Contribution of new technologies to characterization and prediction of adverse effects

Abstract

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.

Keywords:

• adverse effect
• in vitro testing
• mode of action
• omics
• predictive toxicology

Acknowledgements

The authors dedicate this paper to Dr. Christa Hennes. We will miss her as a trusted friend and esteemed colleague. We are grateful to the constructive comments received from the Stewards of the Task Force, in particular Rémi Bars (Bayer) and Bennard van Ravenzwaay (BASF). We also thank the members of the ECETOC Scientific Committee for their feedback.

Declaration of interest

This paper was prepared by a Task Force of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) with the members of the Task Force serving as the authors of the paper along with Dr. Christa Hennes from the ECETOC staff. The ECETOC is a non-profit scientific association funded by its member companies who are manufacturers and users of chemicals. The mission of ECETOC is to promote approaches for ensuring the use of scientific knowledge in the regulation of chemicals, thereby enabling the beneficial use of chemicals while protecting human health and the environment. The employment affiliation of the authors is shown on the cover page of the manuscript. The members of the Task Force were compensated by their employers during the preparation of the paper. The strategic approach used in preparing the paper, the review of the literature and decisions on the criteria for inclusion of literature, the review of papers, the synthesis and integration of the findings and the conclusions drawn are the professional work product of the authors and do not necessarily represent the views of their employers.