Mechanisms of Fibre Toxicity (cross-Unit project)

A major research focus of the MRC Toxicology Unit aims to uncover how particles used for modern manufacturing interact with the body and how to help prevent their harmful effects. Some of these particles (e.g. carbon nanotubes) are similar in their physical and biological properties to asbestos, a well-known cause of human lung disease. The most severe illnesses associated with asbestos fibre exposure are asbestosis, malignant mesothelioma and lung cancer, and they usually manifest themselves after 20-40 years of latency. There is rising concern that nanoparticles may drive toxic effects leading to the onset of similar asbestos-related diseases. By applying cutting-edge technologies to this toxicological question the aim is to identify potential key drivers of particle toxicity and apply this knowledge to inform ‘safe by design’ of nanoparticles, thereby reducing their potential long-term adverse effects.

It is well established that exposure to naturally occurring mineral fibres, such as asbestos, is associated with development of disease, including incurable mesotheliomas. However, the potential of newer manufactured nanofibres e.g. carbon nanotubes (CNTs) to trigger similar disease-associated molecular changes is under-explored. Extensive studies on the toxicity associated with exposure to fibres has led to the fibre pathogenicity paradigm (FPP); the degree of toxicity is related to the diameter, length and biopersistence of the fibre. The data suggest that nanoparticles with a high aspect-ratio (HAR) - long thin rigid fibres - are potentially toxic. By exploiting the combined expertise of two laboratories, the aims of this cross-Unit programme are built around the hypothesis that exposure to biopersistent nanofibres with a HAR initiates a series of events that leads to the development of mesothelioma. Detailed mechanistic information is therefore essential to:
1) construct a “nanofibre-toxicity pathway”
2) identify the key molecular changes that drive the very prolonged process (~40 years) of tumour development.
3) identify novel biomarkers of exposure prior to disease progression.

By employing longitudinal studies in animal models, and comparing this with changes in patients with mesothelioma, we will able to identify at which point these alterations occurred during disease development and thus establish their position in the toxicity pathway. Through the exposure of animals to distinct types of fibres (long CNTs and different classes of engineered nanomaterials, using long asbestos fibres as a reference), we aim to determine the differences and commonalities between these agents at a molecular level and use this information to understand the potential hazards associated with human exposure to CNTs. This research is essential since there is a lack of information about the consequences of pleural exposure of mammals to long CNTs, and the mechanisms underlying carcinogenesis induced by these materials, have not been elucidated.

The data generated through these integrated projects will increase our understanding of the processes of disease development associated with pathogenic fibre-induced toxicity, provide new biomarkers to assess the exposure of the population to potential hazards and inform the future ‘safe by design’ of these new classes of nanomaterials.