title: Systems Toxicology: Real World Applications and Opportunities.
abstract: Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxicology entails the integration of in vitro and in vivo toxicity data with computational modeling. This evolving approach depends critically on data reliability and relevance, which in turn depends on the quality of experimental models and bioanalysis techniques used to generate toxicological data. Systems Toxicology involves the use of large-scale data streams ("big data"), such as those derived from omics measurements that require computational means for obtaining informative results. Thus, integrative analysis of multiple molecular measurements, particularly acquired by omics strategies, is a key approach in Systems Toxicology. In recent years, there have been significant advances centered on in vitro test systems and bioanalytical strategies, yet a frontier challenge concerns linking observed network perturbations to phenotypes, which will require understanding pathways and networks that give rise to adverse responses. This summary perspective from a 2016 Systems Toxicology meeting, an international conference held in the Alps of Switzerland, describes the limitations and opportunities of selected emerging applications in this rapidly advancing field. Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized, from empirical end points to pathways of toxicity. This requires the integration of in vitro and in vivo data with computational modeling. Test systems and bioanalytical technologies have made significant advances, but ensuring data reliability and relevance is an ongoing concern. The major challenge facing the new pathway approach is determining how to link observed network perturbations to phenotypic toxicity.
authors.affiliation: Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health , Baltimore, Maryland 21205, United States.|University of Konstanz, CAAT-Europe , 78457 Konstanz, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-1359-7689
authors.initials: T
authors.lastname: Hartung
authors.affiliation: Swiss Centre for Applied Human Toxicology, University of Basel , 4055 Basel, Switzerland.
authors.forename: Rex E
authors.initials: RE
authors.lastname: FitzGerald
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck , 6020 Innsbruck, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Jennings
authors.affiliation: Centre for Mathematical Medicine & Biology, School of Mathematical Sciences, University of Nottingham , Nottingham NG7 2RD, U.K.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Mirams
authors.affiliation: Department of Research and Development, Philip Morris International , 2000 Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: Centre for Applied Pharmacokinetic Research, University of Manchester , Manchester M13 9PL, U.K.|Simcyp Limited (a Certara Company) , Blades Enterprise Centre, Sheffield S2 4SU, U.K.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: National Center for Computational Toxicology , Research Triangle Park, North Carolina 27711, United States.
authors.forename: Imran
authors.initials: I
authors.lastname: Shah
authors.affiliation: Swiss Centre for Applied Human Toxicology, University of Basel , 4055 Basel, Switzerland.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Wilks
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich , 8092 Zurich, Switzerland.
authors.forename: Shana J
authors.identifier: 0000-0001-6808-5950
authors.initials: SJ
authors.lastname: Sturla
mesh_terms: D006207:Half-Life; D006321:Heart / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D055432:Metabolomics; D008962:Models, Theoretical; D040901:Proteomics; D015262:Xenobiotics / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D015262:Xenobiotics