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Adverse Outcome Pathways

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17 September 2024
CHAPTER 4 . OUR SMOKELESS SCIENCE

Adverse Outcome Pathways

Linking in vitro and clinical studies to potential disease

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.[1] AOPs describe how an exposure to a stimulus can produce a series of changes resulting in a disease or adverse outcome (AO).

Researcher handling petri dish with purple gloves

"The adverse outcome pathway (AOP) has been proposed as a simplified organisational construct to contribute to this transition by linking molecular initiating events and earlier (more predictive) key events at lower levels of biological organisation to disease outcomes."

 

Anna Bal-Price

Developmental Biologist

European Commission Joint Research Centre[5]

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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 disease to develop. To gain scientific acceptance, all AOPs are open to peer review via the OECD AOP wiki online portal.[2]

 

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.[2,3]

 

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

Figure 1. Combined AOP (AOP 411, 424 & 425) for COPD

COPD combined AOP (AOP 411, 424 & 425) - Evidence

Oxidative Stress
Less Cilia & Altered Fluid Uptake
Decreased Cilia Function
Increased Mucus & Viscosity
Decreased Mucus Clearance

Decreased Lung Function

Adverse Outcome

References

[1] OECD., Guidance document for the use of adverse outcome pathways in developing integrated approaches to testing and assessment (IATA). OECD Series on Testing and Assessment, No. 260, OECD Publishing, 2017. DOI: 10.1787/44bb06c1-en

[2] Society for Advancement of AOPs, AOP-Wiki. (Accessed: 12 August 2024)

[3] Luettich, K., et al., An adverse outcome pathway for decreased lung function focusing on mechanisms of impaired mucociliary clearance following inhalation exposure. Front Toxicol, 2021. 3:750254. DOI: 10.3389/ftox.2021.750254

[4] Makena, P., et al., An adverse outcome pathway for the cigarette smoke-mediated oxidative stress in plaque formation. [unpublished manuscript]. British American Tobacco (BAT), 2024.

[5] Bal-Price, A., and Meek, M. E. B., Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther, 2017. 179: p. 84-95. DOI: 10.1016/j.pharmthera.2017.05.006

[6] Gale, N., et al., Changes in biomarkers of exposure and biomarkers of potential harm after 360 days in smokers who either continue to smoke, switch to a tobacco heating product or quit smoking. Intern Emerg Med, 2022. 17(7): p. 2017-2030. DOI: 10.1007/s11739-022-03062-1