Cancers induced by radiation do not differ from cancers due to other causes, so there is no simple way to measure the rate of cancer due to radiation. During the period studied by the Advisory Committee, great effort was devoted to studies of irradiated animals and exposed groups of people to develop better estimates of the risk of cancer due to radiation.
This type of research is complicated by the variety of cancers, which vary in radiosensitivity. For example, bone marrow is more sensitive than skin cells to radiation-induced cancer.
Because the cancers can occur anytime in the exposed person's lifetime, these studies can take seventy years or more to complete. For example, the largest and scientifically most valuable epidemiologic study of radiation effects has been the ongoing study of the Japanese atomic bomb survivors. Other important studies include studies of large groups exposed to radiation as a consequence of their occupation such as uranium miners or as a consequence of medical treatment.
Radiation may alter the DNA within any cell. Cell damage and death that result from mutations in somatic cells occur only in the organism in which the mutation occurred and are therefore termed somatic or nonheritable effects. Cancer is the most notable long-term somatic effect. In contrast, mutations that occur in germ cells sperm and ova can be transmitted to future generations and are therefore called genetic or heritable effects.
Genetic effects may not appear until many generations later. The genetic effects of radiation were first demonstrated in fruit flies in the s. Genetic mutation due to radiation does not produce the visible monstrosities of science fiction; it simply produces a greater frequency of the same mutations that occur continuously and spontaneously in nature. Like cancers, the genetic effects of radiation are impossible to distinguish from mutations due to other causes.
Today at least 1, diseases are known to be caused by a mutation. During the period studied by the Advisory Committee, there was considerable debate among the scientific community over both the extent and the consequences of radiation-induced mutations. In contrast to estimates of cancer risk, which are based in part on studies of human populations, estimates of heritable risk are based for the most part upon animal studies plus studies of Japanese survivors of the atomic bombs.
The risk of genetic mutation is expressed in terms of the doubling dose: the amount of radiation that would cause additional mutations equal in number to those that already occur naturally from all causes, thereby doubling the naturally occurring rate of mutation. It is generally believed that mutation rates depend linearly on dose and that there is no threshold below which mutation rates would not be increased.
Attempts have been made to estimate the contribution of ionizing radiation to human mutation rates by studying offspring of both exposed and nonexposed Japanese atomic bomb survivors.
These estimates are based on comparisons of the rate of various congenital defects and cancer between exposed and nonexposed survivors, as well as on direct counting of mutations at a small number of genes.
For all these endpoints, no excess has been observed among descendants of the exposed survivors. Given this lack of direct evidence of any increase in human heritable genetic effects resulting from radiation exposure, the estimates of genetic risks in humans have been compared with experimental data obtained with laboratory animals.
However, estimates of human genetic risks vary greatly from animal data. For example, fruit flies have very large chromosomes that appear to be uniquely susceptible to radiation. Humans may be less vulnerable than previously thought. Statistical lower limits on the doubling dose have been calculated that are compatible with the observed human data.
Similar estimates for X-linked diseases are not available. The rationale for which rests on the following considerations: 1 the baseline incidence of X-linked diseases is an order of magnitude lower than that of autosomal dominant diseases 0. The committee is cognizant of the fact that selection intensities in present-day human populations are probably lower. For autosomal recessives, the first-generation MC is close to zero.
As mentioned earlier, for most multifactorial diseases, knowledge of the number of genes involved, the types of mutational alterations, and the nature of environmental factors remains limited, and there is no simple relationship between mutation and disease.
Further, unlike the situation for Mendelian diseases, no models have been proposed to explain the stable prevalences of multifactorial diseases in the population. Models such as the multifactorial threshold model of disease liability see Annex 4B are essentially descriptive models. They permit one to explain the transmission patterns of these diseases and make reasonable predictions of recurrence risks in families, but they are not, as such, suitable for the estimation of MC.
There is, however, a wealth of literature about evolutionary population genetic models on the maintenance of quantitative variability and traits in populations, and these incorporate mechanisms reviewed by Sankaranarayanan and others Although there are differences in detail between them and the applicability of these models to multifactorial diseases, all of them are based on equilibrium theory i.
They are therefore similar to the models used to explain the dynamics of single mutant genes underlying Mendelian diseases in populations. However, as discussed later, advances in human molecular biology and radiation genetics during the past few years suggest that it is not biologically meaningful to use the FLTM to estimate MC for congenital abnormalities, and therefore its use is limited to chronic diseases.
As mentioned above, the FLTM uses the concepts of liability and threshold of the MTM appropriately redefined for a finite number of loci and that of mutation-selection equilibrium from evolutionary population genetic models on the maintenance of variability of quantitative traits. The choice of a finite number of loci rests on three main considerations: 1 although precise knowledge of the genetic basis is not yet available for most chronic diseases, for well-studied ones such as coronary heart disease, it is now clear that the number of underlying genes is probably small, and their mutant alleles have small to moderate effects; 2 estimates of the heritability of liability h 2 , a statistic that provides a measure of the relative contribution of genetic factors to the overall phenotypic variability for various chronic diseases, have been published in the literature; and 3 unlike the MTM, the FLTM permits quantitative analysis of the joint effects of mutation and selection.
As emphasized in BEIR V NRC , the heritability of liability mentioned above should not be confused with heritability of the trait , which is very different and much smaller than heritability of liability.
This distinction is important since MC is related more to the heritability of liability than to the heritability of trait see NRC , Table , footnote c , for a mathematical formulation of the approximate relationship between heritability of liability and heritability of trait.
In general terms, the FLTM assumes that the liability underlying a chronic disease, which is made up of both genetic and environmental factors, is a continuous variable and that the environmental contribution has a normal Gaussian distribution. Although the standard MTM assumes numerous essentially an infinite number of genetic factors i. The latter is also true of the threshold.
The effects of specified increases in mutation rate are evaluated in terms of changes in h 2 and MC. The selection coefficients s values used were 0. The data points shown in Figure are from different computer runs using different combinations of parameter values selection coefficients, threshold, and environmental standard deviation. As can be seen, for h 2 values greater than about 0. The effects expected in early postradiation generations i.
Figure compares the h 2 versus MC relationship at equilibrium with that at generation 10 shaded areas in the figure are the ones of interest in MC estimation for chronic diseases. The conclusions from Figure and Figure are reinforced i. The numerical algorithms used for the calculations above have also been used to examine the effects of a one-time increase in mutation rate i.
FIGURE Relationship between heritability of liability h 2 x -axis and mutation component MC y -axis at the new equilibrium between mutation and selection under conditions of radiation exposure in every generation. FIGURE Relationship between heritability of liability h 2 and mutation component for the first, fifth, and tenth postradiation generations, under the same conditions as specified in Figure Note that the scale of the y -axis differs from Figure FIGURE Comparison of the relationship between heritability of liability and mutation component for the tenth postradiation generation with that at the new equilibrium, under the same conditions as those specified for Figure The shaded areas of h 2 range: 0.
Note that in this range, the MC at generation 10 is very small, whereas at the new equilibrium, it is equal to 1. As expected, the first-generation MC is the same i. The effects of gene-gene interactions on quantitative phenotypes at risk of complex diseases are varied and do not lend themselves readily to modeling. However, when some assumptions about these interactions were incorporated in the FLTM, it was found that the results at the new equilibrium as well as for the early postradiation generations were basically the same as those under conditions of no interactions data not shown but discussed in Denniston and others ; ICRP In all of the model predictions discussed thus far, the possibility that some individuals may be affected by the disease for reasons unrelated to their genotypes sporadic cases was not considered.
When these were taken into account, as expected the magnitude of MC was lower, both at the new equilibrium and in the early generations. One would therefore predict that the expected increases in the frequency of chronic diseases relative to the baseline frequency will be even smaller in the first few postradiation generations. A second conclusion, again under conditions of a permanent increase in mutation rate, is that at the new equilibrium between mutation and selection which will be achieved several tens—if not hundreds—of generations later, depending on the amount of increase in mutation rate and selection coefficients , the MC will become 1.
This conclusion holds for several different combinations of assumed parameter values selection coefficients, thresholds, numbers of loci, environmental variances, interactions among genes and consequently can be considered robust. Finally, if the population sustains radiation exposure in one generation only, the increase in MC will be transient and small, followed by a progressive decline to zero. The result will be a transient small increase in disease frequency followed by a decline toward the baseline frequency in subsequent generations.
Mouse data on rates of induced mutations incorporated in the DD estimate provide the basis for genetic risk prediction in humans.
However, thus far, no radiation-induced genetic diseases have been found in the offspring of those who have sustained radiation exposures e. Advances in human molecular genetics and radiation genetics during the last decade support the view that there are several fundamental differences in mechanisms, nature, etc.
Stated differently, the rate at which induced disease-causing mutations are seen in human live births following parental radiation exposures may be much lower than that of induced mutations in mice. Since there is no alternative to the use of mouse data on radiation-induced mutations for risk predictions in humans, methods have to be devised to bridge the gap between induced mutation rates in mice and the risk of genetic disease in humans.
One such method has been developed recently and is based on the incorporation of a correction factor, termed the potential recoverability correction factor PRCF , in the risk equation Sankaranarayanan and Chakraborty a.
As a consequence, the risk now becomes a product of four quantities instead of the original three:. The differences between spontaneous disease-causing mutations in humans and radiation-induced mutations studied in experimental systems, which constitute the basis for the development of the PRCF concept, are discussed in detail by Sankaranarayanan and Sankaranarayanan and Chakraborty b and summarized in Annex 4D.
To assess PRCF, it was necessary first to define criteria on the basis of information available from molecular studies of radiation-induced mutations, to apply these to human genes of interest on a gene-by-gene basis, and to examine which among them can be considered candidates for potentially recoverable induced mutations.
The operative words are the italicized ones, since there is as yet no evidence for a radiation-induced germ cell mutation in humans, our understanding of the structural and functional genomics of the genome is incomplete, and the criteria will undoubtedly change with advances in knowledge.
Under the assumption that a deletion is induced in a genomic region containing the gene of interest, the question asked was, Given the structural and functional attributes of the gene or genomic region, can this deletion be considered potentially recoverable? The criteria developed and how the genes examined are assigned to one of three groups—namely, unlikely to be recovered group 1 , recoverability uncertain group 2 , and potentially recoverable group 3 —summarized in Annex 4D.
Since the starting assumption is that the genomic region containing the gene of interest has sustained a multigene deletion, the assessments only tell us which disease-causing mutations, if induced, may be recovered in live births within the framework of the criteria used; they do not shed light on the absolute radiation risk of a given genetic disease.
Also worth mentioning here is that assignment to group 1 unlikely to be recovered is somewhat less subjective, and therefore more reliable, than that to the other two groups. This aspect is taken into account in defining PRCF i. This fraction is referred to as the unweighted PRCF. The PRCF as estimated above, however, does not take into account differences in the prevalence of diseases assigned to different groups.
For example, if a disease with a high prevalence is assigned to group 1, societal concern about radiation effects will be far less than when it is assigned to the other two groups. Consequently, some weighting for disease prevalence is required.
For the purpose of risk estimation however, it is preferable to use a range provided by the unweighted and weighted PRCF estimates to avoid the impression of undue precision.
A total of 67 genes involved in autosomal dominant 59 or X-linked 8 recessive diseases was included in the analysis. The results, given in Table , show that the unweighted and weighted PRCFs for autosomal dominants are 0. Since the overall estimated prevalence of autosomal dominants is an order of magnitude higher than that of X-linked diseases i.
The recoverability of induced recessive mutations is also subject to constraints imposed by the structure, function, and genomic contexts of the underlying genes. Additionally, induced recessive mutations, at least in the first several generations, do not result in recessive diseases, and as discussed earlier, the MC for recessive diseases is close to zero.
Unweighted PRCF a. In view of all these factors, it does not seem necessary to estimate PRCF for this class of diseases. In the FLTM used to estimate MC for chronic diseases, it is assumed that 1 the genetic component of liability is due to mutations in a finite number of gene loci, 2 the affected individuals are those whose genetic component of liability exceeds a certain threshold, and 3 radiation exposure can cause a simultaneous increase in mutation rate in all of the underlying genes, which in turn causes the liability to exceed the threshold.
Consequently, the requirement for potential recoverability also applies to induced mutations in the underlying genes. A crude approximation of potential recoverability for each chronic disease is the x th power of that for mutation at a single locus, where x is the number of gene loci, assumed to be independent of each other. Since the PRCF for autosomal dominant and X-linked mutations has been estimated to be in the range from 0.
With the assumption of just two loci as a minimum, the PRCF estimate becomes 0. Intuitively, these conclusions are not unexpected given that one is estimating the simultaneous recoverability of induced mutations in two or more independent genes.
Currently available data do not permit the estimation of PRCFs for congenital abnormalities. However, as discussed later, this does not pose any serious problem since at least a provisional estimate of risk for this class of diseases can now be made without recourse to the DD method. Development of the PRCF concept represents an example of how advances in human molecular biology and radiation genetics can be integrated for the purpose of genetic risk assessment. In principle, three ways of incorporating PRCFs into the risk equation i.
Of these, the last possibility has been preferred for two reasons. First, the original definition of the DD a ratio of spontaneous and induced rates of mutations in a set of defined genes and of MC a quantity that predicts the relative increase in disease incidence per unit relative increase in mutation rate, both compared to the baseline can be retained without modifications.
Second, with further advances in structural and functional genomics of the human genome and in the molecular analysis of radiation-induced mutations, there is the real prospect of defining PRCFs with greater precision. In developing the PRCF concept, it has been assumed that the recoverability of an induced deletion is governed more by whether a given genomic region can tolerate large changes and yet be compatible with viability than by genomic organization per se.
Considerable amounts of data exist that strongly support the view that in the case of deletion-associated naturally occurring Mendelian diseases, the deletions do not occur at random i.
A priori , therefore, one would not expect that radiation would be able to reproduce such specificities that nature has perfected over millennia, at least not in all genomic regions.
Should this be the case, even the weighted PRCFs would be overestimates. However, until newer methods are developed to bridge the gap between induced mutation rates in mice and the risk of genetic diseases in humans, the PRCF range of 0.
The PRCF estimate range of 0. Secondly, the data on well-studied chronic diseases such as coronary heart disease CHD , essential hypertension, and diabetes mellitus suggest that more than two loci may be involved. The implication is that the PRCFs for chronic diseases are likely to be smaller than cited above. For example, if there are three loci, the range becomes 0.
All this means is that the PRCF values for chronic diseases may turn out to be lower than 0. The committee uses the PRCF ranges 0. For historical reasons, over the past four decades or so, the focus in the assessment of adverse genetic effects of radiation has been on the risk of inducible genetic diseases. The rationale for this rested on the premise that if spontaneous mutations can cause specific genetic diseases, so can. This rationale gained support from experimental studies demonstrating that radiation-induced mutations in specific marker genes could be recovered in a number of biological systems, including the mouse.
Consequently, efforts at risk estimation proceeded to use the mouse data on rates of induced recessive specific locus mutations as a basis for estimating the risk of genetic diseases due to mutations in single genes and assumed that the mouse rates can be used for this purpose. Now, one can approach the question of adverse genetic effects of radiation from the perspective provided by our current understanding of the mechanism of radiation action, the molecular nature of radiation-induced mutations, increasing knowledge of human genetic diseases, and the mechanisms of their origin.
One important outcome of this approach, discussed in the preceding section, is that it is now possible to conclude that the risk of single-gene diseases is probably much smaller than expected from the rates of induced mutations in mice. A second important outcome is the concept discussed in the present section, namely, that the adverse effects of gonadal irradiation in humans are more likely to be manifest as multisystem developmental abnormalities than as single-gene diseases.
The argument and findings that provide the basis for the above concept come from studies of the mechanism of induction of genetic damage by radiation, the nature of radiation-induced mutations, and the common phenotypic features of naturally occurring multigene deletions in humans.
Some of these are discussed in the preceding section, and these studies and others are briefly considered below see Sankaranarayanan for a detailed review. Ionizing radiation produces genetic damage by random deposition of energy; the predominant type of radiation-induced genetic change is a DNA deletion, often encompassing more than one gene.
The whole genome is the target for radiation action, and deletions and other gross changes can be induced in any genomic region; however, since the recoverability of an induced deletion in a live birth is subject to structural and functional constraints, only a subset of these deletions that is compatible with viability may be recovered.
Further, not all the recoverable deletions may have phenotypes that are recognizable from knowledge gained from naturally occurring genetic diseases. These syndromes result from deletions of multiple, functionally unrelated, yet physically contiguous genes that are compatible with viability in the heterozygous condition.
Many have been reported in the human genetics literature, and they have been found in nearly all human chromosomes, but their distribution in different chromosomal regions seems to be nonrandom.
This is not unexpected in the light of differences in gene density in different chromosomes and chromosomal regions. However, despite their occurrence in different chromosomes, the common features of the phenotypes of many of these deletions include mental deficiency, a specific pattern of dysmorphic features, serious malformations, and growth retardation Schinzel ; Epstein ; Brewer and others In considering all of these together, the concept was put forth that multisystem developmental abnormalities are likely to be among the principal phenotypes of deletions and other gross changes induced in different parts of the human genome.
Because the underlying genetic change is a deletion, generally one would expect that these phenotypes would show autosomal dominant patterns of inheritance. Mouse data supporting the above concept come from studies on radiation-induced skeletal abnormalities Ehling , ; Selby and Selby , , cataracts Kratochvilova and Ehling ; Ehling ; Favor , congenital abnormalities ascertained in utero Kirk and Lyon , ; Nomura , , , ; Lyon and Renshaw ; Rutledge and others and growth retardation Searle and Beechey ; Cattanach and others , The cases analyzed e.
It is worth mentioning here that the data on skeletal and cataract mutations were used earlier by both UNSCEAR and the BEIR committees to provide alternative estimates of the risk of dominant effects using what was referred to as the direct method. The basic data from these studies, however, have now been used by UNSCEAR to obtain a provisional estimate of the risk of developmental defects without recourse to the DD method.
This aspect is considered in the section on risk estimation. There is no conceptual contradiction between naturally occurring and radiation-induced developmental abnormalities.
As discussed earlier, naturally occurring human congenital abnormalities are classified as a subgroup of multifactorial diseases, whereas radiation-induced ones generally are predicted to show autosomal dominant patterns of inheritance. It may therefore seem that there is a conceptual contradiction. In reality, this contradiction is only apparent when. The concept that is emerging is that human developmental abnormalities may be treated as inborn errors in development or morphogenesis in obvious analogy with, and as an extension of, the classical concept of inborn errors of metabolism Epstein Since the mids, several studies have been carried out on the induction of germ cell mutations at expanded simple tandem repeat ESTR loci in mice formerly called minisatellites and at minisatellite loci in humans.
These are regions of the genome that do not code for any proteins but are highly unstable mutable , both spontaneously and under the influence of radiation.
These attributes have facilitated detection of increases in mutation rates at radiation doses and sample sizes substantially smaller than those used in conventional mutation studies with germ cells.
Although these loci do not code for proteins and most spontaneous and radiation-induced mutational changes in them are not associated with adverse health effects, some limited evidence is suggestive of a possible role of minisatellites in human disease reviewed in Bridges Additionally, there is suggestive evidence of an association between the risk of cancer and mutations in the HRAS1 gene Krontiris and others ; Phelan and others Although it is not possible at present to use data from these studies for radiation risk estimation, they are considered in this report because some of the findings have exposed interesting aspects of the radiation response at these loci that have parallelisms to the genomic instability phenomenon recorded in irradiated somatic cell systems and therefore relevant for ongoing debates in radiobiology.
The principal conclusions are summarized here; and details are presented in Annex 4F. Mutations at the ESTR loci can be induced by both low-and high-LET neutrons from californium [ Cf] irradiation of mouse germ cells Dubrova and others , a, b, a, b; Sadamoto and others ; Fan and others ; Niwa and others For both types of radiations, the dose-effect relationship for mutations induced in spermatogonial stem cells is consistent with linearity.
The high frequency of induced mutations strongly supports the view that they are unlikely to result from direct radiation damage to these small genomic loci themselves i. There is evidence that this instability is not the result of a general genome-wide increase in meiotic recombination rate Barber and others This genomic instability is transmissible to at least two generations resulting in increased frequencies of mutations Dubrova and others b; Barber and others These findings add further support to observations on genomic instability recorded in somatic cells—the occurrence of genetic changes in the progeny of irradiated cells at delayed times in terms of cell generations after irradiation.
Data on ESTR mutations obtained in experiments involving irradiated spermatogonial stem cells permit an estimate of the DD of about 0. It should be noted, however, that both the average spontaneous rate 0. There are some discrepancies between the findings of Dubrova and colleagues and those of Niwa and colleagues: 1 In the work of Dubrova and colleagues, post-meiotic germ cells are not sensitive to mutation induction at the ESTR loci, whereas in the work of Niwa and colleagues, all germ cells are sensitive, albeit to different degrees; it is not yet clear whether these differences are due to differences in the mouse strains used or to some other reasons.
The results of Dubrova and colleagues from the three post-Chernobyl studies two in Belarus and one in Ukraine and from a study conducted on the population in the vicinity of the nuclear test site in Semipalatinsk Kazakhstan provide evidence that mutations at minisatellite loci can be induced by radiation in human germ cells Dubrova and others , , b.
The dose-response relationships, however, remain uncertain because of considerable difficulties in the estimation of parental gonadal doses. The mutation frequency in children from the latter group was 1.
In the Ukraine study Dubrova and others b , a 1. In the Semipalatinsk study Dubrova and others a , again there was a 1. In this study, through the use of three-generation families, the authors obtained evidence for a decline in mutation frequency as population doses decreased. Although this is what one normally would expect, it becomes a puzzling observation in view of the earlier evidence from the authors on ESTR loci on transgenerational mutagenesis in mice i.
It is intriguing that in all studies discussed above, there is roughly a twofold increase in mutation rate often less despite the fact that the estimates of doses range from about 20 mSv to 1 Sv. The question of whether the induced mutation frequencies reach a plateau at low doses unlike in the case of ESTR loci in mice remains open. In a more recent study of the children born to Estonian Chernobyl cleanup workers, Kiuru and colleagues found that the minisatellite mutation rate was slightly but not significantly increased among children born after the accident relative to that in their siblings born before the accident; the recorded dose levels at which such an effect was seen were mSv.
At lower doses, there was no effect. It is obvious that much work is needed to validate the potential applications of minisatellite loci for monitoring mutation rate in human populations. As discussed in Annex 4F , ESTR loci in mice and minisatellite loci in humans differ in a number of ways: the composition and size of the arrays, their distribution apparently random in the case of ESTRs and subtelomeric in the case of minisatellites , the manifestation of instability in both somatic cells and germline in the case of ESTRs, but almost completely restricted to the germline in the case of minisatellites, although the end result is the change in the number of repeat cores with both ESTRs and minisatellites , and mechanisms ESTR instability appears to be a replication- or repair-based process involving polymerase slippage during replication, whereas minisatellite instability is due to gene conversion-like events involving recombinational exchanges.
To what extent these differences may help explain the differences in response between mouse ESTR loci and human minisatellite loci remains to be determined. In this section, advances in knowledge reviewed in earlier sections are recapitulated briefly and used to revise the estimates of genetic risks presented in BEIR V NRC Additionally the consistency of the main finding of the genetic studies carried out on atomic bomb survivors in Japan i.
Risks are estimated using the doubling dose method for Mendelian and chronic multifactorial diseases. For congenital abnormalities, mouse data on developmental abnormalities are used without recourse to the doubling dose method.
No separate risks are estimated. The estimates presented are for a population sustaining low-LET, low-dose or chronic radiation exposures at a finite rate in every generation and are applicable to the progeny of the first two postradiation generations. Baseline frequencies of genetic diseases.
The baseline frequencies of Mendelian diseases have now been revised upwards. The revised estimates are the following: autosomal dominant diseases, 15, per million live births; X-linked diseases, per million live births; and autosomal recessive diseases, per million live births. For chromosomal diseases, the estimate remains unchanged at per million live births. For congenital abnormalities and chronic multifactorial diseases, the current estimates respectively, 60, per million live births and , per million individuals in the population are the same as those used in the UNSCEAR , reports.
BEIR V NRC, used lower estimates of 20, to 30, for congenital abnormalities and did not provide any comparable estimate for chronic multifactorial diseases see Table Conceptual change in calculating the doubling dose. Human data on spontaneous mutation rates and mouse data on induced mutation rates are now used to calculate the doubling dose, which was also the case in the NRC report. Although the conceptual basis for calculating the DD is now different and the estimate itself is based on more data than has been the case thus far , its magnitude i.
Mutation component. Methods to estimate the mutation component the relative increase in disease frequency per unit relative increase in mutation rate have now been elaborated for both Mendelian and chronic multifactorial diseases. For X-linked diseases which are considered together with autosomal dominant diseases , the same values are used. For autosomal recessive diseases , MC in the first few generations is close to zero. For chronic multifactorial diseases , MC in the first as well as the second postradiation generations is assumed to be about 0.
For congenital abnormalities, it is not possible to calculate MC, but this does not pose any problem since the risk estimate for these does not use the doubling dose method. Potential recoverability correction factor. A new disease class-specific factor, the PRCF, has been introduced in the risk equation to bridge the gap between radiation-induced mutations in mice and the risk of radiation-inducible genetic disease in human live births.
For autosomal recessive diseases , no PRCF is necessary since induced recessive mutations do not precipitate disease in the first few generations.
For chronic diseases , PRCFs are estimated to be in the range between about 0. It is not possible to calculate PRCF for congenital abnormalities.
The concept that the adverse effects of radiation-induced genetic damage in humans are likely to manifest predominantly as multisystem developmental abnormalities in the progeny of irradiated individuals has now been introduced in the field of genetic risk estimation. The mouse data used to obtain a provisional estimate of the risk of developmental abnormalities considered here under the risk of congenital abnormalities pertain to those on radiation-induced dominant skeletal abnormalities, dominant cataract mutations, and congenital abnormalities ascertained in utero see Table D.
Briefly, the data on skeletal abnormalities Ehling , ; Selby and Selby permit an overall estimate of about 6. This estimate takes into account the proportion of skeletal abnormalities in mice, which—if they occur in humans—are likely to impose a serious handicap.
When these three estimates are com-. This estimate summarizes the overall risk of congenital abnormalities for acute X-irradiation of males. The values used for estimating the first-generation risk are the following:.
For the second postradiation generation, the MC value is 0. Estimates for congenital abnormalities have been obtained using mouse data on developmental abnormalities see Table D ; the DD method was not used. All estimates are per million progeny per gray. As can be seen, the risk is of the order of about to cases for autosomal dominant and X-linked diseases versus 16, cases of naturally occurring ones and zero for autosomal recessive diseases versus cases of naturally occurring ones. For congenital abnormalities, the estimate is about cases versus 60, cases of naturally occurring ones , and for chronic diseases, it is about to cases versus , cases of naturally occurring ones.
Overall, the predicted risks per gray represent 0. Under conditions of continuous radiation exposure in every generation, the risk to the second postradiation genera. The overall increase in risk all classes of disease relative to the baseline is small 0. As evident, in the report 1 the estimates of baseline frequency of Mendelian diseases were lower and 2 no risk estimate was provided for chronic multifactorial diseases. It is worth mentioning that the differences between the current and the estimates stem from differences in the assumptions used see NRC for details.
The genetic theory of equilibrium between mutation and selection that underlies the use of the doubling dose method predicts that when a population sustains radiation exposure in every generation, a new equilibrium between mutation and selection will eventually be reached, albeit after tens or hundreds of generations into the distant future.
In principle, therefore, one can project risks at the new equilibrium. However, in the present report in contrast to NRC , this has not been done and calculations have been restricted to the. Second Generation a. The genetic studies of atomic bomb survivors carried out in Japan represent the largest and most comprehensive of the long-term human studies ever carried out on adverse hereditary effects of radiation. The various papers published over the past four decades on this research program have been compiled by Neel and Schull Since the beginning of these studies, their focus has always been on a direct assessment of adverse hereditary effects in the first-generation progeny of survivors, using indicators of genetic damage that were practicable at the time the studies were initiated in the early s.
While radiation interferes with the crucial process of DNA replication, and repair, the body is extremely resilient and must be exposed to high levels to even seen slight increased likelihoods of cancer among that population. It is hard to quantify the dangers of radiation, as it is difficult to attribute long term effects to solely radiation exposure, and experimental studies exposing humans to high levels radiation cannot be performed due to the harm it would cause to subject.
The author warrants that the work is the author's own and that Stanford University provided no input other than typesetting and referencing guidelines. The author grants permission to copy, distribute and display this work in unaltered form, with attribution to the author, for noncommercial purposes only.
All other rights, including commercial rights, are reserved to the author. Moysich, R. Menenzes, and A.
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