title: Adverse outcome pathway development from protein alkylation to liver fibrosis.
abstract: In modern toxicology, substantial efforts are undertaken to develop alternative solutions for in vivo toxicity testing. The adverse outcome pathway (AOP) concept could facilitate knowledge-based safety assessment of chemicals that does not rely exclusively on in vivo toxicity testing. The construction of an AOP is based on understanding toxicological processes at different levels of biological organisation. Here, we present the developed AOP for liver fibrosis and demonstrate a linkage between hepatic injury caused by chemical protein alkylation and the formation of liver fibrosis, supported by coherent and consistent scientific data. This long-term process, in which inflammation, tissue destruction, and repair occur simultaneously, results from the complex interplay between various hepatic cell types, receptors, and signalling pathways. Due to the complexity of the process, an adequate liver fibrosis cell model for in vitro evaluation of a chemical's fibrogenic potential is not yet available. Liver fibrosis poses an important human health issue that is also relevant for regulatory purposes. An AOP described with enough mechanistic detail might support chemical risk assessment by indicating early markers for downstream events and thus facilitating the development of an in vitro testing strategy. With this work, we demonstrate how the AOP framework can support the assembly and coherent display of distributed mechanistic information from the literature to support the use of alternative approaches for prediction of toxicity. This AOP was developed according to the guidance document on developing and assessing AOPs and its supplement, the users' handbook, issued by the Organisation for Economic Co-operation and Development.
authors.affiliation: Chemicals Safety and Alternative Methods Unit (F.3), Directorate F - Health, Consumers and Reference Materials, Directorate General Joint Research Centre, European Commission, Ispra, Italy.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Horvat
authors.affiliation: Chemicals Safety and Alternative Methods Unit (F.3), Directorate F - Health, Consumers and Reference Materials, Directorate General Joint Research Centre, European Commission, Ispra, Italy. brigitte.landesmann@ec.europa.eu.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Landesmann
authors.affiliation: Chemicals Safety and Alternative Methods Unit (F.3), Directorate F - Health, Consumers and Reference Materials, Directorate General Joint Research Centre, European Commission, Ispra, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lostia
authors.affiliation: Department of In Vitro Toxicology and Dermato-Cosmetology, Center for Pharmaceutical Research, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.affiliation: Chemicals Safety and Alternative Methods Unit (F.3), Directorate F - Health, Consumers and Reference Materials, Directorate General Joint Research Centre, European Commission, Ispra, Italy.
authors.forename: Sharon
authors.initials: S
authors.lastname: Munn
authors.affiliation: Chemicals Safety and Alternative Methods Unit (F.3), Directorate F - Health, Consumers and Reference Materials, Directorate General Joint Research Centre, European Commission, Ispra, Italy.
authors.forename: Maurice
authors.initials: M
authors.lastname: Whelan
mesh_terms: D000478:Alkylation / Q000187:drug effects; D000826:Animal Testing Alternatives; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000503:physiopathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests / Q000379:methods*; D014116:Toxicology / Q000379:methods
chemical_list: D011506:Proteins
keywords: Adverse outcome pathway (AOP); Alternatives to animal testing; Liver fibrosis; Risk assessment; Systems toxicology