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 V-radiolabeled [V]TiO 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 [V]TiO-nanoparticle suspension by intra-esophageal instillation. A completely balanced quantitative body clearance and biokinetics in all organs and tissues was obtained by applying typical [V]TiO-nanoparticle doses in the range of 30-80 μg•kg bodyweight, making use of the high sensitivity of the radiotracer technique. The [V]TiO-nanoparticle content was corrected for nanoparticles in the residual blood retained in organs and tissue after exsanguination and for V-ions not bound to TiO-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 [V]TiO-nanoparticle organ concentrations present in liver (0.09 ng•g), lungs (0.10 ng•g), kidneys (0.29 ng•g), brain (0.36 ng•g), spleen (0.45 ng•g), uterus (0.55 ng•g) and skeleton (0.98 ng•g). Since chronic, oral uptake of TiO 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 [V]TiO-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 TiO nanoparticles.

Safety of titanium dioxide nanoparticles in cosmetics

“…In contrast, the study performed in rats did not show any significant increase of titanium in liver, spleen, kidney and even brain in comparison with the vehicle control group, and no dose–response relationship was observed after nano‐TiO 2 (264.4, 520.8 and 1041.5 mg/kg bw/day) was orally administered daily for 13 weeks . However, a more recent study using radiolabelled nano‐TiO 2 showed nano‐TiO 2 distribution in rat liver, lungs, kidneys, brain, spleen, uterus and skeleton 7 days after administration of a single dose of nano‐TiO 2 (about 40 μg/kg bw), even if the estimated absorbed dose was low (0.09–0.98 ng/g depending on the organ) . These results suggested that upon repeated long‐term oral exposure, nano‐TiO 2 may accumulate in specific organs and thereby present a risk in humans who are orally exposed to nano‐TiO 2 .…”

“…Using an ex vivo model of porcine oral mucosa, nano‐TiO 2 was shown to rapidly interact with the mucous layer, penetrate the oral epithelium and impact on the physiological homeostasis of buccal/sublingual cells in the oral cavity . Three studies performed in vivo in rats showed that oral administration of nano‐TiO 2 either led to extremely low systemic absorption of nano‐TiO 2 from the gastrointestinal tract or did not lead to significant nano‐TiO 2 absorption . The nano‐TiO 2 dose absorbed across the intestinal barrier was estimated to be about 0.6%, 0.2% and 0.05% of the administered dose only, respectively, 1 h, 4 h and 7 days after administration .…”

“…Three studies performed in vivo in rats showed that oral administration of nano‐TiO 2 either led to extremely low systemic absorption of nano‐TiO 2 from the gastrointestinal tract or did not lead to significant nano‐TiO 2 absorption . The nano‐TiO 2 dose absorbed across the intestinal barrier was estimated to be about 0.6%, 0.2% and 0.05% of the administered dose only, respectively, 1 h, 4 h and 7 days after administration . In humans, a 3D organotypic human buccal mucosa model was used to access nano‐TiO 2 penetration in vitro .…”

“…In several studies, nanoparticles were detected in the liver, heart, kidneys, pancreas, spleen, brain or blood after inhalation and translocation through the lung barrier. 31,[35][36][37][38] Nevertheless, this phenomenon does not appear to be predominant as the translocation rate is slower than the lung clearance rate. 39 In conclusion, inhaled nanoparticles can be found in the lungs.…”

“…42 The nano-TiO 2 dose absorbed across the intestinal barrier was estimated to be about 0.6%, 0.2% and 0.05% of the administered dose only, respectively, 1 h, 4 h and 7 days after administration. 35 In humans, a 3D organotypic human buccal mucosa model was used to access nano-TiO 2 penetration in vitro. Nano-TiO 2 penetrated the reconstituted human normal buccal epithelium, with most of the particles remaining in the upper third of the epithelial tissue.…”