1 MESOTHELIOMAS - ASBESTOS EXPOSURE AND LUNG BURDEN G. Berry Department of Public Health, University of Sydney, Australia A.J. Rogers National Occupational Health and Safety Commission, University of Sydney, Australia F.D. Pooley Department of Mining, Geological and Minerals Engineering, University College, Cardiff, Wales, UK Summary. The assessment of asbestos fibres in the lungs at post mortem in groups of mesotheliomas, groups occupationally exposed to asbestos, and controls has shown that all these groups contain significant levels of asbestos as a lung burden. The amounts in each group are dependent on the degree of past exposure, being highest in those cases with a known or extrapolated occupational exposure, less in those cases with recorded neighbourhood or environmental exposure, and less again in those cases with no evidence of exposure to asbestos and in controls. Relative risk estimates and the use of models developed for occupational situations do not provide good estimates of the relevance of environmental fibres in producing mesotheliomas in the general population. This may be the result of differences between the groups in their time periods of exposure and long-term elimination of asbestos from the lungs. The number of mesotheliomas that might be due to low-level environmental exposure to asbestos cannot be determined from lung contents alone, but an assessment based on detailed occupational histories from the Australian Mesothelioma Surveillance Program show that the problem is not one of great importance when compared with other public health issues. Introduction Since the work of Wagner et al. (1960), the link between asbestos exposure and mesothelioma has become well established. Most of the evidence has come from studies of groups with known occupational exposure to asbestos, although it has also been shown that para-occupational exposure, such as household contact with exposed workers, or residence near to an asbestos source can result in mesothelioma (Newhouse & Thompson, 1965; Anderson et al., 1976). Studies on asbestos-exposed groups have indicated that the risk of mesothelioma induction is dependent on the type of asbestos as well as the severity and duration of exposure. National or regional studies indicate that mesotheliomas also occur in those for whom no evidence of either occupational or environmental exposure was obtained from a detailed history. Greenberg and Davies (1974) gave data on 234 mysotheliomas occurring in England, Wales or Scotland in , for whom it had been possible -486-
2 Mesotheliomas - asbestos exposure and lung burden 487 to obtain a history of possible as bestos exposure. Of these, 183 (78%) had definite or possible occupational exposure, 13 (6%) had neighbourhood, domestic or hobby exposure, whilst for 38 (16%) careful enquiry failed to elicit any exposure. Ferguson et al. (1987) reported on 690 mesotheliomas occurring in Australia in for whom an adequate history was available. Definite, probable or possible occupational exposure was found for 456 (66%), neighbourhood, domestic or hobby exposure for 43 (6%), but there remained 191 (28%) with no history of exposure. The annual mesothelioma rate in adults with no history of asbestos exposure is about 1.5 per million (McDonald & McDonald, 1977; Peto, 1984). The etiology of these cases is unknown although some local isolated clusters have similar exposures to environmental agents (Peterson et al., 1984). Low-level environmental exposure to asbestos and asbestiform minerals has been postulated as a factor in these cases (Omenn et al., 1986). One problem in assessing the effect of general environmental asbestos exposure is that of obtaining a measure of the amount of such exposure and relating this to the exposure experienced by those occupationally exposed. Since exposure to asbestos leads to the inhalation and retention of fibres in the lungs, the amount of asbestos in the lungs is, to some extent, a measure of exposure during life. The study of women employed in the assembly of gas-masks (Jones et al., 1980b) showed that there was considerable crocidolite in the lungs (median 86 million fibres per g) years after a short period of exposure. In this paper, an attempt is made to estimate differences in exposure by comparing the lung contents of those with mesothelioma and controls in Australia with similar data from previous series. Attention is restricted to the two commercial amphibole fibres, amosite and crocidolite, because of their known strong association with the induction of mesothelioma. Materials and methods The sources of lung tissue obtained post mortem have been described previously and are only briefly summarized here. Australian series This consists of 189 cases of mesothelioma obtained during by the Australian Mesothelioma Surveillance Program (Ferguson et al., 1987). Based on the examination of a detailed occupational history, these cases were divided into 3 groups: those with occupational exposure to asbestos, those with identified environmental exposure to asbestos, and those with no identified exposure to asbestos. A control series of 50 cases was also included, consisting of male urban dwellers aged from a series of consecutive necropsies (Rogers, 1984). United Kingdom series (1976) A series of 86 mesothelioma cases was obtained from pathologists (Jones et al., 1980a). The pathologists also supplied 56 age-matched controls who had died either of bronchial carcinoma or cerebrovascular disease.
3 488 Berry et ai. United Kingdom series (1977) This series contained three groups (Wagner et al., 1982), the first being a group of 145 cases from the Pneumoconiosis Medical Panels (PMP) in which exposure to asbestos had been considered a factor in the cause of death. About 30% ofthis group had a mesothelioma and another 30% lung cancer. The second group consisted of 25 mesotheliomas. Some of these cases were known to have had occupational exposure to asbestos. The third group was made up of94 controls from consecutive necropsies in adults from 6 hospitals, chosen to represent areas of severe, moderate and low industrial pollution. North American series This series consisted of 99 mesotheliomas collected from pathologists in the USA and Canada in 1976, and from 100 controls matched for age and sex (McDonald et ai., 1982). Tissue analysis Preparation of the specimens for electron microscopy was described in the earlier reports (Jones et al., 1980a; McDonaldet ai., 1982; Rogers, 1984; Wagner et al., 1982). Mineral fibre analysis was carried out on the United Kingdom and North American series in Cardiff using transmission electron microscopy and an energy-dispersive X-ray analysis (EDXA) system (Pooley & Clark, 1979, 1980). Fibres of all sizes that were resolved by the electron microscope were included in the counts, provided that they had an aspect ratio greater than 3 to 1. The Australian series was analysed in Sydney using a transmission electron microscope fitted with the EDXA system. Because of problems of minor contamination from short fibres on the collection filter, only fibres longer than 2,urn were reported (Rogers, 1984). Presentation of results Fibre counts are expressed in units of millions per gram of dry tissue. Results are presented for amosite, crocidolite, and amosite plus crocidolite combined. The distribution of counts is given as relative frequencies (%) in the categories less than 1, 1-9.9, , and 100 million fibres or more per gram. The median fibre counts and interquartile range (25 and 75 percentiles) are also given. In some cases, the lower quartile (and the median) could not be estimated directly since" for more than 25% (or 50%) of the samples, no fibres of the type being considered were identified. In these cases, the quartile (and median) were estimated from a cumulative probability plot on log-probability paper. Such plots showed that the distributions of counts were approximately lognormal. Results The distributions, medians and interquartile ranges are given in Tables 1,2 and 3 for amosite, crocidolite, and amosite and crocidolite combined, respectively. For the Australian series, the occupationally exposed mesotheliomas contained the highest levels of crocidolite and amosite. The environmentally exposed mesotheliomas
4 Mesotheliomas - asbestos exposure and lung burden 489 contained slightly more crocidolite than those with no known exposure to asbestos. The mesotheliomas not exposed to asbestos contained a similar quantity of amosite and crocidolite to that of the controls. The median content of amosite and crocidolite combined was 5 times higher for mesotheliomas with occupational exposure than for controls, and there was considerable overlap between the distributions. Table O.lOa a 0.03a 0.09a Distribution <O.Olb-1.7 Interquartile concentration 96.0 Relative < Omb-O.27 O.05b b-O b-O b-O.26 >100 b-o.35 b-0.20 frequency (million of amosite (%) No. Median 50 fibres atof a in lungs range Panel Mesotheliomas: Occupationally cases amosite Medical for nevertheless differences bestimated The than Panel United North from crocidolite. between acases lognormal exposed considerable Kingdom American had thealso plot; groups more series in the overlap more amosite amounts were for differed than both between larger 25% and mesotheliomas ofrom than amosite samples crocidolite indistributions. no other andamosite Australian crocidolite than series controls. fibres the byseries were controls. were containing detected. but lessthere than The more was <1Pneumoconiosis Medical re detected. Series Inand thegroup United Kingdom series, the mesotheliomas and the Pneumoconiosis
5 490 Berry et al. Discussion In an attempt to determine the proportion of mesotheliomas that may be a result of exposure to low levels of asbestos fibres present in the general environment, two approaches were tried. Relative risk based on amphibole lung burden The Australian, United Kingdom 1976 and North American series are essentially case-control studies of mesotheliomas. In a similar study of mesothelioma in Norway, Mowe et al. (1985) calculated an odds ratio (relative risk) of 8.5 (95% confidence interval (CI), ) for a lung content of more than 1 million fibres per gram of dry tissue compared with lower lung contents. A similar approach here, using amosite and crocidolite combined, gave a relative risk of 8.0 (95% CI, ) for Australia, 7.4 (95% CI, ) for the United Kingdom in 1976 and 3.8 (95% CI, ) for North America. The usefulness of such an approach depends on the extent to which the amount of asbestos fibre in the lungs at post mortem is a valid measure of the risk of mesothelioma as a result of exposure to as best os. If it is assumed that the amount of fibre deposited at any time is proportional to the concentration offibre in the air, and long-term elimination is ignored, then the amount of asbestos in the lungs is proportional to the cumulative exposure. One of the disadvantages of this measure is that it does not take into account the time at which the exposure took place, and it is well established that mesothelioma incidence increases with time since exposure. Occupational exposure to asbestos has often come to an end several years, or even decades, before a mesothelioma occurs. The greater part of the cumulative exposure will have taken place by the end of the occupational exposure. In contrast, background environmental exposure continues throughout life. Thus the ratio of asbestos in the lungs after occupational exposure to that after environmental exposure will be less than the ratio of the mesothelioma incidences. If there is also long-term elimination of dust from the lungs, then the discrepancy between asbestos lung burden and mesothelioma incidence noted above will be greater, since the lung burden of those who have ceased to be occupationally exposed will decline, whilst the mesothelioma incidence increases. Elimination has been demonstrated in animal experiments to take place at a rate of about 20% per year (Wagner et al., 1974). Another difference between occupational and environmental exposures is that the fibres are shorter and generally finer in environmental situations. Studies on the relative rates of clearance from the lung of fibres of various sizes indicates that short fibres are more rapidly removed and that a higher proportion of long fibres remain even after extended periods (Morgan et al., 1978). Risk based on degree of exposure and lung clearance Peto (1984) gave a mathematical formula relating mesothelioma incidence, level of exposure and time since exposure. This formula may be applied to the gas-mask workers studied by Jones et al. (1980b), who had a mesothelioma incidence 1500 times
6 0.02b lb Interquartile concentration <0.01 Relative a-o Ia-o a-o a-1.0 >100 a-o.47 a-o.07 a-o.40 Mesotheliomas frequency (million 140 (%) No. Median fibres atof a- Panel cases Pneumoconiosis Mesotheliomas: OccupationallyMedical exposed <1 Series and group asbestos range exposure and lung burden 491 aestimated from lognormal plot; in more than 25% of samples no crocidolite fibres were detected. bestimated from lognormal plot; in more than 50% of samples no crocidolite fibres were detected. that in the unexposed, to give an estimated asbestos level in the factory about times that in the general environment, if it is assumed that all mesotheliomas are the result of exposure to asbestos (see Appendix). However, the gas-mask workers had at the most 150 times more amphibole fibre in their lungs than controls. This could occur if the elimination rate was about % a year (see Appendix). The gas-mask workers are atypical of the occupationally exposed in both their high mesothelioma incidence and short duration of exposure. As a more typical situation consider occupational exposure leading to a 250-fold relative risk of mesothelioma (this corresponds to about 2% of deaths being due to mesothelioma) and suppose exposure from age 25 to age 35 gives this excess at age 60. Then the
7 b < / Interquartile Relative 16.6 concentration >100 frequency (million 140 (%) No. Median fibres atof a range Berry et a/. Panel cases Mesotheliomas: Pneumoconiosis Occupationally exposed <1 Medical Series and group on of amosite and crocidolite in lungs 0Estimated from lognormal plot; in more than 25% of samples no amosite or crocidolite fibres were detected. bestimated from lognormal plot; in more than 50% of samples no amosite or crocidolite fibres were detected. occupational exposure level would be 2500 times that in the environment. With an elimination rate of 15% per year, the occupational cases would contain about 50 times more asbestos in their lungs than the unexposed population whilst, if the elimination rate was 17.5% per year, the ratio would only be 25. These ratios are greater than that found for the Australian cases (Table 3), where the occupationally exposed had median lung contents only 5 times that of controls. This could be either because the category of occupational exposure corresponded to an average relative risk ofless than 250, or because the elimination rate was higher. In the former case, a greater proportion of the population would have had to be exposed
8 Mesotheliomas - asbestos exposure and lung burden 493 in order for about two-thirds of the mesotheliomas to occur in the occupationally exposed (for a relative risk of 250, 1 person in 125 would have to be occupationally exposed). In the Australian study, the term occupational exposure did not necessarily imply that asbestos processing or handling was a main activity nor that exposure was necessarily high. For the Pneumoconiosis Medical Panel cases in the United Kingdom in 1977, the median content was 60 times that of controls. To be accepted by the Pneumoconiosis Medical Panel, there would have had to be evidence of considerable exposure. The above calculations are based on the assumption that all mesotheliomas are due to asbestos exposure. If only a proportion of mesotheliomas are due to asbestos, then a higher level of occupational exposure and a higher elimination rate would be necessary to fit the data. This analysis does not provide an answer to the question of what proportion of mesotheliomas without occupational or para-occupational exposure to asbestos may be due to background environmental exposure to asbestos. What it does suggest is that there may not be any major discrepancy between the different relative amounts of asbestos in the lungs and the relative risks of mesothelioma. Such differences, as well as the overlap ofthe distributions ofthe occupationally exposed and controls, may be explained by different time patterns of exposure and long-term elimination of fibres from the lungs. The assessment of lung fibre burden at post mortem is important in detecting or confirming heavy exposure, and in identifying the types of asbestos to which there has been exposure. Examination of controls periodically could be useful in monitoring environmental pollution due to asbestos. However, such determinations alone cannot indicate the number of mesotheliomas due to low levels of asbestos in the environment. Extrapolation of the risk data for air-borne exposures, even at relatively high environmental levels, as in asbestos-containing buildings, only accounts for a relatively small proportion of non-occupational mesotheliomas (Doll & Peto, 1985). An upper limit to the number of mesotheliomas due to background environmental exposure is provided by ascertainment of most cases and detailed occupational histories. By such means (Ferguson et al., 1987), it has been found that about 45 mesotheliomas occur each year in Australia without known asbestos exposure. The importance of this in public health terms is not high when compared with 2900 deaths annually due to motor vehicle accidents, and with 5700 bronchogenic cancers, many attributable to cigarette smoking. The differences between these figures indicate the relative priorities to be assigned to preventive measures aimed at reducing road accidents and smoking, as compared with the removal of asbestos from buildings. Acknowledgements The Australian data come from the Australian Mesothelioma Surveillance Program, and we are grateful to Professor D. Ferguson for permission to use these data.
9 494 Berry et al. References Anderson, H.A, Lilis, R., Daum, S.M., Fischbein, A.S. & Selikoff, I.J. (1976) Householdcontact asbestos neoplastic risk. Ann. N. Y. Acad. Sci., 271, Doll, R. & Peto, J. (1985) Effects on Health of Exposure to Asbestos, London, Her Majesty's Stationery Office Ferguson, D., Berry, G., Jelihovsky, T., Andreas, S., Rogers, A., Fung, S.e., Grimwood, A. & Thompson, R. (1987) The Australian Mesothelioma Surveillance Program, Med. J. Aust., 147, Greenberg, M. & Davies, T.AL. (1974) Mesothelioma Register Br. J. Ind. Med., , Jones, J.S.P., Pooley, F.D., Clark, N.J., Owen, W.G., Roberts, G.H., Smith, P.G., Wagner, J.C., Berry, G. & Pollock, D.J. (l980a) The pathology and mineral content oflungs in cases of mesothelioma in the United Kingdom in In: Wagner, J.C., ed., Biological Effects of Mineral Fibres (farc Scientific Publications No. 30), Lyon, International Agency for Research on Cancer, pp Jones, J.S.P., Smith, P.G., Pooley, F.D., Berry, G., Sawle, G.W., Wignall, B.K., Madeley, R.J. & Aggarwal, A (l980b) The consequences of exposure to asbestos dust in a wartime gas-mask factory. In: Wagner, J.e., ed., Biological Effects of Mineral Fibres (farc Scientific Publications No. 30), Lyon, International Agency for Research on Cancer, pp. McDonald, J.C. & McDonald, A.D. (1977) Epidemiology of mesothelioma from estimated incidence. Prevo Med., 6, McDonald, AD., McDonald, J.e. & Pooley, F.D. (1982) Mineral fibre content of lung in mesothelial tumours in North America. Ann. Occup. Hyg., 26, Morgan, A, Talbot, R.J. & Holmes, A. (1978) Signficance of fibre length in the clearance of asbestos fibres from the lung. Br. J. Ind. Med., 35, Mowe, G., Gylseth, B., Harviet, F. & Skaug, V. (1985) Fiber concentration in lung tissue of patients with malignant mesothelioma - a case-control study. Cancer, 56, Newhouse, M.L. & Thompson, H. (1965) Mesothelioma of the pleura and peritoneum following exposure to asbestos in the London area. Br. J. Ind. Med., 22, Omenn, G.S., Merchant, J., Boatman, E., Dement, J.M., Kuschner, M., Nicholson, W., Peto, J. & Rosenstock, L. (1986) Contribution of environmental fibers to respiratory cancer. Environ. Health Perspect., 70,51-56 Peterson, J.T., Greenberg, S.D. & Buffler, P.A (1984) Non-asbestos related malignant mesothelioma - a review. Cancer, 54, Peto, J. (1984) Dose and time relationship for lung cancer and mesothelioma in relation to smoking and asbestos exposure. In: Fischer, ryf. & Meyer, E., eds, Zur Beurteilung der Krebsgefahr durch Asbest, Mtinchen, MMV Medizin Verlag, BGA Schriften, 2/84, pp. Pooley, F.D. & Clark, N.J. (1979) Quantitative assessment of inorganic fibrous particulates in dust samples with an analytical transmission electron microscope. Ann Occup. Hyg., 22, Pooley, F.D. & Clar k, N.J. (1980) The chemical and physical characteristics of fibrous particles detected in human post-mortem lung tissue. In: Wagner, J.C., ed., Biological Effects of Mineral Fibres (farc Scientific Publications No. 30), Lyon, International Agency for Research on Cancer, pp Rogers, AJ. (1984) Determination of mineral fibre in human lung tissue by light microscopy and transmission electron microscopy. Ann. Occup. Hyg., 28, 1-12 Wagner, J.C., Berry, G., Skidmore, J.W. & Timbrell, V. (1974) The effects of the inhalation of asbestos in rats. Br. J. Cancer, 29,
10 Mesotheliomas - asbestos exposure and lung burden 495 Wagner, J.e., Pooley, F.D., Berry, G., Seal, R.M.E., Munday, D.E., Morgan, J. & Clark, N.J. (1982) A pathological and mineralogical study of asbestos-related deaths in the United Kingdom in Ann. Occup. Hyg., 26, Wagner, J.C., Sleggs, e.a. & Marchand, P. (1960) Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br. J. Ind. Med., 17, Appendix Following the formulation given by Peto (1984), the mesothelioma incidence t years after the beginning of continuous exposure to a level d is dt3 5 If the environmental level is denoted by d, then the mesothelioma incidence at age t, me, is given by: Now consider occupational exposure to level do from ages t1 to t2 Assuming that do> >de so that environmental exposure can be ignored, then the mesothelioma risk, mo, at age t(>t2) is: The corresponding amounts of fibre in the lungs, A E and Ao, in the absence of long-term elimination, are: (1) (2) and (3) where k is a constant representing the retention rate. If elimination takes place exponentially at a rate of A per year, then the amounts would become: (4) and AE'=kdl-1(1-e-At) (5) Applying the above to the gas-mask workers (Jones et al., 1980b), the mesothelioma incidence 30 years after a mean exposure of 1 year was 2200 per million per year, about 1500 times the incidence in the unexposed, that is: molme=1500 If the mesotheliomas in the unexposed represent 55 years of environmental exposure, then using equations (1) and (2) we find: (6) dol de = Fibre burdens are available for 14 cases with mean duration of employment 22.5 months. The median lung burden was 120 million amphibole fibres per g, compared
11 496 Berry et al. with about 0.4 for United Kingdom controls. The ratio of lung contents is 300, but scaling down the lung contents of the mesotheliomas to a mean duration of exposure of 1 year gives approximately: A~/A ~ = 150 Then from equations (5) and (6), A = Although these calculations are based on assumptions that are probably oversimplistic, and lung burdens in the gas-mask workers were not available from a representative sample of the group but mainly from those who had died of mesothelioma, they give some indication of the situation. The relative mesothelioma incidence was 10 times the relative amounts of asbestos in the lungs, and this could have occurred as a result of long-term elimination of fibre from the lungs at a rate of 15% per year. If the lung burden in the group as a whole was less than that of the mesotheliomas, then a higher elimination rate would be estimated, e.g., A ~/ A ~ = 75 gives A = An elimination rate of 15% per year means that only 22% offibre in the lungs at the cessation of exposure remains 10 years later; for an elimination rate of 17.5%, only 17% would remain.