Supermutagenicity of ethylnitrosourea in the mouse spot test: comparisons with methylnitrosourea and ethylnitrosourethane.

The effects of the 3 related compounds ethylnitrosourea (ENU), methylnitrosourea (MNU), and ethylnitrosourethane (NEC) were studied in the mouse spot test. ENU induces a large number of recessive spots (RS) and, due to its low toxicity, can be applied at relatively high doses. This combination of properties makes it the most efficient spot-test mutagen, as shown in a comparison with 16 other chemicals, even though, on the basis of molarity, it is not the most potent one. The ENU mutation frequency in cells at risk, calculated per locus, per unit of applied dose, is roughly similar for melanocyte precursors (in the spot test) and spermatogonial stem cells (in the specific-locus test). MNU which, due to its high embryotoxicity, could be tested only at a low dose, is clearly mutagenic, and dose extrapolations indicate it to be more potent than ENU. NEC, though it could be tested at higher molarities than ENU, is only weakly mutagenic. The spot test, in addition to mutational data, also yields information on cytotoxicity (white midventral spots), embryotoxicity, and teratogenicity. The toxicity and teratogenicity findings parallel earlier results in the rat. For all endpoints studied. ENU is more effective than NEC. Relative to MNU, ENU is less toxic, less teratogenic, and less mutagenic in the spot test; but it is much more carcinogenic (transplacentally) and more mutagenic in spermatogonia. We propose that MNU is more effective in inducing gross chromosomal damage than is ENU, while ENU induces relatively more gene mutations. The spot test scores both types of mutational damage, while mostly the latter type is recovered from spermatogonia.