Department of Cell Toxicology, Helmholtz Centre for Environmental Research - UFZ, Permoserstr. 15, 04318 Leipzig, Germany.
Environmental Toxicology, Center for Applied Geoscience, Eberhard Karls University Tübingen, Schnarrenbergstr. 94-96, 72076 Tübingen, Germany.
Chem Res Toxicol. 2021 Apr 19;34(4):1175-1182. doi: 10.1021/acs.chemrestox.1c00037. Epub 2021 Mar 24.
Discussions are ongoing on which dose metric should be used for quantitative -to- extrapolation (QIVIVE) of bioassay data. The nominal concentration of the test chemicals is most commonly used and easily accessible, while the concentration freely dissolved in the assay medium is considered to better reflect the bioavailable concentration but is tedious to measure. The aim of this study was to elucidate how much QIVIVE results will differ when using either nominal or freely dissolved concentrations. QIVIVE and QIVIVE ratios, that is, the ratios of plasma concentrations divided by effect concentrations, were calculated for 10 pharmaceuticals using previously published nominal and freely dissolved effect concentrations for the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) and the activation of oxidative stress response. The QIVIVE ratios were higher than QIVIVE ratios by up to a factor of 60. The risk of effects was classified as being high or low for four chemicals using the QIVIVE and for three chemicals using QIVIVE ratios. Unambiguous classification was possible for nine chemicals by combining the QIVIVE or QIVIVE ratios with the respective specificity ratios (SR or SR) of the effect data, which helps to identify whether the specific effect was influenced by cytotoxicity. QIVIVE models should be preferred as they account for differences in bioavailability between and , but QIVIVE may still be useful for screening the effects of large numbers of chemicals because it is generally more conservative. The use of SR of the effect data as a second classification factor is recommended for QIVIVE and QIVIVE models because a clearer picture can be obtained with respect to the likelihood that a biological effect will occur and that it is not caused by nonspecific cytotoxicity.
目前正在讨论应使用哪种剂量指标来进行定量外推（QIVIVE）生物测定数据。测试化学品的名义浓度最常用且易于获取，而在测定介质中自由溶解的浓度被认为更能反映生物可利用浓度，但测量起来却很繁琐。本研究旨在阐明使用名义浓度或自由溶解浓度时，QIVIVE 结果会有多大差异。使用先前发表的名义和自由溶解效应浓度，为 10 种药物计算了 QIVIVE 和 QIVIVE 比值，即血浆浓度除以效应浓度的比值，以激活过氧化物酶体增殖物激活受体γ（PPARγ）和激活氧化应激反应。QIVIVE 比值最高可比 QIVIVE 比值高出 60 倍。使用 QIVIVE 和 QIVIVE 比值对四种化学物质进行了高或低的 效应风险分类，而使用三种化学物质进行了 QIVIVE 比值分类。通过将 QIVIVE 或 QIVIVE 比值与 效应数据的特异性比值（SR 或 SR）相结合，可以对九种化学物质进行明确分类，这有助于确定特定效应是否受到细胞毒性的影响。由于 QIVIVE 模型考虑了生物利用度在 和 之间的差异，因此应优先选择 QIVIVE 模型，但由于其通常更保守，因此 QIVIVE 仍可用于筛选大量化学物质的作用。建议将 效应数据的特异性比值（SR 或 SR）用作 QIVIVE 和 QIVIVE 模型的第二个分类因素，因为这可以更清楚地了解生物效应发生的可能性以及它是否不是由非特异性细胞毒性引起的。
