Gene-environmental interactions and organophosphate toxicity.

Organophosphates (OPs) are an important class of insecticides that in the UK have been widely used for treating sheep for ectoparasites as well as in other sectors of the farming industry. Health problems associated with acute OP toxicity are well defined but, ill-health induced by chronic exposures to OPs remains controversial. A substantial number of sheep farmers complain of chronic ill-health which they attribute to repeated exposure to OPs. If OPs were associated with chronic ill-health then individuals with specific defects in OP metabolism might be expected to be at greater risk of ill-health following exposure. To examine such a hypothesis, the characterisation of both OP exposure and those pathways which lead to the formation and removal of the active OP metabolites becomes important. A wide range of OPs have previously been used to treat sheep but currently the only OP licenced for treating sheep is diazinon. Immediately after treatment, farmers' urines contain detectable levels of OP metabolites but few farmers have a significant decrease in plasma cholinesterase activity. Diazinon, like chlorpyrifos, is an organothiophosphate which is metabolised, particularly by cytochrome p450s, to the corresponding active oxon form. CYP metabolism also leads to the inactivation of the parent compound and the relative balance of inactivation and activation can depend upon the specific OP and the CYP isoform. OP oxons are inactivated by serum paraoxonase (PON1) and mice lacking PON1 activity are susceptible to oxon and parent OP induced toxicity. PON1 polymorphisms at positions 192 (R form with arginine at 192 and Q with glutamine) and 55 (L form with a leucine and a M form with methionine) influence paroxonase activity. The effect of the Q192R polymorphism is substrate specific with reports indicating that diazoxon is metabolised less by the R isoform. In a study of sheep farmers within the UK, the R allele was associated with an increased risk of self-reported chronic ill-health, a result consistent with the hypothesis that this ill-health may have been caused by OPs. Studies in other populations exposed to pesticides also show associations between ill-health and PON1 Q192R polymorphisms but not consistently so. This is not surprisingly given that exposure is often poorly characterised. In vivo models also suggest that PON1 genotypes may have little influence on susceptibility at low doses of the parent OP. Hence further work is required not only to better characterise OP exposure in humans populations but also to identify those populations susceptible to OP toxicity.