Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of
tumor formation in the mouse lung after exposure to Cyp2F2
ligands. The adverse outcome pathway (AOP) framework offers a theoretical platform to address issues of species specificity that is consistent, transparent, and capable of integrating data from new approach methodologies as well as traditional data streams. A central premise of the AOP concept is that pathway progression from the molecular initiating event (MIE) implies a definable "response-response" (R-R) relationship between each key event (KE) that drives the pathway towards a specific adverse outcome (AO). This article describes an AOP for
lung cancer in the mouse from an MIE of Cyp2F2-specific reactive metabolite formation, advancing through KE that include
protein and/or
nucleic acid adducts, diminished Club Cell 10 kDa (CC10)
protein expression,
hyperplasia of CC10 deficient Club cells, and culminating in the AO of mixed-cell
tumor formation in the distal airways. This
tumor formation is independent of route of exposure and our AOP construct is based on overlapping mechanistic events for
naphthalene,
styrene, ethyl
benzene,
isoniazid, and
fluensulfone in the mouse. This AOP is intended to accelerate the explication of an apparent mouse-specific outcome and serve as a starting point for a quantitative analysis of mouse-human differences in susceptibility to the tumorigenic effects of Cyp2F2
ligands.