The potential for toxic effects of chronic, low-dose exposure to organophosphates

Abstract

Organophosphorus esters have the potential to produce several forms of toxicity. Most produce acute intoxication as a result of inhibition of acetylcholinesterase and, if severe, this can have longer lasting secondary consequences such as intermediate syndrome, or even permanent disability. Some esters produce a very specific syndrome of delayed peripheral neuropathy. This neuropathy is always preceded by severe acute intoxication, except in the case of a few specific agents such as tri-o-cresyl phosphate. All of these effects are reasonably well understood and show a dose threshold. Chronic low level exposure in non-poisoned subjects has been associated with impaired neurobehavioral performance in some, but not all, epidemiological studies. The mechanisms involved are not well understood, but if organophosphates do play a causal role, this will not necessarily be via acetylcholinesterase inhibition. Doses too low to produce cholinergic signs have been shown to produce a variety of effects in experimental animals ranging from enhanced maze learning to slowed nerve conduction. It is likely that other, more sensitive, brain proteins are the targets for such actions. Effects mediated via such target proteins would be expected to show very different structure-activity relationships to acute toxicity mediated by acetylcholinesterase. Hence epidemiological studies expecting similar (class) effects from low-dose exposure to different organophosphorus esters may produce variable results or false negatives.