Appendix A
Information Gathering: Literature Searches

The primary charge to this committee was to analyze the scientific and medical literature published on the health effects of herbicides used in Vietnam. The committee used the following methods to identify, collect, and disseminate the scientific and medical literature that formed the basis of its review.

COMPUTERIZED BIBLIOGRAPHIC DATA BASES

The initial focus of the committee's efforts was a comprehensive search of relevant computerized data bases. Sixteen data bases covering biomedical, toxicological, chemical, historical, and regulatory information were accessed utilizing Dialog, a commercial data base vendor, and the National Library of Medicine's (NLM's) Medical Literature Analysis and Retrieval System (MEDLARS). The majority of the data bases searched were bibliographic (Table A-1), providing citations to scientific literature. Factual data bases (Table A-2) were also searched to provide toxicological and chemical information.

To maximize retrieval, the search strategy incorporated the broad terms ''phenoxy herbicides" and "dioxin," specific chemical names (2,3,7,8-tetrachlorodibenzo-p-dioxin; 2,4-dichlorophenoxyacetic acid; 2,4,5-trichlorophenoxyacetic acid; dimethylarsinic acid; 4-amino-3,5,6-trichloropicolinic acid), abbreviations (TCDD; 2,4-D; 2,4,5-T), and synonyms (Agent Orange, picloram, cacodylic acid). The search term "herbicides/adverse effects" was also used to increase the comprehensive retrieval of the search. Accuracy



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Appendix A Information Gathering: Literature Searches The primary charge to this committee was to analyze the scientific and medical literature published on the health effects of herbicides used in Vietnam. The committee used the following methods to identify, collect, and disseminate the scientific and medical literature that formed the basis of its review. COMPUTERIZED BIBLIOGRAPHIC DATA BASES The initial focus of the committee's efforts was a comprehensive search of relevant computerized data bases. Sixteen data bases covering biomedical, toxicological, chemical, historical, and regulatory information were accessed utilizing Dialog, a commercial data base vendor, and the National Library of Medicine's (NLM's) Medical Literature Analysis and Retrieval System (MEDLARS). The majority of the data bases searched were bibliographic (Table A-1), providing citations to scientific literature. Factual data bases (Table A-2) were also searched to provide toxicological and chemical information. To maximize retrieval, the search strategy incorporated the broad terms ''phenoxy herbicides" and "dioxin," specific chemical names (2,3,7,8-tetrachlorodibenzo-p-dioxin; 2,4-dichlorophenoxyacetic acid; 2,4,5-trichlorophenoxyacetic acid; dimethylarsinic acid; 4-amino-3,5,6-trichloropicolinic acid), abbreviations (TCDD; 2,4-D; 2,4,5-T), and synonyms (Agent Orange, picloram, cacodylic acid). The search term "herbicides/adverse effects" was also used to increase the comprehensive retrieval of the search. Accuracy

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam TABLE A-1 Bibliographic Data Bases Searched Biosis Books in Print Cancer Lit Conference Papers Index Dissertations Abstract Embase Enviroline Environmental Bibliography Federal Register Medline National Institute for Occupational Safety and Health National Technical Information Service (NTIS) Pascal Psych Info Toxline World Translations Index was enhanced in applicable data bases by using Chemical Abstracts Service Registry Numbers, which uniquely identify each individual chemical. Individual searches were customized to reflect the structure of each data base. For MEDLARS data bases, searching was done on the standardized 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 data base serves a unique function, has a distinct subject emphasis, and indexes literature not available elsewhere. To serve the comprehensive goals of this study, it was decided to search all relevant data bases in their entirety for epidemiologic studies, case reports, and secondary literature (reviews, letters, news articles, etc.). The animal toxicology literature on this subject is extensive, and these studies build on and reference previous work. The committee decided to retrieve all animal toxicology citations from 1980 through the present. Throughout the study, searches were updated, and targeted searches were done on specific topics such as porphyria cutanea tarda. TABLE A-2 Factual Data Bases Searched Chemical Carcinogenesis Research Information System Developmental and Reproductive Toxicology Hazardous Substances Data Bank Integrated Risk Information System Registry of Toxic Effects of Chemical Substances

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam OTHER SOURCES Committee staff examined the reference lists of major review articles, books, and reports for relevant citations. Reference lists of individual articles were also scanned for additional relevant references. Literature identification was an ongoing process throughout the study. A valuable source of additional information was the input received both in written and in oral form from veterans, interested persons, and speakers at the public hearings and scientific workshops (see Appendix B). LITERATURE DISSEMINATION All retrieved citations were entered into the study's bibliographic data base, which at the conclusion of the study contained 6,420 references to the health effects of the herbicides used in Vietnam. Given the large number of documents on this topic, it was necessary to determine a method that would organize the material most effectively and serve as a tool in dissemination of the literature to the appropriate committee members. A list of 41 terms was developed for indexing individual articles. Each epidemiologic study was categorized by the population group exposed (occupational, environmental, veteran, Vietnamese) and the general health outcome. Toxicology references were subcategorized by main topic (e.g., mechanism of action, chemistry, pharmacology, genotoxicity). Updated subject bibliographies were distributed to the committee throughout the study to reflect additions to the bibliographic data base. Copies of papers were requested as needed for the committee's information and analysis. EPIDEMIOLOGIC STUDIES At its first meeting, the committee realized that the epidemiologic studies would be a primary source of information for determining associations between individual health outcomes and exposure to herbicides. It was decided that a more detailed approach was necessary in indexing and critiquing these studies, and the committee developed an abstracting form. Information on the form began with descriptions of the study and comparison populations and of the study design. Exposure to herbicides was categorized through source, validation methods, exposure definition, and length of exposure. The form detailed the major health outcome categories, listing cancers by type and site; specific adverse reproductive outcomes; subcategories of neurobehavioral, cardiovascular, respiratory, metabolic, immunologic, and dermatologic disorders; and other health effects. The study's analytical methods were detailed on the form with information including confounding factors, methods used to control confounding, and consideration for latency.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Each epidemiologic study was abstracted by consultants to the committee, and the abstracted data for each study were entered into a computerized data base. The first use of this data base was to sort the studies by health outcome. Completed abstracting forms and studies were then sent to committee members with expertise in that field, who reviewed and verified the abstracted information. Throughout the study, this data base was used extensively to aid committee members in locating relevant studies on a variety of questions ranging from methods of exposure assessment to study design.