Air pollution is an example of a complex environmental mixture with different biological activities, making risk assessment challenging. Current cancer risk assessment strategies that focus on individual pollutants may overlook interactions among them, potentially underestimating health risks. Therefore, a shift towards the evaluation of whole mixtures is essential for accurate risk assessment. This study presents the application of an New Approach Methodology (NAM) to estimate relative cancer potency factors of whole mixtures, with a focus on organic pollutants associated with air particulate matter (PM). Using concentration-dependent activation of the DNA damage-signaling protein checkpoint kinase 1 (pChk1) as a readout, we compared two modeling approaches, the Hill equation and the benchmark dose (BMD) method, to derive Mixture Potency Factors (MPFs). MPFs were determined for five PM samples covering sites with different land uses and our historical pChk1 data for PM samples and Standard Reference Materials. Our results showed a concentration-dependent increase in pChk1 by all samples and a higher potency compared to the reference compound benzo[]pyrene. The MPFs derived from the Hill equation ranged from 128 to 9793, while those from BMD modeling ranged from 70 to 303. Despite the differences in magnitude, a consistency in the relative order of potencies was observed. Notably, PM samples from sites strongly impacted by biomass burning had the highest MPFs. Although discrepancies were observed between the two modeling approaches for whole mixture samples, relative potency factors for individual PAHs were more consistent. We conclude that differences in the shape of the concentration–response curves and how MPFs are derived explain the observed differences in model agreement for complex mixtures and individual PAHs. This research contributes to the advancement of predictive toxicology and highlights the feasibility of transitioning from assessing individual agents to whole mixture assessment for accurate cancer risk assessment and public health protection.

中文翻译：

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应用体外新方法确定基于整体混合物的空气污染物的相对致癌效力因子


空气污染是具有不同生物活性的复杂环境混合物的一个例子，这使得风险评估具有挑战性。当前关注单个污染物的癌症风险评估策略可能会忽视它们之间的相互作用，从而可能低估健康风险。因此，转向评估整个混合物对于准确的风险评估至关重要。本研究提出了应用新方法 (NAM) 来估计整个混合物的相对癌症效力因子，重点关注与空气颗粒物 (PM) 相关的有机污染物。使用 DNA 损伤信号蛋白检查点激酶 1 (pChk1) 的浓度依赖性激活作为读数，我们比较了两种建模方法：希尔方程和基准剂量 (BMD) 方法，以得出混合效力因子 (MPF)。 MPF 是针对涵盖不同土地用途地点的五个 PM 样本以及 PM 样本和标准参考材料的历史 pChk1 数据确定的。我们的结果显示，所有样品的 pChk1 均呈浓度依赖性增加，且与参考化合物苯并[]芘相比具有更高的效力。从 Hill 方程得出的 MPF 范围为 128 至 9793，而 BMD 模型得出的 MPF 范围为 70 至 303。尽管大小存在差异，但观察到效力相对顺序的一致性。值得注意的是，来自受生物质燃烧强烈影响的地点的 PM 样本具有最高的 MPF。尽管在整个混合物样品的两种建模方法之间观察到差异，但单个多环芳烃的相对效力因子更加一致。 我们得出的结论是，浓度响应曲线形状的差异以及 MPF 的推导方式可以解释观察到的复杂混合物和单个 PAH 模型一致性的差异。这项研究有助于预测毒理学的进步，并强调了从评估单个药物过渡到整体混合物评估的可行性，以实现准确的癌症风险评估和公共卫生保护。