Blood lead levels and math learning in first year of school: An association for concern.

Lead is a well-known neurotoxicant that continues to affect children's cognition and behavior. With the aim to examine the associations of lead exposure with math performance in children at the beginning of formal schooling, we conducted a cross-sectional study of first-grade students from 11 schools in Montevideo, Uruguay. Math abilities were assessed with tests from the Batería III Woodcock-Muñoz (Calculation, Math Facts Fluency, Applied Problems, Math Calculation Skills and Broad Maths). Separate generalized linear models (GLM) tested the association of blood lead level (BLL) and each math ability, adjusting for key covariates including age and sex, maternal education, household assets and Home Observation for Measurement of the Environment Inventory score. In a complete-case of 252 first-grade students (age 67-105 months, 45% girls), mean ± SD blood lead level was 4.0 ± 2.2 µg/dL. Covariate-adjusted logistic models were used to examine the association between childhood BLLs and the odds of low math performance. BLL was negatively associated with scores on the Calculation test (ß (95% CI): -0.18 (-0.33, -0.03)), Math Calculation Skills (-1.26 (-2.26, -0.25)), and Broad Maths cluster scores (-0.88 (-1.55, -0.21)). Similarly, performance on the Calculation test, as well as cluster scores for Broad Maths and Math Calculation Skills differed between children with BLLs <5 and ≥ 5 µg/dL (p < 0.01), being lower in children with higher BLLs. Finally, considering the likelihood of low test performance, each 1 µg/dL higher B-Pb was related to 27% higher likelihood for Maths Facts Fluency, 30% for Broad Math and Math Calculation Skills, and 31% for Calculation (p < 0.05). These results suggest that lead exposure is negatively associated with several basic skills that are key to math learning. These findings further suggest that the cognitive deficits related to lead exposure impact student achievement at very early stages of formal education.

Lead exposure and indices of height and weight in Uruguayan urban school children, considering co-exposure to cadmium and arsenic, sex, iron status and dairy intake.

Child growth depends on complex factors including diet, nutritional status, socioeconomic, and sanitary conditions, and exposure to environmental chemicals. Lead exposure is known to impair growth in young children but effects in school-age children are less clear. The effects of co-exposure to low-level lead and other toxic metals on child growth are not well understood. We examined cross-sectional associations of blood lead (BLL) with growth indices (Z scores of body mass index for age, BAZ, and height for age, HAZ) in Uruguayan urban school children (n = 259; ~7 y). Potential differences in these associations in children with lower vs. higher urinary inorganic arsenic metabolites (U-As), urinary cadmium (U-Cd), sex (42% girls), iron deficiency (ID, 39% children), or intake of dairy foods below recommended levels were examined. BLL was measured using AAS, U-As using HPLC-HGICP-MS, and U-Cd using ICP-MS. Dietary information was obtained by two 24-h recalls completed by caregivers. Children's linear growth was within age and sex-appropriate reference values. Overweight (BAZ > 1 2 SD) was found in 20.1%, and obesity (BAZ > 2 SD) in 18.5%, of children. Ranges (5th, 95th percentile) of biomarker concentrations were: BLL, 0.8-7.8 µg/dL; U-Cd, 0.01-0.2 µg/L, and U-As, 4.0-27.3 µg/L. BLL was inversely associated with HAZ ([95% CI]: 0.10 [-0.17, -0.03]) in covariate-adjusted models. Although this association was slightly more pronounced in girls, children without ID, and children with lower U-As, there was little evidence of effect modification due to overlapping CIs in stratified models. BLLs were not associated with BAZ, except for a suggestion of a negative relationship in girls (-0.10 [-0.23, 0.02]) but not boys [0.001 [-0.11, 0.12]). Our findings indicate that exposure to low levels of lead was associated with lower HAZ in apparently normally growing urban school children. Larger future studies should help elucidate if these associations persist over time and across populations.

Vitamin B-6 Intake Is Modestly Associated with Arsenic Methylation in Uruguayan Children with Low-Level Arsenic Exposure.

BACKGROUND: Detoxification of inorganic arsenic (iAs) occurs when it methylates to form monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Lower proportions of urinary iAs and MMA, and higher proportions of DMA indicate efficient methylation. The role of B-vitamins in iAs methylation in children with low-level arsenic exposure is understudied. OBJECTIVES: Our study objective was to assess the association between B-vitamin intake and iAs methylation in children with low-level arsenic exposure (<50 µg/L in water; urinary arsenic 5-50 µg/L). METHODS: We conducted a cross-sectional study in 290 ∼7-y-old children in Montevideo. Intake of thiamin, riboflavin, niacin, vitamin B-6, and vitamin B-12 was calculated by averaging 2 nonconsecutive 24-h recalls. Total urinary arsenic concentration was measured as the sum of urinary iAs, MMA, and DMA, and adjusted for urinary specific gravity; iAs methylation was measured as urinary percentage As, percentage MMA, and percentage DMA. Arsenic concentrations from household water sources were assessed. Linear regressions tested the relationships between individual energy-adjusted B-vitamins and iAs methylation. RESULTS: Median (range) arsenic concentrations in urine and water were 9.9 (2.2-48.7) and 0.45 (0.1-18.9) µg/L, respectively. The median (range) of urinary percentage iAs, percentage MMA, and percentage DMA was 10.6% (0.0-33.8), 9.7% (2.6-24.8), and 79.1% (58.5-95.4), respectively. The median (range) intake levels of thiamin, riboflavin, niacin, and vitamin B-6 were 0.81 (0.19-2.56), 1.0 (0.30-2.24), 8.6 (3.5-23.3), and 0.67 (0.25-1.73) mg/1000 kcal, respectively, whereas those of folate and vitamin B-12 were 216 (75-466) and 1.7 (0.34-8.3) µg/1000 kcal, respectively. Vitamin B-6 intake was inversely associated with urinary percentage MMA (ß = -1.60; 95% CI: -3.07, -0.15). No other statistically significant associations were observed. CONCLUSIONS: Although vitamin B-6 intake was inversely associated with urinary percentage MMA, our findings suggest limited support for a relation between B-vitamin intake and iAs methylation in children exposed to low-level arsenic.

Associations of dietary intakes and serum levels of folate and vitamin B-12 with methylation of inorganic arsenic in Uruguayan children: Comparison of findings and implications for future research.

BACKGROUND: In the human body, inorganic arsenic (iAs) is methylated via the one-carbon cycle to form monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Lower proportions of iAs and MMA, and higher proportions of DMA in urine indicate efficient methylation; formation of DMA is thought to detoxify iAs and MMA. Studies on folate, vitamin B-12 and iAs methylation yield mixed findings, depending on whether folate and vitamin B-12 were assessed from diet, supplements, or using a blood biomarker. OBJECTIVE: First, to compare the associations of serum concentrations and estimated intake of folate and vitamin B-12 with indicators of iAs methylation. Second, to highlight the implications of these different B-vitamin assessment techniques on the emerging evidence of the impact of dietary modifications on iAs methylation. METHODS: The study was conducted among ~7-year-old children from Montevideo, Uruguay. Serum folate and vitamin B-12 levels were measured on the Horiba ABX Pentra 400 analyzer; urinary arsenic was measured using High-Performance Liquid Chromatography on-line with Inductively Coupled Plasma Mass Spectrometry. Dietary intakes were assessed using the average of two 24-h dietary recalls. Linear regressions assessed the associations of serum levels, and dietary intakes of folate (n = 237) and vitamin B-12 (n = 217) with indicators of iAs methylation. Models were adjusted for age, sex, body mass index, total urinary arsenic, and rice intake. RESULTS: Serum folate and vitamin B-12 levels were above the adequacy threshold for 99% of the participants. No associations were observed between serum folate, serum vitamin B-12, or vitamin B-12 intake and iAs methylation. Folate intake was inversely associated with urinary %MMA [ß (95% confidence interval): -1.04 (-1.89, -0.18)]. CONCLUSION: Additional studies on the role of B-vitamins in iAs methylation are needed to develop a deeper understanding of the implications of assessing folate and vitamin B-12 intake compared to the use of biomarkers. Where possible, both methods should be employed because they reflect different exposure windows and inherent measurement error, and if used individually, will likely continue to contribute to lack of consensus.

A cross-sectional study of general cognitive abilities among Uruguayan school children with low-level arsenic exposure, potential effect modification by methylation capacity and dietary folate.

BACKGROUND: Few studies have evaluated the association between low-level arsenic (As) exposure and cognitive performance among children. OBJECTIVES: In this cross-sectional study, we assessed the association between low-level As exposure and cognitive performance among 5-8 year-old children in Montevideo, and tested effect modification by As methylation capacity and children's dietary folate intake. METHODS: We measured total urinary As (UAs) concentrations and the proportion of monomethylarsonic acid (MMA) in the urine of 328 children. Seven subtests of the standardized Woodcock-Muñoz cognitive battery were used to assess cognitive performance, from which, the general intellectual abilities (GIA) score was derived. Total folate intake was estimated from two 24-h dietary recalls. Linear regression analyses were performed. Effect modification was assessed by stratifying at the median %MMA value and tertiles of total folate intake calculated as micrograms (µg) of dietary folate equivalents (dfe). RESULTS: The median UAs was 11.9 µg/l (range = 1.4-93.9), mean folate intake was 337.4 (SD = 123.3) µg dfe, and median %MMA was 9.42 (range = 2.6-24.8). There was no association between UAs and cognitive abilities, and no consistent effect modification by %MMA. UAs was associated inversely with concept formation, and positively with cognitive efficiency and numbers reversed subtest in the lowest folate intake tertile; UAs was also positively associated with sound integration in the second tertile and concept formation in the highest tertile of folate intake. There was no consistent pattern of effect modification by %MMA or folate intake. CONCLUSION: There was no association between low-level As exposure and general cognitive abilities.

Multiple-metal exposure, diet, and oxidative stress in Uruguayan school children.

Oxidative stress (OS) is an important consequence of exposure to toxic metals but it is unclear to what extent low-level metal exposures contribute to OS in children. We examined the cross-sectional association between urinary concentrations of arsenic (As), cadmium (Cd), and lead (Pb) and urinary markers of OS: F2-8α isoprostane and 8-hydroxy-2-deoxy-guanosine (8-OHdG). We also tested effect modification by dietary intakes. Of the 211 children aged 6-8 years living in Montevideo who were eligible for the study because they had at least one OS marker measured via ELISA, 143 were included in a complete-case analysis. Urinary metals were measured with inductively coupled plasma mass spectrometry (ICP-MS: Pb, Cd) and high-performance liquid chromatography online with hydride generation ICP-MS (As-metabolites); concentrations were log2-transformed. All urinary markers were adjusted for specific gravity of urine. Two 24-h dietary recalls were conducted to estimate children's dietary intakes, including total fruit and vegetable consumption and vitamin C, zinc and fiber intake. Ordinary least square (OLS) and weighted quantile sum (WQS) regressions were used to estimate the association between metals and each OS marker as outcome. Metal exposure was generally low: median urinary As, Cd, Pb 9.6 µg/L, 0.06 µg/L and 1.9 µg/L, respectively. Median 8-isoprostane concentration was 1.1 and 8-OHdG 39.6 ng/mL. Log2-transformed urinary As concentrations were positively associated with 8-OHdG concentrations (10.90 [3.82, 17.97]) in covariate-adjusted OLS models which also took account of exposure to Cd and Pb. In WQS, a mixture index was also associated with higher 8-OHdG (8.71 [1.12, 16.3] for each 25% increase in index value), mostly driven by As exposure. There was little evidence of effect modification by dietary antioxidants. In sum, even at low-level, As exposure is associated with detectable oxidative damage to the DNA.

Low-level arsenic exposure: Nutritional and dietary predictors in first-grade Uruguayan children.

Arsenic exposure in children is a public health concern but is understudied in relation to the predictors, and effects of low-level exposure. We examined the extent and dietary predictors of exposure to inorganic arsenic in 5-8 year old children from Montevideo, Uruguay. Children were recruited at school; 357 were enrolled, 328 collected morning urine samples, and 317 had two 24-h dietary recalls. Urinary arsenic metabolites, i.e. inorganic arsenic (iAs), methylarsonic acid (MMA), and dimethylarsinic acid (DMA), were measured using high-performance liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICP-MS), and the sum concentration (U-As) used for exposure assessment. Proportions of arsenic metabolites (%iAs, %MMA and %DMA) in urine were modelled in OLS regressions as functions of food groups, dietary patterns, nutrient intake, and nutritional status. Exposure to arsenic was low (median U-As: 9.9µg/L) and household water (water As: median 0.45µg/L) was not a major contributor to exposure. Children with higher consumption of rice had higher U-As but lower %iAs, %MMA, and higher %DMA. Children with higher meat consumption had lower %iAs and higher %DMA. Higher scores on "nutrient dense" dietary pattern were related to lower %iAs and %MMA, and higher %DMA. Higher intake of dietary folate was associated with lower %MMA and higher %DMA. Overweight children had lower %MMA and higher %DMA than normal-weight children. In summary, rice was an important predictor of exposure to inorganic arsenic and DMA. Higher meat and folate consumption, diet rich in green leafy and red-orange vegetables and eggs, and higher BMI contributed to higher arsenic methylation capacity.

Association of blood lead levels with urinary F2-8α isoprostane and 8-hydroxy-2-deoxy-guanosine concentrations in first-grade Uruguayan children.

Oxidative stress (OS) is a potential molecular mechanism for lead-induced toxicities, yet, we have limited understanding of the relation between low-level lead (Pb) exposure and OS, especially in children. This cross-sectional study examines the association between blood lead level (BLL) and two OS markers-urinary F2-8α isoprostane or isoprostane (a marker of lipid peroxidation) and 8-hydroxy-2-deoxy-Guanosine or 8-OH-dG (a marker of DNA damage) in 211 children, aged 5-8 years, from Montevideo, Uruguay. The role of dietary intakes of vitamin C and zinc in modifying the relation between BLL and OS was also examined. The mean (SD) BLL of the study children was 4.7 (2.2) µg/dL, with 30.2% children having BLL ≥5 µg/dL, the current reference level set by the US Centre for Disease Control for identifying, monitoring and management of children with elevated BLL. In covariate-adjusted analysis, there was a weak positive association between BLL and urinary isoprostane (adjusted for specific gravity) [ß=0.09, p<0.1]. No association was found between children's BLL and urinary 8-OH-dG. Interactions between dietary intakes of vitamin C or zinc and BLL on OS biomarkers were not consistent. However, when BLL and vitamin C or BLL and zinc were modeled together, BLL was independently associated with isoprostane concentration [ß=0.10, p<0.05] but vitamin C or zinc intake was not. These findings suggest that there may be a potential adverse effect of BLL on OS in children with low-level Pb exposure. There is a need to study the effects of Pb on other OS measures, as well as the role of OS in mediating low-level Pb toxicity on functional outcomes.

Secular trends in blood lead concentrations of school-age children in Montevideo, Uruguay from 2009 to 2019.

Lead exposure continues to be a public health problem globally, yet very few countries perform systematic biomonitoring or surveillance of children's blood lead levels (BLLs). Secular trends in children's BLLs have not been well characterized outside North America and Europe. In 2009-19, we conducted a series of non-representative cross-sectional surveys in Montevideo, Uruguay, enrolling children living in areas of the city with known or suspected lead contamination. Lead was measured with atomic absorption spectrometry on fasting venous blood samples. Of the 856 children representing independent (non-sibling) observations, 759 had BLL measures. Other missing data were imputed. Using linear and logistic regression models, we estimated the covariate-adjusted year to year difference in mean BLL and the likelihood of having BLL ≥5 and BLL ≥3.5 µg/dL. At the start of the study, mean ± SD BLL was 4.8 ± 2.6 µg/dL, and at the end 1.4 ± 1.4 µg/dL. The prevalence of BLL ≥5 and BLL ≥3.5 µg/dL also differed markedly between 2009 and 2019 (30.8% vs. 2.7% and 53.8% vs. 5.8%). Similarly, where 80.8% of children had BLL ≥2 µg/dL in 2011, in 2019 that number was 19.3%. The estimated year to year difference in BLL was ∼0.3 µg/dL. Despite this progress, pediatric lead exposure remains a problem in Montevideo. In years 2015-19, between 19 and 48% of school children had BLL ≥2 µg/dL, a level at which adverse neurobehavioral outcomes continue to be reported in the literature. Continued prevention and risk-reduction efforts are needed in Montevideo, including systematic surveillance of BLLs in all children.

Pyrethroid and Chlorpyrifos Pesticide Exposure, General Intellectual Abilities, and Executive Functions of School Children from Montevideo, Uruguay.

Children's developing brains are susceptible to pesticides. Less is known about the effect of exposure to chlorpyrifos and pyrethroids on executive functions (EF). We measured urinary 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of chlorpyrifos, and urinary 3-phenoxybenzoic acid (3-PBA), a general, nonspecific metabolite of pyrethroids in first-grade children from Montevideo, Uruguay (n = 241, age 80.6 ± 6.4 months, 58.1% boys). EFs were assessed with the Intra-dimensional/Extra-dimensional shift (IED), Spatial Span (SSP), and Stockings of Cambridge (SOC) tests from the Cambridge Neuropsychological Test Automated (CANTAB) Battery. General intellectual ability (GIA) was assessed using the Woodcock-Muñoz Cognitive battery. Median (range) urinary TCPy and 3-PBA levels were 16.7 (1.9, 356.9) ng/mg of creatinine and 3.3 (0.3, 110.6) ng/mg of creatinine, respectively. In multivariable generalized linear models, urinary TCPy was inversely associated with postdimensional errors on the IED task ß [95% CI]: -0.11 [-0.17, -0.06]. Urinary 3-PBA was inversely associated with the total number of trials -0.07 [-0.10, -0.04], and the total number of errors -0.12 [-0.18, -0.07] on the IED task. When TCPy and 3-PBA were modeled together, the associations did not differ from single-metabolite models. We found no evidence of effect modification by blood lead level (BLL). Pesticide exposure may affect EF performance in urban children.

Reducing the complexity of high-dimensional environmental data: An analytical framework using LASSO with considerations of confounding for statistical inference.

PURPOSE: Frameworks for selecting exposures in high-dimensional environmental datasets, while considering confounding, are lacking. We present a two-step approach for exposure selection with subsequent confounder adjustment for statistical inference. METHODS: We measured cognitive ability in 338 children using the Woodcock-Muñoz General Intellectual Ability (GIA) score, and potential associated features across several environmental domains. Initially, 111 variables theoretically associated with GIA score were introduced into a Least Absolute Shrinkage and Selection Operator (LASSO) in a 50% feature selection subsample. Effect estimates for selected features were subsequently modeled in linear regressions in a 50% inference (hold out) subsample, first adjusting for sex and age and later for covariates selected via directed acyclic graphs (DAGs). All models were adjusted for clustering by school. RESULTS: Of the 15 LASSO selected variables, eleven were not associated with GIA score following our inference modeling approach. Four variables were associated with GIA scores, including: serum ferritin adjusted for inflammation (inversely), mother's IQ (positively), father's education (positively), and hours per day the child works on homework (positively). Serum ferritin was not in the expected direction. CONCLUSIONS: Our two-step approach moves high-dimensional feature selection a step further by incorporating DAG-based confounder adjustment for statistical inference.

Impacts of multidisciplinary actions on environmental lead exposure in Uruguay.

Environmental lead contamination in Uruguay became a matter of public concern in 2001, when cases of children with blood lead levels (BLL) higher than 20 µg/dl appeared in some low-income neighborhoods of Montevideo, being 10 µg/dl the intervention reference BLL. The aim of this paper is to show the results of multidisciplinary actions taken by decisions makers in social, environmental and healthcare aspects, to minimize lead exposure risks. We evaluated changes in blood lead levels of different children and non-exposed adult populations before and after the actions were taken, from 2001 on. For children populations and non-exposed adults, we found a significant decrease of almost 50% in BLL compared with studies done before the actions were taken. The main action to consider was the phasing out process of leaded gasoline in our country among other. We conclude that the integration of inter and multidisciplinary actions promoted was of high impact on the population, bringing about a public sensitization and growing awareness of the lead environmental risks.

Contribution of household drinking water intake to arsenic and lead exposure among Uruguayan schoolchildren.

BACKGROUND: Food and water are common exposure sources of arsenic and lead among children. Whereas dietary sources of these toxicants are fairly well-studied, the contribution of drinking water to toxicant exposures is not well characterized in many populations, particularly in the Global South. OBJECTIVE: To assess the extent to which consumption of household drinking water contributes to arsenic and lead exposure among Uruguayan schoolchildren with low-level exposure. METHODS: Children, aged 5-8 years, were enrolled into the Salud Ambiental Montevideo study during 2009-2013 from schools in Montevideo, Uruguay. Participants reported water intake as part of two 24-h dietary recalls. Concentrations of arsenic were measured in first morning void urine samples, and adjusted for urinary specific gravity. Lead concentrations were measured in venous blood samples. Drinking water samples were collected from participants' homes and toxicant concentrations measured. Data analyses involved a triangulation approach. First, multivariable linear regressions estimated the associations between toxicant exposure through drinking water, calculated for each child as the product of water intake and water toxicant concentration, and the respective toxicant biomarker concentrations among children with complete data on all variables (Sample A; n = 40). Second, regressions were repeated for participants with complete data on all variables except water intakes (Sample B; n = 195), after water intakes were imputed. Finally, models were constructed for participants of Sample B (n = 195) based on drinking water intakes assumed to be fixed at 25th, 50th, 75th percentile intakes of participants in sample A. RESULTS: Toxicant exposure via drinking water intake was low. The triangulation approach revealed no associations between toxicant exposure through household water intake and the respective toxicant biomarker concentrations. CONCLUSION: Studies with larger samples and repeated measures are needed to confirm these findings. Nevertheless, it appears that at low water toxicant concentrations, typical water consumption is not a major contributor to children's exposure.

Do Neighborhood Factors Modify the Effects of Lead Exposure on Child Behavior?

Lead exposure and neighborhoods can affect children's behavior, but it is unclear if neighborhood characteristics modify the effects of lead on behavior. Understanding these modifications has important intervention implications. Blood lead levels (BLLs) in children (~7 years) from Montevideo, Uruguay, were categorized at 2 µg/dL. Teachers completed two behavior rating scales (n = 455). At one-year follow-up (n = 380), caregivers reported child tantrums and parenting conflicts. Multilevel generalized linear models tested associations between BLLs and behavior, with neighborhood disadvantage, normalized difference vegetation index (NDVI), and distance to nearest greenspace as effect modifiers. No effect modification was noted for neighborhood disadvantage or NDVI. Children living nearest to greenspace with BLLs < 2 µg/dL were lower on behavior problem scales compared to children with BLLs ≥ 2 µg/dL. When furthest from greenspace, children were similar on behavior problems regardless of BLL. The probability of daily tantrums and conflicts was ~20% among children with BLLs < 2 µg/dL compared to ~45% among children with BLLs ≥ 2 µg/dL when closest to greenspace. Furthest from greenspace, BLLs were not associated with tantrums and conflicts. Effect modification of BLL on child behavior by distance to greenspace suggests that interventions should consider both greenspace access and lead exposure prevention.

A Call for Biomonitoring Systems in Latin America and the Caribbean: Considerations for Potentially Toxic Metals/Metalloids.

The Latin America and the Caribbean (LAC) region makes up 8.4% of the world's population. Human biomonitoring (HBM) programs, which can shed light on population-level exposure to environmental contaminants such as toxic metals and thus, improve the health of the populations are inexistent in LAC countries. We call for the creation of HBM programs in the region and identify three viable design options for HBM at the individual level, through national surveys, newborn blood collection, and biobanks. We highlight some of challenges to the implementation of HBM programs, including financial and human resources, technical constrains (laboratory), sample, and data logistics. Finally, we provide the case studies of Brazil, Chile, Mexico, and Uruguay, to illustrate a range of responses to toxic metal exposure in non-occupational populations. Although different in many respects, the individual country responses share two commonalities: 1) academic centers drive the research to raise awareness of governmental entities; 2) reference levels are adapted from international norms rather than arising from the studied populations. Well-designed and sufficiently funded biomonitoring systems need to be established in each country of the LAC region. HBM programs are key to promoting human health by informing the public and contributing to policy processes that establish sustainable environmental controls and health prevention programs.

A mixed methods study examining neighborhood disadvantage and childhood behavior problems in Montevideo, Uruguay.

BACKGROUND: Neighborhood disadvantage (ND) is a risk factor for child behavior problems (CBPs), but is understudied outside the United States and Europe. Our mixed methods study aims to (1) create a culturally meaningful measure of ND, (2) test cross-sectional associations between ND and CBPs and (3) qualitatively explore life in the neighborhoods of families participating in the Salud Ambiental Montevideo (SAM) study. METHODS: The quantitative study (Study 1) comprised 272, ~7-year-old children with geolocation and complete data on twelve behavioral outcomes (Conner's Teachers Rating Scale - Revised Short Form: CTRS-R:S and Behavioral Rating Inventory of Executive Functioning: BRIEF). A ND factor was created at the census segment level (1,055 segments) with 19 potential indicators of ND downloaded from the Municipality of Montevideo Geographic Services. Children were assigned ND scores based on the location of their household within a census segment. Multilevel models tested associations between ND and all CBP scales, controlling for confounders at the individual level. The qualitative study (Study 2) comprised 10 SAM caregivers. Photovoice alongside semi-structured interviews in Spanish were used to foster conversations about neighborhood quality, activities, and raising children. Thematic analysis with inductive coding was used to summarize qualitative study findings. RESULTS: The ND factor consisted of 12 census-based indicators related to education, employment, ethnicity, housing quality, and age characteristics, but unrelated to home ownership and some ethnicity variables. In multivariable models, ND was associated with greater conduct problems (ß = 1.37, p < .05), poor shifting (ß = 1.56, p < .01) and emotional control problems (ß = 2.36, p < .001). Photovoice and semi-structured interviews yielded four themes: physical disorder, recreation, safety and crime, and community resources. Residents discussed improving waste management and transportation, updating playgrounds, and ensuring neighborhood safety. CONCLUSIONS: ND in Montevideo comprised a unique set of census indicators. ND was primarily related to behavioral regulation problems. Hypothesized pathways whereby ND affects CBPs are discussed.

Lead exposure stimulates VEGF expression in the spinal cord and extends survival in a mouse model of ALS.

Exposure to environmental lead (Pb) is a mild risk factor for amyotrophic lateral sclerosis (ALS), a paralytic disease characterized by progressive degeneration of motor neurons. However, recent evidence has paradoxically linked higher Pb levels in ALS patients with longer survival. We investigated the effects of low-level Pb exposure on survival of mice expressing the ALS-linked superoxide dismutase-1 G93A mutation (SOD1(G93A)). SOD1(G93A) mice exposed to Pb showed longer survival and increased expression of VEGF in the ventral horn associated with reduced astrocytosis. Pretreatment of cultured SOD1(G93A) astrocytes with low, non toxic Pb concentrations upregulated VEGF expression and significantly abrogated motor neuron loss in coculture, an effect prevented by neutralizing antibodies to VEGF. The actions of Pb on astrocytes might explain its paradoxical slowing of disease progression in SOD1(G93A) mice and the improved survival of ALS patients. Understanding how Pb stimulates astrocytic VEGF production and reduces neuroinflammation may yield a new therapeutic approach for treating ALS.

Arsenic levels in groundwater and its correlation with relevant inorganic parameters in Uruguay: A medical geology perspective.

The aim of this work was to perform a groundwater quality monitoring in Uruguay, from the Medical Geology perspective, focusing attention on arsenic levels and its correlations with other relevant inorganic parameters. For this purpose, a total of 46 groundwater samples from private wells, out of the scope of the state-run water utility company, were analyzed. The accuracy of the analytical methods was ensured by using certified reference materials. Arsenic concentration range was 1.72-120.5 µg L-1, half of the samples being above the limit of 10 µg L-1 recommended by WHO for drinking water, with the corresponding risks for human health. Pearson correlations were performed, resulting in strong positive correlations for the pairs As/Cl-, As/F-, As/Na and As/V. These relationships between arsenic and other inorganic parameters in groundwater should be deeply studied, to prevent long-term health effects.

Executive functions in school children from Montevideo, Uruguay and their associations with concurrent low-level arsenic exposure.

OBJECTIVE: Arsenic is a known childhood neurotoxicant, but its neurotoxicity at low exposure levels is still not well established. The aim of our cross-sectional study was to test the association between low-level arsenic exposure and executive functions (EF) among children in Montevideo. We also assessed effect modification by arsenic methylation capacity, a susceptibility factor for the health effects of arsenic, and by B-vitamin intake, which impacts arsenic methylation. METHODS: Arsenic exposure was assessed as the specific gravity-adjusted sum of urinary arsenic metabolites (U-As) among 255 ~ 7 year-old children, and methylation capacity as the proportion of urinary monomethylarsonic acid (%MMA). Arsenic concentrations from kitchen water samples at participants' homes were assessed. B-vitamin intake was calculated from the average of two 24-hour dietary recalls. EF was measured using three tests from the Cambridge Neuropsychological Test Automated Battery- Stockings of Cambridge (SOC), Intra-dimensional/extra-dimensional shift task (IED), and Spatial Span (SSP). Generalized linear models assessed the association between U-As and EF measures; models were adjusted for age, sex, maternal education, possessions score, Home Observation for Measurement of the Environment Inventory score, season, and school clusters. Additional analyses were conducted to address issues of residual confounding and sample size. A "B-vitamin index" was calculated using principal component analysis. Effect modification by the index and urinary %MMA was assessed in strata split at the respective medians of these variables. RESULTS: The median (range) U-As and water arsenic levels were 9.9 µg/L (2.2, 47.7) and 0.45 µg/L (0.1, 18.9) respectively, indicating that exposure originated mainly from other sources. U-As was inversely associated with the number of stages completed (ß = -0.02; 95% CI: -0.03, -0.002) and pre-executive shift errors (ß = -0.08; 95% CI: -0.14, -0.02) of the IED task, and span length of the SSP task (ß = -0.01; 95% CI: -0.02, -0.004). There was no clear pattern of effect modification by B-vitamin intake or urinary %MMA. CONCLUSION: Low-level arsenic exposure may adversely affect executive function among children but additional, including longitudinal, studies are necessary to confirm these findings.

Low level arsenic exposure, B-vitamins, and achievement among Uruguayan school children.

OBJECTIVES: Millions of children globally, including the U.S., are exposed to low levels of arsenic from water and food. Arsenic is a known neurotoxicant at high levels but its effects at lower exposure levels are understudied. Arsenic methylation capacity, influenced by B-vitamin intake and status, potentially influences arsenic toxicity. In a cross-secitonal study of 5-8 year-old children from Montevideo, we assessed the relationship between urinary arsenic (U-As) and academic achievement, and tested for effect modification by B-vitamin intake, status, and arsenic methylation capacity. METHODS: Broad math and reading scores were calculated based on six subtests (calculation, math facts fluency, applied problems, sentence reading fluency, letter word identification, passage comprehension) from the Woodcock-Muñoz Achievement Battery. B-vitamin intake was assessed from two non-consecutive 24-h dietary recalls, serum folate and vitamin B-12 levels were measured in a subset of participants. Arsenic methylation capacity was measured as the proportion of urinary monomethylarsonic acid (%MMA). Multiple imputation using chained equations was conducted to account for missing covariate and exposure data. Ordinal regressions assessed associations between U-As and achievement score tertiles in the complete case and imputed samples. A "B-vitamin index" was calculated using principal component analysis. Interactions by urinary %MMA and the B-vitamin index were assessed. RESULTS: Median specific gravity adjusted U-As was 11.7 µg/L (range: 2.6, 50.1). We found no association between U-As and broad math and reading scores, nor effect modification by %MMA or B-vitamins. CONCLUSION: At low-levels of exposure, U-As does not appear to affect children's academic achievement.