Bangladesh

Arsenic Exposure and Birth Outcomes in Bangladesh
(Grant: # R01ES015533 )  Publications
Christiani, David C (dchris@hohp.harvard.edu ) - Harvard School of Public Health
Abstract: Inorganic Arsenic is a toxic compound with significant public health impact. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL), and arsenic has been found in at least 781 of these sites. Arsenic is also a by-product of coal combustion, as well as a naturally occurring water contaminant in many regions of the world, including the USA, Exposure may occur by a variety of pathways including inhalation of dusts in air, ingestion of contaminated soil or water, or through the food chain. Arsenic has been associated with a number of adverse health effects. However, the precise relation of arsenic to pregnancy outcomes has not been established. Thus, we wish to extend the previous work we conducted in Taiwan and Bangladesh to an assessment of birth outcomes in a prospective, repeated measures study of expectant mothers and their newborns in Bangladesh. Currently, an estimated 133 million people in Bangladesh are at risk of disease from drinking arsenic-contaminated drinking water. The proposed studies will evaluate standard birth outcomes at exposure levels that are relevant not only to the U.S. population, but also globally. The proposed studies will assess this risk in a population with a wide range of exposure, from low to high. Together, these data will add substantially to the existing risk assessment information by elucidating birth outcomes after arsenic exposure; the role of methylated forms of arsenic in the urine as biomarkers of exposure and risk; and an evaluation of a new potential marker of adverse outcome (proteomic profiles), as well as the influence of candidate genetic susceptibility traits as risk modifiers. This project is relevant to the overall strategic plan of the NIEHS in several ways. Firstly, we will examine a range of health effects of a significant environmental toxicant, arsenic. Secondly, we will define human biomarkers of exposure, early effects, and genetic susceptibility to arsenic exposure. Thirdly, we will examine exposure-response relationships for arsenic-induced birth outcomes. Fourthly, we will incorporate new, sensitive toxicogenomic technology (proteomics) to assess potentially novel biomarkers of exposure and effect in a molecular epidemiologic setting. Lastly, the study is international, sited in the developing world. The proposed human studies will fill important research gaps in our knowledge of arsenic toxicity and inform clinical and public health interventions.

Arsenic Exposure and Skin Diseases in Bangladesh
(Grant: # R01ES011622 )  Publications
Christiani, David C (dchris@hohp.harvard.edu ) - Harvard University (Sch of Public Hlth)
Abstract: Arsenic is a carcinogen, a Superfund toxic compound, and a common drinking-water contaminant. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL) and arsenic has been found in at least 781 of these sites in the USA. Exposure may occur by a variety of pathways including inhalation of dusts in air, ingestion of contaminated soil or water, or through the food chain. The primary mode of exposure in non-occupationally exposed populations is drinking-water contamination from either alluvial deposits or industrial contamination. The precise relation of arsenic to cancer has not been established at low exposure levels. In addition, arsenic toxicokinetics in humans remains poorly understood. Thus, we propose to assess exposure and skin-lesion risk, as well as arsenic dosimetrics in a population with a wide range of arsenic exposure via drinking-water contamination. The proposal builds upon a small study in which a case-control study has been initiated. This proposal will use the necessary resources to analyze biomarkers of exposure and susceptibility and for statistical analyses of both a case-control study of skin lesions and a repeated-measures biomarker dosimetry study. The proposed studies in Bangladesh will assess this risk in a population with a wide range of exposures - from low to very high. Together, these data will add substantially to the existing risk assessment information by elucidating both early and late outcomes alter arsenic exposure, and the influence of susceptibility traits at all levels of exposure. This project is relevant to the overall aims of NIEHS in several ways: First, we will examine a range of health effects of an important environmental carcinogen. Second, we will define human biomarkers of exposure, early effects, and genetic susceptibility to arsenic exposure. Third, we will examine exposure-response relationships for arsenic-induced non-malignant skin lesions as well as for skin cancers.

Health Effects and Geochemistry of Arsenic and Manganese
(Grant: # P42ES010349 )  Publications
Graziano, Joseph H (jg24@columbia.edu) - Columbia University Health Sciences
Abstract: The overall goal of this program is to understand the effects of arsenic (As) exposure on human health. There are three projects within this proposal that will be performing human epidemiology studies in Bangladesh. The first study proposes to evaluate the effects of various measures of As exposure and metabolism on: i) the incidence of skin lesions and skin cancer, ii) the incidence and mortality from chronic lung disorders and mortality from lung cancers, and iii) the incidence and mortality from Cardio-vascular disease. Additional urine samples will be collected from participants that were enrolled during the first five years. No new recruitment will occur during the next funding cycle. The second study seeks to further test and elaborate on the hypotheses that exposure to As and manganese are associated with deficits in intellectual function in children and to examine whether or not the effects of As on intellectual function are reversible; it takes advantage of a Columbia Earth Institute initiative to provide As-free deep tube-well water to an exposed population in Araihazar, Bangladesh. An additional 300 children will be enrolled and blood, urine and toenail clippings will be collected. The third study will address the relationship between the metabolism of arsenic (As) and b) As-induced oxidative stress and whether these factors contribute to the significant variability seen in the progression from As exposure to clinical manifestations of disease. This study will recruit an additional 375 adults who are currently exposed to As to assess (1) the extent by which urinary As metabolites reflect As metabolites in the circulation, (2) the relationship between higher concentrations of s-adenosylhomocysteine (SAH) and lower concentrations of GSH with reduced As methylation, and (3) the relationships between As exposure and oxidative stress. Blood and urine samples will be collected. Foreign Site 2:Two of the non biomedical research projects focus on understanding the relationships between the characteristics of the geology of the site and release of arsenic into the water supply. Project 5 will focus on field studies designed to investigate the interactions between hydrology, mineralogy, geology and geochemistry that result in naturally-elevated As concentrations (> 10 ng/L) in reducing groundwater. They will determine if there is a roughly linear relationship between groundwater As and groundwater age observed in Araihazar, Bangladesh. Extensive collection of water, soil and other environmental samples will be conducted. Project 7 focuses on how to maintain a low arsenic water supply for the Bangladesh population. The proposed research will focus on the sustainability of continued withdrawals from those aquifers that are currently low in As. Through detailed monitoring and targeted manipulations in the field and in the laboratory, the combination of hydrological, geochemical, and microbial processes that maintain As concentrations at low levels in both very shallow (<10 m) and deep (>30-150 m) aquifers will be investigated.

Nutritional influences on Arsenic Toxicity
(Grant: # R01ES011601 )  Publications
Gamble, Mary V (mvg7@columbia.edu ) - Columbia University Health Sciences
Abstract: The largest known mass exposure to arsenic is presently occurring due to ground water contamination of well water throughout the Ganges-Brahmaputra Delta There is significant inter-individual variability in susceptibility to progression from arsenic exposure to clinical manifestations of arsenic toxicity (e g skin, lung, liver and bladder cancers) Several observational as well as biochemical studies have led to a prevalent hypothesis that nutritional status may account for a substantial portion of this variability, though no controlled clinical studies have addressed this important hypothesis. Methylation of inorganic arsenic (InAs) is generally considered to be a detoxification pathway InAs and DNA are both methylated via one-carbon metabolism, a biochemical pathway which is dependent on folate for de novo generation of one-carbon groups, and also uses vitamins B12 and B6 as cofactors The primary hypothesis of this proposal is that nutritional regulation of one-carbon metabolism, specifically folate availability, contributes substantially to the large inter-individual variability observed in InAs and DNA methylation, and thus progression from arsenic exposure to toxicity This hypothesis will first be tested in cross-sectional studies of adults and children chronically exposed to arsenic-contaminated drinking water in Bangladesh Other nutritional deficiencies, including those of retinol, carotenoids and protein, have also been implicated as possibly influencing progression from arsenic exposure to toxicity, although the mechanistic bases for these interactions are somewhat less clear Exploratory studies will address these possibilities as secondary objectives in children, who are more likely to be deficient in these nutrients A third objective will test whether, in adults or children, arsenic exposure is correlated with lymphocyte DNA hypomethylation, an early event in some cancers. Finally, a 12-week double blind placebo controlled folate supplementation trial of adults with elevated plasma homocysteine concentrations and low plasma folate concentrations will be conducted to determine if folate supplementation results in improved arsenic and/or lymphocyte DNA methylation.

Superfund Toxic Substances--Exposure and Disease
(Grant: # P42ES005947 )  Publications
Monson, Richard R (Karl_Kelsey@Brown.edu) - Harvard University (Sch of Public Hlth)
Abstract: The Harvard School of Public Health Superfund Basic Research Program began in 1992. Currently, it consists of six research projects (4 biomedical, 2 non-biomedical), two research support cores (environmental and biological chemistry, and environmental statistics), and administrative, training and outreach cores. The general goal of this program is to assess and understand the risk to human health from toxic substances in the environment using an approach that integrates exposure assessment, biological pathogenesis and epidemiological studies. The biomedical studies focus on reproductive health, cardio-respiratory health and cancer. Two interrelated projects focus on lead-related health effects. A double-blind, placebo-controlled clinical study in Mexico City is testing the hypothesis that calcium supplements during pregnancy will significantly decrease bone resorption. A second longitudinal study is building on previous studies to focus on the effects of low-level intrauterine toxin exposures on memory and learning. Two molecular epidemiology studies focus on arsenic exposure and cancer. One study is developing biomarkers of exposure, susceptibility and outcome (skin and bladder cancer). The second study is investigating epigenetic mechanisms in bladder cancer etiology. The two non-biomedical projects address the health of the ecosystem and exposures that affect aquatic organisms. These projects focus on: 1) developing and field testing sampling devices that determine the activity of metal and organic contaminants in aquatic sediments in order to provide information on the bioavailability of contaminants; and 2) evaluating the ecological health of New Bedford Harbor by examining physiological and biochemical responses in the macrobiota to pollutants, including effects on their endocrine systems.