ABSTRACT
Toxicity testing is at a turning point now that long-range strategic planning is in progress to update and improve testing procedures for potential stressors. The report by the U.S. National Research Council (NRC)1 envisions a shift away from traditional toxicity testing and toward a focused effort to explore and understand the signaling pathways perturbed by biologically active substances or their metabolites that have the potential to cause adverse health effects in humans. The identi•cation of these toxicity pathways is imperative in order to understand the mode of action (MOA) of a given stimulus and for grouping together different stimuli based on the toxicity pathways they perturb. The •rst component of the vision focuses on pathway identi•cation, which is preferably derived from studies performed in human cells or cell lines using omics assays. The second component of the vision involves targeted testing of the identi•ed pathways in whole animals and clinical samples to further explain toxicity pathway data. This two-component toxicity-testing paradigm, combined with chemical characterization and dose-response extrapolation, delivers a much broader understanding of the potential toxicity associated with a biologically active substance.2-5
Systems biology plays an important role in this paradigm, consolidating large amounts of information that can be probed to reveal key cellular pathways perturbed by various stimuli. Programs such as Next Generation (NexGen) Risk Assessment from the Environmental Protection Agency (EPA)6 encourage the community to incorporate systems biology data into toxicity testing as articulated in a statement of goals for the near future, created at the Prototypes Workshop held in 2011.7 Current systems biology methodology should be reviewed and further developed using an iterative approach. Stimulus-speci•c signature pathways need to be developed by the careful clari•cation of already identi•ed key pathways. Systems data may also provide a means to better correlate in vitro and in vivo •ndings. However, the consistency of data obtained from in vitro and in vivo methodology across species needs to be assessed, and appropriate scaling methods should be developed for in vitro to in vivo correlation.
