Kinetics of Ethylene and Ethylene Oxide in Subcellular Fractions of Lungs and Livers of Male B6C3F1 Mice and Male Fischer 344 Rats and of Human Livers

Li, Qiang; Csanády, György A.; Kessler, Winfried; Klein, Dominik; Pankratz, Helmut; Pütz, Christian; Richter, Nadine; Filser, Johannes G.

doi:10.1093/toxsci/kfr194

Cited by 15 publications

(16 citation statements)

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“…In the rat lung microsomes the EPHX1 activity was, in turn, higher than in the lung microsomes of the mouse, the species most susceptible to the lung carcinogenic action of butadiene (see Table 5). Li et al (2011a) observed in human pulmonary microsomes mEH activity toward ethylene oxide as substrate (but not in pulmonary microsomes of rats or mice). Nishimura and Naito (2006) observed in the human lung modest levels of EPHX2 mRNA.…”

Section: Microsomal Epoxide Hydrolase (Ephx1 or Meh Or Eh1) Transcriptsmentioning

confidence: 74%

“…Abdull Razis et al (2011) observed increases in GST activity toward CDNB as substrate also upon exposure of the precision-cut rat lung slices to the isothiocyanate precursor glucosinolate, glucoraphanin. Li et al (2011a) observed in rat pulmonary cytosol GST activity toward ethylene oxide as substrate. Zheng et al (2014) observed that GST activity toward the prototypic substrate 4-hydroxynonenal was very high in rat lung 9000 g supernatant, higher than in the liver.…”

Section: Gst Transcriptsmentioning

confidence: 87%

“…observed in human lung cytosol GST activity toward butadiene epoxide (a reactive metabolite of the rodent carcinogen butadiene) (6.4 ± 1.9 nmol/min/ mg cytosolic protein), considerably less than in the mouse and rat lung cytosol (162 ± 16 and 186 ± 37 nmol/min/mg cytosolic protein, respectively). Li et al (2011a) observed in human pulmonary cytosol GST activity toward ethylene oxide as substrate.…”

Section: Conjugating Enzymesmentioning

confidence: 90%

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Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.

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Section: Microsomal Epoxide Hydrolase (Ephx1 or Meh Or Eh1) Transcriptsmentioning

confidence: 74%

Section: Gst Transcriptsmentioning

confidence: 87%

Section: Conjugating Enzymesmentioning

confidence: 90%

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Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019

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“…Only one study shows human kinetics data on methyl bromide levels in blood, with the elimination kinetics for up to 21 days after a fatal accident [ 15 ]. Little human literature data indicate that both, methyl bromide and ethylene oxide, have longer half lives in humans than in experimental animals with 12–99 h for ethylene oxide and up to 11 days for methyl bromide (depending on concentration, exposure circumstances and genetic predispositions) [ 15 , 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Accidental exposure to gas emissions from transit goods treated for pest control

et al. 2014

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BackgroundInternational phytosanitary standards ISPM 15 require (since 2007) fumigation or heat treatment for shipping and storage. Those dealing with fumigated freight might be accidentally exposed. In this paper we report a series of three accidents of six storage room workers in a medium sized company regularly importing electronic production parts from abroad.MethodsPatients (n = 6, aged from 32–54 yrs.) and control group (n = 30, mean 40 yrs.) donated blood and urine samples. The fumigants: ethylene oxide, methyl bromide, chloropicrin, ethylene dichloride, other halo-alkanes and solvents were analyzed by headspace gas chromatography/mass spectrometry (GCMS). For the quantitation of long term exposure/s, macromolecular reaction products (hemoglobin adducts) were used (with GCMS) as molecular dosimeter; additionally 8-OHdG and circulating mtDNA (cmtDNA) were analyzed as nonspecific biological effect markers.ResultsThe hemoglobin adducts N-methyl valine (MEV) and N-(2-hydroxy ethyl) valine (HEV) were elevated after exposure to the alkylating chemicals methyl bromide and ethylene oxide. Under the consideration of known elimination kinetics and the individual smoking status (biomonitored with nicotine metabolite cotinine and tobacco specific hemoglobin adduct: N-(2 cyan ethyl) valines, CEV), the data allow theoretical extrapolation to the initial protein adduct concentrations at the time of the accident (the MEV/CEV levels were from 1,616 pmol/g globin to 1,880 pmol/g globin and HEV/CEV levels from 1,407 pmol/g globin to 5,049 pmol/g globin, and correlated with inhaled 0.4-1.5 ppm ethylene oxide. These integrated, extrapolated internal doses, calculated on the basis of biological exposure equivalents, confirmed the clinical diagnosis for three patients, showing severe intoxication symptoms. Both, cmtDNA and 8-OHdG, as non-specific biomarkers of toxic effects, were elevated in four patients.ConclusionThe cases reported here, stress the importance of a suitable risk assessment and control measures. We put emphasis on the necessity of human biomonitoring guidelines and the urgency for the relevant limit values.

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“…At high ET concentrations, the initial ET metabolism to EO is rather fast. Li et al (2011a) calculated on the basis of measurements in liver microsomes maximum rates ( V max ) of the ET metabolism (µmol/h/kg body weight) of 42.9 in mice and 28.9 in rats. The same authors explained why earlier published, much smaller V max values are incorrect.…”

Section: Discussionmentioning

confidence: 99%

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

Filser

Kessler

Artati

et al. 2013

Toxicological Sciences

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The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largest volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are available on the EO burden in ET-exposed rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of between 1 and 10 000 ppm (rodents) or 5 and 50 ppm (humans). Both the compounds were determined by gas chromatography. At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (µmol × h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET concentrations ≤ 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations, levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.

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Kinetics of Ethylene and Ethylene Oxide in Subcellular Fractions of Lungs and Livers of Male B6C3F1 Mice and Male Fischer 344 Rats and of Human Livers

Cited by 15 publications

References 55 publications

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Accidental exposure to gas emissions from transit goods treated for pest control

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

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