Ionizing radiation and genetic risks IX. Estimates of the frequencies of mendelian diseases and spontaneous mutation rates in human populations: a 1998 perspective.

This paper is focused on baseline frequencies of mendelian diseases and the conceptual basis for calculating doubling doses both of which are relevant for the doubling dose method of estimating genetic risks of exposure of human populations to ionizing radiation. With this method, the risk per unit dose is obtained as a product of three quantities, namely, the baseline frequency of the disease class under consideration, the relative mutation risk (which is the reciprocal of the doubling dose, which in turn, is calculated as a ratio of spontaneous and induction rates of mutations) and mutation component, i.e., the responsiveness of the disease class to an increase in mutation rate. The estimates of baseline frequencies of mendelian diseases that are currently used in risk estimation date back to the late 1970s. Advances in human genetics during the past two decades now permit an upward revision of these estimates. The revised estimates are 150 per 10(4) livebirths for autosomal dominants (from the earlier estimate of 95 per 10(4)), 75 per 10(4) livebirths for autosomal recessives (from 25 per 10(4)) and to 15 per 10(4) livebirths for X-linked diseases (from 5 per 10(4)). The revised total frequency of mendelian diseases is thus 240 per 10(4) livebirths and is about twice the earlier figure of 125 per 10(4) livebirths. All these estimates, however, pertain primarily to Western European and Western European-derived populations. The fact that in several population isolates or ethnic groups, some of these diseases (especially the autosomal recessives) are more common as a result of founder effects and/or genetic drift is well known and many more recent examples have come to light. These data are reviewed and illustrated with data from studies of the Ashkenazi Jewish, Finnish, French Canadian, Afrikaner and some other populations to highlight the need for caution in extrapolating radiation risks between populations. The doubling dose of 1 Gy that has been used for the past 20 years for risk estimation is based on mouse data for both spontaneous and induction rates of mutations. In extrapolating the mouse-data-based doubling dose to humans, it is assumed that the spontaneous rates in mice and humans are similar. This assumption is incorrect because of the fact that in humans, for several well-studied mendelian diseases, the mutation rate differs between the two sexes and it increases with paternal age. In estimates of spontaneous mutation rates in humans (which represent averages over both sexes), however, paternal age effects are automatically incorporated. In the mouse, these effects are expected to be much less (if they exist at all), but the problem has not been specifically addressed. The complexities and uncertainties associated with assessing the potential impact of spontaneous mutations which arise as germinal mosaics (and which can result in clusters of mutations in the following generation) on mutation rate estimates (in the mouse) and on mutation rate estimates and disease frequencies (in humans) are discussed. In view of (i) the lack of comparability of spontaneous mutation rates in mice and humans and (ii) the fact that these estimates for human genes already include both paternal age effects and correction for clusters (if they had occurred), it is suggested that a prudent procedure now is to base doubling dose calculations on spontaneous mutation rates of human genes (and induction rates of mouse genes, in the absence of a better alternative). This concept, however, is not new and was used by the US National Academy's Committee on the Biological Effects of Ionizing Radiation in its 1972 report.