Toxicity Profiles

Condensed Toxicity Summary for BENZENE

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

September 1992

Prepared by: Mary Lou Daugherty, M.S., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division*, , Oak Ridge, Tennessee.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

Benzene is absorbed via ingestion, inhalation, and skin application. Experimental data indicate that animals can absorb up to 95% of oral doses and that humans can absorb up to 80% of inhaled benzene (after 5 minutes of exposure) (Sabourin et al., 1987; Srobova et al., 1950). Humans may absorb benzene vapors through the skin as well as the lungs; of the total dose absorbed by the two routes, an estimated 22-36% enters the body through the skin (Susten, 1985).

Autopsy of a youth who died while sniffing benzene revealed that the chemical was distributed to the urine, stomach, bile, liver, kidney, abdominal fat, and brain (Winek and Collum, 1971). The depots for benzene and its metabolites in animals are similar to those in humans, and in addition, include the fetus and placenta, bone marrow, Zymbal gland, and oral and nasal cavities (Ghantous and Danielsson, 1986; Rickert et al., 1979; Low et al., 1989).

Numerous studies indicate that the metabolism of benzene is required for its toxicity (Kalf et al., 1987). The liver is the main site for the metabolism of benzene; the bone marrow, a minor site (ATSDR, 1992). Phenol, hydroquinone, catechol, and benzene oxide are the major metabolites (Kalf et al, 1987; Snyder, 1987). The metabolite(s) of benzene that are responsible for its toxicity have not been positively identified, but likely candidates include muconaldehyde, quinones, and free radicals generated by oxidizing enzymes (Henderson et al., 1989; Snyder, 1987).

Benzene is eliminated either unchanged in expired air or as metabolites in the urine (ATSDR, 1992). The proportions of the administered dose excreted by each route and the half-times for excretion are dependent on route, dose, and duration of exposure.

Lethal oral doses of benzene are estimated to be 10 mL in humans; oral LD50 values for benzene in rats range from 0.93 to 5.96 g/kg (Cornish and Ryan, 1965; Withey and Hall, 1975). These data indicate that benzene is of low acute toxicity (O'Bryan and Ross, 1986).

Limited data show that nonlethal oral doses of benzene can impact the nervous, hematological, and immunological systems. Ingested benzene produces symptoms of neurotoxicity at acute doses of 2 mL for humans and 325 mg/kg for rats (Thienes and Haley, 1972; Clayton and Clayton, 1981; Cornish and Ryan, 1965). A four week exposure of mice to >=8 mg of benzene/kg/day in the drinking water induced the synthesis and catabolism of monoamine neurotransmitters and produced dose-related decreases in red-blood cell parameters and lymphocyte numbers (Hsieh et al., 1988b). Rats and mice that were treated with benzene by gavage for 103 weeks developed a dose-related lymphocytopenia (LOAEL, 25 mg/kg/day) and mice had hyperplasia of the bone marrow and lymphoid depletion of the splenic follicles and thymus (100 mg/kg/day) (Huff et al., 1989).

Inhalation of benzene vapor concentrations of 20,000 ppm for 5-10 minutes can be fatal to humans; death results from central nervous system depression (Clayton and Clayton, 1981). The estimated LC50 value for the rat is 13,700 ppm (Drew and Fouts, 1974).

As with orally administered benzene, the targets for nonlethal concentrations of inhaled benzene include the nervous, hematological, and immunological systems. Neurological symptoms in humans may appear at exposure concentrations of 700 ppm (Clayton and Clayton, 1981). In animals, 1 week of exposure to 300 ppm induced behavioral effects (Drew and Fouts, 1974), and one to four weeks of exposure to benzene concentrations ranging from 21-50 ppm suppressed the bone marrow (NOAEL, 10 ppm) (Cronkite et al., 1985; Toft et al., 1982), the cellular immune response (NOAEL, 10 ppm) (Rosenthal and Snyder, 1985), and the humoral immune response (LOAEL, 50 ppm) (Aoyama, 1986).

Subchronic and chronic exposures to benzene vapors induce a progressive depletion of the bone marrow and dysfunction of the hematopoietic system. Early symptoms of bone marrow depression include leukopenia, anemia or thrombocytopenia, or a combination of the three (Snyder, 1984). A group of workers exposed to benzene concentrations of 30 and 150 ppm for 4 months to 1 year had increased incidences of pancytopenia (Aksoy et al., 1971; Aksoy et al., 1972; Aksoy and Erdem, 1978). A group of patients who had been exposed to benzene concentrations of 150 to 650 ppm for 4 months to 15 years exhibited severe blood dyscrasias and eight of the 32 patients died with thrombocytopenic hemorrhage and infection (Aksoy et al., 1972). The human data are supported by animal data showing bone marrow suppression in mice and rats exposed to benzene concentrations ranging from 10 ppm for 24 weeks to 300 ppm for 13 weeks (Baarson et al., 1984; Ward et al., 1985).

Benzene may also have long-term effects on the central nervous system. Workers exposed to benzene for 0.5 to 4 years exhibited EEG changes and atypical sleep activity consistent with neurotoxicity (Kellerova, 1985). Others exposed to benzene concentrations of 210 ppm for 6-8 years had peripheral nerve damage (Baslo and Aksoy, 1982).

In humans, benzene crosses the placenta and is present in the cord blood in amounts equal to those in maternal blood (Dowty et al., 1976); however, studies of the effects of benzene on human reproduction and development have been confounded by the presence of other chemicals in the environment (USAF, 1989). Benzene does produce developmental effects (fetal toxicity, but not malformations) in the offspring of treated animals, mostly at maternally toxic doses (Nawrot and Staples, 1979; Seidenberg et al., 1986; Keller and Snyder, 1988).

Reference doses/concentrations for benzene have not been established. An oral risk assessment for benzene will be reviewed by an EPA work group and an inhalation risk assessment is currently under review (U.S. EPA, 1992a).

Benzene is carcinogenic in humans and animals by inhalation and in animals by the oral route of exposure. Occupational exposure to benzene has been associated mainly with increased incidences of acute myeloblastic or erythroblastic leukemias and chronic myeloid and lymphoid leukemias among workers (Aksoy, 1989). Workers at risk were exposed in one study to 8-hour TWA concentrations ranging from 10 to 100 ppm (Rinsky et al., 1981) and in another to 8-hour TWA concentrations ranging from <2 to >25 ppm (Ott et al., 1978). In a historical prospective mortality study of chemical workers, Yin et al. (1987) described a dose-response relationship between exposure to benzene and lymphatic and hematopoietic cancers, which adds strength to the association between exposure in the workplace and cancer development. Studies in animals have demonstrated an association between oral and inhalation exposure to benzene and the development of a variety of tumors, including lymphoma and carcinomas of the Zymbal gland, oral cavity, mammary gland, ovaries, lung, and skin (Huff et al., 1989; Maltoni et al., 1989). In one study C57Bl/BNL mice had increased incidences of leukemia, lymphoma, and solid tumors after exposure to 300 ppm for only 16 weeks (Cronkite et al., 1985; Cronkite, 1983).

Based on "several studies of increased incidence of nonlymphocytic leukemia from occupational exposure, increased incidence of neoplasia in rats and mice exposed by inhalation and gavage, and some supporting data", benzene has been placed in the EPA weight-of-evidence classification A, human carcinogen (U.S. EPA, 1991a). The oral and inhalation slope factors for benzene are 2.9E-2 (mg/kg/day)-1 and the oral and inhalation unit risk values are 8.3E-7 and 8.3E-6, respectively, based on the studies of Ott et al. (1978), Rinsky et al. (1981), and Wong et al. (1983) (U.S. EPA, 1992a,b). Retrieve Toxicity Profiles Formal Version

Last Updated 02/13/98