An Intratracheal Instillation Bioassay System for Detection of Lung Toxicity Due to Fine Particles in F344 Rats

Yokohira, Masanao; Kuno, Toshiki; Yamakawa, Keiko; Hashimoto, Nozomi; Ninomiya, Fumiko; Suzuki, Satoshi; Saoo, Kousuke; Imaida, Katsumi

doi:10.1293/tox.22.1

Cited by 18 publications

(22 citation statements)

References 51 publications

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“…Notably, TISMO contains no iron component, therefore the iron accumulation is likely to have derived from an endogenous source in the body. In our previous studies in which TISMO fibers administered by intratracheal instillation to F344 rats (4 mg per rat) were used, only mild inflammatory reactions were observed compared to quartz particles in the lungs after 28 days (21,22). Results of other studies of TISMO administration by chronic inhalation also found limited inflammation in the lung (23,24).…”

Section: Discussionmentioning

confidence: 91%

Potassium octatitanate fibers (TISMO) induce pleural mesothelial cell reactions with iron accumulation in female A/J mice

Yokohira

Hashimoto²,

Yamakawa³

et al. 2010

Oncology Letters

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Abstract. It is crucial to develop therapeutic approaches for malignant mesothelioma, as well as to obtain information involving the possible mechanism involved in the development of mesothelioma. Subsequently, thoracotomy was performed to infuse test particles directly into the thoracic cavity of A/J mice. Fiber-shaped particles of potassium octatitanate (TISMO) and granular-shaped micro-and nano-size order particles of titanium dioxide (TiO 2 ) were employed (1.5 mg in 0.2 ml saline/mouse). The experiment was terminated after 21 weeks to assess responses. Only the fiber-shaped TISMO, morphologically similar to asbestos, induced a severe reaction of the pleura. A number of TISMO fibers were observed in the alveoli, indicating penetration through the pleura. Following Berlin blue staining, positive spots were observed around the TISMO fibers, indicative of iron. These positive spots corresponded with cells that immunostained positively for calretinin, a marker of mesothelial cells. Similar observations were reported for asbestos-induced mesothelioma. The present study showed that only fiber-shaped TISMO induced severe reactions of the mesothelium in the pleura, and these involved iron accumulation derived from endogenous sources. The results indicate that the risk of mesothelial cell reaction does not depend on particle size, but may depend on shape. IntroductionThe incidence of malignant pleural mesothelioma is on the increase and is anticipated to increase further in future decades as a result of widespread exposure to asbestos particularly in unprotected countries (1,2). Epidemiologically, analyses using an age-cohort model in Japan showed that there may be approximately 100,000 deaths due to pleural mesothelioma in the next 40 years (3). Based on US mesothelioma incidence data from 1973 to 2000, it was estimated that the total number of male mesothelioma cases in 2003-2054 will reach approximately 71,000 (4). Thus, it is crucial to develop treatment modalities for the therapy of malignant mesothelioma, and an appropriate animal model is necessary for this purpose. Reports exist on peritoneal mesothelioma induction by chemicals or fibers in conventional rats (5-8) or pleural mesotheliomas in genetically modified animals such as the p53 knockout mouse (9). Lardinois et al also reported the efficacy of the intrapleural application of cisplatin in an immune-competent rat model inoculated with mesothelioma cells (10). Since pleural malignant mesothelioma is the most common form of mesothelioma in humans (11), a bioassay model featuring similar lesions in otherwise normal animals would be optimal. However, to our knowledge no report of pleural mesothelioma in experimental wild-type animals using direct infusion of particles currently exists. In our previous study, 0.2 ml of polymer gel was infused directly into the left cavity of the thorax by thoracotomy to occupy a certain thoracic cavity volume and to examine the influence of physical pulmonary collapse. We demonstrated that a pronounced mesothelial cell reacti...

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Section: Discussionmentioning

confidence: 91%

Potassium octatitanate fibers (TISMO) induce pleural mesothelial cell reactions with iron accumulation in female A/J mice

Yokohira

Hashimoto²,

Yamakawa³

et al. 2010

Oncology Letters

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“…In animal models, inhalation of both nanosized CuO and nanosized ZnO were reported to induce severe acute pulmonary inflammation. In the case of CuO, depending on dose and exposure frequencies, an acute or more chronic inflammation was observed (Wang et al, 2008;Yokohira et al, 2009). Another study found that NP of ZnO and CuO may induce eosinophilic inflammation (Cho et al, 2010), and eosinophils play a key role in mediating asthma and other allergic conditions.…”

Section: Discussionmentioning

confidence: 99%

Comparing Acute Toxicity of Gunshot Particles, from Firing Conventional and Lead-Free Ammunition, in Pulmonary Epithelial Cell Cultures

Bergström

Ekstrand‐Hammarström

Hägglund

et al. 2015

Journal of Toxicology and Environmental Health, Part A

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Numerous studies demonstrated that the use of lead (Pb)-containing ammunition is associated with mainly chronic health problems and also is a burden on the environment and wildlife. Recently, a number of reports showed evidence of undesirable acute health effects related to the use of newly developed Pb-free small-caliber ammunition. In this study, particles from leaded and Pb-free ammunition were collected in liquid collection medium, in a highly controlled chamber, while firing a pistol (9 mm) or a rifle (7.62 × 51 mm). The emitted particles were typically smaller than 4 μm, with the great majority in even smaller size ranges, as shown by gravimetrical analysis and a multistage impactor. Chemical analysis revealed significant differences in content and concentration of several metals in the particles. After administration of the liquids to alveolar and bronchial in vitro cell systems, particles were taken up by the cells; the Pb-free particles displayed higher cytotoxicity (EC50 = 2 μg/cm(2)) than particles from Pb ammunition. High correlation factors (>0.9) were found between cell death and content of copper and zinc. Particles from both Pb-containing and Pb-free ammunition were able to induce oxidative stress and the proinflammatory marker interleukin (IL)-8 in both in vitro systems. These results support previous findings that indicate an association between gunshot emissions and metal fume fever. This study demonstrates the usefulness of combining chemical data with biological in vitro responses in assessing acute toxicological effects from emissions from firing both Pb and Pb-free ammunition.

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“…We have also employed quartz as a positive control for material induced lung inflammation in F344 rats and have established a bioassay model by intratracheal instillation for detection of lung toxicity due to fine particles in F344 male rats 18,26–28 . From these previous experiments in our laboratory, 0.1 mg quartz was concluded to be a sufficient dose to cause inflammation in the lungs of a mouse (estimated average body weight: 20 g) based on our previous findings for 1 mg quartz in F344 rats (estimated average body weight: 200 g) 26,27 .…”

Section: Discussionmentioning

confidence: 95%

Lack of Modifying Effects of Intratracheal Instillation of Quartz or Dextran Sulfate Sodium (DSS) in Drinking Water on Lung Tumor Development Initiated with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Female A/J Mice

et al. 2009

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The purpose of the present study was to investigate the effects of inflammation, induced by intratracheal instillation (i.t.) of quartz as an environmental factor in the lung or drinking of dextran sulfate sodium (DSS) as an environmental factor in the colon on lung tumors in female A/J mice initiated with NNK. For comparison, colonic preneoplastic lesions, aberrant crypt foci (ACF), were also assessed. A/J mice at 6 weeks of age were divided into 5 groups, and Groups 1, 2 and 3 were pretreated with NNK (2 mg / 0.1 ml saline / mouse, intraperitoneal injection) at week 0. For a week, 2% DSS in drinking water was administered to the mice in Groups 2 and 4 beginning in week 1. In week 2, the mice of Groups 3 and 5 were exposed to intratracheal instillation of quartz (0.1 mg/rat) suspended in 25 μl saline. The experiment was terminated after 16 weeks. The results for the lung tumors and colonic ACFs showed a lack of modifying effects of the inflammation in either site. Hematologically and histopathologically, the inflammation induced by 0.1 mg quartz in the lung and 2% DSS in the colon was lacking or only mild at the end of 16 weeks. These results suggest that there may be differences in sensitivity to inflammation that determine tumor promoting potential.

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An Intratracheal Instillation Bioassay System for Detection of Lung Toxicity Due to Fine Particles in F344 Rats

Cited by 18 publications

References 51 publications

Potassium octatitanate fibers (TISMO) induce pleural mesothelial cell reactions with iron accumulation in female A/J mice

Potassium octatitanate fibers (TISMO) induce pleural mesothelial cell reactions with iron accumulation in female A/J mice

Comparing Acute Toxicity of Gunshot Particles, from Firing Conventional and Lead-Free Ammunition, in Pulmonary Epithelial Cell Cultures

Lack of Modifying Effects of Intratracheal Instillation of Quartz or Dextran Sulfate Sodium (DSS) in Drinking Water on Lung Tumor Development Initiated with 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in Female A/J Mice

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