Quantitative structure–mesothelioma potency model optimization for complex mixtures of elongated particles in rat pleura: A retrospective study

Cancer potencies of mineral and synthetic elongated particle mixtures, including asbestos fibers, are influenced by changes in fiber dose composition, bioavailability, and biodurability in combination with relevant cytotoxic dose-response relationships. An extensive rat intrapleural dose characterization data set with a wide variety of elongated particles physicochemical properties facilitated statistical analyses of pleural mesothelioma response data combined from several studies for evaluation of alternative dose-response models. Utilizing logistic regression of individual elongated particle dimensional variations within each test sample, four major findings emerged: (1) Mild acid leaching provides superior prediction of tumor incidence compared to samples that were not leached; (2) sum of the elongated particle surface areas from mildly acid-leached samples provides the optimum holistic dose-response model; (3) progressive removal of dose associated with very short and/or thin elongated particles significantly degrades the resultant particle count and surface area dose-based predictive model fits; and (4) alternative biologically plausible model adjustments provide evidence for reduced potency of elongated particles with aspect ratios less than 8 and lengths greater than 80 µm. Regardless of these adjustments, the optimum predictive models strongly incorporate potency attributable to abundant short elongated particles in proportion to their surface area. Transmission electron microscopy analyses of low-temperature-ashed pleural membrane and lung tissues 5.5 mo post intrapleural exposures do not support hypotheses that short elongated particles that reach the pleural space are rapidly eliminated. Low-aspect-ratio elongated particles were still abundant in pleural membrane tissues but may have reduced potencies due to aggregation tendencies and therefore lower potential for intracellular presence.

矿物和合成细长颗粒混合物（包括石棉纤维）的致癌活性，受颗粒剂量组成、生物可利用性、生物持久性的变化，以及相关细胞毒性剂量-反应关系的共同影响。本研究拥有一套涵盖多种细长颗粒理化特性的大型大鼠胸膜内剂量表征数据集，可支持对多项研究合并得到的胸膜间皮瘤反应数据进行统计分析，以评估不同的剂量-反应模型。通过对每个测试样本中单个细长颗粒的尺寸变异进行逻辑回归分析，得到四项主要结论：(1) 与未浸提的样本相比，轻度酸浸提可更精准地预测肿瘤发生率；(2) 轻度酸浸提样本的细长颗粒总表面积，可构建最优的整体性剂量-反应模型；(3) 逐步去除与极短和/或极细细长颗粒相关的剂量，会显著削弱基于颗粒计数和表面积剂量的预测模型拟合效果；(4) 其他符合生物学合理性的模型调整结果表明，长径比（aspect ratio）小于8且长度大于80 μm的细长颗粒，其致癌活性有所降低。无论是否进行上述调整，最优预测模型均高度纳入了大量短细长颗粒按其表面积计算的致癌活性。对胸膜膜和肺组织在胸膜内暴露5.5个月后进行的低温灰化透射电子显微镜（Transmission electron microscopy）分析结果，不支持“进入胸膜腔的短细长颗粒会被快速清除”这一假说。长径比较低的细长颗粒在胸膜膜组织中仍大量存在，但由于其易发生聚集，进入细胞内的可能性降低，因此致癌活性可能有所减弱。