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

Abstract

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.

• Authors: Carla E Torrey, Henry G Wall, James A Campbell, Puntipa Kwanyuen, Debie J Hoivik, Richard T Miller, Jane S Allen, Manuel J Jayo, Krzysztof Selinger, Paul M Savina, Michael J Santostefano
• Journal: International journal of toxicology (Int J Toxicol) 2005 Sep-Oct Vol. 24 Issue 5 Pg. 313-25 ISSN: 1091-5818 [Print] United States
• PMID: 16257851 (Publication Type: Journal Article)

Chemical References

• Peroxisome Proliferators
• Clofibrate

Topics

• Animals
• Carcinogenicity Tests (methods)
• Clofibrate (administration & dosage, toxicity)
• Dose-Response Relationship, Drug
• Female
• Genes, ras
• Hypertrophy (chemically induced)
• Intubation, Gastrointestinal
• Liver (drug effects, pathology)
• Male
• Mice
• Mice, Transgenic
• Peroxisome Proliferators (administration & dosage, toxicity)
• Risk Assessment
• Time Factors