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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite 2 Methods of Literature Collection and Survey The primary task of this study was a survey of the scientific and medical literature on the health effects of mustard gas and Lewisite published from 1917 to the present. Early on in the course of this study, methods to identify, collect, and disseminate the literature were discussed and decided upon. ONLINE DATABASES The initial emphasis was a comprehensive search of relevant online databases. These computerized databases offer the most effective means of identifying international scientific literature and, in general, cover the time span from 1965 to the present. Databases were accessed through Dialog, a commercial database vendor, and through the National Library of Medicine's (NLM's) Medical Literature Analysis and Retrieval System (MEDLARS). To maximize retrieval, the search strategy incorporated synonymous terms for mustard gas and Lewisite. Thus, the databases were searched by using the following terms: mustard gas, Yperite, sulfur mustard, schwefellost, yellow cross, dichlorodiethyl sulfide, Lewisite, and chlorovinylarsine dichloride. Enhanced accuracy in online searching was gained by using Chemical Abstracts Service (CAS) Registry Numbers, which uniquely identify each individual chemical. The final search strategy combined the CAS Registry Numbers (505-60-2 for mustard gas and 541-25-3 for Lewisite) and the synonymous terms for each chemical. Individual searches were customized to reflect the structure of each database. For applicable databases, searching was done on the standard-
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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite ized terminology and alphanumeric designators for each chemical found in NLM's Medical Subject Headings (MeSH) and the MeSH tree structures. Although there is subject and content overlap, each database serves a unique function, has a distinct subject emphasis, and indexes literature not available elsewhere. For example, the two prominent medical databases, NLM's Medline and Excerpta Medica's EMBASE, have only an approximate 36 percent content overlap. To serve the comprehensive goals of this study, it was decided to search all relevant databases in their entirety. A total of 46 online databases were searched, covering biomedical, toxicological, chemical, and regulatory information. As shown in Table 2-1, the majority of these databases were bibliographic, providing citations to scientific literature. Factual databases, Table 2-2, were also searched to provide toxicological and chemical information. OTHER SOURCES Online databases were developed in the mid-1960s, and few offer retrospective coverage. Identifying the literature published prior to this time required the use of a variety of sources. The volumes of Index Medicus covering the years 1917-1965 were an important bibliographic source. Reference lists of major review articles and books were also examined for relevant citations; several provided extensive reference lists (Goldman and Dacre, 1989; Gray, 1989; Papirmeister et al., 1991; Smith and Dunn, 1991; Somani and Babu, 1989). Document collection of published literature involved accessing the collections of the National Library of Medicine, the National Institutes of Health Library, the Himmelfarb Health Sciences Library of The George Washington University, and the National Research Council Library, as well as the use of interlibrary loans. In conjunction with World War II (WWII) research on chemical warfare agents, scientists collected and reviewed the scientific literature and compiled bibliographies, which recorded the pre-WWII literature as well as ongoing military research. These include the bibliography for the Office of Scientific Research and Development, National Defense Research Committee's Summary Technical Report of Division 9: Chemical Warfare Agents and Related Chemical Problems; chapter reference lists in the three volumes of the National Research Council's Fasciculus on Chemical Warfare Medicine; and an unpublished bibliography compiled by the National Research Council's Committee on Treatment of Gas Casualties, entitled Bibliography of the Medical Aspects of Chemical Warfare: Published Literature. Literature identification was an ongoing process throughout the study and, in addition to the above sources, input was received from
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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite TABLE 2-1 Bibliographic Databases Searched Database No. of Citations Toxline 635 CA Search (Chemical Abstracts) 477 BIOSIS Previews 300 EMBASE 285 Toxlit and Toxlit65 266 Medline 240 Occupational Safety and Health (NIOSH) 172 NTIS (National Technical Information Service) 156 Cancerlit 152 Scisearch 129 Environmental Mutagen Information Center Backfile (Toxnet) 119 Life Sciences Collection 60 Pascal 38 Conference Papers Index 21 SSIE Current Research 19 Analytical Abstracts Online 16 World Translations Index 15 Chemical Industry Notes 12 Dissertation Abstracts Online 11 Federal Register 10 Pollution Abstracts 9 Compendex Plus 8 Environmental Bibliography 8 REMARC 8 Chemical Regulations and Guidelines Systems 7 AGRICOLA 7 Chemical Safety Newsbase 6 International Pharmaceutical Abstracts 5 Enviroline 5 LC MARC Books 5 Developmental and Reproductive Toxicology (Toxnet) 5 Environmental Teratology Information Center Backfile (Toxnet) 5 Books in Print 3 U.S. Copyrights 3 Legal Resource Index 3 Congressional Record 3 Biotechnology Abstracts 2 Psycinfo 2 British Books in Print 1 Nursing and Allied Health 1 Federal Research in Progress 1 veterans, interested persons, committee members, and speakers at committee meetings. All retrieved citations were reviewed to determine whether the citation was relevant to the study, and if relevant whether
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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite TABLE 2-2 Factual Databases Searched Chemical Carcinogenesis Research Information System (CCRIS) Development and Reproductive Toxicology (DART) Genetic Toxicology (GENETOX) Hazardous Substances Data Bank (HSDB) to obtain the full paper or to first obtain an abstract. Citations were entered into the study's bibliographic database, which at the conclusion of the study contained 2,124 references to abstracts, journal articles, books, military and civilian reports, dissertations, and conference proceedings relating to the health effects of mustard gas and Lewisite. SUPPLEMENTAL WORLD WAR II MILITARY REPORTS In addition to the published scientific literature, essential supplemental information was made available to the committee through military and technical reports and also through archival research. Retrieving technical and military documents involved searching archival records of the Office of Scientific Research and Development (OSRD), requesting access to military documents, and ordering technical reports from the National Technical Information Service (NTIS). WWII civilian research was coordinated through the OSRD, and two of its divisions conducted chemical warfare agent research, the National Defense Research Committee (NDRC) and the Committee on Medical Research (CMR). Within NDRC it was Division 9 (Chemistry) that was responsible for overseeing this research, and Division 9 records are stored in Series 29, Record Group 227, Civil Reference Branch, National Archives and Records Administration, Washington, D.C. The records of the CMR's Committee on Treatment of Gas Casualties, the subcommittee involved in chemical warfare agent research, are housed in the National Research Council Archives and are also available in Series 29, Record Group 227 at the National Archives. Military reports were also obtained to supplement the journal literature. Reports obtained from the Naval Research Laboratory (Washington, D.C.) provided background information on WWII test conditions and protocols. Chemical Warfare Service administrative records and correspondence were retrieved from Record Group 175, Suitland Reference Branch of the National Archives, Suitland, Maryland. Freedom of Information Act (FOIA) requests were sent to the U.S. Army Chemical Research Development and Engineering Command (Aberdeen Proving Ground, Maryland), U.S. Army Dugway Proving Ground (Dugway, Utah), and Naval Training Center (Great Lakes, Illinois). The Medical Research Institute of Chemical Defense (Aberdeen Proving Ground, Maryland) was also contacted. Reports on field tests involving sulfur
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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite TABLE 2-3 Foreign Language Citations Database Statistics 2,124 Total records in database 458 Foreign language records French 136 German 128 Japanese 67 Italian 34 Russian 21 Polish 14 Danish 11 Dutch 9 Swedish 7 Czech 7 Hungarian 6 Romanian 5 Spanish 3 Bulgarian 3 Portuguese 3 Hebrew 2 Serbo-Croatian 2 Acquisition and Translation Statistics 250 Foreign language documents acquired 97 English abstracts available or summary section translated 60 Entire articles translated mustard were sent by Dugway Proving Ground. The committee was informed that the archives at the Great Lakes Naval Training Center did not have documents on chemical warfare agent testing. Aberdeen Proving Ground provided information on three publicly releasable documents and reviewed on a case-by-case basis other FOIA requests for military reports. British documents on WWII chemical warfare agent research were sent by the Chemical and Biological Defence Establishment, Ministry of Defence, Great Britain. The Australian Commonwealth Department of Veterans' Affairs provided summary information on the WWII Australian chemical warfare agent testing program. LITERATURE TRANSLATION, DISSEMINATION, AND ANALYSIS As the documents were collected, one of the first considerations was dealing with the significant portion of this literature (22 percent) published in a foreign language. English summaries and translated titles were reviewed, and papers with pertinent original research not available
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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite in English were professionally translated (Table 2-3). Given the large number of documents on this topic, it was necessary early on in the study to determine a method that would most effectively organize the material and serve as a tool in the dissemination of the literature to the committee. A list of index terminology was developed and subsequently revised at the first committee meeting. Each paper was indexed, and updated subject bibliographies were distributed to the committee throughout the study to reflect new acquisitions, allowing committee members to request copies of the papers they needed for their information and analysis. In assessing the associations between exposure and specific health conditions, the committee generally followed the guidelines proposed by Hill (1971). These guidelines include six considerations that can be brought to bear on judgments of causality. Strength of association reflects the relative risk or odds of an association. A dose-response relationship can reinforce the judgment of causality when the strength of association increases with increases in exposure. Further, associations need to be temporally correct; the effect occurs in a reasonable or expected time period following exposure. Consistency and specificity of associations are also important considerations. A consistent association is one that is found in a variety of studies. If, however, a particular health condition is reliably predicted by a given exposure, then specificity of an association is demonstrated. Finally, for an association to be judged causal it must be biologically plausible or explainable by known biological mechanisms. Each of the considerations listed above is based on certain assumptions and requires varying amounts and types of information. In other words, the application of Hill's guidelines can be difficult when assessing literature that is incomplete or sparse. The assumptions made and the difficulties encountered in assessing the literature regarding the health effects of mustard agents and Lewisite are discussed in this report in the chapters dealing with specific organ systems and health conditions. The complete bibliography at the end of this report is divided into three sections: published literature, military reports, and technical reports. Availability information is also provided at the end of the bibliography. A separate subject bibliography has been compiled and is available through the NTIS under the title Health Effects of Mustard Gas and Lewisite: Subject Bibliography. REFERENCES Goldman M, Dacre J. 1989. Lewisite: its chemistry, toxicology, and biological effects. Reviews of Environmental Contamination and Toxicology 110:75-115. Gray PJ. 1989. A Literature Review on the Mechanism of Action of Sulphur and Nitrogen
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Veterans at Risk: The Health Effects of Mustard Gas and Lewisite Mustard. Maribyrong, Australia: DSTO Materials Research Laboratory. AD-A125-070. Hill AB. 1971. Principles of Medical Statistics. 9th ed. New York: Oxford University Press. National Research Council. Division of Medical Sciences. Committee on Treatment of Gas Casualties. 1945. Bibliography of the Medical Aspects of Chemical Warfare: Published Literature. Unpublished, available at the National Research Council Archives, Washington, DC. National Research Council. Division of Medical Sciences. Committee on Treatment of Gas Casualties. 1945. Fasciculus on Chemical Warfare Medicine. 3 vols. Washington, DC: Prepared for the Committee on Medical Research of the Office of Scientific Research and Development. Available at the National Research Council Archives, Washington, DC. Office of Scientific Research and Development. National Defense Research Committee. 1946. Summary Technical Report of Division 9, NDRC. Washington, DC: NDRC. AD-234 249. Papirmeister B, Feister AJ, Robinson SI, Ford RD. 1991. Medical Defense Against Mustard Gas: Toxic Mechanisms and Pharmacological Implications. Boca Raton, FL: CRC Press. Smith WJ, Dunn MA. 1991. Medical defense against blistering chemical warfare agents. Archives of Dermatology 127:1207-1213. Somani SM, Babu SR. 1989. Toxicodynamics of sulfur mustard. International Journal of Clinical Pharmacology, Therapy and Toxicology 27:419-435.
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