Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans

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Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans
Title:
Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans
Journal Title:
Environmental Science & Technology
Publication Date:
18 April 2023
Citation:
Lin, J., Chin, S. Y., Tan, S. P. F., Koh, H. C., Cheong, E. J. Y., Chan, E. C. Y., & Chan, J. C. Y. (2023). Mechanistic Middle-Out Physiologically Based Toxicokinetic Modeling of Transporter-Dependent Disposition of Perfluorooctanoic Acid in Humans. Environmental Science & Technology, 57(17), 6825–6834. https://doi.org/10.1021/acs.est.2c05642
Abstract:
Perfluorooctanoic acid (PFOA) is an environmental toxicant exhibiting a years-long biological half-life (t1/2) in humans and is linked with adverse health effects. However, limited understanding of its toxicokinetics (TK) has obstructed the necessary risk assessment. Here, we constructed the first middle-out physiologically based toxicokinetic (PBTK) model to mechanistically explain the persistence of PFOA in humans. In vitro transporter kinetics were thoroughly characterized and scaled up to in vivo clearances using quantitative proteomics-based in vitro-to-in vivo extrapolation. These data and physicochemical parameters of PFOA were used to parameterize our model. We uncovered a novel uptake transporter for PFOA, highly likely to be monocarboxylate transporter 1 which is ubiquitously expressed in body tissues and may mediate broad tissue penetration. Our model was able to recapitulate clinical data from a phase I dose-escalation trial and divergent half-lives from clinical trial and biomonitoring studies. Simulations and sensitivity analyses confirmed the importance of renal transporters in driving extensive PFOA reabsorption, reducing its clearance and augmenting its t1/2. Crucially, the inclusion of a hypothetical, saturable renal basolateral efflux transporter provided the first unified explanation for the divergent t1/2 of PFOA reported in clinical (116 days) versus biomonitoring studies (1.3–3.9 years). Efforts are underway to build PBTK models for other perfluoroalkyl substances using similar workflows to assess their TK profiles and facilitate risk assessments.
License type:
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the A*STAR - Industry Alignment Fund─Pre-Positioning Programme (IAF-PP)
Grant Reference no. : H18/01/a0/J14

This research / project is supported by the A*STAR - Central Research Fund (Applied and Translational Research)
Grant Reference no. : NA
Description:
ISSN:
0013-936X
1520-5851