van der Ven Leo T M, Verhoef Aart, van de Kuil Ton, Slob Wout, Leonards Pim E G, Visser Theo J, Hamers Timo, Herlin Maria, Håkansson Helen, Olausson Hanna, Piersma Aldert H, Vos Josephus G
Laboratory for Toxicology, Pathology and Genetics, National Institute of Public Health and the Environment, 3720 BA Bilthoven, The Netherlands.
Toxicol Sci. 2006 Dec;94(2):281-92. doi: 10.1093/toxsci/kfl113. Epub 2006 Sep 19.
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.
用六溴环十二烷（HBCD）进行了一项针对大鼠的28天重复剂量研究（经合组织407号试验），该研究增强了对内分泌和免疫参数的检测。大鼠每天通过灌胃接触溶解于玉米油中的HBCD，分为8个剂量组，剂量范围为每天0至200毫克/千克体重（mg/kg bw）。评估包括剂量反应分析，在10%-20%的预定义关键效应大小（CESs）下计算下限95%单侧置信区间（BMDL）的基准剂量。最显著的发现是对甲状腺激素轴的剂量相关效应，即总甲状腺素降低（在CES为10%时，BMDL为55.5 mg/kg bw）、垂体重量增加（在10%时为29 mg/kg bw）以及垂体中促甲状腺激素免疫染色增加、甲状腺重量增加（在10%时为1.6 mg/kg bw）和甲状腺滤泡细胞活化。这些效应仅限于雌性大鼠。雌性大鼠还表现出绝对肝脏重量增加（在20%时为22.9 mg/kg bw）和T4-葡萄糖醛酸转移酶诱导（在10%时为4.1 mg/kg bw），这表明T4的异常代谢触发了甲状腺激素系统的反馈激活。这些效应伴随着可能的继发效应，包括雌性大鼠胆固醇增加（在10%时为7.4 mg/kg bw）、胫骨骨矿物质密度增加（在10%时>49 mg/kg bw），以及雄性大鼠脾细胞计数减少（在20%时为0.3 - 6.3 mg/kg bw；仅在雄性中评估）。总体而言，雌性大鼠似乎比雄性大鼠对HBCD更敏感，基于甲状腺重量增加10%（这是事件序列中最敏感的参数），建议总体BMDL为1.6 mg/kg bw。
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