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PubMed2001

Determination of the structure of 2(benzene-1,3,5-tricarboxylic acid)-1.5(pyrene)-2(methanol) and comparison with that of 2(benzene-1,3,5-tricarboxylic acid)-pyrene-2(ethanol).

The structure of the title methanol complex (P1;, Z = 2) has been determined and compared with that of the title ethanol complex (C2/c, Z = 8) using published data. Both complexes have layer structures, the (essentially planar) layers being constructed from rings of six TMA molecules, hydrogen bonded through four 'carboxyl dimers' and two 'interrupted dimers', where methanol (ethanol) is included in the R4(4)(12) (graph set) ring. The packing of the layers differs in the two complexes, leading to different three-dimensional structures. In the methanol complex, one pyrene molecule is located within the layer and the other, at a centre of symmetry, between the layers in one type of interlayer space, while the methyls of methanol protrude into the other type of interlayer space. In the ethanol complex, the superpositioning of the layers is such that two types of stack are formed; one of these is mixed, containing pyrene and one of the independent TMA molecules in alternating sequence, while the other stack contains only the second type of TMA. Spectroscopic study is needed to establish whether the partial mixed stack arrangement in the crystalline ethanol complex implies donor-acceptor interaction.

Journal Article↗
PubMed2003

Benzene metabolism in rodents at doses relevant to human exposure from urban air.

Benzene is both an environmental pollutant and a component of cigarette smoke, gasoline, and automotive emissions. Although occupational exposure to benzene has been shown to cause blood disorders and cancer in humans, the potential health effects resulting from exposure to low levels of benzene are not known. The goals of this project were to determine how well benzene is metabolized and to assess its binding to macromolecules in rodents at doses more closely mimicking human environmental exposure. To determine whether genotoxic metabolites of benzene are produced at environmental exposure levels. various doses of 14C-benzene were given intraperitoneally to male B6C3F1 mice at doses from 5 ng/kg to 500 mg/kg body weight. Samples of urine, plasma, liver, and bone marrow were taken at selected times up to 48 hours after exposure. Individual benzene metabolites in the samples were measured by accelerator mass spectrometry (AMS*). Metabolites were quantified by determining the area under the curve (AUC) for 24 to 48 hours. The major metabolites found in urine were an unidentified radiolabeled metabolite. phenyl sulfate, phenyl glucuronide. and muconic acid (an indicator of muconaldehyde formation). The major metabolites found in plasma, liver, and bone marrow samples were muconic acid and hydroquinone. Only liver showed a dose response for hydroquinone and muconic acid. The kinetics of both DNA and protein adduct formation were assessed over 48 hours at a 14C-benzene dose of 5 microg/kg body weight. A dose-response study was then conducted using 14C-benzene doses from 5 ng/kg to 500 mg/kg body weight in B6C3F1 mice. Adduct levels were determined by AMS in liver and bone marrow. DNA and protein adducts in liver reached maximum levels 30 minutes after benzene administration, whereas those in bone marrow reached maximum levels after six hours. Both protein and DNA adduct AUCs were greater in bone marrow than in liver. Dose-response assessments at both 1 and 12 hours showed that DNA and protein adducts in liver and bone marrow were dose dependent over doses spanning eight orders of magnitude. Consistent with the benzene metabolism data, these data show that reactive forms of benzene were present in liver and bone marrow after exposure to human-relevant benzene levels. Thus, at low doses, benzene was absorbed and metabolized into reactive intermediates capable of binding to DNA and protein. The relation between benzene metabolism and macromolecular binding was examined by comparing benzene macromolecular adduct formation among strains of male mice (B6C3F1, DBA/2, and C57BL/6) and male rats. These animals have been reported to have different metabolic capacities for benzene and also different tumorigenic and cytotoxic responses to benzene exposure. We hypothesized that differences in the capacity to metabolize benzene affect macromolecular adduct formation and that the amount of macromolecular damage is related to benzene's ability to cause cancer and other blood disorders. 14C-benzene was administered intraperitoneally to all rodents (5 microg/kg body weight) and adduct levels were determined by AMS at selected time points up to 48 hours after exposure. AUCs for protein and DNA adducts in bone marrow, the primary target organ for benzene toxicity, decreased in the following order: B6C3F1, DBA/2, C57BL/6, and rats. Similarly, adduct AUCs in liver were greater in B6C3F1 mice than in rats although the trend was less clear for the DBA/2 and C57BL/6 mouse strains. The results of this work are consistent with previously published work showing that the ability to metabolize benzene follows a similar pattern with these animals and is consistent with the tumorigenicity of benzene in mice and rats. Thus, our data suggest that benzene toxicity is related to the ability to produce macromolecular adducts. Preliminary studies were conducted to assess adduct dosimetry after low-dose inhalation of benzene. Inhalation methods were developed to administer a nominal body burden of 5 microg benzene/kg body weight. Then, 14C-benzene was administered to B6C3F1 mice and rats by both intraperitoneal (IP) administration and by inhalation, and DNA and protein adducts in liver and bone marrow were analyzed by AMS. AUCs for adduct levels were greater after IP benzene administration than after inhalation of benzene. Adduct levels were greater in DNA from B6C3F1 mouse bone marrow than in DNA from liver regardless of exposure route. Collectively, these data show that the internally reactive dose was greater when benzene exposure was by IP administration. In summary, the results suggest that benzene is metabolized to reactive forms capable of binding both protein and DNA in target and nontarget organs of rats and mice at doses encountered by humans through environmental exposure. Macromolecular binding was dose-dependent at low doses of benzene and reflected benzene toxicity, based on its carcinogenicity and ability to cause other blood-related disorders. These data are consistent with macromolecular adducts being indicative of benzene exposure and benzene toxicity although much more research is needed to validate this point. Additionally, benzene metabolism varies among species and among strains within a species of rodent. Thus data are needed in humans to understand how to use the rodent data in risk assessment and ultimately to determine whether macromolecular adducts are a useful indicator of exposure and a useful predictor of risk.

Air Pollutants↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Benzene ranks 16th in production volume for chemicals produced in the United States, with approximately 9.9 billion pounds being produced in 1984, 9.1 billion pounds in 1983, and 7.8 billion pounds in 1982. This simplest aromatic chemical in used in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. Benzene, along with other light, high-octane aromatic hydrocarbons, such as toluene and xylenes, is a component of motor gasoline. Benzene is also used as a solvent, but for most applications, it has been replaced by less hazardous solvents. During the 17-week studies, groups of 10 or 15 male and female F344/N rats and B6C3F1 mice were gavaged 5 days per week with benzene in corn oil (5 ml/kg) at doses of 0 to 600 mg/kg. No benzene-related deaths occurred; in rats that received benzene, final mean body weights were 14%-22% lower compared with vehicle controls and in mice, slight dose-related reductions were observed (less than 10% differences). Doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Two-year toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten additional animals in each of the 16 groups were killed at 12 months and necropsies were performed. Hematologic profiles were performed at 3-month intervals. These studies were designed and conducted because of large production volume and potential human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining potential carcinogenicity in laboratory animals. In the 2-year studies, mean body weights of the 200 mg/kg male rats (-23%) and the 100 mg/kg mice (-14% to -19%) were lower than those of the vehicle controls, and survival of dosed groups decreased with increasing dose (rats--male: vehicle control, 32/50; low dose, 29/50; mid dose, 25/50; high dose, 16/50; female: 46/50; 38/50; 34/50; 25/50; mice--male: 28/50; 23/50; 18/50; 7/50; female: 30/50; 26/50; 24/50; 18/50). At week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Significantly increased (P<0.05) incidences of neoplasms were observed at multiple sites for male and female rats and for male and female mice. Primary neoplasms observed in rats and mice are summarized in Table 1 (see page 12 of the Technical Report). Hematologic data from vehicle control and dosed rats and mice were obtained at 3-month intervals from 0 to 24 months. Reliably identifiable hematologic effects were limited to lymphocytopenia and associated leukocytopenia in benzene-dosed rats and mice. These effects were seen from 3 to 18 months in dosed male rats and in dosed male mice; a similar but less pronounced response was observed in dosed female rats during this same time period. The effect in female mice was limited to 12-18 months. The technical quality of certain of these data was questionable; thus, more detailed analyses (e.g., investig questionable; thus, more detailed analyses (e.g., investigation of the association between hematologic and pathologic changes) are deemed inappropriate for these data. Benzene increased the frequency of micronucleated normchromatic peripheral erythrocytes in male and female mice (rats were not examined); males were more sensitive than females. The hematopoietic system of rats and mice of each sex was affected by benzene in the 2-year studies. The incidences of malignant lymphomas in all dosed groups of mice were greater than those in the vehicle controls (male: 4/49; 9/48; 9/50; 15/49; female: 15/49; 24/45; 24/50; 20/49). Lymphoid depletion of the splenic follicles (rats) and thymus (male rats) was observed at increased incidences. Bone marrow hematopoietic hyperplasia was observed at increased incidences in dosed mice of each sex (male: 0/49; 11/48; 10/50; 25/49; female: 3/49; 14/45; 8/50; 13/49). The incidences of Zymbal gland carcinomas in mid and high dose male rats and in dosed female rats were greater than those in the vehicle controls (male: 2/32; 6/46; 10/42; 17/42; female: 0/45; 5/40; 5/44; 14/46). The incidences of Zymbal gland carcinomas in mid and high dose male mice and in high dose female mice were greater than those in the vehicle controls (male: 0/43; 1/34; 4/40; 21/39; female: 0/43; 0/32; 1/37; 3/31). In mid and high dose male mice and in high dose female mice, the incidences of epithelial hyperplasia of the Zymbal gland were also increased (male: 0/43; 3/34; 12/40; 10/39; female: 1/43; 1/32; 2/37; 6/31). Hyperplasia of the adrenal capsule was observed at increased incidences in dosed mice of each sex (male: 2/47; 32/48; 14/49; 4/46; female: 5/49; 19/44; 34/50; 30/48). The incidence of pheochromocytomas in mid dose male mice was greater than that in the vehicle controls (male: 1/47; 1/48; 7/49; 1/46), whereas the incidences in dosed female mice were lower than that in the vehicle controls (female: 6/49; 1/44; 1/50; 1/48). Hyperplasia of the zona fasciculata of the adrenal cortex was observed at increased incidences in low dose rats of each sex (male: 0/50; 13/49; 0/48; 2/49; female: 0/50; 17/50; 0/47; 0/49). Benzene was associated with increased incidences of neoplasms of the skin and oral cavity of rats. The incidences of squamous cell papillomas and squamous cell carcinomas of the skin in high dose male rats were greater than those in the vehicle controls (squamous cell papilloma: 0/50; 2/50; 1/50; 5/50; squamous cell carcinoma: 0/50; 5/50; 3/50; 8/50). Increased incidences of uncommon squamous cell papillomas or squamous cell carcinomas (combined) of the oral cavity were observed in dosed male and female rats (male: 1/50; 9/50; 16/50; 19/50; female: 1/50; 5/50; 12/50; 9/50). Incidences of squamous cell papillomas or carcinomas (combined) (male: 2/45; 2/42; 3/44; 5/38; female: 1/42; 3/40; 6/45; 5/42), hyperkeratosis, and epithelial hyperplasia of the forestomach were increased in some dosed groups of male and female mice; incidences of hyperkeratosis and acanthosis were increased in high dose male rats. Compound-related effects in the lung, harderian gland, preputial gland, ovary, mammary gland, and liver were seen in mice but not in rats. Administration of benzene was associated with increased incidences of alveolar epithelial hyperplasia in mid and high dose mice (male: 2/49; 3/48; 7/50; 10/49; female: 1/49; 1/42; 9/50; 6/49). Increased incidences of alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined) were observed in high dose male mice (carcinomas: 5/49; 11/48; 12/50; 14/49; adenomas or carcinomas: 10/49; 16/48; 19/50; 21/49). Alveolar/bronchiolar adenomas were seen at increased incidences in high dose female mice (4/49; 2/42; 5/50; 9/49), as were alveolar/bronchiolar carcinomas (0/49; 3/42; 6/50; 6/49) and alveolar/bronchiolar adenomas or carcinomas combined (4/49; 5/42; 10/50; 13/49) in mid and high dose female mice. The incidences of focal or diffuse hyperplasia of the harderian gland were increased in dosed mice of each sex (male: 0/49; 5/46; 11/49; 7/48; female: 6/48; 10/44; 11/50; 10/47). The incidences of harderian gland adenomas (0/49; 9/46; 13/49; 11/48) in dosed male mice were greater than that in the vehicle controls. A marginal increase in the incidence of adenomas or carcinomas (combined) of the harderian gland was seen in high dose female mice (5/48; 6/44; 10/50; 10/47). The administration of benzene to male mice was associated with increased incidences of hyperplasia (1/21; 18/28; 9/29; 1/35) and squamous cell carcinomas (0/21; 3/28; 18/29; 28/35) of the preputial gland. Increased incidences of mammary gland carcinomas were found in mid dose and high dose female mice (0/49; 2/45; 5/50; 10/49) and carcinosarcomas in high dose female mice (0/49; 0/45; 1/50; 4/49). Increased incidences of various uncommon neoplastic and nonneoplastic lesions of the ovary (papillary cystadenoma, luteoma, granulosa cell tumor, tubular adenoma, benign mixed tumor, epithelial hyperplasia, and senile atrophy) were associated with the administration of benzene to female mice. In mid and high dose female mice, the incidences of granulosa cell tumors (1/47; 1/44; 6/49; 7/48) and benign mixed tumors (0/47; 1/44; 12/49; 7/48) were greater than those in the vehicle controls. Increased incidences of hepatocellular adenomas were observed in low dose female mice (1/49; 8/44; 5/50; 4/49) and hepatocellular adenomas or carcinomas (combined) in low dose and mid dose female mice (4/49; 12/44; 13/50; 7/49). An audit of the experimental data was conducted for these 2-year carcinogenesis studies on benzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice, and for female B6C3F1 mice. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. Dose-related lymphocytopenia was observed for male and female F344/N rats and male and female B6C3F1 mice. Synonyms: benzol, cyclohexatriene, pyrobenzol

Journal Article↗
PubMed1995

Benzene oxidation coupled to sulfate reduction.

Highly reduced sediments from San Diego Bay, Calif., that were incubated under strictly anaerobic conditions metabolized benzene within 55 days when they were exposed initially to 1 (mu)M benzene. The rate of benzene metabolism increased as benzene was added back to the benzene-adapted sediments. When a [(sup14)C]benzene tracer was included with the benzene added to benzene-adapted sediments, 92% of the added radioactivity was recovered as (sup14)CO(inf2). Molybdate, an inhibitor of sulfate reduction, inhibited benzene uptake and production of (sup14)CO(inf2) from [(sup14)C]benzene. Benzene metabolism stopped when the sediments became sulfate depleted, and benzene uptake resumed when sulfate was added again. The stoichiometry of benzene uptake and sulfate reduction was consistent with the hypothesis that sulfate was the principal electron acceptor for benzene oxidation. Isotope trapping experiments performed with [(sup14)C]benzene revealed that there was no production of such potential extracellular intermediates of benzene oxidation as phenol, benzoate, p-hydroxybenzoate, cyclohexane, catechol, and acetate. The results demonstrate that benzene can be oxidized in the absence of O(inf2), with sulfate serving as the electron acceptor, and suggest that some sulfate reducers are capable of completely oxidizing benzene to carbon dioxide without the production of extracellular intermediates. Although anaerobic benzene oxidation coupled to chelated Fe(III) has been documented previously, the study reported here provides the first example of a natural sediment compound that can serve as an electron acceptor for anaerobic benzene oxidation.

Journal Article↗
PubMed1998

Benzene in environmental air and human blood.

OBJECTIVE: To study the blood benzene levels resulting from environmental and occupational benzene exposure. METHODS: Benzene in venous blood was measured in 243 nonoccupationally exposed subjects ("normal" people) and in 167 workers occupationally exposed to benzene. All exposed workers gave blood samples at the end of the work shift and on the following morning before resuming work. Blood benzene was assayed by gas chromatography (GC)-mass spectrometry. Occupational benzene exposure was monitored by environmental personal samplers and measured by GC analysis. RESULTS: The mean occupational benzene exposure for all 167 workers studied was 186 ng/l (58 ppb; range 5 1535 ng/l, 2-500 ppb). Overall, the mean blood benzene level of all workers was 420 ng/1 at the end of the shift and 287 ng/l on the morning thereafter. The blood benzene levels measured the morning after turned out to be significantly lower (t=3.6; P < 0.0001) than those measured at the end of the shift. The mean blood benzene level of the 243 "normal" subjects was 165 ng/l, which was significantly lower than that measured in the workers on the morning thereafter (t=5.8: P < 0.0000001). The mean blood benzene concentration was significantly higher in smokers than in nonsmokers in both the general population (264 versus 123 ng/l) and in the exposed workers. In the group of nonsmoking workers, whose workplace exposure to benzene was lower than 100 ng/l, blood benzene levels were similar (210-202 ng/l) to those measured in the nonsmoking general population (165 ng/l). End-of-shift blood benzene correlated significantly with environmental exposure (y=0.91x + 251; r=0.581; n=162; P < 0.00001). Finally, there was also a significant correlation between blood benzene measured at the end of the shift and that determined on the morning thereafter (y=0.45x + 109; r=0.572; n=156; P < 0.00001). CONCLUSION: Nonsmoking workers occupationally exposed to benzene at environmental levels lower than 100 ng/l (mean 35 ng/l) and the nonsmoking general population exposed to ubiquitous benzene pollution have similar blood benzene concentrations. This suggests that it is impossible to distinguish between occupational and environmental exposure when the benzene level in the workplace is less than 100 ng/l.

Air Pollutants↗
PubMed1995

Evaluation of biomarkers for occupational exposure to benzene.

OBJECTIVE: To evaluate the relations between environmental benzene concentrations and various biomarkers of exposure to benzene. METHODS: Analyses were carried out on environmental air, unmetabolised benzene in urine, trans, trans-muconic acid (ttMA), and three major phenolic metabolites of benzene; catechol, hydroquinone, and phenol, in two field studies on 64 workers exposed to benzene concentrations from 0.12 to 68 ppm, the time weighted average (TWA). Forty nonexposed subjects were also investigated. RESULTS: Among the five urinary biomarkers studied, ttMA correlated best with environmental benzene concentration (correlation coefficient, r = 0.87). When urinary phenolic metabolites were compared with environmental benzene, hydroquinone correlated best with benzene in air. No correlation was found between unmetabolised benzene in urine and environmental benzene concentrations. The correlation coefficients for environmental benzene and end of shift catechol, hydroquinone, and phenol were 0.30, 0.70, and 0.66, respectively. Detailed analysis, however, suggests that urinary phenol was not a specific biomarker for exposure below 5 ppm. In contrast, ttMA and hydroquinone seemed to be specific and sensitive even at concentrations of below 1 ppm. Although unmetabolised benzene in urine showed good correlation with atmospheric benzene (r = 0.50, P < 0.05), data were insufficient to suggest that it is a useful biomarker for exposure to low concentrations of benzene. The results from the present study also showed that both ttMA and hydroquinone were able to differentiate the background level found in subjects not occupationally exposed and those exposed to less than 1 ppm of benzene. This suggests that these two biomarkers are useful indices for monitoring low concentrations of benzene. Furthermore, these two metabolites are known to be involved in bone marrow leukaemogenesis, their applications in biological monitoring could thus be important in risk assessment. CONCLUSION: The good correlations between ttMA, hydroquinone, and atmospheric benzene, even at concentrations of less than 1 ppm, suggest that they are sensitive and specific biomarkers for benzene exposure.

Air Pollutants, Occupational↗
PubMed1989

A physiological model for simulation of benzene metabolism by rats and mice.

Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice are more sensitive to the toxic effects of benzene than are F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice and to determine if the observed differences in toxic effects could be explained by differences in the pathways for metabolism of benzene or by differences in uptake of benzene. Major pathways for elimination of benzene included metabolism to hydroquinone glucuronide or hydroquinone sulfate, phenyl glucuronide or phenyl sulfate, muconic acid, and prephenyl mercapturic acid or phenyl mercapturic acid. Model simulations for total benzene metabolized and for profiles of benzene metabolites were conducted for oral or inhalation exposure and compared to data for urinary excretion of benzene metabolites after exposure of rats and mice to [14C]- or [3H]-benzene by inhalation or gavage. Results for total amount of benzene metabolized, expressed per kilogram body weight, indicated that for inhalation exposure concentrations up to 1000 ppm, mice metabolized at least two to three times as much benzene as did rats. Simulations of oral exposure to benzene resulted in more benzene metabolized per kilogram body weight by rats at oral exposures of greater than 50 mg/kg. Patterns of metabolites formed after either route of exposure were very different for F344/N rats and B6C3F1 mice. Rats primarily formed the detoxification metabolite, phenyl sulfate. Mice formed hydroquinone glucuronide and muconic acid in addition to phenyl sulfate. Hydroquinone and muconic acid are associated with pathways leading to the formation of the putative toxic metabolites of benzene. Metabolic rate parameters, Vmax and Km, were very different for hydroquinone conjugate and muconic acid formation compared to formation of phenyl conjugates and phenyl mercapturic acids. Putative toxication pathways could be characterized as high affinity, low capacity whereas detoxification pathways were low affinity, high capacity. Model simulations suggested that for both rats and mice at lower exposure concentrations hydroquinone and muconic acid represented a larger fraction of the total benzene metabolized than at higher exposure concentrations where detoxification metabolites were predominant. Preferential production of a putative toxic metabolite at low exposure concentrations may have important implications in risk assessment for benzene.

Administration, Inhalation↗
PubMed1988

Environmental and occupational exposure to benzene by analysis of breath and blood.

Benzene exposure of chemical workers was studied, during the entire workshift, by continuous monitoring of workplace benzene concentration, and 16 hours after the end of the workshift by the measurement of alveolar and blood benzene concentrations and excretion of urinary phenol. Exposure of hospital staff was studied by measuring benzene concentrations in the alveolar and blood samples collected during the hospital workshift. Instantaneous environmental air samples were also collected, at the moment of the biological sampling, for all the subjects tested. A group of 34 chemical workers showed an eight hour exposure to benzene, as a geometric mean, of 1.12 micrograms/l which corresponded, 16 hours after the end of the workshift, to a geometric mean benzene concentration of 70 ng/l in the alveolar air and 597 ng/l in the blood. Another group of 27 chemical workers (group A) turned out to be exposed to an indeterminable eight hour exposure to benzene that corresponded, the morning after, to a geometric mean benzene concentration of 28 ng/l in the alveolar air and 256 ng/l in the blood. The group of hospital staff (group B) had a benzene concentration of 14 ng/l in the alveolar air and 269 ng/l in the blood. Instantaneous environmental samples showed that in the infirmaries the geometric mean benzene concentration was 58 ng/l during the examination of the 34 chemical workers, 36 ng/l during the examination of the 27 chemical workers (group A), and 5 ng/l during the examination of the 19 subjects of the hospital staff (group B). Statistical analysis showed that the alveolar and blood benzene concentrations in the 34 workers exposed to 1.12 microgram/l of benzene differed significantly from those in groups A and B. It was found, moreover, that the alveolar and blood benzene concentrations were higher in the smokers in groups A and B but not in the smokers in the group of 34 chemical workers. The slope of the linear correlation between the alveolar and the instantaneous environmental benzene concentrations suggested a benzene alveolar retention of about 55%. Blood and alveolar benzene concentrations showed a highly significant correlation and the blood/air partition coefficient, obtained from the slope of the regression line, was 7.4. In the group of the 34 chemical workers no correlation was found between the TWA benzene exposure and the urinary phenol excretion.

Benzene↗
PubMed1976

Effect of phenobarbital pretreatment on in vitro enzyme kinetics and in vivo biotransformation of benzene in the rat.

Phenobarbital pretreatment (50 mg/kg/day for 3 days orally) of male Wistar rats increased Vmax of benzene in vitro hepatic microsomal biotransformation about 6-fold without changing Km. However, benzene blood levels after oral, intraperitoneal, or subcutaneous benzene administration (3-3.5 mmoles/kg) were not influenced by phenobarbital pretreatment. The phenol blood levels after oral or intraperitoneal benzene were increased by phenobarbital pretreatment, but less than expected from in vitro data and only 3 h after benzene administration. Phenol elimination in urine after subcutaneous benzene was not affected by phenobarbital. After oral or intraperitoneal benzene administration, phenol urine excretion closely followed the levels of phenol in blood, i.e., rate of phenol urine excretion was significantly, but shortly increased, and the cumulative urine excretion of phenol increased very little or remained unchanged. Differences between the in vitro and in vivo observations of the effect of phenolbarbital on benzene biotransformation may partly be explained by distribution of benzene, which apparently limited benzene availability for biotransformation (Vd = 5.5) and caused rapid decrease of benzene concentrations in blood. Conditions for enzyme activity may have been substantially different in vitro vs. in vivo: in vitro concentrations of benzene were at least by an order of magnitude higher than phenol concentrations, while in vivo, an opposite relation prevailed making a competition for microsomal monooxygenase possible. Cofactor availability may be another rate-limiting step or factor of in vivo benzene biotransformation, as benzene ring hydroxylation requires high energy. The rate of in vitro hepatic microsomal benzene biotransformation proved to be of limited value when predicting benzene quantitative biotransformation in vivo in contradistinction to various substrates where the in vitro and in vivo biotransformation data are in good agreement.

Administration, Oral↗
PubMed2002

Anaerobic benzene biodegradation--a new era.

Benzene is biodegraded in the absence of oxygen under a variety of terminal electron-accepting conditions. However, the mechanism by which anaerobic benzene degradation occurs is unclear. Phenol and benzoate have been consistently detected as intermediates of anaerobic benzene degradation, suggesting that the hydroxylation of benzene to phenol is one of the initial steps in anaerobic benzene degradation. The conversion of phenol to benzoate could then occur by the carboxylation of phenol to form 4-hydroxybenzoate followed by the reductive removal of the hydroxyl group to form benzoate. 13C-Labeling studies suggest that the carboxyl carbon of benzoate is derived from one of the carbons of benzene. Although the fumarate addition reaction is commonly used to activate many hydrocarbons for anaerobic degradation, the large activation energy required to remove hydrogen from the benzene ring argues against such an approach for anaerobic benzene metabolism. The alkylation of benzene to toluene has been detected in several mammalian tissues, and offers an interesting alternate hypothesis for anaerobic benzene degradation in microbial systems. In support of this, anaerobic benzene degradation by Dechloromonas strain RCB, the only known species to degrade benzene in the absence of oxygen, is stimulated by the addition of vitamin B12 and inhibited by the addition of propyl iodide which is consistent with the involvement of a corrinoid enzymatic step. Alkylation of benzene to toluene is also consistent with labeling data that suggests that the carboxyl carbon of benzoate is derived from one of the benzene carbons. However, it is difficult to envision how phenol would be formed if benzene is alkylated to toluene. As such, it is possible that diverse mechanisms for anaerobic benzene degradation may be operative in different anaerobic microorganisms.

Anaerobiosis↗
PubMed1994

Critical issues in benzene toxicity and metabolism: the effect of interactions with other organic chemicals on risk assessment.

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene are well documented and include aplastic anemia and pancytopenia. Some individuals exposed repeatedly to cytotoxic concentrations of benzene develop acute myeloblastic anemia. It has been hypothesized that metabolism of benzene is required for its toxicity, although administration of no single benzene metabolite duplicates the toxicity of benzene. Several investigators have demonstrated that a combination of metabolites (hydroquinone and phenol, for example) is necessary to duplicate the hematotoxic effect of benzene. Enzymes implicated in the metabolic activation of benzene and its metabolites include the cytochrome P450 monooxygenases and myeloperoxidase. Since benzene and its hydroxylated metabolites (phenol, hydroquinone, and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with competitive inhibition of phenol oxidation by benzene. Other organic molecules that are substrates for cytochrome P450 can inhibit the metabolism of benzene. For example, toluene has been shown to inhibit the oxidation of benzene in a noncompetitive manner. Enzyme inducers, such as ethanol, can alter the target tissue dosimetry of benzene metabolites by inducing enzymes responsible for oxidation reactions involved in benzene metabolism. The dosimetry of benzene and its metabolites in the target tissue, bone marrow, depends on the balance of activation processes, such as enzymatic oxidation, and deactivation processes, like conjugation and excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Age-related changes in benzene disposition in male C57BL/6N mice described by a physiologically based pharmacokinetic model.

A physiologically based pharmacokinetic (PBPK) model was developed to describe the disposition of benzene in 3- and 18-month C57BL/6N mice and to examine the relevant physiologic and/or biochemical parameters governing previously observed age-related changes in the disposition of benzene. The model developed was based on that of Medinsky et al. (Toxicol. Appl. Pharmacol. 99 (1989) 193-206), with the inclusion of an additional rate constant for urinary elimination of benzene metabolites. Experimentally determined tissue partition coefficients for benzene in 3- and 18-month mice, as well as actual body weights and fat compartment volumes, were included as part of the model. Model simulations were conducted for oral exposure of 3-month mice to 10 and 200 mg benzene/kg and for oral exposure of 18-month mice to 10 and 150 mg benzene/kg. Total amount of benzene metabolized, as well as metabolism of benzene to specific metabolites and their elimination, was simulated. Modeling results for total amount of benzene metabolites eliminated in urine over a 24-h period at 10 mg/kg showed that a greater total amount of benzene metabolites would be excreted by 18-month versus 3-month old mice. At saturating doses of 150 and 200 mg/kg, total amount of benzene metabolites excreted 24 h post-dose was predicted to be equivalent in 18-month mice and 3-month old mice, but the rate of elimination over time was shown to be decreased in 18-month vs. 3-month mice. Decreased urinary elimination of total benzene metabolites was simulated by a smaller renal elimination rate constant in 18-month vs. 3-month mice, which is consistent with decreased renal blood flow noted in aging rodents. These model predictions were consistent with observed in vitro and in vivo experimental data. Model simulations for production of specific metabolites from benzene and elimination in urine agreed well with experimental data in showing no significant age-related changes in formation of benzene metabolites, with the exception of hydroquinone conjugates. Model simulations and experimental data showed decreased total urinary elimination of hydroquinone conjugates in 18-month vs. 3-month mice. The change in hydroquinone conjugate elimination with age was simulated in modeling experiments as an age-related increase in Km for production of hydroquinone conjugates from benzene. The results of this study indicate that age-related changes in physiology are primarily responsible for altered disposition of benzene in aged mice and suggest that concentrations for toxicity of benzene and/or metabolites may differ in target tissues of aged mice.

Adipose Tissue↗
PubMed2005

Occupational exposure to benzene in South Korea.

Benzene has been used in various industries as glues or solvents in Korea. Since 1981, a preparation containing more than 1% benzene is not allowed to be manufactured, used or dealt with in the workplace, except in laboratories and in those situations benzene must be used in a completely sealed process as specified in Industrial Safety and Health Act (ISHA). Claims for compensation of hematopoietic diseases related to benzene have been rising even though the work environment has been improved. This study was conducted to assess the status of benzene exposure in different industries in Korea. We reviewed the claimed cases investigated by the Korea Occupational Safety and Health Agency (KOSHA) between 1992 and 2000. The Survey of National Work Environment Status in 1998 was analyzed to assume the number of workers and factories exposed to benzene. In 2000, six factories were investigated to evaluate benzene exposure. Personal air monitoring was performed in 61 workers and urine samples were collected from 57 workers to measure trans,trans-muconic acid (t,t-MA). Hematologic examination has performed. Thirty-four cases of hematopoietic diseases were investigated by KOSHA including eight cases of myelodysplastic syndrome and eight cases of acute myelocytic leukemia. Eight cases were accepted as related to benzene exposure. The number of workers possibly exposed to benzene can be estimated to be 196,182 workers from 6219 factories based on the database. The geometric mean of benzene in air was 0.094 (0.005-5.311) ppm. Seven samples were higher than 1 ppm but they did not go over the 10 ppm occupational exposure limit (OEL) value in Korea. The geometric mean of trans,trans-muconic acid in urine was 0.966 (0.24-2.74) mg/g creatinine. The benzene exposure level was low except in a factory where benzene was used to polymerize other chemicals. The ambient benzene from 0.1 to 1 ppm was significantly correlated with urine t,t-MA concentration (r=0.733, p<0.01). Hematologic parameters did not show significant difference among groups divided into the level of exposure. Korean workers were not highly exposed to benzene and the level of exposure was mostly less than 1 ppm. However, there might be an excessive risk of hematopoietic disorders due to relatively high past exposure. The OEL value of benzene was amended to 1 ppm from 10 ppm in 2002 and was effective since July 2003.

Adult↗
PubMed1993

Benzene and phenol metabolism by mouse and rat liver microsomes.

Benzene, an important industrial solvent and constituent of unleaded gasoline, causes leukemia and aplastic anemia in humans. Mice are more sensitive than rats to benzene toxicity, though neither species has been shown to respond consistently with benzene-induced leukemia. Benzene biotransformation in liver to phenol, hydroquinone, catechol and/or muconaldehyde is thought to be necessary for its hematotoxicity and/or genotoxicity. Our goal is to develop a mathematical simulation model capable of describing the pathways and kinetics of benzene metabolism by rat and mouse liver microsomes and to assess the role of species metabolic differences in species sensitivity. Microsomes were incubated with 4 microM [U-14C]-benzene or 4 microM [U-14C]phenol. Metabolite production was quantified by extraction into ethyl acetate, HPLC separation and liquid scintillation spectroscopy. After 45 min, mouse liver microsomes converted 20% of the benzene to phenol, 31% to hydroquinone and 2% to catechol. Rat liver microsomes converted 23% of benzene to phenol, 8% to hydroquinone and 0.5% to catechol. Production of hydroquinone and catechol continued for 90 min for mouse liver microsomes, while production by rat liver microsomes had virtually ceased by 90 min. Muconic acid production by mouse liver microsomes was < 0.2% and < 0.04% from benzene and phenol respectively after 90 min. A quantitative simulation model was constructed to describe the in vitro metabolism of benzene, incorporating the reaction sequences: benzene-->phenol-->catechol-->trihydroxybenzene and phenol-->hydroquinone-->trihydroxybenzene. In the model, all of the reaction steps are assumed to be catalyzed by the same enzyme(s), cytochrome(s) P450, and benzene, phenol, hydroquinone and catechol in solution are all assumed to compete, through reversible binding, for the same reaction site(s) on cytochrome(s) P450. The simulation model accurately described both the benzene and phenol kinetic data, supporting this proposed mechanism. In particular, this model suggests that the observed inhibition of benzene on phenol metabolism, and of phenol on benzene metabolism, occurs through competition for a common reaction site, which can also bind catechol and hydroquinone.

Animals↗
PubMed1987

Chemical of current interest--benzene.

Benzene is one of the world's major commodity chemicals. It is derived from petroleum and coal and is used both as a solvent and as a starting material in chemical syntheses. The numerous industrial uses of benzene over the last century need not be recounted here, but the most recent addition to the list of uses of benzene is as a component in a mixture of aromatic compounds added to gasoline for the purpose of replacing lead compounds as anti-knock ingredients. The best known and longest recognized toxic effect of benzene is the depression of bone marrow function seen in occupationally exposed individuals. These people have been found to display anemia, leucopenia, and/or thrombocytopenia. When pancytopenia, i.e., the simultaneous depression of all three cell types, occurs and is accompanied by bone marrow necrosis, the syndrome is called aplastic anemia. In addition to observing this decrease in humans and relating it to benzene exposure, it has been possible to establish animal models which mimic the human disease. The result has been considerable scientific investigation into the mechanism of benzene toxicity. Although the association between benzene exposure and aplastic anemia has been recognized and accepted throughout most of this century, it is only recently that leukemia, particularly of the acute myelogenous type, has been related to benzene. The acceptance of benzene as an etiological agent in aplastic anemia in large measure derives from our ability to reproduce the disease in most animals treated with sufficiently high doses of benzene over the necessary time period. Unfortunately, despite extensive efforts in several laboratories, it has not been possible to establish a reproducible, reliable model for the study of benzene-induced leukemia. The recent demonstration that several animals exposed to benzene either by inhalation or in the drinking water during studies by Drs. B. Goldstein and C. Maltoni suggests that such a model may be forthcoming. Nevertheless, at this time it is not clear whether bone marrow damage of the type that leads to aplastic anemia is required for the development of leukemia. Most studies of benzene toxicity have involved dosing animals with benzene either by inhalation or by injection, using high doses to ensure a toxic response. Very few studies have concentrated on the oral route of administration and none have concentrated on administering benzene by mouth at the low doses occasionally detected in drinking water.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollutants, Occupational↗
PubMed1989

Benzene in the blood and breath of normal people and occupationally exposed workers.

Benzene was measured in blood and alveolar air of 168 men, aged 20-58 years, subdivided into four groups: blood donors, hospital staff, chemical workers occupationally exposed to benzene, and chemical workers not occupationally exposed to benzene. The group of exposed workers was employed in work places with a mean environmental exposure to benzene of 1.62 mg/M3 (8 hr TWA). Non-exposed workers were employed elsewhere in the same plant, with an environmental exposure to benzene lower than 0.1 mg/M3. Blood and alveolar air samples were collected in the morning, before the start of the work shift for the chemical workers. The group of exposed workers was found to be significantly different from the other three groups, both for blood and alveolar benzene concentrations. The mean blood benzene concentration was 789 ng/l in the exposed workers, 307 ng/l in the non-exposed workers, 332 ng/l in the hospital staff, and 196 ng/l in the blood donors. Apart from the exposed workers, blood benzene concentration was significantly higher in smokers than in non-smokers. The mean alveolar benzene concentration was 92 ng/l in the exposed workers, 42 ng/l in the non-exposed workers, 22 ng/l in the hospital staff, and 11 ng/l in the blood donors. Alveolar benzene concentration was significantly higher in smokers than in non-smokers in the groups of the hospital staff and non-exposed workers, but not in the blood donors and exposed workers. In the three groups without occupational exposure considered altogether, the alveolar benzene concentration correlated significantly with environmental benzene concentration measured at the moment of the individual examinations, both in the smokers (r = .636; p less than .001) and non-smokers (r = .628; p less than .001). In the same three groups and in the exposed workers, alveolar benzene concentration showed a significant correlation with the blood benzene concentration.

Adult↗