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.

Lithopone was discovered in the 1870s by DuPont. It was manufactured by Krebs Pigments and Chemical Company and other companies.^[2] The material came in different seals, which varied in the content of zinc sulfide. Gold seal and Bronze seals contain 40-50% zinc sulfide, offering more hiding power and strength.^[3] Although its popularity peaked around 1920, approximately 223,352 tons were produced in 1990. It is mainly used in paints, putty, and in plastics.^[1]

The lack of clear regulations and controls explains that P25TiO₂NPs are still found in many of the commercialized sunscreens in the market. Some of them are coated to reduce the photoactivity of the anatase form, which is known to be responsible for tissue damage, but not enough studies were made on these coated forms. The anatase photoactivity could trigger the production of reactive oxygen species (ROS) generation, as it was stated before. The ROS are chemically reactive species containing oxygen, such as peroxides, superoxide, hydroxyl radical, and singlet oxygen. They are regularly produced in the biological milieu and counterbalanced by physiological antioxidant defense mechanisms. However, an abrupt increase of ROS may result in non-reversible damage to the skin cells. The effects of coated and uncoated P25TiO₂NPs need therefore to be studied, and articles on this topic present different conclusions. [11], [12], [13] Recent literature on this topic found that TiO₂NPs inhalation provokes serious genotoxicity and DNA damage [14], [15], [16], [17]. On the other hand, some studies in rats have reported no significant harm to genetic material [18], [19], [20], [21], [22].

The FDA and certain others say titanium dioxide is safe to use in foods and personal care products. The FDA provides strict guidelines on how much can be used in food. The limit is very small: no more than 1% titanium dioxide.

Overall, the Food Directorate's comprehensive review of the available science of TiO₂ as a food additive showed: