2.1. Qualitative risk assessment: testing a larger variety of chemicals and chemical mixtures.

Expanding the number of tested chemicals is an enterprise in qualitative risk assessment. The new rapid and inexpensive model assay systems have an important potential use in such an enterprise. At level 1, which involves in vitro and single-cell assays, tens of thousands of assays could be run per year to test chemicals as substrates for DMEs, as agonists and antagonists of signaling components and genetic regulators of the kind used pervasively in development, and as triggers of molecular-stress and checkpoint pathways. At level 2, which involves tests of chemical effects on the development of nonmammalian animals, thousands of assays could be run per year. Genetically sensitized model organisms (Drosophila, C. elegans, and zebrafish) equipped with various reporter genes would facilitate analysis. Mammalian relevancy and human applications would be further defined in level 3 tests involving mammals—the mouse being the most favorable because of its ease of genetic modification, its vast libraries of mutants, and the advanced knowledge (among mammals) of its development.

2.2. Qualitative risk assessment: assessing toxicant effects across all stages of development.

As noted in Chapter 2, early fetal loss in human development is frequent (20-30% of initial pregnancies). Although many of these losses may be due to chromosomal aberrations for which there are good chemical assay methods, other mechanisms of early loss are less well understood. Recent observations have demonstrated that, contrary to what was previously believed, toxicant exposures during early times in development can not only result in fetal loss but also specific birth defects and adverse functional impacts. In addition, functional impacts occurring as a result of post-organogenesis toxicant exposure have also not been clearly delineated. Further tests of toxicant impacts during these early and late developmental time points are needed and can build on the rapidly expanding body of knowledge about early events such as axis formation, primitive streak formation, and node regression as well as an expanded understanding of functional deficits.

2.3. Quantitative risk assessment: the toxicokinetic differences of test animals and humans should be characterized to improve extrapolations.

The committee recommends that test animals be better characterized with regard to their differences from humans in DMEs and other toxicokinetic variables. With better characterizations, it can be known whether the test conceptus and the hypothetical human conceptus are indeed exposed to the same chemicals at corresponding concentrations and intervals of development. Many DMEs have been identified, and others are known to exist. The profile of activity of mice (level 3 assays) and humans should be determined so that their similarities and differences are known. Some of this effort is already under way, and the com-



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