Ionizing radiation and genetic risks XI. The doubling dose estimates from the mid-1950s to the present and the conceptual change to the use of human data on spontaneous mutation rates and mouse data on induced mutation ratesfor doubling dose calculations

This paper provides an overview of the concept of doubling dose, changes in the database employed for calculating it over the past 30 years and recent advances in this area. The doubling dose is estimated as a ratio of the av erage rates of spontaneous and induced mutations in a defined set of genes. The reciprocal of the doubling dose is the relative mutation risk per unit dose and is one of the quantities used in estimating genetic risks of radi ation exposures, Most of the doubling dose estimates used thus far have bee n based on mouse data on spontaneous and induced rates of mutations. Initia lly restricted to mutations in defined genes (with particular focus on the seven genes at which induced recessive mutations were studied in different laboratories), the doubling dose concept was subsequently expanded to inclu de other endpoints of genetic damage, At least during the past 20 years, th e magnitude of the doubling dose has remained unchanged at similar to1 Gy f or chronic low LET radiation exposures. One of the assumptions underlying the use of the doubling dose based on mou se data for predicting genetic risks in humans, namely, that the spontaneou s rates of mutations in mouse and human genes are similar, is incorrect; th is is because of the fact that, unlike in the mouse, the mutation rate in h umans differs between the two sexes (being higher in males than in females) and increases with paternal age, Further, an additional source of uncertai nty in spontaneous mutation rate estimates in mice has been uncovered. This is related to the non-inclusion of mutations which arise as germinal mosai cs and which result in clusters of identical mutations in the following gen eration, In view of these reasons, it is suggested that a prudent way forwa rd is to revert to the use of human data on spontaneous mutation rates and mouse data on induced mutation rates for doubling dose calculations as was first done in the 1972 BEIR report of the US National Academy of Sciences. The advantages of this procedure are the following: (i) estimates of sponta neous mutation rates in humans, which are usually presented as sex-averaged rates, automatically include sex differences and paternal age-effects; (ii ) since human geneticists count all mutations that arise anew irrespective of whether they are part of a cluster or not, had clusters occurred, they w ould have been included in mutation rate calculations and (iii) one stays c lose to the aim of risk estimation, namely, estimation of the risk of genet ic diseases in humans. On the basis of detailed analyses of the pertinent data, it is now estimate d that the average spontaneous mutation rate of human genes (n = 135 genes) is: (2.95+/-0.64) x 10(-6) per gene and the average induced mutation rate of mouse genes (n = 34) is: (0.36 +/- 0.10) x 10(-5) per gene per Gy for ch ronic low LET radiation. The resultant doubling dose is (0.82 +/- 0.29) Gy. The standard error of the doubling dose estimate incorporates sampling var iability across loci for estimates of spontaneous and induced mutation rate s as well as variability in induced mutation rates in individual mouse expe riments on radiation-induced mutations. We suggest the use of a rounded dou bling dose value of 1 Gy for estimating genetic risks of radiation. Althoug h this value is the same as that used previously, its conceptual basis is d ifferent and the present estimate is based on more extensive data than has so far been the case. (C) 2000 Elsevier Science B.V. All rights reserved.