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t4 workshop report: Pathways of Toxicity

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Andre Kleensang1, Alexandra Maertens1, Michael Rosenberg2, Suzanne Fitzpatrick3, Justin Lamb4, Scott Auerbach5, Richard Brennan6, Kevin M. Crofton7, Ben Gordon8, Albert J. Fornace Jr.9, Kevin Gaido3, David Gerhold10, Robin Haw11, Adriano Henney12, Avi Ma’ayan13, Mary McBride2, Stefano Monti14, Michael F. Ochs15, Akhilesh Pandey16, Roded Sharan17, Rob Stierum18, Stuart Tugendreich19, Catherine Willett20, Clemens Wittwehr21, Jianguo Xia22, Geoffrey W. Patton23, Kirk Arvidson23, Mounir Bouhifd1, Helena T. Hogberg1, Thomas Luechtefeld1, Lena Smirnova1, Liang Zhao1, Yeyejide Adeleye24, Minoru Kanehisa25, Paul Carmichael24, Melvin E. Andersen26, and Thomas Hartung1,27
1 Johns Hopkins University, Bloomberg School of Public Health, Center for Alternatives to Animal Testing, Baltimore, MD, USA;
2 Agilent Technologies, Inc., Santa Clara, CA, USA;
3 US Food and Drug Administration, Center for Food Safety & Applied Nutrition, College Park, MD, USA;
4 Genometry Inc., Cambridge, MA, USA;
5 Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA;
6 Thomson Reuters Inc., Carlsbad, CA, USA;
7 U.S. Environmental Protection Agency, Office of Research and Development, National Center for Computational Toxicology, Research Triangle Park, NC, USA;
8 Dept of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA;
9 Dept. of Biochemistry and Molecular & Cellular Biology, and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA;
10 The National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA;
11 Reactome, Ontario Institute for Cancer Research, Toronto, Canada;
12 The German Virtual Liver Network, University of Heidelberg, Heidelberg, Germany;
13 Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
14 Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA;
15 Johns Hopkins University, School of Medicine, Department of Oncology, Baltimore, MD, USA;
16 Institute of Genetic Medicine and Departments of Biological Chemistry, Oncology and Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA;
17 Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel;
18 TNO Healthy Living, Microbiology & Systems Biology, Zeist, The Netherlands;
19 Ingenuity Systems, Inc., Redwood City, CA, USA;
20 The Humane Society of the United States, Washington, DC, USA;
21 European Commission, Joint Research Centre, Systems Toxicology Unit, Ispra, Italy;
22 Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada;
23 U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Food Additive Safety, College Park, MD, USA;
24 Unilever, Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Bedfordshire, UK;
25 Institute for Chemical Research, Kyoto University, Kyoto, Japan;
26 The Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA;
27 CAAT-Europe, University of Konstanz, Germany


Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. A workshop was organized to explore one key aspect of this transformation – the development of Pathways of Toxicity (PoT) as a key tool for hazard identification based on systems biology. Several issues were discussed in depth in the workshop: The first was the challenge of formally defining the concept of a PoT as distinct from, but complementary to, other toxicological pathway concepts such as mode of action (MoA). The workshop came up with a preliminary definition of PoT as “A molecular definition of cellular processes shown to mediate adverse outcomes of toxicants”. It is further recognized that normal physiological pathways exist that maintain homeostasis and these, sufficiently perturbed, can become PoT. Second, the workshop sought to define the adequate public and commercial resources for PoT information, including data, visualization, analyses, tools, and use-cases, as well as the kinds of efforts that will be necessary to enable the creation of such a resource. Third, the workshop explored ways in which systems biology approaches could inform pathway annotation, and which resources are needed and available that can provide relevant PoT information to the diverse user communities.


Keywords: systems toxicology, pathways of toxicity, adverse outcome pathways, in vitro toxicology, human toxome



ALTEX 31(1), 53–61

DOI: 10.14573/altex.1309261

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