Submitted to: Dioxin Meeting
Publication Type: Proceedings
Publication Acceptance Date: 7/13/2010
Publication Date: 8/30/2010
Citation: Hakk, H., Huwe, J.K., Szabo, D., Diliberto, J., Birnbaum, L.S. 2010. Metabolism of a- and y-hexabromocyclododecane and enanyioselective fractions of a-, ß-, y-isomers in mice. 30th International Symposium on Halogenated Persistant Organic Pollutants (POPs), September 12-17, 2010, San Antonio, TX. Available: http://www.hcdtech.com/dioxin2010/pdf/1436.pdf. Interpretive Summary: Hexabromocyclododecane (HBCD) is a persistent organic pollutant, like dioxins, PCBs and PBDEs. HBCD is an important flame retardant in the construction industry and is a mixture of three major isomers, a, ß, and ', but the '-diastereoisomer predominates (>70%). However, in environmental samples the a-isomer is the predominant isomer detected. Whether this occurs by different rates of metabolism, or by isomerization of the '-diastereoisomer was tested by conducting an metabolism study '-[14C]HBCD in mice. Most of the '-HBCD dose was excreted in the feces (59%) or urine (28%) within 96 hours. Urine contained a highly polar metabolite, but no parent compound was detected. Fecal extracts of '-HBCD mice consisted of a-, ß- and '-HBCD, suggesting isomerization of '-HBCD had occurred, but this was not observed in a-HBCD mice. Fecal metabolites for '-HBCD were the result of hydroxylation, debromination, and unsaturation, while only hydroxylation was observed for a-HBCD. Bile and serum was composed of only polar metabolites indicating that rapid metabolism and elimination of '-HBCD occurred in mice. Each HBCD isomer could also exist as another isomer, called an enantiomer. Each enantionmer was measured and expressed as an Enantiomeric Fraction (EF). For standard a-, ß- and '-HBCD EFs were approximately 0.5 (0.53 to 0.55), but in liver and fat extracts, EFs were 0.63 to 0.84, suggesting selective accumulation of certain HBCD enantiomers in these tissues. Collectively, these data demonstrate that '-HBCD is well absorbed, readily eliminated, and highly metabolized in mice, the data suggest that both metabolism differences and isomerization play a role in environmental levels of HBCD.
Technical Abstract: Commercial HBCD is a mixture of three major isomers, a, ß, and ', with the '-diastereoisomer predominating (>70%). Thus, the prevalence of the a-isomer as an environmental contaminant must be explained by either different pharmacokinetics, or by isomerization of the '-diastereoisomer. a- and '-[14C]HBCD ADME studies were conducted in mice and tissue/excreta were analyzed for dosed compound, a/ß-HBCD isomerization products, and other metabolites. Nearly 90% of the '-[14C]HBCD dose was excreted in the feces (59% of dose) or urine (28% of dose) within 96 hours. Urine from both dose groups contained highly polar metabolites, no parent compound was detected, and radioactivity was not bound to carrier proteins. Fecal extracts from '-HBCD mice consisted of a-, ß- and '-HBCD, suggesting isomerization of '-HBCD had occurred, while no stereoisomerization was observed with the a-HBCD dosed mice. Fecal extracts from '-HBCD mice contained at least one monohydroxylated-debrominated-unsaturated metabolite (M-H 571, 5 Br), and a dihydroxylated-debrominated-unsaturated metabolite (M-H 587, 5 Br); while extracts from a-HBCD dosed mice consisted of a monohydroxylated metabolite by LC/MS (M-H 651, 6 Br). Bile and serum from '-HBCD mice were composed of only polar metabolites by TLC. The Enantiomeric Fraction (EF) of each enantiomeric pair was determined. For a-, ß- and '-HBCD standards EFs were determined to be approximately 0.5 (0.53 to 0.55). Liver and fat extracts analyzed by chiral LC/MS yielded EFs of 0.63 to 0.84, suggesting selective accumulation of certain HBCD enantiomers in this tissue. EF’s from feces were inconclusive, although was suggestive of stereoselectivity of '-HBCD mice in '-HBCD dosed mice.