title: Cytochrome P450-specific human PBPK/PD models for the organophosphorus pesticides: chlorpyrifos and parathion.
abstract: Organophosphorus pesticides (OPs) remain a potential concern to human health because of their continuing use worldwide. Phosphororthioate OPs like chlorpyrifos and parathion are directly activated and detoxified by various cytochrome P450s (CYPs), with the primary CYPs involved being CYP2B6 and CYP2C19. The goal of the current study was to convert a previously reported human pharmacokinetic and pharmacodynamic (PBPK/PD) model for chlorpyrifos, that used chlorpyrifos metabolism parameters from rat liver, into a human CYP based/age-specific model using recombinant human CYP kinetic parameters (V(max), K(m)), hepatic CYP content and plasma binding measurements to estimate new values for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition and to use the model as a template for the development of a comparable parathion PBPK/PD model. The human CYP based/age-specific PBPK/PD models were used to simulate single oral exposures of adults (19 year old) and infants (1 year) to chlorpyrifos (10,000, 1000 and 100 μg/kg) or parathion (100, 25 and 5 μg/kg). Model simulations showed that there is an age dependency in the amount of blood cholinesterase inhibition observed, however additional age-dependent data are needed to further optimize age-specific human PBPK/PD modeling for these OP compounds. PBPK/PD model simulations estimated that a 4-fold increase or decrease in relative CYP2B6 and CYP2C19 content would produce a 9-22% inhibition in blood AChE activity following exposure of an adult to chlorpyrifos (1000 μg/kg). Similar model simulation produced an 18-22% inhibition in blood AChE activity following exposure of an adult to parathion (25 μg/kg). Individuals with greater CYP2B6 content and lower CYP2C19 content were predicted to be most sensitive to both OPs. Changes in hepatic CYP2B6 and CYP2C19 content had more of an influence on cholinesterase inhibition for exposures to chlorpyrifos than parathion, which agrees with previously reported literature that these CYPs are more reaction biased for desulfurization (activation) and dearylation (detoxification) of chlorpyrifos compared to parathion. The data presented here illustrate how PBPK/PD models with human enzyme-specific parameters can assist ongoing risk assessment efforts and aid in the identification of sensitive individuals and populations.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Foxenberg
authors.forename: Corie A
authors.initials: CA
authors.lastname: Ellison
authors.forename: James B
authors.initials: JB
authors.lastname: Knaak
authors.forename: Changxing
authors.initials: C
authors.lastname: Ma
authors.forename: James R
authors.initials: JR
authors.lastname: Olson
mesh_terms: D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D007306:Insecticides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010278:Parathion / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D013045:Species Specificity; D055815:Young Adult
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D010278:Parathion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D010089:Oxidoreductases, N-Demethylating; D004390:Chlorpyrifos