The Effect of Ethylene Exposure on Ethylene Oxide in Blood and on Hepatic Cytochrome P450 in Fischer Rats

Abstract

Ethylene (74-85-1) is an important petrochemical and is produced endogenously. It is metabolized to ethylene oxide (EO) by cytochrome P450. We studied the inhibition of cytochrome P450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood. Male F344 rats were exposed to 1000, 600, and 300 ppm ethylene by nose-only inhalation for up to 6 h. Blood samples were obtained during exposure. On exposure to 600 ppm ethylene, blood EO concentration increased during the first hour of exposure and then decreased to approximately half of the peak blood concentration. A less pronounced decrease was observed at 300 ppm, and at 1000 ppm little change was observed between 10 min and 6 h of exposure. For the analysis of cytochrome P450 and isozyme-specific substrate activities, groups of four male F344 rats were removed for the collection of liver at various times after exposure to 300, 600, or 1000 ppm ethylene. At all concentrations, liver microsomal cytochrome P450 decreased during exposure. Of the various monooxygenase activities measured, 4-nitrophenol hydroxylase was the one most consistently altered, with maximal inhibition (approximately 50%) at 2 h of exposure to 1000 ppm ethylene, 4 h at 600 ppm, and 6 h at 300 ppm. Activity recovered to control levels by 6 h after exposure. Cytochrome P450 2E1 appears to be the major isoform of cytochrome P450 inhibited by exposure to ethylene, and this may explain in part the observed alteration in EO blood kinetics.

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

“…Thereafter, it decreased slowly to 0.1 µg/ml (2.3 µmol/l) at 360min. The Fennell et al (2004) data are similar to the present ones with the exception that the peak and the following decrease of the EO concentration was not seen at 1000 ppm. In the present work, EO peaked in blood even at 10 000 ppm ET (Fig.…”

“…Four minutes later, the concentration had dropped to a rather constant value of about 0.5 µg/g (11 µmol/l). Fennell et al (2004) obtained distinctly different results: at 300 ppm ET, a broad maximum of about 0.08 µg EO/ml blood (1.8 µmol/l) was reached after 2h. Thereafter, the EO concentration decreased continuously to 0.06 µg/ml (1.4 µmol/l).…”

“…A smaller part is metabolically converted to ethylene oxide (EO, CAS No. : 75-21-8), as has been demonstrated directly in vivo in rats (Fennell et al , 2004; Filser and Bolt, 1984; Maples and Dahl, 1993) and in vitro in liver microsomes of rats (Li et al , 2011a; Schmiedel et al , 1983), mice, and humans (Li et al , 2011a). In these species when exposed to ET, the formation of EO-characteristic hydroxyethyl adducts to hemoglobin and/or DNA was shown (mice: Ehrenberg et al , 1977; Segerbäck, 1983; Walker et al , 2000; Wu et al , 1999; rats: Eide et al , 1995; Rusyn et al , 2005; Walker et al , 2000; Wu et al , 1999; humans: Filser et al , 1992; Kautiainen and Törnqvist, 1991; Törnqvist et al , 1989).…”

“…The EO concentrations in blood of ET-exposed rats, however, can be compared with data published by Maples and Dahl (1993) and Fennell et al (2004) in ET-exposed male Fischer 344 rats. The former authors exposed the animals for 1h to 5 or 600 ppm ET, the latter ones for 6h to 300, 600, or 1000 ppm.…”

“…In ET-exposed humans, the EO burden is still uncertain since no measured EO concentrations have been published. IARC (1994a) concluded that “the available data in humans did not allow the Working Group to evaluate the carcinogenicity of ethylene to humans.” Furthermore, only limited data are available on the EO burden in ET-exposed rats (Fennell et al , 2004; Filser and Bolt, 1984; Maples and Dahl, 1993). No measured EO data have been published in ET-exposed mice.…”