Worldwide, millions of children are exposed to toxic metals, including lead (Pb), arsenic (As), cadmium (Cd), and manganese (Mn), with important consequences for their health and development. Research findings con- firm the association between exposure to single toxic metals and neurobehavioral deficits in children. However, metal exposures rarely occur in isolation. Nevertheless, few studies to date have examined interactions among toxic metals on cognitive deficits or behavioral problems, often with mixed results. There is also little under- standing of the long-term consequences of multiple metal exposures on child outcomes. Thus, scarcity of data and methodological limitations have kept this field from making sound recommendations for the protection of children and pediatric practice. The long-term goal of this research is to understand how low-level exposure to multiple toxic metals affects neurobehavioral outcomes across childhood and adolescence, identifying potential synergistic effects of metals on children's outcomes. The objective of the proposed study is to determine how children's exposure to multiple metals affects specific cognitive functions and behavior through middle childhood. The proposed study is a longitudinal cohort study that will take place in Montevideo, Uruguay and builds on previous research in 1st grade children. The study focuses on As, Cd, Mn, Pb because these occur at bio- logically relevant levels in the environment and biological samples collected from the Uruguayan children. The central hypothesis is that within low range of exposures, higher concentrations of As, Cd, Mn and Pb will be individually associated with poorer cognition and behavior over time, and that co-exposure to these metals will produce additive or multiplicative negative effects on neurobehavioral outcomes. The specific aims of this study are to: 1) describe the trends and variability of the long-term exposure to As, Cd, Mn and Pb, 2) characterize the extent to which body burden of the metals is associated with deficits in specific cognitive functions, and 3) characterize the extent to which the metals are associated with reported and observed problem behaviors. The study population will consist of ~760 children. The study has a staggered design, entailing: 1) the follow-up of children who had been evaluated as 1st-graders in 2 previous studies (years 2010-2013), and 2) the enrollment in 1st grade and follow-up of additional cohorts of children. Hair and blood samples will be collected yearly, and children's cognition and behavior will be evaluated in 1st, 3rd and 5th grade. This approach is innovative because, in contrast to previous studies, in employs a longitudinal approach to examine interactions among multiple metals that occur at low levels in the environment, and employs specific process-oriented cognitive outcomes as opposed to IQ, which is a summative measure. This research is significant in its contribution to the communication of health risks associated with exposure to multiple toxic metals, and in its potential contribution to approaches that will prevent or alleviate the developmental consequences of exposure.

Millions of children worldwide are exposed to neurotoxic substances in their environment, such as arsenic, that produce potentially irreversible intellectual and behavioral impairments. Cognitive deficits, most typically measured as IQ in school children living in high-exposure areas, have been associated with higher concentrations of arsenic in drinking water, urine and hair. However, we have limited understanding of the extent to which low- level arsenic exposure is associated with children's cognitive function and behavior. This gap in knowledge limits accurate risk assessment and the communication of health risks associated with arsenic exposure. The long-term goal is to understand how low-level arsenic exposure affects neurobehavioral outcomes across childhood and adolescence, and to identify host and environmental factors (such as age, sex, genetic make- up, nutritional status, and other environmental exposures) that may modify the effects of arsenic on child cognition and behavior. The objective of the proposed study is to determine the effects of low-level arsenic exposure and arsenic methylation capacity on cognitive function and behavior in 6-7 year-old children. The central hypothesis is that within low-range of exposures, higher arsenic concentrations in water and urine (particularly higher fraction of urinary methylarsonic acid) will be associated with poorer cognition and behavior problems. The two specific aims are 1) Determine to what extent low-level arsenic exposure (<50 5g/L) is associated with neurobehavioral outcomes in first-grade children, and 2) Determine to what extent low arsenic methylation capacity impairs cognition and behavior in first-grade children exposed to As. Archived water and urine samples from an ongoing study of first-graders from Montevideo, Uruguay will be utilized to address both aims, in addition to the collection of water and urine samples from newly enrolled children. Results from extensive neurobehavioral assessments of the children and indicators of nutritional status and neurotoxicant exposure will be employed. This approach is innovative because in contrast to previous studies, it systematically examines the effects of low-level arsenic exposure and methylation capacity on child cognition. These methodological advances will result in more accurate risk-assessment of arsenic exposure on its own and provide important data to inform the design of large, systematic investigations of these issues in the future. This research is significant in its contribution to the communication of health risks associated with arsenic exposure. Important strides toward the prevention of exposure and the development of risk-modification strategies can also be achieved once factors associated with the excretion of arsenic (methylation) are identified. Finally, the significance of this research, over the long-term, lies in its potential contribution to policies on arsenic monitoring and action levels in settings, such as the United States, where children typically experience low-level arsenic exposure.

Neurodevelopmental disabilities in children from low-to-middle income countries produce a substantial negative impact on societal and economic growth. Many of the causes of developmental disabilities, such as environmental toxins, nutritional deficiencies, psychosocial stressors, are common in resource-poor countries. Young children are particularly vulnerable to environmental exposures because rapid development creates windows of opportunity for toxins to exert their effects. In areas of the world where little research on neurodevelopmental disabilities has been conducted, it is necessary to assess the prevalence and nature of cognitive and behavioral deficits. In Montevideo, Uruguay, there is evidence that children are exposed to multiple heavy metals. However, to date very little research exists in this unique setting to understand the effects of multiple metal exposures on cognition, behavior, and school performance of urban children. There is also no research on how these exposures could be prevented or mitigated. We propose to conduct an investigation of cognitive performance and behavior in 200 children aged 6-7 years from Montevideo, Uruguay. Early school age is a period of important intellectual and social growth, and it sets up children's scholastic trajectories. At this time, learning disabilities often become manifested and diagnosed in children. It is also an age when environmental insults are clearly manifested. The goal of this project is to build research capacity and infrastructure in environmental epidemiology. Also, it is to investigate the relationship between heavy metal exposures (lead, arsenic, mercury), trace metals (iron and manganese) and cognition, behavior, and school performance in children from Montevideo, Uruguay. In the process of collecting data, we will identify key steps in the research process that will require additional training or resources.