The vision of toxicity testing in the 21st century: moving from discussion to action.
ABSTRACT Over the past year, a series on commentaries have appeared in the Toxicological Sciences Forum Series related to the 2007 National Research Council (NRC) publication, Toxicity Testing in the 21st Century: A Vision and A Strategy. The first article in the series provided an overview of the vision and was accompanied by an editorial by the three editors of Toxicological Sciences. During the past year, eight invited commentaries from the academic, industrial, and regulatory sectors have provided diverse perspectives on the vision, noted challenges to its implementation, and highlighted aspects of toxicity testing that were not addressed in the original NRC report. Here, we offer a summary of the main points raised by the commentators in tabular form, identify a number of common themes, and finish the series by providing our perspective on several key issues in charting the path forward to move from discussion to action.
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ABSTRACT: High visibility efforts in toxicity testing and computational toxicology including the recent National Research Council of the National Academies (NRC) report, Toxicity Testing in the 21st Century: A Vision and Strategy (NRC, 2007a), raise important research questions and opportunities for the field of exposure science. The authors of the National Academies report (NRC, 2007a) emphasize that population-based data and human exposure information are required at each step of their vision for toxicity testing and that these data will continue to play a critical role in both guiding development and use of the toxicity information. In fact, state-of-the-art exposure science is essential for translation of toxicity data to assess potential for risk to individuals and populations and to inform public health decisions. As we move forward to implement the NRC vision, a transformational change in exposure science is required. Application of a fresh perspective and novel techniques to capture critical determinants at biologically motivated resolution for translation from controlled in vitro systems to the open multifactorial system of real-world human-environment interaction will be critical. Development of an exposure ontology and knowledge base will facilitate extension of network analysis to the individual and population for translating toxicity information and assessing health risk. Such a sea change in exposure science is required to incorporate consideration of lifestage, genetic susceptibility, and interaction of nonchemical stressors for holistic assessment of risk factors associated with complex environmental disease. A new generation of scientific tools has emerged to rapidly measure signals from cells, tissues, and organisms following exposure to chemicals. Investment in 21st century exposure science is now required to fully realize the potential of the NRC vision for toxicity testing.Toxicological Sciences 08/2009; 111(2):226-32. · 4.33 Impact Factor
- Toxicological Sciences 06/2009; 110(1):40-6. · 4.33 Impact Factor
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ABSTRACT: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.Environmental Health Perspectives 04/2010; 118(4):485-92. · 7.26 Impact Factor