|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Absorbs UVB rays and protects against sunburn, immunosuppression, DNA damage and structural damage to the skin.
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Table of contents:
- 1. Sources
- 2. Skin penetration
- 3. Effects on the skin
- 4. Stability
- 5. Safety
Titanium dioxide, also known as titanium oxide or titania, is a fine white powder that is insoluble in water. Nearly 70% of all titanium dioxide produced is used as a pigment in paints, but it is also a common additive in food and personal care products. Foods with the highest content of titanium dioxide include candies, sweets and chewing gums while among personal care products, sunscreens contain the highest concentrations. Although titanium dioxide occurs in nature as 4 different mineral forms (anatase, rutile, brookite and akaogiite), the titanium dioxide used in sunscreen products are reportedly composed of rutile and anatase, or a mixture of the two.
Older generations of sunscreens contained titanium dioxide as coarse particles and in microcrystalline form. The large particle size had poor spreadability and left a white film on the skin, limiting its cosmetic elegance. As a result, patents on nanosized titanium dioxide were filed in the 1980s, and from the late 1990s onwards nanosized titanium dioxide began to be incorporated into sunscreens on a large scale. The primary particle size of these nanoparticles ranges from 20-100 nm. However, in sunscreen products titanium dioxide is not present in the form of these primary nanoparticles but as aggregates of a size between 30-150 nm.
2. Skin penetration
Extensive testing of coated and uncoated nanoparticles as well as the non-nano form of titanium dioxide under in vitro, ex vivo and in vivo experimental conditions shows that it generally does not penetrate deeply enough into the skin to reach the viable epidermis or dermis. This is despite the evidence demonstrating that titanium dioxide can enter hair follicles and sweat glands.
The stratum corneum is such as effective barrier to titanium dioxide that in one study, >50% stayed on the surface of the skin after 24 hours, and many studies consistently show titanium dioxide to be restricted to the topmost layers of the stratum corneum. As a result, it is possible to remove virtually all of the applied titanium dioxide from the skin surface by washing with soap. A few reports suggest that titanium dioxide particles may penetrate beyond the stratum corneum, but the amounts are very small and may not be statistically significant.
One study indicated that titanium dioxide nanoparticles can achieve transdermal penetration of mouse skin after prolonged dermal exposure (60 days), in this study some mice were housed in groups of up to 6, which could have allowed the animals to lick the skin of other mice, leading to oral exposure.
Skin that has been damaged by sunburn, hair removal, laser treatment or tape-stripping allows for deeper penetration of titanium dioxide and greater skin deposition, but even then there is still no evidence of transdermal absorption, A similar effect was seen with psoriatic skin, where titanium dioxide nanoparticles permeated into deeper areas of the stratum corneum yet failed to reach living cells.
Interestingly however, exposure to sunlight alone may increase the skin uptake of nano-sized titanium dioxide. One study has demonstrated that absorption of light provides sufficient energy to partially disaggregate titanium nanoparticles, releasing small particles that readily diffused through the dermal profile of pig skin, likely via interstitial spaces. After 90 minutes of light exposure, 0.1% of the applied dose had permeated through the skin.
Encapsulation of microfine titanium oxide particles into liposomes also enables a higher penetration depth of the particles into the skin, whereas the addition of ascorbic acid to titanium oxide formulations enhances the deposition of titanium dioxide on the skin surface without increasing their permeation through the skin layers, possibly by increasing the solubility of the mineral.
3. Effects on the skin
Titanium dioxide is an inorganic sunscreen that has good UV blocking power. It works mainly through UV absorption, with its scattering and reflecting mechanisms significant only in the bands where it absorbs weakly or not at all. It absorbs especially strongly in the wavelengths between 200-300 nm, which includes the UVB spectrum, but absorbs wavelengths longer than 350 nm (long-wave UVA) less strongly.
Sunscreens containing titanium dioxide at varying concentrations and of different particle sizes have demonstrated that it protects against sunburn cell formation, UV-induced immunosuppression, DNA damage, and structural damage. Titanium dioxide also exerted a potent anti-inflammatory effect when tested at its maximum allowable concentration of 25%, which may affect its in vivo SPF value.
Titanium dioxide's UV absorption profile varies depending on the size of its aggregates. It is able to offer both UVA and UVB protection at an average aggregate size of ~100 nm, offers higher UVB but lower UVA protection at an average aggregate size of 50 nm, and offers significantly lower protection from both UVA and UVB radiation at an average aggregate size of 20 nm. More precisely, Monte Carlo simulations indicate that the most attenuating particle size for UV radiation of wavelength 310 nm is a diameter of 62 nm, whereas for 400 nm light a diameter of 122 nm is most protective.
However, a 5% titanium dioxide formulation containing aggregates of 125 nm was still unable to provide the same level of UVA attenuation as formulations containing zinc oxide or photostabilized avobenzone. This result agrees with that of a previous study, which has convincingly shown that zinc oxide provides superior protection against long-wave UVA. The implication is that titanium dioxide cannot be used as a substitute for avobenzone or zinc oxide to confer broad-spectrum protection. On the other hand, titanium dioxide can give a much higher sun protection factor (SPF), owing to its greater UVB absorption.
The UVA:UVB absorption ratio of micronized titanium dioxide can be dramatically increased by manganese doping, which comes with the added advantages of reducing free radical generation rates and the provision of free radical scavenging behaviour. Alternatively, to guarantee a high and balanced UVA + UVB protection, micro-sized titanium dioxide can be combined with micro-sized zinc oxide, which absorbs strongly in the UVA range. Even then, this may still not be sufficient in all cases, as demonstrated by an experiment in which it failed to prevent UVA-specific damage to 2 ex vivo skin models and required the addition of the organic filters Tinosorb M and octinoxate. Stabilizing nano-sized titanium dioxide with a coating and ensuring that the particles are evenly distributed has also been shown to help provide the best UV attenuation.
Compared to conventional titanium dioxide particles, titanium dioxide nanoparticles confer markedly better UVB protection, as shown by its higher SPF value. The combination of octinoxate with both titatnium dioxide and zinc oxide is also able to synergistically improve the SPF of cosmetic preparations.
Adding ascorbic acid to titanium dioxide sunscreens may also be beneficial, as ascorbic acid is capable of increasing the accumulation of titanium dioxide on the skin surface, thereby enhancing its protective efficacy.
3.2 Prevention of photoaging
Since excessive UV exposure is clearly linked to photoaging, it stands to reason that titanium dioxide, which acts as a physical UV blocker, should help prevent photoaging. Indeed, when creams containing titanium dioxide and zinc oxide were topically applied to human skin explants, there was not only a significant decrease in hydroperoxide production, but also an improvement in the elastic fiber and collagen network in the dermis.
Although a later study indicated that 60 days of dermal exposure to 10 nm and 21 nm titanium dioxide nanoparticles led to a reduction of collagen content in mouse skin samples, there was no decrease in the skin of mice treated with 90 nm nanoparticles.
3.3 Antimicrobial and antiparasitic activity
Titanium dioxide nanoparticles have antibacterial effects towards several bacterial species including S. aureus and E. coli, especially when under UV illumination. They also have acaricidal activity against the larvae of R. microplus and the adult of H. bispinosa, 2 species of cattle ticks.
Titanium dioxide is highly stable chemically. Its influence on the photostability of other UV filters has been investigated, revealing that enzacamene, octyl triazone and octocrylene are photostable in its presence even after irradiation with simulated sunlight. Manganese-doped titanium dioxide seems to photostabilize organic UVA absorbers such as avobenzone as well. Titanium dioxide may even be beneficial in protecting photolabile drugs like ketoprofen against sunlight.
Uncoated and un-doped titanium dioxide is known to be photocatalytic in UV light. The anatase form in particular has been shown to be significantly more toxic than anatase-rutile mixtures, which is in turn more reactive than rutile. If photocatalytic nano-TiO2 is present in a sunscreen, it can potentially lead to the generation of reactive oxygen species (ROS) upon exposure to UV light, which have adverse effects on the skin. However, the relevance of titanium dioxide's photocatalytic activity is doubtful considering the absence of dermal penetration and the fact that coatings dramatically reduce photocatalytic activity. For instance, the photocatalytic activity of titanium dioxide when coated with 3.5% silicon dioxide and aluminium oxide is reduced to just 1% of that found in uncoated titanium dioxide.
Due to the apparent lack of penetration of titanium dioxide through the skin, the SCCS considers that the use of titanium dioxide in dermally applied cosmetic products should not pose any significant risk to consumers, but does not recommend the use of nano-sized titanium dioxide as powders or sprayable products.
5.1 Adverse skin reactions
Neither coarse nor nano-sized titanium dioxide caused acute dermal toxicity in rodents, and they were also at most weak irritants and sensitizers on animal and human skins. However, titanium dioxide nanoparticles may aggravate the symptoms of atopic dermatitis, as has been shown in a study on mice.
Allergy to titanium dioxide is rare, and seems to be avoidable through coating of the particles. It has been speculated that titanium dioxide may play a role in positive patch test reactions to gold, by adsorbing gold particles in jewelry that occassionally contacts facial skin, but this hypothesis lacks substantiation.
There are indications that titanium dioxide nanoparticles accumulate at the cell surface and are taken up by human keratinocytes and dermal fibroblasts through endocytosis, autophagy or through penetration of the cell membrane. These nanoparticles are then contained as aggregates in vesicles within the cytoplasm. However, short-term exposure of keratinocytes to up to 100 μg/mL of titanium dioxide nanoparticles did not affect cell viability, and long-term exposure to concentrations up to 10 μg/mL did not significantly alter cell morphology or the cell-cycle distribution. Mitochondrial activity was also not affected in this study, but another study provided data that strongly suggested that titanium dioxide nanoparticles can impair the mitochondrial function of keratinocytes, possibly by inducing electron leakage from the regular respiratory chain path, as well as exert other metabolic effects.
5.2 Production of reactive oxygen species
Titanium dioxide is however a well-known photocatalyst. High-energy surface-trapped electron-hole pairs are created on the surface of titanium dioxide after it absorbs a substantial amount of UV radiation. The holes are capable of oxidizing organic molecules, water, hydroxide ions and hydroxyl groups to generate hydroxyl radicals, whereas the electron can reduce O₂ to superoxide radicals. Other reactive oxygen species (ROS) such as H₂O₂ and singlet oxygen, are also formed.
When exposed directly to cultures of skin cells in vitro, the production of ROS by titanium dioxide nanoparticles results in oxidative stress, which in turn damages cellular and subcellular structures and exerts effects on cell viability, mobility, proliferation, differentiation and apoptosis. Titanium dioxide nanoparticles have also been shown to induce the photocatalytic nitration of tyrosine in keratinocytes, which is potentially hazardous.
Fortunately, the potential toxic risks arising from the photocatalytic activity of titanium dioxide can be mitigated by coatings of silicon dioxide, aluminium dioxide and polymers, among others. These materials function by capturing reactive radicals or inhibiting their formation by preventing contact between the surface of titanium dioxide, O₂ and water.
Encapsulation of titanium dioxide nanoparticles within zeolite also protects cells by decreasing the generation of intracellular ROS. Further, additives like sodium ascorbyl phosphate and ascorbyl palmitate exhibit both antiradical and antioxidant activity, and may scavenge the oxidizing species generated by titanium dioxide nanoparticles as well as protect skin lipids against peroxidation.
The majority of tests on the non-nano form of titanium dioxide agree that it is neither mutagenic nor photo-mutagenic, with a few exceptions. For the testing of nanoparticles, bacterial mutagenicity assays are considered less appropriate compared to mammalian cell systems due to the lack of endocytosis by bacterial cells. Hence, here we review only in vitro studies on human skin and lung cells, taking into consideration the 2 dominant routes of exposure (dermal and inhalation) that are relevant for cosmetic products, plus all in vivo studies.
Apart from influencing cellular functions, the reactive oxygen species generated by titanium dioxide under UV illumination can be genotoxic to human skin cells. The ROS and oxidative stress induced by titanium dioxide nanoparticles are thought to lead to oxidative DNA damage such as double-strand breaks and mitochondrial DNA common deletions in human fibroblasts and keratinocytes, respectively. Micronucleus formation, a probable mechanism of genotoxicity, was also observed to be significantly increased in human keratinocytes and epidermal cells. Titanium dioxide nanoparticles have also been demonstrated to activate the ATM-Chk2 DNA damage response pathway in human dermal fibroblasts, providing further evidence of its genotoxicity. In another experiment on human fibroblasts, titanium dioxide did not cause detectable oxidative damage to cellular DNA, but induced significant levels of photooxidation of RNA, as measured by hydroxylation of guanine bases, suggesting that nucleic acids in general are potential targets for oxidative damage sensitized by titanium dioxide.
Titanium dioxide nanoparticles were also genotoxic to human lung cells in vitro, with studies showing that it induced the formation of DNA adducts in human lung fibroblasts, led to chromosomal damage in human lung epithelial cells and in a human lung cancer cell line, and induced single-strand breaks and oxidative lesions in DNA in adenocarcinomic human alveolar basal epithelial cells. They also seem to impair the ability of cells to repair DNA by inactivating the nucleotide excision repair and base excision repair pathways.
Importantly however, titanium dioxide nanoparticles did not exert genotoxic effects in any of 3 in vivo studies in rodents which were exposed to them via inhalation or intratracheal instillation.
Ascorbic acid may act as a anti-mutagenic agent because of its strong antioxidant activity. In fact, it has been shown to significantly reduce sister-chromatid exchanges and micronuclei formation when added to a cell culture medium simultaneously with titanium dioxide. Similarly, dimetylthiourea (DMTU), an OH• radical trapper and N-acetylcysteine (NAC), a glutathione precursor/H₂O₂ scavenger have displayed the potential to ameliorate the cytogenotoxicity induced by titanium dioxide nanoparticles.
Topically applied titanium dioxide does not promote skin carcinogenesis, probably because it is unable to penetrate through the epidermis to reach the underlying skin structures. In fact, microfine titanium dioxide completely protected against UV-induced promotion and complete carcinogenesis of squamous cell carcinoma in an experiment on mice.
Apart from an isolated case report, there is scant epidemiological evidence of human carcinogenicity to titanium dioxide. Detailed surveys of titanium dioxide manufacturing workers consistently indicate that there is no significant link between occupational exposure to titanium dioxide and an increased risk of lung cancer. Yet, the International Agency for Research on Cancer (IARC) Monographs Working Group acknowledges that titanium dioxide may be possibly carcinogenic to humans on the basis of rodent cancer studies. According to their evaluation titanium dioxide induced lung tumours in 2 inhalation studies with rats, but was negative in 2 other inhalation studies in rats and 1 study in female mice. In addition, intratracheally instilled female rats showed an increased incidence of lung tumours, but this was not observed in hamsters and female mice.
It has been suggested that this tumour promoting activity may be mediated by macrophage inflammatory protein 1alpha (MIP1alpha), which is known to cause cell proliferation in the alveoli and mammary gland and which expression in the lung is significantly increased by titanium dioxide treatment. In addition, the lung load of titanium dioxide nanoparticles must exceed the normal clearance capacity, resulting in inflammatory responses. The persistence of these tissue responses over chronic time periods may lead to tumorigenesis.
Although it is still not known with certainty whether high lung burdens of poorly soluble particles such as titanium dioxide lead to lung cancer in humans via mechanisms similar to those in rodents, some researchers came to a consensus that in the absence of mechanistic data to the contrary it must be assumed that the rat model can identify potential carcinogenic hazards to humans. Therefore, since the apparent responsiveness of the rat model at overload is dependent on coexistent chronic active inflammation and cell proliferation, at lower lung doses where chronic active inflammation and cell proliferation are not present, they do not anticipate a lung cancer hazard.
5.5 Enhanced absorption of herbicides and drugs
Although titanium dioxide does not affect the dermal penetration of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) individually, the application of a sunscreen containing titanium dioxide and octinoxate was found to enhance the transdermal absorption of 2,4-D in ethanol-gavaged rats. Moreover, nanometric titanium dioxide can also act as a skin penetration enhancer for the drug amphotericin, depending on its surface charge (coating) and its oxidative potential (crystalline phase).
5.6 Inhalation toxicity
The fate of titanium dioxide particles in the body after inhalation exposure depends on the primary particle size, with finer particles accessing the pulmonary interstitium to a larger extent than larger particles. It has been shown that the majority of nano-sized titanium dioxide is deposited in the lungs, at least in rats. Pulmonary clearance is also slower for smaller particles, which may explain why smaller particles have been observed to induce greater lung inflammation over the short-term. Other pulmonary effects of exposure include increased breathing rate, lung cell injury and morphological changes in the lung leading to increased lung weight.
Interestingly, the pulmonary inflammation caused by titanium dioxide appears to be reversible, and even the pulmonary lesions induced by relatively long-term exposure (3 months) to titanium dioxide have been observed to regress 1 year following cessation of exposure.
Even among rodents, there are significant inter-species differences in the pulmonary responses to inhaled titanium dioxide. Hamsters seem to be able to clear titanium dioxide particles more rapidly from the lungs than rats or mice, and rats had more severe and persistent inflammatory responses than mice, resulting in the development of progressive epithelial and fibroproliferative changes that were not observed in mice or hamsters.
It is therefore obvious that these studies may or may not be relevant to humans. For instance, an autopsy of a 55-year old man known to have been occupationally heavily exposed to titanium dioxide dust showed extensive pulmonary deposition of the rutile form of titanium dioxide, but there was an absence of inflammatory and fibrotic changes in the lungs, lending support to the view that rutile is biochemically inert.
Nevertheless, the indication of substantial inflammatory responses, epithelial hypertrophy and hyperplasia to rodents at high exposure doses was sufficient for the Scientific Committee on Consumer Safety (SCCS) to not recommend the use of nano-sized titanium dioxide in applications that would lead to significant inhalation exposure, such as powders or sprays.
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