A pilot study on the refinement of acute inhalation toxicity studies: the isolated perfused rat lung as a screening tool for surface-active substances

• Published in: Alternatives to laboratory animals Vol. 40; no. 4; p. 199
• Main Authors: Fischer, Monika, Koch, Wolfgang, Windt, Horst, Dasenbrock, Clemens
• Format: Journal Article
• Language: English
• Published: England 01.09.2012
• Subjects: Acute Lung Injury - chemically induced; Acute Lung Injury - pathology; Acute Lung Injury - physiopathology; Administration, Inhalation; Animal Testing Alternatives; Animals; Female; In Vitro Techniques; Inhalation Exposure; Lung - drug effects; Lung - pathology; Lung - physiopathology; Male; Perfusion; Pilot Projects; Pulmonary Edema - chemically induced; Pulmonary Edema - pathology; Rats; Rats, Wistar; Respiratory Function Tests; Surface-Active Agents - administration & dosage; Surface-Active Agents - toxicity; Toxicity Tests, Acute - methods
• ISSN: 0261-1929
• DOI: 10.1177/026119291204000404

New surface-active agents in waterproofing sprays are frequently tested for acute inhalation toxicity in vivo according to OECD Test Guideline 403. In order to refine and reduce the number of acute inhalation tests performed, we propose a screening test that uses isolated lungs. The test consists of the exposure of isolated, ventilated and perfused rat lungs, to aerosolised formulations of waterproofing agents (mass median aerodynamic diameter = 1μm), and on-line monitoring of respiratory parameters and gross pathology analysis. A pilot evaluation of the isolated perfused rat lung model for use in a screening test was carried out by blind testing 12 surface-active substances. The results obtained compared well with data available from in vivo acute inhalation studies. Substances that triggered harmful effects, such as impaired lung compliance and atelectasis of the isolated perfused lung, were also found to cause changes in respiratory parameters, some of which would be severe enough to lead to death in in vivo tests with rats. The changes in respiratory parameters suggest that the mode-of-action is associated with impairment of the surfactant layer. Therefore, pre-testing in the isolated perfused rat lung allows the identification of surface-active substances with the potential for causing acute inhalation toxicity.