Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents

Committee on Toxicologic Assessment of Low-Level Exposures to Chemical Warfare Agents

Committee on Toxicology

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESERCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu



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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Committee on Toxicologic Assessment of Low-Level Exposures to Chemical Warfare Agents Committee on Toxicology Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESERCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 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 project was supported by Contract No. W81K04-05-C-7006 and DAMD17-99-C-9049 between the National Academy of Sciences and the U.S. Army. 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 0-309-10021-6 Additional copies of this report are available from: The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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. Ralph J. Cicerone 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 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. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents COMMITTEE ON TOXICOLOGIC ASSESSMENT OF LOW-LEVEL EXPOSURES TO CHEMICAL WARFARE AGENTS Members GARY P. CARLSON (Chair), Purdue University, West Lafayette, IN A. JOHN BAILER, Miami University, Oxford, OH JONATHAN BORAK, Yale School of Medicine, New Haven, CT JANICE E. CHAMBERS, Mississippi State University, Mississippi State MARION EHRICH, Virginia Tech, Blacksburg LYNNE HABER, Toxicology Excellence for Risk Assessment, Cincinnati, OH SANFORD S. LEFFINGWELL, HLM Consultants, Auburn, GA DAVID H. MOORE, Battelle Eastern Science and Technology Center, Aberdeen, MD CAREY POPE, Oklahoma State University, Stillwater PETER S. SPENCER, Oregon Health & Science University, Portland NGA LIEN TRAN, Exponent, Inc., Washington, DC NRC Staff KULBIR S. BAKSHI, Project Director CAY BUTLER, Editor AIDA C. NEEL, Program Associate ALEXANDRA STUPPLE, Senior Editorial Assistant

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents COMMITTEE ON TOXICOLOGY Members BAILUS WALKER, JR. (Chair), Howard University Medical Center and American Public Health Association, Washington, DC MELVIN E. ANDERSEN, CIIT-Centers for Health Research, Research Triangle Park, NC EDWARD C. BISHOP, Parsons Corporation, Fairfax, VA GARY P. CARLSON, Purdue University, West Lafayette, IN JANICE E. CHAMBERS, Mississippi State University, Mississippi State LEONARD CHIAZZE, JR., Georgetown University, Washington, DC JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA SIDNEY GREEN, Howard University, Washington, DC MERYL KAROL, University of Pittsburgh, Pittsburgh, PA STEPHEN U. LESTER, Center for Health Environment and Justice, Falls Church, VA DAVID H. MOORE, Battelle Memorial Institute, Bel Air, MD CALVIN C. WILLHITE, State of California, Berkeley, CA GERALD WOGAN, Massachusetts Institute of Technology, Cambridge Staff KULBIR S. BAKSHI, Project Director SUSAN N.J. MARTEL, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer AIDA NEEL, Program Associate TAMARA DAWSON, Senior Program Assistant ALEXANDRA STUPPLE, Senior Editorial Assistant SAM BARDLEY, Librarian

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members JONATHAN M. SAMET (Chair), The Johns Hopkins University, Baltimore, MD RAMÓN ALVAREZ, Environmental Defense, Austin, TX THOMAS BURKE, The Johns Hopkins University, Baltimore, MD JUDITH C. CHOW, Desert Research Institute, Reno, NV RORY B. CONOLLY, CIIT-Centers for Health Research, Research Triangle Park, NC COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie Farr & Gallagher LLP, Washington, DC CHRISTOPHER B. FIELD, Carnegie Institution of Washington, Stanford, CA SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, MA ROBERT HUGGETT, Michigan State University, East Lansing BARRY L. JOHNSON, Emory University, Atlanta, GA JAMES H. JOHNSON, Howard University, Washington, DC JUDITH L. MEYER, University of Georgia, Athens PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON, International Life Sciences Institute, Washington, DC STEWARD T.A. PICKETT, Institute of Ecosystem Studies, Millbrook, NY JOSEPH V. RODRICKS, ENVIRON Corp., Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta MITCHELL J. SMALL, Carnegie Mellon University, Pittsburgh, PA LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Harvard School of Public Health, Boston, MA G. DAVID TILMAN, University of Minnesota, St. Paul CHRIS G. WHIPPLE, ENVIRON Corp., Emeryville, CA LAUREN A. ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering KULBIR BAKSHI, Senior Program Officer for Toxicology EILEEN N. ABT, Senior Program Officer for Risk Analysis K. JOHN HOLMES, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer SUZANNE VAN DRUNICK, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor 1   This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Health Implications of Perchlorate Ingestion (2005) Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (4 volumes, 2000-2004) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (4 volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (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 volumes, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (3 volumes, 1994-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (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 Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004) Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003) Review of Submarine Escape Action Levels for Selected Chemicals (2002) Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001) Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) Acute Exposure Guideline Levels for Selected Airborne Contaminants, Volume 1 (2000), Volume 2 (2002), Volume 3 (2003), Volume 4 (2004) Review of the US Navy’s Human Health Risk Assessment of the Naval Air Facility at Atsugi, Japan (2000) Methods for Developing Spacecraft Water Exposure Guidelines (2000) Review of the U.S. Navy Environmental Health Center’s Health-Hazard Assessment Process (2000) Review of the U.S. Navy’s Exposure Standard for Manufactured Vitreous Fibers (2000) Re-Evaluation of Drinking-Water Guidelines for Diisopropyl Methylphosphonate (2000) Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23, and HFC-404a (2000) Review of the U.S. Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) Toxicity of Military Smokes and Obscurants, Volume 1(1997), Volume 2 (1999), Volume 3 (1999) Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998) 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), Volume 4 (2000)

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Preface In 1998, Congress directed the Secretary of Defense to review and modify U.S. Department of Defense (DOD) policies and doctrines that relate to protecting personnel from low-level exposure to chemical warfare agents (CWAs). In response to that congressional mandate, the Secretary of Defense directed DOD’s Nuclear, Chemical, and Biological Defense Program to develop a research plan to obtain toxicologic and other data to assess health risks to U.S. forces. The data obtained from the proposed research would provide information to the Secretary of Defense to reassess policies and doctrines related to low-level exposures to CWAs. The research is intended to accomplish two objectives. The first is to support operational commanders in the field with information for real-time decision making required to accomplish their missions while not unduly jeopardizing the health and performance capability of their forces. The second is to understand, prevent, or reduce operationally relevant performance decrements, as well as the potential health consequences of low-level exposures that might not manifest immediately but could become evident months or years after exposure. In response, DOD developed the multiyear research program on low-level exposures to chemical warfare agents entitled Department of Defense Low-Level Chemical Warfare Agents (CWAs) Exposure Research Master Plan. DOD requested that the National Research Council (NRC) review that research plan and comment on its adequacy and appropriateness, provide guidance on appropriate risk assessment methods for assessing toxicologic risk from low-level exposures to CWAs, and identify gaps and make recommendations for further research. The NRC

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents convened the Committee on Toxicologic Assessment of Low-Level Exposures to Chemical Warfare Agents. The committee’s report is intended to be helpful in focusing research efforts to improve operational management. The DOD Low-Level CWA Exposure Research Master Plan (Research Plan) details the military’s priorities for research needs and methods to address the effects of low-level agent exposure on operationally relevant performance in military personnel at the time of exposure and on potential delayed adverse health effects at some point after exposure. As stated in the Research Plan, both of these aspects of low-dose exposure “represent different points along the dose-response continuum—not separate problems.” This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure 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 thank the following individuals for their review of this report: Barbara Callahan (University Research Engineers and Associates), Donald J. Ecobichon (consultant), Jeffrey W. Fisher (University of Georgia), David Gaylor (Gaylor & Associates), Ramesh C. Gupta (Murray State University), Rogene Henderson (Lovelace Respiratory Research Institute), Robert MacPhail (U.S. Environmental Protection Agency), and George M. Rusch (Honeywell International). Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Edward C. Bishop of Parsons Corporation. Appointed by the NRC, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. The committee gratefully acknowledges the valuable presentations made by Stephen Channel, Keith R.Vesely, Douglas Somerville, Jeffrey

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Gearhart, Sandra Thomson, and Robert Sheridan, all from the Department of Defense. Aida Neel was the program associate, and Cay Butler was the editor. We are grateful to James J. Reisa, director of the Board on Environmental Studies and Toxicology, for his helpful guidance. The committee particularly acknowledges Kulbir Bakshi, project director for the committee, for bringing the report to completion. Finally, we thank all members of the committee for their expertise and dedicated efforts throughout the development of this report. Gary P. Carlson, Chair Committee on Toxicologic Assessment of Low Level Exposures to Chemical Warfare Agents Bailus Walker, Chair Committee on Toxicology

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Contents     SUMMARY   1 1   INTRODUCTION   11      Background,   13      Charge to the Committee,   14      Organization of Report,   14 2   UNDERSTANDING THE PROBLEM OF LOW-LEVEL EXPOSURE TO CHEMICAL WARFARE AGENTS   16      Background,   18      Toxicologic Studies,   19      Other Animal Studies,   20      Human Exposures,   20      Chemical Warfare Exposure Scenario,   25      Risk Comparisons,   27 3   REVIEW OF THE DEPARTMENT OF DEFENSE MASTER RESEARCH PLAN ON LOW-LEVEL EXPOSURE TO CHEMICAL WARFARE AGENTS   30      Goals, Objectives, and Aims of the Master Research Plan,   30      Overview of the DOD’s Current Research Plan,   31      The Committee’s Evaluation of the DOD Research Plan,   32      Overall Summary of the Evaluation of the DOD Research Plan,   62

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents 4   RESEARCH ISSUES RELATED TO RISK ASSESSMENT OF LOW-LEVEL EXPOSURE TO CHEMICAL WARFARE AGENTS   65     Question 1.  What Is the Critical Adverse Response to Exposure to Low Levels of CWAs?   65     Question 2.  How Much of a Decrement in the Critical Response is Advserse?   66     Question 3.  Are There Biomarkers of CWA Exposure That Can Be Measured and Used in Risk Comparisons?   67     Question 4.  How Should Exposures in “Work” Conditions Be Considered When Extrapolating Animal Models to Human Experience?   69     Question 5.  What is the Relationship Between Exposure Concentration-Duration and Risk?   70     Question 6.  How Should Exposure-Duration Risk Be Communicated for CWAs?   73     Question 7.  What Are Appropriate Approaches for Evaluating the Risk of Exposure to a CWA Mixture?   74     Question 8.  What Information Is Needed to Best Support Extrapolation from Animal Studies to Human Responses? How and When Might a PBPK Model Be Useful for Aiding in Such Extrapolations?   75     Question 9.  What Is the Impact of Experimental Designs on Risk Assessments and Subsequent Efforts to Establish Exposure Guidelines for Military Personnel Protection?   78     Question 10.  How Does One Account for Variability in Human Response to CWAs, and Do CWA-Susceptible Subpopulations of Humans Exist?   79     Question 11.  What Statistical Models Are Appropriate for Concentration-Time Data?   80      Regression Methods for Continuous or Ordered Responses,   85      Experimental Recommendations,   86      The Committee’s Recommendations,   86     REFERENCES   89     ABBREVIATIONS   103

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Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents

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