Diseases associated with exposure to asbestos dusts.
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Biomedical subjects
Publications and source records attributed to J C Wagner.
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Chrysotile asbestos was leached in N hydrochloric acid for varying times to produce a range of magnesium-depleted samples. The protein adsorptive capacity, the haemolytic activity, and the capacity to cause selective release of acid hydrolases from macrophages were measured for the various samples in vitro. The carcinogenicity of the same materials was determined following intrapleural inoculation in rats. The adsorptive capacity for albumin decreased linearly with magnesium removal. The haemolytic activity also declined until about half the magnesium had been removed, after which there was little further change. The selective release of acid hydrolases from macrophages in culture increased up to the point at which half the magnesium had been removed but by 90% depletion had declined rapidly. The carcinogenicity of 50% -depleted chrysotile was similar to that of intact, but at 90% depletion the incidence of mesothelial tumours had fallen considerably. There was no evidence that the leached samples fragmented more than the unleached in vivo.
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Cell cultures were established from pleural effusions of patients with pleural mesothelioma, and peripheral mononuclear effector cells were tested for cytotoxicity against these cells by means of microcytotoxicity assay. Effector cells were obtained from normal healthy donors and from persons exposed occupationally to asbestos, including apparently healthy persons, patients with benign pleural conditions and patients with malignant mesothelioma. The overall incidence of cytotoxicity was low, and there was no evidence of increased cytotoxicity in mesothelioma patients or other asbestos-exposed donors. It is concluded that little or no tumour-directed cell-mediated immunity is detectable against malignant mesothelioma by microcytotoxicity methods.
An experiment in which rats were injected intrapleurally with asbestos, the injection taking place at an age of either 2 or 10 months, is reported. In the former group 19 out of 48 rats developed a mesothelioma compared with 17 out of 90 in the latter group. However, by considering the two groups at equal times after injection, eliminating the effects of natural mortality and also taking into account that not all of the mesotheliomas were the cause of death, it was shown that the incidence rate of mesotheliomas was significantly higher (p less than 0.01) in the rats injected at age 10 months and the relative rate was estimated as about 4, with 95% confidence limits of 1.5 and 12. An alternative explanation that the mesotheliomas occurred in the two groups at similar rates, except that in the group injected at age 10 months they occurred on average 4 months sooner after injection, is discussed. Two other groups were also injected, one at age 17 months and the other at 22 months. In the former group two early mesotheliomas were observed, 10 and 74 days after injection, but the next was not observed until over a year later. No explanation of this finding could be suggested other than the possibility that these two tumours were not associated with the asbestos treatment.
The cellular sequence of events evoked by the intratracheal injection of both respirable mouldy hay dust and zymosan in unsensitized rats and rabbits was markedly similar and contained many features seen in lung biopsies from farmer's lung cases. It is considered that a combination of ability to activate the alternative pathway of complement and the particulate nature of mouldy hay dust and zymosan produced the pulmonary response seen and as such, considerable insight has been gained into mechanisms by which unsensitized individuals respond to dust inhalation. It is suggested that alternative pathway activation may produce an attack of farmer's lung in the absence of precipitins or other forms of hypersensitivity to the dust or its components and that cases designated as 'pulmonary mycotoxicosis' are more rationally explained by this mechanism.
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The nature of the material forming the massive lesions in the lungs of coal workers has never been demonstrated. The concept that it was in fact massive fibrosis, implying that it consisted of collagen impregnated with coal dust, has been challenged only during the last ten years. It was agreed that the best chance of obtaining more definite information was from a combined study of the biochemical, pathological, ultrastructural, and immunological features of a number of lungs containing these lesions. Six cases which were found to contain suitable material were studied. The preliminary results obtained suggest that collagen is present in the capsule of these lesions but that at the centre it is replaced by another insoluble protein or proteins which is probably stabilized by some form of cross-linking. This protein complex accounts for one-third of the weight of the lesions, the remaining two-thirds consisting of approximately equal amounts of mineral dusts and calcium phosphate. Serum proteins were also observed but their association with the lesions has yet to be determined.
Italian talc has been tested on rats using three routes, intra-pleural inoculation, inhalation and ingestion. Groups exposed to superfine chrysotile asbestos and untreated controls were included for comparison. In all the experiments animals were allowed to live out their lives. The intra-pleural inoculation of talc produced no mesotheliomas in contrast to eighteen produced by the chrysotile asbestos. After ingestion, one leiomyosarcoma occurred with Italian talc and one with chrysotile asbestos. Whether these tumours are a consequence of the feeding is uncertain. The inhalation studies demonstrated that with equal dosage, talc can produce a similar amount of fibrosis as asbestos. However, the chrysotile exposed rats developed lung adenomas, adenomatosis and an adenocarcinoma, whereas the only lung tumour seen in animals exposed to talc was a small adenoma, which may have been an incidental finding.
When rats breathed air containing approximately 70 mg m-3 of respirable crystalline silica 7 h daily for 10 days (2000 mg m-3 h) the surface tension forces of the alveolar lining film were reduced. This was shown both by surface tension measurements on lung extracts and by pressure-volume studies with air and saline filling of excised lungs. Larger quantities of inhaled silica produced similar effects. Chrysotile inhalation caused an even more marked decrease in the surface tension forces. In the chrysotile studies these findings were supported by biochemical estimations of the quantity of surfactant in the lungs, which was increased 10-fold by an inhalation of 6500 mg m-3 h. Electron microscopy showed an increased number of the type II alveolar cells which produce surfactant and of free phospholipid lattices in the air spaces of the lungs of rats exposed to chrysotile and silica. Both the surface tension and biochemical estimations on a control group of rats suggest that there is an increase in the amount of surfactant in the lungs up to about 12 months of age.
Two experiments in which SPF Wistar rats were exposed by inhalation to dust clouds of the UICC standard reference samples for periods of between one day and 2 years are described. All the samples of asbestos produced asbestosis which continued to progress after removal from exposure but only a little fibrosis was observed in control rats. Lung tumours, ranging in severity from adenomata to squamous carcinomata, were produced by all samples but in the controls there were only a few adenomata and none of the more serious tumours. Of the 20 tumours which metastasized, 16 occurred after exposure to one or other of the 2 chrysotile samples. In addition, a total of 11 mesotheliomata occurred, 4 of which were with crocidolite and 4 with Canadian chrysotile. Two of the mesotheliomata occurred with only one day's exposure to asbestos. There was a positive association between asbestosis and lung tumours.
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Four experiments in which SPF Wistar rats were inoculated intrapleurally with asbestos or other materials are described. Mesotheliomata were observed in a considerable proportion of animals with all the samples of asbestos used and with a sample of brucite. A few were produced with synthetic aluminium silicate fibres and single ones with barium sulphate, glass powder and aluminium oxide. The risk of developing a mesothelioma at a given time after injection was approximately proportional to the dose. Of the UICC standard reference samples, crocidolite was the most carcinogenic and removal of the oils by benzene extraction did not alter the carcinogenicity of these samples. Chemical properties also seem unlikely to be the main factor producing mesotheliomata but the results support the hypothesis that the finer fibres are the more carcinogenic, and this is additional to the known aerodynamic advantage which the finer fibres have in penetrating to the periphery of the lung.
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