Tumors due to chronic exposure to benzene and biomarkers of exposure

Abstract

Due to occupational activities, many people are exposed to carcinogenic airborne pollutants, such as benzene. Furthermore, benzene is also present in cigarette smoke. The main cancers associated with benzene, toluene, ethylbenzene, and xylenes (BTEX) are lung cancer and malignancies of the blood. At initial stages, lung cancer is often asymptomatic, but progression into metastasis is a huge clinical concern. We performed a review on possible biomarkers for monitoring increased genome instability and downregulation of the immune system in connection with overexposure to BTEX in a subgroup of workers being exposed to BTEX at Brazilian gas stations. The workers are subject to routine blood exams every semester; however, early genomic assessment is not routine. We evaluated available tests to be applied, including measuring benzene-derived metabolites in urine, determination of oxidative and inflammatory markers in blood, immunophenotypical profiling, micronucleus test, comet (single-cell gel electrophoresis) assay, (molecular) cytogenetics, chromosomal microarray, epigenetic-changes oriented tests, determination of mitochondrial (mt)DNA copy numbers, and studies on miRNA-level. However, no consensus was reached about their application and which test combination might be suited best.

Keywords

Benzene / BTEX / lung cancer / blood / biomarker

References

[1] International Agency for Research on Cancer (IARC). Monographs on the evaluation of carcinogenic risks to humans - benzene volume 120. 2018. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Monographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Benzene-2018 [Last accessed on 17 May 2022].

[2] International Agency for Research on Cancer (IARC). Agents classified by the IARC monographs, volumes 1–129. Available from: https://monographs.iarc.who.int/agents-classified-by-the-iarc/ [Last accessed on 17 May 2022].

[3] The National Institute for Occupational Safety and Health (NIOSH). Carcinogenic effects of exposure to diesel exhaust. 1988. Available from: https://www.cdc.gov/niosh/docs/88-116/default.html [Last accessed on 17 May 2022].

[4] International Agency for Research on Cancer (IARC). Diesel and gasoline engine exhausts and some nitroarenes. 2014. Available from: https://publications.iarc.fr/129 [Last accessed on 17 May 2022].

[5] Houot MT,Goulard H,Delabre L.Lifetime occupational exposure proportion estimation methods: a sensitivity analysis in the general population.Int Arch Occup Environ Health2021;94:1537-47

[6] International Agency for Research on Cancer (IARC). 2020. Available from: https://monographs.iarc.who.int/wp-content/uploads/2019/07/Classifications_by_cancer_site.pdf [Last accessed on 17 May 2022].

[7] Angelini S,Bermejo JL.Environmental exposure to benzene, micronucleus formation and polymorphisms in DNA-repair genes: a pilot study.Mutat Res2012;743:99-104

[8] Silva CB,Almeida YR.Environmental exposure to benzene: evaluation of urinary S-PMA and polymorphism (CYP2E1-1293G>C and NQO1 609C>T) in Campos Elíseos residents, Duque de Caxias, Rio de Janeiro State, Brazil.Cad Saude Publica2019;35:e00198618

[9] Smith MT,Gibbons CF.Key Characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis.Environ Health Perspect2016;124:713-21 PMCID:PMC4892922

[10] Loomis D,Grosse Y.Carcinogenicity of benzene.Lancet Oncol2017;18:1574-5

[11] Lan Q,Li G.Hematotoxicity in workers exposed to low levels of benzene.Science2004;306:1774-6 PMCID:PMC1256034

[12] Getu S,Melku M.Assessment of hematological parameters of petrol filling workers at petrol stations in Gondar town, Northwest Ethiopia: a comparative cross-sectional study.Environ Health Prev Med2020;25:44 PMCID:PMC7456503

[13] Abou-ElWafa HS,El-Gilany AH.Some biochemical and hematological parameters among petrol station attendants: a comparative study.Biomed Res Int2015;2015:418724 PMCID:PMC4655017

[14] Melo K,Lucena SBG et al.Aplastic anemia, clinical implications and DNA damage in workers with occupational exposure to aromatic hydrocarbons in Rio de Janeiro.Res Results Biomed2020;6:308-17

[15] Hanahan D.Hallmarks of cancer: the next generation.Cell2011;144:646-74

[16] Santiago F,Pinheiro T.Benzene poisoning, clinical and blood abnormalities in two Brazilian female gas station attendants: two case reports.BMC Res Notes2017;10:52 PMCID:PMC5241924

[17] Vivier E,Baratin M,Ugolini S.Functions of natural killer cells.Nat Immunol2008;9:503-10

[18] Brandão MM,Pugliese L.Phenotype analysis of lymphocytes of workers with chronic benzene poisoning.Immunol Lett2005;101:65-70

[19] Biró A,Major J.Lymphocyte phenotype analysis and chromosome aberration frequency of workers occupationally exposed to styrene, benzene, polycyclic aromatic hydrocarbons or mixed solvents.Immunol Lett2002;81:133-40

[20] Moro AM,Brucker N.Evaluation of immunological, inflammatory, and oxidative stress biomarkers in gasoline station attendants.BMC Pharmacol Toxicol2019;20:75 PMCID:PMC6921377

[21] Silvestre RT,Bravo M.Health survey and assessment of the polymorphisms BRCA1/P871L, BRCA1/Q356R, and BRCA2/N372H in female gas station workers in Rio de Janeiro.Environ Mol Mutagen2017;58:730-4

[22] Zhang L,Smith MT.The nature of chromosomal aberrations detected in humans exposed to benzene.Crit Rev Toxicol2002;32:1-42

[23] Chandirasekar R,Sasikala K.Assessment of genotoxic and molecular mechanisms of cancer risk in smoking and smokeless tobacco users.Mutat Res Genet Toxicol Environ Mutagen2014;767:21-7

[24] Lovreglio P,Carrieri M.Evaluation of chromosome aberration and micronucleus frequencies in blood lymphocytes of workers exposed to low concentrations of benzene.Mutat Res Genet Toxicol Environ Mutagen2014;770:55-60

[25] Mohandas N. Structure and composition of the erythrocyte. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Oliver WP, Burns LJ, Caligiuri, editors. Williams Hematology. 9th edition. New York: Mcgraw Hill, 2016; pp. 467-68.

[26] Celik A,Ergene-Gözükara S.Cytogenetic biomonitoring in petrol station attendants: micronucleus test in exfoliated buccal cells.Mutagenesis2003;18:417-21

[27] Singaraju M,Parwani R.Cytogenetic biomonitoring in petrol station attendants: A micronucleus study.J Cytol2012;29:1-5 PMCID:PMC3307442

[28] Shaikh A,Chandel D.Genotoxic Effects of exposure to gasoline fumes on petrol pump workers.Int J Occup Environ Med2018;9:79-87 PMCID:PMC6466986

[29] Filho APR,do Nascimento CB.Integrative study of cell damage and cancer risk in gas station attendants.Int J Environ Health Res2018;28:1-7

[30] Costa-Amaral IC,Santos MVC.Environmental assessment and evaluation of oxidative stress and genotoxicity biomarkers related to chronic occupational exposure to benzene.Int J Environ Res Public Health2019;16:2240 PMCID:PMC6617122

[31] Gaikwad AS,Beerappa R,Venugopal D.Mitochondrial DNA copy number and cytogenetic damage among fuel filling station attendants.Environ Mol Mutagen2020;61:820-9

[32] Mrdjanović J,Dimitrijević S,Nikolić I.Assessment of micronuclei and sister chromatid exchange frequency in the petroleum industry workers in province of Vojvodina, Republic of Serbia.Food Chem Toxicol2014;69:63-8

[33] Wang TS,Fang Y.Changes in miR-222 expression, DNA repair capacity, and MDM2-p53 axis in association with low-dose benzene genotoxicity and hematotoxicity.Sci Total Environ2021;765:142740

[34] Ostling O.Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells.Biochem Biophysci Res Commun1984;123:291-8

[35] Collins AR.The Comet Assay for DNA Damage and repair: principles, applications, and limitations.Mol Biotechnol.2004;26:249-61

[36] Rossner P,Ceppi M.Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer.Environ Health Perspect2005;113:517-20 PMCID:PMC1257540

[37] Smerhovsky Z,Rössner P.Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations.Environ Health Perspect2001;109:41-5 PMCID:PMC1242049

[38] Gonçalves RO,Rêgo MA.Association between occupational exposure to benzene and chromosomal alterations in lymphocytes of Brazilian petrochemical workers removed from exposure.Environ Monit Assess2016;188:334

[39] Villalba-Campos M,Sánchez-Corredor MC.High chromosomal instability in workers occupationally exposed to solvents and paint removers.Mol Cytogenet2016;9:46 PMCID:PMC4913430

[40] Verdorfer I,Letzel S.Chromosome painting for cytogenetic monitoring of occupationally exposed and non-exposed groups of human individuals.Mut Res/Gene Toxicol Environ Mutagene2001;491:97-109

[41] Zhang L,Guo W.Use of OctoChrome fluorescence in situ hybridization to detect specific aneuploidy among all 24 chromosomes in benzene-exposed workers.Chem Biol Interact2005;153-154:117-22

[42] Holeckova B,Sivikova K.FISH detection of chromosome 1 aberration in human interphase and metaphase lymphocytes after exposure to benzene.Ann Agric Environ Med2008;15:99-103

[43] Zhang L,Guo W.Chromosome-wide aneuploidy study (CWAS) in workers exposed to an established leukemogen, benzene.Carcinogenesis2011;32:605-12 PMCID:PMC3066415

[44] Ji Z.Chromosomics: detection of numerical and structural alterations in all 24 human chromosomes simultaneously using a novel OctoChrome FISH assay.J Vis Exp2012:3619 PMCID:PMC3369631

[45] Santiago F,Otero UB.Monitoring of gas station attendants exposure to benzene, toluene, xylene (BTX) using three-color chromosome painting.Mol Cytogenet2014;7:15 PMCID:PMC3974043

[46] Santiago F,Otero UB.The association of three DNA repair genes polymorphisms on the frequency of chromosomal alterations detected by fluorescence in situ hybridization.Int Arch Occup Environ Health2021;94:1567-77

[47] Liehr T. FISH-technology. lab manual. FISH on chromosome preparations of peripheral blood, Berlin: Springer, 2002. pp. 73–81.

[48] Liehr T. Part IV Multicolor-FISH-Probe sets (MFISH) and immunostaining - multiplex FISH and spectral karyotyping. In: Liehr T, editor, Fluorescence in situ Hybridization (FISH), 2th edition, Berlin: Springer, 2017, pp. 233-39.

[49] Vorsanova SG,Iourov IY.Human interphase chromosomes: a review of available molecular cytogenetic technologies.Mol Cytogenet2010;3:1 PMCID:PMC2830939

[50] Iourov IY,Yurov YB.In silico molecular cytogenetics: a bioinformatic approach to prioritization of candidate genes and copy number variations for basic and clinical genome research.Mol Cytogenet2014;7:98 PMCID:PMC4269961

[51] Wolff S.Differential Giemsa staining of sister chromatids and the study of chromatid exchanges without autoradiography.Chromosoma1974;48:341-53

[52] Goto K,Kano Y.Factors involved in differential Giemsa-staining of sister chromatids.Chromosoma1978;66:351-9

[53] Li K,Yang C.Increased leukemia-associated gene expression in benzene-exposed workers.Sci Rep2014;4:5369 PMCID:PMC4081871

[54] Fustinoni S,Campo L.Monitoring low benzene exposure: comparative evaluation of urinary biomarkers, influence of cigarette smoking, and genetic polymorphisms.Cancer Epidemiol Biomarkers Prev2005;14:2237-44

[55] Bruckner JV,Warren AD. Toxic effects of solvents and vapors, chapter 24. In: Casarett and Doul´s Toxicology, the basic science of poisons, 7th edition. New York: McGraw-Hill, 2008; pp. 1008-1009.

[56] Zhang L,Chen T,Song SZ.Trans, trans-muconic acid as a biomarker of occupational exposure to high-level benzene in China.J Occup Environ Med2011;53:1194-8

[57] Herman JG,Myöhänen S,Baylin SB.Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci USA1996;93:9821-6 PMCID:PMC38513

[58] Silvestre RT,Santiago F.Hypermethylation in gene promoters are induced by chronic exposure to benzene, toluene, ethylbenzene and xylenes.Pak J Biol Sci2020;23:518-25

[59] Bollati V,Hou L.Changes in DNA methylation patterns in subjects exposed to low-dose benzene.Cancer Res2007;67:876-80

[60] Peluso M,Munnia A.DNA methylation differences in exposed workers and nearby residents of the Ma Ta Phut industrial estate, Rayong, Thailand.Int J Epidemiol2012;41:1753-60; discussion 1761 PMCID:PMC3535756

[61] Byun HM,Panni T.Evolutionary age of repetitive element subfamilies and sensitivity of DNA methylation to airborne pollutants.Part Fibre Toxicol2013;10:28 PMCID:PMC3717285

[62] Filograna R,Alsina D.Mitochondrial DNA copy number in human disease: the more the better?.FEBS Lett2021;595:976-1002 PMCID:PMC8247411

[63] Shen M,Bonner MR.Association between mitochondrial DNA copy number, blood cell counts, and occupational benzene exposure.Environ Mol Mutagen2008;49:453-7 PMCID:PMC2957084

[64] Carugno M,Dioni L.Increased mitochondrial DNA copy number in occupations associated with low-dose benzene exposure.Environ Health Perspect2012;120:210-5 PMCID:PMC3279451

[65] Khan S,Panda AC.Cancer-Associated circRNA-miRNA-mRNA Regulatory Networks: A Meta-Analysis.Front Mol Biosci2021;8:671309 PMCID:PMC8149909

[66] Hu D,Liu Y.Overexpression of miR-221 in peripheral blood lymphocytes in petrol station attendants: A population based cross-sectional study in southern China.Chemosphere2016;149:8-13

[67] Rosell R.Implications of blood-based T790M genotyping and beyond in epidermal growth factor Receptor-Mutant Non-Small-Cell Lung Cancer.J Clin Oncol2016;34:3361-2

[68] Taunk K,Pereira JAM.Urinary volatomic expression pattern: paving the way for identification of potential candidate biosignatures for lung cancer.Metabolites2022;12:36 PMCID:PMC8780352