Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm 114 18, Sweden.
Science for Life Laboratory, Biochemical and Cellular Assay Unit, Dept. of Biochemistry and Biophysics, Stockholm University, Stockholm 106 91, Sweden.
Environ Int. 2024 Oct;192:108991. doi: 10.1016/j.envint.2024.108991. Epub 2024 Aug 30.
Chemical risk assessments typically focus on single substances, often overlooking real-world co-exposures to chemical mixtures. Mixture toxicology studies using representative mixtures can reveal potential chemical interactions, but these do not account for the unique chemical profiles that occur in the blood of diverse individuals. Here we used the H295R steroidogenesis assay to screen personalized mixtures of 24 persistent organic pollutants (POPs) for cytotoxicity and endocrine disruption. Each mixture was reconstructed at a human exposure relevant concentration (1×), as well as at 10- and 100-fold higher concentration (10×, 100×) by acoustic liquid handling based on measured blood concentrations in a Swedish cohort. Among the twelve mixtures tested, nine mixtures decreased the cell viability by 4-18%, primarily at the highest concentration. While the median and maximum mixtures based on the whole study population induced no measurable effects on steroidogenesis at any concentration, the personalized mixture from an individual with the lowest total POPs concentration was the only mixture that affected estradiol synthesis (35% increase at the 100× concentration). Mixtures reconstructed from blood levels of three different individuals stimulated testosterone synthesis at the 1× (11-15%) and 10× concentrations (12-16%), but not at the 100× concentration. This proof-of-principle personalized toxicity study illustrates that population-based representative chemical mixtures may not adequately account for the toxicological risks posed to individuals. It highlights the importance of testing a range of real-world mixtures at relevant concentrations to explore potential interactions and non-monotonic effects. Further toxicological studies of personalized contaminant mixtures could improve chemical risk assessment and advance the understanding of human health, as chemical exposome data become increasingly available.
化学风险评估通常侧重于单一物质，往往忽略了化学混合物的实际共暴露情况。使用代表性混合物进行的混合物毒理学研究可以揭示潜在的化学相互作用，但这些研究并未考虑到不同个体血液中发生的独特化学特征。在这里，我们使用 H295R 类固醇生成测定法筛选了 24 种持久性有机污染物 (POPs) 的个性化混合物的细胞毒性和内分泌干扰作用。根据在瑞典队列中测量的血液浓度，每个混合物都以基于声学液体处理的人类暴露相关浓度（1×），以及 10 倍（10×）和 100 倍（100×）更高的浓度进行重建。在测试的 12 种混合物中，有 9 种混合物使细胞活力降低了 4-18%，主要是在最高浓度下。虽然基于整个研究人群的中位数和最大混合物在任何浓度下都不会对类固醇生成产生可测量的影响，但来自总 POPs 浓度最低的个体的个性化混合物是唯一影响雌二醇合成的混合物（在 100×浓度下增加 35%）。根据三个不同个体的血液水平重建的混合物在 1×（11-15%）和 10×（12-16%）浓度下刺激了睾酮的合成，但在 100×浓度下没有。这项基于原理的个性化毒性研究表明，基于人群的代表性化学混合物可能无法充分说明对个体造成的毒理风险。它强调了在相关浓度下测试一系列真实世界混合物以探索潜在相互作用和非单调效应的重要性。进一步的个性化污染物混合物的毒理学研究可以改善化学风险评估，并随着化学暴露组学数据的日益普及，增进对人类健康的理解。
