The 'Particle Overload' Phenomenon and Human Assessment

Abstract

The last decade has seen the publication of an increasing number of scientific papers in which lung tumours have been induced in rats following chronic exposure by inhalation to a range of insoluble, respiratory-sized particulate dusts which hitherto have been considered to be biologically inert. Such substances include talc, titanium dioxide, volcanic ash and carbon black. Such particles have generally been considered ‘nuisance dusts’, possibly capable of eliciting fibrogenic changes, but not cancer. The one feature that all these studies in rats have in common is that the experimental exposures induced ‘overloading’ of the lung as evidenced by an increase in lung weight, retention of particles and chronic and marked inflammatory changes. All of this was preceded by an underlying ‘overloading’ of the alveolar macrophages to the point where they stopped removing particles from the lung. This can happen in a number of experimental species, but it is only the rat that appears to respond with lung tumours as an additional pathological response. This points to the lung tumours being a rat-specific response and thus not a very useful end-point for human risk evaluation for such biologically inert particles. In support of this view is the remarkable observation that in the one well-studied occupational group that routinely has ‘particle overload’ in the lungs, namely coal miners, there is no evidence that they experience an excess risk of lung cancer.

Occupational medicine implications of engineered nanoscale particulate matter

“…The traditional experimental models used to evaluate the toxicity of nanoparticles may not be up to the task and may lead to false-positive or false-negative conclusions. The authors of several early in vitro studies using the colorimetric "MTT" assay to measure toxicity of carbon nanotubes to mitochondria failed to recognize that the carbon nanotubes directly interfered with the test, which resulted in flawed conclusions 8 . Species variability is likely to be substantial, for example the pulmonary toxicity of nanoscale TiO2 at high doses differs substantially between rats and most other species including humans 9-12 .…”