Tolerance can also occur when there is an increase in the proteins other than acetylcholinesterase to which organophosphorous compounds can bind. The alternative binding sites protect animals from organophosphate-induced acetylcholinesterase inhibition. Such sites include other esterases, notably pseudocholinesterase and carboxylesterases that are found in serum, liver, and other tissues. Although their precise physiologic role is unknown, those esterases can be involved in the metabolism of drugs and other compounds that contain ester and amide groups. Quantities of the alternative esterases, especially the carboxylesterases, depend on age, tissue, species, and exposure to agents that induce or inhibit enzymes. Agents that induce or inhibit enzymes include a number of drugs and other foreign compounds. When the esterases are induced, animals and humans are likely to be less susceptible to some of the organophosphorous compounds used as insecticides (Ballantyne and Marrs, 1992; Ecobichon, 2001; Gallo and Lawryk, 1991).

Intermediate syndrome. Clinical manifestations of acute acetylcholinesterase inhibition in humans or animals are not generally long-lasting or delayed, but there are exceptions. An “intermediate syndrome” has been described after severe poisoning: muscle weakness that occurs about 16 to 120 hours after exposure and 7 to 75 hours after the onset of acute poisoning symptoms (He et al., 1998; Shailesh et al., 1994). Overstimulation of nicotinic receptors followed by depression at neuromuscular junctions and muscle necrosis might be contributing factors. The muscle weakness can become severe and result in respiratory insufficiency. If respiration can be sustained, recovery occurs, although it can take weeks. Intermediate syndrome has been reported in humans after exposure to malathion and diazinon (Gallo and Lawryk, 1991).

Organophosphorous-induced delayed neuropathy. Another type of toxicity caused by a few organophosphorous compounds is a progressive, irreversible delayed neuropathy termed organophosphate-induced delayed neuropathy (OPIDN). OPIDN can occur in many species, including humans. Clinical manifestations of OPIDN include progressive, irreversible ataxia that develops weeks to months after exposure. Lesions are found in peripheral nerves and the spinal cord (Ehrich and Jortner, 2001).

OPIDN occurs only if organophosphorous compounds sufficiently, and essentially irreversibly, inhibit neuropathic target esterase (NTE) within hours of exposure. Inhibition of NTE is not related to inhibition of acetylcholinesterase, and organophosphorous compounds used as contact insecticides generally do not inhibit NTE. Organophosphorous compounds are tested for their potential to cause OPIDN before they are registered for use as insecticides, so most commercially available insecticides do not inhibit NTE. Commercially available insecticides that do inhibit NTE, such as chlorpyrifos and dichlorvos, do so only at doses that are sufficient to cause lethal cholinergic poisoning. OPIDN can occur only after rescue from acute chlorpyrifos or dichlorvos poisoning; even then it might not occur. At least six cases of OPIDN have been documented after ingestion of near-lethal doses of chlorpyrifos or dichlorvos (Aiuto et al., 1993; Lotti et al., 1986; Martinez-Chuecos et al., 1992; Vasilescu and Florescu, 1980); all but one occurred after unsuccessful suicide attempts. The absence of documented cases of OPIDN after exposure to diazinon or malathion is consistent with their lack of NTE inhibition in animal models. In fact, the chemical structures of malathion, diazinon, and azamethiphos make them exceedingly unlikely to inhibit NTE at all, and OPIDN has not been produced in experimental animals exposed to either malathion or diazinon (Ballantyne and Marrs, 1992; Cecchine et al., 2000; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy,



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