After eliminating irrelevant or unreliable experiments, a group of leading toxicologists has published an analysis1 that demonstrates that concerns about the safety of TiO2 in food are unfounded.
The European Food Safety Authority (EFSA) has regularly reviewed the safety of TiO2 as a food additive, and did not raise any concerns in their 2016, 2018 and 2019 reviews. However, in 2021 they concluded that the food additive E171 (a specific form of TiO2) has the potential to cause DNA strand breaks and chromosomal damage. Because they could not rule out genotoxicity, the EFSA said it was not possible to set an acceptable daily intake level and no longer considered the use of E171 in food to be safe.
In contrast and as a result of the EFSA Opinion, Health Canada carried out a review and published a report titled State of the Science of Titanium Dioxide (TiO2) as a Food Additive which took into account more recent studies and concluded that it did not identify any compelling health concerns for the use of TiO2 as a food additive. Food Safety Australia New Zealand, the US FDA and the UK Food Safety Agency (FSA) had similar conclusions.
An extensive ‘weight of evidence’ assessment about the ‘genotoxicity’2 of TiO2 was recently carried out by an independent panel of 13 world-renowned experts in genetic toxicology3. They evaluated the existing evidence, in particular examining the relevance and reliability of the available data, to help resolve conflicting opinions about the safety of TiO2 as a food additive.
The expert panel considered 337 datasets (see Figure), the same ones used by the EFSA along with newer studies on TiO2 genotoxicity and unpublished data generated in industrial and contract research laboratories on behalf of TiO2 producers. First, they assessed the studies, and eliminated those categorised as ‘negligible’ or ‘low weight’ (not linked to genetic hazard or tumour formation). Of the 337 datasets, only 192 were ‘moderate’ or ‘high’ weight for genotoxicity and were suitable to include.
Next, the panel used the ToxR tool4, a standardized protocol that rates the quality of studies based on a number of aspects of their design and reporting and which gives a specific (Klimisch5) score. The ToxR tool was extended to also consider the unique properties of nanoparticles, which may also be relevant, to ensure that these studies were evaluated and excluded appropriately.
Only 34 of those 192 datasets provided relevant and reliable data in terms of evaluating genotoxicity. Of these, only 10 had evidence that TiO2 was genotoxic. But all of these came from studies of DNA breakage or chromosome damage which could have resulted from a number of other factors such as those also associated with physiological stress (high cytotoxicity, oxidative stress, inflammation, apoptosis, necrosis, or combinations of these.)
Because it is generally accepted that DNA and chromosome breakage can be secondary to physiological stress, the panel concluded that it is highly likely that the genotoxic effects of TiO2 in these studies were indeed more likely to be physiological stress. Consistent with this, there were no positive results from the gene-mutation studies evaluated.
The expert panel therefore concluded that existing evidence does not support a direct DNA-damaging mechanism for TiO2.
Dr David Lockley, chair of the TDMA’s Scientific Taskforce, said: “The conclusions of the expert panel mark a key milestone that reinforces a growing scientific consensus around the safety of TiO2. This confirms once more the need for a review of the EFSA’s opinion on E171 to ensure that the EU regulation is well-grounded in the available scientific evidence.”
Expert panel members:
- David Kirkland / Kirkland Consulting
- Marilyn Aardema / Marilyn Aardema Consulting, USA
- Rudiger Battersby / EBRC Consulting, Germany
- Carol Beevers / Broughton, UK
- Karin Burnett / Independent consultant, UK
- Arne Burzlaff / EBRC Consulting, Germany
- Andreas Czich / Sanofi R&D, Germany
- Maria Donner / Maria Donner Consulting, Germany
- Paul Fowler / FSTox Consulting, UK
- Helinor Johnston / Nano Safety Research Group, Heriot Watt University, UK
- Harald Krug / NanoCASE, Switzerland
- Stefan Pfuhler / Proctor & Gamble, USA
- Leon Stankowski jr / Charles River Labs, USA
- A weight of evidence review of the genotoxicity of titanium dioxide (TiO2) by Kirkland et al. Regulatory Toxicology and Pharmacology 136 (2022) 105263. doi: 10.1016/j.yrtph.2022.105263
- A genotoxin is something that causes DNA or chromosomal damage, which can lead to cancer.
- The panel was assembled at request of the Titanium Dioxide Manufacturers Association. At that time, none of the panel members were employed by companies that manufacture and sell TiO2. However, due to the widespread use of TiO2, several experts were employed by companies that included TiO2 in their formulated products. It is stated that none of the experts were influenced in any way and prepared an entirely independent opinion.
- ToxR tool. https://joint-research-centre.ec.europa.eu/scientific-tools-and-databases/toxrtool-toxicological-data-reliability-assessment-tool_en
- Klimish score. https://www.chemsafetypro.com/Topics/CRA/How_to_Use_Klimisch_Scoring_System_to_Assess_Toxicology_Data_Reliability.html