Invited critical review
Current issues in organophosphate toxicology

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Abstract

Organophosphates (OPs) are one of the main classes of insecticides, in use since the mid 1940s. OPs can exert significant adverse effects in non-target species including humans. Because of the phosphorylation of acetylcholinesterase, they exert primarily a cholinergic toxicity, however, some can also cause a delayed polyneuropathy. Currently debated and investigated issues in the toxicology of OPs are presented in this review. These include: 1) possible long-term effects of chronic low-level exposures; 2) genetic susceptibility to OP toxicity; 3) developmental toxicity and neurotoxicity; 4) common mechanism of action; 5) mechanisms of delayed neurotoxicity; and 6) possible additional OP targets. Continuing and recent debates, and molecular advances in these areas, and their contributions to our understanding of the toxicology of OPs are discussed.

Section snippets

Organophosphorus: insecticides

Although a number of organic phosphorus (OP) compounds were synthesized in the 1800s, their development as insecticides only occurred in the late 1930s and early 1940s. The German chemist Gerhard Schrader is credited for the discovery of the general chemical structure of anticholinesterase OP compounds and for the synthesis of the first commercialized OP insecticide [Bladan, containing TEPP (tetraethyl pyrophosphate) as an active ingredient], and for one of the most known, parathion, in 1944 [1]

AChE and NTE as primary targets

The primary target for OPs is AChE, a B-esterase whose physiological role is that of hydrolyzing acetylcholine, a major neurotransmitter in the peripheral (autonomic and motor–somatic) and central nervous systems. OPs with a P = O moiety phosphorylate an hydroxyl group on serine in the active (esteratic) site of the enzyme, thus impeding its action on the physiological substrate (Fig. 2). The bond between the phosphorus atom and the esteratic site of the enzyme is much more stable than the bond

Continuing issues in OP toxicology

Despite having been around for over sixty years with an almost as long knowledge of their main mechanism of action and adverse health effects, OPs continue to be the subject of much research efforts. For example, a Medline search (August 2005) with the terms organophosphate/organophosphorus provided around 5000 hits since the year 2000, more than one fourth of all citations since the mid 1950s. The reasons for these research activities, in addition to the continuing high worldwide use of these

Conclusion

The use of OPs as insecticides in the agricultural and urban settings is still high and is expected to remain so, at least in the near future. While other classes of insecticides are gaining market share (e.g., pyrethroids) and new classes have been developed (e.g., neonicotinoids), the efficacy of OPs, their relatively low cost and their lack of bioaccumulation in the ecosystems, would support this prediction. Yet OPs display relatively limited selectivity (one exception may be malathion)

Acknowledgements

Research by the author is supported by grants from the National Institute of Environment Health (ES04696, ES07033, ES09601/EPA-R826886). Views expressed in this paper are solely of the author and not of the funding agencies.

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