Abstract
Evaluation of the possible toxic effects of occupational exposure to anesthetics is of great importance, and the literature is limited in assessing the possible association between occupational exposure to anesthetics and oxidative stress and genetic damage. To contribute to the gap of knowledge in relation to cause-effect, this cohort study was the first to monitor exposure assessment and to evaluate oxidative stress, DNA damage, and gene expression (OGG1, NRF2, HO-1, and TP53) in young adult physicians occupationally exposed to the most modern halogenated anesthetics (currently the commonly used inhalational anesthetics worldwide) in addition to nitrous oxide gas during the medical residency period. Therefore, the physicians were evaluated before the beginning of the medical residency (before the exposure to anesthetics-baseline), during (1 1/2 year) and at the end (2 1/2 years) of the medical residency. Anesthetic air monitoring was performed in operating rooms without adequate ventilation/scavenging systems, and biological samples were analyzed for lipid peroxidation, protein carbonyl content, primary and oxidative DNA damage, antioxidant enzymes and plasma antioxidant capacity, and expression of some key genes. The results showed induction of lipid peroxidation, DNA damage, glutathione peroxidase activity, and NRF2 and OGG1 expression up to the end of medical residency. Plasma antioxidant capacity progressively increased throughout medical residency; oxidative DNA damage levels started to increase during medical residency and were higher at the end of residency than at baseline. Protein carbonyls increased during but not at the end of medical residency compared to baseline. The antioxidant enzyme superoxide dismutase activity remained lower than baseline during and at the end of medical residency, and HO-1 (related to antioxidant defense) expression was downregulated at the end of medical residency. Additionally, anesthetic concentrations were above international recommendations. In conclusion, high concentrations of anesthetic in the workplace induce oxidative stress, gene expression modulation, and genotoxicity in physicians during their specialization period.
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The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
References
Abu-Zidan FM, Plank LD, Windsor JA (2002) Proteolysis in severe sepsis is related to oxidation of plasma protein. Eur J Surg 168:119–123. https://doi.org/10.1080/11024150252884359
Aldini G, Yeum KJ, Russell RM, Krinsky NI (2001) A method to measure the oxidizability of both the aqueous and lipid compartments of plasma. Free Radic Biol Med 31:1043–1050. https://doi.org/10.1016/s0891-5849(01)00684-0
American Institute of Architects (AIA), Guidelines for construction and equipment of hospitals and medical facilities. https://www.aaalac.org/pub/?id=E9011381-DBE1-AFEC-79E3-98304990FA2A, 1992 (accessed 01 December 2022).
Amma RO, Ravindran S, Koshy RC, Jagathnath Krishna KM (2016) A survey on the use of low flow anaesthesia and the choice of inhalational anaesthetic agents among anaesthesiologists of India. Indian J Anaesth 60:751–756. https://doi.org/10.4103/0019-5049.191692
Andresen M, Regueira T, Bruhn A, Perez D, Strobel P, Dougnac A, Marshall G, Leighton F (2008) Lipoperoxidation and protein oxidative damage exhibit different kinetics during septic shock. Mediators Inflamm 2008:168652. https://doi.org/10.1155/2008/168652
Arruda NM, Braz LG, Nogueira FR et al (2019) Inflammation and DNA damage induction in surgical patients maintained with desflurane anesthesia. Mutat Res 846:403073. https://doi.org/10.1016/j.mrgentox.2019.07.003
Aun AG, Golim MA, Nogueira FR, Souza KM, Arruda NM, Braz JRC, Braz LG, Braz MG (2018) Monitoring early cell damage in physicians who are occupationally exposed to inhalational anesthetics. Mutat Res 812:5–9. https://doi.org/10.1016/j.mrfmmm.2018.10.002
Aun AG, Souza KM, Guedes JL, Figueiredo DBS, Lara JR, Silva MAP, Braz LG, Braz MG (2021) Hepatotoxic and neuroendocrine effects in physicians occupationally exposed to most modern halogenated anesthetics and nitrous oxide. Environ Toxicol Pharmacol 81:103515. https://doi.org/10.1016/j.etap.2020.103515
Baysal Z, Cengiz M, Ozgonul A, Cakir M, Celik H, Kocyigit A (2009) Oxidative status and DNA damage in operating room personnel. Clin Biochem 42:189–193. https://doi.org/10.1016/j.clinbiochem.2008.09.103
Braz LG, Braz JRC, Cavalcante GAS, Souza KM, Lucio LMC, Braz MG (2017) Comparison of waste anesthetic gases in operating rooms with or without an scavenging system in a Brazilian university hospital. Rev Bras Anestesiol 67:516–520. https://doi.org/10.1016/j.bjan.2017.02.001
Braz MG, Braz LG, Braz JR, Pierine DT, Correa CR, Ferreira AL, Carvalho LR, Yeum KJ, Salvadori DM (2013) Comparison of oxidative stress in ASA physical status I patients scheduled for minimally invasive surgery under balanced or intravenous anesthesia. Minerva Anestesiol 79:1030–1038
Braz MG, Carvalho LIM, Chen CO et al (2020) High concentrations of waste anesthetic gases induce genetic damage and inflammation in physicians exposed for three years: a cross-sectional study. Indoor Air 30:512–520. https://doi.org/10.1111/ina.12643
Braz MG, Fávero Salvadori DM (2007) Influence of endogenous and synthetic female sex hormones on human blood cells in vitro studied with comet assay. Toxicol In Vitro 21:972–976. https://doi.org/10.1016/j.tiv.2007.02.006
Braz MG, Mazoti MA, Giacobino J, Braz LG, Golim MA, Ferrasi AC, de Carvalho LR, Braz JR, Salvadori DM (2011) Genotoxicity, cytotoxicity and gene expression in patients undergoing elective surgery under isoflurane anaesthesia. Mutagenesis 26:415–420. https://doi.org/10.1093/mutage/geq109
Braz MG, Souza KM, Lucio LMC, Di Renzo GCC, Feliciano LM, Marcondes JPC, Chen CO, Braz JRC, Braz LG (2018) Detrimental effects detected in exfoliated buccal cells from anesthesiology medical residents occupationally exposed to inhalation anesthetics: an observational study. Mutat Res Genet Toxicol Environ Mutagen 832-833:61–64. https://doi.org/10.1016/j.mrgentox.2018.07.001
Chaoul MM, Braz JR, Lucio LM, Golim MA, Braz LG, Braz MG (2015) Does occupational exposure to anesthetic gases lead to increase of pro-inflammatory cytokines? Inflamm Res 64:939–942. https://doi.org/10.1007/s00011-015-0881-2
Chinelato AR, Froes NDTC (2002) Genotoxic effects on professionals exposed to inhalational anesthetics. Rev Bras Anestesiol 52:79–85. https://doi.org/10.1590/S0034-70942002000100010
Collins AR, Dusinská M, Gedik CM, Stĕtina R (1996) Oxidative damage to DNA: do we have a reliable biomarker? Environ Health Perspect 104(Suppl 3):465–469. https://doi.org/10.1289/ehp.96104s3465
Costa Paes ER, Braz MG, Lima JT, Silva MRG, Sousa LB, Lima ES, Vasconcellos MC, Braz JRC (2014) DNA damage and antioxidant status in medical residents occupationally exposed to waste anesthetic gases. Acta Cir Bras 29:280–286. https://doi.org/10.1590/S0102-86502014000400010
Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 329:23–38. https://doi.org/10.1016/S0009-8981(03)00003-2
Dinkova-Kostova AT, Abramov AY (2015) The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 88:179–188. https://doi.org/10.1016/j.freeradbiomed.2015.04.036
Dusinska M, Collins AR (2010) DNA oxidation, antioxidant effects, and DNA repair measured with the comet assay. In: Aldini G, Yeum KJ, Niki E, Russell RM (eds) Biomarkers for antioxidant defense and oxidative damage: principles and pratical applications. Wiley-Blackwell, Iowa, pp 261–282
Eisenach JH, Sprung J, Clark MM, Shanafelt TD, Johnson BD, Kruse TN, Chantigian DP, Carter JR, Long TR (2014) The psychological and physiological effects of acute occupational stress in new anesthesiology residents: a pilot trial. Anesthesiology 121:878–893. https://doi.org/10.1097/aln.0000000000000397
Espinosa-Diez C, Miguel V, Mennerich D, Kietzmann T, Sánchez-Pérez P, Cadenas S, Lamas S (2015) Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol 6:183–197. https://doi.org/10.1016/j.redox.2015.07.008
Ferreira ALA, Machado PEA, Matsubara LS (1999) Lipid peroxidation, antioxidant enzymes and glutathione levels in human erythrocytes exposed to colloidal iron hydroxide in vitro. Braz J Med Biol Res 32:689–694. https://doi.org/10.1590/S0100-879X1999000600004
Figueiredo DBS, Aun AG, Souza KM, Nishimoto IH, Silva MAP, de Carvalho LR, Braz LG, Braz MG (2022) High anesthetic (isoflurane) indoor pollution is associated with genetic instability, cytotoxicity, and proliferative alterations in professionals working in a veterinary hospital. Environ Sci Pollut Res Int 29:71774–71784. https://doi.org/10.1007/s11356-022-20444-2
Freire CMM, Braz MG, Marcondes JPC, Arruda NM, Braz JRC, Rainho CA, Braz LG, DMF (2018) Expression and promoter methylation status of two DNA repair genes in leukocytes from patients undergoing propofol or isoflurane anaesthesia. Mutagenesis 33:147-152. https://doi.org/10.1093/mutage/gey001
Fruhwirth GO, Loidl A, Hermetter A (2007) Oxidized phospholipids: from molecular properties to disease. Biochim Biophys Acta 1772:718–736. https://doi.org/10.1016/j.bbadis.2007.04.009
Halliwell B (2012) Free radicals and antioxidants: updating a personal view. Nutr Rev 70:257–265. https://doi.org/10.1111/j.1753-4887.2012.00476.x
Herzog-Niescery J, Vogelsang H, Gude P, Seipp HM, Uhl W, Weber TP, Bellgardt M (2019) Environmental safety: air pollution while using MIRUS™ for short-term sedation in the ICU. Acta Anaesthesiol Scand 63:86–92. https://doi.org/10.1111/aas.13222
Hua HX, Deng HB, Huang XL, Ma CQ, Xu P, Cai YH, Wang HT (2021) Effects of occupational exposure to waste anesthetic gas on oxidative stress and DNA damage. Oxid Med Cell Longev 2021:8831535. https://doi.org/10.1155/2021/8831535
Huang Y, Li W, Su ZY, Kong AN (2015) The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem 26:1401–1413. https://doi.org/10.1016/j.jnutbio.2015.08.001
Izdes S, Sardas S, Kadioglu E, Karakaya AE (2010) DNA damage, glutathione, and total antioxidant capacity in anesthesia nurses. Arch Environ Occup Health 65:211–217. https://doi.org/10.1080/19338244.2010.486421
Jaloszyński P, Kujawski M, Wasowicz M, Szulc R, Szyfter K (1999) Genotoxicity of inhalation anesthetics halothane and isoflurane in human lymphocytes studied in vitro using the comet assay. Mutat Res 439:199–206. https://doi.org/10.1016/s1383-5718(98)00195-8
Janssen K, Schlink K, Götte W, Hippler B, Kaina B, Oesch F (2001) DNA repair activity of 8-oxoguanine DNA glycosylase 1 (OGG1) in human lymphocytes is not dependent on genetic polymorphism Ser326/Cys326. Mutat Res 486:207–216. https://doi.org/10.1016/s0921-8777(01)00096-9
Kassam A, Horton J, Shoimer I, Patten S (2015) Predictors of well-being in resident physicians: a descriptive and psychometric study. J Grad Med Educ 7:70–74. https://doi.org/10.4300/jgme-d-14-00022.1
Lee Y, Song BC, Yeum K (2015) Impact of volatile anesthetics on oxidative stress and inflammation. Biomed Res Int 2015:242709. https://doi.org/10.1155/2015/242709
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Lucio LMC, Braz MG, do Nascimento P Junior, Braz JRC, Braz LG (2018) Occupational hazards, DNA damage, and oxidative stress on exposure to waste anesthetic gases. Rev Bras Anestesiol 68:33–41. https://doi.org/10.1016/j.bjan.2017.05.001
Magnavita N, Di Prinzio RR, Soave PM (2020) Systemic sclerosis in an anaesthetist. Occup Med (Lond) 70:442–444. https://doi.org/10.1093/occmed/kqaa068
Malekirad AA, Ranjbar A, Rahzani K, Kadkhodaee M, Rezaie A, Taghavi B, Abdollahi M (2005) Oxidative stress in operating room personnel: occupational exposure to anesthetic gases. Hum Exp Toxicol 24:597–601. https://doi.org/10.1191/0960327105ht565oa
Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21:361–370. https://doi.org/10.1093/carcin/21.3.361
McCord JM (2000) The evolution of free radicals and oxidative stress. Am J Med 108:652–659. https://doi.org/10.1016/s0002-9343(00)00412-5
Miyamoto S, Arai H, Terao J (2010) Enzymatic antioxidant defenses. In: Aldini G, Yeum KJ, Niki E, Russell RM (eds) Biomarkers for antioxidant defense and oxidative damage: principles and pratical applications. Wiley-Blackwell, Iowa, pp 21–33
Møller P, Azqueta A, Boutet-Robinet E et al (2020a) Minimum Information for Reporting on the Comet Assay (MIRCA): recommendations for describing comet assay procedures and results. Nat Protoc 15:3817–3826. https://doi.org/10.1038/s41596-020-0398-1
Møller P, Stopper H, Collins AR (2020b) Measurement of DNA damage with the comet assay in high-prevalence diseases: current status and future directions. Mutagenesis 35:5–18. https://doi.org/10.1093/mutage/gez018
Nakamura S, Gomyo Y, Roth JA, Mukhopadhyay T (2002) C-terminus of p53 is required for G(2) arrest. Oncogene 21:2102–2107. https://doi.org/10.1038/sj.onc.1205251
National Institute for Occupational Safety and Health (NIOSH), Recommendations for occupational safety and health. Compendium of policy documents and statements. Cincinnati: Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, 1992 (Publication; n. 92-100).
Neghab M, Kargar-Shouroki F, Mozdarani H, Yousefinejad S, Alipour H, Fardid R (2020) Association between genotoxic properties of inhalation anesthetics and oxidative stress biomarkers. Toxicol Ind Health 36:454–466. https://doi.org/10.1177/0748233720935696
Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P (1997) Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of lifestyle factors. Clin Chem 43:1209–1214
Nogueira FR, Braz LG, Souza KM, Aun AG, Arruda NM, Carvalho LR, Chen CO, Braz JRC, Braz MG (2018) Comparison of DNA damage and oxidative stress in patients anesthetized with desflurane associated or not with nitrous oxide. Anesth Analg 126:1198–1205. https://doi.org/10.1213/ane.0000000000002729
Occupational Safety and Health Administration (OSHA), Anesthetic gases: guidelines for workplace exposures. https://www.osha.gov/dts/osta/anestheticgases/, 2000 (Accessed 11 January 2023).
Oliveira LA, El Dib RP, Figueiredo DBS, Braz LG, Braz MG (2021) Spontaneous abortion in women occupationally exposed to inhalational anesthetics: a critical systematic review. Environ Sci Pollut Res Int 28:10436–10449. https://doi.org/10.1007/s11356-020-11684-1
Peruzzi C, Nascimento S, Gauer B et al (2019) Inflammatory and oxidative stress biomarkers at protein and molecular levels in workers occupationally exposed to crystalline silica. Environ Sci Pollut Res Int 26:1394–1405. https://doi.org/10.1007/s11356-018-3693-4
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616. https://doi.org/10.1016/j.freeradbiomed.2010.09.006
Sherif IO (2018) The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: role of Nrf2/HO-1 pathway. Int Immunopharmacol 61:29–36. https://doi.org/10.1016/j.intimp.2018.05.007
Silva MAP, Figueiredo DBS, Lara JR, Paschoalinotte EE, Braz LG, Braz MG (2023) Evaluation of genetic instability, oxidative stress, and metabolism-related gene polymorphisms in workers exposed to waste anesthetic gases. Environ Sci Pollut Res Int 30:9609–9623
Souza KM, Braz LG, Nogueira FR, Souza MB, Bincoleto LF, Aun AG, Corrente JE, Carvalho LR, Braz JRC, Braz MG (2016) Occupational exposure to anesthetics leads to genomic instability, cytotoxicity and proliferative changes. Mutat Res 791-792:42–48. https://doi.org/10.1016/j.mrfmmm.2016.09.002
Souza KM, De Vivo I, Chen CO et al (2021) Oxidative stress, DNA damage, inflammation and gene expression in occupationally exposed university hospital anaesthesia providers. Environ Mol Mutagen 62:155–164. https://doi.org/10.1002/em.22420
Türkan H, Aydin A, Sayal A (2005) Effect of volatile anesthetics on oxidative stress due to occupational exposure. World J Surg 29:540–542. https://doi.org/10.1007/s00268-004-7658-z
Volinsky R, Kinnunen PK (2013) Oxidized phosphatidylcholines in membrane-level cellular signaling: from biophysics to physiology and molecular pathology. FEBS J 280:2806–2816. https://doi.org/10.1111/febs.12247
Wrońska-Nofer T, Nofer JR, Jajte J, Dziubaltowska E, Szymczak W, Krajewski W, Wąsowicz W, Rydzyński R (2012) Oxidative DNA damage and oxidative stress in subjects occupationally exposed to nitrous oxide (N2O). Mutat Res 731:58–63. https://doi.org/10.1016/j.mrfmmm.2011.10.010
Acknowledgements
The authors would like to thank all the participants of the study besides Prof. Camila Correa, Aline Bueno, and Vickeline Androcioli for their assistance with the study.
Funding
This study was supported by the National Council for Scientific and Technological Development (CNPq) (grant number 446252/2014-0) and São Paulo Research Foundation (FAPESP) (grant numbers 2016/15559-1 and 2018/20143-4). A.G.A. received a scholarship from the Coordination for the Improvement of Higher Education Personnel (CAPES), Y.S.A.L. received a scholarship from CNPq (160136/2017-2), and J.L.G. received a scholarship from FAPESP (2017/21504-8). MGB was a recipient of a fellowship from the CNPq (304107/2018-2).
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Aline G. Aun: conceptualization, methodology, investigation, visualization, and writing—original draft. Débora C. Damasceno: investigation and writing—reviewing and editing. Yuri K. Sinzato: investigation. Flávia R. Nogueira: investigation and validation. Kátina M. Souza: investigation and validation. Youssef S.A. Lawi: validation. Júlia L. Guedes: validation and visualization. Mariane A.P. Silva: validation. Lídia R. de Carvalho: formal analysis. Leandro G. Braz: conceptualization, methodology, supervision, project administration, funding acquisition, and writing—reviewing and editing. Mariana G. Braz: conceptualization, methodology, visualization, supervision, project administration, funding acquisition, writing—original draft, and writing—reviewing and editing
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Aun, A.G., Damasceno, D.C., Sinzato, Y.K. et al. High anesthetic exposure leads to oxidative damage and gene expression changes in physicians during medical residency: a cohort study. Environ Sci Pollut Res 30, 73202–73212 (2023). https://doi.org/10.1007/s11356-023-27577-y
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DOI: https://doi.org/10.1007/s11356-023-27577-y