{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:33:51Z","timestamp":1784259231583,"version":"3.55.0"},"reference-count":7,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T00:00:00Z","timestamp":1600819200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T00:00:00Z","timestamp":1600819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["031L0117"],"award-info":[{"award-number":["031L0117"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["031L0117"],"award-info":[{"award-number":["031L0117"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["031L0117"],"award-info":[{"award-number":["031L0117"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["031L0119"],"award-info":[{"award-number":["031L0119"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["031L0119"],"award-info":[{"award-number":["031L0119"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["681002 (EU-Tox Risk)"],"award-info":[{"award-number":["681002 (EU-Tox Risk)"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["825759 (ENDpoiNTs)"],"award-info":[{"award-number":["825759 (ENDpoiNTs)"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016378","name":"Technische Universit\u00e4t Dortmund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100016378","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In cell biology, pharmacology and toxicology dose-response and concentration-response curves are frequently fitted to data with statistical methods. Such fits are used to derive quantitative measures (e.g. EC<jats:inline-formula><jats:alternatives><jats:tex-math>$$_{20}$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n<mml:msub>\n<mml:mrow\/>\n<mml:mn>20<\/mml:mn>\n<\/mml:msub>\n<\/mml:math><\/jats:alternatives><\/jats:inline-formula> values) describing the relationship between the concentration of a compound or the strength of an intervention applied to cells and its effect on viability or function of these cells. Often, a reference, called negative control (or solvent control), is used to normalize the data. The negative control data sometimes deviate from the values measured for low (ineffective) test compound concentrations. In such cases, normalization of the data with respect to control values leads to biased estimates of the parameters of the concentration-response curve. Low quality estimates of effective concentrations can be the consequence. In a literature study, we found that this problem occurs in a large percentage of toxicological publications. We propose different strategies to tackle the problem, including complete omission of the controls. Data from a controlled simulation study indicate the best-suited problem solution for different data structure scenarios. This was further exemplified by a real concentration-response study. We provide the following recommendations how to handle deviating controls: (1) The log-logistic 4pLL model is a good default option. (2) When there are at least two concentrations in the no-effect range, low variances of the replicate measurements, and deviating controls, control values should be omitted before fitting the model. (3) When data are missing in the no-effect range, the Brain-Cousens model sometimes leads to better results than the default model.<\/jats:p>","DOI":"10.1007\/s00204-020-02913-0","type":"journal-article","created":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T13:02:55Z","timestamp":1600866175000},"page":"3787-3798","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Handling deviating control values in concentration-response curves"],"prefix":"10.1007","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8066-5333","authenticated-orcid":false,"given":"Franziska","family":"Kappenberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Brecklinghaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Albrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Blum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"van der Wurp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan G.","family":"Hengstler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Rahnenf\u00fchrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,23]]},"reference":[{"key":"2913_CR1","doi-asserted-by":"crossref","unstructured":"Albrecht W, Kappenberg F, Brecklinghaus T, Stoeber R, Marchan R, Zhang M, Ebbert K, Kirschner H, Grinberg M, Leist M, Moritz W, Cadenas C, Ghallab A, Reinders J, Vartak N, van Thriel C, Golka K, Tolosa L, Castell J, Damm G, Seehofer D, Lampen A, Braeuning A, Buhrke T, Behr A-C, Oberemm A, Gu X, Kittana N, van de Water B, Kreiling R, Fayyaz S, van Aerts L, Smedsr\u00f8d B, Ellinger-Ziegelbauer H, Steger-Hartmann T, Gundert-Remy U, Zeigerer A, Ullrich At, Runge D, Lee SML, Schiergens TS, Kuepfer L, Aguayo-Orozco A, Sachinidis A, Edlund K, Gardner I, Rahnenf\u00fchrer J, Hengstler JG (2019) Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations. Archives of Toxicology 93(6)","DOI":"10.1007\/s00204-019-02492-9"},{"key":"2913_CR2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/j.1365-3180.1989.tb00845.x","volume":"29","author":"P Brain","year":"1989","unstructured":"Brain P, Cousens RD (1989) An equation to describe dose responses where there is stimulation of growth at low dose. Weed Res 29:93\u201396","journal-title":"Weed Res"},{"key":"2913_CR3","doi-asserted-by":"crossref","unstructured":"Gu X, Albrecht W, Edlund K, Kappenberg F, Rahnenf\u00fchrer J, Leist M, Moritz W, Godoy P, Cadenas C, Marchan R, Brecklinghaus T, Pardo LT, Castell J, Gardner I, Han B, Hengstler JG, Stoeber R (2018) Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes. Arch Toxicol 92(12)","DOI":"10.1007\/s00204-018-2302-0"},{"key":"2913_CR4","doi-asserted-by":"crossref","unstructured":"Krebs A, Nyffeler J, Rahnenf\u00fchrer J, Leist M (2018) Normalization of data for viability and relative cell function curves. ALTEX Altern Anim Exp 35(2)","DOI":"10.14573\/1803231"},{"key":"2913_CR5","unstructured":"R Development Core Team, R (2018) A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna"},{"issue":"1","key":"2913_CR6","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1002\/etc.7","volume":"29","author":"C Ritz","year":"2010","unstructured":"Ritz C (2010) Toward a unified approach to dose-response modeling in ecotoxicology. Environ Toxicol Chem 29(1):220\u2013229","journal-title":"Environ Toxicol Chem"},{"key":"2913_CR7","doi-asserted-by":"crossref","unstructured":"Ritz C, Baty F, Streibig JC, Gerhard D (2015) Dose-Response Analysis Using R. PLoS One 10","DOI":"10.1371\/journal.pone.0146021"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-020-02913-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-020-02913-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-020-02913-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T00:50:21Z","timestamp":1632358221000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-020-02913-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,23]]},"references-count":7,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2020,11]]}},"alternative-id":["2913"],"URL":"https:\/\/doi.org\/10.1007\/s00204-020-02913-0","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,23]]},"assertion":[{"value":"28 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}