SEURAT‑1 liver gold reference compounds: a mechanism‑based review

There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need the European Commission and Cosmetics Europe, have jointly funded a research program for ‘Safety Evaluation Ultimately Replacing Animal Testing’ (SEURAT-1). The goal of this program is the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. A vital component of this effort is assembly of a collection of reference compounds that can be used in the development and validation of the assays. In this review we focus to the selection of the liver “gold compounds”, which represent compounds that induce the major liver pathologies, including cytotoxicity, mitochondrial impairment, oxidative stress, apoptosis and lipid disorders including steatosis, cholestasis, and phospholipidosis. We identified 4 compound classes capable of initiating such events, i.e. chemically reactive compounds, compounds with specific cellular targets, compounds which effect lipid metabolism and compounds which disrupt the plasma membrane. We describe the known molecular mechanisms of these compounds in an attempt to clarify the Molecular Initiating Event (MIE). This information will form the basis of future SEURAT-1 experimental work and will help build Adverse Outcome Pathways (AOP) to aid regulatory decision making processes.

JENNINGS Paul;  SCHWARZ Michael;  LANDESMANN Brigitte;  MAGGIONI Silvia;  GOUMENOU Marina;  BOWER David;  LEONARD Martin;  WISEMAN Jeffrey; 

2014-12-10

SPRINGER HEIDELBERG

JRC91428

0340-5761,   

http://link.springer.com/article/10.1007%2Fs00204-014-1410-8,    https://publications.jrc.ec.europa.eu/repository/handle/JRC91428,   

10.1007/s00204-014-1410-8,