title: Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice.
abstract: Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (α), beta (β), and gamma (γ). γ-HBCD dominates the mixture (∼70%), and despite α-HBCD's minor contribution to global HBCD production and usage (∼10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both γ-HBCD and α-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of α-[(14)C]HBCD- and γ-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to α-HBCD had an overall higher body burden than γ-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the α-HBCD administered dose, whereas pups exposed to γ-HBCD retained 10%. Total body burden in infantile mice after exposure to γ-HBCD was increased 10-fold as compared with adults. Similarly, after exposure to α-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice; whereas distribution patterns are similar, concentrations of each HBCD diastereomer's-derived radioactivity are higher in the pup's liver, fat, kidney, brain, blood, muscle, and lungs than in the adult's. This study suggests that developmental stage may be a risk factor for the harmful effects of α-HBCD and γ-HBCD, when developing animals may be more sensitive to effects and have increased body burden.
authors.affiliation: University of North Carolina-Chapel Hill Curriculum in Toxicology, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. Szabo.David@epa.gov
authors.forename: David T
authors.initials: DT
authors.lastname: Szabo
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Diliberto
authors.forename: Janice K
authors.initials: JK
authors.lastname: Huwe
authors.forename: Linda S
authors.initials: LS
authors.lastname: Birnbaum
mesh_terms: D000367:Age Factors; D000818:Animals; D001822:Body Burden; D005260:Female; D005411:Flame Retardants / Q000493:pharmacokinetics* / Q000633:toxicity; D006842:Hydrocarbons, Brominated / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D005411:Flame Retardants; D006842:Hydrocarbons, Brominated; C089796:hexabromocyclododecane