Submitted to: Xenobiotica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/22/2005
Publication Date: 1/5/2006
Citation: Hakk, H., Huwe, J.K., Low, M.C., Rutherford, D., Larsen, G.L. 2006. Tissue disposition, excretion, and metabolism of 2,2',4,4',6-pentabromodiphenyl ether (BDE-100) in male Sprague-Dawley rats. Xenobiotica 36(1):79-94. Interpretive Summary: The polybrominated diphenyl ethers(PBDEs)have been among the most abundant brominated flame retardants used in many consumer products. Furthermore, a particular subset of five PBDEs are known to be environmentally persistent, among which is 2,2',4,4',6'-pentabromodiphenyl ether, i.e. BDE-100. The purpose of this study was to measure the metabolic behavior of radiolabeled [14C]BDE-100 in male rats for 3 days. BDE-100 was well absorbed, as indicated by >70% retention in tissues at 3 days. Residual carcass, GI tract, adipose tissue, lungs and liver contained the largest portion of the dose. Further fractionation of the carcass revealed approximately half of the radioactivity deposited in the skin. All other tissues contained less than 0.1% of the administered dose at 3 days. Lipophilic tissues contained the highest concentrations of BDE-100, e.g. adipose tissue, GI tract, skin, liver and lungs. Tissue extracts of liver, GI tract, and adipose tissue contained only parent material. Urine and bile excretion were very low, i.e. 0.1 and 1.7% of the dose. No parent was present in the urine, and glucuronide metabolites were suggested. Feces was the major route of BDE-100 excretion. Extractable fecal metabolites were identified by mass spectrometry and indicated hydroxylation and debromination were the only characteristic pathways of rat metabolism of BDE-100. Non-extractable fecal metabolites were hypothesized to be the result of metabolism and binding to protein and/or lipid in the feces. The majority of the 0-72h biliary radioactivity was associated with an unidentified 79 kDa protein and to albumin.
Technical Abstract: Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in the furniture, textile, and electronics industries. Due to their environmental persistence and known toxicological effects, there is an increasing concern about PBDEs. A few PBDEs are consistently found in the environment, among them is 2,2',4,4',6-pentabromodiphenyl ether (BDE-100). Our purpose was to conduct an metabolism study with BDE-100 in male rats for 72h. A single oral dose of [14C]BDE-100 was administered to conventional and bile-duct cannulated, Sprague-Dawley rats. In conventional rats, >70% of the dose was retained in the body at 72h. Although [14C] was detected in all tissues, carcass, GI tract, and fat contained the largest portion of the dose. 50% of the carcass BDE-100 had deposited in the skin. On a concentration basis, the lipophilic tissues, i.e. fat, GI tract, and skin, contained the highest concentration of BDE-100 (>35 nmol/g-tissue fresh weight). Tissue extracts of liver, GI tract, and fat only contained parent material. Cumulative urine and bile excretion amounted to only 0.1 and 1.7% of the dose, respectively. Bile contained 7-17% parent compound and multiple metabolites of BDE-100, some conjugated to glucuronic acid. Feces was the major route of BDE-100 excretion (~20% of dose). Fecal extracts mainly contained parent compound, but metabolites, characterized by derivatization and mass spectrometry, had undergone hydroxylations and debrominations, and no thiol metabolites were observed. Non-extractable radioactivity amounted to 56-87% of the fecal content, and was hypothesized to have been formed by metabolic activation. 65% of 0-72h bile was bound to an unidentified 79 kDa protein and to albumin.