Development of a human biomonitoring method for assessing the exposure to ethoxyquin in the general population
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BIOMONITORING
Development of a human biomonitoring method for assessing the exposure to ethoxyquin in the general population Markus Stoeckelhuber1,2 · Max Scherer1 · Franz Bracher2 · Oliver Peschel3 · Edgar Leibold4 · Gerhard Scherer1 · Nikola Pluym1 Received: 24 April 2020 / Accepted: 12 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Ethoxyquin (EQ) is commonly used as an antioxidant in animal feeds. Although EQ is not permitted for usage in food products for humans within the EU, residues of EQ and its transformation products could be determined in food of animal origin. Despite its widespread use and concerns on its toxicological profile, no information about the systemic exposure to EQ in the general population is available. Hence, we developed a human biomonitoring (HBM) method for EQ. Our approach included a metabolism study with five subjects, who were administered an oral dose of 0.005 mg EQ/kg body weight. Unchanged EQ and the major metabolite 2,2,4-trimethyl-6(2H)-quinolinone (EQI) were identified as urinary excretion products of EQ. While small amounts of EQ could be determined in high concentrated samples from the metabolism study only, 28.5% of the orally applied EQ dose could be recovered as EQI. Toxicokinetic parameters were determined for EQI, the potential biomarker of exposure. In addition, an analytical method for EQI (LOQ = 0.03 µg/L) in urine based on UHPLC-MS/MS comprising enzymatic glucuronide hydrolysis and salt-assisted liquid–liquid extraction was developed, validated and applied to 53 urine samples from the general population. EQI could be quantified in 11 (21%) of the samples in levels up to 1.7 µg/L urine, proving the suitability of the developed method for the intended purpose. Keywords Ethoxyquin · LC–MS/MS · Urine · Human metabolism · Toxicokinetics · Human biomonitoring
Introduction The quinoline-based, synthetic antioxidant ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline; CAS Number 91-53-2; EQ) possesses a broad range of applications because of its antioxidant capacity and its low production Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02871-7) contains supplementary material, which is available to authorized users. * Nikola Pluym nikola.pluym@abf‑lab.com 1
Analytisch-Biologisches Forschungslabor GmbH, Semmelweisstr. 5, 82152 Planegg, Germany
2
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstr. 5‑13, 81377 Munich, Germany
3
Institut für Rechtsmedizin der Universität München, Nussbaumstr. 26, 80336 Munich, Germany
4
BASF SE, Product Safety, 67056 Ludwigshafen, Germany
costs (Błaszczyk et al. 2013; Rodríguez-Gómez et al. 2018). It is globally used as an additive to retard oxidation in animal feed, as a preservative in dried forage crops and spices and was used as an anti-scalding agent in pears and apples in the past (Błaszczyk et al. 2013; Negreira et al. 2017). The anti-oxidative properties of EQ can b
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