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.

Prieto P, Kinsner-Ovaskainen A, Stanzel S, Albella B, Artursson P, Campillo N, Cecchelli R, Cerrato L, Díaz L, Di Consiglio E, Guerra A, Gombau L, Herrera G, Honegger P, Landry C, O'Connor JE, Páez JA, Quintas G, Svensson R, Turco L, Zurich MG, Zurbano MJ, Kopp-Schneider A

Toxicol In Vitro 27 (4) 1357-1376 [2013-06-00; online 2012-08-28]

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 to assess 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 step tiered testing strategies. In summary, four 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 gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50>2000 mg/kg b.w.).

Chemical Biology Consortium Sweden (CBCS) [Collaborative]

PubMed 22922246

DOI 10.1016/j.tiv.2012.07.013

Crossref 10.1016/j.tiv.2012.07.013

pii: S0887-2333(12)00217-2

Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)
ADME of Therapeutics (UDOPP)