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Veterans and Agent Orange: Update 11 (2018) (2018)

Chapter: Front Matter

Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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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.

VAgent eterans and Orange Update 11 (2018) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eleventh Biennial Update) Board on Population Health and Public Health Practice Health and Medicine Division A Consensus Study Report of PREPUBLICATION COPY—Uncorrected Proofs

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This activity was supported by Contract/Task Order No. VA701-16-C-0040 between the National Academy of Sciences and the Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessar- ily reflect the views of any organizations or agency that provided support for this project. International Standard Book Number-13:  International Standard Book Number-10:  Digital Object Identifier:  https://doi.org/10.17226/25137 Additional copies of this publication are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; www.nap.edu. Copyright 2018 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. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25137. 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 charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contri- butions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established 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 typi- cally 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 opin- ions 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

COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (ELEVENTH BIENNIAL UPDATE) IRVA HERTZ-PICCIOTTO (Chair), Director of Environmental Health Sciences Center, Professor of Epidemiology and Environmental Health, Department of Public Health Sciences, School of Medicine, University of California, Davis NANCY BERLINER, Chief, Division of Hematology, Brigham and Women’s Hospital WENDY B. BERNSTEIN, Associate Professor of Medicine, Uniformed Services University of the Health Sciences, and Attending Physician, Department of Hematology Oncology, Walter Reed National Military Medical Center MICHAEL J. CARVAN III, Shaw Professor, School of Freshwater Sciences, University of Wisconsin–Milwaukee ARAVINDA CHAKRAVARTI, Director, Center for Human Genetics and Genomics, New York University School of Medicine DANA C. DOLINOY, NSF International Chair and Professor, Department of Environmental Health Sciences, University of Michigan School of Public Health MARY A. FOX, Assistant Professor, Health Policy and Management, Co- Director, Risk Sciences and Public Policy Institute, Johns Hopkins Bloomberg School of Public Health KARL T. KELSEY, Professor of Epidemiology, Professor of Pathology and Laboratory Medicine, Brown University MOLLY L. KILE, Associate Professor, Environmental and Occupational Health, Oregon State University ANDREW F. OLSHAN, Barbara Sorenson Hulka Distinguished Professor, Department of Epidemiology, University of North Carolina BEATE R. RITZ, Professor of Epidemiology, Center for Occupational and Environmental Health, University of California, Los Angeles, School of Public Health LORI A. WHITE, Associate Professor, Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey v PREPUBLICATION COPY—Uncorrected Proofs

Staff DAVID A. BUTLER, Scholar, Study Director ANNE N. STYKA, Senior Program Officer T. CHERI BANKS, Research Associate ELIZABETH BARKSDALE BOYLE, Program Officer, Board on Environmental Studies and Toxicology (from October 2017) PAMELA RAMEY-MCCRAY, Senior Program Assistant HELENA J. CHAPMAN, Christine Mirzayan Science and Technology Policy Fellow (January–April 2017) ROSE MARIE MARTINEZ, Senior Director, Board on Population Health and Public Health Practice vi PREPUBLICATION COPY—Uncorrected Proofs

Acknowledgments The study committee and the Health and Medicine Division (HMD) project staff take this opportunity to recognize and thank the many individuals who shared their time and expertise to support the committee’s work and inform its deliberations. This study was sponsored by the Department of Veterans Affairs. We thank Dr. Peter Rumm and Dr. Loren Erickson for their guidance and support. The committee benefited greatly from discussions with the individuals who presented at and attended the committee’s open sessions: Victoria Davey, Ralph L. Erickson, Russ Hauser, C. Ola Landgren, Paul S. Mischel, Quinn T. Ostrom, Peter R. Rumm, Aaron I. Schneiderman, and Thaddeus (Thad) Schug. The com- mittee would also like to thank all participants who attended the committees open sessions, including Ann Brazeau, Carla Dean, Maynard Kaderlik, Mokie Porter, Pegi Scarlett, Sidath Vranga, Deborah Watkins, and the many others who attended the September 7, 2017, Minneapolis open session; and all others who made or submitted comments or materials for the committee’s consideration. The committee is grateful to these presenters for volunteering to share their expertise, knowledge, data, and opinions not only with the committee, but also with the members of the public who participated in the committee’s open sessions. The committee also appreciates the efforts of numerous individuals who assisted project staff in identifying the presenters. Furthermore, we acknowledge the many staff within the HMD who provided support in various ways to this project, including Julie Wiltshire, financial associ- ate for the project; Daniel Bearss, senior research librarian, who conducted and compiled all of the literature searches; and Robert Pool for his editorial assistance provided in preparing the final report. vii PREPUBLICATION COPY—Uncorrected Proofs

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Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institu- tional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: Alvaro Alonso, Rollins School of Public Health, Emory University Kate M. Applebaum, Milken Institute School of Public Health, The George Washington University Linda Birnbaum, National Institute of Environmental Health Sciences and National Toxicology Program Bruce Blumberg, University of California, Irvine Melissa L. Bondy, Baylor College of Medicine Victoria A. Cassano, Performance Medicine Consulting, LLC David C. Christiani, Harvard T.H. Chan School of Public Health David L. Eaton, University of Washington School of Public Health S. Katharine Hammond, University of California, Berkeley, School of Public Health Elaine S. Jaffe, Center for Cancer Research, National Cancer Institute ix PREPUBLICATION COPY—Uncorrected Proofs

x REVIEWERS Patricia A. Janulewicz, Boston University School of Public Health Stephen H. Safe, Texas A&M University Judith T. Zelikoff, New York University School of Medicine Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommenda- tions of this report nor did they see the final draft before its release. The review of this report was overseen by Sandro Galea, Boston University School of Public Health, and Martin A. Philbert, University of Michigan. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. PREPUBLICATION COPY—Uncorrected Proofs

Contents ACRONYMS AND ABBREVIATIONS SUMMARY 1 INTRODUCTION Previous Veterans and Agent Orange Reports Charge to the Committee Information Gathering Organization of the Report 2 BACKGROUND The Current Population of Vietnam Veterans Military Use of Herbicides in Vietnam Exposure of Different Groups of Vietnam Veterans Characterizing Exposure Determining Increased Risk in Vietnam Veterans 3 EVALUATION OF THE EVIDENCE BASE Identification and Screening of the Literature Evaluation Process 4 BIOLOGIC MECHANISMS Picloram Cacodylic Acid xi PREPUBLICATION COPY—Uncorrected Proofs

xii CONTENTS Phenoxy Herbicides: 2,4-Dichlorophenoxy Acid and 2,4,5-Trichlorophenoxyacetic Acid 2,3,7,8-Tetrachlorodibenzo-p-dioxin Overarching Toxicologic Issues Related to the Chemicals of Interest Mediators of Health Outcomes 5 BACKGROUND ON SELECTED EPIDEMIOLOGIC STUDIES AND POPULATIONS Vietnam-Veteran Studies Occupational Studies Environmental Studies Case-Control Studies 6 IMMUNE SYSTEM DISORDERS Categories of Immune Dysfunction Conclusions from VAO and Previous Updates Update of Epidemiologic Literature Biologic Plausibility Synthesis Conclusion 7 CANCER Organization of Cancer Groups Biologic Plausibility Current Views of Cancer Mechanisms Overview of Studies That Report Multiple Cancer Outcomes Studies of Overall Cancer Mortality or Incidence Oral, Nasal, and Pharyngeal Cancers Cancers of the Digestive Organs Laryngeal Cancer Lung Cancer Bone and Joint Cancers Soft-Tissue Sarcomas Skin Cancers Breast Cancer Cancers of the Female Reproductive System Prostate Cancer Testicular Cancer Bladder Cancer Renal Cancers Brain Cancer Endocrine Cancers Lymphohematopoietic Cancers PREPUBLICATION COPY—Uncorrected Proofs

CONTENTS xiii 8 REPRODUCTIVE HEALTH EFFECTS AND EFFECTS ON DESCENDANTS Biologic Plausibility of Reproductive Health Effects Male Reproductive Health Female Reproductive Health Gestation and Neonatal Effects in Offspring Effects Occurring Later in Offspring’s Lives Biologic Plausibility of Possible Effects in Subsequent Generations 9 NEUROLOGIC DISORDERS Biologic Plausibility Nervous System Disorders Reported Overall Neurobehavioral, Cognitive, and Neuropsychiatric Disorders Neurodegenerative Diseases Chronic Peripheral Nervous System Disorders Hearing Loss 10 METABOLIC AND CARDIOVASCULAR DISORDERS Type 2 Diabetes Circulatory Disorders 11 OTHER CHRONIC HEALTH OUTCOMES Non-Cancerous Respiratory Disorders Gastrointestinal and Digestive Diseases, Including Liver Toxicity Kidney and Urinary Disorders Thyroid Homeostasis and Other Endocrine Functions Chronic Skin Disorders Eye Problems Bone Conditions 12 CONCLUSIONS AND RECOMMENDATIONS Synopsis of Committee Conclusions Other Committee Recommendations Final Observations REFERENCES APPENDIXES A Public Meeting Agendas B Committee and Staff Biographies PREPUBLICATION COPY—Uncorrected Proofs

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Boxes, Figures, and Tables BOXES 1-1 Committee’s Statement of Task 3-1 Search Terms 3-2 Criteria for Excluding Scientific Articles from Further Consideration 3-3 Statistical Terms Used in This Report FIGURES 2-1 Chemical structures and Chemical Abstracts Service (CAS) numbers for the specific chemicals of interest 2-2 Median serum TCDD levels in various study populations 4-1 Structure of picloram 4-2 Structures of selected arsenic-containing compounds 4-3 Structures of 2,4-D and 2,4,5-T 4-4 Chemical structure of 2,3,7,8-tetrachlorodibenzo-p-dioxin 4-5 Mechanisms of gene regulation by the AHR following activation by TCDD 5-1 Overview of the individual study populations reviewed in the VAO series 7-1 Hematopoiesis of stem cell differentiation 8-1 The partitioning between intergenerational and transgenerational effects due to the exposure of a parent xv PREPUBLICATION COPY—Uncorrected Proofs

xvi BOXES, FIGURES, AND TABLES TABLES S-1 Summary of the Eleventh Biennial Update Findings on Vietnam-Veteran, Occupational, and Environmental Studies Regarding Scientifically Rel- evant Associations Between Exposure to Herbicides and Specific Health Outcomes 2-1 Estimates of the Vietnam Veteran Population 2-2 Military Use of Herbicides in Vietnam (1961–1971) 4-1 World Health Organization Toxicity Equivalence Factors (TEFs) for Dioxin-Like Chemicals 5-1 Distribution of Perceived Herbicide Exposure Among 114,562 Korean Vietnam Veterans 5-2 Distribution of EOI Scores on Two-Level Scale in Epidemiology Studies Among Korean Vietnam Veterans 5-3 Distribution of EOI Scores on Four-Level Scale 7-1 Estimates of New Cases and Deaths from Selected Cancers of the Female Reproductive System in the United States in 2018 10-1 Estimated Number and Percentage of Diagnosed and Undiagnosed Diabe- tes among Adults, Aged ≥18 years, United States, 2015 12-1 Summary of the Eleventh Biennial Update Findings on Vietnam-Veteran, Occupational, and Environmental Studies Regarding Scientifically Rel- evant Associations Between Exposure to Herbicides and Specific Health Outcomes 12-2 Compendium of Research Recommendations from Previous Veterans and Agent Orange Series Reports Related to Effects on Veterans’ Descendants 12-3 Suggested Activities to Follow the Completion of the Veterans and Agent Orange Report Series Mandated by the Agent Orange Act Related to Effects on Veterans’ Descendants PREPUBLICATION COPY—Uncorrected Proofs

Acronyms and Abbreviations 2,4-D 2,4-dichlorophenoxyacetic acid 2,4-DCP 2,4-dichlorophenol 2,4,5-T 2,4,5-trichlorophenoxyacetic acid 2,4,5-TCP 2,4,5-trichlorophenol 2,4,5-TP 2-(2,4,5-trichlorophenoxy) propionic acid, Silvex 4-amino-3,5,6 trichloropicolinic acid (picloram) ACC U.S. Army Chemical Corps ACS American Cancer Society AD Alzheimer disease ADM adrenomedullin ADVA Australia Department of Veterans’ Affairs AFHS Air Force Health Study (also referred to as the “Ranch Hand Study”) AHR aryl hydrocarbon receptor AHR-ARNT heriodimeric complex AHRE AHR-responsive element AHS U.S. Agricultural Health Study AL amyloidosis amyloid light-chain amyloidosis ALL acute lymphocytic leukemia ALS amyotrophic lateral sclerosis (Lou Gehrig’s disease) ALT alanine aminotransferase AML acute myeloid leukemia (previously called “acute myelogenous leukemia”) xvii PREPUBLICATION COPY—Uncorrected Proofs

xviii ACRONYMS AND ABBREVIATIONS AOVS Agent Orange Validation Study (of the CDC) ARNT aryl hydrocarbon nuclear translocator ARVN Army of the Republic of Vietnam ATSDR Agency for Toxic Substances and Disease Registry B[a]P benzo[a]pyrene BMI body mass index CDC U.S. Centers for Disease Control and Prevention CI confidence interval CKD chronic kidney disease CLL chronic lymphocytic leukemia (now regarded as same disease as small lymphocytic leukemia) CML chronic myeloid leukemia CNS central nervous system COI chemical of interest to VAO series (TCDD, 2,4,5-T, 2,4-D, picloram, or cacodylic acid) COPD chronic obstructive pulmonary disease COX-2 cyclooxygenase cPLA2 cytosolic phospholipase A2 CPS Current Population Survey CRP C-reactive protein CSF cerebrospinal fluid CT computed tomography CVD cardiovascular disease DEET N,N-diethyl-meta-toluamide DHA docosahexaenoic acid DHEA dehydroepiandrosterone DIT developmental immunotoxicity DLBCL diffuse large B-cell lymphoma DLC dioxin-like compound (or chemical) DMA dimethyl arsenic acid DMAIII dimethyl arsenic acid of valence 3 DMAV dimethyl arsenic acid of valence 5; form of arsenic found in cacodylic acid DMBA dimethylbenzanthracene DNA deoxyribonucleic acid DOHaD developmental origins of health and disease DXA dual-energy X-ray absorption ECG electrocardiography EDC endocrine-disrupting chemical PREPUBLICATION COPY—Uncorrected Proofs

ACRONYMS AND ABBREVIATIONS xix EOI exposure opportunity index, any metric of possible exposure EPA U.S. Environmental Protection Agency ER estrogen receptor EU European Union FICZ 6-formylindolo[3,2-b]carbazole (an AHR agonist) GAO U.S. Government Accountability Office GIS geographic information system GSH glutathione HCB hexachlorobenzene HCH hexachlorocylohexane HCL hairy-cell leukemia HDL high-density lipoprotein HERBS Herbicide Reporting System HIV human immunodeficiency virus HL Hodgkin lymphoma (previously referred to as Hodgkin’s disease in VAO series) HLA human leukocyte antigen hMSC human mesenchymal stem cells HR hazard ratio HRGC high-resolution gas chromotography HRGS/ID-HRMS high-resolution gas chromatography/isotope-dilution high- resolution mass spectrometry HRMS high-resolution mass spectrometry HSC hematopoietic stem cell HSP90 heat shock protein 90 HVA homovanillin acid IARC International Agency for Research on Cancer ICD-9 (10) International Classification of Diseases, 9th Revision (10th Revision) IFN-γ interferon gamma Ig immunoglobulin IHD ischemic heart disease IL-1RA interleukin-1 receptor antagonist IMT intima-media thickness (of arterial walls) IOM Institute of Medicine KGF keratinocyte growth factor PREPUBLICATION COPY—Uncorrected Proofs

xx ACRONYMS AND ABBREVIATIONS LBW low birth weight LDL low-density lipoprotein LHC lymphohematopoietic cancer LRT log-likelihood ratio test LTL leukocyte telomere length MCPA 2-methyl-4-chlorophenoxyacetic acid MDA malondialdehyde (oxidative stress biomarker) MDS myelodysplastic syndrome MGUS monoclonal gammapathy of undertermined significance MPN myeloproliferative neoplasm MRI magnetic resonance imaging MS multiple sclerosis n number of study participants NCI National Cancer Institute NHANES National Health and Nutrition Examination Survey NHL non-Hodgkin lymphoma NIEHS National Institute of Environmental Health Sciences NIOSH National Institute for Occupational Safety and Health NK cells natural killer cells NLS nuclear-localization signal NTIS National Technical Information Service OC organochlorine OCP organochlorine pesticide OR odds ratio ORH Operation Ranch Hand OSCAR Osteoporosis Cadmium as a Risk Factor cohort PAH polycyclic aromatic hydrocarbon PBPK physiologically based pharmacokinetic (model) PCB polychlorinated biphenyl PCDD polychlorinated dibenzo-p-dioxin PCDD/Fs polychlorinated dioxins and furans combined PCDF polychlorinated dibenzofuran PCI percutaneous coronary intervention PCMR proportionate cancer mortality ratio PCP pentachlorophenol PCT porphyria cutanea tarda PD Parkinson disease picloram 4-amino-3,5,6-trichloropicolinic acid PREPUBLICATION COPY—Uncorrected Proofs

ACRONYMS AND ABBREVIATIONS xxi PIVUS Prospective Investigation of the Vasculature in Uppsala Seniors PL Public Law PMR proportional mortality ratio PNS peripheral nervous system POP persistent organic pollutant ppm parts per million ppt parts per trillion (pg/g) PSA prostate-specific antigen RNA ribonucleic acid ROS reactive oxygen species RR relative risk RTL relative telomere length SEER Surveillance, Epidemiology, and End Results program (National Cancer Institute) SGBS cell Simpson Golabi Behmel Syndrome cell SHR standardized hospitalization ratio SLE systemic lupus erythematosus SMR standardized mortality ratio SNP single-nucleotide polymorphism SR sex ratio STS soft-tissue sarcoma TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TCP trichlorophenol TEF toxicity equivalency factor (i.e., potency of a dioxin-like chemical relative to TCDD) TEQ (total) toxic equivalent TEQ# the total toxic equivalent for # [number] of dioxin-like compounds (TEQ8, for 8 dioxin-like compounds, for example) TGF transforming growth factor TNF tumor necrosis factor TPA tetradeconoyl phorbol acetate TRH thyrotropin-releasing hormone TSH thyroid-stimulating hormone UGI upper gastrointestinal tract UV ultraviolet radiation PREPUBLICATION COPY—Uncorrected Proofs

xxii ACRONYMS AND ABBREVIATIONS VA U.S. Department of Veterans Affairs VAO Veterans and Agent Orange (refers to series of IOM committees and reports; italicized VAO refers to the initial comprehensive review, published in 1994) VE-HEROeS Vietnam Era Health Retrospective Observational Study VES Vietnam Experience Study WHO World Health Organization WHO-UNEP World Health Organization/UN Environment Programme XAP2 X-associated protein 2 XRE xenobiotic-responsive element, recognition motif of the AHR/ARNT complex (also called DRE or AHRE) PREPUBLICATION COPY—Uncorrected Proofs

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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academies of Sciences, Engineering, and Medicine was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations were conducted every two years to review newly available literature and draw conclusions from the overall evidence. Veterans and Agent Orange: Update 11 (2018) examines peer-reviewed scientific reports concerning associations between various health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published between September 30, 2014, and December 31, 2017, and integrates this information with the previously established evidence database.

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