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Gulf War and Health: Insecticides and Solvents, Volume 2
for AML and 4.7 (95% CI=0.6–34.2) for ALL; for shoemakers, the OR was 2.4 (95% CI=0.9–6.9) for AML and 1.3 (95% CI=0.2–10.2) for ALL.
Summary and Conclusion
On the basis of the consistently high relative risks in studies in which the exposure to benzene is well known, the committee decided that the evidence meets the requirement for a conclusion of causality between chronic exposure to benzene and acute leukemia. Furthermore, given the strong positive associations in the cohort studies of highly exposed subjects, it is likely that confounding and selection bias do not account for the findings. Experimental evidence supports a biologic mechanism that strengthens the conclusion. The details of that experimental evidence are provided in Chapter 4 and discussed below.
The metabolism of benzene, which occurs in the liver and to a smaller extent in the bone marrow, plays an important role in its toxicity. Benzene is metabolized to benzene oxide, an epoxide, through an oxidation reaction catalyzed primarily by cytochrome P450 2E1. Benzene oxide can be metabolized to various compounds, including o-benzoquinone and p-benzoquinone, which are thought to be the two main metabolites that mediate the toxicity of benzene. Data on laboratory animals show that benzene affects the bone marrow in a dose-dependent manner, causing anemia, leukopenia, and thrombocytopenia; continued exposure causes aplasia and pancytopenia (Bruckner and Warren, 2001). Benzene also has carcinogenic properties. In experimental animals, increases in incidence of malignant lymphoma and some solid tumors have been seen after exposure to high doses of benzene.
The committee concludes, from its assessment of the epidemiologic and experimental literature, that there is sufficient evidence of a causal relationship between chronic exposure to benzene and acute leukemia.
For exposure to unspecified mixtures of organic solvents, the studies were virtually all positive, including several that were statistical strong. One study provided evidence of an exposure-response relationship in terms of both increasing levels and increasing duration of exposure. Table 6.41 identifies all the studies reviewed by the committee. Unless indicated in the table, the study populations include both men and women.
The committee concludes, from its assessment of the epidemiologic literature, that there is sufficient evidence of an association between chronic exposure to unspecified mixtures of organic solvents and acute leukemia.
TABLE 6.41 Selected Epidemiologic Studies—Acute Leukemia and Exposure to Organic Solvents
Study Population and Cancer Type
Estimated Relative Risk (95% CI)
Ireland et al., 1997
Male Monsanto Company production workers in Sauget, Illinois-ANLL