Abstract
Several recent reports indicate health hazards for workers with below occupational limit exposure to benzene (BZ). Our updated review indicates that such low exposures induced traditional as well as novel toxicity/genotoxicity, e.g., increased mitochondria copy numbers, prolongation of telomeres, impairment of DNA damage repair response (DDRR), perturbations of expression in non-coding RNAs, and epigenetic changes. These abnormalities were associated with alterations of gene expression and cellular signaling pathways which affected hematopoietic cell development, expression of apoptosis, autophagy, etc. The overarching mechanisms for induction of health risk are impaired DDRR, inhibition of tumor suppressor genes, and changes of MDM2–p53 axis activities that contribute to perturbed control for cancer pathways. Evaluation of the unusual dose–responses to BZ exposure indicates cellular over-compensation and reprogramming to overcome toxicity and to promote survival. However, these abnormal mechanisms also promote the induction of leukemia. Further investigations indicate that the current exposure limits for workers to BZ are unacceptable. Based on these studies, the new exposure limits should be less than 0.07 ppm rather than the current 1 ppm. This review also emphasizes the need to conduct appropriate bioassays, and to provide more reliable decisions on health hazards as well as on exposure limits for workers. In addition, it is important to use scientific data to provide significantly improved risk assessment, i.e., shifting from a population- to an individual-based risk assessment.
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Source of Figure: Kaina et al. 2018 (a publication from the corresponding author, WW Au)
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References
Au WW, Salama SA (2006) Cytogenetic challenge assays for assessment of DNA repair capacities. Methods Mol Biol 314:25–42. https://doi.org/10.1385/1-59259-973-7:025
Au WW, Wilkinson GS, Tyring SK et al (1996) Monitoring populations for DNA repair deficiency and for cancer susceptibility. Environ Health Perspect 104 Suppl 3(Suppl 3):579–584. https://doi.org/10.1289/ehp.96104s3579
Au WW, Salama SA, Sierra-Torres CH (2003) Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays. Environ Health Perspect 111(15):1843–1850. https://doi.org/10.1289/ehp.6632
Au WW, Giri AK, Ruchirawat M (2010) Challenge assay: a functional biomarker for exposure-induced DNA repair deficiency and for risk of cancer. Int J Hyg Environ Health 213(1):32–39. https://doi.org/10.1016/j.ijheh.2009.09.002
Cao YY, Wang TS, Xi J et al (2023) Benchmark dose estimation for benzene-exposed workers in China: Based on quantitative and multi-endpoint genotoxicity assessments. Environ Poll 330:121765. https://doi.org/10.1016/j.envpol.2023.121765
Cox LA Jr, Ketelslegers HB, Lewis RJ (2021) The shape of low-concentration dose-response functions for benzene: implications for human health risk assessment. Crit Rev Toxicol 51(2):95–116. https://doi.org/10.1080/10408444.2020.1860903
De Maria L, Ledda C, Caputi A et al (2020) Biological monitoring of exposure to benzene in port workers. Front Public Health 8:271. https://doi.org/10.3389/fpubh.2020.00271
Fang Y, Wu HT, Ye YJ et al (2017) Association between polymorphisms of metabolic enzyme genes and chromosomal damage in benzene-exposed workers in China. J Occup Environ Med 59(11):e215–e220. https://doi.org/10.1097/JOM.0000000000001148
Fenga C, Gangemi S, Costa C (2016) Benzene exposure is associated with epigenetic changes (Review). Mol Med Rep 13(4):3401–3405. https://doi.org/10.3892/mmr.2016.4955
Grigoryan H, Edmands WMB, Lan Q et al (2018) Adductomic signatures of benzene exposure provide insights into cancer induction. Carcinogenesis 39(5):661–668. https://doi.org/10.1093/carcin/bgy042
Gross SA, Paustenbach DJ (2018) Shanghai Health Study (2001–2009): what was learned about benzene health effects? Crit Rev Toxicol 48(3):217–251. https://doi.org/10.1080/10408444.2017.1401581
Guo XL, Zhang L, Wang JY et al (2022) Plasma metabolomics study reveals the critical metabolic signatures for benzene-induced hematotoxicity. Jci Insight. https://doi.org/10.1172/jci.insight.154999
Hallberg LM, Bechtold WE, Grady J et al (1997) Abnormal DNA repair activities in lymphocytes of workers exposed to 1,3-butadiene. Mutat Res 383(3):213–221. https://doi.org/10.1016/s0921-8777(97)00004-9
Harms C, Salama SA, Sierra-Torres CH et al (2004) Polymorphisms in DNA repair genes, chromosome aberrations, and lung cancer. Environ Mol Mutagen 44(1):74–82. https://doi.org/10.1002/em.20031
Jamebozorgi I, Majidizadeh T, Pouryagoub G et al (2018) Aberrant DNA methylation of two tumor suppressor genes, p14(ARF) and p15(INK4b), after chronic occupational exposure to low level of benzene. Int J Occup Environ Med 9(3):145–151. https://doi.org/10.15171/ijoem.2018.1317
Ji B, Xiao LY, Ren JC et al (2021) Gene-environment interactions between environmental response genes polymorphisms and mitochondrial DNA copy numbers among benzene workers. J Occup Environ Med 63(7):e408–e415. https://doi.org/10.1097/JOM.0000000000002225
Jorgensen KM, Faergestad ME, Hovde LK et al (2018) Global gene expression response in peripheral blood cells of petroleum workers exposed to sub-ppm benzene levels. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph15112385
Kaina B, Izzotti A, Xu J et al (2018) Inherent and toxicant-provoked reduction in DNA repair capacity: a key mechanism for personalized risk assessment, cancer prevention and intervention, and response to therapy. Int J Hyg Environ Health 221(7):993–1006. https://doi.org/10.1016/j.ijheh.2018.07.003
Kim DY, Kim HS, Lim DS et al (2022) Benzene exposure assessment of printing workers treating petroleum-based cleaner in South Korea. Ind Health. https://doi.org/10.2486/indhealth.2022-0103
Li W, Schnatter AR (2018) Benzene risk assessment: does new evidence on myelodysplastic syndrome justify a new approach? Crit Rev Toxicol 48(6):417–432. https://doi.org/10.1080/10408444.2018.1437389
Li A, Sun Y, Wang T et al (2020) Effects of micronucleus frequencies and mitochondrial DNA copy numbers among benzene-exposed workers in China. Environ Mol Mutagen 61(3):355–360. https://doi.org/10.1002/em.22354
Linet MS, Gilbert ES, Vermeulen R et al (2020) Benzene exposure-response and risk of lymphoid neoplasms in Chinese workers: a multicenter case-cohort study. Am J Ind Med 63(9):741–754. https://doi.org/10.1002/ajim.23142
Loomis D, Guyton KZ, Grosse Y et al (2017) Carcinogenicity of benzene. Lancet Oncol 18(12):1574–1575. https://doi.org/10.1016/S1470-2045(17)30832-X
Loomis D, Guha N, Hall AL et al (2018) Identifying occupational carcinogens: an update from the IARC Monographs. Occup Environ Med 75(8):593–603. https://doi.org/10.1136/oemed-2017-104944
Lu PCW, Shahbaz S, Winn LM (2020) Benzene and its effects on cell signaling pathways related to hematopoiesis and leukemia. J Appl Toxicol 40(8):1018–1032. https://doi.org/10.1002/jat.3961
McHale CM, Zhang L, Lan Q et al (2011) Global gene expression profiling of a population exposed to a range of benzene levels. Environ Health Perspect 119(5):628–634. https://doi.org/10.1289/ehp.1002546
McHale CM, Zhang L, Smith MT (2012) Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment. Carcinogenesis 33(2):240–252. https://doi.org/10.1093/carcin/bgr297
Menz J, Gotz ME, Gundel U et al (2023) Genotoxicity assessment: opportunities, challenges and perspectives for quantitative evaluations of dose-response data. Rev Arch Toxicol 97(9):2303–2328. https://doi.org/10.1007/s00204-023-03553-w
Mozzoni P, Poli D, Pinelli S et al (2023) Benzene exposure and MicroRNAs expression: in vitro, in vivo and human findings. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph20031920
Qian S, Han Y, Shi Y et al (2019) Benzene induces haematotoxicity by promoting deacetylation and autophagy. J Cell Mol Med 23(2):1022–1033. https://doi.org/10.1111/jcmm.14003
Ramírez-Lopera V, Uribe-Castro D, Bautista-Amorocho H et al (2021) The effects of genetic polymorphisms on benzene-exposed workers: a systematic review. Health Sci Rep 4(3):e327. https://doi.org/10.1002/hsr2.327
Rana I, Dahlberg S, Steinmaus C et al (2021) Benzene exposure and non-Hodgkin lymphoma: a systematic review and meta-analysis of human studies. Lancet Planet Health 5(9):e633–e643. https://doi.org/10.1016/S2542-5196(21)00149-2
Ren JC, Liu H, Zhang GH et al (2020) Interaction effects of environmental response gene polymorphisms and benzene exposure on telomere length in shoe-making workers. Chemosphere 255:126841. https://doi.org/10.1016/j.chemosphere.2020.126841
Salemi R, Marconi A, Di Salvatore V et al (2017) Epigenetic alterations and occupational exposure to benzene, fibers, and heavy metals associated with tumor development (Review). Mol Med Rep 15(5):3366–3371. https://doi.org/10.3892/mmr.2017.6383
Schuz J, Espina C, Wild CP (2019) Primary prevention: a need for concerted action. Mol Oncol 13(3):567–578. https://doi.org/10.1002/1878-0261.12432
Shi B, Su S, Wen C et al (2022) The prediction of occupational health risks of benzene in the printing industry through multiple occupational health risk assessment models. Front Public Health 10:1038608. https://doi.org/10.3389/fpubh.2022.1038608
Smith MT, Guyton KZ, Kleinstreuer N et al (2020) The key characteristics of carcinogens: relationship to the hallmarks of cancer, relevant biomarkers, and assays to measure them. Cancer Epidem Biomar 29(10):1887–1903. https://doi.org/10.1158/1055-9965.Epi-19-1346
Sun R, Xu K, Zhang Q et al (2018) Plasma metabonomics investigation reveals involvement of fatty acid oxidation in hematotoxicity in Chinese benzene-exposed workers with low white blood cell count. Environ Sci Pollut Res Int 25(32):32506–32514. https://doi.org/10.1007/s11356-018-3160-2
Sun R, Xu K, Ji S et al (2020) Benzene exposure induces gut microbiota dysbiosis and metabolic disorder in mice. Sci Total Environ 705:135879. https://doi.org/10.1016/j.scitotenv.2019.135879
Teras LR, Diver WR, Deubler EL et al (2019) Residential ambient benzene exposure in the United States and subsequent risk of hematologic malignancies. Int J Cancer 145(10):2647–2660. https://doi.org/10.1002/ijc.32202
Tian W, Wang TS, Fang Y et al (2020) Aberrant lncRNA profiles are associated with chronic benzene poisoning and acute myelocytic leukemia. J Occup Environ Med 62(7):e308–e317. https://doi.org/10.1097/JOM.0000000000001875
Tongsantia U, Chaiklieng S, Suggaravetsiri P et al (2021) Factors affecting adverse health effects of gasoline station workers. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph181910014
Valdiglesias V, Sanchez-Flores M, Fernandez-Bertolez N et al (2020) Expanded usage of the Challenge-Comet assay as a DNA repair biomarker in human populations: protocols for fresh and cryopreserved blood samples, and for different challenge agents. Arch Toxicol 94(12):4219–4228. https://doi.org/10.1007/s00204-020-02881-5
Vermeulen R, Lan Q, Qu QS et al (2023) Nonlinear low dose hematotoxicity of benzene; a pooled analyses of two studies among Chinese exposed workers. Environ Int 177:108007. https://doi.org/10.1016/j.envint.2023.108007
Wang Q, Ye R, Ye YJ et al (2012) mRNA expression levels among cell regulatory and DNA damage genes in benzene-exposed workers in China. J Occup Environ Med 54(12):1467–1470. https://doi.org/10.1097/JOM.0b013e318223d56c
Wang BS, Han L, Wang K et al (2021a) Gender differences in hematotoxicity of benzene-exposed workers, three cross-sectional studies on 218,061 subjects. Environ Sci Pollut R 28(40):57297–57307. https://doi.org/10.1007/s11356-021-14657-0
Wang TS, Tian W, Fang Y et al (2021b) Changes in miR-222 expression, DNA repair capacity, and MDM2–p53 axis in association with low-dose benzene genotoxicity and hematotoxicity. Sci Total Environ 765:142740. https://doi.org/10.1016/j.scitotenv.2020.142740
Wang TS, Ruchirawat M, Narasumrit P et al (2022) Lymphocyte-based challenge DNA-repair assays for personalized health risk assessment. Mutat Res Rev Mutat Res 790:108427. https://doi.org/10.1016/j.mrrev.2022.108427
Xu J, Sram RJ, Cebulska-Wasilewska A et al (2020) Challenge-comet assay, a functional and genomic biomarker for precision risk assessment and disease prevention among exposed workers. Toxicol Appl Pharmacol 397:115011. https://doi.org/10.1016/j.taap.2020.115011
Yi M, Li A, Zhou L et al (2020) The global burden and attributable risk factor analysis of acute myeloid leukemia in 195 countries and territories from 1990 to 2017: estimates based on the global burden of disease study 2017. J Hematol Oncol 13(1):72. https://doi.org/10.1186/s13045-020-00908-z
Yoon JH, Kwak WS, Ahn YS (2018) A brief review of relationship between occupational benzene exposure and hematopoietic cancer. Ann Occup Environ Med 30:33. https://doi.org/10.1186/s40557-018-0245-9
Yuan Q, Zhang H, Pan Z et al (2020) Regulatory loop between lncRNA FAS-AS1 and DNMT3b controls FAS expression in hydroquinone-treated TK6 cells and benzene-exposed workers. Environ Pollut 261:114147. https://doi.org/10.1016/j.envpol.2020.114147
Zhang GH, Ye LL, Wang JW et al (2014) Effect of polymorphic metabolizing genes on micronucleus frequencies among benzene-exposed shoe workers in China. Int J Hyg Environ Health 217(7):726–732. https://doi.org/10.1016/j.ijheh.2014.03.003
Zhang GH, Ji BQ, Li Y et al (2016) Benchmark doses based on abnormality of WBC or micronucleus frequency in benzene-exposed Chinese workers. J Occup Environ Med 58(2):E39–E44. https://doi.org/10.1097/Jom.0000000000000639
Zhang GH, Ren JC, Luo M et al (2019) Association of BER and NER pathway polymorphism haplotypes and micronucleus frequencies with global DNA methylation in benzene-exposed workers of China: effects of DNA repair genes polymorphisms on genetic damage. Mutat Res Genet Toxicol Environ Mutagen 839:13–20. https://doi.org/10.1016/j.mrgentox.2019.01.006
Zhang L, Sun P, Sun D et al (2022) Occupational health risk assessment of the benzene exposure industries: a comprehensive scoring method through 4 health risk assessment models. Environ Sci Pollut Res Int 29(56):84300–84311. https://doi.org/10.1007/s11356-022-21275-x
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The Foundation of Shanghai Municipal Heath Commission (Grant number: 202040009) for Dr. Yiyi Cao.
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Wang, T., Cao, Y., Xia, Z. et al. Review on novel toxicological effects and personalized health hazard in workers exposed to low doses of benzene. Arch Toxicol 98, 365–374 (2024). https://doi.org/10.1007/s00204-023-03650-w
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DOI: https://doi.org/10.1007/s00204-023-03650-w