Developmental defects are a significant human-health problem. Approximately 3% of human developmental defects are attributed to exposure to toxic chemicals (e.g., lead and mercury) and physical agents (e.g., radiation), including agents found in the environment. Twenty-five percent of developmental defects might be due to a combination of genetic and environmental factors, where those factors are defined broadly to include physical, chemical, and biological agents and conditions, such as infections, nutritional deficiencies and excesses, life-style factors (e.g., alcohol), hyperthermia, ultraviolet radiation, X-rays, and the myriad of manufactured chemicals (e.g., pharmaceuticals, synthetic chemicals, solvents, pesticides, fungicides, herbicides, cosmetics, and food additives) and natural materials (e.g., plant and animal toxins and products). Because of human-health concerns about the developmental toxicity of environmental agents, scientists and regulators have focused efforts on understanding and protecting against the potential hazards of these agents to developing embryos, fetuses, and children. Recent advances in the fields of developmental biology and genomics provide opportunities to further understand the role of environmental agents in human developmental defects and, therefore, the National Research Council (NRC) undertook a project to explore the opportunities in this area.

Contents

• THE NATIONAL ACADEMIES
• Committee on Developmental Toxicology
• Board on Environmental Studies and Toxicology
• Commission on Life Sciences
• Other Reports of the Board on Environmental Studies and Toxicology
• Preface
• List of Abbreviations
• Executive Summary
• 1. Introduction
  • BACKGROUND
  • RECENT ADVANCES IN DEVELOPMENTAL BIOLOGY AND THE PROMISE OF GENOMICS
  • COMMITTEE'S APPROACH TO ITS CHARGE
  • ORGANIZATION OF THE REPORT
• 2. Developmental Defects and Their Causes
  • TOXICANT EXPOSURE AND DEVELOPMENTAL DEFECTS
  • THE CHEMICAL UNIVERSE
  • SUMMARY
• 3. Current Practices for Assessing Risk for Developmental Defects and Their Limitations
  • THE DEVELOPMENTAL TOXICITY RISK ASSESSMENT PROCESS
  • BIOMARKERS
  • LIMITATIONS IN DEVELOPMENTAL TOXICITY RISK ASSESSMENTS
  • SUMMARY
• 4. Mechanisms of Developmental Toxicity
  • HISTORY OF DEVELOPMENTAL TOXICOLOGY: GROWTH OF A NEW FIELD
  • PRINCIPLES OF TERATOLOGY
  • MECHANISMS OF TOXICITY
  • SUMMARY
• 5. Human Genetics and the Human Genome Project
  • GENOTYPE, PHENOTYPE, AND MULTIFACTORIAL INHERITANCE
  • POLYMORPHISMS
  • THE HUMAN GENOME PROJECT
  • RECENT DEVELOPMENTS IN MOLECULAR EPIDEMIOLOGY
  • SUMMARY
• 6. Recent Advances in Developmental Biology
  • A BRIEF HISTORY OF DEVELOPMENTAL BIOLOGY
  • ADVANCES IN DEVELOPMENTAL BIOLOGY
  • SUMMARY
• 7. Using Model Animals to Assess and Understand Developmental Toxicity
  • MODEL ORGANISMS AND THE GENETIC APPROACH
  • THE MAJOR MODEL ANIMALS FOR GENETIC ANALYSIS
  • POSSIBLE APPLICATIONS OF MODEL ANIMAL RESEARCH TO DEVELOPMENTAL TOXICOLOGY
  • GENE EXPRESSION AS DETERMINED BY IN VITRO AND ENGINEERED CELL TECHNOLOGIES
  • SUMMARY
• 8. A Multilevel Approach to Improving Risk Assessment for Developmental Toxicity
  • THE MULTIDISCIPLINARY, MULTILEVEL, INTERACTIVE APPROACH
  • SUMMARY
• 9. Conclusions and Recommendations
  • CONCLUSIONS IN RELATION TO THE CHARGE
  • RECOMMENDATIONS
• References
• Appendixes
  • Appendix A Glossary
  • Appendix B Database Descriptions
  • Appendix C Signaling Pathways
  • Appendix D Biographical Information on the Committee on Developmental Toxicology

This project was supported by the U.S. Department of Defense; (DAMD 17-89-C9086 and DAMD 17-99-C9049), the U.S. Department of Health and Human Services; (PR-470644, PR-470645, 273-MH-901198, 273-MH-913119, P-0158-00-6-00, 0009554547, and 263-MD-635973), the U.S. Environmental Protection Agency; (CR-823615, R-827241-01), the U.S. Department of Veterans Affairs; (V101 P-1578), and the American Industrial Health Council. All contracts and awards were between the sponsoring agency or organization and the National Academy of Sciences. 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.