Assessment of human exposure and susceptibility to chlorpyrifos
Crane, Alice Langford
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Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide in heavy use worldwide and outcomes of chronic exposure to this pesticide remain poorly characterized. Recent work suggests that repeated exposure leads to neurobehavioral deficits. However, it is currently unclear whether current biomarkers of exposure and effect are linked to these outcomes in a dose-dependent manner. This is partly due to a lack of careful longitudinal exposure assessment in human populations. CPF is a pro-poison and must be bioactivated by cytochrome P450 enzymes (CYPs) to the potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitor chlorpyrifos oxon (CPF-O). CPF may also be detoxified by CYPs and paraoxonase 1 (PON1) to 3,5,6-trichloro-2-pyridinol (TCPy) which is excreted in the urine. TCPy serves as a specific biomarker of exposure to CPF while AChE and BChE activity serve as biomarkers of effect. Additionally, there is currently no validated biomarker of susceptibility to CPF exposure which would serve as a mechanism to identify and protect vulnerable populations. Polymorphisms in key enzymes involved in the metabolism of CPF, including CYP2B6 and 2C19 and PON1 are potential biomarkers of susceptibility and genetic variability in these enzymes. The current work seeks to fill in these gaps in our knowledge by conducting longitudinal exposure assessments in occupationally exposed adult and adolescent Egyptian pesticide workers and by identifying the impact of genetic variability in key enzymes on in vitro kinetics of CPF metabolism. Key findings of human studies include the observation of high environmental exposures of Egyptian adolescent non-workers in addition to the occupational exposures of the workers and the identification of a dose-response relationship between biomarkers of exposure and effect of CPF for the first time in occupationally exposed adolescents. In the adult Egyptian population, it was found that there is a lack of personal protective equipment use and a high frequency of reported symptoms associated with OP pesticide exposure. Key findings of the in vitro CPF metabolism studies include the decreased bioactivation of CPF by individuals with the genetic variant CYP2B6*6 due to decreased hepatic protein expression, the null phenotype of CYP2B6*18, and the identification of CYP2B6*4,*5, and *7 as possible biomarkers of increased susceptibility, due to an increased rate of CPF bioactivation. Furthermore, it was found that the kinetics of CPF biotransformation in human liver microsomes followed isoenzyme Michaelis-Menten kinetics better than the traditional Michaelis-Menten kinetics used to study CPF metabolism in this system by previous investigators. In conclusion, these studies will better inform the continuing efforts to assess the health risks associated with occupational and environmental exposures to CPF and provide a better understanding of biomarkers of exposure, effect and susceptibility to this commonly used OP pesticide.