{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T11:21:03Z","timestamp":1777634463668,"version":"3.51.4"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The hazards and potency of skin sensitizers are traditionally determined using animal tests such as the local lymph node assay (LLNA); however, significant progress has been made in the development of non\u2010animal test methods addressing the first three mechanistic key events of adverse outcome pathway in skin sensitization. We developed the epidermal sensitization assay (EpiSensA), which is a reconstructed human epidermis\u2010based assay, by measuring four genes related to critical keratinocyte responses during skin sensitization. Four in vitro skin sensitization test methods (EpiSensA, direct peptide reactivity assay [DPRA], KeratinoSens\u2122, and human cell line activation test [h\u2010CLAT]) were systematically evaluated using 136 chemicals including lipophilic chemicals and pre\/pro\u2010haptens, which may be related to assay\u2010specific limitations. The constructed database included existing and newly generated data. The EpiSensA showed a broader applicability domain and predicted the hazards with 82.4% and 78.8% accuracy than LLNA and human data. The EpiSensA could detect 76 out of 88 sensitizers at lower concentrations than the LLNA, indicating that the EpiSensA has higher sensitivity for the detection of minor sensitizing constituents. These results confirmed the potential use of the EpiSensA in evaluating a mixture of unknown compositions that can be evaluated by animal tests. To combine different information sources, the reconstructed human epidermis\u2010based testing strategy (RTS) was developed based on weighted multiple information from the EpiSensA and TImes MEtabolism Simulator platform for predicting Skin Sensitization (TIMES\u2010SS; RTSv1) or Organization for Economic Cooperation and Development (OECD) QSAR Toolbox automated workflow (RTSv2). The predictivities of the hazards and Globally Harmonized System (GHS) subcategories were equal to or better than the defined approaches (2 out of 3, integrated testing strategy [ITS]v1, and ITSv2) adopted as OECD Guideline 497.<\/jats:p>","DOI":"10.1002\/jat.4551","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T03:24:34Z","timestamp":1697513074000},"page":"415-427","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reconstructed human epidermis\u2010based testing strategy of skin sensitization potential and potency classification using epidermal sensitization assay and in silico data"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8778-1951","authenticated-orcid":false,"given":"Hideyuki","family":"Mizumachi","sequence":"first","affiliation":[{"name":"Safety Science Research Kao Corporation  Haga\u2010gun Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sho","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Safety Science Research Kao Corporation  Haga\u2010gun Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Sakuma","sequence":"additional","affiliation":[{"name":"Safety and Analytical Research Laboratories KOS\u00c9 Corporation  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Midori","family":"Natsui","sequence":"additional","affiliation":[{"name":"Safety Science Research Kao Corporation  Haga\u2010gun Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1488-4292","authenticated-orcid":false,"given":"Noriyasu","family":"Imai","sequence":"additional","affiliation":[{"name":"Safety and Analytical Research Laboratories KOS\u00c9 Corporation  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Miyazawa","sequence":"additional","affiliation":[{"name":"Safety Science Research Kao Corporation  Haga\u2010gun Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/DER.0000000000000304"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0536.2007.00944.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/DER.0000000000000003"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-1873.2005.00707.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2012.05.013"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.2788\/01803"},{"key":"e_1_2_7_8_1","unstructured":"Environmental Protection Agency. (2018).Interim Science Policy: Use of alternative approaches for skin sensitization as a replacement for laboratory animal testing."},{"key":"#cr-split#-e_1_2_7_9_1.1","unstructured":"European Union. (2009).Regulation"},{"key":"#cr-split#-e_1_2_7_9_1.2","unstructured":"(EC) No 1223\/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products. O. J vol 52. pp. 342."},{"key":"e_1_2_7_10_1","unstructured":"GHS. (2017).Globally Harmonized System (GHS) classification criteria for skin sensitization. Dated 2017\u201011\u201008.https:\/\/www.chemsafetypro.com\/Topics\/GHS\/GHS_classification_skin_sensitizer_LLNA_Guinea_pig_maximisation_test_Buehler.html(Accessed 8 May 2021)"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.3727\/105221610x12819686555015"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408444.2018.1429385"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2005.23683.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-015-1634-2"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2014.06.024"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.09.008"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2016.01.009"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2007.10.005"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.4076"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2011.01346.x"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm259"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2023.105333"},{"key":"e_1_2_7_23_1","unstructured":"NICEATM LLNA Database. 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