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

Abstract

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.

Estimating the Equilibrium Distribution of Perfluoroalkyl Acids and 4 of Their Alternatives in Mammals

“…Structural modifications of the alternatives such as the ether bonds do not substantially affect the sorption behavior to proteins. Our results for structural proteins obtained here support our previous assumption that alternatives are likely to be as accumulative as the classical PFAAs (Allendorf et al 2019;Ebert et al 2020). Using…”

“…A more detailed discussion can be found in the references. The variability in the experimental D sp/w for all compounds was relatively high with a standard deviation of about 0.3 log units compared to the results from our other dialysis cell experiments that generally deviated by less than 0.1 log units (Allendorf et al 2019;Ebert et al 2020). This could be due to the more heterogeneous biological extract.…”

“…we could show for their sorption behavior to proteins and membrane lipids (Allendorf et al 2019;Ebert et al 2020). Substantial differences in the accumulation in different species and even different sex within one species increase the already high complexity of the behavior of these compounds (Han et al 2012).…”

“…Previously, we presented a consistent set of distribution coefficients for PFAAs and four of their alternatives to serum albumin and membrane lipids, respectively (Allendorf et al 2019;Ebert et al 2020). In the course of these two publications, we reevaluated distribution coefficients of PFAAs to albumin determined by others.…”

“…Allendorf et al 2019;Ebert et al 2020). The binding affinities to liver FABP were reported elsewhere(Weaver et al 2010;Woodcroft et al 2010;Zhang et al 2013;Sheng et al 2018) and were converted to distribution coefficients (SI-1.9).…”