Binding of Per- and Polyfluoroalkyl Substances (PFAS) to Serum Proteins: Implications for Toxicokinetics in Humans

Per- and polyfluoroalkyl substances (PFAS) are a diverse class of highly persistent anthropogenic chemicals that are detectable in the serum of most humans. PFAS exposure has been associated with many adverse effects on human health including immunotoxicity, increased risk of certain cancers, and metabolic disruption. PFAS binding to the most abundant blood serum proteins (human serum albumin [HSA] and globulins) is thought to affect transport to active sites, toxicity, and elimination half-lives. However, few studies have investigated the competitive binding of PFAS to these proteins in human serum. Here, we use C18 solid-phase microextraction fibers to measure HSA-water and globulin-water distribution coefficients (D_HSA/w, D_glob/w) for PFAS with carbon chains containing 4 to 13 perfluorinated carbons (η_pfc = 4-13) and several functional head-groups. PFAS with η_pfc < 7 were highly bound to HSA relative to globulins, whereas PFAS with η_pfc ≥ 7 showed a greater propensity for binding to globulins. Experimentally measured D_HSA/w and D_glob/w and concentrations of serum proteins successfully predicted the variability in PFAS binding in human serum. We estimated that the unbound fraction of serum PFAS varied by up to a factor of 2.5 among individuals participating in the 2017-2018 U.S. National Health and Nutrition Examination Survey. These results suggest that serum HSA and globulins are important covariates for epidemiological studies aimed at understanding the effects of PFAS exposure.