Most tests in the committee’s vision would be unlike current toxicity tests, which generate data on apical end points. The mix of tests in the vision include in vitro tests that assess critical mechanistic end points involved in the induction of overt toxic effects rather than the effects themselves and targeted in vivo tests that ensure adequate testing of metabolites and coverage of end points. The move toward a mechanism-oriented testing paradigm poses challenges. Implementation will require (1) the availability of suites of in vitro tests—preferably based on human cells, cell lines, or components—that are sufficiently comprehensive to evaluate activity in toxicity pathways associated with the broad array of possible toxic responses; (2) the availability of targeted tests to complement the in vitro tests and ensure overall adequate data for decision-making; (3) models of toxicity pathways to support application of in vitro test results to predict general-population exposures that could potentially cause adverse perturbations; (4) infrastructure changes to support the basic and applied research needed to develop the tests and the pathway models; (5) validation of tests and test strategies for incorporation into chemical-assessment guidelines that will provide direction on interpreting and drawing conclusions from the new assay results; and (6) acceptance of the idea that the results of tests based on perturbations in toxicity pathways are adequately predictive of adverse responses and can be used in decision-making. Development of the new assays and the related basic research—the focus of this chapter—requires a substantial research investment over quite a few years. Institutional acceptance of the new tests and the requisite new risk-assessment approaches—the focus of Chapter 6—also require careful planning. They cannot occur overnight.

Ultimately, the time required to conduct the research needed to support large-scale incorporation of the new mechanistic assays into a test strategy that can adequately and rapidly address large numbers of agents depends on the institutional will to commit resources to support the changes. The committee believes that with



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