, 2009 and Wasserman et al., 2004). The Bangladesh population in general is sensitive relative to the U.S. population with regard to having overall lower intakes of key nutrients for arsenic methylation and greater prevalence of nutritional deficiencies Compound Library and malnourishment,

thereby affecting sensitivity to arsenic toxicity (Chen et al., 2007, Pilsner et al., 2009 and Tseng, 2009). The mean folate intake of 281 μg/day estimated using a food-frequency questionnaire in the HEALS cohort (Zablotska et al., 2008) is below the recommended dietary folate equivalent of 320 μg/day (IOM, 1998). Fortification of foods with folic acid in the 1990s in the United States was estimated to approximately double mean levels of total folate intake for those who did not take supplements (Choumenkovitch et al., 2002). Even before fortification, mean total folate intakes were approximately 360 μg/day without supplements and 1000 μg/day for those

ERK inhibitor order who used supplements. The U.S. population may be more sensitive to CVD from other risk factors (e.g., hypertension, hyperlipidemia, lack of exercise, and obesity), although whether these factors affect the association of arsenic and CVD at lower doses is less clear. A number of studies of individual susceptibility based on differences in arsenic methylation profiles or genetic polymorphism indicate that such effects may result in increased susceptibility at higher arsenic doses, but may be less important at lower arsenic exposures

(Beebe-Dimmer et al., 2012, Karagas et al., 2012 and Steinmaus et al., 2006). Above a critical tissue level of trivalent arsenicals associated with adverse effects, in vitro data from ( Yager et al., 2013) support a consistent 3-fold range for differences in individual response Inositol oxygenase in expression of various signaling pathway genes among primary uroepithelial cells (from U.S. donors) treated with inorganic arsenic and pentavalent or trivalent metabolites. Given factors that may potentially under- or overestimate risks for populations in the United States, an appropriate uncertainty factor for RfD derivation is likely in the range of 1- to 3-fold. An uncertainty factor at the higher end of 3 applied to the NOAEL dose range (8.5–9.4 μg/kg-day) results in a dose of approximately 3 μg/kg-day. In general, the epidemiologic evidence supports an association of elevated arsenic exposure (i.e., >100 μg/L) with CVD involving the heart primarily (e.g., ischemic heart disease) and less so with cerebrovascular disease. Studies that were not included in the main analysis (e.g., cross-sectional, ecologic, and recent reviews) provide additional information on the possible nature of the relationship between arsenic exposure and CVD. Evidence on nutritional deficiencies and genetic polymorphisms affecting one-carbon metabolism hint at susceptibility to arsenical toxicity and interactions with CVD risk.