title: 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.
abstract: 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.).
authors.affiliation: Institute for Health and Consumer Protection, Joint Research Centre, European Commission, Via Fermi 2749, 21027 Ispra, VA, Italy. maria.prieto-pilar@jrc.ec.europa.eu
authors.forename: P
authors.initials: P
authors.lastname: Prieto
authors.forename: A
authors.initials: A
authors.lastname: Kinsner-Ovaskainen
authors.forename: S
authors.initials: S
authors.lastname: Stanzel
authors.forename: B
authors.initials: B
authors.lastname: Albella
authors.forename: P
authors.initials: P
authors.lastname: Artursson
authors.forename: N
authors.initials: N
authors.lastname: Campillo
authors.forename: R
authors.initials: R
authors.lastname: Cecchelli
authors.forename: L
authors.initials: L
authors.lastname: Cerrato
authors.forename: L
authors.initials: L
authors.lastname: Díaz
authors.forename: E
authors.initials: E
authors.lastname: Di Consiglio
authors.forename: A
authors.initials: A
authors.lastname: Guerra
authors.forename: L
authors.initials: L
authors.lastname: Gombau
authors.forename: G
authors.initials: G
authors.lastname: Herrera
authors.forename: P
authors.initials: P
authors.lastname: Honegger
authors.forename: C
authors.initials: C
authors.lastname: Landry
authors.forename: J E
authors.initials: JE
authors.lastname: O'Connor
authors.forename: J A
authors.initials: JA
authors.lastname: Páez
authors.forename: G
authors.initials: G
authors.lastname: Quintas
authors.forename: R
authors.initials: R
authors.lastname: Svensson
authors.forename: L
authors.initials: L
authors.lastname: Turco
authors.forename: M G
authors.initials: MG
authors.lastname: Zurich
authors.forename: M J
authors.initials: MJ
authors.lastname: Zurbano
authors.forename: A
authors.initials: A
authors.lastname: Kopp-Schneider
mesh_terms: D000284:Administration, Oral; D000826:Animal Testing Alternatives; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D003198:Computer Simulation; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D007928:Lethal Dose 50; D051379:Mice; D016571:Neural Networks, Computer; D018384:Oxidative Stress; D051381:Rats; D018570:Risk Assessment; D023382:Toxicity Tests, Acute
chemical_list: D016207:Cytokines