 |
 |
||
 |
     |
   |
|
|
you are here: Science and publications / Monographs and Reports / Health & Safety Executive Health & Safety Executive - 1996 Review of Fibre Toxicology (OELs)
SUMMARY This review starts with an assessment of the current position regarding the human health data for asbestos, as this is where much occupational health attention on fibres has been focussed. The document then moves on to consider more general issues in fibre toxicology
It is concluded that there will be a threshold level of exposure below which no radiological or clinical manifestation of pulmonary fibrosis (asbestosis) will occur. The value for the threshold, and indeed the slope of the dose response curve, depends on fibre type and the fibre size-distribution in the workplace. There appears to be an association between pulmonary fibrosis and lung cancer in that both diseases show a similar dose-response relationship with respect to asbestos exposure, show similar latent periods for development, show a similar dependence on fibre type and size, and both diseases emanate from the same underlying chronic inflammatory condition. These observations suggest that asbestos-induced lung cancer, like fibrosis, is a threshold phenomenon. It can be concluded that exposures which are insufficient to elicit chronic inflammation/cell proliferation (manifest for example, as alveolar Type II cell hyperplasia or fibrosis) will not incur any increased risk of lung cancer. The Doll and Peto (1985) risk assessment for chrysotile-induced lung cancer was based on a linear no-threshold model applied to mortality data from chrysotile textile manufacture. However, the balance of toxicological evidence does not support the no-threshold model for asbestos-induced lung cancer. A practical threshold is likely. Very few cases of mesothelioma can be reliably attributed to chrysotile despite the many thousands of workers who have had massive and prolonged exposures to this type of asbestos. In contrast, mesotheliomas have been observed among some workers who experienced only brief exposures to amphiboles. These differences are most likely explained by the limited durability of chrysotile in the lungs, in contrast to the amphiboles which are more persistent. It would appear that for a fixed level of exposure, the risk of developing mesothelioma is much greater for amphiboles than for chrysotile. Evidence from human studies suggests that amphibole asbestos may lead to the development of mesothelioma at lower levels of cumulative exposure than would be required to cause lung cancer. However, no reliable exposure-response curve can be constructed for asbestos-induced mesothelioma either in animals or in humans, and although a threshold could be postulated on theoretical grounds, the available data do not allow the identification of a threshold level of exposure below which there would be no risk.
Clearance of fibres which deposit in the alveolar regions of the lung takes place by macrophage-mediated phagocytosis which is highly effective for short fibres (< 5 µm), but becomes increasingly difficult with increasing fibre length, so that clearance by this mechanism will be negligible for fibres of lengths around 16 µm or more. In the longer term, some fibres, depending on chemical composition will undergo dissolution or leaching of particular elements from the fibre structure. This may lead to fragmentation into shorter lengths which will facilitate clearance. The pulmonary clearance of chrysotile is more rapid than for amphibole fibres of similar dimensions.
Intratracheal (IT) instillation, whilst addressing the same route of administration as inhalation, does not mimic the pattern of pulmonary deposition for inhaled fibres. The same dose delivered as a single bolus may elicit a more severe inflammatory response in the lungs than when delivered gradually by inhalation. Therefore, for the purpose of evaluating potential human health effects of fibres, small doses given repeatedly, perhaps once or twice weekly over many months, should provide the most meaningful results. It would seem sensible to regard positive carcinogenicity findings in an IT study as valid evidence of carcinogenic potential for inhaled fibres unless counteracted by negative results from one or more well conducted inhalation studies. In contrast, negative results from a well conducted IT study would suggest an absence of hazard, and in the context of a fibre toxicity testing strategy, a move to inhalation carcinogenicity testing would not be justified. The inhalation route is of most relevance to human exposures to fibres. Therefore animal studies using this exposure route should provide a clearer basis for hazard identification and for investigating dose-response relationships. Inhalation studies in rats are able to demonstrate the known human health hazards of asbestos. However, in general, very few mesotheliomas can be produced with this exposure route, therefore large group size of rats (> 100) are needed to reliably identify this end-point.
Airway epithelial damage may facilitate the passage of fibres from the airspaces into the pulmonary interstitium, which appears to be important in the development of pulmonary interstitial fibrosis. The mechanism for the development of pulmonary fibrosis is thought to result from the ability of fibres to provoke a chronic enhancement of the secretion of cytokine growth factor from effector cells. There is evidence for an association between fibre-induced pulmonary interstitial fibrosis and lung cancer, consistent with the view that the enhanced rates of cell proliferation associated with chronic inflammation and fibrogenesis predispose to neoplastic cell transformation. There is a lack of convincing evidence for the ability of fibres to elicit any direct genetic changes which might also lead on to carcinogenesis. The mechanisms of fibre induced mesothelioma are probably similar in principle to those for lung cancer, involving chronic inflammation and increased cell proliferation eventually leading to neoplastic transformation. However, there are still some uncertainties, for example, regarding the process and importance of fibre translocation to the mesothelial tissues. Recent evidence shows that pleural changes can be elicited by indirect effects not involving any actual fibre penetration to the pleural membranes, but resulting from the deposition of fibres in the alveolar regions of the lung in close proximity to the sub-pleural membrane. The significance of this in relation to pleural toxicity is unclear.
Although it is not possible, based on current knowledge, to make a precise prediction of toxicological hazard based on measures of physico-chemical properties, certain properties, such as fibre solubility and surface reactivity are thought to be determinants of toxicity. Therefore measures of these properties, when considered in conjunction with other test data, should provide useful indices of potential toxicity. There is now sufficient understanding of the underlying mechanisms of fibre toxicity to allow meaningful studies of inflammatory, cytotoxic and proliferative effects in short-term animal and in vitro tests. The results from a limited number of such tests should enable decisions to be made on potential toxicity and needs for further testing. Fibres which proved to be relatively soluble, with low surface reactivity, and of low biological activity in well designed short-term toxicity tests, might be judged to be of low concern, and no further testing might be warranted. If these criteria are not met, then the next stage in a toxicity testing strategy would be to conduct a joint lung clearance and histopathology study of perhaps 6 months duration. The results from such study should enable an evaluation of fibrogenic potential as well as provide evidence for fibre dissolution/ leaching and overall clearance kinetics. There should be sufficient information available at this stage in the testing strategy to allow at least cautious predictions of carcinogenic potential. Fibres which have proved to be cytotoxic, capable of inducing cell proliferation and fibrogenesis, and with limited evidence of lung clearance, might be regarded as potentially carcinogenic, and should be treated as such, unless counteracted by negative results in a well conducted life-time carcinogenicity study.
There is little evidence available on the role of fibre diameter. Finer fibres may appear to be more toxic simply due to their greater efficiency of lung deposition following inhalation exposure. There is no evidence that thinner fibres are more toxic than thicker fibres at a cellular level, when comparisons are based on numbers of fibres. Overall, based on considerations of patterns of regional deposition in the respiratory tract in relation to disease development, it is concluded that the focus of concern for counting purposes should continue to be with those fibres which are deemed to be respirable i.e. capable of depositing within the broncho-alveolar regions of the lung. For mineral fibres this would include all fibres <3 µm in diameter. There are no toxicological reasons to suggest that the minimum diameter for a regulated fibres should be reduced below the current value. There is a lack of specific toxicological evidence relating to aspect ratio. HSE BOOKS Mail order: RETAIL HSE priced publications or write to: EH65/30 |
|||||||||||||||||||||||||||||||||
 |
||||||||||||||||||||||||||||||||||
Chrysotile Institute
Print version
| Institut du CHRYSOTILE Institute © 1999-2005 All rights reserved | |
| Legal notice | Sitemap | |