Compared to tertile 1 of BPA (referent), the multivariable-adjusted OR (95% CI) of self-reported CVD was 1.09 (0.18–6.60) for tertile 2, and 1.83 (1.01–3.31) for tertile 3 (p-trend = 0.02). Discussion In a large multiethnic, nationally representa- tive sample, we found that increasing serum BPA levels were strongly associated with PAD. The observed association was indepen- dent of the confounding factors of smoking, BMI, alcohol intake, diabetes mellitus, hyper- tension, and serum cholesterol level. Our study adds to the emerging evidence suggest- ing a role for environmental exposure to BPA in cardiovascular disease in humans (Lang et al. 2008; Melzer et al. 2010). Furthermore, because PAD and low ABI are markers of atherosclerosis, our findings suggest that potential effects of BPA on atherosclerosis may be a mechanism underlying the previ- ously reported association between BPA expo- sure and self-reported CVD (Lang et al. 2008; Melzer et al. 2010). BPA is an environmental chemical used as a constituent monomer in polycarbonate plastics, which are used extensively in drink containers and food packaging and in the production of oxidants used in the lining of canned goods (Vandenberg et al. 2009). Exposure to BPA is believed to be mainly through dietary intake with additional expo- sure through water, dental sealants, inhalation of household dusts, and exposure through skin (Vandenberg et al. 2009). Recent studies from NHANES data have documented that > 93–95% of the general U.S. population has measurable concentrations of BPA metabo- lites in their urine (Calafat et al. 2005, 2008). Several lines of recent evidence suggest that an association between urinary BPA lev- els and PAD may be biologically plausible. Animal studies have suggested that BPA exposure may have a role in CVD develop- ment through several mechanisms, including the role of BPA in weight gain and obesity development potentially through its action on preadipocytes (Masuno et al. 2005; Phrakonkham et al. 2008), role as an estro- gen (Rubin and Soto 2009), potential inter- actions with estrogen-related receptor gamma (Matsushima et al. 2008), actions as a thyroid hormone antagonist (Moriyama et al. 2002), role as a peroxisome proliferator–activated receptor gamma antagonist (Wright et al. 2000) and its role in influencing pancreatic endocrine function (Ropero et al. 2008). Alonso-Magdalena et al. (2006) showed that mice with long-term exposure to environ- mentally relevant levels of BPA developed hyperinsulinemia, insulin resistance, and glucose intolerance. Furthermore, in ani- mal models BPA has been shown to induce Environmental Health Perspectives • volume 120 | number 9 | September 2012 Tertile 3 (> 3.6 ng/mL) 252 55.5 ± 0.9 42.7 75.0 14.4 10.6 16.8 27.6 55.6 21.2 40.0 38.8 39.5 40.0 20.5 39.2 37.5 23.3 17.4 ± 2.2 23.3 38.6 38.1 16.1 51.5 161.8 ± 5.2 80.1 ± 1.9 207.0 ± 3.3 10.0 ± 1.1 9.1 1299 endothelial cell injury mediated through oxi- dative stress (Hennig et al. 2002; Ooe et al. 2005; Stegeman et al. 1995) and elevations in lipids (Marmugi et al. 2012). However, there are few studies in humans for comparison. Two of the few human studies (Lang et al. 2008; Melzer et al. 2010) reported positive associations between urinary BPA levels and self-reported CVD. Also, BPA levels were found to be associated with abnormal liver function enzymes and higher levels of fasting glucose, insulin, and HOMA-IR (homeostasis model of assessment—insulin resistance) (Lang et al. 2008; Melzer et al. 2010), all points sug- gesting that BPA may have a role in CVD. It is in this context that our results on objectively Bisphenol A and peripheral arterial disease measured ABI to define PAD are important. In the present study, we have demonstrated a significant, positive association between higher BPA levels and PAD that persisted after adjustment for multiple confounders. The main strengths of our study include its nationally representative sample and use of rigorous study methods to collect the data and the availability of extensive data on confounders (NCHS 2010a, 2010b). The main study limitation is that the present study is cross-sectional in nature, therefore making it impossible to confirm that exposure preceded the outcome. Another limitation is the possibility of residual confounding. For example, despite adjusting for education and Table 1. Characteristics of the study population by tertiles of urinary BPA levels. Unweighted sample size (weighted PAD prevalence) 253 (2.8%) 240 (4.1%) 252 (9.1%) Age, sex-adjusted OR (95% CI) 1 (referent) 1.53 (0.39, 6.04) 3.73 (2.03, 6.86) < 0.0001 1.57 (1.30, 1.90) Multivariable-adjusted OR (95% CI)a 1 (referent) 1.10 (0.22, 5.39) 2.69 (1.02, 7.09) 0.01 1.38 (1.11, 1.72) aAdjusted for age, sex, race/ethnicity, education, income, smoking status, pack-years of smoking, alcohol intake, BMI, hypertension, diabetes, urinary creatinine, eGFR, and total cholesterol. b1 SD of log-transformed BPA = 1.15 ng/mL. Characteristic Unweighted sample size Age (years) Female (%) Race/ethnicity (%) Non-Hispanic whites Non-Hispanic blacks Mexican Americans and others Education (%) < High school High school > High school Income (%) < $25,000 $25,000–$54,999 ≥ $55,000 Smoking status (%) Never Former Current Pack-years of smoking Alcohol intake (%) Nondrinker Moderate drinker Heavy drinker BMI (%) Normal weight (< 25 kg/m2) Overweight (25–30 kg/m2) Obese (BMI ≥ 30 kg/m2) Diabetes (%) Hypertension (%) Urinary creatinine (mg/dL) eGFR (mL/min/1.73 m2) Total cholesterol (mg/dL) Urinary BPA (ng/mL) PAD (%) BPA (ng/mL) Tertile 1 (< 1.4) Tertile 2 (1.4–3.6) Tertile 3 (> 3.6) p-Trend 1-SD increase in log-transformed BPA (ng/mL)b Data presented are mean ± SE except where indicated. Table 2. Association between urinary BPA and PAD. Tertile 1 (< 1.4 ng/mL) 253 56.7 ± 0.6 56.5 76.3 3.7 20.0 16.5 24.0 59.5 20.1 29.9 50.0 51.7 30.8 17.5 12.6 ± 1.6 29.9 55.1 15.0 31.5 38.7 29.8 11.0 43.4 70.2 ± 5.2 81.5 ± 1.3 210.9 ± 2.3 0.7 ± 0.02 2.8 Tertile 2 (1.4–3.6 ng/mL) 240 55.6 ± 0.7 54.8 81.4 9.1 9.5 19.7 29.5 50.8 23.3 40.1 36.6 41.1 42.5 16.4 52.2 30.1 17.7 13.5 ± 1.0 32.5 35.0 32.5 14.4 45.9 120.5 ± 4.3 80.5 ± 1.3 209.6 ± 3.5 2.4 ± 0.05 4.1