Research Bisphenol A and Peripheral Arterial Disease: Results from the NHANES Anoop Shankar,1 Srinivas Teppala,1 and Charumathi Sabanayagam1,2,3 1Department of Epidemiology, West Virginia University School of Public Health, Morgantown, West Virginia, USA; 2Singapore Eye Research Institute, Singapore; 3Department of Clinical Sciences, Duke–National University of Singapore Graduate Medical School, Singapore Background : Bisphenol A (BPA) is a common chemical used in the manufacture of polycarbonate plastics and epoxy resins, and > 93% of U.S. adults have detectable levels of urinary BPA. Recent animal studies have suggested that BPA exposure may have a role in several mechanisms involved in the development of cardiovascular disease (CVD), including weight gain, insulin resistance, thyroid dysfunction, endothelial dysfunction, and oxidative stress. However, few human studies have exam- ined the association between markers of BPA exposure and CVD. Peripheral arterial disease (PAD) is a subclinical measure of atherosclerotic vascular disease and a strong independent risk factor for CVD and mortality. o Bjectiv : We examined the association between urinary BPA levels and PAD in a nationally rep- resentative sample of U.S. adults. Methods : We analyzed data from 745 participants in the National Health and Nutritional Examination Survey 2003–2004. We estimated associations between urinary BPA levels (in tertiles) and PAD (ankle–brachial index < 0.9, n = 63) using logistic regression models adjusted for poten- tial confounders (age, sex, race/ethnicity, education, smoking, body mass index, diabetes mellitus, hypertension, urinary creatinine, estimated glomerular filtration rate, and serum cholesterol levels). r esult : We observed a significant, positive association between increasing levels of urinary BPA and PAD before and after adjusting for confounders. hTe multi variable-adjusted odds ratio for PAD associated with the highest versus lowest tertile of urinary BPA was 2.69 (95% confidence interval: 1.02, 7.09; p-trend = 0.01). c onclusi : Urinary BPA levels were significantly associated with PAD, independent of tradi- tional CVD risk factors. k ey words : ankle–brachial index, bisphenol A, CVD, NHANES, peripheral arterial disease. Environ Health Perspect 120:1297–1300 (2012). http://dx.doi.org/10.1289/ehp.1104114 [Online 29 May 2012] Bisphenol A (BPA) is a chemical produced in very high volume, with > 2 million metric tons produced worldwide in 2003 (Vandenberg et al. 2009) and used extensively in the manufacture of epoxy resins, polycarbonate plastics, and food and beverage containers (Vandenberg et al. 2009). Consequently, it is one of the most common environmental chemical exposures in humans (Calafat et al. 2005). Data from the nationally representative National Health and Nutrition Examination Survey (NHANES) suggest that detectable levels of BPA are present in the urine of a majority of U.S. adults (Calafat et al. 2005, 2008). BPA is considered to be an endocrine- disrupting chemical, and it has been shown to have estrogenic and thyroid hormone– disrupting effects in experimental studies (Moriyama et al. 2002; Vandenberg et al. 2009). Recent evidence, especially from animal studies, suggests that BPA exposure may be related to insulin resistance and have a role in weight gain and obesity and the subsequent development of diabetes mellitus (Newbold et al. 2009; Rubin and Soto 2009). Two recent human studies reported that higher urinary BPA levels were associated with self-reported cardiovascular disease (CVD) (Lang et al. 2008; Melzer et al. 2010). However, studies examining the relation between BPA exposure and more objective measures of CVD are needed to support this putative association. Peripheral arterial disease (PAD) is a subclinical measure of atherosclerotic vascular disease (Newman et al. 1993) that is an independent predictor of subsequent incident CVD (Murabito et al. 2003; Newman et al. 1993). Criqui et al. (1992) reported that among persons initially free of CVD, an ankle–brachial index (ABI) of < 0.9 was associated with a hazard ratio of 6.6 for future risk of death from coronary heart disease even after adjusting for cardiovascular risk factors including age, sex, body mass index (BMI), smoking, and high cholesterol levels. Published guidelines (American Diabetes Association 2003; Hirsch et al. 2006) exist for defining PAD based on the ABI, which can be measured even in large population- based studies (Selvin and Erlinger 2004). In this context, we examined the independent association between urinary BPA levels and PAD among participants in the 2003–2004 NHANES, a representative, multiethnic sample of U.S. adults. Methods The present study is based on data from NHANES 2003–2004. Detailed descriptions of the NHANES study design and methods are available elsewhere [National Center for Environmental Health Perspectives • volume 120 | number 9 | September 2012 Health Statistics (NCHS) 2010b]. Briefly, the NHANES survey included a stratified multistage probability sample representa- tive of the civilian noninstitutionalized U.S. population. Selection was based on counties, blocks, households, and individuals within households and included the oversampling of non-Hispanic blacks and Mexican Americans in order to provide stable estimates of these groups. Participants provided written informed consent before their participation, and approval was obtained from the Human Subjects Committee in the U.S. Department of Health and Human Services. Measurements of ABI, a subclinical measure of atherosclerosis (Criqui et al. 1992; Newman et al. 1993), were obtained for the subsample of subjects ≥ 40 years of age. The present study sample consisted of participants > 40 years of age among whom urinary BPA was available (n = 971). We further excluded participants with an ABI ≥ 1.5 (n = 3), which is usually related to noncompressible blood vessels in the legs (Newman et al. 1993), as well as those with missing data on covariates included in the multivariable model including level of educa- tion, smoking status, serum or fasting glu- cose levels, systolic or diastolic blood pressure (SBP and DBP, respectively), and cholesterol levels (n = 215). This resulted in 753 partici- pants (47.9% women), 63 of whom had PAD. Subjects who were excluded because of missing covariates were in general similar to the general NHANES cohort in terms of age, sex, race/ethnicity, and education (data not shown). E x p o s u r e m e a s u r e m e n t s . A g e , s e x , race/ethnicity, smoking status, alcohol intake (grams per day), level of education, history of diabetes and oral hypoglycemic intake or insulin administration were assessed using a questionnaire (NCHS 2010b). Participants who had not smoked > 100 cigarettes in their lifetimes were considered never smokers; Address correspondence to A. Shankar, Department of Community Medicine, West Virginia University School of Medicine, P.O. Box 9190, Morgantown, WV 26506-9190 USA. Telephone: (304) 293-0199. Fax: (304) 293-6685. E-mail: ashankar@hsc.wvu.edu This study was funded by grants 1R03ES018888-01 and 5R03ES018888-02 from the National Institutes of Health, National Institute of Environmental Health Sciences, and by a grant from the American Heart Association National Clinical Research Program. The authors declare they have no actual or potential competing financial interests. Received 22 June 2011; accepted 29 May 2012. 1297