Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/29/2010
Publication Date: 6/18/2010
Publication URL: http://handle.nal.usda.gov/10113/53788
Citation: Szabo, D.T., Diliberto, J.J., Hakk, H., Huwe, J.K., Birnbaum, L.S. 2010. Toxicokinetics of the flame retardant hexabromocyclododecane gamma: effect of dose, timing, route, repeated exposure and metabolism. Toxicological Sciences. 117:282-293. DOI:10:1093/toxsci/kfq183. Interpretive Summary: Hexabromocyclododecane (HBCD) is a flame retardant chemical used in many household products. HBCD is a high production volume chemical that now appears to be widely spread in the environment and accumulating in wildlife. Although the commercial mixture is mainly in the gamma form (70%), it is the alpha form that is most often found in wildlife and human tissues. In order to determine why alpha rather than gamma predominates in animals tissues, we have conducted a study in mice to measure the absorption, distribution, and excretion of gamma-HBCD. Results of the study showed that the gamma form of HBCD was readily absorbed from the diet but was also quickly excreted by the mice. This suggests that gamma-HBCD does not have a propensity to accumulate in animal tissues, and this may be the reason it is not as commonly found in wildlife or humans even though it is the predominant form of HBCD commercially produced.
Technical Abstract: 1,2,5,6,9,10-Hexabromocyclododecane-gamma ('-HBCD) is the predominate diastereoisomer in the commercial HBCD mixture used as a flame retardant in a wide variety of consumer products. Three main diastereoisomers, alpha (a), beta (ß) and gamma (') comprise the commercial mixture. Despite the '-diastereoisomer being the major diastereoisomer in the mixture and environmental samples, the a-diastereoisomer predominates in human tissue and wildlife. This study was conducted to characterize absorption, distribution, and elimination parameters of '-HBCD with respect to dose and time following a single acute exposure and repeated exposure in adult female C57BL/6 mice. Results indicate that 85% of the administered dose (3mg/kg) was absorbed after oral exposure. Disposition was dose-independent and didn’t significantly change after 10 days of exposure. Liver was the major depot (<0.3% of dose) four-days after treatment followed by blood, fat and then brain. '-HBCD was rapidly metabolized and eliminated in the urine and feces. For the first time, in vivo stereoisomerization was observed of the '-diastereoisomer to the ß-diastereoisomer in liver and brain tissues, and to the a- and ß-diastereoisomer in feces. Polar metabolites in the blood and urine were a major factor in determining the initial whole-body half-life (1 day) after a single oral exposure. Elimination, both whole-body and from individual tissues, was biphasic. Initial half-lives were approximately 1 day, whereas terminal half-lives were up to 4 days, suggesting limited potential for '-diastereoisomer bioaccumulation. The toxicokinetic behavior reported here has important implications for the extrapolation of toxicological studies of the commercial HBCD mixture to the assessment of risk.