{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:57:13Z","timestamp":1791331033662,"version":"4.3.1"},"reference-count":82,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,2,6]],"date-time":"2016-02-06T00:00:00Z","timestamp":1454716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non\u2010animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co\u2010operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using <jats:italic>in vitro<\/jats:italic>, <jats:italic>in chemico<\/jats:italic> and <jats:italic>in silico<\/jats:italic> information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h\u2010CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read\u2010across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty\u2010four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89\u201396% for the test set and 96\u201399% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non\u2010animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.<\/jats:p>","DOI":"10.1002\/jat.3281","type":"journal-article","created":{"date-parts":[[2016,2,6]],"date-time":"2016-02-06T02:38:07Z","timestamp":1454726287000},"page":"1150-1162","source":"Crossref","is-referenced-by-count":104,"title":["Integrated decision strategies for skin sensitization hazard"],"prefix":"10.1002","volume":"36","author":[{"given":"Judy","family":"Strickland","sequence":"first","affiliation":[{"name":"ILS  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingda","family":"Zang","sequence":"additional","affiliation":[{"name":"ILS  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Kleinstreuer","sequence":"additional","affiliation":[{"name":"ILS  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Paris","sequence":"additional","affiliation":[{"name":"ILS  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Lehmann","sequence":"additional","affiliation":[{"name":"EPA\/NHEERL\/EPHD\/CIB  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neepa","family":"Choksi","sequence":"additional","affiliation":[{"name":"ILS  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Matheson","sequence":"additional","affiliation":[{"name":"U.S. Consumer Product Safety Commission  Bethesda Maryland 20814 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Jacobs","sequence":"additional","affiliation":[{"name":"FDA\/CDER  Silver Spring Maryland 20993 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lowit","sequence":"additional","affiliation":[{"name":"EPA\/OCSPP\/OPP\/HED  Washington District of Columbia 20460 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Allen","sequence":"additional","affiliation":[{"name":"ILS  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren","family":"Casey","sequence":"additional","affiliation":[{"name":"NIH\/NIEHS\/DNTP\/NICEATM  Research Triangle Park North Carolina 27709 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,6]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"Title 29\u2010 Labor","author":"29 CFR 1910.1200","year":"2012"},{"key":"e_1_2_8_3_1","volume-title":"Title 40\u2010 Protection of Environment","author":"40 CFR 158.500","year":"2012"},{"key":"e_1_2_8_4_1","volume-title":"Title 40\u2010 Protection of Environment","author":"40 CFR 161.340","year":"2012"},{"key":"e_1_2_8_5_1","volume-title":"Title 16\u2010 Commercial Practices","author":"16 CFR 1500.3","year":"2014"},{"key":"e_1_2_8_6_1","unstructured":"AltTox.2014.Toxicity Endpoints & Tests: Skin Sensitization.http:\/\/alttox.org\/mapp\/toxicity\u2010endpoints\u2010tests\/skin\u2010sensitization\/[accessed 4 November 2015]."},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/424203"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2011.04.006"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/026119291003800403"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2005.10.012"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2011.05.007"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0278-6915(96)00059-2"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-31301-X_12"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2011.05.030"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2012.05.013"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.1206292"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.105.1.e3"},{"key":"e_1_2_8_18_1","first-page":"1","article-title":"Regulation (EC) No. 1907\/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999\/45\/EC and repealing Council Regulation (EEC) No. 793\/93 and Commission Regulation (EC) No. 1488\/94 as well as Council Directive 76\/769\/EEC and Commission Directives 91\/155\/EEC, 93\/67\/EEC, 93\/105\/EC and 2000\/21\/EC","volume":"396","author":"EC","year":"2006","journal-title":"OJ L"},{"key":"e_1_2_8_19_1","volume-title":"Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7a: Endpoint Specific Guidance (Version 4.0)","author":"ECHA","year":"2015"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2010.03.009"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx034093k"},{"key":"e_1_2_8_22_1","first-page":"26","article-title":"Directive 2003\/15\/EC of the European Parliament and of the Council of 27 February 2003 amending Council Directive 76\/768\/EEC on the approximation of the laws of the Member States relating to cosmetic products","volume":"66","author":"European Union","year":"2003","journal-title":"OJ L"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.2310\/6620.2005.05040"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfp192"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh213"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm064"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2986"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3105"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2869"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.2011.3.211"},{"key":"e_1_2_8_31_1","volume-title":"EURL ECVAM Recommendation on the Direct Peptide Reactivity Assay (DPRA) for Skin Sensitisation Testing","author":"Joint Research Centre of the European Union","year":"2013"},{"key":"e_1_2_8_32_1","volume-title":"EURL ECVAM Recommendation on the KeratinoSens\u2122 assay for skin sensitisation testing","author":"Joint Research Centre of the European Union","year":"2014"},{"key":"e_1_2_8_33_1","volume-title":"EURL ECVAM Recommendation on the human Cell Line Activation Test (h\u2010CLAT) for skin sensitisation testing","author":"Joint Research Centre of the European Union","year":"2015"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.2310\/6620.2009.09038"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq346"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2008.01.019"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-6849-3"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3172"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.2013.4.473"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-012-0867-6"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1080\/000155598442728"},{"key":"e_1_2_8_42_1","volume-title":"Janeway's Immunobiology","author":"Murphy K","year":"2012"},{"key":"e_1_2_8_43_1","first-page":"265","volume-title":"Reducing, Refining and Replacing the Use of Animals in Toxicity Testing","author":"Natsch A","year":"2014"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm259"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfn204"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kft160"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2868"},{"key":"e_1_2_8_48_1","first-page":"68076","article-title":"Request for Information on Alternative Skin Sensitization Test Methods and Testing Strategies and for Comment on ICCVAM's Proposed Activities","volume":"78","author":"NIEHS","year":"2013","journal-title":"Fed. Regist."},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2012.07.001"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0536.2011.01952.x"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2012.11.006"},{"key":"e_1_2_8_52_1","volume-title":"OECD Series on Testing and Assessment No. 102. Guidance Document for Using the OECD (Q)SAR Application Toolbox to Develop Chemical Categories According to the OECD Guidance on Grouping of Chemicals","author":"OECD","year":"2009"},{"key":"e_1_2_8_53_1","volume-title":"OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects","author":"OECD","year":"2010"},{"key":"e_1_2_8_54_1","volume-title":"The Adverse Outcome Pathway for Skin Sensitisation Initated by Covalent Binding to Proteins. Part 2: Use of the AOP to Develop Chemical Categories and Integrated Assessment and Testing Approaches","author":"OECD","year":"2012"},{"key":"e_1_2_8_55_1","volume-title":"The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins. Part 1: Scientific Assessment","author":"OECD","year":"2012"},{"key":"e_1_2_8_56_1","unstructured":"OECD.2014.The OECD QSAR Toolbox.http:\/\/www.oecd.org\/chemicalsafety\/risk\u2010assessment\/theoecdqsartoolbox.htm[accessed 24 November 2014]"},{"key":"e_1_2_8_57_1","unstructured":"OECD.2015a.Draft Proposal for a New Test Guideline. In Vitro Skin Sensitisation: Human Cell Line Activation Test (h\u2010CLAT).http:\/\/www.oecd.org\/env\/ehs\/testing\/Draft\u2010Proposal\u2010for\u2010a\u2010new\u2010Test\u2010Guideline\u2010on\u2010in\u2010vitro\u2010skin\u2010sensitisation\u2010h\u2010CLAT.pdf[accessed 12 August 2015]."},{"key":"e_1_2_8_58_1","volume-title":"OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects","author":"OECD","year":"2015"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1787\/9789264229822-en"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2014.06.001"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.1310151"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2014.10.018"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.1289"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.1411011"},{"key":"e_1_2_8_65_1","volume-title":"The Principles of Humane Experimental Technique","author":"Russell WMS","year":"1992"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1006\/rtph.2001.1496"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2010.05.012"},{"key":"e_1_2_8_68_1","first-page":"653","article-title":"Immunology of metal allergies","volume":"13","author":"Schmidt M","year":"2015","journal-title":"Journal of the German Society of Dermatology"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1080\/10937404.2010.483938"},{"key":"e_1_2_8_70_1","volume-title":"Allergic Contact Dermatitis. Chemical and Metabolic Mechanisms","author":"Smith CK","year":"2001"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3127"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.2131\/jts.38.599"},{"key":"e_1_2_8_73_1","volume-title":"R: A Language and Environment for Statistical Computing. Reference Index","author":"The R Core Team","year":"2013"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0536.2007.01220.x"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2014.01.003"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.18356\/dbde9a22-en"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2014.12.008"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2014.04.018"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-483X(00)00165-7"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1159\/000093248"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440903036056"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2983"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci500667v"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjat.3281","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3281","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T12:30:59Z","timestamp":1760531459000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.3281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,6]]},"references-count":82,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2016,9]]}},"alternative-id":["10.1002\/jat.3281"],"URL":"https:\/\/doi.org\/10.1002\/jat.3281","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,6]]}}}