Organophosphorus Pesticides: Do They All Have the Same Mechanism of Toxicity?

Abstract

Organophosphorus (OP) pesticides are used extensively to control agricultural, household and structural pests. These pesticides constitute a diverse group of chemical structures exhibiting a wide range of physicochemical properties, with their primary toxicological action arising from inhibition of the enzyme acetylcholinesterase (AChE, EC 3.1.1.7). Historically, risk characterizations for these toxicants have been based on hazard and exposure data pertaining to individual chemicals. The Food Quality Protection Act of 1996 now requires, however, that combined risk assessments be performed with pesticides having a common mechanism of toxicity. It is therefore critical to consider whether OP pesticides all exert toxicity through a common mechanism. This brief review evaluates the comparative toxicity of the 38 OP AChE inhibitors currently registered for use as pesticides in the United States and examines the data which suggest that some OP pesticides have toxicologically relevant sites of action in addition to AChE. It is concluded that all OP anticholinesterases potentially have a mechanism of toxicity in common, that is, phosphorylation of AChE causing accumulation of acetylcholine, overstimulation of cholinergic receptors, and consequent clinical signs of cholinergic toxicity. Additional macromolecular targets for some OP pesticides, however, may alter the cascade of events following AChE phosphorylation and thereby modify that common mechanism. Furthermore, other macromolecular targets of some OP pesticides appear capable of altering noncholinergic neurochemical processes. These additional actions may contribute to qualitative and quantitative differences in toxicity sometimes noted in the presence of similar levels of AChE inhibition induced by different OP pesticides. Further investigation of these additional sites of action may allow subclassification and influence the decision to perform combined risk assessments on this class of pesticides based on common mechanism of toxicity.

Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro

“…Similarly, the PC12 model does not permit distinction of effects that interact with sex, a clear limitation of comparing in vitro to in vivo findings. Further, we evaluated only one of the two agents with the in vitro approach, focusing on chlorpyrifos because much more is known about its developmental neurotoxicity than diazinon [60,72,73]. Nevertheless, the basic similarities between effects in neonatal rats and in the cell culture system point to mechanistic conclusions that can be garnered despite these restrictions.…”

“…Although inhibition of cholinesterase provides a common mechanism for the systemic toxicity of organophosphates in adults [56], it is increasingly evident that the developing brain is affected by other mechanisms that operate at nonsymptomatic exposures, extending below the threshold for anticholinesterase activity [18,60,72,73]. At the cellular level, divers neurodevelopmental events are targeted by organophosphates, all converging on the differentiation and assembly of neural circuits, including neuronal and glial cell replication and differentiation, specification of neurotransmitter phenotypes, axonogenesis and synaptogenesis, and synaptic function [11,39,42,60,72].…”

Comparative developmental neurotoxicity of organophosphates in vivo: Transcriptional responses of pathways for brain cell development, cell signaling, cytotoxicity and neurotransmitter systems

“…Despite their widespread use [17], organophosphate insecticides are a major concern for human health because of their propensity to damage the developing brain at exposures below the threshold for signs of systemic intoxication [55,56,62,72,73,86,87,108]. Although it was originally thought that these agents act solely through inhibition of cholinesterase and consequent cholinergic hyperstimulation, it is now evident that there are multiple mechanisms that contribute to neurodevelopmental abnormalities [10,17,42,73,74,77,112].…”

“…Although it was originally thought that these agents act solely through inhibition of cholinesterase and consequent cholinergic hyperstimulation, it is now evident that there are multiple mechanisms that contribute to neurodevelopmental abnormalities [10,17,42,73,74,77,112]. Accordingly, whereas all the organophosphates share cholinesterase as a target, they are likely to differ to a greater or lesser extent in their effects unrelated to that particular mechanism.…”

“…Accordingly, whereas all the organophosphates share cholinesterase as a target, they are likely to differ to a greater or lesser extent in their effects unrelated to that particular mechanism. Indeed, chlorpyrifos (CPF), the best-studied agent, affects brain development through diverse targets such as oxidative stress, cell signaling cascades, expression and function of nuclear transcription factors, and neuronal-glial cell interactions [42,73,86,87,89], mechanisms that may be shared in varying degrees by other organophosphates [1,67,73,75,86,87,91,110].…”