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Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Henry G. Wall

Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA

James A. Campbell
Puntipa Kwanyuen
Debie J. Hoivik
Richard T. Miller

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Jane S. Allen

Jane Allen Consulting, Inc., Raleigh, North Carolina, USA

Manuel J. Jayo

Pathology Associates Inc., Research Triangle Park, North Carolina, USA

Krzysztof Selinger

Forest Laboratories Inc., Bioanalytical and Drug Metabolism Department, Farmingdale, New York, USA

Michael J. Santostefano

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Correspondence: Address correspondence to Michael J. Santostefano, GlaxoSmithKline, Safety Assessment, 5 Moore Drive, Research Triangle Park, NC 27709, USA. E-mail:michael.j.santostefano{at}gsk.com

This study was conducted as part of the International Life Sciences Institute (ILSI) Alternatives to Carcinogenicity Testing program and evaluated the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) agonist following dermal application to transgenic Tg.AC and nontransgenic FVB mice for a minimum of 26 weeks. Clofibrate doses of 12, 28, or 36 mg/200 µl/day were used. Positive controls for papilloma formation were benzene (174.8 mg/200 µl), and 12-o-tetradecanoylphorbol-13-acetate (TPA [0.00250 mg/200 µl]). Clofibrate was tolerated at doses up to 36 mg/200 µl. In Tg.AC mice, clofibrate produced a dose-related increase in the incidence of mice with cutaneous papillomas; and dose-related decreases in mean time to first tumor, mean multiplicity of tumors per mouse, and mean weeks to maximal yield, as well as numerous nonneoplastic microscopic lesions in the liver, kidney, spleen, and skin. Benzene and TPA induced both neoplastic and/or non-neoplastic proliferative lesions in Tg.AC mice. Clofibrate did not increase the incidence or multiplicity of papillomas, or any other tumors in FVB mice. These data show that the Tg.AC dermal model has increased sensitivity in detecting skin papillomas caused by the nongenotoxic rodent carcinogen, clofibrate, compared to wild type FVB mice, at systemic exposures that are 3x higher than the systemic exposure observed in humans taking clofibrate (AUC = 1100 µg·h/ml) at the recommended maximum therapeutic dose of 500 mg. In addition, this study supports the proposed concept that Tg.AC model may detect compounds with nongenotoxic carcinogenic potential in a shorter timeframe than conventional mouse carcinogenicity bioassays.

Key Words: Benzene • Carcinogenicity • Clofibrate • Micronucleus • 12-o-Tetradecanoylphorbol-13-acetate • Tg.AC • TPA

International Journal of Toxicology, Vol. 24, No. 5, 327-339 (2005)
DOI: 10.1080/10915810500208199


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