Application of
Modern Toxicology Approaches
for Predicting Acute Toxicity
for Chemical Defense
Committee on Predictive-Toxicology Approaches for
Military Assessments of Acute Exposures
Committee on Toxicology
Board on Environmental Studies and Toxicology
Board on Life Sciences
Division on Earth and Life Studies
THE NATIONAL ACADEMIES PRESS
Washington, DC
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
This project was supported by Contract W81K04-11-D-0017, TO#8 between the National Academies of Sciences, Engineering, and Medicine and the US Department of Defense. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
International Standard Book Number-13: 978-0-309-37666-2
International Standard Book Number-10: 0-309-37666-1.
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Suggested citation: The National Academies of Sciences, Engineering, and Medicine. 2015. Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense. Washington, DC: The National Academies Press.
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COMMITTEE ON PREDICTIVE-TOXICOLOGY APPROACHES FOR MILITARY ASSESSMENTS OF ACUTE EXPOSURES
Members
DAVID C. DORMAN (Chair), North Carolina State University, Raleigh, NC
WEIHSUEH A. CHIU, Texas A&M University, College Station, TX
HAIYAN HUANG, University of California, Berkeley, CA
ANDY NONG, Health Canada, Ottawa, ON
GRACE PATLEWICZ, US Environmental Protection Agency, Research Triangle Park, NC
DAVID REIF, North Carolina State University, Raleigh, NC
JOHN WADE, Battelle, Arlington, VA
KATRINA WATERS, Pacific Northwest National Laboratories, Richland, WA
BARBARA A. WETMORE, The Hamner Institutes for Health Sciences, Research Triangle Park, NC
YVONNE WILL, Pfizer, Groton, CT
Staff
ELLEN K. MANTUS, Project Director
MARILEE SHELTON-DAVENPORT, Senior Program Officer
KERI STOEVER, Research Associate
NORMAN GROSSBLATT, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE-CRAWFORD, Manager, Editorial Projects
IVORY CLARKE, Senior Program Assistant
Sponsor
US DEPARTMENT OF DEFENSE
COMMITTEE ON TOXICOLOGY
Members
GARY P. CARLSON (Chair), Purdue University (retired), West Lafayette, IN
LAWRENCE S. BETTS, Eastern Virginia Medical School, Norfolk
DEEPAK K. BHALLA, Wayne State University, Detroit, MI
DEBORAH A. CORY-SLECHTA, University of Rochester School of Medicine and Dentistry, Rochester, NY
MARY E. DAVIS, West Virginia University, Morgantown
DAVID C. DORMAN, North Carolina State University, Raleigh
MARGARET M. MACDONELL, Argonne National Laboratory, Argonne, IL
IVAN RUSYN, Texas A&M University, College Station
KENNETH R. STILL, Portland State University, Portland, OR
JOYCE S. TSUJI, Exponent, Inc., Bellevue, WA
Staff
SUSAN N.J. MARTEL, Senior Program Officer for Toxicology
ELLEN K. MANTUS, Scholar and Director of Risk Assessment
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE, Manager, Editorial Projects
TAMARA DAWSON, Program Associate
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1
Members
ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM
PRAVEEN AMAR, Independent Consultant, Lexington, MA
RICHARD A. BECKER, American Chemistry Council, Washington, DC
MICHAEL J. BRADLEY, M.J. Bradley & Associates, Concord, MA
JONATHAN Z. CANNON, University of Virginia, Charlottesville, VA
GAIL CHARNLEY ELLIOTT, HealthRisk Strategies, Washington, DC
DOMINIC M. DITORO, University of Delaware, Newark, DE
DAVID C. DORMAN, North Carolina State University, Raleigh, NC
CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY
WILLIAM H. FARLAND, Colorado State University, Fort Collins, CO
LYNN R. GOLDMAN, The George Washington University, Washington, DC
LINDA E. GREER, Natural Resources Defense Council, Washington, DC
WILLIAM E. HALPERIN, University of Medicine and Dentistry of New Jersey, Newark, NJ
STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY
ROBERT A. HIATT, University of California, San Francisco, CA
PHILIP K. HOPKE, Clarkson University, Potsdam, NY
SAMEUL KACEW, University of Ottawa, Ontario
H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA
THOMAS E. MCKONE, University of California, Berkeley, CA
TERRY L. MEDLEY, E. I. du Pont de Nemours & Company, Wilmington, DE
JANA MILFORD, University of Colorado at Boulder, Boulder, CA
MARK A. RATNER, Northwestern University, Evanston, IL
JOAN B. ROSE, Michigan State University, East Lansing, MI
GINA M. SOLOMON, California Environmental Protection Agency, Sacramento, CA
PETER S. THORNE, University of Iowa, Iowa City, IA
JOYCE S. TSUJI, Exponent, Inc., Bellevue, WA
Senior Staff
JAMES J. REISA, Senior Director
ELLEN K. MANTUS, Scholar and Director of Risk Assessment
RAYMOND A. WASSEL, Scholar and Director of Environmental Studies
DAVID J. POLICANSKY, Scholar
SUSAN N.J. MARTEL, Senior Program Officer for Toxicology
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE-CRAWFORD, Manager, Editorial Projects
__________________
1This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.
OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Review of California’s Risk-Assessment Process for Pesticides (2015)
Sustainability Concepts in Decision Making, Tools and Approaches for the US Environmental Protection Agency (2014)
Rethinking the Components, Coordination, and Management of US Environmental Protection Agency Laboratories (2014)
Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)
Review of the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)
Review of EPA’s Integrated Risk Information System (IRIS) Process (2014)
Review of the Environmental Protection Agency’s State-of-the-Science Evaluation of Nonmonotonic Dose–Response Relationships as They Apply to Endocrine Disruptors (2014)
Assessing Risks to Endangered and Threatened Species from Pesticides (2013)
Science for Environmental Protection: The Road Ahead (2012)
Exposure Science in the 21st Century: A Vision and A Strategy (2012)
A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials (2012)
Macondo Well–Deepwater Horizon Blowout: Lessons for Improving Offshore Drilling Safety (2012)
Feasibility of Using Mycoherbicides for Controlling Illicit Drug Crops (2011)
Improving Health in the United States: The Role of Health Impact Assessment (2011)
A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration (2011)
Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde (2011)
Toxicity-Pathway-Based Risk Assessment: Preparing for Paradigm Change (2010)
The Use of Title 42 Authority at the U.S. Environmental Protection Agency (2010)
Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene (2010)
Hidden Costs of Energy: Unpriced Consequences of Energy Production and Use (2009)
Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects (2009)
Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (2009)
Science and Decisions: Advancing Risk Assessment (2009)
Phthalates and Cumulative Risk Assessment: The Tasks Ahead (2008)
Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution (2008)
Respiratory Diseases Research at NIOSH (2008)
Evaluating Research Efficiency in the U.S. Environmental Protection Agency (2008)
Hydrology, Ecology, and Fishes of the Klamath River Basin (2008)
Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007)
Models in Environmental Regulatory Decision Making (2007)
Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007)
Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007)
Environmental Impacts of Wind-Energy Projects (2007)
Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007)
Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006)
New Source Review for Stationary Sources of Air Pollution (2006)
Human Biomonitoring for Environmental Chemicals (2006)
Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006)
Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006)
State and Federal Standards for Mobile-Source Emissions (2006)
Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005)
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 (nineteen volumes, 2000-2015)
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 (2000)
Hormonally Active Agents in the Environment (1999)
Research Priorities for Airborne Particulate Matter (four 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 (five volumes, 1989-1995)
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
BOARD ON LIFE SCIENCES
Members
JAMES P. COLLINS (Chair), Arizona State University, Tempe, AZ
ENRIQUETA C. BOND, Burroughs Wellcome Fund, Marshall, VA
ROGER D. CONE, Vanderbilt University Medical Center, Nashville, TN
JOSEPH R. ECKER, Salk Institute for Biological Studies, LaJolla, CA
SEAN EDDY, HHMI Janelia Farm Research Campus, Ashburn, VA
SARAH C.R. ELGIN, Washington University, St. Louis, MO
DAVID R, FRANZ, Former Cdr USAMRIID, Consultant, Frederick, MD
STEPHEN FRIEND, Sage Bionetworks, Seattle, WA
ELIZABETH HEITMAN, Vanderbilt University Medical Center, Nashville, TN
RICHARD A. JOHNSON, Global Helix LLC, Washington, DC
JUDITH KIMBLE, University of Wisconsin, Madison, WI
MARY E. MAXON, Science Philanthropy Alliance, Palo Alto, CA
KAREN E. NELSON, J. Craig Venter Institute, Rockville, MD
ROBERT M. NEREM, Georgia Institute of Technology, Atlanta, GA
MARY E. POWER, University of California, Berkeley, CA
MARGARET RILEY, University of Massachusetts, Amherst, MA
LANA SKIRBOLL, Sanofi, Washington, DC
JANIS C. WEEKS, University of Oregon, Eugene, OR
MARY WOOLLEY, Research!America, Alexandria, VA
Staff
FRANCES E. SHARPLES, Director
JO L. HUSBANDS, Scholar/Senior Project Director
JAY B. LABOV, Senior Scientist/Program Director for Biology Education
LIDA ANESTIDOU, Senior Program Officer, ILAR
KATHERINE W. BOWMAN, Senior Program Officer
MARILEE K. SHELTON-DAVENPORT, Senior Program Officer
KEEGAN SAWYER, Program Officer
AUDREY THEVENON, Associate Program Officer
BETHELHEM M. MEKASHA, Financial Associate
ANGELA KOLESNIKOVA, Administrative Assistant
VANESSA LESTER, Research Associate
KANOKO MAEDA, Senior Program Assistant
JENNA OGILVIE, Senior Program Assistant
Preface
The US Department of Defense (DOD) is faced with an overwhelming task in evaluating chemicals that could potentially pose a threat to its deployed personnel. There are over 84,000 registered chemicals, and testing them with traditional toxicity-testing methods is not feasible in terms of time or money. In recent years, there has been a concerted effort to develop new approaches to toxicity testing that incorporate advances in systems biology, toxicogenomics, bioinformatics, and computational toxicology. Given the advances, DOD asked the National Research Council (NRC) to determine how DOD could use modern approaches for predicting chemical toxicity in its efforts to prevent debilitating, acute exposures to deployed personnel.
In this report, the Committee on Predictive-Toxicology Approaches for Military Assessments of Acute Exposures provides an overall conceptual approach that DOD could use to develop a predictive-toxicology system. It reviews the current state of computational and high-throughput approaches for predicting acute toxicity and suggests methods for integrating data and predictions. It concludes with lessons learned from current high-throughput screening programs and suggests some initial steps for DOD investment.
This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC Report Review Committee. The purpose of the 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 of 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 for their review of this report: Ellen Berg, BioSeek, Inc.; David Clapham, Harvard University; Mark Cronin, Liverpool John Moores University; Yvonne Dragan, DuPont; John Jenner, Defence Science and Technology Laboratory; Charles Santerre, Purdue University; Rusty Thomas, US Environmental Protection Agency; Ken Turtletaub, Lawrence Livermore National Laboratory; Daniel Wilson, The Dow Chemical Company; and Menghang Xia, National Center for Advancing Translational Sciences.
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 the report was overseen by the review coordinator, David Eaton, University of Washington, and the review monitor, Mark Cullen, Stanford University. Appointed by the NRC, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the committee and the institution.
The committee gratefully acknowledges the following for their presentations to the committee during open sessions: Alison Director-Myska, Defense Threat Reduction Agency, and Keith Houck, US Environmental Protection Agency.
The committee is grateful for the assistance of the National Research Council staff in preparing this report. Staff members who contributed to the effort are Ellen Mantus, project director; Marilee Shelton-Davenport, senior program officer; Keri Stoever, research associate; James Reisa,
director of the Board on Environmental Studies and Toxicology; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager of the Technical Information Center; Radiah Rose-Crawford, manager of editorial projects; and Ivory Clarke, senior program assistant.
I especially thank the members of the committee for their efforts throughout the development of this report.
David Dorman, Chair
Committee on Predictive-Toxicology Approaches
for Military Assessments of Acute Exposures
Contents
The Committee’s Approach to Its Task
2 CONCEPTUAL FRAMEWORK AND PRIORITIZATION STRATEGY
Acute Toxicity of Classical Chemical-Warfare Agents
Predicting Acute Toxicity of Potential Chemical-Warfare Agents
A Framework and Strategy for Predicting Acute Toxicity of Potential Chemical-Warfare Agents
3 NONTESTING APPROACHES RELEVANT TO PREDICTION OF ACUTE TOXICITY AND POTENCY
Initial Chemical Characterization
In Silico Approaches for Predicting Toxic Effects
Ensuring Scientific Confidence in (Q)SAR Models
4 ASSAYS FOR PREDICTING ACUTE TOXICITY
Nonmammalian In Vivo Animal Models
Assay Considerations for Improving Prediction of Acute Toxicity
5 INTEGRATION AND DECISION-MAKING FOR PREDICTIVE TOXICOLOGY
6 LESSONS LEARNED AND NEXT STEPS
Modern Approaches for the Assessment of Acute Chemical Toxicity
Implementation of the Committee’s Conceptual Model for Assessment of Acute Chemical Toxicity
Development of a Modern Tiered Approach for Predicting Acute Toxicity: Initial Steps
BOXES, FIGURES, AND TABLES
BOXES
2-1 Definitions of Relevant Terms
2-2 Tiered Approach to Predicting Toxicity
3-1 Definitions of Selected Nontesting Approaches
3-2 Primary Data Considered During a Preliminary Characterization of a Chemical of Interest
3-3 In Silico Approaches for Predicting Physicochemical Properties
5-1 Simplified Illustration of Integration and Decision-making
6-1 An Example of an Integrated Testing Strategy for Predicting Drug-Induced Liver Injury
6-3 The Use of HTS Assays for Identifying Endocrine Disrupting Potential
6-4 The Use of the BALB/3T3 Neutral-Red Uptake Cytotoxicity Assay to Predict Acute Toxicity
6-5 The Use of HTS Assays to Evaluate Inhibition of Acetylcholinesterase
FIGURES
3-1 Conceptual framework for the future development of (Q)SARs
4-1 Intended target families and subfamilies for the ToxCast program
5-2 Approaches for integrating disparate data sets with LD50 as an example
5-3 ToxPi model for integration of acute-toxicity potential
TABLES
3-1 Examples of Heuristic Rules to Predict Oral Absorption
3-2 Examples of (Q)SARs for Various Chemical Classes
3-3 Examples of Models and Tools to Predict Acute Oral Toxicity
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