Dose Selection Task Force
Background
Recent opinions published by the RAC on low top dose selection in animal toxicity studies have indicated an apparent intent of increasing dosages systematically in view of the criteria used for classification and labelling and ED assessment. There have also been indications within the regulatory domain of a desire to limit or stop the use of kinetics-based dose level selection. This could potentially lead to inappropriate dose-setting and unnecessary animal suffering.
Objectives
Review state of the science for dose-setting in repeated-dose toxicity studies and provide guidance to support appropriate design and interpretation of toxicity studies.
The following elements will be included:
- Critical review of the basis for using a maximally tolerated dose
- Discussion of the dilemma of identifying hazard versus identifying artefact
- Consider the ECHA Committee for Risk Assessment (RAC) thoughts on the utility of range-finding studies
- Examination of pharmacokinetic and physiological considerations in dose-setting
- Discussion on the question of accuracy versus sensitivity for hazard identification
- Recommendations for dose setting
All aspects in the process of safety assessment of chemicals need consideration, including risk assessment, C&L requirements as well as animal welfare. The aim is to provide the best information to achieve such a balance.
A dedicated subgroup of the Task Force was reactivated in 2023 to further develop the recommendations on dose-setting with a specific focus on developmental and reproductive toxicity (DART) studies. This was in view of some new publications on this topic including the 2022 ECHA Advice on dose-level selection for the conduct of reproductive toxicity studies under REACH.
Timeline and deliverables
- The first phase of the Task Force was active between 2019 and 2022 and published TR 138 and Sewell et al 2022.
- The Task Force subgroup focussing on DART published their findings and recommendation in early 2024: Lewis et al., 2024.
- Webinar: Advancing Best Practices in Dose Selection
- Dose level selection for Developmental and Reproductive Toxicology (DART) studies – A report from the 2024 Eurotox Congress Satellite Workshop, co-organised by the NC3Rs, ECETOC, Charles River Laboratories and ECHA
- Poster on DART dose selection recommendations (2024 EUROTOX Congress in Copenhagen)
- Poster on DART dose selection recommendations (2024 SOT Annual Meeting in Salt Lake City)
- Considerations for the development of guidance on dose level selection for developmental and reproductive toxicity studies (Lewis et al., 2024)
- TR 138 – ECETOC Guidance on Dose Selection
- Recommendations on dose level selection for repeat dose toxicity studies (Sewell et al., 2022)