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Benzene and Non-Hodgkin's Lymphoma

Introduction

While there are many classification systems for lymphomas, most of the classification systems recognize two broad categories of lymphomas: Hodgkin's lymphoma (often called Hodgkin's disease) and non-Hodgkin's lymphoma.

Case-Control Studies

Since 2000, four case-control studies have been conducted which specifically analyze whether exposure to benzene or aromatic hydrocarbons is associated with an increased risk of non-Hodgkin's lymphoma. All four of these studies provide strong evidence of such a causal association. Additionally, four earlier case-control studies also provide evidence of a causal association specifically between benzene and non-Hodgkin's lymphoma.

In 2004, Scandinavian researchers also reported the results of a case-control study for non-Hodgkin's lymphoma and occupational exposures. Dryver, E., et al., "Occupational Exposures and Non-Hodgkin's Lymphoma in Southern Sweden," International Journal of Occupational and Environmental Health 10:13-21 (2004). Using the South Swedish Regional Tumor Registry, they identified 1,414 cases of pathology-confirmed non-Hodgkin's lymphoma in adults between 1990 and 1998. A total of 2,820 individuals matched to the cases by gender, age and parish were sent questionnaires, of which 1,943 (69) returned completed questionnaires. Cases were excluded where matched controls were lacking. The study ultimately involved 859 cases and 1,310 controls. Risk of non-Hodgkin's lymphoma was significantly increased for gasoline exposure to 1.46 (95% CI = 1.04 - 2.05) and further increased to 1.92 (95% CI = 1.20 - 3.08) comparing gasoline exposure greater than 5 years with exposure less than 5 years. Odds were also increased for solvent exposure to 1.20 (95% CI = 0.93 - 1.54) and further increased to 1.59 (95% CI = 1.11 = 2.28) comparing solvent exposure greater than 5 years with exposure less than 5 years. Odds were also increased for exposure to other oil products to 1.41 (95% CI = 1.02 - 1.95) and further increased to 1.54 (95% CI = 1.01 = 2.36) comparing oil products exposure greater than 5 years with exposure less than 5 years. Risk was also significantly increased for exposure to aliphatic or alicyclic hydrocarbon solvents (OR = 1.75, 95% CI = 1.03 - 2.99), aromatic hydrocarbon solvents (OR = 1.45, 95% CI = 1.13 = 1.86), and other organic solvents (OR = 1.88, 95% CI = 1.18 = 2.99), but not for chlorinated hydrocarbon solvents or polycyclic aromatic hydrocarbons. Risks were also increased for employment as an automobile mechanic (OR = 1.82, 95% CI = 1.18 = 2.81), painter (OR = 1.77, 95% CI = 1.13 = 2.76), gas station attendant (OR = 1.62, 95% CI = 0.92 - 2.83), varnisher (OR = 1.52, 95% CI = 0.91 = 2.54), printer (OR = 1.48, 95% CI = 0.87 - 2.52), and for work in the rubber industry (OR = 1.25, 95% CI = 0.75 = 2.11). In a multivariable logistic regression analysis, a dose-response relationship was apparent for exposure to aliphatic or alicyclic hydrocarbon solvents: no exposure (OR = 1.00), medium exposure (OR = 1.42, 95% CI = 0.77 - 2.60), high exposure (OR = 15.66, 95% CI = 1.98 - 123.67); a dose response relationship was also evident for exposure to aromatic hydrocarbon solvents: no exposure (OR = 1.00), low exposure (OR = 1.35, 95% CI = 1.02 - 1.79), medium exposure (OR = 1.72; 95% CI = 0.91 - 3.25), high exposure (OR - 1.95, 95% CI = 0.90 - 4.21). Although the investigators did not specifically report results for benzene, this study is important, because it reports significantly increased risks of non-Hodgkin's lymphoma for persons occupationally exposed to organic solvents, with evidence of a dose-response relationship, and because the study reports significantly increased risks of non-Hodgkin's lymphoma in workers employed in several occupations typically involving exposure to benzene.

In 2003, Chinese researchers reported the results of a case-control study which assessed the relationship between lymphoma and environmental factors in the Sichuan province of China. Xu, A., et al., ["A case-control study for assessing the relation between the incidence of malignant lymphomas and environmental factors in Sichuan province"], Zhonghua Liu Xing Bing Xue Za Zhi. 24(10):875-858 (2003). This was a hospital-based case-control study of 150 cases of malignant lymphoma and 300 controls, using logistic regression analysis. Adjust odds ratios (aOR) were calculated for exposure to various organic solvents. A highly statistically significant excess of malignant lymphoma was found for exposure to benzene (aOR = 2.78; p = 0.001). A significant excess of lymphoma was also found for exposure to paint. (aOR = 1.96, p = 0.023). This study is important because it reported a highly significant almost 3-fold increase in the risk of non-Hodgkin's lymphoma specifically for exposure to benzene. This finding was very robust, the odds of the finding being due to chance alone being only one in one thousand.

In 2001, French investigators reported the results of a case-control study for non-Hodgkin's lymphoma and occupational/environmental exposures. Fabbro-Perray, P., et al., "Environmental risk factors for non-Hodgkin's lymphoma: a population-based case-control study in Languedoc-Roussillon, France," Cancer Causes and Control 12:201-212 (2001). This case-control study collected all 455 cases of non-Hodgkin's lymphoma diagnosed between 1992 and 1995 in the Languedoc-Roussillon region of France. Unmatched controls were selected from electoral lists. Among individuals self-reporting exposure to benzene for at least one year, the odds ratio of having non-Hodgkin's lymphoma was significantly increased to 2.0 (95 % CI = 1.1 - 3.9), compared to those who did not self-report exposure. A dose-response relationship was evident for duration of exposure: for those never exposed to benzene the risk of non-Hodgkin's lymphoma was 1.0; for those exposed 15 years or less, the risk was increased to 1.7 (95% CI = 0.7 - 4.3); for those exposed more than 15 years, the risk was increased to 2.4 (95% CI = 0.9 - 5.9). A dose-response relationship was also apparent for cumulative exposure: for those never or only erratically exposed, the risk was 1.0; for those exposed 810 days or less, the risk was increased to 1.7 (95% CI = 0.4 - 6.8); for those exposed more than 810 days, the risk was significantly increased to 5.7 (95% CI = 1.4 - 23.2). Increased risks were also found for latency of more than 10 years from first exposure (OR = 2.1, 95% CI = 1.1 - 4.1). In the final multivariate model, the best fit with the data was found when exposure to benzene for more than 810 days was included with an odds ratio of non-Hodgkin's lymphoma of 4.6 (95% CI = 1.1-19.2). This study is important because it provides clear evidence of an increased risk of non-Hodgkin's lymphoma among patients occupationally exposed to benzene, with evidence of a dose-response relationship and a latent effect consistent with chemically-induced lymphoma.

These four studies provide strong epidemiologic evidence of a causal association between occupational exposure to aromatic solvents, especially benzene, and non-Hodgkin's lymphoma. In addition to these four recent case-control studies, four earlier case-control studies also evidenced increased risks of non-Hodgkin's lymphoma for persons occupationally exposed to benzene.

In 1997, researchers sponsored by the National Cancer Institute published the results of a case-control study of subtypes of non-Hodgkin's lymphoma in relation to occupational exposures. Tatham, L., et al., "Occupational Risk Factors for Subgroups of Non-Hodgkin's Lymphoma," Epidemiology 8:551-558 (1997). The three subtypes of non-Hodgkin's lymphoma studied were small cell diffuse lymphoma (185 cases), follicular lymphoma (268 cases) and large cell diffuse lymphoma (526 cases). The cases were matched with 1,659 controls for comparison. A significantly increased risk of small cell diffuse lymphoma was found for men occupationally exposed to solvents (OR = 1.60, 95% CI = 1.10 - 2.20). Nonsignificantly increased risks among men occupationally exposed to solvents were found for all lymphomas (OR = 1.10, 95% CI = 0.90 - 1.30). A duration of exposure-response trend was found for small cell diffuse lymphoma in men occupationally exposed to solvents: 9 years of exposure (OR = 1.50, 95% CI = 0.99 - 2.20), > 9 years of exposure (OR = 1.70, 95% CI = 1.10 - 2.60). This study is important because it shows that occupational exposure to organic solvents increases the risk of different subtypes of non-Hodgkin's lymphoma, especially small call diffuse lymphoma, and provides evidence of a dose-response relationship for solvent exposure and this subtype of non-Hodgkin's lymphoma.

In 1995, French investigators published the results of a hospital based case-control study assessing the association between hematological malignancies and occupational exposures to 320 compounds. Hours, M., et al., "Occupational Exposures and Haematologic Malignancies: A Case-Control Study in Lyon (France) [Expositions professionnelles et héemopathies malignes: une enquête cas-témoins réalisée à Lyon (France)," Rev Epidem. et Santé Publ. 43:231-241 (1995). Job histories were obtained by questionnaire for 118 cases (62 non-Hodgkin's lymphomas, 48 acute myeloid leukemias), and 118 controls with diseases other than cancer from the same hospital. Controls were matched for sex, age and nationality. Systematic coding of exposures based on a blind analysis of job histories was done by a team of experts in chemistry and occupational health. Mantel-Haenszel analysis was performed. Significantly increased odds ratios were observed for non-Hodgkin's lymphomas and exposure to "mineral oils," i.e., aromatic/aliphatic hydrocarbons (OR = 14.86, 95% CI = 2.76 - 80.0) and inks (OR = 2.47, 95% CI = 1.09 - 5.17). The category of compounds identified as "mineral oils" refers to aromatic/aliphatic hydrocarbons rather than to mineral oil, as is shown by the description of these compounds which references toluene, mineral spirits, and BTX (benzene, toluene, and xylene) containing more than 5% benzene. Id. at p. 235. The investigators concluded: "The association between mineral spirits with BTX and lymphoma is consistent with earlier reports: in effect, these compounds contain a nonnegligible percentage of benzene, a chemical which today we associate with lymphoma risk, as it has also been associated with leukemia." Id. at p. 239. This study is important because it reported an almost 15-fold statistically significant increase in non-Hodgkin's lymphoma among workers exposed to aromatic solvents with a substantial benzene content.

In 1994, Swedish researchers published the results of a case-control study of non-Hodgkin's lymphoma and some chemical exposures. Hardell, L., et al., "Exposure to Phenoxyacetic acids, Chlorophenols, or Organic Solvents in Relation to Histopathology, Stage, and Anatomical Localization of Non-Hodgkin's Lymphoma," Cancer Research. 54: 2386-2389 (1994). 105 men between the ages of 25 and 85 admitted to the Department of Oncology at the University Hospital in Umea, Sweden were compared to 355 individuals matched from the National Population Registry by age, sex, place of residence, and vital status. A statistically significant 28-fold excess of non-Hodgkin's lymphoma was found in patients who had been exposed to benzene than individuals without the disease. (OR = 28; 95% CI = 1.8 - 730). Development of non-Hodgkin's lymphoma was also significantly associated with exposure to degreasers (OR = 11; 95% CI = 2.9 - 72) and all organic solvents (OR = 2.4; 95% CI = 1.4 - 3.9) . This study is important because it reported an almost 30-fold increased risk of non-Hodgkin's lymphoma among persons occupationally exposed to benzene, a much greater risk than the 2.4-fold increased risk of non-Hodgkin's lymphoma from all organic solvents.

In 1989, Swedish investigators published the results of an interesting case-control study evaluating chromosome abnormalities in non-Hodgkin's lymphoma patients with exposure to organic solvents. Brandt, L., et al., "Relation Between Occupational Exposure to Organic Solvents and Chromosome Aberrations in Non-Hodgkin's Lymphoma," European Journal of Haematology 42:298-302 (1989). Chromosome analysis of lymphoma cells was performed in 54 untreated patients with non-Hodgkin's lymphoma. The patients were categorized as exposed (10 patients who had a history of daily occupational handling of organic solvents for at least one year) and unexposed (44 patients who had never or only briefly worked with solvents). The patients were assigned to three categories: patients with 0-4, 5-9, 94 10 cytogenetic events producing clonal aberrations of the lymphoma cells. The proportions of exposed patients in these categories were 2/26 (8%), 5/20 (25%) and 3/8 (38%) respectively. As the number of cytogenetic events increased, there was an increasing probability of previous exposure to solvents. This relationship was statistically significant (p = 0.035; trend analysis). Five of seven exposed patients (71%) with intermediate or high-grade lymphomas displayed translocations involving the band 14q32. Such 14q+ markers were found in only 5 out of 28 unexposed patients (18%) with lymphomas of comparable malignancy grade (p = 0.01). Among unexposed patients with intermediate or high-grade lymphoma, the most common clonal aberration was 6q-, which occurred in 10 out or 28 patients (36%). This abnormality was not observed in the exposed patients with lymphomas of corresponding malignancy grades (p = 0.08). The authors concluded that the number of clonal chromosomal aberrations is especially large in non-Hodgkin's lymphoma patients with a history of occupational exposure to organic solvents, and that such exposure is likely associated with cytogenetic changes of chromosome 14. This study is important because it shows that intermediate or high-grade non-Hodgkin's lymphoma patients with an occupational history of organic solvent exposure have significantly greater risks of developing translocations involving chromosome 14q23, a specific chromosome abnormality which has been shown to be caused by exposure to benzene and its metabolite, hydroquinone, by researchers in my laboratory.

Many other case-control studies have reported positive associations for organic solvents generally and non-Hodgkin's lymhoma: Olsson, H., et al., "Supradiaphragmatic Presentation of Non-Hodgkin's Lymphoma in Men Occupationally Exposed to Organic Solvents," Acta Medica Scandia 210:415-418 (1981) [predominance of patients exposed to organic solvents with supra-diaphragmatic non-Hodgkin's lymphoma in stage I-II disease highly statistically significant (?2 =15.9, p = 0.0003)]; Hardell, L., et al., "Malignant Lymphoma and Exposure to Chemical Substances, Especially Organic Solvents, Chlorophenols, Phenoxy Acids," British Journal of Cancer 43:169-176 (1981) [risk for exposure to organic solvents was slightly increased among cases with low exposure, (RR = 1.2, 95% CI = 0.5 - 2.6), but significantly increased among those with high exposure (RR = 2.8, 95% CI = 1.6 - 4.8), with the greatest risk found in a subset of those exposed to styrene, chlorinated solvents and benzene (RR - 4.6, 95% CI = 1.9 - 11.4)]; Bernard, S.M., et al., "Aetiologic Factors in Lymphoid Malignancies: A Case-Control Epidemiological Study," Leukemia Research. 8(4):681-689 (1984) [men with non-Hodgkin's lymphoma had a nonsignificantly increased risk of 4.21 of working in petroleum industries]; Everett, G., et al., "Environmental Chemical Exposures as Risk Factors for Leukemia and Non-Hodgkin's Lymphoma," American Journal of Epidemiology 122(3):535-536 (1985) [increased risks of non-Hodgkin's lymphoma found for lacquers/varnishes (OR = 1.24, p<0.1), hydrocarbon coatings (OR = 1.67, p<0.1), hydrocarbon cleaners (OR=2.13, p<0.01), paint aerosols (OR=1.28, p<0.1), and gasoline as a cleaning agent (OR=1.29, p<0.05)]; Fonte, R., et al., "Occupational Exposure to Organic Solvents and Non-Hodgkin's Lymphoma," IRCS Medical Science 13(7):580-581 (1985) [9 of 22 NHL patients (40.9%) had been exposed to organic solvents, compared to 7 of 44 controls (15.9%), concluding that "the findings of this epidemiological survey show that occupational exposure to organic solvents is clearly a risk factor in the onset of NHL."]; Woods, J. S., et al., "Soft Tissue Sarcoma and Non-Hodgkin's Lymphoma in Relation to Phenoxyherbicide and Chlorinated Phenol Exposure in Western Washington," Journal of the National Cancer Institute 78(5):899-910 (1987) [statistically significant excess of non-Hodgkin's lymphoma found for occupational exposure to organic solvents (OR = 1.35, 95% CI = 1.06 - 1.7)]; Olsson, H., et al., "Risk of Non-Hodgkin's Lymphoma among Men Occupationally Exposed to Organic Solvents," Scandinavian Journal of Work and Environmental Health 14: 246-251 (1988) [risk of non-Hodgkin's lymphoma found to increase with duration of exposure to organic solvents; organic solvent exposure found to be an independent risk factor with an odds ratio of 2.0 which was statistically significant (95% CI 1.5-2.6)]; Persson, B., et al., "Malignant Lymphoma and Occupational Exposure: Part 2," in Hogstedt, C., et al., eds., Progress in Occupational Epidemiology Elsevier Science Publishers (1988) [borderline significantly increased risk of lymphomas for occupational solvent exposure (crude rate ratio = 2.0, logistic odds ratio = 1.6, 95% CI = 1.0 - 2.8), and significantly increased risk of non-Hodgkin's lymphoma from non-occupational solvent exposure (crude rate ratio = 3.6, logistic odds ratio = 6.2, 95% CI = 1.1 - 34)]; Persson, B., et al., "Malignant Lymphomas and Occupational Exposures," British Journal of Industrial Medicine 46:516-520 (1989) [crude rate ratios doubled for non-Hodgkin's lymphoma patients those exposed to solvents]; Franceschi, S., et al., "The Epidemiology of Non-Hodgkin's Lymphoma in the Northeast of Italy: A Hospital-Based Case-Control Study," Leukemia Research. 13(6): 465-472 (1989) [nonsignificantly increased risks of non-Hodgkin's lymphoma found for workers in the chemical industry (RR = 1.6, 95% CI = 0.9-3.0) and the petrochemical industry (RR = 1.8, 95% CI = 0.9 -3.8)]; Pasqualetti, P., et al., "Occupational Risk for Hematological Malignancies," American Journal of Hematology 38:147-149 (1991) [a highly significant doubling of hematolymphopoietic cancers found for aromatic hydrocarbons (OR = 2.15, 95% CI = 1.39 - 3.32, p < 0.001)]; Blair, A., et al., "Comments on Occupational and Environmental Factors in the Origin of Non-Hodgkin's Lymphoma," Cancer Research. 52(Suppl.1): 5501s-5502s (1992) [for higher intensity exposure men with non-Hodgkin's lymphoma had nonsignificantly increased odds ratios of 1.5 for benzene and 1.4 for other solvents; 1.9 for follicular lymphoma and 1.8 for diffuse lymphoma]; Blair, A., et al., "Evaluation of Risks for Non-Hodgkin's Lymphoma by Occupation and Industry Exposures From a Case Control Study," American Journal of Industrial Medicine 23:301-312 (1993) [likelihood of having non-Hodgkin's lymphoma and having been exposed to benzene increased with higher intensity benzene exposures]; Blair, A., et al., "Comments on Occupational and Environmental Factors in the Origin of Non-Hodgkin's Lymphoma," Cancer Research Suppl. 52:5501s-5502s (October 1, 1992) [risk of non-Hodgkin's lymphoma increased for benzene exposure (lower intensity: OR = 1.1, 95% CI = 0.8 - 1.4; higher intensity: OR = 1.5, 95% CI = 0.7 - 3.1), solvents other than benzene (lower intensity: OR = 1.1, 95% CI = 0.8 - 1.4; higher intensity: OR = 1.4, 95% CI = 0.8 - 2.5), and paints (lower intensity: OR = 1.1, 95% CI = 0.9 - 1.5, higher intensity: OR = 1.1, 95% CI = 0.5 - 2.6)]; Scherr, P.A., et al., "Non-Hodgkin's Lymphoma and Occupational Exposures," Cancer Research 52(suppl): 5503s-5009s (1992) [nonsignificantly increased risks of non-Hodgkin's lymphoma observed for several solvent-related occupations]; Persson, B., et al., "Some Occupational Exposures as Risk Factors for Malignant Lymphomas," Cancer 72(5):1773-1778 (1993) [increased risks of non-Hodgkin's lymphoma found for occupational solvent exposure (OR = 1.2) and non-occupational solvent exposure (OR = 3.4); risk was also increased comparing those with high versus low solvent exposure (OR = 1.7)]; Fagioli, F., et al., "Primary Gastric Lymphoma: Distribution and Clinical Relevance of Different Epidemiological Factors," Haematologica 79:213-217 (1994) [all patients without prior history of helicobacter pylori infection were exposed to either pesticides or organic solvents, a "particularly interesting observation"]; Massoudi, B. L., et al., "A Case-Control Study of Hematopoietic and Lymphoid Neoplasms: The Role of Work in the Chemical Industry," American Journal of Industrial Medicine 31:21-27 (1997) [statistically significant elevated odds ratio was found for chemical workers who died of non-Hodgkin's lymphoma and who were less than 65 years of age at death (OR = 3.11, p = 0.003); most statistically significant association seen in the combined non-Hodgkin's lymphoma, multiple myeloma, and lymphoid leukemia group, where those who died under age 65 were over three times as likely to have worked in the chemical industry (OR = 3.31, p = 0.001)]; Persson, B., et al., "Some Risk Factors for Non-Hodgkin's Lymphoma," International Journal of Occupational Medicine and Environmental Health 12(2): 135-142 (1999) [risk of non-Hodgkin's lymphoma increased for exposure to solvents (OR = 1.6, 95% CI = 1.0 - 2.5), white spirits (OR = 2.6, 95% CI = 1.3 - 4.7), thinner (OR = 1.9, 95% CI = 1.0 - 3.3), gasoline (OR = 1.9, 95% CI = 0.9 - 3.8), and aviation gasoline (OR = 3.5, 95% CI = 0.6 -17), but not specifically for benzene (OR = 0.8, 95% CI = 0.1 - 3.8)]; Mao, Y., et al., "Non-Hodgkin's Lymphoma and Occupational Exposure to Chemicals in Canada," Annals of Oncology 11(Suppl1): S69-S73 (2000) [odds ratios slightly but mostly nonsignificantly increased among males for benzene (OR = 1.2, 95% CI = 0.8 - 1.9); Rêgo, M.A.V., et al., "Non-Hodgkin's Lymphomas and Organic Solvents," Journal of Occupational and Environmental Medicine 44(9):874-881 (2002) [association between occupational exposure to organic solvents and non-Hodgkin's lymphoma was observed, OR = 1.67 (95% CI, 0.97 to 2.87), especially among individuals less than 64 years old, OR = 1.91 (95% CI, 0.99 to 3.67)]; Zheng, T., et al., "Occupation and Risk of Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia," Journal of Occupational and Environmental Medicine 44(5):469-474 (2002) [noting that several occupations with potential for exposure to solvents showed an increased risk of NHL, although insignificant, including publishing, painting, petroleum and coal production, petroleum refining, transportation services, gas production and distribution ...."]; Band, P. R., et al., "Identification of Occupational Cancer Risks in British Columbia: A Population-Based Case-Control Study of 769 Cases of Non-Hodgkin's Lymphoma Analyzed by Histopathology Subtypes," Journal of Occupational and Environmental Medicine 46(5):479-489 (2004) [concluding that "[o]ur study ... revealed significantly increased odds ratios for occupations and industries for which an association with exposure to various solvents have been suggested such as rail, air, and motor transport operating workers and service station attendants and workers in the printing, painting, dry cleaning, rubber, and construction trade industries."]; Fritschi, L., et al., "Risk of Non-Hodgkin Lymphoma Associated with Occupational Exposure to Solvents, Metals, Organic Dusts and PCBs (Australia)," Cancer Causes and Control 16:599-607 (2005) ["risk of NHL was increased by about 30% for exposure to any solvent with a dose response relationship"]

Union Oil Company of California (Unocal)

One of the most important epidemiologic studies of petroleum industry workers and hematolymphopoietic malignancies is a case-control study of the Unocal cohort conducted by researchers at the University of Alabama School of Public Health. Delzell, E., et al., "A Case-Control Study of Leukemia, NonHodgkin's Lymphoma and Multiple Myeloma Among Employees of Union Oil Company of California" (September 8, 1992). Although this study reported significantly increased risks of non-Hodgkin's lymphoma among benzene-exposed petroleum industry workers, it curiously has never been published. In this study, the investigators noted that "there have been 15 major follow-up studies of petroleum industry workers, including over 190,000 subjects" and that "most of these investigations found a slightly to moderately elevated standardized mortality ratio (SMR) for one or more of the LHC [lymphohematopoietic cancer] categories." The purpose of the study was "to evaluate possible associations between the work history of active and retired Unocal employees and the occurrence of LHC, including leukemia, NHL [non-Hodgkin's lymphoma] and multiple myeloma." The investigators employed a case-control study design. The cohort comprised all men who worked for Unocal for at least one year during the period 1976-1990 or who were retired and still living at any time during 1976-1990. The cases were Unocal employees who died of leukemia, non-Hodgkin's lymphoma or multiple myeloma and who had a record in a corporate mortality file containing death certificate information on persons who died while actively employed or while receiving retirement benefits.

There were 69 cases of leukemia, 42 cases of non-Hodgkin's lymphoma (ICD 200, 202), and 21 cases of multiple myeloma. Four controls from the cohort were selected for each case. Mortality from all types of hematolymphopoietic maligancies was increased in the cohort. A statistically significant excess of non-Hodgkin's lymphoma was found among the oil and gas division workers (RR = 2.4, 95% CI = 1.2-4.9, p value for trend = 0.005), with the increased risk being most pronounced among men who started worked in the division in 1935-1954 (RR = 3.8, 95% CI = 1.5 - 9.5). The relative risk was larger for production-related than nonproduction-related activities in this division. (RR = 2.6 and RR = 1.6, respectively). Analysis by job group indicated an increased risk among production workers (nonexempt, RR = 1.7; exempt, RR = 2.2), with a suggestion of a positive trend for both groups. Evaluation of job groups within divisions yielded a RR of 4.8 (95% CI = 2.0-11) for Oil and Gas workers, compared with subjects never employed in the Oil and Gas division. Marketing division distribution plant and warehouse workers, compared with subjects never in the marketing division, had a RR of 3.0 (95% CI = 0.96 - 9.3). Risk of non-Hodgkin's lymphoma was also increased among distribution/ warehouse workers (nonexempt: RR = 2.0, 95% CI = 0.74 -5.5; exempt: RR = 2.6, 95% CI = 0.57-12), and laboratory workers (RR = 3.0, 95% CI = 0.67-13). The investigators concluded: "The results of this investigation indicate a positive association between employment in the Oil and Gas division and myelogenous leukemia, NHL and multiple myeloma. For each cancer, the observed association is moderate in strength, and there is some evidence of a trend of increasing RRs with increasing duration of employment." The investigators also concluded that "these associations with Oil and Gas division work are unlikely to be due to chance or to bias." It is interesting that this study has not been published, because it presents data which strongly supports benzene induction of non-Hodgkin's lymphoma as well as other hematologic malignancies. That this study has not been published raises a serious issue of non-publication bias, i.e., that the petroleum industry may not be publishing epidemiologic studies that report positive findings for hematolymphopoietic cancers, so that the published literature would not suggest a causal association when one actually exists.

Cohort studies of workers from other oil companies have also reported increased risks of non-Hodgkin's lymphoma among refinery workers.

Shell Oil Company

Marsh, G.M., et al., "Mortality Patterns Among Petroleum Refinery and Chemical Plant Workers," American Journal of Industrial Medicine 19:29-42 (1991). Among refinery workers, mortality due to all lymphopoietic tissue malignancies and lymphosarcoma had a highly significant upward trend associated with increased duration of employment (Trend test p-value = 0.004). Mortality due to lymphosarcoma and reticulosarcoma among those employed 30+ years was significantly increased more than eight-fold (SMR = 816, p < 0.01).

Tsai, S.P., et al., "A Long Term Follow-up Mortality Study of Petroleum Refinery and Chemical Plant Employees," (Sept. 6, 1994) (unpublished). This study updated the Marsh study by extending the vital status follow-up through 1989 and by expanding the cohort to include employees hired after 1972. The Standardized Mortality Ratio (SMR) for lymphosarcoma and reticulosarcoma among the refinery workers was 169.5 (95% CI = 77-322). As in the prior study, for both refinery and chemical plant employees, the mortality rate due to cancers of all lymphopoietic tissue increased with increasing duration of employment. This was also evident for lympho-reticulosarcoma in refinery employees (Trend Test p-value = 0.002). A significant excess of mortality from lympho-reticulosarcoma was found among those workers employed more than 30 years (SMR = 675.1, 95% CI = 248-1469).

Exxon

Shallenberger, L.G., et al., "An Updated Mortality Study of Workers in Three Major United States Refineries and Chemical Plants," British Journal of Industrial Medicine 49: 345-354 (1992). Employees at all three facilities had nonsignificant excesses of lympho/reticulosarcoma deaths, the largest excess occurring at the Baton Rouge facility (SMR=156); the total cohort had a Standardized Mortality Ratio (SMR) of 129 for these malignancies.

Lewis, R. J., et al., "Mortality Among Three Refinery/Petrochemical Plant Cohorts: I. 1970 to 1982 Active/Terminated Workers," Journal of Occupational and Environmental Medicine 42(7):721-729 (2000). Standardized Mortality Ratios (SMRs) for lymphosarcoma/reticulosarcoma, as well as cancers of other lymphopoietic tissues were nonsignificantly elevated (SMR = 114 and 110 respectively). A statistically significant 3.5 fold excess of chronic lymphocytic leukemia was also found.

Mobil Oil Company

Huebner, W.W., et al., "Mortality Updates (1970-1997) of Two Refinery/Petrochemical Plant Cohorts at Baton Rouge, Louisiana, and Baytown, Texas," Journal of Occupational and Environmental Medicine 46(12):1229-1245 (2004). Standardized Mortality Ratios (SMRs) were calculated for 1970-1997 based on death rates in the respective states. SMRs were near or below unity for most causes of death, but were increased at Baton Rouge for chronic lymphocytic leukemia (SMR= 1.58, 95% CI = 1.17-2.08) and non-Hodgkin's lymphoma (SMR = 1.47, 95% CI = 0.98-2.11).

Morgan, R. W., and Wong, O., An Epidemiologic Analysis of the Mortality Experience of Mobil Oil Corporation Employees at the Beaumont, Texas, Refinery (April 10, 1984) (unpublished). Mortality from hematolymphopoietic cancer was increased: 47 deaths were observed, with only 31.89 expected, yielding a SMR of 147.4 which was statistically significant. SMRs were increased for all types of hematopoietic and lymphatic cancers except Hodgkin's disease: lymphosarcoma and retibulosarcoma (SMR = 146.8), leukemia (SMR = 172.8), cancer of other lymphatic tissues (SMR = 157.6). An increasing trend in mortality was detected for lymphatic and hematopoietic cancer by latency. The SMR for those with 40+ years of latency (SMR = 189.9, p < 0.05) was more than 2.5 times that for those with less than 20 years of latency.

Raabe, G.K., et al., "An Updated Mortality Study of Workers at Petroleum Refinery in Beaumont, Texas," American Journal of Industrial Medicine 33:61-81 (1998). Despite a significant decreased mortality of the cohort, there was a significant 58% excess in mortality due to other lymphatic tissue cancers. Among all male employees, mortality due to lymphosarcoma and reticulosarcoma peaked at an SMR of 142 among men whose length of employment was 10-29 years. Mortality due to other lymphatic tissue cancers, however, was highest among men employed for less than ten years where two-fold excess mortality was seen, and decreased with duration of employment while remaining elevated compared to the US general population. The same trend was seen for non-Hodgkin's lymphoma among maintenance craftworkers. Mortality due to other lymphatic tissue cancers was significantly elevated to an SMR of 233, and the mortality risks were higher among men employed in 1950 or later than among men employed before 1950.

Collingwood, K.W., et al., "An Updated Cohort Mortality Study of Workers at a Northeastern United States Petroleum Refinery," International Archives of Occupational and Environmental Health 68: 277-288 (1996). A SMR of 156 was observed for other lymphatic tissue cancers. For all cell types of non-Hodgkin's lymphoma, the SMR was increased in male workers. (SMR = 132; 95% CI = 74-217). Mortality due to other lymphatic tissue cancers increased significantly with duration of employment, reaching a statistically significant doubling of risk among those employed for more than 30 years (SMR = 208, 95% CI = 104-371).

Chevron

Morgan, R. W., et al., (Environmental Health Associates, Inc.), Cause-Specific Mortality Among Employees at the Chevron Richmond and El Segundo Refineries (December 27, 1983) [unpublished]. In contrast to a very low cancer mortality, lymphosarcoma and reticulosarcoma were increased (SMR = 126.6, 95% CI = 73.6 - 202.6), as were other lymphatic tissue cancers (SMR = 141.6, 95% CI = 86.4 - 218.9). The excess of these cancers came from the Richmond refinery, which had excess lymphosarcoma and reticulosarcoma (SMR = 151.3, 95% CI = 80.5 - 258.6) and other lymphatic tissue cancer (SMR = 167.0, 95% CI = 93.3 - 275.6). Excess lymphopoietic malignancy was found at both refineries among laboratory workers (lymphosarcoma and reticulosarcoma SMR = 248.6, other lymphatic tissue cancer SMR = 357.4); maintenance workers (lymphosarcoma and reticulosarcoma SMR = 129.2, other lymphatic tissue cancer SMR = 133.7); and operators (lymphosarcoma and reticulosarcoma SMR = 164.5, other lymphatic tissue cancer SMR = 151.5). Risk was increased for latency of 10-19 years (lymphosarcoma and reticulosarcoma SMR = 180.7; other lymphatic tissue cancer SMR = 263.3), and > 20 years (lymphosarcoma and reticulosarcoma SMR = 128.7, other lymphatic tissue cancer SMR = 121.9).

Bailey, W. J., Case Review of Lymphatic Cancer Deaths at the Chevron USA Richmond and El Segundo Refineries (October 5, 1984). Dr. Bailey found that all but one of the lymphatic death cases were of workers hired before 1948, when benzene exposure was higher at the refineries. The job titles of the workers who died from lymphopoietic tissue cancers included pipefitter, maintenance, operator, cracking, machinist, cleaner, gauger-pumper, mechanic, and laboratory worker - all jobs which entail exposure to benzene.

Wong, O., et al., "An Epidemiological Study of Petroleum Refinery Employees," British Journal of Industrial Medicine. 43:6-17 (1986). In the total cohort, mortality due to lymphosarcoma and reticulosarcoma, and other lymphatic tissue cancers was nonsignificantly increased by 27% and 42%, respectively (SMR = 126.6 and 141.6). Employees in the laboratory, maintenance, and operating all experienced nonsignificantly elevated standard mortality ratios for lymphosarcoma and reticulosarcoma, and other lymphatic tissue cancers. The highest rates of lymphosarcoma and reticulosarcoma mortality were seen after a 10-19 year latency between initial exposure and death, with a SMR of 180.7. Mortality due to lymphosarcoma and reticulosarcoma increased with duration of employment; there were no deaths among those employed for less than five years, and the highest rates were seen among those employed for more than 15 years. Most deaths due to these cancers occurred in individuals first employed in 1948 or earlier, and all leukemia deaths occurred among those employed during this time period.

Dagg, T.G., et al., "An Updated Cause Specific Mortality Study of Petroleum Refinery Workers," British Journal of Industrial Medicine 49:203-212. (1992). Among the men in the entire cohort, the standardized mortality ratios were slightly elevated for lymphosarcoma and reticulosarcoma, and other lymphatic tissue cancers, though there was again a deficit in deaths due to all causes. At the Richmond refinery, mortality due to lymphosarcoma and reticulosarcoma were elevated among men employed for more than 15 years, and peaked among men 10-19 years since first hire. The data showed a nonsignificant duration-response relationship for years of employment greater than 10 years: 10-19 years: SMR = 41; 20-29 years: SMR = 140; 30 years: SMR = 226. Mortality due to other lymphatic tissue cancers was also elevated for all durations of employment at the Richmond refinery. The trends were less clear among workers at the El Segundo refinery due to the small number of cases, but the excess mortality due to lymphosarcoma and reticulosarcoma was also observed among men 10-19 years since first hire. Using California as the reference population, there was no change in the standardized mortality ratios for lymphatic and hematopoietic system cancers.

Texaco

Divine, B.J.,et al., "Texaco Mortality Study: II. Patterns of Mortality Among White Males by Specific Job Groups," American Journal of Industrial Medicine 10:371-381 (1986). The cohort was comprised of Texaco refinery, petrochemical, and research workers employed at least five years, and who worked between 1947 and 1977. The cohort members were followed through 1977, and job changes that occurred at least six months subsequent to the last job were coded. The mortality experience of four job groups presented in the paper (office, maintenance, operations, and laboratory) was compared to the US population. Among white males employed as operators, there was a slight excess in mortality from lymphosarcoma among those employed more than one year in the job, but not more than five years on the job. Mortality due to cancers of other lymphatic tissues (ICD7 Codes 202, 203, 205) was nonsignificantly elevated among operators and maintenance workers employed for more than one year (SMR = 132; 95% CI = 75-214) and for more than five years (SMR = 120; 95% CI = 66-223).

Chinese Chemical Worker Cohort Study

In 1997, researchers from the National Cancer Institute published an important study regarding benzene and hematologic malignancies among benzene-exposed workers in China. Hayes, R.B., et al., "Benzene and Dose-Related Incidence of Hematologic Neoplasms in China," Journal of the National Cancer Institute 89(14):1065-1071 (1997). Elevated risks for non-Hodgkin's lymphoma were seen among all occupations with exposure to benzene, including coatings (RR = 1.6), rubber (RR = 4.0), chemical (RR = 7.8), shoe (RR = 1.6), and other/mixed industries (RR = 4.1). The investigators evaluated dose-response trends based upon several dose metrics: average exposure, constant exposure, duration of exposure, and cumulative exposure. Significant dose-response trends were found for non-Hodgkin's lymphoma for all dose metrics except constant exposure. Based on average exposure, the relative risk of non-Hodgkin's lymphoma was as follows: < 10 ppm RR = 2.7 (95% CI = 0.7 - 10.6), 10-24 ppm RR = 1.7 (95% CI = 0.3 - 10.2), and 25 ppm RR = 4.7 (95% CI = 1.2 - 18.1) (p for trend = 0.04). Based on duration of exposure, the relative risk of non-Hodgkin's lymphoma was as follows: < 5 years RR = 0.7 (95% CI = 0.1 - 7.2), 5-9 years RR = 3.3 (95% CI = 0.7 - 14.7), and 10 years RR = 4.2 (95% CI = 1.1 - 15.9) (p for trend = 0.01). Based on cumulative exposure, the relative risk of non-Hodgkin's lymphoma was as follows: < 40 ppmy RR = 3.3 (95% CI = 0.8 - 13.1), 40-90 ppmy RR = 1.1 (95% CI = 0.1 - 11.1), and 100 ppmy RR = 3.5 (95% CI = 0.9 - 13.2) (p for trend = 0.02).

Conclusion

The foregoing case-control and cohort epidemiologic studies of refinery workers, as well as the NCI's study of benzene-exposed workers in China provide ample evidence that exposure to benzene causes non-Hodgkin's lymphoma.

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