Characterization of human metabolism and exposures to organophosphorus and pyrethroid insecticides
Singleton, Steven Thomas
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Organophosphorus (OP) insecticides have been the most commonly used insecticides in the world for the past 30 years, with chlorpyrifos being the most studied and most commonly used OP. However, the past decade has seen a decline in the use of OPs, due to the increasing risk of adverse human health effects associate with the widespread use of OPs. As OP use is declining there has been an increase in the use of a different class of insecticides, the pyrethroids (PYR). Although PYRs are historically believed to be less toxic than the OPs, there are concerns indicating that PYR exposure may affect neurological development, induce apoptosis, suppress the immune system, induce cancer, and disrupt the endocrine system. The focus of this dissertation was to characterize the metabolism and human exposures to the OP insecticides, chlorpyrifos (CPF) and profenofos (PFF), and the PYR insecticide, alpha-cypermethrin (aCM). OPs and PYRs are the most commonly utilized insecticides within the US and worldwide. These specific agents were chosen for investigation because of our ongoing studies with Egyptian Ministry of Agriculture workers that apply these pesticides to the cotton crop in the Nile delta of Egypt. Characterization of metabolism for these insecticides was performed using human liver fractions, and individual recombinant human cytochrome P-450s that specifically biotransform these insecticides. Additionally, this work examined the relationship between human exposures to CPF and PFF and the inhibition of blood butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) activities, which are sensitive effect biomarkers that may be associated with neurotoxicity. Specific and sensitive urinary metabolites (biomarkers) of aCM were also measured to assess the exposure of Egyptian agricultural workers to this insecticide. Finally, the interaction between OPs and the biotransformation of aCM was assessed in vitro. For the first time, these studies characterized occupational exposures to profenofos and alpha-cypermethrin by assessing urinary levels of 4-bromo-2-chlorophenol (BCP) and cis-3-(2,2-dichlorovinyl)-2,2-dimethylycyclopropane carboxylic acid (cis-DCCA), specific metabolites of these respective insecticides, which serve as biomarkers of exposure. The results indicate that Egyptian agricultural workers have a remarkably wide range of exposures to CPF, PFF and aCM. In addition, a relationship was identified between elevated urinary BCP and a decrease in red blood cell AChE activity in humans exposed occupationally to PFF. In vitro studies using human liver microsomes show that the OP pesticides, chlorpyrifos-oxon and PFF, inhibit the metabolism and resulting detoxfication of aCM. The wide range of exposures to these insecticides allows for assessment of dose-dependent associations between biomarkers of exposure and biomarkers of effect, reporting of neurological symptoms, and deficits in neurobehavioral performance. Taken together, these results will inform worldwide agencies to implement work practices that will reduce the magnitude of insecticide exposures and thus protect the health of workers and the general public.