Establishing scientific confidence in a cell-free method to predict decreased lung function

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. Understanding the effect at the portal-
of- entry, 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. 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.
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. The main function of lung surfactant is to regulate
the surface tension at the respiratory air-liquid surface to avoid alveolar
collapse in vivo, starting a cascade that leads to decreased
lung function. The effect of more than 150 different chemicals andproducts 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. Finally, a case study for the reproducibility within
laboratory will be presented. 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.