Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats

Abstract

ObjectiveThe aim of this study was to obtain kinetic data that can be used in human risk assessment of titanium dioxide nanomaterials.MethodsTissue distribution and blood kinetics of various titanium dioxide nanoparticles (NM-100, NM-101, NM-102, NM-103, and NM-104), which differ with respect to primary particle size, crystalline form and hydrophobicity, were investigated in rats up to 90 days post-exposure after oral and intravenous administration of a single or five repeated doses.ResultsFor the oral study, liver, spleen and mesenteric lymph nodes were selected as target tissues for titanium (Ti) analysis. Ti-levels in liver and spleen were above the detection limit only in some rats. Titanium could be detected at low levels in mesenteric lymph nodes. These results indicate that some minor absorption occurs in the gastrointestinal tract, but to a very limited extent.Both after single and repeated intravenous (IV) exposure, titanium rapidly distributed from the systemic circulation to all tissues evaluated (i.e. liver, spleen, kidney, lung, heart, brain, thymus, reproductive organs). Liver was identified as the main target tissue, followed by spleen and lung. Total recovery (expressed as % of nominal dose) for all four tested nanomaterials measured 24 h after single or repeated exposure ranged from 64-95% or 59-108% for male or female animals, respectively. During the 90 days post-exposure period, some decrease in Ti-levels was observed (mainly for NM-100 and NM-102) with a maximum relative decrease of 26%. This was also confirmed by the results of the kinetic analysis which revealed that for each of the investigated tissues the half-lifes were considerable (range 28–650 days, depending on the TiO2-particle and tissue investigated). Minor differences in kinetic profile were observed between the various particles, though these could not be clearly related to differences in primary particle size or hydrophobicity. Some indications were observed for an effect of crystalline form (anatase vs. rutile) on total Ti recovery.ConclusionOverall, the results of the present oral and IV study indicates very low oral bioavailability and slow tissue elimination. Limited uptake in combination with slow elimination might result in the long run in potential tissue accumulation.

Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations

“…The best publicly available toxicokinetic data for modeling at the start of this work were the data of Geraets et al (2014). The data available to and used by Bachler et al (2015) for calibrating their PBPK model (the data of Xie et al, (2011)) was measured by labeling the TiO 2 NPs with iodine.…”

“…Bachler et al (2015) discussed that it seems that this label was detached from a large part of the NPs at a certain point in time. This instability of the label may provide unreliability in the data of Xie et al (2011) which is not present in the data of Geraets et al (2014). Geraets et al (2014) administered male and female Wistar rats with different forms of TiO 2 NPs (see Supplementary Material, Table S1) by the intravenous (i.v.)…”

“…Recent studies with TiO 2 NPs, however, show that these particles can have toxic effects (e.g. reviews of Iavicoli et al, 2011Iavicoli et al, , 2012Shi et al, 2013) and repeated exposure to these particles may result in significant tissue accumulation at a higher age (Geraets et al, 2014).…”

In vivo and in vitro toxicological effects of titanium dioxide nanoparticles on small intestine

“…Recent studies show that TiO 2 has very low oral bioavailability and slow tissue elimination which might result in the long run in potential tissue accumulation [8]. Moreover, a study performed on humans stated that TiO 2 NP are likely to agglomerate in gastric fluid, reducing the bioavailability of the dose in nanoform during oral exposure and that there is no evidence of significant absorption, regardless of particle size [9].…”

Toxic Effects of Anatase Titanium Dioxide Nanoparticles on Spermatogenesis and Testicles in Male Mice

“…These NPs may then be redistributed into other tissues (such as the liver, heart, and lung), which can induce impairments on organs after unintentional exposure. Although TiO 2 NPs have been demonstrated to accumulate in organs and result in toxicity, data regarding male reproductive toxicity caused by TiO 2 NPs are currently limited [12]. The limited data showed that TiO 2 NPs exhibit male reproductive toxicity.…”