Respiratory tract lesions in noninhalation studies

Abstract

This paper reviews respiratory tract lesions observed in rodents administered various chemicals by noninhalation routes. Chemicals administered by inhalation caused lesions in the respiratory tract and were well described; however, when chemicals were administered by noninhalation routes the effort to evaluate tissues for lesions may have been less or not considered, especially in the upper respiratory tract, and some lesions may have gone undetected. Lesions described in this review mostly occurred in rodent chronic noninhalation studies conducted by the National Toxicology Program; however, some were noted in studies of shorter duration. The nasal cavity was vulnerable to damage when chemicals were administered by noninhalation routes. Changes included respiratory epithelial hyperplasia, degeneration and necrosis of olfactory epithelium, olfactory epithelial metaplasia, adenoma, adenocarcinoma, squamous cell carcinoma, and neuroblastoma. In the lung, compound-related lesions included alveolar histiocytosis, alveolar epithelial hyperplasia, bronchiolar metaplasia of the alveolar epithelium, squamous metaplasia, alveolar/bronchial adenoma and carcinoma, and squamous tumors. Pathogenesis of these lesions included regurgitation of volatiles, metabolites arriving from the blood stream, and additional metabolism by olfactory epithelium or Clara cells. The presence of respiratory tract lesions in noninhalation studies emphasizes the need for a thorough examination of the respiratory tract including nasal passages, regardless of the route of administration.

FIGURE 1

Nose. (A) Respiratory epithelial hyperplasia in nasal septum of a rat with the formation of multiple short papillary epithelial projections and infiltration of inflammatory cells in the lamina propria. (B) Respiratory epithelial metaplasia in the dorsal meatus of a mouse with the formation of multiple short papillary epithelial projections, and dilatation and hyperplasia of Bowman’s glands (g). (C) Olfactory epithelial degeneration in the dorsal meatus of a rat with disorganization and vacuolization (arrow) of the olfactory epithelial layer. (D) Olfactory epithelial atrophy/thinning (arrow) in the dorsal meatus of a rat with atrophy of the olfactory nerves (arrow head). (E) Adenoma in a rat nose formed of cuboidal to columnar epithelial cells with gland-like (g) structures. (F) Adenocarcinoma in a mouse nose arising from respiratory epithelium with papillary formations and invasion (arrow) of lamina propria. (G) Squamous cell carcinoma in a rat nose with the formation of nests and cords of squamous cells, anaplasia, keratin formation (k) and invasion (arrow head) of lamina propria. (H) Neuroblastoma filling one side of the nasal cavity of a rat. Nasal septum (ns) at top. All sections were stained with hematoxylin and eosin.

FIGURE 2

Lung. (A) Alveolar histiocytosis in a rat characterized by the accumulation of macrophages (arrows) with abundant foamy cytoplasm in alveoli. (B) Alveolar epithelial hyperplasia in a rat characterized by an increase in cuboidal type II cells (arrows) lining interalveolar septa (s) which are thickened. (C) Bronchiolar metaplasia of alveolar epithelium in a rat where alveolar type I cells are replaced by columnar ciliated cells (arrows). The alveolar lumen contains a basophilic mucin-like material. (D) Squamous metaplasia in a rat lung characterized by the metaplasia of alveolar epithelial cells to squamous cells (arrow), distortion but not obliteration of the normal architecture, and keratin (arrowhead) formation. (E) Benign cystic keratinizing epithelioma in a rat lung characterized by a complex, thick irregular wall, expansive growth into contiguous alveoli, lack of orderly maturation, and the formation of a large keratin-filled cavity. (F) Squamous cell carcinoma in a rat lung characterized by extension through the pleura (arrow) and scirrhous reaction (arrowhead). (G) A/B adenoma in a mouse lung consisting of cuboidal to polygonal cells in a papillary pattern with a distinct border and mild compression. (H) A/B carcinoma in a mouse lung consisting of anaplastic cells with a heterogeneous growth pattern. All sections were stained with hematoxylin and eosin.