SPECIES-DEPENDENT INDUCTION OF PEROXISOME PROLIFERATION BY HALOXYFOP,AN ARYLOXYPHENOXY HERBICIDE

The potential of haloxyfop (trifluoromethyl)2-pyridinyl)oxy)phenoxy)pr opanoic acid; HAL] to induce the proliferation of hepatocellular perox isomes (PP) was examined in rats, mice, dogs, and monkeys. Chemically induced PP is associated with the development of liver tumors in roden ts via an apparent species-dependent, nongenotoxic mechanism of action . HAL is nongenotoxic yet has been shown to cause liver tumors in fema le B6C3F1 mice. Ingestion of HAL by rats and/or mice (0.1-14 mg/kg/day for 2 to 4 weeks) resulted in significant dose-related PP as evidence d by hepatocellular hypertrophy, increased peroxisome volume density ( VD), and induction of peroxisomal enzymes and CYP4A1. Only a relativel y weak induction of PP was noted at a carcinogenic dosage in female mi ce. In contrast to rodent species, ingestion of up to 20 mg/kg/day HAL by male and female Beagle dogs for 13 weeks failed to increase peroxi somal VD while causing only a slight increase in peroxisomal enzyme ac tivity at the highest dosages. Oral administration of up to 30 mg/kg/d ay HAL by male and female Cynomolgus monkeys for 13 weeks failed to in duce PP. While a direct relationship of PP with tumor formation, at le ast in mice, was not demonstrated, these data still support the concep t that PP represents a potential marker of nongenotoxic tumorigenic ac tivity, at some dosage, in rodents. (C) 1995 Society of Toxicology