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Mesothelioma following exposure to crocidolite (blue asbestos). A fifty-year follow-up study 2nd international Congress on Lung Cancer Oete, Greece 9-13 November 1996 J.SJP- JONES, A.R. GIBBS * J.C. McDONALD ** and ED. POOLEY *** Department of Pathology, City Hospital, Nottingham (GB) * Department ofPathology, Llandough Hospital, Penarth, South Wales (GB) **Department of Occupational and Environmental Medicine National Heart and Lung Institute, London (GB) *** Department of Mineralogy, University College of Wales, Cardiff, South Wales (GB) SUMMARY A chronological review of Che pathological effects of asbestos precedes the results of a survey of 1,172 workers (mainly women) who were exclusively exposed co crocidolite when manufacturing military gas masks in Nottingham during the Second World WarDuring the following fifty years, 67 (or at least 6%) have died of mesothelioma of the pleura or peritoneum. Of these, the shortest exposure period was 10 days. Mineral fibre analysis on post mortem lungs reveals the lowest crocidolite concentration Co be 0.4 million fibres per gram of dried lung. Comparisons are made with other workers exposed to asbestos, including those also in the gas mask industry who were exposed to chrysotile. INTRODUCTION Although used over the centuries since at least A.D.77, it was not until 1889 that asbestos was commercially exploited in factories in France and England. Within 20 years, health hazards in the workers were reported. Montague Murray (1906) Copyright 1996 by Mooduzzi &*!ore S.P.A. - Bologna (Ifaly} 407 2nd International Congress on Lung Cancer Otic. Greece 9*13 November 1996 describe*! pulmonary f ibvosis - la ter to bu designated ASBESTOSIS, in a factory worker. In the !920*s increasing numbers of such eases were reported. During the 1930's and especially during and since the Second World War the asbestos industry expanded enormously, the fibres being incorporated in a widening variety of products. In the lace 1940's concern was expressed about the increasing incidence of LUNG CANCER in asbestos workers. Doll (1955) confirmed this risk, particularly in those who had asbestosis. A second link with malignancy was suggested by Vagner et al in 1960 when a high incidence of the rare mn lignant tumour MESOTHELIOMA was found in the South African crocidolitc. mining communes. Of especial concern was that the asbestos exposure in these individuals was considerably less than that of the British factory workers who had developed lung cancer. Since Wagner's paper rauch world-wide research confirmed his findingsIn order to identify the relative dangers of the different types of asbestos in commercial use (CROCIDGLITE, AMOSXTE & CHRYSOTILE) searches were made Co identify cohorts of workers who had been exclusively exposed to one type of asbestos only (Gilson, 1973). In 1968, Jones first reported two cases of pleural mesothelioma in women who had been exclusively exposed to crocidolicc for a limited period (up to A years) when manufacturing "military" gas mask filter units in Nottingham during the 2nd World W2r. This cohort has been followcd-up during the intervening years and it forms the basis of this study. V MATERIALS AND METHODS Pathology Complete autopsies were carried out on 37 of the 67 esses of mesothelioma (48 pleura; 9 peritoneum). The remaining 10 eases were confirmed by biopsy diagnosis. 408 Microscopy The early eases of tumour were examined by light microscopy, using haematoxyiin and ecsin (K & E) stained sections, followed by diastase-PAS stains to negate the possibility of adenocarcinoma, particularly of ovarian tumours in the peritoneal malignancies. In the later cases additional confirmatory immunohistochcmical techniques including CA, cytokeratin and viraentin stains were used. Lung sections using H & E and elastic Van Gieson stains in addition to 30 micron thick unstained sections were examined by high power light microscopy to assess the presence of asbestosis. TABLE I NUMBER OF DEATHS DUE TO MALIGNANCY IN ADDITION TO THE 67 CASES OF MESOTHELIOMA Number of cases Carcinoma ok Bronchus Breast Stomach Ovary Cervix Pancreas Bladder Vagina/Vulva Colon Carcinomatosis unknown 1 Brain Tumour Carcinoma of: 23 Larynx 1 *3 Oesophagus 3 JO Kidney 1 3 Uterus 5 Tongue 1 1 S Thyroid 1 3 Fibrosarcoma l 2 Ac. Leukaemia 1 2 Hodgkin's Disease 1 5 " TOTAL 90 CASES HWBUI0010314 Mineralogy Representative samples of lung tissue from 69 gas mask workers, including 48 with mesothelioma were examined by electron microscopic and energy dispersal x-ray techniques, using the method of Pooley and Clark (1979) . Epidemiology The tracing of the workers was derived frons:- Company records (mainly the Wages Book) - Medical records (local hospital, general practitioners and patients' own history. A master index was prepared. To date the causes of death of 280 of the 1,172 workers are known, the majority of these (157) being due to malignant disease. (Table I). Further efforts to trace the remainder are in progress. 2nd International Congress on Lung Cancer Crete, Greece 9 *3 November 19S RESULTS Of the factory workforce of over 1,000 women the causes of death are known in 260 out of an estimated total of some 500 deaths. From this group 157 deaths were due to malignant disease, including 67 cases of cesocheliotaa (53 pleural and 14 peritoneal)The other 90 cases of malignancy are seen in Table I. Mesothelioma cases The latent interval between exposure 2nd death varied from 23 to 54 years. (Table II). TABLE H LATENT INTERVALS' BETWEEN THE PERIOD OF ASBESTOS EXPOSURE AND DEATH DUE TO MESOTHELIOMA OF PLEURA & PERITONEUM Asbestos exposure 777T/97* JJ1L Jill D > 3 * # LiJ > y .} H * J) ** > 0*0 > 1 IL 1111111 KEY: Mesothelioma of pleura female: Mesothelioma of peritoneum female: > male: male: O The ages at death ranged from 42 to 84 years. The average age at death from pleural tumour was 68.5 years, and 62.8 years from peritoneal tumour. The shortest period of exposure was 10 days. This woman had 6.5 million crocidolite fibres/gram of dry lung at autopsy * 46 years later. 409 2nd International Congress on Lung Cancer Cele. Greece 943 November 199S The lovest crocidolite count was 0.4 million fibres/grom of dry lung. The average fibre diameters in the Nottingham lungs was 0.2 microns, similar Co the fibre diameters found in Witccnoom and finer than those in the South African cases. The highest fibre counts (over I,000 tnillion/gram) were seen in the 4 cases of overt asbcscosis. Clinical and radiological asbestosis was seldom noted in the remaining cases in this series. DISCUSSION The wartime manufacture of filter units for ''military" gas masks in the United Kingdom was carried out in Nottingham (Jones ct al, 1980; Wignall & Fox, 1982), in Leyland (Acheson et al, 19S2) and in three centres in Canada (McDonald & McDonald, l978) using the same Porton specification. This required the use of fine diameter crocidolite, derived from the mine in Wittenoore, Western Australia. Increased numbers of mesotheliomas have occurred in all these factory areas, and in the Wittenoom mining commune (Hobbs et al, 1980; Berry, 1991). By contrast, none occurred in a factory in Blackburn, ILK., where "civilian" gas masks vere made which incorporated chrysotile instead of crocidolite into the filter (Acheson et al, 1982). Mesotheliomas have also followed exposure to Amosite in the U-S.A. and in a U.K. factory (Gibbs et al,. 1994). There is abundant evidence that mesotheliomas follow exposure to amphibole fibres (including crocidolite and amosite), but not to chrysotile unless it is contaminated with tremolite (McDonald & McDonald, 1996). In the Nottingham factory dust extraction precautions vere taken, and some workers wore simple masks. The factory was bombed and an emergency production line had to be set up else where in Nottingham. The dust levels vere not known, but the fineness of the fibre diameter would have helped dispersal and respirability of the fibres. The dimensions of the fibres were within the range of carcinogenicity as defined by Stanton & Layard (1978). ACHESON ED, GARDNER MJ, P1PPARD EC b GRIME P. Mortality of two groups of women who manufactured gas masks from chrysotile and crocidolite asbestos: a 40 year follow-up. Br.J.Ind.Med.39 344-348 (1982). BERRY C. Predictions of mesothelioma, lung cancer & asbestosis in former Wittenoom asbestos workers. Br-3.lnd.Med. 48 793-802 (1991). HWBUI0010316 TIHBRELL V, WAGfJER JC. eds. Biological Effects of Asbestos. IARC Scientific Publications No.8. Lyon (1973) - HOBBS MST, WOODWARD 50, MURPHY B, MUSK AW* ELDER JEThe incidence of pneumoconiosis, mesothelioma and other respiratory cancer in men engaged in mining and milling crocidolite in Western Australia. In: WAGNER JC, cd Biological Effects of Mineral Fibres. IARC Scientific Publications. No.30. Lyon. 615-635 (1960)- JONES JSP. Discussion on mesotheliomas. Inr HOLSTEIN & ANSPACH, eds. International Konferen* uber die Biologischen Wirkungen des Asbestcs. Dresden 289 (1968). JONES JSP, SMITH PG, POOLEY FD ct al. The consequence of exposure to asbestos dust in a wartime gas mask factory. In: WAGNER JC. ed. Biological Effects of Mineral Fibres. I ARC Scientific Publications No.30. IN5ERM Symposia Series 92637-653 Lyon (1980). McDONALD AD & MCDONALD JC. Mesothelioma after crocidolice exposure during gas mask manufacture. Environ.Res. 17. 340-346 (1978). McDONALD JC & McDonald AD. The epidemiology of mesothelioma in historial context. Euro.Resp.J. 1932-1942 (1996). HURRAY M. Departmental Commission on Compensation for Industrial Diseases. Cmd.3495.14Cmd.3496. 127-128- HMSO London (1906). POOLEY FD & CLARK N. Quantitative assessment on inorganic fibrous particles in dust samples with an analytical transmission electron microscope. Ann.Occup.Hyg. 22? 253-272 (1979). STANTON MF & LAYARD M. The carcinogenicity of fibrous minerals. Nat.Bureau of Standards Special Publication 506. 149 (1978). WAGNER JC, 5LEGGS CA & MARCHAND P. Diffuse pleural mesothelioma. Br.J.INd.Hed. 17 260-271 (1960). WIGNALL BK & FOX AJ. Mortality in female gas mask assemblers. Br.J.Ind.Med. 39 34-38- (1982) 2nd International Congress on Lung Cancer Crei*. Greet 9-13 November 199S 411