Assessing the human health risks of exposure to organophosphorus pesticides
Ellison, Corie Anthony
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Organophosphorus pesticides (OPs) are the most widely used insecticide in the United States and throughout the world, and as such, human exposure to OPs is a concern. The development of human data regarding OP exposure, metabolism, effects and susceptibility are all important needs for the human risk assessment process. The work presented within this dissertation focuses on generating data that will be relevant for the human risk assessment of two common OPs, chlorpyrifos (CPF) and methyl parathion. OPs undergo cytochrome P-450 (CYP) mediated metabolism to form an active, highly toxic oxon intermediate metabolite which is the metabolite primarily responsible for the inhibition of cholinesterase enzymes. Detoxification of the active oxon metabolite occurs primarily by enzymatic hydrolysis by paraoxonase 1 (PON1). The balance between activation and detoxification should, in-part, determine the risk to humans for a given OP. Metabolism of methyl parathion by recombinant human CYPs identified CYP2B6 and CYP2C19 as being the major enzymes involved in methyl parathion metabolism. These results are consistent with previous findings that CYP2B6 and CYP2C19 are the major enzymes involved in other OP metabolism, such as CPF. Additional work was conducted utilizing human biomonitoring data collected from Egyptian agricultural workers with known CPF exposure. Biological sample collection included urine, saliva and blood. Urinary levels of the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy) were determined as a marker of CPF exposure. Saliva was used to genotype participants for polymorphisms within the main enzymes involved in CPF metabolism, CYP2B6, CYP2C19 and PON1. Whole blood was used to monitor cholinesterase activity while serum was used to determine PON1 activity towards chlorpyrifos-oxon (e.g., CPOase activity of PON1). Findings from the Egyptian population demonstrated a dose-effect relationship between urinary TCPy and both plasma butyrylcholinesterase (BuChE) and red blood cell acetylcholinesterase (AChE) in humans exposed occupationally to CPF. The no-effect level (or inflection point) of the exposure-effect relationships has an average urinary TCPy level of 114 μg/g creatinine for BuChE and 3,161 μg/g creatinine for AChE. The most prevalent CYP2B6 genotype combinations within the population were CYP2B6 *1/*1 (44%), *1/*6 (38%), *6/*6 (8%) and *1/*5 (6%), while the frequency of the CYP2C19 genotype combinations were CYP2C19 *1/*1 (93%), *1/*2 (6%), *2/*2 (1%). The PON1 55 (p ≤ 0.05) but not the PON1 192 genotype had a significant effect on CPOase activity. When adjusted for urinary TCPy excretion and stratified by PON1 genotype, CPOase activity did not have a significant effect on cholinesterase inhibition. The biomonitoring data collected from the Egyptian agricultural workers was used to develop and optimize a human physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for dermal CPF exposure. The human PBPK/PD model is able to account for differences in worker habit (e.g. duration of exposure, skin exposure area, time to wash off) as well as interindividual differences in key metabolizing enzymes (i.e. CYP2B6, CYP2C19 and PON1). An assessment of the pharmacokinetics and pharmacodynamics of CPF in rats under exposure conditions which more closely reflects occupational exposure was also conducted. Results from the animal study were used to update an existing PBPK/PD rat model for CPF exposure so that it can account for repeated CPF exposures. Taken together, the results presented within this dissertation will contribute to future risk assessment efforts and mechanistic studies for OP exposure.