Forum Series: the "Vision" for Toxicity Testing in the 21st Century: promises and conundrums.

The ‘‘Forum’’ section of Toxicological Sciences is designed to include discussions and commentaries on relevant topics and timely issues facing toxicologists and to provide an interface between toxicology and public policy. While there are many topics and issues of interest to toxicologists, there are only a few that have the potential to have as great an impact on the science of toxicology, as the vision for ‘‘Toxicity Testing in the 21st Century’’ developed by the National Research Council (NRC) in 2007. In the present issue of the journal, we initiate the latest series of Forum articles which will focus on the promises and conundrums associated with the ‘‘Vision,’’ starting with an article by two members of the National Academies of Science (NAS) committee that developed it over the course of almost 3 years (Andersen and Krewski, 2009). The goal for the series of articles is to facilitate the communication of ideas and to promote open and balanced discussion to enhance the potential to realize the promises by identifying the challenges and conundrums associated with components of the ‘‘Vision. ’’ Many of the methodologies routinely used today in the traditional approach to toxicity testing originated in the 1960s and 1970s and are based on high-dose studies in a variety of animal species. Besides the need for large numbers of animals, the current approach is expensive and time consuming. When the test results are used for human risk assessment, there are formidable challenges associated with dose and species extrapolation and with the application of uncertainty factors. Knowledge of toxicology and testing capabilities has increased dramatically in the last 40 years. Moreover, recent advances in systems biology, testing in cells and tissues, and related scientific fields offer the potential to fundamentally change the way that chemicals are tested for the risks that they may pose to humans. In 2004, the U.S. Environmental Protection Agency and the National Institutes of Environmental Health Sciences contracted with the NAS to establish a committee that would develop strategies to (1) increase the number of chemicals that could be tested, (2) decrease the cost of testing, and (3) increase the ability to determine the human risks of chemical environmental exposure. The NAS Committee completed their assignment in 2007, having published an interim report in 2006, and released the final report on 12 June 2007 (NRC, 2007). The report outlines four options for future toxicity testing strategies and, ultimately, offers a new approach that would rely less heavily on animal studies and, instead, focus on in vitro methods that evaluate chemicals’ effects on biological processes using cells, cell lines, or cellular components, preferably of human origin. This new vision and strategy for toxicity testing in the 21st century would be less expensive and less time consuming than the current approach. The vision would be based primarily on human biology instead of animal biology and would require anywhere between substantially fewer animals and virtually no animals. The vision would be based on measuring perturbations of toxicity pathways as opposed to changes in apical end points and would, thus, make far greater use of advances in mechanistic studies. Finally, because the vision will be based on high-throughput in vitro and in silico screens, a much broader range of doses can be characterized. As noted in the perspective from Andersen and Krewski (2009), ‘‘this vision for toxicity testing is built on defining dose-response relationships for toxicity pathway perturbations that would be expected to lead to adverse health outcomes, if the perturbations were maintained in vivo at a sufficient level of intensity and for a period of sufficiently long duration. ’’ There are clear promises associated with components of the vision, which in many ways are natural extensions of the evolution of toxicology science—including the commitment to the three Rs: replacement, reduction, and refinement and the desire to integrate state-of-the-art mechanistic, modeling, and risk assessment approaches. However, to fully implement the vision, there are also challenges to be identified and obstacles to be overcome. The reliance on cell-based systems and in vitro methods present the long-debated problems with this approach, including the role of metabolism, the ability to extrapolate 1 For correspondence via E-mail: mholsapple@ilsi.org. Fax: (202) 659-3617.