Six samples of tremolite of different morphological type were prepared as dusts of respirable size and used in intraperitoneal injection studies in rats. Three "asbestiform" tremolites produced mesotheliomas in almost all animals, although with significantly different tumor-induction periods. A brittle type of fibrous tremolite which, when manipulated to prepare "respirable dust," produced a sample with relatively few asbestiform fibers remaining nonetheless produced tumors in 70% of rats. Two samples of nonfibrous tremolite produced respirable dust samples containing numerous elongated fragments with aspect ratios greater than 3:1, which therefore fitted the definition of respirable fibers. Both these samples produced relatively few tumors, although one had more long "fibers" than did the brittle tremolite that produced 70% of tumors. This study has therefore demonstrated that different morphologic forms of tremolite produce dusts with very different carcinogenic potential. Carcinogenicity does not depend simply on the number of elongated particles injected, and we need to develop methods of distinguishing carcinogenic tremolite fibers from relatively innocuous tremolite dusts, with similar numbers of elongated particles of similar aspect ratios.
Most authors consider that long-term inhalation studies represent the most reliable method of obtaining data on the pathogenicity of mineral fibers. However, because of the length of time required and the great cost of inhalation work, other methods of examining the biological effects of mineral fibers have been used. The program of work described here was designed to compare a wide range of techniques, including inhalation, for determining the biological effects of a selection of man-made mineral fibers. Silicon carbide whiskers were examined as a very durable material and also a less durable glass microfiber (code 100/475/ as a relatively soluble man-made vitreous fiber. Amosite asbestos was used as a positive control. long-term inhalation studies with full-life-span follow-up demonstrated that amosite and silicon carbide were both fibrogenic and carcinogenic in rats, while glass microfiber produced very little fibrosis and a few benign pulmonary tumors in numbers similar to those found in controls. Silicon carbide was unusual in that most of the tumors produced were pleural mesotheliomas. Early effects of the fibers were examined after a short period of inhalation, and the pathogenic dusts amosite and silicon carbide were found to produce rapid pulmonary inflammation as determined by the presence of significant numbers of neutrophils in pulmonary lavage fluid. Less pulmonary inflammation followed the inhalation of glass microfiber. Similarly, amosite and silicon carbide inhalation was found to cause a rapid increase in the rate of proliferation of bronchoalveolar lining cells, while the rate of cell division in animals treated with microfiber remained normal. When injected into the peritoneal cavities of rats, all three fiber types produced mesothe liomas, although the glass microfiber produced many fewer and these took much longer to develop. An examination of early inflammation in the peritoneal cavity of mice following injection showed little difference between the fiber types, all of which caused raised numbers of neutrophils in peritoneal fluid. fiber durability was examined both in vivo and in vitro. Following inhalation it was found that fewer very long glass microfibers (>20 pm in length) remained in rats lungs after 12 mo of inhalation than amosite or silicon carbide.Subsequently, however, amosite and microfiber were removed from the lung at similar rates for most fiber dimensions, in contrast to silicon carbide fibers, where clearance was much less. When dust was administered by intratracheal injection, these differences in fiber removal from lung tissue were much less marked. An examination of the in vitro solubility of fibers and their chemical composition after extraction from lung tissue demonstrated that glass microfiber showed significant leaching while amosite showed much less and silicon carbide showed almost no change in chemical composition. The possibility of using short-term in vivo and in vitro tests to provide a screening system to eliminate the need for some of the longer and more expe...
Clearance of UICC amosite asbestos from the lungs during chronic-that is, repeatedexposure was investigated by using the scanning electron microscope to measure lung burdens from rats which had inhaled amosite asbestos at an approximately constant concentration of0-1 mg/m3 or, equivalently, 20 fibres/ml for seven hours a day, five days a week for up to 18 months. The lung burdens were compared with previous results for higher exposure concentrations of 1 and 10 mg/m3. Those previous lung burdens had been measured using other analytical methods (infrared spectrophotometry) that were not suitable for the new lower lung burdens. Taken together, these results showed lung burdens rising pro rata with exposure concentration and exposure time. This accumulation of lung burden has been described by a kinetic model that takes account of the sequestration ofmaterial at locations in the lung from where it cannot be cleared. Unlike some earlier models in which lung burdens eventually reach a plateau with equilibrium between deposition and clearance during chronic exposure, this sequestration model shows lung burdens continuing to rise with exposure time. The latest results reported here support the application of such a model to lower exposure concentrations closer to those of asbestos in workplaces.The amount of material retained by the lung during and after exposure to airborne dusts is determined by the physical processes governing inhalation and deposition and the biological processes governing clearance. In some circumstances the dust may be inhaled on a single occasion (which is often the concern with, for example, radioactive aerosols) and the amount of material retained (at any subsequent time) may be estimated from mathematical models describing the clearance of particles from the lung. More In a previous paper we reported the results of an experiment in which two groups of rats were exposed to amosite asbestos at two respirable concentrations (1 and 10 mg/m3) for periods up to one year.7 Under the overload hypothesis it was expected that, for the lower concentration, the lung burden would not reach the critical level at which clearance mechanisms were expected to be overloaded. Moreover, for the lower concentration, it was expected that the rates of deposition DL into, and clearance from, the lung would eventually reach equilibrium and the lung burden BL would reach a plateau during continued chronic exposure at constant concentration. When this occurs, 300 Pulmonary clearance of UICC amositefibres inhaled by rats during chronic exposure at low concentration 301 fibres/ml for fibres longer than 5 gm). The aim is to examine the extent to which ideas developed at higher concentrations may be applied at much lower ones that are more akin to exposure to asbestos at the workplace. MethodsThe experiment was conducted using outbred male SPF Wistar rats of the AF/HAN strain, exposed to airborne dust of UICC amosite in a 1 m3 inhalation chamber in separate groups of 12 animals (with up to 48 in the chamber ...
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