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

Frontiers in Toxicology

Vinita Chauhan¹  Jason M. O’Brien³  Carole L. Yauk⁴  Francesco Marchetti⁴  Elizabeth Huliganga⁴ 

[1]Consumer and Clinical Radiation Protection Bureau, Health Canada, Ottawa, ON, Canada

[2]Department of Biology, University of Ottawa, Ottawa, ON, Canada

[3]Ecotoxicology and Wildlife Health Division, Environment and Climate Change Canada, Ottawa, ON, Canada

[4]Mechanistic Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada

关键词: adverse outcome pathways;    reactive oxygen species;    DNA damage;    genotoxicity;    toxicology;   

DOI  :  10.3389/ftox.2022.827328

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown