Using physiologically based pharmacokinetic (PBPK) modeling for dietary risk assessment of titanium dioxide (TiO₂) nanoparticles

Abstract

Nano-sized titanium dioxide particles (nano-TiO2) can be found in a large number of foods and consumer products, such as cosmetics and toothpaste, thus, consumer exposure occurs via multiple sources, possibly involving different exposure routes. In order to determine the disposition of nano-TiO2 particles that are taken up, a physiologically based pharmacokinetic (PBPK) model was developed. High priority was placed on limiting the number of parameters to match the number of underlying data points (hence to avoid overparameterization), but still reflecting available mechanistic information on the toxicokinetics of nano-TiO2. To this end, the biodistribution of nano-TiO2 was modeled based on their ability to cross the capillary wall of the organs and to be phagocytosed in the mononuclear phagocyte system (MPS). The model's predictive power was evaluated by comparing simulated organ levels to experimentally assessed organ levels of independent in vivo studies. The results of our PBPK model indicate that: (1) within the application domain of the PBPK model from 15 to 150 nm, the size and crystalline structure of the particles had a minor influence on the biodistribution; and (2) at high internal exposure the particles agglomerate in vivo and are subsequently taken up by macrophages in the MPS. Furthermore, we also give an example on how the PBPK model may be used for risk assessment. For this purpose, the daily dietary intake of nano-TiO2 was calculated for the German population. The PBPK model was then used to convert this chronic external exposure into internal titanium levels for each organ.

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

“…This is similar to the approach applied by Bachler et al (2015) in their model; like for other NPs (Lankveld et al, 2010), the kinetics of uptake into tissues of TiO 2 is fast compared to the kinetics of translocation and elimination during the terminal phase; TiO 2 elimination occurs from the liver only (a decrease of liver levels was observed); there is some translocation from the liver to the spleen (an increase of spleen levels was observed long after the last dose). The model was fitted to the entire rat experimental i.v.…”

“…Elimination was found to be low (54-86% of the administered dose remained in the organs after 90 days recovery), thus leading to accumulation of Ti in various organs after repeated dosing. Such an accumulation would not be expected based on the data of Xie et al (2011) and was not included in the PBPK model of Bachler et al (2015).…”

“…The NCI study and its different risk characterization outcome in comparison with the other studies should therefore be interpreted with caution. Bachler et al (2015) also performed a risk assessment for TiO 2 NPs in food, drugs and toothpaste based on internal concentrations, using a PBPK model. They compared the organ concentrations expected in human consumers to the effect concentrations in in vitro studies and concluded that the risk for the German population was small.…”

“…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).…”

“…A first assessment in this direction has been performed by Bachler et al (2015), who estimated the oral intake of TiO 2 NPs for the German population, calculated the resulting steady state organ concentrations, and found that these were lower than the concentrations that have been reported to cause effects in vitro. We currently aim to refine this assessment by (1) inclusion of higher quality data on NP content of E 171, (2) inclusion of more data on TiO 2 levels in products, (3) inclusion of newer and higher quality toxicokinetic data to estimate tissue distribution and accumulation over time, (4) use of in vivo hazard data, selected from an extensive literature review; and (5) inclusion of effect concentrations in reproductive organs, based on recent hazard findings.…”