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1.
Toxicol Appl Pharmacol ; 431: 115742, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34624356

ABSTRACT

Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure by itself is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of the metabolites tested, trans,trans-mucondialdehyde (10 µM, 18h) was the most toxic. It induced caspases-3, -7 and -9 (intrinsic pathway) activation and enhanced microparticle formation by 2.4-fold. Levels of platelet-leukocyte aggregates, platelet macroparticles, and a proportion of CD4+ and CD8+ T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene.


Subject(s)
Benzene/toxicity , Cardiovascular Diseases/chemically induced , Cardiovascular System/drug effects , Animals , Asymptomatic Diseases , Benzene/administration & dosage , Biomarkers/blood , Blood Platelets/drug effects , Blood Platelets/metabolism , Blood Platelets/pathology , Cardiotoxicity , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Cardiovascular System/metabolism , Cardiovascular System/pathology , Cell-Derived Microparticles/drug effects , Cell-Derived Microparticles/metabolism , Cell-Derived Microparticles/pathology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelial Cells/pathology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Inhalation Exposure , Leukocytes/drug effects , Leukocytes/metabolism , Leukocytes/pathology , Male , Mice, Inbred C57BL
2.
J Med Chem ; 64(9): 6179-6197, 2021 05 13.
Article in English | MEDLINE | ID: mdl-33938746

ABSTRACT

Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound 21 possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. 21 also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of 21 can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that 21 significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Benzene/chemistry , Benzene/pharmacology , Drug Design , Drug Resistance, Multiple/drug effects , Neoplasm Proteins/metabolism , Pyrimidines/chemistry , Administration, Oral , Animals , Benzene/administration & dosage , Biological Availability , Drug Interactions , Humans , K562 Cells , Mice , Paclitaxel/pharmacokinetics , Xenograft Model Antitumor Assays
3.
J Appl Toxicol ; 41(8): 1262-1274, 2021 08.
Article in English | MEDLINE | ID: mdl-33269480

ABSTRACT

In order to reduce exposure to toxic chemicals, the European REACH regulation (1907/2006) recommends substituting toxic molecules with compounds that are less harmful to human health and the environment. Toluene is one of the most frequently used solvents in industries despite its toxicity. The objective of this study is to better understand and compare the toxicity of toluene and its homologues in a bronchial cell model. Thus, human bronchial BEAS-2B cells were exposed to steams of toluene, m-xylene, mesitylene (1,3,5-trimethylbenzene), and benzene (20 and 100 ppm). Exposure was carried out using an air-liquid interface (ALI) system (Vitrocell) during 1 h/day for 1, 3, or 5 days. Cytotoxicity, xenobiotic metabolism enzyme gene expression, and inflammatory response were evaluated following cell exposures. BEAS-2B cell exposure to toluene and its homologues revealed the involvement of major (CYP2E1) and minor metabolic pathways (CYP1A1). A late induction of genes (EPHX1, DHDH, ALDH2, and ALDH3B1) was measured from Day 3 and can be linked to the formation of metabolites. An increase in the secretion level of inflammatory markers (TNF-α, IL-6, IL-8, MCP-1, and GM-CSF) was also observed. In parallel, regulation between inflammatory mediators and the expression of transmembrane glycoprotein mucin MUC1 was also studied. This in vitro approach with ALI system points out the relevance of conducting repeated exposures to detect potential late effects. The difference recorded after cell exposure to toluene and its homologues highlights the importance of substitution principle.


Subject(s)
Benzene Derivatives/toxicity , Benzene/toxicity , Bronchi/drug effects , Toluene/toxicity , Xylenes/toxicity , Benzene/administration & dosage , Benzene Derivatives/administration & dosage , Blotting, Western , Bronchi/cytology , Cell Line , Gene Expression/drug effects , Humans , Inflammation/chemically induced , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Toluene/administration & dosage , Xylenes/administration & dosage
4.
Article in Chinese | MEDLINE | ID: mdl-30248740

ABSTRACT

Objective: The main purpose of this study was to ascertain whether (or not) exposure to benzene, toluene, xylene and ethylbenzene (BTXE) , under normal working conditions, was associated with any health effects. Methods: From January to December 2014, the workplaces concentrations of BTXE were measured of 71 enterprises in Suzhou Industrial Park. Occupational health examination were investigated on 764 employees who exposed to BTXE, as well as 4409 employees of the corresponding enterprises who unexposed to BTXE, and analyzed the data of the two groups. Results: A total of 6 monitoring sites in 3 enterprises BTXE concentrations excess of the standards, the unexposed group was under the limit of detection. The means of red blood cell count, hemoglobin, hematocrit, intermediate cell count and percentage of intermediate cells were significantly higher in exposed group than in unexposed group (P<0.05) . Conversely, platelet count was significantly lower in exposed group than in unexposed group (P<0.05) . The proportion of red blood cell volume, lymphocyte count and percentage of intermediate cells were significantly lower in exposed group than in unexposed group (P<0.05) . Both means and proportion of glutamic pyruvic transaminase and urea nitrogen were significantly higher in exposed group than in unexposed group (P<0.05) . The positive rate of protein, urine, urine red blood cell were significantly higher in exposed group than in unexposed group (P<0.05) . The abnormal rate of electrocardiogram, liver and kidney B scan were significantly higher in exposed group than in unexposed group (P<0.05) . Multivariate logistic regression analysis revealed that percentage of intermediate cells increased, urea nitrogen increased, urine protein positived, urine red blood cells positived in exposed group the OR values were 1.689, 3.291, 3.163 and 1.743 (P<0.05) . Conclusion: Occupational exposure to low concentrations of BTXE had a certain impact on the blood system and liver and kidney function of the employees, occupational health surveillance for such people should be strengthened.


Subject(s)
Air Pollutants, Occupational/toxicity , Benzene Derivatives/toxicity , Benzene/toxicity , Occupational Diseases/epidemiology , Occupational Exposure/adverse effects , Toluene/toxicity , Xylenes/toxicity , Air Pollutants, Occupational/blood , Benzene/administration & dosage , Benzene/analysis , Benzene Derivatives/administration & dosage , Benzene Derivatives/blood , Humans , Liver , Occupational Diseases/blood , Toluene/administration & dosage , Toluene/blood , Xylenes/administration & dosage , Xylenes/blood
5.
Anal Chim Acta ; 1036: 195-203, 2018 Dec 07.
Article in English | MEDLINE | ID: mdl-30253832

ABSTRACT

Metabolite profiling can be used as a diagnostic measure for both short and long term co-exposure by individuals to benzene, toluene, ethylbenzene and xylenes (BTEX). A novel one pot derivatization in situ kit (OPDISK) was developed and optimized using a multivariate approach based on central composite design. The OPDISK was designed to simultaneously derivatize, in a urine sample matrix, a series of fourteen carboxylic acid and phenol-bearing urinary metabolites of BTEX to enhance their chromatographic analysis and sensitivity for detection by liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS). Using the reagent kit, the less responsive functional units on the molecules were converted to permanently positively-charged functional units. The kit was composed of three components, 2-fluoro-1-methylpyridinium p-toluenesulfonate (FMP), 3-carbinol-1-methylpyridinium iodide (CMP) and triethylamine (TEA) as a basic catalyst and, only after diluting a urine sample 20 fold with acetonitrile, was applied under mild conditions of room temperature and short reaction time of 20 min. The derivatized biomarkers were then directly analyzed using isotope dilution LC-ESI-MS/MS. The method was sensitive (limit of detection on column ranged from 1.4 pg to 3.1 ng), accurate (mean accuracy from 85% to 114%), and precise (mean coefficient of variation from 1% to 14%). The method results indicated a good linearity (R2 ≥ 0.990) for all metabolites. ClinChek® urine control samples were used successfully to demonstrate the accuracy of the method.


Subject(s)
Carboxylic Acids/urine , Indicator Dilution Techniques , Phenols/urine , Benzene/administration & dosage , Benzene Derivatives/administration & dosage , Biomarkers/metabolism , Biomarkers/urine , Carboxylic Acids/metabolism , Chromatography, Liquid , Humans , Isotopes , Phenols/metabolism , Surface Properties , Tandem Mass Spectrometry , Toluene/administration & dosage , Xylenes/administration & dosage
6.
Arch Toxicol ; 92(1): 259-272, 2018 Jan.
Article in English | MEDLINE | ID: mdl-28733890

ABSTRACT

Exposure to high-dose benzene leads to the inhibition of erythroid differentiation. However, whether lower doses of benzene exposure resemble high-dose effects in erythroid differentiation, as well as the underlying mechanisms, remains largely unknown. To identify the microRNAs (miRNAs) specifically responsible for benzene exposure and their regulatory role in erythroid differentiation, we performed miRNA microarray in CD34+ hematopoietic progenitor cells isolated from human umbilical cord blood after treatment with hydroquinone (HQ), a metabolite of benzene at concentrations of 0, 1.0, 2.5, and 5.0 µM. As a result, HQ treatment inhibited erythroid differentiation in a dose-response manner. miRNA microarray analysis revealed that miRNA-451a, miRNA-486-5p and miRNA-126-3p expression were significantly lower in HQ-treated CD34+ hematopoietic progenitor cells. In vitro studies showed that miRNA-451a and miRNA-486-5p were up-regulated during erythroid differentiation both in CD34+ hematopoietic progenitor cells and K562 cells. The increase in the percentage of benzidine-positive cells and the expression of γ-globin in K562 cells transfected with either miRNA-451a or miRNA-486-5p mimic indicated that both miRNAs played a role in the promotion of erythroid cell differentiation. Overexpression of either miRNA-451a or miRNA-486-5p attenuated the inhibitory effects on erythroid differentiation in HQ-treated K562 cells. In vivo study showed a decreasing count of peripheral red blood cell (RBC) in C57BL/6J male mice treated with aerosol benzene at concentrations of 0, 1, 5, 25 ppm (time weight average, TWA). In addition, the expression of miRNA-451a or miRNA-486-5p was negatively correlated with the concentration of benzene inhalation on erythroid toxicity of C57BL/6J mice. Particularly, the decline in miRNA-451a and miRNA-486-5p expression appeared in male chronic benzene poisoning patients, and was correlated with a constant decrease in their RBC counts over the first 3 months after being diagnosed. These findings indicate that the suppression of miRNA-451a or miRNA-486-5p might be associated with the benzene-induced perturbation of erythroid cell differentiation.


Subject(s)
Benzene/toxicity , Cell Differentiation/drug effects , Hematopoietic Stem Cells/drug effects , MicroRNAs/genetics , Adult , Animals , Benzene/administration & dosage , Benzene/poisoning , CD4 Antigens , Cell Differentiation/genetics , Dose-Response Relationship, Drug , Down-Regulation/genetics , Female , Gene Expression Regulation/drug effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/physiology , Humans , Hydroquinones/administration & dosage , Hydroquinones/toxicity , K562 Cells , Male , Mice, Inbred C57BL , Middle Aged
8.
Toxicol Appl Pharmacol ; 324: 36-44, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28373009

ABSTRACT

Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3mg/m3 FA for 2weeks, mimicking occupational exposure, and were monitored for another 7days post-exposure. Meanwhile, we included benzene (BZ) as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with BZ was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk.


Subject(s)
Benzene/toxicity , Bone Marrow/drug effects , Bone Marrow/metabolism , Formaldehyde/toxicity , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , 8-Hydroxy-2'-Deoxyguanosine , Animals , Benzene/administration & dosage , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/metabolism , Formaldehyde/administration & dosage , Male , Mice , Mice, Inbred BALB C , Random Allocation , Reactive Oxygen Species/metabolism
9.
Life Sci ; 147: 67-70, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26775569

ABSTRACT

AIMS: Benzene metabolism seems to modulate NF-κB, p38-MAPK (mitogen-activated protein kinase) and signal transducer and activator of transcription 3 (STAT3) signalling pathways via the production of reactive oxygen species. This study aims to evaluate the effects of low-dose, long-term exposure on NF-κB, STAT3, p38-MAPK and stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) signal transduction pathways in peripheral blood mononuclear cells in gasoline station attendants. The influence of consumption of vegetables and fruits on these pathways has also been evaluated. MAIN METHODS: A total of 91 men, employed in gasoline stations located in eastern Sicily, were enrolled for this study and compared with a control group of 63 male office workers with no history of exposure to benzene. The exposure was assessed by measuring urinary trans,trans-muconic acid (t,t-MA) concentration. Quantitative analyses were performed for proteins NF-κB p65, phospho-NF-κB p65, phospho-IκB-α, phospho-SAPK/JNK, phospho-p38 MAPK and phospho-STAT3 using an immunoenzymatic assay. KEY FINDINGS: The results of this study indicate significantly higher t,t-MA levels in gasoline station attendants. With regard to NF-κB, phospho-IκB-α and phospho-STAT3 proteins, statistically significant differences were observed in workers exposed to benzene. However, no differences were observed in SAPK/JNK and p38-MAPK activation. These changes were positively correlated with t,t-MA levels, but only phospho-NF-κB p65 was associated with the intake of food rich in antioxidant active principles. SIGNIFICANCE: Chronic exposure to low-dose benzene can modulate signal transduction pathways activated by oxidative stress and involved in cell proliferation and apoptosis. This could represent a possible mechanism of carcinogenic action of chronic benzene exposure.


Subject(s)
Benzene/toxicity , Occupational Exposure/adverse effects , Oxidative Stress/drug effects , Signal Transduction/drug effects , Adult , Apoptosis/drug effects , Benzene/administration & dosage , Cell Proliferation/drug effects , Gasoline , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Reactive Oxygen Species/metabolism , Sicily , Sorbic Acid/analogs & derivatives , Sorbic Acid/metabolism , Transcription Factor RelA/metabolism
10.
Environ Mol Mutagen ; 57(2): 151-8, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26646167

ABSTRACT

DNA damage and cellular repair capacity were studied in 18 male fuel tanker drivers and 13 male filling-station attendants exposed to low and very low concentrations of benzene, respectively, and compared to 20 males with no occupational exposure (controls). Exposure to airborne benzene was measured using passive personal samplers, and internal doses were assayed through the biomarkers t,t-muconic acid, S-phenylmercapturic acid and urinary benzene. DNA damage was evaluated using tail intensity (TI) determined by the comet assay in peripheral lymphocytes. Urinary 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) was measured as a biomarker of oxidative damage. DNA repair kinetics were assessed using the comet assay in lymphocytes sampled 20 and 60 min post H2O2 exposure. Benzene exposure differed significantly between the drivers (median 246.3 µg/m(3)), attendants (median 13.8 µg/m(3)), and controls (median 4.1 µg/m(3)). There were no differences in TI and 8-oxodG among the three groups, or between smokers and non-smokers. DNA repair kinetics were similar among the drivers, attendants and controls, although the comet assay on H2 O2 -damaged lymphocytes after 60 min revealed significantly lower levels of TI only in drivers. The DNA repair process in smokers was similar to that observed in drivers. In conclusion, this study found no relationship between low levels of benzene exposure and DNA damage, although there was evidence that exposure interferes with DNA repair kinetics. The biological impact of this finding on the onset of genotoxic effects in exposed workers has still to be ascertained.


Subject(s)
Benzene/toxicity , DNA Damage/drug effects , DNA Repair/drug effects , Occupational Exposure/adverse effects , 8-Hydroxy-2'-Deoxyguanosine , Acetylcysteine/analogs & derivatives , Acetylcysteine/blood , Adult , Benzene/administration & dosage , Biomarkers , Case-Control Studies , Comet Assay , DNA Repair/physiology , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/urine , Humans , Lymphocytes/drug effects , Lymphocytes/physiology , Male , Middle Aged , Occupational Exposure/analysis , Smoking/adverse effects , Sorbic Acid/analogs & derivatives , Sorbic Acid/analysis
11.
Environ Toxicol Pharmacol ; 39(3): 1161-9, 2015 May.
Article in English | MEDLINE | ID: mdl-25935538

ABSTRACT

Benzene (C6H6) is an organic compound used in petrochemicals and numerous other industries. It is abundantly released to our environment as a chemical pollutant causing widespread human exposure. This study mainly focused on benzene induced toxicity on rat pancreatic islets with respect to oxidative damage, insulin secretion and glucokinase (GK) activity. Benzene was dissolved in corn oil and administered orally at doses 200, 400 and 800mg/kg/day, for 4 weeks. In rats, benzene significantly raised the concentration of plasma insulin. Also the effect of benzene on the release of glucose-induced insulin was pronounced in isolated islets. Benzene caused oxidative DNA damage and lipid peroxidation, and also reduced the cell viability and total thiols groups, in the islets of exposed rats. In conclusion, the current study revealed that pancreatic glucose metabolism is susceptible to benzene toxicity and the resultant oxidative stress could lead to functional abnormalities in the pancreas.


Subject(s)
Benzene/toxicity , Insulin/blood , Islets of Langerhans/drug effects , Oxidative Stress , Animals , Benzene/administration & dosage , Blood Glucose/metabolism , Cell Survival/drug effects , DNA Damage , Glucokinase/metabolism , Islets of Langerhans/enzymology , Lipid Peroxidation , Rats , Rats, Wistar
12.
Toxicol Appl Pharmacol ; 281(1): 109-17, 2014 11 15.
Article in English | MEDLINE | ID: mdl-25283951

ABSTRACT

The overall goal of this research was to further develop and improve an existing skin diffusion model by experimentally confirming the predicted absorption rates of topically-applied volatile organic compounds (VOCs) based on their physicochemical properties, the skin surface temperature, and the wind velocity. In vitro human skin permeation of two hydrophilic solvents (acetone and ethanol) and two lipophilic solvents (benzene and 1,2-dichloroethane) was studied in Franz cells placed in a fume hood. Four doses of each (14)C-radiolabed compound were tested - 5, 10, 20, and 40µLcm(-2), corresponding to specific doses ranging in mass from 5.0 to 63mgcm(-2). The maximum percentage of radiolabel absorbed into the receptor solutions for all test conditions was 0.3%. Although the absolute absorption of each solvent increased with dose, percentage absorption decreased. This decrease was consistent with the concept of a stratum corneum deposition region, which traps small amounts of solvent in the upper skin layers, decreasing the evaporation rate. The diffusion model satisfactorily described the cumulative absorption of ethanol; however, values for the other VOCs were underpredicted in a manner related to their ability to disrupt or solubilize skin lipids. In order to more closely describe the permeation data, significant increases in the stratum corneum/water partition coefficients, Ksc, and modest changes to the diffusion coefficients, Dsc, were required. The analysis provided strong evidence for both skin swelling and barrier disruption by VOCs, even by the minute amounts absorbed under these in vitro test conditions.


Subject(s)
Acetone/metabolism , Benzene/metabolism , Ethanol/metabolism , Ethylene Dichlorides/metabolism , Skin Absorption/physiology , Acetone/administration & dosage , Benzene/administration & dosage , Diffusion Chambers, Culture , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Ethylene Dichlorides/administration & dosage , Forecasting , Humans , Skin Absorption/drug effects
13.
Int J Mol Sci ; 15(3): 4994-5010, 2014 Mar 20.
Article in English | MEDLINE | ID: mdl-24658442

ABSTRACT

Benzene is identified as a carcinogen. Continued exposure of benzene may eventually lead to damage to the bone marrow, accompanied by pancytopenia, aplastic anemia or leukemia. This paper explores the variations of endogenous metabolites to provide possible clues for the molecular mechanism of benzene-induced hematotoxicity. Liquid chromatography coupled with time of flight-mass spectrometry (LC-TOF-MS) and principal component analysis (PCA) was applied to investigate the variation of endogenous metabolites in bone marrow cells and plasma of male C3H/He mice. The mice were injected subcutaneously with benzene (0, 300, 600 mg/day) once daily for seven days. The body weights, relative organ weights, blood parameters and bone marrow smears were also analyzed. The results indicated that benzene caused disturbances in the metabolism of oxidation of fatty acids and essential amino acids (lysine, phenylalanine and tyrosine) in bone marrow cells. Moreover, fatty acid oxidation was also disturbed in plasma and thus might be a common disturbed metabolic pathway induced by benzene in multiple organs. This study aims to investigate the underlying molecular mechanisms involved in benzene hematotoxicity, especially in bone marrow cells.


Subject(s)
Benzene/toxicity , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Metabolome/drug effects , Metabolomics/methods , Animals , Benzene/administration & dosage , Biomarkers/blood , Biomarkers/metabolism , Body Weight/drug effects , Chromatography, Liquid , Dose-Response Relationship, Drug , Injections, Subcutaneous , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Lung/drug effects , Lung/pathology , Male , Mass Spectrometry/methods , Mice, Inbred C3H , Organ Size/drug effects , Spleen/drug effects , Spleen/pathology
14.
G Ital Med Lav Ergon ; 35(4): 251-5, 2013.
Article in Italian | MEDLINE | ID: mdl-24303705

ABSTRACT

AIM: To verify which of the various biomarkers of internal dose of benzene can be considered reliable for biological monitoring of exposure to the low concentrations present nowadays in working and living environments. MATERIALS AND METHODS: The specific literature was analyzed to assess the reliability of the different biomarkers of internal dose. RESULTS AND CONCLUSIONS: T,t-muconic acid is a non specific biomarker for benzene, valid for exposure to concentrations up to one order of magnitude less than the threshold limit of 3250 microg/m3. S-phenylmercapturic acid (SPMA) is a reliable marker even for exposure to concentrations up to two orders below the threshold value of 3250 microg/m3, and can be considered the biomarker of choice for biological monitoring of workers exposed to benzene. Urinary benzene does not seem to have any real advantages over SPMA for monitoring occupational exposure to benzene, but it does seem to be more reliable than SPMA to assess exposure to concentrations like those present in living environments. A smoking habit influences the urinary excretion of all the described biomarkers, and for the current low levels of occupational and environmental exposure to benzene, must be taken into account when interpreting the results of biological monitoring.


Subject(s)
Benzene/toxicity , Environmental Exposure , Environmental Monitoring , Occupational Exposure , Benzene/administration & dosage , Biomarkers/analysis , Humans
15.
G Ital Med Lav Ergon ; 35(4): 263-7, 2013.
Article in Italian | MEDLINE | ID: mdl-24303708

ABSTRACT

DNA methylation, mitochondrial DNA copy number and telomeres shortening are cellular modifications associated with an increasing number of tumors, cardiovascular and aging diseases. In our studies these modifications were evaluated in subjects occupationally exposed to low levels of benzene and in the general population. In peripheral blood lymphocytes a decrease of DNA methylation with the increase of personal benzene exposure was found, both in Alu and LINE-1 repetitive elements, and in the global DNA. Telomere length shortening in subjects exposed to traffic exhausts and an increase in mitochondrial DNA copy number correlated to benzene exposure was also found. DNA methylation measured in specimen repeats collected at intervals of 8 years decreased more markedly in exposed subjects than in controls. Our studies highlighted the association of epigenetic modifications of DNA with low benzene exposure.


Subject(s)
Benzene/toxicity , Epigenesis, Genetic , Benzene/administration & dosage , DNA Methylation , DNA, Mitochondrial , Female , Humans , Male
16.
Environ Sci Pollut Res Int ; 20(9): 6138-49, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23546852

ABSTRACT

The lethal doses (LD50s) of fluorinated, chlorinated, brominated, and iodinated benzene, phenol, and diphenyl ether in mice were ascertained respectively under the consistent condition. The acute toxicity of four benzenes orders in fluorobenzene (FB) < iodobenzene < chlorobenzene≈bromobenzene, that of four phenols orders in 4-iodophenol≈4-bromophenol < 4-chlorophenol (4-MCP) < 4-fluorophenol (4-MFP), and that of four diphenyl ethers orders in 4,4'-iododiphenyl ether < 4,4'-difluorodiphenyl ether < 4,4'-dichlorodiphenyl ether≈4,4'-dibromodiphenyl ether. General behavior adverse effects were observed, and poisoned mouse were dissected to observe visceral lesions. FB, 4-MCP, and 4-MFP produced toxic faster than other halogenated benzenes and phenols, as they had lower octanol-water partition coefficients. Pathological changes in liver and liver/kidney weight changes were also observed. Hepatic superoxide dismutase, catalase activities, and malondialdehyde level were tested after a 28-day exposure, which reflects a toxicity order basically consistent with that reflected by the LD50s. By theoretical calculation and building models, the toxicity of benzene, phenol, and diphenyl ether were influenced by different structural properties.


Subject(s)
Benzene/toxicity , Chemical and Drug Induced Liver Injury/pathology , Phenol/toxicity , Phenyl Ethers/toxicity , Animals , Antioxidants , Benzene/administration & dosage , Benzene/chemistry , Body Weight/drug effects , Dose-Response Relationship, Drug , Female , Halogens/chemistry , Hydrocarbons, Halogenated/chemistry , Hydrocarbons, Halogenated/toxicity , Mice , Mice, Inbred ICR , Oxidants , Phenol/administration & dosage , Phenol/chemistry , Phenyl Ethers/administration & dosage , Phenyl Ethers/chemistry
17.
Risk Anal ; 33(7): 1237-51, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23278103

ABSTRACT

A physiologically-based pharmacokinetic (PBPK) model of benzene inhalation based on a recent mouse model was adapted to include bone marrow (target organ) and urinary bladder compartments. Empirical data on human liver microsomal protein levels and linked CYP2E1 activities were incorporated into the model, and metabolite-specific conversion rate parameters were estimated by fitting to human biomonitoring data and adjusting for background levels of urinary metabolites. Human studies of benzene levels in blood and breath, and phenol levels in urine were used to validate the rate of human conversion of benzene to benzene oxide, and urinary benzene metabolites from Chinese benzene worker populations provided model validation for rates of human conversion of benzene to muconic acid (MA) and phenylmercapturic acid (PMA), phenol (PH), catechol (CA), hydroquinone (HQ), and benzenetriol (BT). The calibrated human model reveals that while liver microsomal protein and CYP2E1 activities are lower on average in humans compared to mice, the mouse also shows far lower rates of benzene conversion to MA and PMA, and far higher conversion of benzene to BO/PH, and of BO/PH to CA, HQ, and BT. The model also differed substantially from existing human PBPK models with respect to several metabolic rate parameters of importance to interpreting benzene metabolism and health risks in human populations associated with bone marrow doses. The model provides a new methodological paradigm focused on integrating linked human liver metabolism data and calibration using biomonitoring data, thus allowing for model uncertainty analysis and more rigorous validation.


Subject(s)
Benzene/administration & dosage , Bone Marrow/metabolism , Models, Theoretical , Urinary Bladder/metabolism , Calibration , Humans
18.
Toxicol Ind Health ; 27(9): 802-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21421681

ABSTRACT

This study was conducted to determine whether there was any exposure to toluene, xylene and benzene and to assess the health impact of these solvents on workers in furniture enterprises in Karabaglar, Izmir. This cross-sectional study covered furniture enterprises in Karabaglar, Izmir. This study was comprised of an exposed group consisting of workers engaged in painting and varnishing and therefore exposed either directly or indirectly toluene, xylene and benzene in the workplace and the non-exposed group engaged in other aspects of production. While a total of 261 individuals completed questionnaires, 210 workers agreed to provide blood samples. Blood solvents levels were determined using gas chromatograph at Ege University, Intoxication Research and Application Centre. The modified EUROQUEST questionnaire was used to assess neuropsychological symptoms and neurological and general examination were performed. Occupational and exposure history, demographic and work-related information was collected. In this study of workers, blood toluene and benzene levels were found to be significantly higher among those engaged in painting and varnishing compared to those who perform other tasks. The average blood toluene and benzene concentrations among exposed workers were 6.95 times and 1.64 times respectively higher than those in the nonexposed groups. Smokers and participants who worked in excess of 8 hours/day had higher blood toluene and benzene levels. The most frequently work-related health complaints were back pain, allergies and asthma. No differences were found in the average scores in the neuropsychological symptoms questionnaire between exposed and non-exposed groups. Neurological examination of two individuals with these complaints revealed a loss of reflexes. The workers were unaware that they were being exposed to solvents at work. Tobacco smoke is a major source of internal exposure to benzene. Improving working conditions in furniture work places is a priority.


Subject(s)
Air Pollutants, Occupational/toxicity , Benzene/toxicity , Neurotoxicity Syndromes/epidemiology , Occupational Diseases/epidemiology , Occupational Exposure , Toluene/toxicity , Xylenes/toxicity , Adolescent , Adult , Air Pollutants, Occupational/blood , Benzene/administration & dosage , Benzene/analysis , Cross-Sectional Studies , Humans , Industry , Interior Design and Furnishings , Male , Middle Aged , Neurotoxicity Syndromes/blood , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/physiopathology , Occupational Diseases/blood , Occupational Diseases/etiology , Occupational Diseases/physiopathology , Paint/toxicity , Smoking/adverse effects , Surveys and Questionnaires , Toluene/administration & dosage , Toluene/blood , Turkey/epidemiology , Xylenes/administration & dosage , Xylenes/blood , Young Adult
19.
G Ital Med Lav Ergon ; 33(3 Suppl): 35-8, 2011.
Article in Italian | MEDLINE | ID: mdl-23393795

ABSTRACT

In the present study we used AOPPs and AGE as early markers of oxidative stress in refinery oil workers. In addition we evaluated whether a genetically determined reduction in the ability to detoxify electrophilic compounds, such as that expected among individuals with glutathione S-transferase (GST) null genotypes might influence the levels of AOPPs thus increasing toxicity. The study was performed on 25 oil refinery workers and in 18 age-matched control subjects. We found a statistically significant increase of AOPPs in exposed workers with respect to controls while AGE levels were not different. Finally serum level of AOPPs and AGE were not correlated with the different GTS genotypes.


Subject(s)
Benzene/adverse effects , Genetic Predisposition to Disease/genetics , Occupational Exposure , Oxidative Stress/genetics , Benzene/administration & dosage , Genetic Markers , Humans
20.
G Ital Med Lav Ergon ; 33(3 Suppl): 39-42, 2011.
Article in Italian | MEDLINE | ID: mdl-23393796

ABSTRACT

INTRODUCTION: Conflicting opinions exist about urinary benzene (UB) as a reliable biomarker of exposure. Objective of our study is to evaluate the effect of low-level environmental exposure on UB levels. METHODS: We monitored UB excretion in 74 non-smoking non- occupationally exposed subjects; a questionnaire interview gathered information on relevant exposures during the day of monitoring. RESULTS: UB excretion was related (p < 0.05) to gender, sampling time, residence, and reported vehicular traffic, but not to passive smoking and body mass index. CONCLUSION: Our findings support the use of unmetabolized UB as a specific and sensitive biomarker of low-level exposure to benzene.


Subject(s)
Benzene/analysis , Environmental Exposure , Environmental Monitoring , Benzene/administration & dosage , Female , Humans , Male , Urine/chemistry
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