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PubMed1984

The effects of ethanol ingestion and repeated benzene exposures on benzene pharmacokinetics.

Two groups of C57Bl/6J mice were exposed to 300-ppm benzene vapor, 6 hr/day, 5 days/week for 20 exposures. One group received 10% ethanol (EtOH) in the drinking water commencing 20 hr prior to the initial exposure and continuing 5 days/week throughout the study. The second group received tap water. The uptake and clearance of benzene was followed in the blood during and after the 1st and 20th exposures. During the first benzene exposures, the mean steady state benzene concentrations in benzene/EtOH-treated mice and benzene/water-treated mice were 5.2 and 10.7 micrograms/ml, respectively. The mean elimination rate constants for the benzene/EtOH- and benzene/water-treated groups were 0.124 and 0.042 min-1, respectively. By 20 exposures, the benzene/EtOH group showed no change in mean blood steady state concentration (Css); however, the Css of the benzene/water group was reduced to 7.9 micrograms/ml. The mean elimination rate constants for the two groups were not different after the 20th exposure. The benzene/water mice exhibited a shift from mono-to biexponential clearance between the 1st and 20th exposures. Monoexponential clearances were observed for the benzene/EtOH group at both time points. These results indicate that 1 day of 10% EtOH consumption causes dramatic effects on benzene kinetics. After 20 days of treatment, the benzene/water and benzene/EtOH animals are kinetically similar. These changes in kinetics can be explained by the ability of ethanol and benzene to alter benzene metabolism.

Animals↗
PubMed1995

In vitro conjugation of benzene metabolites by human liver: potential influence of interindividual variability on benzene toxicity.

In addition to industrial sources, benzene is present in the environment as a component of cigarette smoke and automobile emissions. Toxicity of benzene most likely results from oxidative metabolism of benzene to reactive products. However, susceptibility to these toxic effects may be related to a balance between activation (phase I) and detoxication (phase II) reactions. In the present study, we have estimated kinetic parameters of the two major detoxication reactions for benzene metabolites--phenol sulfation and hydroquinone glucuronidation--in liver subcellular fractions from 10 humans, and single samples from mice and rats. The extent of oxidative metabolism of benzene by these liver samples has been reported previously. Here, initial rates of phenol sulfation varied 3-fold (range 0.309-0.919 nmol/mg protein/min) among human samples. Measured rates were faster in rats (1.195 nmol/mg protein/min) than in mice (0.458 nmol/mg protein/min). Initial rates of hydroquinone glucuronidation by human samples also varied 3-fold (range 0.101-0.281 nmol/mg protein/min). Hydroquinone glucuronidation was more rapid by mouse microsomes (0.218 nmol/mg protein/min) than by rat microsomes (0.077 nmol/mg protein/min). To integrate interindividual differences in various enzyme activities, a physiological compartmental model was developed that incorporates rates of both conjugation reactions and oxidation reactions. Model equations were solved for steady-state concentrations of phenol and hydroquinone attained in human, mouse and rat blood during continuous exposure to benzene (0.01 microM in blood). Among the 10 human subjects, steady-state concentrations of phenol varied 6-fold (range 0.38-2.17 nM) and steady-state concentrations of hydroquinone varied 5-fold (range 6.66-31.44 nM). Predicted steady-state concentrations of phenol were higher in mice compared with rats (2.28 and 0.83 nM respectively). Likewise, higher steady-state concentrations of hydroquinone were predicted in mice than in rats (42.44 and 17.99 nM respectively). Predicted steady-state concentrations of phenol and hydroquinone in mice were higher than predictions for the 10 human subjects, whereas predicted concentrations for rats fell among the human values. As such, our results underscore the importance of considering the balance between activation and detoxication reactions in the elimination of toxicants. Model simulations suggest that both phase I and phase II pathways influence the relative risk from exposure to benzene.

Adolescent↗
PubMed1977

Benzene inhibition of in vitro rabbit reticulocyte haem synthesis at delta aminolaevulinic acid synthetase: reversal of benzene toxicity by pyridoxine.

Benzene (0.113 M) inhibited haem and protein synthesis in rabbit reticulocytes. This inhibition of haem synthesis was found when L-2-[14C]-glycine was used as the radioactive precursor. However, when 4-[14C]delta-aminolaevulinic acid (ALA) was used, there was no significant inhibition. Since ALA measures the haem synthetic pathway beyond the enzyme delta-aminolaevulinic acid synthetase (ALA synthetase), these results suggest that benzene inhibits haem synthesis at or before ALA synthetase. This was confirmed by demonstrating that 1 mM ALA both protected against and reversed the benzene inhibition of reticulocyte protein synthesis. In addition, 1 mM pyridoxine both protected against and reversed the benzene inhibition of reticulocyte protein synthesis. In addition, ImM pyridoxine both protected against and reversed the benzene inhibition of reticulocyte haem and protein synthesis. These results indicate that benzene (or a metabolite) either competes with pyridoxal phosphate at ALA synthetase or competes with pyridoxine for pyridoxal phosphokinase. These results are discussed in terms of their implications for the possible roles of ALA synthetase and the haemin-controlled repressor in benzene-induced aplastic anaemia.

5-Aminolevulinate Synthetase↗
PubMed1998

Anaerobic benzene degradation in petroleum-contaminated aquifer sediments after inoculation with a benzene-oxidizing enrichment.

Sediments from the sulfate-reduction zone of a petroleum-contaminated aquifer, in which benzene persisted, were inoculated with a benzene-oxidizing, sulfate-reducing enrichment from aquatic sediments. Benzene was degraded, with apparent growth of the benzene-degrading population over time. These results suggest that the lack of benzene degradation in the sulfate-reduction zones of some aquifers may result from the failure of the appropriate benzene-degrading sulfate reducers to colonize the aquifers rather than from environmental conditions that are adverse for anaerobic benzene degradation.

Anaerobiosis↗
PubMedDate not supplied

Benzene percutaneous absorption: dermal exposure relative to other benzene sources.

Skin is one of several exposure routes whereby benzene, a widely distributed environmental contaminant that causes leukemia, enters the body, so accurate predictions of its percutaneous absorption are important for risk assessment. Determining benzene's skin-exposure dose and subsequent absorption is difficult because it has a low boiling point and exists as both liquid and vapor. Industrial and environmental benzene is present as a contaminant in other vehicles/solvents, and its percutaneous absorption is in part dependent upon co-solvent volatility. Co-solvents such as benzene in toluene rapidly evaporate from skin, whereas benzene contaminant in water is retained on skin longer due to water's lower volatility. Co-solvents can also affect benzene-skin partition coefficients; thus, permeability coefficients and percentage doses absorbed can vary many-fold. The exposure situation will determine percutaneous absorption, which, if low, can be overwhelmed by benzene intake from the food we eat and the air we breathe.

Air Pollutants↗
PubMed2006

Benzene exposure and multiple myeloma: a detailed meta-analysis of benzene cohort studies.

Case reports and epidemiological studies of workers exposed to benzene have demonstrated associations with a number of lymphohematopoietic diseases, but the association with multiple myeloma (MM) has been less apparent. Data from all of the "benzene cohort studies" conducted to date have been selected and evaluated for inclusion in a meta-analysis. The analysis demonstrates a significant excess in the relative risk (RR) of MM in relation to benzene exposure. Pooling the data from seven cohort studies, a meta-analysis yields a statistically significant weighted RR estimate of 2.13 (95% CI = 1.31-3.46). In the analysis of cohort data, an understanding of the cohort follow-up period in relation to benzene exposure and RR of MM is important. Exposure-related RRs of disease decline after the median latency periods are exceeded, particularly when exposure has terminated decades earlier. The positive epidemiological evidence for benzene as a cause of MM is supported by biological plausibility for such an effect from benzene exposure. Studies of refinery workers are difficult to interpret in relation to benzene exposure and risk of MM, but are limited in the study design and analysis. Nonetheless, they provide some support for an association between refinery work and MM.

Benzene↗
PubMed1989

Peroxidase-dependent metabolism of benzene's phenolic metabolites and its potential role in benzene toxicity and carcinogenicity.

The metabolism of two of benzene's phenolic metabolites, phenol and hydroquinone, by peroxidase enzymes has been studied in detail. Studies employing horseradish peroxidase and human myeloperoxidase have shown that in the presence of hydrogen peroxide phenol is converted to 4,4'-diphenoquinone and other covalent binding metabolites, whereas hydroquinone is converted solely to 1,4-benzoquinone. Surprisingly, phenol stimulates the latter conversion rather than inhibiting it, an effect that may play a role in the in vivo myelotoxicity of benzene. Indeed, repeated coadministration of phenol and hydroquinone to B6C3F1 mice results in a dramatic and significant decrease in bone marrow cellularity similar to that observed following benzene exposure. A mechanism of benzene-induced myelotoxicity is therefore proposed in which the accumulation and interaction of phenol and hydroquinone in the bone marrow and the peroxidase-dependent formation of 1,4-benzoquinone are important components. This mechanism may also be responsible, at least in part, for benzene's genotoxic effects, as 1,4-benzoquinone has been shown to damage DNA and is shown here to induce multiple micronuclei in human lymphocytes. Secondary activation of benzene's phenol metabolites in the bone marrow may therefore play an important role in benzene's myelotoxic and carcinogenic effects.

Animals↗
PubMed2002

Albumin adducts of benzene oxide and 1,4-benzoquinone as measures of human benzene metabolism.

Albumin adducts of benzene oxide (BO-Alb) and 1,4-benzoquinone (1,4-BQ-Alb) were investigated among 134 workers exposed to benzene and 51 unexposed controls in Tianjin, China. Concentrations of both adducts increased with benzene exposure [range = 0.07-46.6 parts/million (ppm); median = 3.55 ppm] and with urinary cotinine. Adduct levels were less than proportional to benzene exposure, suggesting saturable CYP 2E1 metabolism of benzene. Because the transition from linear to saturable metabolism began at approximately 1 ppm, the common assumption of linear kinetics at much higher benzene exposures could lead to substantial underestimation of leukemia risks. Adduct levels were generally lower in older workers, indicating that CYP 2E1 metabolism diminished with age, at approximately 2%/year of life. The ratio of 1,4-BQ-Alb:BO-Alb decreased with age and coexposure to toluene, and increased with alcohol consumption. This indicates that factors affecting CYP 2E1 metabolism exerted a greater role on production of 1,4-BQ than BO, presumably because of the second oxidation step from phenol to hydroquinone. The adduct ratio was also positively associated with urinary cotinine, suggesting that both benzene and hydroquinone from cigarette smoke affected adduct levels. Results of a limited time course study of 11 subjects indicated moderate chemical instability of 1,4-BQ-Alb (half life = 13.5 days compared with 21 days for normal Alb turnover), whereas no evidence of instability of BO-Alb was observed. This study illustrates that Alb adducts can be used to investigate the dispositions of reactive metabolites of procarcinogens in humans, provided that exposures are adequately characterized in the month preceding blood collection.

Adolescent↗
PubMed1991

[Environmental and occupational exposure to benzene by investigation of expiratory benzene].

In this paper, expiratory benzene due to environmental and occupational benzene exposure during the work-shift and the morning after was studied by the analysing benzene concentrations in environmental air, in breathing air and in urinary phenol concentration. The results showed that the concentrations of expiratory benzene and urinary phenol correlated significantly with exposure to benzene. It is suggested that the expiratory benzene is a good indicator in biomonitoring of workers exposed to benzene.

Adolescent↗
PubMed2004

Comparison of the repair of DNA damage induced by the benzene metabolites hydroquinone and p-benzoquinone: a role for hydroquinone in benzene genotoxicity.

The human population is continually exposed to benzene due to its presence in complex environmental mixtures and exposure has been linked to a range of haematotoxic effects, including an increased risk of leukaemia. Several hypotheses have been postulated on how benzene exerts its toxic and carcinogenic effects, one idea being that following metabolism to more reactive species it can react with DNA to form adducts which subsequently give rise to mutations. Previously, we have demonstrated the formation of four major DNA adducts from the reaction of DNA with the benzene metabolites hydroquinone (HQ) and p-benzoquinone (p-BQ) and the mutagenicity of these adducts when analysed using the supF forward mutation assay after replication in a human kidney cell line. This study demonstrates a potential role in the carcinogenicity of benzene for the DNA adducts formed on 2'-deoxyguanosine 3'-monophosphate. As a continuation of this work, benzene metabolite-treated plasmid pSP189 containing the supF reporter gene was transfected into human nucleotide excision repair (NER)-proficient and NER-deficient (xeroderma pigmentosum, complementation group A) fibroblast cells to determine the method of adduct repair. For all metabolite treatments in both cell lines the majority of mutations were single base substitutions occurring at GC base pairs, predominantly GC-->TA transversions and GC-->AT transitions. Comparison of mutation frequencies showed a similarity for the HQ treatment for the two cell lines, whereas for the treatments involving p-BQ, an overall higher mutation frequency was observed in the NER-deficient cells compared with the NER-proficient cells. Mutation spectra were significantly different following treatment with HQ in the two cell lines (P = 0.0004). No difference was observed for the control, p-BQ or the combined treatment. The results suggest the involvement of a different repair mechanism for HQ-induced DNA damage and further highlights the potential different roles for the two benzene metabolites in benzene mutagenicity.

Base Sequence↗
PubMed1983

Inhibition of erythropoiesis by benzene and benzene metabolites.

Mice were injected sc with benzene or one of its metabolites, phenol, catechol, or hydroquinone. The ability of these compound to inhibit erythropoiesis was quantified by measuring the incorporation of 59Fe into developing erythrocytes. Benzene decreased 59Fe incorporation into developing erythrocytes in a dose-dependent manner. Maximum inhibition was observed when benzene was administered 48 hr prior to initiation of the 59Fe uptake test. The three metabolites of benzene also significantly inhibited 59Fe incorporation when they were administered 48 hr prior to initiation of 59Fe uptake assay. The degree of inhibition observed with the metabolites was not as great as that observed with benzene. Coadministration of the microsomal mixed-function oxidase inhibitor, 3-amino-1,2,4-triazole, abolished the erythropoietic toxicity of benzene and phenol but had no effect on the catechol- or hydroquinone-induced toxicity.

Animals↗
PubMedDate not supplied

Identification of benzene metabolites in dermal fibroblasts as nonphenolic: regulation of cell viability, apoptosis, lipid peroxidation and expression of matrix metalloproteinase 1 and elastin by benzene metabolites.

The skin is exposed to benzene and its derivatives, prevalent environmental chemicals. They may impair the structural integrity of the skin by increased expression of matrix metalloproteinase 1 (MMP-1; degrades structural collagen) and elastin, synthesized primarily by the dermal fibroblasts. We examined the metabolism of benzene in dermal fibroblasts and identified the benzene metabolites as toluene, benzaldehyde, aniline and benzoic acid. These metabolites were not toxic to the cells with regard to cell viability, apoptosis and lipid peroxidation, unlike the phenolic benzene metabolites (hydroquinone, t-butyl hydroquinone and phenol) or hydrogen peroxide. Toluene and phenol, which compose cigarette smoke, and benzaldehyde stimulated MMP-1 and/or elastin expression. In summary, the dermal fibroblasts metabolize benzene to nonphenolic metabolites that are less toxic to the cellular components than the phenolic benzene derivatives. Toluene, benzaldehyde and phenol can directly cause facial wrinkling and impaired structural integrity by upregulating MMP-1 and/or elastin.

Aniline Compounds↗
PubMed2004

[Joint inhibition of benzene and monosubstituted benzenes on ammonia-oxidizing activity of sediment].

The joint inhibitions of benzene and three kinds of monosubstituted benzenes (aniline, phenol and nitrobenzene) on ammonia-oxidizing activity of sediment was investigated in order to study the effects of combined pollutants on nitrification process in the nitrogen cycle. The results showed that the joint inhibiton of 11 different kinds of mixtures, including binary or multi-equitoxic mixtures among benzene, aniline, phenol and nitrobenzene, exhibited different effects on ammonia-oxidizing activity of sediment, among which seven were addictive effect, three were synergistic, and only the mixture of benzene and phenol was antagonism. A conclusion could be made that the addition of nitrobenze to a mixture usually exhibited addictive effect. There was a relationship between the half joint inhibition concentrations (IC50, micromol x L(-1)) of benzene and monosubstituted benzenes on ammonia-oxidizing activity of sediment and the mixed electronegativities (MEs): lgIC50 = 2.197 - 0.236ME. With the increase of mixed electronegativities (MEs), the joint inhibitions of mixtures increased.

Ammonia↗
PubMed1994

Monitoring of benzene-exposed workers for genotoxic effects of benzene: improved-working-condition-related decrease in the frequencies of chromosomal aberrations in peripheral blood lymphocytes.

The genotoxic effects of benzene were assessed in peripheral blood lymphocytes of 49 workers occupationally exposed to benzene (3-68.7 mg/m3 in the work environment) for 0-2, 2-10 and more than 10 years (10, 22 and 17 workers, respectively). Chromosomal aberrations, SCEs and UV-induced DNA synthesis were used as indicators of genotoxic effects. Most of the workers were followed up in 1991 and 1992, while the benzene concentrations were reduced to 1-18.4 mg/m3 air. Considered overall, in the "exposed" groups, the frequencies of chromosomal aberrations were significantly higher than in controls thus providing evidence for the clastogenic effects of benzene. However, there seems to be no correlation between aberration frequencies and the duration of prior exposure to benzene. In 1991 and 1992, when the benzene concentrations were brought down, there was a concomitant decrease in the frequencies of chromosomal aberrations; in 1992 the decrease reached one third to one half of the initial frequencies, values still higher than in the controls. With the other genotoxic end-points, the changes were small and not consistent.

Air Pollutants, Occupational↗
PubMed2003

Comparative benzene-induced fatty acid changes in a Rhodococcus species and its benzene-sensitive mutant: possible role of myristic and oleic acids in tolerance.

A Gram positive bacterium of the genus Rhodococcus was isolated from a contaminated site in Sydney, Australia, for its ability to tolerate and degrade high concentrations of benzene. To identify fatty acids that may impart this Rhodococcus sp. with tolerance to toxic solvents, a benzene-sensitive strain, labeled M2b, was isolated using EMS mutagenesis. A comparative analysis of fatty acid profiles showed that strain M2b was unable to increase its saturated:unsaturated ratio of fatty acids to the level achieved by the w-t strain when both strains were challenged with benzene. This was due to M2b's increased abundance of myristic acid, and decreased abundance of oleic acid. In addition, by measuring the generalized polarization of the fluorescent membrane probe laurdan using fluorescence spectroscopy, we have shown for the first time the effects of an aromatic hydrocarbon on the membrane fluidity of a Rhodococcus sp. The fluidity of the membranes increased after only 0.5 hr of exposure to benzene, thus suggesting the partitioning of benzene within the lipid bilayer. The response of this Rhodococcus sp. to benzene may suggest a mechanism for how other microorganisms survive when toxic solvents are released within the vicinity of their environment.

Benzene↗
PubMed1998

Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene.

Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are presumed to be specific biomarkers of exposure to benzene. We analyzed BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a subsample consisting of 19 workers and 19 controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. The adducts were analyzed by gas chromatography-mass spectrometry following reaction of the protein with trifluoroacetic anhydride and methanesulfonic acid. When subjects were divided into controls (n = 42) and workers exposed to < or =31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were 32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure: Spearman r = 0.67, P < 0.0001). To our knowledge, these results represent the first observation in humans that BO-Hb levels are significantly correlated with benzene exposure. Median BO-Alb levels in these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb, respectively, also reflecting a significant correlation with exposure (Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from both Hb and Alb adducts was very similar. These results clearly affirm the use of both Hb and Alb adducts of BO as biomarkers of exposure to high levels of benzene. As part of our investigation of the background levels of BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g) and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the observed background adducts reflect an artifact of the assay, while other portions are indicative of either unknown exposures or endogenous production of adducts.

Benzene↗
PubMed1996

Clinical features of hematopoietic malignancies and related disorders among benzene-exposed workers in China. Benzene Study Group.

Previous occupational cohort studies of benzene-exposed workers have for the most part used only death certificates to validate diagnoses of workers developing leukemia and other hematopoietic and lymphoproliferative malignancies and related disorders (HLD). In a follow-up study of 74,828 benzene-exposed workers and a comparison group of 35,805 nonexposed workers from 12 cities in China, we sought to characterized clinicopathologically and to confirm diagnoses of all cases of HLD. Using medical records, laboratory hematology results, and histopathology, U.S. and Chinese expert hematopathologists, blinded to exposure status, carried out a detailed review using standardized evaluation forms. Key among the findings were a notable diversity of malignant and nonneoplastic hematopoietic and lymphoproliferative disorders, documentation of excess myelodysplastic syndromes among benzene workers, and widespread dyspoiesis involving all hematopoietic cell lines. As sophisticated clinicopathologic characterization and corresponding classification schemes for HLD become increasingly widespread, it is recommended that future epidemiologic investigations of benzene workers incorporate similarly detailed morphologic evaluation. In extending follow-up of this cohort of young workers, we will continue to use all available clinical, laboratory hematology, and pathology data as well as cytogenetic and biochemical markers to characterized various HLD outcomes. These careful surveillance mechanisms should also provide additional insight into carcinogenic mechanisms of benzene and allow comparison of the molecular pathogenesis of HLD induced by benzene versus chemotherapy, radiation, or other exposure.

Adult↗
PubMed2001

Protein adducts of 1,4-benzoquinone and benzene oxide among smokers and nonsmokers exposed to benzene in China.

Hemoglobin (Hb) and albumin (Alb) adducts of the benzene metabolites benzene oxide (BO) and 1,4-benzoquinone (1,4-BQ) were analyzed by gas chromatography-mass spectrometry in 43 exposed workers and 44 unexposed controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. When subjects were divided into controls (n = 44) and workers exposed to </=31 ppm (n = 21) and >31 ppm (n = 22) of benzene, median 1,4-BQ-Alb adducts were 2110, 5850, and 13,800 pmol/g Alb, respectively (correlation with exposure: Spearman r = 0.762; P < 0.0001); median BO-Alb adducts were 106, 417, and 2400 pmol/g Alb, respectively (Spearman r = 0.877; P < 0.0001); and median BO-Hb adducts were 37.1, 50.5, and 136 pmol/g Hb, respectively (Spearman r = 0.757; P < 0.0001). To our knowledge, this is the first observation that adducts of 1,4-BQ are significantly correlated with benzene exposure. When compared on an individual basis, Alb adducts of 1,4-BQ and BO and Hb adducts of BO were highly correlated with each other and with urinary phenol and hydroquinone (P < 0.0001 for all of the comparisons). Although detectable in the assays, Hb adducts of 1,4-BQ and both Hb and Alb adducts of 1,2-BQ produced erratic results and are not reported. Interestingly, cigarette smoking increased Alb adducts of 1,4-BQ but not of BO, suggesting that benzene from cigarette smoke was not the primary contributor to the 1,4-BQ adducts.

Benzene↗