Health Effects of Exposure to Low Levels of Ionizing Radiation BEIR V (1990) / Chapter Skim
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2 Genetic Effects of Radiation
2 Genetic Effects of Radiation
Pages 65-134
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From page 65... ...
Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) has also addressed the genetic effects of radiation exposure on populations.
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From page 66... ...
There are many difficulties in measuring the genetic effects of exposure of the human population to radiation and other mutagens. This is why, more than 20 years after the BEAR Committee first addressed the issues of radiation exposure, there is still uncertainty and controversy.
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From page 67... ...
Deliberate exposure of humans to radiation without diagnostic or therapeutic justification is unacceptable, and therefore, most genetic studies have had to be carried out in experimental organisms, particularly mice. Such studies raise numerous additional problems of their own, including extrapolation of results obtained under experimental conditions to the conditions relevant to population exposure, such as dose rates, fractionation, and other variables; and extrapolation from an experimental organism such as the mouse, in which radiation effects may be estimated with some confidence, to humans, because organisms differ in radiation sensitivity.
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From page 68... ...
The indirect method required estimates of the mutation rates, the incidence of genetic disease in the human population, and the extent to which the incidence depends on recurrent mutation, to infer the increased incidence of genetic disease resulting from radiation exposure. Both immediate, firstgeneration effects and long-term, equilibrium effects were estimated from either the direct or indirect estimates of induced mutation by taking into account the presumed rates of mutant elimination to project the ratio of newly induced genetic damage to that transmitted from previous generations.
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From page 69... ...
Much of the uncertainty in estimating the risks of radiation-induced mutations centers on traits with complex patterns of inheritance that result from the combination of multiple genetic and environmental factors. Risk estimates are determined in part by the degree to which these traits are
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From page 70... ...
. qulllorlum 25e 75e <5 Very slow increase translocations600h<5 Very little increase Trisomies3,800'< 1 < 1 Congenital abnormalities20,000-30,00010' 10-100k Other disorders of complex etiology Heart diseased600,000 Cancer300,000Not estimated Not estimated Selected others300,000 a Risks pertain to average population exposure of 1 rem per generation to a population with the spontaneous genetic burden of humans and a doubling dose for chronic exposure of 100 rem (1 Sv)
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From page 71... ...
(2-1) As a hypothetical example, if the spontaneous burden is 20,000 per million liveborn for some class of genetic disease in the human population, the doubling dose is estimated to be 100 rem, and the average mutation component for these diseases is one-half, then, if the parents in each generation are exposed to 1 rem, the induced burden is 100 cases/106 liveborn/generation.
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From page 72... ...
By definition, the doubling dose is that dose required to induce a number of mutations equal to the spontaneous frequency. However, its use in this report is confined to the range of low doses at which the dose-response curve is essentially linear.
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From page 73... ...
to estimate first-generation effects for dominant mutations rather than relying on the assumption of the proportionate effects implicit in the doubling dose method. In the direct method, the induction rate for a specific class of defects in mice (e.g., cataracts and skeletal anomalies)
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From page 74... ...
The doubling dose range given by the BEAR Committee would now be considered to apply to acute radiation. It must be remembered that at the time that the BEAR report was written, neither the dose-rate effect nor the distinction between premeiotic and postmeiotic cell stage response to radiation were known.
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From page 75... ...
Unlike BEIR I, which constructed a hybrid doubling dose based on the induced mutation rate in mice and the spontaneous mutation rate in humans, BEIR III chose to calculate a doubling dose for mice and extrapolate it to humans. The stated objection to the BEIR I method was that it mixed the induced rate of a set of mouse genes preselected for high mutability with an estimate of a human spontaneous rate for more typical genes.
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From page 76... ...
Additional uncertainties complicate the estimation of human doubling dose. For example, neither the total spontaneous rate nor the induction rates per red (which are not significantly different from zero in the Japanese data)
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From page 77... ...
BEIR III (NRC80) assumed the doubling doses to be in the range of 50-250 R and similar estimates for the spontaneous burden and fitness as in BEIR I, from which the formula estimates 8-40 cases/106 liveborn/R.
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From page 78... ...
= 14 x 10-6 In these and the previous example the correction factors used for low dose rate, fractionation, and sex were all derived from data using the mouse specific locus system for detecting recessive mutations, which is described in a section on animal studies later in this chapter.
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From page 79... ...
Alternatively, one can use Childs' estimates of the spontaneous mutation rates for these disorders, by means of the approximate relation first-generation effect = 2U/doubling dose where U = 409 x 10-6 is the total spontaneous mutation rate (Chaff. The estimate is 8 cases/106 liveborn/R.
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From page 80... ...
If R is between 3 and 1, the proportion of the equilibrium excess cases occurring in the first generation is between 0.15 and 0.25. For a doubling dose of 100 rem, this implies less than 1 case/106 liveborn in the first generation.
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From page 81... ...
If this sum is taken to be on the order of 1 and the spontaneous mutation rate is taken to be 12 x 10-6, (Mo81) , then for a doubling dose of 100 rem, the first-generation effect is less than 1 recessive case/106 liveborn/rem, confirming previous expectations.
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From page 82... ...
= 3.7 x 10-5 balanced translocations/rem, where 1/2 is a dose rate correction, and 0.4 is a relative biological effectiveness (RBE) correction to go from x rays to gamma rays.
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From page 83... ...
NUREG makes a correction for x rays to gamma rays (NCRP80) , but BEIR III does not.
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From page 84... ...
at low doses are at variance with results of subsequent studies (Go81, 1682~. Therefore, notwithstanding the importance of nondisjunction to the spontaneous burden in humans, it appears that the induction of nondisjunction by low-level irradiation of immature oocytes may not present a serious concern.
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From page 85... ...
BEIR III accepted this estimate and combined it with their own doubling dose range of 50-250 R and mutation component range of 5-50% to estimate an equilibrium excess of 20-900 induced cases of irregularly inherited disorders/R/106 liveborn. No first generation effect was estimated.
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From page 86... ...
. The BEIR III Committee dealt with these uncertainties as well as they could and considered a range of mutation component between 5 and FOR.
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From page 87... ...
15 TOTAL 54.1 a All values except birth incidences are rounded to the nearest 5%. b Ranges are +1 standard deviation, i.e., an approximate 68% confidence interval.
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From page 88... ...
In any event, whether the mutation components of these disorders are closer to 5 or 50% (the BEIR III range) , the uniformly low narrow heritabilities would indicate that the approach to equilibrium following a rise in the mutation rate would be very slow indeed.
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From page 89... ...
Consequently, the mutation components are indeterminant without further information, but it seems likely that any change in the frequencies of these diseases caused by a change in the mutation rate would be attained very slowly. The data in Bible 2-4 are for selected diseases and do not include data for cancer and heart disease, which are the most common diseases
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From page 90... ...
Unfortunately, the mutational component is not known even to its order of magnitude, and for this reason, as well as other complexities enumerated in the preceding section on congenital abnormalities, the committee has not estimated risks for this category of traits. While the risks could be negligible, they could also be as large or larger than all the other entries in Able 2-1 combined.
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From page 91... ...
The most dramatic discrepancy is between the data of Stevenson and those of Nimble and Doughty with respect to autosomal dominant disorders. The Stevenson estimate of 30.7/1,000 live births is inflated by the
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From page 92... ...
Estimating Spontaneous Mutation Rates Table 2-6 gives some representative mutation rates estimated in humans. These values are consistent with the values given more than 25 years ago (Pe61, Craft.
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From page 93... ...
CavalliSforza and Bodmer (Ca71) plotted the cumulative frequency of published rates against the log mutation rate and found the plot to be apprommately linear, suggesting that the log-normal distribution is a good distribution for describing mutation rates.
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From page 94... ...
analyzed some 75,000 births, of which 38,000 had at least one parent who was exposed to radiation. No significant effects on still births, birth weight, congenital abnormalities, infant mortality, childhood mortality, leukemia, or sex ratio were found.
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From page 95... ...
The lower 955tO confidence limits in Table 2-8 are for chronic radiation (low dose) ; that is, the acute doubling doses derived directly from the published regression coefficients have all been arbitrarily multiplied by a factor of 3 obtained from mouse data.
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From page 96... ...
Use of the smaller number would bring estimates of human doubling doses more in line with the range of values observed in mice. Data based on the revised dosimetry system, DS86, were not available to this committee in the detail necessary for doubling dose estimates at the time the report was being prepared.
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From page 97... ...
Bible 2-8 provides the minimum doubling dose estimates, based on the one-sided 95% confidence intervals, assuming that the spontaneous rate and correction for low dose are known without error. These estimates tend to be more stable than point estimates, because the minimum estimates are more closely bounded below by zero.
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From page 98... ...
The uncertainties in the data base may be troublesome, but the existence of significant genetic and nongenetic variance is an intrinsic property of mammalian populations. Table 2-9 summarizes estimates of spontaneous mutation rates for various endpoints, and Table 2-10 summarizes the estimated induced mutation rates per red for the same endpoints for high and low dose rates of lowLET radiation exposure and for fission neutrons.
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From page 99... ...
Taking the values in Table 2-11 at face value for the endpoint of congenital malformations, and making no assumptions about the mutational component of this category of traits, the doubling dose for exposed males is at the high end of the range. This endpoint is, arguably, the most closely analogous to the kinds of endpoints in the study of Japanese atomic-bomb survivors, and it is again consistent with the view that the doubling dose obtained from the study of humans in Japan may well be greater than the median of all studies of mice.
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From page 100... ...
Dominant lethal mutations Postgonial, male 10 x 10-4/gamete 5 x 10-4/gamete 75 x 10-4/gamete Gonial, male 10 x 10-5/gamete 2 x 10-5/gamete 40 x 10-5/gamete Recessive lethal mutations Gonial, male 1 x 10-4/gamete Postgonial, female 1 x 10-4/gamete Dominant visible mutations Gonial, male 2 x 10-5/gamete Skeletal 5 x 10-7/gamete Cataract 5-10 x 10-7/gamete Other 5- 10 x 10-7/gamete 1 x 10-7/gamete 25 x 10-7/gamete Postgonial, female 5-10 x 10-7/gamete Recessive visible mutations (specific locus tests) Postgonial, male 65 x 10-~/locus Postgonial, female 40 x 10-~/locus 1-3 x 10-X/locus 145 x 10-~/locus Gonial, male 22 x 10-~/locus 7 x 10-3/locus 125 x 10-~/locus Reciprocal translocations Gonial, male Mouse Rhesus Marmoset Human Postgonial, female Mouse Heritable translocations Gonial, male Postgonial, female Congenital malformations Postgonial, female Postgonial, male Gonial, male Aneuploidy (trisomy)
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From page 101... ...
Such a summary was not included in previous BEIR reports (NRC72, NRC80) , although many critical issues were discussed in a series of notes or appendices to the chapters on genetic effects.
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From page 102... ...
Female Preovulatory oocyte Less mature oocyte Median (mouse, all endpoints, both sexes) Direct estimates Indirect estimates Overall a Values not in parentheses are based on the spontaneous rate divided by the induced rate/red for the low dose rate; values in parentheses are based on the spontaneous rate divided by the induced rate/red at the high dose rate, multiplied by 5-10 to correct for the dose rate effect.
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From page 103... ...
The spontaneous rate is about 8 x 10-6/gamete/generation, and the induced rate for single doses of x rays to spermatogonia is about 5 x 10-7/gamete/R. A study using protracted 60Co gamma rays compared with fission neutrons (mean energy of about 0.7 MeV)
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From page 104... ...
Dominant Lethal Mutations Data for this category of genetic events have been largely ignored in the analysis of genetic risks, because dominant lethal mutation rates have been used principally to measure damage induced in the meiotic and postmeiotic cell stages. Damage in these stages has been considered to be only transient and of limited concern for human populations.
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From page 105... ...
The mutation rate drops to about 5 x 10-4/gamete/rad at low dose rates. For the highLET radiations, such as fission neutrons and 5-MeV alpha particles, the RBE value is about 5 (Gr79, NCRP87~.
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From page 106... ...
These unbalanced gametes behave like the dominant lethals induced directly in postgonial stages and their induction rates reflect the induction rates for the translocations themselves. For example, a translocation-bearing spermatocyte will produce the expected four spermatids, but on average, two spermatids will carry unbalanced chromosome sets and act as lethal mutations.
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From page 107... ...
Continuous exposure induces a steady equilibrium rate reflecting the high sensitivity of the postgonial cell stages. Recessive Autosomal and Sex-Linked Lethal Mutations Mutation rates in this classical category of genetic injury have been somewhat elusive in mammalian genetics because, until recently (Ro83)
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From page 108... ...
There are no data on the influence of dose rate or the effects of fission neutrons. The sex-linked lethal mutation rate is probably no more than 4 x 10~6/X-chromosome/rad and may be one-half this value if one allows for the possible augmenting effect of the split-dose exposure regime used to obtain the only available estimate.
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From page 109... ...
Total dose 2. Dose rate 3.
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From page 110... ...
It seems likely, on the basis of the characteristics of the spontaneous events, that they have occurred predominantly in the stem cells. The induced rate for spermatogonia exposed to single doses of lowLET radiation delivered at high dose rates is generally considered one of the baseline values.
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From page 111... ...
The response to an internally deposited alpha-emitter, 239Pu, is intermediate to those of gamma rays and neutrons, with a rate of 18 x 10-8 at low dose rates and an RBE value of 2 to 3 [data from Russell in Report 89 from the National Council on Radiation Protection and Measurements (NCRP87~. Dose fractionation studies have presented an interesting phenomenon in terms of the mutation rates induced in spermatogonia.
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From page 112... ...
The response of mature oocytes to single doses of x rays delivered at 50 it/minute or greater is distinctly non-linear, concave upward, over the dose range of 50 R to 600 R For progeny conceived during the first week after exposure, a linear-quadratic equation gives a linear term of 39 x 10-~/locus/rad (Lyme.
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From page 113... ...
for single doses of 30, 60 and 120 red. Assuming no dose-rate eRect for neutrons, the RBE value would be 5 at high dose rates of low-LET radiation and 50 or greater at low dose rates.
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From page 114... ...
Exposure of newborn mice to single doses of x rays induced mutation rates of 13.7 x 10-~/locus/rad for males (Se73) and about 10 x 10-~/locus/rad for females (Seem.
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From page 115... ...
. Male Mice In many respects, the variables that influence translocation induction and their effects are similar to those that influence the specific locus mutation rate.
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From page 116... ...
At doses above 100 red, there is no decline in response, so the augmentation factor ranges from about 2 at 100 red to 5 or more at 150 red. The RBE value for protracted exposures, neutrons versus gamma rays, varies with dose rate in low-LET radiation exposures, but approaches 50 at the lowest dose rates (Gr86a)
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From page 117... ...
When small dose increments (less than 50 red) are given at daily or weekly intervals, additivity exists, but the rate of response is less than that seen for comparable single doses, and the magnitude of this drop in response depends on the size of the dose increment, the dose interval, and the instantaneous dose rate (Ly70a, Ly70b, Ly72, Ly73; Gr86b, Great.
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From page 118... ...
The rate rises to about 6 x 10-4/rad during the second and third weeks, a response pattern comparable to that seen for specific locus mutations in oocytes. Also comparable to the specific locus test data is the observation that a significant dose-rate effect exists: reducing the dose rate from about 100 to about 0.04 red/minute reduces the effectiveness by a factor of 7-10 (Brew.
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From page 119... ...
and UNSCEAR (UN77) committees used a value of 7 x 10~4/rad as a reasonable estimate of the human response to low single doses of x rays or gamma rays.
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From page 120... ...
The first class includes traits that have provided some opportunity for rate analysis, and the second includes traits for which evidence exists of a response to increased mutation pressure, but not of sufficient quality or repeatability to yield a risk coefficient. Traits with Quantifiable Rates of Induction Congenital Abnormalities The frequency of congenital malformations, including small stature or reduced growth rate, in the first-generation progeny of x-irradiated male and female mice has been evaluated in late gestation (No82, Ki82, Ki84, Rusty.
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From page 121... ...
and low dose rates of low-LET radiations. The experimentally derived rate induced by single or split doses of x rays delivered at high dose rates was estimated to be 34 x 10-6/gamete/rad by Luning and Searle (Lu71)
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From page 122... ...
The preovulatory oocyte is sensitive to low doses, but less mature oocytes are quite resistant. Multilocus Deletions The specific-locus test has provided useful data on the characteristics or phenotypic manifestations of mutations induced by different radiation qualities and in different germ cell stages.
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From page 123... ...
Thus, a minimum induction rate for this deleterious class of mutations would be one-fourth (1.8 x 10-~/rad) of the rate for spermatogonia exposed to low dose rate, low-LET radiations (7.3 x 10-~/locus/rad)
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From page 124... ...
Higher rates are seen for dominant lethal mutations induced in postgonial cells of male mice, for translocations induced in the spermatogonia of one marmoset species, and for aneuploidy induced in the preovulatory oocyte of female mice. Lower rates pertain to dominant visible mutations; however, except for skeletal and cataract mutations, these are recognized to be systematically underestimated.
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From page 125... ...
The estimated doubling doses derived from Tables 2-9 and 2-10 are summarized In Bible 2-11. Considering all endpoints together, the direct estimates of doubling dose for low dose rate radiation have a median value of 70-80 red, indirect estimates based on high-dose rate experiments have a median of 150 red, and the overall median lies in the range of 100 to 114 red.
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From page 126... ...
1986. The induction of reciprocal translocations in Rhesus monkey stem-cell spermatogonia:.Effects of low doses and low dose rates.
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From page 127... ...
1971. Comparison of radiation- and chemically-induced dominant lethal mutations in male mice.
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From page 128... ...
1986a. Genetic injury in hybrid male mice exposed to low doses of 60Co gamma-rays or fission neutrons.
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From page 129... ...
1988. Genetic injury in hybrid male mice exposed to low doses or 60Co gamma-rays or fission neutrons III.
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From page 130... ...
1987. Genetic effects from internally deposited radionuelides.
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From page 131... ...
1976. Mutagenic effect of various types of radiation in the germ cells of male mice.
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From page 132... ...
1982. Specific locus mutation frequences in mouse stem cell spermatogonia at ve~y low radiation dose rates.
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From page 133... ...
1974. Cytogenetic effects of x-rays and fission neutrons in female mice.
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From page 134... ...
1982. Genetic effects of radiation.
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