Toxicological Assessment

PMI’s toxicological assessment aims to confirm whether the reduced formation of harmful and potentially harmful constituents (HPHCs) leads to reduced toxicity in laboratory models.

Two complementary approaches

PMI conducts a series of in vitro and in vivo studies on smoke-free products, following Good Laboratory Practice (GLP), to determine whether the reduced levels of HPHCs lead to a reduced toxicity compared with cigarette smoke.

PMI takes toxicological assessment one step further by using a new area of science known as systems toxicology. Systems toxicology helps determine whether reduced toxicity leads to reduced risk in laboratory models. Systems toxicology allows a detailed assessment of the disease-relevant biological mechanisms affected by exposure to toxicants. It relies on state-of-the-art high-throughput experimental technologies and advanced computational sciences.

The aim is to demonstrate that the toxicity of the aerosol from smoke-free products is lower than that of cigarette smoke.

First, systems toxicology is applied to identify the biological mechanisms that are altered by cigarette smoke, capturing this knowledge in biological network models. These models are then used to analyze the datasets for product assessment, allowing comparisons between the network alterations caused by the aerosols of smoke-free products and those caused by cigarette smoke. Furthermore, the approach allows quantitative comparison of the overall biological impact of these exposures in the context of toxicological and disease endpoints.

Toxicological assessment of IQOS

Toxicological studies indicate that reduced formation of HPHCs in the IQOS aerosol has the potential to translate into reduced disease risk compared to continued cigarette smoking.

The chart shows our findings concerning the relative in vitro toxicity of IQOS aerosol compared with the smoke from the 3R4F reference cigarette using three in vitro assays (Neutral Red Uptake, Ames and Mouse Lymphoma) commonly used to assess cytotoxicity and genotoxicity. (Reference)

Effects of switching and cessation in mice

PMI conducted a systems toxicology study in an animal model (Apoe-/- mouse) that develops atherosclerotic plaques and emphysema when exposed to cigarette smoke. In this study, mice were exposed to either 3R4F smoke or IQOS aerosol for eight months. A group of mice was first exposed for two months to 3R4F smoke and then randomized to either IQOS aerosol (switching) or fresh air (cessation). Switching to IQOS aerosol following two months of cigarette smoke led to reduced impact on biological mechanisms and disease endpoints associated with chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) in a manner similar to smoking cessation.

STUDY DESIGN

Phillips, B., et al. (2016). An 8-month systems toxicology inhalation/cessation study in Apoe-/- mice to investigate cardiovascular and respiratory exposure effects of a candidate Modified Risk Tobacco Product, THS 2.2, compared with conventional cigarettes. Toxicol Sci 149(2): 411-432. (Reference)

A: DISEASE ENDPOINT FOR COPD – LUNG EMPHYSEMA

B: DISEASE ENDPOINT FOR CVD – ATHEROSCLEROTIC PLAQUE

Disease endpoints in a mouse switching study. Lung emphysema (A) and atherosclerotic plaque volume (B) in Apoe-/- mice that were exposed for eight months to either 3R4F smoke or Platform 1 aerosol.