National Academies Press: OpenBook

The Children of Atomic Bomb Survivors: A Genetic Study (1991)

Chapter: The Comparative Radiation Genetics of Humans and Mice

« Previous: The Children of Parents Exposed to Atomic Bombs: Estimates of the Genetic Doubling Dose of Radiation for Humans
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

THE COMPARATIVE RADIATION GENETICS OF HUMANS AND MICE

James V.Neel

Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109–0618

Susan E.Lewis

Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709

KEY WORDS: mutation rates/induced/mouse, mutation rates/induced/man, genetic doubling dose/radiation/man, genetic doubling dose/radiation/mouse, low-level radiation/genetic effect

CONTENTS

   

 INTRODUCTION

 

328

   

 A PRÉCIS OF THE HUMAN DATA ON THE GENETIC EFFECTS OF ACUTE RADIATION

 

328

   

 THE GENERATION OF AN ESTIMATE OF THE DOUBLING DOSE FROM THE HUMAN DATA

 

335

   

 SOME UNUSUAL FEATURES OF THE ESTIMATE OF THE HUMAN DOUBLING DOSE

 

337

   

 A PRÉCIS OF THE MOUSE DATA ON THE GENETIC EFFECTS OF ACUTE RADIATION

 

338

   

 THE GENERATION OF AN ESTIMATE OF THE DOUBLING DOSE FROM THE MOUSE DATA

 

352

   

 SOME UNUSUAL FEATURES OF THE ESTIMATE OF THE MOUSE DOUBLING DOSE

 

355

   

 CONCLUSIONS

 

356

Reproduced, with permission, from the Annual Review of Genetics, vol. 24, © 1990 by Annual Reviews, Inc.

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

INTRODUCTION

The attempt by geneticists to predict the genetic consequences for humans of exposure to ionizing radiation has arguably been one of the most serious social responsibilities they have faced in the past half century. Important for its own sake, this issue also serves as a prototype for the effort to evaluate the ultimate genetic impact on ourselves of other human perturbations of the environment in which our species functions. Recently we (67–69) have been developing the thesis that according to the results of studies on the children of survivors of the atomic bombings, humans may not be as sensitive to the genetic effects of radiation as has been projected by various committees on the basis of data from the most commonly employed paradigm, the laboratory mouse (cf 12, 104, 105). In this review we attempt as detailed a comparison as space permits of the findings on humans and mice, presenting the data in a fashion that will enable those who at certain critical points in the argument wish to make other assumptions, to do so. We argue that a reconsideration that includes all the data now available on mice brings the estimate of the doubling dose for mice into satisfactory agreement with the higher estimate based on humans.

Since the concept of a doubling dose is critical in these discussions, a clear definition is needed at the outset. The genetic doubling dose of radiation is the amount of acute or chronic radiation that will produce the same mutational impact on a population as occurs spontaneously each generation. To be societally relevant, that estimate is best expressed in terms of morbidity and mortality. For both spontaneous and induced mutation, the reference is customarily first generation effects. This definition in principle encompasses the impact of the gamut of all possible alterations in DNA, from single nucleotide substitutions and very small insertions and deletions to gain or loss of entire chromosomes. The definition is as simple as the concept is useful. Expressing genetic damage as a doubling dose provides a convenient societal frame of reference.

Unfortunately, for neither mice nor humans is the impact of spontaneous mutation each generation as yet satisfactorily defined. Thus, in the calculation of a doubling dose, the errors inherent in estimating the magnitude of a radiation effect may be further compounded by imprecision in the definition of baseline values. We present radiation in the units employed by the investigator, but for our own studies and analyses present the results in gray (1 Gy=100 rad) and sieverts (1 Sv=100 rem). In the experimental settings reviewed herein, one r may be equated to one rad (rem).

A PRÉCIS OF THE HUMAN DATA ON THE GENETIC EFFECTS OF ACUTE RADIATION

This treatment of the human data is confined to the information accumulated in Hiroshima and Nagasaki over the past 40 years, because of their high

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

information content compared to other sets of human data, the relative accuracy of radiation-exposure estimates, and a study design that provides essentially nonoverlapping indicators of radiation effects. The Genetic Program that evolved in Japan has been described in detail on several occasions (4, 39, 6467, 93), Briefly, in the immediate postwar period in Japan, the economic stringencies were such that a rationing program initiated during the war years to benefit pregnant women was continued. This involved registration of the fact of pregnancy at the completion of the fifth lunar month of gestation. By incorporating the registrants into a genetic study, a prospective investigation of pregnancy outcome in Hiroshima and Nagasaki was initiated in February, 1948, that included reference to sex ratio, congenital defect, viability at birth, birth weight, and survival of child during the neonatal period. This more clinical program, which included a physical examination of all newborn infants by a physician, was terminated in February, 1954, but the collection of data on the sex ratio and survival of live-born infants continued, with ascertainment of additional births now through city records. In addition, from the birth registrations in these two cities, the sample for the consideration of these latter two indicators was extended backward in time, to include births between May, 1946, and January, 1948. During the clinical program in Hiroshima, some 62% of all infants who were stillborn or died in the first six days of life were subjected to autopsy. A subset of some 26% of the infants born during this period was reexamined at approximately 9 months of age.

Relatively few survivors beyond 2000 meters from the hypocenter were exposed to radiation from the bombs; the mortality within the 2000 meter zone was high. Accordingly, the original sample of 76,617 children plus subsequent additions contained many more born to parents at distances from the hypocenter >2000 meters ATB, who seldom received increased radiation from the explosions, than to parents within the 2000 meter radius, whose gonadal doses were relatively large. In 1959, to increase the efficiency of the study of survival, three cohorts were defined from the children born in the two cities since the bombings: The first comprised all children born between May 1, 1946, and December 31, 1958, to parents one or both of whom were within 2000 meters of the hypocenter ATB (proximally exposed); the second was composed of age, sex, and city-matched births to parents one or both of whom were distally exposed to the bombs (>2500 meters from the hypocenter); and the third, of age, sex, and city-matched children born to parents now residing in Hiroshima and Nagasaki, neither of whom were in the cities ATB. Children born to parents within the 2000–2500 meter radius of distance from the hypocenter are omitted from consideration, because of the exceptional difficulties in estimating the (low) exposures at this distance and the work involved in following children who would contribute relatively little information regarding radiation effects. Setting the earliest date for admission into the

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

cohort at May 1, 1946, effectively eliminates from the sample all children in utero ATB.

These cohorts have been periodically expanded to include matched numbers of recent births, the limiting factor in the expansion being the number of births to the proximally exposed parents. In 1984, some 39 years after the birth of the first children conceived following the bombings, there were only three births to proximally exposed parents and the cohorts were closed, effective January, 1985. The cohort of children born through 1982 (the cut-off date for analyses) to parents receiving > 0.01 Gy of radiation now equals 31,150. In addition to the study of the survival of these and the “control” children, special studies have been mounted on the physical development of these children during their school years and on the incidence of cancer. In 1968, a search for cytogenetic abnormalities in those children in the cohorts over 12 years of age was initiated, and, in 1975, a search was undertaken in these same cohorts for mutation altering the electrophoretic mobility and/or function of a select battery of proteins. For both these studies, the necessary controls were drawn from the children of parents not receiving increased radiation ATB.

The approach to assigning gonadal doses to the survivors underwent a drastic revision during the early 1980s, resulting in the system known as Dose Schedule 1986 (DS86) (81). All the genetic data have now been analyzed on the basis of the new dosage schedules, supplemented, where DS86 dose are not available, by an ad hoc procedure (cf 74). The radiation resulting from the explosions was predominantly gamma, but included a small neutron component. These two components have been separately estimated, and for these exposure levels, the neutron component assigned a Relative Biological Efficiency (RBE) of 20 (cf 37). This permits assigning the total dose in sieverts. The average conjoint parental gonadal exposures of course vary from study to study, as the composition of the parents of the children examined varies, but in general has been between 0.32 and 0.60 Sv; the distribution of conjoint doses is markedly skewed to the right. Given the chronology of this study, the findings must apply almost exclusively to the results of the radiation of spermatogonia and early, immature oocyte.

We turn now to a consideration of the data.

Untoward pregnancy outcome Because of the interrelatedness of major congenital defect, stillbirth, and neonatal death, we have treated these endpoints as an entity, termed Untoward Pregnancy Outcome (UPO), defined as an outcome resulting in a child with major congenital defect and/or stillborn and/or dying within the first two weeks of life. Between 1948 and 1954, data were collected on these outcomes for a total of 76,617 newborn infants in Hiroshima and Nagasaki, on 69,706 of whom the data were sufficiently

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

complete in all respects to permit inclusion in the analysis (cf 66). A total of 3,498 children were classified as UPOs. The congenital defects considered major are listed in Neel & Schull (66) and Neel (62). Although the data have been analyzed in many ways, we will for this and the subsequent endpoints to be considered present only the results derived from fitting a simple linear dose-response model to the occurrence of the various indicators of radiation-related damage. This model yields a regression coefficient per Sv (ß), and an intercept term, a. Table 1 presents the results of the most recent analysis, based on the use of both DS86 and the ad hoc doses (74). The regression of indicator on dose is positive, and so consistent with the hypothesis that genetic damage was produced, but well below the level of significance.

“Prereproductive” deaths among live-born infants (exclusive of those resulting from a malignant tumor) The mortality data on the three cohorts of live-born children described earlier extend through 1985, when the mean age of the members of the cohorts was 26.2 years. The data are thus relatively complete for death during the prereproductive years. Details of the organization of the study have been presented elsewhere (39, 64). After exclusion of the neonatal deaths included in the analysis of the foregoing section, and cancer deaths (to be discussed in the next section), the three cohorts together include 67,202 individuals, among whom there have been 2,584 deaths. The most recent estimate of the regression of death on parental exposure, employing DS86 doses, is presented in Table 1 (63). Again, the regression is positive, as might be expected if deleterious mutations had been produced, but less than its standard error.

Malignancies in the F1 A minority of certain cancers of childhood, such as retinoblastoma and Wilms' tumor, result from the presence of one defective gene inherited from a parent plus a second defective allele of this gene resulting from a somatic mutation in the child. Most cancers of childhood, however, seem to be entirely due to somatic cell events occurring in the child. Only the frequency of the former type might be expected to respond to parental radiation. The normal alleles at the loci associated with these “genetic” cancers are usually referred to as “tumor-suppressing” genes. In addition, the occurrence of proto-oncogenes is well established; in principal, radiation could introduce mutations in proto-oncogenes, although thus far there are no clear examples in humans of a genetic (inherited) predisposition to cancer (or any other trait) due to a mutant proto-oncogene. On the thesis that the frequency of tumor-suppressor and proto-oncogenes was probably such that collectively they constituted a significant target for radiation, the incidence of cancer in the populations under consideration was studied, using both death

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Table 1 An estimate of the genetic doubling doses that can be excluded at specified confidence levels by the human data. Further explanation in text.

 

Regression

Observed total background

Mutational contribution background*

Mutational component

Lower confidence limit (Sv)

Trait

ßSV

a

(a)

(b)

(%, b÷a)

99%

95%

90%

UPO

0.00264

0.03856

0.0502

0.0017–

3.4–5.4

0.14–

0.18–

0.21–

±0.00277

±0.00582

 

0.0027

 

0.23

0.29

0.33

F1 Mortality

0.00076

0.06346

0.0458

0.0016–

3.5–5.7

0.51–

0.68–

0.81–

±0.00154

±0.00181

 

0.0026

 

0.83

1.10

1.32

F1 Cancer

–0.00008

0.00104

0.0012

0.00002–

2.0–4.0

0.04–

0.05–

0.07–

±0.00028

±0.00033

 

0.00005

 

0.07

0.11

0.15

Sex-chromosome aneuploids

0.00044

0.00252

0.0030

0.0030

100

1.23

1.60

1.91

±0.00069

±0.00043

           

Protein variants

–0.00001

0.00001

0.000013

0.000013

100

0.99

2.27

7.41

±0.00001

±0.00001

           

* per diploid locus

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

certificates and the cancer registries maintained in Hiroshima and Nagasaki (109).

There were 43 cancers in the 31,150 children born to exposed parents and 49 in the 41,066 children of unexposed parents, for an incidence in the latter of 1.2/1000 persons. As shown in Table 1, the regression on exposure was very small and negative, i.e. counter hypothesis. This was true both for all cancers and for those thought most likely to fit the retinoblastoma model, i.e. retinoblastoma, Wilms' tumor, neuroblastoma, embryonal carcinoma of the testis, and sarcomas (considered an alternative expression of the retinoblastoma allele). None of these latter tumors was in this series associated with a positive family history.

Frequency of balanced structural rearrangements of chromosomes and of sex-chromosome aneuploidy Cytogenetic studies on the children of survivors were initiated in the 1960s, involving members of the F1 Mortality Study described earlier (2–4). Two age- and sex-matched samples were established, one drawn from the children of proximally exposed and the other from the children of the distally exposed. To increase participation, no effort was made to obtain the venous blood samples necessary to the study from children under age 13. The study will therefore not supply reliable data on chromosomal abnormalities associated with high childhood mortality (including Down syndrome under the conditions of postwar Japan) but is thought to provide appropriate data on the occurrence of sex-chromosome aneuploidy and balanced structural rearrangements of chromosomes, the latter defined as reciprocal translocations, pericentric inversions, and Robertsonian translocations.

Awa et al (4) detected 19 individuals with sex-chromosome aneuploidy in the 8322 children of proximally exposed parents who were examined, and 25 such individuals in the 7976 children of controls. Individuals with some of these abnormalities are sterile (XXY) and with others may exhibit decreased fertility (XXX); furthermore, XYY and XXX individuals only rarely have similarly affected children (19). Thus a very high proportion of these persons may be presumed to result from primary nondisjunction (i.e. mutation) in a parent, but specific family studies were not undertaken on these individuals. DS86 doses were not available to Awa et al (4); we have now distributed these children according to joint parental gonad exposure and derived the appropriate regressions (67). The regression of incidence on dose (Sv) is 0.00044 ± 0.00069, with an intercept of 0.00252 ± 0.00044 (Table 1).

Awa et al (4) also encountered 18 balanced structural rearrangements in the 8322 children of proximally exposed parents and 25 in the 7976 children of controls. Family studies could be performed on about 60% of the children, and one de novo mutational event was detected in the children of the exposed

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

and one in the controls. With adjustment for the children not subjected to family studies, Awa et al (4) estimate a mutation rate for both groups of 1.0× 10-4/gamete/generation, with a 95% confidence interval between 0.2 and 4.5 ×10-4. The number of mutations was not felt sufficient to warrant a regression analysis.

“Point” mutations affecting protein charge and/or function As used throughout this treatment, the term “point” mutation of necessity encompasses not only specific nucleotide changes but also small insertions/ deletions/rearrangements. Between 1972 and 1985, a battery of 30 serum transport and erythrocyte enzyme proteins were screened for the occurrence of mutations altering electrophoretic mobility, and a subset of 11 of these proteins (all enzymes) were screened for mutations resulting in loss of function (65). Three mutations altering electrophoretic mobility were encountered in the equivalent of 667,404 locus product tests on children of proximally exposed persons, and the same number (3) in the equivalent of 466, 881 tests on the children of distally exposed parents. These mutations were teased out of family studies on some 964 rare protein variants that had the potential of resulting from mutation in the parental generation.

The examination of a subset of 60,529 locus products for loss of enzyme activity in the children of proximally exposed parents yielded 26 rare variants, one of which proved to be a newly arisen mutation; no mutations were encountered in the 21 variants identified in the 61,741 determinations on the children of the comparison group. When the data on the mobility and loss-of-function mutations were combined, the mutation rate in the children of proximally exposed was 0.60×10 -5/locus/generation, with 95% confidence intervals between 0.2 and 1.5×10-5/locus/generation. In the comparison group the rate was 0.64×10-5/locus/generation, with 95% intervals between 0.1 and 1.9×10-5/locus/generation. The average conjoint parental exposure for the proximally exposed was 0.41 Sv and the regression of mutation occurrence on conjoint parental gonadal exposure was –0.00001±0.00001/ Sv with an intercept of 0.00001±0.00001 (Table 1) (67).

Sex ratio The relation of sex ratio to parental radiation history in the Japanese experience has been presented on several occasions. With the discovery of sex-chromosome aneuploids in 1959 and recognition of the Lyonization phenomenon in 1961, it became clear that the interpretation of any observed change in the phenotypic sex-ratio at birth would not be simple, and no further analyses have been conducted on sex-ratio since our 1966 publication. The demonstration of no significant difference in the occurrence of sex-chromosome aneuploidy in the two groups, as described earlier, now indicates this phenomenon is not a complication in our findings regarding

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

sex-ratio. Because of Lyonization, the least complicated data on sex-ratio concern the offspring of exposed mother:unexposed father marriages, where the expectation is for a decrease in the frequency of male offspring if the mutation rate had been increased. In our last analysis (92), the regression, based on the previous (T65DR) dose schedule, was 0.0027±0.0040/Sv, i.e. insignificantly counter hypothesis. Since we see no way to bring these data into the framework of a doubling-dose estimate (see below), these data have not been reanalyzed or extended with the advent of the DS86 dose system.

Anthropometric studies Birthweights were obtained on the 69,706 children examined during the clinical phase of the program, and weight, body length, head circumference, and chest circumference obtained on a subset of 18,498 of these infants reexamined between ages 8 and 10 months (66). In addition, the annual school measurements (height, weight, sitting height, and chest circumference) have for a subset of Hiroshima school children been analyzed in relation to parental radiation exposure, using the T65DR schedule (22–26). No significant or suggestive differences existed between the children of proximally exposed and the control series.

THE GENERATION OF AN ESTIMATE OF THE DOUBLING DOSE FROM THE HUMAN DATA

The attempt to derive both the lower limits to the genetic doubling dose(s) compatible with these data and the most probable doubling dose consistent with all the data has presented a number of unique problems recently described in detail (67). On the other hand, an unusual and favorable feature of this study is that all of its various components have been based on a well-defined population subsampled in various, essentially nonoverlapping ways. The result is a multifaceted appraisal of the genetic impact of the bombs on what is essentially a single cohort. We will enumerate below some of the ways in which these studies lack the elegance that can be achieved in an experimental setting. They are, however, based on a single complex population exhibiting the full range of human heterogeneity. Furthermore, the subjects of the study have been born over a sufficiently extended time interval that we begin to approximate the effects on an entire generation rather than on a “window” of access to a very limited period in the reproductive histories of the parents.

We take the position that in the studies in Hiroshima and Nagasaki we are not testing the hypothesis that radiation is mutagenic. It has been so for every properly studied species of prokaryote and eukaryote, and Homo sapiens cannot be an exception. The present data are thus the best approximation to the genetic effect of the bombs to be available for some years. To explore

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

their precise implications requires specification for each indicator of the contribution of mutation in the parental generation to the frequency of the trait. For sex-chromosome aneuploids, reciprocal chromosome exchanges, and protein variants, this frequency can and has been directly established by the appropriate family studies. For UPOs, and death and cancer among live-born infants, this is not the case; elsewhere we have attempted to generate the estimate of the contribution of spontaneous mutation in the parental generation to these events that is necessary to derive a doubling dose (67).

Table 1 summarizes the results of this effort. Column 4 presents the incidence of the events to be used in subsequent calculations. For the first three items, it is total incidence; for the last two, where it can be specified, it is mutational incidence. Because of the paucity of balanced chromosomal rearrangement that can be attributed to mutation in the parental generation, this indicator is not incorporated in the calculations to come. The fifth column presents the estimated incidence of the trait as a result of spontaneous parental mutation; for the last two indicators it is of course identical with the entry in column 4. The range reflects the uncertainty in the estimate. A detailed justification of these estimates is presented elsewhere (67). Column 6 attempts to provide perspective by indicating the percent of the entry in column 4 to be attributed to spontaneous parental mutation. Note—contrary to Sankaranarayanan's (90) unfortunate erroneous perception of how the doubling dose has been estimated—that only a small fraction of these three indicators, ranging from 2–5%, is attributed to mutation in the parental generation. Finally, by a standard statistical procedure presented elsewhere (67), we have calculated (cols 7–9) for the various indicators lower confidence limits for the doubling dose at the specified probabilities. The range given for the first three indicators results from the range in the estimated mutational component for each.

Such estimates as these five can be combined only on the assumption that they are drawn from a common pool of estimates, i.e. that the doubling doses for the individual phenomenon are essentially the same. An extensive literature suggests that the true doubling dose for radiation-induced sex-linked chromosome aneuploids and protein variants (resulting from nondisjunction and nucleotide substitutions, respectively) is probably higher than the doubling dose for the other three indicators (resulting predominantly from insertion/ deletion/rearrangement events and unrepaired chromosome breaks). We have therefore pooled the first three and last two estimates of Table 1, using a statistical procedure described elsewhere (67). The resulting lower confidence limits, at the 95% confidence limit, are between 0.63–1.04 Sv for the first three indicators pooled and 2.71 Sv for the last two.

The data of Table 1 can also be used to derive the most probable overall doubling dose suggested by these data. For this we assume the effect on the F1

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

of any mutations resulting in protein variants (i.e. point mutations) is subsumed within the UPOs and F1 mortality. Since we are basically working with independent observations on the same cohort, we have suggested that the doubling dose can be derived by dividing the sum of the first four entries in column 4 (0.00632–0.00835) by the sum of the five regression terms (0.00375), resulting in an estimate of 1.69–2.23 Sv. There is satisfactory agreement between this estimate and the minimal 95% probability estimates.

The most probable estimate cannot be compared directly with any estimate based on acutely irradiated mice because with humans, both sexes enter into the estimate, the average conjoint gonadal exposure being 0.3–0.6 Sv, depending on the precise study. Moreover, the dosage curve is highly skewed to the right, some couples having received an estimated joint gonadal dose as high as 6.0 Sv. The mouse data, on the other hand, are largely derived from gonadal doses to one sex, the male, of 3.0 or 6.0 Gy (=Sv). The difference in radiation exposures can in principle be met by converting both the human and mouse data to equivalent results from low-dose rate, low-LET radiation (LET =linear energy transfer). The many difficulties in extrapolating from acute, relatively high-level radiation effects to the effects of low-level, chronic, or intermittent exposure are detailed in Report 64 of the National Council on Radiation Protection (61), and yet the effort must be made, both to render the man-mouse comparison more valid and to supply guidelines for human exposures. Russell et al (89) have demonstrated with the 7-locus system that high-level, acute radiation exposures are at least three times more mutagenic than low-dose pulsed or chronic radiation. Other indicators, notably those on translocation frequencies, have yielded higher dose rate factors (revs, in 98, 106). Following the linear quadratic treatment of the mouse data by Abrahamson & Wolff (1), we suggest applying a dose rate factor of 2 to convert the Hiroshima-Nagasaki data into their low-dose rate, low-LET radiation equivalent. The resulting figure is 3.38–4.46 Sv. This is a conservative estimate, since it does not incorporate three sets of data that showed no hint of an exposure effect, namely, the data on the balanced chromosomal exchanges, the sex-ratio, and physical development. We find it impossible to set limits in the usual statistical sense on this estimate, because of statistical sampling errors and the uncertainty we have described in establishing the contribution of parental spontaneous mutation to the indicators in the control population.

SOME UNUSUAL FEATURES OF THE ESTIMATE OF THE HUMAN DOUBLING DOSE

As we turn to a similar treatment of the accumulated mouse data, the following features of the human data must be kept in mind:

  1. None of the studies has yielded a statistically significant difference be-

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

tween the children of proximally exposed and controls, and the “numerators” for the individual studies are indeed small. On the other hand, collectively these numerators sum to a substantial body of data, based, for the largest study, on approximately 13,395 Sv of parental gonadal exposure.

  1. Exposed males and females contribute about equally to the gonadal exposures of the human data. In the absence of significant radiation effects, there is no prospect of effectively distinguishing the contributions of the two sexes. The human estimate is specific to this situation.

  2. The human data cover the entire postexposure reproductive spans of the exposed males and females, whether they were aged 40 or aged 1 ATB, and not, as is customary in experimental studies, the period of maximum fertility following the treatment of young adults.

  3. The estimates of the mutational contribution to UPOs and prereproductive mortality are time-place specific, in any strict sense valid only for this particular postwar population. In a more favorable environment, the relative and absolute frequency of children dying because of a mutation in the parental generation should be less, and a somewhat different estimate of the doubling dose would be obtained. This fact, plus the nature of the assumptions necessary to obtaining the estimate of the human doubling dose, impart to this estimate a greater error than is typical of an experimental situation.

  4. The parents who were not exposed to the explosions of the bombs (i.e. who came to Hiroshima or Nagasaki following the bombings, as released service men, repatriates, or spouses) were slightly younger and had a little more education and somewhat higher occupational ratings than the exposed (39, 64, 66). It is also assumed that the mother had completely recovered from her exposure when she reproduced. To the extent socioeconomic and maternal effects exist, they will inflate the estimate of the genetic effects of the bombs.

PRÉCIS OF THE MOUSE DATA ON THE GENETIC EFFECTS OF ACUTE RADIATION

The data on mice are summarized in the same sequence as the human data. With rare exceptions, only those murine data are cited that involve transmitted genetic effects following single or double acute exposures to radiation, the effects studied in late fetuses or full-term offspring. The justification is that the primary concern in the societal context is with genetic damage that impacts on the population, whereas damage that results in nonfunctional sperm and eggs, or even the early death of zygotes (i.e. early-acting dominant lethals), although of basic biological importance, does not result in the

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

transmitted effects of most concern to society. We emphasize the data most relevant to the totality of human reproduction following exposure to ionizing radiation, namely, those based on the irradiation of spermatogonia and early oocytes. Since we wish to have maximum comparability with the treatment of the human data, we will, insofar as possible, present the findings in terms of doubling dose rather than rate per unit radiation. One dramatic discovery in radiation genetics was the demonstration by W.L.Russell in 1965 (88) that in his 7-locus system no mutations were recovered in the “late” litters of irradiated females. Unfortunately, because female mice rapidly lose fertility after radiation, for most indicators there is relatively little early oocyte data for mice, a deficiency that greatly complicates the calculation of a mouse doubling dose.

Untoward pregnancy outcome Because parturient mice tend to devour stillborn offspring as well as those dying shortly after birth, the acquisition of reliable data on the frequency of congenital defect, stillbirth, or early postnatal death comparable to the human data is difficult. The pioneer study of Charles et al (11), involving what must be termed on the average high-level chronic radiation (daily, lifetime exposure schedules of either 0.1, 0.5, 1.0, or 10.0 r), scored the offspring of irradiated DBA males×unirradiated C57BL females for defects shortly after birth and also on the basis of an autopsy at maturity. Deceased offspring with major defects present at birth had probably been eaten by the mother by the time of scoring, so that the at-birth data are of limited value. With respect to the autopsy results, many of the malformations listed in their report would have been considered as minor (and not included in the analysis) by the standards of the Japanese studies. The control frequency of rare anomalies at autopsy was 0.73±0.11%. Averaged over all experiments, the regression of scored defect on dose was reported to be 2.4×10-5 per r. The data appear to indicate a dose-rate effect; it would be conservative to consider this an experiment with chronic radiation.

The data on congenital malformation most nearly comparable to the human data were acquired by scoring fetuses obtained from sacrificing pregnant mice at various stages of gestation. Lyon et al (58) exposed the male offspring of a C3H/HeH×101/H cross to 600+600 r of acute radiation and then mated them, at an interval that ensured the results would reflect spermatogonial radiation, with CBA/H females. The females were sacrificed at about 14 days of gestation and scored for corpora lutea and small and large moles, dead embryos, malformed live embryos and normal live embryos. We will not consider the data on preimplantation losses or on numbers of moles (i.e. early postimplantation losses), with respect to which an excess would result from early-acting dominant lethals and would have no counterpart in the human data, and which in the human societal context have relatively little signifi-

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

cance. Of the 1109 control fetuses, 6 were malformed (0.54±0.22%) and 23 dead (2.07±0.43%). Of 955 fetuses in the irradiated series, 3 (0.31± 0.18% were malformed and 25 dead (2.62±0.52%). There was thus no significant difference between the two series, but the very high doses used in this study are at the level where genetic radiation effects “fall off” in many studies, for complex reasons.

In further experiments, Kirk & Lyon (40, 41) sacrificed at 18 days gestation the offspring of male or female F1 hybrid C3H/HeH×101/H mice treated in one experiment with 0, 108, 216, 360, and 504 cGy and in another, with 0 and 500 cGy and scored for moles and living fetuses with gross malformations and dead fetuses (with or without malformation). Since the data on exposed females are based on matings within 28 days of radiation, they presumably reflect the results of radiation of mature or semimature oocytes. Over 50% of the fetuses scored as malformed were “dwarfs” or “runts” (body weight less than 75% of mean of litter mates). Malformations observed in dead fetuses were not scored. There was an increase in defective fetuses with radiation, from values of 1.2±0.2% in the controls to values of 1.8±0.3% in the offspring of males receiving an average of 390 r and 3.4± 0.4% in the offspring of females receiving an average of 278 r, the latter increase significant. To meet the possibility that maternal radiation per se was a teratogenic influence, West et al (107, 108) undertook a further series of experiments involving the transplantation of preimplantation embryos after irradiation of C3H/HeH×101/H females with 3.6 Gy X-rays. These experiments demonstrated that the effect of radiation was truly genetic, as did further experiments with 3.3 or 3.7 Gy of localized (versus whole-body) radiation, which revealed that irradiation that did not involve the ovaries had no effect on the frequency of abnormal embryos.

In other experiments, Nomura (70–73) irradiated male and female ICR mice at doses of 36, 216, and 504 rad, and then scored for anomalies at 19 days gestation and 7 days postpartum. There was a significant effect of radiation in both series (all data combined). Thus, among living fetuses scored on day 19 of gestation, the control value was 0.39±0.19%, whereas following male (spermatogonial) radiation it was 2.20±0.33% and following female radiation 2.65±0.52%, both these latter two frequencies being significantly different from controls. Likewise, among offspring surviving more than 7 days, the control frequency was 0.12±0.12%, whereas following male radiation the frequency was 0.86±0.19% and following female radiation, 1.65±0.31%. Again the differences are significant. The average radiation dose for males was about 250 rad and for females, 200 rad (S. Kondo, personal communication). The female data all appear to have been derived from oocytes treated in the follicular stage.

These experiments establish that radiation increases the frequency of con-

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

genital defect in the F1 of irradiated fathers and mothers, and provide empiric justification for employing this indicator in the human studies. Defective and dead fetuses correspond to the first two components of the triad we have termed an UPO. There are, however, several reasons why care must be exercised in comparing observations of this type made in mice with those on humans (see also 18).

To begin with, the mouse fetus at term differs in many respects from the term human fetus. Otis & Brent (75) have suggested a rough equivalence of a term mouse to about a 100-day old human fetus, but there are many asymmetries in the comparison, and a sweeping generalization is impossible. The equivalence would be somewhat less than 100 days in the above-quoted experiments. In the program in Japan, pregnant women were eligible to register at the completion of the fifth lunar month of pregnancy—140 days of gestation—but there was no penalty for nonregistration and many delayed registration a few weeks or even longer after their eligible date. The data on newborn mice thus correspond in some but not all respects to the first half of the second trimester stage of human development, when, for example, although the bulk of the malformed human fetuses with cytogenetic abnormalities have been eliminated, there is still a higher frequency of defect due to karyotypic abnormality than is observed at term (cf 35), and it is now documented that a significant proportion of these will be lost before term (36). Thus, malformed offspring that would have been aborted before the pregnancy came to attention in the study in Japan may still be represented in the mouse series under discussion.

The findings are further rendered noncomparable to the data on humans by what we will term the litter-size effect, of much less importance in the human data. Postnatal mortality is higher in large litters (11) as well as in very small litters (58). This effect for large litters is also present in the prenatal period; in the controls to the experiments just cited, the intrauterine fetal death rate was higher in large than in small litters. In these irradiation experiments, because of the induction of early-acting dominant lethals (identified in the autopsies as “moles”), the average number of fetuses was decreased in those litters where one or the other parent had been irradiated (40, 41, 58, 71). There is thus a major bias in studying the effect of parental radiation on late fetal death, recognized by Lyon et al (58). But the situation is complicated even further because defective but dead fetuses were not scored as defective in these experiments; since defective fetuses may be expected to compete less well in utero, the elimination of defective offspring may be higher in the larger control litters than in the experimental material.

Finally, there is the question of the comparability of diagnostic standards for the small mouse fetus and the human infant at term. For instance, even severe club foot or hypospadias might not be recognized in a mouse fetus at

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

18 or 19 days of gestation. Thus, while these experiments certainly establish the principle that ionizing radiation increases the frequency of congenital defect in the F1 of treated male and female mice, and provide empiric justification for the use of this indicator in the studies on humans, precise comparisons of the findings in mice and humans are not possible.

“Prereproductive” death among live-born offspring The murine data most comparable to the human data on mortality prior to the age of reproduction are those on preweaning mortality. Given the complications in interpretation introduced through inbreeding when radiation experiments are continued over many generations, in this section we consider only the results of studies on the F1. As noted above, a serious problem with the use of this indicator in the polytocous mouse is the negative correlation of survival with litter size, and the smaller mouse litter size in the offspring of irradiated mice. As recognized by the investigators, this fact vitiates many of the observations on parental radiation and offspring survival (79). The various experimental strains used by investigators also differ in mean litter size. Finally, the relative immaturity of the mouse at birth (and differences in maternal care) may result in different postnatal environment-genotype interactions in mice and humans that render precise comparisons difficult.

A representative set of data (S.E.Lewis, unpublished data) is given in Table 2. We note first the variation in control survival rates in the different experiments, a fact that underscores the importance of concurrent controls in studies of this type. Survival is better in the treated than in the control series in four of six experiments. We note further, however, that litter size averages about one animal more in the controls. To test to what extent this is responsible for the better survival of the offspring of treated animals observed in four of the experiments, we have conducted a preliminary analysis of the last data set in Table 2, in which each control litter greater than size 5 but less than 11 was randomly matched with a litter in the experimental series, the range 6–10 chosen to optimize the likelihood of survival. This resulted in two subsets of 480 births. Survival in the controls was 97.5 ± 0.7% and in the treated series, 91.7±1.3%. A much more extensive analysis along these lines will be presented elsewhere; for now it is sufficient to recognize the need for this type of adjustment, either empirically (as here) or statistically, and the possibility it creates for comparable analyses of human and mouse data.

Malignancies in the F1 Batra & Sridharan (8) reported an increase in leukemia in the offspring of irradiated male mice, but this was not confirmed by Kohn et al (44). More recently, Nomura (70–73) has reported a significant increase in malignant tumors in 8-month-old offspring of both male and female ICR mice following acute radiation exposures of 0, 36, 108, 216, 360,

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Table 2 Preweaning mortality in mice in relation to spermatogonial radiation exposure and litter size.1 Note the impaired survival in the controls in four of six experiments.

 

No. litters

No. progeny at birth

Birth average litter

No. progeny at weaning

% Survival

Female 300R

 

Treated

488

3,265

6.7

2,706

82.9±0.7

Control

51

390

7.6

319

81.2±2.0

Male 300R Spermatogonia

 

Treated

536

3,506

6.5

2,701

77.0±0.7

Control

87

584

6.7

413

70.7±1.9

Male 300R Presterile

 

Treated

454

2,329

5.1

2,010

86.3±0.7

Control

87

643

7.4

521

81.0±1.6

Male 600R Spermatogonia

 

Treated

861

5,569

7.5

4,597

82.5±0.5

Control

175

1,036

5.9

901

87.0±1.0

Male 600R Presterile

 

Treated

337

1,291

3.8

761

58.9±1.4

Control

115

784

6.8

529

67.5±1.7

Male 300R×2 Spermatogonia

 

Treated

547

3,755

6.9

3,478

92.6±0.4

Control

102

776

7.6

715

92.1±1.0

1 S.E.Lewis, unpublished data.

and 504 rad (average dose of 250 rad for males and 200 rad for females). The control data yielded a tumor frequency of 5.29±0.96% whereas the corresponding (consolidated) figure from male exposure was 10.01±0.77%, and from female exposure, 8.74±0.83%. The findings were repeated on a smaller scale in the LT and N5 strains.

The transfer value of these data to the human studies is moot (cf 109). Mouse strains differ widely in their tumor profiles, and Nomura (71) recognized that “the results may be a special property of the mouse strain used.” In the experiments with the ICR strain, 87% of the tumors in the offspring of treated mice were scored as papillary adenomas of the lung. In the experiments with LT and N5 mice, 16.0% and 21.0% of the tumors were pulmonary, 25.3% and 22.8% were ovarian tumors, and 5.3% and 3.9% were leukemias. These endpoints had a relatively high frequency in the appropriate controls. These were not tumors observed with any frequency in the human series, but 8 months covers a relatively larger part of a mouse's life span than the fraction of the human span represented in the human series. These differences in the pattern of malignancy in the two species—which will persist even with further follow-up of the human material—render any detailed comparison of the results from the two species suspect.

Furthermore, none of the human tumors based on the genetic mechanism

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

that presumably should be most responsive to radiation (retinoblastoma, Wilms' tumor, sarcomas of various types, and embryonal carcinoma of the testis) were observed in the mouse series. There is no basis for an estimate of the proportions of the control malignancies that result from mutation in the parental generation, an estimate essential to the derivation of a doubling dose. We conclude that these data represent a special circumstance in mouse strains many of which were at one time selected for high frequencies of malignant tumors, and do not believe the data can be used in the calculation of a mouse doubling dose to be compared with the human doubling dose (for further discussion, see 109).

Frequency of structural rearrangements and of sex-chromosome aneuploidy The subject of sex-chromosome aneuploidy has been comprehensively reviewed by L.Russell (82). Whereas in humans the most commonly encountered abnormalities are the XXY, XYY, and XXX state, in mice the most frequent abnormality is the XO state, and unlike humans with this constitution, these are fertile individuals. Furthermore, XXX mice are extremely rare (17). There are no large-scale cytogenetic surveys of newborn mice comparable to those on humans; the frequencies of sex-chromosome abnormalities have been determined by genetic techniques whereby individuals exhibiting the various types of abnormalities have distinctive phenotypes. To a first approximation the frequency of primary XO and XXY individuals in mice is about 3/1000, very similar to the human total for sex-chromosome aneuploidy, but predominantly due to XOs to which the male parent has not contributed a sex chromosome.

Acute gamma radiation resulted in a clear increase in sex-chromosome anomalies in offspring from males in whom the germ cells were exposed as spermatocytes, spermatids, and spermatozoa, of the order of 2×10 -5/r, but this effect was not observed in offspring resulting from irradiated spermatogonia (Table 7 in 82). The result of the acute radiation of dictyate oocytes as reflected in matings up to 49 days post treatment, based on the occurrence of OXP offspring, appears more variable but is of the order of 1×10-5/r (Table 8 in 82). The collection of data on the effect of acute radiation on immature oocytes has been hampered by the extreme sensitivity of these cells to radiation. Two studies in which small doses of acute radiation were employed revealed no increased incidence of trisomy in midterm fetuses (60, 103). On the other hand, two studies in which larger doses were delivered as chronic radiation revealed either a nonsignificant increase in X-chromosome loss in term mice (82) or a significant increase in hyperhaploidy in metaphase II oocytes (33). These latter findings, while interesting, are of dubious value in establishing a reference point for the situation in Japan.

Spontaneous or induced mutations characterized by structural rearrange-

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

ments of chromosomes will result in zygotes with either a balanced or unbalanced chromosomal complement. In mice, as in humans, the latter are usually eliminated early in pregnancy but some few survive until the later stages of pregnancy. The cytogenetic studies on the children of survivors in Japan were not initiated until age 13 and so would only very rarely detect children resulting from chromosomally unbalanced zygotes. Such of the latter type of children as survived beyond the fifth gestational month presumably were detected as grossly abnormal newborn infants and their impact was scored in the analysis of malformations. Likewise, in the above-referenced murine studies of Lyon and colleagues, the more-or-less comparable impact of the mutations resulting in chromosomally unbalanced gametes should be reflected in the malformations scored on the 18th gestational day although, as we noted, the differences between the human and mouse fetus at term or near-term renders a direct comparison with the human data problematic.

On the basis of the studies of high, acute doses of X-rays to the C3H/HeH ×101/H strain (21, 58, 94), Lüning & Searle (50) suggested a spermatogonial doubling dose for reciprocal translations of about 31 r. They reject from this calculation the data of Reddi (78), which showed a much lesser effect of radiation on the CBA strain. The later data of Generoso et al (27), employing male (101×C3H)F1 mice, with a spontaneous rate for heritable reciprocal translocation in spermatogonia of 1.8×10-4/gamete/generation and an induced rate of 3.9×10-5/r/gamete, yields a doubling-dose estimate of 4.6 r; this estimate rests on a single mutation in the controls. As noted, the sparse human data were deemed insufficient for the calculation of a doubling dose for mutations resulting in reciprocal translocations, but since the findings were nearly identical in the children of exposed and controls, the human data appear to be inconsistent with the mouse doubling dose reported by Generoso et al (27).

“Point” mutations Perhaps in recognition of the various complications in the study of the indicator traits thus far reviewed, most studies of the genetic effects of radiation on mice, especially those of recent years, have involved some version of a specific-locus/specific-phenotype test. Again we use the traditional term “point” mutation but recognize that, in addition to radiation-induced specific nucleotide changes [as suggested by the reversibility of radiation-induced mutations in Neurospora (14, 59)] and intragenic insertions/ deletions/rearrangements, some of the radiation-induced mutations encompass several loci (83), in which case the term “point” is a misnomer, but we use it for convenience. In this section we draw heavily on the excellent reviews of Searle (96) and Favor (20). The estimates obtained with eight different test systems are summarized in Table 3.All entries are based primarily on the results of the acute, relatively high-dose (usually 300 or

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Table 3 A summary of the gametic doubling doses for acute, “high-dose” radiation of spermatogonia yielded by the various specific-locus/specific-phenotype systems developed in the laboratory mouse.

System

Data summarized in:

Doubling dose (Gy)

   

Calculated by:

Origin of treated males

1. Russell 7-locus

16, 96

.44

   

This paper

101×C3H

2. Dominant visibles

50

.16

50

various

3. Dominant cataract

20

1.57

This paper

101/E1×C3H/E1

4. Skeletal malformations

15

.26

50

101

5. Histocompatibility loci

6

>2.60

6

C57BL/6JN

6. Recessive lethals

102

.51

1.77

50

DBA

52, 58

.80

6

C3H/HeH×101/H

52, 95

4.00

6

CBA, C3H

7. Loci encoding for proteins

This paper

.11

   

This paper

various

8. Recessive visibles

58

3.89

This paper

C3H/HeH×101/H

   

Av. 1.35

   

600r) irradiation of spermatogonia. In assembling this table, we have insofar as possible drawn on doubling-dose estimates already in the literature. Each entry requires some brief discussion.

(a) The multiple, specific-loci test system The most widely used murine test system has been that developed by W.L.Russell (84). This entails the cross of an irradiated mouse homozygous for the normal alleles at 7 test loci with a test strain homozygous with respect to mutant alleles at the same 7 loci. A mutation is immediately scorable in the F1. The loci are a, b, c, p, d, se, and s. Because of its efficiency, the method has been widely used and has led to many important insights in radiation genetics. When the results of various laboratories with single or multiple, acute high doses of spermatogonial radiation are combined, (cf summaries in 16, 96), the mutation rate/locus/r is 2.2×10-7 (2,346,687 locus tests), with a control rate of 9.0×10-6/locus/ generation (6,417,082 locus tests). This leads to a doubling-dose estimate of 41 r for acute, high-dose spermatogonial radiation.

Female mice treated with doses readily tolerated by males produce a few posttreatment litters but then rapidly become sterile due to the extreme sensitivity of early oocytes to ionizing radiation. Even so, because of the importance of obtaining data on the results of female radiation, a particular effort has been made to obtain such data with this system. The first few litters conceived by female mice following single, acute radiation doses of 50 r (involving mature dictyate oocytes) revealed an induced rate/r of from 2.1 to 5.5×10 -7, depending on the dose (1,628,277 locus tests), as contrasted with a spontaneous rate/locus/generation of 4.9×10-6 (202,812 locus tests). This yields a doubling dose of 9 to 23 r. However, when breeding of females who

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

had received 50 r continued, no mutations were recovered in the “late” litters of these same females (0 mutations in 547,337 locus tests) (88).

There are major differences between loci in induced rates following acute spermatogonial radiation (96 ; Table 14). Induced mutations are approximately 18 times more frequent at the s than at the a locus. Unfortunately, only fragmentary data seem to have been published on locus differences in spontaneous mutation rates, insufficient for a proper statistical analysis. However, we note (96 ; Table 3) that the 3 (b, d, s) loci (among 7) showing the highest spontaneous rates are those with the highest induced rates, and the 3 with the lowest induced rates are those with 0 spontaneous mutations. We return to the great significance of this later.

An alternative 6-locus system was developed by Lyon & Morris (54 , 55), consisting of the a, bp, fz, In, pa, and pe loci. The rate of mutation induction following acute, high-dose spermatogonial radiation was 7.6×10-8/locus/r (149,004 locus tests), approximately one third of the rate in the Russell 7-locus system at the same exposure level. Unfortunately, no mutations were encountered in the 124,614 control locus tests, so that these observations cannot be put into a doubling-dose context.

(b) The “gross” dominant visible test The observations on the induction of dominant mutations by acute spermatogonial radiation have been well reviewed (96 , 99). Since these data are for the most part an incidental by-product of other (specific-locus) studies, they must be placed on a per gamete rather than per locus basis. Searle's analysis (96) reveals a spontaneous rate of 0.8×10-5/gamete and an induced rate of 4.7×10-7/gamete/rad, resulting in a doubling-dose estimate of 17 rad. Although we include this estimate in our summary, the opportunistic use of certain phenotypes suggests that the estimate is based on the more spontaneously mutable loci, and we have just seen that these loci tend to show the higher induced rates (see below also). Otherwise stated, loci with low spontaneous and/or induced rates that failed to yield any mutations would not enter into this estimate.

(c) The dominant cataract system This approach involves scoring the offspring of male mutagenized mice for lens opacities with the aid of a slit lamp after dilation of the pupils with atropine (47). Animals with such opacities were bred, and only transmitted defects scored. In these studies locus rates are calculated on the assumption that 30 loci may contribute to the phenotype. In fact, the number of loci at which mutation may result in this phenotype is unknown, for mice or humans, and for our purposes it is sufficient to express doubling dose in terms of phenotype. In a recent summary of the data from five different experiments, Favor (20) reported that the phenotypic doubling dose ranged from 0.96 to 2.14 Gy. The unweighted average of these estimates

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

is 1.57 Gy. That this estimate of the doubling dose is based on a single mutation in the control series imparts to it a wide error.

(d) The skeletal malformation system Because of the obvious relevance to human disease and because of the potential immediate expression in the F1 generation, skeletal defects are, like cataract, an attractive mutational endpoint. That dominant mutations resulting in skeletal defects can be identified in the mouse is well documented in M.Green's catalog of known mouse mutations (32). However, dominant skeletal mutations detected through a standard “physical examination” of the mouse in general appear to be relatively rare both as spontaneous (91) and induced (96) occurrences.

The screening of F1 generation, cleared and stained mouse skeletons have provided a means for intensifying and expanding the search for skeletal mutations (15 , 100). The use of these methods has indeed identified skeletal defects that could reasonably be ascribed to treatment of parents with mutagenic agents (15 , 100 , 101). However, the number of minor defects found with this method, possibly due to developmental accidents, produces a large background noise level that confounds the identification of truly heritable events.

Heritability tests of presumed skeletal defects are especially cumbersome because all F1 animals to be tested must be bred to assess transmission of these traits, inasmuch as with this method presumptive mutants can only be identified after death. To offset the need for breeding tests, various criteria have been suggested by Selby & Selby (101) to identify skeletal defects due to mutation. The accuracy of these criteria is yet to be rigorosly validated. Selby & Selby (101) apparently did not include controls in their studies. We will therefore accept for this indicator the doubling-dose estimate of 26 r by Lüning & Searle (50), which employed the data of Ehling (15). However, since this estimate is based on a single mutation in the controls, it has a wide error.

(e) The histocompatability system Bailey & Usama (7 ; see also 5) developed a system of testing for mutations at loci determining histocompatability, by orthoptic tail-skin transplantation involving graft exchange in a ‘reciprocal circle' system that should detect both gain and loss mutations. It was suggested that the system would detect mutation at approximately 30 different loci, but as for the other ‘phenotype tests,' we shall only present a phenotypic doubling dose. Bailey & Kohn (6) report that in experiments in which the male parent received 522 rads acutely, spermatogonial mutant frequency was higher among the control group than among the offspring of treated, although the difference was not significant. This finding precludes the calculation of a doubling dose but does permit assigning it a lower limit. They calculate that the spontaneous rate per gamete is <2.6×10-5, from which the doubling

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

dose is estimated to be >260 rads. Similar data published by Godfrey & Searle (28) and later data published by Kohn et al (46) are consistent with this calculation.

(f) The prenatal recessive lethal system The recessive lethals scored in murine experiments are mostly very early acting, manifesting as moles. The majority of such early-acting lethals could not be recognized in human studies, and their societal impact would come through their heterozygous effects. The murine data are extremely heterogeneous and involved, and cannot be presented in detail in these confines. Very competent investigators have viewed the data in different lights. A basic problem has been to estimate the baseline total gametic rate of mutation to lethals. In general this has been measured indirectly, using assumptions concerning heterozygote disadvantage and the results of inbreeding. Lüning & Searle (50), using the data of Sheridan & Wårdell (102) on 14 generations of male irradiation at 276 r/generation, developed a doubling-dose estimate for this indicator of 51 r (see also 49). On the other hand, Bailey & Kohn (6), using the control data of Lyon (52) and Searle (95) and the radiation data of Lyon et al (58), developed doubling-dose estimates of 80 and 400 rads, respectively, depending on which control figure is used.

Roderick (80), treating DBA/2J males, has described a direct approach to the detection of spontaneous and induced lethals in a chromosomal inversion covering approximately 3% of the mouse genome, but thus far the system does not seem to have been applied to spermatogonial mutation rates. For postspermatogonial cells, however, he adduces, in a small series, a lethal rate per locus of 0.35×10-8/r, based on an estimated 1750 loci in the segment of chromosome 1 being screened. The mutation rate for the same cell stage in the 7-locus system was 45.32×10-8 (84); approximately 80% of these mutations were homozygous lethal. As Roderick points out, this is a 100-fold difference, albeit with a large (indeterminate) error. Unfortunately, there were no lethal mutations in Roderick's control series so that a doubling dose cannot be calculated.

(g) The electrophoretic system In recent years considerable information has accumulated on the frequency in mice of spontaneous and induced mutation that can be detected by the electrophoresis of proteins, either as mobility or absence-of-gene-product variants, or by enzyme activity assays ( 10 , 38 , 76 , 77). In mice, test crosses can often be designed so that the absence-of-geneproduct can be recognized by the absence of an electrophoretic band rather than through the more laborious enzyme assays necessary to the detection of similar variants in humans. In principle, these studies should provide one of the strongest links with the human studies, since there is a substantial overlap in the proteins employed in the two sets of studies. Table 4 summarizes the

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Table 4 The frequency of X-ray induced mutations in mouse spermatogonia involving the electrophoretic mobility or loss of physiological function in proteins.

Attribute

Investigator

Strain

Treatment

No. loci

No. observations

Mutations

Protein Charge

W.Pretsch (See also 20)

101/E1×C3H/E1

0

23

133,676

0

S.E.Lewis, unpubl.

DBA/2J×C57BL/6J

0

32

1,289,500

1

J.Peters, unpubl.

C3H/HeH

0

4

1,452

0

W.Pretsch (See also 20)

101/E1×C3H/E1

3+3Gy

23

23,069

0

S.E.Lewis, unpubl.

DBA/2J×C57BL/6J

3

32

91,105

0

   

3+3

32

115,395

0

   

6

32

142,385

0

J.Peters, unpubl.

C3H/HeH

3+3 Gy

4

40,004

0

Enzyme Activity

D.J.Charles & W.Pretsch

101/E1×C3H/E1

0

12

86,640

0

S.E.Lewis, unpubl.

DBA/2J×C57BL/6J

0

32

1,289,500

0a

J.Peters, unpubl.

C3H/HeH

0

4

1,452

0

D.J.Charles & W.Pretsch

101/E1×C3H/E1

3+3Gy

12

40,656

1b

101/E1×C3H/E1

5.1+5.1 Gy

12

38,244

5c

S.E.Lewis, unpubl.

DBA/2J×C57BL/6J

3

32

40,515

2a ,d

   

3+3

32

49,555

2

   

6

32

66,784

1

J.Peters, unpubl.

C3H/HeH

3+3 Gy

4

40,004

3

a The cross results in heterozygosity at 16 of the loci

b This mutation significantly increased specific activity

c Of these, 2 increased and 3 decreased specific activity

d One of these mutations was detected in a non-heterozygous genotype

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

data currently available. (We omit reference to publications in which there are no control data.)

Inasmuch as absence-of-gene-product can be reliably detected at only a subset of loci, the data presented in the table are not really descriptive of total mutation rates for these types of variants at the loci concerned. Since, however, the proportion of loci scored for nulls is roughly comparable in the experimental and control series, the data on electrophoretic and null frequencies can be combined in this preliminary evaluation of the doubling doses suggested by this system. For the denominator in the calculation, we use the total number of gene products scored for electrophoretic mutations. The mutation frequency is 0.7×10-6/locus/generation in the controls whereas in the experimental series, the probability of mutation/.01 Gy is 6.3×10-8. The doubling dose (based on the occurrence of a single mutation in the controls) is .11 Gy. We note, by comparison with the data on humans (65), a relatively low spontaneous mutation rate for electromorphs; this observation plays a major role in the low doubling dose. It is perhaps pertinent that some 60%–70% of the control data is derived from female mice, whereas the data on induced rates are derived from spermatogonial radiation. Lyon et al (56) have suggested from specific-locus systems data a control spontaneous mutation rate for females of 2×10-6/locus/generation, approximately one fourth the male rate. A rough correction for the use of female controls would increase this doubling dose estimate by at least a factor of 2.

(h) Recessive visible mutations In addition to the test systems designed to detect recessive (and dominant) mutations at specific loci, several experiments have been designed to permit the detection of recessive visible mutations at all loci at which such mutations can occur. In a comprehensive experiment involving the male offspring of a C3H/HeH×101/H cross, Lyon et al (58) recovered one recessive mutation in the equivalent of 142.07 control gametes and six in the equivalent of 142.02 gametes from animals treated with 600+600 r acute spermatogonial radiation. They calculate an overall gamete mutation rate to recessive visibles of 7.0×10-3 in the controls and 28.2×10-3 after radiation. After correction for control frequency, the rate of induction of recessive visible mutations was 1.8×10-5/gamete/r. This leads to a doubling-dose estimate of 3.9 Gy. This estimate is based on a single mutation in the controls and, of course, again implies a large error.

The simple unweighted average of the results of these eight systems is 1.35 Gy. A weighting system and/or the calculation of an error is impossible because the number of loci involved in systems 2, 3, 4, 5, 6, and 8 is unknown. We note, however, that because of the paucity of mutations detected with some of the approaches, the error term should be Poisson in type, i.e. asymmetrical, the upper range at any given probability level exceeding the lower range.

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Sex-ratio In the mouse, the sex-chromosome is about 1/20th of the total genome. Thus, in principle there could be of the order of 1000–2000 genes on the X susceptible to radiation damage, perhaps half of which could yield lethal mutations. The published data on the effect of radiation on the mouse sex-ratio are confusing (reviewed in 29 , 30 , 57). Most early studies found no effect of radiation of males on the sex-ratio of the F1 or F2; in those studies that report findings in the F2 of irradiated males consistent with the induction of sex-linked lethals, efforts to isolate these presumed lethals have failed (cf 29), leading Lüning & Sheridan (51) to conclude that changes in the sex-ratio are an “unacceptable” way to search for sex-linked recessive lethals. Lyon et al (57) met many of the early problems by developing a strain with an X-chromosome inversion encompassing about 85% of the X-chromosome. Treated (500+500 rad) males of the F1 C3H/HeH×101/H stock were mated to females heterozygous for the inversion. Two of 536 irradiated and 0/529 control X-chromosome carried a confirmed lethal, corresponding to a rate for recessive lethals of 1.9×10-6/rad/X-chromosome. The authors suggest that this points to a locus rate much below that of the 7-locus system, but in the absence of control mutations, no doubling dose can be calculated.

The murine data most comparable to the least ambiguous aspects of the human data would be the proportion of males in the offspring of irradiated females. We have found no published murine data of this type. Accordingly, we have tabulated the (tertiary) sex-ratio observed at weaning in several relatively small experiments involving female radiation performed in the laboratory of one of the authors (S.E.L.) (Table 5). Note that these results are based on the radiation of mature oocytes. Two observations are noteworthy. First, in the controls (and irradiated) there is an insignificant excess of females (X2=1.658, d.f.=1, 0.10<p<0.20), whereas in humans at a corresponding stage in development, there is a slight excess of males. Second, the difference between the offspring of control and treated animals is (nonsignificantly) counter-hypothesis in sign (X2=0.124, d.f.=1, 0.70<p <0.80). Once again, loci on the X-chromosome appear resistant to the induction of lethal mutations.

Table 5 The sex ratio at weaning in the offspring of females treated with 300r and mated during the week following treatment.

 

No. litters

No. progeny at birth

Average birth litter size

Females

Males

Total

M/F Ratio

% Survival

Treated

488

3,265

6.7

1,475

1,331

2,806

.902

85.9±0.7

Concurrent control

51

390

7.6

171

148

319

.865

81.8±2.2

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Anthropometrics We have found no analysis of data on mouse body weight or other measurements in the first generation following parental radiation that allows for the litter-size effect. Accordingly, there do not seem to be any data suitable for comparison with the measurements on humans.

THE GENERATION OF A DOUBLING DOSE FROM THE MOUSE DATA

Unlike the human situation, in the various experiments with mice it has usually been possible to drive the system under study with sufficient radiation to obtain significant differences between the experimental and control material. This should increase the precision in estimation procedures and provide us in principle with two alternatives in calculating a doubling dose. On the one hand, we can simply combine the results of the various specific-locus/ specific-phenotype studies. This provides a very definite and clear-cut endpoint, which, however, does not readily translate into a morbidity-mortality figure comparable to the basis for the estimation of the human doubling dose. On the other hand, we can attempt to proceed as with the human data. This requires estimating the contribution of mutation in the parental generation to the incidence of malformed and dead fetuses, preweaning mortality, and sex-chromosome aneuploids, with the specific-locus findings represented in the calculation through their heterozygous effects on malformations and fetal deaths and preweaning mortality. While this procedure produces a more relevant figure, it requires assumptions that are probably even softer for mice than for humans.

In the derivations of a mouse gametic doubling dose to be extrapolated to humans, it is essentially the first approach that has been employed in the past. On this basis, various national and international committees have set the doubling dose of acute low-LET gonidal radiation for humans at 30 to 40 r, with limits of 10 to 100 r (reviewed in 12 , 105). That estimate appears to be based primarily on the data summarized pictorially by Lüning & Searle in 1971 (50 ; see also 97), namely, data on semisterility (=reciprocal translocations), the 7-locus system, dominant visible mutations, dominant skeletal mutations, and recessive lethals. The average of these values at that time was 31 r. Our Table 3 in essence extends the approach of Lüning & Searle (50), adding new data but, for consistency in the use of specific-locus/specific-phenotype results, omitting the findings on reciprocal translations (treated elsewhere in this review). The average of the eight estimates of Table 3 is 1.35 Gy.

As with the human data, these data sets are of variable information content, but none can justifiably be disregarded, and collectively they comprise a formidable body of data. Three of these estimates, however, are based on the

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

occurrence of a single mutation in the controls (cataract, skeletal defects, protein variants). One additional mutation in the controls would double the estimate of the doubling dose for these three outcomes. Thus, this estimate of 1.35 Gy carries a considerable potential for error. For the high doses of radiation employed in these studies, the appropriate dose-rate factor in converting to the effects of low-dose, chronic, or intermittent radiation is no less than 3.0 (86 , 87). This would lead to an estimate of the doubling dose for chronic radiation of approximately 4.0 Gy. The data in Table 3 are based on spermatogonial radiation, and are thus a male-oriented figure. When the failure to recover specific-locus mutations in the late litters of irradiated females (88) is considered, that doubling-dose estimate must be increased, to an indeterminate degree (but less than doubled).

The “information content” of the 7-locus test in particular outweighs that of any of the seven other specific-locus/specific-phenotype systems that have been employed, and some will argue a weighting system should be employed in estimating the doubling dose. However, both empirical and theoretical reasons considerations suggest that the component loci of the 7-locus system may be unusually responsive to the mutagenic effects of radiation. In the context of this discussion, it is important to bear in mind that W.L.Russell in his earliest presentations of the results of the system he had developed expressed concern over the “representativeness” of the loci he had selected (84). Since then significant progress has been made on the subject of “representativeness.”

To begin with, although the existence of mutable loci has been recognized for many years, it is now clear that loci in general show a wide range in spontaneous and induced mutability. In the mouse, five coat-color loci differed in their spontaneous mutability by a factor of 7 (but the individual estimates carry large errors) (31 , 91). Favor (20 ; Table 5) has emphasized the differing responses to radiation of the 7-locus, the cataract, and the enzyme-activity systems; data to that effect have also been presented in this review. With humans, recently we have suggested a tenfold difference in the mutation rates of loci encoding for serum transport proteins and erythrocyte enzymes, these loci having been selected for study only because of the clarity of resolution of their products with one-dimensional electrophoresis (9). We also suggest that the loci responsible for the cellular proteins visualized with two-dimensional polyacrylamide gel electrophoresis and silver staining, proteins sometimes referred to as ‘structural', are as a group less mutable than the loci encoding for erythrocyte and serum transport proteins (63).

Finally, in a recent mutagenization experiment using the TK6 line of lymphocytoid cells and employing ethylnitrosourea as mutagen, the products of 263 loci were scored for the occurrence of mutation resulting in electrophoretic variants, using the two-dimensional gel technique (34). Ten of

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

these 263 loci were known from family-oriented studies on peripheral lymphocytes to be associated with genetic polymorphisms. The induced mutation rate at these 10 loci was 3.6 times greater than at the monomorphic loci, an observation with a probability <0.004. Now, a specific-locus test system such as developed by Russell can only use loci associated with genetic variants. The possibility of a bias towards mutability in selecting the components of the specific-locus system is obvious. On the other hand, there may also be bias towards lesser mutability in some of the other systems; this will presumably become apparent with the passage of time. The least prejudicial procedure at present is simply to average the results of all valid approaches.

The alternative approach to developing an estimate of the doubling dose for the mouse is to attempt to analyze the mouse data in the context of radiation-induced morbidity and mortality, in keeping with the basis for the human estimate. At the outset of this review, it was indeed our intention to proceed in this direction, taking into due consideration the early studies on F1 characteristics following paternal radiation so well summarized by E.Green (30), as well as the later studies on nondisjunction, congenital malformations, and cancer. Unfortunately, as we have progressed, it has become clear that this is simply not feasible. The three dominant components of the human estimate are UPOs, prereproductive mortality among live-born offspring, and sex-chromosome aneuploids. As we have pointed out, each of the murine equivalents of these indicators differs in such important respects from the human data that a valid comparison does not seem possible. Even if this were not the case, however, there is a further reason for the inability to use the first two of these indicators. For the human data, we can estimate, albeit with considerable error, the contribution of mutation in the parental generation to the indicator; this is the necessary basis for an estimate of a doubling dose. For the mouse, no such estimates exist. Indeed, given the complex backgrounds of the various strains of experimental mice used in radiation experiments, it is not clear a normative figure comparable to the estimates for humans could be developed. Finally, relatively few of the published observations on litter size and survival in the older literature are on F1. Under the circumstances, then, we must compare a specific-locus/specific-phenotype estimate from the mouse with an estimate for humans based on the presumed genetic component in neonatal and childhood morbidity-mortality and sex-chromosome aneuploids.

SOME UNUSUAL FEATURES OF THE ESTIMATE OF THE MOUSE DOUBLING DOSE (FROM THE STANDPOINT OF EXTRAPOLATION TO HUMANS)

As with the human data, several features must be born in mind concerning the murine data:

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
  1. In the several decades following the advent of the atomic bombs, when major programs on mammalian radiation genetics were funded to provide guidance for human risks, the effort was about evenly distributed between programs oriented towards specific-locus tests and towards such strain characteristics as litter size, preweaning and lifetime mortality, body weight at various stages, and sex-ratio. When the latter programs failed to reveal the expected strain deterioration even after repeated generations of massive radiation (cf 30), whereas the specific-locus test was revealing rates greatly in excess of those encountered in Drosophila (cf 85), a consensus developed that the “strain deterioration” approach—which should reflect the impact of mutation at all loci—was too blunt an instrument for the problem (cf 30 , 48). At the same time, however, investigators repeatedly suggested that the loci of the specific-locus test of Russell (84) might be unusually sensitive to the genetic effects of radiation (e.g. 42 , 45 , 48 , 80 , 84), and also recognized the many difficulties in extrapolating from mice to humans (see 43 , 48 , 53). The present analysis has attempted to meet those concerns by using all the specific-locus/specific-phenotype data available.

  2. The exclusive use of specific-locus/specific-phenotype data in reaching a murine doubling dose entails fewer assumptions than in the human estimate but also reflects a smaller sampling of the total genome.

  3. A problem with the mouse data that may never be rectified is lack of data on a variety of genetic endpoints in the late litters of irradiated females. If, for whatever reason, all other specific-locus/specific-phenotype indicators behave as do those in the 7-locus test, then the results of female radiation can be only a fraction of the results of male, and the doubling dose of chronic radiation for a normal (two-sexed) mouse population will be substantially higher than the 4.0 Gy we have estimated, and would exceed the estimate for humans, although, given the looseness of these estimates, probably not “significantly” so.

CONCLUSIONS

Studies of eight indicators in the children of atomic bomb survivors and suitable controls have led us to suggest that the gametic doubling dose for the spectrum of acute gonadal radiation experienced by survivors of the atomic bombings is in the neighborhood of 2.0 Sv. Inasmuch as statistically significant effects were not encountered with any of the indicators, this estimate carries a large but indeterminate error. Additional error may be introduced by the assumptions made concerning the extent to which mutation in the parental generation contributes to some of these indicators. For an extrapolation to the effects of chronic radiation, we employ for these specific exposures a dose-rate factor of 2, resulting in an estimate of 4.0 Sv.

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

A review of all of the pertinent murine data was undertaken, organized to be as comparable as possible to the human data. Because of the differences in the maturity of mice and humans at birth, plus radiation-induced litter-size effects that, as we have shown, strongly influence pre-and postnatal survival, much of the mouse data cannot be compared directly with the human data. The strongest aspect of the mouse data—which is the weakest aspect of the human data—are the specific-locus, specific-phenotype studies. Averaged, these lead to a doubling-dose estimate for acute spermatogonial radiation of 1.35 Gy. Because of the higher acute doses employed in the mouse experiments than obtain for the human experience, we suggest a dose-rate factor of not less than 3, leading to a doubling-dose estimate for chronic radiation of approximately 4.0 Gy. Although the situation requires that we express the human and mouse estimates in different units, in any practical sense the human and mouse doubling dose estimates for chronic radiation are very similar.

The current general agreement between these estimates, reached by relatively independent approaches, is noteworthy, albeit, as we have repeatedly emphasized, the error in both estimates is large but essentially indeterminate. There is, of course, no reason to expect identical doubling doses in two such different species. Together, however, these estimates suggest that the genetic risk of low-dose rate, low-LET radiation for humans is less than has generally been assumed during the past 30 years.

As noted in the Introduction, the attempt to develop a rounded appraisal of the genetic effects of radiation on either the mouse or human genome represents one of the most complex undertakings of modern genetics. The forthrightness with which we have dealt with certain problems with both the human and murine data should not divert attention from the great progress that has been made. Inasmuch as the general issue of genetic damage from environmental exposures will be with society for some time to come, we hope that this discussion of the problems inherent in the present data, both human and mouse, will be useful in planning the experiments and observations of the future. Space constraints unfortunately do not permit discussion of possible future developments and especially the exciting prospects inherent in the parallel study in the two species of radiation-induced mutation in DNA.

This review was well along when the most recent report of the Committee on the Biological Effects of Ionizing Radiation (13) appeared. With respect to the human data, the Committee treatment was appropriate to the time, but, unfortunately, the Committee did not have access to the most recent analyses-syntheses of the Japanese data, based on the DS86 dose schedule, which, we suggest, place the human estimates on somewhat firmer footings than previously. With respect to the mouse data, where we have analyzed essentially the same findings, our approach in an effort to use the mouse data most appropriate to the human situation leads to a somewhat higher estimate of the doubling dose of chronic radiation for the mouse than the Committee's, and

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

lessens the apparent conflict between the two sets of data that the Committee identifies in its report.

ACKNOWLEDGMENTS

James V.Neel gratefully acknowledges the support of Department of Energy Grant FG02–8760533 and Susan E.Lewis similarly acknowledges the support of NIH Contract No. 1-ES-55078. We are greatly indebted to Dr. Josephine Peters for critiquing the manuscript and making available unpublished data on mutation rates in an electrophoretic system, and to Drs. Michael Shelby and Robert P.Erickson for a critical reading of the manuscript.

Literature Cited

1. Abrahamson, S., Wolff, S. 1976. Reanalysis of radiation-induced specific locus mutations in the mouse . Nature 264:715–19

2. Awa, A.A. 1975. Cytogenetic study. J.Radiat. Res. 16:75–81 (Suppl.)

3. Awa, A.A., Bloom, A.D., Yoshida, M.C., Neriishi, S., Archer, P. 1968. A cytogenetic survey of the offspring of atomic bomb survivors. Nature 218: 367–68

4. Awa, A.A., Honda, T., Neriishi, S., Sufuni, T., Shimba, H., et al. 1987. Cytogenetic study of the offspring of atomic bomb survivors, Hiroshima and Nagasaki. In Cytogenetics: Basic and Applied Aspects , ed. G.Obe, A.Basler, pp. 166–83. Heidelberg: Springer-Verlag

5. Bailey, D.W. 1963. Histoincompatability associated with the X chromosome in mice. Transplantation 1:70–74

6. Bailey, D.W., Kohn, H.I. 1965. Inherited histocompatability changes in the progeny of irradiated and unirradiated inbred mice. Genet. Res. 6:330–40

7. Bailey, D.W., Usama, B. 1960. A rapid method of grafting skin on tails of mice. Transplant. Bull. 7:424–25

8. Batra, B.K., Stridharan, B.N. 1964. A study of the progeny of mice descended from X-irradiated females with special reference to the gonads. Acta Unio Int.Contra Cancrum 20:1181–86

8a. Baverstock, K.F., Stather, J.W., eds. 1989. Low Dose Radiation: BiologicalBases of Risk Assessment . London: Taylor & Francis

9. Chakraborty, R., Neel, J.V. 1989. Description and validation of a method for simultaneous estimation of effective population size and mutation rate from human population data. Proc. Natl.Acad. Sci. USA 86:9407–11

10. Charles, D.J., Pretsch, W. 1986. Enzyme-activity mutations detected in mice after paternal fractionated irradiation. Mutat. Res. 160:243–48

11. Charles, D.R., Tihen, J.A., Otis, E. M., Grobman, A.B. 1960. Genetic effects of chronic x-irradiation exposure in mice. AEC Res. Devel. Rep. UR-565 . Off. Tech. Serv., Dept. Commerce. 354

12. Comm. Biol. Effects of Ionizing Radiat. 1980. The Effects of Populations of Exposure to Low Levels of Ionizing Radiation (BEIR III) , pp. xv & 524 Washington, DC: Natl. Acad. Press

13. Comm. Biol. Effects of Radiat. 1990. Health Effects of Exposure to LowLevels of Ionizing Radiation (BEIR V) , pp. xiii & 421 Washington, DC: Natl. Acad. Press

14. de Serres, F.J. 1958. Studies with purple adenine mutants in Neurospora crassa. III. Reversion of X-ray-induced mutants. Genetics 43:187–206

14a. de Serres, F.J., Sheridan, W., eds. 1983. Utilization of Mammalian SpecificLocus Studies in Hazard Evaluation and Estimation of Genetic Risk . New York: Plenum

15. Ehling, U.H. 1966. Dominant mutations affecting the skeleton in offspring of X-irradiated male mice. Genetics 54:1381–89

16. Ehling, U.H., Charles, D.J., Favor, J., Graw, J., Kratochvilova, J., et al. 1985. Induction of gene mutations in mice: The multiple endpoint approach . Mutat.Res. 150:393–401

17. Endo, A., Watanabe, T. 1989. A case of X-trisomy in the mouse. Cytogenet. CellGenet. 52:98–99

18. Erickson, R.P. 1989. Why isn't a mouse more like a man?Trends Genet. 5:1–3

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

19. Evans, H.S. 1977. Chromosome abnormalities among live-births. J. Med. Genet. 14:309–12

20. Favor, J. 1989. Risk estimation based on germ cell mutations in animals. Proc. 16th Int. Congr. Genet., Genome 31: 844–52

21. Ford, C.E., Searle, A.G., Evans, E. P., West, B.J. 1969. Differential transmission of translocations induced in spermatogonia of mice by irradiation. Cytogenetics 8:447–70

22. Furusho, T., Otake, M. 1978. A search for genetic effects of atomic bomb radiation on the growth and development of the F1 generation. 1. Stature of 15- to 17-year-old senior high school students in Hiroshima. Hiroshima: RERF Tech. Rep. 4–78. 33 pp.

23. Furusho, T., Otake, M. 1978. A search for genetic effects of atomic bomb radiation on the growth and development of the F1 generation. 2. Body weight, sitting height, and chest circumferences of 15- to 17-year-old senior high school students in Hiroshima. Hiroshima: RERF Tech. Rep. 5–78. 16 pp.

24. Furusho, T., Otake, M. 1979. A search for genetic effects of atomic bomb radiation on the growth and development of the F1, generation. 3. Stature of 12- to 14-year-old junior high school students in Hiroshima. Hiroshima: RERF Tech. Rep. 14–79. 26 pp.

25. Furusho, T., Otake, M. 1980. A search for genetic effects of atomic bomb radiation on the growth and development of the F1 generation. 4. Body weight, sitting height, and chest circumference of 12- to 14-year-old junior high school students in Hiroshima. Hiroshima: RERF Tech. Rep. 1–80. 18 pp.

26. Furusho, T., Otake, M. 1985. A search for the genetic effects of atomic bomb radiation on the growth and development of the F1 generation. 5. Stature of 6- to 11-year-old elementary school pupils in Hiroshima. Hiroshima: RERF Tech. Rep. 9–85. 33 pp.

27. Generoso, W.M., Cain, K.T., Cacheiro, N.C.A., Cornett, C.V. 1984. Response of mouse spermatogonial cells to X-ray induction of heritable reciprocal translocations. Mutat. Res. 126:177–87

28. Godfrey, J., Searle, A.G. 1963. A search for histocompatibility differences between irradiated sublines of inbred mice. Genet. Res. 4:21–29

29. Grahn, D., Leslie, W.P., Verkey, F. A., Lea, R.A. 1972. Determination of the radiation-induced rate for sex-linked lethals and detrimentals in the mouse. Mutat. Res. 15:331–47

30. Green, E.L. 1968. Genetic effects of radiation on mammalian populations. Annu. Rev. Genet. 2:87–120

31. Green, E.L., Schlager, G., Dickie, M. M. 1965. Natural mutation rates in the house mouse: plan of study and preliminary estimates. Mutat. Res. 2:457– 65

32. Green, M.C., ed. 1981. Genetic Vari ants and Strains of the Laboratory Mouse , pp. xvi & 476. New York: Fischer

33. Griffin, C.S., Tease, C. 1988. ?-ray induced numerical and structural chromosome anomalies in mouse immature oocytes. Mutat. Res. 202:209–13

34. Hanash, S.M., Boehnke, M., Chu, E. H.Y. , Neel, J.V., Kuick, R.D. 1988. Nonrandom distribution of structural mutants in ethylnitrosourea-treated cultured human lymphoblastoid cells. Proc. Natl. Acad. Sci. USA 85:165–69

35. Hook, E.B. 1985. The impact of aneuploidy upon public health: mortality and morbidity associated with human chromosome abnormalities. In An euploidy: Etiology and Mechanisms , ed. V.L.Dellarco, P.E.Voytek, A.Hollaender, pp. 7–33. New York: Plenum

36. Hook, E.B., Topol, B.B., Cross, P.K. 1989. The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: New data and estimates of the excess and relative risk of late fetal death associated with 47, & 21 and some other abnormal karyotypes . Am. J.Hum. Genet. 45:855–61

37. Int. Comm. Radiat. Units Meas. 1986. The Quality Factor in Radiation Protec tion. Rep. 40 . Bethesda: ICRUM. 32 pp.

38. Johnson, F.M., Lewis, S.E. 1981. Electrophoretically detected germinal mutations induced in the mouse by ethylnitrosourea. Proc. Natl. Acad. Sci. USA 78:3138–41

39. Kato, H., Schull, W.J., Neel, J.V. 1966. A cohort-type study of survival in the children of parents exposed to atomic bombings. Am. J. Hum. Genet. 18:339– 73

40. Kirk, K.M., Lyon, M.F. 1982. Induction of congenital anomalies in offspring of female mice exposed to varying doses of x-rays. Mutat. Res. 106:73–83

41. Kirk, K.M., Lyon, M.F. 1984. Induction of congenital malformations in the offspring of male mice treated with x-rays at pre-meiotic and post-meiotic stages. Mutat. Res. 125:75–85

42. Kohn, H.I. 1979. X-ray mutagenesis:

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

Results of the H-test compared with others and the importance of selection and/ or repair. Genetics 9 2(Suppl. 1:1):203– 9

43. Kohn, H.I. 1983. Radiation genetics: The mouse's view. Radiat. Res. 94:1– 9

44. Kohn, H.I., Epling, M.L., Guttman, P.H., Bailey, D.W. 1965. Effect of paternal (spermatogonial) X-ray exposure in the mouse: Lifespan, X-ray tolerance, and tumor incidence of the progeny. Radiat. Res. 25:423–34

45. Kohn, H.I., Melvold, R.W. 1976. Divergent x-ray-induced mutation rates in the mouse for H and “7-locus” groups of loci. Nature 259:209–10

46. Kohn, H.I., Melvold, R.W., Dunn, G. R. 1976. Failure of x-rays to mutate Class II histocompatibility loci in BALB/c mouse spermatogonia. Mutat. Res. 37:237–44

47. Kratochvilova, J. 1981. Dominant cataract mutations detected in offspring of gamma-irradiated male mice. J.Hered. 72:302–7

48. Lüning, K.G. 1979. Some problems in the assessment of risks. Genetics 92(Suppl. 1:1): 121–26

49. Lüning, K.G., Eiche, A. 1975. X-ray induced recessive lethal mutations in the mouse. Mutat. Res. 34:63–174

50. Lüning, K.G., Searle, A.G. 1971. Estimates of the genetic risks from ionizing radiation. Mutat. Res. 12:291–304

51. Lüning, K.G., Sheridan, W. 1971. Changes in sex-proportion: an unacceptable way to estimate sex-linked recessive lethals. Mutat. Res. 13:77–83

52. Lyon, M.F. 1959. Some evidence concerning the ‘mutational load' in inbred strains of mice. Heredity 13:341–52

53. Lyon, M.F. 1983. Problems in extrapolation of animal data to humans. See Ref. 14a, pp. 289–305

54. Lyon, M.F., Morris, T. 1966. Mutation rates at a new set of specific loci in the mouse. Genet. Res. 7:12–17

55. Lyon, M.F., Morris, T. 1969. Gene and chromosome mutation after large fractionated or unfractionated radiation doses to mouse spermatogonia. Mutat. Res. 8:191–98

56. Lyon, M.F., Phillips, R.J.S., Fisher, G. 1979. Dose-response curves for radiation-induced gene mutations in mouse oocytes and their interpretation. Mutat. Res. 63:161–73

57. Lyon, M.F., Phillips, R.J.S., Fisher, G. 1982. Use of an inversion to test for induced X-linked lethals in mice. Mutat. Res. 92:217–28

58. Lyon, M.F., Phillips, R.J.S., Searle, A.G. 1964. The overall rates of dominant and recessive lethal and visible mutations induced by spermatogonial xirradiation of mice. Genet. Res. 5:448– 67

59. Malling, H.V., de Serres, F.J. 1973. Genetic alterations at the molecular level in X-ray induced ad-3B mutants of Neurospora crassa . Radiat. Res. 53:77– 87

60. Max, C. 1977. Cytological investigation of embryos in low-dose X-irradiated young and old inbred mice. Hereditas 85:199–206

61. Natl. Counc. Radiat. Prot. Meas. 1980. Influence of dose and its distribution in time on dose-response relationships for low-LET radiations. Washington, DC: NCRP Rep. 64 :vi & 216

62. Neel, J.V. 1958. A study of major congenital defects in Japanese infants. Am. J.Hum. Genet. 10:398–445

63. Neel, J.V. 1990. Average locus differences in mutability related to protein “class”: A hypothesis. Proc. Natl. Acad. Sci. USA 86:9407–11

64. Neel, J.V., Kato, H., Schull, W.J. 1974. Mortality in the children of atomic bomb survivors and controls. Genetics 76:311–26

65. Neel, J.V., Satoh, C., Goriki, K., Asakawa, J-I., Fujita, M., et al. 1988. Search for mutations altering protein charge and/or function in children of atomic bomb survivors: Final report . Am. J.Hum. Genet. 42:663–76

66. Neel, J.V., Schull, W.J. 1956. The effect of exposure to the atomic bombs on pregnancy termination in Hiroshima and Nagasaki. Natl. Acad. Sci. Natl. Res. Counc. Publ. 461 . Washington, DC. pp. xvi & 241

67. Neel, J.V., Schull, W.J., Awa, A.A., Satoh, C., Kato, H., et al. 1990. Children of parents exposed to atomic bombs: Estimates of the genetic doubling dose of radiation for humans. Am. J.Hum. Genet. 46:1053–72

68. Neel, J.V., Schull, W.J., Awa, A.A., Satoh, C., Otake, M., et al. 1989. The genetic effects of the atomic bombs: Problems in extrapolating from somatic cell findings to risk for children. See Ref. 8a, pp. 42–53

69. Neel, J.V., Schull, W.J., Awa, A.A., Satoh, C., Otake, M., et al. 1989. Implications of the Hiroshima-Nagasaki genetic studies for the estimation of the human “doubling dose” of radiation. Proc. 16th Int. Congr. Genet., Genome 31:853–59

70. Nomura, T. 1978. Changed urethan and radiation response of the mouse germ

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

cell to tumor induction. In Tumours of Early Life in Man and Animals , ed. L. Severi, pp. 873–91. Monteluce, Italy: Perugia Quadrenn. Int. Conf. Cancer

71. Nomura, T. 1982. Parental exposure to X-rays and chemicals induces heritable tumours and anomalies in mice. Nature 296:575–77

72. Nomura, T. 1983. X-ray-induced germline mutation leading to tumors. Its manifestation in mice given urethane postnatally. Mutat. Res. 121:59–65

73. Nomura, T. 1986. Further studies on X-ray and chemically induced germ-line alterations causing tumors and malformations in mice. See Ref. 77a, pp. 13–20

74. Otake, M., Schull, W.J., Neel, J.V. 1990. The effects of exposure to the atomic bombing of Hiroshima and Nagasaki on congenital malformations, stillbirths and early mortality among the children of atomic bomb survivors: A reanalysis. Radiat. Res. 122:1–11

75. Otis, E.M., Brent, R. 1952. Equivalent ages in mouse and human embryos. Anat. Res. 120:33–64

76. Peters, J., Ball, S.T., Andrews, S.J. 1986. The datechain of gene mutations by electrophoresis and their analyses . Prog. Clin. Biol. Res. 209B:367–74

77. Pretsch, W. 1986. Protein-charge mutations in mice. Prog. Clin. Biol. Res. 209B:383–89

77a. Ramel, C., Lambert, B., Magnussen, J., eds. 1986. Genetic Toxicology of En vironmetal Chemicals, Part B: Genetic Effects and Applied Mutagenesis. New York: Liss

78. Reddi, D.S. 1965. Radiation induced translations in mouse spermatogonia. Mutat. Res. 2:95

79. Roderick, T.H., ed. 1964. The effects of radiation on the hereditary fitness of mammalian populations . Genetics 50: 1213–17

80. Roderick, T.H. 1983. Using inversions to detect and study recessive lethals and detrimentals in mice. See Ref. 14a, pp. 135–67

81. Roesch, W.C., ed. 1987. US-Japan Reassessment of Atomic Bomb Radiation Dosimetry in Hiroshima and Nagasaki 1:434. Hiroshima: RERF

82. Russell, L.B. 1976. Numerical sex-chromosome anomalies in mammals: Their spontaneous occurrence and use in mutagenesis studies. In Chemical Mutagens. Principles and Methods for Their Detection , ed. A.Hollaender, 4:55–91. New York: Plenum

83. Russell, L.B., Rinchik, E.M. 1987. Genetic and molecular characterization of genomic regions surrounding specific loci of the mouse. Banbury Rep. 28: 109–21

84. Russell, W.L. 1951. X-ray induced mutations in mice. Cold Spring Harbor Symp. Quant. Biol. 16:327–36

85. Russell, W.L. 1956. Comparison of x-ray-induced mutation rates in Drosophila and mice . Am. Nat. 90:69–80

86. Russell, W.L. 1963. The effect of radiation dose rate and fractionation on mutation in mice. In Repair from Genet ic Radiation , ed. F.H.Sobels, pp. 205– 17. London: Pergamon

87. Russell, W.L. 1965. The nature of the dose-rate effect of radiation on mutation in mice . Proc. Conf. Mech. Dose Rate Effect Radiat. Jpn. J.Genet. 40:128–40 (Suppl.)

88. Russell, W.L. 1965. Effect of the interval between irradiation and conception on mutation frequency in female mice. Proc. Natl. Acad. Sci. USA 54: 1552–57

89. Russell, W.L., Russell, L.B., Kelly, E.M. 1958. Radiation dose rate and mutation frequency. Science 128:1546– 50

90. Sankaranarayanan, K. 1988. Prevalence of genetic and partially genetic diseases in man and the estimation of genetic risks of exposure to ionizing radiation. Am. J.Hum. Genet. 42:651–62

91. Schlager, G., Dickie, M.M. 1967. Spontaneous mutations and mutation rates in the house mouse. Genetics 57: 319–30

92. Schull, W.J., Neel, J.V., Hashizume, A. 1966. Some further observations on the sex ratio among infants born to survivors of the atomic bombings of Hiroshima and Nagasaki. Am. J.Hum. Genet. 18:328–38

93. Schull, W.J., Otake, M., Neel, J.V. 1981. Genetic effects of the atomic bombs: A reappraisal. Science 213: 1220–27

94. Searle, A.G. 1964. Effects of low-level irradiation on fitness and skeletal variation in an inbred mouse strain. Genetics 50:1159–78

95. Searle, A.G. 1964. Genetic effects of spermatogonial X-irradiation on productivity of F1, female mice. Mutat. Res. 1:99–108

96. Searle, A.G. 1974. Mutation induction in mice. In Advances in Radiation Biolo gy , ed. J.T.Lett, H.I.Adler, A.Zelle, 4:131–207. New York: Academic

97. Searle, A.G. 1977. Radiological protection and assessment of genetic risk. J. Med. Gen. 14:307–8

98. Searle, A.G. 1989. Evidence from

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×

mammalian studies on genetic effects of low-level irradiation. See Ref. 8a, pp. 123–38

99. Searle, A.G., Beechey, C. 1986. The role of dominant visibles in mutageneity testing. See Ref. 77a, pp. 511–18

100. Selby, P.B., Selby, P.R. 1977. Gamma-ray induced dominant mutations that cause skeletal abnormalities in mice. I. Plan, summary of results, and discussion. Mutat. Res. 43:357–75

101. Selby, P.B., Selby, P.R. 1978. Gamma-ray-induced dominant mutations that cause skeletal abnormalities in mice. II. Description of proved mutations. Mutat. Res. 51:199–236

102. Sheridan, W., Wårdell, I. 1968. The frequency of recessive lethals in an irradiated mouse population . Mutat. Res. 5:313–21

103. Speed, R.M., Chandley, A.C. 1981. The response of germ cells of the mouse to the induction of non-disjunction by X-rays. Mutat. Res. 84:409–18

104. UN Sci. Comm. Effects of At. Radiat. 1977. Sources and Effects of Ionizing Radiation . New York: United Nations. 725 pp.

105. UN Sci. Comm. Effects At. Radiat. 1986. Genetic and Somatic Effects of Ionizing Radiation . New York: United Nations. 366 pp.

106. Van Buul, P.P.W. 1983. Induction of chromosomal aberrations by ionizing radiation in stem cell spermatogonia of mammals. In Radiation-induced Chrom osome Damage in Man , ed. T.Ishihara, M.S.Sasaki, pp. 369–400. New York: Liss

107. West, J.D., Kirk, K.M., Goyder, Y., Lyon, M.F. 1985. Discrimination between the effects of X-ray irradiation of the mouse oocyte and uterus on the induction of dominant lethals and congenital anomalies. I. Embryo transfer experiments. Mutat. Res. 149:221–30

108. West, J.D., Kirk, K.M., Goyder, Y., Lyon, M.F. 1985. II. Localized irradiation experiments. Mutat. Res. 149:231– 38

109. Yoshimoto, Y., Neel, J.V., Schull, W. J., Kato, H., Mabuchi, K., et al. 1990. Malignant tumors during the first two decades of life in the offspring of atomic bomb survivors. Am. J.Hum. Genet. 46:1041–52

Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 451
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 452
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 453
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 454
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 455
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 456
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 457
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 458
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 459
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 460
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 461
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 462
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 463
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 464
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 465
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 466
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 467
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 468
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 469
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 470
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 471
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 472
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 473
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 474
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 475
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 476
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 477
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 478
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 479
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 480
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 481
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 482
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 483
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 484
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 485
Suggested Citation:"The Comparative Radiation Genetics of Humans and Mice." National Research Council. 1991. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: The National Academies Press. doi: 10.17226/1800.
×
Page 486
Next: The Future of These Studies »
The Children of Atomic Bomb Survivors: A Genetic Study Get This Book
×
Buy Paperback | $135.00
MyNAP members save 10% online.
Login or Register to save!

Do persons exposed to radiation suffer genetic effects that threaten their yet-to-be-born children? Researchers are concluding that the genetic risks of radiation are less than previously thought.

This finding is explored in this volume about the children of atomic bomb survivors in Hiroshima and Nagasaki—the population that can provide the greatest insight into this critical issue. Assembled here for the first time are papers representing more than 40 years of research. These documents reveal key results related to radiation's effects on pregnancy termination, sex ratio, congenital defects, and early mortality of children. Edited by two of the principal architects of the studies, J. V. Neel and W. J. Schull, the volume also offers an important comparison with studies of the genetic effects of radiation on mice.

The wealth of technical details will be immediately useful to geneticists and other specialists. Policymakers will be interested in the overall conclusions and discussion of future studies.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!