Childhood exposure to metal neurotoxins can result in irreversible neuropsychological impairments. Metal exposures have declined in the general U.S. population and significant progress has been made in the reduction of certain metals in the environment through effective intervention strategies. However, this problem is far from solved.
In many parts of the world, particularly Low and Middle-income Countries (LMIC), the extent of exposure to and harm from metals is only now gaining recognition. Although most children are exposed to two or more metals at a time, for many years, researchers had focused on studying the effects of single metals on child development. The past 5-10 years, however, ushered an important shift in thinking, and studies now more commonly assess the impact of multiple metal exposures on child health. We still do not know how these multiple metals interact to increase toxicity or neurodevelopmental deficits. In the context of LMICs, children’s nutritional status (malnutrition or deficiency of nutrients like iron) may also play an important role in exacerbating metal toxicity. On the other hand, diet could both promote better metal excretion and be the source of metal exposure. These gaps in understanding how multiple metal exposures and diet/nutrition affect child development form the basis of an NIH-funded research program, Salud Ambiental Montevideo (SAM), led by Dr. Katarzyna Kordas in Uruguay.
Salud Ambiental Montevideo, which stands for Environmental Health Montevideo, has recruited families of first-grade children residing in geographic locations of Uruguay’s capital city with known or suspected sources of environmental metal exposure. Between 2009 and 2013, 357 children were enrolled for a cross-sectional study on multiple metals and diet. Data collection based on questionnaires, neuropsychological tests, home visits, and direct measures was performed. Children’s exposure to metals was assessed in hair, blood and urine; nutritional status was assessed through measures of height and weight and the collection of dietary recalls; a comprehensive battery of neuropsychological tests was administered. The battery included tests of memory, executive functioning, attention, visuo-motor coordination, general cognitive ability, and academic proficiency. This broad collection of measurements gives SAM the ability to fully evaluate multiple metal exposures on a variety of child developmental outcomes. Like in many industrialized countries, children in SAM have low exposure to multiple metals, which allows SAM researchers to make contributions to the understanding of how much of a developmental impact these low-level metals have when they occur together, in a “mixture”. Many children (~40%) also have iron deficiency (ID), allowing for a study of nutrient-metal interactions.
Diet and metal exposures:
Metals and oxidative stress:
Metals, cognition and behavior:
Since 2015, recruitment of additional first-graders has been ongoing, and these children are being followed until 5th grade, with further assessments anticipated beyond elementary school. Through this longitudinal study, we will assess trajectories of cognitive and behavioral development in children exposed to multiple metals. We are also working to incorporate biomarkers and direct measures of exposures to other toxicants with the hope of contributing to the understanding of the totality of children’s environmental exposures during early school years.
We welcome collaborations from colleagues and students that will foster research on the developmental effects of toxicants among children in Uruguay and elsewhere.
Drinking water lead, iron and zinc concentrations as predictors of blood lead levels and urinary lead excretion in school children from Montevideo, Uruguay
Julia Ravenscroft, Aditi Roy, Elena I. Queirolo, Nelly Mañay, Gabriela Martínez, Fabiana Peregalli, Katarzyna Kordas
Published in Chemosphere, December 2018
The global burden of water-based lead (Pb) exposure on children is largely unknown; however, the importance of water sources as a path of Pb exposure is receiving increased attention due to recent prominent exposure events related to corroded plumbing infrastructure in the US. This study investigated the contribution of Pb in household drinking and cooking water to Pb levels in blood (PbB) and urine (PbU) within 353 early school-aged children from Montevideo, Uruguay. Additionally, the analysis considered the child's iron status and the water content of iron (WFe) and zinc(WZn) in relation to water Pb and blood/urine Pb concentrations. Lead concentrations for both PbB and PbU were fairly low (M ± SD: 4.2 ± 2.1 μg/dL; Median [5%, 95%]: 1.9 [0.6, 5.1 μg/L, respectively]); however 21% of the sample had a PbB >5 μg/dL but ≤ 10 μg/dL. Overall, there was little evidence of an association between water metal concentrations and children's PbB/PbU. However, when the sample was stratified by children's iron status, WPb was positively related to PbU, but negatively related to PbB in iron-replete children, even after adjusting for WFe and WZn. In iron-deficient children, there was no elevation in PbU with increasing WPb. In this sample of children with low Pb levels, there were no overwhelming relationships between WPb and either PbB or PbU, however, there was some evidence that iron-replete status promotes excretion of WPb.
Multiple-metal exposure, diet, and oxidative stress in Uruguayan school children
Katarzyna Kordas, Aditi Roy, Marie Vahter, Julia Ravenscroft, Nelly Mañay, Fabiana Peregalli, Gabriela Martínez, Elena I. Queirolo
Published in Environmental Research, October 2018
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.
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
Gauri Desai, Gabriel Barg, Elena I. Queirolo, Marie Vahter, Fabiana Peregalli, Nelly Mañay, Katarzyna Kordas
Published in Environmental Research, July 2018
Few studies have evaluated the association between low-level arsenic (As) exposure and cognitive performance among children.
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.
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).
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.
There was no association between low-level As exposure and general cognitive abilities.
Nutritional status and diet as predictors of children's lead concentrations in blood and urine
Katarzyna Kordas, Rachael Burganowski, AditiRoy, Fabiana Peregalli, Valentina Baccino, Elizabeth Barcia, Soledad Mangieri, Virginia Ocampo, Nelly Mañay, Gabriela Martínez, Marie Vahter, Elena I. Queirolo
Published in Environment International, February 2018
Lead exposure remains an important public health problem. Contaminated foods may act as a source of lead exposure, while certain nutrients may reduce lead absorption. We examined the cross-sectional associations of dietary patterns and the intake of several nutrients and foods with blood (Pb-B) and urinary (Pb-U) lead concentrations in children (5–8 y) from Montevideo, Uruguay. From two 24-hour recalls completed by caregivers, we derived the mean daily intake of select nutrients and food groups (dairy, milk, fruit, root vegetables, foods rich in heme and non-heme iron), as well as “nutrient dense” and “processed” food patterns. Pb-B (n = 315) was measured using atomic absorption spectrometry; Pb-U (n = 321) using ICP-MS. Pb-U was adjusted for specific gravity and log-transformed to approximate a normal distribution. Iron deficiency (ID) and dietary variables were tested as predictors of Pb-B and log-Pb-U in covariate-adjusted regressions. Median [5%, 95%] Pb-B and Pb-U were 3.8 [0.8–7.8] μg/dL and 1.9 [0.6–5.1] μg/L, respectively; ~ 25% of Pb-B above current U.S. CDC reference concentration of 5 μg/dL. ID was associated with 0.75 μg/dL higher Pb-B, compared to non-ID (p < 0.05). Consumption of root vegetables was not associated with Pb-B or log-Pb-U. Higher scores on the nutrient-dense pattern were related with higher Pb-Bs, possibly due to consumption of green leafy vegetables. Dietary intake of iron or iron-rich foods was not associated with biomarkers of lead. Conversely, children consuming more calcium, dairy, milk and yogurt had lower Pb-B and log-Pb-U. Our findings appear consistent with existing recommendations on including calcium-rich, but not iron- or vitamin-C-rich foods in the diets of lead-exposed children, especially where the consumption of these foods is low.
Very low-level metal exposure, dietary intakes, and oxidative stress in children from Montevideo, Uruguay
Katarzyna Kordas, Aditi Roy, Jing Nie, Marie Vahter, Nelly Manay, Gabriela Martinez, and Fabiana Peregalli
Children are concurrently exposed to low levels of multiple toxic metals but it is unclear how these exposures affect molecular processes like oxidative stress (OS), or the extent to which dietary components may reduce OS from these pro-oxidants. In a cross-sectional study of 6–8 y olds from Montevideo, Uruguay, we examined: 1) association of lead (Pb), cadmium (Cd), arsenic (As) and manganese (Mn) levels in urine with markers of OS: urinary F2-8α isoprostane and 8-OHdG; and 2) modification of OS by dietary intake of fruits, and vegetables and select antioxidant nutrients. 191 children provided first morning urine samples; OS markers were measured via ELISA and metals via ICP-MS, with concentratons adjusted for specific gravities. Mothers completed two 24-hr diet recalls at least 2 weeks apart; intake values were averaged. In complete-case analysis (n=143), covariate-adjusted OLS regressions were run separately for each marker of OS, entering metal as log-transformed continuous variables. Models were further stratified by median intake of foods and nutrients. 8-isoprostane and 8-OHdG concentrations were (median [5%, 95%]): 1.6 [0.3, 3.8] and 40.0 [12.2, 135.9] ng/mL, respectively. Urinary As, Cd, Mn and Pb concentrations were 9.92 [4.77, 24.72], 0.06 [0.02, 0.16], 0.11 [0.05, 0.75], 1.9 [0.58, 4.4] μg/L, respectively; metals were modestly correlated (Spearman’s rho 0.17–0.27). Fruit, vegetable and nutrient intake was low (median [5%, 95%]: fruit 120 [0, 462] g/d, vegetable 0 [0, 150] g/d, zinc 2.2 [0.9, 4.6] mg/kcal/d, vit C 19.4 [1.9, 86.5] μg/kcal/d, fiber 1.4 [0.5, 4.2] mg/kcal/d. Urinary metals were not associated with markers of OS. In stratified analyses, higher urinary Mn was associated with lower 8-OHdG concentrations among children with low, but not high, consumption of vitamin C, zinc, and fiber. Higher total urinary As was associated with higher 8-OHdG among children with low but not high vitamin C intake. Multiple metals do not appear to produce higher OS at low-level of exposure. With differential effects in low vs. higher antioxidant nutrient intake, low-level Mn in urine is likely reflecting the mineral’s role as a antioxidant.
Blood lead, iron deficiency and attentional ADHD symptoms in Uruguayan first-graders
Gabriel Barg, Elena I Queirolo, Nelly Manay, Fabiana Peregalli, and Katarzyna Kordas
FASEB Journal, Published April 2017
The combined effect of iron deficiency and lead exposure on attentional ADHD symptoms is not well studied. We investigated the associations among blood lead level (BLL), iron deficiency (ID, serum ferritin <15 μg/L) and inattention/cognitive problems (I/CP-measured by the Conners Teacher Rating Scale) in a cross-sectional study of first-grade children (n=257, age 6.7±0.5 years, 55.6% boys) from Montevideo, Uruguay. Aspects of children’s attention (ex., attention shifting) were measured by teacher reports on the BRIEF questionnaire. Generalized linear models (GLM) accounting for the school-based cluster design and adjusting for maternal education and employment, parental smoking, household crowding and SES, as well as child’s general intelligence and attention problems were used to model the association of BLL and ID with I/CP scores. Mean of BLL was 4.19±2.2 μg/dL, 39% of children had ID and 25% had mild to severe inattention problems (I/CP > 60 T score). BLL and serum ferritin were not independently associated with I/CP. However, in children with ID, BLL was associated with more problematic I/CP scores (0.32±0.14, p=0.026). This was not observed among non-ID children (0.09 ±0.08, p=0.239). General intelligence and maternal education were protective factors against I/CP (both at p<0.000). The ability to shift attention, commonly beneficial for cognitive performance, was negatively associated with I/CP in children with ID, presumably by ID’s negative effect on the ability to control the attentional focus. In sum, our early findings suggest an adverse effect of the combination of ID and higher BLLs on sustained attention, a key competence for learning and socialization.
Elena I Queirolo, MD
Gabriel Barg, PhD
Fabiana Peregalli, MS
Epidemiology and Environmental Health
234A Farber Hall
Epidemiology and Environmental Health
Epidemiology and Environmental Health