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Titanium dioxide and Titanium poisoning

Category: Illness or disabilities

Type

Involuntary

Introduction and description

 
 
 

Titanium dioxide, also known as titanium(IV) oxide or titania, is the naturally occurring oxide of Titanium, chemical formula TiO2. When used as a pigment, it is called titanium white.  It has been used in a wide range of applications, from paint to sunscreen to food colouring.

Titanium dioxide occurs in nature as the minerals rutile, anatase and brookite, but it is mainly sourced from ilmenite ore. This is the most widespread form of titanium dioxide-bearing ore around the world. Rutile is the next most abundant and contains around 98% titanium dioxide in the ore. Anatase and brookite convert irreversibly to the more stable rutile upon heating above temperatures in the range 600–800 °C (1,112–1,472 °F).  The oxides are commercially important ores of Titanium.

Neither Titanium or Titanium dioxide in its natural large granular form as it occurs in minerals appear to be the problem; but Titanium dioxide has started to be used in nanoparticle form.  The following sections describe the problems caused.

Effects

Lung damage

 

Titanium dioxide (TiO2) is one of the most widely used nanomaterials, …. TiO2 is also classified by the International Agency for Research on Cancer (IARC) as a possible human carcinogen. The objectives of this study were to

  • establish a lowest-observed-effect level (LOEL) for nano-scale TiO2,
  • determine TiO2 uptake in the lungs, and
  • estimate toxicity based on physicochemical properties and retention in the lungs.

In vivo lung toxicity of nano-scale TiO2 using varying forms of well-characterized, highly dispersed TiO2 was assessed. Anatase/rutile P25 spheres (TiO2-P25), pure anatase spheres (TiO2-A), and anatase nanobelts (TiO2-NB) were tested. …. [there was] abundant TiO2 inclusions in all exposed animals, …. TiO2-NB displayed .. a significant degree of inflammation …. TiO2 particles had not cleared from alveolar macrophages recovered from the lung. Histological examination showed TiO2-NB produced cellular changes at d 1 that were still evident at d 7. PMID:  24156719

Cystic fibrosis

Nanoparticles in general exacerbate the problems people with cystic fibrosis suffer, but this study shows the specific effects Titanium dioxide nanoparticles have:

Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. ……Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation [in mice]. ….. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. ….. … and provides potential mechanisms for the increased susceptibility of CF patients to air pollution. PMID:  24758489

Throat inflammation and cancer

 Given that titanium dioxide is found in lipsticks, and some sunscreens both of which could be ingested the following is serious:

 

Ultrafine titanium dioxide (TiO(2)) particles have been shown to exhibit strong cytotoxicity when exposed to UVA radiation, but are regarded as a biocompatible material in the absence of photoactivation.
In contrast to this belief, the present results indicate that anatase-sized (10 and 20 nm) TiO(2) particles in the absence of photoactivation, induced oxidative DNA damage, lipid peroxidation, and micronuclei formation, and increased hydrogen peroxide and nitric oxide production in BEAS-2B cells, a human bronchial epithelial cell line.
However, the treatment with anatase-sized (200 and >200 nm) particles did not induce oxidative stress in the absence of light irradiation; it seems that the smaller the particle, the easier it is for the particle to induce oxidative damage. The photocatalytic activity of the anatase form of TiO(2) was reported to be higher than that of the rutile form.
In contrast to this notion, the present results indicate that rutile-sized 200 nm particles induced hydrogen peroxide and oxidative DNA damage in the absence of light but the anatase-sized 200nm particles did not. In total darkness, a slightly higher level of oxidative DNA damage was also detected with treatment using an anatase-rutile mixture than with treatment using either the anatase or rutile forms alone.
These results suggest that intratracheal instillation of ultrafine TiO(2) particles may cause an inflammatory response.  PMID: 15970370

 Immune system destruction leading to Bacterial infection

 

In this study, we investigated the effects of TiO2 NPs on HLE B-3 cells with or without ultraviolet B (UVB) irradiation in vitro.
We found that TiO2 NPs can inhibit HLE [human leukocyte elastase] B-3 cell growth, cause the elevation of intracellular [Ca(2+)], produce excessive reactive oxygen species (ROS), further reduce Ca(2+)-ATPase activity and decrease the expression of plasma membrane calcium ATPase 1 (PMCA1), finally disrupt the intracellular calcium homeostasis and induce cell damage.
Importantly, UVB irradiation can apparently enhance these effects on HLE B-3 cells in the presence of TiO2 NPs. Taken together, the generation of excessive ROS and the disruption of intracellular calcium homeostasis may be both involved in TiO2 nanoparticle-induced HLE B-3 cell damage under UVB irradiation.  PMID: 25059545

Neutrophil elastase is an important protease enzyme that when expressed aberrantly can cause emphysema or emphysematous changes. This involves breakdown of the lung structure and increased airspaces. Mutations of the ELANE gene cause severe congenital neutropenia, which is a failure of neutrophils to mature.  In essence, we destroy our immune system responses Secreted by neutrophils and macrophages during inflammation, it also destroys bacteria, as such a lack of this enzme causes bacterial infection.

Skin cancer and damage

It has been known for more than 30 years that in the presence of titanium dioxide, ultraviolet light will decompose water into its constituent elements.  This has important implications, as we are largely water based organisms with every cell water filled. 
“Eight percent of the total different electromagnetic radiation that regularly irradiates the earth is classified as ultraviolet (UV) radiation. The ozone layer absorbs the most energetic UV rays; consequently, UV-A and UV-B reach the earth surface. UV-A rays heavily contribute to both premature skin aging and skin cancer, while UV-B rays cause sunburn”. 

But using sunscreen with titanium dioxide, especially nanoparticle titanium dioxide which enters the cells is more likely to make it worse.  There may be cell death, there may even be blistering.

Cell death, DNA damage and cancer

 

Titanium dioxide nanoparticles (TiO(2)-NPs) are produced in large quantities, raising concerns about their impact for human health.
The aim of this study was to deeply characterize TiO(2)-NPs genotoxic potential to lung cells, and to link genotoxicity to physicochemical characteristics, e.g., size, specific surface area, crystalline phase.
A549 cells were exposed to a panel of TiO(2)-NPs with diameters ranging from 12 to 140 nm, either anatase or rutile. A set of complementary techniques (comet and micronucleus assays, gamma-H2AX immunostaining, 8-oxoGuanine analysis, H2-DCFDA, glutathione content, antioxidant enzymes activities) allowed us to demonstrate that small and spherical TiO(2)-NPs, both anatase and rutile, induce single-strand breaks and oxidative lesions to DNA, together with a general oxidative stress.
Additionally we show that these NPs impair cell ability to repair DNA, by inactivation of both NER and BER pathways. This study thus confirms the genotoxic potential of TiO(2)-NPs, which may preclude their mutagenicity and carcinogenicity. PMID: 21995316

The following study is for Titanium :

Titanium (Ti) and its alloys are used for implants and other dental materials. In this study, cytotoxicity, DNA damage, cellular uptake and size of three kinds of Ti particles were measured.  Cytotoxicity for Ti microparticles (Ti-MPs, <44 μm), NiTi microparticles (NiTi-MPs, <44 μm), and Ti nanoparticles (Ti-NPs, <100 nm) in (PDL)-hTERT cells was measured ……………….The highest cellular uptake was observed with Ti-NPs, followed by Ti-MPs and NiTi-MPs. Only Ti-NPs were found in the nucleus. PMID:  25910990

Blood circulatory system disorders

One can have what are called ‘Faceted nanomaterials’ or ‘spherical nanomaterials’. The facets are capable of eliciting strong interactions with biological systems.

 

In the present study, the toxicological role of the crystallographic facets of faceted TiO2 nanomaterials was investigated… A series of faceted TiO2 nanocrystals with the morphology of truncated octahedral bipyramid were prepared to expose different percentages of {101} and {001} facets on the surface. Density function theory calculation revealed that {101} facets could only molecularly absorb water molecules while {001} facets due to their surface unsaturated Ti atoms could dissociate the absorbed water molecules to generate hydroxyl radicals.
Biophysical assessments corroborated the increased production of hydroxyl radicals on the {001} facets compared to {101} facets, which endowed {001} facets with strong hemolytic activity and enable to elicit severe toxicities. A series of increased oxidative stress toxicological responses, including cellular ROS production, heme oxygenase-1 expression, cellular GSH depletion and mitochondrial dysfunctions, were triggered by faceted TiO2 nanocrystals with progressively increased {001} percentages, demonstrating the toxicological roles of {001} facets. PMID:  27176653

Intestine disease

Titanium dioxide has a long-standing use as a food additive. Micrometric powders are, e.g., applied as whiteners in confectionary or dairy products. Possible hazards of ingested nanometric TiO(2) particles for humans and the potential influence of varying specific surface area (SSA) are currently under discussion.
Five TiO(2)-samples were analyzed for purity, crystallinity, primary particle size, SSA, ζ potential, and aggregation/agglomeration. Their potential to induce cytotoxicity, oxidative stress, and DNA damage was evaluated in human intestinal Caco-2 cells. Only anatase-rutile containing samples, in contrast to the pure anatase samples, induced significant LDH leakage or mild DNA damage (Fpg-comet assay). Evaluation of the metabolic competence of the cells (WST-1 assay) revealed a highly significant correlation between the SSA of the anatase samples and cytotoxicity. The anatase/rutile samples showed higher toxicity per unit surface area than the pure anatase powders. However, none of the samples affected cellular markers of oxidative stress. Our findings suggest that both SSA and crystallinity are critical determinants of TiO(2)-toxicity toward intestinal cells.  PMID:  22263745

Inflammation

 

This study explores titanium dioxide, one of the most widely manufactured nanomaterials, synthesized into its three most common nanoarchitectures:
 - anatase (7-10 nm),
 - rutile (15-20 nm), and
 - nanotube (10-15 nm diameters, 70-150 nm length).
The fully human autologous MIMIC immunological construct has been utilized as a predictive, nonanimal alternative to diagnose nanoparticle immunogenicity. Cumulatively, treatment with titanium dioxide nanoparticles in the MIMIC system led to elevated levels of proinflammatory cytokines and increased maturation and expression of costimulatory molecules on dendritic cells. Additionally, these treatments effectively primed activation and proliferation of naive CD4(+) T cells in comparison to dendritic cells treated with micrometer-sized (>1 microm) titanium dioxide, characteristic of an in vivo inflammatory response.  PMID: 19769402

Yellow nail syndrome

Yellow nail syndrome is characterized by nail changes, respiratory disorders, and lymphedema. In a yellow nail patient with a skeletal titanium implant and with gold in her teeth, we found high levels of titanium in nail clippings. This study aims to examine the possible role of titanium in the genesis of the yellow nail syndrome.
Nail clippings from patients with one or more features of the yellow nail syndrome were analysed by energy dispersive X-ray fluorescence. Titanium was regularly found in finger nails in patients but not in control subjects. Visible nail changes were present in only half of the patients. Sinusitis with postnasal drip and cough was the most common complaint.
The dominant source of titanium ions was titanium implants in the teeth or elsewhere. The titanium ions were released through the galvanic action of dental gold or amalgam or through the oxidative action of fluorides. In other patients the titanium was derived from titanium dioxide in drugs and confectionary. Stopping galvanic release of titanium ions or canceling exposure to titanium dioxide led to recovery. In one patient with a titanium implant, the symptoms recurred after renewed exposure to titanium. Yellow nail syndrome is caused by titanium.  PMID: 20809268

Environmental problems

There are very very significant effects of Titanium dioxide nanoparticles on the environment.

Fresh Water based environments

In the first paper, it helps to know that Daphnia is a small planktonic crustacean that inhabits a variety of freshwater environments and is broadly distributed throughout the world.  It is widely used in ecological and evolutionary studies, and in ecotoxicology, principally because if it were to disappear, so would fish, as fish eat them and also they are a good indicator species.

In the present study, a comprehensive toxicity assessment of anatase and rutile NPs (individual as well as a binary mixture) has been carried out in a freshwater matrix on Ceriodaphnia dubia under different irradiation conditions viz., visible and UV-A.
Anatase and rutile NPs produced an LC50 of about 37.04 and 48mg/L, respectively, under visible irradiation. However, lesser LC50 values of about 22.56 (anatase) and 23.76 (rutile) mg/L were noted under UV-A irradiation. A toxic unit (TU) approach was followed to determine the concentrations of binary mixtures of anatase and rutile. The binary mixture resulted in an antagonistic and additive effect under visible and UV-A irradiation, respectively…..Maximum uptake was noticed at 0.25 total TU of the binary mixture under visible irradiation and 1 TU of anatase NPs for UV-A irradiation. Individual NPs showed highest uptake under UV-A than visible irradiation. PMID:  27522033

Put simply nanoparticles kill Daphne.  So from this paper we can see that Titanium dioxide kills the Daphne on which many freshwater fish live.  From the next paper it appears the nanoparticles also damage or kill the fish themselves:

Mammalian and in vitro studies have raised concerns about the toxicity of titanium dioxide nanoparticles (TiO2 NPs), but there are very limited data on ecotoxicity to aquatic life. This paper is an observational study where we aim to describe the toxicity of TiO2 NPs to the main body systems of rainbow trout. … Exposure to TiO2 NPs caused some gill pathologies including oedema and thickening of the lamellae. No major haematological or blood disturbances were observed in terms of red and white blood cell counts, haematocrit values, whole blood haemoglobin, and plasma Na+ or K+ concentrations. Tissue metal levels (Na+, K+, Ca2+ and Mn) were generally unaffected. However, some exposure concentration-dependent changes in tissue Cu and Zn levels were observed, especially in the brain. Exposure to TiO2 NPs caused statistically significant decreases in Na+K+-ATPase activity (ANOVA, P<0.05) in the gills and intestine, and a trend of decreasing enzyme activity in the brain…… PMID:  17727975

Soil based environments

Soils are exposed to nanoparticles (NPs) as a result of their increasing use in many commercial products. Adverse effects of NPs on soil microorganisms have been reported in several ecotoxicological studies using microcosms. …. Using a soil column experiment, we compared the influence of single and repeated exposures (one, two, or three exposures that resulted in the same final concentration applied) on the transport of titanium dioxide (TiO2) NPs through soil and the effect of these different exposure scenarios on the abundance and activity of soil nitrifying microbial communities after a 2 month incubation. ….. Significant decreases in nitrification activity and ammonia-oxidizing archaea and bacteria populations were observed only for the repeated exposure scenario (three TiO2 NP contaminations). PMID:  27589234

Salt water based environments

Increased manufacture of TiO2 nanoproducts has caused concern about the potential toxicity of these products to the environment and in public health. .. To this end, we examined the significance of the release of these particles and their toxic effect on the marine diatom algae Thalassiosira pseudonana. Our results indicate that nano-TiO2 sunscreen and toothpaste exhibit more toxicity in comparison to industrial TiO2 and inhibited the growth of the marine diatom T. pseudonana. This inhibition was proportional to the exposure time and concentrations of nano-TiO2. PMID:  27596588

Causes

The following lists some of the applications of Titanium and Titanium dioxide – not just the nanoparticles – in areas where there is a likelihood of high human contact or consumption.  There are many more applications being considered than just these outside direct human contact which could affect the environment.

Food

 

Titanium dioxide is the most widely used white pigment because of its brightness and very high refractive index, in which it is surpassed only by a few other materials. Approximately 4.6 million tons of pigmentary TiO2 are used annually worldwide.  In general it is used to provide whiteness and opacity to products such as paints, coatings, plastics, papers and inks, but it has been used in food.  When used as a food colouring, it has E number E171.

Titanium dioxide “has been shown statistically to increase skimmed milk's whiteness, increasing skimmed milk's sensory acceptance score” [sic]. 

Food grade TiO2 (E171) is a synthetic additive, and widely used as a colouring agent in many foods, pharmaceutical and personal care products. A few reports have highlighted that insoluble particulates (less than 200nm) of food grade TiO2 are found in many foods and confectionary products. However, information regarding the physico-chemical properties (i.e., size and shape)-based food grade TiO2 nanotoxicity related human health issues are limited. The main goal of this study is to examine the presence of nano-sized particulates and its structural characteristics of food grade- TiO2 materials and to assess the acute cellular uptake and metabolic stress induced by these particulates in human lung fibroblast (WI-38) cells. The results of transmission electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction studies indicated that about food grade TiO2 sample contains spherical shaped particulate forms in the nano-scale range, <100nm. The intracellular oxidative stress in human lung fibroblast cells (WI-38) was assessed through studies investigating the cellular uptake of the particles, changes in nuclear and cytoplasmic morphology, intracellular ROS, mitochondrial trans-membrane potential, the cell cycle and the expression of genes linked to metabolic stress markers. Altogether our data clearly indicate that primary metabolic stress indicators such as changes in the intracellular ROS, the dose-dependent loss of the mitochondrial membrane potential, alterations in cell cycle progression (G2/M>S>G0/G1) and changes in the TNF and CYP1A gene expression pattern are linked to cellular stress. Thus, food grade TiO2 as nano-scaled contaminants could not only be potential human health risk factors, suggesting that safety considerations with special respect to a few crucial factors such as size, and shape should be considered and regulated by food regulators. PMID:  25528408

Tattoos

Titanium dioxide is used as a tattoo pigment and in styptic pencils.  It is unknown whether nanoparticles have been used, but as we have seen in the presence of Ultra violet light it matters not whether the particles are nanoparticles or not, damage will occur.

Sunscreen and UV blocking pigments

In cosmetic and skin care products, titanium dioxide is used as a pigment, sunscreen and a thickener. Titanium dioxide is produced in varying particle sizes, oil and water dispersible, and in certain grades for the cosmetic industry.
Titanium dioxide is found in the majority of physical sunscreens.  Nano-scaled (particle size of 30-40 nm) titanium dioxide particles are also used in sun screen lotion because “they scatter visible light less than titanium dioxide pigments while still providing UV protection.”

 

Titanium dioxide and zinc oxide nanoparticles are being increasingly formulated in sunscreens. While the same compounds, in larger particle form, work by reflecting UV radiation, in nanoparticle form, they absorb UV radiation, resulting in photocatalysis, releasing reactive oxygen species. These reactive oxygen species are known to have the capability to alter DNA. Previous studies suggest that this photocatalytic process may not be significant, because the nanoparticles do not penetrate below the level of the stratum corneum. However, some recent studies suggest that nanoparticles may, under certain circumstances, breach that barrier. PMID:  21332685

Cosmetics

Some grades of titanium based pigments as used in pearlescent cosmetics.  Although the descriptions of the process used, is at best convoluted, these pigments are  man-made pigments whose particles have two or more layers of various oxides – often titanium dioxide, iron oxide or alumina – in order to have glittering, iridescent and or pearlescent effects similar to crushed mica.   “In some products, the layer of titanium dioxide is grown in conjunction with iron oxide by calcination of titanium salts (sulfates, chlorates) …on substrates such as mica platelets or even silicon dioxide crystal platelets of no more than 50 µm in diameter. The iridescent effect in these titanium oxide particles is unlike the opaque effect obtained with usual ground titanium oxide pigment obtained by mining, in which case only a certain diameter of the particle is possible and the effect is due only to scattering”.

Titanium dioxide is added to lipstick simply because it has ‘superb covering power’.  A typical lipstick contains 10%, although this can vary.  Lighter shades require more in order to dilute the intensity of the red dyes.

Dental implants and braces

 

Titanium and Titanium alloys are widely used in orthopaedic, dental and other implants, including  fractural fixation devices – plates and screws – and spinal, hip and knee replacements.  Generally speaking they are well tolerated by most patients, but they can degrade by mechanical wear to produce particles or by physiochemical or cell mediated corrosion to produce Ti ions.  Needless to say the end result is inflammation.  Once the particles have been released into the blood stream or lymph nodes, they are potentially toxins.

The aim of this study was to measure titanium (Ti) content in human jawbones and to show that Ti was released from dental implants inserted into these jawbones.  Seven samples from four human subjects with dental implants were analysed as test group and six bone samples of similar topographical regions from six human subjects without implants served as control.
… In the test group the Ti content was significantly higher compared to control group. … The highest Ti content detected in human mandibular bone was 37,700μg/kg-bone weight. … increased Ti intensity was also detected … in human mandibular tissues at a distance of 556-1587μm from implants, and the intensity increased with decreasing distance from implants.  Particles with sizes of 0.5-40μm were found in human jawbone marrow tissues at distances of 60-700μm from implants.  PMID:  27298240

It is worth adding that the nickel in these products, which is toxic, may be as hazardous as the Titanium:

Significant differences in comparison to the control group were found for Cu in the orthodontic group, and for Ni in both, orthodontic and orthodontic+miniscrew groups. [PMID: 26302907]

Titanium binds to transferrin, and in turn can bind to blood lymphocytes.  Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids.  A lymphocyte is one of the subtypes of white blood cell in a vertebrate's immune system. Lymphocytes include natural killer cells (NK cells) (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adaptive immunity), and B cells (for humoral, antibody-driven adaptive immunity). They are the main type of cell found in lymph, which prompted the name lymphocyte.

 

This may explain the blood circulatory system disease and immune system problems.

Metal release is particularly high under acidic conditions and the resulting Ti binds to both small and large serum proteins.  Where the resulting compound is Ti citrate, damage to erythrocytes can result and ‘may do the same to other cell types’Red blood cells (RBCs), also called erythrocytes, are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen (O2) to the body tissues—via blood flow through the circulatory system.

A number of studies have reported increased Ti levels in serum, urine and even hair in experimental animals and in patients with Ti implants, even with well functioning implants…. In other work, both particles and ions migrated to distant tissues.  Reports suggest that Ti metal accumulation in the lungs and lymph nodes, and chronic exposure may cause pulmonary granulomatous disease”.

Particle size was shown to affect the cytotoxicity of Ti released.  Ti particles smaller than cells were determined to be toxic, whereas particles larger than cells were considered to be ‘safer’.

It is worth adding that Titanium biomaterials are highly thrombogenic – clot producing, which brings us onto stents.

Stents

 

Polymer-coated drug-eluting stents (DESs) have become one of the treatments for patients undergoing percutaneous coronary interventions. Although these stents are effective in the sense that they reduce the restenosis rate and the need for repeat intervention by 70% compared with bare-metal stents, concerns have been raised about a series of risks closely related to the metal mesh of the stent and the polymer coating. Thus, in recent years, interest has been renewed in alternative strategies and technologies to promote repair mechanisms after stent implantation.

In general, a DES consists of a platform (made from different alloys) that acts as a scaffold for the vessel, a polymer coating (hardwearing and bioabsorbable) that includes certain copolymers to confer the desired degree of thromboresistance and hemocompatibility on the stent, and the drug which is released to provide the antiproliferative properties of the device.

Most stents are built on a stainless steel platform, the least-expensive stent material available. Unfortunately, stainless steel is not fully compatible with the human body and implantation usually is followed closely by restenosis and thrombosis. In addition, stainless steel can pose difficulties related to some types of imaging, such as magnetic resonance. As such, researchers have developed alternative platform materials such as gold, cobalt-chromium alloy, tantalum alloy, nitinol, several types of polymer and TitaniumNitinol is 55% nickel and 45% titanium, Nickel is a toxic substance so it is unclear why this is being used.

It is worth pointing out that the whole area of stents is under discussion, with some questioning why metal has to be used at all “Fully bioresorbable vascular devices would seem to be a promising alternative, as they allow the vasomotor response and pulsatility of the coronary artery segment to be restored after reabsorption (at approximately 2 years) once the vulnerable or ruptured plaque has been sealed”.  It also avoids the need for immunosuppressants.

Collagen, for example, is very biocompatible and reduces the rate of restenosis and thrombosis.

Pharmaceuticals

Titanium dioxide is employed as a pigment to provide whiteness to medicines i.e. pills and tablets.  It is unknown whether nanoparticles have been used.

Toothpaste

Titanium dioxide is used as a pigment to provide whiteness to toothpaste.  It is unknown whether nanoparticles have been used.

References and further reading

  •  
    J Toxicol Environ Health A. 2013;76(16):953-72. doi: 10.1080/15287394.2013.826567.  Biological response to nano-scale titanium dioxide (TiO2): role of particle dose, shape, and retention.  Silva RM1, Teesy C, Franzi L, Weir A, Westerhoff P, Evans JE, Pinkerton KE.  1a Center for Health and the Environment , University of California Davis , Davis , California , USA.
  • Photochem Photobiol. 2014 Nov-Dec;90(6):1324-31. doi: 10.1111/php.12322. Epub 2014 Sep 9.  UVB irradiation enhances TiO2 nanoparticle-induced disruption of calcium homeostasis in human lens epithelial cells.  Wu Q1, Guo D, Du Y, Liu D, Wang D, Bi H.
  • Nanotoxicology. 2016 Aug 24:1-7. [Epub ahead of print]  Quantity and quality of natural organic matter influence the ecotoxicity of titanium dioxide nanoparticles.  Seitz F1,2, Rosenfeldt RR1,2, Müller M1, Lüderwald S1, Schulz R1, Bundschuh M1,3.
  • ACS Nano. 2016 May 13. [Epub ahead of print]  Crystallographic Facet-Induced Toxicological Responses by Faceted Titanium Dioxide Nanocrystals.  Liu N, Li K, Li X, Chang Y, Feng Y, Sun X, Cheng Y, Wu Z, Zhang H.
  • Aquat Toxicol. 2016 Sep;178:209-21. doi: 10.1016/j.aquatox.2016.08.007. Epub 2016 Aug 9.  Individual and binary toxicity of anatase and rutile nanoparticles towards Ceriodaphnia dubia.  Iswarya V1, Bhuvaneshwari M1, Chandrasekaran N1, Mukherjee A2.
  • Dent Mater. 2015 Jun;31(6):734-44. doi: 10.1016/j.dental.2015.03.017. Epub 2015 Apr 21.  Intracellular uptake and toxicity of three different Titanium particles.  He X1, Hartlieb E2, Rothmund L1, Waschke J2, Wu X3, Van Landuyt KL4, Milz S5, Michalke B6, Hickel R7, Reichl FX1, Högg C8.
  • Dent Mater. 2016 Aug;32(8):1042-51. doi: 10.1016/j.dental.2016.05.012. Epub 2016 Jun 11.  Analysis of titanium and other metals in human jawbones with dental implants - A case series study.  He X1, Reichl FX1, Wang Y1, Michalke B2, Milz S3, Yang Y1, Stolper P4, Lindemaier G5, Graw M5, Hickel R6, Högg C7.
  • Environ Toxicol Pharmacol. 2015 Jan;39(1):176-86. doi: 10.1016/j.etap.2014.11.021. Epub 2014 Dec 5. Identification of titanium dioxide nanoparticles in food products: induce intracellular oxidative stress mediated by TNF and CYP1A genes in human lung fibroblast cells.  Periasamy VS1, Athinarayanan J1, Al-Hadi AM1, Juhaimi FA1, Mahmoud MH2, Alshatwi AA3.
  •  Environ Sci Technol. 2014 Jun 17;48(12):6965-72. doi: 10.1021/es405396a. Epub 2014 Jun 3.  Heavy metal uptake and toxicity in the presence of titanium dioxide nanoparticles: a factorial approach using Daphnia magna.  Rosenfeldt RR1, Seitz F, Schulz R, Bundschuh M.
  • J Trace Elem Med Biol. 2015 Oct;32:13-20. doi: 10.1016/j.jtemb.2015.05.001. Epub 2015 May 21.  In vivo determination of aluminum, cobalt, chromium, copper, nickel, titanium and vanadium in oral mucosa cells from orthodontic patients with mini-implants by Inductively coupled plasma-mass spectrometry (ICP-MS).  Martín-Cameán A1, Jos A2, Puerto M2, Calleja A3, Iglesias-Linares A4, Solano E1, Cameán AM5.
  • Biol Trace Elem Res. 2011 Oct;143(1):1-7. doi: 10.1007/s12011-010-8828-5. Epub 2010 Sep 1.  Titanium, sinusitis, and the yellow nail syndrome. Berglund F1, Carlmark B.
  • Chem Res Toxicol. 2012 Mar 19;25(3):646-55. doi: 10.1021/tx200334k. Epub 2012 Feb 10.  Distinctive toxicity of TiO2 rutile/anatase mixed phase nanoparticles on Caco-2 cells.  Gerloff K1, Fenoglio I, Carella E, Kolling J, Albrecht C, Boots AW, Förster I, Schins RP.
  • Nanotoxicology. 2012 Aug;6(5):501-13. doi: 10.3109/17435390.2011.587903. Epub 2011 Oct 13. Titanium dioxide nanoparticles exhibit genotoxicity and impair DNA repair activity in A549 cells.  Jugan ML1, Barillet S, Simon-Deckers A, Herlin-Boime N, Sauvaigo S, Douki T, Carriere M.
  • Toxicology. 2015 Jan 2;327:1-9. doi: 10.1016/j.tox.2014.10.016. Epub 2014 Nov 3.  Release of titanium ions from an implant surface and their effect on cytokine production related to alveolar bone resorption.  Wachi T1, Shuto T1, Shinohara Y1, Matono Y1, Makihira S2.
  • Aquat Toxicol. 2007 Oct 30;84(4):415-30. Epub 2007 Jul 25.  Toxicity of titanium dioxide nanoparticles to rainbow trout (Oncorhynchus mykiss): gill injury, oxidative stress, and other physiological effects.  Federici G1, Shaw BJ, Handy RD.
  • Environ Sci Technol. 2016 Sep 14. [Epub ahead of print]  Combined Study of Titanium Dioxide Nanoparticle Transport and Toxicity on Microbial Nitrifying Communities under Single and Repeated Exposures in Soil Columns.  Simonin M1,2,3,4, Martins JM4,5, Uzu G4,6, Vince E4,5, Richaume A1,2,3.
  • Part Fibre Toxicol. 2014 Apr 24;11:19. doi: 10.1186/1743-8977-11-19.  Biokinetics of nanoparticles and susceptibility to particulate exposure in a murine model of cystic fibrosis.  Geiser M1, Stoeger T, Casaulta M, Chen S, Semmler-Behnke M, Bolle I, Takenaka S, Kreyling WG, Schulz H.
  • Environ Sci Pollut Res Int. 2016 Sep 5. [Epub ahead of print]  Effects of titanium dioxide nanoparticles derived from consumer products on the marine diatom Thalassiosira pseudonana.  Galletti A1, Seo S1, Joo SH2, Su C3, Blackwelder P4.
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