Genetic analysis of organophosphate metabolism in NC farmworkers

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DESCRIPTION (provided by applicant): Farmworker exposure to pesticides is a widely acknowledged environmental health problem (Arcury et al., 2002; Arcury & Quandt 2003; Reeves & Schafer 2003; Arcury et al., 2006b). Organophosphorus (OP) insecticides are among the most widely used pesticides, and include chlorpyrifos, diazinon, dimethoate, disulfoton, and phosmet. Exposure to OP pesticides is detrimental to human health (Reigart & Roberts 1999), with immediate effects of limited exposure including rash, nausea, and blurry vision, and immediate effects of significant exposure including loss of continence, coma, and death. Delayed effects of exposure may include sterility, birth defects, cancer, and neurodegenerative disease. Sources of pesticide exposure among farmworkers and their families include occupational, para-occupational, residential, and environmental factors (Fenske et al., 2000; Arcury et al., 2006c; Quandt et al., 2006). Farmworkers have little to no control of their exposure (Austin et al., 2001), and have limited access to facilities at work for changing out of work clothes and showering before coming home (United States General Accounting Office (GAO) 2000; Arcury et al., 2001). The housing available to farmworkers is often located near fields to which pesticides are applied (Housing Assistance Council 2001; Early et al., 2006) and is generally substandard, with infestations that lead to residential pesticide application (Quandt et al., 2004; Early et al., 2006). Farmworkers and their spouses are often not provided with the information they need to protect themselves and their families from exposure (Arcury et al., 1999; Rao et al., 2006). The effective dose of pesticide exposure is clearly dependent on the initial environmental exposure, but it is also influenced by an individual's innate ability to metabolize and excrete the toxins. Metabolism of OP pesticides is primarily determined by specific proteins in the cytochrome P450 family and the paraoxonase class of molecules. Several of these genes are clustered in the same chromosomal region, indicating a potential common regulatory mechanism, which may be mediated by genetic variation within or between these genes. Polymorphisms in PON1 have been reported to be correlated with the levels of PON1 enzyme (e.g., (Holland et al., 2006)), suggesting that genetic variation contributes to the level or activity of this enzyme. A comprehensive analysis of the entire PON locus, containing PON1, PON2, and PON3, is necessary to identify the individual single nucleotide polymorphisms (SNPs) or combinations of SNPs that contribute to individual variability in OP metabolism. It has been suggested that lower levels of PON1 activity lead to an increased risk of the damaging effects of OP exposure. The goal of this study is to thoroughly characterize genetic variation of the specific p450 genes involved in OP metabolism and the entire PON locus in an effort to identify those individuals most at risk to the negative health effects of chronic organophosphate exposure. Pesticide exposure is an environmental health problem with both acute and chronic risks to farmworkers. The risk to any given individual can be expressed as an interaction between the quantity of the exposure itself and the rate at which that individual is able to metabolize and detoxify the pesticide. To fully understand the links between pesticide exposure and behavior or environmental factors, analyses must be able to consider genetic variability in pesticide metabolism. The goal of this study is to evaluate the genetic contribution of pesticide metabolism in a population of North Carolina farmworkers, in order to gain a more complete understanding of the potential for long term effects of chronic pesticide exposure.