Characterization of delayed neurotoxicity in the mouse following chronic oral administration of tri-o-cresyl phosphate

The sensitivity of the mouse to organophosphorus-induced delayed neurotoxicity (OPIDN) has been investigated. One group of five mice received two single 1000-mg/kg po doses of tri-o-cresyl phosphate (TOCP) at a 21-day interval (on Days 1 and 21 of the study); a second group of five mice was given 225 mg/kg of TOCP daily for 270 days. A third group of five animals served as an untreated control. All animals were killed 270 days after the start of the experiment. Daily po dosing of 225 mg/kg TOCP caused a decrease in body weight gain, muscle wasting, weakness, and ataxia which progressed to severe hindlimb paralysis at termination. On the other hand, po administration of two single 1000-mg/kg doses of TOCP at a 21-day interval produced no observable adverse effects. Brain acetylcholinesterase (AChE) and neurotoxic esterase (NTE) activity were 35 and 10% of the control, respectively, in daily dosed animals while AChE and NTE in mice receiving two single 1000-mg/kg doses of TOCP were not significantly altered from the control group. Plasma butyrylcholinesterase activity was 12% of the control group in daily dosed animals. Hepatic microsomal enzyme activities of aniline hydroxylase and p-chloro-N-methylaniline demethylase and NADPH-cytochrome P-450 content in daily dosed animals were increased (141 to 161% of the control group) when compared to controls and mice receiving two single 1000-mg/kg doses of TOCP; the latter being not significantly different from each other. Degeneration of the axon and myelin of the spinal cord and sciatic fascicle were observed and were consistent with OPIDN. This study demonstrates that chronic dosing of TOCP produces OPIDN and induces hepatic microsomal enzyme activity in mice. It is concluded that while the mouse is susceptible to OPIDN, it is a less sensitive and a less appropriate test animal for studying this effect when compared to the adult hen.