Gulf War Illnesses: Improved Monitoring of Clinical Progress and
Reexamination of Research Emphasis Are Needed (Letter Report, 06/23/97,
GAO/NSIAD-97-163).

Pursuant to a legislative requirement, GAO analyzed 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 Persian Gulf War, focusing on the: (1)
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) government's research strategy to study the
veterans' illnesses and the methodological problems posed in its
studies; and (3) consistency of key official conclusions with available
data on the causes of veterans' illnesses.

GAO noted that: (1) 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 ongoing epidemiological
research will provide descriptive data on veterans' illnesses,
formidable methodological problems are likely to prevent researchers
from providing answers regarding the causes of veterans' illnesses; (3)
over 100,000 of the approximately 700,000 Gulf War veterans have
participated in DOD and VA health examination programs established after
the war; (4) 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;
(5) while some measures of quality are in place for military or VA
health care, neither agency can now determine the appropriateness or
effectiveness of the treatment received by ill Gulf War veterans; (6)
federal research on Gulf War veterans' illnesses has not been pursued
proactively; (7) without accurate exposure information, the investment
of millions of dollars in further epidemiological research on the risk
factors for veterans' illnesses may result in little return; (8) the
Presidential Advisory Committee on Gulf War Veterans' Illnesses
concluded that stress is likely to be an important contributing factor
to the broad range of illnesses being reported by Gulf War veterans; (9)
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 post-traumatic stress disorder among Gulf War
veterans may be overestimated; (10) 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 has diminished and the Committee
found it unlikely to be "responsible for long term health effects in
Gulf War veterans," but the extent of asymptomatic leishmania infection
is unknown; (11) 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; and (12) unresolved
questions concern the extent to which veterans may have been exposed to*

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  NSIAD-97-163
     TITLE:  Gulf War Illnesses: Improved Monitoring of Clinical 
             Progress and Reexamination of Research Emphasis Are Needed
      DATE:  06/23/97
   SUBJECT:  Armed forces abroad
             Medical research
             Medical examinations
             Chemical warfare
             Biological warfare
             Health services administration
             Hazardous substances
             Military personnel
             Disease detection or diagnosis
             Diseases
IDENTIFIER:  Persian Gulf War
             DOD Comprehensive Clinical Evaluation Program
             DOD Persian Gulf War Health Surveillance System
             VA Persian Gulf War Health Registry
             
******************************************************************
** This file contains an ASCII representation of the text of a  **
** GAO report.  Delineations within the text indicating chapter **
** titles, headings, and bullets are preserved.  Major          **
** divisions and subdivisions of the text, such as Chapters,    **
** Sections, and Appendixes, are identified by double and       **
** single lines.  The numbers on the right end of these lines   **
** indicate the position of each of the subsections in the      **
** document outline.  These numbers do NOT correspond with the  **
** page numbers of the printed product.                         **
**                                                              **
** No attempt has been made to display graphic images, although **
** figure captions are reproduced.  Tables are included, but    **
** may not resemble those in the printed version.               **
**                                                              **
** Please see the PDF (Portable Document Format) file, when     **
** available, for a complete electronic file of the printed     **
** document's contents.                                         **
**                                                              **
** A printed copy of this report may be obtained from the GAO   **
** Document Distribution Center.  For further details, please   **
** send an e-mail message to:                                   **
**                                                              **
**                                            **
**                                                              **
** with the message 'info' in the body.                         **
******************************************************************


Cover
================================================================ COVER


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

Gulf War Illnesses

(713002)


Abbreviations
=============================================================== ABBREV

  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

Letter
=============================================================== LETTER


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. 


--------------------
\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. 


   BACKGROUND
------------------------------------------------------------ Letter :1

During their deployment associated with the Persian Gulf War, U.S. 
troops 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 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.)


   RESULTS IN BRIEF
------------------------------------------------------------ Letter :2

Our review found that (1) although efforts have been made to diagnose
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. 

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
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 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. 


--------------------
\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. 

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


   DOD AND VA HAVE NO SYSTEMATIC
   APPROACH TO MONITORING GULF WAR
   VETERANS' HEALTH AFTER INITIAL
   EXAMINATION
------------------------------------------------------------ Letter :3

DOD and VA officials have testified that whatever uncertainties may
exist about the cause of Gulf War veterans' illnesses, the veterans
are receiving appropriate and effective symptomatic treatment. 
However, DOD and VA have no mechanism to monitor the quality,
appropriateness, or effectiveness of care provided to Gulf War
veterans after their initial examination.  Furthermore, DOD and VA
officials said they had no plans to establish a mechanism to monitor
these veterans' progress.  This monitoring and follow-up is important
not only to ensure that diagnosed 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 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.)


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


   FEDERAL RESEARCH STRATEGY LACKS
   A COHERENT APPROACH
------------------------------------------------------------ Letter :4

The bulk of ongoing federal research currently focuses on the
epidemiological study of veterans' illnesses.  While this approach
may yield descriptive data on veterans' mortality and general health
profiles, 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 FEDERAL
      RESEARCH ARE HINDERING
      OUTCOMES
---------------------------------------------------------- Letter :4.1

Our review of research projects and interviews with agency officials
showed that the vast majority of federal research was not initiated
until 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
currently being provided to Gulf War veterans or to use this
information when funding additional clinical research. 

    Six new   Four new      Seven new     39 new        Eleven new    20 new
Research  studies   studies       studies       studies       studies       studies
program   started   started       started       started       started       started
                                                (including
                                                14 at the
                                                environmenta
                                                l health
                                                centers)

          Four on   Three on      Four on       Shift to      President     $2.5 million
          stress    stress and    infectious    include a     announces     allocated by
          and one   one on        diseases,     greater       formation of  VA to three
          each on   methods       one each on   range of      Presidential  new projects
          oil well                stress, oil   symptoms and  Advisory      examining the
          fires                   fires, and    exposures     Committee     health
          and PB                  methods                     (March)       effects of
                                                                            chemical
                                                                            weapons.
                                                VA
                                                establishes   DOD issues a
                                                three         "Broad
                                                environmenta  Agency        DOD launches
                                                l hazards     Announcement  a $15 million
                                                research      " for         research
                                                centers.      research in   program into
                                                (July)        PB,           the possible
                                                              epidemiology  effects of
                                                              and clinical  low-level
                                                              research as   exposure to
                                                              mandated by   chemical
                                                              Congress in   agents using
                                                              PL 103-337.   $10 million
                                                              $5 million    made
                                                              allocated.    available by
                                                              There were    Congress and
                                                              more than     $5 million
                                                              100           committed by
                                                              responses.    DOD.
                                                              (June)        (September)



                                                                            VA issues a
                                                                            request for
                                                                            proposals for
                                                                            a fourth
                                                                            Environmental
                                                                            Hazards
                                                                            Research
                                                                            Center for
                                                                            Reproductive
                                                                            Outcomes.
                                                                            (May)

Clinical  VA                                    DOD starts    DOD issues    DOD reports
care      develops                              the           its report    on the first
programs  the                                   Comprehensiv  on the first  18,000
          Persian                               e Clinical    10,000        participants
          Gulf                                  Evaluation    participants  in CCEP
          Health                                Program       in CCEP       (April)
          Registry                              (CCEP)        (August)
          (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 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)


--------------------
\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. 


   SOME HYPOTHESES RECEIVED EARLY
   EMPHASIS
------------------------------------------------------- Appendix III:3

Early federal research appeared to emphasize risks associated with
psychological factors such as stress.  To support this emphasis, DOD
pointed out that the psychological state of mind can influence
physical 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). 


--------------------
\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. 


   SOME HYPOTHESES WERE NOT
   INITIALLY PURSUED
------------------------------------------------------- Appendix III:4

While research on exposure to stress received early emphasis, other
hypotheses received scant support.  In its Final Report, IOM
discusses the evidence for a number of disease hypotheses, including
multiple chemical 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)


--------------------
\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. 


   ADDITIONAL HYPOTHESES WERE
   PURSUED IN THE PRIVATE SECTOR
------------------------------------------------------- Appendix III:5

A substantial body of privately funded research suggests that
low-level exposure to certain chemical warfare agents or chemically
related compounds, such as certain pesticides, is associated with
delayed or long-term health effects.  Regarding delayed health
effects of organophosphates, the chemical family used in many
pesticides and 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 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

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


--------------------
\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. 

\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. 


   FEDERAL RESEARCH EMPHASIS
------------------------------------------------------- Appendix III:6


      MOST STUDIES USE AN
      EPIDEMIOLOGICAL APPROACH
----------------------------------------------------- Appendix III:6.1

Sixty-one of the 91 federally sponsored studies (67 percent) are
classified 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
                            ----------------------------------------------------
                                                          Epidemiologi
Primary research focus       Applied     Basic  Clinical           cal     Total
--------------------------  --------  --------  --------  ------------  ========
Birth and reproductive             0         0         0             4         4
 effects
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/                 1         0         0            18        19
 diseases
Muscular                           0         0         0             3         3
Multiple organophosphates          0         6         1             2         9
 (including pyridostigmine
 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 TREATMENT
----------------------------------------------------- Appendix III:6.2

As indicated in table III.5, federal research is currently centered
on studies of the prevalence, nature, and risk factors associated
with veterans' illnesses.  Few studies are focusing primarily on
identification and 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 Projects Identified
                                by PGVCB

Objective                                           Number   Percent\a
----------------------------------------------  ----------  ----------
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. 


   FORMIDABLE METHODOLOGICAL
   PROBLEMS
------------------------------------------------------- Appendix III:7

Our review indicated that most of the ongoing epidemiological studies
focusing on the prevalence or causes of Gulf War-related illnesses
have been hampered by data problems and methodological limitations
and 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
      STUDIES
----------------------------------------------------- Appendix III:7.1

All but one of the research objectives identified by PGVCB (as noted
earlier 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
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
      RISK FACTORS OR CAUSES OF
      ILLNESS
----------------------------------------------------- Appendix III:7.2

As we noted earlier, to ascertain the causes of illnesses, it is
imperative that investigators have valid and reliable methods to
collect information 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 PROBLEMATIC
--------------------------------------------------- Appendix III:7.2.1

The research program to answer basic questions about the illnesses
that 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
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. 



                              Table III.6
                
                 Ongoing Epidemiological Studies Using
                  Measures Other Than Self-Reports to
                          Assess Key Exposures

                                                    Is the exposure
                                Is the study      measured through any
                             collecting data on     means other than
                              this exposure?\a       self-report?\b
                            --------------------  --------------------
                                              No                    No
Exposure                     Yes    No  response   Yes    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           12     5         5     1     8         3
 repellents
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. 

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.)


--------------------
\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. 


         CASE DEFINITION IS
         COMPLICATED BY PRESENCE
         OF NONSPECIFIC SYMPTOMS
--------------------------------------------------- Appendix III:7.2.2

Another major hurdle to the development of a successful research
agenda has been the difficulty in classifying symptoms into one or
more distinct 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 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
--------------------------------------------------- Appendix III:7.2.3

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. 


SUPPORT FOR KEY OFFICIAL
CONCLUSIONS IS WEAK OR SUBJECT TO
DIFFERENT INTERPRETATIONS
========================================================== Appendix IV

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      "It is unlikely     "There were no       We have noted the
warfare agents  the health effects  verified detections  limitations of the U.S.
                reported today by   of anthrax or        detection capability
                Gulf War veterans   botulinum toxin      for biological warfare
                are the result of   during the war.      agents. We agree with
                exposures to        Second, stateside    PAC that the effects of
                biological warfare  examination of soil  at least one of the
                agents"             samples and enzyme   agents that Iraq
                                    assays did not       weaponized might not be
                                    reveal the presence  observed for many
                                    of BW agents."       years.

Chemical        "It is unlikely     "Available           We dispute this
warfare agents  the health effects  scientific evidence  conclusion. There is
                reported by Gulf    does not indicate    evidence from various
                War veterans today  that such long-      sources that chemical
                are the result of   term effects occur   weapons were released
                exposure to OP or   in humans following  at Khamisyah and
                mustard chemical    low-level            elsewhere on the
                warfare agents      exposures, but the   battlefield. Some
                during the Gulf     amount of data from  evidence from animal
                War."               either human or      and epidemiological
                                    animal research on   studies documents the
                                    low-level exposures  potential for delayed
                                    is minimal."         or chronic effects from
                                                         such exposure. Thus, we
                                                         cannot exclude the
                                                         possibility that such
                                                         health effects could
                                                         impact exposed
                                                         veterans.

Depleted        "It is unlikely     "Toxic effects are   We have no comment on
uranium         that health         likely to be         this issue.\a
                effects reported    similar to the
                by Gulf War         kidney toxicity
                veterans today are  observed from
                the result of       inhaled or ingested
                exposure to         uranium. To date,
                depleted uranium    VA has reported no
                during the Gulf     kidney toxicity
                War."               among soldiers
                                    wounded by DU
                                    fragments in
                                    friendly fire
                                    episodes."

Infectious      "It is unlikely     "While               Owing to the invasive
diseases        that infectious     viscerotropic        character of current
                diseases endemic    leishmaniasis can    screening tests for
                to the Gulf region  be difficult to      viscerotropic
                are responsible     confirm, it is not   leishmaniasis it has
                for long term       considered to be a   been impossible to test
                health effects in   cause of widespread  broadly for infection.
                Gulf War veterans,  illness in Gulf War  Although some sources
                except in a small,  veterans. All        have suggested that the
                known number of     veterans diagnosed   rate of leishmania
                individuals."       with viscerotropic   infection may be as
                                    leishmaniasis,       high as 5% of certain
                                    except one, have     groups deployed to the
                                    experienced the      Persian Gulf, there is
                                    signs                currently no means of
                                    characteristic of    screening for
                                    the disease.         asymptomatic infections
                                    From August 1990     which can re-emerge
                                    through July 1991,   during immune system
                                    the U.S. Army        failure. The Center for
                                    deployed             Disease Control and
                                    approximately        Prevention has found
                                    347,000 individuals  evidence of previous Q
                                    to the Gulf region.  fever and sandfly fever
                                    Based on             infection in a
                                    information from     subsample of Gulf War
                                    U.S. Army field      veterans, which would
                                    hospitals, the only  indicate exposure to
                                    infectious diseases  the sandfly that caries
                                    that caused 30 or    leishmania.
                                    more each of
                                    approximately
                                    14,000 admissions
                                    were pneumonia,
                                    intestinal
                                    infections,
                                    inflammation of the
                                    testes and/or
                                    epididymus, chicken
                                    pox, and kidney
                                    infections."

Oil-well fire   "It is unlikely     "Toxic gases that    We have no comment on
smoke           exposure to oil-    can be found in      this issue.\a
                well fire smoke is  oil-well fire
                responsible for     smoke-such as
                symptoms reported   hydrogen sulfide
                today by Gulf War   and sulfur dioxide-
                veterans."          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."

Pesticides      "It is unlikely     "According to DOD,   Our review of the
                that health         after-action         literature identified
                effects and         reports from in-     evidence that exposure
                symptoms reported   theater medical      to organophosphate
                today by Gulf War   personnel did not    agents can induce
                veterans are the    reveal any U.S.      delayed neuropathy
                result of exposure  troops reporting     without causing
                to pesticides       symptoms that would  immediate symptoms.
                during the Gulf     indicate pesticide   Moreover, it has been
                War"                poisoning. Evidence  suggested that
                                    from studies of      treatment with
                                    humans poisoned by   pyridostigmine bromide
                                    organophosphate      following exposure to
                                    pesticides suggests  organophosphates
                                    that low-level       (either OP pesticides
                                    exposures that do    or chemical weapons)
                                    not cause signs and  may actually enhance
                                    symptoms of          the potential for
                                    immediate and        delayed effects.
                                    severe poisoning
                                    will not result in
                                    long-term health
                                    effects."

Petroleum       "It is unlikely                          We have no comment on
products        that health                              this issue.\a
                effects reported
                today by Gulf War
                veterans are due
                to exposure to
                petroleum products
                during the war."

Psychological   "Stress is likely   "Animal studies      Although the evidence
and             to be an important  demonstrate that     that we reviewed
physiological   contributing        stress can have      indicates that stress
stress          factor to the       measurable effects   can have an important
                broad range of      on the brain,        role in symptoms of
                illnesses           immune system,       many physical
                currently being     cardiovascular       illnesses, when stress
                reported by Gulf    system, and various  is present in a patient
                War veterans."      hormonal responses.  with untreated and
                "The entire         Although the human   undiagnosed diffuse
                federal research    body can adapt to    physical symptoms, care
                portfolio should    normal stresses, if  must be taken to
                place greater       the stress lasts     determine whether the
                emphasis on basic   longer it can be     stress is the cause or
                and applied         expressed in a       the effect of the
                research on the     variety of physical  physical symptoms. We
                physiologic         illness symptoms.    found weak support for
                effects of stress   Some researchers     the conclusion that
                and stress-         suspect that the     stress is an important
                related             inadequate           contributing factor in
                disorders."         production of        the broad range of
                                    stress hormones and  illnesses being
                                    stress response      reported by Gulf War
                                    occurs in some (not  veterans; most of the
                                    all) humans with     evidence cited by PAC
                                    chronic fatigue      addressed the effects
                                    syndrome and post-   of stress solely on
                                    traumatic stress     PTSD.
                                    disorder. Based on
                                    this understanding
                                    and supported by
                                    decades of clinical
                                    observations,
                                    physicians
                                    recognize that many
                                    physical, as well
                                    as psychological,
                                    diagnoses are the
                                    consequences of
                                    stress."

Pyridostigmine  "It is unlikely     PB is used in much   Experiments in animal
bromide         that health         higher doses in      models (including one
                effects reported    patients with        study sponsored by DOD)
                today by Gulf War   myasthenia gravis    show that PB has toxic
                veterans are the    than was             effects in combination
                result of exposure  administered to      with other elements,
                simply to PB        military personnel.  such as DEET and
                (emphasis added).                        permethrin, in the Gulf
                Ongoing federally                        War environment. This
                funded studies                           may be particularly
                should help the                          true for animals with a
                scientific                               genetic predisposition.
                community draw                           Cases of such delayed
                conclusions about                        neurotoxic effects in
                the synergistic                          humans exposed to PB
                effects of PB and                        and DEET have been
                other risk                               epidemiologically
                factors."                                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     "The human immune    DOD has not adequately
                that health         system has evolved   monitored the effects
                effects reported    the capability to    of receiving multiple
                by Gulf War         deal with thousands  vaccines.
                veterans today are  of foreign
                the result of       substances, to sort
                exposures to the    them out, and to
                BT or anthrax       regulate immune
                vaccines, used      response. Humans
                alone or in         live among a vast
                combination."       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. 


--------------------
\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. 


   EXTENT OF POSTTRAUMATIC STRESS
   DISORDER MAY BE OVERESTIMATED
-------------------------------------------------------- Appendix IV:1

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

     "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 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. 


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

\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. 

\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. 


   EXTENT OF ASYMPTOMATIC
   LEISHMANIA INFECTION IS UNKNOWN
-------------------------------------------------------- Appendix IV:2

PGVCB concluded that "the likelihood of Leishmania tropica as an
important risk factor for widely reported illness has diminished."\45
While this is the case for observed 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. 

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 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. 


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

\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. 


   EVIDENCE OF EXPOSURE TO
   BIOLOGICAL AND CHEMICAL WEAPONS
   HAS NOT BEEN AGGRESSIVELY
   PURSUED
-------------------------------------------------------- Appendix IV:3

DOD has consistently denied that Gulf War veterans were intentionally
or unintentionally exposed to biological warfare agents, and prior to
June 1996, it denied any exposure to chemical warfare agents.  If
servicemembers were exposed, exposure would have occurred in one of
three ways:  (1) through intentional Iraqi use of chemical or
biological warfare agents, (2) through theaterwide contamination
resulting from air 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
------------------------------------------------------ Appendix IV:3.1

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 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. 


--------------------
\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. 

\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). 


      CHEMICAL WARFARE AGENTS
------------------------------------------------------ Appendix IV:3.2

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 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. 


   IMPACT OF DOD DENIALS ON
   FEDERAL RESEARCH
-------------------------------------------------------- Appendix IV:4

The 1995 PGVCB research plan noted that investigations of chemical
weapons effects were not done because there was no evidence of
exposure.\52

Noting that there had been no mass casualties to indicate 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. 



(See figure in printed edition.)Appendix V

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


COMMENTS FROM THE DEPARTMENT OF
DEFENSE
========================================================== Appendix IV



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)


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

GAO COMMENTS

1.  DOD offers selected excerpts from reports of the Institute of
Medicine (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 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 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. 



(See figure in printed edition.)Appendix VI

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


COMMENTS FROM THE DEPARTMENT OF
VETERANS AFFAIRS
========================================================== Appendix IV

appear at the end of this appendix. 



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)



(See figure in printed edition.)


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

GAO COMMENTS

1.  We have changed the word "illness" in our report title to
"illnesses."

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 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). 

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


COMMENTS FROM THE PRESIDENTIAL
ADVISORY COMMITTEE ON GULF WAR
VETERANS' ILLNESSES
========================================================= Appendix VII

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. 



   (See figure in printed
   edition.)

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, 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). 



   (See figure in printed
   edition.)

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. 

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



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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 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. 



   (See figure in printed
   edition.)

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.)



   (See figure in printed
   edition.)

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.)



   (See figure in printed
   edition.)

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 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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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 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. 



   (See figure in printed
   edition.)

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



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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 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



   (See figure in printed
   edition.)

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."



   (See figure in printed
   edition.)

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. 

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



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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 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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)


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



   (See figure in printed
   edition.)

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 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. 



   (See figure in printed
   edition.)


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. 



   (See figure in printed
   edition.)


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. 



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)


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. 



   (See figure in printed
   edition.)

GAO RESPONSE

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



   (See figure in printed
   edition.)

GAO RESPONSE

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



   (See figure in printed
   edition.)

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 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. 



   (See figure in printed
   edition.)


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. 



   (See figure in printed
   edition.)

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



   (See figure in printed
   edition.)

GAO RESPONSE

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



   (See figure in printed
   edition.)

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. 



   (See figure in printed
   edition.)

GAO RESPONSE

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



   (See figure in printed
   edition.)

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

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 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 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. 


--------------------
\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. 

\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. 

\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. 

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

\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. 

\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.). 

\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)."

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

\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. 

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

\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). 

\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. 

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

\77 "Pyridostigmine," in Clinical Pharmacology
(Online--http://www.cponline.gsm.com), Gold Standard Multimedia Inc.,
1994. 

\78 Op cit., Haley et al. 

\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. 


MAJOR CONTRIBUTORS TO THIS REPORT
======================================================== Appendix VIII

NATIONAL SECURITY AND
INTERNATIONAL AFFAIRS DIVISION,
WASHINGTON, D.C. 

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


GLOSSARY
============================================================ Chapter 0


         AFLATOXIN
------------------------------------------------------ Chapter 0:0.0.1

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


         ANTHRAX
------------------------------------------------------ Chapter 0:0.0.2

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
------------------------------------------------------ Chapter 0:0.0.3

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


         BOTULINUM
------------------------------------------------------ Chapter 0:0.0.4

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


         CHEMICAL AGENT RESISTANT
         COATING
------------------------------------------------------ Chapter 0:0.0.5

A paintable covering used to protect against chemical and biological
attacks. 


         DECONTAMINATING SOLUTION
         2 (DS2)
------------------------------------------------------ Chapter 0:0.0.6

An extremely corrosive and reactive solution used to decontaminate
material of chemical and biological weapons. 


         DEPLETED URANIUM
------------------------------------------------------ Chapter 0:0.0.7

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
------------------------------------------------------ Chapter 0:0.0.8

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


         LEISHMANIA
------------------------------------------------------ Chapter 0:0.0.9

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
----------------------------------------------------- Chapter 0:0.0.10

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
         DELAYED NEUROATHY (OPIDN)
----------------------------------------------------- Chapter 0:0.0.11

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


         PYRIDOSTIGMINE BROMIDE
----------------------------------------------------- Chapter 0:0.0.12

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


         RICIN
----------------------------------------------------- Chapter 0:0.0.13

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
----------------------------------------------------- Chapter 0:0.0.14

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


         VX
----------------------------------------------------- Chapter 0:0.0.15

A persistent and extremely lethal nerve agent. 



RELATED GAO PRODUCTS
============================================================ Chapter 1

VA Health 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). 

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). 


*** End of document. ***