Uptake and Metabolism of Benzene

Although benzene readily penetrates biological membranes, it does not seem to accumulate appreciably in plants, fish, and birds. With a bioconcentration factor of 1.1-2.0, it is unlikely that benzene will accumulate in the food chain, such that most concern for oral exposure would be from drinking of contaminated water. Benzene may become incorporated into plants, the majority of which is believed to occur by air-to-leaf transfer rather than root uptake. Vegetative contamination of exposed food crops used for human consumption and animal forage has been estimated to be 587ngkg(~0.6 ppb). When benzene enters an animal by ingestion of contaminated food or water, it can pass directly through the lining of the gastrointestinal tract into the bloodstream. Due to its lipid solubility, benzene localizes in the liver and bone marrow of animals, where it can be stored temporarily. Benzene is metabolized and ultimately eliminated as conjugated metabolites in the urine. Harmful effects of benzene are associated with production of toxic intermediary metabolites, making organs with oxidative metabolic capacity (such as hepatic mixed function oxidases) especially sensitive to reactive metabolites and targets for the toxic effects. Inhalation or ingestion of benzene can cause acute toxicities including irritation to mucous membranes, as well as neurotoxic effects including restlessness, convulsions, and death from respiratory failure.

Following ingestion, benzene is well absorbed in rodents, with over 90% and 97% absorption in rabbits and rats, respectively. Humans absorb 70-80% of inhaled benzene, which represents the most significant exposure route. Following inhalation, ingestion, or dermal absorption, benzene rapidly distributes throughout the body where it can be metabolized in selected tissues or can be excreted unchanged in exhaled air. Benzene can enter the fetal bloodstream through the placenta, yet it is generally not considered to be teratogenic to experimental animals or humans. Some embryotoxic and fetotoxic effects have been reported in rat studies, such as low birth weight and increased skeletal variations, but exposures less than 10 ppm are not associated with adverse fetal effects. A limited number of studies suggest that benzene can partition into breast milk, but the consequences to neonatal health are not yet known.

Although benzene is classified as a known carcinogen, it is generally thought to require metabolic activation by mixed function oxidases to form one of several DNA damaging nucleophiles. Experiments have shown that 'knockout mice' deficient in the cytochrome P450 2E1 enzyme (CYP2E1) are resistant to the carcinogenic effects of benzene, verifying the requirement for metabolic activation. The predominant benzene metabolite is benzene oxide, a very reactive epoxide which can rearrange nonenzymatically to form phenol (Figure 1). Phenol is the predominant urinary metabolite of benzene in mammals and is a known hematotoxin. Alternatively, benzene oxide can be further acted upon by CYP2E1 to form benzene oxepin (Figure 1), which can undergo iron-catalyzed ring opening to form reactive trans,trans-muconaldehyde. A third possibility involves epoxide hydratase action on benzene oxide to generate catechol (Figure 1 ).

Phenol can be further acted upon by CYP2E1 to generate hydroxyquinone or catechol. A third round of CYP2E1 oxidation of either compound would yield 1,2,4-benzenetriol (Figure 1 ), which can form a semiquinone radical and an active oxygen which are believed to play a role in benzene carcinogenesis. Metabolic detoxification of any of the four phenolic metabolites (phenol, catechol, hydroquinone, and 1,2,4-benzenetriol) can occur by sulfonic or glucuronic conjugation and allowing urinary excretion. Alternatively, benzene oxide can be inactivated

P450 Catechol Oxidation

Figure 1 Metabolic activation and detoxification of benzene. Metabolic activation of benzene proceeds through a series of oxidative reactions catalyzed by mixed function oxidases, such as the 2EI isozyme of cytochrome P450 (CYP2EI) and myeloperoxidase (MPO), as well as dihydrodiol dehydrogenase (DHHD) and NAD(P)H:quinone oxidoreductase (NQ01).

Figure 1 Metabolic activation and detoxification of benzene. Metabolic activation of benzene proceeds through a series of oxidative reactions catalyzed by mixed function oxidases, such as the 2EI isozyme of cytochrome P450 (CYP2EI) and myeloperoxidase (MPO), as well as dihydrodiol dehydrogenase (DHHD) and NAD(P)H:quinone oxidoreductase (NQ01).

by reaction with glutathione to form S-phenylmercapturic acid (Figure 1), which is also excreted in the urine.

Benzene oxepin is found in chemical equilibrium with benzene oxide, and can be acted upon by iron-generated hydroxyls to generation of transrtrans-muconaldehyde (Figure 1 ). This dialdehyde has the potential to form adducts or cross-links with biomolecules, including proteins and/or nucleic acids. Muconaldehyde is detoxified by oxidation to muconic acid by sequential action of alcohol and aldehyde dehydrogenases (Figure 1).

Benzene metabolites of concern include benzene oxide, phenol, hydroquinone, and muconaldehyde. Being an epox-ide, benzene oxide will readily react with nucleophilic centers in amino acids of proteins or bases of DNA. Benzoquinones and hydroquinones are also known to bind to proteins and nucleic acids to form covalent products.

These reactions can cause inactivation of protein function and DNA damage that may lead to mutation and possibly chromosome breakage. Lymphocytes from humans and animals exposed to benzene are known to harbor damaged chromosomes, a condition which can persist for months to years following exposure. The link between specific types of chromosomal damage and subsequent development of leukemia in humans is under intense investigation. An oral reference dose in humans (allowable tolerances in food) is 0.017 mg/kg/day, while the US Environmental Protection Agency (USEPA) has determined the slope factor for carcinogenic risk from oral exposure to be 0.029 mg/kg/day. USEPA estimates of a lifetime daily exposure to 70, 7, and 0.7 mgT benzene in drinking water would equate to a 1:10 000, a 1:100 000, and a 1:1 000 000 elevated cancer risk in humans, respectively.

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