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

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 healthy adult female Wistar-Kyoto rats at retention time-points of 1 h, 4 h, 24 h, 7 d and 28 d after intratracheal instillation of a single dose of an aqueous [⁴⁸V]TiO₂-nanoparticle suspension. A completely balanced quantitative biodistribution in all organs and tissues was obtained by applying typical [⁴⁸V]TiO₂-nanoparticle doses in the range of 40–240 μg·kg⁻¹ bodyweight and making use of the high sensitivity of the radiotracer technique. The [⁴⁸V]TiO₂-nanoparticle content was corrected for residual blood retained in organs and tissues after exsanguination and for ⁴⁸V-ions not bound to TiO₂-nanoparticles. About 4% of the initial peripheral lung dose passed through the air-blood-barrier after 1 h and were retained mainly in the carcass (4%); 0.3% after 28 d. Highest organ fractions of [⁴⁸V]TiO₂-nanoparticles present in liver and kidneys remained constant (0.03%). [⁴⁸V]TiO₂-nanoparticles which entered across the gut epithelium following fast and long-term clearance from the lungs via larynx increased from 5 to 20% of all translocated/absorbed [⁴⁸V]TiO₂-nanoparticles. This contribution may account for 1/5 of the nanoparticle retention in some organs. After normalizing the fractions of retained [⁴⁸V]TiO₂-nanoparticles to the fraction that reached systemic circulation, the biodistribution was compared with the biodistributions determined after IV-injection (Part 1) and gavage (GAV) (Part 2). The biokinetics patterns after IT-instillation and GAV were similar but both were distinctly different from the pattern after intravenous injection disproving the latter to be a suitable surrogate of the former applications. Considering that chronic occupational inhalation of relatively biopersistent TiO₂-particles (including nanoparticles) and accumulation in secondary organs may pose long-term health risks, this issue should be scrutinized more comprehensively.

Keywords:

• Size-selected, radiolabeled titanium dioxide nanoparticles
• intratracheal instillation
• nanoparticle translocation across the air-blood-barrier
• gut-absorption of swallowed nanoparticles
• accumulation in secondary organs and tissues
• different biokinetics patterns after intratracheal instillation and gavage versus intravenous injection

This article is related to:

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

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

Acknowledgements

We thank Sebastian Kaidel, Paula Mayer and Nadine Senger from the Helmholtz Center Munich for their excellent technical assistance, as well as Kamel Abbas, Antonio Bulgheroni, Giulio Cotogno, Izabela Cydzik and Federica Simonelli from the EU-Joint Research Center, who strongly supported the NP radiolabelling task. We also express our sincere gratitude to Prof. Dr. Barbara Rothen-Rutishauser and David Raemy from the 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) and US-NIH grant HL074022.

Disclosure statement

The authors declare that they have no competing interests. The authors alone are responsible for the content and writing of the paper.