Health Risks from Exposure to Low Levels of Ionizing Radiation BEIR VII Phase 2 (2006) / Chapter Skim
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4 Heritable Genetic Effects of Radiation in Human Populations
4 Heritable Genetic Effects of Radiation in Human Populations
Pages 91-131
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From page 91... ...
National Academy of Sci Details of the genetics program that evolved in Japan and ences. The ABCC was renamed the Radiation Effects Re the vast body of data that emerged from these studies have 91
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From page 92... ...
In there are no statistically demonstrable adverse genetic ef the male, these are the stem cell spermatogonia, which confects attributable to radiation exposures sustained by the sur stitute a permanent germ cell population in the testes and vivors. Although cited and discussed in the UNSCEAR and continue to multiply throughout the reproductive life span of BEIR reports over the years, these results did not constitute the individual.
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From page 93... ...
. pected increase in disease frequency per unit dose of radia As mentioned earlier, multifactorial diseases are pre- tion in terms of the baseline frequency of the disease class.
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The amount of increase in mutation frequency, the eases in the population, and subsequently elaborated by time it takes for the population to reach the new equilibrium, Crow and Denniston (1981, 1985) and Denniston (1983)
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From page 95... ...
, data on the distribution of the estimates vary over a wide range, from about 1% in live population in various age intervals (i.e., ages 0, 1, 2, 34, births to a high of about 8.5% in total births (i.e., still- and 59, 1014, .
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96 BEIR VII Estimates of Baseline Frequency of Chromosomal Disease Table 4B-1 (see Annex 4B) summarizes the important developments.
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. least autosomal dominant and X-linked diseases also have to When one considers the large differences in life span be- be corrected upwards to account for this possibility; there is tween humans and mice and the paternal age effect for spon- no reliable way of doing this at present.
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30 6.0 0.3 mice, the committee used all available data on rates of inCleft lip 1 1.0 0.2 duced mutations in defined genes in mice; these relate to Deaf mutism 15 24.0 0.7 recessive specific locus mutations at 12 loci, biochemical Dentinogenesis imperfecta 2 1.0 0 mutations (null enzyme mutations, also recessive at a large Huntington disease 1 5.0 0.2 Hypercholesterolemia 1 20.0 0 number of loci) , and autosomal dominant mutations at 4 loci Marfan syndrome 1 5.0 0.3 incidentally detected in the course of the specific locus exMultiple exotoses 3 7.7 0.3 periments.
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From page 99... ...
and all rates are normalized to single acute X-irradiation conditions. aa: non-agouti; b: brown; c: chinchilla; d: dilute; p: pink-eyed dilution; s: piebald; se: short ear; in the work of Pretsch and others (1994)
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no locus is provides additional substantiation for the dose-rate reduction factor of 3: "The other important baseline value for spermatogonia is for the response double-counted while averaging over all loci, (2) the loci and to low dose-rate, low-LET irradiations .
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SE (× 105) for chronic radiation conditions from the available data.
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. The latter and assume that the fitness of the three genotypes (AA, Aa, can be rewritten as risk per unit dose ÷ P = (1/DD)
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For example, about 40% of retinoblastoma cases are due to germline muof generations following radiation exposure. tations and the remaining ones are sporadic (Vogel 1979)
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following radiation exposure. The than those for autosomal dominant diseases and are detailed effect of an increase in mutation rate on MC is most proin Chakraborty and colleagues (1998b)
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HERITABLE GENETIC EFFECTS OF RADIATION IN HUMAN POPULATIONS 105 TABLE 4-4 Effects of a One-Time or Permanent Doubling of the Mutation Rate on Mutant Gene Frequency (p) , Disease Frequency (P)
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increased permanently to 1.15 × 10 (i.e., a 15% increase) 6 as a result of radiation exposures in every generation.
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at the new equilibrium between mutation and selection under conditions of radiation exposure in every generation. Results are for the five-locus FLTM when the assumed baseline mutation rate of 10 per gene is increased to 1.15 × 10 (i.e., by 15%)
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From page 108... ...
. a given chronic disease, which is unlikely to occur at low In all of the model predictions discussed thus far, the pos- radiation doses, the effective MC in the early generations is sibility that some individuals may be affected by the disease likely to be much less than 12%.
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The result of four quantities instead of the original three: will be a transient small increase in disease frequency followed by a decline toward the baseline frequency in subse- Risk per unit dose = quent generations.
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However, since signed to different groups. For example, if a disease with a induced recessive mutations are first present in the heterozyhigh prevalence is assigned to group 1, societal concern gous condition (and 50% of the gene product is sufficient for about radiation effects will be far less than when it is as- normal functioning)
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From page 111... ...
underlying a chronic dis ease sustaining induced mutations simultaneously. On the PRCFs for Congenital Abnormalities first point, it is obvious that if the PRCFs for single-gene Currently available data do not permit the estimation of mutations change, the PRCFs for chronic diseases will also PRCFs for congenital abnormalities.
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show that the underlying induced ge Ionizing radiation produces genetic damage by random netic changes are multigene deletions. It is worth mentiondeposition of energy; the predominant type of radiation-in- ing here that the data on skeletal and cataract mutations were duced genetic change is a DNA deletion, often encompass- used earlier by both UNSCEAR and the BEIR committees to ing more than one gene.
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. Al- suggesting the occurrence of destabilization in the zygote; though it is not possible at present to use data from these however this occurs only after spermatozoal but not after studies for radiation risk estimation, they are considered in gonial irradiation of the males; in the work of Dubrova and this report because some of the findings have exposed inter- colleagues, the data imply that destabilization occurs in the esting aspects of the radiation response at these loci that have F1 zygote when the spermatozoa used for fertilization reparallelisms to the genomic instability phenomenon recorded ceived irradiation either at the postmeiotic or premeiotic in irradiated somatic cell systems and therefore relevant for stages in spite of observations that postmeiotic germ cells ongoing debates in radiobiology.
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. The dose-response relationships, how lower doses, there was no effect.
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For malities. The estimates presented are for a population congenital abnormalities, it is not possible to calculate MC, sustaining low-LET, low-dose or chronic radiation exposures but this does not pose any problem since the risk estimate for at a finite rate in every generation and are applicable to the these does not use the doubling dose method.
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; estimates without parenRisk to Progeny of the First Postradiation Generation theses are standardized to acute radiation conditions by dividing the above by 2, the factor by which specific locus mutation frequencies are known to As can be seen, the risk is of the order of about 750 to be enhanced under fractionated radiation conditions. 1500 cases for autosomal dominant and X-linked diseases bRates have been corrected for controls in which the frequency was 1/ (versus 16,500 cases of naturally occurring ones)
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the estimates of baseline frequency of Mendelian selection that underlies the use of the doubling dose method diseases were lower and (2) no risk estimate was provided predicts that when a population sustains radiation exposure for chronic multifactorial diseases.
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are basically the same-(exclusive of those resulting from malignancies) , malignan- namely, that at low doses the genetic risks are small comcies in children, frequency of balanced structural rearrange- pared to the baseline risks of genetic diseases.
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Alduced mutations (the denominator in DD calculations) is though statistically such a calculation can be defended, the now based on induced mutations in 34 mouse genes with implicit biological assumption that at low doses of radiation, widely different locus-specific rates.
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120 BEIR VII Overall Conclusions The committee has evaluated Table 4-6 and expresses the view that these estimates of risk are the best that are possible at the present time. ANNEX 4A: MODELS OF INHERITANCE OF MULTIFACTORIAL DISEASES IN THE POPULATION Multifactorial Threshold Model of Disease Liability and the Concept of Heritability Assessment of the relative importance of genetic and environmental factors in the etiology of multifactorial diseases is essential to explain their transmission patterns and predict their risks of recurrence in families.
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HERITABLE GENETIC EFFECTS OF RADIATION IN HUMAN POPULATIONS 121 FIGURE 4A-2 Comparisons of the distribution liability in the general population with those in relatives of affected individuals when there are differences in the prevalence of multifactorial disease, according to the multifactorial threshold model with the additional assumption of different thresholds for disease liability in the two sexes. Based on the properties of the normal distribution of li- VG/VP is called "broad-sense heritability of liability," or "deability (made up of both genetic and environmental compo- gree of genetic determination," and is symbolized by hB .
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and that of zero assumed for females. It was noted, ing absorbed radiation dose is gray (or sievert when consid- however, that the estimate of 0.25 × 10 per locus per rem 7 ering radiations of different qualities)
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linear dose-effect relationship for induced mutations and (2) effect independent of dose rate or dose fractionation.
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until the gether, the direct estimates of doubling dose for low dose population reaches equilibrium between mutation and selecrate radiation have a median value of 7080 rad, indirect tion. Once this occurs, the mutation rate is increased either estimates based on high dose-rate experiments have a me- once or permanently corresponding to radiation exposure in dian value of 150 rad, and the overall median lies in the one generation only or in every generation, and the comrange of 100 to 114 rad.
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whole-gene deletions are rare; Despite the existence of a number of differences be- (3) whole-gene deletions are not rare, but the gene is lotween spontaneous and radiation-induced mutations as out- cated in a putative gene-rich region; and (4)
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From page 126... ...
hence, allele length. The available data suggest that the Subsequent work with X-irradiation doses of 0.5 and 1 Gy ESTR instability is a replication- or repair-based process in established that for mutations induced in the above cell stage, volving polymerase slippage similar to mechanisms sug the dose-effect relationship was consistent with linearity gested for microsatellite instability (Ellegren 2000)
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provided additional evidence for the involvement Direct Studies of ESTR Mutations in Mouse Sperm of radiation-induced germline genomic instability in the origin of induced ESTR mutations. In these experiments in- In a recent paper, Yauk and colleagues (2002)
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Semipalatinsk Nuclear Test Site Further evidence showing an increase in minisatellite mutation frequencies has also been obtained from two stud Dubrova and colleagues (1996) first reported on radia ies, one in the Kiev and Zhitomir regions of Ukraine that tion-induced minisatellite mutations among children born sustained heavy radioactive contamination after the Cherbetween February and September 1994 to parents who were nobyl accident (Dubrova and others 2002b)
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From page 129... ...
When the cleanup workers The discrepancy between the results of Kodaira and col- were subdivided according to their radiation doses, the muleagues, on the one hand, and those of Dubrova and col- tation rate in children born to fathers with recorded doses of leagues (1996, 1998b, 2000a, 2000b) in the Belarus and 200 mSv, showed a nonsignificant increase relative to their other cohorts discussed earlier appears real.
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From page 130... ...
. mutation frequency (1.14% versus 0.79%)
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From page 131... ...
Null enzyme mutations would mates, one can conclude that they are of the same order. be expected to be induced, but they are unlikely to be found The other end points -- namely, F1 mortality, F1 cancers, at the low dose levels experienced by most survivors.
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