Review Epidemiologic Evidence on the Health Effects of Perfluorooctanoic Acid (PFOA) Kyle Steenland,1 Tony Fletcher,2 and David A. Savitz3 1Rollins School of Public Health, Emory University, Atlanta, Georgia, USA; 2London School of Hygiene and Tropical Medicine, London, United Kingdom; 3Mount Sinai School of Medicine, New York, New York, USA osurce nad syntheis words o Bjectiv d at : We reviewed the epidemiologic literature for PFOA. : Perfluorooctanoic acid (PFOA) does not occur naturally but is present in the serum of most residents of industrialized countries (U.S. median, 4 ng/mL). Drinking water is the primary route of exposure in some populations, but exposure sources are not well understood. PFOA has been used to manufacture such products as Gore-Tex and Teflon. PFOA does not break down in the environment; the human half-life is estimated at about 3 years. PFOA is not metabo- lized in the body; it is not lipophilic. PFOA is not directly genotoxic; animal data indicate that it can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems. Data on the human health effects of PFOA are sparse. There is rela- tively consistent evidence of modest positive associations with cholesterol and uric acid, although the magnitude of the cholesterol effect is inconsistent across different exposure levels. There is some but much less consistent evidence of a modest positive correlation with liver enzymes. Most findings come from cross-sectional studies, limiting conclusions. Two occupational cohort studies do not provide consistent evidence for chronic disease; both are limited by sample size and reliance on mor- tality data. Reproductive data have increased recently but are inconsistent, and any observed adverse effects are modest. c onclusi : Epidemiologic evidence remains limited, and to date data are insufficient to draw firm conclusions regarding the role of PFOA for any of the diseases of concern. k ey : epidemiology, health effects, PFOA. Environ Health Perspect 118:1100–1108 (2010). doi:10.1289/ehp.0901827 [Online 27 April 2010] Perfluorooctanoic acid (PFOA, or C8) is a perfluorinated compound (PFC) that does not occur naturally but was introduced in the envi- ronment after World War II. PFCs are fluoro- carbons with at least one additional atom or functional group; PFOA has a carboxylic acid group (C7F15COOH). Most people tested in the United States have PFOA in their serum (measured via perfluorooctanoate, the disassoci- ated ion of PFOA), with a median of 4 ng/mL, but the source of exposure is not clear (Calafat et al. 2007b). PFOA has also been detected in the serum of populations in a number of industrialized countries (Fromme et al. 2009; Kannan et al. 2004; Lau et al. 2007). Limited data suggest that PFOA in water systems may result from wastewater treatment plants, which concentrate PFOA (Becker et al. 2008; Pistocchio and Loos 2009). Levels of PFOA in the serum appear to be decreasing in the U.S. population, because some large users have curtailed emissions (Calafat et al. 2007b; Olsen et al. 2007b). Determinants of PFOA in the general population are known to include age (higher at younger and older ages), sex (males higher), and race (whites higher) (Calafat et al. 2007a, 2007b; Emmett et al. 2006a; Steenland et al. 2009a). However, none of these attributes are very strong predictors. For those living near a point source of contamination, contamination of drinking water has been identified as the major route of exposure (Emmett et al. 2006a; Hölzer et al. 2008; Steenland et al. 2009a). PFOA has been used in the production of a wide variety of industrial and consumer 1100 products, such as Gore-Tex and Teflon. PFOA does not break down once in the environment, because of the strong carbon–fluorine bonds, leading to widespread buildup and bioaccu- mulation. Two studies provide estimates of the half-life for PFOA in humans. In a study of 26 retired fluorochemical production workers (mean years retired at initial blood collection, 2.6), followed up for 5 years, the median half- life was 3.4 years (Olsen et al. 2007a). In a study of 200 people who had been exposed via public water supplies and followed for 1 year after installation of filtration for the water sup- plies, the median half-life was 2.3 years (Bartell et al. 2010). The latter estimate suffers from the short follow-up time (although this popu- lation will be followed for 5 years), whereas the former suffers from small numbers and a lack of data at the time when exposure ceased. PFOA is not metabolized in the body; its tissue distribution in humans is unknown, but studies in rats suggest it is likely to be pres- ent primarily in the liver, kidney, and blood (Kennedy et al. 2004; Lau et al. 2007). It is easily absorbed via the gastrointestinal tract in rats. It is not lipophilic, unlike chlorinated hydrocarbons, but binds to serum albumin and is excreted primarily from the kidney. It is not directly genotoxic (Andersen et al. 2008). There is a considerable amount of animal data on the health effects of PFOA, which has been summarized by others [Kennedy et al. 2004; Lau et al. 2007; U.S. Environmental Protection Agency (EPA) 2005]. The rele- vance of animal (primarily rodent) data for humans is controversial because of a much shorter half-life in rodents (measured in days) and the possible dependence of some animal toxicity on a peroxisome proliferation mech- anism that is likely to be less important in humans (see below). PFOA induces tumors of the testicles, liver, and pancreas in rodents (Biegel et al. 2001; Sibinski 1987; U.S. EPA 2005) via dietary intake, and there is some evidence it also increases mammary tumors (Sibinski 1987; U.S. EPA 2005). The lowest doses at which effects have been observed in these rodent stud- ies appear to be several orders of magnitude higher than human doses from drinking water contaminated at a level of 1 ng/mL. In its draft risk assessment, the U.S. EPA (2005) concluded that evidence was sugges- tive that PFOA is carcinogenic in humans. In its review of that risk assessment, three of the four members of the EPA scientific advisory board concluded more strongly that PFOA was “likely to be carcinogenic in humans” (U.S. EPA 2006). PFOA also reduces birth weight in mice and causes neonatal death in rats (Lau et al. 2007; U.S. EPA 2005). In mice it decreases the B-cell and T-cell immune responses, and in rats it results in atrophy of the spleen and thymus, causes hepatomegaly, and decreases levels of cholesterol (Kennedy et al. 2004; Address correspondence to K. Steenland, Rollins School of Public Health, Emory University, 1518 Clifton Rd., Atlanta, GA 30322 USA. Telephone: (404) 712-8277. Fax: (404) 727-8744. E-mail: nsteenl@emory.edu This research was funded by the C8 Class Action Settlement Agreement (Circuit Court of Wood County, West Virginia) between DuPont and Plaintiffs, which resulted from releases of the chemi- cal perfluorooctanoic acid (PFOA, or C8). The authors are the members of a Court-approved C8 Science Panel established under the same Settlement Agreement. Funds are administered by an agency that reports to the Court. Our work and conclusions are independent of either party to the lawsuit. The task of the Science Panel is to undertake research in the Mid-Ohio Valley in order to evaluate the results and other available information to determine if there are any probable links (as defined in the Settlement Agreement) between PFOA and disease. As we do not yet have sufficient data on exposure and disease in this community we thus have not yet undertaken such a “probable link” determination. Nothing in this article should be inferred as an indication that there are or are not, in the opinion of the Science Panel, any “probable links” between PFOA and disease, as is called for under the Settlement Agreement. The authors declare they have no actual or potential competing financial interests. Received 15 December 2009; accepted 27 April 2010. ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives