Advances in genotoxicity of titanium dioxide nanoparticles in vivo and in vitro

Abbasi-Oshaghi, 2019, NLRP3 inflammasome, oxidative stress, and apoptosis induced in the intestine and liver of rats treated with titanium dioxide nanoparticles: in vivo and in vitro study, Int. J. Nanomedicine, 14, 1919, 10.2147/IJN.S192382 Additives, E. P. o. F, 2016, Re-evaluation of titanium dioxide (E 171) as a food additive, EFSA J., 14 Agnihothram, 2016, Titanium dioxide nanoparticles evoke Proinflammatory response during murine norovirus infection despite having minimal effects on virus replication, Int. J. Nanotechnol. Eng. Med., 1, 63, 10.25141/2474-8811-2016-3.0063 Ahlinder, 2013, Large uptake of Titania and iron oxide nanoparticles in the nucleus of lung epithelial cells as measured by Raman imaging and multivariate classification, Biophys. J., 105, 310, 10.1016/j.bpj.2013.06.017 Alarifi, 2013, Histologic and apoptotic changes induced by titanium dioxide nanoparticles in the livers of rats, Int. J. Nanomedicine, 8, 3937 Ali, 2015, Impairment of DNA in a freshwater gastropod (Lymnea luteola L.) after exposure to titanium dioxide nanoparticles, Arch. Environ. Contam. Toxicol., 68, 543, 10.1007/s00244-015-0132-0 Allouni, 2012, Role of physicochemical characteristics in the uptake of TiO2 nanoparticles by fibroblasts, Toxicol. in Vitro, 26, 469, 10.1016/j.tiv.2012.01.019 Andreoli, 2018, Critical issues in genotoxicity assessment of TiO2 nanoparticles by human peripheral blood mononuclear cells, J. Appl. Toxicol., 38, 1471, 10.1002/jat.3650 Armand, 2016, Long-term exposure of A549 cells to titanium dioxide nanoparticles induces DNA damage and sensitizes cells towards genotoxic agents, Nanotoxicology, 10, 913, 10.3109/17435390.2016.1141338 Asare, 2016, Genotoxicity and gene expression modulation of silver and titanium dioxide nanoparticles in mice, Nanotoxicology, 10, 312, 10.3109/17435390.2015.1071443 Azim, 2015, Amelioration of titanium dioxide nanoparticles-induced liver injury in mice: possible role of some antioxidants, Exp. Toxicol. Pathol., 67, 305, 10.1016/j.etp.2015.02.001 Bachler, 2015, Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO2) nanoparticles, Nanotoxicology, 9, 373, 10.3109/17435390.2014.940404 Bayat, 2015, Vascular toxicity of ultra-small TiO2 nanoparticles and single walled carbon nanotubes in vitro and in vivo, Biomaterials, 63, 1, 10.1016/j.biomaterials.2015.05.044 Bessa, 2017, Moving into advanced nanomaterials. Toxicity of rutile TiO2 nanoparticles immobilized in nanokaolin nanocomposites on HepG2 cell line, Toxicol. Appl. Pharmacol., 316, 114, 10.1016/j.taap.2016.12.018 Bettini, 2017, Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon, Sci. Rep., 7, 40373, 10.1038/srep40373 Biola-Clier, 2017, Comparison of the DNA damage response in BEAS-2B and A549 cells exposed to titanium dioxide nanoparticles, Mutagenesis, 32, 161, 10.1093/mutage/gew055 Blevins, 2019, Evaluation of immunologic and intestinal effects in rats administered an E 171-containing diet, a food grade titanium dioxide (TiO2), Food Chem. Toxicol., 133, 10.1016/j.fct.2019.110793 Botelho, 2014, Effects of titanium dioxide nanoparticles in human gastric epithelial cells in vitro, Biomed. Pharmacother., 68, 59, 10.1016/j.biopha.2013.08.006 Brandao, 2020, Genotoxicity of TiO2 nanoparticles in four different human cell lines (A549, HEPG2, A172 and SH-SY5Y), Nanomaterials (Basel), 10, 10.3390/nano10030412 Browning, 2014, Sr., titanium dioxide nanoparticles are not cytotoxic or Clastogenic in human skin cells, J. Environ. Anal. Toxicol., 4, 10.4172/2161-0525.1000239 Butler, 2014, Assessment of titanium dioxide nanoparticle effects in bacteria: association, uptake, mutagenicity, co-mutagenicity and DNA repair inhibition, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 768, 14, 10.1016/j.mrgentox.2014.04.008 Canesi, 2014, Interactive effects of n-TiO2 and 2,3,7,8-TCDD on the marine bivalve Mytilus galloprovincialis, Aquat. Toxicol., 153, 53, 10.1016/j.aquatox.2013.11.002 Carmo, 2019, Overview of the toxic effects of titanium dioxide nanoparticles in blood, liver, muscles, and brain of a Neotropical detritivorous fish, Environ. Toxicol., 34, 457, 10.1002/tox.22699 Carmona, 2015, Genotoxic testing of titanium dioxide anatase nanoparticles using the wing-spot test and the comet assay in drosophila, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 778, 12, 10.1016/j.mrgentox.2014.12.004 Carvalho Naves, 2018, Assessment of mutagenic, recombinogenic and carcinogenic potential of titanium dioxide nanocristals in somatic cells of Drosophila melanogaster, Food Chem. Toxicol., 112, 273, 10.1016/j.fct.2017.12.040 Chakrabarti, 2019, Exploration of cytotoxic and genotoxic endpoints following sub-chronic oral exposure to titanium dioxide nanoparticles, Toxicol. Ind. Health, 35, 577, 10.1177/0748233719879611 Chen, 2014, Genotoxicity of titanium dioxide nanoparticles, J. Food Drug Anal., 22, 95, 10.1016/j.jfda.2014.01.008 Chen, 2014, Genotoxic evaluation of titanium dioxide nanoparticles in vivo and in vitro, Toxicol. Lett., 226, 314, 10.1016/j.toxlet.2014.02.020 Clemente, 2014, Toxicity assessment of TiO(2) nanoparticles in zebrafish embryos under different exposure conditions, Aquat. Toxicol., 147, 129, 10.1016/j.aquatox.2013.12.024 Clemente, 2015, Biomarker evaluation in fish after prolonged exposure to Nano-TiO2: influence of illumination conditions and crystal phase, J. Nanosci. Nanotechnol., 15, 5424, 10.1166/jnn.2015.10021 Commission Regulation (EU) Cowie, 2015, Suitability of human and mammalian cells of different origin for the assessment of genotoxicity of metal and polymeric engineered nanoparticles, Nanotoxicology, 9, 57, 10.3109/17435390.2014.940407 Cupi, 2016, Methodological considerations for using umu assay to assess photo-genotoxicity of engineered nanoparticles, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 796, 34, 10.1016/j.mrgentox.2015.11.009 D’Agata, 2014, Enhanced toxicity of ‘bulk’ titanium dioxide compared to ‘fresh’ and ‘aged’ nano-TiO2 in marine mussels (Mytilus galloprovincialis), Nanotoxicology, 8, 549, 10.3109/17435390.2013.807446 Danielsen, 2020, Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice, Toxicol. Appl. Pharmacol., 386, 10.1016/j.taap.2019.114830 Dekanski, 2018, Acute toxicity study in mice of orally administrated TiO2 nanoparticles functionalized with caffeic acid, Food Chem. Toxicol., 115, 42, 10.1016/j.fct.2018.02.064 Della Torre, 2015, Titanium dioxide nanoparticles modulate the toxicological response to cadmium in the gills of Mytilus galloprovincialis, J. Hazard. Mater., 297, 92, 10.1016/j.jhazmat.2015.04.072 Demir, 2015, Genotoxic and cell-transforming effects of titanium dioxide nanoparticles, Environ. Res., 136, 300, 10.1016/j.envres.2014.10.032 Di Bucchianico, 2017, Genotoxicity of TiO2 nanoparticles assessed by mini-gel comet assay and micronucleus scoring with flow cytometry, Mutagenesis, 32, 127, 10.1093/mutage/gew030 de Dicastillo, 2020, Antimicrobial effect of titanium dioxide nanoparticles Doak, 2012, In vitro genotoxicity testing strategy for nanomaterials and the adaptation of current OECD guidelines, Mutat. Res., 745, 104, 10.1016/j.mrgentox.2011.09.013 Dobrzynska, 2014, Genotoxicity of silver and titanium dioxide nanoparticles in bone marrow cells of rats in vivo, Toxicology, 315, 86, 10.1016/j.tox.2013.11.012 Donner, 2016, In vivo micronucleus studies with 6 titanium dioxide materials (3 pigment-grade & 3 nanoscale) in orally-exposed rats, Regul. Toxicol. Pharmacol., 74, 64, 10.1016/j.yrtph.2015.11.003 Dorier, 2015, Impact of anatase and rutile titanium dioxide nanoparticles on uptake carriers and efflux pumps in Caco-2 gut epithelial cells, Nanoscale, 7, 7352, 10.1039/C5NR00505A Dorier, 2017, Continuous in vitro exposure of intestinal epithelial cells to E171 food additive causes oxidative stress, inducing oxidation of DNA bases but no endoplasmic reticulum stress, Nanotoxicology, 11, 751 Dorier, 2019, Toxicological impact of acute exposure to E171 food additive and TiO2 nanoparticles on a co-culture of Caco-2 and HT29-MTX intestinal cells, Mutat. Res., 845 Du, 2019, Genotoxicity evaluation of titanium dioxide nanoparticles using the mouse lymphoma assay and the Ames test, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 838, 22, 10.1016/j.mrgentox.2018.11.015 Dubey, 2015, Oxidative stress and nano-toxicity induced by TiO2 and ZnO on WAG cell line, PLoS One, 10, 10.1371/journal.pone.0127493 El Yamani, 2017, In vitro genotoxicity testing of four reference metal nanomaterials, titanium dioxide, zinc oxide, cerium oxide and silver: towards reliable hazard assessment, Mutagenesis, 32, 117, 10.1093/mutage/gew060 El-Din, 2019, Could curcumin ameliorate titanium dioxide nanoparticles effect on the heart? A histopathological, immunohistochemical, and genotoxic study, Environ. Sci. Pollut. Res. Int., 26, 21556, 10.1007/s11356-019-05433-2 Elespuru, 2018, Genotoxicity assessment of nanomaterials: recommendations on best practices, assays, and methods, Toxicol. Sci., 164, 391, 10.1093/toxsci/kfy100 El-Ghor, 2014, Normalization of nano-sized TiO2-induced clastogenicity, genotoxicity and mutagenicity by chlorophyllin administration in mice brain, liver, and bone marrow cells, Toxicol. Sci., 142, 21, 10.1093/toxsci/kfu157 Elje, 2020, Hepato(Geno)toxicity assessment of nanoparticles in a HepG2 liver spheroid model, Nanomaterials (Basel), 10, 10.3390/nano10030545 Elnagar, 2018, Histopathological effects of titanium dioxide nanoparticles and The possible protective role of N-Acetylcysteine on The testes of male albino rats, Int. J. Fertil. Steril., 12, 249 Fadda, 2018, Quercetin and Idebenone ameliorate oxidative stress, inflammation, DNA damage, and apoptosis induced by titanium dioxide nanoparticles in rat liver, Dose-Response, 16, 10.1177/1559325818812188 Fadda, 2019, Prophylactic administration of carnosine and melatonin abates the incidence of apoptosis, inflammation, and DNA damage induced by titanium dioxide nanoparticles in rat livers, Environ. Sci. Pollut. Res. Int. Fadoju, 2019, Evaluation of cytogenotoxicity and oxidative stress parameters in male Swiss mice co-exposed to titanium dioxide and zinc oxide nanoparticles, Environ. Toxicol. Pharmacol., 70, 10.1016/j.etap.2019.103204 Falck, 2009, Genotoxic effects of nanosized and fine TiO2, Hum. Exp. Toxicol., 28, 339, 10.1177/0960327109105163 Farrell, 2017, Absorption, distribution and excretion of four forms of titanium dioxide pigment in the rat, J. Food Sci., 82, 1985, 10.1111/1750-3841.13791 Ferraro, 2016, Overestimation of nanoparticles-induced DNA damage determined by the comet assay, Nanotoxicology, 10, 861, 10.3109/17435390.2015.1130274 Foster, 2011, Photocatalytic disinfection using titanium dioxide: spectrum and mechanism of antimicrobial activity, Appl. Microbiol. Biotechnol., 90, 1847, 10.1007/s00253-011-3213-7 Franchi, 2015, Cyto- and genotoxic effects of metallic nanoparticles in untransformed human fibroblast, Toxicol. in Vitro, 29, 1319, 10.1016/j.tiv.2015.05.010 Frenzilli, 2014, Effects of in vitro exposure to titanium dioxide on DNA integrity of bottlenose dolphin (Tursiops truncatus) fibroblasts and leukocytes, Mar. Environ. Res., 100, 68, 10.1016/j.marenvres.2014.01.002 Fries, 2013, Nano-titanium dioxide (part I): basics, production, applications Garcia-Rodriguez, 2018, Effects of differently shaped TiO2NPs (nanospheres, nanorods and nanowires) on the in vitro model (Caco-2/HT29) of the intestinal barrier, Part. Fibre Toxicol., 15, 33, 10.1186/s12989-018-0269-x Gea, 2019, Shape-engineered titanium dioxide nanoparticles (TiO2-NPs): cytotoxicity and genotoxicity in bronchial epithelial cells, Food Chem. Toxicol., 127, 89, 10.1016/j.fct.2019.02.043 Ghosh, 2017, Cyto-genotoxic and DNA methylation changes induced by different crystal phases of TiO2-np in bronchial epithelial (16-HBE) cells, Mutat. Res., 796, 1, 10.1016/j.mrfmmm.2017.01.003 Girardello, 2016, Titanium dioxide nanoparticles induce genotoxicity but not mutagenicity in golden mussel Limnoperna fortunei, Aquat. Toxicol., 170, 223, 10.1016/j.aquatox.2015.11.030 Gnatyshyna, 2019, Biochemical responses of freshwater mussel Unio tumidus to titanium oxide nanoparticles, Bisphenol A, and their combination, Ecotoxicology, 28, 923, 10.1007/s10646-019-02090-6 Gornati, 2016, Effects of titanium dioxide nanoparticle exposure in Mytilus galloprovincialis gills and digestive gland, Nanotoxicology, 10, 807, 10.3109/17435390.2015.1132348 Gottschalk, 2010, Probabilistic material flow modeling for assessing the environmental exposure to compounds: methodology and an application to engineered nano-TiO2 particles, Environ. Model. Softw., 25, 320, 10.1016/j.envsoft.2009.08.011 Graf, 1984, Somatic mutation and recombination test in Drosophila melanogaster, Environ. Mutagen., 6, 153, 10.1002/em.2860060206 Grissa, 2015, Anemia and genotoxicity induced by sub-chronic intragastric treatment of rats with titanium dioxide nanoparticles, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 794, 25, 10.1016/j.mrgentox.2015.09.005 Grissa, 2017, Rosmarinus officinalis L. ameliorates titanium dioxide nanoparticles and induced some toxic effects in rats’ blood, Environ. Sci. Pollut. Res. Int., 24, 12474, 10.1007/s11356-017-8848-1 Hackenberg, 2017, Genotoxic effects of zinc oxide nanoparticles in nasal mucosa cells are antagonized by titanium dioxide nanoparticles, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 816-817, 32, 10.1016/j.mrgentox.2017.02.005 Hadrup, 2017, Influence of dispersion medium on nanomaterial-induced pulmonary inflammation and DNA strand breaks: investigation of carbon black, carbon nanotubes and three titanium dioxide nanoparticles, Mutagenesis, 32, 581, 10.1093/mutage/gex042 Hanot-Roy, 2016, Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro, Toxicol. in Vitro, 33, 125, 10.1016/j.tiv.2016.01.013 Hashem, 2020, The long-term oral exposure to titanium dioxide impaired immune functions and triggered cytotoxic and genotoxic impacts in rats, J. Trace Elem. Med. Biol., 60, 10.1016/j.jtemb.2020.126473 Hassanein, 2017, Protective effects of thymoquinone and avenanthramides on titanium dioxide nanoparticles induced toxicity in Sprague-Dawley rats, Pathol. Res. Pract., 213, 13, 10.1016/j.prp.2016.08.002 Hattori, 2017, Exposure to nano-size titanium dioxide causes oxidative damages in human mesothelial cells: The crystal form rather than size of particle contributes to cytotoxicity, Biochem. Biophys. Res. Commun., 492, 218, 10.1016/j.bbrc.2017.08.054 Heinrich, 1995, Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium dioxide, Inhal. Toxicol., 7, 533, 10.3109/08958379509015211 Iarc Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006, Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide, IARC Monogr. Eval. Carcinog. Risks Hum., 86, 1 Jain, 2017, Impact of anatase titanium dioxide nanoparticles on mutagenic and genotoxic response in Chinese hamster lung fibroblast cells (V-79): The role of cellular uptake, Food Chem. Toxicol., 105, 127, 10.1016/j.fct.2017.04.005 Jensen, 2019, Telomere length and genotoxicity in the lung of rats following intragastric exposure to food-grade titanium dioxide and vegetable carbon particles, Mutagenesis, 34, 203, 10.1093/mutage/gez003 Jomini, 2012, Modifications of the bacterial reverse mutation test reveals mutagenicity of TiO(2) nanoparticles and byproducts from a sunscreen TiO(2)-based nanocomposite, Toxicol. Lett., 215, 54, 10.1016/j.toxlet.2012.09.012 Jovanovic, 2018, The effects of a human food additive, titanium dioxide nanoparticles E171, on Drosophila melanogaster - a 20 generation dietary exposure experiment, Sci. Rep., 8, 17922, 10.1038/s41598-018-36174-w Jugan, 2012, Titanium dioxide nanoparticles exhibit genotoxicity and impair DNA repair activity in A549 cells, Nanotoxicology, 6, 501, 10.3109/17435390.2011.587903 Kansara, 2015, TiO2 nanoparticles induce DNA double strand breaks and cell cycle arrest in human alveolar cells, Environ. Mol. Mutagen., 56, 204, 10.1002/em.21925 Kazimirova, 2019, Titanium dioxide nanoparticles tested for genotoxicity with the comet and micronucleus assays in vitro, ex vivo and in vivo, Mutat. Res., 843, 57, 10.1016/j.mrgentox.2019.05.001 Kazimirova, 2020, Effects of titanium dioxide nanoparticles on the Hprt gene mutations in V79 hamster cells, Nanomaterials (Basel), 10, 10.3390/nano10030465 Keller, 2013, Global life cycle releases of engineered nanomaterials, J. Nanopart. Res., 15, 10.1007/s11051-013-1692-4 Khan, 2015, Comparative study of the cytotoxic and genotoxic potentials of zinc oxide and titanium dioxide nanoparticles, Toxicol. Rep., 2, 765, 10.1016/j.toxrep.2015.02.004 Kim, 2014, Using citrate-functionalized TiO2 nanoparticles to study the effect of particle size on zebrafish embryo toxicity, Analyst, 139, 964, 10.1039/c3an01966g Kumar, 2016, Role of macrophage (M1 and M2) in titanium-dioxide nanoparticle-induced oxidative stress and inflammatory response in rat, Appl. Biochem. Biotechnol., 180, 1257, 10.1007/s12010-016-2165-x Landsiedel, 2010, Testing metal-oxide nanomaterials for human safety, Adv. Mater., 22, 2601, 10.1002/adma.200902658 Lee, 1985, Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years, Toxicol. Appl. Pharmacol., 79, 179, 10.1016/0041-008X(85)90339-4 Lesniak, 2010, Serum heat inactivation affects protein corona composition and nanoparticle uptake, Biomaterials, 31, 9511, 10.1016/j.biomaterials.2010.09.049 Lesniak, 2012, Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells, ACS Nano, 6, 5845, 10.1021/nn300223w Li, 2017, Factors affecting the in vitro micronucleus assay for evaluation of nanomaterials, Mutagenesis, 32, 151, 10.1093/mutage/gew040 Li, 2017, Genotoxicity and gene expression analyses of liver and lung tissues of mice treated with titanium dioxide nanoparticles, Mutagenesis, 32, 33, 10.1093/mutage/gew065 Liao, 2019, The size-dependent genotoxic potentials of titanium dioxide nanoparticles to endothelial cells, Environ. Toxicol., 34, 1199, 10.1002/tox.22821 Liu, 2020, Continued efforts on nanomaterial-environmental health and safety is critical to maintain sustainable growth of nanoindustry, Small, 16, 10.1002/smll.202000603 Louro, 2014, Integrated approach to the in vivo genotoxic effects of a titanium dioxide nanomaterial using LacZ plasmid-based transgenic mice, Environ. Mol. Mutagen., 55, 500, 10.1002/em.21864 Ma, 2017, Impacts of sediment organic matter content and pH on ecotoxicity of coexposure of TiO2 nanoparticles and cadmium to freshwater snails Bellamya aeruginosa, Arch. Environ. Contam. Toxicol., 72, 153, 10.1007/s00244-016-0338-9 Magdolenova, 2014, Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles, Nanotoxicology, 8, 233, 10.3109/17435390.2013.773464 Marisa, 2018, Bioaccumulation and effects of titanium dioxide nanoparticles and bulk in the clam Ruditapes philippinarum, Mar. Environ. Res., 136, 179, 10.1016/j.marenvres.2018.02.012 Martins, 2017, Evaluation of distribution, redox parameters, and genotoxicity in Wistar rats co-exposed to silver and titanium dioxide nanoparticles, J. Toxicol. Environ. Health A, 80, 1156, 10.1080/15287394.2017.1357376 Meena, 2015, Cytotoxic and genotoxic effects of titanium dioxide nanoparticles in testicular cells of male wistar rat, Appl. Biochem. Biotechnol., 175, 825, 10.1007/s12010-014-1299-y Mohamed, 2015, Estimation of TiO(2) nanoparticle-induced genotoxicity persistence and possible chronic gastritis-induction in mice, Food Chem. Toxicol., 83, 76, 10.1016/j.fct.2015.05.018 Mohamed, 2016, Genotoxicity studies of titanium dioxide nanoparticles (TiO2NPs) in the brain of mice, Scientifica (Cairo), 2016, 6710840 Mottola, 2019, NPs-TiO2 and lincomycin coexposure induces DNA damage in cultured human amniotic cells, Nanomaterials (Basel), 9, 10.3390/nano9111511 Muller, 2019, Genotoxic effect of dimethylarsinic acid and the influence of co-exposure to titanium nanodioxide (nTiO2) in Laeonereis culveri (Annelida, Polychaeta), Sci. Total Environ., 685, 19, 10.1016/j.scitotenv.2019.05.259 Murugadoss, 2020, Agglomeration of titanium dioxide nanoparticles increases toxicological responses in vitro and in vivo, Part. Fibre Toxicol., 17, 10, 10.1186/s12989-020-00341-7 Nel, 2006, Toxic potential of materials at the nanolevel, Science, 311, 622, 10.1126/science.1114397 Nigro, 2015, N-TiO2 and CdCl2 co-exposure to titanium dioxide nanoparticles and cadmium: genomic, DNA and chromosomal damage evaluation in the marine fish European sea bass (Dicentrarchus labrax), Aquat. Toxicol., 168, 72, 10.1016/j.aquatox.2015.09.013 Niu, 2017, Reduction of oxidative damages induced by titanium dioxide nanoparticles correlates with induction of the Nrf2 pathway by GSPE supplementation in mice, Chem. Biol. Interact., 275, 133, 10.1016/j.cbi.2017.07.025 Nunes, 2017, Biochemical responses induced by co-exposition to arsenic and titanium dioxide nanoparticles in the estuarine polychaete Laeonereis acuta, Toxicology, 376, 51, 10.1016/j.tox.2016.05.013 Oberdorster, 2005, Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles, Environ. Health Perspect., 113, 823, 10.1289/ehp.7339 OECD, 2016 OECD, 2016 OECD OECD OECD Osman, 2018, TiO(2) NPs induce DNA damage in lymphocytes from healthy individuals and patients with respiratory diseases-an ex vivo/in vitro study, J. Nanosci. Nanotechnol., 18, 544, 10.1166/jnn.2018.15236 Patel, 2017, Titanium dioxide nanoparticles: an in vitro study of DNA binding, chromosome aberration assay, and comet assay, Cytotechnology, 69, 245, 10.1007/s10616-016-0054-3 Pawar, 2014, Toxicity of titanium oxide nanoparticles causes functionality and DNA damage in buffalo (Bubalus bubalis) sperm in vitro, Toxicol. Ind. Health, 30, 520, 10.1177/0748233712462475 Pele, 2015, Pharmaceutical/food grade titanium dioxide particles are absorbed into the bloodstream of human volunteers, Part. Fibre Toxicol., 12, 10.1186/s12989-015-0101-9 Perez-Iglesias, 2017, L., evaluation of imazethapyr-induced DNA oxidative damage by alkaline Endo III- and Fpg-modified single-cell gel electrophoresis assay in Hypsiboas pulchellus tadpoles (Anura, Hylidae), Ecotoxicol. Environ. Saf., 142, 503, 10.1016/j.ecoenv.2017.04.054 Petković, 2011, DNA damage and alterations in expression of DNA damage responsive genes induced by TiO2 nanoparticles in human hepatoma HepG2 cells, Nanotoxicology, 5, 341, 10.3109/17435390.2010.507316 Picchietti, 2017, Engineered nanoparticles of titanium dioxide (TIO2): uptake and biological effects in a sea bass cell line, Fish Shellfish Immunol., 63, 53, 10.1016/j.fsi.2017.01.044 Piccinno, 2012, Industrial production quantities and uses of ten engineered nanomaterials in Europe and the world, J. Nanopart. Res., 14, 10.1007/s11051-012-1109-9 Prasad, 2014, Cellular interactions and biological responses to titanium dioxide nanoparticles in HepG2 and BEAS-2B cells: role of cell culture media, Environ. Mol. Mutagen., 55, 336, 10.1002/em.21848 Proquin, 2017, Titanium dioxide food additive (E171) induces ROS formation and genotoxicity: contribution of micro and nano-sized fractions, Mutagenesis, 32, 139, 10.1093/mutage/gew051 Reis Ede, 2016, Evaluation of titanium dioxide nanocrystal-induced genotoxicity by the cytokinesis-block micronucleus assay and the drosophila wing spot test, Food Chem. Toxicol., 96, 309, 10.1016/j.fct.2016.08.023 Relier, 2017, Study of TiO2 P25 nanoparticles genotoxicity on lung, blood, and liver cells in lung overload and non-overload conditions after repeated respiratory exposure in rats, Toxicol. Sci., 156, 527 Reuter, 2010, Oxidative stress, inflammation, and cancer: how are they linked?, Free Radic. Biol. Med., 49, 1603, 10.1016/j.freeradbiomed.2010.09.006 Rizk, 2017, Toxicity of titanium dioxide nanoparticles: effect of dose and time on biochemical disturbance, oxidative stress and genotoxicity in mice, Biomed. Pharmacother., 90, 466, 10.1016/j.biopha.2017.03.089 Rocco, 2015, Genotoxicity assessment of TiO2 nanoparticles in the teleost Danio rerio, Ecotoxicol. Environ. Saf., 113, 223, 10.1016/j.ecoenv.2014.12.012 Rocco, 2015, Genomic and chromosomal damage in the marine mussel Mytilus galloprovincialis: effects of the combined exposure to titanium dioxide nanoparticles and cadmium chloride, Mar. Environ. Res., 111, 144, 10.1016/j.marenvres.2015.09.004 Saber, 2019, Toxicity of pristine and paint-embedded TiO2 nanomaterials, Hum. Exp. Toxicol., 38, 11, 10.1177/0960327118774910 Santonastaso, 2019, In vitro genotoxic effects of titanium dioxide nanoparticles (n-TiO2 ) in human sperm cells, Mol. Reprod. Dev., 86, 1369, 10.1002/mrd.23134 Sario, 2018, Titanium dioxide nanoparticles: toxicity and genotoxicity in Drosophila melanogaster (SMART eye-spot test and comet assay in neuroblasts), Mutat. Res. Genet. Toxicol. Environ. Mutagen., 831, 19, 10.1016/j.mrgentox.2018.05.001 Savi, 2014, Titanium dioxide nanoparticles promote arrhythmias via a direct interaction with rat cardiac tissue, Part. Fibre Toxicol., 11, 63, 10.1186/s12989-014-0063-3 Schneider, 2017, In vitro uptake and toxicity studies of metal nanoparticles and metal oxide nanoparticles in human HT29 cells, Arch. Toxicol., 91, 3517, 10.1007/s00204-017-1976-z Sekar, 2014, DNA damage and repair following in vitro exposure to two different forms of titanium dioxide nanoparticles on trout erythrocyte, Environ. Toxicol., 29, 117, 10.1002/tox.20778 Shakeel, 2016, Toxicity of Nano-titanium dioxide (TiO2-NP) through various routes of exposure: a review, Biol. Trace Elem. Res., 172, 1, 10.1007/s12011-015-0550-x Shakeel, 2016, Toxic effects of titanium dioxide nanoparticles and titanium dioxide bulk salt in the liver and blood of male Sprague-Dawley rats assessed by different assays, Biol. Trace Elem. Res., 173, 405, 10.1007/s12011-016-0677-4 Shi, 2015, Reduction of DNA damage induced by titanium dioxide nanoparticles through Nrf2 in vitro and in vivo, J. Hazard. Mater., 298, 310, 10.1016/j.jhazmat.2015.05.043 Shukla, 2014, Titanium dioxide nanoparticle-induced oxidative stress triggers DNA damage and hepatic injury in mice, Nanomedicine (London), 9, 1423, 10.2217/nnm.13.100 Singh, 2009, NanoGenotoxicology: The DNA damaging potential of engineered nanomaterials, Biomaterials, 30, 3891, 10.1016/j.biomaterials.2009.04.009 Skocaj, 2011, Titanium dioxide in our everyday life; is it safe?, Radiol. Oncol., 45, 227, 10.2478/v10019-011-0037-0 Sohm, 2015, Insight into the primary mode of action of TiO2 nanoparticles on Escherichia coli in the dark, Proteomics, 15, 98, 10.1002/pmic.201400101 Sramkova, 2019, Kidney nanotoxicity studied in human renal proximal tubule epithelial cell line TH1, Mutat. Res., 845 Stoccoro, 2016, A panel of in vitro tests to evaluate genotoxic and morphological neoplastic transformation potential on Balb/3T3 cells by pristine and remediated titania and zirconia nanoparticles, Mutagenesis, 31, 511, 10.1093/mutage/gew015 Stoccoro, 2017, Multiple endpoints to evaluate pristine and remediated titanium dioxide nanoparticles genotoxicity in lung epithelial A549 cells, Toxicol. Lett., 276, 48, 10.1016/j.toxlet.2017.05.016 Sun, 2014, Comprehensive probabilistic modelling of environmental emissions of engineered nanomaterials, Environ. Pollut., 185, 69, 10.1016/j.envpol.2013.10.004 Suzuki, 2016, Genotoxicity assessment of intravenously injected titanium dioxide nanoparticles in gpt delta transgenic mice, Mutat. Res. Genet. Toxicol. Environ. Mutagen., 802, 30, 10.1016/j.mrgentox.2016.03.007 Suzuki, 2020, Genotoxicity assessment of titanium dioxide nanoparticle accumulation of 90 days in the liver of gpt delta transgenic mice, Genes Environ., 42, 7, 10.1186/s41021-020-0146-3 Sv, 2017 Tavares, 2014, Genotoxicity evaluation of nanosized titanium dioxide, synthetic amorphous silica and multi-walled carbon nanotubes in human lymphocytes, Toxicol. in Vitro, 28, 60, 10.1016/j.tiv.2013.06.009 Torre, 2015, Influence of titanium dioxide nanoparticles on 2,3,7,8-tetrachlorodibenzo-p-dioxin bioconcentration and toxicity in the marine fish European sea bass (Dicentrarchus labrax), Environ. Pollut., 196, 185, 10.1016/j.envpol.2014.09.020 Uboldi, 2016, Role of the crystalline form of titanium dioxide nanoparticles: rutile, and not anatase, induces toxic effects in Balb/3T3 mouse fibroblasts, Toxicol. in Vitro, 31, 137, 10.1016/j.tiv.2015.11.005 Ursini, 2014, Evaluation of cytotoxic, genotoxic and inflammatory response in human alveolar and bronchial epithelial cells exposed to titanium dioxide nanoparticles, J. Appl. Toxicol., 34, 1209, 10.1002/jat.3038 Vales, 2015, Long-term exposures to low doses of titanium dioxide nanoparticles induce cell transformation, but not genotoxic damage in BEAS-2B cells, Nanotoxicology, 9, 568, 10.3109/17435390.2014.957252 Vasquez, 2010, Combining the in vivo comet and micronucleus assays: a practical approach to genotoxicity testing and data interpretation, Mutagenesis, 25, 187, 10.1093/mutage/gep060 Vicari, 2018, Co-exposure to titanium dioxide nanoparticles (NpTiO2) and lead at environmentally relevant concentrations in the Neotropical fish species Hoplias intermedius, Toxicol. Rep., 5, 1032, 10.1016/j.toxrep.2018.09.001 Vignardi, 2015, Genotoxicity, potential cytotoxicity and cell uptake of titanium dioxide nanoparticles in the marine fish Trachinotus carolinus (Linnaeus, 1766), Aquat. Toxicol., 158, 218, 10.1016/j.aquatox.2014.11.008 Vila, 2018, Titanium dioxide nanoparticles translocate through differentiated Caco-2 cell monolayers, without disrupting the barrier functionality or inducing genotoxic damage, J. Appl. Toxicol., 38, 1195, 10.1002/jat.3630 Wang, 2007, Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration, Toxicol. Lett., 168, 176, 10.1016/j.toxlet.2006.12.001 Wang, 2015, Cytotoxicity, DNA damage, and apoptosis induced by titanium dioxide nanoparticles in human non-small cell lung cancer A549 cells, Environ. Sci. Pollut. Res. Int., 22, 5519, 10.1007/s11356-014-3717-7 Wang, 2018, Shelterin differentially respond to oxidative stress induced by TiO2-NPs and regulate telomere length in human hepatocytes and hepatocarcinoma cells in vitro, Biochem. Biophys. Res. Commun., 503, 697, 10.1016/j.bbrc.2018.06.063 Wang, 2019, Aging-independent and size-dependent genotoxic response induced by titanium dioxide nanoparticles in mammalian cells, J. Environ. Sci. (China), 85, 94, 10.1016/j.jes.2019.04.024 Weir, 2012, Titanium dioxide nanoparticles in food and personal care products, Environ. Sci. Technol., 46, 2242, 10.1021/es204168d Weir, 2012, Titanium dioxide nanoparticles in food and personal care products, Environ. Sci. Technol., 46, 2242, 10.1021/es204168d Winkler, 2018, Critical review of the safety assessment of titanium dioxide additives in food, J. Nanobiotechnol., 16, 51, 10.1186/s12951-018-0376-8 Xiong, 2011, Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrafish: acute toxicity, oxidative stress and oxidative damage, Sci. Total Environ., 409, 1444, 10.1016/j.scitotenv.2011.01.015 Xiong, 2013, Size of TiO(2) nanoparticles influences their phototoxicity: an in vitro investigation, Arch. Toxicol., 87, 99, 10.1007/s00204-012-0912-5 Xu, 2016, Evaluation of health effect among occupational population exposed to nano-titanium dioxide: a cross-sectional study, Zhonghua Yu Fang Yi Xue Za Zhi, 50, 976 Yamashita, 2011, Silica and titanium dioxide nanoparticles cause pregnancy complications in mice, Nat. Nanotechnol., 6, 321, 10.1038/nnano.2011.41 Yang, 2014, Characterization of food-grade titanium dioxide: the presence of nanosized particles, Environ. Sci. Technol., 48, 6391, 10.1021/es500436x Yang, 2018, Impact of titanium dioxide and Fullerenol nanoparticles on Caco-2 gut epithelial cells, J. Nanosci. Nanotechnol., 18, 2387, 10.1166/jnn.2018.14540 Yin, 2012, Phototoxicity of nano titanium dioxides in HaCaT keratinocytes–generation of reactive oxygen species and cell damage, Toxicol. Appl. Pharmacol., 263, 81, 10.1016/j.taap.2012.06.001 Ze, 2014, Neurotoxic characteristics of spatial recognition damage of the hippocampus in mice following subchronic peroral exposure to TiO2 nanoparticles, J. Hazard. Mater., 264, 219, 10.1016/j.jhazmat.2013.10.072 Zhang, 2017, Effect of oxidative stress from nanoscale TiO2 particles on a Physarum polycephalum macroplasmodium under dark conditions, Environ. Sci. Pollut. Res. Int., 24, 17241, 10.1007/s11356-017-9484-5 Zhang, 2018, Nano-sized TiO2 (nTiO2) induces metabolic perturbations in Physarum polycephalum macroplasmodium to counter oxidative stress under dark conditions, Ecotoxicol. Environ. Saf., 154, 108, 10.1016/j.ecoenv.2018.02.012 Zhou, 2021, 231 Ziental, 2020, Titanium dioxide nanoparticles: prospects and applications in medicine, Nanomaterials (Basel), 10, 10.3390/nano10020387 Zijno, 2015, Different mechanisms are involved in oxidative DNA damage and genotoxicity induction by ZnO and TiO2 nanoparticles in human colon carcinoma cells, Toxicol. in Vitro, 29, 1503, 10.1016/j.tiv.2015.06.009