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The Comparative Radiation Genetics of Humans and Mice
Pages 451-486

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From page 452...
... . A PRECIS 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 THE CHILDREN OF ATOMIC BOMB SURVIVORS 452
From page 453...
... 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)
From page 454...
... , 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 THE CHILDREN OF ATOMIC BOMB SURVIVORS 454
From page 455...
... 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 dead THE CHILDREN OF ATOMIC BOMB SURVIVORS 455
From page 457...
... 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 Fit Mortality Study described earlier (2~. 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.
From page 458...
... 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-offunction mutations were combined, the mutation rate in the children of proximally exposed was 0.60 x 10-5/locus/generation, with 95% confidence intervals between 0.2 and 1.5 x 10-5/locus/generation.
From page 459...
... 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 (671.
From page 460...
... 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.
From page 461...
... 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 Inust be kept in mind: 1. None of the studies has yielded a statistically significant difference be THE CHILDREN OF ATOMIC BOMB SURVIVORS .
From page 462...
... PRECIS 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.
From page 463...
... 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 THE CHILDREN OF ATOMIC BOMB SURVIVORS 463
From page 464...
... These experiments establish that radiation increases the frequency of con THE CHILDREN OF ATOMIC BOMB SURVIVORS 464
From page 465...
... 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 (1 1)
From page 466...
... 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.
From page 467...
... 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 THE CHILDREN OF ATOMIC BOMB SURVIVORS 467
From page 468...
... 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~.
From page 469...
... ~ mice, with a spontaneous rate for heritable reciprocal translocation in spermatogonia of 1.8 x 10-4/gamete/generation and an induced rate of 3.9 x 10 s/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 He children of exposed and controls, the human data appear to be inconsistent with the mouse doubling dose reported by Generoso et al (27~.
From page 470...
... 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 X 10-7, depending on the dose (1,628,277 locus tests)
From page 471...
... 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.
From page 472...
... 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~.
From page 473...
... , 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 postsperrnatogonial cells, however, he adduces, in a small senes, a lethal rate per locus of 0.35 x 10-~/r, based on an estimated 1750 loci in the segment of chromosome 1 being screened.
From page 475...
... , 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.
From page 476...
... The munne 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.
From page 477...
... 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 Me THE CHIIDREN OF ATOMIC BOMB SURVIVORS 477
From page 478...
... 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 ery~rocyte enzymes, these loci having been selected for study only because of the clarity of resolution of their products with one-dimensional electrophoresis (9~.
From page 479...
... SOME UNUSUAL FEATURES OF THE ESTIMATE OF THE MOUSE DOUBLING DOSE (FROM THE STANDPOINT OF EXTRAPOLATION TO HUMANS) As win the human data, several features must be born in mind concerning Me murine data: THE CHILDREN OF ATOMIC BOMB SURVIVORS 479
From page 480...
... 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 cames a large but indeterminate error.
From page 481...
... The strongest aspect of the mouse data which is the weakest aspect of We human data are the specific-locus, specific-phenotype studies. Averaged, these lead to a doubling-dose estimate for acute sperrnatogonial radiation of 1.35 Gy.
From page 482...
... 1960. Genetic effects of chronic x-irradiation exposure in mice.
From page 483...
... 1980. A search for genetic effects of atomic bomb radiation on the growth and development of the F
From page 484...
... 1989. The genetic effects of the atomic bombs: Problems in extrapolating from somatic cell findings to risk for children.
From page 485...
... 1981. Genetic effects of the atomic bombs: A reappraisal.
From page 486...
... 1990. Malignant tumors during the first two decades of life in the offspring of atomic bomb survivors.


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