{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:08:44Z","timestamp":1790766524850,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:p>Hazard identification regarding adverse effects on the liver is a critical step in safety evaluations of drugs and other chemicals. Current testing paradigms for hepatotoxicity rely heavily on preclinical studies in animals and human data (epidemiology and clinical trials). Mechanistic understanding of the molecular and cellular pathways that may cause or exacerbate hepatotoxicity is well advanced and holds promise for identification of hepatotoxicants. One of the challenges in translating mechanistic evidence into robust decisions about potential hepatotoxicity is the lack of a systematic approach to integrate these data to help identify liver toxicity hazards. Recently, marked improvements were achieved in the practice of hazard identification of carcinogens, female and male reproductive toxicants, and endocrine disrupting chemicals using the key characteristics approach. Here, we describe the methods by which key characteristics of human hepatotoxicants were identified and provide examples for how they could be used to systematically identify, organize, and use mechanistic data when identifying hepatotoxicants.<\/jats:p>","DOI":"10.1002\/hep.31999","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T08:23:07Z","timestamp":1623226987000},"page":"3486-3496","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":82,"title":["Key Characteristics of Human Hepatotoxicants as a Basis for Identification and Characterization of the Causes of Liver Toxicity"],"prefix":"10.1097","volume":"74","author":[{"given":"Ivan","family":"Rusyn","sequence":"first","affiliation":[{"name":"Department of Veterinary Integrative Biosciences,Texas A&M University,College Station,TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xabier","family":"Arzuaga","sequence":"additional","affiliation":[{"name":"Center for Public Health and Environmental Assessment,Environmental Protection Agency,Washington,DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell C.","family":"Cattley","sequence":"additional","affiliation":[{"name":"Department of Pathobiology,Auburn University,Auburn,AL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Christopher","family":"Corton","sequence":"additional","affiliation":[{"name":"Center for Computational Toxicology and Exposure,Environmental Protection Agency,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"National Toxicology Program,National Institute of Environmental Health Sciences,Research Triangle Park,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"Godoy","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development,Roche Innovation Center Basel, F. Hoffmann\u2010La Roche Ltd.,Basel,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn Z.","family":"Guyton","sequence":"additional","affiliation":[{"name":"Monographs Programme,International Agency for Research on Cancer,Lyon,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Kaplowitz","sequence":"additional","affiliation":[{"name":"Research Center for Liver Disease,University of Southern California,Los Angeles,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5407-6743","authenticated-orcid":false,"given":"Salman R.","family":"Khetani","sequence":"additional","affiliation":[{"name":"Department of Bioengineering,University of Illinois at Chicago,Chicago,IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth A.","family":"Roberts","sequence":"additional","affiliation":[{"name":"ApconiX,Alderley Edge,United Kingdom"},{"name":"School of Biosciences,University of Birmingham,Birmingham,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Roth","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology,Michigan State University,East Lancing,MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyn T.","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Environmental Health Sciences,University of California Berkeley,Berkeley,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"hep31999-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/hep.31173","article-title":"Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD","volume":"72","year":"2020","journal-title":"Hepatology"},{"key":"hep31999-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jhep.2018.09.014","article-title":"Burden of liver diseases in the world","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep31999-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1080\/01926230590522121","article-title":"Do preclinical testing strategies help predict human hepatotoxic potentials?","volume":"33","year":"2005","journal-title":"Toxicol Pathol"},{"key":"hep31999-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s40572-019-00232-w","article-title":"Mechanisms of environmental contributions to fatty liver disease","volume":"6","year":"2019","journal-title":"Curr Environ Health Rep"},{"key":"hep31999-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/10937404.2019.1642586","article-title":"Concordance between sites of tumor development in humans and in experimental animals for 111 agents that are carcinogenic to humans","volume":"22","year":"2019","journal-title":"J Toxicol Environ Health B Crit Rev"},{"key":"hep31999-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.taap.2017.09.006","article-title":"Current nonclinical testing paradigm enables safe entry to first\u2010in\u2010human clinical trials: The IQ consortium nonclinical to clinical translational database","volume":"334","year":"2017","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep31999-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1289\/ehp.1509912","article-title":"Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis","volume":"124","year":"2016","journal-title":"Environ Health Perspect"},{"key":"hep31999-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.tips.2017.11.005","article-title":"Modernizing human cancer risk assessment of therapeutics","volume":"39","year":"2018","journal-title":"Trends Pharmacol Sci"},{"key":"hep31999-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"53P","DOI":"10.1042\/bj1300053P","article-title":"Mechanisms and consequences of the induction of microsomal enzymes of mammalian liver","volume":"130","year":"1972","journal-title":"Biochem J"},{"key":"hep31999-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1177\/0192623310373778","article-title":"Hepatic enzyme induction: histopathology","volume":"38","year":"2010","journal-title":"Toxicol Pathol"},{"key":"hep31999-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/s41575-018-0065-y","article-title":"Apoptosis and necroptosis in the liver: a matter of life and death","volume":"15","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep31999-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/j.2040-4603.2013.tb00507.x","article-title":"Apoptosis and necrosis in the liver","volume":"3","year":"2013","journal-title":"Compr Physiol"},{"key":"hep31999-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1053\/j.gastro.2014.07.018","article-title":"Cell death and cell death responses in liver disease: mechanisms and clinical relevance","volume":"147","year":"2014","journal-title":"Gastroenterology"},{"key":"hep31999-bib-0015-20250824","first-page":"984248","article-title":"Liver development, regeneration, and carcinogenesis","volume":"2010","year":"2010","journal-title":"J Biomed Biotechnol"},{"key":"hep31999-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0378-4274(01)00282-X","article-title":"Role of cytokines in non\u2010genotoxic hepatocarcinogenesis: cause or effect?","volume":"120","year":"2001","journal-title":"Toxicol Lett"},{"key":"hep31999-bib-0017-20250824","article-title":"Molecular mechanisms underlying chemical liver injury","volume":"14","year":"2012","journal-title":"Expert Rev Mol Med"},{"key":"hep31999-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1124\/dmd.114.057539","article-title":"The role of transporters in toxicity and disease","volume":"42","year":"2014","journal-title":"Drug Metab Dispos"},{"key":"hep31999-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1021\/tx034033e","article-title":"Mechanisms of troglitazone hepatotoxicity","volume":"16","year":"2003","journal-title":"Chem Res Toxicol"},{"key":"hep31999-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/toxsci\/65.2.166","article-title":"Mechanisms of hepatotoxicity","volume":"65","year":"2002","journal-title":"Toxicol Sci"},{"key":"hep31999-bib-0021-20250824","first-page":"2","article-title":"Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis","volume":"96","year":"2007","journal-title":"Toxicol Sci"},{"key":"hep31999-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s12072-018-9911-9","article-title":"DAMPs and sterile inflammation in drug hepatotoxicity","volume":"13","year":"2019","journal-title":"Hepatol Int"},{"key":"hep31999-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.3390\/ijms18051018","article-title":"Drug\u2010induced liver injury: cascade of events leading to cell death, apoptosis or necrosis","volume":"18","year":"2017","journal-title":"Int J Mol Sci"},{"key":"hep31999-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/toxsci\/kfq009","article-title":"Mechanisms of immune\u2010mediated liver injury","volume":"115","year":"2010","journal-title":"Toxicol Sci"},{"key":"hep31999-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/0016-5085(95)90032-2","article-title":"Liver cell necrosis: cellular mechanisms and clinical implications","volume":"108","year":"1995","journal-title":"Gastroenterology"},{"key":"hep31999-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.taap.2004.10.001","article-title":"Hepatic mitochondrial glutathione: transport and role in disease and toxicity","volume":"204","year":"2005","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep31999-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jhep.2006.06.004","article-title":"ER stress: can the liver cope?","volume":"45","year":"2006","journal-title":"J Hepatol"},{"key":"hep31999-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1002\/hep.29689","article-title":"New insights into the role and mechanism of c\u2010Jun\u2010N\u2010terminal kinase signaling in the pathobiology of liver diseases","volume":"67","year":"2018","journal-title":"Hepatology"},{"key":"hep31999-bib-0029-20250824","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1053\/j.gastro.2012.06.004","article-title":"A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches","volume":"143","year":"2012","journal-title":"Gastroenterology"},{"key":"hep31999-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/hep.24229","article-title":"Drug\u2010induced cholestasis","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep31999-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1002\/hep.28967","article-title":"Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep31999-bib-0032-20250824","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1002\/hep.23068","article-title":"The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice","volume":"50","year":"2009","journal-title":"Hepatology"},{"key":"hep31999-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/taap.1996.8074","article-title":"Selective protein covalent binding and target organ toxicity","volume":"143","year":"1997","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep31999-bib-0034-20250824","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1055\/s-0039-3399502","article-title":"Mechanotransduction in Liver Diseases","volume":"40","year":"2020","journal-title":"Semin Liver Dis"},{"key":"hep31999-bib-0035-20250824","doi-asserted-by":"crossref","first-page":"108445","DOI":"10.1016\/j.abb.2020.108445","article-title":"Liver fibrogenesis: un update on established and emerging basic concepts","volume":"689","year":"2020","journal-title":"Arch Biochem Biophys"},{"key":"hep31999-bib-0036-20250824","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jhep.2010.11.006","article-title":"Drug\u2010induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver","volume":"54","year":"2011","journal-title":"J Hepatol"},{"key":"hep31999-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3109\/03602532.2011.602688","article-title":"Oxidant stress, mitochondria, and cell death mechanisms in drug\u2010induced liver injury: lessons learned from acetaminophen hepatotoxicity","volume":"44","year":"2012","journal-title":"Drug Metab Rev"},{"key":"hep31999-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.taap.2014.01.004","article-title":"Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans","volume":"275","year":"2014","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep31999-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1080\/00365521.2017.1291719","article-title":"Drug\u2010induced liver injury due to antibiotics","volume":"52","year":"2017","journal-title":"Scand J Gastroenterol"},{"key":"hep31999-bib-0040-20250824","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1021\/acs.chemrestox.6b00253","article-title":"Amoxicillin and clavulanate form chemically and immunologically distinct multiple haptenic structures in patients","volume":"29","year":"2016","journal-title":"Chem Res Toxicol"},{"key":"hep31999-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.bbadis.2017.08.033","article-title":"Drug\u2010induced bile duct injury","volume":"1864","year":"2018","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"hep31999-bib-0042-20250824","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1177\/0192623312468517","article-title":"Toxicant\u2010associated steatohepatitis","volume":"41","year":"2013","journal-title":"Toxicol Pathol"},{"key":"hep31999-bib-0043-20250824","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.jcmgh.2015.05.006","article-title":"Alcoholic, nonalcoholic, and toxicant\u2010associated steatohepatitis: mechanistic similarities and differences","volume":"1","year":"2015","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"hep31999-bib-0044-20250824","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1177\/019262339802600510","article-title":"Mechanisms of ligand\u2010induced aryl hydrocarbon receptor\u2010mediated biochemical and toxic responses","volume":"26","year":"1998","journal-title":"Toxicol Pathol"},{"key":"hep31999-bib-0045-20250824","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3109\/10408444.2013.835787","article-title":"Mode of action and dose\u2010response framework analysis for receptor\u2010mediated toxicity: the aryl hydrocarbon receptor as a case study","volume":"44","year":"2014","journal-title":"Crit Rev Toxicol"},{"key":"hep31999-bib-0046-20250824","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1053\/j.gastro.2019.05.066","article-title":"Aryl hydrocarbon receptor signaling prevents activation of hepatic stellate cells and liver fibrogenesis in mice","volume":"157","year":"2019","journal-title":"Gastroenterology"},{"key":"hep31999-bib-0047-20250824","doi-asserted-by":"crossref","first-page":"122588","DOI":"10.1016\/j.jhazmat.2020.122588","article-title":"TCDD promotes liver fibrosis through disordering systemic and hepatic iron homeostasis","volume":"395","year":"2020","journal-title":"J Hazard Mater"},{"key":"hep31999-bib-0048-20250824","first-page":"556","article-title":"Implementing systematic review techniques in chemical risk assessment: challenges, opportunities and recommendations","volume":"92\u201093","year":"2016","journal-title":"Environ Int"},{"key":"hep31999-bib-0049-20250824","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1093\/carcin\/bgy031","article-title":"Application of the key characteristics of carcinogens in cancer hazard identification","volume":"39","year":"2018","journal-title":"Carcinogenesis"},{"key":"hep31999-bib-0050-20250824","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1039\/C2TX20051A","article-title":"In vitro models for liver toxicity testing","volume":"2","year":"2013","journal-title":"Toxicol Res (Camb)"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31999","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31999","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31999","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:06:23Z","timestamp":1756076783000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,13]]},"references-count":49,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31999","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,13]]},"assertion":[{"value":"2021-03-22","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-07","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}