assessment. It still relies on whole-animal testing and is geared mainly toward deciding which animal tests are required in risk assessment for any specific agent. Although tiered testing might be pursued more formally in a transition to a more comprehensive toxicity-testing strategy, it does not meet most of the design criteria discussed earlier.

In the committee’s view, a more transformative paradigm shift is needed to achieve the objectives for toxicity testing set out in its interim report, represented by Options III and IV in Table 2-1. The committee’s vision is built on the identification of biologic perturbations of toxicity pathways that can lead to adverse health outcomes under conditions of human exposure. The use of a comprehensive array of in vitro tests to identify relevant biologic perturbations with cellular and molecular systems based on human biology could eventually eliminate the need for whole-animal testing and provide a stronger, mechanistically based approach for environmental decision-making. Computational models could also play a role in the early identification of environmental agents potentially harmful to humans, although further testing would probably be needed. This new approach would be less expensive and less time-consuming than the current approach and result in much higher throughput. Although the reliance on in vitro results lacks the whole-organism integration provided by current tests, toxicologic assessments would be based on biologic perturbations of toxicity pathways that can reasonably be expected to lead to adverse health effects. Understanding of the role of such perturbations in the induction of toxic responses would be refined through toxicologic research. With the further development of in vitro test systems of toxicity pathways and the tools for assessing the dose-response characteristics of the perturbations, the committee believes that its vision for toxicity testing will meet the four objectives set out in its interim report.

Full implementation of the high-throughput, fully human-cell-based testing scheme represented by Option IV in Table 2-1



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