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 (PI) 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 proposal 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 proposal 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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Transition Award (R00)
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Study Section
Special Emphasis Panel (NSS)
Program Officer
Kirshner, Annette G
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Boston University
Public Health & Prev Medicine
Schools of Public Health
United States
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Bobb, Jennifer F; Claus Henn, Birgit; Valeri, Linda et al. (2018) Statistical software for analyzing the health effects of multiple concurrent exposures via Bayesian kernel machine regression. Environ Health 17:67
Liu, Shelley H; Bobb, Jennifer F; Lee, Kyu Ha et al. (2018) Lagged kernel machine regression for identifying time windows of susceptibility to exposures of complex mixtures. Biostatistics 19:325-341
Muñoz-Rocha, Teresa Verenice; Tamayo Y Ortiz, Marcela; Romero, Martín et al. (2018) Prenatal co-exposure to manganese and depression and 24-months neurodevelopment. Neurotoxicology 64:134-141
Claus Henn, Birgit; Austin, Christine; Coull, Brent A et al. (2018) Uncovering neurodevelopmental windows of susceptibility to manganese exposure using dentine microspatial analyses. Environ Res 161:588-598
Butler, Lindsey; Gennings, Chris; Peli, Marco et al. (2018) Assessing the contributions of metals in environmental media to exposure biomarkers in a region of ferroalloy industry. J Expo Sci Environ Epidemiol :
Valeri, Linda; Mazumdar, Maitreyi M; Bobb, Jennifer F et al. (2017) The Joint Effect of Prenatal Exposure to Metal Mixtures on Neurodevelopmental Outcomes at 20-40 Months of Age: Evidence from Rural Bangladesh. Environ Health Perspect 125:067015
Claus Henn, Birgit; Bellinger, David C; Hopkins, Marianne R et al. (2017) Maternal and Cord Blood Manganese Concentrations and Early Childhood Neurodevelopment among Residents near a Mining-Impacted Superfund Site. Environ Health Perspect 125:067020
Bauer, Julia Anglen; Claus Henn, Birgit; Austin, Christine et al. (2017) Manganese in teeth and neurobehavior: Sex-specific windows of susceptibility. Environ Int 108:299-308
Chiu, Yueh-Hsiu Mathilda; Claus Henn, Birgit; Hsu, Hsiao-Hsien Leon et al. (2017) Sex differences in sensitivity to prenatal and early childhood manganese exposure on neuromotor function in adolescents. Environ Res 159:458-465
Wang, Zhaoxi; Claus Henn, Birgit; Wang, Chaolong et al. (2017) Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment. Environ Health 16:81

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