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.