In addition to—and independently of—inhibition of acetylcholinesterase, some of these agents are capable of phosphorylating another enzyme present in neural tissue, the so-called neuropathy target esterase (NTE). This results in progressive demyelination of the longest nerves. Associated with paralysis and axonal degeneration, this lesion is sometimes called organophosphorus ester-induced delayed polyneuropathy (OPIDP). Delayed central and autonomic neuropathy may occur in some poisoned patients. Hens are particularly sensitive to these properties and have proved very useful for studying the pathogenesis of the lesion and for identifying potentially neurotoxic organophosphorus derivatives. There is no specific treatment for NTE toxicity.
In humans, progressive chronic axonal neurotoxicity has been observed with triorthocresyl phosphate (TOCP), a noninsecticidal organophosphorus compound. It is also thought to occur with the pesticides dichlorvos, trichlorfon, leptophos, methamidophos, mipafox, trichloronat, and others. The polyneuropathy usually begins as burning and tingling sensations, particularly in the feet, with motor weakness occurring a few days later. Sensory and motor difficulties may extend to the legs and hands. Gait is affected, and ataxia may be present. Central nervous system and autonomic changes may develop still later. There is no specific treatment for this form of delayed neurotoxicity. The long-term prognosis of NTE inhibition is highly variable. Reports of this type of neuropathy (and other toxicities) in pesticide manufacturing workers and in agricultural pesticide applicators have been published (see References).
Recent clinical observation has also defined an intermediate syndrome in severely organophosphate-poisoned patients. This syndrome is characterized by neuromuscular transmission failure, and cardiac failure more typical of nicotinic than muscarinic poisoning. Progressive neuromuscular failure leads to weakness of the respiratory muscles and eventually to death. The physiologic abnormalities are complex but involve a progressive decrement in neuromuscular junction transmission efficiency. Patients who develop this intermediate syndrome are at great risk of cardiorespiratory failure and may require mechanical ventilation. Because organophosphorus poisoning frequently occurs in less developed parts of the world where medical resources are very limited, the development of the intermediate syndrome is frequently a lethal complication. It is not effectively treated with the usual management protocol for organophosphate pesticide poisoning.
2. Environmental toxicology—Organophosphorus pesticides are not considered to be persistent pesticides. They are relatively unstable and break down in the environment as a result of hydrolysis and photolysis. As a class they are considered to have a small permanent impact on the environment, in spite of their acute effects on organisms.
These compounds (Table 56–4) inhibit acetylcholinesterase by carbamoylation of the esteratic site. Thus, they possess the toxic properties associated with inhibition of this enzyme as described
TABLE 56–4 Carbamate pesticides.
1Toxicity rating: Probable human oral lethal dosage for class 4 = 50−500 mg/kg, class 5 = 5−50 mg/kg, and class 6 = ≤ 5 mg/kg. (See Gosselin et al, 1984.) 2ADI, acceptable daily intake (mg/kg/d), data not found.