the literature are broad-sense heritability of liability estimates and are in the range of about 0.3–0.8.

Other Models of Inheritance of Multifactorial Diseases

An important assumption of the MTM as discussed above is that a large number of factors, each with small effects, contributes to liability. However, the assumption of fewer contributing factors is also consistent with data from familial aggregation studies, and for this reason, it is not a good analytical tool for discriminating between different modes of inheritance. Consequently, attempts to fit the familial data to Mendelian models (with appropriate choice of assumptions on the numbers of loci, penetrance, dominance, etc.) or to a combination of major locus and polygenic models have been made, (e.g., Elston and Stewart 1971; Morton and MacLean 1974; Kendler and Kidd 1986); although these models are of interest in catalyzing the search for the genes involved, they are now largely superseded by molecular approaches that hold the potential for direct identification of the genes.


Table 4B-1 provides a broad overview of the data used during the past four decades for estimating doubling doses. It is worth noting that although the present unit for expressing absorbed radiation dose is gray (or sievert when considering radiations of different qualities), in reviewing the earlier estimates in this section the DDs are expressed in the same units employed in the original publications, namely, roentgens (R), rads, roentgen-equivalent-man (rem), grays, and sieverts. Note that for low-LET radiation (e.g., X-rays and γ-rays), 1 Gy = 100 rads ~ 100 R; 1 rem=1rad; and 1Sv=100 rem.

Briefly, the notion that the DD for genetic damage induced in human males at low-dose or chronic low-LET radiation conditions is likely to be of the order of about 100 R was already entertained in the early 1960s (UNSCEAR 1962). This estimate was guided by the findings (from mouse studies on recessive specific locus mutations) that chronic X-irradiation would be only about one-third as effective as acute X-irradiation in males and much less effective in females (Russell and others 1958, 1959). Consequently, it was suggested that the DD for chronic X-irradiation exposure conditions was probably at least three times that for acute X-irradiation (i.e., three times that of about 30 R suggested in the 1958 UNSCEAR report for acute X-irradiation or about 100 R).

In 1971, Lüning and Searle broadened the original concept of the DD to include not only mutations at defined gene loci, but also four other end points of genetic damage (semisterility, dominant visible mutations recovered in the course of studies on recessive specific locus mutations, autosomal recessive lethals, and skeletal abnormalities, all from experiments involving irradiation of male mice [spermatogonial stem cell irradiations]). They found that for acute X-irradiation of males, although individual estimates varied from 16 to 51 R (with wide confidence limits, except for specific locus mutations), the overall average was about 30 R. For low-dose or chronic low-LET radiation exposure, the suggestion was that it would be between three and four times that for acute X-irradiation (i.e., about 100 R). UNSCEAR, however, did not use the DD method in its 1972 report, but in all reports published until 1993, the mouse data-based estimate of 1 Gy has been used.

The BEIR I report (NRC 1972) introduced the concept that DD estimates must be based on the average spontaneous mutation rate of human genes and the average induced rate of mutations in mouse genes. In that report it was assumed that (1) the spontaneous mutation rate of human genes might be in the range of 0.5 × 10−6 to 0.5 × 10−5 per gene and (2) the sex-averaged rate of induced recessive mutations in mouse was about 0.25 × 10−7 per locus per rem for low-LET radiation conditions. With these estimates, a range of DDs from 20 to 200 rem was calculated.

The induced rate of 0.25 × 10−7 per locus per rem mentioned above was the unweighted average of the rate of 0.5 × 10−7 per locus per rem for males (at 12 loci, including 7 of the specific loci have been used in most mouse experiments and the additional 5 used in the studies of Lyon and Morris 1969) and that of zero assumed for females. It was noted, however, that the estimate of 0.25 × 10−7 per locus per rem might be too high for at least two reasons: (1) “the gene loci at which these studies were made, were to some extent preselected for mutability” and (2) “the rate of induction of dominant visible mutations in mice is lower than for recessives by at least an order of magnitude and dominant mutations constitute a substantial part of the human genetic risk.” This procedure of using human data on spontaneous mutation rates was driven by one of the principles stated by the committee—namely, that emphasis should be placed on human data when feasible—the implicit idea being that if the induced rate was extrapolated from mouse to humans, there would be one extrapolation uncertainty and if both spontaneous and induced rates were extrapolated to humans, there would be two such uncertainties.

When UNSCEAR (1977) first used the mouse data-based DD of 100 rads, it did not actually specify the induced rates. This was because the estimate of 100 rads was arrived at by assuming that the DD for low-LET chronic radiation conditions would be three times that of ~30 rads for high-dose-rate acute X-irradiation conditions (for five different end points; see Lüning and Searle 1971).

In BEIR III (NRC 1980), however, the committee abandoned the method that was used in BEIR I, namely, using human data on spontaneous mutation rates and mouse data on induced mutation rates in defined genes. The stated objection to the BEIR I method was that it mixed the induced rate of a set of mouse genes preselected for high mutability

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