S11-03 Lung surfactant interaction assay – a method to predict early signs of acute inhalation toxicity

Acute inhalation toxicity testing for regulatory purposes relies on the use of guideline studies in rodents. Apart from the ethical concerns of exposing animals to toxic chemicals, in vivo testing is expensive and time-consuming. The results from acute inhalation toxicity is systemic (lethal concentration for 50% of the exposed animals) and death obscures effects on the portal-of-entry, i.e. the lungs ^[1]. Understanding the effect on the lungs, is essential for replacement of animals for acute inhalation testing. However, the lung is a complex organ, with different potential targets for toxicity ^[2]. In this presentation, the reliability and relevance of a cell-free method based on the monitoring of lung surfactant biophysical function during exposure to a test chemical for predicting acute effects on the lungs will be discussed ^[3]. The method addresses the molecular initiating event of the adverse outcome pathway AOP 302; “inhibition of lung surfactant function” that can lead to the adverse outcome “decreased lung function” ^[4]. The main function of lung surfactant is to regulate the surface tension at the respiratory air-liquid interface to avoid alveolar collapse in vivo, starting a cascade that leads to decreased lung function. The effect of more than 150 different chemicals and products have been tested, covering consumer products, occupational exposures, inhaled pharmaceuticals and single chemicals. On this background the current applicability domain of the method will be explored, and how the results of this in vitro test relates to outcomes in guideline studies for acute inhalation toxicity ^[5]. This cell-free method is a promising candidate for prioritization and screening of chemicals, and its inclusion in an integrated approach to testing and assessment will contribute to the reduction of the use of rodents for acute inhalation toxicity testing.

This work was partly supported by ‘FFIKA, Focused Research Effort on Chemicals in the Working Environment’ from the Danish Government.