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The use of AOPs in risk assessment: Development of biomarker based on a read across use case on VPA analogues in the Detective project

: Stöber, Werner; Steger-Hartmann, Thomas; Myatt, Glenn J.; Richarz, Andrea; Hengstler, Jan; Escher, Sylvia E.


Toxicology letters 238 (2015), No.2, Supplement, pp.S56-S57, Abstract P01-005
ISSN: 0378-4274
ISSN: 1879-3169
European Societies of Toxicology (EUROTOX Congress) <51, 2015, Porto>
Fraunhofer ITEM ()

Human safety evaluation in chemical risk assessment is currently mainly based on in vivo data i.e. repeated dose (RDT) studies. Along with the restriction of animal testing, e.g. for cosmetics, there is an increasing need to advance the integration of animal free alternative methods eventually reduce or replace animal testing. Aims of the FP7 project DETECTIVE are to gain mechanistic knowledge, define adverse outcome pathways and identify biomarkers of toxicity. Before use for safety assessment, the identified biomarkers reflecting key and/or intermediate events of a given AOP still have to be validated. We here describe the use of a read across case study to contribute to this validation. The biomarkers were identified using transcriptomics data from the TG-Gates database. In this database valproic acid (VPA) was one of the most potent inducers of changes in genes involved in lipid and energy metabolism. Further a causal relationship could be drawn to apical findings in RDT studies with oral exposure, in which VPA induced histopathological alterations such as lipidosis, fatty degeneration or vacuolization of hepatocytes. To test the afore mentioned genes involved in lipid and energy metabolism as possible biomarkers of VPA-like hepatotoxicity, 10 structurally similar compounds to VPA consisting of branched and unbranched carboxylic acids were identified for which RDT studies were available. The databases RepDose, IMI eTOX, ECHA CHEM, Cosmos, Lead scope and Nedo were searched as well as peer reviewed publications. Four VPA analogues induced alterations such as fatty degeneration in the in vivo studies and were therefore classified as ‘in vivo positive’. Five compounds did not cause any adverse effects in the livers of rats up to the highest tested doses and were classified as ‘in vivo negative’. One compound was defined as ‘borderline’, because it showed equivocal evidence of deregulated lipid metabolism. The present poster shows the result of the biomarker testing by quantitative RT-PCRforVPAandthe10read across compounds. Different cell types were studied in vitro; primary human/rat hepatocytes and HepG2 cells. A concept, how to integrate the resulting biomarker data qualitatively in the context of a read across approach and/or quantitatively into risk assessment will be discussed.