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.

Associations between residential proximity to oil and gas extraction and hypertensive conditions during pregnancy: a difference-in-differences analysis in Texas, 1996-2009.

BACKGROUND: Oil and gas extraction produces air pollutants that are associated with increased risks of hypertension. To date, no study has examined residential proximity to oil and gas extraction and hypertensive conditions during pregnancy. This study quantifies associations between residential proximity to oil and gas development on gestational hypertension and eclampsia. METHODS: We utilized a population-based retrospective birth cohort in Texas (1996-2009), where mothers reside <10 km from an active or future drilling site (n = 2 845 144.) Using full-address data, we linked each maternal residence at delivery to assign exposure and evaluate this exposure with respect to gestational hypertension and eclampsia. In a difference-in-differences framework, we model the interaction between maternal health before (unexposed) or after (exposed) the start of drilling activity (exposed) and residential proximity near (0-1, >1-2 or >2-3 km) or far (≥3-10 km) from an active or future drilling site. RESULTS: Among pregnant women residing 0-1 km from an active oil or gas extraction site, we estimate 5% increased odds of gestational hypertension [95% confidence interval (CI): 1.00, 1.10] and 26% increased odds of eclampsia (95% CI: 1.05, 1.51) in adjusted models. This association dissipates in the 1- to 3-km buffer zones. In restricted models, we find elevated odds ratios among maternal ages ≤35 years at delivery, maternal non-Hispanic White race, ≥30 lbs gained during pregnancy, nulliparous mothers and maternal educational attainment beyond high school. CONCLUSIONS: Living within 1 km of an oil or gas extraction site during pregnancy is associated with increased odds of hypertensive conditions during pregnancy.

Associations between Residential Proximity to Oil and Gas Drilling and Term Birth Weight and Small-for-Gestational-Age Infants in Texas: A Difference-in-Differences Analysis.

BACKGROUND: Oil and natural gas extraction may produce environmental pollution at levels that affect reproductive health of nearby populations. Available studies have primarily focused on unconventional gas drilling and have not accounted for local population changes that can coincide with drilling activity. OBJECTIVE: Our study sought to examine associations between residential proximity to oil and gas drilling and adverse term birth outcomes using a difference-in-differences study design. METHODS: We created a retrospective population-based term birth cohort in Texas between 1996 and 2009 composed of mother-infant dyads (n=2,598,025) living <10km from an oil or gas site. We implemented a difference-in-differences approach to estimate associations between drilling activities and infant health: term birth weight and term small for gestational age (SGA). Using linear and logistic regression, we modeled interactions between births before (unexposed) or during (exposed) drilling activity and residential proximity near (0-1, 1-2, or 2-3km) or far (3-10km) from an active or future drilling site, adjusting for individual- and neighborhood-level characteristics. RESULTS: The adjusted mean difference in term birth weight for mothers living 0-1 vs. 3-10km from a current or future drilling site was -7.3g [95% confidence interval (CI): -11.6, -3.0] for births during active vs. future drilling. The corresponding adjusted odds ratio for SGA was 1.02 (95% CI: 0.98, 1.06). Negative associations with term birth weight were observed for the 1-2 and 2-3km near groups, and no consistent differences were identified by type of drilling activity. Larger, though imprecise, adverse associations were found for infants born to Hispanic women, women with the lowest educational attainment, and women living in cities. CONCLUSIONS: Residing near oil and gas drilling sites during pregnancy was associated with a small reduction in term birth weight but not SGA, with some evidence of environmental injustices. Additional work is needed to investigate specific drilling-related exposures that might explain these associations. https://doi.org/10.1289/EHP7678.

Trends in urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) in the non-smoking U.S. population, NHANES 2001-2014.

BACKGROUND: Recent studies indicate airborne PAH levels have decreased in the U.S., but it is unclear if this has resulted in PAH exposure changes in the U.S. OBJECTIVE: Examine temporal trends in urinary metabolites of Naphthalene, Fluorene, Phenanthrene, and Pyrene in U.S. non-smokers, 6+ years old. METHODS: We used biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) program, 2001-2014, (N = 11,053) using survey weighted linear regression. Models were adjusted for age, sex, race/ethnicity, creatinine, BMI, income, diet, and seasonality. Stratified models evaluated the effect of age, sex, and race/ethnicity on trends. RESULTS: Between 2001 and 2014, Naphthalene exposure increased 36% (p < 0.01); Pyrene exposure increased 106% (p < 0.01); Fluorene and Phenanthrene exposure decreased 55% (p < 0.01), and 37% (p < 0.01), respectively. Naphthalene was the most abundant urinary PAH, 20-fold higher than Fluorene and Phenanthrene, and over 50-fold higher than Pyrene compared to reference groups, effect modification was observed by age (Naphthalene, Pyrene), sex (Fluorene, Pyrene), and race/ethnicity (Naphthalene, Fluorene, Phenanthrene, Pyrene). SIGNIFICANCE: This study shows exposure to Naphthalene and Pyrene increased, while exposure to Fluorene and Phenanthrene decreased among the non-smoking U.S. general population between 2001 and 2014, suggesting environmental sources of PAHs have changed over the time period.

Arsenic Drinking Water Violations Decreased across the United States Following Revision of the Maximum Contaminant Level.

Arsenic poses a threat to public health due to widespread environmental prevalence and known carcinogenic effects. In 2001, the US EPA published the Final Arsenic Rule (FAR) for public drinking water, reducing the maximum contaminant level (MCL) from 50 to 10 µg/L. We investigated impacts of the FAR on drinking water violations temporally and geographically using the Safe Drinking Water Information System. Violations exceeding the MCL and the population served by violating systems were analyzed across the conterminous US from 2006 (onset of FAR enforcement) to 2017. The percentage of public water system violations declined from 1.3% in 2008 to 0.55% in 2017 (p < 0.001, slope = -0.070), and the population served decreased by over 1 million (p < 0.001, slope = -106 886). Geographical analysis demonstrated higher mean violations and populations served in certain counties rather than evenly distributed across states. The decline in violations is likely due to the adoption of documented and undocumented treatment methods and possibly from reduced environmental releases. Considering other studies that have shown decreased urinary arsenic levels in the population served by public water systems since the new standard, it may be inferred that the FAR is facilitating the reduction of arsenic exposure in the US.

Development and Validation of an Environmental Health Literacy Assessment Screening Tool for Domestic Well Owners: The Water Environmental Literacy Level Scale (WELLS).

In the U.S., privately owned wells are not subject to any regulatory testing requirements. Well owners must have sufficient environmental health literacy (EHL) to understand and interpret information that contain complex terms and labels to manage their water quality. The objective of this paper is to assess the performance and validity of a new EHL screening tool. The Water Environmental Literacy Level Scale (WELLS) is based on the Newest Vital Sign (NVS) and contains six questions on comprehension, calculations and application of information. Content validity was assessed from expert review. Criterion-related and construct validity were evaluated using an online, convenience sample of adults (n = 869). Percent of correct responses for items ranged from 53% to 96% for NVS and from 41% to 97% for WELLS. Completion time, mean scores, distributions, and internal consistency were equivalent between both scales. Higher scores suggest higher EHL. The scales were moderately correlated (ρ = 0.47, p < 0.001). Kappa agreement was 74%. Bland-Altman plots depicted little mean difference between the scales. Education and income level were positively associated with EHL. WELLS showed criterion-validity with NVS and construct validity with education and income. In practice or research, WELLS could quickly screen individuals for low EHL.

Mediating role of arsenic in the relationship between diet and pregnancy outcomes: prospective birth cohort in Bangladesh.

BACKGROUND: Epidemiological evidence suggests that arsenic (As) exposure during pregnancy may reduce infant birth weight. One significant source of As exposure is diet; thus, As may indirectly affect infant growth by mediating the effect of maternal diet on birth weight (BW). This study evaluated the potential mediating effect of As in the relationship between maternal diet and BW, gestational age (GA), and gestational weight gain (GWG). METHOD: The study used a prospective birth cohort in Bangladesh that captured the dietary habits of 1057 pregnant women through validated semi-quantitative food frequency questionnaires. We applied a causal mediation model with counterfactual approach and performed analyses with and without adjustment for total energy intake. Other potential confounders captured by self-report questionnaire were exposure to secondhand tobacco smoke, betel nut chewing, maternal age, education level, household income level, physical activity level during pregnancy, and daily hours spent cooking over open fire. RESULT: No association was found between maternal toenail As and BW. Higher absolute and energy-adjusted protein, fat and fiber intakes were associated with higher toenail As and lower GA and GWG, while higher absolute and energy-adjusted carbohydrate intake was associated with lower toenail As and greater GA and GWG. Mediation analysis showed significant natural indirect effects by toenail As in the relationships between absolute fat, carbohydrate and fiber intake with GA. Specifically, 3% (95% CI: 1-6%) of the association between carbohydrate intake and GA was mediated by change in toenail As, 6% (95% CI: 1-9%) for absolute fat intake and 10% (95% CI: 4-13%) for absolute fiber intake. After adjusting for total energy, no significant mediating effect was observed, suggesting the mediating effect might be due to measurement error or that absolute amount of As exposure rather than the amount in relationship to total energy intake was a more important factor to consider when understanding the negative implication of As on fetal growth. CONCLUSION: The mediating effect of As in the relationship between maternal diet and birth outcome was small and might be due to measurement error.

A Case Study Describing a Community-Engaged Approach for Evaluating Polycyclic Aromatic Hydrocarbon Exposure in a Native American Community.

In 2015, the Swinomish Indian Tribal Community (SITC) was impacted by an air toxic release from one of two nearby oil refineries. This experience motivated SITC members to learn more about their exposure to air toxics. On the invitation of SITC, this community-based study measured personal exposure to polycyclic aromatic hydrocarbons (PAHs) and conducted interviews with the volunteers to evaluate perceptions of the data and experience of participating. Non-smoking SITC members were recruited in March 2016 (N = 10) and January 2017 (N = 22) with seven volunteers participating both times. Volunteers wore a wristband passive sampler for 7 days and completed daily activity diaries. Wristbands were analyzed for 62 PAHs using gas chromatography mass spectrometry. Wilcoxon exact tests determined if the sum total PAHs (ΣPAH) differed by activity, proximity to the refineries, and time. Aggregated results were shared during community meetings, and volunteers received individual reports. Volunteers (N = 9) participated in individual interviews. All volunteers were exposed to different amounts and types of PAHs. Burning candles or using a wood stove and/or propane heating were associated with higher ΣPAH exposures. While ΣPAH was similar in both sampling periods, the composition of PAHs differed. More priority listed PAHs were detected in January (N = 17) versus March (N = 10). Among volunteers who participated in both sampling events, exposure to four PAHs significantly differed between seasons. Overall, volunteers reported that the study made them more aware of air pollution sources in their community. They also commented that the chemical nomenclature was difficult to understand, but appreciated the individual reports that allowed them to visually compare their data to the distribution of data collected in their community. For volunteers with lower exposures, these comparisons gave them relief. However, volunteers with higher exposures reported concern and several changed their behaviors to reduce their exposure to known PAH sources. This study provided an opportunity for SITC members to learn about their personal exposure to a class of air toxics within the context of their community. While the limitations of the study hindered the ability to identify sources of air toxics in the community, this activity appeared to raise awareness about ambient and indoor air pollution among the volunteers.

Trends in urinary arsenic among the U.S. population by drinking water source: Results from the National Health and Nutritional Examinations Survey 2003-2014.

BACKGROUND: In 2001, the United States revised the arsenic maximum contaminant level for public drinking water systems from 50µg/L to 10µg/L. This study aimed to examine temporal trends in urinary arsenic concentrations in the U.S. population from 2003 to 2014 by drinking water source among individuals aged 12 years and older who had no detectable arsenobetaine - a biomarker of arsenic exposure from seafood intake. METHODS: We examined data from 6 consecutive cycles of the National Health and Nutrition Examination Survey (2003-2014; N=5848). Total urinary arsenic (TUA) was calculated by subtracting arsenobetaine's limit of detection and detectable arsenocholine from total arsenic. Additional sensitivity analyses were conducted using a second total urinary arsenic index (TUA2, calculated by adding arsenite, arsenate, monomethylarsonic acid, dimethylarsinic acid). We classified drinking water source using 24-h dietary questionnaire data as community supply (n=3427), well or rain cistern (n=506), and did not drink tap water (n=1060). RESULTS: Geometric means (GM) of survey cycles were calculated from multivariate regression models adjusting for age, gender, race/ethnicity, BMI, income, creatinine, water source, type of water consumed, recent smoking, and consumption of seafood, rice, poultry, and juice. Compared to 2003-2004, adjusted TUA was 35.5% lower in 2013-2014 among the general U.S. POPULATION: Stratified analysis by smoking status indicated that the trend in lower TUA was only consistent among non-smokers. Compared to 2003-2004, lower adjusted TUA was observed in 2013-2014 among non-smoking participants who used community water supplies (1.98 vs 1.16µg/L, p<0.001), well or rain cistern users (1.54 vs 1.28µg/L, p<0.001) and who did not drink tap water (2.24 vs 1.53µg/L, p<0.001). Sensitivity analyses showed consistent results for participants who used a community water supplier and to a lesser extent those who did not drink tap water. However, the sensitivity analysis showed overall exposure stayed the same or was higher among well or rain cistern users. Finally, the greatest decrease in TUA was among participants within the highest exposure percentiles (e.g. 95th percentile had 34% lower TUA in 2013/2014 vs 2003/2004, p<0.001). CONCLUSIONS: Overall, urinary arsenic levels in the U.S. population declined over a 12-year period that encompassed the adoption of the revised Arsenic Rule. The most consistent trends in declining exposure were observed among non-smoking individuals using public community water systems. These results suggest regulation and prevention strategies to reduce arsenic exposures in the U.S. may be succeeding.

Reference-free deconvolution of DNA methylation data and mediation by cell composition effects.

BACKGROUND: Recent interest in reference-free deconvolution of DNA methylation data has led to several supervised methods, but these methods do not easily permit the interpretation of underlying cell types. RESULTS: We propose a simple method for reference-free deconvolution that provides both proportions of putative cell types defined by their underlying methylomes, the number of these constituent cell types, as well as a method for evaluating the extent to which the underlying methylomes reflect specific types of cells. We demonstrate these methods in an analysis of 23 Infinium data sets from 13 distinct data collection efforts; these empirical evaluations show that our algorithm can reasonably estimate the number of constituent types, return cell proportion estimates that demonstrate anticipated associations with underlying phenotypic data; and methylomes that reflect the underlying biology of constituent cell types. CONCLUSIONS: Our methodology permits an explicit quantitation of the mediation of phenotypic associations with DNA methylation by cell composition effects. Although more work is needed to investigate functional information related to estimated methylomes, our proposed method provides a novel and useful foundation for conducting DNA methylation studies on heterogeneous tissues lacking reference data.

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 cross sectional analysis of behaviors related to operating gas stoves and pneumonia in U.S. children under the age of 5.

BACKGROUND: Poorly ventilated combustion stoves and pollutants emitted from combustion stoves increase the risk of acute lower respiratory illnesses (ALRI) in children living in developing countries but few studies have examined these issues in developed countries. Our objective is to investigate behaviors related to gas stove use, namely using them for heat and without ventilation, on the odds of pneumonia and cough in U.S. children. METHODS: The National Health and Nutrition Examination Survey (1988-1994) was used to identify children < 5 years who lived in homes with a gas stove and whose parents provided information on their behaviors when operating their gas stoves and data on pneumonia (N = 3,289) and cough (N = 3,127). Multivariate logistic regression models were used to examine the association between each respiratory outcome and using a gas stove for heat or without ventilation, as well as, the joint effect of both behaviors. RESULTS: The adjusted odds of parental-reported pneumonia (adjusted odds ratio [aOR] = 2.08, 95% confidence interval [CI]: 1.08, 4.03) and cough (aOR = 1.66, 95% CI: 1.14, 2.43) were higher among children who lived in homes where gas stoves were used for heat compared to those who lived in homes where gas stoves were only used for cooking. The odds of pneumonia (aOR = 1.76, 95% CI: 1.04, 2.98), but not cough (aOR = 1.23, 95% CI: 0.87, 1.75), was higher among those children whose parents did not report using ventilation when operating gas stoves compared to those who did use ventilation. When considering the joint association of both stove operating conditions, only children whose parents reported using gas stoves for heat without ventilation had significantly higher odds of pneumonia (aOR = 3.06, 95% CI: 1.32, 7.09) and coughing (aOR = 2.07, 95% CI: 1.29, 3.30) after adjusting for other risk factors. CONCLUSIONS: Using gas stoves for heat without ventilation was associated with higher odds of pneumonia and cough among U.S. children less than five years old who live in homes with a gas stove. More research is needed to determine if emissions from gas stoves ventilation infrastructure, or modifiable behaviors contribute to respiratory infections in children.

Arsenic exposure and prevalence of the varicella zoster virus in the United States: NHANES (2003-2004 and 2009-2010).

BACKGROUND: Arsenic is an immunotoxicant. Clinical reports observe the reactivation of varicella zoster virus (VZV) in people who have recovered from arsenic poisoning and in patients with acute promyelocytic leukemia that have been treated with arsenic trioxide. OBJECTIVE: We evaluated the association between arsenic and the seroprevalence of VZV IgG antibody in a representative sample of the U.S. METHODS: We analyzed data from 3,348 participants of the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and 2009-2010 pooled survey cycles. Participants were eligible if they were 6-49 years of age with information on both VZV IgG and urinary arsenic concentrations. We used two measures of total urinary arsenic (TUA): TUA1 was defined as the sum of arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid, and TUA2 was defined as total urinary arsenic minus arsenobetaine and arsenocholine. RESULTS: The overall weighted seronegative prevalence of VZV was 2.2% for the pooled NHANES sample. The geometric means of TUA1 and TUA2 were 6.57 µg/L and 5.64 µg/L, respectively. After adjusting for age, sex, race, income, creatinine, and survey cycle, odds ratios for a negative VZV IgG result in association with 1-unit increases in natural log-transformed (ln)-TUA1 and ln-TUA2 were 1.87 (95% CI: 1.03, 3.44) and 1.40 (95% CI: 1.0, 1.97), respectively. CONCLUSIONS: In this cross-sectional analysis, urinary arsenic was inversely associated with VZV IgG seroprevalence in the U.S. POPULATION: This finding is in accordance with clinical observations of zoster virus reactivation from high doses of arsenic. Additional studies are needed to confirm the association and evaluate causal mechanisms.

A cross-sectional study of the association between ventilation of gas stoves and chronic respiratory illness in U.S. children enrolled in NHANESIII.

BACKGROUND: Gas stoves emit pollutants that are respiratory irritants. U.S. children under age 6 who live in homes where gas stoves are used for cooking or heating have an increased risk of asthma, wheeze and reduced lung function. Yet few studies have examined whether using ventilation when operating gas stoves is associated with a decrease in the prevalence of respiratory illnesses in this population. METHODS: The Third National Health and Nutrition Examination Survey was used to identify U.S. children aged 2-16 years with information on respiratory outcomes (asthma, wheeze, and bronchitis) who lived in homes where gas stoves were used in the previous 12 months and whose parents provided information on ventilation. Logistic regression models evaluated the association between prevalent respiratory outcomes and ventilation in homes that used gas stoves for cooking and/or heating. Linear regression models assessed the association between spirometry measurements and ventilation use in children aged 8-16 years. RESULTS: The adjusted odds of asthma (Odds Ratio [OR] = 0.64; 95% confidence intervals [CI]: 0.43, 0.97), wheeze (OR = 0.60, 95% CI: 0.42, 0.86), and bronchitis (OR = 0.60, 95% CI: 0.37, 0.95) were lower among children whose parents reported using ventilation compared to children whose parents reported not using ventilation when operating gas stoves. One-second forced expiratory volume (FEV1) and FEV1/FVC ratio was also higher in girls who lived in households that used gas stoves with ventilation compared to households that used gas stoves without ventilation. CONCLUSIONS: In homes that used gas stoves, children whose parents reported using ventilation when operating their stove had higher lung function and lower odds of asthma, wheeze, and bronchitis compared to homes that never used ventilation or did not have ventilation available after adjusting for other risk factors. Additional research on the efficacy of ventilation as an intervention for ameliorating respiratory symptoms in children with asthma is warranted.

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.

A panel study of occupational exposure to fine particulate matter and changes in DNA methylation over a single workday and years worked in boilermaker welders.

BACKGROUND: Exposure to pollutants including metals and particulate air pollution can alter DNA methylation. Yet little is known about intra-individual changes in DNA methylation over time in relationship to environmental exposures. Therefore, we evaluated the effects of acute- and chronic metal-rich PM2.5 exposures on DNA methylation. METHODS: Thirty-eight male boilermaker welders participated in a panel study for a total of 54 person days. Whole blood was collected prior to any welding activities (pre-shift) and immediately after the exposure period (post-shift). The percentage of methylated cytosines (%mC) in LINE-1, Alu, and inducible nitric oxide synthase gene (iNOS) were quantified using pyrosequencing. Personal PM2.5 (particulate matter with an aerodynamic diameter ≤ 2.5 µm) was measured over the work-shift. A questionnaire assessed job history and years worked as a boilermaker. Linear mixed models with repeated measures evaluated associations between DNA methylation, PM2.5 concentration (acute exposure), and years worked as a boilermaker (chronic exposure). RESULTS: PM2.5 exposure was associated with increased methylation in the promoter region of the iNOS gene (ß = 0.25, SE: 0.11, p-value = 0.04). Additionally, the number of years worked as a boilermaker was associated with increased iNOS methylation (ß = 0.03, SE: 0.01, p-value = 0.03). No associations were observed for Alu or LINE-1. CONCLUSIONS: Acute and chronic exposure to PM2.5 generated from welding activities was associated with a modest change in DNA methylation of the iNOS gene. Future studies are needed to confirm this association and determine if the observed small increase in iNOS methylation are associated with changes in NO production or any adverse health effect.

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.