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Scientific Frontiers in Developmental Toxicology and Risk Assessment
The committee generally agreed that a complete description of the mechanism of action of a developmental toxicant should include the following types of mechanistic information:
The toxicant’s kinetics and means of absorption, distribution, metabolism, and excretion throughout the mother and conceptus.
The toxicant’s interactions (or those of a metabolite(s) derived from it) with specific molecular components of cellular or developmental processes in the conceptus or with maternal or extraembryonic components of processes supporting development.
The consequences of those interactions for the function of components in a cellular or developmental process.
The consequences of an altered process for the developmental outcome, namely, the generation of a defect, functional changes, or altered growth and development.
The committee acknowledges that a complete explanation of mechanism of action is not currently available for any chemical and that having even partial mechanistic information of the kind described above can improve the ability to predict adverse human developmental outcomes.
Toxicokinetics describes the steps of toxicant entry and absorption, distribution, metabolism, and excretion throughout an organism or, in this case, throughout mother and conceptus. Toxicodynamics, in the context of this report, describes the steps of the toxicant’s effects and interaction with the developmental processes. Both are important. Toxicokinetics explains whether, when, and how much of a potential toxicant reaches the embryo or fetus. The understanding of the toxicokinetic steps of detoxification or metabolic potentiation of a chemical holds great promise for safe drug design and preclusion of toxicant effects in humans from environmental agents. Furthermore, human individual differences in susceptibility to toxicants might in large measure result from differences in toxicant uptake and metabolism, and some of the problems of extrapolating toxicity test results from animals to humans can certainly be attributed to differences of laboratory animals and humans in the metabolism of chemicals.
In toxicokinetics, researchers have identified routes and rates of exposure of the conceptus to certain toxicants, and the recent information on drug-metabolizing enzymes (DMEs; the numerous P450 heme oxidases and conjugating enzymes) is very significant. Researchers have been able to verify the presence of parent compounds and metabolites in the mother and the conceptus during development. They have successfully explained some species differences in toxicity responses based on metabolism differences and have explained some human variations in drug responsiveness. Nevertheless, such knowledge about critical metabolites and their reactivity with specific target tissues is lacking for most agents, and much remains to be done in this promising area.