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Benzene and Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) results from an acquired (not inherited) injury to the DNA of a single cell, a lymphocyte, in the bone marrow. This change in the cell’s DNA confers a growth and survival advantage on the cell, which becomes abnormal and malignant (leukemic). The result of this injury is the uncontrolled growth of lymphocytic cells in the marrow leading invariably to an increase in the number of lymphocytes in the blood. The leukemic cells that accumulate in the marrow in chronic lymphocytic leukemia impede normal blood cell production, but not as profoundly as in acute leukemia.

According to the National Center for Chronic Disease Prevention and Health Promotion of the Centers for Disease Control, the incidence of Chronic Lymphocytic Leukemia (CLL) in the United States is about 4 cases per 100,000 population.

Many epidemiologic studies have been conducted of benzene-exposed workforces. While the strongest causal association found in these studies is for benzene and Acute Myelogenous Leukemia (AML), a causal association has also been found for CLL based upon several studies.

In 1970, French investigators published the results of a case-control study in which they found 9 cases of CLL out of 33 benzene-leukemia cases (36.7%), which constituted a greater than four-fold excess of CLL which was statistically significant. Girard, R., et al., “La Frequence d’une Exposition Benzenique au Cours des Hemopathies Graves,” (The Frequency of Benzene Exposure in Severe Hematological Diseases) Nouvelle Rev. Fr. d’hemat.10(4):56-64 (1970).

In the early 1990s a large case-control study was undertaken by the Chinese Epidemiologic Study Group of Leukemia and Aplastic Anemia. In this study 1257 leukemia cases in China were each randomly matched with 2 healthy controls by age, sex and ethnicity. Exposures to x-rays, certain prescription drugs, insecticides, viral hepatitis, familial history of cancer, and benzene were studied in both populations. All four major types of leukemia were increased in cases exposed to benzene. Notably, the greatest risk (a greater than 3-fold increase in leukemia) was found for those cases exposed to benzene who had CLL. Importantly, this finding was statistically significant to a 95% confidence interval. Chinese Epidemiologic Study Group of Leukemia and Aplastic Anemia, “Risk Factors Analysis of Leukemia and Aplastic Anemia in China,” (Chinese), Acta Academiae Mediicinae Sinicae 14(3):185-189 (1992).

In 1989, researchers reported the results of a study investigating mortality from leukemia at a refinery in Illinois. They found significant excesses of lymphocytic leukemia which declined over time: 1950 through 1959 (SMR = 505, 95% CI = 164 to 1180); 1960 through 1969 (SMR = 282, 95% CI = 103 to 615). Wongsrichanalai, C., et al., “Mortality from Leukemia and Other Diseases Among Workers at a Petroleum Refinery,” J. Occup. Med. 31(2):106-111 (1989).

In 1997, British investigators published the results of a case-control study of leukemia in the British petroleum industry. They reported a statistically significant excess of CLL in workers with cumulative benzene exposure between 0.26 and 0.50 ppmy (OR = 10.57; 95% CI 1.27 to 87.92), and an even larger excess of CLL in workers with cumulative benzene exposure between 0.60 and 1.64 ppmy (OR = 11.21; 95% CI 1.20 to 104.4).  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. Envir. Med. 54:152-166 (1997).

In 1997, American researchers published a mortality study of Exxon petrochemical employees. They calculated a Standardized Mortality Ratio (SMR) of 1.81 for chronic lymphocytic leukemia, which was not quite statistically significant (95% CI, 0.90 to 3.24). Huebner, W., et al., “Mortality Experience of a Young Petrochemical Industry Cohort: 1979-1992 Follow-Up Study of US-Based Employees,” J. Occup. Environ. Med. 39(10):970-982 (1997).

In 2000, a further update of the Exxon petrochemical worker cohort was published. In this study, the same excess of CLL was found (SMR 181), but the excess was statistically significant (95% CI = 168 to 645). Lewis, R. J., et al., “Mortality Among Three Refinery/Petrochemical Plant Cohorts: I. 1970 to 1982 Active/ Terminated Workers,” J. Occup. Environ. Med. 42(7):721-729 (2000).

In 2001, Australian investigators published a case-control study of petroleum industry workers with leukemia. They found 11 CLL cases among 33 leukemia cases (33%), which constituted a greater than 7-fold significantly increased risk of CLL in workers with the highest benzene exposure. A dose-response relationship was also observed. Monash University, Lympho-haematopoietic Cancer and Exposure to Benzene in the Australian Petroleum Industry (June 2001).

These epidemiologic studies show that benzene can cause CLL as well as AML.  This conclusion is supported by numerous case reports of benzene-induced CLL.

In 1933, Falconer reported the first case of CLL due to benzene exposure. Falconer, E., “An Instance of Lymphatic Leukemia Following Benzol Poisoning,” Am. J. Med. Sci. 186:353-361 (1933).

In 1963, Tareeff described 16 Russian workers with benzene leukemia, of which 3 (18.7%) had CLL. Tareeff, E. M., “Benzene Leukemias,” Acta Unio Int. Contra Cancrum 19:751-755 (1963).

In 1965, Browning collected 6 cases from the literature, comprising 9.8% of the cases collected.  Browning, E., Toxicity and Metabolism of Industrial Solvents (1965).

In 1967, Goguel reported a series of benzene-leukemias in France of which 8 cases (18.2%) were CLL. Goguel, A., “Les Leucemies Benzeniques De La Region Parisienne Entre 1950 et 1965 (Etude De 50 Observations),” [Benzene Leukemia in the Paris Area Between 1950 and 1965 (Study of 50 Cases)], Nouv. Rev. Fr. d’hemat. 7(5):465-480 (1967).

In 1987, Aksoy described 3 of 58 workers with benzene-induced leukemia, of which 2 had CLL and 1 had HCL. Aksoy, M., “Chronic lymphoid leukaemia and hairy cell leukaemia due to chronic exposure to benzene: report of three cases,” Brit. J. Haematol. 66:209-211 (1987).

The above-described epidemiologic studies and case series together comprise a sufficient body of data to conclude that benzene causes Chronic Lymphocytic Leukemia (CLL).