Technical Report 122

Terms of reference

Although the ‘lung overload’ phenomenon has been known for decades, it has recently become more prominent for the derivation of 'Derived No Effect Levels' (DNEL) under REACH registrations, setting of exposure limits, and for classification and labelling under the Globally Harmonised System of Classification and Labelling of Chemicals (GHS). In its Guidance on Information Requirements, ECHA recently stated that the interpretation of data obtained following high exposures to poorly soluble particles (PSPs) "should be approached with caution and appropriate discussion should be given to the mechanistic driver behind any pathogenic effects detected" (ECHA 2012a). In this respect ECHA also notes, that "effects occurring secondary to a threshold stimulus such as inflammation could also be considered threshold in nature and as such a DNEL can be derived" and that " a possible example of such a driver is the induction of lung overload in experimental animals exposed to poorly soluble low toxicity (nano)particles leading to inflammation, oxidative stress and culminating in lung tumour formation" (ECHA, 2012b).
The aim of the present document therefore was to examine the current scientific understanding of the "lung overload” hypothesis with regard to the anticipated sensitivity and specificity of the rat lung responses, its implications for hazard identification and human risk assessment. For this a `State of the Science Review` on the relevance of effects, for human health, observed after repeated inhalation exposure in rats to PSPs of low inherent toxicity was prepared based on earlier reviews, including recent information in the field of `lung overload`. Special emphasis was given to the following terms of references:
• Discuss new information on lung effects and mechanistic interpretation of lung overload in humans and animals (rodents and non-rodents).
• Identify and agree on parameters that characterise lung overload (parameters for animals and humans separate).
• Compare effect levels from animal studies to realistic worker exposure (e.g. deposited dose for humans) on a quantitative basis.
• Review relevance of existing/new epidemiology studies with regard to observed experimental and human respiratory effects.
• Elaborate on the possibility to include possible ‘lung overload’ effects from nanomaterial inhalation studies.
• Give consideration to the organisation of a workshop to discuss the relevance of rat lung overload for humans in terms of e.g. classification and labelling, and the derivation of DNELs.