for chromosomal diseases since they are assumed to be subsumed in part under the risks for autosomal dominant + X-linked diseases and in part under those for congenital abnormalities. 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.
The equation now used for risk estimation is:
where P is the baseline frequency of the disease class under consideration, 1/DD is the relative mutation risk per unit dose, MC is the disease class-specific mutation component, and PRCF is the disease class-specific potential recoverability correction factor.
1. 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, 15,000 per million live births; X-linked diseases, 1500 per million live births; and autosomal recessive diseases, 7500 per million live births. For chromosomal diseases, the estimate remains unchanged at 4000 per million live births. For congenital abnormalities and chronic multifactorial diseases, the current estimates (respectively, 60,000 per million live births and 650,000 per million individuals in the population) are the same as those used in the UNSCEAR (1993, 2001) reports. BEIR V (NRC, 1990) used lower estimates of 20,000 to 30,000 for congenital abnormalities and did not provide any comparable estimate for chronic multifactorial diseases (see Table 4-1).
2. 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 (1972) 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.e., 1 Gy for chronic low-LET radiation conditions) is the same as that used in the BEIR V.
3. 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 autosomal dominant diseases, the first postradiation generation MC = s = 0.3, where s is the selection coefficient. For the second postradiation generation, MC = 0.51 as given by the equation MCp = [1 − (1 − s)t], where s = 0.3 and t = 2. 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 0.02. 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.
4. 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. The risk now becomes a product of four quantities (see Equation (4-13) above) instead of three, which was the case until the early 1990s (NRC 1990; UNSCEAR 1993). For autosomal dominant and X-linked diseases, the PRCF estimate is in the range 0.15 to 0.30; the lower value represents the “weighted PRCF” (i.e., weighted by disease prevalence), and the higher value, the unweighted one (i.e., the proportion of human genes at which induced disease-causing mutations are potentially recoverable in 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 0.02 and 0.09 under the assumption that the number of genes underlying a given multifactorial disease is equal to 2 (the minimum number) and that the PRCF is the nth power of that for an autosomal dominant disease (i.e., [0.15]2 to [0.3]2). It is not possible to calculate PRCF for congenital abnormalities.
5. 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 4-3D). Details of these abnormalities are discussed in Sankaranarayanan and Chakraborty (2000b) and in UNSCEAR (2001).
Briefly, the data on skeletal abnormalities (Ehling 1965, 1966; Selby and Selby 1977) permit an overall estimate of about 6.5 × 10−4 per gamete per gray for acute X- or γ-irradiation of males (spermatogonial stem cells). 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. The comparable rate for dominant cataracts (Favor 1989) is lower, being ~0.33 × 10−4 per gamete per gray. The rate for congenital abnormalities (corrected for compatibility with live births) is 19 × 10−4 per gamete per gray based on two sets of data (Kirk and Lyon 1984; Nomura 1988). When these three estimates are com-