Abstract
The use of new approach methodologies (NAMs) in support of read-across (RAx) approaches for regulatory purposes is a main goal of the EU-ToxRisk project. To bring this forward, EU-ToxRisk partners convened a workshop in close collaboration with regulatory representatives from key organizations including European regulatory agencies, such as the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA), as well as the Scientific Committee on Consumer Safety (SCCS), national agencies from several European countries, Japan, Canada and the USA, as well as the Organisation for Economic Cooperation and Development (OECD). More than a hundred people actively participated in the discussions, bringing together diverse viewpoints across academia, regulators and industry. The discussion was organized starting from five practical cases of RAx applied to specific problems that offered the oppor-tunity to consider real examples. There was general consensus that NAMs can improve confidence in RAx, in particular in defining category boundaries as well as characterizing the similarities/dissimilarities between source and target substances. In addition to describing dynamics, NAMs can be helpful in terms of kinetics and metabolism that may play an important role in the demonstration of similarity or dissimilarity among the members of a category. NAMs were also noted as effective in providing quanti-tative data correlated with traditional no observed adverse effect levels (NOAELs) used in risk assessment, while reducing the uncertainty on the final conclusion. An interesting point of view was the advice on calibrating the number of new tests that should be carefully selected, avoiding the allure of "the more, the better". Unfortunately, yet unsurprisingly, there was no single approach befitting every case, requiring careful analysis delineating the optimal approach. Expert analysis and assessment of each specific case is still an important step in the process.
Highlights
1.1 Definitions and aim of the workshop Read-across (RAx) is a data-filling technique that allows endpoint information for one chemical to be predicted by using data for the same endpoint fromother chemical(s) considered to be similar in a significant way
Representatives of the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA) actively participated in the discussion to give informal remarks on scientific and regulatory issues, with no intention of providing advice to registrants or other stakeholders, and they were not speaking on behalf of ECHA or EFSA
Case studies contributed to the discussion by Health Canada or the US Environmental Protection Agency (US EPA) were developed for illustrative purposes only, which should not be interpreted as a regulatory decision
Summary
1.1 Definitions and aim of the workshop Read-across (RAx) is a data-filling technique that allows endpoint information for one chemical to be predicted by using data for the same endpoint from (an)other chemical(s) considered to be similar in a significant way. EU-ToxRisk developed specific RAx case studies to evaluate the applicability of NAMs to provide evidence and support for RAx approaches, in particular by using mechanistic data for hazard characterization and state-of-the-art physiologically-based toxicokinetic (PBTK) modelling to address differences in human kinetics/bioavailability of compounds. NAM data generated within the three scenarios should be complemented with toxicokinetic data that are necessary for the confirmation of any RAx hypothesis, defining category boundaries and characterizing dissimilarities between target and source substances This is necessary to derive a point of departure (PoD) for risk assessment, e.g., a human equivalent dose using a quantitative in vitro to in vivo extrapolation (IVIVE) model.
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