Cytotoxicity of binary mixtures of human pharmaceuticals in a fish cell line: Approaches for non-monotonic concentration-response relationships
Cytotoxicity of binary mixtures of human pharmaceuticals in a fish cell line: Approaches for non-monotonic concentration-response relationships
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DOI：
10.1016/j.chemosphere.2014.01.077
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发表时间：
2014-08-01
期刊：
影响因子：
8.8
通讯作者：
Kumar, Anupama
中科院分区：
文献类型：
--
作者：
Bain, Peter A.;Kumar, Anupama
预测环境微污染物混合物的影响是一个优先研究领域。在这项研究中，10种药物对虹鳟鱼细胞系RTG-2的细胞毒性测定使用中性红摄取法。选择氟西汀（FL）、普萘洛尔（PPN）和双氯芬酸（DCF）作为二元混合物进行进一步研究。在暴露于FL和PPN的细胞中观察到双相浓度-反应关系。在PPN的情况下，显微镜检查显示溶酶体肿胀，表明化合物的直接摄取和蓄积。评价了描述非单调浓度-响应关系的三个方程，发现与S形浓度-响应模型相比，其中一个方程始终提供更准确的中位和10%效应浓度估计值。采用浓度相加（CA）概念模型结合非单调浓度-响应关系，对FL、PPN和DCF的二元混合物的影响进行预测建模。使用CA可以充分预测所有三种二元组合的细胞毒性，表明RTG-2细胞中的毒性作用模式与这些化合物的治疗作用模式无关。这里提出的方法是广泛适用于混合物的毒性研究的情况下，观察到的非单调的浓度-响应关系。皇冠版权所有（C）2014由爱思唯尔有限公司出版。保留所有权利。
Predicting the effects of mixtures of environmental micropollutants is a priority research area. In this study, the cytotoxicity of ten pharmaceuticals to the rainbow trout cell line RTG-2 was determined using the neutral red uptake assay. Fluoxetine (FL), propranolol (PPN), and diclofenac (DCF) were selected for further study as binary mixtures. Biphasic concentration-response relationships were observed in cells exposed to FL and PPN. In the case of PPN, microscopic examination revealed lysosomal swelling indicative of direct uptake and accumulation of the compound. Three equations describing non-monotonic concentration-response relationships were evaluated and one was found to consistently provide more accurate estimates of the median and 10% effect concentrations compared with a sigmoidal concentration-response model. Predictive modeling of the effects of binary mixtures of FL, PPN, and DCF was undertaken using an implementation of the concentration addition (CA) conceptual model incorporating non-monotonic concentration-response relationships. The cytotoxicity of the all three binary combinations could be adequately predicted using CA, suggesting that the toxic mode of action in RTG-2 cells is unrelated to the therapeutic mode of action of these compounds. The approach presented here is widely applicable to the study of mixture toxicity in cases where non-monotonic concentration-response relationships are observed. Crown Copyright (C) 2014 Published by Elsevier Ltd. All rights reserved.