The mouse specific-locus test with agents other than radiations: Interpretation of data and recommendations for future work

Abstract

The mouse specific-locus test with visible markers (SLT) has been the only extensively used method for detecting and quantifying the induction of heritable point mutations (intragenic changes and small deficiencies) in mammals. Mutations are detected in first-generation offspring; and scoring is simple, objective, and rapid. Different germ-cell stages can be sampled, including those of greatest pertinence for genetic risk assessment. The differential probability of involving the various loci of the marked set makes the method capable of detecting qualitative (as well as quantitative) differences between the actions of mutagens. Control SLT frequencies for males reported by 4 sets of investigators are in excellent agreement and were summed as a "historical control" (801406 observations) for use in our calculations. Experimental results were classified as positive, negative, or inconclusive based upon a multiple-decision procedure produced by the testing of the following 2 hypotheses: (1) the mutation frequency (induced + spontaneous) of treated mice is not higher than the spontaneous mutation frequency, and (2) the induced mutation frequency of treated mice is no less than 4 times the historical-control mutation frequency. Each hypothesis was tested at the 5% significance level. Because of the low mutation frequency in a very large control, the SLT is capable of yielding positive results in relatively small samples. We reviewed 58 publications, SLT results have been reported for 25 chemical agents, of which 17 (representing 21 chemical classes) gave results that were positive or negative by our criteria. The frequency of positive agents was 6 of 14, 5 of 5, and 0 of 1 conclusively tested, respectively, in spermatogonia, post-spermatogonial stages, and unspecified male germ cells. Depending on the chemical used, post-spermatogonial stages can be of greater, less, or equal sensitivity relative to spermatogonia. The SLT was strongly positive for some chemicals that are not mutagenic (or only weakly so) in lower systems, and there are several examples of the reverse situation. Factors which presumably operated to cause these differences (e.g., metabolism, transport, repair in germ cells) are likely also to operate for transmitted point mutations in man.