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POSSI BLE LONG-TERkl HEALTH EFFECTS OF SHORT-TERM EXPOSURE TO CHEMICAL AGENTS Vo fume 3 Final Report: Current Health Status of Test Sub jects Committee on Toxicology Board on Toxicology and Environmental Health Hazards Commission on Life Sciences National Researc h Council National Academy Press Washington, D.C. 1985

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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Research Council was established by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. This study was prepared under Contracts DAMD-17-83-C-3185 and DAMD-17-83-C-3045 between the National Academy of Sciences and the Department of the Army. Limited number of copies available from: Committee on Toxicology Board on Toxicology and Environmental Health Hazards National Research Council 2101 Constitution Avenue, N.W. Washington, D.C. 20418

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COORDINATING SUBCOMMITTEE Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents Howard Malbach, University of California School of Medicine, San Francisco, California, Chairman William Blot, National Institutes of Health, Bethesda, Maryland Donald Ecobichon, McGill University, Montreal, Quebec, Canada Barbara Hulka, University of North Carolina, Chapel Hill, North Carolina Lewis Kuller, University of Pittsburgh, Pittsburgh, Pennsylvania George Mandel, George Washington University, Washington, D.C. A. Thomas McLellan, University of Pennsylvania, Veterans Administration Medical Center, Philadelphia, Pennsylvania Robert Snyder, Rutgers University, New Brunswick, New Jersey Peter S. Spencer, Albert Einstein College of Medicine, Bronx, New York COMMITTEE ON TOXICOLOGY Roger O. McClellan, Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Mexico, Chairman Carol Angle, University of Nebraska Medical Center, Omaha, Nebraska Rose Dagirmanjian, University of Louisville, Louisville, Kentucky David W. Gaylor, National Center for Toxicological Research, Jefferson, Arkansas Richard Griesemer, Oak Ridge National Laboratory, Oak Ridge, Tennessee William Halperin, National Institute for Occupational Safety and Health, Cincinnati, Ohio Clark W. Heath, Jr., Emory University School of Medicine, Atlanta, Georgia Rogene F. Henderson, Lovelace Environmental and Biomedical Research Institute, Albuquerque, New Mexico Meryl Karol, Graduate School of Public Health, Pittsburgh, Pennsylvania Kathleen Taylor, General Motors Research Laboratory, Warren, Michigan Thomas R. Tephly, The University of Iowa, Iowa City, Iowa National Research Council Staff Devra Lee Davis, Executive Director, BOTEHH Francis N. Marzulli, Project Director Kulbir S. Bakshi, Staff Officer Seymour Jablon, Medical Follow-Up Agency Robert J. Keehn, Medical Follow-Up Agency Norman Grosstlatt, Editor Edna W. Paulson, Chemical Information Specialist Marvin Schneiderman, Consultant, Biostatistician Diane Wagener, Consultant, Epidemiological Geneticist Beulah S. Bresler, Administrative Secretary Jean E. Dent, Senior Secretary

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BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS Gerald N. Wogan, Massachusetts Institute of Technology, Cambridge, Massachusetts, Chairman Donald Hornig, Harvard University, Boston, Massachusetts, Co-Vice-Chairman Philip Landrigan, Mt. Sinai Medical Center, New York, New York, Co-Vice-Chairman John Doull, University of Kansas Medical Center, Kansas City, Kansas Herman N. Eisen, Massachusetts Institute of Technology, Cambridge, Massachusetts - Emmanuel Farber, University of Toronto, Toronto, Ontario, Canada David G. Hoel, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Richard Merrill, University of Virginia Law School, Charlottesville, Virginia Emil Pfitzer, Hoffmann-La Roche Tnc., Nutley, New Jersey Joseph V. Rodricks, Environ Corporation, Washington, D.C. Liane B. Russell, Oak Ridge National Laboratory, Oak Ridge, Tennessee Ellen Silbergeld, Environmental Defense Fund, Washington, D.C. Peter S. Spencer, Albert Einstein College of Medicine, Bronx, New York National Research Council Staff Devra Lee Davis, Executive Director

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PREFACE In the spring of 1980, the Department of the Army asked the Committee on Toxicology of the National Research Council's Board on Toxicology and Environmental Health Hazards to study the possible chronic or delayed adverse health effects incurred by servicemen who had been exposed experimentally to various chemicals at the U.S. Army Laboratories, Aberdeen Proving Ground, Edgewood, Maryland, during 1955-1975. The Edgewood tests were conducted to learn how potential chemical warfare agents might affect humans over a short period and how such affected humans might respond to therapy for the effects of such agents. The Army believed that relevant information could not be obtained from animal experimentation alone and that it was necessary to confirm animal findings by using human volunteers. Some 6,720 soldiers took part in this program. To understand the extent to which they might have experienced unanticipated long-term or delayed adverse effects, an extensive search for reports, records, and other data was undertaken. The search and the study and evaluation of all available information on the five major categories of chemicals involved (anticholinesterases, anticholinergics, cholinesterase Deactivators, psychochemicals, and irritants and vesicants) were accomplished by panels of experts under the direction of the Committee on Toxicology. The present report was prepared by a coordinating committee made up of the chairmen of the five panels involved in earlier reports, epidemiologists who had served on those panels, and one newly appointed person. It is based largely on the work of Robert Keehn of the National Research Council's Medical Follow-up Agency, which had primary responsibility for conducting a questionnaire survey of test subjects to evaluate aspects of their current health, family status, and lifestyle.

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ACKNOWLEDGMENTS The following person provided technical assistance: Virginia Dunkel, Food and Drug Administration, Washington, D.C. Ronald J. Kassel, U.S. Army Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland Mary S. Lyon, Harwell Dicot, England Benjamin J. Tepping, Statistical Consultant, Silver Spring, Maryland Henry Wills, Uniformed Services University of the Health Sciences, Bethesda, Maryland

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EXECUTIVE SUMMARY At the request of the Department of the Army, the Committee on Toxicology in the Board on Toxicology and Environmental Health Hazards of the National Research Council's Commission on Life Sciences under- took a study to investigate possible delayed and long-term effects of experimental chemicals administered to soldiers at the U.S. Army Laboratories, Edgewood, Maryland. A total of 6,720 soldiers volun- teered, of whom 4,826 were exposed to some experimental chemicals. The Edgewood tests, conducted over a 20-year period ending in 1975, were intended to investigate the immediate and short-term human- performance effects of short-term exposure to various chemicals with warfare potential and the subjects' responses to therapy for such effects. Five panels of about 10 scientists each, with appropriate expertise, reviewed the available information on the test chemicals, which were divided into five categories according to pharmacologic class. Available information included reports of acute effects by physician observers and published reports in the scientific literature. Volume 1 of this series was concerned with the possible long-term effects of 15 anticholinesterase and 24 anticholinergic chemicals and was issued in 1982. Volume 2 was concerned with four cholinesterase Deactivators, 12 psychochemicals, mustard gas, and a variety of irritant substances; it was issued in 1984. This report is Volume 3 of the series. Early in this study, the Committee decided that the information on the test materials would be incomplete if the long-term morbidity and mortality among the test subjects were not investigated. It was recognized that the Edgewood tests were intended for short-term and not long-term study and were therefore deficient in adequate long-term controls. The Committee, recognizing these limitations, nevertheless believed that the study might detect major effects if they were present and that the limitations of the study could be appropriately described so its conclusions would not be overinterpreted. Mortality was reported in Volume 1 and is updated in this volume. Morbidity was analyzed through use of a questionnaire that was sent to all living test subjects whose current addresses could be located and through study of Army and Veterans' Administration (VA) hospital admissions of the participants after testing. This volume was prepared cooperatively by the Medical Follow-up Agency of the Commission on Life Sciences and a coordinating committee

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composed of prior panel chairmen, three epidemiologists who had served on the panels, and one newly selected epidemiologist. The charges to the reporting group were as follows: To prepare a final report for the series Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents on the basis of results of a questionnaire regarding current health status of test subjects. To evaluate the implications of findings from the questionnaire for any of the conclusions reported in Volumes 1 and 2. Edgewood test subjects who were alive and could be located received a mailed questionnaire intended to assess their current health status; 82% of those who received the questionnaire responded to it. The long-term health effects of most interest included the possibility of excess cancer risk and adverse mental, necrologic, hepatic, and reproductive effects that might have resulted from experimental exposure to chemicals at Edgewood. Subjects tested with anticholinesterase chemicals, anticholinergic chemicals, cholinesterase reactivators, or psychochemicals did not differ significantly from control subjects or from those tested with other classes of drugs in their replies to questions about their current health status. Almost 90% of all these respondents reported no health problems related to the exposures under scrutiny, and 79% reported good to excellent health. (Subjects tested with LSD were not within the purview of the Committee's investigation, because they had been evaluated and reported on earlier by the U.S. Army, whose evaluation was based on physical examinations. Analysis of responses to the Committee's questionnaire did indicate, however, that there was an increased use of LSD after the Edgewood tests, but there was no evidence of adverse health effects among these subjects.) The subjects tested with irritants and vesicants, including those who developed skin burns from mustard gas, reported no increased prevalence of significant skin cancer or other adverse health effects. The test subjects' current use of tobacco and alcohol and their histories of use of recreational drugs were not unusual. When the observed fertility of men exposed to anticholinergic chemicals was compared with age-adjusted expected values, based on the experience of the men who were tested with other chemicals, there appeared to be a decrease in fertility. However, the men who were exposed to anticholinergics were, by and large, tested during the second half of the 20-year testing period. Because of the national trend toward delayed and smaller families, these analyses were further

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adjusted for the date of testing. When adjustment for age of volunteer when last tested was performed, there was no difference between the observed fertility pattern of the men exposed to anticholinergic chemicals and that expected on the basis of men who were exposed to other chemicals. A review of records of admissions to Army hospitals in calendar years 1958-1983 and admissions to VA hospitals in calendar years 1963-1981 produced some interesting findings with regard to Edgewood test subjects: a barely statistically significant ~ ~ ~ ~ to VA hospitals for malignant neoplasms among men exposed to anticholinesterases and statistically significant admissions to VA hospitals and Army hospitals for nervous system and sense organ disorders among men exposed to LSD. increase in admissions increases in However, the numbers of _ these admissions were small, no dose relationships were noted, and, in the case of anticholinesterase exposures, no clustering of specific chemicals in relation to tumor sites was noted. The experimental methods and the available comparison groups were such that only large effects were likely to be uncovered. The large standard errors, the initial differences between the exposed and nonexposed groups, the possibility that more than one exposure might have led to the same adverse effect, and the self-reporting nature of the questionnaire study all would tend to obscure small differences.

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CONTENTS Introduction The Medical Follow-up Study Analytic Problems Methods of Study Results Discussion Conclusions Tables References 1 3 7 / 12 25 31 33 63 Appendix A. Executive Summaries of Volumes 1 and 2 67 Appendix B. Updated Mortality Study (Summary) 75 Appendix C. Interpretability of the Follow-up Questionnaire Data 83 Appendix D. Appendix E. Cohort Adjustment of Fertility for Anticholinergic Group Using No-Chemical-Test Group for Comparison The Questionnaire and Related Material (Exhibits A, B. C, D, and E) 87 89

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