Arsenic Methyltransferase and Apolipoprotein E Polymorphism in Pregnant Women Exposed to Inorganic Arsenic in Drinking Water in Western Romania.

Previous studies have shown that inorganic arsenic (iAs) exposure may be associated with genotoxic and cytotoxic effects. The aim of this study was to evaluate the relationship between several polymorphisms in AS3MT and APOE genes and urinary As and the relationship between these polymorphisms and pregnancy loss. We determined urinary As concentrations and performed genotyping analysis in 50 cases of spontaneous pregnancy loss and 50 controls, matched to cases on gestational age. The most frequently identified AS3MT polymorphisms in both cases and controls were in rs10748835 (80% cases and 68% controls), rs3740400 (78% cases and 64% controls), rs7085104 (74% cases and 48% controls), and rs1046778 (62% cases and 54% controls). We identified 30 different haplotypes in AS3MT SNPs, with four predominant haplotypes (>8%). Cases with Haplotype 1 had four-fold higher urinary DMA and two-fold higher MMA concentration than those without this haplotype, the MMA levels were lower in cases and controls with Haplotype 4 compared to Haplotype 1, and the DMA levels were significantly lower in cases with Haplotype 4 compared to Haplotype 3. Cases with Haplotype 1 had higher levels of all analyzed biomarkers, suggesting that Haplotype 1 may be associated with greater exposure to iAs and tobacco smoke. Our results suggest the importance of the AS3MT gene in iAs metabolism among pregnant women with low-level drinking water iAs exposure.

Differential effect of the duration of exposure on the carcinogenicity of cadmium in MCF10A mammary epithelial cells.

The carcinogenic role of cadmium (Cd2+) in breast cancer is still debatable. Current data points to duration of exposure as the most important element. In our study, we designed an in vitro model to investigate the effects of 3 weeks versus 6 weeks of low-level CdCl2 exposure on MCF10A cells. Our results demonstrated that after 3 weeks of CdCl2 exposure the cells displayed significant changes in the DNA integrity, but there was no development of malignant features. Interestingly, after 6 weeks of exposure, the cells significantly increased their invasion, migration and colony formation capacities. Additionally, MCF10A cells exposed for 6 weeks to CdCl2 had many dysregulated genes (4905 up-regulated and 4262 down-regulated). As follows, Cd-induced phenotypical changes are accompanied by a profound modification of the transcriptomic landscape. Furthermore, the molecular alterations driving carcinogenesis in MCF10A cells exposed to CdCl2 were found to be influenced by the duration of exposure, as in the case of MEG8. This long non-coding RNA was down-regulated at 3 weeks, but up-regulated at 6 weeks of exposure. In conclusion, even very low levels of Cd (0.5 µM) can have significant carcinogenic effects on breast cells in the case of subchronic exposure.

Urinary arsenic and spontaneous pregnancy loss - a hypothesis-generating case-control investigation in western Romania.

Arsenic occurs as a natural contaminant of drinking water supplies in arsenic endemic areas, posing a threat to public health. Our aim was to evaluate the relationship between urinary arsenic concentrations and spontaneous pregnancy loss in a population with low-moderate level drinking water arsenic exposure (mostly <10 µg/L). We enrolled 150 women with incident spontaneous pregnancy losses and 150 controls with ongoing pregnancies matched by gestational age. We measured arsenic species in urine using high performance liquid chromatography paired to inductively coupled plasma mass spectrometry. Urinary arsenic was not related to spontaneous pregnancy loss in conditional logistic regression models adjusted for confounding factors. However, a 10 µg/L increase in urinary arsenic (III + V) salt concentrations was associated with 8.00-fold (95% CI: 0.68, 3.35 × 105) greater odds of spontaneous loss among women using prenatal vitamins in an interaction model (P for interaction = 0.07), although the effect estimate was imprecise. In an additional interaction model, prenatal vitamin use was associated with lower odds of loss (OR = 0.30; 95% CI: 0.13, 0.66), although the association was diminished in the presence of a 10 µg/L increase in urinary inorganic arsenic (OR = 0.44; 95% CI: 0.70, 3.22). Total urinary arsenic was associated with 1.48-fold (95% CI: 0.20, 11.35) greater odds for loss among women with urinary cotinine >50 µg/L in another interaction model (P for interaction = 0.07). These results suggest a potential modest increase in the odds of pregnancy loss associated with increased total urinary arsenic among women smoking during pregnancy (urinary cotinine >50 µg/L). Prenatal vitamin use may act as a protective factor for arsenic exposure associated pregnancy loss, but appears to be less protective with increasing urinary inorganic arsenic concentrations.

Health effects of air pollutant mixtures (volatile organic compounds, particulate matter, sulfur and nitrogen oxides) - a review of the literature.

The health risks associated with individual air pollutant exposures have been studied and documented, but in real-life, the population is exposed to a multitude of different substances, designated as mixtures. A body of literature on air pollutants indicated that the next step in air pollution research is investigating pollutant mixtures and their potential impacts on health, as a risk assessment of individual air pollutants may actually underestimate the overall risks. This review aims to synthesize the health effects related to air pollutant mixtures containing selected pollutants such as: volatile organic compounds, particulate matter, sulfur and nitrogen oxides. For this review, the PubMed database was used to search for articles published within the last decade, and we included studies assessing the associations between air pollutant mixtures and health effects. The literature search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A number of 110 studies were included in the review from which data on pollutant mixtures, health effects, methods used, and primary results were extracted. Our review emphasized that there are a relatively small number of studies addressing the health effects of air pollutants as mixtures and there is a gap in knowledge regarding the health effects associated with these mixtures. Studying the health effects of air pollutant mixtures is challenging due to the complexity of components that mixtures may contain, and the possible interactions these different components may have.

Emerging roles and mechanisms of semaphorins activity in cancer.

Semaphorins are regulatory molecules that are linked to the modulation of several cancer processes, such as angiogenesis, cancer cell invasiveness and metastasis, tumor growth, as well as cancer cell survival. Semaphorin (SEMA) activity depends on the cancer histotypes and their particularities. In broad terms, the effects of SEMAs result from their interaction with specific receptors/co-receptors - Plexins, Neuropilins and Integrins - and the subsequent effects upon the downstream effectors (e.g. PI3K/AKT, MAPK/ERK). The present article serves as an integrative review work, discussing the broad implications of semaphorins in cancer, focusing on cell proliferation/survival, angiogenesis, invasion, metastasis, stemness, and chemo-resistance/response whilst highlighting their heterogeneity as a family. Herein, we emphasized that semaphorins are largely implicated in cancer progression, interacting with the tumor microenvironment components. Whilst some SEMAs (e.g. SEMA3A, SEMA3B) function widely as tumor suppressors, others (e.g. SEMA3C) act as pro-tumor semaphorins. The differences observed in terms of the biological structure of SEMAs and the particularities of each cancer histotypes require that each semaphorin be viewed as a unique entity, and its roles must be researched accordingly. A more in-depth and comprehensive view of the molecular mechanisms that promote and sustain the malignant behavior of cancer cells is of utmost importance.

Specific lifestyle factors and in vitro fertilization outcomes in Romanian women: a pilot study.

Background: Infertility is an important health concern worldwide. Although lifestyle habits and behaviors have been widely reported as predictors of IVF outcomes by previous studies, they have not been reported for Romanian women undergoing IVF. In this regard, our pilot study aimed to begin to address the data gap by assessing lifestyle predictors of in vitro fertilization (IVF) outcomes in Romanian women. Study design: Our pilot study included 35 participants who completed a first IVF cycle at a single infertility center. We evaluated individual self-reported lifestyle habits and behaviors as predictors of IVF outcomes, and employed principal component analysis (PCA) to characterize multiple lifestyle habits and behaviors into personal care product (PCP) use, and healthy diet and physical activity patterns as predictors of IVF outcomes. Results: Our PCA analysis showed that greater use of PCPs was associated with lower probabilities of pregnancy (RR: 0.92, 95% CI [0.87-0.98]) and live birth (RR: 0.94, 95% CI [0.88-1.01]) while, the healthy dietary habits and physical activity were associated with a higher likelihood of pregnancy, although without statistical significance (RR: 1.10, 95% CI [0.93-1.30]). Conclusions: In this pilot study we identified associations between IVF outcomes among Romanian women and certain lifestyle habits and behaviors including stress, diet and physical activity, and certain PCP use. We also estimated the joint effects of multiple lifestyle factors using PCA and found that PCP use, healthy dietary habits and physical activity were associated with IVF outcomes.

Assessment of formaldehyde levels in relation to respiratory and allergic symptoms in children from Alba County schools, Romania.

Our study assessed the exposure to formaldehyde of Romanian school children in relation to the classroom indoor environment characteristics and respiratory and allergic symptoms reported in a questionnaire survey, using the data collected in the SINPHONIE (Schools Indoor Pollution and Health: Observatory Network in Europe) project. Measurements of formaldehyde and microclimate parameters were conducted in three classrooms per school, in five schools, together with one outdoor measurement at each school. Questionnaires were used to collect information on classroom characteristics and health effects among children. The indoor formaldehyde levels for a school week varied between 15.5 and 66.2 µg/m3, with a median value of 34.8 µg/m3. The adjusted odds ratios for allergy-like, asthma-like, and flu-like symptoms were 3.23 (95% CI 1.31-8.00), 2.69 (95% CI 1.04-6.97), and 2.39 (95% CI 1.04-5.50), respectively, when exposed to higher formaldehyde levels (≥ 35 µg/m3) during a school week, compared to lower formaldehyde level exposure (< 35 µg/m3). Higher levels of indoor formaldehyde were significantly associated with health symptoms in children. The high indoor formaldehyde levels were related to the use of water-resistant paint for ceiling coverings, moisture damage signs, and lower classroom natural ventilation rates.

Assessing associations between indoor environment and health symptoms in Romanian school children: an analysis of data from the SINPHONIE project.

School environment may have an impact on children's health, but few studies have focused on indoor comfort factors such as temperature, humidity, and noise in relation with potential effects on children's health. Our cross-sectional study used data from the European Schools Indoor Pollution and Health Observatory Network in Europe (SINPHONIE) project to assess children's allergy, asthma-like symptoms, and flu-like symptoms in relation with classroom comfort and environmental factors. The study used self-reported data from three questionnaires to identify classroom conditions and student health outcomes for 280 students. We used backwards variable selection and unconditional logistic regression to assess the outcome-environment relationship while controlling for demographics, family history of allergy, and home exposures. We found increased risks for allergy and flu-like symptoms associated with hot classrooms in the heating season, increased risks for asthma-like symptoms associated with noisy classrooms, and a protective effect for allergy associated with good outdoor air quality. Romanian classrooms rely on natural ventilation, which may contribute to increased temperature and humidity in the heating season. Further research warrants the use of SINPHONIE's measurement data to validate our findings.

Teacher respiratory health symptoms in relation to school and home environment.

PURPOSE: Few studies have evaluated teachers' respiratory health, especially its relationship with school/home environment, and school policies. This study assessed asthma and smoking prevalence among teachers in Romania, teacher's perception and knowledge of the school environment, policies and asthma management, and how school and home environment affected asthma, allergy, and respiratory infection symptoms. METHODS: This cross-sectional study obtained information from 104 Romanian teachers utilizing teacher questionnaire data for Romania only, as part of the Schools Indoor Pollution and Health: Observatory Network in Europe (SINPHONIE) study, a multicenter European research project conducted between 2010 and 2012. The SINPHONIE questionnaire collected comprehensive information on school and home environment, respiratory symptoms, smoking, and school policies. We used unconditional logistic regression analysis to examine environment-outcome relationships while controlling for socio-demographics and co-exposures. RESULTS: Our results showed the prevalence of asthma-like symptoms and smoking among teachers in Romania was higher than in other SINPHONIE schools and among US teachers. Factors statistically associated with asthma, allergy, and respiratory infection (all p < 0.05) include perception of health related to poor air quality in school, inappropriate cleaning of ventilation systems, dwelling proximity to busy traffic, and multiple school/home exposures. We also found lack of asthma management and environmental policies in the investigated Romanian schools. CONCLUSION: We concluded that multiple school and home environmental factors were related to respiratory and allergic symptoms. High asthma burden and smoking are important public health problems in Romania. Future studies including larger sample size and exposure measurements are needed to confirm our findings.

Low-level arsenic exposure via drinking water consumption and female fecundity - A preliminary investigation.

High level arsenic exposure is associated with reproductive toxicity in experimental and observational studies; however, few data exist to assess risks at low levels. Even less data are available to evaluate the impact of low level arsenic exposure on human fecundity. Our aim in this pilot study was a preliminary evaluation of associations between low level drinking water arsenic contamination and female fecundity. This retrospective study was conducted among women previously recruited to a hospital-based case-control study of spontaneous pregnancy loss in Timis County, Romania. Women (n=94) with planned pregnancies of 5-20 weeks gestation completed a comprehensive physician-administered study questionnaire and reported the number of menstrual cycles attempting to conceive as the time to pregnancy (TTP). Drinking water samples were collected from residential drinking water sources and we determined arsenic levels using hydride generation-atomic absorption spectrometry (HG-AAS). Multivariable Cox-proportional hazards regression with Efron approximation was employed to evaluate TTP as a function of drinking water arsenic concentrations among planned pregnancies, adjusted for covariates. There was no main effect for drinking water arsenic exposure, yet the conditional probability for pregnancy was modestly lower among arsenic exposed women with longer TTPs, relative to women with shorter TTPs, and relative to unexposed women. For example, 1µg/L average drinking water arsenic conferred 5%, 8%, and 10% lower likelihoods for pregnancy in the 6th, 9th, and 12th cycles, respectively (P=0.01). While preliminary, our results suggest that low level arsenic contamination in residential drinking water sources may further impair fecundity among women with longer waiting times; however, this hypothesis requires confirmation by a future, more definitive study.

Metal contamination in environmental media in residential areas around Romanian mining sites.

Hard-rock mining for metals, such as gold, silver, copper, zinc, iron and others, is recognized to have a significant impact on the environmental media, soil and water, in particular. Toxic contaminants released from mine waste to surface water and groundwater is the primary concern, but human exposure to soil contaminants either directly, via inhalation of airborne dust particles, or indirectly, via food chain (ingestion of animal products and/or vegetables grown in contaminated areas), is also, significant. In this research, we analyzed data collected in 2007, as part of a larger environmental study performed in the Rosia Montana area in Transylvania, to provide the Romanian governmental authorities with data on the levels of metal contamination in environmental media from this historical mining area. The data were also considered in policy decision to address mining-related environmental concerns in the area. We examined soil and water data collected from residential areas near the mining sites to determine relationships among metals analyzed in these different environmental media, using the correlation procedure in the SAS statistical software. Results for residential soil and water analysis indicate that the average values for arsenic (As) (85 mg/kg), cadmium (Cd) (3.2 mg/kg), mercury (Hg) (2.3 mg/kg) and lead (Pb) (92 mg/kg) exceeded the Romanian regulatory exposure levels [the intervention thresholds for residential soil in case of As (25 mg/kg) and Hg (2 mg/kg), and the alert thresholds in case of Pb (50 mg/kg) and Cd (3 mg/kg)]. Average metal concentrations in drinking water did not exceed the maximum contaminant level (MCL) imposed by the Romanian legislation, but high metal concentrations were found in surface water from Rosia creek, downstream from the former mining area.

Perinatal health in the Danube region - new birth cohort justified.

In 2013-2015, a consortium of European scientists - NEWDANUBE - was established to prepare a birth cohort in the Danube region, including most of the countries with the highest air pollution in Europe, the area being one-fifth of the European Union's (EU's) territory, including 14 countries (nine EU member states), over 100 million inhabitants, with numerous challenges: big socioeconomic disparities, and a region-specific environmental pollution. The consortium reflects the EU Strategy for the Danube Region Strategy (2010), which identified 11 thematic Priority Areas - one of which is the environmental risks. Birth cohorts have been established in all other areas of Europe and collaborative efforts in promoting maternal and fetal health by minimizing the environmental exposures have been initiated with national, European, and international financial support. A birth cohort in the Danube area could apply the established methodologies for prenatal exposure and birth outcome measurements and establish a platform for targeted health promotion in couples planning pregnancies. The consortium included a strong socioeconomic part focusing on the participant's active registration of exposures to environmental toxicants and health indicators of disease and wellbeing, combined with investigation of their risk-reducing behavior and interventions to change their lifestyle to avoid the adverse health risks. Willingness to pay for reducing the health risks in children is also proposed to be estimated. Further collaboration and networking is encouraged as the Danube region has several decades of experience and expertise in biomonitoring adult populations exposed environmentally or occupationally. Additionally, some countries in the Danube region launched small-scale birth cohorts encouraged by participation in several ongoing research projects.

Impact of exposure to tobacco smoke, arsenic, and phthalates on locally advanced cervical cancer treatment-preliminary results.

BACKGROUND: Cancer research is a national and international priority, with the efficiency and effectiveness of current anti-tumor therapies being one of the major challenges with which physicians are faced. OBJECTIVE: To assess the impact of exposure to tobacco smoke, arsenic, and phthalates on cervical cancer treatment. METHODS: We investigated 37 patients with locally advanced cervical carcinoma who underwent chemotherapy and radiotherapy. We determined cotinine and five phthalate metabolites in urine samples collected prior to cancer treatment, by gas chromatography coupled to mass spectrometry, and urinary total arsenic by atomic absorption spectrometry with hydride generation. We used linear regression to evaluate the effects of cotinine, arsenic, and phthalates on the change in tumor size after treatment, adjusted for confounding variables. RESULTS: We detected no significant associations between urinary cotinine, arsenic, or phthalate monoesters on change in tumor size after treatment, adjusted for urine creatinine, age, baseline tumor size, and cotinine (for arsenic and phthalates). However, higher %mono-ethylhexyl phthalate (%MEHP), a putative indicator of phthalate diester metabolism, was associated with a larger change in tumor size (ß = 0.015, 95% CI [0.003-0.03], P = 0.019). CONCLUSION: We found no statistically significant association between the urinary levels of arsenic, cotinine, and phthalates metabolites and the response to cervical cancer treatment as measured by the change in tumor size. Still, our results suggested that phthalates metabolism may be associated with response to treatment for locally advanced cervical cancer. However, these observations are preliminary and will require confirmation in a larger, more definitive investigation.

Newborns health in the Danube Region: Environment, biomonitoring, interventions and economic benefits in a large prospective birth cohort study.

BACKGROUND: The EU strategy for the Danube Region addresses numerous challenges including environment, health and socioeconomic disparities. Many old environmental burdens and heavily polluted areas in Europe are located in the Danube Region, consisting of 14 countries, with over 100 million people. Estimating the burden of environmental exposures on early-life health is a growing research area in Europe which has major public health implications, but the data from the Danube Region are largely missing. AIM: This review presents an inventory of current environmental challenges, related early-life health risks, and knowledge gaps in the Danube Region, based on publicly available databases, registers, and literature, as a rationale and incentive for a new integrated project. The review also proposes the concept for the project aiming to characterize in utero exposures to multiple environmental factors and estimate their effect on early-life health, evaluate economic impact, as well as identify interventions with a potential to harness social norms to reduce emissions, exposures and health risks in the Danube Region. METHODS: Experts in environmental epidemiology, human biomonitoring and social science in collaboration with clinicians propose to establish a new large multi-center birth cohort of mother-child pairs from Danube countries, measure biomarkers of exposure and health in biological samples at birth, collect centrally measured climate, air and water pollution data, conduct pre- and postnatal surveys on lifestyle, indoor exposures, noise, occupation, socio-economic status, risk-averting behavior, and preferences; and undertake clinical examinations of children at and after birth. Birth cohort will include at least 2000 newborns per site, and a subset of at least 200 mother-child pairs per site for biomonitoring. Novel biomarkers of exposure, susceptibility, and effect will be applied, to gain better mechanistic insight. Effects of multiple environmental exposures on fetal and child growth, respiratory, allergic, immunologic, and neurodevelopmental health outcomes will be estimated. Parent's willingness to pay for reducing health risks in children will be elicited by survey, while values of cost-of-illness will be gathered from literature and national statistics. Effects of risk reducing interventions will be examined. CONCLUSIONS: The proposed project would provide novel estimates of the burden of early childhood diseases attributable to environmental exposures and assess health impacts of different intervention scenarios in the Danube Region, in an integrated approach combining human biomonitoring, epidemiological and social science research.

Low level arsenic contaminated water consumption and birth outcomes in Romania-An exploratory study.

Women are exposed to drinking water with low arsenic concentrations (<10.0µg/L) worldwide, yet little work has been done to assess the risk. To begin to address this data gap, we conducted an exploratory study of birth outcomes in Timis County, Romania. We prospectively followed 122 women with singleton deliveries, for whom we constructed individual exposure indicators using self-reported water consumption weighted by arsenic measured in drinking water sources. There were no overall confounder-adjusted effects for arsenic exposure on birth outcomes. Yet, higher average arsenic (10µg/L) was associated with a -2.45 lower birth weight Z-score (P=0.021) and a -1.17 shorter birth length Z-score (P=0.029) among smokers. Higher average iAs (10µg/L) was also associated with smaller ponderal index in boys (P=0.023). Our results suggest smoking may potentiate an otherwise benign arsenic exposure. A larger, more definitive biomarker-based study is needed to investigate the potential risks in conjunction with smoking.

A pilot study of low-moderate drinking water arsenic contamination and chronic diseases among reproductive age women in Timis County, Romania.

We conducted a pilot study of associations between drinking water contaminated by inorganic arsenic (iAs), mostly <10 µg/L, and self-reported chronic diseases in 297 pregnant women. Adjusted for confounding variables, we identified a positive association between iAs and heart disease (OR = 1.63, 95%CI 0.81-3.04, p = 0.094), which was stronger for women living at their current residence ≥ 10 years (OR = 2.47, 95%CI 0.87-10.43, p = 0.058). Confounder-adjusted associations were also suggested for iAs with kidney disease (OR = 1.32, 95%CI 0.77-2.21, p = 0.265) and with high blood pressure (OR = 1.36, 95%CI 0.68-2.39, p = 0.300). A post hoc power analysis indicated the need for a larger study with more statistical power.

Consumption of arsenic-contaminated drinking water and anemia among pregnant and non-pregnant women in northwestern Romania.

Anemia is a global health problem. To evaluate the impact of low-moderate water arsenic exposure (mostly <10 µg/L) on anemia, we conducted a cross-sectional study of 217 Romanian women. The adjusted prevalences for 'any' anemia (prevalence proportion ratio (PPR)=1.71, 95% CI 0.75-3.88) and pregnancy anemia (PPR=2.87, 95% CI 0.62-13.26) were higher among drinking water arsenic exposed women than among unexposed women. These preliminary data underscore the need for a more definitive study in this area.

Consumption of low-moderate level arsenic contaminated water does not increase spontaneous pregnancy loss: a case control study.

BACKGROUND: Previous work suggests an increased risk for spontaneous pregnancy loss linked to high levels of inorganic arsenic (iAs) in drinking water sources (>10 µg/L). However, there has been little focus to date on the impact of low-moderate levels of iAs in drinking water (<10 µg/L). To address this data gap we conducted a hospital-based case-control study in Timis County, Romania. METHODS: We recruited women with incident spontaneous pregnancy loss of 5-20 weeks completed gestation as cases (n = 150), and women with ongoing pregnancies matched by gestational age (±1 week) as controls (n = 150). Participants completed a physician-administered questionnaire and we collected water samples from residential drinking sources. We reconstructed residential drinking water exposure histories using questionnaire data weighted by iAs determined using hydride generation-atomic absorption spectrometry (HG-AAS). Logistic regression models were used to generate odds ratios (OR) and 95% confidence intervals (CI) for associations between iAs exposure and loss, conditioned on gestational age and adjusted for maternal age, cigarette smoking, education and prenatal vitamin use. We explored potential interactions in a second set of models. RESULTS: Drinking water arsenic concentrations ranged from 0.0 to 175.1 µg/L, with median 0.4 µg/L and 90th%tile 9.4 µg/L. There were no statistically significant associations between loss and average or peak drinking water iAs concentrations (OR 0.98, 95% CI 0.96-1.01), or for daily iAs intake (OR 1.00, 95% CI 0.98-1.02). We detected modest evidence for an interaction between average iAs concentration and cigarette smoking during pregnancy (P = 0.057) and for daily iAs exposure and prenatal vitamin use (P = 0.085). CONCLUSIONS: These results suggest no increased risk for spontaneous pregnancy loss in association with low to moderate level drinking water iAs exposure. Though imprecise, our data also raise the possibility for increased risk among cigarette smokers. Given the low exposures overall, these data should reassure pregnant women and policy makers with regard to the potential effect of drinking water iAs on early pregnancy, though a larger more definitive study to investigate the potential risk increase in conjunction with cigarette smoking is merited.

Maternal arsenic exposure and birth outcomes: a comprehensive review of the epidemiologic literature focused on drinking water.

Inorganic arsenic (iAs) is a human toxicant to which populations may be exposed through consumption of geogenically contaminated groundwater. A growing body of experimental literature corroborates the reproductive toxicity of iAs; however, the results of human studies are inconsistent. Therefore, we conducted a comprehensive review of epidemiologic studies focused on drinking water iAs exposure and birth outcomes to assess the evidence for causality and to make recommendations for future study. We reviewed 18 English language papers assessing birth weight, gestational age, and birth size. Thirteen of the studies were conducted among populations with frequent exposure to high-level groundwater iAs contamination (>10 µg/L) and five studies were conducted in areas without recognized contamination. Most studies comprised small samples and used cross-sectional designs, often with ecologic exposure assessment strategies, although several large prospective investigations and studies with individual-level measurements were also reported. We conclude that: (1) the epidemiologic evidence for an increased risk of low birth weight (<2500 g) is insufficient, although there exists limited evidence for birth weight decreases; (2) the evidence for increased preterm delivery is insufficient; and, (3) there exists minimal evidence for decreased birth size. In further investigation of birth weight and size, we recommend incorporation of individual susceptibility measures using appropriate biomarkers, with collection timed to windows of vulnerability and speciated arsenic analysis, as well as consideration of populations exposed primarily to drinking water iAs contamination <10 µg/L. Given the large potential public health impact, additional, high quality epidemiologic studies are necessary to more definitively assess the risk.

Spontaneous pregnancy loss in humans and exposure to arsenic in drinking water.

Maternal exposure to high concentrations of inorganic arsenic (iAs) in naturally contaminated drinking groundwater sources has been associated with an increased risk for the spontaneous loss of clinically recognized pregnancies in several epidemiologic studies. Whereas a large worldwide population depends on drinking groundwater sources with high levels of iAs contamination, in quantities exceeding 10 parts per billion (ppb), an even larger population is likely to be exposed to mild-moderate drinking groundwater iAs contamination, in quantities <10ppb. Only a single epidemiologic study to date has considered spontaneous pregnancy loss in association with consumption of drinking water with mild-moderate iAs contamination; the vast majority of published studies of spontaneous loss addressed populations with substantial exposure. The aim of this review is to evaluate the published literature to assess the plausibility for a causal association between exposure to iAs-contaminated drinking water and the spontaneous loss of clinically recognized pregnancy. In spite of numerous methodologic limitations resulting from circumstance or design, a consistent pattern of increased risk for loss is suggested by the epidemiologic literature. Moreover, these study results are corroborated by a large number of experimental studies, albeit usually conducted at concentrations exceeding that to which humans are exposed via contaminated drinking water. In this review, we discuss sources of human iAs exposure, highlight several experimental studies pertinent to a possible causal link between iAs and spontaneous pregnancy loss in humans, and provide a critical review of published epidemiologic studies of pregnancy loss and drinking water iAs exposures, and their limitations. Based on a review of the published literature, we recommend the future conduct of a two-stage comprehensive prospective study of low-moderate iAs drinking water exposure and spontaneous pregnancy loss.