1 16 Determination of Asbestos Exposure by Pathology and Clinical History Allen R. Gibbs The determination of whether an abnormal asbestos exposure took place is important in mesothelioma cases because of the potential for financial compensation and for the assessment of the likelihood of further cases occurring from similar occupational, paraoccupational, or environmental circumstances. One should be aware that not all mesotheliomas are associated with asbestos exposure. Spirtas et al (1) found after careful systematic inquiry that 88% of pleural and 54% of peritoneal mesotheliomas could be attributed to asbestos exposure in men in the United States but only 23% of pleural and peritoneal mesotheliomas could be attributed to asbestos in women in the United States. An earlier study of mesotheliomas in North America showed lower figures 50% in men and 5% in women (2). There are several ways whereby a reasonable determination can be made of whether abnormal asbestos exposure has occurred in an individual. These include (1) a detailed and reliable occupational history; (2) identification of clinical markers of exposure such as pleural plaques, diffuse pleural fibrosis, rounded atelectasis, and asbestosis; (3) histopathologic features, such as pleural plaques and asbestos bodies; and (4) mineral analyses of digested lung tissues. In most, if not all, parts of the world, there are background exposures to asbestos both inside and outside of buildings. These have arisen from natural outcrops and from industrial activity. These are at very low levels, usually less than 0.001F/mL (F stands for the degree of fineness of abrasive particles) but in some countries there are higher environmental exposures, for example, Turkey, Corsica, Cyprus, Russia, Czechoslovakia, Austria, Bulgaria, Greece, and New Caledonia, which have given rise to asbestos-related diseases such as pleural plaques and mesotheliomas. Asbestos fibers have been found in the air and water supplies. Airborne levels of asbetos fibers are generally higher in urban than in rural areas but this has not been accompanied by a detectable increase in nonoccupational mesotheliomas (3). Interestingly, a study of airborne asbestos levels in 12 buildings where friable amosite was used as fireproofing material and generally was in poor condition, found indoor concentrations indistinguishable from outdoor levels, 259
2 260 Chapter 16 Determination of Asbestos Exposure and no evidence of episodic asbestos release was found (4). However, if the fireproofing was knocked out of the ceiling and allowed to fall to the ground, airborne asbestos fiber levels increased for a brief period of time but did not exceed the United States Occupational Safety and Health Administration (OSHA) occupational exposure level for asbestos. There is a continuum from background exposure to industrially derived exposures to asbestos, and there is no sharp boundary between them. This can give rise to difficulties in determining the background ranges of asbestos for various populations. Indeed, much debate centers on what constitutes a realistic set of controls. Another important point is that when mineral fiber concentrations are determined in the lungs of subjects with mesothelioma in order to determine the likelihood of it being asbestos related, it is important to be aware that background levels of asbestos fibers do exist in the lungs of the general population not occupationally or paraoccupationally exposed to asbestos. These background levels should be determined for the laboratory carrying out the analysis in the individual case because there are technical differences in the way the analyses are carried out by different laboratories, and therefore one cannot use the background range for one laboratory and extrapolate it to another (5). One should be aware also that asbestos is not a homogeneous entity. There are two main families of asbestos fibers: serpentine and amphibole. These have important physical, chemical, and pathobiologic differences. The sole constituent fiber of the serpentine asbestos group is chrysotile (white), while the amphibole group includes amosite (brown), crocidolite (blue), tremolite, actinolite, and anthophyllite. When assessing a prior asbestos exposure it is useful to determine the fiber type(s) involved because there is a much lower potential for causing mesothelioma from chrysotile exposure than there is from the amphiboles; a study by Hodgson and Darnton (6) estimated a risk ratio for mesothelioma of chrysotile/amosite/crocidolite of 1: 100: 500. Clinical History It continues to disappoint that inquiries into possible exposures to mineral dust, particularly asbestos, are poorly carried out in hospitals that deal frequently with pulmonary diseases. A reliable occupational history is crucial to assessing the risks of occupational disease in a worker and in attribution of a particular disease to an occupational exposure. With respect to mesothelioma, an appropriate latency period from first exposure to asbestos to onset or death from the tumor is necessary for attribution. A review by Lanphear and Buncher (7) of 1690 cases of mesothelioma found that 99% had a latency period of more than 15 years; 96% had a latency period of at least 20 years, and the median latency period was 32 years. In fact, in the series of cases where there was a well-defined period of asbestos exposure, the latency period was almost always in excess of 20 years and averaged 30 to 40 years.
3 A.R. Gibbs 261 In any individual case a careful inquiry should be made commencing with the individual s first employment and working completely through chronologically until the current or final employment, noting for each the dates of commencement and termination. Careful details of the nature of the various employments should be made because it may not be immediately apparent that there was a potential for asbestos exposure. The reliability of the history varies since in some situations, for example, work as an insulator or in shipbuilding, exposure to asbestos is clear-cut, whereas in other situations, such as the construction industry, the amount and frequency of exposure is variable and depends on the precise work carried out. Direct regular exposure to asbestos is easier to evaluate than indirect intermittent exposures. Sometimes exposures are exaggerated because there is a tendency to assume all visible dust was asbestos, whereas it might have contained other types of mineral dust, particularly where a disease, such as mesothelioma, which is strongly associated with asbestos exposure, is the subject of the inquiry (so-called recall bias) or where there are pending medicolegal proceedings. The recollections of relatives who provide the occupational history of a deceased patient are generally less accurate than if the occupational history had been obtained directly from the patient. Sometimes exposures to asbestos, particularly tremolite or anthophyllite, have occurred environmentally from birth, for example, in Turkey, Greece, Corsica, New Caledonia, Russia, Czechoslovakia, Austria, Bulgaria, and Finland. Mesotheliomas have also resulted from exposures to asbestos brought home on the clothes of other family members who worked in a facility using asbestos. Exposures to asbestos in females are more commonly through the paraoccupational than the direct occupational route and these can be equivalent to occupational exposures, which has been confirmed by lung fiber burden analyses in some cases (8). Therefore, it is necessary to make inquiries as to the occupational activities of other family members and whether, if they were occupationally exposed, they wore their dirty workplace clothes home for laundering during the period appropriate for the latency of the tumor. Accurate, comprehensive, and detailed histories of exposure to agents such as asbestos can be facilitated by the use of questionnaires. Clinical and Radiologic Markers of Exposure The clinical and radiologic markers of exposure include pleural plaques, diffuse pleural fibrosis, rounded atelectasis, and asbestosis. Pleural Plaques Plaques are pearl gray, smooth, raised nodules, often calcified, which are situated on the parietal pleura, most commonly on the posterolateral and basal parts of the chest wall and diaphragm (Fig. 16.1). They are frequently associated with asbestos exposure especially when large,
4 262 Chapter 16 Determination of Asbestos Exposure Figure Pleural plaques appear as pearl gray, smooth, reused nodules. numerous, and bilateral, but there are other causes such as trauma, old tuberculosis, exposures to talc or mica, and idiopathic causes. Pleural plaques are benign, and the great majority of individuals with plaques alone have no symptoms or changes detectable by lung function studies. They appear to be related more to amphibole than to chrysotile asbestos exposure. The study by Gibbs (9) of the Quebec chrysotile miners and millers showed that the incidence correlated with tremolite better than with chrysotile concentrations. Pleural plaques can occur with brief, intermittent, low-level exposure, and they have been found in individuals exposed indirectly to asbestos (paraoccupational, neighborhood, environmental). Plaques related to environmental exposure have been associated with the tremolite or anthophyllite types of fiber. Less than 10% of pleural plaques found at postmortem have been detected in life. This proportion may alter with the increasing use of computed tomography (CT) scanning. Identification of pleural plaques by chest radiographs has a significant error rate, particularly in obese individuals where fat pads can be mistaken for pleural plaques. Pleural plaques do not begin to show themselves until 15 to 20 years after the first exposure and they may take 30 years for calcification. Their incidence in an asbestos-exposed population increases with time since first exposure. Pleural plaques are a marker of asbestos exposure only and do not indicate an increased risk of malignancy (10). For instance, a shipyard worker with plaques is no more likely to develop mesothelioma or lung cancer than a shipyard worker without plaques.
5 A.R. Gibbs 263 Knowledge of their presence is less informative than an accurate occupational history. Diffuse Pleural Fibrosis Diffuse pleural fibrosis predominantly affects the visceral pleura and it can surround the lung completely (11,12). When bilateral and extensive it can be associated with a decrease in vital capacity. It can be associated with quite low exposures to asbestos. The changes are not specific to asbestos and require evidence of an elevated asbestos fiber burden in the lungs to attribute it to asbestos (vide infra). Rounded Atelectasis Rounded atelectasis refers to an asymptomatic, peripheral, rounded pulmonary mass 2 to 7cm in diameter that is attached to the pleura. It can mimic lung cancer on radiologic investigations, but a typical comet s tail of vessels and bronchi may be evident linking into the lateral aspect of the mass, which distinguishes it from neoplasia (13,14). Pathologically it consists of dense pleural fibrosis, which is drawn into atelectatic lung parenchyma. Although most closely associated with exposures to asbestos, because of the latter s tendency to induce pleural fibrosis, it has also been described in association with trauma, infection, and other agents such as silica, which can result in pleural thickening (15). Asbestosis Asbestosis is defined as diffuse interstitial fibrosis of the lung that has been caused by inhalation of asbestos fibers. Clinically evident and radiologic changes of asbestosis are usually associated with prolonged heavy exposures to asbestos, which are far higher than necessary to produce mesothelioma. Changes of asbestosis are frequently absent in cases of mesothelioma. If they are present, then there is usually a strong and convincing history of asbestos exposure. Histopathologic Evaluation of Cases Examination of the pleura at autopsy may reveal the presence of parietal pleural plaques that were not detected during life and it is important that the examiner note their presence, number, and location. Asbestos Bodies The main histopathologic evidence for asbestos exposure is dependent on the finding of asbestos bodies in light microscopic sections of lung tissue either by conventional or iron stains. Asbestos bodies are golden, brown, club-shaped, often beaded structures that contain a clear pale transparent straight needle-like core. They are formed by the coating of the asbestos fiber with ferritin and protein and take months or years
6 264 Chapter 16 Determination of Asbestos Exposure to develop after deposition of the fiber in the lung. If the morphologic criteria are carefully adhered to the majority (greater then 95%) of the asbestos bodies are found on examination by electron microscopy with energy dispersive x-ray spectrometry to contain commercial amphibole (crocidolite or amosite) cores. In some areas of the world with environmental exposures to asbestos they contain tremolite or anthophyllite. Asbestos bodies formed from chrysotile are rare. The finding of one convincing asbestos body by light microscopy in a standard histologic section nearly always signifies an above-background exposure. However, ferruginous bodies that are not formed on asbestos fibers can occur, for example, on talc, mica, kaolin, coal, carbon, rutile, and iron (16). These are distinguished by having cores that are yellow or black or platy rather than fibrous. Particular care has to be exercised by the histopathologist when evaluating cases with mixed dust exposures where substantial amounts of sheet silicates (talc, mica, kaolin, etc.) are present; these silicates can be coated to form ferruginous bodies and although these are platy, they can be cut at such an angle as to appear to be fibrous and can be incorrectly identified as asbestos. If the histopathologist finds clusters of asbestos bodies, this usually signifies very high levels of commercial asbestos fibers. Tissue Digests and Bronchoalveolar Lavage Examinations When conventional light microscopic examination of tissue sections fails to demonstrate the presence of asbestos bodies, other quantitative approaches can be utilized to demonstrate an elevated fiber burden such as counting asbestos bodies or fibers on lung tissue digests or bronchoalveolar lavage (BAL) samples (5,17 19). The former can be done using light microscopy and the latter necessitates phase-contrast microscopy or electron microscopy. For both approaches the standard reference ranges for the normal population should be determined by the laboratory carrying out the analysis since numerous studies have been published from many countries that have demonstrated the presence of asbestos bodies and fibers in digestates of lung from individuals without occupational exposure to asbestos. Asbestos bodies constitute only about 0.01% to 1% of fibers visible by electron microscopy. Further the proportion of asbestos fibers that become coated to form asbestos bodies varies with a number of factors including fiber type, fiber length, fiber number, and the amount of iron in the tissue, and therefore one cannot calculate a precise fiber load by quantifying the number of asbestos bodies. Analyses using electron microscopic techniques are more timeconsuming and costly but are much more sensitive and can provide a precise breakdown of the different fiber types present (20). They should certainly be employed where the light microscopic techniques fail to demonstrate an elevated fiber burden. Samples of sputum can also be evaluated for the presence of asbestos bodies. Their detection indicates heavy occupational exposure to asbestos even years after cessation of exposure (21). However, the examinations are of little practical use in subjects exposed to relatively light or moderate amounts of asbestos.
7 A.R. Gibbs 265 References 1. Spirtas R, Heineman EF, Bernstein L. Malignant mesothelioma: attributable risk of asbestos exposure. Occup Environ Med 1994;51: McDonald AD, McDonald JC. Malignant mesothelioma in North America. Cancer 1980;46: Browne K, Wagner JC. Environmental exposure to amphibole-asbestos and mesothelioma. In: Noland RP, Langer AM, Ross M, Wicks FJ, Martin RF, eds. The Health Effects of Chrysotile Asbestos. The Canadian Mineralogist Special Publication, vol 5. Ottawa, Canada: Mineralogical Association of Canada, 2001: Nolan RP, Langer AM. Concentration and type of asbestos fibres in air inside buildings. In: Nolan RP, Langer AM, Ross M, Wicks FJ, Martin RF, eds. The Health Effects of Chrysotile. The Canadian Mineralogist Special Publication vol 5. Ottawa, Canada: Mineralogical Association of Canada, 2001: De Vuyst P, Karjalainen A, Dumortier P, et al. Guidelines for mineral fibre analyses in biological samples: report of the ERS working group. Eur Respir J 1998;11: Hodgson J, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg 2000;44: Lanphear BP, Buncher CR. Latent period for malignant mesothelioma of occupational origin. J Occup Med 1992;34: Gibbs AR, Griffiths DM, Pooley FD, Jones JSP. Comparison of fibre types and size distributions in lung tissues of paraoccupational and occupational cases of malignant mesothelioma. Br J Ind Med 1990;47: Gibbs GW. Etiology of pleural calcification; a study of Quebec chrysotile asbestos miners and millers. Arch Environ Health 1979;34: Weiss W. Asbestos-related pleural plaques and lung cancer. Chest 1993;103: Stephens M, Gibbs AR, Pooley FD, Wagner JC. Asbestos induced pleural fibrosis. Thorax 1987;42: Gibbs AR, Stephens M, Griffiths DM, Blight BJN, Pooley FD. Fibre distribution in the lungs and pleura of subjects with asbestos related diffuse pleural fibrosis. Br J Ind Med 1991;48: Doyle TC, Lawler GA. CT features of rounded atelectasis of the lung. AJR 1984;143: Gevenois PA, de Maertelaer V, Madani A, et al. Asbestosis, pleural plaques and diffuse pleural thickening: three distinct benign responses to asbestos exposure. Eur Respir J 1998;11: De Vuyst P, Pfitzenmeyer P, Camus PH. Asbestos, ergot drugs and the pleura. Eur Respir J 1997;10: Churg A, Warnock ML. Asbestos and other ferruginous bodies. Am J Pathol 1981;102: Churg A, Warnock ML. Asbestos fibres in the general population. Am Rev Respir Dis 1980;122: Whitwell F, Scott J, Grimshaw M. Relationship between occupations and asbestos fibre content of the lungs in patients with pleural mesothelioma, lung cancer and other diseases. Thorax 1977;32: Ashcroft T, Heppleston AG. The optical and electron microscope determination of pulmonary asbestos fibre concentrations and its relation to the human pathological reaction. J Clin Pathol 1973;26:
8 266 Chapter 16 Determination of Asbestos Exposure 20. Gibbs AR, Pooley FD. Analysis and interpretation of inorganic mineral particles in lung tissues. Thorax 1996;51: Paris C, Galateau-Salle F, Creveuil C, et al. Asbestos bodies in the sputum of asbestos workers: correlation with occupational exposure. Eur Respir J 2002;20: