Veterans
and Agent
           Orange


Update 2012

Committee to Review the Health Effects in
Vietnam Veterans of Exposure to Herbicides
(Ninth Biennial Update)

Board on the Health of Select Populations

INSTITUTE OF MEDICINE
           OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

www.nap.edu



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VAgent eterans and Orange Update 2012 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update) Board on the Health of Select Populations

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THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract/Grant No. VA241-P-2024 between the National Academy of Sciences and the US Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13:  978-0-309-28886-6 International Standard Book Number-10:  0-309-28886-X Additional copies of this report 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; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2014. Veterans and Agent Orange: Up- date 2012. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr. is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examina- tion of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the Na- tional Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE TO REVIEW THE HEALTH EFFECTS IN VIETNAM VETERANS OF EXPOSURE TO HERBICIDES (NINTH BIENNIAL UPDATE) MARY K. WALKER (Chair), Professor, Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque REBECCA A. BETENSKY, Professor, Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts MICHAEL J. CARVAN III, Shaw Associate Professor, School of Freshwater Sciences, University of Wisconsin–Milwaukee SCOTT DAVIS, Professor and Chair, Department of Epidemiology, School of Public Health, University of Washington, Seattle NAIHUA DUAN, Professor, Department of Biostatistics, Columbia University Medical Center, New York, New York STEPHANIE M. ENGEL, Associate Professor, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill JENNIFER R. GRANDIS, Professor and Vice Chair for Research, Department of Otolaryngology and Pharmacology, University of Pittsburgh, Pennsylvania KARL KELSEY, Professor, Epidemiology and Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island STEPHEN B. KRITCHEVSKY, Director, J. Paul Sticht Center on Aging, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina JAMES R. OLSON, Professor, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, New York GAIL S. PRINS, Professor, Department of Urology, University of Illinois, Chicago HELEN H. SUH, Associate Professor, Department of Health Sciences, Bouve School of Health Sciences, Northeastern University, Boston, Massachusetts MARC WEISSKOPF, Associate Professor, Department of Environmental and Occupational Epidemiology, Harvard School of Public Health, Boston, Massachusetts LORI A. WHITE, Associate Professor, Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, New Jersey LUOPING ZHANG, Professor, School of Public Health, University of Califorina, Berkeley v

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Study Staff MARY BURR PAXTON, Study Director JENNIFER A. COHEN, Program Officer TIA S. CARTER, Senior Program Assistant (through March 2013) ANDREA COHEN, Financial Associate FREDERICK (RICK) ERDTMANN, Director, Board on the Health of Select Populations NORMAN GROSSBLATT, Senior Editor vi

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures ap- proved by the National Research Council’s Report Review Committee. The pur- pose of the independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of 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 for their review of the report: Linda S. Birnbaum, National Institute of Environmental Health Sciences Margit L. Bleecker, Center for Occupational and Environmental Neurology Kim Boekelheide, Brown University Norman E. Breslow, University of Washington James Brophy, McGill University David L. Eaton, University of Washington Edward Elton George, Massachusetts General Hospital Elaine S. Jaffe, National Cancer Institute David W. Kennedy, University of Pennsylvania Health System Kevin Kip, University of South Florida, College of Nursing Roderick J.A. Little, University of Michigan John Meeker, University of Michigan School of Public Health Murray A. Mittleman, Harvard School of Public Health Rosemary Polomano, University of Pennsylvania School of Nursing vii

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viii REVIEWERS Noel R. Rose, Johns Hopkins University School of Medicine Hugh H. Tilson, University of North Carolina at Chapel Hill Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or recom- mendations, nor did they see the final draft of the report before its release. The review of the report was overseen by Kristine M. Gebbie, Flinders University School of Nursing and Midwifery, Adelaide, South Australia. Appointed by the Institute of Medicine, she was responsible for making certain that an independent examination of the report was carried out in accordance with institutional pro- cedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface This update focuses on the relevant scientific studies published from October 1, 2010, through September 30, 2012, that is, after the literature considered in Up- date 2010. To accomplish the review, the Institute of Medicine (IOM) established a committee of 15 members representing a wide array of expertise to evaluate the newest scientific evidence and to consider it in light of the studies reviewed in Veterans and Agent Orange (VAO), Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010. A link to the experience and expertise of previous committees was provided by recruiting eight members from committees responsible for earlier updates. All committee members were selected because they are experts in their fields, have no conflicts of interest with regard to the matter under study, and have taken no public positions concerning the potential health effects of herbicides in Vietnam veterans or related aspects of herbicide or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Biographic sketches of committee members and staff appear in Appendix D. In this second decade of evaluation, the committee sought the most accurate information and advice from the widest possible array of knowledgeable sources for consideration. To be consistent with National Academies’ procedures, the committee met in a series of closed sessions in which members could freely examine, characterize, and weigh the strengths and limitations of the evidence. The committee also convened five open meetings—in September, November, and December 2012 and in January and March 2013—to provide an opportunity for veterans and veterans service organizations, researchers, policy makers, and other interested parties to present their concerns, review their research, and exchange information directly with committee members. The oral presentations and written ix

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x PREFACE statements submitted to the committee are listed in Appendix A. The committee thanks the persons who provided valuable insights into the health problems ex- perienced by Vietnam veterans. The committee is grateful to Mary Paxton, who skillfully served as study director for this project. It also acknowledges the excellent work of IOM staff members Jennifer Cohen, Tia Carter, and Frederick (Rick) Erdtmann. Thanks are also extended to Andrea Cohen, who handled the finances for the project; Norman Grossblatt, who provided editorial skills; and William McLeod and Daniel Bearss, who conducted database searches. The committee benefited from the assistance of several scientists and re- searchers who generously lent their time and expertise to give committee mem- bers insight into particular issues, provide copies of newly released research, or answer queries about their work. Lisa Cassis, a professor and chair at the Uni- versity of Kentucky, discussed her research on metabolic and vascular disease. Han Kang, who recently retired as the principal investigator and director of the Environmental Epidemiology Service at the US Department of Veterans Affairs (VA), provided the committee with insight into VA’s research programs (past and present), focusing on US Vietnam veterans. Dr. Kang was again helpful, as was Brenda Eskenazi who is the chair of epidemiology at the University of California, Berkeley, in responding to the committee’s requests for additional information concerning birth weight in their published studies. Andy Olshan, the chair of epi- demiology at the University of North Carolina, and Kim Boekelheide, a professor of medical science at Brown University, joined the committee via conference call to discuss issues related to paternally mediated effects. Mary K. Walker, PhD, FAHA, Chair Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update)

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Contents SUMMARY 1 Charge to the Committee, 2 Committee’s Approach to Its Charge, 3 Evidence Reviewed by the Committee, 5 The Committee’s Conclusions, 7 Committee Recommendations, 12 1 INTRODUCTION 14 Charge to the Committee, 15 Conclusions of Previous Veterans and Agent Orange Reports, 19 Organization of This Report, 26 References, 28 2 EVALUATING THE EVIDENCE 30 Choice of Health Outcomes, 30 Identification of Relevant Literature, 31 Committee’s Approach, 38 Evaluation of the Evidence, 43 References, 52 3 EXPOSURE TO THE HERBICIDES USED IN VIETNAM 54 Military Use of Herbicides in Vietnam, 55 TCDD in Herbicides Used in Vietnam, 57 Exposure of Vietnam Veterans, 59 Exposure of the Vietnamese Population, 64 xi

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xii CONTENTS Models for Characterizing Herbicide Exposure, 66 Methodologic Issues in Exposure Assessment, 70 References, 74 4 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY 80 Picloram, 82 Cacodylic Acid, 85 Phenoxy Herbicides: 2,4-Dichlorophenoxy Acid and 2,4,5-Trichlorophenoxyacetic Acid, 90 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 93 Limitations of Extrapolating Results of Laboratory Studies to Human Responses, 109 Epigenetics, 111 Developmental Immunotoxicity, 113 References, 115 5 EPIDEMIOLOGIC STUDIES: COMPENDIUM OF NEW PUBLICATIONS 128 New Epidemiologic Publications, 129 References, 140 6 EPIDEMIOLOGIC STUDIES: BACKGROUND ON MULTIPLY REFERENCED POPULATIONS 145 Vietnam-Veteran Studies, 147 Occupational Studies, 168 Environmental Studies, 199 Case-Control Studies, 225 References, 232 7 IMMUNE-SYSTEM DISORDERS 271 Categories of Immune Dysfunction, 272 Conclusions from VAO and Previous Updates, 275 Update of the Epidemiologic Literature and Human Studies, 286 Biologic Plausibility, 287 Synthesis, 289 Conclusions, 290 Translation Between Animal and Human Studies, 290 References, 292 8 CANCER 299 Organization of Cancer Groups, 302 Biologic Plausibility, 303 The Committee’s View of “General” Human Carcinogens, 306

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CONTENTS xiii Oral, Nasal, and Pharyngeal Cancer, 309 Cancers of the Digestive Organs, 323 Esophageal Cancer, 325 Stomach Cancer, 333 Colorectal Cancer, 349 Hepatobiliary Cancers, 367 Pancreatic Cancer, 380 Laryngeal Cancer, 393 Lung Cancer, 401 Bone and Joint Cancer, 420 Soft-Tissue Sarcoma, 426 Skin Cancers, 443 Melanoma, 444 Basal-Cell Cancer and Squamous-Cell Cancer (Nonmelanoma Skin Cancer), 458 Breast Cancer, 463 Cancers of the Female Reproductive System, 477 Prostate Cancer, 487 Testicular Cancer, 506 Bladder Cancer, 513 Renal Cancer, 527 Brain Cancer, 537 Endocrine Cancers, 552 Lymphohematopoietic Cancers, 560 Hodgkin Lymphoma, 564 Non-Hodgkin Lymphoma, 580 Multiple Myeloma, 611 AL Amyloidosis, 622 Leukemia, 624 Nonmalignant Myeloid Diseases, 642 References, 644 9 FERTILITY AND GESTATIONAL EFFECTS 673 Biologic Plausibility of Effects on Fertility and Reproduction, 674 Endometriosis, 676 Fertility, 682 Spontaneous Abortion, Stillbirth, Neonatal Death, and Infant Death, 700 Birth Weight and Preterm Delivery, 707 References, 716 10 EFFECTS ON FUTURE GENERATIONS 726 Biologic Plausibility of Effects in Future Generations, 728 Birth Defects, 734

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xiv CONTENTS Cancers in Offspring, 748 Effects Occurring Later in Offspring’s Life or in Later Generations, 756 References, 763 11 NEUROLOGIC DISORDERS 773 Biological Plausibility, 775 Neurobehavioral (Cognitive or Neuropsychiatric) Disorders, 777 Neurodegenerative Diseases, 779 Chronic Peripheral System Disorders, 799 Hearing Loss, 802 References, 804 12 CARDIOVASCULAR AND METABOLIC OUTCOMES 814 Type 2 Diabetes, 815 Circulatory Disorders, 834 References, 869 13 OTHER CHRONIC HEALTH OUTCOMES 879 Respiratory Disorders, 880 Gastrointestinal and Digestive Diseases, Including Liver Toxicity, 906 Thyroid Homeostasis, 913 Eye Problems, 923 Bone Conditions, 924 References, 927 14 CONCLUSIONS AND RECOMMENDATIONS 936 Synopsis of Committee Conclusions, 936 Committee Recommendations, 940 References, 947 APPENDIXES A Issues Raised by the Public and Agendas of Public Meetings Held by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update) and Other Written Submissions to the Committee 948 B Short-Term Adverse Health Responses 958 C Clarification of Cancer Groupings Used in Reporting Results, with Correspondence to National Institute of Occupational Safety and Health Cause-of-Death Codes and International Classification of Diseases Codes for Cancer 971 D Biographies of Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update) and Staff 980

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Figures and Tables FIGURES 1-1 Comparison of TCDD exposures in various populations, 25 2-1 Chemical structures and CAS numbers for specific chemicals of interest, 33 3-1 TCDD formation during 2,4,5-T production, 58 4-1 Structure of picloram, 83 4-2 Structures of selected arsenic-containing compounds, 86 4-3 General pathways of arsenic metabolism after exposure to inorganic arsenic (iAs), 87 4-4 Structures of 2,4-D and 2,4,5-T, 91 4-5 Chemical structure of TCDD, 94 4-6 Mechanism of gene induction and repression after AHR activation by TCDD, 102 6-1 Flowchart of procedures followed and participant involvement in the Air Force Health Study, 150 8-1 Hematopoiesis of stem cell differentiation, 561 xv

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xvi FIGURES AND TABLES TABLES S-1 Summary of Ninth Biennial Update of Findings on Vietnam-Veterans, Occupational, and Environmental Studies Regarding Scientifically Relevant Associations Between Exposure to Herbicides and Specific Health Outcomes, 8 1-1 Summary from Update 2010 (Eighth Biennial Update) of Findings of Veterans, Occupational, and Environmental Studies Regarding Associations Between Exposure to Herbicides and Specific Health Outcomess, 17 3-1 Military Use of Herbicides in Vietnam (1961–1971), 56 3-2 Current Committee Guidance for the Classification of Exposure Information in Epidemiologic Studies That Focus on the Use of Pesticides or Herbicides, and Relevance of the Information to the Committee’s Charge to Evaluate Exposures to 2,4-D and 2,4,5-T (Phenoxy Herbicides), Cacodylic Acid, and Picloram, 72 3-3 Current Committee Guidance for the Classification of Exposure Information in Epidemiologic Studies That Focus on Exposure to Dioxin- Like Chemicals and Relevance of the Information to the Committee’s Charge, 73 4-1 Estimates of TCDD Half-Life in Humans and Animals, 96 4-2 World Health Organization Toxicity Equivalency Factors (TEFs) for Dioxin-Like Compounds (Values Revised as of 2005), 106 5-1 Publications Reporting a Single Health Outcome in New Populations, 130 5-2 Publications on Multiple Health Outcomes in New Study Populations, 134 5-3 Publications on Previously Studied Populations, 136 7-1 Selected Epidemiologic Studies—Immune Effects in Adult Humans, 276 8-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2009–2010 (Numbers in Thousands), 300 8-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in the United States, 310 8-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer, 312 8-4 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in the United States, 324 8-5 Selected Epidemiologic Studies—Esophageal Cancer, 327 8-6 Selected Epidemiologic Studies—Stomach Cancer, 335

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FIGURES AND TABLES xvii 8-7 Selected Epidemiologic Studies—Colon and Rectal Cancers, 351 8-8 Selected Epidemiologic Studies—Hepatobiliary Cancers, 369 8-9 Selected Epidemiologic Studies—Pancreatic Cancer, 382 8-10 Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in the United States, 393 8-11 Selected Epidemiologic Studies—Laryngeal Cancer, 394 8-12 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in the United States, 402 8-13 Selected Epidemiologic Studies—Lung, Bronchus, or Trachea Cancer, 403 8-14 Average Annual Incidence (per 100,000) of Bone and Joint Cancer in the United States, 420 8-15 Selected Epidemiologic Studies—Bone and Joint Cancer, 422 8-16 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of the Heart) in the United States, 426 8-17 Selected Epidemiologic Studies—Soft-Tissue Sarcoma, 429 8-18 Average Annual Cancer Incidence (per 100,000) of Skin Cancers (Excluding Basal-Cell and Squamous-Cell Cancers) in the United States, 443 8-19 Selected Epidemiologic Studies—Melanoma, 446 8-20 Selected Epidemiologic Studies—Other Nonmelanoma (Basal-Cell and Squamous-Cell) Skin Cancer, 459 8-21 Average Annual Incidence (per 100,000) of Breast Cancer in the United States, 463 8-22 Selected Epidemiologic Studies—Breast Cancer, 465 8-23 Estimates of New Cases of Deaths from Selected Cancers of the Female Reproductive System in the United States in 2012, 478 8-24 Selected Epidemiologic Studies—Cervical Cancer, 479 8-25 Selected Epidemiologic Studies—Uterine Cancer, 481 8-26 Selected Epidemiologic Studies—Ovarian Cancer, 484 8-27 Average Annual Incidence (per 100,000) of Prostate Cancer in the United States, 488 8-28 Selected Epidemiologic Studies—Prostate Cancer, 490 8-29 Average Annual Incidence (per 100,000) of Testicular Cancer in the United States, 506 8-30 Selected Epidemiologic Studies—Testicular Cancer, 508 8-31 Average Annual Incidence (per 100,000) of Bladder Cancer in the United States, 514 8-32 Selected Epidemiologic Studies—Urinary Bladder Cancer, 515 8-33 Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancer in the United States, 527 8-34 Selected Epidemiologic Studies—Renal Cancer, 528 8-35 Average Annual Incidence (per 100,000) of Brain and Other Nervous System Cancers in the United States, 538

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xviii FIGURES AND TABLES 8-36 Selected Epidemiologic Studies—Brain Tumors, 540 8-37 Average Annual Incidence (per 100,000) of Endocrine System Cancer in the United States, 552 8-38 Selected Epidemiologic Studies—Endocrine Cancers (Thyroid, Thymus, and Other), 554 8-39 Average Annual Incidence (per 100,000) of Hodgkin Disease in the United States, 565 8-40 Selected Epidemiologic Studies—Hodgkin Lymphoma, 568 8-41 Average Annual Incidence (per 100,000) of Non-Hodgkin Lymphoma in the United States, 581 8-42 Selected Epidemiologic Studies—Non-Hodgkin Lymphoma, 585 8-43 Selected Epidemiologic Studies—Chronic Lymphocytic Leukemia, 604 8-44 Average Annual Incidence (per 100,000) of Multiple Myeloma in the United States, 611 8-45 Selected Epidemiologic Studies—Multiple Myeloma, 613 8-46 Average Annual Incidence (per 100,000) of Leukemias in the United States, 625 8-47 Selected Epidemiologic Studies—Leukemia, 628 9-1 Selected Epidemiologic Studies—Endometriosis, 678 9-2 Selected Epidemiologic Studies—Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility), 684 9-3 Selected Epidemiologic Studies—Female Fertility (Altered Hormone Concentrations, Subfertility, or Infertility), 689 9-4 Selected Epidemiologic Studies—Sex Ratio, 695 9-5 Selected Epidemiologic Studies—Spontaneous Abortion, 703 9-6 Selected Epidemiologic Studies—Birth Weight Following Paternal Exposure, 710 9-7 Selected Epidemiologic Studies—Birth Weight Following Maternal Exposure, 712 10-1 Selected Epidemiologic Studies—Birth Defects in Offspring of Subjects, 736 10-2 Selected Epidemiologic Studies—Neural-Tube Defects in Offspring of Subjects, 743 10-3 Selected Epidemiologic Studies—Childhood Cancer, 750 11-1 Epidemiologic Studies of Herbicide Exposure and Parkinson Disease, 782 11-2 Epidemiologic Studies of Pesticide Exposure and Amyotrophic Lateral Sclerosis, 794

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FIGURES AND TABLES xix 12-1 Prevalence of and Mortality from Diabetes, Lipid Disorders, and Circulatory Disorders in the United States, 2009/2010, 816 12-2 Selected Epidemiologic Studies—Diabetes and Related Health Outcomes, 819 12-3 Selected Epidemiologic Studies—Circulatory Disorders, 837 12-4 Epidemiologic Studies Providing Best Evidence in Terms of Design, Sample Size, and Relevance—Cerebrovascular Disorders/Stroke, 865 13-1 Selected Epidemiologic Studies—Noncancer Respiratory Disease, 884 13-2 Selected Epidemiologic Studies—COPD and Pulmonary Function, 900 13-3 Selected Epidemiologic Studies—Thyroid Homeostasis, 916 14-1 Summary of Ninth Biennial Update of Findings on Vietnam Veterans, Occupational, and Environmental Studies Regarding Scientifically Relevant Association Between Exposure to Herbicides and Specific Health Outcomes, 937 C-1 Mapping of Groupings of Malignant Neoplasms That Are the Subjects of Conclusions in the Veterans and Agent Orange Series with ICD-9 Codes, 972 C-2 Surveillance, Epidemiology, and End Results (SEER) Program Malignant Neoplasm Site Groupings for ICD-9 and ICD-10, 977

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