Veterans and Agent Orange

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VAgent eterans and Orange Update 2006 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update) Board on Population Health and Public Health Practice

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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 No. V101 (93) P-2136, TO#3 between the National Academy of Sciences and 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 view of the organizations or agencies that provided sup- port for this project. International Standard Book Number-13: 978-0-309-10708-2 (Book) International Standard Book Number-10: 0-309-10708-3 (Book) International Standard Book Number-13: 978-0-309-10709-9 (PDF) International Standard Book Number-10: 978-0-309-10709-1 (PDF) Library of Congress Control Number: 2007937818 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2007 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). 2007. Veterans and Agent Orange: Up- date 2006. Washington, DC: The National Academies Press.

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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. Charles M. Vest 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. Charles M. Vest 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 (SIXTH BIENNIAL UPDATE) JOHN J. STEGEMAN (Chair), Senior Scientist, Department of Biology, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts RICHARD A. FENSKE, Professor, School of Public Health and Community Medicine, University of Washington, Seattle JORDAN FIRESTONE, Clinic Director Haborview Medical Center, Occupational and Environmental Medicine, University of Washington, Seattle PETER H. GANN, Professor, Department of Pathology, University of Illinois, Chicago MARK S. GOLDBERG, Associate Professor, Department of Medicine, McGill University, Quebec, Canada CLAUDIA HOPENHAYN, Professor, College of Public Health, University of Kentucky, Lexington NANCY I. KERKVLIET, Professor, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis LINDA A. MCCAULEY, Professor, School of Nursing, University of Pennsylvania, Philadelphia DEJURAN RICHARDSON, Professor of Mathematics and Computer Science, Lake Forest College, Chicago, Illinois HOLLIE I. SWANSON, Associate Professor, College of Medicine, University of Kentucky, Lexington MARY K. WALKER, Professor, Pharmacology and Toxicology, University of New Mexico, Albuquerque STEPHEN D. WALTER, Professor, Clinical Epidemiology and Biostatistics, McMaster University, Ontario, Canada Staff Mary Burr Paxton, Study Director Jennifer A. Cohen, Program Officer Rose Marie Martinez, Director, Board on Population Health and Public Health Practice Tia S. Carter, Senior Program Assistant Sonia J. Cheruvillil, Senior Program Assistant (through June 2006) Norman Grossblatt, Senior Editor v

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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 this 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 for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manu- script remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Christine B. Ambrosone, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York Frederick R. Appelbaum, Fred Hutchinson Cancer Research Center, Seattle, Washington Lesa L. Aylward, Summit Toxicology, Falls Church, Virginia Linda S. Birnbaum, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina Robert L. Black, Stanford University and Private Practice, Pediatrics, Monterey, California Margit L. Bleecker, The Center for Occupational and Environmental Neurology, Baltimore, Maryland David G. Hoel, Department of Biostatistics, Bioinformatics and Epidemiology, Medical University of South Carolina, Charleston vii

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viii REVIEWERS Stephen H. Safe, Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station Robert D. Sparks, TASER Foundation, El Dorado Hills, California G. Marie Swanson, College of Public Health, University of Arizona, Tucson Bailus Walker, Jr., Department of Community Medicine, Howard University, Washington, DC 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 this report was overseen by Kristine M. Gebbie, Columbia University School of Nursing, New York. Appointed by the National Research Council, she was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures 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 In 1991, Congress passed Public Law (PL) 102-4, the Agent Orange Act of 1991, to address the uncertainty about the long-term health effects on Vietnam veterans who during their service in Vietnam were exposed to herbicides (mix- tures of 2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], picloram, and cacodylic acid). That legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to perform a comprehen- sive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of those herbicides, including TCDD. The resulting com- mittee report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO) was published by the NAS Institute of Medicine (IOM) in 1994. That report evaluated and integrated the scientific evidence regarding statistical associations between health outcomes and exposure to the herbicides and TCDD, based on published literature that had accumulated prior to 1994. As required by PL 102-4, the Secretary also asked that NAS conduct updates at least every 2 years for 10 years from the date of the first report, to review newly available literature and draw conclusions from the overall evidence. The first of these updates, Veterans and Agent Orange: Update 1996 (Update 1996) was published in March of that year. The second, Veterans and Agent Orange: Update 1998 (Update 1998) was published in 1999. The third, Veterans and Agent Or- ange: Update 2000 (Update 2000) was published in 2001. The fourth, Veterans and Agent Orange: Update 2002 (Update 2002) was published in 2003, and the fifth, Veterans and Agent Orange: Update 2004 (Update 2004) was published in 2005, concluding 10 years of updates. ix

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x PREFACE PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, extended the period for biennial updates until 2014. The present report is the first of this second 10-year period of evaluation. The focus of this update is on the scientific studies published since the re- lease of Update 2004. To accomplish the review, the IOM established a commit- tee of 12 members representing a wide range of expertise to evaluate the newest scientific evidence and to consider this in light of the studies reviewed in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004. Five of the members of the committee responsible for this report were recruited from the committee responsible for Update 2004, providing a link to the experience and expertise of the previous committees. 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 TCDD exposure. Biographical sketches of committee members and staff appear in Appendix D. Embarking on this second decade of evaluation, the committee approached a number of issues concerning the presentation of the information in the report, as well as seeking the most accurate information and advice from the widest possible range of knowledgeable sources for consideration. Consistent with NAS 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 two open meetings in March and June, 2006, to provide the opportunity for veterans and veterans’ service organizations, researchers, policymakers, and other interested parties to present their concerns, review their research, and exchange information directly with committee mem- bers. The oral presentations and written statements submitted to the committee are listed in Appendix A. The committee thanks the individuals who provided valuable insights into the health problems experienced by Vietnam veterans. The committee is grateful to Mary Paxton, who skillfully served as study director for this project. The committee would also like to acknowledge the excel- lent work of IOM staff members Jennifer Cohen, Tia Carter, Sonia Cheruvillil, David Butler, and Rose Marie Martinez. Thanks are also extended to Christie Bell, who handled the finances for the project; Norman Grossblatt, who provided editorial skills; and William McLeod, who conducted database searches. The committee also benefited from the assistance of several scientists and researchers who generously lent their time and expertise to help give commit- tee members insight on particular issues, provided copies of newly released research, or answered queries concerning their work. Dr. Maria Teresa Landi, an investigator at the National Cancer Institute, gave the committee a very informa- tive presentation on her work on the Seveso Women’s Health Study. Dr. Michael Alavanja, also of the National Cancer Institute, was very helpful in answering questions about the conduct of the Agricultural Health Study, as were Julienell

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xi PREFACE Robinson and Billy Jackson of Brooks Air Force Base in addressing questions about the Air Force Health Study. Special thanks are extended to Dr. Han Kang, Director of the Department of Veterans Affairs’ Environmental Epidemiology Service, for his prompt response in providing supplementary analyses on the data presented in his recent publication on Vietnam-era veterans who served in the Army Chemical Corps. John Stegeman, Ph.D., Chair

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Contents ABBREVIATIONS AND ACRONYMS xvii SUMMARY 1 1 INTRODUCTION 17 Charge to the Committee, 18 Conclusions of Previous Veterans and Agent Orange Reports, 19 Organization of This Report, 27 References, 27 2 EVALUATING THE EVIDENCE 29 Choice of Health Outcomes, 29 Identification of Relevant Literature, 29 Committee’s Approach, 34 Evaluation of the Evidence, 37 References, 46 3 TOXICOLOGY 47 Highlights of Previous Reports, 48 Update Toxicity Profile of 2,4-D, 49 Update Toxicity Profile of 2,4,5-T, 56 Update Toxicity Profile of Cacodylic Acid, 58 Update Toxicity Profile of Picloram, 61 Update Toxicity Profile of TCDD, 62 References, 117 xiii

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xiv CONTENTS 4 EPIDEMIOLOGIC STUDIES—NEW CITATIONS FOR UPDATE 2006 AND BACKGROUND ON REPEATEDLY STUDIED POPULATIONS 139 New Citations Reviewed in Update 2006, 140 Relevant Populations: New Reports with Multiple Endpoints or Results on Previously Studied Groups, 150 Occupational Studies, 151 Environmental Studies, 168 Vietnam-Veteran Studies, 172 References, 186 5 EXPOSURE ASSESSMENT 214 Exposure Assessment in Epidemiologic Studies, 214 Occupational Exposure to Herbicides and TCDD, 221 Environmental Exposures to Herbicides and TCDD, 232 Military Use of Herbicides in Vietnam, 237 Exposure Assessment in Studies of Vietnam Veterans, 240 References, 247 6 CANCER 261 An Exhaustive and Unambiguous System for Addressing Cancer Types, 264 Oral, Nasal, and Pharyngeal Cancer, 267 Lip Cancer, 277 Tongue Cancer, 279 Tonsil Cancer, 281 Cancers of the Digestive Organs, 283 Esophageal Cancer, 286 Stomach Cancer, 291 Colorectal Cancer, 299 Hepatobiliary Cancers, 310 Pancreatic Cancer, 318 Laryngeal Cancer, 325 Lung Cancer, 330 Bone and Joint Cancer, 342 Soft-Tissue Sarcomas, 346 Skin Cancer—Melanoma, 354 Skin Cancer—Basal-Cell and Squamous-Cell Cancer (Non-Melanoma), 366 Breast Cancer, 371 Cancers of the Female Reproductive System, 382 Prostate Cancer, 388

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xv CONTENTS Testicular Cancer, 402 Bladder Cancer, 407 Renal Cancer, 414 Cancers of the Eye and Orbit, 421 Brain Cancer, 423 Endocrine Cancers, 433 Non-Hodgkin’s Lymphoma, 443 Hodgkin’s Disease, 457 Multiple Myeloma, 465 AL Amyloidosis, 472 Leukemia, 474 Chronic Lymphocytic Leukemia, 486 Acute Myelogenous Leukemia, 490 Summary, 494 References, 498 7 REPRODUCTIVE AND DEVELOPMENTAL EFFECTS 517 Fertility, 518 Spontaneous Abortion, 525 Stillbirth, Neonatal Death, and Infant Death, 529 Birth Weight and Preterm Delivery, 531 Birth Defects, 535 Childhood Cancer, 546 Summary, 553 References, 557 8 NEUROLOGIC DISORDERS 566 Neurobehavioral (Cognitive or Neuropsychiatric) Disorders, 568 Movement Disorders, 570 Parkinson’s Disease and Parkinsonism, 570 Amyotrophic Lateral Sclerosis, 580 Peripheral Neuropathy, 585 Summary, 591 References, 593 9 OTHER HEALTH EFFECTS 599 Chloracne, 600 Porphyria Cutanea Tarda, 602 Respiratory Disorders, 604 Immune-System Disorders, 617 Diabetes, 620 Lipid and Lipoprotein Disorders, 632

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xvi CONTENTS Gastrointestinal and Digestive Disease, Including Liver Toxicity, 639 Peptic Ulcer Disease, 640 Liver Disease, 640 Circulatory Disorders, 644 Hypertension, 671 Circulatory Diseases, 673 AL Amyloidosis, 675 Endometriosis, 675 Thyroid Homeostasis, 680 Summary, 686 References, 688 10 RESEARCH RECOMMENDATIONS 699 References, 704 APPENDIXES A Agendas of Public Meetings Held by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update) 705 B Classification of Cancer Groupings Used in Reporting Results, with Correspondence to NIOSH Cause-of-Death Codes and ICD Codes for Cancers 707 C Epidemiologic Tables for Chapter 4 717 D Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sixth Biennial Update) and Staff Biographies 778 INDEX 784

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Abbreviations and Acronyms 2,4-D 2,4-dichlorophenoxyacetic acid 2,4-DB 4-(2,4-dichlorophenoxy)butyric 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 or Silvex 4NQO 4-nitroquinolone 1-oxide ACC Army Chemical Corps AFHS Air Force Health Study on veterans who served in Vietnam in Operation Ranch (Ranch Hand subjects) who were compared to Vietnam-era Air Force veterans who were deployed to Southeast Asia (SEA comparisons) AhR aryl hydrocarbon receptor AHRE Ah-responsive element AhRR aryl hydrocarbon receptor repressor AHS Agricultural Health Study of commercial and private herbicide applicators and the spouses of private applicators in Iowa and North Carolina ALL acute lymphocytic leukemia ALS amyotrophic lateral sclerosis AML acute myelogenous leukemia ARNT aryl hydrocarbon nuclear translocator xvii

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xviii ABBREVIATIONS AND ACRONYMS BCC basal cell carcinoma BIRLS Beneficiary Identification and Record Locator Subsystem BMI body-mass index CADM concentration- and age-dependent elimination model CAS Chemical Abstracts Service CCR California Cancer Registry CDC Centers for Disease Control and Prevention CLL chronic lymphocytic leukemia CNS central nervous system COPD chronic obstructive pulmonary disease CPUR California Pesticide Use Reporting Database CRR crude rate ratio DHT dihydrotestosterone DMA dimethylarsinic acid or cacodylic acid DNA deoxyribonucleic acid DoD Department of Defense EC50 effective concentration for 50 percent of subjects treated EOI exposure opportunity index EPA Environmental Protection Agency FSH follicle-stimulating hormone GCT germ-cell tumor GD gestation day GIS geographic information system HD Hodgkin’s disease HR hazard ratio IARC International Agency for Research on Cancer ICD; ICD-# International Classification of Diseases; specifies edition of ICD IOM Institute of Medicine IUGR intrauterine growth retardation JEM job–exposure matrix LD50 lethal dose to 50 percent of treated animals LH luteinizing hormone

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xix ABBREVIATIONS AND ACRONYMS M molar MCPA 2-methyl-4-chlorophenoxyacetic acid MCPP 2-(2-methyl-4-chlorophenoxy) propionic acid or Mecoprop MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine NAS National Academy of Sciences NCI National Cancer Institute NCV nerve-conduction velocity NHL non-Hodgkin’s lymphoma NIOSH National Institute for Occupational Safety and Health NMDA N-methyl-D-aspartate NOEL no-observed-effect level OR odds ratio ORH Operation Ranch Hand PBPK model physiologically based pharmacokinetic model PCBs polychlorinated biphenyls PCDD/Fs polychlorinated dibenzo-p-dioxins and dibenzofurans PCT porphyria cutanea tarda PD Parkinson’s disease PL Public Law PND postnatal day PNS peripheral nervous system parts per billion (109), equivalent to g/kg or ng/g ppb parts per million (106), equivalent to mg/kg or g/g ppm parts per trillion (1012), equivalent to ng/kg or pg/g ppt PSD presenile dementia PTD preterm delivery PTSD posttraumatic stress disorder RA rheumatoid arthritis RBC red blood cell RR relative risk SCC squamous cell carcinoma SEA Southeast Asia SEER National Cancer Institute Surveillance Epidemiology and End Results SES socioeconomic status SIR standardized incidence ratio SMP submitochondrial particle SMR standardized mortality ratio

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xx ABBREVIATIONS AND ACRONYMS SRMR standardized relative mortality ratio STS soft-tissue sarcoma SWHS Seveso Women’s Health Study TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TCP trichlorophenol (not specifically 2,4,5-TCP) TEF toxicity equivalency factor, potency of a dioxin-like compound relative to TCDD TEQ total toxicity equivalency quotient, sum of TEFs for a mixture of PCDDs, PCDFs, and PCBs TH tyrosine hydroxylase TNF tumor necrosis factor-alpha TPA 12-O-tetradecanoylphorbol-13-acetate UFW United Farm Workers of America VA Department of Veterans Affairs VAO Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, first report in series VAO Veterans and Agent Orange, used to indicate this series of reports (VAO and updates) and the committees responsible for their preparation

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VAgent eterans and Orange Update 2006

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