continuing concern. Current tests also provide little information on modes and mechanisms of action, which are critical for understanding interspecies differences in toxicity, and little or no information for assessing variability in human susceptibility. Thus, the committee looked to recent scientific advances to provide a new approach to toxicity testing.

A revolution is taking place in biology. At its center is the progress being made in the elucidation of cellular-response networks. Those networks are interconnected pathways composed of complex biochemical interactions of genes, proteins, and small molecules that maintain normal cellular function, control communication between cells, and allow cells to adapt to changes in their environment. A familiar cellular-response network is signaling by estrogens in which initial exposure results in enhanced cell proliferation and growth of specific tissues or in proliferation of estrogen-sensitive cells in culture (Frasor et al. 2003). In that type of network, initial interactions between a signaling molecule and various cellular receptors result in a cascade of early, midterm, and late responses to achieve a coordinated response that orchestrates normal physiologic functions (Landers and Spelsberg 1992; Thummel 2002; Rochette-Egly 2003).

Bioscience is rapidly enhancing our knowledge of cellular-response networks and allowing scientists to begin to uncover the manner in which environmental agents perturb pathways to cause toxicity. Pathways that can lead to adverse health effects when sufficiently perturbed are termed toxicity pathways. Responses of cells to oxidative stress caused by exposure to diesel exhaust particles (DEP) constitute an example of toxicity pathways within a cellular-response network (Xiao et al. 2003). In a dose-related fashion, in vitro exposures to DEP lead to activation of a hierarchic set of pathways. First, cell antioxidant signaling is increased. As the dose increases, inflammatory signaling is enhanced; finally, at higher doses, there is activation of cell-death (apoptosis) pathways (Nel et al. 2006). Thus, in the cellular-response network dealing

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