Detection of gene mutation in skin, stomach and liver of MutaTMMouse following oral or topical treatment with Af-methyl-iV'-nitro-./V-nitrosoguanidine or 1-chloromethylpyrene: some preliminary observations

Transgenic mouse assays, such as MutaTMMouse, provide a method to predict the potential target organ carcinogenicity of chemical compounds. As part of a validation study, the effects of the direct-acting mutagens, JV-methylW-nitro-N-nitrosoguanidine (MNNG) and 1-chloromethylpyrene (CMP), were investigated for gene mutation in the tissues of MutaTMMice after a single oral or topical exposure. MNNG (50 or 100 mg/kg) or CMP (25 or 50 mg/kg) were administered as a single oral dose and the mice killed after 3,7 or 10 days. Mutation frequencies were determined in stomach DNA from both MNNG and CMP-treated animals and in liver DNA from the MNNG-treated animals only. The results, although obtained from a limited number of animals, consistently showed that MNNG increased the mutation frequency in stomach DNA, but not apparently in liver DNA, at each exposure time; no clear increase in mutation frequency was seen in the stomach DNA of CMPtreated animals. Also, MNNG (250 or 500 ng) or CMP (5 or 10 ng) in acetone were applied as a single dose to the shorn skin of mice 7, 14 or 21 days prior to death. A positive control group was similarly given dimethylbenz[a]anthracene (DMBA, 40 |ig) and sacrificed after 14 days. Mutation frequencies were determined in the skin DNA extracted from all animals and in the stomach DNA from MNNG-painted animals only. The results, again obtained from a limited number of animals, clearly showed that all test compounds consistently increased the mutation frequency of skin DNA and that these increases were far greater in the DMBAand MNNG-treated mice than the CMP-treated mice. No apparent increases were seen in the stomach DNA from the MNNG-painted mice.