Cappadocian Mesothelioma Villages

By A. Umran Doğan
Ankara University, Department of Geological Engineering, Ankara

Introduction

Malignant pleural mesothelioma (MPM) is a highly lethal disease and clinical and experimental studies have been confirmed the link to erionite, a zeolite group mineral. Extremely high rate of incidence has been observed in the Cappadocian region of Turkey. Previous studies reported that erionite was only found in the three villages of Karain, Sarıhıdır, Tuzköy; and neighboring villages of Karacaören and Tahar (Yeşilöz) reported as non-mesothelioma villages (Temel and Gündoğdu, 1996). In contrast, our detail geological and mineralogical studies of the region confirmed that erionite is not only confined to these three villages. In fact, Karacaören village is also contaminated with erionite both in bedrock and wall rock. Subsequent epidemiological studies showed that previously reported non-mesothelioma villages such as Karacaören has high rate of mesothelioma and established the unequivocal relationship between erionite and non-occupational malignant mesothelioma in these villages.

The valley of Göreme is the site of one of the most fascinating testimonies of human being. The region of Cappadocia includes the Nevşehir province in the Nevşehir-Ürgüp-Avanos triangle and also includes the Ihlara valley within Niğde province and vicinity of Soğanlı within Kayseri province. These villages in the Cappadocian region, including Tuzköy, Karain, and Sarıhıdır, Karacaören, Boyalı, Çökek, Yeşilöz, and Karlık, comprise an extremely important field to conduct comprehensive mineralogical and epidemiologic studies.

The Cappadocia, "Katpatuka" in Old Persian, means land of beautiful horses. Archaeological records indicate that the region was populated by Hittites, Phrygians, Persians, and Romans. After Christianity was accepted as a religion, a monastic life in the region started about 350 AD. Subsequently, Cappadocia occupied by Arabs during 7th and 8th centuries and Byzantium succeeded the Arabs towards the mid 9th century. In 1071, the Eastern Byzantium Empire on central and eastern Anatolia provinces was diminished by the Anatolian Seljucks. From the 14th century onwards, the Ottomans replaced the Seljucks in ruling the region. All empires left their cultural and art properties as a precious heritage. More than 400 rock-hewn churches, the remains of Early Christian and Byzantine art, and Ottoman's hans, caravan serais, medreses, turbes, and mosques. It is believed that zeolitic tuff was first used during the Roman empire, to build houses, construct roads, sewage channels, and milestones (Mumpton, 1975 and 1983). Therefore, it is logical to assume that exposure to erionite has been widespread, thus the diseases associated with the erionite for centuries in these regions. For example, a word from Karain such as "I can not remember my father, and he does not remember his father" supports this theory.

Mesothelioma in Cappadocian Area

MPM is a relatively rare form of a lung cancer in which thick layers of malignant tumor develop on the outer lining of the lung. Regardless of the source of exposure (occupational or environmental) MPM is a highly lethal disease with the majority of patients dying 6-18 months. Current therapy is unsatisfactory. Between 1959 and 1977, approximately 4500 cases of mesothelioma were diagnosed in the world (McDonald and McDonald, 1977). The exposure to materials could be either occupational or environmental. Clinical, epidemiological, and pathological survey, in vivo and in vitro experimental work demonstrates that asbestos was responsible for the etiology of mesothelioma. The high potential of erionite to induce MPM has been confirmed by both epidemiological and experimental studies.

The interest in erionite is grown after the initial reports of the link between erionite and malignant mesothelioma in central Turkish villages of Karain and Tuzköy (Barış, 1975), and later Sarıhıdır (Barış et al., 1978; Ataman, 1978; Artvınlı and Barış, 1979; and Lilis, 1981). Mumpton (1979) observed erionite in the villages where pleural mesothelioma occurs; he also noticed that erionite in other villages such as Sarıhıdır with no reported cases of mesothelioma. Therefore he suggested that some other agent may be responsible for the high incidence of mesothelioma in the region. Barış et al. (1987) and Simonota et al. (1989) have shown that contrary to Mumpton (1979) mesothelioma also occurs at unusually high rates in Sarıhıdır village, Turkey.

Rohl et al. (1982) examined lung tissues and rock samples from the area. They reported significant amounts of tremolite and chrysotile in addition to erionite. They concluded that their findings were consistent with published data showing a relationship between asbestos (chrysotile or amphibole) exposure and pleural disease. Then they speculated on the existence of enhanced tumorigenic effect produced by a combination of asbestos and erionite. Sebastien et al. (1984) reported the high frequency of mesothelioma in the central Turkish villages was related to airborne exposure to natural mineral fibers. Wagner et al. (1985) examined the relationship between erionite exposure and mesothelioma through experimental studies on rats and found that samples of erionite from Turkey and Oregon produced a very high incidence of mesothelioma.

Health effects studies include Barış et al. (1981), Casey at al. (1981), Sebastien et al. (1981), Artvinli and Barış (1982), Maltoni et al. (1982), Suzuki (1982), Hillardal and Barış (1983), Sebastien et al. (1984), Casey et al. (1985), Barış et al. (1987), Kruglikov et al. (1990), Tatrai et al. (1991), and Tatrai et al. (1992). Occasionally, fibrosis of the lung and pleura has been reported among workers to erionite but not to asbestos (Casey et al. 1981, 1985). Several studies have been conducted on the inhabitants of villages in Turkey with environmental exposure to erionite and on the inhabitants of control villages. Ferruginous bodies were found in a higher proportion in the sputa of inhabitants of the contaminated villages than in the control villages (Sebastien et al., 1984). Similar, although not statistically significant differences were found for pleural changes (Barış et al, 1981; Artvinli and Barış, 1982) or pleural plaques (Barış et al. (1987). Hillerdal and Barış (1983), found out that pleural calcifications were more frequent in inhabitants of erionite exposed villages (78/549, 14.2 %) and of asbestos exposed villages (104/446, 22.3 %) than of control villages (3/382, 0.8 %). Carcinogeneity in humans studies include Barış et al., 1978, Artvinli and Barış, 1979, McDonald and McDonald, 1980, Boman et al., 1982, Artvinli and Barış, 1985, Barış et al., 1987, Simonato et al., 1989, and Ozesmi et al., 1990.

No epidemiological studies are available on the carcinogenicity of zeolites other than erionite. Most of the data on the carcinogenicity of erionite in humans come from the experience of the inhabitants of the erionite contaminated villages in Central Cappadocia, Turkey. Barış et al., (1978) reported 25 MPM in population of 575 inhabitants of Karain between 1970-1974 ; Barış et al. (1981) reported 28 MPM in Karain between 1975-1979; and Artvinli and Barış (1985) examined over 25 years of 312 inhabitants of Tuzköy between 1978-1980 and reported 15 MPM, 12 MPEM, and 8 Lung cancer. The incidence or mortality from mesothelioma was above 1 %/year, a rate which is over 10 000 times higher than those seen among populations non-occupationally exposed to asbestos from Western Europe or North America. Barış et al. (1987) conducted an environmental and epidemiological study in three contaminated villages (Karain, Sarıhıdır, and Tuzköy) and one control village (Karlık) in the period of 1979-1983 and reported that fibers in street samples were 2-10, 5-25, 1-29; erionite among fibers (>5 mm) were 80 %, 85 %, 60 %; number of MPM were (males/females) 12/9, 0/5, 2/1; number of MPEM were (males/females) 0/0, 0/4, 0/0; number of lung cancer were (males/females) 2/0, 9/0, 5/1; number of other cancers were (males/females) 20/11, 5/5, 13/4; and number of other causes of death were (males/females) 15/17, 12/6, 13/17; respectively for Karain, Sarıhıdır-Tuzköy, and Karlık. Barış et al. (1987) confirmed that the high mortality from MPM and MPEM, and also quantified an excess of lung cancer mortality in the contaminated villages. The young age at appearance of respiratory neoplasm among inhabitants of these villages was particularly noteworthy.

Boman et al. (1982) and Ozesmi et al. (1990) reported 7 cases of mesothelioma among about 100 men from one of the Cappadocian villages (Karain) who immigrated to Sweden. In this group, mesothelioma was the most common cause of death, with an incidence close to 1 %/year. Metintaş et al. (1998) reported 14 death due to MPM among 162 Turkish emigrant from Karain who resided in Sweden. In addition, there were 5 patients with mesothelioma (4 MPM and 1 MPEM) who were still alive. Thus it is calculated that risk of mesothelioma is for men 135 times and for the women 1336 times greater than for the same sex and age groups in Sweden. The risk increased with time residing in the village. As in the studies from Turkey, mesotheliomas occurred at a young average age. In subsequent analyses, a cumulative dose of 1 fiber/ml-year was estimated to induce a pleural mesothelioma rate of 996 per 100 000 person-years in the exposed population (Simonato et al., 1989).

Zeolite Toxicity Experiments Using Animals

Animal experimental studies include Suzuki and Kohyama, 1984, Wagner et al., 1985, Pylev et al., 1986, Maltoni et al., 1988, Pylev et al., 1989, Davis et al., 1991, Tatrai et al., 1991, Tatrai et al., 1992, and Carthew et al., 1992. Wagner et al. (1985) tested natural erionite, synthetic non-fibrous zeolite with the composition of erionite and crocidolite at a concentration of 10 mg/m3 inhalation in rats. Pleural mesotheliomas were found in 27/28 rats exposed to erionite; 1 pulmonary and one pleural tumor were found in the 28 rats exposed to synthetic zeolite, and 1 lung carcinoma was reported in rats exposed to crocidolite. A number of experiments have been conducted on the intrapleural and intraperitoneal administration of various types of erionite in mice and rats. These experiments have all been positive, showing a very high mesothelioma yield (90 % or above) for amounts of erionite above 0.5 or 1 mg. For higher doses, the time of appearance of tumors was decreased (Davis et al, 1991; Carthew et al, 1992). Other tumors at the site of inoculation as well as lymphomas have been occasionally described. Carthew et al. (1992) compared the relative carcinogenic potency of erionite and asbestos fibers. In experiments based on intrapleural inoculation, erionite was 300-800 times more active than chrysotile, and 100-500 times more active than crocidolite. In intraperitoneal experiments, erionite was 20-40 times more active than chrysotile and 7-20 times more active than crocidolite.

Davis (1979) showed that intrapleural injection of asbestos produces more tumors than following intrapleural injection. Stanton et al. (1981) reported that the tumorigenity of asbestos in relation to mesothelioma is attributable to fibers longer than 8 microns and less than 1.5 microns in diameter. Maltoni et al. (1982) tested erionite and crocidolite fibers for carcinogenicity. They reported pleural mesothelioma after intrapleural injection with erionite fibers and no pleural tumors among the rats treated at the same time and in the same way with crocidolite. Wagner (1983) showed that the inhalation of erionite in comparison with asbestos produces tumors more rapidly and more frequently. Johnson et al. (1984) showed that while tumors induced by asbestos and erionite are morphologically similar. There are differences, which suggest the biological activity of the two dust types is different. Suzuki and Kohyama (1988) studied the effects of intraperitoneal administration of mordenite and two natural erionites in mice. They found that both erionites produced malignant peritoneal tumors at a high rate, but mordenite did not produce any tumor. Coffin et al. (1989a and 1989b) and Palekar et al. (1989a) obtained both in vitro and in vivo results demonstrating that erionite is much more tumorigenic than crocidolite or chrysotile and induces chromosomal abnormalities. Coffin et al. (1989a,b) studied on mechanisms of tumorigenesis and tried to explain why erionite is more tumorigenic than either crocidolite or chrysotile, in spite of the fact that asbestos minerals typically have a far greater percentage of fibers in the length-to-width class considered dangerous. They invoked the high internal surface area of erionite (200 m2/g) compared with the total surface areas for chrysotile (24 m2/g) and crocidolite (8-10 m2/g) as a possible reason for the observed differences in tumorigenesis.

Mortality Studies

Clinical, epidemiological, and pathological survey, in vivo and in vitro experimental work demonstrates that asbestos was responsible for the etiology of mesothelioma. Epidemiological and pathological studies carried in the United Kingdom (Elmes and Simpson, 1971; Greenberg and Davies, 1974; Newhouse and Thomson, 1965; Newhouse, 1969; and Newhouse and Berry, 1976), France (De Lajarte et al., 1976), Germany (Bohlig et al., 1970), South Africa (Harington et al., 1963; and Wagner et al., 1960), Australia (McNulty, 1962; and Milne, 1976), Canada (Elmes and Simpson, 1971; McDonald et al., 1973 and 1974), and USA (Enterline, 1965; Selikoff et al., 1964; and Selikoff, 1976) have emphasized that 70 to 85 % of mesothelioma patients have been exposed to asbestos through occupational, environmental or other means.

Three villages in Central Anatolia, Turkey, namely Tuzköy, Karain, and Sarıhıdır, comprise an extremely important field area and are informally referred to as "the death triangle". Barış investigated this malignant pleural mesothelioma in Tuzköy, Sarıhıdır, and Karain villages in Nevşehir, Turkey and he has kept the patients records of disease including chest x-rays and health statistics. Barış also gathered the data on death records of patients who had died of mesothelioma and other cancers in these villages in Turkey or abroad (i.e., Karain colony villagers in Sweden) indirectly through verbal autopsies with key informants and acquaintances. Extremely high rate of cancer in young-to-middle age group patients observed in the study area. In vitro and in vivo studies done by IARC and WHO also indicate that there is enough evidence that these fibers are carcinogenous and the cancer rate in these regions is about 1000 times more than the normal rate.

In 1975, high incidence of malignant pleural mesothelioma has been recorded in the vicinity of the study area (Barış, 1975 and 1976). These studies showed that erionite type of zeolite minerals, not asbestos, was the major cause of this epidemic in the study area. Detailed electron microscopy study revealed the abundance and types of fibers present. X-ray microanalysis and ICP-MS data obtained from these samples revealed the composition of mineral fibers, and electron diffraction study helped to determine crystal structure of erionite type zeolite mineral. Thus, beside presently known three erionite villages in the Cappadocian area (Tuzköy, Karain, and Sarıhıdır), it is observed for the first time that five other villages in the region contaminated with erionite occurrences. These villages include Karacaören, Boyalı, Çökek, Karlık, and Yeşilöz.

Conclusions

Erionite is the only zeolite whose evidence of carcinogeneity has been evaluated and it is classified as a human carcinogen (IARC, 1987). In Turkey, erionite contaminated villages in Cappadoccia region provide a natural laboratory to study the health effect of these carcinogenic minerals and the villagers who immigrated from Karain to Sweden also form a unique community to study the follow up effects of zeolite exposure. The cancer rate in these regions is about 1000 times more than the normal rate. The local saying of "I don't know my father and my father doesn't know his father" indicate that the cancer has been there for centuries.

This problem must have world immediate attention. Although both the exposures and biological mechanisms are complex, we hope that the multidisciplinary "Medical Geology" studies including genetics will help to find some answers to the fundamental questions and eventually will lead to quantitative, predictive models in time and space.

Reference list is not included in the text due to a space limitation.