title: The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS).
abstract: In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.
authors: Fraunhofer Institute for Toxicology and Experimental Medicine, Nikolai-Fuchs Straße 1, 30625 Hannover, Germany; Institute for Organic Chemistry, Technical University Bergakademie Freiberg, Leipziger Str. 29, 09596 Freiberg, Germany. Electronic address: inga.tluczkiewicz@item.fraunhofer.de.
authors: Inga
authors: I
authors: Tluczkiewicz
authors: Monika
authors: M
authors: Batke
authors: Dinant
authors: D
authors: Kroese
authors: Harrie
authors: H
authors: Buist
authors: Tom
authors: T
authors: Aldenberg
authors: Eduard
authors: E
authors: Pauné
authors: Helvi
authors: H
authors: Grimm
authors: Ralph
authors: R
authors: Kühne
authors: Gerrit
authors: G
authors: Schüürmann
authors: Inge
authors: I
authors: Mangelsdorf
authors: Sylvia E
authors: SE
authors: Escher
mesh_terms: D000818:Animals; D015386:Hazardous Substances / Q000633:toxicity; D018570:Risk Assessment; D012984:Software; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D015386:Hazardous Substances
keywords: 3R principle; Alternative; ITS; Integrated Testing Strategy; Non-testing method; OSIRIS; Repeated-dose; Risk Assessment; TTC; Weighting