cholinergic poisoning. If death occurs, it is due to respiratory failure, usually as a result of a combination of the autonomic effects mediated by the muscarinic and nicotinic acetylcholine receptors and the effects of acetylcholine at CNS receptors. Those effects include excessive fluid in the respiratory tract, paralysis of the respiratory muscles, and depression of the respiratory centers of the CNS.

Of the organophosphorous insecticides shipped from the United States to the Gulf War, oral lethal doses (LD50 values, doses that kill 50% of the animals tested) are highest for malathion (about 1 g/kg), intermediate for diazinon and chlorpyrifos (about 150–250 mg/kg), and lowest for dichlorvos (about 50 mg/kg) (Abou-Donia, 1995; Ballantyne and Marrs, 1992; Brown and Brix, 1998; Cecchine et al., 2000; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991; Kaloianova and El Batawi, 1991; Lotti, 2001; Marrs, 1996; Ware, 1989).

Diagnosis of organophosphorous-induced acute toxicity is based on exposure history, clinical manifestations of acetylcholinesterase inhibition, and laboratory findings. Erythrocyte acetylcholinesterase activity is used as an indicator of enzyme status in the nervous system. Metabolites of organophosphorous compounds to which humans and animals are exposed can also be detected in urine. Toxicity is unlikely to be overt unless blood acetylcholinesterase is substantially decreased (for example, by at least 50%; 70% inhibition is more likely to be correlated with clinical signs). Response to administration of atropine, an anticholinergic agent, has also been used as a diagnostic tool: poisoned organisms will not respond to atropine at doses that a nonpoisoned organism will respond to but require doses about 10 times higher before the expected pupil dilation, increased heart rate, and decreased secretions are noted (Ballantyne and Marrs, 1992; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991; Marrs, 1996).

Treatment for organophosphorous-caused acetylcholinesterase inhibition includes administration of atropine to antagonize acetylcholine stimulation of muscarinic receptors and administration of an oxime (such as pralidoxime) to regenerate acetylcholinesterase that is inhibited but not yet irreversibly bound. In the Gulf War and elsewhere, a carbamate compound (pyridostigmine bromide) has been used prophylactically when exposure to organophosphorous nerve gases was expected, because it inhibits but does not age the enzyme and so provides time for clearance of the organophosphate before sites on acetylcholinesterase are available to bind it irreversibly. Other treatments for acute acetylcholinesterase inhibition are not specific and consist of decreasing absorption, enhancing excretion, and addressing symptoms. Time is needed for recovery of acetylcholinesterase activity after aging because recovery requires synthesis of new enzyme. Weeks of supportive treatment might be needed if acetylcholinesterase remains sufficiently inhibited to cause signs of cholinergic poisoning (Ballantyne and Marrs, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Feldman, 1999; Gallo and Lawryk, 1991; Lotti, 2001).

Delayed Effects

Tolerance. Tolerance can occur after repeated exposure to cholinesterase-inhibiting organophosphorous insecticides. In general, tolerance can develop due to prolonged stimulation of cholinergic receptors by acetylcholine. Those receptors no longer respond as effectively to the neurotransmitter. Tolerance is more likely to occur at muscarinic than at nicotinic receptors and can develop when erythrocyte acetylcholinesterase is low but cholinergic poisoning is not overt (Bushnell et al., 1993).

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