Feiertag Katreece, Karaca Mawien, Fischer Benjamin, Heise Tanja, Bloch Denise, Opialla Tobias, Tralau Tewes, Kneuer Carsten, Marx-Stoelting Philip
German Federal Institute for Risk Assessment, Department Pesticides Safety, Berlin, Germany.
EXCLI J. 2023 Feb 13;22:221-236. doi: 10.17179/excli2022-5648. eCollection 2023.
Plant protection products (PPPs) consist of one or more active substances and several co-formulants. Active substances provide the functionality of the PPP and are consequently evaluated according to standard test methods set by legal data requirements before approval, whereas co-formulants' toxicity is not as comprehensively assessed. However, in some cases mixture effects of active substances and co-formulants might result in increased or different forms of toxicity. In a proof-of-concept study we hence built on previously published results of Zahn et al. (2018[38]) on the mixture toxicity of Priori Xtra and Adexar to specifically investigate the influence of co-formulants on the toxicity of these commonly used fungicides. Products, their respective active substances in combination as well as some co-formulants were applied to human hepatoma cell line (HepaRG) in several dilutions. Cell viability analysis, mRNA expression, abundance of xenobiotic metabolizing enzymes and intracellular concentrations of active substances determined by LC-MS/MS analyses demonstrated that the toxicity of the PPPs is influenced by the presence of co-formulants . PPPs were more cytotoxic than the mix of their active substances. Gene expression profiles of cells treated with the PPPs were similar to those treated with their respective mixture combinations with marked differences. Co-formulants can cause gene expression changes on their own. LC-MS/MS analyses revealed higher intracellular concentrations of active substances in cells treated with PPPs compared to those treated with the respective active substances' mix. Proteomic data showed co-formulants can induce ABC transporters and CYP enzymes. Co-formulants can contribute to the observed increased toxicity of PPPs compared to their active substances in combination due to kinetic interactions, necessitating a more comprehensive evaluation approach.
植物保护产品（PPPs）由一种或多种活性物质和几种辅助配方成分组成。活性物质赋予植物保护产品功能，因此在批准前需根据法定数据要求设定的标准测试方法进行评估，而辅助配方成分的毒性评估则没有那么全面。然而，在某些情况下，活性物质和辅助配方成分的混合效应可能会导致毒性增加或呈现不同形式。因此，在一项概念验证研究中，我们基于扎恩等人（2018[38]）先前发表的关于先正达Xtra和安灭达混合毒性的结果，专门研究辅助配方成分对这些常用杀菌剂毒性的影响。将产品、它们各自组合的活性物质以及一些辅助配方成分以几种稀释度应用于人类肝癌细胞系（HepaRG）。通过细胞活力分析、mRNA表达、异源生物代谢酶的丰度以及通过液相色谱-串联质谱（LC-MS/MS）分析测定的活性物质细胞内浓度表明，植物保护产品的毒性受辅助配方成分的影响。植物保护产品比其活性物质的混合物更具细胞毒性。用植物保护产品处理的细胞的基因表达谱与用各自混合物组合处理的细胞的基因表达谱相似，但存在明显差异。辅助配方成分自身可导致基因表达变化。LC-MS/MS分析显示，与用各自活性物质混合物处理的细胞相比，用植物保护产品处理的细胞中活性物质的细胞内浓度更高。蛋白质组学数据表明，辅助配方成分可诱导ABC转运蛋白和CYP酶。由于动力学相互作用，辅助配方成分可能导致观察到的植物保护产品与其活性物质组合相比毒性增加，因此需要一种更全面的评估方法。
