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

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, eastin{at}niehs.nih.gov

John H. Mennear

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Ray W. Tennant

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Ray E. Stoll

Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877

Dan G. Branstetter

Pharmacia & UpJohn Co., Kalamazoo, Michigan 49007

John R. Bucher

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Bruce Mccullough

Aventis Pharma, Collegeville, Pennsylvania 19426

Robert L. Binder

The Procter & Gamble Co, Cincinnati, Ohio 45217

Judson W. Spalding

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Joel F. Mahler

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 fromgovernmentand 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 clofi brate, an hepatocarcinogenicperoxisome 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 clofi 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, 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.

Key Words: Tg.AC mouse • hemizygous • homozygous • papilloma • short-term • 26-weeks • carcinogenicity • ras gene • transgenic mouse.

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Toxicologic Pathology, Vol. 29, No. 1 suppl, 60-80 (2001)
DOI: 10.1080/019262301753178483


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