The gastrointestinal uptake of titanium dioxide nanoparticles: Studies on Caco-2 cells, perfused intestine and in vivo dietary intake in the rat (Rattus norvegicus)
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The use of nanomaterials (NMs) in orally ingestible products raises concerns about potential hazards. Titanium dioxide (TiO2) particles (of which some are incidentally produced at the nanoscale) are used in cosmetics, biological remediation (photo-catalysis), toothpastes, ingestible pharmaceuticals and food products. The increased surface area to mass ratio of nanoparticles (NPs) potentially makes them more biologically reactive than their coarser (bulk) material counterparts. There is limited data available on the uptake kinetics across the mammalian gastrointestinal tract, and the potential hazard posed to humans. In this study, the uptake and accumulation of TiO2 (nano and bulk) into and across the human intestinal cell line, the isolated perfused rat jejunum and the whole rat were evaluated. Caco-2 monolayers exhibited time-dependent, accumulation, uptake and transport of Ti/TiO2 from TiO2 exposures of 1 mg L-1 over 24 h, which was influenced by the crystal type, irrespective of cell maturity and growth substrate (Chapters 2-3). Electron micrographs of the Caco-2 monolayer showed the presence of particles inside the cells within vesicles and energy dispersive spectroscopy (EDS) confirmed the composition as TiO2. Addition of pharmacological inhibitors altered the Ti concentration in the cells suggesting diffusion is not the primary mechanism of uptake, rather, an active process is responsible (Chapter 2). Whole gut sacs exposures of 1 mg L-1 bulk or nano TiO2 demonstrated the primary regions of the gut associated with accumulation are the small and large intestine, with 70 % or more of the TiO2 accumulating in the mucosa rather than the underlying muscularis. Perfused intestines exposed to 1 mg L-1 bulk or nano TiO2 for 4 h showed a time-dependent accumulation of Ti in the serosal perfusate with the initial rates of Ti flux from the nano exposures being 5 fold higher than the bulk form. Addition of pharmacological inhibitors caused increases in tissue Ti concentration and significantly reduced Ti serosal flux rates for NP exposures. Overall, the data suggests an active absorption mechanism is responsible for Ti uptake from both bulk and nano TiO2 exposures across the perfused rat intestine that is drug sensitive (Chapter 4). In vivo work demonstrated feed status and rat age effected Ti tissue concentrations. Critically, Ti tissue concentrations reduced with increasing age and removal of Ti containing feed caused transient decreases in Ti tissue concentrations in 23 day old rats. Transient decreases in Ti tissue concentration following feed removal were not observed in older rats suggesting young rats may be more sensitive to the uptake hazards presented by titanium (Chapter 5). Overall, the findings presented in this thesis demonstrate Ti/TiO2 from both bulk and nano TiO2 exposures are accumulated and transported across intestinal epithelium and these processes are drug sensitive and affected by crystal structure and particle size. The results in this thesis have contributed to a better understanding of the uptake kinetics and sub-lethal hazards presented by bulk and nano forms of TiO2 exposed to intestinal epithelium which could be used to partially inform policy makers on human dietary risk assessments.
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