oversight

Gulf War Illnesses: Improved Monitoring of Clinical Progress and Reexamination of Research Emphasis Are Needed

Published by the Government Accountability Office on 1997-06-23.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                   United States General Accounting Office

GAO                Report to the Chairmen and Ranking
                   Minority Members of the Senate
                   Committee on Armed Services and the
                   House Committee on National Security

June 1997
                   GULF WAR
                   ILLNESSES
                   Improved Monitoring
                   of Clinical Progress
                   and Reexamination of
                   Research Emphasis
                   Are Needed




GAO/NSIAD-97-163
             United States
GAO          General Accounting Office
             Washington, D.C. 20548

             National Security and
             International Affairs Division

             B-276835

             June 23, 1997

             The Honorable Strom Thurmond
             Chairman
             The Honorable Carl Levin
             Ranking Minority Member
             Committee on Armed Services
             United States Senate

             The Honorable Floyd Spence
             Chairman
             The Honorable Ronald Dellums
             Ranking Minority Member
             Committee on National Security
             House of Representatives

             Many of the approximately 700,000 veterans of the Persian Gulf War have
             complained of illnesses since the war’s end in 1991. Some fear they are
             suffering from chronic disabling conditions because of wartime exposures
             to one or more agents with known or suspected health effects. This report
             responds to the mandate of the fiscal year 1997 defense authorization act
             that we analyze the effectiveness of the government’s clinical care and
             medical research programs relating to illnesses that members of the armed
             forces might have contracted as a result of their service in the Gulf War.1

             Specifically, we evaluated (1) the Department of Defense’s (DOD) and the
             Department of Veterans Affairs’ (VA) efforts to assess the quality of
             treatment and diagnostic services provided to Gulf War veterans and their
             provisions for follow-up of initial examinations, (2) the government’s
             research strategy to study the veterans’ illnesses and the methodological
             problems posed in its studies, and (3) the consistency of key official
             conclusions with available data on the causes of veterans’ illnesses.


             During their deployment associated with the Persian Gulf War, U.S. troops
Background   might have been exposed to a variety of potentially hazardous substances.
             These substances include compounds used to decontaminate equipment
             and protect it against chemical agents, fuel used as a sand suppressant in
             and around encampments, fuel oil used to burn human waste, fuel in

             1
              Our response to the referenced legislation resulted in two additional studies: Defense Health Care:
             Medical Surveillance Has Improved Since the Gulf War, but Results in Bosnia Are Mixed
             (GAO/NSIAD-97-136, May 13, 1997) and a classified report issued earlier this year on biological agent
             defense.



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                   shower water, leaded vehicle exhaust used to dry sleeping bags, depleted
                   uranium, parasites, pesticides, drugs to protect against chemical warfare
                   agents (such as pyridostigmine bromide), and smoke from oil-well fires.
                   DOD acknowledged in June 1996 that some veterans may have been
                   exposed to the nerve agent sarin following the postwar demolition of Iraqi
                   ammunition facilities.

                   Shortly after the war, some veterans began reporting health problems that
                   they believed might be due to exposure to chemicals, pesticides, and other
                   agents used during the war. Accordingly, both DOD and VA established
                   programs through which Gulf War veterans could receive medical
                   examinations and diagnostic services. From 1992 to 1994, VA participants
                   received a regular physical examination with basic laboratory tests, and in
                   1994, VA established a standardized examination to obtain information
                   about exposures and symptoms related to diseases endemic to the Gulf
                   region and to incorporate specific tests to detect the “biochemical
                   fingerprints” of certain diseases. If a diagnosis was not apparent, the
                   standard examination protocols provided for up to 22 additional tests and
                   provided for additional specialty consultations. If the illness defied
                   diagnosis, VA registrants might have been sent to one of four VA Persian
                   Gulf referral centers.

                   DOD initiated its Comprehensive Clinical Evaluation Program in June 1994.
                   It was primarily intended to provide diagnostic services similar to the VA
                   program and employed a similar clinical protocol. However, the VA
                   program was among the first extensive efforts to gather data from
                   veterans regarding the nature of their problems and the types of hazardous
                   agents to which they might have been exposed. (See app. I for details.)


                   Our review found that (1) although efforts have been made to diagnose
Results in Brief   veterans’ problems and care has been provided to many eligible veterans,
                   neither DOD nor VA has systematically attempted to determine whether ill
                   Gulf War veterans are any better or worse today than when they were first
                   examined; (2) while the ongoing epidemiological research will provide
                   descriptive data on veterans’ illnesses, formidable methodological
                   problems are likely to prevent researchers from providing precise,
                   accurate, and conclusive answers regarding the causes of veterans’
                   illnesses; and (3) support for some official conclusions regarding stress,
                   leishmaniasis, and exposure to chemical agents was weak or subject to
                   alternative interpretations.




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Over 100,000 of the approximately 700,000 Gulf War veterans have
participated in DOD and VA health examination programs established after
the war. Based on the examinations and reports provided by DOD and VA,
nearly 90 percent of the examined veterans are symptomatic, reporting a
wide array of health complaints and disabling conditions. While VA and DOD
health examination programs have sought to evaluate these veterans’
problems and refer eligible veterans for further care, neither DOD nor VA
currently has mechanisms in place to determine whether these ill veterans
are any better or worse today than when they were first examined. Both
agencies have tried to measure or ensure the quality of veterans’ initial
examinations. While some measures of quality are in place for military or
VA health care in general, neither agency can now determine the
appropriateness or effectiveness of the treatment received by ill Gulf War
veterans.2

Federal research on Gulf War veterans’ illnesses has not been pursued
proactively. Although these veterans’ health problems began surfacing in
the early 1990s, the vast majority of research was not initiated until 1994 or
later. And, much of this research was associated with legislation or
external reviewers’ recommendations. Thus, although at least 91 studies
have received federal financial support, about four-fifths of the funded
studies are not complete, and certain studies will not be available until
after 2000. Some hypotheses (for example, that veterans’ current
symptoms are due to stress) were pursued earlier and more aggressively
than others (for example, that symptoms are due to low-level exposure to
chemical warfare agents), and some hypotheses that were initially
unfunded by the federal government (for example, that symptoms are due
to the delayed chronic effects of exposure to organophosphates,3 which
were in pesticides used in the Gulf) were pursued with private sector
funding. In recent years, VA and DOD have significantly broadened their
research programs, to include efforts to seek external advice.

Without accurate exposure information, the investment of millions of
dollars in further epidemiological research on the risk factors (or potential
causes) for veterans’ illnesses may result in little return. The government’s
research has primarily involved epidemiological studies, most of which
focus on the nature and prevalence of the veterans’ symptoms and
illnesses or the identification of causes for the illnesses. While mortality

2
 We are conducting further work addressing medical care provided to Gulf War veterans. See VA
Health Care: Observations on Medical Care Provided to Persian Gulf Veterans (GAO/T-HEHS-97-158,
June 19, 1997).
3
 Organophosphates are a class of chemicals found in some pesticides and chemical warfare agents.



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information and data on the prevalence of various problems may be
valuable, because of formidable methodological problems facing
investigators, epidemiological research on Gulf War veterans’ illnesses will
not be able to provide precise, accurate, and conclusive answers regarding
the causes of veterans’ illnesses. Specifically, studies generally are
hampered by the lack of (1) accurate, person-based, dose-specific
exposure data; (2) known biological markers (such as detectable
antibodies to specific agents or diseases); and (3) specific case definition
(definition of particular syndromes or clusters of symptoms to study).

While some prevalence data may be useful, we agree with the Institute of
Medicine and the Presidential Advisory Committee on Gulf War Veterans’
Illnesses.4 that population-based comparisons that group together veterans
with varied exposures may mask higher rates of illness among veterans
with specific exposure histories. The plans for toxicological research on
the health effects of low-level exposures to various agents will be useful in
efforts to determine whether veterans’ current unexplained symptoms or
conditions are consistent with such exposure. To date, the research
program has not included an assessment of the clinical progress of ill Gulf
War veterans, which is critical to identifying the appropriateness and
effectiveness of their treatment and could be useful to provide direction to
the research agenda.

Six years after the war, little is conclusively known about the causes of
Gulf War veterans’ illnesses. Not only were few strong, conclusive
statements made in the executive branch reports we reviewed, but support
was weak or subject to alternative interpretation for three conclusions
made by the Presidential Advisory Committee and endorsed by DOD. In
addition, two questions remain unresolved.

First, the Committee concluded that stress is likely to be an important
contributing factor to the broad range of illnesses currently being reported
by Gulf War veterans and that studies have found higher rates of
posttraumatic stress disorder (PTSD) in Gulf War veterans. However, the
link between stress and these veterans’ physical symptoms is not well
established in the evidence the Committee cited, and the reported
prevalence of PTSD among Gulf War veterans may be overestimated
because of problems in the methods used in studies to identify it (for
example, there were frequent failures to exclude physical causes for



4
See Presidential Advisory Committee on Gulf War Veterans’ Illnesses, Final Report (Washington, D.C.:
GPO), December 1996.



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                       veterans’ symptoms or to conduct structured clinical interviews, which are
                       necessary components of PTSD diagnosis).

                       Second, based on a small number of diagnosed cases, VA and DOD
                       concluded that the likelihood of leishmania tropica (a parasite) as an
                       important risk factor for widely reported illness has diminished and the
                       Committee found it unlikely to be “responsible for long term health effects
                       in Gulf War veterans.” However, the extent of asymptomatic leishmania
                       infection is unknown, and the possibility of prolonged latency and
                       apparent clinical dormancy (up to 20 years) of an infection that may
                       reemerge in the presence of immune deficiency underscores the need to
                       retain leishmania among the potential risk factors.

                       Third, the Committee concluded that it was unlikely that the health effects
                       reported by Gulf War veterans are the results of exposure to
                       organophosphate or mustard chemical warfare agents, even though there
                       is substantial evidence that organophosphate compounds might be
                       associated with delayed or long-term health effects similar to those
                       experienced by the Gulf War veterans.

                       Unresolved questions concern the extent to which veterans may have been
                       exposed to (1) chemical agents as a result of fallout from the destruction
                       of suspected chemical weapons storage sites and (2) the biological agent
                       aflatoxin, the health effects of which may not be known for months, or
                       even years, after exposure.


                       DOD  and VA officials have testified that whatever uncertainties may exist
DOD and VA Have No     about the cause of Gulf War veterans’ illnesses, the veterans are receiving
Systematic Approach    appropriate and effective symptomatic treatment. However, DOD and VA
to Monitoring Gulf     have no mechanism to monitor the quality, appropriateness, or
                       effectiveness of care provided to Gulf War veterans after their initial
War Veterans’ Health   examination. Furthermore, DOD and VA officials said they had no plans to
After Initial          establish a mechanism to monitor these veterans’ progress. This
                       monitoring and follow-up is important not only to ensure that diagnosed
Examination            conditions are properly treated but also because (1) undiagnosed signs
                       and symptoms are not uncommon among ill veterans, (2) treatment for
                       veterans with undiagnosed conditions is based on their symptoms, and
                       (3) veterans with undiagnosed conditions or multiple diagnoses may see
                       multiple providers. These agencies have relied on such mechanisms as
                       training and standards for physician qualification, which may not be
                       sufficient to ensure a given level of effectiveness for the care provided or



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                       do not permit identification of the most effective treatments.4 In contrast,
                       some steps have been taken to monitor quality and patient satisfaction
                       with veterans’ initial registry examinations. (See app. II for details.)


                       The bulk of ongoing federal research currently focuses on the
Federal Research       epidemiological study of veterans’ illnesses. While this approach may yield
Strategy Lacks a       descriptive data on veterans’ mortality and general health profiles,
Coherent Approach      methodological problems facing government epidemiological research on
                       Gulf War veterans’ illnesses will severely limit its ability to identify the
                       potential causes of the illnesses. Initially, the government was not
                       proactive in acknowledging and collecting data on the factors that might
                       have caused Gulf War veterans’ health problems, and the research agenda
                       was not articulated until several years after the war ended.


Delays and Focus of    Our review of research projects and interviews with agency officials
Federal Research Are   showed that the vast majority of federal research was not initiated until
Hindering Outcomes     1994. This 3-year delay has complicated the task facing researchers. In
                       addition, it has limited the amount of completed research currently
                       available. Of the 91 federally sponsored studies, 72 were ongoing when we
                       reviewed them in early 1997, and some of the studies will not be complete
                       until 2000 or later.

                       The focus of federal research has primarily been the epidemiological study
                       of the prevalence and cause of Gulf War illnesses rather than the
                       diagnosis, treatment, and prevention of them. With respect to determining
                       the causes, researchers will likely continue to find it difficult to detect
                       effects of particular wartime exposure and to eliminate alternative
                       explanations for Gulf War veterans’ illnesses because of the absence of
                       valid and reliable data on exposures and the multiplicity of agents to
                       which the veterans were exposed. Data on the prevalence of various
                       health problems can be useful but requires careful interpretation in the
                       absence of better information on the factors to which veterans were
                       exposed. While multiple studies of the role of stress in the veterans’
                       illnesses have been supported with federal research dollars, basic
                       toxicological questions regarding the substances to which they were
                       exposed remain unanswered. Finally, there is an absence of efforts to
                       measure Gulf War veterans’ clinical progress. This leaves the government
                       unable to promptly determine the quality and effectiveness of treatments


                       4
                        See VA Health Care: Observations on Medical Care Provided to Persian Gulf Veterans
                       (GAO/T-HEHS-97-158, June 19, 1997).



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                                 currently being provided to Gulf War veterans or to use this information
                                 when funding additional clinical research.


Methodological Problems          Federal researchers studying Gulf War illnesses have faced a number of
Limit the Effectiveness of       challenges and encountered significant problems in linking exposures or
Ongoing Epidemiological          potential causes to observed illnesses or symptoms.
Research                     •   Researchers have found it extremely difficult to gather information about
                                 unplanned exposures in the Gulf to such things as oil fire smoke and
                                 insects carrying infection, and DOD has acknowledged that records of the
                                 use of pyridostigmine bromide and vaccinations to protect against
                                 chemical/biological warfare exposures were inadequate.
                             •   Gulf War veterans were typically exposed to a wide array of agents,
                                 making it difficult to isolate and characterize the effects of individual
                                 agents or to study their combined effects.
                             •   Most epidemiological studies have relied only on self-reports for
                                 measuring most of the agents to which veterans may have been exposed
                                 during the Gulf War.
                             •   The passage of time following these exposures has made it increasingly
                                 difficult to have confidence in any information gathered about them
                                 through retrospective questioning of veterans. Reliance on self-reporting
                                 to assess exposures has two problems. Veterans’ recall after such a long
                                 time period may be inaccurate or biased. Moreover, there is often no
                                 straightforward way to test the validity of self-reported exposure
                                 information, making it impossible to separate bias in recalled information
                                 from actual differences in the frequency of exposures. As a result, findings
                                 from these studies may be spurious or equivocal.
                             •   Classifying the symptoms and identifying illnesses of Gulf War veterans
                                 have been difficult. From the outset, symptoms reported by veterans have
                                 been varied and difficult to classify into one or more distinct illnesses.
                                 Moreover, several different diagnoses might provide plausible
                                 explanations for some of the specific health complaints. It has thus been
                                 difficult to develop a case definition (that is, a reliable way to identify
                                 individuals with a specific disease), which is a criterion for doing effective
                                 epidemiological research.

                                 Appendix III provides more detailed information on the nature and extent
                                 of the federal government’s research efforts.




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                      In the absence of official conclusions from DOD and VA, we examined
Support for Key       conclusions drawn in December 1996 by the Presidential Advisory
Government            Committee on Gulf War Veterans’ Illnesses, which was established by the
Conclusions Is Weak   President to review the activities of the executive branch regarding Gulf
                      War veterans’ illnesses. In January 1997, DOD endorsed the Committee’s
or Subject to         conclusions about the likelihood that exposure to 10 commonly cited
Alternative           agents contributed to the explained and unexplained illnesses of these
                      veterans. We found that the evidence to support several of these
Interpretations       conclusions is either weak or subject to alternative interpretations.

                      The Committee concluded that “stress is likely to be an important
                      contributing factor to the broad range of illnesses currently being reported
                      by Gulf War veterans.” While stress can induce physical illness, the link
                      between stress and these veterans’ physical symptoms has not been firmly
                      established by the evidence the Committee cited. For example, a
                      large-scale, federally funded study concluded that “for those veterans who
                      deployed to the Gulf War and currently report physical symptoms, neither
                      stress nor exposure to combat or its aftermath bear much relationship to
                      their distress.” The Committee has stated that “epidemiological studies to
                      assess the effects of stress invariably have found higher rates of
                      posttraumatic stress disorder (PTSD) in Gulf War veterans than among
                      individuals in nondeployed units or in the general U.S. population of the
                      same age.” Our review indicated that the prevalence of PTSD among Gulf
                      War veterans may be overestimated due to problems in the methods used
                      to identify it. Specifically, the studies on PTSD to which the Committee
                      refers have not excluded other conditions, such as neurological disorders
                      that produce symptoms similar to PTSD and can also elevate scores on key
                      measures of PTSD. We also believe that the use of broad and heterogenous
                      groups of diagnoses (e.g., “psychological conditions” — ranging from
                      tension headache to major depression) in reporting data from DOD’s
                      clinical program may contribute to overestimation of the extent of serious
                      psychological illnesses among Gulf War veterans.

                      The Committee also concluded that “it is unlikely that infectious diseases
                      endemic to the Gulf region are responsible for long term health effects in
                      Gulf War veterans, except in a small known number of individuals.”
                      Similarly, the Persian Gulf Veterans Coordinating Board (PGVCB)5
                      concluded that because of the small number of reported cases, “the
                      likelihood of Leishmania tropica as an important risk factor for widely
                      reported illness has diminished.” While this is the case for observed

                      5
                       The PGVCB, comprised of the Secretaries of Defense, Veterans Affairs, and Health and Human
                      Services, is charged with coordinating the federal response to Gulf War veterans’ illnesses.



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    symptomatic infection with the parasite, the prevalence of asymptomatic
    infection is unknown, and such infection may reemerge in cases in which
    the patient’s immune system becomes deficient. However, as the
    Committee has noted, the infection may remain dormant up to 20 years.
    Because of this long latency and the lack of widely available screening
    methods, the infected population is hidden, and because even classic
    forms of Leishmaniasis are difficult to recognize, we believe that
    Leishmania should be retained as a potential risk factor for individuals
    who suffer from immune deficiency.

    The Committee also concluded that it is unlikely that the health effects
    reported by many Gulf War veterans were the result of (1) biological
    warfare agents, (2) chemical warfare agents, (3) depleted uranium,
    (4) infectious diseases endemic to the region, (5) oil-well fire smoke,
    (6) pesticides, (7) petroleum products, (8) pyridostigmine bromide, or
    (9) vaccines. However, our review of the conclusions made by the
    Committee indicated the following:

•   While the government found no evidence that biological weapons were
    deployed, during the Gulf War, the United States did not deploy a real-time
    biological warfare agent detection system during the war, and the effects
    of one agent, aflatoxin, would not be observed for many years.
•   Evidence from various sources indicates that chemical agents were
    present at Khamisiyah, Iraq, and elsewhere on the battlefield. The
    magnitude of the exposure to chemical agents has not been fully resolved.
    As we have previously noted, “available bomb damage assessments during
    the war concluded that 16 of 21 sites categorized by Gulf War planners as
    nuclear, biological, and chemical (NBC) facilities had been successfully
    destroyed. However, information compiled by the United Nations Special
    Commission (UNSCOM) since the end of Desert Storm reveals that the
    number of suspected NBC targets identified by U.S. planners, both prior to
    and during the campaign, did not fully encompass all the possible NBC
    targets identified by U.S. planners. UNSCOM has conducted investigations at
    a large number of the facilities suspected by the U.S. authorities as being
    NBC related. Regarding the few suspected chemical weapon sites that have
    not yet been inspected by UNSCOM, we have been able to determine that
    each was attacked by coalition aircraft during Desert Storm and that one
    site is located within the Kuwait theater of operation in close proximity to
    the border, where coalition ground forces were located. However, we have
    yet to learn why these facilities have not been investigated.”6


    6
     Operation Desert Storm: Evaluation of the Air Campaign (GAO/NSIAD-97-134, June 12, 1997), p. 2.



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                     •   Exposure to certain organophosphates can induce a delayed neurological
                         condition without causing immediate symptoms.
                     •   Available research indicates that exposure to combinations of
                         pyridostigmine bromide and other chemicals used during the Gulf War can
                         cause damaging health effects greater than to these agents individually.

                         (See app. IV for details.)


                         Because of the numbers of Gulf War veterans who continue to experience
Recommendations          illnesses that may be related to their service during the Gulf War, we
                         recommend that the Secretary of Defense, in conjunction with the
                         Secretary of the Department of Veterans Affairs, (1) develop and
                         implement a plan to monitor the clinical progress of Gulf War veterans in
                         order to help promote appropriate and effective treatment and provide
                         direction to the research agenda and (2) give greater priority to research
                         on treatment for ill veterans and on low-level exposures to chemicals and
                         their interactive effects and less priority to further epidemiological studies.
                         We also recommend that the Secretaries of Defense and Veterans Affairs
                         refine the current approaches of the clinical and research programs for
                         diagnosing posttraumatic stress disorder consistent with suggestions
                         recently made by the Institute of Medicine, which noted the need for
                         improved documentation of screening procedures and patient histories
                         (including occupational and environmental exposures) and the importance
                         of ruling out alternative causes of impairment.


                         We obtained comments on a draft of this report from DOD, VA, and the
Agency Comments          Presidential Advisory Committee on Gulf War Veterans’ Illnesses. DOD
and Our Evaluation       partially concurred with the report, indicating that the thrust of the
                         recommendations had merit but did not fully take into account the
                         complex set of health outcomes related to the war and did not recognize
                         DOD’s accomplishments. DOD also noted that our findings differed from
                         those of the Institute of Medicine and the Committee and commented that
                         we had not carried out the same level of careful and thoughtful assessment
                         as had those committees.

                         VA commented that although some aspects of our report have merit, our
                         recommendations reflected a lack of understanding of clinical research,
                         epidemiology, and toxicology. VA indicated that (1) the creation of a new
                         database was not likely to provide accurate and valid assessment of these
                         Gulf War veterans’ health status; (2) DOD and VA are already giving greater



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priority to research on low-level exposures to chemicals, but do not want
to give less priority to epidemiological research; and (3) VA was already
making efforts to improve current approaches to PTSD and other
stress-related disorders.

The Presidential Advisory Committee commented that our draft contained
factual errors, did not provide references or citations to scientific
literature, lacked substantiation and analytic rigor, and should not be
issued in its current form. The Committee was particularly concerned with
our finding that the support or evidence it had for some of its conclusions
was weak.

None of the comments we received provide evidence to challenge our
principal findings and conclusions that (1) DOD and VA have no means to
systematically determine whether symptomatic Gulf War veterans are
better or worse today than when they were first examined and (2) ongoing
epidemiological research will not provide precise, accurate, and
conclusive answers regarding the causes of the Gulf War veterans’
illnesses. All of the comments we received seek to shift the onus of
identifying and substantiating the causes of Gulf War illnesses to us, when
in fact we merely reviewed the sufficiency and persuasiveness of the
evidence behind the administration’s conclusions. In some instances, we
found it to be weak or open to alternative interpretation. We believe the
burden of proof is still on those who have made the assertions about the
likely and unlikely causes of the illnesses.

Nevertheless, in light of the comments we received, we have added more
citations to the scientific support and documentation and modified the
language in the text to clarify our position so that other readers will not
misconstrue the meaning of our report. We also double-checked the
information that was challenged in the comments we received and found
that the data as originally presented was correct. Therefore, the thrust of
our message remains unchanged.

Our point-by-point evaluation of the detailed comments provided by DOD,
VA, and the Committee are provided in appendixes V-VII. However,
because the Committee’s comments were the most strident, our evaluation
of its key points is summarized as follows.

Regarding stress, the Committee states that we ignored its analytical
approach, which was to compare the “known health effects of the risk
factor to the symptoms reported by Gulf War veterans.” We found,



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however, that the Committee offered little evidence that stress was an
important contributor of the “broad range” of veterans’ symptoms. Given
the nonspecific nature of the health effects associated with stress, almost
any pattern of symptoms and illnesses would be compatible with it,
making it difficult to scientifically test the hypothesis posed by the
Committee’s approach (that the pattern of veterans’ illnesses is consistent
with the known effects of stress). Although the Committee notes that
scores on PTSD screening questionnaires are higher among Gulf veterans
than among controls, confirmatory psychiatric interviews to eliminate
alternative explanations for elevated PTSD screening scores were generally
not done.

Because we questioned the Committee’s support for its conclusion that the
likelihood of Leishmania infection has diminished as an explanation for
widespread illness, the Committee sought to transfer the burden of proof
to us by asking that we justify any continued concern about asymptomatic
infection. We found that the Committee’s justification for dismissal of
Leishmania as a risk factor rests heavily on two ill-supported assumptions:
(1) that diagnostic programs have been highly likely to detect the disease,
even in the absence of any widely available screening or diagnostic tests
and in the presence of nonspecific symptoms, and (2) that the course of
various forms of leishmaniasis is well understood by scientists and by the
doctors examining the veterans. Insofar as the prevalence of this infection
is still unknown and it is impossible to predict which veterans’ immune
systems will be weakened, and given the inability to identify this hidden
population in the absence of a valid screening test, we believe it is
premature to discount leishmania as a risk factor.

Finally, regarding our evaluation of the Committee’s conclusion that
low-level exposures to chemicals such as pesticides are unlikely to be
associated with veterans’ health conditions, the Committee appears not to
contest the fact that laboratory data document specific health effects in
animals exposed to one or more organophosphate agents that are not
detectable in the usual clinical tests. We find it difficult to reconcile the
Committee’s dismissal of such exposure as an “unlikely” cause of veterans’
health problems with its acknowledgement of an absence of data on an
important exposure scenario. Moreover, where the Committee apparently
found no data to suggest a problem with low-level exposures, we found
some data that do pose concerns. While the Committee argues that these
studies were done on animals, they are consistent with standard
toxicological practice employed by the Environmental Protection Agency
and others. The Committee’s insistence that such effects be demonstrated



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              in humans appears unreasonable, as exposing humans to toxic substances
              for experimental research cannot be done for obvious ethical reasons.
              Also, while the study of occupational or accidental exposures, such as the
              sarin exposures that occurred in Japanese terrorist incidents, may provide
              some degree of information, the value of such information is generally
              limited by the poor description of the actual levels of the exposure in the
              case of accidents, the limited range of exposures (in the case of
              occupational use), or the lack of comparability with the circumstance in
              question. The hypotheses derived from such study would thus require
              confirmation and testing in controlled experimental settings.

              DOD provided two sets of comments, which we have reprinted in appendix
              V. We responded to DOD’s second set of comments, received on June 17,
              1997, by incorporating appropriate changes in our report. VA and the
              Presidential Advisory Committee’s comments are reprinted in appendixes
              VI and VII, respectively.


              To address our first objective—the extent of DOD’s and VA’s clinical
Scope and     follow-up and monitoring of treatment and diagnostic services—we
Methodology   reviewed literature and agency documents and conducted structured
              interviews with DOD and VA officials managing the respective agencies’
              registries for Persian Gulf War veterans that requested postwar
              evaluations. We asked questions designed to identify and contrast their
              methods for monitoring the quality and outcomes of their treatment and
              diagnostic programs and the health of the registered veterans.

              The second objective concerns the government’s research strategy to
              study the veterans’ illnesses and the methodological problems posed in its
              studies. To answer this question we conducted a systematic review of
              pertinent literature and agency documents and reports, including reports
              issued by the Presidential Advisory Committee and the Institute of
              Medicine. We also interviewed representatives of PGVCB’s Research
              Working Group and officials of VA and DOD. We surveyed primary
              investigators of ongoing epidemiological studies. We also collected data
              on project expenditures by fiscal year but did not attempt to
              independently verify these figures.

              Because different methodological standards apply to various types of
              research and because the overwhelming majority of federally sponsored
              research is categorized as epidemiological, we limited our survey of
              investigators to those responsible for ongoing epidemiological studies.



              Page 13                                     GAO/NSIAD-97-163 Gulf War Illnesses
B-276835




With an expert epidemiological consultant, we devised a questionnaire to
assess critical elements of these studies (including the quality of exposure
measurement, specificity of case definition, and steps to ensure adequate
sample size) and to identify specific problems that the primary
investigators may have encountered in implementing their studies. Of the
43 ongoing epidemiological studies identified by PGVCB in the November
1996 plan, we interviewed primary investigators for 31 (72 percent). We
also reviewed and categorized descriptions of all 91 projects identified by
April 1997, based on their apparent focus and primary objective. Finally, to
review the progress of major ongoing research efforts, we visited the
Walter Reed Army Institute of Research, the Naval Health Research
Center, and two of VA’s Environmental Hazards Research Centers.

To address the third objective, we reviewed major conclusions of the
PGVCB and the Presidential Advisory Committee to determine the strength
of evidence supporting these conclusions. The purpose of this review was
not to critique PGVCB’s or the Presidential Advisory Committee’s efforts,
per se, but rather to describe the amount of knowledge about Gulf War
illnesses that has been generated by research 6 years after the war. We
reviewed these conclusions because they were the strongest statements
that we had come across on these matters by any official body. The
Presidential Advisory Committee’s report was significant because the
panel included a number of recognized experts in the scientific questions
at issue who were assisted by a large staff of scientists and attorneys. In
addition, the Committee conducted an extensive review of the research.
Thus, evaluating these conclusions provided important evidence about
how fruitful the federal research had been thus far. To address this
objective, we reviewed scientific literature cited by the Presidential
Advisory Committee as well as others. We also consulted experts in the
fields of epidemiology, toxicology, and medicine and interviewed officials
of DOD, VA, and the Central Intelligence Agency. We checked our own
interpretation of key study findings with the authors and had independent
experts review our draft report.

Because of the scientific and multidisciplinary nature of this issue, we
ensured that staff conducting the work had appropriate backgrounds in
the fields of epidemiology, statistics, psychology, environmental health,
toxicology, engineering, weapon design, and program evaluation and
methodology. In addition, we used in-house expertise in chemical and
biological warfare and in military and veterans health care systems. Also,
experts who reviewed our work had backgrounds in medicine, public
health, and research methods. Moreover, we held extensive discussions



Page 14                                     GAO/NSIAD-97-163 Gulf War Illnesses
B-276835




with experts in academia in each of the substantive fields relevant to this
issue.

Our work was completed between October 1996 and April 1997 in
accordance with generally accepted government auditing standards.


We are sending copies of this report to other interested congressional
committees; the Secretaries of Defense, Veterans Affairs, and Health and
Human Services; the Chair of the Presidential Advisory Committee; and
other interested parties. We will make copies available to others upon
request.

If you have any questions or would like additional information, please
contact me at (202) 512-3092 or Sushil K. Sharma, Ph.D, Dr.P.H., Assistant
Director, at (202) 512-3460. Major contributors to this report are listed in
appendix VIII.




Kwai-Cheung Chan
Director, Special Studies and Evaluations




Page 15                                      GAO/NSIAD-97-163 Gulf War Illnesses
Contents



Letter                                                                                                 1


Appendix I                                                                                            20
                          U.S. Troops’ Exposure to Hazardous Substances                               20
Government Health         Health Examination Programs for Gulf War Veterans                           21
and Research              Government Research Program                                                 23
Programs for Gulf War
Veterans
Appendix II                                                                                           27
                          No Mechanisms Exist to Monitor Veterans’ Quality of Care                    27
No Systematic             Efforts to Ensure Quality and Measure Satisfaction With Initial             28
Approach for                Examination Are Not Adequate
Monitoring Veterans’
Treatment After Initial
Examination
Appendix III                                                                                          30
                          Goals of the Epidemiological Research                                       30
Federal Strategy to       Federal Research Was Delayed and Lacked a Proactive Approach                37
Research Gulf War         Some Hypotheses Received Early Emphasis                                     42
                          Some Hypotheses Were Not Initially Pursued                                  43
Illnesses Lacks a         Additional Hypotheses Were Pursued in the Private Sector                    43
Coherent Approach         Federal Research Emphasis                                                   46
                          Formidable Methodological Problems                                          48

Appendix IV                                                                                           54
                          Extent of Posttraumatic Stress Disorder May Be Overestimated                57
Support for Key           Extent of Asymptomatic Leishmania Infection Is Unknown                      60
Official Conclusions      Evidence of Exposure to Biological and Chemical Weapons Has                 62
                            Not Been Aggressively Pursued
Is Weak or Subject to     Impact of DOD Denials on Federal Research                                   64
Different
Interpretations




                          Page 16                                     GAO/NSIAD-97-163 Gulf War Illnesses
                        Contents




Appendix V                                                                                       65

Comments From the
Department of
Defense
Appendix VI                                                                                      77

Comments From the
Department of
Veterans Affairs
Appendix VII                                                                                    100

Comments From the
Presidential Advisory
Committee on Gulf
War Veterans’
Illnesses
Appendix VIII                                                                                   135

Major Contributors to
This Report
Glossary                                                                                        136


Related GAO Products                                                                            139


Tables                  Table III.1: Research Objectives Identified by PGVCB                     30
                        Table III.2: PGVCB Research Projects                                     32
                        Table III.3: Events Coincident With Changes in PGVCB Research            40
                          Agenda
                        Table III.4: Number of Studies by Primary Research Focus and             46
                          Study Type
                        Table III.5: Primary Emphasis of 91 Federally Sponsored                  47
                          Research Projects Identified by PGVCB




                        Page 17                                  GAO/NSIAD-97-163 Gulf War Illnesses
          Contents




          Table III.6: Ongoing Epidemiological Studies Using Measures                51
            Other Than Self-Reports to Assess Key Exposures
          Table IV.1: PAC Conclusions on Health Effects of Different                 54
            Individual Exposure Agents

Figures   Figure I.1: Percent of 3,181 VA Registrants That Reported Having           23
            Been Exposed to Various Agents During the Gulf War
          Figure I.2: Epidemiologic Study Cycles                                     26
          Figure III.1: Cumulative Percentages of 91 Federally Funded                38
            Studies to Be Completed as a Function of Time




          Abbreviations

          CARC         Chemical agent resistant coating
          CCEP         Comprehensive Clinical Evaluation Program
          CDC          Centers for Disease Control
          CIA          Central Intelligence Agency
          DEET         N,N-diethyl-m-toluamide
          DOD          Department of Defense
          DS2          Decontaminating solution 2
          HHS          Department of Health and Human Services
          IOM          Institute of Medicine
          NBC          Nuclear, Biological, and Chemical
          NHRC         Naval Health Research Center
          OPIDN        Organophosphate-induced delayed neuropathy
          PAC          Presidential Advisory Committee on Gulf War Veterans’
                             Illnesses
          PGHREP       Persian Gulf Health Registry Examination Program
          PGVCB        Persian Gulf Veterans Coordinating Board
          PTSD         Posttraumatic stress disorder
          UNSCOM       United Nations Special Commission on Iraq
          USAMRIID     U.S. Army Medical Research Institute of Infectious
                             Diseases
          VA           Department of Veterans Affairs
          WRAIR        Walter Reed Army Institute of Research
          WRAMC        Walter Reed Army Medical Center


          Page 18                                    GAO/NSIAD-97-163 Gulf War Illnesses
Page 19   GAO/NSIAD-97-163 Gulf War Illnesses
Appendix I

Government Health and Research Programs
for Gulf War Veterans

                        In the aftermath of the Persian Gulf War, which ended on February 28,
                        1991, many veterans have experienced illnesses that they believe they
                        contracted while in the Gulf due to exposures to hazardous materials or
                        chemical and biological warfare agents. The Department of Veterans
                        Affairs (VA) and the Department of Defense (DOD) later initiated health
                        programs offering physical examinations and diagnostic services to these
                        veterans. As it became apparent that the symptoms and causes of these
                        illnesses varied widely and the illnesses were difficult to diagnose, the
                        government began to research the reasons for the veterans’ health
                        problems.


                        During their service in the Gulf, U.S. troops were reportedly exposed
U.S. Troops’ Exposure   before, during, and after the war to a variety of potentially hazardous
to Hazardous            substances. These include decontaminating and protective compounds
Substances              (particularly decontaminating solution 2, or DS2, and chemical agent
                        resistant coating (CARC)), diesel fuel used as a sand suppressant in and
                        around encampments, fuel oil used to burn human waste, fuel in shower
                        water, and leaded vehicle exhaust used to dry sleeping bags. For example,
                        as we reported to staff of the House Subcommittee on Oversight and
                        Investigations in 1994, DS2 was to be widely distributed among Army units
                        and equipment in Saudi Arabia, though the Army did not know how much
                        or where the solution was distributed. The potential effects of DS2 on
                        humans include mild or severe burns, corrosion to tissues of the skin or
                        eye, liver damage, and adverse reproductive effects.7 Other potential
                        hazards associated with Gulf service included infectious diseases (most
                        prominently leishmaniasis, a parasitic infection), the use of pyridostigmine
                        bromide and vaccines (to protect against chemical and biological
                        weapons), depleted uranium (contained in certain ammunition and in the
                        fragments of exploded rounds), pesticides and insect repellents, chemical
                        and biological warfare agents, and compounds and particulate matter
                        contained in the extensive smoke from the oil-well fires at the end of the
                        war.

                        Shortly after the war, some veterans began reporting health problems that
                        they believed might be due to their participation in the war. As we noted in
                        May 1995, the 123rd Army Reserve Unit in Indiana reported unexpected
                        signs and symptoms that could not easily be explained.8 Veterans in other

                        7
                         Also see Hazardous Materials: DOD Should Eliminate DS2 From Its Inventory of Decontaminants
                        (GAO/NSIAD-90-10, Apr. 25, 1990).
                        8
                         Operation Desert Storm: Health Concerns of Selected Indiana Persian Gulf War Veterans
                        (GAO/HEHS-95-102, May 1995).



                        Page 20                                                   GAO/NSIAD-97-163 Gulf War Illnesses
                        Appendix I
                        Government Health and Research Programs
                        for Gulf War Veterans




                        units began to report similar symptoms that also could not be easily
                        explained. Many veterans reported exposure to chemicals, pesticides, and
                        other agents, such as vaccines and pyridostigmine bromide, as possible
                        causes of their illnesses.


                        Consistent with the Veteran’s Health Care Act of 1992, both VA and DOD
Health Examination      have established programs through which they provide medical
Programs for Gulf War   examination and diagnostic services, free of charge, to Gulf War veterans.
Veterans                The VA launched its Persian Gulf Health Registry Examination Program
                        (PGHREP) in 1992, and DOD initiated the Comprehensive Clinical Evaluation
                        Program (CCEP) in June 1994. PGHREP is currently available at most VA
                        medical centers, and DOD’s CCEP examinations are available at 148 sites
                        worldwide.9

                        Initially, PGHREP participants received a regular physical examination with
                        basic laboratory tests. However, in 1994, VA established a standardized
                        examination to (1) obtain information about symptoms and exposures;
                        (2) call the clinician’s attention to diseases endemic to the Gulf region; and
                        (3) direct baseline laboratory studies, including a chest X-ray (if one has
                        not been done recently), blood count, urinalysis, and blood chemistry and
                        enzyme analyses for detection of certain diseases. If a diagnosis is not
                        apparent, facilities follow the clinical evaluation protocol originally
                        developed for VA’s referral centers and now used in VA and military medical
                        centers nationwide. The examination protocol suggests 22 additional
                        baseline tests and additional specialty consultations, from which further
                        diagnostic procedures may be considered, depending on the veteran’s
                        symptoms. If the illness cannot be diagnosed, a VA registrant may be
                        referred to one of four VA Persian Gulf Referral Centers located in
                        Washington, D.C.; Houston, Texas; Los Angeles, California; and
                        Birmingham, Alabama.

                        Although these registry programs are primarily intended to provide
                        diagnostic services, the VA’s registry program, in particular, was among the
                        first extensive efforts to gather data from veterans regarding the nature of
                        their problems and the types of factors to which they might have been
                        exposed. However, during the first 2 years of the PGHREP’s operation, when
                        exposure and symptom information was freshest in most respondents’

                        9
                         A declining proportion of Gulf War veterans are covered by military medical health services. Thus, an
                        increasing number would be eligible only for VA care, and some portion have access to neither VA nor
                        DOD health care services apart from the PGHREP and CCEP examination programs. It is important to
                        note that receipt of a VA registry examination does not entail eligibility for free treatment of any
                        conditions detected.



                        Page 21                                                     GAO/NSIAD-97-163 Gulf War Illnesses
Appendix I
Government Health and Research Programs
for Gulf War Veterans




memory, efforts to collect data on symptoms and self-reported
exposure(s) were more limited in scope.

In February 1997, the VA reported its analysis of the self-reported
exposures to hazardous substances identified by the 3,181 veterans who
registered after the VA revised its data collection forms. Although
interpreting such information is difficult due to self-selection of registry
participants and problems with retrospective reporting based on recall,
many veterans reported exposure to multiple substances. VA reported that
89 percent of these registered veterans believed they had been exposed to
diesel or other petrochemical fumes, 88 percent to passive smoking,
72 percent to smoke from oil fires, 72 percent to skin exposure to fuel,
70 percent to burning trash/feces, 64 percent to smoke from tent heaters,
64 percent to pesticides in cream or spray form, 60 percent to
pyridostigmine bromide, 53 percent to paints or solvents, 34 percent to
microwaves, 32 percent to CARC, 14 percent to depleted uranium,
12 percent to nerve gas, and 6 percent to mustard gas.10 (See fig. I.1.) As of
June 1996, DOD acknowledged the potential exposure of some veterans to
the nerve agent sarin following the postwar U.S. demolition of Iraqi
ammunition facilities.




10
  H. Kang et al., “A Review of the Department of Veterans Affairs Revised Persian Gulf Registry and
In-Patient Treatment Files” (Washington, DC: VA Environmental Epidemiology Service, Feb. 1997),
table 17.



Page 22                                                     GAO/NSIAD-97-163 Gulf War Illnesses
                                                Appendix I
                                                Government Health and Research Programs
                                                for Gulf War Veterans




Figure I.1: Percent of 3,181 VA Registrants That Reported Having Been Exposed to Various Agents During the Gulf War



           Diesel fumes                                                                                        89
       Passive smoking                                                                                        88

            Oil well fires                                                                    72
            Fuels (skin)                                                                      72

     Burning trash/feces                                                                    70

            Tent heaters                                                               64

        Pesticides (skin)                                                              64

Pyridostigmine bromide                                                            60

         Paints/solvents                                                   53
            Microwaves                                    34

                  CARC                                 32
       Depleted uranium               14

              Nerve gas              12
          Mustard agent          6

                             0             20                  40               60                  80                 100
                                                                    Percent

                                                Source: Data provided in H. Kang et al., “A Review of the Department of Veterans Affairs Revised
                                                Persian Gulf Registry and Inpatient Treatment Files” (Washington, D.C.: VA Environmental
                                                Epidemiology Service, Feb. 1997), table 17.



                                                In addition to providing examination services, in the 6 years since the end
Government Research                             of the Gulf War, the federal government, primarily through DOD and VA, has
Program                                         sponsored a variety of research on Gulf War veterans’ illnesses. DOD
                                                research is one component of a broader agenda coordinated under the
                                                aegis of the Persian Gulf Veterans’ Coordinating Board (PGVCB), which
                                                comprises the Secretaries of the Department of Health and Human
                                                Services (HHS), VA, and DOD. The details of this agenda are described in the
                                                PGVCB publication entitled A Working Plan for Research on Persian Gulf
                                                Veterans’ Illnesses, first published in 1995 and revised in November 1996.11


                                                11
                                                   A Working Plan for Research on Persian Gulf Veterans’ Illnesses (First Revision),” Department of
                                                Veterans Affairs, November 1996.



                                                Page 23                                                      GAO/NSIAD-97-163 Gulf War Illnesses
Appendix I
Government Health and Research Programs
for Gulf War Veterans




 This agenda was developed in response to an Institute of Medicine (IOM)
conclusion that

“the DOD and VA should determine the specific research questions that need to be answered.
Epidemiologic studies should be designed with the objective of answering these questions
given the input of experts in epidemiologic research methods and data analysis, along with
the input of experts in the subject matter areas to be investigated.”


Accordingly, most of the research sponsored under this agenda is
characterized by PGVCB as epidemiological.

The objectives of epidemiologic study are to determine the extent of
disease in the population, the causes of disease and its modes of
transmission, the natural history of disease, and the basis for developing
preventive strategies or interventions.12

To conduct such studies, investigators must follow a few basic, generally
accepted principles. First, they must specify diagnostic criteria to
(1) reliably determine who has the disease or condition being studied and
who does not and (2) select appropriate controls (people who do not have
the disease or condition).

Second, the investigators must have valid and reliable methods of
collecting data on the past exposure(s) of those in the study to possible
factors that may have caused the symptoms. The need for accurate,
dose-specific exposure information is particularly critical when low-level
or intermittent exposure to drugs, chemicals, or air pollutants is possible.
It is important not only to assess the presence or absence of exposure but
also to characterize the intensity and duration of exposure. To the extent
that the actual exposure of individuals is misclassified, it is difficult to
detect any effects of the exposure. Another means of linking
environmental factors to disease is to determine whether or not there is
evidence that as the exposure increases, the risk of disease also increases.
However, this dose-response pattern can be detected only if the degree of
exposure among different groups can be determined.

Finally, in addition to specific case definition and dose-specific exposure
information with known accuracy, it is important that a sufficient number
of persons be studied to have a reasonable likelihood of detecting any

12
   A. M. Lilienfeld and D. E. Lilienfeld, Foundations of Epidemiology (New York: Oxford University
Press, 1980); L. Goodis, Epidemiology (Philadelphia, PA: W. B. Saunders Company, 1996); and D. E.
Lilienfeld and P. D. Stolley, Foundations of Epidemiology 3rd ed. (New York: Oxford University Press,
1994).



Page 24                                                     GAO/NSIAD-97-163 Gulf War Illnesses
Appendix I
Government Health and Research Programs
for Gulf War Veterans




relationship between exposures and disease. To the extent that this
relationship is subtle or obscured by loose case definition (that is, a case
definition that is too broad and encompasses different types of illnesses)
or problems in measuring exposure, larger samples would be required. For
example, the IOM has noted that

“very large groups must be studied in order to identify the small risks associated with low
levels of exposure, whereas a relatively small study may be able to detect the effect of
heavy or sustained exposure to a toxic substance. In this way, a study’s precision or
statistical power is also linked to the extent of the exposure and the accuracy of its
measurement. Inaccurate assessment of exposure can obscure the existence of such a
trend and thus make it less likely that a true risk will be identified.”13


Research programs, such as the federal program for Gulf War illnesses, are
designed to lead to information and treatments in a timely and efficient
manner. In the conventional model of epidemiological research, a research
program to investigate a disease outbreak follows a study cycle. (See fig.
I.2 for an illustration of this cycle.)14 First, descriptive studies are
conducted to gather basic information about patterns of illness, the
natural environment, and exposures of interest (step one). Once enough
information is gathered, researchers create hypotheses to explain the
patterns that they see in these descriptive data (step two). Analytic studies
are then conducted to test the hypotheses (step three). The results of
these analytic studies are evaluated (step four). They may suggest a need
to gather additional descriptive data (step one), or they may yield new or
refined hypotheses (step two) to be tested in further analytic studies (step
three). The cycle continues until the disease is adequately understood to
permit the development of treatments. Applying this cycle is a useful way
of organizing a research program when valid descriptive information can
be acquired about exposures and dose/response relationships. However,
when this information is not available, retaining this model, that is
conducting descriptive studies that lead to hypotheses that are then tested,
may not be timely or effective.




13
  Veterans and Agent Orange: Update 1996 (Washington, D.C.: Institute of Medicine, 1996), pp. 99-100.
14
  This research model is shared by other scientific fields that also develop hypotheses and then test
them through field or laboratory research.



Page 25                                                      GAO/NSIAD-97-163 Gulf War Illnesses
                                         Appendix I
                                         Government Health and Research Programs
                                         for Gulf War Veterans




Figure I.2: Epidemiologic Study Cycles


                                                    1. Descriptive studies-
                                                       data aggregation
                                                       and analysis




                4. Analysis of results
                                                                                               2. Model-building and
                   suggests further
                                                                                                  formulation of
                   descriptive studies
                                                                                                  hypotheses
                   and new hypotheses




                                                     3. Analytic studies to
                                                        test hypotheses


                                         Source: Mausner and Bahn, Epidemiology—An Introductory Text, p. 155.




                                         Page 26                                                GAO/NSIAD-97-163 Gulf War Illnesses
Appendix II

No Systematic Approach for Monitoring
Veterans’ Treatment After Initial
Examination
                       Most veterans with symptoms who were evaluated in the VA and DOD
                       health programs received a diagnosis (78 percent and 80 percent,
                       respectively), while at least 20 percent have symptoms or signs that elude
                       diagnosis. However, an analysis of 222 VA registrants in Portland, Oregon,
                       showed that only 19 percent had symptoms that were fully explained by
                       the coded registry diagnoses. This suggests that undiagnosed signs and
                       symptoms may be more common than is apparent from initial analyses of
                       registry data.

                       The most commonly reported symptoms in VA and DOD registries include
                       fatigue, muscle and joint pain, gastrointestinal complaints, headache, skin
                       rashes, depression, neurologic and neurocognitive impairments, memory
                       loss, shortness of breath, and sleep disturbance. It is noteworthy that
                       veterans participate in the registry programs even though (1) participation
                       in the programs is voluntary and some members of the active duty service
                       may perceive it as career-limiting; (2) the health registry programs provide
                       only diagnostic services and treatment incidental to diagnosis (for
                       example, removal of malignancies found during a diagnostic biopsy); and
                       (3) the examination can be lengthy.


                       Officials of both DOD and VA have testified that whatever uncertainties may
No Mechanisms Exist    exist about the cause of veterans’ illnesses, the veterans are at least
to Monitor Veterans’   receiving appropriate and effective symptomatic treatment.15 In the case of
Quality of Care        veterans with no clear diagnosis, treatment is based on symptoms, and
                       veterans with multiple diagnoses may see multiple types of providers.
                       However, these agencies had no mechanisms for monitoring the quality of
                       these veterans’ care or their clinical progress after their initial
                       examination, nor did they describe plans to establish such mechanisms.16
                       VA delegates monitoring responsibilities to local veterans hospitals, which
                       may monitor the quality of a subsample of services.17

                       15
                        Testimony before the House Government Reform and Oversight Committee’s Subcommittee on
                       Human Resources and Intergovernmental Relations by VA’s Chief Public Health and Environmental
                       Hazards Officer, December 11, 1996, and a written statement submitted by Dr. Stephen C. Joseph,
                       Assistant Secretary of Defense for Health Affairs, to a September 25, 1996, joint hearing of the Senate
                       Select Intelligence and Veterans’ Affairs Committees.
                       16
                         Since November 1996, DOD has been working with independent contractors to determine
                       appropriate health outcomes and other metrics that would characterize the current health status of
                       those participating in the CCEP. In addition, a 5-year follow-up policy has been developed for the small
                       number of soldiers suspected of being exposed to depleted uranium particles.
                       17
                         The term “quality assurance” is used to describe prospective processes or requirements—such as
                       licensure, inspections, or training—generally intended to promote a certain level of performance based
                       on criteria that might be the subject of a quality measurement program (that is, indicators of the
                       achievement of program goals or the capacity to achieve such goals).



                       Page 27                                                       GAO/NSIAD-97-163 Gulf War Illnesses
                      Appendix II
                      No Systematic Approach for Monitoring
                      Veterans’ Treatment After Initial
                      Examination




                      VA officials involved in administering PGHREP told us that they regarded
                      monitoring the clinical progress of registry participants as a separate
                      research project, and DOD’s CCEP manager made similar comments. Instead,
                      the two agencies have relied on such quality assurance mechanisms as
                      standards for physician qualification and process measurements, although
                      these do not necessarily ensure a given level of effectiveness for the care
                      provided.18

                      Although VA’s Central Office samples a subset of all veterans having
                      contact with VA hospitals to determine their satisfaction with VA health
                      care, VA officials told us that this sample is not currently large enough to
                      provide information specific to veterans of the Gulf War. Similarly, local
                      facilities may conduct studies of their success with a particular medical
                      treatment (e.g., a coronary bypass), but these are unlikely to provide
                      specific information on Gulf War veterans.19


                      Both VA and DOD have applied some traditional quality assurance and
Efforts to Ensure     measurement strategies to the initial examination of Gulf War veterans.20
Quality and Measure   In response to a recommendation of the IOM, DOD has asked for feedback
Satisfaction With     from CCEP participants; however, we have found some problems with DOD’s
                      approach to analyzing Gulf War veterans’ responses to questionnaires
Initial Examination   relating to their satisfaction with CCEP evaluations. Specifically,
Are Not Adequate
                      (1) Gulf War veterans’ responses were not compared to responses from
                      other groups of patients seeking diagnosis and treatment.




                      18
                       See Long-Term Care: Status of Quality Assurance and Measurement in Home and Community-Based
                      Services (GAO/PEMD-94-19, Mar. 1994).
                      19
                       For previous GAO reviews of performance monitoring and outcomes measurement in VA and DOD
                      health care programs, see Defense Health Care: New Managed Care Plan Progressing, but Cost and
                      Performance Issues Remain (GAO/HEHS-96-128); VA Health Care: Trends in Malpractice Claims Can
                      Aid in Addressing Quality of Care Problems (GAO/HEHS-96-24); VA Health Care: Physician Peer
                      Review Identifies Quality of Care Problems, but Actions to Address Them Are Limited
                      (GAO/HEHS-95-121); Veterans’ Health Care: Veterans’ Perceptions of VA Services and VA’s Role in
                      Health Care Reform (GAO/HEHS-95-14); VA Health Care for Women: In Need of Continued VA
                      Attention (GAO/HEHS-94-114); and VA Health Care: VA Medical Centers Need to Improve Monitoring
                      of High-Risk Patients (GAO/HRD-94-27).
                      20
                        DOD identified the following quality assurance measures that are in place for all DOD eligible
                      individuals: The National Quality Management Program, Clinical Quality Management Program for the
                      Military Health Service System. The National Quality Management Program comprises the following
                      seven components: Medical Readiness, Accreditation of Healthcare Organizations, Licensure,
                      Credentials and clinical Privileges, National Practitioner Data Bank, Utilization Management Oversight,
                      and Special Studies.



                      Page 28                                                     GAO/NSIAD-97-163 Gulf War Illnesses
Appendix II
No Systematic Approach for Monitoring
Veterans’ Treatment After Initial
Examination




(2) DOD combined into a single category the “no opinion” and missing
responses.

(3) It is unclear to what extent responses were included from patients who
voluntarily declined participation in the program or were placed in an
“administrative declination” category for “failure to become actively
involved in the CCEP program.”

In addition, no information is available on the extent to which active duty
veterans have sought evaluations outside the CCEP program, which could
be an indicator of patient dissatisfaction. VA plans to initiate a satisfaction
measure for its PGHREP by incorporating a feedback postcard in the
examination process. However, this plan has been under development for
months, and VA officials told us it remained so as of March 24, 1997.

Both VA and DOD have applied some quality measurement to their registry
examination processes. A VA directive requires VA medical centers to use
the PGHREP Quality Management/Self-Assessment Monitor to review at
least a 10-percent sample of all Persian Gulf registry physical examinations
conducted from January 1, 1996, through September 30, 1996. The results
of this process were submitted to VA’s Environmental Agents Service and
summarized for 167 of the VA’s 173 medical centers. They showed a fairly
high self-reported compliance with various aspects of the examination
among reporting facilities. Although the results of this self-assessment
process suggested that the overwhelming majority of veterans who were
symptomatic at the time of the examination had a follow-up examination
scheduled, 20 percent were not assigned to a primary care team, and
17 percent of their records lacked evidence of a follow-up letter containing
examination results and recommendations.

Similarly, DOD tracks the aging of requests for CCEP examinations and
provides feedback to its regional facilities on examinations that are
overdue or reports that remain incomplete. DOD does not consider an
examination complete until certain fields in the examination report have
been filled in and submitted. Through supervisory personnel at 13 regional
treatment centers, DOD also conducts some oversight of examination
activities at its 148 CCEP administration sites.




Page 29                                        GAO/NSIAD-97-163 Gulf War Illnesses
Appendix III

Federal Strategy to Research Gulf War
Illnesses Lacks a Coherent Approach

                                   The approach to collecting data on Persian Gulf veterans and the factors
                                   that might have caused their health problems has not been proactive, and
                                   articulation of a research agenda came years after the war. The subsequent
                                   research, which is largely epidemiological and still ongoing, has pursued
                                   some hypotheses more aggressively than others and faces formidable
                                   methodological problems.


                                   President Clinton established PGVCB on January 21, 1994, to coordinate
Goals of the                       federal efforts to address health concerns raised by veterans of the Persian
Epidemiological                    Gulf War. Various federal agencies had previously independently
Research                           addressed these concerns. The Research Working Group (RWG) of the
                                   PGVCB has primary responsibility for managing research into Gulf War
                                   illnesses. In August 1995, PGVCB identified three broad goals for research
                                   on veterans’ illnesses: (1) determine the nature and prevalence of
                                   symptoms, illnesses, and unexplained conditions among Persian Gulf
                                   veterans; (2) identify possible causes for any illnesses found among
                                   Persian Gulf veterans; and (3) identify diagnostic tools, treatment
                                   methods, and prevention strategies for illnesses found among Persian Gulf
                                   veterans. These are generally accepted goals for the epidemiologic study
                                   of poorly understood conditions.

                                   To support these research goals, PGVCB identified 21 more specific
                                   research objectives. (See table III.1.)

Table III.1: Research Objectives
Identified by PGVCB                Number       Objective
                                   1            What is the prevalence of symptoms/illnesses in the Gulf War veterans’
                                                population? How does this prevalence compare to that in an appropriate
                                                control group?
                                   2            What was the overall exposure of troops to leishmania tropica?
                                   3            What were the exposure concentrations to various petroleum products
                                                and their combustion products in typical usage during the Gulf War?
                                   4            What was the extent of exposure to specific occupational/environmental
                                                hazards known to be common in the Gulf War veterans’ experience?
                                                Was this exposure different from that of an appropriate control group?
                                   5a           What were the potential exposures of troops to organophosphate nerve
                                                agents and/or sulfur mustard as a result of allied bombing at
                                                Muhammadiyat and Al Muthanna or the demolition of a weapons bunker
                                                at Khamisiyah?
                                   6a           What was the extent of exposure to chemical agents, other than at
                                                Khamisiyah in the Gulf War as a function of space and time?
                                   7            What was the prevalence of pyridostigmine bromide use among Gulf
                                                War troops?
                                                                                                             (continued)



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Federal Strategy to Research Gulf War
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Number           Objective
8                What was the prevalence of various psychophysiological stressors
                 among Gulf War veterans? Is the prevalence different from that of an
                 appropriate comparison population?
9                Are Gulf War veterans more likely than an appropriate comparison group
                 to experience nonspecific symptoms and symptom-complexes?
10               Do Gulf War veterans have a greater prevalence of altered immune
                 function or host defense when compared with an appropriate control
                 group?
11               Is there a greater prevalence of birth defects in the offspring of Gulf War
                 veterans than in an appropriate control population?
12               Have Gulf War veterans experienced lower reproductive success than
                 an appropriate control population?
13               Is the prevalence of sexual dysfunction greater among Gulf War veterans
                 than among an appropriate comparison population?
14               Do Gulf War veterans report more pulmonary symptoms or diagnoses
                 than persons in an appropriate control population?
15               Do Gulf War veterans have a smaller baseline lung function in
                 comparison to an appropriate control group? Do Gulf War veterans have
                 a greater degree of nonspecific airway reactivity in comparison to an
                 appropriate control group?
16               Is there a greater prevalence of organic neuropsychological and
                 neurological deficits in Gulf War veterans compared to appropriate
                 control populations?
17               Can short-term, low-level exposures to pyridostigmine bromide, the
                 insect repellent DEET, and the insecticide permethrin, alone or in
                 combination, cause short-term and/or long-term neurological effects?
18               Do Gulf War veterans have a significantly higher prevalence of
                 psychological symptoms and/or diagnoses than do members of an
                 appropriate control group?
19               What is the prevalence of leishmaniasis and other infectious diseases in
                 the Gulf War veteran population?
20               Do Gulf War veterans have a greater risk of developing cancers of any
                 type when compared with an appropriate control population?
21               Are Gulf War veterans experiencing a mortality rate that is greater than
                 that of an appropriate control population? Are specific causes of death
                 related to service in the Persian Gulf?

a
 Objective was added in 1996, following DOD’s announcement of potential exposures to
chemical warfare agents in postwar operations at three sites.



In connection with these research objectives, 91 specific studies were
identified in the most recent annual report to Congress on federally




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                                             Illnesses Lacks a Coherent Approach




                                             sponsored research on Gulf War veterans’ illnesses.21 (See table III.2.)
                                             According to figures reported by the agencies, through fiscal year 1996,
                                             DOD expended $19.9 million on these research efforts, VA spent
                                             $11.6 million, and HHS attributes expenditures of $5.5 million to the four
                                             projects it has pursued. In all, these agencies spent about $37 million for
                                             research through fiscal year 1996. Additional amounts have been made
                                             available for ongoing and future projects.


Table III.2: PGVCB Research Projects
                                                                                                      Start   Completion        Expenditures
Project no. Title                                                   Status          Location          date          date       through FY96a
DoD-1A      Epidemiologic Studies of Morbidity Among
            Gulf War Veterans: A Search for Etiologic
            Agents and Risk Factors                               Ongoing              NHRC          6/1/94         10/1/96        $3,985,000
DoD-1B      A Search for Etiologic Agents and Risk
            Factors: Study 2                                     Complete              NHRC          7/1/94         10/1/96       See DoD-1A
DoD-1C      A comparative study of pregnancy outcomes            Complete              NHRC          9/1/94          6/1/96       See DoD-1A
DoD-1D      Infertility and Miscarriage in Gulf War Veterans      Ongoing              NHRC        11/1/94           9/1/97       See DoD-1A
DoD-1E      Seabee Health Study                                   Ongoing              NHRC          1/1/96      10/1/2011        See DoD-1A
DoD-1F      A Comparison of Nonfederal Hosp.
            Experience Among Veterans in California ...           Ongoing              NHRC          6/1/95          6/1/97       See DoD-1A
DoD-1G      Epidemiologic Studies of Morbidity —Study
            7: Prevalence of Congenital Anomalies
            Among Children of Persian Gulf War Veterans           Ongoing              NHRC          6/1/95          6/1/97       See DoD-1A
DoD-2       Physiological and Neurobehavioral Effects in                            USAMRD
            Rodents from Exposure to PB, Fuels, and                                  (Wright-
            DEET                                                  Ongoing           Patterson)       7/1/94         10/1/97            $90,000
DoD-4       The General Well-Being of Gulf War Era
            Service Personnel from the States of PA and
            HI                                                   Complete             WRAIR          9/1/92         5/20/94        $1,200,000
DoD-6A      Combat Stress Pharmacotherapy                         Ongoing             WRAIR        10/1/88          9/30/99            $30,000
DoD-6B      Combat Stress Diagnosis: PTSD Prevention              Ongoing             WRAIR        10/1/87          9/30/98                       0
DoD-7A      Health Risk Assessment of Embedded
            Depleted Uranium                                      Ongoing              AFFRI       12/1/94          1/30/98           $703,000
DoD-7B      Carcinogenicity of Depleted Uranium
            Fragments                                             Ongoing                 ITRI     1/26/95        10/30/98            $549,000
DoD-8A      Serologic Diagnosis of Viscerotropic
            Leishmaniasis                                        Complete             WRAIR        10/1/93           9/1/96            $10,000
DoD-8B      Development of Leishmania Skin Test Antigen           Ongoing             WRAIR        10/1/93       1/31/2000            $421,000
                                                                                                                                   (continued)


                                             21
                                              The Research Working Group of the Persian Gulf Veterans Coordinating Board, Annual Report to
                                             Congress: Federally Sponsored Research on Gulf War veterans’ Illnesses (Washington, D.C.:
                                             Department of Veterans Affairs, Apr. 1997). Also see PGVCB, A Working Plan for Research on Persian
                                             Gulf Veterans’ Illnesses (Washington, D.C.: VA, Nov. 1996).



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                                                                                                Start   Completion     Expenditures
Project no. Title                                                  Status        Location       date          date    through FY96a
DoD-9       Identification of the Genetic Factors Which                         USAMRU-
            Control Tropism in Leishmania                        Ongoing           Brazil      7/1/94        7/1/98        $150,000
DoD-10      Pyridostigmine Synergistic Toxicity Study           Complete          CHPPM       11/1/94        3/1/94         $44,000
DoD-11      Male/Female Differential Tolerances to                         South Florida
            Pyridostigmine Bromide                               Ongoing Drug Research        10/1/94        2/1/97        $908,000
DoD-12      Forward Deployable Diagnostics for
            Infectious Diseases                                  Ongoing              MRMC    10/1/93    9/30/2001       $1,546,000
DoD-13      Effects of Persian Gulf War Service on Military
            Working Dogs                                         Ongoing               AFIP    4/1/94      12/1/98         $200,000
DoD-14      Risk Factors Among U.S. Soldiers for
            Enrolling on the Department of Veterans
            Affairs Gulf War Registry                            Ongoing              WRAIR   10/1/93        9/1/96         $70,000
DoD-15      Comparative Mortality Among US Military
            Personnel Worldwide During Operations
            Desert Shield and Desert Storm                      Complete              WRAIR    5/1/94        1/1/95         $20,000
DoD-16      Kuwait Oil Fire Health Risk Assessment              Complete          CHPPM        5/5/91      2/18/94       $1,805,000
DoD-17      Retrospective Studies Involving Military Use
            of PB as a Pretreatment for Nerve Agent
            Poisoning                                           Complete          CHPPM        1/1/91      5/21/92          $21,000
DoD-18      Kuwait Oil Fires Troop Exposure Assessment
            Model (TEAM)                                        Complete          CHPPM       5/31/93     12/31/96       $1,500,000
DoD-19      Persian Gulf Veterans Health Tracking System         Ongoing          CHPPM        4/1/96     12/31/97          $25,000
DoD-20      A Statistical Study Correlating the Reported
            Cases of Gulf War Syndrome to Battlefield
            Locations of Afflicted US Army Personnel                         U.S. Army
            During the Iraq-Kuwait War                          Complete Research Lab.         1/1/94        7/1/95         $50,000
DoD-21      Study of Variability in Pyridostigmine Inhibition                 WRAIR and
            of Blood Cholinesterases in Healthy Adults ...       Ongoing        WRAMC         7/11/95      6/30/97         $138,000
DoD-22      Chronic Organophosphorus Exposure and                             University of
            Cognition                                            Ongoing               GA     4/15/95      5/14/98         $187,000
DoD-23      Acute and Long-Term Impact of Deployment
            to Southwest Asia on the Physical and Mental
            Health of Soldiers and their Families                Ongoing              WRAIR   10/1/93        9/1/98        $326,000
DoD-30      Epidemiological Studies Persian Gulf War                              Klemm
            Illnesses, PG Women’s Health Linkage Study           Ongoing     Analysis, DC      6/1/96      1/31/99         $779,000
DoD-31      Dysregulation of the Stress Responses in the                      Georgetown
            Persian Gulf Syndrome                                Ongoing        Univ., DC      5/6/96        6/6/99        $162,000
DoD-32      Neuropsychological Functioning in Persian
            Gulf Era Veterans                                    Ongoing    VAMC Boston        5/1/96        5/1/99        $353,000
DoD-33      Effects of Pyridostigmine in Flinders Line Rats
            Differing in Cholinergic Sensitivity                 Ongoing       Chapel Hill     7/1/96      6/30/98          $44,000
DoD-34      Characterization of Emissions from Heaters                          Lovelace
            Burning Leaded Diesel Fuel in Unvented Tents                      Biomedical
                                                                            Albuquerque,
                                                                 Ongoing             NM        6/7/96        7/6/98         $36,000
                                                                                                                         (continued)


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                                                                                                  Start   Completion     Expenditures
Project no. Title                                                  Status        Location         date          date    through FY96a
DoD-35      Feasibility of Investigating whether there is a                     March of
            Relationship Between Birth Defects and                                Dimes,
            Service in the Gulf War                                          Sacramento,
                                                                 Ongoing             CA          6/1/96      6/30/98         $110,000
DoD-36      Fatigue in Persian Gulf Syndrome-Physiologic
            Mechanisms                                           Ongoing              Dallas    6/15/96      7/14/98         $138,000
DoD-37      Neurobehavioral and Immunological Toxicity
            of Pyridostigmine, Permethrin, and DEET in
            Male and Female Rats                                 Ongoing       Gainesville       5/1/96        6/1/99        $132,000
DoD-38      Diagnostic Antigens of Leishmania tropica                            Infectious
                                                                                   Disease
                                                                                 Research
                                                                              Inst.,Seattle,
                                                                 Ongoing                WA       6/1/96      5/31/98         $612,000
DoD-39      A Controlled Epidemiological and Clinical
            Study into the Effects of Gulf War Service on
            ... UK Armed Forces                                  Ongoing                 UK      6/1/96      6/30/99         $865,000
DoD-40      Psychological and Neurobiological                                 VAMC West
            Consequences of the Gulf War Experiences             Ongoing         Haven           6/7/96        7/6/99         $90,000
DoD-41      Evaluation of Muscle Function in Persian Gulf
            Veterans                                             Ongoing      Philadelphia      6/15/96     11/14/99         $906,000
DoD-42      The Symptomatic Persian Gulf Veterans
            Protocol: An Analysis of Risk Factors with an
            Immunologic and Neuropsychiatric                                        VAMC
            Assessment                                           Ongoing      Birmingham       10/31/96         2000         $700,000
DoD-44      Investigation of Seminal Plasma                                          Univ.
            Hypersensitivity Reactions                           Ongoing        Cincinnati      11/1/96      10/1/99         $634,000
DoD-45      Physical and Emotional Health of Gulf War
            Veterans Women                                       Ongoing    Ann Arbor, MI        9/1/96      8/31/99         $100,000
DoD-46      Exploratory Data Analysis with the CCEP                               NPGS -
            Database                                             Ongoing          Missouri      10/1/95        9/1/97         $60,000
DoD-47      Study of Mycoplasmal Infections in Gulf War
            Veterans                                             Ongoing          WRAMC        10/10/95      8/30/97         $112,000
DoD-48      Assessment of Genomic Instability via
            Chromosome 7 Inversion Frequency in a
            Gulf-War Syndrome Cohort vs. Selected
            Control Groups                                       Ongoing               AFIP    10/10/95      5/31/97          $74,000
DoD-49      Diagnosis and Dosimetry of Exposure to
            Sulfur Mustard                                       Ongoing      Netherlands       10/1/96    2/28/2000     Not available
DoD-50      Toxicokinetics of VX                                 Ongoing      Netherlands      10/15/96      4/30/98     Not available
DoD-51      Transgenic Engineering of Cholinesterases            Ongoing              Israel    10/1/96    2/28/2000     Not available
HHS-1       Health Assessment of Persian Gulf War
            Veterans from Iowa                                   Ongoing               CDC      12/1/94      1/31/98       $4,772,000
HHS-2       Disease Cluster in a Pennsylvania Air National
            Guard Unit, EPI-AID 95-18                            Ongoing               CDC      12/1/94      3/31/95         $750,000
                                                                                                                           (continued)



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                                                                                              Start   Completion     Expenditures
Project no. Title                                                 Status        Location      date          date    through FY96a
HHS-3       Biomarkers of Susceptibility and Polycyclic
            Aromatic Hydrocarbon Exposure in Urine and
            Blood Cell DNA from US Army Soldiers                           NIH/NCI/DCE
                                                                                                                                 b
            Exposed to Kuwaiti Oil Well Fires                   Ongoing       /LCTP/IVP      1/1/92      1/31/97
HHS-4       Suspected Increase of Birth Defects and
            Health Problems Among Children Born to
            Persian Gulf War Veterans in Mississippi           Complete              CDC     5/1/94        2/1/96         $15,981c
VA-1        Mortality Follow-up Study of Persian Gulf
            Veterans                                           Complete              VACO    7/1/94      7/31/96         $150,000
VA-2        National Health Survey of Persian Gulf
            Veterans                                            Ongoing              VACO    7/1/94      6/30/98       $2,716,000
VA-3        Use of Roster of Veterans Who Served in
            Persian Gulf Area                                   Ongoing              VACO    7/1/94      7/31/96                0
VA-4A       Evaluation of Cognitive Functioning of Persian
            Gulf Veterans                                       Ongoing    VAMC Boston      10/1/94      9/30/99       $2,572,500
VA-4B       Evaluation of Neurological Functioning of
            Persian Gulf Veterans                               Ongoing    VAMC Boston      10/1/94      9/30/99       See VA-4A
VA-4C       Gulf War and Vietnam Veterans Cancer
            Incidence Surveillance                              Ongoing    VAMC Boston      10/1/94      9/30/99       See VA-4A
VA-4D       Evaluation of Respiratory Dysfunction Among
            Gulf War Veterans                                   Ongoing    VAMC Boston      10/1/94      9/30/96       See VA-4A
VA-4E       The Aromatic Hydrocarbon Receptor as a
            Biomarker of Susceptibility                         Ongoing    VAMC Boston      10/1/94      9/30/99       See VA-4A
VA-4F       Validity of Computerized Tests                      Ongoing    VAMC Boston      10/1/94      9/30/99       See VA-4A
VA-5A       Health and Exposure Survey of Persian Gulf                          VAMC E.
            Veterans                                            Ongoing          Orange     10/1/94      9/30/96       $2,572,500
VA-5B       Physiological and Psychological Assessments                         VAMC E.
            of Persian Gulf Veterans                            Ongoing          Orange     10/1/94        3/1/97      See VA-5A
VA-5C       Effects of Exertion and Chemical Stress on                          VAMC E.
            Persian Gulf Veterans                               Ongoing          Orange      4/1/97      9/30/99       See VA-5A
VA-5D       Effects of Genetics and Stress on Responses                         VAMC E.
            to Environmental Toxins                             Ongoing          Orange     10/1/94      9/30/97       See VA-5A
VA-6        Portland Environmental Hazards Research
            Center: Environmental, Veterans Health and
            the Gulf War Syndrome                               Ongoing VAMC Portland       10/1/94      9/30/99       $2,572,500
VA-6A       Psychosocial, Neuropsychological and
            Neurobehavioral Assessment                          Ongoing VAMC Portland       10/1/94      9/30/99         See VA-6
VA-6B       Clinical and Neuroendrocrine Aspects of
            Fibromyalgia (Project II)                           Ongoing VAMC Portland       10/1/94      9/30/99         See VA-6
VA-6C       Neurotoxicity of Environmental Pollutants and
            Warfare Agents (Project III)                        Ongoing VAMC Portland       10/1/94      9/30/99         See VA-6
VA-6D       DNA Damage from Chemical Agents and its
            Repair (Project IV)                                 Ongoing VAMC Portland       10/1/94      9/30/99         See VA-6
VA-7        Desert Storm Reunion Survey                        Complete    VAMC Boston       4/1/91      9/30/95         $122,500
                                                                                                                       (continued)



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                                                                                                Start   Completion     Expenditures
Project no. Title                                                  Status        Location       date          date    through FY96a
VA-8        Psychological Test Data of Gulf War Veterans                           VAMC
            over Time                                                            Mountain
                                                                 Ongoing           Home        7/9/91      9/30/97      Not available
VA-9        Evaluation of Cognitive Functioning in Persian
            Gulf War Veterans Reporting War-related                            VAMC New
            Health Problems                                     Complete         Orleans       4/1/94      9/30/95            $49,000
VA-10       Memory and Attention in PTSD                                       VAMC New
                                                                 Ongoing         Orleans       2/1/94      9/30/98          $156,065
VA-11       Neuropsychological Functioning in Veterans                         VAMC New
                                                                Complete         Orleans       2/1/92        3/1/95     Not available
VA-12       Psychological Assessment of Operation                              VAMC New
            Desert Storm Returnees                               Ongoing         Orleans       8/1/91        9/1/97     Not available
VA-13       Neurobehavioral Aspects of Persian Gulf                                  VAMC
            Experiences: A Pilot Study                          Complete        Pittsburgh     4/1/94      3/31/95          $122,500
VA-15       Vaccine-Mediated Immunity Against                                      VAMC
            Leishmaniasis                                        Ongoing        Cleveland      1/1/93      9/30/99          $315,070
VA-16       Protective Immunity in Experimental Visceral                       VAMC San
            Leishmaniasis                                        Ongoing         Antonio      10/1/94      9/30/97          $296,205
VA-17       Immunological Evaluation of Persian Gulf                                VAMC
            Veterans                                            Complete      Birmingham       4/1/94        5/1/95     Not available
VA-18       Chronic Gastrointestinal Illness in Persian Gulf
            Veterans                                             Ongoing    VAMC Boston       10/1/94      10/1/96      Not available
VA-20       Psychological Adjustment in Operation Desert                           VAMC
            Shield/Storm Veterans                               Complete       Gainesville     7/1/91        7/1/93     Not available
VA-21       A Comparison of PTSD Symptomatology
            among Three Army Medical Units Involved in
            ODS                                                 Complete VAMC Phoenix          1/8/92      12/3/94      Not available
VA-30       Female Gender and Other Potential
            Predictors of Functional Health Status Among
            Persian Gulf War Veterans                            Ongoing    VAMC Boston       9/11/95      3/19/98      Not available
VA-36       Stress Symptoms and their Causal Attribution                            VAMC
            in Desert Storm Veterans                             Ongoing       Clarksburg     12/1/95     12/31/96      Not available
VA-40       Musculoskeletal Symptoms in Gulf War                              VAMC Long
            Syndrome                                             Ongoing          Beach        1/1/94         1999      Not available
VA-46       Diarrhea in Persian Gulf Veterans: An Irritable                        VAMC
            Bowel-Like Disorder                                  Ongoing       Gainesville    11/1/95         1996      Not available
VA-47       Retrospective Validation of Mustard Gas                                VAMC
            Exposure                                             Ongoing         Louisville    1/1/97         2000      Not available
                                                                                                                         $37,067,821

                                                                                                             (Table notes on next page)




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                       a
                        Information on funding was unavailable for some VA intramural projects because these projects
                       were budgeted from medical center overhead. Additional funds may have been obligated for
                       ongoing projects in fiscal year 1997 and later years.
                       b
                        HHS conducted testing on blood samples from persons exposed to the Kuwait oil well fires to
                       assess evidence of exposure to volatile organic compounds. The cost incurred for this work was
                       $33,000.
                       c
                       Federal costs only.




                       The vast majority of federal research was initiated during or after 1994,
Federal Research Was   and relatively few of these studies have been completed. Seventy-two
Delayed and Lacked a   projects (79 percent) were ongoing when we reviewed them in early 1997.
Proactive Approach     Figure III.1, which shows the proportion of completed studies, is based on
                       the rate of progress toward completion of projects based on actual and
                       projected completion dates provided in the most recent research working
                       plan. In some instances, the projected completion dates have not been
                       met. Therefore, figure III.1 slightly overstates the number of projects
                       actually completed. In fact, 28 studies have estimated completion dates
                       prior to 1997, yet only 19 have been flagged as complete in the most recent
                       (April 1997) report to Congress.




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Figure III.1: Cumulative Percentages of 91 Federally Funded Studies to Be Completed as a Function of Time


Percent of 91 studies
100



 80



 60



 40



 20



  0
      1991      1992       1993       1994       1995         1996          1997         1998         1999         2000

                                           Begin Estimated completion



                                          Note: An additional two studies are slated to continue beyond the year 2000.

                                          Source: GAO analysis of information published by the PGVCB.




                                          Many federal research efforts were started in association with legislation
                                          enacted by Congress. For example, legislation enacted in December 1991
                                          required DOD to establish a registry of troop members who were exposed
                                          to fumes from oil well fires and to report annually on its studies of the
                                          health effects of such exposure. Legislation enacted in late 1993



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authorized DOD to make grants for studies on the effects of veterans’
exposure to low levels of hazardous chemicals, including chemical
warfare agents, and on the effects of exposure to depleted uranium. In
1994, Congress required DOD, in consultation with the VA and HHS, to
conduct studies and administer grants for studies to determine the nature
and causes of Gulf War illness, including, among others, studies to
determine the effects of exposure to pyridostigmine bromide. In 1996,
Congress directed DOD to provide for research into the possible exposure
of troops to chemical warfare agents or other hazardous materials and the
use by DOD of combinations of various vaccines and investigational new
drugs.

As noted by external reviewers, since federal research goals and
objectives were not identified until 1995, after most research activities had
been initiated, they appear to reflect a rationalization of ongoing activity
rather than a research management strategy. In March 1995, the
Department of Veterans Affairs issued a report to Congress, entitled
Federal Activities Related to the Health of Persian Gulf Veterans, that
identified most of the projects now covered by the PGVCB’s research
agenda but noted that “this is a list of activities and is not intended to be
construed as a comprehensive research strategy.” Five months later, PGVCB
issued A Working Plan for Research on Persian Gulf Veterans’ Illnesses,
which linked the previously identified projects to 19 specific research
objectives. VA officials acknowledged that the research strategy was
articulated in response to criticism from the IOM, which had said that “VA
and DOD should determine the specific research questions that need to be
answered.” Table III.3 documents other events coincident with changes in
research activity.




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Table III.3: Events Coincident With Changes in PGVCB Research Agenda
                 1991         1992              1993             1994                        1995                  1996
Events and    Operation    Reports of          A staff report to the   The Defense           IOM interim           DOD
reports       Desert       “unexpected signs   Senate Banking          Science Board         report criticizes     acknowledges
              Storm        and symptoms”       Committee states        report states that    agencies for lack     chemical weapon
              (winter)     from the 123rd      that “there is          illnesses were not    of coordination.      release at
                           Army Reserve Unit   substantial             due to exposure to                          Khamisiyah.
                           in Indiana.         evidence                chemical
                           (January)           supporting claims       weapons. (June)
                                               that U.S.
                                               servicemen and                                                      Presidential
                                               women were                                                          Advisory Committee
                                               exposed to low          NIH Technology                              report finds that
                                               level chemical          Assessment                                  “The government’s
                                               warfare agents          Workshop finds                              current research
                                               and possibly            that (1) a                                  portfolio on Gulf War
                                               biological toxins       collaborative                               veterans’ illnesses is
                                               from a variety of       government-                                 appropriately
                                               possible sources.       supported                                   weighted toward
                                               This exposure may       program had not                             epidemiologic
                                               account for many        been established                            studies and studies
                                               of the Gulf War         and (2) the                                 on stress-related
                                               Illness symptoms.”      absence of                                  disorders.”
                                                                       well-designed
                                                                       studies had
                                                                       hampered the
                                                                       development of an
                                                                       appropriate case
                                                                       definition. (April)
                                                                                                                             (continued)




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                                               Federal Strategy to Research Gulf War
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                1991             1992               1993                  1994                  1995                  1996
Research        Six new          Four new studies   Seven new studies 39 new studies            Eleven new studies 20 new studies
program         studies          started            started           started (including        started            started
                started                                               14 at the
                                                                      environmental
                                                                      health centers)
                Four on          Three on stress    Four on infectious    Shift to include a    President             $2.5 million
                stress and       and one on         diseases, one         greater range of      announces             allocated by VA to
                one each on      methods            each on stress, oil   symptoms and          formation of          three new projects
                oil well fires                      fires, and methods    exposures             Presidential          examining the health
                and PB                                                                          Advisory              effects of chemical
                                                                                                Committee (March)     weapons.

                                                                          VA establishes
                                                                          three
                                                                          environmental         DOD issues a          DOD launches a
                                                                          hazards               “Broad Agency         $15 million research
                                                                          research centers.     Announcement” for     program into the
                                                                          (July)                research in PB,       possible effects of
                                                                                                epidemiology and      low-level exposure
                                                                                                clinical research     to chemical agents
                                                                                                as mandated by        using $10 million
                                                                                                Congress in PL        made available by
                                                                                                103-337. $5 million   Congress and $5
                                                                                                allocated. There      million
                                                                                                were more than        committed by DOD.
                                                                                                100 responses.        (September)
                                                                                                (June)


                                                                                                                      VA issues a request
                                                                                                                      for proposals for a
                                                                                                                      fourth Environmental
                                                                                                                      Hazards Research
                                                                                                                      Center for
                                                                                                                      Reproductive
                                                                                                                      Outcomes. (May)
Clinical care   VA develops                                               DOD starts the        DOD issues its        DOD reports on the
programs        the Persian                                               Comprehensive         report on the first   first 18,000
                Gulf Health                                               Clinical Evaluation   10,000 participants   participants in CCEP
                Registry                                                  Program (CCEP)        in CCEP (August)      (April)
                (April)                                                   (June)

                                               Although research activity has recently been accelerated and broadened,
                                               opportunities have been missed to collect critical data that researchers
                                               cannot accurately reconstruct. Even efforts to measure the chemical
                                               content of the oil-fire smoke, begun only 3 months after the fires began
                                               burning, were initiated after most troops had left the affected areas and
                                               the climatological dynamics may have been different. Consequently,
                                               researchers were forced to use statistical models of the behavior of smoke
                                               plumes in order to infer the ground-level exposures experienced by the



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                  large numbers of troops who had departed by the time they began
                  collecting data. Even if such models accurately explain the behavior of the
                  smoke plumes, they have not been validated as measures of individual
                  exposure, and their accuracy for this purpose cannot be presumed. Similar
                  and even more serious problems were caused in the measurement of other
                  exposures by the failure to collect data promptly and maintain adequate
                  records.22

                  The delay in starting research has also hindered accurate reporting of
                  exposures by Gulf War veterans. Questionnaires are being distributed
                  today (6 years after the war ended) requesting information from veterans
                  on their exposure to certain agents during Operation Desert Storm.
                  Regarding one study, the IOM concluded, “This is a well-designed and
                  well-intended study, but it has started at least several years too late. Recall
                  problems and the inability to obtain accurate information on those who
                  died before the study started are major threats to its validity.” (IOM, Final
                  Report, 1996, p. 91)


                  Early federal research appeared to emphasize risks associated with
Some Hypotheses   psychological factors such as stress. To support this emphasis, DOD
Received Early    pointed out that the psychological state of mind can influence physical
Emphasis          well-being. DOD also pointed to a recent argument that from the American
                  Civil War onward (and perhaps even earlier), a small number of veterans
                  have reacted to the stress of war by suffering symptoms similar to those
                  reported by some Gulf War veterans.23

                  Of the 19 studies initiated before 1994, roughly half focused on exposure
                  to stress or the potential for posttraumatic stress disorder (PTSD) among
                  returning troops.24 As late as December 1996, the Presidential Advisory
                  Committee (PAC) on Gulf War Veterans’ Illnesses noted that 25 studies
                  centered on stress or PTSD. However, some early research reflected
                  immediate postwar concerns about other issues, for example, the potential
                  effects of the oil fires set by Iraqi troops departing Kuwait and an unusual
                  form of parasitic infection that had been identified in a small number of
                  patients at Walter Reed Army Medical Center (WRAMC).

                  22
                   See Defense Health Care: Medical Surveillance Has Improved Since the Gulf War, but Results in
                  Bosnia Are Mixed (GAO/NSIAD-97-136, May 13, 1997) and Institute of Medicine, Final Report, p. 5.
                  23
                   K. C. Hyams et al., “War Syndromes and Their Evaluation: From the U.S. Civil War to the Persian Gulf
                  War,” Annals of Internal Medicine, vol. 125 (1996), pp. 398-405.
                  24
                    An additional 3 of the 19 studies did not provide information about veterans’ illnesses but were
                  instead building databases or methods to be used in later studies. Notably, according to the PGVCB,
                  none of these 3 studies has yet been completed.



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                         While research on exposure to stress received early emphasis, other
Some Hypotheses          hypotheses received scant support. In its Final Report, IOM discusses the
Were Not Initially       evidence for a number of disease hypotheses, including multiple chemical
Pursued                  sensitivity and organophosphate-induced delayed neuropathy (OPIDN). IOM
                         found the evidence for none of the hypotheses to be highly compelling
                         when it conducted the review, but it nevertheless highlighted the
                         importance of exploring “all possible avenues to increase our knowledge
                         of such illnesses and to reduce suffering and disability.” Nonetheless, aside
                         from studies examining stress-related symptoms, relatively few studies
                         have been supported to evaluate alternative disease hypotheses. For
                         example, prior to October 1996, only one study focused on the health
                         effects of potential exposure to chemical warfare agents.25 While multiple
                         studies of the role of stress in the veterans’ illnesses have been supported
                         with federal research dollars, some other hypotheses have been pursued
                         largely outside the federal research program.

                         Although veterans raised concerns about potential chemical exposures
                         soon after the war, and DOD had acknowledged one soldier’s accidental
                         exposure to a mustard agent in 1994, the federal research plan was not
                         modified to include an investigation of concerns about such agents until
                         1996, when DOD acknowledged potential exposures to chemical agents at
                         Khamisiyah, Iraq. The failure to fund such research cannot be traced to an
                         absence of investigator-initiated submissions. According to DOD officials,
                         three recently funded proposals on low-level chemical exposure had
                         previously been denied funds.26 (See DOD studies 49, 50, and 51 in table
                         III.2)


                         A substantial body of privately funded research suggests that low-level
Additional               exposure to certain chemical warfare agents or chemically related
Hypotheses Were          compounds, such as certain pesticides, is associated with delayed or
Pursued in the Private   long-term health effects. Regarding delayed health effects of
                         organophosphates, the chemical family used in many pesticides and
Sector                   chemical warfare agents, there is evidence from animal experiments,
                         studies of accidental human exposures, and epidemiological studies of
                         humans that low-level exposures to certain organophosphorus

                         25
                           This study of the impacts of sulfur mustard agent is a collaborative effort between the Portland
                         Veterans Affairs Medical Center and the Oregon Health Sciences University. The principal investigator
                         for the study pointed out that the possibility of chemical warfare exposure seemed plausible even in
                         1994 when he sought initial funding for this research.
                         26
                          The three previously unfunded proposals address central nervous system targets for
                         organophosphates, development of a DNA-based method for assessing mustard agent exposure, and
                         work on the pharmacokinetics of the nerve agent VX.



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compounds, including sarin nerve agents to which some of our troops may
have been exposed, can cause delayed, chronic neurotoxic effects.27 This
syndrome is characterized by clinical signs and symptoms manifested 4 to
21 days after exposure to organophosphate compounds. The symptoms of
delayed neurotoxicity can take at least two forms: (1) a single large dose
may cause nerve damage with paralysis and later spastic movement, or
(2) repetitive low doses may damage the brain, causing impaired
concentration and memory, depression, fatigue, and irritability. These
delayed symptoms may be permanent.

As early as the 1950s, studies demonstrated that repeated oral and
subcutaneous exposures to neurotoxic organophosphates produced
delayed neurotoxic effects in rats and mice. In addition, German personnel
who were exposed to nerve agents during World War II displayed signs
and symptoms of neurological problems even 5 to 10 years after their last
exposure. Long-term abnormal neurological and psychiatric symptoms as
well as disturbed brain wave patterns have also been seen in workers
exposed to sarin in sarin manufacturing plants.28 The same abnormal brain
wave disturbances were produced experimentally in primates by exposing
them to low doses of sarin.29

Delayed, chronic neurotoxic effects were also seen in animal experiments
after the administration of organophosphate.30 These effects include
difficulty in walking and paralysis. In recent experiments, animals given a
low dosage of the nerve agent sarin for 10 days showed no signs of
immediate illness but developed delayed chronic neurotoxicity after 2
weeks.31

27
  Sarin has been used as a chemical warfare agent since World War II, most recently during the
Iran-Iraq war, and by terrorists in Japan.
28
 F. H. Duffy et al., “Long-Term Effects of an Organophosphate Upon the Human
Electroencephalogram,” Toxicology and Applied Pharmacology, vol. 47 (1979), pp. 161-176, and F.R.
Sidell, “Soman and Sarin: Clinical Manifestations and Treatment of Accidental Poisoning by
Organophosphates,” Clinical Toxicology, vol. 7 (1979), pp. 1-17.
29
 J. L. Burchfiel et al., “Persistent Effect of Sarin and Dieldrin Upon the Primate
Electroencephalogram,” Toxicology and Applied Pharmacology, vol. 35 (1976), pp. 365-379.
30
 M. B. Abou-Donia, “Organophosphorus Ester-induced Delayed Neurotoxicity,” Annual Review of
Pharmacological Toxicology, vol. 21 (1981), pp. 511-548, and M. K. Johnson, “The Target for Initiation
of Delayed Neurotoxicity by Organophosphorus Esters: Biochemical Studies and Neurotoxicological
Applications,” Review of Biochemistry and Toxicology, vol. 4 (1982), pp. 141-212.
31
 K. Husain et al., “Assessing Delayed Neurotoxicity in Rodents after Nerve Gas Exposure,” Defence
Science Journal, vol. 44 (1994), pp. 161-164; K. Husain et al., “Delayed Neurotoxic Effect of Sarin in
Mice After Repeated Inhalation Exposure,” Journal of Applied Toxicology, vol. 13 (1993), pp. 143-145;
and K. Husain et al., “A Comparative Study of Delayed Neurotoxicity in Hens Following Repeated
Administration of Organophosphorus Compounds,” Indian Journal of Physiology and Pharmacology,
vol. 39 (1995), pp. 47-50.



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It has been suggested that the ill-defined symptoms experienced by Gulf
War veterans may be due in part to OPIDN.32 This hypothesis was tested in a
privately supported epidemiological study of Gulf War veterans.33 In
addition to clarifying the patterns among veterans’ symptoms by use of
statistical factor analysis, this study demonstrated that vague symptoms of
the ill veterans are associated with objective brain and nerve damage
compatible with the known chronic effects of exposures to low levels of
organophosphates.34 It further linked the veterans’ illnesses to exposure to
combinations of chemicals, including nerve agents, pesticides in flea
collars, N,N-diethyl-m-toluamide (DEET) in highly concentrated insect
repellents, and pyridostigmine bromide tablets.

Toxicological research indicates that agents like pyridostigmine bromide,
which Gulf War veterans took to protect themselves against the
immediate, life-threatening effects of nerve agents, may alter the
metabolism of organophosphates in ways that activate their delayed,
chronic effects on the brain.35 Moreover, exposure to combinations of
organophosphates and related chemicals like pyridostigmine bromide or
DEET has been shown in animal studies to be far more likely to cause
morbidity and mortality than any of the chemicals acting alone.36




32
  R. W. Haley et al., “Preliminary Findings of Studies on the Gulf War Syndrome,” Presentations to the
Intergovernmental Coordinating Board for the Gulf War Illness and the Staff of the Presidential
Advisory Committee on Gulf War Veterans’ Illnesses,” September 16, 1995; R. W. Haley,
“Organophosphate-Induced Delayed Neurotoxicity,” Internal Medicine Grand Rounds, University of
Texas Southwestern Medical Center, Dallas, Texas, October 10, 1996; and G. A. Jamal et al., “The Gulf
War Syndrome: Is There Evidence of Dysfuction in the Nervous System?” Journal of Neurology,
Neurosurgery and Psychiatry, vol. 60 (1996), pp. 449-451.
33
 This research, conducted at the University of Texas Southwestern Medical Center, has been
supported in part by funding from the Perot Foundation.
34
 R. W. Haley et al., “Is There a Gulf War Syndrome? Searching for Syndromes by Factor Analysis of
Symptoms,” Journal of American Medical Association, vol. 277 (1997), pp. 215-222; R. W. Haley et al.,
“Evaluation of Neurologic Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of
American Medical Association, vol. 277 (1997), pp. 223-230; and R. W. Haley et al., “Self-reported
Exposure to Neurotoxic Chemical Combinations in the Gulf War: A Cross-sectional Epidemiologic
Study,” Journal of American Medical Association, vol. 277 (1997), pp. 231-237.
35
 C. N. Pope and S. Padilla, “Potentiation of Organophosphorus Delayed Neurotoxicity,” Journal of
Toxicology and Environmental Health, vol. 31 (1990), pp. 261-273.
36
 M. B. Abou-Donia et al., “Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine
Bromide, DEET, and Chlorpyrifos,” Fundamentals of Applied Toxicology, vol. 34 (1996), pp. 201-222,
and M. B. Abou-Donia et al., “Neurotoxicity Resulting From Coexposure to Pyridostigmine Bromide,
DEET, and Permethrin,” Journal of Toxicology and Environmental Health, vol. 48 (1996), pp. 35-56.



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Federal Research
Emphasis

Most Studies Use an                         Sixty-one of the 91 federally sponsored studies (67 percent) are classified
Epidemiological Approach                    as epidemiological by the Persian Gulf Veterans Coordinating Board. The
                                            remaining 30 studies are classified as basic (20 percent), applied
                                            (10 percent), and clinical (3 percent) research. Table III.4 shows that the
                                            epidemiologic emphasis is present across most major health effects and
                                            risk factors under investigation.


Table III.4: Number of Studies by Primary Research Focus and Study Type
                                                                                        Research type
Primary research focus                                     Applied          Basic         Clinical   Epidemiological          Total
Birth and reproductive effects                                    0                 0           0                   4             4
Cancer                                                            0                 0           0                   1             1
Chemical weapons                                                  1                 3           0                   1             5
Depleted uranium                                                  0                 2           0                   0             2
Fibromyalgia                                                      0                 0           0                   1             1
Gastrointestinal                                                  0                 0           0                   2             2
Genitourinary                                                     0                 0           0                   1             1
Immunological                                                     0                 0           0                   2             2
Infectious diseases                                               4                 3           0                   1             8
Methods                                                           1                 2           1                   6            10
Mortality                                                         0                 0           0                   2             2
Multiple symptoms/diseases                                        1                 0           0                  18            19
Muscular                                                          0                 0           0                   3             3
Multiple organophosphates (including pyridostigmine               0                 6           1                   2             9
bromide)
Neurological/cognitive                                            0                 0           0                   3             3
Oil-well fires                                                    2                 0           0                   0             2
Pulmonary                                                         0                 0           0                   1             1
Stress and PTSD                                                   0                 2           1                  13            16
Total                                                             9            18               3                  61            91



Little Research on                          As indicated in table III.5, federal research is currently centered on studies
Treatment                                   of the prevalence, nature, and risk factors associated with veterans’
                                            illnesses. Few studies are focusing primarily on identification and



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                                      improvement of treatments for Gulf War veterans’ illnesses. Results of our
                                      interviews with principal investigators of ongoing epidemiological projects
                                      are generally consistent with this distribution; none of the investigators we
                                      interviewed identified the primary goal of his work as developing
                                      treatment strategies.

Table III.5: Primary Emphasis of 91
Federally Sponsored Research          Objective                                                         Number           Percenta
Projects Identified by PGVCB          Prevalence                                                              26               29
                                      Nature                                                                  17               19
                                      Cause                                                                   18               20
                                      Diagnosis                                                                6                7
                                      Treatment                                                                3                3
                                      Methodology                                                             14               15
                                      Combination                                                              7                8
                                      a
                                      The individual percentages do not add to 100 due to rounding.

                                      Source: GAO analysis of information provided by PGVCB.



                                      Descriptive studies are useful for providing information about an illness.
                                      But the principal value of doing descriptive studies is to aid in generating
                                      hypotheses that, through careful analytical studies, can lead to isolating
                                      the nature of the illness and developing treatments. Because so little was
                                      initially known about Gulf War veterans’ health, there was a need for
                                      descriptive studies. Most of the epidemiological studies thus far have
                                      focused on descriptive studies of prevalence. With the exception of the
                                      studies that explore the hypothesis that combat stress explains a portion
                                      of Gulf War veterans’ symptoms, research has, by and large, been stuck at
                                      the beginning of the study cycle presented in appendix I, perhaps partly as
                                      a result of a failure to identify hypotheses for further testing, the absence
                                      of exposure data, and a failure to identify one or more case definitions.

                                      If research on treatments must follow the descriptions of illnesses and
                                      causes provided through epidemiological research, then improved
                                      treatments for the illnesses afflicting Gulf War veterans might never be
                                      found. In 1994, Congress directed DOD and VA to research treatments for
                                      ailing Gulf War veterans. Our report shows that such research has largely
                                      not taken place, even though more focused research can be done without
                                      having first answered general descriptive questions.




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                           Our review indicated that most of the ongoing epidemiological studies
Formidable                 focusing on the prevalence or causes of Gulf War-related illnesses have
Methodological             been hampered by data problems and methodological limitations and
Problems                   consequently may not be able to provide conclusive answers in response
                           to their stated objectives, particularly in identifying risk factors or
                           potential causes.


Problems With Prevalence   All but one of the research objectives identified by PGVCB (as noted earlier
Studies                    in table III.1) concern establishing the prevalence of symptoms, exposures,
                           morbidity, or mortality. In fact, the PGVCB research plan states that “the
                           most important question about the health of Persian Gulf veterans is: Are
                           Persian Gulf veterans experiencing a greater prevalence of symptoms and
                           illnesses in comparison with an appropriate control population?” The
                           research plan suggests that the direction of additional exploration is
                           contingent on the answer to this question (for example, greater priority
                           will be given to investigating excess health outcomes).

                           It should be noted that Gulf War veterans, even in theater, may have
                           experienced broadly different sets of circumstances and exposures. For
                           example, according to press reports, none of the French troops have
                           complained of similar illnesses. Some notable differences were that
                           French forces were not in the same places as the other allied forces; the
                           French camps were not sprayed with insecticides; and the French did not
                           vaccinate against anthrax, take preventive measures against botulinum
                           toxin, or administer pyridostigmine bromide. None of the federally funded
                           studies used French troops as a comparison group. In contrast, most of the
                           ongoing studies designed to assess the prevalence of various conditions of
                           Gulf War veterans and others were making broad comparisons between
                           deployed and nondeployed veterans, rather than specific types and levels
                           of exposures. For example, our interviews found that 12 of 13 ongoing
                           cohort studies had defined the exposed cohort with reference to nothing
                           more than deployment status. That is, in almost all cases, the exposure of
                           interest was defined simply as “Gulf War service,” and the prevalence of
                           symptoms or illnesses among Gulf War veterans is being compared to the
                           prevalence of symptoms or illnesses among troops who were not deployed
                           to the Gulf.

                           Such comparisons may have value for providing basic assurances to
                           veterans regarding widespread and severe health consequences of Gulf
                           War service. However, many service-connected illnesses could be
                           obscured by broad comparisons of deployed and nondeployed veterans



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                             without regard to their specific exposure histories. At the same time,
                             illnesses that were not actually service connected could appear to be
                             linked to deployment status due to preexisting group differences. For
                             example, some troops were not deployed for health reasons, potentially
                             biasing the comparison group in the direction of greater illness. Also, due
                             to the failure to compare the prewar health of the groups, the absence of
                             differences is no assurance that one of the groups has not experienced a
                             significantly steeper decline in health.

                             Some investigators have attempted to address some of the problems of
                             systematic differences between deployed and nondeployed veterans by
                             comparing Gulf War veterans to servicemembers who were deployed to
                             locations other than the Gulf. To the extent that such group differences
                             are measured, they can also be statistically controlled. While these are
                             potentially promising solutions, such comparisons must still be carefully
                             evaluated in the absence of evidence of prior similarity between the
                             groups and greater specificity regarding exposure.


Problems With Studies of     As we noted earlier, to ascertain the causes of illnesses, it is imperative
Risk Factors or Causes of    that investigators have valid and reliable methods to collect information
Illness                      on exposures as well as their effects. The need for accurate, dose-specific
                             information is particularly critical for low-level or intermittent exposure(s)
                             to drugs, chemicals, or biological agents. In addition, the investigators
                             must specify diagnostic criteria to (1) reliably determine who has the
                             disease or condition being studied and who does not and (2) select
                             appropriate controls (people who do not have the disease or condition).
                             To the extent that individuals are misclassified regarding disease or
                             exposure, conclusions would be misleading and relationships would be
                             obscured.

Measurement of Exposure Is   The research program to answer basic questions about the illnesses that
Problematic                  afflict Gulf War veterans has at least three major problems in linking
                             exposures to observed illness or symptoms. First, it is extremely difficult
                             to gather information about the unplanned exposures (for example, oil-fire
                             smoke and insects) that may have occurred in the Gulf, and DOD has
                             acknowledged that records of planned or intentional exposures (for
                             example, the use of vaccines and pyridostigmine bromide to protect
                             against chemical/biological warfare agents) were inadequate. Second, the
                             veterans were typically exposed to a wide array of agents with commonly
                             accepted health effects, making it difficult to isolate and characterize the
                             effects of individual factors or study their combined effects. Third, the



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passage of time following these exposures has made it increasingly
difficult to have confidence in any information gathered through
retrospective questioning of veterans.37

In part, the latter difficulty was created by the delayed release of
information about detection of chemical warfare agents during the war as
well as the delayed collection of exposure data. Five years passed before it
was acknowledged that American soldiers may have been exposed to
chemical warfare agents shortly after the war ended in 1991 (at the
Khamisiyah site). Moreover, although chemical detections by Czech forces
have been deemed “credible” by the Central Intelligence Agency (CIA), the
source of these detections remains unknown. In the face of denials by DOD
officials, a few researchers told us that they had considered it pointless to
pursue hypotheses that the symptoms may have been associated with
exposure to chemical weapons.

When we asked investigators responsible for ongoing federally funded
epidemiological projects about how they were collecting data on the
various factors to which Gulf War veterans may have been exposed, we
found that most projects had no means other than self-reports for
measuring most of the factors to which troops may have been exposed.
(See table III.6.) This reliance on self-reports was present even for
exposures such as vaccines for which records might have existed.




37
  Large numbers of veterans questioned during their participation in the VA’s revised health registry
examination program reported they did not know whether they were exposed to certain agents. “Don’t
know” responses were greatest for nerve gas (64.9 percent), mustard gas (60.2 percent), depleted
uranium (52.5 percent), chemical-agent resistant coating (47.8 percent), microwaves (32.8 percent),
paints or solvents (24.9 percent), and pyridostigmine (21.1 percent). To the extent that a response of
some kind reflects greater certainty, veterans were more confident in their reports regarding smoke
from tent heaters, passive smoking, diesel or other petrochemical fumes, skin exposure to fuel,
pesticides in cream or spray form, and burning trash or feces, each of which resulted in fewer than
11 percent of respondents reporting “don’t know.” However, the provision of a response does not
necessarily connote that the reports are accurate.



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Table III.6: Ongoing Epidemiological
Studies Using Measures Other Than                                                                          Is the exposure measured
Self-Reports to Assess Key Exposures                                   Is the study collecting data        through any means other
                                                                            on this exposure?a                  than self-report?b
                                       Exposure                          Yes        No No response           Yes     No No response
                                       CARC                                10        10               2         1      7              2
                                       Biological warfare
                                       agents                              10         9               3         4      3              3
                                       Depleted uranium                    14         6               2         2      8              4
                                       DEET                                11         7               4         1      7              3
                                       Permethrin                          11         7               4         1      7              3
                                       Other pesticides or
                                       repellents                          12         5               5         1      8              3
                                       Pyridostigmine bromide              15         5               2         0    11               4
                                       Vaccines                            13         5               4         6      4              3
                                       Petroleum products                  14         5               3         4      7              3
                                       Oil-fire smoke                      16         5               1         3    11               2
                                       war stressors                       15         5               2         1    10               4
                                       Infectious diseases                 11         7               4         6      5              0
                                       Chemical warfare
                                       agents                              15         4               3         5      5              5
                                       Note: The survey incorporated responses from 31 of the 43 studies identified as ongoing
                                       epidemiological studies by PGVCB in its November 1996 plan. Of these, 22 indicated they were
                                       collecting exposure information.
                                       a
                                       Among the 22 collecting any exposure data.
                                       b
                                           Among those collecting data on the exposure named in the first column.

                                       Source: GAO’s survey of investigators charged with ongoing epidemiological studies.



                                       There are three problems associated with reliance on self-reports for
                                       exposure assessments. First, recalled information may be inaccurate after
                                       such a long time period; that is, some veterans may not remember that
                                       they were exposed to particular factors, while others may not have been
                                       exposed but nonetheless inaccurately report that they were. Second,
                                       recollections also may be biased if, for example, veterans who became
                                       sick following the war recall their exposures earlier, more often, or
                                       differently than veterans who did not become sick. Third, there is often no
                                       straightforward way to test the validity of self-reported exposure
                                       information, making it impossible to separate biased recollections from
                                       actual differences in exposure frequency.




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                                 Some investigators are also relying on a model developed by the U. S.
                                 Army Environmental Hygiene Agency for assessing exposures to
                                 components of oil-fire smoke through the combination of unit location
                                 data and information from models of the distribution of oil-fire smoke.
                                 However, this method requires the use of unit location as a proxy for
                                 exposure, and the validity of this approach is unknown. As PAC noted,
                                 DOD’s Persian Gulf Registry of Unit Locations “lacks the precision and
                                 detail necessary to be an effective tool for the investigation of exposure
                                 incidents.” (See PAC’s Final Report (Washington, D.C.: GPO), p. 35.)

Case Definition Is Complicated   Another major hurdle to the development of a successful research agenda
by Presence of Nonspecific       has been the difficulty in classifying symptoms into one or more distinct
Symptoms                         illnesses. Some veterans complain of gastrointestinal pain, others report
                                 musculoskeletal pain or weakness, and still others report emotional or
                                 neurological symptoms. As explained previously, a specific case definition
                                 is essential to conducting certain types of epidemiological studies.

                                 Although some data on symptoms were collected beginning in 1992 with
                                 the initiation of the VA registry, initial efforts to collect information about
                                 symptoms and exposures from registry participants were limited and
                                 nonspecific, constraining their potential use for improving understanding
                                 of the patterns of veterans’ complaints. The limitations in early registry
                                 data are unfortunate insofar as detailed information about symptoms and
                                 exposures might have yielded earlier, more reliable analyses of the nature
                                 and causes of veterans’ complaints that could have also assisted in arriving
                                 at working case definition(s). Furthermore, clinical effects of a transitory
                                 nature that may have been manifested soon after the war would have been
                                 missed due to delays in setting up and developing studies and registries.

                                 We also found that both the federally supported projects and the federal
                                 registry programs have generally failed to study the conjunction of
                                 multiple symptoms in individual veterans. Articles and briefing documents
                                 that we have obtained report findings that address the incidence of single
                                 symptoms and diagnoses. There are two exceptions. First, the Center for
                                 Disease Control (CDC) and Prevention developed an operational case
                                 definition, which is quite similar to the case definition of chronic fatigue
                                 syndrome. Obviously, this definition cannot be generalized beyond the
                                 population from which it was derived. Second, the studies conducted by
                                 Haley et al. also focused on identifying symptom clusters.

                                 For those ongoing epidemiological projects that are built on case-control
                                 designs, we inquired about how a case was defined. The specificity of this



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              Appendix III
              Federal Strategy to Research Gulf War
              Illnesses Lacks a Coherent Approach




              definition is important because a vague case definition can lead to
              considering multiple kinds of illness together. When this is done, it is not
              surprising to find no commonality of experience among the cases.
              Moreover, the use of specific case definition is particularly critical to
              achieving meaningful results within this type of research design. However,
              in the ongoing studies we surveyed, case definition was quite broad, even
              among studies that depended upon case-control research designs. For
              example, among 13 case-control or nested case-control studies, case
              definitions included such broad descriptors as registry participants, Gulf
              War veterans who are symptomatic without diagnosable illness, and
              veterans with complaints of chronic fatigue and muscle weakness.

Sample Size   Most investigators we interviewed in our survey took steps to estimate the
              size of sample they would require to have a reasonable expectation of
              detecting differences between deployed and nondeployed veterans or
              exposures to hazardous substances. However, many variables are involved
              in such calculations, for example, the size of the investigated exposure’s
              expected impact on health (consistent lethal effects can be detected in a
              smaller sample than more subtle problems) and the prevalence of
              exposure, some of which were unknown at the time the studies were
              planned. Thus, they had to be estimated within somewhat broad
              parameters. Although steps were clearly taken to plan for an adequate
              sample size, some investigators reported difficulty in locating subjects due
              to factors beyond their control, such as the rate of referrals from VA
              examination centers or the rate of identification of subjects that fit highly
              specific case definitions. Moreover, other studies, such as those on
              specific birth defects, require extremely large samples. An investigator on
              a principal study of birth defects indicated that the number of births to
              Gulf War veterans and problems with data collection would mean that
              data would not be sufficient to draw conclusions about a particular defect
              (Goldenhaar syndrome) for 6 years or more.




              Page 53                                      GAO/NSIAD-97-163 Gulf War Illnesses
Appendix IV

Support for Key Official Conclusions Is
Weak or Subject to Different Interpretations

                                             A key measure of the effectiveness of a research program is the extent to
                                             which it has yielded verifiable conclusions regarding the subject of study.
                                             We previously reviewed findings contained in the November 1996 revision
                                             of A Working Plan for Research on Persian Gulf Veterans’ Illnesses and
                                             concluded that PGVCB had formed few strong conclusions based on the
                                             research that it had sponsored and coordinated. To gauge the extent of
                                             knowledge about Gulf War illnesses, we also reviewed other recent
                                             documents and spoke to VA and DOD officials to determine what would
                                             represent the best statement of conclusions. This review indicated that the
                                             most extensive and detailed review of the evidence about Gulf War
                                             illnesses was done by the Presidential Advisory Committee on Gulf War
                                             Veterans’ Illnesses. The 12-member Committee held 18 public meetings
                                             between August 1995 and November 1996 before reaching its conclusions.
                                             In its final report, PAC presents its conclusions about the likelihood that 10
                                             commonly cited exposure agents have contributed to the explained and
                                             unexplained illnesses being suffered by Gulf War veterans. (See table
                                             IV.1.) The PAC report was reviewed by DOD, which endorsed many of the
                                             findings.38


Table IV.1: PAC Conclusions on Health Effects of Different Individual Exposure Agents
Exposure agent        PAC’s conclusion                     Reasons                                        Our assessment
Biological warfare     “It is unlikely the health effects      “There were no verified detections         We have noted the limitations of the
agents                 reported today by Gulf War              of anthrax or botulinum toxin during       U.S. detection capability for
                       veterans are the result of              the war. Second, stateside                 biological warfare agents. We
                       exposures to biological warfare         examination of soil samples and            agree with PAC that the effects of
                       agents”                                 enzyme assays did not reveal the           at least one of the agents that Iraq
                                                               presence of BW agents.”                    weaponized might not be observed
                                                                                                          for many years.
                                                                                                                                      (continued)




                                             38
                                               In endorsing PAC’s conclusion that it is “unlikely” that the symptoms and diseases are due to
                                             exposure to agents during the Gulf War, DOD also noted that “there may still be small groups of Gulf
                                             War veterans that may have illnesses related to exposures during the Gulf War [and that DOD] will
                                             continue...our clinical investigation and research efforts.” According to PAC, VA, HHS, veterans’
                                             service organizations, and individual veterans and veterans’ advocates also reviewed its report.
                                             However, PAC did not provide information on the extent to which these reviewers agreed with its
                                             findings, or whether it incorporated their comments in its reports.



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                                            Support for Key Official Conclusions Is
                                            Weak or Subject to Different Interpretations




Exposure agent        PAC’s conclusion                       Reasons                                  Our assessment
Chemical warfare      “It is unlikely the health effects     “Available scientific evidence does      We dispute this conclusion. There
agents                reported by Gulf War veterans          not indicate that such long-term         is evidence from various sources
                      today are the result of exposure to    effects occur in humans following        that chemical weapons were
                      OP or mustard chemical warfare         low-level exposures, but the             released at Khamisyah and
                      agents during the Gulf War.”           amount of data from either human         elsewhere on the battlefield. Some
                                                             or animal research on low-level          evidence from animal and
                                                             exposures is minimal.”                   epidemiological studies documents
                                                                                                      the potential for delayed or chronic
                                                                                                      effects from such exposure. Thus,
                                                                                                      we cannot exclude the possibility
                                                                                                      that such health effects could
                                                                                                      impact exposed veterans.
Depleted uranium      “It is unlikely that health effects    “Toxic effects are likely to be similar We have no comment on this issue.a
                      reported by Gulf War veterans          to the kidney toxicity observed from
                      today are the result of exposure to    inhaled or ingested uranium. To
                      depleted uranium during the Gulf       date, VA has reported no kidney
                      War.”                                  toxicity among soldiers wounded
                                                             by DU fragments in friendly fire
                                                             episodes.”
Infectious diseases   “It is unlikely that infectious        “While viscerotropic leishmaniasis       Owing to the invasive character of
                      diseases endemic to the Gulf           can be difficult to confirm, it is not   current screening tests for
                      region are responsible for long        considered to be a cause of              viscerotropic leishmaniasis it has
                      term health effects in Gulf War        widespread illness in Gulf War           been impossible to test broadly for
                      veterans, except in a small, known     veterans. All veterans diagnosed         infection. Although some sources
                      number of individuals.”                with viscerotropic leishmaniasis,        have suggested that the rate of
                                                             except one, have experienced the         leishmania infection may be as
                                                             signs characteristic of the disease.     high as 5% of certain groups
                                                             From August 1990 through July            deployed to the Persian Gulf, there
                                                             1991, the U.S. Army deployed             is currently no means of screening
                                                             approximately 347,000 individuals        for asymptomatic infections which
                                                             to the Gulf region. Based on             can re-emerge during immune
                                                             information from U.S. Army field         system failure. The Center for
                                                             hospitals, the only infectious           Disease Control and Prevention
                                                             diseases that caused 30 or more          has found evidence of previous Q
                                                             each of approximately 14,000             fever and sandfly fever infection in
                                                             admissions were pneumonia,               a subsample of Gulf War veterans,
                                                             intestinal infections, inflammation of   which would indicate exposure to
                                                             the testes and/or epididymus,            the sandfly that caries leishmania.
                                                             chicken pox, and kidney infections.”
Oil-well fire smoke   “It is unlikely exposure to oil-well   “Toxic gases that can be found in        We have no comment on this issue.a
                      fire smoke is responsible for          oil-well fire smoke-such as
                      symptoms reported today by Gulf        hydrogen sulfide and sulfur
                      War veterans.”                         dioxide-can cause eye and nose
                                                             irritation, decreased pulmonary
                                                             function, and increased airway
                                                             reactivity. These toxic gases were
                                                             not detected at high levels during
                                                             the fires.”
                                                                                                                               (continued)




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                                              Appendix IV
                                              Support for Key Official Conclusions Is
                                              Weak or Subject to Different Interpretations




Exposure agent         PAC’s conclusion                          Reasons                                   Our assessment
Pesticides             “It is unlikely that health effects and   “According to DOD, after-action           Our review of the literature
                       symptoms reported today by Gulf           reports from in-theater medical           identified evidence that exposure
                       War veterans are the result of            personnel did not reveal any U.S.         to organophosphate agents can
                       exposure to pesticides during the         troops reporting symptoms that            induce delayed neuropathy without
                       Gulf War”                                 would indicate pesticide poisoning.       causing immediate symptoms.
                                                                 Evidence from studies of humans           Moreover, it has been suggested
                                                                 poisoned by organophosphate               that treatment with pyridostigmine
                                                                 pesticides suggests that low-level        bromide following exposure to
                                                                 exposures that do not cause signs         organophosphates (either OP
                                                                 and symptoms of immediate and             pesticides or chemical weapons)
                                                                 severe poisoning will not result in       may actually enhance the potential
                                                                 long-term health effects.”                for delayed effects.
Petroleum products     “It is unlikely that health effects                                                 We have no comment on this issue.a
                       reported today by Gulf War
                       veterans are due to exposure to
                       petroleum products during the war.”
Psychological and      “Stress is likely to be an important      “Animal studies demonstrate that          Although the evidence that we
physiological stress   contributing factor to the broad          stress can have measurable effects        reviewed indicates that stress can
                       range of illnesses currently being        on the brain, immune system,              have an important role in symptoms
                       reported by Gulf War veterans.”           cardiovascular system, and various        of many physical illnesses, when
                       “The entire federal research              hormonal responses. Although the          stress is present in a patient with
                       portfolio should place greater            human body can adapt to normal            untreated and undiagnosed diffuse
                       emphasis on basic and applied             stresses, if the stress lasts longer it   physical symptoms, care must be
                       research on the physiologic effects       can be expressed in a variety of          taken to determine whether the
                       of stress and stress-related              physical illness symptoms. Some           stress is the cause or the effect of
                       disorders.”                               researchers suspect that the              the physical symptoms. We found
                                                                 inadequate production of stress           weak support for the conclusion
                                                                 hormones and stress response              that stress is an important
                                                                 occurs in some (not all) humans           contributing factor in the broad
                                                                 with chronic fatigue syndrome and         range of illnesses being reported
                                                                 post-traumatic stress disorder.           by Gulf War veterans; most of the
                                                                 Based on this understanding and           evidence cited by PAC addressed
                                                                 supported by decades of clinical          the effects of stress solely on PTSD.
                                                                 observations, physicians recognize
                                                                 that many physical, as well as
                                                                 psychological, diagnoses are the
                                                                 consequences of stress.”
                                                                                                                                    (continued)




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                                             Appendix IV
                                             Support for Key Official Conclusions Is
                                             Weak or Subject to Different Interpretations




Exposure agent          PAC’s conclusion                          Reasons                                    Our assessment
Pyridostigmine bromide “It is unlikely that health effects        PB is used in much higher doses in         Experiments in animal models
                       reported today by Gulf War                 patients with myasthenia gravis            (including one study sponsored by
                       veterans are the result of exposure        than was administered to military          DOD) show that PB has toxic
                       simply to PB (emphasis added).             personnel.                                 effects in combination with other
                       Ongoing federally funded studies                                                      elements, such as DEET and
                       should help the scientific                                                            permethrin, in the Gulf War
                       community draw conclusions about                                                      environment. This may be
                       the synergistic effects of PB and                                                     particularly true for animals with a
                       other risk factors.”                                                                  genetic predisposition. Cases of
                                                                                                             such delayed neurotoxic effects in
                                                                                                             humans exposed to PB and DEET
                                                                                                             have been epidemiologically
                                                                                                             inferred and reproduced in hens.
                                                                                                             We note that PB was intended for
                                                                                                             use only when other agents were
                                                                                                             believed to be present or imminent.
                                                                                                             PB remains classified as an
                                                                                                             investigational new drug for the
                                                                                                             purposes for which it was used in
                                                                                                             the Gulf War.
Vaccines                “It is unlikely that health effects       “The human immune system has         DOD has not adequately monitored
                        reported by Gulf War veterans             evolved the capability to deal with the effects of receiving multiple
                        today are the result of exposures to      thousands of foreign substances,     vaccines.
                        the BT or anthrax vaccines, used          to sort them out, and to regulate
                        alone or in combination.”                 immune response. Humans live
                                                                  among a vast population of hostile
                                                                  microorganisms, and
                                                                  vaccinations—even multiple,
                                                                  contemporaneous
                                                                  vaccinations—are a small part of
                                                                  total immune stimulation. Individual
                                                                  vaccines can cause adverse
                                                                  effects, but several studies of the
                                                                  effects of giving multiple
                                                                  vaccinations at one time have
                                                                  found no adverse effects
                                                                  associated with the practice.”

                                             a
                                              This does not mean that we believe that it is not a risk factor.




                                             PGVCB has stated that “some symptoms may be related to PTSD. Published
Extent of                                    findings suggest an increased prevalence of PTSD and other psychiatric
Posttraumatic Stress                         diagnoses, such as depression in some Persian Gulf veterans....stressors
Disorder May Be                              during the Persian Gulf conflict were sufficient to cause significant
                                             psychiatric morbidity.”39 In testimony before the House Appropriation
Overestimated                                Committee, the Assistant Secretary of Defense for Health Affairs has
                                             stated that

                                             39
                                                 PGVCB, A Working Plan for Research on Persian Gulf Veterans’ Illnesses (Nov. 1996), p. 36.



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“one of the most striking findings of our clinical work has been the recognition of
psychological conditions and stress-related symptoms as a major diagnostic category
among veterans cared for in our facilities. Our clinicians have been impressed that stress
experienced during the Gulf War and in its aftermath appears to be a major contributing
factor in the development of psychological conditions as well as the manifestation of
symptoms associated with non-psychological conditions.”


Similarly, PAC has stated that “epidemiological studies to assess the effects
of stress invariably have found higher rates of PTSD in Gulf War veterans
than among individuals in nondeployed units or in the general U.S.
population of the same age.”40 However, the studies to which PAC refers
have not excluded other conditions that produce symptoms similar to PTSD
and can also elevate scores on key measures of PTSD. Although the
reported rates of PTSD in various studies range from 4 to 32 percent, these
rates were based on widely different populations, with high rates of
nonparticipation, and little information on selection bias. Moreover, as
with most scales and tests, a certain number of people will test positive on
any given measure of PTSD even though they do not have PTSD; they may
have a related disorder or no disorder at all. Based on the large numbers of
individuals to whom these scales were administered, such false positives
may be a significant portion of all those who obtained scores indicative of
PTSD. In a CDC-sponsored study of Iowa veterans that achieved a 76-percent
response rate and used a relatively inclusive criterion for identification of
presumptive PTSD, observed rates were quite low, although they were
higher among Gulf-deployed than nondeployed veterans.41

Only 15 percent of the diagnoses categorized as psychological (according
to the International Classification of Diseases-9th Revision (ICD-9)) among
CCEP registrants are clear cases of PTSD. Owing to the breadth and
heterogeneity of ICD-9 categories used to report CCEP data, high
percentages of primary or secondary “psychological conditions” are
reported, but the most frequently diagnosed “psychological condition” was
tension headache. Investigators from the Department of Military
Psychiatry at WRAMC reported, “The major conclusion concerning physical
health of these veterans is that for those who deployed to the Gulf War and
currently report physical symptoms, neither stress nor exposure to combat




40
  PAC, Final Report (Dec. 1996), p. 79.
41
 Iowa Persian Gulf Study Group, “Self-reported Illness and Health Status Among Gulf War Veterans: A
Population Based Study,” Journal of the American Medical Association, vol. 227 (1997), pp. 238-245.



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or its aftermath bear much relationship to their distress; only the fact of
deployment differentiates them from their less-burdened counterparts.”42

Alternative causes for stress-related symptoms may not have been fully
explored. For example, just following the war, experts from Walter Reed
Army Institute of Research (WRAIR) and WRAMC noted,

“Sandfly fever (phlebotomus fever)....has caused substantial epidemics in foreign military
forces in the Middle East. It is an acute, self-limited viral disease with a course of two to
five days and an incubation period of less than one week, whose acute manifestations will
be unlikely in those who have returned from the region. Convalescence, however, is
frequently complicated by depression, fatigue, and weakness that can last months. The
evaluation of a chronic fatigue or post-traumatic stress-like syndrome in those who have
returned from the Persian Gulf should therefore include serologic testing to rule out an
earlier sandfly fever virus infection.”43


Such serologic testing is available only from CDC, in Fort Collins, Colorado,
and from U. S. Army Medical Research Institute of Infectious Disease
(USAMRIID) in Fort Detrick, Maryland. Thus, it is unlikely that testing has
been broadly done to assess veterans’ fatigue symptoms. However, a CDC
analysis of blood taken from 158 volunteer Pennsylvania Air National
Guardsmen found that 5.7 percent showed evidence of previous sandfly
fever infection. For various reasons, including false positives and the
absence of preexposure blood samples for comparison, such evidence can
be difficult to interpret but suggests the importance of reviewing
alternative explanations for diagnoses of PTSD and chronic fatigue
syndrome.

Although widely cited work has argued that ill-defined syndromes have
been observed following many previous military conflicts, it is difficult to
compare current and historical findings due to differences in the
diagnostic capabilities previously available.44 It is highly likely that these
historical groups contained a mix of ailments that would now be
differently diagnosed. Moreover, even if these postwar syndromes
contained overlapping symptoms, it is not a foregone conclusion that
commonalities reflect the common experience of stress.



42
 R. H. Stretch et al., “Physical Health Symptomatology of Gulf War-era Service Personnel From the
States of Pennsylvania and Hawaii”, Military Medicine, vol. 160 (1995), pp. 131-136.
43
 R. A. Gasser et al., “The Threat of Infectious Disease in Americans Returning From Operation Desert
Storm,” The New England Journal of Medicine, vol. 324 (1991), p. 862.
44
 K. C. Hyams et al., “War Syndromes and Their Evaluation: From the U.S. Civil War to the Persian Gulf
War,” Annals of Internal Medicine, vol. 125 (1996), pp. 398-405.



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                           Support for Key Official Conclusions Is
                           Weak or Subject to Different Interpretations




                           PGVCB concluded that “the likelihood of Leishmania tropica as an
Extent of                  important risk factor for widely reported illness has diminished.”45 While
Asymptomatic               this is the case for observed symptomatic infection with the parasite, the
Leishmania Infection       prevalence of asymptomatic infection is unknown, and such infection may
                           reemerge in cases in which the patient’s immune system becomes
Is Unknown                 deficient.

                           Leishmaniasis is an infectious disease caused by a microscopic parasite
                           that invades certain types of white blood cells. While leishmaniasis occurs
                           in Southwest Asia and certain other parts of the world, it is very rarely
                           seen in the United States. The disease is transmitted by sandflies, and a
                           number of different leishmania species are known to infect humans.
                           Personal protective methods are relatively less effective against sandflies
                           than against mosquitoes. Sandfly populations were monitored during the
                           Gulf War and were found to be high from August to November 1990 and
                           again from April to June 1991.

                           Forms of disease that involve low levels of parasite infection can be
                           particularly difficult to diagnose using currently available methods.
                           According to briefings we received by experts at WRAIR, accurate diagnosis
                           of leishmaniasis is important because effective treatment involves the use
                           of potentially toxic drugs currently being investigated as new drugs and
                           not yet approved by the Food and Drug Administration. They noted that
                           such diagnosis is problematic because

                       •   most clinicians would fail to recognize classic forms of leishmaniasis,
                           much less atypical clinical presentations;
                       •   accurate laboratory diagnosis of suspected cases (detection of parasites in
                           biopsy or culture) is not available to most physicians; and
                       •   blood tests can provide supportive evidence of infection but cannot be
                           used alone to establish a diagnosis of leishmaniasis.

                           While blood testing for leishmania infection is problematic, it is the only
                           means currently available of assessing the potential prevalence of such
                           infection. In testing blood collected since the war from 158 Air National
                           Guardsmen, CDC researchers reported positive results for exposure to




                           45
                             PGVCB, A Working Plan for Research on Persian Gulf Veterans’ Illnesses (Nov. 1996), p. 20.



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leishmania donovani in 4.9 percent and leishmania tropica in 4.3 percent.46
Most of these individuals were also among the 5.7 percent showing
evidence of exposure to the sandfly vector that carries leishmania through
positive results on a well-characterized test for sandfly fever. However, the
CDC sample was composed of Air National Guardsmen who volunteered
for a particular study and were deployed from the same area, so the tests
do not represent estimates of the prevalence of the infection for Gulf War
veterans at large. The study also found no clear association between
results for leishmania infection and the presence of a set of symptoms
characteristic of chronic fatigue syndrome.47

Although PGVCB officials told us that the symptoms typical of
leishmaniasis, including enlargement of the liver, were not being observed,
not all ill veterans would show such symptoms. In commenting on a report
on a new form of leishmaniasis, CDC noted that five Gulf War veterans had
been diagnosed with the infection, even though their symptoms were
nonspecific, and none had the marked symptoms typical of visceral
leishmaniasis.48 Approval continues to be pursued for a skin test to assess
the prevalence of asymptomatic infection.




46
  In 1991, tests were run on blood samples from 119 military working dogs that had been in Saudi
Arabia. Five dogs (4.2 percent) were positive for the disease. One of these dogs subsequently
developed the infection, which was confirmed by autopsy. Symptomatic disease and demonstrated
infection have been observed in individuals with serological titers of 1:16. While none of 50 Marines
showed a result at this level before deployment, tests of 488 Desert Storm veterans conducted after the
war showed 5 percent had results of 1:32 or higher. Roughly 5 percent of a sample of troops tested
after the initial identification of viscerotropic leishmaniasis showed positive results using a skin test
involving a slightly different parasite. However, few of those who tested positive were symptomatic,
and the accuracy and appropriateness of the tests for this purpose is controversial. Finally, a Seattle
organization attempting to develop a test for viscerotropic leishmaniasis has reportedly found positive
responses among asymptomatic subjects. WRAIR officials view this test as a highly specific indicator
of exposure to leishmania tropica, but not a specific indicator for the type of the parasite associated
with viscerotropic infection.
47
  Based on concerns about the potential for transmission of this disease through the blood supply,
blood donations were temporarily deferred for all Gulf War veterans returning from Southwest Asia
since August 1, 1990. The blood donation ban was lifted on January 1, 1993. However, an accurate and
noninvasive screening test for this form of leishmaniasis remains commercially unavailable. Although
a study of transfused animals has demonstrated that the parasite retains its infectivity under blood
bank conditions, in lifting the ban, DOD officials observed that there had been no documented case of
transfusion-acquired leishmania tropica.
48
 “Viscerotropic Leishmaniasis in Persons Returning from Operation Desert Storm—1990-1991,”
MMWR, vol. 41, pp. 131-134. Reprinted in Journal of American Medical Association, vol. 267(11) (1992),
pp. 1444-46.


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                            DOD has consistently denied that Gulf War veterans were intentionally or
Evidence of Exposure        unintentionally exposed to biological warfare agents, and prior to
to Biological and           June 1996, it denied any exposure to chemical warfare agents. If
Chemical Weapons            servicemembers were exposed, exposure would have occurred in one of
                            three ways: (1) through intentional Iraqi use of chemical or biological
Has Not Been                warfare agents, (2) through theaterwide contamination resulting from air
Aggressively Pursued        war bombings of Iraq, or (3) through site-specific events.

                            As has been pointed out by the Presidential Advisory Committee, the
                            United States currently has no system that can detect and identify
                            biological warfare agent aerosols rapidly enough to enable troops to take
                            protective measures. Regarding chemical warfare agents, while the United
                            States has a detector/alarm system, according to DOD, it is not as sensitive
                            as some other systems, such as those operated by Czechoslovakian
                            coalition partners. DOD has taken the position that chemical and biological
                            agent exposures can be confirmed only through evidence of mass
                            incidents of morbidity and mortality. Since there were no such instances,
                            DOD asserted that Gulf War veterans were not exposed.



Biological Warfare Agents   According to the CIA, the Presidential Advisory Committee, and others, the
                            Iraqis had weaponized several biological agents at the time of the Gulf
                            War, including Bacillus anthracis, Clostridium botulinum, and aflatoxin.49
                            Apart from aflatoxin (a potent liver carcinogen), these agents are known
                            to have immediate and life-threatening toxic effects. Although the United
                            States took steps to vaccinate troops against anthrax and botulism,
                            according to PAC, “after the war, new data revealed that Iraq had also
                            weaponized aflatoxin.” This agent’s effects may not be observed until
                            decades after low-level exposure via ingestion, and the effects of
                            aerosolized aflatoxin are poorly understood. PAC notes that any effects
                            (notably liver cancer) from exposure to aflatoxin would not be expected
                            until several years passed. PAC also recommended that DOD and VA monitor
                            the Gulf War veteran population.

                            PAC reviewed U.S. Army hospital admission records and identified only one
                            admission for anthrax (a disease indigenous to the Gulf region) and none
                            for botulism. In addition, although Navy and Army researchers tested over
                            800 pairs of prewar and postwar blood samples from Navy Seabees for
                            antibody to anthrax, they found no evidence of acute infections. While
                            many blood samples showed evidence of vaccine-induced immunity, only

                            49
                              J. D. Walker, “Biological Weapons: Attempts to Verify” In Ranger, R. (Ed.) (1996). The Devil’s Brews
                            I: Chemical and Biological Weapons and Their Delivery Systems (Lancaster, UK: The Center for
                            Defence and International Security Studies), pp. 36-8.



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                          one showed evidence of exposure to the wild antigen or similar bacteria.
                          PAC reported that other evidence it examined also failed to support the
                          notion that biological weapons were used.

                          The PAC report documents that Iraq had weaponized aflatoxin. In our
                          discussions with agency officials, the potential use of aflatoxin was
                          dismissed because it would not immediately incapacitate coalition forces
                          and would therefore have no strategic value. Prior to the war, the United
                          States told Iraq that any use of biological or chemical weapons on
                          coalition forces would have devastating consequences for Iraq. The United
                          States did not deploy a real-time detection system for biological weapons.50
                          Therefore, one cannot be certain that such weapons were not used,
                          particularly since the United Nations Special Commission on Iraq (UNSCOM)
                          has not been able to confirm Iraq’s self-declared destruction of these
                          weapons.51

                          Similarly, a USAMRIID official indicated that tests were not available to
                          detect low-dose (i.e., asymptomatic) exposures to various biological
                          agents that the Iraqis had weaponized. While biomarkers may be available
                          for exposure to some of these agents, interpreting the results of such
                          testing in the absence of symptoms is complex, and little such testing
                          appears to have been done.


Chemical Warfare Agents   As with exposures to biological weapons, there were no massive incidents
                          of mortality or morbidity observed in theater that were consistent with
                          known acute effects of exposure to chemical warfare agents. The U.S.
                          Army officer responsible for medical surveillance of chemical/biological
                          warfare agents during the war has testified to the PAC that only one
                          accidental casualty was treated. However, it is important to note that
                          detections of the nerve agent sarin occurred on January 19, 1991, and of
                          mustard gas on January 24, 1991, by coalition partners from
                          Czechoslovakia in areas near Hafir al Batin. DOD has verified the reliability


                          50
                            The Army fielded the interim Biological Integrated Detection System (BIDS) in September 1996. A
                          total of 38 systems have been produced, with a total of 35 located collectively with the 310th Army
                          Reserve Chemical Company (Biological Detection) and the 20th BIDS Detachment (Active Army), at
                          Ft. McClellan, AL. The current BIDS can detect and identify up to four biological agents at a time in 45
                          minutes. Future improvements are expected to enable BIDS to detect and identify more agents in less
                          time. (Sources: Chemical and Biological Defense: Emphasis Remains Insufficient to Resolve
                          Continuing Problems (GAO/NSIAD-96-103, Mar. 29, 1996), p.6; Chemical and Biological Defense:
                          Protection of Critical Overseas Ports and Airfields Remains Largely Unaddressed (GAO/NSIAD-97-9,
                          June 13, 1997), pp. 20-21.
                          51
                           See Chemical and Biological Defense: Emphasis Remains Insufficient to Resolve Continuing
                          Problems (GAO/NSIAD-96-103, Mar. 29, 1996).



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                     Appendix IV
                     Support for Key Official Conclusions Is
                     Weak or Subject to Different Interpretations




                     of the Czech equipment but has never identified the source of these
                     detections, although both DOD and CIA have deemed the detections
                     credible. One cannot rule out the possibility that these detections were the
                     result of fallout from coalition bombings.

                     During late January and February 1991, DOD records indicate that coalition
                     forces successfully conducted a series of aerial bombings on suspect
                     nuclear, biological, and chemical weapons storage and production sites.
                     UNSCOM has not inspected all suspect and targeted sites. As a result, the
                     magnitude of exposures to chemical warfare agents has not been fully
                     resolved.

                     With regard to site-specific exposures identified at Khamisiyah,
                     uncertainties surround the extent of potential exposure. A contractor for
                     CIA had attempted to model the dispersion of chemical warfare agents. But
                     the uncertainties were too great to complete the model. These
                     uncertainties stem from (1) the lack of pertinent meteorological data;
                     (2) gross uncertainties about the amount of chemical warfare material
                     present at the time of demolition; and (3) the behavior of the material on
                     demolition (e.g., vaporization or evaporation) in an open pit.


                     The 1995 PGVCB research plan noted that investigations of chemical
Impact of DOD        weapons effects were not done because there was no evidence of
Denials on Federal   exposure.52 Noting that there had been no mass casualties to indicate
Research             chemical weapons exposure, DOD failed to fund research on the possible
                     long-term health consequences of low-level exposure to chemical warfare
                     agents. In fact, a few researchers told us that, as a result of DOD’s strong
                     position, they believed it would be fruitless to request funding for such
                     research. PGVCB reversed its position in its 1996 plan, following the
                     revelations regarding Khamisiyah. A broad agency announcement seeking
                     research on this issue was subsequently issued and some work has been
                     commissioned. Experts in the field of toxicology told us that had such
                     information been made available earlier, the direction and outcome of
                     research would have been different.




                     52
                       We could not assess this statement, as relevant data were not available for us.



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Appendix V

Comments From the Department of Defense


Note: GAO comments
supplementing those in
the report text appear at
the end of this appendix.




See comment 1.




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See comment 2.




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See comment 3.




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See comment 3.




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See comment 4.




See comment 5.




See comment 6.




See comment 7.




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See comment 8.




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               Comments From the Department of Defense




               The following is GAO’s response to the Department of Defense’s (DOD)
               comments, dated June 9, 1997.


               1. DOD offers selected excerpts from reports of the Institute of Medicine
GAO Comments   (IOM) and the Presidential Advisory Committee (PAC) that leave the
               impression the reports were uncritical of its actions, but this was not the
               case. These reports point out multiple problems and contain numerous
               recommendations for improvement.

               2. The national defense authorization act for fiscal year 1997 requested
               that we conduct an independent and objective review of federal clinical
               care and medical research efforts into Gulf War illnesses. That directive
               included gathering and analyzing information and coming to our own
               conclusions on the matters under review. Our information sources
               included previous reports, such as those by the IOM Committee to Review
               the Health Consequences of Service During the Persian Gulf War and the
               Presidential Advisory Committee on Gulf War Veterans’ Illnesses.
               However, the conclusions presented in our report are ours, and not those
               of other bodies. DOD’s assertion that our assessment was somehow less
               careful or thoughtful than those provided by the PAC and IOM is groundless.

               3. DOD’s comments do not address our specific finding that it has no
               information on whether Gulf War veterans are any better or worse today
               than when they were initially diagnosed. DOD suggests that its current
               approach provides adequate oversight for Gulf War veterans’ care but then
               indicates that it is reviewing a draft proposal on health outcome measures.
               We found that DOD relies on quality assurance mechanisms that do not
               ensure a given level of effectiveness for the care provided. Given the fact
               that DOD has no way to track changes in veterans’ health status, we
               continue to believe that DOD and VA should develop and implement plans to
               monitor the clinical progress of veterans.

               4. DOD incorrectly infers that we have taken the position that a single
               illness or a few illnesses with specific correct treatments account for
               veterans’ complaints. We repeatedly stated in our draft report that
               veterans are experiencing a wide array of symptoms and disabling
               conditions.

               5. DOD’s conclusion that research on treatments should await the results of
               epidemiological studies belies the fact that several illnesses suffered by
               these veterans have already been identified but that imperfect treatment



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Comments From the Department of Defense




exists for these illnesses. Additionally, DOD and VA were directed to
conduct research on treatments for ailing Gulf War veterans in the
national defense authorization act for fiscal year 1995. Our report does not
recommend that any ongoing research be discontinued; rather, it points
out that as a result of the misplaced focus and formidable methodological
problems, much of the ongoing epidemiological research will not be able
to provide precise, accurate, and conclusive answers regarding the
potential causes of the Gulf War veterans’ illnesses. Moreover, given that
the majority of federal research already covers epidemiological issues, we
recommend that DOD give greater priority to research on treatment for ill
veterans and on low-level exposures to chemicals and their interactive
effects and less priority to further epidemiological studies.

6. IOM also commented that any additional nationwide epidemiologic
studies of Gulf War veterans are likely to be of limited scientific value at
this time. At this stage, greater emphasis is warranted on studies that
explore plausible disease hypotheses rather than large-scale
population-based studies of prevalence. While the large-scale federal
studies cited by DOD have yielded descriptive information on the health
profile of Gulf War veterans, they have shed less light on why Gulf War
veterans report more health complaints than nondeployed veterans.

7. Regarding research on low-level exposures to various chemical agents,
DOD refers to an allocation of slightly more than $15 million for this
purpose and describes the process that would be followed to obligate
these funds to specific research projects. However, its comments on our
recommendation provide no detail on its progress in distributing these
funds. In its final report, PAC noted that, “DOD’s intransigence in refusing to
fund [research on possible long-term health consequences of low-level
exposure to chemical warfare agents] until summer 1996 has done
veterans and the public a disservice.”

8. DOD partially concurs with our recommendation that it refine current
approaches of the clinical and research programs for diagnosis of PTSD,
consistent with recent IOM suggestions. IOM recently found that, “In view of
potential exposure to low levels of nerve agents, certain refinements in the
CCEP would increase its value.” IOM recommended improved
documentation of the screening used during Phase I for patients with
psychological conditions such as depression and PTSD, noting that “if there
are long-term health effects of nerve agent exposure, it is possible that
these effects could be manifested as changes in mood or behavior.” IOM
has made other specific recommendations that are consistent with our



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Comments From the Department of Defense




findings, including the recommendation that physicians take more
complete patient histories regarding the onset of health problems and
occupational and environmental exposures to rule out alternative
explanations for neuropsychological findings.53 In its comments, DOD
refers to diagnostic procedures used in Phase II of the CCEP examination,
but these cover a small proportion of participants.




53
 See Institute of Medicine, Adequacy of Comprehensive Clinical Evaluation Program: Nerve Agents
(Washington, D.C.: National Academy Press, 1997), pp. 16-17.



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Appendix VI

Comments From the Department of
Veterans Affairs

Note: GAO comments
supplementing those in
the report text appear at
the end of this appendix.




See comment 1.




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See comment 2.




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                 Comments From the Department of
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See comment 3.




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See comment 4.




See comment 5.




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                 Comments From the Department of
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See comment 6.




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                 Comments From the Department of
                 Veterans Affairs




See comment 7.




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                  Veterans Affairs




See comment 8.




See comment 9.




See comment 10.




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See comment 11.




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See comment 12.




See comment 13.




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See comment 14.




See comment 15.




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               Comments From the Department of
               Veterans Affairs




               The following is our response to the Department of Veterans Affairs’ letter
               dated June 17, 1997.


               1. We have changed the word “illness” in our report title to “illnesses.”
GAO Comments
               2. VA acknowledges that clinical progress cannot be measured with
               existing or new databases. VA also notes that “appropriateness and
               effectiveness of treatment can only be determined for a specific medical
               condition whose pathogenesis and natural history has been well
               characterized.” VA agrees that longitudinal tracking of veterans with
               specific diagnoses could be of value. The majority of veterans have one or
               more diagnoses, which, in combination with their chief health complaints,
               should provide the basis for evaluating their care. Nevertheless, VA
               emphasizes the difficulty of evaluating the clinical progress of individuals
               with undiagnosed conditions. We are not suggesting randomized clinical
               trials of new treatments, as VA appears to imply, but do suggest that the
               Department develop a plan to monitor the condition of undiagnosed
               individuals in order to promote effective symptomatic treatment.

               Although VA asserts that those veterans who receive no diagnosis for their
               illnesses are treated appropriately for their symptoms, they do not indicate
               that they have any means of ensuring this, and they provide no evidence
               for the assertion. As VA suggests, augmenting its collection of data on the
               progress of ill Gulf War veterans with additional comparative data would
               provide valuable additional information. However, at a minimum, it seems
               desirable to collect descriptive information on how veterans’ conditions
               have improved or worsened.

               3. VA agrees that research on low-level exposures to chemicals should be
               given higher priority but does not believe epidemiological studies should
               be given lower priority. Since VA does not provide evidence to dispute our
               findings that ongoing epidemiological studies will not provide accurate,
               precise, or conclusive answers, we continue to believe that emphasis in
               the research should be shifted.

               4. VA does not concur with our recommendation on the basis that it is
               already making efforts to refine current approaches of its clinical and
               diagnostic programs for diagnosing posttraumatic stress disorder (PTSD).
               The emphasis of our recommendation is not upon how PTSD is diagnosed
               at specialty centers but upon how it is diagnosed in the course of ordinary
               registry evaluation and the improved validation of diagnostic methods



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Comments From the Department of
Veterans Affairs




used in establishing its prevalence. VA’s comments offer no corrective plan.
Therefore, we continue to believe that VA should refine the current
approaches of the clinical and research programs for diagnosing PTSD.

5. See comment 1.

6. VA’s comments do not address our specific finding that it has no
information on whether Gulf War veterans are any better or worse today
than when they were initially diagnosed. VA suggests that its current
approach provides adequate oversight for Gulf War veterans’ care. We
found that VA relies on quality assurance mechanisms that do not ensure a
given level of effectiveness for the care provided. VA agrees with us that
the 1996 National Customer Satisfaction Survey was not adequate, and it
plans to correct those deficiencies. However, VA has not provided any
evidence to us to the contrary. Given the fact that VA has no way to track
changes in veterans’ health status, we continue to believe that DOD and VA
should develop and implement plans to monitor the clinical progress of
veterans.

7. While VA agrees that it is indeed possible that a Gulf War-related
exposure to agents may never be precisely linked to Gulf War veterans’
illnesses (regardless of how well a study may be designed or what type of
research is conducted), it believes that epidemiologic research can
provide important information about the health consequences of Gulf War
service. We agree that descriptive studies cited by VA are useful in
understanding group differences, but it is not clear what hypotheses these
studies have generated regarding risk factors. Our conclusion remains
valid regarding the inability of ongoing epidemiological research to
provide precise, accurate, and conclusive answers regarding the causes of
veterans’ illnesses because of formidable methodological problems.

8. Comments from the Presidential Advisory Committee and our responses
are in appendix VII. Our methodology is described on pages 13 and 14 of
our report. We use an extensive quality assurance process for all of our
products, as we did for this report. The expertise of the team who
conducted this review is discussed on page 14.

9. VA notes that our report is thinly supported with few references
(approximately 35). However, as we note in our report, we reviewed not
only the articles that PAC cited in support of its conclusions (which we do
not list) but also articles published in peer-reviewed journals that PAC did
not take into consideration (which we do list).



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Comments From the Department of
Veterans Affairs




10. Our report does not imply the assertion VA is making. In our evaluation
of federal research strategy, we are reporting our findings on the extent to
which the strategy is coherent.

11. Our conclusion is based on PGVCB-provided data, which show that the
vast majority of federal research was initiated during or after 1994 and
relatively few studies have been completed.

12. This is an inaccurate presentation of the statement in our report. We
stated in our report that PAC did not provide evidence in support of its
assertion that stress is an important contributing factor to the “broad
range” of illnesses currently being reported by Gulf War veterans.

13. As our report notes, we reviewed the literature cited by PAC. All but two
of these references from peer-reviewed journal articles deal with the
putative association with PTSD; only two discuss the role of general life
stress. The scientific articles on PTSD do not present convincing evidence
that PTSD is common in Gulf War veterans or that it explains the symptoms
reported by Gulf War veterans. All but one of the peer-reviewed studies on
PTSD in Gulf War veterans relied on psychometric PTSD scales,
unaccompanied by psychiatric interviews, and only minimal elevations of
scores were found. These do not indicate the presence of PTSD. Virtually
any illness that causes primary or secondary emotional concern can
produce minimal elevations of scores on the psychometric PTSD scales.
The fact that minimal elevations of psychometric scales scores were
slightly higher than those of nondeployed veterans proves only that
deployed veterans have more illness of some kind, but it does not establish
that it is related to PTSD or general life stress.

14. VA failed to understand the central message underlying the two
research studies it cited (Jamal et al., 1996, and Haley et al., 1997). These
two studies demonstrate that the syndrome of chronic fatigue, cognitive
problems, balance disturbances, joint aches, diarrhea, etc., could be
neurological injuries from exposure to chemicals in the war. These studies
also suggest that routine medical examinations are incapable of detecting
chronic neurotoxicity. Thus, the statement that “the majority of VA
Registry participants have conventional medical diagnoses and are being
treated with appropriate therapies” is undoubtedly sincerely meant and
true, but irrelevant.

15. We have stated in our report that while the government found no
evidence that biological weapons were deployed during the Gulf War, the



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Comments From the Department of
Veterans Affairs




United States lacked the capability to promptly detect biological agents,
and the effect of one agent, aflatoxin, would not be observed for many
years.




Page 99                                     GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII

Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses

Note: PAC’s comments on
our draft report, along with
our responses to these
comments, are
reproduced here. Due to
the length and highly
technical nature of PAC’s
comments, our response
follows each individual
comment in the letter,
rather than at the end of
the comments.




                               GAO RESPONSE


                               The purpose of our evaluation of PAC’s conclusions with respect to risk
                               factors was to ascertain the amount of knowledge about Gulf War illnesses
                               generated by research 6 years after the Gulf War, and evaluate the
                               evidence supporting conclusions on these issues. We reviewed these
                               conclusions because they are the strongest statements of any official body
                               that we have found on these matters. Moreover, the PAC review panel
                               included a number of recognized experts in scientific questions at issue
                               who were assisted by a large staff of scientists and attorneys. In addition,



                               Page 100                                    GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




PAC extensively reviewed the research on Gulf War veterans’ illnesses.
Thus, evaluating the strength of the PAC’s conclusions provides important
evidence about how fruitful research on Gulf War illnesses has been to
date. We have repeated in our letter the statement on this point that we
had made in appendix IV.

Our report cites PAC’s recommendations and significant conclusions. We
also carefully reviewed the PAC’s interim report, which cites potential
problems for federally funded research. We documented that such
problems affect large portions of the federally sponsored studies (see app.
III).




GAO RESPONSE


Our study is a systematic evaluation of the matters that Congress directed
us to examine. We reviewed the scientific literature and published as well
as unpublished work of internal and external bodies. In reviewing
conclusions, we examined the support cited as well as additional evidence
we gathered and compared these with the official conclusions.




Page 101                                    GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




We have added citations to better reflect our use of scientific literature in
our review.




GAO RESPONSE


As we pointed out in our draft report, the number of studies we cite was
taken directly from the most recent (April 1997) annual report to Congress
by the official sponsoring and coordinating entity for pertinent research,
the Persian Gulf Veterans’ Coordinating Board (PGVCB). PGVCB, which
coordinates research on Gulf War veterans’ illnesses involving VA, DOD, and
HHS, is required under Public Law 102-585 to report annually on the results
and progress of pertinent research activities undertaken or funded by the
executive branch.




GAO RESPONSE


We do not confuse PTSD and stress-related effects. Indeed, it is unclear how
we could both “juxtapose” the distinct issues and simultaneously “treat
them as a single matter,” as the comment alternately suggests. We address




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Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




these items in tandem in order to prevent the very type of
misinterpretation about which the Committee is concerned.

In contrast, PAC’s report blurs the distinction between PTSD (that is, a
specific syndrome caused by emotional trauma) and stress (a potential
risk factor). To support its conclusion regarding the contribution of stress
to veterans’ illnesses, PAC cites 18 reports from peer-reviewed journals, but
these largely assess the association between stress and PTSD. Only two
peer-reviewed articles were presented in support of the broader effects of
stress and neither included measurements of Gulf veterans. Some studies,
while intending to assess the extent of PTSD, found little and instead
discussed “stress symptomatology,” “trauma-related symptoms,” or “PTSD
symptoms,” using these terms to refer to measurements on a PTSD scale
that did not meet the validated cutoff for indication of PTSD.




GAO RESPONSE


As our report notes, we reviewed the literature PAC cited in support of its
conclusion. Only two references from peer-reviewed journals were
provided to substantiate the role of general life stress in the etiology of
veterans’ symptoms.54 Neither reference presented measurements of Gulf
War veterans.

We noted in our report that this quotation is taken from, “R.H. Stretch et
al., “Physical Health Symptomatology of Gulf War-era Service Personnel
From the States of Pennsylvania and Hawaii,” Military Medicine, vol. 160
(1995), pp. 131-36. (See app. II.)



54
 K. C. Hyams & F. S. Wignall, “War Syndromes and Their Evaluation: From the U.S. Civil War to the
Persian Gulf War,” Annals of Internal Medicine, vol. 125 (1996), pp. 398-405 and G. P. Chrousos & P. W.
Gold, “The Concepts of Stress and Stress System Disorders,” Journal of the American Medical
Association, vol. 267 (1992), pp. 1244-1252.



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Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




GAO RESPONSE


Stress can be associated with a wide range of physical illnesses, and we do
not suggest that illnesses that are stress-induced are any less real.
However, we did not find evidence that the broad range of Gulf War
veterans’ physical symptoms were induced by stress. (See our response to
the next comment.)




GAO RESPONSE


We reviewed the reports from the Fort Devens and the New Orleans
studies on PTSD, but these two studies provide little support for
Committee’s conclusion that “stress is likely to be an important
contributing factor to the broad range of illnesses currently being reported
by Gulf War veterans.” First, the primary focus of each of these studies is



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Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




the measurement of PTSD. Second, the symptom measures employed in
both studies focused selectively on psychological, psychosomatic, and/or
stress-related conditions. For example, the New Orleans study employed a
checklist inquiring about 20 conditions—11 taken from a scale of
psychosomatic complaints and 9 other symptoms that are commonly
observed to be stress-related.55 The samples of deployed troops who
indicated high war-zone stress checked more items on this symptom list
than those classed as having low or no war zone stress, but 4 to 10 months
after the war, only three complaints (nervousness, concentration
difficulties, and needing medications to sleep or calm down) showed
statistically significant differences based on war-zone stress. Third, no
physical examination was conducted in these studies, so it is impossible to
determine whether the measured symptoms were selectively related to
war zone stress. Fourth, in both studies, there is some possibility that the
relationships between war zone stress and symptoms are byproducts of
similarities in the methods used to measure them; the Fort Devens study
acknowledges some research showing that self-reports of stress are
vulnerable to bias from a host of event-related and personal
characteristics. Finally, in the Fort Devens study, the total amount of
variation in reported symptoms that was explained by the combination of
combat exposure stress and a variety of other factors was quite modest
(13 percent).56

The Committee’s remark concerning diagnostic methods suggests that the
inclusion of control groups overcomes bias from faulty methods for
measuring PTSD. First, the method recognized by experts in the field of
PTSD research for conclusively making the diagnosis of PTSD is a
psychiatrist’s or psychologist’s clinical interview following a structured
interview protocol, such as the CAPS or SCID. (See app. V, DOD’s response
to GAO’s report.) Of the 18 peer-reviewed studies of Gulf War veterans cited
by the PAC report in support of its conclusions on stress, only one used this
method.57 All others relied on psychometric scales. Second, if the deployed
veterans suffered subtle neurological damage, for example from chronic
pesticide exposures, their scores on the psychometric PTSD scales could be
falsely elevated, while those of the nondeployed controls, not exposed to
pesticides, would not be. The use of a control group would not correct for
this type of bias.

55
 P. B. Sutker, et al., “War-Zone Trauma and Stress-Related Symptoms in Operation Desert
Shield/Storm (ODS) Returnees,” Journal of Social Issues, vol. 49 (1993), pp. 33-49.
56
  J. Wolfe, et al., “Reassessing War Stress: Exposure and the Persian Gulf War,” Journal of Social
Issues, vol. 49 (4) (1993), pp. 15-31.
57
 S. Perconte, A. Wilson et al., “Unit-Based Intervention for Gulf War Soldiers Surviving a SCUD Missile
Attack: Program Description and Preliminary Findings,” vol. 6 (1993), pp. 225-238.


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Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




GAO RESPONSE


We refer to the use of major diagnostic categories from the International
Classifications of Diseases - 9th Revision to report on various types of
conditions as a group. For example, the category “psychological
conditions” is used to report data from DOD’s clinical program. The
diagnoses included in the ICD-9 series for psychological conditions cover
everything from relatively common, transient, and easily treated
conditions, such as tension headache, to more intractable disorders, like
clinical depression. It is not clear what clinical or scientific purpose is
served by discussing these varied diagnoses as a group.

In the PAC report, under the heading “Data on Stress-Related Disorders”
(see p. 71), the Committee notes that “psychological conditions are either
the primary or secondary diagnosis in 36.0 percent of CCEP participants,”
and that “the most common conditions are: major depressive disorder,
neurotic depression (also called dysthymia), depression (not otherwise
specified), PTSD, anxiety disorders, adjustment disorders, alcohol-related
disorders, and substance-related disorders.” However, as noted in the
footnote to the table on page 72 of the PAC report, the single most common
condition in this category is actually tension headache (11.3 percent of
CCEP participants and 2.3 percent of registry participants). Apart from
tension headache, none of the individual diagnoses listed in this category
is the primary diagnosis for more than 3 percent of CCEP registrants.




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GAO RESPONSE


We quoted from page 34 of PAC’s Final Report, “Currently, stress is the risk
factor funded for the greatest fraction of total studies—32 studies
(30 percent).” However, we have now substituted the figure provided by
PAC.




GAO RESPONSE


As PAC notes, we did not conclude that stress was incompatible or
incapable of producing physical symptoms; we concur with PAC’s
assessment of this matter. However, we do not find that PAC has cited
evidence that stress is likely to be an important contributing factor to the




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broad range of illnesses that veterans report. We have revised the
statement in table IV.1 to clarify this point.

Regarding the health effects of low-level exposure to chemical warfare
agents, the Committee suggested in 1996 that “the government should plan
for further research on possible long-term health effects of low-level
exposure to organophosphorus nerve agents, such as sarin, soman, or
various pesticides, based on studies of groups with well-characterized
exposures, including (a) cases of U.S. workers exposed to
organophosphorus pesticides and (b) civilians exposed to the chemical
warfare agent sarin during the 1994 and 1995 terrorist attacks in Japan.
Additional work should include follow-up and evaluation of an appropriate
subset of any U.S. service personnel who are presumed to be exposed
during the Gulf War. The government should begin by consulting with
appropriate experts, both governmental and nongovernmental, on
organophosphorus nerve agent effects. Studies of human populations with
well-characterized exposures will be much more revealing than studies
based on animal models, which should be given lower priority.” (PAC, Final
Report, p. 54)

Accidental and occupational exposures like those cited by PAC are rarely
“well characterized,” and due to the potentially toxic nature of the
exposures, animal studies will be more important to characterizing the
effects, particularly synergistic ones. Although PAC concluded that
“ongoing federally funded studies should help the scientific community
draw conclusions about the synergistic effects of PB and other risk
factors” (Final Report, p. 117), we could find no PAC recommendation for
additional research on the synergistic health effects of pyridostigmine
bromide and other risk factors.




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GAO RESPONSE


All but one of the 18 studies on PTSD in Gulf War veterans cited by the PAC
report based diagnoses of PTSD on psychometric PTSD scales without
confirmatory psychiatric interviews. These instruments are validated for
screening, not diagnosis. In addition, care must be taken in evaluating
elevated scores that do not surpass validated cut-points for discrimination
of PTSD and non-PTSD populations.58




GAO RESPONSE


The PAC states that its review of studies [on PTSD] was based on those with
high participation rates. However, most of the cited studies presented PTSD
survey data based on samples that were not statistically generalizable.
Among those that did employ generalizable samples, participation rates
varied from 25 percent to 58 percent, but no comparison of participants
and nonparticipants was presented to assess the likelihood of selection
bias.

We respond to the Committee’s second and third points elsewhere in this
appendix.




58
 See, for example, the discussion by T. M. Keane et al., “Mississippi Scale for Combat-Related
Posttraumatic Stress Disorder: Three Studies in Reliability and Validity,” Journal of Consulting and
Clinical Psychology, vol. 56(1) (1988), pp. 85-90.



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GAO RESPONSE


Control groups are not a substitute for accurate diagnostic methods. For
example, without accurate diagnosis, it is possible that neurological
symptoms related to war-related exposures apart from stress will be
misattributed to PTSD. In addition, some studies have employed modified
PTSD scales incorporating questions that may become markers for recent
war participation, rather than evidence of PTSD. These questions would
selectively increase scores in the Gulf War group.




GAO RESPONSE


We quote from testimony provided to PAC on March 26, 1996, by Dr. Peter
Spencer, who is the principal investigator of a large, federally funded
study. As known since 1995 and acknowledged in the PAC report (p. 118),
the incubation period for classical visceral leishmaniasis (usually caused
by L. donovani) may exceed 2.5 years.59 In addition, the natural history of a
newly recognized form of the illness (viscerotropic leishmaniasis) is



59
  W. H. Jopling, “Long Incubation Period in Kala-azar,” British Medical Journal, vol. 2:1013 (1955).



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unknown.60 Those whose immune systems become weakened for any
reason will be at particular risk. In such patients, the development of
visceral leishmaniasis (involving malaise, lassitude, weight loss,
splenomegaly, and anemia) up to 20 years after exposure has been
documented.61




GAO RESPONSE


Insofar as no screening or simple diagnostic test is currently available for
newly recognized forms of leishmaniasis, there is an insufficient basis to
assess the success of the clinical examinations in detecting it. However,
this presumption is the primary basis on which the Committee dismisses
the notion that leishmania infection is much of a continuing problem. In a
March 13, 1997, briefing, experts from Walter Reed Army Institute of
Research told us that “most clinicians will fail to recognize ’classic’ forms
of leishmaniasis, much less atypical clinical presentations.” As we note in
the report, a CDC analysis appears to concur that the signs of a newly
recognized form of the disease are nonspecific and that the diagnosed
cases were identified by aggressive case-finding.62 It stands to reason that
diagnosis would be difficult insofar as leishmaniasis is generally unknown
in the United States. While PAC concludes that viscerotropic leishmaniasis
is not considered to be a cause of widespread illness among Gulf War
veterans, PAC acknowledges on p. 118 of its Final Report that
“viscerotropic leishmaniasis can be difficult to confirm.”



60
 A. J. Magill et al., “Viscerotropic Leishmaniasis in Persons Returning from Operation Desert Storm —
1990-1991,” Journal of the American Medical Association, vol. 267(11) pp. 1444-46.
61
  Badaro, Falcoff et al., “Treatment of Visceral Leishmaniasis With Pentavalent Antimony and
Interferon Gamma,” New England Journal of Medicine, vol. 332 (1990), pp. 16-21.
62
 “Viscerotropic Leishmaniasis in Persons Returning from Operation Desert Storm—1990-1991” [CDC
Editorial Note], Journal of the American Medical Association, vol. 267 (11) (1992), pp. 1444-6.


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GAO RESPONSE


We have modified the statements in our letter summarizing our findings to
match the statement in appendix IV, which incorporates the role of the
weakened immune system. It is in cases in which the patient’s immune
system becomes deficient that such reexpression of previously
asymptomatic infection is a concern.63 However, because it is not possible
to predict which persons’ immune systems may become weakened, we
believe that it is important for all veterans and health care professionals to
understand the significance of such potential infection. In addition, the
natural history of the viscerotropic form of leishmaniasis is not well
understood; that is, little is known about the length of incubation and the
course of disease.64

While it could be consistent with some of the Gulf War veterans’
symptoms, we do not contend in our report that leishmaniasis—or any
other illness of which we are aware—would explain the range of
symptoms currently being reported in the veterans.



63
 See, for example, A. J., Magill, et al., “Visceral Infection Due to Leishmania tropica in a Veteran of
Operation Desert Storm Who Presented 2 Years After Leaving Saudi Arabia, Clinical Infectious
Diseases, vol. 19 (Oct. 19, 1994), pp. 805-6. These authors note, “...the presence of a cofactor
depressing cell-mediated immunity (malnutrition, immunosuppressive drug treatments, AIDS, or
malignancy) can lead to symptomatic leishmanial disease....” See also , R. Badaro, et al. “Leishmania
donovani: An Opportunistic Microbe Associated With Progressive Disease in Three
Immunocompromised Patients,” Lancet, vol. 1 (1986), pp. 647-9.
64
 Even infection with the same species of parasite (Leishmania donovani) can take widely different
courses (see Badaro et al., “New Perspectives on a Subclinical Form of Visceral Leishmaniasis,” The
Journal of Infectious Diseases, vol. 154(6), pp. 1003-1011.).



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We noted the reemergence of leishmaniasis in Europe in the context of
noting that the infection can flare when the immune system is weakened;
the comparability of the exposed groups is not relevant to the point that
we were making.65




GAO RESPONSE


We presume that veterans are concerned about their future health as well
as their current health. In the absence of simple diagnostic tests, it is
difficult to judge the extent of current illness attributable to leishmania
infection.

The more important point is whether these veterans are ill as a result of
their exposure. The risk of sandfly fever to U.S. troops in the Gulf was
believed to be high. Although we recognize that it is possible that some of
these veterans may have been deployed to other areas in which they might
have contracted this disease, the blood samples that CDC analyzed were
taken after their return to the United States from the Gulf.




65
  See, for example, Phillip G. Lawyer, “Leishmaniasis Update,” Proceedings of the 1995 DOD Pest
Management Workshop (1995), p. 3 (http://www.afpmb.acq.osd.milpubs/present/htm). He states, “The
emergence of VL [viscerotropic leishmaniasis] as a serious opportunistic infection in AIDS patients in
Europe has alarming implication for leishmaniasis endemic areas where the prevalence of HIV
infection is increasing (Africa, Brazil, Indian subcontinent).”



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GAO RESPONSE


Medical surveillance during the war was imperfect. While some reports
indicate no cases of sandfly fever, at least six cases of febrile illness
compatible with sandfly fever were reported among soldiers of the 1/505
PIR on September 22, 1990, by a preventive medicine officer. In addition,
the risk of sandfly fever was believed to be high. A December 1991
Defense Intelligence Agency report presented tests of blood samples from
Iraqi military personnel involved in the Gulf War. These tests were
conducted to help identify biological warfare agents in the Iraqi inventory
and assess the prevalence of endemic diseases. In discussing naturally
occurring diseases, the report notes, “The large percentage of positive
reactions to sandfly fever (Sicilian and Naples strain) confirms the high
risk this disease poses for US military operations in the region.” For the
Sicilian strain, 98 of 125 samples were positive, and 49 of 126 samples
were positive for the Naples strain. (In contrast, only 21 of 130 samples
were positive for exposure to Q-fever.) Thus, if there were no cases of
sandfly fever, it seems difficult to explain their complete absence.

It is true that the presence of evidence of exposure to sandfly fever did not
distinguish persons with the cluster of fatigue symptoms defined by CDC
from persons who did not fit this definition. However, this does not
obviate the need to exclude such infection in diagnosing particular
veterans’ fatigue and posttraumatic symptoms. Sandfly fever would not
consistently result in such complications, though it might sometimes be
responsible for them.




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GAO RESPONSE


First, references have been provided in footnotes 28-36 of appendix III.

Second, our specific responses to the claim that we have mischaracterized
the Committee’s conclusions are set forth below.

Third, we have clarified statements that may have led the Committee to
infer that we claimed that all organophosphates compounds produce
similar long-term effects.

Fourth, we are careful to distinguish between those individuals who are ill
today and individuals who may become ill in the future. For example, our
discussion of aflatoxin is largely about potential cancers in the future.

Fifth, as directed by Congress, we conducted our own independent,
objective review. Our review included reviewing reports and scientific
literature, interviewing researchers, and analyzing the information




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available to us. Through this review we reached different conclusions from
those of the PAC. In any event, given PAC’s finding that minimal research is
available on the health effects of low-level exposure, it is difficult to
understand the rationale for its conclusion that chemical warfare agent
exposures are unlikely to be consistent with veterans’ health complaints.
Moreover, we note that findings of some studies on such low-level
exposures are not supportive of such a conclusion.

We respond to PAC’s remarks concerning its recommendations elsewhere
in this appendix.

Insofar as the Committee clearly feels strongly about the need for
additional research, we find it difficult to understand the rationale behind
PAC’s conclusion that it is unlikely these exposures could have contributed
to veterans’ health complaints.




GAO RESPONSE


PAC’s(first) comment incorrectly misinterprets our point. As noted, PAC
formed some of its conclusions in the absence of exposure data. However,
we have removed the quotation.

Some of the Committee’s conclusions are inconsistent with the results of
applying its analytic framework. For example, it is difficult to understand
why the Committee concludes that the agent in question is “unlikely” to
have contributed to the health problems reported by veterans even as it
recognizes the need for data on the health effects of low-level exposure.




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GAO RESPONSE


As we noted in an earlier report, “available bomb damage assessments
during the war concluded that 16 of 21 sites categorized by Gulf War
planners as nuclear, biological, and chemical (NBC) facilities had been
successfully destroyed. However, information compiled by the United
Nations Special Commission (UNSCOM) since the end of Desert Storm
reveals that the number of suspected NBC targets identified by U.S.
planners, both prior to and during the campaign, did not fully encompass
all the possible NBC targets in Iraq.” UNSCOM has conducted investigations at
a large number of facilities suspected by the U.S. authorities as being NBC
related. Regarding the few suspected weapons sites that have not yet been
inspected by UNSCOM, we have been able to determine that each was
attacked by coalition aircraft during Desert Storm and that one site is
located within the Kuwait theater of operations in closer proximity to the
border, where coalition ground forces were located. However, we have yet
to learn why these facilities have not been investigated.66




66
 See Operation Desert Storm: Evaluation of the Air Campaign (GAO/NSIAD-97-134, June 12, 1997, p.
2).



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GAO RESPONSE


PAC has misinterpreted our position on the proper sequencing of studies.
Research into the nature of the health effects of agents to which troops
may have been exposed during Operation Desert Storm should not wait
for accurate answers to questions of the magnitude of actual exposures.
We neither state nor imply otherwise.

In its reference to a statement we made in table IV.1, we made that
statement to provide background for our assessment. We have deleted the
word “given,” which may have left the incorrect impression that the
Committee did not take account of the presence of chemical warfare
agents at Khamisiyah and elsewhere on the battlefield.




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GAO RESPONSE


We cite animal studies showing that exposures to certain
organophosphate agents at levels that do not cause acute poisoning are
associated with measurable long-term effects. It appears inconsistent for
the Committee both to conclude that exposures to organophosphate
agents are unlikely to have contributed to veterans’ health problems and
simultaneously to recognize the existence of minimal research on
low-level exposure—the most likely exposure scenario for
organophosphate pesticides.

The Committee may have overlooked a set of articles published in
peer-reviewed journals by Husain et al. addressing the chronic
neurotoxicity of low-level exposure to sarin. In these studies, the
investigators exposed hens and mice, in separate experiments, daily for 10
days to sub-acute doses of sarin orally and through inhalation. The animals
did not require protection by simultaneous administration of atropine and
pralidoxime, often used in high-dose experiments. Fourteen days after the
start of the daily exposures, some of the animals developed effects (for
example, ataxia, muscular weakness), suggesting that sarin can induce
OPIDN. These studies have been discussed since they were published in
1993, 1994, and 1995, and they have received no serious criticism of which
we are aware. It appears that DOD, PGVCB, and PAC have not recognized and
commented on them, while continuing to insist that there is no evidence
that low-level sarin can cause chronic neurotoxicity in the absence of
severe immediate effects.




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GAO RESPONSE


The comment by PAC reflects a selective reading of the work by Duffy and
Burchfiel in the area of the EEG effects of organophosphates. Indeed, the
authors characterized one of the tests that they conducted on the EEGs of
treatment and control groups as “inconclusive.”67 However, they also
reported statistically significant differences between the two groups on
several other measures, such as the increase in the amount of beta activity
in EEGs and an increase in rapid eye movement sleep. The authors
concluded that, “Our EEG findings and the psychological reports in the
literature provide parallel warnings of possible long-term CNS toxicity of
OP agents.”68 Additionally, in recent testimony before the House
Committee on Government Reform and Oversight, Professor Duffy made
the following observations, which support our conclusions about the
effects on the behavior of organophosphates (including sarin):

“It is quite possible to have a biologically significant exposure to OP compounds and not be
aware of it...Sarin can produce long term alteration of brain function. Levels of exposure
capable of producing such late effects may not be recognizable by subjects, especially if
they are unaware of what is happening and/or are distracted by other activities.”69


The Armed Forces Epidemiological Board also reviewed these studies and
found that, “they represent reasonable evidence that even small doses
(exact level is unknown) may result in EEG changes.”70




67
  James L. Burchfiel, et al., “Organophosphate Neurotoxicity: Chronic Effects of Sarin on the
Electroencephalogram of Monkey and Man,” Neurobehavioral Toxicology and Teratology, vol. 4
(1982), pp. 767-778.
68
  Ibid., p. 777.
69
 Frank H. Duffy, M.D. (Department of Neurology, Harvard Medical School), “Evidence that Minor
Exposures to the Nerve Agent Sarin May Lead to Long Term Difference in Brain Function,” testimony
provided to the House Committee on Government Reform and Oversight, Jan. 19, 1997.
70
 Environment Committee, Armed Forces Epidemiological Board, Long-term Health Effects Associated
with Sub-clinical Exposures to GB and Mustard, p. 6.



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GAO RESPONSE


We have cited the work of Dr. Haley and his colleagues as a positive
example of an attempt to refine a case definition in the presence of diffuse
and nonspecific symptoms. His approach, to look for patterns of
correlation among the reported symptoms and explore their relationship
with exposure history, is a reasonable and rational first step upon which
others might build. We discussed Dr. Haley’s approach with two leading
epidemiologists, who agreed that the approach Dr. Haley had taken was
reasonable in an instance in which a case definition was difficult to derive.
In fact, elsewhere in the aforementioned editorial, Dr. Landrigan concurs
with the major thrust of our position:

“Haley et al. suggest that some cases of illness in members of their population may
represent chronic neurotoxicity caused by low-dose exposures to chemical warfare agents.
This is an important question that demands serious investigation... Further research is




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needed to determine whether low-dose exposure to chemical warfare agents can cause
chronicneurotoxicity.71


We agree with Dr. Landrigan on this point. It is also our contention, based
on the evidence presented in our report, that the federal research program
has not pursued this question with sufficient energy.

It is apparent to us, based on the literature that we reviewed and the
references cited, that the hypothesis that some veterans’ illnesses are
OPIDN or similar to OPIDN that may stem from exposure from pesticides,
chemical warfare agents, or pyridostigmine bromide while on duty in the
Persian Gulf is a plausible hypothesis. We disagree with PAC’s conclusions
that these are unlikely exposure scenarios for the illnesses being
experienced by veterans. Moreover, we fail to understand the Committee’s
rationale for endorsing additional studies in this area after discounting the
likelihood of the hypothesis. In fact, it should be noted that CDC took
similar steps to construct a case definition in its review of symptoms
reported by a large group of Gulf War veterans. Dr. Haley’s work has
apparently generated plausible hypotheses for further exploration and
testing.




71
  P. J. Landrigan, Illness in Gulf War Veterans. Journal of the American Medical Association, vol. 277
(1997), pp. 259-261.



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GAO RESPONSE


Concerning exposure to aflatoxin, for the reasons cited earlier, we can
neither confirm nor rule out veterans’ exposure to this agent. The Central
Intelligence Agency has noted that the health effects of exposure to
aerosolized aflatoxin are poorly understood.

Descriptive studies of clearly defined endpoints may be useful in providing
assurance that large numbers of veterans are not suffering the health
problems characteristic of aflatoxin exposure. However, it is important to
note that only in the instance of widespread exposure would this approach
resolve the issue of whether particular veterans’ health problems are
attributable to their Gulf War service.

In response to the general comment concerning the value of epidemiologic
studies of Gulf War veterans, we agree that some basic descriptive
information on veterans’ health may be useful, to include the cancer
surveillance studies identified by PAC, for the purpose of providing
veterans with information about the presence of widespread and serious
health effects. However, it will be very difficult for these studies to resolve
the issue of whether specific veterans’ health problems are related to their
Gulf War service in the absence of (a) widespread exposure; (b)
biomarkers for exposure; or (c) better data on who was exposed and at
what levels.




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GAO RESPONSE


We have added text to note the Committee’s findings. The PAC concluded,
“Aflatoxin...is a liver carcinogen, and increased rates of liver cancer could
result decades following low-level exposure, although available evidence
reviewed by the Committee does not indicate such exposures occurred
during the Gulf War.” (PAC, Final Report, p. 112.) GAO considers exposure
to aflatoxin as an unresolved issue.




GAO RESPONSE


We have added text to clarify our position regarding the likely utility of
further epidemiologic research in light of the absence of adequate
exposure data.




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GAO RESPONSE


We used the methodological categorizations identified by PGVCB as
reported for each study in PGVCB research plans and reports to Congress.
The categories identified by PAC appear to be an amalgam of
methodological approaches and topical emphases.




GAO RESPONSE


Appendix IV contains a more detailed discussion of the PAC’s conclusions
and our assessments.




GAO RESPONSE


Our specific rebuttals to PAC’s individual assertions on these matters are
set forth below.




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GAO RESPONSE


Concerning delayed neurotoxic effects of organophosphates, not all
organophosphates cause these effects; however the Committee is
incorrect in implying that pesticides to which U.S. service people were
exposed in the war could not have caused delayed neurotoxicity.72 As PAC
reports on p. 97 of its Final Report, Chlorpyrifos (Dursban) was shipped to
the Gulf. Dursban has been linked to delayed, chronic neurotoxicity in
laboratory animals. In the past, the delayed, chronic neurotoxic potential
of chlorpyrifos was overlooked.73 The Environmental Protection Agency
has recently penalized the manufacturer for failing to promptly report
human injuries from this pesticide and suggested that the pesticide be
relabeled to withdraw it from many applications, a decision with which
the company acquiesced. In addition, other unknown pesticide chemicals
may have been brought from the United States or purchased from local
suppliers in Saudi Arabia by troops outside the command structure; these
cannot be enumerated by DOD.

Regarding pyridostigmine bromide pretreatment, while pretreatment with
pyridostigmine bromide does not potentiate chronic neurotoxicity from
subsequent organophosphate exposure, studies of similar drugs indicate
that treatment after a sufficient organophospates exposure may potentiate

72
  M. Lotti, “The Pathogenesis of Organophosphate Polyneuropathy,” Critical Reviews in Toxicology,
vol. 21 (1991) pp. 465-487 (esp. pp. 466-7, 472); J.G. Kaplan et al., “Sensory Neuropathy Associated With
Dursban (Chlorpyrifos) Exposure,” Neurology, vol. 43 (1993) pp. 2193-96; C.S. Petty, “Organic
Phosphate Insecticide Poisoning, American Journal of Medicine (Mar. 1958), pp. 467-70; E. Capodicasa,
. et al., “Chlorpyrifos-induced Delayed Polyneuropathy “Archives of Toxicology,” vol. 65 (1991), pp.
150-155; J. Rosenberg, “Organophosphate Toxicity Associated with Flea-Dip Products — California,”
Journal of the American Medical Association, vol. 260 (July 1, 1988), pp. 22-3.
73
 M. Lotti, “The Pathogenesis of Organophosphate Polyneuropathy,” Critical Reviews in Toxicology,
vol. 21 (1991), pp. 465-587 (especially pp. 467 and 473).



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chronic neurotoxicity.74 There is evidence from laboratory studies that
post-exposure treatment can cause chronic neurotoxicity to occur with
organophosphate doses that would ordinarily be too low to cause a
problem (pharmacologic “promotion”), or it could turn a mild case of
organophosphate-induced chronic neurotoxicity into a severe case
(pharmacologic “potentiation”). Several papers have appeared on this
subject since 1990, although studies of post-exposure promotion by
pyridostigmine per se have not been undertaken as far as we know.

In response to the committee’s assertion that the only evidence for
synergism among pyridostigmine bromide, permethrin, and DEET is from in
vivo bioassays using lethal doses, Haley et al. found epidemiologic
evidence that pyridostigmine toxicity and a chemical nerve agent may
have acted synergistically to cause a syndrome they labelled
“confusion-ataxia,” the most severe of the three primary syndromes they
identify.75 They also found both pyridostigmine toxicity and DEET
exposures to be strongly associated with their syndrome 3
(arthro-myo-neuropathy). In any event, standard risk analytic practice
involves study of interactive effects in laboratory animals at doses that
result in acute toxicity and to further characterize the relationship from
that point. We have made the point that further study of the effects of this
as well as other exposures is warranted.




74
 Op cit., M. Lotti, p. 473; C. N. Pope & S. Padilla, “Potentiation of Organophosphorus-Induced Delayed
Neurotoxicity by Phenylmethylsulfonyl Fluoride,” Journal of Toxicology and Environmental Health,
vol. 31 (1990), pp. 261-73.
75
 R.W. Haley and T.L. Kurt, “Self-reported Exposure to Neurotoxic Chemical Contamination in the Gulf
War,” Journal of the American Medical Association, vol. 277 (1997) (3), pp. 231-237.



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GAO RESPONSE


We are uncertain what type of evidence PAC would consider sufficient to
conclude that some effect might have occurred. While studies testing the
toxic effects on humans have not been conducted, available animal studies
provide reasonable evidence of negative effects that make it premature to
conclude this is not a serious a risk factor and indicate that further
research should be conducted. For obvious ethical reasons, it is not
possible to conduct experimental studies on humans of effects that are
feared to be toxic; thus, standard toxicological approaches used by the
government and the private sector focus on research with animals.
Researchers have shown that the neurotoxic phenomenon produced by
organophosphate nerve agents in some poultry varieties was comparable
to the manifestations produced in man.76 In this regard, it is known that
organophosphate compounds that are neurotoxic to chickens will also
produce neurotoxicity in humans under appropriate conditions.

For example, the laboratory studies published by Abou-Donia et al.
demonstrated that pyridostigmine, chlorpyrifos, permethrin, and DEET can
synergistically act to cause delayed, chronic neurotoxicity. The hen is the
EPA-required laboratory model for testing chemicals for the potential to
cause OPIDN. Testing these chemicals for synergism in humans would have
been highly unethical. The doses of permethrin, DEET, chlorpyrifos and
pyridostigmine were intended to be in the range of sublethal human
exposure. Given the severity of the OPIDN that occurred with chemical
combinations in the doses used, it is possible that lower, but still medically
significant, levels of damage would follow even with slightly lower doses
of pyridostigmine.

The Abou-Donia group administered pyridostigmine bromide orally; Gulf
War veterans likewise were administered pyridostigmine orally. The
permethrin, chlorpyrifos, and DEET were injected by needle into the skin
just under the surface (intradermally) to simulate the probable absorption
through the skin. Since under their feathers hens have thicker skin than
humans, it is common laboratory practice to deliver skin exposure to hens
by intradermal injection. We believe the Committee erred in not
considering the findings of the Abou-Donia et al. studies to be indicative of
expected effects on humans.




76
 Stockholm International Institute for Peace Research (SIPRI), Delayed Toxic Effects of Chemical
Warfare Agents (New York: Alonquist and Wiksell International, 1975).



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Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




GAO RESPONSE


We are unaware of studies specifically testing, with sufficiently sensitive
neurophysiologic techniques, for long-term neurotoxic side effects of
pyridostigmine in any prior population taking pyridostigmine regularly. We
are, however, aware that patients taking pyridostigmine are cautioned to
avoid exposure to malathion, which was among the pesticides sent to the
Gulf.77

Concerning the Committee’s assertion that research is in flux,
pyridostigmine bromide may have been used in the presence of
contraindicated coexposures (malathion) and may potentiate the effects of
Dursban.

In response to the Committee’s point about delayed neurotoxic effects, we
have modified our statement to read, “delayed neurotoxic effects in
humans exposed to PB and DEET have been epidemiologically inferred and
reproduced in hens.” Human epidemiologic evidence of the synergistic
effects of pyridostigmine, DEET, chlorpyrifos, and chemical nerve agents
has been presented for an epidemiologic association between patterns of
complaints and reported exposures of these agents in humans.78




77
   “Pyridostigmine,” in Clinical Pharmacology (Online—http://www.cponline.gsm.com), Gold Standard
Multimedia Inc., 1994.
78
  Op cit., Haley et al.



Page 129                                                  GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




GAO RESPONSE


We respond to PAC’s remarks concerning its recommendations elsewhere
in this appendix.




GAO RESPONSE


Concerning the Committee’s observation that DOD was not the only
reviewer of its report, we note that DOD publicly endorsed PAC’s findings.
However, we have added a note that “PAC has asked us to point out that
’DOD was not the only party involved in [its] external review.....VA, HHS,
veterans service organizations, and individual veterans and veterans
advocates also reviewed [its] Interim and Final Report.’ PAC does not
provide information on the extent to which these reviewers agreed with its
findings or had their comments incorporated.” Again, our purpose was not
to conduct a review of PAC’s activities but to identify and assess the
strength of support for conclusions that had been drawn from the
available research.




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Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




GAO RESPONSE


Where the Committee has requested that specific changes be made to
table IV.1, we have incorporated them (see previous comments).




We have presented our detailed responses to the Presidential Advisory
Committee in this appendix. We summarize the major points below:




Page 131                                    GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




Where the Committee has expressed concerns about citations and cross
references to other studies, we have provided additional references and
have modified the language in some instances to ensure that other readers
will not misconstrue the meaning of our report. We double-checked the
information that the Committee challenged and generally found that the
data had been correctly stated. Moreover, a careful review of PAC
comments indicates that they represent a selective presentation of data
that tend to bias the reader’s perception of the issues. Therefore, we have
not changed the overall thrust of our report.

The Committee also takes issue with our reviews of its conclusions
regarding psychological stress, leishmaniasis, and chemical warfare
agents.

Regarding stress, PAC states that we ignored its analytical framework,
which was to presume that stress occurred and determine whether the
types of symptoms and conditions reported by veterans were consistent
with exposure to stress. However, the Committee did not provide evidence
that stress is an important contributing factor to the “broad range” of
illnesses currently being reported by Gulf War veterans. Although we
agree that life stress can be associated with a wide array of physical
symptoms, the research cited by the Committee largely assesses the
relationship between stress and PTSD, which is not a common diagnosis
among Gulf War veterans.

Although the Committee notes that scores on PTSD screening
questionnaires are higher among Gulf War veterans than among controls,
problems are associated with interpreting scores on these scales below the
validated cutoff points for PTSD risk. In addition, confirmatory psychiatric
interviews to eliminate alternative explanations for elevated PTSD
screening scores were not done in most of these studies. Thus, the
possibility remains that Gulf War veterans show higher average scores on
PTSD screening scales due to other conditions or nonstress-related
exposures selectively associated with service. Some studies also modified
PTSD screening instruments to make them more applicable to Gulf War
veterans; an unintended consequence of this modification is the
introduction of information bias (that is, adding questions that selectively
affect the scores of Gulf War veterans). Finally, as we note in our report, at
least one study that examined the relationship between stress and
veterans’ physical symptoms in a large sample found none, and in a
separate report, its authors noted that, “Although the stress that the




Page 132                                      GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




deployed veterans are experiencing can be characterized as substantial, it
is being handled unremarkably.”79

Regarding our evaluation of the conclusion that the likelihood of
leishmania infection has diminished as an explanation for widespread
illness, the Committee asked, based on the low numbers of cases of
leishmaniasis diagnosed in DOD and VA clinical programs, that we justify
any continued concern about asymptomatic infection. While there is no
fundamental disagreement regarding the available facts or the basic
circumstances under which asymptomatic infection is a concern, the
Committee’s justification for dismissal of leishmania as a risk factor rests
heavily on two assumptions: (1) that diagnostic programs have been highly
likely to detect the disease, even in the absence of any widely available
screening or diagnostic tests and in the presence of nonspecific symptoms,
and (2) that the course of various forms of leishmaniasis is well
understood by scientists and by the doctors examining the veterans. As
discussed in our report, we find these assumptions remain open to
question. Moreover, during our exit conference, DOD and VA officials voiced
agreement with our concerns in this regard. Insofar as the prevalence of
this infection is still unknown and it is impossible to predict which
veterans’ immune systems will be weakened, it is premature to discard
leishmaniasis as a risk factor.

Finally, regarding our evaluation of the Committee’s conclusion that
low-level chemical exposures are unlikely to be associated with veterans’
health conditions, the Committee appears not to contest the fact that
laboratory data document specific health effects in animals exposed to
one or more organophosphate agents not detectable by the usual clinical
tests. While the Committee notes that it recommended additional research
in this area, we find it difficult to reconcile the Committee’s dismissal of
such exposure as an “unlikely” contributor to veterans’ health problems
with its acknowledgement of an absence of data on an important exposure
scenario. Moreover, although the Committee apparently found no data to
suggest a problem with low-level exposures, we found some data that do
pose concerns. While PAC argues that these studies were done on animals,
they are consistent with standard toxicological practice employed by the
Environmental Protection Agency and others. The Committee’s insistence
that such effects be demonstrated in humans appears unreasonable
insofar as humans cannot be exposed to toxic substances for experimental
research for obvious ethical reasons. Also, comparing occupational or


79
 R. H. Stretch, P. D. Bliese et al. Psychological Health of Gulf War-Era Military Personnel. Military
Medicine, vol. 161 (1996), pp. 257-61.



Page 133                                                      GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VII
Comments From the Presidential Advisory
Committee on Gulf War Veterans’ Illnesses




accidental exposures, such as the Rocky Mountain Arsenal exposures to
sarin, to the possible exposures experienced by Gulf War veterans would
provide some degree of information, but the value of such information is
generally limited because each situation is different. PAC appears to have
set an unusually restrictive standard for the evidence that would support
any concern in this area.




Page 134                                    GAO/NSIAD-97-163 Gulf War Illnesses
Appendix VIII

Major Contributors to This Report


                        Sushil K. Sharma, Ph.D., Dr.P.H., Assistant Director
National Security and   Betty Ward-Zukerman, Ph.D., Project Manager
International Affairs   Dan Engelberg, Ph.D., Senior Evaluator
Division, Washington,   Nancy Ragsdale, Senior Evaluator (Communications Analyst)
                        Joseph F. Murray, Assistant Director, Report Review
D.C.




                        Page 135                                GAO/NSIAD-97-163 Gulf War Illnesses
Glossary


Aflatoxin                    Any of several carcinogenic toxic substances that are produced especially
                             in stored agricultural crops, by molds.

Anthrax                      An infectious disease of warm-blooded animals caused by a spore-forming
                             bacterium transmissible to man and characterized by external ulcerating
                             nodules or by lesions in the lungs.

Biomarker                    A biological indicator, typically of exposure or of susceptibility to illness.

Botulinum                    A spore-forming bacterium that secretes a toxin that is the cause of
                             botulism, an acute paralytic disease.

Chemical Agent Resistant     A paintable covering used to protect against chemical and biological
Coating                      attacks.

Decontaminating Solution 2   An extremely corrosive and reactive solution used to decontaminate
(DS2)                        material of chemical and biological weapons.

Depleted Uranium             A mixture of about 0.2 percent radioactive U-235 and the rest U-238 which
                             is used in armor-piercing shells and armor plating because of its extreme
                             density.

Fibromyalgia                 A group of common rheumatic disorders characterized by pain, tenderness
                             and stiffness of muscles, areas of tendon insertions and adjacent
                             soft-tissue structures.

Leishmania                   Any of a genus of flagellate protozoans that are parasitic in the tissues of
                             vertebrates. L. tropica is a member of this genus.

Mustard Gas                  Chemical warfare agents that blister the skin or any other part of the body
                             they contact. They act on the eyes, mucous membranes, lungs, skin and
                             blood-forming organs. They also damage the respiratory tract when
                             inhaled and cause vomiting and diarrhea when ingested.

Organophosphate-Induced      A neurological condition characterized by enlarged axons (long, single
Delayed Neuroathy (OPIDN)    nerve cells) and axonal degeneration, caused by exposure to certain
                             chemicals that inhibit cholinesterase, an enzyme important to nervous
                             system functions.

Pyridostigmine Bromide       A drug that was taken by some U.S. troops during the Persian Gulf war to
                             protect them against the nerve agent soman.




                             Page 136                                       GAO/NSIAD-97-163 Gulf War Illnesses
        Glossary




Ricin   A biological warfare agent extracted from the seed of the castor plant. It
        blocks protein synthesis by altering the RNA, thus killing the cell.

Sarin   An extremely toxic chemical warfare agent that affects the nervous
        system.

VX      A persistent and extremely lethal nerve agent.




        Page 137                                     GAO/NSIAD-97-163 Gulf War Illnesses
Glossary




Page 138   GAO/NSIAD-97-163 Gulf War Illnesses
Related GAO Products


              VAHealth Care: Observations on Medical Care Provided to Persian Gulf
              Veterans (GAO/T-HEHS-97-158, June 19, 1997).

              Chemical and Biological Defense: Protection of Critical Overseas Posts
              and Airfields Remains Largely Unaddressed (GAO/NSIAD-97-9, June 13, 1997).

              Operation Desert Storm: Evaluation of the Air Campaign (GAO/NSIAD-97-134,
              June 12, 1997).

              Defense Health Care: Medical Surveillance Has Improved Since the Gulf
              War, but Results in Bosnia Are Mixed (GAO/NSIAD-97-136, May 13, 1997).

              Chemical and Biological Defense: Emphasis Remains Insufficient to
              Resolve Continuing Problems (GAO/NSIAD-96-103, Mar. 29, 1996).

              Operation Desert Storm: Health Concerns of Selected Indiana Persian Gulf
              War Veterans (GAO/HEHS-95-102, May 16, 1995).

              Operation Desert Storm: Potential for Reproductive Dysfunction Is Not
              Being Adequately Monitored (GAO/T-PEMD-94-31, Aug. 5, 1994).

              Operation Desert Storm: Questions Remain on Possible Exposure to
              Reproductive Toxicants (GAO/PEMD-94-30, Aug. 5, 1994).

              Operation Desert Storm: Early Performance Assessment of Bradley and
              Abrams (GAO/NSIAD-92-94, Jan. 10, 1994).

              Operation Desert Storm: Problems With Air Force Medical Readiness
              (GAO/NSIAD-94-58, Dec. 30, 1993).

              Operation Desert Storm: Army Medical Supply Issues (GAO/NSIAD-93-206,
              Aug. 11, 1993).

              Operation Desert Storm: Improvements Required in the Navy’s Wartime
              Medical Care Program (GAO/NSIAD-93-189, July 28, 1993).

              Operation Desert Storm: Army Not Adequately Prepared to Deal with
              Depleted Uranium Contamination (GAO/NSIAD-93-90, Jan. 29, 1993).

              Operation Desert Storm: Full Army Medical Capability Not Achieved
              (GAO/NSIAD-92-175, Aug. 18, 1992).




              Page 139                                    GAO/NSIAD-97-163 Gulf War Illnesses
           Related GAO Products




           Operation Desert Storm: DOD Met Need for Chemical Suits and Masks, but
           Longer Term Actions Needed (GAO/NSIAD-92-116, Apr. 7, 1992).

           Defense Health Care: Efforts to Address Health Effects of the Kuwait Oil
           Well Fires (GAO/HRD-92-50, Jan. 9, 1992).

           Reproductive and Developmental Toxicants: Regulatory Actions Provide
           Uncertain Protection (GAO/PEMD-92-3, Oct. 2, 1991).

           Chemical Warfare: Soldiers Inadequately Equipped and Trained to
           Conduct Chemical Operations (GAO/NSIAD-91-197, May 29, 1991).

           Chemical Protective Suits: No Basis to Question Procuring Agency’s
           Acquisition Strategy (GAO/NSIAD-90-162, May 1, 1990).

           Hazardous Materials: DOD Should Eliminate DS2 From Its Inventory of
           Decontaminants (GAO/NSIAD-90-10, Apr. 25, 1990).

           Army Procurement: Unnecessary Restriction on Competition for New
           Chemical Protective Masks (GAO/NSIAD-88-66, Mar. 2, 1988).




(713002)   Page 140                                   GAO/NSIAD-97-163 Gulf War Illnesses
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