ABSTRACT
This study was conducted in support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of clofibrate, a nongenotoxic peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to neonatal mice. Male and female neonatal CD-1 mice were dosed with clofibrate at doses of 100, 250, and 500 mg/kg or with the positive control, diethylnitrosamine (DEN), at 2 mg/kg by oral gavage on days 9 and 16 post birth and observed for approximately 1 year for the development of tumors. Plasma levels of clofibric acid after the second administration increased with dose, but were not dose proportional. Clofibrate administered by gavage on litter days 9 and 16 to neonatal mice at doses of 100, 250, or 500 mg/kg did not produce a carcinogenic effect. The positive control DEN did produce tumors in the liver and lung (single and multiple adenomas and carcinomas) and harderian gland (adenoma) of both sexes. Non-neoplastic lesions related to DEN treatment were confined to myocardial degeneration/fibrosis and testicular interstitial hyperplasia in males, and to glomerulonephrosis and gastritis in both sexes.
Subject(s)
Clofibrate/pharmacokinetics , Clofibrate/toxicity , Peroxisome Proliferators/toxicity , Animals , Animals, Newborn , Carcinogenicity Tests , Clofibrate/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Intubation, Gastrointestinal , Male , Mice , Models, Animal , Peroxisome Proliferators/administration & dosage , Peroxisome Proliferators/pharmacokinetics , Risk Assessment , Time FactorsABSTRACT
The purpose of the study was to support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of the nongenotoxic carcinogen, clofibrate, a peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to rasH2 mice. Peroxisome proliferators are one of the most widely studied of the nongenotoxic carcinogens and have diverse industrial and therapeutic uses (Gonzalez et al. J. Nat. Cancer Inst. 90: 1702-1709, 1998); however, the nongenotoxic mechanism of carcinogenicity is currently unknown. Male mice were administered doses of clofibrate at 50, 100, or 200 mg/kg/day and female mice were administered doses of 50, 150, or 250 mg/kg/day by oral gavage at 10 ml/kg for 27 weeks. In addition, rasH2 male and female mice were treated with N-nitroso-N-methylurea (NMU). Nontransgenic male and female mice were treated with 200 and 250 mg/kg/day, respectively, of clofibrate. The NMU-treated mice were given a single intraperitoneal dose of 75 mg/kg, which was followed by a 90-day observation period; all others were sacrificed after 6 months of daily dosing. Hepatocellular neoplasms were observed in clofibrate-treated rasH2 male mice after 6 months of treatment but not in nontransgenic males or females. Clofibrate treatment (250 mg/kg/day) of female rasH2 mice was associated with a slight increase in the incidence of various neoplasms (harderian gland, lungs, skin, spleen, tail, thymus, and uterus) compared with untreated transgenic mice and with similarly treated nontransgenic mice. Non-neoplastic changes were found in the liver of transgenic and nontransgenic mice of both sexes and in the kidneys of male mice. NMU produced findings are consistent with previous studies. The data suggest that the rasH2 mice are a good model for testing epigenetic carcinogens in a shorter timeframe than conventional mouse carcinogenicity bioassays.
