The metabolism and disposition of 14C-labelled 2,2',4,4',5-pentabromodiphenyl ether (BDE99) were studied in F344 rats and B6C3F1 mice. Approximately 85% of a 1 micromol kg-1 oral dose was absorbed by male rats and mice. Within 24 h following oral doses ranging from 0.1 to 1000 micromol kg-1 to rats, 39-47% of the dose was excreted in the faeces (including 16% unabsorbed), up to 2% was excreted in the urine, and 34-38% remained in the tissues, mostly in adipose tissue. Mice excreted more in the urine and less in the faeces than rats. Tissue accumulation was observed following repeated dosing to rats. Two dihydrohydroxy-S-glutathionyl and two S-glutathionyl conjugates of BDE99, 2,4,5-tribromophenol glucuronide, two mono-hydroxylated BDE99 glucuronides, and three mono-hydroxylated tetrabromodiphenyl ether glucuronides were identified in male rat bile. 2,4,5-Tribromophenol and its glucuronide and sulfate conjugates, were identified in male rat urine. 2,4,5-Tribromophenol, one mono-hydroxylated tetrabromodiphenyl ether, and two mono-hydroxylated BDE99 were characterized in male rat faeces. BDE99 undergoes more extensive metabolism than does BDE47. Half of the absorbed oral dose in male rats was excreted in 10 days mostly as metabolites derived from arene oxide intermediates.

Polybrominated diphenyl ethers (PBDEs), used as flame retardants, have been detected in the environment and in mammalian tissues and fluids. Evidence indicates that PBDE mixtures induce CYPs through aryl hydrocarbon receptor (AhR)-dependent and -independent pathways. The present work has investigated the effects of individual components of a commercial PBDE mixture (DE71) on expression of CYP1A1, a biomarker for activation of the AhR (dioxin-like), and CYP2B and CYP3A, biomarkers for activation of the constitutive androstane and pregnanexreceptors (CAR and PXR), respectively, in the rat. Male F344 rats were dosed orally on three consecutive days with either DE71, PBDE components, 2,2',4,4'-tetraBDE (BDE47), 2,2',4,4',5-pentaBDE (BDE99), 2,2',4,4',5,5'-hexaBDE (BDE153), representative polybrominated dibenzofurans (PBDFs) present in DE71, or reference PCBs. Differential expression of target genes was determined in liver 24 h after the last dose. Quantitative PCR analysis indicated up-regulation of CYP1A1 by DE71; however, the response was weak compared to that for dioxin-like PCB126. Individual PBDE components of DE71 up-regulated CYP1A1 only at the highest administered dose (100 micromol/kg/day). Representative PBDFs efficiently up-regulated CYP1A1; therefore, they, along with other PBDFs and polybrominated dibenzodioxins detected in DE71 and individual PBDE components, may be responsible for most, if not all, dioxin-like properties previously observed for PBDEs. Conversely, PBDEs appear capable of up-regulating CYP2B and CYP3A in rats at doses similar to that for non-dioxin-like PCB153. These results indicate that in vivo PBDE-mediated toxicity would be better categorized by AhR-independent mechanisms, rather than the well-characterized AhR-dependent mechanism associated with exposure to dioxin-like chemicals.

The metabolism and disposition of (14)C-labelled 2,2',4,4'-tetrabromodiphenyl ether (BDE47) were investigated in F344 rats and B6C3F1 mice. Approximately 75-85% of 1 micromol BDE47 kg(-1) was absorbed following oral administration to either rats or mice. Sex and species differences were observed in tissue distribution and excretion of BDE47-derived radioactivity. Absorption and distribution of (14)C to major tissues were dose-proportional in male rats from 0.1 to 1,000 micromol kg(-1). BDE47-derived radioactivity increased in all rat and mouse tissues examined following repeated daily doses of 1 micromol kg(-1). Accumulation of (14)C in tissues of mice was less than in corresponding rat tissues. Glutathione conjugates of BDE47 were excreted in rat bile. A glucuronide and a sulfate conjugate of 2,4-dibromophenol were detected in the urine of BDE47-treated rats. BDE47 appears to induce its own metabolism. Increased formation of reactive metabolites over time may correlate with toxicological effects in BDE47-treated rodents.

1.The disposition of the 14 C-labeled polybrominated diphenyl ether (PBDE), 2,2′,4,4′,5,5′-hexaBDE (BDE153) was investigated in rodents following single and multiple doses and in a mixture with radiolabeled 2,2′,4,4′-tetraBDE (BDE47) and 2,2′,4,4′,5-pentaBDE (BDE99). 2.In single exposure studies, there was little or no effect of dose on BDE153 disposition in male rats in the range of 1-100 µmol/kg. No major sex or species differences in the in vivo fate of BDE153 were detected. BDE153 was: 1) approximately 70% absorbed in rats or mice following gavage. 2) retained in tissues. 3) poorly metabolized and slowly excreted. 3.Mixture studies indicated that, relative to each other, more BDE47 was distributed to adipose tissue, more BDE153 accumulated in liver, and BDE99 was metabolized to the greatest extent. BDE153 was probably retained in liver due to minimal metabolism and elimination after "first pass" distribution to the tissue following gavage.