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Crystalline silica is an important cause of serious pulmonary diseases, and its toxic potential is known to be associated with its surface electrical properties. However, in vivo data clarifying the relevance of silica's toxic potential, especially its long-term effects, remain insufficient. To investigate the contribution of physico-chemical property including surface potential on the hazard of nanocrystalline silica, we performed single intratracheal instillation testing using five different crystalline silicas in a rat model and assessed time-course changes in pulmonary inflammation, lung burden, and thoracic lymph node loads. Silica-nanoparticles were prepared from two commercial products (Min-U-Sil5 [MS5] and SIO07PB [SPB]) using three different pretreatments: centrifugation (C), grinding (G), and surface dissolving (D). The five types of silica particles-MS5, MS5_C, SPB_C, SPB_G, and SPB_D-were intratracheally instilled into male F344 rats at doses of 0 mg/kg (purified water), 0.22 mg/kg (SPB), and 0.67, 2, or 6 mg/kg (MS5). Bronchoalveolar lavage, a lung burden analysis, and histopathological examination were performed at 3, 28, and 91 days after instillation. Granuloma formation was present in MS5 group at 91 days after instillation, although granuloma formation was suppressed in MS5_C group, which had a smaller particle size. SPB_C induced severe and progressive inflammation and kinetic lung overload, whereas SPB_G and SPB_D induced only slight and transient acute inflammation. Our results support that in vivo toxic potential of nanosilica by intratracheal instillation may involve with surface electrical properties leading to prolonged effect and may not be dependent not only on surface properties but also on other physico-chemical properties.

Occupational exposure to nickel oxide (NiO) is an important cause of respiratory tract cancer. Toxicity is known to be associated with the dissociated component, i.e. nickel (II) ions. To address the relationship between physicochemical properties, including solubility in artificial lysosomal fluid, of NiO and time-course changes in the pulmonary response, we conducted an intratracheal instillation study in male Fischer rats using four different well-characterized NiO products, US3352 (NiO A), NovaWireNi01 (NiO B), I small particle (NiO C), and 637130 (NiO D). The NiOs were suspended in purified water and instilled once intratracheally into male F344 rats (12 weeks old) at 0 (vehicle control), 0.67, 2, and 6 mg/kg body weight. The animals were euthanized on days 3, 28, or 91 after instillation, and blood analysis, bronchoalveolar lavage fluid (BALF) testing, and histopathological examination were performed. The most soluble product, NiO B, caused the most severe systemic toxicity, leading to a high mortality rate, but the response was transient and surviving animals recovered. The second-most-soluble material, NiO D, and the third, NiO A, caused evident pulmonary inflammation, and the responses persisted for at least 91 days with collagen proliferation. In contrast, NiO C induced barely detectable inflammation in the BALF examination, and no marked changes were noted on histopathology. These results indicate that the early phase toxic potential of NiO products, but not the persistence of pulmonary inflammation, is associated with their solubility.

To retrospectively assess data on immune checkpoint inhibitors(ICIs)in an actual clinical setting, examine the factors that contribute to response and survival using real-world data, and compare the effectiveness of the 3 types of ICIs for patients with non-small cell lung cancer(NSCLC).A retrospective analysis of 127 patients with NSCLC treated with ICIs at our hospital was conducted.Nivolumab(56 patients)showed a 3-year survival rate of 21.6% and a disease control rate of 57.1%. These results are consistent with the clinical trials of Nivolumab. Pembrolizumab(36 patients) showed a 2-year survival rate of 60.3%, a response rate of 50.0%, and a disease control rate of 63.9%. Atezolizumab(35 patients)displayed a particularly low response rate with a 1-year survival rate of 58.4%, response rate of 8.6%, and disease control rate of 25.7%. The treatment results for recurrence after surgery for lung cancer were comparable to those for unresectable lung cancer.Anti-PD-1 antibody displayed better therapeutic results than anti-PD-L1 antibody. The efficacy of ICI administration for postoperative recurrent lung cancer was also shown in this study.

Background: Crystalline silica is an important cause of serious pulmonary diseases. The relationship between this hazard and various physicochemical parameters of crystalline silica has been studied for more than a century, and the toxic potential of silica is known to be associated with its surface properties. However, no in vivo dataset has yet been accumulated to clarify the relevance of this, especially regarding longer term effects. To provide new insights into these longer term effects, we performed single intratracheal instillation testing of five different crystalline silicas and assessed the time-course changes in pulmonary inflammation, lung burden, and thoracic lymph node loads. The tested silicas were prepared from two commercial products [Min-U-Sil5 (MS5, US Silica Company) and SIO07PB (SPB, Kojundo Chemical)] by using three different pretreatment steps: centrifugation (C), grinding (G), and surface dissolving (D). The five types of silica particles—MS5, MS5_C, SPB_C, SPB_G, and SPB_D—were suspended in purified water and intratracheally instilled into male F344 rats. Bronchoalveolar lavage, lung burden analysis, and histopathological examination were performed 3, 28, and 91 days after instillation.Results: MS5 and MS5_C provoked similar biphasic inflammation that differed in severity: MS5 induced granuloma generation 91 days after instillation, whereas the smaller particles of MS5_C elicited only macrophage aggregation. SPB_C induced severe and persistent inflammation, whereas SPB_G and SPB_D induced only slight and transient acute inflammation. All of the silicas were dose-dependently retained in the lung. Silicas that induced prolonged responses were translocated to the thoracic lymph nodes as early as 28 days after instillation. Those that induced transient inflammation were removed effectively from the lung with very little lymph node retention. No quantitative association was identified between lung retention and physicochemical properties, although common features of the retained materials seemed to be reduced solubility, similar surface properties, and relatively small particle. Conclusion: Our key findings suggest that prolonged silica toxicity occurs through lymph node retention. Although the main drivers of translocation to the lymph nodes have not yet been clarified, we provide in vivo evidence of the contributions of at least silica solubility, surface properties, and particle size.

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.

Squamous cell papillomas are the most common benign tumors of the larynx (1). A solitary bronchial squamous cell papilloma (BSCP) was first reported in 1954 (2). BSCP is a benign tumor originating from squamous cell epithelium cells, and it accounts for 0.38% of all lung tumors (3). There are two primary clinical features of bronchial papillomas. First, BSCP has a tendency to spread to multiple sites within the bronchial tree.

We assessed the relation between smoking and pneumothorax in patients aged40. Of 526 patients who underwent surgery for pneumothorax in 2011~2015, 311 were under the age of 40 and they were included in this study. Of 311, 54 cases( 17.4%) were diagnosed with spontaneous pneumothorax associated with emphysematous change by pathological assessment. By the multivariate analysis, 2 parameters exhibited significance for the risk of these spontaneous pneumothorax:a Brinkmann index of ≥165 and a smoking period of ≥9.5 years. It was suggested that smoking is strongly related to the onset of spontaneous pneumothorax even in the younger population less than 40 years of age.

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.

We present the transponder design and verification to obtain over 10 Gbit/s capability for an optical feeder link. The transponder employing a transmitter and a receiver supports differential phase shift keying (DPSK) optical communication. In order to provide receiver stability against optical power fluctuations, we utilize the terrestrial technology and devices such as clock data recovery (CDR), a hard-decision forward error correction (FEC) and temperature control of delay line interferometer (DLI) to realize the enhancement of dynamic range of received optical power. We have also investigated reliability of terrestrial devices including photonics integration circuit (PIC) type DLI and CDR for satellites.

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 TiO2 to male F344 rats at 3.0 mg/kg body weight by using two delivery devices (gavage needle or microaerosolizer) and dose volumes of 0.5–3.0 mL/kg (gavage needle) or 0.5–2.0 mL/kg (microaerosolizer). We evaluated the pulmonary deposition and interlobar distribution of TiO2 at both 30 min and 3 days after administration. In addition, the inflammatory components in bronchoalveolar lavage (BAL) fluid were measured 3 days after administration of TiO2. At dose volumes of 0.5–2.0 mL/kg, the BAL values were comparable regardless of the device used. In addition, pulmonary TiO2 burden and lobar concentration patterns were equivalent at all combinations of dose volume and delivery device. In conclusion, the acute pulmonary toxicity of nanomaterials can be assessed effectively by using an IT test in which the test agent is provided to rats at a dose volume of 0.5–2.0 mL/kg with either a gavage needle or microaerosolizer.

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 TiO2 pulmonary microdistribution (per mesh: 100 μm × 100 μm) in lung sections from rats administered an intratracheal dose of TiO2 NPs (6 mg kg−1) via gavage needle or microsprayer. The results revealed that: (i) using a microsprayer appears to reduce the variations in TiO2 content (ng mesh−1) among rats (e.g., coefficients of variation, n = 3, microsprayer vs gavage needle: 13% vs 30%, for the entire lungs); (ii) TiO2 appears to be deposited less in the right middle lobes than in the rest of the lung lobes, irrespective of the chosen intratracheal delivery device; and (iii) similar TiO2 contents (ng mesh−1) and frequencies are deposited in the lung lobes of rats administered TiO2 NPs via gavage needle or microsprayer. This suggests that the physical state of the administered NP suspension does not markedly alter TiO2 pulmonary microdistribution. The results of this investigation are important for the standardization of intratracheal administration methods. Copyright © 2016 John Wiley & Sons, Ltd.

The toxicity of nanomaterials is complex and multifactorial and likely depends on their diverse physicochemical properties. Further development and application of nanomaterials requires a systematic, effective, and efficient method for evaluating their toxicity. One approach in this regard is to ascertain the variability in the physicochemical properties of nanomaterials that exhibit the same toxicity—that is, to establish “equivalence criteria” for nanomaterials. However, this approach requires the acquisition and comparison of toxicity data for various nanomaterials. In this chapter, we summarize our efforts to establish equivalence criteria for nanomaterials in regard to their toxicity after intratracheal instillation. To achieve this objective, we focused on intratracheal administration studies for evaluating nanomaterial toxicity simply and efficiently. Intratracheal instillation offers various advantages and disadvantages compared with inhalation exposure, which is widely used as a screening tool. In this study, we used intratracheal instillation to deliver a total of 20 nanomaterials representing three types (TiO2, NiO, and SiO2) to rats. We then compared the physicochemical properties and pulmonary toxicities of the tested nanomaterials and thus were able to detect characteristic features of their pulmonary toxic effects according to their physicochemical properties. We here demonstrated the effectiveness of using intratracheal administration studies to screen for pulmonary toxicity of nanomaterials. In addition, we anticipate that our proposed equivalence criteria will facilitate toxicity evaluation of nanomaterials.

Intratracheal (IT) instillation is a useful method for screening and hazard identification of inhaled materials, including manufactured nanomaterials. However, many variables regarding sample preparation, experimental equipment, and technical procedures influence results from studies involving IT instillation, and a standard procedure has not yet been validated internationally. These drawbacks prevent accurate comparison of hazard information obtained from different test facilities. In this chapter, we summarize representative IT instillation procedure and present acceptable ranges at which various procedural components do not affect the results. Issues requiring consideration prior to experimentation include the preparation of the dose suspension, appropriate vehicle, and delivery device. In addition, practical aspects of the testing procedure including appropriate forms of anesthesia, animal positioning during IT instillation, intubation methodology, and dosing volume, rate, and frequency are addressed, and recommended endpoints for hazard identification are described. Furthermore, an example recommended procedure for reproducible IT instillation is provided. Technical guidance for reproducible procedures, e.g., a Standard Operating Procedure, is pivotal for the standardization of IT instillation studies, and this chapter contributes validated technical information. In conclusion, IT instillation is poised to occupy an important position regarding hazard screening of manufactured nanomaterials.

The expression levels of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS) and orotate phosphoribosyltransferase (OPRT) may predict the clinical efficacy of 5-fluorouracil-based chemotherapy in patients with cancer. We herein investigated the differences in the mRNA levels of these enzymes in non-small-cell lung cancer (NSCLC) and evaluated their prognostic value for NSCLC treated by surgical resection. The intratumoral mRNA levels of TP, DPD, TS, and OPRT were quantified in 66 patients with pathological stage I and II NSCLC (adenocarcinoma or squamous cell carcinoma) following complete resection according to the Danenberg Tumor Profile method. The TP level was the only significant prognostic factor for disease-specific survival (DSS) following complete resection; the mean TP mRNA level differed significantly between the high and low mRNA expression groups. The DSS at 5 years was significantly higher in the low TP mRNA compared with that in the high TP mRNA expression group (83.4 vs. 58.6%, respectively; P=0.005). A Cox proportional hazards model revealed that pathological stage, sex, and TP expression were independent prognostic factors for DSS in patients with stage I and II NSCLC following complete resection. Thus, TP level may be used to monitor treatment efficacy and predict the outcome of NSCLC patients.

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.

The patient, a 65-year-old woman, visited at her local doctor's office with the chief complaint of pharyngeal pain. After being administered antibacterial drugs, hyperthermia persisted and the pharyngeal pain became exacerbated. She was referred to our hospital and diagnosed as a retropharyngeal abscess and descending necrotizing mediastinitis (DNM). She was urgently hospitalized and surgery was performed. The mediastinal pleura was incised with thoracoscopic guidance and curettage, irrigation, and drainage were performed. Additional drainage was determined to be necessary based on findings from subsequent chest computed tomography and a prolonged inflammatory reaction. Therefore, on hospital day 7, 2nd surgery were performed, and tracheotomy was additionally performed with curettage of the neck abscess. The patient was taken off mechanical ventilation on hospital day 18, and discharged on hospital day 55.

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.

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.

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 (

A 73-year-old woman complained of right chest discomfort. Chest X-ray during the follow-up for rheumatoid arthritis showed a mediastinal tumor. Chest computed tomography (CT) and magnetic resonance imaging (MRI) showed a 65-mm tumor in the right anterior mediastinum. A blood test showed high serum levels of CYFRA 21-1(29.8 ng/ml), white blood cells( WBC 10,800/µl), and C-reactive protein(CRP 16.1 mg/dl). Subsequently, inflammatory reactions improved, and the thymic tumor was resected. Histopathologically, the tumor was a type B2 thymoma with extensive coagulative necrosis. After resection, the serum CYFRA 21-1 level returned to the normal range.

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.