Title: Toxicokinetics of the flame retardant hexabromocyclododecane alpha: effect of dose, timing, route, repeated exposure and metabolism Authors
|Szabo, David -|
|Diliberto, Janet -|
|Birnbaum, Linda -|
Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 29, 2011
Publication Date: June 2, 2011
Citation: Szabo, D.T., Diliberto, J.J., Hakk, H., Huwe, J.K., Birnbaum, L.S. 2011. Toxicokinetics of the flame retardant hexabromocyclododecane alpha: effect of dose, timing, route, repeated exposure and metabolism. Toxicological Sciences. 121(2):234-244. Interpretive Summary: Hexabromocyclododecane (HBCD) is an additive flame retardant in many household products. Commercially, HBCD exists as three isomers, alpha (a), beta (b), and gamma (g). g-HBCD is the major isomer in the commercial mix, while a-HBCD is the main isomer found in biota, including breast milk and blood. The question to address in this research was whether the HBCD pattern in biota is due to greater resistance to metabolism for a-HBCD, or to interconversion of g- and/or b-HBCD into a. Metabolism studies with a-HBCD were conducted with single and repeated doses in mice, while dose level, time, and route of administration were varied. Results indicated that a-HBCD was well-absorbed after oral exposure. Disposition was to fatty tissues, like adipose, liver, muscle and skin, and was not linear with dose level. Elimination, both whole-body and from individual tissues, was rapid for the first few hours, but slowed markedly thereafter. a-HBCD was excreted extensively in the feces as parent and metabolites, and was eliminated to a lesser degree as polar metabolites in the blood and urine. Long half-lives suggested the potential for a-HBCD bioaccumulation, and a repeated dosing study supported this conclusion. Conversion of a-HBCD into the other isomers was not observed, which contrasted with a parallel study with g-HBCD, where significant conversion to a-HBCD and b-HBCD was observed. These data demonstrated that high levels of a-HBCD in biological samples are due to its slow metabolism and the conversion of other HBCD isomers into a-HBCD.
Technical Abstract: Hexabromocyclododecane (HBCD) is an additive flame retardant in many household products. Three stereoisomers, alpha (a), beta (b), and gamma (g), comprise roughly 10%, 10%, and 80% of the mixture, respectively. a-HBCD is the major stereoisomer found in biota, 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 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 administration in female mice. Results indicated that approximately 90% of the administered dose (3 mg/kg) was absorbed after oral exposure. Disposition was (1) dictated by lipophilicity since 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. Presence of polar metabolites in the blood and urine were a major factor in the rapid initial (1-3 day) whole-body half-life after a single oral exposure. Terminal half-lives of 21 days suggested the potential for a-HBCD bioaccumulation, and a 10 day repeated study supported this conclusion. Stereoisomerization of a-HBCD was not observed. The toxicokinetic behavior reported here has important implications to the assessment of risk of a-HBCD.