We observed 77
252 person years during the follow-up period. There were 460 deaths, of which 198 were from diseases of circulatory system (ICD-10 codes I00-I99), accounting for 43% of total mortality in the population and yielding a mortality rate of 256.3 per 100
000 person years. Among the 198 deaths from cardiovascular disease, 85 were from cerebrovascular disease (codes I60-I69); 104 were from ischaemic heart disease (codes I20-I25, n=71) or other forms of heart disease (codes I30-I52, n=33), which included mostly deaths from heart failure (codes I50.0-I50.9, n = 32) and ventricular tachycardia (code I47, n=1); and nine deaths were from pulmonary heart disease, hypertensive heart disease, or multiple valve diseases (codes I08, I11, and I27).
Higher BMI and presence of diabetes were associated with an increased risk of death from ischaemic heart disease and other heart disease (table 1). There was no association between educational level and mortality from either diseases of the circulatory system overall or any of the subtypes of cardiovascular disease. Diastolic and systolic hypertension were related to an increased risk of death from diseases of the circulatory system overall and all subtypes of cardiovascular disease, and the associations were stronger for cerebrovascular disease. Participants who were current smokers, had smoked for at least 20 years, or had accumulated at least 10 pack years at baseline were 1.6 to 1.9 times more likely to die from disease of circulatory system and 2.2 to 2.7 times more likely to die from ischaemic heart disease and other heart disease.
Table 1 Relations between baseline risk factors and mortality from disease of circulatory system
Primary objectives: association between arsenic exposure and cardiovascular disease mortality
We found an increased risk of mortality from diseases of the circulatory system in people with high concentrations of well arsenic. The mortality rate for cardiovascular disease was 214.3 per 100
000 person years in people drinking water containing <12.0 µg/L arsenic compared with 271.1 per 100
000 person years in people drinking water with ≥12.0 µg/L arsenic. Participants exposed to >148 µg/L (mean 265.7 µg/L) of well arsenic were 1.47 (95% confidence interval 0.99 to 2.18) times more likely to die from diseases of the circulatory system compared with their counterparts who were exposed to <12 µg/L (model 2, table 2). There was an increased risk of mortality from ischaemic heart disease and other heart disease in relation to high concentrations of well arsenic, and a dose-response relation remained after adjustment for BMI, smoking status, educational attainment, and changes in arsenic concentration between visits adjusted for urinary creatinine in addition to age and sex (model 2, P=0.0019 for trend). The hazard ratio was 1.29 (1.10 to 1.52, model 2) for a 1 SD increase in well arsenic concentration (115 µg/L). A similar association was observed between baseline well arsenic and mortality from ischaemic heart disease; participants with >148 µg/L of arsenic in well water were 1.94 (0.99 to 3.84) times more likely to die from ischaemic heart disease compared with those with <12 µg/L (model 2, P=0.0294 for trend). The hazard ratio was 1.25 (1.03 to 1.52, model 2) for a 1 SD increase in well arsenic concentration. On the other hand, there was no association between well arsenic and mortality from cerebrovascular disease. Analysis results were similar when we used time weighted arsenic concentration as the exposure measure (see appendix 2 on bmj.com). Additional control for systolic blood pressure, baseline diabetes, and dietary intake of fish and rice did not appreciably change effect estimates (see appendix 3 on bmj.com). When participants with missing values for BMI, education level, smoking status, and changes in urinary arsenic between visits were excluded or imputed by using the median level in the population, the results were similar (data not shown).
Table 2 Association between baseline concentrations of well arsenic (µg/L) and mortality from disease of circulatory system during follow-up
We observed similar patterns of hazard ratios when we used baseline urinary arsenic as the exposure variable in the analyses (table 3). Baseline urinary arsenic was related to an increased risk of mortality from diseases of the circulatory system (model 2, P=0.0065 for trend), and the association was stronger for the combined category of ischaemic heart disease and other heart disease (model 2, P=0.0001for trend). The effect estimates did not materially change when we did not adjust for urinary creatinine. For instance, the association between urinary arsenic and mortality from heart disease in increasing quarters of urinary arsenic concentrations were 1.00 (reference), 1.07 (0.57 to 2.03), 1.44 (0.81 to 2.57), and 2.08 (1.09 to 3.95) (P=0.0001for trend) (data not shown).
Table 3 Association between baseline urinary creatinine adjusted arsenic (µg/g of creatinine) and mortality from disease of circulatory system during follow-up
Spearman correlations of baseline urinary arsenic with urinary arsenic measured at first and second follow-up were both 0.65. Overall, total urinary arsenic decreased by an average of 57.1 µg/g of creatinine from baseline to first follow-up and then essentially remained stable with an average increase of 3.2 µg/g creatinine from first to second follow-up. The hazard ratio was 1.18 (1.03 to 1.36) for total cardiovascular disease mortality in relation to a 1 SD increase in changes in urinary arsenic (240 µg per g of creatinine) between visits, adjustment for age, sex, BMI, smoking status, and baseline well arsenic concentration. The number of deaths in extreme categories of changes in urinary arsenic, however, was not enough for us to evaluate the dose-response relation for specific cardiovascular disease subtypes.
Secondary objectives: synergy between arsenic exposure and cigarette smoking in mortality from heart disease
Although not significant, the risk of mortality from heart disease seemed to be higher for people with high level of arsenic exposure who had ever smoked (fig 2). The risk of dying from ischaemic heart disease and other heart disease associated with moderate (25.3-114.0 µg/L, mean 63.5 µg/L) or high levels of arsenic exposure (>114 µg/L, mean 228.8 µg/L) was consistently higher in those who had ever smoked and especially in current smokers at baseline compared with those who had never smoked. The joint effect of moderate or high levels of arsenic exposure and ever smoking was greater than the sum of their individual effects, with estimates of the relative excess risk due to interaction all greater than zero. In exploratory analyses, when we further classified ever smokers into past and current smokers, the synergistic effect between moderate or high level of arsenic exposure and current smoking was stronger (relative excess risk due to interaction 2.21 (0.11 to 4.31; P=0.036) and 1.43 (0.02 to 3.61; P=0.045), respectively) (fig 2). Figure 3 shows the survival curves by thirds of well arsenic and smoking status in men and women. The synergistic effect between smoking and arsenic exposure was similar in men and women. We found a similar pattern of estimates of relative excess risk due to interaction when we considered well arsenic concentration as a continuous variable. There was a synergy between a 1 SD increase in well arsenic concentration and ever smoking (0.38, 0.02 to 1.35), and the synergy was stronger with current smoking status (0.67, 0.08 to 1.86).
Fig 2 Joint effect of cigarette smoking and concentrations of well arsenic at baseline on mortality from ischaemic heart disease and other heart disease. Hazard ratios adjusted for sex and baseline age (years), BMI, education, and changes in urinary creatinine (more ...)
Fig 3 Multivariate adjusted (education, age, BMI, changes in urinary arsenic over time) survival curves for ischaemic heart disease and other heart disease by baseline concentrations of well arsenic (low, medium, and high), sex, and baseline smoking status. (more ...)