The search for alternatives to bioaccumulative perfluoroalkyl acids (PFAAs) is ongoing. New, still highly fluorinated alternatives are produced in hopes of reducing bioaccumulation. To better estimate this bioaccumulative behavior, we performed dialysis experiments and determined membrane/ water partition coefficients, K mem/w , of six perfluoroalkyl carboxylic acids (PFCAs), three perfluoroalkanesulfonic acids, and four alternatives. We also investigated how passive permeation might influence the uptake kinetics into cells, measuring the passive anionic membrane permeability P ion through planar lipid bilayers for six PFAAs and three alternatives. Experimental K mem/w and P ion were both predicted well by the COSMO-RS theory (log RMSE 0.61 and 0.46, respectively). K mem/w values were consistent with the literature data, and alternatives showed similar sorption behavior as PFAAs. Experimental P ion values were high enough to explain observed cellular uptake by passive diffusion with no need to postulate the existence of active uptake processes. However, predicted pK a and neutral permeabilities suggest that also the permeation of the neutral species should be significant in case of PFCAs. This can have direct consequences on the steady-state distribution of PFAAs across cell membranes and thus toxicity. Consequently, we propose a model to predict pH-dependent baseline toxicity based on K mem/w , which considers the permeation of both neutral and anionic species.

Alternatives to long-chain PFAAs sorb similarly strongly to serum albumin as the classical PFAAs.

Perfluoroalkyl acids (PFAAs) mostly exist as ionic compounds that are of major concern because of their accumulative behavior. The discussion about their risk is ongoing considering the increasing production of structurally similar alternatives. We conducted model calculations based on equilibrium distribution coefficients that allow studying the distribution of PFAAs and their alternatives in various mammalian organs through comparison to empirical measurements in humans and rats. The calculations rely on experimentally determined distribution coefficients of a series of PFAAs and 4 of their alternatives to physiological matrices such as structural proteins, storage lipids, membrane lipids, albumin, and fatty acid binding protein (FABP). The relative sorption capacities in each organ were calculated from the combination of distribution coefficients and physiological data. The calculated distribution of PFAAs and alternatives within the organs showed that albumin and membrane lipids and, to a lesser extent, structural proteins have the highest relative sorption capacities for the compounds. Sorption to FABP is only relevant in the distribution of short‐chain PFAAs. Storage lipids play a minor role in the distribution of all studied compounds. Our calculated distribution of PFAAs was evaluated by comparison to reported PFAA concentrations in various organs. Environ Toxicol Chem 2021;40:910–920. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.