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Executive Summary INTRODUCTION This report, prepared by the National Research Council's Committee on the Biological Effects of Ionizing Radiations (BEIR), is the fifth in a series that addresses the health effects of exposure of human populations to low-dose radiation. Ionizing radiations arise from both natural and man- made sources and can affect the various organs and tissues of the body. Late health effects depend on the physical characteristics of the radiation as well as biological factors. Well demonstrated late effects include the induction of cancer, genetically determined ill-health, developmental abnormalities, and some degenerative diseases (e.g., cataracts). Recent concern has centered on the risks of these eRects following low-dose exposure, in part because of the presence of elevated levels of radon progeny at certain geographical sites and fallout from the nuclear reactor accidents at Three Mile Island in Pennsylvania in 1979 and Chernobyl in the USSR in 1986. In addition, there is concern about radioactivity in the environment around nuclear facilities and a need to set standards for cleanup and disposal of nuclear waste materials. Since the completion of the 1980 BEIR III report, there have been significant developments in our knowledge of the extent of radiation expo- sures from natural sources and medical uses as well as new data on the late health effects of radiation in humans, primarily the induction of cancer and developmental abnormalities. Furthermore, advanced computational techniques and models for analysis have become available for radiation risk assessment. The largest part of the committee's report deals with radiation

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2 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION carcinogenesis in humans, primarily because: (1) there is extended follow- up in major epidemiological studies, particularly those of the Japanese A-bomb survivors and radiotherapy patients treated for benign and malig- nant conditions, and (2) the revision by a binational group of experts of the dosimetric system for A-bomb survivors in Hiroshima and Nagasaki allows improved analyses of the Japanese data. The report also addresses radiation-induced genetic injury and health effects associated with prenatal irradiation. While only limited application of the advances in our under- standing of the molecular mechanisms of cancer induction and genetic disease is possible, these have been examined with the aim of narrowing the range of uncertainties and assumptions inherent in the risk estimation process. RISK ASSESSMENT The 1988 BEIR IV report addressed the health effects of exposure to internally-deposited, alpha-emitting radionuclides: radon and its progeny, polonium, radium, thorium, uranium and the transuranic elements. The current BEIR V Committee report includes information and analyses from the BEIR IV report that are appropriate for cancer and genetic risk assessment. In addition, this report addresses the delayed health effects that are induced by low linear energy transfer (LET) radiations such as x rays and gamma radiation and, where possible, makes quantitative risk estimates based on statistical analyses of the results of human epidemiological studies and laboratory animal experiments. The human data on cancer induction by radiation are extensive; the most comprehensive studies are of the survivors of the atomic bombings of Hiroshima and Nagasaki, x-rayed tuberculosis patients, and persons exposed during treatment for ankylosing spondylitis, cervical cancer, and tinea capitis. Radiation associated cancer risk estimates have been calcu- lated for a number of different organs and tissues, including bone marrow (leukemia), breast, thyroid, lung, and the gastrointestinal organs. 1b the extent possible, the biological differences among human beings that may modify susceptibility to radiation-induced cancer have been taken into account. Considerable progress has been made in our understanding of the mutation process on genes and chromosomes and its expression as genetic disorders. Due to a lack of direct evidence of any increase in human heritable effects resulting from radiation exposure, the estimates of genetic risks in humans are based, primarily, on experimental data obtained with laboratory animals. As in all experimental animal studies, the extent to which the results can be extrapolated to humans and the confidence that

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EXECUTIVE SUMMARY 3 can be placed on such extrapolation remain uncertain. At present, no data are available to provide reliable estimates of the risks of most complex, multifactorial hereditary disorders. Such risks were not evaluated by the committee. During the past decade, extensive data have become available on the developmental anatomy of the mammalian brain, and this information has aided the interpretation of effects observed among Japanese survivors irradiated in utero during the atomic bombings. New analyses of the data on A-bomb survivors exposed in utero, together with the reassessment of the A-bomb dosimetry, have permitted delineation of the time-specific susceptibility to radiation-induced mental retardation, the most prevalent developmental abnormality to appear in humans exposed prenatally, and has allowed the risk of these effects to be estimated. In preparing risk estimates, the committee has relied chiefly on its own evaluations, using recently developed methods for the analysis of population cohort data, rather than relying solely on information in the scientific literature. The Committee recognizes that the application of more sophisticated statistical methods for estimating risks reduces, but does not eliminate, the uncertainties inherent in risk estimation. Throughout the Committee's deliberations consideration was given to both the sources of uncertainty in the data and the potential effect of the assumptions on which the risk estimates are based. The degree of uncertainty in the Committee's risk estimates is presented as an integral part of the risk estimates in this report. STRUCTURE OF THE REPORT The report consists of seven chapters. The first chapter reviews the sci- entific principles, epidemiological methods and the experimental evidence for the biological and health effects in populations exposed to low levels of ionizing radiation. Chapter 2 summarizes the scientific evidence for heritable effects. Chapter 3 includes a discussion of mechanisms involved in the initiation, promotion and progression of cancer induction. Chapter 4 describes the Committee's radiation risk models and the total risk of cancer following whole body exposure. Chapter 5 addresses site-specific cancer risks in the various organs and tissues of the body. Chapter 6 reviews the evidence for fetal and other radiation-induced somatic effects, and the concluding chapter reviews low dose epidemiological studies. As in previous reports, the Committee on the Biological Effects of Ionizing Radiation cautions that the risk estimates derived from epidemio- logical and animal data should not be considered precise. Information on the lifetime cancer experience is not available for any of the human studies.

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4 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION Therefore, the overall risk of cancer can only be estimated by means of models which extrapolate over time. Likewise, estimates on the induction of human genetic disorders by radiation are based on limited data from studies of human populations and therefore rely largely on studies with laboratory animals. It is expected that the risk estimates derived by the Committee will be modified as new scientific data and improved methods for analysis become available. SUMMARY AND CONCLUSIONS Of the various types of biomedical effects that may result from irradia- tion at low doses and low dose rates, alterations of genes and chromosomes remain the best documented. Recent studies of these alterations in cells of various types, including human lymphocytes, have extended our knowledge of the relevant mechanisms and dose-response relationships. In spite of evidence that the molecular lesions which give rise to somatic and genetic damage can be repaired to a considerable degree, the new data do not contradict the hypothesis, at least with respect to cancer induction and hereditary genetic effects, that the frequency of such effects increases with low-level radiation as a linear, nonthreshold function of the dose. Heritable Effects The effects of radiation on the genes and chromosomes of reproductive cells are well characterized in the mouse. By extrapolation from mouse to man, it is estimated that at least 1 Gray (100 red) of low dose-rate, low LET radiation is required to double the mutation rape in man. Heritable effects of radiation have yet to be clearly demonstrated in man, but the absence of a statistically significant increase in genetically related disease in the children of atomic bomb survivors, the largest group of irradiated humans followed in a systematic way, is not inconsistent with the animal data, given the low mean dose level, < 0.5 gray (Gy), and the limited sample size. The Committee's estimates of total genetic damage are highly uncertain, however, as they include no allowance for diseases of complex genetic origin, which are thought to comprise the largest category of genetically- related diseases. ~ enable estimates to be made for the latter category, further research on the genetic contribution to such diseases is required. Carcinogenic Effects Knowledge of the carcinogenic effects of radiation has been signifi- cantly enhanced by further study of such effects in atomic bomb survivors.

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EXECUTIVE SUMMARY 5 Reassessment of A-bomb dosimetry at Hiroshima and Nagasaki has dis- closed the average dose equivalent in each city to be smaller than estimated heretofore; furthermore, the neutron component of the dose no longer ap- pears to be of major importance in either city. As a result, lifetime risk of cancer attributable to a given dose of gamma radiation now appears somewhat larger than formerly estimated. Continued follow-up of the A-bomb survivors also has disclosed that the number of excess cancers per unit dose Induced by radiation is in- creased with attained age, while the risk of radiogenic cancer relative to the spontaneous incidence remains comparatively constant. As a result, the dose-dependent excess of cancers is now more compatible with previous "relative" risk estimates than with previous `'absolute" risk estimates; the Committee believes that the constant absolute or additive risk model is no longer tenable. A-bomb survivors who were irradiated early in life are just now reach- ing the age at which cancer begins to become prevalent in the general population. It remains to be determined whether cancer rates in this group of survivors will continue to be comparable to the increased cancer risk that has been observed among survivors who were adults at the time of exposure. For this reason, estimation of the ultimate magnitude of the risk for the total population is uncertain and calls for further study. The quantitative relationship between cancer incidence and dose in A-bomb survivors, as in other irradiated populations, appears to vary, depending on the type of cancer in question. The dose-dependent excess of mortality from all cancer other than leukemia, shows no departure from linearity in the range below 4 sievert (Sv), whereas the mortality data for leukemia are compatible with a linear-quadratic dose response relationship. In general, the dose-response relationship for carcinogenesis in labo- ratory animals also appears to vary with the quality (LET) and dose rate of radiation, as well as sex, age at exposure and other variables. The influence of age at exposure and sex on the carcinogenic response to radiation by humans has been characterized to a limited degree, but changes in response due to dose rate and LET have not been quantified. Carcinogenic effects of radiation on the bone marrow, breast, thyroid gland, lung, stomach, colon, ovary, and other organs reported for A- bomb survivors are similar to findings reported for other irradiated human populations. With few exceptions, however, the effects have been observed only at relatively high doses and high dose rates. Studies of populations chronically exposed to low-level radiation, such as those residing in regions of elevated natural background radiation, have not shown consistent or conclusive evidence of an associated increase in the risk of cancer. For the purposes of risk assessment, the Committee summarized the epidemiological data for each tissue and organ of interest in the form

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6 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION of an exposure-time-response model for relative risk. These models were fitted to the data on numbers of cases and person-years in relation to dose equivalent, sex, age at exposure, time after exposure, and attained age. Standard lifetable techniques were used to estimate the lifetime risk for each type of cancer based on these fitted models. On the basis of the available evidence, the population-weighted average lifetime excess risk of death from cancer following an acute dose equivalent to all body organs of 0.1 Sv (0.1 Gy of low-LET radiation) is estimated to be 0.8%, although the lifetime risk varies considerably with age at the time of exposure. For low LET radiation, accumulation of the same dose over weeks or months, however, is expected to reduce the lifetime risk appreciably, possibly by a factor of 2 or more. The Committee's estimated risks for males and females are similar. The risk from exposure during childhood is estimated to be about twice as large as the risk for adults, but such estimates of lifetime risk are still highly uncertain due to the limited follow-up of this age group. The cancer risk estimates derived with the preferred models used in this report are about 3 times larger for solid cancers (relative risk projection) and about 4 times larger for leukemia than the risk estimates presented in the BEIR III report. These differences result from a number of factors, including new risk models, revised A-bomb dosimetry, and more extended follow-up of A-bomb survivors. The BEIR III Committee's linear- quadratic dose-response model for solid cancers, unlike this Committee's linear model, contained an implicit dose rate factor of nearly 2.5; if this factor is taken into account, the relative risk projections for cancers other than leukemia by the two committees differ only by a factor of about 2. The Committee examined in some detail the sources of uncertainty in its risk estimates and concluded that uncertainties due to chance sam- pling variation in the available epidemiological data are large and more important than potential biases such as those due to differences between various exposed ethnic groups. Due to sampling variation alone, the 90~o confidence limits for the Committee's preferred risk models, of increased cancer mortality due to an acute whole body dose of 0.1 Sv to 100,000 males of all ages range from about 500 to 1,200 (mean 760~; for 100,000 females of all ages, from about 600 to 1,200 (mean 810~. This increase in lifetime risk is about 455 of the current baseline risk of death due to cancer in the United States. The Committee also estimated lifetime risks with a number of other plausible linear models which were consistent with the mortality data. The estimated lifetime risks projected by these models were within the range of uncertainty given above. The committee recognizes that its risk estimates become more uncertain when applied to very low doses. Departures from a linear model at low doses, however, could either increase or decrease the risk per unit dose.

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EXECUTIVE SUMMARY Mental Retardation 7 The frequency of severe mental retardation in Japanese A-bomb sur- vivors exposed at 8-15 weeks of gestational age has been found to increase more steeply with dose than was expected at the time of the BEIR III report. The data now reveal the magnitude of this risk to be approximately a 4% chance of occurrence per 0.1 Sv, but with less risk occurring for expo- sures at other gestational ages. Although the data do not suffice to define precisely the shape of the dose-effect curve, they imply that there may be little, if any, threshold for the effect when the brain is in its most sensitive stage of development. Pending further information, the risk of this type of injury to the developing embryo must not be overlooked in assessing the health implications of low-level exposure for women of childbearing age. RECOMMENDATIONS There are a number of important radiobiological problems that must be addressed if radiation risk estimates are to become more useful in meeting societal needs. Assessment of the carcinogenic risks that may be associated with low doses of radiation entails extrapolation from effects observed at doses larger than 0.1 Gy and is based on assumptions about the relevant dose-effect relationships and the underlying mechanisms of carcinogenesis. To reduce the uncertainty in present risk estimation, better understanding of the mechanisms of carcinogenesis is needed. This can be obtained only through appropriate experimental research with laboratory animals and cultured cells. While experiments with laboratory animals indicate that the carcino- genic effectiveness per Gy of low-LET radiation is generally reduced at low doses and low dose rates, epidemiological data on the carcinogenic effects of low-LET radiation are restricted largely to the effects of exposures at high dose rates. Continued research is needed, therefore, to quantify the extent to which the carcinogenic effectiveness of low-LET radiation may be reduced by fractionation or protraction of exposure. The carcinogenic and mutagenic effectiveness per Gy of neutrons and other high-LET radiations remains constant or may even increase with decreasing dose and dose rate. For reasons which remain to be determined, the relative biological effectiveness (RBE) for cancer induction by neutrons and other high-LET radiations has been observed to vary with the type of cancer in question. Since data on the carcinogenicibr of neutrons in human populations are lacking, further research is needed before confident estimates can be made of the carcinogenic risks of low- level neutron irradiation for humans. Similarly, the relative mutagenic effectiveness of neutron and other high LET radiation varies with the

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8 EFFECTS OF EXPOSURE TO LOW AILS OF IONIZING MOTION specific genetic end point. Therefore, additional data are also needed on the mutagenicity of low neutron doses to permit more confident projection of genetic risks from animal data to man. The extrapolation of animal data to the human is necessary for genetic risk assessment. No population appears to exist, other than the A-bomb survivors, that could provide a substantial basis for genetic epidemiological study. The scientific basis of the extrapolation must therefore rely upon cellular and molecular homologies. Research needs in this area are clear. As noted previously, the Committee's genetic risk assessment did not attempt to project risk for the category of diseases with complex genetic etiologies. Because genetically related disorders comparable to those in this heterogeneous category of human disorders may have no clearly definable counterparts in laboratory and domestic animals, the required research should be directed towards human diseases whenever feasible. The dose-dependent increase in the frequency of mental retardation in prenatally irradiated A-bomb survivors implies the possibility of higher risks to the embryo from low-level irradiation than have been suspected hereto- fore. It is important that appropriate epidemiological and experimental research be conducted to advance our understanding of these effects and their dose-effect relationships. Finally, further epidemiological studies are needed to measure the cancer excess following low doses as well as large doses of high and low LET radiation. Most of the A-bomb survivors are still alive, and their mortality experience must be followed if reliable estimates of lifetime risk are to be made. This is particularly important for those survivors irradiated as children or in utero who are now entering the years of maximum cancer risk. Studies on populations exposed to internally deposited radionuclides should be continued to assess the risks of nuclear technologies and the effects of radon progeny. Low-dose epidemiological studies may be able to supply information on the extent to which effects observed at high doses and high dose rates can be relied on to estimate the effects due to chronic exposures such as occur in occupational environments. The reported follow- up of A-bomb survivors has been essential to the preparation of this report. Nevertheless, it is only one study with specific characteristics, and other large studies are needed to verify current risk estimates.