A case example of a radiation-relevant adverse outcome pathway to lung cancer

Abstract

Background

Adverse outcome pathways (AOPs) describe how a measurable sequence of key events, beginning from a molecular initiator, can lead to an adverse outcome of relevance to risk assessment. An AOP is modular by design, comprised of four main components: (1) a Molecular Initiating Event (MIE), (2) Key Events (KEs), (3) Key Event Relationships (KERs) and (4) an Adverse Outcome (AO).

Purpose

Here, we illustrate the utility of the AOP concept through a case example in the field of ionizing radiation, using the Organisation for Economic Cooperation and Development (OECD) Users' Handbook. This AOP defines a classic targeted response to a radiation insult with an AO of lung cancer that is relevant to radon gas exposure.

Materials and methods

To build this AOP, over 500 papers were reviewed and categorized based on the modified Bradford-Hill Criteria. Data-rich key events from the MIE, to several measurable KEs and KERs related to DNA damage response/repair were identified.

Results

The components for this AOP begin with direct deposition of energy as the MIE. Energy deposited into a cell can lead to multiple ionization events to targets such as DNA. This energy can damage DNA leading to double-strand breaks (DSBs) (KE1), this will initiate repair activation (KE2) in higher eukaryotes through mechanisms that are quick and efficient, but error-prone. If DSBs occur in regions of the DNA transcribing critical genes, then mutations (KE3) generated through faulty repair may alter the function of these genes or may cause chromosomal aberrations (KE4). This can impact cellular pathways such as cell growth, cell cycling and then cellular proliferation (KE5). This will form hyperplasia in lung cells, leading eventually to lung cancer (AO) induction and metastasis. The weight of evidence for the KERs was built using biological plausibility, incidence concordance, dose-response, time-response and essentiality studies. The uncertainties and inconsistencies surrounding this AOP are centered on dose-response relationships associated with dose, dose-rates and radiation quality.

Conclusion

Overall, the AOP framework provided an effective means to organize the scientific knowledge surrounding the KERs and identify those with strong dose-response relationships and those with inconsistencies. This case study is an example of how the AOP methodology can be applied to sources of radiation to help support areas of risk assessment.

Keywords:

• Adverse outcome pathway
• key events
• molecular initiating event
• key event relationships
• lung cancer

Acknowledgments

The authors would like to acknowledge Ruth Wilkins, Sami Qutob and Daniel Beaton for critical review and Baki Sadi, Fatemeh Nabavi, Sandra Noble, Nadine Adam, and Deepti Bijlani for reference checking and final editing of the AOP.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Vinita Chauhan

Vinita Chauhan is a research scientist at Health Canada.

Samantha Sherman

Samantha Sherman was a research assistant from the University of Ottawa.

Zakaria Said

Zakaria Said was a fourth year Honor student from the University of Ottawa.

Carole L. Yauk

Carole L. Yauk is a research scientist at Health Canada.

Robert Stainforth

Robert Stainforth was a post-doctoral fellow at Health Canada.