Clinical and Subclinical Effects of Arsenic Exposure: Evidence for Risk Assessment

Background: Inorganic exposure to arsenic, a common contaminant of drinking water and food, has been causally linked to cardiovascular disease (CVD). However, the shape of the dose-response across populations exposed to low-moderate and high levels of arsenic in drinking water and the underlying mechanisms of this association remain uncertain. Objectives: We evaluated the shape of the dose-response association between arsenic exposure and incident clinical CVD and the association of low-moderate arsenic exposure with biomarkers of subclinical CVD. Methods: We conducted a systematic review and dose-response meta-analysis of general population epidemiologic studies of arsenic and incident CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories (Aim 1). In the Strong Heart Study, a population-based study of CVD in American Indians, we evaluated cross-sectional and longitudinal associations between baseline urine arsenic (µg/g creatinine) with electrocardiographic markers (Aim 2) and with plasma biomarkers of thrombosis and inflammation (Aim 3) adjusted for socio-demographic and CVD risk factors. Results: Pooling the results of twelve eligible studies, we found significantly elevated pooled relative risks (RR: 95% confidence interval (CI)) in relation to a doubling of water arsenic for non-fatal and fatal overall CVD (RR=1.09: 1.03, 1.14) and CHD (RR=1.11: 1.05, 1.17), and elevated relative risks for non-fatal and fatal stroke (RR=1.08: 0.99, 1.17). There was no statistical evidence of a non-linear dose-response with log-transformed arsenic concentrations, although we had limited power. In the Strong Heart Study main cohort, participants in the highest quartile of urine arsenic had adjusted mean baseline QT intervals (95% CI) that were 7.5 (2.0, 13.0) ms higher in men and 3.3 (-2.7, 9.2) ms higher in women compared to the lowest quartile. In family study participants without diabetes, a comparison of the highest to lowest quartile of arsenic was associated with a 1.8 (-2.4, 5.9) ms difference in QT interval in men and a 4.6 (1.1, 8.0) ms difference in women. We observed a stronger association between arsenic and JT interval, and no significant associations with PR interval, QRS duration, or QT dispersion. In the main cohort, higher urine arsenic was cross-sectionally associated with higher baseline fibrinogen in individuals with diabetes (Geometric mean ratio=1.05, 95% CI: 1.02, 1.07) but not without diabetes (1.01: 0.99, 1.02) (p-interaction=0.014) in fully adjusted models. We observed no association between arsenic exposure and plasma PAI-1 or CRP. Conclusions: This dissertation adds to the evidence for including CHD in the ongoing Environmental Protection Agency risk assessment of inorganic arsenic and strengthens the evidence for an association between low-moderate arsenic exposure and subclinical CVD endpoints, specifically with differences in ventricular repolarization, and inflammation and thrombosis