Abstract
Chemical regulation is challenged by the large number of chemicals requiring assessment for potential human health and environmental impacts. Current approaches are too resource intensive in terms of time, money and animal use to evaluate all chemicals under development or already on the market. The need for timely and robust decision making demands that regulatory toxicity testing becomes more cost-effective and efficient. One way to realize this goal is by being more strategic in directing testing resources; focusing on chemicals of highest concern, limiting testing to the most probable hazards, or targeting the most vulnerable species. Hypothesis driven Integrated Approaches to Testing and Assessment (IATA) have been proposed as practical solutions to such strategic testing. In parallel, the development of the Adverse Outcome Pathway (AOP) framework, which provides information on the causal links between a molecular initiating event (MIE), intermediate key events (KEs) and an adverse outcome (AO) of regulatory concern, offers the biological context to facilitate development of IATA for regulatory decision making. This manuscript summarizes discussions at the Workshop entitled “Advancing AOPs for Integrated Toxicology and Regulatory Applications” with particular focus on the role AOPs play in informing the development of IATA for different regulatory purposes.
Highlights
An Adverse Outcome Pathway (AOP) represents the existing knowledge concerning the causal linkages between the molecular initiating event (MIE) and the cascade of intermediate or key events (KEs) at the subcellular, cellular, tissue and organ level that lead to a specific adverse outcome (AO) at the individual or population level (Ankley et al, 2010; OECD, 2013)
In the context of the European Regulation for Registration, Evaluation, Authorisation and restriction of CHemicals (REACH) (EC, 2006; European Chemicals Agency (ECHA), 2008) the following specific conditions are considered when evaluating in silico models: Non-testing or in silico approaches serve two functions within an Integrated Approaches to Testing and Assessment (IATA), they either provide a way to organize existing information or they are used to make predictions of molecular initiating events (MIE) or other key events (KEs) as defined in an associated AOP
Becker et al (2014) outlined a scientific confidence framework first proposed for high throughput (HT)/high content (HC) screening assays (Patlewicz et al, 2013) and their prediction models (Cox et al, 2014) but adapted it to help in the evaluation of AOPs for different purposes including IATA
Summary
The global economy has witnessed a significant shift in the regulatory environment coupled with the volume and diversity of industrial chemicals being manufactured. An AOP represents the existing knowledge concerning the causal linkages between the molecular initiating event (MIE) and the cascade of intermediate or key events (KEs) at the subcellular, cellular, tissue and organ level that lead to a specific adverse outcome (AO) at the individual or population level (Ankley et al, 2010; OECD, 2013) This conceptual framework enables information and data from different chemicals, different levels of biological organization, and different taxonomic domains relevant for one AOP to be assembled. The synthesis and integration of these elements form the basis for developing Integrated Approaches to Testing and Assessment (IATA) that may be used in regulatory applications This manuscript summarizes discussions from the Workshop entitled ‘‘Advancing AOPs for Integrated Toxicology and Regulatory Applications’’ held in Somma Lombardo, Italy on the 2–7th March, 2014 (https://aopkb.org/saop/workshops/somma.html). A final summary considers how the proposed conceptual framework may impact different regulatory applications
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