Dangers From Gelatin and Titanium Dioxide Sub-Micron Nano Particles

Potential hazards of oral exposure to TiO2 NPs 

The gastrointestinal tract is a complex barrier/exchange system, and is the most important route by which macromolecules can enter the body. The main absorption takes place through villi and microvilli of the epithelium of the small and large intestines, which have an overall surface of about 200 m2. Already in 1922, it was recognized by Kumagai87, that particles can translocate from the lumen of the intestinal tract via aggregation of intestinal lymphatic tissue (Peyer’s patch, containing M-cells (phagocytic enterocytes)). Uptake can also occur via the normal intestinal enterocytes. Solid particles, once in the sub-mucosal tissue, are able to enter both the lymphatic and blood circulation.

In an early study Jani et al.88 administred rutile TiO2 (500 nm) as a 0.1 ml of 2.5 % w/v suspension (12.5 mg/kg BW) to female Sprague Dawley rats, by oral gavage daily for 10 days and detected presence of particles in all the major gut associated lymphoid tissue as well as in distant organs such as the liver, spleen, lung and peritoneal tissue, but not in heart and kidney. The distribution and toxicity of nano- (25 nm, 80 nm) and submicron-sized (155 nm) TiO2 particles were evaluated in mice administered a large, single, oral dosing (5 g/kg BW) by gavage.89 In the animals that were sacrificed two weeks later, ICP-MS analysis showed that the particles were retained mainly in liver, spleen, kidney, and lung tissues, indicating that they can be transported to other tissues and organs after uptake by the gastrointestinal tract. Interestingly, although an extremely high dose was administrated, no acute toxicity was observed. In groups exposed to 80 nm and 155 nm particles, histopathological changes were observed in the liver, kidney and in the brain.

The biochemical serum parameters also indicated liver, kidney and cardiovascular damage and were higher in mice treated with nano-sized (25 or 80 nm) TiO2 compared to submicron-sized (155 nm) TiO2. However, the main weaknesses of this study are the use of extremely high single dose and insufficient characterisation of the particles.

Duan et al.90 administered 125 mg/kg BW or 250 mg/kg BW of anatase TiO2 (5 nm) intragastrically to mice continuously for 30 days. The exposed mice lost body weight, whereas the relative liver, kidney, spleen and thymus weights increased. Particles seriously affected the haemostasis of the blood and the immune system. The decrease in the immune response could be the result of damage to the spleen, which is the largest immune organ in animals and plays an important role in the immune response. Powel et al.91demonstrated that TiO2 NPs may trigger immune reactions of the intestine after oral intake. They showed that TiO2  NPs conjugated with bacterial lipopolysaccharide, but not TiO2 NPs or lipopolysaccharide alone, trigger the immune response in human peripheral blood mononuclear cells and in isolated intestinal tissue.

This indicates that TiO2 NPs may be important mediators in overcoming normal gut-cell hyporesponsiveness to endogenous luminal molecules, which may be particularly relevant to patients with inflammatory bowel disease, which is characterized by an abnormal intestinal permeability.

The National Cancer Institute tested TiO2 for possible carcinogenicity by the oral route of exposure by feeding rats and mice with TiO2 (size not specified) at doses 25,000 or 50,000 ppm TiO2 for 103 weeks. They concluded that TiO2 was not carcinogenic.92 Also, the study with rats fed diets containing up to 5 % TiO2 coated mica for 130 weeks showed no treatment-related carcinogenicity.93 Since the size and other TiO2 properties were not specified or determined, we cannot generalize this conclusion and we have to take into account other possible outcomes of this scenario in different exposure conditions (other size/crystalline structure of TiO2 etc.).

It should also be considered that due to the low pH in the stomach, the increased dissolution of the TiO2particles may increase its bioavailability and may facilitate the entry of titanium ions into the blood circulation.94 Despite the relatively large consumption of TiO2 as a food additive, no studies on the effect of pH on its absorption and bioavailability have been found in the literature. This can be attributed to a general belief that TiO2is completely insoluble. However, this is not completely true, as TiO2 particles show a certain degree of solubility.33