Adverse Outcome Pathways
Adverse outcome pathways (AOPs) were first proposed by the Organisation of Economic Co-operation and Development (OECD), with the goal of reducing the need for animal testing[114]. AOPs describe how an exposure to a stimulus can produce a series of changes resulting in a disease or adverse outcome.
“AOPs are anticipated to facilitate the compilation of information to increase mechanistic understanding of pathophysiological pathways that are responsible for human disease.”
Anna Bal-Price
Developmental Biologist
European Commission Joint Research Centre[115]
In an AOP, a stimulus, such as a chemical exposure, can result in an initial change or molecular initiating event (MIE). The pathway consists of a series of key events (KE) that are adverse changes to cells, tissues and organs. For the purposes of an AOP, any change must be both critical and measurable to become a KE. Any change that leads to a measurable increase in a KE is likely to lead to progress to the next KE and in turn potentially disease.
The use of an AOP pathway allows the use of non-animal data, such as clinical and lab-based studies, to assess the likelihood of a disease developing. To gain scientific acceptance, all AOPs are open to peer review via the OECD AOP wiki online portal[114].
AOPs are currently being used as part of the Tobacco Harm Reduction (THR) programme to look at two of the main smoking-related diseases, COPD and CVD. These investigations will hopefully support clinical studies and product testing in the lab. We have developed a potential CVD AOP and COPD AOP in collaboration with other industry participants[117],[116].
Using the AOP below for COPD (Figure 1), we have mapped evidence from in vitro studies to show how earlier events can lead to disease progression. Some of these changes can be tested in both the lab and in the clinic allowing us to align our testing. These tests can then be used to show how switching to our new Smokeless Products could reduce these changes compared to cigarette smoking.
Figure 1. Combined AOP (AOP 411, 424 & 425) for COPD
COPD combined AOP (AOP 411, 424 & 425) - Evidence
Clinical Testing
Oxidative
Stress
Molecular Initiating Event
glo 360-Day Clinical Trial[36]: 8-epi-prostaglandin F2I Type III (ng/24h) (biomarker for isoprostane) glo and air exposure (quitting) = comparable isoprostane reductions
Continue to smoke
329.5
Switch to glo
258.1
(-22%)
Stop Smoking
259.2
(-21%)
Clinical Testing
Less Cilia & Altered Fluid Uptake
Key Events 1-3
Cigarette smoke
Significant reduction in cilia when exposed to smoke compared to air; air is a proxy for Never Smokers.
Air
In Vitro Testing
Decreased Cilia Function
Key Events 2,4,6
Active function for cilia exposed to glo aerosol comparable to air exposure over a six-week period. Smoke exposure resulted in zero function after four weeks.
In Vitro Testing
Increased Mucus & Viscosity
Key Events 5
Increased goblet cells (blue dots) on cilia observed with smoking. Cilia /goblet number for glo aerosol and air exposure = comparable.
Air
glo
Cigarettes
In Vitro Testing
Decreased Mucus Clearance
Key Events 7
Effective mucus clearance is reduced with smoke exposure. Air exposure results in the most effective mucus clearance.
Adverse Outcome
Decreased Lung Function
References
A full list of references for this page can be found in the section 11. References.
Exclusive access to the Omni™ Newsletter
Join the conversation shaping A Better Tomorrow™. Sign up to receive exclusive access to the Omni™ Newsletter and future Omni™ updates.
Signing up to the Omni™ Newsletter does not constitute consent to receive marketing communications.