Submitted to: Xenobiotica
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/12/2008
Publication Date: 1/1/2009
Citation: Hakk, H., Huwe, J.K., Larsen, G.L. 2009. Absorption, Distribution, Metabolism and Excretion (ADME) Study with 2,2',4,4',5,6' Hexabromodiphenyl Ether (BDE 154) in Male Sprague-Dawley Rats. Xenobiotica. 39:46-56. Interpretive Summary: The polybrominated diphenyl ethers(PBDEs)are among the most abundant brominated flame retardants in use. Furthermore, a particular subset of five PBDEs are known to be environmentally persistent, among which is 2,2',4,4',5,6'-hexabromodiphenyl ether, i.e. BDE-154. The purpose of this study was to measure the metabolic behavior of radiolabeled [14C]BDE-154 in male rats for 3 days. Intestinal absorption was calculated to be approximately 77% of the administered dose. Of this value, 31% was found in tissues of the carcass at 72h and 24% was extractable and non-extractable metabolites in the feces, and about 1% was excreted in the urine. BDE-154 was not readily excreted in the bile (1.3%). The largest portion of the BDE-154 dose was detected in the carcass, GI tract, adipose tissue and liver. Further fractionation of the carcass revealed approximately half of the radioactivity deposited in the skin. When the tissue data is expressed on a concentration basis, the lipophilic tissues had the highest concentration of BDE-154, i.e. adrenals, adipose tissue, GI tract, skin, and liver, although the dose could be found in every tissue sampled. Extractable fecal metabolites were identified by mass spectrometry and indicated hydroxylation and debromination were the only characteristic pathways of rat metabolism of BDE-154. Conjugated metabolites in urine and bile were suspected to be members of the mercapturic acid pathway. Non-extractable fecal metabolites were hypothesized to be the result of metabolism and binding to protein and/or lipid in the feces, therefore, a considerably higher overall metabolism of BDE-154 was suggested when also considering the non-extractable fecal data than from the urine, bile and extractable fecal metabolite data alone.
Technical Abstract: Polybrominated diphenyl ethers(PBDEs)are among the most abundant brominated flame retardants in use in many consumer products. A particular subset of five PBDEs are known to be environmentally persistent, i.e. BDE-47, -99, -100, 153, and -154. Mammalian ADME studies have already been performed for BDE-47, -99, and -100. The purpose of this study was to determine the metabolic behavior of radiolabeled [14C]BDE-154 in conventional and bile-duct cannulated male rats for 3 days. Seventy-one percent of a BDE-154 dose was absorbed at 72hr, and preferentially deposited in the residual carcass (24%), skin (13%), GI tract (3.8%), and epididymal fat (1.8%), although it was detected in every tissue sampled. When the tissue data was expressed on a concentration basis, the lipophilic tissues had the highest concentration of BDE-154, i.e. adrenal gland (30 nmol/g fresh weight),adipose tissue (22), GI tract (18), skin (8), and liver (6). Low excretion to water-soluble metabolites was observed, i.e. 1% of the dose was excreted via the urine, and approximately 1.3% was excreted in the bile after 3 days. Glucuronide and sulfate conjugates were not present in urine and bile, therefore, mercapturic acid pathway metabolites were suspected. Fecal excretion was the major route of elimination (62% at 3 days), and it contained a high level of non-extractable BDE-154 residues (26-42% of daily fecal content). Metabolites identified in the extractable portion of the feces were monohydroxylated, monohydroxylated with an accompanying loss of a bromine, dihydroxylated with an accompanying loss of two bromines. The non-extractable fecal radioactivity was hypothesized to form via metabolic activation followed by covalent binding to proteins and/or lipids. A comparison with other PBDE results demonstrated the importance of conducting individual metabolism studies with PBDEs.