Particle toxicology and health - where are we?

Abstract

Background: Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses. While particulate pollution is one of the leading contributors to the global burden of disease, particles are also increasingly used for medical purposes. Over the past decades we have gained considerable experience in how particle properties and particle-bio interactions are linked to human health. This insight is useful for improved risk management in the case of unwanted health effects but also for developing novel medical therapies. The concepts that help us better understand particles' and fibres' risks include the fate of particles in the body; exposure, dosimetry and dose-metrics and the 5 Bs: bioavailability, biopersistence, bioprocessing, biomodification and bioclearance of (nano)particles. This includes the role of the biomolecule corona, immunity and systemic responses, non-specific effects in the lungs and other body parts, particle effects and the developing body, and the link from the natural environment to human health. The importance of these different concepts for the human health risk depends not only on the properties of the particles and fibres, but is also strongly influenced by production, use and disposal scenarios.

Conclusions: Lessons learned from the past can prove helpful for the future of the field, notably for understanding novel particles and fibres and for defining appropriate risk management and governance approaches.

Fig. 1

Overview on different types of NP’s translocation and clearance in the lungs. Artwork by Mark Miller, reproduced with permission from [14].

Fig. 2

Panel A: Alveolar-macrophage (AM) associated percentages of inhaled NP (20 + 80 nm iridium NP, 20 nm gold + elemental-carbon NP and 20 + 70 nm titanium dioxide NP) versus instilled micron-sized particles (0.5, 3, and 10 μm polystyrene (PSL) particles) found in bronchoalveolar lavage (BAL) of rats 24 h after application [54]. Panel B: Percentages of inhaled NP (20 nm iridium NP from 3 - 180 days and 20 nm gold + titanium dioxide NP from 3 - 28 days after inhalation) found in bronchoalveolar lavage fluids of rats at various time points [54] versus micron-sized particles (either inhaled 3.5 μm PSL [52] or intratracheally instilled fluorescent 2 μm PSL [51]. All percentages are relative to the contemporary lung burden.

Fig. 3

The ratios R_i represent the fractions of TiO₂2NP present in liver, spleen, kidneys and carcass (without organs) and the integral sum of all absorbed fractions determined after IT-instillation that have been absorbed through the GIT relative to the sum of gut-absorbed and ABB-translocated TiO₂NP after 1, 7 and 28 days. Mean ± SEM of n=4 rats at each time point.

Fig. 4

Estimation of chronic NOAEC from subchronic rodent study using the MPPD Model.

Fig. 5

Bioprocessing of inhaled nano-SiO₂ particles: (left) large agglomerates of amorphous precursor material; right) dark field STEM image showing breakdown of SiO₂ NPs in alveolar macrophage (Zone 1) and formation of Zone II.

Fig. 6

Conceptual understanding of the inter-relationships between the 5Bs and the working definitions of these terms as used in this section. Bioavailability indicates the amount of the applied dose that is in the right form to enter the organism, which for NPs depends on the dispersion conditions and the interplay between the medium components and the NP surface. Biopersistence provides an indication of how long the NPs remain in circulation and/or are retained by the organs to which they biodistribute (i.e. the retention half-life) as determined by their adsorbed biomolecule corona. Retention is affected by bioprocessing, which we define as the physicochemical transformation of the NPs by cells or organisms, which are often driven by the acquired biomolecules. Bioprocessing reflects the fact that NPs and their degradation products may impact on the biochemical functioning of the cell or organism, including assimilation into cellular reactions. Finally, bioclearance describes the elimination pathways by which organisms remove NPs, which are dependent upon the uptake route and the biodistribution pattern as different organs have different clearance mechanisms available, as well as the bioprocessing following localisation to the target organs.

Fig. 7

Example of a modern risk governance framework including a wide range of stakeholder communities (adapted by authors from IRGC, http://www.irgc.org/risk-governance/irgc-risk-governance-framework/, accessed July 17, 2015)