Role of Chem/Biol/& DU Exposures in Gulf War Illnesses (1)

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> --------- Forwarded Message ---------
> DATE: Mon, 18 Dec 2000 14:50:44
> From: "Prof. Garth L Nicolson" <gnicolson at immed.org>
>
> Armed Forces Medical Developments 2000
>
> THE ROLE OF CHEMICAL, BIOLOGICAL, AND
> RADIOLOGICAL EXPOSURES IN GULF WAR ILLNESSES
> Prof. Garth L. Nicolson
>
> The Institute for Molecular Medicine (www.immed.org)
> 15162 Triton Lane
> Huntington Beach, California  92649-1041 U.S.A.
>    gnicolson at immed.org
> 1-714-903-2900 / Fax: 1-714-379-2082
>
> Gulf War Syndrome or Gulf War Illnesses (GWI) are a collection of chronic
>illnesses reported by veterans of Operation Desert Storm (ODS, 1991).
>Between 15 and 18% of the veterans of ODS returned and slowly (6-18 months or
>more) presented with a variety of complex signs and symptoms characterized by
>disabling fatigue, intermittent fevers, night sweats, arthralgia, myalgia,
>impairments in short-term memory, headaches, skin rashes, intermittent
>diarrhea, abdominal bloating, chronic bronchitis, photophobia, confusion,
>transient visual scotomata,
> irritability, and depression and other signs and symptoms that until
>recently have defied appropriate diagnoses.[1-3]  GWI signs and symptoms are
>chronic, systemic and in general cannot be placed into ICD-9 diagnosis
>categories.  Also, routine laboratory test results are not consistent with a
>single, specific disease (1), often resulting in veterans not receiving a
>clinical diagnosis for their condition.  GWI has been reported by various
>nations (except France) who's forces were deployed against Iraqi units in
>ODS.  Possible reasons for the French Forces escaping GWI casualties will be
>discussed below as well as some of the possible exposures that
> occurred, the types of illnesses that resulted from these exposures, and
>some of the treatments that have been used on GWI patients.
>
> ANALYSIS OF MULTIFACTORIAL ILLNESSES OF THE GULF WAR
>
> Most investigators do not believe that GWI is a separate, new syndrome.[2,
>3]  It has been called Mucocutaneous-Intestinal-Rheumatic Desert Syndrome by
>Murray-Leisure et al.[4], who placed patients into three broad categories:
> (a) mucocutaneous lesions with pustular dermatitis;
> (b) intestinal disorders with irritable bowels; and,
> (c) rheumatic lllnesses with large-joint polyarthralgias and night sweats.
> Minor criteria included: heartburn, rectal fissures, bleeding or
>hemorrhoids, lactose or meat intolerance, splenomegaly and splenic
>tenderness, weakness and/or chronic fatigue, headaches, muscle aches,
>polymyalgias, memory loss, hair loss, fevers of unknown origin, unexplained
>leukocytosis or neutropenia, nasal ulcers or sores, chronic sinus or nasal
>congestion, atypical chest pain, new-onset asthma or chronic bronchitis, ear
>infections or tinnitus and dental infections.  Using factor analysis six
>syndrome categories were described by Haley et al.[3] after studying 249
>veterans of the U.S. Navy's 24th Reserve Mobile Construction Battalion.  The
>most important were:
> (d) impaired cognition characterized by problems in attention, memory,
>reasoning, insomnia, depression and headaches;
> (e) confusion-ataxia characterized by problems with thinking,
>disorientation, balance, vertigo and impotence;
> (f) artho-myo-neuropathy characterized by polyarthralgias and myalgias,
>muscle fatigue, difficulty lifting and extremity paresthesias (similar to c,
>above);
> (g) phobia-apraxia;
> (h) fever-adenopathy; and,
> (i) weakness-incontinence.
> The last three groups overlapped with groups d and e and involved weaker
>clustering in their analysis[4].  These groups differed from Post-Traumatic
>Stress Disorder (PTSD), depression, somatoform disorder and malingering.[4]
>Baumzweiger and Grove[5] have described GWI as neuro-immune disorders that
>involve the central, peripheral, and autonomous nervous and immune systems.
>They attribute a major source of illness to be brain stem damage due to
>central, peripheral and cranial nerve neuropathy with demyelination.  Their
>patients tended to have muscle spasms, memory deficits, attention deficits,
>ataxia, and increased muscle tone,
> which are often seen in neurotoxin-induced brain stem dysfunction.[5]  GWI
>patients can also have chronic bacterial and viral infections that are an
>important source of morbidity and symptoms.[2, 6, 7]
>
> GWI are usually not fatal[8]; however, there are now thousands of U.S.
>veterans dead after service in ODS.[6]  The possible reasons why these deaths
>have not been reported in official studies could be due to the limited sizes
>of study groups and time intervals used for analysis, the lack of information
>on veterans who have left the Armed Forces, and the primary use of military
>hospitals for such analyses.[9]  In the U.S. estimates of between 15,000 and
>25,000 or more dead have been advanced, but the exact figures are unknown.
>The exact figures have not been carefully analyzed so it is difficult to
>determine if ODS veterans are at higher risk than non-deployed personnel.
>Although for years the U.S Department of Defense and the U.K. Ministry of
>Defense officially stated that there were no unique illnesses associated with
>deployment to ODS[10], just the opposite appears to be the case[3-6],
>although these studies have been questioned on the basis that similar
>clusters can be found in non-ODS veterans deployed to Bosnia.[11]
>
> In a case control study, veterans with GWI have chronic illnesses at higher
>rates than military personnel from the same units that were not deployed to
>the Persian Gulf.[10]  In the four units that were studied, the deployed
>personnel had a variety of chronic illness signs and symptoms that were not
>present at the same frequencies in non-deployed personnel.[10]  For certain
>signs and symptoms, this difference was dramatic (for example, over 13 times
>difference in incidence of diarrhea).  This study showed that ODS deployment
>was an underlying risk for contracting chronic illnesses.
>
> GWI IS NOT PTSD
>
> Since the signs and symptoms of GWI are not well established as criteria for
>particular illnesses found in ICD-9 diagnosis categories[1-3], patients have
>often been diagnosed with an "unknown" disorder, or a somatoform disorder,
>such as Post-Traumatic Stress Disorder (PTSD).[1, 11, 12] GWI has a number of
>significant signs that are different from PTSD, such as neuro-muscular
>problems, skin disorders, gastrointestinal problems, muscle and joint pain
>and temperature
> abnormalities (intermittent fevers).[2-6]  A recent psychiatric analysis
>indicates that PTSD cannot explain symptoms of GWI with fatiguing illness.[13]
>
> The variable incubation time of GWI, ranging from months to years after
>presumed exposure, the cyclic nature of the relapsing fevers and the other
>chronic signs and symptoms and their appearance in immediate family members
>are consistent with organic not psychological disease.[2, 3, 5, 6]  The
>syndromes most similar to GWI are Chronic Fatigue Syndrome (CFS) (or myalgic
>encephalomyelitis, ME) and Fibromyalgia Syndrome (FMS).[2, 7]  We have
>proposed that the signs and symptoms found in many GWI patients may be caused
>by chronic exposures
> to chemical mixtures and host responses to infectious agents, resulting in
>cytokine abnormalities and a variety of other responses that result in a
>CFS/ME- or FMS-like disorder.[2].  When the signs and symptoms of GWI were
>compared to the signs and symptoms of CFS/ME, the similarity was striking
>(Figure 1A,B).[7]  CFS/ME is characterized by persistent or relapsing,
>debilitating fatigue or easy fatigability in a person who has no previous
>history of similar symptoms, that does not resolve with rest and is severe
>enough to reduce or impair average daily activity below 50% of the patient's
>premorbid activity level.  In addition to the absence of clinical conditions
>that could easily explain the symptoms, such as malignancies or autoimmune
>diseases, patients present with mild fever, sore throat, arthralgia, myalgia,
>generalized muscle weakness, headaches, painful lymph nodes, sleep
>difficulties, and neuropsychologic complaints such as memory loss,
>photophobia, confusion, transient visual scotomata, irritability, and
>depression.  These signs and symptoms closely parallel those found in GWI
>(Figure 1A,B).[7]  This suggests that GWI is not a "new" syndrome; it is a
>CFS/ME/FMS-like disorder.[2]  Interestingly, patients with chronic illnesses
>that do not have evidence of chronic infections do
> not display as many signs and symptoms as GWI or CFS/ME/FMS (Figure 1A,B).
>
> There are some differences between GWI and CFS/ME/FMS that may be important
>in determining the various possible causes of GWI. Haley et al.[3] and
>Baumzweiger and Grove[5] have stressed that unlike CFS/ME and FMS, GWI is
>associated with ataxia and increased motor tone, symptomatic of brainstem
>dysfunction, such as cranial nerve and peripheral nerve demyelination,
>brainstem inflammation, limbic system involvement and personality behavioral
>changes.  Using proton magnetic resonance to measure the ratio of plasma
>homovanillic acid
> and 3-methoxy-4-hydroxyphenylgycol Haley et al.[14] examined GWI patients
>for evidence of basal ganglia injury and found reductions in the left basal
>ganglia dopamine production, supporting the theory of brain stem injury to
>dopaminergic neurons in the basal ganglia.  The documentation of brain stem
>damage in GWI patients strongly suggests that stress-related causes, such as
>PTSD, are very unlikely.  Although stress can exacerbate chronic illnesses,
>stress alone is unlikely to be the cause of more than a small fraction of
>GWI.[11, 15]
>
> POSSIBLE CAUSES OF GWI: CHEMICAL EXPOSURES
>
> Part of the confusion in diagnosing GWI is that the overlapping chronic
>signs and symptoms displayed by GWI patients can be caused by quite different
>types of exposures.  Gulf War participants could have been exposed to
>chemical, radiological and/or biological agents, or more likely combinations
>of these (Figure 2).[3-7, 11, 12, 15]  Accurate diagnosis and successful
>treatment of GWI cohorts will depend on identifying the underlying exposures,
>because these illnesses are treated differently if their origins are
>chemical, radiological or biological.[15]
>
> Gulf War veterans were exposed to a variety of chemicals, including
>insecticides, such as the insect repellent N,N-dimethyl-m-toluamide and the
>insecticide permethrin, battlefield smoke and fumes and smoke from burning
>oil wells, the anti-nerve agent pyridostigmine bromide, solvents used to
>clean equipment and a variety of other chemicals, including in some cases,
>possible exposures to low levels of Chemical Warfare (CW) agents.[15]  CW
>exposure may have occurred because of destruction of CW stores in factories
>and storage bunkers during and after the war as well as possible offensive
>deployment of CW agents.[12, 15]
>
> Low level exposures to mixtures of chemicals, such as organophosphates, can
>result in chronic illnesses[3, 5, 11, 15], including chronic neurotoxicity
>and immune supression.  Abou-Donia and Wilmarth [16] found that combinations
>of pyridostigmine bromide, N,N-dimethyl-m-toluamide and permethrin produce
>neurotoxicity, diarrhea, salivation, shortness of breath, locomotor
>dysfunctions, tremors, and other impairments in healthy adult hens.  Multiple
>Chemical Sensitivity Syndrome (MCS) and Organophosphate-Induced Delayed
>Neurotoxicity (OPIDN) are examples of chronic illnesses caused by multiple
>chemical exposures (Figure 2).[16]  Patients with these syndromes can present
>with many (but not all) of the signs and symptoms found in GWI patients, and
>in fact, many GWI cases may eventually be explained by complex chemical
>exposures.[3, 14, 16, 17]  In these patients, memory loss, headaches,
>cognitive problems, severe depression, loss of concentration, vision and
>balance problems, chemical sensitivities,
> among others, typify the types of signs and symptoms found in chronic
>chemically exposed patients.[16, 17]  Arguments have been advanced that such
>exposures do not explain GWI or that they may only be useful for a small
>subset of GWI patients[11], but these arguments are for the most part are
>based on reviewing studies on the effects of single agent exposures, not the
>multiple, complex exposures that were most likely encountered by veterans of
>ODS.  Since it is
> unlikely that any one type of exposure will explain the multiple signs and
>symptoms found in GWI patients, studying subsets or clusters of patients is
>not as limiting as has been suggested.[11]
>
> For most patients, the signs and symptoms of GWI began to present between
>six months to two years or more after the end of the war.  This slow onset of
>clinical signs and symptoms in chemically exposed individuals is not unusual
>for Organophospate-Induced Delayed Neurotoxicity (OPIDN).  As mentioned
>above, exposure to organophosphates was probably quite common in ODS
>veterans.  That delayed, chronic signs and symptoms similar to OPIDN were
>caused by multiple low-level exposure to nerve agents, anti-nerve agents and
>other organo-phosphates remains a distinct possibility[18], especially in
>certain subsets of GWI patients.[16]
> This is considered unlikely by Sartin[11], who argued that low-level single
>agent exposures do not usually cause OPIDN.
>
> Low levels of CW agents were present in the Persian Gulf region from the
>bombing of CW factories and storage facilities (and their demolition after
>the war), and the probable offensive use of CW delivered by SCUD B (SS1)
>missiles, aircraft or vehicles outfitted with CW sprayers or by artillery
>shells and rockets, CW mines and other sources.[12, 15, 19]  Iraqi Armed
>Forces were known to have extensive stores of such weapons, and intelligence
>reports indicated that orders to use offensive CW agents were given.  In
>testimony to the U.S. Congress, Army CBW officers indicated that over 14,000
>CW alarms sounded during but not before or after the ODS air/ground
>offensive, and some soldiers were given medals for identifying the types of
>CW that were released.[19]  Extensive stockpiles of mustard (blister agent HN
>or HT), lewisite (blister agent L), sarin (nerve agent GB or GF), tabun
>(nerve agent GA) and other CW agents were present in the region, and an
>unknown quantity of these weapons were released into the atmosphere during
>the air campaign and by the destruction of Iraqi storage bunkers after the
>conflict.[12, 19]  That low level exposure to nerve agents combined with
>anti-nerve agents and other organophosphate exposures may have resulted in
>delayed casualties in at least some subsets of GWI is a possibility that
>cannot be so easily dismissed.[11]
>
> POSSIBLE CAUSES OF GWI: RADIOLOGICAL EXPOSURES
>
> Depleted uranium (DU) was used extensively in ODS, and it remains an
>important contaminant of the battlefield.[6]  DU, a by-product of uranium
>processing, was used in armor-penetrating ammunition and in protective armor
>on tanks and other vehicles.  Depleted uranium contains about 30% U-235, a
>dangerous radioisotope with a half-life of over 4 billion years.[6]  When a
>DU penetrator hits an armored target, it disintegrates due to the resulting
>kinetic energy transfer that results in extreme heat and formation of uranium
>oxide particles.  The uranium oxide particles that form are usually small,
>and due to their high density they settled quickly onto
> vehicles, bunkers, and onto the surrounding sand where they could be easily
>inhaled.  One particle of <5 5m in diameter trapped in the pulmonary system
>for one year can result in 272-times the annual whole body radiation dose
>permitted U.S. radiation workers.[6]  Fortunately, exposure can be monitored,
>and studies on DU exposures should be initiated as soon as possible to
>determine the prevalence and extent of uranium oxide exposure.
>
> In addition to battlefield DU contamination, civilian nuclear reactors in
>Iraq were destroyed during the air campaign.  This may have resulted in the
>release of long half-life isotopes like Sr-90, U-235, or Co-90.  This could
>have resulted in some blow-back exposures, since the prevailing winds in the
>region were generally unfavorable.  Unfortunately, there appears to be no
>available assessment of regional contamination from the release of nuclear
>reactor materials.[15]
>
> POSSIBLE CAUSES OF GWI: ENVIRONMENTAL EXPOSURES
>
> In addition to the chemicals released by burning oil well fires and ruptured
>petroleum pipelines, soldiers were exposed to fine, blowing sand.  The small
>size of sand particles (~ 0.1 mm) and the relatively constant winds in the
>region resulted in some inhalation.  The presence of small sand particles
>deep in the lungs can produce a pulmonary inflammation disorder that can
>progress to pneumonitis or Al-Eskan Disease.[20]  This usually presents as a
>pneumonia or flu-like condition
> that can eventually progress to more widespread signs and symptoms,
>including fibrosis, immunosuppression and opportunistic infections.  Although
>it is extremely doubtful that many GWI patients have Al-Eskan Disease, the
>presence of silica-induced immune suppression in some soldiers could have
>resulted in the appearance of opportunistic chronic infections in these
>patients.[12, 15]
>
> POSSIBLE CAUSES OF GWI: BIOLOGICAL EXPOSURES
>
> Parasites such as Leishmaniasis and Schistosomiasis and bacteria that cause
>Malaria and Cholera  are endemic to the Middle East and could be the cause of
>illnesses in at least some of the veterans with GWI.[4]  Characteristic signs
>and symptoms occur in these illnesses, and diagnostic tests are available for
>most of these agents.  Moreover, there have been no reports that they are the
>cause of illness in large numbers of GWI patients.[15]  In some patients
>infections by Leishmania tropica, spread by the sandfly Phlebotomus papatasi,
>can result in
> viscerotropic Leishmaniasis and elevated temperature, lymphadenopathy and
> hepatosplenomegaly.[21]  However, most of the common signs and symptoms of
>GWI do not fit with this explanation, and diagnosis of Leishmaniasis is
>relatively uncommon (estimated at less than one hundred) in Gulf War veterans.
>
> Biological toxins were also present.[15]  The Iraqi Army had ample stores of
>aflatoxin (Aspergillus flavus toxin), ricin (from Ricinus communis beans),
>Clostridium botulinum toxin, and possibly other toxins.  They also had
>tricothecene mycotoxins produced by various species of fungi that can act
>quickly by direct cutanous contact and cause erythema accompanied by
>blisters, wheezing, pain and burning sensations.  Some of these toxins can be
>fatal in very low doses (inhaled ricin in extremely small doses can cause
>inflammation of the respiratory mucosa with hemorrhage into the lungs or
>edema, hemorrhage of the GI tract and death within 8-72 hours) or cause
>delayed carcinogenic or immunosuppressive effects (aflatoxin).  The preferred
>method of delivery of these toxins was by BW sprayer onto the sand or by
>aircraft.[12, 15]  Over 50 Italian-made BW sprayers were found fully deployed
>in Southern Iraq and Western Kuwait, and aircraft fitted with BW sprayers
>were captured at airfields in Southern Iraq.
>
> In one subset of GWI patients Murray-Leisure et al.[4] have described an
>association with cutaneous sand exposure.  This is most likely caused by a
>chronic transmittable infection found in sand that is endemic to the region,
>such as Bacillus anthracis or Brucella species.  The risk for sand-associated
>illness appeared to be highest in the fall.  Although no infections were ever
>identified, the slow appearance of the same signs and symptoms in spouses and
>children of veterans with GWI suggested that a slow-growing microorganism was
> being transferred.[4]  Anthrax, caused by the Gram-positive Bacillus
>anthracis, a commonly used BW agent, is found in soil.  It can gain entrance
>through skin wounds but also by inhalation or ingestion.  Anthrax infection
>does not result in a chronic illness, because its signs and symptoms, such as
>malaise, fever, fatigue, headache, respiratory distress and other more severe
>signs and symptoms, usually appear within 1-6 days of exposure.  That anthrax
>exposure caused a subset of GWI is unlikely since the usual signs and
>symptoms of anthrax exposure were not reported in ODS veterans.[15]
>
> There is evidence for the presence of transmittable infectious agents in GWI
>patients.  In many cases, the veterans' immediate family members appear to
>have the same or similar signs and symptoms.[7, 22, 23]  One estimate derived
>from inquiries of >1,200 GWI families indicated that approximately 77% of
>spouses and 65% of children born after the war now have the signs and
>symptoms of GWI (24).  When immediate family members presented with the same
>or similar illness, the onset of their GWI signs and symptoms usually
>occurred from six months to one year or more after the onset of the veteran's
>illness, and not every family member developed GWI signs and symptoms.
>Because of the apparent slow rate of transmission to immediate family
>members, the general public is probably not at high risk for contracting GWI
>from casual contact with GWI patients.[4, 7]
>
> [Cont. in # 2]
>

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