associated transcriptional regulators); (2) conserved molecular-stress and checkpoint pathways; and (3) conserved toxicokinetic components such as those involved in the transport and metabolism of toxicants (e.g., DMEs). It is important to explore how such molecular perturbations can result in altered function and adverse outcomes of development. Model animals such as the fruit fly, roundworm, and zebrafish can be used to study the mechanisms of developmental toxicity. The signaling pathways that operate in the development of the organs of these organisms also operate in the development of mammalian organs; therefore, the effects of chemicals on fundamental processes such as signaling can be detected. Because the same signaling pathways operating in various kinds of organ development in mammals are partially known and will be better known soon, a chemical’s toxicological impact on these pathways can be predicted on the basis of the results in nonmammalian organisms and tested in mammals. Molecular-stress and checkpoint pathways are used by cells to counteract damage to basic cellular functions, including functions involved in development, and investigating these pathways is important to understand the broad responses of cells to environmental stimuli. Multiple pathways are used in the development of organs; however, one pathway at a time can be studied for a specific aspect of development (e.g., the development of a particular organ) by using genetically modified (e.g., sensitized) animals.
Human variability of response to developmental toxicants. To define the genetic basis of variability in human response to developmental toxicants, differences in toxicokinetics, signaling pathways, and molecular-stress and checkpoint pathways need to be characterized. Two approaches to studying variability are recommended: (1) a human epidemiological approach making use of genome information, and (2) a model-animal approach making use of molecular biological techniques and insights. Research should be conducted to assess differences in the genes encoding molecular components among various species, including humans, and among human individuals. As human gene polymorphisms are identified, they should be introduced into the mouse, and molecular biological techniques should be used to assess the organisms’ sensitivity or resistance to various chemicals.
Assaying across the entire developmental period. All periods of development are susceptible to the actions of toxicants. For example, early fetal loss in human development occurs in 20-30% of initial pregnancies and, although many of these losses are due to chromosomal aberrations, exposure to a toxicant during early times in development can lead to loss of the embryo or fetus as well as specific structural defects and functional deficits. Use of genetically modified model systems could provide mechanistic information to improve the understanding of early fetal loss as well as morphological alterations and later functional deficits by providing sensitized systems for evaluating developmental defects.
Extrapolation from animals to humans. Differences in toxicokinetics and toxicodynamics of experimental animals and humans should be better character-