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Editorial________________________ Asbestos and Cancer: The International Lag' By the early 1940s, the question of whether asbes tos caused lung cancer seemed to have been set tled. Asbestosis, the fibrotic changes in the lung resulting from the inhalation of asbestos fibers, bad been recognised for more than 40 years. In 1934 in England, Wood and Gloyne (1) reported 2 cases of lung carcinoma seen at autopsy in 43 cases of asbestosis, and in 1935 Gloyne (2) gave a complete description of these 2 cases. Also in 1935, Lynch and Smith (3) reported one case of lung cancer in an asbestosis case in the United States, and in 1936, Egbert and Geiger (4) re ported a case--also from the United States. In Germany, Nordmann added 2 cases of lung can cer in 2 cases of asbestosis, thus making a total of 6, and concluded, "A cause-effect correlation must be present here, even if 1 had been the only observer. We are indeed facing an occupational cancer which affects asbestos workers" (5). Ger man investigators quickly accepted Nordmann's views (6-6). They were reinforced by an ani mal study in which Nordmann and Sorge report ed pulmonary carcinomas in 2 white mice as the result of asbestos dust inhalation (9). Other Ger man researchers considered this the experimen tal evidence needed for proof and gave Nordmann credit for discovering the relationship be tween asbestos and lung cancer (10, 11). Mean while, in the United States, Hueper declared that, "Aslsestosis cancer of the lung is the most re cent newcomer among the occupational cancers of this organ" (12). In 1950, West Germany class ified cancer of the lung, when associated with asbestosis (of any degree), an occupational dis ease. And yet, in the United States the question of asbestos and lung cancer was debated for another 20 years. What prolonged the debate and pre vented earlier acceptance of a relationship?. i Based on an unpublished manuscript: Asbestos and Cancer, The First Thirty Years. First, Gloyne, to whom credit for the discovery should really have been given, was extremely cautious in interpreting his findings. In his re port of 1935, Gloyne quoted Bridge and Henry (13) on conditions that must be fulfilled in or der that cancer be classified as industrial in ori gin: (I) the incidence in the occupation under review should exceed significantly that in the general population, and (2) in the occupation concerned, there should be sufficient association of the workers with a substance proved experi mentally to have carcinogenic properties. In Gloyne's lifetime, these conditions were not fulfilled. Nearly all of the evidence dealt with the association of asbestosis and cancer as seen at autopsy. In a paper published posthumously in 1951. Gloyne expressed concern for the selection obviously at work in picking cases for autopsy, pointing out that necropsy records at the Lon don Chest Hospital showed 21.3 per cent primary lung cancer, whereas in the general population, only 2.4 per cent of deaths from all causes among persons 15 years of age and more were due to malignant disease of the lung. Lyndi, who actually received credit in the end, was no less skeptical. He was concerned not only with the problem of selection, but also with the lack of experimental evidence (14-19). Only Nordmann and Sorge claimed to have pro duced cancer experimentally with asbestos, whereas experiments by Vorwald and Karr (20), King and associates (21), Vorwald and co-worken (22). Behrens (23), and Hueper (24) had negative results. Moreover, W. E. Smith (25), in a review of work with asbestos and animals, con cluded that the study by Nordmann and Sorge appeared to demonstrate that asbestos did not provoke lung tumors, because of the 2 tumors re ported in animals exposed to asbestos, one was, on the basis of photographs presented, merely a squamous>ceJf metaplasia, whereas the other, as serted to be an adenocarcinoma, "is a type of tu- AMERICAN REVIEW OF RESPIRATORY DISEASE. VOLUME MS. 1971 975 AFC 003601 976 EDITORIAL mor that can arise spontaneously from the mouse adenoma." Even Hueper seemed to agTee with this, and outside of Germany, Smith's views on Nordmann's work gained some acceptance (19, 26,27). Another problem in the United States was the attitude of leaders in the held of pneumoconio sis--particularly Vorwald, Lanza, and Gardner (20, 22, 28-32). Their expressed concern was the lack of experimental data. In addition, the possibility of a different relationship between asbestosis and lung cancer as compared to that between silicosis and lung cancer must have been disturbing. Lanza was also concerned about the English claims of an association in autopsied cases of asbestosis, and he wondered how many cases of lung cancer would be found if lungs from any sort of population were subjected to the same minute scrutiny (29). The situation could have been resolved, from the American point of view, by a report by Merewether (33) who, in 1949, compared lung or pleural cancer in cases of asbestosis reported for compensation with lung or pleural cancer in ca ses of silicosis. This was clearly the most impor tant single study in bringing about a consensus in Great Britain. In America, however, this seems 'o have given birth to a new idea: that there was a relationship between asbestosis and cancer in England and Germany, but not in the United States. This idea apparently originated with W. E. Smith: however, another Smith (K. W.) en larged on this, stating that there was a difference due to the type of fiber used in England and Ger many as compared to that used in the United States (34, 35). Italian writers picked this up as an argument for a difference between Italy and England (36, 37). The argument was also re peated by Eckhardt (38), Gilson (39), and John stone and Miller (40). There was no answer to the question of fibeT type (or fiber contamination), and it no doubt delayed acceptance by those who were uncer tain as to whether a problem truly existed in the United States. There was. however, an answer to the question of selection that so bothered Gloyne and Lynch. In 1955, an epidemiologic study was reported of the type envisioned by Bridge and Henry in which it was shown that the incidence of lung cancer in a group of worker* exposed to asbestos in England greatly exceeded that in a comparable group in the general popu lation (41). This marked an end to a period when conclusions were based largely on patho logic and clinical observations, and opened the door for contributions by biostatisticians and epidemiologists. It probably also set back acceptance of a relationship between asbestos and can cer in the United States by another decade. The epidemiologists demanded epidemiologic evidence. In 1956, for example. Hammond and Machle (42) stated that with regard to a relation ship between asbestos and lung cancer "... there are at present too few cases and coo little epi demiologic data to establish a significant rela tionship." In 1958, the Committee on Occupa tional Cancer of the AMA Council on Occupa tional Health concluded that individual case re ports contribute little to an understanding of occupational cancers and that "specific increases in age, sex, and site-specific cancer incidence above normal incidences for the same age. sex, and site represent the only reliable evidence for the existence of an occupational cancer hazard" (43). The first 2 epidemiologic studies of this kind of workers exposed to asbestos in North Ameri ca in 1958 and 1960 did not show a significant increase in lung cancer (44, 45). Thus, as re cently as 1961, it could be said that "there is no epidemiological evidence [of an association be tween asbestos and lung cancer] among Ameri can workers" (46). So what ended the debate in the United States? Probably 3 things: (7) positive results of epi demiologic studies in the United States in 1963 and 1964, (2) a widely read study of 1960 that showed that asbestos was associated with a rare tumor, malignant mesothelioma, and ()) exper imental evidence in 1962 and 1964 that asbes tos had carcinogenic properties (47-51). Thus, the kind of evidence demanded by Bridge and Henry, and which would have satisfied Gloyne. was finally developed 30 years after Gloyne made his initial observations, and more than 2 decades after the acceptance of a relationship between asbestos and lung cancer in Germany. Clearly, the matter involved a question of what is acceptable and conclusive evidence. Perhaps special rules are needed for relationships such as that between asbestos and lung cancer where some other biologic response, such as asbestosis, can be used as evidence of significant exposure, and the rules proposed by Bridge and Henry were not appropriate after all. Many investiga tors were convinced of a relationship long before epidemiologic and experimental evidence was -available. Aside from the high incidence of lung cancer in patients with asbestosis, they were im pressed by the predominance of cancer in the APC 003602 EDITORIAL 977 lower lobes, the time lapse between exposure and disease, the high incidence in women, and the young age of many of the patients seen. More over, there were reasonable theories concerning mechanisms by which asbestos could cause can cer. In any event, the issue was definitely settled for the United States at a conference on the biologic effects of asbestos held in New York City in 1964 (52). At that conference, additional epi demiologic evidence was presented, and of 20 papers presented in which an opinion was ex pressed, none dissented from the view that as bestos is a cause of cancer. Philip E. Enterline Professor of Biostatislirs Graduate School of Public Health University of Pittsburgh Pittsburgh, Pa. Rafarancas 1. Wood, W. B,, and Gloyne, S. R.: Pulmonary asbestosis: A Review of One Hundred Cases, Lan cet. 1934,2, 1383. 2. Gloyne, S. R.: Two cases of squamous carcinoma of the lung occurring in asbestosis. Tubercle, 1935,77,5. 3. Lynch, K. M.. and Smith. W. A.: Pulmonary asbestosis. III. Carcinoma of the lung in asbestosilicosis. Am J Cancer, 1935, 24, 56. 4. Egbert, D. S.. and Geiger, A. J.: Pulmonary asbestosis and carcinoma: Report of a case with necropsy findings. Am Rev Tuberc, 1936, )4,143. 5. Nordmann, M.: Der Berufskrebs der Asbestarbeiter, Z Krebsforsch, 1938,47,288. 6. Homig, F.: Klinische Betrachtungen zur Frage des Berufskrebes der Asbestarbeiter, Z Krebs forsch, 1938,47,281. 7. Teleky, L.: Der berufliche Lungenkrebs, Acta Union Intern Contr Cancer, 1938,5, 253. 8. Baader, E. W.: Aibestose, Dlsch Med Woehenschr, 1939,6S, 407. 9. Nordmann, M., and Sorge. A.: Lungenkrebs dutch Asbestaub im Tierversuch, Z Krebsforsch. 1941,37,168. 10. 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Arch Ind Health. 1958,17,634. 45. Dunn, J. E,, Linden, G., and Breslow, L.: Lung cancer mortality experience of men in certain occupations in California, Am J Public Health. 1960,30(2), 1475. 46. Johnstone, R. T.: Silicosis and cancer [questions and answers], JAMA, 1961,17S, 353. 47. Mancuso. T. F., and Coulter, E. J.: Methodology in industrial health studies: The cohort ap proach with special reference to an asbestos company, Arch Environ Health. 1963.6,210. 48. Selikoff, I. J., Churg, J., and Hammond, E. C.: Asbestos exposure and neoplasia, JAMA, 1964, 1SS. 22-26. 49. Wagner, J. G, Sleggs, C. A., and Marchand, P.: Diffuse pleural mesothelioma and asbestos expo sure in North Western Cape Province, Br J Ind Med. 1960.77.260. 50. Wagner, J. C.: Experimental production of mesothelial tumours of the pleura by implantation of dusts in laboratory animals. Nature, 1962. 196. 180. 51. Smith, W. E-. Miller. L., Churg. J., and SelikoS, 1. J.: Pleural reaction and mesothelioma in hamsters injected with asbestos [abstract], Proc Am Assoc Cancer Res. 1964, S, 59. 52. Biological effects of asbestos (article 1), Ann NY Aad 5ci. 1965. pp. 1-766. APC 000604