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EU-ToxRisk is spearheading the development and evaluation of new tools and their combinatory power for regulatory risk assessment in Europe. This ambition requires a close interaction of the developers with the scientists affiliated to regulatory authorities. Within the EU-ToxRisk project, this interaction is considered the best way to improve a mutual understanding and to perceive the value systems behind expectations and demands.

EU-ToxRisk started the interaction with regulatory scientists in November 2016, when the case studies were introduced to stakeholders from different national regulatory agencies for the first time within EURL ECVAM's Network for Preliminary Assessment of Regulatory Relevance (PARERE) meeting at the JRC facilities in Ispra, Italy. One significant input from PARERE was that the read-across concepts and the complexity of the case studies needed to be addressed in more detail. It was also indicated that the regulatory relevance needed further evaluation.

For the PARERE meeting in 2017, short descriptions of case studies (CS) 1, 2, 4 and 8 (the more advanced read-across case studies) were provided to the PARERE members prior to the meeting for intensive reviewing. These case studies are focused on read-across of (un-)branched carboxylic acids for the prediction of microvesicular liver steatosis (CS-1); on the effects of valproic acid analogues regarding their developmental and reproductive toxicity (CS-2); on mitochondrial toxicity effects regarding repeated dose toxicity and developmental and reproductive toxicity (CS-4); and CS-8 is focused on read-across of diketones as the trigger for the 'Popcorn Lung'. Enclosed with the CS, a tailored questionnaire, which comprised 20 questions about the regulatory relevance and the acceptability of the read-across concept and the developed tools, was provided to the PARERE members. The questions were answered by ten national regulatory networks and regulatory authorities.

On November 28, 2017, representatives of EU-ToxRisk presented the above-mentioned CS briefly during a workshop within the annual PARERE-ESTAF meeting at the facilities of JRC's EURL ECVAM in Ispra. Sylvia Escher (Fraunhofer Item) introduced the concept of the read-across case studies, especially the difference between case studies starting with structural or biological similarity. Furthermore, she explained the testing of "in vivo negative" compounds. These compounds share structural properties but do not induce the adverse outcome in vivo. We can therefore use them to learn more about the specificity of the non-animal methods (NAMs). Therefore, further analyses of these compounds are considered to refine the view on the specificity of NAMs. Hennicke Kamp (BASF SE) presented the measures taken for the quality assurance of in vitro testing in EU-ToxRisk. This was followed by brief case study presentations given by Sylvia Escher, Dinant Kroese (TNO) and Rabea Graepel (University of Leiden). The members of the PARERE network were introduced to the discussion with a summary presentation of the answers to the questionnaire given by Rabea Graepel.

The first feedback from PARERE hinted at the recognition of EU-ToxRisk having taken up the comments from the first meeting in 2016 and that the case study descriptions had improved significantly. Furthermore, it was recognized that EU-ToxRisk had made tremendous progress over the last year.

It was discussed that the case studies have to focus on pragmatic and precise examples for the development of read-across approaches based on NAMs and could be directly integrated into the regulatory risk assessment concept. Some of the members mentioned that a lot of read-across cases today are solely based on structural and kinetic similarity and indicated that any additional toxicodynamic data could improve these cases. An important aspect would be to know and explain the uncertainty and limitations connected to the abovementioned approaches. It was agreed during the meeting that a good scientific basis is imperative for risk assessment approaches with NAMs. Therefore, some scientific questions per case study will not directly contribute to the IATA but to a better understanding of the robustness and relevance of the NAMs.

During the discussion, it was generally agreed that NAM-based defined approaches and IATA for testing could well be used in regulatory toxicology; however, there was no consensus to what extend this would be possible in the near term. It was also stressed that at the moment it is not foreseeable in how far NAMs, besides read-across, could be used in the mid-term to assess the hazards for compounds (i.e. ab initio testing).

EU-ToxRisk has the great opportunity to generate answers to these questions by showing chances as well as limitations based on the current case study work.

The members of the PARERE network encouraged the consortium to proceed with the work and to update the PARERE network regularly. All participants in the discussion highlighted the value of such interaction and are looking forward to the next discussion in 2018.
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Title Annotation:CORNERS; European Union ToxRisk project
Author:Graepel, Rabea; Daneshian, Mardas
Publication:ALTEX: Alternatives to Animal Experimentation
Geographic Code:4E
Date:Jan 1, 2018
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