Renal Elimination of Perfluorocarboxylates (PFCAs)

Abstract

Sex-, species-, and chain length-dependent renal elimination is the hallmark of mammalian elimination of perfluorocarboxylates (PFCAs) and has been extensively studied for almost 30 years. In this review, toxicokinetic data of PFCAs (chain lengths ranging from 4 to 10) in different species are compared with an emphasis on their relevance to renal elimination. PFCAs vary in their affinities to bind to serum albumins in plasma, which is an important factor in determining the renal clearance of PFCAs. PFCA-albumin binding has been well characterized and is summarized in this review. The mechanism of the sex-, species-, and chain length-dependent renal PFCA elimination is a research area that has gained continuous interest since the beginning of toxicological studies of PFCAs. It is now recognized that organic anion transport proteins play a key role in PFCA renal tubular reabsorption, a process that is sex-, species-, and chain length-dependent. Recent studies on the identification of PFCA renal transport proteins and characterization of their transport kinetics have greatly improved our understanding of the PFCA renal transport mechanism at the molecular level. A mathematical representation of this renal tubular reabsorption mechanism has been incorporated in physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoate (PFOA). Improvement of PBPK models in the future will require more accurate and quantitative characterization of renal transport pathways of PFCAs. To that end, a basolateral membrane efflux pathway for the reabsorption of PFCAs in the kidney is discussed in this review, which could provide a future research direction toward a better understanding of the mechanisms of PFCA renal elimination.

Per- and polyfluorinated substances (PFASs): Environmental challenges

“…The puzzling and unexplained out of line longer half-life of PFHxS in humans, superior to that of its higher homolog PFOS, was confirmed in a study that also noted huge differences between young women and men and older women, with mean half-lives in young females of 6.7 and 7.7 years for PFOS and PFHxS, respectively, versus 34 and 35 years for males and older females [74]. The much slower excretion rate observed for humans as compared to animals was assigned to larger renal saturable resorption efficiency [194,212,213]. The body half-life increase with F-chain length seen for PFCAs parallels that observed for fluorocarbons [2], but these half-lives are about two orders of magnitude higher, for the same F-chain length.…”

“…Liver, lung and kidney are major target organs for PFAAs. In blood, PFAAs bind to plasma proteins, primary albumin [193][194][195]. Two distinct binding sites were identified by NMR in human albumin for PFOA and…”

Repeated dose and reproductive/developmental toxicity of perfluoroundecanoic acid in rats

“…The elimination rate of PFOA in female rats is approximately 40 times faster than in male rats (ATSDR, 2009). Organic anion transport proteins play a key role in PFCAs (C4 to C10) renal tubular reabsorption (Han et al, 2012), and the slower elimination of PFOA in male rats compared to female rats has been attributed to sex hormone modulation of organic anion transporters in the kidney (ATSDR, 2009). In the present study, there were slight gender differences in the hepatotoxicity of PFUA: liver weight increased in males at 0.3 mg/kg/day and above and in females at 1.0 mg/kg/day, and histopathological findings observed in the 1.0 mg/kg/day groups were more numerous and severer in males than in females.…”

Highly Elevated Serum Concentrations of Perfluoroalkyl Substances in Fishery Employees from Tangxun Lake, China

“…17,18 Interestingly, our data displayed similar or slightly lower clearance rates for PFBA compared to PFHxA and PFHpA (Figure 3), although no significant differences were observed for clearance rates among these three PFCAs according to the statistical test. While the reasons for this observation remain unclear, it was proposed by Han et al 55 that the slower elimination of PFBA compared to PFHxA in rats may be due to a different set of transport proteins governing renal excretion. However, since PFHxA and PFHpA displayed a low detection frequency in both urine and serum, it should also be noted that estimated CL renal values for these compounds are associated with a larger uncertainty compared to the other PFASs in this study.…”