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PubMed1996

Measurement of the urinary benzene metabolite trans,trans-muconic acid from benzene exposure in humans.

The concentration of the urinary benzene metabolite trans, trans-muconic acid was measured after exposure to benzene contained in environmental tobacco smoke (ETS). Volunteers were exposed to environmental tobacco smoke at different exposure levels and for different exposure durations. Urine samples were collected preexposure and postexposure for 24 h on exposure days. To determine background levels, urine samples were also collected on three individual days when no exposure to ETS occurred. Urinary muconic acid was elevated following benzene exposure in ETS compared to an individual's background level and can be a useful biomarker in control, characterized studies of sub-parts-per-million (sub-ppm) benzene exposures. However, the use of muconic acid as a bio-marker of benzene exposure at sub-ppm levels in the general population is problematic because of variability in the time between exposure and excretion and in an individual's background excretion rate. Urinary muconic acid associated with benzene in ETS exposure was excreted within 12 h of the exposure. A higher proportion of the benzene dose following environmental exposure in the sub-ppm range was excreted as urinary muconic acid (mean of 25%, range 7.2-58%) than found in either animal or occupational studies at higher benzene doses. The higher proportion of benzene excretion as urinary muconic acid at low benzene exposure indicates that the relationship between exposure and metabolism by the ring opening pathway is nonlinear in humans, and extrapolation from high doses to environmental benzene exposure potentially underestimates health risks mediated by the ring opening metabolic pathway that produces muconic acid, as has been suggested by previous animal data.

Adult↗
PubMed2006

Potential uses of petrochemical products can result in significant benzene exposures: MSDSs must list benzene as an ingredient.

According to 29 CFR1910.1200 (Hazard Communication Standard [HCS]), a material safety data sheet (MSDS) must list a carcinogen as an ingredient if its concentration in a product is 0.1% or more by weight. However, according to the HCS, when the concentration of a carcinogen in a product is less than 0.1% (by weight) it may not be necessary to list it as an ingredient on the MSDS. The standard stipulates that if potential uses of the product can result in exposures to the carcinogen that exceed the Occupational Safety and Health Administration (OSHA) permissible exposure limit or the ACGIH threshold limit value (TLV), then it must be listed. This article focuses on the failure of MSDSs to report benzene as a listed ingredient in products that incorporate petroleum-derived ingredients such as toluene and hexane. In the United States, approximately 238,000 people are occupationally exposed to benzene each year. Only rarely is benzene listed as an ingredient on MSDSs even though it often comprises more than 0.1% of petroleum solvents and, when its concentrations in petroleum-derived products are much less than 0.1%, inhalation exposures to benzene can be much higher that its OSHA PEL of one part per million (ppm) by volume (v/v) andACGIH TLV of/one-half ppm (v/v). As a consequence of benzene's omission from MSDSs as a listed ingredient, employers are frequently unaware of their requirement to implement 29 CFR 1910.1028 (Benzene Standard) and of the need to address employee exposures to benzene in the workplace. This article demonstrates that benzene should be listed as an ingredient on MSDSs, even at concentrations in benzene-containing products that are between one and two orders of magnitude below OSHA's 0.1% threshold. An exposure assessment methodology is presented that is applicable to employees whose conditions of exposure are similar to those in the published study. These workers make up a similar exposure group. The information and methodology presented here are germane to preparation of accurate MSDSs for benzene-containing products, employers who must comply with 29 CFR 1910.1028, and retrospectively estimating exposures to benzene.

Air Pollutants, Occupational↗
PubMed1998

Formation of nitrated and hydroxylated aromatic compounds from benzene and peroxynitrite, a possible mechanism of benzene genotoxicity.

Peroxynitrite, the reaction product of nitric oxide (NO.) and superoxide anion (O2.-) produced during immune activation by a variety of inflammatory cells, may contribute to genotoxicity of benzene through its ability to carry out hydroxylation and nitration. After exposure of benzene to synthesised peroxynitrite, phenol, nitrophenols (p-nitrophenol, o-nitrophenol and m-nitrophenol) and nitrobenzene were identified in the reaction mixture by HPLC separation and single UV wavelength and diode array detection. The formation of phenol, nitrophenols and nitrobenzene showed a linear relationship with both benzene and peroxynitrite concentrations. The molar ratio for phenol/(nitrobenzene and nitrophenols) was approximately 9/5 with a total product yield of 14% hydroxylated and nitrated products as based on peroxynitrite. The physiological relevance of the chemical reaction between benzene and peroxynitrite was tested by detecting the reaction products in human neutrophils (2.5 x 10(7)cells/ml) incubated with 10 mM benzene for 25 min. The concentration of phenol and p-nitrophenol were found to be 1.29+/-0.22 and 1.56+/-0.61 microM (mean+/-SD) in the incubation medium of the neutrophils pretreated with phorbol myristate acetate (500 nM) for 5 min, respectively, whereas no metabolites were detected if the neutrophils were not pretreated. Nitrated aromatic compounds are known to be more carcinogenic than the parent compounds. It is reported that acute and chronic infection increases the risk of cancer at various sites; and that anti-inflammatory agents decrease benzene myelotoxicity. We suggest that the increased production of peroxynitrite during chronic inflammation combined with benzene exposure may increase the carcinogenicity of benzene by a mechanism that includes the formation of metabolites from the chemical reaction between benzene and peroxynitrite. Thus, peroxynitrite mediated hydroxylation and nitration of benzene during immune activation represent a novel in vivo mechanism for generation of proximal carcinogens of benzene.

Benzene↗
PubMed1986

Metabolism of benzene and phenol in macrophages in vitro and the inhibition of RNA synthesis by benzene metabolites.

Benzene may affect hemopoiesis by damaging the bone marrow stroma that provides the microenvironment for hemopoiesis. A possible target of benzene toxicity in the stroma is the macrophage, which is a major source of protein factors required for the proliferation and differentiation of progenitor cells. As an initial approach towards understanding whether benzene inhibits hemopoietic factor production in bone marrow stroma, the metabolism of benzene and phenol has been studied and the effect of benzene and its metabolites on macrophage RNA synthesis has been examined. Benzene is not metabolized in macrophages but phenol, the major metabolite of benzene in bone marrow, is converted by peroxidase in the macrophage to both free metabolites and species which covalently bind to cellular macromolecules. Benzene and its metabolites inhibited RNA synthesis in a dose-dependent manner, with 50% inhibitory concentrations of 5 X 10(-3) M for benzene, 2.5 X 10(-3) M for phenol, 2.5 X 10(-5) M for hydroquinone, and 6 X 10(-6) M for p-benzoquinone; this inhibition was not attributable to loss of cell viability. Benzene, possibly by an inhibition of uridine transport into macrophages, and phenol, by its conversion to covalently binding species, inhibit RNA synthesis in macrophages and thus may inhibit the synthesis of colony stimulating factors required for hemopoiesis.

Animals↗
PubMed2002

Non-linear production of benzene oxide-albumin adducts with human exposure to benzene.

Benzene is initially metabolized to benzene oxide, which either undergoes further metabolism or reacts with macromolecules including proteins. Previously reported levels of benzene oxide-albumin adducts (BO-Alb) are analyzed from 30 workers exposed to 0.2-302 ppm benzene and 43 controls from Shanghai, China. Although both exposed workers and controls had significant levels of BO-Alb in their blood, exposed subjects' adduct levels (GM=378 pmol/g protein) were much greater than those of controls (GM=115 pmol/g protein). When the natural logarithm of the BO-Alb level was regressed upon the natural logarithm of exposure among the 30 exposed subjects, a strong effect of benzene exposure was observed (R(2)=0.612; p<0.0001). Because the slope of the relationship between BO-Alb and benzene exposure was significantly less than one in log-space, we infer that production of benzene oxide was less than proportional to benzene exposure. Since benzene is a substrate for CYP2E1, these results are consistent with saturation of CYP450 metabolism. They indicate that deviations from linear metabolism began at or below benzene exposures of 10 ppm and that pronounced saturation was apparent at 40-50 ppm. To our knowledge, this is the first study to investigate the linearity of human metabolism of a carcinogen based upon protein adducts.

Albumins↗
PubMedDate not supplied

Percutaneous penetration of benzene and benzene contained in solvents used in the rubber industry.

Penetration of benzene through the skin of the rhesus monkey was determined using 14C-benzene, and quantitating the labelled metabolites in urine. The modes of application and amounts of benzene that penetrated the skin (indicated in parentheses) are as follows: (1) a single, direct cutaneous application of liquid benzene (0.172 +/- 0.139%); (2) a single application of benzene-containing [0.36%] solvent (0.0805 +/- 0.03060%); (3) multiple washes with full-strength benzene (0.848 +/- 0.0806%); (4) multiple washes with the benzene-containing [0.35%] solvent (0.431 +/- 0.258%); (5) removal of the stratum corneum followed by application of full-strength benzene (0.909 +/- 0.627%); and (6) application of benzene to the palmar surface (0.651 +/- 0.482%). Until more complete human data becomes available, benzene penetration in the monkey may be used to estimate penetration in man, both for industrial hygiene purposes and general toxicological use.

Animals↗
PubMed1994

Determination of benzene and its metabolites: application in biological monitoring of environmental and occupational exposure to benzene.

Methods for the biological monitoring of benzene and its metabolites in exhaled air, blood and urine are reviewed. Analysis of benzene in breath can be carried out by using an exhaled-air collection tube and direct analysis by GC or GC-MS; however, this technique is less reliable when compared to analysis using blood or urine. For the determination of non-metabolized benzene in blood and urine, GC head-space analysis is recommended. Phenol, the major metabolite of benzene can be monitored by either HPLC or GC methods. However, urinary phenol has proved to be a poor biomarker for low-level benzene exposure. Recent studies have shown that trans,trans-muconic acid, a minor metabolite of benzene can be determined using HPLC with UV detection. This biomarker can be used for detection of low-level benzene exposure. Urinary S-phenylmercapturic acid is another sensitive biomarker for benzene, but it can be detected only by GC-MS. Hydroquinone, catechol and 1,2,4-benzenetriol can be measured using HPLC with either ultraviolet or fluorimetric detection. Nevertheless, their use for low-level assessment requires further studies. Eventually, for the assessment of health risks caused by benzene, biological-exposure reference values need to be established before they can be widely used in a field setting.

Animals↗
PubMed1996

Structure-activity relationships in the mutagenicity and cytotoxicity of putative metabolites and related analogs of benzene derived from the valence tautomers benzene oxide and oxepin.

A series of putative metabolites and related analogs of benzene, derived from the valence tautomers benzene oxide and oxepin, was tested for mutagenicity (reversions to histidine prototrophy and forward mutations to resistance to 8-azaguanine) and for cytotoxicity by the Ames Salmonella mutagenicity test. Benzene was not mutagenic in either assay. The benzene oxide-oxepin system and benzene dihydrodiol induced point mutations but not frameshifts. 4,5-sym-Oxepin oxide, which is a putative metabolite of the oxepin valence tautomer; 3,6-diazo-cyclohexane-1,6-3,4-dioxide, a synthetic precursor of sym-oxepin oxide; and transoid-4,11-dioxatricyclo(5.1 0)undeca-1,6-diene, a stable bridge-head diene analog of sym-oxepin oxide, were toxic but not mutagenic in both assays. 4H-Pyran-4-carboxaldehyde, a stable acid catalyzed rearrangement product of sym-oxepin oxide, was not mutagenic and much less cytotoxic than sym-oxepin oxide. Stable analogs of the valence tautomer benzene oxide, namely syn-indan-3a,7a-oxide and syn-2-hydroxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cytotoxic to Salmonella. Firstly, the apparent decay times of these chemicals, especially that of sym-oxepin oxide, were surprisingly longer than expected, as judged by quantitative plate diffusion assays. Secondly, it is concluded that if benzene oxide is further metabolized in its oxepin tautomeric form, toxic but not mutagenic products are formed. Thirdly, the relatively weak mutagenicity of benzene oxide may be mainly due to its instability and corresponding low probability to reach intracellular polynucleotide targets, whereas stable analogs of benzene oxide are relatively more potent mutagens.

Benzene Derivatives↗
PubMed1997

Measurement of benzene oxide in the blood of rats following administration of benzene.

Although it is generally assumed that metabolism of benzene proceeds through an initial step involving oxidation to benzene oxide (BO) by CYP450 in the liver, the production of BO has never been unambiguously confirmed in animals dosed with benzene. Furthermore, prevailing hypotheses of the mechanism by which benzene causes cancer have ignored the possibility that BO might play a direct role, despite the fact that BO is electrophilic, binds covalently to cell macromolecules and is presumably genotoxic. A likely reason for this lack of attention to the role of BO in the carcinogenesis of benzene is the presumption that this epoxide is too reactive to escape the hepatocyte after it is formed. We employed gas chromatography-mass spectrometry to measure BO in the blood of F344 rats, both in vitro and up to 24 h following oral administration of benzene. Surprisingly, BO was relatively stable in rat blood at 37 degrees C (estimated half-life = 7.9 min) and, after administering a single dosage of 400 mg benzene/kg body wt, a blood concentration of 90 nM BO (8.5 ng/ml) was measured for approximately 9 h. Using a published PBPK model we estimate that approximately 4.3% of the metabolized dose of benzene was released as BO from the liver into blood. This confirms that BO is, indeed, formed from metabolism of benzene and is sufficiently stable to be distributed throughout the body at levels which are likely to be greater than those of the other electrophilic benzene metabolites.

Animals↗
PubMed1994

Comparison of protein adducts of benzene oxide and benzoquinone in the blood and bone marrow of rats and mice exposed to [14C/13C6]benzene.

Protein binding of hemoglobin (Hb) and bone marrow was used to compare in vivo reactions of 3 electrophilic metabolites of benzene, i.e., benzene oxide and 1,2- and 1,4-benzoquinone (1, 2-BQ and 1, 4-BQ), in F344 rats and B6C3F1 mice. Following a single p.o. administration of a mixture of [14C]- and [13C6]benzene between 50 and 400 mg/kg body weight, cysteine adducts of benzene oxide, 1,2-BQ, and 1,4-BQ were assayed, and the proportions of cysteine-bound adducts to total protein binding were estimated. Although dose-related production of each adduct was seen, large differences were observed between species and tissues. With rat Hb, benzene oxide adducts represented 27% of the total Hb binding and 73% of the cysteinyl binding, whereas quinone adducts represented relatively small proportions. However, with mouse Hb, the 1,4-BQ adducts accounted for 5.5% of the total Hb binding and 12.2% of the cysteinyl binding, while 1,2-BQ and benzene oxide each accounted for less than 3% of the total. In the bone marrow of both rats and mice, BQ adducts were more abundant than those of benzene oxide. However, adducts of 1,2-BQ predominated in rat marrow (9% of binding), whereas adducts of 1,4-BQ were more abundant in the mouse (21% of binding). The average blood concentrations of 1,4-BQ were estimated from the adduct levels and reaction-rate constants to be 2-5-fold higher in the mouse than in the rat. This work suggests that BQ binding is favored over that of benzene oxide in the bone marrow; however, high background levels of BQ adducts, observed with Hb and bone marrow proteins, suggest that any toxic effects of the quinones should only arise from high exposures to benzene.

Animals↗
PubMed1985

Low level benzene exposure in Sweden: effect on blood elements and body burden of benzene.

Measurements for benzene exposure were performed for different work places. In addition, breath benzene concentrations were measured in different occupations in order to establish toxico-kinetics of benzene in man; chromosomal aberrations in lymphocytes of exposed workers were also examined. Smoking appears to result in a large increase in benzene concentration in exhaled breath. The smoke from one cigarette contains 60-80 micrograms of benzene. It was found that exposure levels of 10 ppm are rather uncommon among workers handling gasoline or gasoline equipment. It was concluded that the gasoline load of road tankers cannot be responsible for chromosome changes of the driver, as milk truck drivers showed the same changes. These results did not prove that benzene was the cause of the observed changes. Smoking is the confounding factor, with a potency of at least the same order of magnitude as benzene. In addition, our present knowledge about mechanisms of benzene is not sufficiently developed to permit quantitative conclusions as to the human health risks.

Air Pollutants, Occupational↗
PubMed2005

Urinary t,t-muconic acid, S-phenylmercapturic acid and benzene as biomarkers of low benzene exposure.

This research compared the capability of urinary trans,trans-muconic acid (t,t-MA), S-phenylmercapturic acid (S-PMA) and benzene excreted in urine (U-benzene) to monitor low benzene exposure and evaluated the influence of smoking habit on these indices. Gasoline attendants, urban policemen, bus drivers and two groups of referents working in two large Italian cities (415 people) were studied. Median benzene exposure was 61, 22, 21, 9 and 6 microg/m3, respectively, with higher levels in workers than in referents. U-benzene, but not t,t-MA and S-PMA, showed an exposure-related increase. All the biomarkers were strongly influenced by cigarette smoking, with values up to five-fold higher in smokers compared to non-smokers. In conclusion, in the range of investigated benzene exposure (<478 microg/m3 or <0.15 ppm), the smoking habit may be regarded as a major source of benzene intake; among the study indices, U-benzene is the marker of choice for the biological monitoring of occupational and environmental exposure.

Acetylcysteine↗
PubMed2004

Comparison of the mutagenic activity of the benzene metabolites, hydroquinone and para-benzoquinone in the supF forward mutation assay: a role for minor DNA adducts formed from hydroquinone in benzene mutagenicity.

Benzene, a ubiquitous environmental pollutant and occupational hazardous chemical, is a recognised human leukaemogen and rodent carcinogen. The mechanism by which benzene exerts its carcinogenic effects is to date unknown but it is considered that mutations induced by benzene-DNA adducts may play a role. The benzene metabolite, para-benzoquinone (p-BQ) following reaction in vitro with DNA, forms four major adducts, which include two adducts on 2'-deoxyguanosine 3'-monophosphate (dGp). Reaction of DNA with the benzene metabolite hydroquinone (HQ) results in only one major DNA adduct, which corresponds to one of the dGp adducts formed following reaction with p-BQ. The mutagenicity of the adducts formed from these two benzene metabolites was investigated using the supF forward mutation assay. Metabolite-treated plasmid (pSP189) containing the supF gene was replicated in human Ad293 cells before being screened in indicator bacteria. Treatment with 5-20 mM p-BQ gave a 12 to 40-fold increase in mutation rate compared to 5-20 mM HQ treatment, a result reflected in the level of DNA modification observed (8 to 26-fold increase compared to HQ treatment). Treatment with p-BQ gave equal numbers of GC --> TA transversions and GC --> AT transitions, whereas treatment with HQ gave predominantly GC-->AT transitions. The spectra of mutations achieved for the two individual treatments were shown to be significantly different (P = 0.004). A combination of both treatments also resulted in a high level of GC --> AT transitions and a synergistic increase in the number of multiple mutations, which again predominated as GC --> AT transitions. Sites of mutational hotspots were observed for both individual treatments and one mutational hotspot was observed in the multiple mutations for the combined treatment. These results suggest that the dGp adducts formed from benzene metabolite treatment may play an important role in the mutagenicity and myelotoxicity of benzene.

Base Sequence↗
PubMed1996

Indirect validation of benzene exposure assessment by association with benzene poisoning.

We present a validation study of a quantitative retrospective exposure assessment method used in a follow-up study of workers exposed to benzene. Assessment of exposure to benzene was carried out in 672 factories in 12 cities in China. Historical exposure data were collected for 3179 unique job titles. The basic unit for exposure assessment was a factory/work unit/job title combination over seven periods between 1949 and 1987. A total of 18,435 exposure estimates was developed, using all available historical information, including 8477 monitoring data. Overall, 38% of the estimates were based on benzene monitoring data. The highest time-weighted average exposures were observed for the rubber industry (30.7 ppm) and for rubber glue applicators (52.6 ppm). Because of its recognized link with benzene exposure, the association between a clinical diagnosis of benzene poisoning and benzene exposure was evaluated to validate the assessment method that we used in the cohort study. Our confidence in the assessment method is supported by the observation of a strong positive trend between benzene poisoning and various measures, especially recent intensity of exposure to benzene.

Benzene↗
PubMed1996

Repeated oral benzene exposure alters enzymes involved in benzene metabolism.

Benzene is a known carcinogen and hematopoietic toxin in humans and experimental animals. The effect of acute, high-dose exposure to benzene on hepatic bioactivation and detoxication enzymes has been defined, while little is known about the effect of repeated, low-dose benzene exposure on these enzymes. Our objective was to determine whether repeated, oral benzene exposure alters enzymes involved in benzene metabolism. Specifically, we were concerned with cytochrome P-450-2E1, a bioactivation enzyme, and glutathione transferase and aldehyde dehydrogenase, two detoxifying enzymes. Female CD-1 mice were treated by gavage for 3 wk with benzene doses of 5 mg/kg (0.064 mmol/kg) or 50 mg/kg (0.646 mmol/kg) in corn oil. These doses of benzene produced 0.048 and 0.236 mumol muconic acid/d, respectively. We found that repeated exposure to 50 mg benzene/kg/d decreased P-450-2E1 activity by 34% and induced glutathione transferase activity by 30% without affecting aldehyde dehydrogenase activity. These changes in enzyme activities may serve a protective role against repeated exposure to benzene.

Administration, Oral↗
PubMed1988

Toxic effects of benzene and benzene metabolites on mononuclear phagocytes.

Benzene is a potent bone marrow toxin in animals and man. Animal studies have shown that exposure to benzene can alter T lymphocyte functions and decrease the resistance of animals to Listeria monocytogenes and transplanted tumor cells. Mononuclear phagocytes participate in host resistance to Listeria and tumor cells. The purpose of the studies presented here was to determine the effects of benzene and benzene metabolites on macrophage functions and the ability of macrophages to be activated for functions which are important in host defense. Benzene had no effects on macrophage function or activation for any of the functions tested. Conversely, metabolites of benzene, catechol (CAT), hydroquinone (HQ), benzquinone (BQ), and 1,2,4-benzenetriol (BT) had potent and varied effects on macrophage function and activation. BQ inhibited the broadest range of functions including release of H2O2, Fc receptor-mediated phagocytosis, interferon gamma priming for tumor cell cytolysis, and bacterial lipopolysaccharide (LPS) triggering of cytolysis. BQ was also the most potent metabolite causing inhibition at lower concentrations than the other metabolites. HQ inhibited H2O2 release and priming for cytolysis and BT inhibited phagocytosis and priming for cytolysis. CAT only inhibited the release of H2O2. None of the compounds tested inhibited the induction of class II histocompatibility antigens on the cell surface. All of the effects measured occurred using concentrations of compounds which did not disrupt the cell integrity or inhibit general functions such as protein synthesis. Taken together these data suggest that benzene metabolites alter macrophage function through several mechanisms including inhibition of output enzymes and disruption of signal transduction systems.

Animals↗
PubMed1979

Biological threshold limits for benzene based on pharmacokinetics of inhaled benzene in man.

Volunteers were exposed to benzene, 2--10 ppm, under controlled conditions up to 6 h a day during five consecutive days. The accumulation and elimination of benzene was measured by determination of benzene concentration -- down to 0.001 ppm -- in exhaled breath. From these observations, a multicompartment model, which approximately describes the kinetics of benzene elimination and accumulation has been designed. On the basis of this model, benzene concentrations in breath, corresponding to exposure levels of benzene, have been estimated. Thus, at a daily exposure to 10 ppm the exhaled benzene concentration in the morning after a day of exposure will not exceed 0.1 ppm.

Aerosols↗