Veterans and Agent Orange

Update 2010



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

Board on the Health of Select Populations

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES



THE NATIONAL ACADEMIES PRESS
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VAgent eterans and Orange Update 2010 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eighth Biennial Update) Board on the Health of Select Populations

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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, Task Order #20 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 support for this project. International Standard Book Number-13: 978-0-309-21447-6 International Standard Book Number-10: 0-309-21447-5 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 2012 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). 2012. Veterans and Agent Orange: Up- date 2010. 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 (EIGHTH BIENNIAL UPDATE) MARY K. WALKER (Chair), Professor, Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, New Mexico ERIN BELL, Associate 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 RODNEY R. DIETERT, Professor, Department of Microbiology and Immunology, Cornell University, Ithaca, New York NAIHUA DUAN, Professor, Department of Biostatistics, Columbia University, New York, New York RUSS B. HAUSER, Professor, Environmental Health, Harvard School of Public Health, Boston, Massachusetts KARL KELSEY, Professor, Community Health and Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island 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, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina PETER S.J. LEES, Professor, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland LINDA A. McCAULEY, Dean and Professor, Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, Georgia JAMES R. OLSON, Professor, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York JEREMY M. SHEFNER, Professor and Chair, Department of Neurology, Upstate Medical University, Syracuse, New York MICHAEL SKINNER, Professor, Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington LUOPING ZHANG, Associate Adjunct Professor, School of Public Health, University of Califorina, Berkeley, California Study Staff MARY BURR PAXTON, Study Director JENNIFER A. COHEN, Program Officer TIA S. CARTER, Senior Program Assistant ANDREA COHEN, Financial Associate NORMAN GROSSBLATT, Senior Editor FREDERICK (RICK) ERDTMANN, Director, Board on the Health of Select Populations 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: Linda S. Birnbaum, US Environmental Protection Agency Norman Breslow, University of Washington James (Jay) Brophy, McGill University Brenda Eskenazi, University of California Warren G. Foster, McMaster University Chris Gennings, Virginia Commonwealth University David G. Hoel, Medical University of South Carolina Steve Holladay, University of Georgia Robert G. Holloway, University of Rochester Elaine S. Jaffe, National Institutes of Health Mitzi Nagarkatti, University of South Carolina Robert D. Sparks, California Medical Association Foundation Hollie I. Swanson, University of Kentucky Hugh H. Tilson, University of North Carolina Mary H. Ward, National Institutes of Health vii

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viii REVIEWERS 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, Adjunct Professor, Flinders University School of Nursing and Midwifery, Adelaide, South Australia. Appointed by the National Research Council and Institute of Medicine, 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 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 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 the updates, Veterans and Agent Orange: Update 1996 (Update 1996), was pub- lished 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, ex- tended the period for biennial updates to 2014. The first update after the new leg - ix

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x PREFACE islation was Veterans and Agent Orange: Update 2006 (Update 2006), published in 2007, followed by Veterans and Agent Orange: Update 2008 (Update 2008) in 2009. The present report is the third of this second 10-year period of evaluation. The present update focuses on the relevant scientific studies published from October 1, 2008, through September 30, 2010, that is, after the literature consid - ered in Update 2008. To accomplish the review, IOM established a committee of 15 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, Update 2006, and Update 2008. 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 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 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 four open meetings in September, November, and December 2010 and in February 2011 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 statements submitted to the committee are listed in Appendix 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, 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, 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. Arnold Schecter, a professor at the Univer- sity of Texas School of Public Health, discussed research activities concerning herbicide contamination in Vietnam and health of the Vietnamese population. Vaughan Turekian, Chief International Officer of the American Association for the Advancement of Science and its representative to the US–Vietnam Dialogue

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xi PREFACE Group on Agent Orange–Dioxin, also discussed activities involving the Vietnam- ese population. Paul Enright, a professor at the Mel and Enid Zuckerman College of Public Health at the University of Arizona, was helpful in answering questions concerning Agent Orange and chronic obstructive pulmonary disease. Yasmin Cypel and Han Kang, Environmental Epidemiology Service of the Department of Veterans Affairs, responded to questions regarding their recent publication concerning the Army Chemical Corps. Mary K. Walker, Chair Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eighth Biennial Update)

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xx TABLES AND FIGURES 7-39 Average Annual Incidence (per 100,000) of Hodgkin Disease in United States, 457 7-40 Selected Epidemiologic Studies— Hodgkin Lymphoma, 458 7-41 Average Annual Incidence (per 100,000) of Non-Hodgkin Lymphoma in United States, 467 7-42 Selected Epidemiologic Studies—Non-Hodgkin Lymphoma, 468 7-43 Selected Epidemiologic Studies—Chronic Lymphocytic Leukemia, 481 7-44 Average Annual Incidence (per 100,000) of Multiple Myeloma in United States, 489 7-45 Selected Epidemiologic Studies—Multiple Myeloma, 491 7-46 Average Annual Incidence (per 100,000) of Leukemias in United States, 500 7-47 Selected Epidemiologic Studies—Leukemia, 502 8-1 Selected Epidemiologic Studies—Endometriosis, 544 8-2 Selected Epidemiologic Studies—Male Fertility (Altered Hormone Concentrations, Decreased Sperm Counts or Quality, Subfertility, or Infertility), 550 8-3 Selected Epidemiologic Studies—Female Fertility (Altered Hormone Concentrations, Subfertility, or Infertility), 554 8-4 Selected Epidemiologic Studies—Sex Ratio, 560 8-5 Selected Epidemiologic Studies—Spontaneous Abortion, 566 8-6 Selected Epidemiologic Studies—Birth Defects in Offspring of Subjects, 575 8-7 Selected Epidemiologic Studies—Neural-Tube Defects in Offspring of Subjects, 581 8-8 Selected Epidemiologic Studies—Childhood Cancers, 587 9-1 Epidemiologic Studies of Herbicide Exposure and Parkinson Disease, 619 9-2 Epidemiologic Studies of Pesticide Exposure and Amyotrophic Lateral Sclerosis, 629 10-1 Prevalence of Mortality from Diabetes, Lipid Disorders, and Circulatory Disorders in United States, 2006, 648 10-2 Selected Epidemiologic Studies—Diabetes and Related Health Outcomes, 651 10-3 Selected Epidemiologic Studies—Circulatory Disorders, 667 11-1 Selected Epidemiologic Studies—Noncancerous Respiratory Disease, 712 11-2 Selected Epidemiologic Studies—Thyroid Homeostasis, 739

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xxi TABLES AND FIGURES 12-1 Summary from Eighth Biennial Update of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicides, 761 12-2 Research Needs, 770 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, 791 C-2 Surveillance, Epidemiology, and End Results (SEER) Program Malignant Neoplasm Site Groupings for ICD-9 and ICD-10, 797

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Abbreviations and Acronyms 2,4-D 2,4-dichlorophenoxyacetic 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 8-hydroxy-2′-deoxyguanosine 8-OHdG ACC Army Chemical Corps ACS American Cancer Society AD Alzheimer disease AFHS Air Force Health Study (also referred to as the “Ranch Hand Study”) AHR aryl hydrocarbon 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 AIHW Australian Institute for Health and Welfare 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 ALL acute lymphocytic leukemia ALS amyotrophic lateral sclerosis (or Lou Gehrig’s disease) xxiii

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xxiv ABBREVIATIONS AND ACRONYMS AML acute myeloid leukemia [previously called “acute myelogenous leukemia”] ARNT aryl hydrocarbon nuclear translocator BIRLS VA’s Beneficiary Identification Record Locator Subsystem Blimp1 B lymphocyte maturation protein 1 BMD bone mineral density BMI body-mass index BWIS Baltimore–Washington Infant Study CALUX chemical-activated luciferase gene expression bioassay, a test 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 CCR9 chemokine C receptor 9 CD4/CD8 ratio percentage of T-lymphocytes expressing CD4 antigen (T4 or helper T-cells) to percentage of T-lymphocytes expressing CD8 antigen (T8 or suppressor T-cells), also called T4/T8 ratio CDC Centers for Disease Control and Prevention CHD coronary heart disease 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) Con A concanavalin A COPD chronic obstructive pulmonary disease CSF cerebrospinal fluid CT computed tomography CVD cardiovascular disease CYP--- cytochrome P450 (specific members of this family of metabolizing enzymes are indicted by a number-letter- number suffix) DDE p,p´-diphenyldichloroethene, an environmentally persistent metabolite of the insecticide DDT

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xxv ABBREVIATIONS AND ACRONYMS dicamba 2-methoxy-3,6-dichlororbenzoic acid, benzoate herbicide with chemical structure related to phenoxy herbicides 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 DNA deoxyribonucleic 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) DTH delayed-type hypersensitivity, a cell-mediated immune response ECG electrocardiography EOI Exposure Opportunity Index, metric of possible Agent Orange exposure of ground troops generated by the Stellman model EPA US Environmental Protection Agency FEF25–75 forced midexpiratory flow FEV1 forced expiratory volume in 1 second femtogram (10–15 gram) fg FSH follicle-stimulating hormone FVC forced vital capacity g gram GBDS Birth Defects Study GC/MS gas chromatography/mass spectrometry GCT germ-cell tumor GERD gastroesophageal reflux disease g-glutamyltransferase GGT GI gastrointestinal GIS geographic information system HbA1c hemoglobin A1c HCL hairy-cell leukemia HDL high-density lipoprotein HepG2 human hepatocarcinoma cell line HIV human immunodeficiency virus

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xxvi ABBREVIATIONS AND ACRONYMS HL Hodgkin lymphoma (previously referred to as Hodgkin’s disease [HD] in VAO series) 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 HT hypertension 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 ICAM-1 inter-cellular adhesion molecule 1 ICD-# International Classification of Diseases, Revision # (# = version current for records being abstracted) ICD-#-CM International Classification of Diseases, Revision #, Clinical Modification ICDO-II International Classification of Diseases for Oncology, 2nd Edition IFN-g interferon-gamma IHD ischemic heart disease IgE immunoglobulin E interleukin-6 (also called β2-interferon) IL-6 IOM Institute of Medicine IQR inter-quartile range IU international unit IUGR intrauterine growth retardation JEM job–exposure matrix kg kilogram L liter LDL low-density lipoprotein LH luteinizing hormone LHCs lymphohematopoietic cancers LOD limit of detection LPS lipopolysaccharide

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xxvii ABBREVIATIONS AND ACRONYMS M molar (concentration in a solution, molecules per volume) MCF-7 human breast cancer cell line MCPA 2-methyl-4-chlorophenoxyacetic acid MCPP 2-(2-methyl-4-chlorophenoxy) propionic acid or Mecoprop MDS myelodysplastic syndrome mg milligram MGUS monoclonal gammopathy of undetermined significance MI myocardial infarction MIH molar incisor hypomineralization MIP macrophage-inflammatory protein ml milliliter MLR mixed lymphocyte response MM multiple myeloma MMA monomethyl arsonic acid MMAIII monomethyl arsonic acid of valency 3 mmHG millimeters mercury, for blood pressure measurements MMP matrix metalloproteinase MPTP 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine MTD maximum tolerated dose MRI magnetic resonance imaging n number of study participants na not applicable NAS National Academy of Sciences NCI National Cancer Institute ndl not dioxin-like nanogram (10–9 gram) ng NHANES National Health and Nutrition Examination Survey NHL non-Hodgkin lymphoma NIOSH National Institute for Occupational Safety and Health NK T-cell natural killer T-cell NLS nuclear-localization signal NOEL no-observed-effect level nr not reported NRC National Research Council not statistically significant (usually refers to p < 0.05) ns NTP National Toxicology Program NVVRS National Vietnam Veterans Readjustment Study OCDD octachlorodibenzo-p-dioxin (1,2,3,4,6,7,8,9-OCDD is the only dioxin congener with eight chlorines) OFFHS Ontario Farm Family Health Study

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xxviii ABBREVIATIONS AND ACRONYMS OR odds ratio p p-value, probability of the observed result or one more extreme under null hypothesis p23 prostaglandin E synthase PAH polycyclic aromatic hydrocarbons PBDD polybrominated dibenzo-p-dioxin PBDF polybrominated dibenzofuran PBPK model physiologically based pharmacokinetic model PCB polychlorinated biphenyl PCDD polychlorinated dibenzo-p-dioxin PCDD/Fs polychlorinated dioxins and furans combined PCDF polychlorinated dibenzofuran PCP pentachlorophenol PCT porphyria cutanea tarda PD Parkinson disease PE peritoneal endometriosis PeCDD pentachlorodibenzodioxin, a dioxin congener with five chlorines PeCDF pentachlorodibenzofuran, a furan congener with five chlorines picogram (10–12 gram) pg PGE2 prostaglandin E2 PHA polyhydroxyalkanoate picloram 4-amino-3,5,6-trichloropicolinic acid PL Public Law PM proportionate mortality PMR proportional mortality ratio PNS peripheral nervous system POP persistent organic pollutant ppb parts per billion = ng/g ppm parts per million = µg/g = mg/kg ppt parts per trillion = pg/g PSA prostate-specific antigen PSP Progressive Supranuclear Palsy PTD preterm delivery, premature birth at less than 259 days (37 weeks gestation) PTSD post-traumatic stress disorder RA rheumatoid arthritis regulated on activation, normal T-cell–expressed, and RANTES secreted

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xxix ABBREVIATIONS AND ACRONYMS RAST radioallergosorbent RDD random-digit dialing RFP request for proposals RH Ranch Hand, member of Air Force unit primarily responsible for spraying herbicides in Vietnam RNA ribonucleic acid RP relative prevalence RR relative risk (also called “risk ratio”) SCE sister chromatid exchange SE standard error SEA Southeast Asia SEER NCI’s 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 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 TCP trichlorophenol TECK thymus-expressed chemokine TEF toxicity equivalency factor, potency of a dioxin-like compound (DLC) relative to TCDD TEQ (total) toxic equivalent, or by older usage “toxicity equivalent quotient”, i.e., cumulative toxic potency, sum of TEFs for a mixture of PCDDs, PCDFs, and PCBs tetraCDD tetrachlorodibenzo-p-dioxin, any of the 22 dioxin congeners with four chlorines, including TCDD as defined above TGF transforming growth factor TNF tumor necrosis factor Treg regulatory T cell TRH thyrotropin-releasing hormone TSH thyroid-stimulating hormone TTP time to pregnancy TWA time-weighted average

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xxx ABBREVIATIONS AND ACRONYMS UFW United Farm Workers of America UGT UDP-glucuronosyltranserfase US United States VA US Department of Veterans Affairs; previously, Veterans Administration VAO Veterans and Agent Orange (refers to series of IOM committees and reports; italicized VAO, refers to the first comprehensive review published in 1994) VCAM-1 vascular cell adhesion molecule 1 VES Vietnam Experience Study VLDL very-low-density lipoprotein VOC volatile organic compound WBC white blood cell WHO World Health Organization XRE xenobiotic-responsive element, which is the recognition motif of the AHR/ARNT complex (also called DRE or AHRE)