Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon

Abstract

Food-grade titanium dioxide (TiO2) containing a nanoscale particle fraction (TiO2-NPs) is approved as a white pigment (E171 in Europe) in common foodstuffs, including confectionary. There are growing concerns that daily oral TiO2-NP intake is associated with an increased risk of chronic intestinal inflammation and carcinogenesis. In rats orally exposed for one week to E171 at human relevant levels, titanium was detected in the immune cells of Peyer’s patches (PP) as observed with the TiO2-NP model NM-105. Dendritic cell frequency increased in PP regardless of the TiO2 treatment, while regulatory T cells involved in dampening inflammatory responses decreased with E171 only, an effect still observed after 100 days of treatment. In all TiO2-treated rats, stimulation of immune cells isolated from PP showed a decrease in Thelper (Th)-1 IFN-γ secretion, while splenic Th1/Th17 inflammatory responses sharply increased. E171 or NM-105 for one week did not initiate intestinal inflammation, while a 100-day E171 treatment promoted colon microinflammation and initiated preneoplastic lesions while also fostering the growth of aberrant crypt foci in a chemically induced carcinogenesis model. These data should be considered for risk assessments of the susceptibility to Th17-driven autoimmune diseases and to colorectal cancer in humans exposed to TiO2 from dietary sources.

Simultaneous Quantification and Visualization of Titanium Dioxide Nanomaterial Uptake at the Single Cell Level in an In Vitro Model of the Human Small Intestine

“…Due to the ubiquitous role of metal elements for cellular functions, a significant change in the household of these elements could lead to incalculable long term effects on the cell level as well as on the organism level. Long term effects of TiO 2 NMs and E171 on rats were already shown . On the one hand, it was claimed that an acute exposure of one week to rats led to an accumulation of TiO 2 in peyer's patches, but did not induce instestinal inflammation.…”

Nanoscience and nanotechnologies for biobased materials, packaging and food applications: New opportunities and concerns

“…Following an in-depth re-evaluation of this compound based on the data available in early 2016, the European Food Safety Agency had no scientific reason to reject this inorganic compound as a food additive. Scientific questions that have yet to be answered include the impact of such particles from long-term exposure (as in work developed by Bettini et al (2017)) and the fate of the non-excreted fraction (location, clearance, effect) as well as its nanoparticle content. Given the demonstrated differences between E171 and P25 materials, we strongly urge researchers studying the biological effects of ingested TiO2 to consider the food-grade forms in addition to P25 forms.…”

Safety of titanium dioxide nanoparticles in cosmetics

“…In rats, nano‐TiO 2 (10 mg/kg bw/day, 7 days, gavage) was shown to increase dendritic cells frequency in Peyer's patches but not in the spleen. No intestinal inflammation was reported, and no ( in vivo ) or limited ( in vitro ) effects were observed on Treg and Th cell subsets . All other studies were performed in mice.…”

“…Some rodent studies showed nano‐TiO 2 toxicity at several levels: immune system, central nervous system, kidneys, liver, spleen and fertility …”