Biomonitoring of epichlorohydrin and some related compounds

Sammanfattning: This thesis considers epichlorohydrin (ECH), an important industrial chemical, that has been shown to be a carcinogen in experimental animals. The aim of this work is to improve the scientific basis for risk estimation of ECH and to suggest a reliable biomonitoring method for exposure.During this work the formation and elimination of reaction products (adducts) with DNA and hemoglobin were studied in female Wistar rats. The total globin adduct level in vivo in rats was 140 pmol/g globin permmol/kg body weight, suggesting a more efficient detoxification process of ECH than of the related epoxides ethylene oxide and propylene oxide. Further, a new method based on the N-alkyl Edman method for isolation of alkylated N-terminal valines in hemoglobin was developed. Here the adducts are derivatized and cleaved off in one step, enriched by extraction and analyzed by gas chromatography - mass spectrometry. Unfortunately, isolation and analysis of the initial adduct N-(3-chloro-2-hydroxypropyl)valine, was difficult, therefore the secondary adduct N-(2,3-dihydroxypropyl)valine (diHOPrVal) was used for monitoring. DiHOPrVal is more hydrophilic than earlier studied adducts, and thus several new steps, such as acetylation of the hydroxyl groups, were added to the original method. The limit of detection was 1 pmol diHOPrVal/g globin (2 fmol injected derivative).Aside from experimental animals, occupational exposure to ECH of workers in a German factory was studied by monitoring diHOPrVal adducts and cytogenetic endpoints such as sister chromatid exchange (SCE). A significant exposure effect was only found in SCE. In the case of hemoglobin adducts, a significant difference could only be observed if a Swedish group of control persons was added to the study. A background was observed in non-smokers, and the effect of smoking was highly significant with an increase of about 0.7 pmol/g globin per cigarette per day.Finally dietary factors as possible sources of diHOPrVal background adducts, were studied in rats fed fried rat food for a period of 1-2 months. The adduct levels in rats fed the fried diet was about 50 % above adduct levels in control rats, suggesting that glycidol formed during heating of food is a source of diHOPrVal adducts in humans.The new analytical method was also used for studies of butadiene metabolites in vivo.