Document B8mY85JLwL53RoJo2bXVQDmEj

Asbestos and Peritoneal Mesothelioma among College-educated Men LAURA S. WELCH, MD, YAIR I. Z. ACHERMAN, MSC, ELIZABETH HAILE, MS, ROSEMARY K. SOKAS, MD, MOH, PAUL H. SUGARBAKER, MD The proportion of peritoneal mesotheliomas among all ate latency period. Becklake documented a great mesotheliomas has been decreasing, leading some to suggest that peritoneal mesothelioma occurs only after high levels of exposure to asbestos. To investigate the relationship between asbestos exposure and the devel opment of peritoneal mesothelioma, a case-control study examined 40 cases of primary peritoneal mesothe lioma from a single institution. This series differed from previous reports in that 75% of the cases and controls had attended college. Results show an odds ratio of 6.6 for asbestos exposure among this group of primary peri toneal mesothelioma cases with relatively slight asbestos increase in worldwide asbestos use beginning around 1940,7 and others have described additional increases in some countries during and after World War II. In one population-based study, mortality for men in The Netherlands increased from 10.8/million for the period 1970-1978 to 20.9/million in 1979- 1987.8 The rate for women also increased, from 2.5/million to 3.6/million. There was no change in the rates for those under 45, and the highest increase was in those over 65. In addi tion, the geographic distribution across the country exposures. Key words: asbestos; peritoneal mesothe showed a pattern of concentration of deaths among lioma; mesothelioma; case-control study. men in areas with many harbors, shipyards, and heavy INT J OCCUP ENVIRON HEALTH 2005;11:254-258 industry. These patterns mirror the use of asbestos in that country in the 1950s and 1960s, with a 20-30-year latency period. Household exposure has been shown to cause pleural mesothelioma, with relative risk estimates eritoneal mesothelioma is a rare primary peri from fourfold to 23-fold9; similar data for peritoneal Ptoneal surface malignancy. The incidence of mesotheliomas are not available. malignant mesothelioma, pleural and peritoneal, Using population-based cancer registries in the has been rising worldwide since at least the 1970s,1-4 withUnited States, Spirtas et al. reported a significant some evidence only recently of a slowing of this trend.5 increase in mesothelioma incidence during 1970-1980 Price used data from Surveillance, Epidemiology and among men over 55 at the time of diagnosis, with an End Results (SEER) from 1973-1992 to describe the annual increase in three different registries of 12--13%.4 incidence of pleural and peritoneal mesothelioma in the They specifically looked for bias related to increased United States, and to estimate the future incidence.3 He recognition of the disease, and concluded this did not predicted that the total number of cases per year overall account for the increased incidence. Similar increases would decline, with a peak incidence of 2,800 cases/year have been found in Finland,10 as well as in other studies in the year 2000, but there would be a continued upward in the United States,11 Australia,12,13 and Norway.14 trend in older age groups that had had the highest Peritoneal mesotheliomas make up 10-50% of all asbestos exposures in prior decades. mesotheliomas in case series and case-control studies. Since the first report from Wagner et al. in 1960 link Some investigators have advanced the hypothesis that ing asbestos exposure to malignant pleural mesothe- for asbestos to cause peritoneal mesothelioma the lioma,6 many studies have reported asbestos exposure to exposures must be of a higher duration and/or inten be a significant etiologic factor in the pathogenesis of sity than the exposures needed to cause pleural malignant mesothelioma in general, and of peritoneal mesothelioma.15 To address this question, we present a mesothelioma in particular. In several countries, trends case series of peritoneal mesothelioma among a refer in the incidence of deaths from mesothelioma (pleural ral population of men with predominately college edu or all combined) increased in conjunction with increase cations, and conclude that intermittent or low expo in the use of asbestos, taking into account an appropri- sure to asbestos is associated with mesothelioma. Received from the Center to Protect Workers' Rights, Silver Spring, Maryland (LSW, EH); the Washington Cancer Institute, Washington Hospital Center, Washington, DC (YIZA, PHS); and the University of Illinois, Chicago Illinois (RKS). Address correspondence and reprint requests to: Laura S. Welch, MD, Center to Protect Workers' Rights, 8484 Georgia Avenue, Silver Spring, MD 20910, U.S.A.; e-mail: <lwelch@cpwr.com>. METHODS Cases and Controls Potential cases in this study included every patient with a primary peritoneal surface malignancy treated at the 254 Washington Cancer Institute (WCI) between 1989 and 2001. Peritoneal mesothelioma, primary peritoneal adenocarcinoma, desmoplastic small-round-cell tumor, and papillary serous adenocarcinoma were considered primary peritoneal surface malignancies. Cases of pri mary pleural mesothelioma with peritoneal involve ment were excluded. The diagnosis of peritoneal mesothelioma in our 51 patients was made on the basis of a composite of clinical and pathologic features. First, the patients had clinical syndromes compatible with the disease, peritoneal mesothelioma. Second, exami nation of generous biopsies by light microscopy showed histologic features compatible with peritoneal mesothelioma. Third, the proper immunostains (calretinin and CK 5/6) were used to confirm the diagno sis.16 For every potential participant, the diagnosis of cancer had been made at this institution, or pathology data were reassessed and the diagnosis was confirmed if the patient had been referred from another institution for treatment. One control for each case was recruited from all appendiceal cancer patients treated at the Washington Cancer Institute from 1990 to 2000. Cases were matched to controls by sex and age within two years. When a matched control was unavailable for interview or lost to follow-up, a second control was matched to the initial case. For the 52 primary peritoneal mesothe liomas, 40 patients or next of kin were interviewed, for a response rate of 78%; the rest were lost to follow-up. Among these 40, 24 were men and 16 were women. All but three of the mesothelioma cases who were inter viewed were contacted within two years of diagnosis; details of the clinical presentations and clinical courses are described elsewhere.16 This analysis focuses on the male peritoneal mesothelioma cases and controls; results for female case and controls will be presented separately. Exposure Assessment After giving verbal consent, cases and controls under went a detailed telephone interview using the ques tionnaire developed by Spirtas and colleagues17 for a case-control study of mesotheliomas. In the event that cases or controls were not available for interview or were dead, a spouse or next of kin was interviewed. Information collected included sex, age, race, level of education, and lifetime occupational history. We asked whether the study subject, or a person living with the study subject, had ever worked in one of the nine fol lowing high-risk-for-asbestos-exposure processes: 1) tire and/or brake lining installation or repair, 2) furnace or boiler installation or repair, 3) building demolition, 4) plumbing or heating repair, 5) insulation installation or removal, 6) elevator installation or repair, 7) ship building, ship demolition, or shipyard work, 8) pro duction of textiles, and 9) production of paper prod ucts. We also asked whether the subject had ever been exposed to 22 specific substances, one of which was asbestos. In order to evaluate intensity and probability of exposure to asbestos, two occupational medicine spe cialists (LSW, RKS) assigned a score for probability and intensity of exposure to each job identified in the detailed job history taken during the interview. Scores ranging from 0 to 3 were given for probability of expo sure to asbestos, where 0 meant very unlikely, 1 meant some possibility, 2 meant probable, and 3 meant defi nite exposure. Scores of 1 to 3 were also assigned for intensity when the probability score was not zero, with 1 meaning low, 2 meaning medium, and 3 meaning high, based on both the type of work and its duration. Scores were calculated for each job by multiplying intensity and probability, and then the score for all jobs were summed when a subject had held more than one job. We classified jobs as unexposed when the total score was zero or 1. The raters were blind to case or control status. In the analysis, asbestos exposure was classified in five ways. 1. The subject's answer of yes or no to the question: Have you ever been exposed to asbestos? 2. The score assigned by the probability-intensity expert rating 3. A categorization of "exposed" or "not exposed" based on the participant's report of exposure to asbestos in any of nine tasks or processes defined a priori to represent exposure 4. The subject's answer of yes or no as to whether a cohabitant had ever worked with asbestos while resid ing with the subject 5. A cohabitant's exposure to asbestos based on the nine tasks or processes mentioned in 3 above while residing with the subject Overall exposure was defined as any exposure to asbestos in any of these five categories. Statistical Analysis To determine inter-rater reliability between the two occupational medicine specialists, a kappa statistic was used. The kappa was 0.6181, which is a good-to-intermediate kappa.18 We then used the scores of one rater (LSW) to define job exposure to asbestos through expert opinion as a dichotomous variable. We also used the scores of both raters to create an average score for five groups by education level. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for a paired study design. RESULTS The mean age of the male peritoneal mesothelioma cases was 53 years, and that of controls was 55 years, VOL 11/NO 3, JUL/SEP 2005 www.ijoeh.com Mesothelioma in Educated Men 255 TABLE 1 Asbestos Exposures of Male Peritoneal Mesothelioma Subjects and Their Paired Colon Cancer Controls Cases(n = 24) No. (%) Controls (n = 24) No. (%) Ever exposed to asbestos?* 12 (50) 8 (21) Ever performed*: Tire or brake lining work? Furnace or boiler installation? Building demolition work? Plumbing or heating repair? Insulation work? Shipyard or shipbuilding work? Elevator installation? Production of textiles? Production of paper products? At least one of these nine activities? 8 (33) 5 (21) 6 (25) 6 (25) 10 (42) 6 (25) 0 (0) 6 (25) 2 (8) 21 (88) 6 (25) 2 (5) 7 (29) 10 (42) 6 (25) 1 (2) 1 (2) 2 (5) 1 (2) 14 (58) Job exposure by expert rater 21 (88) 9 (38) Cohabitant any of the nine activities 8 (33) 2 (8) Overall reported exposure! Potential No known exposure 22 (92) 2 (8) 15 (62.5) 9 (37.5) *"Yes" answer to the question. f'Yes" answer to "ever exposed to asbestos?" or any one of the nine tasks or cohabitant question or rated by expert rater. with a range from 22 to 87. All but one of the 24 male cases and all of the controls were non-Hispanic whites. Seventy-eight percent of all male participants had com pleted at least some college, and there was no differ ence in race or education distributionsbetween male cases and controls. Interviews were held with the cases 50% of the time, and with the controls 58% of the time; the remainder were held with wives (41% and 29%, respectively) or with other household members (8% and 12%, respectively). Table 1 shows the frequencies and percentages of exposures to asbestos for cases and their paired con trols. All cases classified as exposed by the expert rater were also identified using the nine activities defined a priori to represent asbestos exposure. Five controls reported work in those activities but were not classified as exposed based on expert review of job descriptions. Table 2 shows the educational levels and asbestos exposures of the participants, and an average probabil ity-intensity expert rating score based on averaging scores from both readers for all cases or controls within each educational level. The average exposure to asbestos declined as the educational level increased. Table 3 shows the odds ratios and 95% confidence intervals for exposures to asbestos among this group of male peritoneal cases and controls. The mesothelioma cases had an odds ratio of 6.6 for overall exposure to asbestos, with a confidence interval of 1.16-21.5. DISCUSSION Here we report a significant association between asbestos exposure and peritoneal mesothelioma in exposed men. In addition, we found a relationship between asbestos exposure and peritoneal mesothe lioma in a group of men among whom 75% had attended college, and over 35% had graduated from college. Table 3 shows that the expert ratings of expo sures and intensities among these cases are generally lower than what would be expected for a man who has had a career in the construction industry. For example, a man who has worked for 20 years as an insulator would have a score of at least 9. This study supports the conclusion that asbestos exposures cause peritoneal mesothelioma even at levels lower than exposures sus tained by cohorts previously described. Our study has some unique attributes. All cases were histologically confirmed; this is only the second study including peritoneal mesotheliomas to have done so. It is the largest series of peritoneal mesothe liomas for which an in-depth interview has been con ducted; because peritoneal mesotheliomas represent less than 20% of all mesotheliomas in most studies, this tumor site is often not analyzed separately. Spirtas included 25 peritoneal mesotheliomas in his case-con trol study. Cocco and Dosemici19 described the epi demiology of 657 deaths from peritoneal cancer, but they were not able to clearly identify the histologic types, and exposure was assigned based on occupation on the death certificate. The limitations of this study are ones common to case-control studies. There may have been recall bias among both cases and controls, as may occur in a case-control design. Since cancer patients may have a heightened awareness of exposures to known carcino gens, including asbestos, we chose to use cancer con- 256 Welch et al. www.ijoeh.com INT J OCCUP ENVIRON HEALTH TABLE 2 Probability-Intensity Rating Scores* of Asbestos Exposures of Male Peritoneal Mesothelioma Subjects and Their Paired Colon Cancer Controls by Educational Level 1 Mesothelioma Colon Cancer Individual Level Individual Level Scores Average Scores Average Level 1. < 8th grade Level 2. 8-11 years Level 3. 12 years or HS grad Level 4. Technical school prior to HS completion Level 5. Post-HS technical school Level 6. Some college/completed junior college Level 7. Graduated college Level 8. Postgrad education ---- -- 44 1.5, 4, 14.5, 7.5, 9 7.3 1, 10.5, 0, 4, 0,1,0 2.5 1 1 0.5 0.5 ---- 4.5, 14, 4, 6, 3.5, 4, 3.5, 4 5.4 11,4, 1.5 5.5 2.5, 7.5, 0, 2, 1.4, 1, 1 2.2 2, 0, 2, 0, 0.5, 7.5, 4, 2.1 0.5, 1.5,3 2, 4 3 4, 1.5 2.75 Scores ranging from 0 (very unlikely) to 3 (definite exposure) were given for probability of exposure, intensity was scored 1 (low) to 3 (high). A score for each job was calculated by multiplying intensity and probability. Scores for all jobs of an individual were summed. trots to minimize a difference in recall between our cases and controls. We used two different methods of assigning expo sure, one based on self-report of exposure, and the second based on an expert rating of the subject's occu pational history. Among our cases, these two methods were in full agreement on exposure status, while the two approaches differed somewhat for the controls. Prior studies have used similar methods, and some have included a formal job-exposure matrix created a priori. There is no clear advantage to the use of a jobexposure matrix (JEM) over the other two ways to characterize exposure. Ahrens et al.20 assessed expo sures to asbestos in a lung cancer case-control study, and specifically compared whether use of a supple mentary questionnaire (SQ) completed during an interview led to a different assessment of exposure compared with two different JEMs. In this study, 24% of cases were classified as "certainly exposed" based on aJEM; using the SQ this figure was 68%. Based on the JEM, 16% were certainly not exposed; using the SQ this proportion was 32%. Agreement between the methods was better when exposure definition was restricted to definite exposures (kappa = 0.67 for the two JEMs, and 0.44/0.39 comparing the SQ and each JEM). Both JEM- and SQ-assessed exposures showed dose-response associations with lung cancer in smok ing-adjusted ORs, showing that each method correctly classified cases and controls in relationship to each other. Elsewhere,21 the authors report that misclassification of exposures by the JEM resulted in overestima tion of exposures. They conclude that neither an SQ nor aJEM is superior and both should be used for opti mal epidemiologic performance. Cocco and Dosemici19 used a JEM, and could exclude asbestos exposure for only 1.5% of the population; this also suggests that a JEM may result in overestimation of exposure. Based on these data, we did not find that the absence of a formal JEM limited our conclusions. Our patients were not typical mesothelioma patients, since 75% of all participants had completed at least some college, and more than 35% had graduated. Most investigators do not report this information, but Agudo et al.,22 in a study of mesotheliomas in Spain, found that 64% had not gone further than primary school. We believe the relatively high level of education among our cases is due to a referral bias, in that indi viduals with more education are more likely to seek out state-of-the-art care even if that treatment means travel ing a distance and paying expenses not covered by medical insurance. Persons of higher socioeconomic status would be expected to have a lower probability of exposure to asbestos, and a lower intensity when exposed, since exposure to asbestos in industrial set tings occurs in traditionally blue collar jobs such as shipbuilding and manufacturing. Does asbestos exposure affect the likelihood of peri toneal mesothelioma differently from the way that it affects pleural mesothelioma? Twenty years ago, Browne and Smither put forth the hypothesis that peri toneal mesotheliomas are associated with longer and heavier asbestos exposures.15 More recently, Hodgson and Darnton presented a quantitative risk analysis of mesothelioma related to asbestos exposure, and TABLE 3 Odds Ratios (95% Confidence Intervals) for Asbestos Exposure among Men with Peritoneal Mesothelioma Compared with Men with Colon Cancer Ever exposed to asbestos Ever performed any of the nine activities Job exposure rating by expert Overall exposure to asbestos 2.0 (0.62-6.42) 11.7 (2.7-50.5) 6.6 (1.25-34.94) 5.0 (1.17-21.5) VOL 11/NO 3, JUL/SEP 2005 www.ijoeh.com Mesothelioma in Educated Men 257 reported different relationships between exposures and rates of pleural and peritoneal mesotheliomas.23 They concluded that each additional unit of exposure would add less risk for pleural tumors and more for peritoneal tumors, with the result that highly exposed cohorts would have higher proportions of peritoneal tumors among all mesotheliomas. However, both Browne and Hodgson found some peritoneal mesothe liomas in all the asbestos-exposed cohorts reviewed, and they present no evidence for a threshold for peri toneal mesothelioma. The fact that peritoneal meso theliomas are more common in highly exposed groups does not mean that cases of peritoneal mesothelioma cannot appear among groups with less exposure. Our case series is not a cohort, but the excess risk for asbestos exposure among these peritoneal mesothe lioma cases is consistent with the hypothesis that peri toneal cancers occur in less highly exposed groups. References 1. Hillerdal G. Mesothelioma: cases associated with non-occupational and low dose exposures. Occup Environ Med. 1999; 56:505-13. 2. Enterline PE, Henderson VL. Geographic patterns for pleural mesothelioma deaths in the United States 1968-81. J Natl Cancer Inst, 1987; 79:31-7. 3. Price B. Analysis of current trends in United States mesothe lioma incidence. Am J Epidemiol. 1997; 145:211-8. 4. Spirtas R, Beebe GW, Connelly RR, et al. Recent trends in mesothelioma incidence in the United States. Am J Ind Me.d 1986; 9:397-407. 5. Weill H, Hughes JM, Churg AM. Changing trends in US mesothelioma incidence. Occup Environ Med. 2004; 61:438-41. 6. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothe lioma and asbestos exposure in the North Western Cape Province. Br J Ind Med. 1960; 17:260-71. 7. Becklake M. Asbestos-related diseases of the lung and other organs: their epidemiology and implications for clinical prac tice. Am Rev Respir Dis. 1976; 114:187-227. 8. Meijers JM, Planteydt HT, Slangen JJM, Swaen GMH, van Vliet C, Sturmans F. Trends and geographical patterns of pleural mesotheliomas in The Netherlands 1970-87. Br J Ind Med. 1990; 47:775-81. 9. Bourdes V, Boffetta P, Pisani P. Environmental exposure to asbestos and risk of pleural mesothelioma: review and meta analysis. Eur J Epidemiol. 2000; 16:411-7. 10. Karjalainen A, PE, Mattson K, Tammilehto L, Vainio H. Trends in mesothelioma incidence and occupational mesothelioms in Finland in 1960-1995. ScandJ Environ Health. 1997; 23:266-70. 11. Bruckman L, Rubino RS, Christine B. Asbestos and mesothe lioma incidence in Connecticut. J Air Pollution Control Assoc. 1977; 27:121-6. 12. Leigh J, Davidson P, Hendrie L, Berry D. Malignant mesothe lioma in Australia 1945-2000. Ann Occup Hyg. 2002; 46(suppl 1), 160-5. 13. Armstrong BK, Musk AW, et al. Epidemiology of malignant mesothelioma in Western Australia. Med J Aust. 1984; 141:86-8. 14. Mowe G. The Trend in the Incidence of Malignant Mesothe lioma in Norway (1970-1979). Proceedings of the International Symposium on the Prevention of Occupational Cancer. Helsinki, Finland, 21-24 April 1981. Occupational Safety and Health Series No. 46, ILO, Geneva, Switzerland. Occup Health Safety 1981. 15. Browne K, Smither WJ. Asbestos-related mesothelioma: factors discriminating between pleural and peritoneal sites. Br J Ind Med. 1983; 40:145-52. 16. Sugarbaker PH, Acherman YI, Gonzalez-Moreno S, et al. Diag nosis and treatment of peritoneal mesothelioma: The Washing ton Cancer Institute experience. Semin Oncol. 2002; 29:51-61. 17. Spirtas R, Heineman EF, Bernstein L, et al. Malignant mesothe lioma: attributable risk of asbestos exposure. Occup Environ Med. 1994; 51:804-11. 18. Fleiss JL, Cohen J. The equivalence of weighted kappa and the intraclass correlation coefficient as measures of reliability. Educ Psychol Meas. 1973; 33:613-9. 19. Cocco P, Dosemeci M. Peritoneal cancer and occupational exposure to asbestos: results from the application of ajob-expo sure matrix. Am J Ind Med. 1999; 35:9-14. 20. Ahrens W, Jockel KH, Brochard P, et al. Retrospective assess ment of asbestos exposure--I. Case-control analysis in a study of lung cancer: efficiency of job-specific questionnaires and job exposure matrices. IntJ Epidemiol. 1993; 22(Suppl 2): S83-S95. 21. Orlowski E, Pohlabeln H, Berrino F, et al. Retrospective assess ment of asbestos exposure-- II. At the job level: complementar ity ofjob-specific questionnaire and job exposure matrices. IntJ Epidemiol. 1993; 22(suppl 2): S96-S105. 22. Agudo A, Gonzalez CA, Bleda MJ, et al. Occupation and risk of malignant pleural mesothelioma: A case-control study in Spain. Am J Ind Med. 2000; 37:159-68. 23. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann Occup Hyg. 2000; 44:565-601. 258 Welch et al. www.ijoeh.com INT J OCCUP ENVIRON HEALTH