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A Permeability-Limited Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctanoic acid (PFOA) in Male Rats
journal contribution
posted on 2017-07-31, 00:00 authored by Weixiao Cheng, Carla A. NgPhysiologically
based pharmacokinetic (PBPK) modeling is a powerful
in silico tool that can be used to simulate the toxicokinetics and
tissue distribution of xenobiotic substances, such as perfluorooctanoic
acid (PFOA), in organisms. However, most existing PBPK models have
been based on the flow-limited assumption and largely rely on in vivo
data for parametrization. In this study, we propose a permeability-limited
PBPK model to estimate the toxicokinetics and tissue distribution
of PFOA in male rats. Our model considers the cellular uptake and
efflux of PFOA via both passive diffusion and transport facilitated
by various membrane transporters, association with serum albumin in
circulatory and extracellular spaces, and association with intracellular
proteins in liver and kidney. Model performance is assessed using
seven experimental data sets extracted from three different studies.
Comparing model predictions with these experimental data, our model
successfully predicts the toxicokinetics and tissue distribution of
PFOA in rats following exposure via both IV and oral routes. More
importantly, rather than requiring in vivo data fitting, all PFOA-related
parameters were obtained from in vitro assays. Our model thus provides
an effective framework to test in vitro–in vivo extrapolation
and holds great promise for predicting toxicokinetics of per- and
polyfluorinated alkyl substances in humans.