Application of the comparison approach to open TG-GATEs: A useful toxicogenomics tool for detecting modes of action in chemical risk assessment. (November 2018)

• Record Type: Journal Article
• Authors: Heusinkveld, Harm J.; Wackers, Paul F.K.; Schoonen, Willem G.; van der Ven, Leo; Pennings, Jeroen L.A.; Luijten, Mirjam
• Is Part Of: Food and chemical toxicology. Volume 121(2018)
• Page Start: 115
• Page End: 123
• Publication Date: 2018-11
• Subjects: In vitro -- Gene expression -- Human health risk assessment -- Liver -- Pharmaceuticals -- Transcriptomics; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2018.08.007
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Mode of action information is one of the key components for chemical risk assessment as mechanistic insight leads to better understanding of potential adverse health effects of a chemical. This insight greatly facilitates assessment of human relevance and enhances the use of non-animal methods for risk assessment, as it ultimately enables extrapolation from initiating events to adverse effects. Recently, we reported an in vitro toxicogenomics comparison approach to categorize (non-)genotoxic carcinogens according to similarities in their proposed modes of action. The present study aimed to make this comparison approach generally applicable, allowing comparison of outcomes across different studies. The resulting further developed comparison approach was evaluated through application to toxicogenomics data on 18 liver toxicants in human and rat primary hepatocytes from the Open TG-GATEs database. The results showed sensible matches between compounds with (partial) overlap in mode of action, whilst matches for compounds with different modes of action were absent. Comparison of the results across species revealed pronounced and relevant differences between primary rat and human hepatocytes, underpinning that information on mode of action enhances assessment of human relevance. Thus, we demonstrate that the comparison approach now is generally applicable, facilitating its use as tool in mechanism-based risk assessment. Highlights: Mode of action information is a key aspect of chemical risk assessment. We developed a generically applicable toxicogenomics comparison approach. We tested this approach on data of 18 liver toxicants in primary hepatocytes. Our comparison approach is able to identify (partial) overlap between MOAs.