lubricants), and chemical-warfare agents. Organophosphorous compounds used as contact insecticides during the Gulf War include malathion, diazinon, chlorpyrifos, dichlorvos, and azamethiphos (Abou-Donia, 1995; Chambers and Levi, 1992; Ecobichon, 2001; Kamrin, 1997; Ware, 1989).

Chemistry

The structures of the organophosphorous compounds used as contact insecticides in the Gulf War are shown in Figure 3.1. Organophosphorous compounds that are used as insecticides contain a pentavalent phosphorus atom connected by esteratic, amide, or sulfur linkages to the organic portions of the molecule.

As esters or amides, organophosphorous compounds are chemically unstable and easily inactivated by hydrolysis. Organophosphorous compounds are lipophilic, some are oily liquids, and others are liquids that can be volatilized (Chambers and Levi, 1992; Ware, 1989).

Toxicokinetics

Toxicokinetics plays an important role in the toxicity of organophosphorous compounds. The oil-water partition coefficient, formulation, and route of exposure can affect the extent of and time needed for absorption. Dermal exposure can increase the time needed for absorption and ensuing toxicity. Almost 100% of the dermally administered dose of some of the highly lipophilic organophosphorous compounds can be absorbed. The potential for percutaneous absorption can be increased if formulations include petroleum products, oils, solvents, or surfactants or if occlusive dressings are placed on the skin (Ware, 1989).

Many organophosphorous compounds are supplied commercially in inactive forms (as protoxicants that need to be activated usually by liver mixed-function oxidases). For most organophosphorous compounds, that requires the change of the phosphorus-sulfur bond to a phosphorus-oxygen bond (for example, malathion needs to be oxidized to malaoxon, chlorpyrifos to chlorpyrifos-oxon, and diazinon to diazoxon). That bioactivation is catalyzed primarily by the P450 system. Dichlorvos and azamethiphos, however, are active without the need for biotransformation.

Detoxification of organophosphorous compounds involves hydrolysis, which can occur spontaneously in an aqueous environment. Hydrolysis can also be catalyzed by aryl and aliphatic hydrolases. Glutathione transferases and cytochrome P450s contribute to the detoxification of some organophosphorous compounds. Metabolic activation and inactivation of organophosphorous compounds occurs primarily in the liver, although other tissues also contribute. Extensive metabolism occurs via multiple pathways, and little, if any, unmetabolized organophosphorous compound is excreted.

Differences in biotransformation of organophosphorous compounds are important contributors to differences in potency and in susceptibility among species and individuals. In addition, the effects of organophosphorous compounds on biotransformation enzymes are important in interactions between the compounds and other chemicals (Ballantyne and Marrs, 1992; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991).



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