Document MG1r4Ozz1a9wb9wENj0Dbjxqa

Bril. J. inJustr. Med., I960, 17, 260. PLAINTIFF'S EXHIBIT DIFFUSE PLEURAL MESOTHELIOMA AND ASBESTOS EXPOSURE IN THE NORTH WESTERN CAPE PROVINCE BY J. C. WAGNER, C. A. SLEGCS, and PAUL MARCHAND From the Pathology Dhisioit, Pneumoconiosis Research Unit of the Council for Scientific and Industrial Research, Johannesburg, tt'est End Hospital, Kimberley, and the Department of Thoracic Surgery, University of the H'il* atersrand and Johannesburg General Hospital (RICUVED EOR PUBLICATION APRIL 24, 1960) Primary malignant tumours of the pleura are uncommon. Thirty-three cases (22 males, II females, ages 31 to 68) of diffuse pleural mesothelioma are described; all but one have a probable exposure to crocidolite asbestos (Cape blue). In a majority this exposure was in the Asbestos Hills which lie to the west of Kimberley in the north west of Cape Province. The tumour is rarely seen elsewhere in South Africa. Mesothelioma of the pleura is regarded as an uncommon tumour. In the last four years wc have seen 33 histologically proven cases; 28 of these had some association with the Cape asbestos field and four cases had been exposed to asbestos in industry. The tumour is rarely encountered elsewhere in South Africa. During the past five years, with the exception of the present series, no neoplasm of this nature has been diagnosed amongst 10,000 lungs examined at the Pneumoconiosis Bureau in Johannesburg, or in the Pathology Department of the South African Institute for Medical Research. Higginson and Oeule (1957) did not observe a single the lungs of the first case (Case I), and secondly, 10 of the cases came from a hospital to which suspected cases of tuberculosis were referred from a large asbestos mining area. This hypothesis could not be supported at once from the original histories obtained from the patients, for they included house wives, domestic servants, cattle herders, farmers, a water bailiff, an insurance agent, and an accountant, none of whom were working on the asbestos mines at the time. We therefore undertook a detailed investigation of their past occupation and place of residence, and the association with asbestos ex posure was discovered. The cases are summarized case in their survey of malignant tumours occurring in the Bantu and Cape Coloured population of Johannesburg and the North Eastern Transvaal. Our first necropsy specimen of pleural meso thelioma with asbestosis wu examined at the in Table 3. Previous biopsy specimens were re examined, and new cases diagnosed, including asbestos miners. In only one case do the relatives deny that the patient either visited the asbestos mines or was exposed to asbestos. .. Pneumoconiosis Research Unit in February, 195$ This is a preliminary publication and the problem (Case I). During the early months of that year, is being intensively investigated. one of us (C.A.S.) in the Northern Cape, treated six patients with gross pleural thickening. Pleural biopsies from two of them showed the features of The Asbestos Area of the North-West Cape . mesothelioma. In the ensuing two years, eight According to Hail (1930) asbestos was discovered further cases were found from this region and five by Lichenstein near Prieska during his travels be from elsewhere in the Union. During this period tween 1803 and 180$. Since then it has been C.A.S. had become perturbed at the number of established that the asbestos deposits extend from these unusual tumours occurring amongst his 20 miles south of Prieska, northwards through the patients, and stimulated an investigation. At this western part of the magisterial district of Hay, to stage there were two reasons to suggest that asbestos the eastern portion of the magisterial district of might be implicated. First, asbestos was found in Postmasburg and finally, to the western area of the 260 district o in the si< approxirr "Asbcsto . less long) " whole ar . apart fre important large tract ' have beet and here " vicinity o The typ 2. is crocido ^The chem; "Crocidolit . 'stages of rock thro 1 crocidolite 4 frequently ip). ^ Mining -: district in DIFFUSE PLEURAL MESOTHELIOMA 261 tal tales, ive a i the nour dly. tc, ..nich d from a sis could histories d house* .rmers, a .-ountant, os mines detailed place of rstos eximarized were re* ncluding relatives jsbestos problem Cape covered vels beis been id from ugh the Kay, -trict of a ` district of Kuruman (Fig. 1). These deposits occur in the slopes of a range of hills covering an area of approximately 8,000 square miles. Known as the "Asbestos Mountains'*, these hills extend more or less longitudinally between 22-301 and 23 E. The *ho)e area is $emi*arid, sparsely populated, and, apart from mining, caulc ranching is the only important occupation. In the Kuruman area several large tracts of land in or abutting on these mountains have been reserved for the aboriginal inhabitants and here whites may only reside in the immediate vicinity of the mines. The type of asbestos mined throughout this area is crocidolite, better known as Cape Blue Asbestos. The chemical analysis of the fibre is given in Table l. Crocidolite is the fibrous form of riebcckite and all stages of transformation from a massive riebeckite rock through lamellar riebeckite to asbestiform crocidolite occur in this region. Magnetite is frequently associated with the crocidolite (Vermaas, 1952). ... Mining of asbestos first began in the Prieska district in 1893 and gradually spread northwards. In 1908 production had begun in the Kuruman dis trict. Between 1916 and 1918 a large number of claims were taken up. This northward trend has continued and in about 1950 mining started at Pomfret near the Bcchuanaland border (Table 2). Initially the ore was quarried in numerous small open cast workings. This was followed gradually Table I CHEMICAL ANALYSES OF CROCIDOLITE AND AMOSITE (from Vttmui, 19)21. SiO, Al,0, Fe.O, F0 M*Q CiO N,0 K,0 H,0ll,Qf sST F j Crociilolit* 1 3194 : o:o 1164 19 39 ' \n 0 19 6 07 ' 004 . 0-31 l 2 5* ! *" AmoiiU 49 47 063 4 IS 3563 6-57 0 52 0 02 020 007 2 33 023 061 001 Toul 100 73 100 46 262 BRITISH JOL RSAL OF IS DLSTRIM MFDICISF Tabu 2 POPULATION- OF THE MAGISTERIAL DISTRICTS IN WHICH THE A.SUESFOS HELDS ARE SITUA7LD Uaken from Union Census nd ISMl District Prieska Hay Potmihu(| f ) Whites Population 1921 ' Non-hite 1 Total | 3.4)0 ! 4.1(79 I J.309 | OH 1 16.691 :i.4ii 1 4.494 1 S.SI4 IJ.Ml , Included in the Ha* District White* 1.161 4.SIS :.7>? 4.887 Population I9JI [ Non- et ' 10.847 23.779 9.6H ! 21.019 ------ - Toial ` 2J.906 by a type of shallow mining; inclined shafting be came more common after 1930. According to Frood (1915), the quarrying was a family affair undertaken by the local inhabitants. The men quarried the rock, which was sorted and then hand cobbed by the women and children. Hand cobbing consists of separating the fibre from the banded ironstone by striking the rock cob with a small hammer. As the market was selective, a rotary sieve was sometimes used to grade the fibre and eliminate the small particles of dust. After grading, it was bagged and weighed. The asbestos was then transported by donkey wagon to the nearest rail-head. Before the establishment of the railway in this area between 1923 and 1930, such a journey could last as long as 10 days. This transport was generally undertaken by white youths (farmers* sons) under contract The white inhabitants played very little part in actual recovery of the fibre, being nearly always employed in the role of managers or over seers. issuing stores and supervising the grading and weighing of the fibres. Farming activities were and are still carried out round the mines. Since the 1939-1945 war, the demand for crocidolite has enormously increased. The lucrative claims have been bought by registered companies, others have been abandoned. As deeper and richer deposits have been found, vertical shafts are being sunk. However, the mines with large shallow deposits are still using the inclined shaft and tunnel, and quarrying is still used by the few remaining smaiier producers. With the building of more mills, hand cobbing has diminished. In 1915 the first crushing mill was established at Koegas in the south. This was followed by a large mill at Kuruman (operated between 1926 and 1931) where it was situated within 300 yards of the main street, close to which cobbing was also done for a few years (1927-1930). This was followed by a mill at Prieska in 1930, which was completely rebuilt in 1957. Griquatown had a small mill in 1928. The practice today is for one mill to serve several mines in the immediate vicinity. In the early days the manager and labourers lived within a few yards of their place of work, and even today the non-white prefers to live as close as possible, and the children play on the dumps from the mine and mill. Case Histories The following eight case histories illustrate various aspects of the disease and the different types of exposure to asbestos dust. Case 1.--B.P., a Bantu male. 36 years of age (born 1920), was a mine labourer, and was the first case diagnosed as a mesothelioma with evidence of asbestosis. He was born in the Kuruman district but it is not known whether he worked in the asbestos mines. He was employed on the Witwatersnsnd gold-mines underground for two years and in the change rooms for a further 11 years. A radiograph taken at a mine hospital on August 18, 1955 showed a massive right-sided-pleural effusion^ and 3,000 ml. of fluid was withdrawn. He was admitted to the Witwatcrsrand Native Labour Association Hospital on August 24, 1955, and two days later aspira tion yielded 1,000 ml. of thick gelatinous pus "which could be pulled out in threads". He was treated with frequent aspirations and instillation of variduse but without improvement, and he died on February 15 1956 (Martiny, 1956). ' At autopsy the right thoracic cavity was occupied by a large gelatinous tumour which displaced the mediasti num and compressed the left lung. The tumour had infiltrated the pericardium. The right lung was com pletely compressed by neoplastic tissue (Fig. 2) but the right bronchial tree did not show any evidence of a primary bronchogenic carcinoma. Histological sections of the pleural growth showed a papillary mesothelioma (Fig. 3). There was evidence of asbestosis in both lungs (Fig 4). Case 4.--K.H., a white female, 56 years of age (bom 1898), was a social worker, who could only have had a short exposure to asbestos as a child and probably a further slight exposure as a young woman. She may have paid several short visits to the mines with her husband at a later period. She was bom in Griquatown where she lived until she was 5 years of age. Her family then moved to Kimberley where from 1916 to 1922 she worked as a clerk in an asbestos warehouse. Her husband owned ao asbestos mine from 1933-1940. Fig. 2.--Right lung lung jutwunce- FtO. 3 --Cellular un and cosin. FlO. 4..-Sction* of * {0 Hacmttot ED Total I4.:08 2.9? tijas 25.906 . dose as .mps from DIFFUSE PLEURAL MESOTHELIOMA f* ite various if exposure age (bora first case asbestosis. not known **< was ound - urther \ugust 18, etTusion, % admitted ssociutton cr aspirajs "which ated with ;dase but ruary 15. cupicd by mediasti\our had vas com* } but the nee of a I sections 'theiioma in both :gc {born vc had a -obably a She may -with her ed until oved to ed as a -w ' ah Fto. 2 Tic. 2.--Right lung of Cate I showing a tumour compressing the lung substance. Tic. 3.--Cellular structure of tumour ofCM I. *40 lUemitosylin anU eosin. Tio, 4.---Sections of lung from Cate I showing asbestos bodies, x 40 Haematotyltn ami cosm. Fki. 4 263 2(4 BRITISH JOl'RSAL OF ISDUSTRIAL ULDICISF 266 BRITISH JOURSAl OF ISPUSTRIAL MLDICISE lung substance. Numerous asbestos bodies were present in the air spaces and occasional bodies and fibres were seen in the interstitial tissue. The lung itself was markedly atelectatic. Evidence of asbestosis was observed in the left lung. Case 15.--S.S.V.. a white female. 42 years of age (bom 1916), is a housewife, who lived on a mine near Johannesburg and was treated for tuberculous pleurisy for six months. U was only after the histological diagnosis of a mesothelioma had been made that her previous history was obtained. In addition, it was subsequently learnt that her father (Case 22) had been bom on the asbestos field and had a long mining history. The patient was born in the Griquatown district and went to school at Kuruman. She spent most of her youth in the asbestos belt. She has lived near Johannes* burg for 20 years. In March. 1958 this patient developed right chest pain and rapidly increasing shortness of breath. She was admitted to hospital and 2.500 ml. of slightly blood* stained fluid was removed from the right chest. A thoracoscopic examination was carried out on July 27. when a small biopsy was taken but this consisted of fibrous tissue, llronchoscopy was normal und no neoplastic cells were observed in the bronchial washings. SI. tuberculosis was not cultured from numerous speci* mens of sputa, pleural fluid nor from the bronchial washings. She was admitted to a Johannesburg nursing home on October 16, 1958. Radiographs then showed massive thickening of the right pleura w ith fluid in the right chest. At thoracotomy (Mr. Dennis Fuller) the parietal pleura was 2 cm. thick, "hard as rock" and stripped with great difficulty from the chest wall. The visceral peel stripped fairly easily from the upper lobe but separation became more difficult over the lower lobe where the peel was thicker. During the decortication a necrotic mass was found in the paren* chyma of the left lower lobe. At the base, confluent with the diaphragm and perhaps the mediastinum, was a hard craggy mass which could not be removed. Histological sections of the specimen revealed an adenoid form of tubular mesothelioma. Subsequently three specimens of sputum were examined for asbestos bodies but none were found. The patient is still alive (April, I960), but her condition is deteriorating. Case 22.--D.A.B.. a white male, 68 years of age, and a farmer, was the father of the previous patient. Although a diagnosis of pleural mesothelioma was made in January, 1957 it was not until July, 1959 that details of his exposure to asbestos was obtained. He w-as born in Griquatown and went to school there. He worked in Kuruman. Postmasburg and Griquatown until the age of 62. Between 1918 and 1932 he worked as an asbestos miner underground and was mostly in charge of blasting. Between 1932 and 1944 he farmed in the district but returned to asbestos mining from 1945 to 1952. In January, 1957 the patient consulted his doctor be cause of left-sided chest pain with cough and slight haemoptysis. He was referred to the Johannesburg General Hospital for investigation. The chest radio graph showed gross pleural thickening with a basal pleural effusion on the left side. He was admitted t hospital and on June 10, 1957 a thoracoscopic pleural biopsy was taken. This showed the features of a meso thelioma. On June 24. 1957 an attempt at decortication was made. The left upper lobe was stripped easily but the grossly thickened pleura was so adherent to the lower lobe that the attempt was abandoned. Sections of the pleura confirmed the diagnosis of mesothelioma He died on December 13, 1957. Case 16.--A.N.V., a white male, 50 years of age (born 1906), was a farmer, who was born at Griquatown and went to a village school near an asbestos mine. From 1914-16 he transported asbestos in donkey waggons from Hay to Prieska. During these journeys lie often slept on asbestos bags. In 1914 he worked in an asbestos mine for a month. The patient became ill in December. 1955 with vague substcrnal pain and dyspnoea. A left-sided pleu^i effusion was diagnosed and he was referred to Mr. J k. ftremmer in Pretoria. There was no evidence of malig. nancy in bronchial and scalene biopsies. Some apical pleural thickening and a dense homogeneous opacity at the base of the left lung was seen in the radiograph on August 3. 1956. Thoracotomy (Mr. Bremmer) jn February, 1957 revealed a thickened nodular pleura with a large mass on the left diaphragm. A mesothelioma was seen on histological section. In April, 1959 he was examined by Mr. J. D. Visserin Kimberley who found small nodules in the subcutaneous tissue over the neck and chest. A large firm mass was found in the thoracotomy wound and a mass was present in the left hypochondrium. There was generalized lymphadenopathy and numerous nodules were present on the tongue. Chest radiographs showed the left pleural cavity to be obliterated. He was one of the few cases to develop widespread mclastascs. A biopsy of one of the subcutaneous chest nodules showed a similar appearance to those seen in the original specimen from the pleura. The patient died on May 22, 1959. No necropsy was performed. Case 24.--D.G., a white male, 32 years of age (bom 1922), by profession an accountant, was bom in England but came to South Africa as an infant. He spent his early childhood in Kuruman and left at the age of 7. He later qualified as a chartered accountant in Kimberley. In 1944. at the age of 22, he had been discharged medically unfit from the army because of a left pleural effusion. Neither then nor on many subsequent occasions were acid-fast bacilli found, cither in sputum or pleural fluid. His only subsequent contact with asbestos was the auditing of the books of an amosite mine in the Transvaal. In September, 1953 he complained of left-sided chest pains and shortness of breath. A radiograph of the chest showed flattening of the diaphragm on the left side with obliteration of the costophrcnic angle and thickening of the oblique fissure. He w-a$ seen on numerous occasions Ftu. t0.--Hittolrtfieal tectioni of tumour from Caw U. tUcnutoxyiin anil conn. She was referred to the West End Hospital. Kimberley, on July 19. 1954, because of dyspnoea and right chest discomfort of acute onset. The chest radiograph showed a loculated pleural elTusion at the right base. Straw<olourcd fluid was aspirated, which on examina tion was found to be negative for Af. tuberculosis but contained niesothclial cells arranged in acini. At thoracoscopy in Johannesburg on August 11, 1954 tumour nodules were seen on the parietal pleura. Histo logical examination of the biopsy specimen showed a mesothelioma. Deep therapy and radio-active gold instillation in September. 1955 caused initial regression of both the pleural fluid and nodules but did not arrest the Progress of the disease. She received a further course of 4-ray therapy without improvement and died in January. 1957. The liver was enlarged and nodular before death but no necropsy was done. (Figs. 5. 6, 7. and 8 show the radiological development of (he tumour in this ease.) Case 14.--S.S., a Bantu male. 40 years of age (born 1918), was an asbestos miner. He was bom in the Kuruman district and as a child often played on the asbestos dump near an asbestos mine. He subsequently forked with asbestos for several years, being employed at an asbestos mine weighing fibre from 1938-41. In 194^ he worked on a Witwatersrand gold mine but returned to the Kuruman district in 1943 where he worked as a farm labourer until his final illness. He was admitted to the West End Hospital on March 3. 1959. He had been well until July. 1958 when he became aware of pains in the right side of his chest. In addition he had a slightly productive cough and short ness of breath on exertion. Chest radiograph on March 9. 1959 showed obliteration of the right lung field. Asbestos bodies were found in the sputum. Needle biopsy showed histological features consistent with a mesothelioma. Autopsy.--The right chest was occupied by a huge whitish tumour which intiltrated the mediastinum, extending through the diaphragm onto the superior surface of the liver. A straw-coloured effusion was present in the left pleural sac but the left lung was not affected. The mediastinal, cervical, and para-aortic abdominal lymph glands to the level of the renal arteries were infiltrated with tumour. In the right lung it was found (hat the tumour muss had infiltrated along the interlobar fissures. The lobes of the lung were compressed into three small segments (Fig. 9). On histological section a papillary type of pleura! mesothelioma was seen (Fig. 10) which had infiltrated into the lung parenchyma in some areas. There was marked lymphatic spread throughout the innesburg ;$t radio* a basal mtued to c pleura! !' a meso* irtication :asiiy but ;t to the .ctions of :helioma. >gc (bom own and From ons from i siepi on 10s mine th vague t pleural Mr. I K. >f malig* ie apical nacity at -'oh on ) in pleura hclioma visscr in wancous .ass was . present craiized present i pleural eases to nodules original May 22. c (born ingland ent bis > 7. He iberleyedically ifusion. is were il fluid' .as the m the d chest \t chest de with of IS Fro. 11.--On September it. 1956. FiO. (2..-On Augutl 2J. I9J7. Flos. It anti li--Radiograph* ihomg development of tumour in Cate 24. from 1953 to 1957. A radiograph taken early in 1956 showed the development of a left superior mediastinal shadow which enlarged progressively (Fig. U) and later the development of diffuse nodular pleural thickening on the left. During 1957 similar but less marked changes developed on the right side (Fig. 12). He consented to biopsy in June. 1957. and. at operation, a diffuse pleural malignancy was present. Sections of the parietal pleura only were removed and the histological appearances were those of a meso* thelioma. He died on October 6, 1957. A necropsy was not performed. Case 30.--G.F., a white male. 50 years of age (born 1909). a storekeeper, with a history of industrial **posurc. He has never been near the Cape Asbestos fields. He was born in South West Africa and lived there until the age of 21. From the age of 21 to 26 he worked in a fectory in the Cape as a boiler-maker and fitter. He volunteered the information that he had worked con* tinuously with asbestos, tagging pipes and boilers. He ^marked that the removal of asbestos lagging from old Pipes created a very dusty atmosphere and that he would ^ugh a lot at such work. Between 26 and 32 years of a?e he worked in a factory in Johannesburg in a similar opacity but was not exposed to such heavy dust con* Mirations. For the past 20 years he had not been in Contact with asbestos. Enquiries were made from the factory in the Cape as to the nature of the asbestos used and these have revealed that during the relevant periods Cape crocidolitc was exclusively in use. He was first seen on March 14. 1959 complaining of cough, pain in the right chest and recent onset of breath lessness. Three pints of fluid had been aspirated from the pleura and cytological examination showed the presence of malignant cells. The radiograph showed marked pleural thickening and hydro.pncumothorax. On March 17. 1959. a thoracoscopy was done. The pleura felt thickened and the lung was collapsed and immobile. Several biopsies were taken. These showed the presence of a mesothelioma. The under!) mg lung showed the presence of asbestosis. He was treated with nitrogen mustard imra-pleurally and his condition temporarily improved. When last examined he com. plained of increased breathlessness. Discussion In 1924 Robertson denied the existence of primary malignant tumours of the pleura and con* sidered them to be secondary in origin. Since then, on the one hand. Willis (1948, 1953) and Smart and Hinson (1957) have supported Robertson's views, while on the other hand, primary neoplasms of this nature have been described by many authors in recent years. These include Tobiasscn (1955) in Sweden, Rciloni and Bovo (1957) in Italy. Godwin (1957) in the United States, and McCjughey (1958) BRITISH JOiRSAL OF ISPL'STR/Al. MFDICISE in Britain. Evidence in support of the mcsothclial origin of these tumours can be found in the tissue culture experiments of Stout and Murray (1942) and Sano, Weiss, and Gault (1950). The variegated histological pattern of tumours arising from the mcsothcliutn of the pleura was remarked on by Klemperer and Rabin (1931). Such a variation is appreciated when the multipotcntiality of the cells lining coclomic cavities arc considered. Maximow first demonstrated this feature in 1927. Novak (1931) stated that the mucosa of all parts of the Mullerian canal and the germinal epithelium were derived front these cells. Keasbey (1947) showed that in the embryo, the mesonephros, metanephros, Wolfiian body, genital ridge, and all dependent urogenital structures are derived from the ntcsothclium, Campbell (1950) considered the presence of both epithelial and mesenchymal elements a major diagnostic feature. In describing the histology of 11 of these tumours McCaughcy (1958) demonstrated that either the epithelial or the mesenchymal element might predominate. He classified his cases into the following four groups: Tumours of epithelial character; tumours of mesenchymal type; tumours of mixed type; and tumours of anaplastic type. Using McCaughey's classification on our series of tumours, the majority are, as in Campbell's series, of the mixed type. Of the remainder, a few showed the papillary tubular structure of the "tumours of epithelial character", and there were several of the anaplastic type. One ease had the appearances of a "tumour of mesenchymal type" but even in this case primitive tubular structures were seen. Apart from the original case all (he histological diagnoses were made on biopsy material. Three of these biopsy findings were confirmed at necropsy. In the remainder, we have had to rely on clinical and radiological examination to exclude other primary sites of malignancy. Following the work of Meyer and Chaffee (1939, 1940), the possibility of demonstrating hyaluronic acid in these tumours both chemically and hislo* chemically has been considered as a diagnostic aid. Both these investigations are still in an early stage (Harington, 1959). Preliminary results of the histochemical expert* ments show that there is metachromatic substance in both the stroma and glandular structures of the tumours. This mctachromasia can be reversed by incubation with testicular hyaiuronidasc. This material stains strongly with Hale's (1946) colloidal iron method. The periodic acid Schiff technique has given variable reactions. These results are not specific for hyaluronic acid but are strongly suggestive of its presence. The amount of metachromatic substance in these tumours has varied considerably. This we think is partly due to the fact that until recently we had not appreciated the solubility of hyaluronic acid in aqueous media and the majority of these tumours were fixed in 10% formobsaline. Further, Lison (1953) states that the mctachromasia of hyaluronic acid is optimal at a concentration of 1,10.000 and gradually decreases at higher levels. When the high concentrations that Meyer and Chaffee (1939, 194Qj found in their tumours arc considered, this variation in metachromatic properties scents to have been partially explained. In addition, with the great differences in the histology of the various lesions it would be logical to expect certain tumours with a marked adenoid appearance to secrete more than those with an essentially non-glandular structure. Three of the five autopsies performed showed evidence of peritoneal metastases. In the other two intra*thoracic spread was observed, in one case to the other lung and chest wall, and in the second to the mediastinal lymph glands and pericardium. Biopsy evidence of metastases has been obtained in two eases, one from the omentum and the other from the subcutaneous tissue of the chest wall: while a third patient developed an implantation nodule in the thoracotomy scar which showed a similar appearance to that of the previous biopsy specimen. The first recorded ease of carcinoma of the lung associated with asbestos was described by Lynch and Smith (1935). By 1955, according to Doll, a total of 61 cases had been reported. Included in these eases was one mesothelioma. Cartier (1952) mentioned two eases of diffuse mesothelioma from a Canadian chrysotilc mine. A further three cases were described by van dcr School (1958). Un fortunately no indication is given in the literature regarding the type of asbestos to which the majority of recorded eases of carcinoma were exposed. However, discussion with management and medical officers of two of the factories, in which the majority of the eases reported in Britain were employed, suggest* that most of these workers were handling chrysotile asbestos (Wagner, 1958). The possibility that some of these people may also have beea exposed to crocidolite dust cannot be excluded. Attempts to produce tumours in experimental animals by exposing them to asbestos dust have been made. Vorwald and Karr (1938) were unsuccessful Lynch, Mclvcr, and Cain (1957) succeeded in pro ducing tumours in mice, but lung neoplasms in his control animals were far too numerous for the results to be considered significant. On the other hand Schmahl (1958) working in Druckrey's laboratory has been able to produce sarcomas in rats. This has occurred after subcutaneous and DIFFUSE PLEURAL MESOTHELIOMA 269 tance in these ' intrapcritoncal inoculation of both asbestos fibres is we think is and dust. He states that "mineral asbestos" was )'y we had not onic acid in hese tumours urther, Lison jf hyaluronic 1/10.000 and used but does not name the variety. In our scries of mesothcUomata, histological evidence of asbestosis h3s been observed in eight hen the high of the 10 cases in which lung parenchyma was in* -(1939, 1940) eluded in the specimen examined. No lung tissue this variation was present in the biopsies from the remaining 0 have been 23 cases. It was only in the four cases that came to th the great necropsy that large sections of the lung tissue were )us lesions, it available for examination. In ail of these specimens nours with a evidence of asbestosis was found. c more than At first it was thought that the presence of structure, numerous asbestos bodies, fragments of fibre, and med showed dust immediately below the pleural elastic laminae he other two, in these specimens, might have been significant in ne case to the the pathogenesis of the tumours. However, it is ccond to the more probable that this distribution is a result of the ium. Biopsy marked atelectasis. Similar features have been lined in two thcr from the 'e a third observed in atelectatic lungs of asbestos miners in which no mesotheliomas have been observed. Pleural fibrosis has been a common finding in a in the r appearance cases of asbestosis and in some cases large pleura! plaques measuring up to 10 cm. in thickness have i. been seen. These plaques, w hich were first described 1 of the lung by Gloyne (1933). have been observed following d by Lynch exposure to both amositc and crocidolite asbestos g to Doll, a Included in artier (1952) dusts. In these cases of benign pleural thickening no evidence of stromal mctachromasia has been observed. ioma from a three cases In all the histological sections of pleura examined in the cases of these mesotheliomas and in more 1958). Un ite literature the majority re exposed, than 100 cases of asbestosis, no asbestos bodies, fragments of fibres, or dust have been observed beyond the pleural clastic laminae. .md medical the majority employed. Three patients from the Kuruman district, with clinical and radiological features consistent with those of ditfuse pleural mesothelioma had markedly :rc handling e possibility abnormal cells in the pleural fluid. These cells showed no specific features to distinguish them from have been excluded, xperimental Us originating in secondary malignant pleural deposits nor from the grossly atypical cells some* times seen in non*malignant pleural ctlusions. As st have been ;nsuccessful. no biopsy or autopsy examinations were obtained in these cases they have been excluded from the scries. :ded in pro* lasms in his The pathological evidence for associating these tumours with asbestos exposure is not conclusive. As previously stated, only in eight of the 33 cases Has jus for the 'n the other Druckrey's evidence of asbestos been demonstrated. Of these, six had a definite mining history and one had been .ar'-^mas in exposed to asbestos while lagging steam pipes. The s and other case was bom in the Kuruman district and nothing else is known of him, until his arrival at a Witwatcrsrand gold-mine at the age of 23. In the - - remaining 25 cases we can only present circum* stantial evidence of exposure to asbestos dust (Table 3). Eighteen of these 25 cases were born in the vicinity of the mines and two arrived in the district as infants. Of these 18 people 11 admit definite childhood exposure to the dust and two others were exposed industrially in later life. In addition two patients with childhood exposure later worked in the asbestos mines. Three cases arrived in the region at an older age but were employed either on the mines or in transporting asbestos. A further three of these 25 cases have had industrial exposure, and in only one case do the relatives deny any exposure to asbestos dust. The four industrial cases arc significant. Two of the patients were lagging locomotive boilers and one was lagging steam pipes. A man. who was an upholsterer by trade, was employed in making fire-proof clothing from 1939*1945. As far as can be ascertained these people were never in the Griqualund district. These findings tend to add support to asbestos being the common factor in the development of these tumours, and to counter the suggestion that there may be some other environ* mental cause in the region of Griqualand West. If asbestos dust is a factor in the occurrence of these tumours, similar cases might have been ex pected from the neighbourhood of the Transvaal asbestos mines in the Petersburg and Lydenburg districts, where crocidolite and amositc asbestos is mined. According to Vermaas (1952). crocidolite and amositc occur in the same scams in the Peters burg district. As can be seen from Table 1. amositc is similar in composition to crocidolite. In the past four years the lungs of 24 cases of asbestosis from the Lydenburg district have been examined. In this material two cases of adcno-carcinoma have been observed. The one was in a white miner with 19 years' service, who had an adcno-carcinoma arising from a bronchus. The other case was a Bantu miner who had a peripheral tumour. No service record was obtainable in this case. Only one case of asbestosis has been received from the Petersburg area. All of these men were actually employed on the mines at the time of death, the majority having had a relatively short service. Our findings suggest that mesothelioma occurs 20 to 40 years or more after exposure to dust. Until com paratively recently the mining in the Transvaal has been on a small scale, and there were no settle ments in the vicinity of the mines. The lungs of 20 asbestos miners from the Cape Asbestos Field have been examined, in whom no mesothelioma was observed. One autopsy specimen consisting of three fragments of lung showed asbestosis and an adcno-carcinoma. Radiological features of asbestosis have been observed in many miners from this region, without any suggestion of 270 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 3 DIFFUSE PLEURAL MESOTHELIOMA: ASSOCIATION WITH ASBESTOS (1) Cut No. <:> Year of Binh 1 1920 2 *1913 i 1902 4 1196 5 1025 6 1903 7 1920 1 1194 9 1903 10 1909 I1 t% im 1910 IS 1909 14 I9IS IS 1916 16 1896 17 1911 IS 1920 19 1922 20 1906 21 1912 2a ISS9 22 1895 24 1922 :j 1899 (31 Diagnosis 36 (4) . (5) j Sex 1 ' a .M 42 MXD M S3 B F SS w 1 F 31 8 : M S3 w F 36 W ! M 6) MXD F , ' $2 MXO M 49 W M ' 60 MXD M 48 B < M SO W J F 40 8 j M 42 W F 60 W M 48 MXO F 38 B M 37 MXO M S3 w F 44 w M 68 w M 63 W , F )S w M SO w F (61 Bom on Fields + As * a+ + * + * 4+ * * * 4. + 4_ 26 IS9S 49 W 1 M -- 27 1904 52 w , M _ 21 1899 60 w M 29 191) 44 w M 30 1909 SO w M -- 31 1913 44 w M 0 32 1908 49 w M mm 33 1890 39 w F -- (7) Atbestot Exposure Other history unknown until came to the Wit. wetenrsnd at the age of 23 Mined asbestos from 1930*33: left am at the ate of 27 Lived whole life in a location near an asbestos mill Lived on stbcuot Held* until the ate of $: wotked in asbestos warehouse I9tto20 Spent all bta working life in the vKimty of mines Lived all her life in the vicinity of mines Lived ell htalife in the ncuiityof mines: worked t a miner From the ate of 24 lived in a village serving local mines: often visited muxs: watched cobbing outside houses Whole life spent near mines, digging wells Lived at the mine from age 7-17 years: played on dumps and in mute as e boy: returned to assist from age 21-23 Whole life spent near mutes: miner 19)1-3) Lived near mines until the age of 17; muter 1927 Lived near mine until the age of 21: played with fibre as a child Whole life spent near mines: miner 1938-41; played on dumps as a child Daughter of Case 22: lived at mine until age of 20: went to school near cobbing theda Went to school near mutes: transported atbcstoa 1914.(6 Lived on meior wagon route lUl age of IS: several subsequent visits Whole life m the vtcutuy of the mmea; miner 1945-58 Family lived at mine: miner 19)8.1959 Spent whole life in village on wagon route to Kimberley Lived in the vicinity of mine* until the age of 16: often on dumps at a child Whole life in the vicinity of the mines; miner 1913.32. end 1945-32 Lived m the vicinity of the mines until the age of 30 Lived in tha vicinity of a mill from the age of 1-7; plated on the dump* as e child Lived in a mining area from the age of 10 to t8 yean; slier 1918 spent whole life in tame town at Cate 24 Mined and trantponed atbestot from 1929-33 at overseer Bom in North West Cape; transported atbestot from I92CK24 Lived whole life on farm In mining area from the age of 12: transported atbestot 191^21 Maintaining locomotive boilers I93M5 Maintaining tteam pipes in explosive factories 19)0-40 Worked ei Alter on railways, maintaining locomotive boilers, deles unknown Making atbessos blankets for the Air Force 19)9-43 No history of exposure to atbestot (8> Diagnosed on Biopsy (9) Necropsy <101 (1!) Suravsl Histologies! from Evidence of Initial Asbestotis Sympuo (in moub --* -- * 4- + -- - 4r * 4 + 4> 4- to to to 4to V * to + to 444- - 4- _ * -- * * - -- -- 1 --3 30 -- 24 _5 -5 _ 13 T Still *6 -- StiDtii 0 42 "3 * SltUa-1 li I it SulUit " 13 15 o -- *7 -- Still I* 6 1 S - KEYS: Column 4-- Ran: W - White MXD Mixed (Coloured) 8 -- Bantu Column 6 -- Bom on asbestos IWIdt - Not bom on atbetiot Acids 0 -- Unknown Column 9-- + m Necropsy dona -- m Necropsy not dona * -- Only unail fragments of parxial pleura submitted at autopsy for histological elamination Column 10 i.vid*0? -- Positive hittolog**1 j of etbcxtotis - * No lung tissue 0 - Small fragment* mwi, but no v,det^ asbestosit tumour formation. However, pleural involvement has been a common finding in these cases (Hurwiu, 1959). It is possible that there has not been a sufficient lapse of time after exposure for tumour development in these cases. Further, the factor of individual susceptibility must also be con sidered. We wish to record the great assistance that we have received in this investigation from the medical Pra^' titioners of the Criqualaml West District and the thoracic surg Pretoria, and Wc thank publish this i Bcilom. G . end Campbell. W N Gutter. p tw: discussion Doll. R <!*' Frood. G. L. It Opr Ftt Union ol Gloyne. S R. (r Godwin. M C. Hale. C. W (l<. mu. a. L. utu rndum n Haringion. 1 S Hiumwin. S . n Hurwitr. M (V /. iper/i Ufturemii. Kcavfwy. L. I . (I Klemperer. P. . It. 3t) Loon. L. <I9J3> Gauthier- Lynch. K. M . u - --. Mler. F. Wik. IS. The Jul: Dccomprcssic H. V. li A Comparivo M. dcC Phosgene Po Ill-vcntU A Study on th A. N. U Aerosol Inhai D. Pctrc A Blochcmicr Agnes R A Simplified Clinical, Bro G. L. L The Measure Observations and D. i The AssessmIndustrie Book Review A numb Medical Aw DIFFUSE PLEURAL MESOTHELIOMA 271 (io> | i thoracic surgeons and pathologists in Johannesburg, Pretoria, and Durban. We thank the Secretary of Health for permission to publish this paper. Husolojicjl' fral^ Evidence of Tout] Asbeuojis SymgaJ 1) i: StiU References Sellom. G.. ind Bovo. G. (1957). Ada med. patar., 17. 367, Campbell. W. N. (1930). Amer. J. Path.. 16. 47}. Cinier. P. 1195}). Arch, industr. Hyt, 5. 2b2. (Conmbmion to the diicuuion.) Doll. R. 11**53). Bril. /. industr. Med., 12. SI. Frood, G. E. B. (1913). Memorandum on the Aibetlas InJuilrv in the Cape Province. Report of the Government Mimog Engineer. Union of South Africa, pp. 76-82. Gloyne. S. R. (19331. Tubercle (Land.), 14. 493. Godwin. M C. (1937). Cancer (Philad.l, 10. 398. Hale. C. W. (1946). Suture (Lund.). IS7. 802. Hall. A. L. (1930). Atbettat in the Union of Snath Africa. Memo* randum no. 12. Geological Survey of South Africa. Harington. J. S. (1939). Penonai communication. Higgmton. 3.. and Oettle. A. G. (1937). Acta Un. tnt. Cunt'-. 13. 949. Hurwitr. V4 /IUS91 Prnreedinet n( international Canterence nf Experts on Pneumoconiosis. iohannoburg. Feb. 1959. Churchill. London. (In the preu.) Keasbey, L. C. (1947). Amer. J. Path.. 23. 871. Klemperer. P., and Rabin. C. 8. (1931). Arch. Path. IChtcatoK 11. 383. Liion, L. d`453). Histoehimie rt Cytochimir Animates, pp. 332*337, Gautnier*Vi|[ar>. Pans. Lynch. K. M.. and Smith. W. A. (1935). Amer. J. Cancer, 24. 56. --. Mcher. F. A., and Cam. J. R. (1937), A.M.A. Arth. industr. Hlth, 1$. 207. Martioy, O. (1936). Proe. Transe. Mine mej. Offrt' Ass., 35, 63. Maximow, A. (1927). Arch. exp. Zellfoetth., 4. I. McCaughey. W. T. (1958). J. Path. Bad.. 76. 317. Meyer. K., and Chaffee. E. (1939), Proe. Soe. exp. Bioi. (,V. Y.), 42. 797, -------.-------(1940). J. bioi. Chem., 133. 83. Novak. E. (1931). Amer. J. Obstet. Cynee.. 22. 826. Robertson. H. E. (1924). J. Cancer Res.. 8. 317. Sano. M. E.. W<iu, E., and Gault. E. S. (1930). J. thoeoe. Sure.. 19, 783. SehmJht, O. (1938). Z. Krebtfaexth.. 62, 56t. Smart. J.. and Huuon, K. F. W. (1957). Brit. J. Tubere.. SI. 319. Stout. A. P.. and Murray. M. R. (1942). Arth. Path. IChteato). 34.951. Tobiasscn. G. (1955). Atta path, mternbioi. stand., Suppl. 103, p. 198. van dcr Schoot. U. C M (1958). Ned. T. Cenertk, 102. 1124. Vcrmaat. F. H. S. (l<52l. Trans, trot. Soe. S. Afr., 55. 199. Vorwald. A. 3.. and Karr. J. W. (1938). Amer. J. path., 14. 49. Wagner. 3. C. (1958). Memorandum an Pnrumocontotu Reteareh in Europe. Submitted to the C.S.I.R. Willis. R. A. (1948. lit <d. and 1933). Puthaluty of rumours. Butterworth. London. Addendum By the end of June I960, a total of 47 cases of mesothelioma had been identified. In 45 of these a possible association with exposure to crocidoiite has been established. In one case a mesothelioma of the peritoneum was present. Sull 4: r Sull THE JULY (1960) ISSUE The July (I960) issue contains the following papers:-- 16 Decompression Sickness during Construction of the Dartford Tunnel. By F. Campbell Golding, P. Griffiths, 1: H. V. Hcmplcman, W. D. M. Paton, and D. N. Waldcr. I A Comparison of the " High-altitude " and " High-pressure " Syndromes of Decompression Sickness. By 41 M. de G. Gribblc. Sitl)4 II SH Sull jJ 6 Phosgene Poisoning Caused by the Use of Chemical Paint Removers Containing Methylene Chloride in Ill-vcntilatcd Rooms Heated by Kerosene Stoves. By W. B. Gerritscn and C. H. Buschmann. A Study on the Acute Toxicity of the Tri-ary l Phosphates Used as Plasticizers, By H. F. Bendy, E. J. Field. A. N. Worden, and J. P. W. Hughes. Aerosol Inhalation of CaNajILD.T.A. (Mosatil) by Workers Constantly Exposed to Lead Poisoning. By Lj. Petrovic, M. Stankovii, M. Saviccvui, and D. Polcti. A Biochemical Study of the Urinary Protein of Men Exposed to Metallic Mercury'* By J. C. Smith and Agnes R. Wells. A Simplified Method for the Estimation of Nickel in Urine. By J. Gwynno Morgan. gjCaJviJ*J ,r^ evidenc* * Clinical, Bronchographic, Radiological, and Physiological Observations in Ten Cases of Asbestosis. By G. L. Lcathart. The Measurement of Occupational Mortality. F. D. K. Liddell. Observations on the Occupational Life I listory of the Coal Face Worker at Two Collieries. By O. P. Edmonds and D. S. Kerr. be con* iai we h&ve ,,.j`- ' oract the The Assessment of Eloctrocnccphalographic Changes and Memory Disturbances In Acute Intoxications with Industrial Poisons. By B. Chalupa, J. Synkovd, and M. Seviik. Book Reviews. A number of copies arc still available and may be obtained from the Publishing Manager, British Medical Association. Tjvistock Square, W.C.I, price I7j. 6</.  '*H' .* l : I* jj<r; . i* i . .< i i`c t *--------- 28 /N0l/STJW.. Hr<7/.V y<ND OCCt'P^T/O.V^L A/D/C/.V /*?( ta A/ir*.--Out of 20 white mice used in this experiment, 11 lived a year or more in dust and died or were killed witlwu showing an appreciable degree of pulmonary infection. The reaction to the inhaled dust was limited to phago cytosis by mononuclear ceils. Usually these were widely scattered through the air spaces; a limited number were grouped about the terminal bronchioles, producing tone thickening of their walls. There was no suggestion of fibrosis. Numerous asbestosis bodies were observed io animals killed late in the experi ment Thus these animals exhibited asbestosis bodies without fibrosis. Summary and Interpretation of Inhalation Experiment with Long Fiber Asbestos Dust,--The purpose of this experiment was to evaluate the im]>ortauce ot* long fibers tn the tissue response to inhaled asliestos. The results, in comparison with those of previous investigations, indicate strongly that long fibers are chiefly_ responsible for asl*stosis. Thus, the reaction in guinea pigs developed earlier and became more extensive in this experiment than in previous experiments in spite of a smaller concentration of atmospheric dust and a lower mineral content of the lungs. Furthermore, typical peribronchiolar fibrosis was produced in cats, although in a previous experiment with short fiber dust peribron chiolar fibrosis did not develop in this specks. . The cause of the cellular fibrosis in the lymph nodes of the guinea pigs is not clear. It did not occur in other inhalation experiments with asbestos.. . . . '' ' -' INJECTION EXPONENTS Since the inhalation experiments reported above strongly suggested that long fibers of asbestoi are the significant factor in the causation of asbestosis, a series of injection experiments was inaugurated wherein the dosage and the length of the fibers could be controlled more precisely. Also, by the use of controlled dosages, the relative capacities of .various asbestos minerals to produce reaction could be compared. In these injection experiments, guinea pigs, rabbits, rats and dogs were used, and the mineral dust was injected by the intratracheal, the intraperitoneal and the intravenous technic, but not all the technics were used for each species. For the purpose of simplification the findings in each series of tests, except for dogs, have l>cen condensed and reported in tables, to which reference will be made later. In the case of dogs, only one test was made, and since the findings were negative, no detailed report is included. Exrotftttxrs Using Inteateachiac Technic As the asbestos minerals do not canse typical advanced fibrosis in extrapulmonary tissue, the intratracheal technic is the preferred way of introducing fibrous dust into the experimental animal. In this method the dust suspension is injected by means of a special needle or catheter deep into the trachea, from which it flows into the lungs. Comparison of Fibrous and Nonfibrous Dusts.--To demonstrate that the ability of asbestos to produce fibrosis resides in its fibrous character, the series of injection experiments reported in table H were performed.