TY - JOUR
T1 - A weight of evidence review of the genotoxicity of titanium dioxide (TiO₂)
AU - Kirkland, David
AU - Aardema, Marilyn J.
AU - Battersby, Rüdiger V.
AU - Beevers, Carol
AU - Burnett, Karin
AU - Burzlaff, Arne
AU - Czich, Andreas
AU - Donner, E. Maria
AU - Fowler, Paul
AU - Johnston, Helinor Jane
AU - Krug, Harald F.
AU - Pfuhler, Stefan
AU - Stankowski, Leon F.
N1 - Funding Information:
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul Fowler, David Kirkland, Marilyn Aardema, Carol Beevers, Maria Donner, Helinor Johnston, Arne Burlzaff, Rüdiger Battersby, Karin Burnett, Harald Krug and Leon Stankowski Jr report financial support was provided by Titanium Dioxide Manufacturers Association. Andreas Czitch reports a relationship with Sanofi that includes: equity or stocks.
Publisher Copyright:
© 2022 The Authors
PY - 2022/12
Y1 - 2022/12
N2 - Titanium dioxide is a ubiquitous white material found in a diverse range of products from foods to sunscreens, as a pigment and thickener, amongst other uses. Titanium dioxide has been considered no longer safe for use in foods (nano and microparticles of E171) by the European Food Safety Authority (EFSA) due to concerns over genotoxicity. There are however, conflicting opinions regarding the safety of Titanium dioxide. In an attempt to clarify the situation, a comprehensive weight of evidence (WoE) assessment of the genotoxicity of titanium dioxide based on the available data was performed. A total of 192 datasets for endpoints and test systems considered the most relevant for identifying mutagenic and carcinogenic potential were reviewed and discussed for both reliability and relevance (by weight of evidence) and in the context of whether the physico-chemical properties of the particles had been characterised. The view of an independent panel of experts was that, of the 192 datasets identified, only 34 met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity. Of these, 10 were positive (i.e. reported evidence that titanium dioxide was genotoxic), all of which were from studies of DNA strand breakage (comet assay) or chromosome damage (micronucleus or chromosome aberration assays). All the positive findings were associated with high cytotoxicity, oxidative stress, inflammation, apoptosis, necrosis, or combinations of these. Considering that DNA and chromosome breakage can be secondary to physiological stress, it is highly likely that the observed genotoxic effects of titanium dioxide, including those with nanoparticles, are secondary to physiological stress. Consistent with this finding, there were no positive results from the in vitro and in vivo gene mutation studies evaluated, although it should be noted that to definitively conclude a lack of mutagenicity, more robust in vitro and in vivo gene mutation studies would be useful.Existing evidence does not therefore support a direct DNA damaging mechanism for titanium dioxide (nano and other forms).
AB - Titanium dioxide is a ubiquitous white material found in a diverse range of products from foods to sunscreens, as a pigment and thickener, amongst other uses. Titanium dioxide has been considered no longer safe for use in foods (nano and microparticles of E171) by the European Food Safety Authority (EFSA) due to concerns over genotoxicity. There are however, conflicting opinions regarding the safety of Titanium dioxide. In an attempt to clarify the situation, a comprehensive weight of evidence (WoE) assessment of the genotoxicity of titanium dioxide based on the available data was performed. A total of 192 datasets for endpoints and test systems considered the most relevant for identifying mutagenic and carcinogenic potential were reviewed and discussed for both reliability and relevance (by weight of evidence) and in the context of whether the physico-chemical properties of the particles had been characterised. The view of an independent panel of experts was that, of the 192 datasets identified, only 34 met the reliability and quality criteria for being most relevant in the evaluation of genotoxicity. Of these, 10 were positive (i.e. reported evidence that titanium dioxide was genotoxic), all of which were from studies of DNA strand breakage (comet assay) or chromosome damage (micronucleus or chromosome aberration assays). All the positive findings were associated with high cytotoxicity, oxidative stress, inflammation, apoptosis, necrosis, or combinations of these. Considering that DNA and chromosome breakage can be secondary to physiological stress, it is highly likely that the observed genotoxic effects of titanium dioxide, including those with nanoparticles, are secondary to physiological stress. Consistent with this finding, there were no positive results from the in vitro and in vivo gene mutation studies evaluated, although it should be noted that to definitively conclude a lack of mutagenicity, more robust in vitro and in vivo gene mutation studies would be useful.Existing evidence does not therefore support a direct DNA damaging mechanism for titanium dioxide (nano and other forms).
UR - http://www.scopus.com/inward/record.url?scp=85140993265&partnerID=8YFLogxK
U2 - 10.1016/j.yrtph.2022.105263
DO - 10.1016/j.yrtph.2022.105263
M3 - Article
C2 - 36228836
SN - 0273-2300
VL - 136
JO - Regulatory Toxicology and Pharmacology
JF - Regulatory Toxicology and Pharmacology
M1 - 105263
ER -