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Objective In this study, in order to investigate the usefulness of intratracheal instillation in assessing the pulmonary toxicity of nanomaterials, intratracheal instillation of nickel oxide‐nanoparticles (NiO‐NP) was performed. Methods In this study, rats were administered test materials by intratracheal instillation at five different research institutions in order to assess the validity of using intratracheal instillation for hazard identification of nanomaterials. Eight‐week‐old male SD rats were administered NiO‐NP dispersed in deionized water by a single intratracheal instillation at doses of 0 (vehicle control), 0.2, 0.67, and 2 mg/kg BW. Three days after instillation, histopathological examination of the lungs was performed. Results NiO‐NP was distributed in the vicinity of hilus of the lung and in the alveoli around the bronchioles. Histopathological changes such as degeneration/necrosis of macrophages, inflammation, and proliferation of type II pneumocyte in the lung were observed, and their severity corresponded with increasing dose. The histopathological observations of pulmonary toxicity were almost similar at each institution. Conclusion The similarity of the histopathological changes observed by five independent groups indicates that intratracheal instillation can be a useful screening method to detect the pulmonary toxicity of nanomaterials.

We experienced 3 cases in whom multidisciplinary treatment with pericardial fenestration was effective for malignant pericardial effusion associated with lung cancer. Case 1:Right upper lobectomy for lung adenocarcinoma, EGFR (-) and ALK (-) had been performed. After 34 months, malignant pericarditis occurred and left pericardial fenestration was performed. After fenestration, anticancer drugs and immune checkpoint inhibitor( ICI) were administered. He died of lung cancer in 53 months after fenestration. Case 2:Thirty-three months after left upper lobectomy for lung adenocarcinoma [EGFR (+) and ALK (-)], malignant pleuritis and pericarditis occurred and right pericardial fenestration was performed. After fenestration, anticancer drugs, EGFR-TKI and ICI were administered. He died of lung cancer in 35 months after fenestration. Case 3:Pericardial fenestration was performed for malignant pericarditis due to lung adenocarcinoma with EGFR (-), ALK (-) and PD-L1 [tumor propotion score (TPS) 0%]. After fenestration, anticancer drugs and ICI were administered. The patient died of lung cancer in 15 months after fenestration. Pericardial fenestration for malignant pericarditis is possibly useful for the management of patients, which in turns is also useful in continuing the medical treatment to prolong the prognosis.

The patient was a 72-year-old man with a history of bronchiectasis. He was admitted to our hospital for an examination of hoarseness. Chest computed tomography (CT) showed bronchiectasis in the bilateral lungs and bronchial artery aneurysm in the mediastinum. To prevent rupture of the aneurysm, we imaged the bronchial artery aneurysm by selective bronchial artery angiography and performed bronchial artery embolization (BAE) with 19 platinum coils. Three months after successful BAE, his hoarseness had improved, and the bronchial artery aneurysm was reduced in size after 12 months. To our knowledge, this is the 1st report of BAE improving hoarseness due to bronchial artery aneurysm.

A 65-year-old male was admitted to our hospital for evaluation of an abnormal shadow in the left lung field of chest roentgenogram. A chest computed tomography scan revealed an ill-defined nodule in the superior lingular segment of left lung and a calcified nodule in the left pulmonary apex region. A diagnosis of lung adenocarcinoma in the left lingular was made by transbronchial cytology and the left upper lobectomy with lymph node dissection was performed. Pathological diagnosis was primary lung adenocarcinoma in the superior lingular segment of left lung (pT1aN0M0, stage I A) and hamartoma in the left pulmonary apex region. It was considered to be important to discriminate a hamartoma from a metastasic lesion in order to conduct correct treatment.

We have conducted animal toxicity tests of chemicals for a chemical safety program implemented by the Ministry of Economy, Trade and Industry of Japan. Here we conducted a combined repeated-dose and reproductive/developmental toxicity screening test of benzene, 1,1'-oxybis-, tetrapropylene derivs. (BOTD). BOTD was administered to 9-week-old Crl:CD(SD) male and female rats by gavage at 0, 40, 200, or 1000 mg/kg/day. Males were treated for 42 days including mating period. Females were treated for 42-53 days through the premating, mating, pregnancy, and until Day 4 of lactation periods. Increases in prothrombin time and activated partial thromboplastin time values were observed only in males at 200 and 1000 mg/kg/day. Hypertrophy of centrilobular hepatocytes was observed with increased liver weight in both sexes at 200 and 1000 mg/kg/day, but there was no histologic evidence of hepatotoxicity. Diffuse hypertrophy of follicular cells in thyroid glands was observed in females at 200 mg/kg/day and in both sexes at 1000 mg/kg/day, with an increased blood cholesterol level in females at 1000 mg/kg/day. The conception index was decreased for females at 1000 mg/kg/day; and no abnormalities were detected in the reproductive indices of implantation, delivery, or pups' condition, although a slight increase in the pups' body weight was noted at birth. Our data indicate a no-observed-adverse-effect level of 40 mg/kg/day for repeated-dose toxicity on the basis of the prolongation of blood coagulating time, and of 200 mg/kg/day for reproductive/developmental toxicity on the basis of the decreased conception index.

Background The toxicokinetics of nanomaterials are an important factor in toxicity, which may be affected by slow clearance and/or distribution in the body. Methods Four types of nickel oxide (NiO) nanoparticles were single-administered intratracheally to male F344 rats at three doses of 0.67–6.0 mg/kg body weight. The rats were sacrificed under anesthesia and the lung, thoracic lymph nodes, bronchoalveolar lavage fluid, liver, and other organs were sampled for Ni burden measurement 3, 28, and 91 days post-administration; Ni excretion was measured 6 and 24 h after administration. Solubility of NiO nanoparticles was determined using artificial lysosomal fluid, artificial interstitial fluid, hydrogen peroxide solution, pure water, and saline. In addition, macrophage migration to trachea and phagosome-lysosome-fusion rate constants were estimated using pulmonary clearance and dissolution rate constants. Results The wire-like NiO nanoparticles were 100% dissolved by 24 h when mixed with artificial lysosomal fluid (dissolution rate coefficient: 0.18/h); spherical NiO nanoparticles were 12% and 35% dissolved after 216 h when mixed with artificial lysosomal fluid (1.4 × 10−3 and 4.9 × 10−3/h). The largest irregular-shaped NiO nanoparticles hardly dissolved in any solution, including artificial lysosomal fluid (7.8 × 10−5/h). Pulmonary clearance rate constants, estimated using a one-compartment model, were much higher for the NiO nanoparticles with a wire-shape (0.069–0.078/day) than for the spherical and irregular-shaped NiO nanoparticles (0–0.012/day). Pulmonary clearance rate constants of the largest irregular-shaped NiO nanoparticles showed an inverse correlation with dose. Translocation of NiO from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner for three spherical and irregular-shaped NiO nanoparticles, but not for the wire-like NiO nanoparticles. Thirty-five percent of the wire-like NiO nanoparticles were excreted in the first 24 h after administration; excretion was 0.33–3.6% in that time frame for the spherical and irregular-shaped NiO nanoparticles. Conclusion These findings suggest that nanomaterial solubility differences can result in variations in their pulmonary clearance. Nanoparticles with moderate lysosomal solubility may induce persistent pulmonary inflammation. Electronic supplementary material The online version of this article (10.1186/s12989-017-0229-x) contains supplementary material, which is available to authorized users.

AEROSIL ® P25 titanium dioxide (TiO 2 ) nanoparticles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats at doses of 0 (control), 0.375, 0.75, 1.5, 3.0, and 6.0 mg/kg. The rats were sacrificed under anesthesia at 1 day, 3 days, 7 days, 4 weeks, 13 weeks, and 26 weeks after administration. Ti levels in various pulmonary and extrapulmonary organs were determined using sensitive inductively coupled plasma sector field mass spectrometry. One day after administration, the lungs contained 62–83% of TiO 2 administered dose. Twenty-six weeks after administration, the lungs retained 6.6–8.9% of the TiO 2 administered at the 0.375, 0.75, and 1.5 mg/kg doses, and 13% and 31% of the TiO 2 administered at the 3.0 and 6.0 mg/kg doses, respectively. The pulmonary clearance rate constants from compartment 1, k 1 , were estimated using a 2-compartment model and were found to be higher for the 0.375 and 0.75 mg/kg doses of TiO 2 (0.030/day for both) than for TiO 2 doses of 1.5–6.0 mg/kg (0.014–0.022/day). The translocation rate constants from compartment 1 to 2, k 12 , were estimated to be 0.015 and 0.018/day for the 0.375 and 0.75 mg/kg doses, and 0.0025–0.0092/day for doses of 1.5–6.0 mg/kg. The pulmonary clearance rate constants from compartment 2, k 2 , were estimated to be 0.0086 and 0.0093/day for doses of 0.375 and 0.75 mg/kg, and 0–0.00082/day for 1.5–6.0 mg/kg doses. Translocation of TiO 2 from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner, accounting for 0.10–3.4% of the administered dose at 26 weeks. The measured thoracic lymph node burdens were a much better fit to the thoracic lymph node burdens estimated assuming translocation from compartment 1 to the thoracic lymph nodes, rather than those estimated assuming translocation from compartment 2 to the thoracic lymph nodes. The translocation rate constants from the lungs to the thoracic lymph nodes, k Lung→Lym , were 0.000037–0.00081/day, and these also increased with increasing doses of TiO 2 . Although a small amount of TiO 2 had translocated to the liver by 3 days after the administration (0.0023–0.012% of the highest dose administered, 6.0 mg/kg), translocation to the other extrapulmonary organs was not detected.

Bronchoalveolar lavage fluid (BALF) is commonly examined for pulmonary toxicity in animal studies. Two common means of anesthesia before euthanasia and bronchoalveolar lavage in rats are intraperitoneal injection of pentobarbital and inhalation of isoflurane. Medetomidine-midazolam-butorphanol is an alternative anesthesia to pentobarbital for animal welfare; however, the effect of this combination on BALF and blood chemistry is unknown. Here, we compared the effects of anesthesia by intraperitoneal injection of pentobarbital or one of two combinations of medetomidine-midazolam-butorphanol (dose, 0.375-2.0-2.5 or 0.15-2.0-2.5 mg/kg) or by inhalation of isoflurane on BALF and blood chemistry in rats with or without pulmonary inflammation. In BALF, we determined total protein, albumin, lactate dehydrogenase, total cell count and neutrophil count. In serum, we conducted a general chemistry screen. After anesthesia with pentobarbital or isoflurane, there were no significant differences between any of the BALF or blood chemistry parameters with or without inflammation. After anesthesia with either of the combinations of medetomidine-midazolam-butorphanol, lactate dehydrogenase, total cell count, neutrophil count, and almost all of the blood chemistry parameters were comparable with those observed after pentobarbital or isoflurane; however, BALF albumin and serum glucose were significantly increased in rats without inflammation. After the combination of low-dose medetomidine in rats with inflammation, BALF parameters were comparable with those observed after pentobarbital or isoflurane. Our results show that, of the anesthetics examined, inhalation of isoflurane is the most appropriate means of anesthesia when examining BALF or serum for toxicity studies in rats.

Intratracheal administration methods are used to conduct toxicological assessments of inhaled nanoparticles (NPs), and gavage needles or microsprayers are common intratracheal delivery devices. The NP suspension is delivered in a liquid state via gavage needle and as a liquid aerosol via microsprayer. The differences in local pulmonary NP distribution (called the microdistribution) arising from the different states of the NP suspension cause differential pulmonary responses; however, this has yet to be investigated. Herein, using microbeam X-ray fluorescence microscopy, we quantitatively evaluated the TiO

The intratracheal (IT) test is useful for screening the pulmonary toxicity of inhaled materials, including nanomaterials. However, a standard procedure has not yet been authorized internationally, and the effects of different test parameters are unknown. To determine appropriate experimental conditions for the IT test, we intratracheally administered nano-sized TiO

Background Myelolipoma is an uncommon tumor comprising adipose tissue and normal hematopoietic cells and mainly occurs in the adrenal cortex. Mediastinal myelolipoma is very rare; we report a case of posterior mediastinal myelolipoma that required surgical resection. Case Presentation A 56-year-old male was diagnosed with a posterior mediastinal tumor by computed tomography. The tumor was originally noted in 2005, and during follow-up in March 2014, it was found to have increased in size. During consultation at our hospital, on magnetic resonance imaging (MRI), we considered the possibility that the tumor was malignant. Consequently, we resected the tumor by video-assisted thoracic surgery (VATS). The histopathological findings revealed that the tumor had undergone intrathoracic extramedullary hematopoiesis. However, after considering the patient’s background and histopathological findings, we diagnosed the tumor as a thoracic extra-adrenal myelolipoma. Conclusions Pathological analysis was instrumental in clarifying the diagnosis. We recommend surgery as a treatment option for posterior mediastinal tumors.

We evaluated and compared the pulmonary clearance kinetics and extrapulmonary translocations of seven titanium dioxide (TiO2) nano- and submicron particles with different characteristics, including size, shape and surface coating. Varying doses of TiO2 nano- and submicron particles dispersed in 0.2% disodium phosphate solution were intratracheally administered to male F344 rats. The rats were euthanized under anesthesia for 3, 28 and 91 days after administration. Ti levels in pulmonary and various extrapulmonary organs were determined using inductively coupled plasma-sector field mass spectrometry (ICP-SFMS). The lungs, including bronchoalveolar lavage fluid (BALF), contained 55–89% of the administered TiO2 dose at 3 days after administration. The pulmonary clearance rate constants, estimated using a one-compartment model, were higher after administration of 0.375–2.0 mg/kg body weight (bw) (0.016–0.020/day) than after administration of 3.0–6.0 mg/kg bw (0.0073–0.013/day) for six uncoated TiO2. In contrast, the clearance rate constant was 0.011, 0.0046 and 0.00018/day following administration of 0.67, 2.0 and 6.0 mg/kg bw TiO2 nanoparticle with Al(OH)3 coating, respectively. Translocation of TiO2 from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner. Furthermore, the translocation of TiO2 from the lungs to the thoracic lymph nodes after 91 days was higher when Al(OH)3 coated TiO2 was administered (0.93–6.4%), as compared to uncoated TiO2 (0.016–1.8%). Slight liver translocation was observed (

4-Methoxy-2-nitroaniline (4M2NA) is widely used as an intermediate for the synthesis of dyes, pigments and other chemical compounds. Since 4M2NA has amino-group and nitro-group on the benzene ring, it was expected that it induced obvious hemolytic anemia. We conducted a combined repeated dose and reproductive/developmental toxicity screening test according to Organisation for Economic Co-operation and Development (OECD) Test Guideline No. 422 (OECD TG 422) to enrich the toxic information and ensure the safety of 4M2NA. 4M2NA was administered to Crl:CD(SD) male and female rats by gavage at 0, 12.5, 75 or 450 mg/kg/day for 42 to maximum of 54 days through pre-mating, mating, pregnancy and lactation periods. An extramedullary hematopoiesis and congestion in spleen, and higher reticulocyte ratio were noted in only females at 450 mg/kg/day without decreased anemic parameters in the hematological examination. Hypertrophy of centrilobular hepatocytes in both sexes was observed with increased relative liver weight at 450 mg/kg/day. Furthermore, the diffuse follicular cell hypertrophy of the thyroid was observed in females at 450 mg/kg/day. No abnormalities were detected in the reproductive indices of copulation, delivery or fetal viability. We concluded the no-observed-adverse-effect level (NOAEL) for repeated-dose toxicity was 75 mg/kg/day based on the trace evidences of hemolytic anemia, and the NOAEL for reproductive/developmental toxicity as 450 mg/kg/day based on no toxicological concerns for reproductive endpoints. The hemolytic anemia was much milder than expected. Thus, we discussed the reason of this much less hemolytic effect from the point of view of the structural characteristics of 4M2NA.

tert-Butylhydrazine monohydrochloride was daily administered by gavage to groups of Crl:CD (SD)IGS rats at doses of 0 (control), 0.8, 4, or 20 mg/kg/day. Twelve males per group were treated for a total of 42 days from 14 days before mating. Twelve females per group were treated from 14 days before mating to day 4 of lactation throughout the mating and gestation periods. Recovery groups of five males and five non-pregnant females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in any groups of either sex. There were no considerable changes in body weight, food intake, general appearance, functional observations or biochemical analysis. Values of the anemic parameters were decreased in the 20 mg/kg/day males and in all female dose groups. The relative weight of the liver, kidneys and spleen was significantly increased in 20 mg/kg/day females. Histopathological examination showed congestion and hemosiderin deposition in the spleen at 20 mg/kg/day in both sexes, but there were no changes in the liver or kidneys in either sex. Anemic parameters with hemosiderin deposition did not completely recover in the 20 mg/kg/day group in both sexes after the recovery period. As for reproduction, a significant reduction was only observed in the number of corpora lutea at 20 mg/kg/day. It was thus concluded that the LOAEL was 0.8 mg/kg/day based on the decreased values of the anemic parameters of repeated-dose toxicity, and that the NOAEL was 4 mg/kg/day based on the low number of corpora lutea of reproductive/developmental toxicity.

Since bisphenol F (4,4’-dihydroxydiphenylmethane) has been reported to exhibit estrogen agonistic properties in the uterotrophic assay, we performed a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) on bisphenol F based on the OECD draft protocols to determine whether it has endocrine-mediated properties. Bisphenol F was orally administered at doses 0, 20, 100 and 500 mg/kg per day for at least 28 days, but no clear endocrine-mediated changes were detected, and it was concluded to have no endocrine-mediated effects in young adult rats. On the other hand, the main effect of bisphenol F was concluded to be liver toxicity based on clinical biochemical parameters and liver weight, but without histopathological changes. The no-observed-effect level for bisphenol F is concluded to be under 20 mg/kg per day since decreased body weight accompanied by decreased serum total cholesterol, glucose, and albumin values were observed in the female rats given 20 mg/kg per day or higher doses of bisphenol F.