Chronic Myelogenous Leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate.  Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML is an acquired abnormality that derives from the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22).

CML is a rare form of leukemia. The incidence of CML in persons up to age 70 is approximately 2 cases per 100,000. The incidence increases to about 8-13 cases per 100,000 in persons aged 80 years and older. Since CML is rarer than the other major types of leukemia, epidemiologic studies have limited ability to evaluate causal factors of the disease. The disease is too rare to adequately study in cohort studies, so the available epidemiologic data is largely from case-control studies.

Epidemiologic Studies

In 1975, McMichael reported 8 cases of CML among rubber workers exposed to benzene.  McMichael, A. J., et al., “Solvent Exposure and Leukemia Among Rubber Workers: An Epidemiologic Study,” J. Occup. Med. 17(4):234-239 (1975).

In 1987, Wong reported the results of a cohort mortality study sponsored by the Chemical Manufacturers Association of chemical workers from 7 chemical plants. Of the 7 deaths from leukemia reported, none of the workers died of AML, but there were 2 deaths from CML, 2 from CLL, 1 from ALL and 1 each from lymphatic unspccified and acute unspecified leukemia.  Wong, O., “An Industry Wide Mortality Study of Chemical Workers Occupationally Exposed to Benzene: II. Dose Response Analyses,” Brit. J. Ind. Med. 44:382-395 (1987).

In 1987, Schwartz reported the results of a proportionate mortality study of mechanics and service station workers.  Among the 11 cases of leukemia, 1 auto mechanic and 1 service station worker had CML.  Schwartz, E., “Proportionate Mortality Ratio Analysis of Automobile Mechanics and Gasoline Service Station Workers in New Hampshire,” Amer. J. Ind. Med. 12:91-99 (1987).

In 1988, Linet reported the results of a linked-registry study which examined the leukemia incidence in Swedish men by industry and occupation.  33 cases of CML were found in motor mechanics – a statistically significant 50% increase (SIR = 1.5). Linet, M. S., et al., “Leukemias and Occupation in Sweden: A Registry-Based Analysis,” Amer. J. Ind. Med. 14:319-330 (1988).

In 1989, Yin reported the results of a cohort study of Chinese workers exposed to benzene. Of the 30 cases identified, one-sixth (5 workers) died of CML.  Yin, S.-N., et al., “A Retrospective Cohort Study of Leukemia and Other Cancers in Benzene Workers,” Environ. Health Perspect. 82:207-213 (1989).  Infante subsequently calculated that the Standardized Mortality Ratio (SMR) for CML in this study was 4.24 – a greater than 4-fold excess.  Infante, P. F., “Benzene and Leuekmia: Cell Types, Latency and Amount of Exposure Associated with Leukemia,” Advances Occup. Med. Rehab. 1(2):107-120 at p. 110 (1995).

In 1992, the Chinese Epidemiologic Study Group of Leukemia and Aplastic Anemia reported the results of a large population-based case control study which was conducted to evaluate various factors in the causation of leukemia and aplastic anemia.  The risk of developing CML from benzene exposure was 1.65, which was statistically significant. CESGLAA, “Risk Factors Analysis of Leukemia and Aplastic Anemia in China,” Acta Acadmiae Medicinae Sinicae 14(3):185-189 (1992).

In 1993, Rushton reported the results of an updated cohort mortality study of British refinery and distribution workers. Most types of leukemia were nonsignificantly increased, including CML: 5 cases of CML were observed when less than 4 were expected (SMR = 127, 95% CI = 41-296).  Rushton, L., “A 39-Year Follow-up of the U.K. Oil Refinery and Distribution Center Studies: Results for Kindey Cancer and Leukemia,” Env. Health Perspect. 101 (Suppl. 6):77-84 (1993).

In 1993, Sathiakumar reported the results of a case-control study of leukemia among employees of the Union Oil Company of California.  A total of 15 myelogenous leukemia cases were observed among workers in the Oil and Gas division.  Of these 10 had AML (OR = 3.0, 95% CI = 1.2 – 7.7) and 5 had CML (OR + 1.4, 95% CI = 0.40 – 5.0). Sathiakumar, N., et al., “A Case-Control Study of Leukemia Among Petroleum Workers” (Univ. of Alabama at Birmingham, 1993).

In 1994, researchers from the National Cancer Institute described 34 cases of benzene-induced hematologic diseases among workers exposed to benzene in China.  Of the leukemia cases, 9 were diagnosed with AML, 5 with acute unspecified leukemia, 5 with MDS, 1 with ALL and 4 were diagnosed with CML.  Travis, L. B., et al., “Hematopoietic Malignancies and Related Disorders Among Benzene-Exposed Workers in China,” Leukemia and Lymphoma 14:91-102 (1994).

In 1994, researchers from Mobil Oil Corporation reported the results of an update of a cohort mortality study of refinery workers at the company’s Torrance, California refinery. The only deaths from leukemia reported were 2 cases of CML (SMR = 370, 95% CI = 45-1336).  Milcarek, B. I., et al., “An Updated Cohort Mortality Study of White Male Workers at the Torrance, California Refinery, 1959-1987,” (Mobil Oil Corp. Nov. 1, 1994).

In 1994, Smith evaluated a cluster of 6 leukemia cases among rubber workers at a tire manufacturing plant, and determined that the relative risk of leukemia at the plant was at least 7.  The study is especially interesting, because of the 6 leukemia cases, 4 had CML.  Smith, A. H., et al., “Assessment of Cancer Clusters Using Limited Cohort Data with Spreadsheets: Application to a Leukemia Cluster Among Rubber Workers,” Amer. J. Ind. Med. 25:813-823 (1994).

In 1996, Yin reported the results of an expanded cohort study of Chinese workers exposed to benzene.  This large study reported increased relative risks of all categories of hematologic malignancies in the benzene-exposed workers except for multiple myeloma (which is very rare among the Chinese).  The relative risk for AML was 3.1 (95% CI = 1.2 – 10.7); the relative risk for CML was 2.6 (95% CI = 0.7 – 16.9).  Yin, S.-N., et al., “An Expanded Cohort Study of Cancer Among Benzene-Exposed Workers in China,” Environ. Health Perspect. 104 (Suppl. 6):1339-1341 (1996).

In 1997, Rushton reported the results of a case-control study of leukemias among British petroleum marketing and distribution workers. There were 11 cases of CML in the cohort. A greater than 3-fold nonsignificantly increased risk of CML was found for cumulative exposure to benzene between 0.60 and 1.64 ppmy (OR = 3.29; 95% CI = 0.40 – 27.08), and an almost 5-fold nonsignificantly increased risk of CML was found for cumulative exposure to benzene between 1.65 and 4.78 ppmy (OR = 4.83; 95% CI = 0.54 – 43.21).  Rushton, L., et al., “A Case-Control Study to Investigate the Risk of Leukaemia Associated with Exposure to Benzene in Petroleum Marketing and Distribution Workers in the United Kingdom,” Occup. Environ. Med. 54:152-166 (1997).

In 1999, Australian investigators reported that of 27 workers who were diagnosed with leukemia in the Australian refinery cohort, 4 had CML.  Bisby, J. A., et al., Health Watch: Tenth Report: 1998 (University of Melbourne, 1999).

In 1999, Swedish researchers reported the results of a registry-based study of cancer and occupation.  For CML an increased risk was observed among industrial spray painters, who are occupationally exposed to mixtures of organic solvents, which typically contain benzene.  Pollán, M., et al., Cancer and Occupation in Sweden 1971-1989 (Yrkesmedicin 1999).

In 2000, Hayes reported a nonsignificant 2.6-fold excess of CML in a large cohort of Chinese workers occupationally exposed to benzene. Hayes, R. B., et al., “Benzene and Lymphohematopoietic Malignancies in China,” J. Toxicol. Environ. Health Part A, 61:419-432 (2000).

In 2001, Bjork reported the results of a case-control study of 255 CML patients from southern Sweden to evaluate occupational, hobby, and lifestyle risks of the disease.  An effect was found for exposure to organic solvents of moderate or high intensity (OR = 3.4, 95% CI = 1.1 – 11) and for long duration (15-20 years) of exposure (OR = 2.1, 95% CI = 1.1 – 4.0).  The odds ratio for benzene exposure was nonsignificantly increased by 20%.  Bjork, J., et al., “Are Occupational, Hobby, or Lifestyle Exposures Associated with Philadelphia Chromosome Positive Chronic Myeloid Leukaemia?” Occup. Environ. Med. 58:722-727 (2001).

In 2002, Guénel reported a nonsignificantly increased risk of CML among electric utility workers exposed to benzene.  Guénel, P., et al., “Leukemia in Relation to Occupational Exposures to Benzene and Other Agents: A Case-Control Study Nested in a Cohort of Gas and Electric Utility Workers,” Amer. J. Ind. Med. 42:87-97 (2002).

In 2002, Nisse reported the results of a case-control study which investigated occupational and environmental risk factors for CML.  A highly significant statistical association for CML was found for exposure to solvents (p = 0.004).  Nisse, C., et al., “Occupational and Environmental Risk Factors of Chronic Myeloid Leukaemia,” Abstract No. 067, Epicoh 2002 Congress (2002).

In 2003, Adegoke reported the results of a population-based case-control study of 486 leukemia patients and 502 controls in Shanghai, in which odds ratios were determined for the association between occupational factors and risk of the major leukemia subtypes.  A statistically significant increased risk of 2.5 was found for those diagnosed with CML who had ever been exposed to benzene (95% CI = 1.3 – 4.9), which risk increased to 5.0 among those exposed to benzene for 15 years of more (95% CI = 1.8 – 13.9).  Adegoke, O. J., et al., “Occupational History and Exposure and the Risk of Adult Leukemia in Shanghai,” Ann. Epidemiol. 13:485-494 (2003).

In 2004, Spanish researchers published the results of an observational study in which they investigated environmental factors and karyotype in patients diagnosed with CML in Aragon, Spain.  Highly significant results were found for CML in relation to cigarette smoking, which may be attributed to benzene in cigarette smoke.  The investigators observed that all of the CML patients with histories of toxic exposure to benzene or benzene-containing products such as oil-based paints, petrochemical products, glue, solvents, and pesticides had the classic Philadelphia chromosome abnormality without other karyotypic abnormalities.  Recasens, V., et al., “CML and Environmental Factors Related to Complex Karyotypes,” Blood 104(11): Abstract No. 4654 (2004).

In 2007, Gazdek and others published the results of an epidemiologic study of lymphohematopoietic cancers in an oil exploitation and industrial area in Croatia.  The rate of CML in the combined region of Djurdjevac and Koprivnica was more than doubled (OR = 2.7, 95% CI = 1.41 – 5.05).  An even higher rate of CML was found in the pharmaceutical manufacturing area of Koprivnica alone (OR = 9.7, 95% CI = 2.38 – 39.78).  The authors concluded that the study showed the strongest association between residential oil-gas exploitation exposures and CML.  Gazdek, D., “Lymphohemato-poietic Malignancies and Oil Exploitation in Koprivnica-Krizevci County, Croatia,” Int. J. Occup. Env. Health 13:258-267 (2007).

Case Reports

In addition, several case reports and case series support a causal relationship between benzene and CML and hence the Philadelphia Chromosome abnormality.

The first case report of benzene-induced blood disease, published in 1897, may well have been a case of benzene-induced chronic myelogenous leukemia.  LeNoir, et al., “Sur un Cas de Purpura Attribué à l’Intoxication par le Benzène,” Bull. Mem. Soc. Med. Hôp. Paris 3(14):1251 (1897).

In 1937, Sabrazès reported a case of benzene-induced CML. Sabrazès, J., et al., “Leucémie myéloide chronique chez un Graisseur de Machines,” Gaz. Hebd. Sci. Med. 38:339 (1937); Sabrazès, J., et al., “Leucémies Benzoliques,” Gaz. Hebd. Sci. Ned. 58:387 (1937).

In 1939, Erf reported 9 cases of benzene poisoning, 1 of which died of CML.  Erf, L. A., et al., “The Hematological Effects of Benzene Poisoning,” J. Ind. Hyg. Toxicol. 21(8):421-435 (1939).

In 1942, Chevallier reported 2 cases of benzene-induced CML in a series of 3 cases.  Chevallier, P., et al., “Trois case d’Anémieleucose benzolique,” Sang 15:391-405 (1942).

In 1949, Van Schoenhaven reported a case of benzene-induced CML.  Van Schoonhaven van Buerden, A.J.R.E. “Benzolleucemie,” Nedl. Tijdschr. Genesk. 93:2384 (1949).

In 1950, Marchal reported 2 cases of benzene-induced leukemias with hemolytic anemia, 1 of which was a case of CML in a printer occupationally exposed to benzene for 12 years.  Marchal, G., et al., “L’Anémie Hémolytique dans les Leucémies,” Le Sang 21:254-261 (1950).

In 1950, Bernard reported a case of benzene-induced CML. Bernard, J., et al., “Les Leucoses benzéniques,” Proc. 3^rd. Internl Congr. Soc. Haematol. (Grune & Stratton, 1950).

In 1951, Bousser reported 3 cases of benzene-induced CML.  Bousser, J., et al., “A propos de trois cas de leucémie myéloide chronique provoqués par le benzol,” Arch. des Maladies Prof. de Med. du Trav. 12(4):399-404 (1951).

In 1960, Tolot, F., et al., “Une Observation de Leucose Myéloide due aux Hydrocarbures Benzèniques,” Arch. Mal. Prof. 22:159 (1960).

In 1963, Tareeff reported 5 cases of CML and 1 case of chronic erythroleukemia among 16 cases of benzene-induced leukemias. Tareeff, E. M., et al., “Benzene Leukemias,” Acta Union Internationalis Contra Cancrum 19:751-755 (1963).

In 1965, Browning summarized 61 cases of benzene-induced leukemia that had been reported in the literature.  Of these, about one-third (21) were CMLs – more than any other type of leukemia. Browning, E., Toxicity and Metabolism of Industrial Solvents, Table 4 at p. 51 (Elsevier 1965).

In 1967, Goguel reported 13 cases of benzene-induced CML among 50 cases.  Goguel, A., et al., “Benzene Leukemia in the Paris Area Between 1950 and 1965: Study of 50 Cases,” Nouv. Rev. Fr. D’Hemat. 7(4):465-480 (1967).

In 1970, Girard reported 4 cases of CML among 30 cases of benzene-induced leukemia.  Girard, R., et al., “La Frequence d’une Exposition Benzenique au Cours des Hemopathies Graves,” Nouvelle Rev. Fr. D’Hemat. 14(4):56-64 (1970).

In 1973, Liaudet reported a case of CML in a chemist who used benzene for 18 years.  Liaudet, J., et al., “Chronic Myeloid Leukemia in a Petroleum Chemist Aged 36 Who Handled Benzene Since He Was 18 Years Old,” J. Europeen de Toxicologie 4:309-313 (1973).

In 1976, Aksoy reported 1 case of CML in a study of 34 patients in Istanbul with benzene-induced leukemia.  Aksoy, M., et al., “Types of Leukemia in Chronic Benzene Poisoning: A Study in Thirty-Four Patients,” Acta Haemat. 55:65-72 (1976).

In 1979, Cao reported 1 case of CML among 3 cases of benzene-induced leukemia.  Cao, J.N., et al., “[Leukemia in benzene workers: report of 3 cases] Zhonghua Yu Fang Yi Xue Za Zhi 13(4):226-228 (1979).

In 1980, Aksoy reported that of 44 patients in Istanbul diagnosed with benzene poisoning from 1976 to 1979, 2 (4.5%) were diagnosed with CML.  Aksoy, M., “Malignancies Due to Occupational Exposure to Benzene,” Haematologica 65(3):370-373 (1980).

In 1990, Infante reported a case of benzene-induced CML among 3 mechanics in a municipal garage with benzene-induced leukemia from occupational exposure to gasoline.  Infante, P. F., et al., “Benzene in Petrol: A Continuing Hazard,” Lancet 336:814-815 (Sept. 29, 1990).

In 1996, Dean reported a case of benzene-induced CML in a submariner.  Dean, M.R., “Chronic Myeloid Leukaemia and Occupational Exposure to Benzene in a Royal Navy Submariner,” J. Roy. Nav. Med. Serv. 82:28-33 (1996).

In 1997, Kudla reported 2 cases of benzene-induced CML in printers who were exposed to benzene in inks and solvents.  Kudla, I., “Exposure to Benzene-Contaminated Toluene and Bone Marrow Disorders: A Retrospective Exposure Assessment,” Appl. Occup. Envion. Hyg. 12(1):11-14 (1997).

In 1998, Brenner reported a case of CML from dermal absorption of benzene as a contaminant in organic solvents.  Brenner, D., et al., “Skin Absorption of Benzene as a Contaminant in Other Solvents,” Eur. J. Oncol. 3(4):399-405 (1998).

In 2005, researchers with the Korean Occupational Safety and Health Agency reported 9 cases of benzene-induced hematologic diseases in Korean workers.  1 of these was a communications maintenance worker who developed CML after using benzene for 21 years.  Kang, S.K., et al., “Occupational exposure to benzene in South Korea,” Chem. Biol. Interact. 153-154:65-74 (2005).

Conclusion

The available epidemiologic studies and case reports are sufficient evidence that benzene causes Chronic Myelogenous Leukemia (CML).