A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease

Background: Consistent evidence at high levels of water arsenic (≥100 mg/l), and growing evidence at low-moderate levels ( < 100 mg/l), support a link with cardiovascular disease (CVD). The shape of the dose-response across low-moderate and high levels of arsenic in drinking water is uncertain and critical for risk assessment. Methods: We conducted a systematic review of general population epidemiological studies of arsenic and incident clinical CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories. In a dose-response meta-analysis, we estimated the pooled association between log-transformed water arsenic (log-linear) and restricted cubic splines of log-transformed water arsenic (non-linear) and the relative risk of each CVD endpoint. Results: Twelve studies (pooled N=408 945) conducted at high (N=7) and lowmoderate (N=5) levels of water arsenic met inclusion criteria, and 11 studies were included in the meta-analysis. Compared with 10 mg/l, the estimated pooled relative risks [95% confidence interval (CI)] for 20 mg/l water arsenic, based on a log-linear model, were 1.09 (1.03, 1.14) (N=2) for CVD incidence, 1.07 (1.01, 1.14) (N=6) for CVD mortality, 1.11 (1.05, 1.17) (N=4) for CHD incidence, 1.16 (1.07, 1.26) (N=6) for CHD mortality, 1.08 (0.99, 1.17) (N=2) for stroke incidence and 1.06 (0.93, 1.20) (N=6) for stroke mortality. We found no evidence of non-linearity, although these tests had low statistical power. Conclusions: Although limited by the small number of studies, this analysis supports quantitatively including CVD in inorganic arsenic risk assessment, and strengthens the evidence for an association between arsenic and CVD across low-moderate to high levels.