Most of the TiO₂ particles are taken up in the cells as large intracellular aggregates in vesicles, vacuoles or lamellar bodies by means of phagocytosis. High doses, however, impede phagocytosis thus causing overloading of the cells, for example in the lungs ^[5]. Pinocytotic uptake was observed only in the case of small aggregates (< 30nm) and single particles. After uptake, the TiO₂ particles are mostly bound to the cytoplasmic membranes of the cells. No particles have been found so far in the nuclei of the cells ^{[e.g. 1, 2]}. In-vitro multi-cell systems are preferred to simple cell culture models with only one cell type for simulation of the interaction of different cells in the body and of in-vivo situations. Using sensitive methods, TiO₂ was shown to occur in all cell types of a triple co-culture system as membrane-bound larger aggregates but also freely in the cytoplasm as smaller aggregates or single particles ^[3].

In contrast, transcytosis, i.e. the vesicular transport of macromolecules from one cell to the other, has hardly been investigated in vitro. Measurements that have been taken within NanoCare to assess the transport of nanoparticles through the cells have shown that TiO₂ particles are not transported through monolayer cells ^[4]. Besides, exocytosis (a process where substances are transported from the cell interior to the cell environment) does not take place according to in-vitro tests.
 

Literature

1. L'Azou, B et al (2008) Part Fibre Toxicol 5: 22.
   
2. Zucker, R M et al (2010) Cytometry A 77(7): 677-685.
   
3. Rothen-Rutishauser, B et al (2007) Part Fibre Toxicol 4: 9.
   
4. Schulze C et al (2008) Nanotoxicology, 2(2): 51_61
   
5. Li, J. A et al (2007) Environmental Toxicology and Pharmacology 24(3): 239-244.

Given the fact that the blood-brain barrier is a good protection against penetration of pathogens, it remains to be found out whether or not at all TiO₂ particles can get into the brain. Besides passing the blood-brain barrier, particles, when inhaled, can get directly into the brain via the olfactory nerve.

In a study of rats, no increased amounts of TiO₂ nanoparticles were found in the brains after injection into the bloodstream ^[2]. No titanium was detected in the brains of mice after instillation with TiO₂ ^[3].
 

Literature

1. Long, T C et al (2006) Environ Sci Technol 40(14): 4346-4352.
2. Fabian, E et al (2008) Arch.Toxicol. 82(3): 151-157.
3. Li, Y et al (2010) J Nanosci Nanotechnol 10(12): 8544-8549.

(1) Studies on the influence of environmental conditions on the mobility are concerned in particular with naturally occurring substances in soil or water and their interaction with the nanoparticles. This is particularly the influence of agglomeration , as well as stability and deposition of particles. The natural materials include organic materials (degradation products of plants or animals), such as humic or fulvic acids, which are included in all waters and soils in different proportions. In most cases, binding of such materials to TiO₂ leads to stabilization of the suspension particles and prevents their agglomeration ^{[1,2,3,4,5,6,7]}. As a result, particles rather "float" in the water, thus remain mobile and do not sediment. Stabilization by organic materials is largely independent of the pH and salinity of the environment, i.e. takes place under various environmental conditions. The agglomeration-preventing effect of proteins is similar to that of organic materials ^[8]. However, certain substances (organic acids, e.g. oxalic acid) can also have opposite effects or may not exert any stabilizing effect ^[9]. Minerals or salts also increase agglomeration of the particles ^[10] and reduce their mobility ^[1]. The behavior of the particles is also influenced by their chemical and physical properties. Hence, contaminants (e.g. residues from production) may affect the surface charge and, thus, the behavior of the particles ^[11,5]. However, according to the present studies, the different crystalline structures of TiO₂ and different shapes and sizes have no effect on sedimentation and agglomeration of the particles.
(2) In addition to the natural organic substances, also inorganic substances can bind to titanium dioxide particles and thereby influence their behavior in the environment and their effects on environmental organisms. Titanium dioxide particles can bind toxic heavy metals such as cadmium and arsenic ^[12,13,14]. Carp exposed to cadmium and arsenic-containing water and titanium dioxide particles took up more cadmium and arsenic than carp in particle-free water ^[13,14]. In algae, however, this effect was not observed, because algae do not absorb cadmium-laden particles ^[12].
Due to the photocatalytic effect of TiO₂, arsenic is transformed into a less toxic form ^[15]. Similarly, an increased binding of phosphorus to TiO₂ has been described ^[16]. Thus, TiO₂ nanoparticles in principle bind many substances and increase the availability (see Glossary) for organisms. Whether TiO₂ particles have a significant impact on the availability of other pollutants under field conditions has not been investigated yet.
(3) TiO₂ nanoparticles can also affect processes in the environment, e.g. by changing the properties of sediments with respect to surface area, pore size, and ability to bind to other substances ^[16]. This could for example increase the binding of nutrients in TiO₂-contaminated soils. The precise effects of TiO₂ enrichment, however, are still unexplored. Also, water-purification processes in water treatment plants can be affected by high TiO₂ concentrations. Effects on the removal of nitrogen compounds have been described ^[17].

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13. Sun H et al., 2009, Environ Polut, 157, 1165-1170 .
    
14. Zhang, X. et al., 2007. Chemosphere 67, 160-166 .
    
15. Pena, ME et al., 2005, Water Res, 39, 2327-2337 .
    
16. Luo Z et al., 2011, J Hazard Mater, http://dx.doi.org/10.1016/j.jhazmat.2011.06.050 .
    
17. Zheng X et al., 2011, Envion Sci Technol, 45, 7284-7290 .