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Comparison of primary lung tumor incidences in the rat evaluated by the standard microscopy method and by multiple step sections

: Kolling, A.; Ernst, H.; Rittinghausen, S.; Heinrich, U.; Pott, F.


Experimental and Toxicologic Pathology 60 (2008), Nr.4-5, S.281-288
ISSN: 0940-2993
Fraunhofer ITEM ()
histopathology; step sections; pulmonary neoplasms; granular dusts; amorphous SiO2; rat; carcinogenesis

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, Görlitz 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 Staubkanzerogenität von der Ratte auf den Menschen gerechtfertigt? Teil II: Histologie. Abschlussbericht. Umweltforschungsplan des Bundesministeriums für Umwelt, Naturschutz und Reaktorsicherheit. November 2005.]. 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 250mum 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 0.25mm 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.