Document Exr02L69VXNwg8jnqDEKjpgD4

M '17`7- i' - . .. "t ?. f. ^ --- ; WT*>S3^S^f -j iJ CBOUNRSEUALU.TISNEORVICE W. T. Prior Co.. Inc. Hk(r*xcvn* Md. No. 286649 V Vc)Arch. Ind. Health 17 j634, June 1963. An Epidemiological Study of Lung Cancer in Asbestos Miners OANIU C. t&AUN, M.D.. mnd T. DAVIS T8UAM, M.A., Pittsburgh Ever since the pronounced increase 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 environment of' man. The approach used by some workers has been to suspect one or several sub* stances and then set about in an intensive search for lung cancer among persons who have had any exposure to those materials. In this connection, Smith42 writes: "The tendency of authors reporting the coinci dental occurrence of primary lung cancer with silicosis or with any other theoretical etiologic conditions, has been to emphasize the percentage relationship in extremely small series of cases, vffth control cases which are 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 pneu moconiosis, and because persons who show this form of pneumoconiosis often come to autopsy and provide a ready source of material for study. It was in this way that reports of the simultaneous occurrence of lung cancer and asbestosis began to accu mulate after the report of a case by Lynch and Smith ** in 1935. Within the next 10 years, about 15 additional cases were re ported, and in 1954 Merewether7* reviewed all deaths from asbestosis recorded in Eng land since March, 1924. Lung cancer oc curred in 16% of these cases. Gloyne,41 Accepted for publication Jan. 20. 1958. This study was made possible through a grant from the Quebec Asbestos Mining Association. Medical Director (Dr. Braun) and Statistic! Ccmsuitaat (Mr. -Troon), Industrial Hygiene whose work is also frequently referred to as establishing a connection between asbes tosis and "cancer of the lung, reported in 1951 that cancer of the lung was present in 14.1% of asbestosis cases examined by him. 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 been reported, and, according to Kueperia about 100 such cases had been reported up to 1955. As a result, an association between the two diseases appears to have been ac cepted by many authors, and several writer* were using the term "asbestosis cancer" of the lung. Werber,5* in 1952, stated cate gorically that in 7% to 17% of cases of asbestosis, after a latent period of about 1 Yz to 20 years, carcinoma becomes estab lished in the lung. On the other hand, not all authors ac cepted this alleged association without reservation. 'Saupe * in 1939 reported that he had discovered no cases of lung cancer among 520 cauas of asbestosis which he had examined; and in 1942, Holleb and Angrist41 expressed the opinion that the number of cases of asbestosis with lung cancer was too small tor statistic! evalua tion. In 1947, Wegeiius11 reported 126 radioiogically diagnosed cases of asbestosis among 476 workers in Finland, and found no cases of lung cancer in this group. Goldblatt and Goldblatt in their section of Merewether's latest book,44 state: "But at no stage in all these impressive researches was any due obtained which might have offered any support to the possibility that asbestos could act as a cardnogen. There A. M. A. ARCHIVES OF INDUSTRIAL HEALTH Limiting the investigation to case> coming to autopsy, as has been frequently done in earlier studies, still further restricts its use in generalization. The problem with which we are concerned is whether asbestos miners experience more lung cancer than does the general population. The answer necessitates the collection of reliable infor mation on asbestos miners as a group, as well as on the general population. It seems advisable to discuss the differ ences 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 stud ied to provide meaningful results. Recognizing the difficulty of obtaining such large samples, most earlier writers deviated from the epidemiological method and sought to circumvent the requirement of observing well person^ by (1) compar ing the relative frequency of cancer in vari ous sites; (2) comparing the relative frequency of cancer in a group of hospital ized patients; (3) comparing the relative frequency of cancer in a group of cases coming to autopsy. . ' Attempting to compare two population groups, looking only at the relative fre quency 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 exactly the same in both groups. This is very clearly dem onstrated in the excellent article by Dorn.30 The mortality rate from a particular cause is the true measure of comparison. It is apparent that selected groups such as hospitalized patients or autopsy cases may not be in any way representative of a larger group, and that in dealing with such samples, the observer may easily find more cases of a gives disease than would 63* be found in another 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 valuable for research, but the use of this information in drawing generalizations is necessarily restricted. It is the obligatior of both the investigator and of those wht read his report to make proper comparison; and to draw only those conclusions whiefr are valid and justified. A good statistica study of cases of cancer of the lung occur ring in a group of autopsies can lead to : proper inference concerning the frequency of lung cancer among cases coming tc autopsy, but only to such cases. For in formation from such a study to be pro jected to some larger group, it is necessar that the autopsies represent a good sampi- of that larger group. To assume that suci is the case in any particular series is dan gerous and likely to -oe false. There is some danger that the figure reported by some authors may be miscon strued as applying to asbestos workers o even asbestos miners, when, in fact, *th authors in question do not make this gen eralization. nor can the generalization b made for the reasons stated. Cose study o the reports reveals that the percentage cited relate only to the group of autopsie covered by the particular investigation. The present study, in contrast to th earlier works, has been planned to utiliz the epidemiological method. A well-define- group of miners has been estab lished in such a way that it constitutes i good sample of the whole population o: asbestos miners in Quebec Data for ai members of this group have been coliectec and analyzed. Those concerning lung car cer have received most careful considers tion. Details of the methods employed wi be set forth later, but the type of approac is considered to permit of fair comparison and valid generalizations. Collection and Analysis of Data A preliminary survey of potential source of information in February, 1956, involve - VoL 17. Jvne. 19* a ... -.VC CANCER IN ASBESTOS MINERS is no reliable criterion by which one can anticipate carcinogenicity and, as is well known, relatively minute changes in the structure of a chemical carcinogen are suffi cient to diminish or eliminate carcinogenic action. If asbestos is indeed to be regarded as a (^carcinogen, the need is felt to demonstrate ''"'some property which can be regarded as something more than inertness." These authors advance the theory that, until some more experimental evidence of direct carcinogenesis by asbestos or a de composition product of it can be obtained, asbestos might be considered as a "co-car cinogen" which only induces a further de velopment of a preneoplastic condition brought about by something independent of the asbestos, such as an endogenous factor. G Thus the literature, while tending to sup port the thesis that asbestosis is in some way related to the development of lung cancer, is by no means unanimous. Alto gether, it is perhaps more confusing than enlightening. A careful review shows that the majority of the reports are clinical and . not epidemiological. They lack many ele ments necessary for the application of epidemiological techniques to their content, - and most of the authors do not make claim to having done so. What has happened is Othat succeeding authors have drawn conciusions and generalized beyond the scope of the works which they quote. Nowhere, for example, have we found references to a population of asbestos workers, although several authors who have quoted the ob served incidence of lung cancer in autopsies of persons who also had asbestosis imply that this inadence applies to asbestos work ers, generally. We have likewise been unable to find any study which actually ---\ calculated the incdace 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,** none of those reviewed gave any data on posure and dust concentrations, and even Doll's paper merely mentions Braun Tman ' "scheduled" areas, by which is meant, "those areas where processes are carried on which weTe 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 pub lished literature. For example, the term "asbestosis," as used, may refer to changes observable only by microscopic examination of the lung tissue, or it may mean a radio logically detectable condition. Most of the published reports obviously included women among their cases, but some of them do not give the number or proportion of women involved in the study There is also a lack of uniformity as tc what type of exposure most studies have dealt with. Of 99 oses enumerated b\ Hueper** in 19S5, only 10 appear to have originated in the XTnited States, and 7 ir Canada. Some of the earlier reports ap parently included asbestos miners, but ii can be assumed, since 82 of the 99 case: had originated in England, and since, nc asbestos mining operations are carried or in that country, that most of the reportec cases have involved workers in the textik or fabricating industries. Such factors as smoking habits, famih history of cancer, length of time in the industry, and age of the individual case an also notably absent in the majority of these reports. With this understanding of the limita tions of the existing literature with respect to epidemiological generalization, it may be of value to consider in somewhat more de tail some representative earlier publications a few of which were referred to briefi; above. One of the most deailed studies and on< which deserves the most senous considera tion is that reported by Doll ** in 1955 This study reviews auses of death amcn$ asbestos workers based on coroners' rec ords. It also attempts to estimate the risl by studying records of men who worker for at least 20 years in exposed situations ' 61! -. , . T* -J f :C4 **> V-'.'VCiJ ^T "-- A "- .1 W 4 j. l | V/U\VC7 CANCER IN ASBESTOS MINERS ' *' r discussions with the physicians in charge cohort was then followed by means of the of the asbestos companies' programs and annual physical examination records with clinicians, pathologists, representatives through a six-year interval, 1950 through of City and Provincial health departments 1955. All data regarding this group were and of the Canadian Cancer Society, and then tabulated in order to determine the other interested persons- It was found that characteristics of the cohort. For those who morbidity data, although somewhat limited, survived the entire period, reference was C . >vere available from such sources as the made to the physical examination results ) /'"'hospitals in Montreal and Quebec City, and and x-ray findings at the end of the period. the 13 cancer detection centers in the Prov Those who had died were tabulated sepa ince. However, because of the high mor rately, and the cause of death was tality in lung cancer, it seemed advisable corroborated by examination of the death to depend upon data relating to deaths. certificates. A further search was mad< These we found to be obtainable at the concerning those in the original cohort w'nc vital statistics department of the Ministry remained unaccounted for when the living ' ' of Health in Quebec City. From the pre and the known dead had been tabulated liminary survey, it was apparent that exten- They represent men who had left employ / sive and detailed information could be ment through retirement or resignation gathered with respect to both the persons Eventually, all but a small number of thes (^.employed in the asbestos mining industry were accounted for as either living or deac and the mortality figures for the general and in the latter event, the cause of dead population. was substantiated in a similar manner, an Following this exploAtory survey, the the results added to die original list o initial effort was directed to the collection deaths. . of data relating to all .workers who had Death certinates for the Province c been processed through the clinic at Thet- Quebec for the years 1952 to 1.955, :udt ford Mines since its inception in 1947, and sive, were reviewed in the department c similar information regarding all workers vital statistics of the Provincial Kealt at Asbestos, Que. Data from the clinical Ministry, together with statistical sun records included the age, family and per maries of the auses of deaths in the Pro1' sonal medial histories, smoking habits, Ince by counties. All cases in which deat number .?. y-rrrs.of exposure, an estimate was certified as having been due to pr of wearied exposure, and the course of mary cancer of the lung were examined fc the individual's health status or the cause such information as place of resident of his death. occupation, date of death, hospital in whic From this information it was possible to formulate a "cohort" which could be well defined, should be representative of the whole group, and could be followed for a definite period of time. All of the available experience indicates that the development of asbestosis in less than five years of ex death occurred, and whether or not a autopsy was performed. Cases in whic lung cancer was given as a cause of dearbut in which it was not specified as whether the oncer originated in the lur were also reviewed in an effort to inciu all instances of primary carcinoma of : posure must be somewhat rare. Accord lung in the study. ingly, the cohort was defined as including The statistics for the Province of Queb every miner who had a total exposure of relate to population, total deaths from five or more years, and who was on the auses, total daths from cancer of ail typ* employment rolls in 1950. Office and other and daths from lung cancer. These we nonexposed personnel, regardless of length collected and tabulated by counties and of employment, were not included. This sex for the yean 1950 to 1955. industi Braun -7*ntaw - ( 3 }b s 4 t .. < n l A. M. <d. Of INDUSTRIAL HEALTH From them, death rates for the general population of Quebec and of individual counties were calculated for specific years and analyzed by cause. Practically all employees of one company are covered by a group policy of life insur ance which, fortunately, nearly all 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 this group, the records of the life insurance company were examined for all death claims paid under the policy, and particular notice was taken of the claims in which the proof of death was based on cancer of the lung. Deaths from lung cancer among asbestos miners were thus determined from the clinical records in the medical service of the industry and checked by means of the death certificates and insurance company records. The deaths were then verified individually by reviewing them with the physicians in charge of the medicai services. In this man ner, 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 whicn mng cancer is strongly suspected but not proved as the cause of death were considered separately. Mortality rates have been calculated using both the "proved" and the total of "proved" and "suspected" cases during the years un der observation. Comparisons were then made berween the death rates from the same cause among specific segments of unexposed persons. All lung cancer deaths, both suspected and proved, were carefully ana lyzed to determine possible relationship or correlations between the development of lung cancer and any factor known from the 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 oc curring in the cohort 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 separ ately from those included in the population^, and time-interval under study. A comparison of lung cancer mortality in the asbestos-producing counties has been made with that in counties which are far removed from the asbestos mines and in which, presumably, no asbestos miners live. Finally, in order to broaden the compari son of death rates in different population groups, the rates have been collected for Canada generally, and for the United States, according to the most recent published and unpublished material. - Results and .Interpretation The cohort which was constructed accord ing to the criteria described in the preceding section has been considered individually and compared with the general population. Description of the cohort will be presented here as a preface to the results of the study: Original Cohort Loot Persona Deducted Pinal Cohort . Liruif in 1965 (working and retired) Dead hr 1935 Cancer of long Questionable cancer of !uag Othw rsmea Unknown easaca Smokers Nona mofc era Unknown 6.091 133 5.961 5.771 187' 9 i' 169 6 *,673 1.255 20 Tables 1, 2, 3, and 4 present age. number of years of employment, weighted average exposure, and smoking habits of the cohort. A comparison of the exposure to asbestos dust is presented in Tabie 3. All members of the cohort were placed in one of three categories, representing increasing degrees/ of exposure based on a weighted average of the years spent at various levels of dustiness. The degree of dustiness for each job category was determined after consulta tion with persons familiar with the environ ment and conditions in the various work 640 VoL 17, J**t. LUNG CANCER IN ASBESTOS MINERS TABLE \.--Number and Percentage Distribution Table Z--`Number and Percentage Distribution by ' by Age Length of Employment At* ao-M.. OH.. W*-+A.4.......... Unkoo- \ o a Totail. tn|t A*_ Laa than 0.3%. Number 3.901 1.134 613 313 3 3.931 41 Ptt Cat u 19 10 3 100 Lensth of Employment 4-9...................... 10-19.................... 30-79.................. 30-39................... 40-49.......... 50+...................... Totals. Avoraco 7"*r* of < Numbtf 1.793 13m9* W3 115 33 Ptf Cant 30 *0 19 1a0 i 100 Areas. For the purposes of calculation, the assumption has been made that the relation ship between these categories is linear, and that Category II is twice as dusty, and Category III three times as dusty as Cate gory L ... ... .. ually smoking more than five cigarettes per day. Persons who smoke pipes or cigars exclusively were not considered to be smok ers for the purpose of this study. Table 5 presents the year-by-year ex perience of the cohort and indicates the in Table 3.--Number and Percentage Distribution by Exposure Category ECxapuotrearrya Nvsbar Par CS Oetnoint^................ lfl*t 2.180 1,77I3 3M4 30 Aatnf* Eiponwa--. IMS 100 IS * Lam thu 0.3%. Table 4.--Number and Percentage Distribution by Smoking Habits Smoktsc Habits . SNrimoo<kgc<n^--n............................................ .............. Totals....... .............................. Nosnbar 4L.6M7* S i.Hi Per Cont 7J9J * 100 * La* than 0.3%. The fourth variable, smoking habits, was similarly tabulated and is shown in Table 4. This was included because the informa o tion was available and because smoking was regarded as one of the variables which, besides the environment, could conceivably Influence the development of lung cancer. ' As used In this presentation, the term smoker refers to a cigarette smoker, habit number of deaths each year from specificcauses. In general, a case was considers to be "proved" as one of primary cance of the lung when the records showed tha the diagnosis had been supported by a autopsy or surgical resection of the lun with microscopic examination of the rr moved tisane. In one case so considered however, diagnosis was confirmed by bron Table 5.--Year-by-Year Experience of Cohort and Death Rates per 100,000 Man-Years of Risk 19... 1991... 1933... If If 11 No. Altr* At BcVcmmtsat 3JM L943 3J23 3JB3 U4f 4410 Prytad Primary Ca. of Loss l 0 71 * CuaarftfcwB Suspected Primary Ca. o( Loaf Other Ci 03 0 0l 9 "pjaiad* rata par 100400 man jan of risk 'TmbT* r*a par 100JOO nr<an of rttk CsIbovb ll { 34 Mi&>Yean 9( Risk 5.930 5i..933A ij3 4429 lijnx U l T 6- 1 * 4 \ i i Caw X*. 1 3 3 T S At* U u u 50 a i 66 JT U A. M. A. ARCHIVES OF INDUSTRIAL HEALTH TasLZ 6.--"Proved'' Casts of Primary Career of ike Lung Stnokar Yn Yw Yw Y Yw Yw Yw Yw Yw StVOTUW yr. tn c*u n 34 ft. Ifi Cat. I 37 yr. la Cat. I 32 yr. in Cat. 1 S yr. Ot Cat. II 33 yr. In Cat. Ill 30 yr. is Cat. U 16 yr. la Cat. I art. ia Cat. m DM 10*12-51 V 3-45 7-30-55 0-30-50 -41 4-30-53 11-2-43 5- 444 4- -M Autopsy Yw Yw No Yw Yw Yw Yw -Yw Branch. AtO*tesia Yw No No No Yw Yw No NO choscopy with visualization and biopsy. In another, although there was no autopsy, the diagnosis of primary cancer of the lung seems to have been beyond question. The term "suspected" primary cancer of the lung was applied 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. The terra "man-years of risk" has been used to mean the number of men at risk for the year under obseyation. A person who lived throughout the year was counted as a full man-year of risk, but one who died during the year was counted as one-half a man-year. Deaths occurring in the cohort, and in which lung cancer is considered to have been proved as a cause, are shown in Table 6. In Table 7 are shown three deaths which have been considered as "suspected" lung cancer cases. An indication of the importance of these "suspected" cases in interpreting the results of the calculations is desirable before fur ther discussion of the mortality rates which are derived in later tables. For example, it happens that the rate found for the proved cases is dose to the "expected" rate based on the general population figures for the Province, as will be shown later, and on this basis we should find eight deaths from lung cancer among the cohort. Actually, nine cases were observed. If, however, the 3 additional "suspected" cases were induded, increasing this figure to 12, the total would be very dose to the 95 leve of significance. However, having found jus 12 cases, we are not above this level, anc therefore the hypothesis that asbestos miner: do not have a higher mortality from lung cancer than does the general population can not be rejected. Nevertheless, the occur rence of 12 cases in this sample wouic increase the rate to a point which approache: the significant level. Because of the tre mendous' importance of the questionable cases in this respect, some detail regarding them will be given here. In one of these cases, the `suspicion o: cancer of the lung is based upon the x-ra> interpretation, and, although no autopsy waj performed, the death certificate indicate: that death was due to lung cancer. It i: well known that the x-ray appearance or fibrosis, especially if a localized density ot a superimposed tuberculous lesion is pres ent. can simuiate that of a tumor, and by itself, does not justify the indusion of this case as one of "proved" cancer of the lung. A second case was certified as havingdied by reason of hydrothorax, possibly due to lung cancer, but again there was nc surgery and no postmortem examination In the third case, although it was subjected to autopsy, two pathologists disagreed as tr whether lung cancer was present. The death was certified as having been due to chronic myocarditis with nephritis and pulmonary congestion, and possibly cancer of the lung. On the basis of these facts, it seems unwar ranted to indude these three cases among Ta*lx 7.--'"Suspected? Primary Center of ike Lung Caw No. 1 3 3 642 An 40 4# M taofew Tw Yw Yw tipsnt 33 yr. Cat TTI 13 yr. in Cak in 43 yr. la Cat. DM tO-BHB . . T- -43 1 30 54 AOtDpfT No Arta*a-- No P.ti. 17. 'June. *' LUNG CANCER IN ASBESTOS MINERS "proved" instances of lung cancer. On the ' other hand, they cannot, in fairness,, be dis regarded completely. It is for this reason that mortality rates have been calculated both ways. Table 8 gives the raxes by age groups. The rates by length of employment are shown m Table 9. During the first 40 years *of employment, the rate rises, an observa tion 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 dur. mg the six years, or about 1440 man-years of exposure. When the "suspected" cases are added, one case does show up in this - ... . Table 8.--Lung Cancer Deaths by Age Groups Table 9.--Lung Cancer Deaths by Length oi Employment Number of Fer*e*t* and Number f Lunt Cancer Death* Lenctb of Employment No. of Pweets No. ot Death* I'M**# Toul M........... -.................. 10-19....................... ......... 20-79....................... .......... 30-39............................. .... 40-9........................ .... 30+............................... .. 1.793 1396 98 903 1U 63 0 V 3 S 0 0 0 l 3 7 1 0 Tou!*,,_... LU 12 `-"S.Annul! Cancer Death Rate per 100.000 an-Year* et Eapoeurc LenitB of SmpieyaMOt H........ -...................... ......... Proved 0 30-39............ .............. ....................... ..... 40-49............................................................. J04______ ..._________ ______ _____ 13* 0 t Total 0 M 1M 900 Overall. a 34 Number oi Feuene tad Xambe of Lung Cancer Deaths At* Oreop 20-44_________________ _ 4S-44_________________ UrM-______ ______ ____ 644-______________^ Uatnowu_. Ne.ef P* 1.901 u <u ns a No. of Death* ------- PTOT*d Total 1 31 0 1 3 30 is Annual Lonf Canctf Death Rates per 100.000 Ma.Ycm of Exposure At* troop - Proved Toni 24H0A.V-A4U4t_,.._..._L.._l.l_..._..._. ._,_._..._.._.,._..._._.. TTnt him .. ___ ____.. 184 21*139 4 294n406 Oror-aD...............-___ a 34 period. This would produce a rate of 69 per 100,000, again demonstrating the im portance of these questionable, but un - proved, cases to' the final conclusion, because, if there were no cases in this number of men with long exposure, and if asbestos is a carcinogenic agent, it must be concluded that these 240 men have demon strated considerable resistance. This is a bio logical 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 18, which appears later in this section, in- 'raun >Truam dicates that the members of the coho; did not die from lung cancer at a young? age than the general population. The rates by weighted exposure ar shown in Table 10, and it will be note that they present strong evidence again; asbestos being a carcinogenic agait, for, exposure to asbestos is in any way cor nected to lung cancer, we would expect th; the longer and heavier the exposure, th higher the rate that would be found. Th only possible error in this interpretatic could occur if the weighted exposures we; inversely related to years of empioymen Table 10.---Lung Cancer Deaths by Exposure Category Number at Peroou and Numbtf at Luaf Cancer Dene. Exoerero CunmT Sc. at Deetbs No. of - Perrooa ?rod Total \................................ it..................... m.............. CfltMW......... uai auo urn i 4 035 4 4 40 Total*_______3.966 12 Arnnxl T^atf Canor Death Ram per 100.900 UifrYon of Expwure Caiiiury . * Pro rod OnfcB0wu_........... ........................ . OroreB ......... 9 a Ta 33 11 no M t b- 'm .- - ------ ... .4 V'.-*-- .' .. . sA'JrW.? %>a-v#**r.--,g :-7''-2'r.^A Ti&ffSH m ih~i-^~ * *a V^.&* *--..-y --&er*r-^S- dJ. rirgT-S* '*Ji t .*&'..'**er---.T"-2 r .. ,4. Af. /<. ARCHIVES OF INDUSTRIAL HEALTH^ TaBUX 11.--Number of Persons i* Varions Weighted Exposure Categories by Ltngtk of Employment tVateChtuodinZrruoiomer F.Laupntoryihrnottat - l II m 190--499 9s400---31s99 + Jr934a6UT3t 7743 BM1B 3a nt aa 499 M3044713l Awot Tmtr9poUmlyauruwrt 1631 174 1U9 174 L7T3 144 . koCoo-o 993t1l 1 as Toul 1.799 Smt4oXo uus uus 174 in which case the heaviest weighted ex posure (Category III) would show the shortest leigth of employment. Table 11, which lists the number of persons in various exposure categories by length of employ ment indicates that this error has not oc curred. In fact, the average number of years of employment for each exposure category is almost identical. Table 12, which develops the rates for smokers and nonsmokers, is most striking. It shows that not a single case of lung cancer developed among ^he 1265 non smokers and that ail cases of lung cancer, both "proved" and "suspected," occurred in smokers. Table 12 was. so striking that it was felt that further verification was necessary. It was possible that some abnormal distribu tion may have occurred, e. g., the non- Ta-blcr.1..3*.--Nrrum.-bjevr and P.erce,ntag-e Dirs~tr~ib.u*trion NomOw --:------------- A(0 Ofwv 1M4...... ........... S44P95J-a-9+94Cf.o.._.n_____. _- -_- .__ . ir>mvM--l_*-_ _ SdMkor 1400 IM 411 104 MB3* 4.673 344 Noataokar * TTaksovs <89 S4 203 uo re^m9- 14 444 13 4 2 70 404 Tabus 12.--Lung Cancer Death for Smokers and Nonsmokers Nutnh*r o( P Sreokfa., NPnoTewio<wonktr*... Touts.. nd NwmWr ( Lunf Corner D**Oi by Smohinf H*bit Pmmi 4.673 14MX uus No. of OooxBo Protvd 0 Tout 1399 13 r Annual Lane Cancer Doth Kates per 100.000 Man-Year* of Sxpoouro by Smekinf Habits ' <o. ot OouAs Prorod Tout Nonnnoksr*.___________ _____ Unknown^................ OrfT^fl--... S0 43 9 09 smokers may have included a larger percentage of young men. Consequently, ad ditional Tables, 13, 14, and 15 were con- ' strutted to show the distribution of smokers and nonsmokers by age, length-of employ ment, and degree of exposure. Although there are slight differences, they do not account for the fact that all observed cases of iung 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 con- TasLZ 14,--iVumirr and Percentage Distribution of Smokers and Nonsmokers by Length of Employment Unttbof Zetployassi 5-9.............................. 10-19...................... 20-29............................ 30-J9............................ 4s0o-4*9............................................... Tot*H_______ Ayfn lonctb a.t. Saokta 1.400 1497 ra 433 no a 4.573 174 SouBokd tTakoown rr 10 4 4 199 2 1M 4 75 0 a0 1,206 a 194 144 rS w' t A Oroep a44.-- Pwusuf* DMrtbQtM Isookw Neenwka ......... .. 9 644 544 174 TTsksovB 34 304 . 100% m% u 100% itbaa94B%. 644 LuflTtS of M. _io-io-- to-m__ 40-49....... 304-_______ PtraesuBi Distrtbattfa StaoUr 304 4X1 10.4 94 3.4 0.7 100% NBSC09kr 34 n.7 10.7 13.1 U 14 100% Cmcnewn ifl.n as 10.0 34 04 04 !% rVbl. 17, June, I9SS_ . V 1 l '"U'NG-CANCER IN ASBESTOS MINERS ----~ -- - TaUT 15.--Number end Percentage Distribution of Smokers and Nonsmokers by Exposure Category Exposure C4C(Of7 f . Uotiwwn............ G1 Attract txpocur* a|W7.................... Notebar Smokrrs Nonamokara 143* l.MI 1.433 4 <74 412 239 1 4.973 1481 24 14 Unknown 4` 0 30 24 Ptrrcnuc* Dtttrtbotles Expesura Cu(sr7 Srnokm Nonraoktra tu....... .......-- Tetali 31a3U4u4 i% Ju7.4; a.: OJ 100% Unknown 3&44 <64 04 ioo% osmed, the smokers had worked about 2.3 years less on the average than the non* smokers. 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 almost the same for the two groups. Therefore, this variable seems to be of no importance in accounting for this difference. The result of this additional analysis is ' that none of these factors appears to lessen the effect of Table 12. Comparison of the Cohort Experience G with that of the province of Quebec, Do minion of Canada, and the United States.-- Jn nrrier t. mak* a comparison of the experience among asbestos miners with that of the general population of the Province of Quebec, statistics were gathered, as stated earlier, in the office of the Division of Demography in the Provincial Ministry of Health. The data on total deaths, deaths from all forms of cancer, and deaths from cancer of the lung were obtained by >ex 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 cance: but did not specify the origin, were exam ined for the years 1952 through 1955. Table 16 gives a tabulation of the numbe: of deaths from lung cancer in the Provinc and in the cohort for the years 1950 througi 1955, and shows the annual rate per 100,OCX in these segments. It will be noted from th table that the mortality rate for th "proved" cases in the cohort is only slight! higher than the rate for the Province When the "suspected" cases are included i: the calcination, the rate for the cohort rise to 33.8 per 100,000, which is about 50? higher than the rate for the Province. Thu it will be recalled from the previous dis cussion of the effect of the "suspected cases on the results, approaches but doe not exceed the significant leveL ' One further interesting observation fror Table 16 is the rather marked increase i the total number of cases for the Provinc berween 1950 and 1955. It is assumed ths at least part of this increase is due to irr proved recognition and reporting of lun cancer during the interval. For this reasor the years 1954 and 1955 were thought to b more nearly representative of actual condi tions. Even so, it is quite likely that th? general population is not studied tor !um cancer with the same diligence with whic: (ododtst hMm Tasle 16.--Comparison of Cohort with Province of Quebec Naxubarof . I960 193t Last Cuor Daatte 19S 1954 1941 149444*0*1 1.1934* 199 31 IS* 29 5 m 34S 24004 20 20320 303 1] 3S2 297 , U431 Tool rAiawl*uOalff 100400 1.934 =4- 192 1.113 a244 224 i la tha ymiiMi fliujw. tt baa b--n tswort Ul mala loot eaocar dtha am for aan o<-* ?**** _ ; * approBSBta stdpotnt of tbrnaBnud pvpQisxton lor 196L tad um hubuM popoiatirm (w 1954 (Rapport, Dl?. 4a la I I aotnobM. ' 1 tNombartllra ts cohort at bacisaisc 00933. - -* Braun Truan :i f--rV'A 6 \ 11 1 ; .^ i Act Graff 20-44 46-44 66-64 66+ Total* A. M. A. ARCHIVES OF INDUSTRIAL HEALTh Tals X7.--Lmg Conger Deaths for the Province of Quebec* Popoiadoa 777.000 301000 137.000 12*400 >437400 Humber a/ Drstha 1964 Total Coruflad SpaesOad Primary Tout! Pro*ad Total Pror*d 17 13 11 r 34 a 1m00 U 33 60 M . 296 120 m 9 29 S 20 90 IBM Tout Camfltd 8peei6d Primary TotaJ Tiorad Total Pfovtd *7 9 17 9 40 26 M 22 117 37 119 J7 143 M 140 M mm . 342 US 337 112 Act Oraff 20-44----- .----------------- ..--------------- ... A6-M....................... SS-64______________________________ 6S-K~_______ Our^JL----------------------------- -- Death Ritas per 100.040 IBM Total CmiM Spaeifled Primary Total fW Total Proaad 14 334 73.0 tU7 34 ' 1.7 174 27.7 374 9.7 1.4 214 60.4 444 W4 14 U.4 S.4 344 ~4 1M Total Canlflad Spactflad Primary Total Pwaad Total prorad 14 31.7 U.4 1224 14 24 174 27.7 <1.6 M.7 444 1224 14 1J.1 U.4 u.6 34 124 274 124 * Data from death cartlOsua. 1 Tmmta for population obtaiaad by applyte* 1961 ptreaotaoi for t rroopa (or malas to tbo total popalatlos (or 1964. as tln Is Rapport, Dio. do la DaroocnpAla. this disease is looked for in the miners, and This comparison, summarized in Table it seems probable that the mortality rates 18, shows that the observed number of for the Province may be low. This would deaths in our sample is not significantly appear to be substantialed^y the fact that greater than the expected number of deaths, the reporting of cases in the cohort showed based on the average of the 1954 and 1955 no such increase over the same period. figures for the Province. It is true that, in Table 17 was compiled to show the an the case of the age group of 65 and over, nual age-specific lung cancer rate of cases the five deaths provide a figure which is in which the death certificate merely read almost significant at the 95^ level. How "cancer of the lung," as distinguished from ever, it should be noted that this number those in which the diagnosis was confirmed ' includes one of the suspected but unproved _. by-autopsy, surgery* or biopsy. The term "specified primary" refers to those cases in these two categories in which the tumor was specified as having originated in the lung. It will be noted that, of the total cases reported in 1955, a much higher percentage <ases previously referred to. Furthermore, it is rather HWrly that the rate for the general population is understated in this age group, for the obvious reason that the exact cause of death in the very old is not than in 1954 were specified as primary. The table also shows that a higher percentage of the total cases certified in 1955 were proved, again indicating increasing interest Tails Comparison of the Actual and Expected Number of Lung Cancer Deaihs by Age Among Asbestos Miners in this disease. A comparison has been made between the age-specific rates shown in Table 17, and those for the cohort, shown in Table 8. An average of the 19S4 and 1955 rates for the Province has been used, since the 1955 OraD PrVTlDBi Total Spaciflad Primary Rata par 100400 2&-*4 <6-44 6444 6*+ Uaffnovff 14 944 074 4 Obatr^ed No. Eretrud of Deatfi* No. of No. of Mlstn Daatft* * Pwra Total 3401 U34 U 316 3 ot 1 *l 3 _2 4 0 l 3 3 i 0 figure was higher and may have been ex ceptional. . * T7m arotoad iwwtf 4s biad oe tha o< tha ISM d >866 aoiQKtfte muff lor tha Pnjiiwvef Qiiaoae. ? Aetoally 0.1 ` * * 646 Voi.117, June. 1953 o ? Tasci 19.--Aoe Distribution of Adult Hales for TAACt 20 -- Annual Death Rats p<r 100>00 for the Province of Quebec, 1951 Cancer of the Lump in Coruna Ac* Grwip 30-M--------------- ... ..... ..<MM.________ .... ............ *+........................... Total______ ?ntttci Number Pereoouc* 77T.13S 18S.962 13S.B44 U3.7 U 16 11 10 1.1M.4M 100 PerreeUM in Caftert 96 19 10 1 100 ` TUpport, IBM* a matter of the same intensity of interest as it is in younger persons. Table 18 also answers a question pre viously raised. It shows that the members of the cohort have not died from lung can cer at an age earlier than the general popu lation, and that such an explanation cannot be offered for the absence of lung cancer in 240 men with more than 40 years of O employment referred to on page 643. Before leaving this comparison of the Province with the miners, it should be . shown that their age distributions are rea . sonably the same. That this is the case can be observed from Table 19. ' It should be remembered that the miners retire and consequently, it can be expected that the oldest age grou^ will be larger in the general population. The data presented in Table 20 indicate that the lung cancer rate generally decreases after age 70. There- Ofore, we could expect the rate for ail people over 65 to be smaller than the rate for the group between 65 and 75, which would apply to the oldest group of miners. It is-felt that by using the whole adult male popula tion, we have developed rates for the gen eral population which are somewhat lower than if we had been able to exclude the people in the general population over 75. A comparison between the asbestos miners and the population of the Dominion as a whole was made, using statistical material from several sources. In one source, Phil lips 79 gave age- and sex-specific rates for Canada for three periods between 1931 and 1952. The rates for males are riven in Table 20. These figures show strikingly the increase in rates between 1931 and 1952, and this At* Orvtap Unrter 30 30-34 35-39 40-M ** 50-84 55-40 t4O6--4M0 70-14 7M70 SO-M U4> Afl A|a 1ZZW9S 04 0.B 10 10 13 13 11? Ill 111 30.7 164 L3 11.4 OmiH ( Y*rs 1941-19*4 04 04 34 6.4 134 1IJ 374 a.? 334044 304 374 144 ?J 14 16.7 374 Mr?.47 10X4 WJ 83.9 59.7 T14 U4 * "Mortality (res Lent Cancer in Canada,** 1331 to 1441. increase is particularly marked after age 50, confirming an observation previously made, to the effect that until recently lung cancer has probably been underdiagnosed in the older age groups in the general popu lation. To use these figures for purposes oi comparison, it is necessary to combine the rates for certain age groups in order tc conform to the age distributions used in this study. Since the exact populations in eac: age group for the years indicated is no known, this must be an approximation However, the rates would be somewhat n follows: Ace Group 20-44 4S-S4 5544 45- . Rite s 77 69 -- 90-95 These rates are, in general, lower that those developed for the total (proved an< suspected) cases of lung cancer among th asbestos miners. The only large difference however, is in the age gTOup of 65 years anc over, and it is quite possible that the rate for this group may have increased for Canada between 1952 and 1954 as it die for the Province of Quebec (Tabie 17). A further comparison has been made wir; an over-all rate obtained from the Americaj Cancer Society for respiratory cancer death in Canada in 1953. This rate, for males is 20.8 per 100,000. or 5 more per 100,00( than Phillips' 1950-1952 rate, and compart with 25.3 per 100,000 for proved cases anc 33.8 per 100,000 for total cases among th< rgvn - Tman Y 64: i A. M. A. ARCHIVES OF INDUSTRIAL HEALTH" ' Tasix 2\.--Number of Deaths and Death Rates way, and other countries, at least 50,000 * per 100POO by Age Croups for the Adult Male Population of the United Slates persons must be exposed throughout the An Orvap TtpoloiWfl CtM world, and it can be assumed that this per 100.000 number has been fairly constant in the 20 35-M 4A-54 U-M 4+ Tout 34.544.000 1.065.000 040.000 4.670,000 44,619,000 1379 6.254 6.463 18490 3.6 3U 96.6 U4J 17J years since 1935 when the first case of asbestosis with lung cancer was reported. At least 1,000,000 man-years of exposure has thus been accumulated, and this figure ao* dDi*mt*af.rm "Vital Sutistlo *t tb Volta* Stataa." Vol. i enn be divided by the approximately 150 asbestos miners in this study. It is there fore 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, there fore, possibly more comparable to the data for the miners, age-specific rates were com puted from "Vital Statistics of the United States," Volumes I and II, for 1952. These rates have been tabulated in Table 21. It is apparent that thege rates compare favorably with those for the asbestos miners as shown in Table 8. Still other rates for the United States were obtained from the American Cancer Sodety, and for males, these were 25.3 per 100,000 in 1953, and 2S.0 per 100,000 in 1955. They are not identical with the rate calculated from the figures of the office of Vital Statistics, but this is possibly because the American Can cer Society rates are for males of all ages. Nevertheless, they, too, compare favorably with the rates of 25 (or 34 for total cases) obtaining among the asbestos miners. Turning for a moment to a comparison between the asbestos miners and persons who are exposed to asbestos in one form or another (as distinguished from the gen eral population groups just discused, who cases of lung cancer with asbestosis re ported during the 20-year period. This gives a rate of 15 per 100,000, which is at least indicative that any lung eftneer rate which can be calculated for workers ex posed to asbestos dust is not much greater than that for the unexposed population. Comparison Between Eight Counties Ad jacent to the Asbestos-Producing Areas and Eight Selected Counties.--To compare lung cancer mortality rates in the counties sur rounding the asbestos-producing areas with another group of counties in which no as bestos miners are likely to reside, the rates were computed on the basis of figures for the years 1950 through 1955. The eight counties selected for comparison were Argenreuil, Chateaugay, Montmagny, Portneuf, Richlieu, Riviere-du-Loup, St. Hyadnthe, and Terrebonne, mainiy because they represent a wide geographic distribu tion throughout the Province. The counties selected because of their proximity to the asbestos mines include Anhaoaska, Beauce. Drummond, Frontenac, Megantic, Rich mond, Sherbrooke, and Wolfe. Table 22 shows the number of lung cancer deaths tor 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 have no exposure) an interesting observa County has been shown separately, as has tion can be developed by deduction. Hue- the Province of Quebec and also the Prov I per * has stated that there are about 35,000 ince with the eight "asbestos-producing" persons exposed in the United States, and counties subtracted. Because of its unique we have found that the Canadian mines lung cancer death rate, Montreal et Isle de employ about 8000. Elsewhere, it has been Jesus has also been listed in order to provide estimated that the workers in England who further comparison. have exposure total between 3000 and 5000. It is apparent from the table that the With workers in Africa, Denmark, Nor lung cancer death rate for the eight counties 648 VoL 17, June, 19JS 'LUNG CANCER IN ASBESTOS MINERS TAitt 22.--Number f Lung Cooerr froths and Rote per 100.000 Man-Years Count** MwtuiOe Count? Kieni "Adjacent" Count** Riant ?tktod Count** Pro*mw 91 Ouotee Prortaei of Quebec !* 4**61 "adcnt" eount** Meatml b* d* Adult N1* ronuiAiion ilU 1W 13.100 T7.M9 U.dOO 1.196.000 3 * 3 ioe l.lQO.tB JM.COO 190 3 1951 1 3 10 ao 37 7 Ma* Ln Cfttim Dnuto * 1053 .1 1*A3 1*34 1*33 3314 9 13 3 13 4ft . 13 9 343 303 303 337 234 7*1 290 341 153 in 133 S3 It S astunod that *D Mh tent sumr 0**th occurred *f act 70. Total 13 34 49 1634 137Q no Rdi vrr ioo.n<\ SJl a* 3U immediately surrounding the asbestos-pr^ during 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 in those years 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 p0 greater. This would result in a rate of 40 per 100,000; The only possible conclusion from this comparison is that there Is no evidence that the persons who live and work in the coun ties surrounding and adjacent to the asbestos-produdng areas have any greater incidence of lung cancer than those who live elsewhere in the Province. Comment on All Recorded Lung Cancer Cases, Living and Dead, among the Ashestos Miners.--Although a simple enumera tion of all the known or suspected cases of cancer of the lung in these areas has no particular value from a statistical point of view, it is of interest to summarize such cases for the record. There were nine deaths prior to the beginning of the time period covered by the study, including one in which the diagnosis was mediastinal lymphosar coma. During the period covered by this investigation, there were nine proved cases and three suspected in the cohort Through 1956 and to date in 1957, there were eight deaths, six of which were merely ^rou*--Tnum suggestive of cancer of the lung and in cluded such diagnoses as rr.ediasrina lymphosarcoma, mesothelioma, cancer of th< leg with metastases to lung, abscess of lung and cancer of the pancreas. One other wa diagnosed on the basts of x-ray only. I: addition, there are now living four cases it which the diagnostic evidence is strong!; suggestive of lung cancer. This is a total o 33 cases of all types, including 10 "sus peered" but unproved cases, and 4 that ar still living. The remaining 19 constitute th total of proved cases of cancer of the lun among the asbestos miners since 1940. The proved cases averaged 29 year? o age at death, and varied between 37 year and 68 years. Their working span covere periods' varying from a minimum of 1 years to a maximum of 37 years. Oni three men had less than 25 years of em ployment in the industry. Seven amon those on whom such information is avail able had a weighted exposure placing ther in Category III, and six worked in a exposure represented by Category I. There were only 17 among these provelung cancer cases in which we have ir. formation regarding the presence of as bestosis. Asbestosis was present in nine although it was minimal in two. Two path ologists disagreed regarding its presence i another. At least seven of the 19 prove lung cancers, therefore,- were not accorr panied by asbestosis. Summary and Conclusions Interest in the question of whether ther may be an association between lung cance (A 4 % t A A. M. A. ARCHIVES OF INDUSTRIAL HEALTH i ii and ecposure to asbestos 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 some workers considered the correlation to be inconclusive. The pres ent study was undertaken in an effort to de termine whether a causal relationship did, in fact, exist between exposure to asbestos and cancer of the lung. 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 mentioned, it was apparent that they could not fulfill the re quirements of an epidemiological and sta tistical approach to tl problem. The present 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 their medical records. A cohort was defined as a group of asbestos miners having at least five years of exposure and who were in the industry in 1950. Data relative to their characteristics were collected and their status at the end of a six-year period of observation was de termined. In the case of those who had died, an exhaustive search of death certif icates 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 olculated from statistics collected in the appropriate places. Comparisons of the rates obtained for asbestos workers and for the other popu lation groups were made according to ac cepted statistical methods. Records were obtained on 6091 persons who fulfilled the criteria of the cohort It was not possible to trace 133 of these for the whole period, but 5771 of the remaining 5958 were found to be still bring in 1955 or later. Of the 187 known dead, cancer of the lung was considered to have been reasonably proved in 9 and to be strongly suggested in 3. The members of the- cohort were studied with respect to age, length of employment, a weighted average of their exposure, and their smoking habits. It was found that 4673 were smokers within the definition ot that term as used in this study. Thirty-fouT per cent of the cohort were more than 45 years of age, and thirty per cent had beer employed for longer than 20 years. Thin} per cent had a weighted exposure which placed them in the category of highest ex posure. The mortality rate for lung cancer, a computed on the basis of nine "proved* deaths among the cohort was 2SJ per 100, 000. When the three "suspected" cases wer added, the "total" rate- for the cohort rosto 33.8. The importance of the suspectei but unproved cases in determining thes rates has been reiterated because it is'likeh that such cases would not be included it the statistics for the general population an< because they influence the results so mark edly. According to the findings in this study the mortality rate from lung cancer doenot appear to increase with length of ex posure or with degree of exposure, a fac which presents strong evidence against th carcinogenicity of asbestos. Comparison of the experience among th asbestos miners with that of various se| ments of the unexposed, comparable popi lation shows that the observed number c deaths among the miners is not signifiami greater than the expected number. The ra: for proved cases among the asbestos miner (25.3 per 100,000) compares well with rate of 72JS per 100.000 for the rest of Province, and 20.8 per 100,000 for adu males throughout the Dominion of Canad It also compares satisfactorily with rat- 650 . .. Voi. 17. J\m*. 19' 'r I( `LUNG CANCER IN ASBESTOS MINERS . of 272, 25.3, and 28.0 obtained from various sources for adult males in the United States. Finally, in this matter of comparison, it would appear that the world-wide experience of persons exposed to asbestos dust is not worse with respect to lung cancer than that Oof the unexposed population. The counties surrounding the asbestosproducing areas, in which it is presumed most of the asbestos miners live, have al most identical mortality rates with those of eight ounties wideiy scattered 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 been 19 cases in which the diagnosis of primary cancer of the lung may be considered to have been c proved. Approximately half of these cases ^""^were associated with asbestosis. All but one ' died in the recognized "cancer-age" and at least one-third had only the lightest ex posure (Category I) to asbestos dust. On the basis of what are believed to be complete and reliable daft, it seems fair to conclude that the asbestos miners in the Province of Quebec do pot have a signifiantly higher death rate from lung cancer than do comparable segments of the general population. - o Furthermore, the death rate from lung cancer in the areas contiguous to the asbes tos operations is comparable to that in areas widely scattered throughout the Province of Quebec and is lower than in some urban ized areas within the Province. REFERENCES 1. Alasoo Eseobsr, R.: Bronchial Carcinoma: Review of 200 Cases, J. Internal. Coll. Surgeons 26075-379 (Sept) 1956. E Allen, M. 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Health 11:29^207 (March) 1955 18. Gerens, J.: Rsearch into Pulmonary Asbes tosis in Belgitsn, Arch, beiges med Sodaie 3:557 565 (Nov.) 19SL 19. Qynes: Asbestosis and Silicosis, Brit. M. J 1:379, 193L 20. Coffin, G. J.; Duryee. H. C; Maier. H. C Pardee. H. E B,, and Wynter, E L.: The Ener. of Tobacco Smoking, Panel Meeting, Bull NeYork Acad Med 32:133-156 (Feb.) 1956. 21. Cohart E M.: Lung Cancer and Econonu Status, Cancer 8:1126-1129 (Nov.-Dee.) 195 2X Cooke, W. E: Pulmonary Asbestosis. Bn M. J. 2:1024-1025 (Dee. 3) 1927. 23. Cuieton. R. J. X: Sqtamous Cell Cardnorr Occurring its Asbestosis of the Lung, Brit Cancer 2:249-253 (Sept.) 1948. 24. Cutler, S. J.: Schnddetman. M. A~ ar Greenhouse, S. W.: Some Statistic! Consider 6: tI j LUNG CANCER IN ASBESTOS MINERS .1 \o ;'' -w- ; -~r4) . - J *reT . : ... ... t- *- i: o Health Monograph No. 36, P. H. S. Publication No. 452, U. S. Public Health Service. 1955. 59. Hneper, W. C.: Environmental Causes of 75. Merewether, E. R. A: Annual Repons of the Chief Inspector of Factories, Lcxuion. Hi* Majesty's Stationery Office, 1947. Cancer of the Lung other than Tobacco Smoke, 76. Merewether, . R. A- editor: Industrial Dis. Chest. 30:141-158 (Aug.) 1956. Medicine and Hygiene, London, Buttenvorth k 60. Isseibacher, K. J.; Klaus, Hm and Hardy, Co.. LL 1956. Vo!. 3. H. L: Asbestosis and Bronchogenic Carcinoma: ' Report of One Autopsied Case and Review of Available Literature, Am. J. Med. 15:721-732 O (Nov.) 19S3. 61. Kennnway, E. t~, and Kennaway, N. M.: A 77. Nordmann, M.: Tlte Intlustrial Cancer of Workers in Asbestos, Ztschr. K/ebstmch. 47:2S8302. 1938. 78. Nordmann, M., agd Sorge, .A: Pulmonary Career Produced by Asbestos Dust in Expert Study of the Incidence of Cancer of the Lung mental Animals, Ztschr. Krebsforch. 31:168-183 and Larynx, J. Hyg. 36:236-267 (June) 1936. . 1941. 62. Kennaway, E. L, and Kennaway, N. M.: 79. Phillips. A. J.: Mortality from Cancer o Studies of Incidence of Cancer of the Lung and the Lung in Canada (1931-1952), Cana-i. M. A. Larynx, Brit J. Cancer 5:153-158 (June) 19SI. 71:242-244 (Sept) 1954. 63. Klott, M. 0.: Association of Silicosis and 80. Saupe, E.: Further ComributKuts to th Carcinoma of the Lung, Am. J. Cancer 35J8-49 Roentgenological Diagnosis of Asbestosis, Arc . (Jan.) 1939. Gewerbepath. u. Gewerbehyg. 9:J9l-tf6. 1939. ' 64. Lanza, A. J.; McConnell. W. J., and FehneL 81. Smith, K. W.: Pulmonary Disability J. W.: The Effects of the Inhalation of Asbestos Asbestos Workers, A. M. A. Arch. Indus:. Heal: Dust on the Lungs of Asbestos Workers: Pre- . 22:198-203 (Aug.) 1955. liminary Study, Pub. Health Rep. 50:1-12 (Jan. 4) 82. Smith, L. W.: Pneumoconiosis and Lur ' 1935. Cancer with Special ' Reference to Silicosis a: " ' 65. 7 A. Jn editor: Silicosis and Asbestosis, Asbestosis. Compere. Med. 2:3*10 ( Nov.) 19^ New York and London, Oxford University Press, . 83. Smith, W. E: Survey of Some Cun-e 1938. . British and European Studies of Occupatior 66. Lew, E. A.: Use of Life Insurance Com Tumor Problems: Part IIL Asbestos, A. M. pany Records for Cancer Studies, A. M. A. Arch. Arch. Indust. Hyg. 5:242-263 (March ) 19S2. Indust. Hyg. 5:198-2Q3 (Mgrch) 1952. 84. Stoll, Rl; Bass, R_ and Angrist. .* 67. Linzbach. A. J, and Wedler, H. W,: Occu Asbestosis Associated with Bronchogenic C pational Cancer among Asbestos Workers, Arch, dnoma, A.M.A. Arch. 1st. Med. $8:S31-e path. Anat 307:337-409, 1941. 68. Lynch, !C SL, and `Smith, W, A_: Pul monary Asbestosis: Carcinoma of Lung in Asbesto-Silicosis, Ant J. Cancer 24:56-64 (May) 1931 69. Lynch, K. M_, and Smith, W. A-: Pul monary Asbestosis: A Report of Bronchial Cardnoma and Epithelial Metaplasia. Am. J. Cancer 36-^573 (Aug.) 1939. 70. Lynch. K. M, and Cannon, W. M.: Asbes tosis: Analysis of 40 Neeropsied Cases, Dis. Chest 14:874-889 (Nov.-Dee.) 1948. (Dec.) 1951. 85. Teleky, L-: Occupational Lung Cancer, A< Union imemat. centre Cancer 3:253-273, 192 also. ZentnilbL Gewerbehyg. 77:33, 1940. 86. Vorwald. A. J.; Durkan. T. 1L. and ?n P. C: Experimanl Studies of Asbestos A.M.A. Areh. Indust. Hyg. 3:1-43 (Jan.) 19 87. Wedler, H. W.: Asbestosis and Lv Cancer, Deutsche med. Wehnsdir. 69:575(Aug. 6) 1943. 88. Wegeiius. C: Changes in the Lungs in Cases of Asbestosis Observed is Finland. A ^ 71. McPheeters. S. B.: A Survey of a Group of Employees Exposed to Asbestos Dust, J. Indust. Hyg. 18:229-239 (April) 1936. 72. Merewether, E JL. A.: The Occurrence of Pulmonary Fibrosis and Other Pulmonary Affec tions m Asbestos Workers, J. Inritst Hyg. 12: 198 (May); 239 (June) 193a radiol 28:139-152, 1947. 89. Werber, iL: Pulmonary Asbestosis As dated with Cardnoma, Zentraibl. Arbeitsmed. Arbdtssehutx 2:179-130 (Nov.) 1952. 90. Wood, W. B., and Gtaync S. R.: Puimon Asbestosis Compiiated by Puimonary Tuber losis. Lancet 2:954-956 (Oct. 31) 1931. 73. Merwether, E R. A^ and Price, C W.: 91. Wyen, H.: Asbestosis, Postgrad. Med Report on Effects of Asbestos Dust on the Lungs 631-638 (Dec) 1949. and Dost Suppression in the Asbestos Industry, 92. Wynder, E L, and Graham. * London. Kis Majesty's Stationery Office, 193a Edoiogic Factors is Bronchiogeruc Carsoo 74. Merewether, E R. A.: A Memorandum on with Special Redeaence to Indtatriai Exposnr Asbestosis. Tubereie 15:109; (Dec) 1933; 15: Report of 857 Proved Cases, A. M..A Ar 152 (Jan.) 1934. Indust Hyg. 4:221-235 (Sept) I95L Ilestricted Copy..XI COXFlDESTUi INDUSTRIAL HYGIENE FOUNDATION OF AMERICA, Inc. ': ^ N. r4400 FIFTH AVENUE PITTSBURGH 13, PA. AN EPIDEMIOLOGICAL STUDY OF LUNG CANCER V , IN ASBESTOS MINERS .: . :< * f*., * ; * t. >; * " V* Report to QUEBEC ASBESTOS MINING ASSOCIATION . .. .A. ` . Quebec, Canada ` -* "A~K i *%*' i ` ` A M * . . September, 1957 .' PLAINTIFF'S * EXHIBIT 6t\' H3 1 <5 .- V ' . 9 Lndust ial Hvg:ene Foundation of Am 4400 Fiith Avenue Pittsburgh. 13, Pa. c a T,, C . AN EPIDEMIOLOGICAL STUDY OF LUNG CANCER IN ASBESTOS MINERS For QUEBEC ASBESTOS MINING ASSOCIATION Quebec, Canada July, 1956 to July, 195" By -i i Daniel C. Braun, M. D. \ Medical Director September, 1957 By: C, Richard VVaimer, M. D Managing Director TABLE OF CONTENTS Page Foreword............................................................................................................ i Glossary............................................................................................................ iv I. Introduction....................................................................................................... ' l E. Critical Review of Literature............................................................. 5 III. Principles of the Epidemiological Method............................... 13 IV. Collection and Analysis of. Data . .................................................... IS V. Results and Interpretation.................................................................. 3b Asbestosis and Lung Cancer......................................................... 47 Comparison of the Cohort Experience with that of the Province of Quebec* Dominion of Canada, and the United States................... S3 Comparison Between Eight Counties Adjacent to the Asbestos-Producing Areas and' Eight Selected Counties.......................................... o Discussion of All Recorded Lung Cancer Cases, Living and Dead, at Asbestos and Thetford Mines...................... 68 VI. Summary and Conclusions................................................................... VII. Bibliography.................................................................................................. '8 FOREWORD The success of a study of :ne type herein reported de pends very greatly upon the availability of data from many sources, and the assistance and cooperation of those m 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 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 Thetf-ord 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 the 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 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 same helpful coooeration '-was rendered by Messrs. Hardy and Hopkins of :he Sun Liie Assurance Company of Canada in Montreal, who made available their records of the death claims paid under the group policy cover ing the workers at Asbestos. Valuable suggestions for the conduct of the study were made by Dr. S. A. Vidal, Chairman of the Silicosis Board, and Dr. Guy, Pathologist for the Board, as well as Dr. Gregoire, Deputy Min ister of Health for the Province of Quebec, and Drs. Siraard, Duiresne, and Grouix, in Montreal. Statistics for the mortality races 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, in 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 lung cancer as related to asbestosis and exposure to asbestos. Assistance in planning the study in such a way as to assure a proper epidemiological approach, and all biostatistical applications of the findings were provided by Mr. T. David Truan, formerly of the Graduate School of PubLic Heaith, 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. GLOSSARY For the purpose of clarity and uniformity, the terms used in 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 generalized fibrosis of the lungs diagnosabie 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 ing 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 pipeT'or cigars exclusively were not considered to be smokers for the purpose of this study. I. INTRODUCTION Ever since the pronounced increase 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 has 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 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 extrem ely small series of cases, with control cases which are 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 tea years, about 15 additional cases were reported, and in 1946 Merewether reviewed all deaths from asbestosis re corded in England since March, 1924. Lung cancer occurred, according to Merewether, Ln 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 L 95 t the results of his findings on L205 autopsied cases. This series included 132 asbestos workers, of whom L2L showed asbestosis. Cancer of the Lung was present in L4. 1 % of these asbestosis cases. In L94L, 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 been reported, and, according to Eiueper 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 (205) the lung. Werber in L952, stated categorically that in 7% to 17% of cases of asbestosis, after a latent period of about l l/2 to 20 years, carcinoma becomes established in the lung. On the other hand, not all authors accepted the alleged associa- (ITT) tion. without reservation. Saupe in 1939 had reported that he had discovered no cases of lung cancer among 620 cases of asbestosis which (104) he had examined; and in 1942, Holleb and Angrist expressed the opinion that the number of cases of asbestosis with. Lung cancer was too i. small for statistical evaluation. In 1947, Wegelius U 00) r eocr ted i Z S radiologically diagnosed cases of asbestosis among 476 -workers in Finland, and found no cases of lung cancer in this group. Goidblatt and Goidblatt in their section 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 felt to demonstrate some property which can be regarded as something more than inertness." These authors advance the theory that, until some more experimental evidence of direct carcinogenesis by asbestos or a de 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. Meanwhile, the Canadian Johns-Manviiie Company in Asbestos has been alert to the whole problem, and at the Thetiord 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^^ 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-Manviiie Corporation, and Dr. Cartier, the Quebec Asbestos Mining Association approached Industrial Hygiene 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. n. CRITICAL SEV^W C F 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 generalized 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 incidence 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 scudy 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 (63) Doll , 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 0. "asbestosis", as used, .T.ay refer to changes observable only by microscopic examination of the Lung tissue, or it may mean a radio- logicaily 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 eaumerated'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 no asbestos mining opera 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 generalization, 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. . This 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 of asbestosis of any degree might be higher than Doll imagines. This study, like so many others, involves autopsy records. The number of persons involved in the statistical analysis is only 113 representing only l, 042. 25 man 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. a. I: also seems 'hat this review does no: add anv new cases to the literature, although. Kueper in enumerating 99 cases reported prior to 1955, lists 11 discussed in it. Clearly, also, the paper is not dealing with asbestos miners. Another r.eason why this publication is of 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 Gioyne. " An examination of these references leaves at least some question as to the strength of the evi dence produced, (92) la 1951 Gioyne 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" --presumably asbestosis. Prim wry cancer of the lung occurred 17 times in this group, an incidence rate of 14. 1% for Lung cancer among autoosied asbestosis cases. There were in his series 796 cases with silicosis, and 6.9% of these also showed primary cancer of the lung. The 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%. Gioyne considered "the mortality of the asbestos workers" to be "disturbing". First of ail, it is obvious that the pape.r does not deal with the "mortality of asbestos workers", and secondly, it must be borne in mind that all of Dr. Gloyne's cases were submitted to him :or study because the findings were 'unusual for 'uncomplicated pneumo coniosis. Presumably, all cases, including those of asbestosis, in *hich the findings were not considered unusual were never brought to Dr, Gioyne's attention. As a matter of fact, in the same paragraph in which he expresses concern over the incidence rate in asbestosis, Dr. Gloyr.e himself points out that the rate for lung cancer based on necropsies a: the London Chest Hospital was 2 1.3% while the figures of the Registrar-General showed only 2.4%. He thus recognized chat 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. Glovne's work, its importance as an index of the pre valence of lung cancer in asbestotics has been misinterpreted by those who have quoted him. AU that it really shows is the fact that in a group of 121 cases, selected for special study primarily because they seemed abnormal by preliminary examination, 17, or 14.1% had lung cancer. Merewether 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, 1954, by which time there were 344 deaths including 205 maies 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 asbestotics who did not die of their asbestosis, or in LO. whose death certificate it was r.cc mentioned, may have beer, 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 l fa. The danger of attempting to compare a race 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. (142) ' (139) Lynch, who with smith 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 ashes- tosis. Lynch, himself, points out that, although this is an incidence of 8.2%, "both figures are 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 found only four in stances of lung cancer in 473 cases of asbestosis, a series 11 times as large. Behrens, as quoted in Merewether 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 of generalizing an incidence obtained in a group of cases which were I 1. undoubtedly reported only because some of them showed lung cancer, to possibly hundreds of as'bestocics 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 sources does not justify generalizations with regard to mortality rates. (205) 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 l/2 to 20 years. Finally, mention should be made of some entirely unsupported statements which tend to build up a mistaken view point through mere repetition. One example is a sentence in "Nontuber- (76) culous Diseases of the Chest1' where the authors say simply, "an ex 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 Merewether and the.n es tablishes the causal relation between asbestosis and cancer of the lung as settled. As a final convincing argument, it refers to "recent experimental observations {by) N'ordr-ina and. Sorge ^ This is the experiment in. which squamous carcinoma was said, to have been, produced in about a dozen white mice, and which has not been duplicated by any other in vestigator i Perhaps no one has written so extensively or so dogmati- (109-124) cally on the subject as has Kueper . . In 1955 he reviewed the cases 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- (131) way and Kennawav in an analysis of death certificates and, uniess Merewether's study was incomplete, these cases should have been in cluded in his report. Of the remaining 30, it is quite possible that the 31 contributed by Merewether and the LT by Gloyne contain some dupli cation with each other or with other English authors. In the same paper, Kueper 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 asbestosisi HI. PRINCIPLES OF THE EPIDEMIOLOGICAL METHOD Aa has been indicated, much of what 13 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 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 disease. Epidemiology cannot predict whether a given individual will fail victim to a specific disease, but it can predict the approxi mate number of cases of this disease which will develop in a population of specified sixe, composition, and subject to a given environment. It 14. proceecs 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 sations 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 problem of the study. A serious defect, common to most of 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 autoosied cases, as has been frequently done in earlier studies, still further restricts its use :n gene ralization. The problem w;*h wh;cr. the Quesec 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 on 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 frequency of cancer in various sites. 2. 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 types of cancer may be increased merely by reason of a decrease in the incidence of cancer o: other 3ices. This could be true even though the incidence o lung cancer remained constant, or if it de creased Less 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 autopsy 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 generaliza 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. Tor information from such a study to be projected to 3ome larger :rcuo, it is necessary that the autopsies represent a good sample of that Larger group. To assume that such is the case ui any particular series is dangerous and Likely to be faise. 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 planned to utilize the epidemiological method. A well-defined group of 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 g ene r alizations Su 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 ocher interested persons. It wns 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 3eemed advisable to depend upon data relating to deaths. These we 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 expensive 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 to the collection of data relating to all workers who had been processed through the clinic at Thetford Mines since its inception in 1947. Similar information was obtained regarding ail workers at the Canadian Johns-M.anville Company in Asbestos. Data from the clinical records included the age, family and personal medical histories, smoking habits, number of years of exposure, an estimate of weighted exposure. 19 and the course of the individual's health scares or :he cause of his death Although the data in these two instances were not exactly similar m 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, should be representative of each group, and could be followed for a de finite period of time. All of the available experience indicates that the development of asbescosis in less than five years of exposure must be somewhat rare. Accordingly, the cohorts were defined as including every worker who had a total exposure of five or more years, and who was on the employment rolls at Asbestos or Thetford Mines in 1950. These cohorts were then followed by means of the annual physical ex amination records through a six-year interval, 1950 through 1955. All 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 xray findings at the end of the period. Those who had died were tabulated 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 when the Living and the known dead had been tabulated. They represent men who had left 20. employment thrown retirement or resignation. Hlver.fu.aliy, ail 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 ot Quebec tor the years 1952 to 1955, inclusive, were reviewed in the department ot 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 not 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. The statistics for the Province of Quebec relate to popula tion, total deaths from all causes, total deaths from cancer of 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 coun 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, * ft \l ii l 2i. nearly ail or them continue to carry when they retire. A very few are not covered by this policy, and those who leave the industry tor 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 taken 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. The 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 not proved as the cause of death were considered separately. Mortality rates have been cal culated using both the "proved" and the total 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 and proved, were carefully analyzed to determine possible relationship or correlations between the development of lung cancer and any factor known from the > ) clir-icai recora3 such is family history of cancer, personal history of heavy smoking, coexistence of asbestosls 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-intervai 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 moved from the asbestos mines and in which, presumably, no asbestos miners live. Finally, in order to broaden the comparison of death rates in different population groups, the rates have been collected for Canada 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 beer, 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 m ten, or . 1. However, should a sample of ten marbles be drawn f; 23. no black marbles would be among them, even, though the "expected" number wouid be one. On the ocher 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 Samole 0 1 2 3 4 5 6 7 8 9 10 Total Probability .3486734401 .3874204890 . 1937102445 .0573956230 .0111602610 . 001-4880348 .0001377310 .0000087480 .0000003645 .0000000090 .OOOOOOQCOl L.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* pected 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 ;n slightly more than one trial out of LOO. The actual prob ability of this happening is .012795134, which is determined by adding the probabilities for 4 through 10. In 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 vaiue, but it is possible to state with a known probability that the true vaiue lies within a certain range. If the range is wide enough, the probability may be practically LG0%r. 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 and the binomial distribution are quite small. It is based on the equation: e -no (, no.) x x1 Where e = 2.71323 (the base-of natural logarithms) n s number of man years subject to risk p s incidence rate x s number of cases observed The logic of the statistical approach may also justify a few '*Qv<is of clarification. Generally, in problems of this kind, one sets up a hypothesis, which in our case would be, "Asbestos miners do not v 25. have a higher rate of 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 is clear that even if the asbestos miners and general population had ex actly the same lung cancer mortality rate, it is uniikiey 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 Joxow whether the difference is "statistically significant". If a sample should supply seven 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 Foisson 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 other 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. 2 6. V. RESULTS AND INTERPRETATION The two cohorts which, were constructed according to the criteria described in the preceding section have been considered in dividually and compared with each other as well as with the general population. Description and comparison of these cohorts will be pre sented here as a preface to c.e results of the study. . A tabulated summary of each group and of the combined cohorts is shown beiow: Asbestos Cohort Original Cohort 2327 Lost Persons Deducted 54 Pinal Cohort 2273 Living in 1955 (working and retired} 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 3635 5958 3547 5771 L33 6 3 3 23 6 2742 925 13 LS7 9 3 169 6 4673 1265 20 7~ Tables l, l, 3, and 4 present age, number o 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 Z 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. Ail 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 each job 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 two cohorts had the same average exposure, a larger percentage of the Thetford Mines workers will be found in category H, 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 II 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%. 3. TAB L.E L Mumber and Percentage Distribution of Asbestos and Thetford Mines Cohorts by Age Asbestos Age Mo. lL 20-44 45-54 55-64 65 + Unknown Totals AV, Age L6Q2 447 1 65 39 -- 2273 39 7Q 20 3 2 -- 100% * Less than .5% Thetford Mines Mo. Jl 2299 677 430 276 3 3635 42 62 ia 12 3 * 100% Combined Mo. _% 39Q1 1124 615 315 3 5953 41 66 19 10 5 100% TABLE 2 Number and Percentage Distribution of Asbestos and Thetford Mines Cohorts by Length of Employment Length of Employ- merit Asbestos No. at /* 5-9 880 10-19 364 20-29 342 30-39 163 40-49 L7 50 + 2 Totals 2273 Av, Yrs. o 15 Employment 39 33 15 7 I * 100 % * Less than . 5 % Thetford Mines No. JL 915 1534 580 435 163 53 3635 ' 19 25 42 16 12 4 1 100% Combined No. a/at. 1795 2398 922 603 135 55 5953 ' 13 30 40 16 10 -3 1 100% IJJj i< . <i i i ! 7A3L 3 Number ana Percentage Distribution of Asbestos and Thetford Mines Cohorts by Exposure Category Exoosure Category Asbestos No. % I II III Unknown Totals Av, Exposure 969 564 735 5 2273 1.9 43 25 32 m * Less than . 5 % i hector a Mines No. % 1062 15 36 1037 0 3665 2.G 29 43 23 0 100% Combined No. % 2031 2150 L 772 5 5953 2. Q 34 36 30 * L CO % oo oo TABLE -4 Number and Percentage Distribution of Asbestos and Thetford Mines Cohorts by Smoking Ha*oit3 Smoking Habits Asbestos No. r. Smokers Nonsmokers Unknown Totals 1931 340 2 2272 35 15 Less than . 5% Thetford M mes No. % 2742 925 13 3635 74 25 1 .100% Combined No. J,*: 4673 1265 20 5953 79 21 * 100% I; i t 30. This is a. difference which, could hardly occur by chance because of the large size at the sample. Therefore, it is Likely chat the differ ence is a real one unless the method of recording this information at the tune of employment varies at the two locations. In spite of the minor differences brought out by* these comparisons, it wouid seem chat 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 with the con trol groups. Table 5 presents the year-oy-year experience of the two cohorts and indicates the number of deaths each year from specified causes. In general, a case was considered 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 was no autopsy, the diag nosis of primary cancer of the lung seems to have been beyond question. The term "suspected" primary cancer of the 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. :: t 31. TA3LZ 5 - Parc I Study ot the Asbestos Cohort No. Alive At Beginning Year of Year Cause oi Proved Suspected Primary Primary Ca.of Luna Ca. of Lung Death Other Cause s Unknown ManYear s of Risx 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 L 35 02.5 `Proved'* cancer of lung death, race per 100 , 000 man-years of risk * 22.2 (----- 3 , 13502.5 TABL 5 - Part 11 Study of the Thetford Mines Cohort No. Alive At Beginning Year of Year Cause of Proved Suspected Primary Primary Ca. of Luna Ca. of Luna Death Other Causes Unknown ManYears of Risk 1950 3635 1951 3675 1952 3661 1953 3633 1954 3605 1951 3579 Totals L l 0 2 1 1 6 26 0 12 0 . 23 1 25 0 21 0` 31 3 123 1 3680 ,L 3663 0 3647 0 3619 4 3592 0 3563 o 21769 "Proved" cancer of lung death rate per 100, 000 man-years of risk = 27 6 lZI79> "Suspected" plus proved cancer of lung death rate per 100, 000 man- years of risk = 41 .3 (--2--) 21769 ; i i 32. TA3L 5 - Part III Study Qt Combined Cohorts Combined deacb races per 100, 000 man-years of risk for Asbestos and Thecford Mines ''Proved" cancer of lung death rate per 100, 000 man-years ot risk 25.5 9 t) 35271.5 "Suspected" plus proved cancer oC lung death rate per 100, 000 man- years of risk = 34.0 ( . 12 ) 7 35271.5 In cwo, no autopsy was performed but the clinical signs 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 who lived throughout the year was counted as a full man-year of risk, but one who died during the year was counted as one-half 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 Thetford Mines cohort which have been considered as "suspected" lung cancer cases. i i if }: j:. itt* : }!' f! 33. AS3ESTQSCOHORT "Proved" Cases ot Primary Cancer ot the Lung Name *11 Smoker I. A. J. t. N. P. 3. R. M. 66 65 65 Yes Yes Yes Exposure 26 Yrs. in Cat. 34 Yrs. in Cat. 37 Yrs. in Cat, Died a 10-12-51 I 5- 3-55 I 7-20-55 Au- Asbestoos v tosis Yes Yes No Yes No No THETEORD MINES COHORT "Proved" Cases of Primary Cancer ot the Lung Name Age Smoker IM dX o sure Died Au Asoestopsy tosis L. C. B. 2. A. S. 3. W. F, 4. L. D. 5. E. L. 6. A. R, 59 43 61 56 37 63 Yes Yes Yes Yes Yes Yes 32 Yrs. in Cat* 22 Yrs. in Cat* 33 Yrs. in Cat* 30 Yrs. in Cat. 16 Yrs. in Cat. 23 Yrs, in Cat. I 3-20-50 II * 51 III 4-30-53 II 11-22-53 I 3- 5-54 III 5- -55 Yes Yes Yes Yes Yes Broach,. No Yes Yes Yes No No "Suspected" Primary Cancer of the Lung Name Age Smoker Exposure Died Au- As'oes toosy cosis 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. Ill L 0-25-50 ni 7- -53 u 9-30-55 No Yes No No Yes No Ac Asbestos there were no cases m wmch the diagnosis was questionable, with. the result that the race tor "proves" cases it. this cohort is the only one developed. At Thetford Mines, however, the three cases mentioned earlier were placed in the category of '"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. Tor example, it happens that the rate found for the Asbestos cohort is very close to the "expected" rate based on 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 Thetford Mines group. As 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 of "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 we found ten or more cases. On the other hand, having found nine cases we are not above the 95% level and are not justified in rejecting the hypothesis. Nevertheless, the occurrence of nine cases in this, sample would show 35. 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 the lung is based upon the x-ray interpretation and, although no autopsy* was performed, the death certificate indicates that death was due to lung chncer. 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 hydrothorax, possibly due to lung cancer, but again there was no surgery and no post-mortem examination. In the third case, although it was subjected to autopsy, two pathologists disagreed as to whether lung cancer was pre sent. The death was certified as having been due to chronic myocarditis with nephritis and pulmonary congestion, and possibly cancer of the lung. On the basis of 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 hort have been calculated both ways. Table 6, giving the rates by age groups, reveals different experiences for the two cohorts. It happens that all of the deaths in the 1 ill $i 36. Asbestos cohort tall into one age group, so that the race tor that age category is exceptionally high. At Thettord Mines, a more even distri bution of the deaths by age developed a series of rates wnich 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. TABLE 6 Number of Persons and. Number of Lung Cancer Deaths by Age Groups Age Groues Asbestos Lung Cancer Persons Deaths Thetford Mines Combined Lung Cancer Lung Cancer . Deaths Deaths Persons Proven Total Persons Proven Total 20-44 1602 0 2299 L 1 3901 1 1 45-54 447 0 677 l 3 1124 1 3 55-64 135 0 430 3 3 615 3 3 65"** 39 3 276 L 2 315 4 5 Unknown 0 0 3 0_______ 0 ____ 3_ Q 0 Total 2273 3 3665 6 9 5953 9 12 Annual Lung Cancer Death Hates per LOO, 000 Man-Years of Exposure by Age Croups Azt Croue Asbestos Total 0 1 4 4* 45-54 55-64 65 * Unknown Over-all * No one exposed 0 0 0 1232 * 22 Thetford Mines Proved Tocau 71 25 74 116 116 60 121 00 27 41 Combined Proved Total 4 15 31 212 0 25 4 44 31 265 0 34 a The rates by length of employment (Table ?) 3how that the two groups were quite similar In chi.3 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- elusion, 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 Chat 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 ZZ which ap pears later in this section indicates that the members of the cohorts did not die.from lung cancer ae a younger age chan the general population. The rates by weighted exposure are shown in Table 3, and it will be noeed chat they present strong evidence against asbestos being a carcinogenic agent. For the Asbestos cohort the rates actuadly de crease with increasing degree of exposure, and at Thetford Mines they appear completely independent of exposure, if we count only the "proved" cases. 1 1.1 I i :! f; - ! I 33. TABLE ; Number of Persona and Number of Lung Cancer Deaths by Length of employment Length Asbestos Thetford Mines Combined of Lung Lung Cancer Lung Cancer Employ* Cancer Deaths Deaths men: Persons Deaths Persons Proven Total Persons Proved Total 5-9 10-19 20*29 3Q-39 40-49 50 + Total 330 364 342 163 17 2 2273 0 915 0 0 1795 0 0 0 1534 L 1 2398 1 1 l 530 2 2 922 3 3 2 435 3 5 603 5 7 0 163 0 I 185 0 1 0 53 0 0 55 0 0 3 3635 6 9 5953 ? 12 Annual Lung Cancer Death Rates per 100, 000 Man* Tears of Exposure by Length of Employment Length of Emoio vrr.enc 5-9 1.0-19 20-29 30-39 40-49 50 + Over-all Asbestos ' Totai 0 0 49 198 0 0 22 Thetford Mines Proved Total 00 11 11 57 57 115 192 0 99 00 27 41 Combined Proved Total 00 77 54 54 138 193 0 90 00 25 - 34 4 I ;n 1 39. TABLE 3 Number of Persons and Number of Lang Cancer Deaths by Exposure Category Exp osure Category Asbestos Thetford Mines Combined Lung Cancer Lung Cancer Cancer Deaths Deaths Persons Deaths Persons Proves Total Persons Proved Total I 969 2 1062 2 2 2031 4 4 U 564 L 1586 2 3 2150 3 4 in 735 0 1037 2 4 1772 2 4 Unknown 5 0 00 0 50 0 Total 2273 3 3665 6 9 5956 9 12 Annual Lung Cancer Death Rates per 100, 000 Man-Years of Expos ure by Exposure Cate gory Exposure Cacegorv Asbestos Total I II III UnJmown Over-ail 34 30 0 0 22 * No one exposed Thetford Mines Proved Total 31 31 21 32 32 64 *0 27 41 Combined Proved Total 33 33 23 31 19 37 00 25 34 t li exposure to asbestos is in an/ way connected :o lung cancer, <ve -j/ouud expect that the longer and heavier the exposure, the higher the race chat would be found. The only possible error in this interpreta tion could occur ti the weighted exposures were inversely related to years of employment, in which case the heaviest weighted exposure (category III) would 3how the shortest length of employment. Tables 9, 10, and 11 which list the number of persons in various exposure categories by length of employment indicate chat this error has not occurred. In fact, the average number of years of employment for each exposure category is almost identical. TABLE.9 Number of Persons in Various Weighted Exposure Categories by Length of Employment Asbestos Length of Emolovrr.ent 5-9 10-19 20-29 30-39 40-49 50 + Total Av. Yrs. of Exposure Weighted Exposure Categories l II III Unknown. Total 423 273 159 98 9 2 969 15.5 213 217 39 42. 3 0 564 15. 2 239 373 92 27 4 0 735 14.5 0 1 2 l. 1 0 5 29.0 330 364 342 163 17 2 2273 15.1 1 i \i i i j 4L. TABLE 10 Number of Persons fa Various Weighted Exposure Categories by Length of Employment Thecford Mines 'Length of Emoloyment 5-9 LO-19 20-29 30-39 40-49 50 + Total Av. Yrs. of Exposure Weighted Exoo sure Categories J_ JI 111 Unknown Total 279 390 155 149 67 22 1062 19.9 385 666 274 176 64 21 1586 18.7 251 473 151 110 37 10 1037 18. 1 0 915 0 1534 0 580 0 435 0 163 0 53 0 3635 13. 9 TABLE 11 Number of Persons in Various Weighted Exposure Categories by Length of Employment Combined Asbestos and Thetford Mines Length of Emnlovment 5-9 10-19 20-29 30-39 40-49 50 4Total Av. Yrs. of Exposure Weighted Exnosure Categories I _U in Unknown Total 707 663 314 247 76 24 2031 17.8 598 383 363 213 67 21 2150 17.8 490 851 . 243 137 41 L0 1772 16.6 0 1 2 1 1 0 5 29.0 L 7 95 2398 922 603 185 55 - 5958 17.5 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 3 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 of smokers and nonsmokers by age, length of employment, and degree of 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, this variable seems to be of no importance in accounting for the difference between lung cancer death rates for smokers and nonsmokers. *4 43, K si i *> TABLE 12 T Number of Persons and Number ox Lung Cancer Deaths by Smoking Habits Asbestos Thetford Mines Combined Lung Dung Cancer Lung Cancer Cancer Deaths Deaths Persons Deaths Persons Proved Total Persons Proved Total Smokers Nonsmokers Unknown Total 1931 340 2 2273 3 0 0 3 2742 925 13 3635 6 0 0 6 9 4673 0 1265 0 20 9 5953 9 12 0Q 00 T 12 Annual Lung Cancer Death Races per 100, 000 Man-Years of Exposure by Smoking Habits Smokers Nonsmoker s Unknown Over-all Asbestos Total 26 0 0. 22 Thetford Mines Proved Total 36 55 00 00 27 41 Combined Proved Total 32 43 QQ 00 2S 34 l ii i i <4. I : H; 44. N um ber o f S m o ke r* and N onum okert) by Aye G roup* 696 c 03 -- .2 <*4 _ -- ^4 o' T* fa y 3a n0 <N -J o (M 3 n-- o n ><Vcl -4 . *r a i= ci 30 Oy fa a a. 3 0fa O ogka 2i O 2 u =J< 0 2 oa fa yo 0 Ifo'^Ml U1 i*4 try a f-- sO V try yco < >. -2 a fa y .X 0 2 V3 i 5 _ fsl _ CO r a5 jC a** u I! C*a** *" aa <- ** O in y* a*t a " CO <nm4 ciaNs* <304 rs| 'll (c*4 30 . <*n i = 5 1 - -O o a o 4V0* s a 33< c * ZC0a o as J0aysuC __ C J6 5 w U i Za .Xofya a s- fya fa* o m W 0e 3 3 J24 h e 3 3 QC .X fa H JQ n* rvi in (M r <N| try o o *r m arO a c* a *to* a m O in a a 5' co 4 ys u Ufa 3 y 1 y -x S Q <z 0 a fa C VJ c * V Cfl 3 O <r n T -O 0 c * o o <N ^T> in s3 5 y a < > < a a V co a3 a ooo cc o a o 1*4 -- n n o. n r o a n ~<-- o-- _ -- OV' o -- m <*4 a n a C* a try a ^5sj* * 9 O amm r s_fl o >0. n a n in -- in 3* o a nO c* _ srO* c* o* rT, -- % oooo oo in m a o in -K <= o o 1*4 a o r** ;*4 in i*4 T o* C* a r-- o r* *r m a a i*4 in <r nn n a c ? 0 -2 3 7 t Vn o ea t il.j45 * li I 4 N um ber of S m okers ami N onam okcra by Length of E m ploym ent 45 i5 5 % 3-- i iN ^331j3iN ye u ty c ye P" <3 3 O 3 0 Z 0 r> <*i n v f"<3 ---- > 3^ vO . N3 y aj yei c O n* co r*n ^ o i*i 3 O<N t*1 3 r " <*1 -- -ra r -- i3 3a ye f*l N O 3 I b y a ye a o Z c S <--*g n t N j3 <--*i i--n --r r* N N W y ye o 0a0 0-0 nO n 3s 3 <*i iN -- r* >3 iN V <N r- e c/3 <N -- J I -- -- 000|<N ye b il 3 ^ *3 -- 3 O 3 0 2 *3 -- V .*>4 Z 2a <*1 t*i. U| y yae O <N 3* 3 3 3 >3 V-- iN -- <1 S f- r <m -- 33 w 3 l 0 >. - 3_ | c2 va - ?a 3 3-- 3iN <3*i 3^ -J ?f ? .a| 1303033 > w - n t ii r <; q >. o c a SO cy - > -3 a b y ye a c ac a Z ac y yQge c/3 y rsto # yc y b y 0. i o333c3 5 5o 3 o N o O N [ 1-- ye T3 y b v y6 <33 f- r-- _ a 3 N <*1 <*1 3 i*1 3 3 aa U b yye a mm 4 <o*1 * <NV T- 3 (*l 3 IT N c/3 " 4 V. ^9* 3O o o o f** O <3 ye " iN 3 o N 3O N " b yye o vO <1 <N f* (<**1i 3 >0 O 3 3 O T IN O3 a" b y * * C3 8 <N CO >3 4 3 4 3 o i*1 4O o c O O O o 3 o 5s* c D ? o c o13 O i3 ye b y yoe so 4 >3 <i*314 rl 3# i*1 3, 3 i*i 3 4 w 3 a b y ye a i*1 r(*-i 00 (0*01 <*i 3 P* P O CO oo so a. ye .t e y 3 l 1 <3 o -- 3 <N| ei 3* <N Orl a* 3 *5* O 3 a 3 | i f N um ber of S m okers and N onsm okers by E xposure Cateuor 20 46 s i C S $ 3 T r- U <*n i*4 b a 3 i a 46 a* -4 a -- im 2 3 w r- n *z 3 T . 4-- 0 a 0 >* b i a in -- 3* m -4 *! r to n to i*4 a* c > c o a ("1 3 46 4 U 2b i b 3 e 3 Z a 4ato6 3 a -- fs 4 P* r* -4 in 4 , -- -- 1*4 . *r a c* P <4 P ^r A4. 4 3 2 - - a oIn ^ b i 3 2 2 svno a o-- -- v a za -- a so ^* <--* G* -- ba Is U X a o a ?* = 2a ? - 7? _ 3 .a *j M2>3 =< 0a a 7 <J a b a 0 3. X a >. -3 a b a 3 O Z *2 5 a ba .x o c s3 o* c 0 a aa a ba a C. : $ o, c , - 3 a J2 4 n<** inr --* . r*-. r--9 , 2 2 r- <<n> i*4 a -- " mr4*1. i*4 4 . * . ai i 5 s 3 5 r-. -* r<*n?, , -6 , ..d j. i 4 *4 .** . Z 3 (*^ V -4 i-- a "i -- o i r- a* * 44 - I S *'o o 2 m in 46 afifl it > 3 3 43 Z - *7* *4 -4 a a < C 4 a* in *4 i*4 <*s J5 ! >4 3b If 7a a o| 3- --2 4 = -I 5 u ii( 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 asbestosis, we are immediately aware of a disturbing inconsistency. Various authors report the incidence of asbestosis after 10 or 15 years of exposure as exceeding 50%, and in (133) (135) (147) (154) (195) one study, as high as 37%. However, data on cases of asbestosis from the cohorts at Thetford Mines and Asbestos pro duce a race 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, Or. Cartier has estimated that there are probably 300 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. Instead of 143 cases of asbestosis in the whole working force at Thetford Mines, we should then have perhaps 500, but even this would result in an over-all rate of less than 10%, which is far below those widely reported. In our i ;} .? :i 43. combined cohort, there are 1765 men who have had more than 20 years of employment, and 431 of these have worked in the heaviest average exposure. According to the records, we can account for only 133 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 425 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 may be 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. TABL 16 Distribution of Recorded Asbestosis Cases In Cohort Living Dead Total Asbestos 13 4 22 Thetford 36 30 116 Combined 104 34 138 49. TAB LE L7 - Pa.r: I Number of Asoestosis Cases 3/ Length of Employment and Exposure Category Asbestos .Length of Employment Less than 10 10-19 20-29 30-39 40-49 50 4 Total Av. Yrs. of Employment Exposure Category Ia 111 00 01 27 01 00 _0 JL 29 25 25 0 2 4 4 1 0 11 29 Unknown 0 0 0 0 0 0 Total 0 3 13 5 1 0 22 27 Percentages of Asbestosis Cases By Length of Employment and Exposure Category Length of Employment Exposure Cates orv III Less than 10 10-19 20-29 30-39 40-49 50 + Over-all 00 0 0 . 5 .5 1.3 7.9 4. 3 0 2.4 14.8 0 0 25.0 0* * .2 1.6 1.5 * No one exposed in this group Unknown, * 0 0 0 0 * 0 Total 0 .3 3. a 3. 0 5. 9 0 1.0 5 0. TAB LZ L 7 - Par: II Number of Asbestosis Cases 3y Length, of Employment and Exposure Category Pnetford Mines . Length of Emoiovment Less chan 10 LQ-L9 20-29 40-49 50 + Total Av. Yrs. of Employment Exoosure Category II ill Q0 01 25 2 15 06 02 4 29 30 36 Q 7 21 33 20 2 S3 34 ITnicnown 0 0 0 0 0 0 0 Total 0 a 23 50 26 4 .. 116 34 0 1 N O o Percentages of Asbestosis Cases By Length of Employment and Exposure Category Length of Emolovment Less than 10 10-19 20-29 30-39 40-49 50 4 Over-ail Exoosure Categ orv 1 JL in 0 0 1.3 1.3 0 0 .4 0 .2 1.3 3.5 9.4 9.5 1.3 0 1.5 13.9 30.0 54.1 3.0 * No one exposed in this group CnJoiown * 0 0 0 0 * 0 Total 0 .5 4.3 11.5 15.5 7.5 3. 1 ! 5 l. TA3L i 7 - Parc III Number ox Asbestosis Cases 3y Length of Employment and Exposure Category Asbestos and Thetford Mines Combined Length of Eraaiovmeat Less than 10 10-19 20-29 30-19 40-49 50 + Total Av, Yrs. of Employment Exposure Cate ?orv _L Ji in 0 0 4 2 0 0 6 23 0 2 12 16 6 2 33 33 0 9 25 37 21 2 94 33 Unknown 0 0 0 0 0 0 0 Total 0 11 41 55 27 4 138 33 Percentages of Asbestosis Cases Ey Length of Employment and xp<osure Category Length of Emniovment Exposure Category ill Less than 10 10-19 20-29 30-39 40-49 50 + Over-ail 0 0 1,3 .3 0 0 .3 . 0 .2 3. 3 7.3 9. 0 9. 5 1.3 0 1.0 10,3 27.0 51.2 20. 0 5.3 * No one exposed in this group Unlctown * 0 0 0 0 * "o Total 0 .5 4. 4 9. i 14.6 7. 3 2.0 A percen.ca.ge incidence ci asbestos;* for each, exposure category has been developed as weil as for each. per;od or 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 races round by the authors previously 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 asbestoses cases. The obvious result is a higher relative frequency of lung cancer in association with asbestosis. Table IS compares deaths due to lung cancer and fatal cases with as bestosis, alone and in combination with each other. TABL 13 -Part I Statistical Analysis of the Causes oi Death Asbestos Cause Asbestosis No Asbestosis Total Percentage Lung Cancer 1 ( .2) 2 ( 2.3) 3 6.1 No Lung Cancer 2(3.8) 43(42.2) 46 93.9 Total 4 45 49 Percentage 3.2 91.8 Figures in parenthesis, are the "expected" numbers 53. TABI~ 13 - Par: II Statistical Analysis of the Causes of Death Thetiord Mines Cause Asbestosis No As'oestosis Total Percentage Lung Cancer No Lung Cancer Total Percentage 3 ( 1.3) 35(26.7) 23 21.2 3{ 4.7) 10 l (99.3) 104 73. 8 6 126 132 4. 5 95.5 Figures in parenthesis are the '`expected" numbers TAB L 13 -Part HI 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) 23(30.4) 32 17.7 - 5( 7.4) 144(141.6) 149 32. 3 9 172 131 5.0 95.0 Figures in parenthesis are the "expected" numbers Six deaths from- unlmowa causes not included 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 at the 95% level using the chisquare test of significance. The importance of the under-reporting of asbestosis can be observed in Table 19. 54, TAB L 19 Statistical Anal/sis of the Causes of Death if 20 Nonasbescosis 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 23. 7 5 ( 6.4) _U4<L22.6) 129 71.3 9 ]T2 131 5.0 95,0 Figures in parenthesis are the "expected1* numbers In this table, is has been assumed that 20 oi the cases which did nos have lung cancer and which were reported to have no as'oestosis did, in fact, have asoestosis, the diagnosis of which was missed. Although the cases ox lung cancer wish asoestosis are still higher than would be expected, the difference is no Longer significant at the 95 % level. This still is true if fewer than 2Q 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. On. the other hand, a shift of about 40 cases would produce an expected rate almost equal to the race 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 cue proved cases of Lung cancer and one of the suspected were associated with asbescosis. Since we have oniy 32 deaths in which asbescosis was present according to the records, the incidence in this series is 12,5ft. wnile this is slight!7 lower than the rates found by Merewether, Gloyue, and Wedler, it is still much higher than could be expected it the asbescosis 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, and the United 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 earlier, in the office of the Division of Demography in the Provincial Ministry of Health. The 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, ail 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 Che two cohorts for the years 1950 through 1955, and shows the annual rate per 100,000 in these segments. It will be noted from the cable chat the mortality rate for the Asbestos codort is almost exactly tbe same as chat for the Provtn.ee, while the rate for "proved" cases la the Thetford Mines codort is only slightly higher. When the "suspected" cases are included in the calculation, the rates for the. Thecford 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 rather marked increase in the total number of cases for the Province between 1950 and 1955. It is assumed that at least pare of this increase is due to improved recognition and reporting of 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 the 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 period. Table 21 was compiled to show the annual age-spjsciiie lung cancer rate of cases in which the death certificate merely read "cancer of the lung", as distinguished from those in which the diagnosis was L C o m p a riso n of P ro vin ce o f Quebec w ith Aabeatoa and T h c tfo rd M ine N u m b e r a liv e in c o h o rt at b e g in n in g of 1952. * y y* 8 C --* >0 * <*4 '`4 <9 <4 o :h --,, i*4 '-g <*4 rg o <-t *r -N in "'4 <*4 r<i >45 A 0 > r |S m <M U1 m O <1 oo o<n O <3 OO m (M o SOJ J in <*g O <*4 rg O' ion-' o OO oo <3 0 <n Veg 58 (N O' a <3 ea O Z u o a. in a vO >a o a <OM' u O u_1 u O A0 O a e s _1 a u 58 CA II X u2 a a i4y> C > a <* ?o -O u H CL -3 2 3 Jr o w 6* Q. 1 r <; ou Aa 0* < 57. o a. au Qta 8 *3 a. 8 i confirmed by autopsy, surgery, or biopsy. The term ''soeciiied. primary" refers to chose 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 age-specific races shown in Table Z l, and those 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 may have bees exceptional. This comparison, 'summarized in Table 22, shows chat the observed number of deaths in our sample is not significantly greater than the expected number of deaths, based 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 noted 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 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. .2 'i 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 Groun 20-44 45-54 55-64 65 4* Total Number 727,135 138,952 128,944 113,467 l, 153,498 Percentage 63 16 Li L0 100 Percentage Combined Cohorts 66 19 10 5 100 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. T A U l.u : 21 Sy > o >0 u u y oi i n~ -- I *o oi oi oi ^oi 4-- arl)Ncn yy "a a < o --a 3c 2y > .i i3u, "T wy JU S; a 3 a y - ? C y y ^3 M yC o-- *" y U "3y >w* C2 y i: v2ai. ^--u y Hi fr* I y vft C- *9 y *y 5 |W r9 y * *o s y .X 2y s3 * 93 y c. a u a u < C*' oi f*- *? Ol <*i in oi O--l <--* -Oo n--- 3* M 3M <T> no nn no| C*' __ ^C'-CSl -- -- a* -a '3 I 3s O a 3 O u M y ta y. uu 3 '" '* ya ya. yta asa a -- yy yC w yy a. -- --y ai " *" > ?a v S5 rt|0 -- m mi no >. j i'3 3 -- loi -- Nfi-O --13" -- -- INI y 2* >7 - C5 ?5 0 O o 3 O o 0 O o 0 G o O o o r p cm* O rf*1- -- no r-- f-- <"0 <-- -- fM V -V -- y* o no Oil 0y1 oi 01 Ol >oal 2 a r* yy 2 ,> "a u ca Oy 3^ - Ol Su* a-- a. u U O. 0 s a 13 J* 3 C a. aa y . :u. i ;> I- L1*1 >ic.i . y -. i lr 2\ ii =1L S\ * VI -- 'J 3 J sC|- ; *4O^ -- *r ! , rj r r-- **! nj nj > *r ^4 njlr^j y >a -i u v>C. y^ nj <"1 -O 'O l un -- -- "5,!*4 aZ o o Hy N n* t o N J1 /! N o* o if- no -N no y a. a y - S4 y- c2 N Tf -- * nl ^ -- no no y y z,, M *> y 01 -- 3{ no y -- ^ a ^ oi a y Ol N U1 " r on p <n | f-- y 3 fSi "3 --H * '"in' sr -- P - plcr> -- (M no | < no no O P* oe Nn - m a u O y za y yi O no 01 i 01 y* Ol (01 01 'G u y > O TA3LE 22 Comparison, of the Actual and Expected Number or Lung Cancer Deaths by Ag e Among Asbestos ML::ers Age Group Province Total Specified Primary Hate 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 1.3 24.5 67.6 39.3 -- 3901 1124 615 315 3 0* 2 2 2 -- 1l 13 33 45 00 * Actually . 4 4 The expected number is based on the average of the 1954 and 1955 age-specific rates for the Province of Quebec. 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 240 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 ^ ^ gave age- and sex- specific rates for Canada for three periods between 1931 and 1952. The rates for males are given in Table 23. - TASLZ 23 Annual Death Rates per 100,000 for Cancer or the Lung in Canada* Age Croues Under 30 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 30-34 35 + All Ages 1931 -1933 Grouos of Years 1941-1943 . 0.2 0.9 2.Q 3.Q 5.2 3.2 12.7 12.5 15. i 10.7 15.3 3.2 11.4 2.3 0. 3 0.9 3.2 5.4 12.5 13.9 27.0 33.7 34.5 30. 6 30.0 27.9 14.3 7.1 - 1950-1952 1.0 0.3 3.0 6. 5 16.7 37.2 59.7 77.3 102,9 36.3 33.9 59.7 71.0 15.3 * "Mortality from Lung Cane er in Canada", 1931 to 1952. These figures show strikingly the increase in races be* tween 1931 and 1952, and this increase is particularly marked after age 50, confirming an observation previously made, to the effect that lung cancer has probably been under-diagnosed in the older age groups 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. chis must be an approximation.. However, the rates would be some what as follows: Age Group 20-44 45-54 55-64 65 r Hate 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 have increased for Canada between 1952 and 1954 as it did for the Province of Quebec. (See Table 21) A further comparison has been made 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 20.3 per 100,000, an.increase of 5 per 100,000 over Phillips' 1950-1952 rate, and compares with 25.5 per 100, 000 for proved cases and 34. 0 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. 64. Since it ia probable that figures for the United States are more complete and, therefore, possibly more comparable to the data {or the miners, age-specific rates were computed from "Vital Statis tics of the United States1', Volumes I and II, for 1952. These rates have been tabulated in Table 24. TAB LZ 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 Ae Groun 20-44 45-54 55-64 65 + Total Peculation 24,544,000 3, 065, 000 6,340,000 5,670,000 44,619,000 - Cases 333 2979 6254 6433 16,599 Rate oer 100, COO 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 23.0 per 100, 000 in 1955. They are not identical with the rate calculated from the figures of the office of Vital Statistics, but this is possibly because the American Cancer Society rates are for males of all ages. Nevertheless, they, too, compare favorably with the rates of 25 (or 34 for total cases) obtaining among the asbestos miners. 22 . Returning :o a comparison, between the ascescos miners and persons who are exposed :o asbestos in one form or another (as distinguished from the general population groups just discussed, who have no exposure) an interesting observation can be developed by de- (122) duction. Hueper has stated that there are about 35,000 persons exposed in the United States, and we have found that the Canadian mines employ about S, 000. Elsewhere, it has been estimated that the workers in England who have exposure total between 3, 000 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 20 years since 1935 when the first case of asbestosis with lung 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 ISO 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. oo. Comparison 5 e rw e e n jz'~: Cc:^.".::es Acacer.: :o :he Aaoestos-P rocucir.^ .nr?ii a.no Rijn: 5e.ec :sc Counties To compare lung cancer mortality races in the coun ties surrounding the asbestos-producing areas with another group ot counties ui which no asbestos miners are likely to reside, the races were computed on the basis of figures for the years 1950 through 1955. The eight* counties selected for comparison were Argenteuii, Chaceaugay, Mor.tmagny, Pormeuf, RichLieu, Rivieredu-Loup, St. Hyacinche, 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 Artha'oaska, 3eauce, Drummond, Frontenac, Megantic, Richmond, Sherbrooke, and Wolfe. Table 25 shews the number of lung cancer deaths for the years 1950 through 1955 for each of these counties, and a mortality race, based on the adult male population in 1952. To emphasize the comparison Megansic 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. i u u cs oo* c c o CO -- 03 ^3 C' -g .-g T A B L E 26 It la aaaum ed th a t a ll m a le lu n g c a n c e r d e a th * o c c u rre d a lte r age 20. X i*i ^-g rg o T. 6a. It is apparent from the table chat the lung cancer death race for the eight counties immediately surrounding the asbestosproducing areas is practically identical with that of eight counties selected for comparison. VThile 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 far Montreal. The figure for Montreal would certainly be higher except for the very low numbers of deaths reported for 1950 and 1951, 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 200 greater, and this would result in a rate of -eO per 100,000. The only possible conclusion from this comparison is 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 A,- .^stos 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 of interest to summarize 69. such cases for the record. There were rune deaths prior to the be ginning of the time period covered by- the study, including one in which, the diagnosis was mediastinal lymphosarcoma. All of these nine cases occurred at Thetford Mines. It 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 ao cases have been reported in 1956 and 1957. During the period covered by this investigation, there were six proved cases and three suspected cases at Thetford Mines, as well as three proved eases at Asbestos. Through 1956 and to date in 1957, there were eight deaths at Thetford Mines, six of which were merely suspected awrf included such diagnoses as mediastinal lymphosarcoma, mesothe lioma, cancer of the leg with metastases 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 evidence is strongly suggestive of lung cancer. This is a total of 33 cases of ail 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 Thetford 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 working span covered periods varying decrees, a minimum at 14 years and maximum or 37 years. Only three men. had Less than ZS years or employment in the industry. Seven among those on. whom such iniormation is available had a weighted exposure placing them in category LH, and six worked in an exposure represented by category I. Although they were subjected to post-mortem examination, * there were three among these proved Lung cancer cases in which we do not have iniormation regarding the presence oi asbestosis, Oi the remaining 17, asbestosis was present in nine, although it was minimal in two, and two pathologists disagreed regarding its presence in one. Sight oi the proved lung cancers, thereiore, were not accompanied by asbestosis. VI. SUMMARY AND CONCLUSIONS Interest in the question of whether there may be an as sociation between lung cancer and asbestosis 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 had 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 of 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 consistently high, its uniformity is indicated by the following tabulation. Author Merewether Wedler Wyecs Lynch it Cannon Gloyne Totals Asbestosis Deaths 344 92 115 40 L21 712 Cancer of Lung 55 15 17 3 L7 107 Percentage Incidence 16.0 16. 3 14.3 7.5 14. i 15.0 The notable characteristic of all previous publications is Che adherence to the development of a percentage relationship in (63) a relatively small and very selected group of cases. Only Doll, 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 73. of these operations. Cohorts were defined according to certain cri teria and ail 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 the 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 other 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 not 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 their exposure, and their smoking habits. Pour thousand, six hundred and seventy-three were found to be smokers wit bin the definition of that term as 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 30 years. Thirty percent had a weighted exposure which placed them in' cate gory III. The mortality rates for lung cancer, as computed on the basis of six "proved" deaths among the Thetford Mines cohort and three "proved" deaths among the Asbestos cohort, were 37.6 per 100,000 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 41.3. The rate for the combined cohort was 23. 3 per 100, 000 for "proved" cases, and 34 per 100, 000 for "proved" "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 of exposure or with, degree of exposure, a fact which presents strong evidence a- gaisst the carcinogenicity of asbestos. On the other hand, the study indicates that cigarette smoking is a very important factor in the in cidence 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 .< D under-reporting of asbestosis cases. The ir.cides.ce of asbescosis indicated by the medical records is far below :hat 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 quoted 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 10G,Q0G) compares we LI with the rate of 22.5 per 100, 000 for the rest of the Province, and 20. 3 per 100, 000 for adult males throughout the Dominion of Canada. It also compares satisfacto rily with rates of 37,2, 25,3, and 23.0 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 7 6. 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 been 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 asbestosis. All but one died in the recognized "cancer age" and at least one-third had only the lightest exposure {category t) 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 Thetford 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. Despite this, the results suggest that a miner who develops the disease ashestosis does have a greater likelihood of developing cancer of the lung than a person without this disease. We suspect, however, that under reporting of asbestosis cases had led to a fallacious finding in this con nection. The death rate from lung cancer in the areas continguous to the asbestos operations is comparable to that in areas widely scattered throughout the Province of Quebec and is lower than in some urbanized areas within the Province. 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 the effect of smoking. The value of this investigation would be considerably en hanced by continuing the observation of the cohorts formulated herein on a year-by-year basis. It is strongly recommended that the chest x-rays of all workers be submitted to an independent reading for the diagnosis of asbestosis, since an inaccurately low incidence race for this disease creates an artiiically high relative incidence for lung cancer. :a. VII. BIBLIOGRAPHY 1. Adler, I. Primary malignant growths at the lungs and bronchi. 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