Comparison of the toxicokinetics between perfluorocarboxylic acids with different carbon chain length

Abstract

Toxicokinetics was compared between perfluoroheptanoic acid (PFHA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) in male and female rats. Half lives (t_1/2) in male and female rats were calculated to be 0.10 and 0.05 days, respectively, for PFHA, 5.63 and 0.08 days for PFOA, 29.5 and 2.44 days for PFNA and 39.9 and 58.6 days for PFDA. Total clearance (CL_tot) of PFHA was higher than those of other perfluorocarboxylic acids (PFCAs) in both male and female rats. By contrast, CL_tot of PFDA was extremely low in both sexes. PFCAs having shorter carbon chain length showed higher CL_tot. There was a significant sex-related difference in CL_tot of PFOA and PFNA. Distribution volumes in steady state (V_ss) were not much different between PFCAs and between sexes. To estimate the role of urinary excretion in plasma clearance of PFCA, renal clearance (CL_R) was determined for PFCAs. CL_R of PFCAs were in the order PFHA>PFOA>PFNA≃PFDA and PFHA≃PFOA>PDNA>PFDA in male and female rats, respectively. There was a close relationship between CL_tot and CL_R (r²=0.981). Plasma protein binding, estimated in vitro, was over 98% for all PFCAs tested. The results indicate that CL_R is responsible for the difference in CL_tot between PFCAs having different carbon chain length and between sexes.

Introduction

Perfluorooctanoic acid (PFOA) is an analog of octanoic acid of which all aliphatic hydrogen atoms are substituted by fluorine. PFOA is a potent surfactant and commercially used in a variety of industrial processes (Guethner and Vietor, 1962). Perfluorodecanoic acid (PFDA), its structure is similar to that of PFOA but having two more carbon atoms, was shown to be more toxic than PFOA in rats; LD₅₀-values of PFOA and PFDA were 189 and 41 mg/kg body weight, respectively (Olson and Andersen, 1983). In the previous study, we have shown that the rates of urinary elimination were quite different between perfluorocarboxylic acids (PFCAs) having 7–10 carbon atoms (Kudo et al., 2001). Namely, the shorter the carbon chain length is, the more rapidly was eliminated PFCA into urine. The mechanism responsible for the difference in urinary elimination has not been fully studied yet, although it may be due to the difference in the rate of tubular secretion (Kudo et al., 2002). Moreover, it is difficult to elucidate the rate of disappearance from the body between these PFCAs because no precise toxicokinetic study has been performed on them. Biological half-life (t_1/2) of PFOA in human was calculated to be more than 1 year (Übel et al., 1980), which was far longer than that in rats (Vanden Heuvel et al., 1991a). It is important, therefore, to clarify toxicokinetics of various PFCAs to elucidate the mechanism for bioaccumulation of PFCA. In this study, we estimated the total clearance (CL_tot), t_1/2, and renal clearance (CL_R) of PFCAs having different carbon chain length and between sexes.