{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:40:05Z","timestamp":1786977605363,"version":"build-2736575974"},"reference-count":58,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T00:00:00Z","timestamp":1586908800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Janssen Pharmaceutical Companies of Johnson & Johnson"},{"name":"Johnson & Johnson Consumer, Inc, McNeil Consumer Healthcare Division"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acetaminophen, a nonmutagenic compound as previously concluded from bacteria, in vitro mammalian cell, and in vivo transgenic rat assays, presented a good profile as a nonmutagenic reference compound for use in the international multilaboratory\n                    <jats:italic>Pig\u2010a<\/jats:italic>\n                    assay validation. Acetaminophen was administered at 250, 500, 1,000, and 2,000\u2009mg\u00b7kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7day\n                    <jats:sup>\u22121<\/jats:sup>\n                    to male Sprague Dawley rats once daily in 3 studies (3\u2009days, 2\u2009weeks, and 1 month with a 1\u2010month recovery group). The 3\u2010Day and 1\u2010Month Studies included assessments of the micronucleus endpoint in peripheral blood erythrocytes and the comet endpoint in liver cells and peripheral blood cells in addition to the\n                    <jats:italic>Pig\u2010a<\/jats:italic>\n                    assay; appropriate positive controls were included for each assay. Within these studies, potential toxicity of acetaminophen was evaluated and confirmed by inclusion of liver damage biomarkers and histopathology. Blood was sampled pre\u2010treatment and at multiple time points up to Day 57.\n                    <jats:italic>Pig\u2010a<\/jats:italic>\n                    mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as CD59\u2010negative RBC and CD59\u2010negative RET frequencies, respectively. No increases in DNA damage as indicated through\n                    <jats:italic>Pig\u2010a<\/jats:italic>\n                    , micronucleus, or comet endpoints were seen in treated rats. All positive controls responded as appropriate. Data from this series of studies demonstrate that acetaminophen is not mutagenic in the rat\n                    <jats:italic>Pig\u2010a<\/jats:italic>\n                    model. These data are consistent with multiple studies in other nonclinical models, which have shown that acetaminophen is not mutagenic. At 1,000\u2009mg\u00b7kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7day\n                    <jats:sup>\u22121<\/jats:sup>\n                    , Cmax values of acetaminophen on Day 28 were 153,600\u2009ng\/ml and 131,500\u2009ng\/ml after single and repeat dosing, respectively, which were multiples over that of clinical therapeutic exposures (2.6\u20136.1 fold for single doses of 4,000\u2009mg and 1,000\u2009mg, respectively, and 11.5 fold for multiple dose of 4,000\u2009mg) (FDA 2002). Data generated were of high quality and valid for contribution to the international multilaboratory validation of the in vivo Rat\n                    <jats:italic>Pig\u2010a<\/jats:italic>\n                    Mutation Assay.\n                  <\/jats:p>","DOI":"10.1002\/em.22368","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T17:40:50Z","timestamp":1584553250000},"page":"508-525","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Testing of acetaminophen in support of the international multilaboratory in vivo rat\n                    <i>Pig\u2010a<\/i>\n                    assay validation trial"],"prefix":"10.1002","volume":"61","author":[{"given":"Bas\u2010jan","family":"van der Leede","sequence":"first","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandy","family":"Weiner","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Spring House, Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry","family":"Van Doninck","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"De Vlieger","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Schuermans","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fetene","family":"Tekle","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Geys","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein","family":"van Heerden","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"De Jonghe","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacky","family":"Van Gompel","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development  Beerse, Antwerp Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2007.10.010"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5742(97)00024-0"},{"issue":"2","key":"e_1_2_10_4_1","first-page":"21","article-title":"Genotoxic effect of paracetamol containing tablets in cultured human lymphocytes","volume":"1","author":"Arun T.","year":"2010","journal-title":"International Journal of Biomedical Research"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22122"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.2460\/javma.2001.218.669"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(94)90223-2"},{"key":"e_1_2_10_8_1","volume-title":"Belgian Law (October 18, 1991): Protection of vertebrate animals used for experimental and other scientific purposes. 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