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British Journal of Industrial Medicine 1985;42:746-749 Peritoneal mesothelioma and malignant lymphoma in mice caused by fibrous zeolite M OZESMI,1 T E PATIROGLU,2 G HILLERDAL,3 AND C OZESMI4 From the Medical Faculty,1 Department ofInternal Medicine, Department ofPathology} and Research Centre,3 Ercyies University, Kayseri, Turkey, and the Department ofLung Medicine,* University of Uppsala, Academic Hospital, Sweden abstract Dust from the village of Karain containing the fibrous zeolite erionite, talc, and physio logical saline were tested by intraperitoneal injection in 486 Swiss albino mice. Malignant tumours were found in 84 (41 mesotheliomas, 31 lymphomas, 1 peripheral epidermoid carcinoma, and 11 lymphomas and mesotheliomas together) of the 321 animals which died spontaneously within nine to 32 months after injection of Karain dust (26-1%). Three mesotheliomas and no lymphomas were found among 24 animals injected in the same way with talc during the same time (12-3%). In 46 control animals injected with physiological saline three mesotheliomas and one lymphoma were seen (8*7%). Thus Karain dust appears to be a potent carcinogen, causing both mesotheliomas and malignant lymphomas. Since 1974 the Baris group from Hacettepe University of Ankara, Turkey, has worked on the problem of mesotheliomas in middle Anatolia, where in certain villages there is an endemic occurrence of this disease. The highest incidence is in the village of Karain.1 Volcanic tuffs form the bedrock of the area. In the villages with a high incidence of mesothelioma the tuffs have converted into zeolites, both non-fibrous (clinoptilolite and chabasite) and fibrous (erionite and mordenite.2 3 Erionite fibres can also be found in biopsies of the lung24 and pleura4 in inhabitants of the affected villages. Since some doubt as to the causation of the mesotheliomas still remains,36 it was decided to carry out some experiments beginning in 1980. Material and methods the same way. The suspensions were injected into 6 week old Swiss albino mice. As a control, 1 ml of physiological saline was used in several animals. The animals were checked every day until sponta neous death occurred or until there were obvious signs of tumour, such as a greatly enlarged abdomen. Animals which died before nine months had elapsed after injection were excluded. Postmortem examination was performed on all dead animals. Macroscopical findings were noted and biopsy specimens from the injection site, parietal and visceral peritonea] mesothelium, peritoneal lymph nodes, spleen, liver, kidneys, adrenals, mediastinal lymph nodes, and tumours were taken for micro scopical investigation. The pathologist was unaware of the type of dust to which the animals had been exposed. A rock from Karain was ground to dust at the Geological Institute of Hacettepe University. In this Karain dust (KD) zeolite was shown, both in fibrous and non-fibrous form. There were no signs of any asbestos in the dust. The dust was divided into pack ages of 5, 10, 15, 20, 30, and 40 g and suspended in 1 ml of physiological saline and sterilised with ultra violet light. Commercial talc, 20 mg, was treated in Received 25 February 1985 Accepted 25 March 1985 Results As seen in the table, KD caused tumours in 26-1%, talc in 12-5%, and physiological saline in 8 7% of the animals. There was no evident relation between the amount of dust and the incidence of tumours. No tumours occurred before nine months had elapsed after injection. Of the 321 animals given KD, mesothelioma devel oped in 41, lymphoma in 31, peripheral epidermoid carcinoma in one, and both lymphoma and meso thelioma in 11. Thus in all there were 52 meso- 746 10003138 '* Peritonea! mesothelioma and malignant lymphoma in mice caused by fibrous zeolite oma in 747 'esearch v of Uppsala, c, and physio:nant tumours noma, and 11 ly within nine lphomas were 2-5%). In 46 lphoma were heliomas and injected into 6 ntrol, I ml of I animals. / until spontawere obvious ged abdomen, is had elapsed Dnned on all ere noted and , parietal and toneal lymph mediastinal n for microwas unaware als had been .rs in 26-1%, . 8-7% of the between the umours. No had elapsed iioma develepidermoid and mesoe 52 meso- ' i PeritoneaI mesotheliomas in mice: (A)fibrous mesothelioma withfew mitoses, fB) sarcomatous type. (C) epithelial mesothelioma. (HE stain: original magnification x 400.) 10003139 1 748 Ozesmi, Patiroglu, Hillerdal. and Ozesmi Rendu ofintraperiloneal injection ofKarain dust (KD) and oftalc into mice injected material No of mice Dead before six months Remaining Mesothelioma Lymphomas Both lymphoma 4 mesothelioma Total % honours Saline ss 9 SrisKD 69 14 10 mg KD 97 16 IS ms KD 98 25 20msKD 45 2 30 ms KD 45 6 40 mg KD 37 7 All KD 391 70 Talc (20 mg) 40 16 46 3 55 6 II 12 73 10 43 6 39 3 30 4 321 41 24 3 _1 0 4 _II 4 7 50 41 42 31 II -- 4 87 to 18) 27 33 17 23-3 12* 28 8 20-5 10 33 84* 26*1 3 12-5 One inimal had an epidermoid tumour of the lung. theliomas (16-5%), and 42 lymphomas (13-3%). All types of mesotheliomas (fibrous sarcomatous, and mixed) were seen (figure). The lymphomas were of the malignant lymphomatous type. Depending on the stage ofdisease at death, the liver or spleen, or both, were often invaded in both types of tumours, and in some cases there were also distant meiastases. Discussion The first international report from the village of Karain was published by Baris etal in 1978.' Extremely high incidences of malignant meso thelioma and benign pleural changes were reported, but apart from some asbestos fibres in some of the water used in the village (a finding which has not since been confirmed1), no mineral fibres had been found in the environment to that date. The extensive subsequent investigations showed that fibrous zeolites, the most important of which is erionite, were present in the village of Karain and in two other villages--Tuzkoy and Sarihidir--where meso theliomas also occur.24' There is still some doubt as to whether fibrous zeolite is the cause of the malignant mesotheliomas in this part of Turkey, and it has been suggested that it is mixed fibrous dust, containing asbestos fibres in addition to erionite, that is the culprit.9' It has been claimed that there is some asbestos in the surroundings of Karain,9 and lung biopsy specimens from patients from Karain contained other fibres in addition to erionite.' Measurements of the fibre levels in environmental air samples from Karain have shown such low figures7 that doubt has been cast on their importance. Furthermore, it has been claimed that erionite fibres may be found in nearby villages where there are no known cases of mesotheliomas.9 In an investigation by Mumpton, 15 of 28 probes from the three villages showed erionite fibres, whereas only four of 48 from control villages showed such fibres.9 Forster has since reported that zeolites occur only in the northern part of Karain,9 whereas the probes in Mumpton's study were taken in the south ern part. Asbestos fibres may be seen in the lungs of many people even without occupational exposure and their occurrence in people from Karain could be a chance finding. The vast majority of the fibres in the lungs of the Turkish villagers were erionite, and only a small minority were asbestos.9' In patients from Tuzkoy fibres of erionite in high concentrations and ferruginous bodies on erionite have been found.10 Mesotheliomas in experimental animals after intra pleural or intraperitoneal injection or even inhalation of erionite have also been shown.11'13 The results of the present study confirm that dust from Karain is carcinogenic, and since it contained no asbestos it seems most probable that it is the erionite that caused the mesotheliomas. Maltoni etal state that pure erionite injected intrapleurally in rats causes mesothelioma in the pleura in 90% of the cases,11 and Wagner reported 100% of mesotheliomas with both intrapleural injection and with inhalation.19 In the present material the frequency of tumours was not as high, since dust from Karain was used rather than pure erionite, and perhaps also because the intraperitoneal rather than the intrapleural route was chosen. According to Maltoni etal, erionite causes more mesotheliomas than crocidolite, which is gener ally considered to be the most dangerous type of asbestos in this regard.11 Wagner states that erionite is the only dust so far known to cause mesotheliomas in 100% of experimental animals on inhalation.19 An unexpected observations was the relatively common occurrence of malignant lymphomas in the experimental animals. There are no epidemiological findings to confirm this. Artvinli and Baris, however, state that tumours other than mesotheliomas may not be uncommon in Tuzcoy.4 So far, however, with the exception of lung cancer,7 no tumour other than malignant mesothelioma has been shown to have an increased incidence in the zeolite area. Suzuki used two types of American erionite (from Peritoneal mes Nevada and 1 injection caus 50% of the ar> among anima amosite and 1 with erionite ifive had plasn mesothelioma There were no in the animal seems to be 'at system, which From a stud inhalation of lymphosarcon asbestos show; ular endoth haematopoieti described in p effects of erior asbestos, slinru ultimate forma On the other h crystalline sili> can cause lym Thus it is pos Karain dust- 1 lymphomas ir differences in animals to thrats being raos such a suscept necessitate fur We thank Pro help and supp References 1 Baris Yl, Sshin ihelioma and * i j \ ii 10003140 | nd Ozesmi (Uol V. movrs 8-7 18 1 33 233 * 28 20-5 33 26 1 125 .Teas the ne south- of many md their a chance lungs of a small Tuzkoy ns and round.10 -r intra halation lat dust ined no erionite ai state > causes and -h both In the not as r than intra;e was causes gener/pe of honite iomas t.13 itively in the ogical vcver, ; may . with than ve an ;from Peritoneal mesothelioma and malignant lymphoma in mice caused hy fibrous zeolite 749 Nevada and Colorado), which on intraperitoneal injection caused malignant peritoneal tumours in 50% of the animals,'1 a frequency higher than that among animals injected with asbestos (33V# with amosite and 17% with crysotile). Of the 39 animals with erionite induced malignant peritoneal tumours, five had plasmocytomas, and in two other animals mesothelioma was combined with plasmocytoma. There were no plasmocytomas or lymphoid tumours in the animals exposed to asbestos. Thus erionite seems to be able to cause tumours of the lymphoid system, which fits with the present results. From a study with intraperitoneal inoculation and inhalation of asbestos, Wagner reported some lymphosarcomas.14 All animals that had received asbestos showed pronounced stimulation of the retic ular endothelial system. Tumours of the haematopoietic and lymphatic systems have also been described in people exposed to asbestos.13 Since the effects of erionite are thought to be similar to those of asbestos, stimulation of the lymphatic system with the ultimate formation of lymphomas seems a possibility. On the other hand, Wagner eial have also shown that crystalline silica when injected intrapleurally in rats can cause lymphoproliferation and lymphomas.1617 Thus it is possible that the other ingredients of the ICarain dust--those that are not fibrous--caused the lymphomas in our study. There seem to be great differences in the susceptibility of various strains of animals to the development of lymphomas, Wistar rats being most affected. " Swiss albino mice might be such a susceptible strain of animals. These questions necessitate further studies, which are now in progress. We thank Professors Y Baris and G Ataman for their help and support in the present study. References 1 Bins YI, Sahin AA, Ozconi M, el at. An outbreak of pleural mootheboma and chronic fibrosing pleurisy in the village of Karain/Urgup in Anatolia. Thorax 1978:33. 181-92 'Alaman C. The rrohlic tufts of Cappadocia and their probable association with certain types of lung cancer and pleural meso thelioma. Camples Rendus i'Academic de Sciences de Paris. Serie D. 1978:287:207-10. I Forster H. Einc mineralogisch-petrographische Untersuchung uber moglichc Unachen von Mesolheliomen in Kippadokicn Tfirkei. Zeniralblaii Arbeitsmedizin 1982.32:18-27. * Artvinli M, Baris YI. Malignant mesotheliomas in a small village in the Anatolian region of Turkey: an epidemiological study. JNCt 1979:43:17-22 ' Rohl AN. Linger AM, Moncure G. Selikoff II, Fischbein A. En demic pleural disease associated with eiposure to mned fibrous dust in Turkey. Science 1982:216.318-20. * Bonun G. Schubert V. Svanc B. eial. Malignant mesothelioma in Turkish immigrants residing in Sweden. Scand J Work Environ Health 1982;8:108-12. ' Baris YI. Saracci R. Simonato L. Skidmore JW, Artvinli M. Malig nant mesothelioma and radiological chest abnormalities in two villages in central Turkey. Lancet 1981 ;i.-984-7. 'Artvinli M, Baris YI. Environmental fiber-induced pteuropulmonary diseases in an Anatolian village: an epidemiological study. Arch Environ Health 198237.177-81. * MumpIon FA. Report on reconnaissance study ofthe association of zeolites with mesothelioma cancer occurrences in central Turkey. Brockport, New York: Department of Ibe Earth Sciences. Slate University College. 1979. "Sebastien P. Eng A. Bignon J, Baris YI. Zeolite bodies in human lungs from Turkey. Lab Invest 1981;44:420-3. II Maltoni C, Mikardi F, Movisi L Pleural mesotheliomas in Sprague-Dawlcy rats by erionite: first experimental evidence. Environ Res 1982;29:238-44. "Suzuki Y. Malignant mesothelioma following intraperitoneal ad ministration of asbestos and icoKic. In: Vhh International Pneu moconiosis Conference 191}. Vol 2. Bochum, West Germany: Bergbaugenosamschsft, 1983:1047-31. 11 Wagner JC Experimental studies using erionite fibre. In: Vhh In ternational Pnetanaconiasu Conference 1993. Vol 2. Bochum, West Germany: Bergbaugcnosacaschaft. 1983:1009. "Wagner JC. The induction of tumours by the intrapleural injec tion of various types of asbestos dust. Ik Severil L, ad. Lung tumours hi animals. Proceedings of the 3rd Quadrennial Confer ence on Cancer. Perugia. I96S. Perugia: Division of Cancer Research, 1966:389-408. "Kagan E, Jacobson RJ. Lympoid and plasma cell malignancies: asbestos-related disorders of long latency. Am J Clin Pathol 198330:14-20. "Wagner MMF, Wagner 1C. Lymphomas in the Wistar rat after intrapleural inoculation of silica. INC! 1972:49:81-9. "Wagner MMF. Wagner JC. Davies R, Griffith DM. Sihca-induced malignant lymphocytic lymphoma: incidence linked with strain of rat and type of silica. BrJ Cancer 1980:41:908-17. 10003141