In toxicodynamics, the mechanistic picture of toxicity is less complete. This limitation has been inherent to the field, because so little has been known until recently about the identity and activity of specific molecular components of the developmental processes or about the roles of the processes in the development of the embryo. Hence, little could be said about the developmental consequences of a toxicant’s reduction or exaggeration of a component’s activity. In the absence of such information, hypothesized mechanisms of toxicant action (and evidence for these mechanisms) have had limited ability to ascribe developmental defects to failures of specific components and processes. Furthermore, species differences in developmental components have been poorly discerned, as has human variation in these components.

In a few cases, toxicodynamic hypotheses of mechanism emphasize molecular components and activities. Multiple retinoic acid (RA) receptors have been identified for retinoids in animal models. The molecular function of these receptors in regulating gene expression has been ascribed, and the altered time and place of gene expression has been detected in the presence of the toxicant. The availability of multiple structurally related analogs of RA has helped these investigations. Diethylstilbestrol is also known to bind to other nuclear hormone receptors and alter gene expression, and cyclopamine (a plant alkaloid) is known to bind to signaling components of the Hedgehog signaling pathway and alter inductive responses. Such information, coming from recent molecular studies, has greatly furthered the understanding of the toxicity of those agents. Still lacking, however, is full understanding of the developmental processes affected by this altered gene expression or altered signaling and, hence, the generation of the developmental defect.

Of relevance to the committee’s later proposals, these three examples of advanced toxicodynamic hypotheses concern signaling proteins and transcriptional regulators, the kinds of molecular components the committee recommends for greater attention in future analysis and testing of toxicants. In the near future, developmental toxicology will likely provide more comprehensive explanations of toxicity, but at present, mechanistic information is available for only a small number of toxicants and these have had limited application for risk assessment.

Charge 2: Evaluate the state of the science on testing for mechanisms of developmental effects.

The state of the science has improved greatly in the past decade, indeed even since this committee was first formed. Relevant advances have occurred in developmental biology and genomics (gene sequencing and gene identification), built upon advances in genetics, cell biology, molecular biology, and biochemistry. Developmental processes have been illuminated for the first time in a number of animals at the level of identification of molecular components and their activities, especially of the signaling pathways and genetic regulatory circuits of these processes. The same molecular components are used repeatedly at different



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