Abstract
The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) “toxicity pathways” (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.
Highlights
The goal of toxicity testing should be the collection of appropriate results from test systems in order to assess the likely risks posed to human populations at ambient exposure levels; i.e., provide the data inputs necessary for a realistic assessment of human risk
The highest dose tested is a maximum tolerated dose (MTD), with half or one quarter of the MTD usually selected as additional doses
Health contains reprints of the entire National Research Council (NRC) report [63] and the EPA strategic plan proposed in response [64], as well as 14 articles discussing specific scientific tools that will become the foundation of the methods outlined in the TT21C vision [65,66,67,68, 69,70,71,72,73,74,75,76,77,78]
Summary
The goal of toxicity testing should be the collection of appropriate results from test systems in order to assess the likely risks posed to human populations at ambient exposure levels; i.e., provide the data inputs necessary for a realistic assessment of human risk. The new approaches based on evaluation of in vitro assays that cover a range of toxicity pathways would enable testing across large concentration ranges for multiple modes of action and provide sufficient sensitivity for detection of biological effects at low concentrations unobtainable with conventional animal studies.
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