Medical Causation of the Multi-symptom Medical Causation of the Multi-symptom NO. 94-C-1392
MARSHALL COLEMAN, ETAL § IN THE DISTRICT COURT OF
MEDICAL CAUSATION
CONCERNING THE SARIN EXPOSURES
TO THE HONORABLE JUDGE OF SAID COURT:
SARIN NERVE GAS EXPOSURES
During the Gulf War air campaign, coalition aircraft flew 990 sorties against 23 Iraqi chemical and biological weapons research, production and storage facilities. U.S. Department of Defense, Gulf News, 4(2): at p. 1 (March, 2000). Three months before the air war began, Livermore National Laboratory predicted that chemical warfare agent fallout would cover the positions of U.S. troops in Saudi Arabia. USA Today, p. 1 (August 14, 1997)
. Though this classified research was performed for the U.S. Air Force, the study never reached General Schwarzkopf during the Gulf War. USA Today, p. 1 (August 15-17, 1997). From the beginning of the air war until its end, each of the nearly 14,000 M8A1 chemical alarms deployed in the war went off an average of two or three times a day. U.S. Congress, Committee on Government Reform and Oversight, Gulf War Veterans’ Illnesses: VA, DoD Continue to Resist Strong Evidence Linking Toxic Causes to Chronic Health Effects, at p. 18 (November 17, 1998). The most sophisticated chemical detection equipment in the Gulf War was with the Czech Republic chemical detection forces. They detected the nerve agent Sarin on January 19, 1991, near Hafir al Batin where hundreds of thousands of U.S. troops were massed. Ibid, at pp. 15 & 17. The U.S. Department of Defense has admitted that “the Czech detections were valid.” Ibid, p. 15. French forces also detected nerve gas during the air bombing campaign. Ibid, p. 17. The U.S. Department of Defense has admitted that approximately 100,000 U.S. troops were exposed to low-level sarin nerve gas from the destruction of just one Iraqi ammunition dump in March, 1991, at Khamisiyah. Ibid.There were three different ways Gulf War veterans could be exposed to sarin nerve gas fallout: inhalation of vapors and contaminated dust, ingestion of contaminated drinking water or food and contaminated dust, and dermal contact with contaminated dust and contaminated soil. See J. of Tox. & Env. Health, 59: 281-502 (March, 2000), p. 293. Regarding the binding of chemical warfare agents to the very fine dust in the Persian Gulf, see: Korenyi-Both, Col. A.L., et al., “The Role of the Sand in Chemical Warfare Agent Exposure Among Persian Gulf War veterans: Al Eskan Disease and ‘Dirty Dust’”, Military Medicine, 165:321-336 (May, 2000); and U.S. Department of Defense, Dusty Agents: Implications For Chemical Warfare Protection, AST-2660z-055-88 (formerly secret, now declassified) (January 27, 1998).
GULF WAR ILLNESS
Numerous epidemiological studies, listed below, prove that Gulf War veterans have a higher prevalence of functional impairment, health care utilization, symptoms, and medical conditions, and a higher rate of low general health perceptions, compared with Gulf War era veterans who were not deployed to the Persian Gulf:
1. Stretch, R.H., Bliese, P., Marlowe, D., “Physical Health Symptomatology of Gulf War-Era Service Personnel From the States of Pennsylvania and Hawaii,” Military Medicine, 160:131-136 (March, 1995).
2. Sostek, M.B., et al., “High Prevalence of Chronic Gastrointestinal Symptoms in a National Guard Unit of Persian Gulf Veterans,” The American Journal of Gastroenterology, 91(12): 2494-2497 (December, 1996).
3. “Iowa Persian Gulf Study Group: Self-Reported Illness and Health Among Gulf War Veterans: A Population-Based Study,” Journal of the American Medical Assn., 277:238-45 (1997).
4. Haley, R.W., Hom, J., Roland P.S., et al, “Evaluation of Neurologic Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn. , 277:223-30 (1997).
5. Pierce, P., “Physical and Emotional Health of Gulf War Veteran Women,” Aviation, Space & Environ. Medicine, 68(4):317-321 (April, 1997).
6. Fukuda, K., Nisenbaum R., Stewart, G., et al, “Chronic Multisymptom Illness Affecting Air Force Veterans of the Gulf War,” Journal of the American Medical Assn., 280:981-8 (1998).
7. Goss Gilory, Inc., “Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf.” (1998). Available at http://www.DND.ca/menu/press/reports/health/health.
8. Proctor, S.P., Heeren, T., White, R.F., et al, “Health Status of Persian Gulf War Veterans: Self-Reported Symptoms, Environmental Exposures, and the Effect of Stress,” Int. J. Epidemiol., 27:1000-10 (1998).
9. Unwin C., Blatchley, N., Coker, W., et al, “Health of U.K. Serviceman Who Served in the Persian Gulf War,” Lancet, 353:169-78 (1999).
10. Gray, G., Kaiser, K.S., Hawsworth, A.W., Hall, F.W., Barrett-Connor, E., “Increased Post-War Symptoms and Psychological Morbidity Among U.S. Navy Gulf War Veterans,” Am. J. Trop. Med. Hyg., 60:758-66 (1999).
11. Ishoy, T., et al, “State of Health After Deployment In The Persian Gulf: The Danish Gulf War Study,” Danish Medical Bulletin, 46:416-427 (Nov., 1999).
12. Kang, H.K., et al, “Illness Among United States Veterans of the Gulf War: A Population-Based Survey of 30,000 Veterans,” Journal of Occupational and Environmental Medicine, 42(5):491-500 (May, 2000).
13. Steele, Lea, “Prevalence and Patterns of Gulf War Illness in Kansas Veterans: Association of Symptoms with Characteristics of Person, Place, and Time of Military Service,” American Journal of Epidemiology, 152:992-1002 (2000).
14. Proctor, S.P., “Health-Related Quality of Life in Persian Gulf War Veterans,” Military Medicine, 166(6):510-18 (2001).
In 1998, the Centers for Disease Control and Prevention (CDC) established a case definition for Gulf War Illness. It is defined as:
“having one or more chronic symptoms (present for six months or longer) from at least two of the following categories:
1.) Fatigue;
2.) Mood and cognition (symptoms of feeling depressed, difficulty remembering or concentrating, feeling moody, feeling anxious, trouble finding words, or difficulty sleeping); and
3.) Musculoskeletal (symptoms of joint pain, joint stiffness, or muscle pain).”
Fukuda, K., “Chronic Multisymptom Illness Affecting Air Force Veterans of the Gulf War,” Journal of the American Medical
Assn., 28:981-988, at 983 (September 16, 1998).
Population-based studies in three distinct veteran populations have shown “the excess burden of illness associated with deployment to the Gulf War has consistently been between 25 and 30 percent.” Steele, Lea, “Prevalence and Patterns of Gulf War Illness in Kansas Veterans: Association of Symptoms with Characteristics of Person, Place and Time of Military Service,” American Journal of Epidemiology, 152:992-1002, at 997 (2000). See also: Haley, R.W., Kurt, T.L., Hom, J., “Is There a Gulf War Syndrome? Searching for Syndromes by Factor Analysis,” Journal of the American Medical Assn., 277:215-222 (January 15, 1998); Fukuda, K., et al., Op. Cit.; and Unwin, C., et al., Op. Cit..
MEDICAL CAUSATION
A team of doctors at the University of Texas Southwestern Medical Center, headed by Robert Haley, M.D., (previously with the C.D.C.), has done the leading and most comprehensive research on Gulf War Illness over the years. Their research has been funded by the U.S. Army and the Perot Foundation. The following is a four-page summary of their work quoted from a medical journal published earlier this year:
In early 1995, we derived a working case definition by performing an exploratory two-stage hierarchical factor analysis of symptom data collected from Gulf War veterans of a US Naval Reserve construction battalion (seabees) living in the southeastern US (the developmental sample) (Haley et al., 1997b). The symptoms measured on our questionnaire were those frequently reported by ill Gulf War veterans examined in large registries (Defense Science Board, 1994; NIH Technology Assessment Workshop Panel, 1994; Committee to Review the Health Consequences of Service During the Persian Gulf War, 1995; Department of Defense, 1996) and in our clinical pilot studies of ill Gulf War veterans. We reasoned that, if an epidemic disease or injury had resulted from the war, factor analysis should find clustering, or intercorrelation, of questionnaire responses that reflect common underlying disease processes, i.e. latent factors. If more than one epidemic condition was present, factor analysis should demonstrate several latent factors.
In the first stage, suspecting that difficulty in recognizing syndromic patterns may have been due to ambiguities in the symptom terminology, we analytically disentangled each ambiguous symptom into unambiguous, pathophysiologically meaningful symptom scales before performing syndrome factor analysis (Haley et al., 1997b) (see Appendix A). In the second stage, three primary syndrome factors were identified to serve as a working case definition (Haley et al., 1997b). (see Appendix B). The symptoms scales that loaded most strongly on syndrome factor 1 (‘impaired cognition’) were: distractibility, difficulty remembering; depression; middle and terminal insomnia; fatigue, meaning excessive daytime sleepiness (but not muscle exhaustion); slurring of speech; confused thought process; and migraine-like headaches. Those loading most strongly on syndrome factor 2 (‘confusion-ataxia’) were problems with thinking and reasoning process, such as: reading, writing and spelling; getting confused; not knowing where they are or what they are doing; getting disoriented when trying to locate their car in a parking lot; having problems with keeping their balance; stumbling often and feeling like the room is spinning; having a physician’s diagnosis of PTSD; depression or liver disease; and sexual impotence. Those loading most highly on syndrome factor 3 (renamed ‘central pain’ originally ‘arthro-myo-neuropathy’) were: generalized joint and muscle pains; increased difficulty lifting heavy objects; fatigue, meaning excessive muscle exhaustion after exertion (but not sleepiness); and tingling or numbness of the hands, arms, feet and legs (but not the trunk and groin, or the face, tongue and lips).
In epidemiologic analyses, we found different combinations of neurotoxic chemical exposures to be strongly associated with each of the three primary syndromes (Haley and Kurt, 1997), and animal experiments confirmed the previously unexpected neurotoxic effects of these chemical combinations (Husain et al., 1993, 1995; Abou-Donia et al., 1996a,b; Chaney et al., 2000). In subsequent nested clinical-control studies involving smaller samples of the veterans with the factor-derived syndromes (cases) and matched control subjects drawn from the same battalion, we found the three syndromes to be strongly associated with neurophysiologic evidence of organic brain dysfunction (Haley et al., 1997a; Hom, et al., 1997; Roland et al., 2000) and a genetic marker of susceptibility to chemical nerve agent injury (Haley et al., 1999b). We recently reported results of brain scanning with magnetic resonance (MR) spectroscopy demonstrating neuronal loss in basal ganglia and brain stem in different anatomic distributions in veterans with the three syndromes compared with matched control subjects (Haley et al., 2000b), and described an abnormality of central dopamine metabolism highly correlated with that neuronal loss (Haley et al., 2000a). These findings have established an organic basis for the syndromes of our working case definition.
To attempt to replicate our three-factor model using the same methods as in our original work, we performed confirmatory factor analysis using structural equation modeling to test the goodness-of-fit of a series of factor models to data from both the original battalion of Naval reservists from the southeastern US (the developmental sample) and a new sample of Gulf War veterans primarily serving in active-duty US Army units living in North Texas (the validation sample). The different service branches represented in the two samples provided a test for differences across service branch.
...
4. Discussion. The analysis of Model 1, our primary confirmatory factor model, demonstrated that the apparent three-syndrome structure identified previously in 249 Gulf War veterans from a Naval reserve construction battalion headquartered in the southeastern US (Haley et al., 1997b) was also present in the symptom data of a diverse sample of predominantly Army Gulf War veterans living in North Texas, selected arbitrarily without knowledge of their symptom complaints. This confirmatory finding adds weight to our contention that the symptom complaints of Gulf War veterans constitute a coherent illness rather than a collection of non-specific, unrelated conditions, as suggested by others. ...
This syndrome structure seems reasonable, in view of the virtually simultaneous appearance of all three syndromes during or shortly after the Gulf War and the similarity of action of the different wartime chemical exposures strongly associated with each syndrome (Haley and Kurt, 1997; Haley et al., 1997b). ...
In the intensely political discussions of Gulf War veterans’ illnesses and research findings on the subject, there has been much speculation that publicity about veterans’ symptom complaints might have biased responses to symptom questionnaires, leading to factitious or conversion symptom patterns, both currently and after prior wars (Hyams et al., 1996; Iowa Persian Gulf Study Group, 1997). The assumption of such an effect has been one of the main arguments in favor of a psychological basis for the veterans’ symptom complaints. Our effort to survey one cohort of the validation sample just before the publication of our articles describing the original factor-analytically derived syndromes (Haley and Kurt, 1997; Haley et al., 1997a,b), and a second cohort approximately 1 year after the intense publicity that followed these publications, provided an opportunity to test the effect of publicity on our measurements. If it was true that publicity about our original findings caused veterans to conform to the publicized symptom patterns, one would expect to find that our SEMs fit the post-publicity sample better than the pre-publicity sample. Our analyses, however, found invariance of the five models over the two cohorts, and the LM test substantiated the equality constraints of all the structural components of each model. Thus, we conclude that publicity about our initial findings did not cause veterans to report factitious symptoms.
...
To clinicians caring for Gulf War veterans, these findings, together with our previous research on this problem, suggest a disease classification that predicts cellular pathology in the brain, several related etiologic agents and a specific genetic predisposition (Table 5). We have previously shown that Gulf War veterans with our syndrome 2 (‘confusion-ataxia’), compared with those with the other two syndromes and normal control subjects, are the most seriously ill, as indicated by the unusually high rate of occupational disability from their illnesses (Haley et al., 1997b), have the most severe dysfunction on neuropsychological (Haley et al., 1997a; Hom et al., 1997) and audiovestibular tests of deep brain function and clinical vertigo attacks (Haley et al., 1997a; Roland et al., 2000), have the greatest loss of neuronal mass in both basal ganglia and brain-stem by magnetic resonance spectroscopy (MRS) (Haley et al., 2000b), and demonstrate abnormal central dopamine production (Haley et al., 2000a). The cellular damage to deep brain structures in this group appears to have been etiologically linked with exposure to low-level sarin nerve gas during the Gulf War, possibly synergistically promoted by high blood levels of the prophylactic nerve gas antidote pyridostigmine bromide (Mestinon) taken by most troops in the war (Keeler et at., 1991; Tucker, 1997). Veterans with syndrome 2 were also found to have unusually low blood levels of the type Q isoenzyme of PON1 paraoxonase/aryleserase, a genetically controlled enzyme/aryleserase, a genetically controlled enzyme whose primary known function is to hydrolyze sarin and soman nerve agents to prevent them from gaining access to brain and nerve tissue (Haley et al., 1999b; La Du et al., 2001). In an epidemiologic study, those with syndrome 2 were also eight times more likely to report being in areas where chemical nerve gas alarms sounded, to have been near areas of the Kuwaiti border where sarin was detected just after coalition air strikes destroyed Iraqi chemical weapon depots, and to have experienced unusually severe side effects after taking pyridostigmine bromide tablets (Haley and Kurt, 1997). Organophosphate pesticides and nerve agents such as sarin, as well as pyridostigmine, have been shown in laboratory animal models to damage cellular receptors in basal ganglia (Freed et al., 1976; Fernando et all., 1984; Martin and Hussain, 1985; McDonald et al., 1988; Li et al., 2000), and repetitive exposure to sarin produces clinically detectable neurologic damage in animals (Husain et al., 1993, 1995). Follow-up studies in Japanese civilians exposed to sarin in the Tokyo and Matsumoto subways have reported clinical syndromes similar to our findings in syndrome 2, related to the same genetic predisposition involving the type Q isoenzyme of PON1 enzymes (Yamasaki et al., 1997; Yokoyama et al., 1998a,b).
References:
Abou-Donia, M.B., Wilmarth, K.R., Abdel-Rahman, A.A., Jensen, K.F., Oehme, F.W., Kurt, T.L., “Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos,” Fundamental and Applied Toxicology, 34: 201-222 (1996a).
Abou-Donia, M.B., Wilmarth, K.R., Jensen, K.F., Oehme, F.W., Kurt, T.L., “Neurotoxicity Resulting from Coexposure to Pyridostigmine Bromide, DEET, and Permethrin,” Journal of Toxicology and Environmental Health, 48: 35-56 (1996b).
Chaney, L.A., Wineman, R.W., Rockhold, R.W., Hume, A.S., “Acute Effects of an Insect Repellant, N,N-diethyl-m-toluamide, on Cholinesterase Inhibition Induced by Pyridostigmine Bromide in Rats,” Toxicol. Appl. Pharmacol., 165: 107-114 (2000).
Committee to Review the Health Consequences of Service During the Persian Gulf War, Medical Follow Up Agency, Institute of Medicine, Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action. National Academy Press, Washington, DC. (1995).
Defense Science Board, Report of the Defense Science Board Task Force on Persian Gulf War Health Effects. Office of the Under Secretary of Defense for Acquisition and Technology, Washington, DC. (1994).
Department of Defense, Comprehensive Clinical Evaluation Program for Persian Gulf War Veterans: CCEP Report on 18,598 Participants. Department of Defense, Washington, DC. (1996).
Fernando, J.C., Hoskins, B., Ho, I.K., “Effect on Striatal Dopamine Metabolism and Differential Motor Behavioral Tolerance Following Chronic Cholinesterase Inhibition with Diisopropylfluorophosphate,” Pharmacology, Biochemistry and Behavior, 20: 951-957 (1984).
Freed, V.H., Matin, M.A., Fang, S.C., Kar, P.P., “Role of Striatal Dopamine in Delayed Neurotoxic Effects of Organophosphorus Compounds,” European Journal of Pharmacology, 35: 229-232 (1976).
Haley, R.W., Re: “Is There a Gulf War Syndrome?” Lancet, 354: 1645-1646 (1999b).
Haley, R.W., Kurt, T.L., “Self-Reported Exposure to Neurotoxic Chemical Combinations in the Gulf War: A Cross-Sectional Epidemiologic Study,” Journal of the American Medical Assn., 277: 231-237 (1997).
Haley, R.W., Hom, J., Roland, P.S., Bryan, W.W., Van Ness, P.C., Bonte, F.J., Devous Sr., M.D., Mathews, D., Fleckenstein, J.L., Wians Jr., F.H., Wolfe, G.I., Kurt, T.L., “Evaluation of Neurologic Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277: 223-230 (1997a).
Haley, R.W., Kurt, T.M., Hom., J., “Is There A Gulf War Syndrome? Searching For Syndromes By Factor Analysis of Symptoms,” Journal of the American Medical Assn., 277:215-222 (1997b).
Haley, R.W., Billecke, S., La Du, B.N., “Association of Low PON1 Type Q (Type A) Arylesterase Activity With Neurologic Symptom Complexes in Gulf War Veterans,” Toxicol. Appl. Pharmacol., 157: 227-233 (1999b).
Haley, R.W., Fleckenstein, J.L., Marshall, W.W., McDonald, G.G., Kramer, G.L., Petty, F., “Effect of Basal Ganglia Injury on Central Dopamine Activity in Gulf War Syndrome: Correlation of Proton Magnetic Resonance Spectroscopy and Plasma Homovanillic Acid,” Archives of Neurology, 57: 1280-1285 (2000a).
Haley, R.W., Marshall, W.W., McDonald, G.G., Daugherty, M., Petty, F., Fleckenstein, J.L., “Brain Abnormalities in Gulf War Syndrome: Evaluation by 1H Magnetic Resonance Spectroscopy,” Radiology, 215: 807-817 (2000b).
Hom, J., Haley, R.W., Kurt, T.L., “Neuropsychological Correlates of Gulf War Syndrome,” Archives of Clinical Neuropsychology, 12: 531-544 (1997).
Husain, K., Vijayaraghavan, R., Pant, S.C., Raza, S.K., Pandey, K.S., “Delayed Neurotoxic Effect of Sarin in Mice After Repeated Inhalation Exposure,” Journal of Applied Toxicology, 13: 143-145 (1993).
Hussain, K., Pant, S.C., Raza, S.K., Singh, R., Das Gupta, S., “A Comparative Study of Delayed Neurotoxicity in Hens Following Repeated Adminstration of Organophosphorus Compounds,” Indian Journal of Physiologic Pharmacology, 39:47-50 (1995).
Hyams, K.C., Wignall, F.S., Roswell, R., “War Syndromes and Their Evaluation: From the US Civil War to the Persian Gulf War,” Annals of Internal Medicine, 125: 398-405 (1996).
Iowa Persian Gulf Study Group, “Self-Reported Illness and Health Status Among Gulf War Veterans: A Population-Based Study,” Journal of the American Medical Assn., 277: 238-245 (1997).
Keeler, J.R., Hurst, C.G., Dunn, M.A., “Pyridostigmine Used As A Nerve Agent Pretreatment Under Wartime Conditions,” Journal of the American Medical Assn., 266: 693-695 (1991).
La Du, B.N., Billecke, S., Hsu, C., Haley, R.W., Broomfield, C.A., “Serum Paraoxonase (PON1) Isozymes: The Quantitative Analysis of Isozymes Affecting Individual Sensitivity to Environmental Chemicals,” Drug Metabolism and Disposition, 29: 566-569 (2001).
Li, L., Gunasekar, J.L., Isom, G.E., “Muscarinic Receptor-Mediated Pyridostigmine-Induced Neuronal Apoptosis,” Neurotoxicology, 21: 541-552 (2000).
Matin, M.A., Hussain, K., “Striatal Neurochemical Changes and Motor Dysfunction in Mipafox-Treated Animals,” Methods and Findings in Experimental Clinical Pharmacology, 7: 79-81 (1985).
McDonald, B.E., Costa, L.G., Murphy, S.D., “Spatial Memory Impairment and Central Muscarinic Receptor Loss Following Prolonged Treatment with Organophosphates,” Toxicology Letters, 40: 42-56 (1988).
Technology Assessment Workshop Panel, N.I.H., “The Persian Gulf Experience and Health,” Journal of the American Medical Assn., 272: 391-396 (1994).
Roland, P.S., Haley, R.W., Yellin, W., Owens, K., “Vestibular Dysfunction in Gulf War Syndrome,” Otolaryngology Head & Neck Surgery, 122: 319-329 (2000).
Tucker, J.B., “Evidence Iraq Used Chemical Weapons During the 1991 Persian Gulf War,” Non-Proliferation Review, Spring-Summer, 114-122 (1997).
Yamasaki, Y., Sakamoto, K., Watada, H., Kajimoto, Y., Hori, M., “The Arg192 Isoform of Paraoxonase with Low Sarin-Hydrolyzing Activity is Dominant in the Japanese,” Human Genetics, 101: 67-68 (1997).
Yokoyama, K., Araki, S., Murata, K., Nishikitani, M., Okumura, T., Ishimatsu, S., Takasu, N., “A Preliminary Study of Delayed Vestibulocerebellar Effects of Tokyo Subway Sarin Poisoning in Relation to Gender Difference: Frequency Analysis of Postural Sway,” Journal of Occupational and Environmental Medicine, 40: 17-21 (1998a).
Yokoyama, K., Araki, S., Murata, K., Nishikitani, M., Okumura, T., Ishimatsu, S., Takasu, N., “Chronic Neurobehavioral and Central and Autonomic Nervous System Effects of Tokyo Subway Sarin Poisoning,” Journal of Physiology, (Paris) 92: 317-323 (1998b).
Source: Haley, R.W., Luk, G.D., Petty, F., “Use of Structural Equation Modeling to Test the Construct Validity of a Case Definition of Gulf War Syndrome: Invariance Over Developmental and Validation Samples, Service Branches and Publicity,” Psychiatry Research, 102:175-200 (2001) (Emphasis supplied).
CORROBORATION CONCERNING GENETIC SUSCEPTIBILITY
OF GULF WAR VETERANS WHO BECAME ILL DUE TO
LOW-LEVEL SARIN EXPOSURE
There are two detoxifying enzymes present in the blood of humans to react to sarin exposure, paraoxonase (PON1) and butyryclolinesterase (BchE).
Paraoxonase (PON1) is an enzyme present in the blood of humans that hydrolyses organophosphates to relatively harmless excretable products. There are two genotypes, Q & R. There is evidence that the Q type is much more efficient than the R type at hydrolyzing the organophosphate nerve gas sarin. Regardless of pure genotype, QQ, RR or the combination, QR, there is a vast difference among individuals on the amount of PON1 that their body contains. “There is at least a 13-fold variation in enzyme levels among individuals with the same genotype.” Li, Wan-Fen, et al., “Catalytic Efficiency Determines the In-Vivo Efficiency of PON1 for Detoxifying Organophosphorus Compounds,” Pharmacogenetics, 10:767-779, 768 (2000), (Emphasis supplied). See also: Furlong, C., “PON1 Status and Neurologic Symptom Complexes in Gulf War Veterans,” Genome Research, 10:153-155 (2000); Shih, D., “Mice Lacking Serum Paraoxonase as Supplied to Organophosphate Toxicity and Atherosclerosis,” Nature, 394:284-287 (July 16, 1998); Mackness, B., et al., “Effect of the Molecular Polymorphins of Human Paraoxonase (PON1) on the Rate of Hydrolysis of Paraoxon,” British J. of Pharmacology, 122:265-268 (1997); Li, W., et al., “Paraoxonase (PON1) Gene in Mice: Sequencing, Chromosomal Localization and Developmental Expression,” Pharmacogenetics, 7:137-144 (1997); Li, W., Furlong, C., and Costa, L., “Paraoxonase Protects Against Chlorpyrifos Toxicity in Mice,” Toxicology Letters, 76:219-226 (1995); Clendenning, J.B., et al., “Structural Organization of the Human PON1 Gene,” Genomics, 35:586-589 (1996); Davies, H., et al, “The Effect of the Human Serum Paraoxonase Polymorphins Is Reversed With Diazoxon, Soman and Sarin,” Nature Genetics, 14:334-336 (November, 1996); and LaDu, B.N., “Human Serum Paraoxonase/Arylesterase,” Pharmacogenetics of Drug Metabolism, 51-91 (1992).
In a study of 152 ill British Gulf War veterans, the hydrolysis activity level of PON1 was found to be less than 50% of that found in the 152 non-Gulf War veterans controls. The serum PON1 concentration was also lower in the Gulf War veterans. The study concluded that a decreased capacity to detoxify organophosphates resulting from low serum PON1 activity may have contributed to the development of Gulf War Syndrome. Mackness, B., et al., “Low Paraoxonase in Persian Gulf War Veterans Self-Reporting Gulf War Syndrome,” Biochemical and Biophysical Research Communications, 276:729-733 (2000). This study confirmed the same research results found among American Gulf War veterans. See: Haley, R.W., Billecke, S., & La Du, B.N., in “Association of Low PON1 Type Q (Type A) Arylesterase Activity with Neurologic Symptom Complexes in Gulf War Veterans,” Toxicol. Appl. Pharmacol., 157:227-233 (1999).
Likewise, normal butyryclolinesterase (BchE) reacts with sarin molecules; and the sarin molecules are then not available for inhibiting cholinesterase (a mechanism by which it damages the body). The BchE is inactivated in the process. Thus, the amount of BchE an individual has in his blood stream is significant, as is whether the individual has one of several common genetic variants from the normal, which are not capable of scavenging sarin. Aldrige, W.N., “Serum Esterases,” Biochem J., 53:110-124 (1953); Furlong, C., “PON1 Status and Neurologic Symptom Complexes in Gulf War Veterans,” Genome Research, 10:153-155 (2000); Loewenstein-Lichtenstein, Y., et al, “Genetic Predisposition to Adverse Consequences of Anticholinesterases in ‘Atypical’ BchE Carriers,” Nature Medicine, 10:1082-5 (October, 1995); Polhuijs, M., et al., “New Method for Retrospective Detection of Exposure to Organophosphorus Anticholinesterases: Application to Alleged Sarin Victims of Japanese Terrorists,” Toxicol. Appl. Pharmacol., 146:156-161 (1997); Broomfield, C.A., et al., “Protection by Butyrylcholinesterase Against Organophosphorus Poisoning in Nonhuman Primates,” J. Pharmacol. Exp. Ther., 259:633-638 (1991); and La Du, B.N., et al., “Phenotypic and Molecular Biological Analysis of Human Butyrylcholinesterase Variants,” Clin. Biochem., 23:423-431 (1990).
CORROBORATION REGARDING PYRIDOSTIGMINE BROMIDE
MAKING GULF WAR TROOPS MORE SUSCEPTIBLE TO
LOW-LEVEL SARIN EXPOSURES
U.S. troops in the Gulf War were given pyridostigmine bromide (“p.b.”) pills to protect them from nerve gas. “Based on experience of XVIII Airborne Corps medical personnel, compliance in combat units (in taking the p.b. pills) was well over 99% at the start of hostilities in January, 19991.” Keeler, J., et al, “Pyridostigmine Used as a Nerve Agent Pretreatment Under Wartime Conditions,” Journal of the American Medical Assn., 266(5): 693-695 at 694 (August 7, 1991). Unfortunately, it was not discovered until after the Gulf War that this actually made U.S. troops more vulnerable to any exposure to sarin, rather than protecting them. Research demonstrated that while pyridostigmine bromide pretreatment helped protect against soman nerve gas, it made the person worse concerning sarin nerve gas exposure. See: Koplovitz, I., Harris, L.W., Anderson, D.R., Lennox, W.J., and Stewart, J.R., “Reduction By Pyridostigmine Pretreatment of the Efficacy of Atropine and 2-PAM Treatment of Sarin and VX Poisoning in Rodents,” Fundamental and Applied Toxicology, 18:102-106 (1992); and U.S. Senate Committee on Veterans’ Affairs Staff Report, Is Military Research Hazardous To Veterans’ Heath? Lessons Spanning Half a Century, at p. 26 (December 8, 1994). The U.S. military has been ordered to stop use of p.b. pills. El Paso Times, August 24, 1999.
CORROBORATION REGARDING SYNERGISTIC EFFECTS
“For many years prior to the Gulf War, it has been known that simultaneous or sequential administration of two anti-AChE compounds can have synergistic or potentiating effects.” Jamal, G., “Gulf War Syndrome - A Model For The Complexity of Biological and Environmental Interaction with Human Health,” Adverse Drug. React. Toxicol. Rev., 17(1): 1-17 (1998). See also: McCain, W., et al., “Acute Oral Toxicity Study of Pyridostigmine Bromide, Permethrin and Deet in the Laboratory Rat,” J. of Toxicology and Environ. Health, 50:113-124 (1997).
The Gulf War was obviously a high stress environment. Soldiers had to repeatedly put on their Mission Oriented Protective Posture (MOPP) suit and gas mask, after chemical alarms began going off after the air war began. The MOPP gear, that had to necessarily be worn to help protect from biological and chemical exposure, caused overheating and other stress, itself. For example, in three pre-Gulf War studies of chemical/biological warfare training exercise, 10-20% of the participants experienced moderate to severe psychological symptomatology including anxiety, claustrophobia and panic. Fullerton, C., Ursano, R., “Health Care Delivery in the High-Stress Environment of Chemical and Biological Warfare,” Military Medicine, 159:524-528 (July, 1994); Fullerton, C., Ursano, R., “Behavioral and Psychological Responses to Chemical and Biological Warfare,” Military Medicine, 155:54-59 (February, 1990); and Brooks, F.R., et al., “Psychological Reactions During Chemical Warfare Training,” Military Medicine, 148:232-235 (March, 1983).
Stress is a “toxicity enhancing factor.” Jamal G., “Gulf-War Syndrome - A Model for the Complexity of Biological and Environmental Interaction with Human Health,” Adverse Drug React. Toxicol. Rev., 17(1):1-17, 6 (1998). “[A]n extensive literature documents the ability of stress to worsen other neurological insults ... Synoptic concentrations of acetylcholine - and, thus, neuronal excitability-can be increased by AchE inhibitors and also by stress.” Sapolsky, R., “The Stress of Gulf War Syndrome,” Nature, 393:308-309 (May 28, 1998). For the proposition that stress enhances susceptibility to, and damage from, toxic chemical exposure, see also: Gilbert, G.J., “Focal Breakdown of the Blood-Brain Barrier By Specific Sensory Stimulation,” Trans. Am. Neurolog. Ass’n., 90:246-248 (1965); Angel, C., “Adrenalectomy, Stress and the Blood-Brain Barrier,” Dis. Nerv. Syst., 27:389-393 (1966); Selye, H., Stress in Health and Disease, Butterworths, London (1966); Bondy, S.C., Purdy, J.L., “Selective Regulation of the Blood-Brain Barrier By Sensory Input,” Brain Res., 76:542-545 (1974); Belona, T.I., Jonsson, G., “Blood-Brain Barrier Permeability and Immobilization Stress,” Acta Physiol. Scand., 116:21-29 (1982); Ehrich, M., Gross, B., “Modification of Triorthotolyl Phosphate Toxicity in Chickens By Stress,” Toxicol. Appl. Pharmacol., 70:249 (1983); Estevez, E.E., et al., “Cholinergic Muscarinic Receptors in Rat Cerebral Cortex, Basal Ganglia, and Cerebellum Undergo Rapid and Reversible Changes After Acute Stress,” Neuroscience, 13:1353 (1984); Ryhanen, R., et al., “Physical Exercise Affects Cholinesterase and Organophosphate Response,” Gen. Pharmacol., 19:815 (1988); Sharma, H.S., “EEG Changes Following Increased Blood-Brain Barrier Permeability Under Long-Term Immobilization Stress in Young Rats,” Neurosci. Res., 5:224-239 (1988); Mizukawa, K., et al., “Alteration of Muscarinic Cholinergic Receptors in the Hippo-Campal Formation of Stressed Rat: In Vitro Quantitative Autoradiographic Analysis,” Brain Res., 478:187 (1989); Imperato, A., et al., “Changes in Brain Dopamine and Acetylcholine Release During and Following Stress Are Independent of the Pituitary-Adrenocortical Axis,” Brain Research, 538:111-117 (1991) [Stress causes increased release of dopamine and acetylcholine in the hippocampus]; Sharma, H.S., et al., “Increased Blood-Brain Barrier Permeability Following Acute Short-Term Swimming Exercise in Conscious Normotensive Young Rats,” Neurosci. Res., 10:211-221 (1991); Tsakiris, S., Kontopoulous, A.N., “Time Changes in ... Acetylcholinesterase Activities in the Rat Cerebrum and Cerebellum Caused by Stress,”Pharmacol. Biochem. Behav., 44:339 (1993); Melia, K.M., et al., “Induction and Habituation of Immediate Early Gene Expression in a Rat Brain by Acute and Repeated Restraint Stress,” J. Neurosci., 14:5929-5938 (1994); and Sorg, B., Prasad, B., “Potential Role of Stress and Sensitization in the Development and Expression of Multiple Chemical Sensitivity,” Environmental Health Perspectives, 105(2):467-470 (March, 1997); Asha T., Husain, K., et al., “Delayed Interactive Effects of Sarin, Pyridostigmine and Exercise on the Biochemical and Histopathological Changes in Mice,” Toxicologist, 54(1): 266A (2000).
In 1996, a very important study showed that pyridostigmine bromide (p.b.) did not cross the blood brain barrier (BBB) under normal (non-stress) circumstances, supporting earlier knowledge. However, crossing of the BBB was increased more than 100-fold in stressed animals. The authors concluded that exposing the animals to stress, produced more than 100-fold increase in permeability of the BBB to neurotoxins (such as the anticholinesterase sarin), and a virtual loss of the protective role of the BBB in shielding the brain from these harmful and toxic substances. Friedman, A., et al., “Pyridostigmine Brain Penetration Under Stress Enhances Neuronal Excitability and Induces Early Immediate Transcriptional Response,” Nature Medicine, 2:1382-5 (December, 1996). See also Hanin, I., “The Gulf War, Stress and a Leaky Blood-Brain Barrier,” Nature Medicine, 2(12):1307-1308 (December, 1996).
1. Visual Evoked Potential (VEP).
Sokol, S., “Visual Evoked Potentials,” in Aminoff, M.J. (ed), Electrodiagnosis in Clinical Neurology, Churchill Livingston, New York, pp. 467-503 (1986).
Haley, R.W., Hom, J., Roland, P.S., et al., “Evaluation of Neurological Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3): 223-230 (January 15, 1997).
Murata, K., et al., “Asymptomatic Sequelae to Acute Sarin Poisoning in the Central and Autonomic Nervous System 6 Months After the Tokyo Subway Attack,” J. Neurol., 244:601-606 (1997).
2&3. Brain Stem Auditory Evoked Potentials (BAEPs); and Somatosensory Evoked Potentials (SEPs).
Chiappa, K.H., Evoked Potentials in Clinical Medicine (2d ed.), Raven Press, New York (1990).
Hall, J.W., III, Handbook of Auditory Evoked Responses, Allyn & Bacon, Needham Heights, Mass, pp. 350-353 (1990).
Haley, R.W., Hon, J., Roland, P.S., et al., “Evaluation of Neurological Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3):223-230 (January 15, 1997).
4&5. Electronystagmography; and Bithermal Caloric Testing
Baloh, R.W., Honrubia, V., Clinical Neurophysiology of the Vestibular System, F.A. Davis Co. Publishers, Philadelphia (1983).
Roland, P.S., Otto, E., “Vestibular Dysfunction After Traumatic Brain Injury: Evaluation and Management,” in Ashley, M.J., Krych, D.K. (eds.), Traumatic Brain Injury Rehabilitation, CRC Press, Inc., Baca Raton, FL , pp. 131-169 (1995).
Haley, R.W., Hon, J., Roland, P.S., et al., “Evaluation of Neurological Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3):223-230 (January 15, 1997).
6. Audiovestibular testing
Ronald, P.S., Haley, R., Yellin, W., Owens, K., Shoup, A., “Vestibular Dysfunction in Gulf War Syndrome,” Otolaryngology, Head & Neck Surgery, 122:319-29 (2000).
7. A comprehensive neuropsychological battery of tests.
Korsak, R., Sato, M., “Effects of Chronic Organophosphate Pesticide Exposure on the Central Nervous System,” Clinical Toxicology, 11(1):83-95 (1977).
Haley, R.W., Hon, J., Roland, P.S., et al., “Evaluation of Neurolgoical Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3):223-230 (January 15, 1997).
Hom, J., Haley, R.W., Kurt, T.L., “Neuropsychological Correlates of Gulf War Syndrome,” Archives of Clinical Neuropsychology, 12:531-544 (1997).
Lange, G., et al., “Cognitive Functioning in Gulf War Illness,” Journal of Clinical and Experimental Neuropsychology, 23:240-49 (April, 2001).
8. Computerized postural sway testing (balance dysfunction in Gulf War veterans from toxic brain damage).
Dick, R.B., Bhattacharya, A., Skula, R., “Use of A Computerized Postural Sway Measurement System for Neurobehavioral Toxicology,” Neurotoxicology and Teratology, 12:1-6 (1990).
Jacobson, G.P., Newman, C.W., Kortush, J.M., Handbook of Balance Function Testing,, Mosby-Year Book, Inc., St. Louis, MO. (1993).
Lipp, M., Longridge, N.S., “Computerized Dynamic Posturography: Its Place in the Evaluation of Patients with Dizziness and Imbalance,” J. Otolaryngol., 23:177-183 (1994).
DiFabio, R.P., “Sensitivity and Specificity of Platform Posturography for Identifying Patients with Vestibular Dysfunction,” Phys. Ther., 75:290-305 (1995).
Haley, R.W., Hon, J., Roland, P.S., et al., “Evaluation of Neurolgoical Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3):223-230 (January 15, 1997).
Yokoyama, K., et al., “A Preliminary Study on Delayed Vestibulo-Cerebellar Effects of Tokyo Subway Sarin Poisoning in Relation to Gender Difference: Frequency Analysis of Postural Sway,” Journal of Occupational and Environmental Medicine, 40(1):17-21 (January, 1998).
9. Sinusoidal Harmonic Accelleration at Various Chain Rotation Speeds
Paige, G.D., “Nonlinearity and Asymmetry in Human Vestibulo-Ocular Reflex,” Acta Otolaryngol., 108:1-8 (1989).
Haley, R.W., Hon, J., Roland, P.S., et al., “Evaluation of Neurological Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3):223-230 (January 15, 1997).
10. Quantitative Tests of Cool and Vibratory Sensation in the Extremities
Haley, R.W., Hon, J., Roland, P.S., et al., “Evaluation of Neurological Function in Gulf War Veterans: A Blinded Case-Control Study,” Journal of the American Medical Assn., 277(3):223-230 (January 15, 1997).
11. Genetic testing to determine susceptibility to sarin exposure.
See page 9 above, for applicable citations.
12. Magnetic resonance and abnormal single photon emission computed tomography (SPECT) scans of the brain.
Callender, T.J., Morrow, L., et al, “Three-Dimensional Brain Metabolic Imaging in Patients with Toxic Encephalopathy”, Environmental Research, 60:295-319 (1993).
Bonte, F.J., et al., “Brain Blood Flow in the Dementias: SPECT with Histopathologic Correlation,” Radiology, 186:361-365 (1993).
Heuser, G., et al., “Neurospect Findings in Patients Exposed to Neurotoxic Chemicals,” Toxicology and Industrial Health, 10:561-71 (1994).
Gunes, I., et al., “Acute Organophosphate Poisoning Tc99m HMPAO SPECT Imaging of the Brain,” Clin. Nucl. Med., 19:330-332 (1994).
Simon, T.R., et al., “Single Photon Emission Computed Tomography of the Brain in Patients with Chemical Sensitivities,” Toxicology and Industrial Health, 10:573-577 (1994) [A study of Gulf War veterans].
Fincher, E.F., et al., “Comparison of Single Photon Emission Computed Tomography Findings in Cases of Healthy Adults and Solvent Exposed Adults,” Am. J. Ind. Med., 31:4-14 (1997).
Yilmazlar, A. & Ozyurt, G., “Brain Involvement in Organophosphate Poisoning,” Environmental Research, 74:104-109 (1997).
“Scanning For Gulf War Syndrome,” Science News, 151:245 (April 19, 1997).
Ross, G.H., “Neurotoxicity in Single Photon Emission Computed Tomography Brain Scans of Patients Reporting Chemical Sensitivities”, Toxicology and Industrial Health, 15:415-420 (1999).
Haley, R.W., Marshall, W.W., McDonald, G.G., Daugherty, M., Petty, F., Fleckenstein, J.L., “Brain Abnormalities in Gulf War Syndrome: Evaluation by ‘H Magnetic Resonance Spectroscopy,” Radiology, 215:807-817 (2000).
The following six U.S. Department of Labor Administrative Law Judge decisions were Defense Base Act cases. They involved American civilians, contracted to the Department of Defense, who were in the Gulf War in support of U.S. troops. They were maintaining helicopters, tanks or other military equipment. After a trial in each case objectively proved neurotoxic brain damage, each was found by the Court in their respective cases to have Gulf War Illness. Four of these men were employed by General Dynamics, which has intervened in the present lawsuit to recover the medical and indemnity compensation benefits that they have paid to their employees because of their Gulf War Illness. The six cases that were litigated to a successful conclusion for these men were:
1.) Herman S. Piceynski vs. DynCorp and Insurance Co. of the State of PA., OWCP No. 02-109497, Case No. 1994-LHC-2387, BRB No. 97-1451 (Decision and Order of the Benefits Review Board on July 17, 1998), (Decision and Order of U.S. Administrative Law Judge James W. Kerr, Jr. on Remand - October 18, 1999).
2.) Karl B. Lane vs. Bell Helicopter Co. and Cigna, OWCP No. 02-116605, Case No. 1998-LHC-1012 (Decision and Order of U.S. Administrative Law Judge James W. Kerr, Jr. on June 4, 1999); BRB No. 99-1007 and 99-1007A (Decision and Order of the Benefits Review Board on June 23, 2000).
3.) Donald L. Frans, Jr. vs. General Dynamics Corp. and Travelers Ins. Co., OWCP No. 02-119197, Case No. 2000-LHC-0593 (Decision and Order of U.S. Administrative Law Judge James W. Kerr, Jr. on January 22, 2001).
4.) James T. Keenan vs. General Dynamics Corp. and Travelers Ins. Co., OWCP No. 02-118766, Case No. 2000-LHC-0349 (Decision and Order of U.S. Administrative Law Judge James W. Kerr, Jr. on February 22, 2001).
5.) John W. Knebel vs. General Dynamics Corp. and Travelers Ins. Co., OWCP No. 02-118659, Case No. 2000-LHC-1290 (Decision and Order of U.S. Administrative Law Judge C. Richardson Avery on March 22, 2001).
6.) Larry L. Pascaretti vs. General Dynamics Corp. and Travelers Ins. Co., OWCP No. 2-116652, Case No. 2000-LHC-1293 (Decision and Order of U.S. Administrative Law Judge C. Richard Avery on April 18, 2001).
CITATIONS TO OTHER GENERAL CORROBATORY RESEARCH
1. Grob, D., Harvey, A.M., “The Effects and Treatment of Nerve Gas Poisoning,” American Journal of Medicine, 52-63 (January, 1953); and Grob, D., Harvey, J., “Effects in Man of the Anticholinesterase Compound Sarin,” Journal of Clinical Investigation, 37:350-368 (1958);[Inhibition of ChE by nerve gas is irreversible and cumulative, making one more susceptible because of exposures in previous days or weeks].
2. Holmes, J.H., Gaon, M., “Observations on Acute and Multiple Exposure to Anticholinesterase Agents,” Transactions of the American Clinical and Climatological Assn., 68:86-103 (1956).
3. Spiegelberg, U., “Psychopathologisch-Neurologische Schaden Nach Einwirkung Synthetischer Gifte, in Wehrdienst und Gesundheit,” Vol III, Wehrund Wissen Verlagsgesellschaft mbH, Darmstadt, Germany (1961) [Workers engaged in German chemical warfare production plants showed persistent neurological abnormalities more than 10 years after low-level exposure to nerve agents.].
4. Johnson, M.K., “A Phosphorylation Site in the Brain and the Delayed Neurotoxic Effects of Some Organophosphate Compounds,” Biochem. J., 111:489-95 (1969).
5. Johnson, M.K., “Organophosphorus and Other Inhibitors of Brain ‘Neurotoxic Esterase’ and the Development of Delayed Neurotoxicity in Hens,” Biochem. J., 120:523-531 (1970).
6. Sidell, F.R., “Soman and Sarin: Clinical Manifestations and Treatment of Accidental Poisoning by Organophosphates,” Clinic. Toxicol., 7:1 (1974).
7. Stockholm International Peace Research Institute, Delayed Toxic Effects of Chemical Warfare Agents, Almquist & Wiksell Int., New York (1975).
8. Baron, R.L., “Delayed Neurotoxicity and Other Consequences of Organophosphate Esters,” Ann. Review of Entomology, 26:29-48 (1981).
9. Flynn, C., Wecker, L., “Elevated Choline Levels in Brain: A Non-Chollinergic Component of Organophosphate Toxicity,” Biochem. Pharmacol., 35:3115-3121 (1986).
10. Flynn, C.J., Wecker, L., “Elevated Choline Levels in Brain: A Non-Cholinergic Component of Organophosphate Toxicity,” Biochem. Pharmacol., 35:3115-3121 (1986) [Sarin has another neurotoxic action, in addition to the inhibitory action on brain ChE].
11. Cherniak, M.G., “Organophosphorus Esters and Polyneuropathy,” Annals of Internal Medicine, 104(2): 264-266 (February, 1986).
12. Goldstein, B.D., et al., “Electrophysiological Changes in the Primary Sensory Neuron Following Subchronic Soman and Sarin: Alterations in Sensory Receptor Function,” Toxicol. Appl. Pharmacol., 91:55 (1987).
13. Singer, A.W., Jaax, N.K., Graham, J.S., McLeod, C.G., Jr., “Cardiomyopathy in Soman- and Sarin-Intoxicated Rats,” Toxicol. Letters, 36:243 (1987).
14. Drewes, L.R., Singh, A.K., “Choline Transport and Metabolism in Soman- or Sarin-Intoxicated Brain,” J. Neurochem., 50:868-875 (1988) [Lesions from sarin seem to lie in the cerebral cortex, brainstem and hippocampus].
15. Nieminen, S.A., “Acute Behavioral Effects of the Organophosphates Sarin and Soman in Rats,” Pharmacology & Toxicology, 67:36-40 (July, 1990).
16. Sirkka, U., Nieminem, S.A., Ylitalo, P., “Neurobehavioral Toxicity With Low Doses of Sarin and Soman,” Methods Find. Exp. Clin. Pharmacol., 12:245 (1990).
17. Schupper, H., Rosenberg, P., “Effects of Diisopropyl Phosphofluoridate, Sarin and Soman on the Accessibility of Proteins, in the Electroplax Membrane, to Lactoperoxidase-Catalyzed Iodination,” Biochemical Pharmacology, 42(7):1463-1473 (1991) [Sarin changed protein organization which could be associated with changes in membrane functioning, in addition to ChE inhibition effects].
18. Bucci, T.J., Parker, R.M., Toxicity Studies on Agents GB and BD (Phase II): 90-Day Subchronic Study of GB (Sarin, Type III) in CD-Rats, ADA A 248628, Jefferson, AR: National Center for Toxicological Research (1992).
19. Fitzgerald, B., Costa, L., “Modulation of Muscarinic Receptors and Acetylcholinesterase Activity in Lymphocytes and in Brain Areas Following Repeated Organophosphate Exposure in Rats,” Fundamental and Applied Toxicology, 20:210-216 (1993).
20. U.S. Senate, Committee on Banking, Housing and Urban Affairs, U.S. Chemical and Biological Warfare-Related Dual Use Exports to Iraq and Their Possible Impact on the Health Consequnces of the Persian Gulf War, Washington, D.C. (May 25, 1994).
21. Jamal, G., “Long Term Neurotoxic Effects of Organophosphate Compounds”, Adverse Drug React. Toxicol. Rev., 14(2) 85-99 (1995).
22. Jamal, G., et al., “The ‘Gulf War Syndrome.’ Is There Evidence of Dysfunction in the Nervous System?” J. Neurol. Neurosurg. Psychiat., 60:449-51 (1996).
23. Jamal, G., “Gulf War Syndrome”, Biologist, 43:98-9 (1996).
24. Prendergast, M., Terry, A., Buccafusco, J., “Chronic, Low-Level Exposure to Diisopropylfluorophosphate Causes Protracted Impairment of Spatial Navigation Learning,” Psychopharmacology, 129:183-191 (1997).
25. U.S. Congress, Committee on Government Reform and Oversight, Gulf War Veterans’ Illnesses: VA, DoD Continue to Resist Strong Evidence Linking Toxic Causes to Chronic Health Effects, (November 7, 1997).
26. Eddington, P.G. (former CIA analyst), Gassed In The Gulf, Insignia Pub. Co., Washington, D.C. (1997).
27. Sidell, F., Takafuji, E., Franz, D., Medical Aspects of Chemical and Biological Warfare, U.S. Army Medical Research and Material Command, Ft. Detrick, Md.; Office of the Surgeon General, U.S. Army, Falls Church, Va. (1997) [at p. 240: “mild neuropsychiatric changes occur after even low-dose nerve agent exposure”].
28. Bell, I., et al., “Illness from Low Levels of Environmental Chemicals: Relevance to Chronic Fatigue Syndrome and Fibromyalgia,” American Journal of Medicine, 105:745-825 (September 28, 1998).
29. Jamal, G., “Gulf War Syndrome - A Model for the Complexity of Biological and Environmental Interaction with Human Health,” Adverse Drug React. Toxico. Rev., 17(1): 1-17 (1998).
30. Joellenbeck, L., “Gulf War Veterans’ Illnesses: A Case Study in Causal Inference,” Environmental Research, 79:71-81 (1998).
31. Wolfe, Jessica, et al., “Health Symptoms Reported by Persian Gulf War Veterans Two Years After Return,” American Journal of Industrial Medicine, 33:104-113 (1998) [Reported exposure to poison gas is related to higher symptom reporting].
32. U.S. Department of Defense, DoD Strategy to Address Low-Level Exposures to Chemical Warfare Agents (CWAS), (May, 1999).
33. Urnovitz, H.B., Tuite, J.J., Hagashida, J.M., Murphy, W.H., “RNAs in the Sera of Pesian Gulf War Veterans Have Segments Homologous to Chromosome 22q11.2,” Clinical and Diagnostic Laboratory Immunology, 6(3): 330-335 (May, 1999).
34. Nakajima, T., et al., “Sequelae of Sarin Toxicity at One and Three Years After Exposure in Matsumoto, Japan,” J. Epidemiol. 9(5):337-343 (1999).
35. U.S. Congress Staff Report, V.A. Data Shows Increased Percentage of Undiagnosed Illness and Total Disability Among Certain Groups of Veterans Who Served in Southwest Asia Between August 2, 1990 and July 31, 1991, (October 25, 1999) [The percentage of veterans awarded permanent disability who were within the Khamisiyah nerve gas plume is seven times higher than those deployed to the Persian Gulf in general].
36. Asha, T., Husain, K., et al., “Delayed Interactive Effects of Sarin, Pyridostigmine and Exercise on the Biochemical and Histopathological Changes in Mice,” Toxicologist, 54(1):266A (2000).
37. Jones, K.H., Dech Kovshaia, A.M., Khan, W.A., Abou-Donia, M.B., “Sarin and Stress Modulation of Nicotonic and Muscarinic Acetylcholine Receptors in Sarin Exposed Rats,” Toxicologist, 54(1):324A (2000).
38. Peckerman, A., Lamara, J., Smith, S., “Cardiovascular Stress Responses and Their Relation to Symptoms in Gulf War Veterans with Fatiguing Illness,” Psychosomatic Medicine, 62: 509-516 (2000).
39. Henderson, R.F., et al., “Effect of Low Level Sarin Exposure on Physiological Parameters in Rats,” Toxicologist, 54(1):266A (2000).
Dated: January 9, 2002
Respectfully submitted,
PITTS & ASSOCIATES
______________________________ Gary B. Pitts State Bar No. 16054200 8866 Gulf Freeway, Suite 117 Houston, Texas 77017-6528 (713) 910-0555 (713) 910-0594 Fax
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