tions of chemicals at a cellular level, when considered in light of specific risk questions (human use and exposure paths), can be informative to human risk assessment.

The four information levels for toxicity assessment in model systems (Table 8-1A) are presented below in detail.

Model Systems Information Level 1

This level includes molecular, biochemical, and cell-based assays. Assays should be designed for a high throughput of chemicals, perhaps 105-106 assays per year, to provide basic information on the types of chemicals that disrupt signaling pathways and activate molecular-stress pathways and on the conversion of chemicals by DMEs. Such information will inform hazard identification and the evaluation of modes of action in risk assessment. For hazard identification, such assays will provide

  • structure-activity information,

  • relative potency information for chemicals evaluated in the same assays,

  • information about the activity of chemical mixtures, and

  • some quantitative information across assay end points for estimating relative potency across chemical classes.

When coupled with estimates of actual or impending human exposure, such assay information would be useful in prioritizing chemicals for in vivo assessments at information levels 2 and 3.

With the recent advances in molecular techniques, results from 105-106 tests of chemicals or chemical mixtures are feasible within 1 year. Assays already exist for estrogen receptors (EPA 1998g), and they could be readily modified to include other nuclear-hormone receptors, including the orphan members. Related assays could be devised for the transmembrane receptors, the various transduction intermediates, and the other 16 signaling pathways and their genetic regulatory proteins. Several pharmaceutical companies have active programs to evaluate chemicals in relationship to retinoic acid receptor binding and their pharmaceutical-versus-developmental-toxicity activities. Biochemical assays could involve purified human proteins expressed in bacteria or insect cells. Cell assays could involve mammalian cell lines or yeast into which human receptors (e.g., various receptor tyrosine kinases (RTK)) have been introduced. Molecular-stress pathways, cell-cycle checkpoint pathways, and the apoptosis pathway have already been shown to be especially relevant for environmental toxicants because of their roles in the cell’s response to chemically induced deoxyribonucleic acid (DNA) damage, impaired DNA synthesis, spindle damage, and kinetochore malfunction. The genes encoding these pathways could be introduced into yeast or cell lines equipped with reporter genes for easy assessment.

At this high-throughput level, many chemicals should be assayed as sub-



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