Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are an increasing global health burden affecting hundreds of millions of people worldwide. Despite considerable investment to develop new inhaled drugs, in recent years there has been limited success, in part due to the observation of foamy macrophage responses in rat studies which questions their safety for use in humans. The aim of this work was to use in vitro cell culture models of rat and human alveolar macrophages to better characterise the biological response of these airway immune cells to particulate medicines. U937 (human) and NR8383 (rat) macrophage models were exposed for up to 24 h with 0.01 – 100 mg/ml of amiodarone, salbutamol or salmeterol in cell culture medium. Cells were assessed for a variety of responses including toxicity, induction of phospholipidosis, cytokine and chemokine production, cell signalling pathways and production of volatile organic compounds. No significant difference (p<0.05) was observed for viability between U937 and NR8383 for any of the compounds tested, however phospholipidosis was observed to a greater extent in the rat model in comparison with human cells. Immunological, cell signalling and headspace analysis revealed several potential markers of foamy macrophage induction that were raised in amiodarone treated cells in comparison with untreated controls. It is anticipated that these markers may have the potential to identify the foamy macrophage phenotype in drug screening via longitudinal and less invasive animal studies and gain a better understanding of the safety of airway macrophage responses to inhaled particulates.