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Appendix H
IOM’s Statements of Task and Conclusions for Agent Orange and Gulf War Reports

APPENDIX H-1
Statements of Task for IOM Reports on Agent Orange

1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam

Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides

Statement of Task:

Review and summarize the strength of the scientific evidence concerning the association between herbicide exposure during Vietnam service and each disease or condition suspected to be associated with such exposure. Determine, if possible:

  1. Whether there is a statistical association between the suspect diseases and herbicide use, taking into account the strength of the scientific evidence and the appropriateness of the methods used to detect the association;

  2. The increased risk of disease among individuals exposed to herbicides during service in Vietnam; and

  3. Whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a disease.

The committee was also asked to make recommendations concerning the need, if any, for additional scientific studies to resolve areas of continuing scientific uncertainty and to comment on four particular programs mandated in Public Law 102-4 (the Agent Orange Act of 1991).

1996. Veterans and Agent Orange: Update 1996

Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides

Statement of Task:

Conduct a comprehensive review of the evidence that has become available since the previous (Veterans and Agent Orange) IOM committee report and reassess its determinations and



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Appendix H IOM’s Statements of Task and Conclusions for Agent Orange and Gulf War Reports APPENDIX H-1 Statements of Task for IOM Reports on Agent Orange 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides Statement of Task: Review and summarize the strength of the scientific evidence concerning the association be- tween herbicide exposure during Vietnam service and each disease or condition suspected to be associated with such exposure. Determine, if possible: 1. Whether there is a statistical association between the suspect diseases and herbicide use, taking into account the strength of the scientific evidence and the appropriateness of the methods used to detect the association; 2. The increased risk of disease among individuals exposed to herbicides during service in Vietnam; and 3. Whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a disease. The committee was also asked to make recommendations concerning the need, if any, for ad- ditional scientific studies to resolve areas of continuing scientific uncertainty and to comment on four particular programs mandated in Public Law 102-4 (the Agent Orange Act of 1991). 1996. Veterans and Agent Orange: Update 1996 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides Statement of Task: Conduct a comprehensive review of the evidence that has become available since the previ- ous (Veterans and Agent Orange) IOM committee report and reassess its determinations and H-1

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H-2 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS estimates of statistical association, risk, and biological plausibility. For each disease, deter- mine, to the extent that available data permitted meaningful determinations: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ological methods used to detect the association; 2. The increased risk of the disease among those exposed to herbicides during Vietnam ser- vice; and 3. Whether there is a plausible biological mechanism or other evidence of a causal relation- ship between herbicide exposure and the disease. The committee was also asked to address the following specific areas of concern as requested by the Department of Veterans Affairs (VA): • The relationship between exposure to herbicides and the development of acute and subacute peripheral neuropathy; • The relationship between exposure to herbicides and the development of prostate cancer, hepatobiliary cancer, and nasopharyngeal cancer; and • The relationship between the length of time since first exposed and the possible risk of cancer development. 1999. Veterans and Agent Orange: Update 1998 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Sec- ond Biannual Update) Statement of Task: Conduct a second review and evaluation of the newly published scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in her- bicides used in Vietnam. For each disease, determine, to the extent that available data permit- ted meaningful determinations: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ologic methods used to detect the association; 2. The increased risk of the disease among those exposed to herbicides during Vietnam ser- vice; and 3. Whether there is a plausible biological mechanism or other evidence of a causal relation- ship between herbicide exposure and the disease. The committee also addressed the following specific areas of interest as identified by VA: • The relationship between exposure to herbicides and the subsequent development of dia- betes; • The issue of the latency between exposure to herbicides and development of adverse health outcomes; • The classification of chondrosarcomas of the skull;

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APPENDIX H H-3 • Herbicide exposure assessment for Vietnam veterans; and • The potential for using data combination methodologies to informatively reexamine ex- isting data on the health effects of herbicide or dioxin exposure. 2000. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes Committee to Review the Evidence Regarding the Link Between Exposure to Agent Orange and Diabetes Statement of Task: Conduct a focused review of the scientific evidence regarding the association, if any, be- tween type 2 diabetes and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. Determine, to the extent that available data permitted meaningful determi- nations: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ologic methods used to detect the association; 2. The increased risk of the disease among those exposed to herbicides during Vietnam ser- vice; and 3. Whether there is a plausible biological mechanism or other evidence of a causal relation- ship between herbicide exposure and the disease. 2001. Veterans and Agent Orange: Update 2000 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Third Biennial Update) Statement of Task: Conduct a third review and evaluation of the newly published scientific evidence regarding associations between health outcomes and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. For each disease, determine, to the extent that available data permitted meaningful determinations: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ologic methods used to detect the association; 2. The increased risk of the disease among those exposed to herbicides during Vietnam ser- vice; and 3. Whether there is a plausible biologic mechanism or other evidence of a causal relation- ship between herbicide exposure and the disease. At VA’s request, the committee also examined the possible association between the herbi- cides of concern in this report and AL-type primary amyloidosis, a condition not examined in previous Veterans and Agent Orange reports.

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H-4 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides Statement of Task: Conduct a review of the scientific evidence regarding the association between exposure to dioxin and other chemical compounds in herbicides used in Vietnam and acute myelogenous leukemia in the offspring of Vietnam veterans. Determine, to the extent that available data permitted meaningful determinations: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ologic methods used to detect the association; 2. The increased risk of the disease associated with exposure to herbicides during Vietnam service; and 3. Whether there is a plausible biological mechanism or other evidence of a causal relation- ship between herbicide exposure and the disease. 2003. Veterans and Agent Orange: Update 2002 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update) Statement of Task: Conduct a fourth review and evaluation of the newly published scientific evidence regarding the association between exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other chemical compounds contained in herbicides used in Vietnam and a wide range of health ef- fects. Determine, to the extent that available data permit meaningful determinations: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ological methods used to detect the association; 2. The increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and 3. Whether there exists a plausible biological mechanism or other evidence of a causal rela- tionship between herbicide exposure and the disease. 2004. Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides Statement of Task: Undertake a review and evaluation of the evidence regarding the period between cessation of exposure to herbicides used in Vietnam and their contaminants (2,4-D; 2,4,5-T and its con- taminant TCDD; cacodylic acid; and picloram) and the occurrence of respiratory cancer.

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APPENDIX H H-5 2005. Veterans and Agent Orange: Update 2004 Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fifth Biennial Update) Statement of Task: Determine (to the extent that available scientific data permit meaningful determinations) the following regarding associations between specific health outcomes and exposure to TCDD and other chemical compounds in herbicides: 1. Whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemi- ological methods used to detect the association; 2. The increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and 3. Whether there exists a plausible biological mechanism or other evidence of a causal rela- tionship between herbicide exposure and the disease. 2007. Veterans and Agent Orange: Update 2006. The Sixth Biennial Update report on Veter- ans and Agent Orange was released at the end of July 2007. The report was in development at the same time as and independent of the Committee’s report, and therefore, was unavailable to the Committee during their deliberations. REFERENCES IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health effects of herbicides used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/dioxin exposure and type 2 diabetes. Wash- ington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2002. Veterans and Agent Orange: Herbicide/dioxin exposure and acute myelogenous leu- kemia in the children of Vietnam veterans. Washington, DC: The National Academies Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Acad- emies Press. IOM. 2004. Veterans and Agent Orange: Length of presumptive period for association between exposure and respiratory cancer. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Acad- emies Press. IOM. 2007. Veterans and Agent Orange: Update 2006. Washington, DC: The National Acad- emies Press.

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H-6 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS APPENDIX H-2 Statements of Task for IOM Reports on Gulf War 2000. Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines Committee on Health Effects Associated with Exposures During the Gulf War Summary of Charge: The purpose of this study was to conduct a review of the scientific and medical literature re- garding adverse health effects associated with exposures experienced during the Persian Gulf War. The review included assessments of biological plausibility that exposures, or synergis- tic effects of combinations of exposures, are associated with illnesses experienced by Gulf War veterans. The review also included recommendations for additional scientific studies to resolve areas of continued scientific uncertainty related to the health consequences of Gulf War service. Exposures considered included depleted uranium, chemical warfare agents (sa- rin and cyclosarin), pyridostigmine bromide, and vaccines (anthrax and botulinum toxoid). 2003. Gulf War and Health, Volume 2: Insecticides and Solvents Committee on Gulf War and Health: Literature Review of Pesticides and Solvents Summary of Charge: This committee reviewed the peer-reviewed literature on long-term health outcomes associ- ated with exposure to classes of insecticides (such as organophosphorous compounds) identi- fied as having been used in the Persian Gulf, as well as 53 specific solvents. The committee’s review focused primarily on epidemiologic studies of humans who had been exposed to these insecticides and solvents in occupational settings. Where available, studies of Gulf War vet- erans were included as well. Information on plausible biologic mechanisms of health out- comes came from toxicological and experimental data studies of both humans and animals. 2004. Gulf War and Health: Updated Literature Review of Sarin Committee on Gulf War and Health: Updated Literature Review of Sarin Summary of Charge: Following publication of studies of sarin exposure from terrorist attacks in Japan, toxicologi- cal studies of low-dose exposure to sarin, and possible sarin exposure of veterans during the Gulf War, this ad hoc committee was formed and tasked with conducting an updated assess- ment of the literature on health outcomes associated with exposure to sarin and cyclosarin. The review built upon the information previously developed by earlier IOM reports on health outcomes associated with exposure to sarin and related compounds. In its final report, the committee also outlined recommendations for additional studies to resolve areas of continued scientific uncertainty. 2005. Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants Committee on Gulf War and Health: Literature Review of Selected Environmental Particulates, Pollutants, and Synthetic Chemical Compounds Summary of Charge:

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APPENDIX H H-7 This committee reviewed the scientific literature to examine the health effects of hydrazines, red fuming nitric acid, hydrogen sulfide, oil-fire by-products, diesel-heater fumes, and fuels (for example, jet fuel and gasoline). The committee’s review focused on epidemiologic stud- ies but included other relevant literature with regard to chronic medical effects of exposure, including studies of Gulf War veterans. The committee was also charged with determining, to the extent permitted by available scientific data, the increased risk of illness among people exposed to the putative agents during service in the Persian Gulf. 2006a. Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War Committee on Gulf War and Health: A Review of the Medical Literature Relative to Gulf War Veterans’ Health Summary of Charge: The work of this committee was different from that of prior Gulf War and Health committees in that this study was an attempt to summarize health outcomes associated with deployment, rather than health outcomes associated with a specific biologic or chemical agent believed to have been present in the Gulf. This study was developed to inform the VA of illnesses among Gulf War veterans that might not have been evident at the time. The committee’s specific charge was to review, evaluate, and summarize the peer-reviewed scientific and medical lit- erature addressing the health status of Gulf War veterans. The committee reviewed epidemi- ologic studies to draw conclusions regarding long-term health outcomes (such as cancer, car- diovascular disease, and nervous system disorders) associated with serving in the Gulf War. 2006b. Posttraumatic Stress Disorder: Diagnosis and Assessment Subcommittee on Posttraumatic Stress Disorder of the Committee on Gulf War and Health: Physiologic, Psychologic, and Psychosocial Effects of Deployment-Related Stress Summary of Charge: This committee’s task was to review the scientific and medical literature related to the diag- nosis and assessment of posttraumatic stress disorder (PTSD). The committee was also given a series of specific questions from VA regarding diagnosis and assessment of PTSD. These included, among others, questions regarding accepted diagnostic criteria for PTSD, how best to diagnose and document stressful events, and the components of an evidence-based diagno- sis of PTSD. The committee relied primarily on reviews and other well-documented sources to form conclusions regarding diagnosis and assessment of PTSD. The committee will, at a later date, deliver a second report on PTSD treatments and their efficacy, and also comment on the chronicity of PTSD, the potential for recovery, and the value of early intervention. 2007. Gulf War and Health, Volume 5: Infectious Diseases Committee on Gulf War and Health: Infectious Diseases Summary of Charge: This committee evaluated the scientific and medical literature on long-term adverse human health outcomes associated with nine infectious diseases potentially acquired by veterans during the Gulf War. These infectious diseases included brucellosis, campylobacteriosis, leishmaniasis, malaria, Q fever, salmonellosis, shigellosis, tuberculosis, and West Nile fever.

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H-8 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS The committee’s report also included information on specific diseases and agents reported in the published literature or popular press to have infectious agents and to have caused illnesses in veterans of the Gulf War, Operation Iraqi Freedom, and Operation Enduring Freedom. REFERENCES IOM (Institute of Medicine). 2000. Gulf War and health, volume 1: Depleted uranium, pyri- dostigmine bromide, sarin, vaccines. Washington, DC: National Academy Press. IOM. 2003. Gulf War and health, volume 2: Insecticides and solvents. Washington, DC: The Na- tional Academies Press. IOM. 2004. Gulf War and health: Updated literature review of sarin. Washington, DC: The Na- tional Academies Press. IOM. 2005. Gulf War and health, volume 3: Fuels, combustion products, and propellants. Wash- ington, DC: The National Academies Press. IOM. 2006a. Gulf War and health, volume 4: Health effects of serving in the Gulf War. Washing- ton, DC: The National Academies Press. IOM. 2006b. Posttraumatic stress disorder: Diagnosis and assessment. Washington, DC: The National Academies Press. IOM. 2007. Gulf War and health, volume 5: Infectious diseases. Washington, DC: The National Academies Press. APPENDIX H-3 Conclusions from IOM’s Agent Orange Biennial Reports1 Sufficient Evidence of an Association Evidence is sufficient to conclude that there is a positive association. That is, a positive associa- tion has been observed between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example, if several small studies that are free from bias and confounding show an association that is consistent in magni- tude and direction, there may be sufficient evidence for an association. • Chloracne (1994) Chronic lymphocytic leukemia (CLL) (2003)2 • • Hodgkin’s disease (1994) • Non-Hodgkin’s lymphoma (1994) • Porphyria cutanea tarda (in genetically susceptible individuals) (1994) • Soft tissue sarcoma (1994) 1 NOTE: “Herbicides” refers to the major herbicides used in Vietnam, which include 2,4-D (2,4- dichlorophenoxyacetic acid), 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), TCDD (2,3,7,8-tetrachlorodibenzo-p- dioxin)—2,4,5-T contaminant, cacodylic acid, picloram. The evidence regarding association was drawn from occu- pational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. 2 Previously listed under Inadequate/Insufficient Evidence category (as leukemia).

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APPENDIX H H-9 Limited/Suggestive Evidence of an Association Evidence is suggestive of an association between herbicides and the outcome but is limited be- cause chance, bias, and confounding could not be ruled out with confidence. For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent. • Acute and subacute peripheral neuropathy (1996); acute and subacute transient peripheral neuropathy (1999); early-onset transient peripheral neuropathy (2005) • Acute myelogenous leukemia (AML) in the children of veterans (2001) • Multiple myeloma (1994) • Porphyria cutanea tarda (1996)3 • Prostate cancer (1994) • Respiratory cancers (lung, larynx, trachea) (1994); respiratory cancers (lung/bronchus, larynx, trachea) (1999); respiratory cancer (of lung and bronchus, larynx, and trachea) (2003) • Spina bifida (1996); spina bifida in the children of veterans (1999); spina bifida in the off- spring of exposed individuals (2005) • Type 2 diabetes (2000)4 Inadequate/Insufficient Evidence to Determine Whether an Association Exists The available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to con- trol for confounding, have inadequate exposure assessment, or fail to address latency. • Abnormal sperm parameters and infertility (1994); abnormal sperm characteristics and in- fertility (2003) • AL-type primary amyloidosis (2001) • Birth defects (1994); birth defects (other than spina bifida) (1996); birth defects (other than spina bifida) in the offspring of exposed individuals (2005) • Bone cancer (1994); bone and joint cancer (2005) • Breast cancer (1994) • Childhood cancer in offspring (1994); childhood cancer in offspring, other than AML (2001); childhood cancer in offspring, including AML (2003); childhood cancer (includ- ing AML) in offspring of exposed individuals (2005) • Circulatory disorders (1994) • Cognitive and neuropsychiatric disorders (1994); neurobehavioral disorders (cognitive and neuropsychiatric) (2005) • Effects on thyroid homeostasis (2003) • Endometriosis (2003) 3 Previously listed under Sufficient Evidence of an Association category (as porphyria cutanea tarda [in genetically susceptible individuals]). 4 Previously listed under Inadequate/Insufficient Evidence category (within metabolic and digestive disorders [dia- betes, changes in liver enzymes, lipid abnormalities, ulcers]).

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H-10 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS • Female reproductive cancers (cervical, uterine, ovarian) (1994) • Hepatobiliary cancers (1994) • Immune system disorders (immune modulation and autoimmunity) (1994); immune sys- tem disorders (immune suppression and autoimmunity) (1996) • Leukemia (1994); leukemia (other than CLL) (2003) • Low birthweight (1994); low birthweight in offspring of exposed individuals (2005) • Metabolic and digestive disorders (diabetes, changes in liver enzymes, lipid abnormalities, ulcers) (1994); gastrointestinal, metabolic and digestive disorders (changes in liver en- zymes, lipid abnormalities, ulcers) (2001) • Motor/coordination dysfunction (1994); movement disorders, including Parkinson’s dis- ease and amyotrophic lateral sclerosis (ALS) (2005) • Nasal/nasopharyngeal cancer (1994); oral, nasal, and pharyngeal cancer (2005) • Neonatal/infant death and stillbirths (1994); neonatal or infant death and stillbirth in off- spring of exposed individuals (2005) • Peripheral nervous system disorders (1994); chronic peripheral nervous system disorders (1996) • Renal cancer (1994) • Respiratory disorders (1994) • Skin cancers (1996);5 skin cancers (melanoma, basal, and squamous) (2001); skin cancers (melanoma, basal cell, and squamous cell) (2005) • Spontaneous abortion (1994) • Testicular cancer (1994) • Urinary bladder cancer (1999)6 Limited/Suggestive Evidence of No Association Several adequate studies, covering the full range of levels of exposure that human beings are known to encounter, are mutually consistent in not showing a positive association between ex- posure to herbicides and the outcome at any level of exposure. A conclusion of “no association” is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. • Bladder cancer (1994) • Brain tumors (1994) • Gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, rectal cancer) (1994); gastrointestinal tumors (esophagus, stomach, pancreas, colon, rectum) (2005) • Skin cancer (1994) REFERENCES IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health effects of herbicides used in Vietnam. Washington, DC: National Academy Press. 5 Previously listed under Limited/Suggestive Evidence of No Association category. 6 Previously listed under Limited/Suggestive Evidence of No Association category (as bladder cancer).

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APPENDIX H H-11 IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/dioxin exposure and type 2 diabetes. Wash- ington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Acad- emies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Acad- emies Press. APPENDIX H-4 Conclusions from IOM’s Gulf War and Health Series Volumes 1, 2, 3, 5, and Updated Literature Review of Sarin7 Sufficient Evidence of a Causal Relationship Evidence is sufficient to conclude that there is a causal association between exposure to a spe- cific agent and a specific health outcome in humans. The evidence is supported by experimental data and fulfills the guidelines for sufficient evidence of an association (below). The evidence must be biologically plausible and satisfy several of the guidelines used to assess causality, such as strength of association, dose–response relationship, consistency of association, and a tempo- ral relationship. • Benzene and • acute leukemia (2003) • aplastic anemia (2003) • Coxiella burnettii infection (Q fever) and osteomyelitis (2007) • Malarial infection and ophthamologic, hematologic, and renal manifestations as well as later presentation of or relapse of disease months to years after acute infection (2007) • Mycobacterium tuberculosis infection and occurrence of active (tuberculosis) TB months to decades after infection (2007) • Sarin and a dose-dependent acute cholinergic syndrome that is evident seconds to hours subsequent to sarin exposure and resolves in days to months (2000) Sufficient Evidence of an Association Evidence is sufficient to conclude that there is a positive association. That is, a consistent posi- tive association has been observed between exposure to a specific agent and a specific health outcome in human studies in which chance and bias, including confounding, could be ruled out with reasonable confidence. For example, several high-quality studies report consistent positive 7 The Gulf War Volume 4 summary of evidence is not included in this review because that committee’s charge was to examine health outcomes related to deployment in general, rather than the specific biological or chemical agents believed to have been present in the Gulf region (IOM, 2006).

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H-12 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS associations, and the studies are sufficiently free of bias, including adequate control for con- founding. • Active TB and long-term adverse health outcomes due to irreversible tissue damage from severe forms of pulmonary and extrapulmonary TB (2007) • Anthrax vaccination and transient acute local and systemic effects (2000) • Benzene and adult leukemia (2003) • Botulinum toxoid vaccination and transient acute local and systemic effects (2000) • Brucellosis and • arthritis and spondylitis (2007) • cardiovascular, nervous, and respiratory system infections (2007) • chronic meningitis and meningoencephalitis (2007) • hepatic abnormalities, including granulomatous hepatitis (2007) • orchioepididymitis and infections of the genitourinary system (2007) • uveitis (2007) • Campylobacter infection and reactive arthritis (ReA) if ReA is manifest within 3 months of the infection (2007) • Campylobacter jejuni infection and Guillain-Barre syndrome (GBS) if GBS is manifest within 2 months of infection (2007) • Combustion products and lung cancer (2005) • Coxiella burnetii infection (Q fever) and • chronic hepatitis years after primary infection (2007) • endocarditis years after primary infection (2007) • vascular infection years after primary infection (2007) • Nontyphoid Salmonella infection and ReA if ReA is manifest within 3 months of the in- fection (2007) • Plasmodium falciparum infection with recrudescence weeks to months after the primary infection, but only in the case of inadequate therapy (2007) • Plasmodium malariae infection and manifestation of immune-complex glomerulonephritis years to decades later (2007) • Propylene glycol and allergic contact dermatitis (2003) • Pyridostigmine bromide and transient acute cholinergic effects in doses normally used in treatment and for diagnostic purposes (2000) • Shigella infection and • hemolytic-uremia syndrome (HUS) if HUS is manifest within 1 month of the infection (2007) • ReA if ReA is manifest within 3 months of the infection (2007) • Solvents and acute leukemia (2003) • Visceral leishmaniasis (kala-azar) and • delayed presentation of the acute clinical syndrome (2007) • Post-kala-azar dermal leishmaniasis (PKDL) if PKDL occurs generally within 2 years of the initial infection (2007)

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APPENDIX H H-13 • reactivation of visceral leishmaniasis in the context of future immunosuppression (2007) • West Nile virus infection and variable physical, functional, or cognitive disability, which may persist for months or years or be permanent (2007) Limited/Suggestive Evidence of an Association Evidence is suggestive of an association between exposure to a specific agent and a specific health outcome, but the body of evidence is limited by the inability to rule out chance and bias, including confounding, with confidence. For example, at least one high-quality study reports a positive association that is sufficiently free of bias, including adequate control for confounding. Other corroborating studies provide support for the association, but they were not sufficiently free of bias, including confounding. Alternatively, several studies of lower quality show consis- tent positive associations, and the results are probably not due to bias, including confounding. Cancers • Benzene and non-Hodgkin’s lymphoma (2003) • Carbamates and non-Hodgkin’s lymphoma (2003) • Combustion products and • bladder cancer (2005) • cancers of the nasal cavity and nasopharynx (2005) • cancers of the oral cavity and oropharynx (2005) • laryngeal cancer (2005) • Hydrazines and lung cancer (2005) • Organophosphorus insecticides and • adult leukemia (2003) • non-Hodgkin’s lymphoma (2003) • Solvents and • adult leukemia (2003) • bladder cancer (2003) • multiple myeloma (2003) • myelodysplastic syndromes (2003) • Tetrachloroethylene and dry-cleaning solvents and • bladder cancer (2003) • kidney cancer (2003) Neurologic Effects • Organophosphorus (OP) insecticide exposure with OP poisoning and long-term neurobe- havioral effects (that is, abnormal results on neurobehavioral test batteries and symptom findings) (2003)

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H-14 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS • Plasmodium falciparum infection and neurologic disease, neuropsychiatric disease, or both months to years after the acute infection (2007) • Plasmodium vivax and Plasmodium falciparum infections and demyelinating polyneuropa- thy and GBS (2007) • Sarin at doses sufficient to cause acute cholinergic signs and symptoms and a variety of subsequent long-term neurological effects (2004) • Solvents and neurobehavioral effects (that is, abnormal results on neurobehavioral test bat- teries and symptom findings) (2003) Other Health Effects • Brucellosis and • fatigue, inattention, amnesia, and depression (2007) • myelitis-radiculoneuritis, demyelinating meningovascular syndromes, deafness, sen- sorineural hearing loss, and GBS (2007) • papilledema, optic neuritis, episcleritis, nummular keratitis, and multifocal choroiditis (2007) • Campylobacter jejuni infection and development of uveitis if uveitis is manifest within 1 month of infection (2007) • Coxiella burnetii infection and post–Q fever chronic fatigue syndrome years after the pri- mary infection (2007) • Insecticides and allergic contact dermatitis (2003) • Sarin at doses sufficient to cause acute cholinergic signs and symptoms and subsequent long-term health effects (2000) • Solvents and • chronic glomerulonephritis (2003) • hepatic steatosis (2003) • reactive airways dysfunction syndrome, which would be evident with exposure and could persist for months or years (2003) Reproductive Effects • Combustion products and • low birthweight/intrauterine growth retardation and exposure during pregnancy (2005) • preterm birth and exposure during pregnancy (2005) Respiratory Effects • Combustion products and incident asthma (2005)

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APPENDIX H H-15 Inadequate/Insufficient Evidence to Determine Whether an Association Exists Evidence is of insufficient quantity, quality, or consistency to permit a conclusion regarding the existence of an association between exposure to a specific agent and a specific health outcome in humans. Cancers • Benzene and myelodysplastic syndromes (2003) • Combustion products and • colon cancer (2005) • esophageal cancer (2005) • female breast cancer (2005) • female genital cancers (cervical, endometrial, uterine, and ovarian cancers) (2005) • hepatic cancer (2005) • Hodgkin’s disease (2005) • kidney cancer (2005) • leukemia (2005) • male breast cancer (2005) • melanoma (2005) • multiple myeloma (2005) • nervous system cancers (2005) • non-Hodgkin’s lymphoma (2005) • ocular melanoma (2005) • pancreatic cancer (2005) • prostatic cancer (2005) • rectal cancer (2005) • stomach cancer (2005) • testicular cancer (2005) • Fuels and • bladder cancer (2005) • cancers of the nasal cavity and nasopharynx (2005) • cancers of the oral cavity and oropharynx (2005) • colon cancer (2005) • esophageal cancer (2005) • female breast cancer (2005) • female genital cancers (cervical, endometrial, uterine, and ovarian cancers) (2005) • hepatic cancer (2005) • Hodgkin’s disease (2005) • kidney cancer (2005) • laryngeal cancer (2005) • lung cancer (2005)

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H-16 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS • male breast cancer (2005) • melanoma (2005) • multiple myeloma (2005) • myelodysplastic syndromes (2005) • nervous system cancers (2005) • non-Hodgkin’s lymphoma (2005) • nonmelanoma skin cancer (2005) • pancreatic cancer (2005) • prostatic cancer (2005) • rectal cancer (2005) • stomach cancer (2005) • testicular cancer (2005) • Hydrazines and • bladder cancer (2005) • digestive tract cancers (2005) • hematopoietic and lymphopoietic cancers (2005) • kidney cancer (2005) • pancreatic cancer (2005) • Insecticides and • brain and other central nervous system (CNS) cancers (2003) • lung cancer (2003) • pancreatic cancer (2003) • prostate, testicular, bladder, or kidney cancers (2003) • soft tissue sarcomas (2003) • Insecticides and solvents and • hepatobiliary cancers (2003) • Hodgkin’s disease (2003) • multiple myeloma (2003) • Insecticides, parental preconception exposure, and childhood leukemias, brain and other CNS cancers, and non-Hodgkin’s lymphoma (2003) • Lindane and solvents and breast cancer (2003) • Nitric acid and • bladder cancer (2005) • laryngeal cancer (2005) • lung cancer (2005) • lymphopoietic cancers (2005) • melanoma (2005) • multiple myeloma (2005) • pancreatic cancer (2005) • stomach cancer (2005)

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APPENDIX H H-17 • Solvents and • bone cancer (2003) • melanoma or nonmelanoma skin cancer (2003) • oral, nasal, or laryngeal cancer (2003) • ovarian or uterine cancer (2003) • prostate cancer (2003) • stomach, rectal, or pancreatic cancer (2003) • Solvents other than tetrachloroethylene and dry-cleaning solvents and • bladder cancer (2003) • esophageal cancer (2003) • kidney cancer (2003) • lung cancer (2003) • Solvents other than trichloroethylene and cervical cancer (2003) • Solvents other than trichloroethylene and mixtures of benzene, toluene, and xylene and co- lon cancer (2003) • Solvents, parental preconception exposure to solvents and neuroblastoma and childhood brain cancers (2003) • Specific solvents other than benzene and • acute and adult leukemia (2003) • brain and other central nervous system cancers (2003) • non-Hodgkin’s lymphoma (2003) • Uranium and • bone cancer (2000) • lung cancer at higher levels of cumulative exposure (>200 mSv or 25 cGy) (2000) • lymphatic cancer (2000) Cardiovascular Effects • Combustion products and ischemic heart disease or myocardial infarction (less than 2 years of exposure) (2005) • Hydrazines and ischemic heart disease or myocardial infarction (2005) • Nitric acid and cardiovascular diseases (2005) • Sarin and subsequent long-term cardiovascular effects (2004) • Uranium and cardiovascular effects (2000) Dermal Effects • Combustion products and dermatitis—irritant and allergic (2005) • Fuels and dermatitis—irritant and allergic (2005) • Uranium and dermal effects (2000)

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H-18 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS Neurologic Effects • Combustion products and • Multiple Chemical Sensitivity symptoms (2005) • nervous system subgroupings (or individual nervous system diseases) (2005) • neurobehavioral effects (2005) • posttraumatic stress disorder (2005) • Fuels and • Multiple Chemical Sensitivity symptoms (2005) • neurobehavioral effects (2005) • peripheral neuropathy (2005) • Insecticides and solvents and • ALS (2003) • Alzheimer’s disease (2003) • Parkinson’s disease (2003) • peripheral neuropathy (2003) • Sarin at low doses insufficient to cause acute cholinergic signs and symptoms and subse- quent long-term adverse neurological health effects (2004) • Solvents and • long-term hearing loss (2003) • long-term reduction in color discrimination (2003) • long-term reduction in olfactory function (2003) • multiple sclerosis (2003) • Uranium and nervous system disease (2000) Reproductive Effects • Combustion products and • all childhood cancers identified, including acute lymphocytic leukemia, leukemia, neuroblastoma, and brain cancer (2005) • low birthweight and intrauterine growth retardation and exposure before gestation or during any specific period during pregnancy (for example, the first trimester) (2005) • preterm births and exposure during any specific time period during pregnancy (for ex- ample, the first trimester) (2005) • specific birth defects, including cardiac effects, and exposure before conception (ma- ternal and paternal) or during early pregnancy (maternal) (2005) • Fuels and adverse reproductive or developmental outcomes (including infertility, sponta- neous abortion, childhood leukemia, CNS tumors, neuroblastoma, and Prader-Willi syn- drome) (2005) • Insecticides and solvents and male or female infertility after cessation of exposure (2003) • Insecticides or solvents, parental preconception exposure, and

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APPENDIX H H-19 • congenital malformations (2003) • spontaneous abortion or other adverse pregnancy outcomes (2003) • Uranium and reproductive or developmental dysfunction (2000) Respiratory Effects • Combustion products and • chronic bronchitis (less than 1 year of exposure) (2005) • chronic obstructive pulmonary disease (2005) • emphysema (2005) • Fuels and • asthma (2005) • chronic bronchitis (2005) • emphysema (2005) • nonmalignant respiratory disease (2005) • Hydrazines and emphysema (2005) • Uranium and nonmalignant respiratory disease (2000) Other Health Effects • Anthrax vaccination and long-term adverse health effects (2000) • Botulinum toxoid vaccination and long-term adverse health effects (2000) • Combustion products and sarcoidosis (2005) • Fuels and sarcoidosis (2005) • Hydrazines and hepatic disease (2005) • Insecticides and aplastic anemia (2003) • Insecticides and solvents and • irreversible cardiovascular outcomes (2003) • persistent respiratory symptoms or impairment after cessation of exposure (2003) • Multiple vaccinations and long-term adverse health effects (2000) • Pyridostigmine bromide and long-term adverse health effects (2000) • Sarin, exposure at low doses insufficient to cause acute cholinergic signs and symptoms and subsequent long-term adverse health effects (2000) • Solvents and • alterations in liver function tests after cessation of exposure (2003) • chronic pancreatitis and other persistent gastrointestinal outcomes (2003) • cirrhosis (2003) • the systemic rheumatic diseases: scleroderma, rheumatoid arthritis, undifferentiated connective tissue disorders, and systemic lupus erythematosus (2003) • Solvents other than benzene and aplastic anemia (2003)

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H-20 IMPROVING THE PRESUMPTIVE DISABILITY DECISION-MAKING PROCESS FOR VETERANS • Uranium and • effects on hematological parameters (2000) • gastrointestinal disease (2000) • genotoxic effects (2000) • hepatic disease (2000) • immune-mediated disease (2000) • musculoskeletal effects (2000) • ocular effects (2000) Limited/Suggestive Evidence of No Association Evidence is consistent in not showing a positive association between exposure to a specific agent and a specific health outcome after exposure of any magnitude. A conclusion of no asso- ciation is inevitably limited to the conditions, magnitudes of exposure, and length of observation in the available studies. The possibility of a very small increase in risk after exposure studied cannot be excluded. • Exposure to uranium and lung cancer at cumulative internal dose levels lower than 200 mSv or 25 cGy (2000) • Uranium and clinically significant renal dysfunction (2000) Consensus Not Reached on Category of Association • Benzene and solvents and brain and other CNS cancers (2003) • Mixtures of benzene, toluene, and xylene and colon cancer (2003) • OP insecticide exposure without OP poisoning and long-term neurobehavioral effects (that is, abnormal results on neurobehavioral test batteries and symptom findings) (2003) • Parental preconception exposure to solvents and childhood leukemia (2003) • Solvents and kidney cancer (2003) • Tetrachloroethylene and dry-cleaning solvents and esophageal cancer (2003) • Tetrachloroethylene and dry-cleaning solvents and lung cancer (2003) • Trichloroethylene and cervical cancer (2003) • Trichloroethylene and colon cancer (2003) REFERENCES IOM (Institute of Medicine). 2000. Gulf War and health, volume 1: Depleted uranium, pyri- dostigmine bromide, sarin, vaccines. Washington, DC: National Academy Press. IOM. 2003. Gulf War and health, volume 2: Insecticides and solvents. Washington, DC: The Na- tional Academies Press. IOM. 2004. Gulf War and health: Updated literature review of sarin. Washington, DC: The Na- tional Academies Press. IOM. 2005. Gulf War and health, volume 3: Fuels, combustion products, and propellants. Wash- ington, DC: The National Academies Press.

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APPENDIX H H-21 IOM. 2006. Gulf War and health, volume 4: Health effects of serving in the Gulf War. Washing- ton, DC: The National Academies Press. IOM. 2007. Gulf War and health, volume 5: Infectious diseases. Washington, DC: The National Academies Press.

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