Histopathological assessment of triphenyl phosphite neurotoxicity in the hen

The signs of neurotoxicity observed in the cat and the rat following single or multiple doses of the phosphorous acid ester triphenyl phosphite (TPP) have been reported to differ from the syndrome known as organophosphorous compound induced delayed neuropathy (OPIDN) caused by some phosphoric acid esters. Since the hen is the test animal traditionally used to test compounds for OPIDN, we chose to study the neurotoxicity of single, subcutaneous doses of TPP using the hen. TPP (1000 mg/kg) produced progressive ataxia and paralysis which developed 5-10 days after dosing. The clinical signs were accompanied by axonal damage in the lateral columns of the spinal cord and peripheral nerve. Similar signs were observed following neurotoxic doses of the OPIDN-causing agents tri-o-cresyl phosphate (TOCP) or diisopropyl phosphorofluoridate (DFP). In addition, TPP caused damage to axons in the brain and gray matter of the spinal cord, and chromatolysis and neuronal necrosis were frequently observed in the spinal cord. These latter areas were not affected by TOCP or DFP. The minimum neurotoxic dose of TPP was found to be 500 mg/kg. Prior administration of phenylmethylsulfonyl fluoride (PMSF) reduced the incidence of damage to the peripheral nerve of animals dosed with TPP, but did not prevent toxic effects on the cell bodies in the spinal cord or the clinical effects. The results of this study indicate that TPP causes neuronal damage in addition to the axonal damage observed with OPIDN. Therefore, we conclude that two distinct mechanisms underlie the neurotoxicity of TPP.