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Toxicokinetics of the Flame Retardant Hexabromocylodecane alpha: Effect of dose, timing, route, repeated exposure and metabolism
Citation:
SZABO, D., J. J. DILIBERTO, H. Hakk, J. Huwe, J. Huwe, AND L. Birnbaum. Toxicokinetics of the Flame Retardant Hexabromocylodecane alpha: Effect of dose, timing, route, repeated exposure and metabolism. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 121(2):234-44, (2011).
Impact/Purpose:
This study was conducted in an effort to fully characterize the absorption, distribution, metabolism and elimination of a-HBCD following a single and repeated exposure with respect to dose, time, and route of administraton in female C57BL/6 mice.
Description:
Alpha-hexabromocyclododecane (a-HBCD) is an emerging persistent organic pollutant present in the hexabromocyclododecane (HBCD) commercial mixture. HBCD is used as an additive flame retardant in a wide variety of household consumer products. Three main stereoisomers, alpha (a), beta (P), and gamma (y), comprise roughly 10%, 10%, and 80% of the mixture, respectively. Despite its small contribution to HBCD global production and usage, a-HBCD is the major stereoisomer found in wildlife and human tissues including breast milk and blood in North America, European Union and Asia. No mammalian or human data are currently available regarding the toxicokinetics of a-HBCD. This study was conducted in an effort to fully characterize the absorption, distribution, metabolism and elimination of a-HBCD following a single and repeated exposure with respect to dose, time, and route of administraton in female C57BL/6 mice. Results indicate that approximately 90% of the administered dose (3mg/kg) was absorbed after oral exposure. Disposition was 1) dictated by lipophilicity as adipose, liver; muscle and skin were major depots and 2) was dose-dependent with non-linear accumulation at higher doses. Elimination, both whole-body and from individual tissues, was biphasic. a-HBCD derived radioactivity was excreted in the feces as parent and metabolites whereas, urine only contained metabolites. Presence of polar metabolites in the blood and urine were a major factor in determining the rapid initial whole-body half-life after a single oral exposure. Initial half-lives were ~ 1-3 days and much longer terminal half-lives of 21 days were observed, suggesting the potential for a-HBCD bioaccumulation. A 10 day repeated study supports a-HBCD bioaccumulation potential. Stereoisomerization previously observed after exposure to y-HBCD was not seen after exposure of a HBCD. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk of a-HBCD which is the major stereoisomer found in wildlife and people.
