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VAgent eterans and Orange Update 2008 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Seventh 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#15 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: 978-0-309-13884-0 International Standard Book Number-10: 0-309-13884-1 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 2009 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). 2009. Veterans and Agent Orange: Up- date 2008. 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. 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 (SEVENTH BIENNIAL UPDATE) RICHARD A. FENSKE (Chair), Professor, School of Public Health and Community Medicine, University of Washington, Seattle, Washington ERIN BELL, Assistant Professor, Department of Epidemiology and Biostatistics, University of Albany, SUNY, Rensselaer, New York SCOTT W. BURCHIEL, Professor and Associate Dean, Research College of Pharmacy, University of New Mexico, Albuquerque, New Mexico JANICE E. CHAMBERS, Professor, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi NAIHUA DUAN, Professor, Department of Biostatistics, Columbia University, New York, New York PETER H. GANN, Professor, Department of Pathology, University of Illinois, Chicago, Illinois MARK S. GOLDBERG, Professor, Department of Medicine, McGill University, Quebec, Canada NANCY I. KERKVLIET, Professor, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon STEPHEN B. KRITCHEVSKY, Director, J. Paul Sticht Center on Aging and Rehabilitation, Wake Forest University Baptist Medical Center, Winston- Salem, North Carolina MICHELE MARCUS, Professor, Department of Epidemiology and Department of Environmental and Occupational Health, Emory University, Atlanta, Georgia LINDA A. McCAULEY, Dean, Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, Georgia ALVARO PUGA, Professor, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio JEREMY M. SHEFNER, Professor and Chair, Department of Neurology, Upstate Medical University, Syracuse, New York HOLLIE I. SWANSON, Associate Professor, College of Medicine, University of Kentucky, Lexington, Kentucky Study Staff Mary Burr Paxton, Study Director Jennifer A. Cohen, Program Officer Tia S. Carter, Senior Program Assistant Christie Bell, Financial Officer Rose Marie Martinez, Director, Board on Population Health and Public Health Practice Norman Grossblatt, Senior Editor 

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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 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: Rebecca Betensky, Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts Linda Birnbaum, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina James Brophy, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada Robert F. Herrick, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts Robert G. Holloway, Department of Neurology, University of Rochester Medical Center, Rochester, New York Elaine S. Jaffe, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland Bernard M. Ravina, Department of Neurology, University of Rochester Medical Center, Rochester, New York ii

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iii REVIEWERS David A. Savitz, Disease Prevention and Public Health Institute, Mount Sinai School of Medicine, New York, New York Robert D. Sparks, California Medical Association Foundation, El Dorado Hills, California Jack Thompson, Northwest Center for Public Health Practice, Seattle, Washington Hugh H. Tilson, Public Health Leadership Program, University of North Carolina, Chapel Hill, North Carolina Bailus Walker, Jr., Department of Community Medicine, Howard University, Washington, DC Mary K. Walker, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico Mary H. Ward, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or rec- ommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Kristine M. Gebbie, School of Nursing, Hunter College, City University of New York, 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 with the authoring com- mittee 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 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 on the basis of published material that had accumulated by 1994. As required by Public Law 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 re- view newly available literature and draw conclusions from the overall evidence. The first of the updates, Veterans and Agent Orange: Update 1996 (Update 1996), was published in March 1996. It was followed by Veterans and Agent Orange: Update 1998 (Update 1998) in 1999, Veterans and Agent Orange: Update 2000 (Update 2000) in 2001, Veterans and Agent Orange: Update 2002 (Update 2002) in 2003, and Veterans and Agent Orange: Update 2004 (Update 2004) in 2005. PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, extended the period for biennial updates to 2014. The first update after the new ix

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x PREFACE legislation was Veterans and Agent Orange: Update 2006 (Update 2006), pub- lished in 2007. The present report is the second of this second 10-year period of evaluation. The present update focuses on the scientific studies published since the re- lease of Update 2006. To accomplish the review, IOM established a committee of 14 members representing a wide array of expertise to evaluate the newest scien- tific evidence and to consider it in light of the studies reviewed in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006. A link to the experience and expertise of previous committees was provided by recruiting six members from the committee responsible for Update 2006, two of whom had also served on the committees responsible for Update 2004 and Up- date 2006. 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. Biographic sketches of committee members and staff appear in Appendix C. 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 NAS procedures, the committee met in a series of closed sessions in which members could freely examine, character- ize, and weigh the strengths and limitations of the evidence. The committee also convened three open meetings in March, June, and December 2008 to pro- vide 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 statements submitted to the committee are listed in Ap- pendix A. The committee thanks the persons 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 also acknowledges the excellent work of IOM staff members Jennifer Cohen, Tia Carter, 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 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. Steven Hawthorne, an environmental chemist at the University of North Dakota’s Energy and Environmental Research Center, informed the committee about the ability of organic compounds to codistill dur- ing the production of potable water. Barbara Migeon, a professor at the Institute of Genetic Medicine at the Johns Hopkins University, and Michael Skinner, a professor at Washington State University, gave the committee an informative

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xi PREFACE presentation on the nature of epigenetic mechanisms that may apply to dioxin. Vaughan Turekian, Chief International Officer of the American Association for the Advancement of Science and its representative to the US–Vietnam Dialogue Group on Agent Orange–Dioxin, discussed efforts toward cleanup and the pos- sibility of conducting epidemiologic studies on the Vietnamese population co- operatively with the Vietnamese. Samuel Cohen, of the University of Nebraska Medical Center, was helpful in answering questions about the toxicity of organic arsenic. Christopher Reid, of the Charles Drew University of Medicine and Science, discussed Parkinson disease and herbicides sprayed in Vietnam. Joel Michalek, now of the University of Texas Health Center at San Antonio, joined us to discuss his long experience with the Air Force Health Study. And Douglas Wallace, a professor at the University of California, Irvine, described mitochron- dial disruptions that might contribute to adverse health effects associated with Agent Orange. Richard Fenske, PhD, MPH, Chair Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Seventh Biennial Update)

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xi CONTENTS Exposure of Vietnam Veterans, 51 Exposure of the Vietnamese Population, 55 New Models for Characterizing Herbicide Exposure, 56 Methodologic Issues in Exposure Assessment, 57 References, 61 4 INFORMATION RELATED TO BIOLOGIC PLAUSIBILITY 65 TCDD, 67 Phenoxy Herbicides: 2,4-D and 2,4,5-T, 81 Cacodylic Acid, 84 Picloram, 89 References, 92 5 EPIDEMIOLOGIC STUDIES—NEW CITATIONS AND BACKGROUND ON REPEATEDLY STUDIED POPULATIONS 104 New Citations, 105 Relevant Populations: New Reports with Multiple Health Outcomes or with Results on Previously Studied Groups, 115 Vietnam-Veteran Studies, 115 Occupational Studies, 137 Environmental Studies, 158 References, 167 6 CANCER 202 Organization of Cancer Groupings, 204 Biologic Plausibility, 205 Oral, Nasal, and Pharyngeal Cancer, 209 Cancers of the Digestive Organs, 218 Esophageal Cancer, 219 Stomach Cancer, 223 Colorectal Cancer, 233 Hepatobiliary Cancers, 245 Pancreatic Cancer, 252 Laryngeal Cancer, 259 Lung Cancer, 264 Bone and Joint Cancer, 275 Soft-Tissue Sarcomas, 279 Skin Cancer—Melanoma, 289 Skin Cancer—Basal-cell Cancer and Squamous-cell Cancer (Nonmelanoma Skin Cancers), 297 Breast Cancer, 301 Cancers of the Female Reproductive System, 311 Prostate Cancer, 317

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x CONTENTS Testicular Cancer, 328 Bladder Cancer, 332 Renal Cancer, 339 Brain Cancer, 345 Endocrine Cancers, 354 Lymphohematopoietic Cancers (Lymphomas and Leukemias), 358 Hodgkin’s Disease, 360 Non-Hodgkin’s Lymphoma, 368 Multiple Myeloma, 385 AL Amyloidosis, 392 Leukemia, 394 Chronic Lymphocytic Leukemia and Hairy Cell Leukemia, 406 Summary, 412 References, 414 7 REPRODUCTIVE EFFECTS AND IMPACTS ON FUTURE GENERATIONS 435 Biologic Plausibility of Reproductive Effects, 436 Endometriosis, 438 Fertility, 444 Spontaneous Abortion, 460 Stillbirth, Neonatal Death, and Infant Death, 465 Birth Weight and Preterm Delivery, 467 Birth Defects, 469 Childhood Cancer, 480 Effects Occurring Later in Offspring’s Life or in Later Generations, 489 Summary, 494 References, 495 8 NEUROLOGIC DISORDERS 510 Neurobehavioral (Cognitive or Neuropsychiatric) Disorders, 512 Neurodegenerative Diseases, 515 Parkinson’s Disease and Parkinsonism, 515 Amyotrophic Lateral Sclerosis, 527 Peripheral Neuropathy, 530 Summary, 536 References, 538 9 OTHER HEALTH EFFECTS 546 Chloracne, 547 Porphyria Cutanea Tarda, 549 Respiratory Disorders, 552 Immune-System Disorders, 566

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xi CONTENTS Immune Suppression, 567 Allergy, 567 Autoimmune Disease, 568 Type 2 Diabetes, 571 Lipid and Lipoprotein Disorders, 587 Gastrointestinal and Digestive Disease, Including Liver Toxicity, 593 Peptic-Ulcer Disease, 593 Liver Disease, 594 Circulatory Disorders, 597 Hypertension, 620 Circulatory Diseases, 623 Synthesis, 627 Hypertension, 627 Ischemic Heart Disease, 628 Other Circulatory Disease, 631 Thyroid Homeostasis, 631 Summary, 636 References, 638 10 CONCLUSIONS AND RECOMMENDATIONS 651 Synopsis of Committee Conclusions, 651 Committee Recommendations, 655 References, 661 APPENDIXES A Agendas of Public Meetings Held by the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Seventh Biennial Update) 663 B Clarification of Cancer Groupings Used in Reporting Results, with Correspondence to NIOSH Cause-of-Death Codes and ICD Codes for Cancers 666 C Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Seventh Biennial Update) and Staff Biographies 676

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Abbreviations and Acronyms 2,4-D 2,4-dichlorophenoxyacetic acid 2,4-DB 2-(2,4-diichlorophenoxy) butyric acid 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 ACC Army Chemical Corps ACS American Cancer Society AD Alzheimer’s disease ADME absorption, distribution, metabolism, and excretion AFHS Air Force Health Study AH aryl hydrocarbon AHR AH receptor AHRE AHR-responsive element of the canonical DNA recognition motif of the AHR/ARNT complex, also referred to as the dioxin-responsive element (DRE) or the xenobiotic- responsive element (XRE) AHS Agricultural Health Study AHH aryl hydrocarbon hydroxylase AHRE AHR-responsive element, which is the recognition motif of the AHR/ARNT complex (also called DRE or XRE) AL acute leukemia AL amyloidosis amyloid light chain form of amyloidosis in which the amyloid in deposits in various organs and tissues consists of antibody light chains xii

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xiii ABBREVIATIONS AND ACRONYMS ALL acute lymphocytic leukemia ALS amyotrophic lateral sclerosis (or Lou Gehrig’s disease) AOR VA’s Agent Orange Registry ARNT aryl hydrocarbon nuclear translocator B[a]P benzo[a]pyrene bHLH basic-helix-loop-helix BIRLS VA’s Beneficiary Identification Record Locator Subsystem BMI body mass index CALUX assay for determination of dioxin-like activity in tissue samples CAS No. CAS Number is generated by the Chemical Abstracts Service and serves as unique identifier for every chemical CDC Centers for Disease Control and Prevention CDD chlorinated dibenzo-p-dioxin (usually preceded by indication of number of chlorine atoms substituted on chemical’s rings) CDF chlorinated dibenzofuran (usually preceded by indication of number of chlorine atoms substituted on chemical’s rings) CI confidence interval, as defined by lower (LCL) and upper confidence limits (UCL) CLL chronic lymphocytic leukemia (which is now regarded as being the same disease as small lymphocytic leukemia [SLL] and designated by some as CLL/SLL) CNS central nervous system COIs chemicals of interest to VAO series (i.e., TCDD, 2,4,5-T, 2,4- D, picloram, and cacodylic acid) CVD cardiovascular disease CYP— cytochrome P450 (individual type of these metabolizing enzymes are indicted by a number-letter-number suffix) DEET N,N-dietheyl-m-toluamide, insecticide DEN deep endometriotic nodule dl dioxin-like DLC dioxin-like compound (or chemical) DMA dimethyl arsenic acid DMAIII dimethyl arsenic acid of valency 3 DMAV dimethyl arsenic acid of valency 5; form of arsenic found in cacodylic acid DOD US Department of Defense DRE dioxin-responsive element, which is the recognition motif of the AHR/ARNT complex (also called AHRE or XRE)

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xix ABBREVIATIONS AND ACRONYMS ECG electrocardiography EE ethynyl estradiol EFMA European Fertilizer Manufacturers Association EPA US Environmental Protection Agency EU European Union femtogram (10–15 gram) fg FSH follicle-stimulating hormone GCT germ-cell tumor GD gestation day GERD gastroesophageal reflux disease γ-glutamyltransferase GGT GI gastrointestinal GIS geographic information system HbA1c Hemoglobin A1c HCL hairy cell leukemia HD Hodgkin’s disease (now referred to by some as Hodgkin’s lymphoma) HDL high-density lipoprotein HIV human immunodeficiency virus HLA human leukocyte antigen HOMA-IR homeostasis-model assessment of insulin resistance HpCDD heptachlorodibenzo-p-dioxin, a dioxin congener with seven chlorines HpCDF heptachlorodibenzofuran, a furan congener with seven chlorines HPV human papilloma virus HR hazard ratio hsp heat shock protein HxCDD hexachlorodibenzo-p-dioxin, a dioxin congener with six chlorines HxCDF hexachlorodibenzofuran, a furan congener with six chlorines IARC International Agency for Research on Cancer ICD-# International Classification of Diseases, Revision # (# = version current for records being abstracted) ICDO-II International Classification of Diseases for Oncology, 2nd edition IDL intermediate-density lipoprotein IH industrial hygienist IHD ischemic heart disease

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xx ABBREVIATIONS AND ACRONYMS IgE immunoglobulin E interleukin-6 (also called β2-interferon) IL-6 IRS Internal Revenue Service IU international unit IUGR intrauterine growth retardation JEM job-exposure matrix LCL lower confidence limit LDxx dose lethal to xx% of the animals exposed LDL low-density lipoprotein LEL lowest effect level LH luteinizing hormone M molar (concentration in a solution, molecules per volume) MCPA 2-methyl-4-chlorophenoxyacetic acid MCPP 2-(2-methyl-4-chlorophenoxy) propionic acid or Mecoprop mg milligram MIP macrophage-inflammatory protein MMA monomethyl arsonic acid mmHG millimeters mercury, for blood pressure measurements MMP matrix metalloproteinase MOSC Military Occupational Specialty Code MPTP 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine MTD maximum tolerated dose na not applicable NETRP Neurotoxin Exposure Treatment Research Program nanogram (10–9 gram) ng NHANES National Health and Nutrition Examination Survey NHL non-Hodgkin’s lymphoma NIOSH National Institute of Occupational Safety and Health NK/T-cell natural killer T-cell NLS nuclear-localization signal NOEL no-observed-effect level NPC nasopharyngeal carcinoma nr not reported NRC National Research Council ns not significant (usually refers to p < 0.05) OCDD octachlorodibenzo-p-dioxin (1,2,3,4,6,7,8,9-OCDT is the only dioxin congener with eight chlorines)

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xxi ABBREVIATIONS AND ACRONYMS OCDF octachlorodibenzofuran (1,2,3,4,6,7,8,9-OCDF is the only dioxin congener with eight chlorines) OFFHS Ontario Farm Family Health Study OR odds ratio PAH polycyclic aromatic hydrocarbons PAS Per-ARNT-Sim protein domain of amino-acid sequences related to sequences in ARNT and the Drosophila melanogaster genes period and single minded PBPK model physiologically-based pharmacokinetic model PBDD polybrominated dibenzo-p-dioxin PBDF polybrominated dibenzofuran PCB polychlorinated biphenyl PCDD polychlorinated dibenzo-p-dioxin PCDD/F dioxins and furans combined PCDF polychlorinated dibenzofuran PCP pentachlorophenol PCT porphyria cutanea tarda PD Parkinson’s disease PE peritoneal endometriosis PeCDF pentachlorodibenzofuran, a furan congener with five chlorines picogram (10–12 gram) pg picloram 4-amino-3,5,6-trichloropicolinic acid PL Public Law PM proportionate mortality PMR proportional mortality ratio PND postnatal day PNS peripheral nervous system POP persistent organic pollutant ppb parts per billion = ng/g ppm parts per million = mg/g ppt parts per trillion = pg/g PSA prostate-specific antigen PtCDF pentachlorodibenzofuran PTD preterm delivery, premature birth at less than 259 days (37 weeks gestation) PTSD post-traumatic stress disorder RANTES regulated on activation, normal T cell–expressed, and secreted RDD random-digit dialing

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xxii ABBREVIATIONS AND ACRONYMS RH Ranch Hand, member of Air Force unit primarily responsible for spraying herbicides in Vietnam ROS reactive oxygen species RR relative risk SCE sister chromatid exchange SCL-90 Symptom Checklist-90-Revised SEA Southeast Asia SEER Surveillance, Epidemiology, and End Results SES socioeconomic status SIR Standardized Incidence Ratio SLE systemic lupus erythematosus SLL small lymphocytic lymphoma, which is now recognized as a different stage of CLL, rather than a separate disease SMR standardized mortality ratio SPECT single-photon emission computerized tomography STS soft-tissue sarcoma SWHS Seveso Women’s Health Study T3 triiodothyronine T4 thyroxine TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDF tetrachlorodibenzofuran, a furan congener with four chlorines TEF toxicity equivalency factor, potency of a dioxin-like compound (DLC) relative to TCDD TEQ (total) toxicity equivalent quotient or cumulative toxic potency, sum of TEFs for a mixture of PCDDs, PCDFs, and PCBs tetraCDD tetrachlorodibenzo-p-dioxin, any of the dioxin congeners with four chlororines, including TCDD as defined above TIPA triisopropanolamine TPA 12-O-tetradecanoylphorbol-13-acetate TRH thyrotropin-releasing hormone TSH thyroid-stimulating hormone TWA time-weighted average UFW United Farm Workers of America VA US Department of Veterans Affairs; previously, Veterans Administration VEGF vascular endothelial growth factor VES Vietnam Experience Study VLDL very-low-density lipoprotein

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xxiii ABBREVIATIONS AND ACRONYMS WBC white blood cell WHO World Health Organization XAP2 hepatitis B virus X-associated protein 2 XRE xenobiotic-responsive element, which is the recognition motif of the AHR/ARNT complex (also called DRE or AHRE)

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