The committee has stated that the developments in developmental biology and genomics present an unprecedented opportunity to understand the mechanisms of action of toxicants at a molecular level and that, at some time in the future, perhaps a decade, risk assessors will have primarily “mechanism-based data” from test animals to use in arriving at human toxicity estimates. However, standard toxicant bioassays on mammals do not yet yield comprehensive data on mechanisms and consequences valid for extrapolation to humans.
What can be done in the interim to build on recent advances? In Chapter 8, the committee outlined a multilevel approach to risk assessment that incorporated various assays intended to provide information ranging from molecular interactions to developmental consequences. Advantages and disadvantages of the assays of each level were outlined as well. This approach is briefly described here. There are two domains of information. One contains results from model systems and model-animal tests of toxicant effects on development and of genetic alterations affecting toxicant susceptibility. The results need to be extrapolated to humans. The second domain contains results from human studies of toxicant exposure, toxicant susceptibility (including polymorphisms), and toxicant effect.
There are four levels of model systems for providing information for assessing the effects of toxicants (or the absence of effects): (level 1) in vitro tests and cell tests; (level 2) nonmammalian animal tests of development and the role of genotype; (level 3) mammalian tests of development and the role of genotype; and (level 4) mammalian tests of mechanism and susceptibility. In general, expense increases with each level, and the number of chemicals that can be tested decreases. The questions of extrapolation to humans are greatest at the low levels. As described in Chapter 8, the committee did not develop a tiered approach, but rather showed how information from each level could be used to improve developmental toxicity risk assessments.
Various examples of this information follow.
1.4.1. The metabolism of developmental toxicants.
Knowledge of DMEs is sufficient to devise level 1 tests of the conversions of a large variety of chemicals by a large variety of enzymes. For example, human metabolism genes have been introduced into test cells, such as yeast or human lymphoblast lines, to generate assay systems. Once the specificity range of human enzymes is well characterized, it should be possible to make predictions about the capacity of a battery of enzymes to modify yet-untested chemicals. It is also clear that various animals (Drosophila, C. elegans, and mice) can be constructed with deficiencies or excesses of various metabolizing enzymes to determine whether the developmental toxicity of a chemical is increased or decreased. Much of this work is under way. There is substantial research inquiry about DMEs, their roles, and their synergisms, especially among oxidases and conjugating enzymes. Although the study of the DMEs is relatively advanced, re-