Multicenter prevalidation study demonstrates reliable respiratory toxicity screening using rat precision-cut lung slices, highlighting potential to reduce live animal inhalation testing.
Key Points
To evaluate the inter-laboratory reproducibility and predictive capability of rat precision-cut lung slices (PCLS) as an ex-vivo model for estimating respiratory toxicity.
Conducted a prevalidation study across three independent laboratories using rat precision-cut lung slices exposed to 5 concentrations of 20 industrial chemicals under submerged conditions for 1 hour.
Assessed toxicity after 23 hours of post-incubation by measuring mitochondrial activity (WST-1), lactate dehydrogenase (LDH) leakage, total protein content (BCA), and interleukin-1alpha (IL-1α) release across >900 concentration-response curves.
Calculated log10[IC50] values and developed two predictive models, including a two-group classification model and an IC50-to-LC50 translation model.
Assays evaluating mitochondrial activity (WST-1) and protein content (BCA) demonstrated the highest intra- and inter-laboratory consistency for IC50 determinations.
WST-1 and LDH assays detected toxic effects for most evaluated chemicals, whereas only a subset stimulated extracellular IL-1α release.
Both the two-group classification model and the LC50 prediction model yielded promising accuracy in forecasting respiratory toxicity outcomes.