The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: Results from the European Project ACuteTox

ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6 months, a challenging exercise was conducted focused mainly on the assessment of the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two steps tiered testing strategies. In summary, five in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results from the neutral red uptake assay performed in 3T3 cells, together with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Information on octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage is also considered. This approach allows to improve the identification of not classified chemicals and to reduce the number of under predicted not classified chemicals.

PRIETO PERAITA Maria Del Pilar;  KINSNER-OVASKAINEN Agnieszka;  STANZEL Sven;  ALBELLA Beatrix;  ARTURSSON Per;  CAMPILLO Nuria;  CECCHELLI R;  CERRATO Laura;  DIAZ Laura;  DI CONSIGLIO Emma;  GUERRA Angela;  GOMBAU Lourdes;  HERRERA Guadalupe;  HONEGGER Paul;  LANDRY Christophe;  O'CONNOR Jose Enrique;  PAEZ Juan Antonio;  QUINTAS Guillermo;  SVENSSON Richard;  TURCO Laura;  ZURICH Marie-Gabrielle;  ZURBANO Maria Jesus;  KOPP-SCHNEIDER Annette; 

2013-05-06

PERGAMON-ELSEVIER SCIENCE LTD

JRC66834

0887-2333,   

http://www.sciencedirect.com/science/article/pii/S0887233312002172,    https://publications.jrc.ec.europa.eu/repository/handle/JRC66834,   

10.1016/j.tiv.2012.07.013,