ANNUAL REPORT TO CONGRESS
Federally Sponsored Research on Gulf War Veterans’ Illnesses for 1999
April 2001 The Research Working Group of the Persian Gulf Veterans Coordinating Board
ii
Annual Report to Congress - 1999
Research on Gulf War Veterans’ Illnesses
PERSIAN GULF VETERANS COORDINATING BOARD RESEARCH WORKING GROUP MEMBERS
Department of Defense: Robert E. Foster, Ph.D. John Mazzuchi, Ph.D. James R. Riddle, D.V.M., Lt Col, USAF Craig Hyams, M.D., CAPT, USN E. Cameron Ritchie, M.D., LTC, USA Gennady Platoff, Ph.D., COL, USA
Department of Veterans Affairs: John R. Feussner, M.D., M.P.H. (Chair) Kelley Ann Brix, M.D., M.P.H. Mark Brown, Ph.D. Ron Horner, Ph.D.
Department of Health and Human Services: Drue Barrett, Ph.D., CDR, USPHS M. Moiz Mumtaz, Ph.D. Janice Cordell, R.N., M.P.H. Stephen Hudock, Ph.D.
i TABLE OF CONTENTS
EXECUTIVE SUMMARY...... 1 INTRODUCTION...... 1 RESEARCH RESULTS IN 1999...... 1 RESEARCH FUNDING TRENDS...... 2 NEW RESEARCH PROJECTS AND INITIATIVES...... 2 NATIONAL RESEARCH CONFERENCES...... 3 RESEARCH MANAGEMENT...... 4 RESEARCH PRIORITIES...... 4 I. INTRODUCTION...... 5
II. RESEARCH RESULTS IN 1999...... 5
NEW RESEARCH PUBLICATIONS...... 5 1. Symptoms and General Health Status...... 6 2. Brain and Nervous System Function...... 10 3. Diagnosis...... 15 4. Depleted Uranium...... 16 5. Chemical Weapons...... 19 6. Pyridostigmine Bromide...... 20 7. Interactions of Exposures...... 23 III. RESEARCH FUNDING TRENDS...... 25
A. OVERVIEW...... 25 B. RESEARCH FUNDING...... 26 C. DIVERSITY OF RESEARCH APPROACHES...... 28 IV. NEW RESEARCH PROJECTS AND INITIATIVES...... 30 A. NEW RESEARCH PROJECTS...... 30 A1. New Epidemiology Research on Amyotrophic Lateral Sclerosis (ALS)...... 30 A2. New Research Projects Funded by the 1999 DoD Broad Agency Announcements...... 31 A3. Two New Research Centers Funded by the 1999 VA Request for Proposals for Environmental Hazard Research Centers...... 37 A4. Millennium Cohort Study...... 39
B. NEW RESEARCH INITIATIVES...... 39 B1. DoD Broad Agency Announcement Solicitations for New Research in 2000....39 B2. IOM Study on Identifying Effective Treatments for Gulf War Veterans’ Health Problems...... 41
C. 1999 UPDATE OF KEY RESEARCH PROJECTS AND INITIATIVES...... 41 C1. Progress on Two Treatment Protocols: Exercise/Behavioral Therapy (EBT) Trial and Antibiotic Treatment (ABT) Trial...... 41
ii C2. Military and Veterans Health Coordinating Board...... 43 C3. IOM Study on National Center for Military Deployment Health Research and VA, DoD, and HHS Plans for Implementation of IOM Recommendations. 44 C4. IOM Study on Gulf War Veterans: Measuring Health (IOM, 1999); and Ongoing Longitudinal Cohort Studies of Gulf War Veterans...... 46 C5. IOM Study on Health Effects Associated with Exposures during the Persian Gulf War...... 50 C6. NAS Study on Strategies to Protect the Health of Deployed U.S. Forces...... 52 V. NATIONAL RESEARCH CONFERENCES...... 54
A. 1999 CENTERS FOR DISEASE CONTROL AND PREVENTION CONFERENCE...... 54 B. 1999 CONFERENCE ON FEDERALLY SPONSORED GULF WAR VETERANS’ ILLNESSES RESEARCH...... 54 C. 2001 CONFERENCE ON FEDERALLY SPONSORED GULF WAR VETERANS’ ILLNESSES RESEARCH...... 55 VI. RESEARCH MANAGEMENT...... 57
A. OVERVIEW...... 57 B. OVERSIGHT OF RESEARCH...... 57 C. RESEARCH COORDINATION...... 61 VII. RESEARCH PRIORITIES...... 63 A. RESEARCH PRIORITIES FOR 1995...... 63 B. RESEARCH PRIORITIES FOR 1996...... 64 C. RESEARCH PRIORITIES FOR 1998...... 67 VIII. REFERENCES...... 69
A. GENERAL REFERENCES (FOR ALL SECTIONS, EXCEPT SECTION IV.C4.)...... 69 B. REFERENCES FOR SECTION IV.C4...... 73
iii iv EXECUTIVE SUMMARY pyridostigmine bromide, and interactions of exposures. I. INTRODUCTION 1. Symptoms and General Health Status: The Secretary of Veterans Affairs is required to submit an annual report on the results, status, and Six large studies were published that focused on priorities of research activities related to the symptoms and general health, including causes health consequences of military service in the of hospitalization. (Black, et al, 2000; Gray, et Gulf War, to the Senate and House Veterans’ al, 1999a; Gray, et al, 2000; Kipen, et al, 1999; Affairs Committees. The Research Working McCauley, et al, 1999a; McCauley, et al, 1999b) Group (RWG) of the Persian Gulf Veterans These publications provided the results of studies Coordinating Board (PGVCB) prepared this conducted at four research centers in San Diego, document, the 1999 Annual Report to Congress, Portland, Oregon, Iowa, and New Jersey. Each which is the sixth report on research activities. of these studies included at least several hundred (PGVCB, 1995a; 1996a; 1997; 1998; 1999a) individuals, and four of these studies were population-based. This means that the results of This Annual Report is divided into seven these four studies may have implications for the sections. Section I is an introduction. Section II overall population of 697,000 Gulf War veterans. highlights and summarizes research progress (Gray, et al, 2000; McCauley, et al, 1999a; since the last Annual Report. Section III is an McCauley, et al, 1999b; Black, et al, 2000) analysis of the Federal Government’s portfolio of research on Gulf War veterans’ illnesses. 2. Brain and Nervous System Function: Section IV highlights significant research and research-related events and milestones since the Seven studies were published that focused on last Annual Report. Section V discusses three brain and nervous system function, including national research conferences focusing on posttraumatic stress disorder, major depression, illnesses in Gulf War veterans. Section VI and neuropsychological functioning. (Anger, et discusses the management of Federal Gulf War al, 1999; Binder, et al, 1999; Dlugosz, et al, veterans’ illnesses research programs, including 1999; Lange, et al, 1999; Wagner, et al, 2000; research oversight, peer review, and Wolfe, et al, 1999a; Wolfe, et al, 1999b) These coordination. Section VII discusses priorities publications provided the results of studies established in 1995, 1996, and 1998 for future conducted at four research centers in San Diego, new research, and highlights the progress made Portland, Oregon, Boston, and New Jersey. All to date. four of these research centers utilized psychological and/or neurological evaluations, rather than relying solely on self-administered II. RESEARCH RESULTS IN 1999 surveys. Two of these centers used population- based samples. (Dlugosz, et al, 1999; Anger, et In the past year, there have been several research al, 1999; Binder, et al, 1999) studies that have yielded results that provide new and expanded information on the health 3. Diagnosis: problems of Gulf War veterans. Section II provides brief summaries of research projects for Two studies were published that focused on the which results were published from January 1999 diagnosis of infectious diseases in Gulf War to March 2000. The RWG tracks all Federally veterans, including one study on Mycoplasma funded research projects reported to the RWG fermentans, and one study on four types of related to Gulf War veterans’ illnesses. herpesviruses. (Gray, et al, 1999b; Wallace, et al, 1999) As in previous reports to Congress, research has been categorized according to the particular 4. Depleted Uranium: focus of the research. The research reports summarized in Section II are grouped according Four studies were published that focused on the to seven focus areas: symptoms and general effects of depleted uranium (DU), including two health status, brain and nervous system function, studies of Gulf War veterans who were wounded diagnosis, depleted uranium, chemical weapons, in friendly fire incidents, and two studies of rats treated with DU pellets implanted into muscles.
5 (Hooper, et al, 1999; McDiarmid, et al, 2000; IV. NEW RESEARCH PROJECTS Pellmar, et al, 1999a; Pellmar, et al, 1999b) AND INITIATIVES
5. Chemical Weapons: Besides new research findings appearing in the published scientific literature, there have been Two studies were published that focused on the several important events since last year’s Annual effects of chemical weapons, including one study Report to Congress that deserve discussion. of Gulf War veterans who had potential These include the awarding of new research exposures to very low-levels of sarin due to the projects and the development of new research demolitions at Khamisiyah, Iraq, and one study initiatives including solicitations for new of monkeys exposed to low-level sarin. (Gray , research proposals. et al, 1999c; Pearce, et al, 1999)
6. Pyridostigmine Bromide (PB): IV.A. NEW RESEARCH PROJECTS Four studies were published that focused on the effects of pyridostigmine bromide (PB), IV.A.1. New Epidemiology Research on including one study of Gulf War veterans, and Amyotrophic Lateral Sclerosis (ALS) three laboratory experiments. (Drake-Baumann and Seil, 1999; Hoy, et al, 1999; Kaiser, et al, Recently, some concern has arisen regarding a 2000; Van Haaren, et al, 1999) possible elevated occurrence of amyotrophic lateral sclerosis (ALS) among veterans who 7. Interactions of Exposures: served in the Gulf War, a relatively young population. This epidemiologic investigation of Two animal studies were published that focused ALS among Gulf War veterans will define the on the health effects of interactions of exposures, epidemiology of this neurological disease, to including one study of the combination of PB determine if there is a higher than expected plus swimming stress, and one study of the incidence. This project is jointly funded by DoD combination of PB plus DEET. (Chaney, et al, and VA (projects DoD-118 and VA-61). 1999; Telang, et al, 1999) Procedures to identify ALS cases began in March 2000. Complete ascertainment and III. RESEARCH FUNDING comprehensive evaluation of ALS cases will occur over a one-year period. TRENDS IV.A.2. New Projects Funded by the 1999 The Gulf War Veterans’ Illnesses research DoD Broad Agency Announcements portfolio currently includes 192 projects. These Federal research projects are sponsored by the In 1998, DoD established new funding for VA, DoD, or HHS. The scope of the Federal programmed research. The purpose of this research portfolio is broad, from small pilot program element funding is to address Gulf War studies to large-scale epidemiology studies Illnesses issues, which may also be of concern in involving large populations and major research future deployments. This planned funding is center programs. Currently, the Federal approximately $20 million per year for fiscal Government is projecting cumulative year 1999 through fiscal year 2002 and $5 expenditures of $154.5 million for research from million per year thereafter. DoD published five FY 1994 through FY 2000. As of March 31, Broad Agency Announcements (BAAs) in early 2000, 83 projects were completed and 109 1999. In response to these 5 BAAs, 21 new DoD projects were ongoing. The overall emphasis of funded projects were initiated in FY 1999 (DoD- research has been greatest in the focus areas of 94 to DoD-114), at a total cost of $16.7 million. Symptoms and General Health Status, and Brain There were: and Nervous System Function. The numbers of 7 projects related to Force health protection- projects in each focus area are examined in more deployment health, detail in Section III. 2 projects related to Multidisciplinary studies of fibromyalgia, chronic fatigue syndrome, and multiple chemical sensitivity,
6 5 projects related to Psychosocial and and chronic diseases such as cancer, heart neuroscience research on stress and somatic disease and diabetes. consequences, 2 projects related to Innovative toxicological IV.B. NEW RESEARCH methods and models for assessing mixed INITIATIVES chemical exposures, and 5 projects related to Interactions of drugs, IV.B.1. DoD Broad Agency Announcement biologics, and chemicals in service members Solicitations for New Research in 2000 in deployment environments. DoD published four Broad Agency IV.A.3. Two New Research Centers Funded Announcements (BAAs) in early 2000 related to by the 1999 VA Request for Proposals for illnesses in Gulf War veterans, with a deadline of Environmental Hazard Research Centers July 26, 2000. The specific requests focused on the following areas of research interest: In 1999, VA issued a Request for Proposals to Epidemiological Investigations of establish Environmental Hazard Research Deployment Health Monitoring Methods Centers, which were intended to have a broad Deployment Stress Health and Performance mission that included environmental exposures Consequences that may have occurred during active military Biochemical and Physiological Markers to duty, without specific reference to the Gulf War Assess Toxic Chemical Exposures and or Vietnam War. Two new Centers were funded Health Effects in Deployed Military on April 1, 2000 (Projects VA-64 and VA-65). Personnel Each Center is funded for up to 5 years, for a Toxicity of Militarily Relevant Heavy maximum of $1.6 million. The Boston Center Metals (VA-64) has received new funding in 2000 to continue their ongoing environmental research IV.B.2. IOM Study on Identifying Effective program in the field of behavioral Treatments for Gulf War Veterans’ Health neurotoxicology. The San Antonio EHRC (VA- Problems 65) is a new Center funded in 2000. The Center’s overall goal is to build upon its previous In 1999, VA requested the Institute of Medicine work, which focused on the role of oxidative (IOM) to perform an 18-month study to identify damage, and on the roles that individual genetic effective treatments for health problems in Gulf variations play in the responses to injury from War veterans. The IOM committee held its first environmental exposures. meeting in February 2000. The committee’s charge is threefold, as follows: IV.A.4. Millennium Cohort Study 1. Identify and describe approaches for assessing treatment effectiveness. The Millennium Cohort Study, a prospective 2. Identify illnesses and conditions common study of U.S. military forces, responds to the among Gulf War veterans, including need to systematically collect population-based medically unexplained symptoms, using demographic and health data to evaluate the data obtained from the VA and DoD Gulf health of service personnel throughout their War registries, as well as information in military careers and after leaving military published articles. service. The Millennium Cohort study is a 3. Identify validated models of treatment for probability-based, cross-sectional sample of these identified conditions and illnesses. 100,000 U.S. military personnel that will be The sources for these models include followed prospectively by postal surveys every 3 published literature, clinical practice years over a 21-year period, starting in late 2000. guidelines developed by medical specialty In October 2004 and October 2007, 20,000 new societies, and other sources as appropriate. military personnel will be added to the cohort. The total of 140,000 veterans will be followed until the year 2022. The principal objective of V. NATIONAL RESEARCH the study is to evaluate the impact of military CONFERENCES deployments on various measures of health over time, including medically unexplained symptoms
7 1. 1999 Centers for Disease Control and Development, production, and dissemination Prevention Conference-The Health of the 1995 A Working Plan for Research on Impact of Chemical Exposures During the Persian Gulf Veterans’ Illness (PGVCB, Gulf War: A Research Planning 1995b), and its 1996 revision (PGVCB, Conference 1996b);
From February 28 through March 2, 1999, the Production and dissemination of Annual Centers for Disease Control and Prevention Reports to Congress for 1994 through 1999 (CDC) held a conference in Atlanta, Georgia. on results, status, and priorities of Federal The purpose of this conference was to discuss research activities (PGVCB, 1995a; 1996a; and make recommendations regarding the 1997; 1998; 1999a); direction of future research on undiagnosed illnesses among Gulf War veterans and the Secondary programmatic review and possible links between these illnesses and recommendations on research proposals that multiple chemical and environmental exposures. have been competitively reviewed by In March 2000, CDC published a final funding agencies; conference report, entitled The Health Impact of Chemical Exposures During the Gulf War: A Organization of meetings of Federally Research Planning Conference. (CDC, 2000) funded researchers (four meetings, fifth in planning); 2. 1999 Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research Coordination and oversight of implementation of relevant The RWG organized and hosted an international recommendations of the Institute of meeting, entitled “Conference on Federally Medicine, Presidential Advisory Committee, Sponsored Gulf War Veterans’ Illnesses Senate Veterans Affairs Committee, and the Research,” on June 23-25, 1999 in Arlington, Presidential Review Directive 5 (IOM, 1995, Virginia. The purpose of the meeting was to 1996; PAC, 1996a, 1996b, 1997; SVAC, bring together Federally sponsored researchers 1998; NSTC, 1998); and on Gulf War veterans’ illnesses in a common forum. This was the fourth such conference, and Two national treatment trials it was attended by more than 300 scientists, clinicians, government officials, and veterans. (exercise/behavior therapy trial and The Proceedings for this conference were antibiotic treatment trial). published in late 1999. (PGVCB, 1999b) VII. RESEARCH PRIORITIES 3. 2001 Conference on Federally Sponsored Gulf War Veterans’ Illnesses Research The RWG has identified three sets of research priorities in 1995, 1996, and 1998 (PGVCB, In 2001, the RWG will host another international 1995b; PGVCB, 1996b; PGVCB, 1999a). conference in Alexandria, Virginia. The overall Substantial progress has been made on each of purpose and goals of the meeting will be similar these sets of priorities, which is detailed in to the 1999 meeting. In addition, new research Section VII. findings will be placed within the context of the implications of the completed research to date. The 2001 conference title, “Illnesses in Gulf War Veterans: A Decade of Scientific Research” will reflect this emphasis.
VI. RESEARCH MANAGEMENT
The RWG has accomplished several notable achievements, including:
8 I. INTRODUCTION programs, including research oversight, peer- review and coordination. Section VII discusses On August 31, 1993, in response to section 707 priorities established in 1995, 1996, and 1998 for of Public Law 102-585, President William J. future new research, and highlights the progress Clinton named the Secretary of Veterans Affairs made to date. While no new research priorities (VA) to coordinate research activities undertaken were developed in 1999, the agencies continued or funded by the Executive Branch of the Federal to make substantial progress in addressing the Government into the health consequences of priorities set in previous years. service in the Gulf War. Section 104 of Public Law 105-368 (1998) expanded the range of II. RESEARCH RESULTS IN 1999 activities to be coordinated. VA carries out its research coordinating role through the auspices New Research Publications of the Research Working Group (RWG) of the Persian Gulf Veterans Coordinating Board In the past year, there have been several research (PGVCB). The Secretaries of the Department of studies that have yielded results that provide new Defense (DoD), Health and Human Services and expanded information on the health (HHS), and VA chair the PGVCB. problems of Gulf War veterans. This Section provides brief summaries of research projects for As part of its coordination role, VA is required to which results were published from January 1999 submit to the Senate and House Veterans’ to March 2000. Because all scientifically peer Affairs Committees an annual report on the reviewed research must be considered in any results, status, and priorities of research future science-based assessments of Gulf War activities. This document, the 1999 Annual veterans’ illnesses, these summaries are inclusive Report to Congress, is the sixth report on of both Federally funded and non-federally research and research activities. (PGVCB, funded research. The primary source of 1995a; 1996a; 1997; 1998; 1999a) information on research is from the peer- reviewed scientific literature. The RWG tracks The 1999 Annual Report to Congress reports on all Federally funded research projects reported to research funded by Federal and non-federal the RWG related to Gulf War veterans’ illnesses. institutions. All new peer-reviewed reports of These projects are described in greater detail in high quality research, regardless of funding Appendix A. source, add to and build upon existing knowledge. Unpublished research results may It is important to note that all research studies be discussed with the anticipation of publication have strengths and limitations. Among the in the open peer-reviewed literature. However, limitations, epidemiological studies are the use of non-peer-reviewed research is done frequently subject to a variety of biases. For with caution, because it does not have the weight example, studies that rely on self-reported of peer-reviewed research results. symptoms and exposures are subject to recall bias, and studies that rely on self-selected cohorts This Annual Report is divided into seven (such as registry participants) are subject to Sections. Following this introductory Section, selection bias. Biases can distort the magnitude Section II highlights and summarizes research of differences between cohorts and affect the progress since the last Annual Report. Section strength of associations between exposures and III is an analysis of the Federal Government’s outcomes. Other factors potentially affecting portfolio of research on Gulf War veterans’ epidemiological outcomes include sample size illnesses. Section IV highlights significant and response rate. research and research-related events and milestones since the last Annual Report. Section Research using animal models is also subject to V discusses three national research conferences limitations in its applicability to a specific focusing on illnesses in Gulf War veterans. situation for humans. Sources of limitations Preliminary findings presented at scientific include extrapolation of biological processes meetings have influenced efforts to develop from one animal species to another and reliable models for understanding the reported extrapolation of experimental dosing regimens illnesses. Section VI discusses the management (route of administration, amount, and duration) of Federal Gulf War veterans’ illnesses research
9 from animal experiments to real human exposure situations. 527 Gulf War veterans and 970 non-deployed veterans were studied in 1994-95, who were The presence of limitations in a particular study members of 14 Seabee commands. (Gray, et al, does not necessarily invalidate its findings or 1999a) Gulf War veterans reported significantly conclusions, but must be taken into account in higher rates of 35 of 41 possible symptoms. evaluating a study’s overall weight and impact. Symptoms of post-traumatic stress disorder For this reason, the strengths and limitations of (PTSD) were significantly more frequent in Gulf each of the new reports of study findings are War veterans than non-deployed veterans (15% cited as a guide for the reader. vs. 9%). On pulmonary function tests, there were no differences between Gulf War veterans As in previous reports to Congress, research has and non-deployed veterans. been categorized according to the particular focus of the research. The research reports Chronic fatigue syndrome (CFS) and multiple summarized below are grouped according to chemical sensitivity (MCS) were the focus of seven focus areas: symptoms and general health two studies. (Black, et al, 2000; Kipen, et al, status, brain and nervous system function, 1999) The symptoms of these poorly understood diagnosis, depleted uranium, chemical weapons, conditions were prevalent in Gulf War veterans pyridostigmine bromide, and interactions of who were enrolled in the VA Gulf War Registry. exposures. In each category, the results of (Kipen, et al, 1999) Veterans with CFS or MCS relevant reports are first highlighted in an reported significantly higher rates of psychiatric overview section, then each individual report is disorders than control populations, a finding that summarized. has previously been reported in civilian populations with diagnoses of CFS or MCS. 1. Symptoms and General Health Status (Black, et al, 2000; Kipen, et al, 1999; Lange, et al, 1999) Overview: Reports from two research projects touched upon Six large studies were published that focused on methodological concerns. While self-reported symptoms and general health. These symptoms are frequent in Gulf War veterans, it is publications presented the results of studies impossible without a clinical evaluation to conducted at four Federally funded research determine whether the symptoms can be centers in San Diego, Portland, Oregon, Iowa, explained with a medical diagnosis. (McCauley, and New Jersey. Various studies from each of et al, 1999a; Lange, et al, 1999) The results of these centers have included some form of the medical evaluations in these two projects medical evaluation. Each of these studies highlighted the necessity of caution in the included at least several hundred individuals, and interpretation of surveys, if they are used as the four of these studies were population-based. sole source of diagnostic data. Similarly, This means that the results of these four studies findings, which make sole use of self-reported may have implications for the overall population exposure data, should be viewed with caution. of 697,000 Gulf War veterans. (Gray, et al, In one study, some individuals reported 2000; McCauley, et al, 1999a; McCauley, et al, exposures that were highly improbable given the 1999b; Black, et al, 2000) time period of service in the Persian Gulf, and some individuals’ responses were unreliable In a study of all 697,000 Gulf War veterans, when exposures histories were repeated at two causes for hospitalizations were evaluated in different points in time. (McCauley, et al, military hospitals nation-wide, VA hospitals 1999b) nation-wide, and civilian hospitals in the state of California. (Gray, et al, 2000) Gulf War Symptoms and General Health Status- veterans had a significantly increased rate of Individual Studies: hospitalizations for some injuries, such as fractures, compared to non-deployed veterans. 1. Gray, GC, Smith, TC, Kang, HK and Knoke, These results are consistent with an earlier study JD. Are Gulf War veterans suffering war-related that showed an increased mortality rate due to illnesses? Federal and civilian hospitalizations motor vehicle accidents in Gulf War veterans. examined, June 1991 to December 1994.
10 American Journal of Epidemiology 2000; for the increased rates of injury in Gulf War 151(1):63-71. (DoD-1) veterans were unknown, but these data are consistent with an earlier study that showed an The objective of this study was to compare the increased mortality rate due to motor vehicle hospitalization rates of active-duty Gulf War accidents in Gulf War veterans. (Kang, et al, veterans, Gulf War veterans separated from the 1996) service, and non-deployed veterans. The exposed population included all regular active- 2. Gray, GC, Kaiser, KS, Hawksworth, AW, et duty, Reserve, and National Guard personnel al. Increased postwar symptoms and who served in the Gulf War (652,979). The psychological morbidity among U.S. Navy Gulf comparison population included a random War veterans. American Journal of Tropical sample of non-deployed veterans (652,922). Medicine and Hygiene 1999a; 60(5):758-766. Hospitalization data were examined for the (DoD-1) period of August 1, 1991, to December 31, 1994 from three hospital systems: the Department of The objective of this study was to compare post- Defense (DoD), the Department of Veterans war symptoms between Gulf War veterans and Affairs (VA), and the California Office of non-deployed veterans, who were members of 14 Statewide Health Planning and Development Seabee commands, and who had remained on (CA). The number of hospitalizations identified active-duty from the end of the war, until the for the 1.3 million veterans included 182,164 time of the study. 527 Gulf War veterans and from the DoD, 16,030 from the VA, and 5,185 970 non-deployed veterans were studied in 1994- from the CA system. Overall, the reasons for 95, with a questionnaire, blood and urine hospitalizations that accounted for the highest collections, handgrip strength, and pulmonary proportion in each system were: musculoskeletal function testing. The questionnaire assessed diagnoses (21%) in the DoD system, mental post-war symptoms and environmental disorder diagnoses (32%) in the VA system, and exposures during the war, and it screened for injury and poisoning (38%) in the CA system. chronic fatigue syndrome, post-traumatic stress disorder, and psychological symptoms (Hopkins Proportional morbidity ratios of hospital Symptom Checklist). There was an diagnoses were compared between the Gulf War approximately 53% participation rate among the and non-deployed veterans. For most diagnostic members of the 14 Seabee commands. categories, Gulf War veterans had proportions of hospitalizations similar to or less than those of Some of the earliest Gulf War veterans who non-deployed veterans. In particular, there has reported post-war morbidity were members of a been speculation that some Gulf War veterans Navy Reserve unit, the Naval Mobile may be suffering from difficult-to-diagnose Construction Battalion 24 (24th Seabees). A infectious diseases. In contrast, data from all major advantage of the active-duty Seabee three hospital systems showed that Gulf War population included in this study is that they had veterans were at significantly less risk to be served in the same tasks (construction work) and hospitalized for infectious diseases than non- at the same sites as the symptomatic Reserve deployed veterans. members in the 24th Seabees. However, the active-duty Seabees had not been evaluated In the DoD hospital system, Gulf War veterans previously about their symptoms or exposures had an increase in hospitalizations for diagnoses during the Gulf War. in the injury and poisoning categories, which included an assortment of soft-tissue injuries and 56% of Gulf War veterans and 32% of non- fractures. Similarly, in the CA system, Gulf War deployed veterans reported post-war symptoms veterans had an increase in hospitalizations for lasting more than one month. Gulf War veterans diagnoses in the category of injury and reported significantly higher rates of 35 of 41 poisoning, which included a number of site- possible symptoms. None of the subjects met the specific fractures and other trauma-associated symptom criteria for chronic fatigue syndrome. injuries. In the VA system, Gulf War veterans Symptoms of post-traumatic stress disorder had an increase in hospitalizations for diagnoses (PTSD) were significantly more frequent in Gulf in three categories: respiratory system, digestive War veterans than non-deployed veterans (15% system, and signs, symptoms, and ill-defined vs. 9%). Gulf War veterans scored significantly conditions. The authors stated that the reasons more poorly on each of the 5 dimensions of the
11 Hopkins Symptom Checklist (somatization, differences between symptoms reported on the obsessive-compulsive disorder, interpersonal mail questionnaire and the symptoms that were sensitivity, depression, and anxiety.) On the confirmed at the time of the clinical exam. pulmonary function tests, there were no Differences between symptoms reported on the differences between Gulf War veterans and non- questionnaire and those confirmed on clinical deployed veterans. exam were attributable to resolution of the symptom in the interim, or to finding a clinical Gulf War veterans were significantly more likely diagnosis for the symptom. The agreement to report exposure to 26 of 30 possible between symptoms reported at the two time exposures. Among Gulf War veterans, nearly all points varied across the symptom categories. symptoms and PTSD responses were associated For example, unexplained fatigue was confirmed with nearly all of the 11 most common Gulf War in 79% of the participants at the time of the exposures. No single exposure or group of clinical exam. In contrast, only 20% of the self- exposures was implicated as likely to be reported gastrointestinal symptoms and only 4% etiologic. The overall results of this study are of the dermatological symptoms were confirmed consistent with previous studies, which showed during the clinical exam, yet remained that Gulf War veterans reported a higher unexplained. prevalence of diverse post-war symptoms, and they demonstrated more post-war psychological Over 50% of the participants who were clinically morbidity than non-deployed veterans did. The evaluated for musculoskeletal or skin problems authors concluded it was doubtful that specific received an explanatory diagnosis. In contrast, Gulf War exposures would be implicated or clinical exams yielded explainable diagnoses in ruled out, without more objective exposure and only a minority of the cases with cognitive- clinical data. psychological symptoms. Objective neurological testing results were usually within normal limits, 3. McCauley, LA, Joos, SK, Lasarev, MR, et al. and there were usually no specific diagnoses of Gulf War unexplained illnesses: persistence and neurological disorders that could explain the unexplained nature of self-reported symptoms. veterans’ symptoms. Environmental Research 1999a; 81(3):215-223. (VA-6 and DoD-63) The authors concluded that while self-reported symptoms are frequent in Gulf War veterans, it is The Portland Environmental Hazards Research impossible without a clinical evaluation to Center performed a population-based case- determine whether the symptom can be control study, which was designed to compare explained with a medical diagnosis or how Gulf War veterans, who reported unexplained persistent the symptom is over time. They also illnesses that could not be diagnosed, with concluded that “reports of associations between healthy Gulf War veterans (controls). Cases and symptoms and exposures during the Gulf War controls were selected from respondents to a based solely on questionnaire data should be questionnaire, which was mailed to a random viewed cautiously in the absence of any clinical sample of Gulf War veterans who lived in evaluation.” Oregon or Washington. Questions focused on chronic fatigue, psychological/cognitive 4. McCauley, LA, Joos, SK, Spencer, PS, et al. symptoms, musculoskeletal symptoms, Strategies to assess validity of self-reported gastrointestinal symptoms, and dermatological exposures during the Persian Gulf War. symptoms. Potential cases of unexplained Environmental Research 1999b; 81(3):195-205. illnesses and healthy controls were recruited for (VA-6 and DoD-63) clinical evaluations within 3 months of returning the mail questionnaire. The objectives of this The Portland Environmental Hazards Research particular analysis were to determine the Center performed a population-based case- persistence of symptoms reported on the control study. (McCauley, et al, 1999a) The questionnaire, and to determine if there were objective of this study was to examine the possible explanatory diagnoses at the time of the limitations of self-reported exposure data in a clinical evaluation. systematic manner. (McCauley, 1999b) Previous studies of illnesses in Gulf War Based on the first 225 veterans in the study (158 veterans have relied almost entirely on surveys cases and 67 controls), there were substantial of self-reported exposures. Three different
12 techniques were utilized to measure the 5. Black, DW, Doebbeling, BN, Voelker, MD, magnitude of potential error in self-reports: 1) et al. Multiple chemical sensitivity syndrome: comparison of self-reported exposures among symptom prevalence and risk factors in a veterans who served at different time periods, military population. Archives of Internal during which some exposures, but not others, Medicine 2000; 160(8):1169-1176. (HHS-1) were known to occur; 2) measurement of the The objective of this study was to assess the effect of the news media on self-reported prevalence of and risk factors for symptoms exposures, during the sequential mailing waves suggestive of multiple chemical that occurred from November 1995 to October sensitivities/idiopathic environmental intolerance 1997; and 3) test-retest measures of the (MCS) in Gulf War veterans and non-deployed reliability of self-reported exposure information. veterans from Iowa. In 1995-96, a randomly- selected sample of Iowa military personnel was A total of 939 survey participants were divided surveyed using a telephone interview. Study into 4 categories of deployment periods: pre- subjects were drawn from four groups: Gulf War combat only, combat only, post-combat only, active-duty, Gulf War National Guard/Reserve, and combinations of periods. Exposures that non-deployed active-duty, and non-deployed were only possible for troops who were deployed National Guard/Reserve. A total of 3,695 during the combat period include SCUD missile subjects completed the survey (76% response detonations, chemical warfare agents, and rate). pyridostigmine bromide. The results of the survey demonstrated that some veterans, who The authors developed their own operational were not deployed during the combat period, criteria for MCS using expert consultation and reported exposures to these agents. For example, the medical literature, because there is no 28% of veterans who served only during the pre- consensus case definition for MCS. Persons combat period reported they were possibly diagnosed with MCS frequently report weakness, exposed to chemical warfare agents, as did 47% fatigue, confusion and memory loss, depression, of veterans who served only during the post- respiratory symptoms, gastrointestinal combat period. The authors interpreted these symptoms, and migratory joint pains. These results as revealing “significant overreporting of symptoms considerably overlap with the exposures that can be verified based on the time symptoms of chronic fatigue syndrome, period served in the Persian Gulf.” fibromyalgia, and depression.
The first 305 individuals who received medical The prevalence of symptoms suggestive of MCS evaluations participated in the test-retest in the total population was 3.4% (169 subjects). reliability analysis. Each subject provided retest Medical and psychiatric conditions were highly information on 21 possible exposures, which prevalent among these 169 subjects, in particular, included about one-third of the exposure items symptoms of respiratory conditions (76%), on the original survey. Only one item showed fibromyalgia (59%), cognitive dysfunction excellent test-retest agreement, that is, whether (55%), minor depression (52%), and major or not the veterans had been provided with depression (34%). Gulf War veterans reported a packets of PB pills. 14 items showed fair to significantly higher prevalence of symptoms good test-retest agreement (e.g., exposure to suggestive of MCS than non-deployed veterans chemical weapons); and 6 items showed poor (5.4% vs. 2.6%). Gulf War veterans also test-retest agreement (e.g., exposure to depleted reported more lifestyle changes, and greater uranium). sensitivity to smog, organic chemicals and solvents, vehicle exhaust, and cosmetics, The authors concluded that: “A veteran may perfume, and hair spray. report exposures that are highly improbable given the dates of deployment and, in many Several risk factors were significantly associated instances be unreliable when measured at two with the symptoms of MCS: age over 25 years, different points in time.” They also stated that: female gender, previous professional psychiatric “Findings which make sole use of self-reported treatment, pre-war psychotropic medication use, findings, for both outcome and exposure, must current psychiatric illness, low level of be viewed with caution or suspicion.” preparedness for deployment, and deployment to the Gulf War. After controlling for other factors, previous professional psychiatric treatment, pre-
13 war psychotropic medication use, and current group was chosen from veterans enrolled in the psychiatric illness continued to show a strong VA Persian Gulf Registry. Previous studies have association with symptoms of MCS. The authors shown that the participants in the Registry are cautioned that their findings should not be not a representative population, because interpreted as validating the concept of MCS as a enrollment is voluntary. unique disorder, and that the symptoms of MCS 2. Brain and Nervous System Function overlap with those of many other conditions. Overview: 6. Kipen, HM, Hallman, W, Kang, H, et al. Prevalence of chronic fatigue and chemical Seven studies were published that focused on sensitivities in Gulf Registry veterans. Archives brain and nervous system function. These of Environmental Health 1999; 54(5):313-318. publications presented the results of studies (VA-5) conducted at four Federally funded research centers in San Diego, Portland, Oregon, Boston, The New Jersey Environmental Hazards and New Jersey. All four of these research Research Center has performed a study of centers utilized psychological and/or veterans who were enrolled in the VA Persian neurological evaluations, rather than relying Gulf Registry in 11 northeastern and midwestern solely on self-administered surveys. Two of states. The objective of this study was to these centers used population-based samples, determine the prevalence of symptoms of chronic which means that their results were designed to fatigue syndrome (CFS) and multiple chemical be generalizable to the overall population of Gulf sensitivity (MCS) on a self-administered War veterans. (Dlugosz, et al, 1999; Anger, et questionnaire. CFS was the main focus because al, 1999; Binder, et al, 1999) 4 of the 6 most frequent symptoms among veterans enrolled in the Registry constitute part Posttraumatic stress disorder (PTSD) was of the case definition for CFS (fatigue, evaluated in five of these studies. (Dlugosz, et muscle/joint pain, headache, and loss of al, 1999; Wolfe, et al, 1999a; Wagner, et al, memory). 2000; Wolfe, et al, 1999b; Lange, et al, 1999) In each study, Gulf War veterans were at increased 1,935 veterans were randomly selected from the risk for PTSD in comparison with control Registry and were mailed a detailed populations. One longitudinal study found an questionnaire between the autumn of 1995 and increased prevalence of PTSD over time, from an August 1996. 1,161 veterans responded (60%), evaluation within five days of return from the and were therefore potentially eligible for the war (3%), to an evaluation 18 to 24 months after second stage of the study, which included return (8%). The cause of this increase was thorough medical examinations and psychiatric uncertain, partly because PTSD with delayed- evaluations. (Lange, et al, 1999) The authors onset has not been well studied in other developed a questionnaire-based diagnosis of populations. (Wolfe, et al, 1999a) The CFS, based on the Centers for Disease Control diagnoses of PTSD and/or major depression and Prevention’s 1994 case definition. The were associated with an increased rate of authors developed their own operational case reporting of physical symptoms, an association definition for MCS, because there is no that has been demonstrated in previous veteran consensus case definition for MCS. and civilian populations with diagnoses of PTSD or major depression. (Wagner, et al, 2000; After eliminating individuals with medical Wolfe, et al, 1999b) exclusions for CFS, 15.7% of the participants met the questionnaire criteria for CFS. In In two studies, Gulf War veterans were at addition, 13.1% met the questionnaire criteria for increased risk for major depression, in the authors’ case definition for MCS. 3.3% of comparison to control populations. (Wolfe, et al, the respondents met the criteria for both 1999b; Lange, et al, 1999) In one study, Gulf conditions. There were no associations between War veterans were at increased risk for CFS and gender, race, active-duty vs. reserve hospitalization for alcohol-related and drug- status, or rank. Both women and blacks had a related disorders. (Dlugosz, et al, 1999) In two two-fold increased risk for MCS. The results of studies, a history of pre-war psychiatric this study cannot be generalized to the overall diagnoses was strongly associated with an Gulf War veteran population, because the study
14 increased risk of post-war psychiatric diagnoses. During the follow-up period of June 1, 1991 to (Dlugosz, et al, 1999; Lange, et al, 1999) The September 30, 1993, these nearly 2 million authors stated that this was not a surprising service members had 30,539 initial finding, given the chronic nature of many mental hospitalizations for mental disorders in DoD disorders. facilities (about 1.5% of the cohort). 15.4% of the patients suffered a rehospitalization for the Two studies performed by one research center same condition during the study period. examined objective neuropsychological function. Alcohol-related disorders accounted for 47.2% (Anger, et al, 1999; Binder, et al, 1999) In one of the 30,539 initial hospitalizations. In contrast, study, Gulf War veterans who had chronic, drug-related disorders accounted for only 2.2%; medically unexplained symptoms were compared and acute reactions to stress, which included with healthy Gulf War veterans. (Anger, et al, posttraumatic stress disorder, accounted for only 1999) The ill veterans differed from the healthy 0.7%. veterans on virtually all of 12 psychological test scales, in the direction of increased distress. In After adjustment for confounding variables, Gulf contrast, there was a significant difference in War service was associated with a significantly only one of six neurobehavioral tests. In the increased risk for hospitalization for causes that second study, Gulf War veterans were tested, were alcohol-related, drug-related, or acute who had psychological or cognitive symptoms reactions to stress. In contrast, Gulf War service that remained unexplained after a thorough was associated with a significantly decreased risk medical and neurological evaluation. (Binder, et for hospitalization for adjustment reactions, al, 1999) The results showed that self-reported mood disorders, neurotic disorders, and cognitive problems were more closely related to personality disorders. These associations that affective distress than to objective cognitive had decreased risks were unexpected. For both performance on neuropsychological tests. The men and women, there were no strong or authors recommended that cognitive impairment consistent associations between mental disorders should not be diagnosed, based solely on and possible combat exposure, in terms of Gulf subjective complaints, and that objective War occupation. More important than Gulf War cognitive testing is necessary. occupation was increasing age. Age was an important risk factor for a number of mental Brain and Nervous System Function- disorders, including alcohol and drug-related Individual Studies: conditions, in both men and women. In both Gulf War and non-deployed personnel, pre-war 1. Dlugosz, LJ, Hocter, WJ, Kaiser, KS, et al. hospitalization for a mental disorder was the Risk factors for mental disorder hospitalization strongest predictor of post-war mental disorder after the Persian Gulf war: U.S. Armed Forces, hospitalization. The authors stated that this was June 1, 1991-September 30, 1993. Journal of not a surprising finding, considering the chronic Clinical Epidemiology 1999; 52(12):1267-1278. nature of many mental disorders. (DoD-1) The authors noted that this study had several The objectives of this study were: 1) to describe strengths, however, they noted it is possible that the incidence of mental disorder hospitalization these analyses may have understated the risks of after the Gulf War; 2) to identify risk factors and hospitalization associated with Gulf War service. groups at higher risk for hospitalization for Because military personnel are not eligible for mental disorders; and 3) to evaluate whether deployment unless they are in good health, serving in the Gulf War was a risk factor for individuals who were at high risk for mental post-war hospitalization for mental disorders. disorders prior to the Gulf War may have All regular, active-duty personnel in the four become ineligible for deployment (for example, services who served one or more months on through medical waivers). active-duty between August 2,1990, and July 31, 1991, were included in the study (1,775,236 men 2. Anger, WK, Storzbach, D, Binder, LM, et al. and 209,760 women). About 29% of these Neurobehavioral deficits in Persian Gulf service members were deployed to the Gulf War. veterans: evidence from a population-based study. Journal of the International Neuropsychological Society 1999; 5(3):203-212. (VA-6 and DoD-63)
15 Persian Gulf War veterans. Archives of Clinical The Portland Environmental Hazards Research Neuropsychology 1999; 14(6):531-536. (VA-6 Center performed a population-based case- and DoD-63) control study. (McCauley, et al, 1999a) The goals of this study were to determine if veterans The Portland Environmental Hazards Research with unexplained symptoms had objective Center performed a population-based case- deficits in memory and attention; and to assess control study. (McCauley, et al, 1999a) The psychological conditions that might contribute to goals of this study were to determine the the presentation of the broad range of relationships between subjective cognitive unexplained symptoms. (Anger, et al, 1999) complaints and affective distress, and between This preliminary analysis included the first 66 subjective cognitive complaints and objective cases and 35 controls, who had completed cognitive performance. (Binder, et al, 1999) medical evaluations by December 1996. The Previous studies in a variety of populations have evaluations included a physical exam with an shown that cognitive symptoms were at least as emphasis on neurological and musculoskeletal strongly related to negative affect, as they were systems, a detailed health history, and related to objective cognitive problems. This neurobehavioral and psychological tests. There analysis included the first 100 Gulf War veterans were 12 psychological tests and 6 who had psychological or cognitive symptoms, neurobehavioral tests, which provided objective which remained unexplained after a thorough measures of memory, concentration, complex medical and neurological evaluation. cognitive processing, and response speed. Eight questions, which focused on memory, The cases differed from the controls on virtually decision-making ability, and concentration, were all of the psychological test scales, in the selected from a validated questionnaire (the direction of increased distress. These differences Symptom Checklist 90-Revised) to define the remained significant, even after statistical subjective cognitive complaints scale. Scores on correction for multiple comparisons. The the Beck Depression Inventory and the Beck authors concluded that Gulf War veterans Anxiety Inventory were selected as measures of reporting chronic symptoms reveal increased affective distress. Both of these Beck distress on a broad range of psychological Inventories were significantly correlated with the measures, in comparison to healthy Gulf War subjective cognitive complaints scale (r = 0.59 veterans. and r = 0.58, respectively).
Case performance was inferior to control In contrast, the correlations were modest performance on all six neurobehavioral tests. between the subjective cognitive complaints However, after statistical correction for multiple scale and the objective cognitive performance on comparisons, there was a significant difference 6 neurobehavioral tests. Only 2 of the 6 tests on only one of the six neurobehavioral tests. were significantly correlated with the subjective This particular digit recall test provided a cognitive complaints scale (r = 0.28 and r = 0.23, measure of motivation, attention and memory. respectively). A stronger relationship was The authors concluded that the data did not demonstrated between subjective cognitive support a distribution-wide neurobehavioral complaints and affective distress, than between deficit in the 66 cases. Instead, it appeared that a subjective cognitive complaints and any of the small number of cases (13 of the 66) responded objective cognitive tests. very slowly on the digit recall test. This might indicate that these 13 cases are an unusual Overall, the data demonstrated that self-reported subgroup that is distinct from the other cases, as cognitive problems in symptomatic Gulf War well as the controls. The authors have evaluated veterans were more closely related to affective several hundred additional individuals since distress than to objective cognitive performance. December 1996, and it will be important to The authors recommended that cognitive determine if the results for the larger population impairment should not be diagnosed in Gulf War are consistent with the preliminary results. veterans, based solely on subjective complaints, and that objective cognitive testing is necessary. 3. Binder LM, Storzbach, D, Anger, WK, et al. Subjective cognitive complaints, affective 4. Wolfe J, Erickson DJ, Sharkansky EJ, et al. distress, and objective cognitive performance in Course and predictors of posttraumatic stress
16 disorder among Gulf War veterans: a prospective onset. Delayed-onset PTSD has not been well analysis. Journal of Consulting and Clinical studied. Psychology 1999a; 67(4):520-528. (VA-4, VA- 7, DoD-32, DoD-52) 5. Wagner, AW, Wolfe, J, Rotnitsky, A, et al. An investigation of the impact of posttraumatic The Boston Environmental Hazards Research stress disorder on physical health. Journal of Center has been following 2,949 Army veterans Traumatic Stress 2000; 13(1):41-55. (VA-4, who processed through Fort Devens, VA-7, DoD-32, DoD-52) Massachusetts, at the time of their return from the Gulf War in 1991. This group of veterans The Boston Environmental Hazards Research has been evaluated at four time points, starting Center has been performing a prospective cohort within five days of their return to the U.S., and study. (Wolfe, et al, 1999a) The objectives of again at 18 to 24 months (Time 2), three years this study were to determine if PTSD symptoms (Time 3), and six years (Time 4). The study assessed at Time 1 would predict physical health population includes about 72% Reserve/National problems reported at Time 2, and to determine if Guard and about 28% active-duty, and it includes more health problems would be reported by 84 units with a wide range of military women than by men at Time 2. (Wagner, et al, occupational specialties from several regions on 2000) the U.S. At Time 1, PTSD symptoms were assessed with The objective of this particular study was to use the Mississippi Scale for Combat-Related PTSD. longitudinal data to evaluate rates and risk At Time 1, the overall Brief Symptom Inventory factors for posttraumatic stress disorder (PTSD) (BSI) score was used to assess general over time. (Wolfe, et al, 1999a) At Time 2, psychological distress. The BSI is a 53-item 2,313 subjects participated, which was 78% of questionnaire focusing on symptoms of the original cohort. This included 2,119 men and psychological disorders. At Time 1, seven 194 women. Comparisons were made at Time 1 physical health symptoms were assessed using a and Time 2, focusing on responses on the subscale of the BSI. At Time 2, a questionnaire Mississippi Scale for Combat-Related PTSD, a was used that assessed ten physical health well-validated survey instrument. The Laufer problems, which occurred “over the past few Combat Scale, a validated questionnaire, was weeks.” These included general aches and pains, used to measure combat exposure. headaches, dizziness, upset stomach, and skin rashes. At Time 1, 3% of the cohort met the criteria for PTSD, which increased to 8% at Time 2. PTSD symptoms at Time 1 were predictive of Individuals who met the criteria at Time 1 were health symptoms at Time 2, even after 20 times more likely to meet the criteria at Time controlling for the effects of gender, age, 2, than individuals who did not meet the criteria education, degree of combat exposure, and health at Time 1. Women, as well as individuals who symptoms at Time 1. At Time 1, women were reported relatively high levels of combat significantly more likely to be psychologically exposures, were at significantly increased risk distressed, according to the overall BSI score, for PTSD at both time points. The intensity of and to meet criteria for the diagnosis of PTSD reported combat exposure was significantly (7.8% of women vs. 2.3% of men). At Time 2, associated with PTSD, even though, in general, the women reported significantly higher rates of the level of combat exposure was relatively low 4 of the 10 symptoms than the men did. The during the Gulf War. authors are continuing this prospective study, so that more comprehensive surveys of health Although the rate of PTSD was initially low, it problems, as well as psychiatric evaluations, can increased substantially over time. This increase clarify the reasons for this difference in symptom at Time 2 could be explained two ways. One reporting between female and male Gulf War possible explanation is that the disorder was veterans. present at Time 1, but for some reason it was not detectable, for example, the subject’s positive 6. Wolfe, J, Proctor, SP, Erickson, DJ, et al. mood at the time of return from the war. The Relationship of psychiatric status to Gulf War other explanation is that the observed increase in veterans’ health problems. Psychosomatic PTSD rates at Time 2 represents true delayed
17 Medicine 1999b; 61(4):532-540. (VA-4, VA-7, was that both the PTSD and MDD diagnoses DoD-32, DoD-52) were determined through interviews by clinicians, not just through self-administered The Boston Environmental Hazards Research surveys. Center has been performing a prospective cohort study. (Wolfe, et al, 1999a) The objectives of 7. Lange, G, Tiersky, L, DeLuca J, et al. this study were to provide rigorous psychiatric Psychiatric diagnoses in Gulf War veterans with diagnoses, focusing on posttraumatic stress fatiguing illness. Psychiatric Research 1999; disorder (PTSD) and major depressive disorder 89(1):39-48. (VA-5) (MDD); and to assess the association of these diagnoses with physical health complaints. The New Jersey Environmental Hazards (Wolfe, et al, 1999b) Three groups were Research Center performed a study of veterans evaluated between 1994 to 1996 (Time 3). 148 who were enrolled the VA Persian Gulf Registry. of the Fort Devens cohort were selected on the (Kipen, et al, 1999) The objective of this study basis of either high or low rates of physical was to compare the psychiatric profiles of Gulf symptom reporting. In addition, 56 Gulf War War veterans, who met clinical criteria for veterans from New Orleans were included, who chronic fatigue syndrome (CFS) or multiple had previously been studied in 1991. The chemical sensitivity (MCS), with the profiles of comparison group included 48 members of a unit healthy Gulf War veterans. (Lange, et al, 1999) that had been activated and deployed to Germany One hundred veterans who reported severe in 1991. This comparison unit was included to fatigue and 47 healthy veterans were selected test the hypothesis that deployment to a war zone from 1,161 veterans who were enrolled in the itself constituted a sufficiently severe stressor to VA Persian Gulf Registry, and who had produce physical symptoms. participated in a large mailed questionnaire in 1995-1996. PTSD was measured with two validated scales, the Mississippi Scale for Combat-Related PTSD, These 147 veterans underwent an intensive and the Clinician Administered PTSD Scale medical history, physical exam, and blood tests. (CAPS). Depression was assessed by trained To assess Axis I psychiatric disorders according clinicians, who used a validated instrument, the to DSM-III-R criteria, trained personnel Structured Clinical Interview for DSM-III-R administered a computerized standardized (SCID). Symptoms over the past 30 days were diagnostic interview. 52 of these 147 were assessed with the Health Symptom Checklist, eliminated from the final study, because of which asked about the frequency of 52 medical exclusions in 17 individuals; psychiatric symptoms affecting several organ systems. exclusions in 19 individuals; and 16 individuals Rates of current and lifetime PTSD were were excluded because of insufficient criteria to significantly higher in the Fort Devens and New allow the diagnosis of CFS or MCS. The results Orleans groups than in the comparison group. of these medical evaluations highlight the Rates of current and lifetime MDD were also necessity of caution in the interpretation of significantly higher in the two Gulf War groups. surveys, if they are used as the sole source of diagnostic data. In general, PTSD and MDD diagnoses were associated with the reporting of higher numbers 62% (33 of 53) of veterans reporting fatigue of health symptoms. For example, after fulfilled diagnostic criteria for post-war Axis I controlling for covariates, individuals with psychiatric disorders, which was significantly current PTSD reported an average of 4.7 more higher than the rate of 14% (6 of 42) among health symptoms than individuals without healthy veterans. Significantly more fatigued current PTSD. Gulf War veterans with PTSD or veterans were diagnosed with major depressive MDD reported significantly more health disorder, post-traumatic stress disorder, simple problems than Gulf War veterans without these phobia, and social phobia. These four disorders diagnoses, across nearly every organ system. In were also the most frequent Axis I diagnoses in addition, Gulf War veterans who had no the fatigued veterans. Dysthymia, generalized psychiatric diagnoses reported significantly anxiety disorder, somatization disorder, panic higher rates of symptoms than veterans deployed disorder, and compulsive disorder occurred only to Germany, for the majority of organ systems. in the fatigued group. One of the most important strengths of this study
18 The fatigued group included significantly more that the increased rate of symptom reporting in veterans (43%) with multiple post-war Axis I Gulf War veterans might be due to a mysterious diagnoses, compared with the healthy group infectious disease. Occult infection with (2%). Pre-war psychiatric disorders did not Mycoplasma fermentans has been proposed as a predict the development of post-war severe possible cause. fatigue or post-war psychiatric disorders, except in the subgroup of fatigued veterans who had Symptom data and serum samples from a 1994- multiple psychiatric disorders before 95 survey of Navy Seabees were used to select deployment. symptomatic and asymptomatic Gulf War veterans and non-deployed veterans. (Gray, et al, 3. Diagnosis 1999a) Sera from 96 Seabees were matched to pre-war (before September 1990) archived sera. Overview: Serologic analyses were performed in a blinded fashion, by the University of Alabama Two studies were published that focused on the Diagnostic Mycoplasma Laboratory. The ill diagnosis of infectious diseases. There has been veterans were selected on the basis of 8 some speculation that the increased rate of symptoms that were considered to be the most symptom reporting in Gulf War veterans might consistent with clinical reports of mycoplasma be due to a previously undetected infectious infection: cough, sore throat, pains that move organism. One study compared the rates of from one joint to another, joint swelling, joint antibodies to Mycoplasma fermentans between redness, rash or skin ulcer, fever, and asthma. Gulf War and non-deployed veterans. (Gray, et al, 1999b) Mycoplasma infections occurred both Both Gulf War and non-deployed veterans had before the war and after the war, and these pre-war and post-war serologic evidence of infections occurred at similar rates in Gulf War Mycoplasma fermentans infection, at rates that veterans and non-deployed veterans. Also, were consistent with the rates in the general U.S. Mycoplasma infections were not associated with population. 11% of 64 Gulf War veterans and post-war symptoms in either Gulf War veterans 9% of 32 non-deployed veterans had pre-war or non-deployed veterans. antibodies. Testing of the veterans who had negative pre-war antibodies revealed that 19% of The second study evaluated whether there was the 57 Gulf War veterans and 14% of the 29 non- any correlation between infection with one or deployed veterans had antibody evidence of new more human herpesviruses (HHV) in chronic infections since the war (not significant). None fatigue syndrome (CFS) patients, compared to of the antibody profiles, pre-war or post-war, or controls. (Wallace, et al, 1999) There were no their changes over time, was associated with correlations between the diagnosis of CFS and post-war symptoms, in either Gulf War veterans infection with four viruses (HHV6, HHV7, EBV, or non-deployed veterans. and CMV). The authors concluded “that routine screening for these viruses in CFS patients would The authors concluded that these data were have limited clinical value.” consistent with other studies of Gulf War veterans that have not found evidence of Diagnosis-Individual Studies: emerging infectious disease. These findings are important to Gulf War veterans, because they 1. Gray, GC, Kaiser, KS, Hawksworth, AW, and provide evidence that Mycoplasma fermentans Watson, HL. No serologic evidence of an infections occurred both before the war and after association found between Gulf War service and the war, and these infections occurred at similar Mycoplasma fermentans infection. American rates in Gulf War veterans and non-deployed Journal of Tropical Medicine and Hygiene veterans. However, this study is limited due to 1999b; 60(5):752-757. (DoD-1) the small numbers of veterans involved.
The objective of this study was to compare the 2. Wallace, HL, Natelson, B, Gause, W, and rates of serologic (antibody) evidence of Hay, J. Human herpesviruses in chronic fatigue Mycoplasma fermentans infection between Gulf syndrome. Clinical and Diagnostic Laboratory War veterans and non-deployed veterans. (Gray, Immunology 1999; 6(2):216-223. (VA-5) et al, 1999b) There has been some speculation
19 The New Jersey Environmental Hazards potentially leading to toxic effects in the kidneys Research Center performed a study of veterans and other organs. Many of the 33 individuals who were enrolled in the VA Persian Gulf had persistent impairments directly related to Registry. (Kipen, et al, 1999) The objective of their wounds, including severe burns and this study was to determine if there was any amputations. In 1993, all measures of kidney correlation between infection with one or more function were normal, and the authors concluded human herpesviruses in chronic fatigue that: “These data show no evidence of adverse syndrome (CFS) patients, compared to age, race, clinical outcomes associated with uranium and gender matched controls. (Wallace, et al, exposure at this time in these individuals.” 1999) A viral component in the etiology of CFS In 1997, 29 of the 33 DU-exposed servicemen has been suspected, because some patients returned to the Baltimore VAMC for a present with acute-onset symptoms similar to a comprehensive evaluation. (McDiarmid, et al, viral infection. 2000) In addition, 38 Gulf War veterans were evaluated who were not exposed to DU. Overall, The CFS patient population was composed of the 1997 tests showed that veterans who had rigorously screened Gulf War veterans and embedded fragments continued to excrete civilians who met the Centers for Disease elevated concentrations of urinary uranium, but Control’s 1994 case definition criteria for CFS. there were “relatively few uranium-related The control subjects were healthy Gulf War clinical outcomes documented in this group.” In veterans and civilians who showed no evidence general, there were no abnormalities in kidney of CFS or other exclusionary medical or function. The 1997 tests did demonstrate a few psychiatric conditions. There were 46 Gulf War subtle variations in neurocognitve tests and in veterans diagnosed with CFS, 32 healthy Gulf serum prolactin levels, which were associated War veterans, 76 civilians diagnosed with CFS, with elevated uranium levels. These DU- and 73 healthy civilians. exposed veterans were evaluated again in 1999.
The focus was on the detection of the DNA of Two studies focused on the effects of fragments four human herpesviruses (HHV), by the method of depleted uranium (DU) embedded in the of polymerase chain reaction. These were HHV muscles of Sprague-Dawley rats, over the course 6, HHV 7, Epstein-Barr virus (EBV), and human of 18 months. (Pellmar, et al, 1999a; Pellmar, et cytomegalovirus (CMV). There were no al, 1999b) Significant concentrations of uranium correlations between the diagnosis of CFS and were excreted in the urine throughout the 18- infection with HHV6 or HHV7. In all four month period. (Pellmar, et al, 1999a) The patient groups, there was only one individual kidney and bone were the primary reservoirs for who had detectable DNA for EBV, and no DU redistributed from intramuscularly embedded individuals who had detectable DNA for CMV. fragments. The urinary levels in the rats in the The authors concluded: “that routine screening low-dose group were “comparable” to the for these viruses in CFS patients would have highest urinary levels in Gulf War veterans who limited clinical value.” have retained shrapnel. (Pellmar, et al, 1999b) This means that the low-dose rats would be the 4. Depleted Uranium group with the highest exposures that would have relevance to veterans. Overview: The potential for DU fragments to cause Two human studies and two animal studies were electrophysiological changes in the central published that focused on the effects of depleted nervous system was tested. (Pellmar, et al, uranium (DU). In 1993, the Baltimore Veterans 1999b) DU caused detectable Affairs Medical Center (VAMC) began a electrophysiological changes in the hippocampus prospective study of Gulf War veterans who had at six months and 12 months after implantation. been wounded in friendly fire incidents, to The authors do not explain the relationship of quantify body burdens of uranium over time and electrical changes in brain slices to neurological to detect any adverse health effects from this or behavioral changes in an intact animal; exposure. (Hooper, et al, 1999) The VA and therefore, direct extrapolation to humans is not DoD were concerned that embedded depleted possible. Preliminary behavioral studies in these uranium fragments could dissolve over time, rats focused on locomotor activity, discrimination learning, and a general functional
20 observation battery, and there were no gross All measures of kidney function were normal, performance decrements. and there were no correlations between the levels of urinary uranium and assays of kidney Depleted Uranium-Individual Studies: function. The authors concluded that: “These data show no evidence of adverse clinical 1. Hooper, FJ, Squibb, KS, Siegel, EL, et al. outcomes associated with uranium exposure at Elevated urine uranium excretion by soldiers this time in these individuals.” with retained uranium shrapnel. Health Physics 1999; 77(5):512-519. (Supported by VA and 2. McDiarmid, MA, Keogh, JP, Hooper, FJ, et DoD) al. Health effects of depleted uranium on exposed Gulf War veterans. Environmental The objective of this study was to evaluate the Research 2000; 82(2):168-180. (Supported by health of 33 Gulf War veterans who had been VA and DoD) wounded during friendly fire incidents involving depleted uranium munitions. The Baltimore The objectives of this study were to reevaluate Veterans Affairs Medical Center (VAMC) began the health effects of uranium exposure in Gulf a prospective study of these individuals in 1993 War veterans who were wounded in friendly fire to quantify body burdens of uranium over time incidents, and to compare their health status with and to detect any adverse health effects from this Gulf War veterans who were not exposed to exposure. The VA and DoD were concerned that uranium. In 1997, 29 of the 33 DU-exposed embedded depleted uranium (DU) fragments servicemen returned to the Baltimore VAMC for could dissolve over time, potentially leading to a comprehensive three day evaluation. In toxic effects in the kidneys and other organs. addition, 38 Gulf War veterans were evaluated The study included a comprehensive medical and who were not exposed to DU. The evaluation psychological evaluation, a 24-hour urine included a medical and occupational history, a collection for uranium concentration, and a full- detailed physical exam, laboratory tests of blood body X-ray survey, looking for retained metallic and urine, a 24-hour urine collection for uranium fragments. concentration, a psychiatric assessment, a neurocognitive evaluation, and genotoxicity Many of the 33 individuals had persistent studies. impairments directly related to their wounds, which included severe burns, amputations, In the DU-exposed group, urinary levels were as fractures and concussions. Fifteen veterans had much as 600 times higher than the levels in the multiple tiny DU fragments scattered in their non-exposed group. In general, there were no muscles and soft tissues, which could not be abnormalities in kidney function. There were no surgically removed. X-rays and computed associations between urinary DU levels and tomographic scans showed no evidence of several kidney function tests, including two granuloma formation. Localized concentrations specific tests for proximal tubule damage, the of uranium can deliver alpha radiation to the type of kidney damage caused by high exposures surrounding tissue. Despite this, the Baltimore in laboratory animals. VAMC did not observe any significant localized effects from the DU shrapnel. The DU-exposed group has undergone neurocognitive testing two times, in 1993-4 and The 15 veterans, who had retained shrapnel, had 1997. They performed normally on standard a mean urinary uranium level that was 150 times “pen-and-pencil” tests, which evaluated higher than the mean urinary uranium level of attention, memory and problem solving. On the 18 veterans who did not have retained computerized tests, there was a significant shrapnel. The 18 veterans without shrapnel may relationship between elevated urinary uranium have had substantial short-term inhalation levels and lowered efficiency and accuracy exposure to DU during the first minutes after performance. However, because the number of impact and may also have sustained wound veterans with elevated levels was so small, the contamination. Even so, the mean urinary level clinical significance of the computerized tests is in the veterans without shrapnel was similar to uncertain. The standard “pen-and-pencil” tests the mean levels in unexposed populations in indicated no such relationship, and these previous studies. standard tests have been better validated.
21 The VAMC also evaluated semen characteristics, and bone. At all time points, DU concentrations including volume, sperm count, concentration, in kidney and bone were significantly greater in morphology, and motility. There was no the high-dose rats than in the control rats. apparent effect of elevated uranium levels on Significant concentrations of uranium were these semen measurements. Four reproductive excreted in the urine throughout the 18-month hormones were measured: follicle stimulating period by the medium- and high-dose rats. Very hormone, leutinizing hormone, testosterone, and low levels of DU were observed in serum at all prolactin. There were no significant differences time points. Many other tissues contained in the levels of these hormones, between the high increased DU concentrations in the implanted and low uranium groups, except for the prolactin animals (muscle, spleen, liver, heart, lung, brain, levels. To assess the possibility that DU causes lymph nodes, and testicles). The unexpected genetic damage, white blood cells were cultured accumulation in brain, lymph nodes, and testicles to determine the frequencies of chromosomal could suggest the potential for physiological aberrations and sister chromatid exchanges. consequences; therefore, additional studies were There were no differences in these chromosome designed to evaluate potential neurological and tests between the high and low uranium groups. reproductive toxicity. The authors noted that there have been “no known birth defects in the approximately 20 The authors concluded that kidney and bone are pregnancies fathered by the DU-exposed group the primary reservoirs for DU redistributed from since their return from the Gulf.” intramuscularly-embedded fragments. This was consistent with the results of previous studies of Overall, the 1997 tests showed that veterans who animals and occupationally-exposed miners and had embedded fragments continued to excrete millers. The urinary levels in the rats in the low- elevated concentrations of urinary uranium, but dose group were “comparable” to the highest there were “relatively few uranium-related urinary levels in Gulf War veterans who have clinical outcomes documented in this group.” retained shrapnel. (Pellmar, et al, 1999b) This The 1997 tests did demonstrate a few subtle means that the low-dose rats would be the group variations in neurocognitve tests and in serum with the highest exposures that would have prolactin levels, which were associated with relevance to veterans. There were no elevated uranium levels. These DU-exposed measurements of health effects in this study. veterans were evaluated again in 1999. 4. Pellmar, TC, Keyser, DO, Emery, C, and 3. Pellmar, TC, Fuciarelli, AF, Ejnik, JW, et al. Hogan, JB. Electrophysiological changes in Distribution of uranium in rats implanted with hippocampal slices isolated from rats embedded depleted uranium pellets. Toxicological with depleted uranium fragments. Sciences 1999a; 49(1):29-39. (DoD-7A) Neurotoxicology 1999b; 20(5);785-792. (DoD- 7A) The objective of this study was to determine the distribution of uranium that resulted from The objective of this study was to test the fragments of depleted uranium (DU) embedded potential for DU fragments to cause in the muscle of the rat, over the course of 18 electrophysiological changes in the central months. No previous studies have evaluated the nervous system. (Pellmar, et al, 1999b) This long-term health effects of exposure to uranium study is a continuation of a study in which fragments. In addition, previous studies have Sprague-Dawley rats were surgically implanted focused on the natural or enriched forms of with DU pellets at three dose levels. (Pellmar, et uranium, rather than DU. Sprague-Dawley rats al, 1999a) At six months, 12 months, and 18 were surgically implanted with DU pellets at months, rats were sacrificed, and their brains three dose levels, into the gastrocnemius muscle. were removed. The hippocampus was dissected Biologically inert tantalum pellets were out and cut into slices, and electrophysiological implanted into control animals. At one day, one potentials were measured. At six months and 12 month, six months, 12 months, and 18 months, months, there were significant differences in the the rats were sacrificed and tissue samples were synaptic potentials between DU-exposed rats and analyzed. controls. At 18 months, the differences in synaptic potentials were no longer evident. The As early as one day after implantation, the data suggested that, by 18 months, the effects of greatest DU concentrations were in the kidney
22 aging and DU exposure converged, which The objective of the animal study was to obscured the effects of the metal. determine if the administration of a single low dose of sarin would lead to long-term EEG The authors do not explain the relationship of changes in monkeys (common marmosets). electrical changes in brain slices to neurological (Pearce, et al, 1999) The animals were trained to or behavioral changes in an intact animal; perform complex behavioral test sequences, in therefore, direct extrapolation to humans is not order to assess the functional significance of any possible. The mechanism by which DU caused EEG changes that might be observed. The dose the neurophysiological changes is unknown. of sarin caused no clinical signs of intoxication. Kidney toxicity, leading to secondary nervous Overall, there were no significant changes in system toxicity, does not appear to be a concern. EEG patterns in the sarin-exposed animals over a Despite significant accumulations of uranium in 15-month follow-up period. Also, no deleterious the kidney, a preliminary evaluation did not effects on performance were seen on the indicate any kidney toxicity. behavioral tasks. The results of this study are useful to consider in terms of possible human Preliminary behavioral studies in these rats effects, because of the use of non-human focused on locomotor activity, discrimination primates, the low dose of sarin used, the learning, and a general functional observation relevance of the behavioral testing, and the battery. There were no gross performance extended follow-up period after exposure. decrements, however, these behavioral measures were not sufficiently sensitive to detect subtle Chemical Weapons-Individual Studies: cognitive deficits. Ongoing studies are evaluating performance on more complex 1. Gray, GC, Smith, TC, Knoke, JD, and Heller, learning tasks. JM. The postwar hospitalization experience of Gulf War veterans possibly exposed to chemical 5. Chemical Weapons munitions destruction at Khamisiyah, Iraq. American Journal of Epidemiology 1999c; Overview: 150(5):532-540. (DoD-1)
One human study and one animal study were The objective of this study was to compare the published that focused on the effects of chemical rates and causes of hospitalization between Gulf weapons. Munitions containing sarin and War veterans who were possibly exposed to low cyclosarin were inadvertently destroyed by U.S. levels of nerve agents, and other Gulf War troops at Khamisiyah, Iraq on March 10, 1991. veterans who were not likely to have been U.S. troops may have been exposed to a plume exposed. Munitions containing sarin and that contained concentrations too low to cause cyclosarin were inadvertently destroyed by U.S. immediate symptoms. (Gray, et al, 1999c) troops at Khamisiyah, Iraq, on March 10, 1991. 124,487 veterans were categorized into 4 levels U.S. troops may have been exposed to a plume of estimated exposure. 224,804 veterans were that contained concentrations too low to cause categorized as not exposed. Hospitalization data immediate symptoms (subclinical levels). from all DoD hospitals were evaluated through Multiple sources of meteorological, munitions, September 30, 1995. The rates of hospitalization and toxicology data were used to circumscribe were evaluated for diagnoses in 15 broad ICD-9 geographic areas of vaporized nerve agent for the categories, and for specific neurological 4 days after the demolition. Plume estimates diagnoses, which were possible, subtle nerve were overlaid on military unit positions, and agent-induced effects. There were no exposure levels were estimated for 349,291 associations between the four groups of possibly Army Gulf War veterans (including about 78% exposed veterans and the 15 broad ICD-9 active-duty and 22% reserve). 124,487 veterans diagnostic categories or the specific neurological were categorized into 4 levels of estimated diagnoses. Overall, these data do not support the exposure. 224,804 veterans were categorized as hypothesis that Gulf War veterans are suffering not exposed. post-war morbidity from subclinical nerve agent exposure. Hospitalization data from all DoD hospitals were evaluated from March 10, 1991, to September 30, 1995 (54 months follow-up). At the end of the follow-up period, about 48% of the active-
23 duty service members remained on active-duty. The EEGs were monitored by implantable The rates of hospitalization were evaluated for radiotelemetry. The behavioral tests involved diagnoses in 15 broad ICD-9 categories, and for the presentation of a number of visual specific neurological diagnoses, which were discriminations on a touch sensitive screen. suggested by an expert panel as possible Tests from this battery are suitable for manifestations of subtle, nerve agent-induced, presentation to both humans and non-human neurophysiologic effects (mononeuritis, primates. Individual animals served as their own peripheral neuropathy, toxic neuropathy, and controls on the behavioral tests. Baselines of myoneural disorders, and myopathies). EEGs and behavior were observed to be stable over several months in control animals. The four groups of possibly exposed veterans The EEGs and the behavioral tasks were had similar adjusted risks of “any cause” assessed for up to 15 months after exposure to a hospitalization, compared with the non-exposed single dose of sarin. The dose of sarin caused veterans. Consistent with other hospitalization acetylcholinesterase inhibition of 36% to 67% studies of Gulf War veterans, women, persons (mean of 51%), but no clinical signs of sarin who were hospitalized during the 12 months intoxication. This inhibition returned to baseline before the war, health care personnel, levels in three months, on average. Overall, Reserve/National Guard personnel, and enlisted there were no significant changes in EEG personnel were at increased risk of patterns in the sarin-exposed animals. No hospitalization for “any cause.” There were no deleterious effects on performance were seen on associations between the four groups of possibly the touch screen mediated discrimination tasks. exposed veterans and the 15 broad ICD-9 The results of this study are useful to consider in diagnostic categories or the specific neurological terms of possible human effects, because of the diseases. use of non-human primates, the low dose of sarin used, the relevance of the behavioral testing, and Overall, these data do not support the hypothesis the extended follow-up period after exposure. that Gulf War veterans are suffering post-war morbidity from subclinical nerve agent exposure. 6. Pyridostigmine Bromide One drawback of this study is that the data permit only the comparison of veterans who Overview: remained on active-duty after the conflict or who retired with medical benefits. One human study and three laboratory studies were published that focused on the effects of 2. Pearce, PC, Crofts, HS, Muggleton, NG, et al. pyridostigmine bromide (PB). The objective of The effects of acutely administered low dose the human study was to determine if there was an sarin on cognitive behaviour and the association between intake of pyridostigmine electroencephalogram in the common marmoset. bromide and handgrip strength, which is a Journal of Psychopharmacology 1999; reliable measurement of muscle strength. 13(2):128-135. (Not funded by U.S. (Kaiser, et al, 2000) In 1994-95, self-reported government-British study) PB intake and handgrip strength were evaluated in 527 Gulf War veterans and 969 non-deployed The objective of this study was to determine if veterans. There was little difference in handgrip the administration of a single low dose of sarin strength among Gulf War veterans who used PB, would lead to long-term electroencephogram Gulf War veterans who did not use PB, and non- (EEG) changes in monkeys (common deployed veterans. There was no association in marmosets). The animals were trained to Gulf War veterans between exposure to PB and perform complex behavioral test sequences, in handgrip strength. order to assess the functional significance of any EEG changes that might be observed. One In a study that used tissue cultures, the objective previous study had suggested that the was to evaluate the effects of a single low dose administration of a single large dose of sarin to of PB and continuous exposure to low doses or rhesus monkeys caused subtle EEG changes high doses of PB on the neuromuscular junction several months following exposure, however the (the connection between nerve cells and muscle functional significance of such changes was cells). (Drake-Baumann and Seil, 1999) A unknown. (Burchfiel, et al, 1976) single dose of PB increased neuromuscular
24 activity. This short-term effect was readily The objective of this study was to determine if reversible by removal of the drug from the tissue there was an association between intake of culture solution. Electron microscopy revealed pyridostigmine bromide (PB) and post-war degeneration of the nerve terminals after a two- handgrip strength in Seabees who participated in week exposure to high doses of PB. These the Gulf War. (Kaiser, et al, 2000) In 1994-95, changes were reversible within seven days. The self-reported PB intake, self-reported exposures authors concluded that this reversibility of the to insecticides, and handgrip strength were PB-induced changes indicated that the temporary evaluated in 527 Gulf War veterans and 969 non- abnormalities were not related to the cause of deployed veterans. (Gray, et al, 1999a) An “the fatigue reported by veterans of the Persian objective handgrip strength measurement was Gulf War years after exposure to PB.” used to investigate the potential chronic effects of PB ingestion, by itself and in combination The effects of a single dose of PB or repeated with exposure to insecticides. administration of PB on the acquisition of a novel response (learning) were evaluated in rats. 24.5% of the Gulf War veterans and 6.7% of the (Van Haaren, et al, 1999) Single doses and non-deployed veterans reported unusual fatigue repeated doses of PB produced the same effects or generalized muscle weakness, for at least one on behavior. PB caused the delay of the onset of month since July 1990. Among Gulf War the learned response in some, but not all, of the veterans, 171 subjects reported the use of PB, test subjects. Response acquisition may have and 356 subjects reported no use of PB. No non- been affected by the effect of PB on motor deployed veterans reported the use of PB. Also, activity or the gastrointestinal functioning of the among Gulf War veterans, 495 subjects reported rats. Neither treatment regimen affected brain being exposed to insecticides. The subjects were acetylcholinesterase levels, which implies that stratified into three groups: Gulf War veterans PB did not cross the blood brain barrier. There who used PB, Gulf War veterans who did not use was no follow-up to determine if the behavioral PB, and non-deployed veterans. There was little changes due to PB were prolonged, which is difference in handgrip strength among these relevant to the possible effects on humans. three groups.
The effects of PB on locomotor and thigmotactic As expected, handgrip strength decreased activity of male and female rats were significantly in women or with increasing age. investigated. (Hoy, et al, 1999) Thigmotaxis There was no association in Gulf War veterans means the reaction of an animal to contact with a between handgrip strength and exposure to PB or solid body. In the case of rats, their thigmotactic exposure to insecticides. An advantage of this response is generally to stay close to walls and study was that handgrip strength has been shown other surfaces and not to walk across open areas. to be an easy and reliable instrument for PB caused a significant decrease in locomotion measuring muscle strength. A limitation of this rates, and a significant increase in thigmotaxis. study is the history of exposure to PB and Serum levels of PB were higher in female rats, insecticides relied on self-report four years after and female rats were more affected than male the war. rats at the same doses. There was no follow-up to determine if the behavioral changes due to PB 2. Drake-Baumann, R, and Seil, FJ. Effects of were prolonged, which is relevant to the possible exposure to low-dose pyridostigmine on effects on humans. neuromuscular junctions in vitro. Muscle and Nerve 1999; 22(6):696-703. (VA-6C) Pyridostigmine Bromide-Individual Studies: The objective of this study was to evaluate the effects of a single low dose of PB or continuous 1. Kaiser, KS, Hawksworth AW, and Gray GC. exposure to low doses or high doses of PB on the Pyridostigmine bromide intake during the neuromuscular junction (the connection between Persian Gulf War is not associated with handgrip nerve cells and muscle cells). The strength. Military Medicine 2000; 165(3):165- neuromuscular junctions (NMJ) were studied 168. (DoD-1) under controlled conditions using organotypic spinal cord-muscle cell cultures. These cell cultures develop structural and functional connections similar to tissue organization in an
25 intact animal. In previous animal experiments, approximately equivalent to the doses used large doses of PB had caused impaired during the Gulf War, adjusted for body weight. neuromuscular transmission, and pronounced Both the single dose and repeated doses of PB structural changes in the muscle cells of skeletal produced approximately 50% inhibition of serum muscle. cholinesterase activity.
In this study, PB was dissolved and incorporated Single doses and repeated doses of PB produced into the tissue culture solution or applied by the same effects on behavior. PB caused the microinjection. The low-dose concentration delay of the onset of the learned response in produced 30% to 60% inhibition of some, but not all, of the test subjects. There acetylcholinesterase. (This was similar to the were no behavioral differences between the dose of PB used during the Gulf War, which was single dose and repeated dose groups, indicating intended to produce about 30% inhibition.) The the cumulative effects of smaller doses of PB high-dose concentration used in this study was were similar to those of one much larger dose. ten times higher, a dose that would likely be lethal in intact animals. A single dose of PB Response acquisition may have been affected by increased neuromuscular activity. This short- the effect of PB on motor activity or the term effect was readily reversible by removal of gastrointestinal functioning of the rats. Neither the drug from the tissue culture solution. treatment regimen affected brain acetylcholinesterase levels, which implies that Continuous exposure to PB over one week to PB did not cross the blood brain barrier. There two weeks produced a progressive decrease in was no follow-up to determine if the behavioral the contractile activity of muscle fibers. Electron changes due to PB were prolonged, which is microscopy revealed no abnormalities of the relevant to the possible effects on humans. NMJ after one week of exposure. Degeneration of the nerve terminals was evident after a two- 4. Hoy, JB, Cody, BA, Karlix, JL, et al. week exposure to PB. These changes were Pyridostigmine bromide alters locomotion and reversible within seven days in cultures that had thigmotaxis of rats: gender effects. been exposed for two weeks to high-dose PB. Pharmacology, Biochemistry, and Behavior Intact NMJ and normal nerve terminals were 1999; 63(3):401-406. (DoD-37) present one week following PB withdrawal, and normal muscle fiber activity was observed. The The objective of this study was to determine the authors concluded that this reversibility of the effects of PB on locomotor and thigmotactic PB-induced changes indicated that the temporary activity of male and female Sprague-Dawley abnormalities were not related to the cause of rats. Thigmotaxis means the reaction of an “the fatigue reported by veterans of the Persian animal to contact with a solid body. In the case Gulf War years after exposure to PB.” of rats, their thigmotactic response is generally to stay close to walls and other surfaces and not to 3. Van Haaren, F, De Jongh, R, Hoy, JB, et al. walk across open areas. Rats were divided into The effects of acute and repeated pyridostigmine four groups that were given three different doses bromide administration on response acquisition of PB or distilled water. with immediate and delayed reinforcement. Pharmacology, Biochemistry, and Behavior Thirty minutes after being given PB, the rats 1999; 62(2):389-394. (DoD-37) were videorecorded for two hours in a one square meter open-field arena. The rats’ The objective of this study was to assess the activities were analyzed for the drug’s effect on effects of a single dose of PB or repeated speed. Also, the times that the rats were administration of PB on the acquisition of a observed moving through the central 50% of the novel response (learning) in rats. Male Sprague- arena were determined. PB caused a significant Dawley rats were placed in a situation in which decrease in locomotion rates, and a significant lever presses were followed by food pellet increase in thigmotaxis. These behavioral presentation, either immediately or after a 16 changes followed a dose response relationship in second resetting delay. There were three all groups of rats. The distribution of activity experimental groups: one single higher dose, within the one square meter arena favored the repeated lower doses over seven days, or marginal area in all subjects. distilled water. The repeated lower doses were
26 Serum levels of PB were higher in female rats. The results of these studies in mice and rats These observations suggest that liver metabolism cannot be directly extrapolated to humans or urinary excretion of PB may be modified by because of the extremely high doses that were hormonal status. Female rats were more affected generally lethal within minutes. than male rats at the same doses. In particular, PB caused little effect on locomotor rates in male Interactions of Exposures-Individual rats. There were no measurements of serum or Studies: brain cholinesterase levels; therefore, it is unknown whether PB crossed the blood brain 1. Telang, FW, Ding YS, Volkow, ND, et al. barrier. There was no follow-up to determine if Pyridostigmine, a carbamate acetylcholinesterase the behavioral changes due to PB were inhibitor and reactivator, is used prophylactically prolonged, which is relevant to the possible against chemical warfare agents. Nuclear effects on humans. Medicine and Biology 1999; 26(2):249-250. (Not funded by U.S. government) 7. Interactions of Exposures The objective of this study was to assess whether Overview: acute stress increases blood-brain barrier permeability in mice and enhances the entry of Two animal studies were published that focused radioactively labeled PB into the brain. A on interactions of exposures. The objective of previous study by Friedman had suggested that the first study was to assess whether acute stress PB could enter the brain of stressed animals. increases blood-brain barrier permeability in (Friedman, et al, 1996) Friedman demonstrated mice and enhances the entry of radioactively that in FVB/N mice subjected to forced labeled PB into the brain. (Telang, et al, 1999) swimming, the dose of PB required to produce Increased blood brain barrier permeability to PB 50% inhibition of brain acetylcholinesterase related to stress had been found in a previous (AChE) activity was only 1% of the dose of PB study in FVB/N mice. (Friedman, et al, 1996) required to produce 50% inhibition in non- In Telang’s study, radioactively labeled PB was stressed mice. injected into Swiss-Webster mice undergoing a forced stress swim protocol. No difference in Telang, et al, used the identical stress paradigm brain radioactivity could be documented between as Friedman. Radioactively labeled PB was stressed mice and controls. In fact, stressed mice injected into Swiss-Webster mice undergoing a exhibited a slightly lower brain radioactivity than forced stress swim protocol. The use of the controls. Failure to measure increased blood- radioactively labeled PB allowed the direct brain barrier permeability may have been related measurement of brain uptake of PB. This is in to differences in factors such as species, strain, contrast to the more indirect assessment using age, or dose of PB. The authors concluded that AChE inhibition. No difference in brain “The notion that stress increases the brain radioactivity could be documented between extraction of PB may need to be re-examined.” stressed mice and controls. In fact, stressed mice exhibited a slightly lower brain radioactivity than The objective of the second study was to controls. investigate the effects of administration of anticonvulsant drugs to mice, prior to the Failure to measure increased blood-brain barrier induction of seizures and lethality by PB and/or permeability may have been related to DEET. (Chaney, et al, 1999) Anticholinergic differences in factors such as species, strain, age, drugs were able to protect against seizures or dose of PB. For example, there is some induced by PB, but not seizures induced by experimental evidence that the FVB/N mouse DEET. One drug, which selectively acts on the strain may have an unusually permeable blood- cholinergic receptors in the peripheral nervous brain barrier. The authors stated that they plan to system (PNS), reduced PB induced seizures and use the FVB/N strain of mice in future studies. lethality, which suggests that the PNS had a role An alternative hypothesis is that stress alone may in the production of seizures. In an additional set alter the expression of AChE in the brain. The of experiments, the authors administered high authors concluded that “The notion that stress doses of PB to rats. PB did not enter the brain, increases the brain extraction of PB may need to even at levels that produced seizures and death. be re-examined.”
27 2. Chaney, LA, Rockhold, RW, Wineman, RW, and Hume, AS. Anticonvulsant-resistant seizures following pyridostigmine bromide (PB) and N,N-diethyl-m-toluamide (DEET). Toxicological Sciences 1999; 49(2):306-311. (Not funded by U.S. government)
The objective of this study was to investigate the effects of administration of anticonvulsant drugs to male ICR mice, prior to the induction of seizures and lethality by PB and/or DEET. A previous study showed that an interaction occurs when sublethal doses of PB and the insect repellant DEET are given together, resulting in seizures and lethality within minutes of drug administration. The anticonvulsant drugs selected for this experiment acted through different mechanisms to reduce seizures, for example, diazepam and phenobarbital. The role of the cholinergic system in the toxic interaction between PB and DEET was further investigated by evaluating the effects of three different anticholinergic drugs, including atropine sulfate.
None of the anticonvulsant drugs was able to reduce the incidence of seizures following treatment with PB, DEET, or PB plus DEET. The mechanisms are unclear by which PB or DEET induces seizures. PB appears to operate through a different mechanism to generate seizures than DEET, because anticholinergic drugs were able to protect against seizures induced by PB, but not seizures induced by DEET.
One drug, which selectively acts on the cholinergic receptors in the peripheral nervous system (PNS), reduced PB induced seizures and lethality, which suggests that the PNS had a role in the production of seizures. In an additional set of experiments, the authors administered high doses of PB to rats. There was no acetylcholinesterase inhibition in the brain, therefore PB did not enter the central nervous system, even at levels that produced seizures and death. The results of these studies in mice and rats cannot be directly extrapolated to humans because of the extremely high doses that were generally lethal within minutes.
28 III. RESEARCH FUNDING TRENDS Pyridostigmine bromide A. Overview Mortality experience Appendix A provides details of the Gulf War Veterans’ Research Database. It was last Interactions of exposures (chemical, updated during the second quarter of Fiscal Year environmental, biological, pharmacological, 2000 (through March 31, 2000). Research etc.) projects are grouped according to the Department that is responsible for the conduct or sponsorship Prevention of diseases (i.e., studies that will of the research. produce knowledge that could inform Each entry in the database includes: disease prevention strategies)
Project Title Treatment Responsible Federal Agency Diagnosis (i.e., studies that will improve the Study Location ability to diagnose previously unexplained conditions, or to better refine diagnoses with Project Start-up Date new tools) Project Completion Date (estimated if ongoing) Each project is assigned up to three focus areas as categorical descriptors. This allows Overall Objectives of Project accounting for projects that cover multiple focus Specific Aims of Project areas. For example, a project on the neurophysiological effects of exposure to sarin in Methods of Approach animals would have a focus on the brain and nervous system, and a focus on chemical Expected Products (Milestones) weapons. The number of focus areas (between Current Status/Results one and three) assigned to a project depends on the project itself. Publications Two descriptors can approximately categorize The other descriptor for each project is Research each research project. The first descriptor is a Type. The Federal Government defines series of research focus areas. The current Research as systematic study that is designed to areas of research focus are categorized as develop or contribute to generalizable follows: knowledge, and that is directed toward more complete scientific knowledge or understanding Prevalence and risk factors for symptoms of the subject. Each research project on Gulf and alterations in general health status War veterans’ illnesses uses a method of approach to test a specific research hypothesis. Brain and nervous system function Approaches range in type from mechanistic research, addressing potential biological Chemical weapons mechanisms of causation, to clinical and epidemiological research that attempt to determine illness prevalence and risk factors. Environmental toxicology (e.g. studies Although precise categorization of research types focused on specific environmental toxicants can be difficult because of overlapping such as pesticides, oil well fires, etc.) methodologies, research projects can be divided into the following general types: Reproductive health MECHANISTIC RESEARCH: Research into Depleted uranium underlying mechanisms of diseases and illnesses using in vitro and in vivo models. Leishmaniasis
Immune function
29 CLINICAL RESEARCH: Application of an by monitoring the peer-reviewed published intervention, such as in a controlled drug trial, or scientific literature, attending scientific meetings, use of methodologies such as case-control and even using newspaper reports and personal studies to define disease risk factors. accounts of researchers.
EPIDEMIOLOGY RESEARCH: Includes Regardless of the source of support for particular population-based studies focused on outcomes research projects, the Research Working Group such as mortality, symptoms, hospitalizations, will seek to ensure that all research, that has etc., using devices such as postal surveys, undergone rigorous external peer review and has telephone interviews, and medical records been published in peer reviewed scientific reviews. literature, will ultimately be used in formal assessments of the nature and causes of Gulf In addition to the research on Gulf War veterans’ War veterans’ illnesses. A number of projects illnesses, the RWG also tracks development that were not federally funded have been work. In general, development is the systematic reviewed in Section II. Research Results of this use of the knowledge or understanding gained Annual Report to Congress. from research directed toward the production of materials; devices; systems; or methods, The following sections provide a quantitative including design, development, and improvement overview of the current research portfolio on of prototypes and new processes. Within the Gulf War veterans’ illnesses and the evolution of context of Gulf War veterans’ illnesses, the the portfolio over time since 1994. Topics that RWG categorizes activities as development as are covered include overall research expenditures follows: from 1994-2000 (projected), and the types and areas of research in which the Federal DEVELOPMENT: An activity that satisfies the Government has invested. general definition of development described above, and is directed toward new biologically B. Research Funding based prevention, intervention, and treatment measures. All current Federal research projects directly related to Gulf War veterans’ illnesses are The Gulf War Veterans’ Illnesses Research sponsored by VA, DOD, or HHS. From 1994 Database catalogs only research and through FY’99, the Departments have sponsored development activities that either directly 192 distinct research projects on Gulf War involve Gulf War veterans, or have been initiated veterans’ illnesses. This does not include to answer specific questions about risk factors. research projects that recently have been selected A case of the latter is a research project using for funding but are currently in final contract animal models to determine health effects of negotiations. Nor does it account for anticipated low-level chemical warfare agents. The database projects arising from upcoming competition of does not account for the vast accumulated proposals submitted in response to new knowledge derived from the nation’s investment initiatives, such as the upcoming DoD Broad in biomedical research over the past 40 years. Agency Announcement (BAA) for 2000. The scope of the Federal research portfolio is broad. The Gulf War Veterans’ Research Database only Projects range in size from small pilot studies to contains research that is Federally sponsored. large-scale epidemiology studies and major This includes research conducted by Federal research center programs utilizing significant scientists, as well as that by non-federal scientists amounts of appropriated research funds. supported by Federal research funds through grants, contracts, and cooperative agreements.
It is not possible to accurately track research efforts that fall within the private sector or otherwise outside of the purview of the Federal Government. Notwithstanding, the Research Working Group attempts to stay abreast of all research relevant to Gulf War veterans’ illnesses. The Research Working Group accomplishes this
30 Table III-1. Funding for Research FY’94-99 in $Millions Department FY’94 FY’95 FY’96 FY’97 FY’98 FY’99 FY’94-99 FY’00 DoD $6.2 $11.0 $11.7 $28.9 $12.6 $22.3 $93.5 $16.2 VA $1.2 $2.3 $3.9 $2.8 $4.8 $9.0 $24.0 $11.9 HHS $0.0 $2.5 $1.6 $0.0 $1.6 $1.6 $7.4 $1.5 Total $7.4 $15.8 $17.2 $31.7 $19.0 $32.8 $124.9 $29.6
Table III-1. does not include funds to cover operational costs for administration, infrastructure, etc. For example, the VA research appropriation currently does not pay salaries of physicians who are both clinicians and investigators. In addition, Table III.1. does not include funding for activities performed by members of the Research Working Group (salaries, travel, etc.).
A table in Appendix A lists all of the research research activity (years before a project was and development projects and programs initiated, or years after a project was completed). supported now or in the past by the Federal Government. The appropriated funds centrally Table III-1 is a summary of research distributed to each program or project are shown expenditures by DoD, VA, and HHS between in the fiscal years that funds were obligated. FY’94 and FY’99, and a projection of funding into FY’00. Currently, the Federal Government Many extramural projects are multi-year efforts is projecting cumulative expenditures of $154.5 for which funds are obligated at the beginning of million for research from FY’94 through FY’00. the project period. An entry of $0 is placed in As of September 30, 1999, 60 projects were the fiscal year column for each project for years completed. As of March 31, 2000, an additional in which funds were not obligated, but the 23 projects were completed and 109 projects project was ongoing. Blank entries for a project were ongoing. Table III-2 is a year-by-year in any given fiscal year indicate a period of no account of completed projects and new projects.
Table III-2. Number of New and Completed Projects by Year
Fiscal Year New Completed 1992-1994 61 3 1995 21 8 1996 16 4 1997 35 10 1998 17 15 1999 29 22 2000 13 23*
* Includes all projects completed between 10/01/99 – 3/31/00 For those programs or centers with multiple projects, each project is counted as an individual project for accounting purposes.
31 Figure III-1. Number of research projects by research type from 1994-2000. Note: Figures for 2000 are projections and do not account for possible new project starts in 2000.
80 s
t 70 c e
j 60 o r 50 P
f
o 40
r
e 30 b 20 m u
N 10 0 1994 1995 1996 1997 1998 1999 2000 Fiscal Year
Clinical Research Epidemiology Research Development Mechanistic Research
C. Diversity of Research Approaches Figure III-2. Projects for each focus area are categorized, based on which of the focus areas The funds that have been invested in research on are listed as one of the three areas assigned to Gulf War veterans’ illnesses over the years have each project. The total number of projects by gone into a broad-based portfolio with respect to research focus areas is shown in Figure III-2 in research type and research focus area. Figure two ways. For each focus area, a black bar III-1 illustrates the number of projects of each represents the total number of projects for which research type for each year since FY’94. On that focus area is listed as being primary. A clear average, epidemiology and clinical research have bar represents the total number of projects for each comprised approximately one third of the which the focus area is listed as being secondary total number of projects. The remaining third or tertiary. Thus the total height of a bar has been divided between mechanistic research represents the total number of projects for which and development, with the larger share going to the focus area is listed as primary, secondary, or mechanistic research. In particular, the number tertiary. By showing the data this way the of clinical and mechanistic research projects has multiplicative effects of research investments are increased over time. demonstrated. For example, a project that examines the effects of Pyridostigmine Bromide The distribution of projects across different on the Brain and Nervous System is counted research focus areas is illustrated in under both of these focus areas.
32 Primary Secondary & Tertiary
80 70 s t 60 c e j
o 50 r P
f 40 o
r
e 30 b m
u 20 N 10 0 ) ) ) ) ) ) 5 ) ) ) ) ) ) ) ) 6 1 /0 6 /8 / /6 /0 /0 4 3 /5 2 /7 /2 1 5 /1 6 9 5 8 3 /1 /1 6 /3 9 9 / ( 4 1 ( ( ( 1 2 ( 4 ( 4 1 ( ( n (1 ( 1 4 t ( (1 U o is ty ( th ( n D is x ti s s li n l e S s o c n a a io B a th N W o T n io i rt t P e l tm / C n . u t n o n H a a in g v F c a e . e e a a n ra m M v ro /H r r i E e e h re p . T B D n t is P e p u In e m m L R y Im S Research Focus Areas
Figure III-2. Number of projects in each research focus area. Closed bars represent the number of projects with the focus area as primary; open bars represent the number of projects with the focus area being either secondary or tertiary. The first number within the parenthesis represents the number of projects with a primary research focus area. The second number represents the number of projects with a secondary or tertiary research focus area.
As can be seen in Figure III-2, the overall emphasis of research has been greatest in the focus areas of the Brain and Nervous System and in Symptoms and General Health. This reflects the focus of epidemiological efforts on the prevalence of symptoms and illnesses in Gulf War veterans, and the focus of clinical research efforts on risk factors for illnesses. The focus on the brain and nervous system is a result of both the dominance of health complaints in this area, and the fact that many of the potential exposures in the Gulf are neurotoxins.
The number of research projects in the various research focus areas has changed over time since 1994 as a reflection of the evolution of issues centered on Gulf War veterans’ illnesses. Of note is a relatively greater increase over the years of research on chemical interactions, chemical warfare agents and pyridostigmine bromide. These increases are an outgrowth of increased concern over the health risks posed to veterans by exposures to multiple toxic agents at low levels.
33 IV. NEW RESEARCH PROJECTS AND HHS, CDC, and academic centers of excellence INITIATIVES in neurology, with advice from the ALS Association. Procedures to identify ALS cases Besides new research findings appearing in the began in March 2000. published scientific literature, there have been several important events since last year’s Annual ALS is a fatal neurodegenerative disease that Report to Congress that deserve discussion. destroys the brain and spinal cord nerve cells that These include the awarding of new research control muscle movement. As the brain and projects and the development of new research spinal cord nerve cells die, muscles weaken and initiatives including solicitations for new shrink, and rapid, severe paralysis occurs. research proposals. In addition, this section Neither a cause nor a cure for ALS is known at provides an update of important this time. accomplishments in 1999 for key research projects and initiatives. Through nation-wide ascertainment, a comprehensive description of ALS cases will be Many of the new research projects and initiatives developed among Gulf War veterans and non- are responsive to recommendations from a deployed veterans. Possible etiologic factors variety of sources, including the Presidential will be evaluated, with particular focus on the Advisory Committee on Gulf War Veterans’ role of chemical or biologic factors in the Persian Illnesses (PAC, 1996a; PAC, 1996b; PAC, Gulf area of deployment. 1997); the Institute of Medicine Committee on the Health Consequences of Service During the Complete ascertainment and comprehensive Persian Gulf War (IOM, 1995; IOM, 1996); the evaluation of ALS cases will occur over a one- Senate Veterans’ Affairs Committee (SVAC, year period. The incidence of ALS will be 1998); and the RWG (PGVCB, 1995b; PGVCB, estimated among Gulf War and non-deployed 1996b). veterans. These incidence rates will be compared to each other and to those of non- IV.A. NEW RESEARCH PROJECTS veteran populations. Participants will receive a medical examination by a physician with expertise in diagnosing and treating ALS and Several research projects are described in this other related neurological diseases. section: Preliminary information on ALS cases was the epidemiology study of amyotrophic collected by clinicians at VA and DoD in 1999. lateral sclerosis (ALS); They identified 28 patients with possible ALS 21 new projects funded by the 1999 DoD among the 697,000 service members deployed to Broad Agency Announcements; the Gulf War. A review of these cases indicated two new Centers funded by the VA request no substantial increase in the rate of ALS among for proposals for Environmental Hazards Gulf War veterans. The prevalence of ALS in Research Centers; and the United States is estimated to be between 6 to the Millennium Cohort Study. 8 cases per 100,000 population.
IV.A.1. New Epidemiology Research on This study has significance for both the VA in its Amyotrophic Lateral Sclerosis (ALS) mission to provide health care for veterans, and for the larger society in understanding ALS. Recently, some concern has arisen regarding a From the VA perspective, this project will possible elevated occurrence of amyotrophic indicate whether Gulf War veterans are at lateral sclerosis (ALS) among veterans who elevated risk of ALS. If so, strategies can be served in the Gulf War, a relatively young designed for prompt, appropriate identification population. This epidemiologic investigation of and clinical management of ALS patients in this ALS among Gulf War veterans will define the population. From the broader perspective, a epidemiology of this neurological disease, to study of ALS in relatively young individuals determine if there is a higher than expected may provide knowledge regarding the incidence. This project is funded by DoD and epidemiology and etiology of this disease. VA (projects DoD-118 and VA-61). VA is leading this study, in collaboration with DoD,
34 IV.A.2. New Research Projects in the DoD Military Infectious Disease Research Funded by the 1999 DoD Broad Program (DoD-95). Agency Announcements In coordination with the RWG, DoD developed a new research initiative for Fiscal Year 1999. In 1998, DoD established new funding for Under this initiative, DoD solicited new research programmed research. The purpose of this proposals for studies consistent with current program element funding is to address Gulf War concepts of Force Health Protection. There Illnesses issues, which may also be of concern in were five Broad Agency Announcements future deployments. These include issues (BAAs) with deadlines ranging from March 10 identified in both the research plans of the to May 5, 1999. PGVCB and the Presidential Review Directive 5. (PGVCB, 1995a; PGVCB, 1996a; NSTC, 1998) The specific requests focused on the following This planned funding is approximately $20 five areas of research interest: million per year for Fiscal Year 1999 through Fiscal Year 2002, and $5 million per year 1. Force health protection-deployment health thereafter. This funding makes it possible to organize multi-year research and it improves the The purpose of this research is to improve ability to respond to new research needs based medical prevention and intervention strategies to on discoveries in the currently funded programs. protect service members against health risks in The program is guided by a tri-service DoD future deployments. The force health protection panel and coordinated with the Research concept includes an array of preventive, Working Group. surveillance, and clinical measures needed to ensure the health and safety of service members The overall objective of this effort is to enhance against the many threats present in the modern force health protection in future deployments, military environment. Studies should represent through research specifically targeted to solving unique epidemiologically based research on the problems that emerged from service in the Gulf effectiveness of health assessments and risk War. Specific research solicitations will be used factors in future deployments. to develop focused research efforts in several of these areas. Specific research areas include: 2. Multidisciplinary studies of fibromyalgia, chronic fatigue syndrome, and multiple chemical 1. prevention and treatment of persistent stress sensitivity symptoms, 2. methods to assess health hazards from toxic The focus of this research is on multidisciplinary chemicals and mixtures and to monitor studies of fibromyalgia, chronic fatigue exposures, syndrome, and multiple chemical sensitivity and 3. improved safety assessments of medical the use of research methods of cognitive and materiel, including potential interactions in computational neuroscience. operational environments, 4. epidemiological studies to continue long- 3. Integrated psychosocial and neuroscience term follow-up of Gulf War veterans and to research on stress and somatic consequences improve health status monitoring in future deployments, and These studies are intended to predict, prevent, 5. improved and accelerated research on and treat somatic consequences of psychological prevention, diagnosis, and treatment of stress relevant to chronic undiagnosed symptoms microbial infections. reported by many Gulf War veterans. This research is intended to advance the One of the most important initiatives is the understanding of personal and environmental expansion of efforts of the Naval Health factors that contribute to a service member's Research Center in San Diego as the DoD Center health and perception of wellbeing during and for Deployment Health Research (project DoD- after military deployment. Studies must clearly 96). Science and technology efforts will also represent multidisciplinary research, accelerate in the development of diagnostics, incorporating major contributions from both new medications, and a vaccine for leishmaniasis psychosocial and physiological/neuroscience research disciplines.
35 4. Innovative biologically-based toxicological members in previously untested and militarily methods and models for assessing mixed unique combinations and conditions. Examples chemical exposures of studies include: effectiveness of vaccines administered during periods of high stress; Studies of these toxicological methods and adverse effects of combinations of drugs and models will lead to the development of simple vaccines that might typically be provided to and effective methods to assess exposures of service members; stress-induced alterations in deployed military personnel to toxic chemicals brain access of drugs and biologics; and chemical mixtures, including those environmentally-induced alterations in drug chemicals and mixtures which were a concern toxicity and immune responses; and prospective during the Gulf War. Examples of research studies of troops receiving anthrax and goals include: (1) to identify biomarkers and/or botulinum vaccines. behavioral indicators of exposure, effect, and susceptibility for classes of toxic chemicals A total of 81 proposals were submitted in which were of concern after the Gulf War; and response to these 5 BAAs. These proposals were (2) to develop mechanistically-based alternative scientifically peer-reviewed by the American methods and models for rapid assessment of Institute of Biological Sciences. Highly human exposures to toxic industrial and meritorious proposals were chosen for funding agricultural chemicals and chemical mixtures. by the DoD program review and then were The biomarkers identified through this research referred to the Research Working Group for will be used for biomonitoring of service secondary review based on interagency members and incorporated into epidemiologic programmatic relevance. This review process is surveillance and risk assessment systems. detailed in Section VI. Research Management.
5. Interactions of drugs, biologics, and As a result of this review process, 21 new DoD chemicals in service members in deployment funded projects were initiated in FY-99 (DoD-94 environments to DoD-114), at a total cost of $16.7 million. There were 7 projects related to Force Health These novel studies focus on interactions of Protection, 2 projects related to Multidisciplinary current or anticipated military medical products Studies, 5 projects related to Psychosocial with other drugs, biologics, and chemicals, and Research, 2 projects related to Toxicological in the context of military operational stressors Methods, and 5 projects related to Interactions. (e.g., psychological stress, thermal load, high intensity or prolonged work). This research is Table IV-1. lists each of these new projects, intended to expand on current efforts to ensure providing brief summaries of the research safety and efficacy of current or anticipated approaches. medical products, which may be used by service
36 Table IV-1 New Projects for FY 1999/2000 Funded by the DoD Broad Agency Announcements Project # Title Principal Institution Total Budget Est. Comp. Date Summary Investigator
DoD-94 Combined Analysis of the VA Kenneth C. VA Medical Center $1,524,796 01/09/02 This research project combines (merges) two specific clinical data registries and DoD Gulf War Clinical Hyams, M.D., Washington, DC on Gulf War Veterans to statistically analyze the results. The two registries, Registries: A Study of Clinical M.P.H. and The Department of Defense's Comprehensive Clinical Evaluation Program Findings from Systematic Han K. Kang, (CCEP) and the Veterans Administration (VA) Gulf War Health Examination Medical Examinations of M.D. Registry, should provide insights into reported and diagnosed medical 100,000 U.S. Gulf War conditions on over 100,000 Gulf War Veterans. Veterans. DoD-95 Development of Diagnostic Rodney Army Medical $3,000,000 12/31/02 The overall project objective is to develop effective epidemiological and Tools and Alternative Michael, COL Research and Material clinical tools and measures for managing Leishmania exposure and infection Treatment Drugs for Command, Ft. Detrick, in deployed military forces. This project should: 1) develop diagnostic tools Leishmania. MD that are useful for screening military populations potentially exposed to the Leishmania parasite in regions where it is endemic; 2) develop diagnostic tools that are useful for diagnosing Leishmania infection in symptomatic military personnel; and 3) identify an alternative drug for treatment of military personnel with cutaneous leishmaniasis. DoD-96 Deployment Health Center. Gregory Naval Health Research $3,000,000 Ongoing The Center’s mission includes conducting epidemiological studies to Gray, M.D., Center, San Diego, CA investigate the longitudinal health experience of previously deployed military M.P.H. personnel, and the development and evaluation of appropriate health surveillance strategies. Center research includes studies of symptoms, hospitalizations, reproductive outcomes, mortality, and other health outcomes among DoD beneficiary populations, both military and civilian. These studies involve investigations of personnel who remain on active duty and personnel who have left military service. DoD-97 Surveillance of B. Pertussis Gregory Naval Health Research $324,042 09/30/02 The goal of this study is the development and standardization of a highly among Military Trainees with Gray, M.D., Center, San Diego, CA sensitive and reliable detection method for effective surveillance of B. Respiratory Disease: M.P.H. Pertussis infection among military trainees with respiratory disease. Another Development and Validation of objective is to determine whether or not B. Pertussis infection is one of the a Highly Sensitive PCR and major causes of respiratory disease-related morbidity among military recruits. Beacon Probe based Method The surveillance data obtained might help; in the decision whether to use for Diagnosis of Pertussis. acellular pertussis vaccination as a preventive measure in the military recruits. DoD-98 Investigation of a Baseline Kenneth C. Naval Medical $332,500 09/30/00 The aim of this investigation will be to evaluate the Recruit Assessment Medical Database to Evaluate Hyams, M.D., Research Center, Program (RAP). The RAP will be a DoD program for the routine collection of the Health of Military Forces M.P.H. Rockville, MD baseline demographic, medical, psychological, occupational, and risk factor and Veterans. data from all U.S. military personnel at accession. This information will be maintained in a computerized database. This database will be used: 1) to assist in clinical diagnosis; 2) in the development of preventive health measures by identifying at-risk populations; 3) to evaluate health problems after hazardous overseas assignments by providing pre-deployment health data; and, 4) to help answer fundamental medical questions. DoD-99 DoD-wide Medical Surveillance Gregory Naval Health Research $412,081 09/30/03 The goal of this study is to establish DoD-wide surveillance of hospitalization for Potential Long-Term Gray, M.D., Center, San Diego, CA discharge diagnoses, and link these to data on anthrax immunizations, to help Adverse Events Associated M.P.H. ensure the earliest possible detection of any associations between anthrax with Anthrax Immunization in immunization and a severe disease requiring hospitalization. The surveillance Active Duty Service Members, would help enhance force health protection by helping assure the early Proposal I: Hospitalizations. detection of any as-yet-unknown potential long-term consequences of anthrax immunization.
37 Table IV-1 New Projects for FY 1999/2000 Funded by the DoD Broad Agency Announcements Project # Title Principal Institution Total Budget Est. Comp. Date Summary Investigator
DoD-100 Antibodies to Squalene. Carl Alving, Walter Reed Army $582,756 2000 This project is examining the possibility that antibodies to squalene arise in M.D. Institute for Research, humans following its use as an adjuvant in modern vaccines. Its goal is to Forest Glen, MD provide an appropriate scientific basis for understanding the immunology of squalene and to provide important new information on the biological implications of such antibodies. It aims to answer the question of whether or not antibodies to squalene actually exist and if so if there is a linkage to Gulf War Illnesses. DoD-101 Mechanisms in Chronic Daniel J. Georgetown University, $8,461,408 08/31/01 This project is a comprehensive, multi-disciplinary effort to study the Multisymptom Illnesses. Clauw, M.D. Washington, D.C. mechanisms of Chronic Multi-symptom Illnesses (CMI) such as Gulf War Illnesses (GWI), Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS), and Multiple Chemical Sensitivity (MCS) using cognitive and computational sciences. Its primary goal will be to determine the mechanism(s) responsible for expression of the three most prominent symptoms of these conditions: pain, fatigue, and memory difficulties. DoD-102 Case-control Study of Fatal Gary D. The Henry M. Jackson $503,995 02/01/02 This project involves studying fatal motor vehicle crashes and their Motor Vehicle Crashes Among Gackstetter, Foundation for the antecedents in a large population of current and former military personnel. It Gulf War and Non-deployed Ph.D., M.P.H. Advancement of will test the hypothesis neurologic impairment from exposure to neurotoxic Veterans. Military Medicine, chemicals is a plausible explanation for the significantly higher death rate Rockville, MD caused by motor vehicles experienced by Gulf war veterans compared to other non-deployed veterans. DoD-103 Human Metabolism & Ernest North Carolina State $686,332 01/17/03 This study will address a number of important questions concerning the role Interactions of Deployment- Hodgson, University, Raleigh, NC of metabolism with a number of warfare agents. It will examine biochemical related Chemicals. M.D. metabolism and interactions of xenobiotic toxins important in military deployments as inducers, substrates and/or inhibitors of human enzymes including the important isoforms of these enzymes. This should permit easier extrapolation of past and future animal studies to humans and permit identification of interactions not apparent from animal studies. It may also permit identification of human subpopulations at greater risk from specific xenobiotic toxins and will produce specific analytic methodologies for assessment of future exposures. DoD-104 Clinical Evaluation of a Paul Levine, The George $999,998 02/23/02 This study is designed to test the integrity of the Gulf War (GW) syndrome as Proposed New Gulf War Ph.D. Washington University, a unique disease among GW veterans that is distinct from posttraumatic Syndrome. Washington, DC stress disorder (PTSD) and is associated with exposure to environmental and psychological stressors. Its main objective is to attempt to confirm that a cluster of four symptoms (blurred vision, tremors, speech difficulty, and ataxia/dizziness) constitutes a unique neurologic syndrome associated with adverse health affects resulting from deployment in the Gulf War. It is based on a previous factor analytic study of the population under scrutiny. DoD-105 Neuroplasiticity and Calcium He Li, Ph.D. The Henry M. Jackson $1,900,980 03/1/04 Using intracellular recording and calcium imaging techniques, this study will Signaling in Stressed Rat Foundation for the focus on the roles of norepinephrine (NE) and serotonin (5-HT2) receptors on Amygdala. Advancement of activity-dependent neuroplasticity and calcium signaling in amygdala slice Military Medicine, preparations from traumatically stressed and control rats. Rockville, MD If the study is successful in determining that NE and 5-HT modulate alterations of the amygdala specific to traumatic stress, the information may prove useful in developing therapeutic strategies for the treatment of post traumatic stress disorder (PTSD). DoD-106 The Role of Th1/Th2 Cytokine Mark Guy’s, King’s and St. $584,822 02/28/02 The goal of this epidemiological study is to extend the findings of preliminary Balance in Gulf War-related Peakman, Thomas’ School of studies regarding case control analysis of sick Gulf War veterans and their illness. Ph.D. Medicine, London, U.K. controls. Specifically this study will measure whether or not multiple
38 Table IV-1 New Projects for FY 1999/2000 Funded by the DoD Broad Agency Announcements Project # Title Principal Institution Total Budget Est. Comp. Date Summary Investigator
vaccinations against biological agents promote a shift in the host immune system from a T helper 1 (Th1) towards a T helper 2 (Th2)-dominated cellular response, resulting in chronic fatigue-like illnesses. Successful completion will provide information on interactions of immune function, vaccination history, stress, and GW illness. DoD-107 Stress, Organophosphates and Carey Pope, Oklahoma State $886,198 02/16/04 The goal of this study will be to evaluate the effects of different physical Blood Brain Barrier Integrity. Ph.D. University, Stillwater, stressors on Blood Brain Barrier (BBB) permeability and the entry of OK pyridostigmine into the Central Nervous System to examine the generality of stress-induced BBB changes. The organophosphate paraoxon (OP), will be used as a chemical stressor. It is hypothesized that some OP agents may alter BBB permeability at relatively low levels of exposure and that combined physical/chemical stress will amplify BBB changes and neurotoxicity of agents such as pyridostigmine. Furthermore, the combined simultaneous actions of different stressors will be evaluated to determine if synergistic alterations in BBB are possible leading to more extensive entry and neurotoxicity of drugs such as pyridostigmine. DoD-108 Health Status of Current Susan P. Boston University $498,166 02/23/03 This cross-sectional epidemiology study involving a mail survey to all current National Guard Members. Proctor. School of Public Massachusetts Army National Guard members and those who have left the D.Sc. Health, Boston, MA Army NG within the past 3 years will: describe the current health status of a specific National Guard (NG) population using methods that permit comparison with other populations; examine the effect of job strain of NG service on service members health and civilian job outcomes; and determine whether there is a correlation between attrition from the NG and health status. Successful completion of the protocol will establish a defined cohort of Army NG members useful for longitudinal health status studies and as background for policy decisions in designing strategies to improve the health of NG members. DoD-109 Disordered Responses to Peter C. Johns Hopkins $1,052,821 03/14/02 The aim of this matched case control study is to determine if Gulf War Orthostatic Stress in the Rowe University, Baltimore, Illnesses are related to orthostatic intolerance (OI). Three major research pathogenesis of Gulf War MD objectives of this study relating Gulf War Illnesses with OI are the following: Syndrome Symptoms. To compare orthostatic intolerance (OI) in those with and without Gulf War Illnesses. To assess the genetic susceptibility to neurally mediated hypotension (NMH) by a family study. To examine the association of OI with specific Gulf War exposures after adjusting for family history. Because OI can be treated, the finding of an increased prevalence of neurally mediated hypotension and orthostatic tachycardia in those with GWS would establish a new rationale for subsequent treatment trials. incidence of long- term morbidity following future military conflicts. D0D-110 Predictors of Career and Margaret A.K. Naval Health Research $127,920 09/30/01 This retrospective cohort study describes potential predictors of career and Family Dysfunction in Young Ryan, M.D. Center, San Diego, CA family dysfunction in U.S. Navy enlistees by linkage of the Sailor’s Health Adults Enlisting in the United Inventory Program (SHIP) and databases (Family Advocacy Program States Navy. database and Career History Archival Medical and Personnel Systems database) containing adverse career and family events. Successful completion of the study will determine the predictive value of
39 Table IV-1 New Projects for FY 1999/2000 Funded by the DoD Broad Agency Announcements Project # Title Principal Institution Total Budget Est. Comp. Date Summary Investigator
existing questions on the recruit accession survey and serve as a means of validating screening questions of DoD accession survey programs by linking screening questions to militarily important outcomes. DoD-111 Autonomic Dysfunction in Gulf Antonio Midwest Research $999,481 06/30/03 The goal of this matched case control study will be to attempt to confirm the War Veterans Sastre, Ph.D. Institute, Kansas City, hypothesis that autonomic dysfunction in the cholinergic metabolic pathways Missouri (developmentally or genetically based) is correlated with Gulf War Illnesses. More specifically, it will test the hypotheses that individuals who are autonomically hyperresponsive are more prone to GWI when exposed to physiological and psychological combat stress; and that alteration in the central and peripheral acetylcholine transmitter neural pathways is an underlying factor in the autonomic dysfunction. DoD-112 Role of Respirable Saudi Mohan L. Lovelace Biomedical $256,916 03/10/02 The goals of this of this animal immunologic study are: Arabian Sand and Sopori and Environmental to determine whether inhalation of Saudi Arabian desert sand, in the Pyridostigmine in the Gulf War Research Institute presence or absence of pyridostigmine bromide (PB), will induce/accelerate Syndrome: An Autoimmune autoimmune adjuvant-like disease (AAD), and evaluate the role of “alarm Adjuvant Disease? cytokines” in the development and prevention of this disease. These studies should help to determine the immunotoxicity of the Saudi Arabian sand and its relationship to the development of Gulf War Illnesses, and suggest potential measures for prevention and treatment. DoD-113 Interactions of Subsymptomatic Oscar U. Brentwood Biomedical $913,140 03/13/04 The goal of this study is to examine the ability of low level, repeated exposure Doses of Sarin with Scremin, Research Institute, Los to sarin, alone and in combination with pyridostigmine bromide (PB) to cause Pyridostigmine: M.D., Ph.D. Angeles, CA alterations of the following parameters in an animal model: cholinergic Neurochemical, Behavioral, neurochemistry; behavior; sensory, motor and cerebral cortex function; and and Physiological Effects brain activity as indicated by cerebral blood flow and metabolism. The results of this study should provide information on effects of sublethal sarin exposure coupled with pyridostigmine exposure. DoD-114 A Re-Examination of Roberta Boston University, $593,712 02/23/03 The goals of the study are: Neuropsychological White, M.D. Boston, MA to determine if there is a progressive cognitive decline, within specific Functioning in Persian Gulf domains, in GW deployed veterans; War Veterans to determine any factors correlated with any identified decline. Successful completion of the study will provide information as to whether the veteran population defined in a previous study is suffering a worsening of neuropsychological/cognitive symptoms.
40 IV.A.3. Two New Research Centers review. Two new Centers were funded on April Funded by the 1999 VA Request for 1, 2000 (VA-64 and VA-65). Each Center is Proposals for Environmental Hazard funded for up to 5 years, for a maximum of $1.6 Research Centers million. The objectives of these two new Centers and their pilot projects are summarized here. (See Appendix A-3 for further details on VA recognizes the importance of basic science each of these projects.) and clinical research studies of environmental hazards, particularly studies relating to potential Boston Environmental Hazards Research Center exposures of military personnel or past (VA-64) exposures to chemical and biological hazards by veterans during active military duty. VA funded Overall goal of Center: The Boston EHRC was four Environmental Hazard Research Centers originally funded in 1994 as one of four Centers, (EHRCs) from 1994 to 1999 (Projects VA-4, whose mission was to pursue basic and clinical VA-5, VA-6, and VA-47). The focus of these research in the field of environmental and projects was primarily on the health effects of occupational health. The Boston Center has environmental exposures during the Gulf War. received new funding in 2000 to continue their environmental research program. Specifically, On June 24, 1999, VA issued a Request for the Center will focus on the field of behavioral Proposals to establish new EHRCs. These new neurotoxicology. The Center will emphasize the Centers were intended to have a broader mission application of environmental health, that included environmental exposures that may neuroscience, and neurocognitive methodologies have occurred during active military duty, to issues in the field of behavioral toxicology. without specific reference to the Gulf War or The Center Director is Dr. Roberta White. Vietnam War. These Centers were intended to support groups of VA investigators, who focused VA-64A: Functional Neuroimaging in Lead on areas of environmental exposures through Exposed Adults basic, translational, and/or clinical approaches. The deadline for submission of proposals was The objectives of this pilot project are: October 1, 1999. to develop a methodology for examining The primary focus of a Center could include neurological and neuropsychological effects organ systems that are targets of environmental of lead exposure; and exposures (e.g., central nervous system or liver); to assess the value and validity of using or specific classes of environmental hazards Magnetic Resonance Spectroscopy to (e.g., pesticides or solvents). Within these focus establish the functional and regional patterns areas, specific issues that could be addressed of lead-induced neurotoxic damage in the included: brain.
1. effects of these specific classes of VA-64B: Quantification and Validation of environmental hazards (e.g., carcinogenesis Structure-Function Relationships through or neurobehavioral alteration); Visuospatial Test Performance 2. mechanisms related to the development of health effects of environmental exposures to This pilot project will begin the validation of specific classes of hazards (e.g., genetic neuropsychological tests to be used in the susceptibility, or interactions of multiple assessment of visuospatial function in persons exposures); or who have been exposed to neurotoxicants. The 3. prevention of either the environmental objectives are: exposure or the health effects of exposure. to validate the sensitivity of standard Proposals for Centers were required to support visuospatial tests in neurology patients with training of new investigators, and two to four well-defined focal damage to specific areas pilot research projects. The proposals could also of the brain (Parkinson’s disease, multiple include a request for support of core laboratories sclerosis, parietal/occipital strokes, and and some administrative needs. In December cerebellar atrophy); 1999, the proposals underwent external scientific to explore the sensitivity of these tests to the localization of focal brain damage as
41 confirmed on magnetic resonance imaging to oxidative stress, than are mice that (MRI) in patients with well-defined toxicant express the other human variant. exposures; and to determine correlations in performance VA-65B: The Contribution of Fen-1 to Genetic among the visuospatial tests in each of the Integrity Subsequent to Oxidative Stress subject groups. Oxidizing agents cause a variety of DNA lesions VA-64C: Development of a Structured that result in cell dysfunction, and all animals Neurotoxicant Assessment Checklist for Clinical have evolved with multiple DNA repair Use in Veteran Populations mechanisms that restore the integrity of oxidized DNA. Flap endonuclease-1 (Fen-1) is an This pilot project focuses on the development of enzyme that may have a central role in a standardized questionnaire with established counteracting oxidative DNA damage. The validity, which can be used systematically to objectives of this pilot project are: estimate a patient’s past and current exposures to neurotoxicants. The objectives are: to develop a strain of mice that are deficient in Fen-l; and to design a structured neurotoxicant to determine if mice deficient in Fen-1 will assessment checklist (SNAC); demonstrate increased severity of cellular to validate the SNAC in study groups in dysfunction, when exposed to oxidative whom the levels of neurotoxicant exposure stressors. have been quantified; and administer the SNAC to local VA inpatients VA-65C: The Importance of Hydrogen Peroxide and outpatients. Detoxification in Cellular Protection
San Antonio Environmental Hazards Research Cells have evolved efficient mechanisms to Center (VA-65) detoxify hydrogen peroxide, which is accomplished primarily by two antioxidant Overall goal of Center: The San Antonio EHRC enzymes, catalase and glutathione peroxidase. is a new Center funded in 2000. Its overall goal This pilot project will determine the role of is to develop transgenic/knockout mouse models hydrogen peroxide detoxification in the that may be used to identify genetic deficiencies generation of oxidative damage, in response to that increase sensitivity to environmental hazards environmental exposure to gamma radiation and that cause oxidative damage. The work of this paraquat. The objectives of this pilot project are: Center will build upon their previous work, to determine if mice with increased catalase which focused on the role of oxidative damage, activity will be more resistant to oxidative and on the roles that individual genetic variations damage to lipids, proteins, and DNA; and play in the responses to injury from exposures. to determine if mice with reduced catalase The Center Director is Dr. Arlan Richardson. activity will show increased sensitivity to this oxidative damage. VA-65A: Does a Variant of the Human SOD2 Gene Increase Sensitivity to Environmental VA-65D: Do Defective Gpx1 and Aldh2 Genes Hazards? Increase Sensitivity to Environmental Hazards?
The first lines of defense against the deleterious The structural lipids of the biological membrane effects of reactive oxygen species in humans are are vulnerable to peroxidation when exposed to enzymes called superoxide dismutases (SOD). certain metals, radiation, and certain highly These enzymes scavenge superoxide anions and reactive chemicals, including hydrogen peroxide. convert them to hydrogen peroxide. The The principal enzyme that prevents damage from objectives of this pilot project are: hydrogen peroxide to mitochondrial lipids is glutathione peroxidase (Gpx). The enzyme to develop two strains of mice that can aldehyde dehydrogenase (Aldh) may also play a express two different variants of the human protective role by removing products of lipid SOD2 gene; and peroxidation. The objectives of this pilot project to determine if mice that express one variant are: of the human SOD2 gene are more sensitive
42 to use a strain of mice that are deficient in The principal objective of the study is to evaluate the enzyme Gpx, to test if this increases the impact of military deployments on various sensitivity to long-term, low-level exposures measures of health over time, including to paraquat and ionizing radiation; and medically unexplained symptoms and chronic to develop a strain of mice that are deficient diseases such as cancer, heart disease, and in the enzyme Aldh, to test if this increases diabetes. The Millennium Cohort Study will vulnerability to environmental exposures to serve as a foundation upon which other routine paraquat and ionizing radiation. medical and deployment data, such as DoD and VA hospitalization data, may be added to answer IV.A.4. Millennium Cohort Study future questions regarding the health risks of military deployment, military occupations, and In a report to the Committee on National general military service. Security of the House of Representatives and the Armed Services Committee of the U.S. Senate, The principal investigators of the study are Dr. entitled Effectiveness of Medical Research Greg Gray and Dr. Ed Boyko, for DoD and VA, Initiatives Regarding Gulf War Illnesses, DoD respectively. DoD investigators include identified the need for a coordinated capability to scientists from the Army, Navy, and Air Force. apply epidemiological research to determine The Scientific Steering and Advisory Committee whether deployment-related exposures are includes five distinguished external scientists and associated with post-deployment health three representatives of the largest veterans outcomes. The Millennium Cohort Study, a service organizations. DoD and VA scientists prospective study of U.S. military forces, held several planning meetings in late 1999 and responds to the need to systematically collect early 2000 to develop the study design. population-based demographic and health data to evaluate the health of service personnel DUSD(S&T)/Biosystems has provided initial throughout their military careers and after funding in 2000. Continued funding is leaving military service. programmed from the DoD Program Element for Force Health Protection and Deployment Health This prospective study and its study design were Research. recommended in an Institute of Medicine report, Gulf War Veterans: Measuring Health (1999). IV.B. NEW RESEARCH INITIATIVES This report is described in detail in Section IV.C.4. Additionally, a National Academy of New research initiatives are described in this Sciences report, Strategies to Protect the Health section: of Deployed U.S. Forces (2000), recommends that the Millennium Cohort Study be planned to the 2000 DoD Broad Agency evaluate multidimensional factors relevant to Announcements for new research projects; health, so that these factors can be assessed over and the lifetime of the service member. This report is one ongoing Institute of Medicine project. described in detail in Section IV.C.6. IV.B.1. DoD Broad Agency The Millennium Cohort study is a probability- Announcement Solicitations for New based, cross-sectional sample of 100,000 U.S. Research in 2000 military personnel that will be followed prospectively by postal surveys every 3 years In 1998, DoD established new funding for over a 21-year period, starting in late 2000. The programmed research. The purpose of this 100,000 persons will be comprised of 30,000 program element funding is to address Gulf War veterans who have been recently deployed to Illnesses issues, which may also be of concern in Southwest Asia, Bosnia, or Kosovo, and 70,000 future deployments. These include issues veterans who have not been deployed to these identified in both the research plans of the conflicts. In October 2004 and October 2007, PGVCB and the Presidential Review Directive 5. 20,000 new military personnel will be added to (PGVCB, 1995a; PGVCB, 1996a; NSTC, 1998) the cohort. The total of 140,000 veterans will be This planned funding is approximately $20 followed until the year 2022. million per year for Fiscal Year 1999 through Fiscal Year 2002, and $5 million per year
43 thereafter. This funding makes it possible to subjective/questionnaire assessments). Studies organize multi-year research and improves the are specifically sought in four topic areas: ability to respond to new research needs based on discoveries in the currently funded programs. a. psychological health status, including The program is guided by a tri-service DoD establishment of mental health baselines of panel and coordinated with the Research military populations; Working Group. b. practical methods for large-scale studies to assess changes in male and female The overall objective of this effort is to enhance reproductive fertility; force health protection in future deployments, c. clinical illness associated with high frequency through research specifically targeted to solving of deployments or perceived stress of problems that emerged from service in the Gulf deployments; and War. Specific research areas include: d. coping strategies used by military personnel to alleviate symptoms associated with Gulf 1. prevention and treatment of persistent stress War deployment (e.g., alcohol or symptoms, complementary and alternative medicine). 2. methods to assess health hazards from toxic chemicals and mixtures and to monitor 2. Deployment Stress Health and Performance exposures, Consequences 3. improved safety assessments of medical materiel, including potential interactions in These studies focus on the effects of operational environments, psychological stress on cognitive and 4. epidemiological studies to continue long- physiological consequences. Studies should term follow-up of Gulf War veterans and to quantify the association between clinical health improve health status monitoring in future outcomes or militarily-relevant performance deployments, and measures and various types of stress, which 5. improved and accelerated research on might be typically encountered in military field leishmaniasis prevention, diagnosis, and deployments (e.g., isolation, family separation, treatment. anxiety, inadequate sleep). The studies should explore biological stress measures, which may be In coordination with the RWG, DoD developed a useful predictors of health and performance new research initiative for Fiscal Year 2000. decrements. Under this initiative, DoD solicited new research proposals for studies consistent with current 3. Biochemical and Physiological Markers to concepts of Force Health Protection. There were Assess Toxic Chemical Exposures and Health four Broad Agency Announcements (BAAs), Effects in Deployed Military Personnel each with a deadline of July 26, 2000. These studies focus on applied physiologically The specific requests focused on the following based methods and techniques for assessment of four areas of research interest: toxic chemical exposures in deployed military personnel. The research should improve current 1. Epidemiological Investigations of methods and techniques or identify and develop Deployment Health Monitoring Methods new, readily applied, methods and techniques. Specifically, studies must identify and develop The purpose of these epidemiological studies is biological markers of exposure that enhance to fill critical knowledge gaps for monitoring environmental monitoring or provide markers of soldier health during deployments. Threats to effects related to exposures of individual service health during deployments might include members. Methods and techniques should be psychological stress, toxic chemical exposures, applicable to risk assessment or health environmental stressors, and infectious agents. surveillance of toxic chemicals and chemical Physiologically based methods to assess health mixtures that are a concern in military consequences of a deployment are the focus, deployments. Specific chemicals of interest through a demonstrated change in health. include petrochemical products (including JP8 Projects are required to have a strong biological fuel), insecticides, insect repellents, and basis (i.e., objective measurements instead of Chemical Agent Resistant Coating (CARC).
44 4. Toxicity of Militarily Relevant Heavy Metals 1. Identify and describe approaches for assessing treatment effectiveness. These studies focus on biological effects of 2. Identify illnesses and conditions common heavy metals currently used or contemplated for among Gulf War veterans, including use in armor and as armor penetrators. These medically unexplained symptoms, using data include tungsten and tungsten alloys, depleted obtained from the VA and DoD Gulf War uranium, depleted uranium and titanium alloys, registries, as well as information in and oxidation products of these metals and their published articles. alloys. Inclusion of positive (e.g. lead) and 3. Identify validated models of treatment for negative (e.g. tantalum) controls should be these identified conditions and illnesses. considered in study designs. Outcomes of The sources for these models include special interest include identification of published literature, clinical practice mechanisms of injury to pulmonary, hepatic, guidelines developed by medical specialty renal, and nervous systems from particulate and societies, and other sources as appropriate. solubilized forms; and localized soft tissue responses produced by embedded fragments The committee’s charge is not to examine (distinguishing foreign body, radiation, exposures or causes of health problems, but to toxicological, and acute phase responses). identify effective treatments for health problems Exposures should be based on realistic scenarios, that exist. and should consider current pharmacokinetic and pharmacodynamic knowledge of the metal or The IOM committee held its first two meetings alloy under study. Epidemiological studies could in February and May 2000. A public meeting be included based on exposure models. was held in August 2000 to gather information from veterans, veterans’ service organizations, IV.B.2. IOM Study on Identifying scientists, health care providers, and Effective Treatments for Gulf War congressional staff. Veterans’ Health Problems IV.C. 1999 UPDATE OF KEY Public Law 105-368, which passed on October RESEARCH PROJECTS AND 21, 1998, was entitled the “Veterans Programs INITIATIVES Enhancement Act of 1998.” It mandated that the VA contract with the Institute of Medicine to Several research initiatives are described in this review the available scientific data to: section: Assess whether a methodology could be used by the VA for determining the efficacy the two treatment trials, using of treatments furnished to, and health exercise/behavior therapy or antibiotics; outcomes (including functional status) of, the Military and Veterans Health Persian Gulf War veterans who have been Coordinating Board; treated for illnesses; and two completed Institute of Medicine Identify, to the extent feasible, with respect projects; to each undiagnosed illness prevalent among one ongoing Institute of Medicine project; such veterans and for any other chronic and illness that the NAS determines to warrant one ongoing National Academy of Science such review, empirically valid models of project. treatment for such illness which employ successful treatment modalities for IV.C.1. Progress on Two Treatment populations with similar symptoms. Protocols: Exercise/Behavioral Therapy (EBT) Trial and Antibiotic Treatment In 1999, the VA requested the Institute of (ABT) Trial Medicine to perform an 18-month study to identify effective treatments for health problems In the fall of 1997, the Research Working Group in Gulf War veterans. The committee’s charge is approved a plan initiated by the VA and DoD to threefold, as follows: begin developing treatment trials for Gulf War veterans. In the spring of 1998, the VA Cooperative Studies Program initiated planning
45 for the trials, subsequently known as the EBT (exercise/behavioral therapy) trial and the ABT One or more of these proposed treatment (antibiotic treatment) trial. The planning effort interventions are employed currently for patients for both trials took nine months. VA, in ill with such conditions as Chronic Fatigue collaboration with the DoD, assembled scientists Syndrome, fibromyalgia, arthritis, back pain, from the university community, private sector headaches, and irritable bowel syndrome. The experts, and experts from the Federal CBT intervention is not a singular approach to all Government, including the National Institutes of the patient’s problems. Rather, it is a set of Health, DoD, and VA itself. techniques that can be tailored for specific problems or illnesses. The techniques are used As with all research approved by the Research to produce cognitive change and are based Working Group, both trials underwent intense largely on the development of problem-solving scientific review and scrutiny by the Cooperative skills. CBT works best when the patients take an Studies Evaluation Committee, a Federally active role in the management of their symptoms. Chartered Research Review panel. Also, both A growing body of research supports the idea trials were subjected to intense human studies that patient behavior and patient thinking can review. improve some illnesses to the same or greater degree than traditional medical approaches. Patient characteristics for entry into both CBT may not provide a “cure,” but it may help treatment trials are similar. All Gulf War Gulf War veterans better manage their symptoms veterans who served between August 1990 and and improve their quality of life. August 1991 are eligible for the studies. Inclusion criteria for entry requires that Gulf War The EBT trial is taking place at 18 VA sites and veterans have at least two of the following three two DoD sites. In order to answer the question symptoms, which began after August of 1990 of the benefit of these treatments, about 1,100 and have lasted for more than six months patients have been enrolled. Patients are continuing to the present. Symptoms targeted for allocated to receive both aerobic exercise and treatment in the trials include: 1) Fatigue that CBT together, either treatment individually, or limits usual activity, including work, recreation, usual and customary care. Thus, there are four or social activities; 2) Musculoskeletal pain treatment groups. Patients have been enrolled involving two or more regions of the body; and over a 16-month period, starting in April 1999. 3) Neurocognitive symptoms, for example, They will be followed for an additional year to difficulties in memory, concentration or assess the magnitude of the treatment effect and attention. These symptoms will not be explained the durability of any observed benefit. The by any clearly defined disease condition, like entire study will last about 2.5 years. arthritis. Antibiotic Treatment (ABT) Trial Exercise/Behavioral Therapy (EBT) Trial The ABT trial focuses on a hypothesized The EBT trial focuses on the use of aerobic infectious cause for the variety of symptoms exercise and cognitive behavioral therapy in an experienced by some Gulf War veterans. The effort to provide comprehensive, coherent and putative organism is a species called effective treatments to veterans and active-duty Mycoplasma fermentans. There is no soldiers ill after their service in the Gulf War established, definitive link between infection (projects VA-62 and DoD-115). The primary with this organism and Gulf War veterans’ study objective is to assess whether aerobic illnesses, however, undetermined numbers of ill exercise combined with cognitive behavioral veterans are taking the antibiotic Doxycycline for therapy (CBT) will improve the physical as long as one year, in hopes of improving their functioning of ill patients, and whether the health. In addition, there are anecdotal reports combination of exercise and CBT will be more that this type of tetracycline has been useful in beneficial than either therapy alone. Additional ameliorating the symptoms of Gulf War study objectives include evaluation of any veterans. improvements in the symptoms of pain, fatigue, and cognitive difficulties. The ability to decrease A putative infectious etiology for Gulf War levels of disease-related distress and improve veterans’ illnesses provides an attractive emotional functioning will also be evaluated. hypothesis because antibiotics could possibly
46 cure these patients’ symptoms. Unfortunately, primarily as it relates to deployment and anecdotal reports do not establish treatment redeployment. (NSTC, 1998) The President benefit and a rigorous trial is necessary to also directed the Secretaries of Defense, Health address the question definitively. Accordingly, and Human Services, and Veterans Affairs to the primary hypothesis of the ABT trial is to establish the Military and Veterans Health determine whether a 12-month course of Coordinating Board (MVHCB) to oversee the antibiotic treatment (Doxycycline) directed plan’s implementation. against Mycoplasma species will improve the functional status of Gulf War veterans who are The PRD-5 and its accompanying White House tested as Mycoplasma positive (projects VA-55 directive sets a course to ensure ongoing and DoD-119). cooperation and coordination among DoD, HHS and the VA, while focusing on military, veterans, In order to be eligible to enroll in this trial, and their families who encounter health needs patients who have the above symptom categories related to the adverse effects of deployment and must also test positive for the presence of redeployment. In December 1999, the MVHCB Mycoplasma genetic material. This includes was officially established following the selection tests for the DNA of Mycoplasma fermentans, and hiring of an MVHCB executive director, Dr. Mycoplasma genitalium and Mycoplasma Robert G. Claypool. Dr. Claypool is a senior pneumoniae. The study will also determine VA medical officer with extensive expertise in whether antibiotic treatment reduces symptoms operational medicine within DoD. The executive including pain, fatigue, and neurocognitive director’s first action was recruitment of the difficulties; converts Mycoplasma positive chairpersons for the three working groups called patients to a Mycoplasma negative status; and for by the PRD-5 and the White House directive: whether the treatment benefit persists for six Deployment Health, Health Risk months after the termination of the treatment. Communications, and Research.
The antibiotic trial includes some criteria that The Deployment Health Working Group will may lead to patients being excluded from the coordinate: study, for example, patients with a special the development and requirement for antibiotics for other conditions, sustainment of a healthy, fit, or patients with allergies to tetracycline. and ready military force efforts to identify and The ABT is taking place at 26 VA sites and two minimize adverse health DoD sites. This double-blind study contains two effects on service personnel treatment groups. More than 450 patients have and veterans related to the been allocated to receive either antibiotic hazards of military life treatment or placebo. Patients started enrollment efforts to restore the health of in April 1999, which is now complete. They are service personnel, veterans, treated actively for 12 months, then followed for and their families when an additional six months to assess the magnitude adverse effects of deployment of the treatment effect and the durability of any have impacted their wellbeing observed benefit. The entire study will last about the documentation, storage, 2.5 years and is projected to cost approximately and retrieval of information $12 million. The manufacturer of Doxycycline, relating to changes in health Pfizer Pharmaceuticals, is donating the study status, drug and a matching placebo. The estimated size occupational/environmental of this donation will exceed $5 million. exposures, and unit location from the moment of IV.C.2. Military and Veterans Health recruitment throughout one’s Coordinating Board military career and on into civilian life On Nov 11, 1998, President Clinton announced identification of opportunities the release of the Presidential Review Directive 5 for further research that will (PRD-5), which is an interagency plan to develop and test hypotheses improve the Federal response to the health needs that will improve deployment of our military, veterans and their families, health
47 expertise that can be brought to bear on the The Health Risk Communications Working special needs associated with troop and veteran Group will coordinate: health, relating to past, present, and future an improved military service in the U.S. Armed Forces. This understanding on the part has gone on in the past, but through the activities of service members, of the MVHCB and its working groups, this is veterans, their families, becoming a more focused and effective process. military commanders, and The MVHCB is modeled upon the Persian Gulf health care workers of Veterans Coordinating Board (PGVCB), which potential health threats and has been very successful at improving their countermeasures interagency coordination, especially for research enhanced methods for and clinical care related to health issues of Gulf delivering 1) the right War veterans. amount of information, 2) in the best possible The PGVCB was established in January 1994. manner 3) at the optimal The Secretaries of Defense, Health and Human time and place which 4) Services, and Veterans Affairs also co-chair this meets needs of the target Board. The PGVCB has Clinical, Research, and populations and 5) Disabilities/Benefits working groups. PGVCB enhances the trust and staff includes a VA senior medical officer as credibility of the executive director, a DOD physician, a DOD stakeholders research scientist, a DOD Deployment Health the development of a Specialist, a part time VA health policy analyst, means for stakeholders to and an HHS administrator. The staff is located at provide timely feedback to VA Headquarters. For an interim period, this the government health risk staff is supporting both the MVHCB and the communicators PGVCB. It is expected that the two Boards will vigilance for novel or effectively merge sometime during 2000, as the emerging health threats so MVHCB’s mission is expanded to include the that risk communication ongoing activities of the PGVCB. can be an integral part of an early response The PGVCB has provided a successful forum to the identification of opportunities for address and coordinate DOD, HHS and VA research to develop and test hypotheses for activities regarding health care, benefits, and improved health risk communication research programs for Gulf War veterans and Gulf War veterans’ illnesses. DoD/VA meetings The Research Working Group and DoD participation in interagency task forces will coordinate: responding to PRD-5 further highlighted the an interagency effort for importance of formally continuing research that supports interdepartmental collaboration. (NSTC, 1998) deployment health and The legacy of the successes of the PGVCB will health risk communication be continued under the MVHCB. The PRD-5, as initiatives well as other information on the activities of the the identification of gaps in MVHCB, is accessible on the Internet at needed research www.mvhcb.gov. a technical capability to identify new ideas that may IV.C.3. IOM Study on National Center merit further study for Military Deployment Health Research development of proposals for research and VA, DoD, and HHS Plans for products that may be candidates to be Implementation of IOM transitioned to further development, policy Recommendations formulation, and implementation Public Law 105-368, which passed on October The MVHCB is enhancing the level of 21, 1998, was entitled the “Veterans Programs coordination and communication between Enhancement Act of 1998.” It mandated that Federal agencies that have programs and VA contract with the National Academy of
48 Sciences to assist in the development of a plan that such a center could provide an overarching for the establishment of a national center(s) for research agenda that would identify gaps in the study of war-related illnesses and post- current research. A center could also coordinate deployment health issues. VA supported this existing and future research, focus the infusion Public Law because a research center would of new research funding, and recommend enhance the ability to care for veterans after policies related to such research. The committee conflicts and it would extend VA's research recommended the establishment of a National capabilities in this area. Center for Military Deployment Health Research that would focus on the health of active, reserve, The Public Law stated that the purposes of such and guard forces, and veterans, and their a center could include: families.
1. carrying out and promoting research IOM recommended that the National Center be regarding the etiologies, diagnosis, responsible for four core activities: treatment, and prevention of war-related illnesses and post-deployment health issues; research coordination and priority setting; and research-related policy analysis; 2. promoting the development of appropriate review and analysis of longitudinal health policies, including monitoring, monitoring of deployment-related health; medical record keeping, risk and communication, and use of new facilitating the use of national data sources technologies. for deployment health research.
In December 1998, VA contracted with the IOM recommended that the National Center be Institute of Medicine (IOM) of the National placed under the auspices of the Military and Academy of Sciences to assist in the Veterans Health Coordinating Board (MVHCB). development of a plan. The charge to the IOM (IOM, 1999b) This Board was described in a expert committee was to: previous part of Section IV. of this Annual Report to Congress. 1. assist the VA in developing a plan for establishing a national center(s) for the study VA, DoD, and HHS Plans for Implementation of of war-related illnesses and post-deployment IOM Recommendations issues; and 2. assess preliminary plans and make VA, DoD, and HHS are currently working to recommendations regarding such plans. implement the recommendations of the IOM committee. A workshop was held in December The IOM committee met three times between 1999 to discuss these issues, which included VA, January 1999 and September 1999, and they DoD, and HHS scientists and policy makers, published a report in November 1999. (IOM, university scientists, and IOM committee 1999b) One component of the IOM charge was members. to review the VA’s proposal to establish Centers for the Study of War-Related Illnesses and Post- The IOM committee endorsed the VA proposal deployment Health Issues by using the model of to establish new Centers for the Study of War- the Geriatric Research, Education, and Clinical Related Illnesses. (IOM, 1999b) VA has Centers (GRECCs). The GRECC program has initiated a procedure to create two new Centers. been successful in training health professionals, Based on the successful GRECC model, the plan conducting research, and implementing effective for the new Centers calls for four major program treatment programs. The committee components focusing on veterans’ health issues: recommended that the VA proceed with its proposal to establish centers for the study of war- Research related illnesses, and that these centers be similar Clinical care in structure to the GRECCs. Education Risk communication The second component of the committee’s charge was to make recommendations about a The two Centers would report to the VA Office national center. The committee concluded that of Public Health and Environmental Hazards,
49 and work closely with the VA Office of veterans over time. The IOM established an Research and Development, and the Military and expert committee to consider these Veterans Health Coordinating Board. As methodological questions: appropriate, the Centers would actively collaborate with DoD. “Identify relevant questions regarding the evaluation of the health status of active-duty The Center sites and programs would be chosen troops and veterans deployed to the Gulf through a competitive peer-reviewed selection War; process, and would be required to re-compete on Identify issues to be addressed in the a regular basis. This process would ensure the development of study designs and methods participation of the best possible scientific and that would be used to answer such questions; clinical expertise. VA plans to issue the Request and for Proposals in September 2000. Develop a research design(s) and methods that could be used to address such IOM recommended the establishment of a questions.” (IOM, 1999a) National Center for Military Deployment Health Research (NCMDHR). (IOM, 1999b) The VA, The committee met five times between May DoD, and HHS concur with the general concept 1998 and April 1999 and published a report in of creating the NCMDHR, because it is essential late 1999. The committee determined that the to have broad coordination among the three fundamental questions included: 1) how many departments of VA, DoD, and HHS. VA, DoD, veterans are suffering from health problems that and HHS agree that an evolutionary approach affect their ability to function; 2) whether the towards establishing a new National Center will prevalence of such problems among Gulf War provide the best opportunity to ensure that the veterans is consistent with their prevalence in structure and function that develops can best other populations; and 3) whether the health of meet the needs of service personnel, veterans and veterans is getting better, staying the same, or their families. deteriorating over time.
There are plans to generate a research report The committee recommended that a prospective initially, which describes existing deployment cohort study of Gulf War veterans and health research, identifies gaps and duplicative appropriate comparison groups be conducted. efforts, and makes recommendations for (IOM, 1999a) The committee concluded that a correcting research deficiencies. single study could not satisfy all the information Recommendations for the evolution and needs to answer the three major questions. The maturation of a National Center would be committee realized that such a study could have expected within the next two years. This would important implications for understanding not incorporate input from members of Congress, only the health of Gulf War veterans, but also the active-duty service personnel, veterans, health of veterans of other conflicts. university scientists, and other interested members of the public. The committee recommended that the study investigate the following four questions: IV.C.4. IOM Study on Gulf War Veterans: Measuring Health (IOM, 1999); 1. How healthy are Gulf War veterans? and Ongoing Longitudinal Cohort Studies 2. In what ways does the health of Gulf War of Gulf War Veterans veterans change over time? 3. Now and in the future, how does the health Longitudinal follow-up of the health status of of Gulf War veterans compare with: Gulf War veterans is challenging, especially for the general population ill-defined or medically unexplained conditions. persons in the military at the time In response to questions from Congress and the of the Gulf War but not deployed General Accounting Office, VA and DoD persons in the military at the time contracted with the Institute of Medicine in of the Gulf War who were December 1997 for an 18-month study. (GAO, deployed to non-conflict areas 1997; SVAC, 1998) The overall task was to persons in the military deployed to develop research designs and methods that could other conflicts, such as Bosnia or be used to monitor the health of Gulf War Somalia?
50 4. What individual and environmental VIII.B. References for Longitudinal Cohort characteristics are associated with observed Studies of Morbidity. differences in health between Gulf War veterans and comparison groups? There is also an ongoing mortality study of Gulf War veterans, which will continue indefinitely The committee recommended a portfolio of (Project VA-1). The results of the first two years studies that would include various study designs of follow-up have been published. (Kang, et al, and related methods, because such an approach 1996) would lead to a greater understanding of the long-term effects of Gulf War service. They Boston Environmental Hazards Research recommended that multiple studies be initiated Center with three components: population studies, health services research studies, and biomedical The Boston Veterans Affairs Medical Center and clinical investigations. The committee (VAMC) has been following 2,949 Army recognized that these recommendations would be veterans who processed through Fort Devens, challenging, and that a sustained commitment of Massachusetts, at the time of their return from resources will be required from Congress, VA, the Gulf War in April to July 1991. This group and DoD, and a commitment of time and has been evaluated at five time points, starting cooperation will be required from study within five days of their return to the U.S., at 18 participants. to 24 months (Time 2), three years (Time 3), six years (Time 4), and seven years (Time 5). The VA, DoD, and HHS are currently working to Boston VAMC has recently been funded to implement the recommendations of the IOM continue this study in 2000 to 2003 (Time 6). committee. A workshop was held in December The study population includes about 72% 1999 to discuss these issues, which included VA, Reserve and National Guard and about 28% DoD, and HHS scientists and policy makers, active-duty. It includes 84 units with a wide university scientists, and IOM committee range of military occupational specialties from members. There are five ongoing prospective several regions of the U.S. cohort studies of Gulf War veterans, which are described in the next section. Time 1. (Project VA-7)
Summary of Longitudinal Cohort Studies At the time of their return to the U.S., the cohort of Morbidity among Gulf War Veterans was requested to complete a questionnaire, which focused on physical symptoms, symptoms The purpose of this section is to describe five of posttraumatic stress disorder (PTSD), ongoing longitudinal cohort studies of Gulf War symptoms of major depression, and other veterans. The five studies are being performed psychological symptoms. In addition, combat by scientists in Boston, New Orleans, New exposure, family and unit support factors, and Jersey, Iowa, and the United Kingdom. Each of post-deployment life stressors were assessed. these studies has used questionnaires, which (VA, 1992; Wolfe, et al, 1993; Wolfe, et al, included physical symptoms, psychological 1996) symptoms, and exposures during the Gulf War. Each of these studies has used standardized Time 2. (Project VA-7) psychiatric interviews by clinicians and standardized neuropsychological tests. The New The Boston VAMC recontacted the entire Fort Jersey, Iowa, and United Kingdom studies have Devens cohort about 18 to 24 months after their included comprehensive medical histories and return from the war. 2,313 veterans participated, physical examinations. which included about 78% of the original cohort. The same major health outcomes were assessed. For each study, the following details will be (Wolfe, et al, 1996; Wolfe, et al, 1998a; Wolfe, provided: the funding agency; the years of initial et al, 1998b; Wolfe, et al, 1999a; Wagner, et al, and follow-up evaluations; the numbers and 2000; and Sharkansky, et al, 2000) demographics of the Gulf War and control populations; the major health outcomes Time 3. (Projects VA-4 and VA-9) evaluated; and the publications to date. A complete list of references is included in Section
51 In 1994 to 1996, Projects VA-4 and VA-9 Time 1. (Project VA-12) involved the collaboration of scientists from the Boston VAMC and the New Orleans VAMC, In 1991, the New Orleans VAMC developed a respectively. These studies involved 148 psychological assessment program as part of a veterans from the Fort Devens cohort and 56 series of programs at VAMCs nationwide. The veterans from the New Orleans cohort, described New Orleans research team evaluated 1,520 below. These individuals were selected on the Reserve and National Guard troops who were basis of self-reports at Time 2, of either many mobilized for active-duty during the Gulf War. physical symptoms or few or no physical 396 of these 1,520 troops were activated, but did symptoms. The comparison group consisted of not deploy to the war zone. The initial 48 members of a National Guard unit from assessment took place within a few months of Maine, who had been deployed to Germany the end of the war. Because this large study during the Gulf War. Major health outcomes sample included Reserve and National Guard included physical symptoms, and symptoms of troops in the Army, Navy, Air Force and PTSD, major depression, and other psychiatric Marines, study results are relevant to the health disorders. Structured psychiatric interviews and status of the larger population of Gulf War standardized neuropsychological tests were used. veterans who were members of the Reserve or Combat stress and hazardous environmental National Guard. (VA, 1992; Sutker, et al, 1993; exposures, as well as post-deployment life Sutker, et al, 1995a, Sutker, et al, 1995b) stresses, were assessed. (Proctor, et al, 1998; Wolfe, et al, 1999b) Among the 1,520 military personnel in the New Orleans study, there were 194 members of Time 4. (Project DoD-52) Quartermaster units who were assigned graves registration duties that included handling, In 1996-97, the Boston scientists recontacted the identification, and processing of bodies and body entire Fort Devens cohort. There was an parts. These individuals were evaluated at both approximately 50% response rate. The major Time 1 and Time 2. (Sutker, et al, 1994a; health outcomes were physical symptoms, PTSD Sutker, et al, 1994b) symptoms, functional status, and health perceptions. Environmental and psychosocial Major health outcomes at Time 1 included PTSD exposures during the war were also assessed. No symptoms, other psychological symptoms, and results have been published from Time 4. physical symptoms. Personal and environmental resources and characteristics of war zone Time 5. (Project HHS-5) stressors were also assessed. A subset of the 1,520 underwent structured clinical interviews In 1998 to 2001, three groups of veterans are for psychiatric diagnoses. being re-contacted, who have been evaluated previously. These include 40 symptomatic Gulf Time 2. (Project VA-12) War veterans, 40 non-symptomatic Gulf War veterans, and 40 Germany-deployed veterans. 348 of the 1,520 troops evaluated at Time 1 were Both conventional MRI scans and functional reevaluated one year later in 1992. All of these MRI scans are being used to assess changes in individuals had been deployed to the war zone. brain activation, to examine symptom profiles, The same health outcomes were evaluated at and to examine the relationships between Time 1 and Time 2, which permitted a functional activation and clinical states. longitudinal comparison. (Benotsch, et al, 2000)
Time 6. (Project DoD-114) Time 3. (Projects VA-10 and VA-11; and VA-4 and VA-9) In 2000 to 2003, Gulf War veterans who previously underwent neuropsychological testing There were two simultaneous research activities will be re-evaluated. The same battery of ongoing during 1994 to 1996. Projects VA-10 standardized tests will be used, to determine if and VA-11 focused on veterans from the New there are changes over time. Orleans area. These projects involved 95 Gulf War veterans, some who had PTSD and some New Orleans VA Medical Center who had no psychiatric problems. Structured psychiatric interviews and standardized
52 neuropsychological tests were used. (Vasterling, et al, 1997; Vasterling, et al, 1998) The second stage of the study focused on veterans who reported symptoms of chronic In 1994 to 1996, Projects VA-4 and VA-9 were fatigue and/or multiple chemical sensitivity on also ongoing. These studies involved 56 the initial questionnaire. 100 veterans who met veterans from the New Orleans cohort and 148 screening criteria for these disorders and 47 veterans from the Fort Devens cohort, described healthy veterans participated in the second stage. previously. These individuals were selected on This included a comprehensive medical history, the basis of self-reports at Time 2, of either many physical exam, standardized psychiatric physical symptoms or few or no physical interview, and laboratory tests. After the symptoms. The comparison group consisted of medical evaluations, a subset of these subjects 48 members of a National Guard unit from then participated in a number of specialized Maine, who had been deployed to Germany studies. These included standardized during the Gulf War. Major health outcomes neuropsychological tests and MRIs; blood tests included physical symptoms, and symptoms of to detect viral infection or immunological PTSD, major depression, and other psychiatric abnormalities; and tests for autonomic nervous disorders. Structured psychiatric interviews and system function, at rest or under stressful standardized neuropsychological tests were used. conditions. (Pollet, et al, 1998; Lange, et al, Combat stress and hazardous environmental 1999; Wallace, et al, 1999; Zhang, et al, 1999; exposures, as well as post-deployment life Peckerman, et al, 2000) stresses, were assessed. (Proctor, et al, 1998; Wolfe, et al, 1999b) Time 2. (Project HHS-6)
Time 4. (Project VA-54) In 2000-2001, the 1,161 participants in the New Jersey cohort will be recontacted for a telephone In 1999 to 2003, a sample from Time 1 will be interview. The persistence and stability of reevaluated. (Time 1 included more than 800 symptoms over time will be assessed. The Gulf War veterans and more than 200 non- telephone questionnaire includes physical deployed veterans.) The major health outcomes symptoms, diseases, and a standardized will be PTSD symptoms, other psychiatric psychiatric interview. Medical record reviews symptoms, and physical symptoms. will be performed on a subset of the population. Standardized neuropsychological tests will be used. Characteristics of war zone stressors, Iowa personal resources, and post-deployment life stresses will also be assessed. Time 1. (Project HHS-1)
East Orange, New Jersey Environmental In 1995-96, a randomly-selected sample of Hazards Research Center military personnel were interviewed by telephone, who had listed Iowa as their home of Time 1. (Project VA-5) record. Study subjects were drawn from four groups: Gulf War active-duty, Gulf War National The East Orange, New Jersey Environmental Guard/Reserve, non-deployed active-duty, and Hazards Research Center performed a study of non-deployed National Guard/Reserve. A total veterans who were enrolled in the VA Gulf War of 3,695 subjects completed the survey (76% Registry in 11 northeastern and midwestern response rate). The questionnaire included states. 1, 935 veterans were randomly selected physical symptoms, psychiatric symptoms, from the Registry and were mailed a detailed functional status, and exposures during the Gulf questionnaire between the autumn of 1995 and War. A follow-up study in 2000 is evaluating a August 1996. 1,161 veterans responded (60%), group of veterans who reported symptoms of and were therefore potentially eligible for the asthma, in comparison with an equal number of second stage of the study. The questionnaire veterans who did not report asthma. They are included physical symptoms, psychological undergoing physical examinations and symptoms (PTSD, depression and anxiety), pulmonary function tests to validate the combat experiences, environmental exposures, questionnaire data. (Iowa, 1997; Black, et al, and family and social support. (Kipen, et al, 2000; Doebbeling, et al, 2000) 1999)
53 Time 2. (Project DoD-58) IV.C.5. IOM Study on Health Effects Associated with Exposures during the In 1999-2000, a subset of the Iowa cohort is Persian Gulf War being invited to participate in a comprehensive medical history, physical exam, and laboratory The value of the research on Gulf War veterans’ tests. Several hundred veterans are included: illnesses can only be realized when the results of veterans who reported one of three disorders on many studies are integrated and general the initial interview and an equal number of conclusions are drawn regarding the major veterans who did not report these disorders. The scientific questions. Because of the important three disorders are cognitive dysfunction, implications of such an assessment, VA followed depression, and fibromyalgia. Structured the recommendation of the Presidential Advisory neuropsychological tests and psychiatric Committee on Gulf War Veterans’ Illnesses to interviews are used to evaluate these disorders. contract for an assessment with an independent scientific organization, such as the National United Kingdom Academy of Sciences (NAS). (PAC, 1997) In its Special Report, the PAC recommended that Time 1. (Project DoD-39) the VA contract for a periodic review “of the available scientific evidence The U.S. DoD has funded a large study of British regarding associations between illnesses Gulf War veterans and two control populations. and Gulf War service. The object of such In 1997-98, questionnaires were mailed to about an analysis would be to determine 4,500 Gulf War veterans, 4,500 Bosnia veterans, statistical associations between service in and 4,500 non-deployed veterans. 8,195 the Gulf War and morbidity and mortality, veterans participated (65% response rate). The while also considering whether a plausible questionnaire included physical health (with an biological mechanism exists, whether emphasis on chronic fatigue syndrome), research results are capable of replication psychological symptoms, including PTSD, and of clinical significance, and whether functional status, health perceptions, and the data withstand peer review.” (PAC, exposures during the Gulf War. (Unwin, et al, 1997) 1999; Ismail, et al, 1999; Hotopf, et al, 2000) Public Law 105-368, which passed on October Time 2. (Projects DoD-39 and DoD-106) 21, 1998, was entitled the “Veterans Programs Enhancement Act of 1998.” It mandated that the In 1999-2000, there are two simultaneous VA contract with the NAS to perform a review initiatives. Project DoD-39 is continuing and a and evaluate the available scientific evidence subset of the British cohort is being invited to regarding associations between illness and participate in comprehensive medical service in the Persian Gulf War. The Public Law evaluations. This subset includes 100 ill Gulf stated that the NAS review should: War veterans, 100 healthy Gulf War veterans, 100 ill Bosnia veterans, and 100 ill non-deployed Identify the biological, chemical, or other veterans. In addition to clinical exams, toxic agents, environmental or wartime standardized neuropsychological tests, hazards, or preventive medicines or vaccines psychiatric interviews, and pulmonary function to which members of the Armed Forces may tests are used. have been exposed; Identify the illnesses associated with the In 2000, the U.S. DoD funded a new project agents, hazards, or medicines or vaccines; (Project DoD-106). Blood samples will be and requested from a subset of the veterans in the Identify the illnesses (including diagnosed British cohort. Tests will be done for illnesses and undiagnosed illnesses) for immunological function. Interactions between which there is scientific evidence of a higher immune status, vaccination history, and stress prevalence among populations of Gulf War will be evaluated. veterans when compared with other appropriate populations of individuals.
On June 24, 1998, four months before the passage of the Public Law, VA contracted with
54 the Institute of Medicine (IOM) of the NAS to series of updates of the literature and the carry out the assessment. The purpose of the associations, to be conducted every two or three IOM project is to review the scientific and years. These periodic reviews are consistent medical literature regarding adverse health with the language of Public Law 105-368. effects associated with exposures experienced during the Gulf War. Scientific evidence An Assessment of the Safety of the Anthrax concerning the association of exposures and Vaccine: A Letter Report (IOM, 2000) illness will be examined taking into account: In February 2000, the DoD requested the IOM to the strength of the scientific evidence and provide a report on the safety and efficacy of the the appropriateness of the methods used to anthrax vaccine that could be used to answer identify associations; questions raised by Congress. The IOM agreed whether the evidence indicates the levels of to undertake a comprehensive study for DoD, exposure of the studied populations were which will require approximately 24 months to comparable to the exposures of Gulf War complete. In the meantime, because of veterans; and immediate concerns over the anthrax vaccine whether there exists a plausible biological safety issue, the IOM offered to draw relevant mechanism or other evidence of a causal information from this ongoing VA-funded study relationship between exposure to the risk of the health effects of several Gulf War factor or factors and the medical conditions. exposures. The IOM published a letter report on March 30, 2000, that narrowly focused on the Different types of research findings, e.g., animal committee’s literature review of the safety of the toxicology data, occupational exposure data, and anthrax vaccine. (IOM, 2000) epidemiological data, will need to be analyzed and integrated. The review will include The committee evaluated the primary peer- recommendations for additional scientific studies reviewed literature, and did not draw conclusions to resolve areas of continued scientific from reviews or unpublished data. There are uncertainty related to the health effects of Gulf only a few peer-reviewed studies that examine War service. the safety of the vaccine in humans. There have been no studies in which the long-term outcomes The first phase of the study will summarize the have been systematically evaluated with active medical literature on pyridostigmine bromide, surveillance. This is not surprising, however, depleted uranium, sarin and cyclosarin, and the because few vaccines for any disease have been anthrax and botulinum toxoid vaccines. The two actively monitored for adverse effects over long chemical warfare agents were selected because periods of time. Gulf War veterans may have had low level exposure to them, as a result of the demolitions The committee concluded that in the peer- at Khamisiyah in March 1991. The IOM reviewed literature, there is committee held their first meeting in January “inadequate/insufficient evidence to determine 1999 and they have held six additional meetings whether an association does or does not exist through March 2000. The publication of the between anthrax vaccination and long-term report on this first phase is expected in adverse health outcomes.” The committee September 2000. (Note: As indicated throughout strongly urged the scientists, who have been this annual report, the scope of this report is conducting several studies on the safety of the limited to research projects for which results vaccine, to submit their results to peer-reviewed were published during the period of January journals for publication. The committee also 1999 through March 2000. Although the results concluded “active long-term monitoring of large of this IOM study were published in September populations will provide further information for 2000, as expected, this IOM publication falls documenting the relative safety of the anthrax outside the stated scope of this annual report. vaccine.” In 1999, the Naval Health Research Accordingly, this IOM report will be addressed Center began a large, long-term follow-up of the in detail in next year’s annual report.) rates and causes of hospitalizations among military personnel who have received the anthrax During phase two, a number of additional vaccine (project DoD-99). exposures will be reviewed, including pesticides and solvents. The third phase will consist of a
55 This strategic plan will serve as an important IV.C.6. NAS Study on Strategies to complement to the recently released strategic Protect the Health of Deployed U.S. plan in the Presidential Review Directive 5. Forces (NSTC, 1998) Whereas the PRD-5 plan will provide a broad road map for the government to DoD has requested the advice of the National follow, the NAS plan will provide a greater level Academy of Sciences (NAS) on a long-term of detail with specific recommendations for strategy for protecting the health of military improvements, modernization, or efficiencies. personnel when deployed to unfamiliar environments. The project is drawing on the The overall conclusions of each of the four lessons of the Gulf War and subsequent reports are summarized here. deployments, as well as a variety of other evidence, to offer recommendations on four Strategies to Protect the Health of Deployed tasks: U.S. Forces: Analytical Framework for 1. an analytical framework for assessing the Assessing Risks (NAS, 2000a) (Task 1.) risks to deployed forces from a variety of This report offers a structure for military leaders medical, environmental, and battle-related to use in assessing threats from biological and hazards, including chemical and biological chemical warfare and from non-battle hazards agents (CBA); such as infectious diseases. Unlike more 2. improved technology and methods for traditional risk assessments, this framework detection and tracking of exposures to these organizes threats around possible military risks; activities–such as deployment near an industrial 3. improved technology and methods for facility that houses industrial chemicals-rather physical protection and decontamination, than specific agents. Emphasizing deployment particularly of CBA; and scenarios encourages thinking beyond a standard 4. improved medical protection, health list of recognized hazards. The framework has consequences management and treatment, three major phases of risk assessment: and medical record keeping. Ongoing baseline preparation: During this This three-year study began in October 1997. phase, military planners would strive to During the first two years, principal investigators systematically anticipate potential threats for each task of the project were selected and and the circumstances under which they advisory panels of experts were appointed. A might arise. large number of briefings, workshops, and site Activities during deployment: Various visits were accomplished. The purpose of these kinds of information should be collected activities was to document current procedures, routinely, such as troop positions, as well as equipment, doctrine, and training as well as to soil, water, and air samples, to document review what is being developed or planned for potential hazards and changes in agent the future. concentrations. Data collection should take into account novel and emerging threats, Reports on each of these four tasks were such as local pathogens and long-term, low- published in late 1999 or early 2000. (NAS, level exposures that could lead to delayed 1999a; NAS, 1999b; NAS, 2000a; NAS, 2000b) health problems. These reports will form the basis for the third Activities after deployment: Veterans year’s activity, which is the production of a should be monitored for effects that may strategic plan for protecting the health of appear later, and analyses should be conducted to determine if they are deployed forces in the future. An NAS associated with exposure to potentially committee of experts will analyze and synthesize harmful agents during deployment. Some of the reports on the four tasks into one integrated the information obtained during deployment report, containing a cohesive set of might be used to identify threats that were recommendations. Publication of this final not previously considered. report is expected in September 2000. Strategies to Protect the Health of Deployed U.S. Forces: Detecting, Characterizing, and
56 Documenting Exposures (NAS, 2000b) (Task provides adequate protection to meet current 2.) threats. Current protective equipment cannot be used effectively with other systems, such as This report focuses on DoD’s approaches to night vision goggles. Techniques and training detecting and tracking exposures of deployed for decontamination of personnel and equipment personnel to potentially harmful agents, needs to continue to improve, and better methods including chemical and biological warfare for assessing the effectiveness of agents, toxic industrial chemicals, environmental decontamination are needed. and occupational contamination, and endemic, pathogenic organisms. The report identifies Strategies to Protect the Health of Deployed opportunities for modifying strategies to provide U.S. Forces: Medical Surveillance, Record better protection in future deployments. The Keeping, and Risk Reduction (NAS, 1999b) report makes recommendations on: (Task 4.)
Methods of monitoring and characterizing DoD has put great effort into improving the chemical and biological warfare agents medical surveillance of deployed forces, but present in or released into the deployed these efforts lack the comprehensive planning theater; needed to use systems and resources efficiently. Use of the global positioning system (GPS) This report outlines ways to expand efforts to and other technologies to track troops and monitor personnel medically, to keep better characterize locations and time-activity records, and to extend new protections to reserve patterns of deployed troops, including high- personnel. Standard policies and procedures risk subpopulations; across all three service branches are needed to Fixed-site and mobile methods of detecting ensure that comprehensive medical records fulfill and monitoring concentrations of potentially information needs for individual care, medical harmful agents; surveillance, and population studies. Computational methods and biological markers for estimating exposure DoD should develop an improved strategy to concentrations and patterns of exposure for address medically unexplained symptoms. This individuals or groups; and strategy should include a continuing education Implementation procedures, including program for the military’s primary care providers tactical and administrative process, for to improve their ability to diagnose, treat, and detecting, monitoring, and documenting communicate with patients who have such exposures. symptoms. In addition, a research program should be developed to assess the role of factors Strategies to Protect the Health of Deployed that lead to or perpetuate such symptoms. U.S. Forces: Force Protection and Decontamination (NAS, 1999a) (Task 3.) DoD should formulate a plan to collect baseline health data from all recruits, and to update this This report provides guidance to DoD on information annually for both active-duty and guarding against exposure and harm from reserve personnel. After major deployments, a chemical and biological warfare agents (CBA). sample of veterans should be monitored, as well Commander training needs to be developed to as those remaining on active-duty or in the help leaders make appropriate risk-based reserves. decisions when missions might involve chemical or biological contamination. DoD should use Research should be conducted on the needs of credible, updated CBA battlefield risks to revise service members and their families during materiel requirements, training protocols, and deployments and their return home. The findings operational doctrine. Current doctrine should be used to re-evaluate reintegration emphasizes avoiding contamination, but programs and policies. Risk communication detection technologies must be improved to efforts aimed at military personnel and their provide sufficient time for troops to initiate families make up another vital component. protective measures.
Research must be continued on developing lighter-weight, less restrictive equipment that
57 V. NATIONAL RESEARCH were able to communicate their concerns directly CONFERENCES to researchers and clinicians, who are trying to seek solutions to their health problems. In A. 1999 Centers for Disease Control and addition, the conference focused on defining and Prevention Conference: The Health suggesting research to fill critical data gaps and Impact of Chemical Exposures During suggesting methods for addressing the health concerns of Gulf War veterans. the Gulf War: A Research Planning Conference In March 2000, CDC published a final conference report, entitled The Health Impact of From February 28 through March 2, 1999, the Chemical Exposures During the Gulf War: A Centers for Disease Control and Prevention Research Planning Conference. (CDC, 2000) (CDC) held a conference in Atlanta, Georgia. The purpose of this report is to document the This was planned in coordination with the Office conference workgroup deliberations and to form of Public Health and Science, the National the basis for further discussions regarding the Institutes of Health, and the Agency for Toxic direction of research into illnesses among Gulf Substances and Disease Registry. The meeting War veterans. Chapter 1 reviews the events and was held in response to Congressman Bernard planning leading up to the conference. Chapters Sanders of Vermont, who requested that the 2 to 5 present the specific research CDC examine the role of chemical exposures in recommendations developed by each workgroup. the illnesses of Gulf War veterans. Chapter 6 provides a discussion of the workgroup deliberations and it places the The purpose of this conference was to bring research recommendations in the context of together scientists, clinicians, veterans, veterans' current Gulf War research activities. service organizations, Congressional staff, and other interested parties to exchange ideas. The The conference report has been mailed to all intent was to discuss and make recommendations conference participants. The entire report has regarding the direction of future research on been published on the Internet undiagnosed illnesses among Gulf War veterans (www.cdc.gov/nceh/meetings/1999/gulfwar/). and the possible links between these illnesses and multiple chemical and environmental The Department of Health and Human Services exposures. (HHS) will continue to coordinate its Gulf War related research activities with those of the two The format of the conference included plenary principally responsible agencies, the DoD and sessions and concurrent workshops. In addition, the VA, through the Research Working Group of there was a special Veterans Forum that served the PGVCB. HHS will work with the RWG to as an open discussion for veterans to provide identify the recommendations from this input regarding research priorities. Participants conference that have or have not been addressed took part in concurrent workgroups to develop by the current research portfolio. These issues research recommendations in four areas: will be prioritized for future research initiatives.
the pathophysiology, etiology, and B. 1999 Conference on Federally mechanisms of action of illnesses among Sponsored Gulf War Veterans’ Illnesses Gulf War veterans; Research the most appropriate methods for assessment and diagnosis of these illnesses; The RWG organized and hosted an international the most appropriate treatment approaches; meeting, entitled “Conference on Federally and Sponsored Gulf War Veterans’ Illnesses the prevention of similar illnesses in future Research,” on June 23-25, 1999, in Arlington, military deployments. Virginia. The purpose of the meeting was to bring Federally sponsored researchers on Gulf Conference attendees said that this conference War veterans’ illnesses together in a common provided a valuable opportunity to directly meet forum. and interact with physicians, researchers and experts involved in studying the health effects of This was the fourth such conference. The first chemicals throughout the United States. Veterans was held in Washington, DC, at the Armed
58 Forces Institute of Pathology in 1995, the second current state of the science and lessons learned. in Fort Detrick, Maryland in 1997, and the third New research findings will be placed within the in Arlington, Virginia in 1998. Since 1995, the context of the implications of the completed conference has grown from about 50 participants research to date. The 2001 conference title, to more than 300 scientists, clinicians, “Illnesses in Gulf War Veterans: A Decade of government officials, and veterans. Scientific Research” will reflect this emphasis.
Over the course of three days, the 1999 The general organization will be similar to the conference was organized into three morning three-day conference in 1999. There will be plenary sessions, two afternoon breakout three morning plenary sessions, two afternoon sessions on specific research topics, one evening breakout sessions on specific research topics, one poster session, and an evening Veterans’ Service evening poster session, and an evening Public Organization (VSO) Round Table. In addition, Availability Session. In addition, there will be there were two early morning and one afternoon two early morning and one afternoon clinical clinical seminars addressing treatment and seminars addressing treatment and clinical clinical management of Gulf War veterans’ management of Gulf War veterans’ illnesses. illnesses. The general focus areas will be: The plenary sessions were intended to be of broad appeal to a wide audience of participants. Epidemiology (Mortality, Morbidity, Health Nationally and internationally recognized experts Status, Reproductive, Risk Factors) spoke on their fields of expertise as they relate to issues of illnesses in veterans. The breakout Psychological / Psychosocial sessions and the poster session provided researchers with forums to present their research Neurological / Neuropsychological / findings in a wide range of scientific areas, Neurobiology of Stress including epidemiology, reproductive health, toxicology, neuropsychology, and the Toxicology (Depleted Uranium, Chemical neurobiological correlates of stress. The VSO Warfare, Pyridostigmine Bromide, Round Table provided an opportunity for Interactions, etc.) veterans and their representatives to exchange viewpoints with researchers, clinicians, and Force Health Protection / Prevention/ government officials. Surveillance
The Proceedings for this conference were Treatment (Treatment Trials, Clinical published in late 1999. (PGVCB, 1999b) This Practice Guidelines, etc.) report contains the texts of the presentations provided by each plenary speaker, and Other (Infectious Diseases, Vaccines, Other summaries of each breakout session. A Exposures, etc.) summary of the VSO Round Table is also included, as well as a complete set of submitted The objectives of the conference will be to bring abstracts for each presentation in the breakout Federally sponsored researchers together in a sessions and poster session. The section of the common forum to: Proceedings, which contains the texts of the plenary sessions, has been reprinted as Appendix Provide an opportunity for researchers to B of this Annual Report to Congress for 1999. present and exchange study results. Provide an opportunity for veterans and C. 2001 Conference on Federally veterans groups to learn about ongoing Sponsored Gulf War Veterans’ Illnesses research and to interact directly with Research researchers, clinicians, and government officials. In 2001, the RWG will host another national conference in the Washington, D.C. metropolitan Provide an opportunity to inform executive area. The overall purpose and goals of the and legislative branches of the government meeting will be similar to the 1999 meeting, but about research and clinical initiatives related there will be a greater emphasis placed on the
59 to the Gulf War that should be considered for future deployments.
Inform clinicians of current practices for the treatment of Gulf War veterans’ illnesses, and the latest research findings and their potential impact on clinical care.
Learn from recognized experts about overarching research areas as they relate to the etiology, diagnosis, and treatment of Gulf War veterans’ illnesses.
Encourage communication, cooperation, and collaboration among researchers, clinicians, and veterans.
Evaluate the implications of research on Gulf War veterans’ illnesses: current state of the science and lessons learned.
60 VI. RESEARCH MANAGEMENT are more focused on individual research projects and programs. A. Overview Four of the most important oversight activities Research on Gulf War veterans’ illnesses is a are briefly discussed below. Although each has complex undertaking, involving a number of had a broad mandate that has encompassed different approaches. The Federal research effort virtually all issues related to Gulf War veterans’ on this problem involves scientists in Federal, illnesses, the discussion below will focus on their academic, and private institutions, both in the research oversight activities, findings, and United States and abroad, conducting research recommendations. sponsored by VA, DoD, and HHS. Each of these Departments has distinct, though 1. Institute of Medicine/Medical Follow-up complementary, capabilities and capacities for Agency: Health Consequences of Service conducting and sponsoring research on Gulf War During the Persian Gulf War veterans’ health issues. In addition, each Department has its own appropriation for As directed by Public Law 102-585, VA and extramural and intramural general biomedical DoD jointly entered into a three-year contract research programs. with the Medical Follow-Up Agency (MFUA) of the Institute of Medicine, National Academy of Sciences. The IOM contract started on The biomedical research programs in VA, DoD, September 30, 1993. The IOM was mandated to and HHS have well-established management review existing scientific, medical and other structures for science policy formulation and the information on the health consequences of solicitation, scientific peer review, and funding military service during the Gulf War. The IOM of both extramural and intramural programs. was also mandated to write a report that focused Each Department’s research management on the following: hierarchy for Gulf War veterans’ illnesses research has been linked through an overall coordinated effort carried out by the Research An assessment of the effectiveness of Working Group (RWG) of the Persian Gulf actions taken by the VA and DoD to collect Veterans Coordinating Board (PGVCB). As an and maintain information that is potentially operational policy, RWG works through the useful for assessing the health consequences management authority that each department of military service in the Gulf War; maintains over its intramural scientists, its Recommendations on means of improving scientific program managers who are responsible the collection and maintenance of such for extramural research, and its budgets. information; and However, the RWG has no budget authority Recommendations on whether there is sound itself, which ensures greater objectivity. As a scientific basis for an epidemiological study consequence, all funds for research flow through or studies on the health consequences of the funding agency or department. service in the Gulf War, and the nature of such study or studies. B. Oversight of Research On January 4, 1995, the IOM issued a report, Each Department engaged in research on Gulf entitled Health Consequences of Service During War veterans’ illnesses endorses the need for the Persian Gulf War: Initial Findings and both prospective and retrospective scientific peer Recommendations for Action (IOM, 1995). In review of research. Because of the urgency of general, the IOM panel endorsed previous the health concerns of Gulf War veterans and findings of the Defense Science Board (DSB, their families, and the diverse nature of the 1994) and a National Institutes of Health reported illnesses, review and oversight of Technology Assessment Conference (NIH, 1994) research have been important. VA, DoD, HHS, that no single disease entity could be identified and the Executive Office of the President have for the health complaints expressed by Gulf War established multiple oversight mechanisms to veterans. The panel also strongly emphasized capture the full spectrum of the overall effort; the importance of population-based studies, some oversight mechanisms are broad-based, which are currently ongoing in a number of encompassing all research issues, whereas others areas.
61 The final IOM report of September 1996 stands Strengthen the epidemiologic capabilities of as a separate document from its initial January the armed forces; and 1995 report. It is entitled Health Consequences Submit all research (intra- and extramural) of Service During the Persian Gulf War: for peer review publication in a timely Recommendations for Research and Information manner. Systems. (IOM, 1996) The IOM panel stated that it could find no scientific evidence to date Each of these IOM recommendations has been demonstrating adverse health consequences implemented by VA, DoD, and HHS. The associated with service in the Gulf War beyond progress, to date, is summarized below, in the few documented cases of leishmaniasis, Section VII. Research Priorities. combat-related or injury-related mortality or morbidity, and increased risk of psychiatric As authorized by P.L. 102-585 sec. 706, the sequelae of deployment. The panel went on to agreement with IOM has been extended for the state that there is a strong likelihood that no general purposes of providing core single hypothesis could account for all illnesses epidemiological support for research on military reported by Gulf War veterans, whether or not and veteran populations. This support provides a they resulted from service in the Gulf War. valuable infrastructure to carry out Finally, the panel observed that after previous epidemiological research on Gulf War veterans’ wars and conflicts, a proportion of military illnesses. A number of MFUA projects are service personnel and veterans have had medical underway (DoD-69, DoD-93, DoD-116/VA-63, complaints of varying degrees of severity that are and DoD-117). not explainable based on identifiable health hazards or physical illnesses. This observation 2. Executive Office of the President: Presidential echoes work by Hyams et al. (1996) tracing such Advisory Committee on Gulf War Veterans’ a phenomenon back at least to the Civil War. Illnesses (PAC)
The IOM panel made the following research The President established the PAC by Executive recommendations: Order on May 26, 1995. Between August 1995 and January 1997, the Committee met a total of Determine factors for possible response 23 times either as a full Committee or in differences among active and non-active subcommittees. The 12 member committee was duty service members; composed of scientists, health care professionals, Conduct mortality studies on Gulf War veterans, and policy experts. The Committee veterans out to at least 30 years; was charged with reviewing and providing Determine the reason for excess deaths by recommendations on the full range of activities external causes among Gulf War and other relating to the government’s response to Gulf veterans; War veterans’ illnesses. In addition the Continue and extend the Defense Medical Committee evaluated the available data on the Epidemiological Database; nature of Gulf War veterans’ illnesses and on Refine geographical information systems potential health effects related to Gulf War risk (GIS) for troop locations and plan for future factors. conflicts; Conduct reviews of the Total Exposure The Committee released an interim report in Assessment Methodology used to predict February 1996 (PAC, 1996a). Although the pollutant exposure in the Gulf War; Interim Report stated that VA, DoD, and HHS Study gender issues when assessing health research programs were generally well-designed effects of deployment; and should lead to meaningful answers to issues Conduct studies on the consequences of concerning Gulf War veterans-related health assigning men and women to serve together; issues, it also had several recommendations. The Complete and publish the Naval Health Committee’s recommendations covered issues Research Center epidemiology studies; such as peer review, coordination of agency Complete and publish the VA National research activities, the use of public advisory Survey of Persian Gulf Veterans; committees, and the availability of information Complete evaluation of predictors of VA on troop exposures. The Committee made no registry enrollment; findings about specific illnesses or risk factors in the Interim Report. In response to the Interim
62 Report, the agencies developed a coordinated Collect and archive serum samples from plan of action that responded to the Advisory U.S. service personnel when feasible; Committee’s interim recommendations. Conduct basic and clinical research on the The Final Report of the Committee was released physiologic effects of stress and stress- in December 1996 (PAC, 1996b). The PAC related disorders; and came to the following conclusions: The Research Working Group should consult more thoroughly with other Federal Many veterans have illnesses likely to be agencies. connected to service in the Gulf War. Each of these PAC recommendations has been Current scientific evidence does not support implemented by VA, DoD, and HHS. The a causal link between the symptoms and progress, to date, is summarized below, in illnesses reported today by Gulf War Section VII. Research Priorities. veterans and exposures while in the Gulf to: Because of concern over the adequacy of Pesticides investigations into reports of possible chemical and biological warfare exposure incidents during Chemical warfare agents the Gulf War, and because of a need to follow up Biological warfare agents on recommendations from the Committee’s Final Report, the President extended the Committee Vaccines through October 1997. At that time the PAC Pyridostigmine bromide issued a Special Report (PAC, 1997). In the Special Report the Committee did not alter its Infectious diseases findings and conclusions with respect to potential Depleted uranium causes of Gulf War veterans’ illnesses. The Oil well fires and smoke Special Report did not contain any specific recommendations for research. Petroleum products With respect to Federally funded research on The Final Report also concluded that stress Gulf War veterans' illnesses, the PAC concluded (known to affect the brain, immune system, that the government has been adequately and cardiovascular system, and various hormonal appropriately responding to its responses) is likely to be an important recommendations. The PAC particularly contributing factor to Gulf War veterans’ commended the government for its new illnesses. initiatives targeted on health effects of low-level exposure to chemical warfare (CW) agents. As The Final Report made the following research the PAC noted in its Final Report, "the amount recommendations: of data from either human or animal research on low-level exposures [to CW agents] is minimal." Require any new large-scale epidemiologic However, in its Special Report, the PAC studies to have scientific and public advisory concluded that planned research on the health committees; effects of low-level exposure may address any uncertainties and inconclusiveness identified in Develop more accurate and reliable troop the Final Report. locator systems; The PAC approved of the government's targeted Plan and conduct further research on low- solicitations for research and the process used to level exposure to organophosphate chemical make such awards. However, the Committee warfare nerve agents; expressed reservations about a perceived deficiency in processes for funding some Monitor Gulf War veterans for increased research projects related to Gulf War veterans' rates of cancer through mortality studies; illnesses. The Committee noted that Conduct research on the health status of “competition and external peer review of individuals with embedded depleted research proposals are essential to guarantee uranium fragments; scientific merit, relevance, and level of priority
63 generally.” The Committee acknowledged that In the inherently difficult area of military benefit can accrue from small-scale, short-term health, research that is conducted before funding on a sole source basis for pilot projects illnesses occur, not after the fact, can help to or to address narrow scientific questions. The assure prompt, effective medical treatment; Committee stated, though, that such approaches to prevent adverse health effects in the first should be rare and that protocols still should be place; and to provide clear information to peer reviewed prior to funding, limited in the veterans who may be adversely affects by amount of funds released, and not subject to such exposures. renewal without competition. The SVAC made the following research The RWG of the PGVCB will continue to recommendations: endorse peer review and competition as the means of obtaining the best research products. DoD should fund research into the health effects of depleted uranium exposure. 3. Senate Committee on Veterans’ Affairs: Report of the Special Investigation Unit DoD should establish a program to improve on Gulf War Illnesses the capacity for rapid and early detection of exposures that may affect troop health The Senate Committee on Veterans’ Affairs during and after deployments; for example undertook a year-long investigation in 1997, and to develop technology to rapidly screen published a comprehensive report in 1998. persons exposed to a wide range of chemical (SVAC, 1998) The Special Investigative Unit toxins, including chemical warfare agents. (SIU) examined the policies and actions of the U.S. government that have had an impact on the DoD and VA should monitor the treatment current health of Gulf War veterans. provided to ill Gulf War veterans on an ongoing basis, especially those with Specific areas of concern were encompassed: the unexplained illnesses, to determine whether DoD’s plans and policies; the intelligence those veterans are getting better or worse community’s role; health risks encountered by over time. U.S. troops during the war; record keeping before, during, and after it; and the VA’s DoD and VA should implement methods to accountability to and responsibilities for Gulf monitor the health status of Gulf War War veterans. veterans over time to provide early detection of future illnesses that may emerge years The major conclusions of the SVAC related to later, such as higher rates of cancer. research were: DoD and VA should establish a birth defects While there does not appear to be any single registry for military service members to “Gulf War Syndrome,” there is a gather statistics on possible reproductive constellation of symptoms and illnesses health effects stemming from battlefield whose cause or causes eludes explanation at exposures. this time. DoD and VA should evaluate treatment There is a great need to monitor those protocols that have been useful for persons veterans who are ill, or who may become ill in the general population who suffer from in the future, to assess whether they are illnesses similar to Gulf War veterans’ getting better or worse and to define better unexplained illnesses, and they should fund the long-term effects they may experience. appropriate clinical programs and research in this area. There is insufficient evidence to prove or disprove that there was an actual low level DoD and VA should fund Gulf War health exposure of any troops to chemical weapon research only through an impartial, scientific nerve agents, or that any of the health effects peer review process, except in the case of some veterans are experiencing were caused the most serious circumstances. by such exposure.
64 Each of the SVAC recommendations has been knowledge and conceptual understanding, implemented by VA, and DoD. The progress, to identifying testable hypotheses, identifying date, is summarized below, in Section VII. potential research approaches, reviewing Research Priorities. research concepts as they are developed, collecting and disseminating scientifically peer- 4. Other Oversight reviewed research information, and insuring that appropriate peer review and oversight are applied In addition to the broad oversight that has been to research conducted and sponsored by the provided by the three committees cited above, Federal Government. Membership on the there are several standing and special committees Research Working Group consists of senior responsible for oversight on individual research research scientists and clinical managers from projects and programs. The RWG also continues VA, DoD, HHS, and EPA. to encourage that all large epidemiological studies establish public advisory groups that Programmatic Review of Extramural Research include representation of Gulf War veterans. Proposals Additionally, valuable review and oversight has been provided by the House Committee on An important function of the RWG is Veterans’ Affairs, the House Committee on programmatic review of research proposals that Government Reform, the Presidential Special have been competitively reviewed and Oversight Board, and the General Accounting recommendation to funding agencies. Figure V-1. Office. illustrates the general approach the RWG has taken to extramural research (research funded by an C. Research Coordination agency, but carried out by organizations outside of the agency such as universities, private laboratories, or other independent government agencies). The In 1993, VA, DoD, and HHS recognized the RWG works collectively with VA, DoD, and HHS importance of a coordinated approach to research to establish research needs and identify agency- on Gulf War veterans’ illnesses and formed the specific funding mechanisms to support that “Persian Gulf Interagency Research research. For a specific research funding activity, Coordinating Council.” In January 1994, the the responsible funding agency works in Secretaries of VA, DoD, and HHS formed the coordination with the RWG to develop a targeted Persian Gulf Veterans Coordinating Board. The solicitation for research. Research Coordinating Council became the Research Working Group, operating under the Proposals that are submitted to the funding agency auspices of the Coordinating Board. Because of in response to a solicitation are scientifically peer- the potential link between environmental factors reviewed using agency-specific peer review and Gulf War veterans’ illnesses, the programs. For example, the Department of the Environmental Protection Agency was asked to Army in DoD uses a contract with the American be a member of the Research Working Group. Institute of Biological Sciences. Abstracts of peer- reviewed proposals, summaries of the reviews of The Research Working Group includes various the peer-reviewers, and the scientific merit scores subcommittees that have been in existence over assigned by the peer-reviewers, are provided to a the past several years. The Planning subcommittee of the RWG charged with providing Subcommittee for Annual Meetings of Federal secondary review of proposals for relevance. Researchers has been responsible for organizing Relevance determinations are guided by four meetings of Federally funded researchers, interagency programmatic needs articulated and is currently planning a fifth. These meetings through the RWG process and reflected in the provide an opportunity for researchers to gather Working Plan for Research (1996b). In its together to share recent research results and to secondary review the RWG may re-rank proposals discuss research problems of mutual interest. based on relevance, but it will not recommend The 2001 conference will be an open meeting funding for any non-meritorious proposal, allowing for extensive interactions among irrespective of relevance or funds availability. The researchers, veterans, and other members of the RWG has no budget authority, therefore all final public. funding decisions about research are made by the individual agencies. The RWG is charged with assessing the state and direction of research, identifying gaps in factual
65 66 Figure V-1 RWG Funding Process
RWG Reviews Submissions RWG Re-Ranks RWG Makes for Relevance Submissions Recommendations to Funding Agency
Submissions Peer-Reviewed and Ranked for Merit
Agency RWG Research Funding Develops Need Determination Solicitations
Though scientists within intramural research Coordination and oversight of programs do not compete for their funding in the implementation of relevant same way as non-federal extramural scientists, recommendations of the Institute of the RWG works with agencies to ensure that Medicine, Presidential Advisory intramural programs and projects are adequately Committee, Senate Veterans peer-reviewed. Affairs Committee, and the Presidential Review Directive 5 The RWG will continue to work diligently to (IOM, 1995, 1996; PAC, 1996a, foster the highest standards of competition and 1996b, 1997; SVAC, 1998; NSTC, peer-review for all research on Gulf War 1998); veterans’ illnesses. Two national treatment trials Notable among the activities of the RWG are: (exercise/behavior trial and Development, production, and antibiotic treatment trial); dissemination of the 1995 A Working Plan for Research on Organization of an international Persian Gulf Veterans’ Illness symposium in 1997, in conjunction (PGVCB, 1995b), and its 1996 with the Society of Toxicology on revision (PGVCB, 1996b); the health effects of low-level exposure to chemical warfare nerve Production and dissemination of agents; Annual Reports to Congress for 1994 through 1999 on progress, Development of a strategy for status, and results of Federal research on the health effects of research activities (PGVCB, 1995a; exposure to low-levels of chemical 1996a; 1997; 1998; 1999a); warfare nerve agents;
Secondary programmatic review of Follow-up investigation of research proposals submitted to preliminary reports of positive funding agencies; experimental serological tests for leishmaniasis in Gulf War veterans. Organization of meetings of Federally funded researchers (four meetings, fifth in planning);
67 VII. RESEARCH PRIORITIES 2. Information on the prevalence of symptoms, illnesses, and/or diseases within The Research Working Group has identified the indigenous populations within the Persian three sets of research priorities in 1995, 1996, Gulf area including Saudi Arabia and and 1999. Substantial progress has been made Kuwait. on each of these priorities, which is summarized 3. Information on the prevalence of here. adverse reproductive outcomes among Persian Gulf veterans and their spouses. A. RESEARCH PRIORITIES FOR 1995 4. Simple and sensitive tests for L. tropica infection that could lead to quantification of Since veterans returning from the Gulf War the prevalence of L. tropica infection among began to report symptoms and illnesses in 1992, Persian Gulf veterans. a significant number of research activities have 5. Information on the long-term, cause- been undertaken. In 1995, the scope and specific mortality among Persian Gulf magnitude of the research effort required veterans. implementation of a comprehensive plan. This resulted in the publication of A Working Plan for Each of these research issues has been addressed Research on Persian Gulf Veterans’ Illnesses on since 1995, as follows: August 5, 1995, by the Persian Gulf Veterans Coordinating Board. (PGVCB, 1995b) The 1. The U.S. Government has coordinated Working Plan was coordinated by the its research effort with the UK and Canada, as Department of Veterans Affairs (VA), in coalition partners in the Gulf War. The UK conjunction with the PGVCB. The plan mapped fielded the second largest force during the Gulf out the course by which the following goals War, including 53,000 service members. The could be pursued: US DoD has funded epidemiological research in the UK, which has compared the health of Establish the nature and prevalence of British Gulf War veterans, Bosnia veterans, and symptoms, diagnosable illnesses, and non-deployed veterans (projects DoD-39 and unexplained conditions among Persian Gulf DoD-106). The results of the first phase of the veterans in comparison to appropriate British investigation have been published. control groups. (Unwin, et al, 1999; Ismail, et al, 1999) The Canadian government has published a Identify the possible risk factors for any comprehensive study of the health of Canadian illnesses, beyond those expected to occur, Gulf War veterans, compared to non-deployed among Persian Gulf veterans. veterans. (Goss Gilroy, et al, 1998) Denmark also participated in the Gulf War as a coalition Identify appropriate diagnostic tools, partner, primarily in the post-war period after treatment methods, and prevention April 1991. American scientists are strategies for any excess illness conditions collaborating with researchers in Denmark on a found among Persian Gulf veterans. study of neuropsychological function in Danish soldiers (project HHS-5). A key component of the 1995 Working Plan was an assessment of current knowledge and research 2. Because the health status of Saudi Arabian on Gulf War veterans’ illnesses. This soldiers has not been systematically assessment led to the identification of 19 addressed, a team of U.S. researchers from research questions-later expanded to 21 DoD and CDC started an epidemiology questions-which are included below in the study of the Saudi Arabian National Guard section on research priorities for 1996. in 1999 (DoD-120). The objective is to examine available computerized databases This assessment also led to the identification of for unusual health trends, comparing the following issues for which significant gaps in soldiers who were stationed in a combat area knowledge existed in 1995: in January 1991 (Al Khafji), with soldiers who were stationed in a non-combat area 1. Information on the prevalence of (Riyadh). Rates and causes of symptoms, illnesses, and/or diseases within hospitalizations and outpatient visits will be other coalition forces. compared.
68 3. Nine projects include research objectives a) shorter-term objectives; b) long-term related to the prevalence of adverse objectives; and c) a comprehensive list of 21 reproductive outcomes among Gulf War research questions. veterans and their spouses. Two of these projects have been completed (HHS-4 and a. 1996 Short Term Objectives DoD-1C), and their results have been published. (Penman and Tarver, 1996; Emerging findings from ongoing research in Cowan, et al, 1997; Araneta, et al, 1997) 1995 and 1996, and new factual information on Five of these projects were completed the potential for chemical weapons exposure in recently, but have not published results yet southern Iraq in 1991 led to the following (VA-2, VA-47, DoD-1D, DoD-1G, and specific, near-term recommendations for DoD-44). Two projects are ongoing (DoD- additional research: 30 and DoD-35). 1. More longitudinal follow-up studies of the 4. Eight projects have focused on the health of Persian Gulf veterans, including development of simple, sensitive tests for those with illnesses that are difficult to leishmaniasis that could lead to diagnose. quantification of the prevalence of infection, 2. Critical peer-review of models used to as well as new treatment methods. Five of predict exposure concentrations of these projects have been completed and have environmental pollution (such as the Kuwait led to several publications (VA-6E, VA-16, oil well fires) and chemical warfare agents DoD-8A, DoD-9, and DoD-38). Three of (such as the demolition of weapons storage these projects are ongoing (VA-15, DoD-8B, sites at Khamisiyah in March 1991, and and DoD-95). aerial bombing of chemical weapons facilities during the air war). 5. The long-term mortality of Gulf War 3. Assessment of the potential for clinical veterans will be followed by the VA for investigations of the health status of the many years (project VA-1). Three service members in the vicinity of publications have focused on the causes of Khamisiyah when weapons bunker 73 and mortality among Gulf War veterans, the storage pit were detonated in March compared to non-deployed veterans. 1991. If deemed possible, such clinical (Helmkamp, 1994; Writer, et al, 1996; Kang investigations should be carried out. and Bullman, 1996) The major finding was that there was an increased mortality risk Each of these research issues has been addressed due to external causes (e.g., motor vehicle since 1996, as follows: accidents) among Gulf War veterans. 1. Five studies include longitudinal follow-up B. RESEARCH PRIORITIES FOR 1996 of Gulf War veterans, in Boston, New Orleans, New Jersey, Iowa, and the United In 1995 and 1996, the number of research Kingdom. These studies are summarized in programs investigating Gulf War veterans’ Section IV.C. of this Annual Report for illnesses increased substantially. Many research 1999. programs began to produce results. One major development in 1996 was the information about 2. Several publications have described the potential exposures to chemical weapons due to results of models of the oil well fire smoke the demolitions at Khamisiyah. The addition of and potential releases of chemical weapons, new research, results of ongoing research, and all of which have been peer reviewed. The new information about potential exposures modeling of environmental pollution formed the basis of a new assessment of released by the Kuwaiti oil well fires has knowledge and research. This changed the been described in detail. (Office of the context in which the research was conducted and Special Assistant for Gulf War Illnesses necessitated a revision of the 1995 Working (OSAGWI), 1998; Spektor, 1998) The Plan. The 1996 report was entitled A Working results of modeling of the potential release Plan for Research on Persian Gulf Veterans’ of chemical weapons, due to the demolitions Illnesses, First Revision. (PGVCB, 1996b) This at Khamisiyah in March 1991, have been report identified three sets of research objectives: reported by two agencies. (OSAGWI, 1997;
69 CIA, 1997) The results of modeling of the 1. Many projects are focusing on the risk potential release of chemical weapons, due factors for the development of stress-related to aerial bombing of facilities during the air disorders, including post-traumatic stress war, have also been published by two disorder. Several studies that focused on agencies. (CIA, 1996; OSAGWI, 2000) stress-related disorders were published in Only two sites that were bombed during the 1999. (Anger, et al, 1999; Binder, et al, air war might have released chemical 1999; Dlugosz, et al, 1999; Gray, et al, weapons-Al Muthanna and Muhammadiyat. 1999a; Lange, et al, 1999; Wolfe, et al, Both of these sites were hundreds of 1999a; Wolfe, 1999b) kilometers from the closest U.S. troops. (OSAGWI, 2000) 2. An increased risk for mortality due to external causes has been observed in 3. Three investigations are focusing on the veterans of both the Vietnam War and the potential health effects among service Gulf War. One project funded in 1999 is members who were near Khamisiyah at the evaluating the risk factors responsible for time of the demolitions in 1991 (DoD-1B, the observed increase in mortality due to DoD-63, and DoD-69). One of these studies motor vehicle accidents in Gulf War (DoD-1B) is complete and published. veterans (DoD-102). (Gray, et al, 1999c) 3. Three projects are focusing on the b. 1996 Long Term Objectives development of sensitive, specific biomarkers of exposure to chemical agents, Additional research on health-related issues including organophosphate nerve agents and arising from the Gulf War experience, but with vesicants such as sulfur mustard (VA-6D, potential for more general applicability to future VA-47, and DoD-49). Several studies conflicts, was also recommended in 1996, related to mustard agent have been including: published.
1. Investigation of the risk factors for the 4. Fifteen toxicological projects are focusing development of stress-related disorders on the potential long-term health effects including, but not limited to, post-traumatic resulting from low-level, subclinical stress disorder (PTSD). exposures to chemical agents, including one 2. Investigation of the risk factors responsible project funded in 1999 (DoD-113). Most of for the observed excess mortality due to these projects are focusing on sarin. external causes (e.g., motor vehicle accidents) in veterans of all wars and Four epidemiological research projects are conflicts. focusing on the potential long-term health 3. Exploration of the development of practical, effects resulting from low-level, subclinical sensitive, and specific biomarkers of nerve agent exposures. Three projects are exposure to chemical agents, including focusing on possible sarin exposures due to organophosphate nerve agents and vesicants the demolitions at Khamisiyah. (DoD-1B, such as sulfur mustard. DoD-63, and DoD-69) One project, funded 4. Toxicological and, where feasible, in 1999, is evaluating the long-term effects epidemiological research on the potential for of sarin and other nerve agents on volunteers long-term health effects resulting from low- who participated in experiments at Aberdeen level, sub-clinical exposures to chemical Proving Grounds in the 1950s to 1970s agents, particularly organophosphate agents (DoD-93). such as sarin. 5. Development of a strategic plan for research 5. A strategic research plan was developed, into the potential long-term health entitled “Effects of Low-Level Exposure to consequences of exposure to low-levels of Chemical Warfare Agents: A Research chemical warfare agents. Strategy.” An interagency committee wrote it, including members from VA, DoD, CDC, Each of these research issues has been addressed and the Environmental Protection Agency since 1996, as follows: (EPA). It was published in the Annual
70 Report to Congress for 1997. (PGVCB, KHAMISIYAH, IRAQ, IN THE PERSIAN GULF AS A 1998) FUNCTION OF SPACE AND TIME? c. Comprehensive List of 21 Research Questions 7. WHAT WAS THE PREVALENCE OF PB USE AMONG PERSIAN GULF TROOPS? In 1995, the Research Working Group identified 19 major research questions, to which two 8. WHAT WAS THE PREVALENCE OF VARIOUS additional questions were added in 1996. The PSYCHOPHYSIOLOGICAL STRESSORS AMONG comprehensive Gulf War research portfolio has GULF WAR VETERANS? IS THE PREVALENCE addressed each of these 21 questions, and DIFFERENT FROM THAT OF AN APPROPRIATE relevant results have been published on each one. CONTROL POPULATION? In early 2000, the RWG formed a subcommittee to follow up and write a response to the 1996 9. ARE PERSIAN GULF VETERANS MORE LIKELY Gulf War Research Plan Questions. The THAN AN APPROPRIATE COMPARISON GROUP TO response will be in the format of a coherent EXPERIENCE NON-SPECIFIC SYMPTOMS AND series of peer reviewed journal articles that will SYMPTOM COMPLEXES? be submitted to a major journal. Each article will cover various topics from the 1996 Research 10. DO PERSIAN GULF VETERANS HAVE A GREATER Questions. The Chair of the RWG, Dr. John PREVALENCE OF ALTERED IMMUNE FUNCTION Feussner, is the editor of these articles. OR HOST DEFENSE WHEN COMPARED WITH AN Submission to a journal is expected in 2001. APPROPRIATE CONTROL GROUP?
21 Research Questions Highlighted in the 11. IS THERE A GREATER PREVALENCE OF BIRTH 1996 A Working Plan for Research DEFECTS IN THE OFFSPRING OF PERSIAN GULF VETERANS THAN IN AN APPROPRIATE CONTROL 1. WHAT IS THE PREVALENCE OF POPULATION? SYMPTOMS/ILLNESSES IN THE PERSIAN GULF VETERAN POPULATION? HOW DOES THIS 12. HAVE PERSIAN GULF VETERANS EXPERIENCED PREVALENCE COMPARE TO THAT IN AN LOWER REPRODUCTIVE SUCCESS THAN AN APPROPRIATE CONTROL GROUP? APPROPRIATE CONTROL POPULATION?
2. WHAT WAS THE OVERALL EXPOSURE OF 13. IS THE PREVALENCE OF SEXUAL DYSFUNCTION TROOPS TO LEISHMANIA TROPICA? GREATER AMONG PERSIAN GULF VETERANS THAN AMONG AN APPROPRIATE COMPARISON 3. WHAT WERE THE EXPOSURE CONCENTRATIONS POPULATION? TO VARIOUS PETROLEUM PRODUCTS, AND THEIR COMBUSTION PRODUCTS, IN TYPICAL USAGE 14. DO GULF WAR VETERANS REPORT MORE DURING THE PERSIAN GULF CONFLICT? PULMONARY SYMPTOMS, OR DIAGNOSES, THAN PERSONS IN APPROPRIATE CONTROL GROUPS? 4. WHAT WAS THE EXTENT OF EXPOSURE TO SPECIFIC OCCUPATIONAL/ENVIRONMENTAL 15. DO GULF WAR VETERANS HAVE A SMALLER HAZARDS KNOWN TO BE COMMON IN THE BASELINE LUNG FUNCTION IN COMPARISON TO PERSIAN GULF VETERANS EXPERIENCE? WAS AN APPROPRIATE CONTROL GROUP? DO GULF THIS EXPOSURE DIFFERENT FROM THAT OF AN WAR VETERANS HAVE A GREATER DEGREE OF APPROPRIATE CONTROL GROUP? NON-SPECIFIC AIRWAY REACTIVITY IN COMPARISON TO AN APPROPRIATE CONTROL 5. WHAT WERE THE POTENTIAL EXPOSURES OF GROUP? TROOPS TO ORGANOPHOSPHORUS NERVE AGENT AND/OR SULFUR MUSTARD AS A RESULT OF 16. IS THERE A GREATER PREVALENCE OF ORGANIC ALLIED BOMBING AT MUHAMMADIYAT AND AL NEUROPSYCHOLOGICAL AND NEUROLOGICAL MUTHANNA, OR THE DEMOLITION OF A DEFICITS IN PERSIAN GULF VETERANS WEAPONS BUNKER AT KHAMISIYAH? COMPARED TO APPROPRIATE CONTROL POPULATIONS? 6. WHAT WAS THE EXTENT OF EXPOSURE TO CHEMICAL AGENT, OTHER THAN AT 17. CAN SHORT-TERM, LOW-LEVEL EXPOSURES TO PYRIDOSTIGMINE BROMIDE, THE INSECT
71 REPELLANT DEET, AND THE INSECTICIDE (CFS) and Fibromyalgia (FM). As with Gulf PERMETHRIN, ALONE OR IN COMBINATION, War veterans’ illnesses, no clearly defined CAUSE SHORT-TERM AND/OR LONG-TERM etiologic agent has been identified for CFS and NEUROLOGICAL EFFECTS? FM.
18. DO PERSIAN GULF VETERANS HAVE A With these observations in mind, the RWG SIGNIFICANTLY HIGHER PREVALENCE OF thought that experimental treatment methods that PSYCHOLOGICAL SYMPTOMS AND/OR have been applied to persons with CFS or FM DIAGNOSES THAN DO MEMBERS OF AN deserved further exploration in the context of APPROPRIATE CONTROL GROUP? Gulf War veterans’ illnesses. Consequently, the RWG established the development of treatment 19. WHAT IS THE PREVALENCE OF LEISMANIASIS protocols for unexplained illnesses as a research AND OTHER INFECTIOUS DISEASES IN THE GULF priority. In 1998, VA and DoD designed two WAR VETERAN POPULATION? major multi-site treatment trials. Protocols for these two trials were funded and began recruiting 20. DO GULF WAR VETERANS HAVE A GREATER subjects in 1999. Details of these two trials are RISK OF DEVELOPING CANCERS OF ANY TYPE provided in Section IV.C. of this Annual Report WHEN COMPARED WITH AN APPROPRIATE for 1999. Total investment by VA and DoD for CONTROL POPULATION? these two trials are more than $7 million and $5 million, respectively. 21. ARE GULF WAR VETERANS EXPERIENCING A HIGHER MORTALITY RATE THAN THAT OF AN In addition, VA has funded an Institute of APPROPRIATE CONTROL POPULATION? ARE Medicine study to identify effective treatments SPECIFIC CAUSES OF DEATH RELATED TO for health problems in Gulf War veterans. This SERVICE IN THE PERSIAN GULF REGION? 18-month study started in 1999 and it is described in some detail in Section IV.B. of this C. RESEARCH PRIORITIES FOR 1998 Annual Report for 1999.
During 1998, the Research Working Group 2. Longitudinal Follow-Up for Gulf War reevaluated the issue of research priorities. Veterans’ Illnesses (PGVCB, 1999a) Key factors that guided the RWG in it discussions were: recent research Several individual research projects funded by findings; the current breadth and depth of the the Federal Government have longitudinal research portfolio in key areas; and the components built into them. These projects are availability of resources to develop needed new directed toward understanding the progress of initiatives. Gulf War veterans’ illnesses over time. The RWG has concluded that research approaches to 1. Research on Treatments for Gulf War determine the long-term health of veterans are a Veterans’ Illnesses high priority. In 1999, a number of initiatives were ongoing related to this need for longitudinal The RWG continues to review the growing studies. Currently, there are five studies that population-based epidemiological evidence, include longitudinal follow-up, in Boston, New including recent publications by the CDC Orleans, New Jersey, Iowa, and the United (Fukuda, et al. 1998) and by researchers from Kingdom. These studies are summarized in Great Britain (Unwin, et al. 1999). These Section IV.C. of this Annual Report for 1999. suggested that some Gulf War veterans with unexplained illnesses are suffering from a 3. Disease Prevention complex of symptoms such as fatigue, musculoskeletal pain, and cognitive problems. The substantial proportion of veterans who have These studies, along with smaller clinical studies, reported ill health following deployment to the have been unable to define a specific syndrome Gulf War represents a significant level of to date, or to assign a specific cause for these morbidity that might be preventable. To ensure symptom complexes. These symptom that future health problems in future deployments complexes significantly overlap with other can be prevented, the RWG has endorsed future symptom complexes identified in the civilian research aimed generally at disease prevention, population such as Chronic Fatigue Syndrome and more specifically at prevention of stress-
72 related symptoms and conditions. As a result of 5. improved and accelerated research on RWG recommendations in the past, the Federal prevention, diagnosis, and treatment of investment focusing on the pathophysiology of microbial infections. stress-related illnesses has markedly increased. There are currently about 75 projects with a primary or secondary focus on the Brain and Nervous System. With this investment in better understanding of the pathophysiology of stress- related illnesses, it is also appropriate to initiate research that can take advantage of new findings in that area and how they might lead to better disease prevention and treatment.
4. Improved Hazard Assessment
The Presidential Review Directive-5 recognized that the ability to better anticipate potential environmental and occupational hazards prior to deployments could reduce morbidity associated with unintended or unanticipated exposures. (NSTC, 1998) The RWG, in conjunction with the Working Groups that developed the PRD-5, recommended enhanced research efforts aimed at improving methods of hazard identification and risk assessment for environmental and occupational hazards. Such research efforts should emphasize the reality of complex multiple exposures to more than one hazardous agent.
In 1998, the DoD established new funding for programmed research. The purpose of this program element funding, explicitly put into DoD’s budget requests, was to address issues of Gulf War Veterans’ Illnesses, which may also be of concern in future deployments. The funding is approximately $20 million per year for Fiscal Years 1999 to 2002, and $5 million per year thereafter. The overall objective is to enhance force health protection in future deployments. The program is guided by a tri-service DoD panel and is coordinated with the RWG. Specific research thrust areas in 1999 and 2000 have included:
1. prevention and treatment of persistent stress symptoms, 2. methods to assess health hazards from toxic chemicals and mixtures and to monitor exposures, 3. improved safety assessments of medical materiel, including potential interactions in operational environments, 4. epidemiological studies to continue long- term follow-up of Gulf War veterans and to improve health status monitoring in future deployments, and
73 VIII. REFERENCES at the Khamisiyah Pit. Washington, DC: CIA and DOD; 1997. VIII.A. General References (for all sections, except Section IV.C.4.) Cowan, DN, DeFraites, RF, Gray, GC, Goldenbaum, MB, and Wishik, SM. The risk of Anger, WK, Storzbach, D, Binder, LM, birth defects among children of Persian Gulf War Campbell, KA, Rohlman, DS, McCauley, L, veterans. New England Journal of Medicine Kovera, CA, and Davis, KL. Neurobehavioral 1997; 336(23):1650-6. deficits in Persian Gulf veterans: evidence from a population-based study. Journal of the Defense Science Board. Final Report: Defense International Neuropsychological Society 1999; Science Board Task Force on Persian Gulf War 5(3):203-212. Health Effects. Washington, DC: Office of the Under Secretary of Defense for Acquisition and Araneta, MR, Moore, CA, Olney, RS, Edmonds, Technology; 1994. LD, Karcher, JA, McDonough, C, Hiliopoulos, KM, Schlangen, KM, and Gray, GC. Goldenhar Dlugosz, LJ, Hocter, WJ, Kaiser, KS, Knoke, JD, syndrome among infants born in military Heller, JM, Hamid, NA, Reed, RJ, Kendler, KS, hospitals to Gulf War veterans. Teratology and Gray, GC. Risk factors for mental disorder 1997; 56:244-51. hospitalization after the Persian Gulf war: U.S. Armed Forces, June 1, 1991-September 30, Binder LM, Storzbach, D, Anger, WK, 1993. Journal of Clinical Epidemiology 1999; Campbell, KA, and Rohlman, DS. Subjective 52(12):1267-1278. cognitive complaints, affective distress, and objective cognitive performance in Persian Gulf Drake-Baumann, R, and Seil, FJ. Effects of War veterans. Archives of Clinical exposure to low-dose pyridostigmine on Neuropsychology 1999; 14(6):531-536. neuromuscular junctions in vitro. Muscle and Nerve 1999; 22(6):696-703. Black, DW, Doebbeling, BN, Voelker, MD, Clarke, WR, Woolson, RF, Barrett, DH, and Friedman, A, Kaufer, D, Shemer, J, Hendler, I, Schwarz, DA. Multiple chemical sensitivity Soreq, H, Tur-Kaspa, I. Pyridostigmine brain syndrome: symptom prevalence and risk factors penetration under stress enhances neuronal in a military population. Archives of Internal excitability and induces early immediate Medicine 2000; 160(8):1169-1176. transcriptional response. Nature Medicine 1996; 2(12):1382-1385. Burchfiel, JL, Duffy, FH, and Van Sim, M. Persistent effects of sarin and dieldrin upon the Fukuda, K, Nisenbaum, R, Stewart, G, primate electroencephalogram. Toxicology and Thompson, WW, Robin, L, Washko, RM, Noah, Applied Pharmacology 1976; 35(2);365-379. DL, Barrett, DH, Randall, B, Herwaldt, BL, Mawle, AC, and Reeves, WC. Chronic Centers for Disease Control and Prevention multisymptom illness affecting Air Force (CDC). The Health Impact of Chemical veterans of the Gulf War. Journal of the Exposures During the Gulf War: A Research American Medical Association 1998; Planning Conference. Atlanta: CDC; 2000. 280(11):981-8.
Chaney, LA, Rockhold, RW, Wineman, RW, GAO (General Accounting Office). Gulf War and Hume, AS. Anticonvulsant-resistant Illnesses: Improved Monitoring of Clinical seizures following pyridostigmine bromide (PB) Progress and Reexamination of Research and N,N-diethyl-m-toluamide (DEET). Emphasis Are Needed (GAO/NSIAD-97-163). Toxicological Sciences 1999; 49(2):306-311. Washington, DC: U.S. Government Printing Office; 1997. CIA (Central Intelligence Agency). CIA Report on Intelligence Related to Gulf War Illnesses. Washington, DC: CIA; 1996.
CIA and Department of Defense (DoD). Modeling the Chemical Warfare Agent Release
74 Goss Gilroy, Inc. and Canadian Department of IOM (Institute of Medicine). An Assessment of National Defence. Health Study of Canadian the Safety of the Anthrax Vaccine: A Letter forces personnel involved in the 1991 conflict in Report. Washington, DC: National Academy the Persian Gulf. Ottawa, Ontario: Goss Gilroy, Press; March 30, 2000. Inc.; 1998. IOM. Gulf War Veterans: Measuring Health. Gray, GC, Kaiser, KS, Hawksworth, AW, Hall, Washington, DC: National Academy Press; FW, and Barrett-Connor, E. Increased postwar 1999a. symptoms and psychological morbidity among U.S. Navy Gulf War veterans. American IOM. Health Consequences of Service During Journal of Tropical Medicine and Hygiene the Persian Gulf War: Initial Findings and 1999a; 60(5):758-766. Recommendations for Immediate Action. Washington, DC: National Academy Press; Gray, GC, Kaiser, KS, Hawksworth, AW, and 1995. Watson, HL. No serologic evidence of an association found between Gulf War service and IOM. Health Consequences of Service During Mycoplasma fermentans infection. American the Persian Gulf War: Recommendations for Journal of Tropical Medicine and Hygiene Research and Information Systems. Washington, 1999b; 60(5):752-757. DC: National Academy Press; 1996.
Gray, GC, Smith, TC, Kang, HK and Knoke, JD. IOM. National Center for Military Deployment Are Gulf War veterans suffering war-related Health Research. Washington, DC: National illnesses? Federal and civilian hospitalizations Academy Press; 1999b. examined, June 1991 to December 1994. American Journal of Epidemiology 2000; Ismail, K, Everitt, B, Blatchley, N, Hull, L, 151(1):63-71. Unwin, C, David, A, and Wessely, S. Is there a Gulf War syndrome? Lancet 1999; 353:179-82. Gray, GC, Smith, TC, Knoke, JD, and Heller, JM. The postwar hospitalization experience of Kaiser, KS, Hawksworth AW, and Gray GC. Gulf War veterans possibly exposed to chemical Pyridostigmine bromide intake during the munitions destruction at Khamisiyah, Iraq. Persian Gulf War is not associated with handgrip American Journal of Epidemiology 1999c; strength. Military Medicine 2000; 165(3):165- 150(5):532-540. 168.
Helmkamp, JC. United States military casualty Kang, HK, and Bullman, TA. Mortality among comparisons during the Persian Gulf War. U.S. veterans of the Persian Gulf War. New Journal of Occupational Medicine 1994; England Journal of Medicine 1996; 36(6):609-615. 335(20):1498-1504.
Hooper, FJ, Squibb, KS, Siegle, EL, McPhaul, Kipen, HM, Hallman, W, Kang, H, Fiedler, N, K, and Keogh, JP. Elevated urine uranium and Natelson, BH. Prevalence of chronic fatigue excretion by soldiers with retained uranium and chemical sensitivities in Gulf Registry shrapnel. Health Physics 1999; 77(5):512-519. veterans. Archives of Environmental Health 1999; 54(5):313-318. Hoy, JB, Cody, BA, Karlix, JL, Schmidt, CJ, Tebbett, IR, Toffollo, S, Van Haaren, F, and Lange, G, Tiersky, L, DeLuca, J, Peckerman, A, Wielbo, D. Pyridostigmine bromide alters Pollet, C, Policastro, T, Scharer, J, Ottenweller, locomotion and thigmotaxis of rats: gender JE, Fiedler, N, and Natelson, BH. Psychiatric effects. Pharmacology, Biochemistry, and diagnoses in Gulf War veterans with fatiguing Behavior 1999; 63(3):401-406. illness. Psychiatric Research 1999; 89(1):39-48.
Hyams, KC, Wignall, FS, and Roswell, R. War McCauley, LA, Joos, SK, Lasarev, MR, syndromes and their evaluation: from the U.S. Storzbach, D, and Bourdette, DN. Gulf War Civil War to the Persian Gulf War. Annals of unexplained illnesses: persistence and Internal Medicine 1996; 125(5):398-405. unexplained nature of self-reported symptoms. Environmental Research 1999a; 81(3):215-223.
75 McCauley, LA, Joos, SK, Spencer, PS, Lasarev, OSAGWI. Oil Well Fires Environmental M, and Schuell, T. Strategies to assess validity Exposure Report. Washington, DC: DoD; 1998. of self-reported exposures during the Persian Gulf War. Environmental Research 1999b; OSAGWI. The Use of Modeling and Simulation 81(3):195-205. in the Planning of Attacks on Iraqi Chemical and Biological Warfare Targets. Washington, DC: McDiarmid, MA, Keogh, JP, Hooper, FJ, DoD; 2000. McPhaul, K, Squibb, K, Kane, R, DiPino, R, Kabat, M, Kaup, B, Anderson, L, Hoover, D, Pearce, PC, Crofts, HS, Muggleton, NG, Ridout, Brown, L, Hamilton, M, Jacobson-Kram, D, D, and Scott, EA. The effects of acutely Burrow, B, and Walsh, M. Health effects of administered low dose sarin on cognitive depleted uranium on exposed Gulf War veterans. behaviour and the electroencephalogram in the Environmental Research 2000; 82(2):168-180. common marmoset. Journal of Psychopharmacology 1999; 13(2):128-135. NAS (National Academy of Sciences). Strategies to Protect the Health of Deployed Pellmar, TC, Fuciarelli, AF, Ejnik, JW, U.S. Forces: Analytical Framework for Hamilton, M, Hogan, J, Strocko, S, Emond, C, Assessing Risks. Washington, DC: National Mottaz, HM, and Landauer, MR. Distribution of Academy Press; 2000a. uranium in rats implanted with depleted uranium pellets. Toxicological Sciences 1999a; 49(1):29- NAS. Strategies to Protect the Health of 39. Deployed U.S. Forces: Detecting, Characterizing, and Documenting Exposures. Pellmar, TC, Keyser, DO, Emery, C, and Hogan, Washington, DC: National Academy Press; JB. Electrophysiological changes in 2000b. hippocampal slices isolated from rats embedded with depleted uranium fragments. NAS. Strategies to Protect the Health of Neurotoxicology 1999b; 20(5);785-792. Deployed U.S. Forces: Force Protection and Decontamination. Washington, DC: National Penman, AD, and Tarver, RS. No evidence of Academy Press; 1999a. increase in birth defects and health problems among children born to Persian Gulf War NAS. Strategies to Protect the Health of veterans in Mississippi. Military Medicine 1996; Deployed U.S. Forces: Medical Surveillance, 161(1):1-6. Record Keeping, and Risk Reduction. Washington, DC: National Academy Press; PGVCB (Persian Gulf Veterans Coordinating 1999b. Board). Federal Activities Related to the Health of Persian Gulf Veterans. Washington, DC: NIH (National Institutes of Health Technology Department of Veterans Affairs (VA); 1995a. Assessment Workshop Panel). The Persian Gulf experience and health. Journal of the American PGVCB. A Working Plan for Research on Medical Association 1994; 272(5):391-396. Persian Gulf Veterans’ Illnesses. Washington, DC: VA; 1995b. NSTC (National Science and Technology Council). Presidential Review Directive 5: A PGVCB. Annual Report to Congress: Federally National Obligation-Planning for Health Sponsored Research on Persian Gulf Veterans’ Preparedness for and Readjustment of the Illnesses for 1995. Washington, DC: VA; 1996a. Military, Veterans, and Their Families after Future Deployments. Washington, DC: PGVCB. A Working Plan for Research on Executive Office of the President, Office of Persian Gulf Veterans’ Illnesses, First Revision. Science and Technology Policy; 1998. Washington, DC: VA; 1996b.
OSAGWI (Office of the Special Assistant for PGVCB. Annual Report to Congress: Federally Gulf War Illnesses). U.S. Demolition Sponsored Research on Persian Gulf Veterans’ Operations at the Khamisiyah Ammunition Illnesses for 1996. Washington, DC: VA; 1997. Supply Point. Washington, DC: DoD; 1997.
76 PGVCB. Annual Report to Congress: Federally impact of posttraumatic stress disorder on Sponsored Research on Gulf War Veterans’ physical health. Journal of Traumatic Stress Illnesses for 1997. Washington, DC: VA; 1998. 2000; 13(1):41-55.
PGVCB. Annual Report to Congress: Federally Wallace, HL, Natelson, B, Gause, W, and Hay, J. Sponsored Research on Gulf War Veterans’ Human herpesviruses in chronic fatigue Illnesses for 1998. Washington, DC: VA; 1999a. syndrome. Clinical and Diagnostic Laboratory Immunology 1999; 6(2):216-223. PGVCB. Proceedings of the Conference on Federally Sponsored Gulf War Veterans’ Wolfe J, Erickson DJ, Sharkansky EJ, King, Illnesses Research. Washington, DC: VA; DW, and King, LA. Course and predictors of 1999b. posttraumatic stress disorder among Gulf War veterans: a prospective analysis. Journal of PAC (Presidential Advisory Committee on Gulf Consulting and Clinical Psychology 1999a; War Veterans’ Illnesses). Interim Report. 67(4):520-528. Washington DC: U.S. Government Printing Office; February 1996a. Wolfe, J, Proctor, SP, Erickson, DJ, Herren, T, Friedman, MJ, Huang, MT, Sutker, PB, PAC. Final Report. Washington DC: U.S. Vasterling, JJ, and White, RF. Relationship of Government Printing Office; December 1996b. psychiatric status to Gulf War veterans’ health problems. Psychosomatic Medicine 1999b; PAC. Special Report. Washington DC: U.S. 61(4):532-540. Government Printing Office; October 1997. Writer, JV, DeFraites, RF, and Brundage, JF. SVAC (Senate Veterans’ Affairs Committee). Comparative mortality among U.S. military Report of the Special Investigation Unit on Gulf personnel in the Persian Gulf region and War Illnesses. Washington DC: U.S. worldwide during Operations Desert Shield and Government Printing Office; 1998. Desert Storm. Journal of American Medical Association 1996; 275(2):118-21. Spektor, DM. Oil Well Fires: A Review of the Scientific Literature as It Pertains to Gulf War Illnesses. Washington, DC: RAND; 1998.
Telang, FW, Ding YS, Volkow, ND, Molina, PE, and Gatley, SJ. Pyridostigmine, a carbamate acetylcholinesterase inhibitor and reactivator, is used prophylactically against chemical warfare agents. Nuclear Medicine and Biology 1999; 26(2):249-250.
Unwin, CE, Blatchley, N, Coker, W, Ferry, S, Hotopf, M, Hull, L, Ismail, K, Palmer, I, David, A, and Wessely, S. Health of United Kingdom servicemen who served in the Persian Gulf War. Lancet 1999; 353:169-78.
Van Haaren, F, De Jongh, R, Hoy, JB, Karlix, JL, Schmidt, CJ, Tebbett, IR, and Wielbo, D. The effects of acute and repeated pyridostigmine bromide administration on response acquisition with immediate and delayed reinforcement. Pharmacology, Biochemistry, and Behavior 1999; 62(2):389-394.
Wagner, AW, Wolfe, J, Rotnitsky, A, Proctor, SP, and Erickson, DJ. An investigation of the
77 VIII.B. References for Section IV.C.4.: diagnoses in Gulf War veterans with fatiguing Longitudinal Cohort Studies of Morbidity illness. Psychiatric Research 1999; 89(1):39-48.
Benotsch, EG, Brailey, K, Vasterling, JJ, Uddo, Peckerman, A, LaManca, JL, Smith, SL, Taylor, M, Constans, JI, and Sutker, PB. War zone A, Tiersky, L, Pollet, C, Korn, LR, Hurwitz, BE, stress, personal and environmental resources, and Ottenweller, JE, and Natelson, BH. PTSD symptoms in Gulf War veterans: a Cardiovascular stress responses and their relation longitudinal perspective. Journal of Abnormal to symptoms in Gulf War veterans with fatiguing Psychology 2000; 109(2):205-213. illness. Psychosomatic Medicine July-August 2000: 62(4): 509-516. Black, DW, Doebbeling, BN, Voelker, MD, Clarke, WR, Woolson, RF, Barrett, DH, and Pollet, C, Natelson, BH, Lange, G, Tiersky, L, Schwartz, DA. Multiple chemical sensitivity DeLuca, J, Policastro, T, Desai, P, Ottenweller, syndrome: symptoms prevalence and risk factors J, Korn, L, Fiedler, N, and Kipen, H. Medical in a military population. Archives of Internal evaluation of Persian Gulf veterans with fatigue Medicine 2000; 160(8):1169-1176. and/or chemical sensitivity. Journal of Medicine 1998; 29(3&4):101-113. Doebbeling, BN, Clarke, WR, Watson, D, Torner, JC, Woolson, RF, Voelker, MD, Barrett, Proctor, SP, Heeren, T, White, RF, Wolfe, J, DH, and Schwartz, DA. Is there a Gulf War Borgos, MS, Davis, JD, Pepper, L, Clapp, R, syndrome? Evidence from a large population- Sutker, PB, Vasterling, JJ, and Ozonoff, D. based survey of veterans and nondeployed Health status of Persian Gulf War veterans: self- controls. American Journal of Medicine 2000; reported symptoms, environmental exposures 108(9):695-704. and the effect of stress. International Journal of Epidemiology 1998; 27(6):1000-1010. Hotopf, M, David, A, Hull, L, Ismail, K, Unwin, C, and Wessely, S. Role of vaccinations as risk Sharkansky, EJ, King, DW, King, LA, Wolfe, J, factors for ill health in veterans of the Gulf War: Erickson, DJ, and Stokes, LR. Coping with Gulf a cross sectional study. British Medical Journal War combat stress: mediating and moderating 2000; 320:1363-1367. effects. Journal of Abnormal Psychology 2000; 109(2):188-197. Iowa (Iowa Persian Gulf Study Group). Self- reported illness and health status among Gulf Sutker, PB, Davis, JM, Uddo M, and Ditta, SR. War veterans: a population-based study. Journal Assessment of psychological distress in Persian of American Medical Association 1997; Gulf troops: ethnicity and gender comparisons. 277(3):238-245. Journal of Personality Assessment 1995a; 64(3):415-427. Ismail, K, Everitt, B, Blatchley, N, Hull, L, Unwin, CE, David, A, and Wessely, S. Is there a Sutker, PB, Davis, JM, Uddo, M, and Ditta, SR. Gulf War syndrome? Lancet 1999; 353:179-182. War zone stress, personal resources, and PTSD in Persian Gulf returnees. Journal of Abnormal Kang, HK, and Bullman, TA. Mortality among Psychology 1995b; 104(3):444-452. U.S. veterans of the Persian Gulf War. New England Journal of Medicine 1996; Sutker, PB, Uddo, M, Brailey, K, and Allain, 335(20):1498-1504. AN. War-zone trauma and stress-related symptoms in Operation Desert Shield/Storm Kipen, HM, Hallman, W, Kang, H, Fiedler, N, (ODS) returnees. Journal of Social Issues 1993; and Natelson, BH. Prevalence of chronic fatigue 49(4):33-50. and chemical sensitivities in Gulf Registry veterans. Archives of Environmental Health Sutker, PB, Uddo M, Brailey, K, Allain, NA, and 1999; 54(5):313-318. Errera, P. Psychological symptoms and psychiatric diagnoses in Operation Desert Storm Lange, G, Tiersky, L, DeLuca, J, Peckerman A, troops serving graves registration duty. Journal Pollet, C, Policastro, T, Scharer, J, Ottenweller, of Traumatic Stress 1994a; 7(2):159-171. JE, Fiedler, N, and Natelson, BH. Psychiatric
78 Sutker, PB, Uddo, M, Brailey, K, Vasterling, JJ, Ursano, RJ and Norwood, AE. Washington, DC: and Errera, P. Psychopathology in war-zone American Psychiatric Press, Inc.; 1996. deployed and nondeployed Operation Desert Storm troops assigned graves registration duties. Wolfe, J, Proctor, SP, Davis, JD, Borgos, MS, Journal of Abnormal Psychology 1994b; and Friedman, MJ. Health symptoms reported 103(2):383-390. by Persian Gulf War veterans two years after return. American Journal of Industrial Medicine Unwin, C, Blatchley, N, Coker, W, Ferry, S, 1998a; 33(2):104-113. Hotopf, M, Hull, L, Ismail, K, Palmer, I, David, A, and Wessely, S. Health of UK servicemen Wolfe, J, Proctor, SP, Erickson, DJ, Heeren, T, who served in the Persian Gulf War. Lancet Friedman, MJ, Huang, MT, Sutker, PB, 1999; 353:169-178. Vasterling, JJ, and White, RF. Relationship of psychiatric status to Gulf War veterans’ health VA (Department of Veterans Affairs) Northeast problems. Psychosomatic Medicine 1999b; Program Evaluation Center. Returning Persian 61(4):532-540. Gulf Troops: First Year Findings. West Haven, CT: VA; 1992. Wolfe, J, Sharkansky, EJ, Read, J, Dawson, R, Martin, J, and Ouimette, PC. Sexual harassment Vasterling, JJ, Brailey, K, Constans, JI, Borges, and assault as predictors of PTSD A, and Sutker, PB. Assessment of intellectual symptomatology among U.S. Persian Gulf War resources in Gulf War veterans: relationship to personnel. Journal of Interpersonal Violence PTSD. Assessment 1997; 4(1):51-59. 1998b; 13:40-57.
Vasterling, JJ, Brailey, K, Constans, JI, and Zhang, Q, Zhou, XD, Denny, T, Ottenweller, JE, Sutker, PB. Attention and memory dysfunction Lange, G, LaManca, JJ, Lavietes, MH, Pollet, C, in posttraumatic stress disorder. Gause, WC, and Natelson, BH. Changes in Neuropsychology 1998; 12(10):125-133. immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue Wallace, HL, Natelson, B, Gause, W, and Hay, J. syndrome. Clinical and Diagnostic Laboratory Human herpesviruses in chronic fatigue Immunology 1999; 6(1):6-13. syndrome. Clinical and Diagnostic Laboratory Immunology 1999; 6(2):216-223.
Wagner, AW, Wolfe, J, Rotnitsky, A, Proctor, SP, and Erickson, DJ. An investigation of the impact of posttraumatic stress disorder on physical health. Journal of Traumatic Stress 2000; 13(1):41-55.
Wolfe, J, Brown, PJ, and Kelley, JM. Reassessing war stress: exposure and the Persian Gulf War. Journal of Social Issues 1993; 49(4):15-31.
Wolfe, J, Erickson, DJ, Sharkansky, EJ, King, DW, and King, LA. Course and predictors of posttraumatic stress disorder among Gulf War veterans: a prospective analysis. Journal of Consulting and Clinical Psychology 1999a; 67(4):520-528.
Wolfe, J, Keane, TM, and Young, BL. From soldier to civilian: acute adjustment patterns of returned Persian Gulf veterans; in Emotional Aftermath of the Persian Gulf War, edited by
79