Organophosphate toxicology: Safety aspects of nonacetylcholinesterase secondary targets

OPs have been the major insecticides in number and market share for many decades, and they are still essential tools in crop protection and public health (229). They were the first highly effective systemics moving throughout plants to protect even the growing tip from sucking insect pests for several days or weeks. Their selective toxicity is based on specificity differences in the AChE targets, more rapid detoxification in mammals than insects, and the use of proinsecticides undergoing preferential activation in insects as compared with mammals. Their facile biodegradation and low environmental persistence are coupled with toxic effects more likely due to acute rather than chronic exposure. The OPs have been more extensively studied than any other class of pesticides (10, 230, 231), and the risks are summated for all AChE inhibitors (232). Great care has been taken to ensure their safe use based on AChE as the primary target. Safety evaluations in OP toxicology have evolved from focusing on AChE as the single most important target to consideration of several OP sensitive serine hydrolases and receptors as secondary targets. The toxicological relevance of each of the main targets considered here depends on its sensitivity to inhibition in vitro and in vivo, the physiological significance of the disruption or lesion, and the level of exposure and degree of inhibition that take place under actual use conditions. The mechanism studies often rely on designer compounds of outstanding potency and selectivity to accentuate specific phenomena for ease of evaluation. High-dose laboratory experiments with animal models (e.g., mice, rats, and chickens) are difficult to relate to low-dose, long-term environmental exposure and particularly to actual risks for people. The findings reviewed reconfirm the importance of AChE as the primary target and NTE-LysoPLA as the secondary target of greatest interest (Figure 1). The safety of the continued use of OPs in agriculture and potential expanded use in medicine depends on understanding the relevance not only of AChE inhibition but also of these secondary targets in the health effects of acute and long-term exposures.