Doubts cast on link between PSPs and lung cancer in humans

Experimental study findings in which chronic inhalation of poorly soluble particles (PSPs) gives rise to lung tumours in rats have been questioned in terms of their relevance and applicability to humans, according to an article in the journal Regulatory Toxicology and Pharmacology. The phenomenon, known as ‘lung overload’, was described and discussed in ECETOC’s Technical Report 122.



  • Inhalation of high concentrations of PSPs leads to pro-inflammatory responses and pulmonary toxicity in all species.
  • In humans, inhalation exposure to PSPs is not associated with development of lung tumours.
  • Interstitialisation of PSPs in humans is a key factor in the difference in pathological response between rats and humans.
  • The rat model is sensitive and valuable for detecting early and thresholded responses of inflammatory markers.


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.