Development of a transgenic mouse model for carcinogenesis bioassays: Evaluation of chemically induced skin tumors in Tg.AC mice

Transgenic rodent models have emerged as potentially useful tools in the as sessment of drug and chemical safety. The transgenic Tg.AC mouse carries an inducible v-Ha-ras oncogene that imparts the characteristic of genetically initiated skin to these animals, The induction of epidermal papillomas in the area of topically applied chemical agents, for duration of not more tha n 26 weeks, acts as a reporter phenotype that defines the activity of the t est article. We describe here the activity of six chemicals that have been previously characterized for activity in the standard 2-year bioassay condu cted by the National Toxicology Program (NTP). Homozygous female Tg.AC mice were treated with benzene (BZ), benzethonium chloride (BZTC), o-benzyl-p-c hlorophenol (BCP), 2-chloroethanol (2-CE), lauric acid diethanolamine (LADA ) and triethanolamine (TEA), BZ and LADA induced skin papillomas in a dose- dependent manner, while BCP induced papillomas only at the highest dose. BZ TC, 2-CE, and TEA exhibited no activity. The correspondence of chemical act ivity in Tg.AC mice with that in the 2-year bioassay was high. A comparison of responsiveness to BZ and LADA was made between hemizygous and homozygou s female Tg.AC mice. Both genotypes appear to be equally sensitive to maxim um doses of active compounds. The results reported here indicate that the T g.AC transgenic mouse model can discriminate between carcinogens and noncar cinogens and that both mutagenic and nonmutagenic chemicals can be detected . These studies provide support for the adjunctive use of the Tg.AC transge nic mouse skin tumor model in drug and chemical safety assessment and for t he prediction of the carcinogenic potential of chemicals.