Morphological and Chemical Mechanisms of Elongated Mineral Particle Toxicities

Much of our understanding regarding the mechanisms for induction of disease following inhalation of respirable elongated mineral particles (REMP) is based on studies involving the biological effects of asbestos fibers. The factors governing the disease potential of an exposure include duration and frequency of exposures; tissue-specific dose over time; impacts on dose persistence from in vivo REMP dissolution, comminution, and clearance; individual susceptibility; and the mineral type and surface characteristics. The mechanisms associated with asbestos particle toxicity involve two facets for each particle's contribution: (1) the physical features of the inhaled REMP, which include width, length, aspect ratio, and effective surface area available for cell contact; and (2) the surface chemical composition and reactivity of the individual fiber/elongated particle. Studies in cell-free systems and with cultured cells suggest an important way in which REMP from asbestos damage cellular molecules or influence cellular processes. This may involve an unfortunate combination of the ability of REMP to chemically generate potentially damaging reactive oxygen species, through surface iron, and the interaction of the unique surfaces with cell membranes to trigger membrane receptor activation. Together these events appear to lead to a cascade of cellular events, including the production of damaging reactive nitrogen species, which may contribute to the disease process. Thus, there is a need to be more cognizant of the potential impact that the total surface area of REMP contributes to the generation of events resulting in pathological changes in biological systems. The information presented has applicability to inhaled dusts, in general, and specifically to respirable elongated mineral particles

Effect of erionite on the pleural mesothelium of the Fischer 344 rat

OBJECTIVE: This study sought to assess the fibrogenic and carcinogenic potential of erionite (a fibrous zeolite) on the pleural mesothelium of the Fischer 344 rat (n = 24). DESIGN: The study was designed to examine rat pleural mesothelial changes by three independent observers at timed intervals, ranging from 1 to 480 days postinoculation using erionite from the Pine Valley, Nevada (USA) area. The mean length and width of the erionite fibers were 2.29 and 0.48 microns, respectively. Only microscopic observations made by majority (2/3) or unanimity (3/3) were accepted for final diagnosis. RESULTS: Pleural and lung tissue were available for examination in 21 of the 24 rats. Fibrosis, chronic inflammation, and foreign body reaction occurred in 6 of 21 rats. Mesothelial hyperplasia and dysplasia occurred in 9 and 3 of the 21 rats, respectively. A single mesothelioma was identified at 434 days in a rat that had gross nodular pleural lesions. CONCLUSIONS: The findings reported herein confirm the strong fibrogenic potential of erionite but are at variance with previous studies reporting much higher yields of mesothelioma. The reasons for the low yield of mesothelioma in this study are not known, but may be related to the study design, the strict criteria used for histopathologic diagnosis, and/or possible differences in erionite physicochemical properties, associated with its geographic distribution, most previous animal studies having used erionite from the Rome, Oregon (USA) area

Effect of fibrous glass on rat pleural mesothelium. Histopathologic observations

Female Fisher 344 rats (n = 25) were inoculated intrapleurally with a single 20-mg dose of (JM-100) fibrous glass. The mean length (2.2 microns) and width (0.15 microns) of the fibrous glass particles was within respirable range. Following inoculation, the rats were killed at timed intervals ranging from 2 to 430 d from inoculation. The pleural histopathologic changes were independently observed by a panel of three pathologists blinded to the time elapsed from inoculation. Fibrous adhesions, nodular lesions, and grossly evident tumor were noted in 15, 2, and 1 rat, respectively. In 1 rat there were combined adhesive and nodular changes, and in 6 there were no grossly detectable abnormalities. Chronic inflammation, fibrosis, and foreign body reaction were found in 9, 18, and 10 rats, respectively. Mesothelial hyperplasia and dysplasia were observed in 16 and 9 rats, respectively. Of 16 rats with the severest degree of hyperplasia and dysplasia, 3 developed malignant mesothelioma. This study suggests that a spectrum of rat pleural mesothelial histopathologic changes occurs before development of mesothelioma. The association of severe dysplasia in 3 rats with fully developed mesothelioma suggests that there may be a gradual progression from mesothelial hyperplasia or dysplasia to mesothelioma. Multivariate analysis further suggests that gross pleural nodular lesions and dysplasia may be significantly associated with the development of mesothelioma in this experimental model