Malignant Mesothelioma and Erionite

15 Malignant Mesothelioma and Erionite

A. Umran Dogan

Cancer has been known for millennia, but the understanding we have of its origins and causes are comparatively recent. Ancient Egyptians first recorded cancer as a disease some 4500 years ago. However, it wasn’t until the 18th century that observations on environmental cancers were made, as people started to look for a connection between certain environments, including working practices and human cancer incidence patterns. The idea emerged that the causes of cancer may be divided roughly into two broad categories: exogenous, which is environmental and occupational, and endogenous, which is something inherent in the person. While this has been a useful distinction, advances in genetics now seem to be blurring the boundary. The result is that cancer research has concentrated on the identification of environmental and occupational causes of human cancer. By the late 19th century the study of cancer tissues had revealed that cancer cells were markedly different in biology and cell structures when compared with the normal cells in the surrounding tissue. During the 20th century, the research in cancer increased in an almost exponential fashion. Advances in genetics, biochemistry, and molecular biology have begun to allow some insight into what was happening when a normal cell was changed into a cancerous one and often why it happened. Gene therapy approaches for inherited and acquired lung diseases are reviewed else- where (1). Modification of erionite and its effects on in vitro activity is discussed in Brown et al (2). The genetic susceptibility to mesothelioma has been introduced and discussed in the literature (3–6). Cancer can take many forms and is usually named after the cell type from which it is transformed. Once a cancer cell has arisen, clonal expansion without regard for the surrounding tissue, accounts for the clinical symptoms of the disease. As the tumor grows, continuous dedifferentiation occurs and cells break away to form new cancers at other sites in the body. It is this metastatic growth that accounts for most of the mortality from this disease. A few tumor types are so aggressive in their development that they kill the host before metas- tasis even begins. One such cancer is mesothelioma, which is a cancer of the lining of the body cavity and named for its development from

242 A.U. Dogan 243 the mesothelium. Although these cancers had been known for a long time, only in the past 40 to 50 years have they been accepted as real mesothelial neoplasms, and not secondary tumors. In 1960, Wagner et al (7) described 33 cases of malignant pleural mesothelioma that they believed had developed through environmental exposure to crocidolite, which is blue asbestos. Up to this time, human tumors for which an external cause had been suggested were believed to arise through heavy occupational exposure. That tumors could arise through specific environmental exposure meant that a very much larger population could be at risk. Then, about 30 years ago, the fear that this discovery engendered was underlined when Professor Izzetin Baris identified large numbers of human mesotheliomas in several villages in central Turkey, in the region known as Central Anatolia. This time, crocidolite, or indeed any other amphibole mineral, was not to blame. Such minerals were not found in this part of the country, although it did seem probable that a fibrous mineral was responsible for the unprecedented level of disease. Examination of the volcanic rock formations that dominate this part of the country revealed the presence of a fibrous zeolite known as erionite, which contained a high percentage of respirable fibers. Animal experiments have now shown that this may be the most potent natural mineral carcinogen in nature. It was far more carcinogenic than crocidolite. With this knowledge, Baris and his colleagues have demonstrated that a major cause of the mesotheliomas (in some cases five out of six family members have presented with mesothelioma) is the erionite. Any role it may have in other cancers is unclear, but in some Cap- padocian villages in Central Anatolia cancer is the predominant cause of death, maybe as high as 80% of total deaths, and some 50% of these deaths result from mesothelioma. Since the villagers have constructed their houses from tuffs carved from the often erionite-rich volcanic rock, and because they till the ground containing respirable fibers of erionite, they are exposed to the fibers continuously, indoors and out, throughout their lives. Current attempts at cancer prevention in these villages (now a unique human laboratory) has led to research efforts involving molecular and cellular changes in mineral fiber carcinogenesis, carcinogen avoidance techniques, human lifestyle analysis, nutritional consumption patterns, and chemical/drug prevention concepts. The Turkish Ministry of Health has begun to support efforts aimed at reducing this preventable human cancer problem by establishing hos- pitals in central Turkey and by sponsoring international meetings in attempts to understand better environment and cancer interrelation- ships and to identify possible means of prevention. The problems of natural environmental pollution by mineral fibers are not unique to Turkey, although Turkey has suffered more than any other country. Also, considering the concept of nutritional prevention of cancers, understanding and ensuring good nutrition is a global concern. However, Turkey is a geographically vast country with a large heterogeneous rural community. Most Turkish people survive through subsistence farming, and have a variety of foods, which is a luxury few can experience. 244 Chapter 15 Malignant Mesothelioma and Erionite

Brief History of the Region

The Cappadocia, “Katpatuka” in Old Persian, means land of beautiful horses. Archaeologic records indicate that Hittites, Phrygians, Persians, and Romans populated the region. After Christianity was accepted as a religion, a monastic life in the region started about 350 a.d. Sub- sequently, Cappadocia was occupied by Arabs during the 7th and 8th centuries, and Byzantium succeeded the Arabs toward the mid-9th century. In 1071, the Anatolian Seljuks diminished the Eastern Byzantium Empire in the Central and Eastern Anatolia provinces. From the 14th century onward, the Ottomans replaced the Seljuks in ruling the region. All empires left their cultural inﬂuences as a precious heritage: more than 400 rock-hewn churches, the remains of Early Christian and Byzantine art, and the Ottomans’ 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 (8,9). Therefore, it is logical to assume that exposure to erionite has been continuous and widespread. Thus the diseases associated with erionite have occurred over many centuries in these regions.

Zeolite-Group Minerals

In general, zeolite-group minerals have excellent physical and chemical properties and they are used widely in industry. However, a ﬁbrous form of zeolite, called erionite, has been proven to be the most toxic mineral in humans. The word zeolite comes from the Greek word meaning boiling stone, because of the loss of water when it is heated. Cronsted discovered stilbite, a zeolite-type mineral, in 1756. Currently, a zeolite mineral is deﬁned as a crystalline substance with a structure characterized by a framework of several linked tetrahedra, each consisting of four O atoms surrounding a cation. In the hydrated phases, dehydration occurs at temperatures mostly below about 400°C and is largely reversible. The framework may be interrupted by (OH, F) groups; these occupy a tetrahedron apex that is not shared with adjacent tetrahedra. The tetrahedral arrangement forms lattice structures with relatively

large cavities connected by channels. These cavities contain H2O mole- cules, and monovalent and divalent cations that balance the charge resulting from a trivalent aluminum ion replacing a quadrivalent silicon ion in the tetrahedra. The cations in the cavities can be exchanged with other cations including mainly sodium, potassium, calcium, magne- sium, and also less often barium, strontium, copper, zinc, lead, silver, rubidium, cesium, and ammonium. The zeolite group of minerals included 32 naturally occurring minerals before 1997. The number of minerals almost tripled when the zeolite-group minerals were reclassiﬁed and 13 of them rose to a series status (10,11). A.U. Dogan 245

Mineralogy of Erionite

Eakle defined erionite from Durkee, Oregon, in 1898. The mineral occurred as white woolly fibers associated with opal in cavities in rhy- olitic welded ash flow tuff. Eakle proposed the name erionite, from the Greek word for wool, because of its woolly aspect. Earlier erionite studies included Deffeyes (12), Staples and Gard (13), Ames (14), Eberly (15), and Kawahara and Curien (16). Deffeyes (12) improved the crystallographic data of erionite and described erionite from the northern Jersey Valley, Sonoma Range Quadrangle, Nevada; Shoshone Range and valley of Reese River, Nevada; Pine Valley, Nevada; east of Sand Draw, Wyoming; and White River formation, South Dakota. Erionite, in different parts of the world, has been studied: in the United States by Deffeyes (12), in Italy by Passaglia et al (17) and Passaglia and Tagliavini (18), in Germany by Rinaldi (19), in Crimea by Suprychev and Prokhorov (20), in Antarctica by Vezzalini et al (21), in Mexico by Garcia-Sosa and Rios-Solache (22), and in Japan by Kawahara et al (23), Harada et al (24), Shimazu and Yoshida (25), and Shimazu and Mizoda (26). The morphology of erionite is hexagonal prisms terminated with the basal pinacoid. Erionite usually occurs as thin fibers, often forming a compact felt, sometimes with a delicate woolly appearance. The occurrence of intergrowth with offretite is common, because both minerals have similar structures. Sometimes a single erionite crystal contains some stacking faults of the offretite, as shown by the transmission elec- tron microscopy (TEM) technique (27). Macro intergrowths have been described by Rinaldi (19). Fibrous erionite-offretite intergrowths over levyne lamellae have been observed by Gottardi and Galli (28).

Deﬁnition of Erionite Series

Three types of erionite are described as erionite-Na, the type specimen by Sheppard and Gude (29), erionite-K, the type specimen by Passaglia et al (30), and erionite-Ca, the type specimen by Harada et al (24). If all reliable chemical analyses of erionite and offretites available in the literature are plotted in a discriminatory diagram based on the above chemical parameters, it is evident that none of the proposed criteria satisfactorily deﬁnes appropriate compositional ﬁelds apt to describe the literature information (30). Chemical analyses are considered to be reliable if (Si + Al) = 36, on the basis of 72 atoms, and balance error (E) < 10%. E% (31) is

100 ¥ [(A1 + Fe)ob -Alth]/Alth where Alth = Na + K + 2 ¥ (Ca + Mg + Sr + Ba). Studies of the crystal structure and crystal chemistry of erionite in general, but not Turkish erionite, include those of Alberti et al (32), Gualteri et al (33), and Passaglia and Sheppard (34). 246 Chapter 15 Malignant Mesothelioma and Erionite

Geologic and Medical Studies of the Region

Previous geologic studies of the area include Sassano (35), Beekman (36), Pasquare (37), Batum (38), Aydin (39), Atabey et al (40,41), Ercan et al (42), Schumacher et al (43), and Le Pennec et al (44). After endemic mesothelioma in the Cappadocia region was reported by Baris (45), Ataman (46,47), Mumpton (48), Forster (49), Bish and Chipera (50), and Temel and Gundogdu (51) surveyed the region and found zeolite- group minerals including erionite. Previous medical studies of the area include those of Elmes (52,53), Pooley (54,55), Sebastien et al (56,57), Rohl et al (58), Suzuki (59), and Ozesmi et al (60,61).

Mesothelioma and Asbestos

Malignant pleural mesothelioma (MPM) is a relatively rare form of a lung cancer in which thick layers of malignant cancer 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 within 6 to 18 months. Current therapy is unsatisfactory. Malignant mesothelioma and exposure to different asbestos group minerals have been studied by many, including McDonald and McDonald (62,63), Hillerdal and Ozesmi (64), Kohyama (65), Leigh et al (66), De Klerk et al (67), Dogan and Emri (68), and Gibbons (69). Between 1959 and 1977, approximately 4500 cases of mesothelioma were diagnosed in the world by McDonald and McDonald (62). The exposure to these carcinogenic materials could either be occupational or environmental. Clinical, epidemiologic, and pathologic surveys and in vivo and in vitro experimental work demonstrate that asbestos is responsible for the etiology of mesothelioma.

Mesothelioma and Erionite

The interest in erionite, a ﬁbrous form of a zeolite-group mineral, has grown after the initial reports of a high incidence of malignant mesothelioma in the villages of Karain and Tuzkoy in Cappadocian region of Turkey by Baris (45), and later a village of Sarihidir by Baris et al (70). Baris et al (70), Ataman (48), Artvinli and Baris (71), Ataman (47), Lilis (72), and Ozesmi et al (60,61) studied the region and attempted to ﬁnd a relationship between MPM and erionite. Mumpton (48) reported erionite in the villages where pleural mesothelioma occurs. He also reported that erionite in other villages, such as Sarihidir, reported no cases of mesothelioma. Therefore, he suggested that some other agent might be responsible for the high incidence of mesothelioma in this region. Baris et al (73) and Simonata et al (74) have shown that, contrary to Mumpton (48), mesothelioma also occurred at unusually high rates in Sarihidir village, Turkey. A.U. Dogan 247

Rohl et al (58) examined lung tissues and rock samples from this area. They reported significant amounts of tremolite and chrysotile, in addi- tion to erionite. They concluded that their findings were consistent with the published data, which showed a relationship between asbestos (chrysotile or amphibole) exposure and pleural disease. Then they speculated on the existence of an enhanced tumorigenic effect, which was probably produced by a combination of asbestos and erionite. Sebastien et al (75) reported that the high frequency of mesothelioma in the central Turkish villages was related to airborne exposure from the natural mineral fibers. Wagner et al (76) examined the relationship between erionite exposure and mesothelioma, using experimental studies on rats, and found that samples of erionite from Turkey and Oregon produced a very high incidence of mesothelioma. Health effects of these mineral studies include those of Baris et al (73,77), Casey et al (78,79), Sebastien et al (56,57), Artvinli and Baris (80), Maltoni et al (81), Suzuki (59), Hillerdal and Baris (82), Sebastien et al (75), Kruglikov et al (83), and Tatrai et al (84,85). Casey et al (78,79) reported that fibrosis of the lung and pleura among workers was related to erionite but not to asbestos. Several studies have been conducted on the inhabitants of “mesothelioma” 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 by Sebastien et al (75). Similarly, although not statistically significant, differences were found for pleural tissue changes by Baris et al (77) and Artvinli and Baris (80) or pleural plaques by Baris et al (73). Hillerdal and Baris (82) reported that pleural calcifications were more frequent in inhabitants of erionite-exposed villages (78/549, 14.2%) and of asbestos-exposed villages (104/446, 23.3%) than of control villages (3/382, 0.8%). Carcinogeneity studies include those of Baris et al (70,73), Artvinli and Baris (71), McDonald and McDonald (86), Boman et al (87), Artvinli and Baris (88), Simonato et al (74), and Ozesmi et al (60). 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. Baris et al (70) reported 25 cases of MPM in a population of 575 inhabitants of Karain between 1970 and 1974; Baris et al (77) reported 28 MPMs in Karain between 1975 and 1979; and Artvinli and Baris (88) examined over 25 years of 312 inhabitants of Tuzkoy between 1978 and 1980 and reported 15 MPMs, 12 malignant peritoneal mesothelioma (MPeMs), and eight lung cancers. The incidence or mortality from mesothelioma was above 1%/year, a rate that is 10,000 times higher than observed among populations nonoccupationally exposed to asbestos from Western Europe or North America. Baris et al (73) conducted an environmental and epidemiologic study in three contaminated villages (Karain, Sarihidir, and Tuzkoy) and in one control village (Karlik) in the period of 1979 to 1983. They reported that fibers taken from street samples were 2–10, 5–25, 1–29, respectively for Karain, Sarihidir-Tuzkoy, and Karlik; erionite amounts among fibers (>5mm) were 80%, 85%, 60%; numbers of MPeM cases were 248 Chapter 15 Malignant Mesothelioma and Erionite

(males/females) 12/9, 0/5, 2/1; numbers of MPeM cases were (males/females) 0/0, 0/4, 0/0; numbers of lung cancer cases were (males/females) 2/0, 9/0, 5/1; numbers of other cancers cases were (males/females) 20/11, 5/5, 13/4; and numbers of other causes of death were (males/females) 15/17, 12/6, 13/17; Baris et al (73) confirmed the high mortality from MPM and MPeM, and showed an excess of lung cancer mortality in the contaminated villages. The young age of the patients at the appearance of this respiratory neo- plasm was particularly noteworthy. Boman et al (87) and Ozesmi et al (89) reported seven cases of mesothelioma among about 100 men from one of the Cappadocian villages (Karain) who had immigrated to Sweden. In this group, mesothelioma was the most common cause of death, with an incidence of nearly 1%/year. Metintas et al (90) reported 14 deaths due to MPM among 162 Turkish emigrants from Karain who resided in Sweden. In addi- tion, there were five patients with mesothelioma (four MPM and one MPeM) who were still alive. Thus it is calculated that the risk of mesothelioma for men is 135 times and for the women it is 1336 times greater than for the same sex and age groups in Sweden. The risk increased with time of 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 by Simonato et al (73).

Zeolite Toxicity Experiments Using Animals

Animal experimental studies include those of Suzuki and Kohyama (91), Wagner et al (76), Pylev et al (92,93), Maltoni and Minardi (94), Davis et al (95), Tatrai et al (84,85), and Carthew et al (96). Wagner et al (76) tested natural erionite, synthetic nonﬁbrous zeolite with the composition of erionite and crocidolite at concentrations of 10mg/m3 inhalation in rats. Pleural mesotheliomas were found in 27/28 rats exposed to erionite; one pulmonary and one pleural tumor were found in the 28 rats exposed to synthetic zeolite, and one 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, and showed a very high mesothelioma yield (90% or above) for amounts of erionite above 0.5 or 1mg. For higher doses, the time of appearance of the tumors was decreased (95,96). Other solid tumors, at the site of inoculation, as well as lymphomas have been occa- sionally described. Carthew et al (96) compared the relative carcinogenic potency of erionite and asbestos ﬁbers. In experiments based on intrapleural inoculation, erionite was 300 to 800 times more active than chrysotile, and 100 to 500 times more active than crocidolite. In intraperitoneal experiments, erionite was 20 to 40 times more active than chrysotile and 7 to 20 times more active than crocidolite. A.U. Dogan 249

Davis (97) showed that intrapleural injection of asbestos produced more tumors than following intrapleural injection. Stanton et al (98) reported that the tumorigenity of asbestos in relation to mesothelioma is attributable to fibers longer than 8mm and less than 1.5mm in diam- eter. Maltoni et al (81) tested erionite and crocidolite fibers for carcinogenicity. They reported pleural mesothelioma after intrapleural injection with erionite fibers, but no pleural tumors among the rats treated at the same time and in the same way with crocidolite. Johnson et al (99) showed that tumors induced by asbestos and erionite are mor- phologically similar; however, the biologic activity of the two mineral types was different. Suzuki and Kohyama (91) 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 cancer. Wagner et al (76) showed that the inhalation of erionite in comparison with asbestos produced tumors more rapidly and more frequently. Palekar et al (100) and Coffin et al (101,102), using both in vitro and in vivo methods, demonstrated that erionite was much more tumorigenic than crocidolite or chrysotile and induced chromosomal abnormalities. Coffin et al studied mechanisms of tumorigenesis and tried to explain why erionite was 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 to be dangerous. They invoked the high internal surface area of erionite (200m2/g) when compared with the total surface areas for chrysotile (24m2/g) and crocidolite (8–10m2/g) as a possible reason for the observed differences in tumorigenesis.

Mortality Studies

Clinical, epidemiologic, and pathologic surveys and in vivo and in vitro experimental studies demonstrate that asbestos is responsible for the etiology of mesothelioma. Epidemiologic and pathologic studies were carried out in South Africa by Wagner et al (7); in the United Kingdom by Newhouse and Thomson (103); in Germany by Bohlig et al (104); in Canada by McDonald et al (105); in France by De Lajarte et al (106); in Australia by Milne (107); and in the United States by Selikoff et al (108), Enterline (109), and Selikoff (110). These studies have emphasized that approximately 70% to 85% of mesothelioma patients have been exposed to asbestos through occupational, environmental, or other means. Three villages in Central Anatolia, Turkey, namely Tuzkoy, Karain, and Sarihidir, comprise an extremely important ﬁeld area and are infor- mally referred to as “the death triangle.” Since 1975, Baris has been investigating this malignant mesothelioma in these three villages in Nevsehir, Turkey, and he has maintained all patient records of this disease including chest x-rays and personal health statistics. He also gathered the data on the death records of patients who had died of 250 Chapter 15 Malignant Mesothelioma and Erionite

mesothelioma and other cancers in these villages in Turkey or abroad (i.e., Karain colony villagers in Sweden). Epidemiologic records for these eight villages between the years 1994 and 1997 have been studied. An extremely high rate of cancer in the young-to-middle-age group was observed in the study area. In vitro and in vivo studies performed by the International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) also indicate that there is enough evidence to conclude that these ﬁbers are carcinogenic and that the cancer rate in this region is about 1000 times more than the normal rate.

Genetic Studies Suggest Predisposition to Erionite Carcinogenesis

Since erionite was elevated to the group status in 1997 there have been no studies performed that quantitatively characterized erionite-Na, erionite-K, and erionite-Ca in the various erionite villages. Thus we do not know to what types of erionite these villagers are exposed. Family pedigree analyses conducted in the village of Tuzkoy suggested that the carcinogenicity of erionite was more pronounced in certain families. Families with a high incidence of erionite were identified, while in other families living in the same village the incidence of mesothelioma was low. It did not appear that these differences could be explained by different exposures to erionite since all villagers should be exposed to similar amounts of erionite dust. Previous studies suggested that erionite was carcinogenic at very low doses compared to asbestos (77). Thus, the hypothesis of genetic predisposition to erionite carcinogenicity was formulated (4,6). However, this hypothesis must be verified in the other two mesothelioma villages of Karain and “Old” Sarihidir. Moreover, the hypothesis that mineralogic differences among houses within the same village is not responsible for the different incidence of mesothelioma among families in the same village should also be verified by quantitative characterization of the erionite found in these houses. It remains to be demonstrated that there are no chemical differences among different houses in the same villages, or among nearby villages, that could account for the different incidence of mesothelioma. Our research team is investigating these possibilities.

Erionite in Turkey

Previous studies reported that erionite was found only in the three villages of Karain, Sarihidir, Tuzkoy, and that the neighboring villages of Karacaoren (also called Karacaviran) and Yesiloz (also called Tahar) were reported as nonmesothelioma villages by Temel and Gundogdu (51). In contrast, our detailed geologic and mineralogic study of the region showed that erionite is not conﬁned just to these three villages (111,112). In fact, the Karacaoren village is also contaminated with erionite both in the bedrock and the wall rock. Subsequent epidemiologic studies showed that the previously reported nonmesothelioma villages such as A.U. Dogan 251

Karacaoren had a high rate of mesothelioma. Therefore, it was estab- lished that there was a direct relationship between erionite and nonoc- cupational malignant mesothelioma in all of these villages in the region. In Central Anatolia, Turkey, eruptions of volcanoes, mainly Erciyes (3917m) and Hasandag (3268m), caused the region to be covered with a thick stratum of lava, volcanic ashes, and a dense tuff layer that formed on the earth’s surface. In the Cappadocian region, tuffs accu- mulated in topographically low areas through both direct airfall con- tributions and the reworking of larger widespread ash mantles. In time, natural factors such as rain and wind created extraordinary shapes, deep valleys, and natural sculptures of fairy chimneys in the tuff formations of this Cappadocian area. Single-tuff deposits consist of successive accumulations of ash from more than one eruption event. Following deposition, tuffs have undergone a series of geochemical changes involving an early dissolution of glass surfaces and precipita- tion of grain coating smectite, followed by erionite growth in the pore spaces. A chemical environment of increasing alkalinity is suggested to explain the observed mineralogic changes. Activity diagrams of zeolites by Birsoy (113) also support this theory. In the United States there are deposits of fibrous zeolites specifically in the western portion of the country. There are homes made of zeolite (erionite) in Oregon and weigh stations made of the same materials in Nevada. Very large amounts of zeolites were also used in pozzolanic cements such as those used in the construction of the Los Angeles aque- duct in California. Recently, a few cases of zeolite-related pulmonary diseases have been reported in the U.S. Therefore, the possibility of increased exposure to zeolites in the western U.S. is anticipated and potential carcinogenic dangers must be evaluated. Erionite is the only zeolite whose evidence of carcinogeneity has been evaluated. It is classified as a human carcinogen by the IARC (114). In Turkey, erionite-contaminated villages in the Cappadocia 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 higher than the normal rate. The local saying, “I don’t know my father and my father doesn’t know his father,” indicates that the cancer has been there for centuries. This problem requires worldwide immediate attention. Although both the exposures and biologic mechanisms are complex, we hope that the multidisciplinary medical geology studies, which combine high- resolution mineralogy and human genetics, will help us understand and control this very malignant human disease.

Conclusion

Mesothelioma, malignant pleural mesothelioma (MPM), or malignant peritoneal mesothelioma (MPeM), is a very lethal disease. Clinical and experimental studies have conﬁrmed a carcinogenic linkage to 252 Chapter 15 Malignant Mesothelioma and Erionite

erionite, a zeolite-group mineral. In 1975 an extremely high rate of MPM incidence was observed in some villages in the Cappadocian region of Turkey. Further studies showed that the erionite type of zeolite minerals, not asbestos, was the major cause of the epidemic in this area. The high potential of erionite to induce MPM has been confirmed by both epidemiologic and experimental studies. The World Health Organization (WHO) classified erionite, a zeolite group mineral, as a group I carcinogen (114). The classification is based on evidence in humans, specific diseases from occupational exposures, and health effects noted in animal and cell experiments. Three types of erionite have been described: erionite-Na, erionite-K, and erionite-Ca (10,11). Erionite is observed in the previously reported villages and also in several new villages in the Central Anatolian region of Turkey (111,112).

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