Project Summary/Abstract Metals are known neurotoxicants in children, but less attention has been given to the impact of metal mixtures on cognitive function. Further, few studies of metals have examined the role of iron status on cognitive outcomes in adolescents. Our study aims to describe the neurotoxicity of an industrial-relevant metal mixture (Mn, Pb, Cu, Cr) on the domains of attention and verbal learning and memory in adolescents, and to identify subpopulations that may have greater susceptibility to metals by elucidating the role of iron status in metal- induced toxicity. This proposed study will use previously collected data from the Public Health Impact of Mixed element Exposure (PHIME) study, a cohort of 720 Italian children aged 10-14 years. Children in PHIME were recruited from three distinct geographic regions of the Brescia Province with varying exposure to airborne ferromanganese alloy industry. Under the mentorship of a multidisciplinary team of experts in environmental epidemiology, biostatistics, exposure science, neurobehavioral toxicology, and mixtures, Samantha Schildroth (PI) proposes the following aims: 1) describe associations of metal mixtures with attentional function and verbal learning and memory in adolescents; 2) assess the role of iron status as a) a modifier of metals neurotoxicity that alters associations between the metal mixture and cognition, and b) a mediator that is impacted by the metal mixture and affects cognition. Metals in PHIME were measured in multiple biomarkers (hair, nails, blood, saliva, urine) and iron status parameters were measured in whole blood (ferritin, transferrin, and hemoglobin) and using hematocrit/serum iron levels. Objective measures of cognitive function were used to assess attention (Conners-Wells Rating Scales) and verbal learning and memory (California Verbal Learning Test). We will use state-of-the-art statistical approaches for mixtures, including Bayesian Kernel Machine Regression and quantile-based g-computation, to address our proposed aims. The research outlined in this proposal will contribute to our current understanding of the neurotoxicity of a metal mixture relevant for communities living in proximity to ferroalloy emissions, an industry that is expanding globally, on two domains necessary for the overall cognitive function of children and will examine iron status as a potential susceptibility factor. The proposed training and research will expand upon the applicant's strong foundation in environmental epidemiology and provide her with additional skills needed to study the joint effects of multiple metals on cognition, while considering iron status. This research will 1) address the large data gap on health effects of metal mixtures in adolescents, and 2) help characterize modifiable environmental factors, including dietary factors like iron status, in adolescence that may be targets for future public health intervention.

Project Narrative Metals are known neurotoxicants and can have profound impacts throughout the lifespan, but little is known about the cognitive effects of exposure to metal mixtures, or the role of iron status as a susceptibility factor enhancing metal toxicity. This study aims to describe associations of metal mixtures in adolescence with domains of particular importance for cognitive function, attention and verbal learning and memory, and to evaluate the role of iron status. We will investigate joint and interactive effects of multiple metals and mediation and/or modification of these associations by iron status.