Exposure to polychlorinated biphenyls (PCBs) can alter the metabolism of organophosphorus (OP) insecticides. Female rats were fed vanilla wafers containing either 4 mg/kg/day of Aroclor 1254 (PCB-treated) or safflower oil (oil-treated) for 50 days. Rats were then injected, ip, with corn oil, parathion (P=S), methyl parathion (MP=S), chlorpyrifos (C=S), paraoxon (P=O), methyl paraoxon (MP=O), or chlorpyrifos-oxon (C=O). In the livers of rats treated with PCBs but not OP compounds, there was induction of desulfuration (activation) of P=S, MP=S, and C=S, but dearylation (detoxication) was induced only with P=S and MP=S. Hepatic A-esterase hydrolysis of all three oxons was induced. Cholinesterase (ChE) activity was determined in the medulla-pons, hippocampus, corpus striatum, cerebral cortex, skeletal muscle, lung, and heart at 2 and 24 h post exposure. With C=S, P=S, and MP=S, differences in brain ChE inhibition were observed at 2 h (MP=S > P=S > C=S) but few differences were observed between oil- and PCB-treated rats. By 24 h, the level of brain ChE inhibition had increased with P=S and C=S but had decreased with MP=S. In rats exposed to P=S and C=S but not MP=S, ChE inhibition was lower in PCB-treated rats than in oil-treated rats. This suggests that pre-exposure to PCBs has a protective effect against the acute toxicity of P=S and C=S, but not MP=S. This protective effect does not appear to be related to the alteration of the metabolism of these compounds. The slower rate of ChE inhibition following P=S and C=S compared to MP=S suggests that the protection may be mediated by the PCB-induced increase in A-esterase activity. This protection appears to be related to the time between exposure and inhibition of ChE. With the oxons at 2 h, inhibition of ChE was substantial and no differences were present between the PCB- and oil-treated rats. Thus, the rapid rate of inhibition of ChE by the oxons does not afford time for the increase in A-esterase hydrolysis to effectively provide protection against inhibition of ChE. However, while no differences between oil- and PCB-treated rats were observed with MP=O by 24 h, PCB-treated rats exposed to P=O and C=O had lower ChE inhibition than did oil-treated rats with greater differences observed with P=O than C=O.