In this article we report the results of analysis of the baseline data from the prospective cohort study of the association between time-weighted water arsenic exposure and risk of skin lesions. Although skin lesions have been linked previously with exposure to arsenic-contaminated drinking water, there is a recognized lack of information on the modifying effects of local diet on this relationship (McCarty et al. 2006
). To our knowledge, this is the first systematic analysis of the association between micronutrient intake and prevalence of arsenic-induced skin lesions.
We estimated an ERR of 1.6 (95% CI, 1.0–2.1) per 131-μg/L time-weighted water arsenic and an ERR of 4.91 (95% CI, 1.8–8.1) per 130-μg/L urinary arsenic concentration. Thus, those exposed to a dose equal to 50 μg/L water arsenic, the currently permissible arsenic limit in Bangladesh (and in the United States, until recently), had a 59% higher risk of skin lesions compared with those with dose zero. Even a small dose of water arsenic equal to the current water arsenic concentration limit in the United States of 10 μg/L carried a 12% increase in risk compared with those with zero doses.
We found that riboflavin; pyridoxine; vitamins A, C, and E; and folic acid were significant strong modifiers of the effects of ingested arsenic. Our results suggest that consumption of a diet rich in these vitamins and anti-oxidants can significantly reduce the harmful effects of water arsenic on the development of skin lesions. Those in the highest percentile of consumption had a significant reduction in risks, ranging from 46% (ERR decreased from 2.4 to 1.3) for pyridoxine to 68% (ERR decreased from 3.4 to 1.1) for vitamin C, at a given level of arsenic exposure ().
It is noteworthy that in our population, the consumption of riboflavin, pyridoxine, and vitamin A were significantly lower than the RDA values for India (Gopalan et al. 1996
) (data not shown). For example, the recommended daily amount for both males and females for pyridoxine is 2 mg, but our cohort members consumed, on average, 0.66 and 0.61 mg/day (males and females, respectively). Vitamin consumption was better for folic acid and vitamin C. In our study, the potential protective modifying effects of these vitamins were restricted within the medium and upper quartiles of consumption. Thus, it appears that beneficial effects of riboflavin; pyridoxine; vitamins A, C, and E; and folic acid are associated with consumption of amounts greater than the current recommended daily amounts for the population.
Among the major strengths of the present study are use of individual-level, time-weighted water arsenic measures, micronutrient measure from a validated instrument, and the large size of the study population. Caution should be exercised while interpreting these findings, as they are based on numerous comparisons and could be due to chance. In addition, our analyses are based on the prevalent skin lesions. We are continuing follow-up of the cohort and will analyze the data on the incident skin lesion identified during the first and second two-yearly follow-up visits. The use of FFQ introduced inevitable measurement errors. If present, this measurement error would attenuate the association (bias it toward the null effect). Future studies with biochemical measures of nutrient intakes, especially for vitamins A, C, and E, are needed to further evaluate the effects of these nutrients.
The evidence on the health effects of arsenic from food is limited. Although several studies have documented arsenic contents in rice collected in arsenic-affected areas (Misbahuddin 2003
; Roychowdhury et al. 2003
), the bioavailability of arsenic from rice and other food items is not known. The findings of the present study would not be affected by the potential role of arsenic in rice, as rice is not the main source of the nutrients found to have a modifying effect. If arsenic in rice indeed has an effect on skin lesions, the measurement error in total arsenic exposure may lead to a bias toward the null for the observed dose–response relationship. Furthermore, arsenic in food is considered to be present largely in organic forms, and the content depends on the arsenic concentration in the soil as well as in the water used for washing, cooking, and irrigation (Roychowdhury et al. 2003
). Future studies are needed to consider the potential role of arsenic in food items. Finally, many participants drank water from the same well (59.2% of study participants drank from a well with ≥ 3 subjects/well, 31.9% from a well with two study subjects/well, and the remaining 8.9% of subjects from individual wells), making well water arsenic concentration a shared characteristic. These correlated errors arising from shared wells would affect the width of the CIs, but should not affect the magnitudes or directions of the point estimates.
Methylation of arsenic, a hypothesized detoxification pathway, requires the conversion of S
-adenosylmethionine to S
-adenosylhomocysteine and depends partly on the one-carbon metabolism in which riboflavin, pyridoxine, cobalamin, and folic acid all play a role (Selhub 2002
). Previous studies have shown that intake of vitamins influences the efficiency of arsenic methylation (McCarty et al. 2006
; Steinmaus et al. 2005
). Our findings that riboflavin, pyridoxine, and folic acid modified the risk of skin lesions are consistent with the hypothesis that individuals with insufficient intakes of nutrients related to arsenic metabolism are more susceptible to the health effect of arsenic exposure. These findings further suggest that riboflavin, pyridoxine, and folic acid may play a more important role in modifying arsenic toxicity.
Although folic acid is readily available in many food items, its deficiency is not uncommon, primarily because naturally occurring folates are highly susceptible to oxidative degradation, for example, during cooking (Gamble et al. 2005b
). We reported previously that there is a high prevalence of folate deficiency and hyperhomocysteinemia in Araihazar, Bangladesh (Gamble et al. 2005a
) and that these conditions are associated with reduced arsenic methylation (Gamble et al. 2005b
Intracellular antioxidants such as vitamins A, C, and E decrease arsenic toxicity by reversing disturbances in lipid peroxidation, generation of nitric oxide, reactive oxygen species, and apoptosis initiated by arsenic metabolites (Chattopadhyay et al. 2002
; National Research Council 1999
). β-Carotene may also scavenge free-radical species (Krinsky 1989
). Previous studies have shown that low serum levels of carotene modified the effect of arsenic exposure on the risk of ischemic heart disease (Hsueh et al. 1998
). Several studies have found that prevalence of vitamin A deficiency is high in Bangladesh (Ahmed 1999
), possibly explaining the important modifying effect of vitamin A observed in this study. Given that vitamin A consumption in the Bangladeshi diet is mostly from plant sources, the correlation between beta carotene intake and vitamin A in our study was nearly perfect (r
= 0.99), explaining the similarity of modifying effects of vitamin A and beta carotene on arsenic-related skin lesions.
Overall malnutrition, defined as either a general calorie deficit or a diet adequate in calories but nutritionally poor, is an important cofactor in arsenic poisoning affecting the timing and the intensity of arsenic-related problems. Guha Mazumder et al. (1998)
showed that subjects with lower BMIs had higher prevalence of arsenic skin lesions compared with subjects with similar arsenic exposures but higher BMIs. Similarly, in our previous analysis of this cohort, we showed that study subjects with lower BMIs were at increased risk of skin lesions (Ahsan et al. 2006b
). Current analysis indicates that BMI has an independent effect on the development of skin lesions, and thus, subjects with lower consumption of vitamins and antioxidants had higher risk of skin lesions, indicating significant effects of individual nutrients beyond what can be explained by general calorie intake.
Findings on the modifying effect of sunlight exposure on arsenic-related skin lesions have been described elsewhere (Chen et al. 2006
). Because women in Bangladesh universally wear traditional dresses that almost completely cover the skin of their trunk, sunlight exposure of female respondents was considered minimal and therefore was not assessed in the study. In men, we observed an additive effect of higher arsenic exposure and excessive sunlight exposure, such that the risk of skin lesions associated with any given level of arsenic exposure was greater in males with excessive sun exposure. In the present analysis, we empirically assessed whether sunlight exposure is a potential confounder. Adjustment for sunlight exposure did not change the effect estimate and therefore we did not include it in the model.