Charles Grantley D, Gennings Chris, Tornesi Belen, Kan H Lynn, Zacharewski Timothy R, Bhaskar Gollapudi B, Carney Edward W
Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48674, USA.
Toxicol Appl Pharmacol. 2007 Feb 1;218(3):280-8. doi: 10.1016/j.taap.2006.11.029. Epub 2006 Dec 5.
In the evaluation of chemical mixture toxicity, it is desirable to develop an evaluation paradigm which incorporates some critical attributes of real world exposures, particularly low dose levels, larger numbers of chemicals, and chemicals from synthetic and natural sources. This study evaluated the impact of low level exposure to a mixture of six synthetic chemicals (SC) under conditions of co-exposure to various levels of plant-derived phytoestrogen (PE) compounds. Estrogenic activity was evaluated using an in vitro human estrogen receptor (ER) transcriptional activation assay and an in vivo immature rat uterotrophic assay. Initially, dose-response curves were characterized for each of the six SCs (methoxyclor, o,p-DDT, octylphenol, bisphenol A, beta-hexachlorocyclohexane, 2,3-bis(4-hydroxyphenyl)-propionitrile) in each of the assays. The six SCs were then combined at equipotent ratios and tested at 5-6 dose levels spanning from very low, sub-threshold levels, to a dose in which every chemical in the mixture was at its individual estrogenic response threshold. The SC mixtures also were tested in the absence or presence of 5-6 different levels of PEs, for a total of 36 (in vitro) or 25 (in vivo) treatment groups. Both in vitro and in vivo, low concentrations of the SC mixture failed to increase estrogenic responses relative to those induced by PEs alone. However, significant increases in response occurred when each chemical in the SC mixture was near or above its individual response threshold. In vitro, interactions between high-doses of SCs and PEs were greater than additive, whereas mixtures of SCs in the absence of PEs interacted in a less than additive fashion. In vivo, the SC and PE mixture responses were consistent with additivity. These data illustrate a novel approach for incorporating key attributes of real world exposures in chemical mixture toxicity assessments, and suggest that chemical mixture toxicity is likely to be of concern only when the mixture components are near or above their individual response thresholds. However, these data suggest that extrapolation from in vitro assays to in vivo mixture effects should be approached with caution.
在评估化学混合物毒性时，开发一种评估范式是很有必要的，该范式应纳入现实世界暴露的一些关键属性，特别是低剂量水平、大量化学物质以及来自合成和天然来源的化学物质。本研究评估了在共同暴露于不同水平的植物源性植物雌激素（PE）化合物的条件下，低水平暴露于六种合成化学物质（SC）混合物的影响。使用体外人雌激素受体（ER）转录激活试验和体内未成熟大鼠子宫增重试验评估雌激素活性。最初，在每种试验中对六种SC（甲氧滴滴涕、o,p-滴滴涕、辛基酚、双酚A、β-六六六、2,3-双（4-羟苯基）丙腈）中的每一种进行剂量反应曲线表征。然后将六种SC以等效比例混合，并在5至6个剂量水平下进行测试，范围从非常低的亚阈值水平到混合物中每种化学物质都处于其个体雌激素反应阈值的剂量。SC混合物还在不存在或存在5至6种不同水平的PE的情况下进行测试，总共36个（体外）或25个（体内）处理组。在体外和体内，相对于单独由PE诱导的反应，低浓度的SC混合物均未能增加雌激素反应。然而，当SC混合物中的每种化学物质接近或高于其个体反应阈值时，反应会显著增加。在体外，高剂量的SC与PE之间的相互作用大于相加作用，而在不存在PE的情况下，SC混合物的相互作用小于相加作用。在体内，SC和PE混合物的反应符合相加性。这些数据说明了一种将现实世界暴露的关键属性纳入化学混合物毒性评估的新方法，并表明只有当混合物成分接近或高于其个体反应阈值时，化学混合物毒性才可能令人担忧。然而，这些数据表明，从体外试验推断体内混合物效应时应谨慎。
