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Toxicokinetic differences between two major HBCD stereoisomers: Effect of dose, time, repeated exposure and route
Citation:
SZABO, D., J. J. DILIBERTO, H. Hakk, J. Huwe, AND L. S. BIRNBAUM. Toxicokinetic differences between two major HBCD stereoisomers: Effect of dose, time, repeated exposure and route. Presented at Society of Toxicology 49th Annual meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
This study examines the toxicokinetic differences between alpha HBCD and gamma HBCD (2 major stereoisomers ofHBCD) on the effect ofdose, time, repeated exposure and route in adult C57BLl6 mice,
Description:
Hexabromocyclododecane (HBCD) is a flame retardant primarily added to foam insulation used in buildings. Current demands for energy-efficient construction are increasing its use worldwide. This emerging global contaminant is a mixture of 3 stereoisomers [alpha (a), beta (B), gamma (y)] where a shift from the predominance ofy in the mixture to a in humans has been observed. To aid in predicting health risks, the kinetics ofy and a were investigated. For dose/response (3-100 mg/kg), time course (3mgikg up to 14 days), route (3mg/kg oral or iv) and repeated dose (3mg/kgiday for 10 days); 60 day old C57BL/6 female mice were treated with a single oral dose (except iv) of 14C_y or -a and put in metabolism cages. Tissues were collected 4 days post exposure except for time course. 14C was measured by combustion, LSS and LC-MS/MS. Disposition after 14C_y exposure was dose independent and linear across all doses with highest levels (% dose/g) in liver (0.28), blood (0.08) and fat (0.001). It was rapidly eliminated (1 day) in urine (23%) and feces (50%) with a 3 day half-life. Liver and feces contained metabolites (79-86%) and to a lesser extent parent (4-6%). Hydroxylation, debromination, and stereoisomerization of y to ~ and a (11-15%) were identified. After y or a, blood, bile and urine contained metabolites. Oral absorption of both was >95%. After 14C_a exposure, tissue levels were higher than 14C_y (::::15x) and deposition was a function of dose in fat, liver, muscle and skin. Bioaccumulation was supported by repeated exposure. 14C_a was eliminated slower in urine (16%) and feces (26-42%) by 1 day with a longer half life (21 days). In liver and feces, a predominated (:s62%) with no stereoisomerism. Dose-dependent decreases in fecal elimination suggest saturation of hepatic enzyme/transporters. Biological persistence of y in mice is limited and may explain low levels ofy in biota. Predominance of a in biota is likely due to selective metabolism and stereoisomerism. Abstract does not reflect USEPA, USDA and NCIINIEHS policy. Support: EPA CR833237