Submitted to: Toxicological Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/9/2011
Publication Date: 6/24/2011
Publication URL: http://handle.nal.usda.gov/10113/53779
Citation: Szabo, D.T., Diliberto, J.J., Huwe, J.K., Birnbaum, L.S. 2011. Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice. Toxicological Sciences. 123(1):256-263. Interpretive Summary: Hexabromocyclododecane (HBCD) is a high-production-volume flame retardant chemical used in many household products. Public health concerns have focused on the exposure of infants and young children to HBCD due to reports of adverse developmental effects from rodent toxicity studies. HBCD is composed of two major forms (gamma-HBCD and alpha-HBCD); therefore, in this study we dosed juvenile mice with each of the HBCD forms and measured the tissue levels in the mice over time. The data were compared to determine any differences between the two HBCD forms in young mice, and also were compared to data from a previous study in adult mice to determine any differences due to age. The results showed that alpha-HBCD accumulated in the juvenile mice to more than twice as high a concentration as the gamma-HBCD and stayed in their bodies longer. Compared to adult mice, the juvenile mice had 2-times and 10-times higher levels of alpha-HBCD and gamma-HBCD, respectively, in their bodies. These results suggest that young animals may accumulate higher concentrations of both HBCD forms and, therefore, may be at higher risk than adults to the potentially harmful effects of HBCD.
Technical Abstract: HBCD is a mixture of three main stereoisomers, alpha (a), beta (b) and gamma (g). Despite its minor contribution to global hexabromocyclododecane production and usage, a-HBCD is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of 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 nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in disposition of both g-HBCD and a-HBCD in infantile mice reported to be susceptible to HBCD. The tissue distribution of a-[14C]HBCD and g-[14C]HBCD derived radioactivity was monitored in postnatal day 10 (PND 10) C57BL/6 mice following a single oral dose of either compound at 3 mg/kg. Mice were held up to 7 days in shoebox cages when pups were sacrificed, tissue collected and internal dosimetry was measured. 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. Developing mice exposed to a-HBCD had an overall higher body burden than g-HBCD at every time point measured; at 4 days post exposure they retained 22% of the a-HBCD administered dose while pups exposed to g-HBCD retained 10%. Total body burden in infantile mice after exposure to g-HBCD was increased 10 fold as compared to adults. Similarly, after exposure to a-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. This study suggests that age may be a risk factor for the harmful effects of both HBCD diastereomers when developing animals may have increased susceptibility.