A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.

2.50
Hdl Handle:
http://hdl.handle.net/10029/6727
Title:
A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.
Authors:
Ven, Leo T M van der; Verhoef, Aart; Kuil, Ton van de; Slob, Wout; Leonards, Pim E G; Visser, Theo J; Hamers, Timo; Herlin, Maria; Håkansson, Helen; Olausson, Hanna; Piersma, Aldert H; Vos, Josephus G
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.
Citation:
Toxicol. Sci. 2006, 94(2):281-92
Issue Date:
1-Dec-2006
URI:
http://hdl.handle.net/10029/6727
DOI:
10.1093/toxsci/kfl113
PubMed ID:
16984958
Type:
Article
Language:
en
ISSN:
1096-6080
Appears in Collections:
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Full metadata record

DC FieldValue Language
dc.contributor.authorVen, Leo T M van der-
dc.contributor.authorVerhoef, Aart-
dc.contributor.authorKuil, Ton van de-
dc.contributor.authorSlob, Wout-
dc.contributor.authorLeonards, Pim E G-
dc.contributor.authorVisser, Theo J-
dc.contributor.authorHamers, Timo-
dc.contributor.authorHerlin, Maria-
dc.contributor.authorHåkansson, Helen-
dc.contributor.authorOlausson, Hanna-
dc.contributor.authorPiersma, Aldert H-
dc.contributor.authorVos, Josephus G-
dc.date.accessioned2007-01-02T13:02:22Z-
dc.date.available2007-01-02T13:02:22Z-
dc.date.issued2006-12-01-
dc.identifier.citationToxicol. Sci. 2006, 94(2):281-92en
dc.identifier.issn1096-6080-
dc.identifier.pmid16984958-
dc.identifier.doi10.1093/toxsci/kfl113-
dc.identifier.urihttp://hdl.handle.net/10029/6727-
dc.description.abstractA 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.en
dc.format.extent370297 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.titleA 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.en
dc.typeArticleen
dc.format.digYES-

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