Content area
Abstract
PFAS are persistent environmental pollutants with widespread biological implications due to their bioaccumulate nature and potential toxicity. Understanding how PFAS distribute within biological systems—their toxicokinetics—is critical to assessing their potential impacts across species. While prior research identified general trends in PFAS bioaccumulation, the molecular mechanisms underlying tissue-specific distribution remain poorly defined, particularly for structurally diverse PFAS and at varying exposure concentrations.
Phospholipid membranes and protein-binding interactions aim to advance mechanistic insights into PFAS distribution by examining how chemical structure influences their interactions with biological components. A library of PFAS spanning multiple subclasses and functional groups is evaluated using a combination of laboratory measurements, biomimetic chromatography, and computational modeling. Emphasis is placed on quantifying membrane-water partition coefficients and human serum albumin (HSA) binding affinities as key determinants of tissue distribution. Computational docking techniques and quantitative structure activity relationships are employed to characterize binding behavior and identify structural features predictive of biological affinity.
To mechanistically characterize PFAS distribution and accumulation in biological tissues, an integrated modeling framework incorporates both experimental and in silico data. A concentration-dependent partitioning model, which accounts for the competition between protein binding and membrane association, along with the adaptation of biomimetic chromatography metrics for tissue distribution modeling, are incorporated. Multivariate regression analyses demonstrate that models integrating both membrane and protein affinity parameters exhibit superior predictive performance across a variety of species, compared with single-parameter partitioning models based solely on hydrophobicity.
Finally, a physiologically based pharmacokinetic (PBPK) model is extended to incorporate permeability-limited transport and tissue structure, consisting of a free aqueous phase and a bound phase representing interactions with membranes and intracellular proteins. The framework enables more biologically realistic simulations of PFAS kinetics and bioaccumulation patterns, providing a robust platform for extrapolating tissue-specific distribution across species and PFAS chemistries. Collectively, the proposed work contributes to a mechanistic, cross-disciplinary understanding of PFAS behavior and supports the development of predictive tools for environmental and human health risk assessment.
Details
