Positive genetic hazard predictions from short-term tests have proved false for results in mammalian spermatogonia with all environmental chemicals so far tested.

Eleven chemicals for which there has been considerable human exposure were chosen for study by the mouse specific-locus method because of their positive mutagenic action in other test systems. All were positive in the Drosophila sex-linked recessive lethal test, and all of the ten tested in mammalian somatic cells proved mutagenic. Positive results were also obtained in other tests. In contrast, in mouse stem-cell spermatogonia none of the chemicals, even at maximum tolerated dose, has given a specific-locus mutation frequency higher than the control, and the mutation frequency for all eleven combined (12 mutations in 298, 502 offspring) is actually less than the historical control, though not, of course, significantly lower. Absence of mutation induction cannot be attributed to: failure of the chemicals to reach the testis (10 of them are known to reach the testis in active form), small sample size (the samples are large), insensitivity of the test (the test is not insensitive: a positive control gave a mutation frequency 132 times higher than the historical control). It is concluded that mammalian stem-cell spermatogonia have an effective repair capability. This is supported by the dose-response and dose-fractionation results with ethyl-nitrosourea. Therefore, positive genetic hazard predictions from short-term tests on chemicals may frequently give false warning of what to expect in mammalian spermatogonia, the cells considered to be of major concern for genetic risk in human males.