Organ and tissue accumulation of titanium dioxide after acute, subacute, subchronic, and chronic oral exposure in mice and rats: a systematic review

Abstract

Background Titanium dioxide (TiO2) is a compound that is often used as a white pigment. Commercial TiO2, such as the food additive E171, contains a mix of particle sizes, including a fraction in the nanoscale range (< 100 nm). It is an ingredient in everyday products such as toothpaste, dietary supplements, and pharmaceuticals. Although the oral and gastrointestinal (GIT) tracts are the initial sites of exposure, in vivo studies have shown that TiO2 can cross the intestinal epithelium, enter systemic circulation, and accumulate in vital organs, where elimination is slow. This accumulation has been associated with oxidative stress, inflammation, cytotoxicity, and altered cellular function.

Main body This systematic review assesses titanium (Ti) accumulation in vital organs of rats and mice following oral TiO2 exposure, focusing on dose- and time-dependent patterns across acute, subacute, subchronic, and chronic durations. Following PRISMA guidelines, 3,012 records were identified and screened by title and abstract, with 54 studies meeting predefined inclusion criteria. The findings reveal that acute oral exposure to TiO2 consistently results in minimal titanium accumulation across all major organs, indicating limited gastrointestinal absorption and rapid excretion. In contrast, subacute and subchronic exposures lead to significant, dose-dependent titanium accumulation, especially in the liver, spleen, kidneys, gastrointestinal tract, and brain. Chronic exposure studies, though fewer, indicate persistent Ti presence, especially in the liver, kidneys, and colon. Ti was also found in the brain, pancreas, and reproductive tissues, with histopathological changes indicating broader systemic effects. A few studies reported negligible accumulation even at high doses.

Conclusion This review highlights the organ-specific and exposure-dependent biodistribution of titanium following oral TiO2 intake in rodents. The evidence emphasizes the need for standardized reporting and experimental methodologies to improve data comparability across studies. Importantly, it underscores significant gaps in our understanding of chronic and low-dose exposures, conditions more reflective of real-world human scenarios, warranting further investigation to better assess long-term health risks.