Formation of DNA adducts and induction of mutagenic effects in rats following 4 weeks inhalation exposure to ethylene oxide as a basis for cancer risk assessment

Ethylene oxide (EO) is mutagenic in various in vitro and in vivo test syste ms and carcinogenic in rodents. EO forms different adducts upon reaction wi th DNA, N7-(2-hydroxyethyl)guanine (N7-HEG) bring the main adduct. The majo r objectives of this study were: (a) to determine the formation and persist ence of N7-HEG adducts in liver DNA of adult male rats exposed to 0, 50, 10 0 and 200 ppm by inhalation (4 weeks, 5 days/week, 6 h/day) and (b) to asse ss dose-response relationships for Hprt gene mutations and various types of chromosomal changes in splenic lymphocytes. N7-HEG adducts were measured 5, 21, 35 and 49 days after cessation of expos ure. By extrapolation, the mean concentrations of N7-HEG immediately after cessation of exposure ('day 0') to 50, 100 and 200 ppm were calculated as 3 10, 558 and 1202 adducts/10(8) nucleotides, respectively, while the mean co ncentration in control rats was 2.6 adducts/10(8) nucleotides. Ar 49 days, N7-HEG values had returned close to background levels. The mean levels of N -(2-hydroxyethylvaline) adducts in haemoglobin were also determined and amo unted 61.7, 114 and 247 nmol/g globin, respectively. Statistically significant linear relationships were found between mean N7-H EG levels ('day 0') and Hprt mutant frequencies at expression times 21/22 a nd 49/50 days and between mean N7-HEG ('day 0') and sister-chromatid exchan ges (SCEs) or high frequency cells (HFC) measured 5 days post-exposure. At day 21 post-exposure, SCEs and HFCs in-part persisted and were significantl y correlated with persistent N7-HEG adducts. No statistically significant d ose effect relationships were observed for induction of micronuclei, nor fo r chromosome breaks or translocations. In conclusion, this study indicates that following sub-chronic exposure, EO is only weakly mutagenic in adult rats. Using the data of this study to pr edict cancer risk in man resulting from low level EO exposures in conjuncti on with other published data, i.e., those on (a) genotoxic effects of EO in humans and rats, (b) DNA binding of other carcinogens, (c) natural backgro und DNA binding and (d) genotoxic potency of low energy transfer (LET) radi ation, it is not expected that long term occupational exposure to airborne concentrations of EO at or below 1 ppm EO produces an unacceptable increase d risk in man. (C) 2000 Elsevier Science B.V. All rights reserved.