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Quantitative structure - mesothelioma potency model optimization for complex mixtures of elongated particles in rat pleura: A retrospective study
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: A retrospective study. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH - PART B: CRITICAL REVIEWS. Taylor & Francis, Inc., Philadelphia, PA, 19(5):266-288, (2016).
Major challenges for the accurate assessment of fiber exposure to humans leading to the development of asbestosis and mesotheliomas include the identification of the appropriate dose metric (eg. number of particles) and defining the relative potencies of individual fibers in an environmental mixture of elongated particles. To date, regulation of exposure to elongated particles has been largely accomplished by using predefined dimensions focused entirely on long and thin fibers within a mixture to the exclusion of the vast majority of particles with dimensions outside of those limited bounds. In this paper, we developed a model with empirically derived data to predict frequencies of mesothelioma from rat studies with both high quality transmission electron microscopy exposure estimates and effects characterization. The model is then used to rank the potencies of several different fiber/mineral types relative to a standardized mineral often tested in toxicological studies investigating the potential incidence of disease. The model can be used to predict the relative potencies of a mixture of elongated particles based on the sum of the surface area of the particles in the mixture. This relationship was found to be significant across mineral types and chemical characteristics.
Cancer potencies of mineral and synthetic elongated particle (EP) mixtures, including asbestos fibers, 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 that 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.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
MID-CONTINENT ECOLOGY DIVISION