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Thyroidal and orbital lymphocytic infiltration in Graves' disease, as well as identification of somatostatin receptors on lymphocytes, has provided a rationale for receptor imaging with the radiolabeled somatostatin analog pentetreotide. Recently, we demonstrated that in contrast to controls, Graves' patients showed markedly increased orbital accumulation of pentetreotide.indium penetreotide orbital accumulation in Grave's.doc

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumour characterized by the production and secretion of calcitonin. MTC tumours may express functional somatostatin receptors (hSSTR). A significant proportion of hSSTR receptor-positive MTC tumours, including metastatic disease, may be visualized in vivo through 111In-pentetreotide scintigraphy.indium penetreotide and medulary thyroid carcinoma.doc

Management of thyroid-associated ophthalmopathy remains a topic of controversy. Immunosuppressive treatments have to be applied at peak disease activity and before criteria of severity develop. Expression of somatostatin receptors on activated lymphocytes allows scintigraphic imaging with indium-111 pentetreotide. We conducted a prospective study with 17 patients who presented severe ophthalmopathy (11 Graves' disease, four Hashimoto's thyroiditis, two isolated in appearance: Means' syndrome). Each patient underwent hormonal (free T3 and TSH) and immunological (TBII) assessment, an orbital computed tomography scan or magnetic resonance imaging, a visual functional examination and 111In-pentetreotide orbital scintigraphy before undergoing treatment by steroids and/or radiotherapy, independently of scintigraphic results. All ten patients in whom scintigraphy was considered positive were clinically improved at 6 months, and of the seven patients in whom scintigraphy was negative, six were not improved. Nevertheless, objective quantitative analysis did not succeed in confirming these results. We conclude that 111In-pentetreotide scintigraphy requires further developments, including quantitative single-photon emission tomographic acquisition, if its role as a guide to therapeutic strategy in thyroid-associated ophthalmopathy is to be confirmed.indium-111-pentetreotide treatment for opthalmopathy.doc

Thyroid associated ophthalmopathy (TAO) is a disorder involving the soft tissues and extraocular muscles of the orbit seen mainly in cases of Graves' disease. Although an immunogenic pathogenesis has been proposed, the actual mechanisms of the in vivo retrobulbar involvement are not well defined. The recent introduction of the 111In-labeled somatostatin analog, octreotide, which can bind in vivo to the cell membrane of activated lymphocytes expressing somatostatin receptors, has provided a new investigational tool for diseases with a presumed immunological background. Based on this property, octreotide scans can be expected to be positive in cases of immunological disease showing tracer accumulation within affected sites. The aim of this study was to evaluate the utility of scintigraphic imaging with octreotide of the retrobulbar space in cases of TAO, including sequential studies of patients undergoing immunosuppressive therapy. We studied a series of 51 patients who had Graves' disease with varying degrees of TAO. Nine patients had received immunosuppressive therapy. The degree of orbital inflammation was classified according to the clinical activity score of Mourits. Both planar and tomographic imaging of the orbit were carried out using 111 MBq of the 111In-labeled octreotide (OctreoScan) 2 h after tracer injection. A significant tracer accumulation in the retrobulbar space was seen in all 20 patients with a high activity score, in 8 of 16 cases with a negative score, and in 11 of 20 cases with an intermediate Mourits' score. In cases of persistent eye disease in spite of immunosuppressive therapy, the octreotide scan remained positive. Successful therapy either with prednisolone, external radiation, or i.v. immunoglobulins showed a significant diminution of tracer uptake after finishing the therapeutic regime. Three-dimensional reconstruction of the images also revealed a significant tracer accumulation in the areas of the lacrimal gland, the nasal region, and the pituitary. Controls cases (n = 30) showed no uptake in the orbital region. We conclude that 111In octreotide scintigraphy is an objective method that identifies patients with active inflammatory eye disease, i.e., having significant tracer uptake in the retrobulbar space. This uptake appears to reflect an immunological process, since immunosuppressive therapy will significantly decrease tracer accumulation. indium-111-octreotide is taken up in opthalmopathy.doc

Indium pretreatment of rats and mice has been reported to decrease the concentration of cytochrome P-450, thereby reducing the activity of some cytochrome P-450 dependent enzymatic reactions. The present study reveals that pretreatment of C57Bl/6JHan mice of both sexes with one s.c. dose of 120 mg of In2(SO4)3.5 H2O per kg of body weight decreases the concentration of cytochrome P-450 to about 65% of control levels. Neither cytochrome b5 nor NADPH-cytochrome P-450 reductase is affected. Hepatic microsomal ethoxyresorufin O-deethylase activity declines to about 75% of control values. In contrast, with coumarin substrates, a sex dependence in the direction of change is observed: in female mice indium decreases the activity to about 75%, whereas in males it enhances the activity to 140%. Moreover, with 7-(methoxy-14C)coumarin as substrate, indium-pretreated male mice exhale about 180% and females about 65% of 14CO2 compared to the corresponding controls. A close correlation between the in vivo and in vitro effects of indium on the metabolism of the coumarin derivatives is suggested. After isolation and purification of cytochrome P-450, SDS-PAGE indicates in indium-pretreated male mice an intensification of a 48.5 kDa protein band which is decreased in females. Immunological studies using antibodies raised against control female cytochrome P-450 show cross reactivity among all microsomes used in these experiments. High percentages of inhibition occur in microsomes with high molecular activity towards coumarin derivatives. The in vitro kinetics of antibody-inhibited O-deethylation of 7-ethoxycoumarin seems to obey a non- or partial-competitive type of inhibition. Indium pretreatment of mice produces sex-dependent effects on the metabolism of coumarin derivatives.indium.sex differences.coumarin.cytochrome p-450.doc

Visualization of malignant lymphomas and granulomatous disease is possible by [111In-DTPA-D-Phe1]octreotide scintigraphy through binding of the radioligand to somatostatin receptors on activated leukocytes. Because thyroidal and orbital tissues are infiltrated by activated leukocytes in Graves' disease, a cross-sectional study to visualize disease activity with [111In-DTPA-D-Phe1]octreotide scintigraphy was performed. A correlation between thyroidal [111In-DTPA-D-Phe1]octreotide accumulation and free T4 (disease expression) and thyroid binding-inhibiting immunoglobulins (disease activity) is present in untreated hyperthyroid Graves' disease. There is also a correlation between orbital [111In-DTPA-D-Phe1]octreotide uptake and the clinical activity score (disease activity) and total eye score (disease expression), respectively, in Graves' orbitopathy. Visualization of thyroidal and orbital Graves' disease is feasible, but further investigation is necessary to establish the role of [111In-DTPA-D-Phe1]octreotide scintigraphy in representing disease activity and expression and in predicting therapeutical outcome.indium uptake in Grave's eye disease.doc

Until recently there was no imaging technique available which could demonstrate pathological changes in orbital tissues and could be regarded as a reliable measure of inflammation in thyroid eye disease (TED). Pentetreotide (a synthetic derivative of somatostatin) labelled with 111In has been used to localize tumours which possess surface or membrane receptors for somatostatin in vivo using a gamma camera (1). This technique visualizes somatostatin receptors in endocrine-related tumours in vivo and predicts the inhibitory effect of the somatostatin analogue octreotide on hormone secretion by the tumours (1). By applying 111In-DTPA-d-Phe octreotide scintigraphy (octreoscan), accumulation of the radionuclide was also detected in both the thyroid and orbit of patients with Graves' disease (2-4). If peak activity in the orbit 5h after injection of radiolabelled octreotide is set at 100%, a decrease to 40+/-4% is found at 24h, significantly different from the decrease in blood pool radioactivity, which is 15+/-4% at 24h. Accumulation of the radionuclide is most probably due to the presence in the orbital tissue of activated lymphocytes bearing somatostatin receptors (5). Alternative explanations are binding to receptors on other cell types (e.g. myoblasts, fibroblasts or endothelial cells) or local blood pooling due to venous stasis by the autoimmune orbital inflammation.indium uptake in thyroid and orbit in Grave's.doc

Octreotide, a potent synthetic long-acting somatostatin analogue, has been shown to have a beneficial effect in thyroid eye disease (TED). Orbital scintigraphy using ocetreoscan-111 is a useful study, which can be used to visualize somatostatin-receptor-bearing cells and also to select patients who might benefit from octreotide therapy. One major limitation of this therapy is that the drug must be administered parenterally and used several times daily. Lanreotide, a new somatostatin analogue, has a much longer duration of action in comparison with octreotide, and has recently been found to have a beneficial effect in the treatment of thyroid eye disease. The aim of this study was to investigate the orbital Indium-111-pentetreotide activity after treatment with octreotide and lanreotide in patients with thyroid ophthalmopathy. Fourteen patients were studied. 12 with bilateral and 2 with unilateral thyroid eye disease, (10 females and 4 males) and all with moderately severe symptoms of ophthalmopathy. All were treated with antithyroid drugs and were euthyroid at the time of the study. All patients were investigated with orbital scintigraphy using octreoscan-111 and selected for study on the basis of a positive octreoscan. Five patients received 30 mg lanreotide intramuscularly once every 2 weeks over a period of 3 months, and 5 patients received octreotide 100 microg subcutaneously thrice daily for 3 months. Four patients served as controls and received no treatment. The octreoscan-111 scintigraphy was repeated in all patients 3 months after the first examination. The NOSPECS classification and the clinical activity score (CAS) of thyroid ophthalmopathy were also evaluated before and 3 months after the initiation of treatment. All patients who received treatment had a negative follow-up octreoscan while controls had a positive octreoscan. NOSPECS score and CAS were improved with treatment, but unchanged in control patients. The reduced uptake of octreoscan may be the result of blocking of somatostatin receptors, or reduction in receptor-expressing tissues, downregulation of somatostatin receptors in target tissues, or a combination of these factors.indium--octreotide and lanreotide treatment of GED.doc

Octreotide is a synthetic analog of the peptide hormone somatostatin (SMS). A wide variety of tumors express enhanced numbers of SMS receptors, notably neuroendocrine tumors and lymphomas, but also some of the more common adenocarcinomas. Octreotide contains only eight amino acids, some of which are in the (D) configuration in order to enhance the stability of the molecule in vivo. Tyrosine and DTPA-containing analogs of octreotide have been synthesized and labeled with iodine-123 and indium-111, respectively, with the intention of targeting SMS receptor-containing tumors for diagnostic purposes. Both radiopharmaceuticals demonstrate a high sensitivity and specificity for these tumors, indicating a clinical role for these agents in management of these diseases. Lessons can be learned from the success of these agents when designing improved antibody-based molecules. Tumor uptake of radiolabeled octreotide is very rapid, occurring within minutes of administration. Blood clearance is also rapid, such that tumors are soon visible even in areas of high blood background. An interesting finding has been the differences between the pharmacokinetics of the iodinated and indium-labeled species. Although the majority of 123I-Tyr3-octreotide undergoes hepatobiliary excretion, 111In-DTPAPhe1-octreotide is eliminated predominantly by the kidneys. These results suggest that the smallest possible antibody-like tracers are likely to have advantages over native immunoglobulins and conventional Fab-like fragments.indium and iodine labeled octreotide differences.doc

We present the case of a 52-year old patient diagnosed with carcinoid tumour of the rectum with liver metastases in which treatment with somatostatin analogues (octreotide) proved very effective in the disappearance of the symptomatology and dramatic efficacy in the regression of the tumour. Imaging by octreoscan was always negative. The role of octreotide in the treatment of carcinoid tumour and the usefulness of In-111-pentetreotide (octreoscan) in the localization and prediction of the response to treatment with octreotide is discussed. We conclude that the negative result of the scintigraphic image with octreoscan does not necessarily suppose the inefficacy of octreotide treatment. We believe that this may constitute an important issue since some patients may be denied octreotide treatment in the absence of a positive octreoscan result.indium-octreotide regresses carcinoid tumor.doc

Recently, [111In]-DTPA-D-phenylalanine-octreotide was introduced for clinical use. This radioligand binds specifically to somatostatin receptors and is suitable for SPECT examinations. The aim of this study was to clarify whether an increased somatostatin receptor density can be imaged and quantified in patients with endocrine ophthalmopathy (e.o.). 7 patients between 34 and 55 years with e.o. at stages III to VI and 4 controls between 38 and 63 years were examined. All patients and controls received approximately 200 MBq [111In]-DTPA-D-phenylalanine-octreotide by IV injection. A SPECT examination was performed 4 hours after injection and a normalised tracer uptake (A(n)) was calculated for both orbitae. In patients with e.o. the values of A(n) were significantly higher compared with controls (P = 0.002). There was a correlation between A(n) and exophthalmus stages according to Hertel with r = 0.844 (P = 0.001). These results indicate that [111In]-DTPA-D-phenylalanine-octreotide SPECT might be useful for the in vivo assessment of an increased somatostatin receptor density in e.o. These findings could have an impact on the treatment with somatostatin analogous in e.o.indium orbital accumulation higher in pts with opthalmopathy.doc

In contrast to controls (median 5 counts per voxel per millibecquerel (cts/vox/MBq) injected activity), TED patients showed threefold increased orbital accumulation of Pentetreotide (15 cts/vox/MBq, p = 0.003). When considering patients with active TED only, even higher uptake was registered (23 cts/vox/MBq, p = 0.0006 vs. controls, sensitivity for active TED 61/68, 90%; specificity 12/12, 100%). In 40 patients with active TED, the radionuclide accumulation decreased sharply after completion of immunosuppressive therapy. A high pretreatment Pentetreotide orbit-to-brain ratio correlated with a response to therapy (positive and negative predictive values 28/32, 88%, and 8/8, 100%, respectively).indium pentetreotide orbital accumulation higher in Graves.doc

After the intravenous administration of a radiolabeled somatostatin analogue (octreotide), normal thyroid and neoplastic and nonneoplastic thyroid lesions can be visualized. The authors present the cases of two patients who underwent somatostatin receptor scintigraphy (SSRS) using In-111 pentetreotide: one for the study of suspected paraneoplastic ACTH hypersecretion, and the other for a restaging of breast carcinoma with neuroendocrine features. In both patients, SSRS revealed increased uptake in the thyroid, corresponding to "cold" nodules on Tc-99m pertechnetate imaging. Cytologic and histologic examinations showed the typical features of thyroid goiters without lymphocytic infiltration.indium uptake greater in goiters.doc

Until recently there was no imaging technique available which could demonstrate pathological changes in orbital tissues and could be regarded as a reliable measure of inflammation in thyroid eye disease (TED). Pentetreotide (a synthetic derivative of somatostatin) labelled with 111In has been used to localize tumours which possess surface or membrane receptors for somatostatin in vivo using a gamma camera (1). This technique visualizes somatostatin receptors in endocrine-related tumours in vivo and predicts the inhibitory effect of the somatostatin analogue octreotide on hormone secretion by the tumours (1). By applying 111In-DTPA-d-Phe octreotide scintigraphy (octreoscan), accumulation of the radionuclide was also detected in both the thyroid and orbit of patients with Graves' disease (2-4). If peak activity in the orbit 5h after injection of radiolabelled octreotide is set at 100%, a decrease to 40+/-4% is found at 24h, significantly different from the decrease in blood pool radioactivity, which is 15+/-4% at 24h. Accumulation of the radionuclide is most probably due to the presence in the orbital tissue of activated lymphocytes bearing somatostatin receptors (5). Alternative explanations are binding to receptors on other cell types (e.g. myoblasts, fibroblasts or endothelial cells) or local blood pooling due to venous stasis by the autoimmune orbital inflammation.indium retained longer by thyroid and orbit.doc

OBJECTIVE: Octreotide, a potent long-acting synthetic somatostatin analogue, has been reported to have a beneficial effect in thyroid eye disease (TED), but the precise mechanism of action remains unexplained. 111In-DTPA-D-Phe1-octreotide (Octreoscan-111) has been used to localize a number of endocrine tumours and visualize somatostatin receptors in the retrobulbar tissue of patients with TED. Furthermore, this technique can predict the inhibitory effect of octreotide on hormone secretion by endocrine tumours, as there is a close relation between the clinically observed inhibition and visualization of the tumour using Octreoscan-111. The aims of the present study were to confirm the beneficial effect of octreotide in patients with TED, to investigate the presence of somatostatin receptors in the orbital area and also, if possible, to ascertain whether this technique could select those patients with TED who might benefit from treatment with octreotide. DESIGN: A prospective study. SETTING: An endocrine clinic of a national hospital. PATIENTS: Twenty treated thyrotoxic patients with TED, 5 treated thyrotoxic patients without TED and 5 normal individuals were studied. In 12 patients with TED, 5 without TED and 5 normal individuals, Octreoscan-111 scintigraphy of the orbits was performed. The remaining 8 patients with ophthalmopathy served as controls. In patients with TED who were investigated with Octreoscan-111, 300 micrograms octreotide daily was given for 12 weeks. RESULTS: Six patients in both eyes and one patient in one eye showed an improvement in ocular manifestations as assessed by clinical criteria and changes in the NOSPECS score, while the rest showed no improvement. The patients who showed an improvement had a high number of somatostatin receptors and positive orbital scans, while with one exception the patients who did not respond had a low number of receptors and negative orbital scans (P < 0.02). None of the 5 patients without TED nor the normal individuals had a positive orbital scan. Seven out of 8 control patients with TED showed no change in the disease during the trial, while 1 deteriorated. CONCLUSIONS: We conclude that octreotide has a beneficial effect in thyroid eye disease and that Octreoscan-111 could predict those patients with thyroid eye disease who might benefit from this treatment.indium octreotide treatment benefits thyroid eye disease.doc

Pregnant rats were treated with a single intravenous or oral administration of indium chloride (InCl3) on day 9 of pregnancy and their fetuses were examined for growth and malformation on day 20 of pregnancy. By intravenous administration, fetal weight was significantly decreased and the incidences of fetal mortality and malformation were significantly increased at 0.4 mg In/kg. Fetal malformations of the tail and digits, e.g., kinked tail, brachyury, and oligodactyly, were observed at high incidences. By oral administration, similar tendencies in the fetal effects were observed, but there were no significant differences compared to the control even at 300 mg In/kg. Indium concentrations in the serum of pregnant rats showed low bioavailability of indium by oral administration. It was concluded from these results that indium showed teratogenicity in rats. Oral treatment with indium may be developmentally toxic at 300 mg In/kg, but this is difficult to state with certainty given the limited number of animals that were used in this study.indium--developmental toxicty.doc

Copper gallium diselenide (CGS), copper indium diselenide (CIS), and cadmium telluride (CdTe) are novel compounds used in the photovoltaic and semiconductor industries. This study was conducted to characterize the relative toxicities of these compounds and to evaluate the pulmonary absorption and distribution after intratracheal instillation.indium--copper indium diselenide.doc

The use of mercury in dental amalgam restorations has become the subject of political controversy despite its long history of safe clinical use, and alternative materials based on gallium and indium rather than mercury have been developed. The biological safety of these metals must be evaluated, as part of their assessment as mercury substitutes. The cytotoxicities of mercury (II) nitrate, gallium (III) nitrate, and indium (III) nitrate were assessed at concentrations between 0.001 mmol/L and 1.0 mmol/L, using L929 mouse fibroblasts and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay and scanning electron microscopy. The mitochondrial dehydrogenase activity at each metal ion concentration as a percentage of the control was calculated from the absorbance values. The 50% inhibition concentration of mercury (II) nitrate was 0.35 mmol/L for cells in the rapid-growth phase and at confluence; gallium (III) nitrate and indium (III) nitrate did not significantly inhibit dehydrogenase activity in either the growing or confluent phase. Gallium and indium ions were not significantly toxic under the conditions of this assay.indium nitrate.gallium nitrate cytotoxicity.doc

Normal iron metabolism can be perturbed with iron chelators, toxic metals that bind to transferrin, toxic metals bound to transferrin or antineoplastic agents covalently linked to transferrin. These agents cause significant inhibition of tumor cell growth in cell culture and have been shown to have significant in vivo antineoplastic activity. Cell culture studies showed that deferoxamine mesylate inhibits cell growth and division in both the MCF-7 human breast and HeLa human cervical carcinoma cell lines. Animal studies demonstrated that when deferoxamine mesylate is injected intravenously into rats that are on a low iron diet, there is a significant reduction in the growth of 13762NF mammary adenocarcinomas. Gallium, indium and the antineoplastic agent cisplatin were bound to the iron binding site of transferrin and inhibit the growth of malignant carcinoma cell lines. Gallium-transferrin and indium-transferrin were at least 10 times more inhibitory to both MCF-7 and HeLa cell lines than their free salts.indium and gallium bind iron and inhibit cancer.doc

Investigations into the use of streptavidin-conjugated antibodies and labeled biotin to improve radioimmunotargeting have shown background levels drastically reduced over the conventional approach. Nevertheless, accumulation of 111In-biotin in normal tissue as well as streptavidin-independent accumulation in tumor, was observed. In this work, the effect of altering the biotin molecule to reduce this nonspecific uptake without decreasing specific localization has been investigated. Three EDTA and DTPA derivatives of biotin have been synthesized and investigated along with a commercial biotin derivative (DTPA-B2). The labeled biotin chelates were administered i.p. to normal mice implanted with avidin beads in one thigh. A wide variation in biodistribution was seen among the biotin derivatives. The most favorable results were obtained with biotinyl-hydrazino-EDTA (EDTA-B1), which showed the lowest accumulation in normal tissues but equivalent uptake in the target with respect to the other compounds. Averaged over 8 tissues sampled, the target-to-nontarget ratio was 140 vs 9 for EDTA-B1 vs DTPA-B2 (N = 6) at 24 h post administration. Similar observations have been made in culture with two tumor cell lines: positive accumulation of both DTPA-B2 and EDTA-B1 was measured in tumor cells independent of streptavidin-antibody conjugate, however in the case of the latter derivative, this accumulation was 3-5 fold lower. These studies show that modification of the biotin species can alter accumulation in normal tissues as well as the antibody-streptavidin independent accumulation in tumor tissue.indium-111 labeled biotin derivatives.doc

To better understand the factors that govern the target-to-background ratios of 111In-diethylenetriaminepentaacetic acid (DTPA) polypeptides, we studied 111In-DTPA-octreotide and a model nontargeted compound, 111In-DTPA-poly(D)lysine-biotin. We evaluated the fate of 111In-DTPA-octreotide after it localizes in somatostatin receptor-positive tissues and sought to determine why such a large fraction of these and other 111In-DTPA-polypeptides accumulate in the liver and kidneys. Biodistribution studies in rats with an implanted pancreatic adenocarcinoma demonstrated rapid accumulation of 111In-DTPA-octreotide in the pancreas and tumor. Indium-111 also accumulated in the liver and kidneys. Subcellular fractionation of the liver, kidneys, tumor, and pancreas showed that the majority of the radioactivity copurified with lysosomal enzymes.indium-111-DTPA-octreotide.doc

The attractive properties of avidin (streptavidin) and biotin, in particular their strong affinities (Kd = 10(-15)M), may be used to advantage in imaging applications. These molecules have been used in this preliminary investigation to improve the targeting of 111In in animals. Antibodies have been conjugated with biotin and administered unlabeled while, at a later time, the radiolabel was administered attached to DTPA-coupled avidin or streptavidin. An alternative procedure was also considered whereby the antibodies were conjugated with avidin and administered before the administration of radiolabeled biotin. Using a model in which the target consisted of conjugated agarose beads deposited in the peritoneum of mice, it has been shown that the target/nontarget radioactivity ratios may be significantly improved with respect to the conventional procedures through the use of this approach.indium imaging--use of avidin and biotin.doc

The efficacy of imaging breast cancer with 111In-pentetreotide (somatostatin receptor scintigraphy) was evaluate before surgery. METHODS: Seventy-one whole-body scintigrams in 24 patients with known breast cancer and 24 whole-body scintigrams in 8 controls were obtained at 0.5, 5 and 24 hr after intravenous injection of 110 MBq 111In-pentetreotide. Anterior and posterior projection images were acquired simultaneously. SPECT of the thorax was performed at 5 or 24 hr after injection in all breast cancer patients. The specimens were imaged immediately after surgery and the distribution of pentetreotide was assessed qualitatively and quantitatively. RESULTS: Somatostatin receptor-positive tumors were found in 18/24 patients with breast cancer. Pentetreotide uptake was significantly greater in breast cancer patients compared to control patients. In all patients with positive images, the early scintigram (0.5 hr) showed abnormal uptake. It was possible to delineate three different dynamic patterns. Increased uptake was visually most distinct at each time (9 patients). Moreover, bilaterally increased pentetreotide uptake was observed in 10/18 true-positive patients (in 8 at each time and in 2 patients only at 5 hr), but only one patient had a known bilateral tumor. CONCLUSION: We found higher incidence of somatostatin receptors in patients with breast cancer than in the control group. Moreover, bilaterally increased pentetreotide uptake in clinically unilateral disease was an unexpected finding.indium-111 pentetreotide uptake in breast cancer.doc

Endocrine neoplasms are rare tumors that have traditionally been imaged with ultrasound, CT, magnetic resonance imaging, and angiography. Additional imaging modalities are now available. Endoscopic ultrasound is a new imaging approach to islet cell tumors of the pancreas, in which they typically appear round, homogeneous, and slightly hypoechoic compared with the pancreatic parenchyma. Carcinoid tumors can now be localized with 111In octreotide scintigraphy, which binds to the somatostatin receptors in the tumor. Pheochromocytomas have a distinctive appearance on magnetic resonance imaging, but important advances have occurred using 131I metaiodobenzylguanidine (MIBG). 131I MIBG scanning has a high diagnostic accuracy in detecting pheochromocytoma, with sensitivity greater than 90%. The various tumors and recent advances in their imaging are discussed.indium and iodine imaging of pheos.doc

Several group IIIa metal salts, eg, aluminum nitrate, gallium nitrate, indium nitrate, and thallium chloride, have been evaluated for in vivo toxicity in mice and rats, for cytotoxicity in tumor cells in vitro, and for activity against a broad spectrum of experimental rodent tumors. The position of these agents in the periodical table roughly parallels their toxicity, the LD50s decreasing with increasing atomic weights. This parallel also exists with regard to in vitro cytotoxicity to Walker 256 carcinosarcoma cells. Although all of the metal salts had activity against the ascites Walker 256 carcinosarcoma, they were ineffective in ascites leukemias, plasma cell tumors, or Ehrlich carcinoma. Gallium nitrate was particularly active against solid tumors transplanted subcutaneously, suppressing the growth of six of eight tumors more than 90%. Because of its demonstrated antitumor activity in rodents and its uptake and concentration by various animal and human tumors, gallium nitrate has potential usefulness in the treatment of solid tumors in man and has been entered into a phase I study at the National Cancer Institute.gallium nitrate.indium nitrate.cancer suppression.doc

Extracorporeal whole blood immunoadsorption (ECIA) accelerates the clearance of radiolabeled monoclonal antibodies (mAbs) without significantly affecting tumor uptake by removing the excess of these mAbs from the blood, thus increasing tumor:normal tissue (T:N) ratios. The present study is focused on comparing the capacity of ECIA in tumor targeting with the same mAb (chiBR96-biotin) labeled with either (111)In or 125I. Forty-five Brown Norwegian rats with syngeneic rat colon carcinoma isografted both in liver and intramuscularly were used. chiBR96 is a highly tumor-specific mAb directed against the Lewis-type antigen. ECIA of whole blood was started 15 h after the injection of 125I- or (111)In-labeled BR96-biotin. The procedure lasted for 2 h and was repeated for (111)In-labeled BR96-biotin in a few rats after 3 or 24 h. ECIA reduced the whole body activity by the same magnitude (between 39% and 52%), irrespective of whether (111)In- or 125I-labeled chiBR96 was used. A similar observation was also made for the reduction in blood radioactivity after ECIA (79-94%). Time-activity curves during ECIA showed that the major reduction (approximately 85%) in blood radioactivity occurred during the first 45-60 min. Repeating the ECIA with (111)In-BR96 caused only an additional minimal reduction of blood activity, whereas a further reduction of whole body activity of 14-20% was achieved. The T:N uptake ratios were significantly enhanced immediately after ECIA with (111)In- or 125I-labeled chiBR96. Due to greater accumulation of (111)In-BR96 in tumors, a long-term improvement in T:N ratios was obtained after ECIA compared with 125I-labeled BR96. Our results therefore indicate that (111)In/(90Y)-labeled BR96-biotin could be more advantageous than 125I/131I for radioimmunotargeting/radioimmunotherapy in combination with ECIA due to better activity retention by the tumor.indium and monoclonal antibody chiBR96-biotin.doc

Substance P, an 11-amino acid neuropeptide, has an important role in modulating pain transmission through neurokinin 1 and 2 receptors. Substance P and other tachykinins may also play a role in the pathogenesis of inflammatory diseases. In this study we present the results concerning the metabolism of the substance P analogue [111In-DTPA-Arg1]-substance P in man, as well as the visualization of the thymus in patients with immune-mediated diseases. Twelve selected patients were investigated, comprising five with inflammatory bowel disease, one with ophthalmic Graves' disease, one with sclerosing cholangitis, one with Sjogren's syndrome, one with rheumatoid arthritis, one with systemic lupus erythematosus and two with myasthenia gravis. During and after intravenous administration of 150-250 MBq (2.5-5.0 microg) [111In-DTPA-Arg1]-substance P, blood pressure, heart rate and oxygen saturation were monitored. Radioactivity was measured in blood, urine and faeces during the 48 h after injection. Planar and single-photon emission tomographic images were obtained 4 and 24 h after injection. After administration of [111In-DTPA-Arg1]-substance P, a transient flush was observed in all patients. Degradation of [111In-DTPA-Arg1]-substance P started in the first minutes after administration, resulting in a half-life of 10 min for the total plasma radioactivity, and of 4 min for the intact radiopharmaceutical, as identified with high-performance liquid chromatography. Urinary excretion accounted for >95% of the radioactivity within 24 h post injection, and up to 0.05% was found in the faeces up to 60 h. In all patients uptake of radioactivity was found in the areolae mammae (in women), liver, spleen, kidneys and urinary bladder. In eight patients a high uptake of [111In-DTPA-Arg1]-substance P was observed in the thymus. We conclude that, despite its short half-life, [111In-DTPA-Arg1]-substance P, a new radiopharmaceutical, can be used to visualize the thymus. This may contribute to the investigation of the role of thymus in immune-mediated diseases. In addition, inflammatory sites in various diseases could be visualized.indium.substance P.thymus.autoimmune.doc

Indium-111-DTPA-D-Phe1-octreotide is avidly concentrated within thymic tumors, but it is not concentrated by thymic hyperplasia, which allows differential diagnosis. Thus, in patients with myasthenia gravis, SRS may have a role in characterizing thymic masses, thereby overcoming the limits of cross-sectional imaging modalities.indium.thymic tumors.myasthenia gravis.doc

We have compared the expression of somatostatin receptor (sstr) subtypes with the outcome of somatostatin receptor scintigraphy and the effect of somatostatin receptor activation in patients with disseminated carcinoid tumours. Tumour tissues from nine patients with midgut carcinoids (ileal) and three patients with foregut carcinoids (gastric, thymic) were analysed using Northern blotting. Expression of somatostatin receptors was demonstrated in all tumours (12 out of 12), with all five receptor subtypes present in 9 out of 12 tumours. Somatostatin receptor scintigraphy using [111In]DTPA-D-Phe1-octreotide visualized tumours in all patients (12 out of 12). The 111In activity concentrations in tumour tissue (T) and blood (B) were determined in three tumours 1-7 days after injection of the radionuclide. The T/B 111In activity concentration ratios ranged between 32 and 651. Clinically, treatment with the long-acting somatostatin analogue octreotide resulted in marked symptom relief accompanied by a significant reduction in tumour markers, for example urinary-5-HIAA levels (28-71% reduction). Incubation of midgut carcinoid tumours in primary culture with octreotide (10 microM) resulted in a reduction in spontaneously secreted serotonin (45-71% reduction) and 5-HIAA (41-94% reduction). The results demonstrate that carcinoid tumours possess multiple somatostatin receptor subtypes and that somatostatin analogues such as octreotide, which preferentially bind to somatostatin receptor subtype 2 and 5, can be used in the diagnosis and medical treatment of these tumours. In the future, novel somatostatin analogues with subtype specific receptor profiles may prove to be of value for individualizing the treatment of disseminated carcinoid tumour disease.indium octreotide treatment of carcinoid tumors.doc

Tissues of rats and mice fed a nonessential metal in drinking water for life were analyzed for the essential metals chromium, copper, manganese and zinc. The study involved 505 rats and 843 mice. Livers, lungs, hearts, kidneys and spleens were pooled in groups according to age at death, averaging 5 for rats and 8 for mice, in order to provide adequate sample weight. Copper was significantly higher in livers of rats fed tin, germanium, niobium and zirconium than in controls. Similarly, niobium was associated with deposition of manganese in heart and zinc deposition in liver. Chromium levels were depressed in heart, kidney and spleen by germanium. In mice the greatest effects occurred when indium and rhodium were fed, all four essential trace metals exhibiting raised levels principally in kidney but also in heart and spleen. Chromium levels were raised in all organs but heart when hexavalent chromium was fed. From these data it is apparent that the ingestion of a nonessential metal can enhance the retention of an essential trace metal, perhaps thus avoiding toxicity from the nonessential one.indium and rhodium increase levels of cu, zn, cr, mn.doc

Thymomas are rare neoplasms that are usually associated with parathymic syndromes, pure red cell aplasia, myasthenia gravis, hypogammaglobulinaemia and other mainly immunological disorders. Therefore, the management of thymoma patients is often complex and presents many diagnostic and therapeutic issues. Controversies concerning the definition of the histological subtypes and the role played by thymoma-associated syndromes are of primary importance in determining the oncological approach. Although low-stage thymomas have a high percentage of recovery, thymomas which are locally advanced, metastatic or previously treated with standard therapeutic options have no well-defined and effective treatment approaches. The data previously described by us on somatostatin receptor scintigraphy showing high uptake of indium-labelled octreotide by thymic masses and the successful treatment of a patient with thymoma and pure red cell aplasia with octreotide and prednisone has provided us the rationale for using such treatment in patients with advanced thymoma.indium--thymoma successfully treated with indium-octreotide.doc

Solutions of salts of the five Group-IIIA elements were given, intravenously, to mature Japanese quail. By 18 h, the accumulation maxima in the major tissues were: leg bones, 20% for Ga+3 (67Ga label) in estradiol-treated males; liver, 51% for Al+3 (26Al label) in control males; kidneys, 32% for In+3 (114mIn label) in estradiol-treated males; and growing oocytes plus ova, 37% for In. Accumulations of Tl+1 (202Tl label) were 6 times those for Ga or In in the brain and muscles, and .1 times in plasma. The cumulative maxima in egg components over 8 (B; Tl) or 10 (Al; Ga; In) days were B, 23% in albumen; Al, 38%, Ga 27%, In, 43% in yolks; Tl, 12% in shells. The accumulation of thallium in the eggshells markedly exceeded (P less than .001) the deposits of the other IIIA elements in shells, Al being the next highest at .54%.indium, ga, al, tl, b accumulation in quail.doc

Vitamin B12 is essential for life. Lack of it results in pernicious anemia and death. Conversely, the demand for vitamin B12 increases in rapidly dividing tumors. This is secondary to the direct involvement of vitamin B12 in mitochondrial metabolism as well as its indirect role in the production of thymidylate and S-adenosylmethionine. The latter 2 substances are needed for DNA synthesis and cellular methylation reactions, respectively. Novel radiolabeling of adenosylcobalamin has proven to be useful in the imaging of transplanted and spontaneous tumors in animals. Herein, we describe what we believe to be the first human to have imaging with conventional gamma cameras of vitamin B12 metabolism in a breast tumor.indium labeled vitamin B12.doc

Carcinoid tumors and endocrine pancreatic tumors often express somatostatin receptors (sst). Tumor spread may be visualized by sst scintigraphy using [(111)In-DTPA-D-Phe1]-octreotide. In this study, tumor targeting therapy with [(111)In-DTPA-D-Phe1]-octreotide at high doses (6 GBq every third week) was used to treat patients with sst-expressing tumors. Five patients entered the protocol and three were evaluable for response, while all could be evaluated for toxicity. Two patient responded with a significant reduction in tumor markers (> 50%). The third patient showed increasing levels of tumor markers. Side effects were expressed as depression of bone-marrow function. In one patient a grade 4 reduction in platelet count was observed requiring several thrombocyte transfusions. In another two patients platelet counts decreased significantly. We conclude that treatment with [(111)In-DTPA-D-Phe1]-octreotide can be used in patients with neuroendocrine tumors but blood parameters have to be carefully monitored to avoid severe side effects.indium-111 octreotide treatment causes platelet reduction.doc

We report here the results of a validation study of the avidin/indium-111 biotin approach in patients with skeletal lesions.indium-111 biotin.doc

The effects of somatostatin and its analogs have been studied in different subclasses of patients with Cushing's syndrome (due to Cushing's disease, ectopic corticotropin [ACTH]- and/or corticotropin-releasing hormone [CRH]-secreting tumors, or ACTH-independent Cushing's syndrome) and in patients with Nelson's syndrome. In most patients with untreated Cushing's disease, octreotide does not suppress ACTH release, a finding that is supported by in vitro studies. However, octreotide or somatostatin inhibits pathological ACTH secretion in Nelson's syndrome. Short-term octreotide treatment has caused a significant initial response (decreased serum cortisol, ACTH, and cortisoluria) in 24 of 38 (64%) patients with ectopic ACTH/CRH Cushing's syndrome, and long-term treatment caused a persistent response in 10 of 14 (71%) cases. Pentetreotide scintigraphy may help to identify those patients with ectopic ACTH/CRH tumors who will have an initial response to octreotide, and is useful for locating ectopic ACTH/CRH-secreting tumors and their metastases. To date, octreotide has been shown to temporarily suppress gastric inhibitory peptide (GIP)-induced cortisol secretion in GIP-dependent (ACTH-independent) Cushing's syndrome, but has not shown any therapeutic benefit in other forms of ACTH-independent Cushing's syndrome.indium--octreotide use in Cushing's syndrome.doc

The role of the lysosome during the intracellular concentration of diverse mineral elements has been evidenced by the electron probe X-ray microanalysis (EPMA). This highly sensitive technique allows an in situ chemical analysis of any chemical element with an atomic number greater than 11, present in ultra-thin tissue sections. Therefore, it has been demonstrated by using this EPMA that 21 out of the 92 elements of the periodic table, once injected in a soluble form, were selectively concentrated within lysosomes of several types of mammalian cells. Amongst these 21 elements, 15 are concentrated and precipitated in an insoluble from in association with phosphorus whereas the other 6 are precipitated in association with sulphur. Amongst the 15 elements which precipitate with phosphorus in lysosomes, there are: 3 group IIIB elements of the periodic system, (aluminium, gallium and indium); the rare-earth elements (cerium, gadolinium, lanthanum, thulium and samarium); 2 group IVA elements (hafnium and zirconium), two actinides (uranium and thorium) and elements such as chromium and niobium. The 6 elements which precipitate with sulphur comprise the 3 group VIII elements of the classification (nickel, palladium, platinum) and the 3 group IB elements (copper, silver and gold). The mechanisms responsible for this selective concentration involve enzymatic processes and predominantly acid phosphatases for elements precipitating as phosphates and arylsulfatases for elements precipitating with sulphur.trace element concentrations in lysosomes.doc

The spleen and bone marrow have important hematologic functions. Evaluation of bone marrow alone may be incomplete, unless the function of the spleen is studied also. In addition to hematologic functions, each organ has unique characteristics that may need to be evaluated in assessing its activity. The evaluation of the distribution of reticuloendothelial cells, through the phagocytosis of radioactive particles, provides the basis for most of the morphological and functional studies of these organs. During the past three decades, a variety of radioactive agents have been prepared and examined. Among them, colloids of 99mTc, heat-damaged 99mTc labeled RBCs, and the radionuclides of iron and indium, make possible the functional and morphological examination of the spleen and bone marrow by external scintigraphy.indium taken up by spleen and bone marrow.doc

Natl Toxicol Program Tech Rep Ser 2001 Jul;499:1-343

Toxicology and carcinogenesis studies of indium phosphide (cas no. 22398-90-7) in f344/N rats and b6c3f1 mice (inhalation studies).

National Toxicology Program.

Indium phosphide is used to make semiconductors, injection lasers, solar cells, photodiodes, and light-emitting diodes. Indium phosphide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to indium phosphide (greater than 99% pure) by inhalation for 14 weeks or 2 years. The frequency of micronuclei was determined in the peripheral blood of mice exposed to indium phosphide for 14 weeks. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of indium phosphide with a mass median aerodynamic diameter of approximately 1.2 m at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14) or 7 days per week (weeks 5 through 9) to accommodate a concurrent teratology study. One male in the 100 mg/m3 group died before the end of the study. Body weight gains of all males and females exposed to 100 mg/m3 were less than those of the chamber controls. As a result of indium phosphide exposure, the lungs of all exposed rats had a gray to black discoloration and were significantly enlarged, weighing 2.7- to 4.4-fold more than those of the chamber controls. Indium phosphide particles were observed throughout the respira-tory tract and in the lung-associated lymph nodes. A spectrum of inflammatory and proliferative lesions generally occurred in the lungs of all exposed groups of rats and consisted of alveolar proteinosis, chronic inflammation, interstitial fibrosis, and alveolar epithelial hyperplasia. Pulmonary inflammation was attended by increased leukocyte and neutrophil counts in the blood. The alveolar proteinosis was the principal apparent reason for the increase in lung weights. Indium phosphide caused inflammation at the base of the epiglottis of the larynx and hyperplasia of the bronchial and mediastinal lymph nodes. Exposure to indium phosphide affected the circulating erythroid mass. It induced a microcytic erythrocytosis consistent with bone marrow hyperplasia and hematopoietic cell proliferation of the spleen. Hepatocellular necrosis was suggested by increased serum activities of alanine aminotransferase and sorbitol dehydrogenase in all exposed groups of males and in 10 mg/m3 or greater females and was confirmed microscopically in 100 mg/m3 males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of indium phosphide with a mass median aerodynamic diameter of approximately 1.2 m at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14) or 7 days per week (weeks 5 through 9). Although the effects of indium phosphide exposure were similar in rats and mice, mice were more severely affected in that all males and females in the 100 mg/m3 groups either died or were removed moribund during the study. One male and three females in the 30 mg/m3 group were also removed before the end of the study. In general, body weight gains were significantly less in males and females exposed to 3 mg/m3 or greater compared to those of the chamber controls. Mice exposed to 30 or 100 mg/m3 were lethargic and experienced rapid, shallow breathing. As in rats, lungs were discolored and enlarged 2.6- to 4.1-fold greater than those of chamber controls due to the exposure-induced alveolar proteinosis. Indium phosphide particles were observed in the nose, trachea, larynx, and lymph nodes of some exposed males and females. Alveolar proteinosis, chronic active inflam-mation, interstitial fibrosis, and alveolar epithelial hyperplasia were observed; these effects were more severe than in rats. Hyperplasia in the bronchial lymph nodes and squamous metaplasia, necrosis, and suppurative inflammation of the larynx were observed in some exposed males and females. Exposure to indium phosphide induced a microcytic erythrocytosis which was consistent with the observed hematopoietic cell proliferation of the spleen. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day, 5 days per week, for 22 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 group were maintained on filtered air from exposure termination at week 22 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation: Exposure to indium phosphide for 3 months caused a microcytic erythrocytosis and also caused enlarged lungs and lesions in the respiratory tract and lung-associated lymph nodes. Although qualitatively similar to those observed in the 14-week studies, these effects were considerably less severe. However, the lesions in the lungs of rats exposed to 0.1 or 0.3 mg/m3 were considered sufficiently severe that exposure was discontinued in these groups, and the groups were allowed to continue unexposed for the remainder of the study. Survival, Body Weights, and Clinical Findings: Exposure to indium phosphide had no effect on survival or body weight gain. During the last 6 months of the study, rats in the 0.03 and 0.3 mg/m3 groups became lethargic and males breathed abnormally. Pathology Findings: At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar adenomas and carcinomas in rats. Squamous cell carcinoma of the lung occurred in four male rats exposed to 0.3 mg/m3. As observed in the 14-week study and at the 3-month interim evaluation, a spectrum of inflammatory and proliferative lesions of the lung were observed in all exposed groups of males and females; however, the extent and severity of the lesions were generally greater and included atypical hyperplasia, chronic inflammation, alveolar epithelial hyperplasia and metaplasia, alveolar proteinosis, and interstitial fibrosis. Exposure to indium phosphide also caused increased incidences of benign and malignant pheochromocytomas of the adrenal gland in males and females. Marginal increases in the incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day, 5 days per week, for 21 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 groups were maintained on filtered air from exposure termination at week 21 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation: Exposure to indium phosphide for 3 months affected the circulating erythroid mass and caused enlarged lungs and lesions in the respiratory tract and lung-associated lymph nodes. These effects, although qualitatively similar to those observed in the 14-week studies, were considerably less severe. However, the lesions in the lungs of mice exposed to 0.1 mg/m3 and greater were considered sufficiently severe that exposure was discontinued in these groups and the groups were allowed to continue unexposed for the remainder of the study. Survival and Body Weights: In general, exposure to indium phosphide for 2 years reduced survival and body weight gain in exposed males and females. Pathology Findings: At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar carcinomas in males and alveolar/bronchiolar adenomas and carcinomas in females. In addition to the alveolar proteinosis and chronic active inflammation seen at earlier time points, serosa fibrosis and pleural mesothelial hyperplasia were also present. The incidences of hepatocellular neoplasms were also significantly increased in exposed males and females. Exposed groups of males and females had increased incidences of eosinophilic foci of the liver at 2 years. Marginal increases in the incidences of neoplasms of the small intestines in male mice may have been related to exposure to indium phosphide. Exposure to indium phosphide also caused inflammation of the arteries of the heart, primarily the coronary arteries and the proximal aorta, and to a lesser extent the lung-associated lymph nodes in males and in females. TISSUE BURDEN ANALYSES: Deposition and clearance studies of indium following long term exposure of rats and mice to indium phosphide by inhalation were performed. Although there were quantitative differences in lung burden and kinetic parameters for rats and mice, qualitatively they were similar. Deposition of indium in the lungs appeared to follow a zero-order (constant rate) process. Retained lung burdens throughout the studies were proportional to exposure concentration and duration. No differences in elimination rates of indium from the lungs were observed as a function of exposure concentration in either rats or mice. These studies indicated that elimination of indium was quite slow. Mice exhibited clearance half-times of 144 and 163 days for the 0.1 and 0.3 mg/m3 groups, respectively, as compared to 262 and 291 days for rats exposed to the same concentrations. The lung deposition and clearance model was used to estimate the total amount of indium deposited in the lungs of rats and mice after exposure to 0.03 mg/m3 for 2 years or to 0.1 or 0.3 mg/m3 for 21 or 22 weeks, the lung burdens at the end of the 2-year study, and the area under lung burden curves (AUC). For both species, estimates at the end of 2 years indicated that the lung burdens in the continuously exposed 0.03 mg/m3 groups were greater than those in the 0.1 or 0.3 mg/m3 groups. The lung burdens were lowest in the 0.1 mg/m3 groups. Because of the slow clearance of indium, the lung burdens in the 0.1 and 0.3 mg/m3 groups were approximately 25% of the maximum levels in rats and 8% in mice approximately 83 weeks after exposure was stopped. The AUCs and the total amount of indium deposited per lung at the time exposure was stopped indicate that the 0.3 mg/m3 groups were exposed to a greater amount of indium phosphide than were the 0.03 or 0.1 mg/m3 groups, with the 0.1 mg/m3 group receiving the lowest exposure. In rats and mice, the second-year AUC for the 0.03 mg/m3 group was equivalent to that of the 0.3 mg/m3 group. Regardless of how the total dose of indium to the lung was estimated, total exposure to indium in the 0.1 mg/m3 groups was less than that in the other two groups implying that in these studies, 0.1 mg/m3 may be considered the low dose. GENETIC TOXICOLOGY: No significant increases in the frequencies of micronucleated normochromatic erythrocytes were noted in peripheral blood samples of male or female mice exposed to indium phosphide for 14 weeks. Although there was a significant increase in micronucleated polychromatic erythrocytes in 30 mg/m3 male mice, there was no increase in female mice, and the percentage of polychromatic erythrocytes was not altered in males or females. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of indium phosphide in male and female F344/N rats based on increased incidences of benign and malignant neoplasms of the lung. Increased incidences of pheo-chromocytoma of the adrenal medulla in males and females were also considered to be exposure related. Marginal increases in incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. There was clear evidence of carcinogenic activity of indium phosphide in male B6C3F1 mice based on increased incidences of malignant neoplasms of the lung and benign and malignant neoplasms of the liver. Marginal increases in incidences of adenoma and carcinoma of the small intestine may have been related to exposure to indium phosphide. There was clear evidence of carcinogenic activity of indium phosphide in female B6C3F1 mice based on increased incidences of benign and malignant neoplasms of the lung. Increased incidences of liver neoplasms in females were also considered to be exposure related. Exposure to indium phosphide by inhalation resulted in nonneoplastic lesions in the lung of male and female rats and mice, the adrenal medulla of female rats, and the liver and heart of male and female mice.

PMID: 12087422 [PubMed - as supplied by publisher]