Compendium of the most significant studies with reference to properties, intake, effects.

Grande F, Tucci P. Titanium Dioxide Nanoparticles: a Risk for Human Health? Mini Rev Med Chem. 2016;16(9):762-9. doi: 10.2174/1389557516666160321114341.

Abstract. Titanium dioxide (TiO₂) is a natural oxide of the element titanium with low toxicity, and negligible biological effects. The classification as bio-inert material has given the possibility to normal-sized (>100 nm) titanium dioxide particles (TiO₂-NPs) to be extensively used in food products and as ingredients in a wide range of pharmaceutical products and cosmetics, such as sunscreens and toothpastes. Therefore, human exposure may occur through ingestion and dermal penetration, or through inhalation route, during both the manufacturing process and use.

Fuster E, Candela H, Estévez J, Vilanova E, Sogorb MA. Titanium Dioxide, but Not Zinc Oxide, Nanoparticles Cause Severe Transcriptomic Alterations in T98G Human Glioblastoma Cells. Int J Mol Sci. 2021 Feb 19;22(4):2084. doi: 10.3390/ijms22042084.

Abstract. Alterations to the transcriptome suggests that exposure to titanium dioxide nanoparticles might, potentially, compromise the integrity of the blood brain barrier integrity and cause neuroinflammation.

Murugadoss S, Brassinne F, Sebaihi N, Petry J, Cokic SM, Van Landuyt KL, Godderis L, Mast J, Lison D, Hoet PH, van den Brule S. Agglomeration of titanium dioxide nanoparticles increases toxicological responses in vitro and in vivo. Part Fibre Toxicol. 2020 Feb 26;17(1):10. doi: 10.1186/s12989-020-00341-7.

Abstract. ...We tested two TiO2 NPs with different primary sizes (17 and 117 nm) and prepared ad-hoc suspensions composed of small or large agglomerates with similar dispersion medium composition....Mainly, we observed that large agglomerates of 117 nm TiO2 induced higher pulmonary responses in aspirated mice and blood DNA damage in gavaged mice compared to small agglomerates....

Grasso A, Ferrante M, Zuccarello P, Filippini T, Arena G, Fiore M, Cristaldi A, Conti GO, Copat C. Chemical Characterization and Quantification of Titanium Dioxide Nanoparticles (TiO2-NPs) in Seafood by Single-Particle ICP-MS: Assessment of Dietary Exposure. Int J Environ Res Public Health. 2020 Dec 20;17(24):9547. doi: 10.3390/ijerph17249547. 

Abstract. Since the aquatic environment is highly sensitive to contamination by TiO2-NPs, this work aimed to give a preliminary assessment of the contamination of packaged seafood, where the food additive TiO2 (E171) is not to be intentionally added.

Haynes VN, Ward JE, Russell BJ, Agrios AG. Photocatalytic effects of titanium dioxide nanoparticles on aquatic organisms-Current knowledge and suggestions for future research. Aquat Toxicol. 2017 Apr;185:138-148. doi: 10.1016/j.aquatox.2017.02.012.

Abstract. The purpose of this review is to summarize the current knowledge of the photocatalytic effects of TiO2 nanoparticles on aquatic organisms, discuss the limitations of these studies, and outline environmentally-relevant factors that need to be considered in future experiments.

Wu J, Bosker T, Vijver MG, Peijnenburg WJGM. Trophic Transfer and Toxicity of (Mixtures of) Ag and TiO₂ Nanoparticles in the Lettuce-Terrestrial Snail Food Chain. Environ Sci Technol. 2021 Nov 29. doi: 10.1021/acs.est.1c05006.

Abstract. The increasing application of biosolids and agrochemicals containing silver nanoparticles (AgNPs) and titanium dioxide nanoparticles (TiO₂NPs) results in their inevitable accumulation in soil, with unknown implications along terrestrial food chains.

Jimeno-Romero A, Gwinner F, Müller M, Mariussen E, Soto M, Kohl Y. Sea Bass Primary Cultures versus RTgill-W1 Cell Line: Influence of Cell Model on the Sensitivity to Nanoparticles. Nanomaterials (Basel). 2021 Nov 20;11(11):3136. doi: 10.3390/nano11113136.

Abstract. Data shows that more variables significantly influenced the outcome of toxicity tests when the primary cultures were exposed to the different nanoparticles. Toxicity tests performed in RTgill-W1 were influenced only by exposure time and nanoparticle concentration. The whole data set was integrated in a biological response index to show the overall impact of nanoparticle exposures.

Boland S, Hussain S, Baeza-Squiban A. Carbon black and titanium dioxide nanoparticles induce distinct molecular mechanisms of toxicity. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2014 Nov-Dec;6(6):641-52. doi: 10.1002/wnan.1302.

Abstract. In the present manuscript we discuss the similarities and differences in molecular pathways of toxicity after carbon black (CB) and titanium dioxide (TiO₂) nanoparticle exposures and identify the main toxicity mechanisms induced by these two nanoparticles which may also be indicative for the mode of action of other insoluble nanomaterials.

Onishchenko GE, Erokhina MV, Abramchuk SS, Shaitan KV, Raspopov RV, Smirnova VV, Vasilevskaya LS, Gmoshinski IV, Kirpichnikov MP, Tutelyan VA. Effects of titanium dioxide nanoparticles on small intestinal mucosa in rats. Bull Exp Biol Med. 2012 Dec;154(2):265-70. doi: 10.1007/s10517-012-1928-9.

Abstract. Penetration of titanium dioxide nanoparticles into enterocytes after their administration into isolated loop of rat small intestine was shown in vivo by transmission electron microscopy.

Swidwińska-Gajewska AM, Czerczak S.  Titanium dioxide nanoparticles: occupational exposure limits. Med Pr. 2014;65(3):407-18.

Abstract.  Titanium dioxide nanoparticles are increasingly applied in cosmetics, textiles and plastics as the ultraviolet light blocker. This contributes to a growing occupational exposure to TiO₂ nanoparticles. Nanoparticles are potentially responsible for the most adverse effects of titanium dioxide.

Yamashita K, Yoshioka Y, Higashisaka K, Mimura K, Morishita Y, Nozaki M, Yoshida T, Ogura T, Nabeshi H, Nagano K, Abe Y, Kamada H, Monobe Y, Imazawa T, Aoshima H, Shishido K, Kawai Y, Mayumi T, Tsunoda S, Itoh N, Yoshikawa T, Yanagihara I, Saito S, Tsutsumi Y. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol. 2011 May;6(5):321-8. doi: 10.1038/nnano.2011.41.

Abstract. The increasing use of nanomaterials has raised concerns about their potential risks to human health. Recent studies have shown that nanoparticles can cross the placenta barrier in pregnant mice and cause neurotoxicity in their offspring, but a more detailed understanding of the effects of nanoparticles on pregnant animals remains elusive. Here, we show that silica and titanium dioxide nanoparticles with diameters of 70 nm and 35 nm, respectively, can cause pregnancy complications

E171 is a chemical compound, an ingredient listed in the European Food Additives List as a colour and in the Colour Index International as CI 77891. Its chemical name is Titanium dioxide.

The name defines the structure of the molecule:

• Titanium is a chemical element with symbol Ti and atomic number 22. It is a bright transition metal, silver in color, not very dense and very durable. It is a bright, silver-colored, low-density, high-strength transition metal. Titanium is resistant to corrosion in seawater, aqua regia and chlorine.
• dioxide: This term indicates the presence of two oxygen atoms for each titanium atom present in the compound. The prefix "di-" comes from the Greek word "two", while "-oxide" indicates the presence of oxygen.

The synthesis process takes place in several stages:

• Sol-Gel Method: This method involves the transition of a system from a liquid phase "sol" to a solid phase "gel". The precursors are mixed in a solvent and then the solvent is evaporated slowly to induce the formation of a gel-like diphasic system.
• Hydrothermal/solvothermic methods: These methods involve the use of high temperatures and pressures to dissolve and recrystallize materials and form crystals. The precursors are dissolved in a solvent and the solution is heated in a sealed container; the pressure inside the container increases and the precursors react to form titanium dioxide.
• Template methods: A template is used in these methods to guide the structure of titanium dioxide. The precursors are deposited on the mask and then this is removed, leaving the titanium dioxide structured.
• Microwave method: This method involves the use of microwave radiation to heat the precursors and induce the reaction to form titanium dioxide.

Titanium dioxide (TiO₂) is a polycrystalline chemical compound, titanium oxide obtained from titanium minerals such as rutile, anatase, ilmenite by chlorination, sulphation or pyrolysis. The chemical chlorination process has replaced the obsolete sulphuric acid process. Titanium dioxide must not only be chemically extracted, but also purified, which is done at high temperature.

It occurs in the form of a liquid or ultra-fine white crystalline powder, high specific surface area, odourless, tasteless, stable at room temperature. Good thermal and chemical stability, good catalytic and photocatalytic efficiency, photoactive under UV radiation, anatase structure. In silicone elastomers it has a thermostructuring effect. Its particles have regular arrangements with a reticular structure.

For more information: Titanium dioxide

What it is used for and where

White pigment that creates a white or opaque colouration. It is present in many applications: cosmetics, paints, paper, sunscreens, pharmaceutical additives and is often found in the coatings of medicinal tablets, beverages, and the anti-UV filter in sunscreens.

It is widely used as an additive in the food industry as a bleaching agent (E171).

Titanium dioxide has so far been considered safe and inert.

A brief history on the evolution of scientific studies on the safety of this chemical component.

                                                       2011 - 2016

Titanium dioxide in our everyday life; is it safe? The answer is cautious : "we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure." (1).

Some studies recognize a positive value in the biomedical applications of titanium dioxide (2).

Other studies do not reveal any toxicological problems (3).

In 2016, EFSA gave an opinion with a review on the safety of titanium dioxide (TiO₂, E171) when used as a food additive.
Present Opinion has dealt with the re‐evaluation of the safety of titanium dioxide (TiO₂, E 171) when used as a food additive. From the available data on absorption, distribution and excretion, the EFSA Panel on Food Additives and Nutrient Sources added to Food concluded that the absorption of orally administered TiO₂ is extremely low and the low bioavailability of TiO₂ appears to be independent of particle size. The Panel also concluded that the use of TiO₂ as a food additive does not raise a genotoxic concern. From a carcinogenicity study with TiO₂ in mice and rats, the Panel chose the lowest non-observed adverse effects levels (NOAEL) which was 2,250 mg TiO₂/kg body weight (bw) per day for males from the rat study, the highest dose tested in this species and sex. The Panel noted that possible adverse effects in the reproductive system were identified in some studies conducted with material which was either non‐food‐grade or inadequately characterised nanomaterial (i.e. not E 171). There were no such indications in the available, albeit limited, database on reproductive endpoints for the food additive (E 171). The Panel was unable to reach a definitive conclusion on this endpoint due to the lack of an extended 90‐day study or a multigeneration or extended‐one generation reproduction toxicity study with the food additive (E 171). Therefore, the Panel did not establish an acceptable daily intake (ADI). The Panel considered that, on the database currently available and the considerations on the absorption of TiO₂, the margins of safety (MoS) calculated from the NOAEL of 2,250 mg TiO₂/kg bw per day identified in the toxicological data available and exposure data obtained from the reported use/analytical levels of TiO₂ (E 171) would not be of concern. The Panel concluded that once definitive and reliable data on the reproductive toxicity of E 171 were available, the full dataset would enable the Panel to establish a health‐based guidance value (ADI) (4).

                                                            2017 - 2021

Since 2017, some studies carried out using ultramodern nano techniques (European Synchrotron of Grenoble) attributed to genotoxide genotoxic characteristics.

If Titanium Dioxide is inlaid in the skin, as in the case of tattoos,  additional laboratory-based mass spectrometric methods demonstrated simultaneous transport of organic pigments, heavy metals and titanium from the skin to regional lymph nodes. The toxicity of TiO₂  depends on its speciation (crystal structure) which can be either rutile or the more harmful photocatalytically active anatase. The contribution of tattoo inks to the overall body load on toxic elements, the speciation of TiO₂, and the identities and size ranges of pigment particles migrating from subepidermal skin layers towards lymph nodes have never been analytically investigated in humans before. The average particle size in tattoo inks may vary from 1 µm. Therefore most tattoo inks contain at least a small fraction of particles in the nano range (5).

The deposit of particles leads to chronic enlargement of the respective lymph node and lifelong exposure. With the detection of the same organic pigments and inorganic TiO₂ in skin and lymph nodes, we can provide strong analytical evidence for the migration of pigments from the skin towards regional lymph nodes in humans. So far, this has only been assumed to occur based on limited data from mice and visual observations in humans (6).

This study by 19 researchers at the University of Toulon were coincerned that the daily intake of TiO₂ nanoparticles, as they overcame the normal defenses of the human body, was associated with an increased risk of chronic intestinal inflammation and carcinogenesis (7).

This 2018 study confirmed the relationship between titanium dioxide nanoparticles and the EMT process in colorectal cancer cells (8).

In 2019 this study suggests that ocean acidification would enhance the accumulation of titanium dioxide nanoparticles in edible bivalves and might therefore increase the health risk to seafood consumers (9).

2019 - French law prohibits the use of titanium dioxide (LOI n° 2018-938 du 30 octobre 2018) in the food sector.

2020 - French law. Order of December 21, 2020 suspending the marketing of food products containing the additive E 171 (titanium dioxide - TiO₂).(Arrêté du 21 décembre 2020 portant suspension de la mise sur le marché des denrées contenant l'additif E 171 (dioxyde de titane - TiO₂) - Légifrance (legifrance.gouv.fr) )

The results of this 2021 study indicated long-time dietary intake of TiO₂ particles could induce element imbalance and organ injury. The liver displayed more serious change than other organs, especially under the treatment with TiO₂ NPs. Further research on the oral toxicity of TiO₂ NPs should pay more attention to the health effects of element imbalances using realistic exposure methods (10).

11-6-2020 I wrote to the European Directorate for Health and Food Safety (DG SANTE) reiterating doubts about the safety of parabens and E171 titanium dioxide. Finally, also from this body came the answer that clarifies all doubts:

"Regarding the use of methyl- and propylparaben as excipients in oral medicinal products for human use, I would advise you to look at the information provided by the EMA (European Medicines Agency) at https://www.ema.europa.eu/en/use-methyl-propylparaben-excipients-human-medicinal-products-oral-use This discussion paper deals with methyl- and propylparaben, as these are the parabens predominantly used in oral pharmaceutical formulations. The focus of this paper is on possible endocrine disrupting effects in humans.

Regarding titanium dioxide, the European Food Safety Authority published its opinion on May 6, 2021 and concluded that, based on all available evidence, a concern for genotoxicity cannot be ruled out, and given the many uncertainties, E 171 can no longer be considered safe when used as a food additive. As mentioned in a tweet on the same day, following EFSA's new scientific opinion on the food additive E171, we will propose to ban its use in the EU. https://twitter.com/food_eu/status/1390347410476523521

Regarding medicinal products, the Commission has asked the European Medicines Agency to assess the effect on the use of TiO₂ in medicinal products and the feasibility of alternatives to replace TiO₂, if possible, without impact on the quality, safety and efficacy of medicinal products. A decision will be made by the Commission based on the analysis provided by the Agency."

Now, how long will it be before these ingredients are permanently removed from our medicines?

7-2-2022 The use of Titanium Dioxide (TiO₂ - E171) as a food additive has been banned and is no longer permitted in the EU as a result of Commission Regulation (EU) 2022/63 amending Annexes II and III of Regulation (EC) No. 1333/2008.

The transition period is 6 months and ends on 7 August 2022. Until the end of this transitional period, food produced in accordance with the rules applicable before 7 February 2022 may continue to be placed on the market. After 7 August 2022, foods containing TiO2 may no longer be placed on the EU/NI market, however, foods already on the market may remain on the market until they reach the minimum durability or expiry date.

Unfortunately, titanium dioxide (TiO₂ - E171) continues to be permitted as additive in pharmaceuticals. Unacceptable  decision!

Titanium dioxide studies

Optimal typical characteristics of the commercial product Titanium dioxide

• Molecular Formula: TiO₂ o O₂Ti
• Molecular Weight : 79.865 g/mol
• CAS : 13463-67-7   1317-80-2   1317-70-0   98084-96-9
• UNII    15FIX9V2JP
• EC Number: 236-675-5
• DSSTox Substance ID: DTXSID3021352    DTXSID9050432    DTXSID6052827
• MDL number  MFCD00011269
• PubChem Substance ID   24882641
• InChI=1S/2O.Ti
• InChI Key    GWEVSGVZZGPLCZ-UHFFFAOYSA-N
• SMILES     O=[Ti]=O
• IUPAC dioxotitanium
• ChEBI    32234

Synonyms :

 [TiO2] 100292-32-8 101239-53-6 1025343-79-6 116788-85-3 12000-59-8 12036-20-3 1205638-49-8 1236143-41-1 12701-76-7 12767-65-6 12789-63-8 1309-63-3 1317-70-0 1317-80-2 1344-29-2 13463-67-7 1377807-26-5 1385RN 59 1393678-13-1 1400974-17-5 158518-86-6 1700 White 185323-71-1 185828-91-5 188357-76-8 188357-79-1 195740-11-5 221548-98-7 224963-00-2 234DA 246178-32-5 252962-41-7 37230-92-5 37230-94-7 37230-95-8 37230-96-9 39320-58-6 39360-64-0 39379-02-7 416845-43-7 494848-07-6 494848-23-6 494851-77-3 494851-98-8 500HD 55068-84-3 55068-85-4 552316-51-5 62338-64-1 63B1 White 767341-00-4 859528-12-4 861455-28-9 861455-30-3 866531-40-0 97929-50-5 98084-96-9 A 200 (pigment) A 330 (pigment) AC1L1AA6 Aerolyst 7710 Aerosil P 25 Aerosil P 25S6 Aerosil P 27 Aerosil T 805 Aeroxide® P25 A-Fil A-Fil Cream A-FN 3 AI3-01334 AK 15 (pigment) AKOS015913799 Amperit 780.0 AMT 100 AMT 600 AN-49054 Anatase Anatase (TiO2) Anatase titanium dioxide Atlas white titanium dioxide AUF 0015S austiox Austiox R-CR Austiox R-CR 3 B 101 (pigment) Bayer R-FD 1 bayeri tian Bayertitan Bayertitan A Bayertitan AN 3 Bayertitan R-FD 1 Bayertitan R-FK 21 Bayertitan R-FK-D Bayertitan R-KB 2 Bayertitan R-KB 3 Bayertitan R-KB 4 Bayertitan R-KB 5 Bayertitan R-KB 6 Bayertitan R-U 2 Bayertitan R-U-F Bayertitan R-V-SE 20 Bayertitan T Baytitan bis(oxido)titanium Bistrater L-NSC 200C Blend White 9202 BR 29-7-2 Brookite C 97 (oxide) C.I. 77891 C.I. Pigment White 6 Cab-O-Ti Calcotone White T CCRIS 590 CCRIS 9317 CCRIS 9325 CG-T CHEBI:32234 CI 77891 CI Pigment white 6 CL 310 component of A-Fil Cosmetic Hydrophobic TiO2 9428 Cosmetic Micro Blend TiO2 9228 Cosmetic White C47-5175 Cosmetic White C47-9623 CTK5H9706 C-Weiss 7 C-Weiss 7 [German] D01931 DB09536 dioxido de titanio dioxotitanium dioxyde de titane DTXSID3021352 E 171 EC 215-282-2 EC 236-675-5 EINECS 215-280-1 EINECS 215-282-2 EINECS 236-675-5 Flamenco FT-0645791 Hombikat hombita n Hombitan Hombitan R 101D Hombitan R 610K Horse head a-410 Horse head a-420 Horse head r-710 HSDB 869 I14-43300 I14-43301 I14-45012 J-006053 JR 600A KH 360 KH360 Kronos Kronos 1002 Kronos 2073 Kronos CL 220 Kronos RN 40P Kronos RN 56 Kronos titanium dioxide Levanox White RKB LS-144047 LS-19300 LS-194104 LS-785 MC 50 (oxide) MFCD00011269 NCGC00187590-01 NCI-C04240 NCI-C0424O NSC 15204 NSC15204 NSC-15204 NT 100 (oxide) O2Ti Octahedrite Octahedrite (mineral) Orgasol 1002D White 10 Extra Cos oxido de titanio(IV) P 25 P 25 (oxide) Pigment white 6 R 680 R 830 (mineral) Rayox RO 2 ru na arh 200 Runa ARH 20 Runa ARH 200 Runa rh20 Rutile Rutile (TiO2) Rutile titanium dioxide Rutiox CR S 150 (oxide) s212 Sagenite T-3875 Tichlor Tin dioxide dust Tinoc M 6 TiO2 Tiofine tiona t.d Tiona t.d. Tiona td Tioxide Tioxide AD-M Tioxide A-DM Tioxide A-HR Tioxide R XL Tioxide R.XL Tioxide R-CR Tioxide RHD Tioxide RSM Tioxide R-SM Tipaque Tipaque R 820 Ti-Pure ti-pure r 101 ti-pure r 90 0 Ti-Pure R 900 Ti-Pure R 901 ti-pure r 915 Titafrance Titan White Titandioxid Titandioxid (sweden) Titandioxid [Swedish] Titania Titania paste, reflector Titania paste, transparent Titanic acid anhydride Titanic anhydride Titanic oxide Titanii dioxidum Titanium (IV) oxide TITANIUM DIOXIDE (ANATASE) Titanium dioxide (TiO2) Titanium dioxide (USP) Titanium dioxide [USP] Titanium dioxide P25 Titanium Dioxide Rutile Titanium oxide (JP17) Titanium oxide (TiO2) Titanium oxide (VAN) Titanium oxide, TiO2 Titanium peroxide titanium peroxide Titanium peroxide (TiO2) Titanium White Titanium( cento) oxide Titanium(IV) oxide Titanium(IV) oxide, rutile Titanium(IV)Dioxide Titanox Titanox 2010 Titanox RANC Trioxide(s) Tronox Unitane Unitane 0-110 Unitane 0-220 Unitane o-110 Unitane o-220 Unitane OR Unitane OR 450 unitane or 572 Unitane OR 650 Unitane or-150 Unitane or-340 Unitane or-342 Unitane or-350 Unitane or-540 Unitane or-640 Uniwhite AO Uniwhite KO Uniwhite OR 450 Uniwhite OR 650 WLN: TI O Zopaque Zopaque LDC 

References___________________________________________________________________

(1) Skocaj M, Filipic M, Petkovic J, Novak S. Titanium dioxide in our everyday life; is it safe? Radiol Oncol. 2011 Dec;45(4):227-47. doi: 10.2478/v10019-011-0037-0. 

(2) Fei Yin Z, Wu L, Gui Yang H, Hua Su Y.  Recent progress in biomedical applications of titanium dioxide. Phys Chem Chem Phys. 2013 Feb 28. 

(3) Naya M, Kobayashi N, Ema M, Kasamoto S, Fukumuro M, Takami S, Nakajima M, Hayashi M, Nakanishi J. In vivo genotoxicity study of titanium dioxide nanoparticles using comet assay following intratracheal instillation in rats.   Regul Toxicol Pharmacol. 2012 Feb;62(1):1-6. doi: 10.1016/j.yrtph.2011.12.002. 

(4) Re-evaluation of titanium dioxide (E 171) as a food additive. EFSA Journal 2016;14(9):4545 [83 pp.].

(5) Ines Schreiver, Bernhard Hesse, Christian Seim, Hiram Castillo-Michel, Julie Villanova, Peter Laux, Nadine Dreiack, Randolf Penning, Remi Tucoulou, Marine Cotte & Andreas Luch Synchrotron-based ν-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin  Article | OPEN | Published: 12 September 2017 Scientific Reports 7, Article number: 11395 (2017)  https://doi.org/10.1038/s41598-017-11721-z

(6) Lehner K, Santarelli F, Vasold R, Penning R, Sidoroff A, König B, Landthaler M, Bäumler W. Black tattoos entail substantial uptake of genotoxicpolycyclic aromatic hydrocarbons (PAH) in human skin and regional lymph nodes.  PLoS One. 2014 Mar 26;9(3):e92787. doi: 10.1371/journal.pone.0092787. eCollection 2014.

(7) Sarah Bettini, Elisa Boutet-Robinet, Christel Cartier, Christine Coméra, Eric Gaultier, Jacques Dupuy, Nathalie Naud, Sylviane Taché, Patrick Grysan, Solenn Reguer, Nathalie Thieriet, Matthieu Réfrégiers, Dominique Thiaudière, Jean-Pierre Cravedi, Marie Carrière, Jean-Nicolas Audinot, Fabrice H. Pierre, Laurence Guzylack-Piriou and Eric Houdeau Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon  Sci Rep. 2017; 7: 40373.  doi: 10.1038/srep40373

(8) Setyawati MI, Sevencan C, Bay BH, Xie J, Zhang Y, Demokritou P, Leong DT. Nano-TiO2 Drives Epithelial-Mesenchymal Transition in Intestinal Epithelial Cancer Cells. Small. 2018 Jul;14(30):e1800922. doi: 10.1002/smll.201800922. 

(9) Shi W, Han Y, Guo C, Su W, Zhao X, Zha S, Wang Y, Liu G. Ocean acidification increases the accumulation of titanium dioxide nanoparticles (nTiO2) in edible bivalve mollusks and poses a potential threat to seafood safety. Sci Rep. 2019 Mar 5;9(1):3516. doi: 10.1038/s41598-019-40047-1.

(10) Duan SM, Zhang YL, Gao YJ, Lyu LZ, Wang Y. The Influence of Long-Term Dietary Intake of Titanium Dioxide Particles on Elemental Homeostasis and Tissue Structure of Mouse Organs. J Nanosci Nanotechnol. 2021 Oct 1;21(10):5014-5025. doi: 10.1166/jnn.2021.19351.