In this document the subject of lung overload of inhaled non-toxic and poorly soluble particles is reviewed. The terms “poorly soluble” and “non-toxic” need clear definitions. We suggest to denote inhaled particles as poorly soluble when their dissolution half-life measured in artificial lung fluids i.e. interstitial fluid (pH 7.4), artificial lysosomal fluid (pH 4.5), and artificial alveolar fluid (pH 7.4) is larger than the macrophage mediated clearance times. This ensures that macrophage clearance, and not dissolution, determines the particle residence time in the lung. Particles are considered to be non-toxic if they are chemically inert and without any known specific toxicity, i.e. there is no (bio)chemical reaction between the molecules at their surface or dissolved from their surface and the embedding lung fluid. It should be noted, that particles exhibiting significant surface related (cyto)toxicity like crystalline silica (quartz) and/or other specific toxic properties do not fall under this definition and are not considered specifically in this document (also Chapter 3 `Biosolubility`).
The concept of lung overload has been developed in the past four decades based on evidence gained primarily from rat inhalation studies carried out with a variety of technical powders. Using current terminology, many of the test substances investigated such as carbon black, titanium dioxide, “baytubes” etc. are classified as nano-powders because their primary building blocks have dimensions in the nanometre range. In reality, aerosols generated from these powders appear mainly as aggregated and/or agglomerated structures with aerodynamic or mobility diameter larger than a few hundred nanometres and this is also how they are administered to the animals and exhibit toxicity. As will be shown in the following discussions, two metrics are concurrently used to correlate the biological effect with the administered dose. These are particle volume and surface area. Both metrics are integral quantities of the aerosol and require principally no specific consideration of particle size. Particle size enters the dosimetry only via the particle size dependent lung deposition fraction which is required to calculate the administered dose from the exposure concentration. Exposure concentration is usually given in mass concentration. The density and specific surface area of the product, which are preferentially determined in the stage of administration, link the measured quantity mass to the dose metric volume and surface area, respectively. The (envelope) density of a particle can be defined as its mass divided by the displacement volume in a non-wetting liquid. This takes properly into account the particle porosity and represents the volume displacement of a particle when engulfed in a macrophage. The specific surface area is the externally accessible surface area divided by the particle mass. Based on this arguments there is no need to distinguish between nano-powders and micro-powders as far as the lung overload of non-toxic PSPs is concerned.