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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2
Estimates of Baseline Frequency of Chromosomal Disease
The BEIR V report (NRC 1990) and the UNSCEAR (1993) report assessed the baseline prevalence of chromosomal diseases to be of the order of about 0.4% in live births. The present committee sees no reason to alter this estimate.
Summary of Current Estimates of Baseline Frequencies of Genetic Diseases and Comparison with Those in BEIR V
Table 4-1 presents these comparisons showing that the current estimates for Mendelian diseases are higher than those used in 1990, while those for the other classes remain essentially unchanged.
The Doubling Dose
As discussed earlier DD is one of the important quantities used in the equation for the doubling dose method of risk estimation. Although the DD concept was formulated by Muller (1951, 1954, 1959) in the 1950s and several possible estimates and/or ranges of DDs were discussed in the BEAR report (NRC 1956), in UNSCEAR (1962), and in Lüning and Searle (1971), actual use of the method to obtain quantitative estimates of risk began only in 1972 (NRC 1972). Changes in the conceptual basis and database used for DD estimates from the mid-1950s to the early 1990s have recently been reviewed (Sankaranarayanan and Chakraborty 2000a).
TABLE 4-1 Estimates of the Baseline Prevalences of Genetic Diseases Used in BEIR VII and BEIR V
aBEIR V included these diseases under “other disorders of complex etiology.”
bIncluded under chronic multifactorial diseases in BEIR VII.
cNot specifically considered in this chapter.
SOURCE: Table reproduced with permission from Chakraborty and others (1998b).
Table 4B-1 (see Annex 4B) summarizes the important developments. As evident from that Table, with one exception, most of the DD estimates used in risk estimation by UNSCEAR and the BEIR committees were based on data on both spontaneous and induced mutation rates in mice. The one exception was BEIR I (NRC 1972), which used data on spontaneous rate of mutations of human genes and induced rate of mutations in mouse genes. As discussed below, reevaluation of the assumptions underlying the use of mouse data on spontaneous mutation rate for DD calculations has shown that these are incorrect and that the use of human data on spontaneous mutation rates along with mouse data on induced rates is correct.
Incorrectness of the Assumption of Similarity of Spontaneous Mutation Rates in Mice and Humans—The Need to Use Human Spontaneous Mutation Rates for DD Calculations
Extrapolation of the mouse-based DD to humans for risk estimation implies the assumption that both the spontaneous and the induced rates of mutations are similar in the two species. The assumption of similarity of induced rates of mutations in both species is defensible on the grounds of generally similar gene organization, 70–90% homology in DNA sequence of genes, and substantial conservation of synteny for many chromosomal regions between humans and mice. However, the situation is different with respect to spontaneous mutations.
The reasons spontaneous mutation rates in humans are unlikely to be similar to those in mice have been discussed (Sankaranarayanan 1998). Briefly, these have to do with the differences in the number of cell divisions between the zygote and the mature germ cell in the two species. Vogel and Motulsky (1997) estimate that in human females, the number of cell divisions from zygote to the mature egg (Nf) is of the order of about 24. For the mouse female, estimates of Drost and Lee (1995) suggest that Nf is of the same order. So, from the standpoint of Nf, human and mouse females are similar.
In human males, however, the comparable number of cell divisions is much higher; it is about 30 until the age of puberty (taken to be 15 years), ~23 per year thereafter, and 6 for proliferation and meiosis. Thus, the number of cell divisions prior to sperm production (Nm) in a 20-year-old male can be estimated to be 30 + (5 × 23) + 6 = 151, increasing to 381 at age 30 years, 611 at age 40 years, and 841 at age 50 years (Crow 1999). The Nm/Nf thus increases with paternal age, being 6.3 at age 20, 15.9 at age 30, 25.5 at age 40, and 35.0 at age 50. In the male mouse, the number of cell divisions from zygote to sperm is of the order of about 62 at age 9 months, assuming a 9-month generation (Chang and others 1994; Drost and Lee 1995; Li and others 1996). The Nm/Nf ratio in the mouse is therefore 2.5 (i.e., 62/25), which is much lower than in humans. The committee notes that in