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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.

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The increasing use of gold nanoparticles leads to a possible increase of exposure by inhalation. Therefore, we have studied the deposition patterns of inhaled 20 nm gold nanoparticles (AuNP) in 7-90 day old rats and their biokinetics in 60 day old ones. Wistar-Kyoto rats inhaled intratracheally 20 nm Au-radiolabeled AuNP by negative pressure ventilation over 2 h. Immediately afterward lungs were excised, inflated and microwave dried. AuNP deposition was analyzed by single-photon emission computed tomography, computed-tomography and autoradiography. Completely balanced, quantitative biodistributions in major organs and all body tissues and total excretion were analyzed from 1 h to 28 d after inhalation. Intratracheal inhalation caused AuNP deposition predominately in the caudal lungs, independent of age. About 30% AuNP were deposited on airway epithelia and rapidly cleared by mucociliary clearance. About 80% of AuNP deposited in alveoli was relocated from the epithelium into the interstitium within 24 h and was inaccessible to broncho-alveolar lavage. During interstitial long-term retention, re-entrainment within macrophages back onto the lung epithelium and to the larynx and gastrointestinal tract (GIT) dominated AuNP clearance (rate 0.03 d) In contrast, AuNP-translocation across the air-blood barrier was much smaller leading to persistent retention in secondary organs and tissues in the ranking order liver > soft issue > spleen > kidneys > skeleton > blood > uterus > heart > brain. The age-independent, inhomogeneous AuNP deposition was probably caused by the negative pressure ventilation. Long-term AuNP clearance was dominated by macrophage-mediated transport from the interstitium to the larynx and GIT. Translocation across the rat air-blood barrier appeared to be similar to that of humans for similar sized AuNP.

Submicrometer TiO particles, including nanoparticulate fractions, are used in an increasing variety of consumer products, as food additives and also drug delivery applications are envisaged. Beyond exposure of occupational groups, this entails an exposure risk to the public. However, nanoparticle translocation from the organ of intake and potential accumulation in secondary organs are poorly understood and in many investigations excessive doses are applied. The present study investigates the biokinetics and clearance of a low single dose (typically 40-400 μg/kg BW) of V-radiolabeled, pure TiO anatase nanoparticles ([V]TiONP) with a median aggregate/agglomerate size of 70 nm in aqueous suspension after intravenous (IV) injection into female Wistar rats. Biokinetics and clearance were followed from one-hour to 4-weeks. The use of radiolabeled nanoparticles allowed a quantitative [V]TiONP balancing of all organs, tissues, carcass and excretions of each rat without having to account for chemical background levels possibly caused by dietary or environmental titanium exposure. Highest [V]TiONP accumulations were found in liver (95.5%ID after one day), followed by spleen (2.5%), carcass (1%), skeleton (0.7%) and blood (0.4%). Detectable nanoparticle levels were found in all other organs. The [V]TiONP content in blood decreased rapidly after 24 h while the distribution in other organs and tissues remained rather constant until day-28. The present biokinetics study is part 1 of a series of studies comparing biokinetics after three classical routes of intake (IV injection (part 1), ingestion (part 2), intratracheal instillation (part 3)) under identical laboratory conditions, in order to test the common hypothesis that IV-injection is a suitable predictor for the biokinetics fate of nanoparticles administered by different routes. This hypothesis is disproved by this series of studies.

The biokinetics of a size-selected fraction (70 nm median size) of commercially available and V-radiolabeled [V]TiO 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 [V]TiO-nanoparticle suspension. A completely balanced quantitative biodistribution in all organs and tissues was obtained by applying typical [V]TiO-nanoparticle doses in the range of 40-240 μg·kg bodyweight and making use of the high sensitivity of the radiotracer technique. The [V]TiO-nanoparticle content was corrected for residual blood retained in organs and tissues after exsanguination and for V-ions not bound to TiO-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 [V]TiO-nanoparticles present in liver and kidneys remained constant (0.03%). [V]TiO-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 [V]TiO-nanoparticles. This contribution may account for 1/5 of the nanoparticle retention in some organs. After normalizing the fractions of retained [V]TiO-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 TiO-particles (including nanoparticles) and accumulation in secondary organs may pose long-term health risks, this issue should be scrutinized more comprehensively.

Our data show that inhaled Au NP are retained in the mouse lungs and are translocated after a short time, and that SP-D has only a minor effect on Au NP translocation and clearance at a very early time point.