ATLA::Alternatives to Laboratory Animals

Volume 30, Number 3

Development of an in vitro test battery for the estimation of acute human systemic toxicity: an outline of the EDIT project.

Cecilia Clemedson,¹ Marika Nordin-Andersson,² Henning F. Bjerregaard,³ Jørgen Clausen,³ Anna Forsby,² Helena Gustafsson,² Ulrika Hansson,⁴ Boris Isomaa,⁵ Carsten Jørgensen,³ Ada Kolman,⁶ Natalia Kotova,⁷ Gunter Krause,⁸ Udo Kristen,⁹ Kalle Kurppa,¹⁰ Lennart Romert¹¹ And Ellen Scheers¹²

¹Expertrådet AB, Högklintavägen 7, 172 64 Sundbyberg, Sweden; ²Department of Neurochemistry and Neurotoxicology, Stockholm University, 106 91 Stockholm, Sweden; ³Department of Life Sciences and Chemistry, Roskilde University, P.O. Box 260, 4000 Roskilde, Denmark; ⁴Animal Rights Sweden, P.O. Box 2005, 125 02 Älvsjö, Sweden; ⁵Department of Biology, Åbo Akademi University, Artillerigatan 6, 20520 Åbo, Finland; ⁶Department of Molecular Biology and Functional Genomics, Stockholm University, 106 Stockholm, Sweden; ⁷Department of Genetic and Cellular Toxicology, Stockholm University, 106 91 Stockholm, Sweden; ⁸Analytisch-biologisches Forschungslabor, Goethestrasse 20, 80336 Munich, Germany; ⁹1nstitut für Allgemeine Botanik, Universität Hamburg, Ohnhorststrasse 18, 22609 Hamburg, Germany; ^1ODepartment of Environmental Toxicology, University of Tampere, P.O. Box 607, 33101 Tampere, Finland; ¹¹Swedish National Chemicals Inspectorate, P.O. Box 1384, 171 27 Solna, Sweden; ¹²Institute of Public Health, Laboratory Biochemical Toxicology, Wytsmanstraat 14, 1050 Brussels, Belgium

SUMMARY

The aim of the Evaluation-guided Development of New In Vitro Test Batteries (EDIT) multicentre programme is to establish and validate in vitro tests relevant to toxicokinetics and for organ-specific toxicity, to be incorporated into optimal test batteries for the estimation of human acute systemic toxicity. The scientific basiS of EDIT is the good prediction of human acute toxicity obtained with three human cell line tests (R2 = 0.77), in the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. However, the results from the MEIC study indicated that at least two other types of in vitro test ought to be added to the existing test battery to improve the prediction of human acute systemic toxicity -- to determine key kinetic events (such as biotransformation and passage through biological barriers), and to predict crucial organ-specific mechanisms not covered by the tests in the MEIC battery. The EDIT programme will be a case-by-case project, but the establishment and validation of new tests will be carried through by a common, step-wise procedure. The Scientific Committee of the EDIT programme defines the need for a specific set of toxicity or toxicokinetic data. Laboratories are then invited to perform the defined tests in order to provide the "missing" data for the EDIT reference chemicals. The results obtained will be evaluated against the MEMO (the MEIC Monograph programme) database, i.e. against human acute systemic lethal and toxicity data. The aim of the round-table discussions at the 19th Scandinavian Society for Cell Toxicology (SSCT) workshop, held in Ringsted, Denmark on 6-9 September 2001, was to identify which tests are the most important for inclusion in the MEIC battery, i.e. which types of tests the EDIT programme should focus on. It was proposed that it is important to include in vitro methods for various kinetic events, such as biotransformation, absorption in the gut, passage across the blood-brain barrier, distribution volumes, protein binding, and renal clearance/accumulation. Models for target organ toxicity were also discussed Because several of the outlier chemicals (paracetamol, digoxin, malathion, nicotine, paraquat, atropine and potassium cyanide) in the MEIC in vivo-in vitro evaluation have a neurotoxic potential, it was proposed that the development within the EDIT target organ programme should initially be focused on the nervous system.

Keywords: acute toxicity testing, basal cytotoxicity, biotransformation, blood-brain barrier models, human toxicity, kinetics, neurotoxicity, quantitative structure-activity relationships, target organ toxicity