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Benzene and Myelodysplatic Syndrome (MDS)

Introduction

Myelodysplastic Syndromes (MDS) are clonal diseases of stem cells characterized by single or multilinease cytopenia and various bone marrow abnormalities. More information on Myelodysplastic Syndrome >>

Case Reports and Case Series

In 1979, Belgian researchers published a report of two cases of preleukmia in benzene-exposed workers. One of the patients was a 25-year-old draftsman who used gasoline containing 2.2% benzene for about 4 years to clean metal sheets. This patient had a familial translocation t(3;16)(q11,p11). The other patient was a 67-year-old retired carpenter who had used benzene-containing glues for many years and who had a monosomy 7 chromosomal abnormality. Van den Berghe, H., et al., "Chromosome Analysis in Two Unusual Malignant Blood Disorders Presumably Induced by Benzene," Blood 53(4):558-566 (1979).

In 1982 Turkish researchers published a series of eight benzene-exposed shoemakers with neurological abnormalities. Six of the patients were diagnosed with aplastic anemia and two were diagnosed with "preleukemia," i.e., MDS. Baslo, A., et al., "Neurological Abnormalities in Chronic Benzene Poisoning: A Study of Six Patients with Aplastic Anemia and Two with Preleukemia," Environ. Res. 27:457-465 (1982).

In 1989, European researchers conducted clinical, cytomorphologic, and cytogenetic investigations in a series of 78 secondary MDS and ANLL. Of the 78 cases, all but 3 were cases of therapy-related MDS and ANLL. Of the 3 occupational cases, all developed MDS. Two had occupational exposure to benzene and progressed to ANLL; the third worked in the leather industry and may have had benzene exposure as well. Iurlo, A., "Cytogenetic and Clinical Investigations in 76 Cases with Therapy-related Leukemia and Myelodysplastic Syndrome," Cancer Genet. Cytogenet. 43:227-241 (1988).

In 1990, Italian researchers reported the results of a survey of cases of leukemia and myelodysplastic disorders exposed to organic solvents. Of 57 patients identified, 22 had Acute Nonlymphocytic Leukemia (ANLL), 11 had a myelodysplastic disorder, and the remainder had other hematologic diseases. All the patients were interviewed to identify potential exposure to organic solvents. Cytogenetic analyses were performed in 40 of the 57 patients. Unlike previous investigations, no association was found between the occurrence of chromosomal abnormalities and exposure to organic solvents. However, a strong association between solvent exposure and myelodysplastic disorders (4 certainly exposed and 1 possibly exposed out of 11 patients). Vineis, P., et al., "Cytogenetics and Occupational Exposure to Solvents: A Pilot Study on Leukemias and Myelodysplastic Disorders," Tumori 76:350-352 (1990). Extending the period of the study to include 79 patients, the same investigators collected 15 cases of MDS, of which 5 were certainly exposed to organic solvents and 3 were possibly exposed. The proportion of exposed subjects among those affected by MDS exceeded by far the proportion expected in the same age group. Vineis, P., et al., "Solvent Exposure and Myelodysplastic Syndrome," Scand. J. Work Envioin. Health 16:444-445 (1990).

In 1992, Japanese physicians reported a case of MDS in a worker with long-term exposure to organic solvents. A 64-year-old painter with a 40-year history of exposure to organic solvents presented in November 1990 with a 3-month history of fatigue and pain of the lower extremities. The hemogram showed pancytopenia and chromosomal analysis of bone narrow cells revealed a t(3;21)(q26.2, q22.1) chromosome translocation. Based on these findings a diagnosis of Refractory Anemia with Excess Blasts (RAEB), a type of MDS, was made. He was treatment with vitamin therapy, rather than cytotoxic agents. He remained in remission until September 1991, when balst cells appeared in the peripheral blood again. A bone marrow aspiration performed in February 1992 showed hyperceullarity with 58.4% myeloblasts and monoblasts, establishing a diagnosis of acute myelomonocytic leukemia. The physicians concluded that mutagens in the organic solvents may have played a role in causing the translocation between 3q26 and 21a22 and subsequent leukemogenesis. Tasaka, T., et al., "Translocation (3;21)(q26.2, q22.1) Found in a Patient with Myeldosyplastic Syndrome and Long-Term Exposure to Organic Solvents," Brit. J. Haematol. 28:473-474 (1992).

In 1992, researchers from Heinrich Heine University in Dusseldorf reviewed the histories of 584 cases of MDS. Thirty-one patients (5.3%) were determined to have secondary MDS because of previous treatment with cytotoxic chemotherapy and/or irradiation for a variety of malignancies. Twelve patients were identified with substantial occupational exposure to organic solvents. Aul, C., et al., "Age-related Incidence and Other Epidemiological Aspects of Myelodysplastic Syndromes," Brit. J. Haematol. 82:358-367 (1992).

In 1999, Korean researchers reported a case of MDS in 37-year-old man with a history of exposure to benzene for one year prior to admission. The patient was diagnosed with refractory anemia with excess blasts (a type of MDS) which transformed into acute myelomonocytic leukemia with eosinophilia with a der (1;7)(q10:p10) chromosomal translocation abnormality. Kim, S-H., et al., "Myelodysplastic Syndrome that Progressed to Acute Myelomonocytic Leukemia with Eosinophilia Showing Peculiar Chromosomal Abnormality," J. Korean Med. Sci. 14:448-450 (1999).

In 2001, Taiwanese researchers published a case report of a petrochemical worker with benzene-induced myelodysplastic syndrome. The patient was a 45-year-old man who had started working at a petrochemical plant in 1977. The plant used benzene as a raw material for the production of caprolactam, which is used in the manufacture of nylon and plastic products. The man's job was adding benzene into a reactive kiln. Routine annual medical examinations showed that the patient had anemia, leukocytopenia, and thrombocytopenia since May 1994. In 1996 pathological examination of a bone marrow aspiration showed myelodysplastic syndrome. Chen, Y-H., et al., "Benzene-Induced Myelodysplastic Syndrome," J. Am. Board Fam. Pract. 14(1):71-74 (2001).

In 2003, Chinese researchers published a series of five cases of MDS or AML with t(1;7) . Of the five patients, three had substantial occupational exposure to benzene. Of the three benzene-exposed patients, two were diagnosed with refractory anemia (a type of MDS) and one with AML. The investigators concluded that exposure to benzene may be the cause for Chinese MDS and AML patients with the t(1;7) translocation. Shen, Y., et al., "Clinical, Cytogenetic and Dual-Color FISH Studies on Five Cases of Myelodysplastic Syndrome or Acute Myeloid Leukemia Patients with 1;7 Translocation," Chinese Med. J. 116(2):231-234 (2003).

Case Control Studies

In 1989, researchers from the University of Wales published the results of a case-control study of the occupational and environmental exposures of patients with myelodysplasia. 63 preleukemia cases (39 males and 24 females) diagnosed during the study period, for which an equal number of controls were selected. There was a highly statistically significant difference in the numbers of cases and controls who reported exposure to petrol/diesel liquids (29 cases, 14 controls, p < 0.01). Farrow, A., et al., Myelodysplasia, Chemical Exposure and Other Environmental Studies.

In 1991 researchers from Texas studied a subset of patients with Acute Nonlymphocytic Leukemia (ANLL) who had evidence of MDS, low infiltrate leukemia, or other preleukemic conditions to determine whether MDS might act as a marker for environmentally caused-ANLL. In 270 ANLL patients, 46 had a preleukemic phase. Increased odds ratios adjusted for logistic regression for a preleukemic phase were found for ANLL patients who hobbies with potential for chemical exposure (OR = 4.8, 95% CI = 1.7 - 13.5), an occupation involving exposure at time of diagnosis (OR = 2.2, 95% CI = 0.5 - 9.9), prior chemotherapy (OR = 3.1, 95% CI = 0.5 - 21.6), and exposure to pesticides (OR = 20.4, 95% CI = 3.1 - 132.4). Crane, M.M., et al., "Exposure Histories in Acute Nonlymphocytic Leukemia Patients With a Prior Preleukemic Condition," Cancer 67:2211-2214 (1991).

In 1992 Italian researchers published the results of a case-control study of 70 AML patients, 30 of whom were occupationally exposed to pesticides (21 cases) or to organic solvents (9 cases). Cytologically, trilineage myelodysplasia was observed in 21 exposed patients, whereas morphologic aberrations of the non-blast cell population were confined to a minority of cells in most patients non-exposed. Cuneo, A., et al., "Morphologic, Immunologic and Cytogenetic Studies in Acute Myeloid Leukemia Following Occupational Exposure to Pesticides and Organic Solvents," Leukemia Research 16(8):789-796 (1992).

In 1994 the Italian Leukemia Study Group published the results of a case-control study of firsk factors for leukemia and pre-leukemic conditions. The cases comprised 252 patients with Acute Myeloid Leukemia (AML), 100 patients with Acute Lymphocytic Leukemia (ALL), 111 patients with refractory anemia with excess blasts (RAEB, a type of MDS), and 1,161 controls. Risks of developing RAEB was increased among shoemakers (OR = 4.3, 95% CI = 0.9 - 21.1) and painters (OR = 5.4, 95% CI = 0.5 - 61.0), occupations long associated with exposure to benzene . Mele, A., et al., "Hair Dye Use and Other Risk Factors for Leukemia and Pre-leukemia: A Case-Control Study," Amer. J. Epidemiol. 139(6):609-619 (1994).

In 1995 researchers from the University of Wales published the results of a case-control study of MDS patients and lifetime exposure through occupation, environment or hobby. Exposure histories of 400 individually matched pairs were compared. The authors concluded: "The present study suggests that both organic chemicals as a group and halogenated organics as a group may be associated with myelodysplastia, although the odds ratio for no individual chemical was high or statistically significant (at p < 0.05). Chemicals implicated include aromatic, heterocyclic and aliphatic organics, the benzene groups with nitrated, methylated carboxyl and hydrox side-chains as well as heterocyclic nigtogen, sulphur and oxygen compounds." West, R.R., et al., "Occupational and Environmental Exposures and Myelodysplasia: A Case-Control Study," Leukemia Research 19(2):127-139 (1995).

In 1995 French researchers published the results of a case-control study of occupational and environmental factors in MDS. The cases were 100 patients diagnosed with MDS at a hospital who did not have prior antineoplastic agent therapy. The cases were matched for age and sex with an equal number of controls. Increased risks were found for exposure to exhaust gases (OR = 2.19, 95% CI = 0.95 - 5.06). The number of cases exposed to petrol and diesel fumes or liquids was equivalent, but the mean exposure index was significantly more elevated in MDS cases (p = 0.03). Nisse, C., et al., "Exposure to Occupational and Environmental Factors in Myelodysplastic Syndromes: Preliminary Results of a Case-Control Study," Leukemia 9(4):693-699 (1995).

In 1995, researchers at the National Institute of Environmental Health Sciences published the results of a case-control study of 158 incident pathologically confirmed MDS patients age 25 and over and 556 randomly selected population controls. Patients were more often exposed to petroleum distillates (OR = 2.1, 95% CI = 1.2 - 3.4), including those of low aromatic content (OR = 2.6, 95% CI = 1.5-4.5), high aromatic content (OR = 2.2, 95% CI = 1.2 - 4.3), and pure aromatic content (OR = 2.5, 95% CI = 1.3 - 5.1). Notably, all patients with chromosome 7 deletions were exposed to petroleum distillates. Sandler, D. P., et al., "Exposure to Chemicals and Risk for Myelodysplastic Syndrome (MDS)," Amer. J. Epidemiol. 141(11 Supp.): Abstract No. 239 (1995).

In 1996 Japanese researchers published the results of a case-control study of MDS in Japan. 116 cases of MDS were diagnosed at 32 hospitals and age, sex, and hospital-matched controls were selected for each case. They reported a nonsignificant 1.5-fold increased risk of MDS among workers exposed to organic solvents. Ido, M., et al., "A Case-Control Study of Myelodysplastic Syndromes Among Japanese Men and Women," Leukemia Research 21(9):727-731 (1996).

In 1998 Italian researchers reported the results of a case-control study of 178 MDS patients and an equal number of controls matched for sex and age. They reported a robust 7-fold increased risk for MDS for exposure to solvents (OR = 7.11, 95% CI = 2.42 - 20.88, p = 0.00005). Rigolin, G. M., et al., "Exposure to Myelotoxic Agents and Myelodysplasia: Case-Control Study and Correlation with Clinicobiological Findings," Brit. J. Haematol. 103: 189-197 (1998).

In 1999, Japanese researchers published the results of a case-control study to evaluate associations between hair dye and organic solvents and MDS. Histories of 111 MDS cases and 830 population-based controls were compared. Associations with MDS were confirmed for hair dye use (OR = 1.00, 95% CI = 1.17 - 3.38) and exposure to organic solvents (OR = 1.99, 95% CI = 0.97 - 4.10). Nagata, C., et al., "Hair Dye Use and Occupational Exposure to Organic Solvents as Risk Factors for Myelodysplastic Syndrome," Leukemia Research 23:57-62 (1999).

In 2000, researchers from the University of Wales College of Medicine published another report of their case-control study, evaluating cytogenetic abnormalities. The odds ratios for all exposures combined were higher among cytogenetically abnormal (OR = 2.0, 95% CI = 0.8 - 5.9) than normal (OR = 1.0, 95% CI = 0.4 - 195.1) patients. For exposure to organic chemicals, the odds ratios for both cytogenetically abnormal patients (OR = 1.8, 95% CI = 0.6 - 6.0) and cytogenetically normal patients (OR = 1.3, 95% CI = 0.6 - 2.9) were marginally raised. West, R.R., et al., "Cytogenetic Abnormalities in the Myelodysplastic Syndromes and Occupational or Environmental Exposure," Blood 95:2093-2097 (2000).

In 2001, French investigators reported the results of a case-contol study to assess the relationship between occupational or environmental factors and MDS in 204 patients with MDS and an equal number of controls matched for age and sex. Increased risks of MDS were found for exposure to solvents (OR = 2.6, 95% CI = 1.6 - 5.4), petrol (OR = 2.5, 95% CI = 0.9 - 7.7), oil (OR - 4.2, 95% CI = 2.0 - 9.9), glue adhesives (OR = 2.8, 95% CI = 0.8 - 11.8), as well as other factors. Nisse, C., et al., "Occupational and Environmental Risk Factors of the Myelodysplastic Syndromes in the North of France," Brit. J. Haematol. 112:927-935 (2001).

Cohort Studies

In 1991 researchers at Shell Oil Company published results of a medical surveillance program for employees and retirees from the company's Deer Park, Illinois Petrochemical Complex. The program began in 1985 and medically monitored 2,086 current and retired employees. After four years of observation, the corporate researchers reported four cases of MDS in the cohort. The Standardized Incidence Ratio for MDS in the cohort was significantly increased more than four-fold (SIR = 4.6; 95% CI = 1.26 - 11.77). In the age group 50-59 the increase was 50-fold (SIR = 50; 95% CI = 1.27 - 278.5). Cowles, S. R., et al., "Medical Surveillance for Leukemia at a Petrochemical Manufacturing Complex: Four-Year Summary," J. Occup. Med. 33(7):808-812 (1991). In fact, the standardized incidence ratio for MDS was even higher, because there was a fifth case that the researchers did not count in the published article. Cowles, S. R., et al., "MDS During Medical Surveillance of a Refinary [sic] Population," Second Int'l Conf. Myelodysplastic Syndromes (Abstract No. B6, 1991) . A followup study reported another 4 cases of MDS in the cohort. Tsai, S.P., et al., "Medical Surveillance for Hematological Disorders Among Active and Retired Oil Refinery Workers,' J. Occup. Environ. Med. 40(5):475-480 (1998).

In 1994, researchers from the National Cancer Institute published the results of a followup study of a large cohort of 74,828 benzene-exposed workers and 35,805 non-exposed workers in China. In the follow-up study pathology reports, medical records, and histopathological material were reviewed for all patients with hematopoietic malignancies to ensure correct classification and to provide clinicopathologic descriptions. Eighty-two patients with hematopoietic neoplasms and related disorders were identified among benzene-exposed workers, including 7 cases of MDS. There were no MDS cases in the controls. Travis, L. B., et al., "Hematopoietic Malignancies and Related Disorders Among Benzene-Exposed Workers in China," Leukemia and Lymphoma 14:91-102 (1994). In a subsequent report, the investigators determined that the relative risk for MDS for benzene exposure in the study was infinity (RR = 8, 95% CI = 1.7 - 8). Yin, S-N., et al., "A Cohort Study of Cancer Among Benzene-Exposed Workers in China: Overall Results," Amer. J. Ind. Med. 29:227-235 (1996).

Conclusion

Based upon published case reports, case-control and cohort epidemiologic studies, there is ample evidence to conclude that exposure to organic solvents, especially benzene, causes myelodysplastic syndrome.

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