Spontaneous and Dosing Route–related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies

Abstract

This study was conducted to characterize lung microscopic lesions in control beagle dogs from inhalation and oral gavage toxicity studies, to determine differences associated with the route of administration, and to discuss distinguishing features from compound-induced lung lesions. Samples from 138 control dogs from oral gavage studies and 124 control dogs from inhalation (vehicle control) studies were evaluated microscopically. There was no significant sex-related difference in the incidence of all lesions. Perivascular mononuclear cell infiltration, centriacinar mixed cell infiltration, bronchopneumonia, subpleural septal fibrosis, and alveolar macrophage accumulation were the most common lesions. Aspiration pneumonia was more common in dogs from gavage studies, suggesting reflux after gavage dosing or accidental administration of test formulation as possible causes. Centriacinar mixed cell infiltration was more common in dogs from inhalation studies, suggesting mild irritation by the vehicles used. Vascular lesions, which included pulmonary arteriopathy and smooth muscle mineralization, were observed in a few animals. Some of the spontaneous lesions are similar to lesions induced by test compounds. Compared to spontaneous lesions, compound-induced lesions tend to be multifocal or diffuse, follow a pattern of distribution (e.g., centriacinar, perivascular, and interstitial), show a dose response in the incidence and severity, and may show cell-specific toxicity.

Acute and Sub-chronic Toxicity of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br. in Beagle Dogs

“…Accordingly, the changes were deemed incidental with minimal toxicological consequences for dogs treated with oral doses of 20, 60 and 120 mg/kg.bw TA. Notably, the incidence and severity of interstitial pneumonia were similar between the TA administration and control groups, consistent with a previous report that reflux after gavage dosing or accidental administration of test formulation led to higher frequency of pneumonia in dogs [42]. Lesions of other organs showed no dose-or time-dependent relationships and were not physiologically significant.…”

Multisite Analysis of Lesions in the Respiratory Tract of the Rat and Nonhuman Primate (Cynomolgus Monkey) Exposed to Air, Vehicle, and Inhaled Small Molecule Compounds

“…Compared to spontaneous lesions, lesions induced by exposure to small molecules test articles tend to be multifocal or diffuse, follow a pattern of distribution (eg, centriacinar, PV, and interstitial) and show a dose response in the incidence and severity. 11 Other common incidental findings in rats that may be observed in association with increased alveolar macrophages include focal hemorrhage, hemoglobin crystalline material, other cell types such as neutrophils, pyknotic debris, and type II pneumocyte hyperplasia. 5,22 Focal hemorrhage and crystalline material may be associated with inhalation anesthesia, whereas alveolar macrophages with inflammation or granuloma may increase due to histiocytic inflammation or granulomas secondary to aspiration of feed or bedding materials.…”

“…5 Although it is possible that these results may reflect recording or sampling bias inherent to inhalation studies and previously discussed, they may also reflect the possibility that some nebulized or powdered vehicle may induce phagocytic clearance by alveolar macrophages. 11 The presence of potential recording or sampling bias inherent to inhalation studies could also explain differences in the incidence of URT findings related to irritation between inhalation and non-inhalation studies.…”

“…10 The differentiation of background from treatment-related changes is further hampered by a paucity of information on the comparative pathology and the relevant incidence (historical control data [HCD]) of the more commonly occurring background or incidental pathology findings in some laboratory animal test species. 11 -13 Rodents have been extensively used in inhalation studies, and therefore, the response of the rodent respiratory tract to a wide variety of inhaled toxicants is well documented. 7,9,14 -16 Much less information is published on dogs and primates.…”

Extraintestinal Pathogenic Escherichia Coli Causes Necrohemorrhagic Pneumonia in Multiple Research Dogs

“…Pneumonia is an uncommon but serious cause of morbidity in purpose-bred beagle research dogs and is often associated with gavage error, aspiration pneumonia, or potential test article–related effects. 1 In dogs in dense housing situations, outbreaks of fatal necrotizing and hemorrhagic pneumonia due to infectious etiologies such as canine influenza, Streptococcus equi spp. zooepidemicus , or leptospirosis have been reported.…”