Membrane/Water Partitioning and Permeabilities of Perfluoroalkyl Acids and Four of their Alternatives and the Effects on Toxicokinetic Behavior

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 irev anionic membrane permeability P-ion through planar lipid bilayers for six PFAAs and three alternatives. Experimental and P-mem/w 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.