Triphenyl phosphite neurotoxicity in the hen: inhibition of neurotoxic esterase and of prophylaxis by phenylmethylsulfonyl fluoride.
Arch Toxicol 1988; 62(5):375-380
The neurotoxic effects of triphenyl-phosphite (101020) (TPP) were compared to organophosphorus compound induced delayed neurotoxicity (OPIDN) resulting from exposure to diisopropyl-phosphofluoridate (55914) (DFP) or tri-o-cresyl-phosphite (2622084) (TOCP) in the hen. White-leghorn-hens were given subcutaneous injections of DFP at a dose of 1.7mg/kg; TPP at doses of 250, 500, 750, and 1000mg/kg; or TOCP at doses of 62.5, 125, 250, 500, 750, or 1187mg/kg with and without pretreatment with 30mg/kg phenylmethylsulfonyl-fluoride (PMSF). The animals were assessed clinically using a six point scale ranging from normal to completely paralyzed, and neurotoxic- esterase (NTE) activity was determined in the brain and sciatic nerve at between 1 to 21 days after dosing. The clinical signs of TPP toxicity were similar to those observed after injections of TOCP or DFP, but ataxia and paralysis developed considerably earlier following TPP injection. The median effective dose values for paralysis and ataxia were 500 and approximately 375mg/kg for TPP as compared to values between 125 and 250mg/kg and 62.5 and 125mg/kg for TOCP. Pretreatment with PMSF completely protected the animals against DFP neuropathy but not against neuropathy produced by the highest doses TPP or TOCP. All the animals given PMSF plus 1,000mg/kg TPP were paralyzed by 21 days post treatment whereas only 15 of 21 animals treated with TPP alone were paralyzed at that time. A dose of 1,000mg/kg TPP decreased brain NTE activity by 80 percent and completely inhibited activity of the enzyme in the sciatic nerve. NTE activity in the brain but not the sciatic nerve recovered at approximately 14 days post treatment. Equimolar doses of TOCP completely inhibited brain and sciatic nerve NTE without observable recovery. The dose response relationship for the TPP inhibition of neurotoxic-esterase and the additive neurotoxicity of TPP and DFP were discussed. The authors conclude that TPP produces OPIDN in the hen through a mechanism involving the inhibition of neurotoxic-esterase.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Organo-phosphorus-compounds; Fluorinated-hydrocarbons; Toxic-effects; Central-nervous-system; Neuropathology; Plasticizers; Enzymatic-effects; Animal-studies
Pharmacology Duke University Department of Pharmacology Durham, N C 27710
101-02-0; 55-91-4; 2622-08-4
Neurotoxic Disorders; Neurotoxic-effects
Archives of Toxicology
Duke University, Durham, North Carolina