THE ROLE OF ARSENIC METABOLISM IN MORTALITY, DIABETES, AND KIDNEY DISEASE
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Abstract Experimental and epidemiological evidence supports the role of chronic arsenic exposure in a broad scope of adverse health effects at a wide range of exposure levels. However, little is known regarding arsenic metabolism and health risk. The objective of this dissertation was to investigate the role of arsenic metabolism in mortality, diabetes, and kidney disease. First, we conducted a systematic review of the epidemiologic evidence examining the relation between arsenic metabolism and cancer, cardiovascular diseases, and adiposity. We identified 12 eligible studies for cancer, 9 for cardiovascular diseases, and 7 for adiposity. The higher proportion of monomethylarsonate [MMA%] in the urine tended to be associated with cancer and cardiovascular disease risk, whereas the lower MMA% tended to associated with an increase in adiposity. However, rather heterogeneous statistical approaches and limited prospective evidence prevented a conclusive inference from this review. In variability analysis, the range of between-population variation in MMA% is relatively narrow compared to the proportion of inorganic arsenic [iAs%] and dimethylarsinate [DMA%] in urine. Second, we measured arsenic metabolism defined by relative proportions of inorganic arsenic, MMA and DMA over their sum in the baseline urine of Strong Heart Study participants aged 45-74 years to evaluate the role of arsenic metabolism in all-cause, cardiovascular disease and cancer mortality. The adjusted hazard ratio of all-cause mortality for an interquartile increase in DMA% was 1.16 (95% CI 1.01-1.33) when it substituted iAs% whereas MMA% did not explain the risk of all-cause mortality. For cardiovascular mortality, the adjusted hazard ratio for an interquartile change increase in MMA% was 1.52 (1.16-1.99) and 1.17 (1.01-1.35) when it substituted iAs% and DMA%, respectively. For cancer mortality, the adjusted hazard ratio for an interquartile increase in MMA% was 0.73 (0.55-0.98) and 0.81 (0.67-0.97) when it substituted iAs% and DMA%, respectively. Third, we examine the prospective association between arsenic metabolism and diabetes in the Strong Heart Study. The adjusted hazard ratios of diabetes for an interquartile range increase in MMA% was 0.69 (95% CI 0.52-0.90) and 0.76 (0.65-0.89) when it was substituted for iAs% and DMA%, respectively. The association between arsenic metabolism and diabetes was similar by age, sex, study site, obesity, and the sum of inorganic and methylated arsenic concentrations. Fourth, we evaluated the role of arsenic metabolism in the development of chronic kidney disease among Strong Heart Study participants without baseline kidney disease. Incident kidney disease was defined by estimated glomerular filtration rate(eGFR) <60 ml/min/1.73m2 with a drop in eGFR ≥ 25%. The adjusted hazard ratio for an interquartile range increase in MMA% was 1.76 (95% CI 1.26-2.47) and 1.22 (1.02-1.45) when it was substituted for iAs% and DMA%, respectively. And when an interquartile range increase in DMA% with a corresponding decrease in iAs%, the adjusted hazard ratio was 1.83 (95% CI 1.29-2.61). In conclusion, arsenic metabolism was significantly associated with the risk of mortality, diabetes, and kidney disease and the associations were independent of total chronic arsenic exposure. Our results support that urine biomarkers of arsenic metabolism may reflect individual susceptibility to arsenic-related health effects and provide a novel perspective on the dynamic modeling of arsenic metabolism. In addition to replicating these finding across diverse populations and geographical areas to advance risk assessment and risk management of arsenic, future research needs to evaluate mechanisms for the connection between arsenic metabolism and health outcomes.