Review of the U.S. Army's Health Risk Assessments For Oral Exposure to Six Chemical-Warfare Agents

Subcommittee on Chronic Reference Doses For Selected Chemical-Warfare Agents

Committee on Toxicology

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

National Academy Press
Washington, D.C.



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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Review of the U.S. Army's Health Risk Assessments For Oral Exposure to Six Chemical-Warfare Agents Subcommittee on Chronic Reference Doses For Selected Chemical-Warfare Agents Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council National Academy Press Washington, D.C.

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 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. 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 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. William 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. Kenneth I. Shine is president of the Institute of Medicine. 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 Academy's 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. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council. This project was supported by Contract Nos. DAMD 17-89-C-9086 and DAMD 17-99-C-9049 between the National Academy of Sciences and U.S. Department of Defense. Any opinions, findings, conclusions, or recommendations 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. International Standard Book Number 0-309-06598-4 Additional copies of this report are available from: National Academy Press 2101 Constitution Ave., NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents SUBCOMMITTEE ON CHRONIC REFERENCE DOSES FOR SELECTED CHEMICAL-WARFARE AGENTS ROBERT SNYDER (Chair), Rugters University College of Pharmacy and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey MOHAMED B. ABOU-DONIA, Duke University, Durham, North Carolina EDSON X. ALBUQUERQUE, University of Maryland School of Medicine, Baltimore, Maryland JEFFREY I. DANIELS, Lawrence Livermore National Laboratory, Livermore, California DONALD E. GARDNER, Inhalation Toxicology Associates, Raleigh, North Carolina DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson, Arkansas ROGENE F. HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico JOHN T. JAMES, National Aeronautics and Space Administration, Houston, Texas SANFORD S. LEFFINGWELL, HLM Consultants, Auburn, Georgia JOSEPH J. SAADY, Commonwealth of Virginia, Richmond, Virginia PETER S. SPENCER, Oregon Health Sciences University, Portland, Oregon BERNARD M. WAGNER, Consultant, Short Hills, New Jersey BARRY W. WILSON, University of California, Davis California Staff KULBIR S. BAKSHI, Project Director SUSAN N.J. PANG, Program Officer RUTH E. CROSSGROVE, Editor LINDA V. LEONARD, Senior Project Assistant STEPHANIE PARKER, Assistant Information Specialist Sponsor: U.S. DEPARTMENT OF DEFENSE

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents COMMITTEE ON TOXICOLOGY BAILUS WALKER, JR. (Chair), Howard University Medical Center, Washington, D.C. MELVIN E. ANDERSEN, Colorado State University, Denver, Colorado GERMAINE M. BUCK, State University of New York at Buffalo GARY P. CARLSON, Purdue University, West Lafayette, Indiana JACK H. DEAN, Sanofi Pharmaceuticals, Inc., Malverne, Pennsylvania ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia, Pennsylvania PAUL M.D. FOSTER, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson, Arkansas JUDITH A. GRAHAM, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina SIDNEY GREEN, Howard University, Washington, D.C. WILLIAM E. HALPERIN, National Institute for Occupational Safety and Health, Cincinnati, Ohio CHARLES H. HOBBS, Lovelace Respiratory Research Institute and Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico FLORENCE K. KINOSHITA, Hercules Incorporated, Wilmington, Delaware MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver, Colorado MORTON LIPPMANN, New York University School of Medicine, Tuxedo, New York THOMAS E. MCKONE, University of California, Berkeley, California ERNEST E. MCCONNELL, ToxPath, Inc., Raleigh, North Carolina DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Maryland GÜNTER OBERDÖRSTER, University of Rochester, Rochester, New York JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, New York GEORGE M. RUSCH, Allied Signal, Inc., Morristown, New Jersey MARY E. VORE, University of Kentucky, Lexington, Kentucky ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tennessee Staff KULBIR S. BAKSHI, Program Director SUSAN N.J. PANG, Program Officer ABIGAIL STACK, Program Officer RUTH E. CROSSGROVE, Publications Manager KATHRINE J. IVERSON, Manager, Toxicology Information Center LUCY V. FUSCO, Project Assistant LEAH PROBST, Project Assistant EVELYN SIMEON, Project Assistant

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GORDON ORIANS (Chair), University of Washington, Seattle, Washington DONALD MATTISON (Vice Chair), March of Dimes, White Plains, New York DAVID ALLEN, University of Texas, Austin, Texas INGRID C. BURKE, Colorado State University, Fort Collins, Colorado WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta, Georgia JOHN DOULL, The University of Kansas Medical Center, Kansas City, Kansas CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, California JOHN GERHART, University of California, Berkeley, California J. PAUL GILMAN, Celera Genomics, Rockville, Maryland BRUCE D. HAMMOCK, University of California, Davis, California MARK HARWELL, University of Miami, Miami, Florida ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico CAROL HENRY, Chemical Manufacturers Association, Arlington, Virginia BARBARA HULKA, University of North Carolina, Chapel Hill, North Carolina JAMES F. KITCHELL, University of Wisconsin, Madison, Wisconsin DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario JAMES A. MACMAHON, Utah State University, Logan, Utah MARIO J. MOLINA, Massachusetts Institute of Technology, Cambridge, Massachusetts CHARLES O'MELIA, Johns Hopkins University, Baltimore, Maryland WILLEM F. PASSCHIER, Health Council of the Netherlands KIRK SMITH, University of California, Berkeley, California MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. TERRY F. YOSIE, Chemical Manufacturers Association, Arlington, Virginia Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology CAROL A. MACZKA, Senior Program Director for Toxicology and Risk Assessment RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering KULBIR BAKSHI, Program Director for the Committee on Toxicology LEE R. PAULSON, Program Director for Resource Management

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents COMMISSION ON LIFE SCIENCES MICHAEL T. CLEGG (Chair), University of California, Riverside, California PAUL BERG (Vice Chair), Stanford University, Stanford, California FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOHN C. BAILAR III, University of Chicago, Chicago, Illinois JOANNA BURGER, Rutgers University, Piscataway, New Jersey SHARON L. DUNWOODY, University of Wisconsin, Madison, Wisconsin DAVID EISENBERG, University of California, Los Angeles, California JOHN EMMERSON, Portland, Oregon NEAL FIRST, University of Wisconsin, Madison, Wisconsin DAVID J. GALAS, Keck Graduate Institute of Applied Science, Claremont, California DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, California ARTURO GOMEZ-POMPA, University of California, Riverside, California COREY S. GOODMAN, University of California, Berkeley, California HENRY HEIKKINEN, University of Northern Colorado, Greeley, Colorado BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina HANS J. KENDE, Michigan State University, East Lansing, Michigan CYNTHIA KENYON, University of California, San Francisco, California MARGARET G. KIDWELL, University of Arizona, Tucson, Arizona BRUCE R. LEVIN, Emory University, Atlanta, Georgia OLGA F. LINARES, Smithsonian Tropical Research Institute, Miami, Florida DAVID LIVINGSTON, Dana-Farber Cancer Institute, Boston, Massachusetts DONALD R. MATTISON, March of Dimes, White Plains, New York ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena, California ROBERT T. PAINE, University of Washington, Seattle, Washington RONALD R. SEDEROFF, North Carolina State University, Raleigh, North Carolina ROBERT R. SOKAL, State University of New York, Stony Brook, New York CHARLES F. STEVENS, The Salk Institute, La Jolla, California SHIRLEY M. TILGHMAN, Princeton University, Princeton, New Jersey JOHN L. VANDEBERG, Southwest Foundation for Biomedical Research, San Antonio Texas RAYMOND L. WHITE, University of Utah, Salt Lake City, Utah Staff WARREN R. MUIR, Executive Director JACQUELINE K. PRINCE, Financial Officer BARBARA B. SMITH, Administrative Associate KIT W. LEE, Administrative Assistant

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Research Priorities for Airborne Particulate Matter: II. Evaluating Research Progress and Updating the Portfolio (1999) Ozone-Forming Potential of Reformulated Gasoline (1999) Risk-Based Waste Classification in California (1999) Arsenic in Drinking Water (1999) Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998) Brucellosis in the Greater Yellowstone Area (1998) The National Research Council's Committee on Toxicology: The First 50 Years (1997) Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests (1997) Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (5 reports, 1989–1995) Review of EPA's Environmental Monitoring and Assessment Program (3 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) Copies of these reports may be ordered from the National Academy Press (800) 624-6242 (202) 334-3313 www.nap.edu

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Other Reports of the Committee on Toxicology Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998) Review of A Screening Level Risk Assessment for the Naval Air Facility at Atsugi, Japan (Letter Report) (1998) Review of Acute Human-Toxicity Estimates for Selected Chemical-Warfare Agents (1997) The National Research Council's Committee on Toxicology: The First 50 Years (1997) Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests (1997) Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests: Answers to Commonly Asked Questions (1997) Toxicity of Military Smokes and Obscurants, Volume 1 (1997) and Volume 2 (1999) 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), 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)

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Preface Several military bases contaminated with chemical-warfare agents as a result of storage and past disposal practices are slated to be closed pursuant to the Base Realignment and Closure Act. Before those military bases can be transferred to civilian use, contaminated soil and water must be cleaned to levels that are considered safe. To help make decisions on restoration required at contaminated sites and on the potential uses of the former military installations (e.g., for housing, occupational, or wildlife purposes), the U.S. Army developed interim chronic oral reference doses and, where appropriate, oral slope factors for six chemical-warfare agents that are likely to be encountered at contaminated sites. Similar information for inhalation exposure is under development. In this report, the Subcommittee on Chronic Reference Doses for Selected Chemical-Warfare Agents of the National Research Council's (NRC's) Committee on Toxicology reviews the scientific validity of the Army's interim values for the six chemical-warfare agents—GA, GB, GD, VX, sulfur mustard, and lewisite. The NRC report is intended to be useful to the Army in making site-specific cleanup decisions. This report has been reviewed in draft form by individuals chosen for their technical expertise and diverse perspectives in accordance with procedures approved by the NRC's Report Review Committee for reviewing NRC and Institute of Medicine reports. The purpose of that independent review was to provide candid and critical comments to assist the NRC in making the published report as sound as possible and to ensure

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals, who are neither officials nor employees of the NRC, for their participation in the review of this report: Joseph Borzelleca, Virginia Commonwealth University; John Doull, University of Kansas Medical Center; Ronald W. Estabrook (report review committee monitor), University of Texas Southwestern Medical Center; Florence Kinoshita, Hercules Inc.; Loren Koller (report review coordinator), Oregon State University; John O'Donoghue, Eastman Kodak Company; and Joseph Rodricks, Life Sciences Trust. The individuals listed above have provided many constructive comments and suggestions. It must be emphasized, however, that responsibility for the final content of this report rests entirely with the authoring committee and the NRC. We gratefully acknowledge Veronique Hauschild, Joe King, and Steve Kistner (all of the U.S. Army Center for Health Promotion and Preventive Medicine) and Dennis Opresko, Robert Ross, Annetta Watson, and Robert Young (all of Oak Ridge National Laboratory) for providing background information and for making presentations to the subcommittee. We are grateful for the assistance of the NRC staff for preparing the report. Staff members who contributed to this effort are James J. Reisa, director of the Board on Environmental Studies and Toxicology; Carol A, Maczka, senior program director for toxicology and risk assessment; Ruth E. Crossgrove, editor; and Linda Leonard, senior project assistant. We especially wish to recognize the major contributions of the project director, Kulbir S. Bakshi, and the program officer, Susan N.J. Pang, who directed the preparation of the subcommittee's report. Their knowledge of the scientific and technical literature and their tireless effort to obtain information and to organize the subcommittee meetings and the 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. Robert Snyder, Ph.D. Chair, Subcommittee on Chronic Reference Doses For Selected Chemical-Warfare Agents Bailus Walker, JR., Ph.D., M.P.H. Chair, Committee on Toxicology

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents Contents     Summary   1 1   Introduction   9     References,   16 2   Derivation of Reference Doses   17     Reference-Dose Calculation,   17     Benchmark Dose,   19     Uncertainty Factors,   20     Conclusions,   22     References,   22 3   Evaluation of the Army's Interim Reference Dose for GA   24     Derivation of the Army's Interim RfD,   24     Appropriateness of the Critical Study,   25     Appropriateness of the Critical End Point,   27     Appropriateness of Uncertainty Factors,   29     Weight and Strength of Evidence,   32     Conclusions,   32     Data Gaps and Research Recommendations,   33     References,   33

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 4   Evaluation of the Army's Interim Reference Dose for GB   36     Derivation of the Army's Interim RfD,   36     Appropriateness of the Critical Study,   37     Appropriateness of the Critical End Point,   38     Appropriateness of Uncertainty Factors,   40     Weight and Strength of Evidence,   43     Conclusions,   43     Data Gaps and Research Recommendations,   44     References,   44 5   Evaluation of the Army's Interim Reference Dose for GD   48     Derivation of the Army's Interim RfD,   48     Appropriateness of the Critical Study,   49     Appropriateness of the Critical End Point,   50     Appropriateness of Uncertainty Factors,   51     Weight and Strength of Evidence,   55     Conclusions,   55     Data Gaps and Research Recommendations,   55     References,   55 6   Evaluation of the Army's Interim Reference Dose for VX   59     Derivation of the Army's Interim RfD,   59     Appropriateness of the Critical Study,   60     Appropriateness of the Critical End Point,   62     Appropriateness of Uncertainty Factors,   63     Weight and Strength of Evidence,   65     Conclusions,   66     Data Gaps and Research Recommendations,   66     References,   67 7   Evaluation of the Army's Interim Reference Dose and Slope Factor for Sulfur Mustard   70     Evaluation of the Army's Interim RfD,   71     Evaluation of the Army's Interim Cancer Slope Factor,   76     Conclusions,   80     Data Gaps and Research Recommendations,   80     References,   81

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Review of the U.S. Army's Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents 8   Evaluation of the Army's Interim Reference Dose for Lewisite   83     Derivation of the Army's Interim RfD,   83     Appropriateness of the Critical Study,   85     Appropriateness of the Critical End Point,   87     Appropriateness of Uncertainty Factors,   88     Weight and Strength of Evidence,   89     Conclusions,   90     Data Gaps and Research Recommendations,   90     References,   91     Glossary   93 Appendix A:   Health Risk Assessment for the Nerve Agent GA   97 Appendix B:   Health Risk Assessment for the Nerve Agent GB   131 Appendix C:   Health Risk Assessment for the Nerve Agent GD (Soman)   167 Appendix D:   Health Risk Assessment for the Nerve Agent VX   197 Appendix E:   Health Risk Assessment for Sulfur Mustard (HD)   235 Appendix F:   Health Risk Assessment for Lewisite   275 Appendix G:   Inhibition of Cholinesterases and an Evaluation of the Methods Used to Measure Cholinesterase Activity   295

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