Biomarkers of organophosphate exposure

The Environmental Protection Agency has approved 38 different organophosphates (OPs) for pesticide use. At nonlethal doses, the signs of toxicity caused by each OP are distinct. This suggests that each OP reacts not only with acetylcholinesterase (AChE), but also with additional targets. A more complete understanding of the proteins modified by exposure to OPs will aid in understanding why some people cannot tolerate doses of OPs that are harmless to the majority. Identification of new biomarkers of OP exposure aides in diagnosis of exposure. This chapter defines biomarkers of OP agent exposure as proteins that covalently bind OPs. In OP-exposed humans, only three proteins-AChE, BuChE, and neuropathy target esterase-have been shown to covalently bind OPs. From in vivo-treated rodents, six additional OP-binding proteins have been identified: acylpeptide hydrolase in brain and red blood cells, carboxylesterase in plasma, arylformamidase in liver, M2 muscarinic receptor in lung, fatty acid amide hydrolase in brain, and albumin in plasma. The hypothesis of this chapter is that a given OP reacts with a set of proteins, and that the set of OP-reactive proteins is unique to each OP, although almost all OPs also covalently bind AChE and BuChE. The signs of toxicity are characteristic of a particular OP, and reflect the set of proteins that have reacted with that particular OP. Proof of this hypothesis is expected to come through the use of new mass spectrometry tools. This chapter presents the evidence for this hypothesis.