A Case Study on Integrating a New Key Event Into an Existing Adverse Outcome Pathway on Oxidative DNA Damage: Challenges and Approaches in a Data-Rich Area

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DOI

https://doi.org/10.3389/ftox.2022.827328

Language of the publication
English
Date
2022-04-28
Type
Article
Author(s)
  • Huliganga, Elizabeth
  • Marchetti, Francesco
  • O’Brien, Jason M.
  • Chauhan, Vinita
  • Yauk, Carole L.
Publisher
frontiers

Abstract

Adverse outcome pathways (AOPs) synthesize toxicological information to convey and weigh evidence in an accessible format. AOPs are constructed in modules that include key events (KEs) and key event relationships (KERs). This modular structure facilitates AOP expansion and network development. AOP development requires finding relevant information to evaluate the weight of evidence supporting each KER. To do this, the use of transparent/reproducible search methods, such as systematic review (SR), have been proposed. Applying SR to AOP development in a data-rich area is difficult as SR requires screening each article returned from a search. Here we describe a case study to integrate a single new KE into an existing AOP. We explored the use of SR concepts and software to conduct a transparent and documented literature search to identify empirical data supporting the incorporation of a new KE, increase in cellular reactive oxygen species (ROS), upstream of an existing AOP: “Oxidative DNA Damage Leading to Chromosomal Aberrations and Mutations”. Connecting this KE to the AOP is supported by the development of five new KERs, the most important being the first adjacent KER (increase in ROS leading to oxidative DNA damage). We initially searched for evidence of all five KERs and screened 100 papers to develop a preliminary evidence map. After removing papers not containing relevant data based on our Population, Exposure, Comparator and Outcome statement, 39 articles supported one or more KERs; these primarily addressed temporal or dose concordance of the non-adjacent KERs with limited evidence supporting the first adjacent KER. We thus conducted a second focused set of searches using search terms for specific methodologies to measure these first two KEs. After screening, 12 articles were identified that contained quantitative evidence supporting the first adjacent KER. Given that integrating a new KE into an existing AOP requires the development of multiple KERs, this approach of building a preliminary evidence map, focusing evidence gathering on the first adjacent KER, and applying reproducible search strategies using specific methodologies for the first adjacent KER, enabled us to prioritize studies to support expansion of this data-rich AOP.

Plain language summary

Health Canada (HC) is increasingly using ‘mechanistic tests’ to determine the molecular targets of chemicals to inform how they cause toxicity and whether these effects are relevant to human health. Importantly, many of these mechanism-based tests are done in cell cultures to reduce animal testing. A primary challenge is determining how the molecular changes in cells inform or predict the detrimental health effects in organs and organisms. To do this, researchers are using a new organizational framework known as Adverse Outcome Pathways (AOPs). AOPs synthesize toxicological information to describe how chemicals interact with molecules in cells to cause health effects. This study focused on an AOP that describes how chemicals that cause increases in reactive oxygen species (ROS) lead to permanent genetic damage. ROS are reactive molecules generated by oxygen in cells. ROS are important for normal cell functioning, but chemical exposures can lead to high levels that damage DNA and proteins. HC researchers applied literature review tools to gather knowledge to support the relationship between increase in ROS observed in cells and consequent DNA damage. The initial search retrieved over 200,000 papers from the peer reviewed literature. After application of a filtering strategy using freely-available software tools, 12 articles describing how much of an increase in ROS is associated with specific levels of increases in DNA damage, were identified and used to establish the relationship between chemical induced ROS generation and DNA damage. This type of data is critical for building models that allow prediction of health effects before their manifestation. These results will be used by HC scientists to advance AOP development and promote the use of data from new non-animal test methodologies to increase their utility in risk assessment.

Subject

  • Health,
  • Health and safety

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Healthy environments, consumer safety and consumer products

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