Mode of Action:
Recent developments, regulatory application and future work
A mode of action/human relevance (MOA/HR) framework has been developed in initiatives of the International Life Sciences Institute Risk Sciences Institute (ILSI RSI) and the World Health Organisation International Programme on Chemical Safety (IPCS). It derives from earlier work on MOA in animals of the US Environmental Protection Agency (US EPA) and IPCS, and has involved large numbers of scientists internationally. The framework is described in several publications listed below.
In November 2009, a workshop of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) / ILSI Research Foundation (RF) / Health and Environmental Sciences Institute (HESI) addressed how MOA information can improve regulatory decision-making and made several recommendations, amongst them:
- Establish an expert working group to oversee the creation of a repository or reference database of agreed MOAs.
- Continue and extend training and educational programmes based on risk assessment practices using MOA.
- Promote a change in the present risk assessment paradigm to encompass early focus on hazard characterisation including MOA.
- Provide guidance on the generation of information during standard toxicity tests that could be of value in MOA analysis.
- Develop predictive methods for MOAs, focusing on key events.
- Agree and harmonise MOA terminology on a global level.
A subsequent meeting in October 2010, convened by WHO, recommended an umbrella plan for future international collaborative work on MOA. The plan identified activities in the following areas:
a) Updating of the MOA framework guidance.
b) Development of case studies.
c) Implementation of MOA in category approaches.
e) Development of an MOA database.
A WHO Steering Committee is overseeing implementation of this plan. The Committee comprises experts from Imperial College London, US EPA, University of Ottawa, EFSA, ECHA, JRC, IARC, OECD, ECETOC and ILSI/HESI, and activities are implemented by the institutions concerned.
In line with these developments, the MOA/HR framework has recently been updated to reflect increasing experience in integrating information from different levels of biological organisation, including that from evolving technologies. It addresses context-specific implications for priority setting, risk assessment and testing strategies for both individual chemicals and groups. An increasing number of case studies are being prepared to illustrate its application in regulatory guidance and assessments. The framework is expected to inform qualitative and quantitative analysis of species concordance, consideration of human variability, dose-response extrapolation and read-across, and effects of combined exposures.