Testing the Limit: Evaluating Drinking Water Arsenic Regulatory Levels Based on Adverse Pregnancy Outcomes in Bangladesh.

(1) Background: Arsenic (As) is a common drinking water contaminant that is regulated as a carcinogen. Yet, As is a systemic toxicant and there is considerable epidemiological data showing As adversely impacts reproductive health. This study used data from a birth cohort in Bangladesh (2008−2011) to examine associations between drinking water As levels and reproductive outcomes. (2) Methods: Pregnant individuals (n = 1597) were enrolled at <16 weeks gestation and drinking water As was measured. Participants with live births (n = 1130) were propensity score matched to participants who experienced miscarriage (n = 132), stillbirth (n = 72), preterm birth (n = 243), and neonatal mortality (n = 20). Logistic regression was used to examine drinking water As recommendations of 50, 10, 5, 2.5, and 1 µg/L on the odds of adverse birth outcomes. (3) Results: The odds of miscarriage were higher for pregnant women exposed to drinking water ≥2.5 versus <2.5 µg As/L [adjusted odds ratio (OR) 1.90, 95% Confidence Interval (CI): 1.07−3.38)]. (4) Conclusions: These preliminary findings suggest a potential threshold where the odds of miscarriage increases when drinking water As is above 2.5 µg/L. This concentration is below the World Health Organizations and Bangladesh's drinking water recommendations and supports the re-evaluation of drinking water regulations.

A case-control analysis of maternal diet and risk of neural tube defects in Bangladesh.

OBJECTIVES: Mothers need a nutrient-rich diet for healthy neural tube development. Neural tube defect risk can be reduced through fortifying grain products with folic acid and taking folic acid supplements. Fortification is not required in Bangladesh. Maternal supplement use rates are low, similar to other countries. This study evaluates maternal dietary intake during pregnancy to identify possible interventions. METHODS: A food frequency questionnaire (FFQ) assessed maternal diet. The primary aim compared dietary intake (calories, fat, carbohydrate, protein, fiber, vitamins, and minerals) between mothers of infants with myelomeningocele (cases) and mothers of controls. Secondary aims included (i) comparing foods consumed and (ii) evaluating if rice intake correlated with arsenic exposure. Paired t-tests, Wilcoxon signed rank tests, McNemar's chi-squared test, and linear regression were used. RESULTS: This study included 110 matched mother-infant pairs (55 cases/55 controls). Mothers of cases and mothers of controls had similar caloric intake [median 2406 kcal/day vs. 2196 kcal/day (p = 0.071)]. Mothers in both groups consumed less than half the daily recommended 600 µg of folate. Diets were potentially deficient in vitamins A, D, E, potassium, sodium, and iron. Steamed rice was the primary food consumed for both groups, and this rice intake was not associated with toenail arsenic. CONCLUSIONS: Dietary interventions should increase folate, vitamins A, D, E, potassium, sodium, and iron intake in Bangladeshi mothers. Folic acid fortification of grain products maybe the only viable strategy to achieve adequate folate intake for mothers. Given the central role of rice to the Bangladeshi diet, fortifying rice may be a viable option.

Regulation of gasdermin D by miR-379-5p is involved in arsenite-induced activation of hepatic stellate cells and in fibrosis via secretion of IL-1ß from human hepatic cells.

Arsenic is an environmental toxicant and human carcinogen. The liver is the main site of arsenic storage and metabolism. Exposure to excessive arsenic causes liver damage and release of pro-inflammatory factors, which in turn lead to liver fibrosis. Gasdermin D (GSDMD), a mediator of pyroptosis, has low expression in hepatic tumor cells. In L-02 cells, arsenite caused increases of GSDMD and cleaved caspase-1 levels and decreases of caspase-1 and miR-379-5p levels. It also promoted the release of IL-1ß in a concentration- and time-dependent manner. Luciferase reporter assays showed that GSDMD was a direct target of miR-379-5p. In L-02 cells, the over-expression of miR-379-5p blocked the arsenite-induced increases of GSDMD levels and the release of IL-1ß, effects that were reversed by up-regulation of GSDMD. LX-2 cells, cultured in the media from arsenite-treated L-02 cells, showed elevated levels of proliferating cell nuclear antigen (PCNA), collagen I, vimentin, and α-smooth muscle actin (α-SMA), which indicated activation of these cells. Activation of LX-2 cells by media from arsenite-treated L-02 cells was inhibited by IL-1ß neutralizing antibody. The media from arsenite-treated L-02 cells transfected with an miR-379-5p mimic inhibited the activation of LX-2 cells, a process that was reversed by up-regulation of GSDMD and by co-treatment with human recombinant IL-1ß. Chronic exposure to arsenite induced, in liver tissue of mice, morphological damage, collagen deposition, and activation of hepatic stellate cells (HSCs). In liver tissue of arsenite-exposed mice, the levels of miR-379-5p were lower, but the levels of GSDMD and cleaved caspase-1 were elevated, and in sera from arsenite-exposed mice, the IL-1ß levels were elevated. These results indicate that, by elevating the secretion of IL-1ß, miR-379-5p regulation of GSDMD is involved in arsenite-induced activation of HSCs and in hepatic fibrosis. This establishes a previously unknown molecular mechanism for arsenite-induced liver damage, inflammation, and fibrosis.

A cross sectional study of anemia and iron deficiency as risk factors for arsenic-induced skin lesions in Bangladeshi women.

BACKGROUND: In the Ganges Delta, chronic arsenic poisoning is a health concern affecting millions of people who rely on groundwater as their potable water source. The prevalence of anemia is also high in this region, particularly among women. Moreover, arsenic is known to affect heme synthesis and erythrocytes and the risk of arsenic-induced skin lesions appears to differ by sex. METHODS: We conducted a case-control study in 147 arsenic-exposed Bangladeshi women to assess the association between anemia and arsenic-induced skin lesions. RESULTS: We observed that the odds of arsenic-related skin lesions were approximately three times higher among women who were anemic (hemoglobin < 120 g/L) compared to women with normal hemoglobin levels [Odds Ratio (OR) = 3.32, 95% Confidence Intervals (CI): 1.29, 8.52] after adjusting for arsenic levels in drinking water and other covariates. Furthermore, 75% of the women with anemia had adequate iron stores (serum ferritin ≥ 12 µg/L), suggesting that the majority of anemia detected in this population was unrelated to iron depletion. CONCLUSIONS: Considering the magnitude of arsenic exposure and prevalence of anemia in Bangladeshi women, additional research is warranted that identifies the causes of anemia so that effective interventions can be implemented while arsenic remediation efforts continue.

A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism, and skin cancer genes might influence susceptibility to arsenic-induced skin lesions. METHODS: A case-control study was conducted in Pabna, Bangladesh (2001-2003), and the drinking-water arsenic concentration was measured for each participant. A panel of 25 candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in the skin lesion risk, with adjustments for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls. RESULTS: In the discovery population, genetic variants in the one-carbon metabolism genes phosphatidylethanolamine N-methyltransferase (rs2278952, P for interaction = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene interleukin 10 (rs3024496, P for interaction =.04), and the skin cancer genes inositol polyphosphate-5-phosphatase (INPP5A; rs1133400, P for interaction = .03) and xeroderma pigmentosum complementation group C (rs2228000, P for interaction = .01) significantly modified the association between arsenic and skin lesions after adjustments for multiple comparisons. The significant gene-environment interaction between a SNP in the INPP5A gene (rs1133400) and water arsenic with respect to the skin lesion risk was successfully replicated in an independent population (P for interaction = .03). CONCLUSIONS: Minor allele carriers of the skin cancer gene INPP5A modified the odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity.

A prospective cohort study of the association between drinking water arsenic exposure and self-reported maternal health symptoms during pregnancy in Bangladesh.

BACKGROUND: Arsenic, a common groundwater pollutant, is associated with adverse reproductive health but few studies have examined its effect on maternal health. METHODS: A prospective cohort was recruited in Bangladesh from 2008-2011 (N = 1,458). At enrollment (<16 weeks gestational age [WGA]), arsenic was measured in personal drinking water using inductively-coupled plasma mass spectrometry. Questionnaires collected health data at enrollment, at 28 WGA, and within one month of delivery. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) for self-reported health symptoms were estimated for each arsenic quartile using logistic regression. RESULTS: Overall, the mean concentration of arsenic was 38 µg/L (Standard deviation, 92.7 µg/L). A total of 795 women reported one or more of the following symptoms during pregnancy (cold/flu/infection, nausea/vomiting, abdominal cramping, headache, vaginal bleeding, or swollen ankles). Compared to participants exposed to the lowest quartile of arsenic (≤0.9 µg/L), the aOR for reporting any symptom during pregnancy was 0.62 (95% CI = 0.44-0.88) in the second quartile, 1.83 (95% CI = 1.25-2.69) in the third quartile, and 2.11 (95% CI = 1.42-3.13) in the fourth quartile where the mean arsenic concentration in each quartile was 1.5 µg/L, 12.0 µg/L and 144.7 µg/L, respectively. Upon examining individual symptoms, only nausea/vomiting and abdominal cramping showed consistent associations with arsenic exposure. The odds of self-reported nausea/vomiting was 0.98 (95% CI: 0.68, 1.41), 1.52 (95% CI: 1.05, 2.18), and 1.81 (95% CI: 1.26, 2.60) in the second, third and fourth quartile of arsenic relative to the lowest quartile after adjusting for age, body mass index, second-hand tobacco smoke exposure, educational status, parity, anemia, ferritin, medication usage, type of sanitation at home, and household income. A positive trend was also observed for abdominal cramping (P for trend <0.0001). A marginal negative association was observed between arsenic quartiles and odds of self-reported cold/flu/infection (P for trend = 0.08). No association was observed between arsenic and self-reported headache (P for trend = 0.19). CONCLUSION: Moderate exposure to arsenic contaminated drinking water early in pregnancy was associated with increased odds of experiencing nausea/vomiting and abdominal cramping. Preventing exposure to arsenic contaminated drinking water during pregnancy could improve maternal health.

Epigenome-wide DNA methylation changes with development of arsenic-induced skin lesions in Bangladesh: a case-control follow-up study.

Studies have found an association between aberrant DNA methylation and arsenic-induced skin lesions. However, little is known about DNA methylation changes over time in people who develop arsenic-induced skin lesions. We sought to investigate epigenome-wide changes of DNA methylation in people who developed arsenic-induced skin lesions in a 10-year period. In 2009-2011, we conducted a follow-up study of 900 skin lesion cases and 900 controls and identified 10 people who developed skin lesions since a baseline survey in 2001-2003. The 10 cases ("New Cases") were matched with 10 controls who did not have skin lesions at baseline or follow-up ("Persistent Controls"). Drinking water and blood samples were collected, and skin lesion was diagnosed by the same physician at both time points. We measured DNA methylation in blood using Infinium HumanMethylation450K BeadChip, followed by quantitative validation using pyrosequencing. Two-sample t-tests were used to compare changes in percent methylation between New Cases and Persistent Controls. Six CpG (cytosine-phosphate-guanine) sites with greatest changes of DNA methylation over time among New Cases were further validated with a correlation of 93% using pyrosequencing. One of the validated CpG site (cg03333116; change of %methylation was 13.2 in New Cases versus -0.09 in Persistent Controls; P < 0.001) belonged to the RHBDF1 gene, which was previously reported to be hypermethylated in arsenic-exposed cases. We examined DNA methylation changes with the development of arsenic-induced skin lesions over time but nothing was statistically significant given the small sample size of this exploratory study and the high dimensionality of data.

Association of low to moderate levels of arsenic exposure with risk of type 2 diabetes in Bangladesh.

Chronic exposure to high levels of arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM), but the association between lower levels of arsenic and T2DM is more controversial. Therefore, this study evaluated the association between low to moderate arsenic exposure and T2DM. In 2009-2011, we conducted a study of 957 Bangladeshi adults who participated in a case-control study of skin lesions in 2001-2003. The odds ratio of T2DM was evaluated in relationship to arsenic exposure measured in drinking water and in subjects' toenails (in 2001-2003) prior to the diagnosis of T2DM (in 2009-2011). Compared with those exposed to the lowest quartile of arsenic in water (≤ 1.7 µg/L), the adjusted odds ratio for T2DM was 1.92 (95% confidence interval (CI): 0.82, 4.35) for those in the second quartile, 3.07 (95% CI: 1.38, 6.85) for those in the third quartile, and 4.51 (95% CI: 2.01, 10.09) for those in the fourth quartile. The relative excess risk of T2DM was 4.78 for individuals who smoked and 8.93 for people who had a body mass index (weight (kg)/height (m)(2)) greater than 25. These findings suggest that exposure to modest levels of arsenic in drinking water was associated with increased risk of T2DM in Bangladesh. Being overweight or smoking was also associated with increased risk of T2DM.

Prenatal arsenic exposure and DNA methylation in maternal and umbilical cord blood leukocytes.

BACKGROUND: Arsenic is an epigenetic toxicant and could influence fetal developmental programming. OBJECTIVES: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes. METHODS: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure. RESULTS: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 µg/L (range: < 1-230 µg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation. CONCLUSIONS: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.

A pathway-based analysis of urinary arsenic metabolites and skin lesions.

Inorganic arsenic is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Limited evidence suggests that the ability to fully metabolize arsenic into DMA influences susceptibility to disease. To determine whether percentage of MMA was predictive of disease, the authors used data from a case-control study conducted in Bangladesh (2001-2003). Persons who were diagnosed with keratosis, melanosis, Bowen's disease, or squamous cell carcinoma were matched on age, sex, and village to persons without these conditions. This analysis was restricted to persons who had no missing data on covariates (859 cases, 868 controls). A path analysis was used to evaluate simultaneously the association between the percentage of all urinary arsenic metabolites and the odds of skin lesions using PROC CALIS in SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina) and Mplus, version 6.1 (Muthén & Muthén, Los Angeles, California). The odds of skin lesions were significantly associated with log(10) percentage of MMA (adjusted odds ratio (OR(adj)) = 1.56, 95% confidence interval (CI): 1.15, 2.12) but not log(10) percentage of inorganic arsenic (OR(adj) = 1.06, 95% CI: 0.75, 1.50) or log(10) percentage of DMA (OR(adj) = 1.07, 95% CI: 0.33, 3.46). This novel analysis confirmed that persons who excrete a higher proportion of MMA have a greater risk of skin lesions after data are adequately controlled for urinary arsenic metabolites, current arsenic exposure, and other risk factors.

Variability in biomarkers of arsenic exposure and metabolism in adults over time.

BACKGROUND: Urinary arsenic metabolites (UAs) are used as biomarkers of exposure and metabolism. OBJECTIVES: To characterize inter- and intraindividual variability in UAs in healthy individuals. METHODS: In a longitudinal study conducted in Bangladesh, we collected water and spot urine samples from 196 participants every 3 months for 2 years. Water arsenic (As) was measured by inductively coupled plasma-mass spectrometry and urinary As [arsenite, arsenate, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)] were detected using high-performance liquid chromatography-hydride-generated atomic absorption spectrometry. We used linear mixed-effects models to compute variance components and evaluate the association between UAs and selected factors. RESULTS: The concentrations of UAs were fairly reproducible within individuals, with intraclass correlation coefficients (ICCs) of 0.41, 0.35, 0.47, and 0.49 for inorganic As (InAs), MMA, DMA, and total urinary As (TUA). However, when expressed as a ratio, the percent InAs (%InAs), %MMA, and %DMA were poorly reproducible within individuals, with ICCs of 0.16, 0.16, and 0.17, respectively. Arsenic metabolism was significantly associated with sex, exposure, age, smoking, chewing betel nut, urinary creatinine, and season. Specificity and sensitivity analyses showed that a single urine sample adequately classified a participant's urinary As profile as high or low, but TUA had only moderate specificity for correctly classifying drinking water exposures. CONCLUSIONS: Epidemiologic studies should use both urinary As concentrations and the relative proportion of UAs to minimize measurement error and to facilitate interpretation of factors that influence As metabolism.

GSTM1 and APE1 genotypes affect arsenic-induced oxidative stress: a repeated measures study.

BACKGROUND: Chronic arsenic exposure is associated with an increased risk of skin, bladder and lung cancers. Generation of oxidative stress may contribute to arsenic carcinogenesis. METHODS: To investigate the association between arsenic exposure and oxidative stress, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) was evaluated in a cohort of 97 women recruited from an arsenic-endemic region of Bangladesh in 2003. Arsenic exposure was measured in urine, toenails, and drinking water. Drinking water and urine samples were collected on three consecutive days. Susceptibility to oxidative stress was evaluated by genotyping relevant polymorphisms in glutathione-s transferase mu (GSTM1), human 8-oxoguanine glycosylase (hOGG1) and apurinic/apyrimidinic endonuclease (APE1) genes using the Taqman method. Data were analyzed using random effects Tobit regression to account for repeated measures and 8-OHdG values below the detection limit. RESULTS: A consistent negative effect for APE1 was observed across water, toenail and urinary arsenic models. APE1 148 glu/glu + asp/glu genotype was associated with a decrease in logged 8-OHdG of 0.40 (95%CI -0.73, -0.07) compared to APE1 148 asp/asp. An association between total urinary arsenic and 8-OHdG was observed among women with the GSTM1 null genotype but not in women with GSTM1 positive. Among women with GSTM1 null, a comparison of the second, third, and fourth quartiles of total urinary arsenic to the first quartile resulted in a 0.84 increase (95% CI 0.27, 1.42), a 0.98 increase (95% CI 033, 1.66) and a 0.85 increase (95% CI 0.27, 1.44) in logged 8-OHdG, respectively. No effects between 8-OHdG and toenail arsenic or drinking water arsenic were observed. CONCLUSION: These results suggest the APE1 variant genotype decreases repair of 8-OHdG and that arsenic exposure is associated with oxidative stress in women who lack a functional GSTM1 detoxification enzyme.

Susceptibility to arsenic-induced skin lesions from polymorphisms in base excision repair genes.

Genetic polymorphisms in the base excision DNA repair pathway may influence individual susceptibility to arsenic and the development of arsenic-induced skin lesions. Data from a case-control study of 792 cases and 792 matched controls conducted in Bangladesh from 2001 to 2003 were analyzed using conditional logistic regression to assess the associations between four common base excision repair (BER) genetic polymorphisms X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, XRCC1 Arg194Trp, human 8-oxoguanine DNA glycosylase (hOGG1) Ser326Cys and apurinic/apyrimidinic endonuclease (APE1) Asp148Glu and arsenic-induced skin lesions including melanosis and keratosis. Adjusted for toenail arsenic, body mass index, education, smoking and betel nut use, individuals with the APE1 148Glu/Glu polymorphism had a 2-fold increased odds of skin lesions compared with individuals with the 148Asp/Asp genotype (1.93; 95% confidence interval 1.15, 3.19). Gene-environment interactions between toenail arsenic and XRCC1 Arg194Trp and APE1 Asp148Glu were observed. Within the lowest arsenic tertile, APE1 148Glu/Glu had 2.5 times the odds ratio compared with wild-type, whereas within the highest tertile of arsenic the odds ratios for skin lesions did not differ. In contrast, at low arsenic levels, the odds ratios for skin lesions did not differ much by XRCC1 Arg194Trp genotype. However, at the highest tertile of arsenic, the XRCC1 194Arg/Arg polymorphism conferred a 3-fold larger odds ratio for skin lesions compared with XRCC1 194Trp/Trp. Individuals may have different odds for developing skin lesions based in part on their genetic profile for BER and their arsenic exposure history. Future research on arsenic-induced skin lesions should consider the impact of genetic variation to individual susceptibility to arsenic toxicity.

A case-control study of GST polymorphisms and arsenic related skin lesions.

BACKGROUND: Polymorphisms in GSTT1, GSTM1 and GSTP1 impact detoxification of carcinogens by GSTs and have been reported to increase susceptibility to environmentally related health outcomes. Individual factors in arsenic biotransformation may influence disease susceptibility. GST activity is involved in the metabolism of endogenous and exogenous compounds, including catalyzing the formation of arsenic-GSH conjugates. METHODS: We investigated whether polymorphisms in GSTT1, GSTP1 and GSTM1 were associated with risk of skin lesions and whether these polymorphisms modify the relationship between drinking water arsenic exposure and skin lesions in a case control study of 1200 subjects frequency matched on age and gender in community clinics in Pabna, Bangladesh in 2001-2002. RESULTS AND DISCUSSION: GSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10-2.19). The GSTP1 GG polymorphism was associated with greater odds of skin lesions compared to GSTP1 AA, (OR 1.86 (95%CI 1.15-3.00). No evidence of effect modification by GSTT1, GSTM1 or GSTP1 polymorphisms on the association between arsenic exposure and skin lesions was detected. CONCLUSION: GSTT1 wildtype and GSTP1 GG are associated with increased risk of skin lesions.

Gender-specific protective effect of hemoglobin on arsenic-induced skin lesions.

Chronic arsenic poisoning remains a public health crisis in Bangladesh. As arsenic has been shown to bind to human hemoglobin (Hb), hematologic mechanisms may play a role in the pathway through which arsenic exerts its toxicity. Two separate studies, a case-control and a cohort, were conducted to investigate the role of Hb in the development of arsenic-induced skin lesions. In the first, conditional logistic regression was used to investigate the effect of Hb on skin lesions among 900 case-control pairs from Pabna, Bangladesh, in which individuals were matched on gender, age, and location. In the second, mixed linear regression models were used to examine the association between toenail arsenic, urinary arsenic, and Hb within a cohort of 184 individuals from 50 families in the same region who did not have arsenic-induced skin lesions. Hb was significantly associated with skin lesions but this association was gender specific. In males, a 40% reduction in the odds of skin lesions occurred for every 1 g/dL increase in Hb (odds ratio, 0.60; 95% confidence interval, 0.49-0.73). No effect was observed for females (odds ratio, 1.16; 95% confidence interval, 0.92-1.46). In the cohort of 184 individuals, no associations between toenail arsenic or urinary arsenic species and Hb levels were observed. Low Hb levels may exacerbate the detrimental health effects of chronic arsenic poisoning. Whereas providing clean water remains the optimal solution to Bangladesh's problem of arsenic poisoning, improving nutrition and reducing iron-deficiency anemia may ameliorate negative health effects, such as skin lesions in individuals who have been exposed.

The impact of diet and betel nut use on skin lesions associated with drinking-water arsenic in Pabna, Bangladesh.

An established exposure-response relationship exists between water arsenic levels and skin lesions. Results of previous studies with limited historical exposure data, and laboratory animal studies suggest that diet may modify arsenic metabolism and toxicity. In this study, we evaluated the effect of diet on the risk of arsenic-related skin lesions in Pabna, Bangladesh. Six hundred cases and 600 controls loosely matched on age and sex were enrolled at Dhaka Community Hospital, Bangladesh, in 2001-2002. Diet, demographic data, and water samples were collected. Water samples were analyzed for arsenic using inductively coupled plasma mass spectroscopy. Betel nut use was associated with a greater risk of skin lesions in a multivariate model [odds ratio (OR) = 1.67; 95% confidence interval (CI), 1.18-2.36]. Modest decreases in risk of skin lesions were associated with fruit intake 1-3 times/month (OR = 0.68; 95%CI, 0.51-0.89) and canned goods at least 1 time/month (OR = 0.41; 95% CI, 0.20-0.86). Bean intake at least 1 time/day (OR = 1.89; 95% CI, 1.11-3.22) was associated with increased odds of skin lesions. Betel nut use appears to be associated with increased risk of developing skin lesions in Bangladesh. Increased intake of fruit and canned goods may be associated with reduced risk of lesions. Increased intake of beans may be associated with an increased risk of skin lesions. The results of this study do not provide clear support for a protective effect of vegetable and overall protein consumption against the development of skin lesions, but a modest benefit cannot be excluded.

An eight-year study report on arsenic contamination in groundwater and health effects in Eruani village, Bangladesh and an approach for its mitigation.

Based on several surveys during 1997-2005 and visits of a medical team to Eruani village, Laksham upazila, Comilla district, Bangladesh, the arsenic contamination situation and consequent clinical manifestations of arsenicosis among the villagers, including dermatology, neuropathy, and obstetric outcome, are reported here. Analysis of biological samples from patients and non-patients showed high body burden of arsenic. Even after eight years of known exposure, village children were still drinking arsenic-contaminated water, and many of them had arsenical skin lesions. There were social problems due to the symptoms of arsenicosis. The last survey established that there is a lack of proper awareness among villagers about different aspects of arsenic toxicity. The viability of different options of safe water, such as dugwells, deep tubewells, rainwater harvesting, and surface water with watershed management in the village, was studied. Finally, based on 19 years of field experience, it was felt that, for any successful mitigation programme, emphasis should be given to creating awareness among villagers about the arsenic problem, role of arsenic-free water, better nutrition from local fruits and vegetables, and, above all, active participation of women along with others in the struggle against the arsenic menace.

Toenail arsenic concentrations, GSTT1 gene polymorphisms, and arsenic exposure from drinking water.

Toenail arsenic (As) concentrations were evaluated as a biomarker of inorganic As (As(in)) exposure in a population residing in an As-endemic region of Bangladesh. Drinking water and toenail samples were collected from 48 families (n = 223) every 3 months for 2 years and analyzed for As using inductively coupled plasma-mass spectrometry. Drinking water collected 3, 6, and 9 months before each toenail sample collection was combined into a weighted lagged exposure variable. The contribution of each water sample to the measured toenail As concentration was estimated using maximum likelihood that accounted for fluctuations in drinking water exposure and toenail growth. The best model attributed 69%, 14%, and 17% of the toenail As content to drinking water exposures that occurred 3, 6, and 9 months before toenail collection [95% confidence intervals (95% CI), 0.46-0.97, 0.00-0.31, and 0.03-0.35, respectively]. Generalized additive mixed models using penalized regression splines were employed to model the data. Below a drinking water concentration of 2 mug As/L, no relationship between drinking water As and toenail As concentrations was observed. Above this concentration, toenail As content increased in a dose-dependent fashion as drinking water As increased. Age was a significant effect modifier of drinking water As exposure on toenail As (beta = 0.01; 95% CI, 0.002-0.02). Individuals possessing GSTT1-null genotypes had significantly more As in their toenails in contrast to GSTT1 wild-type individuals (beta = 0.11; 95% CI, 0.06-0.2). Therefore, it seems that GSTT1 modifies the relationship between As(in) exposure and toenail As(in) content.