University of Applied Sciences Northwestern Switzerland, Muttenz, Switzerland.
Aquat Toxicol. 2010 Feb 18;96(3):167-81. doi: 10.1016/j.aquatox.2009.11.021. Epub 2009 Dec 21.
Widespread occurrence of traces of pharmaceuticals (ng/L to microg/L) has been reported in aquatic systems. However, their effects on the environment and their environmental risks remain elusive. Generally, the acute toxicity towards non-target organisms has been assessed in laboratory experiments, but chronic toxicity studies have been performed only rarely. The guideline issued by the European Medicines Agency in 2006 is aimed at estimating the potential environmental risks of human pharmaceuticals by a tiered approach. The predicted environmental concentration (PEC) of a compound is estimated in phase I, and pharmaceuticals having a PEC above or equal 10ng/L undergo phase II testing. Otherwise they are not expected to pose a risk to the environment. Because some highly active compounds (HC) such as 17-alpha-ethinylestradiol, equine estrogens, trenbolone and the progestin levonorgestrel display adverse effects at concentrations below 10ng/L the question arises, whether additional HC compounds exist, and how they can be identified for undergoing environmental risk assessment. We addressed this question by searching for HC in the literature, and by developing a concept for identification of HC. The suggested mode of action concept is based on (i) the mode of action of the pharmaceutical taking the available toxicological information into account, (ii) the degree of sequence homology between the human drug target and the potential target in aquatic organisms and (iii) the importance of pathways affected by the pharmaceutical. We evaluated the mode of action concept by comparison to existing approaches, the fish plasma model (Huggett et al., 2003) and a QSAR model, called VirtualTox Lab (www.biograf.ch). All concepts result in similar classifications of the selected pharmaceuticals. However, there are some differences not only in the model assumptions, but also in its results. Our study leads to the conclusion that the mode of action concept is most suitable for the identification of HC. A refinement can be achieved by complementing this concept by the QSAR model (VirtualTox Lab), whereas the fish plasma model seemed to be less suitable due to the necessity of environmental concentration above 10ng/L for the identification of a risk.
已在水生系统中报道了痕量药物（纳克/升至微克/升）的广泛存在。然而，它们对环境的影响及其环境风险仍然难以捉摸。通常，在实验室实验中评估了对非目标生物的急性毒性，但很少进行慢性毒性研究。欧洲药品管理局于 2006 年发布的准则旨在通过分层方法估计人类药物的潜在环境风险。在第一阶段估算化合物的预测环境浓度（PEC），PEC 高于或等于 10ng/L 的药物将进行第二阶段测试。否则，预计它们不会对环境构成风险。由于某些高活性化合物（HC），如 17-alpha-乙炔雌二醇、马雌激素、群勃龙和孕激素左炔诺孕酮，在低于 10ng/L 的浓度下显示出不良影响，因此出现了这样的问题，即是否存在其他 HC 化合物，以及如何识别它们进行环境风险评估。我们通过在文献中搜索 HC 并开发 HC 识别概念来解决这个问题。建议的作用模式概念基于（i）考虑到可用毒理学信息的药物的作用模式，（ii）人类药物靶标与水生生物中潜在靶标的序列同源性程度，以及（iii）受药物影响的途径的重要性。我们通过与现有方法（Huggett 等人，2003 年的鱼类血浆模型）和称为 VirtualTox Lab（www.biograf.ch）的 QSAR 模型进行比较来评估作用模式概念。所有概念都导致对所选药物的类似分类。然而，不仅在模型假设方面，而且在其结果方面，都存在一些差异。我们的研究得出的结论是，作用模式概念最适合识别 HC。通过将该概念与 QSAR 模型（VirtualTox Lab）补充，可以实现改进，而鱼类血浆模型由于识别风险所需的环境浓度高于 10ng/L，因此似乎不太合适。
