Costanza Rovida
Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany
Tara Barton-Maclaren
Existing Substances Risk Assessment Bureau, Health Canada, Ottawa, Canada
Emilio Benfenati
Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
Francesca Caloni
Università degli Studi di Milano, Department of Veterinary Medicine (DIMEVET) Milan, Italy
P. Charukeshi Chandrasekera
Canadian Centre for Alternatives to Animal Methods, University of Windsor, Ontario, Canada
Christophe Chesné
Biopredic International, Saint Grégoire, France
Mark T. D. Cronin
Liverpool John Moores University, School of Pharmacy and Biomolecular Sciences, Liverpool, UK
Joop De Knecht
Centre for Safety of Substances and Products, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
Daniel R. Dietrich
Human and Environmental Toxicology, University of Konstanz, Konstanz, Germany
Sylvia E. Escher
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany
Suzanne Fitzpatrick
US Food and Drug Administration, Center for Food Safety and Applied Nutrition, MD, USA
Brenna Flannery
US Food and Drug Administration, Center for Food Safety and Applied Nutrition, MD, USA
Matthias Herzler
German Federal Institute for Risk Assessment (BfR), Berlin, Germany
Susanne Hougaard Bennekou
Danish Environmental Protection Agency, Copenhagen, Denmark / Danish Technical University, FOOD, Lyngby, Denmark
Bruno Hubesch
European Chemical Industry Council (Cefic), Brussels, Belgium
Hennicke Kamp
Experimental Toxicology and Ecology, BASF SE, Ludwigshafen, Germany
Jaffar Kisitu
In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany
Nicole Kleinstreuer
NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States
Simona Kovarich
S-IN Soluzioni Informatiche S.r.l., Vicenza, Italy
Marcel Leist
Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany; In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany
Alexandra Maertens
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University, Baltimore, MD, USA
Kerry Nugent
Australian Government Department of Health, Canberra, Australia
Giorgia Pallocca
Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany
Manuel Pastor
Research Programme on Biomedical Informatics (GRIB), Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Dept. of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
Grace Patlewicz
Center for Computational Toxicology & Exposure (CCTE), U.S. Environmental Protection Agency, Research Triangle Park, NC, USA;
Manuela Pavan
Innovatune S.r.l., Padova, Italy
Octavio Presgrave
Departamento de Farmacologia e Toxicologia, Instituto Nacional de Controle da Qualidade em Saúde, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil
Lena Smirnova
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University, Baltimore, MD, USA
Michael Schwarz
University of Tübingen, Tübingen, Germany
Takashi Yamada
National Institute of Health Sciences, Kanagawa, Japan
Thomas Hartung
Center for Alternatives to Animal Testing, CAAT-Europe, University of Konstanz, Konstanz, Germany; Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University, Baltimore, MD, USA
[hide affiliations]
Abstract
Read-across (RAx) translates available information from well-characterized chemicals to a substance for which there is a toxicological data gap. The OECD is working on case studies to probe general applicability of RAx, and several regulations (e.g., EU-REACH) already allow this procedure to be used to waive new in vivo tests. The decision to prepare a review on the state of the art of RAx as a tool for risk assessment for regulatory purposes was taken during a workshop with international experts in Ranco, Italy in July 2018. Three major issues were identified that need optimization to allow a higher regulatory acceptance rate of the RAx procedure: (i) the definition of similarity of source and target, (ii) the translation of biological/toxicological activity of source to target in the RAx procedure, and (iii) how to deal with issues of ADME that may differ between source and target. The use of new approach methodologies (NAM) was discussed as one of the most important innovations to improve the acceptability of RAx. At present, NAM data may be used to confirm chemical and toxicological similarity. In the future, the use of NAM may be broadened to fully characterize the hazard and toxicokinetic properties of RAx compounds. Concerning available guidance, documents on Good Read-Across Practice (GRAP) and on best practices to perform and evaluate the RAx process were identified. Here, in particular, the RAx guidance, being worked out by the European Commission’s H2020 project EU-ToxRisk together with many external partners with regulatory experience, is given.
