BEST OF 2022 | In the EU, the use of titanium dioxide as a food additive is now prohibited. However, we continue swallowing the pigment on a daily basis – in the form of drugs. This raises the question: Do we really need to worry about that?
When the European Commission banned the usage of titanium dioxide (TiO2) as a food pigment in January this year, it generated a lot of fuss. On the one hand, you had the TiO2 producing industry which immediately cried ‘unfair!’, while on the other hand consumers were understandably worried: Does that mean we’ve eaten toxic dye the whole time? (To answer that right here, right now – you didn’t).
Medicine is not uninvolved in the matter: Obviously it’s interesting to know, whether or not human health is affected, but the ban also has implications for drug production as the additive with the name E171 is ubiquitous in the pharmaceutical industry: Thousands of drugs authorized in the European Union contain TiO2. Because it’s not feasible to change the formulation of so many pharmaceuticals at a short notice without risking the medical supply, and danger is not imminent, the E171 ban does not extend to pharmaceuticals as of now; the pharmaceutical industry is given a few more years to come up with alternatives.
This begs the question: Is it a health risk if TiO2 remains in pharmaceutics despite being banned in food – or was the ban maybe an overreaction on the European Commission’s part?
Let’s start at the beginning: TiO2 is one, if not the most popular white color pigment. You can find it pretty much everywhere white color is desired: Wall paint, varnishes, toothpaste, candy and pill coatings, mozzarella cheese… The list goes on. The reasons for its popularity are quite simple: TiO2 particles have an exceptionally high refractive index, which results in a great hiding power and brilliancy. Furthermore, it’s thermally stable, cheap and – most important for its use as a food and pharma additive – chemically inert and nearly insoluble. Its physico-chemical properties render it a generally safe and toxicologically inoffensive material.
Next to it’s use as a pigment TiO2 is also used for UV-protection – again, owed to its high dispersion and adsorption. That includes the application in sunscreens and also in pharmaceutics, where TiO2 is not only used for the clean look of the finished pills, but is also used to increase storability by protecting more delicate ingredients from UV-light.
A cancerogenic effect of TiO2 has been the topic of debate for quite a few years now. Indeed, the European Chemicals Agency (ECHA) did classify the material as a potential cancerogenic – but only if inhaled. However, as an international Expert Panel recently pointed out, this effect however only appeared under extreme chronic exposure in rats; it has not been observed in humans. It is most probable that the observed cancerogenic effect is merely a secondary effect of inert dust particles in general, if the inhaled concentration vastly exceeds the amount of foreign material the lung can clear by itself – so an overload, not an effect of TiO2 in itself.
The real bone of contention is probably a study conducted by the French food safety agency ANSES: In 2017 they found that frequent oral exposure to E171 negatively impacted the immune system of rats and can lead to inflammations in the colon, which in turn could influence cancerogenesis. Other studies showed the ability of TiO2-nanoparticles to accumulate in different tissues throughout the human body and hinted at an ability to induce DNA-strand breaks, which lead ANSES to suspend the further use of E171 already back in 2020.
In 2021 then the European Food Safety Authority (EFSA) followed suite. In its safety reassessment it came to the conclusion that while no conclusive evidence for toxicity could be found, due to missing data genotoxicity could not be completely ruled out either – hence the ban. This evaluation revised the outcome of EFSAs previous 2016 assessment. The deciding factor: in 2016 studies regarding the toxicity of TiO2 nanoparticles were excluded from the evaluation, as their relevance for human consumption was considered low. Newer data showed however, that the percentage of nanoparticles in food grade E171 was higher than originally anticipated – thus, the studies were now included and led to a different assessment.
The caution the EU displays in regard of consumer safety should be applauded. But could it be that in this case, EFSA overdid it? Opinions differ on this point, as evidenced by the United Kingdom and Canada whose Food Safety Agencies also took a look at the existing data and came to the conclusion that there is no evidence for any adverse effects of TiO2 as a food additive. But not only the agencies, also the toxicologists DocCheck News talked to for their evaluation, disagree.
Dr. Carsten Schleh – who studied the toxicology of nanoparticles at the Helmholtz Centrum Munich – personally agrees with the EFSA decision although he can also understand how UK and Canada ended up with a different interpretation as he estimates the risk from TiO2 as low. “There are many, many studies with titanium dioxide. Many have shown that it does nothing at all and there are also some studies that have shown that these phenomena [breaks in the DNA-strands and aberrant cryptic foci] occur.” It may be very well plausible that the additive has no effects in the long run. But: “Let’s be honest, TiO2 simply does not have any important function in food”. So as there is nothing to gain from E171 but a potential risk and banning it doesn’t lead to problems, Schleh says it is a fair decision to play it completely safe.
Meanwhile Prof. Harald Krug does not understand the recent wariness of the pigment. In the context of his participation in numerous expert panels on the toxicology of nanoparticles, he co-authored a recent weighted evidence review of TiO2-genotoxicity which found no sound support of a direct DNA damaging mechanism: “I don't know of any well-done study that has shown an effect for normal concentrations in food, even at slightly higher doses.” Everything published so far that showed adverse effects is either poorly made, contaminated or with extremely high doses, he claims. “You can't really take that as a basis for judging the toxicity.” He also points out that the EFSA assessment relies on authors' conclusions, which can be inflated and sometimes misleading, instead of the raw data.
Krug does have a point, if we take a closer look at the animal studies. One example, which other media outlets like to cite in this context, is a 2017 study conducted by Swiss researchers: up to 500 mg TiO2 /kg bodyweight were administered daily to rats with induced acute colitis in their drinking water, which worsened the inflammation. Further investigations showed an increased formation of reactive oxygen species generations in human intestinal epithelial cells and also increased titanium levels in the blood of patients with ulcerative colitis. While this does sound worrisome, Krug points out a quite a few limitations which unfortunately are not exclusive to this particular study.
First of all, the dose is a lot higher than the estimated daily intake of TiO2 through food in humans (1,28 mg /kg bodyweight per day), so effects might simply be a consequence of overloading the cells – which should not happen in normal levels of consumption. Secondly, the particles used were not of food-grade and weren’t necessarily sterile, leaving the potential for bacterial endotoxins and other contaminations bound to the material, which could also induce the inflammatory processes. In the paper it is not indicated, whether or not the researchers accounted for that, which should be a standard for research on the toxicity of nanoparticles. Krug puts it plainly: “Without these analyses the examinations are worthless.” What the study does indicate is “that individuals with a defective intestinal barrier function and preexisting inflammatory condition, such as IBD, might be negatively impacted by ingestion of TiO2 nanoparticles. But it says nothing about food-grade TiO2 and normal individuals!”
Both Schleh and Krug point out that the observed effects (or at least a large part of it) are not due to an inherent property of TiO2 but rather unspecific particle effects that every insoluble, inert material possesses – similar to the observed effects upon inhalation. Krug: “All materials of this size, if they do not dissolve in the body, have the same effect as TiO2: If we overdose it, our lungs react. But only in overload. It's the same with intestinal cells.” So: People with IBD or Morbus Crohn should in general stay clear of such particles in their diet. For healthy individuals, the risk is very low either way.
Which is a very good message, considering that TiO2 will stay with us for much longer in pharmaceutics. The problem isn’t that the mineral fulfills essential functions, Schleh explains: “These are whitening agents, some of them also UV protection, but whether the drugs are white is not a real problem and with UV protection, the worst thing that could happen is that drugs may not have a shelf life of 5 years, but only 3. The main problem with the drugs is that the TiO2 has been well incorporated into the overall formulation so far and affects the complete production mechanism.”
A ban on E171 in pharmaceutical products would likely result in delivery delays or even companies pulling their product from the European market entirely; while substitute materials for TiO2 do exist, the complete formulation for meds has to be adjusted and depending on what is added, this also calls for new approval studies – which takes years to accomplish and generates huge costs, which the companies are likely to recoup through price increases. The thing is: The substitutes might bring their own problems with them. Other inert and insoluble pigments and carriers like barium sulfate (BaSO4) would likely have the same particle effects, while soluble compounds like calcium carbonate (CaCO3) aren’t inert and might interact with the active component as well as our bodies chemistry in some way, which needs to be tested first. “We already have a shortage of certain drugs due to our current global political problems. If we now ban TiO2, even with a lead time of 2 to 3 years, it could lead to a greater shortage of certain drugs in our country” Schleh points out.
A lot of hassle for something that poses minimal danger at best. Krug states it bluntly: “As a drug additive it’s the same as in food: It’s harmless.” Schleh agrees: “When we take it in medication, we are not taking it for fun. I would advise no one to stop taking a medicine because they are afraid of TiO2. The possibility of getting harmed by TiO2 in medications is much smaller than that of getting harmed by not treating a disease.” Should a patient be worried about the additive they can consult with their physician whether a drug with the same active agent without TiO2 exists. Schleh points out however that possible substitutes should be explored by the pharmaceutical industry, as they might be safer for patients who already have existing inflammatory bowel diseases (who should avoid such particles, as mentioned earlier.)
Image source: Artiom Vallat, unsplash
