Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM)
Benzene Toxicity
Physiologic Effects
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Benzene primarily affects the CNS and the hematopoietic system.
Benzene exposure affects the CNS and hematopoietic system and may affect the immune system. Death due to acute benzene exposure has been attributed to asphyxiation, respiratory arrest, CNS depression, or cardiac dysrhythmia. Pathologic findings in fatal cases have included respiratory tract inflammation, lung hemorrhages, kidney congestion, and cerebral edema.
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At very high concentrations, benzene rapidly causes CNS depression, which can lead to death.
Acute benzene exposure results in classic symptoms of CNS depression such as dizziness, ataxia, and confusion. These effects are believed to be caused by benzene itself rather than its metabolites, because the onset of CNS effects at extremely high doses is too rapid for metabolism to have occurred.
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All three blood cell lines may be adversely affected by benzene.
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Pluripotential stem cells and lymphocytic cells are the probable targets of benzene toxicity.
Benzene can cause dangerous hematologic toxicity such as anemia, leukopenia, thrombocytopenia, or pancytopenia after chronic exposure. These effects are believed to be caused by the metabolites of benzene, which most likely damage the DNA of the pluripotential stem cells. All of the blood's components (i.e., erythrocytes, leukocytes, and thrombocytes [platelets]) may be affected to varying degrees. The accelerated destruction or reduction in the number of all three major types of blood cells is termed pancytopenia. Potentially fatal infections can develop if granulocytopenia is present, and hemorrhage can occur as a result of thrombocytopenia. Paroxysmal nocturnal hemoglobinuria, a disorder in which the breakdown of the red blood cells is accelerated and results in bleeding into the urine during sleep when the condition is active, has been associated with benzene exposure. Cytogenetic abnormalities of bone marrow cells and circulating lymphocytes have been observed in workers exposed to benzene-abnormalities not unlike those observed after exposure to ionizing radiation. Myelodysplastic effects also can be seen in the bone marrow of persons chronically exposed to benzene.
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Benzene-induced aplastic anemia is caused by chronic exposure at relatively high levels.
Aplastic anemia is caused by bone marrow failure, resulting in hypoplasia with an inadequate number of all cell lines. Severe aplastic anemia typically has a poor prognosis and can progress to leukemia, whereas pancytopenia may be reversible. Benzene-induced aplastic anemia is generally caused by chronic exposure at relatively high doses. Fatal aplastic anemia following benzene exposure was first reported in workers in the nineteenth century.
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Benzene-induced leukemia has a usual latency period of 5 to 15 years and, in many cases, is preceded by aplastic anemia.
Several agencies (e.g., the U.S. Department of Health and Human Services, the U.S. Environmental Protection Agency [EPA], and the International Agency for Research on Cancer) classify benzene as a confirmed human carcinogen. EPA estimates that a lifetime exposure to 4 ppb benzene in air will result in, at most, 1 additional case of leukemia in 10,000 people exposed. EPA has also estimated that lifetime exposure to a benzene concentration of 100 ppb in drinking water would correspond to, at most, 1 additional cancer case in 10,000 people exposed.
Cohort studies of benzene-exposed workers in several industries (e.g., sheet-rubber manufacturing, shoe manufacturing, and rotogravure [a special printing process]) have demonstrated significantly elevated risk of leukemia-predominantly acute myelogenous leukemia, but also erythroleukemia and acute myelomonocytic leukemia. The latency period for benzene-induced leukemia is typically 5 to 15 years after first exposure. Patients with benzene-induced aplastic anemia progress to a preleukemic phase and develop acute myelogenous leukemia. However, a person exposed to benzene may develop leukemia without having aplastic anemia.
Studies addressing the risk of leukemia associated with occupational exposures to low levels of benzene (less than approximately 1 ppm) have been inconclusive. Death certificates do not reveal increased leukemia mortality among workers potentially exposed to low levels of hydrocarbons and other petroleum products.
However, in recent case-control studies, significantly more patients with acute nonlymphocytic leukemia were employed as truck drivers, filling station attendants, or in jobs involving exposure to low levels of petroleum products than were the controls.
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There is insufficient evidence to indicate a causal relationship between benzene and nonhematologic tumors.
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Benzene has not been shown to be teratogenic in humans.
Several reports relate benzene exposure to a variety of lymphatic tumors including non-Hodgkin lymphoma and multiple myeloma. Although this is plausible, there is no scientific proof of a causal relationship. The association between exposure to benzene and development of nonhematologic tumors remains inconclusive.
Information on the reproductive toxicity of benzene in humans is meager. Some effects on the testes have been noted in animals exposed via inhalation. Benzene has not been proven teratogenic in humans. In animals, high levels of benzene have resulted in decreased fetal weights and minor skeletal variants.
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