Short-term Clinical and Neuropathologic Effects of Cholinesterase Inhibitors in Rats

Abstract

Adult male Long Evans rats were given a single administration of 3 dosage levels of the organophosphorus compounds tri-ortho-tolyl phosphate (TOTP), diisopropyl fluorophosphate (DFP), phenyl saligenin phosphate (PSP), mipafox, malathion, and dichlorvos or the carbamate carbaryl. Acetylcholinesterase and neurotoxic esterase activities were inhibited in a dose-dependent manner, with the highest dosages of all of these compounds inhibiting activities of these enzymes in brain by at least 37% and 64%, respectively, at 4 and 48 hours after administration. Rats given the high doses of TOTP (1000 mg/kg), DFP (3 mg/kg), malathion (2000 mg/kg), and carbaryl (160 mg/kg) weighed significantly less than control rats 14 days after administration. A functional observational battery (FOB) was used to screen for neurotoxic effects 1, 2, and 3 weeks after exposure. All 7 test compounds were capable of causing changes in parameters indicative of behavioral and central nervous system excitability. In addition, dose-related alterations in response to approach were seen in rats given DFP, malathion, dichlorvos, and carbaryl. Mild to moderate myelinated fiber degeneration was seen in the rostral levels of the fasciculus gracilis in rats given TOTP, DFP, PSP and mipafox, but no significant neuropathologic lesions were noted in rats given dichlorvos, malathion, or carbaryl.