The Future of Toxicity Testing

Abstract

In 2007, the U.S. National Research Council (NRC) released a report, "Toxicity Testing in the 21st Century: A Vision and a Strategy," that proposes a paradigm shift for toxicity testing of environmental agents. The vision is based on the notion that exposure to environmental agents leads to adverse health outcomes through the perturbation of toxicity pathways that are operative in humans. Implementation of the NRC vision will involve a fundamental change in the assessment of toxicity of environmental agents, moving away from adverse health outcomes observed in experimental animals to the identification of critical perturbations of toxicity pathways. Pathway perturbations will be identified using in vitro assays and quantified for dose response using methods in computational toxicology and other recent scientific advances in basic biology. Implementation of the NRC vision will require a major research effort, not unlike that required to successfully map the human genome, extending over 10 to 20 years, involving the broad scientific community to map important toxicity pathways operative in humans. This article provides an overview of the scientific tools and technologies that will form the core of the NRC vision for toxicity testing. Of particular importance will be the development of rapidly performed in vitro screening assays using human cells and cell lines or human tissue surrogates to efficiently identify environmental agents producing critical pathway perturbations. In addition to the overview of the NRC vision, this study documents the reaction by a number of stakeholder groups since 2007, including the scientific, risk assessment, regulatory, and animal welfare communities.

Assessment of food toxicology

“…For example, the knowledge gained on the effects of toxicants on lipids stems from the similarity of lipid metabolism between mini pigs and humans, whereas the rat appears to be an unsuitable model for the study of cholesterol levels [2]. Higher specificity was also achieved by the use of new genetically diverse in vivo high-content models simulating the genetic heterogeneity of humans or transgenic animals modeling common diseases and/or genetic polymorphisms considering specific groups within the general population that may be at particular risk following exposure to a food component [2,6,7,42,51].…”

New Directions in Toxicity Testing

“…Whereas pharmacokinetic modeling is presently used to calibrate in vivo and human dosimetry, future kinetic models will facilitate the translation of doses in cellular systems to doses in human organs and tissues (12). Critical toxicity pathways that are identified in in vitro studies may be used to interpret populationbased studies in the context of human health risk assessment, and appropriate biomarkers could be used to measure toxicity pathway perturbations directly in humans (3,55).…”

“…As indicated in Figure 2, dose-response assessment involves the combined analysis of affected pathways, measures of dose in vitro, and dose-response analysis of perturbations of toxicity pathways. Modeling would use functional genomics, bioinformatics, and systems biology to describe pathway circuitry, pathway function, and key pathway components in a dosedependent manner (3,55).…”

“…Reaction to the NRC vision can be gauged by a series of nine invited commentaries on this article from the academic, industrial, and regulatory sectors (13,16,18,34,39,43,60,64,101). One of the main issues discussed was the requirements needed to extrapolate from in vitro cellular assays to in vivo acute and chronic health effects in animal models (3,5). Overall, these commentaries expressed support for the NRC vision but noted that considerable work would be needed to build the science base on which the vision rests (5).…”

“…This special issue contains reprints of both the 2007 NRC report and the 2009 EPA strategic plan, as well as 14 additional papers discussing specific aspects of the vision in some detail (3,11,25,35,44,47,51,59,81,83,85,87,89,107). Since the publication of the NRC vision for the future of toxicity testing, considerable progress has been made, not only on developing the scientific foundations on which the vision rests, but also on understanding its implications for regulatory risk assessment (21,59).…”