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PubMed1991

[Modification of metabolism and toxicity of benzene by ethanol in pregnant rats].

In last decade it was suggested that the metabolism and toxicity of some xenobiotics may be modified by several compounds that alter the activities of microsomal oxidative and conjugating enzymes. In present study the effect of ethanol on benzene metabolism and benzene-induced hemotoxicity in pregnant rats was investigated. Pregnant female Wistar rats were exposed to benzene vapors for 6 hr/day from Days 8 through 15 of gestation at concentrations of 1500 and 3000 mg/m3 or combination ethanol and benzene at the same concentrations. Ethanol was administered intragastrically at a dose of 2.5 g/kg directly before exposure to benzene or 18 hrs before. An air-exposed or ethanol treated control rats were also studied. Before, during and after exposure blood samples for leukocyte and lymphocyte counts were obtained and urine for free phenol and conjugated phenol determinations was collected. Exposure to benzene alone decreased the maternal body weight and reduced leukocyte and lymphocyte counts in peripheral blood. Ethanol administered directly before exposure to benzene in principle had no effect on the metabolism and toxicity of benzene. It reduced the conversion of benzene to free and conjugated phenol, and protected animals from reduction of body weight and lymphopenia when was given 18 hrs before. Obtained results indicate that the early phases of benzene metabolism and its toxicity may be modified by ethanol.

Animals↗
PubMed2001

Is benzene oxide homoaromatic? A microcalorimetric study.

Rate constants and heats of reaction for the aromatization of benzene oxide (1) and the acid-catalyzed aromatization of benzene hydrate (2) in highly aqueous solution giving phenol and benzene, respectively, have been measured by heat-flow microcalorimetry. The measured heat of reaction of benzene oxide, DeltaH = -57.0 kcal mol(-1), is much larger than that of benzene hydrate, DeltaH = -38.7 kcal mol(-1), despite an unusually low reactivity of benzene oxide, rate ratio 0.08. The measured enthalpies agree with those calculated using the B3LYP hybrid functional corrected with solvation energies derived from semiempirical AM1/SM2 calculations. Comparison with the measured enthalpies of the corresponding reactions of the structurally related 1,3-cyclohexadiene oxide (3) and 2-cyclohexenol (4) of DeltaH = -24.9 kcal mol(-1) (includes a small calculated correction of -1.2 kcal mol(-1)) and DeltaH approximately 0 kcal mol(-1), respectively, gives a smaller aromatization energy for the benzene oxide than for the benzene hydrate reaction (DeltaDeltaDeltaH = 6.6 kcal mol(-1)). This suggests that benzene oxide is unusually stabilized by a significant amount of homoaromatization as has been proposed previously (J. Am. Chem. Soc. 1993, 115, 5458). This unusual stability accounts for more than half of the approximately 10(7) times lower than expected reactivity of benzene oxide toward acid-catalyzed isomerization. The rest is suggested to originate from an unusually high energy of the carbocation-forming transition state.

Calorimetry↗
PubMed2005

Spectroscopic study of mutual solubilities of water and benzene at high temperatures and pressures.

Near-infrared and ultraviolet absorption of water-benzene mixtures has been measured at temperatures and pressures in the ranges of 323-673 K and 50-400 bar, respectively. Concentrations of water and benzene in both the water-rich phase and the benzene-rich phase of the mixtures were obtained from absorption intensities of near-infrared bands of water and benzene and ultraviolet bands of benzene. Mutual solubilities in molar fractions increase remarkably with increasing temperature at pressures in the two-liquid-phase coexistence region, and are consistent with previously reported values. It proves that the solubility of benzene in water is an order of magnitude smaller than that of water in benzene throughout the two-phase region. In addition, it is found that effect of pressure on the solubilities is opposite between water in benzene and benzene in water. These solubility properties are discussed on the basis of a cavity-based solvation model. It is suggested that the asymmetry in the mutual solubility and the opposite direction of the pressure effect are caused by difference in molecular size and difference in thermal compressibility, respectively, between water and benzene.

Journal Article↗
PubMed1996

The role of CYP2E1 and 2B1 in metabolic activation of benzene derivatives.

CYP2B1 and 2E1 oxidized toluene, aniline and monochlorobenzene (MCB) to water-soluble metabolites and to products covalently binding to microsomal proteins from male Wistar rats at high efficiency. Oxidation of benzene to covalently binding metabolites was catalysed by CYP2B1 and 2E1 more effectively than the formation of water-soluble metabolites, especially at low benzene levels. Thus, the formation of covalently binding products was inversely related but formation of soluble metabolites was proportional to benzene concentration. 1,4-Benzoquinone was responsible for the majority of covalent binding to microsomal proteins, being suppressed by ascorbate; 1,4-semiquinone was not important, since alpha-tocopherol did not inhibit the covalent binding and ESR showed its rapid decay, if NADPH was available. Specific antibodies and inhibitors confirmed the role of CYP2B1 and 2E1 induction. Covalent binding of benzene to DNA was largely due to benzene oxide; approximately 50% was due to N-7 guanine adduct. CYP2E1 oxidizing benzene via phenol to 1,4-hydroquinone appeared to mediate its further oxidation to 1,4-benzoquinone, which also occurred spontaneously, but was reversed in a reducing environment of microsomes with NADPH. Production of OH radicals in microsomes with NADPH was greatly stimulated by HQ and less by BQ, especially in CYP2E1 induced microsomes, although the quinones themselves failed to produce OH radicals. The quinones could act by simulation of the CYP futile cycle. Therefore, CYP2B1 and 2E1 in rats appeared essential for metabolic activation of benzene derivatives to potentially genotoxic products; BQ dominated the covalent binding of benzene to proteins, whereas DNA adducts were largely due to benzene oxide.

Animals↗
PubMed1997

Potential biomarkers of benzene exposure.

Biological markers or biomarkers of exposure are indicators for the evaluation of the internal dose of a xenobiotic. Biomarkers integrate exposure from all routes and sources. This review presents a short overview of potential biomarkers of benzene exposure currently under investigation, the methodology used for their determination, and experimental findings and their usefulness and specificity in assessing exposure to benzene. Potential biomarkers of benzene exposure are benzene, benzene metabolites, and adducts formed by reactive benzene metabolites with cellular constituents. The potential biomarkers of benzene exposure described in this review are: (1) benzene, the parent hydrocarbon; (2) ring-hydroxylated urinary metabolites, phenol, catechol, hydroquinone, and 1,2,4-trihydroxybenzene; (3) trans,trans-muconic acid, a urinary ring-opened metabolite; (4) N-acetyl-S-(2,5-dihydroxyphenyl)-L-cysteine, a urinary metabolite of benzene, phenol, and hydroquinone; (5) S-phenylmercapturic acid, a glutathione-derived adduct; (6) N7-phenylguanine, a DNA adduct; and (7) S-phenylcysteine and N-phenyl-valine, hemoglobin/protein-derived adducts.

Animals↗
PubMed2006

Modeling human metabolism of benzene following occupational and environmental exposures.

We used natural spline (NS) models to investigate nonlinear relationships between levels of benzene metabolites (E,E-muconic acid, S-phenylmercapturic acid, phenol, hydroquinone, and catechol) and benzene exposure among 386 exposed and control workers in Tianjin, China. After adjusting for background levels (estimated from the 60 control subjects with the lowest benzene exposures), expected mean trends of all metabolite levels increased with benzene air concentrations from 0.03 to 88.9 ppm. Molar fractions for phenol, hydroquinone, and E,E-muconic acid changed continuously with increasing air concentrations, suggesting that competing CYP-mediated metabolic pathways favored E,E-muconic acid and hydroquinone below 20 ppm and favored phenol above 20 ppm. Mean trends of dose-specific levels (micromol/L/ppm benzene) of E,E-muconic acid, phenol, hydroquinone, and catechol all decreased with increasing benzene exposure, with an overall 9-fold reduction of total metabolites. Surprisingly, about 90% of the reductions in dose-specific levels occurred below about 3 ppm for each major metabolite. Using generalized linear models with NS-smoothing functions (GLM + NS models), we detected significant effects upon metabolite levels of gender, age, and smoking status. Metabolite levels were about 20% higher in females and decreased between 1% and 2% per year of life. In addition, levels of hydroquinone and catechol were greater in smoking subjects. Overall, our results indicate that benzene metabolism is highly nonlinear with increasing benzene exposure above 0.03 ppm, and that current human toxicokinetic models do not accurately predict benzene metabolism below 3 ppm. Our results also suggest that GLM + NS models are ideal for evaluating nonlinear relationships between environmental exposures and levels of human biomarkers.

Adolescent↗
PubMed1996

Hematotoxicity among Chinese workers heavily exposed to benzene.

Benzene is a well-established hematotoxin. However, reports of its effects on specific blood cells have been somewhat inconsistent and the relative toxicity of benzene metabolites on peripheral blood cells in humans has not been evaluated. We compared hematologic outcomes in a cross-sectional study of 44 workers heavily exposed to benzene (median: 31 parts permillion [ppm] as an 8-hr time-weighted average [TWA] and 44 age and gender-matched unexposed controls from Shanghai, China. All hematologic parameters (total white blood cells [WBC], absolute lymphocyte count, platelets, red blood cells, and hematocrit) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume (MCV), which was higher among exposed subjects. In a subgroup of workers who were not exposed to more than 31 ppm benzene on any of 5 sampling days (n = 11, median 8 hr TWA = 7.6 ppm, range = 1-20 ppm), only the absolute lymphocyte count was significantly different between exposed workers (mean [sd]1.6 [0.4] x 10(3) mu L) and controls (1.9 [0.4] x l0(3) uL, p = 0.03). Among exposed subjects, a dose response relationship with various measures of current benzene exposure (i.e., personal air monitoring, benzene metabolites in urine) was present only for the total WBC count, the absolute lymphocyte count, and the MCV. Correlations between benzene metabolites and hematologic parameters were generally similar, although hydroquinone was somewhat more strongly associated with a decrease in the absolute lymphocyte count, and catechol was more strongly associated with an increase in MCV. Morphologic review of peripheral blood slides demonstrated an excess of red blood cell abnormalities (i.e., stomatocytes and target cells) only in the most heavily exposed workers, with no differences in granulocyte, lymphocyte, or platelet morphology noted. Although benzene can affect all the major peripheral blood elements, our results support the use of the absolute lymphocyte count as the most sensitive indicator of benzene-induced hematotoxicity.

Adult↗
PubMed1994

Cohort study among workers exposed to benzene in China: II. Exposure assessment.

This report describes a retrospective exposure assessment method used in a follow-up mortality study of workers exposed to benzene. The approach quantified historical exposure to benzene in a multi-industry, multicenter cohort, involving 672 factories in 12 cities in China. Historical exposure data were collected to obtain exposure information related to 1,427 work units (departments) and 3,179 unique job titles from benzene-producing or -using factories in which written records and other data sources were evaluated. The basic unit for exposure assessment was a factory/work unit/job title combination which was considered separately during each of seven calendar-year time periods between 1949 and 1987 for a total of 18,435 exposure assignments. Historical information collected to estimate exposure included benzene monitoring data; lists of raw materials and factory products, and the percentage of benzene in each; the total amount and dates of use of benzene or benzene-containing materials; use of engineering controls and personal protective equipment; and other available exposure information. Overall, 38% (ranging from 3% for the earliest periods to 67% for the last period) of the estimates were based primarily on benzene monitoring data. In the absence of job-specific benzene monitoring data for a given calendar period, measurement results or exposure estimates for similar jobs and/or other calendar periods were used in conjunction with other exposure information to derive estimates. Estimated exposure levels are presented by industries and occupations. The highest average exposures during 1949-1987 were observed for the rubber and plastic industry (30.7 ppm), and for rubber glue applicators (52.6 ppm).

Benzene↗
PubMed1995

Enhanced anaerobic degradation of benzene by enrichment of mixed microbial culture and optimization of the culture medium.

A heterogeneous mixed culture, originally collected from two different sources, namely cow-drug and sludge from the city waste-water treatment plant, was grown in mineral medium containing 1% glucose and then adapted on benzene as the carbon and energy source. Under anaerobic conditions benzene was degraded via benzoic acid as a major intermediate in the benzene degradation pathway. The degradation rate of benzene was improved stepwise by the number of enrichments and optimization of the culture medium. The effects of microaerobic conditions and/or physicochemical treatment with H2O2 prior to anaerobic degradation were studied with respect to variations in benzene degradation rate, growth of biomass and gas composition. It was noticed that the amount of gas produced is less than the theoretical value expected and the percentage of methane in the product gas was very small (3%-3.5%). The reason for this is not well understood but it is presumed that the major group of benzene-degrading bacteria present in the culture medium are sulphate reducers and the mixed consortium is unable to degrade certain complex aromatic intermediates in the benzene degradation pathway under the experimental conditions. For an actual explanation of the situation arising in this study, further investigations must be carried out. However, the mixed culture is capable of oxidizing benzene more rapidly to intermediate compounds and also partly into gas under the culture conditions, compared to the published data for the anaerobic degradation of benzene.

Anaerobiosis↗
PubMed1988

Mutual metabolic suppression between benzene and toluene in man.

The exposure intensity during a shift and the metabolite levels in the shift-end urine were examined in male workers exposed to either benzene (65 subjects; the benzene group), toluene (35 subjects; the toluene group), or a mixture of both (55 subjects; the mixture group). In addition, 35 non-exposed male workers (the control group) were similarly examined for urinary metabolites to define background levels. A linear relationship was established between the intensity of solvent exposure and the corresponding urinary metabolite levels (i.e. phenol, catechol and quinol from benzene, and hippuric acid and o-cresol from toluene) in each case when one of the three exposed groups was combined with the control group for calculation. Comparison of regression lines in combination with regression analysis disclosed that urinary levels of phenol and quinol (but not catechol) were lower in the mixture group than in the benzene group when the intensities of exposure to benzene were comparable, indicating that the biotransformation of benzene to phenolic compounds (excluding catechol) in man is suppressed by co-exposure to toluene. Conversely, metabolism of toluene to hippuric acid was suppressed by benzene co-exposure. Conversion of toluene to o-cresol was also reduced by benzene, but to a lesser extent. The significance of the present findings on the mutual suppression of metabolism between benzene and toluene is discussed in relation to solvent toxicology and biological monitoring of exposure to the solvents.

Air Pollutants, Occupational↗
PubMed1984

Covalent binding of benzene and its metabolites to DNA in rabbit bone marrow mitochondria in vitro.

Rabbit bone marrow mitochondria, stripped of their outer membrane (mitoplasts), have been shown to carry out the NADPH-dependent bioactivation of radiolabelled benzene in vitro to metabolites capable of covalently binding to mtDNA, thereby inhibiting transcription. The metabolites of benzene produced in bone marrow cells by the microsomal cytochrome P-450 are thought to be phenol, catechol, hydroquinone and p-benzoquinone (Andrews et al., Life Sci., 25 (1979) 567; Irons et al., Chem.-Biol. Interact., 30 (1980) 241). Incubation of mitoplasts from rabbit bone marrow cells in vitro with varying concentrations of the putative microsomal metabolites showed a concentration-dependent inhibition of RNA synthesis. The 50% inhibitory molar concentration (IC50) for each metabolite was determined to be: 1,2,4- benzenetriol , 6.3 X 10(-7); p-benzo-quinone, 2 X 10(-6); phenol, 2.5 X 10(-5); hydroquinone, 5 X 10(-5); catechol, 2 X 10(-3); benzene, 1.6 X 10(-2). DNA, isolated from rabbit bone marrow cell or rat liver mitoplasts prelabelled in DNA with [3H]dGTP and exposed to [14C]benzene in vitro, was enzymatically hydrolyzed to nucleosides which were chromatographed on a Sephadex LH-20 column to separate free nucleosides from nucleoside-adducts. The elution profiles indicated that rat liver mtDNA contained six guanine nucleoside-adducts and rabbit bone marrow cell mtDNA contained seven guanine nucleoside-adducts. Incubation of bone marrow mitoplasts in vitro in the presence of benzene and the hydroxyl radical scavenger, mannitol, resulted in the inhibition of formation of four of the guanosine-adducts. When [3H]dATP was substituted as the prelabelled precursor nucleotide, the LH-20 column profile indicated that two adenine nucleoside-adducts were also formed from benzene in vitro. Furthermore, a comparison of the Sephadex LH-20 column profiles of purine adducts derived from [14C]benzene- and [3H]dGMP-labelled mtDNA with profiles generated by individually incubating each of the putative unlabelled metabolites with bone marrow mitoplasts in vitro has indicated that p-benzoquinone, phenol, hydroquinone and 1,2,4- benzenetriol form adducts with guanine. One of the two adenosine-adducts may arise from hydroquinone; the compound forming the other adduct is unknown at the present time. Exposure of mitoplasts to catechol in vitro resulted in the formation of a guanine nucleoside-adduct that was present in rat liver mtDNA but absent from the DNA isolated from rabbit bone marrow cell mitoplasts exposed to [14C]benzene in vitro. This suggests that catechol is probably not a major metabolite of benzene formed in bone marrow cell mitochondria.

Animals↗
PubMed1989

Effect of exposure concentration, exposure rate, and route of administration on metabolism of benzene by F344 rats and B6C3F1 mice.

To determine the effect of exposure concentration and the route of administration on benzene metabolism, male F344/N rats and B6C3F1 mice were orally exposed to 1, 10, and 200 mg benzene/kg, and by inhalation for 6 hr to 5, 50, and 600 ppm benzene vapor. The effect of different exposure rates on the metabolism of benzene was determined by exposing rodents over different time intervals to the same total amount of benzene [constant concentration X time factor (C X T) = 300 ppm.hr]. Water-soluble metabolites constituted greater than 90% of the metabolite dose to the tissues and were used as a measure of the metabolism of benzene via different pathways. Water-soluble metabolites were measured in the blood, urine, liver, lung, and bone marrow from animals killed following oral exposures and during and following inhalation exposures. The total "dose" to the tissue of individual metabolites was determined by the area under the curve (AUC). The results indicated a shift in metabolism from putative toxification pathways to detoxification pathways as the exposure concentration or oral dose increased. In mice, hydroquinone glucuronide and muconic acid (markers of toxification metabolic pathways) represented a greater percentage of the administered dose at low doses than at high doses. At high doses, phenylglucuronide and prephenylmercapturic acid (detoxification products) increased as a percentage of the administered dose. This same metabolic shift was observed in rats, except that hydroquinone glucuronide was a minor metabolite of benzene at all concentrations. The AUC of phenylsulfate (detoxification pathway) was proportional to the exposure concentration in both species. Within the range of C X T factors studied, the rate of the inhalation exposure to benzene did not affect the AUC of metabolites in tissues of rats; however, a high dose rate (600 ppm 0.5 hr) in mice caused a shift in metabolism to phenyl conjugates. The comparison of oral and 6-hr inhalation exposures indicated that, in terms of metabolite dose to tissues, there is no simple relationship between these two routes of administration. An oral dose and an inhalation exposure concentration which produce an equal dose of one metabolite produce very different doses of another metabolite. These studies demonstrated a species difference in benzene metabolism, as well as a metabolic shift in benzene metabolic pathways as the exposure concentration was increased.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Inhalation↗
PubMed1990

Effects of exposure to benzene in vivo on the murine mononuclear phagocyte system.

Exposure to benzene has been shown to decrease resistance to challenges by Listeria monocytogenes or tumor cells in mice. Alterations of T-lymphocytes have been suggested as one probable cause. Macrophages are also critical participants in resistance to Listeria and to tumor cells. We have previously shown that exposure of macrophages in vitro to benzene metabolites, but not to benzene, inhibited several functions of macrophages that are critical for host resistance. The present studies were conducted to determine the effects of exposure to benzene in vivo on the murine mononuclear phagocyte system. Treated animals received daily subcutaneous injections of benzene (800 mg/kg) for 5 days. Macrophages were obtained by lavage from the peritoneal cavity after ip injection of sterile eliciting agents. Enumeration, peroxidase histochemistry, and a series of functional assays were performed. Animals exposed to benzene displayed a decreased number of macrophages elicited by peptone injection. Specific alterations of macrophage functions included a 50% decrease of Fc-receptor-mediated phagocytosis and 70% inhibition of tumor cell cytolysis but an enhancement of TPA-stimulated H2O2 release. There was no effect on interferon-gamma stimulated expression of Ia antigen. The observations that the elicited macrophage populations were composed of newly immigrated cells and that benzene treatment was terminated 3 days before the functional analyses were performed suggest that benzene was affecting monocytes in the blood and precursor cells in the bone marrow. Alterations of macrophage functions in injection controls suggested that determining the primary effect of exposure to benzene may be complicated by the inflammation induced by treatment at the site of injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Metabolism of [14C]benzene by cynomolgus monkeys and chimpanzees.

Rodent bioassays indicate that B6C3F1 mice are more sensitive to the carcinogenicity of benzene than are rats. The urinary profile of benzene metabolites is different in rats vs mice. Mice produce higher proportions of hydroquinone conjugates and muconic acid, indicators of metabolism via pathways leading to putative toxic metabolites, than do rats. In both species, metabolism to hydroquinone and muconic acid is favored at low concentrations of benzene, indicating that these pathways are easily saturated. These species differences in the metabolism of benzene make it difficult to predict the health risk to humans and how this risk varies with dose. For this reason, the metabolism of [14C]benzene by cynomolgus monkeys and chimpanzees, animals phylogenetically closer to humans than rodents, was studied. Monkeys were dosed ip with 5, 50, or 500 mg [14C]benzene/kg body wt. Urine was collected for up to 24 hr following exposure and was analyzed for benzene metabolites. The proportion of the administered 14C excreted in the urine of monkeys decreased from approximately 50 to 15% as the dose increased. Phenyl sulfate was the major urinary metabolite. The proportion of hydroquinone conjugates and muconic acid in the monkey's urine decreased as the dose increased. The proportion of catechol conjugates was not affected by dose. The proportion of these metabolites in the urine was quite variable from animal to animal, but the proportion of muconic acid was consistently much lower in the monkey than in the mouse or rat. Three chimpanzees were administered 1 mg [14C]benzene/kg body wt, iv; essentially all of the injected 14C was recovered in the urine. Of the total urinary metabolites, 79% were accounted for by phenyl conjugates and less than 15% by hydroquinone conjugates or muconic acid. Catechol conjugates were not detected. The metabolism of benzene appeared to be qualitatively similar but quantitatively different in the species studied. The mouse, the sensitive rodent species, forms the highest levels of hydroquinone conjugates and muconic acid and the chimpanzee, the lowest. In all animal species studied for the effect of dose on benzene metabolism, as the dose decreased, a larger proportion of the benzene metabolites was represented by hydroquinone conjugates and muconic acid.

Animals↗
PubMed1984

An overview of environmental and toxicological aspects of aromatic hydrocarbons. I. Benzene.

The salient aspects of the exposure to benzene were reviewed via an initial examination of the production, use, occurrence and dispersion of benzene, as well as populations at potential risk. Although benzene is ubiquitous in the environment, the major source of benzene in ambient air is via its use and occurrence in gasolines and subsequent emissions. Exposure to benzene in the general population is suggested to be several orders of magnitude less than to occupational cohorts. Levels of benzene exposure in the workplace have dropped considerably from that which was manifest in the 1940-1950 decade (e.g., 10-100 ppm) also due to the decreasing use of benzene as a solvent. The effects on humans and animals as well as genetic effects of benzene were also reviewed following an initial consideration of its absorption and elimination. The toxic effects on the hemopoietic system were cited with special consideration to the long-term exposure to benzene and the occurrence of leukemia.

Animals↗
PubMedDate not supplied

Prevention of benzene-induced myelotoxicity and prostaglandin synthesis in bone marrow of mice by inhibitors of prostaglandin H synthase.

Administration of benzene to mice causes bone marrow toxicity and elevations in prostaglandin E2 (PGE2), a negative regulator of myelopoiesis. In these experiments, benzene (400 mg/kg; 2 x/day for 2 days) administered to DBA/2 or C57Bl/6 mice decreased bone marrow cellularity and myeloid progenitor cell development (measured as colony-forming units per femur) by 40%. When inhibitors of the cyclooxygenase component of prostaglandin H synthase (PHS) (either indomethacin, 2 mg/kg; aspirin, 50 mg/kg; meclofenamate, 4 mg/kg) were coadministered with benzene, myelotoxicity and the elevation in bone marrow PGE level were prevented. Additionally, when indomethacin (1 microM) was added to cultures of bone marrow cells from benzene-treated mice, myeloid progenitor cell development was the same as the controls. The doses of indomethacin used had no affect on the hepatic conversion of benzene to its major metabolite, phenol. Using purified PHS, indomethacin (10 microM) inhibited the arachidonic acid-dependent oxidation of hydroquinone to p-benzoquinone, a putative reactive metabolite of benzene. Indomethacin (10 microM) had no effect on the H2O2-driven oxidation of hydroquinone catalysed by either PHS-peroxidase or myeloperoxidase. Coadministration of the benzene metabolites, phenol and hydroquinone, has been reported previously to reproduce the myelotoxicity of benzene. In our studies, phenol and hydroquinone (50 mg/kg each; 2 x/day for 2 days) decreased bone marrow cellularity by 40%; however, coadministration of indomethacin (2 mg/kg) or meclofenamate (4 mg/kg) with these metabolites did not prevent the decrease in bone marrow cell number. Our results implicate marrow PHS in mediating the short-term myelotoxicity of benzene.

Animals↗
PubMed1984

Modifications in the myeloclastogenic effect of benzene in mice with toluene, phenobarbital, 3-methylcholanthrene, Aroclor 1254 and SKF-525A.

Benzene was studied in its target organ of effect, the bone marrow, with the micronucleus test and metaphase analysis. Male and female CD-1 mice were treated with 2 doses of benzene (440 mg/kg) or toluene (860 or 1720 mg/kg) or both 24 h apart, and sacrificed 30 h (or 54 h) after the first dose. Benzene-treated animals were pretreated with phenobarbital (PB), 3-methylcholanthrene (3-MCA), SKF-525A, or Aroclor 1254. Toluene showed no clastogenic activity and reduced the clastogenic effect of benzene when the mixture was given. None of the pretreatments protected against the clastogenic effect of benzene. 3-MCA pretreatment greatly promoted benzene myeloclastogenicity. Females were consistently more resistant to benzene than males. Dose-response curves in benzene-treated mice were much steeper with 3-MCA induction than without. Chromosomal damage was higher with p.o. than i.p. benzene administration.

Animals↗
PubMed1990

Benzene hemoglobin adducts in mice and rats: characterization of formation and physiological modeling.

Benzene is a myelotoxin and a human leukemogen. Humans are exposed to this compound, both occupationally and environmentally. This study was conducted to determine whether formation of benzene-derived adducts with blood hemoglobin (Hb) can be used as a biomarker of exposure to benzene. B6C3F1 mice and F344/N rats were given 0.1 to 10,000 mumol [14C]benzene/kg body wt, orally. Twenty-four hours later, animals were euthanized, and globin was isolated from blood samples. The globin was analyzed by liquid scintillation spectrometry for the presence of [14C]benzene-derived adducts. Hb adduct formation was linear with respect to dose for amounts of up to 500 mumol [14C]benzene/kg body wt, for both rodent species. Within this linear dose-response range, mice formed adducts from [14C]benzene approximately 3.5 times less efficiently [0.022 +/- 0.010 (pmol adducts/mg globin)/(mumol/kg body wt dose)] than did rats [0.076 +/- 0.014 (pmol adducts)/(mumol/kg body wt dose)]. Benzene-derived Hb adducts also accumulated linearly when mice and rats were given up to three daily doses of 500 mumol [14C]benzene/kg body wt. These data were used to develop a physiological model for benzene-derived Hb adduct formation. Both first-order and saturable pathways for adduct formation were incorporated. The results showed that the model simulated the levels of Hb adducts in both mice and rats after oral exposures to benzene and predicted the levels of Hb adducts present after inhalation exposure. These studies suggest that Hb adducts might be useful biomarkers for human exposures to benzene.

Animals↗