Metabolism of some polychlorinated biphenyl and polybrominated diphenyl ether congeners in the rat

Abstract: For the understanding of the metabolic fate of xenobiotics, in vivo studies are needed. In this thesis the metabolism of CB-28 and CB-77 and BDE-209 in the rat are determined. In addition, pharmacokinetic studies of CB-28 and BDE- 209 are included. The compounds were radiolabelled and their excretion and tissue distribution determined. The metabolites were characterised by their behaviour in the clean-up steps. The analysis of non-conjugated metabolites was performed by GC/MS. For other metabolites, HPLC with radioactivity monitoring and LC/MS were used for the characterisation. The absorption of BDE-209 has previously been reported to be low, <1%. In this work the bioavailability of BDE-209 was determined to be as high as 26% and strong indications that its absorption was even higher. Lipophilic compounds are generally distributed to lipid-rich tissues. CB-28 was rapidly distributed to adipose tissue, which over time had the highest concentration. BDE-209 was not readily distributed to adipose tissue, the liver and plasma showing the highest concentrations instead. Selective distribution can be explained by selective affinity for certain tissue proteins. Orthohydroxylated CB-28 metabolite was selectively retained in the brain. There were indications that hydroxylated BDE-209 metabolites were selectively retained in plasma. The terminal half-life of BDE-209 in rat plasma was 57 h and metabolism and faecal excretion the major routes of elimination.Common for all compounds was that the metabolic pathway included reactive metabolites. Non-extractable, water-soluble and lipid-bound metabolites were also found. For CB-77, the lipid-bound metabolites were studied and these were shown to be associated to polar lipids, e.g. phospholipids. There were indications that they were formed in the liver.In conclusion, this thesis discusses the metabolism of two PCB congeners and BDE-209. The importances of metabolism studies are emphasised for risk assessment and the understanding of levels in biota. The clearance, metabolism and distribution of a compound are essential for an understanding of biological and toxicological effects.