In vitro cytotoxicity of different dental resin-cements on human cell lines.

Adhesive resin-cements are increasingly used in modern dentistry. Nevertheless, released substances from resin materials have been shown to cause cellular toxic effects. Disc-shaped specimens from 12 different resin cements and one conventional zinc phosphate cement were prepared and used for direct stimulation of five different human cell lines via transwell cell culture system or in an indirect way using conditioned cell culture media. Cytotoxicity was determined using LDH and BCA assays. All tested cements led to a decrease of cell viability but to a distinct extent depending on cell type, luting material, and cytotoxicity assay. In general, cements exhibited a more pronounced cytotoxicity in direct stimulation experiments compared to stimulations using conditioned media. Interestingly, the conventional zinc phosphate cement showed the lowest impact on cell viability. On cellular level, highest cytotoxic effects were detected in osteoblastic cell lines. All resin cements reduced cell viability of human cells with significant differences depending on cell type and cement material. Especially, osteoblastic cells demonstrated a tremendous increase of cytotoxicity after cement exposure. Although the results of this in vitro study cannot be transferred directly to a clinical setting, it shows that eluted substances from resin cements may disturb osteoblastic homeostasis that in turn could lead to conditions favoring peri-implant bone destruction. Thus, the wide use of resin cements in every clinical situation should be scrutinized. A correct use with complete removal of all cement residues and a sufficient polymerization should be given the utmost attention in clinical usage.

Organ burden of inhaled nanoceria in a 2-year low-dose exposure study: dump or depot?

No detailed information on in vivo biokinetics of CeO2 nanoparticles (NPs) following chronic low-dose inhalation is available. The CeO2 burden for lung, lung-associated lymph nodes, and major non-pulmonary organs, blood, and feces, was determined in a chronic whole-body inhalation study in female Wistar rats undertaken according to OECD TG453 (6 h per day for 5 days per week for a 104 weeks with the following concentrations: 0, 0.1, 0.3, 1.0, and 3.0 mg/m3, animals were sacrificed after 3, 12, 24 months). Different spectroscopy methods (ICP-MS, ion-beam-microscopy) were used for the quantification of organ burden and for visualization of NP distribution patterns in tissues. After 24 months of exposure, the highest CeO2 lung burden (4.41 mg per lung) was associated with the highest aerosol concentration and was proportionally lower for the other groups in a dose-dependent manner. Imaging techniques confirmed the presence of CeO2 agglomerates of different size categories within lung tissue with a non-homogenous distribution. For the highest exposure group, after 24 months in total 1.2% of the dose retained in the lung was found in the organs and tissues analyzed in this study, excluding lymph nodes and skeleton. The CeO2 burden per tissue decreased from lungs > lymph nodes > hard bone > liver > bone marrow. For two dosage groups, the liver organ burden showed a low accumulation rate. Here, the liver can be regarded as depot, whereas kidneys, the skeleton, and bone marrow seem to be dumps due to steadily increasing NP burden over time.

Best Practice Approach for Assessment of Microchip-associated Tumors in Preclinical Safety Studies: Position of the Registry of Industrial Toxicology Animal-data (RITA).

Microchip (passive radio-frequency identification device) implantation is a common and widely employed means of animal identification in laboratory animal facilities. However, these devices have been associated with tumors of the skin and subcutis in rodents. While microchip-associated tumors are rare, they pose a challenge for accurate diagnosis and documentation in preclinical toxicity studies. Documentation of these tumors should differentiate microchip-associated lesions with spontaneously occurring or test article-induced tumors. Standardizing criteria for microchip-associated lesions will aid the diagnostic process and allow for preclinical regulatory standardization. To this end, the Registry of Industrial Toxicology Animal-data have developed clear recommendations for diagnosis and documentation of microchip-associated lesions.

Separation of 103Ru from a proton irradiated thorium matrix: A potential source of Auger therapy radionuclide 103mRh.

Ruthenium-103 is the parent isotope of 103mRh (t1/2 56.1 min), an isotope of interest for Auger electron therapy. During the proton irradiation of thorium targets, large amounts of 103Ru are generated through proton induced fission. The development of a two part chemical separation process to isolate 103Ru in high yield and purity from a proton irradiated thorium matrix on an analytical scale is described herein. The first part employed an anion exchange column to remove cationic actinide/lanthanide impurities along with the majority of the transition metal fission products. Secondly, an extraction chromatographic column utilizing diglycolamide functional groups was used to decontaminate 103Ru from the remaining impurities. This method resulted in a final radiochemical yield of 83 ± 5% of 103Ru with a purity of 99.9%. Additionally, measured nuclear reaction cross sections for the formation of 103Ru and 106Ru via the 232Th(p,f)103,106Ru reactions are reported within.

Effects from a 90-day inhalation toxicity study with cerium oxide and barium sulfate nanoparticles in rats.

BACKGROUND: Nanomaterials like cerium oxide and barium sulfate are frequently processed in industrial and consumer products and exposure of humans and other organisms is likely. Generally less information is given on health effects and toxicity, especially regarding long-term exposure to low nanoparticle doses. Since inhalation is still the major route of uptake the present study focused on pulmonary effects of CeO2NM-212 (0.1, 0.3, 1.0, 3.0 mg/m3) and BaSO4NM-220 nanoparticles (50.0 mg/m3) in a 90-day exposure setup. To define particle-related effects and potential mechanisms of action, observations in histopathology, bronchoalveolar lavage and immunohistochemistry were linked to pulmonary deposition and clearance rates. This further allows evaluation of potential overload related effects. RESULTS: Lung burden values increased with increasing nanoparticle dose levels and ongoing exposure. At higher doses, cerium clearance was impaired, suggesting lung overload. Barium elimination was extremely rapid and without any signs of overload. Bronchoalveolar lavage fluid analysis and histopathology revealed lung tissue inflammation with increasing severity and post-exposure persistency for CeO2. Also, marker levels for genotoxicity and cell proliferation were significantly increased. BaSO4 showed less inflammation or persistency of effects and particularly affected the nasal cavity. CONCLUSION: CeO2 nanoparticles penetrate the alveolar space and affect the respiratory tract after inhalation mainly in terms of inflammation. Effects at low dose levels and post-exposure persistency suggest potential long-term effects and a notable relevance for human health. The generated data might be useful to improve nanoparticle risk assessment and threshold value generation. Mechanistic investigations at conditions of non-overload and absent inflammation should be further investigated in future studies.

In-vitro cytocompatibility of dental resin monomers on osteoblast-like cells.

OBJECTIVES: Dental resin-based materials are widely used in modern dentistry. Especially, resin cements enjoy great popularity and are utilized in many applications. Nevertheless, monomers could be released from the resinous matrix, thus interact with surrounding tissues, cause adverse biological reactions and may lead in cases of implant retained restorations to peri-implant bone destruction. Hence, we performed an in-vitro study to determine cytotoxicity of resin monomers on osteoblast-like cells. METHODS: Three permanent osteoblast-like cell lines from tumor origin (MG-63 and Saos-2) as well as immortalized human fetal osteoblasts (hFOB 1.19) were used and treated with different concentrations of the main monomers: BisGMA, UDMA, TEGDMA and HEMA. The impact on cell viability was monitored using three different cytotoxicity tests: alamarBlue, XTT, and LDH assay. Mean±SEM were calculated and statistical analysis was performed with GraphPad Prism software. RESULTS: All monomers tested caused concentration dependent cytotoxic effects on the three investigated osteoblast-like cell lines. Although all three cell viability assays showed comparable results in cytotoxic ranking of the monomers (BisGMA > UDMA > TEGDMA > HEMA), higher differences in the absolute values were detected by the various test methods In addition, also a cell line dependent influence on cell viability could be identified with higher impact on the immortalized hFOB 1.19 cells compared to both osteosarcoma cell lines (MG-63, Saos-2). CONCLUSIONS: Monomer concentrations detected in elution studies caused toxic effects in osteoblast-like cells. Although the results from in-vitro studies cannot be directly transferred to a clinical situation our results indicate that released monomers from composite resin cements may cause adverse biological effects and thereby possibly lead to conditions favoring peri-implantitis and bone destruction. CLINICAL SIGNIFICANCE: The wide use of composite resin cements especially in implant-prosthetic treatments should be scrutinized to avoid possible clinical implications between eluted resin monomers and bone cells leading to conditions favoring peri-implantitis and bone destruction.

Biological effects of carbon black nanoparticles are changed by surface coating with polycyclic aromatic hydrocarbons.

BACKGROUND: Carbon black nanoparticles (CBNP) are mainly composed of carbon, with a small amount of other elements (including hydrogen and oxygen). The toxicity of CBNP has been attributed to their large surface area, and through adsorbing intrinsically toxic substances, such as polycyclic aromatic hydrocarbons (PAH). It is not clear whether a PAH surface coating changes the toxicological properties of CBNP by influencing their physicochemical properties, through the specific toxicity of the surface-bound PAH, or by a combination of both. METHODS: Printex®90 (P90) was used as CBNP; the comparators were P90 coated with either benzo[a]pyrene (BaP) or 9-nitroanthracene (9NA), and soot from acetylene combustion that bears various PAHs on the surface (AS-PAH). Oxidative stress and IL-8/KC mRNA expression were determined in A549 and bronchial epithelial cells (16HBE14o-, Calu-3), mouse intrapulmonary airways and tracheal epithelial cells. Overall toxicity was tested in a rat inhalation study according to Organization for Economic Co-operation and Development (OECD) criteria. Effects on cytochrome monooxygenase (Cyp) mRNA expression, cell viability and mucociliary clearance were determined in acute exposure models using explanted murine trachea. RESULTS: All particles had similar primary particle size, shape, hydrodynamic diameter and ζ-potential. All PAH-containing particles had a comparable specific surface area that was approximately one third that of P90. AS-PAH contained a mixture of PAH with expected higher toxicity than BaP or 9NA. PAH-coating reduced some effects of P90 such as IL-8 mRNA expression and oxidative stress in A549 cells, granulocyte influx in the in vivo OECD experiment, and agglomeration of P90 and mucus release in the murine trachea ex vivo. Furthermore, P90-BaP decreased particle transport speed compared to P90 at 10 µg/ml. In contrast, PAH-coating induced IL-8 mRNA expression in bronchial epithelial cell lines, and Cyp mRNA expression and apoptosis in tracheal epithelial cells. In line with the higher toxicity compared to P90-BaP and P90-9NA, AS-PAH had the strongest biological effects both ex vivo and in vivo. CONCLUSIONS: Our results demonstrate that the biological effect of CBNP is determined by a combination of specific surface area and surface-bound PAH, and varies in different target cells.

Developing attributes for discrete choice experiments in health: a systematic literature review and case study of alcohol misuse interventions.

Discrete choice experiments (DCEs) become increasingly popular to value outcomes for health economic studies and gradually gain acceptance as an input into policy decisions. Developing attributes is a key aspect for the design of DCEs, as their results may misguide decision-makers if they are based on an inappropriate set of attributes. However, the area lacks guidance, and current health-related DCE studies vary considerably in their methods of attribute development, with the consequent danger of providing an unreliable input for policy decisions. The aim of this article is to inform the progress toward a more systematic approach to attribute development for DCE studies in health. A systematic review of the published health-related DCE literature was conducted to lay the foundations for a generic framework which was tested in a case study of alcohol misuse interventions. Four stages of a general attribute development process emerged: (i) raw data collection; (ii) data reduction; (iii) removing inappropriate attributes; and (iv) wording. The case study compared and contrasted a qualitative and mixed-methods approach for the development of attributes for DCEs in the area of alcohol misuse interventions. This article provides a reference point for the design of future DCE experiments in health.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Skeletal Tissues (Bones, Joints, and Teeth).

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is an initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the skeletal tissues and teeth of laboratory rats and mice, with color photomicrographs illustrating examples of many common lesions. The standardized nomenclature presented in this document is also available on the internet (http://www.goreni.org/). Sources of material were databases from government, academic and industrial laboratories throughout the world.

Spontaneous malignant craniopharyngioma in an aged Wistar rat.

Craniopharyngiomas are extremely rare epithelial tumors of the sellar region in human beings and domestic and laboratory animals. A craniopharyngioma, 0.6 cm in diameter, was observed grossly in the sellar and parasellar regions of an untreated 23-month-old male Wistar-derived rat sacrificed moribund. The tumor was composed of cords, columns, and nests of neoplastic stratified squamous epithelium with marked hyperkeratosis and parakeratosis. Neoplastic cells formed solid or cystic areas, infiltrating the base of the skull, brain, and pituitary gland. Immunocytochemical evaluation revealed a strong cytoplasmic reaction for pan-cytokeratin in all tumor cells. Malignant craniopharyngioma should be considered a differential diagnosis in the rat when a tumor with stratified squamous epithelial features and a locally aggressive growth pattern is observed in the sellar or suprasellar region.

Pharmacokinetic Analysis of Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium in Calcineurin Inhibitor-Free Renal Transplant Recipients.

BACKGROUND: Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS: In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS: Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS: The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

Effects of different blood collection methods on indicators of welfare in mice.

Blood collection is a common experimental procedure for which there are many different methods, each with its own advantages and disadvantages. Researchers should use methods that minimize pain, suffering, distress and lasting harm to animals while meeting study requirements. The authors evaluated stress, activity and tissue damage in BALB/cO1aHsd mice after collecting blood using one of six methods: retrobulbar bleeding with thin or thick capillaries, tail vein bleeding, saphenous vein bleeding, facial vein bleeding or jugular vein bleeding. The authors compared in-cage activity, corticosterone concentration and performance in open-field tests between treatment groups and collected histologic samples at 1 h, 3 d and 14 d after bleeding. Mice that underwent retrobulbar bleeding with a thick capillary had a smaller change in corticosterone concentration and higher in-cage activity immediately after blood collection, whereas mice that underwent jugular vein bleeding had a greater change in corticosterone concentration and lower in-cage activity and open-field activity. Mice that underwent saphenous vein bleeding had a high incidence of histological change at 1 h, 3 d and 14 d after blood collection, but few indicators of histological change were present in other groups at 14 d after blood collection. These results suggest that, when collecting a small volume of blood, retrobulbar bleeding with a thick capillary and without anesthesia causes the least stress in mice, whereas jugular vein bleeding and facial vein bleeding cause the most stress and saphenous vein bleeding causes the most lasting damage in mice.

Spontaneous nonneoplastic lesions in control Syrian hamsters in three 24-month long-term carcinogenicity studies.

Information about the incidence of spontaneously occurring, nonneoplastic background findings in Syrian hamsters is essential if Syrian hamsters are to be used for toxicity studies. Male and female Syrian hamsters of the strain Han:AURA from the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) breeding colony were maintained as control animals for carcinogenicity studies and were examined for the presence of nonneoplastic background findings either when they died or when the study was terminated. The nonneoplastic background lesions observed at an incidence of >50% (high), >25% (moderate), and >10% (low) in either male or female animals or in both sexes in one or more long-term studies are detailed. The results are compared to previous published reports of nonneoplastic, spontaneous background lesions in Syrian hamsters. Background information about the incidence of background lesions in Syrian hamsters on short- and long-term studies is useful to both toxicologists and toxicological pathologists.

The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats.

BACKGROUND: Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods. METHODS: A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 109 or 5 × 109 WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (108 WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans. RESULTS: Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D - the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis. CONCLUSION: We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.

Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: interim results.

Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (>20 µm) cleared quickly with T(½) estimated as 30 and 33 days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T(½)>1000 days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91 days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation.

Pulmonary toxicity of printer toner following inhalation and intratracheal instillation.

The pulmonary effects of a finished toner were evaluated in intratracheal instillation and inhalation studies, using toners with external additives (titanium dioxide nanoparticles and amorphous silica nanoparticles). Rats received an intratracheal dose of 1 mg or 2 mg of toner and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months. The toner induced pulmonary inflammation, as evidenced by a transient neutrophil response in the low-dose groups and persistent neutrophil infiltration in the high-dose groups. There were increased concentrations of heme oxygenase-1 (HO-1) as a marker of oxidative stress in the bronchoalveolar lavage fluid (BALF) and the lung. In a 90-day inhalation study, rats were exposed to well-dispersed toner (mean of MMAD: 3.76 µm). The three mass concentrations of toner were 1, 4 and 16 mg/m(3) for 13 weeks, and the rats were sacrificed at 6 days and 91 days after the end of the exposure period. The low and medium concentrations did not induce neutrophil infiltration in the lung of statistical significance, but the high concentration did, and, in addition, upon histopathological examination not only showed findings of inflammation but also of fibrosis in the lung. Taken together, the results of our studies suggest that toners with external additives lead to pulmonary inflammation and fibrosis at lung burdens suggest beyond the overload. The changes observed in the pulmonary responses in this inhalation study indicate that the high concentration (16 mg/m(3)) is an LOAEL and that the medium concentration (4 mg/m(3)) is an NOAEL.

Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure.

DNAzymes are single-stranded catalytic DNA molecules that bind and cleave specific sequences in a target mRNA molecule. Their potential as novel therapeutic agents has been demonstrated in a variety of disease models. However, no studies have yet addressed their toxicology and safety pharmacology profiles in detail. Here we describe a detailed toxicological analysis of inhaled hgd40, a GATA-3-specific DNAzyme designed for the treatment of allergic bronchial asthma. Subacute toxicity, immunotoxicity, and respiratory, cardiovascular, and CNS safety pharmacology were analyzed in rodents and non-rodents, and genotoxicity was assessed in human peripheral blood. Overall, hgd40 was very well tolerated when delivered by aerosol inhalation or slow intravenous infusion. Only marginal reversible histopathological changes were observed in the lungs of rats receiving the highest dose of inhaled hgd40. The changes consisted of slight mononuclear cell infiltration and alveolar histiocytosis, and moderate hyperplasia of bronchus-associated lymphoid tissue. No local or systemic adverse effects were observed in dogs. No compound-related respiratory, cardiovascular, or CNS adverse events were observed. The only relevant immunological findings were very slight dose-dependent changes in interleukin-10 and interferon-γ levels in bronchoalveolar lavage fluid. Taken together, these results support direct delivery of a DNAzyme via inhalation for the treatment of respiratory disease.

Spontaneous neoplastic lesions in control Syrian hamsters in 6-, 12-, and 24-month short-term and carcinogenicity studies.

Male and female Syrian hamsters of the strain Han: AURA from the Fraunhofer Institute for Toxicology and Experimental Medicine breeding colony were maintained as control animals for five toxicity/carcinogenicity studies and were examined for the presence of neoplastic disease either when they died or when the study terminated. In total, 250 male animals and 250 female animals in three carcinogenicity studies were analyzed as well as the results of a 6-month study (fifty males and fifty females) and a 12-month study (fifty males and fifty females). In the 24-month studies, in the male animals, twenty-five organs were affected with malignant and benign tumors. In the female animals, twenty-four organs were affected with malignant and benign tumors. The most frequently affected tissue in the three 24-month studies was the adrenal gland where 141 cortical adenomas (56.4%) were noted in 250 male animals and 115 cortical adenomas (46%) noted in 250 female animals. In addition, a high incidence of squamous cell papilloma in the vagina was noted in female hamsters on the 24-month studies. A moderate incidence of squamous cell papilloma of the nonglandular forestomach, benign granulosa cell tumor of the ovary, lymphoma of the hemopoietic system, endometrial stromal polyp, and adenocarcinoma of the uterus and islet cell adenoma of the pancreas were also observed on the 24-month studies.

Vacuolation and mineralisation as dominant age-related findings in hamster brains.

Syrian golden hamsters (Mesocricetus auratus) are laboratory animals increasingly used for research and toxicological studies. Despite the need for an adequate knowledge of spontaneously occurring lesions, studies investigating the background pathology of different organ systems in hamsters are lacking. The aim of this study was to investigate the occurrence of spontaneous, age-dependent lesions in the central nervous system of this species. Multiple brain and spinal cord transverse sections of 520 hamsters of 1, 3, 6, 12, and 24 months of age were investigated using histology and immunohistochemistry. Vacuolation of grey matter neuropil and mineralisation especially in the brain stem were the most prominent findings. They gradually increased in severity and frequency with age. Vacuolation and mineralisation affected approximately 100% and 50% of 24-month-old hamsters, respectively. In addition, pigment deposition and mast cell infiltration were commonly detected. Whether vacuolation and mineralisation represent an incidental finding or are related to a cognitive dysfunction syndrome remains to be determined.