ized to improve extrapolations from animals to humans. For example, the study of differences in DMEs between humans and experimental animals will improve the ability to extrapolate from animal test results to humans, because it will be known whether the animal embryo or fetus and the human embryo or fetus are exposed to a chemical at corresponding concentrations and times during development. Also, when the differences between animal and human DME activities are understood, mice can be genetically modified to make them more similar to humans in chemical metabolism. Studies on developmental components, such as signaling components and transcriptional regulators, that are similar to those discussed here for DMEs also should be conducted. Sequence information from the human and mouse genomes will facilitate these studies, as will studies on mice bearing targeted gene alterations.
Extrapolations from high to low doses. Because exposure to a chemical at high doses might affect a variety of developmental processes, while exposure at low doses might affect only one critically sensitive pathway, studies using model test animals should be conducted to distinguish dose effects and, in particular, to distinguish effects that could potentially occur at exposure levels relevant to humans. Because a large number of chemicals cause apoptosis (cell death) in the embryo and fetus, the molecular-stress and checkpoint pathways should be given particular attention. Studies using sensitized model animals should be especially useful for defining low-dose responses.
Improved access to information. To support the growth of knowledge in developmental toxicology and to organize information in a way that is useful for risk assessment, an inclusive national developmental toxicant database should be established, with entries from industry, academia, and government. The developmental toxicant database should include chemical toxicant information as well as information on known molecular targets and associations with developmental defects, both from animal tests and from humans. Steps should be taken to link this database with the databases of developmental biology (e.g., the database of phenotypes of mice with mutations in their signaling components, which are being generated by genetic modification techniques), and genomics. Databases describing metabolic pathways for drugs and environmental agents, and DME and transporter protein polymorphisms should be linked as well. Ideally, a separate relational database in which signaling pathways are grouped should be established and used when chemicals are identified as interacting with an element of the pathway. This relational database could help to suggest potential biological interactions of a chemical with other chemicals that affect components of the same pathway and record the involvement of signaling pathways in all aspects of development from a wide range of organisms.
Multidisciplinary outreach. The challenges that investigators face when trying to work across fields, such as developmental biology, developmental toxicology, and risk assessment, are a key issue that the committee identified early in its deliberations. This issue previously impeded the successful application of the