Lau et al. 2007; Loveless et al. 2006). Several experimental studies have reported that PFCs impair thyroid hormone homeo- stasis. Depression of serum triiodothyronine (T3) and/or thyroxine (T4) in PFOA- and PFOS-exposed rats and monkeys has been reported (Butenhoff et al. 2002; Lau et al. 2007), but without an expected correspond- ing elevation of thyroid-stimulating hor- mone (TSH) through feedback stimulation of the hypothalamic–pituitary–thyroid axis. However, it has been hypothesized these asso- ciations could be an artifact of the use of ana- log methods for assessment of free thyroid hormones and are absent if the equilibrium dialysis method is used (Chang et al. 2007; Lau et al. 2007). One mechanism that has been proposed for these effects in rodents is peroxisome proliferation. In animals, PFOA is a strong peroxisome proliferator in the liver, and this proliferation has been shown to alter lipids, liver enzymes, and liver size (Kennedy et al. 2004; Lau et al. 2007; Loveless et al. 2006). Proxisome proliferation and the resulting activation of a nuclear receptor [peroxisome proliferator-activated receptor α (PPARα)] have also been proposed as a mechanism for tumor induction and for the immune and hormonal changes seen in rodents (Lau et al. 2007). However, it is not known if this mech- anism is relevant to humans, where peroxisome proliferation is generally less apparent (Dewitt et al. 2008; Klaunig et al. 2003). Furthermore, new observations question whether this mech- anism is specifically relevant to liver carcino- genesis in rodents (Guyton et al. 2009). This issue remains a subject of active investigation. In the United States, the only popula- tions exposed above background levels are occupational cohorts and two communities in Minnesota and West Virginia/Ohio. The two communities have been exposed via water contamination coming from adjacent indus- trial plants; in Minnesota the mean PFOA was 15 ng/mL as measured recently (Minnesota Department of Health 2009), whereas in the Mid-Ohio Valley the mean was 82 ng/mL in 2005 (Emmett et al. 2006a; Frisbee et al. 2009; Steenland et al. 2009a). In the Mid- Ohio Valley population, a great deal of health information and clinical chemistries, as well as serum measurements of PFCs, were gathered in a 2005–2006 survey of 69,000 residents of contaminated water districts. Descriptions of these data have been posted on the C8 Health Project web site (C8 Health Project 2009). PFOA is often correlated in human serum with another PFC, perfluorooctanesulfonic acid (PFOS). PFOS is also present in most human serum in the United States, with a median serum level of 21 ng/mL, although as with PFOA, the sources of this expo- sure are poorly characterized (Calafat et al. 2007a). Until recently PFOS has been used in the manufacture of Scotchgard (3M, St. Paul, MN) among other products (also until recently Scotchgard could emit PFOA as it degraded). Its half-life has been estimated at 5.4 years (Olsen et al. 2007a). PFOS is also considered an animal carcinogen by U.S. EPA (2005). The epidemiology of PFOS is even more limited than that of PFOA. We do not review epidemiologic studies of PFOS per se here but mention findings for PFOS in stud- ies that consider both PFOA and PFOS, to help interpret the PFOA results. Lipids, Uric Acid, Diabetes, and Cardiovascular and Cerebrovascular Disease Lipids. A positive association of PFOA with cholesterol was observed in six occupational studies (Costa et al. 2009; Olsen and Zobel 2007; Olsen et al. 2000, 2003; Sakr et al. 2007a, 2007b), three studies of a highly exposed community (Emmett et al. 2006b; Frisbee et al. in press; Steenland et al. 2009b), and one general population study (Nelson et al. 2010). Six of these studies showed a sta- tistically significant association (at the p = 0.05 level; all references in this article to statistical significance refer to p ≤ 0.05), whereas two occupational studies (Olsen and Zobel 2007; Olsen et al. 2000) and the smaller of the two community studies (Emmett et al. 2006b) did not. All of these studies were cross-sec- tional except for three: Sakr et al. (2007b) had data on 454 workers with multiple PFOA and cholesterol measurements over an average of 10 years, Costa et al. (2009) had data on 56 workers with such multiple measurements, and Olsen et al. (2003) had data on 174 work- ers with two measurements. All three of these studies found a significant correlation over time between cholesterol and PFOA levels. The risk of high cholesterol (≥ 240 mg/dL) also increased in relation to PFOA in some studies. For example, in Steenland et al. (2009b), comparing the highest quartile of PFOA versus the lowest yielded an odds ratio (OR) for high cholesterol of 1.38 [95% confi- dence interval (CI), 1.28–1.50]. Many studies also showed positive rela- tionships of PFOA with other lipids (i.e., low density lipoprotein cholesterol and triglycer- ides), with the exception of high density lipo- protein cholesterol, which was consistently not found to be associated with PFOA. Several studies (Frisbee et al. in press; Nelson et al. 2010; Steenland et al. 2009b) also showed associations of lipids with PFOS that were similar in magnitude to those with PFOA. This finding raises the question of whether all PFCs are associated with increased lipids via some common mechanism. PFOA and PFOS are generally correlated in the serum; in two large studies, the correlations were Environmental Health Perspectives • volume 118 | number 8 | August 2010 Epidemiology of PFOA 0.31 (in a population with high-PFOA expo- sure; Steenland et al. 2009b) and 0.65 (in a general population with background PFOA and PFOS exposures; Nelson et al. 2010). Generally, models including both compounds showed an attenuation of the association for both PFOA and PFOS, without one being clearly dominant. Only one study (Olsen et al. 1999) addressed the effect of PFOS alone, an occupational cross-sectional study that showed a significant positive correlation with cholesterol at one plant but not at another. Given the cross-sectional nature of most of these studies, it is not clear whether a) PFOA increases cholesterol and other lip- ids; b) both PFOA and cholesterol are jointly affected by some other attribute, substance, or mechanism that causes their correlation; or c) high lipids might cause increased reten- tion of PFOA in the body (reverse causality). Some evidence against this last hypothesis is provided by Steenland et al. (2009b), where those who had taken statins, associated with a large decrease in cholesterol, had PFOA levels similar to those who had not taken sta- tins. The three longitudinal studies indicating that cholesterol and PFOA were related over time in subjects with repeated measurements (Costa et al. 2009; Olsen et al. 2003; Sakr et al. 2007b) strengthen the case for a causal relationship, although they do not preclude a relationship in which both PFOA and choles- terol jointly covary with some biologic process that is also changing over time. The strength of the association of PFOA and cholesterol varied considerably by study, making interpretation even more problem- atic: The lower the range of PFOA that was studied, the greater the change in cholesterol per unit change in PFOA. Thus, the stud- ies of community populations report larger shifts in cholesterol per unit change in PFOA levels than do the occupational studies (which have higher exposures). Table 1 summarizes the changes in cholesterol associated with changes in PFOA. Assuming a linear rela- tionship between the two (not always the case), the slope relating PFOA to cholesterol varied by two to three orders of magnitude. One possibility that might explain some of this discrepancy would be if the slope of an exposure–response relationship was steep at low PFOA levels and then flattened out, as might be the case, for example, if some bio- logical pathways were saturated. There is a suggestion of such flattening in some stud- ies (Frisbee et al. in press; Steenland et al. 2009b). Most studies did not examine the exposure–response curve in detail. The findings ofassociations between PFOA and increased cholesterol in humans contra- dict what would be expected from animal studies, where PFOA decreases, not increases, serum lipids (Lau et al. 2007). However, as 1101