Iraq invaded Kuwait in August 1990. The United States and several other na-
tions responded to this invasion by sending troops to the Persian Gulf. After a
period of preparation, these troops fought both an air and a ground war.
Hostilities ended in March 1991 after less than three months of combat. The
Department of Defense (DoD) has estimated that nearly 700,000 U.S. troops
served in Operations Desert Shield and Desert Storm (ODS/DS).
Many veterans of that conflict have reported a range of health problems. The
most commonly reported symptoms include joint pains, sleep disorder, mem-
ory loss, and fatigue. Some of these symptoms are self-reported more fre-
quently by Gulf War veterans than by persons who did not deploy to the Gulf.
These reported health problems are of continuing concern to veterans and
policymakers alike. This concern has prompted efforts to evaluate whether
exposures of veterans to various risk factors during ODS/DS might be linked to
their reported symptoms.
PURPOSE OF THE STUDY
This report is part of the ongoing effort to gain a better understanding of the
possible causes of undiagnosed symptoms reported by some ODS/DS veterans.
It examines the scientific literature on the potential health effects of pesticides
that were present during ODS/DS. A majority of the American troops who
served in the conflict probably were exposed to pesticides, including repellents.
Although toxicity may vary by individual, improper use of certain classes of pes-
ticides can result in symptoms similar to those reported by some Persian Gulf
War veterans (PGWV).
This report reviews literature on 12 of the 35 pesticides that are likely to have
been used during ODS/DS. It focuses on these 12 because the Office of the
Special Assistant for Gulf War Illnesses (OSAGWI) considers them to be of po-
tential concern because of either toxicity or expected exposure:
One organochlorine pesticide (lindane)
One repellent (DEET)
Two pyrethroid pesticides (permethrin, d-phenothrin)
Five organophosphate pesticides (azamethiphos, chlorpyrifos, diazinon,
Three carbamate pesticides (bendiocarb, methomyl, propoxur)
This review summarizes reports in the scientific literature of known pesticide
exposures or doses and related health outcomes. It should be read in conjunc-
tion with two other studies: Pesticide Use During the Gulf War: A Survey of Gulf
War Veterans (Fricker et al., 2000), a review of the findings from a survey of
some 2,000 PGWV regarding patterns of pesticide use during the Gulf War; and
Pesticides Environmental Exposure Report (OSAGWI, 2000), a report being pre-
pared by OSAGWI that investigates pesticide exposures during ODS/DS and
draws conclusions based on all the available evidence.
Lindane belongs to the organochlorine pesticide class. Few organochlorines
are in use today, and lindane has not been produced in the United States since
1977, although it is imported in multiple forms for pharmacological and indus-
trial use. Lindane has been used on a wide variety of insect pests in agricultural,
public health, and medicinal applications. However, the U.S. Environmental
Protection Agency (EPA) restricts its use, and it can be applied only by certified
Two lindane products were shipped to the Gulf, where they were used in dust
form during ODS/DS as delousing agents. The primary route of potential ex-
posure in veterans was dermal; lindane can be absorbed efficiently through the
skin. The dust formulation used in the Gulf would also make inhalation a fea-
Lindane has been used for many years, is well known, and has been extensively
studied. Its effects are primarily neurotoxic. Lindane generally produces a
rapid response and was designed to increase insect respiration to lethal levels.
Acute human exposure can result in neurologic changes, including hyper-
excitability, tremor, seizure, and coma. The symptoms are generally reversible
with supportive care, although ingestion of large amounts of lindane has re-
sulted in death. Epidemiologic studies in the literature also suggest the possi-
bility of subtle long-term neurologic and reproductive health effects; however,
subjects in these studies were exposed to a number of different potentially toxic
substances, making it difficult to attribute findings specifically to lindane.
Acute human exposure has usually resulted from accidents either in the manu-
facture of lindane or in its application in agricultural settings. Acute symptoms
reported in humans exposed to lindane include headache, nausea, vomiting,
restlessness, ataxia (loss of muscular coordination), tremor, and excitability.
Seizure has been reported with more extensive exposures, although specific
levels at the times of exposure are not reported.
Few studies specifically evaluate the effects of chronic dermal exposure to lin-
dane, since the intended use of lindane for treating parasitic infection (e.g., lice)
generally requires only a single application. However, some studies document
human hematological manifestations, including bone marrow hypoplasia and
aplastic anemia, following prolonged dermal exposures.
Individuals employed in the manufacture of lindane are exposed to a combina-
tion of hexachlorocyclohexane (HCH) isomers (chemical forms) with different
effects in biological systems. (Lindane is the gamma isomer.) Humans are also
exposed to lindane as an environmental toxicant. Lindane has been used in va-
porizers and included among other chemicals in wood preservatives and has
been used as an agricultural pesticide. Some situations have precipitated unin-
tentional prolonged exposures to low levels of lindane in the environment. Re-
ports in the literature are either anecdotal or of an epidemiologic case-control
nature, where subjects may have been exposed to a number of chemical toxi-
cants simultaneously, making it difficult to attribute specific effects to individ-
ual chemical exposures.
Because of the potential risks associated with lindane, its use is no longer rec-
ommended as the first-line drug therapy for treating scabies and body lice. Al-
though it should be used with caution, when used appropriately, lindane is
generally considered a safe and effective pesticide.
N,N-Diethyl-m-toluamide, also known as DEET, is an aromatic amide that re-
pels a wide range of insects. DEET was first developed by the U.S. Department
of Agriculture for military use in 1946, and it has been estimated that approxi-
mately 38 percent of the U.S. population uses DEET-containing repellents an-
nually. DEET insect repellent is part of a complete repellent system used by
U.S. military personnel. Three different DEET products were shipped to the
Gulf, where they were applied to the skin in cream, liquid, or stick forms. Until
1989, the standard-issue insect repellent of the U.S. military consisted of 75 per-
cent DEET in an alcohol base. This has been replaced with a slow-release,
polymer-based product containing 33 percent DEET, which is also available to
the general public.
DEET can enter the body through several pathways, including dermal and ocu-
lar exposures, inhalation, and ingestion. It is an ideal permeant of skin and has
been reported to accelerate the dermal penetration of pharmaceuticals, raising
the concern that DEET may also increase dermal penetration of pesticides,
since they are often used together. Uncertainty about how much DEET humans
absorb complicates any assessment of effects. Generally, the magnitude of
DEET that permeates the skin is closely related to the repellent formulation.
Animal studies have shown DEET to affect the cardiovascular and nervous sys-
tems. As with many pesticides, the majority of health effects reported to be
caused by DEET result from acute exposure. In fact, no evidence in the litera-
ture suggests that chronic low-level exposure to DEET will result in long-term
effects (with the exception of rare reports of scarring). Therefore, there is no
evidence to suggest such a scenario is of great concern in predicting the poten-
tial health effects of DEET on PGWV.
Most reviews of DEET toxicity conclude that the risk of adverse effects from the
use of DEET-containing repellents as directed by the label appears low. This
conclusion is based on reviews of human effects reports, animal toxicology, and
possible alternate etiologies for symptoms reported in most patients. In fact,
hypersensitivity may be required for severe acute toxic effects to occur, and a
suite of data from animal studies generated to support DEET registration pro-
vides no evidence of adverse long-term effects related to DEET exposure. Gen-
erally, patients who are reported to present severe symptoms related to DEET
use recover without reported further effects.
A correlation between the concentration of DEET in a repellent and the fre-
quency or severity of effects is not supported by the literature. Further, it is dif-
ficult to quantify consistently the temporal relationship between the onset of
central nervous system (CNS) symptoms and exposure to DEET, but the reac-
tion is generally rapid, as is the resolution in most cases. There have been rela-
tively few severe adult effects related to DEET exposure. While a pattern of po-
tentially severe neurotoxicity in children who have been exposed to DEET is
emerging, the total number of reported cases is very small compared with the
population exposed. This pattern has not been observed in adults. The reasons
for this disparity are unknown but may relate to a different surface-area-to-
volume ratio in children than in adults.
Concern about the interactive effect of DEET with other chemicals may be war-
ranted, but the available literature is not adequate to permit definitive conclu-
sions at this point. As difficult as it is to extrapolate the results of animal studies
to long-term human effects, the presence of chemical interactions compounds
the uncertainty inherent in this process. This is not to say, however, that fur-
ther research should not be undertaken. A prudent approach may be first to
determine more accurately which exposures warrant further study. Research to
explain the broad variety of outcomes associated with DEET exposure may also
be warranted, especially to explain cases of hypersensitivity.
Pyrethroids are synthetic pesticides based on the pyrethrins, which are derived
from chrysanthemums. Pyrethrins are a “natural” environmental product that
is of low toxicity to mammals. They degrade quickly in sunlight, and the cost of
reapplying them has limited their widespread agricultural use. Pyrethroids
have been synthesized to be similar to pyrethrins but more stable in the envi-
ronment. Some commercial pyrethroid products also contain organophos-
phate (OP) or carbamate insecticides because the rapid paralytic effect of
pyrethrins on insects is not always lethal. Pyrethroids are formulated as emul-
sifiable concentrates, wettable powders, granules, and concentrates.
Two pyrethroid pesticides are of interest in the Gulf War setting: permethrin
and d-phenothrin. As part of the DoD Insect Repellent System, permethrin was
issued in ODS/DS as a ready-to-use insect repellent labeled for use on clothes
such as the battle dress uniform (BDU) and bed netting. The second com-
pound, d-phenothrin, is an indoor-use aerosol insecticide, used most com-
monly for spraying bed netting (to kill insects trapped inside after installation)
or spraying inside aircraft to prevent transport of insects.
The literature discussing permethrin stresses its relative safety. Individuals with
occupational exposure have been reported to experience facial skin sensations
(burning or itching), usually within a few hours of exposure. Ingestion of per-
methrin has resulted in epigastric pain, nausea, and vomiting. Acute poisoning
symptoms relate primarily to the effects of pyrethroids on the nervous system
and include dizziness, headache, nausea, anorexia, and fatigue. Very large ex-
posures cause muscle fasciculation and altered consciousness.
After permethrin was introduced as an alternative treatment for head lice in
humans, data were gathered regarding possible adverse effects. Approximately
2.2 adverse events were reported per 1,000 administrations. These events, al-
though perhaps underreported, were not clinically serious. The most common
ones were itching and a rash. Other effects (e.g., shortness of breath, gastro-
intestinal effects) occurred in a few patients.
Data on chronic human exposure to permethrin come primarily from studies of
pest-control workers and clinical evaluation of patients treated for scabies and
lice infestations. Data again support the conclusion that permethrin is ex-
tremely safe when used in conventional applications. Furthermore, reproduc-
tive studies do not show any attributable adverse impact from fairly high doses
of permethrin. Animal studies of subacute and chronic exposure, even at high
doses, generally fail to show any lasting effects. Only at extremely high doses do
animals begin to demonstrate evidence of neurologic impairment.
We uncovered few references for d-phenothrin. Those that were available re-
peatedly address the relative safety of this insecticide and the pyrethroids in
general. The effects of d-phenothrin on animals include acute toxicity but only
at extremely high doses and in routes inconsistent with conventional exposure
of humans. Similarly, studies of the chronic effects of d-phenothrin on animals
show toxicity but only at extremely high oral doses. Even at these high expo-
sures, reproductive, genetic, and carcinogenic effects were not observed. The
literature does not provide evidence of d-phenothrin toxicity to humans.
Pyrethroids, particularly permethrin and d-phenothrin, are safe and effective
when used in recommended applications. Studies show that these compounds
are potentially toxic at extremely high exposures; however, when used in con-
ventional ways, only minor skin irritation in sensitive individuals results, and
the irritation subsides after short periods when the irritant is removed.
Organophosphate Compounds. Organophosphate (OP) compounds were first
synthesized in significant amounts during the 1940s, when tetraethylpyrophos-
phate was developed as an insecticide.
Azamethiphos is an OP pesticide that was probably procured locally during
ODS/DS as a fly bait. It has been used in Canada, Scandinavia, the United
Kingdom, and France to control sea lice infestations and in Mexico, primarily
for fly control. Commercially available azamethiphos products include Al-
facron 10 and Snip. Alfacron 10 is used as a wettable powder, and Snip is a 1
percent azamethiphos granular fly bait. Both were reported to have been used
during ODS/DS, and both were probably obtained locally.
Chlorpyrifos is a broad-spectrum insecticide. It is registered for a variety of uses
and sites and is effective in controlling cutworms, corn root worms, cock-
roaches, grubs, flies, termites, and fire ants. It is available in a variety of formu-
lations, including granules, wettable powder, dustable powder, and emulsifi-
Diazinon is an insecticide used to control cockroaches, silverfish, ants, and fleas
in buildings. Diazinon is also commonly used in home gardens and on farms to
control a wide variety of sucking and leaf-eating insects. It is available in dust,
granules, seed dressings, wettable powder, and emulsifiable solution formula-
Dichlorvos is effective against flies, aphids, spiders, and caterpillars. It acts
against insects as both a contact and a stomach poison. Dichlorvos is used as a
fumigant and has also been used to make pet collars and pest strips.
Malathion is a wide-spectrum insecticide. It is used to control sucking and
chewing insects on fruits and vegetables and also to control mosquitoes, flies,
household insects, and animal parasites. During ODS/DS, malathion was pri-
marily intended for use as an outdoor spray to control mosquitoes and flies.
Potential Health Effects of Organophosphates. OP agents bind to and inhibit
the normal action of acetylcholinesterase (AChE), an enzyme. Acetylcholine
(ACh) is a major nerve-signaling chemical that acts as a chemical messenger
both in the brain and elsewhere in the body. AChE serves a critical role in regu-
lating nerve signaling to other nerve cells or to muscle cells. When AChE is in-
hibited by an OP, an excessive accumulation of ACh occurs in the synapse, fol-
lowed by excessive binding of ACh to the receptors on the receiving cell. Con-
sequently, cells are excessively stimulated.
In cases of toxicity from OP exposure, symptoms can range from mild tremors
to more severe muscle contractions, impaired cognition, dizziness, shortness of
breath, and vomiting. In severe cases, respiratory failure and death can result.
Other effects include excess secretions (sweating, tearing, and salivation),
bradycardia, miosis, insomnia and sleep abnormalities, headaches, dizziness,
effects on mood (depression and anxiety), effects on personality (aggressive-
ness, irritability, and paranoia), effects on cognition (confusion, and en-
hancements and reductions in measures of attention, concentration, memory,
learning, and psychomotor speed), tremor, ataxia, dysarthria, hypotension,
respiratory depression or arrest, convulsions, and coma.
The severity of acute symptoms relates to the amount and route of exposure.
There were no systematic reports in the literature of acute toxicity resulting
from any pesticide exposures during ODS/DS. For this reason, this report fo-
cuses primarily on chronic exposures and long-term effects, as chronic health
effects are of greater relevance to Gulf War illnesses.
As with other pesticides, most of what is known about the effects of persistent
OP exposure in humans is based on observational studies. These studies are
usually focused on occupational exposures, and they commonly involve a
mixture of pesticides and possibly other compounds. Many of the studies in-
volve assessing symptoms of a study group that is exposed to pesticides sea-
sonally. Further, a combination of acute and chronic exposures and effects is
often present, and this combination is usually undefined. Other knowledge is
gained from case reports, many of which involve household pest control. These
types of studies were reviewed for the reported ranges of chronic symptoms as-
sociated with OP exposure, including fatigue, joint and muscle symptoms, sleep
effects, headaches, skin effects, cognitive effects (memory loss, confusion),
mood effects, and neurological effects. These classes of symptoms are also seen
frequently in ill PGWV.
Carbamate Compounds. The use of carbamates as insecticides began in the
1950s, and approximately 25 carbamate compounds are in use today as pesti-
cides or pharmaceuticals. Carbamates are among the most popular pesticides
for home use, both indoors and on gardens and lawns.
Bendiocarb is a broad-spectrum insecticide used to control disease vectors,
such as mosquitoes and flies, and household and agricultural pests. Most for-
mulations of bendiocarb are registered for general use, except for Turcam and
Turcam 2.5G, which are restricted products. Perhaps the best known
bendiocarb product is Ficam. Formulations include dusts, granules, ultra-low-
volume (ULV) sprays, and wettable powders. Bendiocarb was primarily
available during ODS/DS as a wettable powder for indoor surface treatment.
The EPA classifies methomyl as highly toxic to humans and restricts its use.
Methomyl was introduced in 1966 as a broad-spectrum insecticide and was first
registered in 1968. It was re-registered in 1998, with the U.S. EPA concluding
that methomyl products did not pose unreasonable risk to humans or the envi-
ronment when labeled and used correctly. Methomyl can be formulated as a
wettable powder, a soluble concentrate or liquid, a dust, or a solid bait. It was
intended to be used exclusively as a fly bait during the Gulf War.
Propoxur was introduced in 1959 as an insecticide, and it was first registered in
the United States in 1963. Like methomyl, it has both contact and systemic ac-
tivity against insects and is used on a variety of pests in both agricultural and
other applications. Propoxur is a general-use pesticide, although some formula-
tions may be for professional use only. Propoxur is characterized as having a
fast knockdown and long residual effect, which makes it a popular choice for
pest control. It is used primarily indoors, with limited outdoor applications.
Propoxur is available in a variety of formulations, including emulsifiable con-
centrate, wettable powder, dustable powder, granules, aerosol generator,
smoke generator, and baits. During ODS/DS, propoxur (Baygon) was available
to control pests in cracks and crevices (e.g., cockroaches) and could also be
sprayed on building surfaces and screens to control pests outdoors.
Potential Health Effects of Carbamates. Carbamates have the same presumed
primary mechanism of toxicity that characterizes OPs: They are AChE in-
hibitors. For this reason, OPs and carbamates are often considered together.
But whereas OPs irreversibly inhibit AChE, requiring more enzyme to be pro-
duced for function to be restored, carbamates inhibit the enzyme reversibly.
The body of literature regarding the acute and chronic effects of carbamates is
largely covered in the discussion of OPs.
Symptoms found to occur following exposure to AChE inhibitors such as OP
and carbamate pesticides include fatigue, joint and muscle symptoms, sleep
effects, headaches, skin effects, cognitive effects, mood effects, and neurological
effects. These classes of symptoms are also seen frequently in ill PGWV.
Part of the difficulty in evaluating possible effects of pesticides on PGWV is that
a number of factors confound the evaluation. Primary among these are the in-
herent differences among individuals and potential interactions among pesti-
cides and other influences, including drugs and the environment.
A number of individual differences complicate the analysis of the effect of pesti-
cides on PGWV. First, genetic differences occur among individuals. For exam-
ple, DEET is potentially more toxic to people with genetic or acquired defects in
ammonia metabolism, such as carriers of ornithine carbamoyl transferase
(OCT) deficiency. Second, many factors may affect the rate and magnitude of
pesticide absorption. Protective clothing and differences in skin properties and
integrity influence dermal exposure, and inhalation exposure may vary with
ventilation or as a result of other factors, including properties of airway mem-
branes. Furthermore, the rates at which pesticides are cleared depend on
amounts, genotype, and activity of enzymes involved in their metabolism.
Some evidence points to differences in metabolizing enzymes among PGWV.
Finally, individual differences in cofactors that modify the effect of pesticides,
are essential for metabolism of pesticides, or permit or inhibit toxic effects by
pesticides may contribute to differences in clinical effects. Such cofactors can
include vitamins C and E, phytochemicals, and cholesterol.
Pesticides in combination with other factors may exert effects different from
those experienced with pesticides alone. Moreover, effects from two pesticides
may differ from those expected from exposure to either separately. It is not
feasible to predict the toxicity of pesticide mixtures (or pesticides in combina-
tion with other exposures) on the basis of the results of the toxicity of single
compounds. Moreover, the number of possible combinations increases expo-
nentially with the number of agents as 2n; thus, 10 compounds have more than
1,000 possible combinations that could have different consequences. The ef-
fects of interactions may be additive, synergistic, or antagonistic, and the char-
acter of the interactions may differ for different effects of the compounds.
Nevertheless, it is possible that multiple exposures to pesticides and other
compounds occurred during ODS/DS, underscoring the need to further investi-
gate the nature of these potential exposures. Some data are available on inter-
actions of substances relevant to ODS/DS, including interactions among DEET,
pyridostigmine bromide (PB) (a carbamate drug given to protect against nerve
agents), and pesticides; among pyrethroids, OPs, and carbamates; and among
pesticides and drugs or other exposures.
DEET has been reported to enable other chemicals to penetrate the skin more
easily. A scenario involving a soldier using DEET, wearing a uniform treated by
permethrin, and taking PB is quite plausible. Data concerning the combination
of DEET, PB, and pesticides show a greater-than-additive effect when two or
three of the chemicals are present. However, the doses used in the studies of
these combinations were exceptionally high. For example, in one study, a 160-
pound subject would have to take 467 PB tablets and apply 76 tubes of a 33 per-
cent DEET solution to achieve an equivalent exposure. These levels make it
difficult to understand the implications for health effects at much lower levels.
However, the increased effect demonstrated when the compounds are used in
combination indicates that this phenomenon warrants further attention.
Effects on the ACh system constitute one mechanism by which interactions of
pyrethroids with OP and carbamate pesticides may occur (other mechanisms of
interaction are also possible). Some animal studies have found pyrethroids in
the fat and brain of exposed subjects and in poisoned cotton sprayers, so the
possibilities of interactions occurring even with a delay following pyrethroid
exposure remain a concern.
One report on PB characterizes interactions between that carbamate and heat,
stress, caffeine, nicotine, and antihistamines. Because other carbamates, as
well as OPs, share PB’s major pharmacological effect (AChE inhibition), the data
on potential interactions with these agents also have bearing. The use of PB in