Possible Adverse Effects of Food Additive E171 (Titanium Dioxide) Related to Particle Specific Human Toxicity, Including the Immune System

Abstract

Titanium dioxide (TiO₂) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO₂ and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO₂ warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO₂, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO₂ and nano-sized TiO₂ in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO₂.

Keywords: E171; TiO2; adverse health effects; food additive; food safety; mode of action; nano size; nanomaterial; oral exposure; review; titanium dioxide; toxicity.

Figure 1

Example of E171 particle characterization. Prior analysis the samples were dispersed according to the NanoGenotox dispersion protocol at a final concentration of 2.56 mg/mL in 0.05% BSA solution and probe sonicated on ice for 16 min (4 W). (A) Transmission Electron Microscope picture of E171. (B) Size distribution of E171 particles, measured by single-particle ICP-MS, with a median particle size of 79 nm and 72% of particles < 100 nm.

Figure 2

Postulated Adverse Outcome Pathway of TiO₂ after ingestion and related to inflammation and carcinogenicity, adapted and extended from Braakhuis et al. [3]. Abbreviation: ROS, reactive oxygen species; PAMPs, Pathogen-Associated-Molecular-Patterns; LPS, Lipopolysaccharides; IBD, Inflammatory Bowel Disease; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3, TLR, Toll-like receptor.