Wistar rats were exposed for 2 y r to diesel engine exhaust, carbon black (Printex 90, Degussa, FRC), and ultrafine TiO, (P25, Degussa, FRC) and were subsequently kept in clean air for 6 mo. Particle exposure concentration was increased during the course of the experiment for carbon black and TiO, to reach particle lung loads similar to those found in the diesel soot-exposed rats. The average particle exposure concentrations for diesel soot, carbon black, and JiO, were 7, 11.6, and 70 mg/m', respectively. Lung tumor rates in these rats increased with increasing cumulative particle exposure (mg/m3 x h) independent of the type of particle employed. The exposure to 2.5 mg/m3 diesel soot also induced a significantly increased lung tumor rate, but 0.8 mg/m' diesel soot did not. With this study, it could be demonstrated that the carbon core of diesel soot is mainly responsible for the occurrence of diesel engine exhaust-related lung tumors; the role of diesel soot-attached polycyclic aromatic hydrocarbons (PAH) and NO,-PAH is probably of minor importance in the rat lung. Agglomerates of ultrafine carbon and TiO, particles seem particularly suited to exert toxic effects primarily on alveolar macrophages and alveolar lung particle clearance. Although such lung toxic effects were also seen with the lowest diesel soot exposure concentration (0.8 mg/m3) used, no increased lung tumor rate was detected in this group of rats. Whether this result implies a threshold for the particle-related lung tumor induction mechanism as already discussed by Vostal (7986) or whether the tumor effect was simply not observed because of statistical reasons needs further research on the possible mode of action of ultrafine insoluble particles in the lung. NMRl mice that were kept in the same exposure atmospheres (high diesel soot, car6on black, TiOJ as the rats did not show an increased lung tumor rate. furthermore, there was no treatment-related tumor response in NMRl nor in C57BL/6N mice exposed to diesel exhaust containing 4.5 mg/m3 diesel soot or to the same exhaust dilution but devoid of soot particles. C57BU6N mice were exposed for 24 mo and were subsequently kept in clean air for another 6 mo. Not only the average survival time but also the particle load per gram lung wet weight of the C57BL/6N mice was very similar to rats exposed to 7 mg/m' diesel soot.In 1986, the lung tumor-inducing activity of diesel engine exhaust in rats exposed to diesel soot concentrations of at least 2.2 mg/m3 was observed by various laboratories (Brightwell et al., 1986;Heinrich et al., 1986a;Mauderly et al., 1986). In 1987, based o n these results, diesel exhaust was classified in Germany as a carcinogenic working material. In

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 non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the respiratory tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature 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 lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for respiratory tract lesions 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.

Our results identify and validate a BAL signature that predicts mortality in IPF and improves the accuracy of outcome prediction based on clinical parameters. The BAL signature associated with mortality unmasks a potential role for airway basal cells in IPF.

BackgroundBiological 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.MethodsA 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.ResultsTreatments 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.ConclusionWe showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.

The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process.