Organophosphorus-induced neurotoxicity in the absence of neuropathy targetesterase inhibition: The effects of triphenyl phosphine in the European ferret

Abou-Donia et al. (in Toxicologist, Vol. 30, 1996) have reported that repea ted oral administration of the organo-phosphorus compound triphenyl phosphi ne (TPPn) to the domestic chicken results in neuropathological changes in t he spinal cord and peripheral nerves, accompanied by ataxia and paralysis. This study also noted that single doses of TPPn resulted in no inhibition o f the enzymes neuropathy target esterase (NTE) and acetylcholinesterase (AC hE). We undertook the present study to determine the biochemical, neuropath ological, and clinical effects of single doses of TPPn in the European ferr et, a mammalian species shown to be susceptible to organophosphorus-induced neurotoxicity. Eight 12-week-old ferrets were each injected subcutaneously with either 250 mg TPPn/kg bw or 500 mg TPPn/kg bw, or with the peanut oil /ethyl ether vehicle. Twenty-four h after dosing, the brains of 5 animals f rom each dose group were examined for NTE and AChE activities. The remainin g 3 animals in each group were observed for 6 days for the development of c linical signs, after which their brains were processed for the presence of axonal degeneration using the Fink-Heimer silver impregnation method. Singl e injections of TPPn had no effect on the activities of whole-brain NTE or AChE 24 h after injection. The animals observed for clinical signs showed i ncreasing trunk and hindlimb ataxia beginning 4 days after injection, culmi nating in fore-and hindlimb paralysis 6 days after injection. All brains ex posed to either dose of TPPn showed widespread axonal degeneration extendin g from the brainstem and cerebellum into midbrain and forebrain areas. The results of this study support the hypothesis that TPPn-induced neurotoxicit y is a separate and distinct form of organophosphorus-induced neurotoxicity not dependent on NTE inhibition, and therefore not a variant of organophos phorus-induced delayed neurotoxicity (OPIDN).