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Quantitative structure-mesothelioma potency model optimization for complex mixtures of elongated particles in rat pleura: A retrospective study.
Journal of Toxicology and Environmental Health, Part B: Critical Reviews ( IF 7.2 ) Pub Date : 2016-10-06 , DOI: 10.1080/10937404.2016.1195326
Philip M Cook 1 , Joseph Swintek 2 , Timothy D Dawson 2 , David Chapman 3 , Mathew A Etterson 1 , Dale Hoff 1
Affiliation  

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.

中文翻译:

定量分析大鼠胸膜中细颗粒的复杂混合物的间皮瘤效能模型优化:一项回顾性研究。

矿物和合成长颗粒混合物(包括石棉纤维)的致癌能力受纤维剂量组成,生物利用度和生物耐久性的变化以及相关的细胞毒性剂量反应关系的影响。广泛的大鼠胸膜内剂量表征数据集,具有多种细长颗粒的理化特性,促进了对数种研究的胸膜间皮瘤反应数据的统计分析,以评估替代的剂量反应模型。利用每个测试样品中单个细长颗粒尺寸变化的逻辑回归,得出了四个主要发现:(1)与未浸出样品相比,轻度酸浸提供了更好的肿瘤发生率预测;(2)来自轻度酸浸样品的细长颗粒表面积的总和提供了最佳的整体剂量反应模型;(3)逐步去除与非常短和/或细的细长颗粒相关的剂量会大大降低所得的颗粒数和基于表面积剂量的预测模型拟合;(4)生物学上可行的替代模型调整为长径比小于8和长度大于80 µm的细长颗粒的效力降低提供了证据。不管这些调整如何,最佳预测模型都将强大的效能归因于与表面积成比例的大量短长形颗粒。透射电镜分析低温灰化的胸膜和肺组织5。胸膜内暴露后5个月不支持以下假设:迅速消除到达胸膜间隙的短而细长的颗粒。低纵横比的细长颗粒在胸膜组织中仍然很丰富,但是由于聚集的趋势可能降低了效价,因此降低了细胞内存在的可能性。
更新日期:2019-11-01
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