{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T14:18:55Z","timestamp":1793456335834,"version":"4.5.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A breakthrough in oncology research was the discovery of doxorubicin (Dox) in the 1960\u2019s. Unlike other chemotherapy drugs, Dox was determined to have a greater therapeutic index. Since its discovery, Dox has, in part, contributed to the 5\u201310-year survival increase in cancer patient outcomes. Unfortunately, despite its efficacy, both in adult and pediatric cancers, the clinical significance of Dox is tainted by its adverse side effects, which usually manifest as cardiotoxicity. The issue stems from Dox\u2019s lack of specificity which prevents it from accurately distinguishing between cancer cells and healthy cell lines, like cardiomyocytes. In addition, the high binding affinity of Dox to topoisomerases, which are abundantly found in cancer and cardiac cells in different isoforms, potentiates DNA damage. In both cell lines, Dox induces cytotoxicity by stimulating the production of pro-oxidants whilst inhibiting antioxidant enzymatic activity. Given that the cardiac muscle has an inherently low antioxidant capacity makes it susceptible to oxidative damage thereby, allowing the accumulation of Dox within the myocardium. Subsequently, Dox drives the activation of cell death pathways, such as ferroptosis, necroptosis and apoptosis by triggering numerous cellular responses that have been implicated in diseases. To date, the exact mechanism by which Dox induces the cardiotoxicity remains an aspect of much interest in cardio-oncology research. Hence, the current review summarizes the proposed mechanisms that are associated with the onset and progression of DIC.<\/jats:p>","DOI":"10.1007\/s00204-022-03262-w","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T05:03:08Z","timestamp":1648184588000},"page":"1541-1550","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: a graphical representation"],"prefix":"10.1007","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8400-3967","authenticated-orcid":false,"given":"Nonhlakanipho F.","family":"Sangweni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwazi","family":"Gabuza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Huisamen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Mabasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derick","family":"van Vuuren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabia","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"3262_CR1","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1038\/s41598-018-37862-3","volume":"9","author":"CS Abdullah","year":"2019","unstructured":"Abdullah CS, Alam S, Aishwarya R, Miriyala S, Bhuiyan MAN, Panchatcharam M, Pattillo CB, Orr AW, Sadoshima J, Hill JA, Bhuiyan MdS (2019) Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration. Sci Rep 9:2002. https:\/\/doi.org\/10.1038\/s41598-018-37862-3","journal-title":"Sci Rep"},{"key":"3262_CR100","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1038\/emboj.2010.43","volume":"29","author":"C Artus","year":"2010","unstructured":"Artus C, Boujrad H, Bouharrour A, Brunelle M-N, Hoos S, Yuste VJ, Lenormand P, Rousselle J-C, Namane A, England P, Lorenzo HK, Susin SA (2010) AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX. EMBO J 29:1585\u20131599. https:\/\/doi.org\/10.1038\/emboj.2010.43","journal-title":"EMBO J"},{"key":"3262_CR3","doi-asserted-by":"publisher","first-page":"2950","DOI":"10.1038\/s41598-019-39588-2","volume":"9","author":"AH Barczewski","year":"2019","unstructured":"Barczewski AH, Ragusa MJ, Mierke DF, Pellegrini M (2019) The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface. Sci Rep 9:2950. https:\/\/doi.org\/10.1038\/s41598-019-39588-2","journal-title":"Sci Rep"},{"key":"3262_CR4","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.3390\/cells9061451","volume":"9","author":"S Bose","year":"2020","unstructured":"Bose S, Banerjee S, Mondal A, Chakraborty U, Pumarol J, Croley CR, Bishayee A (2020) Targeting the JAK\/STAT signaling pathway using phytocompounds for cancer prevention and therapy. Cells 9:1451. https:\/\/doi.org\/10.3390\/cells9061451","journal-title":"Cells"},{"key":"3262_CR5","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s12013-011-9153-0","volume":"60","author":"M-B Chen","year":"2011","unstructured":"Chen M-B, Wu X-Y, Gu J-H, Guo Q-T, Shen W-X, Lu P-H (2011) Activation of AMP-activated protein kinase contributes to doxorubicin-induced cell death and apoptosis in cultured myocardial H9c2 cells. Cell Biochem Biophys 60:311\u2013322. https:\/\/doi.org\/10.1007\/s12013-011-9153-0","journal-title":"Cell Biochem Biophys"},{"key":"3262_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2018.04.009","volume":"348","author":"T Cunha-Oliveira","year":"2018","unstructured":"Cunha-Oliveira T, Ferreira LL, Coelho AR, Deus CM, Oliveira PJ (2018) Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol 348:1\u201313. https:\/\/doi.org\/10.1016\/j.taap.2018.04.009","journal-title":"Toxicol Appl Pharmacol"},{"key":"3262_CR7","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.brainres.2009.05.029","volume":"1286","author":"VV Dukhande","year":"2009","unstructured":"Dukhande VV, Isaac AO, Chatterji T, Lai JCK (2009) Reduced glutathione regenerating enzymes undergo developmental decline and sexual dimorphism in the rat cerebral cortex. Brain Res 1286:19\u201324. https:\/\/doi.org\/10.1016\/j.brainres.2009.05.029","journal-title":"Brain Res"},{"key":"3262_CR8","doi-asserted-by":"publisher","first-page":"455","DOI":"10.4103\/1673-5374.266054","volume":"15","author":"E Font-Belmonte","year":"2019","unstructured":"Font-Belmonte E, Gonz\u00e1lez-Rodr\u00edguez P, Fern\u00e1ndez-L\u00f3pez A (2019) Necroptosis in global cerebral ischemia: a role for endoplasmic reticulum stress. Neural Regen Res 15:455\u2013456. https:\/\/doi.org\/10.4103\/1673-5374.266054","journal-title":"Neural Regen Res"},{"key":"3262_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1096\/fj.03-0331fje","volume":"17","author":"M Fuchs","year":"2003","unstructured":"Fuchs M, Hilfiker A, Kaminski K, Hilfiker-Kleiner D, Guener Z, Klein G, Podewski E, Schieffer B, Rose-John S, Drexler H (2003) Role of interleukin-6 for left ventricular remodeling and survival after experimental myocardial infarction. FASEB J 17:1\u201320. https:\/\/doi.org\/10.1096\/fj.03-0331fje","journal-title":"FASEB J"},{"key":"3262_CR10","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1007\/s00395-008-0728-x","volume":"103","author":"BN Fuglesteg","year":"2008","unstructured":"Fuglesteg BN, Suleman N, Tiron C, Kanhema T, Lacerda L, Andreasen TV, Sack MN, Jonassen AK, Mj\u00f8s OD, Opie LH, Lecour S (2008) Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion. Basic Res Cardiol 103:444. https:\/\/doi.org\/10.1007\/s00395-008-0728-x","journal-title":"Basic Res Cardiol"},{"key":"3262_CR12","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","volume":"25","author":"L Galluzzi","year":"2018","unstructured":"Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FK-M, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D\u2019Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin K-M, DeBerardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, Garc\u00eda-S\u00e1ez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, J\u00e4\u00e4ttel\u00e4 M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, L\u00f3pez-Ot\u00edn C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine J-C, Martin SJ, Martinou J-C, Medema JP, Mehlen P, Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, Mu\u00f1oz-Pinedo C, Nagata S, Nu\u00f1ez G, Oberst A, Oren M, Overholtzer M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon H-U, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486\u2013541. https:\/\/doi.org\/10.1038\/s41418-017-0012-4","journal-title":"Cell Death Differ"},{"key":"3262_CR14","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1084\/jem.20051556","volume":"203","author":"A Golks","year":"2006","unstructured":"Golks A, Brenner D, Krammer PH, Lavrik IN (2006) The c-FLIP\u2013NH2 terminus (p22-FLIP) induces NF-\u03baB activation. J Exp Med 203:1295\u20131305. https:\/\/doi.org\/10.1084\/jem.20051556","journal-title":"J Exp Med"},{"key":"3262_CR15","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1161\/CIRCRESAHA.110.226928","volume":"108","author":"JW Gordon","year":"2011","unstructured":"Gordon JW, Shaw JA, Kirshenbaum LA (2011) Multiple facets of NF-\u03baB in the heart: to be or not to NF-\u03baB. Circ Res 108:1122\u20131132. https:\/\/doi.org\/10.1161\/CIRCRESAHA.110.226928","journal-title":"Circ Res"},{"key":"3262_CR16","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3389\/fcvm.2019.00150","volume":"6","author":"Z Harhous","year":"2019","unstructured":"Harhous Z, Booz GW, Ovize M, Bidaux G, Kurdi M (2019) An Update on the Multifaceted Roles of STAT3 in the Heart. Frontiers in Cardiovascular Medicine 6:150. https:\/\/doi.org\/10.3389\/fcvm.2019.00150","journal-title":"Frontiers in Cardiovascular Medicine"},{"key":"3262_CR17","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.3390\/molecules22101589","volume":"22","author":"R Johnson","year":"2017","unstructured":"Johnson R, Shabalala S, Louw J, Kappo AP, Muller CJF (2017) Aspalathin reverts doxorubicin-induced cardiotoxicity through increased autophagy and decreased expression of p53\/mTOR\/p62 signaling. Molecules 22:1589. https:\/\/doi.org\/10.3390\/molecules22101589","journal-title":"Molecules"},{"key":"3262_CR19","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1111\/j.1742-4658.2010.07975.x","volume":"278","author":"I Kitazumi","year":"2011","unstructured":"Kitazumi I, Tsukahara M (2011) Regulation of DNA fragmentation: the role of caspases and phosphorylation. FEBS J 278:427\u2013441. https:\/\/doi.org\/10.1111\/j.1742-4658.2010.07975.x","journal-title":"FEBS J"},{"key":"3262_CR20","doi-asserted-by":"publisher","unstructured":"Koleini, N., Kardami, E., 2017. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Oncotarget 8, 46663\u201346680. https:\/\/doi.org\/10.18632\/oncotarget.16944","DOI":"10.18632\/oncotarget.16944"},{"key":"3262_CR21","doi-asserted-by":"publisher","unstructured":"Liu, D., Ma, Z., Xu, L., Zhang, X., Qiao, S., Yuan, J., 2019. PGC1\u03b1 activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades. Aging (Albany NY) 11, 10061\u201310073. https:\/\/doi.org\/10.18632\/aging.102418","DOI":"10.18632\/aging.102418"},{"key":"3262_CR22","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/616149","volume":"2014","author":"C Loreto","year":"2014","unstructured":"Loreto C, La Rocca G, Anzalone R, Caltabiano R, Vespasiani G, Castorina S, Ralph DJ, Cellek S, Musumeci G, Giunta S, Djinovic R, Basic D, Sansalone S (2014) The role of intrinsic pathway in apoptosis activation and progression in peyronie\u2019s disease. Biomed Res Int 2014:e616149. https:\/\/doi.org\/10.1155\/2014\/616149","journal-title":"Biomed Res Int"},{"key":"3262_CR23","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s13046-018-0772-9","volume":"37","author":"HJ Park","year":"2018","unstructured":"Park HJ, Bae JS, Kim KM, Moon YJ, Park S-H, Ha SH, Hussein UK, Zhang Z, Park HS, Park B-H, Moon WS, Kim JR, Jang KY (2018) The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma. J Exp Clin Cancer Res 37:107. https:\/\/doi.org\/10.1186\/s13046-018-0772-9","journal-title":"J Exp Clin Cancer Res"},{"key":"3262_CR25","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.15943","volume":"13","author":"E Proskuriakova","year":"2021","unstructured":"Proskuriakova E, Jada K, Kakieu Djossi S, Khedr A, Neupane B, Mostafa JA (2021) Mechanisms and potential treatment options of heart failure in patients with multiple myeloma. Cureus 13:e15943. https:\/\/doi.org\/10.7759\/cureus.15943","journal-title":"Cureus"},{"key":"3262_CR26","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1177\/1091581815614261","volume":"35","author":"J Rong","year":"2016","unstructured":"Rong J, Li L, Jing L, Fang H, Peng S (2016) JAK2\/STAT3 pathway mediates protection of metallothionein against doxorubicin-induced cytotoxicity in mouse cardiomyocytes. Int J Toxicol 35:317\u2013326. https:\/\/doi.org\/10.1177\/1091581815614261","journal-title":"Int J Toxicol"},{"key":"3262_CR27","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1007\/s11897-021-00519-w","volume":"18","author":"M Russo","year":"2021","unstructured":"Russo M, Bono E, Ghigo A (2021) The interplay between autophagy and senescence in anthracycline cardiotoxicity. Curr Heart Fail Rep 18:180\u2013190. https:\/\/doi.org\/10.1007\/s11897-021-00519-w","journal-title":"Curr Heart Fail Rep"},{"key":"3262_CR29","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1007\/s12012-018-9483-x","volume":"19","author":"I Studneva","year":"2019","unstructured":"Studneva I, Palkeeva M, Veselova O, Molokoedov A, Ovchinnikov M, Sidorova M, Pisarenko O (2019) Protective effects of a novel agonist of galanin receptors against doxorubicin-induced cardiotoxicity in rats. Cardiovasc Toxicol 19:136\u2013146. https:\/\/doi.org\/10.1007\/s12012-018-9483-x","journal-title":"Cardiovasc Toxicol"},{"key":"3262_CR30","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1253\/circj.CJ-13-0835","volume":"77","author":"RL Thomas","year":"2013","unstructured":"Thomas RL, Gustafsson \u00c5B (2013) Mitochondrial autophagy. Circ J 77:2449\u20132454","journal-title":"Circ J"},{"key":"3262_CR31","doi-asserted-by":"publisher","first-page":"H37","DOI":"10.1152\/ajpheart.01057.2004","volume":"289","author":"M Tokarska-Schlattner","year":"2005","unstructured":"Tokarska-Schlattner M, Zaugg M, da Silva R, Lucchinetti E, Schaub MC, Wallimann T, Schlattner U (2005) Acute toxicity of doxorubicin on isolated perfused heart: response of kinases regulating energy supply. Am J Physiol-Heart Circulatory Physiol 289:H37\u2013H47. https:\/\/doi.org\/10.1152\/ajpheart.01057.2004","journal-title":"Am J Physiol-Heart Circulatory Physiol"},{"key":"3262_CR32","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1161\/CIRCRESAHA.119.314681","volume":"126","author":"KB Wallace","year":"2020","unstructured":"Wallace KB, Sard\u00e3o VA, Oliveira PJ (2020) Mitochondrial determinants of doxorubicin-induced cardiomyopathy. Circ Res 126:926\u2013941. https:\/\/doi.org\/10.1161\/CIRCRESAHA.119.314681","journal-title":"Circ Res"},{"key":"3262_CR33","doi-asserted-by":"publisher","first-page":"12815","DOI":"10.1073\/pnas.0707715105","volume":"105","author":"JG Walsh","year":"2008","unstructured":"Walsh JG, Cullen SP, Sheridan C, L\u00fcthi AU, Gerner C, Martin SJ (2008) Executioner caspase-3 and caspase-7 are functionally distinct proteases. PNAS 105:12815\u201312819. https:\/\/doi.org\/10.1073\/pnas.0707715105","journal-title":"PNAS"},{"key":"3262_CR34","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.3389\/fphar.2020.528267","volume":"11","author":"W Wang","year":"2020","unstructured":"Wang W, Fang Q, Zhang Z, Wang D, Wu L, Wang Y (2020) PPAR\u03b1 ameliorates doxorubicin-induced cardiotoxicity by reducing mitochondria-dependent apoptosis via regulating MEOX1. Front Pharmacol 11:1605. https:\/\/doi.org\/10.3389\/fphar.2020.528267","journal-title":"Front Pharmacol"},{"key":"3262_CR35","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1124\/mol.119.115725","volume":"96","author":"N Wenningmann","year":"2019","unstructured":"Wenningmann N, Knapp M, Ande A, Vaidya TR, Ait-Oudhia S (2019) Insights into doxorubicin-induced cardiotoxicity: molecular mechanisms, preventive strategies, and early monitoring. Mol Pharmacol 96:219\u2013232. https:\/\/doi.org\/10.1124\/mol.119.115725","journal-title":"Mol Pharmacol"},{"key":"3262_CR36","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1089\/ars.2017.7216","volume":"28","author":"W Xiao","year":"2018","unstructured":"Xiao W, Wang R-S, Handy DE, Loscalzo J (2018) NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid Redox Signal 28:251\u2013272. https:\/\/doi.org\/10.1089\/ars.2017.7216","journal-title":"Antioxid Redox Signal"},{"key":"3262_CR37","doi-asserted-by":"publisher","first-page":"4839","DOI":"10.1074\/jbc.M113.496315","volume":"289","author":"W Yang","year":"2014","unstructured":"Yang W, Park I-J, Yun H, Im D-U, Ock S, Kim J, Seo S-M, Shin H-Y, Viollet B, Kang I, Choe W, Kim S-S, Ha J (2014) AMP-activated protein kinase \u03b12 and E2F1 transcription factor mediate doxorubicin-induced cytotoxicity by forming a positive signal loop in mouse embryonic fibroblasts and non-carcinoma cells. J Biol Chem 289:4839\u20134852. https:\/\/doi.org\/10.1074\/jbc.M113.496315","journal-title":"J Biol Chem"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-022-03262-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-022-03262-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-022-03262-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T18:07:25Z","timestamp":1652292445000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-022-03262-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,25]]},"references-count":32,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["3262"],"URL":"https:\/\/doi.org\/10.1007\/s00204-022-03262-w","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,25]]},"assertion":[{"value":"12 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The author declares that there are no known conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}