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Genetic Effects of Radiation INTRODUCI ION Ionizing radiation damages the genetic material in reproductive cells and results in mutations that are transmitted from generation to generation. The mutagenic effects of radiation were first recognized in the 1920s, and since that time radiation has been used in genetic research as an important means of obtaining new mutations in experimental organisms. Although occupational exposure to high levels of radiation has always been of concern, not until during and after World War II was there a concerted effort to evaluate the genetic effects of radiation on entire populations. These efforts were motivated by concern over the effects of extremely large sources of radiation that were being developed in the nuclear industry, of radioactive fallout from the atmospheric testing of atomic weapons and of the rapidly increasing use of radiation in medical diagnosis and therapy. In 1956 the National Academy of Sciences-National Research Council (NAS- NRC) established the Committee on the Biological Effects of Atomic Radiation (denoted the BEAR Committee), which was the forerunner of the subsequent NAS-NRC committees on the Biological Effects of Ionizing Radiation (BEIR committees; of which this BEIR V report is one). A series of reports from the U.N. Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has also addressed the genetic effects of radiation exposure on populations. Although there is a continuing need to assess the genetic effects of radiation exposure, for several reasons the perspective has changed somewhat from that in the 1950s. First, it is now clear that the risk of cancer 65
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66 EFFECTS OF EXPOSURE TO LOW DEALS OF IONIZING MOTION in individuals exposed to radiation is significant and that limiting exposure to radiation to reduce the risk of cancer also limits the genetically significant exposure. Second, the instruments and techniques used in medical radiation have improved significantly, so that the overall doses used in medical diagnoses are reduced and patient exposure in all but the targeted organs is lessened. Third, in regard to the induction of mutations, the greater current risk seems to result from exposure to chemical mutagens in the environment rather than from the exposure of populations to radiation. Despite changed conditions, estimating the genetic effects of radiation remains important for setting exposure standards, both for the general population and for those exposed in their occupations. There are many difficulties in measuring the genetic effects of exposure of the human population to radiation and other mutagens. This is why, more than 20 years after the BEAR Committee first addressed the issues of radiation exposure, there is still uncertainty and controversy. The following are some of the difficulties and considerations that must be kept in mind. The genetic effects of radiation are expressed, not in irradiated indi- viduals, but in their immediate or remote offspring. The time lag is great because of the duration of the human life cycle, and massive epidemiologic studies with long-term follow-up are needed to accumulate sufficient data for statistical analysis. Moreover, for risk estimation of exposures that are not uniformly or randomly delivered to the entire population, the age and sex distribution of the exposed population and the different probabilities of having children for members of the population of each age and sex must be taken into account. The mutations induced by radiation can also occur spontaneously. When humans are exposed to low doses of radiation, it is difficult to estimate what small increment of mutations is induced by radiation above that from spontaneous background radiation. However, radiation has been found to be mutagenic in all organisms studied so far, and there is no reason to suppose that humans are exempt from radiation's mutagenic effects. These mutagenic effects are expected to be harmful to future generations because, in experimental organisms, the majority of new mutations with detectable effects are harmful, and it is assumed that humans are affected similarly. Indeed, the harmful effects of mutations that occur spontaneously in humans are well documented, because many of them result in genetic disease. The genetic effects of radiation must be detected through the study of certain endpoints, for example, visible chromosome abnormalities, proteins with altered conformations or charges, spontaneous abortions, congenital malformations, or premature death. In addition, radiation induced muta- tions may affect different endpoints to different degrees. For example, the dose of radiation required to double the incidence of one endpoint need
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GENETIC EFFECTS OF RADL4TION 67 not be the same as that required to double the incidence of a different endpoint. The BEIR I Committee (NRC72) espoused five general principles of risk estimation. Subsequent committees have generally followed these strictures whenever possible, as has the present committee. They are as follows: 1. Use relevant data from all sources, but emphasize human data when feasible. In general, when data of comparable accuracy exist, place greater emphasis on organisms closest to man. 2. Use data from the lowest doses and dose rates for which reli- able data exist, as being more relevant to the usual conditions of human exposure. 3. Use simple linear extrapolation between the lowest reliable dose data and the spontaneous or zero dose rate. In order to get any kind of precision from experiments of manageable size, it is necessary to use dosages much higher than those expected for the human population. Some mathematical assumption is necessary, and the linear model, if not always correct, is likely to err on the safe side. 4. If cell stages differ in sensitivity, weight the data in accordance with the duration of the stage. 5. If the sexes differ in sensitivity, use the unweighted average of data for the two sexes. Deliberate exposure of humans to radiation without diagnostic or therapeutic justification is unacceptable, and therefore, most genetic stud- ies have had to be carried out in experimental organisms, particularly mice. Such studies raise numerous additional problems of their own, including extrapolation of results obtained under experimental conditions to the con- ditions relevant to population exposure, such as dose rates, fractionation, and other variables; and extrapolation from an experimental organism such as the mouse, in which radiation effects may be estimated with some confidence, to humans, because organisms differ in radiation sensitivity. UNSCEAR (UN86) has summarized three principal assumptions that are necessary for extrapolating data from mice and other suitable mammals to humans: 1. The amount of genetic damage induced by a given type of radiation under a given set of conditions is the same in human germ cells and in those of the test species used as a model. 2. The various biological (e.g., sex, germ cell stage, age, etc.) and physical (e.g., quality of radiation, dose rate, etc.) factors affect the magni- tude of the damage in similar ways and to similar extents in the experimental species from which extrapolations are made and in humans.
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68 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION 3. At low doses and at low dose rates of low-LET (linear energy transfer) irradiation there is a linear relationship between dose and the frequency of genetic effects studied. Direct studies of the genetic effects of radiation exposure to human populations have been carried out on the children of the Japanese pop- ulations in Hiroshima and Nagasaki who were irradiated in the atomic bombings in August 1945. Results of these careful and very extensive stud- ies, when taken at face value, suggest that humans may be somewhat less sensitive to radiation than mice. The BEIR I Committee (NRC72) used two methods of estimating ge- netic effects. One method relied on direct estimates. This method was used whenever possible, for example with reciprocal translocations. The other method was indirect and was used for such endpoints as gene mutation. The indirect method required estimates of the mutation rates, the incidence of genetic disease in the human population, and the extent to which the incidence depends on recurrent mutation, to infer the increased incidence of genetic disease resulting from radiation exposure. Both immediate, first- generation effects and long-term, equilibrium effects were estimated from either the direct or indirect estimates of induced mutation by taking into account the presumed rates of mutant elimination to project the ratio of newly induced genetic damage to that transmitted from previous genera- tions. The BEIR III Committee (NRC80) reviewed and updated the BEIR I report (NRC72~. New estimates caused some changes in the previous estimates, and some new methods of estimation were added. The BEIR V Committee has reviewed and reevaluated the data that are pertinent to the estimation of genetic risks in humans. The present report summarizes the methods and conclusions of previous committees. In deriving new risk figures, it places rather more emphasis on the results of the studies of Japanese atomic-bomb survivors than have previous BEIR reports. However, the committee has also made use of the extensive radiation studies carried out with mice, which are briefly reviewed. SUMMARY OF CONCLUSIONS Based on our review of relevant data from humans, other mammals, and mice, the BEIR V Committee believes that the values in Able 2-1 give the current best estimates of risk based on the conclusion that the doubling dose in humans is not likely to be smaller than the approximate 1 Sv (100 rem) obtained from studies in mice. Ibble 2-1 gives the estimated genetic effects of an average population exposure of 1 rem/30-year generation. Admittedly there are uncertainties, but the calculated risks are based on an impressive body of data and knowledge of radiobiological principles.
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GENETIC EFFECTS OF RADIATION 69 As will be reviewed below, attempts to estimate doubling doses from data on Japanese atomic-bomb survivors have consistently led to values larger than those derived from the animal data, and consequently they imply lower risks. Although risks calculated from animal data have large confidence intervals, estimates from those exposed to radiation in Hi- roshima and Nagasaki are known with even less precision. In spite of these uncertainties, the data suggest a real difference, with the estimated lower 95% confidence limit of the human data approximating the median of a large number of values obtained in mice. If it is assumed that the apparent difference is real, humans would be less sensitive to radiation induction of mutations in germ cells than mice, and the risks in Able 2-1 should be considered conservative. On the other hand, the human data might be biased too low for reasons that are not presently understood, in spite of all the careful work that has gone into their collection and analysis. The BEIR V Committee is in no better position to decide the issue than were the previous groups and individuals who have grappled with it. Considering the uncertainty, the BEIR V Committee has adopted what it considers a prudent position in basing its risk estimates on the approximate lower 95% confidence limit for humans. This approach, while admittedly conservative, has the advantage of leading to risk estimates that, if anything, are too high rather than estimates that subsequent data may prove to be too low. The background and methodology for the estimates given in Table 2-1 are provided in the following sections. The material not only provides the background for Able 2-1 but also summarizes the methods and conclusions of previous BEIR, UNSCEAR, and other reports. It must be emphasized again that virtually all mutations have harmful effects. Some mutations have drastic effects that are expressed immedi- ately, and these are eliminated from the population quite rapidly. Other mutations have milder effects and persist for many generations, spread- ing their harm among many individuals in the distant future. However, many of the long-term effects are impossible to estimate given present data and understanding, and for this reason the present committee emphasizes the effects of mutations that manifest themselves in the first generation, since these are of immediate concern and can be estimated with some confidence. The effects in the first generation are primarily those caused by simple Mendelian dominant and X chromosome-linked recessive traits because of their high heritabilities. Other kinds of mutations may be more important in the long run and constitute a significant burden for future generations. Much of the uncertainty in estimating the risks of radiation-induced mutations centers on traits with complex patterns of inheritance that result from the combination of multiple genetic and environmental factors. Risk estimates are determined in part by the degree to which these traits are
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70 EFFECTS OF EXPOSURE TO LOW AILS OF IONIZING MOTION TABLE 2-1 Estimated Genetic Effects of 1 rem per Generationa Additional Cases/106 Liveborn Current Incidence . . . Offspr~ng/rem/Generat~on per Million Lovelorn Offspring Type of Disorder Autosomal dominant Clinically severer Clinically mildf X-linked Recessive Chromosomal Unbalanced 2,sooc 7,500g 400 2,500 <1 <1 First Generation 5 - 20d 1 - 15d E.... . qulllorlum 25e 75e <5 Very slow increase translocations600h<5 Very little increase Trisomies3,800'< 1 < 1 Congenital abnormalities20,000-30,00010' 10-100k Other disorders of complex etiology Heart diseased600,000 Cancer300,000Not estimated Not estimated Selected others300,000 - a Risks pertain to average population exposure of 1 rem per generation to a population with the spontaneous genetic burden of humans and a doubling dose for chronic exposure of 100 rem (1 Sv). b Assumes that survival and reproduction are reduced by 20-80% relative to normal (s = 0.2- 0.8), which is consistent with the range of values in Table 2-2. c Approximates incidence of severe dominant traits in Table 2-2. d Calculated using Equations (2-7), with s = 0.2- 0.8 for clinically severe and s = 0.01- 0.2 for clinically mild. ~ Calculated using Equation (2-1), with the mutational component = 1. f Assumes that survival and reproduction are reduced by 1-20 percent relative to normal (s = 0.01-0.2~. g Obtained by subtracting an estimated 2,500 clinically severe dominant traits from an esti mated total incidence of dominant traits of 10,000. h Estimated frequency from UNSCEAR (UN82,UN86~. i Most frequent result of chromosomal nondisjunction among liveborn children. Estimated frequency from UNSCEAR (UN82, UNTO. Based on worst-case assumption that mutational component results from dominant genes with an average s of 0.1; hence, using Equation (2-3), excess cases <30,000 x 0.35 x 100-~ x 0.1 = 10. k Calculated using Equation (2-1), with the mutational component 5-35%. Lifetime prevalence estimates may vary according to diagnostic criteria and other factors. The values given for heart disease and cancer are round-number approximations for all varieties of the diseases, and the value for other selected traits approximates that for the tabulation in Table 2-4. mNo implication is made that any form of heart disease is caused by radiation among exposed individuals. The effect, if any, results from mutations that may be induced by radiation and expressed in later generations, which contribute, along with other genes, to the genetic component of susceptibility. This is analogous to environmental risk factors that contribute to the environmental component of susceptibility. The magnitude of the genetic component in susceptibility to heart disease and other disorders with complex etiologies is unknown.
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GENETIC EFFECTS OF RADIATION 71 Table 2-1 Continued Most genes affecting the traits are thought to have small effects, and new mutations would each contribute a virtually insignificant amount to the total susceptibility of the individuals who carry them. However, a slight increase in genetic susceptibility among many individuals in the population may produce, in the aggregate, a significant effect overall. Because of great uncertainties in the mutational component of these traits and other complexities, the committee has not made quantitative risk estimates. The risks may be negligibly small, or they may be as large or larger than the risks for all other traits combined. determined by mutations, but the mutational component of many of the most common traits is very uncertain. The BEIR V Committee recom- mends that more research be carried out on such complex disorders to sort out their genetic and environmental causes. METHODS OF RISK CALCULATION Table 2-1 is based on the doubling dose method, which is summarized below, along with several other methods that have been used. The Doubling Dose Method The doubling dose method is based on the following equation: induced burden = spontaneous burden x (doubling dose)~i x mutation component x dose. (2-1) As a hypothetical example, if the spontaneous burden is 20,000 per million liveborn for some class of genetic disease in the human popu- lation, the doubling dose is estimated to be 100 rem, and the average mutation component for these diseases is one-half, then, if the parents in each generation are exposed to 1 rem, the induced burden is 100 cases/106 liveborn/generation. That is, after the population has reached a new equi- librium between selection and mutation (which is inflated by the added increment of radiation), one expects 100 additional cases of genetic disease in each generation because of the increased radiation. Although the doubling dose method is based on equilibrium consid- erations, the method can be used to estimate the effects of an increase in the mutation rate on the first few generations by taking a proportion of the equilibrium damage. For example, for a permanent increase in the mutation rate, the effect of a dominant mutation in the nth generation is 1 - (1-sin of the equilibrium damage, where (1-s) is the fitness of carriers of the dominant gene.
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72 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION In previous BEIR reports the reciprocal of the doubling dose has been called the relative mutation risk, and Equation (2-1) can be written as follows: induced burden = spontaneous burden x (relative mutation risk) x mutation component x dose. (2-2) This was done, in part, to avoid the concept of doubling dose, which is sometimes misunderstood. By definition, the doubling dose is that dose required to induce a number of mutations equal to the spontaneous frequency. However, its use in this report is confined to the range of low doses at which the dose-response curve is essentially linear. We thus have m = mO + aD, where mO is the spontaneous frequency, D is the dose, a is the induction rate, and m is the total mutation frequency (spontaneous plus Induced). The doubling dose is then mO/a and its reciprocal, a/mO= (m -mO) mOD is the relative mutation risk, that is, the number of mutations induced as a fraction of the spontaneous number per unit dose. If the sexes differ in doubling dose, then the overall doubling dose is a weighted average of the sex-specific doubling doses. Denoting the male and female sexes as 1 and 2, respectively, and again attending only to the linear part of the dose-response curve, the following equation is obtained: m = ma ~ m2 + aide + a2D2 (~2-3) where m:, al, Do and m2, as, D2 are the sex-specific spontaneous fre- quencies (m), induction rates (a), and doses (D) for males and females, respectively. If a population were exposed to D, = DD: = meat and D2 = DD2 = m2/a2, the mutation burden would double. DD, and DD2 are the sex-specific doubling doses for males and females respectively. The common dose to both sexes that will double the mutation rate is: DD = Amp + m2~/(a~ + a2) which is the a-weighted average of the sex-specific doubling doses. (~2-4~) Doubling doses from experimental mouse data are usually based on the exposure of a single parent and are sometimes referred to as gametzc. Doubling doses estimated from the data from Japanese atomic-bomb sur- vivors are sometimes based on joint parental exposure and are referred to as zygotic. For example, Neel and Schull (Ne74) have regressed various endpoints such as early infant death and malformations on the sum of the
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GENETIC EFFECTS OF RADIATION 73 mother's and the father's doses. In this situation the linear part of the response curse can be written as (assuming a mutation component of 1) m = me or me + a(`D~ + D24. (~2-5) An estimate of the doubling dose of (m~ + m2~/a is then the summed parental dose that would double the mutation rate. Neel and Schull and collaborators have called this the zygotic doubling dose. 1b convert this to an average, or gametic doubling dose for the sexes, the zygotic doubling dose is divided by 2. The Direct Method The direct method of risk calculation was pioneered by Ehling (Eh76a,b) and Selby and Selby (Se77) to estimate first-generation effects for dominant mutations rather than relying on the assumption of the pro- portionate effects implicit in the doubling dose method. In the direct method, the induction rate for a specific class of defects in mice (e.g., cataracts and skeletal anomalies) is measured directly by using high-dose-rate radiation, and the results are corrected for dose rate. Then, the proportion of serious dominant genetic disorders in humans that involves similar defects is estimated, and this is used as a proportionality factor to estimate the effect of radiation on all dominant mutations in humans. For example, if the spermatogonial chronic induction rate for skeletal defects in the mouse was 4 x 10-6/rad/gamete, and in humans about one in five serious dominant disorders involved the skeleton, then the first-generation effect of spermatogonial chronic radiation would be estimated by this method as 20 induced cases/106 liveborn/rad. The committee had little confidence in the reliability of the individual assumptions required by the direct method let alone the product of a long chain of uncertain estimates that follow from these assumptions. Therefore, they did not place heavy reliance on the direct method in making their risk estimates, but used it only as a test of consistency. The Gene Number Method In the gene number method, one attempts to estimate the total number of mutations produced by exposure to radiation by using the equation: No. of induced mutations = No. of genes Reinduction rate/gene/unit dose) x dose. (2-6) This approach dates back to the BEAR Committee (NRC56) and Muller's elegant concept of "genetic death." BEAR states:
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74 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION One way of thinking about this problem of genetic damage is to assume that all kinds of mutations on the average produce equivalent damage, whether as a drastic effect on one individual who leaves no descendants because of this damage, or a wider effect on many. Under this view, the total damage is measured by the number of mutations induced by a given increase in radiation, this number to be multiplied in one's mind by the average damage from a typical mutation. In other words, each harmful mutation ultimately causes one genetic death, which is either expressed all at once in the death of a single individual or is perhaps spread out as smaller effects over hundreds of individuals and hundreds of generations. One difficulty with this approach is that it is difficult to translate it usefully into societal cost and human suffering. Another problem is that no satisfactory definition or estimate of the total number of mutable genes is available. For these and other reasons, the BEIR V Committee eschewed risk estimates based on gene number. PREVIOUS ESTIMATES OF HUMAN DOUBLING DOSE BEAR (1956) The BEAR Committee (NRC56) concluded that "the actual value of the doubling dose is almost surely more than 5R and less than 100R. It may very well be from 30R to 80R." The exact calculations from which these values, in roentgens, were obtained are not included in the report, except to say that the calculations which lead to an estimate of this 'doubling dose' necessarily involve the rates of both spontaneous and radiation-induced mutations in man. Neither of these rates has been directly measured; and the best one can do is to use the excellent information on such lower forms as fruit flies, the emerging information for mice, the few sparse data we have for man and then use the kind of biological judgement which has, after all, been so generally successful in interrelating the properties of forms of life which superficially appear so unlike but which turn out to be remarkably similar in their basic aspects. No distinction between acute and chronic dose was made. The doubling dose range given by the BEAR Committee would now be considered to apply to acute radiation. It must be remembered that at the time that the BEAR report was written, neither the dose-rate effect nor the distinction between premeiotic and postmeiotic cell stage response to radiation were known. BEIR I (1972) The BEIR I (NRC72) estimate of the doubling dose was given as a range of 20-200 rem, which was determined as follows. A chronic radiation
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GENETIC EFFECTS OF RADL4TION 75 dose to mouse spermatogonia was said to yield about 0.5 x 10-7 recessive mutations/rem/gene. The comparable figure for mouse oocytes was taken to be zero, giving an average of 0.25 x 10-7. The spontaneous mutation rate was estimated from human dominant and X chromosome-linked mutation data to be in the range 0.5 x 10-6 to 0.5 x 10-5, giving the doubling dose range of 20-200 rem. The figure of 20 rem was considered as being probably too low after a rough minimum doubling dose was calculated from the data then available from survivors in Hiroshima and Nagasaki. BEIR III (NRC80) Although BEIR III (NRC80) subscribed to the general principles of BEIR I (NRC72), it disagreed with the calculation of the doubling dose. Unlike BEIR I, which constructed a hybrid doubling dose based on the induced mutation rate in mice and the spontaneous mutation rate in humans, BEIR III chose to calculate a doubling dose for mice and extrapolate it to humans. The stated objection to the BEIR I method was that it mixed the induced rate of a set of mouse genes preselected for high mutability with an estimate of a human spontaneous rate for more typical genes. BEIR III took as an induced rate 6.6 x 10-8 mutations/locus/rem, from mouse spermatogonia irradiated at 0.009 rem/minute and below. The corresponding spontaneous rate was 7.5 x 10-6, giving a point estimate of the doubling dose (for chronic radiation) of 114 rem. The committee then doubled and halved this figure to arrive at a final range of 50-250 rem to take into account uncertainties raised by the mouse oocSrre data and the data from atomic-bomb survivors in Japan. Other Estimates Based on Mice Abrahamson and Wolff's (Ab76) linear-quadratic analysis of the mouse data lead to doubling dose estimates in the range of 43-131 red. Analyses of data from Russell (Ru77) and Russell and Kelly (Ru82a) on low-dose- rate data in female and male mice, respectively, give a range of 99-160 red. Finally, Denniston's (De82) analysis of the mouse data using the Lea (1947) model Y = a + bD + cD2G yielded a point estimate of 109 red. The Japanese Data In contrast to the doubling dose estimates In mice, those derived from the human data have tended to be larger, sometimes by a factor of 3 or more. For example, Schull et al. (Sc81) state: In general, human exposure to radiation will not be acute and of the magnitude experienced by the inhabitants of Hiroshima and Nagasaki, but either interrupted
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124 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION According to Nomura's data, an increased prevalence of tumors is observed on the basis of a one-t~me sampling of the Fat population at 8 months of age. The increase is from about 5% in the control to 25% at a 504-rad dose to cells in postmeiotic stages in males, spermatogonia, or oocytes. There was no shift in the spectrum of tumor types, and 90% were pulmonary ade- nomas, which is a common neoplasm in some strains of mice. The one-time sample leaves unanswered the question of whether the increased frequency is due to a shift in the time of appearance or is due to a real increase in the total number of tumors over the mouse's lifetime. Previous studies of this type gave negative results (Ko65), although there was evidence of reduced life expectancy in the Fit progeny of irradiated parents in an early study by Russell (Rump. As life expectancy in the mouse can be closely related to age, rate, and type of tumor occurrence, Russell's results could have indicated an induced change in death rates from tumors; however, the results of Russell's 1957 study have not been confirmed. Summary of Data on Mice and Other Laboratory Mammals Tables 2-9 and 2-10 summarize the data on eight genetic endpoints that have reasonably representative mutation rates. All these data have been derived from studies that were specifically directed toward the particular endpoint; thus, the rates for multilocus mutations are not included because of their indirect derivation. Standard errors are not given because they tend to reflect experimental factors more than they do the true level of biological uncertainty. Most rates have been rounded so as not to imply greater precision than that which may actually exist. The available data are predominantly from studies in which high- dose-rate exposures with low-LET radiations were used. This reflects the availability or unavailability of appropriate facilities to carry out low-dose- rate irradiations or irradiations with high-LET sources. It also probably reflects the shifting level of interest from radiation mutagenesis to chemical mutagenesis over the past 15-20 years. The effect of this shift has been to leave large gaps in our matrix of information. For the high-dose-rate, low-LET radiations, mutation rates per gamete or per cell generally fall in the range of 10-5 to 10~4/rad, although there are several exceptions. Higher rates are seen for dominant lethal mutations induced in postgonial cells of male mice, for translocations induced in the spermatogonia of one marmoset species, and for aneuploidy induced in the preovulatory oocyte of female mice. Lower rates pertain to dominant visible mutations; however, except for skeletal and cataract mutations, these are recognized to be systematically underestimated. Rates per locus are in the range of 10-8 to 10-7. Low-dose-rate exposures cause the mutation rate to drop by a factor
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GENETIC EFFECTS OF RADL9TION 125 of 5 or greater, and a factor of 10 accommodates the range of values, with one notable exception. The dose-rate factor for the male specific- locus mutation rate Is only 3. This Is a firmly established value. The reason for this rather low dose-rate factor Is not clear, although it Is not dissimilar from some values derived from other radiobiological studies on tumorigenesis and life shortening (NCRP Report 64, 1980~. RBE values for fission neutron exposures are about 5 for high-dose-rate comparisons and range from 15 to 50 for low dose rates. Spontaneous mutation rates Table 2-9) are understandably less well known than the induced rates; this appears to be largely a matter of inadequate sampling statistics. The values for the specific locus test are well defined, although even here they are not free of controversy because of the occurrence of clusters of events. For other endpoints, such as translocations in mice, the range of values often reflects genetic diversity and not uncertainty per se. On this point, the committee notes that there Is considerable diversity in the spontaneous rates among all the known specific recessive and dominant genes in mice and humans. The estimated doubling doses derived from Tables 2-9 and 2-10 are summarized In Bible 2-11. Considering all endpoints together, the direct estimates of doubling dose for low dose rate radiation have a median value of 70-80 red, indirect estimates based on high-dose rate experiments have a median of 150 red, and the overall median lies in the range of 100 to 114 red. These estimates support the view that the doubling dose for low-dose- rate, low-LET radiation in mice Is approximately 100 red for venous genetic endpoints. This contrasts with the results of the human data obtained from the study of Japanese atomic-bomb survivors, as discussed earlier in this chapter, which suggest that the value of 100 red represents an approximate lower 955S confidence limit for the human doubling dose. REFERENCES Ab76 Ab85 Ad82 Ad88 A185 Abrahamson, S., and S. Wolff. 1976. Re-analysis of radiation induced specific locus mutations in the mouse. Nature 264:715-719. Abrahamson, S. 1985. Risk estimates for genetic erects. In: Assessment of Risk from Low Level Exposure to Radiation and Chemicals: A Critical Overview. A. D. Woodhead et al., eds. New York, Plenum Press. Adler, I. D. 1982. Male germ cell cytogeneties. Pp. 249-276 in (:ytogenetic Assays of Environmental Mutagens, T. C. Hsu, ed. Totowa, N.J.: Allanheld, Osmun. Adler, I. D., and C. Erbelding. 1988. Radiation-induced translocations in spermatogonial stem cells of Macaca fasciculans and Macaca mulatta. Mutat. Res. 198:337-342. Alavantie, D., and A. G. Searle. 1985. Effects of posti~radiation time interval on translocation frequency in male mice. Mutat. Res. 142:65-68.
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Representative terms from entire chapter: