Dissertationen zum Thema „Arsenic Health aspects Bangladesh“

Considered the king of poisons, arsenic occurs naturally in the environment being present in air, soil, water and food. Its presence in drinking water is of global concern. Initial chronic exposure is manifested by skin lesions. Additionally, arsenic consumption impairs certain visceral organs: bladder, liver, prostate, etc. More over, arsenic is a recognized carcinogenic substance.When in Bangladesh started the program to lead safe drinking water in the 60’s, they never imagined the catastrophic consequences. Water wells were drilled in the whole country. The arsenic problem was recognized recently in the 90’s.  In order to understand the nature of arsenic  in the environment and how it could possibly reach groundwater in Bangladesh, this work explains some chemical characteristics of arsenic, the geological formation of the basin, and its mobility.The origin of arsenic contamination in the Bangladesh Delta is due to the geologic nature of the basin rather than the possibility of an arsenic rich mineral. The profile of sediments shows that the Delta is not homogeneous, but rather heterogeneous even in closer areas. The driving process for arsenic mobility is mainly the reduction by iron oxyhydroxides coupled with organic matter, including other factors such as particle size, depth, morphology, metal content, as well

Thesis: Ph. D. in Environmental Engineering, Massachusetts Institute of Technology, Department of Civil and Environmental Engineering, 2018.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references.
Naturally-occurring groundwater arsenic can threaten human health and food security. In Bangladesh, >50 million people are estimated to have chronically consumed water with arsenic above the World Health Organization (WHO) guideline of 10 μg/L, which can contribute to cancer, cardiovascular disease, and reproductive and developmental effects. Studies relating arsenic exposure to health impacts generally estimate dose based on participants' primary household wells. Using a mass-balance for arsenic and water, we estimate that participants in Araihazar, Bangladesh obtain 37±8% of their water from primary household wells and 31±14% from other wells, and we thus recommend the inclusion of other wells in dose estimation. Concentrations of arsenic in well water are spatially variable, enabling many exposed households to switch to nearby lower-arsenic wells in response to area-wide well testing. Following well testing and education in Araihazar, arsenic exposure declined and remained lowered for at least eight years. Participants with arsenic-unsafe wells were 6.8 times more likely to switch wells over the first two years and 1.4-1.8 times more likely to switch wells over the ensuing decade. Rice comprises more than 70% of calories consumed in Bangladesh, and rice yield is negatively impacted by the buildup of arsenic in soil from irrigation with high-arsenic water. We investigated the effect of soil arsenic on yield using a controlled study design where we exchanged the top 15 cm of soil between high-arsenic and low-arsenic plots. Differences in yield were negatively correlated to differences in soil arsenic between adjacent soil replacement and control plots, suggesting that boro rice yield countrywide may be diminished by 7-26% due to arsenic in soil. Soil testing and removal of high-arsenic soil may enable farmers to mitigate the impacts of arsenic on rice. Twelve measurements made with the ITS Econo-Quick field kit could be used to estimate whether soil arsenic was above or below a 30 mg/kg intervention threshold with 80-90% accuracy. A soil inversion, where deep low-arsenic soil was exchanged with surface high-arsenic soil, decreased soil arsenic, organic carbon, nitrogen, and phosphorus concentrations by about 40% in the top 20 cm of soil and improved rice yield by 15-30%.
by Brittany Lynn Huhmann.
Ph. D. in Environmental Engineering

The aim of this thesis was to analyse possible effects of prenatal arsenic exposure on foetal and infant health. The setting is Bangladesh, where two cohorts were studied, both part of a health and demographic surveillance system in Matlab. A historical cohort 1991-2000 included 29,134 pregnant women with information on drinking water sources and arsenic testing of tube well water. A prospective cohort study included pregnant women 2002 - 2003 where urinary arsenic concentrations were assessed twice during pregnancy; 2,924 women and their pregnancy outcomes were evaluated for foetal loss, perinatal and infant mortality; 1,578 mother-infant pairs were analysed for size at birth; and 1,552 were analysed for morbidity during infancy. Women exposed to arsenic levels ≥ 50 µg/L in water had an increased risk of foetal loss and infant death in comparison with women exposed to arsenic levels < 50 µg/L. These findings were confirmed in the prospective cohort study. Women with urine arsenic concentrations at the 5th quintile had 62% increased risk of spontaneous abortion (OR 1.62, 95% CI 1.04 - 2.55) in comparison with women who had arsenic concentrations at the 1st quintile level. Increased risks of perinatal morality (RR 3.01, 95% CI 1.07 - 8.45) and infant mortality (RR 5.01; 95% CI: 1.41 - 17.84) were also observed at the 5th quintile of exposure. Significant negative dose-effect associations were found between arsenic exposure and birth weight, head and chest circumferences at a relatively low level of exposure (<100 µg/L in urine). In this range of exposure birth weight decreased by 1.68 g (SE 0.62) for each 1 µg/L increase of arsenic in urine. In comparison with exposure at the 1st quintile level the risk of lower respiratory tract infection was significantly increased (RR 1.68, 95% CI 1.35-2.07) for women who had urinary arsenic concentrations at the 5th quintile level. The risk was also increased for diarrhoeal diseases. The study findings highlight the negative effects of arsenic exposures on pregnancy outcomes and infant health. Mitigation programs need to be strengthened and women of reproductive ages should be prioritized in arsenic affected regions worldwide.

This thesis is composed of three independent essays. In the first chapter, I analyze the effect of a biofuel-favorable policy in the U.S. on fetal health. I show that the policy led to an expansion in the production of corn, a pesticide-intensive crop, and to increased risk of fetal conditions previously associated with exposure to corn pesticides. In the second chapter, I examine the role of agricultural productivity as a mechanism linking rainfall shocks to civil wars in African countries. I show that rainfall over agricultural land and during the growing season has a hump-shaped relationship with agricultural output, which is mirrored by a U-shaped relationship with civil war risk. In the third chapter, I examine the effect of various selling schemes for testing tubewell water for arsenic on test uptake and, conditional on adverse news, on health-protective behavior. I find that uptake is increased by fees that depend on test results, and that social networks and public information can promote health-protective behavior.
Esta tesis consta de tres ensayos independientes. En el primer capítulo, analizo el efecto de una ley estadounidense que favorece la producción de biocombustibles sobre la salud fetal. Demuestro que la ley aumentó la producción de maíz, un cultivo con altos requerimientos de pesticidas, y el riesgo de enfermedades fetales asociadas con la exposición a pesticidas. En el segundo capítulo, estudio cómo la productividad agrícola puede mediar la relación entre shocks de lluvia y guerras en países africanos. Midiendo el nivel de lluvia sobre el territorio agrícola y durante la fase de crecimiento, demuestro que éste tiene una relación en forma de U-invertida con la producción agrícola, y una relación en forma de U con la incidencia de guerras civiles. En el tercer capítulo, estudio el efecto de diversas modalidades de venta de pruebas de arsénico para agua de pozo sobre la demanda por las mismas y, para familias que reciben noticias adversas, sobre su comportamiento para evitar el arsénico. Encuentro que la demanda aumenta cuando el precio a pagar depende de los resultados de la prueba, y que las redes sociales e información pública pueden promover medidas para evitar el agua contaminada.

Background: Chronic arsenic (As) exposure in a global public health concern. Arsenic exposure through drinking water affects over 140 million people in at least 70 countries, including 40 million people in Bangladesh. In the United States (US), 2.4 million people rely on private wells or public water systems with As levels above the US maximum contaminant level. Ingested inorganic arsenic (InAs) is methylated to monomethyl (MMAs)- and dimethyl (DMAs)-arsenical species using the methyl donor S-adenosylmethionine (SAM). Full methylation of InAs to DMAs decreases As toxicity and facilitates urinary As excretion. Arsenic methylation capacity is influenced by nutrients involved in one-carbon metabolism (OCM), the biochemical pathway that synthesizes SAM. Folate recruits one-carbon units for the remethylation of homocysteine and the synthesis of SAM. The availability of one-carbon units is also impacted by nutrients including the alternative methyl donor betaine, its precursor choline, and possibly the cofactor vitamin B12. In addition, As methylation capacity may also be influenced by creatine; an estimated 50% of SAM is consumed by the final step of endogenous creatine synthesis. The adverse health outcomes associated with chronic As exposure include impaired intellectual function, cardiovascular disease, diabetes, inflammation, and cancers of the bladder, lung, kidney, liver, and skin. In utero As exposure is associated with adverse birth outcomes include decreased birth weight and gestational age. Elevated health risks persist after exposure has been reduced or ended, leading to the hypothesis that epigenetic dysregulation, including changes in DNA methylation, may be a biological mechanism linking As exposure to health outcomes. Objectives: This research has three main objectives: (1) to investigate the influence of OCM nutritional factors on As methylation by evaluating effects of folic acid (FA) and creatine supplementation on As methylation capacity, and effect modification by baseline status of OCM-related nutrients; (2) to examine associations between As exposure and loci-specific DNA methylation in an epigenome-wide association study (EWAS); and (3) to assess mediation of the association between in utero As exposure and birth outcomes (i.e., gestational age and birth weight) by DNA methylation of target genes identified in an EWAS, as well as the candidate gene DNA methyltransferase 3 alpha (DNMT3A), a protein-coding gene involved in de novo DNA methylation. Methods: This research used data from three studies of As-exposed individuals. To address the first objective, we used data from the Folic Acid and Creatine Trial (FACT), a 24-week randomized clinical trial of FA (400 or 800 μg/day) and/or creatine supplementation (3 g/day or 3 g creatine and 400 μg FA/day) among As-exposed adults in Bangladesh recruited independent of folate status (N = 622). We investigated overall FA and creatine treatment effects on mean within-person changes in As metabolite proportions in urine compared to the placebo group (weeks 0 to 12). Rebound of As methylation capacity following the cessation of FA supplementation was assessed from weeks 12 to 24. We also assessed effect modification by baseline choline, betaine, vitamin B12, and plasma folate of treatment effects on changes in homocysteine, guanidinoacetate (GAA) (biomarkers of OCM and endogenous creatine synthesis, respectively), total blood As, and urinary As metabolite proportions and indices. To address the second objective, we used data from the Strong Heart Study (SHS), a population-based prospective cohort of American Indians with low-moderate levels of As exposure. DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array, which interrogates > 850,000 loci. We tested for differentially methylated positions (DMPs) and regions (DMRs), and conducted gene ontology (GO) enrichment analysis to understand functions of genes containing differential methylation. To address the third objective, we used data from a prospective birth cohort in Bangladesh. In a discovery phase, an EWAS was conducted to identify CpGs with methylation measured in cord blood that are associated with maternal water As levels and birth outcomes (N = 44). In a validation phase, DNA methylation in cord blood was measured using bisulfite pyrosequencing at three target CpGs annotated to miR124-3, MCC, and GNAL (N = 569). We applied structural equation models (SEMs) to assess mediation of the association between in utero As exposure and gestational age by DNA methylation. In addition, mediation of the association between in utero As exposure and birth outcomes by DNA methylation of the candidate gene DNA methyltransferase alpha (DNMT3A) was assessed. Results: In FACT, the mean within-person decreases %InAs and %MMAs and increase in %DMAs were greater among all groups receiving FA supplementation at weeks 6 and 12 compared to placebo (P < 0.05) (Chapter 3). Stratified by median choline and betaine concentrations at baseline, we observed a trend towards greater FA treatment effects among participants with levels below the median of both nutrients compared to participants above the median (Chapter 4). Among participants who discontinued FA supplementation, at week 24, %InAs and %DMAs were not significantly different than baseline levels, suggesting a rebound in As methylation capacity with cessation of FA supplementation. We observed a significantly greater mean within-person decreases in %MMAs with creatine supplementation compared to placebo at weeks 1, 6, and 12; mean within-person changes in %InAs and %DMAs did not differ significantly between the creatine and placebo groups (Chapter 3). The mean within-person decrease in urinary %MMAs at week 12 with creatine treatment was significantly greater than placebo among participants with baseline choline concentrations below the median, but did not differ from placebo among participants with choline concentrations above the median (Chapter 4). In an EWAS conducted in SHS, we identified 20 DMPs associated with urinary As levels at FDR < 0.05; five DMPs were significant at PBonferroni < 0.05 (Chapter 5). The top significant CpG, cg06690548, was located in solute carrier family 7 member 11 (SLC7A11 ), part of the amino-acid transporter cystine:glutamate antiporter system xc-, which is involved in biosynthesis of the endogenous antioxidant glutathione (GSH). Additional Bonferroni-significant CpGs were located in ANKS3, LINGO3, CSNK1D, and ADAMTSL4. We identified one FDR-significant DMR (chr11:2,322,050-2,323,247) including the open reading frame C11orf21 and tetraspanin 32 (TSPAN32 ). Mediation of the association between in utero As exposure and birth outcomes by cord blood DNA methylation was assessed in a Bangladeshi birth cohort. In the discovery phase (N = 44), the association between maternal water As levels and gestational age was fully mediated by DNA methylation of the top 10 CpGs associated with both variables. In a discovery phase (N = 569), there were significant indirect effects of maternal water As levels on gestational age through DNA methylation of miR124-3 and MCC ; the indirect effect through DNA methylation of GNAL was not significant (Chapter 6). In an adjusted SEM including miR124-3 and MCC, mediation of the association between in utero As exposure and gestational age by DNA methylation of miR124-3 was borderline significant (P = 0.06); DNA methylation of MCC did not act as a mediator. We also assessed mediation by DNA methylation of DNMT3A (Chapter 7). In an adjusted SEM including birth weight and gestational age, there was a significant indirect effect of maternal toenail As levels on gestational age through DNMT3A methylation, the indirect effect on birth weight was borderline significant (P = 0.082). However, the indirect effects of maternal toenail As levels on birth weight through all pathways including gestational age were statistically significant. A doubling in maternal toenail As concentrations had a total effect of a decrease in gestational age of 2.1 days and a decrease in birth weight of 28.9 g. Conclusions: Results from FACT (Chapters 3 and 4) provide evidence of the associations between OCM-related nutrients and As methylation capacity. Specifically, FA and creatine supplementation may increase As methylation capacity by increasing the availability of SAM, and treatment effects may be greater among individuals with low betaine and choline status, respectively. In addition, results reported in Chapters 5-7 support the hypotheses that chronic As exposure is associated with epigenetic dysregulation, and that changes in the epigenome may mediate the association between As exposure and adverse health effects. Findings from the research presented here may help inform public health interventions to reduce the adverse health effects of chronic As exposure. However, further research is needed to fully understand the biological mechanism that influence As methylation and that underlie the associations between chronic As exposure and adverse health outcomes.

Inorganic arsenic exposure is a well-known toxicant of which we are still discovering harmful effects. People are exposed to inorganic arsenic in the environment through either drinking arsenic-contaminated groundwater or consuming arsenic-contaminated food. Regarding global public health, drinking water is still the most important source of inorganic arsenic exposure and is the main focus of this work. The overall goal of this dissertation is to answer some pointing epidemiological questions about exposure to inorganic arsenic: How much do we know about inorganic arsenic and non-malignant lung disease in the general population? To what extent are adolescents with lifetime arsenic exposure susceptible to the respiratory consequences seen in adults? And what actions can be taken to effectively reduce exposure from arsenic-contaminated drinking water? First, we conducted a systematic review of 29 peer-reviewed articles from various populations around the world. The review focused on the different ways in which arsenic is associated with respiratory health to help inform policy makers and public health researchers on the existing evidence. In short, associations between arsenic and respiratory health were noted throughout the lifespan: in infancy, there was growing evidence that in utero arsenic exposure was associated with increased frequency and severity of respiratory tract infections; in childhood, evidence of respiratory symptoms also began to appear; and in adulthood, there was consistent evidence that arsenic exposure was associated with deficits in lung function and increased reports of coughing and breathing problems. The review also uncovered some research gaps, including few studies with strong exposure history from early life and few studies examining respiratory effects during adolescence. Next, we used a life course epidemiological approach to create a more precise understanding of arsenic exposure and respiratory health during the teenage years. This study examined the relationship between lifetime arsenic exposure and lung function in 14-17 year olds, thus studying the period of maximal lung function before natural decline. Overall, higher arsenic exposure was associated with lower lung function levels; however, these associations were only observed in males. This study used a sensitive marker of lung function to investigate early signs of small airway disease. Incorporating this common marker of small airway disease and airflow limitation in future studies on arsenic and respiratory health may help clarify how inorganic arsenic contributes to the development of chronic respiratory disease. Lastly, we evaluated the effectiveness of arsenic removal filters at the household-level in rural Bangladesh. Identifying sustainable ways of reducing exposure to arsenic from naturally contaminated groundwater has been a major environmental health challenge. Although lab-approved arsenic removal water filters exist, there was limited evidence of their prolonged efficacy in the field. To our knowledge, this was the largest and longest deployment of filters accompanied by monitoring of urinary arsenic. Our results demonstrated that filters can temporarily reduce arsenic exposure for weeks to a few months, but should not be considered as a long-term arsenic mitigation option. This failed attempt to reduce exposure confirmed that alternative mitigation strategies need to be employed in Bangladesh, particularly among more vulnerable populations, including pregnant women and young children. This dissertation has important policy implications for future arsenic research and mitigation efforts and should be effectively communicated to policy makers, public health officials, and the general population. Given the pervasive nature of arsenic exposure and the growing evidence of health consequences at different stages throughout the life course, the continued integration of information on inorganic arsenic and research collaborations across disciplines is critical for the prevention and mitigation of arsenic-induced health consequences.

Elevated concentrations of arsenic in groundwater pose a public health threat to millions of people worldwide. While arsenic is an established human carcinogen, a mode of action has yet to be determined for arsenic carcinogenesis. However, the oxidative stress and DNA repair pathways have been implicated in arsenic toxicity and have been hypothesized to underlie arsenic carcinogenesis. To date, few epidemiologic studies have evaluated genetic susceptibility to arsenical skin lesions based on single nucleotide polymorphisms (SNPs) in antioxidant enzyme or DNA repair genes. Utilizing cross-sectional data from the 2000-2002 survey of the Health Effects of Arsenic Longitudinal Study (HEALS) for 610 prevalent arsenical skin lesion cases and 1,079 randomly selected controls, I evaluated the associations of SNPs in genes encoding antioxidant enzymes and DNA repair enzymes on skin lesion prevalence. I also evaluated potential interactions between the SNPS as well as SNP-environment interactions in determining skin lesion prevalence. In the first study of this dissertation (Chapter 2), I assessed the relationship between SNPs in antioxidant enzyme genes and skin lesion prevalence, as well as possible interactions of these associations on the additive scale by various environmental factors. There were no statistically significant associations between these SNPs (SOD2, rs4880; CAT, rs1001179; GPX1, rs1050450; and MPO, rs2333227) and skin lesion prevalence. Additionally, there was no evidence of additive interaction by arsenic exposure levels, body mass index, smoking status, or fruit and vegetable intake with the SNPs in relation to skin lesion prevalence. However, there was marginal evidence that skin lesion prevalence was increased among individuals who carried 4 or more risk alleles compared to individuals carrying 0-3 risk alleles in these SNPs. Additionally, I observed a significant departure from additivity for the risk allele score and primary methylation index on skin lesion prevalence. In the second study of this dissertation (Chapter 3), I assessed the relationship between SNPs in DNA repair genes (OGG1, rs1052133; XRCC1, rs25487 and rs1799782; XRCC3, rs861539; ERCC2, rs1052559; ERCC5, rs17655; and LIG4, rs1805388) and skin lesion prevalence, as well as possible interactions of these associations on the additive scale by various environmental factors. In logistic regression models controlling for sex, age, and well water arsenic concentration, no associations were observed between measured SNPs and skin lesion prevalence. The results did not vary by arsenic exposure levels, body mass index, or smoking status. However, I did observe a significant inverse association of total fruit and vegetable consumption with skin lesion prevalence, and its additive interaction with the polymorphism in ERCC5. In the third study of this dissertation (Chapter 4), I utilized a multi-analytic approach to explore gene-gene, gene-environment, and higher-order interactions among 10 SNPs related to the oxidative stress and DNA repair pathways by MDR, CART, and logistic regression models. As shown in Chapters 2 and 3, none of these SNPs were associated with skin lesion prevalence, however, were evaluated for potential SNP-SNP interactions. MDR and CART modeling approaches were utilized for the selection of potential gene-gene and gene-environment interactions. Considerable overlap of the interactions detected by both these methods was observed, which were further evaluated by logistic regression. Results from logistic regression modeling, provided some evidence of these statistical interactions; however, their biological interpretation was limited. In summary, there was marginal evidence that skin lesion prevalence was increased among individuals who carried 4 or more risk alleles in genotyped SNPs related to the oxidative stress pathway compared to individuals carrying 0-3 risk alleles in these SNPs and, a significant departure from additivity was observed for the risk allele score and primary methylation index on skin lesion prevalence. Additionally, a significant inverse association of total fruit and vegetable consumption with skin lesion prevalence was observed and, a significant interaction between the polymorphism in ERCC5 and total fruit and vegetable intake was observed in relation to skin lesion prevalence on the additive scale. However, these finding require replication in other studies.

Millions of villagers in Bangladesh drink water which exceeds the Bangladesh arsenic (As) standard of 50 micrograms per liter. Exposure to elevated levels of inorganic As (As) is associated with cancers of the skin, bladder, and lung, developmental effects, cardiovascular disease, skin lesions, and decreased children's intellectual functioning. Arsenic mitigation typically involves an outsider coming into a village to test the well water for As. After the results of the As test are provided this person typically leaves the village without providing the resources to address health concerns or give advice on mitigation options. In this dissertation, in an effort to provide ongoing resources on the health implications of As and to reduce As exposure, we sought to evaluate community level intervention strategies that could be used for successful As mitigation in Bangladesh. In Singair, Bangladesh, we conducted a household drinking water survey of 6649 households. The results of our survey indicated that 80% of wells were untested for As. Furthermore, we demonstrated that testing all of these untested wells would increase the number of households that lived with fifty meters of an As safe drinking water source by nearly 2.5 fold. In a cluster based randomized control trial (RCT) of 1000 households, we evaluated the effectiveness of having community members, compared to outside representatives, disseminate As education and conduct water As (WAs) testing. In 10 villages, a community member disseminated As education and provided WAs testing. In a second set of 10 villages an outside representative performed these tasks. Overall, fifty three percent of respondents with unsafe wells at baseline switched after receiving the As education and WAs testing intervention. There was no significant association observed between the type of As tester and well switching (Odds ratio (OR) =0.77; 95% confidence interval (CI) (0.37-1.61)). At follow-up, the average UAs concentrations for those with unsafe wells at baseline who switched to safe wells significantly decreased. In both intervention groups a significant increase in knowledge of As was observed at follow-up compared to baseline. The unavailability of As-safe drinking water sources in some villages was the most substantial barrier to well switching identified. The Hach EZ As field test kit measurements conducted by the As testers were highly correlated with laboratory results. This finding indicates that the As testers were able to accurately measure the WAs concentration of wells. Furthermore in our pilot study, the performance of the Econo-Quick (EC) kit, a new field WAs testing kit, was comparable to that of the commonly used EZ kit and the Wagtech Arsenator kit. The EC kit has the advantage of a substantially shorter reaction time of only 12 minutes in comparison to the 40 minutes required by these other kits. Through this dissertation, we have demonstrated that As education and WAs testing programs can be used as an effective method to reduce As exposure and increase As awareness in many As affected areas of Bangladesh. Furthermore, our findings indicated that many households are using tubewells that are untested for As therefore demonstrating the urgent need for access to water As testing services.

In rural Bangladesh people drink water from an estimated 10-11 million tube wells, many with arsenic concentrations well above the national standard of 50µg/L. Characteristic skin lesions and more serious health effects are probable. The research reported here was designed to determine the relation between arsenic concentration and skin lesions on hands and feet controlling for education, use of tube well water, protein consumption and body mass index (BMI). The investigation included a well survey, a prevalence survey and a nested case-referent analysis. Studies were conducted in two villages (population 11670) in northern Bangladesh. In the well survey 1509 wells in use were identified and measurements of arsenic concentration made in 1422 (94%). Three estimates were made for each well, which yielded correlation among repeats = 0.93. The overall median was 47mg/L and the highest recorded 1760 mg/L. Paramedics examined soles and palms of 11087 individuals for skin lesions and identified 168 cases (1.5%). In the third phase, cases (over 16 years) were matched by age, gender and village to referents (target of 3) without skin lesions. Cases and referents were interviewed about protein in diet, use of well water, education and residential history. Conditional logistic regression was used to assess the effects of arsenic concentration, controlling for confounders. Subjects with lesions had a higher median concentration (250µg/L) than those without (47µg/L). Prevalence increased with both age and arsenic concentration, reaching 26.7% in those over 50 years of age and >500 µg/L. Of the 160 cases (≥16 years) 137 were interviewed, 127 with arsenic concentration measured in well water, together with their 504 referents. Cases were somewhat more likely to have lived in the villages throughout their lives and less likely to report using tube well water for cooking. The final model confirmed the high risk of lesions associated with arsenic concentrations. Using ≤50µg/L for comparison, an odds ratio of 15.2 (95%CI 7.2-32.2) was observed for those using tube wells with concentrations >500 µg/L, adjusting for use of tube well water in cooking and lifetime residence in the villages. The results from this research provide continuing support for the use of 50µg/L as a useful national standard. While the enforcement of this standard has immediate value, it cannot be considered final without comparable information on more serious health risks.

Background: Environmental exposure to inorganic arsenic (InAs) is a considerable worldwide problem, and over 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. Ingested inorganic arsenic (InAs) undergoes hepatic methylation generating monomethyl- (MMAs) and dimethyl- (DMAs) arsenic species in a process that facilitates urinary As (uAs) elimination. Of these three metabolites (InAs, MMA and DMA), MMA the most toxic, InAs is the second most toxic, and DMA is the least toxic. Consequently, increased MMAs is associated with increased risk of As-related adverse health outcomes. One-carbon metabolism (OCM), the biochemical pathway that provides methyl groups for As methylation, is influenced by folate and B12. A growing body of research, including cell-culture, animal-model, and epidemiological studies, have demonstrated the role of OCM-related micronutrients in As methylation. While folate supplementation is known to increase As methylation and lowers blood As (bAs) in adults, little data is available for adolescents. OCM also supports nucleotide and amino acid synthesis, particularly during periods of rapid growth, such as adolescence. In Bangladesh, deficiencies in folate and vitamin B12 are widespread. These micronutrients are essential for OCM and As methylation, and they are also critical for neural development, since they are necessary for the synthesis of neurotransmitters and myelin, and critical for generation of S-adenosyl-methionine (SAM) via OCM. Deficiencies in folate and B12 have been shown to negatively influence cognitive function in adults and children, but this has not been adequately characterized in adolescents. Individuals living in Bangladesh, facing As exposure and nutritional deficiency, also experience environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb). These metals have been linked to adverse neurocognitive outcomes in adults and children, though their effects on adolescents are not yet fully characterized. Additionally, previous studies have linked selenium (Se) levels to protective effects against toxicity of these other metals, as Se is an essential nutrient. Metal mixtures are also understudied in adolescents, and more research is needed. Objectives: Firstly, the research presented in this dissertation will examine the previously published evidence that nutritional status and nutritional interventions can influence the metabolism and toxicity of As, with a primary focus on folate. Secondly, the associations between OCM-related micronutrients and As methylation in Bangladeshi adolescents chronically exposed to As-contaminated drinking water will be studied. Thirdly, this dissertation will investigate the associations between folate and B12 nutritional status, homocysteine, and cognitive function as measured by two different test instruments in Bangladeshi adolescents. Finally, the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents will be examined. Methods: The Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 738 Bangladeshi adolescents aged 14-16 years, whose parents were enrolled in our group’s previous Health Effects of Arsenic Longitudinal Study (HEALS). Venous blood samples were collected from adolescent participants for measurement of plasma folate, red blood cell (RBC) folate, plasma B12, plasma homocysteine (Hcys), blood As (bAs), blood cadmium (bCd), blood manganese (bMn), blood lead (bPb), and blood selenium (bSe). Urine samples were collected for measurement of urinary arsenic and urinary arsenic metabolites (InAs, MMA, and DMA) expressed as a percentage of total urinary As: %InAs, %MMAs, %DMAs. Additionally, participants completed a modified version of the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and an abbreviated version of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Associations between predictors and outcomes were assessed using linear regression analyses. Associations for the mixture of metals were also examined via Bayesian Kernel Machine Regression (BKMR), which assessed the effects of the metals mixture in addition to examining the effects each individual metal component. Results: In the linear regression analyses examining associations between nutritional status and arsenic methylation profiles controlling for water As and BMI, in girls we observed that RBC folate was inversely associated with bAs, plasma B12 was inversely associated with uAs, and, somewhat unexpectedly, plasma Hcys was inversely associated with %MMA. Among boys, we saw that plasma folate was inversely associated with %InAs and positively associated with %DMA, RBC folate was inversely associated with %InAs and positively associated with %MMA, while Hcys was positively associated with %InAs. In linear regression analyses examining the associations between nutritional status and cognitive function controlling for covariates, we found no significant associations between nutritional status and cognitive function as measured by WISC. For cognitive function as measured by CANTAB, we observed positive associations between plasma folate and spatial recognition memory, and between plasma B12 and spatial working memory. In our investigation of the associations between metal exposures and cognitive outcomes, linear regression analysis revealed negative associations between exposure to As and Mn and spatial working memory. Negative associations were also seen between bCd and Spatial Recognition Memory, and between bPb and Delayed Match to Sample. Finally, a positive association was seen between bSe and Spatial Span Length. Our BKMR results showed no overall effect of the mixture but further characterized the associations for individual metals within the mixture. BKMR analyses indicate that bPb has a negative association to Delayed Match to Sample, and that there are positive associations between bSe and Planning, Reaction Time, and Spatial Span. BKMR also showed higher concentrations of bCd to be negatively associated with Spatial Recognition Memory. Posterior inclusion probability consistently rated Se, which has a protective effect, as the most influential component of the mixture. Conclusions: These findings suggest that associations between OCM nutritional status, blood arsenic, and distribution of urinary As metabolites in adolescents are similar to previously reported observations in adults and in children. The inverse association between Hcys and %MMA in girls is unexpected since Hcys is known to be an indicator of impaired OCM and low folate/B12 in adults. These findings also suggest that associations between nutritional status and cognitive function in adolescents are consistent with previously reported associations in adults and children. The observation of positive associations between folate and spatial recognition memory and between B12 and spatial working memory are consistent with findings in animal models, children, and adults, all of which link deficiencies in these two micronutrients to memory deficits. The findings of the metals investigation are also consistent with previously reported observations in adults and children, and these results also suggest agreement between linear regression and BKMR analysis of the mixed metal exposure, with the BKMR further demonstrating associations seen in the linear regression analysis. Generally, Se had a protective effect for cognitive outcomes, whereas Mn and As were linked to poorer working memory, and Cd and Pb were linked to poorer visual recognition and memory. BKMR reinforced and further characterized results of the linear regression analyses. Overall, these results indicate that the associations between OCM-related micronutrients, arsenic methylation, metal exposure, and cognitive function in adolescents are generally similar to prior findings in adults and children. However, additional studies are needed to evaluate the impact of OCM and As methylation on As-related adverse health outcomes (such as cancer and cardiovascular disease) in people exposed to As during adolescence. These results also suggest that further investigation into the associations between nutritional status and measures of cognitive function in adolescents is merited, and that further exploration of homocysteine’s role in adolescent physiology is needed. Most importantly, these findings suggest that both nutritional interventions involving B12 and folate supplementation and metal exposure mitigation efforts may have a positive impact on overall health and well-being for individuals facing these environmental exposures. In the long term, interventions to reduce exposure to metals and nutritional deficiency, and interventions to attenuate the effects of these exposures have the potential to influence lifelong cognitive function, possibly influencing professional achievement and economic outcomes in regions having a high prevalence of nutritional deficiencies, arsenic exposure, and environmental exposure to metals mixtures.

This dissertation examines topics related to development, environment and health in developing countries using empirical methods. In the first chapter, I study how developing countries can increase enforcement to reduce subsidy leakage in public programs, by investing in the state capacity to target program beneficiaries. This chapter further attempts to understand how the formal sector and black market respond to a policy that reduces diversion of a subsidized commodity. I explore these questions using the case of a Unique ID-based direct fuel subsidy transfer policy in India. Second chapter focuses on the health and wealth trade off near mineral mining operations in developing countries. Using extensive data on mining, health outcomes and assets from 44 developing countries, this study quantifies the wealth gain and adverse health impact of mineral mining. With a number of empirical strategies, this study shows that, despite high wealth gains, how heavy metal mining significantly increases the level of anemia in women and stunting in children living near mines. In the third chapter, I estimate demand for a water quality diagnostic product -- arsenic testing, when it is offered at a price. I further look into various aspects related to selection, learning and households behavioral response to the information. This study is based on a field experiment in Bihar, India.

Reducing population exposure to inorganic arsenic (iAs), a known carcinogen and highly toxic metalloid of great public health concern, remains an ongoing challenge worldwide and in the United States (US). In the US, the Environmental Protection Agency (EPA) regulates the maximum contaminant level (MCL) for total arsenic in public drinking water supplies through the Safe Drinking Water Act. In 2001, the US EPA implemented the Final Arsenic Rule, which lowered the MCL for arsenic in public drinking water supplies from 50 to 10 µg/L. Reductions in iAs exposure and subsequent related disease associated with this important regulatory change have not been quantified. Currently, no national-level exposure estimates of iAs drinking water exposure are available for US residents reliant on public drinking water. There is a critical need to identify susceptible subgroups of the US population who remain at risk for elevated iAs drinking water exposure. This dissertation aimed to quantify the reduction in drinking water iAs exposure resulting from the US EPA MCL regulatory change, to estimate drinking water iAs exposure for US residents reliant on public drinking water, to identify susceptible subgroups across the US whose water iAs remains high, and to determine if iAs exposure was associated with heart disease mortality in the general US population. Chapter 1 provides background information necessary to contextualize the work contained in this dissertation. In Chapter 2, we conducted a cross-sectional analysis of dietary sources of iAs exposure in the Strong Heart Family Study, a cohort of American Indian adults followed primarily for cardiovascular disease, using a self-reported food frequency questionnaire and urinary iAs measurements. Self-reported intake of rice, organ meat, processed meat, and non-alcoholic drinks was associated with increased urinary iAs concentrations. Diet alone explained only 3% of total variability in urinary iAs concentrations, indicating that the majority of iAs exposure for SHFS participants occurs from drinking water. Second, (in Chapter 3), we explored trends in water iAs exposure in the general US population associated with the EPA’s MCL change using the National Health and Nutrition Examination Survey (NHANES) from 2003-2014, separately for participants reliant on public drinking water vs. private well water (which is not subject to US EPA regulation). We estimated that implementation of the new US EPA MCL was associated with a 17% reduction in drinking water iAs exposure for all participants reliant on public drinking water; the corresponding reduction was 32% for Mexican-American participants. No reduction was observed for participants reliant on private wells. Third (in Chapter 4), we estimated drinking water iAs exposure at the community water system and county-level across the entire US from 2006-2011 using the US EPA’s Six Year Review of Contaminant Occurrence database. We estimated that nationwide public drinking water iAs concentrations decreased by 8.5% and 21.6% at the 80th and 99th percentiles of the water iAs distribution in accordance with the MCL implementation, with significant differences across US subgroups. Greater decreases in iAs concentrations were reported for systems reliant on groundwater, systems serving smaller populations, and systems in the Northeast, Central Midwest, and Southwestern regions of the US. Susceptible subgroups whose public drinking water iAs exposure remains high include populations served by small community water systems reliant on groundwater, communities in the Southwestern US, Semi-Urban, Hispanic communities, and Rural, American Indian communities. Fourth (in Chapter 5), we assessed six-year average arsenic concentrations in community water systems exclusively serving correctional facilities in the US (e.g. prisons, jails, detention centers) compared to other community water systems. Average arsenic concentrations were twice as high in correctional facility community water systems located in the Southwest (6.41 µg/L, 95% CI 3.48, 9.34) compared to all other community water systems in the Southwest (3.11 µg/L, 95% CI 2.97, 3.24). Over a quarter of correctional facility systems in the Southwest reported a six-year average arsenic concentration exceeding the 10 µg/L MCL. Persons incarcerated in the Southwestern US were at disproportionate risk of drinking water arsenic exposure and related disease from 2006-2011. Fifth (in Chapter 6), we multiply imputed urinary arsenic concentrations below the limit of detection (LOD) in NHANES 2003-2016 using a Bayesian Tobit regression model. Epidemiological analyses of urinary arsenic data in NHANES are limited by the relatively high analytical LODs and large proportion of participants with undetectable values. Distributions of urinary arsenic originally reported in NHANES, which replace values below the LOD with the LOD divided by the square root of two, likely overestimate iAs exposure at the lowest exposure levels and may introduce significant bias. Bayesian-multiply imputed datasets may improve the assessment of iAs exposure in cohorts with high analytical LODs for arsenic species. Finally (in Chapter 7), we evaluated the association between urinary iAs concentrations (internal dose) and heart disease mortality as recorded in the National Death Index in NHANES 2003-2014 participants. We found a positive but non-significant prospective association between increasing iAs exposure and heart disease mortality for all participants (hazard ratio 1.15, 95% CI 0.77, 1.70), and a significant positive association for non-Hispanic white participants using flexible spline models. Geometric mean ratios of iAs exposure were higher among cases compared to non-cases, especially for Mexican-American participants (1.30, 95% CI 0.90, 1.88). These findings further support the potential association between low- to moderate- iAs exposure and cardiovascular disease in the US population, and indicate that further high-quality prospective studies of Hispanic and Latino Americans are needed to investigate the potential increased susceptibility of Mexican-Americans to iAs-related cardiovascular disease. Taken together, these studies suggest that while the implementation of the US EPA’s 10 µg/L MCL has reduced drinking water arsenic exposure for many Americans reliant on public drinking water systems, these reductions were not uniform across all US populations. Populations who remain at risk of elevated drinking water arsenic exposure include those reliant on domestic wells, those located in the Southwest, persons incarcerated in the Southwest, tribal communities, and Hispanic communities. Further high-quality epidemiologic research is needed to evaluate the association between low- to moderate iAs exposure and cardiovascular disease in these populations. Stronger federal regulations, targeted compliance enforcement and technical assistance, and other public health interventions are needed to reduce drinking water arsenic exposure in these communities.

This dissertation discusses three questions of development and environmental economics. First, it assesses the impact of mineral mining on the health and wealth of households in local communities across 44 developing countries, using micro data. Secondly, it presents evidence from a randomized controlled trial on the cost-shared provision of well-water tests for arsenic. Finally, it analyzes measurement error in a satellite night light data product widely used in development research, and investigates the scope for using the data in very high spatial resolution.