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. 2024 Mar 29;12(4):253.
doi: 10.3390/toxics12040253.

Species-Specific Unbound Fraction Differences in Highly Bound PFAS: A Comparative Study across Human, Rat, and Mouse Plasma and Albumin

Sangwoo Ryu  1   2 , Woodrow Burchett  2 , Sam Zhang  2 , Seyed Mohamad Sadegh Modaresi  1 , Juliana Agudelo Areiza  1 , Emily Kaye  1 , Fabian Christoph Fischer  1   3 , Angela L Slitt  1
Affiliations

Species-Specific Unbound Fraction Differences in Highly Bound PFAS: A Comparative Study across Human, Rat, and Mouse Plasma and Albumin

Sangwoo Ryu et al. Toxics. .

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a diverse group of fluorinated compounds which have yet to undergo comprehensive investigation regarding potential adverse health effects and bioaccumulative properties. With long half-lives and accumulative properties, PFAS have been linked to several toxic effects in both non-clinical species such as rat and mouse as well as human. Although biological impacts and specific protein binding of PFAS have been examined, there is no study focusing on the species-specific fraction unbound (fu) in plasma and related toxicokinetics. Herein, a presaturation equilibrium dialysis method was used to measure and validate the binding of 14 individual PFAS with carbon chains containing 4 to 12 perfluorinated carbon atoms and several functional head-groups to albumin and plasma of mouse (C57BL/6 and CD-1), rat, and human. Equivalence testing between each species-matrix combination showed positive correlation between rat and human when comparing fu in plasma and binding to albumin. Similar trends in binding were also observed for mouse plasma and albumin. Relatively high Spearman correlations for all combinations indicate high concordance of PFAS binding regardless of matrix. Physiochemical properties of PFAS such as molecular weight, chain length, and lipophilicity were found to have important roles in plasma protein binding of PFAS.

Keywords: PFAS; equilibrium dialysis; protein binding; toxicology.

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Conflict of interest statement

Woodrow Burchett and Sam Zhang were employed by the company Pfizer Worldwide Research & Development, Pfizer Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Fraction unbound (fu) values for 14 PFAS for human, rat, and mouse plasma (A) and albumin (B) in binding assays plotted against ascending molecular weight (MW) of the PFAS.
Figure 2
Figure 2
Fraction unbound (fu) for 14 PFAS using human, rat, and mouse (CD-1 and C57BL/6) plasma and albumin. (A) fu versus molecular weight (MW) (g/mol) and (B) fu versus logD.
Figure 3
Figure 3
Fraction unbound (fu) of plasma and albumin for human, rat, and mouse CD-1 and C57BL/6. The black line represents 1:1 agreement, with fu(plasma) = 0.97 × fu(albumin) − 0.06, R2 = 0.94; SD = 0.25.
Figure 4
Figure 4
Pairwise comparison of fu for human, rat, and mouse plasma and albumin. Dotted red lines represent 1:1 agreement.
Figure 5
Figure 5
ℓ-correction adjusted TOST equivalence tests conducted for within-matrix pairwise comparisons fu values for all species and plasma/ albumin combinations organized from least to highest geomean fold difference. The dashed line represents a fold difference of 1. The 2-fold difference thresholds were employed to determine equivalence accounting for established assay variance and are shown as black lines (0.5 and 2).
Figure 6
Figure 6
Fractions unbound in human plasma against the number of perfluorinated carbons of the PFAS. PFAS with similar number of perfluorinated carbons but different functional group (carboxylic vs. sulfonic acids) are highlighted in the figure.
Figure 7
Figure 7
Linear relationship between fu in human and mouse plasma measured in this study and elimination half-lives for PFAS observed in humans (A) and mice (B).
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