In a Government/Industry/Academic partnership to evaluate alternative approaches to carcinogenicity testing, 21
pharmaceutical agents representing a variety of chemical and pharmacological classes and possessing known human and or rodent carcinogenic potential were selected for study in several rodent models. The studies from this partnership project, coordinated by the International Life Sciences Institute, provide additional data to better understand the models' limitations and sensitivity in identifying
carcinogens. The results of these alternative model studies were reviewed by members of Assay Working Groups (AWG) composed of scientists from government and industry with expertise in toxicology, genetics, statistics, and pathology. 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 describes the results and AWG interpretations of studies conducted on 14 chemicals administered by the topical and oral (gavage and/or diet) routes to Tg.AC genetically manipulated mice.
Cyclosporin A, an immunosuppresant human
carcinogen,
ethinyl estradiol and
diethylstilbestrol (human
hormone carcinogens) and
clofibrate, an hepatocarcinogenic peroxisome proliferator in rodents, were considered clearly positive in the topical studies. In the oral studies,
ethinyl estradiol and
diethylstilbestrol were negative,
cyclosporin was considered equivocal, and results were not available for the
clofibrate 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
clofibrate, 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,
sulfisoxazole) regardless of route of administration. Based on the observed responses in these studies, it was concluded by the AWG that the Tg.AC model was not overly sensitive and possesses utility as an adjunct to the battery of toxicity studies used to establish human carcinogenic risk.