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Does Asbestos Exposure Cause Non-Hodgkin's Lymphoma or Related Hematolymphoid Cancers? A Review of the Epidemiologic Literature
Comprehensive Review Does Asbestos Exposure Cause Non-Hodgkin’s Lymphoma or Related Hematolymphoid Cancers? A Review of the Epidemiologic Literature Dennis D. Weisenburger1 and Brian C.H. Chiu2
Abstract Asbestos exposure has been linked to non-Hodgkin’s lymphoma (NHL) and other types of hematolymphoid cancer (HL-CA) in several case reports and epidemiologic studies. This review covers the scientific and medical literature on the issue of whether asbestos exposure is a cause of NHL or other HL-CAs. Studies of animals exposed to asbestos have not shown an increase in NHL or other types of HL-CA. Although some patients with asbestosis have mild immunologic abnormalities, 32 of 35 epidemiologic studies of asbestos exposure in humans are negative for NHL or other HL-CAs. Therefore, it can be concluded that there is no increased risk of NHL or other HLCAs associated with asbestos exposure.
Clinical Lymphoma, Vol. 3, No. 1, 36-40, 2002 Key words: Immunology, Lymphoma, Leukemia, Hodgkin’s disease, Plasma cell myeloma, Lymphatic cancer
Introduction Non-Hodgkin’s lymphoma (NHL) and the closely related disorders, chronic lymphocytic leukemia and plasma cell myeloma, are cancers of the immune system and are part of a large family of cancers of hematopoietic origin.1,2 The NHLs are subdivided by the cell of origin into B-cell and T-cell types. There are many different histological subtypes of NHL, some of which are considered to be distinctive disease entities in themselves.1,2 The NHLs and related disorders are among the few cancers that are increasing in incidence, a phenomenon that is largely unexplained.3,4 Known risk factors for the development of NHL include a familial predisposition; severe congenital or acquired immunodeficiency; an autoimmune disorder; certain infections; and occupational and environmental exposures to solvents, certain pesticides, and possibly the use of hair dyes.3-5 Asbestos exposure in significant amounts is known to cause interstitial pulmonary fibrosis (asbestosis), malignant mesothelioma of the pleural and peritoneal cavities (primarily due to amphibole types of asbestos), bronchogenic carcinoma of the lung, and possibly other cancers.6 Although the pathobiology of these asbestos-related diseases is not fully understood, chronic inflammation related to asbestos deposition in the lungs and pleura appears to play an important role.7,8 Two early studies of mortality in asbestos workers9,10 suggested that cancers of the hematolymphoid system (HL-CA) may also be increased, lead1Department 2Department
of Pathology and Microbiology of Preventive and Societal Medicine University of Nebraska Medical Center, Omaha, NE Submitted: Mar. 29, 2002; Revised: May 6, 2002; Accepted: May 10, 2002 Address for correspondence: Dennis D. Weisenburger, MD, 983135 Nebraska Medical Center, Omaha, NE 68198-3135 Fax: 402-559-6018; e-mail: [email protected]
36 • Clinical Lymphoma June 2002
ing to a number of case reports describing such an association.11-20 These reports hypothesized that chronic stimulation of the immune system or perturbations in immunologic function due to defective immunoregulation associated with asbestosis may play a role in the etiology of HL-CA. The issue of whether asbestos exposure is a cause of NHL or related HL-CA is the subject of this review. The medical and scientific literature on this subject since 1970, including both animal and human studies, are reviewed in an attempt to answer this question.
Asbestos Exposure in Animals An extensive review of the carcinogenicity of asbestos in animals was published by the International Agency for Research on Cancer in 1976.21 It documented that asbestos causes mesothelioma, lung carcinoma, and a variety of other cancers in animals, but does not cause NHL or other forms of HL-CA. Extensive studies by Wagner et al and Suzuki and Kohyama also failed to show an increase in NHL or HL-CA in animals exposed to asbestos.22-25
Asbestos Exposure in Humans Immunologic Studies The immunologic abnormalities commonly associated with asbestosis have been reviewed.26-28 Abnormalities of B-cell function include polyclonal hypergammaglobulinemia, an increased frequency of non–organ-specific autoantibodies, and the presence of circulating immune complexes. Abnormalities of cellular immunity have included decreased peripheral blood T cells, decreased blood T-cell responses to mitogens, cutaneous anergy, and decreased natural killer cell activity. Studies of bronchoalveolar lavage fluid have shown increased T cells, particularly CD4+
Table 1
Mortality Studies of Asbestos Workers with Data on Hematolymphoid Cancer Workers
Disease
Observed/ Expected
Risk
95% CI
17,800 asbestos insulation workers
Leukemia Lymphoma
33/28.7 39/43.2
1.15 0.90
NS NS
Mancuso and Coulter34
1495 asbestos workers
HL-CA
2/3.3
0.60
NS
Puntoni et al35
2190 shipyard workers
Lymphoma and leukemia
12/11.1
1.08
NS
Robinson et al36
3276 asbestos workers
Lymphoma
7/3.3
2.13
NR
Kaminski et al37
3369 plumbers and pipefitters
HL-CA Hodgkin’s disease
77/64.2 8/6.9
1.20 1.15
NS NS
Acheson et al38
4820 amphibole asbestos workers
Hodgkin’s disease Leukemia
1/1.6 4/2.6
0.64 1.54
NS NS
385 sheet metal workers
HL-CA Non-Hodgkin’s lymphoma Leukemia
12/7.1 5/2.1 7/3.0
1.70 2.36 2.32
0.96-2.99 1.00-5.56 1.12-4.79
331 sheet metal workers
HL-CA Lymphatic cancer Leukemia
8/6.5 6/2.4 1/2.3
1.23 2.52 0.44
0.62-2.44 1.17-5.43 0.07-2.96
6931 asbestos cement workers
Lymphatic cancer
16/20.6
0.78
NS
Enterline et al42
1074 asbestos workers
HL-CA
9/10.8
0.84
NS
Armstrong et al43
6505 crocidolite miners/millers
Lymphoma and myeloma
6/NR
0.97
0.44-2.16
Raffn et al44
7996 asbestos cement workers
Lymphoma Myeloma Leukemia
14/15.7 8/4.8 9/13.5
0.89 1.68 0.67
0.49-1.50 0.72-3.31 0.30-1.27
7317 amphibole miners
HL-CA
12/12.8
0.93
0.48-1.63
McDonald et al46
5335 chrysotile miners/millers
HL-CA
56/47.9
1.17
NR
Menegozzo et al47
1534 railway carriage construction workers
HL-CA
4/3.7
1.09
0.37-2.51
616 female asbestos workers
Leukemia
0/0.6
-
0-6.16
3022 asbestos workers
HL-CA
19/NR
0.96
0.63-1.40
Giaroli et al50
3268 asbestos cement workers
HL-CA
7/6.9
1.02
0.48-1.91
Magnani et al51
3367 asbestos cement workers
Leukemia
10/8.3
1.20
0.58-2.21
Study Selikoff et al32,33
Zoloth and Michaels39,40
Hughes et al41
Sluis-Cremer et al45
Rösler et
al48
Dement et
al49
Abbreviations: CI = confidence interval; NR = not reported; NS = not statistically significant (P > 0.05)
cells. However, these immunologic abnormalities are generally mild and nonspecific and are thought to be secondary to chronic inflammation and fibrosis in the lungs and pleura.26,29 In fact, very similar immunologic abnormalities have been noted in patients with other forms of pulmonary fibrosis (pneumoconiosis) such as silicosis.26,30 In patients with asbestosis, these immunologic abnormalities appear to be epiphenomena associated with asbestosis. They do not result in severe clinical immunodeficiency, such as that seen in patients with acquired immune deficiency syndrome or in those treated with immunosuppressive drugs to prevent the rejection of a transplanted organ. Epidemiologic Studies Epidemiologic studies in humans, such as those linking certain asbestos fiber types to mesothelioma and bronchogenic carcinoma, provide the best and most convincing data linking
environmental exposures to cancer.6 In 1965, Sir Austin Bradford-Hill, a British statistician, proposed a set of guidelines to determine whether an environmental agent is a cause of a disease.31 The most important guidelines are the consistency and strength of an observed association between an environmental agent and a cancer over many different epidemiologic studies. Therefore, we reviewed the epidemiologic literature on asbestos exposure and its association with NHL and other forms of HL-CA. These studies are summarized in Tables 1-3.32-68 Studies Against a Link Between Hematolymphoid Cancer and Asbestos Exposure A landmark study linking asbestos exposure to cancer was published by Selikoff et al in 1979 and updated in 1991.32,33 In that large retrospective cohort study, 17,800 asbestos insulation workers were observed over 301,592.6 person-years.
Clinical Lymphoma June 2002 • 37
Asbestos and Hematolymphoid Cancer Table 2
Cohort Studies of Asbestos Workers with Data on Hematolymphoid Cancer Study
Workers
Disease
Observed/ Expected
Risk
95% CI
Clemmesen and Hjalgrim-Jensen52
5686 asbestos cement workers
Lymphatic cancer
8/11
0.63
NR
Tola et al53
7775 shipyard workers
Lymphoma Leukemia
16/18.2 19/16.6
0.88 1.14
0.50-1.43 0.69-1.79
Nokso-Koivisto and Pukkala54
8391 locomotive drivers
Non-Hodgkin’s lymphoma Hodgkin’s disease Leukemia
19/24 7/8 21/24
0.78 0.83 0.87
0.47-1.21 0.34-1.72 0.54-1.32
Abbreviations: CI = confidence interval; NR = not reported
Significantly increased risks for mesothelioma, lung carcinoma, and a variety of other cancers were found, but no increased risks were found for leukemia or lymphoma. Therefore, Selikoff and Seidman concluded that “one can be fairly confident that, at least for this asbestos exposure, at this time, the negative finding can be accepted with some assurance” for certain cancers, including leukemia and lymphoma.33 In addition to that study, 34 other epidemiologic studies of asbestos and HL-CA have been published,34-68 and all but 4 reports from 3 studies39,40,55,64 have failed to demonstrate a significantly increased risk for the various types of HL-CA (Tables 13). Thus, 32 of 35 such studies are considered negative for HL-CA. However, most of the mortality and cohort studies found increased risks for mesothelioma and/or lung carcinoma (Tables 1 and 2). Overall, the evidence from these epidemiologic studies strongly indicates that there is no increased risk for NHL or other types of HL-CA associated with asbestos exposure. Studies Suggestive of a Link Between Hematolymphoid Cancer and Asbestos Exposure The 3 positive studies for various types of HL-CA provide very weak evidence, at best, for a link with asbestos.39,40,55,64 The two papers by Zoloth and Michaels39,40 describe a mortality study of a small cohort of sheet metal workers who were exposed to asbestos (Table 1). The original study showed no increase in risk for all HL-CA, a borderline increase for NHL based on only 5 cases, and a small increase for leukemia based on only 7 cases.39 In a subsequent study, they again found no increase in risk for all HL-CA, a small increase for some forms of NHL (ie, lymphatic cancer) based on only 6 cases, and no increase for other forms of NHL (ie, lymphosarcoma and reticulosarcoma) or leukemia.40 The results of this study are inconsistent internally and were not confirmed by the other cohort studies (Tables 1 and 2). The authors suggest that their findings may also be explained by the frequent exposure of these workers to solvents, although no risk adjustments were made for potential confounders. The study by Ross et al55 is a very small case-control study of 28 cases of diffuse large-cell (histiocytic) lymphoma primary to the gastrointestinal tract and oral cavity (Table 3). The study began with 56 patients selected from a larger case-control study of 405 patients, but only 28 patients were included
38 • Clinical Lymphoma June 2002
because 18 had died and 10 either refused to participate or could not be contacted. Each patient was matched to 1 neighborhood control based on age, sex, and race. Asbestos exposure was evaluated by personal interviews and according to job titles. The authors found a remarkably high risk for NHL (12fold) based on 12 exposed patients and only 1 exposed control. Of these, 5 lymphoma patients and none of the controls were workers in the shipbuilding industry. In this study, a history of malaria was an important confounder that increased the risk of NHL by 10-fold. No analysis of other confounding exposures such as solvents or pesticides was reported, and no risk adjustments were made. The study design and the small number of lymphoma patients and controls suggest a possible selection bias. Two subsequent reports failed to confirm the results of this study.69,70 Also, the reason why asbestos would cause oral and gastrointestinal NHL, but not NHL in the lungs and pleura or other sites, is unexplained. The study by Pasqualetti et al64 was a large hospital-based, case-control study of various types of HL-CA (Table 3). This report is rather brief and difficult to evaluate. The study included 620 patients with HL-CA and 1240 age/sex-matched control patients with various medical diseases other than cancer. The cases of HL-CA included acute nonlymphoblastic leukemia (n = 59), acute lymphoblastic leukemia (n = 29), chronic lymphocytic leukemia (n = 65), Hodgkin’s disease (n = 69), NHL (n = 108), various myeloproliferative disorders (n = 44), myelodysplastic syndromes (n = 48), and myeloma and related disorders (n = 198). Exposures were evaluated by personal interviews and according to job titles. However, only 59% of the HL-CA patients were directly interviewed, whereas 85% of the control patients were directly interviewed. In the other patients, the information was obtained from relatives, and the authors do not provide information on whether adjustments were made for the different types of respondents. A matched-pair analysis was used to calculate the relative risks as estimated by the odds ratios of discordant pairs. The authors found that 68 HL-CA patients and 59 control patients had been exposed to asbestos and reported increased risks for all HL-CA, myeloma, and chronic lymphocytic leukemia (Table 3), but no increased risks associated with asbestos were found for the other types of HL-CA including NHL. However, increased risks for various types of HL-CA were associated with other exposures, including fertilizers, aromatic hydrocar-
Dennis D. Weisenburger and Brian C.H. Chiu Table 3
Case-Control Studies of Hematolymphoid Cancer with Data on the Risk for Asbestos Exposures Study
Cases/Controls
Disease
Risk
95% CI
28/28
Oral/gastrointestinal non-Hodgkin’s lymphoma
12.0
NR
Morris et al56
698/1683
Myeloma
1.3
0.5-3.1
Linet et al57
342/342
Chronic lymphocytic leukemia
0.37 1.12
0.14-0.95 0.43-2.91
Linet et al58
100/100
Myeloma
3.5
1.0-12.0
Schwartz et al59
429/1683
Chronic lymphocytic leukemia Myeloma
1.1-1.4 0.9-1.1
0.8-2.3 0.7-1.8
Schumacher and Delzell60
501/596
Non-Hodgkin’s lymphoma
0.78 1.16
0.59-1.03 0.58-2.30
Cusick and De Stavola61
399/399
Myeloma
3.5
NS
Boffetta et al62
282/1128
Myeloma
0.7 1.3
0.2-2.4 0.6-2.9
Siemiatycki63
215/2357
Non-Hodgkin’s lymphoma
0.8 1.0
0.4-1.3 0.7-1.4
Pasqualetti et al64
620/1240
HL-CA Myeloma Chronic lymphocytic leukemia
3.04 4.61 4.71
1.79-5.14 1.63-12.30 1.23-18.05
Eriksson and Karlsson65
275/275
Myeloma
0.5
0.29-0.82
Blair et al
622/1245
Non-Hodgkin’s lymphoma
1.2
0.99-1.6
Hardell et al67
105/335
Non-Hodgkin’s lymphoma
1.7
0.8-4.0
1469/5073
Non-Hodgkin’s lymphoma
1.1 1.2
0.6-2.1 0.9-1.6
Ross et al55
66
Mao et al68
Abbreviations: CI = confidence interval; NR = not reported; NS = not statistically significant (P > 0.05)
bons, mineral oils, pesticides, radiation, and farm work, but no risk adjustments were made for these confounders. Thus, taken together, these 3 studies do not provide convincing evidence linking HL-CA and asbestos exposure.39,40,55,64
Conclusion In judging whether an association between an exposure and a disease is causal, the Hill guidelines are an important part of the scientific reasoning process.31 Objective scientific information, rather than subjective opinion based on a few epidemiologic studies and scattered case reports, must form the basis of any judgment regarding causation. In the case of asbestos and NHL or other forms of HL-CA, one cannot ignore the lack of a strong or consistent epidemiologic association. Our findings are similar to those of 2 less comprehensive reviews71,72 and are supported by the negative carcinogenesis tests for HL-CA in animals exposed to asbestos. Thus, we conclude that asbestos exposure does not cause NHL or other forms of HL-CA in workers. If no association is found among highly exposed workers, a logical presumption is that there would also be no increased risk with relatively lower environmental exposures. Although additional epidemiological studies of environmental factors and the risk of NHL and other forms of HL-CA are clearly needed, we believe that these studies should focus on other factors since the
extensive data already available on asbestos is negative.
Acknowledgement This work was supported in part by U.S. Public Health Services Grant CA36727 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
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Abstract Asbestos exposure has been linked to non-Hodgkin’s lymphoma (NHL) and other types of hematolymphoid cancer (HL-CA) in several case reports and epidemiologic studies. This review covers the scientific and medical literature on the issue of whether asbestos exposure is a cause of NHL or other HL-CAs. Studies of animals exposed to asbestos have not shown an increase in NHL or other types of HL-CA. Although some patients with asbestosis have mild immunologic abnormalities, 32 of 35 epidemiologic studies of asbestos exposure in humans are negative for NHL or other HL-CAs. Therefore, it can be concluded that there is no increased risk of NHL or other HLCAs associated with asbestos exposure.
Clinical Lymphoma, Vol. 3, No. 1, 36-40, 2002 Key words: Immunology, Lymphoma, Leukemia, Hodgkin’s disease, Plasma cell myeloma, Lymphatic cancer
Introduction Non-Hodgkin’s lymphoma (NHL) and the closely related disorders, chronic lymphocytic leukemia and plasma cell myeloma, are cancers of the immune system and are part of a large family of cancers of hematopoietic origin.1,2 The NHLs are subdivided by the cell of origin into B-cell and T-cell types. There are many different histological subtypes of NHL, some of which are considered to be distinctive disease entities in themselves.1,2 The NHLs and related disorders are among the few cancers that are increasing in incidence, a phenomenon that is largely unexplained.3,4 Known risk factors for the development of NHL include a familial predisposition; severe congenital or acquired immunodeficiency; an autoimmune disorder; certain infections; and occupational and environmental exposures to solvents, certain pesticides, and possibly the use of hair dyes.3-5 Asbestos exposure in significant amounts is known to cause interstitial pulmonary fibrosis (asbestosis), malignant mesothelioma of the pleural and peritoneal cavities (primarily due to amphibole types of asbestos), bronchogenic carcinoma of the lung, and possibly other cancers.6 Although the pathobiology of these asbestos-related diseases is not fully understood, chronic inflammation related to asbestos deposition in the lungs and pleura appears to play an important role.7,8 Two early studies of mortality in asbestos workers9,10 suggested that cancers of the hematolymphoid system (HL-CA) may also be increased, lead1Department 2Department
of Pathology and Microbiology of Preventive and Societal Medicine University of Nebraska Medical Center, Omaha, NE Submitted: Mar. 29, 2002; Revised: May 6, 2002; Accepted: May 10, 2002 Address for correspondence: Dennis D. Weisenburger, MD, 983135 Nebraska Medical Center, Omaha, NE 68198-3135 Fax: 402-559-6018; e-mail: [email protected]
36 • Clinical Lymphoma June 2002
ing to a number of case reports describing such an association.11-20 These reports hypothesized that chronic stimulation of the immune system or perturbations in immunologic function due to defective immunoregulation associated with asbestosis may play a role in the etiology of HL-CA. The issue of whether asbestos exposure is a cause of NHL or related HL-CA is the subject of this review. The medical and scientific literature on this subject since 1970, including both animal and human studies, are reviewed in an attempt to answer this question.
Asbestos Exposure in Animals An extensive review of the carcinogenicity of asbestos in animals was published by the International Agency for Research on Cancer in 1976.21 It documented that asbestos causes mesothelioma, lung carcinoma, and a variety of other cancers in animals, but does not cause NHL or other forms of HL-CA. Extensive studies by Wagner et al and Suzuki and Kohyama also failed to show an increase in NHL or HL-CA in animals exposed to asbestos.22-25
Asbestos Exposure in Humans Immunologic Studies The immunologic abnormalities commonly associated with asbestosis have been reviewed.26-28 Abnormalities of B-cell function include polyclonal hypergammaglobulinemia, an increased frequency of non–organ-specific autoantibodies, and the presence of circulating immune complexes. Abnormalities of cellular immunity have included decreased peripheral blood T cells, decreased blood T-cell responses to mitogens, cutaneous anergy, and decreased natural killer cell activity. Studies of bronchoalveolar lavage fluid have shown increased T cells, particularly CD4+
Table 1
Mortality Studies of Asbestos Workers with Data on Hematolymphoid Cancer Workers
Disease
Observed/ Expected
Risk
95% CI
17,800 asbestos insulation workers
Leukemia Lymphoma
33/28.7 39/43.2
1.15 0.90
NS NS
Mancuso and Coulter34
1495 asbestos workers
HL-CA
2/3.3
0.60
NS
Puntoni et al35
2190 shipyard workers
Lymphoma and leukemia
12/11.1
1.08
NS
Robinson et al36
3276 asbestos workers
Lymphoma
7/3.3
2.13
NR
Kaminski et al37
3369 plumbers and pipefitters
HL-CA Hodgkin’s disease
77/64.2 8/6.9
1.20 1.15
NS NS
Acheson et al38
4820 amphibole asbestos workers
Hodgkin’s disease Leukemia
1/1.6 4/2.6
0.64 1.54
NS NS
385 sheet metal workers
HL-CA Non-Hodgkin’s lymphoma Leukemia
12/7.1 5/2.1 7/3.0
1.70 2.36 2.32
0.96-2.99 1.00-5.56 1.12-4.79
331 sheet metal workers
HL-CA Lymphatic cancer Leukemia
8/6.5 6/2.4 1/2.3
1.23 2.52 0.44
0.62-2.44 1.17-5.43 0.07-2.96
6931 asbestos cement workers
Lymphatic cancer
16/20.6
0.78
NS
Enterline et al42
1074 asbestos workers
HL-CA
9/10.8
0.84
NS
Armstrong et al43
6505 crocidolite miners/millers
Lymphoma and myeloma
6/NR
0.97
0.44-2.16
Raffn et al44
7996 asbestos cement workers
Lymphoma Myeloma Leukemia
14/15.7 8/4.8 9/13.5
0.89 1.68 0.67
0.49-1.50 0.72-3.31 0.30-1.27
7317 amphibole miners
HL-CA
12/12.8
0.93
0.48-1.63
McDonald et al46
5335 chrysotile miners/millers
HL-CA
56/47.9
1.17
NR
Menegozzo et al47
1534 railway carriage construction workers
HL-CA
4/3.7
1.09
0.37-2.51
616 female asbestos workers
Leukemia
0/0.6
-
0-6.16
3022 asbestos workers
HL-CA
19/NR
0.96
0.63-1.40
Giaroli et al50
3268 asbestos cement workers
HL-CA
7/6.9
1.02
0.48-1.91
Magnani et al51
3367 asbestos cement workers
Leukemia
10/8.3
1.20
0.58-2.21
Study Selikoff et al32,33
Zoloth and Michaels39,40
Hughes et al41
Sluis-Cremer et al45
Rösler et
al48
Dement et
al49
Abbreviations: CI = confidence interval; NR = not reported; NS = not statistically significant (P > 0.05)
cells. However, these immunologic abnormalities are generally mild and nonspecific and are thought to be secondary to chronic inflammation and fibrosis in the lungs and pleura.26,29 In fact, very similar immunologic abnormalities have been noted in patients with other forms of pulmonary fibrosis (pneumoconiosis) such as silicosis.26,30 In patients with asbestosis, these immunologic abnormalities appear to be epiphenomena associated with asbestosis. They do not result in severe clinical immunodeficiency, such as that seen in patients with acquired immune deficiency syndrome or in those treated with immunosuppressive drugs to prevent the rejection of a transplanted organ. Epidemiologic Studies Epidemiologic studies in humans, such as those linking certain asbestos fiber types to mesothelioma and bronchogenic carcinoma, provide the best and most convincing data linking
environmental exposures to cancer.6 In 1965, Sir Austin Bradford-Hill, a British statistician, proposed a set of guidelines to determine whether an environmental agent is a cause of a disease.31 The most important guidelines are the consistency and strength of an observed association between an environmental agent and a cancer over many different epidemiologic studies. Therefore, we reviewed the epidemiologic literature on asbestos exposure and its association with NHL and other forms of HL-CA. These studies are summarized in Tables 1-3.32-68 Studies Against a Link Between Hematolymphoid Cancer and Asbestos Exposure A landmark study linking asbestos exposure to cancer was published by Selikoff et al in 1979 and updated in 1991.32,33 In that large retrospective cohort study, 17,800 asbestos insulation workers were observed over 301,592.6 person-years.
Clinical Lymphoma June 2002 • 37
Asbestos and Hematolymphoid Cancer Table 2
Cohort Studies of Asbestos Workers with Data on Hematolymphoid Cancer Study
Workers
Disease
Observed/ Expected
Risk
95% CI
Clemmesen and Hjalgrim-Jensen52
5686 asbestos cement workers
Lymphatic cancer
8/11
0.63
NR
Tola et al53
7775 shipyard workers
Lymphoma Leukemia
16/18.2 19/16.6
0.88 1.14
0.50-1.43 0.69-1.79
Nokso-Koivisto and Pukkala54
8391 locomotive drivers
Non-Hodgkin’s lymphoma Hodgkin’s disease Leukemia
19/24 7/8 21/24
0.78 0.83 0.87
0.47-1.21 0.34-1.72 0.54-1.32
Abbreviations: CI = confidence interval; NR = not reported
Significantly increased risks for mesothelioma, lung carcinoma, and a variety of other cancers were found, but no increased risks were found for leukemia or lymphoma. Therefore, Selikoff and Seidman concluded that “one can be fairly confident that, at least for this asbestos exposure, at this time, the negative finding can be accepted with some assurance” for certain cancers, including leukemia and lymphoma.33 In addition to that study, 34 other epidemiologic studies of asbestos and HL-CA have been published,34-68 and all but 4 reports from 3 studies39,40,55,64 have failed to demonstrate a significantly increased risk for the various types of HL-CA (Tables 13). Thus, 32 of 35 such studies are considered negative for HL-CA. However, most of the mortality and cohort studies found increased risks for mesothelioma and/or lung carcinoma (Tables 1 and 2). Overall, the evidence from these epidemiologic studies strongly indicates that there is no increased risk for NHL or other types of HL-CA associated with asbestos exposure. Studies Suggestive of a Link Between Hematolymphoid Cancer and Asbestos Exposure The 3 positive studies for various types of HL-CA provide very weak evidence, at best, for a link with asbestos.39,40,55,64 The two papers by Zoloth and Michaels39,40 describe a mortality study of a small cohort of sheet metal workers who were exposed to asbestos (Table 1). The original study showed no increase in risk for all HL-CA, a borderline increase for NHL based on only 5 cases, and a small increase for leukemia based on only 7 cases.39 In a subsequent study, they again found no increase in risk for all HL-CA, a small increase for some forms of NHL (ie, lymphatic cancer) based on only 6 cases, and no increase for other forms of NHL (ie, lymphosarcoma and reticulosarcoma) or leukemia.40 The results of this study are inconsistent internally and were not confirmed by the other cohort studies (Tables 1 and 2). The authors suggest that their findings may also be explained by the frequent exposure of these workers to solvents, although no risk adjustments were made for potential confounders. The study by Ross et al55 is a very small case-control study of 28 cases of diffuse large-cell (histiocytic) lymphoma primary to the gastrointestinal tract and oral cavity (Table 3). The study began with 56 patients selected from a larger case-control study of 405 patients, but only 28 patients were included
38 • Clinical Lymphoma June 2002
because 18 had died and 10 either refused to participate or could not be contacted. Each patient was matched to 1 neighborhood control based on age, sex, and race. Asbestos exposure was evaluated by personal interviews and according to job titles. The authors found a remarkably high risk for NHL (12fold) based on 12 exposed patients and only 1 exposed control. Of these, 5 lymphoma patients and none of the controls were workers in the shipbuilding industry. In this study, a history of malaria was an important confounder that increased the risk of NHL by 10-fold. No analysis of other confounding exposures such as solvents or pesticides was reported, and no risk adjustments were made. The study design and the small number of lymphoma patients and controls suggest a possible selection bias. Two subsequent reports failed to confirm the results of this study.69,70 Also, the reason why asbestos would cause oral and gastrointestinal NHL, but not NHL in the lungs and pleura or other sites, is unexplained. The study by Pasqualetti et al64 was a large hospital-based, case-control study of various types of HL-CA (Table 3). This report is rather brief and difficult to evaluate. The study included 620 patients with HL-CA and 1240 age/sex-matched control patients with various medical diseases other than cancer. The cases of HL-CA included acute nonlymphoblastic leukemia (n = 59), acute lymphoblastic leukemia (n = 29), chronic lymphocytic leukemia (n = 65), Hodgkin’s disease (n = 69), NHL (n = 108), various myeloproliferative disorders (n = 44), myelodysplastic syndromes (n = 48), and myeloma and related disorders (n = 198). Exposures were evaluated by personal interviews and according to job titles. However, only 59% of the HL-CA patients were directly interviewed, whereas 85% of the control patients were directly interviewed. In the other patients, the information was obtained from relatives, and the authors do not provide information on whether adjustments were made for the different types of respondents. A matched-pair analysis was used to calculate the relative risks as estimated by the odds ratios of discordant pairs. The authors found that 68 HL-CA patients and 59 control patients had been exposed to asbestos and reported increased risks for all HL-CA, myeloma, and chronic lymphocytic leukemia (Table 3), but no increased risks associated with asbestos were found for the other types of HL-CA including NHL. However, increased risks for various types of HL-CA were associated with other exposures, including fertilizers, aromatic hydrocar-
Dennis D. Weisenburger and Brian C.H. Chiu Table 3
Case-Control Studies of Hematolymphoid Cancer with Data on the Risk for Asbestos Exposures Study
Cases/Controls
Disease
Risk
95% CI
28/28
Oral/gastrointestinal non-Hodgkin’s lymphoma
12.0
NR
Morris et al56
698/1683
Myeloma
1.3
0.5-3.1
Linet et al57
342/342
Chronic lymphocytic leukemia
0.37 1.12
0.14-0.95 0.43-2.91
Linet et al58
100/100
Myeloma
3.5
1.0-12.0
Schwartz et al59
429/1683
Chronic lymphocytic leukemia Myeloma
1.1-1.4 0.9-1.1
0.8-2.3 0.7-1.8
Schumacher and Delzell60
501/596
Non-Hodgkin’s lymphoma
0.78 1.16
0.59-1.03 0.58-2.30
Cusick and De Stavola61
399/399
Myeloma
3.5
NS
Boffetta et al62
282/1128
Myeloma
0.7 1.3
0.2-2.4 0.6-2.9
Siemiatycki63
215/2357
Non-Hodgkin’s lymphoma
0.8 1.0
0.4-1.3 0.7-1.4
Pasqualetti et al64
620/1240
HL-CA Myeloma Chronic lymphocytic leukemia
3.04 4.61 4.71
1.79-5.14 1.63-12.30 1.23-18.05
Eriksson and Karlsson65
275/275
Myeloma
0.5
0.29-0.82
Blair et al
622/1245
Non-Hodgkin’s lymphoma
1.2
0.99-1.6
Hardell et al67
105/335
Non-Hodgkin’s lymphoma
1.7
0.8-4.0
1469/5073
Non-Hodgkin’s lymphoma
1.1 1.2
0.6-2.1 0.9-1.6
Ross et al55
66
Mao et al68
Abbreviations: CI = confidence interval; NR = not reported; NS = not statistically significant (P > 0.05)
bons, mineral oils, pesticides, radiation, and farm work, but no risk adjustments were made for these confounders. Thus, taken together, these 3 studies do not provide convincing evidence linking HL-CA and asbestos exposure.39,40,55,64
Conclusion In judging whether an association between an exposure and a disease is causal, the Hill guidelines are an important part of the scientific reasoning process.31 Objective scientific information, rather than subjective opinion based on a few epidemiologic studies and scattered case reports, must form the basis of any judgment regarding causation. In the case of asbestos and NHL or other forms of HL-CA, one cannot ignore the lack of a strong or consistent epidemiologic association. Our findings are similar to those of 2 less comprehensive reviews71,72 and are supported by the negative carcinogenesis tests for HL-CA in animals exposed to asbestos. Thus, we conclude that asbestos exposure does not cause NHL or other forms of HL-CA in workers. If no association is found among highly exposed workers, a logical presumption is that there would also be no increased risk with relatively lower environmental exposures. Although additional epidemiological studies of environmental factors and the risk of NHL and other forms of HL-CA are clearly needed, we believe that these studies should focus on other factors since the
extensive data already available on asbestos is negative.
Acknowledgement This work was supported in part by U.S. Public Health Services Grant CA36727 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD.
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