (Sv-1) from the RERF analyses of the atomic bomb survivors .....46 Table 4-2 Studies of the atomic bomb survivors ...... 54 Table 5-1 Nuclear weapons test participants ...... 65 Table 5-2 Fallout from the Semipalatinsk test site in Kazakhstan ...... 66 Table 5-3 Fallout from the Nevada test site ...... 67 Table 5-4 South Pacific exposures to fallout from nuclear weapons testing ...... 69 Table 6-1 Leukemia in nuclear workers and atomic bomb survivors...... 88 Table 6-2 Facility-specific studies of occupational exposure ...... 90 Table 6-3 Studies of occupational exposure using combined datasets ...... 95 Table 7.1 Dose (Gy) received by Mayak workers at each of the three main facilities and auxiliary plants ...... 98 Table 7-2 Studies of Mayak workers ...... 101 Table 8-1 Comparison of miner data with residential radon studies ...... 109 Table 8-2 Studies of radon exposure in underground miners ...... 110 Table 9-1 Studies of cancer in flight personnel ...... 116 Table 10-1 Preconception irradiation and leukemia and non-Hodgkin’s lymphoma (LNHL) ...... 124 Table 10-2 Preconception irradiation and solid cancers ...... 126 Table 10-3 Preconception irradiation and stillbirths and congenital malformations ...... 128 Table 11-1 Studies of health effects around Three Mile Island ...... 138 Table 11-2 Health effects in Chernobyl cleanup workers ...... 139 Table 11-3 Childhood thyroid cancer in Chernobyl downwinders ...... 141 Table 11-4 Childhood leukemia in Chernobyl downwinders ...... 143 Table 11-5 Noncancer disease in Chernobyl downwinders ...... 144 Table 12-1 Cancer incidence (adult or all ages) near nuclear facilities ...... 156 Table 12-2 Childhood cancer incidence near nuclear facilities ...... 160 Table 12-3 Childhood cancer mortality near nuclear facilities ...... 164 Table 12-4 Adverse birth outcomes near nuclear facilities ...... 166 Table 13-1 Significantly positive risk estimates at low doses ...... 170 Table 13-2 Estimated risk of non-CLL leukemia in adults ...... 172 Table B-1 Thyroid cancer risk estimates for various exposures ...... 186 Table C-1 Candidate studies for inclusion ...... 188 Table C-2 Pooled result for paternal preconception x-rays ...... 190 Table C-3 Pooled result for paternal radiation occupation ...... 191 Table C-4 Exposure to a total preconception dose > 50 mSv ...... 192 Table C-5 Exposure to a total preconception dose in the 6 months before conception of > 5 mSv ...... 192

vi List of Figures

Figure 1-1 Average worldwide exposure to radiation sources; total exposure averages 2.8 mSv per year ...... 2 Figure 1-2 The evolution of health protection standards for nuclear workers ...... 4 Figure 1-3 The atom ...... 5 Figure 1-4 Types of radiation ...... 5 Figure 1-5(a) Alpha particle radiation occurs when an unstable nucleus (the parent nucleus) releases a particle equivalent to the nucleus of a helium atom (2 neutrons and 2 protons) thus leaving a nucleus with 2 less protons and neutrons (the daughter nucleus) ...... 6 Figure 1-5(b) Beta particle radiation occurs when a parent nucleus releases an electron (this is called a beta particle to differentiate it from the electrons that orbit the nucleus) ...... 6 Figure 1-5(c) After a decay reaction, the nucleus is often in an “excited” state...... 6 Figure 1-6 Examples of dose-response relationships ...... 11 Figure 2-1 A bar graph showing average annual natural radiation doses worldwide ...... 14 Figure 2-2. High background radiation areas around the world ...... 15 Figure 2-3 A map created by the EPA showing average indoor radon levels by county ...... 16 Figure 3-1 Average doses from diagnostic radiation exposures ...... 20 Figure 3-2 In the 1950s the panoramic X-ray machine was invented to take a picture of the whole mouth with just one exposure ...... 21 Figure 3-3 Relative risk of myeloid leukemia among adults according to the number of x-ray exams of the trunk (torso) in the period up to six months before leukemia diagnosis ...... 22 Figure 3-4 Thyroid cancer SIRs for patients who had been diagnosed for reasons other than suspicion of a thyroid tumor ...... 22 Figure 3-5 CAT scans deliver some of the highest doses of medical radiation to patients...... 23 Figure 3-6 In the late 1940s chest x-rays were used to screen for tuberculosis ...... 24 Figure 4-1 The bomb dropped over Nagasaki on August 9, 1945 was called Fat Man ...... 43 Figure 4-2 A view of the destruction of the city of Hiroshima ...... 44 Figure 4-3 A view from the air of the bombing of Nagasaki ...... 44 Figure 4-4a These figures show how the radiation exposure of the cities of Hiroshima and Nagasaki were studied ...... 47 Figure 4-4b These figures show how the radiation exposure of the cities of Hiroshima and Nagasaki were studied ...... 47 Figure 4-5 ERR estimates for total solid cancer incidence by gender and age at exposure ...... 48 Figure 4-6 Incidence ERR by age at exposure for selected cancer sites ...... 49 Figure 5-1 A map showing the approximate locations of worldwide nuclear bomb test sites ...... 58 Figure 5-2 Military observers shield their faces from the Teapot Test in 1955 ...... 59 Figure 5-3 Atmospheric test Grable conducted in 1953 at the Nevada Test Site ...... 60 Figure 5-4 Per capita thyroid doses resulting from all exposure routes from all test ...... 62 Figure 5-5 A nuclear test conducted as part of Operation Crossroads off Bikini atoll in the Marshall Islands in 1946 ...... 63 vii viii List of Figures

Figure 6-1 The United States nuclear weapons complex comprised dozens of industrial facilities and laboratories across the country ...... 71 Figure 6-2(a) The first external monitoring devices were pocket ionization chambers and pocket dosimeters (basically tubes the size of pens containing a wire with an electrical charge that decreased upon exposure to radiation) ...... 72 Figure 6-2(b) Pocket dosimeters were replaced by film badges. A worker here is pictured checking film badges in 1974 ...... 72 Figure 6-3 Located at the Hanford site in Washington and completed in September 1944, the B Reactor was the world’s first large-scale plutonium production reactor ...... 74 Figure 6-4 Plutonium is handled through a glovebox at the Plutonium Finishing Plant at the Hanford site ...... 75 Figure 6-5 A low-level solid waste burial ground at Oak Ridge National Laboratory ...... 76 Figure 6-6 The effect of exposure age on the risk of cancer mortality in Oak Ridge workers ...... 77 Figure 6-7 Radiation-safety technicians check workers for contamination before they exit a Rocky Flats facility ...... 77 Figure 6-8 Today the X-Y Retriever Room at Rocky Flats is used to store surplus plutonium ...... 78 Figure 6-9 Association between lung dose and lung cancer mortality among Rocky Flats workers employed for 15-25 years ...... 79 Figure 6-10 A pool type reactor at the Livermore facility is pictured here ...... 80 Figure 6-11 Dr. John Gofman (second from left) at the time that this photo was taken (1960s) was the first Associate Director for the Biomedical Program at Lawrence Livermore National Laboratory ...... 80 Figure 6-12 Barrels of transuranic waste site on a concrete pad at the Savannah River Site ...... 81 Figure 6-13 A worker holding uranium metal product at Fernald ...... 82 Figure 6-14 A facility at Hanford for treating persons injured by embedded radioactive particles (circa 1967) ...... 86 Figure 8-1 The process of uranium mining and milling from ore to its reactor useable form is depicted here ...... 103 Figure 8-2 Uranium mines in the US are predominantly located in the southwest and central parts of the country ...... 105 Figure 8-3 Many uranium mines were located on Native American reservations ...... 107 Figure 8-4 Dependence of lung cancer risk estimate on dose based on a combined analysis of the lung cancer mortality risk in 11 cohorts of miners ...... 108 Figure 11-1 Radiation emissions and incidence of lung cancer, 1981-1985, in the TMI 10-mile area ...... 130 Figure 11-2. Researchers at the Lawrence Livermore National Laboratory map the plumes of radiation originating from the Chernobyl accident ...... 132 Figure 12-1 A map showing the approximate location of worldwide commercial nuclear plants 145 Figure 12-2 A leaky drum at the 903 pad at Rocky Flats. Photo courtesy of the U.S. Department of Energy ...... 148 Figure 12-3 Native Americans from San Ildefonso Pueblo and Los Alamos residents ...... 149 Figure 13-1 Estimated solid cancer mortality risk coefficient over increasing ranges of dose ...... 174 Figure A-1 Leukemia risk across exposure ages in populations downwind of Chernobyl and the Nevada Test Site ...... 180 Acknowledgments

We are indeed grateful to those who have helped bring about this document, assisting us in the research, writing, and compilation of figures, tables, and images. Without Abel Russ, Research Associate at the George Perkins Marsh Institute, Clark University, this project would not have been realized. He was the primary researcher and writer of this document. Casey Burns provided thoughtful research and lead writing on major sections of the manuscript. Several research assistants, Jessica Cook, Rose Heil, and Katie Scott explored some of the many studies included in this document.

Our discussions with Rob Goble, Research Professor at the Marsh Institute and Physics Professor at Clark University, in the early conceptual stages of the book, helped us get off to a good start. Seth Tuler, Research Fellow at the Marsh Institute, encouraged us and made suggestions along the way. Lu Ann Pacenka, Desktop Publisher at the Marsh Institute, played a key role in the layout and design of this document.

We are grateful also to the members of the Western Shoshone tribes in Nevada and California, Southern Paiutes bands in Utah, members of the Laguna and Acoma Pueblos in New Mexico and organizational members of the Alliance for Nuclear Accountability with whom we have worked over the years and all of whom have inspired us to produce this manuscript.

The production of this resource was made possible through a grant from RESOLVE, Inc. on behalf of the Citizens’ Monitoring and Technical Assessment Fund (CMTA). The Fund was created as part of a 1998 court settlement between the U.S. Department of Energy and 39 nonprofit peace and environmental groups around the country. The Fund provided financial support to organizations, such as ours, to conduct technical and scientific reviews and analyses of environmental management activities at DOE sites and to disseminate those reviews and analyses.

My thanks and appreciation to all.

Octavia Taylor, Program Manager Community-Based Hazard Management George Perkins Marsh Institute Clark University Worcester, MA

ix 1 INTRODUCTION dial painters. In light of the ongoing generation of relevant information we have decided to consider 1.1 Goals our overview a work in progress and plan to release supplements of this initial review in the future. The health risks of exposure to low levels of Our intended audience is not necessarily one that ionizing radiation are disputed within the scientific has been scientifically trained and so scientific terms community. Risks associated with exposure to high will be discussed and defined in a glossary found at levels of radiation are widely accepted and well the end of the overview. The two following terms documented based primarily on the studies of the from our title defined the scope of our overview: atomic bomb survivors in Nagasaki and Hiroshima. Ionizing radiation refers to radiation that has Some feel that the best way to estimate risk for low- enough energy to remove an electron from a neutral level exposures is to extrapolate from higher doses, atom or molecule, creating a free radical. Ionizing although there is some clear evidence of low-dose radiation is capable of creating DNA damage that risk. In this overview we have attempted to give an can lead to cancer. Radiations from sources such as unbiased summary of the available research with power lines, cell phones, and traffic radars are all an emphasis on the lower doses. The strengths and classified as non-ionizing radiation because they weaknesses of the studies are explained in order are not capable of removing an electron. There is to help assess the variety of sometimes conflicting ongoing research concerning health effects of non- evidence. ionizing radiation but it will not be covered in this Not every epidemiological study that has ever overview. been done on the risks of radiation is included in Low dose. Although we have collected studies this overview. The body of research is simply too of a wide range of exposures we should define a low great for us to have collected and read every study. dose as a reference point for the reader. Generally We attempted to collect studies generally considered speaking, a dose is low relative to doses where to be key for the various sources of exposure and the evidence of a health risk is more robust. The to exhaust our own capabilities to collect as many Department of Energy’s (DOE) Low Dose Radiation studies as possible. Our search methodology Research Program2 has the fuzzy definition of any included the use of the PubMed search engine dose not documented to show significant health risks; and smaller follow-up searches through the end of they generally consider a low dose to be below 10 2003. Another source of epidemiologic data is the rem or 0.1 Sieverts (Sv). The Health Physics Society DOE Office of Environment, Safety and Health’s recommends that exposures below 0.1 Sv only be “Comprehensive Epidemiologic Data Resource”1, evaluated qualitatively as the risks are too small to which provides data sets and studies relating to be observed. For the purposes of our overview we worker health at DOE facilities, populations residing have considered doses below 0.1 Sv to be low. near DOE sites, atomic bomb survivors, and radium

1 http://cedr.lbl.gov 2 www.lowdose.org 1 2 Introduction

1.2 A brief history of radiation domestic testing location that could ease logistical and security concerns. Prior to this tests had been The history of the relationship between science, conducted in the South Pacific. The fallout from radiation and health goes back to the late 19th the test sites and the occupational hazards of the century. X-rays were first discovered in late 1895 workers in the mines and in the weapons factories and dangers associated with exposure became were adding to the range of radiation exposures that apparent very quickly. In 1896 the first injuries we experience. due to x-ray exposure were recorded and in 1904 Thomas Edison’s assistant Clarence Dally was the 1.3 Exposure first person recorded to have died as a result of x-ray exposure. Despite the risk, the use of x-rays for a People are exposed to ionizing radiation from many variety of applications rapidly caught on. During the different sources. The exact amount depends on where First World War portable x-ray machines were used they live, what their jobs are, what their lifestyles are on both sides to locate shrapnel and to set broken like and so on. Over 80% of total average exposure bones. comes from natural sources. Manmade sources such Radium was discovered in 1898 and its use in as consumer products that emit radiation, fallout medicine also spread very quickly. In the 1920s, from the US and global nuclear tests, diagnostic and sickness and death in watch dial painters, who therapeutic medicine, radiation from nuclear plants ingested small amounts of radium in their work, and occupational exposures make up the rest. The taught scientists and doctors that internal exposure following pie chart gives the estimated worldwide to radium could be harmful. It was also during the average exposure spectrum. 1920s that the cancer risks of radiology became It should be noted that illustrations such as the apparent. Some awareness was beginning to spread pie chart (Figure 1-1) presented here can be used that radiation exposure from the new technologies to minimize the importance of manmade sources of could be harmful and in 1928 the first internationally radiation. For example, one may argue that fallout recognized radiation safety guidelines were from test sites contributes a mere fraction, less than published. 1%, of the total exposure to ionizing radiation. On There was still a popular enthusiasm about the other hand this is an involuntary exposure that radiation during this time. Between 1920 and 1950 ������������������������� ������������� patents were registered for radium toothpaste, radium �������������������� ����� hearing aids and radium tonic water. As World War II emerged in the 1930s plans for building a nuclear bomb were made. Plutonium was discovered in ���������� �������������� 1940 and the Manhattan Project, with its goal to ������� ��������� ��� “make the bomb”, was initiated in 1942. On July 16, ��� 1945 the first nuclear weapon was detonated in New Mexico. At the time of the test the type of fallout that ����������������� ���������������� ��� ���������� would result was something of a mystery. In August ��� of 1945 two nuclear bombs were dropped on Japan in Nagasaki and Hiroshima. In the weeks after the bombs, radiation exposure was not discussed in the ������������������� �������������� US press. ��� In the 1950s the US government began a campaign for a more friendly attitude toward nuclear science and promoted civil nuclear power. There were hundreds of uranium mines across the country serving both the nuclear power industry Figure 1-1. Average worldwide exposure to radiation and the nuclear weapons industry. In 1951 the US sources; total exposure averages 2.8 mSv per year established the Nevada Test Site in order to have a (UNSCEAR 2000). Introduction 3 may be of little benefit to those who bear the burden Postal Service (USPS), and the Department of risk. of Transportation (DOT). Naturally occurring A figure such as this can also be misleading radionuclides are normally regulated by state because of the variability of individual exposure governments. Twenty nine states regulate byproduct histories. For example, a person who works in a radioactive material and radiation devices within the nuclear facility will probably be exposed to more state.3 manmade radiation than a person who does not; this Two series of reports provide much of the data will alter the distribution of the pie chart and the used in radiation standard setting. The reports are overall amount of exposure. A person who lives in produced by the National Academy of Sciences’ an area of particularly high fallout from the Nevada Committee on the Biological Effects of Ionizing Test Site will also have a different exposure pattern Radiation (NAS/BEIR) and the United Nations than the average American, and so will someone Scientific Committee on the Effects of Atomic with a history of extensive diagnostic radiation for a Radiation (UNSCEAR). Both committees prepare medical condition such as scoliosis. reports as new data or analyses are made available indicating that previous risk estimates need to be 1.4 Standards revised either up or down. A relatively new radiation protection advisory In 1946 the Atomic Energy Act established the committee was formed in 1997, the European Atomic Energy Commission (AEC) to maintain Committee on Radiation Risk (ECRR). This control of atomic technology and to further its use committee was formed by the Green Group in the for military purposes. In 1954 Congress passed new European Parliament to discuss details of recent legislation outlining three roles for the AEC: 1) progress in radiological protection standards. continue its weapons program, 2) promote the private The ECRR strives to make no assumptions about use of atomic energy for peaceful application, and 3) radiation safety based on preceding analyses and protect public health and safety from the hazards of to remain independent of previous risk assessment commercial nuclear power. It soon became apparent committees such as the ICRP and the UNSCEAR. A that there was a conflict of interest with the same report from the ECRR was released in 2003. agency promoting the use of nuclear power and Over the years, as the general consciousness setting the standards of safety for this use. In 1974 has evolved about the risks of radiation exposure, Congress divided the AEC into the Energy Research the international and national radiation protection and Development Administration (ERDA) and standards have dramatically changed. Figure 1- the Nuclear Regulatory Commission (NRC). The 2 depicts the change in protection standards for NRC is not the sole agency with regulatory power nuclear workers. Because there is no one standard regarding nuclear safety. The Federal Radiation that all facilities and workplaces follow, the figure Council, established in 1959 and consolidated into is based on recommendations of a variety of sources the Environmental Protection Agency (EPA) in and summarizes the overall trend of standards. 1970, advises the President regarding radiation and health. The EPA’s radiation protection guides (RPG) 1.5 Radiation basics are approved by the President and have the force and effect of law as all federal agencies are required to The physics and chemistry of radiation can be follow them. NRC regulations, which nuclear power confusing, and the extensive terminology associated facilities must follow, must be consistent with the with radiation makes the problem much worse. RPGs. Other agencies responsible for regulating We present below a minimum of information to aspects of radiation exposure include the Food avoid clouding our focus on epidemiology. Much and Drug Administration (FDA), the Occupational more information is available online in the form of Safety and Health Administration (OSHA), the tutorials and factsheets4.

3 www.fpm.wisc.edu/safety/Radiation/2000%20Manual/chapter3.pdf 4 For example: www.physics.isu.edu/radinf/cover.htm or www.nirs.org/factsheets/whatisradiation.htm 4 Introduction (Department of Energy, Office of Environmental (Department of Energy,

Figure 1-2. The evolution of health protection standards for nuclear workers Management 1996). Introduction 5

speed electrons that are emitted from an unstable nucleus. Since these are smaller than alpha particles they can penetrate deeper, roughly a centimeter, into tissue. In order for alpha and beta particles to cause biological damage they must enter the body (through inhalation or ingestion). Gamma rays are photons, or packets of light energy. Gamma radiation represents the energy lost when the particles within the nucleus reorganize into more stable arrangements and they accompany other forms of radiation. X-rays, like gamma rays, are photons. Unlike gamma rays, x-rays originate Figure 1-3. The atom. A simple depiction of a helium atom in electron fields around the nucleus5. Gamma and with approximate locations of the positively charged x-rays can pass through the body and are thus are protons and the neutrally charged neutrons in the atom’s the most important source of external radiation nucleus and the negatively charged electrons orbiting exposure. outside the nucleus (www.ocrwm.doe.gov/.../images/ Different types of radiation have distinct damage ymp0403graphics.htm). potential described by their Linear Energy Transfer (LET). LET refers to the energy deposited in the Ionizing radiation is typically emitted when a surrounding medium, and thus potential damage, radioactive, unstable nucleus rearranges itself into a per unit of distance traveled. Alpha radiation is high- more stable state. A stable atom has an equal number LET because it deposits a relatively large amount of of protons and neutrons in its nucleus (Figure 1- energy in a small area before it stops. Beta, gamma 3). Stable iodine, for example, has 53 protons and and x-radiation are low-LET because they deposit 53 neutrons. An atom is defined by the number of energy in a more diffuse pattern. protons it has; iodine is iodine because it has 53 protons. An atom can have a different number of neutrons, however, and in this case it is an unstable isotope of the atom. Iodine-131, for example, an important isotope in nuclear fallout, has 53 protons and 78 neutrons. We call it Iodine-131 because the combined number of protons and neutrons is 131. This number is also commonly written as a superscript prefix, for example “131I”. This isotope is radioactive, meaning that it will spontaneously rearrange itself at some point in the future. When it does it will emit one or two forms of ionizing radiation. The three major types of ionizing radiation that radioactive substances emit are alpha particles, beta Figure 1-4. Types of radiation. Alpha particles are comparatively large and are not able to pass through particles and gamma rays (Figures 1-4, 1-5). Alpha skin or a sheet of paper. A beta particle is smaller and can particles consist of two protons and two neutrons, pass through a piece of paper but is stopped by a sheet of making them identical to the nucleus of a helium aluminum foil. A gamma ray can pass through both paper atom (Figure 1-3). These particles are relatively and aluminum foil (and the human body) but is stopped large and can only travel short distances. They are by lead or concrete (www.ocrwm.doe.gov/.../images/ also easily stopped by skin. Beta particles are high- ymp0403graphics.htm).

5 The generation of x-rays is largely artificial. A good, simple, online illustration is available at http://www.colorado. edu/physics/2000/xray/making_x-rays.html 6 Introduction

Figure 1-5(a). Alpha particle radiation occurs when an unstable nucleus (the parent nucleus) releases a particle equivalent to the nucleus of a helium atom (2 neutrons and 2 protons) thus leaving a nucleus with 2 less protons and neutrons (the daughter nucleus).

Figure 1-5(b). Beta particle radiation occurs when a parent nucleus releases an electron (this is called a beta particle to differentiate it from the electrons that orbit the nucleus).

Figure 1-5(c). After a decay reaction, the nucleus is often in an “excited” state. This means that the decay has re- sulted in a nucleus which still has excess energy to get rid of. Rather than emitting another beta or alpha particle, this energy is lost by emitting a pulse of electromag- netic radiation called a gamma ray (www.doh.wa.gov/.../ Fact%20Sheet%203.htm). Introduction 7

The terminology associated with radiation and 1.6 Epidemiological methods radiation dose is very confusing. There are units of radioactivity, of energy deposited in matter, and of Epidemiology is the statistical study of disease in biologically relevant dose. In addition, two common human populations. In epidemiological studies units (rad and rem) have been replaced with larger researchers attempt to identify and analyze units for the same things (grays and sieverts). The relationships between health effects and possible units are: causes. This is difficult, in general, because there are many confounding factors in any study that make a • Curie (Ci). The curie is a unit used to simple cause-and-effect relationship hard to isolate. measure radioactivity. One curie is a quantity In studies of cancer these confounding factors might of a radioactive material that will have include, among other things, genetic predisposition 37,000,000,000 transformations, or nuclear or exposure to carcinogens other than the one decays, in one second. Often radioactivity is being studied. If a study population demonstrates expressed in smaller units like a thousandth of a an elevated cancer rate these confounding factors curie (mCi), a millionth of a curie (uCi) or even make it hard to determine the cause. There is also a billionth of a curie (nCi). considerable uncertainty in any epidemiological • Becquerel (Bq). A Becquerel is a unit that study. Researchers can never exactly quantify describes one radioactive disintegration per exposure or the true background rate of a disease, second and is therefore a much smaller version for example. Uncertainties in studies of cancer are of the curie. There are 37,000,000,000 Bq in one compounded by the random nature of cancer: Out Ci. of a group of people exposed to a carcinogen some • Gray (Gy). The gray is a unit of absorbed dose. might get cancer and some might not; this is partly This relates to the amount of energy actually determined by chance. deposited in some material, and is used for any Epidemiological studies of low-dose radiation type of radiation and any material. present several unique challenges. People are exposed • Rad. The rad (radiation absorbed dose) is the to radiation from a variety of sources, both natural older unit of absorbed dose. One rad is equal to and manmade, and as we discussed above there is 0.01 Gy. considerable variability in this exposure. Although • Sievert (Sv). The sievert is used to express we can estimate average exposures we never know effective dose, or the biological damage exactly how much radiation an individual has been potential of some amount of radiation. Effective exposed to or from what sources this radiation dose is typically calculated by multiplying the came. When we consider that people are always absorbed dose by a factor specific to the type of experiencing some background radiation exposure radiation. This is usually called a quality factor (and exposure to other carcinogens), and that there or relative biological effectiveness factor. For is always a background cancer rate, the effects of low-LET radiations this factor is typically close small additional doses can be very hard to detect. to or equal to one so that one Sv is approximately In some cases, such as workers at nuclear weapons equal to one Gy. For high-LET radiations like facilities, researchers have some idea of individual alpha particles the factor might be as high as exposures from measurements that have been made. twenty. In other cases, for example communities around • Rem. The rem (roentgen equivalent in man) is nuclear facilities, there are no such measurements. the older unit of effective dose. One rem is equal Statistical significance. Because of these to 0.01 Sv. difficulties epidemiological studies cannot prove or disprove causation. Instead epidemiological For this overview we have chosen to use units of Gy studies can suggest associations; these associations or Sv for dose. Where the primary source used rad carry statistical power based on how strong the or rem we have made the appropriate conversion. relationship is and how well the study was designed. 8 Introduction

In epidemiological studies researchers often look the scientific community is less enthusiastic about for and highlight “significant results”. This is publishing statistically inconclusive findings. There confusing because the word ‘significant’ has a is an even stronger potential bias when a statistically statistical meaning that is different from its everyday inconclusive result is held up as evidence that “there meaning. To a person concerned about health risks was no effect”. In cases where conditions prevent a from an exposure, any disease, risk or exposure robust epidemiological design, for example a small is significant. When epidemiologists speak of community exposed to a small amount of radiation, a significance, however, they are talking about a very real effect might not be detected and the community specific definition. Statistical significance typically will be faced with a scientific publication implying refers to the circumstance where the results of a that there was no risk from the exposure. In 1991 study have less than a 5% likelihood of occurring by the National Research Council’s Committee on chance. The standard for calling a result significant Environmental Epidemiology went so far as to can vary, but in any credible scientific report a study say that conventional approaches to environmental author will always provide the criteria that they use epidemiology may not only place an unfair burden for significance. In this overview we will frequently on communities for proving causation but may refer to the significance of results; we will use the actually be promoting bad science. The report stated scientific definition of the word. that “under some circumstances this stipulation Statistical power depends on large numbers. [the high threshold for statistical significance] can Imagine a very small community of two people. stifle innovation in research when studies that fail to Each person has a small chance of getting cancer and meet the conventional criteria for a positive finding when they are exposed to a carcinogen this chance are prematurely dismissed”. There is a classic and increases. Imagine that these people are exposed to important phrase relating to this issue: the absence of a small amount of a carcinogen and ten years later evidence is not evidence of absence. In other words, one of them develops cancer. You could fairly say it can never be proven that there was “no risk”, even that half of the community developed cancer. On the when we can’t detect a significant increase. We other hand it would be very difficult to show that it discuss further the notation of significance in the wasn’t just by chance. As a more realistic example ‘risk terminology’ section below. consider a community of several thousand people. In Study designs. There are two categories of this community, based on national rates, we expect epidemiological study design, descriptive and that 80 people will get cancer during our study. This analytical. Descriptive studies explore associations is an uncertain rate, however, varying from place to between exposure and disease and sometimes precede place, and so 75 or 85 cases of cancer might not be more expensive and time-consuming analytical unusual. But what if this community is exposed to studies. Ecologic studies, for example, compare radiation from a small nuclear release and in our study disease rates between populations based on public period 87 people get cancer? These are 7 cases more records and use data at the group level (county, town, than we expected, but there is still some possibility etc.) and not the individual level. Descriptive studies that this increase was just bad luck. Epidemiology are capable of generating suggestive evidence of a is based on estimating the likelihood that the result cause-and-effect relationship but are not very good occurred by chance and calculating the significance at ruling out alternative explanations for an observed of the result. In our example an epidemiologist effect. might say that there was a 12% chance of getting 87 Analytical studies are usually considered to be cancer cases without any exposure. In this case the stronger and more reliable than descriptive studies result would not be significant. If the epidemiologist because they can address confounding variables said that there was only a 2% chance of getting this and help rule out alternative explanations. The two result, however, it would be significant. analytical study designs are known as case-control The 5% level is a widely accepted convention studies and cohort studies. In a case-control design for significance but it is of course an arbitrary cutoff. people who have a particular disease (cases) are Statistical significance can introduce a bias when matched with people who do not (controls). The cases Introduction 9 and controls are matched according to potentially 1.5. This unit becomes more important in describing confounding variables (age, smoking, gender, etc.). dose-response relationships, described below. The cases and controls are assessed to determine if Odds Ratio (OR). An odds ratio compares the a certain risk factor like radiation is more prominent odds of a disease among an exposed population to the among the cases. odds of a disease among an unexposed population. Cohort studies look at things the other way “The odds” in this case means the number of times around, comparing populations based on known an event happens versus the number of times it does exposures rather than known disease outcomes. In a not happen. In the example given above the odds typical cohort study design an exposed population is of an exposed person getting cancer are 5/9,995 = followed through time to see if they develop diseases 0.00050025, because 5 out of the 10,000 had cancer more than a non-exposed population. Cohort studies and 9,995 did not. The odds of an unexposed person can either be done retrospectively (looking back in getting cancer are 2/9,998, or 0.00020004. In order time) or prospectively (following a population into to find the odds ratio, you would divide the odds of the future). the exposed person by the odds of the unexposed The result of any of these epidemiological person. The odds ratio in this example would be designs is an expression of the rate of a disease in the 2.50075. For rare outcomes like cancer the odds study population compared to some reference value, ratio is very similar to the relative risk. Odds ratios and this could be matched controls from within the can sometimes be difficult to interpret intuitively study, national disease rates, or some other standard. although they can be mathematically beneficial. This is discussed more below. Odds ratios are often used in case-control studies where disease prevalence is unknown among the 1.7 Risk terminology general population. Excess Absolute Risk (EAR). The excess Researchers use different terms when quantifying absolute risk describes the exact number of cases of risk depending on study design and their own a disease that we should expect, without reference goals and preferences. Some of these concepts can to the background rate. In our example we have 5 be applied to either disease incidence or disease cancer deaths, which are two more than we expected. mortality. The following list scratches the surface of The EAR in this case is 2/10,000 or 0.0002. EAR, an epidemiologist’s glossary but should be sufficient like ERR, is often used to describe dose-response for our purposes: relationships (discussed below). Relative Risk (RR). The relative risk is a ratio Standardized Incidence Ratio (SIR) is a ratio of disease rates in exposed and unexposed groups of the number of cases of a disease observed in the without units of dimension. If, for example, the study population to the number of cases that would cancer rate in an exposed population is 5 out of be expected in the study population. The expected 10,000, and in the unexposed population the rate number is calculated by recreating a hypothetical is 2 out of 10,000, the relative risk would be 5 study population out of a standard reference group. divided by 2, or 2.5. Relative risks are sometimes This standardization helps to eliminate differences given in percentages. An author may explain the between the study population and the reference above example by saying that the RR equals 250%, group. For example, if our study population were meaning that the risk in the study population is comprised of 70 children and 8 adults we would not 250% of the risk in the unexposed population. A want to base our expected number on the average Rate Ratio is typically equivalent to a relative risk, US. Instead we would calculate the US incidence particularly at low disease rates. Both incidence and among children and the US incidence among adults mortality can be described with a relative risk. and combine these rates in proportions that are Excess Relative Risk (ERR) is simply the appropriate for our study group. relative risk minus 1. This number refers to the Standardized Mortality Ratio (SMR) is additional risk of a disease that can be associated similar to SIR but measures mortality rather than with an exposure. In the example given above the incidence. Studies using SMRs and SIRs are usually ERR would be equal to the RR (2.5) minus one, or ecologic studies and are rarely done with enough 10 Introduction precision to detect low-dose effects. result. In general, if the low end of the confidence P-value. As we discussed above, there is interval is greater than 1 (for odds ratios and relative considerable uncertainty in any study of low-dose risks) then the result is significant. radiation and in epidemiologic studies generally. To deal with this problem there are statistical ways of 1.8 Dose-response curves describing how well we know what we know. The simplest way is to say whether a result is significant When describing risk over a range of doses, scientists or not. This is accomplished with the p-value, which usually define a dose-response relationship. This is gives an estimate of the probability that the result a way of eliciting some general pattern of behavior occurred by chance. A p-value of 0.01, for example, from the data. There are two primary questions to ask indicates that the result could have happened by when determining what a dose-response relationship chance only 1 out of 100 times. The results of a really looks like. The first question is where the line study are often given with an indirect reference to starts. The second question is whether or not the the p-value by saying that the p-value is less than line is straight. We show examples of the common some threshold (0.1, 0.01, 0.05, etc.). This is done curves in Figure 1-6 and discuss them below. to demonstrate that the result passes the significance It is generally assumed that risk is proportional test. The threshold for significance, as we mentioned to dose; the simplest version of this assumption is above, is usually a 5% probability of the result the linear dose-response relationship (Figure 1-6, occurring by chance, and so a p-value less than 0.05 curve A). Much research has shown that a linear is generally indicative of a significant result. model fits well, especially at low doses. With this Confidence interval. A confidence interval model 2 Gy should be twice as effective as 1 Gy at gives a range of possible results, and for some generating a risk, and one tenth of a Gy should be purposes this is more informative than the ‘best one tenth as effective. Results based on this model guess’. This range of possibilities could theoretically are typically expressed in terms of excess relative extend into infinity and so it is usually truncated risk (or excess absolute risk) per dose. You will read at some predetermined level of certainty. A 95% below, for example, that thyroid cancer following confidence interval, for example, will include the childhood exposure to external radiation has an range within which we are 95% sure the true answer ERR of 7.7/Gy. This means that that a dose of 1 Gy lies. The confidence interval typically follows a risk is expected to result in an excess relative risk of 7.7. estimate in the following manner: RR 2.13 (95% CI A dose of 0.1 Gy is expected to result in an excess 2.00-2.26). This means that the true relative risk is relative risk of 0.77; 0.01 Gy is expected to result in probably between 2.00 and 2.26, the author is 95% an excess relative risk of 0.077. Remember that the sure that it is, and the most likely estimate is 2.13. relative risk is equal to (the excess relative risk + The confidence interval gives us a shortcut to 1). assessing the significance of a result. Consider a If there is some dose below which no risk is relative risk. A relative risk of 1 signifies that an expected then the dose-response curve does not exposed group has the same risk as a control group originate at zero, it originates at the threshold dose. and there is thus no evidence of an additional risk. If This is also shown in Figure 1-6 (curve B). With this we have a relative risk of 1.01, and a 95% confidence model we assume zero risk for all doses less than interval of 0.98-1.08, then we have a positive the threshold and assume that risk is proportional to result but not a significantly positive result. This is dose above the threshold. because our range of possibilities, indicated by our At doses over a few Gy the dose-response confidence interval, includes the possibility that there relationship is not linear and there is evidence for is no additional risk (RR=1) and even the possibility nonlinearity at lower doses for certain types of that the exposure decreased our risk (RR<1). If, on cancer. There are different types of these curved the other hand, we have a relative risk of 1.06 and a lines. A quadratic model predicts that biological 95% confidence interval of 1.03-1.12, then we can effects increase faster than increases in dose; this say that we are 95% confident that the true risk is is not typically used to describe a cancer response greater than 1; this would be a significantly positive by itself but is often combined with a linear model Introduction 11

in a linear-quadratic curve (Figure 1-6, curve C). The standard model used by agencies responsible In this case the linear term predominates at lower for radiation protection is the linear no-threshold doses and the quadratic term predominates at higher model. As we mentioned, this model assumes that doses. This model has been applied to some types of risk is directly proportional to dose and that every leukemia in the atomic bomb survivors, for example6. dose carries some amount of risk. This is the simplest It seems to fit the data at relatively low doses but model, and although there is evidence for departure is less appropriate for high doses. A sigmoid curve from the model in some cases it tends to fit the data (Figure 1-6, curve D) is concave-up at low doses and reasonably well. concave-down at higher doses. This is not commonly used although it is good at describing the response 1.9 Overview structure pattern at higher doses where cell-killing becomes an important consideration. The supralinear model Epidemiological studies based on low-dose radiation (Figure 1-6, curve E) has been found to fit some data exposure are often inconclusive and it is difficult sets well, especially those focusing on low doses, and or impossible to show links of causation with there are biological reasons why we might expect certainty. The best way to assess the reality of risk this kind of curve in some cases. In this model, the is to examine the overall body of studies, pool the line is steeper at lower doses (the effect per dose is many years of research, and weigh the evidence. We greater at low doses). have tried to make this task easier by collecting the

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Figure 1-6. Examples of dose-response relationships.

6 There are biological reasons why this shape would be chosen, aside from the fact that it tends to fit the data. Little (2000), for example, suggested that the shape of the dose-response curve for leukemia in the atomic bomb survivors is similar to that for radiation-induced chromosome damage in blood cells (although the comparison was highly uncertain). 12 Introduction available information and presenting the essence of Leukemia, CML, etc.) and we also periodically each study with a minimum of interpretation. adopt a convention for grouping leukemia and The optimal organization scheme depends on the non-Hodgkin’s lymphoma as LNHL. intent and interest of the reader; some readers may • The difference between absolute and relative risk be interested in a particular disease, others may be rests on important biological assumptions. If we interested in a particular type of radiation, and others assume that radiation increases an underlying may be interested in specific sources of radiation. We probability of cancer then we use the relative have organized the overview primarily by radiation risk. For example, the number of stomach source. Natural background exposure and medical cancer cases that we expect might depend on the exposure are covered in sections 2 and 3, exposure underlying stomach cancer risk. This is different to fallout from the atomic bombs and from weapons between the US and Japan because of diet and testing are covered in sections 4 and 5, and sections maybe other factors. 6-9 deal with various occupational exposures. If, on the other hand, we assume that Section 10 addresses the risks of exposure prior radiation confers an independent risk, not to conception of a child (also mainly occupational affected by the underlying risk, then we use exposures). Section 11 deals with the accidents at the absolute risk concept. Under absolute risk Chernobyl and Three Mile Island and Section 12 assumptions a certain dose would produce the covers studies of communities near nuclear power same number of cancers in any population. and nuclear weapons facilities. We have also included We have kept our emphasis on the relative risk appendices that deal with specific diseases, leukemia model, rather than the absolute risk model, and thyroid cancer, and an appendix that presents an based on a belief that the relative risk model is analysis of the risks associated with preconceptional more plausible biologically and in order to keep exposure (following up on section 10). Each section the presentation of results less cluttered. includes a brief introduction followed by a review of • The 95% confidence level is by far the most the available epidemiological studies for that source common degree of confidence; we have of exposure. At the end of each section we have simplified the notation by dropping the ‘95% included a table where we list both quantitative and CI’ when the confidence interval is 95%, writing qualitative information about each study. We have out the confidence level only in those cases not attempted any kind of comprehensive summary; where the author uses another percentage. For the effects of radiation vary by dose, by age at example ‘RR 2.13 (2.00-2.26)’ should be read exposure, and so on, and so such a simple answer as ‘a relative risk of 2.13 with a 95% confidence to the question at hand would be misleading. Our interval of 2.00 to 2.26’. concluding section (section 13) is a discussion that • We have chosen to use units of Gy or Sv for dose. returns the focus to low doses and considers some Where the primary source used rad or rem we possible interpretations of the data. have made the appropriate conversion. We have A few notes on the conventions we adopted for also frequently used units of mGy (thousandth writing this overview: of a Gray) or mSv (thousandth of a Sievert).

• Several acronyms appear regularly throughout If you read through the overview in order you might the overview. We have supplied a list of acronyms notice small differences from section to section. This along with the glossary. The most common will is because we wrote this as a large and revolving team be the risk units described above (RR, ERR, and authorship varied by section. We have done our OR) and the names of certain agencies (National best to preserve the document’s fluidity and intent Cancer Institute, NCI, and Department of throughout. Any questions, suggestions for updates, Energy, DOE). Types of leukemia are often or comments can be addressed to Octavia Taylor at refered to by their common acronyms (Acute the George Perkins Marsh Institute. Lymphocytic Leukemia, ALL, Chronic Myeloid 2

BACKGROUND RADIATION include chromosomal aberrations and childhood and adult cancers including leukemia, osteosarcoma, and 2.1 Introduction melanoma (Henshaw et al. 1990). Indeed, as of 1989 according to Caufield, “most scientists believe[d] Exposures to ionizing radiation that result from that natural radiation cause[d] about one per cent of human activities such as nuclear testing often receive all fatal cancers”. significant popular attention. However, the largest Estimates of average annual background proportion of radiation around the world is emitted radiation exposure center around 0.003 Sv (3 mSv), by natural sources. Most of the exposure typically about two-thirds of which comes from radon. There received by the public is produced by cosmic rays, is considerable variability in individual annual terrestrial radiation, and internally deposited natural exposure according to geology, elevation, and radionuclides (Samet 1997). According to Hoel other factors. Smokers, for example, are exposed (1995), radon alone, one source of background to roughly twice as much radiation as nonsmokers radiation that enters indoor environments from due to radionuclides in tobacco smoke1. These are the soil and irradiates the lung through inhalation, within the range of doses that would be considered accounts for over fifty percent of the world’s total low, although a lifetime dose can exceed our cutoff estimated effective dose of radiation. (as we have defined it, <0.1 Sv). While these exposures are termed “natural Few natural radiation studies have been able to radiation” this does not indicate an inherently fully attribute health effects to background radiation benign nature. It is necessary to look further into exposure, which by its nature is often received the health effects of background radiation because over a prolonged period of time and at low levels. “there is a mistaken tendency to assume that natural According to our best understanding of radiation, radiation is harmless” (Caufield 1989). Claims that the effect of background sources is probably man-made exposures are the same or only a fraction subtle; many researchers admit that other (non- higher than natural radiation levels imply that the background radiation) variables easily confound effects are insignificant, and this is a false assurance. study results and conceal the radiation effect being A substantial body of research suggests that natural tested, a phenomenon which epidemiologists refer radiation can be harmful, and as we increase to as the “signal-to-noise problem”. Henshaw et al. our exposure through intensified dependence on (1990) note that even when background rates can mineral processing, airplane flights, phosphate be identified, we do not yet have the capability to and potassium fertilizers and fossil fuels, we also “separate the contribution from radon and background increase our exposure and related health risks. gamma radiation”. Additionally, it is difficult to Outcomes associated with background radiation determine whether background exposure is additive

1 There are many sources for background radiation exposure estimates online and they tend to agree well with one another. In addition to EPA or DOE sites we have found that University sites offer interesting perspective on the estimates (for example: http://web.princeton.edu/sites/ehs/osradtraining/backgroundradiation/background.htm). 13 14 Background Radiation

Figure 2-1. A bar graph showing average annual natural radiation doses worldwide. The radiation is measured in mSv and shows the approximate distribution of natural radiation doses from radon, indoor gamma, outdoor gamma and cosmic rays (http://www.uic.com.au/ral.htm). or multiplicative in its effect combined with other x-rays in the induction of childhood cancer. The US doses (Samet 1997). Due to these weaknesses and study analyzed the area within 10 miles of the Three constraints, most researchers advocate for more Mile Island nuclear power plant in Pennsylvania, research to be dedicated to understanding the with a population of about 160,000 (Hatch and impacts of background radiation and other chronic Susser 1990). Annual estimated gamma exposure in low-dose exposures (Hoel 1995, Ron 1998). the area ranged from 0.5-0.9 mGy. When comparing childhood cancers in areas with 0.8-0.9 mGy against 2.2 Summary of studies areas with 0.5-0.6 mGy the authors found an OR of 2.4 (1.2-4.6). External exposure. Two ecologic studies A highly questionable ecologic experiment conducted in Great Britain and the US found which assessed the cancer death rates of the Rocky positive correlations between childhood cancers Mountain states compared with the Gulf Coast states and external gamma exposure. In Great Britain a did not find any correlation between background positive correlation was found for fetal exposures radiation and cancer mortality (Jagger 1998). and childhood cancers (Knox et al. 1988). This Jagger did not address any confounding factors in study used gamma exposure estimates for Great his analysis, used speculative estimates of radon Britain in a grid of 10-km squares; the average dose exposure levels, and his approach was inherently accumulated by a fetus during gestation was estimated incapable of generating meaningful results; this was to be ~0.2 mGy. After controlling for a variety of effectively demonstrated in a response by Archer factors including maternal age and prenatal x-rays (1999). this study estimated that prenatal gamma exposures High exposure areas. Several locations have were about 3.6 times as effective, per Gy, as prenatal become notorious for their high levels of background Background Radiation 15

Figure 2-2. Areas around the world having high external exposure to terrestrial radiation (mSv/yr) (http://www.angelfire. com/mo/radioadaptive/ramsar.html). radiation due primarily to radioactive elements in the attributable to high background radiation rates in soil. These include Kerala, South India; Yangjiang, Yangjiang. This study did not detect an elevated China; Guarapari, Brazil; and Ramsar, Iran (Figure cancer risk (Sun et al. 2000, Tao et al. 2000, Zou et 2-2). Chromosome aberrations, evidence of DNA al. 2000). A simple cross-sectional survey conducted damage that could also lead to cancer, are often in Kerala, in panchayats with background exposures measured to assess the potential risk associated with as high as 70 mGy/yr, did not find a correlation an exposure, and several rudimentary explorations between cancer incidence and exposure (Nair et al. of chromosome aberrations in these areas have been 1999). Although radiation measurements were made made. In Guarapari, an area with 10-100 times the in over 60,000 houses, the correlation analysis was normal background exposure, researchers found made on the panchayat level and did not address any an increase of about 30% in chromosome breaks potential confounding factors. compared to a control area (Barcinski et al. 1975). Radon. As we mentioned above, radon is the In Kerala exposure has been estimated to be 15-30 major source of background radiation exposure. times higher than surrounding areas. Kochupillai Studies of radon in homes and in mines are hard to et al. (1976) found a significant increase in some compare with other studies of radiation because of types of aberrations but not others2. Preliminary the nature of radon and the exposure terminology assessments of Ramsar and Yangjiang have not associated with it. Radon exposure is in truth detected increases in aberrations compared to local exposure to both radon and airborne decay products control areas (Ghiassi-nejad et al. 2002, Hayata et of radon, or radon daughters. Radon in mines is al. 2000). A series of papers published following typically measured in working level months (WLM), a collaboration between Chinese and Japanese a unit that is described in more detail in the section researchers assessed possible health effects on miners (section 8). Radon in homes is commonly

2 There was a roughly 2-fold increase in chromatid-type aberrations (not significant) and a significant 10-fold increase in chromosome-type aberrations. 16 Background Radiation

Figure 2-3. A map created by the EPA showing average indoor radon levels by county (ehpnet1. niehs.nih.gov/docs/1994/102-10/focus.html). measured in Bq/m3 or pCi/L, units of concentration confounding factors. Results from miners exposed in air (Figure 2-3). to radon are not directly comparable since there are In a broad ecologic survey Henshaw et al. (1990) no children in miner cohorts, but Darby et al. (1995) found a several significantly positive correlations did detect a significant excess of leukemia mortality with radon. National rates of myeloid leukemia in miners3. and childhood cancer (including leukemia) were Most studies of radon focus on lung cancer, and correlated with national mean radon exposure residential lung cancer risks were for a long time levels. Acute myeloid leukemia was also correlated estimated based on the experience of miners. Case- with radon in Canadian provinces. These authors control studies of indoor radon have been carried out estimated that 13-25% of myeloid leukemia around the world and these have had mixed results. worldwide might be attributable to radon exposure. Recently, however, researchers have conducted meta- Although these are interesting results, it is important analyses or pooled the data from various studies and to keep the limitations of ecologic studies in mind, produced relatively stable estimates of the residential particularly the within-group variations in exposure radon risk4. Lubin and Boice (1997) combined the and response and the inability to account for potential results of 8 case-control studies on radon exposure

3 This study found a significant excess in the observation window defined as the first ten years after first exposure (21 observed, 11 expected, p<0.01). For the full follow-up period there were 138 observed and 119 expected deaths. Leukemia mortality was not related to dose (Darby et al. 1995). 4 These are two ways of combining information from more than one study. Meta-analysis is a statistical technique for combining results from multiple studies and ‘pooling’ refers to combining the raw data from multiple studies and analyzing the combined data directly. Background Radiation 17 and lung cancer incidence from around the world. 2.3 Discussion If these studies were assessed individually it would be hard to draw a conclusion; four studies indicated Studies of background radiation have been largely a significantly positive risk and four did not. When of ecologic design and this type of study is limited Lubin and Boice combined the results, however, a in its informative ability. Based on the linear significantly positive risk estimate was obtained for no-threshold model we can expect some cancer an exposure level of 150 Bq/m3 (RR 1.14, 1.0-1.3). risk to be associated with background radiation. This estimate is in agreement with the estimated Detecting this risk is very challenging because of risk from radon in mines at the same concentration uncertainty and variability in individual exposure (RR 1.13, 1.0-1.2). The authors also detected a to both radiation and the variety of other factors significant log-linear5 dose-response relationship. contributing to background cancer risk. Studies like Recently, Lubin et al. (2004) have pooled the results the meta-analysis of Lubin and Boice (1997) are of two case-control studies in China, one urban and useful in demonstrating that background radiation one rural. The estimated RR at 150 Bq/m3 based risk estimates are consistent with other estimates, in on this analysis would be 1.2-1.56. Krewski et al. this case miner data. Knox et al. (1988) and Hatch (2005) pooled the data of seven North American and Susser (1990) have generated childhood cancer case-control studies. This analysis would estimate risk estimates that are larger than what we might a RR at 150 Bq/m3 of 1.177. Finally, Darby et al. expect based on studies of in utero x-ray exposures (2005) pooled the data of 13 European case-control or risk estimates from larger exposures. Although studies. The RR at 150 Bq/m3 based on this analysis the exact magnitude of the background risk from would be 1.248. All of these estimates are similar and radiation exposure is unclear we can see that there all are compatible with miner-based risk estimates is likely to be some risk; natural radiation is not (see section 8); these data therefore lend support harmless. This is an important context in which to to the conclusion of the BEIR VI committee that consider the additional exposures that we discuss in residential radon may account for 10-15% of lung the rest of the overview. cancer in the US (NRC 1999).

5 In a log-linear model the logarithm of the relative risk is directly proportional to exposure level; at low levels of risk the differences between log-linear and linear models are minimal. 6 Lubin et al. (2004) used a linear excess odds ratio model and calculated excess odds ratios at 100 Bq/m3 of 0.133 (0.01-0.36) and 0.315 (0.07-0.91), the latter estimate for a more restricted cohort with better dose estimates. 7 Like Lubin et al. (2004), Krewski et al. (2005) used a linear excess odds ratio model and presented the risk estimate at 100 Bq/m3 (RR 1.11, 1.00-1.28). 8 Darby et al. (2005) used a linear excess relative risk model. At 100 Bq/m3 the ERR was reported to be 0.16 (0.05- 0.31) after correction for random errors in dose estimation. 18 Background Radiation . n s i a r e e o n a e t c c o d d r ) e n n % e r d n n u 6 a e a . a a 3 s a a v e c i d r 4 2 o r t i y - d d - a p a c d c n e d e e 2 l i i 5 l . x o n t s s p u e i ~ e t s o 1 e o r o o y ( r s t s r e , h r t p p ) 1 - a e - e 4 d n x x n 5 m e . r e c l i v e e i o 1 r o 2 h n a . o m c c e h d a e n n 1 o y c n r R c - a e e k m i s n a 3 s e e G 0 d o O e i d o k l m r ( n r 8 t n e m w w � o . a o o / t t d a � 1 r r r o e r 0 e � w e e q s n t e e ( r t a h v h ) � b a b i c y i n e p r B b c d � t 6 e s n l o y b e e ) r � a m i / e 9 0 a c n s n l c c . a s e i y R h ’ 5 c � e o n n m a 0 a n k c i r e n 1 G e R e e e t o d r o u ( s r r r ) t r o s i a R w m o e t u e t a e e n l a a 7 l o t s l o f f o R a e e 6 l e 6 ) f f . a l r o r . h d i i m D n o v r e e 3 0 i y c p i 1 i d . r t - d d o r r l o t t - o i n d x r r i 1 5 l t g t i l e c a . n 5 e - n h o l e h a n n g 0 s s o 4 a t c y c y 0 e d c ( a a y . . l n l r a a a c r w e t t t t s c c 0 a 1 e e e o e n i i i m o v ( l n n n n ( n r r i o r h l i f f r r t a a a a t i i a a m a o c h a . 7 e r e 4 i c c c c t n n l l e l s t s r a i p i i s i 8 1 4 ) o . g g f f f f . o o a v e o v a a b u i i i i i i e i 3 r r r r b r c 0 1 e q t s s o t t t r n n n n h g 0 a r n a n n d e n e g g g g g c n l 0 u o o o R R a r i i i i i . o o n b o a e n u S G N c S h N c S a 0 i r S a r R N C c O s o p x 3 e ) f l ) t 0 l o m s a 5 / a r i s n ~ q n f r e n r t e i B e n e t a t h r o r x 6 t i x y t e 4 / e e y a r f y d b r d t u o n G s d n n a � e n o a r e m � l n c o p y l i a i / � f a n x 6 t � n e y e a o n 7 r � d r r c e G t n o � e t s t t n e a a � n m i e n i r d r p i w i d ( � c r 0 r y y ( u e / / a e n r ) 6 w y r , s r e r / y y a o 2 r d m a e u e y y l y c r s y G G s e / / t r / y y o m a G u y y y / S o / y m m / p u y o v G G m v R x w U a G 9 5 h S 3 e m . . S h 0 m m i m n n e m 0 0 c m m 3 x a a - - m w / 4 4 - 0 n a e e m 5 . o 5 - 1 4 4 q a l - 4 . . 5 . . o 6 2 ; 6 ( M 0 M B 0 1 M P 1 s 6 6 ) r y / y , s f g g n G h o 0 n t n n o t i e m 1 u i a u 5 y a l t i 5 e e 9 o 8 e j m n a f . i r c r 9 v g 9 o S 0 o r r h r n l 9 - 1 , n t G e u s e - a d i 8 1 e e a a . b s l e - e n d 5 n i 0 i i w a a Y m m 7 � g 7 ( c y s r d c i r r � o o s 8 n e r 9 n e e u n s e s e g i e l 9 � t y i 1 s i � c c m o o r o c K � s ’ t 1 t l r y � r a n n o l � a n l n t � e n m i m o n a a s a a i h � a n i o � c l a z c o o u c i c w n o r c p l � � r r a i a e n t s q o h t o p r � r d d h h a h m n l n r � e s e C c c D c o o o r B a o n d o o � a C � r h , i o o u c f f f f , n o n t � t , n � i s h - g m h h � � o a o o o o d a o g r f o c e l i � n r d d r a � t a n s s l l p o y y y r y a � f d r e � i i a I i a � p a x e e e e e c o j n i y h h a n c c e j � � v v v b v e a i n r g r a c c l d r r r r t y a i g � � h i a a e 8 n 9 a s t u u f u f u u e t � n d c � 5 t i r a u e 7 f s s s e s o o v � n a s M n u 9 f i 9 r o � l l l l I G Y m n m � l m o 9 y y o Y e a a a a 1 u � f a e s y o o o - h 1 n s d n d e i r n n n n r k s r � t i i y n - e r I s d 3 t u u i o o a o o u o � y u t t d h 9 i h i i i , s s y 5 n t r n t s t e s t d t � l r o a u 7 i n n l 9 T m o a t c c c c a a n � y S 9 c c o o c 1 s o n m e s f e e e a i i n m b i i d � i - , r 1 s s i s s t t i t o o a g g � n r l e a r m h d a a - i o l a n s m s s s s e o e o s � e r r l a c o i i a a l l a s s s s a r n a r r c i l e t e t n � c r h i l R o o i o o i o o p c e e d e e n r d i y f e r r r r r o h � c c r b b n a a n e n � C a P i E m C a A m E B C a I M c C K C C A c d � s � a � , w � 0 0 � e r � 0 0 d u a � 0 0 i � 0 s j 7 � a 2 2 � o 9 e l 5 2 0 0 8 6 9 0 9 i d d � � . . l p 9 n l l � 7 0 0 9 8 i 7 9 0 9 n n k - w � x 1 a a i � 9 0 0 9 9 p 9 9 0 s a a 1 a e � a s r t t 1 2 2 1 1 u 1 1 2 n t h � s � i h n e h e e e x � ...... a s h i a c c s c l l l l l l r l l g i o c i � t y n i i b u r s n o a a a a a a a a h a a e n o a � a o u a o u u H t t t t t t t t � B e G e H S H e H e K e K e L B N e S T Z e 1 3 MEDICAL EXPOSURES type of concern that has led to changing medical practice (for example more judicious and sparing 3.1 Introduction use of x-rays). On the other side of the coin, many authors say that emphasizing the potential harmful Approximately fifteen percent of the public’s total effects of therapeutic radiation is counter-productive. ionizing radiation exposure is artificial and much of For example, Schaefer et al. (2002) question this this comes from routine diagnostic or therapeutic type of inquiry noting that many patients would die medical procedures (Ron 2003). In the early without the treatment that might eventually lead years of nuclear medicine, radiation was used at to cancer later in life. Skolnick (1995) asserts that dangerously high doses putting patients and medical any claims of carcinogenic effects of x-rays might workers at risk. Radiation protection has improved discourage women from getting mammograms, and dramatically over the past century, and medical ultimately lead to higher mortality rates. Regardless professionals still find many useful applications for of any controversy we are still in the possession of radiation. Gamma radiation, applied at doses of 450 a large body of research that can help the decision- to 500 Sv in the 1940s and 50s, is still used today making process. at more conservative doses to identify and target Medical exposures can be divided into malignant growths. Iodine-131, the most common characteristically different groups. Diagnostic beta emitter used for nuclear medicine, has been exposures are generally much lower than therapeutic used with doses of up to 1,000 Gy in the past. It is exposures. Exposures received by patients are still used to diagnose and treat thyroid cancers and also different than exposures received by medical hyperthyroidism. X-rays are also, of course, a very professionals. Radiologists were one of the earliest common diagnostic tool. occupational groups to be exposed to ionizing John Gofman was the first director of the radiation. Their particular type of exposure is Biomedical Research Division at the Atomic Energy characterized by cumulative, fractionated1, and Commission’s (now DOE) Lawrence Livermore external low doses. Patients, on the other hand, National Laboratory. Gofman (1996) stirred up a lot receive a wider range of doses depending on the of controversy when he conducted a review of all procedure, are exposed both internally and externally, major sources, mostly medical sources, of women’s and receive exposures over a shorter time period exposure to ionizing radiation in the US and related (including one-time doses). Another categorization them to breast cancer risk. Based on his analysis involves age at exposure; childhood exposures are of the atomic bomb survivor data he estimated that likely to carry a higher risk than adult exposures. approximately 75% of all breast cancers in the US While precautions in the use of radiation for were caused by medical exposure. Gofman is a strong medical purposes are becoming increasingly strict, advocate of the position that there is no such thing as the possible long-term effects of any exposure are a “safe dose” and that the doses routinely received a topic of intense debate and concern. The studies by patients confer some cancer risk. Clearly it is this reviewed here vary from those that focus on a few

1 A fractionated dose is one that is received as a series of small doses rather than one large dose. 19 20 Medical Exposures

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large doses to many small doses. Because most of • Patients undergoing radiotherapy, particularly the doses have been administered in a controlled cancer therapy, may have a predisposition to way we have very good dose information for these the same effects that the therapy can be causing; patients and they can provide good insight into distinguishing the underlying risk from the the patterns of radiation risk. Studies of the health radiation-induced risk can be difficult. effects of medical radiation also provide important • Exposure is often received in adulthood and insights into risks of a variety of exposure patterns, many radiotherapy-induced cancers, with long into risks of cancers with long latency, and into the latent periods, may go unnoticed. relevance of in utero risk estimates to adult cancers. • The healthy worker effect is an issue in studies These studies can also organize unique sets of data of radiologists and technicians. It has often been about the effect of fractionated doses due to the observed that health care professionals have scheduled dose patterns that many patients receive. lower mortality and morbidity rates than the Despite having good exposure information, general population and this can complicate the medical radiation studies, like other radiation interpretation of results. studies, are uncertain. Study results and estimates • Retrospective studies often lack individual dose of risk vary2. Uncertainty in this area comes from a information and therefore researchers are unable number of factors: to make dose-response relationship estimates or comparisons with other studies of radiation • Dose distributions are often anatomically exposure (Berrington 2001). Although it is heterogeneous; administration of iodine-131 for possible to estimate doses based on the number hyperthyroidism will result in a huge dose to the of years a worker was certified or the number of thyroid but a negligible dose to the brain or the x-rays a person thinks she had over the years, bones. this can lead to misclassification errors (Doody 1998).

2 This variability is exemplified in the difference between Gofman’s (1996) estimate that medical x-rays are responsible for 62-90% of breast cancer and Evan’s (1986) estimate of fewer than 1%. Medical Exposures 21

years and for the most part have been strategically reduced over time. Doses currently vary by procedure and by organ. A dental x-ray, for example, might result in a thyroid dose of 0.1 mGy while a CT chest scan3 could result in doses of over 20 mGy to the breast, lung and esophagus. Figure 3-1 shows one set of “average” dose estimates for various procedures. A good source of organ-specific dose estimates is Berrington de Gonzalez and Darby 2004. Because these exposures are so common and are so carefully controlled (especially in recent years), they are a good source of data for epidemiologic research. Diagnostic x-rays. There is some evidence linking diagnostic x-rays with leukemia. Gibson et al. (1972) conducted a case-control study of leukemia Figure 3-2. In the 1950s the panoramic X-ray machine was in adults who had been exposed to diagnostic x- invented to take a picture of the whole mouth with just one exposure (www.nist.gov/public_affairs/licweb/dental. rays in upstate New York, in Baltimore, and in htm). Minneapolis-St.Paul. This study found significant risks of acute myeloid leukemia (AML) and chronic There is a vast and growing literature on myeloid leukemia (CML) in males. The RRs for the this topic and we have not included all of the lowest category of exposure, 11 or more x-rays, were available information; the studies reviewed here 1.61 (p<0.05) for AML and 1.60 (p<0.05) for CML. are representative. Included in this section are These risk estimates increased with the number of studies focusing on diagnostic exposure, treatment x-rays taken and were also higher when the analysis for non-cancerous diseases, treatment for cancer, was restricted to x-rays of the torso (see Figure 3-3). irradiation of adults and of children, in-utero Leukemia was not significantly increased in female exposure, and radiologists’ occupational exposure. subjects although there was some evidence of a trend As a practical matter an individuals’ decision to with number of x-rays and the power of the study to accept medical radiation exposure will always be detect a risk in women was lower (fewer subjects). a matter of balancing risks; hopefully this section This study also found a curious increase in the risk can help inform that decision. Tables 3-1 through of male chronic lymphocytic leukemia, a type that 3-4 summarize the studies discussed below. Table is not associated with radiation in other situations. 3-1 includes diagnostic exposures to x-rays, tables The RR with 21 or more x-rays was 2.03 (p<0.05). 3-2 and 3-3 include other exposures for diagnosis It should be noted that these exposures occurred at or treatment of benign disease, and Table 3-4 covers a time when doses were likely to be much higher cancer survivors who received radiation therapy. than they are today. Preston-Martin et al. (1989) conducted a case-control study of chronic myeloid 3.2 Diagnostic exposures leukemia (CML) and found that cases were more likely than controls to have received radiographic Diagnostic radiation, commonly used in modern examinations of the back, gastrointestinal tract and medicine to detect the presence of health problems kidneys. A significant trend with estimated dose 4 such as a bone break or a tumor, is the largest man- was also found, with an ERR of 30/Gy , although made source of radiation exposure to the general the authors caution that the doses were probably public. The doses that patients have received from underestimated causing an inflation of the ERR. this type of exposure have varied greatly over the Infante-Rivard (2003) focused on childhood cases

3 CT or CAT scans are procedures involving x-rays. CT stands for computed tomography. 4 The ERR of 30/Gy was estimated for all exposures 3-20 years prior to diagnosis. If the period 6-10 years prior to diagnosis was isolated then the ERR estimate was 76/Gy. 22 Medical Exposures

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Figure 3-3. Relative risk of myeloid leukemia among adults according to the number of x-ray exams of the trunk (torso) in the period up to six months before leukemia diagnosis. Data from Gibson et al. (1972). “*” indicates significant risk (p<0.05).

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� Figure 3-4. Thyroid cancer SIRs for patients who had been diagnosed for reasons other than suspicion of a thyroid tumor. Labels indicate thyroid dose category. (Data from Dickman et al. 2003). Medical Exposures 23 of acute lymphocytic leukemia and found that doses on the order of 1 Gy. Studying these patients diagnostic x-rays (postnatal) increased the risk of is complicated by the fact that they have already ALL by roughly 50% (OR 1.48, 1.11-1.975). demonstrated a potential thyroid cancer risk. One Other studies have dealt with solid cancers. Swedish cohort that was originally established Preston-Martin et al. (1988) conducted a case-control in the late 1980s to assess thyroid cancer risk has analysis of tumors of the parotid gland6 in patients been revisited twice. Holm et al. (1988) found a who had received medical and dental x-rays. There thyroid cancer SIR of 1.27 (0.94-1.67), although was a significant risk with cumulative doses over the comparison with national rates was potentially 0.5 Gy in this cohort (RR 3.4, 1.02-11.46). Doody misleading, as pointed out by Archer (1989)8. After et al. (2000) found that women who had received six more years of follow-up this cohort showed a diagnostic radiographs for scoliosis during childhood significant excess (SIR 1.35, 1.05-1.71) although had an increased risk of breast cancer. These women risk was not significantly related to dose and the received an average of 25 radiographic exams each, excess was concentrated in those patients who had with a mean dose to the breast of 10.8 cGy. It was been examined based on the suspicion of a thyroid found that breast cancer risk was significantly related tumor. The most recent follow-up (Dickman et to both number of exams and cumulative dose, and al. 2003), which continued to make comparisons an ERR of 2.5/Gy (-0.3-8.9) was calculated7. These women were exposed at a mean age of 10 years; this risk estimate compares with an estimated ERR of 2.77/Sv (90% CI 1.70-4.26) for women exposed to the atomic bombs between ages 5 and 14 (Land et al. 2003). A recent paper by Berrington de Gonzalez and Darby (2004), while not an epidemiologic study, is an interesting paper to consider. These authors estimated the risk of cancer from diagnostic x-rays for the UK and 14 other countries using recent estimates of dose and risk estimates from the atomic bomb survivor data. They calculated that 0.6% of cumulative cancer risk to the age of 75 (in the UK) could be attributable to diagnostic x-rays; this is approximately equivalent to 700 cases per year. Figure 3-5. CAT scans deliver some of the highest doses In 13 other countries investigated the attributable of medical radiation to patients. CAT scans work by taking percentage of cancer cases ranged from 0.6-1.8% x-ray pictures of the patient in slices to generate a three- while in Japan the percentage was >3%. dimensional image of a person’s body from two-dimensional Diagnostic iodine-131. Iodine-131 has been x-ray pictures (www.health.gov.mt/.../epilessija/Epilessija. used to help with the diagnosis of thyroid disease at htm).

5 Doses were not estimated; this OR is for children receiving 2 or more x-rays vs. none. 6 The parotid gland, located below and in front of the ear, is the largest salivary gland. 7 Some women (11% of the cohort) had scoliosis but never received diagnostic radiographs indicating less severe disease. It was suggested that the degree of scoliosis might be correlated with reproductive history, a potentially confounding breast cancer risk factor, and when these women were excluded the unadjusted ERR was 2.7 (-0.2-9.3). The unadjusted ERR for the full cohort was 5.4 (1.2-14.1). These differences apparently disappeared, however, when the ERR was adjusted for age at first exposure, and both groups showed estimates of 2.5/Gy (-0.3-8.9). 8 Archer suggested that a dose-response analysis within the cohort would find much stronger evidence of a significant trend; although the low-dose groups within the cohort had lower than expected rates of thyroid cancer, this may be due to the screening effect of the original diagnosis. Figure 3-4 shows a dose-response graph from the most recent follow-up of this cohort. 24 Medical Exposures with national rates, continued to be inconclusive. 49.9). The dose rates estimated by these authors were Although an increased risk persisted in the cohort 220 mGy per year for the liver and 1-5 mGy per as a whole (SIR 1.77, 1.45-2.14), a risk among year for other organs. Dos Santos Silva et al. (2003) patients who had not been examined on suspicion studied Portuguese patients who received estimated of a thyroid tumor was not evident (SIR 0.91, 0.64- liver doses of 400 mGy per year. In addition to a 1.26). Risk in this cohort appeared to decline over high incidence of liver cancer (RR 42.4, 13.9-210) time9 and dose-response analysis was inconclusive there was a notable increase in non-CLL leukemia (see Figure 3-4). (RR 10, 1.24-471). The estimated bone marrow The radiation-induced risk of thyroid cancer is dose rate in this study was 100 mGy per year and the known to be much greater in childhood, particularly leukemia risk estimate was compatible with those of early childhood (Ron et al. 1995). The Swedish cohort other Thorotrast cohorts. was unfortunately not very informative regarding children since only 7% of the subjects were under 3.3 Radiotherapy for non-cancer disease age 20 at the time of exposure. Hahn et al. (2001) focused on exposures to diagnostic iodine-131 in Radiation is still used in some circumstances to a German cohort of adolescent children (median treat non-cancer disease, although not nearly as age 14 years). This study, with only five observed cases of thyroid cancer, was inconclusive (RR 0.9, 0.1-5.1). Thyroid cancer observations are discussed further in appendix B. Thorotrast. Thorotrast was a commercially prepared alpha-emitting solution that was used for a variety of different diagnostic procedures10 from the late 1920s into the early 1950s; at this time the toxic properties of the treatments were becoming clear and its use was discontinued. Thorotrast remains in the patient’s body for life, thus giving a lifetime of alpha radiation exposure and high cumulative doses, particularly to the liver. Although several studies have addressed these patients11 we only present two representative studies here; since these exposures were unusually high they are of limited applicability to our low-dose area of interest. Nyberg et al. (2002) investigated cancer incidence among patients who had been exposed to Thorotrast in Sweden and found elevated SIRs Figure 3-6. In the late 1940s chest x-rays were used to of various cancers12. Liver and gallbladder cancer screen for tuberculosis (http://profiles.nlm.nih.gov/RR/B/ showed a dramatic 40-fold increase (SIR 39.2, 30.2- B/B/Z/_/rrbbbz.jpg).

9 For the full cohort the central estimates of SIR were 3.07, 2.53, 1.18 and 1.70 for 2-5, 5-10, 10-20 and >20 years after exposure. 10 For example, cerebral angiography, a process in which arterial pulse movement is tracked through the vascular system of the brain. 11 See, for example, LB Travis et al. (2001). Mortality following cerebral angiography with or without radioactive Thorotrast: An international cohort of 3143 two-year survivors. Radiat Res 156:136-50. 12 Again, doses and consequent cancer risks were quite high. SIRs for various cancer sites were: stomach 10.5 (3.9-23), small intestine 12 (2.4-35.2), pancreas 2.9 (1.1-6.4), kidney 3.4 (1.4-7.0), brain and CNS 3.1 (1.0-7.4), connective tissue 8.3 (1.7-24.4), leukemia 6.1 (2.9-11.2) and all sites combined 3.0 (2.8-3.7) Medical Exposures 25 frequently or as intensively as it was in the early and the ERR estimate from the fluoroscopy group was middle part of the 20th century. This section reviews roughly half that from the atomic bomb survivors, studies of treatment of various diseases including the absolute risks were essentially the same13. tuberculosis, ankylosing spondylitis, and childhood This implies that the induction of breast cancer by skin conditions (hemangiomas and tinea capitis). radiation is independent of the underlying breast Tuberculosis. Fluoroscopy, a form of x-ray cancer risk, which is much lower in Japan. Brenner examination, was frequently used in the past to (1999), however, observed that fluoroscopy radiation both diagnosis and treat tuberculosis. Although should be more biologically effective (damaging) exposures varied, this procedure resulted in average than the atomic bomb radiation14. He concluded that doses on the order of 1 Gy to the chest (lungs, breast, the dose fractionation of the fluoroscopic treatment esophagus), and ~0.1 Gy to the bone marrow and probably reduced the risk per dose. stomach organs. Ankylosing spondylitis. Ankylosing spondylitis Davis et al. (1989) looked at a cohort of is a chronic, progressive inflammation of the Massachusetts fluoroscopy patients and found vertebrae. Over 14,000 patients in the UK, between evidence for an increased risk of mortality from 1935 and 1954, were treated for this disease with cancer of the breast (SMR 1.4) and esophagus (SMR high doses of x-rays15. Weiss et al. (1994, 1995) 2.1). A largely overlapping cohort was revisited studied the cancer mortality in this cohort through by Boice et al. (1991) to assess the risk of breast 199116. The researchers found that there was cancer in more detail. This study found a significant increased risk of cancer mortality (RR 1.30, 1.24- dose-response relationship that depended on age 1.35), particularly non-CLL leukemia mortality (RR at exposure; the estimated relative risk for women 3.11, 2.37-4.07), which peaked in the 1-5 years after exposed to 1 Gy at age 15 was 2.0; corresponding first treatment. The dose-response relationship for estimates for exposure at ages 20, 35 and 45 were 1.7, cancer mortality was best described with an ERR 1.2 and 1.1, respectively. Howe (1995) investigated of 0.28/Gy17 (the atomic bomb survivors estimate is the lung cancer risk associated with fluoroscopies 0.47/Gy; Preston et al. 2003). administered in Canada. There was no evidence for Leukemia results were analyzed by Weiss et such a risk in this cohort, and the estimated RR at al. in a 1995 paper. The dose-response relationship 1 Gy was 1.00 (0.94-1.07), significantly lower than for leukemia showed a maximum risk in the 0.01- the estimate from the atomic bomb survivors of 1.60 1.0 Gy dose range (RR 6.58, 2.22-15.98). This is (1.27-1.99). likely to be a result of cell killing at higher doses- if The fact that these observations differ markedly cells that might otherwise develop into a cancer are from atomic bomb survivor data has been explained killed then the risk per unit dose can be less18. Weiss as an effect of dose fractionation. Although et al. (1995) modeled leukemia mortality with a cumulative doses averaged ~1 Gy, the fluoroscopic complicated linear-exponential model that allowed regimen included an average of 90 separate exposures for this effect and also calculated total risk as the received at a rate of two per month. Regarding breast sum of the risks in different bone marrow regions. cancer, Little and Boice (1999) showed that although This compartmental component of the model took

13 The EAR estimates were 5.48/10,000 PY-Sv (0.90-10.43) for the fluoroscopy cohort and 4.95/10,000 PY-Sv (3.37- 6.71) for the atomic bomb survivors (Little and Boice 1999). 14 Fluoroscopic x-rays and gamma radiation from the atomic bombs are types of photons that have different energies. Fluoroscopic x-rays have a lower energy but a higher linear energy transfer, or LET. At low doses these photons are expected to be 1.6 to 1.9 times more damaging than the gamma radiation from the atomic bombs (Brenner 1999). 15 Weiss et al. (1994) report mean total body and bone marrow doses of 2.64 and 5.10 Gy. 16 An earlier analysis through 1982 was published by Darby et al. (1987). 17 Although an estimated ERR of 0.1/Gy (0.04-0.18; all cancers except leukemia) was derived with a simple linear model, the linear term in a linear-quadratic model was reported to be 0.28/Gy (0.07-0.48); this would be a more appropriate value to use when considering low doses. 18 It was estimated that the ERR at 1 Gy was reduced by 47% (17-79%) due to the effect of cell killing. 26 Medical Exposures localized exposures into account; some regions might Radiotherapy for other non-cancer diseases. have been exposed with doses in the cell killing range Inskip et al. (1990) found that patients treated for while others received more carcinogenic exposures. uterine bleeding with radiotherapy were at an This type of model fit the data better than more elevated risk for cancer, specifically leukemia. This conventional models and the linear term, which we procedure, which was used mainly in the 1930s and are interested in because it applies directly to low 40s, involved either radium implants or x-rays and doses, described an ERR of 12.37/Gy (2.25-52.07) resulted in median bone marrow doses of 0.5 Gy for 10 years after first treatment. The risk declined (radium) and 2.5 Gy (x-rays). The SMR for cancer with time so that the ERR was 5.18/Gy (0.81-23.63) was 1.3 (1.2-1.4) and for leukemia was 2.0 (1.4-2.8). 25 years after first treatment. Leukemia risk was dependent on dose with an ERR Damber et al. (1995, 2002) studied the risks of of 1.9/Gy (0.8-3.2). In a larger cohort20 Inskip et al. x-ray treatment of spondylitis and related diseases in (1993) analyzed leukemia, lymphoma and multiple Sweden. The 1995 study found increased incidence myeloma mortality. The mean bone marrow dose in of leukemia (SIR 1.18, 0.98-1.42; SMR 1.25, 0.99- this cohort was 1.2 Gy; non-CLL leukemia mortality 1.45); bone marrow doses were estimated to have was significantly elevated (SMR 1.7, 1.3-2.3) been about 0.4 Gy. The 2002 study demonstrated although a dose-response trend was not evident. an increased risk of thyroid cancer (SIR 1.60, 1.00- X-rays were used to treat peptic ulcers at the 2.42); thyroid doses were estimated to have been University of Chicago between 1937 and 1965; doses about 1 Gy. from this procedure were very high (mean stomach Hyperthyroidism. Hyperthyroid patients who dose 14.8 Gy). Carr et al. (2002) analyzed the were treated with iodine-131 have been studied in cancer mortality patterns in 3,719 exposed patients. the US (Ron et al. 1998), the UK (Franklyn et al. Observed increases in mortality included stomach 1999) and Sweden (Hall et al. 1992). This procedure cancer (RR 2.6, 1.33-5.09), lung cancer (RR 1.50, involves very high thyroid doses (50-100 Gy); 1.08-2.08) and all cancers combined (RR 1.41, 1.18- although this is intended to kill the thyroid there 1.67). Leukemia risk was also elevated (RR 2.46, are significant risks of cancer developing in the 0.75-8.01); the estimated mean bone marrow dose remaining tissue. The SIR for thyroid cancer was was 1.6 Gy. Analysis of dose-response was not very estimated to be 3.25 (1.69-6.25) in the UK cohort, informative owing largely to a narrow distribution and SMRs of 3.94 (2.52-5.86) and 1.95 (1.01-3.41) of relatively high doses. were reported for the US and Sweden cohorts. Radiotherapy for non-cancer disease in Although the thyroid doses in these cohorts were children. Hemangiomas of the skin are benign high, the doses received by other parts of the body lesions that have been treated in infancy with x- were relatively low19. Cancer sites with elevated rays or radium21. Lindberg et al. (1995) investigated mortality in the Swedish cohort included the digestive a cohort that had been treated at Sahlgrenska tract (SMR 1.14, 1.03-1.25) and the respiratory tract University Hospital in Gothenburg, Sweden. (SMR 1.26, 1.06-1.49). The US cohort exhibited This study found significantly positive SIRs for increased mortality from lung cancer (SMR 1.1, 1.0- all malignancies (1.21, 1.06-1.37), cancers of the 1.2), kidney cancer (SMR 1.3, 1.0-1.6) and breast central nervous system (1.85, 1.28-2.59), thyroid cancer (SMR 1.2, 1.1-1.3). The UK cohort showed cancer (1.88, 1.05-3.09), and other endocrine gland increased incidence of cancer of the small intestine cancers (2.58, 1.64-3.87). Lundell and Holm (1995) (SIR 4.81, 2.16-10.72). assessed the cancer risk in people who had been

19 In the Swedish cohort, for example, estimated doses to the stomach wall, small intestine, and bone marrow were 0.25, 0.14 and 0.06 Gy. 20 Inskip et al. (1990) studied 4,483 women treated in Massachussets. Inskip et al. (1993) studied 12,995 women treated in any of 17 hospitals in New England or New York State. 21 Although radium-226 is an alpha-emitter, it was used in these cases by placing it next to the hemangiomas, exposing the skin to beta particles and gamma radiation. Medical Exposures 27 treated at the Radiumhemmet in Stockholm, Sweden The study also examined the effects of doses to the and found similar results. Specifically, this study thyroid, which averaged 0.06 Gy; with two cases found an increased cancer risk (SIR 1.11, 0.99-1.24) the results were inconclusive (SIR 0.98, 0.16-3.24). that was mainly attributable to breast cancer (SIR There was, however, a significant thyroid cancer 1.24 0.98-1.3422) and thyroid cancer (SIR 2.28, 1.33- excess in Israeli children treated for tinea capitis 3.65)23. The dose-response trend for thyroid cancer (RR 4.0, 2.3-7.9; Ron et al. 1989)26. There has also showed an ERR of 4.9 (1.3-10.2); this is compatible been evidence for increased cancer of the breast and with other studies (see appendix B). Karlsson et al. nervous system in the Israeli cohort. The estimated (1998) pooled the two Swedish skin hemangioma mean breast dose in these patients was low, 1.6 cGy, cohorts to assess the risks of intracranial (brain but Modan et al. (1989) detected a twofold increase and central nervous system) tumors. Although the in breast cancer incidence (RR 2.11, 90% CI 1.05- mean brain dose in the pooled cohort was 8 cGy, 4.24). The tissue of the nervous system received individual doses ranged as high as 11.5 Gy. The relatively high doses (mean 1.5 Gy) and Ron et al. study found a significant risk (SIR 1.42, 1.13-1.75) (1988) found a significant excess of neural tumors and a significant dose-response relationship (ERR (RR 6.9, 4.1-11.6), particularly those of the head 2.2/Gy, 0.2-5.9). Risks associated with low doses and neck (RR 8.4, 4.8-14.8). (<0.1 Gy) were elevated, and an argument could be Yeh et al. (2001) looked at children who had made for statistical significance24. The study also received radium treatment for hyperplastic growth indicated that the risk was higher for those that were in the nasopharynx. This procedure resulted in brain exposed earlier in life25. doses of ~0.8 Gy and thyroid doses of ~0.1 Gy. Another commonly cited childhood medical These authors found non-significant increases in exposure is x-ray treatment for ringworm of the both brain cancer (RR 14.8, 0.76-286.3) and thyroid scalp, or tinea capitis. X-rays were used to treat cancer (RR 4.2, 0.38-46.6), although the small tinea capitis since the very early 1900s and were study population limited the power of the study. the therapy of choice until 1959 when they were Children who were treated for enlarged tonsils at replaced by an antifungal agent. Shore et al. (2003) the Michael Reese Hospital have been followed examined the risk of cancer and other diseases in prospectively for cancer and noncancer diseases. thousands of children who were treated between Cohen et al. (1990) reported a 2- to 3-fold increase 1940 and 1959 at the New York University/Bellevue in hyperparathyroidism, a condition defined by an Hospital in New York City. The authors were overproduction of parathyroid hormone, in this particularly interested in leukemia; although 90% cohort27. of the bone marrow in the patients received very In 1995 Ron et al. published a pooled analysis low doses from these treatments the bone marrow in of thyroid cancer in several cohorts of people who the skull received doses of ~ 4 Gy. The study found had received external radiation exposures. The significantly elevated risks of leukemia (SIR 3.2, results for childhood exposures indicated a linear 1.5-6.1) and also brain cancer (SIR 3.0, 1.3-5.9). dose-response relationship with an ERR of 7.7/Gy

22 The dose-response results for breast cancer were unclear due to a typographical error: the reported ERR was 0.6 (0.97-1.6). 23 Mean breast and thyroid doses were 0.39 and 0.26 Gy, respectively. 24 The SIR associated with exposure to <0.01 Gy was 1.31 (0.79-2.00); the SIR associated with 0.01-0.09 cGy was 1.24 (0.88-1.69). If these dose groups were pooled then the combined SIR would be statistically positive. 25 The ERR estimates at <5 months, 5-7 months, and >7 months at exposure were 4.5/Gy, 1.5/Gy and 0.4/Gy, respectively. 26 The mean thyroid dose in this cohort was 0.09 Gy. It is interesting to note that although the thyroid cancer results of Shore (2003) were inconclusive, they were compatible with results from the Israeli cohort. This suggests that there was a risk in the US cohort that the study could not detect; the lack of significance is in this case a reflection on the power of the study and not on the presence or absence of a risk. 27 Relative risks were 2.9 (1.6-4.3) and 2.5 (1.1-3.9) for cases diagnosed at ages <40 or 40-60. 28 Medical Exposures

(2.1-28.7). This paper is discussed in greater detail consideration in these cases. The incidence of in appendix B. cancers of the rectum, bladder, and genital organs was significantly increased. The thyroid received an 3.4 Radiotherapy for cancer average dose of 0.11 Gy and showed a nonsignificant twofold increase in cancer risk (RR 2.35, 0.6-8.7). Radiation is an important cancer therapy tool. Travis et al. (2000) examined men who had Although the benefits of radiation therapy obviously been treated for testicular cancer with radiation to outweigh the risks in many cases, researchers see if they had an increased incidence of leukemia. and doctors have long been concerned about the The mean bone marrow dose in this cohort was 12.6 possibility of second cancers in cancer patients. Gy. Patients who had been treated with radiation and Two types of potential risk factors converge in these not chemotherapy were found to have a threefold patients; genetic or environmental predisposition leukemia risk (RR 3.1, 0.7-22) compared to patients to cancer, demonstrated by the first cancer, and the who had not received radiation or chemotherapy. therapy, either chemotherapy or radiation. These Risk appeared to be significantly related to dose factors make information about cancer patients a hard although the relationship was not quantified. body of evidence to compare with other studies. The Gilbert et al. (2003) investigated the lung cancer underlying genetic cancer risk can be accounted for, risk among Hodgkin’s disease patients. This study to some degree, by focusing exclusively on cancer benefited from estimates of radiation dose for patients and assessing the dose-response patterns or specific locations of the lung where cancer later using cancer patients not treated with radiation as developed. The authors were also able to control for controls. Doses are typically very high, so we do not chemotherapy treatments and smoking. There was a go into these studies in depth and only discuss a few significant dose-response relationship in this cohort representative papers. Little et al. (1999) provide (ERR 0.15/Gy, 0.06-0.39) and even though most a comprehensive review of the field in relation to doses were above 30 Gy there was little evidence atomic bomb survivor-based risk estimates28. for departure from linearity, indicating similar dose- Boice et al. (1987, 1988) have studied radiation response relationships for lower doses30. It was treatment for cancer of the cervix using case- found that the interaction between chemotherapy control methods. Doses to bone marrow were on the and radiation was almost exactly additive while the order of several Gy from this procedure. The 1987 interaction between radiotherapy and tobacco use paper focused on leukemia and found a marginally seemed to be multiplicative. Hancock et al. (1993) significant doubling of risk (RR 2.0, 90% CI 1.0- found that women who were treated for Hodgkin’s 4.2). The risk appeared to increase with dose up disease had an increased risk of breast cancer to about 4 Gy and the authors fit the data with a incidence and mortality (incidence RR 4.1, 2.5-5.7); linear-exponential model with compartmentalized this risk was particularly evident in women who dose estimates (see Weiss et al. 1995, above). In this had been treated before the age of 15 (incidence RR case the linear estimate of ERR was 0.88/Gy29. The 136, 34-371). Most tumors arose in tissues receiving 1988 paper focused on second cancers generally. ~44 Gy. These authors also found evidence for an Tissues close to the cervix received doses ranging increased incidence of thyroid disease in this cohort as high as 200 Gy or more; cell killing is an obvious (thyroid cancer RR 15.6, 6.3-32.5; Hancock et al. 1991).

28 They found that in almost all cases the atomic bomb survivor-based risk estimates were higher. The authors speculated that cell sterilization from the scheduled high doses of the medical exposure were largely responsible for the difference. 29 This is substantially lower than the estimated ERR of 5.18/Gy (0.81-23.63) from the ankylosing spondylitis cohort (Weiss et al. 1995). 30 The lung cancer incidence pattern in the atomic bomb survivors showed a higher ERR of 0.95/Gy (0.60-1.36; Thompson et al. 1994). Doses among atomic bomb survivors were acute, single doses about 100 times lower than the fractionated doses in these Hodgkin’s disease patients. Medical Exposures 29

Radiotherapy for childhood cancer. Tucker et among nonhereditary retinoblastoma patients was al. (1987), investigating leukemia after childhood 1.6 (0.7-3.1). cancer therapy, found an excess associated with alkylating agents but not radiation therapy. Garwitz et 3.5 In utero exposures al. (2000), on the other hand, concluded that radiation was the most important treatment-related risk factor Studies of prenatal exposure to radiation, mainly for the development of a second malignant neoplasm through obstetric x-rays, have clearly demonstrated in children who were exposed under the age of 20 risks at relatively low doses. Alice Stewart and for a first malignant neoplasm. The irradiated group others published results linking prenatal exposure had a RR of 4.3. Chemotherapy appeared to play and childhood cancer in the 1950s (Stewart et al only an accessory role of potentiating the effects of 1956, 1958), and this study grew into the Oxford radiotherapy. Loning et al. (2000) found that children Survey of Childhood Cancers (OSCC). Although the that received cranial radiation for the treatment of OSCC contains the majority of the data pertaining acute lymphoblastic leukemia had a higher risk to this association, other studies have generated for developing secondary neoplasms. The risk of consistent results. One of the challenges in analyzing thyroid cancer was specifically investigated by de these data is the lack of good dose information; the Vathaire et al. (1999b). Cases where the first cancer average dose of an x-ray exam has declined over had been thyroid cancer were excluded from this the years and precise estimates of dose per exam cohort of French and English children. The mean are not available34. The studies discussed below thyroid dose was quite high (7 Gy), and although have attempted to make reasonable inferences about the estimated risk was unusually high, suggesting dose and apply them to observed childhood cancer a predisposition to cancer, the dose-response outcomes. relationship within the cohort was consistent with The OSCC grew to include all childhood cancers radiation-induced thyroid cancer patterns in other in Great Britain and in 1981 consisted of 15,276 case- cohorts31. Acharya et al. (2003) looked at 33 cases of control pairs. Initial observations found increased thyroid neoplasms in cancer survivors who had been risks of childhood leukemia (RR 1.92, 1.12-3.28) treated with radiation. Thirteen of these neoplasms and other childhood cancers (RR 2.28, 1.31-3.97) were malignant, more than would be expected based after prenatal x-rays of the mother’s abdominal area on a 5% malignancy rate in the general population. (Stewart et al. 1956, Doll and Wakeford 1997). As Again, doses had been quite high (10-42 Gy) and prenatal exposure has decreased, so has the estimated these patients were possibly predisposed to cancer. risk. Knox et al. (1987) estimated an average relative Wong et al. (1997) examined retinoblastoma32 risk of 1.94 over the period 1953-79. This analysis patients; these patients are expected to have a also suggested that the relative risk was highest for strong genetic predisposition to cancer. The authors cancers at age 4-7. Gilman et al (1988) also looked demonstrated a much higher risk in patients whose at the OSCC and argued that the timing of the primary cancer was hereditary, as expected, but also exposure in the pregnancy was more important than demonstrated a dose-response trend for sarcomas of the dose in increasing cancer risk. Specifically, these bone and soft tissue33. The OR for any second cancer authors found that x-rays taken in the first trimester

31 With a dose of 0.5 Gy the SIR was 35 (90% CI 10-87). The ERR was stated to be between 4 and 8 per Gy; this can be compared to the estimate from Ron et al. (1995) of 7.7/Gy 32 Retinoblastoma is a cancer of the eye that typically affects young children and is largely hereditary. 33 The odds ratios for sarcomas (1.9, 3.7, 4.5, 10.7) increased with median dose (7, 20, 40, 98 Gy) compared to the 0-5 Gy dose group. 34 Knox et al. (1987) cite the National Radiological Protection Board estimate that the mean fetal gonadal dose per exposure in 1977 was 3.5 mGy. The United Nations Scientific Committee on the Effects of Atomic Radiation estimated that the mean fetal dose per film was 18.0 mGy between 1947 and 1950 and 5.0 mGy between 1958 and 1960. Mole (1990) used an estimated mean dose of 6 mGy for the period 1958-61. 30 Medical Exposures posed 2.69 times more risk than those taken in the small (~1,200) and the expected number of childhood third trimester. Mole (1990) demonstrated that the cancer deaths in exposed children was less than association seen in the OSCC was similar in both one. This statistical uncertainty is responsible for singleton and twin pregnancies. This finding was the wide confidence intervals noted above. It might confirmed in the US by Harvey et al. (1985). Bithell also be the case that a few childhood cancer deaths (1993) combined the OSCC data with estimates of occurred in the few years between the bombings and in utero dose to generate an estimated ERR of 51/Gy the onset of the studies; given the small numbers of (28-76). cancers observed any additional cases would change Studies in the US have produced similar results the risk estimates appreciably. It is also important to to those seen in the OSCC. MacMahon (1962) and consider that atomic bomb exposures were over a Monson and MacMahon (1984) looked at children wide range of doses. Effects such as cell sterilization born and discharged alive from maternity hospitals or fetal death might have reduced the observed in the northeastern states and found a RR of 1.47 childhood cancer risk at higher doses. (1.22-1.77) with prenatal x-rays. It was found that Wakeford and Little (2003) conclude that the excess cancer mortality was most marked in the atomic bomb survivor data are compatible with the ages of 5-7, where the relative risk was closer to prenatal x-ray exposure data and that the evidence 2. With adjustments made for confounding factors, supports a cause and effect relationship. The preferred MacMahon determined a relative risk value for risk estimate is an ERR of 51/Gy, equivalent to an prenatal x-ray exposure of 1.52 for all cancers. EAR of 8%/Gy. Most importantly, these authors Harvey et al. (1985), mentioned above, estimated conclude that there is evidence of significant risk to the childhood cancer incidence RR to be 2.4 (1.0- doses as low as 10 mGy. 5.9) with an average dose of 10 mGy. Bithell (1993) made a meta-analysis of all available data, including 3.6 Parental exposures the studies mentioned above and several others. The overall RR was 1.38 (1.31-1.47) and the studies Boice et al. (2003) analyzed the genetic effects of were remarkably consistent35. radiotherapy. Specifically, they examined whether Several reviews of these data provide much there was evidence that children of patients who more insight into the issue than we cover here36, but received radiotherapy for cancer had an increased comments regarding the compatibility of atomic risk of cancer themselves. The authors found that bomb survivor data bear repeating. Boice and children of radiotherapy patients did have elevated Miller (1999) provide a skeptical voice, noting that cancer risks but found that the risk was concentrated the estimated risks from prenatal x-rays and in utero in the diseases known to have a strong hereditary atomic bomb exposure are apparently not compatible component (retinoblastoma). This study is very (among other concerns37). Wakeford and Little (2002, different from other preconceptional exposure 2003), however, decided that the atomic bomb ERR studies in that the exposures in this case occurred estimate for childhood cancer mortality was in fact during childhood. Other human and animal studies compatible with the ERR estimate of 51/Gy (28- suggest that risk is associated with paternal exposures 76) from the OSCC38. The atomic bomb data might that occur within a few months of conception; these not be a useful comparison for several reasons. The childhood cancer survivors do not fit that description at-risk subgroup of the atomic bomb survivors was and may therefore be uninformative on the issue.

35 The OSCC estimate was 1.39 (1.30-1.49) and the combined estimate from all other studies was 1.37 (1.22-1.53). 36 Good sources of further reading include Doll and Wakeford (1997) and Wakeford and Little (2003). 37 Boice and Miller (1999) also suggest that the in utero risks should not be greater than risks following exposures in infancy, that some cohort studies have been inconclusive, and that leukemia and solid cancer risks should not be so similar on biological grounds. 38 The atomic bomb survivors exposed in utero produced only one childhood cancer death. An ERR of 7/Gy (-3-45) was estimated based on Japanese background rates and an estimate of 23/Gy (2-88) was based on rates among LSS subjects with little or no exposure (Delongchamp et al. 1997). Medical Exposures 31

Preconceptional exposures are discussed in detail in with historical exposures can be quantified, the section 10 and appendix C. risks associated with the low doses that radiologists currently receive would be too small to be detected 3.7 Radiologists’ occupational exposures by epidemiological methods (Brenner and Hall 2003). In contrast to estimates of the controlled exposure received by patients, exposure estimates for 3.8 Conclusions radiologists are uncertain and often based on the number of years a radiologist is certified. Exposures There are several areas of medical radiation have decreased dramatically over time, so that a epidemiology that have a particularly strong body although radiologist in the 1920s or 30s might have of evidence associating low doses and risk. Several been exposed to 1 Gy per year, exposures today important characteristics of these risks have been are about a thousand times less (0.5 mGy per year; described in the studies discussed above: Berrington et al. 2001). Doody et al. (1998) and Mohan et al. (2003) • There is a wide body of research that shows conducted a cohort study of radiologists in the US. that radiation therapy for non-cancer disease Mortality was lower, overall, than in the general can cause cancer in patients, although these population, indicating a healthy worker effect. are typically high-dose exposures. Radiation Comparisons between radiologists first employed in therapy varies according to the disease being the 1940s or 50s and radiologists entering the field treated, the parts of the body that are exposed, more recently are useful because, as noted above, and the cancer sites that might respond. exposure has declined over time. Radiologists in Leukemia and cancers of the pancreas, stomach, the 1950s were likely exposed to 50-100 mGy per small intestine, liver, gall bladder, kidney, brain, year (Berrington et al. 2001). Mohan et al. found central nervous system, connective tissue, increased risks of breast cancer (RR 2.92, 1.22- breast, and thyroid have all been associated 7.00) and leukemia (RR 1.64, 0.42-6.31) making with therapeutic exposure. Davis et al. (1989), such comparisons39. This study also found that the Boice et al. (1991) and Little and Boice (1999) risk of breast cancer or leukemia was related to the show some of the most compelling evidence for number of years working in the field before 1950. the risks of low dose and fractionated exposure Sigurdson et al. (2003) found that radiologists who where fluoroscopy patients who were exposed were employed in the US between 1926 and 1982 to small doses over time show risks similar to were at elevated risk of all solid tumors, breast those observed in the atomic bomb survivors. cancer, melanoma, and thyroid cancer. Although • Comparisons of medical exposure and atomic the eligibility requirements for the study were that bomb studies seem to show that some cell-killing radiologists must have been certified in the US and risk attenuation effects may occur with between 1926 and 1982, thus allowing for earlier fractionated doses (Little et al. 1999), but there employees who may have had higher exposures, is also evidence suggesting that radiosensitive 78% of the cohort was first certified in 1960 or tissues such as the breast may be more sensitive later. This implies that the doses that radiologists to fractionated doses (Boice et al. 1991, Doody received were low, although there are no direct et al. 2000, Davis et al. 1999). dose estimates available. Berrington et al. (2001) • Gibson et al. (1972), Preston Martin et al. (1988), looked at occupational exposure in the UK and Preston-Martin et al. (1988), and Doody et al. found again that there was a significant risk only for (2000) have found risks of leukemia, parotid those radiologists who had been registered for over gland tumors and breast cancer associated 40 years. In conclusion, although risks associated

39 The breast cancer risk estimate compares first employment before 1940 to after 1960; the leukemia risk estimate compares first employment before or after 1950. 32 Medical Exposures

with diagnostic exposure. Preston-Martin et al. (1989) found a significant trend associated with cumulative bone marrow doses. • Thyroid cancer is an important topic in medical radiation research because the thyroid is one of the most radiosensitive tissues in the body. Children have demonstrated particularly high risks with linear dose response relationships appearing down to doses as low as 0.1 Gy (De Vathaire et al. 1999, Modan et al. 1977). The most convincing evidence for childhood thyroid cancer risk associated with medical irradiation is the pooled analysis of Ron et al. (1995), where the ERR was found to be 7.7/Gy. • In-utero diagnostic x-ray exposure has been convincingly related to cancer risk, and although the magnitude of the risk per unit dose is uncertain, there does appear to be evidence of a significant risk at doses as low as 10 mGy (Wakeford and Little 2003). Medical Exposures 33 L d d e e r n M v y o a d r e f a C e r n s e r n l e - s i e e d e b a t r s s r x b s ; r c n t t r s e ) a d o e a s n e e o i 8 e c t e w r t v a . i h s g L n c t e o c ) f 1 n i n i L o s e - u 1 t e t l f m . o M e a s 5 r r e f o . M 2 p r a e g i o e A - s y 0 r w s f e c o d A t ( r r 3 e f r a b a . s r l e e f a e 1 o b r 9 - 1 s d , b e s . o k R 1 ; ( e r ) t e r k o y 0 r s l i s e o s 3 o o r h 9 M f . i u f c t k t u 0 i e ) r . R 6 s t 3 S s s w n ) . 4 ) r c i 1 ( d o e n e e R . 0 1 e 3 o n e y r p a n R v 4 f h 9 s R a v 9 a e h i t . a x u . i i R 1 t t f c ) o 9 t ) e l i u 1 - h ) q f i 9 t l p - i 1 s 2 m a o 2 . s 5 l M t e ( . . x 3 d e e o 2 e a 1 o o S . v e r m 1 1 r 0 - k h p t i p . r n ( - 2 r t y , o 2 u s n i / 1 o . t ) g 1 2 e y e y e a y . s l ( f s v R l m l 1 c l u 5 n t c t . 1 o ( e a i G n b S o 1 9 n ( R t / 2 d n f p L r i a ( a t i 4 7 5 ( t e a m 4 m ; . . . s 9 s c L c . r n n s c 4 l S s i 1 0 1 2 i r t e g e 5 s 5 e g f . C o . u t f . s r i e i r - n r i 1 s 0 s g R R R a a t 0 c m ) n u i R n o n a 4 e s a p n s n g g o o R g r d R M M M i e h 9 a m x p o o i e n r p S r R N s c S S 1 B E S a e a N c p a u o x s ) s e e o 4 ) , k 6 p y ) n w 9 x d y 6 G ) u . e o 1 . e s r i c ) r G ( 3 t ’ r f 0 u 6 ( i . s 8 a m v t e y g t . 0 7 1 r . r x S s a y y 0 4 m i G e e s 5 . o n h y e b b 1 c m g ) e e 7 y s 8 p r s m m s r R o G . e y d d i n s e 5 l o u t d a r s m o r e e 0 r o s R , l s 9 G o a a n o d r o n n ( ) i u e f b c o 7 i i e a x e e s s ( d . , d o f f s d 1 p e y v ) h 0 o t 0 i 0 e e e g a t y 1 s x s s o f f r 5 p o 7 r d d n e e e f a r G o o u E 9 x 1 d ) s s u s d e e e o - y s d l e s 1 n s s a o o r r r e 9 l 0 h o , r r s a n l s c t d d u b u t 0 y o r e e p a ( . a a l s e s ) s r e b b t r x n n n n u e 0 a o g o 0 s y c r a e a a a a n n e p n p e 6 m m n c d e e e e e . r i G o n a x x k ( a e u u n b r c 1 p n c A d M M ( a E n M ( E n M m ( v o u R d c S r t s n R m ( o a e h 3 5 S c t r r ) i s g , 7 0 i n 8 t o o U r 5 n y 5 5 3 s . m i , w ) e u , p , m l o 7 1 a 5 2 h ) 3 f w o d ( t n 1 0 r x s 6 1 0 c r o e n r e g 8 5 4 o g l t 0 i 9 s , 2 o l e a n h 9 9 a 4 n 1 e o i i 3 t 1 , 3 n c i o y e 6 i - r r , 9 d t d f , 4 4 4 r n i d y 9 o 1 o n t 1 n l 2 1 w t r r a i ( u 5 d n u i a a e e c s l d i l m l t s n n d t t 9 n 3 f c v s c l i a i r n f 7 r e n a i y n 1 k t l 0 n a S l n a o s 9 h r o a s o e a y y , i 0 ) a t i i r i o t t o s 9 o ( s i a t m t r m 2 4 c i i - r 1 i p e n l l 1 n a a 3 e x o 1 r r w m s - a 0 a a n . d g o f p r m t e t e i i 5 a e i 7 r a c 0 2 m h r d r e c c i i c . u o s 6 t ( n d e g 9 1 t r e l i r o o i s - k n n d e t c e n 8 s s , s a o 4 y i a a o 2 r u a ) v n f w m m s 1 o o t 1 c c 4 e h r t 1 s e p l 0 m a l t , n n n r r e M 4 r e n t t 5 n 9 0 a c x 9 u , I t a e e g s f f s s , e e t K 9 e c 1 3 x n 9 1 c c a i i a g a s b e o o r - y e ( i t 1 , l o t Y 9 1 n U n s e e s y n e o - d - a s d o y y r n r S 8 a a e e 0 a u b N 5 e 6 p d r u e r e p l L d d c b c b 9 r o 2 r i u U t 2 r h 2 u t o e - o t t u u s 1 f t f f f f e t 9 u 9 t t i s S r - M 9 e a x t o o o o o e s a s s s m 1 g 1 o n 0 1 t h t w p r i e ( C i c t o t l l , p r s y y y y y , 8 i i u S s s f e o o l y t s s v x m o p d d d d d s i 9 n r r t s t 4 s o i e R s p o t t y u S u u u u u o 1 s s e u 1 t t t t t o 5 c i i o s o , b n n r p , n n s s s s s 4 l h s 0 M 9 c n g g s k . o o o x n c l o o t t t t t u d s r 1 S s g o o c c e i i e e 1 . r r r r r a i e l c l o - l t t o - - m o ) a t r r s r t d o o o o o i r d f i o o a a a 5 e e e i t l t 9 s i e i i i e r h h h h h e . s o l s s e 2 d n u a e i s d b d m d d u o o o o o a a a u 1 w v 9 o d f v a l a e a a a v s u ( i i C r C t 1 C M f C r C f r C r c B C a S t o e e t o i r r r i s p s e s c s o e x d o n i a e i p d p d l a w y y l u y a l l t l t t t b u r t 1 S d n n n o n e d 0 a a . n a n h c 3 n 0 c c a 1 n c a r o i i 1 1 9 8 0 2 a - i 2 t f f o c u , f 0 9 8 9 0 7 i i t 3 n s i ) n o i 0 9 9 9 0 9 s a n n g n n i e 7 a y y u S 2 1 1 1 2 1 e . g g l n s g e o h i i i d d q ...... i i 1 m b s c l r l l l l l l M S ( T S s o o i v l s r a b a a a a a a a o o i a ä e o t t t t t t T 1 2 3 4 B e B e D e D e D e G e H N 34 Medical Exposures f - o e ) 0 r . 7 o R 1 0 8 - ( . R m 4 e 1 . s 4 E r - . 1 v o o 4 2 h S d d t 9 5 i . e t n 3 0 c - a e n w ( r n a 2 s y e d u c 0 t y i a s d n 0 a a f r i . o e i r - ) c r - 1 p n x t 0 n x s x g i 5 t i e R 1 e . e l r s s r r r R 1 e u n ; - o o o s c s o f y f 0 i e n t m p s i ) 8 ) a s l . R r o 5 c 4 e a 0 y o n t 8 5 r 3 l ) ( . . ) r d - 1 g e 5 2 ) 1 e 7 o o 9 d a 5 v - 0 i s 5 r i e 1 . o 0 d t m . 7 - d o 0 o 0 h u . c n f 1 8 6 r d . e d < n 0 e e l e ) 9 r i t r d 0 i . p p < t c t 7 ( o n ( s n h 1 e f n n 9 a p t ( e a e c . 6 e 4 2 a ( o c r s a i 1 r 1 c b 9 4 6 c v , n . - f . . . y ( o m i S s y o g 1 1 i f 1 1 4 r ) n t G ) p n 1 / s G 1 a s . g s 9 R R R R R u i e c . e 0 e t 1 e r R 5 L a O ( R R R y r S 3 + R u 0 s R 5 o E p n d 6 y x e n w 1 e h G . a o t v 0 ’ , n m S s e y 0 y k t t o ; t 8 5 b 2 s a n G - i d l 1 0 e u p f d . - e 5 g m t r e u n 1 2 3 o s n i a l u b 0 , s o i e e s o m i 1 d r e 5 m s s i t l o i a s c 2 o o t e a d u p x s - o s s d d a o e e x 5 m d e o r l r d g f y f t E w d a d o n t o d o o e f e G s e m e r u t i r n n c n s l f a g u a i e h a e s a t x s 0 b n n s r e e m s e ; o 2 a a i 6 o e s s e - m ” t r p e e i d v o o y s e u 0 d x p r e A M D M p D e n 1 E G t o o a c f s ) m o s i d 0 2 4 0 . t r ) e n 7 s 5 0 s 3 o 9 n a e 1 d i 9 a 0 1 u , 7 r , s l n - c 1 9 4 e y f e h 2 a - o 4 t t n n 1 t d 6 . 8 s i 3 i 7 i i d ) s - g l s s a n 2 0 4 r n d n e ) ) 9 n 3 a ( n o o c w r u i i 4 t i s e e s s 9 a s 6 5 ( e r l l L L s a 6 d v 1 e 1 d y y 9 9 c . L s o o o s t c l o s e o 0 , n n u i r r 1 1 n r 5 t y s L i i ( a l p t t l - 7 m S a 9 a s a o c c a ( ) d x n n d s s 0 r e c A n e 5 r t o U a e - r n o n o r n m s r r y y 3 o 6 e 7 i t d d i d x a t c c u , a a a u o y g ( 9 c 3 l n t s t s a r r o o s l 4 a “ ) 1 n e 1 8 - 6 - t g a e a o r m n o o a 1 ( a 9 e d t t 3 - 0 x x e r n n y a p i h h r ; c l 9 m b a t u e x 4 1 h u . E x L e c c d d i C t e y r c n o i i s l l ( t l d t e 5 c i d r , d t d t i i r k o i e t - a a o M o a i s l s s o n f r a t n n 3 h h l y c l 7 0 p p o a a h o o a a a c c C n p p 9 a e t N o 8 8 c x e h I s r n n . r n r 9 f f f f f n o i r 5 4 9 e - t t e d g g 0 o g 1 s o o o o o e n l h y s 8 8 1 x n ( h a a - i y n o - o t o i i d 9 9 m l o y y y y y l w w 0 h a 2 u 0 p d d a c 1 1 u C . l d d d d d u r c n 8 r t s - - t 5 n i c e - 2 u u u u u h 9 h y h y e f f a d n e 6 9 9 t t t t t S r t t t t t c s , x i s r 1 o e o n i i i s s s s s e 7 7 1 ) n n n y o e , d h c l l l l l n b , 9 9 5 l y w a y w u w u a r i s d c r i o o o o o l r u y 1 1 t c 0 t d d o o p t r r r r r . o - h n n n s e o p a t t t t t u u d C d C c d b r x 3 s t o t o o o g o n n n n n n t i i i - e e e s m s o l t t s t s n c n s a 3 s s o o o o o n 4 i t i t t a h o s a a e a e g c c c 9 4 c c t t o o o r i r i l i l 8 c d h o - - - - - w . a a c 5 2 e e c n c n c t e o o a r i , e e e e e d j o 0 n a 7 g g o l g o g o h h l o s n s s s s ( 1 , 4 d i b l e s s s a a h n n a o a a a o a a u 0 4 3 r i i t s h s s f u o l 6 . C f s C C f C a 7 C c 1 C 7 p C d a A C d a A o d 1 e s t f e a i o t t t 2 d e e s s 6 u e s n n t t d 9 r i i r a t t S 1 o e r r a . h m c a a 5 n v t i 1 i r 5 7 t 9 o - u M M s u 8 8 R 9 h a 3 - - e - o 8 9 9 9 a 1 n n y e e e 8 8 S 1 1 t l e o o e R h M x t 9 t 9 . . n b 3 v l l c s s R T w o 1 1 a r a 0 a a a e e f a o n . . r r 0 t t l l T 5 6 n H e H I 2 K e M P a P a Medical Exposures 35 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � s � � � � � � � � � � � � � t � � � � � � � � � � � � � l � � � � � � � � � � � � � � � � � � � � � � � � u � � � � � � � � � � � � � s � � � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � R � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � ) � � � � � � � � � � � � � � � � � � � � � � d � � � � � � � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � � � � � � � � � u � � � � � � � � � � � � � � � � � � � � � � � � � � n � � � � � � � � � � � � � � i � � � � � � � � � � � � � � � � � � t � � � � � � � � � � � � � � � � � � � � � � � n � � � � � � � � � � � � � � � � � � � � � � � � � � o � � � � � � � � � � � � � � � � � � � � � � � � � c � � � � � � � � � � � � � � � � � � � � ( � � � � � � � � � � � � � � � � � � � � � � � � � ) � � � � � � � � � � � � � � � � � � s � � � � � � � � � � � � � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � � � � � � r � � � � � � � � � � � � � � � � � � � � � � � � � u � � � � � � s � � � � � � o � � � � � � p � � � � � � x � � � � � e � � � � � � ’ � � s � � � � t � � � s � � � � i � � � � � � � � � e � � � � � � g � � � � � � � r � � o � � � � � � � � � l � u � � � � � s o � � � � � � � � � i � o � � � � � � � � � � � � � � � d � � p � � � � � � � � � � a � � x � � � � � � r � � � � � � � � � � � � E � � � � � � d � � � � � � � � � � � � n � � � � � � � � � � � a � � � � � � � � � � � � � � � � � s � � � � � � � � � � e � � � � � � i � � � � � � � � � � � p � � � � � � � � � � � o � � � � � � c � � � � s � � � � � o � � � � r � � � � � � � � � � � o � � � � � � � � � � � � � � � � � u � � � � � � � � � l � � � � � � � � � � � � � � f � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � g � � � � � � � � � � � � � � � � � � � � � � � � � � � � n � � � � � � � � � � � i � � � � � � � � � � � � � � � � � � � � � � � � � � d � � � � � � � � � � � � � � � � � � � � � � � � � u � � � � � � � � � � � � � l � � � � � � � � � � � � � � � � � c � � � � � � � � � � n � � � � � � � � � � � n � � � � � � � � � � � o � � � i � � � � � � � i � � � � � � � � � ( � � � � � � � t � � � � � � � � � � � � � � � � � a � e � � � � � � � � � � � � � � � � � � � � r � � � � � � � � � � � � � � � � m � � � � � � � � � � � u � � � � � � � � � � r � � � � � � s � � � � � � � � � � � � � � � � � � � � � o � � � � � � o � � � � � � � f � � � � � � � � � � � � � � � � � p � � � � � � � � � � � � n � � � � � � � � � � � � x � � � � I � � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � � � � � y � � � � � � � � � � � � � � � � � y � � � � � � � � � � � d � � � � � � � � � � � � � � � a � � � � � � � � u � � � � � � � � � � r � � � � � � � t � � � � � � � - 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- n �� �� � s � � 5 � � � � ed a ed � � 0 s i a o o o o � �� �� �� �� �� �� � l r e d 0 3 0 � � o � 2 t � � � � 0 l p r �� �� �� ��� h h h h � � � � � � � � o � �� �� 6 , 6 4 n er i p �� �� � � � d r r e � o i � � � � � � � � � � � � v 9 1 9 9 e � � � �� � � reat � � � t w � m d � Co o t Co ch 1 Po ex 6 Co fo 1 Co fo 1 � �� �� �� r l � ���� ���� ���� ���� e � � � � n o t �� � �� �� � �� �� � �� �� � � �� � �� �� � �� a � � � e � a p ��� h � � � r t � e ��� e � � � � r d . r p � � � t l �� � � i o �� � n al � 9 � � n � h � 9 5 2 3 � � � s o � 8 r � e c ’ � � � � � �� � � � � 8 9 0 0 � � � et e � �� 9 e � d �� � � � � � � � � 4 � 9 9 0 0 � � b � � e v 1 � � � ffe � � � � � � � �� 2 � � 1 1 2 2 � s a � � ��� � , s � an �� � � � � � 2 r � �� a . . . . � � � � a , � re � 7 ae d � � � � � � � �� � �� � � �� n n B G h 2 � o � 7 al al al al � �� �� �� �� � �� � � � � � �� �� �� �� �� � 9 � � � � 3 4 5 � � �� Mo 1 Ro et Ro et Sch et Sh et � � �� �� �� � �� � �� � �� � �� � � 38 Medical Exposures d ) - n 7 a 4 s 0 , e b re 2 . d k . e a s i u s 4 s s m e 1 e n s a - R m o o h ro ri h , o o t 7 t o d w b R y t 0 p - p r 3 h f . e h c E 3 o p i t o r w . f en ; ex u o res (2 1 s 9 m m d l s - ); r 6 e y o 1 e o e l 1 6 e er t . en c s p 1 a h m 8 s . 1 t RR i n x o ’ 2 aft e t ( 3 a e r ep n - d o h 0 i c t o r d t 8 t 1 �� ) f k R . er - e ) d g t n ars g 7 cer v e i f 7 n n R �� t e d (0 i 4 a o a 0 can a me - o y y a n . an , i �� 5 s i fi d 4 t l c 2 m a r H G . i 5 1 i � / - c a 5 mi t f n d 2 m e 7 e - 8 n s (0 e o ren g o t 4 d y e o 5 t l i . k an es , 2 n RR k 2 s e e 0 0 rs t . . e 7 t g , s i y r r 4 eu f 4 e a s fi a s p n - l r ri r u r (2 o i m 5 s e e u s h u h ro L t s e mo y c o 2 c R h u t s i l ed RR t o n p c L u s r o n R p G t a a p w x i r / o g C o t a E c f e x l i ) 7 - e n n ari e r r ce u g n h 5 3 n R v at ri . e t o r a n creas 3 t o i m e R . f u 2 f u t m o , l a In 1 rel o N w d 1 Brai can f t E a a d s s A d r m s e n . e a r l r t o a y e a e a a 4 h . n e y d p p G m o y 4 o i l 5 y m t m 6 y e o 2 e . m o s y r G - c s l c e 2 G r o 5 o r a s 9 s e e i ’ 8 o e m d e 0 h s . h n h 7 F n r � i t . T i o 0 T . w o l k . r 0 d . y l g e e �� l 5 d e f e l � d y e v 2 rro n d o p o d d o an d o d i o o m �� H ) 8 o i ma es - k m i b s n m 3 s r n . l e d e �� a o c a o 1 ai al i n n i p r t n d t t ) s a n o a i b e o n a f d , �� r t b i e r ) h o r d w t e n cal 8 e a s ro i �� r d o 1 k R u . w y o p d � p s q f 0 y i R a o h y x - - l r r e 7 e Mean Mean G T (l (t 4 b ��� - a e 8 h r 0 , . e t . v a e i 1 n 0 t t e s i ��� ( i l a r o n t s t t i e g � y o s a l o c � n d o h l p G i n n r / e a i s a w t p y �� men 1 n t c l o , . i n � , t l l 7 e n 0 e e a l n c K e y i 5 �� i u e a e p m reat k 9 s c U t c m d b t i s i � r 1 e 7 i f f eo e a - t an o d � i f k 6 t p m h p 5 e n n e u t 7 7 u a o 3 , d g e v 5 m i i 7 l c i e 9 n 4 e t o - 2 t s i 5 r r ���� 1 1 c c , a n 9 e u a , e , rad o 5 r � s a e n m � n 2 ed e n i i 1 ) o n K f t � n i �� l 0 p s w n o l l y n o eal U i �� e x t 6 i a c e e i g e reat � 9 r m e e s , r t �� h y n r e r s a t c 1 al t h o � e s e i t - h e , t F t t t �� rt w � ) n 3 f en . r al , n ary 8 a o y 4 i ) e a d �� en t h �� 4 rt b e i i e 9 s . mo � . � l p m r ci c , n 0 1 i e � a i at ed a a o - n g t n t r � l , mo i e r p e 7 n r u � d r e y as o r r 0 s u e mi s �� . e l h �� i n o reat v e f e t m 0 t , an t � ce ce e p o i ( v l k o x s r r i l x s i t f e ��� n d y �� t t y e c eu t e y y x d can can l G r s . r n n / e en �� ed r ) e i n G a a f f f i i t l 8 / s n l 3 � f c o f o o o c 2 7 , (Mary o 0 e at a . p e e a s 3 p e 0 y y y i p s . 0 �� d a d s h s 2 t r d d d 2 e ( o s e m g 7 k a ex . r i 1 r u u u b l e o s t a c e t t n t ��� 5 e i i f i a i k h s s s n y r l y v 9 ) o s t u a d m a �� y o 3 1 e 5 e l e o een rt rt rt p e - l i l R 6 d h � 2 m - 1 . b o o o , k t n 5 y n � , R n 0 3 n u h h h n o . ch 3 r k y o t o e 2 a E o l e 1 s l 9 l ad - l p n n h �� v e 1 d o t a 1 Co s Co an 1 Co h i o r r e r e c t 8 s t e o . P e , a r w f ( a n 0 ��� s n o o ( w s o e u m R i h r i g �� t m g y t , i o R R a r � s n d d G v 4 5 1 h e E R e / i � �� o o d c � 9 9 0 p i i 8 v e e e a r r n o 9 9 0 � g 1 h h h e . �� s a u e n 1 1 2 s s � T r s I e c p T T 5 . . . s s �� �� al al al ei ei eh 0 7 8 9 1 �� W et W et Y et Medical Exposures 39 d ) - n 7 a 4 s 0 , e b re 2 � . d � k . � e a s i � u s � � 4 s s m e � � 1 e � n s a - R m o o h ro � ri h , � o � o � t �� 7 t o � d w � � b � R � y � t 0 � p - � � � p ��� r 3 h � f � � � � � � �� . e � � h c � E 3 � � � � o � p � � � i t o r � w . � � � � � � � f en � � ; ex � � � � u � o � res (2 1 � � �� s � 9 m m d l � � s �� � - ); r 6 �� � � � � � � � � e y �� o ��� � � 1 e o �� � e � l � 1 6 e er t � � ���� � � � � . � � en c s � p � � 1 � a �� h m 8 � s � � . ��� �� 1 �� t � �� RR � i n x o �� ’ � � � �� �� 2 � � aft �� e t ( � 3 a � � e r ep n � � �� - d o � � �� � � � � h 0 � i �� c t � ��� o r ���� � d t � 8 �� t 1 � � � �� � � � ) f k � R . er � - e �� � ) �� �� �� d g � �� �� � � � t � �� n ars g � � 7 � cer � v e � � i f 7 n n R �� � t � � e d (0 � i �� � 4 �� �� �� �� ��� a o � a � � �� 0 can a me ��� � � - � ��� o y � y a n . � an � � , ��� �� � i �� � 5 � s i � � fi d 4 � �� ��� t l � c 2 �� � m a r � � H G � . � i � �� 5 1 � � i �� �� � / � � - c �� � � a � � 5 � � mi t f � � � � � � n d ��� 2 �� m � � e 7 e - � � 8 n � � �� � s � (0 e � � � �� � o � � ren g o � t �� 4 d �� y e o � � 5 � � � � t l � i . k � � � � � an � � � � es , � 2 � � �� n RR � � � � � k 2 s e � ��� � e 0 0 rs t . � � � �� . ���� e � � � 7 t g � � , s i � � � � � y � � r � r 4 ��� eu � f 4 �� � � e �� a s fi a � � � � � s p � � n � � � - l � � �� � � � r ri r u r � (2 � o i � � � � m � � � � � � � 5 s � e e � u s � � h � u � � �� h � � � � ro � � � � � � � L t s e mo � y c o 2 �� � � � � c R h � � u � � � t s i � l �� � � � � ed � RR t �� o n p c L u s r � � � � � o �� n R p G �� � � t � � ��� � a a p w �� �� �� � x i r / o � � � � � � �� �� g �� C o t � a E c �� � � f e � x � � l � i ) 7 � � � � � - e n �� � � n � � � �� ari � �� e � � � � � � �� r � � r ce �� � u � � g � � n h 5 3 �� n � � � � � � � � R v � � at �� ri . � � � e t o r � � � � � � � � �� a � n creas � 3 � � t o i � � � � � � � � � m e R � � . f u 2 �� � � � f � � u � � � t m � � � � � � � o , l �� � � �� a In 1 rel o N w d 1 Brai can � f t E �� � � � ��� � a �� � � � � � a � ����� � � � � � �� � � � � d s � s A � d � � � � � � ���� r m s � e n � . e � � � a �� � ��� � � �� �� �� � ��� � ��� �� �� �� � �� ��� �� �� r l r t � o a � � � y e a e a a � 4 h � � � . n e y d p � � p G � m � � o y 4 � o � � � i l 5 y � m � t m � 6 � � y e o 2 e �� . m o s � y r � G � - � � c � s l c e � � 2 G � � � r � o 5 � � � � � o r � a s 9 � s e � � � � � e � i ’ � � 8 o e m ��� � d e �� � � 0 h � � s � � � . h n h 7 F n � r � � � � i � t . T i � o � � 0 �� T . � w o l � � � �� k �� � � . � r 0 d � � . y � � � � l � � � g � � � e e �� l 5 d e f � � e � l � � � � � d y � � � e � � v 2 rro �� n � d � o p � � � �� o � d � d � o � an � � d � � o � � d � � � i � o � o m � �� � H � � � ) � � 8 o i � � ma es � - k m � � � i b � �� � � � � ��� s n m � 3 � � � s r � �� � n . l � � � e � � d � �� � e �� � �� a � o c � � a o � 1 � � � ai � �� al i n n � i � � � p � � � r t � � n d t � � � t ) � s � a n �� � � o � � � � � a i �� � � b � e o � n a f d � � � , � � �� � r � � � � t b i � � e � r � ) h � o �� r � � � � � � d � � w t � � e � � � n cal 8 � e � � � � a s � ��� � � ro � i �� � r �� � � d � � o � � 1 � � � k R u . �� � � � w y o p � � � � d � � � p � � s � � q f � �� 0 �� y i R a � � o h y � � � x - � - � l � � r �� � ��� �� �� � � r � e 7 � e � Mean Mean G T (l (t �� � 4 � � �� � b � ��� � - a � e � �� �� 8 � � h r � � � � 0 � , � . � e � � t . � �� v � � � � �� a � � � e � i 1 � � n � � � 0 t � � � t � e � s � i �� ��� �� ( 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� � �� � � �� � � �� �� �� � �� � � �� � �� �� �� � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � �� �� �� � � � � � � � �� � �� � � � � � � � � �� � � � � � � � � � � �� � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � �� � � � � � � � � � � � � �� �� � � � � � � � � � � � � �� � � � � � �� � �� � �� �� �� �� � �� � �� � � �� Medical Exposures 41 n l i l l 19 a , n L a , e r L ue nt a 4 or s dr 2) C f s ne , . l , - 1. i e ) t 4 om gna s t hi ge - o i a . i l s c 0 17 um e ) t . non a a t ve s a a 120) i i n he 1 c 4. n t - r i t d m i - e 1 c I of t g r s e n e s a ’ 50 i C nobl 79 r na ( n v 5 i i ks nc e t ; he y 1. s k gi e t � e 3 i ( onne l w ghe . g � r 80 r ge � c nc 6 d s va a - hi 90% of o va � d e R ( 80 0 or � e e . e s of H k f R � s r 1 gna 0 nd 2. s r ( s i pr i or a e a o l a r � r f 2. f e 5 r R a e r ; t 6 nc e . h, nodul R be n R a m 115) 2 c nc e 2) nc - : c d nc . R a i nom d a t d i m a 6 e c t n oi a 34 c - y c a a i r 5% l ( r nd r e om 0 : , a a . t r o t ) o m t nt f s ohor c hy 3 t h a t a 66 ( gnos e c c , i ) t l c d a r a i , s i 3 h uke r h m f of a c m ohor oi 56 s di e e i r - w o 4. l c t t dde ni 9 s l y s nc gni a l uke a S R hyr r ; i ont a G 3. i e 0 c 39% c publ A S l bl D c ( U T R f . 4 5 - 2 1 . 1 - 1 ) y ( 0 2 nd . f 8 G a gh 7 o 0 24 . y s e hi nd 2 r e y) e ( 45 y a , bone y) a s - ) r r o d � G y G m dos e y d e � i dos ge dne t d 1 G d d � a G d c d pr a r dde 42 ki a 7. l - oi n 2 a �� 1 por oi b o e ve s e ; on bl g nd 10 e a r e ( �� 5 a hyr . n t hyr i d � 8 dos y t h ng - e d dos t ) dos c 9 not G 2 nge e n . ge t a a r a d l a 1 s n a ow ndi r e ( u r e r m um ( s 60 di i r t 5 ga t om - e pe e nc a c 0 y r t ona ve y os r s . a s e , 4 M G E m O ( 30 r G de c A G D e , l ) p m m s u a . t x c m he 96 y c e t py - e s G r r a a n di ; 1998 r o 5 i r - f nd 8 ng 1985 h 4 . i o , t a - - s n he opl 2 r � a i r t 1943 2 - 847 N 6880 e � nd or 2 f r m ( . ne � ow 745 a 6, o vo e o l 1970 1 N t nc ng s ope nd ( s d s i nd s , 1942 r n a a vi �� ol e a i a nc s a 3 nd u c , l f s � oi ) a nd 8 a �� b ur vor o e . s E ow c a K � S k s s o d l 1 e s r vor s vi a �� s n , U e r hyr i U d nom �� u ) i � ol t e a r ( s a e e vi a f ur s c r i a n n � � ope r ond de s y he e c o dhood k ur nc r r e m c di a t l 86 r g s s e ur o a e �� - i �� e nc c d k � c s r s n r nc hi E i � i a r u t nd � e a c � oi e nc 195 a 4188 o c � n a d l c i onda ( ( of 970 i a � e l ne m nc t c � e c � 1 L l a r m u a e hyr t u L c � e 096 s c ge t k s l nc 1991) ond C dhood r � �� e udy udy udy a - vi a - l 4, � � r t t t nc c a uke a n r r of of of n s s s i , a e � e c e n hi F o e p �� l s i c i r c � c s n r dhood nm ol l ol ol u n l o s ; e r r i r i e s 1960 a of of dhood 2 a udy udy udy �� or k) n of . o l hi c t t t s m s f D ) ) r a � 4 p s s s c a r s s e - n a hi ont ont ont x vi A c i c t t t 0 e e r c i c c c r . �� ol ol r py vor nd r nom - - - l e h 1 r r i o a t a ( a e dr nm e e e c � f 120 r l c vi s s s n e 33 � 2 r i y m or S � ohor a a ohor ohor a 0 ont ont hi a ount ur or D p n he . m � C i C c f A C c t N C c U ( C c s C 25, c a 2 o r � d ) e � I b h � t a e C . . . t r t l l l n g i e e a a a �� � % o n i � i � 0 t t t t z ha v � 9 � a e e e t l c ya i ( 1999 i a o r � d e e e � . v R a �� w c c c V l n 2003 2000 ha r R R i � a c . e a . �� oi oi oi l t l 1 2 � A a B 1987 B 1988 B 2003 D e G a 42 Medical Exposures . n i a ge ) 4 nd a nd s a a ; om a 47 e t l - s l 5) or a a py om f r 26 a c ( nd r 32. r be a - a nobl 3 ove s he 30 i nt m t s 6. ot s e e ( 7) a r . nd � di di m 6 5 n a � t a y 39) � - e r r l a oi l 5 � e a e 0. 3 . 15. t � h a s r - t 2 r t � i ( hyr di y . R 06 h 13) ) � e w t . 1 2 R r nl i py ove i 0. 5 3 m 5) r a 4. ( - - a w . s r he e 4 2 22) y hypot ) m 1 R - - 14 di h . 19) he . nc t G - 0 n 1 7 R i k . 0 a . . i oi ( s ot s ( c 371 e 1 0 i e w y s 15 - ( ( r s 15/ m ( e d s a G hyr nc r / s 86 7 1 c t 0. 34 e 9 a he oi r nt l ( 0. 1. 3. 17 1 e de c e e a . R i t r i nc 0 t o R R R R a t R hyr s nc nc a E R T i hyp I 136 15 R R not R pa C 5 w n o s a y d e e m 6 t G s o i a c 32 s y b r y 12. a e 24 c s s G i G p e s f r a a u i i 0 o e e o dos c f r r r 1. dos g � a a R 200 e pe ) � py s ~ R gnos k k w 3 � a . E a c c o r o o 5 dos r t t e 1 �� di r ne ne h - d he e a r 1 T . up �� e oi ot . m 1 he he s s � , t t dos a di nc e 3 . a a hyr o o m n y r t t t 5 c o a c G n e n dos y y bone R r I a a a l � G G S m n s a ( ung 30 di di a � e l - e e e d � u y; y oc 40 40 e s � s s M G of M ~ ~ 12 M G L i o � t � p t � x f a e e o - - i n l s n i �� s a o e m � e r n � or nt r s m e k, e d e e e � 1994) 1970 i nc 1979 w f n s t uke - � 006 or , a t t a 4 e � nc s 5 n de l ) a a c 4 Y 1787 5, a pa i i 789) 1 ny, f c . ( d �� d d r a n 88 n a o 5 w n nc vor i i f � 1965 e e e h i 1 a t t e t n o m - , s 227 e i i vi a a l s r r om r 5 ( nc �� s N . a e e �� t e 1997 � e r e a w a r r � ur udy s 0 s - e t t m c t e s , G a �� nc d udy ona 1989 1990 s o � s nd nc ( 2 s s t i r - - . c a e nc a a t s r vor s � e 4 c di a c nt nt a ol �� s c s 1989 ung r e e t vi na � R nobl d d l �� nc ol i i t o r i I , t � t t � r vor a t e e s e gnos S ur 1961 1961 oi oi t � � c e ( ont s s a a ond of vi � r � pa pa nt y y c o e c r d ont i 131 t t e - di hus e e a e e i i � ur e hyr - hyr c s , e s r t t br s c s s s s I s - �� a s � n s o e r r ul a a a � udy e 604 e e a p t � s c e e s L w ol s of of of of i � c x s s s s �� ve ve i r a t 1, e dr L 0 � a l � s c l 7 D di di ni ni 118) h n ol e A t , i t M s r hi �� ont s s s o r U U udy udy udy udy 1 c nd � c t t t t ona e e ( b n i s s s s a n’ n’ n’ c i d d t r n ont n t t t t t nc o �� 1984 567 a c d a f or or - - na c e � 455 r d m dhood de t e � hout nf nf l i d r e e s a 18, � t t a a n odgki e i odgki odgki a ohor ohor ohor ohor ohor e t t a � nd hi o nt n nc r v c C H a C G w C H S C H S C c 1995) I i 1993 C i t 1914 � e e � l s e � . t t 9 . l e l r 9 e e a t �� t e a 1 � t � e t e k k f � w t e � e t o � e s r s oc oc t � ng R � u I vi �� be 2003 1991 1993 2000 2000 hn nc nc S O l a ong � i . a a . a . . . �� oni r l l l l l 3 4 � G a H 2001 H a H a L a T a W 1997 4

ATOMIC BOMB SURVIVORS RERF research. Many of the RERF studies reviewed here are based on a roster including 4.1 Introduction over 284,000 survivors (known as the Master Sample). Studies conducted by the ABCC/RERF The bombings of Hiroshima and Nagasaki in have used subsets of the Master Sample including August of 1945 were terrible events that have the Life Span Study (LSS) cohort, which includes come to symbolize the destructive potential of our all survivors whose permanent place of family civilization. They have also been a grim opportunity registration was Hiroshima or Nagasaki. The LSS to study the health effects of radiation exposure in sample was divided into four groups corresponding humans and have become the standard reference to where people were at the time of the bombing: point for what radiation does to our bodies. The story within 2,000 meters of the hypocenter, 2,000-2,499 of the bombs and their health effects is complicated meters from the hypocenter, 2,500-10,000 meters and continually evolving. In the months immediately from the hypocenter (the people in this group were after the bombings there was little understanding matched with the first group by city, age, and sex), among the general population about possible health and outside of both cities (also matched with people risks. Dr. Harold Jacobson, a former Manhattan in the first group). The LSS was expanded in the late Project scientist, warned that the effects of an 1960s and again in 1980. Most of the LSS analyses atomic bomb could be long lasting and was widely have focused on the 93,741 cohort members who criticized for his comments by members of the War were in the cities at the time of the bombings. Other Department and Manhattan Project officials. A team of Manhattan Project doctors and technicians traveled to the two cities to prove that there was no residual radioactivity from the bombs. In the American press, radiation was rarely mentioned and President Truman was quoted as saying the bombs were “just another piece of artillery”. This ignorance was short lived, however. After two years excess cases of leukemia began to develop and in 1946 The Atomic Bomb Causality Commission (ABCC) was created to collect information about the increasingly apparent health effects in the survivors. The Radiation Effects Research Foundation (RERF) was Figure 4-1. The bomb dropped over Nagasaki on organized in 1975 out of the ABCC as a scientific August 9, 1945 was called Fat Man. It weighed 10,000 research institution financially supported by the lbs and had a 21,000 ton yield (http://library.thinkquest. governments of the United States and Japan. Today, org/20176/atomicbomb.htm&h=161&w=250&sz=31&tbnid many radiation protection standards are largely =CHSWCuBAVGoJ:&tbnh=68&tbnw=106&start=6&prev=/ dependent on the data and analysis generated by the images%3Fq%3Da-bomb%2B%2522fat%2Bman%2522%26 ABCC and RERF. hl%Den%26lr%3D).

43 44 Atomic Bomb Survivors

risk in people who were in utero at the time of the bombings and have examined, with inconclusive

results, risks in the F1 generation (children born to survivors). Much more information is available at the RERF website2 including periodic updates on the latest developments in the research project. Doses. Reliable estimates of exposure are critical in accurately assessing the risks associated with the atomic bombs. When the bombs were first dropped in 1945 the immediate effects of the bombs were expected but the lasting effects were unknown; at the time of the bombing there was no system of Figure 4-2. A view of the destruction of the city of Hiroshima. measuring doses in place. It wasn’t until excess The building in the top right corner still stands as a leukemia became apparent a few years later that monument to the event (www.ww2guide.com/atombomb. particular attention was paid to estimating doses. shtml). During the 1950s and 1960s Japanese scientists created the T57D and then T65D dosimetry sub-samples of the Master Sample include a sample systems. Gamma and neutron doses were inferred of those survivors who were exposed in utero and for these dosimetry systems from calculations and a cohort of the first generation children born to experiments performed at the Nevada Test Site. survivors. The RERF has released the results of its Neutron doses were not considered to be of great LSS studies in a series of papers that describe cancer importance in these initial systems. In 1986 the and noncancer mortality, solid cancer incidence, and DS86 dosimetry system was developed as part of an leukemia incidence. These documents have provided international effort to refine dose estimates. In the important insights into the effects of radiation new system there was a considerable reduction in exposure and have been updated and expanded over the estimated neutron doses; it was concluded that time1. neutrons were much less significant than gamma Over the years RERF researchers have radiation in contributing to health effects. The consistently demonstrated associations between DS86 system also takes into account the survivor radiation exposure and many diseases, cancer distance from the epicenter, shielding (both by and non-cancer. Thompson et al. (1994) found housing and by the posture of the person at the time significant excesses of total solid tumors and tumors of the digestive system, stomach, colon, liver, respiratory system, trachea, bronchus, lung, skin (nonmelanoma), breast, ovary, kidney, urinary bladder, and thyroid. Preston et al. (1994) found positive correlations between radiation exposure and the incidence of non-solid cancers including acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelocytic leukemia (CML) and lymphoma in males. Shimizu et al. (1999) demonstrated excess mortality from noncancer Figure 4-3. A view from the air of the bombing of Nagasaki diseases of the circulatory, respiratory, and digestive (http://www.astrosurf.com/lombry/quantique-bombes- systems. Other studies have demonstrated increased atomiques-pic.htm).

1 As of January 1998, 48% of the exposed cohort was still alive; follow-up will be incomplete and ongoing into the near future. 2 www.rerf.or.jp/eigo/experhp/rerfhome.htm Atomic Bomb Survivors 45 of the bombing), orientation (facing away from or medical exposures). Because of this complication, towards the hypocenter) and the age of the person comparing observations from atomic bomb survivors at the time of the bombing. The DS86 system will and other cohorts is less straightforward (see, for soon be replaced by a new system (DS02) that example, Brenner’s 1999 discussion of comparisons will incorporate moderate changes in neutron dose with fluoroscopy cohorts). estimates, changes in methods for gamma radiation This section is organized according to outcome; dose computation and better adjustments for external solid cancer, leukemia, and noncancer disease are shielding by factory buildings and local terrain treated separately, and mortality and incidence features (Kellerer and Rühm 2002). are discussed independently (although they are Some may wonder why the atomic bomb studies, obviously related). The atomic bomb survivors data which are usually considered to be high-dose studies, are a rich source from which to derive estimates of would be included in a low-dose overview. Although dose-response coefficients (ERR/Sv or ERR/Gy) and it is true that many people received high doses of these coefficients are the basis for many radiation radiation from the detonation of the bombs, 75% of protection guidelines. Unfortunately the description the exposed survivors had doses between 0.005 and of dose-response patterns is not simple: risks have 0.2 Sv (Pierce and Preston 2000). At the same time been found to depend on factors including age at the cohort is also representative of a wide range of exposure, time since exposure, and gender, and doses, from less than 1 mSv to several Sv, making it when the dose-response curve is not linear there is useful for dose-response analysis. an additional complication. An estimate of leukemia Uncertainties. As with all scientific endeavors, risk, for example, would be very different for young studies of the atomic bomb survivors are associated girls than it would be for old men. Table 4-1 presents with various complexities and uncertainties that can a set of ERR estimates for various causes of death; impact our interpretations of the data. Stewart and these are ‘average’ risk coefficients, meaning that Kneale (1993) and Stewart (1997) have challenged they reflect the long-term risk experienced by the sampling accuracy of the LSS on the grounds that an average person, in this case someone who is the initial exposures may have caused an unequal exposed as an adult. Risks associated with childhood distribution of deaths among those who had strong exposures tend to be higher, as discussed below. For and weak immune defenses. If this is true then the outcomes with nonlinear dose-response patterns, surviving population is unusually strong and risk like some types of leukemia, the ERR per dose is not estimates based on the cohort may underestimate a valid description of risk and for these outcomes we risks in the general population. Stewart and Kneale present the ERR at a fixed dose (1 Sv). found evidence of this ‘healthy survivor’ phenomena in the data; there is a significant deficit of those who 4.2 Cancer mortality were <10 or >50 years old and those who were <8 weeks of fetal age in the study; these subgroups are Cancer mortality was analyzed for the period 1950- thought to have weaker immune systems. 1990 (Pierce et al. 1996) and again for an extended Another complexity involves the type of radiation period of time and including only solid cancers released from the atomic bombs. Although there was (1950-1997; Preston et al. 2003a). These analyses a small neutron component to the total exposure, the have generally shown that solid cancer is best majority of the doses received came from gamma described by a linear or supralinear (concave-down) radiation. Straume (1995) reported, based on the dose-response curve. Leukemia mortality, on the DS86 system, that nearly all of the exposure that other hand, is better fit with a linear-quadratic model people received from the bombs was in the form of that is concave-up (see Figure 1-6). unusually high-energy gamma rays (in the 2-5 MeV The ERR estimate for all solid cancers was range). These gamma rays are expected to be less 0.37/Sv in the 1996 analysis and appeared linear up effective at inducing biological damage than most to a dose of ~3 Sv3. The authors point out, however, other exposures that people experience (for example that the dose-response curve is steeper at low doses,

3 At higher doses the risk per dose (ERR per Sv) begins to decline due to the effects of cell killing. 46 Atomic Bomb Survivors

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������ ��������� ����� ������� ���� ��� ��� ��������� �������� �� ��� ������ �� ��������� ��� �������� ���� �������� ��� �������� ����� ��� ���� ��� �� ��� ��������� ���� ��������� �������������������������������������� 48 Atomic Bomb Survivors approximating a supralinear curve. For example, rate among proximal survivors for a few years after over the dose range 5-20 mSv the ERR estimate is the bombings; the people that were strong enough 2.6/Sv and it declines steadily as dose increases4. to survive the bombings were apparently healthier Solid cancer mortality depends on age at exposure than average. This effect diminished over time; to and gender; specifically, risks are higher for females account for this effect noncancer mortality risks and for childhood exposure. The 2003 analysis were estimated based on data from 1968-1997 generated an average ERR estimate of 0.47/Sv (Preston et al. 2003). Generally the noncancer (averaged for both sexes and assuming exposure at mortality rates were associated with dose, although age 30). As in the 1996 analysis, the dose-response the effect was smaller than that seen for cancer, and curve was steeper at lower doses so that the ERR the dose-response pattern could be described as estimate was 0.74/Sv (0.1-1.5) for doses less than linear. Deaths from stroke, heart disease, respiratory 120 mSv. The effect of age at exposure was described disease, and digestive disease increased by 10-20% as a decrease in the ERR estimate by 36% per 10-yr per Sv (ERR 0.1-0.2/Sv). Blood diseases were an increase in age at exposure. Exposures in infancy, exception, showing a stronger effect with an ERR for example, would be associated with a solid of 1.9/Sv (1.2-2.9; Shimizu et al. 1999). There was cancer mortality ERR of ~1.9/Sv5. Delongchamp some evidence, not significant, of an effect of age at et al. (1997) calculated a similar ERR estimate of exposure that was similar to that seen with cancer 1.4/Sv (90% CI 0.4-3.1) for adult cancer mortality mortality. after exposures in early childhood (less than 6 years old). 4.4.1 Solid cancer incidence The dose-response pattern of leukemia mortality is best described with a nonlinear model so that Thompson et al. (1994) analyzed the incidence of one estimate of ERR/Sv would be misleading. solid tumors over the period 1958-1987. Generally, Pierce et al. (1996) presented summary estimates there was a linear dose-response relationship for of leukemia mortality risk with an ERR of 4.6/Sv cancer incidence with an ERR of 0.63/Sv (0.52- (90% CI 3.3-6.4), apparently based on a linear 0.74). There was a two-fold greater ERR for females model. The effect of age at exposure on leukemia (0.84/Sv) than for males (0.38/Sv), and a strong mortality was complicated. Exposures in childhood effect of age at exposure (Figure 4-5)6. were associated with higher risks in the first 10 or 20 years after exposure. If we consider the risk over the entire follow-up period to date, however, then risks are about the same for all ages at exposure. This pattern can also be described by saying that leukemia mortality risks declined over time, and this decline was steeper for people exposed in childhood.

4.3 Noncancer mortality

Noncancer mortality through 1990 was assessed by Shimizu et al. (1999) and additional follow- up through 1997 was discussed by Preston et al. (2003). The pattern of deaths from noncancer Figure 4-5. ERR estimates for total solid cancer incidence diseases showed a strong healthy survivor effect. by gender and age at exposure (based on data from This was evident in a lower noncancer mortality Thompson et al. 1994).

4 At doses of 20-50, 50-100, 100-200, and 200-500 mSv the ERR estimates are 1.6, 0.60, 0.43, and 0.38/Sv, respectively. 5 Based on the following model: ERR = 0.50d{exp[-0.045(agex-30)]} (Preston et al. 2003). 6 The ERR estimates were 1.90, 1.21, 0.58, and 0.37/Sv for ages 0-9, 10-19, 20-39 and 40+ at exposure. Atomic Bomb Survivors 49

Site-specific risks were all compatible with a The risk of basal cell carcinoma after exposure at linear dose-response model (see Table 4-1). Gender- ages 0-9, for example, had an ERR of 21/Sv (4-73). specific risks were significantly different for skin The liver cancer risk estimate was improved with cancer and cancers of the digestive, respiratory, better pathology review by Cologne et al. (1999). and excretory (kidney and bladder) systems; in all This study found an ERR of 0.81/Sv (0.32-1.43) cases the ERR estimates for females were 2- to 4- and this was similar for males and females. Risk fold higher than for males7. Age at exposure was appeared to be higher after exposure at ages 10-30. a significant factor in the risks of skin, breast, and Sharp et al. (2003) demonstrated that liver cancer thyroid cancer and cancers of the digestive system risk was increased dramatically with combined risk and central nervous system (Figure 4-6). Land et factors of radiation and the hepatitis C virus9. al. (2003) reanalyzed the breast cancer incidence in depth and reaffirmed that risk was higher with 4.4.2 Incidence of leukemia and related cancers exposure before age 208. Skin cancer risk was further explored by Ron Preston et al. (1994) analyzed the incidence of cancers et al. (1998). This study found an overall ERR of of the blood and lymph through 1987. These include 0.62/Sv (90% CI 0.23-1.3) for non-melanoma skin leukemias, lymphomas, and multiple myeloma, cancer. The risk of basal cell carcinoma, a subtype a cancer that originates in the liquid part of blood of skin cancer, was higher (ERR 1.9/Sv) and was and lymph and infiltrates bone marrow. Leukemia found to depend significantly on age at exposure. was subdivided into subtypes: acute lymphocytic

Figure 4-6. Incidence ERR by age at exposure for selected cancer sites (based on data from Thompson et al. 1994).

7 Estimates of ERR/Sv (females/males) were 1.4/0.4 (nonmelanoma skin), 0.5/0.3 (digestive system), 1.7/0.4 (respiratory system), and 2.3/0.7 (kidney and urinary organs) 8 ERR estimates were 3.9, 2.8, 2.7, 1.3 and 0.5/Sv after exposure at ages 0-4, 5-14, 15-19, 20-39, and 40+, respectively. 9 The ERR estimate was 58/Sv (2.0-∞) for HCV-positive, cirrhosis-free hepatocellular carcinoma. 50 Atomic Bomb Survivors

(ALL), acute myeloid (AML), chronic myeloid with incidence and mortality. Some cases were (CML) and adult T-cell leukemia (ATL). A fourth excluded from the main analysis because they had subtype, chronic lymphocytic leukemia (CLL), is high doses (>4 Gy) or because their first primary typically not associated with radiation. The study cancer diagnosis was not multiple myeloma. If these found strong evidence for radiation induced risks of cases were included then a significant dose-response all leukemia subtypes except ATL, some evidence relationship was observed (ERR 0.9/Sv, p = 0.02). for a lymphoma risk, and no significant evidence for Little et al. (1999) pooled the leukemia data from a multiple myeloma risk. the atomic bomb survivors, cervical cancer patients The shapes of the dose-response curves and the treated with radiation, and ankylosing spondylitis effects of age and gender appeared to be distinctly patients also treated with radiation. These medically different among these diseases. The pattern of ALL exposed cohorts received much higher doses than the risk was consistent with a linear dose-response atomic bomb survivors and therefore contribute more model having a high risk coefficient (ERR 10.3/ information about high-dose dynamics and little or Sv, 4.3-25). Risk appeared higher for childhood no information about low-dose effects. These authors exposures and declined over time. CML risk was used a model that included an exponential decline in also consistent with a linear dose-response model risk as doses increase; this accounts for the killing of and a decline in risk over time. Age at exposure was precancerous cells and has been used to model the not found to have a significant effect on risk; the risks of the medical exposure in other contexts (see average ERR estimate for this subtype was 6.2/Sv. sections 3.3 and 3.4). This analysis demonstrated The dose-response pattern for AML was nonlinear, the differences among leukemia subtypes. When concave-up, and less dependent on age at exposure all leukemias were modeled together the cohorts or time since exposure. The estimated ERR at 1 Sv were not showing compatible risk estimates; when was 3.3 (Preston et al. 1994). leukemia subtypes were modeled independently the It is important to point out that the LSS follow- cohorts were consistent with each other. up began in 1950, five years after the bombings. Leukemia has a latent period of as few as 2 years, 4.5 Incidence of noncancer disease so a significant number of early cases were probably missed. Preston et al. (1994), after considering some Wong et al. (1993) examined noncancer disease information about these early cases, estimated that incidence through 1986. This study found significant leukemia risk estimates might have been 10-15% linear dose-response patterns for thyroid disease higher if these early cases had been included. (ERR 0.3/Gy, 0.16-0.47), chronic liver disease and Results for the other diseases studied by cirrhosis (ERR 0.14/Gy, 0.04-0.27), and uterine these authors were inconclusive. ATL is endemic myoma10 (ERR 0.46/Gy, 0.27-0.70). Results for to Nagasaki and rare in Hiroshima and has been Parkinson’s disease were based on 50 cases and were associated with the HTLV-1 virus. Of the 25 ATL cases suggestive although not significantly positive (ERR in the cohort, 24 were from Nagasaki, suggesting 0.44/Gy, -0.06-1.57). When analysis was restricted that the virus may have independently caused the to the 1968-1986 time period there was an apparent leukemia cases. Furthermore, when analysis was risk of heart attack among those who were younger limited to Nagasaki there was no evidence of a dose- than 40 at the time of the bombings (ERR 0.57/Gy, response pattern. There was some evidence of an 0.26-1.76). Hayashi et al. (2003) reported a dose- increased risk of non-Hodgkin’s lymphoma among dependent increase of certain proteins in the blood males but there was not a significant relationship (interleukin 6, C-reactive protein) that indicate between dose and ERR. Multiple myeloma was not an inflammatory response. These measurements significantly related to dose in the main analysis, were made in 1995-1997, so they indicate a long- although previous analyses had shown an association term change in the status of the blood, and this

10 A uterine myoma is a common benign tumor of the uterine muscle, present in about 40% of adult women and usually asymptomatic. Atomic Bomb Survivors 51 inflammatory condition has been associated with section 10 and appendix C. The information on this cardiovascular disease. exposure pathway from the atomic bomb survivors Thyroid disease risk was highest for people is limited and inconclusive. In a survey covering exposed as children, and in fact the dose-response the period 1946-1982 it was shown that childhood pattern was not significant for people exposed at age cancers in the F1 generation (born to survivors) 20 or older. For exposure before age 20 the ERR was were not significantly elevated with 43 observed 0.38/Gy (0.21-0.60; Wong et al. 1993). Nagataki and 37 expected cases, including 16 observed et al. (1994) specifically examined thyroid disease and 13 expected childhood leukemia cases. It is incidence among survivors exposed in Nagasaki. important to consider, however, that only about 2% The researchers found significantly more cases of of the children in this sample were conceived within thyroid nodules and spontaneous antibody-positive 6 months of the bombings; there is strong evidence hypothyroidism than expected11. The dose-response from animal studies and other human studies that pattern for solid nodules was apparently linear and this is the critical window of exposure. The RERF there was a suggestion of higher risk at younger data are not very informative on the issue in this exposure ages (neither was quantified). The dose- case (Yoshimoto 1990). response relationship for hypothyroidism, on the The in utero atomic bomb survivors had uniquely other hand, was nonlinear (linear-quadratic) and traumatic gestations. The health status of children risk peaked at a dose around 0.7 Sv with an odds in the womb was already compromised by food ratio of around 2.6. The concave nature of the dose- shortages and other stress before the bombings and response indicates a need for further research into this problem increased after the bombings (Yamazaki low-dose effects on the thyroid. Yoshimoto et al. and Schull 1990). The stress and direct radiation (1995) demonstrated a similar dose-response curve effects of the bombs compounded the problem. As for chronic thyroiditis12 among autopsy results from an illustration, 98 pregnant women in Nagasaki were Hiroshima (1951-1985), with a maximum odds ratio within 2 km of the bomb and 19 of these children of ~2.4 in the dose range 0.5-1 Gy. died before birth or in infancy; this effect was Shintani et al. (1999) analyzed the data from the more prominent among women who experienced Hiroshima Tumor Registry to examine a possible radiation sickness. Other fetal deaths undoubtedly correlation between brain radiation dose from the occurred before a woman knew she was pregnant13. Hiroshima bomb and incidence of meningioma, a This high rate of prenatal and infant death may have tumor of the brain membrane. The study investigated obscured other health endpoints by leaving a cohort patients who had been surgically treated for with unusually strong immune systems. At the same meningioma between 1975 and 1992 and found that time, high doses may have caused long-lasting bone there was evidence of a correlation between brain marrow and immune system damage. Although dose and meningioma incidence; a relative risk of these two effects may cancel each other out overall, 6.5 was estimated for those who were within 1 km they show that a comparison between the in utero of the bomb (compared to the unexposed group). atomic bomb survivors and other in utero cohorts is not straightforward (Stewart and Kneale 1993). 4.6 Preconception and prenatal exposures Yamazaki and Schull (1990) reviewed studies of in utero exposure and reported dose-dependent Exposure of parents to radiation before they conceive increases in microcephaly (small head size) and a child is a controversial risk factor that many mental retardation. The maximum period of scientists disregard. We discuss this issue in depth in vulnerability to radiation was from the beginning

11 Thyroid nodules include cancer, goiter, and benign growths on the thyroid. Antibody-positive hypothyroidism is a condition where the thyroid is not producing enough thyroid hormone in conjunction with the presence of destructive antibodies targeting the thyroid. 12 Chronic thyroiditis is related to hypothyroidism and describes a condition in which the immune system is attacking the thyroid. 13 There was a significant deficit of children in the in utero cohort who were <8 weeks of gestational age at the time of the bombing indicating that these embryos were relatively more sensitive to the effects of the bombs. 52 Atomic Bomb Survivors of the 8th week to the end of the 15th week after the tissues in a child’s body are growing rapidly. conception; within this period the dose response for The ERR of solid cancer mortality was ~1.9 per Sv mental retardation can be described as linear with after exposure in infancy according to Preston et al. an apparent ERR of 43/Gy14. In a later review Otake (2003), compared to 0.47 per Sv after exposure at and Schull (1998) expanded these observations to age 30. The risks of solid cancer incidence followed include impaired school performance and decreased a similar pattern, and this was true of several types, IQ, both outcomes related to dose and restricted to notably thyroid cancer (see Figures 4-1 and 4-2). the gestational period of 8-25 weeks. Leukemia risk follows a more complicated pattern Delongchamp et al. (1997) found that there was and only ALL shows a clear effect of age at exposure, a significantly elevated risk of cancer mortality for with childhood exposures carrying a higher risk. those exposed in utero with an ERR of 3/Sv (90% CI Leukemia, however, has a very short latent period 0.6-7.2) based on 8 cases. The risk of childhood cancer of as few as 2 years and follow-up of the LSS cohort could not be easily observed in this cohort; based on began 5 years after the bombings. A number of 1 case the ERR estimate was 23/Sv (1.7-88). This is cases are therefore not included in these analyses; very uncertain but consistent with the estimated dose- inclusion of these cases might have increases the response pattern of childhood cancer after prenatal estimated leukemia risk and might have shed more x-rays (51/Gy, 28-76; Wakeford and Little 2003). light on the effects of age at exposure (Preston et al. 1994). 4.7 Discussion Some major confounders can be addressed in this cohort. Pierce et al. (2003), for example, considered Age, time and gender. It is clear from the above the effect of smoking on lung cancer incidence rates discussion that age and gender play critical roles in in the a-bomb cohorts. The authors analyzed the the patterns of risk associated with exposure to the smoking histories of 45,113 members of the LSS atomic bombs. Generally, relative risks are higher for cohort and found that smoking and radiation are younger ages at exposure and for females. Preston likely additive in effect and are almost certainly not (2000) summarizes the influence of age and gender multiplicative. in the RERF analyses. Time can be a complicated Dose-response curves. The atomic bomb confounding variable because it can be represented survivor data have been analyzed many times to in different ways. Age at exposure is one way, and examine dose-response patterns in detail. This another is time since exposure. Different models research has consistently found no evidence of a make use of one or both of these factors. Pierce and threshold dose below which there is no cancer risk Mendelsohn (1999) have argued that attained age, (Thompson et al. 1994, Pierce et al. 1996, Preston et the age of subjects at the time of diagnosis or death, al. 1994, 2003a, 2003b, Little and Muirhead 1997). is the best way to model the effect of time on solid The linear dose-response model has been cancer incidence. They found that excess relative commonly applied to solid cancer incidence and risk decreases throughout life in proportion to 1/age. mortality data because it is simple and intuitive and Although these alternative models are interesting, because it fits the data better than a linear-quadratic it may be the case that several models fit the data or some other upward-turning curve. Some detail equally well. Heidenreich et al. (2002) have argued is obscured by a simple linear model, however. At that the atomic bomb survivors, despite being the doses above a few Gy the estimated ERR per dose standard reference cohort, may not be sufficiently begins to plateau; these doses are approaching the large to illuminate the fine points of the cancer acutely lethal dose range and the dynamics of the response to radiation. biological response are very different from low- What we can say with little doubt is that dose scenarios. At low doses, as we mentioned childhood exposure presents more of a risk than adult above, a simple linear model might underestimate exposures. This is mechanistically reasonable since the true risk. The ERR for solid cancer mortality, for

14 The dose-response was described in the text as having a linear increase in frequency of 0.44 per Gy (0.26-0.62) and a background frequency of 0.01. Atomic Bomb Survivors 53 example, was reported to be 0.47 per Sv (Preston et representative of a general public of all ages, also al. 2003a). This would imply a RR of 1.047 at 0.1 makes this cohort a useful reference point. Sv, or a 5% increase in risk. For doses less than 0.12 Some other characteristics of the cohort are Sv, however, these authors estimate an ERR of 0.74 problematic, however. The initial trauma of the per Sv. This estimate implies a relative risk of 1.074 bombings may have caused the disproportionate at 0.01 Sv, or a 7.4% increase in risk. For even lower death of weaker individuals in Hiroshima and doses, 0.005-0.02 mSv, Pierce et al. (1996) report Nagasaki, those that were very young, very old, or an ERR of 2.6 per Sv. Pierce and Preston (2000) had compromised immune systems. This would lead reported a similar pattern for solid cancer incidence, to the healthy survivor effect discussed above, and where the risk below 0.3 Sv is underestimated by a there is evidence for such an effect in the patterns of linear dose-response model. Although this kind of noncancer disease. The follow-up of the cohort didn’t supralinear effect has not been formally assessed it begin right away and the missing data are important is important to keep in mind for low-dose exposure for leukemia, with a latent period of just a couple scenarios. of years. Finally, the atomic bombs exposed people The leukemia data are very different from the to a single, acute exposure, and most exposures of solid cancer data in that a linear dose-response concern to the general public today are chronic or model tends to overestimate risks at low doses. It in small fractions, for example a series of low-dose has been shown that leukemia subtypes have unique diagnostic medical exposures or ongoing exposure dose-response patterns; ALL and CML have been to very small doses from a nuclear facility. There described with linear dose-response models while are biological reasons to expect acute and chronic AML appears linear-quadratic (Preston et al. 1994). exposures to have very different effects on the Applicability to other contexts. The atomic human body; generally scientists assume that a dose bomb survivors are often seen as the standard spread out over time is less dangerous than a dose reference cohort for the effects of radiation. This received all at once, but this is not necessarily true is true for a couple of reasons in addition to the in every case. The atomic bomb survivor studies size of the cohort. The range of doses covered the are an undeniably powerful body of evidence, but entire range of interest, from doses a little higher these uncertainties should be kept in mind when than background to doses that can be acutely estimating risks in other contexts. lethal. The demographic distribution of the cohort, 54 Atomic Bomb Survivors . d r ). d n o t e rs RR o - l f n a . e e s 4 a p E , s ex s a c i 9 t re R al r t . RR n res y l er at es u e 0 e o u O E e an l r s ( d d al ear ( ( e s can p h es o e h er t ). n 4 o aft mu fo (s i en d p L b 4 l p i t s . w w g res Sv rat d - ep e er - ma; 1 o o M fi ex s c e n ro t h ex 7 e , ek o e, al an . o o ) C e y el s g e n n v i a 0 d n h b o i cro eas ag d er t o w h ero w my d m i s h t a 3 f ma at t i t rv o w o d 5 u e an i mi 0 o o d n % u h y ar e 1 n i 0 ) s h s n w 0 - s n c e an es i m cep i 2 5 e ’s 4 8 n t a h eri r . s n i 2 e n rv en e t g ed mp - d e at o n s i o L d fect al u i ce y 3 o s d d a eas r at . . h cu l r ci ) e ef aft d n �� 4 et r reco t h t y en i e ci h b n eri t t , t e i u s p cre d i o i , �� i an p fo ; h ex n s n n t ci g t mi w i al ark w 0 e i Sv s m o k �� cers / n t n as t s 7 P s k rt p d i l i . i � 3 s ee . ed ri u Izu 1 r d d eas en , rd - - es i an 0 can s . (s res l at cers d Mo d 7 a o es h i 1 fo - 1 l s an t u r ro e 2 . g d e ci . i e d en an y al e p y s n rn R e o 1 l t reg t ect h o can ( h y o e o s r i v er g t o t R i t ep ; n i e d v g 6 o n b s al mat E d n i as fo eff v at t 4 d i n l - ( i p u u . o rt i t i o p e s 7 i s l ary y 1 m y ear cl s L e, an u farct 7 o e , v es h s at fo . y d n n i ) o i s s n mo L f i cl s 3 b u i l d d n i d R o t s al r . i eas n A co s t t s o s ard y s n R e eak al o r i an ed fo p r ro i In o co et G v p g a. h E ces d i t i y r r e n fo t n ; t can can l fo x r ). i 1 i ari h m i d res t l fi ex fi i E - c v d al o es i y t i es card t o ral e at Sv ern u cep g mat n d n d ro el o / ). t p s e i rv n g efu n g u g t y cl 6 2 ee y o v me . . s at a u h i n Si men co RR St (s Si t my s H p 2 D t cu 6 my O es u i e s a e s i n 7 i d 1 e 8 r ma 4 9 h e 6 o t ed n d 7 , 1 v s i h i - 8 9 l n o i 0 an 5 ; , p n 5 ed 7 i mp e 6 2 s 9 2 d c y 4 ex . o l 1 n 4 1 ce 9 i , p an - en 8 1 . a rs 4 , d ) en 9 ren ex o 0 ce y n . d 1 ci t d v o i l 1 i i n emi i een ci en ( h t i � al ren k c n d g rv w � 4 r i d ch d rt u u 1 a l ci �� eu . et f e i s g l n � an 1 ro b n i n i f mo 6 , h ch y � ) l t e o eas 9 t t rs e 7 � a i s n 6 i s o p i i 8 , a d al ce amo v �� u d eas 9 3 fan r e i e - s rt � a s 1 9 n c i i en � i - c es w rv d �� i d n d o , 4 cer o t u i en � mo l i y 8 s d d ci l d �� � i i es r an 9 � al m n o o c ci i 1 fo r t 6 ; ro ma ag ce n n y �� 2 8 y e o i ��� rm h ri o h rs t 6 � 9 h h rn t o . an r i el n t t � o 1 o ; 1 c n 9 - v f f f w - car b 7 ce � i f 8 8 3 s o o o 4 ) my ab r 9 o . 8 5 rv � an 0 . o y y y 1 1 e 9 mi n c - u 5 0 - l d d d ) ( 1 s rt o 6 cal 1 f 9 f p �� u u u 0 , i i s i 1 t t t o 5 4 o o t . 2 � 1 g s s s rs l h ri 1 9 � 1 . o o ak ( a w w 1 (9 l (3 1 rt rt rt v � co e e 0 i mu as o o o i i 2 d ro 3 mp h h h S �� . n 8 d rv ero ero ag a � 1 S t t 9 eu u ) Rev n u Rev u 1 Co s Co N Co an Co L e e r �� s e � a w e � s � y i 4 d G 9 s �� 9 ’ 1 3 0 n t 1 9 9 a o 4 . ��� 9 s d 9 9 s . 1 al n �� 1 e 9 i �� t . an 0 al k 1 � a o et 9 r i �� al t . � a i 9 m et � i P al 1 t et � �� n s ; zak ak mo l i e � l o 7 g et t at h 4 5 u n . s R ma �� n 9 o 2 a o ag R 9 �� Y Sch Y W N Pres 1 Ro 1 Atomic Bomb Survivors 55 � � � � � � � � � � � � � � �� �� � � � � �� � � � � � � � � ��� � � �� � � � �� �� � � �� �� � � � �� �� � � �� � � � � � ��� �� � � �� � �� � � �� � � � � � � � � � � �� ��� �� �� � � �� � � � � � ��� � �� � � � � � �� � � � � � � � �� ��� �� � � � ��� � ��� �� �� � � � � � � � � � � � �� � � � � ��� �� � � �� � ��� �� � � �� �� � � � � � �� � � � � ��� � �� � � �� � � �� � �� �� � � �� ��� � � � � �� � �� � � � � � � � � � �� � � � �� � �� � � � � � � � �� � � � � � � � � �� � � � � �� � � � � ��� � � � � �� � � � � �� � �� �� � � � �� � �� � � � � � � � � �� � �� �� �� � ��� � � � � � �� � � � � � � � �� � � � �� �� � � � �� � � � � � � � � � � � ��� � �� � � � � � � � � � �� � ��� � � � � �� � � � � �� � � � � � � 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� � � � � � � � � � � � � � �� � � �� � �� � � � � � � � � � � � � �� � � � � � � � � �� � � � � �� � � � � � � � � � �� � � � � � �� �� � � � � � � � ��� � � � �� � � � ��� � � � � � � � � � � � � � �� �� ��� � � � � � �� � � �� ��� � � �� � � � � ��� � � � � � � � � � � �� ��� � �� � � �� � � � � � ��� �� ��� � � � � �� � � � � � � �� � � � � � � � � � � �� � � � � � � � � ��� � � � � � � � � � � � � � �� ��� �� � � � � � � ��� � � � � �� � � � � �� � � � � � � � �� �� �� � � �� � �� � � � � � � � � � � �� � ��� � � � �� � �� � � � � �� � �� � � � �� � � � � � �� � � � � � � � � � �� �� �� � �� � � � � � � � �� � � � � � � � � �� � � � � �� � � � � � �� � � � �� �� � � ��� � � � � � � � �� � � �� �� � � � �� � � � � � � � � �� � � � �� � � � � �� � �� � � ��� ��� � � � � � � � � �� �� � � � � � � � ��� �� � �� � � � �� � � � � � � � � ��� � � ��� � �� � � � � � ��� � � � � � �� � � �� � � �� � � � � � � � � ��� � �� � � � � � � � � �� � � � � � � �� � � �� � � � � � ��� � � �� � � � 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Nuclear Weapons Testing 5.1 Military personnel

Over 500 nuclear weapons have been detonated Several cohorts of participants in U.S. and British above-ground since 1945 at test sites in Kazakhstan, tests have been studied. Dose estimates were Russia, the United States, and the South Pacific. provided for three of these cohorts and average Other tests have been conducted underground. doses were less than 5 mSv in all cases. Knox et Figure 5-1 shows nuclear test sites around the world. al. (1983a, 1983b) assessed cancers, particularly Some of the radioactive fallout that was generated blood and lymph cancers1, in British servicemen was deposited locally, and some of it was dispersed involved in nuclear tests in 1957 and 1958. After around the globe after entering the upper atmosphere. calculating the expected number of these cancers Adverse health effects, mainly leukemia and thyroid based on servicemen from the same period who disease, have been observed in military personnel were not involved in the tests, the authors began participating in nuclear tests and in people living collecting cases of cancer in test veterans. With only downwind of the test sites. This section reviews a fraction of the veterans responding to requests for what we know about these exposures and effects. information it was clear that there was an excess

Figure 5-1. A map showing the approximate locations of worldwide nuclear bomb test sites (www.atomicarchive.com/ Almanac/Testing.shtml).

1 Knox et al. looked at leukemia, myeloma, lymphoma, and polycythemia vera, lumping the cancers as reticuloendothelial (RES) neoplasms. Classifications are different today. 58 Nuclear Weapons Testing 59

in both leukemia incidence (RR 2.50; 1.20-4.60) and leukemia mortality (RR 2.58; 1.11-5.09). The same authors, looking at the same cohort, also found four cases of polycythemia vera, another type of blood neoplasm, when 0.2 cases would be expected in this population based on national rates (Caldwell et al. 1984). This translates into a relative risk of 20.2 (5.5-51.7). Dalager et al. (2000) found statistically significant increases in mortality from lymphopoietic cancers (RR 3.72; 1.28-10.83) and all-cause mortality (RR 1.22; 1.04-1.44) when comparing U.S. test veterans with high doses (> 50 mSv) to veterans with “minimal” doses. The leukemia association is less clear in some other studies of U.S. veterans. Johnson et al. (1997) studied the mortality of approximately 40,000 participants in Operation Crossroads, a 1946 test series at the Bikini atoll. Leukemia mortality was not significantly elevated (RR 1.02; 0.75-1.39) although all-cause mortality was (RR 1.05; 1.02-1.07).4 Watanabe et al. (1995) also found a nonsignificant Figure 5-2. Military observers shield their faces from the increase in leukemia mortality among the 1,094 Teapot Test in 1955 (http://www.aracnet.com/~pdxavets/). personnel exposed to more than 1 cGy of gamma radiation during the 1958 test series “Hardtack I” of blood and lymph cancers including leukemia. (RR 1.73; 0.39-7.56). This study looked at a total of Darby et al. (1988, 1993) and Muirhead et al. (2003) 8,554 veterans and also found significant increases conducted a cohort follow-up of 20,000 British test in total cancer mortality (RR 1.42; 1.03-1.96) and veterans through 1998 and found that the leukemia liver cancer mortality (RR 6.42; 1.17-3.53). mortality rate, while not much greater than the national rate, was significantly higher than in a 5.2 Semipalatinsk Test Site downwinders control population (servicemen not participating in the tests). For the follow up through 25 years the There were 118 atmospheric tests at the relative risk (RR) was 3.38 (90% CI 1.45-8.25).2 Semipalatinsk Test Site between 1949 and 1963, New Zealand servicemen also participated in the and over 300 underground tests through 1989, some same tests as the British servicemen and were also of them releasing radioactive material when they found to have increased leukemia mortality (RR 5.6; broke the surface (vented). 95% of the collective 90% CI 1.0-41.7; Pearce et al. 1990, 1997).3 dose received by nearby residents is thought to Several studies of U.S. servicemen have also have come from four tests in 1949, 1951, 1953 and found evidence of increased leukemia. Caldwell et 1956. In 1994 Zaridze et al. published a paper that al. (1983) followed 3,217 participants in the 1957 examined the relationship between childhood cancer test “Smoky” through 1979 and found an increase incidence and distance from the test site. They began

2 For the extended follow-up (through 1998) the RR for non-CLL leukemia mortality was significant but lower (1.83, 90% CI 1.15, 2.93). Leukemia incidence risks were similar to those of mortality (Muirhead et al. 2003). 3 In this cohort the RR of leukemia incidence was the same as the RR of leukemia mortality. There was also a significant excess of all hematologic cancers, with a RR of 1.9 (0.8-4.3) for incidence and 3.8 (1.4-10.8) for mortality (Pearce et al. 1997). 4 The subgroup of Operation Crossroads participants having an Engineering and Hull specialty showed a leukemia risk that was close to statistical significance (RR 1.51; 0.94-2.44) (Johnson et al. 1997). 60 Nuclear Weapons Testing by distinguishing three sites where 1) above ground another group found no increase in translocations tests were conducted, 2) underground tests were (Stephan et al. 2001). The most recent report from conducted, and 3) a reservoir was created with four this area is a cohort study of DNA mutations: parents nuclear explosions in 1965 (Atom Lake). The three directly exposed to fallout displayed nearly twice as sites are relatively close to each other and located many germline mutations, mutations that are passed in the center of Kazakhstan, so distance-dependent on to children, as control parents (Dubrova et al. risk calculations produce similar results for the three 2002). These results follow on similar results from sites. The authors found that all cancers and leukemia an earlier Dubrova study around the Chernobyl plant were significantly correlated with distance; when (Dubrova et al. 1996). The implications of these comparing regions within 200 km of the test sites to mutations for health are still unknown. those more than 400 km away relative risks of 1.7- 2.0 were derived, suggesting that rates of cancer, 5.3 Nevada Test Site downwinders and leukemia in particular, were roughly doubled in children closest to the test sites5. Leukemia. The number of atmospheric tests at A leukemia study with dose information was the Nevada Test Site was similar to the number at conducted by Abylkassimova et al. (2000). They the Semipalatinsk Test Site and they were conducted found a doubling of risk for people exposed to >2 over roughly the same period.7 We would therefore Sv as compared to those exposed to <0.5 Sv but did expect health effects to show the same time pattern in not detect a dose-response relationship below 2 Sv. both exposed populations. Cancer rates downwind of Gusev et al. (1998) studied solid cancer incidence the Nevada Test Site have been studied extensively in two groups of Semipalatinsk residents- 10,000 since the late 1970s. In 1979 a University of Utah exposed to roughly 2 Sv and 10,000 exposed to 70 team led by Joseph Lyon published their analysis of mSv. Stomach, liver, esophagus and lung cancer childhood cancer deaths in Utah. Utah children born rates were all elevated in the exposed group.6 1951-58 appeared to experience increased leukemia Another source of information regarding the mortality relative to children born 1944-50 and health effects of testing at Semipalatinsk are case 1959-75, particularly for the southern counties of reports; while these are not usually seen as strong evidence of an effect, they can indicate areas for future research and contribute to a broader understanding of a situation. One such paper analyzed all thyroid surgeries in three regions of Kazakhstan from 1966- 1996. Before 1982 thyroid cancers were less than 5% of the thyroid abnormalities among surgical patients; since 1982 over 10% of abnormalities have been cancer (Zhumadilov et al. 2000). Two other analyses of case reports were done on the cellular level. These papers give conflicting evidence regarding chromosome aberrations in people close Figure 5-3. Atmospheric test Grable conducted in 1953 at to the test sites; one group found an increase in the Nevada Test Site (http://www.astrosurf.com/lombry/ lymphocyte micronuclei (Tanaka et al. 2000) while quantique-bombes-atomiques-pic.htm).

5 The leukemia RR estimates were 1.76 (1.19, 2.59) for the atmospheric test site, 1.70 (1.15, 2.52) for the underground test site, and 1.72 (1.20, 2.47) for Atom Lake. The RR estimates for all cancers were 2.02 (1.59, 2.56) , 1.75 (1.37, 2.21), and 1.77 (1.41, 2.22) (Zaridze et al. 1994). 6 From 1960 through 1994 cancer rates were consistently higher in the exposed group. The RR estimate was not significant in every case, but in 1970 the RR estimates were 2.79 (all cancers), 2.34 (esophagus cancer), 2.17 (stomach and liver cancer), and 3.74 (lung cancer). 7 Roughly 100 tests were conducted from 1951 to 1962 at the NTS, compared to 118 from 1949 to 1963 at the STS. The four major tests at each site were in 1952, 1953, 1955, and 1957 (NTS) and 1949, 1951, 1953, and 1956 (STS). Nuclear Weapons Testing 61

Utah (thought to have had greater fallout exposure). five states ranked in the bottom five; these became In response to this study a group of National Cancer the most exposed and least exposed states, with Institute scientists conducted their own analysis all others classified as intermediate9. Leukemia based on the Lyon study design and using data from mortality rates in all states were higher in the 1960s the National Center for Health Statistics (NCHS) than in the 1950s or 1970s, but this by itself would (Land et al. 1984). These authors eliminated the first be only slightly suggestive of a link with fallout. control group, the 1944-50 birth cohort, because An additional piece of evidence for a possible the NCHS only provides data since 1950. This left association is that the high exposure group showed them with two groups to compare, the exposed birth a higher mortality rate than the intermediate group, cohort and a 1959-78 birth cohort. Since leukemia and both were higher than the low-exposure group. rates declined from 1950 to 1978 in the United States Finally, only the radiogenic leukemias (myeloid and generally, Land et al. claimed that the evidence did acute) showed a temporal association with fallout. not support the leukemia association; without an A couple of critical characteristics make this paper early birth cohort, however, this study was not very statistically weak, however, including the huge informative. groupings of cases (states) and the lack of control Carl Johnson (1984) conducted an analysis for possible confounding factors. In addition, the of cancer among Utah Mormons, a group with exposure groups are not consistent with the recent extensive health records and low background cancer NCI/CDC feasibility report bone marrow dose rates. Separating six towns as high fallout areas, estimates (NCI 2001). Johnson found excess cancer, particularly leukemia The most rigorous study to address the leukemia and breast, bone and thyroid cancer. He also assessed issue was presented in 1990 by Walter Stevens, cancer incidence among Mormons who remembered Joseph Lyon and others. They estimated doses for experiencing acute radiation effects such as skin 1,177 leukemia deaths and 5,330 matched controls burns, hair loss or nausea. These subjects appeared to from the deceased membership file of the Mormon have excess leukemia, lymphoma, and stomach and Church. Both cases and controls were born before breast cancer relative to all Utah Mormons. Again November 1958 and died in the period 1952-1981. the same three scientists from the NCI answered This group also estimated bone marrow dose with a reanalysis using NCHS data (Machado et al. based on the Town and County Databases of the 1987). Their study differed from Johnson’s in that it Department of Energy’s Offsite Radiation Exposure used mortality rather than incidence as the endpoint Review Project. This study found increasing risk of concern, used county-level data for the three with dose for all ages and all types of leukemia, but southwestern Utah counties of Washington, Iron this overall excess was not significant. Focusing and Kane, and used a slightly different definition of specifically on leukemia deaths in children, a the high-exposure time period group8. They failed to significant RR of 5.82 (1.55-21.8) was found when find the excess cancers that Johnson found, with the comparing high doses (6-30 mGy) to low doses notable exception of leukemia. (0-3 mGy), and a significant trend with dose was Another ambitious paper associated leukemia observed. Similar results were found when limiting with fallout nationwide (Archer 1987). This simple the response to acute lymphocytic leukemia, and a correlation experiment used state-level leukemia significant trend was also observed when limiting data and compared them with three indexes of observations to deaths between 1952 and 1957 (this exposure: Strontium-90 in cow milk, Stronium- study is discussed further in appendix A). 90 in human bone, and Strontium-90 in diet. Five Thyroid disease. Two studies have looked states ranked in the top five of all three indexes, and

8 Johnson defined the high exposure group as people born in 1962 or earlier and diagnosed with cancer in 1958 or later. Machado et al. defined the high exposure group as people born in 1957 or earlier and dying after 1954 (of leukemia or bone cancer) or after 1963 (of other cancers). 9 The high-exposure states were Georgia, Louisiana, Mississippi, North Carolina and Minnesota. The low-exposure states were California, Florida, Hawaii, New Mexico and Texas. 62 Nuclear Weapons Testing

Figure 5-4. Per capita thyroid doses resulting from all exposure routes from all test (http://rex.nci.nih.gov/massmedia/ fig1.html). at thyroid disease in relation to NTS fallout, one estimates, also from the NCI (Gilbert et al. 1998, close to the test site and one nationwide in scope. Figure 5-4). While they did not find any associations The same group that found the strong evidence for for all ages, they did find that exposures received a childhood leukemia excess conducted a cohort in the first year of life were associated with thyroid study for thyroid disease, estimating thyroid doses cancer incidence and mortality; one Gray of thyroid of radioiodine (iodine-131) and selecting subjects dose was estimated to double thyroid cancer that had been children living in a high fallout area incidence and lead to even larger increases in thyroid during the peak fallout years (Kerber et al. 1993).10 cancer mortality12. A significant relationship was also This study showed excess thyroid neoplasms, found for the 1955 birth cohort. These results are nodules, and carcinomas; it also showed a significant more valuable than the Archer results for leukemia dose response for neoplasms similar to that found discussed above since they do include estimates of in externally exposed children and a marginally dose at a finer level of detail. However, they still significant dose-response for carcinomas11. suffer the limitations inherent in an ecological study, The national study was conducted by NCI staff a fact noted by the authors. For example, almost 20% and used county- and state- level 131I thyroid dose of the U.S. population changes county of residence

10 The 2,473 subjects were born from 1945 through 1956 and were enrolled in school in either Washington County UT, Lincoln County NV, or Graham County AZ. They were examined for thyroid abnormalities in 1965-70 and in 1985-86. 11 Kerber et al. found an ERR for neoplasms of 7/Gy, comparable to 7.7/Gy in the case of external exposures (Ron et al. 1995). The ERR for carcinomas was 8/Gy (Kerber et al. 1993). 12 The mortality ERR for county-specific thyroid doses was 10.6 (–1.1-29) and the incidence ERR was 2.4 (-0.5-5.6). The state-specific relationship was a marginally significant ERR of 16.6 (-0.2-43). Nuclear Weapons Testing 63

5.5 Health effects in Scandinavia

We should mention two studies dealing with leukemia and thyroid cancer in Scandinavia; doses received by these populations are unclear but researchers have attempted, as in some of the studies mentioned above, to correlate disease patterns with probable peak fallout years. Darby et al. (1992) looked at leukemia rates in Nordic countries and compared them with global fallout exposure trends in England, assuming that the time patterns of exposure should be similar. No relationships were found. Lund and Galanti (1999) compared the 1951-1962 birth cohort in Sweden and Norway to the birth cohort of Figure 5-5. A nuclear test conducted as part of Operation 1963-70; they were looking for a relationship with Crossroads off Bikini atoll in the Marshall Islands in 1946 arctic testing at Novaya Zemlya, where major tests ((http://www.astrosurf.com/lombry/quantique-bombes- occurred from 1957-1962. They found a significant atomiques-pic.htm). increase in thyroid cancers diagnosed before age in any five-year period. The authors also make the 14 (RR 1.7; 1.0-3.0) and there was also a non- important caveat that “…errors in dose estimation significant increase in thyroid cancers for the 1947- have almost certainly led to underestimation of risk 1950 cohort relative to the 1963-70 cohort (these in our study” (Gilbert et al. 1998, p. 1659). people would have been 7-15 years old during peak fallout exposures). These authors also made 5.4 South Pacific testing estimates of thyroid dose based on measurements of radioactivity in Norwegian milk; the maximum South Pacific Islanders have suffered greater calculated dose was 1.8 cGy for people born in 1957 exposures than downwinders in the U.S. or and 1958. Kazakhstan but in much smaller populations. The most intensely exposed Marshall Islanders have 5.6 Discussion shown clear increases in thyroid nodules (Howard et al. 1997).13 Two studies have correlated distance In summary, the studies of atomic veterans, cohorts with thyroid nodules for all Marshall Islanders, with average gamma doses of less than 10 mSv, have predictably indicating that proximity to the tests consistently found increases in leukemia. Increases increased the exposure to 131I and therefore the risk in other related diseases such as multiple myeloma of developing thyroid nodules (Hamilton et al. 1987, and polycythemia vera have been observed as well. Takahashi et al. 1997). A study of French Polynesia Children downwind of the test sites in Nevada and residents exposed to fallout from French nuclear Kazakhstan have also shown evidence of an increase tests (1966-74) found that the subjects had thyroid in leukemia and thyroid cancer. These results cancer rates 2-3 times greater than those in Maoris are discussed in comparison with other sources or Hawaiians, but this was true for people exposed of exposure in the leukemia and thyroid disease as adults as well as those exposed as children, sections of this report. indicating that the difference may not be due to The studies discussed above address exposures radiation exposures (de Vathaire et al. 2000). to local fallout, meaning fallout that was generated

13 Of 67 Rongelap Islanders exposed to fallout from the Bravo test (190 rads of external radiation), 24 developed thyroid nodules by 1990. 26 out of 167 exposed residents of Utirik (11 rads) developed nodules (Howard et al. 1997). 64 Nuclear Weapons Testing near the place of exposure. Nuclear weapons tests The test sites can of course be a health risk also deposited large amounts of fallout in the after testing stops. Marshall Islanders returning upper atmosphere and this was dispersed globally. to Rongelap and Utirik have, since moving home, Exposure to global fallout is estimated to have received external doses greater than the average produced a global average dose of 1 mSv before the Nevada Test Site downwinder and roughly equal year 2000, largely due to the radionuclide Cesium- to the average Semipalatinsk downwinder. Internal 137.14 Certain subgroups may have received higher doses were slightly greater than external doses doses. One example is arctic people who consume (Lessard et al. 1984). If Aboriginal Australians reindeer meat- a simple food chain links lichen, a reoccupy the Maralinga and Emu test sites they plant with a known ability to concentrate fallout, may receive even greater internal doses than the with humans through reindeer. Alaskan Eskimos Marshallese, mainly through the inhalation of and Russian reindeer herders have received doses at Plutonium-239 (Johnston et al. 1992, Haywood and least 10 times greater than the global average in this Smith 1992). way (Hanson 1982, Ramzaev et al. 1993).

14 Exposure to global fallout residue will continue into the future with annual doses of less than 0.6 mrem, largely from Carbon-14 (Bouville et al. 2002). Nuclear Weapons Testing 65 n i d nd - nd s a a ha 8) e on y s , nt l gh t ough l 3. a i a N a ye l e i hi c e hr . l r R a i of t ough r t ough f c nt e . e r r R r e 5) s a he y n h a ( onne h h r o h t i t 0 i c t t s i t a i s nc gni l r r m f r i 1. m a a y nt e of e t t ye c ndot pe a i R ong s l r c nd gni or nc nc ons r i uke a i R oe a 25 a m f t a e s ( e vy ve m N r c a l c t e i ul a o l s y l nc a l c na t r l gni y. i , a s a i nc i i t m t a nd l m f y d i c a c s 73) e t a l a - o . a e i r de t l i a w l i 1 s t he a nd ogi om r e on or t e . m t ye i r he a r nc R ) o � t f i ol N n m � xpos t or m a i R � m nc m . he y a a ( e uke t e t a � i of e m r i r r e � nt y l m e l r r une us a t m � pl gna a i i 1 e i e nom a i t ve l n t de o he l nc � a c i t a m > l - a a a nc nc t or ul vi 1992 uke l i e e c a a l e e e s m m c or c a l m ve om m . m a i uke r k ) n t e ve d f m n n n n e s i y 6 i dos r a i he i i i of l i e t l r a y s ough s s bl 5. a i e e e e e e t 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RADIATION WORKERS and injury reports1. Regulations establishing allowable levels of radiation exposure have changed Introduction dramatically over the years as the state of knowledge concerning radiation risk has evolved. Most limits This section deals with occupational exposure. for occupational exposure are higher than limits ‘Occupational exposure’ specifically refers to for exposure to the general public for a couple of exposure incurred by a worker, attributable to reasons. Occupational exposure is thought to be a the job, and occurring during a period of work. voluntary risk and so a higher level of exposure is Occupational exposure to radiation occurs in a ethically acceptable. Public exposures potentially range of industries including medicine, flight, involve a much larger exposed population, increasing nuclear power and nuclear weapons. This section the total absolute risk at a given exposure level. specifically deals with the manufacture of nuclear Furthermore, the general public includes sensitive weapons and the generation of nuclear power; subgroups, for example young children, that are these workers are similar in that they are generally screened out of worker populations. The ICRP and exposed to low levels of radiation over a long period the NCRP have recommended that the exposure of time. Other types of occupational exposure are level for large populations should not exceed 1/30th addressed in sections 3 (the medical industry), 8 the occupational limit. The Nuclear Regulatory (uranium miners and millers), and 9 (exposure in Commission (NRC) occupational dose limits for the airline industry). Workers at the Mayak facility adults include: in Russia were exposed to particularly high levels of radiation and are addressed in a separate section • 5 rem (0.05 Sv) per year for the total effective (section 7). The effects of occupational exposure on dose equivalent (TEDE), which is the sum of the offspring of the workers are addressed in section the deep dose equivalent (DDE) from external 10. exposure to the whole body and the committed Exposure limits. The United Nations Scientific effective dose equivalent (CEDE) from intakes Committee on the Effects of Atomic Radiation of radioactive material. (UNSCEAR) reported that approximately 11 million • 50 rem (0.5 Sv) per year for the total organ dose workers were being monitored for exposure to equivalent (TODE), which is the sum of the ionizing radiation worldwide in 2000 (UNSCEAR DDE from external exposure to the whole body 2000). A variety of systems have been developed and the committed dose equivalent (CDE) from to monitor and control occupational exposure intakes of radioactive material to any individual to radiation including dose reduction programs, organ or tissue other than the lens of the eye. emergency preparedness planning, routine physical • 15 rem (0.15 Sv) per year for the lens dose examinations of workers, accident and incident equivalent (LDE), which is the external dose to investigations, and the preparation of accident the lens of the eye.

1 http://tis.eh.doe.gov/ohre/new/findingaids/epidemiologic/rockyplant/employ/intro.html 70 Radiation Workers 71 Figure 6-1. The United States nuclear weapons complex comprised dozens of Office industrial facilities and Department of laboratories Energy, across the country. of Environmental Management 1996 72 Radiation Workers

• 50 rem (0.5 Sv) per year for the shallow dose many film badges worn from 1953 to 1967 had been equivalent (SDE), which is the external dose to consistently misinterpreted, causing exposures to be the skin or to any extremity. underestimated3. In the early stages of monitoring • For workers under 18, the annual occupational workers for radiation exposure nasal swipes were dose limits are 10 percent of the dose limits for used for internal alpha radiation monitoring; this adult workers. method was later found to be unreliable. Urine • For protection of the embryo/fetus of a declared and blood sampling was added, and when used in pregnant woman, the dose limit is 0.5 rem (5 conjunction with the nose swipes, provided better mSv) during the entire pregnancy2. estimates of internal exposure3. Assessing risks. There are many factors to In order to remain in compliance with consider when determining the health risk involved occupational exposure regulations the owners of with occupational exposure. Researchers can compare nuclear facilities must monitor the exposure of their disease incidence among workers with national or employees. The first external monitoring devices were local populations, for example using standardized pocket ionization chambers and pocket dosimeters; mortality ratios (SMRs), but this task is complicated these were basically pen-sized tubes containing a by the fact that workers usually exhibit lower wire with an electrical charge that decreased upon disease rates and lower death rates than the general exposure to radiation (Figure 6-2a). These devices population. This is a predictable situation because were later replaced by film dosimeters, which were the ill, weak and disabled are usually excluded from less expensive, more reliable, and could be attached employment; among epidemiologists this pattern is to a worker’s security badge. The film on the badges referred to as the healthy worker effect. This can be reacted to radiation by darkening and could later dealt with by comparing disease rates in exposed be analyzed to estimate exposure (Figure 6-2b). workers to disease rates in similar groups of workers Some facilities switched to thermoluminescent who are not exposed to radiation. In section 5, for dosimeters in the early 1970s. These dosimeters example, we saw how military personnel who were contain light-emitting crystal phosphors that can be exposed to fallout from nuclear weapons testing read by a computer after they have been exposed to were compared to military personnel who were not radioactive energy. In 1994 researchers found that present at the tests. This is often not done, however.

Figure 6-2(a). The first external monitoring devices were pocket ionization chambers and pocket dosimeters (basically tubes the size of pens containing a wire with an electrical charge that decreased upon exposure to Figure 6-2(b). Pocket dosimeters were replaced by film radiation) (http://www.ieer.org/sdafiles/vol_8/8-4/devices. badges. A worker here is pictured checking film badges in html). 1974 (imglib.lbl.gov/...index/97702936html.

2 www.state.ma.us/dph/rcp/faq13.htm 3 tis.eh.doe.gov/ohre/new/findingaids/epidemiologic/ rockyplant/employ/intro.html Radiation Workers 73

When we look at an analysis of SMRs, for example, in a study of workers from three countries was 40 we should consider each estimate in the context mSv and 80% of workers had doses below 0.05 of the overall SMR for the cohort. If workers at a Sv (Cardis et al. 1995). In a large Canadian study facility have an SMR of 0.8 overall then they are a the mean dose was even lower (6.6 mSv) because healthy cohort with mortality rate 20% lower than it included exposure in medical professions; in this average. Judging SMRs for specific diseases by case 97% of workers had doses below 0.05 Sv (Sont whether or not they are significantly greater than 1 is et al. 2001). misleading in this case, because they should in fact Sections 6.2 and 6.3 discuss studies of worker be lower than 1 in a healthy cohort. Any SMRs that health by facility. Examining facilities individually are significantly greater than 1 become very strong can reveal information and risks that “a common evidence of an effect. estimator” from a multi-site study may obscure (Ritz Another common factor involves time; 1999). On the other hand, many facility-specific researchers often represent workplace exposure with studies have been inconclusive because the cohorts a proxy variable like years of employment. This is are small and because the healthy worker effect affected by the fact that sick people are weeded out limits meaningful comparisons to analyses within of employment over the years. A person with lung the cohort. Because of this, a number of large pooled cancer, for example, is unlikely to remain working analyses have been undertaken, some general and for very long. This results in a situation where the some focused on specific disease endpoints. These people who have been working the longest can be are addressed in Section 6.4. Section 6.5 presents a expected to be unusually healthy. This is known summary and discussion of health effects in nuclear as the healthy survivor effect. Baillargeon and workers. Wilkinson (1999) studied the healthy survivor effect among workers at Hanford; they found that there 6.2 US facilities was a stepwise decline in the standardized mortality ratios of workers with increasing employment length Hanford. Hanford, managed by the DOE, is and that workers in the highest employment duration located in Richland, Washington and covers 560 category showed a significant survival advantage square miles. From 1944 to the late 1980s, Hanford over other workers. operated as a plutonium production facility for Other methodological limitations associated the nuclear weapons complex. More than 100,000 with occupational exposure studies include: people have worked at Hanford over the years. In our literature review for Hanford it became clear that • relatively low numbers of excess deaths, reducing there had been something of an academic battle over precision in risk estimation interpretation of the occupational exposure research • missing or incomplete workplace employment for this facility. Stewart and Kneale (1991) provide and exposure records (this is especially true for some background as follows: In the early years of older data) standard setting for occupational radiation exposure • confounding variables such as smoking that are there was a lot of fluctuation and disagreement. difficult to control The Atomic Energy Commission (AEC) lowered • poor records of disease incidence leading to a its exposure limits as risk awareness increased. reliance on mortality data However, after hearing that significant risk was difficult to detect in low-dose survivors of the Despite these limitations, many researchers atomic bomb, the AEC wished to relax its standards. look to studies of occupational exposure as a key In 1964 the AEC agreed to sponsor a lifetime health resource for data on health effects of chronic, low- mortality study of all of its employees in order to level radiation exposure. These workers constitute gather more definitive information by which to set a large population for whom exposure monitoring, standards. They hired Thomas Mancuso, of the although far from ideal, is relatively thorough. University of Pittsburgh School of Public Health, Furthermore, the majority of doses received by to lead the study and Mancuso decided to focus on these workers are relatively low. The mean dose data from Hanford. Shortly after Mancuso began his 74 Radiation Workers work, reports from another researcher indicated that there was significant health risk related to exposure at Hanford. The AEC contacted Mancuso and asked him to refute these claims and Mancuso responded that he would be unable to do so until he completed his own research. Mancuso was shortly thereafter told that his contract would not be renewed; with two years left on his contract he invited British epidemiologists Alice Stewart and George Kneale to help conduct the remaining research. At the end of Mancuso’s contract, the DOE appointed Ethel Gilbert as chief scientist of the Hanford study. Mancuso, Stewart and Kneale were able to continue their work with a grant from the National Institute of Figure 6-3. Located at the Hanford site in Washington and completed in September 1944, the B Reactor was Occupational Safety and Health (NIOSH). the world’s first large-scale plutonium production reactor Gilbert et al. published an analysis of the (http://ma.mbe.doe.gov/me70/history/b_reactor.htm). mortality risk in Hanford employees in 1989, covering employee data from 1945-1981, and then published a follow-up analysis in 1993, covering Kneale and Stewart 1993) as well as a review of the 1945-1986. The 1989 analysis found a strong healthy issues of age, exposure and dose recording (Stewart worker effect, with low standardized mortality ratios and Kneale 1993). In a preliminary analysis Mancuso (SMRs), and cancer was generally not significantly et al. (1977) used methods involving cumulative related to dose. This study did find a significantly mean doses and proportional mortality. They found elevated risk of multiple myeloma and a significant that workers who died of cancers that might be trend with dose for this disease4. The 1993 analysis related to radiation (leukemias and myelomas, lung generally confirmed the results of the 1989 analysis cancer, etc.) had higher mean doses than workers and aside from the multiple myeloma association who died of other cancers. They also found that the there was no significant evidence of a health risk. It death from these cancers occurred more frequently, was also clear, however, that the results were very as a proportion of total mortality, than in the general uncertain and not inconsistent with atomic bomb population5. In addition, risk was found to be higher survivor data. For example, the solid cancer ERR for those exposed at younger and older ages. This estimate was –0.04/Sv but had a 90% CI of –1.7 study was controversial because of the methods to 1.25/Sv (compared to the atomic bomb survivor used and also because it estimated higher risks estimate of 0.47/Sv; Preston et al. 2003). than would be expected based on the atomic bomb Mancuso, Stewart and Kneale also published survivor data. Life tables and regression models a series of studies examining cancer mortality at were used by Kneale et al. (1981) and Kneale and Hanford (Mancuso et al. 1977, Kneale et al. 1981, Stewart (1993) for follow-up through 1977 and then

4 In exposure categories 0-19, 20-49, 50-149 and 150+ mSv the RR estimates were 1.0, 0.0 (no deaths), 8.5 (based on two deaths) and 14.7 (based on one death). Multiple myeloma had by this time also been associated with exposure to radiation at the Sellafield facility in England (Smith and Douglas 1986). 5 This proportional mortality method assumes that, for example, if 10% of cancers in the general population are prostate cancers then 10% of workers’ cancers should also be prostate cancers. This avoids the healthy worker effect because the overall mortality rate is not compared across populations. According to this method, Mancuso et al. found 11 myeloid leukemia deaths where 5.8 would be expected; similar excesses were apparent for cancers of the lung (192 vs. 144 expected), kidney (21 vs. 15) and pancreas (49 vs. 37) and for multiple myeloma (11 vs. 7.6) and lymphoma (34 vs. 27.7). 6 Life tables are a way of arranging data to allow for year-to-year accounting of exposure and mortality; regression models are used to account for a variety of confounding factors. Radiation Workers 75

Ridge employees, there are a variety of ways in which characteristics such as date of hire, job description, race, gender, follow-up time, and other factors were used to define cohorts. Some studies, for example, have focused specifically on the Y-12 and/or X-10 plants in Oak Ridge since these had higher documented exposures than the other Oak Ridge facilities. Other studies exclude or analyze separately the years during which Y-12 was used for uranium enrichment. Researchers have also used different interpretations of cause of death. The variety of cohort definitions in Oak Ridge studies have contributed to the variety of results you will Figure 6-4. Plutonium is handled through a glovebox at the Plutonium Finishing Plant at the Hanford site. Department see below. of Energy, Office of Environmental Management 1996. A retrospective cohort study of white male employees (Checkoway et al. 1985) generally found low SMRs, predictably demonstrating the 19866. In the 1981 analysis the dose-response pattern healthy worker effect. For prostate cancer, leukemia appeared supralinear, although this suggestion did and lymphoma, however, SMRs were positive7. not hold with further follow-up (Stewart and Kneale Leukemia mortality appeared to be related to dose, 1993, Kneale and Stewart 1993). The 1993 analysis although this was not quantified. In a 1988 paper suggested that age at exposure was a very important Checkoway et al. restricted their analysis to workers factor and that exposure at older ages (60 and older) at the Y-12 plant employed during 1947-1974. can carry a particularly high risk. The overall risk Elevated SMRs were found for cancers of the lung8 was described with a doubling dose of ~260 mSv; (1.36; 1.09-1.67), brain and CNS (1.80; 0.98-3.02) this is equivalent to an ERR of roughly 4/Sv (again, and ‘other lymphatic cancers9’ (1.86; 0.85-3.53), this can be compared to the atomic bomb survivor but not leukemia (SMR 0.50; 0.14-1.28). US rates estimate of 0.47/Sv; Preston et al. 2003). were not available for multiple myeloma but based Oak Ridge. Oak Ridge, a 58 square mile on Tennessee rates an SMR of 1.43 (0.39-3.66) was reservation located near Knoxville, Tennessee, estimated. The authors note that although these risk was established in 1943 as a laboratory to produce estimates lack statistical power they do suggest risks enriched uranium for the Manhattan Project. During at relatively low doses. A positive dose-response the 1950s and 1960s Oak Ridge was a center for relationship for lung cancer was apparent, but this the study of nuclear energy and related research. In relationship was weakened when a 10 year latency the 1970s, with the creation of the Department of was assumed and ten years is considered a minimum Energy, Oak Ridge expanded research to include for radiation-induced lung cancer. energy production, transmission and conservation. The association with CNS cancers was revisited It is now the location of the K-25 and Y-12 plants as by Carpenter et al. (1987) in a case-control study well as the Oak Ridge National Laboratory (ORNL), that included white males and white females who also known as X-10. were employed 1943-1979. This was a very small The Oak Ridge studies are a good example of study (27 cases with external and 47 with internal how cohort selection can affect a study. Although dose estimates) and the results were uncertain. In all researchers were drawing from a list of Oak a comparison of workers with doses greater or less

7 Prostate cancer (1.16), Hodgkin’s disease (1.10), leukemia (1.48). These were not significantly positive, but this should be taken with a grain of salt since the overall SMR was low (0.73). 8 Polednak and Frome (1981) calculated SMRs for workers employed at the Y-12 plant between 1943 and 1947 and also found excess lung cancer (SMR 1.51 95% CI 1.01-2.31). 9 This category includes codes 202, 203, and 208 of the International Classification of Diseases, 8th revision. 76 Radiation Workers

appeared to provide the most significant result, an estimated ERR of ~5/Sv11. The lung cancer trend was similar, with an ERR of ~5.2/Sv, and this was unaffected by choice of lag time. The leukemia dose- response trend was high (ERR ~9/Sv with 20-year lag) but not significant. These estimates are much higher than corresponding atomic bomb survivor estimates and were not apparent in earlier studies with fewer years of follow-up. The results were also surprising because of the low level of exposure: over 99.8% of annual reported doses were less than 50 mSv. These researchers conducted another SMR Figure 6-5. A low-level solid waste burial ground at Oak analysis of all workers employed 1943-1984, in Ridge National Laboratory (http://www.doedigitalarchive. addition to cross-facility comparisons and a dose- doe.gov/ImageDetailView.cfm?ImageID=2001089&page=se response analysis (Frome et al. 1997). This analysis arch&pageid=thumb). was different in a few ways. The Wing et al. (1991) analysis included both underlying cause of death than 0.05 Sv there were no cases in the low-dose and ‘contributing cause’ of death in defining cases; group; the OR in this case was 0, with a 95% upper the new analysis only included underlying causes of confidence limit of 2.3. This study was therefore not death. Dose categories were defined differently in inconsistent with the estimate of Checkoway et al. the newer study and some analytical methods were (1988) and was largely inconclusive. changed. Finally, the dose-response analysis was Loomis and Wolf (1996) performed a separate expanded to include workers at the Y-12 facility, analysis of mortality in Y-12 workers, in this case increasing the eligible cohort from 8,318 to 28,347. defining the cohort as all workers (including women This SMR analysis revealed excess lung cancer and nonwhite men) who were employed between mortality among white males (SMR 1.18) and 1943 and 1974. Uranium enrichment was done at Y- excess cancer of the large intestine among nonwhite 12 until 1947 and workers employed in this project males (SMR 1.73); the leukemia excess was no were assessed separately. Results for the 1947-1974 longer evident. The dose-response analysis revealed employment cohort were predictably close to those significant, although lower, ERR estimates for of Checkoway et al. (1988)10. lung cancer (1.68/Sv; 0.03-4.94) and for all cancer Steve Wing and colleagues (1991) published (1.45/Sv; 0.15-3.48). Cross-facility comparison a study of a cohort defined as X-10 workers hired showed significant heterogeneity in lung cancer 1943-1972 and followed through 1984. The addition and leukemia mortality rates; specifically, the X-10 of several years of follow-up produced findings that facility showed unusually low lung cancer mortality were quite different from earlier studies, particularly and unusually high leukemia mortality relative to a significantly positive SMR for leukemia (1.63; the Y-12 facility. 1.08-2.35) that was even higher among workers Oak Ridge and age at exposure. In 1999, monitored for internal deposition of radionuclides Richardson and Wing published two papers further (2.23; 1.27-3.62). Dose-response curves were fit for analyzing the Oak Ridge data, followed through cancers generally and for lung cancer and leukemia; 1990, and focusing specifically on the effect of lag times of 0, 10 or 20 years were assumed to test age. The first paper (Richardson and Wing 1999a) the effect of time since exposure. The cancer trend only considered white males and found a significant was significant at all lag times, but a 20-year lag trend with age at exposure (see Figure 6-6).

10 Elevated SMRS of lung cancer (1.17; 1.01-1.34), prostate cancer (1.31; 0.91-1.81), CNS cancers (1.29; 0.79-2.00), kidney cancer (1.30; 0.74-2.11) and ‘other lymphatic tissue’ (1.32; 0.82-1.99). 11 Reported as 4.94% increase per 10 mSv based on an exponential relative risk model. Radiation Workers 77

have been studied by Hal Morgentstern, Beate Ritz, and other researchers at UCLA (summarized by Morgenstern and Ritz 200112). Workers in this cohort have been exposed to radiation externally, they have potentially taken radionuclides into their bodies and been exposed internally, and they have also been exposed to chemical toxins. The UCLA study analyzed each of these exposure pathways for risk. As in other studies, the SMRs for this cohort were not significantly elevated, although the leukemia SMR Figure 6-6 The effect of exposure age on the risk of cancer was suggestive of an effect13. The authors attributed mortality in Oak Ridge workers. The estimated % increase these results to the healthy worker effect. per cSv is roughly the same as an estimate of ERR per Sv An analysis that grouped workers into dose at low doses. These data assume a 10-year lag time in the categories found associations between high doses development of cancer. Error bars show the standard error and mortality from leukemia/lymphoma, lung of the estimate (based on Richardson and Wing 1999a). cancer, cancers of the upper aerodigestive tract, and all cancers14. Significant positive dose-response Richardson and Wing (1999b) published another analysis including all workers; estimated risks were greater with the inclusion of all workers although the greater diversity in the larger cohort increased the uncertainty of the results. These results are at odds with those of the atomic bomb survivors, which generally show constant or declining risk at increasing ages at exposure. In addition, a large international pooled study of workers, discussed below, did not detect such an effect (Cardis et al. 1995). At the same time, it is a plausible concept mechanistically because cellular repair mechanisms are known to become less efficient with age. Rocketdyne. The Santa Susana Field Laboratory in southern California has been the site of nuclear activities under two companies that merged in 1984 (Atomics International and Rocketdyne, a division of Boeing). Since the 1950s the area has been used for various projects including rocket testing, the Figure 6-7. Radiation-safety technicians check workers development and testing of nuclear reactors, the for contamination before they exit a Rocky Flats decladding of irradiated reactor fuel, and storage facility (Department of Energy, Office of Environmental of radioactive material. Health impacts on workers Management 1996).

12 Reports from this study have been published by Morgenstern et al. (1997) and Ritz et al. (1999a and 1999b). 13 The SMR for externally exposed workers was 1.60 (0.95-2.52); for internally monitored workers it was 1.46 (0.63- 2.88). 14 The highest category of external dose, 200 mSv or more, was significantly associated with mortality from all cancers (RR 3.10, 1.13-8.48), lymphopoietic cancers (RR 15.7, 3.33-73.5) and lung cancer (RR 4.70, 1.05-21.0). The highest category of internal dose (30 mSv or more) was also associated with mortality from all cancers (RR 2.56, 0.93- 7.09) and lymphopoietic cancer (RR 44.6, 5.64-353), but there were no lung cancer deaths in this category. The highest category of internal dose was also associated with upper aerodigestive tract cancers including cancers of the pharynx, esophagus, mouth, and stomach (RR 57.2, 8.17-401). 78 Radiation Workers

Wilkinson et al. (1987) analyzed mortality rates among workers who dealt with plutonium and among other workers. SMRs were generally low, reflecting the healthy worker effect. Analysis of plutonium exposure inside the body made use of urine measurements; workers with more than 2 nCi of plutonium in the body were compared to workers with less than this amount15. Results from this analysis were largely inconclusive because of the small numbers of deaths in each disease category, but there was a very suggestive excess of lymphopoietic cancers (RR 7.69, 90% CI 0.99-72.93) based on four deaths among exposed workers and assuming a two- year lag time16. Analyses of workers with more or less than 1 cSv of external dose were again largely inconclusive, although with a ten-year lag time there Figure 6-8. Today the X-Y Retriever Room at Rocky Flats was some evidence of three-fold increases in the risk is used to store surplus plutonium (Department of Energy, of mortality from CNS tumors, myeloid leukemia, Office of Environmental Management 1996). or lymphosarcomas. Ruttenber et al. (2003) analyzed the health trends were apparent for external radiation and of Rocky Flats workers from 1952-1989. SMRs lymphopoietic cancers, lung cancer, or all cancers. generally reflected a healthy worker effect, The RR at 100 mSv was estimated to be 1.22 although the SMR for unspecified CNS cancers (0.86-1.73) for all cancers, compared to the atomic was significantly positive (2.51, 1.14-4.76) based bomb survivor estimate of 1.05 (1.04-1.06). Ritz on Colorado rates. Lung cancer was assessed in a et al. (1999a) reported external exposure results case-control analysis within this cohort (Ruttenber for leukemia and other lymphopoietic diseases et al. 2003, Brown et al. 2004). Workers with separately: the RR for leukemia at 100 mSv, based cumulative internal lung doses of over 400mSv on 13 deaths, was 1.76 (0.71-4.32). The estimate had a statistically significantly lung cancer risk for multiple myeloma and lymphoma, based on 15 (OR roughly 2-3 depending on adjustments and lag deaths, was very similar (RR 2.27; 1.18-4.39). time). When the analysis strictly examined workers This study also detected an effect of age at who were employed 15-25 years at Rocky Flats, the exposure, finding that the risk of lung cancer (and odds ratio increased with increasing internal lung radiosensitive solid cancers generally) was higher dose categories in a statistically significant linear if exposure occurred after age 50. The reverse trend (See Figure 6-9). The levels of risk found appeared to be the case for leukemia/lymphoma, in this cohort are compatible with risk coefficients although the estimated risk at exposure age 50-66 derived from workers at the Mayak facility who was very uncertain for this cause of death (RR 0.06, were exposed to much higher doses (see section 7). 0.00-114). Lawrence Livermore National Laboratory. Rocky Flats. Rocky Flats, located 16 miles Lawrence Livermore National Laboratory (LLNL) northwest of Denver, CO, was the site of plutonium is a high technology, high energy physics research pit production for nuclear weapons from 1952-1989. facility located in Livermore in Alameda County, Over 23,000 people have worked at the plant. California. A physician working at LLNL first

15 This cannot be easily translated into dose due to the influence of time and the variability among tissues, but it can be compared to the occupational standard maximum body burden of 40 nCi. 16 These four deaths included one lymphosarcoma, one non-Hodgkin’s lymphoma, one multiple myeloma and one myeloid leukemia. The estimate was slightly higher assuming a 5-year lag time (RR 9.86, 90% CI 1.26-94.03). Radiation Workers 79

melanoma and occupational exposure to radiation. As a follow-up to the melanoma study Reynolds and Austin (1985) investigated the incidence of other cancers in relation to LLNL employment. Although they did not find an excess of radiosensitive cancers as a group they did detect excess salivary gland tumors (4 observed and 0.8 expected); salivary gland tumors have been associated with radiation from the atomic bombs and from medical exposures indicating that this may be more than a chance finding. Savannah River Site. Savannah River Nuclear Figure 6-9. Association between lung dose and lung cancer Fuels (also known as the Savannah River Site, or mortality among Rocky Flats workers employed for 15-25 SRS) opened in 1951 near Aiken, South Carolina and years (based on data from Ruttenber et al. 2003). has been involved in uranium processing, nuclear fuel fabrication, nuclear reactor operation, nuclear brought attention to an apparent increase in reactor refueling, and nuclear fuel reprocessing, malignant melanoma among the employees in the among other activities. Seventeen thousand people 1970s. Although rates of malignant melanoma were have worked at the facility over the years. Employees already high in the counties surrounding the facility, of the plant have been exposed to both external it appeared that the rate among LLNL employees radiation and internally deposited radionuclides was even higher. including tritium, uranium and plutonium. A study jointly funded by LLNL and the State An SMR analysis of SRS workers found of California (Austin et al. 1981) used case-control generally low SMRs, consistent with a healthy methods within Alameda and Contra Costa counties worker effect, but did find an elevated leukemia and found an incidence ratio of 2.9 (1.5-5.9) based mortality rate among hourly workers who were hired on 16 observed cases. Possible sources of bias in the before 1955 and who were employed between 5 and data included a study group that had more access to 10 years (SMR 2.75, p<0.5; Cragle et al. 1988). In medical care, higher probability of reporting disease, an unpublished follow-up paper (Cragle et al. 1998; and a higher socioeconomic status. Reynolds and see reference list for web address) these authors Austin (1985) confirmed this result using different detected a positive dose-response trend for leukemia methods (7 observed and 1.35 expected cases). mortality with an ERR of 13.6/Sv (0.6-50.6)17. Austin and Reynolds had also suggested that the risk Wartenberg et al. (2001) examined mortality of malignant melanoma was higher among workers risk at Savannah River and specifically looked who had worked around radiation. Schwartzbaum at differences in risk across races. The only et al. (1994) confirmed that workers with recorded significantly elevated SMR in this study was chronic exposure were at a higher risk (OR 10.8, 1.4-85.1). lymphocytic leukemia (CLL) among African Austin and Reynolds (1997) calculated a lower American males (SMR 5.35; 1.01-13.118); this was a risk for work around radiation (OR 2.3, 1.0-7.6) surprising result as CLL is not typically considered after controlling for other potential occupational a radiosensitive disease. This study was limited by risk factors (chemical exposures). Moore et al. a lack of information regarding job titles or other (1997), using different criteria for matching cases socioeconomic factors, information about previous and controls, did not find an association between employment, or any exposure data.

17 Another unpublished study apparently found significant excess leukemia mortality using case-control methods. The excess was largely comprised of chronic lymphocytic leukemia (CLL; Fayerweather et al. 1991). Summaries of this and other unpublished SRS research are available at http://sti.srs.gov/fulltext/eshwhs2002005/eshwhs2002005.htm 18 Based on three cases. Georgia and South Carolina mortality rates were used as the standard. If US rates were used the SMR estimate was 5.01 (0.95-12.3). 80 Radiation Workers

one case of osteogenic sarcoma, a notable finding since it is a rare bone cancer that has been related to plutonium exposure in animal studies. There was also an elevated risk of lung cancer among workers monitored for internal exposure to plutonium (RR 1.78, 0.79-3.99). This finding is notable because lung cancer mortality was relatively low among externally exposed workers indicating a strong healthy worker effect. Significantly positive dose- response relationships were found between external exposure and brain/CNS cancer, esophageal cancer, and Hodgkin’s disease. Hodgkin’s disease is not typically associated radiation exposure. Portsmouth Uranium Enrichment Plant. The Portsmouth Uranium Enrichment Plant site, located in Pike County, Ohio, covers approximately 4,000 acres. Uranium enrichment activities began in 1954 and continued through 1981. During the years of operation the plant employed approximately 3,000 people. Studies of this cohort have not been peer- reviewed and have been largely inconclusive. Figure 6-10. A pool type reactor at the Livermore facility is Brown and Bloom (1987) investigated mortality pictured here (http://www.llnl.gov/timeline50s.html). over a relatively short study period, with a maximum observation period of only 28 years. 40% of the Los Alamos National Laboratory. Los Alamos cohort was hired after 1965 leaving only 17 years for National Laboratory (LANL) is located on 27,000 follow-up. These authors did find elevated SMRs for acres of land 35 miles west of Santa Fe, NM. LANL stomach cancer (1.69, 0.81-2.10) and lymphopoietic was established in 1943 as a secret laboratory (then cancers (1.46, 0.92-2.18). Ahrenholz et al. (2001) known as Project Y) with a mission to design, also examined risks at the Portsmouth plant and construct and test the first atomic bomb. Nuclear again found non-significant increases in cancers of research has continued at the laboratory since then. Primary forms of radiation that workers at Los Alamos are exposed to are x-rays, gamma rays and neutrons (externally), and tritium and plutonium (internally). After observations at Lawrence Livermore National Laboratory of increased malignant melanoma among employees, researchers at Los Alamos were prompted to investigate disease incidence in their workforce. Acquavella et al. (1982) reported 6 cases of malignant melanoma, not significantly more than the 5.7 expected cases. In 1983, Acquavella et al. published a case- control analysis of LANL workers and again found no association between radiation exposure and malignant melanoma; this report suggested that Figure 6-11. Dr. John Gofman (second from left) at the time melanoma incidence increased with educational level that this photo was taken (1960s) was the first Associate (potentially reflecting lifestyle risk factors). Wiggs Director for the Biomedical Program at Lawrence Livermore et al. (1994) conducted a more general analysis of National Laboratory (http://www.llnl.gov/50th_anniv/ mortality rates at Los Alamos. This study reported decades/1960s.htm). Radiation Workers 81

alpha emitter polonium-210 (Po-210). This isotope was separated from lead and used to generate neutrons to trigger nuclear reactions. Po-210 activities were conducted at Mound between 1944 and 1972; exposure to Po-210 occurred primarily through inhalation although ingestion may also have occurred. This study did not find any significantly elevated SMRs, although more lung cancers were observed than expected (SMR 1.19, 0.98-1.43; 82 deaths). The assignment of Po-210 dose estimates was done retroactively and may have been in error; no significant dose-response trends were observed. Mallinckrodt Chemical Works. Mallinckrodt Chemical Works, in St. Louis, Missouri, processed uranium ore into pure uranium tetrafluroide metal between 1943 and 1966. Daily average uranium dust Figure 6-12. Barrels of transuranic waste site on a concrete concentrations were sometimes between 100 and pad at the Savannah River Site (Department of Energy, 200 times the maximum allowable concentration of Office of Environmental Management 1996). 50 µg/m3 in some areas of the plant. Dupree-Ellis et al. (2000) analyzed mortality rates at the facility the stomach and lymphopoietic system in addition and found that, although SMRs were not elevated, to increases in cancers of female genital organs and there was a significantly positive dose-response bone19. relationship for kidney cancer (ERR 10.5/Sv; 90% The Mound Facility. The Mound Facility, CI 0.6-57.4). As discussed below, this may have located in Miamisburg, Ohio, was established as the more to do with the chemical nature of uranium than first permanent Atomic Energy Commission facility with its radiological nature. for atomic weapons research in 1944. Activities Linde Air Products Company Ceramics at the facility included process development, Plant. The Linde Air Products Company Ceramics production engineering, manufacturing surveillance Plant is located in Buffalo NY and processed and evaluation of explosive components for the uranium between 1943 and 1949. Workers at the site nuclear arsenal until its closing in 1989. were exposed to ionizing radiation as well as a wide A cohort mortality study of Mound workers variety of chemicals, and uranium contributed to was published in 1991 (Wiggs et al. 1991b). SMRs both types of exposure. The site’s occupational limit were low, indicating a healthy worker effect, and for lung dose was 150 mSv/year during the time of comparisons between workers with more or less than operation and the exposure levels often approached 10 mSv of cumulative dose were not significant due this limit. One intention of Dupree et al. (1987), who to small numbers of deaths. Dose-response trends, studied the risks of the occupational cohort, was to however, were significantly positive for leukemia20. test the effectiveness of the limit, and this study Wiggs et al. (1991a) studied mortality in Mound found elevated SMRs for a number of endpoints21. workers with emphasis on potential exposure to the

19 Elevated SMRs, with 95% CI and number of deaths, were reported for stomach cancer (1.2, 0.7-1.9, 15 deaths), lympho-reticulosarcoma (SMR 1.4, 0.6-2.8, 7 deaths), Hodgkin’s disease (1.4, 0.5-3.2, 5 deaths), bone cancer (1.7, 0.2-6.0, 2 deaths) and cancer of female genital organs (1.3, 0.5-2.8, 6 deaths). 20 There were two cases of lymphocytic leukemia (including one CLL case) and two cases of myeloid leukemia in this cohort. Comparing workers with 50+ mSv to workers with <10 mSv the Rate Ratio was 15.4 (1.8-130) for all leukemia, 31.7 (2.0-506) for lymphocytic leukemia, and 5.5 (0.3-88) for myeloid leukemia. 21 The researchers found elevated SMRs for all causes of death (1.2, 1.1-1.3), all cancers (1.1, 0.8-1.3), and cancers of the digestive system (1.3, 0.9-1.9), stomach (1.7, 0.7-3.4), respiratory system (1.1, 0.7-1.7), and larynx (4.5, 1.4- 10.4). 82 Radiation Workers

Feed Material Production Center (Fernald site). The Fernald site is located in Fernald, Ohio. Its primary function during its operation was to produce high-purity uranium products for other sites in the nuclear weapons complex. The plant became fully operational in 1954, employment peaked in 1956 with 2,879 employees, and in 1989-91 the plant was closed and remediation began. Ritz (1999) found that there were non- significantly raised SMRs for all cancers and cancers of the prostate, brain, bladder, lymphopoietic system, digestive organs and peritoneum. Since the number of deaths was low, dose-response analyses were limited to groups of 1) all cancers, 2) all Figure 6-13. A worker holding uranium metal product at radiosensitive solid cancers, 3) lung cancer, and 4) Fernald (http://www.fernald.gov/50th/fppp.htm). blood and lymph cancers. Mortality from each of these causes was associated with external dose22, membrane surrounding the lungs, was a prominent and the effect was most pronounced in association cause of death in this cohort, reflected in a with exposure after age 40. significantly positive SMR (3.5, p<0.001). All of the 14 pleural cancer deaths occurred among radiation 6.3 UK facilities workers, resulting in a significant excess in radiation workers relative to non-radiation workers. Although In the UK, nuclear weapons development, acquisition the SMR for leukemia mortality was significantly and deployment occurs within the organizational negative, there were positive dose-response trends structure of the Ministry of Defense. British Nuclear for leukemia mortality with a 2-year lag (p=0.05), for Fuels (BNFL) is the primary nuclear energy company myeloma mortality with a 20-year lag (p=0.02), and in the UK, and some of the facilities that operate for all blood and lymph cancer mortality with a 20- under BNFL also double as weapons production year lag (p=0.03). With a twenty-year lag there were facilities. also significant dose-response trends for incidence Sellafield. Sellafield is an English reprocessing of all blood and lymph cancers (p=0.005) as well plant located on the northwest coast of England, as incidence of brain/CNS cancers (p=0.03). There 13 miles north of the town Barrow-in-Furness on was also a significant negative association between the Irish Sea. The plant is owned and operated by kidney cancer and dose, in contrast to the results of BNFL. The site includes four nuclear reactors, two Dupree-Ellis (2000) for Mallinckrodt workers24. reprocessing plants and one waste management Cellular studies of genetic damage in the blood plant for handling high-level liquid waste. In the and lymph of Sellafield workers have been published 1950s and 60s, Sellafield played a crucial part in several times (Cole et al. 1995, Whitehouse et al. the British nuclear weapons program. The plant is 1998, Tawn et al. 2000, 2003). Cole et al. (1995) one of the three remaining reprocessing plants in the found that the frequency of one particular mutation world. was not higher among exposed workers. In contrast, Omar et al. (1999) assessed the mortality Whitehouse et al. (1998) found higher rates of and morbidity of Sellafield workers following chromosome aberrations among workers exposed to on previous analyses23. Cancer of the pleura, a external radiation or internally deposited plutonium.

22 The RR estimates at 100 mSv with a 10-year lag were 1.8 (1.1-2.9; all cancers), 1.9 (1.1-3.3; radiosensitive solid cancers), 2.1 (1.1-4.2; lung cancer) and 2.1 (0.4-11.2; blood and lymph cancers). 23 Smith and Douglas 1986 and Douglas et al. 1994 (same authorship as Omar et al. 1999) followed this cohort over shorter time periods. 24 These dose-response relationships were based on external radiation dose. Radiation Workers 83

Tawn et al. (2000, 2003) found positive, although not trend with prostate cancer in this cohort, although significant, dose-response curves for chromosome this is not typically thought to be a radiogenic damage and for one type of mutation; the trends cancer. Based on two deaths, the SMR of pleural suggested that chronic exposure was less effective cancer was elevated, but not significantly so (2.63, p than acute exposure at inducing these forms of = 0.35; McGeoghegan and Binks 2001). damage. Other UK facilities. McGeoghegan and Binks 6.4 Multi-site studies (2000a, 200b, 2001) have analyzed the health data for three UK facilities (Springfields, Capenhurst and It is clear from this review that results vary from Chapelcross, respectively) in parallel reports. In all facility to facility, and in an effort to distill common cases SMRs were low, indicating a healthy worker trends several efforts have been made to combine effect. Although results were largely inconclusive the data. This can be a complicated process in each case, there is general evidence of increased because of differences in background demographic risks of pleural cancer, bladder cancer, and cancer characteristics and non-radiation risk factors, of the blood and lymph when the three sites are workplace exposure monitoring, and follow-up considered together. The three reports are described time. In addition, workplace exposures to external briefly below. radiation, internally deposited radionuclides, The cohort of workers from Springfields, and chemicals vary according to the work being a uranium processing plant, included 19,589 performed. The reports discussed below all found employees. Dose-response trends were significantly low SMRs, consistent with a healthy worker effect, positive for incidence of blood and lymph cancers, and SMR results are not discussed unless they were lung cancer, pleural cancer, and all cancer. The ERR notably elevated. estimate for solid cancer mortality in this cohort was Pooled UK data. Beral et al. (1985) analyzed 0.64/Sv (-0.95-2.67). Hodgkin’s disease and bladder mortality risk for employees of the United Kingdom cancer mortality were also significantly related to Atomic Energy Authority (AEA), including the dose (McGeoghegan and Binks 2000a). facilities of Harwell, Culham, London, Dounreay, Capenhurst is a gaseous diffusion plant where Winfrith, Risley, and Culcheth. The only significant uranium is enriched. The dose-response for total evidence for risk in this cohort was an increase in cancer incidence in this cohort of 12,540 workers was mortality from prostate cancer, and this appeared to be not significant (ERR –0.9/Sv, <-1.6-3.8); the dose- related to tritium exposure. Of the 19 prostate cancer response relationship for non-Hodgkin’s lymphoma deaths among workers with radiation exposure, 6 of mortality was marginally significant with a 2-year these were in workers who had been monitored for lag time (p = 0.08). Bladder cancer incidence was tritium; the expected number of deaths in this group also associated with dose assuming a twenty-year was less than 1 and the SMR was 8.9 (p<0.001). lag. There was a significant excess of pleural cancer The dose-response trend for prostate cancer was mortality in this cohort based on five cases (SMR significantly positive. Although not significant, 4.96, p = 0.009; McGeoghegan and Binks 2000b). dose-response trends for total cancer, leukemia and Chapelcross is a facility in Scotland that runs multiple myeloma were positive in this cohort. four nuclear reactors and produces tritium. The dose- Other studies have grouped larger cohorts of UK response for total cancer incidence in this cohort of workers. The UK National Radiological Protection 2,628 workers was significantly positive (ERR 1.80/ Board (NRPB) maintains the National Registry Sv, 0.03-4.45) and higher than the corresponding for Radiation Workers (NRRW), which contains male atomic bomb survivors estimate of 0.38/Sv information about the radiation exposure levels of (Thompson et al. 1994). The dose-response trend workers as well as other data (sex, date of birth, for mortality from blood and lymph cancers was of job title, and so on). This roster includes workers at borderline significance but was not quantified by the British Nuclear Fuels sites (Sellafield, Chapelcross, authors25. There was also a significant dose-response Capenhurst, Springfields), the AEA workers covered

25 Depending on lag time, the p-value for the dose-response trend ranged from 0.06-0.10. 84 Radiation Workers by Beral et al. (1985), nuclear power plant workers, of internal dose are so uncertain. Urine analysis and military personnel. The NRPB analyzed the can help describe the amount of a radionuclide NRRW in a 1992 report (Kendall et al.) and again in the body, but depending on how the nuclide is with more follow-up in 1999 (Muirhead et al.). transported and stored in the body the doses to SMRs were predictably low in this cohort, but they individual tissues can vary. Carpenter et al. (1998) were significantly positive for thyroid cancer in the analyzed the same cohort as Carpenter et al. (1994) first analysis (SMR 3.0, p<0.01) and for pleural with an emphasis on internal exposures to tritium, cancer in the second analysis (SMR 2.0, 1.4-2.7)26. plutonium, and other radionuclides. Workers who Estimates of excess relative risk in the second had ever been monitored for a radionuclide were analysis were 2.55/Sv (90% CI –0.03-7.16) for considered exposed for purposes of analysis and non-CLL leukemia, 0.09/Sv (90% CI –0.28-0.52) compared to workers who had never been monitored for solid cancer, and 4.11/Sv (90% CI 0.03-14.8) for any radionuclides. This simplifies the problem for multiple myeloma; each of these estimates was but is still uncertain because some workers may have higher in the first analysis27. been monitored as a precaution and never actually Alternative analyses of UK workers, based on exposed. Monitoring for tritium, which is uniformly a slightly different cohort, were made by a group distributed throughout the body, was associated of academic researchers including the authors of the with increased risks lung cancer (RR 1.2, 0.9-1.6), 1985 AEA analysis described above. Carpenter et al. prostate cancer (RR 1.3, 0.7-2.4) and testicular (1994) included AEA workers, Sellafield workers, cancer (RR 8.4, 1.5-43). Monitoring for plutonium, and workers at the Atomic Weapons Establishment which concentrates in bone, liver or lung tissue, plant at Aldermaston; this cohort largely overlaps was associated with increased risks of lung cancer with the NRRW but does not include workers at (RR 1.2, 1.0-1.4) and pleural cancer (RR 2.0, 0.7- smaller military and commercial power facilities. 5.5). Monitoring for other radionuclides, including This analysis found high SMRs for pleural cancer uranium, polonium and actinium, was associated (1.3) and thyroid cancer (1.8), and monitored with lung cancer (RR 1.3, 1.1-1.6), uterine cancer workers showed a significantly increased risk of (RR 7.3, 1.1-48), and prostate cancer (RR 1.7, 1.0- pleural cancer relative to unmonitored workers (RR 2.7). This study also assessed risks according to the 7.1, 1.6-43). There was also an apparent increase time between first exposure and death and found that in the risk of cancer of the uterus or cervix among risks associated with plutonium tended to increase monitored female workers28. Significantly positive over time. Finally, the relationship between cancer dose-response trends were detected for melanoma, and exposure to external radiation was assessed leukemia, and multiple myeloma. The ERR for separately for workers who had been monitored for non-CLL leukemia, with a two-year lag time, was internal exposures. In this case the dose-response estimated to be 4.2/Sv (0.4-13.4). Multiple myeloma trends for leukemia and melanoma were significantly was only significantly related to dose with a 20-year positive among both monitored and unmonitored lag time and a risk coefficient not presented. The workers. The trend for multiple myeloma, on the estimated ERR for solid cancer was negative but other hand, was only positive among workers who compatible with the atomic bomb survivor data29. had been monitored for internal exposures and this Most studies of workplace exposure to radiation trend was not significant. deal with external exposure because estimates Pooled Canadian data. Ashmore et al. (1998)

26 Pleural cancer was not analyzed separately in the first analysis; the thyroid cancer SMR in the second analysis was 1.8 (0.9-3.2). 27 ERR estimates from the first analysis were 0.47/Sv, 4.28/Sv, and 6.9/Sv for mortality from all cancer, non-CLL leukemia, and multiple myeloma, respectively (Kendall et al. 1992). 28 Relative to unmonitored workers, monitored workers had estimated RRs of 3.0 (1.6-5.9) for uterine cancer and 2.3 (0.8-6.2) for cervical cancer. The estimated RR for ovarian cancer was 1.3 (0.6-2.8). 29 Assuming a ten-year lag time, The ERR for solid cancer (cancer other than leukemia) was -0.02/Sv (-0.5-0.6); the corresponding atomic bomb survivor estimate for mortality was 0.47/Sv (see Table 4-1; Preston et al. 2003). Radiation Workers 85 and Sont et al. (2001a) analyzed cancer mortality (90% CI <0-1.2) for all cancers except leukemia. and incidence using the National Dose Registry for The ERR estimate for all cancer increased with Canada, a database for radiation workers. This study assumed lag time to a maximum of 2.8/Sv with a is a useful addition to the literature for a number of 25-year lag time. In addition, the risk estimate reasons. First, this cohort is large, including roughly associated with death after age 75 was significantly 200,000 workers. Second, this cohort is truly a positive (6.1/Sv, 90% CI 2.2-14). These results low-dose cohort, with a mean dose of 6 mSv and suggest high risk with exposures at older ages and a relatively large proportion of workers with dose for cancers with relatively long latent periods; the less than 100 mSv30. Finally, this study included an same conclusion was reached by Kneale and Stewart analysis of cancer incidence, which can be more regarding Hanford workers in particular and US revealing than mortality studies, particularly for workers in general33. cancers with good survival rates. One of the reasons There was notable variability in results from the that doses were so low is that the cohort includes three facilities. The dose-response trends for cancers medical and dental occupations. This can be seen of the esophagus and larynx were based on strong as a limitation because it increased the variability in results from Oak Ridge, for example, and 24 out exposure conditions and dose estimation methods. of 25 multiple myeloma deaths were at Hanford. Incidence data were analyzed by Sont et al. Leukemia trends were negative at Oak Ridge and (2001a). Risk estimates based on dose-response Hanford but positive at Rocky Flats. It is important trends were very uncertain due to the relatively to keep this variability in mind because it may reflect low number of higher doses but were significantly real differences in exposures and monitoring among positive for a number of sites31. Leukemia had an these cohorts. ERR of 5.4/Sv (0.2-20). This was higher than the The effect of exposure age in US workers has corresponding mortality estimate, although that been noted in other pooled analyses. Wing et al. estimate was very uncertain (Ashmore et al. 1998)32. (2000) conducted a pooled analysis of facilities in Solid cancer (cancer other than leukemia) showed the United States, in this case Hanford, Los Alamos, an ERR of 2.3/Sv (1.1-3.9), very similar to the Oak Ridge, and the Savannah River Site; in this mortality estimate of 3.0/Sv (1.1-4.9; Ashmore et al. analysis the authors looked specifically at mortality 1998) but much higher than in other large studies from multiple myeloma and the effect of exposure including the atomic bomb survivors (see Table 4- age on risk. Cumulative dose was not associated 1). with multiple myeloma in general but significant Pooled US data. Gilbert et al. (1993) conducted risk was found for exposures at older ages (ERR an analysis of mortality data for workers at the 6.9/Sv). Hanford, Oak Ridge, and Rocky Flats facilities. Dupree et al. (1995) analyzed lung cancer This study focused exclusively on dose-response mortality in four uranium processing or fabrication relationships within the cohort and found significant facilities in Missouri, Ohio and Tennessee. In all trends. Hodgkin’s disease and cancers of the four facilities internal alpha exposure from airborne esophagus and larynx. The dose-response trend for uranium compounds in dust was a major concern. multiple myeloma was positive and of borderline The authors reported that odds ratios were higher significance while the dose-response trend for for workers hired at age 45 or later, and although leukemia was negative. Pooled ERR estimates were dose-response trends were not significantly positive –1.3/Sv (90% CI <0-1.1) for leukemia and 0.3/Sv the age effect was apparent in association with both

30 Only 2% of the Canadian cohort had cumulative doses exceeding 100 mSv, compared to 8% of the NRRW cohort and 20% of the atomic bomb survivors. 31 Lung cancer had an ERR of 3/Sv (0.5-6.8). Testicular cancer among males had an ERR of 38/Sv (90% CI 1-148). Cancer of the rectum had an ERR of 14/Sv (4-34). 32 Non-CLL leukemia among males had an ERR of 2.7 (<0-19) in the incidence study and 0.4/Sv (-4.9-5.7) in the mortality study. 33 Kneale and Stewart (1995a), in a response to the Gilbert et al. (1993) study, comment on earlier findings. Kneale and Stewart (1995b) report on a combined analysis of workers from five sites. 86 Radiation Workers

of pictures, and this variety can be partly explained by differences in the analytical methods that were employed by the authors. This is particularly true in the case of Hanford; utilizing basically the same data pool Gilbert et al. (1993) found no significant evidence of heath risks aside from multiple myeloma while Kneale and Stewart (1993) found risks greater than would be expected based on the atomic bomb survivor data and also detected an increased sensitivity in association with exposure at older ages. Perhaps more important than methodological differences are differences among facilities. The range of radiological and chemical exposures that workers experience depends on the type of activity a facility is engaged in; some workers experience Figure 6-14. A facility at Hanford for treating persons external exposure to gamma radiation and other injured by embedded radioactive particles (circa 1967). In workers inhale one or more radionuclides. In this shielded operating cell, a mock patient is flanked by a addition, exposure monitoring has varied by surgeon (right) and a radiation monitor (left) (www.eh.doe. facility and over time. Interpreting the results of gov/.../photos/handord/fig1.html). facility-specific studies is complicated by these real differences and is further complicated by the role internal and external radiation exposure. of chance and small numbers of workers at risk. In Pooled international data. Cardis et al. (1995) general, inconsistencies are expected and individual pooled data from the Canadian, UK and US cohorts. results should be judged in a broader context. This combined cohort of 95,673 workers included The kidney cancer mortality results from a few fewer Canadian workers (11,355) than the analyses of the studies described above provide a useful of Asmore et al. (1998) and Sont et al. (2001), but illustration. Dupree-Ellis et al. (2000) reported that included virtually the entire cohorts analyzed by there was a significantly positive dose-response trend Gilbert et al. (1993) and Carpenter et al. (1994, for kidney cancer mortality among Mallinckrodt 1998). In the combined group there were significant Chemical Works workers. This was based on ten trends with dose for leukemia, multiple myeloma and deaths and had wide a confidence interval (ERR uterine cancer34. There was also a significant dose- 10.5/Sv, 0.6-57.4). Omar et al. (1999), on the other response trend for noncancer circulatory disease. hand, reported the reverse relationship in Sellafield The pooled estimates of risk for leukemia and solid workers. This study found a significantly negative cancer (all cancer except leukemia) were 1.55/Sv dose-response relationship based on thirteen deaths. (90% CI –0.2-4.7) and –0.07 (90% CI –0.4-0.3). The Follow-up time was very similar in these two studies central estimate for solid cancer risk from the three- (1942-1993 and 1947-1992) and so was mean dose country cohort is negative and the upper confidence (48 and 130 mSv), so something else must explain limit is less than the atomic bomb survivors estimate the difference in the results. This could be study of 0.47/Sv (Preston et al. 2003). The leukemia risk design, although this would probably not result in by subtype is shown in Table 6-1 and is discussed such dramatic differences. But the difference could further below. also be chance. Although Mancuso et al. (1977) and Loomis and Wolf (1996) found evidence suggesting 6.5 Discussion a kidney cancer risk at Hanford and Oak Ridge, this result has not been confirmed in other studies. The studies reviewed in this section paint a variety The international pooled workers study found no

34 The estimated ERR of multiple myeloma was 4.2/Sv (90% CI 0.3-14.4). Radiation Workers 87 significant dose-response trend for kidney cancer demonstrated significant risks in workers exposed (Cardis et al. 1995), and the atomic bomb survivors to more than 10 mSv (RR 1.8, 90% CI 1.2-2.7). A have also not shown an effect (ERR –0.02/Sv, <- more detailed illustration of leukemia risk can be 0.3-1.1; Preston et al. 2003). Another plausible made by looking at the results of the three-country explanation involves the type of work that each study, the Canadian workers study, and the atomic cohort was engaged in- Sellafield workers were bomb survivors. Table 6-1 presents a breakdown of potentially exposed to relatively high amounts of leukemia by subtype. It can be seen here that the plutonium while Mallinckrodt workers processed atomic bomb survivors were a characteristically uranium. Uranium is known to be associated with different cohort; roughly one-third of the cohort kidney effects based on its chemical properties35. were children at the time of the bombings and this It is hard to imagine that radiation might help is reflected in relatively more cases of ALL. The prevent kidney cancer in a dose-dependent manner, risk coefficient (ERR/Sv) for this subtype is quite and the result for Sellafield workers is probably a high among atomic bomb survivors and very low chance finding. On the other hand, the Mallinckrodt among workers. The risk coefficient for CML, on results may not reflect a radiological risk if the the other hand, is roughly twice as high among principle uranium effect was chemical in nature. workers. It seems wise to consider these differences The results of the atomic bomb survivors studies when making comparisons between the two cohorts; and the three-country workers study suggest that although the ERR estimates for total leukemia appear kidney cancer is not related to radiation dose; this very close, differences in age at exposure and type information is all compatible if we consider that the of exposure (acute vs. chronic) could still produce kidney cancer in Mallinckrodt workers would appear very different patterns of response over time and to be associated with dose, even if radiation was not across subtypes36. involved, because both radiological and chemical Another difference apparent in Table 6-1 exposures were from the same source (uranium). involves chronic lymphocytic leukemia (CLL). CLL Some of these differences among facilities are is often excluded from lists of radiosensitive cancers washed out when data are pooled, and this is one and studies of associations between radiation of the major drawbacks of combining data. On the and leukemia often use the category “non-CLL other hand, large numbers bring greater statistical leukemia”. This is largely because CLL was not seen power. Wilkinson and Dreyer (1991), for example, in the atomic bomb survivors. After correcting for could demonstrate a significant 2-fold increase misclassification there were only four cases among in leukemia risk when they combined a group of the survivors through 1987 (Richardson et al. 2005). less robust results. Interpreting pooled data, like At the same time, CLL is extremely rare in Asian interpreting facility-specific studies, requires a populations, so a large excess would not be expected certain degree of caution. The rest of this section based on a relative risk assumption. In contrast, discusses occupational study results according to 18% the leukemia deaths in the three-country study cancer type, gender, dose, and age at exposure. were CLL; although the dose-response trend of Leukemia and multiple myeloma. Leukemia these data is not significantly positive, the estimated has been a cancer of particular attention in worker ERR could be as high as 9/Sv. We should also note studies. Wilkinson and Dreyer (1991) reviewed that Wartenberg et al. (2001) found a significant all epidemiological studies of leukemia mortality risk of CLL among African-American workers at among white male workers through January 1989. the Savannah River Site. Richardson et al. (2005) Individually, the studies had little statistical power to reviewed the evidence of radiation and CLL show evidence of risk. The pooled results, however, generally, and based on a mixed body of evidence

35 Uranium is similar to other heavy metals (lead, mercury, cadmium) in this regard (ML Zamora et al. 1998. Chronic ingestion of uranium in drinking water: a study of kidney bioeffects in humans. Toxicol Sci 43:68-77). 36 We might also want to be open-minded about the estimated ERR. The dose-response for leukemia mortality among Sellafield workers was described with an uncertain estimate of 13.9/Sv (90% CI 1.9-70.5; Douglas et al. 1994); this might help define our upper bound sense of leukemia risk. 88 Radiation Workers

Table 6-1. Leukemia in nuclear workers and atomic bomb survivors. Number of cases or deaths (%) and ERR estimate from each study where available1.

Three-country mortality Canadian workers Atomic bomb survivors (Cardis et al. 1995) incidence (Sont et al. 2001) incidence (Preston et al. 1994) Total 146 deaths 98 cases 231 cases 1.6/Sv 5.4/Sv 3.9/Sv ALL 11 (8%) - 32 (14%) -0.9/Sv 10.3/Sv AML 32 (22%) 26 (27%) 103 (45%) 3.4/Sv 5.2/Sv 3.3/Sv CML 28 (19%) 25 (26%) 57 (25%) 11/Sv - 6.2/Sv CLL 27 (18%) - 4 (2%) 0/Sv2 -

1 Although this table is comparing mortality to incidence data, the proportions of subtypes should be relatively similar. There is some overlap between the Canadian cohort and the three-country study. 2 The estimated ERR for CLL was –0.95/Sv (90% CI <0-9.4). concluded that the association cannot be ruled out. Second, the cumulative dose received by workers Multiple myeloma has been significantly was spread out over time, and this might potentially associated with radiation at Hanford, Oak Ridge, affect the risk estimate38. Finally, exposures to Rocketdyne, Sellafield, and in pooled cohorts. The internally deposited radionuclides could cause mortality ERR estimate from the three-country facility-specific increases in certain types of cancer study was 4.2/Sv (90% CI 0.3-14.4), very close to according to where various nuclides concentrate the estimate of the NRPB (4.1/Sv, 90% CI 0.03-14.8; in the body (iodine in thyroid tissue, plutonium in Muirhead et al. 1999). This estimate is almost 4 times bone, etc.); these facility-specific cancer risks would higher than the atomic bomb survivors estimate be washed out to some degree in a pooled study. This (1.15/Sv, 90% CI 0.30-2.7; Preston et al. 2003). In a being the case, it is worth noting that certain cancers separate analysis of workers at four US sites Wing et have appeared to be associated with radiation at al. (2000) found a significant multiple myeloma risk several facilities. Apparent excesses of lung cancer among workers exposed to radiation after age 45, have been detected at Oak Ridge, Rocketdyne, and the estimated ERR for these workers was ~7/Sv Rocky Flats, and LANL, and cancers of the pleura, assuming a 5-year lag time37. the membrane enclosing the lung, have been seen Solid cancer. The estimated ERR for solid cancer in excess in UK workers, particularly Sellafield in the three-country workers study was negative workers. Brain and CNS cancer risk appeared to be and the upper confidence limit was lower than the high among workers at Y-12, LANL, Rocky Flats, estimate from the atomic bomb survivors. There is Fernald and Sellafield. Finally, prostate cancer was probably some explanation for this difference, and linked with radiation at Oak Ridge, Fernald, and in it might include a number of factors. First, there pooled UK data. These associations may or may not were no children among the workers, and children be causal, but they are noteworthy. are often more sensitive to the effects of radiation.

37 The estimate for all ages at exposure was ~1/Sv (not significant). 38 Agencies such as the EPA and the ICRP often assume that low-LET radiation at a lower dose rate is less damaging, although the possibility that low dose rates are more damaging cannot be ruled out. Radiation Workers 89

Female workers. Although it is widely accepted reasons why we are sensitive at the beginning and that the magnitude of radiation-related cancer risks end of life may be different. Children are growing can be different in women than in men, occupational rapidly and cells are dividing at a relatively high studies have less information to contribute to this rate; this can present better opportunities for cancer issue. The international pooled cohort, for example, to start. Older adults, on the other hand, may have was less than 15% female, and female doses were DNA repair mechanisms that are slowly breaking almost ten times lower, on average, than male down. Whatever the biological mechanisms, there doses (Cardis et al. 1995). In that analysis the solid does seem to be some evidence for a sensitivity in cancer risk estimate for women was 0.97/Sv but was later adulthood. Figure 6-6 shows the age effect as it accompanied by a high degree of uncertainty (90% was detected in Oak Ridge workers by Richardson CI <0.9-8.2); this can be compared to the estimate and Wing (1999a). Analyses of Hanford workers of –0.07/Sv for men, and given the wide confidence are consistent with the idea that workers exposed to interval the two estimates are not significantly radiation after age 45 are at higher risk of cancer, and different. The leukemia risk estimate for women that the latency of these cancers is around 25 years. was too uncertain to be useful39. Wilkinson et al. The result is an apparent concentration of risk among (2000), in a report to NIOSH and the CDC, analyzed deaths after age 75 (Kneale and Stewart 1995). mortality data for female workers at 12 nuclear Morgenstern and Ritz (2001) noted that lung cancer weapons facilities in the US and found that external risk among Rocketdyne workers was apparently radiation dose was associated with leukemia, breast higher if exposure occurred after age 50, and Ritz cancer, and all cancers. Although an alternative risk (1999) found similar results in Fernald workers model was used, ERRs were approximately equal to for lung cancer, blood and lymph cancers, and all 13/Sv (leukemia), 5/Sv (breast cancer) and 3/Sv (all cancers. There is also some evidence for late-age cancer)40. sensitivity in other exposure scenarios, for example Age at exposure. An important trend found medical irradiation in association with leukemia risk in many epidemiological studies is the effect that (Darby et al. 1987, Inskip et al. 1993). age has on risk. Because the working population is comprised exclusively of adults, childhood sensitivity is not a factor, but many studies have detected a sensitivity to the effects of radiation as age increases beyond 40 or 50 years. The biological

39 The leukemia ERR was –2.67 (90% CI <0-127) for women, compared to 2.2/Sv (90% CI 0.1-5.8) for men. 40 Based on reported values of the RR/rem. 90 Radiation Workers � es � i ze; � al t � i � i � s � e g � � v s 3 l Sv ern i n . � � / e t n o � i u � 2 6 n d l . � at � i a, act a t s mal � 3 g s � � s h 1 al ed m t n � � mi ce � ro o o o u � e a at t � l p l eri b k � � ) an RR e p t ev d � at o � u �� Rs eu t E � el rk l el een d m � an � � �� o y k ; r m can � � t w e y 2 ed ) s e i � t SM w fi �� e � v d fo 6 i � ri et at i . r s r al � u � h � n an b f 0 t t o eas � el ct rt i g s n � o ce ce 5 s Rs r d � i a n i - � g � w s e r o o i d 6 � M i i mo � al v t . ce � n � can i can ce S o � 0 at a � ’s s o � en i ) S S I mal rad u n ern � (n i d � 6 t ed mi r at � i . C can N N cl d r � k rrel e � 7 � at n n ci g C C ex fo g - k � ev � ce % u co o d n 0 � � d d d ev s . 0 co � R o o eu l u o � � N O as aro (1 In n an E H can L an an L (9 � � � � � � � � � � � � , � a � � al � h � � p � � Sv � ern mSv � mSv t � � (al m � 0 2 � � 1 1 7 � g (ex � � � ~ 1 n d � � e e re mSv mSv � � �� � s s an u rs � mo � 2 5 � o o s � e ) . a 8 � d d o � g e 0 �� ) � rk � f p s n � 4 e o � al al o � o e e u � s ) l l �� l ex � d w o � � al es e � d ern ern ab ab g al s t t � l l � h t n t o � red al o ern � � u ai ai ex ex d t t l o o mSv t t � � n � i av av i ern � 0 e t n t t � � 7 s d o o � 2 � o � � N N Mean mean ~ Mean Mean d (ex mo Mean an � � � � � � � � � - n � 5 1 0 � i 9 � � 7 8 6 � 6 � e � 3 7 8 9 , , , ��� c ma � l � � ers � 1 8 6 9 o � er en ro � n n n rk c t � � rs ral �� d i i i an � 7 t o � n 0 e � � 7 � ci y y y � 8 9 � w �� t t t 6 can en 9 n rk � co � i i i 9 7 � � i � mel - c 8 e 1 � o 1 9 � - al al al e � 9 g f - f a S) � 1 w � �� 3 � 1 rt rt rt d 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s Rs . � o o o i al n ma t rv 3 d d d eal can � d i d co - o M Sv t t t i n t ared fi / � 2 cu S i s o � k . e ’s 8 en K . � n , n 0 e p r n g ) � can can can i 3 g s , , ed � i 9 e ee k fo ~ n fi fi fi ap 8 . s � s i i i at g o 5 1 al Sv a � n n n t h - / d p t e ev g g g u � 9 5 at i o RR RR l . . � � E 0 E Si 1 w Si H Si fem E ag res D (b � � � � � � e e e e s s s s � �� e o o o o mSv � � v � d d d d i �� 7 � ed 1 � � �� at al al al al s e l � � l ~ o � mSv ��� e p ern ern ern ern ab � �� s mu t t t t l 8 � . o ex � ai ��� 7 cu ex ex ex ex d �� � g 4 ers mSv av n � e mSv mSv mSv � rk t 0 s � ��� o o � 3 o 3 3 3 � � N Mean d Mean amo w Mean 2 Mean 2 Mean 2 Mean ~ � �� � � � � � � es es es � 0 e e e 7 � 2 n n n y y y 7 i i i �� � 4 0 s , o o o 9 � � n 1 l l l cal y y y � 5 6 ct i 1 t t t 5 �� - i i i 9 u , 0 5 � y 4 mi 9 d 2 1 t 8 � al al al �� i � e � 4 emp emp emp 9 n n n rt rt rt ro � � 9 i i i al � 1 �� P 1 - �� � Ch rd rd rd rt y y y � 5 r � t t t mo mo mo t � i � i i i fo fo fo 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at ag 3 C l l - � R , mp ) ev r er g 6 � l e y . 5 R y d n � l 1 y 4 at E o w t - � t 0 d l i > ad l � s o < 1 l ( l e ( al � b an ro h ral o t rt er p t d av d e i � d Sv , h o v l / � y w g an t o mo o 9 � O i . n e e . v � d 0 c u Bl s i er l � t cers – . c o i ag an � en e e l s d � s d ) h � r ag t can o �� 5 can l en ci � f d s 2 � ea r 4 n e een �� � o i e < y y h � ( - - at s t w ced r � ed �� t i 0 0 o u s et � � 2 1 er d ce w d � b cers g n a a h � reas i an n t n Pro ed � c i c h h u e o . � t t can n i ) at r i i o w h i � k k r t 5 y at � ci s s w w e fo 4 � fo . o ed ri ri ci at � e e at s 4 av R o � h c c f f at h - t � s h t o o as R Rs 3 � ci t en en d E 0 � as y o . . � d d M l ce ce t t s es � t 0 an S ci ci g ey may n , � as en en n n g n � i i re can can d d ca s ed u � d i i Sv u r r rs i fi fi s / ers d � fi s i i at k i � 0 o ev ev a o ce ce ce n n � rk n 8 � d p ev g g . o o o at g � l eri � i � N E an D w ex p Si can can Si (1 s can N � � � � � � � � � 6 � � . 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re u b w i r � y ren 1 � 5 u u rs u l . s t L l � �� � � et mi g 3 m o ce . r d e ce ag t � e � b � ) 1 u MR MR s h � i � Fi - k 6 an s fo � S S n an 1 an � p n re 0 ears 4 c 1 n e . c o � . � o eu o u d y e o l � t p 5 s ed ed i Sv h � o (1 � - es u en / � 5 f (s o me � l o at at at 1 i e 5 2 o � 4 l p res e t e p . - 3 � - � mp ~ b ci . s w h d ev ev 5 � 5 e t � h y ex � o o 1 f � t l s ag 1 et ) R s f el el i / � , d r l o � 0 o b r � ren o d R 8 � es w 1 y y t d as g k � fo s l l o ar 8 � E men 2 fo s t t t t t n . � n o - e � � rat l u R ri � o y � l (2 i � ees cers b m ed - a ed an � can can can can can � y u c 0 y n at ed � SR al i r, rs i o fi fi fi fi fi 2 � o l � l i i i i i n � ci l can at mat � e; ce ce n n n n n o i h � o ern s l t t d � g g g g s g t � meri ev i mp s o o � n � � Si can Si can emp i Si A Caro Si d as p Si an E el E w � � � � � � � � � � e e � s s � rs � o o � e g � d d � � n al � rk �� � o Sv al al e e e e rn � �� l l l l � mo � e w � m � �� t a � � ern ern ab ab ab ab � � 0 t t l l l l �� � ex � 1 � red � Sv Sv � ai ai ai ai f ex ex ��� < o � �� � o t m m i av av av av � � es n � 7 3 � ��� t t t t % s . . � o o o o � 0 o 9 7 � 7 d N N Mean 2 mo N N Mean 1 � � � ��� � � � � � � � � l � �� 9 � � ers � d 7 � ro at � t � 9 � rk 7 � n n � n an � 1 i i o 2 2 8 � - � e 2 0 7 1 ers � y w y � co 2 , �� c t t 7 4 3 - � � RS 5 i i , 5 , � s rk e 9 � 9 � S 4 1 8 en � �� � o al al 1 at 1 as - d � � n n n n � rt rt w c � i i i i 4 Fl � �� 4 �� 9 0 � ci r 4 g � 8 � 8 9 y y y y n ers � y � t t 9 t t mo mo n i �� 9 9 9 i i i i i � � ce � 1 � r r r rk 1 1 1 s � ck � � - al al al al - - � o � � an 3 ce ce ce 1 3 es rt rt rt rt � � �� c w � ers Ro 4 c 5 4 9 � � � � � 9 9 s g 9 � 8 3 � rk ro � can can mo mo mo can mo 1 1 n 1 � 9 0 at o �� � � p f f f f f f f u � � 1 3 e l , - w o t o o o o o o �� Fl � � �� i m ers 6 ers 2 t � d s y y y y y y y � y � u 1 5 �� i d d d d d d d rk � rk � d ��� 9 an an 9 n � � u u u u u u u o ck o i 1 t t t t t t t � 8 � al y � Pl s s s s s s s ran w w t � s 9 �� i i u � Ro � rn d 1 s rt rt rt rt rt rt rt L ers L � � - n al � 4 3 o o y o o o o o 2 Fe N u � N rt 1 1 rk h h h h h h h � � ���� 5 al e 0 4 R o � A , 9 , � � � h � � Co 4 t Co mo an 1 Co w Co Mo Co L Co 5 Co O � � �� � � � � � � � � . �� � � � al al � � et � � . . � � et � et . � � � al al �� n d � � � al erg 9 � � o er b � 9 � et et �� s 1 an � b et � 9 n 0 s s � a b en � i � � 1 � � en �� 0 g g g � 3 1 1 4 7 1 � k t � � � z 2 g g l n �� t 0 9 9 9 8 9 art t i i i i � � � � . 0 9 9 9 9 9 � � �� Ri Ru 2 W al W 1 1 W 1 W 1 W 1 � � Radiation Workers 95 , g es , ) ed L – n 9 0 d . L u . at f d d l 3 i al o mat C cer l ci (8 an t , l e e i - an s t o o . 0 ’s h n al . at e ), s s t k en ern m e t n o RR es t a can l ; a) s h ; i s f u ( t (3 at as n i p 0 l 0 k ri ) l o t i ma) f R ex ; 2 ro t e 3 g 4 al . e o . l o g ri r 7 emi emi p R d 1 rs . t 1 cer v r 0 n u - k k el r i - MR o E 5 - Sv s t o o 2 - ce 2 mu fo i 0 t S l an t . re ers H o fo eu eu m 1 s 1 c ; 3 l u l c 2 . my . p . r h an e s 4 t re ; 0 ; 0 I 0 e . 0 c e i s can Po o cer u ra RR 6 1 4 l fo - ex I n – 4 C . n . can s p fi w h p > I E s ). 1 i t 3 o 3 C i fe o eu - i m t . d i r d eri n l 1 p 1 C can ex % CI p l rs 1 l t 3 u - - �� g w p . i % 0 u i fo d an 0 n 4 n er 0 ce i ex cers n % . 0 s % ren res i d �� 4 o mu c (9 d t - o . I 0 n r ed 0 t ro e ; (9 (0 e an 0 �� o o e an C s u an y at c 6 (9 can (9 ma, s at rad Sv ) can � N o h l g MRs 4 ) / n o ci c t Pl Sv Sv 3 - CI % . h d n i er 1 S . 1 / / d o o t . . 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MAYAK WORKERS for a long time resulting in chronic exposure to alpha particles; the mean alpha lung dose in this cohort 7.1 Introduction was 0.2 Gy. Exposure profiles varied by facility as shown in Table 1. The cohort of Mayak workers is distinctly different from other worker cohorts in that the average 7.2 Health effects exposures of these workers were much higher and women made up a greater fraction of the workforce. Two approaches to this cohort have been pursued For this reason we have devoted a separate section to by different teams of scientists from Chelyabinsk this cohort. Mayak has also made a profound impact and their colleagues- case-control studies of lung on the communities along the Techa River; this is cancer (Tokarskaya et al. 1995, 1997, 2002) and discussed in Section 12. cohort studies of total mortality and various causes Mayak (the Mayak Production Association), in of death. These studies have been reviewed by the the southern Urals region of Chelyabinsk, was the United Nations Scientific Committee on the Effects first nuclear complex in the Soviet Union. The plant of Atomic Radiation (UNSCEAR 1994, 2000), by included a nuclear reactor, a plutonium production the Radiological Assessments Corporation for an facility, and a radiochemical fuel separation facility. analysis of plutonium risks around Rocky Flats Radiation exposures during the first few years of Plant (RAC 2000), and recently by Harrison and operation were quite high, with average annual Muirhead for a comparison of risks from external external doses of roughly 0.5 Gy. Exposures declined and internal radiation (2003). A comprehensive following a 20-fold reduction in the maximum daily cohort study of mortality in all 21,557 Mayak permissible dose in 1952 (Koshurnikova et al. 1999), workers was presented in 2003 (Shilnikova et al.). but were still relatively high- the mean lifetime The most apparent health effects in Mayak workers dose received by Mayak workers averaged 0.8 Gy, have been the cancers associated with plutonium- roughly an order of magnitude higher than mean lung, liver, and bone cancer and leukemia. lifetime doses in most worker cohorts (see Section Lung cancer. Tokarskaya et al. (1995) found 6). In addition to external radiation these workers that lung cancer was associated with plutonium were exposed to plutonium. Inhaled plutonium exposures, gamma exposures, and smoking. No is deposited most heavily in the lungs, and of the dose-response analysis was performed for gamma plutonium that migrates to the rest of the body about exposures but the plutonium dose-response curve 50% is deposited in the skeleton (Koshurnikova et that they generated was nonlinear with a threshold al. 2000). Deposited plutonium remains in the body at 0.8 Gy1. In 2002 Tokarskaya et al. used an

1 Issues with this dose-response analysis were raised by Jan Beyea (1998); he noted that case-control studies are not able to distinguish between non-linear dose-response relationships and differences in exposure distributions between cases and controls. 97 98 Mayak Workers Table 1. Dose (Gy) received by Mayak workers at each of the three main facilities and auxiliary plants (from Shilnikova et al. 2003) Plutonium Nuclear production Radiochemical Auxiliary Total (all reactor facility plant plants facilities) N 4,396 7,892 6,545 2,724 21,557 % female 22% 25% 27% 19% 24% Mean external dose 0.66 0.44 1.21 0.17 0.81 Mean lung dose (alpha) 0.01 0.32 0.06 0 0.18 alternative odds ratio calculation to assess the 2000 report it was concluded that the Mayak cohort combined effects of smoking, plutonium exposure, showed no dose-reponse for gamma radiation and and gamma exposure on lung cancer risk. They lung cancer. In Kreisheimer et al. (2000), however, a suggested that the combined effects of smoking dose-response relationship was reported, although it and radiation exposure can be multiplicative had a wide confidence interval. The ERR for gamma and that the combined effects of gamma and exposures was estimated to be 0.20/Sv at age 60 (– alpha radiation can be supramultiplicative, 0.04, 0.69); without adjusting for age the ERR was meaning that the combined effect is greater than 0.27/Sv. the two individual effects multiplied together. All of these cohort studies of lung cancer were The reports of the cohort studies conducted consistent with a linear, no-threshold dose-response by Koshurnikova, Kreisheimer, Khokhryakov model. The lowest dose range showing significant and others present a range of risk estimates for excess lung cancer mortality risk was 0-0.08 incorporated plutonium lung doses (alpha radiation) Gy of absorbed alpha radiation dose to the lung and lung cancer mortality. Stated in terms of excess (Kreisheimer et al. 2000). relative risk, three papers report estimates of 0.3/Sv Bone cancer and liver cancer. A pair of papers (Koshurnikova et al. 1998), 0.6/Sv (Kreisheimer et published in 2000 analyzed bone and liver cancers al. 2000), and 0.8/Sv (Khokhryakov et al. 1998). among the same Mayak cohort, this time followed This range is slightly higher than the corresponding from the beginning of employment (1948-1958) estimate from the male atomic bomb survivors of through 1996. The bone cancer analysis included 0.34/Sv (Thompson et al. 1994). Differences among 27 deaths3 of which only 7 had plutonium exposure analyses can be partly explained by different risk information, yet a significant mortality trend with models and model fitting procedures2 and may also plutonium dose was observed (p<0.001). The be partly explained by the gender composition of the association with external gamma dose was marginally study populations- Koshurnikova et al. (1998) and significant (p = 0.11) but the dose-response results Kreisheimer et al. (2000) included only men while were not reported. 33 out of 60 deaths in the liver Khokhryakov et al. (1998) also included women. cancer study had plutonium exposure information, At the time of publication of the UNSCEAR and again a significant trend with plutonium body

2 For example, Khokhriakov and Romanov estimated an ERR of 1.9/Sv in 1996 using a ‘least-squares’ model fitting procedure and estimated an ERR of 0.8/Sv in 1998 using a ‘maximum likelihood’ model fitting procedure. 3 24/27 deaths were directly attributable to bone cancer and three had bone cancer listed on the death certificate. 56/60 deaths in the liver cancer study were directly attributable to liver cancer. Mayak Workers 99 burden was observed (p<0.001). The external quadratic, and quadratic curves and they chose to gamma dose-response was marginally significant report results for the linear model (at lower doses the here, as well (p = 0.05), but again the results were differences between these models would be small). not reported. What we can generally conclude is that The authors observed a strong effect of the time workers at these facilities experienced elevated bone between exposure and disease onset consistent with and liver cancer risk from both alpha and gamma the commonly observed short latency of leukemia. exposures. They therefore presented risk estimates for discrete Shilnikova et al. (2003), in the most recent and time windows; the ERR for the period 3-5 years comprehensive study of Mayak workers, presented after exposure was 6.9/Gy (2.9, 15) while the ERR one external radiation risk estimate4 for bone, lung, for the period more than five years after exposure and liver cancers as a group. They determined that was 0.45/Gy (0.1, 1.1). For the entire post-exposure the most appropriate dose-response curve for this period the ERR was 1/Gy (0.5, 2). response was linear-quadratic and concave down, Non-cancer disease. Another analysis of this meaning in this case that the ERR is highest at a dose cohort examined cardiovascular mortality. The of 4-5 Gy. The dose-response relationship at low cohort had a lower rate of cardiovascular mortality doses is approximately linear and can be estimated than the general public and mortality did not depend by the linear term in the dose-response relationship. on external gamma dose (Bolotnikova et al. 1994). For all solid cancers the ERR estimated in this way was 0.30/Gy (90% CI 0.18, 0.43)5. The ERR for 7.3 Summary lung, liver and bone cancers was 0.54/Gy (90% CI 0.27, 0.89). There was no evidence of a difference in These studies have shown significant excess mortality the risk estimate between genders. from liver, lung, and bone cancer and from leukemia Leukemia and related cancers. Study results among Mayak workers, and both gamma and alpha for leukemia were reported in two papers. In the (plutonium) exposures have been implicated by first analysis (Koshurnikova et al. 1994), rates of dose-response relationships that were statistically blood and lymph cancers (including leukemia) significant or marginally significant. Although good among exposed workers were compared to USSR low-dose (<0.1 Sv) data are not available from these rates. Male workers hired after 1954 to work in the studies, most of the evidence is in agreement with radiochemical facility showed an ERR for blood a linear no-threshold dose-response model. The and lymph cancers of 1.45/Gy. The excess mortality range of results obtained using various analytical observed in this cohort was largely comprised approaches to different subsets of the Mayak cohort of a rise in acute leukemia 3-11 years after the demonstrates the uncertainties involved in the choice beginning of workplace exposures. Koshurnikova of statistical method. The strongest results are from et al. (1996) analyzed SMRs for workers from all the analysis of the entire cohort by Shilnikova et three Mayak facilities with the control group being al. (2003) because of the large number of cases Mayak workers who never received doses above the and the also because of the fact that they accounted allowable level. This analysis provided evidence for plutonium doses when estimating the effect of that leukemia mortality risks were elevated for men external gamma exposures. Their estimated ERR and women, but particularly for men employed in for lung, liver, and bone cancers of 0.54/Gy can be the radiochemical facility (SMR 3.2, 1.5-6.9). The compared to estimates of 0.2-1.9/Sv for lung cancer ERR for this subgroup, for the period 1948-1992, obtained in various studies that assessed exposure in was estimated to be 1.25/Gy. combined alpha and gamma exposures or uncorrected Shilnikova et al. (2003) determined that the exposures from alpha particles or gamma rays. dose-response relationship for external radiation and Their estimated ERR for leukemia of 1/Gy can be leukemia was equally consistent with linear, linear- compared to 1.25/Gy and 1.45/Gy obtained for male

4 The ERR estimates presented by the authors were calculated controlling for internal exposures and using doses with a 5-year time lag. 5 Compared to the atomic bomb survivors estimate of 0.47/Sv (Table 4-1; Preston et al. 2003) 100 Mayak Workers workers at the radiochemical facility using gamma doses and no apparent correction for plutonium exposures (Koshurnikova et al. 1994, 1996). It is important to make note of some of the details that Shilnikova et al. (2003) present. Although the risk of lung, liver and bone cancers was higher than the risk of other cancers, the risk of other cancers was also significant, with an ERR of 0.21/Gy (90% CI 0.06-0.37). For all solid cancers it appeared that risk decreased with age at hire; those workers that were hired when they were relatively young showed a higher radiation-induced cancer risk. This is generally consistent with the experience of the atomic bomb survivors but at odds with some of the results from other occupational cohorts that suggest risks might increase with exposure age after age 50. Finally, radiation-induced leukemia in this cohort appears to have developed quickly, with an ERR of ~7/Gy in the 3-5 years after exposure. This result is consistent with the atomic bomb survivor studies and other studies of leukemia. Mayak Workers 101 � �� �� � � � � � � � � � �� �� � � �� � � ��� � � � � � � � � � � � � � ��� � � � �� � � �� � � � �� � � ��� �� ��� � � � � � � � �� ��� � � �� � � ��� � � �� �� � � � � � ���� � �� � �� � ���� � � �� � � � � � � � � ��� �� � �� �� �� � � � � �� � �� � � �� � � � ��� � � � � � � �� � � � � � � � � � � � ��� � � � �� � �� ���� � � � ��� � �� � �� � � � � � � � � � � �� � � ��� � � � � �� � � � � � � �� � � � � �� � � ��� � � �� � � � � �� � � � � � � � � � �� �� �� � ��� � ��� � � � ��� � ��� � � � � ���� �� � �� � �� � � � � � � � � � � � �� � � � �� � � � � � � �� ��� � � ��� � � �� �� � �� � �� � � � � � � � � � � �� � � � �� � � � � �� � � � � � � � � � �� � �� � � � � � � � � �� � �� � � � � � � � � � � � � � � � � � � �� � � �� � � � �� � � ����� � �� � � � �� �� � ��� � � � � � � � �� � � � � � � � �� � � �� � �� � � � � �� � �� � �� � � � � � � � ��� � � � � �� �� � � � ��� � �� � � � � � �� � � � � � �� � � � � � �� � � � � � � � � � �� �� �� ��� � ��� � � ��� ��� � � �� � � � �� � �� � �� �� �� � � � � �� � � �� �� �� � � ��� � �� � � � � � � � � � �� � �� � � � � � � � � � � ���� ��� � � � � �� � � � � � � �� � � � ��� � � � � � � � � �� ��� � �� �� � �� � � �� � � � �� � �� � � � � �� � � � � �� ��� � � � ��� � �� � �� � � � � � �� � � � � ��� � �� � � �� �� � �� � �� �� � � � � � �� � � �� � �� ��� � � � �� �� � � � � ��� � � ��� �� � � ��� �� � � � � �� � � � � � � ��� � � � � �� � � �� � �� �� � � �� ���� �� � � ��� � � � � �� � ��� ��� � � ��� � �� � � � � �� �� � �� � � � � � ��� �� �� ����� � � � � � � � � �� � �� � � � � �� � � �� ��� �� �� �� � � �� � �� �� ��� �� ��� � ��� � � � � � � � � � � � �� � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � ��� � � �� �� � � �� � � � � � � � � � � � � � � � � �� � � � � � � � �� �� � � � � � � � � � � � � � � � � � � � �� � � � � � �� � � � �� �� �� ��� ��� ��� � � � �� � � ��� � � �� � �� �� � � � � �� � ��� � �� � � �� � � � � � �� �� �� � � � � � � �� � � �� �� �� �� � � � � � �� �� �� � � � � � � � �� �� �� � �� �� � � � � � � � �� � � � � � � �� �� � � � ��� ��� � � � �� � � � � � � ��� � � � � � � � � � ��� ��� � � � ��� � �� ��� ��� � � � � � � � � � � � � � � � �� �� �� � � � � � � � � � � � �� �� � � �� �� � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� �� � � � � � � � � � � �� �� � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � �� �� �� � � � � � � � � � �� � � ��� � � � � � � � � � � � � � � � � � � �� �� � � � � �� �� � � �� � � � � � � � � � � �� �� � � � ��� � � � � � � � �� � � � �� � � � � � ��� ��� � � � � �� �� � � �� �� � � � � � � � � � ��� � � � � � � �� �� � � � � � �� �� �� � � � ��� � � � � � � � � � ��� ��� �� �� � � � � � � � � �� � � � � ��� �� � � � � � � � � � � � � �� �� � �� �� � �� � �� � � � � � �� �� � � � � � �� �� ��� � � � �� �� �� � � � � � � �� �� �� � � � � � � � � � �� � � � � � ��� ��� ��� ��� ��� ��� ��� � ��� �� � �� ��� ��� �� ��� ��� � � �� � � � � ��� � � � �� � �� �� � � � � �� � � � � � � � � � �� � � � � � � � � � � �� �� � � � � � � �� � � � � � � � � � �� �� � � � � � � � � � � � �� � � � � � � � � ��� ��� � � � � � � �� � � � � �� �� � � � � � � � � �� � �� � �� �� �� � �� � �� � 102 Mayak Workers � s � � , � � � �� a � e � � � � � t � r �� � � � � w � � a e d � � � � � � � l �� � � h � �� � � � � � � �� m R � o � � � � i g � � � � �� � � � i t �� � r �� R � � � � � � � � s � h � � y � �� � ��� � � � � e e � �� � - 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URANIUM MINERS involves crushing the ore to pebbles and sand, separating uranium from this sand, usually by 8.1 Introduction leaching (a process where acid is added to take out the uranium), and then taking out the non-uranium Uranium mining has a long history going back at least waste products from the mixture. The milling process to the mining of ore in Europe in the 1400s (Caufield isolates the compound uranium oxide (U3O8). A 1989). The United States started mining uranium third stage in making the uranium useful is done in when the Atomic Energy Act in 1946 guaranteed enrichment facilities. The final enriched uranium a price for uranium mined in the US (Brugge and product is used for nuclear power and nuclear Goble 2002). Mining in the US subsided after 1971 weapons2. In some cases the milling of uranium ore when government purchase of uranium decreased, is done where the mining occurred, but sometimes but commercial demand still drives mining in it is conducted at separate milling facilities or at the many countries1. The association between uranium mining and adverse health effects is well known, and associations between the mine environment and lung disease predate the classification of lung cancer in the late 19th century (Eisenbud 1987). This connection is evidenced in many of the epidemiological studies of miners worldwide and is also reflected in compensation legislation like the Radiation Exposure Compensation Act (RECA) of the US. Uranium mining and milling are two separate processes (Figure 8-1). Uranium mining is simply the removal of uranium ore from the ground. This has typically meant physical removal in underground mines or open pit mines, although newer techniques Figure 8-1. The process of uranium mining and milling from involve leaching. The milling of the ore is a more ore to its reactor useable form is depicted here (web.ead. involved process that isolates the uranium. This anl.gov/uranium/guide/uf6/index.cfm).

1 Countries still actively mining uranium include but are not limited to: US, Canada, Australia, Ukraine, Bulgaria, Portugal, Romania, Russia, China, India, Kazakhstan, Mongolia, Pakistan, Uzbekistan, Namibia, South Africa, Niger and Brazil (http://www.antenna.nl/wise/uranium/#UMMSTAT). 2 The depleted uranium byproduct is of course also used for various applications including munitions. The health effects of depleted uranium are the subject of intense scrutiny, and most evidence indicates that the chemical properties of uranium are responsible for the observed effects. One source for more information on this topic from an activist perspective is the Depleted Uranium Education Project: http://www.iacenter.org/depleted/du.htm. 103 104 Uranium Miners enrichment facilities. The exposures of millers have of WLM to sieverts is not straightforward because it not been studied as intensively as the exposures depends on breathing rate and the size of the radon of miners or radiation workers generally. Some of daughter aerosols. UNSCEAR (2000) suggests that the papers that we discuss in this section include the average value is roughly 5.7 mSv per WLM3. the exposures of millers, and some of the papers in Although there has been an awareness of the section 6 discuss exposure at uranium processing hazards of mining for over a centrury, it was not and enrichment facilities. The bulk of this section, until 1959 that the US passed a radon safety standard however, is focused on the exposures of miners. for workers’ health at 1 WL (or 12 WLM per year). The mine environment is dangerous is many This standard was adjusted in 1971 to an annual ways, and lung cancer risk factors include silica, allowable exposure of 4 WLM (Caufield 1989). arsenic, chromium, and nickel. Exposure to radiation Still, by 1971 many miners in the US and elsewhere in mining typically occurs through inhalation of had already been exposed to much greater amounts air and dust containing radon (Rn-222); the term of radiation than standards allowed, and the earlier “radon” is usually used in reference to an air epidemiological reports easily showed correlations mixture of alpha-emitters including radon and its between exposure to radiation in uranium mining radioactive decay products, or daughters. Radon activities and adverse health effects. daughters can be retained in the lungs for long periods, so exposure continues long after the initial 8.2 US studies inhalation. It should be noted that although Rn-222 is a decay product of uranium, exposure to radon Early US studies looked at large groups of uranium is not at all limited to uranium mining--miners of miners from various mines in the western part of other ores and residents of many homes are exposed the country (see Figure 8-2). Wagoner et al. (1964) to the naturally occurring decay products of both showed a significant excess of lung cancer mortality uranium and thorium. The exposures of uranium among uranium miners and millers (15 observed miners are thus comparable to exposures in some vs. 6.9 expected, p<0.01), and this was particularly other mines and to residential radon exposures, concentrated among white miners with five or although residential exposures are usually lower in more years of employment in underground mines magnitude. Comparisons with residential exposures (11 observed deaths vs. 1.1 expected, p<0.01). are discussed at the end of this section, but based Deaths from any cancer were also significantly on the availability of exposure information and the elevated, although most of these deaths were due relatively high exposures, epidemiological data on to lung cancer4. Archer et al. (1973) updated this miners provides some of the best information that observation and reported 70 observed lung cancer we have about alpha radiation exposure, especially deaths among white underground miners vs. 11.7 lung exposure due to inhalation. expected (p<0.01)5. These authors also noted that Studies of miners and other radon-exposed the ratio of observed to expected deaths increased cohorts are hard to compare to the rest of the with exposure in WLM. A much more recent case- radiation epidemiology field because exposure is control study that also looked at a large group of not measured in conventional units. Exposure to western US miners found a linear relationship radiation in mines is measured in “working levels” between RR and the number of WLM up to about which correspond to 200 pCi (picocuries) of radon 750 WLM (Gilliland et al. 2000b). The relative lung daughters per liter of air. Exposure to the equivalent cancer risk for miners with 1,450 WLM exposure of one working level for one month of work is called versus those with less than 80 WLM was 29.2 (5.1- one Working Level Month (WLM). The conversion 167.2). An inverse dose-rate effect was observed

3 Based on a reported conversion factors of 9 nSv per Bq h m-3, 0.27e-03 WL per Bq m-3, and 170 hr per WM. 4 Among miners generally there were 36 observed deaths vs. 31.4 expected (ns), and among miners with five or more years underground there were 17 observed deaths vs. 4.8 expected (p<0.05). 5 These miners were a generally unfortunate cohort, suffering significantly elevated mortality from tuberculosis and violence in addition to lung cancer. Uranium Miners 105

Figure 8-2. Uranium mines in the US are predominantly located in the southwest and central parts of the country (www. eia.doe.gov/.../page/reserves/uresarea.html). in this study, suggesting that a radon dose received ERR estimate of 0.0082/WLM was reported based slowly is potentially more damaging than a radon on a model that included a smoking term and used dose received quickly. adjusted doses. Hornung et al. analyzed the cohort The Colorado Plateau cohort was assembled periodically (1987, 1998; reviewed in Hornung by the US Public Health Service in the early years 2001) and have consistently shown an inverse dose- of US mining (1950) and consists of 4,126 miners rate effect and have also shown that the interaction with at least one month of underground experience between smoking and radon appears to be more in the mines of the Colorado Plateau (including the than additive but less than multiplicative7. Hornung “four corners” states of Colorado, New Mexico, (2001) gave an estimated ERR of 0.011/WLM below Arizona and Utah). Roscoe (1997) found elevated age 60 with lower risk estimates for older ages. Park SMRs for several diseases in this cohort6. For lung et al. (2002) presented an alternative risk description cancer and pneumoconiosis standardized rate ratios for the Colorado Plateau cohort and calculated lost increased with increasing exposure or duration of life expectancy attributable to mine work. These employment. Stram et al. (1999) assessed the risk authors considered death from leukemia and non- patterns in this cohort with adjustments for various cancer respiratory diseases to be attributable to the cancer factors and additional adjustment for dose mine environment in addition to lung cancer8; they measurement error. These authors found that risks estimated that each year of work in an underground declined with exposure age (after age 54) and were mine was associated with 8-9 months of lost life higher within the 10 or 20 years after exposure. An expectancy.

6 SMRs for the following diseases were significantly elevated: pneumoconiosis (24.1, 16.0-33.7), lung cancer (5.8, 5.2-6.4), tuberculosis (3.7, 1.9-6.2), chronic obstructive respiratory diseases (2.8, 1.0-3.5), emphysema (2.5, 1.9- 3.2), benign and unspecified tumors (2.4, 1.0-4.6), and diseases of the blood and blood forming organs (2.4, 1.0- 5.0). 7 The combined risk from smoking and radon was greater than (smoking risk + radon risk) but less than (smoking risk x radon risk). 8 Significantly elevated SMRs were observed for leukemia (1.8, 1.1-2.9), tuberculosis (4.5, 2.6-7.3) and diseases of the respiratory system (2.9, 2.6-3.3) based on US rates. 106 Uranium Miners

Samet et al. (1991) evaluated risks for a small-cell tumors in the central area than in the cohort of 2,469 New Mexico miners that partially middle and peripheral regions. Non-miners’ smoke overlapped with the Colorado Plateau cohort. Miners and other small carcinogens are deposited deeper or in New Mexico were typically exposed to lower more peripherally judging from the localization of levels of radiation than those employed in Colorado their tumors. due to the fact that their exposure began almost a decade later then the Colorado miners and so there 8.3 Studies of miners in other countries was greater awareness of radiation risk. The ERR estimate for this group was 0.018/WLM (0.007- Australia. The Radium Hill uranium mine 0.054), although the estimate for younger workers in South Australia operated from 1952 to 1961 (<55 years) was much higher (0.102/WLM, 0.002- (Woodward et al. 1991). Total exposures received 6.58). The lung cancer risks of smoking and radon by these miners were relatively low with a mean of 7 exposures appeared multiplicative in this study. WLM. Lung cancer risk was significantly associated Navajo miners. Western uranium mining areas with exposure and an ERR of 0.005/WLM was tended to be on or near Navajo lands and many apparently derived10. Navajo men worked in the mines. Unlike white Canada. Howe et al. (1986) focused on the miners, Navajo miners tended to nonsmokers or Beaverlodge uranium mine in Saskatchewan, light smokers, and most lung cancer cases among the Canada. This mine opened in 1949, commenced full Navajo can be attributed to working in the mines9. production in 1953, and closed in 1982; most of the Because of this dramatic impact on the community, men ever employed at the mine were included in Navajo risks have been assessed independently. this analysis (8,487 workers). The estimated ERR Roscoe et al. (1995) assessed the risks in the Navajo for lung cancer in this cohort was 0.035/WLM miners from the Colorado Plateau cohort. The (0.027-0.043). The study also found that age at SMRs for lung cancer and noncancer respiratory first exposure had a significant effect on risk where diseases were significantly elevated based on state individuals first exposed before age 30 had a lower non-white rates, and an ERR of 0.02/WLM was risk then those first exposed at age 30 or over. Howe estimated. Gilliland et al. (2000a) conducted a case- et al. (1987) assessed the lung cancer risk in workers control study of lung cancer in Navajo miners. This at a different mine in the Northwest Territories, Port study showed that two-thirds of the lung cancer Radium. This mine began operations in 1930 and cases diagnosed in Navajos between 1969 and 1993 closed in 1960 and exposures were much greater were in former uranium miners and a relative risk than in the Beaverlodge mine (mean cumulative of 28.6 (13.2-61.7) was calculated for underground dose 243 WLM vs. ~10 WLM). The ERR estimate mine workers compared to non-miners. Brugge and for the Port Radium mine was much lower (0.003/ Goble (2002) describe in more detail the story of Sv, 0.001-0.004), but the authors suggested that this Navajo uranium miners. might be attributable to an inverse dose-rate effect; Pathological observations. Saccomanno et al. Beaverlodge workers were exposed to 5 WLM per (1996) looked specifically at lung tumor localization year while Port Radium workers were exposed to patterns of lung tumors in miners and non-miners. 109 WLM per year. The miners included in the study were all smokers Kusiak et al. (1993) studied a large cohort of but it was shown that location of the tumors in the 21,346 Ontario uranium miners. Risk in this cohort miners and non-miners differed. In miners, inhaled was found to be the greatest 5-14 years after exposure dust, radon and cigarette smoke combine to form and also greater for men exposed under the age of large particulates that deposit in the central bronchial 55. Although an ERR of 0.012/WLM was estimated tree. It was found that there were ten times as many for a simple linear model, the authors’ preferred

9 Brugge and Goble (2002) discuss in more detail the story of the Navajo uranium miners including the huge health burden and the struggle for compensation that contributed to the passage of the Radiation Exposure Compensation Act. 10 This estimate was cited by Xiang-Zhen et al. (1993). Uranium Miners 107

Herault, and the Massif Central. Exposures in the first ten years of mining were relatively high (~5-50 WLM/yr) and in 1956 radiation protection protocols were implemented throughout the industry resulting in lower exposures thereafter (~1-4 WLM/yr)11. Tirmarche et al. (1992) conducted a cohort study of French uranium miners who worked for at least 2 years in underground mines between 1946 and 1972. Rogel et al. (2002) expanded the cohort and derived an overall ERR of 0.008/WLM. An inverse dose-rate effect was found, and the estimated ERR Figure 8-3. Many uranium mines were located on Native was much higher for exposure after 1956, when the American reservations. Navajo miners are pictured here dose rate was reduced (ERR 0.024/WLM). (www.ancestral.com/.../ _north_america/navajo.html). Germany. Underground uranium mining was a major industry in East Germany in the years after model included several additional terms to account World War II as East Germany, through the former for the effects of age, time, and arsenic exposure. Wismut Company, was the main supplier of uranium Morrison et al. (1998) assessed the lung cancer for the Soviet Union. According to Enderle and risk in Newfoundland miners of fluorspar, a mineral Friedrich (1995), working conditions were initially composed of calcium and fluorine. Risks appeared very poor although compliance with international to be higher at younger exposure ages and again an radiation protection standards was attained by 1970. inverse dose-rate effect was noted. The estimated Uranium production generally stopped in the region ERR was 0.0076/WLM for exposure durations over in 1990. Although the Wismut Company workers 20 years. represent the largest epidemiologic cohort study China. Xiang-Zhen et al. (1993) examined a of miners in the world with over 60,000 subjects, cohort of 17,143 underground tin miners in Yunnan risk estimates have not yet been published (Kreuzer Province, Southern China. At the time of the study it et al. 1999). A preliminary analysis of a subcohort was the largest study of radon-exposed underground (Bruske-Hohlfeld et al. 1997) indicated that risks miners. Lung cancer mortality risk was related to were compatible with the joint analysis of 11 miner exposure, although the slope of the dose-response cohorts discussed below. relationship was shallower after adjustment for Sweden. Radford and Renard (1984) studied arsenic exposure (ERR 0.0016/WLM, 0.001-0.002). iron miners from the Luossovaara-Kiirunavaara Risk also declined with attained age, with years Aktiebolaget mine in Arctic Sweden. Among 1,415 since exposure, and with increasing exposure rate. miners there were 50 lung cancer deaths through Czechoslovakia. A report by Sevc et al. (1976) 1976 where 13 were expected based on national documented a significant association between radon rates. The ERR was estimated to be 0.036/WLM exposure and lung cancer in Czech miners. Tomasek (90% CI 0.025-0.048). and Placek (1999) updated this assessment with a cohort of 2,552 miners who had worked underground 8.4 Combined estimates of risk between 1952 and 1959. The overall ERR estimate in this cohort was 0.023/WLM (0.009-0.038); risk The National Institute for Occupational Safety and was apparently higher at younger exposure ages and Health (NIOSH) reviewed epidemiological studies decreased with time since exposure. of uranium miners in 1985. All studies showed France. Uranium mining in France began in associations with lung cancer, and five primary 1946 and has been carried out at mines in Vendee, studies with exceptionally good background data

11 Based on interquartile ranges depicted in Tirmarche et al. (1992). 108 Uranium Miners were selected12. Two studies indicated that excess The effects of time and age have been consistently lung cancer was associated with exposures as low apparent in these studies as well. The final BEIR VI as 40-90 and 80 WLM (in Ontario and Sweden, report (NRC 1999) chose not to emphasize a single respectively). The concluding estimates of ERR risk coefficient and instead presented two alternative were 0.009/WLM to 0.014/WLM depending on models where risk estimates could be generated exposure rate. according to the characteristics of a hypothetical The National Institute of Health (NIH) exposure scenario. Although this is inconvenient in combined data from eleven studies, including most some ways, making it much harder for a lay reader of the studies described above, for a total cohort of to understand what the risks of radon might be, for 68,000 miners (Lubin et al. 1994). The inverse dose- example, it is in many ways a more honest approach rate effect noted in many of the studies above was to the complexities of the interaction between evident in the combined cohort. Risk was also found radiation and the human body. to depend significantly on attained age and time Comparisons with residential radon studies. since exposure. A summary estimate of ERR was The NIH analysis of 11 miner studies projected presented as 0.005/WLM (0.002-0.01), although risks to residential radon exposures and estimated more complex models were presented to account for that roughly one-third of lung cancer deaths among the strong influence of non-radon factors. Lubin et al. nonsmokers could be attributed to radon (Lubin et al. (1995, 1997) also presented more focused analyses 1994). This kind of estimate is not straightforward of the inverse dose-rate effect and risk estimates at because we know that the relationship between radon the low end of miner exposures. These models were and lung cancer risk depends on dose rate, attained updated and used in the BEIR VI report on the health age, and time since exposure. Figure 8-4 shows the effects of radon (NRC 1999)13. estimated ERR for different ranges of cumulative exposure. It can be seen here that the risk coefficient 8.5 Discussion is probably higher at low levels of total exposure; Lubin et al. (1997) assessed the ERR for all workers Studies of uranium miners and other miners have with cumulative doses less than 50 WLM and derived consistently demonstrated a linear relationship an estimate of 0.012/WLM (0.002-0.025). This between radon exposure and lung cancer risk and might be more informative for residential exposures risk estimates generated by these studies have where most people accumulate less than 20 WLM. been remarkably similar. All studies have noted an On the other hand, the dose rate in the miners with apparent inverse dose-rate effect, where the total dose received by the lung tissue is more damaging if it is spread out over time. The theoretical basis for this effect lies in the number of alpha particles crossing a cell. High dose rates are more likely to result in more than one alpha particle crossing a cell. The possibility that a cell might develop into a cancer decreases after the first ‘hit’ because, among other possibilities, it becomes more likely that the cell will simply be destroyed. The inverse dose-rate effect is not expected to be important at very low doses because the probability that any one cell will be hit twice is incredibly small (the probability that a cell will be hit even once is small). Lubin et al. Figure 8-4 Dependence of lung cancer risk estimate on (1995) observed that the inverse dose-rate effect dose based on a combined analysis of the lung cancer appeared to diminish below 50 WLM. mortality risk in 11 cohorts of miners (Lubin et al. 1994).

13 The BEIR VI report derived a summary estimate ERR of 0.0076/WLM (NRC 1999). Uranium Miners 109

<50 WLM was about 3.6 WLM/yr, substantially section. Lung cancer risk estimates from radon are higher than the 0.2 WLM/yr received in the average very consistent with each other. If we assume that 1 home (Lubin et al. 1994). WLM delivers 5.7 mSv of lung dose (UNSCEAR Several studies have recently estimated the risk 2000), then the excess relative risks observed in of residential radon directly. These are discussed in radon studies are in the area of 1 to 2/Sv, slightly more detail in section 2, but Table 8-1 shows the higher than the lung cancer mortality risks observed results of residential studies along with a list of the in the atomic bomb survivors (see Table 4-1). risk estimates from the miner data discussed in this

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RADIATION EXPOSURE IN FLIGHT is limited; we know how many years each individual worked but have only a rough sense of what the The earth is constantly bombarded by cosmic ionizing average annual dose might be. This means that other radiation in the form of gamma rays, neutrons and factors associated with flight may be contributing to protons, and much of this radiation is filtered out by any observed risks. In addition to cosmic radiation the atmosphere. At high altitudes the atmosphere is these cohorts are exposed to magnetic fields a less effective filter and flight crews are therefore generated by aircraft electrical systems and toxins exposed to more of this kind of radiation. The flight- associated with fuel (such as benzene). Other factors related doses they receive, on the order of 1-10 mSv/ include disruptions in circadian rhythms when flying yr, fall between the current recommended maximum through many times zones in a short period and, in the exposure for the public (1 mSv/yr) and that for case of pilots, a possible predisposition to colorectal radiation workers (20 mSv/yr) (ICRP 1991). One cancers associated with the sedentary nature of the researcher has estimated that this level of exposure job (all of the studies that we looked at discussed for twenty years would create a risk of fatal cancer some or all of these possible confounders). Another on the order of 1 in 1000 (Friedberg et al 1989). The important consideration is the healthy worker effect- investigations into the radiological hazards of flying airline pilots and crew are selected for health and have dealt with flight personnel because of the high physical fitness and receive thorough routine health doses that they experience relative to passengers. evaluations. Since most of the studies discussed Passengers probably experience doses of 3-6 uSv per below used simple incidence and mortality ratios hour of flying, depending on the route (Bottollier- to compare the exposed groups to national cancer Depois et al. 2003). This is several times higher than rates this healthy worker effect was not adequately typical background exposure rates but still amounts controlled for. Under these circumstances radiation- to a relatively low dose for occasional fliers. Here related health effects are harder to detect and any we look at several epidemiological studies of cancer significant cancer increases should be considered rates in flight crews and also look at a few cell-level with special attention. laboratory studies using blood samples from flight The earliest report that we looked at was a cohort crews. study of 2,740 Canadian pilots (Band et al. 1996). Compared with the general Canadian population 9.1 Epidemiological studies these pilots showed significantly higher incidence of myeloid leukemia (and acute myeloid leukemia The studies that we looked at were all based in specific (AML) specifically) and prostate cancer1. Malignant countries and focused on either cockpit crew or melanoma of the skin was elevated. The occupational cabin crew. Exposure information for these cohorts association with leukemia was strengthened by the

1 The pilots had significantly lower rates of mortality from both cancer and other diseases and significantly lower total cancer incidence, indicating the healthy worker effect. 113 114 Radiation Exposure in Flight fact that AML incidence apparently increased with evidence of increased total leukemia risk in addition the duration of employment2. An American study to a clear increase in skin cancer incidence. of pilots found elevated prostate cancer mortality The most consistent finding in these studies was and significantly increased mortality from cancer increased skin cancer and it is not clear that this is of the kidney or renal pelvis. This study showed linked to radiation. The Danish study found similar equivocal leukemia results (16 observed cases and skin cancer results in high- and low-altitude pilots, ~15 expected) but did not separate leukemia cases evidence against a radiation cause. One author has by type (Nicholas et al 1998). suggested that flying over multiple time zones might The rest of the studies that we looked at were contribute to skin cancer (melanoma) by disrupting conducted in northern Europe and compared cancer circadian rhythms and thus the homeostasis of rates in flight crew to national rates. All but one melatonin (Raffnson et al 2000), and various authors of these studies found significantly increased skin have proposed that lifestyle factors unique to flight cancer incidence, and one found a significant skin crew (excessive sunbathing) might be involved or cancer trend with dose (Pukkala et al 2002)3. A that increased detection plays a role. On the other study of Danish pilots found a three-fold increase hand the largest study found a significant skin cancer in AML but the result was not significant (4 cases, trend with dose (Pukkala et al 2002). 1.4 expected cases). When dividing the cohort by type of aircraft flown, however, jet pilots (who 9.2 Cell studies fly at higher altitudes) were observed to have a significantly increased risk of AML4 (Gundestrap Several studies have looked for cell-level and Storm 1999). A study of Norwegian flight abnormalities in pilots and other flight crew with attendants found significantly increased incidence of mixed results. Two studies by an Italian research cancer of the skin, liver, upper respiratory tract, and team looked for chromosome abnormalities and gastric tract in men, and of skin cancer in women. DNA damage. These authors found increased Total cancer rates were also increased (Haldorsen et ‘stable’ chromosome abnormalities (translocations, al 2001). A study of German flight attendants found gaps and breaks), nonsignificant elevations of no significant mortality differences with the general ‘unstable’ abnormalities (micronuclei, dicentrics, population (Blettner et al 2002) but did not analyze fragments and rings), and a nonsignificant increase cancer incidence. in DNA single or double strand breaks (RR 1.36; Each of these studies alone is somewhat limited 0.46, 3.98). In another Italian study Romano et al. by small numbers and so it is useful to attempt a (1997) found roughly twice as many dicentric and meta-analysis that pools multiple study results. ring chromosomes in Italian flight personnel as in Elsebeth Lynge from the University of Copenhagen controls. Heimers (2000) found increased numbers did this in 2001: among male pilots there were of dicentric chromosomes (~8-fold increase) and increases in three types of cancer- prostate cancer translocations (~4-fold increase) in British Concorde (SIR 1.3), skin cancer (SIR 2.0) and AML (SIR 3.8, pilots exposed to 3-6 mSv/yr. Nicholas et al. (2003) 1.9-6.7). Among female flight attendants there was found a roughly threefold increase in translocations evidence of increased breast cancer risk (SIR 1.4) among pilots. In a study of Dutch flight engineers and among men there was evidence of increased two types of effects were studied- DNA damage and liver and upper respiratory tract cancer (perhaps due DNA protection and repair. Flight engineers were to drinking). Flight attendants also showed weak shown to have significantly higher rates of oxidative

2 For two cases with less than 20 years of employment the SIR was 3.8 (90% CI 0.7, 11.9); for four cases with over twenty years of employment the SIR was 5.4 (90% CI 1.8, 12.4) 3 Compared to pilots with less than 3 mSv of cumulative dose, pilots with more than 20 mSv were almost three times more likely to develop melanoma (RR 2.78; 1.30, 5.93). 4 Among all jet pilots 3 cases of AML were observed versus 0.65 expected (SIR 4.6; 0.9, 13.4). All of these cases were in pilots with more than 5000 flight hours, bringing the SIR for that group to 5.1. Among non-jet pilots there was 1 case of AML (0.75 expected). Radiation Exposure in Flight 115

DNA damage (a chemical change in DNA) than exposure, solar flares may contribute substantial controls selected from ground crew. Chromosome additions to dose in a random way so that cumulative aberrations and micronuclei were slightly elevated measures such as hours or years flying are unreliable. but the difference was not significant. On the other Furthermore, radiation is not the only hazard in hand, unscheduled DNA synthesis, a measure of flight. Although it is challenging to deal with the DNA repair, was almost twofold higher in flight various potential cancer factors involved with engineers. This evidence of a DNA protection and flying (like chemicals or sleep/wake patterns), it is repair process was found to be dose-dependent: plausible that these effects are the result of cosmic oxidative DNA damage was inversely related to radiation. In some cases the cellular studies help cumulative dose, meaning that damage declined to clarify the origins of the observed cancers. For with increasing exposure, and both DNA repair and example, Lynge (2001) points out that among seven total antioxidant capacity were found to increase aircrew with myelodysplasia5 or AML that were with cumulative exposure (Zwingmann et al 1998). analyzed for chromosome changes, four had changes that tend to be associated with radiation exposure 9.3 Discussion (deletion or loss of chromosome 7). In her study of Concorde pilots, Heimers (2000) found an increase Pilots and flight crew appear to have higher than in micronucleated cells, which are a common effect normal rates of prostate cancer, skin cancer, and of radiation, but did not find an increase in sister acute myeloid leukemia in addition to cellular chromatid exchanges, an effect typically associated evidence of chromosome damage. From the available with chemical exposures. This suggests that the information it is hard to speculate about any kind radiation exposures experienced by flight personnel of radiation dose-response relationship, primarily might be more important than exposures to chemicals because dose information is highly uncertain. In when considering the observed cancer outcomes. addition to uncertainty in routine cosmic radiation

5 Myelodysplasia is a condition in which the bone marrow does not produce sufficient quantities of normal blood cells; it can be an early stage of acute leukemia. 116 Radiation Exposure in Flight � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 10

PRECONCEPTION EXPOSURES and cancer in children. The study followed a journalist’s suggestion in 1983 that childhood Several epidemiological studies have examined the leukemias in Seascale, England might be linked to possible association between occupational exposure the Sellafield nuclear installation. A government of parents to radiation and the development of cancer survey determined that the Millom rural district, in their children. The theoretical mechanism for this including the village of Seascale, had 6 childhood kind of effect originally involved reproductive cells- leukemia deaths in 1968-78 when only 1.4 would if a sperm or egg is irradiated then the genetic material be expected based on national rates. A follow-up in the cell could be altered. These mutations would case-control study (Gardner et al. 1990) revealed occur before conception but they would be passed increased risks of leukemia and non-Hodgkin’s on to the child and could increase the child’s risk of lymphoma (LNHL) in children born near Sellafield developing cancer. More complex mechanisms are of fathers employed at the plant (RR 2.44, 1.04- now considered plausible, as discussed below and 5.71). The risk was particularly high for children in appendix C. of fathers with total preconception doses (external) The majority of studies focus on exposure of of greater than 100 mSv (RR 6.42, 1.57-26.3). In fathers, largely because men are more frequently addition, the leukemias were occurring at younger exposed to radiation in the workplace, and this ages than expected, indicating that the damage was type of exposure is typically referred to as paternal occurring very early in the development of the child preconception irradiation, or PPI. The first disease (Gardner and Snee 1990). The proposed explanation, to be highlighted as a possible effect of PPI was an external radiation-induced heritable mutation in leukemia and it has subsequently received a great fathers that increased leukemia risk, became known deal of attention. In these studies leukemia is as the “Gardner hypothesis”. commonly grouped with non-Hodgkin’s lymphoma, and these diseases are collectively referred to as The Gardner hypothesis was challenged on several LNHL (leukemia and non-Hodgkin’s lymphoma). grounds: The exposure of children in the womb is not addressed in this section because the effect would not • Children of nuclear workers in other places were be inherited, it would be caused by direct exposure generally not showing the same relationship as the to the child in an early stage of development. This Sellafield workers’ families living in Seascale (for topic is covered largely in the medical irradiation example see Little et al. 1995). More information section (section 3). has since been collected and many studies do in fact demonstrate similar associations. This is 10.1 The Seascale leukemia cluster and the discussed below. Gardner hypothesis • No leukemia was observed in children of the The case-control study by Martin Gardner et al. atomic bomb survivors (discussed by Watson (1990) was the first to bring attention to a link (1991) and others). between fathers’ occupational radiation exposure 117 118 Preconception Exposures

• The biological mechanism seemed unlikely. Doll et significant (RR 2.9, 0.6-9.8). It is important to note al. (1994) make this point with several arguments that monitored workers were shown to have higher including the fact that radiation damages the external doses than unmonitored workers (75 mSv genome randomly, so if preconception radiation median dose vs 27 mSv); this seems to suggest that is affecting sperm cells, other heritable diseases internal and external dose could be correlated. If should show an increase along with leukemia. true, this would support the idea that the leukemia Evidence for these effects is discussed below. cluster might be at least partly attributable to internal exposures. • There were other possible explanations for the Addressing another alternative explanation for the excess in Seascale. Specifically, the external cluster, population mixing and viruses, Dickinson dose measurements used by Gardner may have and Parker (2002a) found that population mixing been correlated with the dose received from could statistically account for a large part of the radionuclides in the body (such as uranium, leukemia excess in the children of Sellafield workers: plutonium and tritium). In this case the internal The observed excess during 1950-1991 gave a RR dose or the combined external and internal dose of 1.9 (1.0-3.1); this was reduced in the 1969-1991 may have been the true cause. Another proposed time window to a RR of 1.1 (0.3-2.8) adjusted for explanation for the Seascale cluster was that a high population mixing1. On the other hand they showed degree of population mixing in the communities a significant preconception radiation dose-response that the workers lived in might have increased the relationship within the Sellafield cohort that was not general exposure to a virus; this virus may have strongly affected by population mixing2. played a role in the development of leukemia. Several other studies have looked at LNHL and paternal preconception irradiation beyond Sellafield. 10.2 Further studies of the Gardner hypothesis One case-control study was based in Scotland (Kinlen in the UK et al. 1993) and found no significant associations between PPI and LNHL although all odds ratios Both of the alternative explanations for the Seascale calculated by the authors were positive. cluster were explored in a follow-up cohort study The case-control study reported by Roman et al. of all 274,170 live births in the county of Cumbria (1993) was important because it found a positive 1950-1991 (Dickinson and Parker 2002a). The association with relatively low doses. The subjects in new cohort study included three more cases of this study lived near the Aldermaston and Burghfield leukemia in the children of workers and generally nuclear weapon plants in England. Although the confirmed the Gardner result (RR 1.9, 1.0-2.2). fathers who worked at the plant had received less Although dose estimates for internal radionuclides than 5 mSv of external preconception dose there was were apparently not available, researchers typically a significant LNHL risk associated with exposure to identify those workers who experienced significant radiation on the job (RR 9.0, 1.0-107.8). internal exposures by looking at who was monitored, In a later cohort study of UK nuclear workers assuming that a worker would only be subjected to Roman et al. (1999) again found an elevated LNHL monitoring if they were potentially exposed. In the rate in children of men who were monitored for cohort study Dickinson and Parker found a 3-fold radiation (rate ratio 3.0, 0.7-13.0). For those cases increase in LNHL risk in the children of monitored in which dose information was available there were workers (controlling for external exposures), but elevated rates of LNHL that became significant for the result was based on 3 leukemia cases and not the highest dose groups3. There was also evidence

1 Among children of radiation workers born 1969-1991 and aged 0-6 years 63% of the cases were estimated to be attributable to population mixing and 18% were estimated to be attributable to PPI. (Dickinson and Parker 2002b). 2 The rate ratio per 100 mSv was 1.6 (1.0-2.2) before adjusting for population mixing and 1.4 (0.2-3.1) after adjustment. 3 Leukemia rate ratios were 3.9 (1.0-15.7) for cumulative external doses of ≥100 mSv and 5.4 (1.4-20.5) for doses of ≥10 mSv in the 6 months before conception. Preconception Exposures 119 of risk in the lowest dose groups, particularly when and was very uncertain (RR 4.0, 0.40-196.5). the cases that may have been used by Gardner were excluded. For example, the Rate Ratio with 10.3 Preconception exposure in other settings cumulative preconception doses of <50 mSv was 2.3 (0.8-7.2) excluding the possible Gardner cases. All In a case-control analysis of the German Childhood risk estimates in this study were higher for leukemia Cancer Registry Meinert et al. (1999) found elevated alone than they were for LNHL. risks of leukemia with paternal preconception There have also been a series of case-control radiation exposure at work (OR 1.80, 0.71-4.58) studies that made use of the Oxford Survey of and significantly increased risks with paternal Childhood Cancers. Sorahan and Roberts (1993) preconception x-rays (OR 1.33, 1.10-1.61). looked at LNHL (and other cancers) in relation to A case-control study in Ontario (McLaughlin et parents’ exposure to radiation on the job, including al. 1993) found no significant associations between the nuclear industry and also a long list of medical paternal preconception exposure and LNHL. One and research occupations. Doses were calculated interesting result of this study was an elevated risk for the 6 months prior to conception but cumulative of leukemia with occupational radon exposure of doses were apparently not calculated. Occupational greater than 50 working level months (OR 5.14, exposure to external radiation was associated with a 0.48-55.2). nonsignificant increase in leukemia risk (RR 1.45, A couple of case-control studies by Shu et al. 0.76-2.78). The authors also found that LNHL risk provide evidence for PPI effects from both medical was roughly doubled in association with exposure x-rays and occupational exposures. The first used to radionuclides that might deposit inside the body, the tumor registry of the Shanghai Cancer Institute controlling for external exposures, but this was to identify 309 cases of childhood leukemia in also not significant (RR 2.09, 0.52-8.34). No dose- Shanghai (Shu et al. 1988). They found a significant response trends were observed. A couple of years excess of leukemia in association with 6 or more later Sorahan et al. (1995) published an analysis preconception x-rays to fathers5, and a significant indicating that employment in these occupations, positive trend with number of x-rays, but no particularly the nuclear industry, was a risk factor associations for preconception x-rays to mothers. for leukemia but that the risk was just as high, or The second study was based on 302 cases of infant higher, when the paternal exposure occurred after leukemia (diagnosed up to 18 months of age) from conception4. the Children’s Cancer Group of Canada and the The 1997 case-control study by Draper et al. set US (Shu et al. 1994). This study found increased out to test the Gardner hypothesis on a large scale. risks of infant leukemia in association with x-rays This study compiled childhood cancer cases from the of specific anatomical areas. For example, paternal Oxford Survey of Childhood Cancers, the National preconception x-rays of the lower GI tract or Registry of Childhood Tumors, and the subjects abdomen showed an infant leukemia OR of 2.24 of the 1993 Kinlen study in Scotland, for a total (1.44-3.47). Significantly increased risk was also of 35,949 cases and 38,323 matched controls. The seen with x-rays of the chest, limbs, or upper GI tract, general result was a positive significant association and significant positive trends with the number of x- between LNHL and paternal radiation work (RR rays were observed for all of these x-ray categories. 1.77, 1.05-3.03), and this estimate was higher for This study also found increased infant leukemia risk radiation workers who were monitored for internal with reported occupational exposure to radiation exposures. The authors also found an elevated risk (OR 1.7, 1.07-2.71) or reported radiation badge with preconception employment of mothers in monitoring (OR 2.25, 1.16-4.37). These studies have radiation work, but the result was based on 4 cases a potentially strong bias as the exposure information

4 The leukemia OR was 2.22 (0.97-5.54) for preconceptional employment in the nuclear industry and 3.14 (1.30-8.72) for postconceptional employment. 5 OR 2.4 (1.5-5.0) for 6-10 preconceptional x-rays and 3.9 (1.7-8.6) for 11 or more x-rays. 120 Preconception Exposures was collected by interview. result in a random pattern of mutations that would Finally we should mention a study that was result in various health effects in addition to LNHL. conducted in the early 1960s, before the Gardner The next subsections summarize the results of hypothesis controversy (Graham et al. 1966). This analyses on solid cancers and stillbirths. case-control study was based in New York but included childhood leukemia cases from several 10.4 Solid cancers in association with metropolitan areas (Baltimore, Minneapolis-St. preconception exposures Paul, and all urban New York areas outside of New York City). This study was focused on diagnostic The effects of preconception radiation exposure radiation (x-rays), and although x-ray histories on solid cancer rates were explored along with were obtained by interview they were also validated leukemia rates in the studies that followed the by review of medical records. Leukemia risk was Gardner hypothesis. The recent analyses of the significantly increased with maternal preconception Cumbria cohort by Dickinson et al. (2002) found exposures (RR ~1.66), particularly in association with a significant two-fold increase in solid cancers in x-rays of the abdomen, pelvis, spine or femur (RR Sellafield workers’ children based on 12 cases (RR 2.1, p<0.001). The risk with paternal preconception 1.9, 1.0-3.3)7. Adjusting this relationship for parental x-rays was elevated but not significant (RR 1.31, p migration and community mixing slightly weakened = 0.16). The combined RR (exposure of the father the estimate (RR 1.7, 0.8-3.2). Among the children and/or mother) was 1.47 (p = 0.006). There was of radiation workers there was no detectable dose- also evidence of a weak dose-response trend with response relationship (Dickinson et al. 2002). The the number of preconception maternal x-rays but the UK-wide studies generally agree with this result: trend was not quantitatively evaluated. Sorahan and Roberts (1993) found a nonsignificant From the above discussion it is clear that there increase in solid cancers8 in association with external might be a relationship between childhood LNHL radiation exposures (RR 1.29, 0.74-2.24) and a and preconception exposure to radiation. The largest significant increase in association with exposure and most recent studies (Dickinson and Parker 2002a, to radionuclides that might deposit internally Draper et al. 1997) confirmed that radiation workers (RR 3.56, 1.04-12.12, controlling for external are more likely to have children at risk for leukemia. exposures). Draper et al. (1997) found an increased More uncertain is the dose-response relationship: risk with maternal radiation work (RR 5.5, 1.2-51.0) Dickinson and Parker observed a significant trend but not with paternal work, and no dose-response while Draper et al. did not. This likely has to do trend was observed. In the UK nuclear workers with the fact that measurements of external dose are cohort study Roman et al. (1999) found increased correlated with unknown internal doses, making the risks of solid cancers in the highest dose group of total dose received by the parents very uncertain. paternal exposures9, and also found increased risk These leukemia results leave at least one major with maternal preconception employment without question about the Gardner hypothesis unanswered- monitoring (Rate Ratio 3.9, 1.0-14.4). The study exposure of reproductive cells to radiation should of the German Childhood Cancer Registry also

6 Confidence intervals were not reported, but the probability of the estimate being different from 1 (p-value) was reported. Estimates were adjusted for several potentially confounding factors, but not all at once. For example, adjusted for year of birth, age of the mother, and birth order the RR was 1.55 (p = 0.003). Adjusted for age of mother, previous miscarriages or stillbirths, and pregnancy order, the RR was 1.73 (p < 0.001). All combinations of confounding factors produced highly significant risks in the range 0f 1.55-1.73. 7 The group of cancers considered for this result did not include Hodgkin’s disease, brain or spinal tumors, or gender- specific tumors. 8 Sorahan and Roberts (1993) calculated risks for ‘cancers other than LNHL’. 9 For all cancers except LNHL the Rate Ratios were 4.0 (1.2-13.6) for cumulative external doses of ≥100 mSv and 4.4 (1.1-18.5) for doses of ≥10 mSv in the 6 months before conception. These estimates were based on 3 and 2 cases, respectively. Preconception Exposures 121 found elevated solid cancer risk with occupational and also found that fathers of stillborn children or exposure to radiation prior to conception, and this children with birth defects had worked longer, on was true for both paternal and maternal exposure, average, in the mines (Shields et al. 1992). Mothers but neither relationship was significant (Meinert et occupationally exposed to x-rays in metropolitan al. 1999). Atlanta showed increased neural tube defects in their children (RR 5.49, 1.20-25.03) (Matte et al. 1993) 10.5 Adverse birth outcomes in association with and medical radiographers in Jordan show evidence preconception exposures of increased rates of birth defects and stillbirths (Shakhtreh 2001). Parker et al. (1999) examined the rate of stillbirths in the Cumbria cohort. There were significant dose- 10.6 Cell studies response relationships for stillbirths and external radiation, with both total preconception dose (OR Several studies have investigated DNA damage in the 1.24 per 100 mSv, 1.04-1.45) and the dose over the children of atomic bomb survivors (Neel et al. 1990, 90 days before conception (OR 1.86 per 10 mSv, Kodaira et al. 1995, Satoh et al. 1996), Chernobyl 1.21-2.76). The relationship with total preconception downwinders (Dubrova et al. 1996, 2002a), dose was even steeper for stillbirths with neural tube Semipalatinsk test site downwinders (Dubrova et al. defects (OR 1.69 per 100 mSv, 1.10-2.32). These 2002b), and Chernobyl cleanup workers (Livshits et results were received with the same skepticism as al. 2001, Weinberg et al. 2001, Kiuru et al. 2003). the Gardner analysis of leukemia, again because The results are confusing and perhaps conflicting as the results are not compatible with birth outcome discussed below. analyses of the atomic bomb survivors. In addition, Studies of genetic effects in children of the atomic the log-linear risk model used by Parker et al. is bomb survivors have included 50 families with at unconventional for radiation effects, where the least one exposed parent. In these families most linear model is more common (Little 1999). children were born at least 10 years after the bomb. There are a few studies that mirror the results of Only one child was born to two exposed parents; Parker et al. both in the UK and elsewhere. In a cohort of the remaining children roughly half were born to study of UK nuclear workers Doyle et al. (2000) an exposed mother and the other half to an exposed found an increased rate of stillbirth and miscarriage father. No increase in DNA damage was found in among preconceptionly monitored mothers (OR 2.2, this group (Kodaira et al. 1995, Satoh et al. 1996). 1.0-4.6), and an elevated stillbirth risk in association In contrast to the atomic bomb survivors, studies with paternal preconception doses ≥ 50 mSv (OR of Chernobyl downwinders have found increased 1.3, 0.9-2.0) or ≥ 100 mSv (OR 1.4, 0.9-2.4). mutations. Dubrova et al. (1996, 2002a) examined Studies of the communities around the Hanford 79 exposed Belarussian families and 256 exposed site in Washington found excess neural tube defects Ukrainian families. In each case a significant (Sever et al. 1988b) and a significant dose-response increase in mutations of the paternal germline10 was relationship for neural tube defects (Sever et al. found, on the order of 1.6- to 2-fold. These were 1988a), with an estimated OR of 1.46 (0.99-4.5) also shown to be correlated with the level of Cs- at 10 mSv of combined preconception workplace 137 ground contamination. Dubrova et al. (2002b) exposure to both parents. Other birth defects were found a similar 1.8-fold increase in the children of also found in excess. A study of Navajo families parents exposed to fallout from weapons testing in living and working in the New Mexico uranium Kazakhstan. mining area found that birth defects were higher Chernobyl cleanup workers (almost all male) for mothers living near mine dumps or tailings (this were exposed to average whole-body external implies possible exposures in utero or after birth) doses on the order of 10 cGy (Kiuru et al. 2003).

10 Mutations in DNA can be attributed to either parent according to their location on a chromosome; mutations attributable to the father are known as paternal germline mutations. 122 Preconception Exposures

Livshits et al. (2001) studied the families of 161 animal studies was conducted by Taisei Nomura Ukrainian cleanup workers and overall found no (1982). This study involved the exposure of 2,904 increase in the mutation rate. There was, however, parent mice to x-rays. Preconception x-ray exposure an apparent nonsignificant increase in mutations in of either parent significantly increased the tumor children conceived within two months of exposure. rate in the offspring, and this included leukemia. Weinberg et al. (2001) studied 41 Ukrainian and It appeared from the results that paternal exposure Israeli children who were conceived after their after the formation of sperm was more likely to fathers’ exposures. In this study there was a 7-fold cause this increase than exposure to spermatogonia increase in the mutation being analyzed and the (sperm-producing cells). Put another way, exposure mutation rate declined with increasing time between closer to conception was a more clearly defined risk exposure and conception. Kiuru et al. (2003) studied factor. Mohr et al. (1999) conducted a similar study 155 Estonian children born to cleanup workers and and found similar results. Lord and Hoyes (1999) found a nonsignificant increase in mutation rate. injected male mice with plutonium-239 three months The odds ratio for mutations was almost significant before conception, exposed the offspring to gamma for cases in which the father was exposed to >20 cSv radiation or a chemical carcinogen, and observed (OR 3.0, 0.97-9.30). the rate of leukemia. This study demonstrated that Although these results may appear to be in conflict, preconception exposure caused the offspring to be they are generally consistent with a scenario in which more sensitive to carcinogens that they were exposed the critical exposure is experienced by the father in to after birth. Together these and other studies have the months leading up to conception. This implies provided more evidence that cancer risk can be that the sperm-producing cells (spermatogonia) increased by preconception exposure in mammals. are not as vulnerable as the developing sperm cells Studies that have tried to establish the most sensitive (spermatocytes). In this case the atomic bomb stage of spermatogenesis for radiation-induced survivor data are not very informative because mutations in mice have produced conflicting results. half of the exposure was maternal and most of the Although these have not been resolved, they may children were born 10 or more years after exposure. be partly attributable to differences in the strains The chronic exposures of Chernobyl downwinders of mice used (Niwa 2003). This is important to and Chernobyl cleanup workers are more likely to consider when drawing inferences for humans from have affected the developing sperm of the exposed the mouse studies. fathers; these studies generally show an increase in germline mutations. 10.8 Discussion

10.7 Animal evidence Clearly the Seascale leukemia cluster has received a lot of attention and analysis, but given the small Although we have avoided discussions of animal number of cases we must be satisfied with likely studies in the rest of this overview we feel that this explanations rather than answers. There is good information is important here. Other health effects evidence that radiation played a role in creating a discussed in this overview, mainly cancer in the leukemia risk, and both external and internal radiation same individual that is exposed to radiation, have should be suspected. In addition, population mixing been accepted as results of radiation exposure is another plausible childhood leukemia risk factor. although people continue to debate the nature of the Neither of these factors should be ignored and an dose-response relationship. In these cases animal interaction between these factors seems plausible evidence is not as enlightening as the abundant (Little 1995,1999, Wakeford 2002; see also the human data. With preconception radiation exposure discussion of animal evidence above). and heritable effects, however, a debate continues The reported doses of radiation involved in these over whether these effects even exist in humans at studies were relatively low; one obvious example all. Thus it is useful to see if these effects have been is the LNHL excess with occupational doses below observed in other mammals. 5 mSv (Roman et al. 1993). Stillbirths among One of the earliest and most frequently cited nuclear workers were almost tripled with maternal Preconception Exposures 123 preconception doses between 2.5 and 10 mSv (diagnosed at age <20) in 41,066 control individuals, (OR 2.8, 1.0-7.6), although this was not part of a a rate of of ~4 in 10,000. This is a measure of the detectable dose-response trend (Doyle et al. 2000). background or spontaneous leukemia rate. Out of In one result that almost certainly has a lot to do the 31,150 children born to exposed parents we with chance, LNHL risk appeared 8 times higher would therefore expect 12 or 13 cases even without with paternal preconception exposure to less than exposure to the atomic bomb. However, only ~2% of 0.1 mSv in the UK case-control study (RR 8.17, the study sample were conceived in the six months 1.18 - ∞) based on 6 cases and 0 controls in that after the bombing. If this is considered to be the at- dose range (Draper et al. 1997). These findings are risk group then a spontaneous case of childhood remarkable but they are also persistent; most of leukemia would be unlikely. Furthermore, exposure the exposed workers in these studies had received of mothers and fathers were not segregated in these officially reported doses of less than 100 mSv before studies- if the sample were limited to children born conception of their children11. to men who conceived a child within six months of Studies of the children of atomic bomb survivors the bombing then the sample would be much too have not produced significant findings, occasionally small to detect an effect12. leading to claims that there is no transgenerational Taken together the results of studies on leukemia effect in this cohort. It may be the case, however, and non-Hodgkin’s lymphoma, solid cancers, and that this cohort cannot provide sufficient evidence stillbirths and birth defects make a compelling case to make claims in either direction. Based on the for the risks of preconception exposure to low doses information reviewed in this chapter it seems of radiation. The magnitude of the effect is still very reasonable to consider that the exposure of the uncertain but these exposures should be treated with father in the months leading up to conception may precaution. Appendix C presents a more quantitative be the critical exposure for transgenerational effects. assessment of the evidence for a preconception If this is the case then we should look carefully at exposure risk and discusses the possible mechanism the atomic bomb survivor data. Yoshimoto (1990) in more detail. reported that there were 17 childhood leukemia cases

11 The higher doses received by a small percentage of these workers is probably not enough to explain observed excesses, particularly when we can look at dose categories and see the excesses in lower dose ranges. On the other hand it is important to question the accuracy of these doses, especially considering unknown internal doses received by workers, and if we could know perfectly how much radiation each worker received we might find that we were looking at effects in a higher range of doses. Still we would be seeing an effect of relatively low levels of radiation exposure. 12 The mean gonadal dose reported by Yoshimoto was 435 mSv. Gardner et al. (1990) give a RR of 6.4 for fathers exposed to > 100 mSv; Roman et al. (1999) give a RR of 7.7 for doses ≥ 10 mSv in the 6 months before conception; and according to the dose-response coefficient (RR)of 1.6 per 100 mSv (Dickinson and Parker 2002a) a mean dose of 435 mSv would give a RR of (1.64.35 = 7.7). If the exposed cohort of 31,150 individuals is restricted to the 2% that were conceived within 6 months of the bombing and further restricted by the assumption that half of the exposed parents were men then we are left with 312 individuals. In this case we should expect 0.17 spontaneous cases of childhood leukemia and, according to the risk estimates mentioned above, about 1 case of radiation-induced leukemia. Given the random nature of carcinogenesis it would be virtually impossible to recognize this effect in this cohort. 124 Preconception Exposures � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � s � � � � � � � � � � � � t � � � � � � � � � � � � l � � � � � � � � � � � � � � � � � � � � � u � � � � � � � � � � � � � � s � � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � R � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � ) � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � L � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � H � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � N � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � L � � � � � � � � � � � � � � � � � � � ( � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � a � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � om � h � � � � p � � � � � � � � � � � � � � � � � � � � � � � � � � ym � � � � � � � l � � � � � � � � � � � � � � � � � e � � � � s � � � r � � � � � � � ’ � � � � � � � � � � u � � � � � � n � � � s � � � � � � � � � i � � � � � � � � o � � � � � � � � � � � � � � � � p � � � � � � � � � � gk � x � � � � � � � � � � � � � � � � � � � � � � � E � � � � � � � � � � � � � � � � � � od � � � � � � � � � � � � � � � � � � � � � � � � � H � � � � � � � � � � � � � � � - � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � on � � � � � � � � � � � � � � � � � � � n � � d � � � � � � � � � � � � � � � � � � n � � � � an � � � � � � g � � � � i � � � � � � � � � � � � � � � � � � � � � � � s � � � � a � � � � � � � � � � � � � i e � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � D � � � � � � � � � � � � � � � � � � m � � � � � � � � � � � � � � � � � � � � � � � � y e � � � � � � � � � � � � � � � � � � � � � � � � � d � � � � � � � k � � � � � � � � � � � � � � � � � � � u � � � � � � � � � � � � � � u � � t � � � � � � � � � � � � � � � � � � � � � � � � e S � � � � � � � � � � � � � � � � � l � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � d � � � � � � � � an � � � � � � � � � � � � � � � � � � � � � on � � � � � � i � � � � � � � � � � � � � at � � � � � i � � � � � � � � � � � � � � � � � � � � � � � � � � � ad � n � � � � � � � � � � r � � o � � � � � � � � i � � � � r � � � � � t � � � � � � i � � � � � � � a � � � � � � � � � � � � � � c � � � � � � � � � � � � o � � � � � � � on � � � � � � � � i L � � � � � � � � � � � � t � � � � � � � � � � � � � � � � � p � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � � � � c � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � on � � � � � � � � � � � � � � � c � � � � � � � � � � � � � � � e � � � � � � � � � � � � � � � r � � P � � � � � 1. � � � - � � � � � e � � � � � � � � � c � � � � 10 � � � � r � � � � � � � � � � � u � � e � � � � � � � � � � l o � � � � � � � � � � � � � S � � � � � � � � � � � � � � � � � � � � ab � � � � � � � � � � � T � � � � � � � � � � � � Preconception Exposures 125 - o t k x i r r , t e d o o 0 n s a . e r h 5 t 8 o n t w . r i R o n 0 a n r o t e . 1 o i f t c n a o o p O f p . 1 c i a o c f ( o s ) t s e R ) i i 1 o r e r ) c R t f 5 p e a s 8 r . i t e O i . a o e d 0 n : s - . i ( a 6 n f k 4 4 c a n e o r r m d 1 s 9 g I a s 2 n c d i r e o a a r 3 - 1 P e o o i s e r e - - e k v r 3 c w d P v . l h 9 0 u h a p S m t r . a 1 e 4 o g d e o d e a s 1 l ( . t i h n m e f e s ( n k t a r t 0 h r s r i 8 b t u 0 e . , d n 7 o w o o t a e o . u t 0 w i e a 5 0 l p a i r r ) 7 e f b 1 d 0 o x p r n k s . o p o n . ) a s � d i s t d e e i s s o ) l 4 t i i n s 3 h e t e n h s a r r 0 a e l e n t h 0 m . c a e r s o t u . 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� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � Preconception Exposures 129 r e y s k e l ) o n c s p t h f i a 5 l ) n h . r ) e T a m l e 7 g 3 R s r r . a i u d 6 - r m t ) l . e u e O d i 0 y f s e 3 2 . e s n f n - e d i n 0 a 1 2 h d o e . . 8 t e n i e d , r a t i g t 5 r 5 4 , ) 3 o h . a a ( e n c 2 s f s m l 8 - 0 c h o s n h s . e m a ( t f i t r e 0 o c e i e 1 g r l u t ( s o t o s 2 i s 3 t n a s . s u n a i a i b s R 1 p a 0 v 1 r l . E c o c b d e l g 0 r S , O 1 . d . i , p f c a n t n ( 9 p s s a e i 0 f i o m i n c s l l s e 4 s h 1 i o s . h o r r o s t i o 0 g a r r c s e 5 l c e t t d 1 e n R e e r y a h e m i s n t r t r f ( e h a R n g R i d t o o a a r p i e o n - R w 6 a c u e d a i l ) h d l ( e t x 9 F n t � f a s 5 c . s s g p . h � s r . n n o � t a t n a o 1 g e n ) e 4 r i t a r c s � - c n i o e 7 h w c w d , i r e � t i d 8 c n b s 0 p f n e � v s f � a . e n 9 o e i l a i e r a . h d s p i l 0 r � o c a � t e n t d , i 0 t n o i g e a � s ) t i h h g ( l = a r e f r p t t i s o a n a � i i p e a b x 6 h S p a p e n f t d l h e l � u 4 w m . 5 u ; r a g t t . a � r a r u i s e c d r t h n y o � 1 l d r o r o r n t l b c s o f l e l a r i f y g u n o l t o M r s c a f e t f i s o n b a t �� l t e u f 8 . l n i f n o a . t o a s s s e � u o a c a o o t ( p 3 l n p s o � i n e m o ( c t x a a n e d H k 0 s t a g d e � a r e c h s o s i t l s f 0 a i t l i i n p s . i n f a a a t e g r n h a o i u k 7 e a d t d r n �� o p r w c s n y r t i s i , � g a i l n e t t o c ) e g u t d n n n n e i s c h s p R o b d n n o e �� o s o e e e e g r u a m c l s o i f c i e g t o t c l r d c a y e p l h v � e l o i n l n r a e i l s i o n i d f t h e a n l o a i a r h e h r m c t a e c h r �� p e n n s l c r a u t d r o o e � g b a a g e r o i e r a a f m o n i u h T s e t n p F p t h w h M o c R a �� � l 0 a r n �� 2 d y y o � - / l i a � t 0 v h v n � p 1 � 4 g S S o e e ) � u l r d g c m m �� � o a u n l n r � s a n 5 7 a o � r f - o 7 n ) c �� . e l o � 2 p t o e n � d 2 a i � r f x s a t n e r n f w e p o p � a o r � a ( o i o m p s e t n n e t n u e e u a a v a y a s s s k r �� c e e S s o c o n u 0 m � M d ( m A o d u M d 1 � � � � 5 y y y n � 1 d d e 2 6 d d � � 9 u 0 n � u 7 u 6 , t � 7 m ) � t t a 9 s � 6 2 4 � s s a 2 , � s l 7 6 , , , d � l l 8 0 r � ) ) ) y e o 7 6 , o o e 8 r s 8 1 0 d 9 2 3 r r � t � h 9 t t 8 8 8 o u n t p d d d 1 � . n 9 n 9 9 p s o a . s s s s n n n o 1 o 1 1 x � �� t l l l r l t - a - a - a C c c e r � a o o o g n - - - 7 4 8 � n s r s r s r o e t o e e e t t t 5 6 6 e e e i r u � h e �� s s s n n n s s s 9 9 9 a d � a a a o r 0 a o a o a o 1 1 1 a p e C ( c c C ( c c C ( c c C r 9 �� v h � t e o S d n b ( �� i n n s � a e o a m e s k t t e � r h i ’ u c i h t l � n i e r e s o T o r r o n h o r o n t ) e i p u a r p h p g s n r s i k a � o a �� e a e s e e r l r u r � t o e i h � e v t n t � a � o a i g p n B i S a e � l ( n c ( o x i � M w s ) m � e i u N m e t e � n e n a � n f d A i m e N i o s e e o o � � t r o a n n a o c , S t t r i i i o G r h f a t o � k t a g g s n d , c l n d s a c i o e �� n n r f a u d a f e l i g i i v t o n h i h e l � o o c r t o k r l n i h h a m n i f a s l i i t e � s s n p a i d d a e n v a s i n l m � a m a l a r i m e a a n e t b e r h a o b o a � e W c H W F N S m U R H f A F m J a t t a �� a � m a i n h t 8 2 3 o e s � �� r 8 9 9 e � t d 9 9 9 s � a � e k 1 1 1 � d h s � r e s l . . . t a i 1 e k � l l l e t i a 0 v a a a � B R a �� e h h 0 t t t � S e S e M e S 2 4 5 11

NUCLEAR POWER ACCIDENTS distress1, but several cancer outcomes appear to have been elevated as described below. The two nuclear power accidents eligible for this Hatch et al. (1990) analyzed cancer incidence review are not the only two in human history, but they according to levels of dose, comparing incidence are the only two with substantial epidemiological among those in the highest quartile to incidence analysis of health outcomes in surrounding among those in the lowest quartile2. Incidence populations. The Three Mile Island (TMI) accident was further broken down in according to years of in Pennsylvania was relatively low-level, although observation. 1975-1979 was the pre-accident period; it was the largest accidental release of radiation 1981-1985 and 1984-1985 are periods defined from a commercial power facility in the US, but according to the assumed latency of various cancers the Chernobyl accident was a major catastrophe. (2 or 5 years). Non-Hodgkin’s lymphoma and lung This section begins with a short review of the TMI accident and goes on to explore in some depth the follow-up of the effects of Chernobyl.

11.1 Three Mile Island

The partial meltdown at TMI on March 28, 1979 released several million curies of xenon and iodine isotopes into the air. The average whole-body gamma dose for a person within 5 miles of TMI was estimated to be about 0.1 mSv (Hatch, et al. 1990; Talbott, et al. 2000; see Figure 11-1). This amount of radiation is low, and detecting risks at this level is not likely using standard epidemiological methods. On the other hand, there were problems with dose estimation, including legal restrictions on how the doses could be estimated and missing data for critical periods immediately after the accident (Wing et al. 1997). Based on the official dose estimates, an early Figure 11-1. Radiation emissions and incidence of lung report from a President’s Commission concluded cancer, 1981-1985, in the TMI 10-mile area (http://ehp.niehs. that the only possible health impact would be mental nih.gov/members/2003/6200/6200.html#accci).

1 JG Kemeny et al. 1979. Report of the President’s Commission on the Accident at Three Mile Island – The Need for Change: The Legacy at TMI. ISBN 0-93578-003. Washington, DC: Govt. Printing Office. 2 Dividing a group into quartiles means creating four groups; the lowest 25% of dose, the highest 25% of doses, and two groups in the middle (25-50% and 50-75%). 130 Nuclear Power Accidents 131 cancer were both associated with the accident of radiation in history. Approximately 320 million according to this scheme3. Childhood leukemia data curies of radioactive material were released over were too few to produce meaningful results. This Belarus, Russia, Ukraine and other countries, study also presented evidence that the incidence of including 54 million curies of iodine-131 (I-131), lung cancer and non-Hodgkin’s lymphoma may be the radionuclide associated with thyroid cancer influenced by routine emissions from the facility. (UNSCEAR 2000). In the wake of this disaster we The authors were reluctant to interpret these results have increased knowledge; the populations exposed as evidence of a causal association, however, and to this release are one of the most important sources subsequently published an analysis attempting to of information about the health effects of radiation. ascribe the results to accident-related stress (Hatch The generation and synthesis of information from et al. 1991). Chernobyl is ongoing, but the body of literature Wing et al. (1997) reanalyzed the TMI accident that has already been created is staggering- a simple data according to the structure used by Hatch et search on the National Library of Medicine search al. (1990). Dose information from the Hatch study engine6 pulls up a list of over 1,800 peer-reviewed had originally been stated in terms of relative papers with “Chernobyl” in the title. This article will dose, and Wing and his colleagues used the same not attempt to summarize all of this literature but dose information in the original relative form4. The will be concerned with some key recent findings; statistical approach to modeling risks was different these are organized into a brief discussion of in this case, and significant associations between dose reconstruction, studies regarding workers at accident dose and lung cancer and leukemia were Chernobyl after the accident, and studies regarding found. children affected by fallout from the accident. More recently, a study by Talbott et al. (2000) looked at mortality over a longer time period (1979- 11.2.1 Dose reconstruction for Chernobyl 1992) using different estimates of dose. Aside from downwinders a positive dose-response relationship for breast cancer, no associations between cancer mortality Within the first two weeks following the Chernobyl and the TMI accident were found. In an update, accident about 50,000 people were evacuated Talbott et al. (2003) reported elevated SMRs for from the 30-km zone around the reactor. For the male lung cancer (117) and leukemia (SMR 127) days between the accident and evacuation these and female breast cancer (SMR 106) and blood populations were exposed to significant amounts and lymph cancers including leukemia (SMR 122). of radiation. Two papers present estimates of these Evidence of dose-response trends for male blood doses through both the inhalation and the ingestion and lymph cancers and female breast cancers was pathways (Mück et al. 2002 and Pröhl et al. 2002). suggestive of an effect5. Dose-response trends did With models that used such input parameters as not include children under the age of 18 (Talbott et cesium deposition, food chain models, and internal al. 2000, 2003). dose models of the International Commission on Radiological Protection (ICRP), these researchers 11.2 Chernobyl have come up with some numbers that we can compare with other downwinder populations. In the The accident at the Chernobyl nuclear power plant case of Chernobyl, early evacuees were exposed in April of 1986 was the largest accidental release externally and through inhalation, and later evacuees

3 The OR estimates for the 1984-1985 period, comparing the highest and lowest dose quartiles, were 2.01 (1.15-3.49) for non-Hodgkin’s lymphoma and 1.72 (1.33-2.22) for lung cancer. No associations were evident in the pre-accident period. 4 Relative doses would be on a spectrum of higher to lower exposures without units of dose. 5 Relative risk estimates for male blood and lymph cancers increased with category of maximum gamma exposure (1.00, 1.16, 2.54, 2.45) as did the estimates for female breast cancer (1.00, 1.08, 1.13, 1.31). 6 http://www.ncbi.nlm.nih.gov/entrez/uery.fcgi 132 Nuclear Power Accidents

ranging up to several Gy, and there remains significant uncertainty in individual estimates. The majority of Chernobyl cleanup workers who arrived soon after the accident were exposed to external doses of over 10 cGy. Most workers who arrived after 1986 received less than 10 cGy (Ivanov et al. 1997b).

11.2.2 Chernobyl emergency workers

The cleanup of the Chernobyl accident was very labor-intensive and the exact number of cleanup Figure 11-2. Researchers at the Lawrence Livermore workers, sometimes referred to as ‘emergency National Laboratory map the plumes of radiation originating workers’ or ‘liquidators’, is uncertain. Roughly from the Chernobyl accident (http://ehp.niehs.nih.gov/ 300,000 people from many countries within docs/1996/104-6/forum.html). the former Soviet Union may have participated (Kuzmenok et al. 2003, Melnov et al. 2002). were additionally exposed through ingestion of V.K. Ivanov and colleagues at the Russian contaminated food and milk. Internal doses were Academy of Medical Sciences have published several 10-40 times greater than external doses. About 40% investigations into cancer incidence and mortality in of the total inhalation dose, and 60-90% of the total Russian workers. Roughly 170,000 Russian workers ingestion dose, was from I-131, indicating that the are registered with the Russian National Medical thyroid dose should be the primary point of concern. and Dosimetric Registry (RNMDR) and received The highest exposed settlement in the evacuation mean cumulative doses of ~10 cGy. Those workers zone was Usov, and here the mean thyroid dose who started work within a year of the accident were from both pathways was estimated to be roughly exposed to higher external doses (averaging 17 cGy 200 mSv for adults and 1,200 mSv for infants (Pröhl in 1986) than those who started work later (average et al. 2002). The adult dose is comparable to the of 4 cGy for workers who began after 1987) (Ivanov mean doses received in Hiroshima and Nagasaki et al. 2001). (264 mSv; Thompson et al. 1994). The mean child In 1997 these researchers analyzed 47 cases of (age 9-19) dose in Washington County, Utah, during solid cancer and 48 cases of leukemia in the group the peak nuclear testing years of 1951-1958 was 170 of ~170,000 workers (Ivanov et al. 1997a,b). They mSv (Kerber et al. 1993). For extra comparison, these found significant dose-response relationships for thyroid doses are a small fraction of the adult doses both cancers. The ERR for thyroid cancer was 5.31/ received by Marshall Islanders exposed to testing Gy (0.04-10.58) and for leukemia it was 4.3/Gy fallout (3 and 21 Sv on Utrik and Rongelap atolls, (0.83-7.75). A later analysis of 41 leukemia cases respectively; Hamilton et al. 1987). Parts of Belarus, that were diagnosed more than two years after the Ukraine and Russia were contaminated with fallout person was hired yielded a larger and much less and many children received thyroid doses in excess certain estimate; the ERR in this study was 15.6/Gy of 1 Gy (Buglova et al. 1996, Stiller et al. 2001). (-24.9-56.1) (Konogorov et al. 2000). External doses from radionuclides deposited on In a 1998 report Ivanov et al. studied broader the ground have been lower; Livhtarev et al. (2002), categories of cancer incidence among 114,504 of for example, project that the mean external dose the workers with an average dose of 11 cGy. There in the 11 most heavily contaminated settlements were a total of 983 solid cancers in this cohort where in Ukraine will be ~6 cSv by 2055; since nuclides only 800 would be expected based on cancer rates decay over time most of this exposure has already in Russian males. This is a significant excess and occurred. it was shown to depend on external dose with an Chernobyl cleanup doses averaged ~10 cGy but ERR of 1.13/Gy (0.14-2.13). Digestive system there was a large degree of variability in exposure, cancers had a higher risk estimate (ERR of 2.41/Gy; Nuclear Power Accidents 133

0.10-4.71) while respiratory system cancers had a 183 children born to Chernobyl cleanup workers and nonsignificant estimate (ERR of 1.04/Gy; -0.89- in 163 controls. Dose estimates were only available 2.96). for 28% of the cleanup workers and they ranged A 2000 report (Ivanov et al. 2000) presented from 0.05 to 1.2 Sv. No significant differences risk estimates for non-cancer diseases among 68,309 were found between exposed and control families, workers. Significant dose-response relationships although children conceived within 2 months were found for endocrine and metabolic disorders of exposure showed a nonsignificant increase in (including thyroid disease, ERR 0.58/Gy), mental mutations compared to children conceived 4 months disorders (ERR 0.4/Gy), nervous system disease after exposure or later. This is in agreement with (ERR 0.35/Gy), digestive system disease (ERR observations in mice that suggest that the most 0.24/Gy), cerebrovascular disease (ERR 1.17/Gy) sensitive time for this type of effect is during sperm and essential hypertension (ERR 0.52/Gy). maturation. Kiuru et al. (2003) measured a group of A 2001 report addressed mortality in 65,905 mutations (largely overlapping with the mutations workers (Ivanov et al. 2001). Although mortality for measured by Livshits et al.) in 192 Estonian families this group was no higher than for the general Russian with children born before and after the father was population, this could be explained by assuming exposed at Chernobyl. There was a nonsignificant that the workers were healthier than average and increase in mutations in the exposed group (children had a lower mortality risk before they were exposed born after the father’s exposure). This increase was (the healthy worker effect). The authors did detect greater, and almost significant, for paternal external significant dose-response relationships for malignant doses between 20 and 30 cSv, with an OR of 3 neoplasms and cardiovascular disease. Using the (0.97-9.3). No effect of time between exposure and general Russian population as a control group they conception was found. determined that there was an ERR of 2.1/Sv (1.3- Studies of these workers must be interpreted 2.9) for cancer mortality and 0.5/Sv (0.2-0.9) for with some caution because individual doses are not cardiovascular disease mortality. known with much certainty. Another consideration, We looked at two studies of the immune system potentially more important than uncertainty in doses, response of Chernobyl clean-up workers. Kurjane et is the fact these workers were screened for health al. (2001) studied the immune status of 385 Latvian effects at a higher rate than average Russians. This clean-up workers exposed at Chernobyl. They found was because of the known occupational hazard that evidence of impaired immune systems including they had been exposed to and it may have led to an a reduction in T cells and neutrophil phagocyte overestimate of the risk. activity. The authors also detected altered levels of certain antibodies. Kuzmenok et al. (2003) also 11.2.3 Childhood thyroid cancer found evidence of impaired immune systems in 134 Belarussian cleanup workers although they found The most prominent health effect of the Chernobyl normal numbers of T-cells. accident has been childhood thyroid cancer. The Investigations into genetic damage in cleanup thyroid is a gland in the neck that uses iodine in workers have shown persistent damage in exposed the synthesis of thyroid hormone. Since it can’t workers but have not shown clear evidence of distinguish between radioactive iodine and stable elevated mutations in the offspring of exposed iodine, iodine isotopes in fallout can accumulate workers. Melnov et al. (2002) showed an apparent in the thyroid. This is particularly important in the increase in aberrations over time and Neronova fast-growing thyroids of young children. The major et al. (2003) found persistent 10-fold increases in isotope involved is iodine-131 (I-131). aberrations up to 13 years after exposure. Mutations One 1997 review article commented on the initial in the germ cells of exposed workers might be passed skepticism among the scientific community about on to offspring. This has been seen in families living potentially substantial disease outcomes in people near Chernobyl or the Semipalatinsk Test Site and it living near Chernobyl; this eventually gave way to has also been observed in mice (Dubrova et al. 2003). a consensus acceptance of a dramatic increase in Livshits et al. (2001) measured specific mutations in childhood thyroid cancer (Schwenn and Brill 1997). 134 Nuclear Power Accidents

Several studies have examined thyroid cancer in case then the thyroids of these children would have children and adolescents in Belarus, Russia, Ukraine absorbed more I-131 from the Chernobyl accident. and elsewhere to characterize the magnitude, time This second possibility was addressed in another pattern, and dose-response relationship of this study of Bryansk children (ages 6-18) by Shaktarin increase. et al. (2003). These authors studied 2,590 children In 1996 a group of Belarussian physicians from 75 settlements in Bryansk. Dietary iodine was reported that the rate of childhood thyroid cancer in determined from urine samples and I-131 doses were Gomel, a heavily contaminated area of Belarus, had reconstructed assuming sufficient dietary iodine. A increased over 100-fold since the accident (about total of 34 thyroid cancer cases were identified (this 200 cases; Antonelli et al. 1996). An increase of this small number contributed to large uncertainty in the magnitude was later reported for the larger heavily results). The study demonstrated that there was a contaminated area that included parts of Russia and degree of iodine deficiency in the region and that Ukraine (about 800 cases; Pacini et al. 1999). it affected thyroid dose and thyroid cancer risk. For In 1998 Astakhova et al. reported a case-control all children the ERR was 18.1/Gy (11.3-26.9) but as study of Belarussian children. 107 cases were dietary iodine increased the risk estimate declined considered with two groups of matched controls, such that children with sufficient dietary iodine had all children aged 0-11 years at the time of the a lower (and much less certain) estimated ERR of accident. The first group of controls was drawn 13/Gy (-11-71.2). from the general population and the second group Shibata et al. (2001) looked at over 20,000 was selected to have had the same opportunity for children within a 150-km radius of Chernobyl and diagnosis as the cases7. In both tests a significant described increased thyroid cancer incidence by pattern was observed; when using the first group comparing people with different birth dates. I-131 of controls an OR of 5.84 (1.96, 17.3) was found has a half-life of just eight days, so virtually all of between high dose (>1 Gy) and low dose (<0.3 Gy) the I-131 released from Chernobyl decayed within a children. A similar odds ratio was found using the few months of the accident. The unexposed control second group of controls (OR 5.04; 1.5-16.7). group in this study therefore included 9,472 children The dose-response relationship for childhood born after January of 1987. There were no thyroid thyroid cancer was explored by Jacob et al. (1999). cancers in this group. There were two exposed groups These authors reconstructed thyroid doses for analyzed in this study: The first group included children (age 0-15 at the time of the accident) in 2,409 children who were born between the date of Belarus and in the Bryansk district of Russia. Three the Chernobyl accident and December of 1986; one cities and over 2,700 settlements were included in cancer was found in this group. 9,720 children were the study. Thyroid doses ranged up to just over 2 born between January of 1983 and April of 1986; Gy. An ERR of 23/Gy (8.6-82) was derived for this these subjects were all infants and toddlers at the cohort, and this is roughly three times higher than the time of the accident. There were 31 cases of thyroid estimate generated by a study of children exposed to cancer in this group. medical irradiation (7.7/Gy; Ron et al. 1995). Part of There has been one study of thyroid cancer the reason may be the difference in length of follow- in adolescents and adults exposed to Chernobyl up. Ron et al. pooled many data that spanned decades fallout. Ivanov et al. (2003) studied the thyroid of post-exposure time while Jacob et al. included the cancer incidence in Bryansk residents age 15-69 years 1991-1995. The relative risk is expected to be at the time of the accident; the mean dose in this higher in the early years because the background population was 2.3 cGy. The overall standardized incidence of cancer in children is so low. Another incidence ratio comparing the exposed individuals possibility is that the children in the study had a diet to general Russian rates was not different from the that was deficient in natural iodine. If this were the ratio for unexposed individuals. The dose-response

7 This second control group was selected to address the idea that intensive screening after the accident may have turned up more cancer cases than would have been detected normally, thus artificially increasing the cancer rate. Nuclear Power Accidents 135 relationship was not significant for the whole cohort 2003). This was not an epidemiological study but it but it was significant for the subjects younger than did present dose estimates and is worth considering 30 at exposure using internal controls; the ERR for as a reference point. These authors concluded that a this group was 8.65 (0.81-11.47)8. In all cases (male small excess of thyroid cancer, 1-20 cases, may have or female, internal or external controls) the ERR been caused by the Chernobyl accident. Tukiendorf estimate declined with age. The results of this study et al. (2003) compared thyroid cancer incidence in are suggestive of some effect but they are not clear Opole province, Poland (1994-1998) to levels of and they contrast with the conventionally held view cesium isotopes on the ground. Deposited cesium in that radiation exposure in adulthood is unlikely to fallout decays slowly and can therefore be used as a lead to cancer. rough guide to the pattern of iodine deposition that The rate of thyroid cancer has clearly increased, occurred immediately after the accident. Thyroid and it may also be the case that these radiation- cancer proportional mortality rates (thyroid cancer induced cancers are different than background mortality as a fraction of total cancer mortality) thyroid cancers. Ukrainian surgeon S. J. Rybakov were correlated with cesium deposition for females and colleagues (2000) operated on over 339 (94 cases) but not for males (27 cases)10. Increased children between 1981 and 1998, 330 of these after levels of radiation were detected as far away as the Chernobyl accident. They report that cancers Connecticut, where one researcher noted that in children who had been exposed to high levels of childhood and adult thyroid cancer incidence had radiation were more extensive, more highly invasive, increased 4-7 years after the accident (Mangano et and more likely to be accompanied by nodal al. 1996). metastases. Similar findings had been reported by Pacini et al. in 1997. They found that post-Chernobyl 11.2.4 Childhood leukemia thyroid cancers in Belarus were more likely to affect younger subjects, were less influenced by gender, Leukemia rates following Chernobyl appear to have were more aggressive, and were more frequently increased, and like thyroid cancer this effect is seen in associated with autoimmunity when compared to children. Exposure at young ages, including prenatal naturally occurring cancers in Italy and France. exposure, has been investigated to determine the Several studies have investigated thyroid cancer influence of age at exposure and dose. rates outside of the immediate vicinity of Chernobyl. Petridou et al. (1996) compared leukemia rates Cotterill et al. (2001) studied northern England in Greek children who were born in 1986-1987 (in and found that there was an increase in incidence utero at the time of the accident) to rates in children immediately following the Chernobyl accident. born 1980-1985 and 1988-1990. Leukemia in the The excess in Cumbria, the region receiving the first year of life was more than twice as likely in heaviest fallout in England, was particularly high the exposed (in utero) group (rate ratio 2.6, 1.4- (rate ratio of 12.2, 1.5-101, comparing 1968-1986 5.1)11. Infant leukemia rates for the in utero cohort to 1987-1997), but this was based on 1 case before were also shown to increase with surface soil the accident and 6 cases after the accident9. A study measurements of fallout radioactivity. Michaelis et of Turkish children did not find any cancers in al. (1997) used the same time windows to study in exposed or unexposed regions (Emral et al. 2003). utero exposure in Germany and found a rate ratio of A French risk assessment dealt with children in 1.48 (1.02-2.15) but did not find a correlation with eastern France where thyroid doses ranged from ground deposition of Cs-137. A study of childhood 1-10 mSv; these are ~100 times lower than doses leukemia across Europe (the European Childhood in exposed areas of Belarus and are comparable to Leukemia-Lymphoma Incidence Study, ECLIS) average background radiation doses (Verger et al. found that childhood leukemia risk was related to

8 Using external controls (Russian rates) the ERR estimate for this group was 0.74 (-2.69-4.21). 9 The rate ratio was 12.2 (1.5-101) comparing 1968-1986 to 1987-1997. 10 It was unclear what the ages of exposure or diagnosis were in this study. 11 Leuekemia rates were also observed for ages 1-4 but no effect was seen (Petridou et al. 1996). 136 Nuclear Power Accidents average fallout dose for each country (Hoffmann 10 years old when they were exposed to radiation 2002) and was roughly compatible with the in utero from the Chernobyl accident (13 children were in exposure results from Greece and Germany. In all utero at the time of the accident). When compared of these cases the doses received by the developing to a control group from a less-exposed province a fetuses were low (less than 1 mSv; Michaelis et al. significant elevation of circulating thyroid antibodies 1997, Hoffmann et al 2002). was found. This is thought to indicate a higher Noshchenko et al. have published two papers that probability of disease development, although at the describe a link between Chernobyl and leukemia in time of the study disease rates were similar. A study the Ukraine. The first paper (2001) found an increase of 53 Ukrainian children found elevated levels of in all leukemias, and in lymphocytic leukemias thyroid-stimulating hormone (TSH), a sign that the specifically, when comparing the Zhitomir (exposed) pituitary gland is stimulating the thyroid in response and the Poltava (unexposed) regions of the Ukraine. to underactivity (Vykhovanets et al. 1997). Elevated The exposed and unexposed groups in this study TSH was also found in girls from Belarus, Russia were comprised exclusively of the 1986 birth cohort and Ukraine who had moved to Israel (Quastel et in order to focus on effects of exposure in utero. al. 1997). Goldsmith et al. (1999) studied 160,000 The second paper by Noshchenko et al. (2002) children from Belarus, Russia and Ukraine who reports on a case-control study based in Zhitomir were exposed to Chernobyl fallout before age 10. and Rivno regions. 272 cases of leukemia were These authors defined hypothyroidism by elevated identified in people that had been age 0-20 at the TSH and reduced thyroid hormone (thyroxin) and time of the accident (72 more cases than predicted compared hypothyroid incidence to individual body based on pre-accident leukemia rates). Bone marrow burdens of cesium-137 (Cs-137), a rough proxy for doses were estimated for these cases and for controls thyroid I-131 dose. They found that hypothyroidism matched by age, gender, and type of settlement. (148 cases) was correlated with Cs-137 although the Increased risks of leukemia generally, and acute, correlation was only significant for boys. acute lymphocytic, and acute myeloid leukemias Radiation can cause mutations in sperm or egg specifically, were observed for males and for both cells, also called germ cells, and these mutations can genders combined. The authors found their risk be passed on to children as ‘germline mutations’. estimates to be similar to the estimates of Stevens Exposure of parents prior to the conception of a et al (1990) with residents downwind of the Nevada child can therefore lead to effects in the children. Test Site12. There was also a distinct age effect in This is discussed briefly above in relation to this study with the earlier ages at exposure showing Chernobyl cleanup workers and in our chapter on a higher risk. preconceptional exposure (appendix C). Studies of families living downwind of Chernobyl have 11.2.5 Non-cancer effects in children demonstrated that germline mutations did occur as a result of the accident although it is not clear what When Schwenn and Brill wrote their review in the health implications of these mutations might 1997, it appeared that the increase in thyroid cancer be. Dubrova et al. (1996) collected blood samples was the only significant health effect of the accident. from 79 families in Belarus and 105 families in the Since that time, a few new findings have suggested U.K. (controls) and looked for genetic mutations in that other health effects have developed. One children born in 1994. If the particular mutation was effect is thyroid autoimmune disease, a condition not present in either parent then it was assumed to where the immune system attacks the thyroid. An have been a germline mutation. In this study the rate associated condition is an underactive thyroid of germline mutation in Belarus was twice as high (hypothyroidism). Pacini et al (1998) looked at 287 as in the U.K. Furthermore, the rate of mutation in children from the village of Hoiniki who were up to parts of Belarus with high cesium deposition was 1.5

12 Noshchenko et al found an odds ratio for acute lymphocytic leukemia of 3.1 (1.5-6.4) when comparing bone marrow doses >10 mSv to doses <2 mSv. Stevens et al found an odds ratio of 1.69 (1.01-2.84) when comparing marrow doses of 6-30 mGy to doses <3 mGy. Nuclear Power Accidents 137 times higher than in less-contaminated areas. This impaired immune systems in emergency and clean- paper was widely challenged on the grounds that the up workers. A dramatic increase in childhood thyroid control group (British families) was too different cancer has been seen among Chernobyl downwinders from the experimental group, that several potentially in addition to evidence of an increase in childhood confounding factors were not accounted for, and leukemia, an increase in thyroid autoimmune that the A-bomb survivor research was not detecting disease, effects on mental health in children exposed a genetic effect. Schwenn and Brill described the in utero, and an increase in germline mutations in Dubrova results as “highly suspect”. In 2002, the children of exposed parents. The thyroid cancer however, Dubrova et al. published new results that excess was larger than expected based on old thyroid confirm the earlier findings. A study of 256 Ukrainian cancer risk models (Buglova et al. 1996). Newer families, using Ukrainian children born before the models based on childhood medical exposures to Chernobyl accident as controls, found a 1.6-fold external radiation are closer to the observed excess increase in germline mutations (Dubrova et al. around Chernobyl. Remaining differences between 2002a). The mutations only appeared in the paternal observed and expected cancer rates might be partially germlines. These researchers also investigated attributable differences in dietary iodine (although germline mutations around the Semipalatinsk there is still insufficient data for anything more nuclear test site in Kazakhstan, and again found a than speculation on this point) and to differences in similar increase of 1.8-fold over controls (Dubrova follow-up time of exposed children. The dramatic et al. 2002b). In this study Dubrova et al. were also effect of age at exposure is clear in the Chernobyl able to detect a smaller increase in mutations in the downwinders as it is in medically exposed children. next generation. Of roughly 800 childhood cancer cases in the heavily Effects on the development of children who contaminated areas around Chernobyl, 98% were were exposed in utero, and mental health effects in in children under age 10 and 65% were in children particular, have also been studied. Although children under age 5. Childhood leukemia rates measured from contaminated area tend to show some negative by Noshchencko et al. (2002) are compatible with impacts on IQ or mental and behavioral function, it the estimated leukemia effects of nuclear weapons becomes very hard to disentangle effects of radiation testing in Nevada. The suggestive evidence of from effects of family stress associated with infant leukemia following in utero exposure in evacuation, resettlement, and anxiety concerning Europe involves very low doses in the range of the accident (Kolominsky et al. 1999, Igumnov and background radiation. Germline mutation results for Drozdovitch 2000). Chernobyl have been replicated around the test site in Semipalatinsk and demonstrate that the children of exposed parents have been affected in some way 11.2.6 Chernobyl discussion (Dubrova 2003).

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COMMUNITIES NEAR NUCLEAR FACILITIES Furthermore, workers tend to have better available dose information and the approach to research is 12.1 Introduction distinctly different. Workers are discussed in a separate section (sections 6-8), and in one section This section focuses on communities living around and an appendix we discuss the effects of exposures military and commercial nuclear facilities (Figure that occur before workers conceive children (section 12-1 shows commercial facilities). Exposures 10, appendix C). discussed in this section are relatively low-level, Epidemiological studies of communities near generally less than background radiation exposures, nuclear facilities frequently follow vocal public and individual dose information is not typically concern. The Three Mile Island and Chernobyl available. accidents helped to increase awareness of the health Several types of exposure are not included in effects of radiation, and although these facilities this section. Nuclear weapons fallout and accidental operate according to regulations that limit maximum releases from nuclear facilities clearly affect nearby radiation releases to theoretically ‘safe’ levels, many communities, but the magnitude of exposure is much community members have understandably persistent greater; these exposures are discussed in separate concerns. At the same time, many regulatory agencies sections (sections 5 and 11). Workers at these and research institutions recognize the importance facilities are members of nearby communities but of undertaking studies to determine whether or not are also often exposed to higher levels of radiation. citizens are at risk when living in close proximity to

Figure 12-1. A map showing the approximate location of worldwide commercial nuclear plants (crystals.llnl.gov/energy. html). 145 146 Communities Near Nuclear Facilities the facilities for long periods of time; these exposures conventional risk models are reasonable, then we are very different from the acute exposures of, for should not expect to see obvious evidence of a health example, atomic bomb survivors. impact. Types of studies. Epidemiological studies of It is important to remember that these studies these communities are particularly challenging. One are very limited in what they can tell us: if no effect of the biggest problems confronting researchers is is observed it might mean that there is no effect or the lack of exposure information. It is very difficult it might mean that the effect is too small to detect. to estimate an average dose for a community near a If an effect is observed, without dose information facility and almost impossible to recreate individual and a dose-response relationship the result is often doses. insufficient to support causality. Since dose information is so hard to come by, many researchers have adopted an ecologic approach 12.2 US studies to studying these communities. People are grouped according to where they live with the expectation Hanford. The Hanford site in Washington that people near a facility will show a particular produced plutonium for nuclear weapons from health effect more frequently than people far from the 1940s to the mid 1980s. In the mid 1980s, a facility. This is still a challenging approach for information was released that documented large several reasons including the fact that exposure releases of iodine-131 and other radioactive to radioactive emissions is unlikely to be a simple materials from 1944 to 1957. Studies of possible function of distance. An airborne radioactive plume, health effects in surrounding communities began for example, might touch ground some distance soon after this information became available. The away from the plant, and over time radioactive most recent and comprehensive publication from plumes may tend to travel in one direction according these efforts is the federal government’s Hanford to prevailing winds. Drawing a circle around a Thyroid Disease Study, performed by researchers facility and assuming that everyone inside was at the Fred Hutchinson Cancer Research Center potentially exposed, a common study design, is in Seattle (Davis et al. 2002). This is one example overly simplistic. of a study with dose estimates, and in this case the Another problem involves legal limits on estimated mean thyroid dose of 131I was 17.4 cGy. radioactive releases. If plants are adhering to Out of 3,440 study participants, all exposed in exposure standards then doses received by the early childhood, 20 were diagnosed with thyroid public should be low and adverse health outcomes cancer and there was not a detectable significant are expected to be rare. The Nuclear Regulatory dose-response relationship. Non-cancerous thyroid Commission allows a maximum annual dose of 1 disease was also studied and again no significant mSv to an exposed member of the public while EPA dose-response trends were detected. Despite being allows a maximum dose of 0.1 mSv. These doses a very expensive effort the study is inconclusive and are lower than average background radiation doses cannot rule out a relatively strong effect of Hanford of ~3 mSv and variations in background radiation, emissions1. in addition to variability in such factors as age and Studies conducted in collaboration between exposure to other carcinogens, are very hard to downwind communities and scientists (in the control for. This creates a ‘signal to noise’ problem Northwest Radiation Health Alliance) have employed where the subtle health impacts of nuclear facilities informal community survey-based methods to assess are hard or impossible to detect within the dramatic potential health impacts of Hanford. Grossman et al. variations in disease incidence of a community. If (1996) reported more miscarriages in hypothyroid exposure is truly below the regulatory limit, and women than in women with normal thyroid hormone

1 It is interesting to note that Kerber et al. (1993) found positive results in a cohort of people exposed to the same mean dose (~17 cGy) of 131I from NTS fallout (see the fallout and thyroid cancer sections). Ruttenber et al. (2004) point out that, due to substantial errors in accounting for uncertainty, the results of HTDS can be seen as consistent with no effect or with a relatively strong effect. Communities Near Nuclear Facilities 147 levels (this could not in itself be attributed to Hanford Clapp et al. (1987) observed that leukemia emissions). Goldsmith et al. (1999) compared incidence in five coastal Massachusetts towns near a information about hypothyroidism in children commercial reactor (Pilgrim) were higher than local exposed to Chernobyl fallout to information about or state rates for 1982-84; this was five to ten years hypothyroidism in juveniles exposed to the Hanford after peak radioactive releases from the facility. emissions. Their analysis suggested increased rates Poole et al. (1988) showed that this increase was of juvenile hypothyroidism at a time and place not evident in 1985 and 1986. The Massachusetts implicating Hanford emissions2. Grossman et al. Department of Public Health followed up with a (2002, 2003) reported excesses of thyroid cancer and case-control study for the years 1978-86 (Morris thyrotoxicosis (hyperthyroidism, Graves’ disease, and Knorr 1996). This study found an association toxic goiter) that were, according to the authors, between cases of leukemia and proximity to the plant unlikely to be pure artifacts of the informal survey during 1974-77 (years of high emissions). Residence methods used. These authors also noted a significantly within 4 miles of the plant was associated with an higher prevalence of thyrotoxicosis in HTDS cases OR of 3.88 (0.81-10.64). It is very unlikely that this who lived in the exposed area compared to those result could be entirely explained by releases from that moved out of the area before major 131I releases the Pilgrim reactor unless the releases were much occurred (Grossman et al. 2002). Sever et al. (1988) greater than the legal standard; this result might measured congenital malformations in communities mean that some leukemia risk factors, which may near Hanford and observed significantly increased include Pilgrim emissions, coincided in the area. rates of neural tube defects (40 observed vs. 23 Johnson (1981) reported that certain cancers expected cases)3. appeared to be associated with proximity to the Other US facilities. Most studies of nuclear Rocky Flats plant in Colorado. Crump et al. (1987) facilities are limited to an ecological design with replicated these results, showing a positive correlation average, usually county-level, rates of disease between proximity to Rocky Flats and incidence of incidence or mortality. These studies are further total cancer and radiosensitive cancers for 1969- limited, as discussed above, by a lack of dose 1971. This study showed the same correlation for estimates, and often use dimensions of space 1979-1981 although the authors claimed that the (closeness to a facility) and time (cancer effects effect did not persist when controlling for distance should appear several years after exposure). Joseph from the state capitol. Mangano (1994), for example, looked at cancer Enstrom (1983) found a decrease in the rates mortality within 100 miles of the nuclear weapons of overall cancer mortality during 1960-1978 for plant in Oak Ridge, TN. He compared mortality the communities around the San Onofre plant in rates in 1950-1952, around the beginning of California, consistent with the overall decrease in operations at Oak Ridge and before an effect would cancer rates in both the United States and California, appear, with mortality rates in 1987-89. He found suggesting that the plant did not contribute to cancer that mortality rates increased 34.1% in this area, mortality. A 1985 letter (Enstrom 1985) reported compared to a 28.2% increase in the Southeast and that leukemia mortality and infant mortality was a 5.1% increase nationwide. Both differences were not unusual within 25 miles of San Onofre through statistically significant4. This doesn’t prove that Oak 1983. Ridge caused the increase but it is consistent with A pair of papers looked at town-level cancer that possibility. incidence (and mortality) near two nuclear materials

2 An apparent increase in juvenile hypothyroidism occurred during the 1950s and was spatially coincident with areas estimated by the Hanford Environmental Dose Reconstruction to have received the highest doses from Hanford emissions. 3 These authors report in a separate article that neural tube defects can be associated with workplace exposure of cases’ parents at Hanford (see preconceptional exposure section). 4 Mangano (1994) also showed that cancer mortality increased more in rural than in urban areas, more in mountains than in valleys, and more in the county where Oak Ridge is located than in surrounding counties. 148 Communities Near Nuclear Facilities

the Shiprock uranium mining area (Shields et al. 1992). These authors found an increased risk of congenital birth defects in mothers living near tailings or mine dumps (OR 1.83, 1.0-3.5) or mines (OR 1.43, 0.72-2.56)6. Multi-site studies in the US. A National Cancer Institute study looked at cancer mortality rates in 107 counties adjacent to 61 nuclear facilities (mainly commercial power facilities) and did not detect any mortality excess (Jablon et al. 1991). This study did, however, find significantly increased childhood leukemia incidence in four Connecticut and Iowa counties. Mangano et al. (2002) studied areas Figure 12-2. A leaky drum at the 903 pad at Rocky Flats. downwind of eight nuclear plants before and after Photo courtesy of the U.S. Department of Energy http:// the plants closed. They found that infant mortality www.rfets.gov/doe/HAER/RockyFlats_HistoryBook_ and childhood cancer incidence declined after plant rev2.pdf closure and that the declines were significantly greater than average declines nationwide. This was processing plants in Pennsylvania (Boice et al. followed by an assessment of childhood cancer 2003a, 2003b). The Apollo and Parks facilities were incidence in counties adjacent to 14 east coast less than three miles apart and could be treated as one nuclear power plants (Mangano et al. 2003). At all source of exposure. Although the local rates of colon sites there was an apparent excess and the overall cancer and cervical cancer were significantly higher excess of ~12% was highly significant. This study than Pennsylvania rates, the cancers associated also determined that Pennsylvania counties within with likely exposures from the plants were not 30 miles of a nuclear power facility (about half significantly increased and the total cancer incidence of the state) had a childhood leukemia rate 10.8% was not increased (SIR 1.01, 0.93-1.10). There were higher than the national average7. 18 leukemia cases, compared to 12.4 expected, for a SIR of 1.45 (0.86-2.30). Cancer mortality rates were 12.3 UK studies not different from the rates for control counties in Pennsylvania but there did appear to be an increase There have been many studies of cancer clusters in mortality from multiple myeloma, leukemia and in the UK, particularly childhood leukemia clusters, all cancers after the plants started up5. and some of these occur near nuclear facilities. One Communities exposed to contamination from controversial explanation of these clusters involves uranium mining and milling may experience health fathers who work at the facilities. It has been risks. Au et al. (1998) measured chromosome proposed that radiation exposure before conception aberrations in residents next to mining and might damage sperm cells and pass a cancer risk on milling sites of Karnes, Texas. The study found a to the child. Although this possibility is relevant to nonsignificant increase in chromosome aberrations, communities living near the facilities, we deal with it and significantly compromised DNA repair separately in our preconceptional irradiation section responses, compared to controls. Another study and in an appendix. The studies that we discuss focused on birth outcomes in Navajo families near below involve exposures received by communities

5 During 1950-64, 1965-79 and 1980-95 the relative risks for multiple myeloma were 0.91, 0.92 and 1.04. Corresponding estimates for leukemia were 0.89, 0.86 and 0.97, and for solid cancer 0.96, 0.95 and 0.98. The two facilities began operations in 1957 and 1960. 6 Shields et al. (1992) also found evidence that occupational or residential exposure of fathers could be a risk factor. This is discussed further in the section on preconceptional exposures. 7 Childhood leukemia in the rest of the state was 11.5% below the national average (Mangano et al. 2003). Communities Near Nuclear Facilities 149

uncertainty information was provided. Predictions of radionuclides in the bodies of Seascale residents were consistent with several sets of measurements suggesting that the dose estimates were reasonable (Simmonds et al. 1995). The rate of stillbirth around Sellafield was also evaluated. Wakeford and McElvenny (1994) reported that the stillbirth rate within 25 km of Sellafield was normal (these authors were at the time working for British Nuclear Fuels, the public liability corporation running Sellafield). Dummer et al. (1998), controlling for year of birth, social class Figure 12-3. Native Americans from San Ildefonso Pueblo and Los Alamos residents (http://www.lanl.gov/history/ and birth order, also found a normal stillbirth rate in communities/index.shtml). this area generally. Stillbirths were further analyzed by distance from Sellafield (Dummer et al. 1998). when radiation leaves the site of a facility. These This kind of analysis is problematic because the studies frequently use as an endpoint the group of deposition of airborne pollutants does not always cancers including leuekemia and non-Hodgkin’s correspond to distance from a facility. A high lymphoma; we refer to this group below as LNHL. smokestack, for example, might cause pollutants Sellafield. Epidemiological studies of childhood to pass above houses close to a facility and wind cancer near nuclear facilities in the UK began in direction might cause pollutants to be deposited in 1983 when a television program suggested that a spatially nonuniform way. The authors considered there was a cluster of childhood leukemia in the 5 km rings around Sellafield out to 25 km and village of Seascale, a couple of miles from the found no stillbirth trend with distance. They did, Sellafield reprocessing facility in England (Gardner however, find significantly increased stillbirth rates et al. 1991). An independent government inquiry 10-15 km north of Sellafield in 1950-1959 and 15- established that the excess, although based on a 20 km northeast of Sellafield in 1980-1989 and also small number of cases, did appear to exist (Black determined that there was a significant excess in 1984, Gardner 1991). Draper et al. (1993) conducted the north-northeast direction at all distances9. Some a similar analysis through 1990 that confirmed the Sellafield discharges to the sea have blown ashore excess of childhood LNHL in Seascale 1963-1983 over the years and Dummer et al. (1999) evaluated and showed a continuing excess for 1984-1990 stillbirths a second time according to distance from in addition to a possible excess of other cancers8. the coast in 2.5-km rings; no trend with distance was There was no evidence of an increase in areas found. immediately surrounding Seascale and Sellafield. Dounreay. The Dounreay nuclear reprocessing In the 1995 the National Radiological Protection plant in Caithness, Scotland was the subject of a public Board published a dose reconstruction and risk inquiry in 1986 that was followed by several studies. assessment for 1348 children born in Seascale It became apparent that there was a leukemia cluster between 1945 and 1992 (Simmonds et al. 1995). near the facility but researchers have been unable The expected number of radiation-induced LNHL to find a cause or to rule out any possible causes. In cases in the cohort was 0.46, and Sellafield releases the first study of Dounreay, Heasman et al. (1986) were estimated to contribute only 10% of this risk reported excess cases of childhood leukemia within (the rest being natural radiation); unfortunately no 12.5 kilometers of the facility from 1979 to 1984;

8 For ages 0-24 there were 5 cases of LNHL in 1963-83 (0.49 expected) and 2 cases in 1984-90 (0.12 expected). In 1984-1990 there were two cases of ‘other’ cancers; there was only an 8.3% chance of these two cases occurring based on national rates. 9 The Odds Ratio for one northeast direction category was 1.12 (1.00-1.24) and for an adjacent north-northeast category was 1.07 (0.96-1.19). Many of the stillbirths in these directions occurred more than 25 km from Sellafield. 150 Communities Near Nuclear Facilities

5 cases were observed vs. 0.5 expected (p<0.001). compared to 69.3 expected, and that this excess This study was followed by a case-control study of was concentrated in 0-4 year-olds. The authors also childhood leukemia and non-Hodgkin’s lymphoma presented evidence suggesting that risk was higher (LNHL) in Caithness (Urquhart et al. 1991). With within 5 or 10 km of the facilities13. A follow-up case- only 13 eligible cases the results were not very control study suggested that some of this risk might informative10. Black et al. (1994) showed that the come from paternal exposure while working at the excess of childhood LNHL near Dounreay was still facilities (Roman et al. 1993; see preconceptional apparent throughout the 1980s. For the period 1968- irradiation section). 1991 there were 12 cases within 25 km of Dounreay Ewings et al. (1989) reported an excess of compared to 5.2 expected for a significant incidence childhood LNHL cases near the Hinkley Point ratio of 2.32. Watson and Sumner (1996) performed nuclear power plant in Somerset. From 1964-1986 urinary and whole-body radiation measurements there were 137 cases in Somerset, significantly more on Caithness leukemia cases and on controls, and than the 110 expected based on national rates. The although they claimed that there was no evidence area within 12.5 km of Hinkley Point demonstrated of increased radioactivity in cases compared to an excess that was slightly larger than the Somerset- controls, many results were not presented11. wide excess14. Other UK facilities and multi-site studies. Many reports have attempted to synthesize data Reports of the Seascale and Caithness clusters from multiple locations within the UK. Hole and were followed by a series of investigations of Gillis (1986) pointed out that childhood leukemia other facilities across the United Kingdom. During rates during 1974-1985 near four nuclear facilities the course of the original government inquiry in the West of Scotland were comparable to rates into Seascale, Heasman et al. (1984) reported a in the rest of the West of Scotland. These authors significant excess, during 1975-81, of all childhood also showed that during 1964-85 there were leukemia within 10 miles of the Hunterston facility nonsignificant excesses in areas adjacent to each in Scotland (18 observed an 9 expected cases). No site. Roman et al. (1987; discussed above) combined significant excesses were found near the Chapel their own results with childhood leukemia rates near Cross or Dounreay facilities (although these authors Sellafield, Dounreay, and the four sites assessed by would later report the cluster around Dounreay). Hole and Gillis (1986). They showed a significantly Roman et al. (1987)12 contributed a study positive incidence ratio for the full set of data of 1.5 of childhood leukemia in the West Berskshire, (1.2-1.8). Basingstoke, and North Hampshire District Sharp et al. (1996) examined childhood LNHL communities, lying adjacent to the Atomic Weapons rates near seven nuclear sites in Scotland- the Research Establishment at Aldermaston and the Dounreay reprocessing plant, three power plants, Royal Ordnance Factory at Burghfield. It was shown and three submarine bases. Four of these sites that there was an excess of childhood leukemia in had also been included in the pooled estimate of the districts during 1972-85, with 89 observed cases Roman et al. 1987, but in this study the incidence

10 None of prenatal x-rays, paternal preconceptional exposure at work, drugs taken during pregnancy, or lifestyle factors were found to be significantly associated with the leukemia cases (and none could be ruled out). 11 For example, the authors report that there were significant inter-group differences for whole body measurements in the original analysis. The results are not shown and the authors claim that further corrections caused the difference to become nonsignificant. Americium measurements of the head appeared higher in cases in a figure but the quantitative comparison of cases to controls was not provided. 12 This report expanded on earlier report by Barton et al. (1985). 13 The incidence ratio for all ages was 1.3 (1.0-1.6); for 0-4 year-olds, with 53 observed and 34 expected cases, the ratio was 1.6 (1.2-2.0). The incidence ratio for 0-4 year olds within 5 km of a facility was 2.3 (1.1-4.4) and within 10 km was 2.0 (1.3-2.9). 14 The standardized registration ratio for areas within 12.5 km of Hinckley Point was 1.82 (1.10-2.85) and the ratio for the rest of Somerset was 1.18 (0.98-1.41). The difference between these two ratios was not quite significant (p = 0.058). Communities Near Nuclear Facilities 151 of leukemia was measured over a larger area around began operating in 1966. Cancer mortality around each site. The only site associated with a significant La Hague was analyzed by Dousset (1989), who excess of cases was Dounreay. In a similar analysis found no difference between rates within 10 km of of childhood brain cancer and other non-LNHL the facility and rates in the rest of the departement cancers at the seven sites Sharp et al. (1999) showed de la Manche (where the facility is located). Viel a significant excess in only one case, central nervous and Richardson (1990), after considering the reports system (CNS) tumors around the Rosyth nuclear from Seascale and Caithness, focused on childhood submarine base (136 observed and 111.5 expected leukemia mortality. Between 1968 and 1986 there cases). were 21 deaths from childhood leukemia within 35 The Office of Population Censuses and Surveys km of La Hague, consistent with rates for the rest of (OPCS) published a comprehensive report on cancer the departement. Hattchouel et al. (1995) examined mortality near nuclear facilities in the UK in 1987 childhood leukemia mortality nationwide and found (Cook-Mozaffari et al. 1987, Forman et al. 1987). what appeared to be a decrement with an SMR of Many relative risk estimates were made for different 0.80 (0.62-1.01); younger ages did not appear to be groupings of age at exposure, facility, and cancer; at higher risk in this study. 13 estimates were significantly positive and 38 In contrast to these results for leukemia mortality, were significantly negative. For example, childhood studies of childhood leukemia incidence around La lymphoid leukemia mortality at all facilities was Hague demonstrated an apparent cluster17 within significantly increased (RR 2.00, p=0.005) while 10 km of the site (Viel et al. 1993, Viel et al. 1995, adult mortality from leukemia, myeloma, or any Guizard et al. 2001) and led to a case-control study cancer was significantly below normal15. Childhood that was published in 1997 (Pobel and Viel). The leukemia results were in some cases confusing- case-control study presented evidence that exposure mortality increased with proximity to five facilities to local beaches and seafood were risk factors that began operations before 1955 but this trend for childhood leukemia. Cases and controls were was reversed for seven facilities running since grouped according to how often mothers spent time 1960. Overall, however, the evidence supports at local beaches, how often children spent time at an increased leukemia risk. When the young age local beaches, and how often children ate local fish group was restricted to 0-9 years the results became and shellfish. In all three cases there were significant stronger: within 6 miles of the pre-1955 facilities exposure-response trends. Children who played at the lymphoid leukemia RR was 3.95 (p=0.001) and the beach more than once a month showed a relative there was a stronger trend with proximity to the risk of 2.87 (1.05-8.72) and children who ate local facilities (p=0.035). These results were validated seafood more than once a week showed a relative using a different methodological approach (Cook- risk of 2.66 (0.91-9.51). These authors also found Mozaffari et al. 1989a) and it was shown that a significant risk associated with living in granite potential sites of nuclear installations did not have homes, a potential radon risk (RR 1.18; 1.03-1.42). the same childhood leukemia risk as existing sites Hoffman et al. (1997) investigated a childhood (Cook-Mozaffari et al. 1989b)16. leukemia cluster in Elbmarsch, Germany, near the Krummel nuclear power plant. From 1990 to 1995 12.4 Nuclear facilities outside the US and UK there were six diagnosed cases within 5 km of Krummel, giving an SIR of 4.6 (2.1-10.3). All six La Hague reprocessing plant in Normandy, France cases were from the south side of the Elbe river,

15 The relative risks of adult leukemia, myeloma, and all cancers were 0.88 (p=0.04), 0.79 (p=016), and 0.96 (p<0.001), respectively, for all facilities combined. 16 Specifically, the relative risk of childhood lymphoid leukemia was 1.20 near existing sites and 1.09 near potential sites of nuclear installations. 17 Within 10 km of La Hague, from 1978-92, there were 4 observed cases in the 0-24 age group vs. 1.4 expected cases, giving an SIR of 2.8 (0.8-7.2). Guizard et al. updated the description of this cluster in 2001, showing 5 observed and 2.7 expected cases from 1978-98 (SIR 2.17; 0.71-5.07). 152 Communities Near Nuclear Facilities which cut across the middle of the study area. Five a pattern that there is no observable effect. Although of the cases were diagnosed between February they were not presented in the paper, it is possible to 1990 and May 1991, six years after Krummel calculate combined estimates of relative risk from began operations. To evaluate possible exposures the data that were presented: For example, there were in the community, Schmitz-Feuerhake et al. (1997) 33 observed childhood leukemia cases during 1973- measured chromosome aberrations in local residents 1987, compared to 31.05 expected, for a SMR of and made a series of environmental radiation 1.06. The SMR for corresponding matched control measurements. Dicentric chromosomes were areas was 0.91. The relative risk is thus 1.06/0.91 significantly elevated in 21 residents18. There was = 1.17. The leukemia relative risk estimate for all also evidence of increased chronic gamma radiation ages was also 1.17. The non-Hodgkin’s lymphoma close to Krummel (~0.1 mSv/yr, below the German relative risk estimates were 1.26 and 1.09 for ages permissible limit of 0.3 mSv/yr), increased cesium 0-14 and all ages, respectively. We did not calculate isotopes in rainfall and air downwind of Krummel, confidence intervals around these estimates, and they and strontium and cesium contamination in local are likely to be nonsignificant, but they do suggest soil and vegetation. the possibility of an increased risk. Michaelis et al. (1998) compiled information Studies in Spain and the Slovak Republic on childhood cancer rates within 15 km of twenty have addressed cancer risk at all ages near nuclear West German nuclear power plants, 1980-1990, and facilities. Lopez-Abente et al. performed two compared them with rates in control regions. No consecutive comparative studies of several nuclear significant differences were found although there was facilities in Spain (1999, 2001). Areas within 30 evidence of excess acute leukemia19. In a follow-up km of nuclear power plants or nuclear fuel facilities study Kaatsch et al. (1998) examined subgroups of were considered to be potentially exposed; areas 50- disease type and age during 1991-95 and again found 100 km from each facility were used as controls. The no significant differences; in this study the relative first study looked at mortality from hematological risk for acute leukemia among 0-4 year-olds within tumors (leukemia, lymphoma and myeloma) at all 5 km of a facility was 1.39 (0.69-2.57). Waller et al. ages. Around nuclear power plants generally only (1995) applied novel statistical techniques to look myeloma mortality was elevated (RR 1.47; 0.92- for clusters of childhood leukemia in Sweden; they 2.36)21. Around nuclear fuel facilities generally found no significant clustering generally or around there was no evidence of any increased risk although the four Swedish nuclear power plants20. there was suggestive evidence of excess leukemia Iwasaki et al. (1995) examined blood and lymph near two facilities22. No childhood leukemia clusters cancers in communities around 18 nuclear power were detected in this study. The second study facilities in Japan. Results were presented for each investigated solid tumor mortality; around nuclear site and the authors point out apparently random power plants again there were no generally increased fluctuations in the data, with some positive and some risks. Around nuclear fuel facilities the total solid negative results. They conclude from the absence of cancer risk was slightly but significantly increased

18 At the same time, Bruske-Hohlfeld et al. (2001), including two of the same authors, did not detect increased dicentric and ring chromosomes in 42 local children compared to children from a control area. 19 Although we never retrieved the full article, these authors report a RR of 1.06 for acute leukemias and in a technical report (Kaletsch et al. 1997) they report a RR of 2.87 (1.34-6.86) for acute leukemias in ages 0-4 within 5 km of facilities. 20 Using one statistic (Stone’s “T”) the authors derived a maximum relative risk of 2.182 around the four facilities with a p-value of 0.426. 21 Myeloma mortality around the Zorita power plant was significantly increased (RR 4.35; 1.50-12.66) and the risk appeared even higher within 15 km of the facility (RR 5.65; 1.61-19.85). 22 Within 30 km of the Andujar facility the RR was 1.30 (1.03-1.64). Within 15 km of the Ciudad Rodrigo facility the RR was 1.68 (0.92-3.08). Communities Near Nuclear Facilities 153

(RR 1.06; 1.00-1.11) and risks of several cancer the Mayak nuclear weapons production complex types were also significantly positive23. The Zorita in Russia have been much greater than exposures and Trillo facilities from 1989-99 were specifically received by communities in other settings. The investigated in a case-control study (Silva-Mato et facility began operation in 1948 and until 1956 al. 2003). Cancer risk was significantly increased nuclear waste was discharged directly into the Techa within 10 km of the Trillo plant, particularly for the River. Between 1953 and 1961 over 7,000 people group of cancers known to be induced by radiation were evacuated and over 100,000 people have been (OR 1.86; 1.22-2.83). The excess was concentrated exposed to elevated levels of radiation. Kossenko in the 1997-99 period (OR 4.61; 1.96-10.9), ten years (1996) investigated the health status of residents after Trillo began operations, and this is consistent who lived along the river and used river water for with the latency of solid cancers. Risk declined with drinking and food preparation; roughly two-thirds distance from both facilities although the trend was of this cohort had bone marrow doses greater than only significant in the case of Trillo. 0.2 Gy and 8% of the cohort had doses greater Gulis and Fitz (1998) studied 1985-95 cancer than 1 Gy. The leukemia mortality dose-response incidence near the Jaslovske Bohunice nuclear relationship corresponded to a linear model or a facility in the Slovak Republic using five zones of model with reduced risk at higher doses; the relative distance away from the facility. This study found risk estimates for the three lowest dose categories significantly increased risks of several cancers were 1.0 (0.4-2.3) at 0.17 Gy, 2.0 (1.3-3.1) at 0.18 at some distances but also found about as many Gy, and 2.6 (0.9-7.1) at 0.29 Gy of bone marrow significantly reduced risks; with over 100 SIRs dose. The solid cancer dose-response did not fit any presented these results could be largely explained conventional risk models and risk estimates were as random variations in the data, and indeed the not significantly different from each other. The solid mix of positive and negative results does not appear cancer mortality relative risk estimates for the three consistent with radiation-induced cancers in other lowest dose categories were 1.1 (0.9-1.2) at 0.03 settings. The correlation between proximity to the Gy, 1.2 (1.1-1.3) at 0.04 Gy and 1.3 (1.1-1.6) at 0.05 facility and cancer incidence was calculated but Gy24. these data also show a mix of positive and negative results with no clear pattern. 12.5 Discussion Gadekar and Gadekar (1994) looked at congenital malformations near the Rajasthan Atomic Studies of communities near nuclear facilities, and Power Station near Rawatbhata India. This study studies of childhood leukemia in particular, have considered the exposed (proximal) area to be the been reviewed several times (for example Shleien et area within 10 km of the plant and downwind during al. 1991, Laurier and Bard 1999, Laurier et al. 2002). monsoon season (when precipitation and deposition These reviews note that although many studies of pollutants would be greatest). The control area have produced estimates of elevated risk, most do was 50-60 km upwind of the plant and was similar not have the information on exposure and dose geographically, industrially, and socially. The that would be necessary to make a strong case for authors found a significant excess of deformities in causation. A leukemia cluster near a facility might proximal villages. Children born since the start of be caused by emissions from a facility but it might both reactors at the facility had a relative risk of 5.08 also be caused, in part or totally, by a different risk (2.14-12.06) for birth defects. factor. Kinlen (1988), for example, has presented Exposures of community residents around evidence that childhood leukemia clusters might be

23 The following relative risks were calculated for all nuclear fuel facilities: 1.12 (1.02-1.25; lung cancer), 1.51 (1.05- 2.18; bone cancer), 1.53 (1.12-2.08; ovarian cancer), 1.37 (1.07-1.76; kidney cancer), 1.15 (1.01-1.32; colorectal cancer). 24 Relative risk estimates from Kossenko (1996) were extracted from figures and are therefore less exact than they appear. 154 Communities Near Nuclear Facilities caused by viruses that are transmitted more readily 1.3-3.1) and a significantly positive solid cancer risk in areas where new population mixing is occurring; at 0.04 Gy soft-tissue dose (RR 1.2; 1.1-1.3). some of the towns near new nuclear facilities fit this Studies of adults (or all ages combined) at lower description. doses have had variable results (Table 12-1). Studies These studies are further limited in many cases of Oak Ridge and Rocky Flats, both weapons plants, by simplistic and uninformative study designs. For have produced evidence of increased local cancer example, in most studies a circle of distance is drawn risks attributable to the plants (Mangano 1994, around a facility and everyone inside is assumed Johnson 1981, Crump 1987). These facilities have to have the same potential risk25. Radioactive had unique operating histories with greater potential contamination from a facility is unlikely to be for radioactive releases than commercial nuclear dispersed so uniformly. Soil plutonium around Rocky sites. Most studies of commercial facilities have Flats, for example, is distributed almost exclusively not detected a significant excess of adult cancer in a south-east direction (Johnson 1981). In some and no individual cancer site stands out from these cases we can see disease patterns that suggest analyses as a unique high-risk endpoint. Based nonuniform patterns of contamination. Hoffman et on studies of nuclear workers we might have an a al. (1997) found six cases of childhood leukemia priori interest in myeloma among adults. Dousset within 5 km of the Krummel nuclear power plant in (1989) found 3 cases (1.1 expected) within 10 Germany where only 1.3 cases were expected. All km of La Hague and Lopez-Abente et al. (1999) six cases occurred on the south bank of the Elbe, found relative risks of 1.62 (0.73-3.58) and 1.13 which cut the study area in half (Krummel is on the (0.70-1.85) around Spanish power plants and fuel north bank). This may have occurred by chance, but facilities, respectively. Boice et al. (2003b) found only 20% of the population in the study area lived on an increased myeloma incidence around the Apollo the south side. If it were the case that contamination and Parks facilities in Pennsylvania (SIR 1.91; 0.95- from Krummel only affected the south side of the 3.42). Forman et al. (1987), on the other hand, found river then we would want to calculate the risk for that myeloma mortality was significantly less than that area: the SIR for the whole 5-km radius was 4.6 expected around nuclear sites in England and Wales. (2.1-10.3) while considering only the south half of Since no consistent patterns emerge from studies of the circle gives an estimate of 24.0 (10.8-53.4). commercial facilities we can conclude that any real Although the studies are limited in many ways risks are presumably low and masked by the variety there is still a great deal of information that we of background rates and study designs. can try to interpret. Although we have little or no Childhood cancer, on the other hand, and dose information we do have information on some childhood leukemia in particular, appear to be important differences in endpoints. Studies of adults consistently associated with nuclear facilities. and children have produced different results, and This is most apparent in studies of leukemia (and this is not surprising considering what we know lymphoma) incidence (Table 12-2). Each site has about the unique sensitivity of children. We can had a unique history of radioactive releases, each also differentiate between studies of mortality and study design is different from the next, and each studies of incidence, or between studies of different study area has a unique pattern of background types of nuclear facility. cancer; for these reasons we should not expect risk The highest exposures considered in this section estimates to be of a similar value. That said, looking were experienced by Techa River residents near the at Table 12-2 we see that most studies of childhood Mayak facility in Russia. Studies of this community leukemia around nuclear facilities have found a have shown a significantly positive leukemia risk at significant or nearly significant excess; an ‘average’ doses as low as 0.18 Gy bone marrow dose (RR 2.0; excess would be two-fold or less. There is not much

25 There were some exceptions in this section. Gadekar and Gadekar (1994), Mangano (1994), Mangano et al. (2002) and Morris and Knorr (1996) all took weather patterns into account to some degree and Johnson (1981) and Crump et al. (1987) made use of soil plutonium measurements. Communities Near Nuclear Facilities 155 more that we can say about this apparent risk. We associated with relatively high exposures. Mangano have very little information on doses received by et al. (2002) present evidence of an association these children before or after birth so any kind of between US nuclear facilities and infant mortality. dose-response analysis is impossible. Pobel and Viel Studies of stillbirth around Sellafield have not (1997) make a convincing case for exposure through shown an elevated risk. These are intriguing results use of beaches or consumption of local seafood near that give us small clues about an issue that could be la Hague. Other risk factors such as preconception studied more thoroughly. radiation exposure or population mixing and viral In summary we can say that living near a nuclear infection might be involved as well. facility is probably a risk factor for childhood Birth outcomes have not been studied as leukemia and that the magnitude of the risk varies by extensively as cancer but evidence from Hanford in site. The risk to adults is small, if it exists, although Washington, Shiprock mining areas in New Mexico it may be higher near some facilities with histories and the Rajasthan facility in India all points to a of relatively high radioactive releases. birth defect risk. All three of these locations may be 156 Communities Near Nuclear Facilities � � �� �� � � �� � � �� � � � � � � � � � � � � ��� � � � � � � �� �� �� �� � � � � � � �� � ���� � � � � � � � �� �� � � � � � � � � � � � ��� �� ��� � � � ��� � � � �� �� � � � � �� �� � �� � � � �� � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � �� � � � � ��� ��� � � � �� �� � � � ��� � � � � � �� � � �� � �� �� � � �� � � � � �� �� �� � � � � � � � �� � � �� � � � � � � � �� � � � � � ���� ���� � � �� �� � � � �� ��� � � � � � � ��� � � � � � � � � � � � � �� � ��� � � � ��� � � � �� � � � � � �� � � � � �� � � � � �� � � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � �� � � �� � � �� �� ��� � � � � � �� �� �� � �� �� � �� � � � �� � �� � �� � � � � �� � � � �� �� � � � �� � � ��� � � � � � � ��� �� � �� � � � � ��� ��� ��� �� �� ��� � �� � � � � � � � �� � � � � � � � � �� � ��� ��� ��� ���� � �� �� � ��� � � ��� � � � � � � � � � � � � �� � � � � �� �� �� � � � � � � � � � � � � � � �� � � � � � � � � � � �� � � � �� �� � � � �� � � �� �� � �� � �� � � � � � ��� � � �� �� �� � ��� �� � � � � � �� � � � � � � � � �� �� � � � � ��� �� � �� � � � � � �� �� � � � � � �� � � ��� ��� �� ���� � �� � � � � � � � � � � � ��� � ��� � �� ��� �� � � � � � � � � �� � � � � �� � � � � � � � � �� � � � � � � � � � � � � �� �� � � � � � � � � � � � � � �� � � � � � � �� � � � � � � � �� � � � � � � � �� � � � � � � � � ��� � � � �� �� �� � � � ��� � � � � � � � � � � � �� � � �� � � � � �� � � � � � �� �� � � � � � � �� � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � �� � �� � �� �� �� � � � � � � � � � � � � � � � � � � � � � � � � �� �� ���� � � � � � �� � � � � � � � � �� � � � � � �� � � � � �� � � � �� � � � � � � ��� �� �� � � � � �� � � � � � � � � � � � � � � � �� � �� � � � ��� � � � � �� � � � � � � � � � � � �� �� �� � � � � �� � � � � � � � � � � � � �� � �� � � � � � ��� � � �� ��� � � � � � � � � � ��� � � � � � � � ���� ���� �� �� � �� �� �� �� �� �� � � � � � � � � �� �� �� �� �� � � � � ��� � � � � � � � �� �� � � � ��� � � � � � � � � � �� �� �� �� � � � � � �� � � � �� � ��� � � �� � � � � � � � � � �� �� �� � � � � � � � � � � � �� �� �� �� �� � � � � � � � � �� � �� � � � ��� ��� � � �� � � � � �� � � � � ��� � ��� � � ���� ��� � � ��� ���� ��� � ��� � � � � � � � � � � � � � � � � � � �� � � � �� � � �� � � � � � �� �� � � � � �� � � � � � � � � �� � � � � �� � � �� � � � � � � �� �� �� �� � � � � � �� � � � � � � �� � � � � �� �� � ��� �� � �� �� � � � � Communities Near Nuclear Facilities 157 � �� � �� � � � � ��� � � � � � � � � � �� �� � � � � � � � � � ��� � � � � � �� � �� �� � � � � �� � � � � � � �� � � ���� � � � � � �� � � � � � � � � � � � � � � � �� �� �� � � � � � � � �� � �� � ���� � � � � � � �� � � � � � � �� � � � � � ��� � � � �� �� � ��� � �� � � � � � � �� � � � �� �� � �� � � � � � � � � �� �� � � �� � � � � � �� � � � � � � � � �� � � � �� � � �� � � � � � � � � � ��� � � � � � � �� � � �� �� � �� � �� � �� � � � � � � � � � � �� � � �� �� �� � � � � � � � � � ��� � � �� �� � � � � � � � � � � � � ���� �� � � � � � � � � � � � � � � � � � � �� �� �� � �� �� �� �� ��� ��� � �� � � �� � � ��� � � �� � � � � � � � � �� �� � � � � �� � � � � � � � � �� �� �� � � � � � �� � � � � � � � � � � � �� � � � � �� � � �� ���� � � � � � ��� �� � � � �� � ��� � � � � ��� � � � �� �� �� � ��� � � �� �� � �� � �� � � �� � � � �� � � � � � �� � ��� � � � � �� �� � �� � � � �� �� � � �� �� �� � � � �� � � � �� � �� � � � �� � � � � � � � ��� � � � � �� �� � �� �� � � � �� ��� ��� � � � � � � � �� ���� �� �� �� � � � � � ��� � �� � � � � �� �� � � � ��� � � �� � � � � � � �� � ���� �� �� � � � � � � � � � ���� � �� � ��� � � � � �� � � � � � � � � � � � � � � � � � � �� � � �� � ��� � � � � � � � � ��� � � �� � ��� � � � � � � � � � � �� � �� � � �� � � � � � � �� �� � � � �� � � �� � � � �� � � � � ��� � � � � �� � � � � �� �� � �� � � ��� � � �� � � �� � �� � � � � � � �� � � ��� � � � � � � � � �� � � � � �� � � � � � � � � � � � � � � �� � � � �� � � � � ���� � � �� �� � �� �� �� �� �� �� � �� � � � � � �� �� �� �� � � �� � � � � � � ��� � � �� �� �� � � � ���� � � � � � � �� �� �� � ��� � �� �� � � � � � � � � ��� � �� �� � � � � ��� � � � � �� �� � � � � � � � �� �� � �� �� �� �� � � � � � � � �� �� �� �� � � � � � � �� �� � � �� �� �� �� � � � � � � � ��� � �� ��� � � � �� ���� � � � ��� �� �� � � � � � � � �� �� � � � � �� � � � �� ��� ��� � � � � � � � � �� �� � � � � � � � � � � � �� �� � �� � � �� � � � �� �� �� �� �� � � � � �� �� �� �� �� � �� �� �� � � �� � �� ��� � 158 Communities Near Nuclear Facilities 4 m ; 0 3 3 i . r 1 2 t es 0 6 . re g t i l 9 4 t 1 i o r . i 0 at co l . 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DISCUSSION assume that any dose of radiation, no matter how small and including radiation that we are exposed Our intention in creating this review was to provide to naturally, carries a risk. This risk is assumed to accessible information regarding exposures to low be proportional to dose so that a very small dose doses of ionizing radiation. We ended up including is associated with a very small risk. This model of studies of people exposed to a wider range of the health effects of radiation is often named the doses, including unknown doses, because all of linear no-threshold hypothesis; linear refers to the these studies have generated important and relevant proportional relationship between dose and risk. All information. In this concluding section we return to major agencies and committees support this model our original mission, focusing specifically on low (BEIR 1990, ICRP 1991, EPA 1999, UNSCEAR doses of ionizing radiation. Given the substantial 2000, Upton 20032). uncertainty and complexity1 associated with low The linear no-threshold model is not universally doses of radiation we do not attempt to quantify accepted, however, and some experts still present risks but instead review the challenge of interpreting threshold doses as a way of demonstrating that a these data and making decisions in a ‘gray’ area. particular exposure was harmless. The Agency for We begin by returning to one approach to low-dose Toxic Substances and Disease Registry (ATSDR), radiation modeling, the threshold. for example, occasionally uses a threshold model The idea of a threshold dose. People who of risk in its Public Health Assessments. One such are exposed to low doses of radiation might find document claimed that there is a human cancer themselves talking with a health expert who tells threshold of 0.1 Sv, and that doses below 0.1 Sv them that they were exposed to a harmless dose. would not lead to cancer3. The Health Physics Society This message can be conveyed in many ways but has stated that “below 5-10 rem (0.05-0.1 Sv), risks it rests on an important assumption, the assumption of health effects are either too small to be observed that there is a dose of radiation below which no or are nonexistent” and they recommend that risks health effects will occur. This dose is often referred below this level not be estimated (HPS 2004). This to as a ‘threshold’ dose. is a minority perspective but it maintains credibility Based on evidence from epidemiology, animal among some people, including those who have an studies, cellular studies, and the basic physics of the interest in relaxed exposure standards. interaction of radiation with matter, most scientists Positive results at low doses. Despite claims assume that there is no threshold dose. They to the contrary there have been many statistically

1 Risks have been shown in this review to depend on age at exposure, time since exposure, dose rate, type of radiation, background cancer risk factors, gender, and the endpoint of concern. 2 The National Council on Radiation Protection and Measurements (NCRP) recently formed a Scientific Committee to reassess the model and they determined that it was the most plausible perspective on dose response in Report No. 136 (Upton 2003). 3 The document stated that “studies of children who received x-rays in utero indicate that there is a threshold dose for radiogenic leukemia that lies in the range of 10 to 50 rad (0.1 to 0.5 Gy)” (ATSDR 2002). 167 168 Discussion significant findings of cancer following exposures 2000). Incidence in the low-dose region is of less than 0.1 Sv. From our review we have the also consistent with the linear dose-response following examples (Summarized in Table 13-1): seen over a wider dose range (ERR 0.63/Sv; Thompson et al. 1994). There is some evidence • Prenatal (in utero) exposures. The childhood of risk greater than the linear fit for the 0.1-0.3 cancer risk associated with prenatal radiation Sv dose range (Pierce and Preston 2000). exposure was first observed by Alice Stewart • Solid cancer among Techa River residents. and others in 1956. This study led to the Community residents around the Mayak nuclear Oxford Survey of Childhood Cancers (OSCC), weapons production complex in Russia were a database of cancer deaths in Great Britain exposed to a wide range of doses. Although the before age 16. Based on the OSCC the relative pattern of response did not fit conventional risk risk estimate over the period 1953-1981 for models there was evidence of a significant solid prenatal radiation exposure was 1.39 (1.30- cancer mortality risk in the three lowest dose 1.49). This estimate has confirmed by a series of categories. The relative risk estimates were 1.1 smaller studies whose combined estimate was (0.9-1.2) at 0.03 Gy, 1.2 (1.1-1.3) at 0.04 Gy and 1.37 (1.22-1.53)4. Although the doses received 1.3 (1.1-1.6) at 0.05 Gy (Kossenko et al. 1996). by these children while in the womb are thought • Leukemia downwind of Chernobyl and the to have been low they are very uncertain. Mole Nevada Test Site. Studies of these two cohorts (1990) studied the period 1958-61 and found a have derived remarkably similar risk estimates. mean fetal whole-body dose of 0.006 Gy; this Noshchenko et al. (2002) studied Ukrainian was associated with an odds ratio of 1.23 (1.04- children exposed to Chernobyl fallout. The 1.48). Recent reviews have concluded that a mean bone marrow dose among the children in fetal dose of 0.01 Sv is sufficient to significantly the study was 0.0045 Sv and the maximum dose increase the risk of childhood cancer (Doll and was 0.1 Sv. Among children with doses 0.01-0.1 Wakeford 1997). Sv the leukemia odds ratio was 2.5 (1.1-5.4). • Solid cancer in atomic bomb survivors. The The risk was higher for acute leukemia and majority of the atomic bomb survivors were appeared to decrease with age7. Leukemia in exposed to doses less than 0.1 Sv. Solid cancer communities downwind of the Nevada Test Site mortality was elevated in this dose range with was studied by Stevens et al. (1990). Within the a relative risk of approximately 1.02. Although high-dose group (bone marrow doses 0.006-0.03 this estimate is not significantly positive (95% Gy) there was a significant excess of leukemia CI 0.99-1.05)5, there is a low probability of a mortality (OR 1.69, 1.01-2.84). This excess was positive estimate occurring by chance (p=0.30) more dramatic for childhood exposure or death and it is consistent with the estimated risk over in childhood8. a wider range of doses (ERR 0.47/Sv). It is • Leukemia among nuclear workers. Cardis interesting to note that the relative risk estimate et al. (1995) analyzed mortality in 95,673 is almost exactly the same for the lower dose nuclear workers in the US, the UK and Canada. range of 0-0.05 Sv6 (Preston et al. 2003). This comprehensive group of workers is a Unlike solid cancer mortality estimates, predominantly low-dose cohort with 80% of solid cancer incidence in the 0-0.1 Sv range the workers having dose estimates less than is significantly positive (Pierce and Preston 0.05 Gy. Mortality from leukemia (particularly

4 These figures were presented by Doll and Wakeford (1997) and come from a meta-analysis by Bithell (1993). 5 These confidence intervals were calculated from the SE around the central risk estimate as depicted in Brenner et al. (2003). The p-value is apparently in reference to the dose-response slope over the dose range. 7 The OR for age at exposure 0-4 yrs was 3.5 (1.4-8.7). 8 The OR for acute leukemia in the 0-19 yr age at exposure group was 3.97 (1.18-13.3). The OR for acute leukemia in cases where the patient died before age 20 was 5.82 (1.55-21.80). 6 RR 1.02 (0.99-1.05), p=0.15. Discussion 169

myeloid leukemia) was significantly associated been received by one patient who had 22 back with dose as was mortality from multiple x-rays; at 247-749 mrad per exam this would be myeloma9. Wilkinson and Dreyer (1991) pooled a cumulative dose of 0.05-0.16 Gy. This group the leukemia mortality results of seven worker showed a significant dose-response relationship studies. These authors found a significant risk with an estimated ERR of 30/Gy. When analysis among workers with doses of 0.01-0.05 Sv was restricted to the period within 6-10 years of (Rate ratio 2.1, 90% CI 1.4-3.3). diagnosis the ERR estimate was 76/Gy and the • Leukemia among nuclear weapons test OR for the 0.01-0.02 Gy exposure group was veterans. Veterans who were involved with significantly positive (3.1, p<0.05). nuclear weapons testing were typically exposed • Medical exposures and breast cancer. Young to low doses of radiation10. Muirhead et al. (2003) scoliosis patients are given frequent diagnostic did not detect any significant dose-response x-rays during development; one study of breast trends in a subgroup of UK veterans with dose cancer among women with scoliosis found that information, but this is not surprising given the the cumulative mean dose to the breast from low numbers of cases11. UK veterans followed such exams was 0.1 Gy (Doody et al. 2000). through 1983 showed increased mortality from Among 2580 patients with breast doses of 0.01- leukemia (RR 3.45, 90% CI 1.50-8.37) and 0.09 Gy there were 39 breast cancer deaths vs. multiple myeloma (6 deaths among participants 22 expected, a significant excess (SMR 1.76, and zero deaths among controls); total cancer 1.3-2.4; RR 2.51), and there was evidence of mortality was not different from controls (RR a dose-response relationship (ERR 2.5/Gy12). 0.96, 90% CI 0.86-1.08). A purely low-dose The risk was highest 30 or more years after cohort was studied by Caldwell et al. (1983); exposure and with exposure at ages 10-13. these were veterans of one test (Smoky, 1957) • Medical exposures and thyroid cancer. Ron who had a mean dose of 0.005 Sv and a maximum et al. (1989) studied children who had been dose of 0.1 Sv. Among these veterans there was irradiated for the scalp condition tinea capitis. a significant excess of leukemia, registered as Thyroid doses in this cohort ranged from 0.04 either incidence or mortality (incidence RR to 0.07 Gy (mean 0.062 Gy). The thyroid cancer 2.5, 1.2-4.6), and total cancer mortality was not relative risk in these children was 3.3 (1.6-6.7); different from expected (incidence RR 0.95, higher risks were seen when only 0-4 year-old 0.78-1.14). children were considered (RR 5.0, 2.7-10.3). A • Medical exposures and leukemia. Studies of pooled analysis of thyroid cancer and external diagnostic x-rays are of limited utility because radiation exposure in childhood included the they typically lack dose estimates. In one study tinea capitis study and others (Ron et al. 1995). that did estimate doses there was evidence of In the dose range 0.01-0.09 Gy (mean 0.05 Gy) a chronic myeloid leukemia risk at low doses the thyroid cancer relative risk was 2.5 (2.0- (Preston-Martin et al. 1989). Out of 130 cases 4.0). and 130 matched controls 80% had estimated • Radon and lung cancer. A pooled analysis cumulative bone marrow doses less than 0.02 of 11 miner studies (Lubin et al. 1997) found Gy. The maximum dose in this group would have significantly elevated risks in the range of

9 Risk estimates (ERR) were 2.18/Sv (90% CI 0.13-5.7) for non-CLL leukemia, 11.00/Sv (90% CI 2.9-30.9) for chronic myeloid leukemia, 3.38/Sv (90% CI <0-14.9) for acute myeloid leukemia, and –0.89/Sv (90% CI <0-7.3) for acute lymphocytic leukemia. The ERR for multiple myeloma mortality was 4.2/Sv (90% CI 0.3-14.4). 10 For example, among 1,716 UK veterans with radiation badge readings greater than zero the mean dose was 0.01 Gy (Muirhead et al. 2003). 11 There were 8 cases of non-CLL leukemia, only 2 of which were diagnosed in the 2-25 year follow-up period, and there were 8 cases of multiple myeloma (Muirhead et al. 2003, supplemental information from the journal website, www.occenvmed.com). 12 The ERR of 2.5/Gy (-0.3-8.9) is adjusted for age at first exam. 170 Discussion

����� ����� ������������� �������� ���� ��������� �� ��� �����

����� ����������� �� ����� ���� ����� ���� ���� ��������

Prenatal diagnostic exposure and 0.006 OR 1.23 childhood cancer mean whole-body dose (1.04-1.48)

Solid cancer mortality in atomic bomb 0.005-0.1 RR 1.02 survivors colon dose (0.99-1.05)

Solid cancer incidence in atomic bomb 0.005-0.1 RR ~1.02 survivors colon dose

Solid cancer mortality in Techa River 0.03-0.05 RR 1.2 residents (1.1-1.3)

Childhood acute leukemia incidence 0.01-0.1 OR 3.1 downwind of Chernobyl bone marrow dose (1.5-6.4)

Childhood acute leukemia mortality 0.006-0.03� OR 5.82 downwind of the Nevada Test Site bone marrow dose (1.55-21.8)

Leukemia mortality among nuclear 0.01-0.05 Rate Ratio 2.1 workers (90% CI 1.4-3.3)

Leukemia incidence among veterans of 0-0.1 RR 2.5 the “Smoky” nuclear weapon test (1.2-4.6)

Chronic Myeloid Leukemia (incidence?) 0.01-0.02 OR 3.1 bone marrow dose (p<0.05)

Breast cancer mortality among women 0.01-0.091 RR 2.5� exposed to diagnostic x-rays for scoliosis breast dose

Thyroid cancer among children exposed 0.01-0.09 RR 2.5 to external medical irradiation (2.0-4.0)

Lung cancer in underground miners 0.001-0.02 Sv� RR 1.37 exposed to radon lung dose (1.0-2.0)

� �������� ���� ������������ ���� �� ����� �� ��� ����� ���� ��������� ���� ����� �� ����� ��� ����� �� �������� ��������� �������� �� ��� ������ �� ���������� ���� �� ��� � �������� � ���������� �������� ��� ���� �������� ���� �������� ��� ��� ��������� ��� ��� ��� ���� ���� �������� ��� ���� ���������� � �������� ��� ��� ��� ��� �������� ������ Discussion 171

0.1-3.5 WLM; this is roughly equivalent to a attempt to describe our understanding in terms that range of 1-20 mSv lung dose according to the are meaningful if not precise. conversions suggested by UNSCEAR (2000). As an illustration we can consider the leukemia risk of adult exposures to low doses of radiation. Uncertainty and judgement. At low doses, with We have seen convincing evidence that there is a low associated risks, it is difficult for epidemiology leukemia risk in children exposed to low doses of to detect an excess incidence of disease. Background radiation in utero, from Chernobyl, or from the variations in the rate of a disease, caused by variations Nevada Test Site (above and in the leukemia section). in demographic characteristics, unknown risk There are physiological reasons why adult risks factors, and the stochastic nature of cancer, create might be different, including different rates of blood situations where it is often impossible to say with production; we can see evidence of this difference any statistical certainty that an observed outcome is in the fact that childhood leukemia is often the acute attributable to a particular exposure. This problem is lymphocytic type and adult leukemia is often the exacerbated by small study populations. Land (1980) chronic myeloid type. It is therefore worthwhile to presents a good discussion of statistical power. examine adult risks independently, keeping in mind Studies with low expected risks tend to have low what we know about childhood risks. power because the size of a cohort needed to detect The best sets of data on adult exposures the risk is unrealistic. In these cases we introduce a come from nuclear workers and the atomic bomb bias when we only consider risk estimates that are survivors, and we might also consider veterans who significantly greater than zero (Land 1980). participated in nuclear weapons testing. As noted As an example of this problem we might above, Cardis et al. (1995) found a significant dose consider atomic bomb survivors who were exposed response for non-CLL leukemia mortality among to radiation in utero. In this group there were two workers in three countries. This dose-response cases of childhood cancer; based on the background estimate included doses over 0.4 Sv and so it is cancer rate less than one case was expected. This is not, by itself, evidence of a risk at low doses. The not a statistically significant excess and one might authors note, however, that although the slope is not say something like “atomic bomb survivors exposed significant at lower doses it is compatible with the in utero did not demonstrate an increase in childhood estimate for the full cohort (unfortunately this data cancer”. On the other hand, the excess relative risk is not shown in the report). In a study of Canadian estimate based on these two cases could be as high as workers, over 98% of whom received doses less 44 per Gy13. Another example is multiple myeloma than 0.1 Sv, a similar estimate of the leukemia risk incidence among veterans of the 1957 nuclear test (for incidence) was derived (Sont et al. 2001), and a “Smoky”; although one case of the disease was compatible mortality risk estimate was also derived expected, none were observed. This outcome might (Ashmore et al. 1998). Gilbert (2001) compares have occurred by chance even if the true relative these estimates to the male atomic bomb survivors risk was as high 2.814. The most truthful assessment who were exposed as adults and an estimate from of data such as these is that they are insufficient to the National Registry of Radiation Workers (UK)15. tell us anything specific and they are consistent with Table 13-2 is based on a table presented by Gilbert a wide range of possibilities. (2001). Although three of the estimates presented Synthesis of information. Although many in Table 13-2 are not significant there is notable individual studies of low doses are inconclusive by consistency; the estimate of Cardis et al. (1995) is themselves they become more meaningful when stronger in this context. The vast majority of these they are considered together with other information. workers were exposed to low doses. With a set of uncertain information in hand we can In addition to these dose-response estimates we

13 The ERR estimate for childhood cancer incidence following in utero exposure to the atomic bombs was reported to be 11/Gy with a 95% confidence interval of –1 to 44 (Wakeford and Little 2003). 14 The RR for multiple myeloma incidence was 0.0 (0.0-2.8; Caldwell et al. 1983). 15 There is some overlap between the UK study and the three-country study. 172 Discussion

Table 13-2. Estimated risk of non-CLL leukemia in adults

Cohort ERR Sv-1 (90% CI) Canadian workers (incidence) 2.7 Sont et al. 2000 (<0-19) Canadian workers (mortality) 0.4 Ashmore et al. 1998 (-4.9-5.7) UK workers (mortality) 2.6 Muirhead et al. 1999 (-0.03-7.2) Three-country workers (mortality) 2.2 Cardis et al. 1995 (0.13-5.7) Adult male atomic bomb survivors (mortality) 2.2 Gilbert 2001 (0.4-4.7) have a couple of examples of significant risks in the assumed this type of relationship; the linear term in low-dose region. their dose-response model was higher than those reported above by a factor of 2 (see section 3.3). A • Wilkinson and Dreyer (1991) found a more skeptical perspective on these data could be significantly positive rate ratio of 2.1 (1.4- that the low-dose estimates are, by chance, too high, 3.3) in workers with doses of 0.01-0.05 Sv. and that the risk at 0.1 Sv is closer to 20% based on • Caldwell et al. (1983) found a significantly the dose-response estimate of Cardis et al (1995). positive relative risk of 2.5 (1.2-4.6) in This would be a defensible position since so many nuclear test veterans exposed to less than large studies have derived similar risk estimates. It 0.1 Sv. would be hard to justify, however, the idea that there is a threshold dose below which there is no leukemia These estimates of risk are substantially higher than risk. what we would expect based on the dose-response Other syntheses of information have been made, estimates presented in Table 13-2. including informative meta-analyses. Lubin and What can we learn from the data presented in Boice (1997) combined the results of 8 case-control this example? We might characterize this information studies on domestic radon exposure and lung cancer as a relatively robust dose-response estimate and incidence. If these studies were assessed individually two risk estimates at low doses that deviate from it would be hard to draw a conclusion; four studies this dose-response curve. Concluding anything indicated a significantly positive risk and four did from this information is largely a value-based not. When Lubin and Boice combined the results, decision and there is not one right answer. Based however, a significantly positive risk estimate was on a precautionary approach we might assume that obtained for an exposure level of 150 Bq/m3 (RR the low dose risk estimates are valid, and that the 1.14, 1.0-1.3). Another synthesis, a pooled analysis leukemia risk might be as high as 3- or 4-fold with of radon exposures in mines, produced a very exposures to less than 0.1 Sv in some situations. similar estimate (RR 1.13, 1.0-1.2; Lubin et al. 1997, We might also look at these data and consider the Lubin and Boice 1997). Thus we have substantial possibility that the dose-response relationship is agreement between eleven studies of miners and not linear and that the risk at low doses is higher, eight studies of domestic radon exposures and we per sievert, than the risk at moderate doses. The can have some confidence in estimates that 10-14% ankylosing spondylitis analysis of Weiss et al. (1995) of US lung cancer risk is attributable to domestic Discussion 173 radon (Lubin et al. 1997). These results have since estimates. Instead of choosing one model or the been confirmed in two other large pooled analyses other, Land created a hypothetical dose-response of North American and European studies (Krewski relationship by combining a linear no-threshold et al. 2005, Darby et al. 2005). model with a threshold-type model, allowing each Our appendix on preconceptional exposures model to have a weight equal to the probability of is a less formal meta-analysis. It suggests that it being correct. Not surprisingly, the estimated risk preconceptional exposure of fathers, particularly in a decreases as we increase the likelihood of a threshold. relatively small window of time prior to conception, But the risk estimate is uncertain; there is an upper can lead to a cancer risk in the children that are confidence limit on our estimated risk and this is conceived. We can statistically demonstrate that this the more important value for purposes of radiation is likely to be true. We can also respond to some protection. Land shows that this confidence limit skepticism from the scientific community--atomic is only affected by a threshold likelihood greater bomb survivors might not be informative on this than ~80%. We can’t easily quantify the likelihood issue, for example, so we shouldn’t consider a lack of a threshold, but we can look at other, biological of evidence from this cohort to be crucial. We should observations get a rough idea; it would be very hard be open to the abundant evidence that animal studies to argue that the likelihood could be this high. bring to this issue (this issue is discussed further in Some biological phenomena, such as the section 10 and in appendix C). adaptive response17, suggest possible threshold doses These are just a couple of illustrations; any and even lend support to a theory of hormesis. Other particular topic in this overview could be explored biological phenomena that have been observed at further with varying degrees of effort. We find that if low doses include the bystander effect and genomic we consider an issue carefully and comprehensively instability (see for example Morgan 2003). These we can come to a very different conclusion than observations suggest that radiation can hit a cell those who look at a few study results individually and cause effects in descendents of the hit cell or in or who are constrained by a preconceived judgment. cells surrounding the hit cell. Based on these types It is very important to keep an open mind. With that of effects, which only appear to be significant at perspective we should return one last time to the low doses, we might expect a dose-response curve idea of a threshold. that has a low-dose region where the linear model What if there is a threshold dose? It is would underestimate the true risk. This type of dose- impossible to completely rule out the possibility. response is suggested in the atomic bomb survivor We find it hard to justify a threshold of 0.1 Sv but data as shown in Figure 13-1; here we see that the maybe a much lower threshold exists. It could estimate of the ERR/Sv at low doses tends to be be, for example, that damage caused by a small higher than it is over the whole range of doses. amount of radiation, maybe 0.001 Sv, is perfectly Biological observations at low doses therefore repaired with no long-term consequences. This is of present mechanisms that pull in two directions, course a possibility, although evidence from other potentially reducing and enhancing low-dose risk fields of study tends to stack up against it16. Land at the same time18. Brenner et al. (2003) wrote a (2002) published an interesting illustration of the very good review of the state of low-dose radiation implications of the possibility of a threshold on risk risk research that considered evidence from both

16 For example, it has been shown that a single track of radiation can damage DNA and that DNA repair mechanisms such as non-homologous end-joining do not work perfectly. Thus any amount of radiation could theoretically cause a cancer-initiating mutation. Land (2002), Upton (2003) and Brenner et al. (2003), among others, consider epidemiological evidence in light of biological considerations. 17 Adaptive response refers to experiments where cells are exposed to a small dose of radiation followed by a large dose. In some cases the small dose appears to reduce the effects of the larger dose. It has been suggested that the small dose might induce DNA repair mechanisms so that the cell is then better equipped to deal with the large dose. 18 This puzzle was recently the subject of a special issue of Mutation Research (volume 568, 2004). 174 Discussion

Figure 13-1. Estimated solid cancer mortality risk coefficient over increasing ranges of dose (data of Preston et al. 2003). epidemiology and biology. The authorship of this because it does not affect our sense of the upper- paper included the leaders in the field19, and in their bound risk estimates at low doses. conclusion they stated the following: We now know from direct observation that the responses of biological systems to radiation are In light of the evidence for downwardly curving not as simple as the linear model predicts, but we dose responses20, this linear assumption is not cannot say with any certainty what the net effect necessarily the most conservative approach, of these dynamic responses are. The linear model as sometimes has been suggested, and it is is still the preferred model because it is generally likely that it will result in an underestimate compatible with epidemiological data and because of some radiation risks and an overestimate it includes assumptions about the average behavior of others. Given that it is supported by of biological systems that are reasonable given our experimentally grounded, quantifiable, limited understanding. biophysical arguments, a linear extrapolation Perhaps the most important lesson from this of cancer risks from intermediate to very review is that there is not one risk estimate that fits low doses currently appears to be the most all circumstances. Different tissues within the body appropriate methodology. respond very differently in response to radiation. Tissues in young people react to radiation in different Conclusion. What does this mean for the ways than tissues in older people. Acute exposures traditional linear no-threshold model of cancer risk? and chronic exposures can influence the body Although a threshold is a possibility, it is a remote differently. The interaction of radiation and other possibility, and we know that it would have to be risk factors is not simple or well understood. All much lower than 0.1 Gy because epidemiologic of these factors make it important to consider both studies have detected risks at lower doses. The the general behavior of radiation-induced cancer, as small possibility of a threshold, as Land (2002) described by the standard linear risk models, and the demonstrates, should not affect radiation protection observations of specific situations.

19 The authors included several leaders in the field of biological research as well as leading epidemiologists from the RERF (Dale Preston) and the NCI (Charles Land, Jay Lubin and Elaine Ron). 20 The “downwardly curving” dose-response pattern mentioned here is a reference to the suggestion of supralinearity in the atomic bomb survivors. Appendix A

Leukemia increases with age and it is roughly four times more common in adults than ALL. This type can origi- Leukemia, a general term to describe cancers of the nate in immature white (myeloid, monocytic) or red blood, was among the first effects to be observed (erythrocytic) blood cells or immature platelet cells in survivors of the atomic bomb. There is also in- (megakaryocytes). Over 10,000 cases of AML are formation regarding the nature of radiation-induced diagnosed each year in the U.S. leukemia from nuclear workers, people exposed to Chronic Lymphocytic Leukemia (CLL). CLL is radiation for medical reasons, and people exposed to another common type of leukemia in the U.S. with fallout from Chernobyl and nuclear weapons tests. about 7,000 new cases diagnosed each year. At the This chapter begins by describing the disease and same time it is the only leukemia subtype for which then covers what we know and don’t know about the the evidence of a radiation association is equivocal. dose-response relationship for leukemia. CLL is almost always comprised of malignant B- cells. A.1 About the Disease Chronic Myeloid Leukemia (CML). CML is sometimes called chronic granulocytic leukemia Leukemia is diagnosed in about 30,000 Americans because one of the distinguishing characteristics is each year. Variations of the disease are typically overproduction of granulocytes, the largest group of grouped into several types and we will try to keep white blood cells. CML incidence peaks in young the distinctions clear because the different types of adulthood and is diagnosed in over 4,000 Americans leukemia appear to have distinct patterns of response each year. to radiation. Leukemias are divided into acute and All of these types have been clearly associated chronic types; this used to refer to the duration of the with radiation except CLL. For this reason many re- illness but the newer classification refers to the matu- searchers will study the incidence or mortality of all rity of the cells in question--acute leukemias develop leukemias excluding CLL (or non-CLL leukemia). from immature cells and chronic leukemias develop Unlike most solid cancers, which can take many from more mature cells. Leukemias are further di- years to develop, leukemia has a short latency pe- vided by cell type--malignant lymphoid cells (white riod of just a couple of years and generally declining blood cells involved in immune response including risk after a peak period. This makes it important to B-cells and T-cells) are classified as lymphoblastic consider how many years have passed since expo- or lymphocytic leukemias; malignant myeloid cells, sure. There is also an apparent sensitivity at younger as well as malignant red blood cells, are classified as ages making it important to consider childhood ex- myelocytic or myeloid leukemias. This gives us the posures as a separate category. Since leukemia is following four major types of leukemia: likely to originate in bone marrow researchers have Acute Lymphoblastic Leukemia (ALL). ALL made estimates of the bone marrow dose when pos- originates in immature lymphoid cells in the bone sible. The dose-response curve for leukemia is of- marrow, blood, or body tissues. This is the most ten described as non-linear, concave-up, or linear- common malignancy in children, affecting over quadratic, but dose-response models will typically 3,000 children in the U.S. each year, but it also af- include a linear term that plays a more important fects about half as many adults. role at lower doses. When appropriate and possible Acute Myeloid Leukemia (AML). AML risk we will mention these linear terms as a guide to the 175 Appendix A 176 likely dose-response relationship at low doses. exposure to other anatomical regions.

A.2 Atomic Bomb Survivors Adult medical exposures

This section briefly reviews the leukemia experience Treatment for ankylosing spondylitis in the U.K. has of the atomic bomb survivors; they will be further exposed patients to total body doses averaging ~200 discussed in comparison with other exposures in the cGy; these doses are unevenly distributed over the concluding section below. Of the 93,696 survivors body but mean marrow doses have been on the or- followed in the Life Span Study, 339 developed leu- der of a few Gy (Smith and Doll 1982, Weiss et al. kemia between 1950 and 1987. The first 5 years of 1995). Smith and Doll (1982) showed that the leuke- follow-up are not included in the RERF reports be- mia risk in this cohort of ~14,000 patients was high- cause data were missing or poor for this period, but est 3-5 years after exposure. Weiss et al. (1995) es- it is known that excess cases of leukemia began to timated that non-CLL leukemia mortality was three appear within two years of the bombings. Preston times more common in exposed patients. Depending et al. (1994) discuss some leukemia incidence data on the length of follow-up, the ERR in the low dose- for the 1948-1950 period and state that inclusion of region was estimated to be about 5-10/Gy. these data might increase the leukemia risk estimates Damber et al. (1995) studied Swedes treated by 10-15%. This is not surprising based on what we for benign locomotor lesions with x-rays. The mean know about the time-response of leukemia, with an marrow dose received by these patients was 0.4 Gy early peak in risk that declines over time. Overall the and they showed an elevated incidence of acute leu- ERR for leukemia incidence was 3.9 at 1 Gy, with kemia (SIR 1.27, 0.92-1.71) The estimated ERR for type-specific estimates of 9.1, 3.3 and 6.2 for ALL, incidence was 0.46/Gy (Damber 1995). AML and CML respectively. Risks after childhood Inskip et al. (1993) studied 12,995 women who exposure reached a higher early peak and declined had been treated for benign gynecological disorders more quickly over time than risks following adult with radium, x-rays or non-radiation methods. The exposures. Over the whole follow-up period ALL average marrow dose to radiation-treated patients risk was clearly higher after childhood exposures; was about 1 Gy. The RR for non-CLL leukemia this increased risk is not as clear for AML or CML mortality was 3.7 (1.3-16) comparing exposed to (Preston et al. 1994). Mortality risks were similar to unexposed patients but there was no reported evi- incidence risks, with an ERR of 4.62 at 1 Sv (3.28- dence of a dose-response trend. 6.40) for all leukemias (Pierce et al. 1996) based on Adults treated for hyperthyroid disease with a linear model. iodine-131 received bone marrow doses of ~5 cGy with each treatment and were generally treated once A.3 Medical Exposures or twice. In Sweden, Hall et al. (1992) did not ob- serve any increase in leukemia risk overall and nei- X-rays have been used for diagnosis in medicine ther did Ron et al. in the U.S. (1998). When Ron et and also to treat several benign conditions includ- al. restricted the analysis to deaths 5-9 years after ing ankylosing spondylitis, locomotor lesions, gy- treatment, however, they saw a SMR of 1.62 (1.01- necological disorders, cervical cancer, ringworm, 2.45). and skin hemangiomas in infants. Individual dose Thorotrast is a contrast medium that was once estimates from diagnostic x-rays are uncertain over used in radiography; it stays in the body for the life the history of the practice but it is clear that they of the patient exposing them chronically to alpha ra- have been declining over time. Today diagnostic ra- diation. Cumulative lifetime doses to bone marrow diation contributes an average of 14% of our total may average a few Gy (dos Santos Silva et al. 2003). radiation exposure and each individual exam carries Thorotrast-exposed patients have shown a substan- an exposure of <1 cGy (Berrington de Gonzalez and tially increased leukemia risk but no dose-response Darby 2004). Doses from therapeutic radiation tend information is available. to be higher although the dose is often focused on a Boice et al. (1987, 1988) studied women who specific part of the body resulting in relatively less had been treated with x-rays and/or radium for cer- 177 Appendix A vical cancer. The doses to these patients were quite timated ERR is negative but is very uncertain with high, averaging 7 Gy. Risk was greater in younger an upper 95% confidence limit of 50/Gy; the atomic patients and highest in the first few years after expo- bomb survivor data are therefore roughly compat- sure. The estimated ERR at lower doses was 0.88/ ible with the OSCC and other prenatal x-ray studies Gy (Boice et al. 1987). (Wakeford and Little 2002, 2003).

Childhood medical exposures Radiology occupations

Infants and young children are not often exposed to Cohorts of radiologists and radiologic technologists radiation but there is some evidence for a leukemia are limited by the fact that the doses they received risk associated with such exposures. A study of post- are unknown or very uncertain. It is known that av- natal x-rays in Quebec found that 1 x-ray increased erage annual doses have been decreasing over the the risk of childhood ALL with an OR of 1.13 (0.84- years as occupational standards evolve and leuke- 1.50) and that 2 or more x-rays increased the OR mia risk associated with these occupations has been to 1.47 (1.11-1.97) (Infante-Rivard 2003). Infants declining in parallel (Mohan et al. 2003, Berrington treated with external radium for hemangiomas, a et al. 2001), but dose-response inferences would be birthmark-like skin condition, showed a non-sig- purely speculative based on the available data. nificant elevation in leukemia risk (SIR 1.54, 0.82- 2.63); bone marrow doses were not estimated but A.4 Workers other organs received doses ranging from 5-15 cGy (Lindberg et al. 1995). Shore et al. (2003) studied Many studies of nuclear workers have been carried children treated with x-rays for ringworm of the out over the years and each one was limited by the scalp; this procedure resulted in skull marrow doses size of the study population. In 1995 Cardis et al. of ~4 Gy. The rate ratio for total leukemia was 4.7 published the results of a study that pooled the data (0.8-107). from worker cohorts in the U.S., Canada and the U.K. The pooled data set included almost 100,000 Medical exposure in utero workers and allowed for much more precise esti- mates of risk. In these workers the mean external The pioneering work of Dr. Stewart with childhood dose was 40.2 mSv and increased leukemia risk was leukemia cases first drew attention to the possible clearly correlated with external dose: The overall risk of prenatal x-rays in 1956. This marked the be- non-CLL leukemia ERR was 2.18/Sv (0.1-5.7), the ginning of the Oxford Survey of Childhood Cancers ERR for AML was 3.38/Sv (<0-14.9) and for CML (OSCC), a cohort that came to include over 15,000 it was 11/Sv (2.9-30.9). ALL risk was not elevated, case-control pairs. The most recent estimate of the consistent with the idea that this is predominantly childhood leukemia mortality risk associated with a childhood leukemia type. Although nuclear work- prenatal x-ray exposure in this cohort is a RR of ers are potentially exposed to beta- or alpha-emitters 1.39 (1.30-1.49), a value remarkably consistent with that can enter the body, leukemia risk among UK all other prenatal x-ray studies combined (RR 1.37, workers who were monitored for these kinds of ex- 1.22-1.53; Doll and Wakeford 1997). The doses re- posures was not different from unmonitored work- ceived from these x-rays are uncertain, but they have ers (Carpenter et al. 1998). been declining over the past 50 years and the leuke- Mayak workers received mean external doses mia risk has been declining in parallel. The best cur- of 0.81 Gy. In the 3-5 years after exposure the ERR rent estimate of the average dose per x-ray over the for leukemia was 7.6 (90% CI 3.2-17) and this risk years is around 3 or 4 mGy and the corresponding was predictably reduced when considering all years ERR estimate is ~50/Gy. after exposure (ERR 1.0/Gy, 0.5-2.0). The dose- Although no leukemia cases were diagnosed response relationships in this case appeared linear among the atomic bomb survivors who were ex- (Shilnikova et al. 2003). posed in utero, less than 1 case of leukemia would Chernobyl cleanup workers have also shown have occurred spontaneously in this cohort. The es- elevated leukemia risk, and although reasonably Appendix A 178 good dose information is available for this cohort Studies of people living downwind of the Ne- estimates of the ERR are uncertain. Ivanov et al. vada Test Site have consistently shown an elevated (1997) calculated an ERR for all leukemia of 4.3/Gy leukemia risk in southwestern Utah, particularly (0.83-7.75) based on 48 cases. among children (Lyon et al. 1979, Machado et al. Finally, although flight occupations are associ- 1987, Stevens et al. 1990). Stevens et al. demon- ated with very low doses, several studies have noted strated a dose-response trend for non-CLL leukemia evidence of an AML risk. Lynge (2001) calculated that was not quite significant, but showed significant an overall SIR of 3.8 (1.9-6.7) based on 11 cases trends for ALL specifically and for childhood leu- from three cohorts in Canada, Iceland and Den- kemia mortality. The odds ratio for ALL in the high mark. dose group (6-30 mGy) was 5.28 (1.66-16.7). The odds ratio for childhood exposure to high doses was A.5 Fallout 3.97 (1.18-13.3). These results were roughly con- sistent with several other studies of this population Nuclear Weapons Testing (Stevens et al. 1990).

The cancer history of UK servicemen participating Chernobyl in weapons tests has been well documented (Darby et al. 1988, Darby et al. 1993, Muirhead et al. 2003). Populations living close to Chernobyl have shown The data prevent a meaningful dose-response analy- increases in leukemia related to fallout from the ac- sis, but it is clear that risk has been declining over cident. Noshchenko et al. (2001) showed evidence time- the RR for non-CLL leukemia incidence was that Ukrainian children exposed in utero were three 3.97 (1.73-9.61) in the first 25 years of follow-up times more likely to develop leukemia, particularly and 1.41 (0.9-2.09) for the whole follow-up period ALL, than unexposed children. In 2002 Noshchen- (Muirhead et al. 2003). The peak risk may have been ko et al. published the results of a case-control study as early as five years after exposure (Darby et al. of leukemia in Ukrainians exposed to Chernobyl 1993). US servicemen exposed to nuclear weapons fallout as children. Significant dose-response trends testing fallout show similar risks (Watanabe et al. were noted for all leukemias and acute leukemias. 1995, Caldwell et al. 1983). Participants in Opera- Results from this cohort were consistent with the tion Crossroads (1946) did not show an elevated results of Stevens et al. (1990) for Nevada Test Site leukemia risk overall, but servicemen with ‘engi- downwinders in both the magnitude and the age-de- neering and hull’ specialties showed a RR of 1.51 pendence of the response. (0.94-2.44) (Johnson et al. 1997). 528 New Zealand Further from Chernobyl some researchers have participants in Pacific tests showed a substantially observed evidence of elevated risks and rough cor- higher RR, relative to non-exposed servicemen, of relations between leukemia clusters and fallout as 5.51 (1.03-41.1) (Pearce et al. 1990). measured by cesium-137 concentrations but these Communities living downwind of test sites results have been inconsistent (see for example have shown some evidence of leukemia risk. Darby Tukiendorf 2001, Petridou et al. 1996 and Michaelis et al. (1992) showed in Nordic countries that leuke- et al. 1997). mia risk was higher in people who were infants dur- ing years of peak fallout, principally from Russian A.6 Discussion testing (1962-65). It was estimated that these people received doses on the order of 200-400 mSv/yr dur- These studies consistently demonstrate a few quali- ing that time. Zaridze et al. (1994) showed a corre- tative characteristics of leukemia in response to ra- lation between closeness to the Semipalatinsk Test diation. Risk is generally highest a few years after Site and acute leukemia and in a case-control study exposure and it reaches a higher peak and declines Abylkassimova et al. (2000) found that downwind- more quickly after childhood exposures. Risk ap- ers exposed to more than 2 Sv were roughly twice as pears to increase in a non-linear way up to a few Gy likely to develop leukemia as those exposed to less and then decline with increasing dose. Researchers than 0.5 Sv. with the National Radiological Protection Board in 179 Appendix A England have found it convenient to model leuke- 50%) or an excess absolute risk of ~0.02% per cGy mia risk with equations that include a term account- (2 leukemia cases out of 10,000 exposed children) ing for this decline in risk at higher doses; this term (Doll and Wakeford 1997). represents the idea that severely damaged cells will The clearest examples of leukemia following not reproduce and therefore cannot lead to cancer. low-dose exposure are in children downwind of Studies of people exposed to high doses of radia- Chernobyl and the Nevada Test Site. Noshchenko tion in cancer treatment, for example, have gener- et al. (2002) compared leukemia risk in children ally shown low risks of leukemia in later years and with bone marrow doses of 1-10 cSv to children these are roughly compatible with A-bomb survivor with marrow doses of <0.2 cSv. There was a clear data using such a model (Little et al. 1999). Three risk of all leukemia types (OR 2.5, 1.1-5.4), of ALL of the exposed groups discussed above, the atomic specifically (OR 3.1, 1.3-7.8), and also of AML spe- bomb survivors, cervical cancer patients, and anky- cifically (OR 3.2, 1.0-10.0). Trends with dose were losing spondylitis patients, have been analyzed to- significant for each of these leukemia categories. It gether using the same type of model (Little et al. was also clear that risk was higher at young ages. 1999). Although the three exposure groups showed Stevens et al. (1990) reported very similar results. different patterns of total leukemia response, obser- They compared children with bone marrow doses of vations restricted to specific types of leukemia were 0.6-3.0 cGy to children with doses of <0.3 cGy and compatible and each type showed a peak in risk at a found an OR of 1.69 (1.01-2.84) for all leukemia dose of 3-4 Sv. types and an OR of 5.28 (1.66-16.7) for ALL. Dose- Most of the evidence that we have for radia- response trends were significant for death before age tion-induced leukemia, like other cancers, is for 20 and for acute leukemias and there was again a relatively high doses. At lower doses (<10 cGy) ex- clear trend with age at exposure. Figure A-1 com- cess cases of leukemia are hard to detect. In a re- pares the results of these two cohorts. These results cent assessment of risks from diagnostic radiation suggest that childhood exposures to radiation doses exposure, for example, the authors predict that 1-2% of a few cGy can roughly double the risk of leuke- of leukemia cases could be attributable to the diag- mia. They also clearly show a particularly high risk nostic exposures. Out of 1,348 cases of leukemia in of ALL and demonstrate the sensitivity of younger the UK each year they predict that 26 could be as- ages. The fact that these risks are compatible with sociated with the diagnostic exposures (Berrington the in utero risk estimates presented above demon- de Gonzalez et al. 2004). Risk following exposure strates important consistency in the bigger picture of to 1 cGy in utero may be associated with an ERR radiation-induced leukemia risk. of around 0.5 (increasing background incidence by Appendix A 180

Figure A-1. Leukemia risk across exposure ages in populations downwind of Chernobyl (top) and the Nevada Test Site (bottom) 1.

1 Top: Leukemia incidence in the Ukraine after Chernobyl, 1987-1997, comparing bone marrow doses of 10-101 mSv to 0-1.9 mSv (Noshchencko et al. 2002). Bottom: Leukemia mortality downwind of the Nevada Test Site (Utah), 1952-1981, comparing bone marrow doses of 6-30 mGy to 0-2.9 mGy (Stevens et al. 1990). Appendix B

Thyroid disease or by autoimmune disease (such as Hashimoto’s thyroiditis) in which the immune system attacks the Thyroid cancer is a relatively rare cancer, affecting thyroid. less than 0.01 % of the U.S. population. At the same The thyroid is known to be particularly sensi- time, the thyroid has been shown to be among the tive to radiation-induced cancer. This is often hard most radiosensitive organs in the body. This section to observe in epidemiological studies because thy- begins with a brief overview of the thyroid and then roid cancer is rare, affecting fewer than 1 in 10,000 goes on to discuss evidence for radiogenic thyroid people. Exposure to external gamma radiation is cancers following exposures to radiation from the known to cause cancer and internal exposure to beta atomic bomb, Chernobyl, nuclear weapons test- radiation from iodine isotopes is also known to cause ing, and diagnostic and therapeutic medicine. We cancer. This is because the thyroid collects iodine to also discuss non-cancer thyroid disease and its as- make thyroid hormone and cannot distinguish be- sociation with radiation exposures. External and tween radioactive and stable iodine. When substan- internal radiation are discussed separately because tial amounts of 131I are released, for example fol- of uncertainties in the dose calculations for internal lowing the Chernobyl accident, thyroid cancer risk exposures and possible differences in observed out- increases dramatically. comes. Children are given particular attention be- Thyroid cancer is typically divided into sev- cause of apparent sensitivity at young ages. eral subcategories based on the cellular origin and structure of the tumor. Papillary tumors originate in B.1 Introduction to the Thyroid the inner lining of the thyroid and are mushroom- shaped. Follicular tumors are slow-growing and The thyroid is a butterfly-shaped gland located just originate in the follicles of the thyroid. These two below the voice box that captures iodine from the types account for the majority of thyroid cancer cas- blood to create, store and release thyroid hormone, es and some tumors fit both descriptions. Medullary a hormone that controls metabolism. Thyroid func- cancers develop in the cells that make calcitonin, a tion is a self-regulating system; if there is too little calcium regulating hormone. Anaplastic cancers are thyroid hormone circulating in the blood then the unusually aggressive and are comprised of cells that brain causes the pituitary gland to release more thy- are different from normal thyroid cells. roid-stimulating hormone (TSH), and the thyroid re- Much more information can be found online. sponds by capturing more iodine and making more The National Cancer Institute’s website (http://nci. thyroid hormone. nih.gov/cancerinfo/types/thyroid/) is a good source Thyroid dysfunction is commonly divided into of statistics and basic information and the website of hyperthyroidism and hypothyroidism. In hyperthy- the American Thyroid Association is another good roidism the thyroid becomes overactive leading to source of easy-to-read information (http://www.thy- symptoms such as anxiety, heart palpitations, weight roid.org/patients/faqs.html). The website of Endo- loss, and hair loss. The most common hyperthyroid crine Education Inc. (http://www.thyroidmanager. disease is known as Grave’s disease. In hypothy- org/thyroidbook.htm) includes a wonderful, com- roidism the thyroid is underactive; this can lead to prehensive discussion that is aimed at public health weight gain, fatigue, dry skin and mood swings. professionals; almost any question can be answered Hypothyroidism can be caused by iodine deficiency here if you are willing to spend some time wading 181 Appendix B 182 through dense, vocabulary-heavy text. observed a significant dose-response relationship with an ERR of 4.9/Gy (1.3-10.2). Lindberg et al. B.2 External Radiation and Thyroid Cancer (1995) studied 11,807 subjects treated Sahlgrenska University Hospital. Again a significant dose-re- External exposures to radiation that have been as- sponse relationship was observed, with an ERR of sociated with thyroid cancer include the atomic 7.5/Gy (0.4-18.1). bomb, medical exposures, and exposures during the There are also additional data regarding medi- cleanup of Chernobyl. The atomic bomb survivors, cal exposures in adults from Sweden. One study with a mean whole-body dose of 0.264 Sv (26.4 failed to show a significant risk for adults exposed rem) showed a clear increase in thyroid cancer. The to low diagnostic x-ray doses of ~7 mGy (Hallquist dose-response relationship has been described as and Näsman 2001). Another study did see a signifi- linear (Thompson et al. 1994) and there is no evi- cant risk of much higher therapeutic doses of ~1 Gy dence for a low-dose threshold (Little and Muirhead (Damber et al. 2002). The adult patients in this study 1997). The dose-response relationship for the entire were treated for benign conditions such as arthrosis cohort was described with an Excess Relative Risk and showed an ERR of 5.8/Gy. (ERR) of 1.2/Sv (0.48-2.1) (Thompson et al. 1994). Studies of radiation therapy for other diseases The highest risk among A-bomb survivors has been can be complicated, especially when the disease seen in children. The ERR broken into different age being treated is cancer. There is always the possi- groups clearly shows this: for children age 0-10 at bility that the people being treated are especially the time of the bombing the value was 9.46/Sv and susceptible to cancer even before being exposed to for children age 10-20 the value was 3.02/Sv. The radiation. A study of English and French children dose coefficient in adults, an ERR of 0.10/Sv (<- irradiated for cancer (other than thyroid cancer) did 0.23-0.75), was not significantly positive (Thomp- in fact show that the incidence of second cancers in son et al. 1994). these subjects was higher than expected based on A great deal of information has been obtained standard rates in Europe and also higher than would from external medical exposures to radiation, usu- be expected based on their radiation exposure. Sub- ally in the form of x-rays. Ron et al. (1995) pooled jects who were treated for neuroblastoma were at the data of seven such studies including children a particularly high risk of subsequently developing irradiated for a variety of conditions and women thyroid cancer. In this case it was useful to conduct treated for cervical cancer with a combination of a dose-response analysis within the cohort to isolate radium implants and x-rays. Atomic bomb survi- the effect of radiation. The radiation doses in this vor data were also included in this pooled analysis. study were quite high (mean of ~7 Gy) and at very The results were consistent with the atomic bomb high doses cell-killing seemed to reduce the linear survivors in that the risk was highest for children dose-response relationship. In the region up to a few and not significant for adults. The ERR was 7.7/Gy Gray the ERR was reported to be between 4 and 8 (2.1-28.7) for children and the risk was highest for per Gy, depending on how the data were adjusted children exposed when they were younger than 5. (de Vathaire et al. 1999). This is consistent with the The two studies with adult data gave estimates of atomic bomb survivors and the pooled analysis of 34.9/Gy (-2.2-∞) for cervical cancer patients and 0.4 medical exposures. Another study looked at the risk (-0.1-1.2) for atomic bomb survivors, both estimates of thyroid cancer in children and adults irradiated nonsignificant. for Hodgkin’s disease. In this group the thyroid can- Additional studies of medical exposures in chil- cer risk was 15.6 times the expected risk, but it was dren include two studies that addressed the treatment unclear what role the radiation exposures played in of hemangioma in Swedish infants from the 1920s that increase (Hancock et al. 1991). through the mid-1960s. The treatment involved the People that were hired to clean and entomb the placement of beta-, gamma- or x-ray emitters next Chernobyl facility received external doses ranging to the hemangioma; the mean dose to the thyroid up to 0.25 Gy and averaging ~0.1 Gy (Ivanov et was 10-30 cGy. Lundell and Holm (1995) studied al. 1998). Ivanov et al. (1997a and 1997b) reported 14,351 subjects treated at the Radiumhemmet and on the follow up of 167,862 cleanup workers from 183 Appendix B 1986 through 1995. These workers showed a clear the true risk. increase in thyroid cancer incidence and also dem- Specific risk estimates for exposures to fallout onstrated a significant dose-response relationship from the Semipalatinsk test site in Kazakhstan have with an ERR of 5.31/Gy (0.04-10.58). not been made but Zhumalidov et al. (2000) noted a dramatic increase in thyroid cancer (as a fraction B.3 Internal Radiation and Thyroid Cancer of thyroid surgeries in the region) that peaked in the late 1980s. As noted above, iodine isotopes are uniquely as- Testing in the Marshall Islands exposed a small sociated with thyroid cancer because the thyroid number of people to a wide range of doses, but dose concentrates the iodine in the body for the produc- estimates only exist for the atolls closest to Bikini. tion of thyroid hormone. Since the thyroid cannot An alternative way of calculating risk uses distance distinguish between radioactive iodine and stable as a proxy for dose; this is particularly convenient iodine, any radioiodine in the body poses a risk to in the Marshall Islands because each individual the thyroid. Radioiodines (principally 131I) are can recall reasonably well which atoll they were on generated in large quantities during nuclear weapon when the BRAVO test was detonated. Hamilton et explosions, so communities downwind of test sites al. (1987) and Takahashi et al. (1997) observed cor- in Nevada, Kazakhstan, and the Marshall Islands relations between closeness to the Bikini test site at are important to consider. The Chernobyl accident the time of testing and thyroid nodules. Hamilton et also released large quantities of 131I. Finally, 131I al. also derived an absolute risk estimate (EAR) for has been used to diagnose and treat thyroid diseases thyroid nodules of 11 cases per 10,000 PY Gy. and the follow-up of these patients is another good Thyroid cancer in French Polynesia was source of evidence. roughly correlated with closeness to the test site on Mururoa, but not significantly, and although thyroid Fallout cancer in the region has been more common than in other Pacific Islander populations the incidence has Although fallout from the Nevada Test Site was not changed over time in a way that would suggest deposited across the country, areas immediately an association with testing (de Vathaire et al. 2000). north and east of the test site received particularly heavy amounts. In 1984 Johnson et al. noted that Chernobyl Mormons in southwestern Utah developed thyroid cancer more frequently than Mormons elsewhere in After the accident at Chernobyl in 1986, increased the state in the periods 1958-1966 (6 observed cases thyroid cancer was seen in Ukraine (Rybakov et al. vs. 1.4 expected) and 1972-1980 (14 observed vs. 2000), Belarus (Astakhova et al. 1998; Buglova et 1.7 expected). Kerber et al. (1993) developed spe- al. 1996; Pacini et al. 1997; Shibata et al. 2001) and cific risk estimate based on 2,473 people age 0-7 in Russia (Jacob et al. 1999; Shakhtarin et al. 2003; 1953 from three counties close to the test site with a Stiller 2001) in addition to suggestive evidence for mean dose of 0.98 mGy. For the period 1965-1986 increases in more distant places including Poland the ERR for thyroid neoplasms was 7/Gy (p=0.019) (Tukiendorf et al. 2003) and the United Kingdom and the ERR for thyroid carcinomas was 7.9/Gy (Cotterill et al. 2001). These cases occur at young- (p=0.096). er ages and seem to be more aggressive than typi- Nationwide risks from the test site have been cal thyroid cancer cases (Pacini et al. 1997; Stiller very roughly approximated. Gilbert et al. (1998) cal- 2001). culated risk estimates based on county-level aver- A case-control study (Astakhova et al. 1998) of age dose estimates. The risk for the 1950-1959 birth Belarussian children found a significant relationship cohort was positive but not significant (ERR for between thyroid dose of 131I and thyroid cancer , thyroid cancer incidence 0.3/Gy, -0.7-1.4); the same and risk coefficients have been derived by Jacob et was true of the risk for people exposed as infants al. (1999) for children and adolescents and by Iva- (ERR 2.4/Gy, -0.5-5.6). The authors observed that nov et al. (2003) for adolescents and adults. Jacob et uncertainties in dose caused them to underestimate al. (1999) studied children (born in 1971-1985) in 3 Appendix B 184 cities and 2,729 settlements in Russia and Belarus that only 300 subjects in their study were under the and found an ERR of 23/Gy (8.6-82). The dose-re- age of 10, the period of highest observed sensitivity sponse relationship in this study appeared linear and in other studies. Another study of diagnostic 131I, a significant risk was observed in the lowest dose again with an average dose of ~1 Gy, was carried group (< 0.1 Gy, mean thyroid dose of 0.05 Gy). out in Germany (Hahn et al. 2001). This study found Ivanov et al. (2003) studied adolescents and adults no increase in risk (RR 0.86, 0.14-5.13) but, as in (aged 15-69 at the time of the accident) in the Bry- the case of the Swedish cohort, was largely limited ansk district of Russia. There was no evidence of in- to adults. creased thyroid cancer risk in the total cohort, which Radiation treatment for hyperthyroidism in- is consistent with other studies. However, the subco- volves 131I doses in the tens or hundreds of Gy. hort aged 15-29 at the time of the accident showed a A cohort of Swedish patients showed an elevated significant ERR of 8.65/Gy (0.81-11.47). SMR (1.95, 1.01-3.41)) and a nonsignificant dose- These risk estimates left a possible confound- response pattern with thyroid cancer mortality (Hall ing issue unaccounted for- a relatively low intake et al. 1992). A UK study found an SIR of 3.25 (1.69- of natural iodine in the diet of children near Cher- 6.25) and an SMR of 2.78 (1.16-6.67) (Franklyn nobyl may have increased their thyroid cancer risk et al. 1999). A U.S. study found an SMR of 3.94 by increasing the amount of radioiodine sequestered (2.52-5.86) and noted a marginally significant dose- by the thyroid. This possibility was addressed in response relationship (Ron et al. 1998). Although another study of Bryansk children (ages 6-18) by these three studies generally agree with each other in Shakhtarin et al. (2003). These researchers found terms of the magnitude of mortality risk that hyper- that dietary iodine did play a role in radiation-in- thyroid patients face with 131I treatment, they offer duced cancer risk so that although the overall ERR little insight on the question of low doses to healthy was 18.1/Gy (11.3-26.9), the ERR in areas with suf- people because the thyroid was severely damaged ficient dietary iodine was 13/Gy (-11-71.2). Another and there was an underlying thyroid disease in all of important consideration in interpreting these studies the study subjects. is the fact that follow-up was for a small number of years after exposure. Since background cancer risk B.4 Non-cancer Thyroid Disease is low in children, relative risk estimates based on childhood cancer incidence may overestimate life- Non-cancer effects of radiation have been observed time risks. in the exposed populations described above, al- though they haven’t been examined with the same Medical exposures quantitative detail as cancer. The atomic bomb sur- vivors have shown an excess of thyroid disease, a Iodine-131 has been used at low doses to diagnose general category that includes hypothyroidism, thy- thyroid disease and at high doses to treat hyperthy- roiditis, goiter and thyrotoxicosis. It has been esti- roidism by killing off part of the thyroid. Results of mated that 16% of the thyroid disease in the Adult an ongoing cohort follow-up in Sweden have been Health Study can be attributed to a-bomb radiation published a few times (Holm et al. 1988, Hall et al. exposures (Wong et al. 1993). A significant dose-re- 1996, Dickman et al. 2003). The study participants sponse relationship was observed in this study with had received average doses of ~1 Gy of 131I be- an ERR of 0.30/Gy (0.16-0.47); this was attributed tween 1951 and 1962. Holm et al. found an SIR of to the effects of exposure at younger ages. Hypo- 1.27 (0.94-1.67) and a positive dose-response re- thyroidism was also specifically analyzed in this co- lationship that was not quantified. Hall et al. con- hort by Nagataki et al. (1994), who found a concave firmed the elevated SIR (1.35, 1.05-1.71) and quan- dose-response curve with a maximum incidence of tified the dose-response relationship for patients hypothyroidism (OR ~2.5) occurring with a dose of younger than 20 (ERR 0.25/Gy, 0-2.7). Dickman et ~0.7 Sv. Below 0.5 Sv the dose-response relation- al. did not report either an elevated SIR or a signifi- ship was linear with an apparent ERR of ~3/Sv. cant dose-response relationship (although the data Autoimmune thyroid disease is a condition suggest a positive dose-response), but note the fact where the immune system attacks the thyroid. Evi- 185 Appendix B dence of this disease includes elevated levels of Gy thyroid dose, and then count the thyroid cancers circulating autoantibodies, molecules that are pro- that evolve. If there were only half as many cancers duced to destroy thyroid cells or thyroid hormone. in the iodine-exposed group then the relative bio- One of the more common forms of autoimmune logical effectiveness (RBE) of 131I would be 0.5. thyroid disease is known as Hashimoto’s thyroid- If there were twice as many cancers in the iodine- itis. Children around Chernobyl have demonstrated exposed group then the RBE would be 2. Typically evidence of autoimmune thyroid disease including beta emitters like 131I are assumed to have an RBE elevated levels of autoantibodies (Pacini et al. 1998, of one or slightly less, indicating that they are about Vykhovanets et al. 1997, Vermiglio et al. 1999) and as destructive as gamma radiation or x-radiation. elevated levels of thyroid-stimulating hormone, a The choice of RBE can be very important when sign that the pituitary gland is compensating for thy- risks are being estimated, as we see in the case of the roid damage (Quastel et al. 1997, Vykhovanets et al. estimated thyroid cancer impact of Nevada Test Site 1997). Since the follow-up of this cohort has still fallout. The National Cancer Institute has estimated been relatively short it has been suggested that these that approximately 50,000 thyroid cancer cases may observations may be an early stage in the develop- eventually develop because of the test site, and this ment of hypothyroidism (Pacini et al. 1999). Gold- number is fairly uncertain (95% CI 11,300-212,000) smith et al. (1999) report a significant correlation (NCI 2001). This was based on the assumption that between body burden of cesium-137, a very rough 131I has an RBE of 0.66. However, Land (1997) proxy for 131I dose, and hypothyroidism in boys noted that there is also evidence for an RBE of 1, and around Chernobyl; the relationship was not signifi- that this is more likely to describe events at lower cant among girls. Ivanov et al. (2000) reported on doses. A review of the 1997 NCI report (NAS 1999) the incidence of endocrine and metabolic disease, a decided that an RBE of 1 was just as defensible as category that includes thyroid disease, in Chernobyl an RBE of 0.66, and that, based on the Chernobyl cleanup workers who had average doses of ~100 experience, the RBE is not likely to be any lower mGy. They found an ERR of 0.58/Gy (0.3-0.87). than 0.66. If an RBE of 1 is assumed then the num- Thyroid disease has also been diagnosed in 28% of ber of thyroid cancer cases attributable to Nevada the Mayak Children’s Cohort, residents of Ozyorsk, Test Site fallout is 75,000 (17,000-324,000). Russia who were exposed as children to routine re- Children appear to be more susceptible to radia- leases of 131I from the Mayak complex. tion-induced thyroid cancer than adults, as shown in Table B-1. Based on the available data we can con- B.5 Discussion clude that the ERR of thyroid cancer after childhood radiation exposure is in the area of 5-10 per Gy. Most It is clear that radiation exposure can lead to thyroid studies have observed a linear dose-response rela- cancer. The more detailed story involves a discus- tionship without evidence of a threshold; expressed sion of the relative abilities of internal 131I and ex- in various ways we can assume that a child expe- ternal gamma rays and x-rays to cause damage and riencing a thyroid dose of 0.01 Gy would have an also involves a discussion of age. ERR of 0.1, a relative risk of 1.1, or a 10% increase Different forms of radiation are often compared in thyroid cancer risk. Risks in adults are much more to gamma radiation or x-radiation by observing how uncertain than risks in children, and although there much damage is caused by the same dose of each may be some thyroid cancer risk following radia- kind of radiation. For example, researchers might tion exposure, it appears to be relatively low (Ron expose one group of rats to 1 Gy of x-rays, expose 2003). another group of rats to enough 131I to give a 1-

Appendix B 186

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Analysis of preconception exposure studies of the weights (SEp = 1/√∑w). Approximate 95% confidence limits were estimated as (exp(ln(ORp) ± This analysis is intended to supplement the review 1.96 SEp)). The standard error for each individual of paternal preconception exposure studies in sec- study was estimated as the difference in the natural tion 10. As indicated in that review several studies logs of the 95% confidence limits divided by 3.92. have noted elevated risks of leukemia, non-Hodg- In one case (Graham et al. 1966) the standard error kin’s lymphoma, solid cancers, or adverse birth out- had to be estimated from the p-value (0.16). In this comes following paternal and sometimes maternal case (SE= (ln(ORp)/1.4)) where 1.4 is the unit-nor- preconception exposure. This analysis deals with mal test statistic corresponding to a p-value of 0.16. leukemia following paternal exposure because this Pooled risk estimates were calculated for preconcep- subset of the evidence is the largest. Non-Hodgkin’s tion x-ray exposure, for any occupational exposure, lymphoma (NHL) was sometimes grouped with for total preconception dose greater than 50 mSv, leukemia (leukemia/non-Hodgkin’s lymphoma, and for a dose in the 6 months leading up to concep- LNHL) so that the results were not separable. Only tion of greater than 5 mSv. case-control study designs were included and stud- The pooled estimate for diagnostic x-ray expo- ies were selected so that there was no overlap among sure is presented in Table C-2. The data from Shu study populations. Table C-1 lists the studies that we et al. (1988) for specific categories of exposure initially chose to consider with some methodologi- were combined (using the same methods described cal notes. Included in this table is a study of atomic above) prior to pooling the studies. The final pooled bomb survivors that was not included in the analy- result, an odds ratio of 1.4 for preconception diag- sis (not a case-control study). This group of studies nostic x-ray exposure, is significantly positive (95% is not always well-suited for meta-analysis because CI 1.2-1.7). Limitations of this comparison include there is very little consistency among exposure vari- the different time periods considered for exposure ables. For example, diagnostic x-ray exposure stud- and the inclusion of infant leukemia in the com- ies might use information about x-rays at any time parison with childhood leukemias. Interview-based before conception or only for a fixed period of time exposure information was not validated by Shu et (one month, one year, etc.) before conception. Nev- al. (1988), introducing possible recall bias, but there ertheless, a group of studies with generally positive was a significant dose-response trend in this study. although not statistically significant results can be The odds ratio estimate for any x-ray with one year combined for a result that will help establish the (OR = 1.32) was higher than the estimate from that presence of a significantly positive effect even if the study for an x-ray ever (1.08, 0.42-2.81) and lower central estimate is not precise or even meaningful. than that for any x-ray within one month (2.56, 0.67- Study results were presented as odds ratios and 9.75). Because of the low weight attached to this were combined following the methods presented by study, however, the pooled result would be virtually Greenland (1987). Specifically, the natural log of the same using any of these estimates. It should also the pooled odds ratio (ln(ORp)) was estimated as be noted that this study found higher and signifi- the weighted mean of individual ln(OR) estimates; cantly positive estimates for x-rays of the abdomi- weights were the inverse variance of each estimate nal region; for any x-ray ever the odds ratio is 2.24 (w = 1/SE2). The pooled standard error was calcu- (1.44-3.47) and for any x-ray within one month the lated as the inverse of the square root of the sum odds ratio is 5.93 (1.52-23.1). Meinert et al. (1999) 187 Appendix C 188 �� k r �� �� � o � �� � �� Y �� � � � � � � � w � � e �� �� �� �� � � N � � � � f �� �� � � � o �� �� � � �� � �� e � � � v �� � � � �� ��� i � � � s � � � � � �� � u ��� � l � � � c �� � �� ��� � x � �� e � �� �� � � ���� , � � � e � t . �� � � �� ��� �� � ��� ” � a � � � t s � � �� s � � n � ��� � � �� o k �� � � i r � � �� t �� � ��� o � � a l �� � � Y �� �� u �� � � � � � p � w ���� � � � o � ��� e �� �� � � � �� � p � N � � � l �� �� a n � � � � �� ��� �� ��� � r i u s r e i d � t � n � n � �� a � � u � � �� n o � � ��� � � a � � c � � � � b l � � � � r � a � � � � � r u ��� � � � � � u b � � � � � � r � � u � �� � �� ��� � � � � s g � � ��� � � � � � n g � �� � � � � �� �� i � � � � n � � � d � i � � � �� � ��� �� n � d �� � � � � ��� u �� � u l � ��� �� � o ��� c �� r �� �� ��� � � r ��� �� n � �� �� � �� i � u � � � �� �� � � , s � �� �� �� � �� � � � s � � � d � a � � � n e � � �� �� � �� r a �� ��� � � a �� �� � � � �� ���� s � � � � r ��� � � � n � � ���� � � e a � t �� � t � �� � �� �� i � � � n l �� � � � �� � e � � � o c � � � � � ��� � � � ��� �� p n o r o t i t e � a � � � l � m � � � � � u �� � d � p � � r � � � � � o a � ��� ��� ��� � � � � � �� � p � d � � � � � � � � � n � n � �� � � � � � � � � a a ��� � t � � � � � � � � . b � s � � � � r � � � e � � �� �� �� �� l � � � t � � � u � � � . � � � � � � � � u e � � s l � l � � � � a � � � � � � � i �� l � � � � p s a P � � � � � � � � � � “ y � �� �� �� �� . � m � � � � � � l t o a � �� � � �� � ��� � � � � � � � �� d S c �� e n - n s a d i i �� l � u n l s � i o � c � a �� p � n d a � w i �� e � e ��� ��� � ) s s � � n �� r 6 u � �� n �� �� o 6 t �� �� i t � �� �� �� 9 o � c �� � M 1 n �� a � �� � � ( f � �� � � d a � �� �� . �� � t t � l n � � � � �� �� n a � � a a � e � � � d �� � � t � �� e �� � � r e � m � r 2 � t �� o ��� �� � �� � o ��� s � � �� v � m �� �� � i u � � m a � j �� � � i v t h d r ��� ��� � � �� � � � � l a a �� u a r s � n B G � o b � � , e � n y m h �� l � �� t � o l o � i � a t b � � � d �� � �� � � c � a n � i c �� � i � f a �� � � m i �� � , r � � c m � � � � � �� y o e �� o � t ��� f � � � � t � i � p �� �� n �� � � � � � � �� I S C A � � � � � � �� � � �� � �� � � � �� �� 1 2 3 189 Appendix C , y , n d ear h o u i n t rt cl � s i o u i �� b cat h n s f u i a �� t zat o t i ed o � , ar c � an ear e e S n y rb e ag , u h ���� t e g ce , al n ar y d � i t ag en e n i k , l d a ern cl i n , n s ri r Pat d U Sex res faci o m u d T d an o r; o d h ea n ear cal d y o l y an i i 1 h mi 1 �� at f o f al o i n C t t o h i �� o t f o at h � i o t re rad rs (t i w u an ear y s r w ��� s y ea al t y es o � s y i b 1 ) p ri re ay � g 2 r n ern o s u n e t - ex o i s n i x R eg ay h i o t ex t l r al h ��� p i - at a al t � n o x t i c x n w t o cep e o o ; i w e t i n �� t n s re re ; s at a o o s u u co p red i �� s s N d t ay f o al � o o r t e o i - p p h ccu . er; eri n x t s cep ) o , h ex ex n y 4 s rk t ���� r ); 9 mo o n � mat e co al al 9 an ; � c / rn w n n 1 f e n n n � o . o o mo o v al a n o o l i i i i i n w a o t t h 6 C i at at t t e d p p e n n act n mi at g i o i o o o cep cep u i i h o cu cu t h n d n ad h mo c i c S d ( l O (b rad 1 reg Rad w O co ab co i p h u C o , - r f e 5 r 2 g o ) 1 o �� 9 s - ag y / d l t L � ) e e 3 a 0 e i n � v 8 H r an 1 r � r / ag l t �� fan � ai , t u N 1 t l n e �� / 5 S a r efo r 1 � 1 (i �� c b o d i . , � r s e e n (Bri (Sco a a � t i o efo h a) ��� l � f 8 t e b 6 0 ag l c x 8 n mi mi � � 8 9 / p e L e e - - O � 1 re emi v � m k k 2 2 i e H 3 4 mo k t o / 5 5 h 9 a c t �� N eu eu 8 2 9 9 / efo r eu n e i L 1 l 1 L 1 1 L b 9 �� m p s � o o � a r o f � 7 w c y s ) s b e a �� 0 r e s d s 9 o r h a i t o t 9 ed c �� c d � i o p ce a g d � d (1 h f u �� ry e n an t u . o d t �� an i s n t l r . �� n i � i i d s al C � e S a G u . t . �� n r m b ) et ’s Ch cl t U e �� o � o 3 Reg i s c , � 9 ) 6 u a r er n ex j at �� an ren � 9 7 a p l n , d d 1 9 . ad ce u u a C �� l ( 9 rd rm i p K . � s 1 n . l a e ro ’ o ( � a o n . Ch G Can U p G G Can t l e � n e r a o � d i t n l t � e i . e � a l h r et al 7 n � m e C i r �� 9 p ert � er o e K a et 9 . n f 4 9 r h f 1 �� n ap u 9 9 al I T D o ��� . r 9 9 �� Sh 1 D al Mei et 1 5 6 7 Appendix C 190

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also found a higher odds ratio for x-rays of the ab- of childhood leukemia/NHL with this exposure al- dominal area within 2 years (1.76, 0.88-3.56). though the result is not significantly positive. The The pooled estimate for the risk of paternal ra- choice of leukemia or LNHL results from Gardner diation occupation, the most general category de- et al. (1990) does not substantially affect the result. fined by most studies, is presented in Table C-3. In Table C-5 gives the result for a total dose within 6 this case there were options for combining results months of conception of at least 5 mSv. This expo- according to exposure definitions. For the primary sure category is also associated with a roughly 2-fold result we chose the category of ‘exposure to radio- increase in risk; in this case the choice of leukemia active materials’ from Shu et al. (1994) and the cat- or LNHL from the Gardner study makes the differ- egory of ‘any paternal occupational exposure’ from ence in statistical significance. Using the leukemia Meinert et al. (1999). These are the more appropriate estimate the pooled odds ratio is 2.5 (1.0-5.9); using categories for comparison with other studies. Using the LNHL estimate the odds ratio is 1.9 (0.8-4.5). these categories the odds ratio is significantly posi- The only study not included in analysis was the tive (1.4, 1.1-1.8). Using the more specific catego- atomic bomb survivors study (Yoshimoto 1990). ries of exposure from these two studies (with greater Since this study is in many ways the standard of evi- uncertainty around the estimated odds ratios) the es- dence for radiation-induced disease it does deserve timate is higher (1.7, 1.2-2.4). It should be noted that some discussion. We could not use it in our analysis the contributing studies include one study of infant because no case-control analysis was made by the leukemia and one study of LNHL. original authors. A simple analysis of the rate ratio The pooled estimates for occupational exposure shows that there were 16 leukemias in the children with dose information are more precise since the of 31,150 parents exposed to at least 10 mSv of ra- exposure categories are consistent among studies; diation from the bomb and 17 leukemias in 41,066 on the other hand, only three studies provide suit- children of unexposed parents, a rate ratio of 1.2. able results. In this case one study reported results This is not significantly positive (95% CI 0.6-2.5), for LNHL (Draper et al. 1997), one study reported but it is also not inconsistent with the other data. As results for leukemia (McLaughlin et al. 1993) and discussed in the accompanying section on precon- Gardner et al. (1990) reported both. Results are ception irradiation, the atomic bomb survivors may combined using both the leukemia and the LNHL be relatively uninformative on this issue since less results of Gardner et al. (1990). Table C-4 gives than 2% of the F1 cohort was conceived in the six the result for total preconception dose of at least 50 months before the bombings and of these roughly mSv. There is an apparent 2-fold increase in the risk half would have been born to an exposed father. If 191 Appendix C 5 9 4 4 0 9 8 � 7 5 3 2 3 3 1 4 � 1 ...... � . �� 0 0 0 0 0 0 0 � 0 � 9 3 7 4 4 8 6 � 4 � ...... � . 5 2 2 4 3 1 4 � 2 , , , , , , , � , � 7 5 1 2 1 8 7 � 2 � ...... � . � 0 0 1 1 1 0 0 � 1 � �� �� 0 1 7 3 8 2 8 � 7 ...... � . � 2 1 1 2 1 1 1 � 1 �� � at e al ear n y ri o rk e e ��� o n � n i w o h mat t �� i n at i e d w h v e �� �� t el i rk g i � o � re w afi � u act ad w l �� s o b � er i o rk � ��� at n p o rk Sel o � o �� i rad w ex ed at � w s at o i at t o n ed p red � o ��� ad y i ed ed r o � � o t ex s s l i at �� � e o i o r r n rk e p p o �� o mp v x x ear E E E w W Rad E Mo y �� � � � d ert � n an �� ) � . �� al Mei ( e �� et v � i re’ u u �� s act )) o o (Sh . i p ��� e al g ex rad �� et ad y � o t b ert �� �� n ‘an n re � o u i d s �� ��� 3 at o an Mei i 9 p ( ) 9 ��� . 1 ex rad 0 re 9 9 al ( ( . 9 7 u �� 9 9 � s � � 9 9 al 9 9 et � � � o 1 9 1 1 4 4 � � � u p . 1 et . . 9 9 � . � � 9 9 al n al al ex � i al 1 1 �� �� (Sh l � et . . � et et h s �� �� et g red al al � al er o ) ert ert t � n er au ) �� �� et et i . n n � � eri L i n rd �� � � ap u u al a r � � �� G Mc Sh Sh D Mei Me � mat et � mo Appendix C 192

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������ �������� ������ ���� ��� ���� ��� ���� ������� ���� ������� �� ���� 193 Appendix C we consider this group of a few hundred children to tion mutations can occur following preconception be the cohort at risk then a spontaneous case of leu- exposures (Niwa 2003), and it is therefore not nec- kemia would be unlikely and an excess of the degree essary to have a germ cell mutation. In vivo and in that is seen in other studies would be impossible to vitro studies (not transgenerational studies) have de- detect. tected elevated levels of instability for as long as two In conclusion, this analysis supports the idea years after exposure in exposed mice. If this kind of that paternal preconception exposure to radiation is persistence is assumed to hold for transgenerational a risk factor for childhood leukemia. Under the tra- instability then leukemogenic mutations could theo- ditional statistical ‘null hypothesis’ that there is no retically occur during embryogenesis, or even later, real relationship, there would be, at most, about a following preconception exposures. Evidence for 7% chance of generating data as suggestive of a real such an effect has in fact been generated in mice. relationship as these in the absence of a true rela- It is also puzzling that many discussions have tionship (based on the second pooled result in Table implicitly treated two potential leukemia factors, C-4). This is, we believe, an informative measure of preconception irradiation and viruses transmitted the overall state of the science and one that is intui- during high population mixing, as independent and tive enough to be useful in dealing with the public. mutually exclusive. Again, animal studies provide Even without such results it could be argued that, useful information. In an early study, dramatic reduc- in the context of a body of literature that has shown tions in radiation-induced leukemias were observed the same effect in mice and has also shown evidence in mice that were housed in a microbe-free environ- of increases in solid cancer and adverse birth out- ment (Warburg 1968). More recently, preconception comes, the standard test of statistical significance irradiation of male mice has been shown to increase should not be the sole criterion by which we judge the sensitivity of offspring to chemical- or radiation- this risk. induced leukemias (Lord et al. 1998). Two risk fac- It is our interpretation of the discussions ac- tors such as radiation and a virus could be linked in companying many of these studies that the scientific a two-mutation model of leukemogenesis, through community has been unwilling to consider this as a a model of induced instability and oxidative stress serious issue, even in light of convincing evidence, (Clutton et al. 1996, Limoli et al. 2003), or through primarily because a) it seems mechanistically un- some unknown mechanism; in any case, interpreta- likely that a sperm cell mutation could be a leuke- tions of the Seascale leukemia cluster, where both mia risk factor in the child (which would carry such factors have been implicated, could consider them a mutation in the paternal allele of every cell), and jointly. Finally, the atomic bomb survivor data have b) the atomic bomb survivors have not demonstrated very simply not demonstrated the absence of an ef- an effect. fect and they are in fact not very informative data. One potential solution to the first problem in- This has not been adequately appreciated in most volves recent animal studies in the area of chromo- discussions. somal instability--these indicate that post-concep- Appendix D

Recent information Techa River cohort

Three critical references became available after we Residents of the Techa River region were exposed to completed our overview. These are discussed briefly external and internal radiation from the Mayak fa- below. cility in the Southern Urals. In section 12.4 we dis- cussed an earlier analysis of this cohort (Kossenko Fifteen-country worker study 1996). Since the publication of that paper substantial improvements in dose estimation have been made. Cardis et al. (2005) published the results of an in- Krestina et al. (2005) published an analysis covering ternational cohort study of cancer mortality among the period 1950-1999. radiation workers. This cohort drew over 400,000 This cohort includes almost 30,000 individu- workers from fifteen countries receiving an average als who were exposed to mean doses of 30 mGy cumulative external dose of 19.4 mSv. Confounding (stomach; used to calculate solid cancer risks) and by internal radiation exposures was controlled by 300 mGy (bone marrow; used to calculate leukemia excluding workers who potentially received more risks). This cohort is different from the atomic bomb than 10% of their total cumulative dose from inter- survivors, and similar to the cohorts of radiation nally-deposited radionuclides. workers, in that exposures were chronic in nature. The ERR for solid cancer mortality was estimat- The cohort is also distinct in that residents were ex- ed to be 0.87/Sv (0.03-1.88) . Among male atomic posed to both external and internal sources of ra- bomb survivors aged 20-60 at exposure the corre- diation; the atomic bomb survivors were exposed to sponding estimate is 0.32/Sv (0.01-0.50) . These external radiation only and analyses of workers tend are statistically compatible estimates, but we might to avoid the effect of internal radiation exposures want to consider the possibility that they reflect a (as in Cardis et al. 2005). Although it is important true difference in risk. These workers differ from to keep these differences in mind, it is interesting atomic bomb survivors in that they were exposed to note that solid cancer mortality risk estimates are to lower cumulative doses spread out over time. remarkably consistent among the recent study of The mean dose among the workers was 19.4 mSv. workers and Techa River residents and the analysis Among atomic bomb survivors with doses less than of atomic bomb survivors exposed to similar doses: 50 mSv the solid cancer mortality ERR was 0.93/Sv These numbers are consistent with the idea that (Figure 13-1), a figure much closer to what was ob- the linear model may underestimate risks at lower served among the workers. These data are therefore doses and also suggest that risks from chronic expo- consistent with the idea that the linear model might sure are not less than risks from acute exposure. underestimate risks at low doses, although there is Relative risks among the Techa River cohort considerable uncertainty around these estimates. tended to be higher for women. The ERR for solid This study assessed leukemia risks using a lin- cancer was 0.6/Gy for men and 1.2/Gy for women. ear excess relative risk model. The ERR estimate for This difference is consistent with recent analyses of non-CLL leukemia mortality was 1.93/Sv (<0-8.47), the atomic bomb survivors, where the ERR estimate not significantly positive but consistent with previ- for females was 1.7 times higher than that for males ous analyses of workers (see Table 13-2). (Preston et al. 2003).

194 195 Appendix D Low-dose atomic bomb Nuclear workers Techa River survivors (Preston et al. (Cardis et al. 2005) (Krestinina et al. 2005) 2003) Mean dose 0.02 Sv1 (colon) 0.02 Sv (colon) 0.03 Gy (stomach) ERR for 0.93/Sv 0.87/Sv 0.92/Gy solid cancer (SE 0.85) (0.0-1.9) (0.2-1.7)

(Footnotes) 1 This group received colon doses of 0-0.05 Sv.

Leukemia risk (excluding CLL) among the Te- the committee states that this kind of exposure is cha River cohort appeared to be linear with dose, known to lead to adverse health effects in mice and with an ERR of 6.5/Gy (1.8-24). This is higher than we should therefore assume that the same is true for the estimate from the recent analysis of nuclear humans. It states, however, that such effects have workers (1.9/Sv, <0-8.5; Cardis et al. 2005) and not been observed in humans, and we would dis- slightly higher than the linear estimate of leukemia agree with this conclusion for reasons described in mortality among the atomic bomb survivors (4.6/ Section 10 and Appendix C. The summary of pre- Sv, 3.3-6.4; Pierce et al. 1996). Uncertainties in the conception effects in BEIR VII, as in previous re- shape of the dose-response curve for leukemia and views, does not discuss some plausible mechanisms the effects of age and time on risk limit the useful- by which these diseases could be caused. Although ness of this comparison. the committee makes reference to studies demon- strating that a) preconception radiation exposure can BEIR VII lead to mutations in the zygote after conception, and b) the sensitive stage of the sperm cell cycle for this The National Academy of Sciences Committee on type of effect would be spermatozoa, it continues the Biological Effects of Ionizing Radiations (BEIR) the tradition of estimating risks based on strictly de- last published a review in 1990 (BEIR V). A report fined heritable diseases. These are diseases that are on radon was published as BEIR VI in 1999. The known to arise from mutations of critical genes in current comprehensive review of the health effects the germ cell of the exposed parent. Risk estimates of radiation is known as BEIR VII. This report, like are based on studies exposing the sperm stem cells BEIR V, is an attempt to guide the process of esti- of mice (spermatogonia). These heritable diseases mating risks from radiation exposure on the basis may be one small part of the total risk associated of the atomic bomb survivor data, although other with preconception radiation exposure, however, epidemiological information is considered. Several and the committee has not addressed this possibil- prominent features of the atomic bomb survivor data ity. are reiterated, notably the relative sensitivity of chil- In deriving risk estimates the committee chose dren and females to some forms of cancer. to use the average prediction of two models, the The BEIR VII report concludes that the linear relative risk model and the absolute risk model. The no threshold model of radiation carcinogenesis is committee also divided low-dose risk estimates by the most appropriate model for estimating risks. Al- a dose and dose-rate effectiveness factor (DDREF) though the committee makes reference to biologi- of 1.5 to account for the assumption that low dos- cal observations that might suggest overestimates es of radiation and doses spread out over time are or underestimates of risk at low doses, it concludes less damaging than acute doses of moderate or high that the net effect of various complexities in the bio- magnitude. The resulting estimates of risk are lower logical response is unknown. The committee does than the relative risk results of the UN Committee explicitly reject the idea that low doses of radiation (UNSCEAR 2000), which reported results for rela- might be beneficial (hormesis). tive and absolute risk models separately and did not In regards to preconception radiation exposure use a DDREF. Acronyms & Abbreviations Acronyms LSS Life Span Study NAS National Academy of Sciences AEA Atomic Energy Authority NCHS National Center for Health Statistics ALL acute lymphocytic leukemia NCI National Cancer Institute AML acute myelogenous leukemia NCRP National Council on Radiation Protection BEIR Committee on the Biological Effects of and Measurements Ionizing Radiation NRC Nuclear Regulatory Commission CDC Centers for Disease Control and Prevention NRPB UK National Radiological Protection CEDE committed effective dose equivalent Board CLL chronic lymphocytic leukemia NRRW National Registry for Radiation Workers CML chronic myeloid leukemia OPCS Office of Population Censuses and Surveys CNS central nervous system ORNL Oak Ridge National Laboratory CT computed tomography, or CAT scan OSCC Oxford Survey of Childhood Cancers LNHL leukemia and non-Hodgkin’s lymphoma OSHA Occupational Safety and Health DOE Department of Energy Administration AEC Atomic Energy Commission PPI paternal preconception irradiation ABCC Atomic Bomb Causality Commission RAC Radiological Assessments Corporation RERF Radiation Effects Research Foundation RBE relative biological effectiveness NTS Nevada Test Site RNMDR Russian National Medical and STS Semipalatinsk Test Site Dosimetric Registry SRS Savannah River Site RPG radiation protection guides SMR standardized mortality ratio SDE shallow dose equivalent SIR standardized incidence ratio TEDE total effective dose equivalent RR relative risk TMI Three Mile Island DDE deep dose equivalent TSH thyroid-stimulating hormone DNA deoxyribo nucleic acid UK United Kingdom DOT Department of Transportation UNSCEAR United Nations Scientific DREF dose rate effectiveness factor Committee on the Effects of Atomic EAR excess absolute risk Radiation ECRR European Committee on Radiation Risk WL Working Level EPA Environmental Protection Agency WLM Working Level Month ERDA Energy Research and Development Administration Abbreviations ERR excess relative risk FDA Food and Drug Administration Bq Becquerel HTDS Hanford Thyroid Disease Study Gy Gray ICRP International Commission on Radiological Km Kilometer Protection Rad radiation absorbed dose LDE lens dose equivalent Rem Roentgen equivalent in man LET linear energy transfer Sv Sievert LLNL Lawrence Livermore National Laboratory 196 Glossary of Terms for Epidemiology and Radiation

Absolute Risk: The excess risk attributed to exposure to hazard and usually expressed as the numeric difference between exposed and non-exposed populations (e.g., 1 case of cancer per million people irradiated annually per Gy). Absolute risk may be given on an annual basis or lifetime basis.

Acute Lymphocytic Leukemia (ALL): A hematological (associated with blood and blood forming tissues) malignancy marked by the unchecked multiplication of immature lymphoid cells (a white blood cell responsible for much of the body’s immune protection) in the bone marrow, blood, and body tissues. See also leukemia.

Acute Myeloid (Myelogenous) Leukemia (AML): A group of hematological (associated with blood and blood forming tissues) malignancies in which neoplastic cells develop through replacement of normal bone marrow and circulation of immature cells in the peripheral blood. Immature cells include ones that are of myleloid (marrow-like), monocytic (white blood cell used for defense), erythrocytic (pertaining to red blood cells), or megakaryocytic (bone marrow cell from which platelets are derived) origins.

Additive Effect: The effect of a combination of two or more substances that is equal to the sum of the individual effects.

Adult T-cell Lukemia-Lmphoma (ATL): A lymphoproliferative disease of malignant T-cells. It is associated with infection by human T-cell leukemia virus, a retrovirus.

Alpha Particle: A positively charged particle ejected spontaneously from the nuclei of some radioactive elements. It is identical to a helium nucleus that has a mass number of 4 and an electrostatic charge of +2. It has low penetrating power and a short range (a few centimeters in air). The most energetic alpha particle will generally fail to penetrate the dead layers of cells covering the skin and can be easily stopped by a sheet of paper. Alpha particles are hazardous when an alpha-emitting isotope is inside the body.

Alpha Radiation: Radiation consisting of helium nuclei that are discharged by radioactive disintegration of some heavy elements, including uranium-238, radium-226, and plutonium-239. Alpha, the first letter of the Greek alphabet, is written as α.

Analytical Studies: There are two standard types of epidemiological study design (with sub-types within each): analytical and descriptive. Analytical studies are usually considered the strongest and most reliable. In analytical studies, populations who have had exposures to a hazard or increased incidence of a disease are compared with unexposed or healthy populations. 197 198 Glossary

Anaplastic Cancers: A malignancy that has lost cellular differentiation and function (characteristic of most malignancies).

Ankylosing Spondylitis: A chronic progressive inflammatory disorder that, unlike other rheumatological diseases, affects men more often than women. It involves primarily the joints between articular processes, costovertebral joints, and sacroiliac joints, and occasionally, the iris or the heart valves. Bilateral sclerosis of sacroiliac joints is a diagnostic sign. Affected persons have a high incidence of a specific human leukocyte antigen (HLA-B27), which may predispose them to the disease. Changes occurring in joints are similar to those seen in rheumatoid arthritis. Ankylosis may occur, giving rise to a stiff back (poker spine). Nonsteroidal anti-inflammatory drugs and physical therapy are the primary forms of treatment.

Antibody: An immunoglobulin produced by B lymphocytes in response to a unique antigen. Each antibody molecule combines with a specific antigen to destroy or control it. All antibodies, except natural antibodies (e.g., antibodies to different blood types), are created by B cells linking with a foreign antigen, typically a foreign protein, polysaccharide, or nucleic acid. Antibodies neutralize or destroy antigens in several ways. They can initiate lysis of the antigen by activating the complement system, neutralizing toxins released by bacteria, coating (opsonizing) the antigen or forming a complex to stimulate phagocytosis, promoting antigen clumping (agglutination), or preventing the antigen from adhering to host cells.

Atomic Bomb Casualty Commission (ABCC): In 1946, the Atomic Bomb Casualty Commission was established in accordance with a US presidential directive from Harry S. Truman to the US National Academy of Sciences-National Research Council to undertake long-term investigations of the late medical and biological effects of radiation among the atomic-bomb survivors in Hiroshima and Nagasaki. Initial funding was from the US Atomic Energy Commission and was later supplemented by the US Public Health Service, the National Cancer Institute, and the National Institute of Heart and Lung Diseases. Formal Japanese participation commenced in 1948 under the auspices of the Japanese National Institute of Health of the Japanese Ministry of Health, Labor and Welfare. ABCC was the predecessor of the Radiation Effects Research Foundation, which was established in April 1975. Autoimmune Disease: A disease produced when the body’s normal tolerance of the antigens on its own cells (i.e., self-antigens or autoantigens [AAg]) is disrupted.

Autoimmunity: The body’s tolerance of the antigens present on its own cells. Antigens are proteins or oligosaccaride markers on the surface of cells that identify the cell as self or non-self. This recognition is necessary in order for the cell to neutralize or destroy itself in the presence of foreign antigens. Intolerance, lack of autoimmunity, may result in self-destruction of tissues and inflammation.

Becquerel (Bq): Becquerel is a unit used to measure radioactivity. One Becquerel is that quantity of a radioactive material that will have 1 transformation in one second. Often radioactivity is expressed in larger units like: thousands (kBq), millions (MBq) or even billions (GBq) of becquerels. There are 3.7 x 1010 Bq in one curie.

Benign: Neoplasms or tumors that are not recurrent or progressive, nonmalignant.

Beta particle: A beta is a high-speed particle, identical to an electron, that is emitted from the nucleus of an atom. Glossary 199

Beta radiation: Streams of beta particles are known as beta ray or beta radiation. Beta rays may cause skin burns and are harmful within the body. A thin sheet of metal can afford protection to the skin.

Biokinetic Models: A method used for measuring radiation dose effects by describing the deposition and movement of material throughout the body. It is derived from biokinetics, the study of growth changes and movements in developing organs. This is valuable to radiation risk studies as it incorporates the unique responses of individuals with different physiological properties and metabolic processes.

Biological Effects of Ionizing Radiation (BEIR): A committee put together by the National Research Council, USA to study the effects of radiation to evaluate risk and create safety standards.

Birth Defect: A physiological or structural abnormality that develops at or before birth and is present at the time of birth, especially as a result of faulty development, infection, heredity, or injury. Also called congenital anomaly.

Bystander Effects: The response of cells that are not directly traversed by radiation but respond with gene induction and production of potential genetic and carcinogenic changes. In short, cells not directly exposed to radiation may still be affected adversely.

Cancer: Malignant neoplasia marked by the uncontrolled growth of cells, often with invasion of healthy tissues locally or throughout the body.

Case Report/Case Survey: Report of a single case of a disease.

Case-Control Study: A case-control study is a method of studying the relative risks of having or developing a disease or condition. In this study methodology, the exposure experience of cases (persons with the condition) is compared to that for controls (persons without the condition). Case- control studies are efficient designs for estimating the relative risks of developing disease (including controlling for other factors, such as age or sex), but they generally are not used for measuring the prevalence or incidence of conditions.

Central Nervous System (CNS): The brain and spinal cord.

Cerebral Angiography: A radiology procedure using x-ray and opaque dye that helps identify abnormalities of the blood vessels within the brain.

Chromosome aberrations: An abnormality in chromosomes regarding their number or material.

Chronic Lymphocytic Leukemia (CLL): A malignancy in which abnormal lymphocytes (a white blood cell responsible for much of the body’s immune protection), usually B cells, proliferate and infiltrate body tissues, often causing lymph node enlargement and immune dysfunction.

Chronic Myelogenous Leukemia (CML): A hematological malignancy marked by a sustained increase in the number of granulocytes (a large glanular white blood cell), splenic enlargement, and a specific cytogenetic anomaly (of abnormal cell structure or function) in the bone marrow.

Circadian Rhythm: Diverse yet predictable changes in physiological variables, including sleep, appetite, temperature, and hormone secretion, over a 24-hour period. 200 Glossary

Cohort study: A study in which a population (i.e., a cohort) is defined according to the presence or absence of a factor that might influence the probability of occurrence of a given disease or other outcome. The cohort is then followed to determine if those exposed to the factor are indeed at greater risk of the outcome.

Committed dose equivalent: The dose equivalent to organs or tissues of reference that will be received from an intake of radioactive material by an individual during the 50 year period following the intake.

Committed Effective Dose Equivalent: The sum of the products of the weighting factors applicable to each of the body organs or tissues that are irradiated and the committed dose equivalent to these organs or tissues.

Confidence Intervals: The computed interval with a given probability (i.e., 95%) that the true value of the statistic—such as a mean, proportion, or rate—is contained within the interval.

Congenital Malformations: Abnormal shapes or structures present at birth.

Continuous Variable: A variable that can take any value measured on a continuous scale, for example: height, weight, age.

Cross-Sectional Surveys: Descriptive studies that compare disease status, demographics and distance from a hazardous facility of a randomly selected group near a facility with a randomly selected group located not near the facility.

Curie (ci): The curie is a unit used to measure radioactivity. One curie is that quantity of a radioactive material that will have 37, 000, 000, 000 transformations in one second. Often radioactivity is expressed in smaller units like thousandths (mCi), millionths (uCi) or even billionths (nCi) of a curie. A becquerel is a unit that describes one radioactive disintegration per second.

Cytogenetics: The study of chromosomes.

Deep Dose Equivalent: Applies to external whole-body exposure and is the dose equivalent at a tissue depth of one centimeter (1000 mg/cm2).

Descriptive Studies: Descriptive studies explore associations between exposure and disease incidence and sometimes precede more expensive and time-consuming analytical studies. Ecologic studies are descriptive studies that compare disease incidence between populations based on public records and so do not use case specific data. Dose: The absorbed dose, given in rads (or in SI units, (Gy) grays), that represents the energy in ergs or Joules absorbed from the radiation per unit mass of tissue. Furthermore, the biologically effective dose or dose equivalent, given in rem or sieverts, is a measure of the biological damage to living tissue from radiation exposure.

Dose Rate Effectiveness Factor (DREF): A factor by which the effect caused by a specific type of radiation changes at low as compared to high dose rate.

Dose-response: Correlation between a quantified exposure (dose) and the proportion of a population demonstrating a specific effect (response). Glossary 201

Dosimetry: Measurement or estimation of doses. Dosimeter: A device for measuring x-ray output. Doubling Dose: Amount of radiation needed to double the natural incidence of a genetic or somatic abnormality.

Ecologic Studies: Descriptive studies that compare disease incidence between populations based on public records and so do not use case specific data.

Epidemiology: The study of the distribution and determinants of health-related states and events in populations, and the application of this study for managing health problems.

Excess Absolute Risk: The excess number of cases induced by one (EAR) unit exposure, in addition to the spontaneous number of cases. EAR is usually expressed as number of cases per year per 10 000 persons exposed to a dose of 1 Gy.

Excess Relative Risk (ERR): The fraction by which the risk for an exposed person exceeds that of a person who was not exposed. An excess relative risk of 1 means the person’s risk is double that of an unexposed person. ERR = Relative Risk – 1. Extrapolate: To apply data learned about one range of doses to another range of doses.

Follicular Tumors: Tumors of or relating to follicles.

Fractionated exposure: Exposure to radiation that occurs in several small acute exposures, rather than continuously as in a chronic exposure.

Free Radical: A molecule with an unpaired electron. Because they have a free electron, such molecules are highly reactive.

Gamma Radiation: High-energy, short wavelength, electromagnetic radiation emitted from the nucleus. Gamma radiation frequently accompanies alpha and beta emissions and always accompanies fission. Gamma rays are very penetrating and are best stopped or shielded by dense materials, such as lead or depleted uranium. Gamma rays are similar to x-rays.

Gamma Ray: Gamma rays are electromagnetic waves or photons emitted from the nucleus (center) of an atom.

Gardner Hypothesis: A hypothesis that says that childhood leukemia and non-Hodgkin lymphoma can be caused by paternal exposure to ionizing radiation before the conception of the child.

Germline Mutation: A mutation in the genetic content of a sperm or egg.

Goiter: Thyroid gland enlargement. An enlarged thyroid gland may be caused by thyroiditis, benign thyroid nodules, malignancy, iodine deficiency, or any condition that causes hyperfunction or hypofunction of the gland.

Graves’ disease: A distinct type of hyperthyroidism caused by an autoimmune attack on the thyroid gland. It typically produces enlargement of the thyroid gland and also may cause ocular findings. 202 Glossary

Gray (Gy): The gray is a unit used to measure a quantity called absorbed dose. This relates to the amount of energy actually absorbed in some material, and is used for any type of radiation and any material. One gray is equal to one joule of energy deposited in one kg of a material. The unit gray can be used for any type of radiation, but it does not describe the biological effects of the different radiations. Absorbed dose is often expressed in terms of hundredths of a gray, or centrigrays (cGy). One centrigray is equivalent to one rad.

Hairy cell leukemia: A chronic low-grade hematological malignancy (associated with blood and blood forming tissues) of abnormally shaped, like “hairy cells”, B lymphocytes (a white blood cell responsible for much of the body’s immune protection).

Hashimoto’s thyroiditis: A common autoimmune illness in which there is inflammation, and then destruction and fibrosis of the thyroid gland, ultimately resulting in hypothyroidism. Thyroid hormone replacement is required. Women are much more commonly affected than men.

Healthy Survivor Effect: a variant of the healthy worker effect. When present, bias results because workers must remain healthy to continue their employment. Continued employment is associated with increasing age and increasing exposure but not necessarily increasing risk of disease. Thus long term employees are long term survivors.

Healthy Worker Effect: A type of selection bias that occurs in occupational cohorts in which the general population is used as the comparison group. In these studies, workers tend to have lower overall morbidity and mortality rates than the general population because people in employment are by definition healthier than the population as a whole which includes those people too ill to work.

Hemangioma: A benign tumor of dilated blood vessels.

Hematological Tumors: sometimes also known as “liquid tumors”—are chiefly comprised of lymphomas, myelomas and leukemias.

High-LET: Linear energy transfer refers to the measurement of the number of ionizations which radiation causes per unit distance as it traverses the living cell or tissue. The concept involves lateral damage along the path, in contrast to path length or penetration capability. Medical X-rays and most natural background radiation are low LET radiation, while alpha particles have high LET.

Hodgkin’s disease: A malignant lymphoma (neoplasms originating from white blood cells responsible for much of the body’s immune protection) marked by the Reed-Sternberg cell, a giant, multinucleated cell.

Hormesis: the stimulating effect of a small dose of radiation that is toxic in larger doses; as well as the controversial hypothesis that very low doses of ionizing radiation may not be harmful and may even have beneficial effects.

Hyperthyroidism: A disease caused by excessive levels of thyroid hormone in the body.

Hypocenter: The location on the ground vertically below the air burst point of an atomic bomb. Glossary 203

Hypothyroidism: The clinical consequences of inadequate levels of thyroid hormone in the body. When thyroid deficiency is long-standing or severe, it results in diminished basal metabolism, intolerance of the cold temperatures, fatigue, mental apathy, physical sluggishness, constipation, muscle aches, dry skin and hair, and coarsening of features.

IgM: Immunoglobulin M, the most efficient antibody in stimulating complement activity.

Incidence: The frequency of new cases of a disease or condition in a specific population or group.

In utero: Within the uterus. In utero exposures are those received by a fetus while in the womb.

In vitro: Studies carried out in cell or culture systems outside the whole organism.

Incidence: The number of new cases of a disease in a population over a period of time.

Infant Mortality: The number of deaths of children younger than 1 year of age per 1000 live births per year.

International Commission on Radiation Protection (ICRP): An international not-for-profit organization that studies the effects of radiation to evaluate risk and create safety standards.

Inverse Exposure-Rate Effect: The enhancement of an effect as the intensity of the exposure decreases (i.e., low-level chronic exposures would be riskier than high-level more acute exposures)

Iodine-131: A radioactive isotope of iodine. Iodine is an element required in small amounts for healthy growth and development. It is mainly concentrated in the thyroid gland where it is needed to synthesize thyroid hormones. 131I is used as a radioactive tracer in nuclear medicine and is found in fallout from nuclear testing. 131I has been demonstrated to cause thyroid cancer in humans. Iodine- 131 has a relatively short physical half-life (8 days).

Ionizing radiation: Ionizing radiation is radiation with enough energy so that during an interaction with an atom, it can remove tightly bound electrons from their orbits, causing the atom to become charged or ionized. Examples are gamma rays and neutrons.

Irradiation: Exposure to radiation.

Lag: The period of time between the application of a stimulus and the resulting reaction. Note: “lag” is used in epidemiological studies to describe the statistical factoring of a “latency period” in a risk analysis.

Latency Period: The time from the stimulus (radiation exposure) to the response of the tissue stimulated (cancer).

Leukemia: A class of hematological (associated with blood and blood forming tissues) malignancies in which immortal clones of immature blood cells multiply at the expense of normal blood cells. As normal blood cells are depleted from the body, anemia, infection, hemorrhage or death result. Types include chronic or acute, myeloid or lymphocytic, and these are often abbreviated (CML, CLL, AML, ALL). 204 Glossary

Linear Energy Transfer (LET): The amount of energy deposited per unit of distance that the radiation travels in tissue.

Least-Squares’ Model: Finds the line minimizing the sum of distances between observed points and the fitted line.

Lens dose equivalent (LDE): applies to the external exposure of the lens of the eye and is taken as the dose equivalent at a tissue depth of 0.3 centimeter (300 mg/cm2).

Life Span Study (LSS): Research conducted by the Radiation Effects Research Foundation to study whether the life span and causes of death among atomic-bomb survivors differ from those of unexposed individuals. This research program includes both incidence and mortality studies based on vital-statistics surveys, death-certificate information, and other sources.

Linear Model: A straight line with the formula: y = a + bx

Linear Quadratic Model: Expresses the effect (e.g., mutation or cancer) as partly proportional to the dose (linear term) and partly proportional to the square of the dose (quadratic term). The linear term predominates at lower doses, the quadratic term at higher doses.

Low-Dose Radiation: Low rates of radiation doses that are either less than 10 mSv received at high rates in single events, or dose rates less than 20 mSv per year received continuously.

Lymphocyte: A white blood cell responsible for much of the body’s immune protection.

Lymphoma: A malignant neoplasm originating from lymphocytes.

Malformation: Deformity; abnormal shape or structure.

Malignancy: A neoplasm or tumor that is cancerous as opposed to benign.

Maximum Likelihood Model: Assigns a weight to each individual factor A, B, C instead of each combination of environments can be predicted accurately by assigning weights to each individual factor, then these factors can be said to operate independently, and the reduction of individual rules to a rule schema is justified.

Mediastinal: Relating to the mediastinum.

Mediastinum: A septum or cavity between two principal potions of an organ.

Medullary Carcinoma: Carcinoma in which there is a predominance of cells and little fibrous tissue.

Melatonin: A peptide hormone produced by the pineal gland that influences sleep-wake cycles and other circadian rhythms. It has a sedative effect and has been used to treat sleep disorders and jet lag, even though its impact on these conditions remains unclear.

Meningioma: A slow-growing tumor that originates in the meninges. Glossary 205

Metastasis: 1. Movement of bacteria or body cells (esp. cancer cells) from one part of the body to another. 2. Change in location of a disease or of its manifestations or transfer from one organ or part to another not directly connected.

MeV: megaelectron volt = 1.60217646 × 10-13 Joules

Mortality: The number of deaths in a population.

Multiple-myeloma: A malignant disease characterized by the infiltration of bone and bone marrow by neoplastic plasma cells.

Multiplicative Effect: The combined effect of factors that is equal to the independent effect of the factors being multiplied together

Myelocytic Leukemia: a group of malignant disorders characterized by the replacement of normal bone marrow with abnormal, primitive hematopoietic cells

Myelogenous: Producing or originating in marrow.

Myeloid: 1. Medullary; marrow-like. 2. Resembling a myelocyte, but not necessarily originating from bone marrow.

National Council on Radiation Protection (NCRP): a private corporation that formulates and widely disseminates information, guidance and recommendations on radiation protection and measurements which represent the consensus of leading scientific thinking.

Neoplasia: A new growth of benign or malignant tissue. A synonym of neoplasm.

Neoplasm: A new and abnormal formation of tissue, as a tumor or growth. It serves no useful function, but grows at the expense of the healthy organism.

Neural tube defects: A group of defects present at birth that result from a failure of the embryonic neural tube to close during development. The neural tube is the tube formed from fusion of the neural folds from which the brain and spiral cord arise.

Neuroblastoma: malignant hemorrhagic tumor composed principally of cells resembling neuroblasts that give rise to cells of the sympathetic system, especially adrenal medulla. This tumor occurs chiefly in infants and children. The primary sites are in the mediastinal and retroperitoneal regions.

Neutrophil: A granular white blood cell (WBC), the most common type (55% to 70%) of WBC.

Nodule: 1. A small node. 2. A small cluster of cells.

Non-Haemopoeietic Neoplasms: abnormal cell growth not pertinent to the production and development of blood cells.

Non-Hodgkin’s Lymphoma: A group of malignant tumors of B or T lymphocytes that are newly diagnosed in about 45,000 Americans annually. 206 Glossary

Non-solid cancer: Cancer usually not resulting in the formation of solid tumors; Non-solid cancers related to radiation exposure often include leukemia illnesses such as acute lymphoctic leukemia, acute myelogenous leukemia, chronic myelocytic leukemia and lymphoma.

Non-Threshold Model: According to such a model theoretically all radiation exposures have the potential to cause cancer

Nuclear Regulatory Commission (NRC): United States Agency that formulates policies and develops regulations governing nuclear reactor and nuclear material safety, issues orders to licensees, and adjudicates legal matters.

Odds ratio: The ratio of two odds. It is used frequently in case control studies where it is the ratio of the odds in favor of getting disease, if exposed, to the odds in favor of getting disease if not exposed.

Ordinal Variable: A type of categorical variable: an ordinal variable is one that has a natural ordering of its possible values, but the distances between the values are undefined. Ordinal variables usually have categorical scales. For example, when asking people to choose between Excellent, Good, Fair and Poor to rate something, the answer is only a category but there is a natural ordering in those categories.

Papillary Tumor: Neoplasm composed of or resembling enlarged papillae.

Parotid Gland: The largest of the salivary glands, located below and in front of the ear. It is a compound tubuloacinous serous gland. Its secreting tubules and acini are long and branched, and it is enclosed in a sheath, the parotid fascia. Saliva lubricates food and makes it easier to taste, chew, and swallow.

Perinatal: Conerning the period beginning after the 28th week of pregnancy and ending 28 days after birth.

Phagocyte: White blood cells (neutrophils and macrophages) with the ability to ingest and destroy microorganisms, cell debris, and other particles in the blood or tissues.

Platelet: A round or oval disk found in the blood as fragments of large cells found in the bone marrow. They play an important role in blood coagulation, hemostasis, and blood thrombus formation.

Polycythemia Vera: A chronic, life-shortening myeloproliferative disorder resulting from the reproduction of a single cell clone; characterized by an increase in red blood cell mass and hemoglobin concentration that occurs independently of erythropoietin stimulation. Prenatal: Before birth.

Proximal Communities: Communities that live next to nuclear facilities.

Rad (Radiation absorbed dose): The rad is a unit used to measure a quantity called absorbed dose. This relates to the amount of energy actually absorbed in some material, and is used for any type of radiation and any material. The unit rad can be used for any type of radiation, but it does not describe the biological effects of the different radiations. One gray is equivalent to 100 rads.

Radiation: Radiation is energy in transit in the form of high-speed particles and electromagnetic waves. We encounter electromagnetic waves every day. They make up our visible light, radio and television Glossary 207

waves, ultra violet (UV), and microwaves with a large spectrum of energies. These examples of electromagnetic waves do not cause ionizations of atoms because they do not carry enough energy to separate molecules or remove electrons from atoms. We are concerned with the health effects caused by alpha, beta, and gamma radiation.

Radiation Effects Research Foundation: The Board on Radiation Effects Research (BRER) is responsible for National Academies’ activities related to the study of the health effects in the atomic bomb survivors at the Radiation Effects Research Foundation (RERF) in Hiroshima and Nagasaki. RERF is a Japanese not-for-profit private foundation and its research has been supported as a binational project for over 50 years. RERF is the successor to the Atomic Bomb Casualty Commission (ABCC), which was established in 1947 by Presidential Directive.

Radioactive Contamination: Unwanted and/or hazardous radioactive material distributed over some area, equipment or person.

Radioactive Material: Radioactive material is any material that contains radioactive atoms. Radioactivity: Radioactivity is the spontaneous transformation of an unstable atom and often results in the emission of radiation. This process is referred to as a transformation, decay or a disintegration of an atom.

Radiogenic Cancers: Cancers that have been shown to be able to be caused by radiation exposure.

Radiosensitive: Readily effected by radiation

Radium dial painters: In the early 1920’s radium based paint, used for its luminescent attributes for glow-in-the-dark products, like watch dials. The painters of the products inhaled and consumed, through licking their paint brushes to create finer lines, low doses of radium. However low the dose, the internal exposure eventually resulted in many radiation related deaths.

Radon daughters: Short-lived decay products of radon-222 (Po-218, Pb-214, Bi-214, Po-214).

Relative Biological Effect: The effectiveness of types of radiation compared with that of x-rays or gamma rays.

Relative risk: The ratio between the number of cancer cases in the irradiated population to the number of cases expected in the unexposed population. A relative risk of 1.1 indicates a 10 percent increase in cancer due to radiation, compared to the “normal” incidence.

Renal cancer: Cancer to the kidney.

Reticuloendothelial System (RES): An old name for mononuclear phagocytic system.

Retrospective cohort studies: A clinical study in which patients or their records are investigated after the patients have experienced the disease, condition, or treatment.

Rem (Roentgen Equivalent in Man): This relates the absorbed dose in human tissue to the effective biological damage of the radiation. To determine equivalent dose (rem), you multiply absorbed dose (rad) by a quality factor that is unique to the type of incident radiation. For gamma and beta

208 Glossary

radiation, one rem equals one rad. For alpha radiation one rad equals 20 rems. One sievert (sv) is equal to 100 rem.

Roentgen: A unit for describing the exposure dose of x-rays or gamma rays. One unit can liberate enough electrons and positrons to produce emissions of either charge of one electrostatic unit of electricity per 0.001293 g of air (the weight of 1 cm3 of dry air at 0°C and at 760 mm Hg).

Sievert (Sv): The sievert is a unit used to derive a quantity called equivalent dose. This relates the absorbed dose in human tissue to the effective biological damage of the radiation. Not all radiation has the same biological effect, even for the same amount of absorbed dose. Equivalent dose is often expressed in terms of millionths of a sievert, or micro-sievert. To determine equivalent dose (Sv), you multiply absorbed dose (Gy) by a quality factor (Q) that is unique to the type of incident radiation. One sievert is equivalent to 100 rem.

Significance: See statistical significance

Spontaneous abortion: the unaided termination of pregnancy before the fetus reaches a viable age (between 20 to 24 weeks).

Statistical Significance: “Statistical significance” means statistical analysis has revealed an effect unlikely to have occurred by chance alone. The level of significance refers to the degree to which the result could be explained by chance. At the .05 (5%) level the result could have occurred by chance 1 time in 20; at the .01 (1%) level the result could have occurred by chance only 1 time in 100. Any effect observed in a study or experiment carries with it some degree of uncertainty, or imprecision, because of randomness and variability in most biological phenomena. Statistical techniques evaluate an observed effect in view of its precision to determine with what probability it might have arisen by chance (the level of significance). Values with a low probability of occurring by chance are called “statistically significant” and are thought to represent a real effect.

Standardized incidence ratio (SIR): a ratio of the measured incidences of a disease to the number of expected incidences based on the general population’s rates.

Standardized mortality ratio (SMR): The number of deaths observed in the study population to the number of deaths that would be expected in the study population standardized to the general population.

Stillbirth: The birth of a dead fetus.

Supramultiplicitive: The combined effect of factors that is more than the independent effect of the factors being multiplied together

T Cell: A lymphoid cell from the bone marrow that migrates to the thymus gland, where it develops into a mature differentiated lymphocyte that circulates between blood and lymph, serving as one of the primary cells of the immune response.

Tailing: The refuse material resulting from washing, concentrating, or treating ground/crushed ore that is discharged from a mill.

Threshold: A minimum dose that will produce an effect Glossary 209

Thyroid Disease: disease occurring in the thyroid, a hormonal secretion gland in the neck, anterior to and partially surrounding the thyroid cartilage and upper rings of the trachea. Hypothyroidism is an example of a thyroid disease, resulting in inadequate levels of thyroid hormones in the body.

Thyroiditis: Inflammation of the thyroid gland.

Thyrotoxicosis: A condition resulting from exposure of body tissues to excessive levels of thyroid hormones. This may be caused by an overactive or damaged thyroid gland or by the administration of excessive doses of thyroid hormone

Total Effective Dose Equivalent: The sum of the effective dose equivalent from external exposure and the 50-year committed effective dose equivalent from internal exposure.

Translocation: The alteration of a chromosome by transfer of a portion of it either to another chromosome or to another portion of the same chromosome.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR): a committee established by the United Nations to study the effects of radiation to evaluate risk and create safety standards.

Uranium: A naturally occurring material used for nuclear technology. There are a variety of uranium isotopes that include uranium-235 (which decomposes over millions of years) and uranium-238 (which decomposes over billions of years).

Working Level (WL): Any combination of short-lived radon daughters in 1 liter of air that will result in the ultimate emission of 1.30×105 MeV of potential alpha particle energy. For 220Rn Daughters: The nuclides 216Po, 212Pb, 212Bi, and 212Po. For 222Rn Daughters: The nuclides 218Po, 214Pb, 214Bi, and 214Po.

Working Level Month (WLM): An exposure to 1 working level for 170 hours. This duration is derived from taking 2,000 working hours per year, dividing by 12 months per year, and rounding to 170 hours.

X-rays: Penetrating electromagnetic radiation (photon) having a wavelength that is much shorter than that of visible light. These rays are usually produced by excitation of the electron field around certain nuclei.

Sources of Definitions:

Low Dose Radiation Research Program, DOE. Glossary of Terms. Online at http://lowdose.org/pubs/ glossary.html.

The Why Files, University of Wisconsin. Radiation Reassessed, Glossary. Online at http://whyfiles. org/020radiation/glossary.html.

Idaho State University Physics Department. Radiation Related Definitions. Online at http://www. physics.isu.edu/radinf/terms.htm#top. 210 Glossary

Venes, D. (ed). Taber’s Cyclopedic Medical Dictionary, edition 19. F.A. Davis Company. Philadelphia, 2001.

Scott, B. Bobby’s Radiation Glossary for Students. Lovelace Respiratory Research Institute Online at http://www.lrri.org/radiation/radgloss.htm http://www.nap.edu/books/0309072832/html/237.html http://www.nrc.gov/reading-rm/basic.ref/glossary/ http://www.wirc.org/glossary/index.shtml http://www.cdc.gov/nohss/GLMain.htm http://dels.nas.edu/potassium_iodide/glossary.html http://www.epa.gov/narel/erams/glossary.html http://www.rerf.or.jp/eigo/glossary/ http://www.ieer.org/sdafiles/vol_8/8-4/glossary.html http://www7.nationalacademies.org/brer/RERF_Home.html

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Actinium, 84 Atomic bomb survivors, 43-57 Acute lymphocytic leukemia (ALL), 175 and childhood cancer, 30, 48 and atomic bomb survivors, 44, 49-50, 52 and children, 87, 123 in children, 23, 179 and chronic lymphocytic leukemia, 87 and flight personnel, 113 data on adult exposures, 171 and nuclear weapons testing, 178 and DNA damage, 121 and radiotherapy, 29 estimating risks from radiation exposure, and X-rays, 23 195 Acute myeloid leukemia (AML), 21, 175 and leukemia, 117, 176, 179 and atomic bomb survivors, 50 and non-cancer disease, 48, 50-51 and Chernobyl, 179 and preconception exposure, 187, 190, 193 and flight personnel, 114, 115 and solid cancer, 168 and radiation exposure, 44 studies, 54-57 and radon, 16 and thyroid cancer, 182 Adult t-cell leukemia (ATL), 50 and thyroid disease, 184 African Americans, 79, 87-88 and in utero exposure, 171, 177 Age at exposure, 19 Atomic Energy Act, 103 and atomic bomb survivors, 48, 49, 51, 52 Atomic Energy Commission, 3, 73 and breast cancer, 25 Atomic Weapons Research Establishment, and childhood leukemia after Chernobyl, 150 135 Australia, 106 at Hanford, 74, 75 Autoimmune disease, 136, 181, 184-85 and lung cancer, 106 Autoimmunity, 135 and Mayak workers, 100 and Oak Ridge, 76-77 Background radiation, 7, 13-18 and radiation-related cancer risks, 85, 89 and nuclear facilities, 146 and Rocketdyne workers, 78 studies, 18 and uranium mining, 105 Basal cell carcinoma, 49 Agency for Toxic Substances and Disease BEIR, 3 Registry (ATSDR), 167 BEIR VII, 195 Alpha particles, 5, 6, 97, 99, 108 Beta particles, 5, 6, 177, 181, 185 Alpha radiation, 24, 98, 104, 176, 177 Bikini test site, 59, 183 Analytical study, 8-9 Biological Effects of Ionizing Radiation. See Anaplastic cancers, 181 BEIR Animal studies, 122, 133, 173, 193, 195 Birth defects, 121, 128-29 Ankylosing spondylitis, 25-26, 172, 176, 179 and nuclear power facilities, 155 Apollo and Parks facility, 148, 154 and Shiprock uranium mining area, 148 Atomic bomb, 80 studies of incidence near nuclear facilities, Atomic Bomb Causality Commission (ABCC), 166 43 Bladder cancer, 28

243 244 Index

and atomic bomb survivors, 49 mortality and atomic bomb survivors, 45-46, and UK nuclear weapons plants, 83 48 Blood cancer, 175. See also Leukemia and radiotherapy, 28 and atomic bomb survivors, 49 studies of incidence near nuclear facilities, and Fernald site, 89 156-59 and Mayak workers, 99 and Three Mile Island, 130-31 in military personnel, 59 and Zorita and Trillo facilities, 153 and Sellafield, 82 Capenhurst facility, 83 and Three Mile Island, 131 Carcinomas, 62 and UK nuclear weapons plants, 83 Cardiovascular disease, 51, 99 Bone cancer, 80 Case control study, 28, 97, 134, 151 and Mayak workers, 98-99 Case reports, 60 and Nevada Test Site, 61 CAT scans, 23 Brain cancer Central nervous system (CNS), 26 and Fernald site workers, 88 and atomic bomb survivors, 49 and Los Alamos National Laboratory and Chernobyl, 133 workers, 80, 88 and Los Alamos National Laboratory and Oak Ridge workers, 75, 88 workers, 80 and radiotherapy in children, 27 and nuclear facilities, 151 and Rocky Flats workers, 88 and Oak Ridge workers, 75-76 and Sellafield workers, 88 and radiotherapy in children, 27 Breast cancer Cerebrovascular disease, 133 and atomic bomb survivors, 49 Cervical cancer, 28, 176-77, 179, 182 and exposure to ionizing radiation, 19 and Apollo and Parks facility, 148 and flight attendants, 114 in UKNRBP workers, 84 and fluoroscopy, 25 Cesium-137, 64, 136, 178, 185 and medical exposure, 169 Chapelcross facility, 83, 150 and Nevada Test Site, 61 Chernobyl, 130, 131-37 and occupational exposure, 31 and childhood leukemia, 135-36, 143, 171, and radiotherapy, 28 179 and radiotherapy in children, 27 and childhood thyroid cancer, 133-35, 141- and Three Mile Island, 131 42, 183-84 and women radiation workers, 89 children of cleanup workers, 133 and X-rays, 23, 26 cleanup workers and cancer, 132 British Nuclear Fuels (BNFL), 82 cleanup workers and leukemia, 177-78 Bystander effect, 173 cleanup workers and thyroid cancer, 182-83 and DNA damage in children, 121-22 Caithness, Scotland, 150 health effects on communities around, 145 Canada and leukemia, 168, 178, 179, 180 and miners’ health, 106-7 non-cancer disease, 144 pooled data for radiation workers, 84-85 and non-cancer effects in children, 136-37 Cancer. See also Childhood cancer; specific studies of health effects in cleanup workers, types, i.e. Breast cancer 139-40 and age at exposure, 89 and thyroid disease, 185 and Chernobyl, 132 Childhood cancer, 14. See also Cancer and female workers, 89 and acute lymphocytic leukemia, 23 and flight personnel, 114 and atomic bomb survivors, 48 and Hanford workers, 74-75 and background radiation, 17 mortality among radiation workers, 194 and Chernobyl, 133-35, 141-42, 143 Index 245

and Nevada Test Site, 60-61, 62 Chromosome aberrations nuclear facilities, 154-55 and Apollo and Parks facility, 148 and parental exposure, 30-31 and background radiation, 15 and prenatal exposure, 117, 119, 168 and flight personnel, 114-15 and radiotherapy, 29 near Krummel nuclear power plant, 152 and radon, 16 and preconception exposure, 193 and Sellafield, 149 and Sellafield, 82-83 and Semipalatinsk Test Site, 59-60 and Semipalatinsk Test Site, 60 studies of incidence near nuclear facilities, Chronic lymphocytic leukemia (CLL), 50, 175 160-65 and pooled international data, 87 and in utero exposure, 29-30, 168 and Savannah River Site, 79 Childhood leukemia, 29-30 and X-rays, 21 and Chernobyl, 135-36, 143, 171, 179 Chronic myeloid leukemia (CML), 21, 175 and communities near nuclear power and nuclear workers, 177 plants, 152 and radiation exposure, 44 and Krummel nuclear power plant, 154 Circadian rhythms, 113, 114 and medical exposure, 177 Circulatory disease, 86 near Dounreay, 149-50 Cirrhosis, 50 near La Hague reprocessing plant, 151 Cleanup workers, 132, 133, 139-40, 177-78, near nuclear facilities in the UK, 148 182-83 and Nevada Test Site, 171 Cohort study, 9 and nuclear power facilities, 148, 154-55 Mayak workers, 97 and paternal preconception exposure, 193 military personnel, 58 and preconception exposure, 190 Mound facility, 81 and viruses, 153-54 Oak Ridge workers, 75 Children UK Atomic Energy Authority employees, 83 and acute lymphocytic leukemia, 23 Colon cancer, 148 and atomic bomb survivors, 48, 87 Colorectal cancer, 113 and background radiation, 14, 17 Cosmic radiation, 113, 115 and Chernobyl, 133-35, 137, 141-42, 143, Czechoslovakia, 107 178 and hypothyroidism, 147 Descriptive studies, 8 medical exposures, 177 Diagnostic exposure, 19, 21-24. See also near Sellafield, 149 Medical exposure and Nevada Test Site, 60-61, 62 and leukemia, 176, 179 and nuclear power facilities, 154-55 studies, 33-35 and parental exposure, 30-31 Digestive system and prenatal exposure, 117, 168 and atomic bomb survivors, 49 and radiotherapy, 26-28, 29 and Chernobyl, 132, 133 and radon, 16 and Rocketdyne workers, 77-78 and Semipalatinsk Test Site, 59-60 DNA damage sensitivity to some forms of cancer, 195 and children of atomic bomb survivors, 121 studies of incidence near nuclear facilities, and flight personnel, 114-15 160-65 and Semipalatinsk test site, 60 and thyroid cancer, 24, 26, 27, 32, 133-35, uranium mining, 148 169, 183-84, 185 Dose-response analysis, 10-11 and thyroid disease around Chernobyl, 185 and atomic bomb survivors, 45, 52-53 and in utero exposure, 29-30, 168 and Chernobyl, 178 China, 107 and leukemia, 178 246 Index

and Oak Ridge workers, 76 Fathers and thyroid cancer, 182 and childhood cancer, 117, 121-22, 148 Dosimetry, 44-45, 72 Feed Material Production Center (Fernald Doubling dose, 75 site), 82 Dounreay, 149-50, 150, 151 Fernald site, 82, 88, 89 Downwinders Flight personnel Chernobyl, 136, 168 and leukemia, 178 and childhood leukemia, 179 and radiation exposure, 113-16 and childhood thyroid cancer, 141-42 studies of cancer in, 116 and leukemia, 178, 180 Fluoroscopy, 25, 33-35 Nevada Test Site, 60-63, 180 Fluorspar, 107 Semipalatinsk Test Site, 59-60 Follicular tumors, 181 DS86 dosimetry system, 44-45 Fractionated exposure, 25 France, 107 Ecologic studies, 8, 146, 147 Emergency workers. See Cleanup workers Gallbladder cancer, 24 Endocrine system Gamma radiation, 5, 6, 14, 19, 80 and Chernobyl, 133 and atomic bomb survivors, 45 and childhood cancer, 26 and flight personnel, 113 metabolic disease, 185 and Mayak workers, 97, 98, 99 Energy Research and Development and thyroid disease, 185 Administration (ERDA), 3 Gardner hypothesis, 117-19 Environmental Protection Agency (EPA), 3 Gender. See also Men; Women Epidemiological studies, 7-9 and atomic bomb survivors, 48, 52 communities near nuclear facilities, 146 and cancer among flight personnel, 114 flight personnel, 108 and childhood cancer, 117 of uranium miners, 107 and diagnostic exposures, 21 Eskimos, 64 and Mayak workers, 97 Esophageal cancer, 25 and Oak Ridge workers, 75 and Los Alamos National Laboratory, 80 and radiation-related cancer risks, 89 and pooled U.S. data, 85 and Savannah River Site workers, 79 and Semipalatinsk Test Site, 60 Genetic damage, 128-29 European Committee on Radiation Risk and atomic bomb survivors, 121 (ECRR), 3 and Chernobyl, 133, 136 Excretory system, 49 and Sellafield, 82-83 External exposure, 14, 118 Genital organs, 28 and benign disease studies, 36-38 Genomic instability, 173 and Chernobyl, 132 Germ cells, 133, 136, 137, 193 and Mayak workers, 99, 194 Germany, 107 and nuclear workers, 177 Germline mutations, 60 and relationship to cancer, 84 Goiter, 184 and Rocketdyne workers, 77-78 Grave’s disease, 181 and Sellafield workers’ children, 120 and stillbirths, 121 Hanford, 73-75 and thyroid diseases, 182-83 and childhood cancer, 155 health effects on communities around, 146- F1 generation, 51 47 Fallout, 2, 5, 58, 61, 62, 64, 132, 178, 183 and multiple myeloma, 86, 88 studies, 66-68, 69 and neural tube defects, 121 Index 247

Hashimoto’s thyroiditis, 185 Iodine-131, 5, 19, 20, 62, 131, 132, 133, 134, Healthy survivor effect, 45, 48, 53, 73 146, 147, 176, 181, 183, 184, 185 Healthy worker effect, 20, 72 and hyperthyroidism, 26 and Chernobyl, 133 and South Pacific testing, 63 and flight personnel, 113 and thyroid cancer, 23-24 at Hanford, 74 Ionizing radiation and Los Alamos National Laboratory, 80 defined, 1 and Mound Facility, 81 exposure, 2-3 at Oak Ridge, 75 at Rocketdyne, 77 Japan, 152 at Rocky Flats, 78 Jaslovske Bohunice nuclear facility, 153 Heart attack, 50 Hemangioma, 25, 26, 182 Kidney cancer Hinkley Point nuclear power plant, 150 and atomic bomb survivors, 49 Hiroshima. See Atomic bomb survivors and flight personnel, 114 Hodgkin’s disease and Mallinckrodt Chemical Works, 81, 86 and Los Alamos National Laboratory, 80 and pooled international data, 87 and pooled U.S. data, 85 and Sellafield, 82, 86 and radiotherapy, 28, 182 and X-rays, 26 and Springfields facility, 83 Krummel nuclear power plant, 151-52, 154 Hormesis, 173, 195 Hunterston facility, 150 La Hague reprocessing plant, 151, 155 Hyperparathyroidism, 27 Large intestine cancer, 76 Hypertension, 133 Larynx, 85 Hyperthyroidism, 19, 20, 26, 176, 181, 184 Lawrence Livermore National Laboratory, 78- Hypothyroidism, 181, 184, 185 79 around Hanford, 146 Leukemia. See also Blood cancer; Childhood and atomic bomb survivors, 51 leukemia in children, 136, 147 and Apollo and Parks facility, 148 association with radiation, 87 ICRP (International Commission on and atomic bomb survivors, 49-50, 52, 88, Radiological Protection), 131 176 Immune system, 133, 136, 181, 184 and Chernobyl, 132, 143, 178, 180 In utero exposure, 29-30 and childhood medical exposures, 177 and atomic bomb survivors, 44, 51, 171 and downwinders, 168 and Chernobyl, 178 estimated risk in adults, 172 and childhood cancer, 168 in flight personnel, 113-14, 178 and childhood leukemia, 135-36 following paternal exposure, 187 and leukemia, 177 and Mayak workers, 99, 153 Infant mortality, 148 and medical exposure, 169, 176 Internal radiation, 118, 120 in military personnel, 59 and Chernobyl, 132 and Mound Facility, 81 and diagnosis or treatment studies, 39-40 near Dounreay, 149-50 and Mayak workers, 194 near Pilgrim power plant, 147 and thyroid cancer, 183 and Nevada Test Site, 60-61 and thyroid disease, 181 and nuclear facilities, 148, 151, 152 International Commission on Radiological and nuclear weapons testing, 58, 169 Protection (ICRP), 131 in nuclear workers, 88, 168-69, 177-78 Intracranial tumors, 27 and Oak Ridge workers, 75, 76 248 Index

and occupational exposure, 31, 119 and fluoroscopy, 25 overview, 175-80 and Los Alamos National Laboratory, 80, 88 and pooled data, 85, 86, 87-88 and Mayak workers, 97-98 and preconception irradiation, 117, 119, in miners, 104-5, 106-7 120, 124-25 and Mound facility, 81 and radiotherapy, 27, 28 and Oak Ridge workers, 75, 76, 88 at Rocketdyne, 77-78 and pooled data, 85-86, 108 and Savannah River Site, 79 and radiotherapy, 28 in Scandinavia, 63 and radon, 16-17, 108-9, 169 and Sellafield, 82 at Rocketdyne, 77-78, 88, 89 and Three Mile Island, 131 at Rocky Flats, 78, 88 in UKNRBP workers, 84 and Semipalatinsk Test Site, 60 and uranium miners, 105 and Three Mile Island, 130-31 and in utero exposure, 177 in UKNRBP workers, 84 and women radiation workers, 89 and X-rays, 26 and X-rays, 21, 22, 25-26, 26 Lung disease, 103 Leukemia and non-Hodgkins lymphoma. See Lung tumors, 106 LNHL (leukemia and non-Hodgkins Lymph cancer lymphoma) and Fernald site, 89 Life Span Study (LSS), 43-44, 176 and Mayak workers, 99 Linde Air Products Company Ceramics Plant, in military personnel, 59 81 and Oak Ridge workers, 75 Linear dose-response, 168 and Sellafield, 82 and atomic bomb survivors, 46 and Three Mile Island, 131 and thyroid cancer, 182 and UK nuclear weapons plants, 83 and thyroid disease, 185 Lymph system, 49 Linear energy transfer (LET), 5 Lymphocyte micronuclei, 60 Linear model, 194 Lymphoma Linear no-threshold model, 11, 17, 98, 167, and Nevada Test Site, 61 173, 174, 195 and Oak Ridge workers, 75 Linear quadratic model, 11, 45, 51, 99, 175 and radiation exposure, 44 Liver cancer, 24 at Rocketdyne, 77-78 and atomic bomb survivors, 49 Lymphopoietic cancer, 59, 78, 80 and flight personnel, 114 and Mayak workers, 98-99 Magnetic fields, 113 and Semipalatinsk Test Site, 60 Malignant melanoma Liver disease, 50 and flight personnel, 113 LNHL (leukemia and non-Hodgkins at Lawrence Livermore National Laboratory, lymphoma), 117-18 79 near Dounreay, 150 and Los Alamos National Laboratory, 80 near Hinkley Point nuclear power plant, 150 Malignant neoplasms, 133 near Sellafield, 149 Mallinckrodt Chemical Works, 81, 86 and preconception exposure, 120, 124-25, Manhattan Project, 2, 43, 75 187 Marshall Islands, 63, 132, 183 Los Alamos National Laboratory, 80, 88 Maternal preconception exposure, 120, 123 Low dose radiation Mayak workers, 97-102, 168, 194. See also defined, 1 Occupational exposure; Techa River and risk estimates, 170 children and thyroid disease, 185 Lung cancer and leukemia, 153, 154, 177 Index 249

studies, 101-2 and Sellafield, 82 Medical exposure, 19-42. See also Diagnostic exposure Nagasaki. See Atomic bomb survivors and breast cancer, 169 National Institute for Occupational Safety and childhood, 177 Health (NIOSH), 107 conclusions about risks, 31-32 National Registry for Radiation Workers, 83-84 and leukemia, 169, 176-77 National Registry of Childhood Tumors, 119 and thyroid cancer, 169, 182, 184 Navajo, 106, 121, 148 Medullary cancer, 181 Neoplasms, 29, 62 Melanoma, 79, 80, 84 Neural tube defects, 121, 147 Men. See also Gender Neuroblastoma, 182 and acute myeloid leukemia, 114 Nevada Test Site, 2, 60-63 and cancer of the gastric tract, 114 and childhood leukemia, 171, 179 and prostate cancer, 114 fallout, 183 and skin cancer, 114 and leukemia, 168, 178, 180 Meningioma, 51 studies, 67-68 Mental disorders, 133 and thyroid cancer, 185 Mental health, 137 NIOSH (National Institute for Occupational Mental retardation, 51-52 Safety and Health, 107 Meta-analysis, 172-73 Non-cancer disease, 48 and preconception exposure, 187 and atomic bomb survivors, 48, 50-51 Metabolic disorders, 133 and Chernobyl, 136-37, 144 Microcephaly, 51 and Mayak workers, 99 Military personnel, 58-59 and radiotherapy, 24-28, 31 Miners, 103-12 Non-Hodgkins lymphoma, 117 and chromosome aberrations, 148 near Dounreay, 150 and radon, 16, 109, 110-12 near nuclear power plants, 152 uranium, 103-12 and preconception exposure, 187 Miscarriages, 121, 146 and Three Mile Island, 130-31 Mormons, 61, 183 Nuclear facilities Mound Facility, 81 adverse birth outcome studies, 166 Multiple myeloma and childhood leukemia, 148 and Apollo and Parks facility, 148 communities near, 145-66 and atomic bomb survivors, 49, 50 studies of cancer incidence, 156-59 and Hanford workers, 86 studies of childhood cancer incidence, 160- and nuclear weapons test veterans, 169 65 and nuclear workers, 169 Nuclear medicine, 19 and Oak Ridge workers, 75 Nuclear power accidents, 130-44 and pooled data, 85, 86, 87-88, 88 Nuclear Regulatory Commission (NRC), 3, 70, in UKNRBP workers, 84 72 Multiplicative effect, 98 Nuclear weapons, 71, 73 Myelodysplasia, 115 Nuclear weapons testing, 58-69, 171 Myeloid leukemia, 16, 22, 113 discussion, 63-64 Myeloma and leukemia, 169, 178 and Apollo and Parks facility, 154 studies, 65 and communities near nuclear power Nuclear workers, 70. See also Occupational plants, 152 exposure and nuclear power workers, 154 and childhood cancer, 121-22 and pooled U.S. data, 85 data on adult exposures, 171 250 Index

health protection standards, 4 and thyroid cancer, 27-28, 182 and leukemia, 168-69, 177-78 UKNRBP, 83-84 and stillbirths and miscarriages, 121, 122- and uranium mining, 107-8 23 U.S. radiation workers, 85-86 Portsmouth Uranium Enrichment Plant, 80-81 Oak Ridge, 75-77 Preconceptional exposure, 117-29 and age at exposure, 76-77 analysis of studies, 187-93 and cancer in nearby communities, 154 animal studies, 195 and lung cancer, 88 and atomic bomb survivors, 51 and multiple myeloma, 88 and Chernobyl, 136-37 and prostate cancer, 88 and childhood leukemia, 148 Occupational dose limits, 70, 72 dose studies, 192 Occupational exposure, 31, 70-96, 117. See of fathers, 119 also Mayak workers; Nuclear workers; and LNHL, 124-25 Radiologists maternal, 123 assessing risks, 72-73 meta-analysis, 173 facility-specific studies, 90-94 and solid cancers, 126-27 paternal, 191 and stillbirths and congenital malformations, pooled studies, 190 128-29 studies using combined datasets, 95-96 studies, 188-89 Osteogenic sarcoma, 80 Prenatal exposure, 14, 117-29 Oxford Survey of Childhood Cancers, 119, and atomic bomb survivors, 51 168, 177 and childhood cancer risk, 168 and childhood leukemia, 29, 135-36 P-value, 10 and leukemia, 177 Papillary tumors, 181 Prostate cancer Parental exposure, 30-31 and Chapelcross facility, 83 and childhood leukemia, 148 and employees of UKAEA, 83 Parkinson’s disease, 50 and Fernald site workers, 88 Paternal preconception irradiation (PPI), 117, and flight personnel, 113, 114, 115 119, 120, 123, 173, 187, 190 and Oak Ridge workers, 75, 88 and childhood leukemia, 148, 193 and pooled UK data, 88 studies, 191 in UKNRBP workers, 84 Peptic ulcers, 26 Pilgrim power plant, 147 Quadratic model, 10-11. See also Linear Pleural cancer, 82, 83, 84, 88 quadratic model Plutonium, 2, 73, 78, 80, 82, 84, 87, 97, 98, 154 Radiation Pneumoconiosis, 105 and association with leukemia, 87 Polonium-210, 81, 84 background, 13-18 Polychythemia vera, 59 basics, 3-7 Pooled studies, 172-73 epidemiological methods, 7-9 Canadian data, 84-85 exposure, 2-3 employees of UKAEA, 83 and flight personnel, 113-16 international data, 86 history, 2 and nuclear workers, 177-78 and non-solid cancers, 44 occupational exposure, 190 and solid tumors, 44 and radon, 17 types of, 5-6 and solid cancer, 88 Radiation Effects Research Foundation Index 251

(RERF), 43 and multiple myeloma, 88 Radiation Exposure Compensation Act Rocky Flats, 78 (RECA), 103 and brain cancer, 88 Radiation therapy, 182 and cancer, 147 Radiation workers, 70-96 and cancer in nearby communities, 154 cancer mortality, 194 and contamination, 154 and childhood leukemia, 120 and lung cancer, 88 Radiography, 176 Rosyth nuclear submarine base, 151 Radioiodine. See Iodine-131 Royal Ordnance Factory, 150 Radiologists, 19. See also Occupational Russian National Medical and Dosimetric exposure Registry (RNDMR), 132 and leukemia, 177 occupational exposure to radiation, 31 Salivary gland, 79 studies about risks, 33-35 San Onofre plant, 147 Radiotherapy, 20 Savannah River Site, 79, 87-88 for cancer, 28 Scandinavia, 63 for childhood cancer, 29 Scoliosis, 169 for non-cancer disease, 24-28 Seascale, 117-18, 122, 193 parental exposure and childhood cancer, and childhood cancer, 149 30-31 Sellafield, 82-83, 117 studies, 41-42 and brain cancer, 88 Radium, 2 and childhood cancer, 149 Radon, 13, 15-17 and kidney cancer, 86 and childhood cancer, 16 and multiple myeloma, 88 and leukemia, 119 and pleural cancer, 88 and lung cancer, 16-17, 108, 169 workers’ children, 120-21 and miners, 16, 104, 107, 110-12 Semipalatinsk Test Site, 59-60 and myeloid leukemia, 16 and DNA damage in children, 121 residential studies, 108-9 fallout, 183 and smoking, 105 and germline mutations, 137 Rajasthan Atomic Power Station, 153, 155 and leukemia, 178 Rectal cancer, 28 studies, 66 Reindeer, 64 Shiprock uranium mining area, 148, 155 Renal cancer, 114 Skin cancer RERF (Radiation Effects Research and atomic bomb survivors, 49 Foundation), 43 and flight personnel, 114, 115 Respiratory system Slovak Republic, 152, 153 and atomic bomb survivors, 49 Small intestine cancer, 26 and cancer among flight personnel, 114 Smoking, 13, 52, 97, 98, 105, 106 and Chernobyl, 133 Solid cancer. See also Tumors, solid diseases among Navajo miners, 106 and atomic bomb survivors, 45-46, 48-49, and mine workers, 105 52-53, 168 Retinoblastoma, 29, 30 and Chernobyl, 132 Ringworm, 27 and communities near nuclear power Risk assessment, 72-73 plants, 152 Risk terminology, 9-10 and Mayak nuclear weapons production Rocketdyne, 77-78 complex, 153 and age at exposure cancer risks, 89 and pooled data, 85, 86, 88 and lung cancer, 88 and preconception exposures, 120-21, 126- 252 Index

27 in Scandinavia, 63 and radiation workers, 194 and Semipalatinsk Test Site, 60 and Semipalatinsk test site, 60 and South Pacific testing, 63 and Techa River residents, 168 in UKNRBP workers, 84 and UKNRBP workers, 84 and X-rays, 26 and X-rays, 23 Thyroid disease, 181-86 South Pacific testing, 63, 69 around Hanford, 146 Soviet Union and atomic bomb survivors, 50, 51 Mayak Production Association, 97-102 and Nevada Test Site, 61-63 Spain, 152 and nuclear weapons testing, 58 Springfields facility, 83 and radiation, 184-85 Stillbirths, 121, 122-23 and South Pacific testing, 63 around Sellafield, 149 Thyroiditis, 51, 184 and preconception irradiation, 128-29 Thyrotoxicosis, 147, 184 studies of incidence near nuclear facilities, Time since exposure, 52 166 and Oak Ridge, 76 Stomach cancer, 26 and uranium mining, 108 and Nevada Test Site, 61 Tinea capitis, 25, 27, 169 and Portsmouth Uranium Enrichment Plant, Tobacco, 13, 28 80 Translocations, 60 and Semipalatinsk Test Site, 60 Tritium, 80, 83, 84 Strontium-90, 61 Tuberculosis, 25 Supralinear model, 11, 45-46, 48, 75 Tumors, solid, 181 Sweden, 107, 152 and atomic bomb survivors, 44, 48-49 and mine workers, 106 T-cells, 50, 133 Techa River, 97, 153, 168, 194. See also Ulcers, 26 Mayak workers United Kingdom Testicular cancer, 28, 84 and childhood leukemia, 148 Therapeutic exposures, 28-29 and diagnostic X-rays, 23 Thorotrast, 24, 176 nuclear weapons facilities, 82-84 Three Mile Island, 130-31 pooled data for radiation workers, 83 and childhood cancer, 14 United Nations Scientific Committee on health effects on communities around, 145 the Effects of Atomic Radiation. See studies of health effects, 138 UNSCEAR Threshold dose, 167, 173-74 United States Thyroid cancer, 22, 26 nuclear weapons facilities, 73-82 and atomic bomb survivors, 49 pooled data for radiation workers, 85-86 and Chernobyl, 131, 132, 133-35, 141-42 studies of uranium miners, 104-7 in children, 24, 26, 27, 133-35, 185 UNSCEAR, 3 and external radiation, 182-83 and Mayak workers, 97 and Hanford, 146, 147 worker exposure limits, 70 and Hodgkin’s disease, 182 Uranium, 81, 82, 84, 85, 87. See also Miners and internal radiation, 183 and chromosome aberrations, 148 and Iodine-131, 23-24 miners, 103-12 and medical exposure, 19, 32, 169 at Oak Ridge, 75, 76 and Nevada Test Site, 61, 62 Uterine bleeding, 26 and radiotherapy, 27, 28 Uterine cancer, 84, 86 risk estimates for various exposures, 186 Uterine myoma, 50 Index 253

Viruses, 118, 154, 193

West Germany, 152 Women. See also Gender and cervical cancer, 176-77 and exposure to ionizing radiation, 19 and Mayak, 97 and radiation-related cancer risks, 89 sensitivity to some forms of cancer, 195 and skin cancer among flight personnel, 114

X-rays, 2, 19, 21-23, 80 and ankylosing spondylitis, 25 and cancer, 23 and childhood leukemia, 120 and leukemia, 21, 22, 25-26, 176 and preconception exposure, 119, 120, 187, 190 prenatal, 14, 30, 177 studies, 33-35 and thyroid cancer, 182

Y-12. See Oak Ridge

Zorita and Trillo facilities, 153