ASSESSMENT OF THE NEUROTOXIC POTENTIAL OF CHLORPYRIFOS RELATIVE TO OTHER ORGANOPHOSPHORUS COMPOUNDS - A CRITICAL-REVIEW OF THE LITERATURE

Chlorpyrifos (diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate) is a broad-spectrum organophosphorus (OP) insecticide. Anticipated increa ses in the already extensive use of this compound have prompted this r eassessment or its neurotoxicity. Because chlorpyrifos and other OP in secticides are designed to produce acute cholinergic effects through i nhibition of acetylcholinesterase (AChE) and some OP compounds can cau se OP compound-induced delayed neurotoxicity (OPIDN) via chemical modi fication of neurotoxic esterase (neuropathy target esterase, NTE), thi s review focuses on the capacity of chlorpyrifos to precipitate these and other adverse neurological consequences. Chlorpyrifos exhibits onl y moderate acute toxicity in many mammalian species, due largely to de toxification of the active metabolite, chlorpyrifos oxon, by A-esteras es. Rats given large doses of chlorpyrifos (SC in oil) have prolonged inhibition of brain AChE, possibly due to slow release of the parent c ompound from a depot. Associated cognitive and motor deficits return t o normal well before recovery of AChE activity and muscarinic receptor down-regulation, as expected from classic tolerance. Controlled studi es of OP compound exposures in humans also indicate that cognitive dys function requires substantial AChE inhibition. information is relative ly sparse on neurological dysfunction that is secondary to theoretical reproductive, developmental, or immunological effects, but the best a vailable data indicate that such effects are unlikely to result from e xposures to chlorpyrifos. In accord with the much greater inhibitory p otency of chlorpyrifos oxon for AChE than for NTE, clinical reports an d experimental studies indicate that OPIDN from acute exposures to chl orpyrifos requires doses well in excess of the LD50, even. when follow ed by repeated doses of the OPIDN potentiator phenylmethanesulfonyl fl uoride (PMSF). Likewise, studies in hens show that subchronic exposure s at the maximum tolerated daily dose do not result in OPIDN. Although exposure to chlorpyrifos as a result of normal use is unlikely to pro duce classical OPIDN, a recent report stated that mild reversible sens ory neuropathy had occurred in eight patients who had been exposed sub chronically to unknown amounts oi chlorpyrifos. It is not clear whethe r these cases represent an incorrect linkage of cause and effect, a ne wly disclosed reversible sensory component of OPIDN, or an entirely ne w phenomenon. The question of the potential for chlorpyrifos to cause this mild sensory neuropathy could be resolved by the use of quantitat ive tests oi sensory function in animal experiments and/or prospective studies of humans with known exposures to chlorpyrifos.