Mechanism of Action of TiO₂: Recommendations to Reduce Uncertainties Related to Carcinogenic Potential

The Risk Assessment Committee of the European Chemicals Agency issued an opinion on classifying titanium dioxide (TiO₂) as a suspected human carcinogen upon inhalation. Recent animal studies indicate that TiO₂ may be carcinogenic through the oral route. There is considerable uncertainty on the carcinogenicity of TiO₂, which may be decreased if its mechanism of action becomes clearer. Here we consider adverse outcome pathways and present the available information on each of the key events (KEs). Inhalation exposure to TiO₂ can induce lung tumors in rats via a mechanism that is also applicable to other poorly soluble, low-toxicity particles. To reduce uncertainties regarding human relevance, we recommend gathering information on earlier KEs such as oxidative stress in humans. For oral exposure, insufficient information is available to conclude whether TiO₂ can induce intestinal tumors. An oral carcinogenicity study with well-characterized (food-grade) TiO₂ is needed, including an assessment of toxicokinetics and early KEs.