Kinetically-derived maximal dose (KMD) indicates lack of human carcinogenicity of ethylbenzene.

Autor: Burgoon LD; Raptor Pharm & Tox, Ltd, Apex, NC, USA., Borgert CJ; Applied Pharmacology and Toxicology, Inc., University of Florida College of Veterinary Medicine, Gainesville, FL, USA. cjborgert@apt-pharmatox.com., Fuentes C; Oregon State University, Corvallis, OR, USA., Klaunig JE; Indiana University School of Public Health, Bloomington, IN, USA.
Jazyk: angličtina
Zdroj: Archives of toxicology [Arch Toxicol] 2024 Jan; Vol. 98 (1), pp. 327-334. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1007/s00204-023-03629-7
Abstrakt: The kinetically-derived maximal dose (KMD) is defined as the maximal external dose at which kinetics are unchanged relative to lower doses, e.g., doses at which kinetic processes are not saturated. 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's (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 V max and K m for the Michaelis-Menten equation that governs the elimination kinetics. Analysis of the Michaelis-Menten elimination curve generated from those V max and K m values indicated KMD ranges for venous ethylbenzene of 8-17 mg/L in rats and 10-18 mg/L in humans. Those venous concentrations are produced by inhalation concentrations of around 200 ppm 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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