Exposure to benzene at high doses is hematotoxic and can result in destruction of bone-marrow precursor cells and, in turn, in a decrease in white-cell, red-cell, and platelet counts (Goldstein, 1988). The hematotoxicity and carcinogenicity of benzene have been extensively reviewed (e.g., ATSDR, 1997; IARC, 1987), and a brief overview of the toxicologic information is provided in Chapter 4. The metabolism of benzene, which occurs in the liver and to a lesser 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. Cytochrome P450 2E11/6 also participates in benzene biotransformation. Benzene oxide can then 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 from laboratory animals and humans show that benzene affects the bone marrow in a dose-dependent manner, causing anemia, leukopenia, and thrombocytopenia; continued exposure causes aplasia and pancytopenia1 (Bruckner and Warren, 2001). Benzene also has carcinogenic properties. In experimental animals, an increased incidence of malignant lymphomas and some solid tumors have been seen after exposure to high doses of benzene. As discussed in Chapter 6, benzene has also been associated with some types of leukemia in humans.

Most of the human evidence associating benzene exposure with aplastic anemia comes from case studies (many published in the early to middle 1900s). Although exposure characterization methods were poor, it is estimated that benzene concentrations often exceeded 100 ppm2 (as summarized in Smith, 1996). The hypothesis of an association with benzene exposure raised by the case reports has been confirmed by several epidemiologic studies, although most of the population-based studies have focused on the relationship between exposure to benzene and hematopoietic cancers (see Chapter 6).

As early as 1897, the deaths of four workers at a Swedish bicycle-tire factory were attributed to aplastic anemia associated with exposure to high concentrations of benzene (cited in Aksoy, 1985). A retrospective cohort study by Paci and colleagues (1989) examined exposures to potentially high concentrations of benzene among shoe-factory workers in Florence, Italy. During the period from 1953 to 1960, glues—estimated to be as much as 70% benzene by weight—were used in shoe manufacturing. When the researchers compared mortality rates for the 1950–1984 cohort of workers with national rates, they found increases for aplastic anemia in women (one case versus 0.2 expected) and in men (six cases versus 0.38 expected). The Italian national mortality rates combined all blood diseases, and the analysis resulted in standardized mortality ratios (SMRs) of 4.16 (95% CI not provided) for women and 15.66 (95% CI=5.47–32.64) for men.

A retrospective cohort study examined hematopoietic malignancies and related disorders in a group of 74,828 workers in China who were employed in 1972–1987 in benzene-exposed departments of 672 factories (Dosemeci et al., 1994; Travis et al., 1994; Yin et al., 1996a,b). Mortality and morbidity data on this cohort were compared with data on 35,805 nonexposed workers employed during the same period. Physician investigators blinded to exposure information reviewed histopathologic information, pathology reports,


Pancytopenia is a nonfatal condition with below normal values of red cells, white cells, and platelets.


The allowable occupational-health standard for benzene has steadily decreased in the United States. In 1987, the permissible exposure limit (PEL) set by the Occupational Safety and Health Administration was reduced from 10 ppm to 1 ppm TWA (time-weighted average).

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