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Filser, J.G. ; Klein, D.

A physiologically based toxicokinetic model for inhaled ethylene and ethylene oxide in mouse, rat, and human.

Toxicol. Lett. 286, 54-79 (2017)
Verlagsversion Postprint Forschungsdaten DOI PMC
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Ethylene (ET) is the largest volume organic chemical. Mammals metabolize the olefin to ethylene oxide (EO), another important industrial chemical. The epoxide alkylates macromolecules and has mutagenic and carcinogenic properties. In order to estimate the EO burden in mice, rats, and humans resulting from inhalation exposure to gaseous ET or EO, a physiological toxicokinetic model was developed. It consists of the compartments lung, richly perfused tissues, kidneys, muscle, fat, arterial blood, venous blood, and liver containing the sub-compartment endoplasmic reticulum. Modeled ET metabolism is mediated by hepatic cytochrome P450 2E1, EO metabolism by hepatic microsomal epoxide hydrolase or cytosolic glutathione S-transferase in various tissues. EO is also spontaneously hydrolyzed or conjugated with glutathione. The model was validated on experimental data collected in mice, rats, and humans. Modeled were uptake by inhalation, wash-in-wash-out effect in the upper respiratory airways, distribution into tissues and organs, elimination via exhalation and metabolism, and formation of 2-hydroxyethyl adducts with hemoglobin and DNA. Simulated concentration-time courses of ET or EO in inhaled (gas uptake studies) or exhaled air, and of EO in blood during exposures to ET or EO agreed excellently with measured data. Predicted levels of adducts with DNA and hemoglobin, induced by ET or EO, agreed with reported levels. Exposures to 10000 ppm ET were predicted to induce the same adduct levels as EO exposures to 3.95 (mice), 5.67 (rats), or 0.313 ppm (humans). The model is concluded to be applicable for assessing health risks from inhalation exposure to ET or EO.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Physiologically Based Toxicokinetic Model ; Ethylene ; Ethylene Oxide ; Mouse ; Rat ; Human ; Hemoglobin Adducts ; Dna Adducts; Hemoglobin Adducts; Alkylating-agents; Fischer-344 Rats; Propylene-oxide; Dna-adducts; Gas Uptake; In-vivo; Pharmacokinetic Model; Inhalation Exposure; Molecular Dosimetry
Sprache englisch
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 0378-4274
e-ISSN 1879-3169
Zeitschrift Toxicology Letters
Quellenangaben Band: 286, Heft: , Seiten: 54-79 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Molecular Toxicology and Pharmacology (TOX)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-505200-002
DOI 10.1016/j.toxlet.2017.07.896
WOS ID WOS:000425268000007
PubMed ID 28774830
Erfassungsdatum 2017-09-12
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