with estimates of human spontaneous rates for more typical genes. The BEIR III committee adopted the view that it was preferable to use a DD estimate obtained from spontaneous and induced mutations in the same set of loci in the same species and used exclusively the data on the seven specific loci obtained in experiments with male mice. The figures used were 7.5 × 10−6 per locus for spontaneous rates and 6.6 × 10−8 per locus per rem for induced rates from which “the best substantiated” DD estimate of 114 R was calculated. To derive DDs for risk predictions, it approximately halved and doubled the above estimate of 114 R to obtain a range of 50 to 250 rem.
In BEIR V (NRC 1990), the committee again used primarily mouse data but included several additional end points in both sexes (dominant lethals, recessive lethals, dominant visibles, recessive visibles, reciprocal translocations, congenital malformations, and aneuploidy). On the basis of all these data, it concluded that “considering all endpoints together, the direct estimates of doubling dose for low dose rate radiation have a median value of 70–80 rad, indirect estimates based on high dose-rate experiments have a median value of 150 rad, and the overall median lies in the range of 100 to 114 rad. These estimates support the view that the doubling dose for low dose-rate, low-LET radiation in mice is approximately 100 rad for various genetic endpoints.”
Table 4B-1 also shows that the DD estimates made over the years based on genetic data from A-bomb survivors (Neel and others 1974, 1982, 1990; Schull and others 1981, 1982; Otake and others 1990; Neel 1998) were at least some three to four times that of 1 Gy used by UNSCEAR and the BEIR committee; the so-called Japanese DD estimates, however, were never used by the above committees. For the first time, the BEIR V (NRC 1990) report gave a formal “status” to the Japanese results by noting that “a doubling dose of 100 rem approximates the lower 95% confidence limit for the data from atomic bomb survivors in Japan and it is also consistent with the range of doubling doses in mice.”
The assumptions and specifications of the FLTM have been discussed in detail by Denniston and colleagues (1998) and in the ICRP (1999) Task Group report. Briefly, the FLTM assumes that (1) the genetic component of liability of a chronic multifactorial disease is discrete and is determined by mutant alleles at a finite number (n) of autosomal gene loci; the total number of mutant alleles at these n loci in a given genotype is a random variable g; (2) the environmental component is continuous and represented by a random variable e, which has a Gaussian distribution with mean of zero and variance of Ve; (3) the total liability x = f(g) + e, where f(g) is a function of the number of mutant alleles in the n-locus genotype of the individual and e is the environmental effect; (4) individuals with liability exceeding the threshold T (i.e., x > T) are affected by the disease, and those for whom x < T are unaffected; and (5) unaffected individuals have a fitness of 1 and unaffected ones of (1 − s). The impact of an increase in total mutation rate as a result of radiation exposures—from m to m(1 + k), with k measuring the increase relative to the baseline—is assessed in terms of changes in heritability of liability (hx2), and consequent changes in the MC. This assessment was carried out by assuming that the effects of the mutant alleles are either additive or synergistic.
Unlike the case of Mendelian diseases, the algebraic formulations of the FLTM do not permit expressing the effects in the form of a single equation. However, the predictions of the model can be evaluated iteratively using the computer program that was developed for this purpose. The program is first run using a specified set of parameter values (mutation rate, selection coefficients, threshold, etc.) until the population reaches equilibrium between mutation and selection. Once this occurs, the mutation rate is increased either once or permanently corresponding to radiation exposure in one generation only or in every generation, and the computer run is resumed with the new mutation rate while the other parameters remain the same. The changes in mutation component and its relationship to heritability of liability are then examined in desired generations and at equilibrium. It is worth mentioning that the h2 estimates are not inputs but outputs of the program obtained using different combinations of s values, environmental standard deviation, and threshold.
The molecular alterations recorded in spontaneous disease-causing mutations in humans include a wide variety ranging from base-pair changes to whole-gene deletions and some multigene deletions. Radiation-induced mutations studied in experimental systems (including the mouse), however, are often multigene deletions, although scored through the phenotype of the marker loci. The extent of the deletion varies with the locus and the genomic region in which it is located.
Spontaneous mutations arise through a number of different mechanisms, and most are dependent on the DNA sequence organization of the genes and their genomic context. In contrast, radiation-induced mutations originate through random deposition of energy in the cell. One can, therefore, assume that the initial probability of radiation inducing a deletion may not differ between different genomic regions. However, their recoverability in live-born offspring seems dependent on whether the loss of the gene or genomic region is compatible with viability in heterozygotes.