Lung Fibrosis

 

Our current safety risk assessment for biopersistent materials present in aerosol products relies on estimating lung exposure in consumers coupled with the use of chemical-specific data from historical in vivo inhalation toxicity studies. Our aim is to replace the need for animal study data using a combination of exposure-based waivingand an understanding of the Adverse Outcome Pathways for key events in lung responses.

A sector-relevant inhalation threshold of toxicological concern has been derived using a database of studies representative of chemicals and substances commonly used in cosmetic and consumer products.  Work is ongoing to address the challenges around estimating human lung exposure for non-spherical materials. We are developing qualitative (e.g. electron microscopy) and quantitative methods and adapting currently available predictive models of exposure in the lower lung.

One of the key adverse responses to chronic inflammation resulting from lung exposure to biopersistent materials is lung fibrosis. Using reverse engineering we have been able to identify genomic responses to case study materials, such as polymers, linked to histopathology in the lung and to idiopathic pulmonary fibrosis. The common pathways identified as critical were: oxidative stress, cell death and regeneration, inflammation signalling pathways, cell differentiation, and fibrosis and remodelling. We have identified readout markers that can be used in surrogate test systems to detect significant changes related to lung fibrosis.

We are now evaluating this approach by testing a number of well-characterized biopersistent materials in relevant in vitro systems and examining the dose responses using these readout markers. An initial collaboration with TNO (Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek; The Netherlands Organisation for Applied Scientific Research) identified a relevant cell type, HFL-1, which gave genomic and proteomic readouts for detecting lung fibrosis. We then looked to increase the sensitivity of these by using cell culture systems primed towards fibrotic responses (BioMap® in vitro systems), and plans are in place to use these findings to evaluate the use of micro co-cultures to determine the fibrotic potential of materials.  We are also currently investigating state-of-the-art aerosol exposure systems coupled with relevant cell models, in order to reproduce more closely the real-life exposure of the human respiratory tract to inhaled substances.

Latest presentation

Prototype inhalation risk assessment for biopersistents using adverse outcome pathway (AOP) approaches

Latest publication

Coming soon……

Dr. Bobbie Bradford