Adducts with haemoglobin and with DNA in epichlorohydrin-exposed rats

Epichlorohydrin (1-chloro-2,3-epoxypropane; ECH) is an important industrial chemical and a carcinogen in experimental animals. The main aims of the pr esent study were to characterize the adduct formation in female Wistar rats and to identify adducts that could potentially be used in human biomonitor ing studies. The total binding of radioactivity to haemoglobin in rats admi nistered 0, 0.11, 0.22, 0.43, or 0.97 nnmol [H-3]ECH/kg body weight by i.p. injection, and sacrificed 24 h after treatment, was linearly related to a dose up to 0.43 mmol/kg body weight. The binding at the highest dose was hi gher than predicted by extrapolation from lower doses, indicating saturatio n of a metabolic process for elimination of ECH. Ion-exchange chromatograph y of a globin hydrolysate showed one major radioactivity peak corresponding to S-(3-chloro-2-hydroxypropyl)cysteine. The half-life of this adduct was estimated as about 4 days by analysis of globin from rats administered 0.43 mmol/kg body weight and sacrificed after 1, 2 and 9 days. Crosslinking of the adduct, presumably with glutathione, appeared to be the predominant sec ondary reaction. Hydrolysis of N-(3-chloro-2-hydroxypropyl)valine, the prim ary reaction product of ECH with N-terminal valine, would give N-(2,3-dihyd roxypropyl)valine. A sensitive gas chromatography/mass spectrometry method for the dihydroxypropyl adduct was used to follow its formation and removal after administration of nonlabelled ECH (0.11 mmol/kg body weight). The le vel of this adduct reached a maximum of about 20 pmol/g globin after a few weeks, corresponding to about 0.1% of the initial binding of ECH to globin. N-7-(3-Chloro-2-hydroxypropyl)guanine was detected in rats administered 0. 97 mmol [H-3]ECH/kg body weight and sacrificed 6 h after treatment, The add uct levels in haemoglobin and DNA were compared with previously reported ad duct levels in male Fischer 344 rats exposed to propylene oxide. Despite it s higher chemical reactivity, the capacity of ECH to alkylate macromolecule s in vivo was found to be somewhat lower than that of propylene oxide. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.