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1.  Serum Polyfluoroalkyl Concentrations, Asthma Outcomes, and Immunological Markers in a Case–Control Study of Taiwanese Children 
Environmental Health Perspectives  2013;121(4):507-513.
Background: Perfluorinated compounds (PFCs) are ubiquitous pollutants. Experimental data suggest that they may be associated with adverse health outcomes, including asthma. However, there is little supporting epidemiological evidence.
Methods: A total of 231 asthmatic children and 225 nonasthmatic controls, all from northern Taiwan, were recruited in the Genetic and Biomarkers study for Childhood Asthma. Structure questionnaires were administered by face-to-face interview. Serum concentrations of 11 PFCs and levels of immunological markers were also measured. Associations of PFC quartiles with concentrations of immunological markers and asthma outcomes were estimated using multivariable regression models.
Results: Nine PFCs were detectable in most children (≥ 84.4%), of which perfluorooctane sulfonate (PFOS) was the most abundant (median serum concentrations of 33.9 ng/mL in asthmatics and 28.9 ng/mL in controls). Adjusted odds ratios for asthma among those with the highest versus lowest quartile of PFC exposure ranged from 1.81 (95% CI: 1.02, 3.23) for the perfluorododecanoic acid (PFDoA) to 4.05 (95% CI: 2.21, 7.42) for perfluorooctanic acid (PFOA). PFOS, PFOA, and subsets of the other PFCs were positively associated with serum IgE concentrations, absolute eosinophil counts (AEC), eosinophilic cationic protein (ECP) concentrations, and asthma severity scores among asthmatics.
Conclusions: This study suggests an association between PFC exposure and juvenile asthma. Because of widespread exposure to these chemicals, these findings may be of potential public health concern.
doi:10.1289/ehp.1205351
PMCID: PMC3620752  PMID: 23309686
asthma; AEC; ECP; IgE; perfluorinated compounds
2.  The in Vitro Estrogenic Activities of Polyfluorinated Iodine Alkanes 
Environmental Health Perspectives  2011;120(1):119-125.
Background: Polyfluorinated iodine alkanes (PFIs) are important intermediates in the synthesis of organic fluoride products. Recently, PFIs have been detected in fluoropolymers as residual raw materials, as well as in the ambient environment.
Objectives: High production volumes and potential environmental releases of PFIs might become a concern, but the exposure risk and toxicity of these chemicals are still unclear. In this study, we investigated the potential estrogenic effects of PFIs.
Methods: We studied the estrogenic effects of fluorinated iodine alkanes (FIAs), fluorinated telomer iodides (FTIs), and fluorinated diiodine alkanes (FDIAs) using the E-screen and MVLN assays and the evaluation of estrogen-responsive genes in MCF-7 cells.
Results: FIAs have an iodine atom at one end of the perfluorinated carbon chain. 1-Iodoperfluorohexane (PFHxI) and 1-iodoperfluorooctane (PFOI) promoted the proliferation of MCF-7 cells, induced luciferase activity in MVLN cells, and up-regulated the expression of TFF1 and EGR3. In these assays, other FIAs gave negative responses. FDIAs have an iodine atom at each end of the perfluorinated carbon chain, and all the FDIAs showed estrogenic effects. The estrogenic potencies of FIAs and FDIAs correlate well with the carbon chain length of the chemicals. The optimum chain length for estrogenic effects is six carbons, and then eight and four carbons. All FTIs have a single iodine atom at the end of a partially fluorinated carbon chain. None of the FTIs showed estrogenic effects in the tests.
Conclusions: The estrogenic effects of PFIs are dependent on the structural features of iodine substitution and chain length. This research will be helpful in further understanding the estrogenic effects of perfluorinated compounds.
doi:10.1289/ehp.1103773
PMCID: PMC3261944  PMID: 21990342
endocrine disruptor; estrogenic effects; in vitro assay; perfluorinated chemicals; polyfluorinated iodine alkanes
3.  Blood Lead Concentration and Thyroid Function during Pregnancy: Results from the Yugoslavia Prospective Study of Environmental Lead Exposure 
Environmental Health Perspectives  2014;122(10):1134-1140.
Background: Although maternal hypothyroidism increases the risk of adverse neonatal and obstetric outcomes as well as lower IQ in children, the environmental determinants of maternal thyroid dysfunction have yet to be fully explored.
Objectives: We aimed to examine associations between mid-pregnancy blood lead (BPb) and concomitant measures of thyroid function among participants in the Yugoslavia Prospective Study of Environmental Lead Exposure.
Methods: As part of a population-based prospective study of two towns in Kosovo—one with high levels of environmental lead and one with low—women were recruited during the second trimester of pregnancy, at which time blood samples and questionnaire data were collected. We measured concentrations of BPb, free thyroxine (FT4), thyroid-stimulating hormone (TSH), and thyroid peroxidase antibodies (TPOAb) in archived serum samples.
Results: Compared with women from the unexposed town, women from the exposed town had lower mean FT4 (0.91 ± 0.17 vs. 1.03 ± 0.16 ng/dL), higher mean TPOAb (15.45 ± 33.08 vs. 5.12 ± 6.38 IU/mL), and higher mean BPb (20.00 ± 6.99 vs. 5.57 ± 2.01 μg/dL). No differences in TSH levels were found. After adjustment for potential confounders, for each natural log unit increase in BPb, FT4 decreased by 0.074 ng/dL (95% CI: –0.10, –0.046 ng/dL), and the odds ratio for testing positive to TPOAb was 2.41 (95% CI: 1.53, 3.82). We found no association between BPb and TSH.
Conclusions: Prolonged lead exposure may contribute to maternal thyroid dysfunction by stimulating autoimmunity to the thyroid gland.
Citation: Kahn LG, Liu X, Rajovic B, Popovac D, Oberfield S, Graziano JH, Factor-Litvak P. 2014. Blood lead concentration and thyroid function during pregnancy: results from the Yugoslavia Prospective Study of Environmental Lead Exposure. Environ Health Perspect 122:1134–1140; http://dx.doi.org/10.1289/ehp.1307669
doi:10.1289/ehp.1307669
PMCID: PMC4181923  PMID: 24866691
4.  Early Postnatal Exposure to Ultrafine Particulate Matter Air Pollution: Persistent Ventriculomegaly, Neurochemical Disruption, and Glial Activation Preferentially in Male Mice 
Environmental Health Perspectives  2014;122(9):939-945.
Background: Air pollution has been associated with adverse neurological and behavioral health effects in children and adults. Recent studies link air pollutant exposure to adverse neurodevelopmental outcomes, including increased risk for autism, cognitive decline, ischemic stroke, schizophrenia, and depression.
Objectives: We sought to investigate the mechanism(s) by which exposure to ultrafine concentrated ambient particles (CAPs) adversely influences central nervous system (CNS) development.
Methods: We exposed C57BL6/J mice to ultrafine (< 100 nm) CAPs using the Harvard University Concentrated Ambient Particle System or to filtered air on postnatal days (PNDs) 4–7 and 10–13, and the animals were euthanized either 24 hr or 40 days after cessation of exposure. Another group of males was exposed at PND270, and lateral ventricle area, glial activation, CNS cytokines, and monoamine and amino acid neurotransmitters were quantified.
Results: We observed ventriculomegaly (i.e., lateral ventricle dilation) preferentially in male mice exposed to CAPs, and it persisted through young adulthood. In addition, CAPs-exposed males generally showed decreases in developmentally important CNS cytokines, whereas in CAPs-exposed females, we observed a neuroinflammatory response as indicated by increases in CNS cytokines. We also saw changes in CNS neurotransmitters and glial activation across multiple brain regions in a sex-dependent manner and increased hippocampal glutamate in CAPs-exposed males.
Conclusions: We observed brain region– and sex-dependent alterations in cytokines and neurotransmitters in both male and female CAPs-exposed mice. Lateral ventricle dilation (i.e., ventriculomegaly) was observed only in CAPs-exposed male mice. Ventriculomegaly is a neuropathology that has been associated with poor neurodevelopmental outcome, autism, and schizophrenia. Our findings suggest alteration of developmentally important neurochemicals and lateral ventricle dilation may be mechanistically related to observations linking ambient air pollutant exposure and adverse neurological/neurodevelopmental outcomes in humans.
Citation: Allen JL, Liu X, Pelkowski S, Palmer B, Conrad K, Oberdörster G, Weston D, Mayer-Pröschel M, Cory-Slechta DA. 2014. Early postnatal exposure to ultrafine particulate matter air pollution: persistent ventriculomegaly, neurochemical disruption, and glial activation preferentially in male mice. Environ Health Perspect 122:939–945; http://dx.doi.org/10.1289/ehp.1307984
doi:10.1289/ehp.1307984
PMCID: PMC4154219  PMID: 24901756
5.  Drinking-Water Disinfection By-products and Semen Quality: A Cross-Sectional Study in China 
Environmental Health Perspectives  2014;122(7):741-746.
Background: Exposure to disinfection by-products (DBPs) has been demonstrated to impair male reproductive health in animals, but human evidence is limited and inconsistent.
Objective: We examined the association between exposure to drinking-water DBPs and semen quality in a Chinese population.
Methods: We recruited 2,009 men seeking semen analysis from the Reproductive Center of Tongji Hospital in Wuhan, China, between April 2011 and May 2012. Each man provided a semen sample and a urine sample. Semen samples were analyzed for sperm concentration, sperm motility, and sperm count. As a biomarker of exposure to drinking-water DBPs, trichloroacetic acid (TCAA) was measured in the urine samples.
Results: The mean (median) urinary TCAA concentration was 9.58 (7.97) μg/L (interquartile range, 6.01–10.96 μg/L). Compared with men with urine TCAA in the lowest quartile, increased adjusted odds ratios (ORs) were estimated for below-reference sperm concentration in men with TCAA in the second and fourth quartiles (OR = 1.79; 95% CI: 1.19, 2.69 and OR = 1.51; 95% CI: 0.98, 2.31, respectively), for below-reference sperm motility in men with TCAA in the second and third quartiles (OR = 1.46; 95% CI: 1.12, 1.90 and OR = 1.30; 95% CI: 1.00, 1.70, respectively), and for below-reference sperm count in men with TCAA in the second quartile (OR 1.62; 95% CI: 1.04, 2.55). Nonmonotonic associations with TCAA quartiles were also estimated for semen parameters modeled as continuous outcomes, although significant negative associations were estimated for all quartiles above the reference level for sperm motility.
Conclusion: Our findings suggest that exposure to drinking-water DBPs may contribute to decreased semen quality in humans.
Citation: Zeng Q, Wang YX, Xie SH, Xu L, Chen YZ, Li M, Yue J, Li YF, Liu AL, Lu WQ. 2014. Drinking-water disinfection by-products and semen quality: a cross-sectional study in China. Environ Health Perspect 122:741–746; http://dx.doi.org/10.1289/ehp.1307067
doi:10.1289/ehp.1307067
PMCID: PMC4080533  PMID: 24695319
6.  Effects of Arsenic on Osteoblast Differentiation in Vitro and on Bone Mineral Density and Microstructure in Rats 
Environmental Health Perspectives  2014;122(6):559-565.
Background: Arsenic is a ubiquitous toxic element and is known to contaminate drinking water in many countries. Several epidemiological studies have shown that arsenic exposure augments the risk of bone disorders. However, the detailed effect and mechanism of inorganic arsenic on osteoblast differentiation of bone marrow stromal cells and bone loss still remain unclear.
Objectives: We investigated the effects and mechanism of arsenic on osteoblast differentiation in vitro and evaluated bone mineral density (BMD) and bone microstructure in rats at doses relevant to human exposure from drinking water.
Methods: We used a cell model of rat primary bone marrow stromal cells (BMSCs) and a rat model of long-term exposure with arsenic-contaminated drinking water, and determined bone microstructure and BMD in rats by microcomputed tomography (μCT).
Results: We observed significant attenuation of osteoblast differentiation after exposure of BMSCs to arsenic trioxide (0.5 or 1 μM). After arsenic treatment during differentiation, expression of runt-related transcription factor-2 (Runx2), bone morphogenetic protein-2 (BMP-2), and osteocalcin in BMSCs was inhibited and phosphorylation of enhanced extracellular signal-regulated kinase (ERK) was increased. These altered differentiation-related molecules could be reversed by the ERK inhibitor PD98059. Exposure of rats to arsenic trioxide (0.05 or 0.5 ppm) in drinking water for 12 weeks altered BMD and microstructure, decreased Runx2 expression, and increased ERK phosphorylation in bones. In BMSCs isolated from arsenic-treated rats, osteoblast differentiation was inhibited.
Conclusions: Our results suggest that arsenic is capable of inhibiting osteoblast differentiation of BMSCs via an ERK-dependent signaling pathway and thus increasing bone loss.
Citation: Wu CT, Lu TY, Chan DC, Tsai KS, Yang RS, Liu SH. 2014. Effects of arsenic on osteoblast differentiation in vitro and on bone mineral density and microstructure in rats. Environ Health Perspect 122:559–565; http://dx.doi.org/10.1289/ehp.1307832
doi:10.1289/ehp.1307832
PMCID: PMC4050517  PMID: 24531206
8.  Chronic Arsenic Exposure and Angiogenesis in Human Bronchial Epithelial Cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway 
Environmental Health Perspectives  2014;122(3):255-261.
Background: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.
Objectives: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.
Methods: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.
Results: We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis.
Conclusion: The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis.
Citation: He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255–261; http://dx.doi.org/10.1289/ehp.1307545
doi:10.1289/ehp.1307545
PMCID: PMC3948041  PMID: 24413338
9.  Estimation and Uncertainty Analysis of Impacts of Future Heat Waves on Mortality in the Eastern United States 
Background: Climate change is anticipated to influence heat-related mortality in the future. However, estimates of excess mortality attributable to future heat waves are subject to large uncertainties and have not been projected under the latest greenhouse gas emission scenarios.
Objectives: We estimated future heat wave mortality in the eastern United States (approximately 1,700 counties) under two Representative Concentration Pathways (RCPs) and investigated sources of uncertainty.
Methods: Using dynamically downscaled hourly temperature projections for 2057–2059, we projected heat wave days that were defined using four heat wave metrics and estimated the excess mortality attributable to them. We apportioned the sources of uncertainty in excess mortality estimates using a variance-decomposition method.
Results: Estimates suggest that excess mortality attributable to heat waves in the eastern United States would result in 200–7,807 deaths/year (mean 2,379 deaths/year) in 2057–2059. Average excess mortality projections under RCP4.5 and RCP8.5 scenarios were 1,403 and 3,556 deaths/year, respectively. Excess mortality would be relatively high in the southern states and eastern coastal areas (excluding Maine). The major sources of uncertainty were the relative risk estimates for mortality on heat wave versus non–heat wave days, the RCP scenarios, and the heat wave definitions.
Conclusions: Mortality risks from future heat waves may be an order of magnitude higher than the mortality risks reported in 2002–2004, with thousands of heat wave–related deaths per year in the study area projected under the RCP8.5 scenario. Substantial spatial variability in county-level heat mortality estimates suggests that effective mitigation and adaptation measures should be developed based on spatially resolved data.
Citation: Wu J, Zhou Y, Gao Y, Fu JS, Johnson BA, Huang C, Kim YM, Liu Y. 2014. Estimation and uncertainty analysis of impacts of future heat waves on mortality in the eastern United States. Environ Health Perspect 122:10–16; http://dx.doi.org/10.1289/ehp.1306670
doi:10.1289/ehp.1306670
PMCID: PMC3888568  PMID: 24192064
10.  Air Pollution–Mediated Susceptibility to Inflammation and Insulin Resistance: Influence of CCR2 Pathways in Mice 
Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects.
Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5-mediated inflammation and IR.
Methods: Wild-type C57BL/6 and CCR2–/– male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography.
Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2–/– mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2–/– mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency.
Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR.
Citation: Liu C, Xu X, Bai Y, Wang TY, Rao X, Wang A, Sun L, Ying Z, Gushchina L, Maiseyeu A, Morishita M, Sun Q, Harkema JR, Rajagopalan S. 2014. Air pollution–mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice. Environ Health Perspect 122:17–26; http://dx.doi.org/10.1289/ehp.1306841
doi:10.1289/ehp.1306841
PMCID: PMC3888572  PMID: 24149114
11.  Long-Term Exposure to Concentrated Ambient PM2.5 Increases Mouse Blood Pressure through Abnormal Activation of the Sympathetic Nervous System: A Role for Hypothalamic Inflammation 
Background: Exposure to particulate matter ≤ 2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown.
Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation.
Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system.
Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure–induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor–kappaB (NF-κB) pathway activation.
Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation.
Citation: Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. 2014. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79–86; http://dx.doi.org/10.1289/ehp.1307151
doi:10.1289/ehp.1307151
PMCID: PMC3888575  PMID: 24240275
12.  A Dose–Response Study of Arsenic Exposure and Global Methylation of Peripheral Blood Mononuclear Cell DNA in Bangladeshi Adults 
Environmental Health Perspectives  2013;121(11-12):1306-1312.
Background: Several studies employing cell culture and animal models have suggested that arsenic (As) exposure induces global DNA hypomethylation. However, As has been associated with global DNA hypermethylation in human study populations. We hypothesized that this discrepancy may reflect a nonlinear relationship between As dose and DNA methylation.
Objective: The objective of this study was to examine the dose–response relationship between As and global methylation of peripheral blood mononuclear cell (PBMC) DNA in apparently healthy Bangladeshi adults chronically exposed to a wide range of As concentrations in drinking water.
Methods: Global PBMC DNA methylation, plasma folate, blood S-adenosylmethionine (SAM), and concentrations of As in drinking water, blood, and urine were measured in 320 adults. DNA methylation was measured using the [3H]-methyl incorporation assay, which provides disintegration-per-minute (DPM) values that are negatively associated with global DNA methylation.
Results: Water, blood, and urinary As were positively correlated with global PBMC DNA methylation (p < 0.05). In multivariable-adjusted models, 1-μg/L increases in water and urinary As were associated with 27.6-unit (95% CI: 6.3, 49.0) and 22.1-unit (95% CI: 0.5, 43.8) decreases in DPM per microgram DNA, respectively. Categorical models indicated that estimated mean levels of PBMC DNA methylation were highest in participants with the highest As exposures.
Conclusions: These results suggest that As is positively associated with global methylation of PBMC DNA over a wide range of drinking water As concentrations. Further research is necessary to elucidate underlying mechanisms and physiologic implications.
Citation: Niedzwiecki MM, Hall MN, Liu X, Oka J, Harper KN, Slavkovich V, Ilievski V, Levy D, van Geen A, Mey JL, Alam S, Siddique AB, Parvez F, Graziano JH, Gamble MV. 2013. A dose–response study of arsenic exposure and global methylation of peripheral blood mononuclear cell DNA in Bangladeshi adults. Environ Health Perspect 121:1306–1312; http://dx.doi.org/10.1289/ehp.1206421
doi:10.1289/ehp.1206421
PMCID: PMC3855504  PMID: 24013868
13.  Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications 
Environmental Health Perspectives  2013;121(11-12):1245-1252.
Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years.
Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967
doi:10.1289/ehp.1306967
PMCID: PMC3855519  PMID: 23933572
14.  Chronic Arsenic Exposure and Blood Glutathione and Glutathione Disulfide Concentrations in Bangladeshi Adults 
Environmental Health Perspectives  2013;121(9):1068-1074.
Background: In vitro and rodent studies have shown that arsenic (As) exposure can deplete glutathione (GSH) and induce oxidative stress. GSH is the primary intracellular antioxidant; it donates an electron to reactive oxygen species, thus producing glutathione disulfide (GSSG). Cysteine (Cys) and cystine (CySS) are the predominant thiol/disulfide redox couple found in human plasma. Arsenic, GSH, and Cys are linked in several ways: a) GSH is synthesized via the transsulfuration pathway, and Cys is the rate-limiting substrate; b) intermediates of the methionine cycle regulate both the transsulfuration pathway and As methylation; c) GSH serves as the electron donor for reduction of arsenate to arsenite; and d) As has a high affinity for sulfhydryl groups and therefore binds to GSH and Cys.
Objectives: We tested the hypothesis that As exposure is associated with decreases in GSH and Cys and increases in GSSG and CySS (i.e., a more oxidized environment).
Methods: For this cross-sectional study, the Folate and Oxidative Stress Study, we recruited a total of 378 participants from each of five water As concentration categories: < 10 (n = 76), 10–100 (n = 104), 101–200 (n = 86), 201–300 (n = 67), and > 300 µg/L (n = 45). Concentrations of GSH, GSSG, Cys, and CySS were measured using HPLC.
Results: An interquartile range (IQR) increase in water As was negatively associated with blood GSH (mean change, –25.4 µmol/L; 95% CI: –45.3, –5.31) and plasma CySS (mean change, –3.00 µmol/L; 95% CI: –4.61, –1.40). We observed similar associations with urine and blood As. There were no significant associations between As exposure and blood GSSG or plasma Cys.
Conclusions: The observed associations are consistent with the hypothesis that As may influence concentrations of GSH and other nonprotein sulfhydryls through binding and irreversible loss in bile and/or possibly in urine.
Citation: Hall MN, Niedzwiecki M, Liu X, Harper KN, Alam S, Slavkovich V, Ilievski V, Levy D, Siddique AB, Parvez F, Mey JL, van Geen A, Graziano J, Gamble MV. 2013. Chronic arsenic exposure and blood glutathione and glutathione disulfide concentrations in Bangladeshi adults. Environ Health Perspect 121:1068–1074; http://dx.doi.org/10.1289/ehp.1205727
doi:10.1289/ehp.1205727
PMCID: PMC3764071  PMID: 23792557
15.  A Prospective Study of Arsenic Exposure, Arsenic Methylation Capacity, and Risk of Cardiovascular Disease in Bangladesh 
Environmental Health Perspectives  2013;121(7):832-838.
Background: Few prospective studies have evaluated the influence of arsenic methylation capacity on cardiovascular disease (CVD) risk.
Objective: We evaluated the association of arsenic exposure from drinking water and arsenic methylation capacity with CVD risk.
Method: We conducted a case–cohort study of 369 incident fatal and nonfatal cases of CVD, including 211 cases of heart disease and 148 cases of stroke, and a subcohort of 1,109 subjects randomly selected from the 11,224 participants in the Health Effects of Arsenic Longitudinal Study (HEALS).
Results: The adjusted hazard ratios (aHRs) for all CVD, heart disease, and stroke in association with a 1-SD increase in baseline well-water arsenic (112 µg/L) were 1.15 (95% CI: 1.01, 1.30), 1.20 (95% CI: 1.04, 1.38), and 1.08 (95% CI: 0.90, 1.30), respectively. aHRs for the second and third tertiles of percentage urinary monomethylarsonic acid (MMA%) relative to the lowest tertile, respectively, were 1.27 (95% CI: 0.85, 1.90) and 1.55 (95% CI: 1.08, 2.23) for all CVD, and 1.65 (95% CI: 1.05, 2.60) and 1.61 (95% CI: 1.04, 2.49) for heart disease specifically. The highest versus lowest ratio of urinary dimethylarsinic acid (DMA) to MMA was associated with a significantly decreased risk of CVD (aHR = 0.54; 95% CI: 0.34, 0.85) and heart disease (aHR = 0.54; 95% CI: 0.33, 0.88). There was no significant association between arsenic metabolite indices and stroke risk. The effects of incomplete arsenic methylation capacity—indicated by higher urinary MMA% or lower urinary DMA%—with higher levels of well-water arsenic on heart disease risk were additive. There was some evidence of a synergy of incomplete methylation capacity with older age and cigarette smoking.
Conclusions: Arsenic exposure from drinking water and the incomplete methylation capacity of arsenic were adversely associated with heart disease risk.
doi:10.1289/ehp.1205797
PMCID: PMC3701993  PMID: 23665672
arsenic; arsenic methylation capacity; Bangladesh; cardiovascular disease; case–cohort study
16.  Concentrations and Potential Health Risks of Metals in Lip Products 
Environmental Health Perspectives  2013;121(6):705-710.
Background: Metal content in lip products has been an issue of concern.
Objectives: We measured lead and eight other metals in a convenience sample of 32 lip products used by young Asian women in Oakland, California, and assessed potential health risks related to estimated intakes of these metals.
Methods: We analyzed lip products by inductively coupled plasma optical emission spectrometry and used previous estimates of lip product usage rates to determine daily oral intakes. We derived acceptable daily intakes (ADIs) based on information used to determine public health goals for exposure, and compared ADIs with estimated intakes to assess potential risks.
Results: Most of the tested lip products contained high concentrations of titanium and aluminum. All examined products had detectable manganese. Lead was detected in 24 products (75%), with an average concentration of 0.36 ± 0.39 ppm, including one sample with 1.32 ppm. When used at the estimated average daily rate, estimated intakes were > 20% of ADIs derived for aluminum, cadmium, chromium, and manganese. In addition, average daily use of 10 products tested would result in chromium intake exceeding our estimated ADI for chromium. For high rates of product use (above the 95th percentile), the percentages of samples with estimated metal intakes exceeding ADIs were 3% for aluminum, 68% for chromium, and 22% for manganese. Estimated intakes of lead were < 20% of ADIs for average and high use.
Conclusions: Cosmetics safety should be assessed not only by the presence of hazardous contents, but also by comparing estimated exposures with health-based standards. In addition to lead, metals such as aluminum, cadmium, chromium, and manganese require further investigation.
doi:10.1289/ehp.1205518
PMCID: PMC3672908  PMID: 23674482
cosmetic safety; health risk; lipstick; metal; susceptible populations
17.  Short-Term Effects of the 2008 Cold Spell on Mortality in Three Subtropical Cities in Guangdong Province, China 
Environmental Health Perspectives  2012;121(2):210-216.
Background: Few studies have been conducted to investigate the impact of extreme cold events on mortality in subtropical regions.
Objective: In the present study we aimed to investigate the effects of the 2008 cold spell on mortality and the possibility of mortality displacement in three subtropical cities in China.
Methods: Daily mortality, air pollution, and weather data were collected from 2006 to 2009 in Guangzhou, Nanxiong (no air pollutants), and Taishan. We used a polynomial distributed lag model (DLM) to analyze the relationship between the 2008 cold spell and mortality. To observe the mortality displacement of the cold spell, we estimated the cumulative effects at lag0, lag0–6, lag0–13, lag0–20, and lag0–27 separately.
Results: During the 2008 cold spell, the cumulative risk of nonaccidental mortality increased significantly in Guangzhou [relative risk (RR) = 1.60; 95% CI: 1.19, 2.14] and Taishan (RR = 1.60; 95% CI: 1.06, 2.40) when lagged up to 4 weeks after the cold spell ended. Estimated effects at lag0–27 were more pronounced for males than for females, for respiratory mortality than for cardiovascular mortality, and for the elderly (≥ 75 years of age) than for those 0–64 years of age. Most of the cumulative RRs increased with longer lag times in Guangzhou and Taishan. However, in Nanxiong, the trend with cumulative RRs was less consistent, and we observed no statistically significant associations at lag0–27.
Conclusion: We found associations between the 2008 cold spell and increased mortality in the three subtropical cities of China. The lag effect structure of the cold spell varied with location and the type of mortality, and evidence of short-term mortality displacement was inconsistent. These findings suggest that extreme cold is an important public health problem in subtropical regions.
doi:10.1289/ehp.1104541
PMCID: PMC3569675  PMID: 23128031
climate change; cold spell; mortality; subtropical cities; temperature
18.  Association between Residential Proximity to Fuel-Fired Power Plants and Hospitalization Rate for Respiratory Diseases 
Environmental Health Perspectives  2012;120(6):807-810.
Background: Air pollution is known to cause respiratory disease. Unlike motor vehicle sources, fuel-fired power plants are stationary.
Objective: Using hospitalization data, we examined whether living near a fuel-fired power plant increases the likelihood of hospitalization for respiratory disease.
Methods: Rates of hospitalization for asthma, acute respiratory infection (ARI), and chronic obstructive pulmonary disease (COPD) were estimated using hospitalization data for 1993–2008 from New York State in relation to data for residences near fuel-fired power plants. We also explored data for residential proximity to hazardous waste sites.
Results: After adjusting for age, sex, race, median household income, and rural/urban residence, there were significant 11%, 15%, and 17% increases in estimated rates of hospitalization for asthma, ARI, and COPD, respectively, among individuals > 10 years of age living in a ZIP code containing a fuel-fired power plant compared with one that had no power plant. Living in a ZIP code with a fuel-fired power plant was not significantly associated with hospitalization for asthma or ARI among children < 10 years of age. Living in a ZIP code with a hazardous waste site was associated with hospitalization for all outcomes in both age groups, and joint effect estimates were approximately additive for living in a ZIP code that contained a fuel-fired power plant and a hazardous waste site.
Conclusions: Our results are consistent with the hypothesis that exposure to air pollution from fuel-fired power plants and volatile compounds coming from hazardous waste sites increases the risk of hospitalization for respiratory diseases.
doi:10.1289/ehp.1104146
PMCID: PMC3385425  PMID: 22370087
asthma; COPD; particulates; respiratory infection; SO2
19.  Modeling the Residential Infiltration of Outdoor PM2.5 in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) 
Environmental Health Perspectives  2012;120(6):824-830.
Background: Epidemiologic studies of fine particulate matter [aerodynamic diameter ≤ 2.5 μm (PM2.5)] typically use outdoor concentrations as exposure surrogates. Failure to account for variation in residential infiltration efficiencies (Finf) will affect epidemiologic study results.
Objective: We aimed to develop models to predict Finf for > 6,000 homes in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air), a prospective cohort study of PM2.5 exposure, subclinical cardiovascular disease, and clinical outcomes.
Methods: We collected 526 two-week, paired indoor–outdoor PM2.5 filter samples from a subset of study homes. PM2.5 elemental composition was measured by X-ray fluorescence, and Finf was estimated as the indoor/outdoor sulfur ratio. We regressed Finf on meteorologic variables and questionnaire-based predictors in season-specific models. Models were evaluated using the R2 and root mean square error (RMSE) from a 10-fold cross-validation.
Results: The mean ± SD Finf across all communities and seasons was 0.62 ± 0.21, and community-specific means ranged from 0.47 ± 0.15 in Winston-Salem, North Carolina, to 0.82 ± 0.14 in New York, New York. Finf was generally greater during the warm (> 18°C) season. Central air conditioning (AC) use, frequency of AC use, and window opening frequency were the most important predictors during the warm season; outdoor temperature and forced-air heat were the best cold-season predictors. The models predicted 60% of the variance in 2-week Finf, with an RMSE of 0.13.
Conclusions: We developed intuitive models that can predict Finf using easily obtained variables. Using these models, MESA Air will be the first large epidemiologic study to incorporate variation in residential Finf into an exposure assessment.
doi:10.1289/ehp.1104447
PMCID: PMC3385439  PMID: 22534026
air exchange; attenuation; deposition; exposure misclassification; penetration; ventilation
20.  Effects of Decabrominated Diphenyl Ether (PBDE-209) in Regulation of Growth and Apoptosis of Breast, Ovarian, and Cervical Cancer Cells 
Environmental Health Perspectives  2012;120(4):541-546.
Background: Polybrominated diphenyl ethers (PBDEs), commonly used in building materials, electronics, plastics, polyurethane foams, and textiles, are health hazards found in the environment.
Objective: In this study we investigated the effects of PBDE-209, a deca-PBDE, on the regulation of growth and apoptosis of breast, ovarian, and cervical cancer cells as well as the underlying protein alterations.
Methods: We used MCF-7 and MCF-7/ADR (multidrug-resistant MCF-7) breast cancer cell lines, the HeLa cervical cancer cell line, the OVCAR-3 ovarian cancer cell line, and the normal CHO (Chinese hamster ovary) cell line to assess the effects of PBDE-209 using cell viability, immunofluorescence, and flow cytometric assays. Western blot assays were used to detect changes in protein expression. To assess the effects of PBDE-209 on apoptosis, we used the protein kinase Cα (PKCα) inhibitor Gö 6976, the extracellular signal-regulated kinase (ERK) inhibitor PD98059, and tamoxifen.
Results: Our data indicate that PBDE-209 increased viability and proliferation of the tumor cell lines and in CHO cells in a dose- and time-dependent manner. PBDE-209 also altered cell cycle distribution by inducing the S phase or G2/M phase. Furthermore, PBDE-209 partially suppressed tamoxifen-induced cell apoptosis in the breast cancer cell lines (MCF-7 and MCF-7/ADR) but suppressed Gö 6976- and PD98059-induced apoptosis in all cell lines. At the molecular level, PBDE-209 enhanced PKCα and ERK1/2 phosphorylation in the cell lines.
Conclusions: Our data demonstrate that PBDE-209 is able to promote proliferation of various cancer cells from the female reproductive system and normal ovarian CHO cells. Furthermore, it reduced tamoxifen, PKCα, and ERK inhibition-induced apoptosis. Finally, PBDE-209 up-regulated phosphorylation of PKCα and ERK1/2 proteins in tumor cells and in CHO cells.
doi:10.1289/ehp.1104051
PMCID: PMC3339458  PMID: 22472210
cell proliferation; ERK1/2; female reproductive cancer; PBDE-209; PKCα
21.  Maternal Prenatal Urinary Phthalate Metabolite Concentrations and Child Mental, Psychomotor, and Behavioral Development at 3 Years of Age 
Environmental Health Perspectives  2011;120(2):290-295.
Background: Research suggests that prenatal phthalate exposures affect child executive function and behavior.
Objective: We evaluated associations between phthalate metabolite concentrations in maternal prenatal urine and mental, motor, and behavioral development in children at 3 years of age.
Methods: Mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), and four di-2-ethylhexyl phthalate metabolites were measured in a spot urine sample collected from 319 women during the third trimester. When children were 3 years of age, the Mental Development Index (MDI) and Psychomotor Development Index (PDI) were measured using the Bayley Scales of Infant Development II, and behavior problems were assessed by maternal report on the Child Behavior Checklist.
Results: Child PDI scores decreased with increasing loge MnBP [estimated adjusted β-coefficient = –2.81; 95% confidence interval (CI): –4.63, –1.0] and loge MiBP (β = –2.28; 95% CI: –3.90, –0.67); odds of motor delay increased significantly [per loge MnBP: estimated adjusted odds ratio (OR) = 1.64; 95% CI: 1.10, 2.44; per loge MiBP: adjusted OR =1.82; 95% CI: 1.24, 2.66]. In girls, MDI scores decreased with increasing loge MnBP (β = –2.67; 95% CI: –4.70, –0.65); the child sex difference in odds of mental delay was significant (p = 0.037). The ORs for clinically withdrawn behavior were 2.23 (95% CI: 1.27, 3.92) and 1.57 (95% CI: 1.07, 2.31) per loge unit increase in MnBP and MBzP, respectively; for clinically internalizing behaviors, the OR was 1.43 (95% CI: 1.01, 1.90) per loge unit increase in MBzP. Significant child sex differences were seen in associations between MnBP and MBzP and behaviors in internalizing domains (p < 0.05).
Conclusion: Certain prenatal phthalate exposures may decrease child mental and motor development and increase internalizing behaviors.
doi:10.1289/ehp.1103705
PMCID: PMC3279439  PMID: 21893441
behavior; child; mental; phthalates; prenatal; psychomotor
22.  Health Risks of Limited-Contact Water Recreation 
Environmental Health Perspectives  2011;120(2):192-197.
Background: Wastewater-impacted waters that do not support swimming are often used for boating, canoeing, fishing, kayaking, and rowing. Little is known about the health risks of these limited-contact water recreation activities.
Objectives: We evaluated the incidence of illness, severity of illness, associations between water exposure and illness, and risk of illness attributable to limited-contact water recreation on waters dominated by wastewater effluent and on waters approved for general use recreation (such as swimming).
Methods: The Chicago Health, Environmental Exposure, and Recreation Study was a prospective cohort study that evaluated five health outcomes among three groups of people: those who engaged in limited-contact water recreation on effluent-dominated waters, those who engaged in limited-contact recreation on general-use waters, and those who engaged in non–water recreation. Data analysis included survival analysis, logistic regression, and estimates of risk for counterfactual exposure scenarios using G-computation.
Results: Telephone follow-up data were available for 11,297 participants. With non–water recreation as the reference group, we found that limited-contact water recreation was associated with the development of acute gastrointestinal illness in the first 3 days after water recreation at both effluent-dominated waters [adjusted odds ratio (AOR) 1.46; 95% confidence interval (CI): 1.08, 1.96] and general-use waters (1.50; 95% CI: 1.09, 2.07). For every 1,000 recreators, 13.7 (95% CI: 3.1, 24.9) and 15.1 (95% CI: 2.6, 25.7) cases of gastrointestinal illness were attributable to limited-contact recreation at effluent-dominated waters and general-use waters, respectively. Eye symptoms were associated with use of effluent-dominated waters only (AOR 1.50; 95% CI: 1.10, 2.06). Among water recreators, our results indicate that illness was associated with the amount of water exposure.
Conclusions: Limited-contact recreation, both on effluent-dominated waters and on waters designated for general use, was associated with an elevated risk of gastrointestinal illness.
doi:10.1289/ehp.1103934
PMCID: PMC3279449  PMID: 22030231
environmental microbiology; epidemiology; gastrointestinal illness; wastewater; water pollution; water recreation
23.  Transportation Noise and Blood Pressure in a Population-Based Sample of Adults 
Background: There is some evidence for an association between traffic noise and ischemic heart disease; however, associations with blood pressure have been inconsistent, and little is known about health effects of railway noise.
Objectives: We aimed to investigate the effects of railway and traffic noise exposure on blood pressure; a secondary aim was to address potentially susceptible subpopulations.
Methods: We performed adjusted linear regression analyses using data from 6,450 participants of the second survey of the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA 2) to estimate the associations of daytime and nighttime railway and traffic noise (A-weighted decibels) with systolic blood pressure (SBP) and diastolic blood pressure (DBP; millimeters of mercury). Noise data were provided by the Federal Office for the Environment. Stratified analyses by self-reported hypertension, cardiovascular disease (CVD), and diabetes were performed.
Results: Mean noise exposure during the day and night was 51 dB(A) and 39 dB(A) for traffic noise, respectively, and 19 dB(A) and 17 dB(A) for railway noise. Adjusted regression models yielded significant effect estimates for a 10 dB(A) increase in railway noise during the night [SBP β = 0.84; 95% confidence interval (CI): 0.22, 1.46; DBP β = 0.44; 95% CI: 0.06, 0.81] and day (SBP β = 0.60; 95% CI: 0.07, 1.13). Additional adjustment for nitrogen dioxide left effect estimates almost unchanged. Stronger associations were estimated for participants with chronic disease. Significant associations with traffic noise were seen only among participants with diabetes.
Conclusion: We found evidence of an adverse effect of railway noise on blood pressure in this cohort population. Traffic noise was associated with higher blood pressure only in diabetics, possibly due to low exposure levels. The study results imply more severe health effects by transportation noise in vulnerable populations, such as adults with hypertension, diabetes, or CVD.
doi:10.1289/ehp.1103448
PMCID: PMC3261938  PMID: 21885382
blood pressure; diabetes; epidemiology; hypertension; noise
24.  Arsenic Exposure and Motor Function among Children in Bangladesh 
Environmental Health Perspectives  2011;119(11):1665-1670.
Background: Several reports indicate that drinking water arsenic (WAs) and manganese (WMn) are associated with children’s intellectual function. Very little is known, however, about possible associations with other neurologic outcomes such as motor function.
Methods: We investigated the associations of WAs and WMn with motor function in 304 children in Bangladesh, 8–11 years of age. We measured As and Mn concentrations in drinking water, blood, urine, and toenails. We assessed motor function with the Bruininks-Oseretsky test, version 2, in four subscales—fine manual control (FMC), manual coordination (MC), body coordination (BC), and strength and agility—which can be summarized with a total motor composite score (TMC).
Results: Log-transformed blood As was associated with decreases in TMC [β = –3.63; 95% confidence interval (CI): –6.72, –0.54; p < 0.01], FMC (β = –1.68; 95% CI: –3.19, –0.18; p < 0.05), and BC (β = –1.61; 95% CI: –2.72, –0.51; p < 0.01), with adjustment for sex, school attendance, head circumference, mother’s intelligence, plasma ferritin, and blood Mn, lead, and selenium. Other measures of As exposure (WAs, urinary As, and toenail As) also were inversely associated with motor function scores, particularly TMC and BC. Square-transformed blood selenium was positively associated with TMC (β = 3.54; 95% CI: 1.10, 6.0; p < 0.01), FMC (β = 1.55; 95% CI: 0.40, 2.70; p < 0.005), and MC (β = 1.57; 95% CI: 0.60, 2.75; p < 0.005) in the unadjusted models. Mn exposure was not significantly associated with motor function.
Conclusion: Our research demonstrates an adverse association of As exposure and a protective association of Se on motor function in children.
doi:10.1289/ehp.1103548
PMCID: PMC3226503  PMID: 21742576
arsenic; Bangladesh; bodily coordination; fine motor control; manganese; motor function; neurotoxicity; selenium
25.  Manganese Exposure from Drinking Water and Children’s Classroom Behavior in Bangladesh 
Environmental Health Perspectives  2011;119(10):1501-1506.
Background: Evidence of neurological, cognitive, and neuropsychological effects of manganese (Mn) exposure from drinking water (WMn) in children has generated widespread public health concern. At elevated exposures, Mn has been associated with increased levels of externalizing behaviors, including irritability, aggression, and impulsivity. Little is known about potential effects at lower exposures, especially in children. Moreover, little is known regarding potential interactions between exposure to Mn and other metals, especially arsenic (As).
Objectives: We conducted a cross-sectional study of 201 children to investigate associations of Mn and As in tube well water with classroom behavior among elementary school children, 8–11 years of age, in Araihazar, Bangladesh.
Methods: Data on exposures and behavioral outcomes were collected from the participants at the baseline of an ongoing longitudinal study of child intelligence. Study children were rated by their school teachers on externalizing and internalizing items of classroom behavior using the standardized Child Behavior Checklist-Teacher’s Report Form (CBCL-TRF).
Results: Log-transformed WMn was positively and significantly associated with TRF internalizing [estimated β = 0.82; 95% confidence interval (CI), 0.08–1.56; p = 0.03], TRF externalizing (estimated β = 2.59; 95% CI, 0.81–4.37; p =0.004), and TRF total scores (estimated β = 3.35; 95% CI, 0.86–5.83; p = 0.008) in models that adjusted for log-transformed water arsenic (WAs) and sociodemographic covariates. We also observed a positive monotonic dose–response relationship between WMn and TRF externalizing and TRF total scores among the participants of the study. We did not find any significant associations between WAs and various scales of TRF scores.
Conclusion: These observations reinforce the growing concern regarding the neurotoxicologic effects of WMn in children.
doi:10.1289/ehp.1003397
PMCID: PMC3230445  PMID: 21493178
Bangladesh; children; externalizing behavior; internalizing behavior; manganese; water

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