APPENDIX ACHOLINESTERASE INHIBITORS AND MULITSYMPTOM

ILLNESSES
Numerous studies of Gulf War veterans have identified an association between self-
reported multisymptom illness and self-reported exposures to several cholinesterase-
inhibiting agents, including the drug pyridostigmine bromide (PB), cholinesterase-
and noncholinesterase-inhibiting pesticides, and the cholinesterase-inhibiting nerve
gases, sarin and cyclosarin. This appendix reviews some of the known health effects
that can result from these potential exposures and addresses the evidence potentially
linking those exposures to multisymptom illness, including what is often called Gulf
War illness. This appendix discusses how Gulf War veterans might have been
exposed to cholinesterase inhibitors, the physiologic and toxicologic actions of these
chemicals, and reviews some of the studies that have attempted to link various
chemical agents to symptoms indicative of cholinesterase inhibition of veterans.
When a person chooses to move a body part such as a finger, the brain sends a signal
first down through the spinal cord, then from the spinal cord out the nerves of the arm
and into the hand. The nerves carry an impulse down their length somewhat like an
electrical current is conducted down a wire. This impulse reaches the muscles of the
finger and the muscle contracts in response and the finger moves. These nerves, which
carry the signal, are long nerves called motor neurons. Despite the analogy, the
conduction of the impulse differs from electricity moving through a wire in several
respects. First, the impulse moves along the nerve as a result of the nerve cell
changing its internal charge from negative to positive along its length in a wave like
fashion. Second, when a nerve connects with the muscle it does not transmit the
electrical signal directly, like electricity crossing a wired junction, but instead the end
of the nerve fiber releases a chemical (called a neurotransmitter). This chemical
moves across a narrow space (called a synapse) between the nerve and the muscle and
binds to molecules on the surface of the muscle that are concentrated around the
synapse. When the neurotransmitter binds to these molecules, the molecules cause a
change in the membrane of the muscle cell, which causes the muscle to contract. This
same phenomenon of nerve impulse and chemical transmitter crossing a synapse
occurs when nerves connect to other nerves, and when nerves connect to glands, such
as the salivary glands. In these situations, the neurotransmitter crossing the synapse
results in the continuation of the nerve impulse or the secretion of the gland.
There are several neurotransmitters in the body, with acetylcholine being one of the
most common. Neurons that use acetylcholine as a neurotransmitter are referred to as
cholinergic. The enzyme cholinesterase plays an essential role in terminating the
chemical signal between a cholinergic neuron and the nerve, muscle, or gland that is
being stimulated. Acetylcholinesterase (AChE) acts to quickly metabolize
acetylcholine into choline and acetic acid, rendering it inactive. It is critical for the
normal function of the nervous system. When AChE is inhibited, acetylcholine can
accumulate causing overstimulation of the cholinergic junctions and organs controlled
by cholinergic neurons. Tissues innervated by cholinergic neurons include muscles
(both smooth and voluntary); glands such as salivary, pancreas, and lachrymal; and
certain parts of the brain. Thus inhibition of cholinesterase can cause overactivity of a
wide variety of bodily functions. This overactivity is characteristic of poisoning by
cholinesterase inhibitors (Bardin et al., 1994).

Pesticides
Pesticides are defined by the federal Fungicide Insecticide Fumigant Rodenticide Act
as any substance that kills, repels, or mitigates a pest. Under this definition, insect
repellents such as diethyltoluamide (DEET) would be considered pesticides. Several
types of pesticides were used in the Gulf War theater, among the most common were
organophosphates, carbamates, and pyrethroids.
Organophosphate pesticides are chemicals in wide use as insecticides in agricultural
and nonagricultural applications. They were initially developed by German scientists
prior to World War II. They range in toxicity from very mildly toxic to extremely
toxic and are toxic by mouth, inhalation, or dermal absorption. Most organophosphate
pesticides require activation by an enzyme system known as the cytochrome P450
system. This system oxidizes a portion of the molecule making it much more toxic
than the parent compound. It is this active molecule that binds to the cholinesterase
molecule, blocking the action of the enzyme and leading to the accumulation of the
neurotransmitter acetylcholine. This accumulation of acetylcholine and the
overstimulation of the nerves, glands, and muscles that are innervated by cholinergic
neurons, lead to the signs and symptoms seen in organophosphate poisonings. The
organophosphate binds to the active site and slowly forms a covalent bond with the
enzyme, thus irreversibly inhibiting the cholinesterase enzyme. The enzyme is
replaced by the body over time.
Carbamates are a group of chemicals that, like organophosphates, are commonly used
as insecticides. They also inhibit cholinesterase. The inhibition they cause tends to be
less long lasting than inhibition with organophosphates, because unlike
organophosphates, they do not go through a permanent bonding (covalent bonding)
with the cholinesterase molecule. They are short acting, and the enzyme reactivates
when the concentration of the carbamate in the system is reduced.
Permethrin is a low to moderate toxicity pesticide in the class of pesticides known as
pyrethroids. This class is derived from natural pesticides, which are found in
chrysanthemums. Permethrin alters the function of nerve ion gates by destabilizing the
neuronal ion balance. This instability results in neurons firing more easily and in
uncoordinated neuronal discharges. These uncoordinated discharges are largely
responsible for the insecticidal effect of the chemical.
The most serious consequence of overexposure to pyrethroids is seizure activity. This
however, is rare in humans as the toxicity of pyrethroids is far less for warm-blooded
animals than for cold-blooded ones. Acute exposure in humans is generally
characterized by burning or irritating sensations in the fingers and lips.
DEET is a liquid insect repellent that can be applied to the skin or clothing. Despite
the wide use of the chemical, there have been relatively few reports of systemic
toxicity. Children appear to be most at risk for DEET toxicity, particularly when it is
used excessively.
Illnesses associated with DEET include contact dermatitis and eye irritation. DEET is
efficiently absorbed across the gut and skin. High blood levels can lead to
encephalopathy, which can have severe long-term consequences including flaccid
paralysis and areflexia. Fatal poisonings have been reported. No studies of chronic
low-level exposure to DEET in humans were identified by the Update committee

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