Species-dependent induction of peroxisome proliferation by haloxyfop, an aryloxyphenoxy herbicide

The potential of haloxyfop [2-(4-((3-chloro-5-(trifluoromethyl)-2- pyridinyl)oxy)phenoxy)propanoic acid; HAL] to induce the proliferation of hepatocellular peroxisomes (PP) was examined in rats, mice, dogs, and monkeys. Chemically induced PP is associated with the development of liver tumors in rodents via an apparent species-dependent, nongenotoxic mechanism of action. HAL is nongenotoxic yet has been shown to cause liver tumors in female 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 evidenced by hepatocellular hypertrophy, increased peroxisome volume density (VD), and induction of peroxisomal enzymes and CYP4A1. Only a relatively weak induction of PP was noted at a carcinogenic dosage in female mice. 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 peroxisomal VD while causing only a slight increase in peroxisomal enzyme activity at the highest dosages. Oral administration of up to 30 mg/kg/day HAL by male and female Cynomolgus monkeys for 13 weeks failed to induce PP. While a direct relationship of PP with tumor formation, at least in mice, was not demonstrated, these data still support the concept that PP represents a potential marker of nongenotoxic tumorigenic activity, at some dosage, in rodents.