Evaluation of the carcinogenic potential of clofibrate in the FVB/Tg.AC mouse after oral administration--part I.

This study was conducted as part of the International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist following oral administration to Tg.AC (transgenic) and wild-type FVB (nontransgenic) mice for a minimum for 6 months. Clofibrate was well tolerated at doses up to 500 (males) and 650 (females) mg/kg/day. Oral administration of clofibrate to Tg.AC or FVB (wild-type) male and female mice for 6 months did not result in the increased formation of neoplastic lesions. Epithelial hyperplasia in the urinary bladder (Tg.AC and FVB) and prostate gland (Tg.AC only), and interstitial-cell hyperplasia in the testes (Tg.AC) were noted at 500 mg/kg/day. Non-neoplastic nonproliferative findings included hepatic hypertrophy and hematopoietic changes (myeloid hyperplasia, myelodysplasia, lymphoid depletion, and erythropoiesis) in Tg.AC and FVB mice of both sexes; reproductive (cystic degeneration and dilatation, hypospermia, spermatocele, dilated inspissated protein) and urogenital (tubular-cell hypertrophy, degenerative/regenerative nephropathy, necrosis/fibrosis) changes in Tg.AC and FVB male mice; congestion in the lung in male Tg.AC mice; gall bladder dilatation in female Tg.AC mice; and adrenal (intracellular lipofuscinosis and atrophy) and heart (eosinophillic myofibers) findings in Tg.AC mice of both sexes and in female FVB mice. The results of this study indicate that the clofibrate is not carcinogenic when administered to Tg.AC mice by oral gavage for 6 months at doses up to 500 (males) and 650 (females) mg/kg/day, which did produce liver hypertrophy.

Evaluation of the carcinogenic potential of clofibrate in the p53+/- mouse.

This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to p53+/- heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+/- than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+/- mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+/- mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+/- mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.

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.