A new frontier in understanding the mechanisms of developmental abnormalities

Recent advancements in molecular developmental biology afford an opportunity to apply newly developed tools for understanding the mechanisms of both normal and abnormal development. Although a number of agents have been identified as causing developmental abnormalities, our knowledge of the mechanisms by which these alterations occur is minimal. This paper reviews some of the important issues in this area that may lead to understanding the basic developmental processes and mechanisms by which toxic agents may interfere with these processes. Approximately 70% of developmental defects are of unknown etiology. Historically, it has been assumed that these defects were most likely to be induced by exposure to chemical or physical agents during organogenesis. There is now convincing evidence that exposure during preorganogenesis developmental stages to certain agents can also lead to fetal abnormalities as a result of direct damage to the exposed early conceptus. Thus, pre- or postimplantation exposure of the developing conceptus to toxicants may result in a "derailment" in the genetic control of development and the coordinated cascade of events that occur during normal development. For example, developmental abnormalities may be induced by disrupting the coordinated expression of developmental genes involved in genomic imprinting, cell lineage specification, cell mixing and recognition, cell-cell interaction, cell migration and differentiation, and segmentation, depending on the time of exposure. Because of our lack of knowledge about the molecular and cellular bases of chemically induced abnormal development, a number of assumptions are currently used in the process of evaluating and interpreting data for developmental toxicity studies. The study of mechanisms of normal and abnormal development and the pharmacokinetic-pharmacodynamic relationships in humans and experimental animals are key to the development of appropriate risk assessment assumptions and dose-response models for characterizing the risk for developmental toxicity in the human population. This article summarizes the discussions of the workshop on developmental abnormalities organized by the Committee on Toxicology of the National Research Council.