The Risk Assessment Information System

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.

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EXECUTIVE SUMMARY

1. INTRODUCTION

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS

4. CARCINOGENICITY

4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS

5. REFERENCES

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.

EXECUTIVE SUMMARY

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).

1. INTRODUCTION

Benzene (C₆H₆, CAS No. 71-43-2) is a volatile, colorless liquid with a characteristic "aromatic" odor (Snyder, 1987). Benzene has a molecular weight of 78.12, a vapor pressure (at 26C) of 100 mm Hg, a vapor density of 2.77, and a density (at 20C) of 0.87865 g/mL (Snyder, 1987).

Benzene is used primarily in the production of other chemicals such as ethylbenzene, cumene, and cyclohexane (ATSDR, 1989). Benzene has also been used as a solvent, but this use is declining, coincidental with the replacement of benzene with other organic solvents (ATSDR, 1989). Benzene is emitted into the workplace and the environment (aquatic, terrestrial, and atmospheric) from industrial and other manmade sources, including gasoline from filling stations, smoking tobacco products, and auto exhaust (ATSDR, 1989).

Workers employed in industries that produce or use benzene are at risk for exposure to high levels of the chemical. According to OSHA (1985), an estimated 17,336 workers are potentially exposed to 8-hour time-weighted-average (TWA) concentrations of benzene ranging from 5.1 to 10 ppm. More recent data were not available. Exposure of the general population to benzene may occur in residential areas near chemical manufacturing sites; exposure has also been associated with the ingestion of contaminated food and drinking water, cigarette smoking, and pumping gas. Estimated daily intake values for 70-kg adults average 2.86 g/kg/day for drinking water, 7.8 g/kg/day for smoking 20 cigarettes/day, and 2.76 g/kg/day for exposure to emissions from nearby chemical manufacturing plants (ATSDR, 1989).

Because of benzene's high vapor pressure, inhalation is the most likely route of exposure to the chemical, particularly in the workplace. OSHA (1987) has set air exposure limits for benzene of 1 ppm (8-hour TWA) and 5 ppm (15-minute STEL).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

No data were found for the oral absorption of benzene in humans. Rabbits given 340-500 mg/kg benzene orally absorbed at least 90% of the dose and rats and mice given 0.5-150 mg/kg absorbed >97% of the dose (Sabourin et al., 1987).

Human and animal studies indicate that inhaled benzene is absorbed rapidly. Srbova et al. (1950) studied respiratory uptake in humans inhaling benzene concentrations of 47-110 ppm for 2-3 hours. Uptake (the difference between the amount of benzene in inhaled and exhaled air expressed as a percent of the concentration in inhaled air) was 70-80% during the first 5 minutes of exposure and approximately 50% by 1 hour (Srbova et al., 1950). For another group of volunteers, exposed to 52-62 ppm benzene for 4 hours, respiratory uptake was approximately 47% and retention (benzene that was absorbed and not excreted through the lungs) was approximately 30% (Nomiyama and Nomiyama, 1974a). Animal data also confirm that benzene is absorbed rapidly through the lungs. In dogs exposed to benzene concentrations of 200-1300 ppm, blood levels of the chemical reached a steady state in about 1 hour (Schrenk et al., 1941).

Recent studies have indicated that absorption of benzene through the skin my be a significant route of exposure, particularly for workers. Susten et al. (1985) estimated that employees in tire-building operations could absorb 4-8 mg of benzene/day through intact skin; this is approximately 22-40% of the total dose absorbed via skin and inhalation. These data are supported by the work of Blank and McAuliffe (1985), who calculated that 17% of the total absorbed dose of ambient benzene (skin plus inhalation) could be absorbed by the skin.

2.2. DISTRIBUTION

No data were found for the distribution of orally administered benzene in humans. In rats, the pattern of distribution for ingested benzene is similar to that of inhaled benzene. Low et al. (1989) observed that the bone marrow and adipose tissue were depots for doses of benzene >=15 mg/kg. With regard to the unconjugated metabolites, hydroquinone appeared in the liver, kidney, and blood, and phenol appeared in the oral cavity, nasal cavity and kidney. The conjugated metabolites, phenyl sulfate, hydroquinone glucuronide, and trans, trans-muconic acid, appeared in the blood, bone marrow, oral cavity, kidney and liver, whereas phenyl glucuronide was present in the Zymbal gland and nasal cavity.

Case studies have provided most of the information regarding the distribution of inhaled benzene in humans. Benzene was present in tissue samples taken at autopsy from a youth who died while sniffing the reagent grade chemical. The specimens contained the following amounts of benzene: 2.0 mg% in blood, 3.9 mg% in brain, 1.6 mg% in liver, 1.9 mg% in kidney, 1 mg% in stomach, 1.1 mg% in bile, 2.23 mg% in abdominal fat, and 0.06 mg% in urine (Winek and Collom, 1971).

In pregnant mice exposed to benzene concentrations of 2,000 ppm for 10 minutes, the parent compound and its metabolites were found in lipid-rich tissues, such as brain and fat, and in well-perfused tissues such as liver and kidney, as well as in the fetuses and placenta (Ghantous and Danielsson, 1986). In rats exposed to 500 ppm benzene, levels of the chemical reached a steady-state concentration in the blood (11.5 g/mL) within 4 hours, in the fat (164.4 g/g) within 6 hours, and in the bone marrow (37 g/g) within 2 hours (Rickert et al., 1979). The kidney, lung, liver, brain, and spleen also contained benzene. After 6 hours of exposure, metabolites of benzene (phenol, catechol, and hydroquinone) were detected in the blood and in the bone marrow, where levels of the metabolites exceeded those in the blood. The levels of phenol in the blood and bone marrow declined more rapidly than did those of catechol or hydroquinone. This suggests that catechol and hydroquinone may accumulate.

For ¹⁴C-benzene applied to the skin of male rats, the kidney, liver, and treated skin were the target sites for radioactivity (Skowronski et al., 1988).

2.3. METABOLISM

Numerous studies indicate that the metabolism of benzene is required for its toxicity (reviewed by Kalf et al., 1987). The liver is the major site for the transformation of benzene, the bone marrow a minor site. It appears that benzene metabolism (qualitative at least) is similar for different routes of administration and for different species, including humans (ATSDR, 1992). Benzene can stimulate its own metabolism, and can therefore increase the rate of the formation of toxic metabolites (ATSDR, 1992).

Phenol, hydroquinone, catechol, and benzene oxide are the major metabolites of benzene (Kalf et al., 1987). Snyder (1987) summarized the complex scheme for the metabolism of benzene: "The metabolism of benzene initially involves the formation of hydroxylated benzenes. Only small amounts of ring-opened metabolites are formed due to the stability of the aromatic ring. The enzymes catalyzing these hydroxylations are the mixed function cytochrome monooxygenase enzymes, which are found predominantly in the liver, but also in the bone marrow, which is the putative target organ of benzene toxicity. The oxidizing moieties produced by the enzymes probably involve a cascade of reactive oxygen species, including free radicals. These reactive oxygen species may contribute to benzene-induced cell damage. The substitution of hydroxyl groups onto the benzene ring proceeds by at least two pathways: an indirect pathway through an epoxide intermediate and a direct pathway involving direct insertion of hydroxyl groups. Both pathways appear to proceed through an enone intermediate. The hydroxylated benzenes can undergo conjugation reactions to form glucuronides and sulfate esters, or can be further oxidized to benzoquinones. The benzoquinones are probably the electrophilic species which covalently bind to macromolecules including DNA, and therefore may be the ultimate carcinogenic forms of benzene."

Figure 1 illustrates the pathways related to the biotransformation of benzene. One pathway of detoxification is via the formation of glutathione conjugates of benzene oxide and its subsequent metabolism to phenyl mercapturic acid, which is excreted via the bile (Henderson et al., 1989; Sabourin et al., 1988); another pathway of detoxification is via the formation of water-soluble urinary metabolites, which are the glucuronide or sulfate conjugates of phenol (Henderson et al., 1989). Phenol can also undergo metabolism to catechol and trihydroxy benzene that are excreted as sulfate or glucuronide conjugates (ATSDR, 1992). The formation of two proposed toxic metabolites, benzoquinone and muconaldehyde, proceeds through the further oxidation of hyroquinone, and the opening of the ring of benzene oxide followed by aromatization, respectively (Henderson et al., 1989).

Recent metabolic studies on benzene have focused on identifying both the moiety that initially oxidizes benzene and the electrophilic benzene metabolite(s) that react with cellular macromolecules to initiate damage (Snyder, 1987). Previously, a benzene epoxide was the suspect cytotoxic species, but the results of recent studies indicate that the benzoquinones and possibly free radicals generated by the oxidizing enzymes are the more likely candidates (Snyder, 1987).

2.4. EXCRETION

Benzene is eliminated either unchanged in expired air or as metabolites in the urine (ATSDR, 1992). The combined results of two studies show that human volunteers exposed to 47-110 ppm of the chemical for 2-4 hours excreted 16-41.6% of absorbed benzene through the lungs within 5-7 hours (Nomiyama and Nomiyama, 1974a; Srbova et al., 1950). In one of the studies, the subjects excreted only 0.07-0.2% of the retained benzene in the urine (Srbova et al., 1950).

Porteus and Williams (1949) and Parke and Williams (1953, 1954) quantified the excretion of benzene and its metabolites by rabbits given oral doses of ¹⁴C-labeled benzene. The animals eliminated approximately 43% of the dose as unchanged benzene in exhaled air and about 35% of the radioactivity in the urine. The isolated urinary metabolites consisted of phenol (68% of radioactivity), hydroquinone (14%), catechol (6%), trans,trans-muconic acid (4%), phenylmercapturic acid (1%) and 1,2,4-trihydroxybenzene (1%). Similar patterns of excretion have been observed for humans (Teisinger et al., 1952), cats and dogs (Oehme, 1969), rats (Cornish and Ryan, 1965), and mice (Longacre et al., 1981). In humans and rats, the excretion of benzene in expired air appears to biphasic. The half-times for benzene eliminated by rats in expired air were 0.7 hours for the rapid phase and 13.1 hours for the slow phase (Rickert et al., 1979). The half-times increase with duration of exposure.

During a 32-hour period following application of 0.0024 mg/cm^{2 14}C-benzene to the skin, human volunteers excreted approximately 0.0023% of the dose in the urine (Franz, 1984). Excretion of the label was greatest in the first 2 hours following application, and more than 80% of the label had been eliminated in 8 hours.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

The central nervous system and cardiovascular system are the targets of acute benzene toxicity in humans. The ingestion of benzene produces staggering gait, vomiting, loss of consciousness, delirium and death (Clayton and Clayton, 1981); 2 mL may produce symptoms, whereas 10 mL may be fatal (Thienes and Haley, 1972). Death results from cardiac failure or respiratory arrest. A man who swallowed an unspecified quantity of benzene survived, but developed severe gastritis and eventual pyloric stenosis (Greenburg, 1926).

3.1.1.2. Animal

Animal lethality data indicate that the oral acute toxicity of benzene is low (O'Bryan and Ross, 1986). Oral LD₅₀ values for benzene in rats range from 0.93 to 5.96 g/kg (Cornish and Ryan, 1965; Withey and Hall, 1975). The oral LD₅₀ for benzene in mice is 4.7 g/kg (Sandmeyer, 1978).

Sublethal acute oral doses of benzene affect the nervous system and liver. Single oral doses of benzene to Sprague-Dawley rats produced slight nervous system depression at 352 mg/kg and tonic clonic convulsions at 1,870 mg/kg (Cornish and Ryan, 1965). Benzene induced synthesis and catabolism of monoamine neurotransmitters, but no behavioral effects in CD-1 mice given 8, 40, or 180 mg/kg/day of the chemical in drinking water for 4 weeks (Hsieh et al., 1988a). In rats, benzene (1400 mg/kg/day for 1-3 days) altered drug metabolism and lipid peroxidation in the liver, decreased the protein content in the postmitochondrial supernatant, and increased liver weight (Pawar and Mungikar, 1975).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

No data were found.

3.1.2.2. Animal

The main targets for the oral subchronic toxicity of benzene are the hematopoietic and immune systems. Dose-related decreases in red-blood cell parameters and lymphocyte numbers were observed in mice fed >=8 mg of benzene/kg/day in the drinking water for 4 weeks (Hsieh et al., 1988b). In a 17-week gavage study, Fischer-344 rats developed leukopenia and lymphoid depletion of the spleen at 200 mg of benzene/kg/day (NOAEL, 100 mg/kg/day), and B6C3F₁ mice exhibited leukopenia at 400 mg/kg/day (NOAEL, 200 mg/kg/day) (Huff et al., 1989). Rats treated by gavage with benzene for 6 months exhibited leukopenia at 10 mg/kg/day and decreased erythrocyte counts at 50 mg/kg/day (NOAEL for both effects, 1 mg/kg/day) (Wolf et al., 1956).

Impairment of the immune system can result from effects on the blood-forming organs, thus decreased lymphocyte numbers, such as those observed above, can indicate immunosuppression. In addition, immunological responses of CD-1 mice to orally administered benzene for four weeks were either biphasic or suppressed in studies conducted by Hsieh et al. (1988b). For example, the splenic lymphocyte proliferative response to B- and T-cells was enhanced at 8 mg/kg/day and depressed at 40 and 180 mg/kg/day; cell-mediated immunity showed a similar biphasic response. The humoral immune response was suppressed at 40 and 180 mg/kg/day.

3.1.3. Chronic Toxicity

3.1.3.1. Human

No data were found.

3.1.3.2. Animal

In a chronic toxicity study conducted by the NTP (Huff et al., 1989), male rats were given benzene doses of 0, 50, 100, or 200 mg/kg/day in corn oil by gavage 5 days/week for 103 weeks; female rats and male and female mice were given doses of 0, 25, 50, or 100 mg/kg. Males and females of both species had decreased body weights and reduced survival at the highest doses and a dose-related lymphocytopenia (LOAEL, 25 mg/kg/day). Mice given the highest dose also had hyperplasia of the bone marrow and lymphoid depletion of the splenic follicles and thymus.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

No data were found.

3.1.4.2. Animal

Oral doses of 0.5 and 1.0 mL/kg of benzene, given to pregnant mice on days 6-15 of gestation, produced resorptions and maternal deaths, but did not induce malformations (Nawrot and Staples, 1979). A dose of 1.3 g/kg/day of benzene given to pregnant mice on gestation days 8-12 caused significant reductions in fetal body weights (Seidenberg et al., 1986).

3.1.5. Reference Dose

A risk assessment for benzene is currently under development and will be reviewed by an EPA work group (U.S. EPA, 1992a).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

The central nervous system (CNS) is the target of acute inhalation exposure to benzene. Depending on the concentration of benzene and duration of exposure, symptoms may range from mild manifestations such as headache and lightheadedness (50-250 ppm) to more severe effects that include convulsions, respiratory paralysis, and death (20,000 ppm, 5-10 minutes) (Finkel, 1983; Clayton and Clayton, 1981). Concentrations up to 25 ppm have not produced effects (Clayton and Clayton, 1981).

3.2.1.2. Animal

The estimated LC₅₀ value for benzene in the rat is 13,700 ppm (Drew and Fouts, 1974). Nonlethal concentrations of benzene can affect the hematological, immunological, and neurological systems.

The hematological effects of benzene are evident in both the peripheral blood and the bone marrow. These may occur at low concentrations and include lymphocytopenia in mice exposed to 25 ppm of benzene 5 days/week for 2 weeks (NOAEL, 10 ppm) (Cronkite et al., 1985) and increased micronuclei and decreased numbers of cells per tibia and colony-forming units (granulocytic stem cells) per tibia in mice exposed to 21 ppm, continuously, for 4-10 days (LOAEL) (Toft et al., 1982).

Impairment of the immune response can result from effects on the blood-forming organs; thus the finding of leukopenia in rats exposed to 100 ppm benzene for 1 week and lymphopenia in mice exposed to 25 ppm for 2 weeks (Li et al., 1986; Cronkite et al., 1989), suggest potential suppression of the cellular immune response by benzene. Immunological studies have demonstrated that benzene can affect both the cellular and humoral immune response. Mice inhaling 30 ppm benzene 6 hours/day for 12 days exhibited decreased resistance to infection by Listeria monocytogenes (cellular response; NOAEL, 10 ppm) (Rosenthal and CA Snyder, 1985). Mice inhaling 50 ppm had depressed T-lymphocytes (cellular response) and B-lymphocytes (humoral response) (Aoyama, 1986).

The neurotoxicity of benzene in animals is characterized by narcosis in rabbits exposed to 45,000 ppm (Carpenter et al., 1944); increased licking of sweetened milk by mice exposed for 1 week to 300 ppm; a 90% decrease in hind limb grip strength after one exposure to 1,000 or 3,000 ppm; and tremors after one exposure to 3,000 ppm (Dempster et al., 1984).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Workers exposed to benzene concentrations of 30 and 150 ppm for 4 months-1 year had increased incidences of pancytopenia; 25% of the workers died (Aksoy et al., 1972).

3.2.2.2. Animal

The hematopoietic system is a major target for the subchronic toxicity of benzene in animals. Ward et al. (1985) observed leukopenia and lymphopenia in both mice and rats exposed to benzene 6 hours/day, 5 days/week for 13 weeks (LOAEL for mice and rats, 300 ppm; NOAEL, 30 ppm). Histopathological examination revealed that mice exposed to 300 ppm also had depletion of the splenic periarteriolar lymphoid sheath, depletion of the lymphoid elements in the mesenteric lymph nodes, and plasma cell infiltration of the mandibular lymph node (NOAEL, 30 ppm). Baarson et al. (1984) demonstrated that a much lower concentration of benzene (10 ppm) depressed the numbers of circulating lymphocytes and progenitor red blood cells in the spleen when exposure duration was increased to 24 weeks (6 hours/day, 5 days/week).

Cronkite et al. (1989) observed stem-cell depression in the bone marrow of C57BL/6 mice exposed to benzene concentrations of 300 ppm for 4-16 weeks. In animals exposed for 16 weeks, stem cell numbers had recovered to 92% of normal by 25 weeks after exposure.

3.2.3. Chronic Toxicity

3.2.3.1. Human

The main targets of chronic exposure to benzene are the bone marrow, the immune system, and the central nervous system.

Early symptoms of bone marrow depression by benzene include leukopenia, anemia or thrombocytopenia, or a combination of the three (Snyder, 1984). At this stage, the effects may be reversible (IARC, 1983). Another early symptom of benzene toxicity, occurring in some cases, is bone marrow hyperplasia (Goldstein, 1977). With continued exposure, bone marrow damage becomes more severe, progressing to pancytopenia (deficiency of all cellular elements of the blood), and aplastic or hypoplastic anemia (Proctor and Hughes, 1978). The life-threatening consequences of these conditions involve increased susceptibility to infection and hemorrhagic conditions (Goldstein, 1977). For example, a group of 32 patients who had been exposed to benzene concentrations of 150 to 650 ppm for 4 months to 15 years, exhibited severe blood dyscrasias, and 8 of the 32 patients died with thrombocytopenic hemorrhage and infection (Aksoy et al., 1972).

Researchers generally agree that the lowest levels of benzene that can produce a decrease in human circulating blood cells are in the range of 40-50 ppm (Snyder, 1984). However, one investigator estimated from a study of 119 benzene-exposed workers that hematological changes could occur at 10 ppm (Chang, 1972) and others have reported (infrequently) the presence of chromosomal aberrations in the bone marrow and peripheral lymphocytes of individuals exposed to <10 ppm (USAF, 1989). Aberrations induced at levels >100 ppm may persist for many years after exposure has ceased (IARC, 1983); some investigators have linked irreversible chromosome damage and/or injury to the bone marrow with the development of leukemia (Snyder, 1984).

The chronic effects of benzene also include rare cases of the following: lymphocytosis; pseudo-Pelger Huet anomaly changes in the leukocyte osmotic resistance; decreased phagocytic function of granulocytes; reduced glycogen content and inhibited peroxidase activity of neutrophils; decreased alkaline phosphatase, myeloperoxidase, and lipid content of the neutrophils; a decrease in E_a and E₁₈ rosettes (T cells); increased leukoagglutinins; the presence of giant platelets; and increased fibrinolytic activity (Aksoy, 1988).

There is limited evidence to suggest that benzene has long-term effects on the central nervous system. Workers exposed to benzene for 0.5 to 4 years have 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).

3.2.3.2. Animal

Mice exposed to benzene 6 hours/day, 5 days/week for life developed anemia, lymphopenia, and bone marrow hypoplasia (LOAEL, 100 ppm) (Snyder et al., 1980).

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

Benzene crosses the placenta and is present in the cord blood in amounts equal to those in maternal blood (Dowty et al., 1976). 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). Studies at two Superfund sites where benzene was identified did not reveal clusters of birth defects (Budnick et al., 1984; Heath, 1983).

3.2.4.2. Animal

Benzene concentrations ranging from 50 to 940 ppm did not induce malformations, but did produce fetal toxicity in the offspring of pregnant rats, rabbits, and mice (ATSDR, 1989; 1992). The levels tested induced increased resorptions, reduced fetal weight, and skeletal variations, and were maternally toxic. In one study, the offspring of mice exposed to 20 ppm 6 hours/day on gestational days 6-15 had reduced numbers of erythroid precursors (Keller and Snyder, 1988). The available data indicate that benzene has not induced developmental effects at 1 ppm, the current OSHA standard (ATSDR, 1989).

Mice exposed subchronically to benzene concentrations of 300 ppm for 13 weeks developed ovarian cysts and testicular atrophy/degeneration; in addition, the numbers of spermatozoa were decreased and the incidence of abnormal sperm increased (Ward et al., 1985). Mice exposed to 30 ppm had no reproductive effects.

3.2.5. Reference Dose/Concentration

A risk assessment for benzene is under review by an EPA work group (U.S. EPA, 1991a).

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Benzene is irritating to the skin and may produce erythema, vesiculation, and dry and scaly dermatitis by defatting of the keratin layer (Sandmeyer, 1981).

3.3.1.2. Animal

In the rabbit eye, benzene is a moderate irritant, causing conjunctival irritation and transient corneal injury. Grant (1974) reports that 50% of the rats exposed to vapor concentrations of 50 ppm developed cataracts after more than 600 hours of exposure. Benzene is slightly to moderately irritating to the skin of laboratory animals (Wolf et al., 1956).

3.3.2. Subchronic Toxicity

3.3.2.1. Human

No data were found.

3.3.2.2. Animal

No data were found.

3.3.3. Chronic Toxicity

3.3.3.1. Human

No data were found.

3.3.3.2. Animal

No data were found.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

No data were found.

3.3.4.2. Animal

Benzene, applied dermally to rats at doses of 64 or 320 mg/kg/day for 4 months, did not affect the fertility of males, or the ability of females to conceive (Malysheva, 1980). However, the numbers of spermatogonia in the males was decreased and the mortality of the first generation offspring was increased.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

1. Hematopoietic system: Animals treated with chronic oral doses of benzene developed lymphocytopenia, hyperplasia of bone marrow and lymphoid depletion of the splenic follicles and thymus.
2. Immune system: Effects on the hematopoietic system, such as lymphocytopenia and lymphoid depletion of the splenic follicles and thymus, can impact the immune system.
3. Nervous system: Symptoms of neurotoxicity are produced in humans and animals, mainly by high acute doses; however, subacute exposure to low doses affected levels of neurotransmitters in animals.

3.4.1.2. Other Target Organs

1. Reproductive system: Benzene produces fetal toxicity at maternally toxic doses.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

1. Hematopoietic system: Subchronic and chronic exposure can suppress the bone marrow in humans and animals. The effects are progressive, and death can result from thrombocytopenic hemorrhage.
2. Immune system: Benzene suppresses the immune response in both humans and animals. Chronically exposed workers have died from infections.
3. Nervous system: Chronically exposed workers exhibited EEG changes and peripheral nerve damage.

3.4.2.2. Other Target Organs

1. Reproductive system: Benzene produces fetal toxicity at maternally toxic doses.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

No data were found.

4.1.2. Animal

The NTP (1986; Huff et al., 1989) conducted an oral (gavage) carcinogenicity study in F344/N rats and B6C3F₁ mice. Doses of benzene, ranging from 25 to 200 mg/kg, were administered 5 days/week for 103 weeks. Both species developed dose-related lymphocytopenia. Rats exhibited increased incidences of carcinoma of the Zymbal gland and squamous cell carcinoma of the oral cavity and skin. The mice had increased incidences of carcinomas of the Zymbal gland, malignant lymphomas and alveolar/bronchiolar carcinomas, and tumors of the ovaries and mammary glands. The increased incidences of the different tumor types (in both sexes, both species) were generally dose-related and statistically significant at p<0.05.

In another study, Maltoni et al. (1989) administered oral doses of 50 to 500 mg of benzene/kg to Sprague-Dawley and Wistar rats, 4-5 days/week for 52 or 104 weeks. The animals had increased incidences of carcinomas of the Zymbal gland, oral cavity, nasal cavity, forestomach and liver. Swiss mice given 500 mg of benzene/kg/day for 52 weeks developed mammary carcinomas (Maltoni et al., 1989).

4.2. INHALATION EXPOSURES

4.2.1. Human

Occupational exposure to benzene has been associated with increased incidences of acute myeloblastic or erythroblastic leukemias and chronic myeloid and lymphoid leukemias among workers (Aksoy, 1989). A few investigations suggest that benzene may also be involved in the development of malignant lymphoma, multiple myeloma (Aksoy, 1980; Aksoy et al., 1984, Rinsky et al. 1987), and lung cancer (Aksoy, 1976). The U.S. EPA (1985) used the epidemiologic studies of Rinsky et al. (1981), Ott et al. (1978), and Wong et al. (1983) to derive quantitative estimates of carcinogenic risk for benzene.

In a retrospective cohort mortality study, Rinsky et al. (1981) observed seven deaths from leukemia among 748 white workers who were exposed to benzene in rubber manufacturing facilities and followed for at least 24 years. The increased incidence was statistically significant (standard mortality ratio [SMR] was 560). Five leukemia deaths occurred among workers with more than 5 years of exposure (SMR, 2100). Exposures ranged from 10-100 ppm 8-hour TWA.

In another retrospective cohort mortality study, Ott et al. (1978) observed three deaths from leukemia (0.8 expected; SMR, 375) among 594 workers exposed to benzene in three production areas of a chemical company and followed for at least 23 years. The increase was not statistically significant. Exposures ranged from <2 to >25 ppm for an 8-hour TWA.

In a historical prospective mortality study, Wong et al. (1983) examined a study population of 4062 workers from seven chemical plants whose jobs were categorized according to peak exposure. The workers were exposed to benzene for at least 6 months. Dose-dependent increases in leukemia and lymphatic and hematopoietic cancer were found. For leukemia, 7 deaths were observed, 5.96 were expected (SMR, 117.4); this is not statistically significant. (However, the unexposed subjects exhibited a less than expected incidence of neoplasia, complicating the interpretation of the results.)

Other studies, such as that of 28,500 workers in the shoe manufacturing industry (Aksoy et al., 1974), support the association between exposure to benzene and the development of leukemia. The workers had been exposed to benzene levels of 210 to 650 ppm for durations ranging from 1 to 15 years. The annual incidence rate for leukemia was 13/100,000 for the shoe manufacturers, compared with 6/100,000 for the general population. Aksoy (1977) later revised their estimated incidence of leukemia among the general population in Turkey to 2.5 to 3/100,000, increasing the significance of leukemia in the exposed workers.

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. The cohort consisted of 4602 male workers who were occupationally exposed to benzene for at least six months. The controls were male chemical workers employed at the plants during the same period, but never exposed to benzene. Cohort members were divided into three exposure groups: <180 ppm-months, 180-719 ppm-months, and >=720 ppm-months. The dose-response relationships between the cumulative exposure to benzene and mortality from all lymphopoietic cancers combined and from leukemia were statistically significant (p=0.02 and p=0.01, respectively), while the dose response relationship between cumulative exposure and non-Hodgkin's lymphopoietic cancer was of borderline statistical significance (p=0.06).

Various other epidemiologic and case studies, reporting an increased incidence or a causal relationship between leukemia and exposure to benzene, have been reviewed by, among others, Goldstein (1977), IARC (1982), Infante and White (1983), Snyder (1984), Aksoy (1989), (USAF, 1989), (ATSDR, 1989), and Brett et al. (1989).

4.2.2. Animal

Benzene vapors are carcinogenic to both rats and mice. Sprague-Dawley rats exposed to vapor concentrations of 200-300 ppm benzene 4-7 hours daily for 104 weeks developed mammary carcinomas (incidence, 26.6%), hepatomas (2.3%) and leukemia (1.4%) (Maltoni et al., 1983). C57Bl/J6 mice exposed to vapor concentrations of 300 ppm, 6 hours/day, 5 days/week for life had an increased incidence of thymic lymphoma (Snyder et al., 1980; C57Bl/BNL mice exposed to 300 ppm, 6 hours/day, 5 days/week for only 16 weeks developed increased incidences of leukemia, lymphoma, and solid tumors over several months of observation (Cronkite et al., 1985; Cronkite, 1986).

4.3. OTHER ROUTES OF EXPOSURE

4.3.1. Human

No data were found.

4.3.2. Animal

Papillomas did not develop in mice given topical applications of 800 mg/kg/day of benzene (initiator) and 1 g of 12-0-tetradecanoylphorbol-13-acetate (promoter) and observed for 52 weeks (Bull et al., 1986).

4.4. EPA WEIGHT-OF-EVIDENCE

4.4.1. Oral

Classification--A, human carcinogen

Basis--"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" (U.S. EPA, 1992a).

4.4.2. Inhalation

Classification--A, human carcinogen

Basis--"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" (U.S. EPA, 1992a).

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

• SLOPE FACTOR: 2.9E-2 (mg/kg/day)^-1 (U.S. EPA, 1992a)
• ORAL UNIT RISK: 8.3E-7 (g/L)^-1 (U.S.EPA, 1992a)
• PRINCIPAL STUDIES: Ott et al. (1978), Rinsky et al. (1981), and Wong et al. (1983).
• VERIFICATION DATE: 10/09/87
• COMMENT: Route-to-route extrapolation is based on increased incidences of leukemia in occupational inhalation studies (U.S. EPA, 1991a). Pharmacokinetic data that could impact the oral risk assessment are undergoing evaluation by the EPA (U.S. EPA, 1991a).

4.5.2. Inhalation

• SLOPE FACTOR: 2.9E-2 (mg/kg/day)^-1 (U.S. EPA, 1992b)
• INHALATION UNIT RISK: 8.3E-6 (g/m³)^-1 (U.S. EPA, 1992a)
• PRINCIPAL STUDIES: Ott et al. (1978), Rinsky et al. (1981), and Wong et al. (1983)
• VERIFICATION DATE: 10/09/87

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