Abstract
Studies suggest that chronic lead (Pb) exposure may induce deoxyribonucleic acid (DNA) damage. However, there is no synthesised evidence in this regard. We systematically reviewed existing literature and synthesised evidence on the association between chronic Pb exposure and markers of genotoxicity. Observational studies reporting biomarkers of DNA damage among occupationally Pb-exposed and unexposed controls were systematically searched from PubMed, Scopus and Embase databases from inception to January 2022. The markers included were micronucleus frequency (MN), chromosomal aberrations, comet assay, and 8-hydroxy-deoxyguanosine. During the execution of this review, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Mean differences in the biological markers of DNA damage between Pb-exposed and control groups were pooled using the random-effects model. The heterogeneity was assessed using the Cochran-Q test and I2 statistic. The review included forty-five studies comparing markers of DNA damage between Pb-exposed and unexposed. The primary studies utilised buccal and/or peripheral leukocytes for evaluating the DNA damage. The pooled quantitative results revealed significantly higher DNA damage characterised by increased levels of MN and SCE frequency, chromosomal aberrations, and oxidative DNA damage (comet assay and 8-OHdG) among Pb-exposed than the unexposed. However, studies included in the review exhibited high levels of heterogeneity among the studies. Chronic Pb exposure is associated with DNA damage. However, high-quality, multicentred studies are required to strengthen present observations and further understand the Pb’s role in inducing DNA damage. CRD42022286810.
Highlights
-
The synthesized evidence indicates that chronic Pb exposure is associated with DNA damage.
-
The DNA damage markers with Pb exposure include higher levels of micro-nuclei (with nuclear buds and nucleoplasmic bridges), sister chromatid exchange frequency, chromosomal aberrations and oxidative DNA damage.
Similar content being viewed by others
Data availability statement
Not applicable.
References
(2010) IARC monographs on the evaluation of carcinogenic risks to humans. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans https://doi.org/10.1136/jcp.48.7.691-a
(2012) CDC Preventing lead poisoning in young children Atlanta, GA: US Department of Health and Human Services
Akram Z, Riaz S, Kayani MA et al (2019) Lead induces DNA damage and alteration of ALAD and antioxidant genes mRNA expression in construction site workers. Arch Environ Occup Health. https://doi.org/10.1080/19338244.2018.1428523
Aksu İ, Anlar HG, Taner G et al (2019) Assessment of DNA damage in welders using comet and micronucleus assays. Mut Res Gen Toxicol Environ Mutag 843:40–45. https://doi.org/10.1016/j.mrgentox.2018.11.006
Alabi OA, Adeoluwa YM, Bakare AA (2020) Elevated serum Pb, Ni, Cd, and Cr levels and DNA damage in exfoliated buccal cells of teenage scavengers at a major electronic waste dumpsite in Lagos, Nigeria. Biol Trace Element Res. https://doi.org/10.1007/s12011-019-01745-z
Albertini RJ, Anderson D, Douglas GR et al (2000) IPCS guidelines for the monitoring of genotoxic effects of carcinogens in humans. Mutat Res Rev Mutat Res. https://doi.org/10.1016/S1383-5742(00)00049-1
Altman D, Machin D, Bryant T, Gardner M (2000) Statistics With Confidence 2nd ed - D. Altman, et al., (BMJ, 2005) WW.pdf. VI International Conference on Photon Correlation and Other Techniques in Fluid Mechanics
Augusto LGDS, Lieber SR, Ruiz MA, De Souza CA (1997) Micronucleus monitoring to assess human occupational exposure to organochlorides. Environ Mol Mutagen. https://doi.org/10.1002/(SICI)1098-2280(1997)29:1%3c46::AID-EM6%3e3.0.CO;2-B
Bagepally BS, Balachandar R, Kalahasthi R et al (2021) Association between aluminium exposure and cognitive functions: a systematic review and meta-analysis. Chemosphere 268:128831
Balachandar R, Bagepally BS, Kalahasthi R, Haridoss M (2020) Blood lead levels and male reproductive hormones: a systematic review and meta-analysis. Toxicology 443:152574
Balasubramanian B, Meyyazhagan A, Chinnappan AJ et al (2020) Occupational health hazards on workers exposure to lead (Pb): a genotoxicity analysis. J Infect Public Health. https://doi.org/10.1016/j.jiph.2019.10.005
Batra J, Thakur A, Juyal D, Meena SK (2020) Lead induced oxidative DNA damage among the occupationally exposed workers: a case-control study. J Clin Diagn Res. https://doi.org/10.7860/jcdr/2020/43682.13572
Bauchinger M, Schmid E, Einbrodt HJ, Dresp J (1976) Chromosome aberrations in lymphocytes after occupational exposure to lead and cadmium. Mutat Res Genet Toxicol. https://doi.org/10.1016/0165-1218(76)90023-9
Bilban M (1998) Influence of the work environment in a Pb-Zn mine on the incidence of cytogenetic damage in miners. Am J Ind Med. https://doi.org/10.1002/(SICI)1097-0274(199811)34:5%3c455::AID-AJIM6%3e3.0.CO;2-P
Bonassi S, Znaor A, Ceppi M et al (2007) An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans. Carcinogenesis. https://doi.org/10.1093/carcin/bgl177
Carere A, Antoccia A, Crebelli R et al (1995) Genetic effects of petroleum fuels: cytogenetic monitoring of gasoline station attendants. Mutat Res Fundam Mol Mechan Mutag. https://doi.org/10.1016/0027-5107(95)00081-9
Centers for Disease Control and Prevention (CDC) (2013) Very high blood lead levels among adults - United States, 2002–2011. MMWR Morb Mortal Wkly Rep 62
Chen Z, Huo X, Chen G et al (2021) Lead (Pb) exposure and heart failure risk. Environm Sci Pollut Res 28:28833–28847
Chen Z, Lou J, Chen S et al (2006) Evaluating the genotoxic effects of workers exposed to lead using micronucleus assay, comet assay and TCR gene mutation test. Toxicology. https://doi.org/10.1016/j.tox.2006.03.016
Cheong HSJ, Seth I, Joiner MC, Tucker JD (2013) Relationships among micronuclei, nucleoplasmic bridges and nuclear buds within individual cells in the cytokinesis-block micronucleus assay. Mutagenesis. https://doi.org/10.1093/mutage/get020
Das U, De M (2013) Chromosomal study on lead exposed population. Int J Hum Genet. https://doi.org/10.1080/09723757.2013.11886197
DerSimonian R, Laird N (2015) Meta-analysis in clinical trials revisited. Contemp Clin Trials 45:139–145
de Souza ID, de Andrade AS, Dalmolin RJS (2018) Lead-interacting proteins and their implication in lead poisoning. Crit Rev Toxicol 48:375–386
Dobrakowski M, Pawlas N, Kasperczyk A et al (2017) Oxidative DNA damage and oxidative stress in lead-exposed workers. Hum Exp Toxicol. https://doi.org/10.1177/0960327116665674
Dönmez H, Dursun N, Özkul Y, Demirtaş H (1998) Increased sister chromatid exchanges in workers exposed to occupational lead and zinc. Biol Trace Elem Res. https://doi.org/10.1007/BF02784046
Duydu Y (2022) Derivation of a biological limit value (BLV) for inorganic lead based on lead-induced genotoxicity in workers using the benchmark dose approach (BMD). J Trace Elem Med Biol. https://doi.org/10.1016/j.jtemb.2021.126894
Duydu Y, Süzen HS, Aydin A et al (2001) Correlation between lead exposure indicators and sister chromatid exchange (SCE) frequencies in lymphocytes from inorganic lead exposed workers. Arch Environ Contam Toxicol. https://doi.org/10.1007/s002440010244
Fenech M (1998) Important variables that influence base-line micronucleus frequency in cytokinesis-blocked lymphocytes - A biomarker for DNA damage in human populations. Mutat Res Fundam Mol Mechan Mutag 404:155–165
Fenech M, Bonassi S (2011) The effect of age, gender, diet and lifestyle on DNA damage measured using micronucleus frequency in human peripheral blood lymphocytes. Mutagenesis 26:43–49
Fenech M, Kirsch-Volders M, Rossnerova A et al (2013) HUMN project initiative and review of validation, quality control and prospects for further development of automated micronucleus assays using image cytometry systems. Int J Hyg Environ Health. https://doi.org/10.1016/j.ijheh.2013.01.008
Ferraz GA, Costa Neto A de O, Cerqueira E de MM, Meireles JRC (2016) Effects of age on the frequency of micronuclei and degenerative nuclear abnormalities. Revista Brasileira de Geriatria e Gerontologia https://doi.org/10.1590/1809-98232016019.150155
Flora G, Gupta D, Tiwari A (2012) Toxicity of lead: a review with recent updates. Interdisciplin Toxicol 5:47
Fracasso ME, Perbellini L, Soldà S et al (2002) Lead induced DNA strand breaks in lymphocytes of exposed workers: role of reactive oxygen species and protein kinase C. Mutat Res Genet Toxicol Environ Mutag 515:159–169
Furness DLF, Dekker GA, Hague WM et al (2010) Increased lymphocyte micronucleus frequency in early pregnancy is associated prospectively with pre-eclampsia and/or intrauterine growth restriction. Mutagenesis. https://doi.org/10.1093/mutage/geq032
García-Lestón J, Roma-Torres J, Vilares M et al (2012) Genotoxic effects of occupational exposure to lead and influence of polymorphisms in genes involved in lead toxicokinetics and in DNA repair. Environ Int. https://doi.org/10.1016/j.envint.2012.03.001
Glei M, Schneider T, Schlörmann W (2016) Comet assay: an essential tool in toxicological research. Arch Toxicol 90:2315–2336
Grover P, Rekhadevi PV, Danadevi K et al (2010) Genotoxicity evaluation in workers occupationally exposed to lead. Int J Hyg Environ Health. https://doi.org/10.1016/j.ijheh.2010.01.005
Hamurcu Z, Donmez H, Saraymen R, Demirtas H (2001) Micronucleus frequencies in workers exposed to lead, zinc, and cadmium. Biol Trace Elem Res. https://doi.org/10.1385/BTER:83:2:097
Hayashino Y, Noguchi Y, Fukui T (2005) Systemic evaluation and comparison of statistical tests for publication bias. J Epidemiol. https://doi.org/10.2188/jea.15.235
Hozo SP, Djulbegovic B, Hozo I (2005) Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol 5:1–10
Iarmarcovai G, Sari-Minodier I, Chaspoul F et al (2005) Risk assessment of welders using analysis of eight metals by ICP-MS in blood and urine and DNA damage evaluation by the comet and micronucleus assays; influence of XRCC1 and XRCC3 polymorphisms. Mutagenesis. https://doi.org/10.1093/mutage/gei058
Ionescu ME, Ciocirlan M, Becheanu G et al (2011) Nuclear division index may predict neoplastic colorectal lesions. Maedica 6:173
Jannuzzi AT, Alpertunga B (2016) Evaluation of DNA damage and DNA repair capacity in occupationally lead-exposed workers. Toxicol Ind Health. https://doi.org/10.1177/0748233715590919
Kalahasthi R, Nagaraju R, Balachandar R, Bagepally BS (2022) Association between occupational lead exposure and immunotoxicity markers: a systematic review and meta-analysis. Toxicology 465:153047
Karakaya AE, Ozcagli E, Ertas N, Sardas S (2005) Assessment of abnormal DNA repair responses and genotoxic effects in lead exposed workers. Am J Ind Med. https://doi.org/10.1002/ajim.20145
Kašuba V, Milić M, Zeljezić D et al (2020) Biomonitoring findings for occupational lead exposure in battery and ceramic tile workers using biochemical markers, alkaline comet assay, and micronucleus test coupled with fluorescence in situ hybridisation. Arh Hig Rada Toksikol. https://doi.org/10.2478/aiht-2020-71-3427
Kašuba V, Rozgaj R, Milić M et al (2010) Evaluation of lead exposure in battery-manufacturing workers with focus on different biomarkers. J Appl Toxicol. https://doi.org/10.1002/jat.1497
Kašuba V, Rozgaj R, Milić M et al (2012) Evaluation of genotoxic effects of lead in pottery-glaze workers using micronucleus assay, alkaline comet assay and DNA diffusion assay. Int Arch Occup Environ Health. https://doi.org/10.1007/s00420-011-0726-4
Kauppinen T, Pajarskiene B, Podniece Z et al (2001) Occupational exposure to carcinogens in Estonia, Latvia, Lithuania and the Czech Republic in 1997. Scand J Work Environ Health. https://doi.org/10.5271/sjweh.623
Kauppinen T, Toikkanen J, Savela A et al (2000) Occupational exposure to carcinogens in the European Union. Occup Environ Med. https://doi.org/10.1136/oem.57.1.10
Kayaalti Z, Yavuz I, Söylemez E et al (2015) Evaluation of DNA damage using 3 comet assay parameters in workers occupationally exposed to lead. Arch Environ Occup Health. https://doi.org/10.1080/19338244.2013.787964
Khan MI, Ahmad I, Mahdi AA et al (2010) Elevated blood lead levels and cytogenetic markers in buccal epithelial cells of painters in India. Environ Sci Pollut Res. https://doi.org/10.1007/s11356-010-0319-x
Kumaravel TS, Vilhar B, Faux SP, Jha AN (2009) Comet assay measurements: a perspective. Cell Biol Toxicol 25:53–64
Kuraeiad S, Kotepui M (2021) Blood lead level and renal impairment among adults: a meta-analysis. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph18084174
Leelapongwattana S, Bordeerat NK (2020) Induction of genotoxicity and mutagenic potential of heavy metals in Thai occupational workers. Mutat Res Genet Toxicol Environ Mutag. https://doi.org/10.1016/j.mrgentox.2020.503231
Liao LM, Friesen MC, Xiang YB et al (2016) Occupational lead exposure and associations with selected cancers: The Shanghai men’s and women’s health study cohorts. Environ Health Perspect. https://doi.org/10.1289/ehp.1408171
Liou SH, Lung JC, Chen YH et al (1999) Increased chromosome-type chromosome aberration frequencies as biomarkers of cancer risk in a blackfoot endemic area. Cancer Res 59:1481–1484
Lodovici M, Casalini C, Cariaggi R et al (2000) Levels of 8-hydroxydeoxyguanosine as a marker of DNA damage in human leukocytes. Free Radical Biol Med. https://doi.org/10.1016/S0891-5849(99)00194-X
Lundström NG, Nordberg G, Englyst V et al (1997) Cumulative lead exposure in relation to mortality and lung cancer morbidity in a cohort of primary smelter workers. Scand J Work Environ Health. https://doi.org/10.5271/sjweh.174
Mäki-Paakkanen J, Sorsa M, Vainio H (1981) Chromosome aberrations and sister chromatid exchanges in lead-exposed workers. Hereditas. https://doi.org/10.1111/j.1601-5223.1981.tb01764.x
Martino-Roth MG, Viégas J, Roth DM (2003) Occupational genotoxicity risk evaluation through the comet assay and the micronucleus test. Genet Mol Res 2:410–417
Meng Y, Wang K, Wang T et al (2021) Early occupational exposure to lead on neutrophil-to-lymphocyte ratio and genotoxicity. Environ Int. https://doi.org/10.1016/j.envint.2021.106448
Minozzo R, Deimling LI, Gigante LP, Santos-Mello R (2004) Micronuclei in peripheral blood lymphocytes of workers exposed to lead. Mutat Res Genet Toxicol Environl Mutag. https://doi.org/10.1016/j.mrgentox.2004.09.003
Nersesyan A et al (2021) Use of micronucleus experiments for the detection of human cancer risks: a brief overview. Proceeding of the Shevchenko Scientific Society. Proceeding of the Shevchenko Scientific Society Medical Sciences 65
New york state Lead expsoure in adults, A guide for health care providers. https://www.health.ny.gov/publications/2584.pdf New yorks
Norppa H, Bonassi S, Hansteen IL et al (2006) Chromosomal aberrations and SCEs as biomarkers of cancer risk. Mutat Res Fundam Mol Mechan Mutag. https://doi.org/10.1016/j.mrfmmm.2006.05.030
Nsonwu-Anyanwu (2021) Chronic exposure to toluene and heavy metals and changes in indices of liver function, inflammation and oxidative DNA damage among automobile workers. Asia Pacific J Med Toxicol 10:53–60
OECD (2010) OECD guidliness for chemcials, Proposal for updating Test Guideline 487. https://www.oecd.org/chemicalsafety/testing/50108793.pdf
Olewińska E, Kasperczyk A, Kapka L et al (2010) Level of DNA damage in lead-exposed workers. Ann Agric Environ Med 17:231–236
Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A (2016) Rayyan-a web and mobile app for systematic reviews. Syst Rev. https://doi.org/10.1186/s13643-016-0384-4
Page MJ, McKenzie JE, Bossuyt PM, et al (2021) The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. The BMJ 372
Palus J, Rydzynski K, Dziubaltowska E et al (2003) Genotoxic effects of occupational exposure to lead and cadmium. Mutat Res Genet Toxicol Environ Mutag. https://doi.org/10.1016/S1383-5718(03)00167-0
Pawlas N, Olewinska E, Markiewicz-Górka I, et al (2017) Oxidative damage of DNA in subjects occupationally exposed to lead. Adv Clin Experim Med https://doi.org/10.17219/acem/64682
Peters JL, Sutton AJ, Jones DR et al (2010) Assessing publication bias in meta-analyses in the presence of between-study heterogeneity. J R Stat Soc Ser A Stat Soc. https://doi.org/10.1111/j.1467-985X.2009.00629.x
Pilger A, Rüdiger HW (2006) 8-Hydroxy-2′-deoxyguanosine as a marker of oxidative DNA damage related to occupational and environmental exposures. Int Arch Occup Environ Health 80:1–15
Pinto D, Ceballos JM, García G et al (2000) Increased cytogenetic damage in outdoor painters. Mutat Res Genet Toxicol Environ Mutag. https://doi.org/10.1016/S1383-5718(00)00024-3
Podrimaj-Bytyqi A, Borovečki A, Selimi Q et al (2018) The frequencies of micronuclei, nucleoplasmic bridges and nuclear buds as biomarkers of genomic instability in patients with urothelial cell carcinoma. Sci Rep. https://doi.org/10.1038/s41598-018-35903-5
Qu W, Du GL, Feng B, Shao H (2019) Effects of oxidative stress on blood pressure and electrocardiogram findings in workers with occupational exposure to lead. J Int Med Res. https://doi.org/10.1177/0300060519842446
Rosefort C, Fauth E, Zankl H (2004) Micronuclei induced by aneugens and clastogens in mononucleate and binucleate cells using the cytokinesis block assay. Mutagenesis. https://doi.org/10.1093/mutage/geh028
Ruiz-Ruiz B, Arellano-García ME, Radilla-Chávez P et al (2020) Cytokinesis-block micronucleus assay using human lymphocytes as a sensitive tool for cytotoxicity/genotoxicity evaluation of AgNPs. ACS Omega. https://doi.org/10.1021/acsomega.0c00149
Shen HM, Chia SE, Ong CN (1999) Evaluation of oxidative DNA damage in human sperm and its association with male infertility. J Androl 20:718–723
Singh et al (2013) Evaluation of oxidative stress and genotoxicity in battery manufacturing workers occupationally exposed to lead manufacturing workers occupationally exposed to lead. Toxicol Int 20:95
Singh P, Mitra P, Goyal T et al (2021) Blood lead and cadmium levels in occupationally exposed workers and their effect on markers of DNA damage and repair. Environ Geochem Health. https://doi.org/10.1007/s10653-020-00696-y
StataCorp (2019) Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC. In: StataCorp LLC
Steenland K, Barry V, Anttila A et al (2019) Cancer incidence among workers with blood lead measurements in two countries. Occup Environ Med. https://doi.org/10.1136/oemed-2019-105786
Szymańska-Chabowska A, Beck A, Porȩba R et al (2009) Evaluation of DNA damage in people occupationally exposed to arsenic and some heavy metals. Polish J Environ Stud 18:1131–1139
Tucker JD, Preston RJ (1996) Chromosome aberrations, micronuclei, aneuploidy, sister chromatid exchanges, and cancer risk assessment. Mutat Res Rev Genet Toxicol. https://doi.org/10.1016/S0165-1110(96)90018-4
Upadhyay K, Viramgami A, Pagdhune A et al (2021) Hematological and cardiovascular effects of chronic low level lead exposure: a study on e-waste recyclers. Clin Epidemiol Global Health. https://doi.org/10.1016/j.cegh.2020.09.009
Vaglenov A, Creus A, Laltchev S et al (2001) Occupational exposure to lead and induction of genetic damage. Environ Health Perspect. https://doi.org/10.1289/ehp.01109295
Valavanidis A, Vlachogianni T, Fiotakis C (2009) 8-Hydroxy-2′ -deoxyguanosine (8-OHdG): a critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev. https://doi.org/10.1080/10590500902885684
Virgolini MB, Aschner M (2021) Molecular mechanisms of lead neurotoxicity. Adv Neurotoxicol 24:595–600
Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. https://doi.org/10.1186/1471-2288-14-135
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M (2013) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa, Ontario, Canada: Ottawa Hospital Research Institute
Wu et al (2004) Lack of association of d-aminolevulinic acid dehydratase genotype with cytogenetic damage in lead workers. Int Arch Occup Environ Health 77:395–400
Wu FY, Chang PW, Wu CC, Kuo HW (2002) Correlations of blood lead with DNA-protein cross-links and sister chromatid exchanges in lead workers. Cancer Epidemiol Biomark Prev 11:287–290
Wu Y, Liu Y, Ni N et al (2012) High lead exposure is associated with telomere length shortening in Chinese battery manufacturing plant workers. Occup Environ Med. https://doi.org/10.1136/oemed-2011-100478
Yedjou CG, Tchounwou HM, Tchounwou PB (2015) DNA damage, cell cycle arrest, and apoptosis induction caused by lead in human leukemia cells. Int J Environ Res Public Health. https://doi.org/10.3390/ijerph13010056
Yu L, Tu Y, Huang J et al (2018) Hypermethylation of CpG islands is associated with increasing chromosomal damage in Chinese lead-exposed workers. Environ Mol Mutagen. https://doi.org/10.1002/em.22194
Zeljezic D, Garaj-Vrhovac V (2002) Sister chromatid exchange and proliferative rate index in the longitudinal risk assessment of occupational exposure to pesticides. Chemosphere. https://doi.org/10.1016/S0045-6535(01)00073-X
Zendehdel R, Vahabi M (2022) Formaldehyde carcinogenicity risk assessment using benchmark doses approach based on genotoxic effects in occupational exposure. J Chem Health Risks https://doi.org/10.22034/jchr.2021.1928582.1296
Acknowledgements
None.
Funding
No funding support for this work.
Author information
Authors and Affiliations
Contributions
NR: conceptualisation, data curation, formal analysis, original draft.: KR: conceptualisation, data curation, methodology, review and editing, inputs on the original draft. BR: inputs on the original draft, review and editing. BBS: conceptualisation, formal analysis, inputs on original draft, investigation, methodology, software, review and editing.
Corresponding author
Ethics declarations
Conflict of interest
None.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Nagaraju, R., Kalahasthi, R., Balachandar, R. et al. Association between lead exposure and DNA damage (genotoxicity): systematic review and meta-analysis. Arch Toxicol 96, 2899–2911 (2022). https://doi.org/10.1007/s00204-022-03352-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-022-03352-9