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Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM)
Benzene Toxicity
Biological Fate
Benzene is rapidly and extensively absorbed by inhalation and ingestion. Absorption through the skin is rapid but not extensive, as most of it evaporates quickly. In humans, approximately 50% of inhaled benzene is absorbed after a 4-hour exposure to approximately 50 ppm benzene in air. An in vivo study on human volunteers indicated that approximately 0.05% of a benzene dose applied to the skin was absorbed, whereas in an in vitro study of human skin, the absorption of benzene was consistently 0.2% after exposure to doses ranging from 0.01 to 520 microliters per square centimeter. Oral absorption has not been studied in humans. In animals, at least 90% of benzene was absorbed following oral ingestion of a dose of 340 to 500 milligrams per kilogram per day (mg/kg/day).
After exposure, benzene is found throughout the body, but it preferentially distributes into the bone marrow and tissues with either high perfusion rates or high lipid content. Thus, autopsies of people who died after acute exposure showed that lipid-rich tissues, such as the brain and fat, and well-perfused tissues, such as the kidney and the liver, have higher levels of benzene than other tissues.
Once absorbed, benzene is initially metabolized in the liver and later in the bone marrow. Although the total quantity of metabolites is greater in blood than marrow, the concentrations of those metabolites in the marrow can be 400 times greater than in blood. Benzene metabolism in the liver involves oxidation, with phenol as the major metabolite. Further metabolic products are formed in liver and in bone marrow by the enzymatic addition of hydroxyl groups to the benzene ring. Such metabolites include hydroquinone, catechol, and 1,2,4-trihydroxybenzene, which are further conjugated and excreted in the urine. These hydroxylated metabolites can be further oxidized to their corresponding quinones or semiquinones. Benzene oxide may also be metabolized via glutathione conjugation to form S-phenyl mercapturic acid. Additionally, urinary excretion of small amounts of muconic acid, a straight-chain dicarboxylic acid, indicates that the benzene ring also is opened during metabolism.
Bone marrow is the main target organ of chronic benzene toxicity. One or more benzene metabolite is suspected to be responsible for the hematogenous toxicity, although the identity of the ultimate toxicant is unknown. In the marrow, the metabolites may bind covalently to cellular macromolecules (e.g., proteins, DNA, and RNA), causing disruption of cell growth and replication.
Approximately 17% of absorbed benzene is excreted unchanged via the lungs after a 4-hour exposure to 52 to 62 ppm benzene. Respiratory elimination is triphasic, with approximate half-lives of 1, 3, and greater than 15 hours. Urinary excretion of phenol conjugates is biphasic, with half lives of 5.7 and 28 hours. Approximately 33% of absorbed benzene is excreted in urine, primarily as phenol conjugates, muconic acid, and S-phenyl-N-acetyl cysteine.
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