A physiologically based pharmacokinetic model of diethyl phthalates in humans

Abstract

Phthalates are a family of industrial and consumer product chemicals, among which diethyl phthalate (DEP) has been widely used. DEP is metabolized into the active metabolite monoethyl phthalate (MEP) and exposure to DEP may induce male reproductive toxicity, developmental toxicity and hepatotoxicity. To better assess the toxicity of DEP and MEP, it is important to understand and predict their internal concentrations, especially in reproductive organs. Here we present a human physiologically based pharmacokinetic (PBPK) model of DEP. Implemented in R, the PBPK model consists of seven tissue compartments, including blood, gut, liver, fat, skin, gonad, and rest of body (RB). In the blood both DEP and MEP partition into free and bound forms, and tissue distribution is considered as blood flow-limited. DEP is metabolized in the gut and liver into MEP which is further glucuronidated and cleared through the urine. The chemical-specific parameters of the model were predicted in silico or estimated based on published human urinary MEP data after exposure to DEP in the air at 250 or 300 μg/m3 for 3 or 6 h through inhalation and dermal absorption. Sensitivity analysis identified important parameters including partition coefficients of DEP for fat, RB, and skin compartments, and the rate constants for glucuronidation of MEP and urinary excretion, with regard to Cmax, area under the curve (AUC), and clearance half-lives of DEP and MEP. A subset of the sensitive parameters was then included in hierarchical population Bayesian Markov chain Monte Carlo (MCMC) simulations to characterize the uncertainty and variability of these parameters. The model is consistent with the notion that dermal absorption represents a significant route of exposure to DEP in ambient air and clothing can be an effective barrier. The developed human PBPK model can be utilized upon further refinement as a quantitative tool for DEP risk assessment.