title: Adverse Outcome Pathway (AOP) Informed Modeling of Aquatic Toxicology: QSARs, Read-Across, and Interspecies Verification of Modes of Action.
abstract: Alternative approaches have been promoted to reduce the number of vertebrate and invertebrate animals required for the assessment of the potential of compounds to cause harm to the aquatic environment. A key philosophy in the development of alternatives is a greater understanding of the relevant adverse outcome pathway (AOP). One alternative method is the fish embryo toxicity (FET) assay. Although the trends in potency have been shown to be equivalent in embryo and adult assays, a detailed mechanistic analysis of the toxicity data has yet to be performed; such analysis is vital for a full understanding of the AOP. The research presented herein used an updated implementation of the Verhaar scheme to categorize compounds into AOP-informed categories. These were then used in mechanistic (quantitative) structure-activity relationship ((Q)SAR) analysis to show that the descriptors governing the distinct mechanisms of acute fish toxicity are capable of modeling data from the FET assay. The results show that compounds do appear to exhibit the same mechanisms of toxicity across life stages. Thus, this mechanistic analysis supports the argument that the FET assay is a suitable alternative testing strategy for the specified mechanisms and that understanding the AOPs is useful for toxicity prediction across test systems.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool, L3 3AF England.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Ellison
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool, L3 3AF England.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Piechota
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool, L3 3AF England.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Madden
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool, L3 3AF England.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Enoch
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Byrom Street, Liverpool, L3 3AF England.
authors.forename: Mark T D
authors.initials: MT
authors.lastname: Cronin
mesh_terms: D000818:Animals; D059001:Aquatic Organisms / Q000187:drug effects*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D016014:Linear Models; D009285:Naphthoquinones / Q000737:chemistry / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D013045:Species Specificity; D018675:Toxicity Tests / Q000379:methods*; D015027:Zebrafish / Q000196:embryology
chemical_list: D009285:Naphthoquinones; C005134:juglone