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 to determine how DOD could use modern approaches for predicting chemical toxicity in its efforts to prevent debilitating, acute exposures to deployed personnel. This report provides an overall conceptual approach that DOD could use to develop a predictive toxicology system. Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense reviews the current state of computational and high-throughput approaches for predicting acute toxicity and suggests methods for integrating data and predictions. This report concludes with lessons learned from current high-throughput screening programs and suggests some initial steps for DOD investment.

Contents

• The National Academies of Sciences, Engineering, and Medicine
• COMMITTEE ON PREDICTIVE-TOXICOLOGY APPROACHES FOR MILITARY ASSESSMENTS OF ACUTE EXPOSURES
• COMMITTEE ON TOXICOLOGY
• BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
• OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
• BOARD ON LIFE SCIENCES
• Preface
• Summary
  • CONCEPTUAL FRAMEWORK AND STRATEGY
  • NONTESTING APPROACHES FOR PREDICTING ACUTE TOXICITY
  • BIOLOGICAL ASSAYS FOR PREDICTING ACUTE TOXICITY
  • INTEGRATION AND DECISION-MAKING FOR PREDICTIVE TOXICOLOGY
  • LESSONS LEARNED AND NEXT STEPS
• 1. Introduction
  • STUDY BACKGROUND
  • THE COMMITTEE AND ITS TASK
  • THE COMMITTEE'S APPROACH TO ITS TASK
  • ORGANIZATION OF THIS REPORT
  • REFERENCES
• 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
  • FINDINGS AND RECOMMENDATIONS
  • REFERENCES
• 3. Nontesting Approaches Relevant to Prediction of Acute Toxicity and Potency
  • INITIAL CHEMICAL CHARACTERIZATION
  • USE OF PHYSICOCHEMICAL PROPERTIES TO PREDICT PHYSICAL HAZARDS, CHEMICAL REACTIVITY, AND PHARMACOKINETICS
  • IN SILICO APPROACHES FOR PREDICTING TOXIC EFFECTS
  • ENSURING SCIENTIFIC CONFIDENCE IN (Q)SAR MODELS
  • FINDINGS AND RECOMMENDATIONS
  • REFERENCES
• 4. Assays for Predicting Acute Toxicity
  • IN VITRO ASSAYS
  • NONMAMMALIAN IN VIVO ANIMAL MODELS
  • EMERGING TECHNOLOGIES
  • METABOLIC CONSIDERATIONS
  • ASSAY CONSIDERATIONS FOR IMPROVING PREDICTION OF ACUTE TOXICITY
  • FINDINGS AND RECOMMENDATIONS
  • REFERENCES
• 5. Integration and Decision-Making for Predictive Toxicology
  • GENERAL APPROACH TO INTEGRATION AND DECISION-MAKING
  • APPROACHES TO INTEGRATION
  • APPROACHES TO CATEGORIZATION
  • FINDINGS
  • REFERENCES
• 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
  • OTHER CONSIDERATIONS
  • FINDINGS AND RECOMMENDATIONS
  • REFERENCES
• APPENDIXES
  • Appendix A Biographical Information on the Committee on Predictive-Toxicology Approaches for Military Assessments of Acute Exposures
  • Appendix B Available Data or Databases

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.

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.