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      Titanium dioxide in our everyday life; is it safe?

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          Abstract

          Background

          Titanium dioxide (TiO 2) is considered as an inert and safe material and has been used in many applications for decades. However, with the development of nanotechnologies TiO 2 nanoparticles, with numerous novel and useful properties, are increasingly manufactured and used. Therefore increased human and environmental exposure can be expected, which has put TiO 2 nanoparticles under toxicological scrutiny. Mechanistic toxicological studies show that TiO 2 nanoparticles predominantly cause adverse effects via induction of oxidative stress resulting in cell damage, genotoxicity, inflammation, immune response etc. The extent and type of damage strongly depends on physical and chemical characteristics of TiO 2 nanoparticles, which govern their bioavailability and reactivity. Based on the experimental evidence from animal inhalation studies TiO 2 nanoparticles are classified as “possible carcinogenic to humans” by the International Agency for Research on Cancer and as occupational carcinogen by the National Institute for Occupational Safety and Health. The studies on dermal exposure to TiO 2 nanoparticles, which is in humans substantial through the use of sunscreens, generally indicate negligible transdermal penetration; however data are needed on long-term exposure and potential adverse effects of photo-oxidation products. Although TiO 2 is permitted as an additive (E171) in food and pharmaceutical products we do not have reliable data on its absorption, distribution, excretion and toxicity on oral exposure. TiO 2 may also enter environment, and while it exerts low acute toxicity to aquatic organisms, upon long-term exposure it induces a range of sub-lethal effects.

          Conclusions

          Until relevant toxicological and human exposure data that would enable reliable risk assessment are obtained, TiO 2 nanoparticles should be used with great care.

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          Most cited references217

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          Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties.

          Nanomaterials (NM) exhibit novel physicochemical properties that determine their interaction with biological substrates and processes. Three metal oxide nanoparticles that are currently being produced in high tonnage, TiO(2), ZnO, and CeO(2), were synthesized by flame spray pyrolysis process and compared in a mechanistic study to elucidate the physicochemical characteristics that determine cellular uptake, subcellular localization, and toxic effects based on a test paradigm that was originally developed for oxidative stress and cytotoxicity in RAW 264.7 and BEAS-2B cell lines. ZnO induced toxicity in both cells, leading to the generation of reactive oxygen species (ROS), oxidant injury, excitation of inflammation, and cell death. Using ICP-MS and fluorescent-labeled ZnO, it is found that ZnO dissolution could happen in culture medium and endosomes. Nondissolved ZnO nanoparticles enter caveolae in BEAS-2B but enter lysosomes in RAW 264.7 cells in which smaller particle remnants dissolve. In contrast, fluorescent-labeled CeO(2) nanoparticles were taken up intact into caveolin-1 and LAMP-1 positive endosomal compartments, respectively, in BEAS-2B and RAW 264.7 cells, without inflammation or cytotoxicity. Instead, CeO(2) suppressed ROS production and induced cellular resistance to an exogenous source of oxidative stress. Fluorescent-labeled TiO(2) was processed by the same uptake pathways as CeO(2) but did not elicit any adverse or protective effects. These results demonstrate that metal oxide nanoparticles induce a range of biological responses that vary from cytotoxic to cytoprotective and can only be properly understood by using a tiered test strategy such as we developed for oxidative stress and adapted to study other aspects of nanoparticle toxicity.
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            Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm.

            Nanomaterial properties differ from those bulk materials of the same composition, allowing them to execute novel activities. A possible downside of these capabilities is harmful interactions with biological systems, with the potential to generate toxicity. An approach to assess the safety of nanomaterials is urgently required. We compared the cellular effects of ambient ultrafine particles with manufactured titanium dioxide (TiO2), carbon black, fullerol, and polystyrene (PS) nanoparticles (NPs). The study was conducted in a phagocytic cell line (RAW 264.7) that is representative of a lung target for NPs. Physicochemical characterization of the NPs showed a dramatic change in their state of aggregation, dispersibility, and charge during transfer from a buffered aqueous solution to cell culture medium. Particles differed with respect to cellular uptake, subcellular localization, and ability to catalyze the production of reactive oxygen species (ROS) under biotic and abiotic conditions. Spontaneous ROS production was compared by using an ROS quencher (furfuryl alcohol) as well as an NADPH peroxidase bioelectrode platform. Among the particles tested, ambient ultrafine particles (UFPs) and cationic PS nanospheres were capable of inducing cellular ROS production, GSH depletion, and toxic oxidative stress. This toxicity involves mitochondrial injury through increased calcium uptake and structural organellar damage. Although active under abiotic conditions, TiO2 and fullerol did not induce toxic oxidative stress. While increased TNF-alpha production could be seen to accompany UFP-induced oxidant injury, cationic PS nanospheres induced mitochondrial damage and cell death without inflammation. In summary, we demonstrate that ROS generation and oxidative stress are a valid test paradigm to compare NP toxicity. Although not all materials have electronic configurations or surface properties to allow spontaneous ROS generation, particle interactions with cellular components are capable of generating oxidative stress.
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              Towards a definition of inorganic nanoparticles from an environmental, health and safety perspective.

              The regulation of engineered nanoparticles requires a widely agreed definition of such particles. Nanoparticles are routinely defined as particles with sizes between about 1 and 100 nm that show properties that are not found in bulk samples of the same material. Here we argue that evidence for novel size-dependent properties alone, rather than particle size, should be the primary criterion in any definition of nanoparticles when making decisions about their regulation for environmental, health and safety reasons. We review the size-dependent properties of a variety of inorganic nanoparticles and find that particles larger than about 30 nm do not in general show properties that would require regulatory scrutiny beyond that required for their bulk counterparts.
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                Author and article information

                Journal
                Radiol Oncol
                Radiol Oncol
                RADO
                Radiology and Oncology
                Versita, Warsaw
                1318-2099
                1581-3207
                December 2011
                16 November 2011
                : 45
                : 4
                : 227-247
                Affiliations
                [1 ] Jožef Stefan Institute, Department for Nanostructured Materials, Ljubljana, Slovenia
                [2 ] National Institute of Biology, Department for Genetic Toxicology and Cancer Biology, Ljubljana, Slovenia
                Author notes
                Correspondence to: Saša Novak, Jožef Stefan Institute, Department for Nanostructured Materials, Jamova 39, SI-1000 Ljubljana, Slovenia. Phone: +386 1 4773 271; Fax: +386 1 4773 221; E-mail: sasa.novak@ 123456ijs.si

                Disclosure: No potential conflicts were disclosed.

                Article
                rado-45-04-227
                10.2478/v10019-011-0037-0
                3423755
                22933961
                59605576-1904-4d6b-aa74-70485547e35a
                Copyright © by Association of Radiology & Oncology

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 07 October 2011
                : 27 October 2011
                Categories
                Review

                Oncology & Radiotherapy
                applications,toxicity,safety,titanium dioxide,nanoparticles
                Oncology & Radiotherapy
                applications, toxicity, safety, titanium dioxide, nanoparticles

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