Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats: Part 2

Abstract

The biokinetics of a size-selected fraction (70 nm median size) of commercially available and ⁴⁸V-radiolabeled [⁴⁸V]TiO₂ nanoparticles has been investigated in female Wistar-Kyoto rats at retention timepoints 1 h, 4 h, 24 h and 7 days after oral application of a single dose of an aqueous [⁴⁸V]TiO₂-nanoparticle suspension by intra-esophageal instillation. A completely balanced quantitative body clearance and biokinetics in all organs and tissues was obtained by applying typical [⁴⁸V]TiO₂-nanoparticle doses in the range of 30–80 μg•kg⁻¹ bodyweight, making use of the high sensitivity of the radiotracer technique. The [⁴⁸V]TiO₂-nanoparticle content was corrected for nanoparticles in the residual blood retained in organs and tissue after exsanguination and for ⁴⁸V-ions not bound to TiO₂-nanoparticles. Beyond predominant fecal excretion about 0.6% of the administered dose passed the gastro-intestinal-barrier after one hour and about 0.05% were still distributed in the body after 7 days, with quantifiable [⁴⁸V]TiO₂-nanoparticle organ concentrations present in liver (0.09 ng•g⁻¹), lungs (0.10 ng•g⁻¹), kidneys (0.29 ng•g⁻¹), brain (0.36 ng•g⁻¹), spleen (0.45 ng•g⁻¹), uterus (0.55 ng•g⁻¹) and skeleton (0.98 ng•g⁻¹). Since chronic, oral uptake of TiO₂ particles (including a nano-fraction) by consumers has continuously increased in the past decades, the possibility of chronic accumulation of such biopersistent nanoparticles in secondary organs and the skeleton raises questions about the responsiveness of their defense capacities, and whether these could be leading to adverse health effects in the population at large. After normalizing the fractions of retained [⁴⁸V]TiO₂-nanoparticles to the fraction that passed the gastro-intestinal-barrier and reached systemic circulation, the biokinetics was compared to the biokinetics determined after IV-injection (Part 1). Since the biokinetics patterns differ largely, IV-injection is not an adequate surrogate for assessing the biokinetics after oral exposure to TiO₂ nanoparticles.

Keywords:

• Size-selected, radiolabeled titanium dioxide nanoparticles
• gavage
• gut-absorption
• accumulation in secondary organs and tissues
• different biokinetics pattern after gavage versus intravenous injection

This article is related to:

Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3

Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats: Part 1

Note

Acknowledgements

We are most grateful for in-depth discussions with Prof. Dr. J. Powell and Dr. L. Pele from Cambridge University, MRC Human Nutrition Research, about the physiology of nanoparticle transport from the gut towards blood circulation. We also thank Sebastian Kaidel, Paula Mayer and Nadine Senger from Helmholtz Center Munich for their excellent technical assistance, as well as Antonio Bulgheroni, Kamel Abbas, Federica Simonelli, Izabela Cydzik, and Giulio Cotogno from the EU-Joint Research Center who strongly supported the nanoparticle radio-labeling task. We also express our sincere gratitude to Prof. Dr. Barbara Rothen-Rutishauser and David Raemy, University of Fribourg, Switzerland, who performed the TEM analysis of the TiO₂NP.

This work was partially supported by the German Research Foundation SPP 1313, the EU-FP6 project Particle-Risk (012912 (NEST)), and the EU FP7 projects NeuroNano (NMP4-SL-2008-214547), ENPRA (NMP4-SL-2009-228789) and InLIveTox (NMP-2008-1.3-2 CP-FP 228625-2).

Disclosure statement

The authors declare that they have no financial, consulting, and personal relationships with other people or organizations that could influence (bias) the author’s work.

Notes

1 See Materials and Methods where we explain: no further animals were sacrificed for a 28-day biodistribution study after observing in the seven-day experiment that fecal excretion of [⁴⁸V]TiO₂NP was already complete after 4–5 days.