Quantification of endogenous carcinogens: The ethylene oxide paradox

Abstract

Although ethylene oxide is a proven genotoxic carcinogen in experimental animals, its human carcinogenicity is still being debated. Alkylations (hydroxyethylation) of DNA and proteins by ethylene oxide are well established. Ethylene oxide is metabolically formed from ethylene, which is a natural body constituent. Thus, endogenous sources of ethylene/ethylene oxide contribute to background alkylations of physiological macromolecules. There are now experimentally well established data sets on the background hydroxyethylations of the N-terminal valine of hemoglobin and of the 7-N position of guanine in DNA, in laboratory animals as well as in humans. A review of these data leads to the conclusion that these background levels display remarkable consistency between the different species studied and, as far as DNA adducts are concerned, also between different tissues. From the existing database it can be deduced that in rats a hemoglobin alkylation, equivalent to the level of normal background, would be caused by repetitive external atmospheric exposures to ethylene oxide (6 hr/day, 5 days/week for several weeks) of about 30 ppb. On the contrary, in the same species, a DNA alkylation, equivalent to the level of normal background, would be caused by similar repetitive exposures to ethylene oxide at about 1–2 ppm. This paradox is unresolved. It points, however, to the biological importance of endogenous DNA alkylations and questions current regulatory procedures of assessing the risk of minute doses of exogenous carcinogens.