Steenland et al. also noted, it is not known whether peroxi- some proliferation, the mechanism of action involved, is relevant to humans, where it is generally less apparent. Uric acid. Uric acid is a natural product of purine metabolism and has both oxidant and antioxidant properties. There is consider- able epidemiologic evidence that elevated uric acid is a risk factor for hypertension (Feig et al. 2008; Shankar et al. 2006). Three cross-sectional studies report posi- tive associations between PFOA and uric acid. Two are occupational studies [Costa et al. 2009 (n = 160); Sakr et al. 2007a (n = 1,000)], and one is a community study [Steenland et al. 2010 (n = 55,000)]. No detailed results are provided in Sakr et al. (2007a). Costa et al. (2009), using a cross-sectional analysis, found mean uric acid levels of 6.29 µg/mL for 34 cur- rently exposed workers, versus 5.73 µg/mL for 34 matched nonexposed workers (p = 0.04). In addition, using repeated measures of both PFOA and uric acid over a 7-year period to perform a longitudinal analysis of this group (n = 56), Costa et al. (2009) found a signifi- cant positive association between uric acid and PFOA; the two varied together over time. In the cross-sectional study by Steenland et al. (2010), both PFOA and PFOS were significantly associated with uric acid. An increase from the lowest to highest decile of either PFOA or PFOS was associated with an increase of 0.2–0.3 mg/dL uric acid. Risk of abnormally high uric acid (hyper- uricemia, defined as > 6.0 mg/dL for women, > 6.8 mg/dL for men) increased modestly with increasing PFOA; the ORs by quintile of PFOA were 1.00, 1.33 (95% CI, 1.24–1.43), 1.35 (95% CI, 1.26–1.45), 1.47 (95% CI, 1.37–1.58), and 1.47 (95% CI, 1.37–1.58; test for trend, p < 0.0001). A positive but less pronounced trend was seen for PFOS. Inclusion of both correlated fluorocarbons in the model indicated that PFOA was a more important predictor than was PFOS. Inclusion of albumin in the model, which binds with PFOA, had little effect on these results. The overall strength of association between PFOA and uric acid is modest in both the Steenland et al. (2010) and Costa et al. (2009) studies. Causality cannot be inferred from these cross-sectional data. There are mech- anisms by which reverse causality might be applicable. For example, uric acid and PFOA may share renal transport systems (organic ion transporters 1 and 3) governing excretion of each substance (Eraly et al. 2008; Nakagawa et al. 2008), so it is possible that if the levels of PFOA increase, the secretion of urate is decreased and therefore blood urate levels may secondarily increase. However, whether this shared transporter hypothesis is relevant in humans remains speculative at this point. Cardiovascular disease. Given the find- ings for cholesterol and uric acid noted above, it is reasonable to ask whether PFOA is associ- ated with cardiovascular disease. The data on cardiovascular disease, however, are limited in quantity and quality, consisting primarily of mortality studies among relatively small cohorts of workers. The mortality of workers (n = 6,207) at a DuPont plant using PFOA, who were employed between 1948 and 2002, has been studied by Leonard et al. (2008) and Sakr et al. (2009). Serum PFOA levels among all workers at this plant in 2004 averaged 240 ng/mL, with an average of 490 ng/mL among workers in the PFOA areas (Sakr et al. 2007a). Standardized mortality ratios (SMRs) were calculated using several different referent populations. SMRs for ischemic heart disease (IHD) compared with U.S. and state general populations were < 1.0, as might be expected because of the healthy worker effect. Sakr et al. (2009) conducted dose–response analyses of these same data using a job–exposure matrix (Kreckmann et al. 2009), which used job cate- gories and measured serum levels for 1,000 workers in 2004 to assign all cohort members to four quartiles of cumulative serum PFOA. The mean serum was 231 ng/mL. Categorical dose–response analyses for IHD using differ- ent lags (0. 5, 10, 15, 20 years) and different methods of forming quartiles (based on case exposures or entire cohort exposures) showed no significant positive trends at the p = 0.05 level, but the analysis using a 10-year lag and quartiles formed based on the PFOA distribu- tion of the entire cohort did suggest a positive trend [risk ratios (RRs) = 1.0, 1.0, 1.4, and 1.6; p for trend = 0.06]. Workers at the 3M plant in Minnesota are the other principal occupational cohort exposed to PFOA. The most recent mortality update of this cohort is from Lundin et al. (2009) (n = 3,922). Workers were divided into not exposed, probably exposed, and definitely exposed groups based on job category, with ranges of median serum levels in the probably exposed job categories of 300–1,500 ng/mL and in the definitely exposed job categories of 2,600–5,200 ng/mL. Mortality by the three exposure groups showed rate ratios of 1.0, 1.2 [95% confidence interval (CI), 0.9–1.7), and 0.9 (95% CI, 0.4–2.1), with observed deaths of 92, 103, and only 6 in the definitely exposed job categories. Analyses by cumulative weighted years of exposure (weights for unexposed, prob- ably exposed, and definitely exposed groups were 1, 30, and 100) showed rate ratios of 1.0 (138 observed), 1.2 (95% CI, 0.9–1.8; 42 observed), and 0.8 (95% CI, 0.5–1.2; 21 observed). There is little or no evidence of a positive trend in these data. Cumulatively, the two studies provide insufficient data for infer- ences regarding an association between PFOA and cardiovascular disease. Finally, Melzer et al. (2010) found no trend in self-reported history of heart dis- ease in data from the National Health and Nutrition Examination Survey (NHANES), after dividing PFOA serum levels into quartiles. These data are limited by the low range of exposure (background levels in the Table 1. Changes in cholesterol in relation to changes in PFOA levels. Change in PFOA (ng/mL) Change in cholesterol (mg/dL) Slope (assumes linearity)a Frisbee et al. in press Steenland et al. 2009b Sakr et al. 2007a Sakr et al. 2009b Nelson et al. 2010 Costa et al. 2009 Emmett et al. 2006b Olsen et al. 2000 Olsen and Zobel 2007 Olsen et al. 2003 NA, not available. 1102 Study description Cross-sectional; 12,476 high-exposed children; mean PFOA = 69 ng/mL Cross-sectional; 46,294 high-exposed adults; mean PFOA = 80 ng/mL Cross-sectional; 1,024 workers; mean PFOA = 428 ng/mL Longitudinal; 454 workers; mean PFOA = 1,130 ng/mL Cross-sectional; 860 adults, general population; mean PFOA = 4 ng/mL Longitudinal, 54 workers; mean PFOA ~ 12,000 ng/mLb Cross-sectional; 371 high-exposed adults; median PFOA, 354 ng/mL Cross-sectional (three time points); 111, 80, and 74 workers; mean PFOA ~ 22,000 ng/mL Cross-sectional, 506 workers; mean PFOA = 2,210 ng/mLd Longitudinal, 174 workers; mean PFOA ~ 1,500 ng/mLb 400 340 1,000 1,000 5 4,000 (estimated from slope) ~ 22,000 10 11 5 1 10 22 ~ 16 0.03 0.03 0.005 0.001 2.0 0.001 0.006c 0.0007c 0.001 0.001 aChange in cholesterol per ng/mL change in PFOA, assuming a linear relationship, which is not always apparent in some studies. Slopes were calculated for this table from published data; some studies presented different results for different subsamples. bResults were presented for the log of cholesterol versus parts per million PFOA (coefficients = 0.032 and 0.028, respectively), prohibiting extraction of a linear slope. cNot significant at p = 0.05. dThe result presented was the coefficient relating the log of cholesterol to the log of PFOA in parts per million (0.0076). We have approximated a linear slope for the range 0–1,000 ng/mL by using predicted cholesterol values at those two points. ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives