Biological Systems Research, Philip Morris International R&D, Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland
Systems Toxicology is aimed at decoding the toxicological blueprint of active substances. It integrates principles of toxicology and systems biology by combining high content experimental data – obtained at the molecular, cellular, organ, organism, and population levels – with computational sciences to identify Pathways of Toxicity and the key events in Adverse Outcome Pathways. Systems Toxicology also provides a basis for translation between models (in vitro to in vivo) and study systems (animal model to human). These findings are then applied to perform a mechanism-by-mechanism evaluation of the impact of products on these pathways.
Smoking causes serious diseases such as cardiovascular diseases, lung cancer and chronic obstructive pulmonary disease. Philip Morris International is therefore developing novel products that may have the potential to reduce smoking-related disease risk compared to conventional combustible cigarettes. To determine whether such potentially reduced-risk products (RRP) have the potential to reduce disease risk, we compared their biological impact with that of a combustible reference cigarette (3R4F) on a mechanism-by-mechanism basis in vitro and in vivo using a Systems Toxicology-based approach.
To exemplify the application of Systems Toxicology, cases studies conducted in vitro and in vivo will be presented. These studies demonstrate how transcriptomics-based biological network analysis provides mechanistic insights into the biological impact of combustible cigarette smoke, and how this type of analysis can be used to assess the mechanism-by-mechanism effect of an RRP in comparative studies. While these data alone do not substantiate reduced risk of an RRP, they provide a solid foundation to design further studies, including clinical studies, to be conducted with RRPs.