Exudative Inflammatory Lesions in the Nasal Cavities of the 26-Week Tg.rasH2 Mice Oral Gavage Carcinogenicity Studies

Madhav G Paranjpe,Reem H Elbekai,Marie E Mckeon,Dayauna R Richardson,Caren Brown,Tom Vidmar,Peter C Mann,Jessica L Belich

doi:10.1177/1091581816673583

Abstract

Three levels of nasal cavity sections (anterior, middle, and most posterior) are routinely examined as protocol required tissues in our 26-week carcinogenicity studies involving Tg.rasH2 mice. Exudative inflammation of the nasal cavity was noted in the most posterior section of both males and females that were administered vehicle and/or test article via oral gavage, particularly when the vehicle and/or test article had irritant properties, was in the form of a salt, had a low pH, and/or was viscous. The exudative inflammatory lesion was characterized by the presence of eosinophilic proteinaceous fluid, fibrin, mucin, sloughed cells, and degenerate neutrophils within the nasal cavities. In lesions of increased severity, there was often degeneration, necrosis, and erosion of the underlying mucosa. Often, there was hyperplasia as well as squamous metaplasia of the mucosa. Retrospective analysis of our data, involving thirty-two 26-week Tg.rasH2 carcinogenicity studies, revealed that despite the presence of these exudative inflammatory changes with degeneration, necrosis, and mucosal hyperplasia, progression to tumor formation in the nasal cavities was rare and the incidence of nasal tumors was comparable in animals with or without exudative inflammatory lesions.

Highlights

The 2-year rodent carcinogenicity assays involving conventional rats and mice have been conducted for over 3 decades
As described in this article, exudative inflammation in the nasal cavities of Tg.rasH2 mice was commonly present in gavage studies, when the vehicle and/or test article were in the form of a salt, had a low pH, had irritant properties, and/or was viscous
Based on the evaluation of the studies that we have performed, we feel that gastric reflux is the most likely cause of these lesions rather than the direct toxic effect of the test article

Summary

Introduction

The 2-year rodent carcinogenicity assays involving conventional rats and mice have been conducted for over 3 decades. There have been many papers published, mainly in rats, that have shown exudative inflammatory lesions commonly in the most posterior sections and concurrent erosion, necrosis, hyperplasia, squamous metaplasia in (noninhalation) oral gavage studies, most likely caused by gastric reflux.[4,5,6,7,8,9] The occurrence of neoplasia in these gavage rat studies is very rare.[10] These authors[4,5,6,7,8,9,10] identified several causes for the inflammatory lesions in nasal cavities with (noninhalation) gavage studies, which included irritant properties, low pH, and/or viscosity of the vehicle and/or the test article. Accompanying the exudative inflammatory changes were degeneration, necrosis, erosion of underlying mucosa as well as hyperplasia and squamous metaplasia of International Journal of Toxicology 36(1)

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Conclusion