You are here:
Quantitative structure - mesothelioma Potency Model Optimization for Complex Mixtures of Elongated Particles in Rat Pleura
Citation:
Cook, P., J. Swintek, T. Dawson, D. Chapman, M. Etterson, AND D. Hoff. Quantitative structure - mesothelioma Potency Model Optimization for Complex Mixtures of Elongated Particles in Rat Pleura. SETAC North America, Salt Lake City, UT, November 01 - 05, 2015.
Impact/Purpose:
not applicable
Description:
Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including fibers from asbestos, are influenced by changes in fiber dose composition, bioavailability and biodurability in combination with relevant cytotoxic dose-response relationships. A unique and comprehensive rat intra-pleural (IP) dose characterization data set with a wide variety of EP size, shape, crystallographic, chemical, and bio-durability properties facilitated extensive statistical analyses of 50 rat IP exposure test results for evaluation of alternative dose pleural mesothelioma response models. Utilizing logistic regression, maximum likelihood evaluations of thousands of alternative dose metrics based on hundreds of individual EP dimensional variations within each test sample, four major findings emerged: (1) data for simulations of short term EP dose changes in vivo (mild acid leaching) provide superior predictions of tumor incidence compared to non-acid leached data; (2) sum of the EP surface areas (ÓSA) from these mildly acid leached samples provides the optimum holistic dose response model; (3) progressive removal of dose associated with very short and/or thin EPs significantly degrades resultant ÓEP or ÓSA dose based predictive model fits, as judged by Akaike’s Information Criterion (AIC); and (4) alternative, biologically plausible, model adjustments provide evidence for reduced potency of EPs with length/width (aspect) ratios < 8 and lengths > 80 µm. Regardless of these adjustments, the optimum predictive models strongly incorporate potency attributable to abundant short EPs in proportion to their ÓSA. TEM analyses of low temperature ashed pleural membrane and lung tissues 5.5 months post IP exposures do not support hypotheses that short EPs which reach the pleural space are rapidly eliminated. Low aspect ratio (AR) EPs were still abundant in pleural membrane tissues but may have reduced potencies due to aggregation tendencies and therefore lower potential for intracellular presence.