The adverse outcome pathway concept: a pragmatic tool in toxicology

Toxicology. 2013 Oct 4;312:158-65. doi: 10.1016/j.tox.2013.08.011. Epub 2013 Aug 23.


Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of critical toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of intermediate steps and key events, and an adverse outcome. Development of AOPs ideally complies with OECD guidelines. This also holds true for AOP evaluation, which includes consideration of the Bradford Hill criteria for weight-of-evidence assessment and meeting a set of key questions defined by the OECD. Elaborate AOP frameworks have yet been proposed for chemical-induced skin sensitization, cholestasis, liver fibrosis and liver steatosis. These newly postulated AOPs can serve a number of ubiquitous purposes, including the establishment of (quantitative) structure-activity relationships, the development of novel in vitro toxicity screening tests and the elaboration of prioritization strategies.

Keywords: 5′-NT; 5′-nucleotidase; ALP; ALT; AO(P)(s); AST; Adverse outcome pathway; BSEP; CAR; CD36; CYP2B10/3A4/7A1; ChREBP; Chemical risk assessment; DPRA; FAS; FXR; GGT; In vitro test development; LXR; MIE; MPP; MRP2/3; MUSST; Mechanistic toxicology; NTCP; OATP1B1; OSTα/β; PXR; Prioritization strategies; QSAR; Quantitative structure–activity relationship; SCD1; SHP; SREBP-1c; SULT2A1; TGF-β1; UGT2B4; adverse outcome (pathway(s)); alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; bile salt export pump; carbohydrate response element binding protein; constitutive androstane receptor; cytochrome P450 2B10/3A4/7A1; dehydroepiandrosterone sulfotransferase; direct peptide reactivity assay; farnesoid X receptor; fatty acid synthase; fatty acid translocase; gamma-glutamyl transpeptidase; hCLAT; human cell line activation test; liver X receptor; mitochondrial permeability pore; molecular initiating event; multidrug resistance-associated protein 2/3; myeloid U937 skin sensitization test; organic anion transporter 1B1; organic solute transporter α/β; pregnane X receptor; quantitative structure–activity relationship; small heterodimeric partner; sodium/taurocholate cotransporter; stearoyl-coenzyme A desaturase 1; sterol response element binding protein 1c; transforming growth factor beta 1; uridine 5′-diphosphate-glucuronosyltransferase 2B4.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cholestasis / chemically induced
  • Fatty Liver / chemically induced
  • Hepatic Stellate Cells / drug effects
  • Humans
  • Skin / drug effects
  • Structure-Activity Relationship
  • Toxicology / methods*