Richardson R J
Department of Environmental and Industrial Health, University of Michigan, Ann Arbor 48109-2029.
J Toxicol Environ Health. 1995 Feb;44(2):135-65. doi: 10.1080/15287399509531952.
Chlorpyrifos (diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate) is a broad-spectrum organophosphorus (OP) insecticide. Anticipated increases in the already extensive use of this compound have prompted this reassessment of its neurotoxicity. Because chlorpyrifos and other OP insecticides are designed to produce acute cholinergic effects through inhibition of acetylcholinesterase (AChE) and some OP compounds can cause OP compound-induced delayed neurotoxicity (OPIDN) via chemical modification of neurotoxic esterase (neuropathy target esterase, NTE), this review focuses on the capacity of chlorpyrifos to precipitate these and other adverse neurological consequences. Chlorpyrifos exhibits only moderate acute toxicity in many mammalian species, due largely to detoxification of the active metabolite, chlorpyrifos oxon, by A-esterases. Rats given large doses of chlorpyrifos (sc in oil) have prolonged inhibition of brain AChE, possibly due to slow release of the parent compound from a depot. Associated cognitive and motor deficits return to normal well before recovery of AChE activity and muscarinic receptor down-regulation, as expected from classic tolerance. Controlled studies of OP compound exposures in humans also indicate that cognitive dysfunction requires substantial AChE inhibition. Information is relatively sparse on neurological dysfunction that is secondary to theoretical reproductive, developmental, or immunological effects, but the best available data indicate that such effects are unlikely to result from exposures to chlorpyrifos. In accord with the much greater inhibitory potency of chlorpyrifos oxon for AChE than for NTE, clinical reports and experimental studies indicate that OPIDN from acute exposures to chlorpyrifos requires doses well in excess of the LD50, even when followed by repeated doses of the OPIDN potentiator phenylmethanesulfonyl fluoride (PMSF). Likewise, studies in hens show that subchronic exposures at the maximum tolerated daily dose do not result in OPIDN. Although exposure to chlorpyrifos as a result of normal use is unlikely to produce classical OPIDN, a recent report stated that mild reversible sensory neuropathy had occurred in eight patients who had been exposed subchronically to unknown amounts of chlorpyrifos. It is not clear whether these cases represent an incorrect linkage of cause and effect, a newly disclosed reversible sensory component of OPIDN, or an entirely new phenomenon. The question of the potential for chlorpyrifos to cause this mild sensory neuropathy could be resolved by the use of quantitative tests of sensory function in animal experiments and/or prospective studies of humans with known exposures to chlorpyrifos.
毒死蜱（3,5,6 - 三氯 - 2 - 吡啶基硫代磷酸二乙酯）是一种广谱有机磷杀虫剂。预计该化合物使用量本就广泛，其使用量还会增加，这促使人们对其神经毒性进行重新评估。由于毒死蜱和其他有机磷杀虫剂旨在通过抑制乙酰胆碱酯酶（AChE）产生急性胆碱能效应，且一些有机磷化合物可通过对神经毒性酯酶（神经病变靶酯酶，NTE）进行化学修饰而导致有机磷化合物诱导的迟发性神经毒性（OPIDN），因此本综述重点关注毒死蜱引发这些及其他不良神经后果的能力。在许多哺乳动物物种中，毒死蜱仅表现出中度急性毒性，这主要是由于活性代谢产物毒死蜱氧磷被A - 酯酶解毒。给大鼠大剂量注射毒死蜱（油剂皮下注射）会使脑AChE受到长时间抑制，这可能是由于母体化合物从储存库缓慢释放所致。与经典耐受性预期一致，相关的认知和运动缺陷在AChE活性恢复和毒蕈碱受体下调之前就已恢复正常。对人类有机磷化合物暴露的对照研究也表明，认知功能障碍需要AChE受到显著抑制。关于继发于理论上的生殖、发育或免疫效应的神经功能障碍的信息相对较少，但现有最佳数据表明，此类效应不太可能由毒死蜱暴露引起。与毒死蜱氧磷对AChE的抑制效力远大于对NTE的抑制效力一致，临床报告和实验研究表明，急性接触毒死蜱导致的OPIDN需要远超半数致死剂量（LD50）的剂量，即使随后重复给予OPIDN增强剂苯甲磺酰氟（PMSF）也是如此。同样，对母鸡的研究表明，以最大耐受日剂量进行亚慢性暴露不会导致OPIDN。尽管正常使用毒死蜱不太可能产生典型的OPIDN，但最近一份报告称，8名亚慢性接触未知量毒死蜱的患者出现了轻度可逆性感觉神经病变。目前尚不清楚这些病例是因果关系的错误关联、新发现的OPIDN可逆性感觉成分，还是全新的现象。毒死蜱导致这种轻度感觉神经病变的可能性问题，可以通过在动物实验中使用感觉功能定量测试和/或对已知接触毒死蜱的人类进行前瞻性研究来解决。
