Generation of physiologically relevant kinetic data for the refinement of a human CYP-specific physiologically based Pharmacokinetic/Pharmacodynamic model to improve the risk assessment of two organophosphate pesticides: parathion and chlorpyrifos
Foxenberg, Robert John
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As Organophosphorous Pesticides (OPs) are the most widely utilized pesticide class worldwide, unintentional human contact is nearly unavoidable. OPs are neurotoxic, inhibiting cholinesterases. Regulating pesticide use to protect human health is dependent upon relevant estimations of the toxicological threshold or dose which is free of adverse effects. Physiologically Based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modeling is one means of extrapolating in vivo exposure and doses from relevant in vitro data. Two model compounds, parathion and chlorpyrifos, are inactive in their parent form and are dependent upon cytochrome P-450 (CYP) - mediated bioactivation or direct detoxification. Paraoxonase 1 (PON1) is responsible for metabolic detoxification of the activated OP. In 2002, Timchalk et al. published a PBPK/PD model for human exposures to chlorpyrifos. Many parameters in this model were derived in non-human systems including those involved in the activation and detoxification steps. Refining this model with parameters generated utilizing human enzymes should allow more predictive estimates of human exposures and resulting toxicological responses. Through using enzyme specific activity along with age-dependent enzyme content, differences in the metabolism potential of adults and children should also be identified. PON1 kinetics and the extent of non-specific OP protein binding were also investigated. PBPK/PD model simulations, with refined human parameters, were performed to investigate enzyme inhibition for children and adults as regulated by enzyme content. Modeling a single exposure to 10,000μg/kg chlorpyrifos resulted in 19.3% or 34.4% butyrylcholinesterase (BuChE) inhibition for a 1yr and 19yr old, respectively. Modeling an exposure to 50μg/kg parathion resulted in BuChE inhibition of 30.4% or 35.8% for the 1yr and 19yr old, respectively. These results demonstrate, for the first time, that PBPK/PD models for exposures to OPs can estimate enzyme inhibition in an age dependent manner which is not solely scaled by age-dependent changes in body weight. PBPK/PD models which include enzyme specific parameters will better assist regulators in identifying the most susceptible individuals to OPs and other classes of hazardous chemicals. To best protect human health, it is critical to identify and protect the most susceptible populations, such as children.