Applying the classical dose/response toxicology paradigm to the unique pleural pathology seen with asbestos and other fibre exposures, it may be assumed that since the response occurs at the pleura, the dose must be applied at the pleura. It might be argued therefore that since fibres produce pleural pathology whilst particles do not, fibres must reach the pleura and particles must not. However, a body of literature exists to the effect that in fact a proportion of all deposited particles reach the pleura, pass through the pleural space and exit through the stomata. In the process of this they elicit range of low to higher grade responses there in the form of parietal pleural 'black spots'.
Evidence that all particles pass through the pleura comes from a substantial literature concerning the almost universal existence of these "black spots", observable on the parietal pleural wall at autopsy. These mark the stomata and arise where particles must focus to exit the pleural space at the stomata and where they enter the sub-mesothelial connective tissue around the stomatal mouths. In the study by Mitchev et al
], 150 consecutive necropsies of urban dwellers were examined in Belgium. Of the 96 male and 54 female necropsies, whose age ranged from 22-93 years, black spots were almost invariably seen (>90% of autopsies) on the parietal pleura. The authors noted that their location appeared to be related to the structures responsible for the lymphatic drainage of the pleural cavity and they considered these to mark the points of pleural fluid resorption. Black spots were also present on the pleural face of the diaphragm, suggesting that there is pleural fluid outflow in a caudal direction. The black spots in the Mitchev study of normal individuals at autopsy clearly reflects that deposited soot particles normally pass through the pleura some of them accumulating in the parietal pleural wall forming black spots. The black spots contain particles and elicit a tissue response which is a low grade in city dwellers, where there is accumulation of dust-laden macrophages and lymphocytes. In coal miners, however, with their large exposures to particles, the mixed dust particles trigger a higher-grade inflammatory reaction of the parietal pleura with concomitant low grade fibrosis in the 'black spots' which are very pronounced [42
]. Occasionally pleural inflammatory reactions to interstitialisation of the mixed dust at the black spots are more pronounced, producing more severe granulomatous structures with concentrically arranged collagen fibres [42
]. In one study [42
], 12 patients with black spots (8 at autopsy and 4 surgically) who were largely miners, had their black spots removed and sectioned for histological purposes. As might be expected with such high dust exposure, the black spots were extremely well-demarcated and followed the lines of lymph flow across and through the parietal pleura.
The most severe and frequently-documented example of pleural response to dust is asbestos pleural plaques. Pleural plaques are commonly seen in asbestos-exposed individuals occurring only on the parietal pleura and diaphragm as discrete, raised, irregularly shaped areas a few millimetres to 10 centimetres in size, having a greyish to ivory white colour depending on their thickness [43
]. It is important to note that pleural plaques occur in greatest profusion in exactly the sites where the stomata are in greatest profusion i.e. pleural plaques are '...most commonly found on the posterior wall of the lower half of the pleural spaces, those in the intercostal space tended to have an elliptical shape and ran parallel to the ribs above and below...'. On histological section plaques can be seen to be composed of dense bands or weaves of avascular and largely acellular collagen, with only the occasional fibroblast nucleus to be seen; they are sometimes calcified [44
]. These collagenous plaques, whilst commonly seen in association with asbestos exposure are not unique to it, being found following pleural infection or trauma and so can be presumed to be the way that the pleura reacts to injury [44
Thus there is clear evidence that a proportion of all deposited particles, most commonly urban particulate matter, reach the parietal pleura where they may interstitialise around the stomata and elicit responses. The severity of the response is dependent on the intrinsic toxicity of the dust, with increasing levels of inflammatory/fibrotic response as follows:- soot < mixed mineral dust < short asbestos. The benign nature of asbestos pleural plaque-type responses is evident in the lack of reports of mesothelioma in city dwellers or coalminers despite the prevalence of black spots in these populations and the notable lack of asbestos pleural plaque progression to malignancy [45
]. Since normal asbestos pleural plaques are benign and not pre-cancerous, we hypothesise that pleural plaques are a special case of a 'black' spot caused by short asbestos fibres which elicit an unusually florid collagenous response, or as a result of a very high dose of short fibres reaching the peri-stomatal wall. The emphasis on shortness here is important since the key feature of black spots, we contend, is that the particles and short fibres are small enough to negotiate the stomatal openings where they mostly clear to the lymph nodes whilst some interstitialise into the sub-mesothelial interstitium through the proximal lymphatic capillary walls. As described below, this contrasts with events that may occur with long fibres; these cannot negotiate the stomata leading to retention at the stomatal openings, initiating a very different pathobiological sequence of events culminating in a different pathological outcome.
Our knowledge regarding the pathway by which particles reach the pleura from the lung parenchyma is well summed up in a recent review '... How asbestos fibres that have impacted the airway wall migrate to the pleural surface ..... is quite obscure. ..' [1
]. Lymphatic flow from the parenchyma to the pleural space is one obvious possibility [46
] but such a pathway, if it exists, is not well-documented [1
]. A fluid dynamics model of fibre translocation highlights two possible pathways [47
], the first of these being by normal lymph flow centrally to the mediastinum and then into the blood via the thoracic duct followed by extra-vasation in the pleural capillaries during the formation of pleural fluid. This rather tortuous route disregards the filtering role of the lymph nodes and seems to us to be intuitively unlikely. The second route requires inflammation in the parenchyma, caused by the fibres, to reverse both the normal flow of lymph and the normal trans-pleural pressure, resulting in a net flow of fluid and fibres directly into the pleural space from the underlying parenchyma [47
]. This latter process cannot be the explanation for normal transit of particles to the pleura that gives rise to black spots (see above) in normal people, who have no pulmonary inflammation. Therefore, even if such an inflammation-dependent pathway exists, a pathway that is independent of inflammation clearly operates for compact particles in normal people. Further research is needed to establish the mechanism of transport of fibres to the pleural space.