{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T05:22:50Z","timestamp":1770441770346,"version":"3.49.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2015,4,21]],"date-time":"2015-04-21T00:00:00Z","timestamp":1429574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2015,8,14]],"date-time":"2015-08-14T00:00:00Z","timestamp":1439510400000},"content-version":"vor","delay-in-days":115,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"DBU (Deutsche Bundesstiftung Umwelt) Scholarship Program AZ","award":["30013\/436"],"award-info":[{"award-number":["30013\/436"]}]},{"name":"CEE Countries and the supported by the Czech Ministry of Education","award":["L01214"],"award-info":[{"award-number":["L01214"]}]},{"name":"DBU (Deutsche Bundesstiftung Umwelt) Scholarship Program AZ","award":["30013\/436"],"award-info":[{"award-number":["30013\/436"]}]},{"name":"CEE Countries and the supported by the Czech Ministry of Education","award":["L01214"],"award-info":[{"award-number":["L01214"]}]}],"content-domain":{"domain":["setac.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,4,21]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>\u2003<\/jats:title><jats:p>Omics-based methods are increasingly used in current ecotoxicology. Therefore, a large number of observations for various toxic substances and organisms are available and may be used for identifying modes of action, adverse outcome pathways, or novel biomarkers. For these purposes, good statistical analysis of toxicogenomic data is vital. In contrast to established ecotoxicological techniques, concentration\u2013response modeling is rarely used for large datasets. Instead, statistical hypothesis testing is prevalent, which provides only a limited scope for inference. The present study therefore applied automated concentration\u2013response modeling for 3 different ecotoxicotranscriptomic and ecotoxicometabolomic datasets. The modeling process was performed by simultaneously applying 9 different regression models, representing distinct mechanistic, toxicological, and statistical ideas that result in different curve shapes. The best-fitting models were selected by using Akaike's information criterion. The linear and exponential models represented the best data description for more than 50% of responses. Models generating U-shaped curves were frequently selected for transcriptomic signals (30%), and sigmoid models were identified as best fit for many metabolomic signals (21%). Thus, selecting the models from an array of different types seems appropriate, because concentration\u2013response functions may vary because of the observed response type, and they also depend on the compound, the organism, and the investigated concentration and exposure duration range. The application of concentration\u2013response models can help to further tap the potential of omics data and is a necessary step for quantitative mixture effect assessment at the molecular response level. Environ Toxicol Chem 2015;34:2167\u20132180. \u00a9 2015 SETAC<\/jats:p><\/jats:sec>","DOI":"10.1002\/etc.3025","type":"journal-article","created":{"date-parts":[[2015,4,21]],"date-time":"2015-04-21T21:09:47Z","timestamp":1429650587000},"page":"2167-2180","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["High-throughput concentration\u2013response analysis for omics datasets"],"prefix":"10.1093","volume":"34","author":[{"given":"So\u0148a","family":"Smetanov\u00e1","sequence":"first","affiliation":[{"name":"UFZ - Helmholtz Centre for Environmental ResearchDepartment of Bioanalytical Ecotoxicology Leipzig Germany"},{"name":"Research Centre for Toxic Compounds in the Environment (RECETOX)Faculty of ScienceMasaryk University Brno Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet","family":"Riedl","sequence":"additional","affiliation":[{"name":"UFZ - Helmholtz Centre for Environmental ResearchDepartment of Bioanalytical Ecotoxicology Leipzig Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitar","family":"Zitzkat","sequence":"additional","affiliation":[{"name":"UFZ - Helmholtz Centre for Environmental ResearchDepartment of Bioanalytical Ecotoxicology Leipzig Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolf","family":"Altenburger","sequence":"additional","affiliation":[{"name":"UFZ - Helmholtz Centre for Environmental ResearchDepartment of Bioanalytical Ecotoxicology Leipzig Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wibke","family":"Busch","sequence":"additional","affiliation":[{"name":"UFZ - Helmholtz Centre for Environmental ResearchDepartment of Bioanalytical Ecotoxicology Leipzig Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,4,21]]},"reference":[{"key":"2025010315525787400_etc3025-bib-0001","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1021\/es2038036","article-title":"Mixture toxicity revisited from a toxicogenomic perspective","volume":"46","author":"Altenburger","year":"2012","journal-title":"Environ Sci Technol"},{"key":"2025010315525787400_etc3025-bib-0002","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1093\/toxsci\/kfs092","article-title":"Concentration-response analysis of differential gene expression in the zebrafish embryotoxicity test following flusilazole exposure","volume":"127","author":"Hermsen","year":"2012","journal-title":"Toxicol Sci"},{"key":"2025010315525787400_etc3025-bib-0003","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1073\/pnas.1319388111","article-title":"Linking toxicity and adaptive responses across the transcriptome, proteome, and phenotype of Chlamydomonas reinhardtii exposed to silver","volume":"111","author":"Pillai","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025010315525787400_etc3025-bib-0004","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1002\/em.20302","article-title":"US Environmental Protection Agency's activities to prepare for regulatory and risk assessment applications of genomics information","volume":"48","author":"Benson","year":"2007","journal-title":"Environ Mol Mutagen"},{"key":"2025010315525787400_etc3025-bib-0005","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4018\/978-1-60960-491-2.ch004","volume-title":"Handbook of Research on Computational and Systems Biology: Interdisciplinary Applications","author":"Ding","year":"2011"},{"key":"2025010315525787400_etc3025-bib-0006","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1002\/etc.7","article-title":"Toward a unified approach to dose-response modeling in ecotoxicology","volume":"29","author":"Ritz","year":"2010","journal-title":"Environ Toxicol Chem"},{"key":"2025010315525787400_etc3025-bib-0007","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1002\/etc.2294","article-title":"Simplifying complexity: Mixture toxicity assessment in the last 20 years","volume":"32","author":"Altenburger","year":"2013","journal-title":"Environ Toxicol Chem"},{"key":"2025010315525787400_etc3025-bib-0008","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1126\/science.1127291","article-title":"The challenge of micropollutants in aquatic systems","volume":"313","author":"Schwarzenbach","year":"2006","journal-title":"Science"},{"key":"2025010315525787400_etc3025-bib-0009","first-page":"10","author":"European Commission.","year":"2012"},{"key":"2025010315525787400_etc3025-bib-0010","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.cbd.2007.04.007","article-title":"Transcriptomics and proteomics: Applications to ecotoxicology","volume":"2","author":"Calzolai","year":"2007","journal-title":"Comp Biochem Physiol Part D Genomics Proteomics"},{"key":"2025010315525787400_etc3025-bib-0011","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1039\/B612802P","article-title":"Fish \u201cn\u201dchips: The use of microarrays for aquatic toxicology","volume":"3","author":"Denslow","year":"2007","journal-title":"Mol Biosyst"},{"key":"2025010315525787400_etc3025-bib-0012","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/toxsci\/kft178","article-title":"Incorporating new technologies into toxicity testing and risk assessment: Moving from 21st century vision to a data-driven framework","volume":"136","author":"Thomas","year":"2013","journal-title":"Toxicol Sci"},{"key":"2025010315525787400_etc3025-bib-0013","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ecoenv.2011.10.010","article-title":"Concentration-response concept in ecotoxicoproteomics: Effects of different phenanthrene concentrations to the zebrafish (Danio rerio) embryo proteome","volume":"76","author":"G\u00fcndel","year":"2012","journal-title":"Ecotoxicol Environ Saf"},{"key":"2025010315525787400_etc3025-bib-0014","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1093\/toxsci\/kfn083","article-title":"Automated quantitative dose-response modeling and point of departure determination for large toxicogenomic and high-throughput screening data sets","volume":"104","author":"Burgoon","year":"2008","journal-title":"Toxicol Sci"},{"key":"2025010315525787400_etc3025-bib-0015","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1186\/1471-2164-8-387","article-title":"BMDExpress: A software tool for the benchmark dose analyses of genomic data","volume":"8","author":"Yang","year":"2007","journal-title":"BMC Genomics"},{"key":"2025010315525787400_etc3025-bib-0016","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1002\/etc.5620200228","article-title":"A general best-fit method for concentration-response curves and the estimation of low-effect concentrations","volume":"20","author":"Scholze","year":"2001","journal-title":"Environ Toxicol Chem"},{"key":"2025010315525787400_etc3025-bib-0017","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1093\/toxsci\/kfm092","article-title":"A method to integrate benchmark dose estimates with genomic data to assess the functional effects of chemical exposure","volume":"98","author":"Thomas","year":"2007","journal-title":"Toxicol Sci"},{"key":"2025010315525787400_etc3025-bib-0018","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.mrgentox.2012.01.007","article-title":"Integrating pathway-based transcriptomic data into quantitative chemical risk assessment: A five chemical case study","volume":"746","author":"Thomas","year":"2012","journal-title":"Mutat Res"},{"key":"2025010315525787400_etc3025-bib-0019","first-page":"1","article-title":"Current approaches in the statistical analysis of ecotoxicity data: A guidance to application","volume":"33","author":"Organisation for Economic Co-operation and Development.","year":"2006","journal-title":"OECD Series on Testing and Assessment"},{"key":"2025010315525787400_etc3025-bib-0020","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1093\/toxsci\/62.2.330","article-title":"The frequency of U-shaped dose responses in the toxicological literature","volume":"62","author":"Calabrese","year":"2001","journal-title":"Toxicol Sci"},{"key":"2025010315525787400_etc3025-bib-0021","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.envpol.2007.04.019","article-title":"Is the integration of hormesis and essentiality into ecotoxicology now opening Pandora's Box?","volume":"151","author":"Kefford","year":"2008","journal-title":"Environ Pollut"},{"key":"2025010315525787400_etc3025-bib-0022","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.envpol.2004.10.001","article-title":"Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences","volume":"138","author":"Calabrese","year":"2005","journal-title":"Environ Pollut"},{"key":"2025010315525787400_etc3025-bib-0023","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1093\/toxsci\/kfq236","article-title":"Automated dose-response analysis and comparative toxicogenomic evaluation of the hepatic effects elicited by TCDD, TCDF, and PCB126 in C57BL\/6 mice","volume":"118","author":"Kopec","year":"2010","journal-title":"Toxicol Sci"},{"key":"2025010315525787400_etc3025-bib-0024","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/aja.1002030302","article-title":"Stages of embryonic development of the zebrafish","volume":"203","author":"Kimmel","year":"1995","journal-title":"Dev Dyn"},{"key":"2025010315525787400_etc3025-bib-0025","author":"Agilent Technologies.","year":"2015"},{"key":"2025010315525787400_etc3025-bib-0026","author":"National Center for Biotechnology Information.","year":"2015"},{"key":"2025010315525787400_etc3025-bib-0027","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nature Protoc"},{"key":"2025010315525787400_etc3025-bib-0028","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"2009","journal-title":"Nucl Acids Res"},{"key":"2025010315525787400_etc3025-bib-0029","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1007\/s12302-010-0171-0","article-title":"Myriophyllum spicatum als \u00f6kotoxikologischer Testorganismus: Methodenentwicklung eines sedimentfreien Testsystems und erste Ergebnisse mit 3,5-Dichlorphenol","volume":"22","author":"Maletzki","year":"2010","journal-title":"Umweltwissenschaften und Schadstoff-forsch"},{"key":"2025010315525787400_etc3025-bib-0030","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.aquabot.2012.03.017","article-title":"Spatial and temporal variation in metabolic fingerprints of field-growing Myriophyllum spicatum","volume":"102","author":"Riedl","year":"2012","journal-title":"Aquatic Botany"},{"key":"2025010315525787400_etc3025-bib-0031","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s11306-008-0139-x","article-title":"A metabolomics approach to assessing phytotoxic effects on the green alga Scenedesmus vacuolatus","volume":"5","author":"Kluender","year":"2009","journal-title":"Metabolomics"},{"key":"2025010315525787400_etc3025-bib-0032","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1021\/ac051437y","article-title":"XCMS: Processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification","volume":"78","author":"Smith","year":"2006","journal-title":"Anal Chem"},{"key":"2025010315525787400_etc3025-bib-0033","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1016\/j.marenvres.2009.12.004","article-title":"Anchoring metabolic changes to phenotypic effects in the chlorophyte Scenedesmus vacuolatus under chemical exposure","volume":"69","author":"Sans-Pich\u00e9","year":"2010","journal-title":"Mar Environ Res"},{"key":"2025010315525787400_etc3025-bib-0034","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s11306-010-0198-7","article-title":"Decision tree supported substructure prediction of metabolites from GC-MS profiles","volume":"6","author":"Hummel","year":"2010","journal-title":"Metabolomics"},{"key":"2025010315525787400_etc3025-bib-0035","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/0-387-29362-0_23","volume-title":"Bioinformatics and Computational Biology Solutions Using R and Bioconductor","author":"Smyth","year":"2005"},{"key":"2025010315525787400_etc3025-bib-0036","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc Ser B"},{"key":"2025010315525787400_etc3025-bib-0037","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1021\/es403899t","article-title":"Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays","volume":"48","author":"Escher","year":"2014","journal-title":"Environ Sci Technol"},{"key":"2025010315525787400_etc3025-bib-0038","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/9780470316757","volume-title":"Nonlinear Regression Analysis and Its Applications","author":"Bates","year":"1988"},{"key":"2025010315525787400_etc3025-bib-0039","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v012.i05","article-title":"Bioassay analysis using R","volume":"12","author":"Ritz","year":"2005","journal-title":"J Stat Softw"},{"key":"2025010315525787400_etc3025-bib-0040","author":"Bornkamp","year":"2014"},{"key":"2025010315525787400_etc3025-bib-0041","author":"Chongsuvivatwong","year":"2012"},{"key":"2025010315525787400_etc3025-bib-0042","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/bimj.200810425","article-title":"Simultaneous inference in general parametric models","volume":"50","author":"Hothorn","year":"2008","journal-title":"Biometrical J"},{"key":"2025010315525787400_etc3025-bib-0043","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","article-title":"A new look at the statistical model identification","volume":"19","author":"Akaike","year":"1974","journal-title":"IEEE Trans Automat Contrib"},{"key":"2025010315525787400_etc3025-bib-0044","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.scitotenv.2008.06.008","article-title":"Hormesis in mixtures: Can it be predicted?","volume":"404","author":"Belz","year":"2008","journal-title":"Sci Total Environ"},{"key":"2025010315525787400_etc3025-bib-0045","doi-asserted-by":"crossref","first-page":"e33432","DOI":"10.1371\/journal.pone.0033432","article-title":"Modeling effective dosages in hormetic dose-response studies","volume":"7","author":"Belz","year":"2012","journal-title":"PLoS One"},{"key":"2025010315525787400_etc3025-bib-0046","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/S0022-2496(02)00028-7","article-title":"Tutorial on maximum likelihood estimation","volume":"47","author":"Myung","year":"2003","journal-title":"J Math Psychol"},{"key":"2025010315525787400_etc3025-bib-0047","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4614-6396-2","volume-title":"Outlier Analysis","author":"Aggarwal","year":"2013"},{"key":"2025010315525787400_etc3025-bib-0048","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"Barretina","year":"2012","journal-title":"Nature"},{"key":"2025010315525787400_etc3025-bib-0049","doi-asserted-by":"crossref","first-page":"5410","DOI":"10.1021\/es200455p","article-title":"A new transcriptional effect level index (TELI) for toxicogenomics-based toxicity assessment","volume":"45","author":"Gou","year":"2011","journal-title":"Environ Sci Technol"},{"key":"2025010315525787400_etc3025-bib-0050","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.taap.2013.05.037","article-title":"Transcriptomic analysis on deh developing zebrafish embryoafter compound exposure: Individual gene expression and pathway regulation","volume":"272","author":"Hermsen","year":"2013","journal-title":"Toxicol Appl Pharmacol"},{"key":"2025010315525787400_etc3025-bib-0051","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/pmic.200900470","article-title":"Proteins in ecotoxicology: How, why and why not?","volume":"10","author":"Lemos","year":"2010","journal-title":"Proteomics"},{"key":"2025010315525787400_etc3025-bib-0052","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/0470867132.ch16","volume-title":"PAHs: An Ecotoxicological Perspect","author":"Altenburger","year":"2003"}],"container-title":["Environmental Toxicology and Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fetc.3025","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/etc\/article-pdf\/34\/9\/2167\/60112876\/etc3025.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/etc\/article-pdf\/34\/9\/2167\/60112876\/etc3025.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T20:20:29Z","timestamp":1747945229000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/etc\/article\/34\/9\/2167\/7761570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,21]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2015,4,21]]},"published-print":{"date-parts":[[2015,4,21]]}},"URL":"https:\/\/doi.org\/10.1002\/etc.3025","relation":{},"ISSN":["0730-7268","1552-8618"],"issn-type":[{"value":"0730-7268","type":"print"},{"value":"1552-8618","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,9,1]]},"published":{"date-parts":[[2015,4,21]]},"assertion":[{"value":"2014-10-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-04-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-08-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}