title: 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.
authors.affiliation: Department of Pathology and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA. walker@wadsworth.org
authors.forename: V E
authors.initials: VE
authors.lastname: Walker
authors.forename: K Y
authors.initials: KY
authors.lastname: Wu
authors.forename: P B
authors.initials: PB
authors.lastname: Upton
authors.forename: A
authors.initials: A
authors.lastname: Ranasinghe
authors.forename: N
authors.initials: N
authors.lastname: Scheller
authors.forename: M H
authors.initials: MH
authors.lastname: Cho
authors.forename: J S
authors.initials: JS
authors.lastname: Vergnes
authors.forename: T R
authors.initials: TR
authors.lastname: Skopek
authors.forename: J A
authors.initials: JA
authors.lastname: Swenberg
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005027:Ethylene Oxide / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D005030:Ethylenes / Q000493:pharmacokinetics* / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D006454:Hemoglobins / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D013601:T-Lymphocytes / Q000201:enzymology; D014633:Valine / Q000031:analogs & derivatives* / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D005030:Ethylenes; D006454:Hemoglobins; C057442:2-hydroxyethylvaline; C035018:N(7)-hydroxyethylguanine; D006147:Guanine; D004247:DNA; C036216:ethylene; D007041:Hypoxanthine Phosphoribosyltransferase; D014633:Valine; D005027:Ethylene Oxide