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PART I .
THE SPECTRUM OF ASBESTOS-RELATED DISEASE
Asbest0s-Associated Deaths among Insulation Workers in the United States and Canada, l967-1987 IRVING J. SELIKOFF AND HERBERT SEIDMAN Mount Sinai School of Medicine of the City University of New York New York, New York 10029-6574 The first information in the scientific literature concerning hazards associated with exposure to asbestos appeared as descriptions of disease in individual patients. This was logical: it would hardly be expected that populations of exposed workers would be studied in the absence of evidence that disease was occurring. It also emphasizes the value of individual case reports to point to potential risks, so that further investigations can be mounted to estimate problems in quantitative terms, as a guide to control.
DISEASE ASSOCIATED WITH THE MANUFACTURE OF ASBESTOS PRODUCTS In 1924, Cooke reported the death from pulmonary fibrosis of a young woman employed in a British asbestos factory,' a case which, later described in greater detail, gave the disease its name, "pulmonary asbestosis."2 Additional such instances) led to a survey of the manufacturing branch of the industry and, in 1931, to regulations for exposure controL4 A similar sequence of events led to the identification of lung cancer as a hazard in asbestos production: single cases starting in 19355-9were followed by examination of a collected series in 1947.1° This process was associated with inherent constraints, however. Lung cancer could be identified, but not necessarily other neoplasms, let alone the full spectrum of this family of diseases.
ASBESTOS DISEASE AMONG USERS OF ASBESTOS PRODUCTS The same general pattern occurred with the use of asbestos materials. Starting in 1918, asbestosis was found in individual patients with pulmonary problems; in that year, Pancoast, Miller, and Landis reported X-ray abnormalities in a marine fireman." In 1930, Albert E. Russell, Chief Surgeon of the U.S. Bureau of Mines, reported a case of asbestosis in a man who had been exposed to asbestos while doing maintenance work in a government hospital, and who received compensation for it.IZ In 1934, Ellman reported asbestosis in an insulation worker') and eight years later, Holleb and Angrist added lung cancer to the list of conditions seen with such use of asbestos.14 These findings were supplemented in 1951 by the work of Stoll, Bass and Angrist, who reported a case of lung cancer and asbestosis and emphasized "the hazards of industrial exposure . . . and the need for preventive measures."" 1
2
ANNALS NEW YORK ACADEMY OF SCIENCES
Alerted by the finding of asbestos-associated disease in construction workers, Breslow and coworkers (1954) prepared a special code for such employees in their analysis of lung cancer in California. This allowed asbestos exposure to be sought among plumbers, gas fitters and steamfitters. “These occupations should now be intensely studied,” they advised.I6 The Chief Inspector of Factories in Great Britain published equally pertinent warnings in his Annual Report for the year 1949 concerning asbestos hazards in ships or in buildings” and again in his Annual Report for 1956, in which he called attention to problems with asbestos cement work, with removing insulation, or with breaking of sacks containing asbestos.18 Asbestos exposure in shipyards was of concern in these years. In 1943 the U.S. Navy required airline respirators or dust respirators for workers in asbestos jobs.19 This concern was later found to have been justified, when McCaughey, Wade, and Elmes reported a number of pleural mesotheliomas in workers in Belfast shipyards.20 Similarly, after the first case of asbestosis was observed in Sweden in 1953,21a survey of 60 more workers was undertaken, including seven in insulation and two who had sprayed asbestos; the latter were found to have advanced asbestosis.22
ASBESTOS DISEASE IN INSULATION WORKERS Development of information concerning hazards with the use of asbestos in insulation work is an example of how such data accumulate and helps to spur efforts for avoidance of risks.
Industrial History The early descriptions of the use of asbestos vary somewhat, although, overall, R. H. Jones’ brilliant monograph is perhaps the best source material for the history of asbestos utilization and d e v e l ~ p m e n t including ,~~ the earliest modern use of Italian asbestos and, soon afterwards, chrysotile (originally dubbed “asbestic”). The first Italian mine was opened in Lombardy in 1866 and the first Canadian mine about 1877, although asbestos had been exhibited as a mineralogical curiosity as early as 1862.24Writing in 1897, Jones reported that in New York, there were “. . . hundreds of buildings plastered with a ~ b e s t i c . ” ~ ~ Berger has written that asbestos was first used for heat insulation in 1866.25 While the exact year may be in dispute, there is no doubt that it was utilized in insulation materials before the turn of the c e n t ~ r y . Bettes ~ ~ . ~ has ~ provided an interesting historical account: Henry G. Keasbey and Richard C. Mattison, upon graduation from the Philadelphia College of Pharmacy in 1873, began the manufacture of pharmaceutical preparations in Philadelphia. Among their products was carbonate of magnesia, and they discovered that dolomite in Ambler, Pennsylvania provided a very good basic product. At about the same time steam power was developing rapidly, which required efficient insulation. In 1882, Hiram Hanmore, an insulation contractor, was impressed by the extremely light weight of magnesium carbonate and applied it like plaster to a steam boiler. Dr. Mattison, curious to know what was being done with the relatively large amount being purchased by Hanmore, contacted him and entered into an arrangement to sell insulating materials, manufacture molded pipe covering and block insulation and magnesium cement. Hanmore had used shredded hemp which deteriorated rapidly and Dr. Mattison conceived the
SELIKOFF & SEIDMAN: DEATHS IN ASBESTOS INSULATION WORKERS
3
idea of using heat-resisting asbestos fibers as the reinforcement and thus was born “85% magnesia” insulation, destined to become the standard high-temperature thermal insulation for many years. These events subsequently led to K&M’s becoming a leading manufacturer of asbestos-based products including asbestos textiles . Z R
Correlating well with this was the history of the insulation workers’ union in the United States and Canada. Formed in New York City in 1884 under a charter issued by the Knights of Labor (predecessor of the American Federation of Labor), the union was chartered by the A.F. of L. in 1910 as the International Association of Heat and Frost Insulators and Asbestos Workers; the title is still used by this union group.29
Early Observations Ellman’s report of asbestosis in an insulation worker in 193413began the recapitulation of what had been seen with the manufacture of asbestos products. Collected series contained additional cases. John Gilson in his Wyers Memorial Lecture30 noted that of the 100 cases of asbestosis recorded by four National Insurance Panels in Great Britain before 1933, 59 occurred in insulation workers and only 18 in textile workers; of Newhouse’s 31 patients with mesothelioma at the London Hospital who had a history of asbestos exposure, eight had suffered this in insulation work.31Similarly, in the review of lung cancer in workers with asbestosis undertaken by the Chief Inspector of Factories in 1946,’Oeight were in insulator^.^^ At about this time (1944), a warning about asbestos risk had been published in an industry journal in the United States by F. W. H u t ~ h i n s o n . ~ ~ Awareness of asbestos disease risks among insulators led to a survey of members of the Insulation Workers Union in Copenhagen in 1956.34Frost, Georg, and Moller found 22 of 31 workers examined to have abnormal X-rays, of which 19 showed pleural changes. Pendergrass, too, emphasized radiological changes in insulation work.35 Lung cancer in an insulation worker had been reported in 194214and again in 19S1.I5 This was followed by pleural mesothelioma in 194736 and later37, and peritoneal mesothelioma in 1961.38
Dimensions of the Problem Scientific observations established hazard associated with exposure to asbestos in the manufacture and use of asbestos products, including insulation work. It remained for appropriate epidemiological studies to provide quantitative measures of the mortality risk. This was accomplished for factory workers by Doll in 195539and for insulation workers by Selikoff, Churg, and Hammond in 1964.40 Nevertheless, these initial investigations were limited. Doll’s data reflected observation of I13 men between 1935 and 1953, with only 39 deaths. In the insulation worker study, there were 2.55 deaths between 1943 and 1962 in a cohort of 625 men who had begun work 20 or more years before. Because of the limited experiences reviewed, neither the factory nor the insulation worker investigation had the power to allow for adequate analysis of the full spectrum of cancer risk, especially since experience with adequate latency (person-years of observation 25, 30, 35, 40 or more years from onset of asbestos work)4twas fragmentary or unavailable.
4
ANNALS NEW YORK ACADEMY OF SCIENCES
To some extent, this situation was remedied by 1979. In that year, the mortality experience of 17,800 insulators in the United States and Canada was reported.42These had been observed prospectively from January 1, 1967 to December 31, 1976, with 166,853 person-years of observation and 2,271 deaths. The data obtained confirmed the increased incidence of the major categories of asbestosassociated neoplasms (lung cancer, pleural and peritoneal mesothelioma, gastrointestinal cancer) and of asbestosis, and provided limited experience concerning the increased incidence of several other neoplasms. The data also yielded important additional information regarding the association between asbestos exposure and cigarette smoking,43which had been first reported in 1968,44and shed light upon the equally important influence of latency in evaluating mortality risks of asbestos exposure.41Still, even this extensive series of observations was inadequate to permit unequivocal judgment as to increased risk of cancer at several other sites, such as the pancreas.45
PRESENT STUDY We have continued our observation of the survivors of the 1967 cohort, from January 1, 1977 to December 31, 1986. The total 20-year experience, 1967-1986, now covers 301,592.6 person-years of observation. TABLE1 provides data concerning person-years of observation relative to age distribution and years from onset of employment.
Ascertainment of Cause of Death As of January 1, 1967, 17,800 men were enrolled as members of the insulators’ union in the United States and Canada (The International Association of Heat and Frost Insulators and Asbestos Workers, AFL-CIO, CLC). Much information was available for each from union records, including date of birth, date of onset of insulation work, and employment history. Data concerning smoking, medical symptoms, and use of respirators were obtained from the men by mail questionnaire. Observation of the entire cohort has been maintained since 1967, with the valuable assistance of the international union offices and union officials in each of the approximately 120 local unions in the different states and provinces. Whenever a man dies, we are notified and a death certificate is forwarded to us. If it is not, we obtain it from appropriate official agencies. The cause of death as listed on the death certificate is categorized by an experienced nosologist (“death certificate” diagnosis [DC]). Early notification facilitates investigation of the circumstances of the fatal illness. For each death, whatever the death certificate category, information is sought: clinical data from treating physicians and hospitals as well as histopathological material from pathology facilities. X-rays are obtained and reviewed, and histological material is studied by our Pathology Unit headed by Prof. Yasunosuke Suzuki. Cause of death ascertained after review of all available material is recorded as “best evidence” (BE). Where no clinical or histopathological material is made available, which occurs in about 10% of the cases, the “best evidence” is the death certificate; such is frequently the case for suicides, plane crashes, or sudden cardiovascular deaths, for example. On the other hand, for
Total 182.50 4.886.14 15.463.17 28,282.30 41,420.90 48.690.19 46,547.52 39,666.25 29,579.94 19,871. I8 12,665.75 7,446.50 3,850.32 1.794. I4 1,245.80
301.592.60
Age 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85 +
Total
61.655.41
182.50 4.886.14 15.45 1.67 23,019.83 12,273.97 3.818.88 967.37 557.37 334.77 133.41 29.00 0.0 0.50 0.0 0.0
il5
57.595.36
5,248.47 23,037.03 15.63 1.22 5,569.98 1,598.71 872.38 483.01 203.52 48.69 3.00 2.00 0.0
52.709.5 I 50.5 18.64
0.0 0.0 14.49 5.205.3 1 19,676.28 14,699.71 6,066. I 1 2,714.37 1,396.91 528.82 188.06 28.58 0.0
0.0 0.0
25-29
37.165.80
0.0 16.50 3,817.19 14,216.83 10,673.76 4,672.91 2,226.99 1.054.90 357.80 111.31 17.61
0.0 0.0
0.0 0.0
30-34
Duration from Onset of Work (yr) 0.0 0.0
20-24
0.0 14.00 6,095.41 24,018.28 16.567.21 6,417.74 2,363.77 1.327.29 580.97 220.51 46.89 3.00 0.29
11.50
0.0 0.0
15-19
20.339.96
0.0 0.0 9.49 2,169.89 8.004.39 5,501.76 2,598.82 1,250.81 572.31 164.76 67.73
0.0
0.0 0.0 0.0
35-39
10.200.48
0.0 0.0 0.0 6.00 1.259.26 4.273.70 2.643.23 1,157.89 544.25 220.90 95.25
0.0 0.0
0.0 0.0
40-44
5.256.48
0.0 0.0 0.0 5.50 761.24 2.503.58 1,281.85 425.52 184.59 94.20
0.0 0.0 0.0 0.0 0.0
45-49
of Asbestos Insulation Workers in the United States and Canada, 1967-1986: Person-Years of Observation and Age Distribution in 5-Year Periods from Onset of Asbestos Work
TABLE 1. Observation
6,150.96
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.49 482.73 1,903.03 1,711.99 1,079.00 970.72
0.0
50+
6
ANNALS NEW YORK ACADEMY OF SCIENCES
mesothelioma, it has been our practice not to accept the death certificate or clinical record category for the neoplasm unless the histopathological material is seen by our pathologist and its nature verified, generally with the use of special immunocytochemical and histochemical stains.46
Comparison of Observed and Expected Deaths Expected deaths have been calculated from age- and year-specific rates for U.S. white males as given by the U.S. National Center for Health Statistics (NCHS), 1967-1986. The statistical methods used have been reported else-
here.^^.^^ Observed deaths are reported in two ways: as categorized on the death certificate (DC) and as ascertained after review of all available material, “best evidence” (BE).42Very often, the two are identical (DC = BE), which speaks well for the diagnostic acumen of U.S. and Canadian physicians and the skills of pathologists in these countries, although, as in all series, some death certificate diagnoses may be faulty. (Comparisons between DC and BE diagnoses will be reported in detail later for various categories of causes of death, together with the quality of ascertainment.)
Results Tables 2 and 3 compare observed and expected deaths by cause. Four thousand nine hundred fifty-one men died during the 20-year period; 3,453.5 had been expected to die, had their experience been the same as that of all U.S. white males. The major causes of excess deaths from cancer remained lung cancer, pleural and peritoneal mesothelioma, and gastrointestinal cancer. Asbestosis also continued as a major cause of death (TABLE2). In addition, cancer of a number of other sites increased in incidence, including cancer of the oropharynx and buccal cavity, larynx, kidney, pancreas, and gallbladder and bile ducts (TABLE3).
Cancer Not Increased in Incidence It is always difficult to obtain enough data to warrant an opinion concerning the absence of increased risk of disease. However, the present study seems sufficiently extensive to warrant at least a tentative conclusion that, under these circumstances, at this time, and in this group, there was no increased incidence of cancer of the urinary bladder, prostate, testes, primary cancer of the liver (hepatoma), primary neoplasms of the brain, and leukemia and lymphoma (TABLE3). Findings with regard to cancer of the brain, liver, and pancreas are of particular interest, and point to the importance of considering both death certificate and best-evidence categorization. 1. According to death certificates, there were 40 deaths attributable to neoplasms of the brain (29 of which were malignant); 26.35 and 22.55 were expected, respectively, according to data of the NCHS. Ordinarily, the fact that the NCHS accepts death certificate diagnoses, without verification by clinical or histopathological review, would not be of great moment, since it could be assumed that both the study group and the general
SELIKOFF & SEIDMAN: DEATHS IN ASBESTOS INSULATION WORKERS
7
(NCHS) population had the same or similar rates of misdiagnosis. But in our investigation, the potential for misdiagnosis was significantly increased since the study group had a markedly increased risk of lung cancer, with the possibility of brain metastases mimicking primary tumors of the brain. In the event, this turned out to be the case. According to best evidence, only 33 brain tumors occurred, with 27 deaths due to malignant brain tumors: there was thus no statistically significant increased incidence of brain neoplasms among these asbestos-exposed 3). To have concluded to the contrary, on the bases of a compariworkers (TABLE son of the numbers recorded on death certificates and expected deaths as determined by NCHS data, would have been misleading.
17,800 Asbestos Insulation Workers in the United States and Canada, January 1. 1967-December 31, 1986
TABLE 2. Deaths among
Underlying Cause of Death
Expected Deathsu
Observed DCb BE'
Total deaths. all causes Total cancer, all sites Lung cancer Pleural mesotheliomaf Peritoneal mesotheliomaf Gastrointestinal cancer# Gastrointestinal cancer, extendedh Noninfectious pulmonary diseases, total Asbestosis' All other causes
3,453.50 761.41 268.66 135.69 191.66 144.82 2,547.27
4,951 2,127 1,008 89 92 188 324 465 201 2,359
4,951 2,295 1,168 173 285 189 269 507 427 2,149
SMR Valuesd DC BE' 143*** 279*** 375*** 139*** 169*** 321*** 93***
143*** 301*** 435*** 139*** 140*** 350*** 84***
a Expected deaths are based upon white male, age-specific death rates of the U.S. National Center for Health Statistics, 1967-1986. DC: Number of deaths as recorded from death certificate information only. BE: Best evidence. Number of deaths categorized after review of best available information (autopsy, surgical. clinical). Where no such data were available, the death certificate diagnosis was used. SMR: Standardized mortality ratio. Observed deathslexpected deaths x 100. Calculated for information only, since it utilized "best evidence" vs. "death certificate" diagnoses, which are not strictly comparable because of different ascertainment and verification. f Rates are not available since these have been rare causes of death in the general population. R Includes cancer of stomach, esophagus, and colon/rectum. Includes cancer of stomach, esophagus, colon/rectum, liver, gallbladder, and bile ducts. LEVELS:* p < 0.05; ** p < 0.01; *** p < 0.001. PROBABILITY
2 . The same mistake was avoided for "cancer of the liver." The NCHS data predicted 1 1.06 deaths, but 31 such were recorded on death certificates. Was there thus an increased incidence of liver cancer among asbestos insulation workers? No. After review, only 12 were ascertained to be due to primary liver cancer. Again, the "excess" was due to misdiagnosis, primarily the result of metastases to the liver from cancer at primary sites known to be increased among asbestos insulation workers (lung, gastrointestinal, pancreas). 3. The situation with regard to cancer of the pancreas was in the same direction but quantitatively different. In 1976, there seemed to be an increased incidence of pancreatic cancer (expected = 17.5; 49 were recorded on the death
8
ANNALS NEW YORK ACADEMY OF SCIENCES
certificate). On the basis of death certificates only, one could have concluded that there was a statistically significant increase. But after review, only 23 could be so categorized on best evidence, an increase that was not sufficiently robust to warrant this c o n c l ~ s i o n It . ~ was ~ considered that additional data were needed, particularly after ascertainment by best evidence. These data are now at hand (TABLE3). A total of 39.52 deaths by pancreatic cancer would be expected on the basis of NCHS statistics; however, 54 deaths were actually categorized as such on best evidence. This is a statistically significant increase, albeit not as great as indicated by death certificate categorization. TABLE 3. Less Common Malignant Neoplasms: Deaths among 17,800 Asbestos
Insulation Workers in the United States and Canada, January I , 1967-December 31. 1986 Site of Cancer Causing Death Increased incidence at these sites: Larynx Oropharynx Kidney Pancreas Esophagus Stomach Colon/Rectum Gall bladderlbile ducts No increased incidence at these sites: Urinary bladder Prostate Liver Brain tumors (all) Cancer of brain Leukemia Lymphoma
Observed
Ratio o/e
Expected Deaths“
DCb
BE‘
DC
BE”
10.57 22.02 18.87 39.52 17.80 29.36 88.49 5.37
17 38 32 92 29 34 125 13
I8 48 37 54 30 38 121 14
I .6l 1.73** I .70** 2.33*** 1.63* 1.16 1.41*** 2.42**
1.70* 2.18*** I .96*** I .37* I .68* 1.29 1.37** 2.61**
20.77 52.56
17 59
22 61 12 33 27 33 39
0.82 1.12 2.80* * * 1.52* I .29 1.11 0.76
1.06 1.16 1.08 1.25 1.20
11.06
31
26.35 22.55 28.74 43.24
40 29 32 33
1.15
0.90
Expected deaths are based upon white male, age-specific death rates of the U.S. National Center for Health Statistics. 1967- 1986. * DC: Number of deaths as recorded from death certificate information only. BE: Best evidence. Number of deaths categorized after review of best available information (autopsy, surgical, clinical). Where no such data were available, the death certificate diagnosis was used. Calculated for information only, since it utilized “best evidence” vs. “death certificate” diagnoses, which are not strictly comparable because of different ascertainment and verification. PROBABILITY RANGE:* p < 0.05; ** p < 0.01; *** p < 0.001.
Latency Very similar findings for latency were obtained in 1967-1976 and 1977-1986. TABLES4 , 5 , 6 , and 7 and FIGURES I , 2 and 3 demonstrate that the major increases for all cancer, lung cancer, mesothelioma, and asbestosis occurred later than 20 years from onset of work exposure. Comparatively few excess deaths were observed in fewer than 25 or more years from onset of exposure, and one might be apprehensive about being able to evaluate results of studies with little experience 25 or more years from onset or
SELIKOFF & SEIDMAN: DEATHS IN ASBESTOS INSULATION WORKERS
9
Deaths from Lung Cancer among 17,800 Asbestos Insulation Workers in the United States and Canada (1967-1986): Duration from Onset of Employment
TABLE 4.
Observed Deaths Years from Onset
< I5 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50+
Total
PersonYears
Expected Deaths"
DC" No.
BEh Ratio
61,655.4 52,709.5 57,595.4 50.5 18.6 37,165.8 20,340.0 I 0,200.5 5,256.5 6,151.0
3.87 I 1.62 27.47 46.62 57.36 46.75 30.79 18.81 25.38
7 34 85 172 252 193 129 66 71
1.81 2.93*** 3.09*** 3.69*** 4.38*** 4.13*** 4.18*** 3.51*** 2.80***
301,592.6
268.68
1008
3.75***
No.
Ratio' 2.32* 3.18*** 3.46*** 3.93*** 4.90***
9
37 95 183 281 239
5.11***
75 94
5.03*** 3.99*** 3.70***
1,168
4.35***
155
Expected deaths are based upon age- and year-specific death rates, 1967-1986. of the U.S. National Center for Health Statistics for white males ("DC"). Best evidence ("BE"); ascertained after review of all available autopsy, surgical, and clinical material. Where no such data were available, death certificate diagnosis was utilized. Calculated for information only since observed deaths are based on best evidence, whereas expected deaths are those calculated from death certificate rates of the U.S. National Center for Health Statistics, 1967-1986, for white males. The two are not strictly comparable since they reflect different quality and precision of ascertainment (death-certificate diagnoses are not generally subjected to investigation and verification). PROBABILITY RANGE: * p < .05; ** p < . O l ; *** p < ,001. i
Deaths from Pleural Mesothelioma among 17,800 Asbestos Insulation Workers in the United States and Canada (1967-1986): Duration from Onset of Employment
TABLE 5.
Years from Onset
PART I .
THE SPECTRUM OF ASBESTOS-RELATED DISEASE
Asbest0s-Associated Deaths among Insulation Workers in the United States and Canada, l967-1987 IRVING J. SELIKOFF AND HERBERT SEIDMAN Mount Sinai School of Medicine of the City University of New York New York, New York 10029-6574 The first information in the scientific literature concerning hazards associated with exposure to asbestos appeared as descriptions of disease in individual patients. This was logical: it would hardly be expected that populations of exposed workers would be studied in the absence of evidence that disease was occurring. It also emphasizes the value of individual case reports to point to potential risks, so that further investigations can be mounted to estimate problems in quantitative terms, as a guide to control.
DISEASE ASSOCIATED WITH THE MANUFACTURE OF ASBESTOS PRODUCTS In 1924, Cooke reported the death from pulmonary fibrosis of a young woman employed in a British asbestos factory,' a case which, later described in greater detail, gave the disease its name, "pulmonary asbestosis."2 Additional such instances) led to a survey of the manufacturing branch of the industry and, in 1931, to regulations for exposure controL4 A similar sequence of events led to the identification of lung cancer as a hazard in asbestos production: single cases starting in 19355-9were followed by examination of a collected series in 1947.1° This process was associated with inherent constraints, however. Lung cancer could be identified, but not necessarily other neoplasms, let alone the full spectrum of this family of diseases.
ASBESTOS DISEASE AMONG USERS OF ASBESTOS PRODUCTS The same general pattern occurred with the use of asbestos materials. Starting in 1918, asbestosis was found in individual patients with pulmonary problems; in that year, Pancoast, Miller, and Landis reported X-ray abnormalities in a marine fireman." In 1930, Albert E. Russell, Chief Surgeon of the U.S. Bureau of Mines, reported a case of asbestosis in a man who had been exposed to asbestos while doing maintenance work in a government hospital, and who received compensation for it.IZ In 1934, Ellman reported asbestosis in an insulation worker') and eight years later, Holleb and Angrist added lung cancer to the list of conditions seen with such use of asbestos.14 These findings were supplemented in 1951 by the work of Stoll, Bass and Angrist, who reported a case of lung cancer and asbestosis and emphasized "the hazards of industrial exposure . . . and the need for preventive measures."" 1
2
ANNALS NEW YORK ACADEMY OF SCIENCES
Alerted by the finding of asbestos-associated disease in construction workers, Breslow and coworkers (1954) prepared a special code for such employees in their analysis of lung cancer in California. This allowed asbestos exposure to be sought among plumbers, gas fitters and steamfitters. “These occupations should now be intensely studied,” they advised.I6 The Chief Inspector of Factories in Great Britain published equally pertinent warnings in his Annual Report for the year 1949 concerning asbestos hazards in ships or in buildings” and again in his Annual Report for 1956, in which he called attention to problems with asbestos cement work, with removing insulation, or with breaking of sacks containing asbestos.18 Asbestos exposure in shipyards was of concern in these years. In 1943 the U.S. Navy required airline respirators or dust respirators for workers in asbestos jobs.19 This concern was later found to have been justified, when McCaughey, Wade, and Elmes reported a number of pleural mesotheliomas in workers in Belfast shipyards.20 Similarly, after the first case of asbestosis was observed in Sweden in 1953,21a survey of 60 more workers was undertaken, including seven in insulation and two who had sprayed asbestos; the latter were found to have advanced asbestosis.22
ASBESTOS DISEASE IN INSULATION WORKERS Development of information concerning hazards with the use of asbestos in insulation work is an example of how such data accumulate and helps to spur efforts for avoidance of risks.
Industrial History The early descriptions of the use of asbestos vary somewhat, although, overall, R. H. Jones’ brilliant monograph is perhaps the best source material for the history of asbestos utilization and d e v e l ~ p m e n t including ,~~ the earliest modern use of Italian asbestos and, soon afterwards, chrysotile (originally dubbed “asbestic”). The first Italian mine was opened in Lombardy in 1866 and the first Canadian mine about 1877, although asbestos had been exhibited as a mineralogical curiosity as early as 1862.24Writing in 1897, Jones reported that in New York, there were “. . . hundreds of buildings plastered with a ~ b e s t i c . ” ~ ~ Berger has written that asbestos was first used for heat insulation in 1866.25 While the exact year may be in dispute, there is no doubt that it was utilized in insulation materials before the turn of the c e n t ~ r y . Bettes ~ ~ . ~ has ~ provided an interesting historical account: Henry G. Keasbey and Richard C. Mattison, upon graduation from the Philadelphia College of Pharmacy in 1873, began the manufacture of pharmaceutical preparations in Philadelphia. Among their products was carbonate of magnesia, and they discovered that dolomite in Ambler, Pennsylvania provided a very good basic product. At about the same time steam power was developing rapidly, which required efficient insulation. In 1882, Hiram Hanmore, an insulation contractor, was impressed by the extremely light weight of magnesium carbonate and applied it like plaster to a steam boiler. Dr. Mattison, curious to know what was being done with the relatively large amount being purchased by Hanmore, contacted him and entered into an arrangement to sell insulating materials, manufacture molded pipe covering and block insulation and magnesium cement. Hanmore had used shredded hemp which deteriorated rapidly and Dr. Mattison conceived the
SELIKOFF & SEIDMAN: DEATHS IN ASBESTOS INSULATION WORKERS
3
idea of using heat-resisting asbestos fibers as the reinforcement and thus was born “85% magnesia” insulation, destined to become the standard high-temperature thermal insulation for many years. These events subsequently led to K&M’s becoming a leading manufacturer of asbestos-based products including asbestos textiles . Z R
Correlating well with this was the history of the insulation workers’ union in the United States and Canada. Formed in New York City in 1884 under a charter issued by the Knights of Labor (predecessor of the American Federation of Labor), the union was chartered by the A.F. of L. in 1910 as the International Association of Heat and Frost Insulators and Asbestos Workers; the title is still used by this union group.29
Early Observations Ellman’s report of asbestosis in an insulation worker in 193413began the recapitulation of what had been seen with the manufacture of asbestos products. Collected series contained additional cases. John Gilson in his Wyers Memorial Lecture30 noted that of the 100 cases of asbestosis recorded by four National Insurance Panels in Great Britain before 1933, 59 occurred in insulation workers and only 18 in textile workers; of Newhouse’s 31 patients with mesothelioma at the London Hospital who had a history of asbestos exposure, eight had suffered this in insulation work.31Similarly, in the review of lung cancer in workers with asbestosis undertaken by the Chief Inspector of Factories in 1946,’Oeight were in insulator^.^^ At about this time (1944), a warning about asbestos risk had been published in an industry journal in the United States by F. W. H u t ~ h i n s o n . ~ ~ Awareness of asbestos disease risks among insulators led to a survey of members of the Insulation Workers Union in Copenhagen in 1956.34Frost, Georg, and Moller found 22 of 31 workers examined to have abnormal X-rays, of which 19 showed pleural changes. Pendergrass, too, emphasized radiological changes in insulation work.35 Lung cancer in an insulation worker had been reported in 194214and again in 19S1.I5 This was followed by pleural mesothelioma in 194736 and later37, and peritoneal mesothelioma in 1961.38
Dimensions of the Problem Scientific observations established hazard associated with exposure to asbestos in the manufacture and use of asbestos products, including insulation work. It remained for appropriate epidemiological studies to provide quantitative measures of the mortality risk. This was accomplished for factory workers by Doll in 195539and for insulation workers by Selikoff, Churg, and Hammond in 1964.40 Nevertheless, these initial investigations were limited. Doll’s data reflected observation of I13 men between 1935 and 1953, with only 39 deaths. In the insulation worker study, there were 2.55 deaths between 1943 and 1962 in a cohort of 625 men who had begun work 20 or more years before. Because of the limited experiences reviewed, neither the factory nor the insulation worker investigation had the power to allow for adequate analysis of the full spectrum of cancer risk, especially since experience with adequate latency (person-years of observation 25, 30, 35, 40 or more years from onset of asbestos work)4twas fragmentary or unavailable.
4
ANNALS NEW YORK ACADEMY OF SCIENCES
To some extent, this situation was remedied by 1979. In that year, the mortality experience of 17,800 insulators in the United States and Canada was reported.42These had been observed prospectively from January 1, 1967 to December 31, 1976, with 166,853 person-years of observation and 2,271 deaths. The data obtained confirmed the increased incidence of the major categories of asbestosassociated neoplasms (lung cancer, pleural and peritoneal mesothelioma, gastrointestinal cancer) and of asbestosis, and provided limited experience concerning the increased incidence of several other neoplasms. The data also yielded important additional information regarding the association between asbestos exposure and cigarette smoking,43which had been first reported in 1968,44and shed light upon the equally important influence of latency in evaluating mortality risks of asbestos exposure.41Still, even this extensive series of observations was inadequate to permit unequivocal judgment as to increased risk of cancer at several other sites, such as the pancreas.45
PRESENT STUDY We have continued our observation of the survivors of the 1967 cohort, from January 1, 1977 to December 31, 1986. The total 20-year experience, 1967-1986, now covers 301,592.6 person-years of observation. TABLE1 provides data concerning person-years of observation relative to age distribution and years from onset of employment.
Ascertainment of Cause of Death As of January 1, 1967, 17,800 men were enrolled as members of the insulators’ union in the United States and Canada (The International Association of Heat and Frost Insulators and Asbestos Workers, AFL-CIO, CLC). Much information was available for each from union records, including date of birth, date of onset of insulation work, and employment history. Data concerning smoking, medical symptoms, and use of respirators were obtained from the men by mail questionnaire. Observation of the entire cohort has been maintained since 1967, with the valuable assistance of the international union offices and union officials in each of the approximately 120 local unions in the different states and provinces. Whenever a man dies, we are notified and a death certificate is forwarded to us. If it is not, we obtain it from appropriate official agencies. The cause of death as listed on the death certificate is categorized by an experienced nosologist (“death certificate” diagnosis [DC]). Early notification facilitates investigation of the circumstances of the fatal illness. For each death, whatever the death certificate category, information is sought: clinical data from treating physicians and hospitals as well as histopathological material from pathology facilities. X-rays are obtained and reviewed, and histological material is studied by our Pathology Unit headed by Prof. Yasunosuke Suzuki. Cause of death ascertained after review of all available material is recorded as “best evidence” (BE). Where no clinical or histopathological material is made available, which occurs in about 10% of the cases, the “best evidence” is the death certificate; such is frequently the case for suicides, plane crashes, or sudden cardiovascular deaths, for example. On the other hand, for
Total 182.50 4.886.14 15.463.17 28,282.30 41,420.90 48.690.19 46,547.52 39,666.25 29,579.94 19,871. I8 12,665.75 7,446.50 3,850.32 1.794. I4 1,245.80
301.592.60
Age 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85 +
Total
61.655.41
182.50 4.886.14 15.45 1.67 23,019.83 12,273.97 3.818.88 967.37 557.37 334.77 133.41 29.00 0.0 0.50 0.0 0.0
il5
57.595.36
5,248.47 23,037.03 15.63 1.22 5,569.98 1,598.71 872.38 483.01 203.52 48.69 3.00 2.00 0.0
52.709.5 I 50.5 18.64
0.0 0.0 14.49 5.205.3 1 19,676.28 14,699.71 6,066. I 1 2,714.37 1,396.91 528.82 188.06 28.58 0.0
0.0 0.0
25-29
37.165.80
0.0 16.50 3,817.19 14,216.83 10,673.76 4,672.91 2,226.99 1.054.90 357.80 111.31 17.61
0.0 0.0
0.0 0.0
30-34
Duration from Onset of Work (yr) 0.0 0.0
20-24
0.0 14.00 6,095.41 24,018.28 16.567.21 6,417.74 2,363.77 1.327.29 580.97 220.51 46.89 3.00 0.29
11.50
0.0 0.0
15-19
20.339.96
0.0 0.0 9.49 2,169.89 8.004.39 5,501.76 2,598.82 1,250.81 572.31 164.76 67.73
0.0
0.0 0.0 0.0
35-39
10.200.48
0.0 0.0 0.0 6.00 1.259.26 4.273.70 2.643.23 1,157.89 544.25 220.90 95.25
0.0 0.0
0.0 0.0
40-44
5.256.48
0.0 0.0 0.0 5.50 761.24 2.503.58 1,281.85 425.52 184.59 94.20
0.0 0.0 0.0 0.0 0.0
45-49
of Asbestos Insulation Workers in the United States and Canada, 1967-1986: Person-Years of Observation and Age Distribution in 5-Year Periods from Onset of Asbestos Work
TABLE 1. Observation
6,150.96
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.49 482.73 1,903.03 1,711.99 1,079.00 970.72
0.0
50+
6
ANNALS NEW YORK ACADEMY OF SCIENCES
mesothelioma, it has been our practice not to accept the death certificate or clinical record category for the neoplasm unless the histopathological material is seen by our pathologist and its nature verified, generally with the use of special immunocytochemical and histochemical stains.46
Comparison of Observed and Expected Deaths Expected deaths have been calculated from age- and year-specific rates for U.S. white males as given by the U.S. National Center for Health Statistics (NCHS), 1967-1986. The statistical methods used have been reported else-
here.^^.^^ Observed deaths are reported in two ways: as categorized on the death certificate (DC) and as ascertained after review of all available material, “best evidence” (BE).42Very often, the two are identical (DC = BE), which speaks well for the diagnostic acumen of U.S. and Canadian physicians and the skills of pathologists in these countries, although, as in all series, some death certificate diagnoses may be faulty. (Comparisons between DC and BE diagnoses will be reported in detail later for various categories of causes of death, together with the quality of ascertainment.)
Results Tables 2 and 3 compare observed and expected deaths by cause. Four thousand nine hundred fifty-one men died during the 20-year period; 3,453.5 had been expected to die, had their experience been the same as that of all U.S. white males. The major causes of excess deaths from cancer remained lung cancer, pleural and peritoneal mesothelioma, and gastrointestinal cancer. Asbestosis also continued as a major cause of death (TABLE2). In addition, cancer of a number of other sites increased in incidence, including cancer of the oropharynx and buccal cavity, larynx, kidney, pancreas, and gallbladder and bile ducts (TABLE3).
Cancer Not Increased in Incidence It is always difficult to obtain enough data to warrant an opinion concerning the absence of increased risk of disease. However, the present study seems sufficiently extensive to warrant at least a tentative conclusion that, under these circumstances, at this time, and in this group, there was no increased incidence of cancer of the urinary bladder, prostate, testes, primary cancer of the liver (hepatoma), primary neoplasms of the brain, and leukemia and lymphoma (TABLE3). Findings with regard to cancer of the brain, liver, and pancreas are of particular interest, and point to the importance of considering both death certificate and best-evidence categorization. 1. According to death certificates, there were 40 deaths attributable to neoplasms of the brain (29 of which were malignant); 26.35 and 22.55 were expected, respectively, according to data of the NCHS. Ordinarily, the fact that the NCHS accepts death certificate diagnoses, without verification by clinical or histopathological review, would not be of great moment, since it could be assumed that both the study group and the general
SELIKOFF & SEIDMAN: DEATHS IN ASBESTOS INSULATION WORKERS
7
(NCHS) population had the same or similar rates of misdiagnosis. But in our investigation, the potential for misdiagnosis was significantly increased since the study group had a markedly increased risk of lung cancer, with the possibility of brain metastases mimicking primary tumors of the brain. In the event, this turned out to be the case. According to best evidence, only 33 brain tumors occurred, with 27 deaths due to malignant brain tumors: there was thus no statistically significant increased incidence of brain neoplasms among these asbestos-exposed 3). To have concluded to the contrary, on the bases of a compariworkers (TABLE son of the numbers recorded on death certificates and expected deaths as determined by NCHS data, would have been misleading.
17,800 Asbestos Insulation Workers in the United States and Canada, January 1. 1967-December 31, 1986
TABLE 2. Deaths among
Underlying Cause of Death
Expected Deathsu
Observed DCb BE'
Total deaths. all causes Total cancer, all sites Lung cancer Pleural mesotheliomaf Peritoneal mesotheliomaf Gastrointestinal cancer# Gastrointestinal cancer, extendedh Noninfectious pulmonary diseases, total Asbestosis' All other causes
3,453.50 761.41 268.66 135.69 191.66 144.82 2,547.27
4,951 2,127 1,008 89 92 188 324 465 201 2,359
4,951 2,295 1,168 173 285 189 269 507 427 2,149
SMR Valuesd DC BE' 143*** 279*** 375*** 139*** 169*** 321*** 93***
143*** 301*** 435*** 139*** 140*** 350*** 84***
a Expected deaths are based upon white male, age-specific death rates of the U.S. National Center for Health Statistics, 1967-1986. DC: Number of deaths as recorded from death certificate information only. BE: Best evidence. Number of deaths categorized after review of best available information (autopsy, surgical. clinical). Where no such data were available, the death certificate diagnosis was used. SMR: Standardized mortality ratio. Observed deathslexpected deaths x 100. Calculated for information only, since it utilized "best evidence" vs. "death certificate" diagnoses, which are not strictly comparable because of different ascertainment and verification. f Rates are not available since these have been rare causes of death in the general population. R Includes cancer of stomach, esophagus, and colon/rectum. Includes cancer of stomach, esophagus, colon/rectum, liver, gallbladder, and bile ducts. LEVELS:* p < 0.05; ** p < 0.01; *** p < 0.001. PROBABILITY
2 . The same mistake was avoided for "cancer of the liver." The NCHS data predicted 1 1.06 deaths, but 31 such were recorded on death certificates. Was there thus an increased incidence of liver cancer among asbestos insulation workers? No. After review, only 12 were ascertained to be due to primary liver cancer. Again, the "excess" was due to misdiagnosis, primarily the result of metastases to the liver from cancer at primary sites known to be increased among asbestos insulation workers (lung, gastrointestinal, pancreas). 3. The situation with regard to cancer of the pancreas was in the same direction but quantitatively different. In 1976, there seemed to be an increased incidence of pancreatic cancer (expected = 17.5; 49 were recorded on the death
8
ANNALS NEW YORK ACADEMY OF SCIENCES
certificate). On the basis of death certificates only, one could have concluded that there was a statistically significant increase. But after review, only 23 could be so categorized on best evidence, an increase that was not sufficiently robust to warrant this c o n c l ~ s i o n It . ~ was ~ considered that additional data were needed, particularly after ascertainment by best evidence. These data are now at hand (TABLE3). A total of 39.52 deaths by pancreatic cancer would be expected on the basis of NCHS statistics; however, 54 deaths were actually categorized as such on best evidence. This is a statistically significant increase, albeit not as great as indicated by death certificate categorization. TABLE 3. Less Common Malignant Neoplasms: Deaths among 17,800 Asbestos
Insulation Workers in the United States and Canada, January I , 1967-December 31. 1986 Site of Cancer Causing Death Increased incidence at these sites: Larynx Oropharynx Kidney Pancreas Esophagus Stomach Colon/Rectum Gall bladderlbile ducts No increased incidence at these sites: Urinary bladder Prostate Liver Brain tumors (all) Cancer of brain Leukemia Lymphoma
Observed
Ratio o/e
Expected Deaths“
DCb
BE‘
DC
BE”
10.57 22.02 18.87 39.52 17.80 29.36 88.49 5.37
17 38 32 92 29 34 125 13
I8 48 37 54 30 38 121 14
I .6l 1.73** I .70** 2.33*** 1.63* 1.16 1.41*** 2.42**
1.70* 2.18*** I .96*** I .37* I .68* 1.29 1.37** 2.61**
20.77 52.56
17 59
22 61 12 33 27 33 39
0.82 1.12 2.80* * * 1.52* I .29 1.11 0.76
1.06 1.16 1.08 1.25 1.20
11.06
31
26.35 22.55 28.74 43.24
40 29 32 33
1.15
0.90
Expected deaths are based upon white male, age-specific death rates of the U.S. National Center for Health Statistics. 1967- 1986. * DC: Number of deaths as recorded from death certificate information only. BE: Best evidence. Number of deaths categorized after review of best available information (autopsy, surgical, clinical). Where no such data were available, the death certificate diagnosis was used. Calculated for information only, since it utilized “best evidence” vs. “death certificate” diagnoses, which are not strictly comparable because of different ascertainment and verification. PROBABILITY RANGE:* p < 0.05; ** p < 0.01; *** p < 0.001.
Latency Very similar findings for latency were obtained in 1967-1976 and 1977-1986. TABLES4 , 5 , 6 , and 7 and FIGURES I , 2 and 3 demonstrate that the major increases for all cancer, lung cancer, mesothelioma, and asbestosis occurred later than 20 years from onset of work exposure. Comparatively few excess deaths were observed in fewer than 25 or more years from onset of exposure, and one might be apprehensive about being able to evaluate results of studies with little experience 25 or more years from onset or
SELIKOFF & SEIDMAN: DEATHS IN ASBESTOS INSULATION WORKERS
9
Deaths from Lung Cancer among 17,800 Asbestos Insulation Workers in the United States and Canada (1967-1986): Duration from Onset of Employment
TABLE 4.
Observed Deaths Years from Onset
< I5 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50+
Total
PersonYears
Expected Deaths"
DC" No.
BEh Ratio
61,655.4 52,709.5 57,595.4 50.5 18.6 37,165.8 20,340.0 I 0,200.5 5,256.5 6,151.0
3.87 I 1.62 27.47 46.62 57.36 46.75 30.79 18.81 25.38
7 34 85 172 252 193 129 66 71
1.81 2.93*** 3.09*** 3.69*** 4.38*** 4.13*** 4.18*** 3.51*** 2.80***
301,592.6
268.68
1008
3.75***
No.
Ratio' 2.32* 3.18*** 3.46*** 3.93*** 4.90***
9
37 95 183 281 239
5.11***
75 94
5.03*** 3.99*** 3.70***
1,168
4.35***
155
Expected deaths are based upon age- and year-specific death rates, 1967-1986. of the U.S. National Center for Health Statistics for white males ("DC"). Best evidence ("BE"); ascertained after review of all available autopsy, surgical, and clinical material. Where no such data were available, death certificate diagnosis was utilized. Calculated for information only since observed deaths are based on best evidence, whereas expected deaths are those calculated from death certificate rates of the U.S. National Center for Health Statistics, 1967-1986, for white males. The two are not strictly comparable since they reflect different quality and precision of ascertainment (death-certificate diagnoses are not generally subjected to investigation and verification). PROBABILITY RANGE: * p < .05; ** p < . O l ; *** p < ,001. i
Deaths from Pleural Mesothelioma among 17,800 Asbestos Insulation Workers in the United States and Canada (1967-1986): Duration from Onset of Employment
TABLE 5.
Years from Onset
