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4
POSSIBLE LONG TERM HEALTH
CONSEQUENCES OF GULF WAR EXPOSURES:
AN INDEPENDENT EVALUATION
INTRODUCTION
T
his chapter provides an independent examination of the long-term health consequences of Gulf
War exposures by nationally recognized scientific experts. Chapter Three reviewed many of the
complexities associated with the question of “Why are Gulf War veterans ill?” as well as some of the
reasons why this question may never be answered. In an effort to examine what is known regarding
the health effects of some of the exposures experienced by troops during the Gulf War, the SIU
contracted with the following scientists.
This chapter contains the brief reports prepared by the consultants listed below. (The
consultants’ affiliations are provided for identification purposes only.) They are, in the order their
reports appear in this chapter:
FredricGerr, M.D., Peachtree Environmental Consultants Inc., Decatur, Georgia; and Associate
Professor, Department of Environmental and Occupational Health, Rollins School of Public Health
of Emory University, Atlanta, Georgia. Dr. Gerr examined the chemicals that were in the Gulf, such
as solvents, pesticides, depleted uranium, and others, for their potential health effects particularly
upon the brain and nervous system. (Dr. Gerr’s detailed report is at Appendix II.)
MatthewKeifer, M.D., M.P.H., Assistant Professor, Occupational and Environmental Medicine
Program, Departments of Medicine and Environmental Health, Harborview Medical Center,
Universityof Seattle, Washington. Dr. Keifer examined the total range of health effects to exposures
to pesticides and related chemicals such as pyridostigmine bromide and some chemical nerve agents
that are similar to pesticides. (Dr. Keifer’s detailed report is at Appendix JJ.)
James Moss, Ph.D., Gainesville, Florida. Dr. Moss looked at the use of PB as it acts with
combinations of other agents such as certain pesticides.
Richard Letz, Ph.D., Peachtree Environmental Consultants Inc., Decatur, Georgia; and Associate
Professor,Department of Behavioral Sciences and Health Education, Rollins School of Public Health
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of Emory University, Atlanta, Georgia. Dr. Letz evaluated the health effects of stress as an
occupational and or environmental exposure in the Gulf.
Michael Lebowitz, Ph.D., Professor of Medicine, Pulmonary and Critical Care Medicine;
Professor and Director of Epidemiology, Arizona Prevention Center; Chair, Epidemiology Graduate
Interdisciplinary Program, University of Arizona, Tucson. Dr. Lebowitz examined the long-term
health effects of sources of indoor and outdoor air pollutants during the Gulf War including oil well
fires, sand, space heaters used in unvented tents, and other sources. (Dr. Lebowitz’s detailed report
is at Appendix KK.)
Kevin Dybvig, Ph.D., Professor, Departments of Comparative Medicine and Microbiology,
University of Alabama at Birmingham. Dr. Dybvig evaluated the potential role of infection with
Mycoplasma fermantans in the health problems of Gulf War veterans.
Shanna Swan, Ph.D., Chief, Reproductive Epidemiology Section, California Department of
HealthServices. Dr. Swan evaluated reproductive health issues from an epidemiological perspective.
(Dr. Swan’s detailed report is at Appendix LL.)
Melissa McDiarmid, M.D., M.P.H., Associate Professor of Medicine, Occupational Health
Project, University of Maryland; and Director, Depleted Uranium Follow-up Program, Baltimore
Veterans’ Affairs Medical Center. Dr. McDiarmid examined the chemicals that were in the Gulf,
suchas solvents, pesticides, and depleted uranium, for their potential to adversely affect reproductive
health outcomes. Dr. McDiarmid also examined the chemicals associated with the Gulf War
deployment for their potential to increase the risk of cancer among Gulf War veterans. (Dr.
McDiarmid’s detailed reports are at Appendix MM and NN.)
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HEALTH EFFECTS OF EXPOSURES TO NEUROTOXIC
AGENTS USED IN THE PERSIAN GULF WAR
Prepared by: Fredric Gerr, M.D., Peachtree Environmental Consultants, Inc., Decatur,
Georgia; and Department of Environmental and Occupational Health, Rollins School of Public
Health of Emory University, Atlanta, Georgia
SUMMARY
T
he purpose of this report is to review in detail the known health effects of chemical agents
potentially hazardous to the nervous system to which military personnel may have been exposed
during the Persian Gulf War. This review is made with special attention to possible relationships
between these agents and symptoms and health complaints that have been reported by a large
number of Persian Gulf War veterans.
OnAugust 2, 1990, Iraq invaded Kuwait and set in motion the events that would eventually lead
to US military intervention in the Persian Gulf. On August 8, 1990, the first US Air Force planes
arrived in Saudi Arabia and, on the following day, the first US ground forces arrived. The ground
war began and ended in February, 1991. The last of the US service members who served in the
ground war were returned to the United States in June, 1991.
In all, the United States had approximately 697,000 troops stationed in the Persian Gulf.
Following their return, mounting concern has focused on symptoms and unexplained illness
experienced by some. In response to concern about unexplained illness, the VA Persian Gulf Health
Registry was created. As of June, 1994, over 17,000 veterans, either ill or concerned about illness,
had enrolled. The ten most frequent complaints among those in the Registry were fatigue (17.4%),
rash (16.8%), headache (14.1%), muscle and or joint pain (13.9%), neuropsychologic complaints
(10.5%), shortness of breath (7.5%), sleep disturbances (4.9%), gastrointestinal disturbance (4.1%),
cough (3.8%), and other respiratory complaints (3.3%) (Persian Gulf Veterans Coordinating Board,
1995). The registry has not shed light on any distinctive demographic, exposure, or geographic risk
factor, with the possible exception that nearly half of the veterans with symptoms were
reservists/National Guard personnel, a group that accounted for only 17% of all troops deployed in
the Persian Gulf (Persian Gulf Veterans Coordinating Board, 1995).
Numerous possible risks to health were present in the Persian Gulf at the time of the Gulf War.
These included poor living conditions, characterized by heat and humidity, initially, and cold during
the actual combat. Troops slept in temporary housing with little personal privacy. Food consisted
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mainly of prepackaged meals. Flies and other insects were prevalent. Chemical warfare alarms
sounded frequently, although virtually all were false. Such alarms, nevertheless, resulted in donning
of air purifying masks and chemical protective clothing. Attention has been paid to possible
chemicalwarfare agent exposure in the Gulf occurring as a result of destruction of a chemical warfare
agent facility at Kamisiyah. Iraq was reported to have stockpiled biological warfare agents as well.
Concern about health effects from exposure to these weapons as well as to indigenous infectious
diseases lead to an extensive vaccination program. In addition, an estimated quarter of a million
troopstook the chemical warfare agent protective drug pyridostigmine bromide. Pesticides were used
to control insect populations and insect repellents were provided to troops for personal use. Some
troopswere exposed to solvents from jet fuel, paint vapors, and other sources. Depleted uranium was
usedin special applications during the Gulf War and tetra-ethyl lead was formulated in gasoline used
inmotor vehicles. Finally, some troops were exposed to non-ionizing radiation from microwaves and
radar installations (PAC, 1996).
In order to better characterize the health complaints of Gulf War veterans and to determine
whether exposure to hazardous substances in the Gulf had caused them, health investigations of
morbidity and mortality among Persian Gulf War veterans have been performed.
The largest and most methodologically sound study investigation included nearly five thousand
subjects and involved inquiry about symptoms and exposure to known hazards in the Persian Gulf
(Schwartzet al., 1997). Military personnel who served in the Persian Gulf War reported significantly
more symptoms of depression, PTSD, chronic fatigue, cognitive dysfunction, bronchitis and asthma
than non-Persian Gulf War personnel. Most of the self-reported exposures to hazards were
statistically significantly related to virtually all of the health outcomes studied.
The results of the study indicate that subjective symptoms, including those consistent with
nervous system impairment, occur more frequently among those who served in the Persian Gulf War
than Persian Gulf War-era personnel who were not stationed in the Persian Gulf. The associations
between multiple, unrelated exposures and multiple, unrelated symptoms, however, is more
consistent with differential recall of exposure as a function of symptoms experience than a toxic
response to a single or even several agents.
Several other studies intended to characterize with more objective measures the neurological
health of Gulf War Veterans have been published. Authors of some suggest that the results show
neither increased nervous system impairment nor a consistent pattern of illness suggestive of a
common etiology (Amato et al., 1997; Jamal et al, 1996). Conversely, others conclude that their
results show an increase in nervous system impairment and a pattern consistent with exposure to
specific neurotoxicants (Haley et al., 1997). Unfortunately, nearly all of these studies were
performed on “samples of convenience” and, as a result, cannot be used to draw conclusions about
the larger but unstudied group of all Gulf War veterans. This body of literature has added little to
the collective understanding of symptoms and health concerns among Persian Gulf War veterans.
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Epidemiologic investigation of relationships between potentially toxic substances and ill health
require accurate and unbiased assessment, on an individual basis, of both health status and the
intensity and type of exposures experienced among a sample of persons representative of the entire
group at risk. Of these requirements, the task that appears nearly impossible at this time is a person
by person estimation of the intensity and type of exposures experienced by military personnel who
served during the Persian Gulf War. Characterization of exposure to hazards was, apparently, not
performed during the actual deployment of troops. As a result, estimation of the magnitude of past
hazardousexposure at this time requires either direct questioning of veterans with resulting reporting
bias or historical exposure reconstruction of unknown validity. As indicated above, reporting bias
likely accounts for the associations observed in one study between symptoms and a very wide range
of potential hazards.
As an alternative to epidemiologic investigation, another approach to investigating associations
betweenhealth and hazardous exposure is to focus separately on 1) health problems among veterans
and 2) exposures which they might have experienced. If a characteristic illness is observed among
GulfWar veterans, then known causes for it can be explored. If particular hazards were encountered
byveterans in the Gulf, the known health effects of exposure to them can be reviewed and compared
to reported health problems among veterans. As neither approach attempts to relate exposure to
illness on an individual basis, considerable caution must be exercised in their execution and
interpretation. This report employs the latter of these two approaches and provides a systematic
review of health effects of substances potentially toxic to the nervous system to which military
personnelmay have been exposed during the Persian Gulf War. A summary of the review is provided
below.
Pyridostigmine bromide is an anticholinesterase drug given to tens of thousands of military
personnel in the Persian Gulf war as a protective pre-treatment for exposure to “nerve gas” type
chemical warfare agents (Dirnhuber et al, 1979). It is a member of the carbamate class of chemical
agents and has been used for decades in humans as a treatment for the neurological disorder
Myasthenia Gravis as well as a short acting accelerator of recovery from certain anesthetic agents.
Pyridostigmine bromide acts by binding reversibly to, and consequently inhibiting, the enzyme
acetylcholinesterase, which is necessary for normal function of the nervous system. This action is
the basis for its ability to protect against the lethal effects of nerve agents which bind irreversibly to
this enzyme. Pyridostigmine bromide is known to cause short-term discomfort and its use in the Gulf
War was associated with abdominal distress, nausea, and diarrhea (Keeler et al., 1991; Sharabi et al.,
1991). Little epidemiologic information is available about its long-term effects healthy young human
populations,however, several factors suggest few or no long term effects on the nervous system. First,
it has been used for decades for treatment of neurological illness with no systematic occurrence of
symptoms resembling those experienced by Gulf War veterans. Second, the agent is not known to
pass through the natural barrier that protect the brain from many drugs and chemicals (the “blood
brain barrier”), thereby making effects on the brain unlikely. Third, the class of drugs and chemical
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agents to which Pyridostigmine belongs, carbamates, have been used extensively in agriculture for
decades and are not known to cause persistent adverse effects on the nervous system in that setting.
Chemical warfare agents, known as “nerve gas”, are members of the organophosphate class of
chemical compounds. The organophosphate nerve agents act to irreversibly bind the enzyme
acetylcholinesterase (Grob and Harvey, 1957). Accumulation of the intended substrate of
acetylcholinesterase, the neurotransmitter acetylcholine, results in a characteristic complex of
symptoms. Unlike pyridostigmine, which also binds the enzyme acetylcholinesterase (reversibly,
however), the organophosphate chemical warfare agents are capable of freely penetrating the brain
and producing acute and chronic central nervous system toxicity.
Most of what is known about the effects of chemical warfare agents is a result of experimental
studies of exposure to animals (Blick et al, 1994). However, several studies or case reports of acute
human effects of exposure were identified in the literature (Grob and Harvey, 1957; Sidell, 1974).
In addition, because of their chemical and toxicological similarity to organophosphate pesticides,
some inferences about their toxicity can be made from the considerable literature about the
organophosphate pesticides. Short term, acute exposure to chemical warfare agents produces a
characteristic array of symptoms including sweating, diarrhea, urination, muscle twitching, pinpoint
pupils, confusion, seizures, and, with sufficient exposure, death. Some credible medical evidence
suggests that, upon recovery from toxic effects of acute exposure, chronic impairment of the central
nervous system may occur (Sidell, 1974; Burchfiel and Duffy, 1982). Little evidence is available to
suggest that exposures insufficient to produce acute toxicity are associated with long term
neurological effects. Reportedly, no military personnel were treated for acute effects of nerve agent
exposure, making unlikely that chronic effects of such exposure are the cause of symptoms
experienced by Persian Gulf War veterans.
Organophosphate pesticides were used in the Persian Gulf for control of insects. Because of
widespread use of organophosphate pesticides worldwide, a larger body of literature about the acute
and chronic health effects of organophosphate pesticides on human populations, including chronic
effectson the CNS, is available than is available for organophosphate chemical warfare agent agents.
Inaddition to the organophosphate class of pesticides, carbamate, pyrethroid, and organochlorine
pesticides were also used. Only the organophosphate pesticides are known to cause, under certain
exposurecircumstances, long-term adverse effects on the nervous system. The carbamate pesticides,
although similar in acute toxicity to organophosphates, are not known to result in long-term adverse
neurological effects. Similarly, long-term adverse neurological effects of pyrethroid insecticides, and
Lindane, the one organochlorine pesticide used in the Persian Gulf, have not been reported in the
peer reviewed medical literature.
Exposure to organophosphate pesticides has been most convincingly associated with chronic
adverse central nervous system health effects only when the exposure intensity is sufficient to
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produce acute toxicity consistent with acetylcholinesterase inhibition (Steenland et al, 1994; Ames
et al., 1995; Savage et al., 1988; Rosenstock et al., 1991). Only one report in the literature related
exposures to levels of organophosphate pesticides insufficient to produce acute effects to long-term
adverse effects on the central nervous system (Korsak and Sato, 1977). This finding has not been
duplicated by other investigators. Given the apparent absence of documented signs and symptoms
characteristic of acute organophosphate pesticide toxicity among soldiers deployed to the Persian
Gulf, it unlikely that long-term health effects of pesticide toxicity is responsible for symptoms
described by Persian Gulf veterans.
Lead, in the form of tetra-ethyl lead, was an octane boosting additive in gasoline used to fuel
motor vehicles used by US forces in the Persian Gulf. Tetra-ethyl lead had been used in gasoline in
theUnited States for decades and was widely discontinued from such use, for protection of the public
health,beginning in the 1970’s. Exposure to lead in the Persian Gulf War was limited to that emitted
from vehicles in which leaded gasoline was used.
Both organic and inorganic lead are known to be toxic to the nervous system. Clinically,
symptoms of lead intoxication include abdominal pain, fatigue, joint pain, headache, irritability and
other mood disturbances, and muscle and joint pain. On clinical examination, physical signs of
peripheral neuropathy, including paresthesias and motor weakness may be present (Culen et al.,
1983). Clinical examination is insensitive to central nervous system impairment; however, when
subjected to formal clinical neurobehavioral evaluation, patients with lead intoxication often show
impairment of multiple central nervous system functions (Bordo et al., 1982; Baloh et al., 1980;
Valciukas et al., 1978a. Valciukas et al., 1978b. Stollery et al., 1989; Hanninen et al., 1979;
Mantere et al., 1984; Baker et al., 1985; Ashby, 1980).
Although leaded fuels were used in the Persian Gulf, it is unlikely that exposures to tailpipe
emissions were of sufficient duration or intensity to produce any kind of clinically apparent toxicity
from lead exposure. While long-term exposure to lead does result in accumulation of lead in
long-term storage pools in the human body, short-term exposures result in little long-term
accumulation. Failure of symptoms to remit for years following exposure is inconsistent with lead
as an etiology of unexplained symptoms experienced by some Gulf War veterans. Furthermore,
leaded fuels were used in the United States for decades and are still in use in many other countries
worldwide. No reports of symptoms identical to those experienced by Persian Gulf veterans have
emerged despite such widespread and long-term use.
Depleted uranium is a by-product of the extraction of uranium-235 (U235) from naturally
occurring uranium. Military applications for this material include munitions production (armor
piercing bullets and artillery shells) and armor for tanks and personnel carriers. The PGW was the
first US use, in actual military conflict, of depleted uranium tipped shells and depleted uranium
armored tanks and other vehicles (United States General Accounting Office, 1993).
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At the current time, estimates of the total number of military personnel who had any exposure
to depleted uranium are not available. Exposure may have occurred to personnel in vehicles
penetrated by depleted uranium rounds as well as personnel involved in recovery and repair of
vehicles damaged by depleted uranium containing rounds. The Army has identified 35 soldiers who
were injured in combat vehicles damaged by depleted uranium munitions, 22 of whom likely were
wounded by DU containing shrapnel. In addition, 27 soldiers involved in damage assessment and
preparation for shipment of damaged combat vehicles have reported exposure to DU during those
activities (United States General Accounting Office, 1993).
Exposure to uranium, depleted or non-depleted, is not known to produce adverse effects on the
nervous system (Thun et al., 1985; Leggett, 1989; Morris and Meinhold, 1995). Reports of exposure
to depleted uranium to soldiers in the Persian Gulf, although uncertain, suggest limited numbers of
involved personnel. These facts make extremely unlikely that exposure to depleted uranium during
the Gulf War is responsible, wholly or in part, for the array of symptoms observed among Gulf War
veterans.
DEET,the common name for N,N-Diethyl-m-toluamide, is widely regarded as the most effective
topical insect repellent available and is the major active ingredient in virtually all products marketed
for this purpose (Robbins and Cherniack, 1986; Osimitz and Murphy, 1997). It was registered for
use by the general public in 1957 and has been in civilian and military use since then. DEET has
beena remarkably successful commercial product and is currently estimated to be used, in some form,
by approximately 80 million persons in the United States, annually (Stinecipher and Shah, 1997).
Despite relatively long-term use by millions, only a few reports of toxicity were found in the medical
literature. Most descriptions of human toxicity come from case reports of individual exposures or
fromsmall case series. Among the 20 individuals described in case reports, the group most frequently
affected by DEET exposure were children and the most commonly reported effects involved the
nervous system (Osimitz and Murphy, 1997).
Several factors suggest that DEET is not responsible for the symptoms reported by some veterans
of the Persian Gulf War. First, the product appears to have adverse effects only on a very small
proportion of those who use it (Veltri et al., 1994). Second, the main adverse neurological effect
appears to be seizures, a condition not reported commonly among Gulf War veterans, although one
study of occupationally exposed workers has associated DEET with neurological symptoms with some
similarity to those experienced by Gulf War veterans (as reported by Osimitz and Murphy, 1997 and
Robbins and Cherniack, 1986). The symptoms were experienced at the time of exposure to DEET,
however; no long-term follow-up was reported. All clinical studies of adverse effects of DEET
suggest full recovery occurs after withdrawal of exposure. No literature is available to suggest that
topical use of DEET results in long-term health consequences.
Solvents are simple organic substances that are (1) liquid at room temperature, (2) relatively
non-reactive, and (3) able to dissolve a wide range of organic compounds (i.e., lipophilic). Most
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solvents are quite volatile. The primary uses of solvents in the PGW were as motor vehicle and jet
fuel, carriers for paint and coatings, and as an agent for control of airborne dusts blown from sand.
Solvents can affect the central nervous system (CNS), the peripheral nervous system (PNS), or
both. Short term exposure to organic solvents can cause reversible anesthesia-like depression of the
CNS. Long-term, heavy exposure to solvents may cause persistent, potentially irreversible
impairment in cognitive function and affect, which may be associated with structural changes in
neural tissue (NIOSH, 1987). Solvents can also cause impairment of peripheral nerve function
(Spencer and Schaumburg, 1985).
Peripheral nervous system effects are well-established for a few specific solvents, none of which
appear to have been used in the Persian Gulf (Spencer and Schaumburg, 1985). Acute, reversible
CNS effects (i.e., acute intoxication) are common with all solvents (Laine and Riihim�ki, 1986).
Chronic, apparently fixed, adverse effects of solvents on the CNS have been reported in the
literature, with general agreement that long-term occupational exposure to solvents is associated
with adverse effects on multiple CNS domains and that persons who suffer from such effects may
report symptoms similar to those reported by some Persian Gulf War veterans, including depression,
impaired concentration, and memory loss (Hanninen, 1986; Danish Ministry of the Environment,
1991; Hogstedt, 1994; Spurgeon et al., 1992; Rasmussen et al., 1993; White et al., 1995; Daniell et
al., 1993; H�nninen et al., 1991). The duration and intensity of exposure required to cause such
effects and the potential severity of such effects is somewhat controversial, although most authorities
agree that at least ten years of occupational (daily or near daily) exposure is required before effects
are seen (Mikkelsen et al., 1988). Exposures to organic solvents in the Persian Gulf appear to be of
insufficient duration, and may also have been of insufficient intensity, to produce chronic adverse
effects on the CNS.
In summary, multiple agents with potential toxicity to the nervous system were used by military
personnel in the Persian Gulf War. Such agents include pyridostigmine bromide, chemical warfare
agents (“nerve gas”), pesticides, heavy metals, DEET, and organic solvents. Each of these agents or
class of agents has been associated, in the biomedical literature, with acute or chronic toxicity to the
central or peripheral nervous systems.
Soldiers returning from the Persian Gulf have reported numerous symptoms compatible with
nervous system dysfunction including fatigue, headache, sleep disturbance, depression and memory
impairment.
The concurrence of exposures with potential toxicity to the nervous system and the reporting of
symptoms compatible with nervous system toxicity has lead to considerable scrutiny of a possible
causal association between them. Review of the biomedical literature suggests, at this time, that
neurotoxicity from exposure to pyridostigmine bromide, chemical warfare agents (“nerve gas”),
pesticides, heavy metals, DEET, and organic solvents is not a likely explanation for symptoms
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experienced by Persian Gulf War veterans. Reasons for this conclusion vary for each individual
agent or class of agents but include insufficient duration of exposure, evidence of insufficient
intensity of exposure, incompatibility of effects of exposure with symptoms reported by military
personnel, and the chronicity of illness following removal from exposure.
While currently available evidence does not support a neurotoxicological etiology for symptoms
reported by many Persian Gulf War veterans, some key issues remain unclear. To close these gaps
in knowledge, the following recommendations are made:
To better characterize the neurological health status of Persian Gulf War veterans, a large study
of a randomly selected sample of Persian Gulf War veterans and Persian Gulf War era veterans who
did not serve in the Gulf in which objective measures of neurological and neurobehavioral function
are used to assess neurological health should be performed.
Because clinical experience among healthy adults is limited, additional investigation of the
long-term human health effects of pyridostigmine bromide in among healthy adults should be
performed. Should pyridostigmine bromide be used by the US military in future conflicts, accurate
records should be kept to permit fruitful long-term assessment of dose-effect relationships.
To determine whether exposure to pyridostigmine bromide altered military personnel responses
to stress, investigation of the effect of pyridostigmine on physical and psychological responses to
perceived threat of physical harm should be performed.
Because exposure to hazards rarely occurs in isolation, investigation of the effects of combined
exposure to potentially toxic agents used in the Persian Gulf War should be performed. While such
investigationsmay necessarily be performed on animals, the exposures used should be similar in route
of administration, intensity, and duration to those experienced by humans under actual exposure
conditions.
Inthe future, better efforts should be made to characterize objectively both health and hazardous
exposuresamong US military personnel facing hazardous duty. Standardized, objective neurological
and neurobehavioral testing of military personnel before deployment would provide useful baseline
information about health status to which results of repeat testing, following deployment, could be
compared. Quantitative assessment of exposure to potential hazards would provide information to
compare to changes in health status that might be detected. The feasibility of such an effort should
be explored.
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Arch Int Med 155:262-268; 1995.
30. Presidential Advisory Committee on Gulf War Veterans’ Illness: Final Report (Washington,
DC: US Government Printing Office, December 1996).
31. Rasmussen K, Arlien-Soborg P, Sabroe S. Clinical neurological findings among metal
degreasers exposed to chlorinated solvents. Acta Neurol Scand. 1993; 87:200-204.
32. Robbins PJ, Cherniack MG. Review of the biodistribution and toxicity of the insect repellent
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33. Rosenstock L, Keiffer M, Daniell WE, McConnell R, Claypoole K, et al. Chronic central
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34. Savage EP, Keefe TJ, Mounce LM, Heaton RK, Lewis JA, Burcar PJ. Chronic neurological
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40. Steenland K, Jenkins B, Ames RG, O’Malley M, Chrislip D, Russo J. Chronic neurological
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45. Valciukas JA, Lilis R, Eisinger J, Blumberg WE, Fischbein A, Selikoff IJ. Behavioral indicators
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Report of the Special Investigation Unit on Gulf War Illnesses
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PERSISTENT HEALTH EFFECTS OF PESTICIDES AND OTHER
CHEMICALS USED IN DESERT STORM AND DESERT SHIELD
Prepared by: Matthew Keifer, M.D., M.P.H., Occupational and Environmental Medicine
Program, Departments of Medicine and Environmental Health, Harborview Medical Center,
University of Washington, Seattle, Washington.
T
his report reviews the classes of pesticides, nerve gas, and prophylactic medication
(pyridostigmine bromide) to which the Gulf War (GW) personnel were exposed, or potentially
exposed, for the possibility that such exposure might be responsible for the chronic health problems
known collectively as the Gulf War Syndrome. Recommendations for future research are also
included.
Several different types of pesticides were imported to the Persian Gulf and acquired locally by
Americanforces during Desert Storm and Desert Shield. While use patterns of neither imported nor
locally acquired pesticides are documented, the quantities of imported pesticides are documented.
Most of the imported pesticides were insecticides or repellents. Pesticides are by nature poisons most
ofwhich affect the nervous system. The potential for long term health effects resulting from exposure
to many of these chemicals has been demonstrated in numerous studies and case reports with the
nervous system being the principal focus of the majority of these reports.
The oganophosphates, a potent class of pesticides, appear to have been imported in large
quantities. These chemicals have been clearly identified in many studies as a cause of both central
and peripheral chronic neurological effects in persons who have sustained a heavy exposure (Keifer
1997,Rosenstock 1991, Steenland 1994, Savage 1988, McConnell 1994, Lotti 1986). It is important
to note that nearly all cases of chronic neurological effects attributed to organophosphates resulted
from overexposure which caused acute severe clinical illness. Most studies of subjects who have
sustained less severe exposures or only chronic low level exposure have not observed these chronic
neurological outcomes (Ames 1995, Fiedler 1997, Engel 1998).
One organophosphate, chlorpyriphos, which was shipped in large quantities (1580 gallons pure
active ingredient, 3841 gallons of formulated product) and has been identified as capable of causing
peripheral neuropathy in human beings following heavy exposure (Lotti 1986, Kaplan 1993), has
recently come under careful scrutiny in the US because of its extremely broad use by both private
citizens and pesticide applicators. The Health Effects Division of the Environmental Protection
Agency reviewed the published literature and unpublished case reports and concluded that
chlorpyriphos “may be a significant cause of chronic neurobehavioral effects”. Unfortunately the
report provided no exposure context in which these “chronic effects” might be expected to occur
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(Blondell1997). A recent study of morbidity by investigators from the manufacturer of chlorpyriphos
identified an elevated risk for five diagnostic categories among its employees exposed to
chlorpyriphos: 1. diseases of the ear and mastoid process; 2. acute respiratory infections; 3. other
diseases of the respiratory system; 4. general symptoms, signs, and ill defined conditions; and 5.
symptoms, signs and ill defined conditions involving the digestive system. (Burns et al. 1998). The
illness categories identified by these investigators as showing higher rates in exposed workers reflect
a broad assortment of signs and symptoms but of particular interest is the inclusion of the general
symptoms category (numbers 4, ICD9 780-799).
The medical conditions included in this category are generally those that do not permit strict
disease diagnosis by clinicians but interestingly this symptom category is the same as the third most
common diagnosis identified by the Comprehensive Clinical Evaluation Program (CCEP) in
evaluating 20,000 Persian Gulf veterans (Joseph et al. 1997). This overlap of diagnosis between
workers exposed in an industrial setting and personnel exposed during the Gulf War experience
potentially to the same chemical is intriguing. However, it should be pointed out that the situations
are not directly comparable. How this chemical was used by personnel in the Gulf is not clearly
documented (IOM 1996) where as exposure to the chemical is estimated in the Burns study.
Additionally the workers who were reporting these illnesses through the company medical program
were presumably actively exposed at the time of their reported illnesses and the CCEP study group
was examined and questioned at time when presumably exposure to chlorpyriphos had ceased.
Before conclusions that an excess prevalence of this diagnostic category in the CCEP study
population is reached an adequate control population would be needed. There was no association
drawn in either the EPA report or the morbidity study between chlorpyriphos and peripheral
neuropathy, a condition affecting 0.2% of 20,000 veterans examined by the CCEP (Joseph et al
1997).
The other organophosphate pesticides included in the list of imported pesticides include one,
dichlorvos, which has been identified in animal models as an inducer of peripheral neuropathy.
However this chemical as used in the Gulf was enclosed in pest strips making significant
overexposure less likely. No reports were found in the literature that environmental exposure to
these pest strips caused significant illness or peripheral neuropathy.
The N-methyl-carbamates were imported in large quantities and while sharing the acute
toxicological characteristics of organophosphates, have only rarely been associated with persistent
health effects, and then only after chronic heavy exposure (Ecobichon et al 1982). The carbamates
are in the same family of chemicals as pyridostigmine, the chemical used to prophylax personnel
against nerve gas in the gulf. The pyrethroids, another category of pesticides, were brought over in
large quantities, but are of relatively low acute toxicity and appear to be relatively safe pesticides
(Aldridge 1990, He 1994).
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Aluminum phosphide, a fumigant, was also imported in substantial quantities (20,020 tablets).
These chemical tablets produce phosphine gas when combined with water. Phosphine is a very toxic
gas which can produce severe illness in the setting of sufficient exposure. The illness produced by
phosphine exposure would not be easily overlooked (Morgan 1989). Furthermore, based on how
aluminum phosphide is generally used it is highly unlikely that low dose exposure to phosphine
occurred. There is no evidence in the literature that chronic illness results from low dose exposure
to phosphine.
In the absence of massive overexposure, each of these pesticides by itself, organophosphates, n-
methyl-carbamates and pyrethroids, or phosphine, is not likely to have resulted in chronic health
effects among even a substantial minority of U.S. troops.
Diethyl-m-toluamide (DEET) was imported in large quantities and presumably used widely as an
insect repellent during the conflict (DOD on Aug 27, 1997 to Senator A. Specter). It is also widely
used by the U.S. population in general and given its broad use (30+ % of the US population), the
chemical has a reasonably good safety record (Veltri 1994). Case reports indicate that this chemical
can induce central nervous system effects when absorbed in sufficient quantity but cases usually
involve excessive exposure and often involve young children or infants. No reports in the literature
describe the long term toxicity of DEET among humans with low level chronic exposure though
some permanent residual effects have been noted in at least one case following recovery from what
appeared to be an acute intoxication (Knowles 1992). The possibility that even relatively heavy
exposure to DEET alone could induce chronic health effects in the Gulf personnel is unlikely.
Pyridostigmine bromide (PB), used by the U.S. forces as a prophylactic agent against the toxicity
of nerve gas has demonstrable toxicity for both animal models and humans when given in relatively
high dosage. The standard 30 mg three time per day dosage provided to U.S. forces may have caused
acute toxicity in particularly susceptible populations such a asthmatics or soldiers with a unique
serum cholinesterase phenotype (Loewenstein-Lichtenstein 1995), or in soldiers who received high
per weight dosage because of small body mass (Gouge 1994) but this dosage has been shown to be
generally well tolerated by the majority of the population (Blick 1994, Borland 1985, Cook 1992,
Glikson 1991).
Studies on animals suggests that under stressful situations the lack of central nervous system
penetration which makes PB an attractive prophylactic may not be assured. This central nervous
system penetration may lead to acute central nervous system symptoms. Symptom persistence
resulting from this increased penetration has not been reported to date in human or animal models,
although evidence from one study presented indicated that a central nervous system feedback
mechanism may account for changes which may outlast the acute cholinergic effects of the drug
(Freidman et al 1996).
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No information was found as to whether the bromide in the preparation might have had
deleterious effects given bromide’s long half-life and the desert conditions of chronic high heat and
salt depletion. Despite these caveats, the years of experience in treating patients for myasthenia
gravis with PB at doses often much higher than those taken by Gulf War service personnel would
suggest that the development of persistent health effects among Gulf War personnel from PB alone
isunlikely. The pyridostigmine is rapidly metabolized and the bromide is excreted over several weeks
once the drug administration is stopped. The penetration of the blood brain barrier by
pyridostigmine under the stress of a combat situation may potentially result in acute effects given
sufficient blood levels, but with metabolism of the drug and the reversal of the acute effects, it is
unlikely that long term effects would ensue.
The health effects of exposure to nerve gases has been only periodically addressed in the
mainstream literature. One excellent study which examined most of the important nerve gases for
production of peripheral neuropathy showed that sarin was capable only at super-lethal doses of
potentiallyinducing neuropathy (Gordon et al. 1983). Few cases of known human exposure to nerve
gases are available to examine for long term effects, so predictions must be modeled mostly from
animal experiments. The Center for Disease Control concluded in 1988 that there appeared to be
little risk of adverse health effects from low level long-term exposure to GA, GB, VX, H, HD, HT
or lewisite (CDC 1988). In a review of the literature on nerve agents, Gunderson et al. concluded
that persistent effects such as psychological and behavioral problems, could result after acute
exposure, but that no evidence supported persistent effects from low level exposure to these
chemicals (Gunderson et al.1992). A recently published study on survivors of the Japanese subway
sarin gas incidents identifies possible delayed effects on balance among surviving female victims.
These authors also cite an as yet unpublished manuscript identifying neurobehavioral abnormalities
among other victims 6-8 months after the poisoning (Yokoyama et al. 1998). These findings are
consistent with problems identified among persons previously poisoned with organophosphate
pesticides (Keifer et al. 1997, Steenland et al.1994, Rosenstock et al. 1991, McConnell et al. 1994,
Savage et al.1980, Lotti et al. 1986), which are related to the military nerve gases. The literature
does not provide evidence to support persistent neurological or other health effects from low-level
exposure to nerve gases.
From the information presently available, it does not appear that the DOD has a policy for
monitoring cholinesterase or for assessing the physiological effects of the prescribed standard
prophylactic dose of pyridostigmine bromide. The broad application of cholinesterase monitoring
for all those taking PB doses would probably not be beneficial. Most people taking the drug would
probably have a very predictable response to the dosage. The drug generally appears to be safe when
takenby individuals of average size (70 kg), with normal uninhibited cholinesterase activity and with
no illnesses which would make them particularly susceptible to ill effects from the PB. However,
there is a substantial minority of individuals who may be smaller in stature, have illnesses such as
asthma or, in rare cases, have congenitally low cholinesterase which makes them sensitive to PB even
when taken in the prescribed dose. A mechanism should be in place to identify those who might
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Report of the Special Investigation Unit on Gulf War Illnesses
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suffer ill effects and determine how their dosage should be adjusted in order to avoid complications
while still providing protection from nerve gases.
Cholinesterase monitoring has long been used among pesticide applicators to identify
overexposure to organophosphates. It also can potentially be used to identify personnel exposed to
organophosphate nerve gas. Accurate interpretation requires a pre-exposure baseline on a subject
against which to compare subsequent values. This limitation, and problems with the accuracy of
commerciallyavailable test kits, makes cholinesterase testing complicated. Recently, a new approach
to identifying overexposure to organophosphate nerve gas has been described. This method
reactivates inhibited cholinesterase and reconstitutes the nerve gas molecule which can then be
measured (Polhuijs et al. 1997). If this technique shows itself to be sound, it has potential
application in determining whether personnel have sustained exposure to nerve gas even several
weeks after exposure.
The potential for chronic health effects resulting from mixtures of chemicals and from mixtures of
pyridostigmine bromide and pesticides is a subject of interest and recent investigation, though relatively
little has been published to date. Studies on laboratory animals have demonstrated that in sufficient
dosage, damage to the nerves of the body can occur with mixtures of some of the chemicals used by
service personnel in the Gulf War conflict (Abou donia 1996a & b). An important caveat to these
studies is that the dosages used to induce these damages were well above what would have been
expected to occur by regular use of these chemicals. Studies of the effects of DEET on the absorption
of pyrethroids and carbaryl (an n-methyl-carbamate) do not support the contention that more
chemical is absorbed in the presence of DEET (Baynes et al 1997).
SUMMARY
A
fair degree of uncertainty surrounds the exposures that may have occurred to personnel during
Desert Shield and Desert Storm. Nevertheless, based on the information available in the
literature regarding the pesticides and anti-personnel chemicals to which troops may have been
exposed in the GW, chronic health effects would not be expected in any significant number due to
low level exposure to these chemicals or to combinations of these chemicals. A small percentage of
the population may have had reactions to these chemicals not predicted by animal research or
human studies and given exposure sufficient to result in acute toxicity, chronic problems would not
be surprising. Information sited in this report does raise questions about the possible non-specific
symptoms reported by a substantial percentage of CCEP subjects and how this might relate to
pesticide exposures which occurred in GW personnel. This relationship is uncertain but intriguing.
The use of PB by the Gulf War personnel would probably not cause significant illness in most
individuals but might cause problems in some with small stature, asthma or unique biochemistry.
The two greatest limitations in identifying illness due to exposures in a theater of war are the virtual
absence of exposure information and the difficulty of evaluating the health status of a self-selected
group. In future conflicts, better collection of exposure information and prospective follow-up of a
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176
statistically valid sample of the combatant population with an appropriate non-combatant control
group would facilitate the identification and characterization of emerging illnesses.
RECOMMENDATIONS
A
sincere and scientifically valid effort to explore and address health concerns of veterans from
military conflicts is an extremely important responsibility that our government has toward its
veterans. But communicating in an open, non-defensive manner with the concerned service
personnel and the public about the state of knowledge and the progress of knowledge is potentially
the greatest challenge facing the Department of Defense and the Veterans Administration with
regard to issues of post conflict health of veterans. While the health problems from which Gulf War
veterans suffer may never be completely ascribed with certainty to specific exposures that occurred
during service in the Gulf, the challenge of identifying, and caring for the health of veteran’s and
responding to the health concerns of veterans will continue as long as there are veterans. Effective
risk communication is essential to maintaining and optimized three way dialog between the veteran-
active duty community, the citizenry and the responsible government branches.
SPECIFIC RECOMMENDATIONS
T
his author can not substantially improve on the scientific comprehensiveness of the
recommendations made by the Institute of Medicine on improving the surveillance and
monitoringcapabilities of the DOD regarding health effects of combat service (Institute of Medicine,
IOM,1996). I do believe it is important to add that the IOM report fails to recommend a mechanism
whereby the veterans, the U.S. public and active duty personnel might participate in the functioning
of an ongoing system of health outcomes monitoring. Potentially the most important predictor of
success of this program as judged by these constituencies is the degree to which they can claim
ownership of the process. I strongly encourage that a mechanism be established to assure active
participation by representatives of the U.S. public, veterans groups and active duty personnel of
varied ranks and branches in the design and conduct of any program that is adopted. A mechanism
should also be established to regularly communicate with all veterans providing them with ongoing
information about new developments and knowledge regarding the effect of service and health.
RESEARCH IN BASIC AND APPLIED SCIENCE
S
upport for further research on technology for detecting environmental release and personal
exposure to war gases should be a particular emphasis of the DOD. Monitors should be
developed that are portable, collect and report real time information, and have data storage
capabilities and are easily applied by combatants.
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Research should be undertaken to develop profiles of individuals who may potentially suffer
untoward effects from war gas antidotes (e.g. asthmatics, smaller individuals). Those individuals
should have personal drug dosing profiles developed and confirmed by cholinesterase activity levels
appropriate to the prophylactic medication taken. Routine cholinesterase testing of all personnel
is probably not warranted, but the test should be available on a routine basis for evaluating ill
combatants both for overdose of prophylactic medication and for evaluating war gas exposure.
A new technique described by Polhuijs (1997) potentially represents a very significant
breakthrough in the detection of cholinesterase inhibited by the nerve gas sarin. Whether this
technique is applicable to other nerve gases and pesticides has not been demonstrated to date. This
technique should be explored and amplified if possible for application to exposure assessment of
subjects potentially exposed to nerve gases and pesticides.
REFERENCES
1.
Abou-Donia MB, Wilmarth KR, Abdel-Rahman AA, Jensen, KF, Oehme FW, Kurt TL:
Increasedneurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and
chlorpyrifos. Fundam Appl Toxicol 1996; 34:201-222.
2.
Abou-Donia MB, Wilmarth KR, Jensen KF, Oehme FW, Kurt TL: Neurotoxicity resulting
from coexposure to pyridostigmine bromide, DEET, and permethrin: Implications of Gulf War
chemical exposures. J Toxicol Environ Health 1996; 48(1):35-56.
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Aldridge WN. An assessment of the toxicological properties of pyrethroids and their
neurotoxicity. Crit Rev Toxicol 1990; 21(2):89-104
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Ames RG, Steenland K, Jenkins B, Chrislip D and Russo J. Chronic neurologic sequelae to
cholinesteraseinhibition among agricultural pesticide applicators. Arch Environ Health 1995;
50:440-444.
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Baynes R, Halling K, Riviere J. The influence of diethyl-m- tolumamide (DEET) on the
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144:332-339.
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Blick DW, Murphy MR, Brown GC, Yochmowitz MG, Fanton JW and Hartgraves SL. Acute
behavioral toxicity of pyridostigmine or soman in primates. Toxicol Appl Pharmacol 1994;
126:311-318.
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