Titanium Dioxide Nanoparticles are Toxic & Prodiabetic. Is the Same True for the Common Food Additive / Color E171?

Chewing gum is one of the food products highest in E171 aka Titanium DiOxide (TiO2); and despite the fact that "regular" E171 is not all nano-sized there is a significant quantity of very small molecules even in "food-grade" Titanium dioxide.

In a recent study in the Journal of Applied Toxicolology, researchers from the Harbin Institute of Technology in China present disturbing evidence that titanium dioxide nano-particles that are commonly used in sunscreen and other cosmetics, and can occur in foods containing the common food additive E-171 can induce insulin resistance in previously healthy rodents.

Despite the fact it has to be taken into consideration that the mice were exposed to low to high doses of TiO2 nanoparticles (0, 64 and 320 mg/kg body weight for 14 weeks), the effects the scientists observed appear to confirm previous disconcerting in-vitro data which suggests that E-171 may not be super safe.
Western blotting showed that oral administration of TiO2 nanoparticles induced insulin resistance (IR) in mouse liver, shown by increased phosphorylation of IRS1 (Ser307) and reduced phosphorylation of Akt (Ser473).

Figure 1: Effects of TiO2 ingestion on fasting glucose levels (Hu. 2015).

As the scientist point out these effects were probably mediated by increases in ROS productio, TNF-alpha and IL-6, as well as increases of the redulating proteins JNK1 and p38 MAPK in the liver of the rodents liver; changes that accumulated as the TiO2 occumulated in the body of the rodents and were pronounced enough for the scientists to conclude that their results "that oral administration of TiO2 nanoparticles increases ROS, result[s] in IR and increasing plasma glucose in mice" (Hu. 2015) and raise the question, whether TiO2 nanoparticles, which are widely utilized in many fields such as pharmaceuticals, cosmetics, paints and paper can actually be considered GRAS.

Whether titanium dioxide is safe or not may depend on its molecular form and route of administration - so what do we know about that?

Titanium dioxide (TiO2) nanoparticles are a highly stable, anticorrosive and photoactive nanoparticles and are frequently used as an important industrial material for products such as pharmaceuticals, antibacterial, cosmetics and food additives (Helinor. 2009; Shi. 2013). Human exposures to TiO2 nanoparticles may occur during both manufacturing and use. For workers, gravimetric concentrations of TiO2 nanoparticles at workplaces ranged from 0.1 to 4.99 mg/m³, and for ordinary people, a typical diet may be the major exposure route that contributes 300–400 μg per day (Shi. 2013).
With human equivalents of 5mg/kg and 25mg/kg the dosages in the rodent study at hand were significantly higher than this previously determined average exposure through the human diet.

This does not change the fact that cell studies revealed that cells treated with TiO2 nanoparticles showed a series of morphological changes, including decreased cell size, membrane blebbing, peripheral chromatin condensation and apoptotic body formation (Gurevitch. 2012; Hussain. 2010), as well as inflammatory problems specifically of the digestive tract (Schneider. 2007), but it still highlights that the nano-version of the common food ingredient E171 which is particularly high in foods like candies, sweets, and chewing gums (see Figure 2), may be something to keep in mind, when we investigate the effects of these foods and personal care products, toothpastes and select sunscreens which contain 1% to 10% titanium by weight on our health.
References:

• Gurevitch, Diana, et al. "TiO2 nanoparticles induce insulin resistance in liver-derived cells both directly and via macrophage activation." Nanotoxicology 6.8 (2012): 804-812.
• Hu et al. "Titanium dioxide nanoparticles increase plasma glucose via reactive oxygen species-induced insulin resistance in mice." J. Appl. Toxicol. (2015): Ahead of print.
• Helinor, Johnston J., et al. "Identification of the mechanisms that drive the toxicity of TiO." Particle and Fibre Toxicology 6 (2009): 33.
• Hussain, Salik, et al. "Research Carbon black and titanium dioxide nanoparticles elicit distinct apoptotic pathways in bronchial epithelial cells." (2010).
• Schneider, Jordan C. "Can microparticles contribute to inflammatory bowel disease: Innocuous or inflammatory?." Experimental Biology and Medicine 232.1 (2007): 1-2.
• Shi, Hongbo, et al. "Titanium dioxide nanoparticles: a review of current toxicological data." Part Fibre Toxicol 10.1 (2013): 15.
• Weir, Alex, et al. "Titanium dioxide nanoparticles in food and personal care products." Environmental science & technology 46.4 (2012): 2242-2250.