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Molecular Dosimetry of Ethylene Oxide: Formation and Persistence of N-(2-Hydroxyethyl)valine in Hemoglobin following Repeated Exposures of Rats and Mice¹

Chemical Industry Institute of Toxicology, Research Triangle Park 27709 [V. E. W., J. P. M., M. J. T., T. R. F.]; Department of Environmental Sciences and Engineering [J. A. S.] and Department of Pathology [V. E. W.], University of North Carolina, Chapel Hill 27599; and Department of Pathology, Duke University Medical Center, Durham 27710 [V. E. W.], North Carolina

The formation of N-(2-hydroxyethyl)valine (HEVal) in hemoglobin was investigated in male F344 rats (10/group) and B6C3F1 mice (20/group) exposed to 0, 3, 10, 33, 100, or 300 (rats only) ppm ethylene oxide (ETO) by inhalation for 6 h/day for 4 weeks (5 days/week) or exposed to 100 (mice) or 300 ppm (rats) ETO for 1 or 3 days or 1, 2, or 4 weeks (5 days/week). The persistence of HEVal was studied in animals killed up to 10 days after cessation of the 4-week time-course studies. HEVal was determined by a modified Edman degradation and quantitation of the resulting pentafluorophenylthiohydantoin derivative, using gas chromatography-mass spectrometry. The resulting experimental data were compared to simulations derived with a model for the formation and removal of hemoglobin adducts (T. R. Fennell, S. C. J. Sumner, and V. E. Walker, Cancer Epidemiol., Biomarkers & Prev., 1: 213–219, 1992). Repeated exposures of rats and mice for 4 weeks to 300 and 100 ppm ETO, respectively, led to an accumulation of HEVal that was 14 (rats) and 15 (mice) times greater than that found after 1 day of exposure [28 ± 2 (SE) and 9.4 ± 0.4 (SE) pmol HEVal/mg globin in rats and mice, respectively]. After cessation of exposures, HEVal was lost faster than predicted by the normal erythrocyte life span alone. An initial phase of rapid decline in HEVal concentrations was consistent with the removal of older, more heavily alkylated populations of RBCs, accompanied by a burst of erythropoiesis. The dose-response curves for HEVal were linear between 3 and 33 ppm ETO, with 3.5 ± 0.2 and 3.4 ± 0.3 pmol adduct/mg globin formed in rats and mice, respectively, after 4 weeks of exposure to 3 ppm ETO. Above 33 ppm ETO, the slope of the dose-response curves increased. Comparison of the dose response for HEVal in rats exposed to ETO for 4 weeks to the dose-response for N^T-(2-hydroxyethyl)histidine in rats exposed to the same concentrations of ETO for 2 years (S. Osterman-Golkar et al., Teratog. Carcinog. Mutagen., 3: 395–405, 1983) suggested that exposures to ETO can reduce the life span of erythrocytes in a concentration- and time-dependent manner. Correlation of the experimental data and simulations for the formation and removal of HEVal demonstrated that perturbations in erythropoiesis and RBC life span complicate the estimation of exposures to ETO when estimates are based upon hemoglobin adduct measurements in heavily exposed individuals. However, results of these rodent studies indicate that ETO-induced erythroclastic effects are associated with high cumulative doses of the epoxide and are unlikely to occur in workers exposed near or below the current Occupational Safety and Health Administration standard of 1 ppm (8-h time-weighted average).

¹ This is the first of two papers on this topic. Funded in part by the Ethylene Oxide Industry Council of the Chemical Manufacturers Association. V. E. W. was the recipient of a graduate fellowship from the Department of Pathology, Duke University.

² To whom requests for reprints should be addressed, at the University of North Carolina at Chapel Hill, Department of Pathology, CB 7525, Chapel Hill, NC 27599-7525.

Received 2/20/92. Accepted 6/ 9/92.

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