JRC scientists contributed to the comparison of the biokinetics of single doses of titanium dioxide nanoparticles applied in rats by intravenous injection, oral exposure by gavage and intratracheal instillation.
The animal experiments using radiolabelled nanoparticles suggest that tiny fractions may cross the gastro-intestinal and air-blood barrier. Titanium dioxide is used in many consumer products including food. As a part of these particles may be smaller than 100 nm, it is important to understand the potential health risks. A quantitative approach is necessary to provide a detailed overview of the nanoparticle biokinetics and fate.
Therefore, JRC scientists provided titanium dioxide nanoparticles radiolabelled with 48-vanadium in order to have full control over the fate of nanoparticles in animal studies carried out by collaborators in two Institutes of the Helmholtz Center Munich in Germany.
The high sensitivity achievable with radiotracers enabled the use of low doses as required in realistic exposure scenarios. By measuring the radioactive content in all organs, tissues and excretions of each animal reliable biodistribution and biokinetics data were obtained in spite of the tiny fractions that passed the intestinal and lung epithelium barriers.
Clearly detectable amounts of nanoparticles were retained in the animals (0.05% of the applied dose one week after gavage and 0.3% four weeks after intratracheal instillation) which were distributed over various organs. This raises issues concerning a possible accumulation of titanium dioxide nanoparticles after repeated ingestion as food additive or due to chronic professional exposure via inhalation.
As the biodistributions after gavage and intratracheal instillation are very different from that after intravenous injection, the hypothesis that intravenous injection of a small dose of nanoparticles could predict the biodistribution of nanoparticles that passed the gastro-intestinal barrier or the air-blood barrier were experimentally disproved
Due to the use of radiolabelled nanoparticles the data are not affected by environmental or dietary exposure of the animals to titanium or by artefacts from specimen preparation. The data allowed the reconstruction of the effectively applied dose, which was found to be subject to significant scatter and smaller than the nominal dose loaded into the application syringes.
The mismatch was caused by nanoparticles retained in syringes and catheters that were quantified by radiation measurements. This effect is presumably due to electrostatic adhesion of nanoparticles to plastic materials and may be considered a general phenomenon of handling nanoparticles in the laboratory.
Since many experiments presented in literature quantify nanoparticles only in selected organs such an uncertainty in the applied dose will remain undiscovered and could be one reason for the large scatter in published data. The issue deserves further attention since it could lead to dose uncertainties in the application of nanomedicines at least for certain types of drug carriers.
Read more in:
W.G. Kreyling et al.: "Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats: Part 1", Nanotoxicology 11 (2017) 434-442, doi: 10.1080/17435390.2017.1306892
W.G. Kreyling et al: "Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats: Part 2", Nanotoxicology 11 (2017) 443-453, doi: 10.1080/17435390.2017.1306893
W. G. Kreyling et al.: "Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3", Nanotoxicology 11 (2017) 454-464, doi: 10.1080/17435390.2017.1306894