Technical report 122

PHYSICO-CHEMICAL ASPECTS ASSOCIATED WITH `LUNG OVERLOAD`

Particle overload (also referred to as `lung overload` or `clearance overload`) describes a condition of slowed/impaired (macrophage mediated) clearance in the lung after prolonged exposure to poorly soluble particles of low inherent toxicity. This condition is further characterised by an increased transfer of particles to lymph nodes, accumulation of particles in the lung, increases in lung weight, pulmonary inflammation, epithelial hyperplasia (proliferation), fibrosis and eventually cancer (in the rat). A rat-specific effect pattern can be assumed as evidenced by greater pulmonary inflammatory -, fibrotic -, hyperplastic – and particularly a unique tumorigenic responses to particle exposures as compared to other species (e.g. mice, hamster, non-human primates, humans). Although a mechanistic understanding in terms of species differences is not yet fully established, factors determining the deposition characteristics of inhaled particles, like particle size, airway geometry, ventilation rate and clearance rate seem to be important while persistent inflammation and epithelial cell proliferation are dominant mechanistic drivers. Additionally, various physico-chemical characteristics like particle density, particle surface area or particle volume, may influence the establishment of an overload of alveolar macrophages. Although doses are normally expressed in terms of particle mass, other metrics have shown stronger associations with the extent of the overload-related events observed during chronic particle exposures.

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