Ethylene Oxide as a Biological Reactive Intermediate of Endogenous Origin
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Reactive intermediates can be monitored in vivo through their reaction products (adducts) with macromolecules. Sensitive methods, based on gas chromatography/mass spectrometry which permit structural identification and quantification, have been developed for the determination of adducts to hemoglobin (Hb). In studies of exposed animals, occupationally exposed workers and smokers a number of Hb adducts have been observed in unexposed control individuals. Methods for the determination of Hb adducts have, particularly through the use of tandem mass spectrometry, reached a sensitivity permitting studies of adducts from reactive intermediates due to “background exposure”. N-(2-Hydroxethyl)valine (HOEtVal) is one of the background Hb adducts observed. This adduct has been used as a model in studies of sources of background adducts and determinants of their levels.
From the rate of exhalation of ethene by humans and application of a pharmacokinetic model it was concluded that about 70% of the background HOEtVal in non-smokers originates from ethylene oxide (EO) as the metabolite of endogenously produced ethene. Contributions from ethene in urban air or environmental tobacco smoke are relatively small. Smoking of 2 cig./day approximately doubles the background. In twin studies it was shown that the variations in adduct level are partly due to hereditary factors and family traditions. Animal experiments demonstrate a role of intestinal flora and diet (unsaturated fatty acids, selenium), partly due to influences on metabolic rate. Furthermore, an interaction of dietary fat and intestinal flora is indicated.
From the adduct levels measured and knowledge of the identity of the causative reactive intermediate and of the rate constant for adduct formation, the dose of the reactive intermediate could be calculated. The associated cancer risk could then be estimated through the radiation-dose equivalence of the chemical dose determined in mutation experiments in vitro and application of the cancer risk coefficient for radiation. The risk contribution from the endogenous production of EO has been estimated by this approach to be of approximately the same magnitude as the risk due to background radiation.
KeywordsEthylene Oxide Environmental Tobacco Smoke Intestinal Flora Annual Dose Adduct Level
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