Institute of Cancer Research, Department of Internal Medicine I, Borschkegasse 8a, Vienna, 1090, Austria.
National Institute of Biology, Department for Genetic Toxicology and Cancer Biology, Večna pot 111, SI-1000, Ljubljana, Slovenia.
Water Res. 2019 Nov 1;164:114953. doi: 10.1016/j.watres.2019.114953. Epub 2019 Aug 4.
Anticancer drugs are among the most toxic chemicals, which are commercially produced; therefore, their release in aquatic ecosystems raised concerns in regard to potential adverse effects. This article describes the results of risk assessments concerning their environmental safety, which are based on data generated in the frame of a coordinated EU project ("Cytothreat"). Eight research institutions participated in the project and four widely used anticancer drugs with different mechanisms of therapeutic action (5-fluorouracil 5FU, cisplatin CDDP, imatinib mesylate IM and etoposide ET) were tested in a variety of indicator organisms (cyanobacteria, algae, higher plants, rotifers, crustacea, fish and also in human and fish derived cell lines) in acute/subacute/chronic toxicity assays. Furthermore, genotoxic effects in micronucleus assays, single cell gel electrophoresis experiments and γH2AX tests were studied in plants, crustacea, fish and in various cell lines. We used the results to calculate the predicted no effect concentrations (PNEC) and risk quotients (RQ) by comparing PNEC with predicted environmental concentrations (PEC values) and measured concentrations (MEC) in wastewaters. The most sensitive species in experiments concerning acute toxic and long term effects were in general crustacea (daphnids) after chronic treatment the most pronounced effects were detected with IM followed by CDDP and 5FU. Comparisons between PNEC and PEC values indicate that it is unlikely that the release of these drugs in the aquatic environments leads to adverse effects (RQ values < 1). However, when the assessments were performed with MEC found in highly contaminated municipal wastewaters and hospital effluents, RQ values were obtained which are indicative for moderate adverse effects of IM. Calculations with data from genotoxicity experiments and PEC values are indicative for increased RQ values for all compounds except ET. The most sensitive species were fish (Danio rerio) which were highly responsive towards 5FU and daphnids which were sensitive towards CDDP and IM. When environmental data (from waste waters) were used for the calculations, high RQ values (>100) were obtained for CDDP and IM. These overall conclusions were not substantially altered when the effects of other frequently used cytostatic drugs and combined effects of mixtures of anticancer drugs were taken into consideration. The results of these assessments underline the importance of efficient removal of these chemicals by improved sewage treatment strategies and the need for further investigations of adverse the long term effects of cytostatics in aquatic biota as a consequence of damage of the genetic material in highly sensitive species.
抗癌药物是商业生产的最有毒的化学物质之一，因此它们在水生生态系统中的释放引起了人们对潜在不良影响的关注。本文描述了基于协调的欧盟项目（“Cytothreat”）中生成的数据进行的环境安全性风险评估的结果。八个研究机构参与了该项目，四种具有不同治疗作用机制的广泛使用的抗癌药物（5-氟尿嘧啶 5FU、顺铂 CDDP、甲磺酸伊马替尼 IM 和依托泊苷 ET）在各种指示生物（蓝藻、藻类、高等植物、轮虫、甲壳类动物、鱼类以及人类和鱼类衍生的细胞系）中进行了急性/亚急性/慢性毒性试验。此外，还在植物、甲壳类动物、鱼类和各种细胞系中研究了微核试验、单细胞凝胶电泳实验和 γH2AX 试验中的遗传毒性效应。我们使用这些结果通过将预测无影响浓度 (PNEC) 与预测的环境浓度 (PEC 值) 和废水中的测量浓度 (MEC) 进行比较，计算出预测的环境浓度 (PEC 值) 和测量浓度 (MEC)。在急性毒性和长期效应实验中最敏感的物种通常是甲壳类动物（水蚤），在慢性处理后，IM 检测到最明显的效应，其次是 CDDP 和 5FU。将 PNEC 与 PEC 值进行比较表明，这些药物在水生环境中的释放不太可能导致不良影响（RQ 值<1）。然而，当使用从高度污染的城市废水中和医院废水中发现的 MEC 进行评估时，获得的 RQ 值表明 IM 具有中度不良影响。使用遗传毒性实验数据和 PEC 值进行计算表明，除 ET 外，所有化合物的 RQ 值均升高。最敏感的物种是鱼类（斑马鱼），它们对 5FU 反应强烈，水蚤对 CDDP 和 IM 敏感。当使用环境数据（来自废水）进行计算时，CDDP 和 IM 获得了高 RQ 值（>100）。当考虑到其他常用细胞抑制剂的作用和抗癌药物混合物的联合作用时，这些总体结论并没有实质性改变。这些评估的结果强调了通过改进污水治理策略有效去除这些化学物质的重要性，以及需要进一步研究细胞抑制剂对水生生物群遗传物质的长期损害造成的不良影响。
