C mately 3% of cancer in the United States. This

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1 Cancer of the Pancreas among Asbestos Insulation Workers IRVING J. SELIKOFF, MD, AND HERBERT SEIDMAN, MBA ANCER OF THE PANCREAS accounts for approxi C mately 3% of cancer in the United States. This incidence is aggravated by high lethality: Only 2% survive five years after diagnosis. Cancer of the pancreas accounts for 5.2% of all cancer deaths, exceeded only by lung, colonrectum, breast and prostate. With this unhappy experience, considerable thought has been given to identification of possible causes. Search has been spurred by reports of experimental production of pancreatic cancer by specific chemical carcinogens and by the epidemiologic observation that at least one exogenous agentcigarette smokingcan increase the risk of pancreas cancers in humans.2 Among the factors that have been investigated have been occupation, diabetes, alcoholism, diet, radiation, racial and ethnic differences, as well as geographic variations. None has been demonstrated to exert an important, unqualified influence with statistical certainty. Hampered by the absence of appropriate smoking data in most cases and comparable populations, the numerous studies that have examined these various aspects have not allowed firm conclusions.' Asbestos has been found to be associated with increased cancer risk at a number of sites (lung cancer, pleural mesothelioma, peritoneal mesothelioma, cancer of the esophagus, stomach, colonrectum, pharynx and buccal cavity, larynx, and kidneyr). It has been of interest, therefore, to study the possibility that cancer of the pancreas might also be so associated. The knowl Presented at the International Meeting on Pancreatic Cancer, Louisiana State University School of Medicine, New Orleans, Louisiana, March 0, 980. From the Envirorimental Sciences Laboratory, Department of Community Medicine, Mount Sinai School of Medicine of the City University of New York, and the Department of Epidemiological Research and Statistics of the American Cancer Society, New York, New York. Supported by Center Grant ES00928 of the National Institute of Environmental Health Sciences and Research Grant R38 of the American Cancer Society. Address for reprints: Irving J. Selikoff, MD, Environmental Sciences Laboratory, Mount Sinai School of Medicine of the City University of New York, New York, NY. The authors thank Dr. Yasunosuke Suzuki and Dr. Jacob Churg for reviewing the histologic material and Janet S. Kaffenburgh, Frances Perez, Julia Roberts, Judy Marmor, Selma Annenberg, and Richard Ashley for helping conduct the research. Accepted for publication August 20, 980. edge that hematogenous dissemination of the fine fibers can occur after either their inhalation or ingestion and the observation that renal cancer was increased in incidence among exposed workers made such investigation of increased interest. Materials and Methods There were 7,800 men on the rolls of the asbestos workers union in the United States and Canada on January, 967.* A good deal of information concerning these men was available, including date of birth, date of first insulation work, employment status, and, for a majority of the men, history of smoking habits. We have maintained observation of this cohort since 967, with the assistance of the local and international officers of the union. The men are registered in approximately 20 local unions in the various parts of the United States and Canada. Whenever an insulation worker associated with the union dies, we are notified. Information is then sought concerning the details of the circumstances of death, including clinical data, roentgenograms, histologic material obtained at surgery or at autopsy. The underlying cause of death is ascertained according to the best evidence available (BE); the underlying cause of death assigned on the basis of death certificate only (DC) is also recorded. At the outset of the study, the majority of the men were below the age of 0 (0,0 of the 7,800) and the majority had yet to achieve 20 years from first exposure (2,683) (Table I). From January, 967 to December 3, 976, the cohort changed its age and duration from onset distribution with the passage of time. Many of the men who were in the less than 20 years from onset group achieved 20+ years from onset during the period of observation. Altogether, 2,683 men, with 89,62 manyears of experience suffered 325 deaths in a period before 20 years. There were 96 deaths among 2,05 men who had achieved 20+ years from onset, with 77,39 manyears of observation. The average age during observation was 36.3 for the shorter group and 53.8 years for those with longer duration from onset (Table 2). * International Association of Heat and Frost Insulators and Asbestos Workers, AFLCIO, CLC X/8/035/69 $ American Cancer Society 69

2 ~~ ~~~ ~ ~~ ~ ~ ~~ ~ 70 CANCER MurcJi 5 Suppleriient 98 VOJ. 7 TABLE. Membership of Asbestos Insulation Workers' Union.* January I. 967, Classified by Age and Years from First Exposure to Asbestos Dust No. of yrs since first exposure to asbestos Age, Total no. of (yrs) members 09 0 I I ,695 2,2 2,762 2,988 2,260, Ill G66 I I L 7 I I TOTAL I7,8OO * Membership in the United States and Canada of the International Association of Heat and Frost lnsulators and.asbestos Workers, AFLCIO, CLC. ~ The deaths have been analyzed during the decade of observation, with particular reference to the 2,05 men 20 or more years from onset, in view of the special risk that increases with the passage of time after onset of asbestos exposure.s.r*9 Expected deaths were computed on the basis of white male agespecific mortality data of the U. S. National Center for Health Statistics, These data were then compared with deaths observed categorized in two ways: according to death certificate (DC) and the number of deaths categorized after review of best available information (BE). Expected and observed deaths of the pancreas have been analyzed by smoking history in 967, utilizing data in the American Cancer Society's prospective cancer prevention study3 to obtain age, year, and smokingspecific death rates, for comparison. Results Table 3 records the mortality experience of the 7,800 asbestos insulation workers, There were 227 deaths although only were expected. Cancer TABLE 2. Observation of 7.800Asbestos Jnsulation Workers in the United States and Canada January, 967 December 3 I. 976 <20 yrs 20+ yrs Total from onset from onset No. of men ,683 2,05 Manyears of observation 66,853 89, Deaths Average age during observation of a number of sites accounted for most of the increase. Although only were anticipated, 995 occurred. There were 86 deaths of cancer of the lung, 63 of pleural mesothelioma. 2 of peritoneal mesothelioma, 99 of gastrointestinal cancer. Review of the death certificate data suggested that there was a significant increase of cancer of the pancreas among these workers. This diagnosis was listed on 9 death certificates, although only 7.5 were expected, based upon the age distribution of the men under observation. Analysis of the deaths indicated. however, that such a conclusion could not be supported by more detailed information. After review of all deaths, it was ascertained that there were only 23 deaths of cancer of the pancreas (22 so categorized on death certificate, and one listed as myocardial infarction). On the other hand, there were 27 instances in which deaths had been listed on death certificates as due to cancer of the pancreas but further study had shown other causes. Cancer of the lung accounted for four deaths, peritoneal mesothelioma for 6, cancer of the colon for two, and disseminated carcinomatosis, primary site not ascertained, for five deaths. The differences between expected and observed deaths according to BE and DC is recorded in Table, which also includes information on other malignant neoplasms less commonly seen among asbestos workers. The diagnostic basis for categorization is outlined in Table 5. Two groups of cases have been analyzedthose listed on death certificate as due to cancer of the pancreas, with this diagnosis supported by the result5 of investigation, and cases noted on death certificate

3 No. 6 PANCREATIC CA AND ASBESTOS. ScilikojJ mid Seidrntrn 7 to be cancer of the pancreas, but where another diagnosis was established following review. An attempt has been made to determine whether they might be substantially different. Tables 6 and 7 indicate that the two groups were fairly comparable with regard to duration from onset of employment and age at death. although those dying of peritoneal mesothelioma tended to be somewhat younger than those with cancer of the pancreas. Association with Cigarette Smoking Even in the absence of cigarette smoking, asbestos increases the risk of lung cancer. This is statistically the case. But from a clinical and public health point of view, the brunt of the asbestoslung cancer burden will be borne, by far. among the smoking asbestos workers.".' Death rates for lung cancer (per 00 thousand manyears, standardized for age) were, in one study, I I.3 for men who neither worked with asbestos nor smoked cigarettes, 58. for men who worked with asbestos but did not smoke for cigarette smokers who hiid not worked with asbestos, and 60.6 for those unfortdnate enough to have had both exposurescigarettes and asbestos.:' Cancer of the esophagus and laryngeal and oropharyngeal cancers occur in excess primarily in asbestos workers who have a history of cigarette smoking: the incidence of colon. rectum, and renal cancers, and peritoneal and pleural mesotheliomas. is increased whether or not the workers have smoked. In view of the reported increase of death of cancer of the pancreas associated with cigarette smoking,' it has been of interest to inquire whether there might be a multiple factor interaction between cigarette smoking and asbestos exposure among insulation workers. Table 8 compares observed and expected deaths of cancer of the pancreas among the 2,05 asbestos insulation workers 20 or more years after onset of work, according to their smoking histories in 967. No significant smokingspecific influence was found:.2 deaths were expected among these workers who had smoked cigarettes based upon smoking specific data in the American Cancer Society study and ten deaths were observed. Discussion It is widely known that causes of death as recorded on death certificates may be in error and that, even when accurate, these may be coded with considerable variation among different agencies, despite the existence of agreed upon international rules and recommendations:' Yet death rates based upon large series of deaths are nevertheless useful and widely utilized. This distinction. however, leads to the understanding that TABLE 3. Deaths among Asbestos Insulation Workers in the United States and Canada January I, 967December 3, 976 Observed Ratio ole Underlying cause EXof death pected* (BE) (DC) (BE) (DC) Total deaths, all causes Total cancer. all sites Cancer of lung Pleural mesothelioma t Peritoneal mesothelioma I2 2 Mesothelioma, n.0.s Cancer of esophagus Cancer of stomach Cancer of colonrectum Cancer of larynx.7 I I Cancer of pharynx, buccal 0. I Cancer of kidney All other cancer Noninfectious pulmonary diseases, total Asbestosis All other causes No. of men = Manyears of observation = 66,853. * Expected deaths are based upon white male agespecific U. S. death rates of the U. S. National Center for Health Statistics Rates are not available, but these have been rare causes of death in the general population. (RE) Rest evidence. Number of deaths categorized after review of best available information (autopsy. surgical, clinical). (DC) Number of deaths as recorded from death certificate information only. TAM f. Deaths of less common malignant neoplasms among Asbestos Insulation Workers in the United States and Canada January, 967December 3, 976 Observed Ratio o/e Underlying cause Ex ~ of death pected" (BE) (DC) (BE) (DC) Total deaths, all causes Cancer. all sites Deaths of less common malignant neoplasms Pancreas Liver. biliary passages Bladder Testes 9. I I Prostate eukemia 3. I I Lymphoma 20. I Skin Brain No. of men = Manyears of observation * Expected deaths are based upon white male agespecific U. S. death rates of the U. S. National Center for Health Statistics, (BE) Best evidence. Number of deaths categorized after review of best available information (autopsy, surgical. clinical). (DC) Number of deaths as recorded from death certificate information only.

4 72 CANCER March 5 Supplement 98 VOl. 7 TABLE 5. Diagnostic Ascertainment of Cancer of the Pancreas Basis for diagnosis ~ ~ ~ ~ Autopsy Surgical Clinical DC + surgical Autopsy specimen data only Total. BE = CA pancreas DC = Not CA pancreas 2. BE = Not CA pancreas DC = CA pancreas 3. BE = CA pancreas DC = CA pancreas I BE = Best evidence. comparisons between observed causes of death and those expected should not be considered in rigid exact terms, especially when comparing the mortality experience of various specific groups. For these there are no perfect controls that take into account varying age distribution, ethnic derivation, smoking habits, economic circumstances, prior personal, social and occupational history, and so on. The matter is further complicated by the fact that deaths in the general population, which provide the basis for comparison death rates, are not verified by investigation or examination of available data concerning the circumstances associated with the deaths. Of course, one may elect to treat the deaths in the study population in exactly the same way, with no attempt to review data other than that recorded on the death certificate, explicitly accepting whatever errors might exist in causes of death recorded and implicitly hoping that whatever errors exist are very much the same in the two sets of data, those in the general population, and those in the group under investigation. But this method has a number of drawbacks. Where the distribution of causes of death in the group under investigation is different from that found in the general population, one may expect that the distribution of in DC = Death certificate. herent error might also be different. Second, when data are available that can shed light on the causes of death under investigation, not including such information permits the risk of reporting results that are simply inaccurate. It is perhaps inadequate comfort to skirt this difficulty by clearly stating that only death certificate diagnoses are reported; this only gives the reason for the inaccuracy. The results in this study illustrate this difficulty. In 9 cases, cancer of the pancreas was listed on the death certificate as cause of death. Only 7.5 such deaths were expected. If we were to accept the cause of death as listed on the death certificate to establish the observed number of deaths for this disease, we would have had to conclude that cancer of the pancreas is significantly increased among asbestos insulation workers. This was not the case. When all available material was reviewed, it was found that only 23 deaths were due to cancer of the pancreas rather than the 9 so categorized on the death certificate. Four were the result of metastatic lung cancer, 6 were found to be cases of peritoneal mesothelioma, and five deaths were due to abdominal carcinomatosis, with primary site not established. Two were due to cancer of the colon. This is not to say that we have established that there TABLE 6. Duration from Onset of Employment of 23 Asbestos Insulation Workers Dying of Cancer of the Pancreas, Cause of death (BE) Duration from Expected deaths: onset of U. S. white Cancer of Cancer of Peritoneal Carcino Cancer of employment males the pancreas* the lungt mesotheliomat matosist the colon? < I TOTAL * Twentytwo had been listed on death certificates as cancer of the pancreas; one as myocardial infarction (57 years after onset of employment). t All had been categorized on death certificates as cancer of the pancreas.

5 No. 6 PANCREATIC CA AND ASBESTOS. Selikoff and Seidman 73 TABLE 7. Age at Death of 23 Asbestos Insulation Workers Dying from Cancer of the Pancreas, Cause of death Expected deaths: Age at U. S. white Cancer of Cancer of Peritoneal Carcino Cancer of death males the pancreas* the lungt mesotheliomat matosist the colont < TOTALS * Twentytwo had been listed on death certificates as cancer of the pancreas; one as myocardial infarction (age 75). is no increased incidence of cancer of the pancreas among asbestos workers. It is possible that there is some limited increase. We are cognizant of the uncertainties inherent in the computation of expected rates for cancer of the pancreas, since it may well be that some of the cases so categorized in the general population from which the expected rates were derived TABLE 8. Observed and Expected Deaths of Cancer of the Pancreas among 2,05 Asbestos Insulation Workers 20 or More Years after Onset of Work, , by Smoking History in 967 Expected deaths (ACS smokingspecific) Observed Blue deaths collar U. S. white white Smoking history BE* DC* malest males$ Total History of cigarettes Current smokers (total) <Pack/day I.o.o Pack +/day 7 IS Unknown amount Exsmokers (total) < Pac k/day Pack +/day Unknown amount Pipe/cigar only Never smoked regularly 3 0. I.3 Unknown history * BE = Best evidence. DC = Death certificate. t Expected deaths were based upon age and smoking specific experience in the American Cancer Society prospective study, , of bluecollar white males, men with at most a high school education, with a history of occupational exposure to dust, fumes, chemicals, gases or radiation, except farmers. The American Cancer Society study rates were extrapolated to according to changes in age specific death rates in total U. S. white males between , and $ Expected deaths were based on age specific data of the U. S. National Center for Health Statistics for white malek and without regard to smoking habits. t All had been categorized on death certificates as cancer of the pancreas. Might really be instances of lung cancer, colon cancer, or even of peritoneal mesothelioma. However, such discrepancies in the general population can at most be of a minor order of magnitude. Thus, unpublished data from the first six years of followup of the American Cancer Society s prospective cancer prevention study3 show that, for cancer of the pancreas in males, there were 557 best evidence deaths compared with 579 death certificate ones. In 58 of these instances, the BE and DC categorizations agreed. These experiences suggest particular caution in analyzing experiences associated with exposure to agents that can increase the risk of cancer at more than one site, where such sites either by local (intraabdominal) spread or by metastases can be confused with cancer of the pancreas. In such circumstances, detailed case ascertainment appears to be useful in evaluation of suggested increased risk of cancer of the pancreas. REFERENCES. Berg JW, Connelly RR. Updating the epidemiologic data on pancreatic cancer. Seinin Oncol 979; 6: Hammond EC. Smoking in relation to death rates of million men and women. In: Epidemiological Study of Cancer and other Chronic Diseases, Monograph 9. Bethesda, MD: National Cancer Institute, 966: Hammond EC, Selikoff IJ, Seidman H. Asbestos exposure, cigarette smoking and death rates. Ann NY Acnd Sci 979; 330: Percy C, Dolman A. Comparison of the coding of death certificates related to cancer in seven countries. Pub Healrh Rep 978: 93i Seidman H, Selikoff IJ, Hammond EC. Short term asbestos work exposure and long term observation. Aim NY Actrd Sci 979; 330: Selikoff IJ, Hammond EC. Asbestos and smoking. JAMA 979; 22: Selikoff IJ, Hammond EC, Churg J. Asbestos exposure, smoking and neoplasia. JAMA 968; 20: Selikoff IJ, Hammond EC, Seidman H. Mortality experience of insulation workers in the United States and Canada, Ann NY Acad Sci 979; 330: Selikoff IJ, Hammond EC, Seidman H. Latency of asbestos disease among insulation workers in the United States and Canada. In press, Cancer 980