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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.

Bonner Jahrbücher, Bd. 161 (1961): Bonner Jahrbücher

Rezension zu: Kai Brodersen, Das römische Britannien. Spuren seiner Geschichte, Darmstadt: Wissenschaftliche Buchgesellschaft, 1998. X und 260 Seiten., Göttinger Forum für Altertumswissenschaft, Bd. 4 (2001): Göttinger Forum für Altertumswissenschaft

Jahreshefte des Vereins für Vaterländische Naturkunde in Württemberg : zugl. Jahrbuch d. Staatlichen Museums für Naturkunde in Stuttgart, Bd. 67, 1911

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.

This 90-day repeated-dose inhalation toxicology study of brake-dust (BD) (brakes manufactured with chrysotile) in rats provides a comprehensive understanding of the biokinetics and potential toxicology in the lung and pleura. Exposure was 6 h/d, 5d/wk., 13wks followed by lifetime observation (~20 % survival). Control groups included a particle control (TiO2), chrysotile, commercial crocidolite and amosite asbestos. Aerosol fiber distributions of the chrysotile, crocidolite and amosite were similar (fibers L > 20 mm/cm3: chrysotile-Low/High 29/72; crocidolite 24; amosite 47 fibers/cm3; WHO-fibers/cm3: chrysotile-Low/High 119/233; crocidolite 181; amosite 281 fibers/cm3). The number of particles/cm3 in the BD was similar to that in the chrysotile, crocidolite & amosite exposures (BD 470-715; chrysotile 495-614; crocidolite 415; amosite 417 particles/cm3). In the BD groups, few fibers L > 20 mm were observed in the lungs at the end of exposure and no fibers L > 20 mm at 90d post exposure. In the chrysotile groups, means of 204,000 and 290,000 fibers(L > 20 mm)/lung were measured at 89d. By 180d, means of 1 and 3.9 fibers were counted on the filter corresponding to 14,000 and 55,000 fibers(L > 20 mm)/lung. In the crocidolite and amosite groups mean lung concentrations were 9,055,000 and 11,645,000 fibers(L > 20 mm)/lung at 89d. At 180d the means remained similar with 8,026,000 and 11,591,000 fibers(L > 20 mm)/lung representing 10-13% of the total lung fibers. BAL determined the total number of macrophages, lymphocytes, neutrophils, eosinophils, epithelial-cells and IL-1 beta, TNF-alpha and TGF-beta. At the moderate aerosol concentrations used in this study, neutrophil counts increased ~5 fold in the amphibole asbestos exposure groups. All other groups and parameters showed no important differences at these exposure concentrations. The exposure and lung burden results provide a sound basis for assessing the potential toxicity of the brake dust in comparison to the TiO2 particle control and the chrysotile, crocidolite and amosite asbestos control groups. The BAL results provide an initial indication of the differential response. Part 2 presents the presentation and discussion of the histopathological and confocal microscopy findings in this study through 90 days post exposure.

The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1–3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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.

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/c01aHsd 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.

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This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length>20mum/cm(3): Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm(3): Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm(3) in the brake-dust was similar to that in the chrysotile (Brake-dust 710-1065; Chrysotile 532-1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score

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.

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. Wheth er vacuolation and mineralisation represent an incidental finding or are related to a cognitive dysfunction syndrome remains to be determined.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic 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 lesions observed in the soft tissues including skeletal muscle as well as the mesothelium of rats and mice. The standardized nomenclature of lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions in soft tissues, skeletal muscle and mesothelium in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. (DOI: 10.1293/tox.26.1S; J Toxicol Pathol 2013; 26: 1S–26S)

The psychiatrist Herman Wedel Major planned Gaustad asylum in collaboration with his brother-in-law, the architect Heinrich Ernst Schirmer. The planning of Gaustad took place in parallel with the preparation of the first Norwegian Mental Health Act, adopted by the Storting on 30 July 1848, and Gaustad's architecture provides a good illustration of the ideals behind the mental health reform of the 19th century. In particular, Major's and Schirmer's Gaustad represents a break with Frederik Holst's ideal of the panoptic institution. Whereas Holst and his architect Christian Heinrich Grosch promoted a radial plan institution based on the type used for penitentiaries, Schirmer and Major designed a modern, pavilion-style hospital with wards placed independently in the landscape.

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.

This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust (from brakes manufactured with chrysotile) in a 28-day repeated multi-dose inhalation toxicology study (6 h/d, 5 d/wk. 4 wk) followed by 28-days of exposure free recovery and served as a range finding study for a subsequent ongoing 90-day repeated dose inhalation toxicology study with lifetime recovery. Comparative fiber control groups were included of a similar grade commercial chrysotile as used in the brakes and a commercial crocidolite asbestos sample. The aerosol fiber distribution of the chrysotile (chry) and crocidolite (croc) asbestos were similar (Fibers L > 20 mm/cm3: Chry-LD 42, Chry-HD 62; Croc-LD 36, Croc-HD 55; WHO fibers/cm3 Chry-LD 192, Chry-HD 219; Croc-LD 211, Croc-HD 255). The total number of particles in the aerosol of the brake dust groups was similar to that in the chrysotile groups (Part/cm3: B-D 710 - 1065; Chry 532 - 1442). A macrophage dose-response to the brake dust groups was observed with no fiber related effects. In the fiber control groups, the study differentiated between similar exposures to chrysotile and crocidolite asbestos. The chrysotile exposure resulted in a dose-dependent particle laden macrophage response characterised as Wagner Grade 1 to 3. In contrast, following crocidolite exposure there was a dose-response accumulation of fiber laden macrophages and interstitial fibrosis during exposure (Wagner score Grades 3 to 4) which increased in incidence following exposure (Wagner score Grade 4). Confocal microscopy images (determined following deep freezing of the chest wall at sacrifice) revealed no difference between the air control, brake dust and chrysotile high-dose exposure groups and no difference in the visceral or parietal pleura thickness at 28 or 56 days. The crocidolite exposure resulted in more than double the thickness of the visceral pleura and parietal pleura, with associated extensive inflammatory response and collagen development observed including adhesions between the visceral and parietal surfaces. These results provided a basis for the design of the 90 day study. (Study funded by Honeywell International Inc).

The data presented in this paper have been derived from a carcinogenicity experiment with rats as part of a comprehensive research project focused on experimental studies on the toxicity and carcinogenicity of intratracheally instilled granular dusts [Ernst H, Rittinghausen S, Bartsch W, Creutzenberg O, Dasenbrock C, Gorlitz B-D et al. Pulmonary inflammation in rats after intratracheal instillation of quartz, amorphous SiO 2 , carbon black, and coal dust and the influence of poly-2-vinylpyridine- N -oxide (PVNO). Exp Toxicol Pathol 2002; 54: 109–26; Ernst H, Kolling A, Bellmann B, Rittinghausen S, Heinrich U, Pott F. Pathogenetische und immunbiologische Untersuchungen zur Frage: Ist die Extrapolation der Staubkanzerogenitat von der Ratte auf den Menschen gerechtfertigt? Teil II: Histologie. Abschlussbericht. Umweltforschungsplan des Bundesministeriums fur Umwelt, Naturschutz und Reaktorsicherheit. November 2005. http://www.umweltdaten.de/publikationen/fpdf-l/3033.pdf ]. The results of the standard approach to histological sampling in rodent carcinogenicity inhalation studies were compared to those obtained after supplemental evaluation of step sections at intervals of 250 μm through the entire lung. Seven lung tissue specimens (six sections) each of 251 rats (55 rats of the control group, 53 rats of the group treated with quartz DQ 12, 56 rats of the group treated with quartz DQ 12 and PVNO (poly-2-vinylpyridine- N -oxide), 53 rats of the group treated with amorphous SiO 2 , and 17 rats each of the groups treated with coal dust and carbon black) were evaluated by light microscopy. At least 60 hematoxylin and eosin (H&E)-stained sections per lung were evaluated of 99 female rats (30 rats of the control group, 7 rats each of the groups treated with quartz, quartz and PVNO, and carbon black, 31 rats of the group treated with amorphous SiO 2 , and 17 rats treated with coal dust). For the neoplastic and pre-neoplastic lesions detected in the serial slides an approximate value of the whole tumor volume was calculated. The detection of tumors with a diameter of 0.25 mm was possible. Based on the size distribution of 75 tumor volumes, the probability of detecting a tumor was 86% when using 12 sections. The addition of step sections enhanced the tumor detection rate from 17 to a total number of 44 lung tumors in the quartz-treated rats, from 6 to 10 in the quartz- and PVNO-treated rats, from 4 to 11 in the amorphous SiO 2 -treated rats, and from 4 to 10 in the carbon black-treated rats. Both the tumor multiplicity and the number of rats with pre-neoplastic lesions increased. These additional data corroborated the initial findings in all experimental groups and provided statistically significant results confirming the equivocal evidence of carcinogenic activity of amorphous SiO 2 in female Wistar rats. This technique offered accurate information on the incidence, histological type, size, and location of proliferative lesions in the entire lung, but the benefit must be balanced against the extra financial effort.

This 90-day study was aimed at characterizing the differences in biological activity between a crystalline ground reference quartz (DQ12) and a quartz with occluded surfaces ( quartz isolate) obtained from a clay deposit formed 110 to 112 million years ago. In different test groups, rats were dosed with the same total mass and quartz level by intratracheal instillation, with a total high dose of 15.2 mg/kg ( body weight, bw) or approximately 4.7 mg/rat of each quartz species in a saline suspension. The reference quartz was mixed with titanium dioxide to achieve a positive control mixture, which contained the same quartz content as in the quartz isolate. At 3 days post dosing, both quartz groups showed a significant inflammatory response based on total and differential cell counts from bronchoalveolar lavageate (BAL) analysis. At 28 and 90 days, the quartz isolate values were no longer statistically different from vehicle control group values; however, the positive control group values were approximately 12 and 65 times greater than those of the control group, respectively. After 28 days, histopathological evaluation showed moderate effects in the quartz isolate group compared to the saline control animals. These effects did not progress in severity at 90 days. In contrast, the positive control group exhibited more severe effects than the quartz isolate group and these effects showed a progression to a persistent and self-perpetuating inflammatory state. The toxicological properties of quartz particles can vary significantly dependent on their surface characteristics. Toxicity can range from a high-dose-induced, modest, transient inflammation from quartz with occluded surfaces, to a severe and persistent inflammatory state caused by ground quartz with fractured surfaces.

Peroxisome proliferator-activated receptors (PPAR) are involved in the pathogenesis of insulin resistance, diabetes, and related complications. Consequently, the identification of PPAR subtypes and the potential for their activation provides promising therapeutic targets for the management of type 2 diabetes mellitus. Available data from rodent carcinogenicity studies, however, demonstrate that PPAR agonists can be tumorigenic in one or more species of rodents at multiple sites. In 2005, the Health and Environmental Sciences Institute (HESI) PPAR Agonist Project Committee was established by a group of pharmaceutical companies to advance research on and to understand the modes of action and human relevance of this emerging rodent tumor data for PPAR agonists. Since the most commonly observed tumor types reported in rodents are hemangiosarcomas, fibrosarcomas and liposarcomas, the PPAR Agonist Project Committee approved a Pathology Working Group (PWG) to develop consensus of morphologic criteria for tumor diagnoses and consistency of diagnoses across multiple studies for hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats. Therefore, the focus of the PWG review was to establish consistent tumor diagnostic criteria, to assess evidence of potentially preneoplastic changes and to identify distinguishing morphologic differences which may exist between spontaneous changes present in control animals with similar changes from treated animals. Specific diagnostic criteria and nomenclature are recommended for the classification of proliferative vascular lesions which may be present in mice or hamsters and for proliferative mesenchymal changes in rats in studies that are conducted with PPAR agonists.

Fraunhofer ICT and partners have combined the LFT direct process technology with high gloss polymer films for exterior body panels. The technology is a promising starting point for the manufacturing of large automotive exterior parts. Oliver Geiger, Dr Frank Henning and Prof. P. Eyerer of Fraunhofer ICT, Germany, and R. Brüssel and Heinrich Ernst of Dieffenbacher GmbH & Co KG, Germany, explain.

Frank Henning, Heinrich Ernst and Richard Brussel of Dieffenbacher GmbH + Co KG, and Oliver Geiger and Wenzel Krause from the Fraunhofer Institut Chemische Technologie, discuss the latest processing technologies for long fibre reinforced thermoplastics.

Precise and repeatable measurements of pulmonary function in intact mice are becoming increasingly important for experimental investigations on various respiratory disorders including asthma. Here, we present validation of a novel in vivo method that, for the first time, combines direct and repetitive recordings of standard pulmonary mechanics with cholinergic aerosol challenges in anesthetized, orotracheally intubated, spontaneously breathing mice. We demonstrate that, in several groups of nonsensitized BALB/c mice, dose-related increases in pulmonary resistance and dynamic compliance to aerosolized methacholine are reproducible over short and extended intervals without causing detectable cytological alterations in the bronchoalveolar lavage or relevant histological changes in the proximal trachea and larynx regardless of the number of orotracheal intubations. Moreover, as further validation, we confirm that allergic mice, sensitized and challenged with Aspergillus fumigatus, were significantly more responsive to cholinergic challenge ( P < 0.01) and exhibited marked eosinophilia and lymphocytosis in bronchoalveolar lavage fluids as well as significant pathological alterations in laryngotracheal histology compared with nonsensitized mice. We suggest that this approach will provide useful and necessary information on pulmonary mechanics in studies of various respiratory disorders in mice, including experimental models of asthma and chronic obstructive pulmonary disorder, investigations of pulmonary pharmacology, or more general investigations of the genetic determinants of lung function.