Understanding Mechanisms of PFAS Absorption, Distribution, and Elimination Using a Physiologically Based Toxicokinetic Model

Exposures to some per- and polyfluoroalkyl substances (PFAS), including perfluoroalkyl acids (PFAA), have been associated with diverse adverse health effects. Physicochemical properties of PFAA are known to influence their toxicokinetics in mammals, but mechanistic models capable of identifying the key drivers of absorption, distribution, and elimination are limited. Here, we develop and evaluate a physiologically based toxicokinetic (PBTK) model parameterized to an <i>in vivo</i> mouse model using data from <i>in vitro</i> studies. We simulated tissue concentrations of 9 PFAA with perfluorinated carbon chains (η_pfc) ranging from 4 to 10 in wild-type mice, and for perfluorooctanesulfonic acid in knockout mice, following intravenous and oral exposures. The PBTK model quantifies blood flow, binding to tissue proteins and phospholipids, membrane permeability, hepatic and renal transporters, and fecal and urinary excretion. Model evaluation comparing experimental and simulated mice blood and tissue concentrations showed <i>R</i>² values of ≥ 0.65 and relative root-mean-square errors of ≤ 122% for most PFAA. Model sensitivity analyses showed that permeability and phospholipid binding strongly influenced the elimination and distribution of long-chain PFAA (η_pfc ≥ 7), while elimination for short-chain PFAA (η_pfc ≤ 6) was more sensitive to renal transporters and albumin binding. This study illustrates how integrating <i>in vitro</i>-derived parameters into PBTK models enables mechanistic evaluation of PFAS toxicokinetics across diverse compounds and physiological conditions.