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Upon inhalation NVP was carcinogenic in the rat, liver tumor formation is starting already at the rather low concentration of 5\u00a0ppm. Hence, differentiation whether NVP is a genotoxic carcinogen (presumed to generally have no dose threshold for the carcinogenic activity) or a non-genotoxic carcinogen (with a potentially definable threshold) is highly important. In the present study, therefore, the existing genotoxicity investigations on NVP (all showing consistently negative results) were extended and complemented with investigations on possible alternative mechanisms, which also all proved negative. All tests were performed in the same species (rat) using the same route of exposure (inhalation) and the same doses of NVP (5, 10 and 20\u00a0ppm) as had been used in the positive carcinogenicity test. Specifically, the tests included an ex vivo Comet assay (so far not available) and an ex vivo micronucleus test (in contrast to the already available micronucleus test in mice here in the same species and by the same route of application as in the bioassay which had shown the carcinogenicity), tests on oxidative stress (non-protein-bound sulfhydryls and glutathione recycling test), mechanisms mediated by hepatic receptors, the activation of which had been shown earlier to lead to carcinogenicity in some instances (Ah receptor, CAR, PXR, PPAR\u03b1). No indications were obtained for any of the investigated mechanisms to be responsible for or to contribute to the observed carcinogenicity of NVP. The most important of these exclusions is genotoxicity. Thus, NVP can rightfully be regarded and treated as a non-genotoxic carcinogen and threshold approaches to the assessment of this chemical are supported. However, the mechanism underlying the carcinogenicity of NVP in rats remains unclear.\n<\/jats:p>","DOI":"10.1007\/s00204-021-03151-8","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T21:03:19Z","timestamp":1633035799000},"page":"3717-3744","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enigmatic mechanism of the N-vinylpyrrolidone hepatocarcinogenicity in the rat"],"prefix":"10.1007","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7607-1329","authenticated-orcid":false,"given":"Franz","family":"Oesch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Fruth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan G.","family":"Hengstler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Fabian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz Ingo","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3756-1904","authenticated-orcid":false,"given":"Robert","family":"Landsiedel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"3151_CR1","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/S0076-6879(81)77050-2","volume":"77","author":"TPM Akerboom","year":"1981","unstructured":"Akerboom TPM, Sies H (1981) Assay of glutathione disulfide and glutathione mixed disulfides in biological samples. 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