Titanium dioxide nanoparticles (TiO2 NPs) have been used in food additives, paints, pharmaceuticals, and cosmetics. Recently, there has been a growing debate on the carcinogenicity of this popularly used nanoparticle. Researchers determined TiO2 NPs carcinogenicity by conducting a twenty-six weeks inhalation exposure experiment using a CByB6F1-Tg(HRAS)2Jic (rasH2) mice model. This study has been published in Scientific Reports.
Study: No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model. Image Credit: Meowcyber/Shutterstock.com
Importance of Titanium Dioxide
Based on particle size, surface modification, and crystal structure, TiO2 has been categorized into many types. In nature, TiO2 exists as three mineral crystal structures, namely, rutile, anatase, and brookite. Under normal physiological conditions, TiO2 exhibits poor solubility and persists for a prolonged period, even after a short period of exposure.
Before the development of TiO2 NPs, TiO2 had been used as a white pigment for about 100 years. The pigment grade TiO2 has been popularly used in paints due to its natural bright white color and high refractive index. TiO2 NPs, with significant ultraviolet scavenging potential and transparency, have been applied to sunscreens.
Are Titanium Dioxide Nanoparticles Carcinogenic?
As TiO2 has been applied widely, humans are exposed to it via several exposure pathways. Recently, a huge controversy has surfaced related to the carcinogenic classification of TiO2. For instance, oral administration of food-grade TiO2 induced epithelial hyperplasia in mice and rats’ intestines. Additionally, several studies have also raised questions about whether TiO2 triggers the manifestation of tumors in the gastrointestinal tract. Nevertheless, several other studies have strongly contradicted these results and did not document any carcinogenic effect related to the oral administration of TiO2.
The majority of observations regarding TiO2 have been based on short-term animal studies and in vitro experiments. Interestingly, minor to significant carcinogenicity was observed in rats subjected to TiO2 inhalation. The carcinogenic effect was found to be dependent on TiO2 concentration.
Although, based on these findings, the International Agency for Research on Cancer (IARC) deemed TiO2 to be a possible carcinogenic agent to humans, no concrete evidence has been reported to support the same. Additionally, apart from rats, no other animals, including mice and hamsters, indicated any carcinogenicity when exposed to TiO2. These contradictory results instigated the need for further validation of TiO2 carcinogenicity in other animals.
In recent years chronic inhalation studies have reduced significantly due to their high cost and animal welfare issues. Therefore, there is a need to introduce new experimental models to evaluate carcinogenicity accurately and rapidly.
Effectiveness of RasH2 Transgenic Mice Model to Evaluate Chronic Carcinogenicity
In a recent study, scientists developed a rasH2 transgenic mice model to evaluate the carcinogenic potential of chemicals when exposed for a prolonged period, i.e., eighteen months. In addition, this model could be utilized to determine the carcinogenicity of chemicals for a shorter period, e.g., six months. Determination of carcinogenicity of food additives showed that compared to a p53 heterozygous mouse model, rasH2 mice were more sensitive to both genotoxic and non-genotoxic carcinogens.
In a recent study, the rasH2 mice model was used to determine the effect of the systemic inhalation exposure of TiO2 NPs for 26 weeks. Scientists evaluated the risk of tumor development in various organs.
In the 26-week inhalation experimental study, rasH2 mice were exposed to a very high concentration, i.e., 32 mg/m3, of TiO2 NPs. It was observed that the presence of TiO2 NPs phagocytosed macrophages in the alveolar regions in exposed mice, which formed inflammatory foci. This finding was consistently found in both sexes. However, the incidence of tumors, hyperplasia, or fibrosis was not observed. Additionally, enhancement of cell proliferation capacity of AEC2 in lesions did not occur, the occurrence of which indicates the origin of lung tumors. Tumors were not found in any other organs that were tested.
Previous studies associated with the evaluation of TiO2 exposure in mice and hamsters faced various challenges, such as too short exposure time (mice model) or shorter life span (hamster model), to determine the incidence of lung tumors in the later stages. However, the findings of these studies were consistent with the outcomes of the present rasH2 mice model that indicated no carcinogenic effect of TiO2 in any organ.
Persistent inflammation was only observed in mice exposed to 32 mg/m3 TiO2 NPs but not in those who were subjected to below 8 mg/m3. Nevertheless, TiO2 NPs deposition was detected in the mediastinal lymph nodes in the 32 mg/m3 exposure group. This result indicated that chronic inhalation increased the risk of long-term health problems related to secondary organs.
Taken together, the effect of systematic inhalation exposure of TiO2 NPs using the rasH2 mice model revealed no incidence of gastrointestinal preneoplastic lesions, inflammatory lesions, and tumors in the exposed mice. Additionally, no manifestation of pulmonary fibrosis and enhancement of collagen deposition in alveolar septa was observed in all the studied groups. This study confirms that TiO2 NPs exhibit minor fibrotic or carcinogenic effects on mice.
Yamano, S., Takeda, T., Goto, Y. et al. (2022) No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model. Scientific Reports, 12, 14969. https://www.nature.com/articles/s41598-022-19139-y