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Toxicol In Vitro. 2019 Sep;59:44-50. doi: 10.1016/j.tiv.2019.04.005. Epub 2019 Apr 4.

A mode-of-action ontology model for safety evaluation of chemicals: Outcome of a series of workshops on repeated dose toxicity.

Author information

Cosmetics Europe Science & Research Department, Herrmann-Debrouxlaan 40, 1060 Brussels, Belgium. Electronic address:
Experimental Toxicology and Ecology, BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen, Germany.
Institute for Risk Assessment Sciences, Division of Toxicology, Utrecht University, PO Box 80.177, 3508TD, Utrecht, the Netherlands.
Centre for Pharmacology & Therapeutics, Imperial College London, Hammersmith Campus, Ducane Road, London W12 0NN, United Kingdom.
Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire MK43 7DW, United Kingdom.
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, United Kingdom.
Product Safety, Syngenta Jealotts Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom.
Global Product Stewardship, Procter & Gamble, 8700 Mason Montgomery Road, Cincinnati, OH, USA.
LRI Programme, Cefic, Rue Belliard 40, 1040 Brussels, Belgium; HubeschConsult BVBA, Madeliefjeslaan 10, 1600 Sint-Pieters-Leeuw, Belgium.
Division of Molecular and Computational Toxicology, Amsterdam Institute for Molecules, Medicines and Systems, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands.
Cosmetics Europe Science & Research Department, Herrmann-Debrouxlaan 40, 1060 Brussels, Belgium.
Department of Risk Analysis for Products in Development, TNO Healthy Living Unit, Utrechtseweg 48, 3704 HE Zeist, the Netherlands.
Central Product Safety, Procter & Gamble Technical Centres Ltd, Whitehall Lane, Egham, Surrey, TW209NW, United Kingdom.
L'Oreal R&I, Alternative Methods and Reconstructed Skin Department, 1 Avenue Eugene Schueller, 93601 Aulnay sous bois, France; Center for Health Protection, National Institute for Public Health and the Environment, Leeuwenhoeklaan 9, 3720BA Bilthoven, The Netherlands.
Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
European Commission, Joint Research Centre, Ispra, Italy.
Department of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, Eberhard Karls University, Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany.
Division of Drug Discovery and Safety/Leiden Cell Observatory High Content Imaging Screening Facility, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, the Netherlands.
Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.


Repeated dose toxicity evaluation aims at assessing the occurrence of adverse effects following chronic or repeated exposure to chemicals. Non-animal approaches have gained importance in the last decades because of ethical considerations as well as due to scientific reasons calling for more human-based strategies. A critical aspect of this challenge is linked to the capacity to cover a comprehensive set of interdependent mechanisms of action, link them to adverse effects and interpret their probability to be triggered in the light of the exposure at the (sub)cellular level. Inherent to its structured nature, an ontology addressing repeated dose toxicity could be a scientific and transparent way to achieve this goal. Additionally, repeated dose toxicity evaluation through the use of a harmonized ontology should be performed in a reproducible and consistent manner, while mimicking as accurately as possible human physiology and adaptivity. In this paper, the outcome of a series of workshops organized by Cosmetics Europe on this topic is reported. As such, this manuscript shows how experts set critical elements and ways of establishing a mode-of-action ontology model as a support to risk assessors aiming to perform animal-free safety evaluation of chemicals based on repeated dose toxicity data.


Adverse outcome pathway; Mode-of-action; Ontology model; Repeated dose toxicity


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