Technical Report 122

Particle size (fine, ultrafine, nano)

The term size refers to the linear extension of the particles. In order to take into account density and shape the particle diameter is expressed as so called equivalent diameter: the aerodynamic diameter for particles larger than 0.5 μm and the diffusion equivalent diameter for the smaller size fraction. The term nanoparticle is used for objects with two or three dimensions smaller than 100 nm. Engineered nanomaterials consist of nanoparticles and are produced intentionally and are designed to possess specific properties. In parallel there are ultrafine particles being defined as nanoparticles generated unintentionally such as in combustions processes or by reactions in the atmosphere. Most engineered nanomaterials released into the air occur as agglomerates or aggregates of much smaller primary building blocks (primary/constituent particles). Aggregates are groups of primary particles held together by firm forces such as sinter bridges, whereas agglomerates are loosely tied together by van der Waals forces. The (equivalent) diameter of these agglomerates and aggregates is an important parameter in the estimation of the pulmonary dose (Section 2.3). Importantly, recent experiments have demonstrated that the de-agglomeration of agglomerates consisting of nano-sized constituents is not a significant event in vivo (Creutzenberg et al, 2012, Morfeld et al, 2012, Morfeld et al, 2013, Creutzenberg et al, 2013).

The particle size is also directly associated with the surface-based dose metric. Pulmonary toxicity per unit mass of the same material appears to be enhanced with decreasing particle size in a number of studies with various exposure regimes (inhalation and intratracheal instillation) and for a variety of PSPs (Ferin et al, 1991, Oberdörster et al, 1992, Heinrich et al, 1995, Borm et al, 2000, Gallagher et al, 2003, Renwick et al, 2004, Gilmour et al, 2004, Gurr et al, 2005, Sager and Castranova 2009, Kolling et al, 2011). It has also been demonstrated that smaller sized particles exhibit longer residence times in the lungs following exposures compared to larger particles, indicative of slower clearance rates. As small particles may more readily translocate to the pulmonary interstitium, AM-mediated clearance may be hindered which results in prolonged retention times of particles in the lung (Oberdörster et al, 1994; Kreyling et al, 2002) (Geiser & Kreyling, 2010) (Scherbart et al, 2011). The possibility of nano-sized particles originating from inhaled agglomerates and escaping the major particle scavenging pathways is however limited in real-life situations (Landsiedel et al, 2012; Morfeld et al, 2012).

A higher biological activity of smaller particles is however not universal as Eydner et al, did not observe significant changes in elicited effects or translocation behaviour between groups exposed to nano or fine titanium dioxide particles (Eydner et al, 2012). An issue under debate is whether there is truly a universal size limit at which the size-behaviour relationship displays an inflection point A recent report by Hassinger and Sellers stated that neither the experimental data nor the theoretical explanations currently suffice to define the size at which the properties of materials are changed to ‘nanospecific' properties (Hassinger & Sellers, 2012). Regarding the relationship between the "classic” particle toxicology and the nanotoxicology, Donaldson and Seaton stated: ”Nanotoxicology now dominates particle toxicology and for many people nanoparticle toxicology is particle toxicology” (Donaldson & Seaton, 2012).

Comparable findings of no dependency of lung toxicity with particle size and surface area were revealed when comparing TiO2 nano- and fine particles (25 nm and 100 nm) of different sizes, surface areas, and crystal structure. Although the difference in surface areas were as large as 30 fold, the observed lung inflammatory responses following intratracheal instillation to rats (1 and 5 mg/kg body weight, 24 hours, 1 week and 3 months), the observed lung responses were almost the same for the two particle sizes investigated (Warheit et al, 2006).

A recent critical review article (Donaldson and Poland 2013) makes a well-argued case, based upon a thorough review of the existing data, that conventional particle toxicology is in general, both useful and relevant to the toxicological evaluation of nanoparticle hazards and that there is no clear evidence to show that particles below 100 nm show any kind of step-change in their hazard status and for the onset of any novel nano-specific hazard. For this reason the ECETOC Task Force was of the opinion that there is no need to include any specific section in this report on nanostructured materials and that most of the findings for conventional particles will apply to nanostructured materials. This reasoning is reinforced by the fact that much of the scientific information that has gone into this report are based on studies using carbon black and ultrafine TiO2, both of which are nanostructured materials.