Mixtures are a common exposure scenario but are rarely studied. Metals comprise a class of chemicals to which co-exposure is common and whose neurotoxic effects, particularly, can be severe, making them a potentially paradigm class of chemicals for mixtures research. Research on individual metals, such as lead, has been robust; but research on metal mixtures is lacking. Major challenges impeding progress in mixtures research include the lack of sufficient exposure data for multiple metals. Even when multiple metal exposure biomarkers are collected, there remains a lack of analytical tools to fully evaluate interactions. Under the mentorship of Drs. Coull and Lucchini, Dr. Claus Henn (principal investigator) will overcome barriers in mixtures research by using cutting-edge statistical learning methods, combined with robust data on host exposure to mixed metals. By doing so, she will evaluate the joint effects of multiple metals on neurodevelopment. This K99/R00 application builds upon Dr. Claus Henn's experience in environmental epidemiology and exposure science to cross train her in child development and biostatistics and prepare her to become an independent investigator specializing in chemical mixtures and pediatric environmental health. In the K99 phase of the award, Dr. Claus Henn will use tutorials, didactic instruction, and seminars/conferences to receive training in: 1) advanced quantitative methods for use in analyzing combined exposures, and 2) childhood neurodevelopment from the prenatal period through adolescence. These areas of training represent a new cross-disciplinary goal for Dr. Claus Henn. Her training will subsequently be applied in an existing cohort of 750 Italian adolescents in the Public Health Impact of Mixed Element exposure (PHIME) study. Dr. Claus Henn will apply structural equation models, random forests, and kernel regression machines to examine cognitive effects of concurrent exposure to combinations of metals. In the R00 phase, Dr. Claus Henn will evaluate whether cognitive effects of exposure to combinations of metals depend on exposure timing. Using data from the Early Life Exposure in Mexico to Environmental NeuroToxicants (ELEMENT) longitudinal birth cohort, she will apply the aforementioned methods at multiple exposure time points, across the prenatal period and childhood. This cross-disciplinary proposal represents a unique opportunity to efficiently use existing data in an innovative yet cost-effective manner. The proposed training and research will provide Dr. Claus Henn with the skills to study the joint effects of multiple chemicals and multiple time points on neurodevelopment in future research. This research will 1) address the large data gap on health effects of chemical mixtures, and 2) help characterize critical windows of susceptibility to neurotoxicants; both are NIEHS strategic goals and public health priorities. Public Health Relevance: Research on chemical mixtures is a critical public health need, because the neurotoxicity of an individual chemical is likely modified in the presence of other chemicals; yet research on the effects of metal mixtures is lacking. Further complicating this issue is that timing of exposure to mixtures may also result in differential toxicity. This application will use an integrated training plan in neurodevelopment and advanced biostatistics to train Dr. Birgit Claus Henn, an environmental epidemiologist and exposure assessment expert, to conduct high-level research in metal mixtures and children's neurodevelopment at several critical time points of development, from the prenatal period through adolescence. ExpandCollapse Abstract