Systems Toxicology: Real World Applications and Opportunities

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.

[1]  Benno Schwikowski,et al.  From the exposome to mechanistic understanding of chemical-induced adverse effects. , 2017, Environment international.

[2]  Nancy C Baker,et al.  Computational Model of Secondary Palate Fusion and Disruption. , 2017, Chemical research in toxicology.

[3]  Thomas Hartung,et al.  21st Century Cell Culture for 21st Century Toxicology. , 2017, Chemical research in toxicology.

[4]  Thomas Hartung,et al.  Utility of the adverse outcome pathway concept in drug development , 2017, Expert opinion on drug metabolism & toxicology.

[5]  L. Smirnova,et al.  A Human Brain Microphysiological System Derived from Induced Pluripotent Stem Cells to Study Neurological Diseases and Toxicity , 2016, ALTEX.

[6]  Anton Simeonov,et al.  Good Cell Culture Practice for stem cells and stem-cell-derived models. , 2016, ALTEX.

[7]  Francois Busquet,et al.  The need for strategic development of safety sciences. , 2017, ALTEX.

[8]  Thomas Hartung,et al.  Pathway-Based Approaches for Environmental Monitoring and Risk Assessment. , 2016, Environmental science & technology.

[9]  S. Polak,et al.  Virtual Clinical Trial Toward Polytherapy Safety Assessment: Combination of Physiologically Based Pharmacokinetic/Pharmacodynamic-Based Modeling and Simulation Approach With Drug-Drug Interactions Involving Terfenadine as an Example. , 2016, Journal of pharmaceutical sciences.

[10]  Bas J Blaauboer,et al.  Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods. , 2016, ALTEX.

[11]  T. Hartung,et al.  Pathway-Based Approaches for Environmental Monitoring and Risk Assessment. , 2016, Chemical Research in Toxicology.

[12]  David M. Reif,et al.  Analysis of the Effects of Cell Stress and Cytotoxicity onIn Vitro Assay Activity Across a Diverse Chemical and Assay Space , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[13]  David Allen,et al.  Integrated decision strategies for skin sensitization hazard , 2016, Journal of applied toxicology : JAT.

[14]  Aleksandra Galetin,et al.  Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation , 2016, The AAPS Journal.

[15]  Emilio Benfenati,et al.  Novel chemical hazard characterisation approaches , 2016 .

[16]  Participants,et al.  Moving Beyond Prioritization Toward True In Vitro Safety Assessment , 2016 .

[17]  Lu Gaohua,et al.  Development of a permeability-limited model of the human brain and cerebrospinal fluid (CSF) to integrate known physiological and biological knowledge: Estimating time varying CSF drug concentrations and their variability using in vitro data. , 2016, Drug metabolism and pharmacokinetics.

[18]  M. Baker 1,500 scientists lift the lid on reproducibility , 2016, Nature.

[19]  Uwe Marx,et al.  Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing. , 2016, ALTEX.

[20]  Mardas Daneshian,et al.  Highlight report: Launch of a large integrated European in vitro toxicology project: EU-ToxRisk , 2016, Archives of Toxicology.

[21]  Gary R. Mirams,et al.  Uncertainty and variability in computational and mathematical models of cardiac physiology , 2016, The Journal of physiology.

[22]  Rick A. Fasani,et al.  Information-dependent enrichment analysis reveals time-dependent transcriptional regulation of the estrogen pathway of toxicity , 2016, Archives of Toxicology.

[23]  Fabian P. Steinmetz,et al.  Using Molecular Initiating Events to Develop a Structural Alert Based Screening Workflow for Nuclear Receptor Ligands Associated with Hepatic Steatosis. , 2016, Chemical research in toxicology.

[24]  T. Colatsky,et al.  A New Perspective in the Field of Cardiac Safety Testing through the Comprehensive In Vitro Proarrhythmia Assay Paradigm , 2016, Journal of biomolecular screening.

[25]  David M. Reif,et al.  Using ToxCast™ Data to Reconstruct Dynamic Cell State Trajectories and Estimate Toxicological Points of Departure , 2015, Environmental health perspectives.

[26]  T. Hartung,et al.  Metabolomic network analysis of estrogen-stimulated MCF-7 cells: a comparison of overrepresentation analysis, quantitative enrichment analysis and pathway analysis versus metabolite network analysis , 2016, Archives of Toxicology.

[27]  Alexandra Maertens,et al.  t4 Workshop Report* , 2017, ALTEX.

[28]  Paul Jennings,et al.  Development of an in vitro renal epithelial disease state model for xenobiotic toxicity testing. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[29]  Annette Kopp-Schneider,et al.  Application of RPTEC/TERT1 cells for investigation of repeat dose nephrotoxicity: A transcriptomic study. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[30]  Annette Kopp-Schneider,et al.  Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[31]  Stephan Aiche,et al.  Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[32]  Judy Strickland,et al.  Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy , 2015, Archives of Toxicology.

[33]  M Jamei,et al.  Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs , 2015, CPT: pharmacometrics & systems pharmacology.

[34]  David Vidal,et al.  Large-Scale Predictive Drug Safety: From Structural Alerts to Biological Mechanisms. , 2015, Chemical research in toxicology.

[35]  Paul Jennings,et al.  "The future of in vitro toxicology". , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[36]  A. Natsch,et al.  Reporter cell lines for skin sensitization testing , 2015, Archives of Toxicology.

[37]  Mathieu Vinken,et al.  Adverse Outcome Pathways and Drug-Induced Liver Injury Testing. , 2015, Chemical research in toxicology.

[38]  Manuel C. Peitsch,et al.  Enhancement of COPD biological networks using a web-based collaboration interface , 2015, F1000Research.

[39]  Alexandra Maertens,et al.  MPTP’s Pathway of Toxicity Indicates Central Role of Transcription Factor SP1 , 2015, Archives of Toxicology.

[40]  Andreas Luch,et al.  Moving from rats to cellular omics in regulatory toxicology: great challenge toward sustainability or “up-shit-creek without a paddle”? , 2015, Archives of Toxicology.

[41]  M. Greiner,et al.  Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions , 2015, Archives of Toxicology.

[42]  Huixiao Hong,et al.  Predicting hepatotoxicity using ToxCast in vitro bioactivity and chemical structure. , 2015, Chemical research in toxicology.

[43]  Joachim D Pleil,et al.  Probe molecule (PrM) approach in adverse outcome pathway (AOP) based high-throughput screening (HTS): in vivo discovery for developing in vitro target methods. , 2015, Chemical research in toxicology.

[44]  Melvin E Andersen,et al.  The Human Toxome Project , 2015, ALTEX.

[45]  L. Smirnova,et al.  Cellular resilience. , 2015, ALTEX.

[46]  Alexandra Maertens,et al.  t4 Workshop Report , 2017, ALTEX.

[47]  Thomas Hartung,et al.  Integrated Testing Strategies (ITS) for safety assessment. , 2015, ALTEX.

[48]  Andrew Worth,et al.  Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA). , 2014, Regulatory toxicology and pharmacology : RTP.

[49]  Sharon Munn,et al.  Adverse outcome pathway development II: best practices. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  Catherine Mahony,et al.  SEURAT: Safety Evaluation Ultimately Replacing Animal Testing—Recommendations for future research in the field of predictive toxicology , 2014, Archives of Toxicology.

[51]  Timothy E H Allen,et al.  Defining molecular initiating events in the adverse outcome pathway framework for risk assessment. , 2014, Chemical research in toxicology.

[52]  A. Limonciel,et al.  Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. , 2014, Toxicology and applied pharmacology.

[53]  Mardas Daneshian,et al.  Current approaches and future role of high content imaging in safety sciences and drug discovery. , 2014, ALTEX.

[54]  A Rostami-Hodjegan,et al.  Application of a Physiologically Based Pharmacokinetic Model to Predict OATP1B1-Related Variability in Pharmacodynamics of Rosuvastatin , 2014, CPT: pharmacometrics & systems pharmacology.

[55]  Robert J Kavlock,et al.  Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms , 2014, Nature Biotechnology.

[56]  Thomas Hartung,et al.  3D - a new dimension of in vitro research. , 2014, Advanced drug delivery reviews.

[57]  Paul Jennings,et al.  Interleukin-19 as a translational indicator of renal injury , 2014, Archives of Toxicology.

[58]  Gary Gintant,et al.  Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. , 2014, American heart journal.

[59]  R Jeffrey Lewis,et al.  Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence , 2014, Journal of applied toxicology : JAT.

[60]  Ovanes Mekenyan,et al.  A mechanistic approach to modeling respiratory sensitization. , 2014, Chemical research in toxicology.

[61]  Henggui Zhang,et al.  hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment , 2014, Journal of cardiovascular electrophysiology.

[62]  Rémi H. J. Dulize,et al.  Systems biology approach for evaluating the biological impact of environmental toxicants in vitro. , 2014, Chemical research in toxicology.

[63]  Maarten L J Coonen,et al.  Classification of hepatotoxicants using HepG2 cells: A proof of principle study. , 2014, Chemical research in toxicology.

[64]  A O Aptula,et al.  Electrophilic reactivity and skin sensitization potency of SNAr electrophiles. , 2014, Chemical research in toxicology.

[65]  Manuel C. Peitsch,et al.  Systems Toxicology: From Basic Research to Risk Assessment , 2014, Chemical research in toxicology.

[66]  M E Meek,et al.  New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis , 2013, Journal of applied toxicology : JAT.

[67]  A. Limonciel,et al.  Translational Biomarkers, In Vitro and In Vivo , 2014 .

[68]  Dean P. Jones,et al.  The nature of nurture: refining the definition of the exposome. , 2014, Toxicological sciences : an official journal of the Society of Toxicology.

[69]  Thomas Hartung,et al.  Glossary of reference terms for alternative test methods and their validation. , 2014, ALTEX.

[70]  J. Haycock,et al.  State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology. , 2014, ALTEX.

[71]  Thomas Hartung,et al.  Pathways of Toxicity. , 2014, ALTEX.

[72]  Thomas Hartung,et al.  Review: Toxicometabolomics , 2013, Journal of applied toxicology : JAT.

[73]  Andrzej M. Kierzek,et al.  QSSPN: dynamic simulation of molecular interaction networks describing gene regulation, signalling and whole-cell metabolism in human cells , 2013, Bioinform..

[74]  Masoud Jamei,et al.  Application of permeability-limited physiologically-based pharmacokinetic models: part I-digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux. , 2013, Journal of pharmaceutical sciences.

[75]  Donald M Bers,et al.  Ranolazine for Congenital and Acquired Late INa-Linked Arrhythmias: In Silico Pharmacological Screening , 2013, Circulation research.

[76]  M. Jamei,et al.  A Mechanistic Framework for In Vitro–In Vivo Extrapolation of Liver Membrane Transporters: Prediction of Drug–Drug Interaction Between Rosuvastatin and Cyclosporine , 2013, Clinical Pharmacokinetics.

[77]  J. Verducci,et al.  MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes , 2013, Scientific Reports.

[78]  Gary R. Mirams,et al.  Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment , 2013, Journal of pharmacological and toxicological methods.

[79]  A. Rostami-Hodjegan,et al.  Do Children Have the Same Vulnerability to Metabolic Drug–Drug Interactions as Adults? A Critical Analysis of the Literature , 2013, Journal of clinical pharmacology.

[80]  Gary R. Mirams,et al.  Evaluation of an in silico cardiac safety assay: Using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge , 2013, Journal of pharmacological and toxicological methods.

[81]  Paul Jennings,et al.  Delineation of the Key Aspects in the Regulation of Epithelial Monolayer Formation , 2013, Molecular and Cellular Biology.

[82]  Bas J Blaauboer,et al.  Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress. , 2013, Journal of proteomics.

[83]  Lu Gaohua,et al.  Accounting for Transporters in Renal Clearance: Towards a Mechanistic Kidney Model (Mech KiM) , 2013 .

[84]  Whelan Maurice,et al.  Perspectives on Validation of High-Throughput Pathway-Based Assays Supporting the 21st Century Toxicity Testing Vision , 2013 .

[85]  Alexandra Maertens,et al.  Integrated testing strategies for safety assessments. , 2013, ALTEX.

[86]  D. Blacker Food for thought. , 2013, JAMA neurology.

[87]  Martin Stephens,et al.  Mechanistic validation. , 2013, ALTEX.

[88]  Arthur N. Mayeno,et al.  Computational Toxicology , 2013, Methods in Molecular Biology.

[89]  Thomas Hartung,et al.  Perspectives on validation of high-throughput assays supporting 21st century toxicity testing. , 2013, ALTEX.

[90]  Henggui Zhang,et al.  High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment. , 2013, American journal of physiology. Heart and circulatory physiology.

[91]  L. Smirnova,et al.  Metabolomics in toxicology and preclinical research. , 2013, ALTEX.

[92]  P. Jennings,et al.  Stress response pathways, toxicity pathways and adverse outcome pathways , 2012, Archives of Toxicology.

[93]  Sebastian Polak,et al.  Prediction of concentration-time profile and its inter-individual variability following the dermal drug absorption. , 2012, Journal of pharmaceutical sciences.

[94]  A. Rostami-Hodjegan,et al.  Physiologically Based Pharmacokinetics Joined With In Vitro–In Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology , 2012, Clinical pharmacology and therapeutics.

[95]  Mardas Daneshian,et al.  Validation and quality control of replacement alternatives - Current status and future challenges , 2012 .

[96]  Denis Noble,et al.  How the Hodgkin–Huxley equations inspired the Cardiac Physiome Project , 2012, The Journal of physiology.

[97]  H. Mistry,et al.  An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment. , 2012, American journal of physiology. Heart and circulatory physiology.

[98]  Imran Shah,et al.  Using pathway modules as targets for assay development in xenobiotic screening. , 2012, Molecular bioSystems.

[99]  J. Jaworska,et al.  Systems toxicology. , 2012, ALTEX.

[100]  A. Limonciel,et al.  An overview of transcriptional regulation in response to toxicological insult , 2012, Archives of Toxicology.

[101]  Paul Jennings,et al.  Lactate is an ideal non-invasive marker for evaluating temporal alterations in cell stress and toxicity in repeat dose testing regimes. , 2011, Toxicology in vitro : an international journal published in association with BIBRA.

[102]  Denis Noble,et al.  Is it time for in silico simulation of drug cardiac side effects? , 2011, Annals of the New York Academy of Sciences.

[103]  N. Trayanova,et al.  A Computational Model to Predict the Effects of Class I Anti-Arrhythmic Drugs on Ventricular Rhythms , 2011, Science Translational Medicine.

[104]  Gary R. Mirams,et al.  Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk , 2011, Cardiovascular research.

[105]  L Zhang,et al.  Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review , 2011, Clinical pharmacology and therapeutics.

[106]  Erwin van Vliet,et al.  Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century. , 2011 .

[107]  Erwin van Vliet,et al.  Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century. , 2011, ALTEX.

[108]  Thomas Hartung,et al.  Food for Thought ... on mapping the human toxome. , 2011, ALTEX.

[109]  Stephen M Rappaport,et al.  Environment and Disease Risks , 2010, Science.

[110]  Imran Shah,et al.  Virtual Tissues in Toxicology , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[111]  J. Bailar,et al.  Toxicity Testing in the 21st Century: A Vision and a Strategy , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[112]  David Dix,et al.  Computational Toxicology as Implemented by the U.S. EPA: Providing High Throughput Decision Support Tools for Screening and Assessing Chemical Exposure, Hazard and Risk , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[113]  W. Nie,et al.  Characterization of two human lung adenocarcinoma cell lines by reciprocal chromosome painting. , 2010, Dong wu xue yan jiu = Zoological research.

[114]  Marcel Leist,et al.  Food for thought ... considerations and guidelines for basic test method descriptions in toxicology. , 2010, ALTEX.

[115]  R. Preston,et al.  Application of Key Events Analysis to Chemical Carcinogens and Noncarcinogens , 2009, Critical reviews in food science and nutrition.

[116]  T. Hartung Toxicology for the twenty-first century , 2009, Nature.

[117]  M. Greenberg,et al.  Toxicity Testing in the 21st Century , 2009, Risk analysis : an official publication of the Society for Risk Analysis.

[118]  Paul Jennings,et al.  hTERT alone immortalizes epithelial cells of renal proximal tubules without changing their functional characteristics. , 2008, American journal of physiology. Renal physiology.

[119]  Alan R. Boobis,et al.  IPCS Framework for Analyzing the Relevance of a Noncancer Mode of Action for Humans , 2008, Critical reviews in toxicology.

[120]  Amin Rostami-Hodjegan,et al.  Simulation and prediction of in vivo drug metabolism in human populations from in vitro data , 2007, Nature Reviews Drug Discovery.

[121]  Monica Nordberg,et al.  Glossary of terms used in toxicology, 2nd edition (IUPAC Recommendations 2007) , 2007 .

[122]  M. Nordberg,et al.  GLOSSARY OF TERMS USED IN TOXICOLOGY, 2 nd EDITION , 2007 .

[123]  Alan R. Boobis,et al.  IPCS Framework for Analyzing the Relevance of a Cancer Mode of Action for Humans , 2006 .

[124]  Michael Balls,et al.  Guidance on Good Cell Culture Practice , 2005, Alternatives to laboratory animals : ATLA.

[125]  Valérie Zuang,et al.  A Modular Approach to the ECVAM Principles on Test Validity , 2004, Alternatives to laboratory animals : ATLA.

[126]  E. Lattman In Silico , 2003, Proteins.

[127]  A Wolman,et al.  The environment and disease. , 1976, Bulletin of the Pan American Health Organization.