Evaluation of the carcinogenic potential of clofibrate in the FVB/Tg.AC mouse after dermal application--part II.
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) alpha 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 microl/day were used. Positive controls for papilloma formation were benzene (174.8 mg/200 microl), and 12-o-tetradecanoylphorbol-13-acetate (TPA [0.00250 mg/200 microl]). Clofibrate was tolerated at doses up to 36 mg/200 microl. 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 microg.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.
Torrey
Carla E
CE
GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina 27709, USA.
Wall
Henry G
HG
Campbell
James A
JA
Kwanyuen
Puntipa
P
Hoivik
Debie J
DJ
Miller
Richard T
RT
Allen
Jane S
JS
Jayo
Manuel J
MJ
Selinger
Krzysztof
K
Santostefano
Michael J
MJ
D000279:Administration, Cutaneous; D000818:Animals; D015197:Carcinogenicity Tests; D002994:Clofibrate / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D011905:Genes, ras; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced*; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000633:toxicity*; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000139:chemically induced*; D013997:Time Factors
D020025:Peroxisome Proliferators; D002994:Clofibrate