Comparative Pharmacokinetics of Perfluorobutyrate in Rats, Mice, Monkeys, and Humans and Relevance to Human Exposure via Drinking Water

Perfluorobutyrate (PFBA) has been detected in precipitation, surface waters, water treatment effluent, and in public and private wells in Minnesota at up to low mg/l concentrations. We evaluated the pharmacokinetics of PFBA in rats, mice, monkeys, and humans to provide a rational basis for dose selection in toxicological studies and to aid in human-health-risk assessment. Studies included (1) rats—iv and oral; (2) mice—oral; (3) monkeys—iv; and (4) humans—occupationally exposed volunteers. PFBA was determined in serum (all species), liver (rats and mice), urine (rats, mice, and monkeys), and feces (rats and mice). In addition, we characterized serum PFBA concentrations in 177 individuals with potential exposure to PFBA through drinking water. Mean terminal serum PFBA elimination half-lives for males (M) and females (F), respectively, in h were (1) for rats given 30 mg/kg, 9.22 and 1.76 (oral), and 6.38 and 1.03 (iv); (2) for mice given oral doses of 10, 30, or 100 mg/kg ammonium PFBA, 13.34 and 2.87 at 10 mg/kg, 16.25 and 3.08 at 30 mg/kg; and 5.22 and 2.79 at 100 mg/kg; (3) for monkeys given 10 mg/kg iv, 40.32 and 41.04; and (4) for humans, 72.16 and 87.00 (74.63 combined). Volume of distribution estimates indicated primarily extracellular distribution. Among individuals with plausible exposure via drinking water, 96% of serum PFBA concentrations were < 2 ng/ml (maximum 6 ng/ml). These findings demonstrate that PFBA is eliminated efficiently from serum with a low potential for accumulation from repeated exposure. Perfluorobutyrate (C3F7CO2 , PFBA) is a perfluorinated alkyl carboxylate formed by industrial synthesis and by the metabolism and environmental degradation of certain fluorinated chemicals (D’Eon and Mabury, 2007; D’Eon et al., 2006; Martin et al., 2006). PFBA has recently been detected in precipitation, surface waters, and water treatment facility effluent in low ng/l concentrations (Scott et al., 2006a, b; Skutlarek et al., 2006) and in public and private wells in communities in Minnesota at up to low lg/l concentrations (http://health.state.mn.us/divs./eh/hazardous/topics/pfbasemetro. html). PFBA exposure may also result from occupational or environmental exposure to materials that can be metabolized or degraded to PFBA, such as N-alkyl-perfluorobutanesulfonamides or perfluoroalkylphonates (D’Eon and Mabury, 2007; D’Eon et al., 2006). Occupational exposure to N-alkyl perfluorobutyl ethers could also result in metabolism to PFBA via CYP450 oxidation of the ether to form the perfluorobutyryl fluoride and subsequent hydrolysis to form PFBA or the oxidation of heptafluoro-1,1-dihydrobutanol (Jay F. Schulz, personal communication). In recent years, perfluorinated alkyl carboxylates with higher carbon numbers, such as perfluorooctanoate (PFOA), perfluoronanoate, perfluorohexanesulfonate (PFHxS), and perfluorooctanesulfonate (PFOS), have been the subject of extensive investigation due to the fact that they are found widely in blood-derived samples from the general population (Calafat et al., 2007a; Olsen et al., 2003). PFOA, PFHxS, and PFOS have low elimination rates in humans, with serum elimination halflives of several years (Olsen et al., 2007a). Recent evidence indicates that these concentrations are declining in the United States general population (Calafat et al., 2007b; Olsen et al., 2007b), likely the result of 3M Company’s decision in May of 2000 to phase out manufacturing of ammonium PFOA and materials based on perfluorooctanesulfonyl fluoride. Unlike the eight-carbon perfluoroalkyl carboxylate, PFOA, which has been studied extensively (Kennedy et al., 2004; Kudo and Kawashima, 2003; Lau et al., 2007), there have been Notice: It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. 1 To whom correspondence should be addressed at 3M Company, Medical