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

The purposes of the present study were: (i) to investigate the potential us e of several biomarkers as quantitative indicators of the in vivo conversio n of ethylene (ET) to ethylene oxide (EO); (ii) to produce molecular dosime try data that might improve assessment of human risk from exogenous ET expo sures. 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), N7-(2-hydroxyethyl) guanine (N7-HEG) and Hprt mutant frequenc ies were assessed as potential biomarkers for determining the molecular dos e of EO resulting from exogenous ET exposures of rats and mice, compared wi th background biomarker values. N7-HEG was quantified by gas chromatography coupled with high resolution mass spectrometry (GC-HRMS), HEV was determin ed by Edman degradation and GC-HRMS and Hprt mutant frequencies were measur ed by the T cell cloning assay. N7-HEG accumulated in DNA with repeated exp osure of rodents to 3000 p.p.m. ET, reaching steady-state concentrations ar ound 1 week of exposure in most tissues evaluated (brain, fiver, lung and s pleen). The dose-response curves for N7-HEG and HEV were supralinear in exp osed rats and mice, indicating that metabolic activation of ET was saturate d at exposures greater than or equal to 1000 p.p.m. ET. Exposures of mice a nd rats to 200 p.p.m. EO for 4 weeks las positive treatment controls) led t o significant increases in Hprt mutant frequencies over background in splen ic T cells from exposed rats and mice, however, no significant mutagenic re sponse was observed in the Hprt gene of ET-exposed animals. Comparisons bet ween 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 th e results of the rodent carcinogenicity studies of ET and EO suggest that t oo little EO arises from exogenous ET exposure to produce a significant mut agenic response or a carcinogenic response under standard bioassay conditio ns.