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Experimental and clinical toxicology of anticholinesterase agents.

Toxicology Letters 1998 December 29
Several organophosphorus compounds (OP) and carbamates (CA) are used as insecticides or warfare agents (OPs only). Their acute toxic effect in the central and peripheral nervous system is due to inhibition of acetylcholinesterase (AChE) at nerve endings which causes accumulation of acetylcholine and consequently overstimulation of the nicotinic and muscarinic receptors. The cholinergic syndrome appears at approximately 50% AChe inhibition whereas death is believed to occur at > 90%. Inhibition of AChE (phosphorylation) by most OPs is irreversible whereas CAs reversibly inhibit AChE (spontaneous reactivation with a t(1/2) of minutes); dimethylphosphorylated AChE partially and slowly (t(1/2) = 1-2 h) reactivates. Although long-term, mild neurobehavioural changes of questionable significance have been reported in some instances, recovery from the cholinergic syndrome appears to be complete, unless lesions develop in the central nervous system as a consequence of either convulsions or anoxia. Certain OPs and CAs have been reported to interact with cholinergic receptors in vitro. The toxicological relevance of these interactions is still not clear. Certain OPs cause OP-induced delayed polyneuropathy (OPIDP) which develops 2-5 weeks after an acute poisoning. The molecular target is believed to be neuropathy target esterase (NTE). OP insecticides are more potent AChE inhibitors rather than NTE inhibitors and therefore, the dose required to cause OPIDP is much higher than that causing the cholinergic syndrome. In the experimental animal, OPIDP is associated with > 70% NTE inhibition after single or repeated exposures. The threshold in man is not known, although there are indications that it is similar. Some non-neuropathic esterase inhibitors (OPs, CAs, sulfonyl fluorides) exacerbate the clinical outcome of OPIDP and other chemical axonopathies, and of nerve crush. The phenomenon has been called promotion and has so far been observed in experimental animals only.

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