A Permeability-Limited Physiologically Based Pharmacokinetic (PBPK) Model for Perfluorooctanoic acid (PFOA) in Male Rats

Abstract

Physiologically 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.

Per‐ and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research

“…An implication is that population outcomes that occur in the presence of either albuminuria or moderate to severe renal disease such as hypertension (Jain 2020) increasing presence of and uric acid (a biomarker of renal disease; Jain and Ducatman 2019a; Zeng et al 2019) can be underestimated in cross‐sectional studies; in other words, the link between these health outcomes and PFAS exposure is obscured in these studies because of enhanced PFAS excretion patterns in the presence of either albuminuria or moderate to severe kidney disease. Furthermore, the strong influence of renal reabsorption on the long half‐lives of long chain PFAS is consistent with both human protein binding of PFAS and experimental PFAS excretion rates in high‐dose rodent studies (Cheng and Ng 2017).…”

Estimating the Equilibrium Distribution of Perfluoroalkyl Acids and 4 of Their Alternatives in Mammals

“…The sorption to FABP was proposed to play a key role in the accumulation of PFOA in the (rat) liver (Cheng and Ng 2017). According to our calculations, sorption to FABP actually seems to be relevant for PFOA and short-chain compounds such as…”

“…High sorption of PFAAs to either albumin or membrane lipids has already been reported (Armitage et al 2012; Ng and Hungerbühler 2014). Previously published physiologically based models focused mainly on 1 of these 2 matrices, whereas other sorption processes were summarily estimated or not considered (Armitage et al 2013; Cheng and Ng 2017). Our results suggest that both matrices should be considered explicitly to adequately predict the distribution of PFAAs in an organism.…”

“…considered (Armitage et al 2013;Cheng and Ng 2017). Our results suggest that both matrices should be considered explicitly in order to adequately predict the distribution of PFAAs in an organism.…”

Capturing the applicability of in vitro-in silico membrane transporter data in chemical risk assessment and biomedical research

“…Importantly, the focus of the study here was active transport. However, passive as well as facilitated diffusion via membrane channels or via binding to human serum albumin, have to be taken into consideration ( Cheng and Ng, 2017 ), especially for lipophilic contaminants, as most of the industrial chemicals are.…”