Nephrotoxicity Evaluation of Indium Phosphide Quantum Dots with Different Surface Modifications in BALB/c Mice.

InP QDs have shown a great potential as cadmium-free QDs alternatives in biomedical applications. It is essential to understand the biological fate and toxicity of InP QDs. In this study, we investigated the in vivo renal toxicity of InP/ZnS QDs terminated with different functional groups-hydroxyl (hQDs), amino (aQDs) and carboxyl (cQDs). After a single intravenous injection into BALB/c mice, blood biochemistry, QDs distribution, histopathology, inflammatory response, oxidative stress and apoptosis genes were evaluated at different predetermined times. The results showed fluorescent signals from QDs could be detected in kidneys during the observation period. No obvious changes were observed in histopathological detection or biochemistry parameters. Inflammatory response and oxidative stress were found in the renal tissues of mice exposed to the three kinds of QDs. A significant increase of KIM-1 expression was observed in hQDs and aQDs groups, suggesting hQDs and aQDs could cause renal involvement. Apoptosis-related genes (Bax, Caspase 3, 7 and 9) were up-regulated in hQDs and aQDs groups. The above results suggested InP/ZnS QDs with different surface chemical properties would cause different biological behaviors and molecular actions in vivo. The surface chemical properties of QDs should be fully considered in the design of InP/ZnS QDs for biomedical applications.

Nitrative DNA damage in lung epithelial cells exposed to indium nanoparticles and indium ions.

Indium compounds have been widely used in manufacturing displays of mobile phones, computers and televisions. However, inhalation exposure to indium compounds causes interstitial pneumonia in exposed workers and lung cancer in experimental animals. 8-Nitroguanine (8-nitroG) is a mutagenic DNA lesion formed under inflammatory conditions and may participate in indium-induced carcinogenesis. In this study, we examined 8-nitroG formation in A549 cultured human lung epithelial cells treated with indium compounds, including nanoparticles of indium oxide (In2O3) and indium-tin oxide (ITO), and indium chloride (InCl3). We performed fluorescent immunocytochemistry to examine 8-nitroG formation in indium-exposed A549 cells. All indium compounds significantly increased 8-nitroG formation in A549 cells at 5 ng/ml after 4 h incubation. 8-NitroG formation was largely reduced by 1400 W, methyl-ß-cyclodextrin (MBCD) and monodansylcadaverine (MDC), suggesting the involvement of nitric oxide synthase and endocytosis. 8-NitroG formation in A549 cells was also largely suppressed by small interfering RNA (siRNA) for high-mobility group box-1 (HMGB1), receptor for advanced glycation and end products (AGER, RAGE) and Toll-like receptor 9 (TLR9). These results suggest that indium compounds induce inflammation-mediated DNA damage in lung epithelial cells via the HMGB1-RAGE-TLR9 pathway. This mechanism may contribute to indium-induced genotoxicity in the respiratory system.

The toxicology of gallium oxide in comparison with gallium arsenide and indium oxide.

Gallium arsenide (GaAs) and indium oxide (In2O3) are used in electronic industries at high and increasing tonnages since decades. Gallium oxide (Ga2O3) is an emerging wide-bandgap transparent conductive oxide with as yet little industrial use. Since GaAs has received critical attention due to the arsenic ion, it seemed reasonable to compare its toxicology with the respective endpoints of Ga2O3 and In2O3 toxicology in order to find out if and to what extent arsenic contributes. In addition, the toxicology of Ga2O3 has not yet been adequately reviewed, Therefore, this review provides the first evaluation of all available toxicity data on Ga2O3. The acute toxicity of all three compounds is rather low. Subchronic inhalation studies in rats and mice revealed persistent pulmonary alveolar proteinosis (PAP) and/or alveolar histiocytic infiltrates down to the lowest tested concentration in rats and mice, i.e. 0.16 mg Ga2O3/m3. These are also the predominant effects after GaAs and In2O3 exposure at similarly low levels, i.e. 0.1 mg/m3 each. Subchronic Ga2O3 exposure caused a minimal microcytic anemia with erythrocytosis in rats (at 6.4 mg/m3 and greater) and mice (at 32 and 64 mg/m3), a decrease in epididymal sperm motility and concentration as well as testicular degeneration at 64 mg/m3. At comparable concentrations the hematological effects and male fertility of GaAs were much stronger. The stronger effects of GaAs are due to its better solubility and presumed higher bioavailability. The database for In2O3 is too small and subchronic testing was at very low levels to allow conclusive judgements if blood/blood forming or degrading and male fertility organs/tissues would also be targets.

Biodistribution and acute toxicity of cadmium-free quantum dots with different surface functional groups in mice following intratracheal inhalation.

Indium phosphide/zinc sulfate (InP/ZnS) quantum dots (QDs) are presumed to be less hazardous than those that contain cadmium. However, the toxicological profile has not been established. The present study investigated the acute toxicity of InP/ZnS QDs with different surface modifications (COOH, NH2, and OH) in mice after pulmonary aerosol inhalation. InP/ZnS QDs were able to pass through the blood-gas barrier and enter the circulation, and subsequently accumulated in major organs. No obvious changes were observed in the body weight or major organ coefficients. Red blood cell counts and platelet-related indicators were in the normal range, but the proportion of white blood cells was altered. The InP/ZnS QDs caused varying degrees of changes in some serum markers, but no histopathological abnormalities related to InP/ZnS QDs treatment was observed in major organs except that hyperemia in alveolar septa was found in lung sections. These results suggested that the effects of respiratory exposure to InP/ZnS QDs on the lungs need to be fully considered in future biomedical application although the overall toxicity of quantum dots is relatively low.

Near-Infrared-Light-Triggered Antimicrobial Indium Phosphide Quantum Dots.

The emergence of multidrug-resistant (MDR) pathogens represents one of the most urgent global public health crises. Light-activated quantum dots (QDs) are alternative antimicrobials, with efficient transport, low cost, and therapeutic efficacy, and they can act as antibiotic potentiators, with a mechanism of action orthogonal to small-molecule drugs. Furthermore, light-activation enhances control over the spatiotemporal release and dose of the therapeutic superoxide radicals from QDs. However, the limited deep-tissue penetration of visible light needed for QD activation, and concern over trace heavy metals, have prevented further translation. Herein, we report two indium phosphide (InP) QDs that operate in the near-infrared and deep-red light window, enabling deeper tissue penetration. These heavy-metal-free QDs eliminate MDR pathogenic bacteria, while remaining non-toxic to host human cells. This work provides a pathway for advancing QD nanotherapeutics to combat MDR superbugs.

The role of lysosomes in the phenomenon of concentration of aluminum and indium in the female reproductive system. An ultrastructural study.

The female reproductive system is one of the most complex systems in the body taking into account the hormonal fluctuations associated with ovarian and uterine menstrual cycles. The purpose of this work was to study the impact of aluminum nitrate and indium sulfate on the uterus and the ovary of a pregnant rat. The experiment was performed on adult female rats of Wistar strain weighing approximately 250g. The Transmission Electron Microscopy (TEM) showed the presence of electron-dense material in lysosomes of both uterine cells (myometrium and endometrium cells) and in the cells of the ovary (internal theca and granulosa cells). In addition to the presence of aluminum and indium deposits in the uterine and ovarian tissue, impaired endoplasmic reticulum, mitochondria and vacuolation were also identified. We concluded that lysosomes of uterus and ovary cells had the function to extract aluminum and indium introduced into the body in a soluble form. Then, the two elements were sequestrated within these organelles in an insoluble form most probably as phosphate salts such as reported for other kind of cells; kidney, liver, bone morrow Berry, 1996 [1]. This mechanism seems to be a defense one in which the lysosome would play a central role. Our results concerning the impact of the aluminum or indium presence in the lysosome of female reproductive system will be further used in order to assess their effects on the fertility and viability of oocytes in the pregnant treated rats.

In Vitro and In Vivo Evaluation of 89Zr-DS-8273a as a Theranostic for Anti-Death Receptor 5 Therapy.

Background: DS-8273a, an anti-human death receptor 5 (DR5) agonistic antibody, has cytotoxic activity against human cancer cells and induces apoptosis after specific binding to DR5. DS-8273a is currently being used in clinical Phase I trials. This study evaluated the molecular imaging of DR5 expression in vivo in mouse tumor models using SPECT/CT and PET/MRI, as a tool for drug development and trial design. Methods: DS-8273a was radiolabeled with indium-111 and zirconium-89. Radiochemical purity, immunoreactivity, antigen binding affinity and serum stability were assessed in vitro. In vivo biodistribution and pharmacokinetic studies were performed, including SPECT/CT and PET/MR imaging. A dose-escalation study using a PET/MR imaging quantitative analysis was also performed to determine DR5 receptor saturability in a mouse model. Results:111In-CHX-A″-DTPA-DS-8273a and 89Zr-Df-Bz-NCS-DS-8273a showed high immunoreactivity (100%), high serum stability, and bound to DR5 expressing cells with high affinity (Ka, 1.02-1.22 × 1010 M-1). The number of antibodies bound per cell was 32,000. In vivo biodistribution studies showed high and specific uptake of 111In-CHX-A″-DTPA-DS-8273a and 89Zr-Df-Bz-NCS-DS-8273a in DR5 expressing COLO205 xenografts, with no specific uptake in normal tissues or in DR5-negative CT26 xenografts. DR5 receptor saturation was observed in vivo by biodistribution studies and quantitative PET/MRI analysis. Conclusion:89Zr-Df-Bz-NCS-DS-8273a is a potential novel PET imaging reagent for human bioimaging trials, and can be used for effective dose assessment and patient response evaluation in clinical trials.

A Case of Focal Bone Marrow Reconversion Mimicking Bone Metastasis: The Value of 111Indium Chloride.

We present a case of a 66-year-old man with esophageal carcinoma. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for evaluating distant metastasis and staging revealed 18F-FDG uptake in the third lumbar vertebra and other vertebrae. Magnetic resonance imaging could not differentiate bone metastases from benign bone lesions. We considered the possibility of bone marrow reconversion. 111Indium chloride (111In-Cl3) scintigraphy with single-photon emission computed tomography/computed tomography (SPECT/CT) revealed erythroid bone marrow components in the bone lesions. The diagnosis of bone marrow reconversion was pathologically confirmed by a bone biopsy of the third lumbar vertebra. The patient underwent esophagectomy and has remained disease-free in the 2 years since. To the best of our knowledge, this is the first report to describe the usefulness of 111In-Cl3 with SPECT/CT for the diagnosis of bone marrow reconversion.

Indium oxide (In2O3) nanoparticles induce progressive lung injury distinct from lung injuries by copper oxide (CuO) and nickel oxide (NiO) nanoparticles.

Indium is an essential element in the manufacture of liquid crystal displays and other electronic devices, and several forms of indium compounds have been developed, including nanopowders, films, nanowires, and indium metal complexes. Although there are several reports on lung injury caused by indium-containing compounds, the toxicity of nanoscale indium oxide (In2O3) particles has not been reported. Here, we compared lung injury induced by a single exposure to In2O3 nanoparticles (NPs) to that caused by benchmark high-toxicity nickel oxide (NiO) and copper oxide (CuO) NPs. In2O3 NPs at doses of 7.5, 30, and 90 cm(2)/rat (50, 200, and 600 µg/rat) were administered to 6-week-old female Wistar rats via pharyngeal aspiration, and lung inflammation was evaluated 1, 3, 14, and 28 days after treatment. Neutrophilic inflammation was observed on day 1 and worsened until day 28, and severe pulmonary alveolar proteinosis (PAP) was observed on post-aspiration days 14 and 28. In contrast, pharyngeal aspiration of NiO NPs showed severe neutrophilic inflammation on day 1 and lymphocytic inflammation with PAP on day 28. Pharyngeal aspiration of CuO NPs showed severe neutrophilic inflammation on day 1, but symptoms were completely resolved after 14 days and no PAP was observed. The dose of In2O3 NPs that produced progressive neutrophilic inflammation and PAP was much less than the doses of other toxic particles that produced this effect, including crystalline silica and NiO NPs. These results suggest that occupational exposure to In2O3 NPs can cause severe lung injury.

Comparison of three remote radiolabelling methods for long-circulating liposomes.

Long-circulating liposomes (LCL) are often used as a drug carrier system to improve the therapeutic index of water-soluble drugs. To track these LCL in vivo, they can be radiolabelled with (111)In-oxine. For this labelling method, generally DTPA is encapsulated in the aqueous phase of LCL (DTPA-LCL). Alternatively, LCL can be labelled with (111)InCl3 after incorporation of DTPA-conjugated DSPE in the lipid bilayer (DTPA-DSPE LCL). Here, we compared the in vitro properties of DTPA-DSPE LCL with those of DTPA LCL and empty LCL. Additionally, we compared the in vivo performance of DTPA-DSPE LCL with those of DTPA LCL in mice. DTPA LCL (88 nm) and empty LCL (84 nm) were labelled with (111)In-oxine, and DTPA-DSPE LCL (83 nm) were labelled with (111)InCl3. Labelling efficiency at increasing specific activity was determined. In vitro stability of (111)In-labelled LCL was determined in human serum at 37 °C. The in vivo properties of (111)In-labelled LCL were determined in mice with a Staphylococcus aureus infection in the thigh muscle. Image acquisition, blood sampling and biodistribution studies were performed 1, 4 (blood sampling only), 24, 48 and 72 h p.i. of (111)In-labelled LCL. DTPA-DSPE LCL could be labelled efficiently at a much higher specific activity compared to DTPA LCL and empty LCL: > 90% at 15 GBq/mmol, > 90% at 150 MBq/mmol and 60­65% at 150 MBq/mmol, respectively. (111)In-labelled DTPA-DSPE LCL and DTPA LCL were stable in human serum, regarding label retention, for at least 48 h at 37 °C (> 98% retention of the radiolabel). In contrast, only 68% radiolabel was retained in empty LCL after 48 h. In vivo targeting of (111)In-DTPA-DSPE LCL to the abscess was comparable to targeting of (111)In-DTPA LCL (3.5 ± 0.9%ID/g and 3.4 ± 0.9%ID/g abscess uptake respectively, 48 h p.i.). In conclusion, labelling of DTPA-DSPE LCL with (111)InCl3 represents a robust, easy and fast procedure which is preferred over the more laborious conventional labelling of DTPA-LCL with (111)In-oxine.

Treatment of severe chronic graft-versus-host disease with decidual stromal cells and tracing with (111)indium radiolabeling.

Decidual stromal cells (DSCs) isolated from fetal membranes of term placentas are easily expanded and are highly immunosuppressive in vitro. These cells express high levels of integrins that are of importance in homing to inflamed tissues. In this study, we investigated DSCs as a cellular therapy for chronic graft-versus-host disease (cGvHD), a severe complication after allogeneic hematopoietic stem cell transplantation. Subsequent to transplantation, three patients developed severe extensive cGvHD and were treated with DSCs (1-2.8 × 10(6) cells/kg). One-third of the DSCs administered to two patients were labeled with (111)Indium, and the in vivo distribution was tracked for 48 h. The (111)In-labeled DSCs were initially located in the lungs, followed by dissemination to the liver and spleen. The DSCs induced a partial response in two of the patients. Blood samples from the patients were extensively evaluated by flow cytometry, luminex, and enzyme-linked immunosorbent assay. The nonresponder had the highest proportion of T-cells with Th17 and Th2 phenotypes and the highest median plasma concentrations of IL-17 and IL-4. The same patient also had high frequencies of HLA-DR(+) T-cells and regulatory T-cells. To conclude, DSCs are safe to infuse with no adverse effects. We determined how stromal cells are distributed in vivo after infusion in a cGvHD setting. The methods established for analysis of blood samples will be useful in determining the effect of DSCs in a study comprising a larger patient material. This pilot study may provide a basis for further controlled investigations with DSCs in a clinical setting.

Liquid-solid phase transition alloy as reversible and rapid molding bone cement.

Acrylic bone cement has been an essential non-metallic implant used as fixing agent in the cemented total joint arthroplasty (THA). However, the currently available materials based mainly on polymethylmethacrylate (PMMA) still encounter certain limitations, such as time-consuming polymerization, thermal and chemical necrosis and troublesome revision procedure. Here from an alternative way, we proposed for the first time to adopt the injectable alloy cement to address such tough issues through introducing its unique liquid-solid phase transition mechanism. A typical cement along this way is thus made of an alloy Bi/In/Sn/Zn with a specifically designed low melting point 57.5 °C, which enables its rapid molding into various desired shapes with high plasticity and ultimate metallic behaviors. The fundamental characteristics including the mechanical strength, biocompatibility and phase transition-induced thermal effects have been clarified to demonstrate the importance of such alloy as unconventional cement with favorable merits. In addition, we also disclosed its advantage as an excellent contrast agent for radiation imaging on the bone interior structure which is highly beneficial for guiding the surgery and monitoring the therapeutic effects. Particularly, the proposed alloy cement with reversible phase transition feature significantly simplifies the revision of the cement and prosthesis. This study opens the way for employing the injectable alloy materials as reversible bone cement to fulfill diverse clinical needs in the coming time.

Oxidative stress in blood and testicle of rat following intraperitoneal administration of aluminum and indium.

Aluminum (Al) and indium (In) have embryotoxic, neurotoxic and genotoxic effects, oxidative stress being one of the possible mechanisms involved in their cytotoxicity. We have recently demonstrated that indium intraperitoneal (ip) administration induced histological disorganization of testicular tissue. In the present research we aimed at investigating the effect of Al and In ip administration on systemic and testicular oxidative stress status. Studies were performed on Wistar rats ip injected with Al, In or physiological solution for two weeks. Our results showed that In significantly decreased the absolute weight of testicles. Measurements of lactate dehydrogenase (LDH) and paraoxonase (PON) activities showed that In induced a significant augmentation in the first parameter but no changes were observed in the second. Both Al and In caused oxidative stress in testicles by increasing malondialdehyde (MDA) and protein carbonyls (PC) production. Concomitantly, thiol group (-SH) and glutathione (GSH) level were enhanced in the testicles. In the blood, while concentrations of MDA was not changed, those of GSH was significantly decreased in the Al and In groups. Our results indicated that Al and In cause oxidative stress both in blood and testicles but In has cytotoxic effect as well as negative impact on testicle weights. These findings could explain the testicular histological alterations previously described after In ip administration.

Comparative cytotoxicity of gold-doxorubicin and InP-doxorubicin conjugates.

Direct comparisons of different types of nanoparticles for drug delivery have seldom been performed. In this study we compare the physical properties and cellular activity of doxorubicin (Dox) conjugates to gold nanoparticles (Au) and InP quantum dots of comparable diameter. Although the Au particles alone are non-toxic and InP is moderately toxic, Au-Dox is more effective than InP-Dox against the Dox-resistant B16 melanoma cell line. Light exposure does not augment the efficacy of InP-Dox, suggesting that conjugates are breaking down. Electron and confocal microscopy and atomic absorption spectroscopy reveal that over 60% of the Au-Dox conjugates reach the cell nucleus. In contrast, InP-Dox enters cell nuclei to a very limited extent, although liberated Dox from the conjugates does eventually reach the nucleus. These observations are attributed to faster Dox release from Au conjugates under endosomal conditions, greater aggregation of InP-Dox with cytoplasmic proteins, and adherence of InP to membranes. These findings have important implications for design of active drug-nanoparticle conjugates.

Role of parietal and principal gastric mucosa cells in the phenomenon of concentration of aluminum and indium.

The subcellular behavior of aluminum and indium, used in medical and industrial fields, was studied in the gastric mucosa and the liver after their intragastric administration to rats, using, two of the most sensitive methods of observation and microanalysis, the transmission electron microscopy, and the secondary ion mass spectrometry. The ultrastructural study showed the presence of electron dense deposits, in the lysosomes of parietal and principal gastric mucosa cells but no loaded lysosomes were observed in the different studied hepatic territories. The microanalytical study allowed the identification of the chemical species present in those deposits as aluminum or indium isotopes and the cartography of their distribution. No modification was observed in control rats tissues. In comparison to previous studies describing the mechanism of aluminum concentration in the gastric mucosa and showing that this element was concentrated in the lysosomes of fundic and antral human gastric mucosa, our study provided additional informations about the types of cells involved in the phenomenon of concentration of aluminum and indium, which are the parietal and the principal cells of the gastric mucosa. Our study demonstrated that these cells have the ability to concentrate selectively aluminum and indium in their lysosomes, as a defensive reaction against intoxication by foreign elements.

Microscopy and microanalysis study of the indium (In) behavior in the intestinal mucosa, the liver, the kidney and the testicle.

Several studies have demonstrated that In used in medicine has several impacts on organs like spleen and lungs after its systemic administration. In the present study, ultrastructural and microanalytical methods were used to investigate the impact of the presence of this element in the intestinal mucosa, the liver, the kidney and the testicle after its administration in two ways. After intraperitoneal administration, In was selectively concentrated in the lysosomes of hepatocytes, of tubular proximal convoluted cells and of Sertoli and Leydig cells. After intragastric administration, ultrastructural study showed that this element was concentrated in the lysosomes of duodenal enterocytes. Microanalytical methods showed that In was precipitated in those organelles in the form of insoluble phosphate salts. Similarly to other studies, it seemed that since In is a foreign element for the organism, it was precipitated in lysosomes, very probably due to the activity of an intralysosomal enzyme the acid phosphatase, to avoid its invasion to organism via the blood. This mechanism of precipitation of the mineral elements is of great interest in the process of defensive reaction of the organism against intoxication by foreign elements.

[Intestinal and hepatic subcellular localization of aluminium and indium administered orally to rat]. / Localisation subcellulaire intestinale et hepatique de l'aluminium et de l'indium administres par voie orale chez le rat.

Aluminium and indium are two elements used in industrial and medical fields. The purpose of this work was to study the subcellular localization of these elements, after their single and simultaneous oral administration to rats. 2h after the administration of these two elements, the small intestine and the liver were removed.Ultrastructural study showed the presence of electron dense deposits in the lysosomes of apical parts of duodenal enterocytes. When the minerals were administered simultaneously, deposits were observed in lysosomes of duodenal and jejunal enterocytes. No deposits were seen in the hepatic tissue of treated and control rats. Microanalysis identification showed that the deposits are constituted of aluminium, indium as well as phosphorus. Our results suggested that the elements are concentrated, in lysosomes, under the form of insoluble phosphate salts and it seemed that there are no specific lysosomes for the concentration of minerals since the two elements were concentrated in the same lysosome when they are administered simultaneously.

Determinação dos fatores de recuperação do 111In e do 99mTc na quantificação de atividade com imagens SPECT / Determination of 111In and 99mTc recovery in the quantification of activity with SPECT imaging

OBJETIVO: Determinar, experimentalmente, os coeficientes de recuperação do 111In e do 99mTc usando imagens SPECT. MATERIAIS E MÉTODOS: Quatro diferentes concentrações de 111In e de 99mTc foram usadas para quantificar a atividade em esferas de diferentes tamanhos. As imagens foram obtidas com um equipamento híbrido SPECT/CT, com dois detectores. A reconstrução das imagens foi realizada usando o método iterativo ordered subset expectation maximization (OSEM). A correção de atenuação foi realizada com o uso de um mapa de atenuação e a correção de espalhamento foi realizada usando a técnica das janelas de energia. RESULTADOS: Os resultados mostraram que o efeito do volume parcial foi observado de forma mais significativa para as esferas com volume < 6 ml. Para o 111In, os resultados mostram uma dependência com relação às concentrações usadas nas esferas e ao nível de background usado. Para o 99mTc, pôde-se observar uma tendência à subestimação dos resultados quando os níveis mais altos de background foram utilizados. CONCLUSÃO: É necessário usar os fatores de correção para compensar o efeito do volume parcial em objetos com volume < 6 ml para ambos os radionuclídeos. A subtração das contagens espúrias presentes nas imagens SPECT foi o fator que mais influenciou na quantificação da atividade nessas esferas.

OBJECTIVE: To experimentally determine the 99mTc and 111In activity recovery coefficients in SPECT imaging. MATERIALS AND METHODS: Four different 99mTc and 111In concentrations were utilized for quantifying activity in spheres of four different sizes. Images were obtained with a hybrid dual-head SPECT-CT imaging system. The ordered subset expectation maximization (OSEM) iterative method was utilized for images reconstruction. An attenuation map was utilized for attenuation correction, and the multiple energy window technique for scattering correction. RESULTS: Results for spheres < 6 ml in volume were significantly affected by the partial volume effect. For 111In quantification, results show a dependence on sphere concentrations and background levels. For 99mTc quantification, there was a tendency towards values underestimation with higher background levels. CONCLUSION: Correction factors must be utilized for compensating the partial volume effect on objects with < 6 ml in volume for both radionuclides. Background subtraction to compensate spurious count present on SPECT images has a significant influence on the quantification of activity, especially for the smaller objects.

Chronic pulmonary toxicity study of indium-tin oxide and indium oxide following intratracheal instillations into the lungs of hamsters.

OBJECTIVES: The aim of this study was to clarify the chronic toxicological effects of indium-tin oxide (ITO) and indium oxide (In(2)O(3)) on laboratory animals. METHODS: Male Syrian golden hamsters were intratracheally administered 3 mg/kg or 6 mg/kg of ITO particles, or 2.7 mg/kg or 5.4 mg/kg of In(2)O(3) particles, containing 2.2 mg/kg or 4.5 mg/kg of indium, twice a week, for 8 wk. Control hamsters were given vehicle of distilled water only. The hamsters were euthanized serially up to 78 wk after the final instillation and the toxicological effects were determined. RESULTS: Body weight gain was significantly suppressed in the ITO 6 mg/kg-treated hamsters compared with the control group, but not in the ITO 3 mg/kg-treated or In(2)O(3)-treated hamsters. Relative lung weights among all the indium-treated groups were significantly increased compared to that in the control group throughout the observation period. The serum indium concentration among all the indium-treated groups gradually increased up to the end of the observation period. Histopathologically, foci of slight to severe pulmonary inflammatory response with diffuse alveolar or bronchiolar cell hyperplasia, expansion of the alveolar spaces and interstitial fibrotic proliferation were present in all the indium-treated hamsters and the severity of these lesions worsened with the passage of time. Lung benign adenomas were only manifest in 3 out of 15 of the ITO 6 mg/kg-treated hamsters. CONCLUSIONS: The present results clearly demonstrate that ITO and In(2)O(3) particles caused chronic pulmonary toxicity when repeated intratracheal instillations were given to hamsters.

Pleural effects of indium phosphide in B6C3F1 mice: nonfibrous particulate induced pleural fibrosis.

The mechanism(s) by which chronic inhalation of indium phosphide (InP) particles causes pleural fibrosis is not known. Few studies of InP pleural toxicity have been conducted because of the challenges in conducting particulate inhalation exposures, and because the pleural lesions developed slowly over the 2-year inhalation study. The authors investigated whether InP (1 mg/kg) administered by a single oropharyngeal aspiration would cause pleural fibrosis in male B6C3F1 mice. By 28 days after treatment, protein and lactate dehydrogenase (LDH) were significantly increased in bronchoalveolar lavage fluid (BALF), but were unchanged in pleural lavage fluid (PLF). A pronounced pleural effusion characterized by significant increases in cytokines and a 3.7-fold increase in cell number was detected 28 days after InP treatment. Aspiration of soluble InCl(3) caused a similar delayed pleural effusion; however, other soluble metals, insoluble particles, and fibers did not. The effusion caused by InP was accompanied by areas of pleural thickening and inflammation at day 28, and by pleural fibrosis at day 98. Aspiration of InP produced pleural fibrosis that was histologically similar to lesions caused by chronic inhalation exposure, and in a shorter time period. This oropharyngeal aspiration model was used to provide an initial characterization of the progression of pleural lesions caused by InP.