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No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model.

ABSTRACT: With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. We performed a 26-week inhalation exposure studies of titanium dioxide nanoparticles (TiO₂ NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) mice model for detecting carcinogenicity. Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m³ of TiO₂ NPs for 6 h/day, 5 days/week for 26 weeks. All tissues and blood were collected and subjected to biological and histopathological analyses. TiO₂ NPs exposure induced deposition of particles in lungs in a dose-dependent manner in each exposure group. Exposure to TiO₂ NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of alveolar epithelial type 2 cells was examined, and it was not increased by exposure to TiO₂ NPs. This is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO₂ NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m³, which is considered to be a high concentration.

SUBMITTER: Yamano S

PROVIDER: S-EPMC9440215 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model.

Yamano Shotaro S Takeda Tomoki T Goto Yuko Y Hirai Shigeyuki S Furukawa Yusuke Y Kikuchi Yoshinori Y Kasai Tatsuya T Misumi Kyohei K Suzuki Masaaki M Takanobu Kenji K Senoh Hideki H Saito Misae M Kondo Hitomi H Umeda Yumi Y

Scientific reports 20220902 1

With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. We performed a 26-week inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) mice model for detecting carcinogenicity. Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 h/day, 5 days/week for 26 w ...[more]

PMID: 36056156

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Project description:BackgroundMost toxicological studies on titanium dioxide (TiO2) particles to date have concentrated on carcinogenicity and acute toxicity, with few studies focusing of pneumoconiosis, which is a variety of airspace and interstitial lung diseases caused by particle-laden macrophages. The present study examined rat pulmonary lesions associated with pneumoconiosis after inhalation exposure to TiO2 nanoparticles (NPs).MethodsMale and female F344 rats were exposed to 6.3, 12.5, 25, or 50 mg/m3 anatase type TiO2 NPs for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. After the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses.ResultsNumerous milky white spots were present in the lungs after exposure to 25 and 50 mg/m3 TiO2 NPs. Histopathological analysis revealed that the spots were alveolar lesions, characterized predominantly by the agglomeration of particle-laden macrophages and the presence of reactive alveolar epithelial type 2 cell (AEC2) hyperplasia. We defined this characteristic lesion as pulmonary dust foci (PDF). The PDF is an inflammatory niche, with decreased vascular endothelial cells in the interstitium, and proliferating AEC2 transformed into alveolar epithelial progenitor cells. In the present study, the AEC2 in the PDF had acquired DNA damage. Based on PDF induction, the lowest observed adverse effect concentration for pulmonary disorders in male and female rats was 12.5 mg/m3 and 6.3 mg/m3, respectively. The no observed adverse effect concentration for male rats was 6.3 mg/m3. There was a sex difference in lung lesion development, with females showing more pronounced lesion parameters than males.ConclusionsInhalation exposure to TiO2 NPs caused PDF, an air-space lesion which is an alveolar inflammatory niche containing particle-laden macrophages and proliferating AEC2. These PDFs histopathologically resemble some pneumoconiosis lesions (pulmonary siderosis and hard metal pneumoconiosis) in workers and lung disease in smokers, suggesting that PDFs caused by exposure to TiO2 NPs in rats are an early pneumoconiosis lesion and may be a common alveolar reaction in mammals.

Project description:BackgroundThis study aimed to compare the toxic effects of three different titanium dioxide nanoparticles encoded in the European nanomaterial repository as NM-103 (rutile, hydrophobic), NM-104 (rutile, hydrophilic), and NM-105 (anatase/rutile, hydrophilic), suggesting different toxic potentials after uptake in the lungs. Wistar rats were exposed by nose-only inhalation to aerosol concentrations of 3, 12 and 48 mg/m3 for 4 weeks. This dosing scheme should induce non, partial and complete lung overload. The 4-week inhalation period was followed by 3-, 45- and 94-day exposure-free periods. Investigations according to the OECD 412 guideline were performed. Additional examinations, such as transmission electron microscopy and image analysis of tissue slides and cytospots, were performed to reveal possible differences among the three particle types.ResultsBronchoalveolar lavage fluid from the groups exposed to low concentrations of NM-103 or NM-104 presented slight inflammation. In the mid- and high-exposure groups, this was also present for the NM-105 group, however, weaker than those of NM-103 and NM-104. Histologically, all three groups presented similar distributions of particles in the respiratory tract. Although marginal differences in the degree of some changes exist, no obvious differences in the degree or characteristics of the induced lesions were observable. In general, compared with the higher exposure groups, all the middle exposure groups presented a greater accumulation and aggregation of macrophages at the terminal bronchi. Using transmission electron microscopy, particles were detected mainly in intraalveolar macrophages, followed by type 1 pneumocytes in the low- and mid-concentration groups and intraalveolar free particles in the high-concentration groups. Compared with the other groups, the NM-103 group presented greater numbers of free particles in the alveoli and fewer in the macrophages. With image analysis, the movement of particles to the bronchus-associated lymphoid tissue and lymph nodes could be detected comparably for the three different particle types.ConclusionsThe no observed adverse effect concentration was 3 mg/m3 for all three different TiO2 particles. Despite minimal differences, a ranking mainly based on granulocyte influx into the lung was NM-104 > NM-103 > NM-105.

Project description:Titanium dioxide nanoparticles (TiO2NPs) are widely used in industrial and medicinal fields and in various consumer products, and their increasing use has led to an increase in the number of toxicity studies; however, studies investigating the underlying toxicity mechanism have been rare. In this study, we evaluated potential toxic effects of TiO2NPs exposure on lungs as well as the development of asthma through the ovalbumin (OVA)-induced mouse model of asthma. Furthermore, we also investigated the associated toxic mechanism. TiO2NPs caused pulmonary toxicity by exacerbating the inflammatory response, indicated by an increase in the number and level of inflammatory cells and mediators, respectively. OVA-induced asthma exposed mice to TiO2NPs led to significant increases in inflammatory mediators, cytokines, and airway hyperresponsiveness compared with those in non-exposed asthmatic mice. This was also accompanied by increased inflammatory cell infiltration and mucus production in the lung tissues. Additionally, TiO2NPs decreased the expression of B-cell lymphoma 2 (Bcl2) and the expressions of thioredoxin-interacting protein (TXNIP), phospho-apoptosis signal-regulating kinase 1, Bcl2-associated X, and cleaved-caspase 3 were escalated in the lungs of asthmatic mice compared with those in non-exposed asthmatic mice. These responses were consistent with in vitro results obtained using human airway epithelial cells. TiO2NPs treated cells exhibited an increase in the mRNA and protein expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α with an elevation of TXNIP signaling compared to non-treated cells. Moreover, pathophysiological changes induced by TiO2NP treatment were significantly decreased by TXNIP knockdown in airway epithelial cells. Overall, TiO2NP exposure induced toxicological changes in the respiratory tract and exacerbated the development of asthma via activation of the TXNIP-apoptosis pathway. These results provide insights into the underlying mechanism of TiO2NP-mediated respiratory toxicity.

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No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model.

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No evidence for carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model.

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