title: Evaluation of the carcinogenic potential of clofibrate in the neonatal mouse.
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.
authors.affiliation: GlaxoSmithKline, Safety Assessment, Ware, United Kingdom. sarah.r.nesfield@gsk.com
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Nesfield
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Williams
authors.forename: Debie J
authors.initials: DJ
authors.lastname: Hoivik
authors.forename: Richard T
authors.initials: RT
authors.lastname: Miller
authors.forename: Jane S
authors.initials: JS
authors.lastname: Allen
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selinger
authors.forename: Douglas
authors.initials: D
authors.lastname: Rickert
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Santostefano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015197:Carcinogenicity Tests; D002994:Clofibrate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007441:Intubation, Gastrointestinal; D008297:Male; D051379:Mice; D023421:Models, Animal; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D020025:Peroxisome Proliferators; D002994:Clofibrate