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Toxicity produced at doses above the KMD can be qualitatively different from toxicity produced at lower doses. Here, we test the hypothesis that neoplastic lesions reported in the National Toxicology Program\u2019s (NTP) rodent cancer bioassay with ethylbenzene are a high-dose phenomenon secondary to saturation of elimination kinetics. To test this, we applied Bayesian modeling on kinetic data for ethylbenzene from rats and humans to estimate the <jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub> and <jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub> for the Michaelis\u2013Menten equation that governs the elimination kinetics. Analysis of the Michaelis\u2013Menten elimination curve generated from those <jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub> and <jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub> values indicated KMD ranges for venous ethylbenzene of 8\u201317\u00a0mg\/L in rats and 10\u201318\u00a0mg\/L in humans. Those venous concentrations are produced by inhalation concentrations of around 200\u00a0ppm ethylbenzene, which is well above typical human exposures. These KMD estimates support the hypothesis that neoplastic lesions seen in the NTP rodent bioassay occur secondary to saturation of ethylbenzene elimination pathways and are not relevant for human risk assessment. Thus, ethylbenzene does not pose a credible cancer risk to humans under foreseeable exposure conditions. Cancer risk assessments focused on protecting human health should avoid endpoint data from rodents exposed to ethylbenzene above the KMD range and future toxicological testing should focus on doses below the KMD range.<\/jats:p>","DOI":"10.1007\/s00204-023-03629-7","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T08:02:30Z","timestamp":1701936150000},"page":"327-334","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Kinetically-derived maximal dose (KMD) indicates lack of human carcinogenicity of ethylbenzene"],"prefix":"10.1007","volume":"98","author":[{"given":"Lyle D.","family":"Burgoon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2981-9012","authenticated-orcid":false,"given":"Christopher J.","family":"Borgert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Fuentes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James E.","family":"Klaunig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,12,7]]},"reference":[{"key":"3629_CR1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.3109\/10408448109059563","volume":"9","author":"ME Andersen","year":"1981","unstructured":"Andersen ME (1981) Saturable metabolism and its relationship to toxicity. 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SIRC reviewed and commented on the initial draft of the manuscript. The methodologies, analyses, interpretations, content of the manuscript, and the decision to submit it for publication were made solely by the authors and did not depend on approval from SIRC.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding and conflict of interest"}}]}}