A prospective study of low arsenic exposure, type 2 diabetes and fatal myocardial infarction in Washington County, Maryland

Biological and epidemiological evidence supports a role for high-chronic arsenic exposure in diabetes and atherosclerosis development. At low-chronic exposure the role is unknown. The objective of this dissertation was to investigate the association of arsenic with diabetes and myocardial infarction in a cohort of subjects from Washington County, Maryland exposed to low levels of arsenic in drinking water (<1 mug/L).; First, we conducted a systematic review of the epidemiological and experimental evidence on arsenic and glucose metabolism. We identified 15 in vitro , 9 in vivo and 18 epidemiological studies. Arsenic interfered with transcription factors involved in insulin related gene expression. In cellular experiments in the absence of insulin, arsenic increased glucose uptake in most cells. In animals, the effect of arsenic was inconsistent. In humans, high arsenic in drinking water was associated with an increased diabetes risk in Taiwan and Bangladesh but the association was inconclusive in other populations.; Second, we measured toenail arsenic using instrumental nuclear activation analysis in a case-cohort analysis of participants 40 to 65 years old to evaluate incident diabetes over 9 years of follow-up. Arsenic levels were lower in diabetes cases compared to the random cohort sample. After multivariable adjustment, hazard ratios of diabetes comparing quartiles 2 to 4 of arsenic to the lowest quartile were 0.66 (95% confidence interval 0.33--1.35), 0.82 (0.42--1.62), and 0.45 (0.22--0.96), P trend = 0.003.; Third, we conducted a systematic review of the evidence on arsenic and cardiovascular disease. We identified 25 studies in general and occupational populations. Arsenic in drinking water was associated with increased coronary and peripheral arterial disease in Taiwan, in some occupational studies and in some studies from other countries. No clear association was found for stroke. Epidemiological studies, however, had important methodological limitations.; Fourth, we measured toenail arsenic and evaluated incident myocardial infarction over 11 years of follow-up in a case-cohort analysis of participants ≥35 years old. Arsenic levels were slightly lower in myocardial infarction cases compared to the random cohort sample. After multivariable adjustment, hazard ratios of myocardial infarction comparing quartiles 2 to 4 of arsenic to the lowest quartile were 0.82 (95% confidence interval 0.35--1.88), 0.69 (0.30--1.58), and 0.90 (0.38--2.11), respectively.; In conclusion, in a population exposed to low arsenic levels, increasing levels were not associated with increased risk of diabetes or myocardial infarction. On the contrary, subjects with the lowest toenail arsenic had increased diabetes risk and maybe increased myocardial infarction mortality. Because little is known regarding the possible essentiality of arsenic and arsenic is a well known poison and carcinogen at high doses, these findings need to be interpreted with caution. However, they are potentially important and need to be replicated in other epidemiological studies.