A Clinical Perspective on Arsenic Exposure and Development of Atherosclerotic Cardiovascular Disease.

Cardiovascular risk has traditionally been defined by modifiable and non-modifiable risk factors, such as tobacco use, hyperlipidemia, and family history. However, chemicals and pollutants may also play a role in cardiovascular disease (CVD) risk. Arsenic is a naturally occurring element that is widely distributed in the Earth's crust. Inorganic arsenic (iAs) has been implicated in the pathogenesis of atherosclerosis, with chronic high-dose exposure to iAs (> 100 µg/L) being linked to CVD; however, whether low-to-moderate dose exposures of iAs (< 100 µg/L) are associated with the development of CVD is unclear. Due to limitations of the existing literature, it is difficult to define a threshold for iAs toxicity. Studies demonstrate that the effect of iAs on CVD is far more complex with influences from several factors, including diet, genetics, metabolism, and traditional risk factors such as hypertension and smoking. In this article, we review the existing data of low-to-moderate dose iAs exposure and its effect on CVD, along with highlighting the potential mechanisms of action.

Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment.

The possibility of an association between inorganic arsenic (iAs) exposure and cardiovascular outcomes has received increasing attention in the literature over the past decade. The United States Environmental Protection Agency (US EPA) is currently revising its Integrated Risk Assessment System (IRIS) review of iAs, and one of the non-cancer endpoints of interest is cardiovascular disease (CVD). Despite the increased interest in this area, substantial gaps remain in the available information, particularly regarding the mechanism of action (MOA) by which iAs could cause or exacerbate CVD. Few studies specifically address the plausibility of an association between iAs and CVD at the low exposure levels which are typical in the United States (i.e., below 100 µg As/L in drinking water). We have conducted a review and evaluation of the animal, mechanistic, and human data relevant to the potential MOAs of iAs and CVD. Specifically, we evaluated the most common proposed MOAs, which include disturbance of endothelial function and hepatic dysfunction. Our analysis of the available evidence indicates that there is not a well-established MOA for iAs in the development or progression of CVD. Few human studies of the potential MOAs have addressed plausibility at low doses and the applicability of extrapolation from animal studies to humans is questionable. However, the available evidence indicates that regardless of the specific MOA, the effects of iAs on physiological processes at the cellular level appear to operate via a threshold mechanism. This finding is consistent with the lack of association of CVD with iAs exposure in humans at levels below 100 µg/L, particularly when considering important exposure and risk modifiers such as nutrition and genetics. Based on this analysis, we conclude that there are no data supporting a linear dose-response relationship between iAs and CVD, indicating this relationship has a threshold.