Estimation of the delayed neurotoxic potential and potency for a series of triaryl phosphates using an in vitro test with metabolic activation.
The delayed neurotoxic potential of 0,0-diphenyl-o-tolyl phosphate (MOCP), tri-o-tolyl phosphate (TOCP), 0,0-diphenyl-m-tolyl phosphate (MMCP), tri-m-tolyl phosphate (TMCP), 0,0-diphenyl-p-tolyl phosphate (MPCP) and tri-p-tolyl phosphate (TPCP) was determined using an in vitro neurotoxic esterase test with metabolic activation. None of the 6 compounds inhibited hen brain neurotoxic esterase activity in vitro when tested in the absence of metabolic activation using concentrations as high as 100 microM. Both MOCP and TOCP markedly inhibited activity in vitro after metabolism with rat liver microsomes. MOCP was twice as potent as TOCP and IC50 values were 6.2 and 12 microM, respectively. Adult hens were treated with 10 mg/kg MOCP, 10 mg/kg TOCP, 1000 mg/kp MMCP, 1000 mg/kg TMCP, and 1000 mg/kg TPCP. There was no inhibition of brain neurotoxic esterase 24 hours after MMCP, TMCP or TPCP. Inhibition by MOCP and TOCP was 86.8% and 40.7% respectively. The in vitro neurotoxicity test showed that MOCP and TOCP, 2 known neurotoxicants, had delayed neurotoxic potential and metabolism was required. The test also showed that the potency of MOCP was twice that of TOCP. This was confirmed in hens dosed with the 2 compounds since MOCP produced twice the inhibition of brain neurotoxic esterase as that produced by an equal dose of TOCP.
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002645:Chickens; D003408:Cresols / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D014317:Tritolyl Phosphates / Q000378:metabolism / Q000633:toxicity*
D003408:Cresols; D014317:Tritolyl Phosphates; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase