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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Page xiii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Environmental Neuroscience: Advancing the Understanding of How Chemical Exposures Impact Brain Health and Disease: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25937.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Lisa Bain, Sheena M. Posey Norris, and Clare Stroud, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division Board on Environmental Studies and Toxicology Division on Earth and Life Studies PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by contracts between the National Academy of Sci- ences and Alzheimer’s Association; Cohen Veterans Bioscience; Department of Health and Human Services’ Food and Drug Administration (5R13FD005362- 05) and National Institutes of Health (NIH) (75N98019F00769 [Under Master Base HHSN263201800029I]) through National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and NIH Blueprint for Neuroscience Research; Department of Veter- ans Affairs (VA240-14-C-0057); Eisai Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Janssen Research & Development, LLC; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; Sanofi; Society for Neuroscience; Takeda Pharmaceuticals International, Inc.; The University of Rhode Island; and Wellcome Trust. Any opinions, findings, conclusions, or recom- mendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25937 Additional copies of this publication are available for from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2020 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. Environmental neuroscience: Advancing the understanding of how chemical expo- sures impact brain health and disease: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/25937. PREPUBLICATION COPY—Uncorrected Proofs

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the char- ter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was estab- lished in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY—Uncorrected Proofs

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY—Uncorrected Proofs

PLANNING COMMITTEE ON ENVIRONMENTAL NEUROSCIENCE1 DEBORAH CORY-SLECHTA (Co-Chair), Department of Environmental Medicine, University of Rochester School of Medicine & Dentistry WALTER KOROSHETZ (Co-Chair), National Institute of Neurological Disorders and Stroke, National Institutes of Health PATRICK BREYSSE, National Center for Environmental Health, Agency for Toxic Substances and Disease Registry, Centers for Disease Control and Prevention RAY DORSEY, Department of Neurology, University of Rochester School of Medicine & Dentistry CARL HILL, Alzheimer’s Association FRANCES JENSEN, Department of Neurology, University of Pennsylvania Perelman School of Medicine DAVID JETT, National Institute of Neurological Disorders and Stroke, National Institutes of Health CINDY LAWLER, National Institute of Environmental Health Sciences, National Institutes of Health GARY MILLER, Columbia University Mailman School of Public Health TREVOR PENNING, Department of Environmental Health Sciences, University of Pennsylvania Perelman School of Medicine ALLISON WILLIS, Department of Neurology, University of Pennsylvania Perelman School of Medicine Health and Medicine Division Staff CLARE STROUD, Director, Forum on Neuroscience and Nervous System Disorders SHEENA M. POSEY NORRIS, Program Officer PHOENIX WILSON, Senior Program Assistant ANDREW M. POPE, Senior Director, Board on Health Sciences Policy 1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rap- porteurs and the institution. v PREPUBLICATION COPY—Uncorrected Proofs

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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1 FRANCES JENSEN (Co-Chair), University of Pennsylvania JOHN KRYSTAL (Co-Chair), Yale University SUSAN AMARA, National Institute of Mental Health RITA BALICE-GORDON, Muna Therapeutics KATJA BROSE, Chan Zuckerberg Initiative EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai SARAH CADDICK, Gatsby Charitable Foundation MARIA CARRILLO, Alzheimer’s Association EDWARD CHANG, University of California, San Francisco TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University ROBERT CONLEY, Eli Lilly and Company JAMES DESHLER, National Science Foundation BILLY DUNN, Food and Drug Administration MICHAEL EGAN, Merck Research Laboratories NITA FARAHANY, Duke University JOSHUA GORDON, National Institute of Mental Health MAGALI HAAS, Cohen Veterans Bioscience RAMONA HICKS, One Mind RICHARD HODES, National Institute on Aging STUART HOFFMAN, Department of Veterans Affairs JONATHAN HORSFORD, National Institute of Dental and Craniofacial Research YASMIN HURD, Icahn School of Medicine at Mount Sinai STEVEN HYMAN, Broad Institute of Massachusetts Institute of Technology and Harvard University MICHAEL IRIZARRY, Eisai Inc. GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke STORY LANDIS, National Institute of Neurological Disorders and Stroke (Director Emeritus) ALAN LESHNER, American Association for the Advancement of Science (Emeritus) 1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY—Uncorrected Proofs

JOSEPH MENETSKI, Foundation for the National Institutes of Health STEVEN PAUL, Voyager Therapeutics EMILIANGELO RATTI, Takeda Pharmaceuticals International, Inc. TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research DAVID SHURTLEFF, National Center for Complementary and Integrative Health SANTA TUMMINIA, National Eye Institute NORA VOLKOW, National Institute on Drug Abuse ANDREW WELCHMAN, Wellcome Trust DOUG WILLIAMSON, Lundbeck STEVIN ZORN, MindImmune Therapeutics, Inc. Health and Medicine Division Staff CLARE STROUD, Forum Director SHEENA M. POSEY NORRIS, Program Officer PHOENIX WILSON, Senior Program Assistant BARDIA MASSOUDKHAN, Senior Finance Business Partner ANDREW M. POPE, Senior Director, Board on Health Sciences Policy viii PREPUBLICATION COPY—Uncorrected Proofs

BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY WILLIAM H. FARLAND (Chair), Colorado State University LESA AYLWARD, Summit Toxicology, LLP ANN M. BARTUSKA, Resources for the Future GERMAINE M. BUCK LOUIS, George Mason University E. WILLIAM COLGLAZIER, American Association for the Advancement of Science FRANCESCA DOMINICI, Harvard University GEORGE M. GRAY, The George Washington University R. JEFFREY LEWIS, ExxonMobil Biomedical Sciences, Inc. LINSEY MARR, Virginia Polytechnic Institute and State University R. CRAIG POSTLEWAITE, Department of Defense (Retired) REZA J. RASOULPOUR, Corteva Agriscience IVAN RUSYN, Texas A&M University DEBORAH L. SWACKHAMER, Public Health Institute JOSHUA TEWKSBURY, Future Earth SACOBY M. WILSON, University of Maryland Division on Earth and Life Studies Staff CLIFFORD DUKE, Board Director RAYMOND WASSEL, Scholar TAMARA DAWSON, Program Coordinator ix PREPUBLICATION COPY—Uncorrected Proofs

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Reviewers This Proceedings of a Workshop was reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical com- ments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: BRIANA R. DE MIRANDA, University of Alabama at Birmingham PHILIPPE GRANDJEAN, Harvard University GEORGE GRAY, The George Washington University GARY W. MILLER, Columbia University BEATE RITZ, University of California, Los Angeles Although the reviewers listed above provided many constructive com- ments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by MARK CULLEN, Stanford University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully consid- ered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. xi PREPUBLICATION COPY—Uncorrected Proofs

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Contents 1 INTRODUCTION AND BACKGROUND 1 Workshop Objectives, 3 Organization of Proceedings, 4 2 NEUROTOXICANTS AND THEIR RISKS TO HUMAN HEALTH 5 Lead, 7 Agricultural Chemicals: Herbicides, Pesticides, Insecticides, and Fungicides, 9 Industrial Chemicals and Flame-Retardant Chemicals, 9 Air Pollution, 14 Assessing the Risk of Exposures, 14 3 THE EXPOSOME AND EXPLORING THE MULTIPLE FACTORS THAT CONTRIBUTE TO NEUROTOXICITY 17 The Exposome, 18 Genetic Factors, 20 LRRK2, 23 Epigenetics, 24 Concurrent Risk Factors: Stress and Poverty, 27 xiii PREPUBLICATION COPY—Uncorrected Proofs

xiv CONTENTS 4 CHEMICAL TOXICANTS AS DRIVERS OF ABNORMAL NEURODEVELOPMENT AND NEURODEGENERATION 29 Neurodevelopment, Autism, and Attention-Deficit Hyperactivity Disorder, 30 Neurodegenerative Disorders: Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis, 32 5 RESEARCH GAPS AND OPPORTUNITIES 39 Adverse Outcome Pathways, 42 Standardized Data Collection, 43 New Tools Are Advancing Environmental Neuroscience, 44 Population and Real-World Studies, 46 6 POTENTIAL OPPORTUNITIES FOR ACTION AND MULTIDISCIPLINARY COLLABORATIONS 49 Policy Implications for Environmental Neuroscience, 50 Opportunities for Multidisciplinary Collaboration, 52 Motivating Action, 55 APPENDIXES A References 57 B Workshop Agenda 67 PREPUBLICATION COPY—Uncorrected Proofs

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Humans are potentially exposed to more than 80,000 toxic chemicals in the environment, yet their impacts on brain health and disease are not well understood. The sheer number of these chemicals has overwhelmed the ability to determine their individual toxicity, much less potential interactive effects. Early life exposures to chemicals can have permanent consequences for neurodevelopment and for neurodegeneration in later life. Toxic effects resulting from chemical exposure can interact with other risk factors such as prenatal stress, and persistence of some chemicals in the brain over time may result in cumulative toxicity. Because neurodevelopmental and neurodegenerative disorders - such as attention-deficit hyperactivity disorder and Parkinson's disease - cannot be fully explained by genetic risk factors alone, understanding the role of individual environmental chemical exposures is critical.

On June 25, 2020, the National Academies of Sciences, Engineering, and Medicine's Forum on Neuroscience and Nervous System Disorders hosted a workshop to lay the foundation for future advances in environmental neuroscience. The workshop was designed to explore new opportunities to bridge the gap between what is known about the genetic contribution to brain disorders and what is known, and not known, about the contribution of environmental influences, as well as to discuss what is known about how genetic and environmental factors interact. This publication summarizes the presentation and discussion of the workshop.

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