Toxicity testing of poorly soluble particles, lung overload and lung cancer

In 2013, an ECETOC Task Force evaluated scientific understanding of the 'lung overload' hypothesis. As there is no evidence that humans develop lung tumours following exposure to poorly soluble particles (PSPs), emphasis was given to the observed higher sensitivity and specificity of rat lung responses and potential impacts of this on human risk assessment. Key arguments and outcomes are summarised here, together with discussion of additional findings published since 2013. Inhalation exposure to PSPs in all species is associated with localised pulmonary toxicity initiated by a persistent pro-inflammatory response to particle deposition. Events in the rat indicate a plausible adverse outcome pathway for lung tumour development following exposure to PSPs under overload conditions. A different particle lung translocation pattern compared to rats make humans less sensitive to developing comparable lung overload conditions and appears to also preclude tumour formation, even under severe and prolonged exposure conditions. Evidence continues to suggest that the rat lung model is unreliable as a predictor for human lung cancer risk. However, it is a sensitive model for detecting various thresholded inflammatory markers, with utility for non-neoplastic risk assessment purposes. It is noteworthy that preventing inflammatory rat lung responses will also inhibit development of neoplastic outcomes.