Document bBN2yqQO7Xzmvbm6Q88eeXzD6

*IOS MINING Quebec. Canada September. 1957 Industrial Hygiene Foundation of America. Inc. '* 4400 Fifth Avenue Pittsburgh 13, Pa. . ft AN EPIDEMIOLOGICAL STUDY OF LUNG CANCER IN ASBESTOS MINERS For QUEBEC ASBESTOS MINING ASSOCIATION Quebec, Canada July, 1956 to July, 1957 By- Daniel C. Braun, M.D. Medical Director * September, 1957 By: Richard Walmer, M.D. Managing Director TABLE OF CONTENTS P*K Foreword.............................................................................................................. ` Clouary...................................................................................................................... iv I. Introduction.............................................................. 1.............................................. 1. 12. Critical Review of Literature................................................................... 5 HI. Principles of the Epidemiological Method.................................. 13 TV. Collection and Analysis of Data............................................................. IS V. Results'and Interpretation........................................................................ -6 Asbestosis and Lung Cancer.............................................................. Comparison of the Cohort Experience with that of the Province of Quebec, Dominion of Canada, and theUnited States.......................... 55 Comparison Between Eight Counties Adjacent to the Asbestos-Producing Areas and Eight Solocted Counties.............................................. v Discussion of All Recorded Lur.g Cancer Cases, Living and Dead, at Asbestos and Thetford Mines. .......................................... ...................................... ..... . 66 68 VI. Summary and Conclusions ......................................................................... 71 VII. Bibliography...............................................................................................................78 FOREWORD The success of * study of the type herein reported de pends very greatly upon the availability of data from many sources, and the assistance and cooperation of those in possession of these data. Industrial Hygiene Foundation was fortunate in having the wholehearted cooperation of the asbestos-producing companies, and particularly of their medical and nursing personnel who have the re- l sponsibility for maintaining the medical records of the workers. In this connection, we are especially indebted to Dr. Paul Cartier and his staff at the Thetford Industrial Clinic, and to Dr. T. R. Grainger and the nurses at Asbestos. All records in these two medical cen ters were put completely at our disposal, and she care and complete ness with which they are maintained assisted considerably in the preparation of the material relative to the worker population. Data on population figures and on the causes of death in the Province of Quebec were obtained with the utmost assistance and co operation from Dr. Paul Parrot, Head of the Department of Demogra- a phy in the Ministry of Health. Not only were all vital statistics and reports made readily available to us. but Dr. Parrot and his entire staff rendered valuable assistance in many ways, including the location and interpretation of death certificates. Especially helpful in this part of the work was Miss Gauthier of Dr. Parrot's staff. _The jame helpful I * _ "t _ v:? * -- cooperation was rendered by Messrs. Hardy and Hopkins of the Sun Life Assurance Company of Canada in Montreal, who made available their record* of the death claims paid under Che group policy cover ing the workers at Asbestos. Valuable suggestions for the conduct of the study were made by Dr. J. A. Vidal, Chairman of the Silicosis Board, and Dr. Guy, Pathologist for the Board, as well as Dr. Gregoire. Deputy Minister of Health for the Province of Quebec, and Drs. Sircard. Duiresne, and Grouix, in Montreal. Statistics for the mortality rates for the Dominion of Canada were obtained through the kindness of Dr. Dean F. Davies, Administra tor for Research on Lung Cancer for the American Cancer Society, and those for the United States were graciously furnished by Miss Guralnick in the National Office of Vital Statistics, Department of Health, Education, and Welfare of the United States Government. Finally, the very great assistance rendered by Dr. Kenneth W. Smith. Medical Director of JohnsManville Corporation, and Mr. Ivan Sabourin, General Counsel for the Association, ih making the necessary contacts, in travel arrangements, and in so many other ways, is gratefully acknowledged. The methodology of this research is believed to be unique among the reported studies of lur.g cancer as related to asoestosis and exposure to asbestos. Assistance in planning the study in such a way as iii. to assure a proper epidemiological approach, and all biostatistical application* of the findings were provided by Mr. T. David Truan, formerly of.the Graduate School of Public Health, University of Pitts burgh, and the staff of the Industrial Hygiene Foundation. The report is believed to present the findings in an objec tive manner and is respectfully submitted for the consideration of the Association. 1 GLOSSARY For the purpose o clarity and uniformity, the terms used la this report are herewith defined according to the manner of their use. Asbestos workers: Workers exposed to asbestos dust in other than mining operations. Asbestos miners: Workers engaged in the mining and prepara tion of asbestos in the areas under study. Asbestosis: A generalised fibrosis of the lungs diagaosable by x-ray, or by microscopic examina tion of the lung tissue, but not necessarily accompanied by symptoms or by disability. Cohort: A segment of the population, defined accord- . iag to certain criteria, and representative of the whole population. Specifically in this study, a group of asbestos miners having at least five years of exposure in the industry and who were in the industry during 1950. Lung cancer, cancer of the lung: A neoplasm of the lung or bronchus, wher ever situated, and including adenocarcinoma, squamous cell, and undifferentiated, round, or "oat cell" histological types. Primary cancer of the lung means such a neoplasm originating in the lung, and not secondarily in the lung as the result of a metastasis from another primary location in the body. Smoker: As used in this presentation, the term smoker refers to a cigarette smoker, habitually smok ing more than five cigarettes per day. Persons who smoke pipes or cigars exclusively were not considered to be smokers for the purpose - of this study.. . .... -- . -- --............ --------- I. INTRODUCTION Ever since the pronounced increese in the incidence of lung cancer among males became apparent, there have been attempts to associate it with one or another of the various elements in the en vironment of man. The approach used by some workers baa been to suspect one or several substances and then set about in an intensive search for lung cancer among persons who have had any exposure to those compounds. In this connection. Smith (l82* writes: "The ten- * dency of authors reporting the coincidental occurrence of primary lung cancer with silicosis or with any other theoretical etiologic con ditions, has been to emphasize the percentage relationship in extremely small scries of cases, with control cases which arc not in any way comparable." . It would seem inevitable that, asbestos should come under scrutiny in this manner, because prolonged exposure to this material is known to cause a specific type of pneumoconiosis, and because persons who show this form of pneumoconiosis often come to autopsy and pro vide a ready source of material for study. It was in this way that re ports of the simultaneous occurrence of lung cancer and asbestosis be gan to accumulate after the report of a case by Lynch and Smith in 1935. Within the next ten years, about 15 additional oases were reported, and in 1946 Merewethcr (155i reviewed all deathsjrom asbestosis re-. _ corded in England since March. 1924. Lung cancer occurred, according 2. to Merewether, in 13.2% of these cases. Continuing this study to include December, 1954, Merewether counted 55 cases of cancer of the lung among 344 cases of asbestosis, raising the incidence to 16%. (92) Gloyne, whose work is also frequently referred to as establishing a connection between asbestosis and cancer of the lung, reported in 1951 the results of his findings on 1205 autopsied cases. This series included 132 asbestos workers, of whom 121 showed asbestosis. Cancer of the lung was present in 14.1% of these asbestosis cases. In 1941, Nordmann and Sorge claimed to have produced lung cancer in mice which they exposed to asbestos dust. Since 1951. additional cases of cancer of the lung coexisting with asbestosis have beer, reported, anc, according to Hueper <'2-' about 100 such cases had been reported up to 1955. As a result, an associa tion between the two diseases appears to have been accepted by many authors and several writers were using the term "asbestosis cancer" of the lung. Werber <25) in 1952, stated categorically that in 7% to 17% of cases of asbestosis, alter a latent period of about i i/2 to 20 years, carcinoma becomes established in the lung. On the other hand, no: all authors accepted the alleged associa U77) tion without reservation. Saupe in 1939 had reported that he had discovered no cases of lung cancer among 620 cases of asbestosis which be had examined; and in 1942, Holleb and Angrist ^ ^ expressed the opinion that the number of cases of asbestosis with lung cancer was too 3 aid all for statistical evaluation. In 1947, Wegeliua reported 126 radiologically .diagnosed cases of asbeatoais among 476 workers in Finland, and found no cases of lung cancer in Ibis group. Goldblatt and Goldblatt in their aection of Merewether's latest book. state: "But at no stage in all these impressive researches was any clue obtained which might have offered any support to the possi bility that asbestos could act as a carcinogen. There is no reliable criterion by which one can anticipate carcinogenicity and, as is well known, relatively minute changes in the structure of a chemical car cinogen are sufficient to diminish or eliminate carcinogenic action. If asbestos is indeed to be regarded as a carcinogen, the need is feltio demonstrate some property which can be regarded as something more than inertness." k- These authors advance the theory that, until some more experimental evidence of direct carcinogenesis by asbestos or a de Mr composition product of it can be obtained, asbestos might be considered as a "co-carcinogen" which only induces a further development of a pre neoplastic condition brought about by something independent of the as bestos. such as an endogenous factor. Thus the literature, while tending to support the thesis that asbestosis is in some way related to the development of lung cancer, is by no means unanimous. Altogether, it is perhaps more confusing than enlightening. 4. .. Meanwhile, the Canadian Johns-Manville Company in Asbestos has been alert to the whole problem, an^ at the Tbclford Industrial Clinic, Dr. Paul Cartier was studying the situation among a working population of about 6000, and made notable contri butions to the literature just cited*42"44*. Between these two areas, a number of cases had been recognized and tabulated by the spring of 1956. At this time, at the suggestion of Dr. Kenneth W. Smith, Medical Director of the Johns-Manville Corporation, and Dr. Cartier, the Quebec Asbestos Mining Association approached Industrial Hygsene Foundation to determine whether it would be feasible to conduct an epidemiological study in order to discover whether the incidence of lung cancer was. in fact, greater'among asbestos miners than among the general popula tion, and whether there was a correlation between lung cancer and the disease asbestosis. The Foundation submitted, in March, 1956, a pro posal for such a study based upon a preliminary survey of the type and accessibility of data which might be available. This proposal was ac cepted by the Association through its Secretary, Mr. W. H. Soutar, and its General Counsel, Mr. Ivan Sabourin, Esq. 5. n. CRITICAL REVIEW OF LITERATURE A careful review of the published material on this sub ject shows that the majority of the reports are clinical and not epi demiological. They lack many elements necessary for the applica tion of epidemiological techniques to their content and most of the authors do not make claim to having done so. What has happened is that succeeding authors have drawn conclusions and generalised 1 beyond the scope of the works which they quote. Nowhere, for ex- - ample, have we found references to a population of asbestos workers, although several authors who have quoted the observed L-.cidence of lung cancer in autopsies of persons who also had asbestosis imply that this incidence applies to asbestos workers. We have likewise been unable to find any study which actually calculated the incidence of lung cancer among a population of persons who had asbestosis, and not just those who came to autopsy. With the exception of a paper by Doll *63^, none of those reviewed gave any data on exposure and dust concentrations, and even Doll's paper merely mentions "scheduled" areas, by which is meant, "those areas where processes are carried on which were scheduled under the Asbestos Industry Regulations of 1931 as being dusty." . There is, furthermore, a complete lack of definition of terms as used in the published literature. For example, the term ___ 6. "asbestosis", as used, may refer to changes observable only by microscopic examination of the lung tissue, or it may mean a radio- logic&lly detectable condition. Most of the published reports obviously included women among their cases, but some of them do not give the number or pro portion of women involved in the study. There is also a lack of uniformity as to what type of ex posure most studies have dealt with. Of 99 cases enumerated by . (122) Hueper in 1955, only ten appear to have originated in the United States, and seven in Canada. Some of the earlier reports apparently included asbestos miners, but it can be assumed, since 82 of the 99 cases had originated in England, and since nc asbestos mining opera A tions are carried on in that country, that most of the reported cases * have involved workers in the textile or fabricating industries. Such factors as smoking habits, family history of cancer, length of time in the industry, and age of the individual case are also notably absent in the majority of these reports. With this understanding of the limitations of the existing literature with respect to epidemiological generalisation, it may be of value to consider in somewhat more detail some representative earlier publications, a few of which were referred to briefly in the previous section One of the most detailed studies and one which deserves (63) the most serious consideration is that reported by Doll in 1955. This study, reviews causes of death among asbestos workers based on coroners' records. It also attempts to estimate the risk by study ing records of men who worked for at least 20 years in exposed situa tions. Doll concluded that lung cancer was a specific industrial hazard of certain asbestos workers and that, after 20 years of exposure, the risk is ten times as great as for the general population. Tiiis article is important for several reasons, in addition to the definite conclusions at which it arrives. For example, it begins by stating that "in view of the infrequency of asbestosis, this large num ber of cases^61 cases of lung cancer) suggests--but does not prove -- that lung cancer is an occupational hazard of asbestos workers." Neither this article or any previous one which we have examined presents any figures to prove that asbestosis is an infrequent occurrence. Es timates of the number of persons potentially exposed to asbestos dust in the United States alone vary from 10. 000 to 35, 000 and the incidence v of asbestosis of any degree might be higher than Doll imagines. This study, like so many othersi involves autopsy records. The number of persons involved in the statistical analysis is only 113 representing only 1,042.25 mar. years of life. It is also true that in selecting men who had been employed for at least 20 years, the study automatically excluded those who died from other causes after shorter employment. It also seems that this review does not add any new cases to the literature, although Hueper in enumerating.99 cases reported prior to 1955, lists 11 discussed in it. Clearly, also, the paper is not dealing with asbestos miners. Another reason why this publication is ol importance is a statement which-it contains to the effect that "the strongest evidence that it (lung cancer} may be a hazard (in asbestos workers} has been produced by Merewether and by Cloyne." 'An examination of these references leaves at least some question as to the strength of the evi dence produced. (92} ' In 1951 Cloyne presented a review of 1205 autopsies on persons who had worked in various dusty occupations. This num ber included 132 asbestos workers, of whom 121 showed "pneumoconiosis a --presumably asbestosis. Primary cancer of the lung occurred 17 times in this group, ar. incidence rate of 14. 17* for lung cancer amcr.g autonsiec asbestosis cases. There were in his series 796 cases with silicosis, and 6.9% of these also showed primary cancer of the lung. Toe incidence of lung cancer in other forms of pneumoconiosis was 6.7% . and in 169 cases which proved not to have any type of pneumoconiosis it was 8.3%. Gloyne considered "the mortality of the asbestos workers" to be "disturbing". First of all, it is obvious that the paper does not deal with the "mortality of asbestos workers", and secondly, it must b< borne in mind that all of Dr. Gloyne's cases were submitted to him 9. for study because the findings were unusual lor uncomplicated pneumo / coniosis. Presumably, all cases, including those of asbestosis, in which the findings were cot considered unusual were never brought to Dr. Gloyne*s attention. As a matter of fact, in the same paragraph in which he expresses concern over the incidence rate in asbestosis. Dr. Gloyne himself points out that the rate for lung cancer based on necropsies at the London Chest Hospital was 21. 3% while the figures of the Registrar-General showed only 2.4%l. He thus recognized that autopsies on a certain selected group of cases were not representative of the general population. It would seem, then, that notwithstanding the value of Dr. Gioyne's work, its importance as an index of the pre valence of luSg cancer in asbestoucs has been misinterpreted by those who have quoted him. All that it really shows is the fact that m a group of 121 cases, selected for special study primarily because they seemed *# abnormal by preliminary examination, 17, or 14. If. bad lung cancer. Merewether *155* in 1947, in the report of the Chief In spector of Factories, reviewed all cases reported between 1924 and 1946 in which asbestosis was the cause of death or a coexisting con . dition. This work was Later extended to include all such cases reported up to December, 19o4, by which time there were 344 deaths including 205 males and 139 females. Among them were 55 cases (16%) of cancer . of the lung, 41 in males and 14 in females. It is quite possible that a large number of asbescotics who did not die of their asbestosis, or in 10. whose death certificate it was not mentioned, may have been missed. The import of this 16% is enhanced by the simultaneous statement that the incidence of lung cancer in autopsies of the general popu lation is only 1%. The danger of attempting to compare a rate found in 344 cases with the rate for the general population without respect to age, occupation, and many other variables, such as smoking habits. is obvious. Lynch.*142* who with Smith *`3`* had reported the first case in 1935. reported four cases of carcinoma of the lung in a series of 49 autopsies on workers in an asbestos manufacturing plant who were shown to have "demonstrable deposits of asbestos in the lungs." This, of course, is not necessarily identical with the disease as'oes- tosis. Lynch, himself, points out that, although this is an incidence of 8.2%, "both figures arc too small for very serious statistical types of calculation." Nevertheless, later writers have used this paper to . strengthen the case for an association of carcinoma of the lung with asbestosis. It is of interest to note that Klotz *'32* found only four in- % stances of lung cancer in 47S cases of asbestosis, a scries 11 times as Urge. Behrens, as quoted in Merewcthcr estimated that, of 309 cases of asbestosis in the literature. 44 showed associated # cancer of the lung--giving an incidence of 14.2%. This is another case ------ -- - - ww I tm -- ... * cf generalizing an incidence obtained in a group ot cases which were 11 undoubtedly reported only became lowe of them showed lung eineer. to possibly hundreds of asbestotics whose cases were never reported. The same applies to the conclusion of Teleky who appears to have reviewed reports of 39 autopsies on persons with asbestosis among which six cases of lung cancer occurred. Information from those source! does not justify generalisations with regard to mortality rates. Werber ^ ** who made the unequivocal statement that lung cancer would result in from 7% to 17% of Cases of asbestosis. allowed himself considerable latitude by qualifying it, as regards time, to an interval of 1 1/2 to 20 years. Finally, mention should be made of some entirely unsupported statements which tend to build up a mistaken view point throug'::"mere repetition. One example is a sentence in "Nontuber- culous Diseases of the Chest" *l!>> where the authors say simply, "an ex V 1i * cessive incidence of pulmonary cancer has occurred among workers in other occupations, such as asbestos industries, nickel-copper refineries, stokers in generator plants, etc." without substantiating reference. As an illustration of the ease with which a few reports which merely suggest a certain conclusion can. through the lack of a sufficiently critical attitude, be summarized to produce the conclusion in a definite (69) form, an editorial in the Journal of the American Medical Association mentions the work of Wedler and the report of Mcrcwether and then es tablishes the causal relation between asbestosis and cancer of the lung as settled. As a final convincing argument, it refers to "recent experimental 12 observations (by) Nordmann and Sorge This is the experiment in which squamous carcinoma was said to have been produced is about a dozen while mice, and which has not been duplicated by any other in- , vestigator! Perhaps no one has written so extensively or so cogmaci- . (109-124) cally on the subject as has Kueper . In 1955 he reviewed the cases *122* reported prior to that date and enumerated a total of 99. (63) Eleven of these were those discussed by Doll and appear to have been cases covered by other authors. Eight were discovered by Kenna- way and Kennaway in an analysis of death certificates and. unless Merewether's study was incomplete, these cases should have been in cluded in hi ^"report. Of the remaining 80, it is quite possible that the *> 31 contributed by Merewether and the 17 by Gloycc contain some dupli cation with each other or with other English authors. In the same paper, Hueper dismisses the idea of determining the frequency of pulmonary cancer among the total worker population of the asbestos industry on the grounds that it is immaterial how many workers in the industry develop lung cancer, since some of them have no exposure and therefore do not develop asbestosis! ' ' ' w !b - * t b N 'M 1 13. HI. PRINCIPLES OF THE EPIDEMIOLOGICAL METHOD As has been indicated, much of what ib now thought to be pertinent concerning the comparative frequency of lung cancer in different population groups has been developed from the analysis of clinical material, particularly surgical and autopsy records. This has been supplemented to some extent by the reported impressions of various clinicians based upon their personal observations. More re- i cently, however, attention has turned to the systematic investigation of this problem by the same methods that have proved so successful previously in the study of communicable diseases, that is to say, by epidemiological methods. Epidemiology is the method of investigating a specific disease in human populations in relation to certain variable character istics, including the environment. In contrast to the clinical method which is primarily concerned with the characteristics of the disease in individuals, epidemiological research involves the investigation of the disease as a mass phenomenon. It seeks to discover what propor tion of persons in a given set of circumstances will eventually develop the diaea.se. Epidemiology cannot predict whether a given individual will fall victim, to a specific disease, but it car. predict the approxi mate number of cases of this disease which will develop ir. a population of specified siac, composition, and subject to a given environment. It U proceeds by first carefully and accurately describing character istics of the disease in different population groups and its essential objective is the formulation, testing, and verification of generali zations concerning the disease in question. In order to apply this method of investigation to the pro blem under discussion, the Foundation was of the opinion that a study should be planned so as to provide: 1. A well defined population group. 2. Available data for all members of this pop ulation, including the healthy as well as the ill. 3. A sample which is truly representative of the population. 4. Reliable and valid observations relating to the k problem of the study. A serious defect, common to most o' the studies which have been reported, is that little or no information concerning the healthy people in the group seems to have been available to the author. Therefore, results of these studies cannot properly be generalized to include such people. In order to draw a generalization regarding all asbestos workers.it is necessary for a study to include living persons as well * as the dead. Limiting the investigation to autopsied cases, as has been frequently done in earlier studies, still further restricts its use in generalisation. The problem with which the Quebec Asbestos Mining Association is concerned is whether asbestos miners ex perience more lung cancer than does the general population. The answer necessitates the collection of reliable information or. asbestos miners as a group, as well as on the general population. It seems advisable to discuss the differences between the epidemiological approach and that used in the studies which have been reported to date. A very important consideration is the fact that lung cancer, in spite of its increasing numbers, is still a disease of low incidence; that is. in a given population not many persons will contract this particular disease. This fact requires that large samples or groups must be studied to provide meaningful results. Recognising the difficulty of obtaining such large samples, most earlier writers deviated from the epidemiological method and sought to circumvent the requirement of observing well persons by: 1-. Comparing the relative freouency of cancer in various sites. Z. Comparing the relative frequency of cancer in a group of hospitalized patients. 3. Comparing the relative frequency of cancer In a group of cases coming to autopsy. * . The frequency of cancer of the lung relative to the total of all typcs'of cancer may be increased merety'by"reason*of~a decrease in the Incidence of cancer of other sites. This could be true even though the incidence of lung cancer remained constant, or if it de creased les rapidly than that of the other types. Attempting to compare two population groups, looking only at the relative frequency of cancer in various body sites, may result in finding a higher percentage (relative frequency) in one of the groups, when, in fact, the mortality rate of cancer of a particular organ is ex actly the same in both groups. This is because the relative frequency of cancer in other organs may be lower in the second group. The mor tality rate from a particular cause is the true measure of comparison. It is apparent that selected groups such as hospitalized patients or atftopsy cases may not be representative in any way of a larger group, and that in dealing with such samples, the observer may easily find more cases of any kind than would be found in a group of the same size, but representative of the general population. It is true that investigation of cases from such a sample can furnish information valu able for research, but the use of this information in drawing generalisa tions is necessarily restricted. It is the obligation of both the investi gator and of those who read his report to make proper comparisons and to draw only those conclusions which are valid and justified. A good statistical study of cases of cancer of the lung occurring in a group of autopsies can lead to a proper inference concerning the frequency of lung cancer among cases coming to autopsy, but only to such cases. For 17. information from such, a study to be projected to some larger group, it is necessary that the autopsies represent a good sample of that larger group. To assume that such is the case in any particular series Is dangerous and likely to be false. There is some danger that the figures reported by some authors may be misconstrued as applying to asbestos workers or even asbestos miners, when, in fact, the authors in question do not make this generalization, nor can the generalization be made for the reasons stated. Close study of the reports reveals that the percentages quoted relate only to the group of autopsies covered by the particular investiga tion. The present study, in contrast to the earlier works, has been 3 planned to utilize the epidemiological method. A well-defined group of h* asbestos miners has been established in such a way that it constitutes a good sample of the whole population of asbestos miners in Quebec. Data for all members of this group have been collected and analyzed. Those concerning lung cancer have received most careful consideration. De tails of the methods employed will be set forth in a later section, but the type of approach is considered to permit of fair comparisons and valid generalizations. . IV. COLLECTION AND ANALYSIS OF DATA A preliminary survey of potential sources of information in February of 1956 involved discussions with the physicians in charge of the asbestos companies' programs and with clinicians, pathologists, representatives of City and Provincial health departments and of the Canadian Cancer Society, and other interested persons. It was found that morbidity data, although somewhat limited, were available from such sources as the hospitals in Montreal and Quebec City, and ' the 13 Cancer Detection Centers in the Province. However, because of the high mortality in lung cancer, it seemed advisable to depend upon data relating to deaths. These w found to be obtainable at the vital statistics department of the Ministry of Health in Quebec City. From the preliminary survey, it was apparent that extensive and detailed in formation could be gathered with respect to both the persons employed in the asbestos mining industry and mortality figures for the general population. Following this exploratory survey, the initial effort was directed Co the collection of data relating to all workers who had beer, processed through the clinic at Thecford Mines since its inception in 1947. Similar information was obtained regarding all workers at the Canadian Johns-Manville Company in Asbestos. Da\g_from the clinical ----- records included the age, family and personal medical histories, smoking habits, number of years of exposure, ir. estimate of weighted exposure. 19 and the course of the individual's health status or the cause of his death. Although the data in these two instances were not exactly similar in form, the inclusion of records from the personnel department at As bestos covering employees who had retired, died or become disabled provided data sufficiently alike for the purpose of the study. From this information it was possible to formulate for both Asbestos and Thetford Mines "cohorts" which could be well defined, 1 should be representative of each group, arid could be followed for a de r finite period of time. All of the available experience indicates that the development of asbestosis in less than five years of exposure must be somewhat rare. Accordingly, the cohorts were defined as inducing every workemwho had a total exposure of five or more years, and who was on the employment rolls at Asbestos or Thetiorc Mines in 1950. These cohorts were then followed by means of the annual physical ex- _ amir.atios records through a six-year interval, 1950 through 1955. AU data regarding these groups were then tabulated in order to determine the characteristics of the cohorts. For those who survived the entire period, reference was made to the physical examination results and x- ray findings at the end of the period. Those'who had died were tabulated m separately and the cause of death corroborated by examination of the death certificates. A further search was made concerning those in the original cohorts who remained unaccounted for whenThe living and the known dead had been tabulated. They represent men who had left employment through retirement or resignation. Eventually, all but a small number of these were accounted for as either living or dead, * and in the latter event, the cause of death was substantiated in a similar manner, and the results added to the original list of deaths. Death certificates for the Province of Quebec for the years 1952 to 1955, inclusive, were reviewed in the department of vital sta tistics of the Provincial Health Ministry, together with statistical sum maries of the causes of deaths in the Province by counties. All cases in which death was certified as having been due to primary cancer of the lung were examined for such information as place of residence, oc cupation, date of death, hospital in which death occurred, and whether or not an autopsy was performed. Cases in which lung cancer was given as a cause of death, but in which it was no: specified as to whether the cancer originated in the lung, were also reviewed in an effort to in clude all instances of primary carcinoma of the lung in the study.. Tee statistics for the Province of Quebec relate to popula tion, total deaths from all causes, total deaths from cancer cf all types, and deaths from lung cancer. These were collected and tabulated by counties and by sex for the years 1950 to 1955, inclusive. From them, death rates for the general population of Quebec and of individual conn ties were calculated for specific years and analyzed by cause. * Practically all employees of the Canadian Johns-Manville Company are covered by a group policy of life insurance which, fortunately. nearly jOI of them continue to carry when they retire. A very few are not covered by this policy, and those who leave the industry for one reason or another except retirement usually are no longer covered, but this is likewise a small number. As an additional check upon the information obtained from the clinical records on the group at Asbestos, the records of the life insurance company were examined for all death claims paid under the policy, and particular notice was taker, of the claims in which the proof of death was based on cancer of the lung. Deaths from lung cancer among asbestos workers were thus determined from the clinical records in the medical service of the industry and checked by means of the death certificates and insur ance company^records. Tae list of deaths was then verified individually by reviewing them with the physicians in charge at Canadian JohnsManville Company and at Thetford Mines. In this manner, there was established a list of cases in which primary cancer of the lung is con sidered to have been proved as the cause of death. A few cases in which lung cancer is strongly suspected but r.ot proved as the cause of death were considered separately. Mortality rates have been cal culated using both the "proved" and the local of "proved" and "suspected" cases during the years under observation. Comparisons were then made between the death rates from the same cause among specific segments of unexposed persons. All lung cancer deaths, both suspected anc proved, were carefully analyzed to determine possible relationship or correlations Detweer. the development of lung cancer ar.d any factor known from the 22. clinical records such as family history of cancer, personal history of heavy smoking, coexistence of asbestosis or exposure to asbestos. In addition to this analysis of deaths occurring in the co horts and during the years under observation, every known death from cancer of the lung, as well as every case diagnosed but still living, has been tabulated and analyzed. They will be discussed separately from those included in the population and time-interval under study. A comparison of lung cancer mortality in the asbestos pro ducing counties has been made with that in counties which are far re t moved from the asbestos mines and in which, presumably, no asbestos miners live. Finally, in order to broaden the comparison of death rates a in different population groups, the rates have beer, collected for Canada h generally, and for the United States, according to the most recent pub lished and unpublished material. In order that the method by which these comparisons have been made may be more easily understood, it seems advisable to discuss briefly some of the fundamental statistical concepts which have been followed. The principle of calculating the probability of a given sample representing the true condition of a large group can be illustrated by imagining a container in which there are 1000 marbles of which 900 are white and 100 black. The actual probability of drawing a black marble is one in ten, or . I. However, should a sample of ten marbles be drawn from the container, it would not be unlikely that two, three, or even no black marbles would be among them, even though the "expected" number would be one. On the other hand, ii all ten were to be black, that sample would unquestionably be "extraordinary". The following tabulation shows a calculation of the probability that a given number of black marbles will be found in a sample of ten: No. of Black Marbles in Samoie 0 1 2 3 4 5 6 7 8 9 10 Total Probability .3486784401 .3874204890 .1937102443 .0573956280 .0111602610 .0014880348 .0001377810 .0000087480 .0000003645 .0000000090 0000000001 1.0000000000* From these probabilities, it is evident that one might ex pect a sample of ten to include no black marbles or one, two, or three, but for the sample to consist entirely of black marbles would be ex peeled only once in ten billion trials. Finding three black marbles in the sample would be expected in almost six samples out of 100, and it would be anticipated that the sample would contain four or more black 24. marbles in slightly more than one trial out of 100. The actual prob ability of this happening is .012795184, which is determined by addins the probabilities for 4 through 10. la practical applications of sam pling. the percentage of "black marbles" is. of course, unknown and must be computed from the results found in the sample. There are limitations to the accuracy of such a computed value, but it is possible to state with a known probability that the true value lies within a certain range. If the range is wide enough, the probability may be practically 100%. The usual practice is to require 95% certainty. In the present study, since the probability of having lung cancer is so small and since the sample size was fairly large, the Poisson distribution was used instead of the binomial distribution, which has just been described. This is a substitution frequently made under these conditions, because the Poisson distribution is tabulated and the differences between it acc the binomial distribution are quite small. It is based on the equation: e`n? (no)X x: Where e * 2.71828 (the base of natural logarithms) n = number of man years subject to risk p = incidence rate * = number of cases observed The logic of the statistical approach may also justify a few words of clarification. Generally, in problems of this kind, one sets up a hypothesis, which in our case would be, ''Asbestos miners do not hive a higher rate o mortality from lung cancer than the general popu lation. " The hypothesis is then tested by means of the study of data on asbestos miners and on the general population, including the observed number of cases of lung cancer. From what has been said earlier, it fis clear that even if the asbestos miners and general population had ex actly the same lung cancer mortality rate, it is unlikley that in any single sample this identical rate would be found. Some difference is likely to be observed, but the important question is whether this differ- ence is greater than might be expected merely as a matter of chance. In other words, we wish to know whether the difference is "statistically significant". If a sample should supply sever, cases when the expected number (based on the rate for the general population) is five, one must inquire concerning the probability that this would occur purely as a matter of chance. It is this probability value which is calculated by the Poisson distribution. If, on this basis, a value is found in the sample which is so much larger than the expected value that it (or some larger value) would occur less than. 5 % of the time by chance, there is sufficient evi dence to reject the original hypothesis. If. on the ether hand, the value observed, even though larger than the expected value, is no greater than might occur by chance in fewer than 5% of trials, we have insufficient evidence to reject the original hypothesis. Calculations and conclusions based on the results of the find -- ings in this study have been made in conformity with these statistical concepts. They will be presented in the following section. 26 V. RESULTS AND INTERPRETATION The rwo cohort* which were constructed according to the criteria described is the preceding section have been considered in dividually and compared with each other as well as with the general population. Description and comparison oi these cohorts will be pre sented here as a preface to the results oi the study. A tabulated summary of each group and of the combined cohorts is shown below: Asbestos Cohort Original Cohort 2327 Lost Persons Deducted 54 Final Cohort Living in 1955 (working and retired) 2273 2224 Dead by 1955 Ca. of lung Questionable Ca. of lung Other Causes Unknown Causes 49 3 0 46 0 Smokers Nonsmokers Unknown 1931 340 2 Thetford Mines Cohort Summary of Combined Cohorts 3764 6091 79 133 3685 5958 3547 5771 138 6 3 ) 23 6 2742 925 18 187 9 3 169 6 4673 1263 .20 4 . 27. Tables 1, 2, 3, and 4 present age, number of years of employment, weighted average exposure and smoking habits of these two groups. It will be observed from Table 1 that the Thetford Mines workers had a higher average age than the Asbestos group (42 years vs. 39 years). Consistent with this finding, Table 2 indicates that they also had worked longer as asbestos miners (19 years as against 15 years). A comparison of the exposure to asbestos dust is presented in Table 3. All workers were placed in one of three categories, re presenting increasing degrees of exposure based on a weighted average of the years spent at various levels of dustiness. The degree of dusti ness for eaciTjob category was determined after consultation with per sons familiar with the environment and conditions in the various work areas. Although it will be noted that the wo cohorts had the same average exposure, a larger percentage of the Thetford Mines workers will be found in category II, while the Asbestos group occupy mainly the extremes of exposure. For the purposes of calculation, the assumption has been made that the relationship between these categories is linear, and that category U is twice as dusty, and category III three times as dusty as category I. The fourth variable, smoking habits, was similarly tabulated and is shown in Table 4. A larger percentage of smokers is indicated here for the Asbestos cohort - 85.0% compared with 74.4%. ZB. TABLE 1 Number and Percentage Distribution of Asbestos and Thetford Mines Cohorts by Age Asbestos Age No. %_ 1 20-44 45-54 55-64 65 Unknown Totals AV. Age 1602 44? 185 39 2273 39 70 20 8 2 mm Too?. * Less than .5% Thetforc Mines_____ No. _% 2299 677 430 276 3 3685 42 62 18 12 .8 ft 100% Combined No. _% 3901 1124 615 315 3 5958 41 66 19 10 5 Too?. TABLE 2 Number and Percentage Distribution of Asbestos and Thetford Mines Cohorts by Length of Employment Length of Employ- meat Asbestos No. _% 5-9 880 10-19 864 20-29 342 30-39 166 40-49 17 50.4 2 Totals 2273 of -IS- Employment 39 38 15 7 1 100% Less than .5% Thetford Mines Combined Nc. 915 1534 580 435 168 53 3685 --------- 19 _% No. %_ 25 42 16 12 4 1 100% 1795 2398 922 603 185 -- 55 5958 --------- --18 30 40 16 10 3 1 100? 29. TABLE-3 Number and Percentage Distribution of Asbestos and Thetford Mines Cohorts by Exposure Category Exposure Catecorv Asbestos No. ft 1 'n m Unknown Totals Av. Exposure 969 564 735 5 2273 1.9 43 25 32 Too?.. Less than .5ft Theefor c Mines No. ft 1062 1586 1037 0 3665 2. 0 29 43 28 0 100ft Combined No. ft 2031 2150 1772 5 5956 2.0 34 36 30 10C ft TA3LE 4 Number and Percentage Distribution of Asbestos and Taetford Mines Cohorts by Smoking Habits Smoking Habits Asbestos No. ft Smokers Nonsmokers Unknown Totals 1931 34C ___2 2273 85 IS 100% * Less than -5ft Thetford M ine s No. ft 2742 925 18 3683 74 25 ___1__ 100ft Combined No. ft 4673 1265 20 5956 79 21 100ft This is a difference which could hardly occur by chance because o' the large size of the sample. Therefore. It is likely that the differ ence is a real one unless the method of recording this information at the time of employment varies at the two locations. In spite of the minor differences brought oUt by these comparisons, it would seem that the two cohorts are quite similar with regard to the variables of age. length of employment, degree of exposure and. although less so, in regard to smoking habits. These variables appear to us to be those most closely related to the problem, and will be taken into account in comparing the workers witn the con trol groups. Table 5 presents the year-oy-year experience of the two cohorts and indicates the number os deaths each year from specified causes. In general, a case was considerec to be "proved" as one of primary cancer of the lung when the records showed that the diagnosis had been supported by an autopsy or surgical resection of the lung with microscopic examination of the removed tissue. In one case so con sidered. however, diagnosis was confirmed by bronchoscopy with visuali zation and biopsy. In another, although there w*t no autopsy, the diag nosis of primary cancer o' the lung seems to have beer, beyond question. The term "suspected" primary cancer of-ihe lung was ap plied to those cases in which the diagnosis remains in doubt but some of the evidence points to cancer of the lung. There were three such cases. 31 xh to - TABLE 5 - Part I Study of the Asbestos Cohort No. Alive At Beginning Year of Year C lust of Proved Suspected Primary Primary Ca.of Lung Cl. of Lung Death Other Causes Unknown ManYears of Risk 1950 2273 1951 2267 1952 2261 1953 2252 1954 2243 1955 2231 . Totals 0 1 0 0 0 2 3 0 6 0 2270 0 5 0 2264 0 9 0 2256.5 0 9 0 2247.5 0 12 0 2237 0 5 0 2227.5 0 46 0 13502.5 "Proved" cancer of lung death rate per 100.000 man-years of risk a 222 `unr?* TABLE 5 - Part U Study of the Thetforc Mines Cohort C a u s e of Death No. Alive Proved Suspected Man- At Beginning Primary Primary Other Years of - Year of Year Ca. of Lung Ca. of Lung Causes Unknown Risk 1950 3665 1951 3675 1952 3661 1953 3633 1954 3605 1955 3579 Totals 1 1 0 2 1 1 6 26 0 12 0 23 1 25 0 21 0 31 3 TIT i 3680 i 3668 0 3647 0 3619 4 3592 0 3563 21769 "Proved" cancer of lung death rate per 100. 000 man-years of risk = 27.6 ( 21769 "Suspected" plus proved cancer of lung death rate per 100.000 man- years of risk -41.3 ( 9 21769 32. TABLE 5 - Part El Study of Combined Cohorts Combined death rates per 100, 000 man-years of risk for Asbestos and Thctford Mines "Proved" cancer of lung death rate per 100,000 man-years of risk 25.5 35271.5' "Suspected" plus proved cancer of lung death rate per 10C, 000 mas 12 years of risk = 34. 0 { 35271.5 J In two. no autopsy was performed but the clinical s;gr.s and symptoms were such that the death certificates read "cancer of the lung", and "suspected lung cancer". The third case came to au topsy but there was a difference of opinion between two pathologists as to whether lung cancer was present. The term "man-years of risk" has been used to mean the number of men at risk for the year under observation. An individual wbo lived throughout the year was counted as a full man-year of risk, but one who died during the year was counted as one-bali a man-year. Deaths occurring in these two cohorts, and in which lung cancer is considered to have been proved as a cause, are shown.in tabulated form on the next page. Also shown are three deaths in the Thctford Mines cohort-which have been considered as .'.'suspected" lung cancer cases. 33. ASBESTOS COHORT "Proved" Cases of Primary Cancer of the Lung Name Age Smoker Exposure Died 1. A. J. i. N. P. 3. R. M. 66 65 65 Yes Yes Yes 26 Yrs. in Cat. 34 Yrs. in Cat. 37 Yrs. in Cat. n 10-12-51 i 5- 3-55 i 7-20-55 Au- Asbes toP*v toses Yes Yes No Yes No No TKETFORD MINES COHORT "Proved" Cases of Primary Cancer of the Lung - Name Age Smoker Exoosure Died Au - Asbes tops V tos:* 1. C. B. 2. A. S. 3. W. F. 4. L. D. 5. E. L. 6. A. R. 5? 48 61 56 37 68 Yes Yes Yes Yes Yes Yes 32 Yrs. in Cat. 22 Yrs. in Cat33 Yrs. in Cat. 30 Yrs. in Cat. 16 Yrs. in Cat. 28 Yrs. in Cat. I 8-20-50 n 51 111 4-30-53 U 11-22-53 I 8- 5-54 m 5- -55 Yes Yes Yes Yes Yes Bronch. No Yes Yes Yes No No "Suspected" Primary Cancer of the Lung Name Afil . Smoker Exoosure Died 1. J. T. 2. R. D. 3. P. P. 49 46 65 Yes Yes Yes 32 Yrs. in Cat. 33 Yrs. in Cat. 42 Yrs. in Cat.' m 10-25-50 in 7- -53 u 9-30-55 Au- Asbestoosv tosis No Yes No No Yes No At Asbestos there were no cases in which the diagnosis was questionable, with the result that the rate for_"proved" cases in this cohort is the only one developed. At Thetford Mines, however, the three cases mentioned earlier were placed in the category oi "suspected" primary cancer of the lung. An indication of the impor tance of these cases in interpreting the results of the calculations is desirable before further discussion of the mortality rates which are derived in later tables. For example, it happens that the rate found for the Asbestos cohort is very dose to the "expected" rate based or. the general population figures for the Province as will be shown later, and on this basis, we should find five deaths from lung cancer among the Thetforc-Mines group. A3 was explained in the section on "Col lection and Analysis of Data", it would then not be unlikely for six cases to occur in our sample. This is, in fact, the number o; "proved" cases found in the Thetford Mines cohort. If, however, the three additional "suspected" cases are included, increasing this figure to nine, the whole situation changes from a statistical point of view. Since the 95 level of probability in this case falls between 9 and 10, we would reject the hypothesis that there is no difference between the incidence of lung cancer in miners and that in the general population if wc found ten or w more cases. On the other hand, having found nine cases we are not above the 95% level and are no: justified in rejecting the hypothesis. Nevertheless, the occurrence of nine cases in this sample would show 35. ..w . an increase in race which approaches the significant level. Because of the tremendous importance of the questionable, cases in this res pect, some detail regarding them will be given here. In one of these cases, the suspicion of cancer of (he lung is based upon the x-ray interpretation and, although no autopsy was performed, the death certificate indicates that death was due to lung cancer. It is well known that the x-ray appearance of fibrosis, es pecially if a localized density or a superimposed tuberculous lesion is present, can simulate that of a tumor, and by itself, does not justify the inclusion of this case as one of "proved" cancer of the lung. A second case was certified as having died by reason of hydroihorax. possibly due-to lung cancer, but again there was no surgery anc no post-mortem examination. In the third case, although it was subjected tc * autopsy, two pathologists disagreed as to whether lung cancer was pre sent. The death was certified as having beer, due to chronic myocarditis with nephritis andpulmonary congestion, and possibly cancer of the lung. On the basis cf these facts, it seems unwarranted to include these three cases among "proved" instances of lung cancer. On the other hand, they cannot, in fairness, be disregarded completely. It is for this reason that mortality rates for the Thetford Mines cohort and the combined co- bort have been calculated both ways. Table 6. giving the rates by age groups."revals different experiences for the two cohorts. It happens that all of the deaths in the 36. Asbestos cohort fall into one age group. so that the rate for that age category is exceptionally high. At Thetford Mines, a more even distri bution of the deaths by age developed a series of rates which are less extraordinary and, as will be seen, are not widely divergent from the expected rates for each age category. The unusual rate in the Asbestos cohort for the age group 65 years and over, is the sort of thing which happens when the sample is small. For example, of these three deaths, two were exactly 65 years of age and would have been in another age group had the limits been increased by one year. TABLZ 6 Number of Persons and Number of Lur.g Cancer Deaths by Age Groups . Aft Crouos Asbestos Lung Cancer Persons Deaths Thetford Mines Combined Lung Cancer Lung Cancer Death s Deaths Persons Frovec Total Persons Proves Tctai 20-44 45-54 55-64 65* Unknown Total 1602 44 > 185 39 0 2273 0 C 0 3 0 1 2299 677 430 276 3 36o5 1 l 3901 l 1 1 3 1124 1 3 33 615 3 3 l2 315 9 5 0 0 ____ 1 0 -0 6 9 5953 9 12 Annual Lung Cancer Death Rates per 100,000 Man-Years of Exposure by Age Croups Aft Croco Total Thetford Mines Proved Total Combined Proveo Total 20-44 0 45-34 0 A5&0- XO-ll - -- _________ o -- _______ i5* Unknown 1282 Over-all . v.----------------'----------i 77 7 25 i if, 60 0 77 * 4 4 74 15 - f 16 1i Aw -------* -___ a l 44 - - . aO t6 - 121 . 212 265 0 00 41 75 77 37. The rates by length of employment (Table 7) show that the two groups were quite similar in this respect. During the first 40 years of employment, the rate rises, an observation which seems plausible since the men were growing older. However, after 40 years of exposure there are no "proved" cases reported for a total of 240 men during the six years, or about 1440 man-years of exposure. When the "suspected" cases are added, one case does show up in this period. This would produce a rate of 69 per 100,000, again demonstrating the importance of these questionable but unproved cases to the final con clusion, because, if there were no cases in this number of men with long exposure, and if asbestos is a carcinogenic agent, it must be con cluded that these 240 men have demonstrated considerable resistance. This is a biological phenomenon which has been observed previously and is consistent with the theory of an intrinsic or endogenous factor in can cer. The only other explanation would be that the susceptible members of this age group had died earlier of lung cancer. Table 22 which ap pears later In this section indicates that the members of the cohorts did not die from lung cancer at a younger age than the general population. The rates by weighted exposure are shown in Table 6, and it will be noted that they present strong evidence against asbestos being a carcinogenic agent. For the Asbestos cohort the rates actually de crease with increasing degree of exposure, and at Thetford Mines they appear completely independent of exposure, if we count only the "proved*1 cases TABLE- 7 Number of Persons and Number of Lung Cancer Deaths by Length of Employment Length Asbestos Thetford Mines Combined of Lung Lung Cir.cer Lung Cancer Employ Cancer Deaths Deaths ment Persons Deaths Persons Proves Total Persons Proved io:al 5-9 10-19 20-29 30-39 40-49 50+ Total 880 864 342 168 17 2 un 0 915 0 c 1795 0 0 0 1534 1 l 2398 1 1 1 580 2 2 922 3 3* 2 435 35 603 5 7 0 168 0 1 1SS 0 1 0 53 0 0 ___55 0 0 7 3bo5 6 9 5956 9 77 Annual Lung Cancer Deatb Rates per 100, COO Man-Years of Exposure by Length of Employment Length of Employment Asbestos Total 5-9 10-19 20-29 30-39 40-49 50 + Over-all 0 0 49 . 198 0 _0 22 Thetford M ines Proved Total 0 11 57 115 0 _0 27 C n 57 192 99 0 77 Combined Proven .total 0 7 54 136 0 0 25 0 7 54 193 90 0 't; 39 TABLE 8 Number of Persons and Number of Lung Cancer Deaths by Exposure Category Exposore Cate gory Thetford Mines Combined Lung Cincer Luag Cancer Cancer Deaths Deaths Persona Deaths Persons Provec iota! Persons .-roved Total I II IE Unknown Total 969 564 735 5 2273 . 2 1 0 0 3 1062 1586 1037 ____ 0 368s 2 2 2 0 6 2 203! 4 4 3 2150 3 4' 4 1772 2 4 0 50 0 9 5958 ? 7? Annual Lung Cancer Death Kates per 100,000 Man-Years o Exposure by Exposure Category Exposure Category Asbestos Total 1 n m Unknown Over-all 34 30 0 _o 22 ' No one exposed Thetford Mines Provec Total 31 31 21 32 32 64 _o 27 41 Combined Proved Total 33 33 23 31 19 37 00 25 34  L i > 41. TABLE 10 Number of Persons in Various Weighted Exposure Categories by Length of Employment Thetford Mines `Length oi Employment 5-9 10-19 20-29 30-39 40-49 50 4 Total Av. Yrs. of Exposure Weighted Exposure Categories _U_ U1 Unsown Total 279 390 155 149 67 ___ 22 1062 19.9 385 666 274 176 64 21 1586 18.7 251 478 151 110 37 10 1037 18. 1 0 915 0 1534 0 580 0 435 0 168 ' 0 53 0 3685 18. 9 TABLE 11 Number of Persons in Various Weighted Exposure Categories by Length-of Employment Combined Asbestos and Thetford Mines Length of Emolovment 5-9 10-19 20-29 30-39 40-49 50 4 Total Av. Yrs. of Exposure Weighted Exsosure Categories 1 _LJ_ in Unknown 707 663 314 247 76 24 2031 17.6 598 883 363 218 67 2! 2150 17.8 490 851 243 137 41 1C 1772 16.6 0 1 2 1 1 _o_ 5 -29.0 Total 1795 2398 922 603 . 185 55 5958 17.5 ti 8 . ' //' *. * * . . ' * 'V * . smokers, ia most striking cancer developed among tt lung cancer, both "proved A comparison of Tables 8 a greater hazard than expc Table 12 was t fication was necessary. 1 bction may have occurred, a larger percentage of you 13. 14, and 15 were const and nonsmokers by age, 1< Although there are slight c that all observed cases of age (Table 13) the combine less than that of the nonsrr of employment is concern* less on the average than t! greater age, one would e* rate if lung cancer were d Table 15 show most the same for the twe be of no importance in ac death rates for smoker* * f 42 Table 12, which develops the rates for smokers and non smokers, is most striking. It shows that not a single case of lung cancer developed among the 1265 nonsmokers and that all cases of lung cancer, both "proved" and "suspected", occurred in smokers. A comparison of Tables 8 and 12 certainly suggests that smoking is a greater hazard than exposure to asbestos in the mining operations. Table 12 was so striking that it was felt that further veri fication was necessary. It was possible that some abnormal distri bution may have occurred, e.g., the nonsmokers may have included a larger percentage of young men. Consequently, additional Tables. 13. 14. and 15 were constructed to show the distribution o: smokers and nonsmokers by age. length of employment, and degree o: exposure. Although there are slight differences, they do not account for the fact that all observed cases of lung cancer were In smokers. In respect to age (Table 13) the combined average age of the smokers was 4.9 years less than that of the nonsmokers. Table 14 shows that as far as length of employment is concerned, the smokers had worked about 2.3 years less on the average than the nonsmokers. With longer exposure and greater age, one would expect the nonsmoking group to show a higher rate if lung cancer were due to asbestos. Table 15 shows that the average exposure category was al most the same for the two groups. Therefore, thiwariable seems to be of no importance in accounting for the difference berween lung cancer death rates for smokers and nonsmokers. ' 43. TABLE 12 Number of Person* and Number of Lung Cancer Death* by Smoking Habit* Asbestos Thctford Mine* . Combined Lung Cancer Lung Cancer Death* Lung Cance Death* Persons Deaths Persons Provec Total Persons Proved Tot: Smokers Nonsmokers Unknown Total 1931 340 2 2273 3 0 _0 3 2742 925 18 3635 6 0 0 6 9 4673 0 1265 0 20 9 59S8 9 12 0 0 0C 9 12 Annual Lung Cancer Death Rate* per 100,000 Man-Years cf Exposure by Smoking Habits Smokers Nonsmokers Unknown Over-all Asbestos Total 26 0 0 22 Thctford Mine* Provec Total 36 55 00 0 _o 27 41 Combined Proved Total 32 43 00 00 25 34 <- '- 4 52. A percentage incidence of asbestosis for each exposure category has been developed as well as for each period of employ ment. Tbis information is shown in Table 17. 9% It will be noted that within an exposure category, the incidence rises with increased length of employment. It is also apparent that the incidences, even in the category of heaviest ex posure, are far below the rates sound by the authors preyiously re ferred to. It seems clear, that unless concentrations of asbestos dust to which the miners are exposed are very much lower than those which obtain in all the other studies, there has been a gross under reporting of the asbestosis cases. The obvious result is a higher relative frequency of lung cancer is association with asbestosis. Table 18 compares deaths due to lung cancer and fatal cases with as bestosis, alone and in combination with each other. TABLE 18 - Part I Statistical Analysis c: the Causes of Death Asbestos Cause Lung Cancer No Lung Cancer Total Percentage Asbestosis No Asbestosis 1 ( .2) _3 (3.3) 4 8.2 2 ( 2.8) .0(42.2) 45 91.8 Total Pere entaec 3 6.1 46 93.9 49 Figures in parenthesis are the "expected" numbers 53 TABLE 18 - Part U Statistical Analysis of the Causes of Death The'Joed Mines Cause Asbestosis No Asbeatosia Total Percentage Lung Cancer No Lung Cancer Total Percentage 3( 1.3) _Z5(26.7) 28 21.2 3( 4.7) 101(99.3) 104 78.8 6 128 132 4.5 95.5 Figures in parenthesis are the "expected" numbers TABLE 18 - Par: HI Statistical Analysis of the Causes oi Death <Asbestos and Thetford Mines Combined Cause Asbestosis No Asbestosis Total Percentage Lung Cancer No Lung Cancer Total Percentage 4(1.6) 23(30.4) 32 17.7 S( 7.4) 144 (141.6) 149 82.3 9 172 181 Figures in parenthesis are the "expected" numbers 5.0 95.0 Six deaths from unknown causes no: induced The number of lung cancer deaths combined with asbestosis is larger than would be expected in each cohort and in the combined cohorts. This difference is significant a: the 95% level using the chisquare test of significance. The importance of the under-reporting of asbestosis can be observed in Table 19. 54 TABLE 19 Statistical Analysis of the Causes of Death if 20 Nonasbestosia Cases had been Diagnosed as Asbestosis Cases Cause Asbestoais No Asbestoais Total Percentare Lung Cancer No Lung Cancer Total Percentage 4( 2.6) .48(49.4) 52 28.7 5 ( 6.4) .124(122. 6) 129 71.3 9 172 181 5.0 95.0 Figures in parenthesis are the "expected" numbers In this table, it has been assumed that 20 of the cases which did not have lung cancer and which were reported to have no asbestosis did, in fact, have asbcstosis. the diagnosis of which was missed. Although the cases of lung cancer with asbestoais are still higher than would be expected, the difference is no longer significant at the 95 ft level. This still is true if fewer than 20 cases were shifted but it is reasonable to expect that at least 20 of the 144 might have shown asbestosis had they been subject to autopsy. Cn the other hand, a shift of about 40 cases would produce an expected rate almost equal to the rate found. Explanation of this effect of under-reporting of as bestosis has been stressed because it seems so obvious that in under reporting asbestosis the relationship between it and lung cancer.has been made to appear more significant than it probably is.------- .. 55. Four of the proved cases of lung cancer and one of the suspected were associated with asbestosis. Since we have only 32 deaths in which asbestosis was present according to the records, the incidence in this series is 12.5%. wnile this is slightly lower than the rates found by Merewether, Gloyne, and Wedler. it is still much higher than could be expected if the asbestosis incidence were anywhere near the experience reported by other authors. Comparison of the Cohort Experience with that of the Province of Quebec, Dominion of Canada, ana the Unitec States In order to make a comparison of the experience among asbestos miners with that of the general population of the Province of Quebec, statistics were gathered, as stated eariier, in the office of the Division of Demography in the Provincial Ministry of Health. Toe data on total deaths, deaths from all forms of cancer, and deaths from cancer of the lung were obtained by sex and by county for the years 1950 through 1955. In addition, all death certificates which specified primary cancer of the lung, and all those which indicated lung cancer but did not specify the origin, were examined for the years 1952 through 1955. Table 20 gives a tabulation of the number of deaths from lung cancer in the Province and in the two cohorts for the years 1950 . through 1955. and shows the annual rate per 100, COO in these segments. H' rC_ T A 1 IL E 13 44 51 ^ ^ ~ - "IS r'. o sis C> N O OliA nj N O ^ |>C N N- ^ OO-f N " O - >0 If O fM t -- K> u c o M < i* -N- =% AX O - a; c* c o r t* ^ a ^ m na . E a C 26 VO so o 2 *3 ?*m0<c nii^a co C * n in ** rM rg - | f C' I^ ^ *O A c itE ------- l~ to _v in *g -- HE 3 f nj nj m 2 *i to I |J? ? ?.! I * OI^Tino D ^ < J! o in m cO O ^4 - * ou C 2 oE c o Z u V o5 E O mf o* T f * in -- -- -- >* -3 u u y O in nj in o mm 4 C -- 10 g ,c > 5 o* -2 # f n -- -- m. in C I k. c c * c o 2 -i c cD m in iA* --" u f o to----w of O' ** -- c o c c D Q c m m -- 0 am V 11 O N O r *g c o V V X E to in rg v O' o lo o f vlT c w C. t 3 UO <^ mr o na in -r m m m c ) oa* X 3 D o TADLE H 0 H is. * ,11 N hi * >o* <1 o) ig o O ON^ f* - E U o - u E o c 3 5I o E - 0(0 C* t/3 sn -- <c z= i IS iNsT O i. c* S25 c I O OO O> i ** + ** H < 8o Z c * C cn | ** % c C U S. 46 r-cojj -^ ^ M ^ In * X 0 sf\ <T> xf\ ^ E w o o o Ol^ ii <o \n #n o ,oo r f--l>* -08 * o x 0p ^^1^^0 0^ Io-- 1 * j1 n O Ol>^ i Jps s 1?. * d jc O I 3N NO.QI^ E : j: * . . Jo 0 O *r ^ O ^ C A4 I -- y5 -- c r* |^ IH-P-- *8 ClAJ ^ ^ I -- v!l E VJ c o jo o 3 Spftifl I I 1 w \n r- c** |Y^ 2 r" ~ u *-- s OIn A N C| -4 ~ I- <o: 47. The result of this additional analysis is that none of these factors appear to lessen the effect of Table 12. which is therefore strongly suggestive of the importance of smoking as compared to the other variables. Asbestosis and Lung Cancer When we attempt to relate the lung cancer deaths occurring in the cohort with the reported cases of asbestoois. we are immediately aware of a disturbing inconsistency. Various authors report the incident of asbestosis after 10 or 15 years of exposure as exceeding 50%, and in V U33) <135> U*M1S41 (195) one study, as high as Bi%. However, data on cases of asbestosis from the cohorts at Tbeu'ord Mines anc Asbestos pro duce a rate of only about 5%. It is true that these data are based on only those cases which have been proved at autopsy, and those whose most re cent x-ray interpretation resulted in a diagnosis of asbestosis. This in cidence may be far lower than if based on microscopic examination of the lung tissue. As a matter of fact, Dr. Cartier has estimated that tbcre ar probably JOG workers who do not show radiological evidence of asbestosis but who have some degree of fibrosis. He also estimates that there are perhaps 40 workers who may have died or retired with this disease. Instc of 143 cases of asbestosis in the whole working force at Thetford Mines, we should then have perhaps 500, but even this woifTd result in an over-al rate of less than 10%, which is far below those widely reported. In our Ha. combined cohort, there ere 1765 men who have had more than 20 years of employment, and 431 of theae have worked in the heaviest average exposure. According to the records, we can account for only 13S cases of asbestosis in the combined cohorts. If even 25% of the workers with more than 20 years'exposure develop asbestosis, we should expect about H25 cases. This leads us to believe that there is a very considerable under-reporting of asbestosis. Such a hypothe sis is easily conceivable when one considers that many chest x-rays in this group may be considered normal by comparison with others in the same group whereas, if they were to be compared with what are considered as normal chest x-rays elsewhere, they maybe inter preted as showing fibrosis. Cases of asbestosis which were accumulated from the au topsy records and from the periodical physical examinations result in a distribution which is shown in Table 16. TABLE 16 Distribution of Recorded Asbestosis Cases In Cohort Living Dead Total Asbestos 18 H 27 Thetford 86 30 116 Combined 104 'J4 138 TABLE 17 - Par: I . Number of Asbestosis Cases By Length of Employment and Exposure Category - Asbestos .Length of Employment Less than 10 10-19 20-29 30-39 40-49 50 Total Av. Yrs. of Employment Exposure Category 1 _U u: 00 01 27 01 00 00 2T 25 25 0 2 4 4 1 _0 11 29 Unbown Total 00 03 0 13 05 01 _0_ 0 0 22 27 Percentages of Asbestosis Cases By Length of Employment and Exposure Category Length of Employment Exposure Cateeor v -L JL U1 Less than 10 10-19 20-29 30-39 40-49 50 Over-all 0 0 1,3 0 0 0 .2 0. .5 7.9 2.4 0 * 1.6 0 .5 4. 3 14.8 25. 0 * 1.3 No one exp osed in this group Unknown 0 0 0 0 " Total 0 .3 3. 8 3.0 5.9 0 1.0 50 TAB1-E 17 - Part II Number of Asbestosis Cases By _ Length of Employment and Exposure Category Thetford Mines Length of Employment Less than 10 10-19 20-29 30-39 40-49 50 Total Av. Yrs. of Employment Exposure Cetceorv . _U m 00 01 25 2 15 06 _0_ 2 4 79 30 36 0 7 21 33 20 _2 83 34 Unknown Total 0 o 0 0 0 0 7 0 a 28 50 26 ____ 4_ 116 34 Percentages of Asbestosis Cases By Length of Employment and Exposure Category Length of Emolovment Exposure Cateecr V i_ n_ ill Less than 10 10-19 20-29 30-39 40-49 50 4 Over-all o o 1.3 1.3 0 0 .4 0 .2 1.8 8.5 9.4 9.5 1.8 0 1.5 13.9 30.0 54.1 20.0 8.0 No one exposed in this group Unknown 0 0 0 0 7 Total 0 .5 4.8 11.5 15.5 7.5 3. 1 51. TABLE 17 - Part lH Number of Asbestosis Cases By Length of Employment and Exposure Category Asbestos and Thetford Mines Combined Length of Employment Less than 10 10-19 20-29 30-39 40-49 50 Total Av. Yrs. of Employment Exposure Cateporv J_ m 00 02 4 12 2 16 06 02 T 38 26 33 o 9 25 37 21 2 94 33 Unknown Total 0 '0 0 0 0 0 "o 0 11 41 55 27 ___ 4_ 138 33 Percentages of Asbestosis Cases By Length of Employment and Exposure Category Length of Employment Exposure Catee U_ Less than 10 10-19 20-29 30-39 40-49 50 + Over-all 0 0 1.3 .8 0 0 .3 0 .2 3.3 7.3 9.0 9,5 1.1 No one exp osed in this group _m 0 1.0 10. 3 27.0 51.2 20. 0 5.3 Unknown 0 0 0 0 "o Total 0 .5 4. 4 9. 1 14.6 7. 3 2.0 52. A percentage incidence of asbestosis for each exposure category has been developed as eli as for each period of employ ment. This information is shown in Table 17. It will be noted that within an exposure category, the incidence rises with increased length of employment. It is also apparent that the incidences, even in the category of heaviest ex posure, are far below the rates found by the authors previously re ferred to. It seems clear, tnat unless concentrations of asbestos dust to which the miners are exposed are very much lower than those which obtain in all the other studies, there has been a gross under reporting of the asbestosis cases. The obvious result is a higher relative freojieacy of lung cancer in association with asbestosis. `i . ^ Table 18 compares deaths due to lung cancer and fatal cases with as bestosis, alone and in combination with each other. TABLE IS - Part I Statistical Analysis of the Causes of Death Asbestos Cause Asbestosis No Asbestosis Total Percentage Lung Cancer No Lung Cancer Total Percentage 1 ( .2) J. <**> 4 8.2 2( 2.3) _4J<2.2) 45 91.8 3 46 49 6.1 93.9 Figures in parenthesis are the'"expected" numbers TABLE 18 - Part E Statistical Analysis of the Causes of Death Thetford Mines Cause Asbestosis No Asbestosis Total Fercentaee Lung Cancer No Lung Cancer Total Percentage J< 1.3) 25(28.7) 28 21.2 3 ( 4.7) 101(99.3) 104 78.8 6 126 132 4.5 95.5 Figures in parentb esis arc the ' expected" numbers TABLE 18 - Par: 21 Statistical Analysis of the Causes of Death -^Asbestos and Thetford Mines Combined \ Cause Asbestosis No Asbestosis Total Percentage Lung Cancer No Lung Cancer Total Percentage 4{ 1.6) 28(30.4) 32 17.7 5( 7.4) 144 (141.6) 149 82.3 9 172 181 5.0 95.0- Figures in parenthesis are the " expected" numbers Six deaths from unknown causes not included The number of long cancer deaths combined with asbestosis is larger than would be expected tn each cohort and in the combined cohorts. This difference is significant at the 957". level using the chisquare test of significance. The Importance of the under-reporting of asbestosis can be observed in Table J9. > 54. TABLE 19 Statistical Analysis of the Causes of Death if 20 Nonasbestosis Cases had been Diagnosed as Asbestosis Cases Cause Asbestosis No Asbestosis Total Percentage Lung Cancer No Lung Cancer Total Percentage 4( 2.6) 48.(49.4) 52 28.7 5( 6.4) _124^(122.6) 129 71.3 9 .172 181 5.0 95.0 Figures in parenthesis are the "expected" numbers In this table, it has been assumed that 20 of the cases which did not have lung cancer and which were reported to have no as'oestcsis did. intact, have asbestosis, the diagnosis of which was missed. Although the cases of lung cancer with asbestosis are still higher than would he expected, the difference is no longer significant at the 95% level. This still is true if fewer than 20 cases were shifted but it is reasonable to expect that at least 20 of the 144 might have shown asbestosis had they been sublect to actepsy. On the other hand, a shift of about 40 cases would produce an expected rate almost equal to the rate found. Explanation of this effect of under-reporting of as bestosis has been stressed because it seems so obvious that in under reporting asbestosis the relationship between it and lung cancer.has been made to appear more significant than it probably is._____ Four of the proved cof lung cancer *rd one of the suspected were associated with asbestosis. Since we have only 32 deaths in which asbestosis was present according to the records, the incidence in this series is 12.5%, wnile this is slightly lower than the rates found by Meriwether, Gloyne, and Wedler, it is still much higher than could be expected ii the asbestosis incidence were anywhere near the experience reported by other authors. Comparison of the Cohort Experience with that of the Province of Quebec, Domruon of Canada, and the Unitec States In order to make a comparison of the experience among > asbestos miners with that of the general population of the Province o: Quebec, statistics were gathered, as stated earlier, in the office of the Division of Demography in the Provincial Ministry of Health. Toe data on total deaths, deans from all forms of cancer, and deaths from cancer of the lung were obtained by sex and by county for the years 1950 through 1955. In addition, all death certificates which specified primary cancer of the lung, and all those which indicated lung cancer but did not specify the origin, were examined for the years 1952 through 1955. Table 20 gives a tabulation of the number of deaths from lung cancer in the Province and in the two cohorts for the years 1950 . through 1955, and shows the annual rate per 100,000 in these segments. 56. It will be noted from the table that the mortality rate for the Asbestos cohort is almost exactly the same as that for the Province, while the rate for "proved" cases in the Thetford Mines cohort is only slightly higher. When the "suspected" cases are included in the calculation, the rates for tha Thetford Mines cohort rises to 41.4 per 100.000 which is nearly twice as high as the rate for the Province. This, it will be recalled from the previous discussion of the `'suspected" cases, ap proaches but does not exceed the significant level. . One further interesting observation from Table 20 is the ratber marked increase in the total number o: cases for the Province between 1950 and 1955. It is assumed that at least part of this Increase is due to improved recognition and reporting oi lung cancer during the interval. For this reason, the years 1954 and 1955 were thought to be more nearly representative of actual conditions. Sven so. it is quite likely that the general population is not studied for lung cancer with the same diligence with which this disease is looked for in the miners, and it seems probable that Che mortality rates for the Province would tend to be low. This would appear to be substantiated by the fact that the reporting of cases in the combined cohort showed no such increase over the same oeriod. Table 21 was compiled to show the annual age-specific lung cancer rate of cases \a which tb* death certificate merely read "cancer of the lung", as distinguished from those in ~hich~th diagnosis was T A IIL E 20 A p p ro x im a te m id -p o in t o f Ih e e n u m e ra te d p o p u la tio n fo r 1 0 5 1 , a n d tl.e c a t (m a te d p o p u la tio n fo r 1954 (R a p p o rt. Illv , de la D e m o g ra p h ic) M a * 58. confirmed by autopsy, surgery, or biopsy. The term "specified primary" refer* to those cases in these same two categories in which the tumor was specified as having originated in the lung. It will be noted that, of the total cases certified in 1955, a much higher percentage than in 1954 was specified as primary. The table also shows that a higher percentage of the total cases certified in 1955 were proved, again indicating increasing Interest in this disease. A comparison has been made between the agc-specific rates shown in Table 21, and these for the cohort shown in Table 6. An average of the 1954 and 1955 rates for the Province has been used, since the 1955 figure was higher and =ay have been exceptional. This comparison, summarised m Table 22, shows that the observed number of deaths in our sample is not significantly greater than the expected number of deaths, baaed on the average of the 1954 and 1955 figures for the Province. It is true that, in the case of the age group of 65 and over, the five deaths provide a figure which is al most significant at the 95 level. However, it should be acted that this number includes one of the suspected but unproved cases previously referred to. Furthermore, it is rather likely that the rate for the gen eral population is understated in this age group, for the obvious reason w that the exact cause of death in the very old is not a matter of the same intensity of interest as it is in younger persons. 59. Before leaving this comparison of the Province with the miners, it should be shown that their age distributions are reasonably the same. That this is the case can be observed from the following tabulation: Age Distribution of Adult Males for the Province of Quebec, 1951 (Rapport, 1954) Age Grouo 20-44 45-54 55-64 65 * Total Number 727,135 188,952 128,944 113.467 1,158.496 Percer.taee 63 16 11 10 100 Percentage Combined Cohorts 66 19 10 5 ICO It should be remembered that the miners retire and con sequently. it can be expected that the oldest age group will be larger in the general population. The data presented in Table 23 indicates that the lung cancer rate generally decreases after age 70, and we could expect the rate for all people over 65 would be smaller than the rate for a group of 65 to 75, which would apply to the oldest group of miners. It is felt that by using the whole adult male population, we have developed rates which are somewhat lower than if we had been able to exclude the general population over 75. *; - if T A B L E 21 ^ IA f- ^(lA lA lAltA oi* VU II i*\ u n s= 5= 8.^ MV *A ~ C' . --> M - C. o a c- * o --- * < OAAA ^ AOr uO o ws 2- Jl - 2. o aa 60. i <r f O t m 1* m *r -N N ZZZ . l ? O lA *A lA * n y>^0 61. TABLE 22 Comparison oi the Actual and Expected Number of Lung Cancer Deaths by Age Among Asbestbs Miners Age Cr ouo Province Total Specified Primary Bate per 100, 000 No. of Miners Expected** No. of Deaths Observed No. of Deaths Proved Total 20-44 45-54 55-64 65 4 Unknown 1.8 24.5 67.6 89. 3 3901 1124 615 315 3 0 2 2 2 mm . 1 1 3 4 0 1 3 3 5 0 Actually . 4 * The expected number is bated on the average of the 1954 and 1955 age-specific rates for the Province of Cueoec. Table 22 also answers a question previously raised. It shows that the members of these cohorts have not died from lung can cer at an age earlier than the general population, and that such an ex- planation cannot be offered for the absence of lung cancer in 24G men with more than 40 years of employment referred to on page 37. A comparison between the asbestos miners and the popu lation of the Dominion as a whole was made, using statistical material from several sources. In one source. Phillips ll'l) gave age- and sex- specific rates for Canada for three periods between 1931 and 1952. Toe rates for males are given in Table 23. -- , TABLE 23 Annual Death Rates per 100,000 for Cancer of the Lung in Canada* Age Grouss Under 30 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85 4 All Ages 1931-1933 Grouss of Years 1941-1943 0.2 0.9 2.0 3.0 5.2 8.2 12.7 12.5 15.1 10.7 15.8 8.2 11.4 2.8 0.3 0.9 3.2 5.4 12.5 18.9 27.0 33.7 34.5 30.6 30.0 27.9 14.3 7.1 1950-1952 1.0 0.8 3. 0 6.5 16.7 37.2 59.7 77.8 102.9 66. 3 S3.9 59.7 71.0 15.S * "Mortality from Lung Cancer in Canada". 1931 to 1952. These figures show strikingly the increase in rates be tween 1931 and 1952, and this Increase is particularly marked alter age 50. confirming an observation previously mace, to the effect that lung cancer has probably been under-ciagnosed in the older age group in the general population. To use these figures for purposes of comparison, it is necessary to combine the rates for certain age groups in order to conform to the age distributions used in this study. Since the exact populations in each age group for the years indicated is not known. 63 this must be an approximation. However, the rates would be some what as follows: Age Group 20-44 45-54 55-64 65 Rate 5 27 69 90-95 These rates are, in general, lower than those developed . for the total (proved and suspected) cases of lung cancer among the asbestos miners. The only large difference, however, is in the age group of 65 years and over, and it is quite possible that the rate for this group may havo increased for Canada between 1952 and 1954 as it did for the Province of Quebec. (See Table 21) A further comparison has been mace with an over-all rate obtained from the American Cancer Society for respiratory can cer deaths in Canada in 1953. This rate, for males, is 20.8 per 100,000, an increase of 5 per 100,000 over Phillips' 1950-1952 rate, and compares with 25. 5 per 100, 0C0 for proved cases and 34. C per 100, 000 for total cases among the asbestos miners in this study. It is therefore obvious that there are no important differences between the rates for asbestos miners and those for the general population of Quebec and the Dominion of Canada.  Since it is probable that figures for the United States are more complete and, therefore, possibly more comparable to the data for the miners, age-specific rates were computed from "Vital Statis tics of the United States". Volumes I and II. for 1952. These rates have been tabulated in Table 24. TABLZ 24 Number of Deaths and Death Rates per 100,000 by Age Groups for the Adult Male Population of the United States--Data From "Vital Statistics of the United States", Volumes I and II, 1952 Are Groan 20-44 45-54 55-64 .+ Total "T Population 24,544,000 8,065,000 6.340, 000 5.670.COO 44.6i9.000 Cases 833 2979 6254 6463 16.599 Rate per 100, 0CC 3.6 36.9 98.6 114.3 37.2 It is apparent that these rates compare favorably with those for the asbestos miners as shown in Table 6. Still other rates for the United States were obtained from the American Cancer Society, and for males, these were 25. 3 per 100, 000 in 1953, and 28. 0 per 100, 0C0 in 1955. They are net identical with the rate calculated from the figures of the office of Vital Statistics, but this is possibly because the American 0 Cancer Society rates are for males of all ages. Nevertheless, they, too. compare favorably with the rates of 25 (or 34 for total casesl obtaining among the asbestos miners. . Returning to a comparison between the asbestos miners and person* who arc exposed to asbestos in one form or another (a* distinguished from the general population groups just discussed, who have no exposure) an interesting observation can be developed by de duction. Hneper ' has stated that there are about 35,000 persons exposed in the United States, and we have found that the Canadian mines employ about 6.000. Clsewherc, it has been estimated that the workers ir. England who have exposure total between 3. 0C0 and 5.000. With workers in Africa. Denmark, Norway, and other countries, at least 50,000 persons must be exposed throughout the world, and it can be assumed that this number has been fairly constant in the 10 years since 1935-when the first case of asbestosis w;th lun; cancer was re ported. At least a million man-years of exposure has thus been accumu lated. and this figure can be divided by the approximately 150 cases of lung cancer with asbestosis reported during the 20-year period. This gives a rate of 15 per 100. 000 which is at least indicative that any lung cancer rate which can be calculated for workers exposed to asbestos dust Is not much greater than that for the unexposed persons. 66. Comoarison Between Eight Counties Adjacent to ihe Asbestos-ProducinE Areas ar.e Eight Selected Counties To compare lung cancer mortality rates in the coun ties surrounding the asbestos-producing areas with another group o' counties in which no asbestos miners are lively to reside, the rates were computed on the basis of figures for the years 1950 through 1955. Tot eight counties selected for comparison were Argenteuil, Chateaugay, Montmagny. Pormeuf, Richlieu, Kivieredu-Loup, St. Hyacinthe, and Terrebonne, mainly because they re present a wide geographic distribution throughout the Province. The counties selected because of their proximity to the asbestos mines include Artlfabaska. 3eauce, Drummond, Fror.tenac, Megantic. Richmond. Sherbrooke, and Wolfe. Table 25 shows the number of lung cancer deaths for the years 1950 through 1955 for each of these counties, and a mortality rate, based on the adult male population in 1952. To emphasize the comparison Megantic County has been shown separately, as has the Province of Quebec and also the Pro vince with the eight "asbestos-producing" counties subtracted. Be cause of its unique lung cancer death rate, Montreal et Isle de Jesus has also been listed in order to provide further comparison. 6?  It is apparent frora the table that the lung cancer death rate for the eight counties immediately surrounding the asbestosproducing areas is practically identical with that of eight counties selected for comparison. While Megantic County has a rate nearly twice that of the combined eight selected counties, it is lower than the rate for the Province, and considerably lower than the rate for Montreal. The figure for Montreal would certainly be higher except for the very low numbers of deaths reported for 1950 and 1951, and it would appear that some error in reporting has undoubtedly been made. On the basis of the other years, 1950 and 1951 deaths would be expected to be about 20C greater, and this would result in a rate of -*0 per I0C000. The only possible conclusion frora this comparison is '.1 that there is no evidence that the persons who live in the counties surrounding and adjacent to the asbestos-producing areas have any greater incidence of lung cancer than those who live elsewhere in the Province. Discussion of All Recorded Lung Cancer Cases. Living and Dead, at Aeatos and Thetford Mines Although a simple enumeration of all the known or sus pected cases of cancer of the lung in these areas has no particular value from a statistical point of view, it is 0f interest to summarise 69. such cases for the record. There were nine deaths prior to the be ginning of the time period covered by the study, including one in which the diagnosis was mediastinal lymphosarcoma. AU of these nine cases occurred at Tbetford Mines. I: is somewhat surprising that there is no record of any lung cancer deaths among the Asbestos group in the interval preceding the beginning of the study and equally so that no cases have been reported in 1956 and 1957. During =be period covered by this investigation, there were six proved cases and three suspected cases at Thctforc Mines, as well as three proved cases at Asbestos. Through 1956 and to date in 1957, there were eight deaths at Tbetford Mines, six of which were merely suspected and included'Such diagnoses as mediastinal lymphosarcoma, mesothe lioma, cancer of the leg with xnetastases to lung, absess of lung, and cancer of the pancreas. One other was diagnosed on the basis of x-ray only. In addition, there are now living four cases in which the diagnostic evidenco is strongly suggestive of lung cancer. This is a total of 33 cases of all types, including ten "suspected" but unproved cases, and four that are still living. The remaining 19 constitute the total of proved cases of cancer of the lung in both areas since 1940. Sixteen of these have been at Tnetford Mines and only three at Asbestos, all of which occurred during the period of the study. The proved cases averaged 59 years of age at death, and varied between 37 years~and 68 years.'"Their workmg'span covered 70 periods varying between, a minimum of 14 years and maximum of 37 years. Only three men had less than 25 years of employment in the industry. Seven among those or. whom such information is available had a weighted exposure placing them in category XXX. and six worked in an exposure represented by category!. Although they were subjected to post-mortem examination, there were three among these proved lung cancer cases in which we do not have information regarding the presence of asbestosis. Of the remaining 17, asbestosis was present In nine, although it was minimal in two, and two pathologists disagreed regarding its presence in one. Eight of the proved lung cancers, therefore, were not accompanied by asbestosis.*^ 71 . VI. SUMMARY AND CONCLUSIONS Interest in the question of whether there may be an as % sociation between lung cancer and asbeatosis or exposure to asbes tos has been evident since the report in 1935 by Lynch and Smith of a case in which lung cancer and asbestosis were both present. As additional cases in which the two diseases coexisted were reported, a causal association appears to have been gradually accepted by many authors, although a few workers considered the correlation to be in- * conclusive. Cases of lung cancer which had occurred among the as bestos miners in Quebec bad been carefully recorded over the years, and the present study was commissioned in an effort to determine whether a causal relationship did, in fact, exist between exposure to asbestos and cancer of the lung. Reference to the literature shows a remarkable uniformity both of method and of conclusions. In general, the method has been to study a circumscribed series of cases of asbestosis and to enumerate those in which lung cancer occurred. The series may consist cf cases coming to autopsy or of death certificates mentioning asbestosis, and the total number has served as the denominator by which the number of lung cancer cases is divided to produce a certain "incidence rate". This rate, as reported by various authors has been.consistcntly high, and its uniformity is indicated by the following tabulation.--------- ---------------- 72. Author Merewether Wcdler Wyers Lynch fa Cannon Gloyne Totals Asbestosis Deaths 344 92 115 40 121 712 Cancer . of Lung 55 15 17 3 17 107 Percentage Incidence 16.0 16.3 14.8 7.5 14. 1 15.0 The notable characteristic of all previous publications is the adherence to the development of a percentage relationship in a relatively small and very selected group of cases. Only Doll.'631 among all of these authors, has described a representative population group and studied it for the mortality rate from lung cancer and com pared this rate with that for a control group. His investigation dealt with only 113 men in the study population. Since most earlier studies had been limited to enumerating the lung cancers found in certain selected samples, such as cases coming to autopsy or death certificates in which asbestosis was men tioned, it was apparent that they could not fulfill the requirements of an epidemiological and statistical approach to the problem. The pre sent study was, therefore, designed to meet the requirements of this method. _________After a preliminary survey to explore the availability_of reliable information, data were gathered on workers in the asbestos mines in Quebec, based on medical records at the two main locations of these operations. Cohorts were defined according to certain cri teria and all workers who met these criteria were included in the study. Through their medical records, data relative to their charac teristics were collected and their status at tho end of a six-year period of observation was determined, in the case of those who had died, an exhaustive search of death certificates and insurance records was carried out in order to determine as nearly as possible the exact cause of death. Mortality rates from lung cancer for the general population of the Province of Quebec and its various counties and for the Dominion of Canada, as well as the United States were calculated from statistics collected in the appropriate places. Comparisons of the rates obtained for asbestos workers and for the otter population groups were made according to accepted statistical methods which have been explained in some detail in section IV. Records were obtained on 6091 persons who fulfilled the criteria of our cohorts. It was no: possible to trace 133 of these for the whole period, but 5771 of the remaining 5958 were found to be still living in 1955 or later. Of the 187 known dead, cancer of the lung was considered to have been reasonably proved in nine and to be strongly suggested in three. The members of the cohorts were studied with respect to age,- length of employment, a weighted average of teir exposure, and their smoking habits. Four thousand, six hundred and seventy-three were found to be smokers within the definition of that term *3 used in this study. Thirty-four percent of the cohort were more than 45 years of age, and 30% had been employed for longer than 2C years. Thirty percent had a weighted exposure which placed them in cate gory 111. . The mortality rates for lung cancer, as computed on the basis of six "proved" deaths among the Thetford Mines cohort and throe "proved" deaths among the Asbestos cohort, were 27.6 per 10C. 000 for the Thetford Mines group, and 22.2 per 100,000 for the Asbestos group. When the three "suspected" cases were added, the "total" rate for the Thetford Mines cohort rose to 4i.3. The rate for the combined cohort was 23.5 per 100,000 for "proved" cases, and 34 per 100,000 for "proved" and "suspected" cases. The importance of the suspected but unproved cases in determining these rates has been reiterated be cause it is likely that such cases would not be included in the statistics for the general population. According to the findings in this study, the mortality rate from lung cancer does not appear to increase with length cf exposure or with degree of exposure, a fact which presents strong evidence a gainst the carcinogenicity of asbestos. On the other hand, the study indicates that cigarette smoking is a very important factor in the in- cider.ce of cancer of the lung. A comparison of relative frequency of lung cancer and as- bestosis is less reassuring, but we believe that this is because of an 75. under-reporting of asbestosis cim. The incidence of asbestosis indicated by the medical records ia far below that which would be expected on the basis of all previously published figures. Naturally, when the cases of lung cancer are compared with an artificially low figure, its relative incidence will be higher than it should. However this may be, 12.5% of the recorded cases of asbestosis in this study developed lung cancer, a figure slightly lower than those o.uoted by authors who confined themselves to this type of comparison. Comparison of the experience among the asbestos miners with that of various segments of the unexposed, comparable population shows that the observed number of deaths among the miners is not % significantly greater. The rate for proved cases among the asbestos miners (25.5 per 100,000) compares well with the rate of 22.5 per 100, 000 for the rest of the Province, and 20. 8 per 100, 000 for adult males throughout the Dominion of Canada. It also compares satisfacto rily with rates of 37.2, 25.3, and 28.0 obtained from various sources for adult males in the United States. Finally, in this matter of com parison, it would appear that the world-wide experience of persons ex posed to asbestos dust is not worse with respect to lung cancer than that of the unexposed population. The counties surrounding the asbestos-producing areas, and in which it is presumed most of the asbestos miners live, have almost identical mortality rates with those of eight counties widely scattered 76. through the Province, and are lower than those for the remainder of the Province, and much lower than the rate for Montreal. Since 1940, there have beer. 19 cases in which the diag nosis of primary cancer of the lung may be considered to have been proved. Approximately half of these cases were associated with aabestosis. All but one died in the recognized "cancer age" and at least one-third had only the lightest exposure (category I) to asbestos dust. Conclusions On the basis of a careful and detailed study of what are believed to be complete and reliable data, it seems fair to conclude that the asbestos miners at Tnetford Mines and Asbestos in the Pro vince of Quebec do not have a significantly higher death rate from lung cancer than do comparable segments of.the general population. Dcapitd this, the results suggest that a miner who develops the disease asbes- tosis does have a greater likelihood of developing cancer of the lung than a person without this disease. We suspect, however, that under reporting of asbestosia cases had led to a fallacious finding in this con nection. The death rate from lung cancer in the areas ccntinguous to the asbestos operations is comparable to that in areas widely scattered throughout the Province of Quebec and is lower than in some urbanised areas within the Province. 77. The present study indicates that the effect of cigarette smoking is a much more important consideration in the production of lung cancer than is exposure to asbestos, and in this respect, it tends to confirm recent studies dealing with tbe effect of smoking. The vilue of this investigation would be considerably en hanced by continuing the observation of the cohorts formulated herein on a yexr-by-year basis. It is strongly recommended that the chest x-rays of all workers be subminec to an independent reading for the^ diagnosis of asbestosis, since an inaccurately low incidence rate for this disease creates an artifically high relative incidence for lung cancer. I 78. VII. BIBLIOGRAPHY 1. Adler, I. Primary malignant growths of the lungs and bronchi. London, Longmans. Green U Co.. 1912. p.39. 2. Alascio, Escobar R. Bronchial carcinoma; review of two hundred cases. J. lnternat. Coll. Surgeons. 26: 375-379, September, 1956. . 3. Allen. M.L. Bronchiogenic carcinoma associated with pneumoconiosis; report of two cases. J. Indust. Hyg. 16: 346-347. November. 1934. 4. Amberson, J.B. Some clinical features of pneumoconiosis. New York State J. Med. 49: 830-832, April 1. 1949. 5. American Cancer Society, Inc. Cancer of the lung; an evalua tion of the problem. Proceedings of the Scientific Section, Annual Meeting, Nov. 3-4, 1953. American Cancer Society, Inc. New York, 1956. 322 pp. 6. Anderson, C.S. and Diole, J.K. Silicosis and carcinoma of the lung. J. Hygiene. 38: 185-204, March, 1938. 7. Anderson, R. J. Lung cancer yield in urban mass x-ray surveys. Proceedings of the Scientific Section, Annual Meeting. Nov. .3-4, 1953. American Cancer Society, lac. 8. Ariel, I. M., Avery, E., Kaater, L., Head, J., and Langston, H. Primary carcinoma of the lung; clinical study of 1205 cases. Cancer. 3: 229-239, March, 1950. 9. Arkin. A., and Wagner, D.H. PrLmary carcinoma of the lung; diagnostic study of 135 cases in 4 years. J.A.M.A. 106: 587-591. February 22. 1936. 10. Aufses, A.H. Primary carcinoma of the lung; a 14-year survey. J. Mi. Sinai Hosp. 20: 212-228, SeptemberOctober. 1953. * ll-.Baader, E.W. Asbestosis. Deutsche med. VTochschr. 65: ________ 407-408, March 17. 1939. 79. 12. Banyai, A. L. Nontuberculous diseases of tie chest. Springfield. 111., Charles C. Thomas. 1954. 1139 pp. 13. Banyai, A.L., ar.d Peabody, J. W. Pulmonary adenoma tosis. Non tuberculous diseases of the cheat. Springfield, 111., Charles C. Thomas, 1954. pp. 416-422. 14. Bastenier. H., Denolir., H.. Dccoster, A., and DenoiinReubens.R. A clinical and pathological study of a case of pulmonary asbestosis. Arch. Beiges Med. Sociale. Hyg., Med. Trivial et Med. Legale. 10:61-70, February, 1952. 15. Bauer, J.T. A review of the primary carcinomas of the lungs and pleurae occurring in six thousand consecutive necropsies. Bull. Ayer Clin. Lab. Pennsylvania Kosp. 3: 139-188, October, 1938. 16. Behrens, W. Experimental asbestosis. Schwela. Ztschr. Allg. Path. U. Bakt. 14: 275-297, 1951. 17. Behrens, W. Jr. The clinical picture and pathology oi asbestosis. Z. Uniallmcd. u. Berufkrankh. 45: 129-140, June 15, 1952. 18. Berbiiager, W. Increase of lung cancer and diseases due to dust Inhalation. Med. Kiln. 27: 1337-1342, September 11, 1931. 19. Berenblum. 1. Irritation and carcinogens. Arch. Path. 38: 233-244, October, 1944. 20. Berg, B.N. A pilot program for cancer detection in industry. A.M.A. Arch. Indust. Hyg. 3: 279-286. March, 1951. 21. Bittner, J. J. Spontaneous lung carcinoma in mice. Pub. Health Rep. 53:2197-2202, December 16, 1938. 22. Black, K., and Ackerman, L.V. The importance of epider moid carcinoma in situ in the histogenesis of carcinoma of the lung. Ann. Surg. 136: 44-55, July, 1952. 9 23. ' Bloch, R.C., Adams, W.F., Thornton, T. F*. Jr., and ----------------- Bryant, J. E. .Difficulties in the differential diagnosis of---------bronchiogenlc carcinoma. J. Thoracic Surg. 14: 83-9", April. 1945. BO. 24. Boemke, F. Das lungenkarzinom in der asbeststaublunge . Med. Monatsschr. 7: 77-81, February, 1953. 25. Bohlig, H., and Jacob, G. New viewpoints on pulmonary cancer in asbestos workers. Deutsche med. Wochschr. 81: 231-233. February 17, 1956. 26. Bohme. A. Asbestosis. Deutsche med. Wochschr. 62: 928-930. 1936. 27. Bohme, A. Results of periodical examinations of workers in an asbestos factory. Beitr. r. Silikose Forsckung. 11: 34. 1951. 28. Bondi, G., and Leites, V. Malignant neoplastic disease discovered in chest x-ray surveys. New England J. Med. 247: 506-512, October 2. 1952. 29. Bonner, L. Primary lung tumor; report of six cases with necropsies. J.A.M.A. 94: 1044-1049, Aprils, 1930. 30. Bonser, G.M., Faulds, J.S., and Stewart, M.J. Occupational can"cer of the urinary biadder in dyestuffs operatives and of the lung in asbestos textile workers and iron-ore miners. Am. J. Clin. Path. 25: 126-134, February. 1955. 31. Bowles, O. Asbestos-milling, marketing and fabrication. U. S. Bur. Mines Inf. Cixc. No. 6869. 1-26, 1935. 32. Boyd, W. Some reasons for recent increase of bronchial carcinoma. (Thomas Dent Mutter lecture). Tr. Stud. Coll. Physicians. Philadelphia. 6: 317-328, February, 1939. 33. Brandt. A. Report on examinations carried out in the Schneeberg district at the instigation of the Reich Comm ittee for Cancer Research. Ztschr. . Krebsforsch. 47: 108-111, 1938. 34. Breslow, L. Occupational factors in lung cancer; preliminary report. Pub. Health Rep. 68: 286-288, March, 1953. 35. Breslow, L., Hoaglin, L.. Rasmussen, G., -nd Abrams; H. K. Occupations and cigarette smoking as factors in lung ---------------- cancer.- Am. J. Pub. Health. 44: 171-181. February, 1954 81. 36. Breslow, L. Industrial aspects of bronchiogenic neoplasm#. Dis. Chest. 28: 421-430, October. 1955. 37. Brindley. G. V.. Jr. Early recognition of pulmonary neoplasms. GP, Journal of the American Academy of General Practice. 12: 62-73, October. 1955. 38. Bristol. L. J. Roentgenologic aspects of silicosis and asbestosis. A. M.A. Arch. Indust. Kyg. 11: 189-195. March. 1955. 39. Brockbank, W. Occupational incidence of primary lung cancer. Quart. J. Med. 1: 31-40, January. 1932. 40. Bromley. J. F., Wood. W.B., Elbr.ao. P. Pneumoconiosis. Part II and 111. Pulmonary asbestos. Brit. J. Radiology. 7: 277-280:281-295. 1934. 41. Brown. J.H., Cook. K.M., Ney, F.G.. and Hatch, T. Influence of particle sire upon the retention of particulate matter In the human lung. Am. J. Pub. Health. 40: 450-458. April. 1950. % 42. Cartier. P. A contribution to the study of asbestosis. Arch. mal. profess. 10: 539-595. 1949. 43. Cartier, P. Discussion on asbestosis cancer of the lung. A. M.A. Area. Indust. Hyg. L Occup. Med. 5: 262-263, 1953. 44. Cartier, P. Some clinical observations of asbestosis in mine and mill workers. A.M.A. Arch. Indust. Health. 11: 204-207. 1955. 45. Clerens, J. Research into pulmonary asbestosis in Belgium. Arch. Beige* Med. Sociale. Hyg., Med. du Travail and Legale. 8: 557-565, November, 1951. 46. Clcrf, L.H.. and Crawford. B.L. Eronchiogenic carcinoma; with special reference to classification, prognosis and treatment. J. Thoracic Surg. 3: 73-85. October, 193$. 47. Clynes. Asbestosis and silicosis. Brit. Mod. J. 1: 379, 1931. 82 48. Coffin. G.J., Duryee, H.C., Maler. K.C.. Pardee, H.E.B.. ' and Wynter, E. L. The effects of tobacco smoking. Panel Meeting. Bull. New York Acad. Med. 32: 133-156, February, 1956. 49. Cohart, E.M. Lung cancer and economic status. Cancer. 8: 1126-1129, Novcmber-December, 1955. 50. Cooke, W.E. Pulmonary asbestosis. Brit. Med. J. 2: 1024 1025, December 3, 1927. 51. Cooke, W.E. Fibrosis of the lungs due to the inhalation of asbestos dust. Brit. Med. J. 2: 149, 1927. 52. Cooper, E.H. An important factor in the causation of industrial cancer. Med. Press. 187: 397-398, 1933. 53. Cornfield, J. A method of estimating comparative rates from clinical data: application to cancer of the lung, breast and cervix. J. Nat. Cancer Inst. 11: 1269-1275, June, 1951. 54. Cruickshaak. W.K. Report on cancer in industry. Division Industrial Hygiene, Ontario, Canada. 14. 1941. 55. Cureton, R. J.R. So.uarr.ous cell carcinoma occurring in asbestosis of the lung. Brit. J. Cancer. 2: 249-253, September, 1948. . 56. Cutler. S.J.. Schneiderman. M.A., and Greenhouse. S.W. Some statistical consideration in the study of cancer In industry. Am. J. Pub. Health. 44: 1159-1166, September, 1954. 57. Davies, D. F. Current status of lung cancer research; some pathogenetic aspects. Ca, American Cancer Society, Inc. 6: 169-174. September, 1956. 58. Dennis. J.M., Raby. W.T., and KSlder.brand. E.J.C. Pulmonary adenomatosis. Ann. Ir.t. Med. 36: 667-678, (Pt. 2) February. 1952. 59. Desmeules, R. . Rousseau, L., Giroux, M. , and Sirois, A. Amiantose et cancers puimonaires. Scmaiae d. hop. __________ Paris..2JliJ.829r.LH3- August 7. 1947.________________ 60. Dhers. V. Asbestos and pulmonary asbestosis. Med. Trav. 2: 147-209. 1930. 61. Dick, J.C. Carcinoma of the bronchus; investigation into incidence and pathological features of 131 cases from Glasgow Royal Infirmary. Glasgow Med. Jour. 134: 63-78, September, 1940. 62. Doll,' R. Bronchial carcinoma; incidence and aetiology (Milroy lectures, abridged). Brit. Med. J. 2: 521-52", September 5. 1953; 585-590. September 12. 1953. 63. Doll, R. Mortality from lung cancer among asbestos workers. Brit. J. Indust. Med. 12: 81-86, 1955. 64. Donnelly, J. Pulmonary asbestosis. Am. J. Pub. Health. 23: 1275-1281, December. 1933. 65. Dorn, H.F. Incidence and prevalence of cancer of the lung. Pub. Health Rep. 58: 1265-1271. August 20. 1943. 66. Dorn, K.F. The increase in cancer of the lung. Incust. Med. aadSurg. 23: 253-257, June, 1954. 67. Dorn. H.F., and Cutler, S.J. Morbidity' from cancer in the^Cnited States. Pub. Health Monograph No. 29. P.H.S. Publication No. 418. Washington, U.S. Government Printing Office, 1955. 121 pp. 68. Dorn, K.F. Cancer morbidity surveys; a tool fox testing theories of cancer etiology. Am. J. Pub. Health. 45: 615-621, May. 1955. 69. Editorial. Asbestosis and cancer of the lung. J.A.M. A. 140: 1219-1220. August 13. 1949. 70. Editorial. Atmospheric carcinogens, i-ancet. 2; 30. July S. 1952. 71. Egbert. D.S., and Geiger, A.J. Pulmonary asbestosis and carcinoma: report of a case with necropsy findings. Am. Rev. Tuberc. 34: 143-150. July. 1936. 72. Ehlcr, A.. Stranahan, A., and Olson, K. B. Bronchogenic carcinoma: a study of 51" cases. New England J. hied. 251: 207-213. August 5. 1954. --. 73. . " Ellman. P.~Pulmonary asbestosis; its-ciinical radiological. -- and pathological features anc associated risk of tuberculosis Infection. J. Indust. Hyg. 15: 165-183. July. 1933. 84. 74. 75. Eliman, P. Pulmonary asbestosis. Proc. Roy. Soc. Med. 34: 557, July, 1941. Farber, S.M., and Tobias, G. Primary cancer of the lung. Rev. Pan-Americana de Mcdicina Y Cirugia Del Torax. 1: 82, 1947. 76. Farber, S.M., and Alston, E.F. Primary carcinoma of the lung. Nontuberculous diseases of the chest. Springfield, 111, Charles C. Thomas, 1954. pp. 394-416. 77. Faulds, J., cited in Bor.ser, G.M., Faulds, J., and Stewart, M.J. Occupational cancer. Am. J. Clin. Path. 25: 126-134, 1955. 78. Fell, A. Pneumoconiosis in asbestos workers. Presse rr.ed. 39: 1872-1874, December 19. 1931. 79. Feil, A. Relation between pneumoconiosis and pulmonary carcinoma. Presse med. 43: 212, February 6, 1935. 80. F owlet,- R. Some observations on the epidemiology of lung cancer. Med. J. Australia. 1: 485-494, April 27, 1955. 81. Freedlander, S.O., and Greenfield, J. Hemoptysis in metastatic rumors of the lung simulating bronchiogenic carcinoma. J. Thoracic Surg. 12: 109, 1942. 82. Fulton, J.S. Carcinoma of the lung. (President's address). Proc. Roy. Soc. Med. 42: 775-782, October, 1949. - ' 83. Fulton, W.B., Dooley, A., Matthews, J. L., and Houtz, R. L. Asbestosis. Part III, The effects of exposure to dust encountered in asbestos fabricating plants on the health of a group of workers. Special Bull. No. 42, Penn. Dept, of Labor and Industry. Bur. of Indust. Standards, September 20, 1935. - -' . 84. Gardner, L.U. Chrysotile asbestos as indicator of subtile differences in animal tissues. Am. Rev. Tuberc. 45: 762-766, June, 1942. 85. Gardner, L._U., and Cummings, D. ._ Studies_on..experimental pneumoconiosis; inhalation of asbestos dust: its effect upon primary tuberculous infection. J. Indust. Hyg. 13: 65-81, February; 97. March. 1931. 86. George, A.W., and Leonard, R.D. An x-ray study of the ' lungs of workmen In the asbestos industry covering a period"bf ten years. Radiology. 33: 196-202, August. 1939. 87. Gerbis, H., and Ucko. Asbestosis. Deutsche med. Wochschr. 58: 285-287, February 19. 1932. 88. Gibbon. J.H., and Nealon. T.F. Cancer of the lung. Seminar (Sharpe L Dohme). 20-28, Fall, 1953. 89. Gilliam, A.G. Mortality trends in lung cancer. Cancer. 8: 1130-1136. November - December, 1955. 90. Gilliam, A.G. Mortality attributed to lung cancer in the large cities of the United States in 1948 and 1949. J. Nat. Cancer Inst. 15: 1307-1312, 1955. 91. Gloyne. S.R. Two cases of squamous carcinoma of the lur.g occurring in asbestosis. Tubercle. 17:5-10, October. 1935. 92. Gloyne* S.R. Pneumoconiosis; a histological survey of necropsy material in 1205 cases. Lancet. 1: 810-814, April 14, 1951. 93. Gloyne, S.R. A case of oat-cell carcinoma of the lung occurring in asbestosis. Tubercle. 18: 100-101, December, 1936. 94. Gloyne, S.R., and Merewether, E.R.A. Asbestos. Occupa tion and Health, Supplement to Endyelopedia on Occupation and Health. Geneva, Internal. Lab. Office, 1938. 95. Goldblatt, M.W., and Goldblatt. J. Industrial carcinogenesis and toxicology. Edited by E. R.A . Merewether. Indust. Med. i- Kyg. 3: 185-188, 19S6. London. Butterworth L Co.. Ltd. 96. Gordon, E.. Jr. Pulmonary asbestosis. Pennsylvania Med. J. 35: No. 9. 637-639. June. 1932. ' 97.. Haddow, A.C. Clinical aspects of puimonary-asbestosis.' _Br11. Med. J. 2: 580-58i. September 28, 1929- _ 86. 98. Haeaszel, W.M. Epidemiological tests of theories on ' lung cancer etiology. Pub. Health Rep. 71: 163-172, February. 1956. A 99. Haenszel. W.M., Marcus, S.C., and Zimrr.erer, E.C. Cancer morbidity in urban and rural Iowa. Pub. Health Monograph No. 37. P.H.S. Publication No. 462. Washington, U.S. Government Printing Office, 1956. 100. Hammond, E.C. Lung cancer and common inhalant*. Cancer. 7: 1100-1108, November. 1954. 101. Hammond, E.C. Etiology of bronchiegeaic carcinoma. Ca., American Cancer Soc. , Inc. 6: 156-168, September, 1956. 102. Heston, W.E. Genetics in cancer of the lung. Cancer of the lung. Proceedings of the Scientific Section, Annual Meeting, Nov. 3-4. 1953. American Cancer Society, Inc. 103. Hewitt, D., and Brooksbaak. W.E.C. A comparative study of cancer mortality in England and the United States. Am^J. Pub. Health. 42: 980-992, August, 1952. 104. Hoileb, H.B., and Angrist, A. Bronchiogenic carcinoma in association with pulmonary asbestosis; report of two cases. Am. J. Path. 18: 123-135, January. 1942. 105. Homburger, F. The co-incidence of primary carcinoma of lungs and pulmonary asbestosis: analysis of literature and report of two cases. Am. J. Path. 19: 797-807, September, 1943. 106. Horn, D. Is lung cancer or. the increase? Evaluation of present day evidence. Cancer of the lung. Proceedings of the Scientific Section, Annual Meeting, Nov. 3-4. 1953. American Cancer Society, Inc. 107. Kornig, F. Clinical considerations on the o.uestlon of industrial cancer of asbestos workers. Ztschr. f. Krebsforsch. 47:281-287, 1938. ' 108. Homing, E.S. Studies on induction of lung cancer in mice. Brit. J. Cancer. 4: 235-244. June, 1950. B7 109. Hueper, W.C. Cancer in it* relation to occupation and environment. Bull. Are. Soc. Control Cancer. 25: 63-69. June. 1943. . 110. Hueper, V/.C. Significance of industrial cancer in the problem of cancer. Occup. Med. 2: 190-200, September,, 1946. 111. Hueper, W.C. Industrial management and occupational cancer. J.A.M.A. 131: 738-741. June 29. 1946. 112. Hueper, W.C. Clinical aspects of occupational cancer. Occup. Med. 5: 157-165, February, 1948. 113. Hueper, W.C. Environmental and occupational cancer. Pub. Health. Supplement 209. Washington, D.C.. 1949. 69 pp. 114. Hueper, W.C. Present and potential occupational cancer hanards and carcinogenic operations in modern industry. Southern Med. J. 43: 118-124, February, 1950. 115. Hueper, W.C. Carcinogen* and carcinogenesis. Am. J. Med. 8:355-371, March. 1950. 116. Hueper. W.C. Environmental factors in the etiology of cancer. Medical Annals of the District of Columbia. 19: 10-17. January, 1950. 117. Hueper, W.C. A methodology for environmental and occupational cancer surveys. Pub. Health Monograph No. 1. P.H.S. Publication No. 12. Washington. U. S. Government Printing Office, 1950. 118. Hueper, W.C. Environmental lung cancer. and Stirg. 20:49-62, February, 1951. Indust. Med. 119. Hueper. V/.C. Age aspects of environmental and occupa tional cancer. Pub. Health Rep. 67: 773-779, August, 1952. 120. Hueper, W.C. Occupational and environmental pulmonary cancers with speciai reference to pneumoconiosis. Proceedings7"0' Saranac Symposium'on Pneumoconiosis. 1952. 121. Hueper, W.C. Environmental lung cancer. Indust. Med. and Surg. 23: 463-467, October 1. 1934. 122. Hueper, W.C. A quest into the environmental causes of cancer of the lung. Pub. Health Monograph No. 36. P1H.S. Publication No. 452-. Washington, U.S. Government Printing Office. 1955. 123. Hueper, W.C. Lung cancers and their causes. Ca., American Cancer.Soc.. Inc. 5: 95-100, May, 1955. 124. Hueper, W.C. Environmental causes of cancer of the lung other than tobacco smoke. Dis. Chest. 30: 141-158, August, 1956. 125. Hunter, D. The diseases of occupations. Boston, little Brown U Co.. 1955. pp. 874-884. 126. Isselbacner. K. J.. Klaus, H., and Hardy, H. L. Asbestosis and bronchogenic carcinoma: report of one autopsied case and review of available literature. Am. J. Med. 15: 721732,-Novetr.ber, 1953. 127. - Jacob. G., and Bohlig, K. Roentgenographic complications of pulmonary asbestosis. Fortschr. Geb. Rontgenstrahlen. 83: 515-525. October. 1955. 128. Jacob. G., and Bohlig, H. Incidence and characteristics of lung cancer in asbestos workers. Arch. Gewerbepath. Gewerbehyg. 14: 10-28, 1955. 129. Jones, J.C., Robinson, J.L. , and Meyer, B.W. Primary bronchiogenic carcinoma of lung. Statistical study of seven hundred four private patients. A.M.A. Arch. Surg. 70: 265-275, February. 1955. 130. Kenaaway. E.L... and Kennaway, N.M. A study o! the incidence of cancer of the lung anc larynx. J. Hygiene. 36: 236-267. June. 1936. 131. Kennaway, E.L., and Kencaway, N.M. Studies of incidence . of cancer of the lung and larynx. Brit. J, Cancer. 5: 153 _158, June. 1951 . ________________ ___________________________ 132. IGota, M.O. Association of silicosis and carcinoma of the lung". Am- J. Cancer. 35: 38-49. January, 1939. 133. Lanza. A.J.. McConnell, W.J., and Fehnel, J.W. The effects of the inhalation of asbestos dust on the lungs of asbestos workers; preliminary study. Pub. Health Rep. 50: 1-12. January 4. 1435. 134. Lanza, A. J. Asbestosls. J.A.M.A. 106: 368-369, February 1, 1936. *135. Lanza. A.J. Silicosis and asbestosis. New York, London, Oxford University Press, 1938. 39 pp. 136. Levin. M. L.. Kraua. A.S.. Goldberg. I.D.. and Gerhardt. F.R. Problems in the study of occupation and smoking in relation to lung cancer. Cancer. 8: 932-936, September-October, 1955. 137. Lew, E.A. Use of life insurance company records for cancer studies. A.M.A. Arch. Indust. Hyg. 5: 195 203, March, 1952. 138. Linzbach, A.J.. and Wedler, H.W. Occupational cancer among asbestos workers. Virchows Arch. f. path. Anacr 307: 387-409. 1941. 139. Lynch, K.M., and Smith, V/.A. Pulmonary asbestosis; carcinoma of lung in asbesto-silicosls. Am. J. Cancer. 24:56-64. May, 1935. 140. Lynch. K.M., and Smith. W.A. PuLmonary asbestosis: a report of bronchial carcinoma and epithelial meta plasia. Am. J. Cancer. 36: 567-573, August, 1939.. 141. Lynch, K.M., and Cannon, V.'.M. Asbestosis: analysis of forty necropsied cases. Dis. Chest. 14:874-889, November-Decembcr, 1948. 142. Lynch, K.M. Asbestos. Cancer of the lung. Proceedings of the Scientific Section, Annual Meeting, Nov. 3-4, 1953. American Cancer Society, Inc. pp. 115-118. 143. . Lynch, K.M., and Pratt-Thomas, H. R. Carcinoma of the lung in asbestosis: report of two additional cases. Southern Med. J. 48: 565-568, June, 1955." , 144. Lynch. K.M.. Melver." F.A., an'd~Cain.-J7R7 ' Pulmonary tumors in mice exposed to asbestos dust. A.M.A. Arch, of Isdust. Health. 15: 207-214, March. 1957. 90 145. MacDonald, I. Environmental factor* of occupational origin related to carcinogenesis. J.A.M.A. 157: 5-7, J&nuiry 1, 1955. . 146. McConnell, R. B., Gordon. K.C.T., and Jones, T. Occupational and personal factors in the etiology oi carcinoma of the lung. Lancet. 2: 651-656, October 4, 1952. 147. McPheeters. S.B. A survey of a group of employees exposed to asbestos dust. J. Indust. Hyg. and Toxicol. 18: 229-239. April. 1936. 148. Mata, P.B. Incidence of primary bronchiogenic car cinoma. J.A.M.A. 111: 2056-2092, December 3, 1938. 149. Mayer, Edgar and Rappaport, I. Industrial diseases of the lung; the pneumoconiosis. Nontuberculous diseases of the lung. Springfield, 111., Charles C. Thomas, 1954, pp. 716-768. 150. Mayers, M.R. Industrial cancer of the lungs. Compens. Med. 4: 11-18, March-May, 1952. 151. Mesne. F.R.. and Anderson, M.W. Bronchiogenic carcinoma; incidence in the Pacific Northwest with commentary on 84 cases. J.A.M.A. 117; 2215-2222, December 27, 1941. 152. Merewether, E.R.A. The occurrence of pulmonary fibrosis and other pulmonary affections in asbestos workers. J. Indust. Hyg. 12: 198, May; 239, June, 1930. 153. Merewether, E.R.A., and Price, C.'A*. Report on effects of asbestos dust or. the lungs and dust suppression in 'hr asbestos industry. London, H.M.S. O., 1930. 154. Merewether. E.R.A. A memorandum on asbestosis. Tubercle. 15: 69-81, November. 1933: 109, December. 1933; 15: 152. January. 1934. . 155. Merewether. E.R.A. Annual reports of the chief inspector of factories. London, H.M.S.C., 1947. 156. Merewether, E.R.A. Industrial medicine and hygiene. 3: London, Butterworth L Co.. Ltd., 1956. 617 pp. 92. 169. Paul. L. W.. and Ritchie. G. Pulmonary adenomatosis. ` Radiology. 47: 334-343. October. 1946. 170. Peterson. E. W.. and Houghton. J. D. Pulmonary adeno matosis; report of two cases. New England J. Med. 244: 429-433. March 22. 1951. 171. Phillips, A. J. Mortality from cancer of the lung in Canada (1931-1952). Canad. Med. A. J. 71: 242-244. September. 1954. 172. Pullen. R.L. (Editor). Pulmonary diseases. Philadelphia. Lea and Febiger. 1955. 669 pp. 173. Pulmonary Abstracts. Volumes I and U. New York. Toronto, and London. Pitman Publishing Corp.. 1953. 174. Rombola. G. Asbestosis and pulmonary carcinoma in an asbestos spinner; notes on the induction of lung cancer by asbestos fibers. Med. lavoro. 46: 242-250. April. 1955. 175. Rosenblatt. Milton 3.. and Lisa. J. Cancer of the lung. New York. Oxford University Press. 1956. 176. Salta. G. Occupational tumors of the lung. Mec. lavoro. 39: 105-116. April. 1948. 177. Saupe. E. Further contributions to the roentgenological diagnosis of asbestosis. Arch. f. Gewerbepath. u. Gewerbehyg. 9: 391-406. 1939. 178. Sayago. G., and Rocca. J. B. Frequency of cancer of the lung ir. private practice. To rax. 2: 47-32. March. 1953. 179. Schilling. R.S:F.. Hughes. J.P.W.. and Dingwall-Fordyce. J. Disagreement between observers in an epidemiological study of respiratory disease. Brit. Mec. J. 1: 65-68, January 8. 1955. 180. . Siltabach. L. E. Carcinoma simulating pulmonary tubercu losis; differential diagnosis in presymptomatic stage in two cases. Am. Rev. Tuberc. 55: 170-176, February. 1947. . - 93 181. Smith, K. W. Pulmonary disability in asbestos workers. ' A.M.A. Arch. Lndust. Hyg. 12: 198-203. August. 1955. 182. Smith. L.W. Pneumoconiosis arc lung cancer with special reference to silicosis and asbestosis. Cotnpens. Med. 2: 3-10, November. 1949. 183. Smith, W.E. Survey of some current British and European studies of occupational tumor problems. Part III, Asbestos. A.M.A. Arch. Indust. Hyg. 5: 242-263. March. 1952. 184. Stewart. K. L. Geographic considerations in the iungcancer problem. Cancer of the Lung. Proceedings of the Scientific Section. Annual Meeting. Nov.3-4. 1953. American Cancer Society, Inc. 185. Stewart. M. J., and Haddow, A. C. The Immediate diag nosis of pulmonary asbestosis at necropsy. Brit. Med. J. 2: 509. 1928. 186. Stocks. P. Regional and local differences in cancer death rates; studies on medical and population suojects. No. 1. Great Britain. H. M.S. O.. General Register Office. 1947. 46 pp. 187. Stocks. P. Endemiology of cancer of the lung in England and Wales. Brit. J. Cancer.- 6: 99-111. June, 1952. 188. Stocks. P. Statistics of cancer of the lung. J. Pac. Radiologists. 6: 166-173. January. 1955. 169. Stoll. R., Bass. R.. and Angrist. A. Asbestosis associated with broacbiogenlc carcinoma. A.M.A. Arch. Int. Med. 88: 831-634, December. 1951. 190. Stone. M.J. Clinical studies in asbestosis. Am. Rev. Tuberc. 41: 12-21. January. 1940. 191. Swain. W. Cases of tumors of the lungs and mediastinum simulating pulmonary tuberculosis. Med. Record. 84: 888, 1913. . 192. Telcky. L._ Der berufllche lungenkrebo. Acts Unio Internat. Contra Cane rum. Paris. 3: 253-273. 1938.' ''Also. Zentr. Gewerbehyg. Unfallverbut. 27: 33. 1940. 94 193. Tylecote, F.E.. a ad Dunn. J.S. Case of asbestos-like bodies in lungs of coal miner who had never worked in asbestos. Lancet. 2: 632-633, September 19, 1931. 194. Uniker. W. Broachlogenic carcinoma in situ. Cancer. 5*: 369, March. 1952. 195. U. S. Public Health Service. asbestos textile industry. August, 1938. A study of asbestoais in the Public Health Bull. No. 241, 196. Vorwald. A.J.. and Karr. J. W. Pneumoconiosis and pulmonary carcinoma. Am. J. Path. 14: 49-58, January. 1938. 19". Vorwald. A.J. Variations In individual susceptibility to industrial dusts inhaled into the lungs. Am. Rev. Tuberc. 62: No. IB. 13-21. July. 1950. 198. Vorwald. A.J.. Durkan. T.M.. and Pratt. P. C. Experimental studies of asbestosis. A.M. A. Arch. Indust. Hyg. 3: 1-43. January. 1951. v 199. W.eler, H. W. Asbestose und lungenkrebs. Deutsche med. Wocbscbr. 69; 575-576. August 6. 1943. 200. Wegelius, C. Changes in the lungs in 126 cases of asbesto sis observed In Finland. Acta radiol. 28: 139-152, 1947. 201. Weil. C.S. Asbestosis: a literature review. May. 1943. (Unpublished). 202. Weiss, A. Pleural cancer associated with pulmonary asbestosis verified morphologically. Medizinische. 4: 93-94. January 17, 1953. 203. Wells, H.G.. Slye. M.. and Holmes. H.F. The occur rence and pathology of spontaneous carcinoma of the lung in mice. Cancer Research. 1: 259-261. April, 1941. 204. . Welz. A. Further observations on occupational carcinoma in asbestos workers. Arch. f. Gewerbcpath. u. Gewerbehyg. 11: 536-560, November 10. 1942. 95. 205. . Werber, M. Pulmonary asbestosis associated with carcinoma. Zentralbl. Arbeitsmed. u. Arbeitschutz. 2: 179-180. November. 1952. ' _ 206. Wood. W. B., and Gloyne. S.R. Pulmonary asbestosis complicated by pulmonary tuberculoaii. Lancet. 2: 954-956. October 31. 1931. 207. Wood. W.B., and Gloyne. S.R. Pulmonary asbestosia. Lancet! 1: 445-448, March 1. 1930. 208. Wood. W.B. , and Gloyne. S.R. Pulmonary asbestosia: a review o one hundred cases. Lancet. 2: 1383-1385. December 22. 1934. , 209. Worth. G. Die pneumokoniosen; geschicbte. pathogenete. morphologie. kllnik und rcntgenologie. von Gunther Work und Erich Schiller. Staufen Veriag. Koln. 1954. 898 pp. 210. Wyers, K. Asbestoals. Postgrad. M. J. 25: 631-638, December, 1949. 211. Wynder. E. L.. and Graham. E.A. Etiologic factors In bronchiogenic carcinoma with special reference to industrial exposures; report of eight hundred fifty-seven proved cases. A. M.A. Arch. Incust. Hyg. 4: 221-235. September. 1951.