The authors speculated that the enhanced toxicity may result from interference with detoxification processes and raised the possibility of polymorphisms in esterases that play a determining role in toxic outcomes. Similarly, combinations of very large doses of PB, DEET and permethrin have been reported to increase the lethality of these agents in rats (McCain et al., 1997). The use of such large dosage levels in these studies makes interpretation of possible toxic synergisms problematic. A number of hypothetical mechanisms of interactions have been offered (Golomb, 1999).

There is no a priori reason to suspect that PB is capable of causing OPIDN. PB is not known to inhibit NTE, a hallmark of chemicals causing OPIDN. Although PB is known to inhibit butyrylcholinesterase (BuChE), it does not appear to be a substrate for paraoxonase;5 hence it seems biologically implausible that there is a genetic susceptibility for OPIDN to be induced by PB via this mechanism. Further, there are insufficient data to determine whether exposure to other chemicals, either before or after PB, enhances its potential to produce delayed neurotoxicity.

There are reports of other classes of chemicals interacting with PB to modify its toxicity. Chaney et al. (1997, 1998) noted that adrenergic agents varied in their ability to potentiate the toxicity of PB without apparent structure–activity relationships. The toxicity of PB was enhanced by certain beta-receptor agonists, and also by some alpha-receptor antagonists, whereas other adrenergic agents were without effect. Catecholamines (epinephrine and norepinephrine) were reported to be additive with PB toxicity. Both potentiation and addition were blocked by atropine, clearly pointing to the cholinergic link in this complex toxicity. In another study, the same authors (Chaney et al., 1999) noted that a toxic interaction of PB and DEET resulted in seizures, which—although resistant to conventional anticonvulsant drugs—were blocked by muscarinic antagonists such as atropine.

Keeler (1990) reviewed possible interactions between PB and drugs used in combat anesthesia and predicted the greatest potential for drug interaction to be with the neuromuscular blocking drugs. The author also recognized potential interactions leading to overstimulation of muscarinic receptors and, hence, to unwanted effects such as laryngospasm and bradycardia.

Available studies in which the toxicity of PB, alone or in combination with other chemicals, has been assessed in laboratory animals have been reviewed. Although data derived from laboratory investigations may have general applicability to humans, there are enough differences in toxic responses to the ChE inhibitors as a class to caution against making direct inferences to humans. For instance, although chickens are reported to be highly sensitive to OPIDN, this disorder is difficult to induce in laboratory rats, except at extremely high doses of organophosphates. Thus, although some general principles from laboratory


Paraoxonase is an enzyme which plays a role in reducing the toxicity of organophosphorous compounds.

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