Tg.AC Genetically Altered Mouse: Assay Working Group Overview of Available Data

In aGovernment/Industry/Academicpartnershiptoevaluatealternativeapproachestocarcinogenicity testing,21pharmaceuticalagentsrepresenting avariety ofchemical and pharmacological classes and possessing known human and or rodent carcinogenicpotential wereselected forstudy in several rodent models. The studies from this partnership project, coordinated by the International Life Sciences Institute, provide additional data to better understand themodels’ limitationsand sensitivity in identifying carcinogens. Theresultsof these alternativemodelstudieswerereviewed by members ofAssayWorkingGroups (AWG)composedofscientistsfromgovernmentand industrywith expertiseintoxicology,genetics,statistics,andpathology. The Tg.AC genetically manipulated mouse was one of the models selected for this project based on previous studies indicating that Tg.AC mice seem to respond to topical application of either mutagenic or nonmutagenic carcinogens with papilloma formation at the site of application. This communication describestheresultsandAWGinterpretationsofstudiesconducted on 14 chemicalsadministeredbythetopicalandoral (gavageand/or diet) routes to Tg.AC genetically manipulated mice. Cyclosporin A, an immunosuppresant human carcinogen, ethinyl estradiol and diethylstilbestrol (human hormone carcinogens ) and cloe brate,an hepatocarcinogenicperoxisomeproliferator in rodents, were considered clearly positivein thetopical studies. In the oral studies, ethinyl estradiol and diethylstilbestrol were negative, cyclosporin was considered equivocal, and results were not available for the cloe brate study. Of the 3 genotoxic human carcinogens (phenacetin, melphalan, and cyclophosphamide ), phenacetin was negative by both the topical and oral routes. Melphalan and cyclophosphamide are, respectively, direct and indirect DNA alkylating agents and topical administration of both caused equivocal responses. With the exception of cloe brate, Tg.AC mice did not exhibit tumor responses to the rodent carcinogens that were putative human noncarcinogens, (di(2-ethylhexyl) phthalate, methapyraline HCl, phenobarbital Na, reserpine, sulfamethoxazole or WY-14643, or the nongenotoxic, noncarcinogen, sule soxazole ) regardless of route of administration. Based on the observed responses in these studies, it was concluded by the AWG that the Tg.AC model wasnot overly sensitiveand possesses utility as an adjunct to thebattery of toxicity studies used to establish human carcinogenic risk.