ToxSci Advance Access originally published online on September 19, 2006
Toxicological Sciences 2006 94(2):281-292; doi:10.1093/toxsci/kfl113
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A 28-Day Oral Dose Toxicity Study Enhanced to Detect Endocrine Effects of Hexabromocyclododecane in Wistar Rats
* Laboratory for Toxicology, Pathology and Genetics, 3720 BA Bilthoven, The Netherlands
Centre for Substances and Integrated Risk Assessment, National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
Institute for Environmental Studies, Vrije Universiteit Amsterdam, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands
Department of Internal Medicine, Room Ee 502, Erasmus Medical Center, 3000 Dr Rotterdam, The Netherlands
¶ The Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
Received July 14, 2006; accepted September 13, 2006
A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the lower 95% one-sided confidence bound (BMDL) at predefined critical effect sizes (CESs) of 10–20%. The most remarkable findings were dose-related effects on the thyroid hormone axis, that is, decreased total thyroxin (TT4, BMDL 55.5 mkd at CES – 10%), increased pituitary weight (29 mkd at 10%) and increased immunostaining of TSH in the pituitary, increased thyroid weight (1.6 mkd at 10%), and thyroid follicle cell activation. These effects were restricted to females. Female rats also showed increased absolute liver weights (22.9 mkd at 20%) and induction of T4-glucuronyl transferase (4.1 mkd at 10%), suggesting that aberrant metabolization of T4 triggers feedback activation of the thyroid hormone system. These effects were accompanied by possibly secondary effects, including increased cholesterol (7.4 mkd at 10%), increased tibial bone mineral density (> 49 mkd at 10%), both in females, and decreased splenocyte counts (0.3–6.3 mkd at 20%; only evaluated in males). Overall, female rats appeared to be more sensitive to HBCD than male rats, and an overall BMDL is proposed at 1.6 mkd, based on a 10% increase of the thyroid weight, which was the most sensitive parameter in the sequence of events.
Key Words: hexabromocyclododecane; brominated flame retardants; endocrine disruption; thyroid hormones; rats; hazard identification; risk assessment.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. M. L. Dingemans, H. J. Heusinkveld, A. de Groot, A. Bergman, M. van den Berg, and R. H. S. Westerink Hexabromocyclododecane Inhibits Depolarization-Induced Increase in Intracellular Calcium Levels and Neurotransmitter Release in PC12 Cells Toxicol. Sci., February 1, 2009; 107(2): 490 - 497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Crump, S. Chiu, C. Egloff, and S. W. Kennedy Effects of Hexabromocyclododecane and Polybrominated Diphenyl Ethers on mRNA Expression in Chicken (Gallus domesticus) Hepatocytes Toxicol. Sci., December 1, 2008; 106(2): 479 - 487. [Abstract] [Full Text] [PDF]
|
|