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i Review of Acute Human-Toxicity Estimates for Selected Chemical- Warfare Agents Subcommittee on Toxicity Values for Selected Nerve and Vesicant Agents Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS WASHINGTON, D.C., 1997
ii National Academy Press 2101 Constitution Avenue, NW Washington, DC 20418 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 project was supported by contract DAMD 17-89-C-9086 between the National Academy of Sciences and the U.S. Department of Defense. Any opinions, findings, conclusions, or recommenda- tions expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Additional copies of this report are available from the Board on Environmental Studies and Toxicol- ogy, 2101 Constitution Ave., N.W., Washington, D.C. Copyright 1997 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.
iii Subcommittee on Toxicity Values for Selected Nerve and vesicant Agents LOREN D. KOLLER (Chair), Oregon State University, Corvallis, Oreg. DONALD E. GARDNER, Inhalation Toxicology Associates, Raleigh, N.C. DAVID W. G AYLOR, U.S. Food and Drug Administration, Jefferson, Ark. SIDNEY GREEN, Corning Hazleton, Inc., Vienna, Va. ROGENE F. HENDERSON, Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.Mex. BERNARD M. WAGNER, Wagner Associates, Inc., Millburn, N.J. Staff KULBIR S. BAKSHI, Project Director LUCY V. FUSCO , Project Assistant RUTH E. CROSSGROVE, Editor Sponsor.: U.S. Department of Defense
v Committee on Toxicology ROGENE F.HENDERSON(Chair), Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.Mex. DONALD E. GARDNER (Vice-Chair), Inhalation Toxicology Associates, Raleigh, N. C. GERMAINE M. BUCK, State University of New York at Buffalo, N.Y. GARY P. C ARLSON, Purdue University, West Lafayette, Ind. JACK H. DEAN, Sanofi Winthrop, Inc., Malverne, Pa. KEVIN E. DRISCOLL, Procter & Gamble Company, Cincinnati, Ohio ELAINE M. FAUSTMAN, University of Washington, Seattle, Wash. CHARLES E. FEIGLEY, University of South Carolina, Columbia, S.C. DAVID W. G AYLOR, US Food and Drug Administration, Jefferson, Ark. JUDITH A. GRAHAM, U.S. Environmental Protection Agency, Research Triangle Park, N.C. IAN A. GREAVES, University of Minnesota, Minneapolis, Minn. SIDNEY GREEN, Corning Hazleton, Inc., Vienna, Va. WILLIAM E. HALPERIN, National Institute for Occupational Safety and Health, Atlanta, Ga. LOREN D. KOLLER, Oregon State University, Corvallis, Oreg. DNIEL KREWSKI, Health Canada, Ottawa, Ont. THOMAS E. MCKONE, University of California, Berkeley, Calif. MICHELE A. MEDINSKY, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, N.Y. ROBERT SNYDER, Environmental and Occupational Health Sciences Institute, Piscataway, N.J. BERNARD M. WAGNER, Wagner Associates, Inc., Millburn, N.J. ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tenn. HANSPETER R. WITSCHI, University of California, Davis, Calif. GAROLD S. YOST, University of Utah, Salt Lake City, Utah
vi Staff KULBIR S. BAKSHI, Program Director MARGARET E. MCVEY, Program Officer RUTH E. CROSSGROVE, Editor CATHERINE M. KUBIK, Senior Program Assistant LINDA V. LEONARD, Senior Project Assistant LUCY V. FUSCO , Project Assistant
vii Board on Environmental Studies and Toxicology PAUL G. R ISSER (Chair), Oregon State University, Corvallis, Oreg. MAY R. B ERENBAUM, University of Illinois, Urbana, Ill. EULA BINGHAM, University of Cincinnati, Cincinnati, Ohio PAUL BUSCH , Malcolm Pirnie, Inc., White Plains, N.Y. EDWIN H. CLARK II, Clean Sites, Inc., Alexandria, Va. ELLIS COWLING, North Carolina State University, Raleigh, N.C. GEORGE P. DASTON, The Procter & Gamble Co., Cincinnati, Ohio PETER L. DEFUR, Virginia Commonwealth University, Richmond, Va. DAVID L. EATON, University of Washington, Seattle, Wash. DIANA F RECKMAN, Colorado State University, Ft. Collins, Colo. ROBERT A. FROSCH, Harvard University, Cambridge, Mass. DANIEL KREWSKI, Health & Welfare Canada, Ottawa, Ont. RAYMOND C. LOEHR, The University of Texas, Austin, Tex. WARREN MUIR, Hampshire Research Institute, Alexandria, Va. GORDON ORIANS, University of Washington, Seattle, Wash. GEOFFREY PLACE, Hilton Head, S.C. BURTON H. SINGER, Princeton University, Princeton, N.J. MARGARET STRAND, Bayh, Connaughton and Malone, Washington, D.C. BAILUS WALKER, JR., Howard University, Washington, D.C. GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge, Mass. TERRY F. YOSIE, Ruder Finn Inc., Washington, D.C.
viii Senior Staff Officers JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Applied Ecology KULBIR S. BAKSHI, Program Director for the Committee on Toxicology CAROL A. MACZKA, Program Director for Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering
ix Commission on Life Sciences THOMAS D. POLLARD (Chair), The Salk Institute, La Jolla, Calif. FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOHN C. BAILAR III, University of Chicago, Chicago, Ill. PAUL BERG, Stanford University School of Medicine, Stanford, Calif. JOHN E. BURRIS, Marine Biological Laboratory, Woods Hole, Mass. SHARON L. DUNWOODY, University of Wisconsin, Madison, Wisc. URSULA W. G OODENOUGH, Washington University, St. Louis, Mo. HENRY W. HEIKKINEN, University of Northern Colorado, Greeley, Colo. HANS J. KENDE, Michigan State University, East Lansing, Mich. SUSAN E. L EEMAN, Boston University School of Medicine, Boston, Mass. THOMAS E. LOVEJOY, Smithsonian Institution, Washington, D.C. DONALD R. MATTISON, University of Pittsburgh, Pittsburgh, Pa. JOSEPH E. MURRAY, Wellesley Hills, Mass. EDWARD E. P ENHOET, Chiron Corporation, Emeryville, EMIL A. P FITZER, Research Institute for Fragrance Materials, Hackensack, N.J. MALCOLM C. PIKE , University of Southern California, Los Angeles, Calif. HENRY C. PITOT III, University of Wisconsin, Madison, Wisc. JONATHAN M. SAMET, The Johns Hopkins University, Baltimore, Md. CHARLES F. STEVENS, The Salk Institute, La Jolla, Calif. JOHN L. VANDEBERG, Southwest Foundation for Biomedical Research, San Antonio, Tex. PAUL GILMAN, Executive Director
OTHER RECENT REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND x TOXICOLOGY Other Recent Reports of the Board on Environmental Studies and Toxicology Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (Urinary Toxicology (1995), Immunotoxicology (1992), Environmental Neurotoxicology (1992), Pulmonary Toxicology (1989), Reproductive Toxicology (1989)) Review of EPA's Environmental Monitoring and Assessment Program (three reports, 1994-1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Waste Sites for Remedial Action (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Dolphins and the Tuna Industry (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Tracking Toxic Substances at Industrial Facilities (1990) Copies of these reports may be ordered from the National Academy Press (800) 624-6242 (202) 334-3313
OTHER RECENT REPORTS OF THE COMMITTEE ON TOXICOLOGY xi Other Recent Reports of the Committee on Toxicology Toxicity of Military Smokes and Obscurants, Volume 1 (1997) Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996) Permissible Exposure Levels for Selected Military Fuel Vapors (1996) Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994), Volume 2 (1996), and Volume 3 (1996) Nitrate and Nitrite in Drinking Water (1995) Guidelines for Chemical Warfare Agents in Military Field Drinking Water (1995) Review of the U.S. Naval Medical Research Institute's Toxicology Program (1994) Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms (1994) Health Effects of Ingested Fluoride (1993) Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (1993) Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants (1992) Review of the U.S. Army Environmental Hygiene Agency Toxicology Division (1991) Permissible Exposure Levels and Emergency Exposure Guidance Levels for Selected Airborne Contaminants (1991)
xii The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institutedicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academyâs purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org
PREFACE xiii Preface Due to the Existence of large stocks of chemical-warfare (CW) agents, their easy producibility from ordinary industrial chemicals, and their potential lethal effects, there is a critical need to determine as precisely as possible the exposure levels at which CW agents cause toxic effects. This information could aid in protecting soldiers in the event of a CW attack. This report, by the Subcommittee on Toxicity Values for Selected Nerve and Vesicant Agents of the National Research Council's Committee on Toxicology, is intended to assist the U.S. Army by assessing the scientific validity of existing human-toxicity estimates for several CW agents. The estimates considered in this report were proposed recently in the Army's Chemical Defense Equipment Process Action Team (CDEPAT) report entitled Review of Existing Toxicity Data and Human Estimates for Selected Chemical Agents and Recommended Human Toxicity Estimates Appropriate for Defending the Soldier (1994). The report was authored by S.A. Reutter, Ph.D., and W.A. Wade, D.V.M.; it is classified ''secret" and can be obtained only with permission from the director of the U.S. Army Edgewood Research, Engineering and Development Center, Edgewood, Md. We gratefully acknowledge Carl Curling, Jerry Glasow, William
PREFACE xiv Klenke, Francis O'Donnell, Forrest Oliverson, Gerald Palmer, Sharon Reutter, Harry Salem, and Sandra Thomson (all from the U.S. Army) for providing background information. We also thank Gail Charnley (Commission on Risk Assessment and Risk Management) and Annetta Watson (Oak Ridge National Laboratory) for making presentations to the subcommittee and providing useful information. We are grateful for the assistance of the National Research Council staff in preparing this report. Staff members who contributed to this effort are Paul Gilman, executive director of the Commission on Life Sciences; James J. Reisa, director of the Board on Environmental Studies and Toxicology; Carol A. Maczka, program director for toxicology and risk assessment; Ruth E. Crossgrove, editor; Lucy V. Fusco, project assistant, and Catherine M. Kubik, senior program assistant. We especially wish to recognize the major contributions of the project director, Kulbir S. Bakshi, who directed the preparation of the subcommittee's report. His knowledge of the scientific and technical literature and his tireless efforts to obtain information and to organize the study plan, the subcommittee meetings, and the subcommittee's report aided in the successful completion of the project. Finally, we would like to thank all the members of the subcommittee for their dedicated efforts throughout the development of this report. LOREN D. KOLLER, PH.D. CHAIR, SUBCOMMITTEE ON TOXICITY VALUES FOR SELECTED NERVE AND VESICANT AGENTS ROGENE F. HENDERSON, PH.D. CHAIR, COMMITTEE ON TOXICOLOGY
CONTENTS xv Contents Summary 1 1 Introduction and Background 17 2 Review of Acute Human-Toxicity Estimates for GA (Tabun) 20 Percutaneous Vapor Exposure 20 Inhalation Vapor Exposure 22 Percutaneous Liquid Exposure 24 Conclusions and Recommendations 25 3 Review of Acute Human-Txicity Estimates for GB (Sarin) 28 Percutaneous Vapor Exposure 28 Inhalation Vapor Exposure 29 Percutaneous Liquid Exposure 31 Conclusions and Recommendations 32 4 Review of Acute Human-toxicity Estimates for GD (Soman) 35
CONTENTS xvi Percutaneous Vapor Exposure 35 Inhalation Vapor Exposure 37 Percutaneous Liquid Exposure 38 Conclusions and Recommendations 40 5 Review of Acute Human-toxicity Estimates for GF 43 Percutaneous Vapor Exposure 43 Inhalation Vapor Exposure 45 Percutaneous Liquid Exposure 46 Conclusions and Recommendations 47 6 Review of Acute Human-toxicity Estimates for VX 50 Percutaneous Vapor Exposure 50 Inhalation Vapor Exposure 53 Percutaneous Liquid Exposure 55 Conclusions and Recommendations 56 7 Review of Acute Human-toxicity Estimates for HB 59 Percutaneous Vapor Exposure 59 Inhalation Vapor Exposure 61 Percutaneous Liquid Exposure 63 Conclusions and Recommendations 64 8 Evaluation of the Risk-estimation Procedures Used in the CDEPAT 67 Report Use of Log-Probit Analysis 67 Use of the ECt50 68 Use of Confidence Limits 71 References 72 Glossary 77 Appendix 80