Excerpt

The committee approached its charge by identifying, defining, and describing several proposed applications of toxicogenomics to hazard-identification screening, mechanism-of-action studies, classification of compounds, exposure assessment, defining genetic susceptibility, and reducing the use of animal-based testing. Studies supporting each of these putative applications were then critically evaluated to define limitations, to enumerate remaining challenges, and to propose viable solutions whenever possible. Finally, the committee outlined realistic expectations of how these applications can be validated and how they can be used in risk assessment. The second part of this summary reviews these applications and what is needed for each of them.

Contents

• The National Academies
• Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology
• Board on Environmental Studies and Toxicology
• Board on Life Sciences
• Other Reports of the Board on Environmental Studies and Toxicology
• Other Reports of the Board on Life Sciences
• Preface
• Acknowledgments
• Acknowledgment of Review Participants
• Abbreviations
• Summary
  • COMMITTEE’S CHARGE
  • COMMITTEE’S RESPONSE TO ITS CHARGE
  • OVERARCHING CONCLUSIONS AND RECOMMENDATIONS
  • SPECIFIC APPLICATIONS OF TOXICOGENOMICS
  • ETHICAL, LEGAL, AND SOCIAL ISSUES
  • EDUCATION AND TRAINING IN TOXICOGENOMICS
  • CONCLUSIONS
• 1. Introduction
  • BACKGROUND
  • COMMITTEE CHARGE AND RESPONSE
• 2. Toxicogenomic Technologies
  • GENOMIC TECHNOLOGIES
  • TRANSCRIPTOMIC TECHNOLOGIES
  • PROTEOMIC TECHNOLOGIES
  • METABOLOMIC TECHNOLOGIES
  • MS-Based Metabolomics
  • TECHNOLOGY ADVANCEMENT AND ECONOMY OF SCALE
• 3. Experimental Design and Data Analysis
  • EXPERIMENTAL DESIGN
  • TYPES OF EXPERIMENTS
  • TOXICOGENOMICS AND BIOMARKER DISCOVERY
  • CONCLUSIONS
  • RECOMMENDATIONS
• 4. Application to Exposure Assessment
  • CONVENTIONAL BIOMARKERS OF EXPOSURE AND RESPONSE
  • STATE OF THE ART: TOXICOGENOMIC APPROACHES TO THE DEVELOPMENT OF EXPOSURE BIOMARKERS
  • EVALUATION OF EXPOSURE IN RISK ASSESSMENT
  • SCIENTIFIC CHALLENGES
  • CONCLUSIONS
  • RECOMMENDATIONS
• 5. Application to Hazard Screening
  • DESCRIPTION AND PROPERTIES OF CURRENT HAZARD SCREENING METHODS
  • IN VITRO VERSUS IN VIVO TESTING
  • DEVELOPMENT OF PREDICTIVE ALGORITHMS FOR SCREENING PURPOSES
  • STATE OF THE ART
  • POTENTIAL APPLICATIONS
  • CHALLENGES AND LIMITATIONS
  • CONCLUSIONS
  • RECOMMENDATIONS
• 6. Application to Analyzing Variation in Human Susceptibility
  • STATE OF THE ART IN ASSESSMENT OF INDIVIDUAL VARIATION
  • RISK ASSESSMENT
  • CHALLENGES
  • CONCLUSIONS
  • RECOMMENDATIONS
• 7. Application to the Study of Mechanisms of Action
  • STATE OF THE ART IN TRANSCRIPTOMIC ANALYSES
  • CONCLUSIONS
  • RECOMMENDATIONS
• 8. Other Potential Applications of Toxicogenomic Technologies to Risk Assessment
  • POTENTIAL APPLICATIONS TO RISK ASSESSMENT
  • IMPLICATIONS FOR BETTER USE AND POTENTIAL REDUCTION IN THE USE OF EXPERIMENTAL ANIMALS
  • IMPLICATIONS OF TOXICOGENOMICS FOR RISK ASSESSMENT INFRASTRUCTURE NEEDS
  • CONCLUSIONS
  • RECOMMENDATIONS
• 9. Validation
  • LEVELS OF VALIDATION
  • CONCLUSIONS
  • RECOMMENDATIONS
• 10. Sample and Data Collection and Analysis
  • LEVERAGING SAMPLES AND INFORMATION IN POPULATION-BASED STUDIES AND CLINICAL TRIALS FOR TOXICOGENOMIC STUDIES
  • EXISTING TOXICOGENOMIC DATA REPOSITORIES: STANDARDIZATION, AVAILABILITY, AND TRANSPARENCY
  • CONCLUSIONS
  • RECOMMENDATIONS
• 11. Ethical, Legal, and Social Issues
  • RESEARCH ISSUES
  • ETHICAL AND SOCIAL ISSUES
  • REGULATORY IMPLICATIONS
  • LITIGATION
  • COMMUNICATION AND EDUCATION
  • CONCLUSIONS AND RECOMMENDATIONS
• 12. Conclusions and Recommendations
  • A NEW HUMAN TOXICOGENOMICS INITIATIVE
  • DATA ANALYSIS TOOLS
  • EXPOSURE ASSESSMENT
  • HAZARD SCREENING
  • VARIABILITY IN SUSCEPTIBLITY
  • MECHANISTIC INFORMATION
  • DOSE-RESPONSE RELATIONSHIPS
  • CROSS-SPECIES EXTRAPOLATION
  • DEVELOPMENTAL EXPOSURES
  • MIXTURES
  • VALIDATION
  • ETHICAL, LEGAL, AND SOCIAL ISSUES
  • EDUCATION AND TRAINING IN TOXICOGENOMICS
• References
• Appendices
  • A Biographic Information on the Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology
  • B Minimum Information About a Microarray Experiment for Toxicogenomics
  • C Overview of Risk Assessment

This project was supported by Contract No. N01-OD-4-2139 between the National Academy of Sciences and the U.S. Department of Health and Human Services. 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.

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.