Biomarkers of exposure and effect as indicators of potential carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide

Abstract

The purposes of the present study were: (i) to investigate the potential use of several biomarkers as quantitative indicators of the in vivo conversion of ethylene (ET) to ethylene oxide (EO); (ii) to produce molecular dosimetry data that might improve assessment of human risk from exogenous ET exposures. Groups (n = 7/group) of male F344 rats and B6C3F1 mice were exposed by inhalation to 0 and 3000 p. p.m. ET for 1, 2 or 4 weeks (6 h/day, 5 days/week) or to 0, 40, 1000 and 3000 p.p.m. ET for 4 weeks. N:-(2-hydroxyethyl)valine (HEV), N:7-(2-hydroxyethyl) guanine (N7-HEG) and HPRT: mutant frequencies were assessed as potential biomarkers for determining the molecular dose of EO resulting from exogenous ET exposures of rats and mice, compared with background biomarker values. N7-HEG was quantified by gas chromatography coupled with high resolution mass spectrometry (GC-HRMS), HEV was determined by Edman degradation and GC-HRMS and HPRT: mutant frequencies were measured by the T cell cloning assay. N7-HEG accumulated in DNA with repeated exposure of rodents to 3000 p.p.m. ET, reaching steady-state concentrations around 1 week of exposure in most tissues evaluated (brain, liver, lung and spleen). The dose-response curves for N7-HEG and HEV were supralinear in exposed rats and mice, indicating that metabolic activation of ET was saturated at exposures >/=1000 p.p.m. ET. Exposures of mice and rats to 200 p.p.m. EO for 4 weeks (as positive treatment controls) led to significant increases in HPRT: mutant frequencies over background in splenic T cells from exposed rats and mice, however, no significant mutagenic response was observed in the HPRT: gene of ET-exposed animals. Comparisons between the biomarker data for both unexposed and ET-exposed animals, the dose-response curves for the same biomarkers in EO-exposed rats and mice and the results of the rodent carcinogenicity studies of ET and EO suggest that too little EO arises from exogenous ET exposure to produce a significant mutagenic response or a carcinogenic response under standard bioassay conditions.

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

“…Nitrosated bile salts are carboxymethylating agents. Ethylene produced from gut microbial metabolism and lipid peroxidation is further metabolized to ethylene oxide (EO), which produces 7-(2-hydroxyethyl)guanine (N7-HEG), which is also formed by environmental ethylene and ethylene oxide exposure (Rusyn et al, 2005;Walker et al, 2000). The major aldehydes of lipid peroxidation in vivo are crotonaldehyde, acrolein, 4-hydroxynonenal and malondialdehyde (MDA); each of these can react with DNA to form exocyclic adducts and 7-(2-oxoethyl)guanine, which are also formed by vinyl chloride and ethylcarbamate (Morinello et al, 2002;Nair et al, 1999).…”

C2H4O sensing properties for thick film sensor using La2O3-modified SnO2

“…On the other hand, the same gas is also known as an excellent disinfectant which is penetrative and effective at room temperature, so that it has been used popularly for disinfection of heat-sensitive materials and equipments in hospital and food industry [1][2][3]. As recently recognized, ethylene oxide is hazardous to human beings, causing reproductive disorder, genetic disorder, cancer, and so on [3][4][5][6][7][8]. Therefore, its safety standard at working places has been regulated to be 1 ppm in Japan, US and Europe.…”

Development of SnO2-based gas sensor sensitive to dilute ethylene oxide in air

“…On the other hand, the same gas is also known as an excellent disinfectant which is penetrative and effective at room temperature, so that it has been used popularly for disinfection of heat-sensitive materials and equipments in hospital and food industry [1][2][3]. As recently recognized, ethylene oxide is hazardous to human beings, causing reproductive disorder, genetic disorder, cancer, and so on [3][4][5][6][7][8]. Therefore, its safety standard at working places has been regulated to be 1 ppm in Japan and US.…”