Evaluation of 14 PFAS for permeability and organic anion transporter interactions: Implications for renal clearance in humans

Authors

Sangwoo Ryu, University of Rhode Island
Emi Yamaguchi, Pfizer
Seyed Mohamad Sadegh Modaresi, University of Rhode Island
Juliana Agudelo, University of Rhode Island
Chester Costales, Pfizer
Mark A. West, Pfizer
Fabian Fischer, University of Rhode IslandFollow
Angela L. Slitt, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

6-8-2024

Department

Biomedical and Pharmaceutical Sciences

Abstract

Per- and polyfluoroalkyl substances (PFAS) encompass a diverse group of synthetic fluorinated chemicals known to elicit adverse health effects in animals and humans. However, only a few studies investigated the mechanisms underlying clearance of PFAS. Herein, the relevance of human renal transporters and permeability to clearance and bioaccumulation for 14 PFAS containing three to eleven perfluorinated carbon atoms (η_pfc = 3–11) and several functional head-groups was investigated. Apparent permeabilities and interactions with human transporters were measured using in vitro cell-based assays, including the MDCK-LE cell line, and HEK293 stable transfected cell lines expressing organic anion transporter (OAT) 1–4 and organic cation transporter (OCT) 2. The results generated align with the Extended Clearance Classification System (ECCS), affirming that permeability, molecular weight, and ionization serve as robust predictors of clearance and renal transporter engagement. Notably, PFAS with low permeability (ECCS 3A and 3B) exhibited substantial substrate activity for OAT1 and OAT3, indicative of active renal secretion. Furthermore, we highlight the potential contribution of OAT4-mediated reabsorption to the renal clearance of PFAS with short η_pfc, such as perfluorohexane sulfonate (PFHxS). Our data advance our mechanistic understanding of renal clearance of PFAS in humans, provide useful input parameters for toxicokinetic models, and have broad implications for toxicological evaluation and regulatory considerations.

Publication Title, e.g., Journal

Chemosphere

Volume

361

Citation/Publisher Attribution

Sangwoo Ryu, Emi Yamaguchi, Seyed Mohamad Sadegh Modaresi, Juliana Agudelo, Chester Costales, Mark A. West, Fabian Fischer, Angela L. Slitt. Evaluation of 14 PFAS for permeability and organic anion transporter interactions: Implications for renal clearance in humans, Chemosphere, Volume 361, 2024. https://doi.org/10.1016/j.chemosphere.2024.142390.