Delayed neurotoxic effects of tri-o-tolyl phosphate in the European ferret

The development of organophosphorus-induced delayed neurotoxicity (OPIDN) was studied in the European ferret (Mustela putorius furo). A single oral or dermal dose of 250, 500, or 1000 mg tri-o-tolyl phosphate (TOTP)/kg body weight was administered to adult male ferrets. Corn oil served as the vehicle in the oral test and 95% ethanol was the vehicle in the dermal test. At 48 h posttreatment, half the animals in each group were killed by cervical dislocation for assessment of whole-brain neuropathy target esterase (NTE) activity. The remaining 5 animals per group were observed and examined neurologically on a daily basis for a subsequent 54 d. All ferrets dosed dermally with 1000 mg TOTP/kg body weight developed clinical signs characteristic of OPIDN ranging from ataxia to partial paresis. Ferrets administered 250 and 500 mg TOTP/kg body weight via the dermal route displayed variable degrees of hind limb weakness and ataxia. Of the animals dosed orally, only those in the 1000 mg TOTP/kg body weight group showed clinical signs indicative of OPIDN. These signs did not progress beyond mild ataxia. Small amounts of axonal degeneration were noted in the dorsolateral part of the lateral funiculus and in the fasciculus gracilis of spinal cords in ferrets receiving dermal doses of 1000 mg TOTP/kg body weight. Whole-brain neuropathy target esterase activity was also maximally inhibited (46%) in animals receiving 1000 mg TOTP/kg dermally. These results suggest that the ferret is a species that is susceptible to OPIDN.