Percutaneous toxicity and delayed neurotoxicity of organophosphates in the scaleless hen

The acute toxicity of tri-ortho-cresyl phosphate (TOCP) and the development of delayed neurotoxicity were characterized in the scaleless hen, a featherless mutant, and compared to the responses observed in normally feathered birds. Brain acetylcholinesterase (AChE) activity was comparable between scaleless and normal hens, but nonspecific cholinesterase (ChE) activities of brain and plasma were significantly higher in scaleless birds. The acute ID50 of TOCP for plasma ChE activity was 690 mg/kg for scaleless birds and 240 mg/kg for normal ones following sc administration. However, there was no difference in the ID50 for plasma ChE activity between normal and scaleless hens treated sc with the active metabolite of TOCP, 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphoran-2-one, or parathion. The onset of clinical signs of delayed neurotoxicity in scaleless birds was 8 to 14 days after sc or dermal treatment with TOCP and caused typical axonal fragmentation in the sciatic nerve. Plasma creatine phosphokinase activity was significantly increased following the onset of delayed neurotoxicity in both lines of birds. Dermal application of TOCP to a 50-cm2 area on the backs of scaleless hens inhibited plasma ChE activity in a dose-related manner (ID50 = 115 mg/kg), and the lowest dose of TOCP, 114 mg/kg, did not produce delayed neurotoxicity. The results show that the scaleless hen can be used to determine a no-observable effect level for delayed neurotoxicity which regulatory agencies could use to extrapolate a safe level of human dermal exposure to organophosphates that produce delayed neurotoxicity.