STUDIES OF ESTERASE CHANGES IN ORGANOPHOSPHORUS ESTER-INDUCED DELAYED NEUROTOXICITY IN SWINE (TRI-O-TOLYL PHOSPHATE, CHOLINESTERASE, NEUROTOXIC)

Organophosphorus (OP) ester-induced delayed neurotoxicity (OPIDN) is a distal axonopathy developing 8-14 days following a single oral dose of certain neurotoxic compounds. Assessment of neurotoxic esterase (NTE) activity, an enzyme found in the central nervous system, peripheral lymphocytes, platelets and the placenta, the first 48 hours following administration of a test compound can be used to predict OPIDN development. The purpose of this research was to evaluate the use of lymphocyte NTE as a biomonitoring system in swine. The similarities in response of NTE and cholinesterase (ChE) in the brain and blood were determined at 6, 12, 24 or 48 hours following acute oral administration of TOTP. Then, a chronic 21-day study assessed the clinical manifestations and the sensitivity of lymphocyte NTE, red blood cell (RBC) ChE and plasma ChE of swine receiving single oral doses of 400, 800 or 1000 mg TOTP/kg of body weight.; After administration of a single oral dose of 800 mg TOTP/kg of body weight, NTE was depressed maximally in brain and peripheral lymphocytes at 12 hours post-dosing. Brain NTE correlated with lymphocyte NTE at 6 hours post-TOTP dosing, but became less at later times following TOTP administration. Lymphocyte NTE activity responded more acutely to TOTP administration and recovered more rapidly than did the central nervous system (CNS) esterase. The CNS ChE and that in the blood reached its lowest point 24 hours following TOTP administration. The closest correlation between the blood and brain enzyme activities occurred at 12 hours post-TOTP dosing. Red blood cell ChE more accurately reflected the ChE activity in the CNS than did plasma ChE.; Swine surviving the acute cholinergic effects of 400, 800 or 1000 mg TOTP/kg of body weight developed delayed neurotoxicity 10 - 12 days post-TOTP dosing. Neurotoxic esterase activity in peripheral lymphocytes during the first 48 hours after TOTP administration accurately predicted development of clinical neuropathy. Depression of NTE activity was dose dependent. Plasma ChE activites did not correlate with the severity of clinical signs. Red blood ChE activity accurately reflected the acute toxic effects of TOTP in most cases.; These studies demonstrated the usefulness of lymphocyte NTE activity as a biomonitoring system for predicting OPIDN development and established the appropriateness of swine as a mammalian model for this syndrome.