title: A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.
abstract: 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.
authors.affiliation: Laboratory for Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands. l.van.der.ven@rivm.nl
authors.forename: Leo T M
authors.initials: LT
authors.lastname: van der Ven
authors.forename: Aart
authors.initials: A
authors.lastname: Verhoef
authors.forename: Ton
authors.initials: T
authors.lastname: van de Kuil
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
authors.forename: Pim E G
authors.initials: PE
authors.lastname: Leonards
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Timo
authors.initials: T
authors.lastname: Hamers
authors.forename: Maria
authors.initials: M
authors.lastname: Herlin
authors.forename: Helen
authors.initials: H
authors.lastname: Håkansson
authors.forename: Hanna
authors.initials: H
authors.lastname: Olausson
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.forename: Josephus G
authors.initials: JG
authors.lastname: Vos
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000145:classification / Q000633:toxicity*; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D006842:Hydrocarbons, Brominated / Q000145:classification / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000378:metabolism; D013977:Tibia / Q000187:drug effects / Q000378:metabolism; D018675:Toxicity Tests
chemical_list: D052244:Endocrine Disruptors; D006842:Hydrocarbons, Brominated; C089796:hexabromocyclododecane; D013972:Thyrotropin; C117189:thyroxine-UDP-glucuronosyltransferase; D014453:Glucuronosyltransferase