Bayesian evaluation of a physiologically based pharmacokinetic (PBPK) model for perfluorooctane sulfonate (PFOS) to characterize the interspecies uncertainty between mice, rats, monkeys, and humans: Development and performance verification. (August 2019)

• Record Type: Journal Article
• Authors: Chou, Wei-Chun; Lin, Zhoumeng
• Is Part Of: Environment international. Volume 129(2019)
• Page Start: 408
• Page End: 422
• Publication Date: 2019-08
• Subjects: ASC average serum concentration -- AUC area under the curve -- HED human equivalent dose -- EFSA European Food Safety Authority -- IV intravenous -- MCMC Markov chain Monte Carlo -- MOA Mode of action -- NOAEL no-observed-adverse-effect-level -- OATs organic anion transporters -- PBPK physiologically based pharmacokinetic -- PFOA perfluorooctanoic acid -- PFOS perfluorooctane sulfonate -- POD point of departure -- PTCs proximal tubule cells -- RfD reference dose -- TK toxicokinetic -- U.S. EPA United States Environmental Protection Agency -- WHO World Health Organization; Interspecies extrapolation -- Markov chain Monte Carlo (MCMC) -- Perfluoroalkyl substances (PFAS) -- Perfluorooctane sulfonate (PFOS) -- Physiologically based pharmacokinetic (PBPK) modeling -- Risk assessment; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2019.03.058
• Languages: English
• ISSNs: 0160-4120

Abstract

Abstract: A challenge in the risk assessment of perfluorooctane sulfonate (PFOS) is the large interspecies differences in its toxicokinetics that results in substantial uncertainty in the dosimetry and toxicity extrapolation from animals to humans. To address this challenge, the objective of this study was to develop an open-source physiologically based pharmacokinetic (PBPK) model accounting for species-specific toxicokinetic parameters of PFOS. Considering available knowledge about the toxicokinetic properties of PFOS, a PBPK model for PFOS in mice, rats, monkeys, and humans after intravenous and oral administrations was created. Available species-specific toxicokinetic data were used for model calibration and optimization, and independent datasets were used for model evaluation. Bayesian statistical analysis using Markov chain Monte Carlo (MCMC) simulation was performed to optimize the model and to characterize the uncertainty and interspecies variability of chemical-specific parameters. The model predictions well correlated with the majority of datasets for all four species, and the model was validated with independent data in rats, monkeys, and humans. The model was applied to predict human equivalent doses (HEDs) based on reported points of departure in selected critical toxicity studies in rats and monkeys following U.S. EPA's guidelines. The lower bounds of the model-derived HEDs were overall lower than the HEDs estimated by U.S. EPA (e.g., 0.2 vs. 1.3 μg/kg/day based on the rat plasma data). This integrated and comparative analysis provides an important step towards improving interspecies extrapolation and quantitative risk assessment of PFOS, and this open-source model provides a foundation for developing models for other perfluoroalkyl substances. Highlights: An open-source PBPK model for PFOS in mice, rats, monkeys and humans was developed. A Bayesian approach was used to characterize parameter uncertainty between species. Human equivalent doses (HEDs) and reference doses (RfDs) were calculated. Calculated RfDs were close to EFSA's guidance value, but lower than EPA's RfDs.