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National Research Council (US) Committee on the Biological Effects of Ionizing Radiation (BEIR V). Health Effects of Exposure to Low Levels of Ionizing Radiation: Beir V. Washington (DC): National Academies Press (US); 1990.

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Health Effects of Exposure to Low Levels of Ionizing Radiation: Beir V.

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2Genetic Effects of Radiation


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 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 individuals, 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 mutations may affect different endpoints to different degrees. For example, the dose of radiation required to double the incidence of one endpoint need 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:


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.


Use data from the lowest doses and dose rates for which reliable data exist, as being more relevant to the usual conditions of human exposure.


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.


If cell stages differ in sensitivity, weight the data in accordance with the duration of the stage.


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 studies 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 conditions 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:


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.


The various biological (e.g., sex, germ cell stage, age, etc.) and physical (e.g., quality of radiation, dose rate, etc.) factors affect the magnitude of the damage in similar ways and to similar extents in the experimental species from which extrapolations are made and in humans.


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 populations in Hiroshima and Nagasaki who were irradiated in the atomic bombings in August 1945. Results of these careful and very extensive studies, 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 genetic 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 generations. 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 Table 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. Table 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.

TABLE 2-1. Estimated Genetic Effects of 1 rem per Generation.


Estimated Genetic Effects of 1 rem per Generation.

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 Hiroshima 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 Table 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 Table 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 immediately, and these are eliminated from the population quite rapidly. Other mutations have milder effects and persist for many generations, spreading 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 determined by mutations, but the mutational component of many of the most common traits is very uncertain. The BEIR V Committee recommends 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:

Image img00052.jpg

As a hypothetical example, if the spontaneous burden is 20,000 per million liveborn for some class of genetic disease in the human population, 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/10 6 liveborn/generation. That is, after the population has reached a new equilibrium 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 considerations, 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 – s)n of the equilibrium damage, where (1 – s) is the fitness of carriers of the dominant gene.

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:

Image img00053.jpg

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 = (mmº) 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:

Image img00054.jpg

where m1, a1, D1 and m2, a2, D2 are the sex-specific spontaneous frequencies (m), induction rates (a), and doses (D) for males and females, respectively. If a population were exposed to D1 = DD1 = m1/a1 and D2 = DD2 = m2/a2, the mutation burden would double. DD1 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:

Image img00055.jpg

which is the a-weighted average of the sex-specific doubling doses.

Doubling doses from experimental mouse data are usually based on the exposure of a single parent and are sometimes referred to as gametic. Doubling doses estimated from the data from Japanese atomic-bomb survivors 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 mother's and the father's doses. In this situation the linear part of the response curve can be written as (assuming a mutation component of 1)

Image img00056.jpg

An estimate of the doubling dose of (m1 + 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. To 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 proportionate 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 × 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:

Image img00057.jpg

This approach dates back to the BEAR Committee (NRC56) and Muller's elegant concept of ''genetic death." BEAR states:

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 dose to mouse spermatogonia was said to yield about 0.5 × 10–7 recessive mutations/rem/gene. The comparable figure for mouse oocytes was taken to be zero, giving an average of 0.25 × 10–7. The spontaneous mutation rate was estimated from human dominant and X chromosome-linked mutation data to be in the range 0.5 × 10–6 to 0.5 × 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 × 10–8 mutations/locus/rem, from mouse spermatogonia irradiated at 0.009 rem/minute and below. The corresponding spontaneous rate was 7.5 × 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 oocyte 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 rad. 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 rad. Finally, Denniston's (De82) analysis of the mouse data using the Lea (1947) model Y = a + bD + cD2G yielded a point estimate of 109 rad.

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 or chronic, and at much lower levels. Under such circumstances, the genetic yield of chronic radiation in mice is approximately one-third that of acute radiation. If mice and people are similar in this respect, the doubling dose for human chronic exposure suggested by these data becomes 468 rems, in contrast to the estimate of 100 rems for low LET, low dose, low-dose-rate exposure recently adopted by a committee of the International Commission on Radiological Protection.

Past committees have been reluctant to make heavy quantitative use of the data from Japan, despite their careful collection and analysis, in part because doubling doses derived from them are highly sensitive to several assumptions. For example, with respect to the two endpoints untoward pregnancy outcome and F1 mortality, Neel, Schull, and collaborators have usually assumed a spontaneous rate of about 5% and a mutation component of about 5%, giving a spontaneous rate due to mutation of 0.0025. This is the numerator in a doubling dose estimate. However, a problem that these investigators have always been keenly aware of is that the doubling dose estimates are extraordinarily sensitive to these assumptions. For example, if the mutation component of untoward pregnancy outcome were actually 3% rather than 5%, a difference well within the range of plausible values, then the published doubling dose would be 40% too high. On the other hand, if the true mutation component were 7%, the published doubling dose would be 40% too low. Similarly, using 4% rather than 5% as the mutational component decreases the doubling dose by 20%, and using 6% as the mutational component increases the doubling dose by 20%.

Additional uncertainties complicate the estimation of human doubling dose. For example, neither the total spontaneous rate nor the induction rates per rad (which are not significantly different from zero in the Japanese data) are known with much precision. In addition, it is not obvious that the factor of 3 often used to convert the Japanese data from a high to a low dose rate is entirely appropriate. This factor was obtained from irradiation of mouse spermatogonia. Given that mouse data are the only data available on this point, the inference from the Japanese data that the mean radiosensitivity of humans is different from that of mice suggests that the dose rate conversion factor may also differ. Additional uncertainties in interpreting the conversion factor for mice are that it comes from comparison of acute high doses and chronic high doses and not from the more relevant comparison of acute low doses and chronic low doses, and the mouse data are based in part on experiments with radiation of different qualities (x rays, 137Cs gamma rays, and 60Co gamma rays), although radiation quality is unlikely to contribute much to the difference. These issues are admittedly difficult, but the doubling doses quoted for chronic radiation are very sensitive to the conversion factor. Prudence again seems to dictate that risks be based on a lower confidence limit rather than a point estimate.

Calculation of Risk Estimates

The risks in Table 2-1 are based on the assumption of a doubling dose of 100 rem. This is in agreement with the UNSCEAR reports of 1972, 1977, 1982, and 1986. A doubling dose of 100 rem approximates the lower 95% confidence limit for the data from atomic-bomb survivors in Japan, and it is also consistent with the range of doubling doses observed in mice. While it is somewhat arbitrary, the number has the advantage of arithmetic simplicity and is a round number that does not invite an unwarranted assumption of high accuracy. To the extent that the risks in Table 2-1 may be inaccurate, they are to be regarded as probably being too high rather than too low. For purposes of setting radiation standards, it is wiser to estimate risks that might be too large rather than risks that might be too small.

Estimating First Generation and Equilibrium Effects

Dominant Disorders

Several approaches to dominant disorders are possible. BEIR I (NRC72) essentially used the formula:

Image img00058.jpg

where 1 – s is the assumed average fitness of individuals suffering from dominant disorders. The BEIR I committee (NRC72) assumed a spontaneous burden of 1%, a doubling dose of between 20 and 200 R, and they estimated s as about 1/5, giving a first generation effect of 10 to 100 cases/106 liveborn/R. BEIR III (NRC80) assumed the doubling doses to be in the range of 50-250 R and similar estimates for the spontaneous burden and fitness as in BEIR I, from which the formula estimates 8-40 cases/10 6 liveborn/R. (However, BEIR III used the direct method for calculating dominants, see below). Raising the lower bound from 20 to 50R has a significant effect on the estimated risks.

The very different direct method for estimating first-generation effects of dominant disorders was pioneered by Ehling (Eh76a,b) and Selby and Selby (Se77), as described earlier in this chapter. BEIR III (NRC80) invoked the following argument using the data of Selby and Selby (Se77) on the induction of skeletal mutations in mice by gamma irradiation:

risk= induction rate of skeletal mutations (37/2646)(600–1)
× correction for dose rate and fractionation (1/3)(1/1.9)
× multiplication factor for extrapolating skeletal to all dominants (5 – 15)
× correction for seriousness of traits (0.25 – 0.75)
× correction for sex (1.44)
= 5 – 65 × 10–6

This argument gave a risk of 5-65 dominant disorders/106 liveborn in the first generation after exposure of the entire population (both sexes) to 1 rem, but the calculation requires the multiplication of several factors of uncertain magnitude. The argument also implies that the average fitness for dominant disorders is 0.675-0.875 (bracketing the value of 0.8 assumed in BEIR I), which is in good agreement with the value of 0.83 calculated from the data of Childs (Ch81) in Table 2-2 (discussed below).

TABLE 2-2. Live Birth Frequencies, Reproductive Fitness, and Mutation Rates for Dominant Disorders.


Live Birth Frequencies, Reproductive Fitness, and Mutation Rates for Dominant Disorders.

Ehling (Eh78) used data on the induction of cataracts due to a dominant mutation in mice from gamma irradiation to estimate the risk following 1 rem as:

risk= induction rate per rem (1.3 × 10–6)
× correction for dose rate and fractionation (0.3 × 0.85)
× multiplication factor for total dominant damage (32.4)
× extrapolation factor from mouse to human (1.2)
= 14 × 10–6

In these and the previous example the correction factors used for low dose rate, fractionation, and sex were all derived from data using the mouse specific locus system for detecting recessive mutations, which is described in a section on animal studies later in this chapter.

NUREG/CR-4214 (NUR85) gave an estimate of 110 cases of newly induced dominant disorders in 490,000 births after an exposure of approximately 8 R. This corresponds roughly to 30 cases/106 liveborn/R.

A somewhat different approach is as follows. Childs (Ch81) has assembled data on some 25 dominant human genetic disorders or groups of disorders, the most severe of which are listed in Table 2-2. The total birth frequencies in Childs' tabulation is given as 5,840 × 10–6, with an average selection coefficient of about 1/6. Assuming a doubling dose of 100 R, the Childs' data give a first generation effect of about 10 dominant cases per million liveborn per R.

Alternatively, one can use Childs' estimates of the spontaneous mutation rates for these disorders, by means of the approximate relation

first-generation effect = 2U/doubling dose,

where U = 409 × 10–6 is the total spontaneous mutation rate (Ch81). The estimate is 8 cases/106 liveborn/R. The two estimates from Childs' data are not independent, but they demonstrate the consistency of the data.

This approach has the positive feature that it is based on a reasonably well-defined set of diseases that, in fact, constitute a substantial portion of the incidence of dominant disorders in humans.

All these risk estimates for dominant disorders are roughly in agreement and compatible with a doubling dose on the order of 100 rem (1 Sv). The BEIR V Committee has divided the autosomal dominant disorders into categories based on their relative fitness as related to the severity of clinical symptoms. When both categories are combined, the estimate is 6-35 cases of dominant disorders induced in the first generation/106 liveborn/rad, with an equilibrium value of 100. The time required to go halfway to equilibrium is about 0.693/s generations (Mo82); for s in the range of 0.2-0.8 (clinically severe), this is approximately 4-9 generations, and for s in the range of 0.01-0.2 (clinically mild), it is approximately 4-70 generations.

X Chromosome-Linked Disorders

The dynamics of X chromosome-linked genes are much the same as those of autosomal genes and for this reason they are often included with dominant mutations. Trimble and Doughty (Tr74) give the birth frequency of X-linked disorders as about 400/106; Childs (Ch81) cites a value closer to 300/106 liveborn. For an X chromosome-linked gene, the proportion of the equilibrium excess of cases that appears in the first generation is approximately s/(2 + R), where 1 – s is the fitness of affected males and R is the ratio of male to female mutation rates. In the Childs (1981) compilation, the average value of s is about 0.75. If R is between 3 and 1, the proportion of the equilibrium excess cases occurring in the first generation is between 0.15 and 0.25. For a doubling dose of 100 rem, this implies less than 1 case/106 liveborn in the first generation.

Using the same estimates given above, the per-generation excess attained after the population reaches equilibrium between mutation and selection is less than 5 cases/106 liveborn/rad. The time required to go halfway to equilibrium is about 0.693(3/s), (Mo82), or in this case about 3 generations.

Recessive Disorders

Past BEIR committees have concluded that the increase in disease due to recessive mutations following an increase in the mutation rate from chronic radiation will be too slight or too remote in the future to justify quantitative estimation. Some geneticists disagree (e.g., Neel Ne57). Searle and Edwards (Se86a) have recently addressed whether the induction of recessive mutations significantly increases the mutational burden. The essence of their result is that the first generation effect after a population exposure of 1 R is about [2 u/DD] Σq, where u is the average spontaneous mutation rate, DD is the doubling dose, and Σq is the sum of the recessive equilibrium gene frequencies for all recessive disorders. The sum of the q values reflects the meeting of a newly induced mutation with a previous mutation already established in the population. If this sum is taken to be on the order of 1 and the spontaneous mutation rate is taken to be 12 × 10–6, (Mo81), then for a doubling dose of 100 rem, the first-generation effect is less than 1 recessive case/106 liveborn/rem, confirming previous expectations.

The equilibrium between selection and mutation when the mutation rate is increased is attained so slowly that it is relevant only to a hypothetical population existing in the distant future. The time required to go halfway to equilibrium is about 0.693/2 Qs where Q = (u/s)0.5 (Mo82). For this reason the present committee has not attempted a quantitative risk estimate for recessive mutations at equilibrium.

Moreover, there are good reasons to believe that the majority of recessive mutations are actually partially dominant in their effects on fitness. For example, in Drosophila melanogaster, spontaneous recessive lethal mutations reduce heterozygous viability by 4-5%, but lethal mutations isolated from natural populations cause a 1-2% reduction. Based on allele frequencies, the average recessive lethal allele appears to persist in a Drosophila melanogaster population for about 50 generations before it is eliminated by selection, which is far too short a time to be entirely a result of homozygous lethality.

In humans, also, there is some indication that recessive mutations are partially dominant. The evidence comes from consanguineous matings and the often unexpectedly low equilibrium frequencies of recessive genotypes. Whether partial dominance also applies to radiation-induced recessive mutations is less certain, but to the extent that it does, such mutations act like dominant mutations for the purpose of risk calculations.


BEIR I (NRC72) estimated a first generation effect of 70 recognized abortions and 12 unbalanced rearrangements born/106 liveborn/R. The equilibrium values were only slightly larger. These estimates were based on an estimated mouse spermatogonial induction rate for semisterility of 1.5 × 10–5/gamete/rad for low dose irradiation, and the conservative assumption is that females would have a similar frequency.

To calculate the risk from induced translocations, BEIR III (NRC80) utilized data from humans and the marmoset (Br75). The frequency of multivalent translocations in the primary spermatocytes of humans and marmoset was taken to be about 7 × 10–4/rem, based on high dose-rate 250 kV x ray doses of 78 R in humans (371 cells examined) and doses of 25 R, 50 R and 100 R in marmosets (600 cells examined at each dose). The present committee's review of the relevant data suggests that a value of 2 × 10–4/rem would be more appropriate (see the later section in this chapter on chromosome aberrations in mice and other mammals). In any case, the BEIR III calculation of risk of induced transmitted balanced translocations was (7 × 10–4)(2/3)(1/2)(0.45/2) = 5.25 × 10–5 translocations/rem, where 2/3 is the assumed ratio of the observed incidence of partial sterility to that calculated on the basis of the incidence of multivalent translocations in primary spermatocytes, 1/2 is the correction for dose rate, and 0.45 is the assumed frequency of alternate segregation of which 1/2 yield balanced translocation gametes. To accommodate the uncertainties regarding the dose rate reduction factor, the BEIR III Committee preferred to use the order-of-magnitude range 1.7 × 10–5 to 1.7 × 10–4 translocations/rem.

The corresponding calculation for unbalanced products was (7 × 10–4) (2/3)(1/2)(0.55)(0.05)(1/4) = 1.6 × 10–6 unbalanced zygotes/rem, where 0.55 is the assumed frequency of adjacent segregation, 5% of such translocation gametes are assumed to be capable of producing viable aneuploids, of which 1 in 4 lead to viable zygotes. Again, an order-of-magnitude range was given as 0.5 × 10–6 to 5 × 10–6 unbalanced zygotes/ rem. Multiplying by 2 (assuming females are about as inducible as males) leads to BEIR III's conclusion (Table IV-2 in BEIR III) that fewer than 10 cases/106 of induced chromosomal aberrations would appear in the first generation following exposure to 1 rem of radiation.


The U.S. Nuclear Regulatory Commission NUREG report (NU85) also used experimental data obtained from marmosets and humans. They took the induction rate of multivalent translocations in spermatogonia irradiated by x rays at and below 100 R (4 data points, one human and three marmosets) as 7.4 × 10–4. Their calculations were (7.4 × 10–4)(1/2)(0.4)(1/4) = 3.7 × 10–5 balanced translocations/rem, where 1/2 is a dose rate correction, and 0.4 is a relative biological effectiveness (RBE) correction to go from x rays to gamma rays. Again, 1/4 of the segregants were assumed to be balanced translocations. For unbalanced products, the calculation was (7.4 × 10–4)(1/2)(0.4)(1/2)(1/10) = 7.4 × 10–6 unbalanced zygotes/rem, where 1/2 is the frequency of adjacent segregation and 1/10 is the probability of survival. These values are for males. In females, the induced translocations are expected to result from chromatid breaks, so the corresponding calculations were (7.4 × 10-4) (1/2)(0.4)(1/16) = 9.25 × 10–6 balanced translocations/rem, and (7.4 × 10–4)(1/2)(0.4)(6/16)(1/10) = 5.6 × 10–6 unbalanced zygotes/rem.

Comparing the NUREG calculations with the BEIR III results, three differences are seen. BEIR III makes a correction for transmission but NUREG does not (Ge84). NUREG makes a correction for x rays to gamma rays (NCRP80), but BEIR III does not. These differences approximately cancel out each other. Finally, NUREG attempts to calculate explicitly the effect of radiation on oocytes, whereas BEIR III formally assumed that the female rate was equal to the male rate but suspected that the female rate was actually lower.


UNSCEAR (UN82), summarizing another UNSCEAR report (UN77), calculated (7.4 × 10–4)(1/4)(1/10 to 1/2)(2)(0.06) = (2.1 to 10.5) × 10–6 unbalanced zygotes/rem, where, again, the marmoset and human data were used, 1/4 is the conversion factor from multivalents to semisterility and segregation, the range 1/10 to 1/2 is used for dose rate correction, and twice as many unbalanced as balanced gametes are expected, of which about 6% would survive. The result is similar to the previous ones. In addition, UNSCEAR concluded that the female rate could be considerably lower and ''…should it turn out that the rate of induction in human spermatogonia is more similar to that in the rhesus monkey, the estimates may need revision downward, and consequently the quantitative figures arrived at must be considered provisional at present."

As noted, the BEIR V Committee's review of the relevant data suggests a rate of translocation induction of 2 × 10–4/rem, with a dose rate effect somewhat larger than previously thought. These revisions imply that previous estimates were somewhat too high. The committee suggests that an appropriate upper limit to the first generation effect caused by unbalanced products arising out of induced reciprocal translocations is less than 5 cases/106 liveborn/rad. It does not appear that Robertsonian translocations, which are such a prominent feature of the spontaneous burden in humans, are readily induced by radiation.


For a number of years, there has been an unresolved possibility that low doses of radiation, such as those used in diagnostic radiology, might induce chromosome nondisjunctions in exposed women. Most concern has focused on the possible induction of trisomy-21 (Down syndrome). The frequency of Down syndrome is strongly influenced by maternal age, rising to nearly 4% of all live births among women over 40 years of age, and the possibility that radiosensitivity also increases with age must be considered. The issue was addressed in Note 15 of Chapter IV in BEIR III (NRC80), in recent UNSCEAR reports (UN77, UN82, UN86), and in a review by de Boer and Tates (de83). The following provides a brief review of the subject.

Of 13 studies on the Down syndrome in humans discussed by Denniston (De82), 9 were retrospective and 4 prospective. No claim has been made for an effect caused by paternal radiation, but four of the studies found a significant effect caused by maternal radiation (one prospective and three retrospective studies). Of the remaining nine studies in which no statistical significance was attained, five were in the positive direction, two showed no difference, and two were in the negative direction. Overall, looking only at the direction of the data and ignoring whether or not they were statistically significant, there were nine showing positive effects and two showing negative effects. This is significant at the 0.033 level, assuming no effect. However, because of the way some of the data were collected (reliance on subject's memory of past irradiation), there is likely a bias in the positive direction. If, under the hypothesis of no association, the probability of observing data in the positive direction is only as high as 0.53, the sign test for consistency is no longer significant at the 5% level.

No effect on nondisjunction has been seen in the data from survivors of the Hiroshima and Nagasaki bombings (Aw87), and the claim of an effect on the incidence of Down syndrome in a high-background-radiation area of India has been severely criticized on statistical grounds.

Although nondisjunction can be induced with relatively large doses (1 to 6 Gy) of x irradiation in various dictyate oocyte maturation stages in mice (Te85), other studies have concluded that, at low doses, (<1 Gy) nondisjunction is not induced to any significant degree (Sp81, Te82). The positive results obtained by Uchida and Lee (Uc74) at low doses are at variance with results of subsequent studies (Go81, Te82). Therefore, notwithstanding the importance of nondisjunction to the spontaneous burden in humans, it appears that the induction of nondisjunction by low-level irradiation of immature oocytes may not present a serious concern. However, as discussed below in the section on chromosomal nondisjunction in mice, preovulatory oocytes, within three hours of ovulation, are extremely sensitive to the induction of aneuploidy at doses as low as 10 rads (Te82, Te86). Even if this effect occurs in humans, the brevity of the sensitive period would leave the risk estimates essentially unchanged.

Irregularly Inherited Traits

The so-called irregularly inherited disorders are those for which a genetic component has been established or seems likely, but which do not give simple Mendelian ratios. Irregular inheritance poses a serious problem to risk estimation. Although these traits constitute a significant portion of the total genetic burden in human populations, their response to an increase in the mutation rate from radiation is not predictable with any great confidence because of the uncertainty in their mode of inheritance.

An important concept relevant to irregularly inherited traits is the mutation component. If the incidence (I) of a condition can be written as I = a + bu, where u is the mutation rate and a and b are constants, then the mutation component of the condition is M = bu/( a + bu). M is the proportion of the incidence attributable to recurrent mutation, and a/(a + bu) is the part attributable to other causes. If the mutation rate is increased from u to u(1 + k), the incidence eventually increases from I to I(1 + Mk).

The heritability of a trait is a measure of that part of the total phenotypic variability that can be ascribed to genetic variability in the population. The ratio of the total genetic variance to the total phenotypic variance is called the "broad-sense heritability"; the ratio of the "additive" genetic variance (only part of the total genetic variance) to the total phenotypic variance is called the "narrow-sense heritability." For a trait maintained by balance between directional selection and mutation, if both broad-sense and narrow-sense heritability are high, then M is high. If both are low, then M is low. If the broad-sense heritability is high and the narrow-sense heritability is low, M cannot be predicted unless the specific mode of inheritance is known; however, any increase in the incidence following an increase in the mutation rate should be very slow (Cr81).

Trimble and Doughty (Tr74) estimated that about 9% of all liveborn humans are seriously handicapped at some time during their lifetimes by genetic disorders of complex etiology, either congenital abnormalities, anomalies that are expressed later, or constitutional and degenerative diseases. Their estimate is somewhat indirect. They adjusted data based on incidences prior to age 20 to account for disorders appearing later in life. BEIR III accepted this estimate and combined it with their own doubling dose range of 50-250 R and mutation component range of 5-50% to estimate an equilibrium excess of 20-900 induced cases of irregularly inherited disorders/R/106 liveborn. No first generation effect was estimated.

Estimating the equilibrium effect on irregularly inherited disorders due to an increase in the mutation rate raises several problems:


The mutation components are not known for these disorders, even approximately. Many of the traits are genetically and environmentally heterogeneous—a mixture of simple Mendelian etiologies, multifactorial threshold factors, and purely environmental causes. To the extent that the traits are accurately described by a multifactorial threshold model, the mutation component is undoubtedly low and the approach to equilibrium is very slow. To the extent that the traits include a simple Mendelian component, the mutation component is high and the approach to equilibrium depends on the exact nature of the model (e.g., dominant versus recessive, overdominance versus mutation-selection balance). The BEIR III Committee dealt with these uncertainties as well as they could and considered a range of mutation component between 5 and 50%.


Irregularly inherited disorders are diverse in terms of the nature of the defects represented (e.g., anencephaly versus varicose veins), severity (e.g., cleft lip versus club foot), time of action (birth to old age), and so on. This diversity makes it difficult to present a single overall measure of impact on the population. For example, the spontaneous frequency is determined by the rather arbitrary definition of what constitutes a serious disorder rather than one that is clinically significant.


Irregularly inherited disorders—even those with a substantial mutation component—have a slow rate of approach to equilibrium following a change in the mutation rate. Measures, such as excess number of cases per generation at equilibrium, are virtually meaningless because the very slowness of the approach may mitigate the seriousness of the threat to the population. The potential impacts cannot be quantified because the increased genetic load is spread out over so many generations into the future in an environment that is totally unpredictable at the present time.

Since the BEIR III report (NRC80), new information on the spontaneous incidence and the genetic nature of irregularly inherited disorders has become available (Cz84a, Cz84, UN86, Cz88). For purposes of the present discussion, it will be convenient to divide the irregularly inherited disorders into isolated congenital abnormalities and all others.

Congenital Abnormalities: Table 2-3 lists nine congenital abnormalities with an estimated combined birth incidence in Hungary of about 5%, and estimates of the heritabilities both of their liabilities and of the traits themselves. All such tabulations are somewhat vague in the diagnostic criteria used to identify the traits, and the high incidence of congenital dislocation of the hip in Hungary is so exceptional as to suggest overreporting. The BEIR V Committee estimates the birth incidence of congenital abnormalities at 20,000-30,000/106 liveborn (Table 2-1), which is consistent with the data in Table 2-3 when the high value for congenital dislocation of the hip is discounted.

TABLE 2-3. Selected Isolated Congenital Abnormalities.


Selected Isolated Congenital Abnormalities.

The distinction between the heritability of a trait's liability, assuming a threshold model, and the heritability of the trait itself is crucial, because the mutation component is more related to the heritability of the trait than to the heritability of liability. In the threshold model it is assumed that underlying each trait is a quantitative variable called liability, which is normally distributed and the result of many genetic and environmental terms of small effect. Individuals with a value of liability above a threshold are affected; those below the threshold are normal. By observing the population incidence of a trait p and the recurrence risk for relatives of affected individuals q, an estimate of the narrow heritability of liability can be obtained (Fa65, Sm70, Cu72). These estimates depend not only on the accuracy of the estimates of p and q but also on the assumptions of the threshold model.

Alternatively, the disorder itself can be thought of as a quantitative trait taking either of two values: 0 for normal and 1 for affected. An estimate of the narrow heritability of the trait is obtained from relatives by the formula RhT2 = (qp)/(1 – p), where R is the coefficient of relationship. An approximate relation between the heritability of liability hL2 and the heritability of the trait hT2 is given in footnote c in Table 2-3. The concordance between monozygotic (MZ) twins may be considered as an approximate maximum estimate of the broad-sense heritability of the disorder.

In Table 2-3 all numbers except the birth incidences and heritabilities of traits have been rounded to the nearest 5%. The incidences, liability heritabilities, and MZ twin concordances are from Cz84a. All estimates, especially those from the twin data, are inflated to an unknown extent by environmental correlations. The twin data also yield very unstable estimates because of small sample size.

In general, the estimates of trait heritabilities from sibling data do not differ much from those in the entire data of Czeizel and Tsunady (Cz84a) or those derived indirectly by using estimates of liability heritabilities from the threshold model. (One exception is congenital dislocation of the hip.) In rough terms, the heritabilities of the traits themselves are about 1/10 those of the liabilities.

At face value, the MZ concordances suggest that broad-sense heritabilities are much larger than narrow-sense heritabilities. This discrepancy is more likely caused by environmental correlations peculiar to twins rather than to a large amount of dominance and epistatic variance. In any event, whether the mutation components of these disorders are closer to 5 or 50% (the BEIR III range), the uniformly low narrow heritabilities would indicate that the approach to equilibrium following a rise in the mutation rate would be very slow indeed. On the other hand, to the extent that any of these disorders includes a significant proportion of cases with a simple monogenic origin (which have a mutation component of 1), the overall mutation component would be increased.

The risk estimates for this category of traits are listed in Table 2-1. The equilibrium value is based on Equation (2-1) with the assumption that the mutation component of the traits is between 5 and 35%. The upper limit of 10 for the first-generation effect is based on the worst-case assumption that the mutational component is due entirely to dominant genes.

Other Disorders of Complex Etiology: The data in Table 2-4 are taken from a recent set of data from Hungary presented in preliminary form by UNSCEAR (UN86). The table shows (1) large total lifetime prevalence (over 30%) and (2) large estimated heritabilities of liability based on a multifactorial threshold model. However, the heritabilities of the traits themselves are much smaller (see preceding section).

TABLE 2-4. Selected Diseases of Complex Etiology.


Selected Diseases of Complex Etiology.

If anything, the disorders in Table 2-4 are even more heterogeneous than the congenital abnormalities in Table 2-3. In Table 2-4, lifetime prevalences rather than birth frequencies are given. Many of the disorders have a rather late age of onset. The total lifetime prevalence for the selected disorders tabulated is about 30%. Assuming independence, approximately 27% of individuals suffer from at least one of these diseases sometime during their lifetimes.

The heritabilities in Table 2-4 again pertain to liability calculated from the Hungarian data and with the assumption of a multifactorial threshold etiology. The narrow heritabilities of the traits themselves are approximately 1/10 of these values (see preceding section). To the extent that these disorders are heterogeneous and confounded with monogenic or simple Mendelian disorders whose equilibrium frequencies result from a balance between mutation and selection, the mutation components would be elevated. On the other hand, several of the disorders are known to be correlated with variation in the HLA histocompatibility complex (e.g., ankylosing spondylitis, rheumatoid arthritis, psoriasis, coeliac disease, and diabetes). To the extent that population variation in the HLA complex is caused by balancing of selection, the mutation components of these disorders would be reduced correspondingly.

As in the case of the congenital abnormalities, data on twins generally show substantially higher concordances in monozygotic (MZ) than dizygotic (DZ) twins, testifying to a likely significant genetic component in these disorders. The general pattern is that the broad-sense heritabilities of the traits are considerably larger than the narrow-sense heritabilities. Consequently, the mutation components are indeterminant without further information, but it seems likely that any change in the frequencies of these diseases caused by a change in the mutation rate would be attained very slowly.

The data in Table 2-4 are for selected diseases and do not include data for cancer and heart disease, which are the most common diseases with complex etiologies. Cancer and heart disease are listed separately in Table 2-1, and the lifetime prevalence figures are approximations in round numbers for the prevalence of all varieties of the diseases. By enumerating heart disease in Table 2-1, the committee makes no implication that radiation can induce heart disease in exposed individuals. The effect of radiation on this and other diseases with complex etiologies (with the exception of cancer) is through new mutations that may increase the susceptibilities of their carriers to the onset of the diseases. From a genetic point of view, the mutational component of diseases with complex etiologies results from a number of genes, usually with small individual effects, that in combination determine susceptibility to environmental factors causing the disease. In the case of heart disease, for example, these environmental factors include diet and tobacco smoking. Any individual mutation is extremely unlikely to tip the balance between a person's health and disease. Rather, each new mutation is an additional genetic risk factor that combines with other genetic and relevant environmental risk factors. For the individual, a new mutation may contribute a marginally insignificant amount to the overall risk, but for the population, the small individual effects are cumulative and may become very significant.

For diseases with complex etiologies, the lifetime prevalences sum to greater than 100%, which means that few individuals escape them completely, and many suffer from more than one. Since the prevalence is one component of the risk estimate (Equation 2-1), this factor is very large. However, the prevalence factor is offset in part by an unknown, but presumably low, mutational component. Unfortunately, the mutational component is not known even to its order of magnitude, and for this reason, as well as other complexities enumerated in the preceding section on congenital abnormalities, the committee has not estimated risks for this category of traits. While the risks could be negligible, they could also be as large or larger than all the other entries in Table 2-1 combined.

Background Data from Humans

Three key sets of background data for humans concern the genetic burden resulting from spontaneous mutation, the rate of spontaneous mutation, and the data from survivors of the bombings of Hiroshima and Nagasaki. These are briefly reviewed below.

The Spontaneous Genetic Burden

Table 2-5 shows estimates of spontaneous frequencies of genetic disorders. The estimates used by the BEIR V Committee are also summarized. The categories of disorders are autosomal dominant, X chromosome-linked recessive, autosomal recessive, chromosomal abnormalities, congenital abnormalities, and other multifactorial traits. The last category is made up of a group of disorders for which the exact mode of inheritance is unknown. Some may prove to be monogenic in origin; others are undoubtedly threshold traits, for example, the congenital abnormalities. Five entries in Table 2-5 are based on original data: those of Stevenson (St59), Trimble and Doughty (Tr74), Carter (Ca77), Czeizel and Sankaranarayanan (Cz84), and Childs (Ch81). The remaining entries are consensus estimates of committees based largely on data from the first four studies listed in the table. A discussion of the main points presented in Table 2-5 follows.

TABLE 2-5. Estimated Spontaneous Burden (per 1,000 live births).


Estimated Spontaneous Burden (per 1,000 live births).

The most dramatic discrepancy is between the data of Stevenson and those of Trimble and Doughty with respect to autosomal dominant disorders. The Stevenson estimate of 30.7/1,000 live births is inflated by the incorporation of a number of traits that are now known not to be autosomal dominant, of traits of inconsequential clinical importance, or both (Tr77). The 10 most frequent traits in the Stevenson list make up about 70% of the total frequency, and most of these fall in the above categories of inappropriateness. On the other hand, the value of 0.8/1,000 from Trimble and Doughty is undoubtedly an underestimate because it is based on studies of individuals from birth to 21 years of age. Consequently, the estimate does not include serious genetic diseases due to single dominant genes that are manifested later in life. It can be seen from Table 2-5 that committees have chosen a middle course, with an estimate of about 10/1,000, often lumping dominant and X chromosome-linked traits together because of their similar responses to an increase in the mutation rate.

Over the years the estimated frequencies of recessive disease and chromosomal abnormalities have increased somewhat. Estimates of congenital abnormalities have increased substantially. Like the autosomal dominant traits, the estimate for congenital abnormalities is highly dependent on the definition of "serious." The value of 60/1,000 from Czeizel and Sankaranarayanan, which was also used by UNSCEAR (UN86), is so high, in part, because of the unusually high frequency of congenital dislocation of the hip in Hungary. The surprisingly high value of 600/1,000 for lifetime prevalence of other multifactorial disorders given by UNSCEAR (UN86) includes such entities as diabetes mellitus, gout, schizophrenia, affective psychoses, epilepsy, glaucoma, hypertension, varicose veins, asthma, psoriasis, ankylosing spondylitis, and juvenile osteochondrosis of the spine. Disorders with such high frequencies are, of course, not strictly independent, but the message, nevertheless, is that virtually all humans suffer from ill health at some time in their lives, and ill health can usually be attributed in part to genetic factors.

Estimating Spontaneous Mutation Rates

Table 2-6 gives some representative mutation rates estimated in humans. These values are consistent with the values given more than 25 years ago (Pe61, Cr61).

TABLE 2-6. Selected Mutation Rates.


Selected Mutation Rates.

It is well recognized that published mutation rates are probably a biased estimate of all mutation rates, because it is more likely that those loci with higher natural rates will be studied. A simple correction for this bias is to use the harmonic mean of the studied loci.

From the data collected by Vogel and Rathenberg (Vo75) and Childs (Ch81) (Table 2-6), the harmonic means for dominant and X chromosome-linked traits are both about 8 × 10–6 if the Von Hippel-Lindau syndrome is omitted from the dominant traits, or 3 × 10–6 if the Von Hippel-Lindau syndrome is included. On the other hand, for X chromosome-linked traits from the data of Stevenson and Kerr (Table 2-7), a supposedly far less biased sample, the median is about 0.1 × 10–6 and the mean is about 3 × 10–6. The Morton estimates give harmonic means of 4 × 10 –6 for dominant traits and 3 × 10–6 for X chromosome-linked traits. Cavalli-Sforza and Bodmer (Ca71) plotted the cumulative frequency of published rates against the log mutation rate and found the plot to be approximately linear, suggesting that the log-normal distribution is a good distribution for describing mutation rates. From the fitted line they estimated the median to be 0.16 × 10–6 and the mean to be about 7 × 10–6. All of these estimates are derived from overlapping sets of data.

TABLE 2-7. Mutation Rates for X-Linked Recessives.


Mutation Rates for X-Linked Recessives.

In sum, the spontaneous per-locus mutation rate for dominant and X chromosome-linked traits has a mean of approximately 5 × 10–6 and a median perhaps an order of magnitude lower.

The mutation rate of autosomal recessives is much less certain. Morton (Mo81) has examined this problem in detail. Using the harmonic mean argument, he derives an estimate of 12 × 10–6 clinically detectable mutations/locus/generation. In this regard, Neel (Ne57) commented that ''it is entirely conceivable that the loci thus far selected for study in man are those at which a high proportion of all possible alleles results in readily detectable effects, but at which the per locus mutation rate is fairly representative of the human species." In that case the arithmetic mean of 22 × 10–6 is more appropriate.

The Hiroshima-Nagasaki Data

A pregnancy termination study (Ne56) analyzed some 75,000 births, of which 38,000 had at least one parent who was exposed to radiation. No significant effects on still births, birth weight, congenital abnormalities, infant mortality, childhood mortality, leukemia, or sex ratio were found. A significant distortion of the sex ratio had been reported (Ne53), but the effect subsequently disappeared. In 1960 the pregnancy termination study was augmented with additional children of survivors and controls. A cohort, the F1 mortality sample, was created, consisting of (1) all infants who were liveborn in the two cities between May 1946 and December 1958, one or both of whose parents were within 2,000 meters of the hypocenter, (2) an age-matched and sex-matched group of children with one parent who was more than 2,500 meters from the hypocenter and the other parent who was the same distance from the hypocenter or who was not exposed at all, and (3) an age-matched and sex-matched group of children neither of whose parents were exposed. No statistically significant effects of radiation have been demonstrated to date (Ne74, Sc81, Sc81a, Sa82).

A cytogenetic study of the children of exposed parents was begun in 1968 (Aw75). Ten metaphase preparations are routinely examined from each child. No significant effect has been demonstrated (Aw87).

The investigation of rare electrophoretic variants in children born to proximally and distally exposed parents was begun in 1972 as a pilot study and was begun in earnest in 1976 (Ne80). Each child is examined for rare electrophoretic variants of 28 proteins of the blood plasma and erythrocytes, and since 1979, a subset of the children is further examined for deficiency variants of 10 erythrocytic enzymes. If the variant is not found in either parent and a discrepancy in biological parentage can be excluded, a mutation has been identified. Among the children of proximally exposed parents, the equivalent of 667,404 locus tests have been done, yielding three probable mutations. The corresponding value for the comparison groups is three mutations in 466,881 tests. The point estimate of the mutation rate is higher in the control population, but the difference is not significant (Ne88).

Table 2-8 provides the lower 95% confidence limits of doubling dose estimated for various endpoints in the data from the Japanese atomic-bomb survivors summarized by Schull et al. (Sc81a). Other data from the studies of the atomic-bomb survivors give comparable results (Ne74, Sa82). Prior to calculating the doubling doses from the regression coefficients, negative regression coefficients were set equal to zero. In all cases, following Schull et al. (Sc81), a spontaneous rate of 0.0025 was used in the calculation. Schull et al. stated "…during the interval covered by this study, characterized by an infant and childhood mortality of about 7 percent, we could assume that approximately one in each 200 liveborn infants die before reaching maturity because of mutation (point or chromosomal) in the previous generation…. We still believe that this estimate is valid, but to err on the conservative side we will reduce the figure to one in 400 and apply it not only to the survival data but also to the data on untoward pregnancy outcomes." All lower 95% confidence limits shown are gametic doubling doses, assuming an equal contribution by the mother and father when necessary. The lower 95% confidence limits in Table 2-8 are for chronic radiation (low dose); that is, the acute doubling doses derived directly from the published regression coefficients have all been arbitrarily multiplied by a factor of 3 obtained from mouse data. As emphasized earlier, the factor of 3 is based on acute single doses in mice that are much greater than those experienced in Hiroshima or Nagasaki, and the factor of 3 cannot be applied to the Japanese data with great confidence. Although the Committee believes that the factor of 3 may overestimate the risks, this point is arguable. Conceivably, the true correction factor for the dose rate in humans at the relevant doses could be as small as 1 or as large as 5. Use of the smaller number would bring estimates of human doubling doses more in line with the range of values observed in mice.

TABLE 2-8. Estimated Lower 95% Confidence Limits of Doubling Dose from Chronic Radiation for Malformations, Stillbirths, Neonatal Death, and All Untoward Pregnancy Outcomes—Hiroshima and Nagasaki Data.


Estimated Lower 95% Confidence Limits of Doubling Dose from Chronic Radiation for Malformations, Stillbirths, Neonatal Death, and All Untoward Pregnancy Outcomes—Hiroshima and Nagasaki Data.

Data based on the revised dosimetry system, DS86, were not available to this committee in the detail necessary for doubling dose estimates at the time the report was being prepared. However, while the committee's calculations are based on the old T65DR dosimetry system, reanalysis based on the revised DS86 dosimetry seems to present essentially the same results (Ot87). The various entries in Table 2-8 are not independent, because they are derived from different subsets of the data for which different methods of analysis, removing different sets of concomitant variables by regression (e.g. inbreeding, parental ages, year of birth), were used. Most of the confidence limits have not been published as such by the investigators who are most familiar with the data (although the estimated limits are based on published regression coefficients), and the lower 95% confidence limits given in Table 2-8 are included here simply to give a general qualitative impression. All estimates were calculated by using regression coefficients, none of which are significantly different from zero, and all estimates depended heavily on estimated gonadal doses, the estimated spontaneous rate (about 5%) and the estimated mutation component (about 5%).

Table 2-8 provides the minimum doubling dose estimates, based on the one-sided 95% confidence intervals, assuming that the spontaneous rate and correction for low dose are known without error. These estimates tend to be more stable than point estimates, because the minimum estimates are more closely bounded below by zero. The values are somewhat scattered, in part because of the small sample size. The medians of the 95% confidence limits for both the adjusted and unadjusted data are about 60 rem, and the mean for the adjusted data is 86 rem. Rather than take the estimates literally and impute to them more accuracy than is warranted, the committee has rounded the estimate to the nearest 100 rem and used this as an approximate lower 95% confidence limit for the human doubling dose. The calculations in Table 2-1 are based on this 100 rem minimum doubling dose. It is noteworthy that the range 50-100 rem includes the majority of the minimum estimates in Table 2-8.

Background Data from Mice and Other Mammals

Over the years the mouse has been the main source of experimental information regarding the genetic effects of radiation in mammals, and previous committees have relied heavily on mouse data to substantiate their estimates. The mouse radiation studies are briefly reviewed here to demonstrate their general consistency and to show that the mouse doubling dose is on the order of 100 rads.

Summarizing the mouse results as a whole, the following qualitative and semiqualitative conclusions are drawn primarily from Russell (Ru60) and subsequent papers:


Radiation-induced mutation rates are higher in mice than in Drosophila melanogaster (this original finding, in a sense, stimulated much of the subsequent work on mice because of its obvious greater relevance to estimating radiation risks in humans).


For specific locus mutations induced in the spermatogonial stage, there is no significant change in mutation rate with time after irradiation (i.e., the risk does not decrease with time after exposure).


Radiation-induced mutation rates differ markedly from locus to locus.


Mutations induced in spermatogonia and postspermatogonial stages differ with respect to absolute frequency and relative frequencies among loci and by radiation quality.


A significant proportion of mutations detected in the specific locus test (see below) have proved to be recessive lethals.


Some of the recessive lethal mutations have had a heterozygote effect dramatic enough to be identified in specific individuals.


Dominant effects on viability are demonstrable in the first-generation progeny of irradiated males.


Chronic irradiation is considerably less effective in inducing mutations in both spermatogonia and oocytes. This dose rate effect appears to be greater in females than in males.


A significant proportion of radiation-induced mutations in the specific locus test are small deletions.


The immature mouse oocyte is highly sensitive to cell killing.

A detailed summary of quantitative results in the mouse and other mammals is provided in Tables 2-9 and 2-10. Standard errors are not given because they tend to reflect experimental factors more than they do the true level of biological uncertainty. Rates have also been rounded so as not to imply greater precision than that which may actually exist. Although there is a significant amount of recognized genetic and nongenetic variance in the mutation rates, the uncharacterized variance is likely to be greater than that identified and measured under laboratory conditions. The uncertainties in the data base may be troublesome, but the existence of significant genetic and nongenetic variance is an intrinsic property of mammalian populations.

TABLE 2-9. Estimated Spontaneous Mutation Rates (Primarily Mouse).


Estimated Spontaneous Mutation Rates (Primarily Mouse).

TABLE 2-10. Estimated Induced Mutation Rates per Rad (Primaril Mouse).

TABLE 2-10

Estimated Induced Mutation Rates per Rad (Primaril Mouse).

Table 2-9 summarizes estimates of spontaneous mutation rates for various endpoints, and Table 2-10 summarizes the estimated induced mutation rates per rad for the same endpoints for high and low dose rates of low-LET radiation exposure and for fission neutrons. Comparing the values for low and high dose rates in Table 2-10 for the endpoint recessive visible mutations (specific locus tests), the conversion factor for acute to chronic radiation is 22/7, or very nearly 3. This is the factor often used previously to convert acute doses to chronic doses in humans. It was argued earlier that application of any such conversion factor from mice to humans might warrant some skepticism, notwithstanding the fact that mice are the only mammal in which relevant data exist. Table 2-10 shows, however, that a conversion factor of 5-10 in mice could be defended just as easily. The evidence cited below suggests that the conversion factor may differ according to the particular endpoint. In any event, if the highest conversion factors are applied to the data from the Japanese atomic-bomb survivors, they imply a human doubling dose of greater than 1,000 rem. This value might be taken as a possible upper limit of the human doubling dose, and risk values based on it can be obtained from Table 2-1 by dividing the tabulated values by 10.

Table 2-11 provides estimated doubling doses for chronic radiation exposure primarily in mice. Values in parentheses are based on high dose rates and have been converted to chronic dose rates by using the factor range 5-10. The medians for all endpoints are summarized at the bottom of Table 2-11. The direct estimates strongly suggest a doubling dose of about 100 rads. The indirect and combined estimates also support this value, but are slightly higher, possibly because the conversion factor 5-10 is somewhat too high. Overall, considering the uncertainties in the value of the conversion factor, the data are in excellent agreement with the proposed chronic doubling dose of 100 rad in mice.

TABLE 2-11. Estimated Doubling Doses for Chronic Radiation Exposure (Primarily Mouse).

TABLE 2-11

Estimated Doubling Doses for Chronic Radiation Exposure (Primarily Mouse).

Taking the values in Table 2-11 at face value for the endpoint of congenital malformations, and making no assumptions about the mutational component of this category of traits, the doubling dose for exposed males is at the high end of the range. This endpoint is, arguably, the most closely analogous to the kinds of endpoints in the study of Japanese atomic-bomb survivors, and it is again consistent with the view that the doubling dose obtained from the study of humans in Japan may well be greater than the median of all studies of mice.

The studies on which the data in Tables 2-9 to 2-11 are based are summarized briefly in the following discussion.

The Mouse and Other Laboratory Mammals: A Summary of Present Knowledge

The BEIR V Committee decided to include a brief summary of the present knowledge of the genetic effects of ionizing radiation in laboratory mammals. Such a summary was not included in previous BEIR reports (NRC72, NRC80), although many critical issues were discussed in a series of notes or appendices to the chapters on genetic effects. Prior committees deferred to the excellent detailed reviews of radiation genetics published by the United Nations (UN72, UN77), and the present committee continues that tradition to include the most recent documents (UN82, UN86). The thorough reviews of mutation induction in mice by Searle (Se74) and by Selby (Se81) are also recommended as excellent sources of information. We believe, however, that present and future users of the BEIR committee reports could benefit from a concise summary that identifies the scope and limitations of our understanding.

The information is presented under several general headings of genetic endpoints and under each endpoint includes the information that can contribute either to the projection of radiation-induced genetic risks to humans or, if not directly appropriate for such use, to a better appreciation of the range of information available from studies with experimental animals.

Dominant Mutations

By definition, mutations in this category are detected in the immediate F1 progeny of the irradiated generation. Tests for heritability are straightforward, unless the method of detection requires sacrificing the animals, as in the case of mutations affecting the skeletal system, in which the animals under scrutiny must be bred prior to final evaluation to prevent the loss of any potential new mutations. Information in this general category falls into three subclasses: mutations causing (1) skeletal abnormalities, (2) abnormalities of the lens, and (3) all other dominant mutations. All data have been obtained from the study of mice.

Skeletal Abnormalities

In the original studies by Ehling (Eh65, Eh66), the mutation rate for single doses of x rays was estimated to be about 1 × 10–5/gamete/R for spermatogonia and about 3 × 10–5/gamete/R for the postspermatogonial cell stages. Both values were corrected for control occurrences.

A major study by Selby and Selby (Se77) gave a spermatogonial rate of 2.3 × 10–5/gamete/R of 137Cs gamma rays. The exposure involved a 100 R and a 500 R exposure separated by 24 hours. This type of fractionation procedure is often used in mouse genetics to augment the yield of mutations per unit dose while avoiding excessive cell killing (Ru62). These data were used in the BEIR III report as an integral part of the risk analysis for dominant disabilities. However, the mutation rate was adjusted for both dose rate and dose fractionation factors for that application.

Abnormalities of the Lens (Cataracts)

All available data are from studies by Ehling and colleagues (Eh85) and Graw et al. (Gr86b). For x-and gamma-irradiated spermatogonia, the mutation rate ranges between about 3 × 10–7 and 13 × 10–7/gamete/R. Both single and split doses (24-hour interval) were used, but no consistent variation related to exposure factors was seen. Limited information on postspermatogonial stages indicates a rate per gamete that is two-to fivefold greater than that for spermatogonia.

All Other Dominant Mutations

This is a heterogeneous class of mutations that includes, but is not limited to, changes in growth rate, coat color, limb and tail structure, hair texture, eye and ear size, congenital malformation incidence, and histo-compatibility. For most traits, detection can be done nondestructively by consistent evaluation of the F1 progeny. The study of malformations requires prenatal observation, and the data in this subclass, although limited, will be presented later in this chapter in the section on complex traits.

Efforts to determine a mutation rate for histocompatibility loci have been essentially negative. No significant increase in mutation frequency was noted for either x-irradiated sperm or spermatogonia (Du81, Ko76). The failure to detect significant increases suggests that these loci are either much less mutable or more liable to lethal mutation than expected on the basis of known mutation rates for specific recessive visible mutations in mice.

The balance of the quantitative data on dominant visible mutations is from the Medical Research Council Radiobiology Unit, Harwell, United Kingdom (Lu71, Se74). The spontaneous rate is about 8 × 10 –6/gamete/generation, and the induced rate for single doses of x rays to spermatogonia is about 5 × 10–7/gamete/R. A study using protracted 60Co gamma rays compared with fission neutrons (mean energy of about 0.7 MeV) gave spermatogonial mutation rates of 1.3 × 10–7/gamete/rad for gamma rays and 25.5 × 10–7/gamete/rad for neutrons resulting in an RBE value of 20 (Ba66). Dominant visible mutations were also scored in a study on x-irradiated females exposed to single doses of 200, 400, and 600 rad (Ly79). The induced rates were between 5 × 10–7 and 10 × 10–7/gamete/rad.

These data on dominant mutations have usually been considered to be minimum estimates because of incomplete ascertainment of all classes of mutation events. Other studies reported by Searle and Beechey (Se85, Se86) with a different marker stock suggests that the rate may be as high as about 3 × 10–6/gamete/rad of x rays (1,000 rad given in two 500-rad doses with a 24-hour interval), which implies that the value of 5 × 10–7 may be low by a factor of 3-6.

In summary, data on dominant visible mutations have yielded rates that vary by a factor of 20 for comparable types of exposure, but this range is no more than that observed for other genetic endpoints. Although the data are limited in the range of doses and exposure factors used, they demonstrate dose rate and LET factors or ratios that agree closely with those observed in more extensive studies with other endpoints.

Dominant Lethal Mutations

Data for this category of genetic events have been largely ignored in the analysis of genetic risks, because dominant lethal mutation rates have been used principally to measure damage induced in the meiotic and postmeiotic cell stages. Damage in these stages has been considered to be only transient and of limited concern for human populations. In addition, most of the mutations would be eliminated early in gestation, and many would be eliminated prior to implantation (see Note 14 in NRC80). This class of injury now requires some consideration because (1) the endpoint has been used for broad comparisons of dose rate and LET factors, (2) the category has been broadened to include the results of extensive retrospective analyses of data on litter size changes and preweaning mortality from earlier genetic studies (UN86), and (3) the concern about continuous low levels of environmental or occupational exposure requires that consideration be given to damage that is being induced continuously in the meiotic and postmeiotic cell stages.

Dominant lethal mutations, generally called simply dominant lethals, are scored among the first-generation progeny of an irradiated generation, essentially by their absence. Compared with appropriate controls, a deficiency in the number of offspring is measured at any time from conception to weaning age, which is at about 21 days of age in mice, the species for which most data have been obtained. Lethal mutations that express themselves between conception and implantation in the uterine wall (preimplant losses) are not as reliable a measure as those that occur between implantation and birth (postimplant losses) or as those that are manifested as postnatal reductions in litter size at any time from birth to weaning.

Dominant lethals are attributed to the induction of one or more major chromosome or chromatid aberrations that interfere with the complex sequence of cell and tissue differentiations that occur during organogenesis and fetal growth. The chromosome imbalances that typify these lethal mutations are usually selectively eliminated during mitotic cell division, so they do not persist in the stem cell population. Rates of induction are sensitive to cell stage in gametogenesis, with the highest rates occurring in the postgonial stages.

Postgonial Stages

There is a remarkable uniformity among the results of many individual studies that used high-dose-rate, low-LET irradiation of male mice that were then bred for the first 4 to 5 weeks after exposure. A rate of about 10 × 10–4/gamete/rad has generally been observed (Eh71, Sc71, Gr79, Gr84, Ki84). Although control values vary among different genetic strains of mice, these values range only between about 0.025 and 0.1/gamete.

Dose rate has only a small influence on the mutation rate in the postgonial stages, and the small amount of repair implied by this dose rate effect is probably due to induced unscheduled DNA synthesis. The mutation rate drops to about 5 × 10–4/gamete/rad at low dose rates. For the high-LET radiations, such as fission neutrons and 5-MeV alpha particles, the RBE value is about 5 (Gr79, NCRP87). Protracted exposure to neutrons appears to act in the opposite manner seen for low-LET radiation exposure and the mutation rate for lethal mutations increases at low total doses (less than 10 rads of neutrons) by about 50%, so the neutron/gamma RBE value increases to about 15.

Data for irradiated females are sparse, but a study by Kirk and Lyon (Ki82) for the period from 1 to 28 days postirradiation indicates that the rate varies with time but averages about the same as that seen for the male, about 10 × 10–4/gamete/rad. Data from the same institution involving guinea pigs, rabbits, and golden hamsters suggest that mice may have a higher rate than other species for lethal mutations induced in males, but a similar rate exists for all species when compared with dominant lethals induced in irradiated females (Ly70, Co75).

Age does not appear to influence the induced mutation rate for dominant lethals, although the control rate may increase. It should be noted that when male mice are periodically scored for induction rate after continuous or repeated exposure to gamma rays or neutrons, a steady state value for the postgonial cell stages develops that is essentially equal to the sum of values for all injuries accumulated during the 5-week postgonial period (Gr86a).

Stem Cell (Gonial) Stage

In a strict genetic sense, most dominant lethals cannot persist in the stem cell population. Although they are induced in these cells, most are quickly eliminated at cell division because of lethal chromosome imbalance. Balanced chromosome aberrations do persist, however, and are transmitted through the series of mitotic divisions occurring in the proliferative phase of gametogenesis. Balanced translocations induced in the stem cell segregate chromosomally unbalanced gametes during the meiotic divisions. These unbalanced gametes behave like the dominant lethals induced directly in postgonial stages and their induction rates reflect the induction rates for the translocations themselves. For example, a translocation-bearing spermatocyte will produce the expected four spermatids, but on average, two spermatids will carry unbalanced chromosome sets and act as lethal mutations. One spermatid will be balanced and viable (the transmission of the original aberration), and the other will be chromosomally normal and viable.

Lüning and Searle (Lu71) summarized the available data to about 1970, in which the average rate for dominant lethals induced in spermatogonia by high-dose-rate, low-LET radiation was about 9 × 10–5/gamete/R. More recent data give values between 7 × 10–5 and 10 × 10–5/rad for both x rays and gamma rays. A significant dose-rate effect has been seen for gamma radiation; the rate drops to about 3 × 10–5/rad for weekly exposures to 1.4 × 10–5/rad for continuous, low-intensity gamma radiation exposure (Gr79, Gr83). No dose-rate effect was seen for single versus weekly neutron exposures in these studies. The fission neutron-induced rate is about 40 × 10–5/gamete/rad, which gives RBE values of 4 to 5 for single doses, 10 to 15 for weekly exposures, and 25 or greater for continuous irradiation.

The 1986 UNSCEAR report (UN86) summarized data originally taken in the form of litter size reductions at birth, at weaning, or both, which is essentially a neonatal to postnatal measure of dominant lethals induced in spermatogonia. The data are from Selby and Russell (Se85), Lüning (Lu72), and Searle and Papworth (UN86). The data from Searle were from a study published in 1966 by Batchelor et al. (Ba66), and the analysis by Selby used data collected by the Russell's at the Oak Ridge National Laboratory (ORNL), Oak Ridge, Tenn., in the 1950s. The UNSCEAR analysis made several adjustments to the findings to make them consistent with regard to the response to low-dose rate and low-LET radiations. The rates from the three sets of data were 11 × 10–6, 19 × 10–6, and 24 × 10–6/R or equivalent, which is not significantly different from the value of 14 × 10–6 given previously for losses measured in utero. These results were surprisingly similar, and the variation among the values is certainly within the limits of experimental error for the type of measurements involved. These mutation rates predominantly reflect the chromosomally unbalanced gametes segregating from balanced translocations. Higher rates would normally be expected for observations made at weaning compared with those made in utero, but no study has examined this type of lethality longitudinally over the full 6-week period from conception to weaning.

In summary, dominant lethal mutations show consistent rates among different studies. For postgonial stages, it is about 10 × 10–4/gamete/rad for high-dose-rate, low-LET exposure. Low-dose-rate exposure reduces the value by a factor of 2. For spermatogonial stages, the high-dose-rate value is about 1 × 10–4. The dose-rate factor is about 7, and the low-dose-rate value lies between 10 × 10–6 and 25 × 10–6/gamete/rad, depending upon method of ascertainment. RBE values for fission neutrons are between 5 and 15 at a high dose rate and 20 to 40 at a low dose rate. Continuous exposure induces a steady equilibrium rate reflecting the high sensitivity of the postgonial cell stages.

Recessive Autosomal and Sex-Linked Lethal Mutations

Mutation rates in this classical category of genetic injury have been somewhat elusive in mammalian genetics because, until recently (Ro83), no chromosome inversion stocks were available to facilitate the detection and isolation of new mutations. The methods that have been used, for example, the Haldane swept-radius procedure or the outcross-backcross test (Ha56), are not efficient, as they require a series of test generations and close attention to the sampling variance of litter size. The majority of the available data have been reviewed by Lüning and Searle (Lu71) and Searle (Se74).

Recessive Autosomal Lethal Mutations

The reviews noted previously gave an estimated mutation rate for spermatogonia exposed to high-dose-rate x irradiation of about 1 × 10–4/gamete/R. This value has been confirmed by Lüning and Eiche (Lu75). A test with 14.5-MeV neutrons by Lunning et al. (Lu75a) yielded a mutation rate in the same range. More recently, a study by Lüning and Eiche (Lu82) with x-irradiated adult and fetal female mice has produced mutation rate estimates in the range of 0.8 × 10–4 to 1.3 × 10–4/gamete/rad (maturing oocytes) and no indication of a significant difference in mutagenic sensitivity for oogonia. A multigeneration study with x-irradiated rats (Ta69) has given mutation rates for recessive lethals varying from 1 × 10–4 to 1.6 × 10–4/gamete/R, depending on the age at which the litter size was measured. The lowest value was at birth and the highest was at 69 days of age.

There are limited data from studies using an inversion of a major portion of chromosome 1 of mice (Ro83). Two lethal mutations were detected in 364 gametes tested after exposure to 892 R of x rays. These data were from exposed postgonial cells. The rate, 6.2 × 10 –6/gamete/R, relates to about 3.5% of the genome. Assuming this portion is representative of the whole genome, the rate multiplies up to 1.8 × 10–4/gamete/R, which is a reasonable expectation for postgonial cells compared to data available from spermatogonia.

Sex-Linked Lethal and/or Detrimental Mutations

Efforts by Auerbach et al. (Au62), Schröder (Sc71), and Grahn et al. (Gr72) to determine the mutation rate for sex-linked lethal and/or detrimental mutations were uniformly unsuccessful, although Grahn et al. generated an unproven estimate of 8.5 × 10–5/X chromosome/R. Recently, the discovery and use of a large inversion of the X chromosome has succeeded in providing a proven estimate (Ly82). The inversion scores 85% of the X chromosome. An x ray dose of 500 rad + 500 rad (24 hour interval) to the spermatogonia gave a mutation rate of 3.7 × 10–6/X chromosome/rad.

In summary, the recessive autosomal lethal mutation rate is about 1 × 10–4 to 2 × 10–4/gamete/rad, for both sexes. There are no data on the influence of dose rate or the effects of fission neutrons. The sex-linked lethal mutation rate is probably no more than 4 × 10–6/X-chromosome/rad and may be one-half this value if one allows for the possible augmenting effect of the split-dose exposure regime used to obtain the only available estimate.

Recessive Visible Mutations

The data in this category are all from studies in which the specific locus test system in mice was used. Experiments in which this test procedure was used have been performed for about 40 years in several major laboratories. The data base is extensive. In a few instances, the data are complex and even controversial, but for the most part, data from this test are both uncomplicated and quantitative. They have, as a result, provided the principal basis for understanding the effects of most physical and biological variables that influence the mutation rate. The previous BEIR Committee reports (NRC72, NRC80) and all UNSCEAR reports (UN58, UN62, UN66, UN72, UN77, UN82, UN86) have relied heavily on the data obtained from the results of this test. Due to the scope of the data and the availability of many detailed reviews and summaries, this overview only presents the principal mutation rates that define the importance of the major influencing variables. The variables are as follows:

Physical variables:


Total dose


Dose rate


Fractionation pattern Size of dose increment Interval between doses



Biological variables:


Cell stage




Age at exposure Age at breeding test (time since last exposure)


Test stock or locus at risk

The test procedure uses a genetic marker stock that carries, in the homozygous state, a number of easily identifiable recessive mutations with known viabilities and locations in the genome. An irradiated wild-type male or female is crossed to the multiple recessive test stock and a new mutation at any of the marker loci can be detected in the F1 progeny. Subsequently, a series of test matings can be performed to ensure allelism, to test for viability, and to establish the new mutant stock for any additional detailed genetic analysis. Principally, however, the detection of a mutation in the F1 progeny can be considered unequivocal evidence for the occurrence of a new mutation.

Several tester stocks have been developed, but nearly all data are from one stock developed at ORNL by Russell (Ru51). This stock consists of seven recessive visible mutants: six coat color mutants and one structural (ears) mutant. A second tester stock was developed at Harwell, United Kingdom (Ly66), and was used only briefly. It carries six recessive mutants, one common to the ORNL line (a color mutant), four other coat color mutants, and one structural (skeletal) mutant. A third stock has been developed in the Soviet Union (Ma76) from Ehling (Eh78), but it apparently has not been used in radiation studies. Recently, a fourth stock carrying three pairs of closely linked mutants has been developed at Harwell by Searle and colleagues (Se85a, Se86). Where data are available, the differences among the stocks would seem to devolve to differences among the loci themselves, not to the different genetic backgrounds (Fa87).

The intrinsic value of the specific locus test system is in the clarity of the endpoint and its utility for testing concomitant variables quantitatively. Nevertheless, the reader should be cautioned to appreciate that data principally based on only seven loci should not be presumed to represent the full genome of the mouse, let alone the genomes of other mammals, including that of humans.

As noted, the data from the specific locus test are too extensive to be presented in detail. This overview is, therefore, limited to the principal estimates that define the influence of the major physical and biological variables. The interested reader can find detailed information from the UNSCEAR reports, collectively, from the reviews by Green and Roderick (Gr66), Searle (Se74), and Selby (Se81), and from more topical summaries by Russell et al. (Ru58), Russell (Ru65, Ru77), Russell and Kelly (Ru82a,b), Ehling and Favor (Eh84), Batchelor et al. (Ba66), and Lyon et al. (Ly72a).

Studies with Males

The spontaneous mutation rate for the seven-locus tester stock is between 8 × 10–6 and 8.5 × 10–6/locus on the basis of pooled data from the three principal laboratories (ORNL, Harwell, and Neuherberg) that involve observations on over 800,000 control progeny. The best estimate presently available is 8.1 ± 1.2 × 10–6/locus (Ru82b). This value is not cell-stage specific and can be used for comparisons with data from any study. It seems likely, on the basis of the characteristics of the spontaneous events, that they have occurred predominantly in the stem cells.

The induced rate for spermatogonia exposed to single doses of low-LET radiation delivered at high dose rates is generally considered one of the baseline values. The present best estimate is 21.9 ± 1.9 × 10–8/locus/rad (Ru82b) at single doses of x rays between 300 and 700 rads. Above this dose level, the mutation rate drops sharply to less than 10 × 10–8/locus/rad, a phenomenon attributed to the overriding effect of cell killing.

The data for postgonial cell stages are not as complete, but the rate per locus per rad is two-to threefold greater than for spermatogonia and reaches a level of about 65 × 10–8 to 70 × 10 –8 among progeny conceived during the first 4 weeks after exposure to 300 rad of x rays (data from Russell in Se78).

The other important baseline value for spermatogonia is for the response to low-dose-rate, low-LET radiations (in this instance 137Cs and 60Co gamma rays). The rate is 7.3 ± 0.8 × 10–8/locus/rad for total doses between 35 and 900 rad (Ru82a). The dose-rate factor is 3.0 ± 0.4. This value of 3 is low in comparison with the effect for specific locus mutations in oocytes and for translocations induced in both sexes. (See discussions earlier in this chapter of the application of this factor to the human data obtained from survivors of the atomic bombings of Hiroshima and Nagasaki.) Russell et al. (Ru58) noted that there is little or no dose-rate effect for cells exposed at postgonial stages.

The rate for fission neutron doses below 100 rads is between 100 and 150 × 10–8/locus/rad (Ru65, Ba66, Se67). Dose rate has no influence, and the derived rate depends upon the dose-response model used. Above 100 rad the response to a single neutron dose drops significantly below that which is expected, a finding comparable to that seen with high doses (about 1,000 rad) of x rays. Neutron dose protraction causes the mutation rate at these higher doses to rise above the single-dose value to a level consistent with a linear projection from the lower doses. This is the so-called reversed dose-rate effect reported by Batchelor et al. (Ba67), a phenomenon sometimes seen in other neutron radiobiology studies. Unfortunately, there are no data available for doses below about 50 rad, so the mutation rate at low neutron doses (less than 10 rad) is unknown. It could be as high as about 200 × 10–8, as judged from the responses seen for other genetic and somatic endpoints. RBE values are 5 to 7 at high dose rates and up to 20 or more at low dose rates.

The response to an internally deposited alpha-emitter, 239Pu, is intermediate to those of gamma rays and neutrons, with a rate of 18 × 10–8 at low dose rates and an RBE value of 2 to 3 [data from Russell in Report 89 from the National Council on Radiation Protection and Measurements (NCRP87)].

Dose fractionation studies have presented an interesting phenomenon in terms of the mutation rates induced in spermatogonia. Russell (Ru62) reported a highly significant augmentation of the mutation rate when 1,000 R was delivered in two 500 R increments separated by a 24-hour interval. The observed rate was about double the rate expected on the basis of linear extrapolation from the responses at 300 R and 600 R. A shorter interval or a greater number of fractions did not duplicate this finding, while a 15-week interval produced an additive response to the two increments. Russell also demonstrated that the augmentation phenomenon occurred with a total dose of 600 R given in 100-R and 500-R fractions 24 hours apart (Ru64). Cattanach and Moseley (Ca74) have extended the information to include intervals of 4 and 7 days and found the two 500-R doses to be roughly additive. In further studies, Cattanach and Jones (Ca85) tested fractions of 100 R + 900 R and found the results to be subadditive, so that dose size and dose interval are both factors in this type of response. The augmentation effect was also reported by Lyon and Morris (Ly69) for both specific locus and dominant visible mutations induced in the six-locus Harwell tester stock. It has been assumed that this augmentation effect is a general one and would be seen with all other genetic endpoints. It is not seen for the induction of translocations however (Ca74), so the assumption of universality may not be appropriate.

Studies with Female Mice

Data from female mice are not as extensive as those for male mice and are limited by the fact that most data are from mature and maturing oocytes. The adult female may be fertile only for about 6 weeks following a single exposure of 100 rad or more because of the killing of oocytes at their resting stage in the process of oogenesis, the dictyate stage. For those circumstances in which fertility does continue, no significant increase in the mutation rate has been seen for conceptions occurring 7 weeks or later after irradiation (Ru77, Ly79). This observation incorporates data from many experiments that have provided a total of 325,000 offspring and only 4 observed mutants. This approximates the spontaneous mutation rate.

The procedure for estimating the induced mutation rate for maturing oocytes has involved some controversy, which was discussed in Note 9, Chapter IV of BEIR III (NRC80) and by UNSCEAR (UN77, UN82). In simple terms, the controversy arose from differences in the interpretation applied to the mutation rate data that would account for (1) the observed nonlinear response to single doses and (2) a vanishingly small mutation response to low-dose-rate exposures. The alternative interpretations concerned the emphasis placed upon a more classical cytogenetic model for the mutational event (Ab76) compared with that on the existence of complex repair mechanisms (Ru58, Ly79). At present, the issue is moot, because, as Denniston (De82) noted in a review of genetic risk estimates, curve-fitting cannot resolve the controversy, given the lack of adequate data.

The spontaneous mutation rate estimated in the female has been an integral part of the noted controversy, because, of the eight spontaneous mutations reported by Russell over a series of studies (Ru77), two occurred as single events and six occurred in one cluster. Lyon et al. (Ly79) concur with Russell (Ru77) in the position that the cluster should be treated as one event, for a total of three events, giving a spontaneous rate of 2.1 × 10–6/locus. Upper and lower estimates would be 1.4 × 10–6 and 5.6 × 10–6 respectively, depending upon the assumptions that either three or eight events would be used. The assumption of two events was included in the analysis presented by Lyon (Ly79), but this assumption is not favored by either Russell or Lyon.

The response of mature oocytes to single doses of x rays delivered at 50 R/minute or greater is distinctly non-linear, concave upward, over the dose range of 50 R to 600 R. For progeny conceived during the first week after exposure, a linear-quadratic equation gives a linear term of 39 × 10–8/locus/rad (Ly79). Data from the first full 6 weeks, while less complete than those for the first week, indicate that the nonlinear response persists and the mutation rate (linear term) remains high, with the possibility it can approach a value of 50 × 10–8/locus/rad (Se74, NRC80). Protracted exposures delivered either as continuous low-dose-rate exposures or multiple-increment fractionated exposures give a linear response over the dose range of 200 R to 600 R. The mutation rate is between 1.1 × 10–8 and 3.0 × 10–8/locus/rad, depending on certain assumptions concerning the spontaneous rate and the use of data from older females (Ru77). This is clearly below the value for males by a factor of 2 or more, while the high-dose-rate value is greater than the value for males by nearly a factor of 2. The dose-rate factor is therefore at least 10 for females, compared with only 3 for males.

The limited data for fission neutrons give a mutation rate of about 145 × 10–8/locus/rad, as derived from the data of Russell (Ru72) for single doses of 30, 60 and 120 rad. Assuming no dose-rate effect for neutrons, the RBE value would be 5 at high dose rates of low-LET radiation and 50 or greater at low dose rates.

Other Variables


Age may influence the response in two ways: from variation in age at exposure and age at testing, which may also be confounded with elapsed age since the last exposure. For young adult male mice exposed for 12 weeks and then mated for the following 18 months, there was no age-related variance in the mutation rate; the rate remained essentially constant (Ba66). In a study reported by Russell and Kelly (Ru82a) four groups of males were each exposed to radiation for 8 weeks. The first group began receiving radiation at 9 weeks of age, and the three subsequent groups began exposure at 90-day intervals. No significant dependence on age was observed. Thus, for adult male mice, age does not appear to influence the mutation rate.

For female mice, the elapsed time since last exposure is critical because of the sensitivity of the dictyotene oocyte to the lethal effects of exposure. The mutation rate in the first week is usually somewhat lower than that in the second through sixth weeks, whereupon the rate drops to zero (Ru77). One set of data reported by Russell (Ru63) suggested that older females (6 to 9 months of age compared with those 2 to 4 months of age) had a significantly higher mutation rate in their second litters but not in their first litters. This seems to have been an isolated observation that has not been confirmed.

Some data are also available on the response of male and female mice exposed during prenatal, neonatal, and juvenile age periods. The data are from a mixture of experiments and conditions. Searle and Phillips (Se71) exposed mice to 108 rad of fission neutrons over a 1 week period prior to day 12 of gestation and then test-mated the animals as young adults. Mutation rates were 42 × 10–8/locus/rad for the males and 58 × 10–8/locus/rad for the females. Both values are only about one-third those found with irradiated adults.

At 17.5 days of fetal life, a single dose of 200 R produced mutation rates of 21 × 10–8/locus/R for males and 7 × 10–8/locus/R for females (Ca60). Exposure of newborn mice to single doses of x rays induced mutation rates of 13.7 × 10–8/locus/rad for males (Se73) and about 10 × 10–8/locus/rad for females (Se80). Selby (Se73a) exposed male mice at the ages of 2, 4, 6, 8, 10, 14, 21, 28, and 35 days and the mutation rates tended to dichotomize into the two periods of 2-6 days compared to 8-35 days. The rate was 17.5 × 10–8/locus/rad at 2-6 days and 30.6 × 10–8/locus/rad at 8-35 days. As the average rate for single exposures is about 22 × 10–8/locus/rad, the Committee considers that none of the values from birth through 5 weeks of age differed significantly from those for adults. However, the newborn males do seem to have a lower rate. In general, prenatal, newborn, and juvenile animals of both sexes appear to be less sensitive than their adult counterparts.

Tester Stock or Locus at Risk

The two Harwell stocks have produced mutation rates about one-third the value seen with the ORNL stock (Ly66, Ly69, Se85a, Se86). This variation probably reflects differences in the loci at risk in the three stocks rather than an effect of the background genotype. Favor et al. (Fa87) have tested six of the seven loci in the ORNL stock in two unrelated inbred backgrounds, the BALB/c and DBA/2 mouse strains. Mutation rates were identical with those found in the hybrid tester stock.

The observed frequency of mutations among the seven loci varies by at least 30-fold, and 50% or more of the induced mutations have occurred at only two loci, the brown (b) and piebald (s) loci. Less than 20% were at the agouti (a), dilute (d), and short-ear (se) loci, while the remaining 25% occurred at the albino (c) and pink-eye (p) loci. Only the ORNL stock has tested the b and s loci, and only the a, d, and se loci have been common loci for the several stocks. It would be expected therefore that the overall mutation rates for the different stocks should differ by at least a factor of 2.

Chromosome Aberrations

In 1964 a new procedure became available for making cytological preparations of mammalian spermatocytes in meiosis that permitted reliable screening for the occurrence of chromosome and chromatid aberrations (Ev64). The technique soon became widely used, and much quantitative data have since been collected on the cytogenetic effects of radiation exposure of the male germ line and, to a lesser extent, the female germ line. Most of the quantitatively useful data involve the induction of balanced or symmetrical chromosome translocations. These translocations are of concern because they produce an increase in prenatal losses through the segregation of chromosomally unbalanced germ cells during gametogenesis. They also perpetuate themselves by segregating chromosomally balanced but translocation-bearing gametes (the heritable translocation).

The kinetics of translocation induction and the genetic consequences of their occurrence were discussed in Notes 3 and 14, Chapter IV, BEIR III (NRC80). A principal concern was the risk that a small number of carriers of an unbalanced chromosome set segregating from a balanced translocation heterozygote would survive to birth and thus add to the frequency of severe physical or mental abnormalities among the offspring of irradiated parents. There was no discussion in the BEIR III report of the parameters and variables influencing the induction of the original translocations. Because the induction rates for translocations depend on many important variables, such as LET and other exposure parameters, and data are now also available from a number of mammalian species other than mice, the major aspects of translocation induction rates will be summarized here. It is not possible to provide a detailed summary because the data are too diverse and because many investigations have used the translocation endpoint for the study of mechanisms of damage and repair, which goes beyond our immediate interests. The following overview identifies only the major variables and the magnitude of their influence on the rate of translocation induction. Detailed reviews of the original studies can be found in UNSCEAR reports (UN72, UN77, UN82, UN86), and in Leonard (Le71), Adler (Ad82), and van Buul (Bu83). Much of the information comes from a series of studies from Harwell (Cattanach, Lyon, Searle), ORNL (Brewen, Preston), Mol, Belgium (Leonard and colleagues), and the Soviet Union (Pomerantseva and colleagues).

Male Mice

In many respects, the variables that influence translocation induction and their effects are similar to those that influence the specific locus mutation rate. Similar to the specific locus test data, a baseline value is seen for the rate of translocations induced in spermatogonia by exposure to single-dose, high-dose-rate, low-LET radiations. Although there is some variation among different mouse strains and hybrids, the average induced linear rate is 1 × 10–4 to 3 × 10–4 cells with translocations/rad over a dose range up to about 300 rad. The spontaneous rate also varies among different mouse strains and hybrids, but generally ranges between 2 × 10–4 and 2 × 10–3 cells with translocations. Under ideal conditions for collection and scoring, the response to x rays or gamma rays is nonlinear and shows a classical linear-quadratic dose-response relationship up to about 600 rads (Pr73). At higher doses, the response levels off and later drops. This is attributed to cell killing.

After a single exposure, the rate tends to remain unchanged for about 3-6 months, followed by a modest (20-30%) decrease in value (Le70, Al85). The decrease may not always be detected because there may also be a general increase in the spontaneous frequency of aberrations in older animals (Mu74, Pa83).

Several studies have examined the influence of dose rate, and the results have been consistent in demonstrating that there is a steady decline in the basic induction rate per rad as the dose rate decreases from about 100 rad/minute down to about 0.1 rad/minute. The induction rate declines by a factor of 10, down to about 1.5 × 10–5/rad. An absolute minimum rate would probably be about 1 × 10–5/rad (Se76, Br79a). At low dose rates, the response is linear over wide dose ranges (greater than 1,000 rad), and it is this linear regression on dose that steadily declines as the dose rate declines. In other words, there does not appear to be a single linear term in a series of linear-quadratic equations.

Several studies with fission neutrons have also provided generally consistent results (Gr84). The response peaks at about 100 rad and then drops sharply when single doses are used. Up to 100 rad, the response may be either linear or nonlinear with a negative dose-squared term. The RBE value for linear terms at low doses is about 5. When neutron doses are protracted or are given in repeated small fractions, the response is either equal to or greater than the response to low single doses (Gr83). The augmentation of response is probably no greater than about 25% at low doses. At doses above 100 rad, there is no decline in response, so the augmentation factor ranges from about 2 at 100 rad to 5 or more at 150 rad. The RBE value for protracted exposures, neutrons versus gamma rays, varies with dose rate in low-LET radiation exposures, but approaches 50 at the lowest dose rates (Gr86a).

Studies with alpha-emitters have not given consistent results. Nevertheless, the response is no greater than that seen with fission neutrons and it may be less (Se76, Gr83). High-energy neutrons are also less effective than fission neutrons.

Dose fractionation has been used extensively to study cell stage sensitivity, cell synchronization and repair, and the interaction of mutagenic and lethal actions (see, for example, Cattanach and colleagues Ca74, Ca76). For the purposes of this report, the findings can be reduced to a few general observations. For split doses with intervals of less than 1 day, variable responses are seen that are usually subadditive. Intervals of 18 to 36 hours yield responses that are generally additive for the two doses. It is important to note that superadditivity or augmentation of injury is not observed with the 24-hour interval as is observed in the specific locus test (Ca74). With intervals of days to weeks, subadditive responses are seen to at least a 3-week interval in some studies and up to 6 weeks in others. Eight-week intervals produce clear additivity of the individual doses, even when exposures are repeated beyond only a single pair of doses (Pr76). With long intervals between doses, the decline in response seen for high single doses does not occur.

When small dose increments (less than 50 rad) are given at daily or weekly intervals, additivity exists, but the rate of response is less than that seen for comparable single doses, and the magnitude of this drop in response depends on the size of the dose increment, the dose interval, and the instantaneous dose rate (Ly70a, Ly70b, Ly72, Ly73; Gr86b, Gr88). As there are no generalized formulations to describe or predict responses to repeated exposures, most analyses are empirical. Lyon has made the suggestion that some resistance to subsequent exposures may even be induced, although such an effect would have to be short-lived (less than 1 week). In any event, the responses to repeated low doses are not greater than the effect of single doses and are not less than the response to low-dose-rate (less than 0.1 rad/minute) continuous or near-continuous exposures.

The cell stage in spermatogenesis is an important factor, although the data are not as clear or complete as they are for spermatogonia (Ad82). Spermatocyte stages, spermatids, and spermatozoa are more sensitive than spermatogonia, with spermatids being the most sensitive, according to data from F1 male progeny derived from irradiated sires. The damage induced in spermatocytes and scored at first metaphase is complex, because rearrangements involve both chromosomes and chromatids. Fragments and deletions are also seen from the exposure of spermatocytes. Results from different studies are not consistent, but generally, the rates of induction for translocations are about two-to fourfold greater than they are for stem cells. Dose-rate factors are limited because meiotic and postmeiotic stages have a limited repair capacity. Fission neutrons may have high RBE values, comparable to those for stem cell exposures, because of their efficiency in producing chromosome or chromatid breaks and fragments. Alpha particles, on the other hand, are not as efficient as neutrons because of their extremely dense ionization track (Gr83).

Female Mice

The data from adult female mice are quite limited in comparison with those from male mice because the information is largely restricted to mature and maturing oocytes that can be screened for only the first 6 weeks after exposure to radiation. However, a recent report by Griffin and Teage (Gr88a) has shown that significant increases in structural and numerical chromosome abnormalities can be induced in immature oocytes by low-dose-rate gamma irradiation to total doses of 1, 2, or 3 Gy.

Data have been obtained by both cytological and breeding tests. Because the oocyte stage is exposed, the responses involve chromatid as well as chromosome aberrations and include interchanges, fragments, and deletions. Direct comparison with males is difficult because the stage at which the oocyte rests during postnatal life, the dictyotene stage, has no exact parallel in spermatogenesis.

Irradiated oocytes express cytogenetic damage in complex ways, and chromosome fragments make up 30-50% of the total damage (Ca77). Fragments would usually be lost in the next cell division, so that deletions or deficiencies would occur in the zygotes formed from the resulting gametes. Induction rates either for total cytogenetic damage or for rearrangements alone are generally similar for cells of both sexes that are in comparable stages. Response kinetics for single doses are nonlinear, with a strong positive quadratic (dose-squared) term evident at doses above 200 rad. For rearrangements, the rate below 200 rad for oocytes is 1 × 10–4 to 2 × 10–4/rad during the first week after exposure (Br79). The rate rises to about 6 × 10–4/rad during the second and third weeks, a response pattern comparable to that seen for specific locus mutations in oocytes.

Also comparable to the specific locus test data is the observation that a significant dose-rate effect exists: reducing the dose rate from about 100 to about 0.04 rad/minute reduces the effectiveness by a factor of 7-10 (Br77). Evidence of repair capability is also seen in the results of split-dose studies with short intervals of 90 minutes to 1 day.

Age is another factor for females. The spontaneous frequency and induced rates of common chromosome aberrations are higher in female mice of about 1 year of age or greater (Se85a).

Although several attempts have been made to detect aberrations induced by neutron irradiation, no clear evidence has been obtained (Se74a). Aberrations are certainly induced in oocytes by neutrons, however, because there is clear evidence of an increase in the frequency of dominant lethal mutations, which are attributable to complex cytogenetic damage.

Mammals Other Than Mice

At least eight mammalian species have been screened for the induction of reciprocal translocations in spermatogonia by single doses of low-LET radiation. At least six different inbred or F1 hybrid strains of mice have been studied, along with three other small laboratory mammals (guinea pigs, rabbits, and hamsters) and several primate species, including rhesus monkeys and humans. The basic dose-response curve is similar for all species. There is an initial linear increase with dose, a plateauing of the response, and then a decrease in the induction rate as cell killing intervenes. The response for mice peaks (for single doses of low-LET radiation) at about 600 rad, but for all other species the maximum response is at 300 rad or less. The initial linear coefficients fall within the limits of about 0.8 × 10–4 and 3.5 × 10–4 translocations/cell/rad for all the species except for the marmoset, Saguinus fuscicollis (Ma85). In this species, the rate of response is estimated to be 7.4 × 10–4/rad (Br75). The limited data available for humans give a rate of about 3.4 × 10–4/rad, which is near the high end of the range (Br75). The highest value for mice, however, is about 2.6 × 10–4/rad, which is not significantly below the human value. The response of the rhesus monkey is 0.86 × 10–4/rad (Bu83, Bu86). However, recent studies with two species of Macaca indicate that the best value for this genus is about 2 × 10–4/rad (Ad88).

As noted earlier, both the BEIR III (NRC80) and UNSCEAR (UN77) committees used a value of 7 × 10–4/rad as a reasonable estimate of the human response to low single doses of x rays or gamma rays. That value was derived from a combination of data from marmosets and humans at doses of 100 rad or less. Only one datum point, at 78 rad, was taken from the human data, while three data points, at 25, 50, and 100 rads, were taken from the marmoset data. A control value of zero events, which was the case for both species, was used to complete the analysis. In this manner the value of 7 × 10–4 was derived from a merged data set from two species, a practice not commonly used in extrapolation modeling. In more recent UNSCEAR reports, more emphasis was placed on direct estimates from studies with rhesus and crab-eating monkeys. These two primate species produced the maximum difference in the rates of response noted previously (0.86 × 10–4 to 7.4 × 10 –4). In addition, UNSCEAR (UN86) also noted some preliminary (unpublished data) dose-rate data with the crab-eating monkey that suggest a factor of 10 reduction in effectiveness for a dose rate of 0.002 rad/minute compared with a dose rate of 25 rad/minute. The factor of 10 is similar to that seen in mice.

Other Aberrations

Irradiation of the meiotic stage in gametogenesis in either sex has demonstrated that chromosome and chromatid breaks, leading to the formation of fragments, deletions, and dicentrics, are readily induced. Rates of induction are not consistent among different studies and are dependent on the exact cell stage in gametogenesis and on the quality of the cytological preparations. On average, following administration of single doses of x rays or gamma rays, the rate of other aberrations would probably be about equal to the rate of rearrangements alone, which was noted above to be at least two-to fourfold greater than the rate of induction of stem cells. While the chromosomally unbalanced gametes that would result from these other aberrations would be eliminated early in fetal life and would not contribute to the transmissible genetic burden, they would increase the frequency of reproductive failures early in gestation.

Finally, chromosome inversions have been induced experimentally in mice and have been characterized in order to be used in other studies. The rate of induction by radiation is not clear, but it probably does not exceed 4 × 10–5/gamete/rad for cells exposed at postmeiotic stages (Ro71).

Complex Traits

Complex traits are difficult to study in the laboratory, and therefore mutation rates or comparable coefficients of induced risk have not been available for use in genetic risk assessments. Nevertheless, the data from animal studies on complex traits carried out over the past decade have achieved some modest success, and the summary of information in this category will be presented in terms of two classes of traits. The first class includes traits that have provided some opportunity for rate analysis, and the second includes traits for which evidence exists of a response to increased mutation pressure, but not of sufficient quality or repeatability to yield a risk coefficient.

Traits with Quantifiable Rates of Induction

Congenital Abnormalities

The frequency of congenital malformations, including small stature or reduced growth rate, in the first-generation progeny of x-irradiated male and female mice has been evaluated in late gestation (No82, Ki82, Ki84, Ru86). Irradiated oocytes yield consistent dose-response data between 100 and 500 rad. The rate is 1 × 10–4 to 2 × 10–4/gamete/rad, but it is slightly lower among progeny conceived in the first postirradiation week. For male mice, the average response to doses between 100 and 500 rad is 4 × 10–5/gamete/rad for the postmeiotic cell stages of sperm and spermatids, while irradiated spermatogonia yielded a value of 2 × 10–5 to 3 × 10–5/gamete/rad (Ki84). Initially, Nomura (No82) did not see a significant response for the exposed male parent, but recent data (No88) suggest a rate of about 6 × 10–5/gamete/rad for spermatogonia. Rutledge et al. (Ru86) observed a yield of 0.5 × 10 –5 to 2 × 10–5/gamete/rad for spermatogonia exposed to 2,000 rads given in four increments of 500 rad each separated by 4-week intervals.

The genetic basis of the observed malformations has not been fully ascertained. Recent studies suggest a major proportion could be due to dominant mutations with a high penetrance that are expressed and lost in the first generation. A small number with a low penetrance may persist into later generations (Ly88, No88). The spectrum of induced abnormalities appears to be typical for mice. About one-half of the traits are classified as dwarfism, which is defined as a body size smaller than 75% of the average of all littermates. Reduced stature has also been seen as a common expression for some specific-locus mutants (piebald, s, for example) and has been successfully evaluated for heritability in recent studies on dominant visible traits (Se86). Nevertheless, the observation that dwarfism constitutes about 50% of all abnormalities urges some caution in the use of these data as a surrogate for human malformations.

Heritable Translocations

Balanced reciprocal translocations are generally transmissible to subsequent generations. Their frequency should theoretically be about one-fourth the induction rate in spermatogonia. In laboratory studies with mice, the value of one-fourth has been achieved only at a dose of 150 rad, the lowest dose used by Generoso et al. (Ge84). Ford et al. (Fo69), in their detailed cytogenetic evaluation of the transmissibility of balanced translocations, concluded that only about one-half of the expected number would be found in the F1 progeny (that is, only one-eighth of the induced frequency rather than one-fourth). It is reasonable to expect the value of one-fourth to pertain to balanced translocations induced at all low doses (less than 50 rad) and low dose rates of low-LET radiations.

The experimentally derived rate induced by single or split doses of x rays delivered at high dose rates was estimated to be 34 × 10 –6/gamete/rad by Lüning and Searle (Lu71) and 39 × 10–6/gamete/rad by Generoso et al. (Ge84). The spontaneous rates were given as 1 × 10–3/gamete by Lüning and Searle and about 1 × 10–4/gamete by Generoso et al. Pomerantseva et al. (Po76) observed a rate of 31 × 10–6/gamete/rad following three exposures to 300 rad of gamma rays with a 4-week interval between exposures, but no control estimate was given. A rate of 15 × 10–6 to 30 × 10–6/gamete/rad has been observed for 5-MeV alpha particles from gonadal burdens of 239Pu (Ge85) suggesting an RBE of 1 or less for this high-LET radiation. There are no substantive data from neutron irradiations, but RBE values should mimic those seen for reciprocal translocation induction and, therefore, should range from about 5 to 45.

Data from irradiated female mice are extremely limited, but the summaries given in UNSCEAR reports of 1977 and 1982 suggest a value no greater than about one-half that seen for males (15 × 10–6/gamete/rad following a single x-ray dose of 300 rad).

Chromosomal Nondisjunction

Relevant human data on the possible induction of nondisjunction by radiation was discussed earlier in this chapter. Studies of mice by Tease (Te82, Te85) are pertinent and quantitative. The preovulatory oocyte of the female mouse is sensitive to the induction of nondisjunction (specifically, hyperhaploidy) at low doses of x rays (10, 25, and 50 rad). The rate is 6 × 10–4 to 7 × 10–4/cell/rad, and there is no influence of age on this rate of induction, although the intercept increases 10-fold in 1-year-old females compared with that in 90-day-old females. Less mature oocytes (those scored between 9.5 and 23.5 days after exposure) were significantly less sensitive and gave linear rates of 5 × 10–5 to 7 × 10–5/rad over the dose range of 100 to 600 rad. The mechanisms of induction are not clear, but the frequencies of all structural aberrations observed in preovulatory oocytes were considered sufficient to account for the majority of nondisjunction events (Te86). Thus, in mice at least, age is not a factor in radiosensitivity. The preovulatory oocyte is sensitive to low doses, but less mature oocytes are quite resistant.

Multilocus Deletions

The specific-locus test has provided useful data on the characteristics or phenotypic manifestations of mutations induced by different radiation qualities and in different germ cell stages. Many of the new mutations apparently involve a deletion of a small portion of the chromosome where the marker gene is located, although some would also appear to be at least the equivalent of an intragenic mutation. Deletions that clearly involve more than the specific locus (multilocus deletions) have recently attracted more attention in genetic risk analysis because they will generally have deleterious effects on the heterozygous carriers and are nearly always lethal when they are homozygous (Ru87, de87). The deleterious manifestations in the heterozygote include reductions in viability, growth rate, and fertility and are seen in a variety of organisms, including, in addition to the mouse, both Drosophila melanogaster and Neurospora species (Se87).

Russell and Rinchik (Ru87) have presented information on the characteristics of about 300 radiation-induced mutations involving the d, se, and c loci in mice. The frequency of intragenic mutations is small; only 15% of the spontaneous mutations and 11% or less of the induced mutations are in this class. Depending on the cell stage and radiation quality, about 25% to 75% of induced mutations are multilocus deletions, while less than 5% are seen in controls. The balance, from about 25 to 80%, are classed as viable null mutations that could be intragenic mutation, single-gene deletions, or multilocus deletions. About 25% of the low-LET mutations induced in spermatogonia (with no apparent dose-rate effect), and about 55% of those induced in postgonial stages and oocytes result from multilocus deletions. With neutrons, the figures are 35% in spermatogonia and over 70% in postgonial cells and oocytes respectively. Thus, a minimum induction rate for this deleterious class of mutations would be one-fourth (1.8 × 10–8/rad) of the rate for spermatogonia exposed to low dose rate, low-LET radiations (7.3 × 10–8/locus/rad). The rate would be about the same for females, allowing for their lower mutation rate, but higher probability of giving rise to the multilocus deletion.

It is likely that this class of detrimental mutations overlaps with mutations that are characterized as producing congenital malformations, dominant visible mutations, and possibly, heritable translocations. These latter categories have induced rates per gamete, the multilocus class is per locus, so there is no simple means of distinguishing them.

Traits Acknowledged to Be Influenced by New Mutations but Lacking Sufficient Data for Risk Analysis

Several studies have endeavored to determine the impact of an increased mutation rate on the general fitness of a population, where fitness incorporates a variety of generally quantitative or continuously distributed traits. The biological components of fitness include all aspects of viability and reproduction, from conception to death. Some specific attributes are evaluated categorically, such as dominant lethal mutations, congenital malformations, and litter size. Many attributes, however, do not lend themselves to the type of rate or risk analysis necessary for the modeling of projected risks to human populations, even though fitness traits are important for the survival and reproduction of a species. Radiation-induced mutations and the concomitant increases in the genetic variance have been used successfully to improve productivity for several economic crops, but in the field of mutation genetics, the quantitative analysis of fitness attributes, in general, has been unsuccessful.

Excellent summaries have been given in a symposium edited by Roderick (Ro64), in a review article by Green (Gr68), and in a tabular review by UNSCEAR (UN72). The issue was also discussed in BEIR III, Note 12 of Chapter IV (NRC80).

The summarized studies dealt with early mortality, growth, reproduction, and long term survival. More recent studies have dealt with growth rate and stature (Se86) (discussed earlier in this chapter in the section on dominant visible mutations) and with the induction of changes in the susceptibility to spontaneous or induced tumors in the mouse (No82, No83).

According to Nomura's data, an increased prevalence of tumors is observed on the basis of a one-time sampling of the F1 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 adenomas, 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 F1 progeny of irradiated parents in an early study by Russell (Ru57). 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 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 Table 2-11. Considering all endpoints together, the direct estimates of doubling dose for low dose rate radiation have a median value of 70-80 rad, indirect estimates based on high-dose rate experiments have a median of 150 rad, and the overall median lies in the range of 100 to 114 rad. These estimates support the view that the doubling dose for low-dose-rate, low-LET radiation in mice is approximately 100 rad for various 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 rad represents an approximate lower 95% confidence limit for the human doubling dose.


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Copyright © 1990 by the National Academy of Sciences.
Bookshelf ID: NBK218706


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