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Use of new approach methods to support chemical read-across: The EU-ToxRisk experience

: Water, Bob van de; Kamp, Hennicke; Escher, Sylvia E.; Kroese, Dinant


Toxicology letters 295 (2018), Supplement 1, S.S10, Abstract CEC5-40
ISSN: 0378-4274
ISSN: 1879-3169
European Societies of Toxicology (EUROTOX Congress) <54, 2018, Brussels>
Fraunhofer ITEM ()

The large-scale EU-ToxRisk project is an integrated European ‘flagship’ program with the vision to establish a paradigm-shift in toxicity testing and risk assessment for the 21st century by implementing mechanism-based integrated testing strategies using non-animal new approach methods (NAMs). To accomplish this the EU-ToxRisk project has united all relevant scientific disciplines covering in silico QSAR modelling, cellular toxicology, bioinformatics and PBPK modelling. We test the integration of the different NAMs in various case studies, ultimately establishing: (i) pragmatic, read-across procedures incorporating mechanistic and toxicokinetic knowledge; and (ii) ab initio hazard and risk assessment strategies of chemicals with little background information. Here we report on the results of several EU-ToxRisk read across case studies that are focused on repeated dose systemic toxicity (RDT) as well as developmental/reproduction toxicity (DART). The integration of the various NAMs in defined read across case studies allows the assessment of the overall applicability domain and contribution of these NAMs in read across approaches chemical hazard and ultimate risk assessment. Case studies are centred around several chemical groups with structural similarity and related to specific in vivo toxicity endpoints e.g. (i) microvesicular liver steatosis induced by valproic acid analogues; (ii) the prediction of teratogenic effects of valproic acid analogues; (iii) lung toxicity induced by diketones. The results established by our NAM toolbox indicate that structural similar compounds which show equal in vivo rodent toxicity also demonstrate similar responses in experimental systems in vitro. Therefore we propose that the application of NAMs can provide biological support for read across. Further challenges will be discussed.