Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism.
Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism.
复制标题
DOI：
10.1289/ehp.8195
复制
发表时间：
2005-11
影响因子：
10.4
通讯作者：
DeVito MJ
中科院分区：
文献类型：
--
作者：
Crofton KM;Craft ES;Hedge JM;Gennings C;Simmons JE;Carchman RA;Carter WH Jr;DeVito MJ
环境污染物造成的内分泌干扰与多种不良后果有关。关于干扰内分泌的外源性物质的一个担忧是混合物可能产生相加或协同（即大于相加）效应。已经开发出一种短期剂量模型来检查环境混合物对甲状腺稳态的影响。原型甲状腺干扰化学物质（TDC），如二恶英、多氯联苯（PCB）和多溴二苯醚，已被证明可以改变该模型中的甲状腺激素稳态，主要是通过至少两种机制上调甲状腺激素的肝脏分解代谢。我们目前的努力测试了以下假设：TDC 混合物将以剂量累加的方式影响血清总甲状腺素 (T4) 浓度。年轻雌性 Long-Evans 大鼠连续 4 天通过灌胃给药 18 种不同的多卤代芳香烃 [2 种二恶英、4 种二苯并呋喃和 12 种 PCB，包括二恶英类和非二恶英类 PCB]。在最后一次给药后 24 小时收集的样品中通过放射免疫测定法测量血清总 T4。针对个别化学品确定了广泛的剂量反应函数（基于每种化学品七到九个剂量）。根据环境浓度，按照化学物质的比例定制合成混合物。该混合物的连续稀释范围从大约背景水平到比人类每日摄入量背景高 100 倍。在相同的 4 天测定中测试了混合物的六种连续稀释液。使用适用于具有不同剂量阈值和最大效应渐近线的化学品的灵活的单一化学品所需方法，计算与对照 (ED30) 相比 TH 降低 30% 相关的单个化学品的剂量以及预测的混合物结果。在没有和有混合物数据的情况下对单一化学数据进行建模，以分别确定预期的混合物响应（加和性模型）和实验观察到的混合物响应（经验模型）。似然比检验显示，剂量相加性存在统计学上的显着偏差。在混合物的最低剂量下，相加性没有偏差，但在三个最高混合物剂量下，存在大于相加效应。在高剂量下，加和模型将经验效应低估了 2 到 3 倍。这些结果首次表明 TDC 具有剂量依赖性加和性和协同作用，可能通过复杂混合物中的不同机制发挥作用。结果表明，在评估暴露于含有 TDC 的化学混合物的风险时，应考虑累积风险方法。
Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and poly-brominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T4) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T4 was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose–response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED30), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs.
登录
查看更多内容
影响因子：
2
作者：
BERENBAUM, MC
通讯作者：
BERENBAUM, MC
影响因子：
3.8
作者：
Khan, MA;Lichtensteiger, CA;Hansen, LG
通讯作者：
Hansen, LG
影响因子：
3.5
作者：
Khan, MA;Hansen, LG
通讯作者：
Hansen, LG
DOI：
10.1198/108571104x3406
发表时间：
2004-09-01
影响因子：
1.4
作者：
Casey, M;Gennings, C;Simmons, JE
通讯作者：
Simmons, JE
影响因子：
3.8
作者：
Hood, A;Klaassen, CD
通讯作者：
Klaassen, CD