Potentiation and antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin effects in a complex environmental mixture.
Potentiation and antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin effects in a complex environmental mixture.
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复杂环境混合物中 2,3,7,8-四氯二苯并-对-二恶英效应的增强和拮抗作用。
DOI：
10.1006/taap.1993.1065
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发表时间：
1993
影响因子：
3.8
通讯作者：
Lipinskas,T
中科院分区：
文献类型：
--
作者：
Silkworth,JB;Cutler,DS;O'Keefe,PW;Lipinskas,T
越来越需要了解复杂环境混合物的毒性。Love Canal化学品倾倒场的渗滤液（OPL）的有机相是一种复杂的混合物，含有100多种有机化合物，其中包括0.74 ppm的2，3，7，8-四氯二苯并-p-二恶英（TCDD）。用Ah基因同源小鼠评价OPL的几种毒性作用，包括免疫功能和肝酶诱导。在C57 BL/6 J Ahb/band同种C57 BL/6Ahd/d（B6.D2）小鼠中比较了OPL和纯TCDD的毒性。小鼠单次口服剂量高达2 g OPL/kg或100 μg TCDD/kg，免疫，并在7天后进行评估。在C57 BL/6 J和B6.D2小鼠中，OPL的TCDD当量分别为3.9和5.0 ppm。这是TCDD含量的六倍。通过将在B6.D2菌株中引起效应所需的剂量除以在C57 BL/6 J菌株中引起相同效应的剂量来计算Ah表型依赖性反应比。基于ED 50和最低观察到的不良反应水平的比率被用来确定每个不良反应是否是Ah表型依赖性的，在何种程度上TCDD有助于效果，是否有相互作用的AhR配体和nonligands之间的影响，如果他们是添加剂，拮抗剂，或协同作用，以及是否响应是可预测的基础上已知的化学成分的混合物。得出的结论是，非TCDD成分增强TCDD免疫抑制，并可能胸腺萎缩，通过AhR机制。相反，该分析表明，非TCDD成分的OPL拮抗的TCDD成分诱导肝AHH活性的能力，而OPL肝肿大主要是由非TCDD成分的OPL。这项研究表明，含有TCDD的混合物的毒性可能无法准确预测的TCDD含量单独的基础上，这种方法可能是有用的毒理学评估和环境污染管理。
There is increasing need to understand the toxicity of complex environmental mixtures. The organic phase of a leachate (OPL) from the Love Canal chemical dump site is a complex mixture that contains over 100 organic compounds, including 0.74 ppm 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD). Mice congenic at the Ah locus were used to evaluate several toxic effects of the OPL, including immune function and hepatic enzyme induction. OPL toxicity was compared with that of pure TCDD in both C57BL/6J Ahb/band congenic C57BL/6 Ahd/d(B6.D2) mice. Mice were given single oral doses of up to 2 g OPL/kg or 100 μg TCDD/kg, immunized, and evaluated after 7 days. The TCDD equivalent of the OPL was determined to be 3.9 and 5.0 ppm in C57BL/6J and B6.D2 mice, respectively. This is six times the TCDD content. The Ah phenotype-dependent response ratio was calculated by dividing the dose required to cause an effect in the B6.D2 strain by the dose causing the same effect in the C57BL/6J strain. Ratios based on both ED5Os and the lowest observed adverse effect levels were used to determine whether each adverse effect was Ah phenotype-dependent, the extent to which TCDD contributed to the effect, whether there were interactive effects between the AhR ligands and nonligands and if they were additive, antagonistic, or synergistic, and whether the response was predictable based on the known chemical composition of the mixture. It was concluded that the non-TCDD component potentiated TCDD immune suppression, and possibly thymic atrophy, through AhR mechanisms. In contrast, this analysis indicated that the non-TCDD component of the OPL antagonized the ability of the TCDD component to induce hepatic AHH activity whereas OPL hepatomegaly was caused primarily by the non-TCDD component of the OPL. This study demonstrates that the toxicity of mixtures containing TCDD may not be accurately predicted based on the TCDD content alone and that this approach could be useful in the toxicologic assessment and management of environmental contamination.