In a 2016 study published in Scientifica (Cairo), Egyptian researchers examined the effects of titanium dioxide nanoparticles on the organs of mice by orally administering the food additive daily, for five days. The results showed that the exposure produced “mild to moderate changes in the cytoarchitecture of brain tissue in a time dependent manner.” Furthermore, “Comet assay revealed the apoptotic DNA fragmentation, while PCR-SSCP pattern and direct sequencing showed point mutation of Presenilin 1 gene at exon 5, gene linked to inherited forms of Alzheimer’s disease.” The researchers wrote: “From these findings, “the present study concluded that TiO2NPs is genotoxic and mutagenic to brain tissue which in turn might lead to Alzheimer’s disease incidence.”

French researchers studied how and where E171 nanoparticles enter the bloodstream, first studying the route through pigs and then in vitro with human buccal cells, for a 2023 study published in the journal Nanotoxicology. The research showed that the nanoparticles absorbed quickly through the mouth and then into the bloodstream, before damaging DNA and hindering cell regeneration.

In a 2017 study published in Scientific Reports, researchers exposed rats to human-relevant levels of E171 to examine the effects of intestinal inflammation and carcinogenesis. They saw that “a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model.” They continued: “Stimulation of immune cells isolated from Peyer’s Patches [which are clusters of lymphoid follicles found in the intestine] showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased,” researchers wrote. “A 100-day titanium dioxide treatment promoted colon microinflammation and initiated preneoplastic lesions.” The scientists concluded: “These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2 from dietary sources.”

The basic scenario of resistive switching in TiO₂ (Jameson et al., 2007) assumes the formation and electromigration of oxygen vacancies between the electrodes (Baiatu et al., 1990), so that the distribution of concomitant n-type conductivity (Janotti et al., 2010) across the volume can eventually be controlled by an external electric bias, as schematically shown in Figure 1B. Direct observations with transmission electron microscopy (TEM) revealed more complex electroforming processes in TiO₂ thin films. In one of the studies, a continuous Pt filament between the electrodes was observed in a planar Pt/TiO₂/Pt memristor (Jang et al., 2016). As illustrated in Figure 1C, the corresponding switching mechanism was suggested as the formation of a conductive nanofilament with a high concentration of ionized oxygen vacancies and correspondingly reduced Ti³⁺ ions. These ions induce detachment and migration of Pt atoms from the electrode via strong metal–support interactions (Tauster, 1987). Another TEM investigation of a conductive TiO₂ nanofilament revealed it to be a Magnéli phase Ti_nO_2n−1 (Kwon et al., 2010). Supposedly, its formation results from an increase in the concentrations of oxygen vacancies within a local nanoregion above their thermodynamically stable limit. This scenario is schematically shown in Figure 1D. Other hypothesized point defect mechanisms involve a contribution of cation and anion interstitials, although their behavior has been studied more in tantalum oxide (Wedig et al., 2015; Kumar et al., 2016). The plausible origins and mechanisms of memristive switching have been comprehensively reviewed in topical publications devoted to metal oxide memristors (Yang et al., 2008; Waser et al., 2009; Ielmini, 2016) as well as TiO₂ (Jeong et al., 2011; Szot et al., 2011; Acharyya et al., 2014). The resistive switching mechanisms in memristive materials are regularly revisited and updated in the themed review publications (Sun et al., 2019; Wang et al., 2020).

While IARC listed titanium dioxide as “possibly carcinogenic to humans,” they also add that “there is inadequate evidence in humans for the carcinogenicity of titanium dioxide.” Of the four human studies that they reviewed, only one showed a potential risk for occupational workers inhaling titanium dioxide particles and lung cancer, while the other three showed no risk for cancer at all. And it’s key to note that IARC did not assess the effects of titanium dioxide found in foods.

Background 

Lithopone was discovered in the 1870s by DuPont. It was manufactured by Krebs Pigments and Chemical Company and other companies. 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. Although its popularity peaked around 1920, approximately 223,352 tons were produced in 1990. It is mainly used in paints, putty, and in plastics.

The cytotoxic effect was tested through the colorimetric assay employing 3′-[1-[(phenylamino) -carbonyl]−3,4-tetrazolium]-bis(4‑methoxy-6-nitro) benzene-sulfonic acid hydrate (XTT) by reading the absorbance at 490 nm after 3 h of incubation post treatment [28]. The absorbance is proportional to the metabolic rate of viable (live) cells.