Use of micro-CT to determine tracheobronchial airway geometries in three strains of mice used in inhalation toxicology as disease models.

Aerosol dosimetry estimates for mouse strains used as models for human disease are not available, primarily because of the lack of tracheobronchial airway morphometry data. By using micro-CT scans of in-situ prepared lung casts, tracheobronchial airway morphometry for four strains of mice were obtained: Balb/c, AJ, C57BL/6, and Apoe-/- . The automated tracheobronchial airway morphometry algorithms for airway length and diameter were successfully verified against previously published manual and automated tracheobronchial airway morphometry data derived from two identical in-situ Balb/c mouse lung casts. There was also excellent agreement in tracheobronchial airway length and diameter between the automated and manual airway data for the AJ, C57BL/6, and Apoe-/- mice. Differences in branch angle measurements were partially due to the differences in definition between the automated algorithms and manual morphometry techniques. Unlike the manual airway morphometry techniques, the automated algorithms were able to provide a value for inclination to gravity for each airway. Inclusion of an inclination to gravity angle for each airway along with airway length, diameter, and branch angle make the current automated tracheobronchial airway data suitable for use in dosimetry programs that can provide dosimetry estimates for inhaled material. The significant differences in upper tracheobronchial airways between Balb/c mice and between C57BL/6 and Apoe-/- mice highlight the need for mouse strain-specific aerosol dosimetry estimates.

Reduced Chronic Toxicity and Carcinogenicity in A/J Mice in Response to Life-Time Exposure to Aerosol From a Heated Tobacco Product Compared With Cigarette Smoke.

We conducted an inhalation study, in accordance with Organisation for Economic Co-operation and Development Test Guideline 453, exposing A/J mice to tobacco heating system (THS) 2.2 aerosol or 3R4F reference cigarette smoke (CS) for up to 18 months to evaluate chronic toxicity and carcinogenicity. All exposed mice showed lower thymus and spleen weight, blood lymphocyte counts, and serum lipid concentrations than sham mice, most likely because of stress and/or nicotine effects. Unlike THS 2.2 aerosol-exposed mice, CS-exposed mice showed increased heart weight, changes in red blood cell profiles and serum liver function parameters. Similarly, increased pulmonary inflammation, altered lung function, and emphysematous changes were observed only in CS-exposed mice. Histopathological changes in other respiratory tract organs were significantly lower in the THS 2.2 aerosol-exposed groups than in the CS-exposed group. Chronic exposure to THS 2.2 aerosol also did not increase the incidence or multiplicity of bronchioloalveolar adenomas or carcinomas relative to sham, whereas CS exposure did. Male THS 2.2 aerosol-exposed mice had a lower survival rate than sham mice, related to an increased incidence of urogenital issues that appears to be related to congenital factors rather than test item exposure. The lower impact of THS 2.2 aerosol exposure on tumor development and chronic toxicity is consistent with the significantly reduced levels of harmful and potentially harmful constituents in THS 2.2 aerosol relative to CS. The totality of the evidence from this study further supports the risk reduction potential of THS 2.2 for lung diseases in comparison with cigarettes.