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This article reviews the uses, benefits, and safety of titanium dioxide.

Different dermal cell types have been reported to differ in their sensitivity to nano-sized TiO₂ . Kiss et al. exposed human keratinocytes (HaCaT), human dermal fibroblast cells, sebaceous gland cells (SZ95) and primary human melanocytes to 9 nm-sized TiO₂ particles at concentrations from 0.15 to 15 μg/cm² for up to 4 days. The particles were detected in the cytoplasm and perinuclear region in fibroblasts and melanocytes, but not in kerati-nocytes or sebaceous cells. The uptake was associated with an increase in the intracellular Ca²⁺ concentration. A dose- and time-dependent decrease in cell proliferation was evident in all cell types, whereas in fibroblasts an increase in cell death via apoptosis has also been observed. Anatase TiO₂ in 20–100 nm-sized form has been shown to be cytotoxic in mouse L929 fibroblasts. The decrease in cell viability was associated with an increase in the production of ROS and the depletion of glutathione. The particles were internalized and detected within lysosomes. In human keratinocytes exposed for 24 h to non-illuminated, 7 nm-sized anatase TiO_2, a cluster analysis of the gene expression revealed that genes involved in the “inflammatory response” and “cell adhesion”, but not those involved in “oxidative stress” and “apoptosis”, were up-regulated. The results suggest that non-illuminated TiO₂ particles have no significant impact on ROS-associated oxidative damage, but affect the cell-matrix adhesion in keratinocytes in extracellular matrix remodelling. In human keratinocytes, Kocbek et al. investigated the adverse effects of 25 nm-sized anatase TiO₂ (5 and 10 μg/ml) after 3 months of exposure and found no changes in the cell growth and morphology, mitochondrial function and cell cycle distribution. The only change was a larger number of nanotubular intracellular connections in TiO₂-exposed cells compared to non-exposed cells. Although the authors proposed that this change may indicate a cellular transformation, the significance of this finding is not clear. On the other hand, Dunford et al. studied the genotoxicity of UV-irradiated TiO₂ extracted from sunscreen lotions, and reported severe damage to plasmid and nuclear DNA in human fibroblasts. Manitol (antioxidant) prevented DNA damage, implying that the genotoxicity was mediated by ROS.

What’s recently changed with titanium dioxide and regulations?

For a review published in 2023 in the journal Environmental Pollution, researchers examined E171 as a possible factor promoting obesity-related metabolic disorders. Because gut microbiota play an important role in immune function maintenance and development, and because titanium dioxide as a food additive has been shown to alter gut microbiota, researchers wanted to review “the dysregulations along the gut microbiota-immune system axis after oral TiO2 exposure compared to those reported in obese or diabetic patients, and to highlight potential mechanisms by which foodborne TiO2 nanoparticles may increase the susceptibility to develop obesity-related metabolic disorders.” The study authors discovered recurrent changes in the gut microbiota composition when exposed to titanium dioxide nanoparticles, with an imbalance of intestinal symbiotic microbiota. These changes and imbalances were also reported and played a role in the development of obesity, the authors wrote. This highlights “foodborne TiO2 nanoparticles as an endocrine disruptor-like chemical promoting obesity-related disorders,” the authors concluded.

The risks associated with titanium dioxide exposure depend on a variety of factors, including the form of the mineral, the route of exposure (such as being inhaled or consumed), and the duration and intensity of exposure.

Avoiding exposure

A review published in 2022 in the journal NanoImpact evaluated the latest research related to genotoxic effects of titanium dioxide through in vivo studies and in vitro cell tests. Researchers summarized the results by stating TiO2 nanoparticles “could induce genotoxicity prior to cytotoxicity,” and “are likely to be genotoxic to humans.”

On November 23, 2022, the General Court of the European Union reversed the conclusion that titanium dioxide was carcinogenic and released a statement (1,2):

“First, the Commission made a manifest error in its assessment of the reliability and acceptability of the study on which the classification was based and, second, it infringed the criterion according to which that classification can relate only to a substance that has the intrinsic property to cause cancer.”
 
As part of our mission at CRIS we base our safety assessments on the currently available scientific evidence and consider many variables (e.g., study quality, journal of publication, etc.), even if it goes against previous conclusions. Evidence-informed decisions making is critical to ensure that the laws and regulations put into place are for the benefit of the population.
 
The EU General Court maintains that the scientific evidence presented wasn’t the complete picture for the ingredient, “in the present case, the requirement to base the classification of a carcinogenic substance on reliable and acceptable studies was not satisfied.”