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ARS Home » Plains Area » Fargo, North Dakota » Edward T. Schafer Agricultural Research Center » Food Animal Metabolism Research » Research » Publications at this Location » Publication #321298
Title: Comparative metabolism studies of hexabromocyclododecane (HBCD) diastereomers in male rats following a single oral dose

Author
item Hakk, Heldur

Submitted to: Environmental Science and Technology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/2/2015
Publication Date: 1/5/2016
Publication URL: http://handle.nal.usda.gov/10113/5363094
Citation: Hakk, H. 2016. Comparative metabolism studies of hexabromocyclododecane (HBCD) diastereomers in male rats following a single oral dose. Environmental Science and Technology. 50(1):89-96.

Interpretive Summary: Hexabromocyclododecane (HBCD) is an important brominated flame retardant that is considered persistent, toxic, and bioaccumulative. Commercial-grade HBCD is comprised of three isomers, called alpha-, beta-, and gamma-HBCD, but is dominated by gamma-HBCD. Biological samples, on the other hand, are dominated by the alpha-HBCD isomer. We hypothesized that metabolism determines these isomer pattern differences between manufactured product and living tissue. In laboratory studies, we administered three groups of rats each one of the three HBCD isomers, and followed the isomers in the urine, feces, and tissues. Consistent with our hypothesis, when we measured the total metabolism, it was clear that alpha-HBCD was more poorly metabolized than beta- or gamma-HBCD. We also identified that both beta- and gamma-HBCD could be converted into alpha-HBCD, contributing to additional accumulation of this isomer. Tissue levels of HBCD isomers were highest in fatty tissues, and the concentration of alpha-HBCD was always much higher than beta- or gamma-HBCD. Finally, we identified unique metabolites of each HBCD isomer, and concluded that each isomer underwent a slightly different metabolic pathway. Our findings confirm that it is likely that alpha-HBCD is the dominant HBCD isomer in biological samples because it is metabolized the least, formed by conversion of beta- and gamma-HBCD, and retained in the tissues to the highest extent.

Technical Abstract: Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively 42% of dose for alpha-HBCD, 59% for beta-HBCD, and 53% for gamma-HBCD. Urine was also an important route of HBCD excretion, containing 13% of dose for alpha-HBCD, 30% for beta-HBCD, and 21% for gamma-HBCD. Total metabolism of HBCD diastereomers followed the rank order beta > gamma > alpha, and was >65% of that administered. The metabolites formed were distinct in male rats: alpha-HBCD was not debrominated, two hydroxylated metabolites were produced, and was not stereoisomerized; beta- and gamma-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. beta-HBCD was biotransformed to three mercapturic acid pathway metabolites. The metabolites of beta- and gamma-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that alpha-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the beta- and gamma- diastereomers.