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Health & Safety Executive - 1996

Review of Fibre Toxicology (OELs)

by M Meldrum

 



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.

Human health effects of exposure to asbestos

All forms of asbestos may cause pulmonary fibrosis, lung cancer and mesothelioma, but the degree of hazard depends on fibre type (greater with amphiboles than with chrysotile) and on the fibre size distribution (long fibres more hazardous than short). From this it is apparent that meaningful comparisons of the incidence of disease observed in different occupational cohorts should take careful account of differences not just in fibre type, but also in the airborne fibre size distributions.

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.

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Deposition and clearance

The regional deposition efficiency of inhaled fibres is largely a function of fibre diameter and density, with length and aspect ratio being of minor importance. Maximum alveolar deposition efficiency of inhaled fibres in humans is expected to occur with mineral fibre diameters of about 1 µm, and to fall off with values above this, so that above 3 µm in diameter, fibres would be essentially non-respirable. For organic fibres with a lower density, values slightly greater than this may apply.

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.

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Animal studies

Different routes of administration have been used in animal studies with fibres. Intrapleural (IPL) and intraperitoneal (IP) administrations provide direct exposure of fibres to the target tissue (mesothelial membranes), and therefore represent maximum sensitivity as a test for the capacity to produce mesothelioma; however, these routes appear to be overly sensitive in relation to mesothelioma, in that fibres which perhaps because of effective lung clearance mechanisms do not pose a hazard by the inhalation route, can elicit mesothelioma when instilled directly as a large bolus dose into the pleural or peritoneal cavities. Hence, positive results should be treated with caution. In contrast, negative results for mesothelioma induction by mineral fibres in a well conducted IP or IPL study would suggest an absence of carcinogenic hazard towards the mesothelial tissues. IPL and IP studies may be inappropriate for investigating organic fibres, because the physical properties of these fibres preclude the ability to inject a homogeneous suspension. In this case negative data may be unreliable.

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.

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Mechanisms of fibre pathogenicity

There has been considerable progress in recent years towards understanding the mechanisms of fibre toxicity and carcinogenicity. The development of pulmonary interstitial fibrosis is preceded by injury to the alveolar and bronchiolar epithelium. This results from direct toxicity caused by long fibres, but not short, and indirect toxicity caused by the release of oxidants and enzymes from macrophages and neutrophils following the incomplete phagocytosis of long fibres. Cytotoxicity may also result from reactions catalysed at the fibre surface leading to the generation of oxygen-containing free radicals.

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.

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Fibre toxicity testing strategy

The successful design of a fibre toxicity testing strategy requires an understanding of the mechanisms of fibre toxicity, and also of which physico-chemical properties most closely relate to toxicological hazard. There are still some uncertainties in these areas. Furthermore, the lack of standardised test methods has been a limiting factor. However, from the progress which has been made in the field of fibre toxicology in recent years, a testing strategy can be proposed which should provide a rational basis for hazard identification.

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.

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Relationship between fibre size and toxicity

The definition of a regulated fibres as used for counting purposes according to the UK Health & Safety Executive and the World Health Organization is that of a particle of length >5 µm, and diameter <3 µm, and with an aspect ratio (length to diameter) of >3:1. There is good evidence that longer fibres are more toxic than equal masses of shorter fibres of the same composition. Evidence from animal studies suggests that short fibres (< 5 µm) pose little if any concern for disease development at any site; fibres of lengths at least in the region of 10 - 15 um are necessary to produce disease in the lungs; but shorter fibres in the region of 8 - 10 µm can cause mesothelioma. There is no biological reason to suppose that a sharp cut-off value in fibre length would separate hazardous from non-hazardous fibres. This suggests that there would be no justification for increasing the current value of 5 µm as the length of a "regulated" fibre.

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.

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