An advanced case of indium lung disease with progressive emphysema.

OBJECTIVES: To report the occurrence of an advanced case of indium lung disease with severely progressive emphysema in an indium-exposed worker. CASE REPORT: A healthy 42-year-old male smoker was employed to primarily grind indium-tin oxide (ITO) target plates, exposing him to indium for 9 years (1998-2008). In 2004, an epidemiological study was conducted on indium-exposed workers at the factory in which he worked. The subject's serum indium concentration (In-S) was 99.7 µg/l, while his serum Krebs von den Lungen-6 level was 2,350 U/ml. Pulmonary function tests showed forced vital capacity (FVC) of 4.17 l (91.5% of the JRS predicted value), forced expiratory volume in 1 s (FEV1) of 3.19 l (80.8% of predicted), and an FEV1-to-FVC ratio of 76.5%. A high-resolution chest computed tomography (HRCT) scan showed mild interlobular septal thickening and mild emphysematous changes. In 2008, he was transferred from the ITO grinding workplace to an inspection work section, where indium concentrations in total dusts had a range of 0.001-0.002 mg/m3. In 2009, the subject's In-S had increased to 132.1 µg/l, and pulmonary function tests revealed obstructive changes. In addition, HRCT scan showed clear evidence of progressive lung destruction with accompanying severe centrilobular emphysema and interlobular septal thickening in both lung fields. The subject's condition gradually worsened, and in 2015, he was registered with the Japan Organ Transplant Network for lung transplantation (LTx). CONCLUSIONS: Heavy indium exposure is a risk factor for emphysema, which can lead to a severity level that requires LTx as the final therapeutic option.

Respirable indium exposures, plasma indium, and respiratory health among indium-tin oxide (ITO) workers.

BACKGROUND: Workers manufacturing indium-tin oxide (ITO) are at risk of elevated indium concentration in blood and indium lung disease, but relationships between respirable indium exposures and biomarkers of exposure and disease are unknown. METHODS: For 87 (93%) current ITO workers, we determined correlations between respirable and plasma indium and evaluated associations between exposures and health outcomes. RESULTS: Current respirable indium exposure ranged from 0.4 to 108 µg/m(3) and cumulative respirable indium exposure from 0.4 to 923 µg-yr/m(3) . Plasma indium better correlated with cumulative (rs = 0.77) than current exposure (rs = 0.54) overall and with tenure ≥1.9 years. Higher cumulative respirable indium exposures were associated with more dyspnea, lower spirometric parameters, and higher serum biomarkers of lung disease (KL-6 and SP-D), with significant effects starting at 22 µg-yr/m(3) , reached by 46% of participants. CONCLUSIONS: Plasma indium concentration reflected cumulative respirable indium exposure, which was associated with clinical, functional, and serum biomarkers of lung disease. Am. J. Ind. Med. 59:522-531, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Generation of hybrid sinograms for the recovery of kV-CT images with metal artifacts for helical tomotherapy.

PURPOSE: The overall goal of this study is to restore kilovoltage computed tomography (kV-CT) images which are disfigured by patients' metal prostheses. By generating a hybrid sinogram that is a combination of kV and megavoltage (MV) projection data, the authors suggest a novel metal artifact-reduction (MAR) method that retains the image quality to match that of kV-CT and simultaneously restores the information of metal prostheses lost due to photon starvation. METHODS: CT projection data contain information about attenuation coefficients and the total length of the attenuation. By normalizing raw kV projections with their own total lengths of attenuation, mean attenuation projections were obtained. In the same manner, mean density projections of MV-CT were obtained by the normalization of MV projections resulting from the forward projection of density-calibrated MV-CT images with the geometric parameters of the kV-CT device. To generate the hybrid sinogram, metal-affected signals of the kV sinogram were identified and replaced by the corresponding signals of the MV sinogram following a density calibration step with kV data. Filtered backprojection was implemented to reconstruct the hybrid CT image. To validate the authors' approach, they simulated four different scenarios for three heads and one pelvis using metallic rod inserts within a cylindrical phantom. Five inserts describing human body elements were also included in the phantom. The authors compared the image qualities among the kV, MV, and hybrid CT images by measuring the contrast-to-noise ratio (CNR), the signal-to-noise ratio (SNR), the densities of all inserts, and the spatial resolution. In addition, the MAR performance was compared among three existing MAR methods and the authors' hybrid method. Finally, for clinical trials, the authors produced hybrid images of three patients having dental metal prostheses to compare their MAR performances with those of the kV, MV, and three existing MAR methods. RESULTS: The authors compared the image quality and MAR performance of the hybrid method with those of other imaging modalities and the three MAR methods, respectively. The total measured mean of the CNR (SNR) values for the nonmetal inserts was determined to be 14.3 (35.3), 15.3 (37.8), and 25.5 (64.3) for the kV, MV, and hybrid images, respectively, and the spatial resolutions of the hybrid images were similar to those of the kV images. The measured densities of the metal and nonmetal inserts in the hybrid images were in good agreement with their true densities, except in cases of extremely low densities, such as air and lung. Using the hybrid method, major streak artifacts were suitably removed and no secondary artifacts were introduced in the resultant image. In clinical trials, the authors verified that kV and MV projections were successfully combined and turned into the resultant hybrid image with high image contrast, accurate metal information, and few metal artifacts. The hybrid method also outperformed the three existing MAR methods with regard to metal information restoration and secondary artifact prevention. CONCLUSIONS: The authors have shown that the hybrid method can restore the overall image quality of kV-CT disfigured by severe metal artifacts and restore the information of metal prostheses lost due to photon starvation. The hybrid images may allow for the improved delineation of structures of interest and accurate dose calculations for radiation treatment planning for patients with metal prostheses.

Serial evaluations at an indium-tin oxide production facility.

BACKGROUND: We evaluated the effectiveness of workplace changes to prevent indium lung disease, using 2002-2010 surveillance data collected by an indium-tin oxide production facility. METHODS: We assessed pulmonary function using lower limits of normal. Blood indium concentration and personal air sampling data were used to estimate exposure. RESULTS: Abnormalities were uncommon at hire. After hire, prevalence of spirometric restriction was 31% (n = 14/45), about fourfold higher than expected. Excessive decline in FEV1 was elevated at 29% (n = 12/41). Half (n = 21/42) had blood indium ≥5 µg/l. More recent hires had fewer abnormalities. There was a suggestion that abnormalities were more common among workers with blood indium ≥5 µg/l, but otherwise an exposure-response relationship was not evident. Peak dust concentrations were obscured by time averaging. CONCLUSIONS: Evolving lung function abnormalities consistent with subclinical indium lung disease appeared common and merit systematic investigation. Traditional measures of exposure and response were not illustrative, suggesting fresh approaches will be needed. Workplace changes seemed to have had a positive though incomplete impact; novel preventive interventions are warranted.

Relationship between indium exposure and oxidative damage in workers in indium tin oxide production plants.

PURPOSE: The study aimed to assess the relationship between indium exposure and surfactant protein and any oxidative damage in indium tin oxide (ITO)-exposed workers. METHODS: The study was conducted in two typical ITO-manufacturing plants in Taiwan. One hundred and seventy manufacturing workers and 132 administrators were recruited. RESULTS: The geometric mean serum indium (S-In) level in the workers of the manufacturing department was 1.26 µg/l, which was significantly higher than those in the administrative department (0.72 µg/l). The S-In levels of 49 workers were higher than 3 µg/l (49/302, 16.2%), exceeding an occupational exposure limit suggested by the Japan Society for Occupational Health. Significant positive relationships were found between S-In and surfactant protein A (SP-A), and surfactant protein D (SP-D) levels. SP-A and SP-D levels were elevated significantly in the workers with moderately high indium exposure. CONCLUSION: The present study indicates a significant elevating trend of SP-A and SP-D levels in ITO-manufacturing workers, which are sensitive markers of interstitial lung disease. Though the indium exposure is not directly linked to all indicators of oxidative DNA damage, the ITO-manufacturing workplace is suggested to be related to oxidative DNA damage for the workers in the current study. Therefore, in addition to the indium exposure, there might be other occupational hazards in the ITO workplace to cause oxidative damage.

Oral lichenoid reaction associated with tin component of amalgam restorations: a case report.

Amalgam or its components may cause type IV hypersensitivity reactions on the oral mucosa. Majority of the reported cases involved a delayed hypersensitivity to mercury. A case of bilateral oral lichenoid reaction is presented, which was present in relation to amalgam restorations. Histopathological features were compatible with lichenoid mucositis. Patch test was positive with pulverized amalgam and tin. The lesion healed up after replacement of restorations with an intermediate restorative material. The clinician should be aware of all possible pathological etiologies of white lesions. If there is any doubt about the nature or management of an unusual oral lesion, referral to appropriate specialists is mandatory.

Pulmonary alveolar proteinosis in workers at an indium processing facility.

Two cases of pulmonary alveolar proteinosis, including one death, occurred in workers at a facility producing indium-tin oxide (ITO), a compound used in recent years to make flat panel displays. Both workers were exposed to airborne ITO dust and had indium in lung tissue specimens. One worker was tested for autoantibodies to granulocytemacrophage-colonystimulating factor (GM-CSF) and found to have an elevated level. These cases suggest that inhalational exposure to ITO causes pulmonary alveolar proteinosis, which may occur via an autoimmune mechanism.

[Three cases of indium lung].

The production of indium tin oxide (ITO) has been increasing during the past decade because of its use in liquid crystal and plasma display panels. Following the first report on lethal lung injury in a ITO worker in 2001, we began pulmonary check-ups for 115 workers in the plant in our capacity of industrial physicians of the plant. Hence, we report interstitial pulmonary disease in 3 workers who had engaged in wet-surface grinding of ITO for 8 to 12 years and had significant lung injuries. The serum indium level and serum concentration of KL-6 were significantly elevated in all 3 cases. One non-smoker case among them showed severe obstructive changes on spirometry and had an episode of repeated bilateral pneumothorax before and during the follow-up period. All 3 cases showed both interstitial and/or emphysematous changes on HRCT. It is suggested that inhaled indium compounds can cause a new and unique interstitial pulmonary disease.

Pulmonary fibrosis in an individual occupationally exposed to inhaled indium-tin oxide.

Despite the increasing industrial use of indium-tin oxide (ITO) to manufacture flat-panel displays, such as liquid-crystal displays or plasma display panels for televisions, little is known about the potential health hazard induced by occupational exposure to indium compounds. The current study describes a case of fibrotic lung disease that developed after a 4-yr exposure to ITO. The pathology of the lung demonstrated pulmonary fibrosis with the presence of cholesterol granulomas. In conclusion, more attention needs to be paid to the possible toxic effects of indium compounds, and maximum healthcare measures should be taken to protect industry workers from these toxicities.

Comparative assessment of gastrointestinal irritant potency in man of tin(II) chloride and tin migrated from packaging.

Tin is present in low concentrations in most canned foods and beverages, the highest levels being found in products packaged in unlacquered or partially lacquered tinplate cans. A limited number of case-reports of acute gastrointestinal disorders after consumption of food containing 100-500 mg/kg tin have been reported, but these reports suffer many insufficiencies. Controlled clinical studies on acute effects of tin migrated from packaging suggest a threshold concentration for adverse effects (AEs) of >730 mg/kg. Two separate randomised, single-centre, double-blind, crossover studies, enabling comparison of the tolerability of tin added as tin(II) chloride at concentrations of <0.5, 161, 264 and 529 mg/kg in 250 ml tomato juice in 20 volunteers (Study 1) and tin migrated from packaging at concentrations of <0.5, 201 and 267 mg/kg in 250 ml tomato soup in 24 volunteers (Study 2) were carried out. Distribution studies were conducted to get insight in the acute AEs of low molecular weight (<1000 Da) tin species in the soluble fraction of food products. Results show that the chemical form of tin and not the elemental concentration per se determines the severity of AEs. A clear dose-response relationship was only observed when tin was added as tin(II) chloride in tomato juice. No clinically significant AEs were reported in Study 2 and comparison of the incidence of tin-related AEs showed no difference between the dose levels (including control). Tin species of low molecular weight in supernatant represented 31-32% of total tin in canned tomato soup versus 56-61% in juice freshly spiked with tin(II) chloride. Differences in the incidence of AEs following administration of tomato juice with 161 and 264 mg of tin per kg and tomato soup with 201 and 267 mg of tin per kg likely results from differences in the concentration of low molecular weight tin species and in the nature of tin complexes formed. The results of this work demonstrate that tin levels up to 267 mg/kg in canned food cause no AEs in healthy adults and support the currently proposed tin levels of 200 mg/kg and 250 mg/kg for canned beverages and canned foods, respectively, as safe levels for adults in the general population.

Dna damage in peripheral blood nuclear cells assessed by comet assay from individuals submitted to scintigraphic examinations.

Stannous chloride (SnCl2) is employed as a reducing agent to obtain Technetium-99m-labelled radiophamaceuticals in nuclear medicine kits, being injected endovenously in humans. Toxic effects of these kits were not studied, thus making it important to evaluate their impact in humans. In this study, the toxic effects were evaluated from peripheral blood nuclear cells (PBNC) from patients who received radiopharmaceuticals obtained using such kits. The analyses included results performed by comet assay. DNA damage was visualized in PBNC samples collected within a time up to 2 hr, and 24 hr after radiopharmaceutical injection in the patients. Initially we observed an increase of comet signals, which subsequently were reduced to zero after 24 hr. The diminishing of comet amounts probably is associated with DNA repair of damaged cells or with the elimination by apoptosis of cells whose DNA are not repaired.

Genotoxidade do íon estanoso e sua associação ao DNA / Stannous ion genotoxic and ist association of DNA

O estanho é um agente químico de uso amplamente difundido nos mais diferentes setores da atividade humana, podendo ser encontrado, por exemplo, em preparações biocidas; como conservante em refrigerantes; na composição de cremes dentais e enxagüantes orais (como veiculador de flúor); como agente anticorrosivo na cobertura de outros metais em embalagens metálicas contendo alimentos e na pigmentação de tintas especiais. Na forma de cloreto estanoso (SnCl2), este agente é utilizado como agente redutor do Tecnécio 99m para a obtenção de radiofármacos e outras moléculas de interesse biológico. Uma vez que a literatura apresenta vários efeitos biológicos indesejáveis atribuídos ao SnCl2, este trabalho teve por objetivo avaliar a sua atividade genotóxica, bem como a ação antioxidante de algumas substâncias naturais (cartilagem e boldina), através do bloqueio das lesões produzidas por este sal em plasmídeos e células bacterianas, com o fim de estudar a ação do íon estanoso sobre o DNA. O emprego das técnicas de análise de sobrevivência bacteriana, capacidade transformante, eletroforese em gel de agarose, espectrofotometria de luz ultravioleta e de absorção atômica, reveram que: i) O cloreto estanoso provoca lesões, mediadas pela produção de espécies reativas de oxigênio, tanto in vivo quanto in vitro; ii) os danos induzidos pelo SnCl2 provocam diminuição da capacidade transformante do plamídeo pUC9.1; iii) o número de lesões formadas no DNS é diretamente proporcional ao tempo de incubação com SnCl2; iv)o íon estanoso é capaz de se associar à molécula de DNA, induzindo a geração de espécies reativas de oxigênio próximo ao local de ligação, promovendo modificações na estrutura da macromolécula; v) essa associação parece acarretar um ataque preferencial às bases nitrogenadas, fato que poderia estar associado a uma potencialidade mutagênica do estanho

Molecular, enzymatic, and regulatory characterization of rat kidney cytochromes P450 4A2 and 4A3.

The cDNAs encoding cytochromes CYP 4A2 and 4A3 were cloned by RT-PCR amplification of male rat kidney and liver RNAs, respectively. Sequence analysis demonstrated that these cDNAs were nearly identical to the published sequences for CYPs 4A2 and 4A3. CYP 4A2 and 4A3 share extensive sequence homology that extends into their 3'- and 5'-untranslated segments ( approximately 97% overall nucleotide identity). Analysis of cDNA and genomic DNA sequences shows that a sequence of 123 bp, recognized as an intron during the processing of CYP 4A2 transcripts, is conserved in the 4A3 mRNAs and that these otherwise highly homologous genes show different exon-intron distributions. The CYP 4A2 and 4A3 cDNAs were expressed in a baculovirus-insect cell expression system. Purified recombinant CYP 4A2 oxidized arachidonic acid to a mixture of 19- and 20-hydroxyeicosatetraenoic acids (20 and 80% of the total products, respectively). Reaction rates were maximal when CYP 4A2 was reconstituted in the presence of an equimolar concentration of cytochrome b5 and a 10-fold molar excess of NADPH-cytochrome P450 reductase. Studies using microsomal fractions isolated from noninfected insect cells and from cells infected with CYP 4A3 recombinant baculoviruses showed (a) the presence of an endogenous lauric acid omega-hydroxylase and arachidonic acid epoxygenase in the noninfected cells, (b) the CYP 4A3-dependent oxidation of lauric acid to 11- and 12-hydroxylaurate (24 and 76% of the total products, respectively), and (c) the lack of arachidonic acid metabolism by microsomal recombinant CYP 4A3. Nucleic acid hybridization and immunoelectrophoresis studies demonstrated that (a) CYP 4A2 transcripts are abundantly expressed in the female kidney and that CYP 4A3 is expressed in female but not in male liver, (b) anti-CYP 4A2 immunoreactive material was detected only in the male kidney, (c) male and female livers or kidneys support only low levels of CYP 4A3 translation, and (d) excess dietary salt does not alter the kidney levels of mRNA transcripts encoding CYP 4A1, 4A2, or 4A3 or change the levels of microsomal anti-4A1 or -4A2 immunoreactive proteins. Finally, no significant differences were observed between Dahl salt resistant or Dahl salt sensitive rats in the levels and/or salt regulation of mRNA transcripts enecoding CYP 4A1, 4A2, or 4A3 or the in levels of the corresponding proteins.

Mutational potentiality of stannous chloride: an important reducing agent in the Tc-99m-radiopharmaceuticals.

Stannous chloride (SnCl2) is frequently used in nuclear medicine as a reducing agent to label many radiopharmaceutical products with technetium-99m (99mTc). The aim of the present paper was to study the role of DNA repair genes in the repair of SnCl2-induced damage, using mutant strains of Escherichia coli lacking one or more DNA repair genes. Our results suggest that the product of the xthA gene, exonuclease III, is required for the repair of lesions induced by SnCl2. We further investigated the mutagenic properties of SnCl2 to a molecular level by using the supF tRNA gene as target in a forward mutational system. We have found that the survival of E. coli cells was strongly reduced with increasing concentrations of SnCl2. Moreover, when the shuttle vector pAC189 carrying the supF gene was treated with SnCl2, and then transfected to E. coli, we observed that its transformation efficiency dropped when compared to the non-treated control, with a parallel increase in mutation frequency after the damaged plasmids have replicated in bacterial cells. The mutation spectrum induced by SnCl2 reveals a high frequency of base substitutions, involving guanines. Sequence analysis of 41 independent supF mutant plasmids revealed that 39 mutants contained base substitutions, with 21 G:C to T:A and 17 G:C to C:G transversions. G to T transversions presumably resulted from 8-oxoG. However, the G to C one may be due to a yet unidentified lesion.