and the uncertainties associated with the extrapolation of data among humans due to the variability in their susceptibility to chemicals, and with the extrapolation of data from animals to humans. The committee attempted to determine whether those limitations could be addressed by recent advances in the understanding of normal development, gene-environment interactions, and human susceptibility. In particular, the committee evaluated new developmental biology data from model animals (e.g., fruit fly, roundworm, zebrafish, and mouse), including genetically modified model animals, and from new molecular biology approaches utilizing in vitro and cellular assays. It developed approaches to show how such new information could improve hazard identification and dose-response assessment and clarify the mechanisms of developmental toxicity. The committee also evaluated data on new technologies for assessing human variability in genes involved in developmental processes and the metabolism of chemicals and determined whether the new technologies could improve risk characterization by reducing uncertainty and variability. Finally, the committee evaluated how this information could be integrated into an overall risk-assessment framework. The committee’s major conclusions and recommendations, organized in response to each of the committee’s tasks, are discussed in the remainder of this summary.

CONCLUSIONS IN RELATION TO THE CHARGE

Charge 1: Evaluate the Evidence Supporting Hypothesized Mechanisms of Developmental Toxicity. There are only a few compounds (e.g., retinoic acid, diethylstilbesterol (DES), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) for which the mechanism of developmental toxicity is partially explained and no compound for which it is fully explained. Reasons for this incomplete understanding include the lack of knowledge about normal developmental processes, the complexity of developmental toxicity, the broad spectrum of agents and chemical mixtures present in the environment, and the variety of potential mechanisms by which they might cause toxicity.

Ideally, a full description of the mechanism of action by which a chemical causes developmental toxicity includes the following types of mechanistic information:

  1. the chemical’s toxicokinetics (i.e., its absorption, distribution, metabolism, and excretion) within the mother, fetus, and embryo;

  2. the chemical’s toxicodynamics (i.e., how the chemical or a metabolite derived from it interacts with specific molecular components of developmental processes in the embryo and fetus or with maternal or extraembryonic components of processes supporting development);

  3. the consequences of those interactions on cellular or developmental processes (also part of toxicodynamics); and

  4. the consequence of the altered process for a developmental outcome, namely, the generation of a defect.



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