Towards grouping concepts based on new approach methodologies in chemical hazard assessment

Sylvia E. Escher, Hennicke Kamp, Susanne H. Bennekou, Annette Bitsch, Ciarán Fisher, Rabea Graepel, Jan G. Hengstler, Matthias Herzler, Derek Knight, Marcel Leist, Ulf Norinder, Gladys Ouédraogo, Manuel Pastor, Sharon Stuard, Andrew White, Barbara Zdrazil, Bob van de Water, Dinant Kroese

Read-across is one of the most frequently used alternative tools for hazard assessment, in particular for complex endpoints such as repeated dose or developmental and reproductive toxicity. Read-across extrapolates the outcome of a specific toxicological in vivo endpoint from tested (source) compounds to “similar” (target) compound(s). If appropriately applied, a read-across approach can be used instead of de novo animal testing. The read-across approach starts with structural/physicochemical similarity between target and source compounds, assuming that similar structural characteristics lead to similar human hazards. In addition, similarity also has to be shown for the toxicokinetic and toxicodynamic properties of the grouped compounds. To date, many read-across cases fail to demonstrate toxicokinetic and toxicodynamic similarities. New concepts, in vitro and in silico tools are needed to better characterise these properties, collectively called new approach methodologies (NAMs). This white paper outlines a general read-across assessment concept using NAMs to support hazard characterization of the grouped compounds by generating data on their dynamic and kinetic properties. Based on the overarching read-across hypothesis, the read-across workflow suggests targeted or untargeted NAM testing also outlining how mechanistic knowledge such as adverse outcome pathways (AOPs) can be utilized. Toxicokinetic models (biokinetic and PBPK), enriched by in vitro parameters such as plasma protein binding and hepatocellular clearance, are proposed to show (dis)similarity of target and source compound toxicokinetics. Furthermore, in vitro to in vivo extrapolation is proposed to predict a human equivalent dose, as potential point of departure for risk assessment. Finally, the generated NAM data are anchored to the existing in vivo data of source compounds to predict the hazard of the target compound in a qualitative and/or quantitative manner. To build this EU-ToxRisk read-across concept, case studies have been conducted and discussed with the regulatory community. These case studies are briefly outlined.

Department of Pharmaceutical Chemistry
External organisation(s)
Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), BASF SE, Technical University of Denmark (DTU), Certare UK Ltd, Leiden University, Leibniz Research Centre IfADo, German Federal Institute for Risk Assessment (BfR), European Chemicals Agency (ECHA), Universität Konstanz, Stockholm University, L’Oréal Rechearch & Innovation, University Pompeu Fabra, The Procter and Gamble Company, Unilever, Netherlands Organisation for Applied Scientific Research
Archives of Toxicology
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Publication date
Peer reviewed
Austrian Fields of Science 2012
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