ABSTRACT
Characterization of toxicity has remained unchanged for many years; assessment has focused on apical endpoints related to observed adverse effects in laboratory animals treated with high doses of agents. This approach, while the core to safety assessment of pharmaceuticals and industrial chemicals, is costly (e.g., test article, animals, and time). Advancements in high-throughput screening, in vitro model systems, and computational biology provide an opportunity to revolutionize toxicology. Such applications are expected to provide more mechanistic insight into the basis of toxicity. Chemical genetics and target deconvolution strategies, used since the 1990s in drug discovery work, have been adapted by toxicologists to enable toxicological characterization to be conducted proactively. To this end, cell culture and simple organismal systems are currently being integrated into discovery-phase screening assays to characterize various types of toxicity, providing a toxicity or teratogenic liability profile that can facilitate optimization of lead selection for the drug development phase. In response to recent legislation in Europe, the chemical industry is faced with the daunting task of assessing the toxicity of all chemicals sold in Europe in quantities of more than 1 ton/year. Standard toxicological assessment is not feasible since ≥68,000 compounds will require testing, and the task is required to be complete within the next decade. The National Research Council has provided a vision for toxicological assessment that requires a complete paradigm shift in testing approaches, eventually minimizing or eliminating whole-animal testing. Instead, assessment will rely upon a mechanistic systems-based approach integrating biological/molecular response from panels of cell-based assays that will determine whether the compound has potential to alter toxicity pathways. If successful, it is envisioned that this form of testing will affect how compounds are assessed in both the pharmaceutical and chemical industries. This chapter will review the needs set by the industry for advancements in toxicity testing, provide an overview of the efforts that are being undertaken to meet these needs, and discuss the potential challenges that are expected to be encountered during this process.
