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' (<(,j5KvV\^o The Relationship Between Lung Cancer and Asbestos Exposure* Takumi Kishimoto, M.D.; and Kcisei Okada, M.D. NiosH-ooie2aio This study supports the theory that asbestos exposure may be implicated ir. a recent upsurge of terminal lung cancer cases in Kure, Japan. The number of asbestos bodies found in the lung during autopsy of 158 subjects from 1984 to 1986 suggests that 70.4 percent of the 51 diagnosed lung cancer cases could be attributed to asbestos exposure. Of the 107 subjects in whom death was not caused by cancer. 38.4 percent had significant asbestos exposure. Types of asbestos bodies found in diagnosed lung cancer cases were analyzed using scanning electron microscopy and x-rayanalyzer. Chrysotile was the most widely found component. but amphiboles such as crocidolite and amosite also were detected. Residents of Kure had high exposure to the inhalation of asbestos bodies, possibly related to the upsurge in lung cancer deaths. In our earlier report, asbestos exposure was implicated in the increased incidence of malignant mesothelioma in Kure, an active Japanese ship building port since the 1920s. Our current findings indicate that asbestos exposure may be a pathogenic factor in lung cancer in world seaports where asbestos exposure has been prevalent. (Chest 1988; 94:486-90} T^rom 19S-1 through 1986, there was a significant increase in the rate of death from lung cancer in Japan. This increase is particularly evident in the male population and in certain geographic areas including Kure, Japan. We previously reported a similar increase in the death -ate front malignant mesothelioma and provided evidence for an etiologic relationship to asbestos exposure. In the current study, our data suggest that asbestos exposure may also be the under lying cause of the recent upsurge in lung cancer. Material and Methods In the three-year period from 1984 to 1986. iuitnp'iy was per formed at Kure Kyosai Hospital on 158 patients who had resided in the city or suhurDS of Kure, Japan. Fifty-one cases were of Inns: cancer and seven malignant mesothelioma, and 100 were nonesmcerous. The number of asbestos Ixxlies in the lung tissue of these 158 cases were counted by the modified method of Smith and Naylor.1 Briefly. 1 g of lung tissue (inferior lobe without tumor involvement) was lysed in sodium hyjjochlorite for 4-S hours. Asbestos bodies were separated by the use of equal volume <20 ml) ofchloroform (Wako) and 50 percent ethanol (Waku) am! centrifuged at ISO g for five minutes. The bottom fraction was filtered on 5M-m Milliporc fiber. Finally, the number of asbestos IxxJies were counted on the filter hv light microscopy (x 2(X)>. For cases with 'mg cancer. we recorded sex. age. histology lateral involvement, originating lobe, smoking history, occupational bislorv and the duration of asbestos exposure. Detected asbestos 1 ><.)<, were coated with carbon, then analyzed by using scanning electron microscopy (T-330. JEOL) and x-ray analyzer (Seiko). The type of asbestos bodies was determined according the UICC standard reference.1* For identification, we measured the types and percen tages of metals in the asbestos bodies and determined the kind of asbestos bodies. Wc analyzed at least 20 asbestos Ixxlies in each From the Department of Clinical Investigation. Kure Kyosai Hospital. Kure, Japan. * Manuscript received September 8; revision accepted February 2. Reprint requests. Dr. Kishimoto, 2-3*28 Xishlchvo, Kut Chi/, jo/vm 73f 486 caw. Asbestos bodies were also counted in nom;nic<*v cases; 15 cases of cerebral vascular accident (CVA'. 27 myocardial infarction, eight tuberculosis of the lung. 21 liver eirrhoris. )8 pneumonia, and !1 others (two hypoplastic anemia, two sepsis, three renal failure, three diabetes mellitus. and one suicide/. For control, we referred to the number of asbestos bodies found in aulopsied lungs in other parts of Japan .and estimated the baseline of the significant number of asbestos bodies per 1 g of lung lissue.4 ' In this study we used nonparametric analysis using the Krushal-Wallis one-way analysis of variance and the multiple comparison method of Dun.*1 _ Rksclts Figure 1 .shows the number of asbestos bodies per gram of lung tissue in lung cancers, mesotheliomas, and noneancer patients. All patients with malignant mesotheliomas had asbestos bodies numbering more than 500/g of lung tissue, whereas 36 of 51 (70.6 percent) patients with hmg cancer had more than JOO/g (up to 3<SJ .025/g). This is significantly (p<0.01) higher than that of noneancer eases {38.6 percent). In the noneancer group there were 18 eases whose count of asbestos bodies exceeded 500/g. All of these cases had established occupational histories of asbestos ex posure. but the other 36 patients did not have definite occupational histories of asbestos exposure. Figure 2 shows the classification of eases with Umg cancer according to sex. Of the six cases in women, two had more than 100 asbestos hodies/g. By contrast, 75.6 percent oT eases in men had more than 100 hodies/g. The difference is statistically significant (pcO.OJ). All of (lie men had occupational histories of asbestos exposure. Figure 3 rbwsifies the cases of hmg cancer according to histologic diagnosis: 21 cases of squamous cell carcinoma. 24 adenocarcinoma and large coll carci noma, and six small cell carcinoma. The a\trage number of asbestos bodies in the squamous cell t\pe Lung Ctncr and Absto Exposure fKishfmofo. OfcMfeJ O 381025 O 89740 O 15514 ' 10123 Fk:i hk I. Number of usbesJos !xxiit" per uram oflnne Iismu- in cases without cancer and in patients who died from hme cancer and mevnlheliotna Number of ;isl>rstos bodies in case> with lun.c cancer and mesothelioma is .significantly hither ip<O.OJl than that of m>j)canccr cases: lung cancer. 10,-132" 7.77-S: mmcMmrr. tuesoihclioma. 37,IIS - 19.723. was higher than those of other types, especially compared with the small cell type. Cases with rifiJit lung involvement (4.065 1.974) had more asbestos bodies than those of the left side (19,952 19.02S), arid those in the superior lobe (17.481 13.338) more than inferior (698 238). According to the smoking history o' these 51 lung cancer patients. 36 were more than 400 by the Brinkman Index (BI!.: The women patients were not heavy smokers, hut 78.6 percent of the men were heavy smokers. Occupational history indicate:) that 25 of these men worked in the Japanese naval shipyard before or during World War 11. Another six patients had occupational histories in other ship yards A total of 36 eases had definite history of asbestos exposure. The duration of asbestos exposure in these cases was six months to 48 years (average, nine sears). Occurrence of death following initial exposure was 15 to 48 years (average. 27 years). Chrysatile was the major component ofasbestos bodies l-'tiutu: 2. Dislrilmtiim of tunc cancer according tn sex. Tire 6 cases in oilmen had cnmuierahly Icwi-r asbestos bodies than men. Occupational hislorv in males may explain this difference. Male. 11,339 8.450: female. 129 - 79. ' detected in lung tissue of patients with lung cancer. Figure 4 shows typical results of analysis ofan asbestos bods' found in a lung cancer case. According to the percentages of Mg. Ca. Fe. and Si. we determined this asbestos body to be ebrysotile. Some crocidolites and umosiles also were found. Ordinarily we would expect to find these three types of asbestos in the same patient, but ehrysotiles were the main compo nent found in 70 percent of patients with lung cancer. Discussion The incidence of lung cancer, which has recently increased in Japan, has shown a pronounced upsurge in sp cific regions such as Kurc City in Hiroshima Prefecture, particularly in male patients (Table 1). CHEST ' 94 / 3 ' SEPTEMBER. 1988 487 >500- o ?a o tOI?? O it O 2i85 O O MIMS '5iu 0 O O Soua'rous ce'i carcinoma Adenocoarrcinoma Small coil carc-noma Large cell carcinoma =?! >- 6 Fk:ure 3. Distribution oflung cancer ciises according to histology A higher ntimbe- of asbestos bodies was seen in patients with squamous ccM carcinoma and adenocarcinoma. There is a significant difference between squamous and small cell cases (p<0.0H Squa mous cel! carcinoma. 6.121 -- 4.675: adenocarcinoma, and large cell carcinoma 13.51S ~ 12.865; small cell carcinoma. 134 g: 53. 1N-5500AXXR-&4O X-ray Rnalyser Cursor: 0.000keV = G ROl Japan is a major industrial country in which asbestos minerals have been utilized for about 50 years. Since the 1920s, Kures naval shipyards have been wellknown, and shipbuilding has continued in Kure and its suburbs since 1945. Most male residents over 70 years old have had at least some occupational connec tion with naval shipbuilding in Kure. We recently documented that the recent upsurge of incidence of malignant mesothelioma could be related to asbestos exposure." This is consistent with several other reports demonstrating asbestos exposure in ship yards.910 In the present study we extended our work to cancer of the lung. We evaluated 51 cases of lung cancer on whom autopsy was done in an attempt to relate the appearance of cancer to asbestos exposure. To estimate the extent of asbestos exposure, we set a limit of 100 asbestos bodies/g of lung tissue as the baseline. This measurement is high enough to compare the volume ofasbestos bodies detected in any Japanese person with asbestos exposure4-5 as well as to compare data with other reports." 11 According to this criterion, 70.6 percent of patients with lung cancer had more than baseline asbestos exposure than 38.6 percent of noncanccr patients. In addition, almost all of them had an occupational history of work in Japanese naval shipyards. Therefore, it is likely that asbestos exposure is an etiologic factor in the recent upsurge in lung cancer in Kure City These patients were also heavy cigarette smokers (B1 more than 400), and smoking is thought to be an important factor in pathogenesis of asbestos-induced lung cancer.11" The latency of lung cancer after KR1 12-DEC-36 15:23 CO') 3.120: 3.420 . Fiontr. -I. Typical analysis of an asbestos lastly from a lime earner case. Acvssnlini! In the VICICI stambml reference, wc determined ibis Imtly to be chrysolite. 488 Long Cancer ane Asbestos Exposure fKrSWmoto. Okeot)  V Tabic I---Cancer and Lung Cancer Mortality in Males Exposed to Asbestos in Kure, Japan, Compared with Other Parts ofJapan, 1985S7 Kure Hiroshima Average, Year No. City Prefecture J;ip;m 1985 Total cancer cases in Kure /31 Lum: cancer cases in Kure 70 30.5' Male: Total cancer cases 255 Lung cancer cases 50 44.7 Female: Total cancer cases 176 19-S6 Limp cancer cases 20 17.0 Total eaneer cases in Kure 42: Lime cancer cases in Kure 73 31.8 Male: Total cancer cases 2-SI Emus cancer cases 5S 51 8 Female: Total cancer cases 146 Luntl cancer ease* 15 13.7 25.9* 37.2 13.1 25.6 3-8'. 0 M. I 23..V M.fi 12.3 23.S .35.3 12.7 Ter HI KXI asbcstus exposure is estimated to be more than 20 years. Onr data were consistent with those of Bulilig and Otto.15 Three major kinds of asbestos bodies (ehrysi:tile, crocidolite, and amosite) induce cancers. Amph holes such as crocidolite and amosite are the major components of asbestos bodies thought to be involved in the pathogenesis of lung cancer.'" o Other articles describe chrysotile-induced lung cancer.1' Interestingly, ehrysotile is the major component in onr eases, and crocidolitcs and amosites were dominant in only 30 percent of cases with lung cancer. In all of our cases, ehrysotile and amphibolous were mixed together in cases of lung cancer, a result consistent with that of the Howard report.1,1 According to the histologic type, squamous cell carcinoma had a much higher incidence, and small cell types were rare in our series. Most eases originated on the right side, with higher incidence in the inferior lobe. Adenocarcinoma and inferior lobe origin were dominant in other reports of asbestos-induced lung cancer.5111 In long-term cigarette smokers, squamous metaplasia occurs and replaces the normal ciliary epithelium.24 The presence of smoking history in addition to ehrysotile exposure could be responsible for this discrepancy. Some investigators have indicated that the baseline number of asbestos bodies in 5 g lung tissue is less than ]()0.'15 jr We think that this baseline is too low: and 100 per/1 gram lung tissue is a more realistic figure. Geographically, Kure City is surrounded on three sides by mountains and on the fourth side bv the Japan Inland Sea. Since the 1920s, shipyards have been the major economic resource of the city, and eonsequentlv exposure to asbestos has been universal. Because of the relative latency of asbestos-induced cancer, the upsurge in incidence of asbestos-induced cancer has- been expected to peak in the 1980s, and we think that the recent upsurge in lung cancer may be explained on this basis. Refehences 1 Smith MJ, Naylor B. A method for extracting ferruginous bodies from sputum and pulmonary tissue. Am J Clin Pathol 19<2; 58:250*5-4 2 Timbrel] V Gilson JC, Webster I. U1CC standard reference samples of asbestos. Int J Cancer 1968; 3:406-08 3 Larger AM. Rubin Hi, SelikolUJ. Chemical characterization of asbestos body core by electron microprobe analysis. J Histochem Cylochcm 1972: 20:723-34 4 Matsmbi M. A study of the asbestos body: detection of the asbestos body from the autopsy hmij. Jpn J Iborac Ois 19/5; 13:40-43 5 Morai V. Kitagawa M. The number of asbestos booies from the autopsy lung in Hnkuriku area. Japan. Lung Cancer 1984; -24:239-45 6 Hollander M. Wolfe D. Nonparamelrie statistical methods. New York: John Wiley &; Sons. 1973 7 Stevens RG. Mnohjavkar S'H. A cohort analysis of hint,' cancer and smoking in Rritish males. Am J Epidemiol 1984. 119:624 41 8 Kishimoto T, Okada K, Sato T, Onu "I, ito H. Evaluation of the pleural malignant mesothelioma patients with the relation of asbestos exposure. Environ Res tin press' 9 Srlikoir 1J. Lilis R. Nicholson Wj. .Asbestos disease in Enited States shipyards. Ami NY Acad Sei 1979: 330:29.5-311 10 Harries l'G. Experience with asbestos disease, and its control in Great Rritain Naval dockyards. Environ Res 1976; 11:261-6/ 11 Riirnon J. Coni J. Botmaud G. Incidence of pulmonary ferrugi nous bodies in France. Environ Res 1970: 5:430-42 12 Hoj:eli V Greenberg SD. Seit/.man UK MeGavran MM. Hurst _ GA. Spivey CO. ot al. Pulmonary fibrosis, carcinoma and * fernminnm body counts in amosite asbestos workers. Ain J Clin Pathol J9-S0: 73:496-503 13 Sclikoll 1J. Hammond EG. Churn J. Asbestos exposure, smoking and neoplasia. JAMA 1968: 204:106-12 14 Hammond EC. Selikoll" JJ. Seidman H. Asbestos exposure, eiuarette smoking and death rales. Ann NY Acad Sci 19.9. 330:473-90 15 Bnfd/i! H. Otto H. Asbrst uru! Mesothelioma. .Stuttgart: Ihiemr \erlaji, 1975 16 Aclierson ED. Carden MJ. Asbestos; final report of the advisory committee. 1-ondon: HMSO. 1979 17 Royal Commission on Matters of Health and Safety. Canada. Report ol the Royal Commission on Matters ol Health and Safety arising from the use of asbestos in Ontario. Toronto: Ontario Ministry of Government Services. 1984 IS Umtier AM. Selikolf IJ. Sartre A. Chrysolile asbestos in the him!* of persons in New York Gitv. Arch Environ Health 19.1: 22:348-61 19 Aclierson Kl). Gardner MJ. Asbestos, the control limit for asbestos; an update of the relevant sections of the ill ellects of asbestos upon health. Health ami Safety Commission. Condon: HMSO. 198.3 26 Howard IK. Relative cancer risks from ex|xsuiv to dilleivut asbestos fibre types. N Z Med J 19S4: 26.646*49 21 Kannerstein M. Clmn! J. Pulholony of carcinoma of the loins associated with asbestos exposure. Cancer 1972; .MhU-fH 22 Warnoek ME. Churn AM. Association of asbestos and homehnurine carcinoma in a population with low aslieslos e\|>osmv. Cancer 1975; 3-5.12.36-42 23 Riilie P Ktiolmtical and hisfolncica) slutlv of 448 cases ol hmu eaneer. Ann Intern Met! 1981. 132:12-18 CHEST 94 3 SEPTEMBER. '986 489 24 Woodworth CD. Mossman BT. Craighead )E. Squamous meta plasia of the respiratory tract--possible palhocertic role in asbestos-associated bronchogenic carcinoma. Lab Invest 1983: 48:578-84 25 Rosen R Melamed M, Savino A. The "ferruginous body' content of lung tissue: a quantitative studv of eighlv-six patients. Acta Cyto! (Baltimore) 1972; 16:207-11 ' ' 26 Sera Y. Komshiike J. The defection of asbestos bodies in the lung at random autopsies and surgical pulmonary resection. Irvo 1974; 30:1125-31 27 Chnrg A. Warnock ML. Correlation of quantitative asbestos body counts and occupation in urban patients. Arch 1'alhrji 197#; 101:629-30 AMA National Conference on Impaired Health Professionals: Visions and Values The American Medical Association will present this conference, co-sponsored by other health professional organizations, at the Chicago Marriott Hotel. October 26-30. The purpose cf the conference is to encourage development of programs that include the major components of prevention, education, case-finding, intervention, treatment referral, aftercare/monitoring and re-entry/retraining to encourage an increased level of funding for such comprehensive programs; and to better help those programs provide rehabilitative help while ensuring public safety. The conference will bring together the varying disciplines and organizations concerned with the impairment and well-being of health professionals and l<> stimulate the creation of working relationships among these based on common concerns and mutual respect so as to better utilize existing resources. In addition, the conference will provide a forum for the interchange of ideas and approaches that can be replicated to help programs function more effectively. The conference welcomes anyone involved, or wishing to become involved, in programs to identify; treat, rehabilitate or discipline health professionals suffering from alcoholism, drug dependence, psychiatric illness or other potentially impairing problems, such as hospital administrators, risk managers, and medical staff coordinators; licensing board members, staff, investigators: deans/faculty members from medical and dental schools, etc; residency training chrectors/programs directors and staff/professionals in training: spouses of physicians and other health professionals: professionals in recovery: treatment providers. For information, contact the AMA Department of Registration Serv ices. 335 North Dearborn Street, Chicago 60610 (800-621-S335).