The framework outlined in Figure 2-2 forms the basis of the committee’s vision for toxicity testing in the 21st century. The figure indicates that the initial perturbations of cell-signaling motifs, genetic circuits, and cellular-response networks are obligatory changes related to chemical exposure that might eventually result in disease. The consequences of a biologic perturbation depend on the magnitude of the perturbation, which is related to the dose, the timing and duration of the perturbation, and the susceptibility of the host. Accordingly, at low doses, many biologic systems may function normally within their homeostatic limits. At somewhat higher doses, clear biologic responses occur. They may be successfully handled with adaptation, although some susceptible people may respond. A more intense or persistent perturbation may overwhelm the capacity of the system to adapt and lead to tissue injury and possibly to adverse health effects.
In this framework, the goals of toxicity testing are to identify critical pathways that when perturbed can lead to adverse health outcomes and to evaluate the host susceptibility to understand the effects of perturbations on human populations. To implement the new toxicity-testing approach, toxicologists will need to evolve a comprehensive array of test procedures that will allow the reliable identification of important biologic perturbations in key toxicity pathways. And epidemiologists and toxicologists will need to develop approaches to understand the range of host susceptibility within populations. Viewing toxic responses in that manner shifts the focus away from the apical end points emphasized in the traditional toxicity-testing paradigm, toward biologic perturbations that can be identified more efficiently without the need for whole-animal testing and toward characterizing host vulnerability to provide the context for assessing the implications of test results.