with oxidative stress, the antioxidant pathways activated by DEPs are normal adaptive signaling pathways that assist in maintaining homeostasis; however, they are also toxicity pathways in that they lead to adverse effects when oxidant exposure is sufficiently high. The committee capitalizes on the recent advances in elucidating and understanding toxicity pathways and proposes a new approach to toxicity testing based on them.

New investigative tools are providing knowledge about biologic processes and functions at an astonishing rate. In vitro tests that evaluate activity in toxicity pathways are elucidating the modes and mechanisms of action of toxic substances. Quantitative high-throughput assays can be used to expand the coverage of the universe of new and existing chemicals that need to be evaluated for human health risk assessment (Roberts 2001; Inglese 2002; Inglese et al. 2006; Haney et al. 2006). The new assays can also generate enhanced information on dose-response relationships over a much wider range of concentrations, including those representative of human exposure. Pharmacokinetic and pharmacodynamic models promise to provide more accurate extrapolation of tissue dosimetry linked to cellular and molecular end points. The application of toxicogenomic technologies and systems-biology evaluation of signaling networks will permit genomewide scans for genetic and epigenetic perturbations of toxicity pathways. Thus, changes in toxicity pathways are envisioned as the basis of a new toxicity-testing paradigm for managing the risks posed by environmental agents instead of apical end points from whole-animal tests.

This chapter provides an overview of the committee’s vision but first discusses the limitations of current toxicity-testing strategies, the design goals for a new system, and the options that the committee considered. Key terms used throughout this report are listed and defined in Box 2-1.



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