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Thorax. IVKU. 35, S64-561* Pleural calcification, pleural mesotheliomas, and bronchial cancers caused by tremolite dust S YA2ICIOGLU. R ILCAYTO. K BALCI. B S SAYLI. AND B YORULMAZ From the Departments of Chest Diseases and Pathology. Diyarhakir University Medical Faculty, and the Department of Genetics. Diyarhakir and Ankara Medical Faculties. Turkey ph-urt* i Jistric Chest ,.f pU ineidc also clinic: tun Ik Tin- Imanidnc r McllK abstract Around ihc town of Cermik in south-east Turkey there are many deposits of asbestiform minerals, some of which are used to make whitewash or stucco. A sample of 7000 of the population rescaled 461 (6-5%) with pleural thickening and calcification, of whom 103 (l-47,, of the total) had evidence oT'illieistilial puliiiouaiy fibi usiS.'Torty-one patients with respiratory cancer were admitted to the Diyarhakir Chest Hospital from around Cermik and from a comparable area of equal population (but without asbestos deposits) in 1977-8. Of these 23 were mesotheliomas. 22 coming from around Cermik. in addition, II of the 18 primary bronchial cancers came from around Cermik. ^ similar excess of mesothelioma and bronchial cancer had been admitted from I Fieun die miner sbadir crops exploi Cermil and h the Cermik a.ea in previous years. The whitewash or stucco material has been shown to contain distric fibrous tremolite and non-fibrous antigorite/lizardite, chlorite, and talc. A lung biopsy of a patient from Cermik contained large numbers'of tremolite fibres, both free and forming asbestos bodies. There were only occasional chrysotile fibres. Thr name from chest Cermik is a town in south-east Turkey. Since 1973 we have been reporting on investigations into the cause of "Cermik disease."1-* In the present report we add new mineralogical and epidemiological information and discuss the significance of the pleuropulmonary disease in the district. Around the town of Cermik arc numerous outcrops of asbestiform minerals which are used to make whitewash and stucco for the walls and rcofs of the houses. The first pulmonary ab normality to be noted was a high prevalence of pleural thickening with calcification. Sub sequently it was noted that, compared with other who c in whi end d The fi worki: Diy distric The p in tat ; that c Durin Xddreu for reprim requests: Dr S Yaaicioglo. Department of Chest Diwjift. Diyarhakir Uitivcnity Medical Faculty, Diyarhakir. Turkey. 564 Fig I Map of south-east Turkey showing the districts served hy the Diyarhakir Chest Hospital. The districts hatched horizontally and nhliituely show the highest incidence of Cermik disease." Coses have also been reported from the districts hatched vertically. Asbestos deposits occur and are worked in all these districts,-but do not occur in the unhatched districts. Table i iintl pm , hy dies I l*e trotipx tvM :i-.io Xt-40 * *1-50 I M-l j SI-70 I 70fuiiils Touift ' rulethcolitn:. P-l`"ru* ">es<i:helii>inas. and brnr.chiai cancers 565 . ,t ir. ilie jrej served hy the Diyarbakir Hospital, there was a very high incidence eural mesothelioma and a relatively high e.-nee of primary lung cancer. There were "eases of benign fibrosing pleurisy. The ,jl picture was similar to that reported from her est in Turkey (Karainj.; " :r.c investigations were undertaken to deter.. the cause of this local excess of pleural : pulmonary disease in pan of Turkey. o.ihods ..re I shows a map of this part of Turkey, districts where outcrops of asbestifortn rrals occur are shaded. These with vertical iJing were not investigated in detail. The out > are both most frequent and most frequently railed in the three districts around Ergani. .-.mk. and Cungu* which are shaded obliquely horizontally. The population of these three . -.rriets is 100 800. three thousand, seven hundred men and 3300 . ren over the age of 20 years were selected n these three districts and investigated with ->: radiography. These individuals were those could be persuaded to attend from villages -hich fibrous minerals were known to be used. .'Jo.not represent a random sample (table 1). : films were all read by three chest physicians king independently. . iiAarhakir Chest Hospital serves these three "cts as well as the others shown on the map. : population of the five asbestos districts listed -hie 2. 227 000. is approximately equal to of the seven non-asbestos districts. 217 000. *.ng the period of the survey (1977 and 1978) cl Age and sex distributions ofpleural calcification -.i/nmmirv fibrosis among 7000 individuals screened if rodiography Ir.r Stouber% Pfruruf (ufrifiialiotii Xumber Pulmonary fibroiis Xumbee M 774 F 740 4 0*51 * 0*27 *M 1169 50 2 56 3 F 1052 2* 2 66 1 M 1062 49 4 61 . 7 F 960 St 622 5S 6*04 6 89 144* ** . F 441 ftl 18 36 IS M 94 F 54 M 15 PQ 70 74-46 20 32 59-25 16 11 84 61 6 7 77 77 5 M rn 1 52T6 255 2o* 6 79 6)4 57 46 -- 0-25 0 09 0*65 0*62 3 46 4-06 21*27 29 6) 46 15 55 55 1-5) 1-40 -ml 71100 461 6 5* 10) 1 47 Table J Distribution of 41 patients with nutiignant mesothelioma and bronchogenic carcinoma bet ween asbestos mid nmwtsbesios districts fuwm Put*!** Pteuru/ turn* m`uf*iuhm> Aumber Pair Pu/mumtrr Xumber flute* Tutu/ Xumber flute* Aibestoi Jltfrku Cttmik 34 297 Efi,*arti 30 766 9 15 73S 3 Madcn 36 594 * Siterek 90 027 3 Tout* 227 422 91* AwH6ri/of diurkti Lie* JS 422 -- Kulp >5 761 ___ Oicte 28 737 -- Hiai IS 192 ___ Silvan 52 196 -- Hairo 16 310 ___ CiAir 28 344 1 Total 217962 t: 14 37 17 72 19-06 5 46 3 33 9 67 __ -- -- -- -- -- ) 52 0 43 Data from 1970 centaas * Per 100 000 inhabitants i x1 * 16 55 highly significant 112 "0)6 not significant 1 3 1 1 Hi 1 3 1 1 1 -- -- 7* 1166 3-90 6 3$ 2-7J 4 S3 9 12 4 3 5 33 2 60 8*38 3*47 5 49 1*91 -- -- 3*21 .1 * 1 1 1 -- 1 8 26 24 23-63 23 42 3 19 5.55 14 50 2 60 8*38 3*47 5*49 1*91 -- 3-52 3-67 Tabic 3 Diagnostic procedures carried out on the 41 patients with malignant tumours of lung and pleura OiogooMIk procedure Sombre of com Bronchoscopy Broatchial biopsy Needle biopsy Hung) Needle biopsy (pleura) Plaural biopsy at thorascopy Cytological examination of pkurat affusion Regional node biopsy Thoracotomy Cytological casminatioft of sputum Radiological asamination 2* 26 6 10 1) 2? 4 2 4f 41 there were 86 admissions to the Chest Hospital for neoplasms of the lung and pleura. These were analysed and only those 41 patients coming from the five asbestos districts and seven non asbestos districts were considered. The diagnoses were established by the usual techniques and the frequency with which each diagnostic procedure was used is listed in table 3. Results POPULATION SURVEY There were 451 cases of pleural calcification and thickening among the 7000 individuals selected (6-5%. table I). There was no significant differ ence between the sexes but there was an increase in frequency with age. Few cases were seen in the 21-30 year age group but 69% were affected before the age of 70. The probability of devel oping pleural changes appeared to be normally distributed about an average of 50% at 65 years in this population. 566 5 ) 'am inglti ct u. Fig 2 Chest radiograph of a man aged 36 years from Cermik with shell-like calcification of the parietal and diaphragmatic pleurae. There is also thickening of the pleura at both apices. Pulmonary changes appeared about 10 years later than the pleural changes and affected about 50% of the population over the age of 70 (table 1). The pleural change was sometimes very extensive. Figure 2 shows advanced pleural calci fication in a man of only 36 years also from Cermik. Only six cases of pulmonary tuberculosis were detected in the population survey, rather fewer than was expected for the general population of this region. ADMISSIONS TO HOSPITAL Of the 86 patients with primary tumours of the lungs and pleura admitted to Diyarbakir hospital in 1977-8, 33 came from the asbestos exposed districts and only eight from the control districts (table 2). There were 23 patients with malignant pleural mesotheliomas, of whom only one came from the non-asbestos districts. The incidence appeared highest in the three districts where the radio logical survey had been carried out (Cermik. Ergani, and CQngiis). In these villages there were 17 cases during the period from a population of 100 000. The rate in Maden and Siverek was less than a third of this. Figure 3 shows a hydro pneumothorax with tumour on the chest wall in a man of 65 years from Ergani. The fluid con tained hyaluronic acid. Bilateral pleural calci- Fig 3 Chest radiograph of a man aged 63 years from Ergani showing a right hydrtipnetrnnthorax. Tumour (mesothelioma) is imi on the parietal wall on the right side. The fluid < untamed hyaluronic acid. Ililateral calcified pleural plat/ues are present. fleation is also prernnt Men and women were affected in equal numbers although the three patients under 40 years of age were all women (table 4). All the men and none of the women smoked cigarettes. Primary bronchial cancer occurred in both asbestos and non-asbestos districts table 2), II cases from the former, and seven from the latter. The difference is not statistically significant but when the figures are combined with those for the Table 4 Age and sex distribution of 41 patients with pleural and pulmonary malignant tununtrs Age groups (yr) 21-30 31-40 41-30 31-40 61-70 71- Tout* Pleural tumour Stole Frumie Total _ __ --3 15 41 5* -- 3 6 5 7 2 12 It 23 Puhnomity tut* Mol* FenmU J-ul I _ 41 12 c1 21 -- - 13 < 1 5 J b 2 -- | Total 1 < 7 If 10 3 41 Table 5 Pleural and pulmotutry cancers from ubestos and non-asbestos districts in this amI previous studies Years covered 1960-76 1977-6 Asbestos centre* Pleural Pulmoaa tumours tumours 24 (10 33) (9-43I 32 (14-07) tl (4-63) Pleural tumour* ; i <11 4-1 i < tires Pulmonary turnouts i: *5 501 ? (5 21) IW'.fP. --' . if-- vr-> /' *'1 15192589 .JS. c ;f/ hrattchiai cancers Fig 4 I'liolti" . v /urtS Imuf fr ~ : . 42 .veor.t froK shown to hau ; **.. ...... (idenocorciimr-.: :. -; hiop\y of a lung and bio lymph nodei. - containt nun:: - . : . hauurated. hu :<y.-- asbestos bodic 0 * : .i magnification H s-.: i cl - * at. n t v*- u : u ,ll f* V ! r* i>*.s 76 th.- difltrenc: :? 5:.-- Scant (Xs= i (table 51 : : jl-c ji hich thes: developed -. j.-cJ to he Ir-Acr than fer .Tiis-rthilioma and jrrcj.-cd !< hi rr.rre men (who . irJ> than v.omtr. (wh: die r::> bu: these ' .r.c> uers no: stat.ittciL; significant . l.samtr.atior. of th: lur; biopsies for the r-'- ;nts from the -trestos area showed numerous asbestos bodies tfij - MINERAL XtICAL INVESTIGATIONS During earlier investigations the *hi:r>.i>h -tzz stucco material had been examined a: th: i.a:e Institute of Mineralogical Research ir.i by x-ray analysis to contain wrpcrtr.t r.tr- erals and talc. It was assumed that '.te element was chrysolite because cf tht jreserct of the serpentine. On this occasion r.rs r. of both whitewash or stucco fr.m Crm r l: : lung material from the patient wh?:-: !--.> shown in fig 4 were sent for more dr.Lit; analysis including electron microsrop- t.'.d analysis of individual fibres. The stucco was shown to consist of -.res fibrous phases--chlorite, talc, rr.d a :erpe* r.. (antigorite/liurdite). The fibrous minm,- m: amphibole, tremolite (fig 5). The serpentine r.:r.- eral did not include chrysotile fibre: I.*. :.t; biopsy specimen most of the nbroi: par.:..t: were tremolite with a very small perttnu;: :f chrysotile (fig 6). The elemental ana!;- :s <.' fibres of tremolite in the stucco and tht were found to be very similar. su;xt\i:*i s common source. Discussion .. */. The use of stucco material containinj a f:v... mineral appears to be the cause of th: plt.ra' reactions, pulmonary fibrosis, and nalivt.v. tumours of the lungs and pleura in f,rr.it area. The inhabitants of Cermik and 'tighv. ing communities are unaware that th:- nutria; -j as thicknesses. causes these diseases. While initial ar.alyvit tjg. gested that the fibrous mineral was rhryv.tii*. l-o- c CvNv\-- 15192590 56.X i' ) uzuinyln ,,/ Fig 6 Electron micrograph of dun obtained from the histological section shown in fig S. showing short straight fibres which on probe analysis had the same elemental composition as the tremolile fibres shown in fig 6. Original magnification x 12 000. more detailed analysis showed it to be the am* phibole tremolite. The material also contains talc and non-fibrous serpentine but the detailed composition may vary from place to place within the area. The material is quarried from the mountains by the male population both for local use and for sale elsewhere. It is used as a whitewash for the walls and floors of the houses. The application is usually done by women who grind the material to a powder and suspend it in water. The process is repeated each year. Consequently householders are repeatedly exposed from an early age. and this exposure can be described as both environmental and occupational but not industrial. The exposure leads to the diseases usually associated with exposure to asbestos.**11 The first obvious sign is the development of "geographic" calcified plaques in the pleura.11*14 Radiographic changes of pulmonary fibrosis de- Tablc 6 Results of radiological surreys Sitrvry \um6fr of Htufu! i tticifituium PuhtMmary /tbfmh inJirUuuh .\ nmhrr \*rt\>ou% Mud** 15 25V This 7000 J** 461 2*55 s: 6-50 toy o-M 1-47 Tout* 22 25* 150 iss o-w velop later in a proportion of the population described by Meurman"' and Selikotr." In this environment the exposure is lifelong, from birth to death, as long as the individual remains in the area. Probably for this reason .'uc radiographic changes appear early and are \gr\ extensive. We have encountered many ease* of non-malignant pleural efTusions associated v. hi, these changes similar to the cases described hy Chretien15 and Lemanagcr.,`- There is also thick', ening of the apical pleura in many cases which has not been described previously. Although the prevalence of the non-malier.-m changes increases with age. it is variable in extent. Unless further study indicates wide vari ations in levels of exposure this suggests an inherent difference in susceptibility between , in dividuals. The incidence of tuberculosis in this community is relatively low but further work is needed to see whether exposure to asbestos carries any protection against tuberculosis. Individuals have been detected who spent their infancy in the asbestos a ea and then moved away. With no further exposure they have de veloped radiographic changes 20 to 25 years later and some have subsequently developed a respir atory neoplasm. This emphasises the relative im pedance of childhood exposure and of the long latent interval between critical exposure and the first detectable signs of disease. On the other hand adult exposure can also be significant as is exemplified by the wife of a government official who lived for only three years, from the age of 22 to 25 years, in Cermik and yet was found to have pleural calcification when she developed bronchial cancer 35 years later. A similar clinical picture has been described in patients outside the areas of the present survey in Palu and Adiyaman to the North and West (fig 1). The population of the whole area which appears to be at risk is over half a million. So far the investigation covers about half the urea and the numbers of people examined is only a small fraction of the total. Although suppon has been provided by the Tuberculosis Units ot the Turkish Ministry of Health and Welfare it has cnlv been possible to take radiographs of about 5*V. of the population at risk. More important than the benign change* in the lungs and pleura are the related neoplasms. The malignant mesotheliomas arc both the most frequent and most clearly related to asbestos exposure. This has been widely reported elsewhere.11*55 The bronchial cancer* arc not only slightly less frequent but only a proportion (perhaps one-third) can be attributed to the j ! j j . j i < I : ashc beer fibre can men and of t clia" al*u A disc mea aim not and The help the Wei'; stuc1 was of Carp Rcfe I J 6 7 X i i j> in-.- Ju-t: . vc: v i-! *::: I I' l>i.- p.i: f Ivari. : a" I i:~ tit:. (k : exw-. the: OvcJ r dvlater ;spir: iniIon* i the ather as i' ffieial ge of .id to loped ;rihed urvej West which ji. So . area nly a rt has }f the it ha about j , 1 " . ! ! i j I | I : I jes in lasnis. t most, jbestos j else- 1 onb eft ion P ih< i I I t>\nca! . alcilicaiitm. /ilcitral mesorhvlitinias. unit bronchia! cant ers 569 besti ' exposure. Whereas mesotheliomas have i-;er. produced experimentally with asbestos ^hres. :: has been less easy to show that asbestos .-an e.. use primary bronchial cancers experir.-.enta!').'-'S1 In the case of both mesothelioma .ad br- achial cancer the relatively low frequency t-f these tumours in comparison with the benign change- suggests that individual susceptibility is Jso important. As there is no effective treatment for these disease- it is imperative that efficient preventive measures are taken immediately. They should be minted at protecting the whole population and rot it:-: ihe men while they quarry the material and the women while they apply the whitewash. The work was carried out with the continuous help of Harndi Acan MD. General Director of the Tuberculosis Unit. Ministry of Health and Welfare. Turkey. The special analysis of the stucco material and the dust in the lung biopsy as carried cut by Dr FD Pooley. Department rf Mineral Exploitation. University College. Cardiff. Wales. References I Yazicioglu S. C'ermik vc civarinda sik gorulen pU-vra kalisitikasyonlarinin ctyo-patogenesi uzerinde arastirma. Docentlik Tezi 1973-1974. 3 Yazicioglu S. Asbcstosis arastirmasi. DL'TFD 19-4; 3:61-77. 3 Yazicioglu S. Pleural calcification associated with exposure to chrvsotilc asbestos in southeast Turkey. Chest 1976; 70:43-47. 4 Yazicioglu S. Okiem K. llcayto R. Balci K.Mutlu T. Asbcstosis ve solunum sisteminin primer malin tumorleri. Arasindaki iliskiler uzerinde arastirma. Tub Toraks 1975; . 23: 91-103. 5 Yazicioglu S. llcayto R. Balci K. Celik T. Yorulmaz B. Asbcstosisle mevdana gclen selim plorcziler. DL'TFD 1977; 6:1-12. 6 Yazicioglu S. Oktem K. llcayto R. Balci K. Sayli BS. Association between malignant tumors of the lungs and pleurae and asbestosis. A retro spective study. Chest 1978; 73:52-6. 7 Paris YI. Pleural mesotheliomas and asbestos pieuresis due to environmental asbestos exposure ir. Turkev. An analvsis of 120 cases. Hacettepe H:.!l Med Surg 1975; 8:165-85. 8 Baris YI. Sahin AA. Ozcsmi M et at. An out break of pleural mesothelioma and chronic tihrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 1978; 33:181-92. 9 Kiviluoto R. Pleural calicification as a roentgeno logic sign of non-occupational endemic anthophvllite-asbestosis. Acta Radial I960: suppl mi 194:1-67. 10 Meurman L. Asbestos bodies and pleural plaques in a Finnish series of autopsy cases. Acta Pathol Microbiol Scand 1966; suppl no 181:1--.107. 11 Selikoff 1J. The occurrence of pleural calcification among asbestos insulation workers. Ann Is' Y Acad Sci 1965; 132:351-67. 12 Hourihanc DOB. Lessor L. Richardson PC. Hyaline and calicified pleural plaques as an index of exposure to asbestos. A study of radiological and pathological features of 100 cases with a consideration of epidemiologv. Br Med J 1966; 1: 1069-74. 13 Soutar CA. Simon G. Turncr-Warwick M. The radiologv of asbestos-induced disease of the lungs. Br J Dis Chest 1974 ; 68:235-52. 14 Tevssier L. Lesobre R. Les plaques pleuralcs de l'asbestosc non professionnelie. J Fr.Med Chir Thorae 1968; 22:797-808. 13 Chretien J. Chahiniar. Ph. Hirseh A. Nebut K.. Plcuresies non tumorales de I'asbestc. Rev Fr Mol Resp 1976; 4:87-92. 16 Lemenager J. Rousselot P. Mandard JC. !.e Bouffant L. Borel B. Les pleuresies benignes de Tasbcste. Rev Fr Mai Resp 1976; 4:75-86. 17 Wagner JC. Sleggs CA. Marchand P. Diffuse pleural mesothelioma and asbestos exposure in Northwestern Cape Province. Br J Industr Med I960; 17:260-71. 15 Lajartre M de. Cornet E. Corroller J et at. Etude clinique et professionnelie de 54 mdsothdliomes pleuraux diffus. Rev Fr Mai Resp 1976; 4:63-74. 19 Lieben J. Pistawka H. Mesothelioma and asbestos exposure. Arch Environ Health 1967; 14:559-63. 20 Selikoff IJ. Churg J. Hammond EC. Asbestos exposure and neoplasia. JAMA 1964; 188:22-6. 21 Selikoff IJ. Hammond EC. Churg J. Asbestos exposure, smoking and neoplasia. JAMA 1968; 204:106-12. 22 Turiaf J. Chabol J. Basset F." Cancer bronchique et mesotheliome pleural asbestosiques. Poumon Coeur 1966: 24:559-80. 23 Turiaf J. Baitesii JP. Le pouvoir cancdrigdne de Tnmiante sur les voies aeriennes. Rev Fr Mai Resp 1976; 4:39-50. 24 Wagner JC. Berry G. Mesotheliomas in rats following inoculation with asbestos. Br J Cancer 1969; 23:567-81. 25 Wagner JC. Berry G. Skidmore JW. Timbrell V. The effects of the inhalation of asbestos in rats. Br J Cancer 1973: 29:252 69.