Discovery of numerous clusters of spontaneous mutations in the specific-locus test in mice necessitates major increases in estimates of doubling doses

Abstract

Both the precision with which mutations can be quickly identified and the extensive application of the method make results from specific-locus experiments in mice especially important for estimating the doubling dose, which is the radiation exposure that induces a mutation frequency equal to the total spontaneous mutation frequency per generation. Because of gonadal mosaicism and the mechanism by which it occurs, the frequency with which new spontaneous mutations occur per generation is much higher than has been thought. While it will be some time before many of the newly-apparent uncertainties related to understanding this phenomenon can be resolved, consideration of what is known suggests that it would already be reasonable to raise the doubling dose from 1 to 5 Gy for low-dose-rate exposures to X and gamma radiation. Doing so would reduce risk estimates made by the doubling-dose method fivefold. Because the doubling dose for chemical mutagens is also calculated by division of the total spontaneous mutation frequency per generation by the induced mutation frequency per unit of chemical exposure, hereditary risks for chemicals have also been considerably overestimated if they are based on specific-locus data.