{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:34:32Z","timestamp":1789929272758,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,9,16]],"date-time":"2018-09-16T00:00:00Z","timestamp":1537056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Japan Chemical Industry Association","award":["16_s01-02-2"],"award-info":[{"award-number":["16_s01-02-2"]}]},{"name":"The Japanese Society for Alternatives to Animal Experiments"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The amino acid derivative reactivity assay (ADRA) is an in chemico alternative to animal testing for skin sensitization that solves certain problems found in the use of the direct peptide reactivity assay (DPRA). During a recent validation study conducted at multiple laboratories as part of the process to include ADRA in an existing OECD test guideline, one of the nucleophilic reagents used in ADRA\u2014<jats:italic>N<\/jats:italic>\u2010(2\u2010(1\u2010naphthyl)acetyl)\u2010<jats:sc>l<\/jats:sc>\u2010cysteine (NAC)\u2014was found to be susceptible to oxidation in much the same manner that the cysteine peptide used in DPRA was. Owing to this, we undertook a study to clarify the cause of the promotion of NAC oxidation. In general, cysteine and other chemicals that have thiol groups are known to oxidize in the presence of even minute quantities of metal ions. When metal ions were added to the ADRA reaction solution, Cu<jats:sup>2+<\/jats:sup> promoted NAC oxidation significantly. When 0.25\u00a0\u03bc<jats:sc>m<\/jats:sc> of EDTA was added in the presence of Cu<jats:sup>2+<\/jats:sup>, NAC oxidation was suppressed. Based on this, we predicted that the addition of EDTA to the NAC stock solution would suppress NAC oxidation. Next, we tested 82 chemicals used in developing ADRA to determine whether EDTA affects ADRA's ability to predict sensitization. The results showed that the addition of EDTA has virtually no effect on the reactivity of NAC with a test chemical, yielding an accuracy of 87% for predictions of skin sensitization, which was roughly the same as ADRA.<\/jats:p>","DOI":"10.1002\/jat.3707","type":"journal-article","created":{"date-parts":[[2018,9,16]],"date-time":"2018-09-16T22:45:36Z","timestamp":1537137936000},"page":"191-208","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Cause of and countermeasures for oxidation of the cysteine\u2010derived reagent used in the amino acid derivative reactivity assay"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4345-1154","authenticated-orcid":false,"given":"Masaharu","family":"Fujita","sequence":"first","affiliation":[{"name":"Fujifilm Corporation, Safety Evaluation Centre  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Fujifilm Corporation, Safety Evaluation Centre  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Lion Corporation, Human &amp; Environmental Safety Evaluation Center  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsunetsugu","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Lion Corporation, Human &amp; Environmental Safety Evaluation Center  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Wakabayashi","sequence":"additional","affiliation":[{"name":"Mitsui Chemicals, Inc. Chemical Safety Department  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Tahara","sequence":"additional","affiliation":[{"name":"Mitsui Chemicals, Inc. Chemical Safety Department  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Horie","sequence":"additional","affiliation":[{"name":"Sumitomo Chemical Co., Ltd. Environmental Health Science Laboratory  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Sumitomo Chemical Co., Ltd. Environmental Health Science Laboratory  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Kusakari","sequence":"additional","affiliation":[{"name":"Nissan Chemical Corporation, Biological Research Laboratories  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Kurokawa","sequence":"additional","affiliation":[{"name":"Nissan Chemical Corporation, Biological Research Laboratories  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Kawakami","sequence":"additional","affiliation":[{"name":"National Institute of Health Sciences Division of Environmental Chemistry  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohichi","family":"Kojima","sequence":"additional","affiliation":[{"name":"Food and Drug Safety Center Hatano Research Institute  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Kojima","sequence":"additional","affiliation":[{"name":"National Institute of Health Sciences Biological Safety Research Center, Division of Risk Assessment  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ono","sequence":"additional","affiliation":[{"name":"Okayama University, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Division of Pharmaceutical Sciences  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Katsuoka","sequence":"additional","affiliation":[{"name":"Fujifilm Corporation, Safety Evaluation Centre  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideto","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Fujifilm Corporation, Research &amp; Development Management Headquarters Analysis Technology Center  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Fujifilm Corporation, Research &amp; Development Management Headquarters Analysis Technology Center  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Kasahara","sequence":"additional","affiliation":[{"name":"Fujifilm Corporation, Safety Evaluation Centre  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,9,16]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfp030"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(07)23002-2"},{"key":"e_1_2_6_4_1","unstructured":"Casati S. Aschberger K. Asturiol D. Basketter D. Dimitrov S. Dumont C. \u2026Worth A.(2016)Ability of non\u2010animal methods for skin sensitisation to detect pre\u2010 and pro\u2010haptens\u2014Report and Recommendations of an EURL ECVAM Expert Meeting. Available athttps:\/\/eurl\u2010ecvam.jrc.ec.europa.eu\/eurl\u2010ecvam\u2010status\u2010reports\/pre\u2010prohapten\u2010workshop\u2010report"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2002.02851.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R113.462929"},{"key":"e_1_2_6_7_1","volume-title":"Allergic Contact Dermatitis to Simple Chemicals: A Molecular Approach","author":"Dupuis G.","year":"1982"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.3891\/acta.chem.scand.43-0177"},{"key":"e_1_2_6_9_1","volume-title":"The chemistry and biochemistry of the sulfhydryl group in amino acids, peptides, and proteins","author":"Friedman M.","year":"1973"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2014.06.001"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfh213"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm064"},{"key":"e_1_2_6_13_1","volume-title":"Quantitative Chemical Analysis","author":"Harris D. C.","year":"2010"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj0181009"},{"key":"e_1_2_6_15_1","article-title":"Oxidation of thiols by oxygen catalysed by copper(II)ions or vitamin B12 Eindhoven","author":"Kuijpers F. P. J.","year":"1974","journal-title":"Technische Hogeschool Eindhoven"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.64.4.625"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.64.5.717"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-80331-4"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/152308603768295168"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/psc.1100"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/es702420h"},{"key":"e_1_2_6_22_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0021-9258(18)91608-X","article-title":"The action of metals and strong salt solutions on the spontaneous oxidation of cystein","volume":"6","author":"Mathews A. P.","year":"1909","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp508308y"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj0240472"},{"key":"e_1_2_6_25_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S0021-9258(20)79958-8","article-title":"Oxidation\u2010reduction systems of biological significance: I. The reduction potential of cysteine: Its measurement and significance","volume":"79","author":"Michaelis L.","year":"1928","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2003.12.015"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4973"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1179\/135100001101536427"},{"key":"e_1_2_6_29_1","first-page":"203","volume-title":"Organic Sulfur Chemistry: Structure and Mechanism","author":"Oae S.","year":"1991"},{"key":"e_1_2_6_30_1","unstructured":"OECD. (2012a).Direct Peptide Reactivity Assay (DPRA) ECVAM Validation Study Report Institute for Health and Consumer Protection European Union Reference Laboratory for Alternative Methods to Animal Testing (ECVAM); Available at:https:\/\/eurl\u2010ecvam.jrc.ec.europa.eu\/eurl\u2010ecvam\u2010recommendations\/files\u2010dpra\/DPRA%20Validation%20Study%20Report.pdf"},{"key":"e_1_2_6_31_1","unstructured":"OECD. (2012b).The Adverse Outcome Pathway for Skin Sensitization Initiated by Covalent Binding to Proteins; Available at:http:\/\/www.oecd.org\/env\/the\u2010adverse\u2010outcome\u2010pathway\u2010for\u2010skin\u2010sensitisation\u2010initiated\u2010by\u2010covalent\u2010binding\u2010to\u2010proteins\u20109789264221444\u2010en.htm"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi1008694"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.1289"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-4203(00)00027-X"},{"key":"e_1_2_6_35_1","doi-asserted-by":"crossref","unstructured":"Saul P.(1993).Sulphur\u2010Containing Functional Groups (1993): PATAI'S Chemistry of Functional Groups.https:\/\/doi.org\/10.1002\/9780470034408","DOI":"10.1002\/9780470034408"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(75)90272-7"},{"issue":"9","key":"e_1_2_6_37_1","first-page":"935","article-title":"Addition of bisulfite ions to methyl vinyl ketone and methacrolein relevant to atmospheric processes","volume":"20","author":"Szmigielski R.","year":"2013","journal-title":"Ecological Chemistry and Engineering A"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00017a044"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2015.11.045"},{"key":"e_1_2_6_40_1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S0021-9258(18)76452-1","article-title":"The oxidation catalysis of crystalline glutathione with particular reference to copper","volume":"93","author":"Voegtlin C.","year":"1931","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja01073a039"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2013.03.031"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3139"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjat.3707","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3707","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T19:05:48Z","timestamp":1760555148000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.3707"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,16]]},"references-count":42,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1002\/jat.3707"],"URL":"https:\/\/doi.org\/10.1002\/jat.3707","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,16]]},"assertion":[{"value":"2017-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}