Organ Specific Toxicity

In addition to gastrointestinal irritation, acute high-dose ingestion of benzene causes neurological toxicity, most likely due to the rapid uptake of benzene into tissues with high lipid content, such as the nervous system. Acute highdose inhalation can also lead to cardiotoxicity, due to over-sensitization of the cardiac muscle to the constrictive effects of catecholamines, such as epinephrine. Chronic, low-dose benzene ingestion also causes hematotoxicity, which can manifest as aplastic anemia, pancytopenia, or any combination of anemia, leucopenia, thrombocytopenia, and acute myelogenous leukemia (AML).

The chronic toxicity of benzene is known to be mediated by metabolic activation in susceptible tissues. For example, the liver is know to contain high levels of mixed function oxidases, such as the major benzene-metabolizing enzyme CYP2E1. Some evidence suggests that CYP2B1 and CYP2F2 may also be involved. There is also evidence that CYP2E1-mediated activation of benzene occurs in the bone marrow, a major target of its toxicity and carcinogenicity. Bone marrow stroma cells of rats contain higher levels of glutathione and quinine reductase than their counterparts in mice. These represent major detoxification systems and their lower levels in mice could explain their higher susceptibility to benzene-induced hematoxicity than rats.

Benzene is able to stimulate its own metabolism in liver tissues, presumably by inducing synthesis of elevated levels of CYP2E1. Metabolites of benzene, such as phenol, hydroquinone, benzoquinone, and catechol, have also been shown to induce cytochrome levels in human hematopoietic tissues. It is thought that exposure to chemicals able to simulate these enzymes may inadvertently increase the toxic potential of benzene to these tissues. Benzene can be metabolized by a variety of major and minor pathways. As explained previously, predominate routes of metabolism are hepatic oxidative pathways leading to formation of phenol, catechol, and quinol (dihydroxybenzene). Phenol and the other hydroxyben-zenes are further conjugated with inorganic sulfate or phenyl sulfate and excreted in the urine. However, saturation of the major pathways of benzene metabolism can occur, so that lesser pathways can become important, such as conjugation of phenol with cysteine to form phe-nylmercapturic acid or further oxidation of phenol to trihydroxybenzene. It has been suggested that more toxic metabolites are formed by the high-affinity, low-capacity pathways, such as those which become most readily saturated. This may explain why some studies have found that slightly higher doses of benzene do not lead to formation of corresponding higher levels of toxic metabolites. This may inadvertently provide a protective response from metabolic activation of benzene.

The predominant health hazard of benzene in humans is an association with AML. Metabolites assumed to be involved in the hematotoxic and leukemogenic effects of benzene include benzene oxide and the reactive products of the phenol pathway such as phenol, catechol, hydro-quinone, and 1,4-benzoquinone. Metabolic activation of benzene does not occur to an appreciable degree in bone marrow tissues, complicating a mechanistic approach to understanding the leukemogenic process. Chronic benzene exposure can cause a progressive decline in functional blood cells, apparently associated with a cyto-toxic effect on all lineages of hematopoietic progenitor cells. Although it is beyond the scope of this discussion of benzene ecotoxicity, readers are referred to several excellent reviews which have been recently published and are listed as additional readings.

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