The FDA has not updated its general guidance on safety assessments since 2007. Within that time, there has been a significant increase in research on the confluence of toxicology, nanotechnology and human health. The EU updates its guidance regularly with new science available to offer proper safety assessments, with its most recent update published in 2021.

In a study published in the journal Toxicology, researchers examined the effects of exposing human colon cancer cell line (HTC116) titanium dioxide food additives in vitro. “In the absence of cytotoxicity, E171 was accumulated in the cells after 24 hours of exposure, increasing granularity and reactive oxygen species, inducing alterations in the molecular pattern of nucleic acids and lipids, and causing nuclei enlargement, DNA damage and tubulin depolymerization,” the scientists wrote. Researchers removed the additive from the culture, then examined the results 48 hours later. They found, “The removal of E171 was unable to revert the alterations found after 24 h of exposure in colon cells. In conclusion, exposure to E171 causes alterations that cannot be reverted after 48 h if E171 is removed from colon cells.”

In a 2019 study published in the journal Nanotoxicology, researchers recreated the first phase of digestion in mice and fed them titanium dioxide, then examined whether accumulation occurred in the organs. Researchers wrote: “Significant accumulation of titanium was observed in the liver and intestine of E171-fed mice; in the latter a threefold increase in the number of TiO2 particles was also measured. Titanium accumulation in the liver was associated with necroinflammatory foci containing tissue monocytes/macrophages. Three days after the last dose, increased superoxide production and inflammation were observed in the stomach and intestine. Overall, [this] indicates that the risk for human health associated with dietary exposure to E171 needs to be carefully considered.”

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.

Preparation of Lithopone:

In short, no, research demonstrates that E171 is safe when consumed in normal situations.

Moreover, how we're exposed to an ingredient matters significantly in terms of our health and potential toxicity.   

Research shows that inhaling titanium dioxide particles in significant quantities over time can cause adverse health outcomes. Unless you work in an industrial setting, inhaling substantial amounts of titanium dioxide is highly unlikely. 

Research supports that applying titanium dioxide to the skin in the form of sunscreens, makeup, and other topical products does not pose a health risk. 

Overwhelmingly, research that's relevant to human exposure shows us that E171 is safe when ingested normally through foods and drugs (1,2).

Again, other research suggests that E171 could cause harm; however, those research processes did not design their studies to model how people are exposed to E171. Research that adds E171 to drinking water, utilizes direct injections, or gives research animals E171 through a feeding apparatus is not replicating typical human exposure, which occurs through food and medicine consumption.

Read more in-depth about the titanium dioxide risk at go.msu.edu/8Dp5. 

The effects of TiO₂ NPs in plants

THE OBSCURE HISTORY OF A UBIQUITOUS PIGMENT: PHOSPHORESCENT LITHOPONE AND ITS APPEARANCE ON DRAWINGS BY JOHN LA FARGE

But that depends on how titanium dioxide is being used and how you might come into contact with it. The International Agency for Research on Cancer (IARC) has classified titanium dioxide as possibly carcinogenic to humans based on studies that showed more lung tumors in rats associated with breathing in titanium dioxide.

China's titanium dioxide enterprises are currently in the stage of capacity expansion and upgrading. With the recovery of the world economy, Caiqing Technology seized the opportunity to occupy the market, titanium dioxide has been exported to more than 90 countries and regions, and has been recognized and unanimously praised by customers in the United States, Singapore, India, Saudi Arabia, Vietnam, Brazil, and other countries. Our company will continue to increase the research and development of titanium dioxide, and provide high-quality titanium dioxide for various industries around the world.

Lithopone powder, chemically known as zinc sulfide/zinc oxide, is a white pigment produced through a precipitation process involving zinc sulfate and barium sulfate. It is characterized by its high refractive index, excellent hiding power, and resistance to UV radiation, making it an ideal choice for various applications.

In a 2020 study published in the Journal of Trace Elements in Medicine and Biology, researchers conducted an in vitro experiment to analyze the effects of TiO2 nanoparticles on a human neuroblastoma (SH-SY5Y) cell line. The scientists evaluated “reactive oxygen species (ROS) generation, apoptosis, cellular antioxidant response, endoplasmic reticulum stress and autophagy.” The results showed that exposure to the nanoparticles “induced ROS generation in a dose dependent manner, with values reaching up to 10 fold those of controls. Nrf2 nuclear localization and autophagy also increased in a dose dependent manner. Apoptosis increased by 4- to 10-fold compared to the control group, depending on the dose employed.” 

Food recalls:Some Jif peanut butter products recalled over salmonella outbreak concerns 

Yes. According to the FDA and other regulatory agencies globally, “titanium dioxide may be safely used for coloring foods”. Titanium dioxide is safe to use, and the FDA provides strict guidance on how much can be used in food. The amount of food-grade titanium dioxide that is used is extremely small; the FDA has set a limit of 1 percent titanium dioxide for food. There is currently no indication of a health risk at this level of exposure through the diet.