Baseline characteristics including blood and urine metal levels in the Trial to Assess Chelation Therapy 2 (TACT2).

BACKGROUND: The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. METHODS: TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2's participants. RESULTS: At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. CONCLUSIONS: TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185.

A mass-balance approach to evaluate arsenic intake and excretion in different populations.

Unless a toxicant builds up in a deep compartment, intake by the human body must on average balance the amount that is lost. We apply this idea to assess arsenic (As) exposure misclassification in three previously studied populations in rural Bangladesh (n = 11,224), Navajo Nation in the Southwestern United States (n = 619), and northern Chile (n = 630), under varying assumptions about As sources. Relationships between As intake and excretion were simulated by taking into account additional sources, as well as variability in urine dilution inferred from urinary creatinine. The simulations bring As intake closer to As excretion but also indicate that some exposure misclassification remains. In rural Bangladesh, accounting for intake from more than one well and rice improved the alignment of intake and excretion, especially at low exposure. In Navajo Nation, comparing intake and excretion revealed home dust as an important source. Finally, in northern Chile, while food-frequency questionnaires and urinary As speciation indicate fish and shellfish sources, persistent imbalance of intake and excretion suggests imprecise measures of drinking water arsenic as a major cause of exposure misclassification. The mass-balance approach could prove to be useful for evaluating sources of exposure to toxicants in other settings.

Mixed metals exposure and cognitive function in Bangladeshi adolescents.

BACKGROUND: Over 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. They also face environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb), all of which have been previously observed in environmental and biological samples for this population. 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) to protective effects against the toxicity of these other metals. OBJECTIVES: To examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. METHODS: The Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 572 Bangladeshi adolescents aged 14-16 years, whose parents were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Biosamples were collected from these adolescents for measurement of whole blood metalloid/metal levels of As, Cd, Mn, Pb, and Se. Participants also completed an abbreviated version of The Cambridge Neuropsychological Test Automated Battery (CANTAB), a cognitive function test designed to measure performance across several aspects of executive function. Linear regression was used to examine associations for each metal while controlling for the other metals. Bayesian Kernel Machine Regression (BKMR) assessed the overall mixture effect in addition to confirming the effects of individual metal components observed via linear regression. RESULTS: Linear regression revealed negative associations for Spatial Working Memory and both As and Mn (As B=-2.40, Mn B=-5.31, p < 0.05). We also observed negative associations between Cd and Spatial Recognition Memory (B=-2.77, p < 0.05), and Pb and Delayed Match to Sample, a measure of visual recognition and memory (B=-3.67, p < 0.05). Finally, we saw a positive association for Se and Spatial Span Length (B=0.92, p < 0.05). BKMR results were largely consistent with the regression analysis, showing meaningful associations for individual metals and CANTAB subtests, but no overall mixture effect. Via BKMR, we observed negative associations between Pb and Delayed Match to Sample, and Cd and Spatial Recognition Memory; this analysis also showed positive associations for Se and the Planning, Reaction Time, and Spatial Span subtests. BKMR posterior inclusion probability consistently reported that Se, the only component of the mixture to show a positive association with cognition, was the most important member of the mixture. CONCLUSIONS: Overall, we found Se to be positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. Our observations are consistent with previous reports on the effects of these metal exposures in adults and children. Our findings also suggest agreement between linear regression and BKMR methods for analyzing metal mixture exposures. Additional studies are needed to evaluate the impact of mixed metals exposure on adverse health and poorer cognition later in life for those exposed during adolescence. Findings also suggest that metal exposure mitigation efforts aimed at adolescents might influence lifelong cognitive outcomes in regions where environmental exposure to metals is endemic.

An atlas of metallome and metabolome interactions and associations with incident diabetes in the Strong Heart Family Study.

BACKGROUND: Chronic exposure to certain metals plays a role in disease development. Integrating untargeted metabolomics with urinary metallome data may contribute to better understanding the pathophysiology of diseases and complex molecular interactions related to environmental metal exposures. To discover novel associations between urinary metal biomarkers and metabolism networks, we conducted an integrative metallome-metabolome analysis using a panel of urinary metals and untargeted blood metabolomic data from the Strong Heart Family Study (SHFS). METHODS: The SHFS is a prospective family-based cohort study comprised of American Indian men and women recruited in 2001-2003. This nested case-control analysis of 145 participants of which 50 developed incident diabetes at follow up in 2006-2009, included participants with urinary metal and untargeted metabolomic data. Concentrations of 8 creatinine-adjusted urine metals/metalloids [antimony (Sb), cadmium (Cd), lead (Pb), molybdenum (Mo), selenium (Se), tungsten (W), uranium (U) and zinc (Zn)], and 4 arsenic species [inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), and arsenobetaine (AsB)] were measured. Global metabolomics was performed on plasma samples using high-resolution Orbitrap mass spectrometry. We performed an integrative network analysis using xMWAS and a metabolic pathway analysis using Mummichog. RESULTS: 8,810 metabolic features and 12 metal species were included in the integrative network analysis. Most metal species were associated with distinct subsets of metabolites, forming single-metal-multiple-metabolite clusters (|r|>0.28, p-value < 0.001). DMA (clustering with W), iAs (clustering with U), together with Mo and Se showed modest interactions through associations with common metabolites. Pathway enrichment analysis of associated metabolites (|r|>0.17, p-value < 0.1) showed effects in amino acid metabolism (AsB, Sb, Se and U), fatty acid and lipid metabolism (iAs, Mo, W, Sb, Pb, Cd and Zn). In stratified analyses among participants who went on to develop diabetes, iAs and U clustered together through shared metabolites, and both were associated with the phosphatidylinositol phosphate metabolism pathway; metals were also associated with metabolites in energy metabolism (iAs, MMA, DMA, U, W) and xenobiotic degradation and metabolism (DMA, Pb) pathways. CONCLUSION: In this integrative analysis of multiple metals and untargeted metabolomics, results show common associations with fatty acid, energy and amino acid metabolism pathways. Results for individual metabolite associations differed for different metals, indicating that larger populations will be needed to confirm the metal-metal interactions detected here, such as the strong interaction of uranium and inorganic arsenic. Understanding the biochemical networks underlying metabolic homeostasis and their association with exposure to multiple metals may help identify novel biomarkers, pathways of disease, potential signatures of environmental metal exposure.

Nutrition, one-carbon metabolism and arsenic methylation in Bangladeshi adolescents.

BACKGROUND: Over 57 million people in Bangladesh are 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. One-carbon metabolism (OCM), a biochemical pathway that is influenced by folate and vitamin B12, facilitates the methylation of As. OCM also supports nucleotide and amino acid synthesis, particularly during periods of rapid growth such as adolescence. While folate supplementation increases As methylation and lowers blood As (bAs) in adults, little data is available for adolescents. OBJECTIVES: To examine the associations between OCM-related micronutrients and As methylation in Bangladeshi adolescents chronically exposed to As-contaminated drinking water. METHODS: We conducted a cross-sectional study of 679 Bangladeshi adolescents, including 320 boys and 359 girls aged 14-16 years. Nutritional status was assessed by red blood cell (RBC) folate, plasma folate, plasma B12 and homocysteine (Hcys). Arsenic-related outcomes included blood arsenic (bAs), urinary arsenic (uAs), and urinary arsenic metabolites expressed as a percentage of total urinary As: %InAs, %MMAs, %DMAs. RESULTS: Boys had significantly lower B12, higher Hcys, higher bAs, higher uAs, higher %MMAs, and a trend toward lower RBC folate compared to girls. Therefore, regression analyses controlling for water As and BMI were sex stratified. Among girls, RBC folate was inversely associated with bAs, plasma B12 was inversely associated with uAs, and plasma Hcys was inversely associated with %MMA. Among boys, 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. CONCLUSIONS: These findings suggest that associations between OCM nutritional status, bAs, and distribution of As metabolites in adolescents are similar to previously reported observations in adults and in children. The As methylation findings are statistically significant among boys but not among girls; this may be related to estrogen which more strongly influences OCM in females. The inverse association between Hcys and %MMA in girls is somewhat unexpected given that Hcys is known to be an indicator of impaired OCM and low folate/B12 in adults. Overall, these results indicate that the associations between OCM-related micronutrients and arsenic methylation in adolescents are generally similar to prior findings in adults, though these associations may differ by sex. Additionally, these findings suggest that more investigation into the role of Hcys in adolescent physiology is needed, perhaps particularly for girls. 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.

Early Cardiovascular Risk in E-cigarette Users: the Potential Role of Metals.

PURPOSE OF REVIEW: Electronic cigarettes (e-cigs) are a source of metals. Epidemiologic and experimental evidence support that metals are toxic to the cardiovascular system. Little is known, however, about the role that e-cig metals may play as toxicants for the possible cardiovascular effects of e-cig use. The goal of this narrative review is to summarize the evidence on e-cig use and metal exposure and on e-cig use and cardiovascular toxicity and discuss the research needs. RECENT FINDINGS: In vitro studies show cytotoxicity and increased oxidative stress in myocardial cells and vascular endothelial cells exposed to e-liquids and e-cig aerosols, with effects partially reversed with antioxidant treatment. There is some evidence that the heating coil plays a role in cell toxicity. Mice exposed to e-cigs for several weeks showed higher levels of oxidative stress, inflammation, platelet activation, and thrombogenesis. Cross-over clinical experiments show e-cig use alters nitric oxide-mediated flow-mediated dilation, endothelial progenitor cells, and arterial stiffness. Cross-sectional evidence from large nationally representative samples in the USA support that e-cig use is associated with self-reported myocardial infarction. Smaller studies found associations of e-cig use with higher oxidized low-density protein and heart variability compared to healthy controls. Numerous studies have measured elevated levels of toxic metals in e-cig aerosols including lead, nickel, chromium, and manganese. Arsenic has been measured in some e-liquids. Several of these metals are well known to be cardiotoxic. Numerous studies show that e-cigs are a source of cardiotoxic metals. Experimental studies (in vitro, in vivo, and clinical studies) show acute toxicity of e-cigs to the vascular system. Studies of long-term toxicity in animals and humans are missing. Longitudinal studies with repeated measures of metal exposure and subclinical cardiovascular outcomes (e.g., coronary artery calcification) could contribute to determine the long-term cardiovascular effects of e-cigs and the potential role of metals in those effects.

Long-Term Effects of Environmental Lead on Erythropoietin Production in Young Adults: A Follow-Up Study of a Prospective Cohort in Kosovo.

Background and Aims: Epidemiologic cross-sectional studies examining the relationship between environmental lead (Pb) exposure and erythropoietin (EPO) production have reported contrasting results. It is unknown, however, if exposure to Pb earlier in life has an effect on EPO production later in life. Here, using a prospective study, we evaluate the association between prenatal, early childhood, and concurrent Pb exposure and EPO concentration in young adulthood. Methods: From our prospective birth cohort study in Mitrovica (a mining town) and Pristina (a control town), Kosovo, from 1985 to 1998, we located and assessed blood lead concentration (BPb) and serum EPO in 101 participants (mean age 24.9 years) in 2011. We examined the association between BPb and EPO, stratified by hemoglobin (Hgb), and controlling for potential confounders. Results: These results resemble the findings in the original full cohort at 4.5 and 6.5 years of age, at which time we reported that the maintenance of a normal Hgb required increased EPO production among participants exposed to high levels of environmental Pb. In contrast, when the original cohort was 9.5 and 12 years of age, they were no longer capable of hyper-production of EPO in order to maintain normal levels of Hgb, suggestive of cumulative toxicity to the peritubular cells of the kidney that are responsible for EPO synthesis. Conclusion: Our results, along with previously reported findings on this cohort, suggest that a dramatic reduction of Pb exposure may allow for a reversal of the impact that prolonged Pb exposure may have on EPO production.

Early-Life Arsenic Exposure, Nutritional Status, and Adult Diabetes Risk.

PURPOSE OF REVIEW: In utero influences, including nutrition and environmental chemicals, may induce long-term metabolic changes and increase diabetes risk in adulthood. This review evaluates the experimental and epidemiological evidence on the association of early-life arsenic exposure on diabetes and diabetes-related outcomes, as well as the influence of maternal nutritional status on arsenic-related metabolic effects. RECENT FINDINGS: Five studies in rodents have evaluated the role of in utero arsenic exposure with diabetes in the offspring. In four of the studies, elevated post-natal fasting glucose was observed when comparing in utero arsenic exposure with no exposure. Rodent offspring exposed to arsenic in utero also showed elevated insulin resistance in the 4 studies evaluating it as well as microRNA changes related to glycemic control in 2 studies. Birth cohorts of arsenic-exposed pregnant mothers in New Hampshire, Mexico, and Taiwan have shown that increased prenatal arsenic exposure is related to altered cord blood gene expression, microRNA, and DNA methylation profiles in diabetes-related pathways. Thus far, no epidemiologic studies have evaluated early-life arsenic exposure with diabetes risk. Supplementation trials have shown B vitamins can reduce blood arsenic levels in highly exposed, undernourished populations. Animal evidence supports that adequate B vitamin status can rescue early-life arsenic-induced diabetes risk, although human data is lacking. Experimental animal studies and human evidence on the association of in utero arsenic exposure with alterations in gene expression pathways related to diabetes in newborns, support the potential role of early-life arsenic exposure in diabetes development, possibly through increased insulin resistance. Given pervasive arsenic exposure and the challenges to eliminate arsenic from the environment, research is needed to evaluate prevention interventions, including the possibility of low-cost, low-risk nutritional interventions that can modify arsenic-related disease risk.

Early life and adolescent arsenic exposure from drinking water and blood pressure in adolescence.

OBJECTIVES: Evidence of the association between inorganic arsenic (As) exposure, especially early-life exposure, and blood pressure (BP) in adolescence is limited. We examined the association of As exposure during early childhood, childhood, and adolescence with BP in adolescence. METHODS: We conducted a cross-sectional study of 726 adolescents aged 14-17 (mean 14.75) years whose mothers were participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS). Adolescents' BP was measured at the time of their recruitment between December 2012 and December 2016. We considered maternal urinary As (UAs), repeatedly measured during childhood, as proxy measures of early childhood (<5 years old, A1) and childhood (5-12 years old, A2) exposure. Adolescents' current UAs was collected at the time of recruitment (14-17 years of age, A3). RESULTS: Every doubling of UAs at A3 and maternal UAs at A1 was positively associated with a difference of 0.7-mmHg (95% confidence interval [CI]: 0.1, 1.3) and a 0.7-mmHg (95% CI: 0.05, 1.4) in SBP, respectively. These associations were stronger in adolescents with a BMI above the median (17.7 kg/m2) than those with a BMI below the median (P for interaction = 0.03 and 0.03, respectively). There was no significant association between any of the exposure measures and DBP. The Weighted Quantile Sum (WQS) regression confirmed that adolescents' UAs at A3 and maternal UAs at A1 contributed the most to the overall effect of As exposure at three life stages on SBP. Mixture analyses using Bayesian Kernel Machine Regression identified UAs at A3 as a significant contributor to SBP and DBP independent of other concurrent blood levels of cadmium, lead, manganese, and selenium. CONCLUSION: Our findings suggest an association of current exposure and early childhood exposure to As with higher BP in adolescents, which may be exacerbated by higher BMI at adolescence.

Urinary metals and metal mixtures in Bangladesh: Exploring environmental sources in the Health Effects of Arsenic Longitudinal Study (HEALS).

INTRODUCTION: Environmental exposure to toxic metals and metalloids is pervasive and occurs from multiple sources. The Health Effects of Arsenic Longitudinal Study (HEALS) is an ongoing prospective study predominantly focused on understanding health effects associated with arsenic exposure from drinking water. The goal of this project was to measure a suite of elements in urine to better understand potential exposure patterns and to identify common environmental sources of exposure among this semi-rural Bangladeshi population. METHODS: In a random sample of 199 adult HEALS participants (50% female), the concentrations of 15 urinary elements (As, Ba, Cd, Co, Cs, Cu, Mn, Mo, Ni, Pb, Se, Sr, Tl, W, Zn) were assessed by Inductively-Coupled Plasma Mass Spectrometry (ICP-MS) to assess commonalities with sociodemographic characteristics and potential sources of exposure. We used principal component analysis (PCA) with varimax normalized rotations, and hierarchical cluster analysis (CA), using Ward's method with Euclidean distances, to evaluate these relationships. RESULTS: PCA and CA showed similar patterns, suggesting 6 principal components (PC) and 5 clusters: 1)PC: Sr-Ni-Cs/ CA: Sr-Ni-Co; 2) Pb-Tl/Pb-Tl-Se-Cs; 3) As-Mo-W/As-Mo-W; 4) Ba-Mn/Ba-Mn; 5) Cu-Zn/Cu-Zn-Cd; and 6) Cd. There was a strong significant association between the As-Mo-W PC/cluster and water arsenic levels (p < 0.001) and between the Cd PC and betel nut use (p = 0.003). The Sr-Ni-Cs PC was not related to any of the socio-demographic characteristics investigated, including smoking status and occupation. The first PC, Sr-Ni-Cs, explained 21% of the variability; the third PC, As-Mo-W, explained 12.5% of the variability; and the sixth PC, Cd, explained 10% of the variability. Day laborers appeared to have the highest exposure. CONCLUSIONS: Groundwater and betel nut use are likely important sources of metal and metalloid exposure in this population. These findings will guide future exposure assessment research in Bangladesh and future epidemiologic research investigating the degree to which metal mixtures play a role in disease development.

A cross-sectional study of water arsenic exposure and intellectual function in adolescence in Araihazar, Bangladesh.

BACKGROUND: Exposure to inorganic arsenic (As) from drinking water is associated with modest deficits in intellectual function in young children; it is unclear whether deficits occur during adolescence, when key brain functions are more fully developed. OBJECTIVES: We sought to determine the degree to which As exposure is associated with adolescent intelligence, and the contributory roles of lead, cadmium, manganese and selenium. METHODS: We recruited a cross-section of 726 14-16 year olds (mean age = 14.8 years) whose mothers are participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS), and whose household well water As levels, which varied widely, were well characterized. Using a culturally modified version of the WISC-IV, we examined raw Full Scale scores, and Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed Indices. Blood levels of As (BAs), Mn, Pb, Cd and Se were assessed at the time of the visit, as was creatinine-adjusted urinary As (UAs/Cr). RESULTS: Linear regression analyses revealed that BAs was significantly negatively associated with all WISC-IV scores except for Perceptual Reasoning. With UAs/Cr as the exposure variable, we observed significantly negative associations for all WISC-IV scores. Except for Se, blood levels of other metals, were also associated with lower WISC-IV scores. Controlling for covariates, doubling BAs, or UAs/Cr, was associated with a mean decrement (95% CI) of 3.3 (1.1, 5.5), or 3.0 (1.2, 4.5) points, respectively, in raw Full scale scores with a sample mean of 177.6 (SD = 36.8). Confirmatory analyses using Bayesian Kernel Machine Regression, which identifies important mixture members, supported these findings; the primary contributor of the mixture was BAs, followed by BCd. CONCLUSIONS: Our data indicate that the adverse consequences of As exposure on neurodevelopment observed in other cross-sectional studies of younger children are also apparent during adolescence. They also implicate Cd as a neurotoxic element that deserves more attention.

Long-Term Effects of Environmental Lead Exposure on Blood Pressure and Plasma Soluble Cell Adhesion Molecules in Young Adults: A Follow-Up Study of a Prospective Cohort in Kosovo.

Background and Aims: Epidemiologic studies examining the relationship between environmental lead (Pb) exposure and blood pressure (BP) generally report small associations between blood lead concentration (BPb) and BP. However, these studies are predominantly cross-sectional. In addition, no epidemiologic studies evaluate associations between either current or past Pb exposure and serum levels of markers of systemic inflammation and endothelial dysfunction, including soluble vascular adhesion molecule (sVCAM-1) and soluble intercellular cell adhesion molecule (sICAM-1). We prospectively investigate these associations later in life: Methods. From our original prospective birth cohort study in Mitrovica (a mining town) and Prishtina (a control town), Kosovo, from 1985 to 1998, we located and assessed BPb and BP in 101 participants (mean age of 24.9 years old) in 2011. Results: We found highly statistically significant association between concurrent BPb and sVCAM-1 in men and a marginally significant association between concurrent PBb and sICAM.-1 in women. We did not find evidence of mediation. Conclusion: Current study results, along with previously reported findings on this cohort, provide evidence for the hypothesis that exposure to Pb leads to small increases in sBP and perhaps to increased circulating levels of sVCAM-1 and sICAM-1 later in life.

A cross-sectional study of well water arsenic and child IQ in Maine schoolchildren.

BACKGROUND: In recent studies in Bangladesh and elsewhere, exposure to arsenic (As) via drinking water is negatively associated with performance-related aspects of child intelligence (e.g., Perceptual Reasoning, Working Memory) after adjustment for social factors. Because findings are not easily generalizable to the US, we examine this relation in a US population. METHODS: In 272 children in grades 3-5 from three Maine school districts, we examine associations between drinking water As (WAs) and intelligence (WISC-IV). RESULTS: On average, children had resided in their current home for 7.3 years (approximately 75% of their lives). In unadjusted analyses, household well WAs is associated with decreased scores on most WISC-IV Indices. With adjustment for maternal IQ and education, HOME environment, school district and number of siblings, WAs remains significantly negatively associated with Full Scale IQ and Perceptual Reasoning, Working Memory and Verbal Comprehension scores. Compared to those with WAs < 5 µg/L, exposure to WAs ≥ 5 µg/L was associated with reductions of approximately 5-6 points in both Full Scale IQ (p < 0.01) and most Index scores (Perceptual Reasoning, Working Memory, Verbal Comprehension, all p's < 0.05). Both maternal IQ and education were associated with lower levels of WAs, possibly reflecting behaviors (e.g., water filters, residential choice) limiting exposure. Both WAs and maternal measures were associated with school district. CONCLUSIONS: The magnitude of the association between WAs and child IQ raises the possibility that levels of WAs ≥ 5 µg/L, levels that are not uncommon in the United States, pose a threat to child development.

Water arsenic exposure and intellectual function in 6-year-old children in Araihazar, Bangladesh.

BACKGROUND: We recently reported results of a cross-sectional investigation of intellectual function in 10-year-olds in Bangladesh, who had been exposed to arsenic from drinking water in their home wells. OBJECTIVES: We present results of a similar investigation of 301 randomly selected 6-year-olds whose parents participated in our ongoing prospective study of the health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. METHODS: Water As and manganese concentrations of tube wells at each home were obtained by surveying all study region wells. Children and mothers were first visited at home, where the quality of home stimulation was measured, and then seen in our field clinic, where children received a medical examination wherein weight, height, and head circumference were assessed. We assessed children's intellectual function using subtests drawn from the Wechsler Preschool and Primary Scale of Intelligence, version III, by summing weighted items across domains to create Verbal, Performance, Processing Speed, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and were asked to provide blood samples for blood lead measurements. RESULTS: Exposure to As from drinking water was associated with reduced intellectual function before and after adjusting for water Mn, for blood lead levels, and for sociodemographic features known to contribute to intellectual function. With covariate adjustment, water As remained significantly negatively associated with both Performance and Processing Speed raw scores; associations were less strong than in our previously studied 10-year-olds. CONCLUSION: This second cross-sectional study of As exposure expands our concerns about As neurotoxicity to a younger age group.

Water manganese exposure and children's intellectual function in Araihazar, Bangladesh.

Exposure to manganese via inhalation has long been known to elicit neurotoxicity in adults, but little is known about possible consequences of exposure via drinking water. In this study, we report results of a cross-sectional investigation of intellectual function in 142 10-year-old children in Araihazar, Bangladesh, who had been consuming tube-well water with an average concentration of 793 microg Mn/L and 3 microg arsenic/L. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children's intellectual function was assessed on tests drawn from the Wechsler Intelligence Scale for Children, version III, by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead, As, Mn, and hemoglobin concentrations. After adjustment for sociodemographic covariates, water Mn was associated with reduced Full-Scale, Performance, and Verbal raw scores, in a dose-response fashion; the low level of As in water had no effect. In the United States, roughly 6% of domestic household wells have Mn concentrations that exceed 300 microg Mn/L, the current U.S. Environmental Protection Agency lifetime health advisory level. We conclude that in both Bangladesh and the United States, some children are at risk for Mn-induced neurotoxicity.

A rapid and precise procedure for Pb isotopes in whole blood by Fe co-precipitation and MC-ICPMS analysis.

Elevated Pb levels in humans through environmental exposure are a significant health concern requiring scientific study of the sources of, and physiological response to this toxin. This requires a simple and precise method for measuring radiogenic Pb isotopes and Pb levels in blood. Presented here is a combination of methods for separation and analysis of Pb previously used predominantly for geologic samples. This includes separation of Pb from the complex matrix of blood samples using an Fe co-precipitation method, followed by isotopic analysis by multi-collector inductively coupled plasma mass spectrometry. Evaluation of the efficacy of this procedure shows that the precision of sample preparations as measured by % difference between the (207)Pb/(206)Pb of duplicate analyses averages 0.064% (n = 48). Using the same preparation and analysis techniques to measure Pb concentrations by isotope dilution resulted in a reproducibility of better than 6%. The method was successfully used to measure uptake of ingested soil Pb in a study of the bioavailability of Pb in contaminated soils.

Water arsenic exposure and children's intellectual function in Araihazar, Bangladesh.

Exposure to arsenic has long been known to have neurologic consequences in adults, but to date there are no well-controlled studies in children. We report results of a cross-sectional investigation of intellectual function in 201 children 10 years of age whose parents participate in our ongoing prospective cohort study examining health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. Water As and manganese concentrations of tube wells at each child's home were obtained by surveying all wells in the study region. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children's intellectual function on tests drawn from the Wechsler Intelligence Scale for Children, version III, was assessed by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead and hemoglobin concentrations. Exposure to As from drinking water was associated with reduced intellectual function after adjustment for sociodemographic covariates and water Mn. Water As was associated with reduced intellectual function, in a dose-response manner, such that children with water As levels > 50 microg/L achieved significantly lower Performance and Full-Scale scores than did children with water As levels < 5.5 microg/L. The association was generally stronger for well-water As than for urinary As.

Promotion of well-switching to mitigate the current arsenic crisis in Bangladesh.

OBJECTIVE: To survey tube wells and households in Araihazar upazila, Bangladesh, to set the stage for a long-term epidemiological study of the consequences of chronic arsenic exposure. METHODS: Water samples and household data were collected over a period of 4 months in 2000 from 4997 contiguous tube wells serving a population of 55000, the position of each well being determined to within +/- 30 m using Global Positioning System receivers. Arsenic concentrations were determined by graphite-furnace atomic-absorption spectrometry. In addition, groundwater samples collected every 2 weeks for an entire year from six tube wells were analysed for arsenic by high-resolution inductively coupled plasma-mass spectrometry. FINDINGS: Half of the wells surveyed in Araihazar had been installed in the previous 5 years; 94% were privately owned. Only about 48% of the surveyed wells supplied water with an arsenic content below 50 micro g/l, the current Bangladesh standard for drinking-water. Similar to other regions of Bangladesh and West Bengal, India, the distribution of arsenic in Araihazar is spatially highly variable (range: 5-860 micro g/l) and therefore difficult to predict. Because of this variability, however, close to 90% of the inhabitants live within 100 m of a safe well. Monitoring of six tube wells currently meeting the 50 micro g/l standard showed no indication of a seasonal cycle in arsenic concentrations coupled to the hydrological cycle. This suggests that well-switching is a viable option in Araihazar, at least for the short term. CONCLUSIONS: Well-switching should be more systematically encouraged in Araihazar and many other parts of Bangladesh and West Bengal, India. Social barriers to well-switching need to be better understood and, if possible, overcome.