SINGLE-DOSE AND 13-WEEK REPEATED-DOSE NEUROTOXICITY SCREENING STUDIESOF CHLORPYRIFOS INSECTICIDE

Chlorpyrifos (CPF), a widely used organophosphate insecticide, was scr eened for neurotoxic effects in Fischer 344 rats using United States E nvironmental Protection Agency 1991 guidelines for single-dose and 13- wk repeated dose studies. The studies emphasized a functional observat ional battery (which included grip performance and hindlimb splay test s), automated motor activity testing and comprehensive neurohistopatho logy of perfused tissues. Doses of up to 100 mg/kg body weight in corn oil by gavage in the single-dose study and up to 15 mg/kg body weight /day in diet for 13 wk in the repeated dose study were administered. I t is known that CPF and other phosphorothionates can be activated to t he oxon in local (extrahepatic) tissues. Local activation could possib ly cause different effects in different tissues with cholinergic inner vation, and thereby create syndromes unique to each phosphorothionate according to their structure. Consequently, the conduct of CPF neuroto xicity screening studies by contemporary guidelines offered an opportu nity to characterize the CPF over-exposure syndrome in rats. Single-do se high levels of oral exposure to CPF caused a range of clinical sign s characteristic of cholinergic overstimulation. Although there was no clinical evidence of wide differences in sensitivity of one cholinerg ic response versus another, motor dysfunction (inco-ordination etc.) w as more prominent than other signs, for example soiling. Effects were much more apparent in females and regressed over several days. Effects were minimal in the 13-wk study, and there was no evidence of accumul ation of toxicity during the 13 wk of daily dietary exposure. Motor ac tivity was decreased at the high dose in males and females at wk 4, bu t was not significantly different from controls in subsequent weeks. T he 'normalization' of motor activity later in the study was interprete d as tolerance to repeated administration of CPF. Comprehensive neurop athological examination revealed no treatment-related lesions in eithe r study. (C) 1996 Elsevier Science Ltd. All rights reserved.