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Persistent Elongated Particle Total Surface Area Dose to Rat Pleura is Optimum Predictor of Mesothelioma Incidence
Citation:
COOK, P. M., J. SWINTEK, T. DAWSON, D. CHAPMAN, AND M. ETTERSON. Persistent Elongated Particle Total Surface Area Dose to Rat Pleura is Optimum Predictor of Mesothelioma Incidence. Presented at American Society for Testing and Materials, Burlington, VT, July 25 - 29, 2011.
Impact/Purpose:
To document research results.
Description:
Based on preliminary statistical analyses of 29 reanalyzed (quantitative TEM) diverse elongated particle (EP) test samples from the well known and often cited study of Stanton et al. 1981, total surface area (TSA) of biodurable EPs was reported at the 2008 Johnson Conference to be a good predictor of pleural mesothelioma incidence in intrapleural (IP) exposed rats. This conclusion was important because TSA could be most representative of the toxicologically relevant dose of active particles in the pleural membranes and would be consistent with the particle surface as the locus for mechanism of action. This further would provide a general, holistic, mechanism of action relevant model based on graded relative potencies associated with EP size and shape in vivo. The existence of such a model contradicts models which ascribe high potency for unique size fractions of long, thin EPs and negligible potency for all other EPs in the dose. The TSA dose metric does support the concept of increased individual particle potency as a function of greater length. The TSA model, on an individual particle basis, appears to contradict the perception of greater potency as a function of individual particle thinness because a wider EP has greater surface area than a thin EP of the same length. However, for toxicity tests based on comparisons of equivalent mass dose exposures, it can be shown that the strong correlation of EP thinness with both greater particle number and surface area concentrations should result in greater tumor incidence as is observed.