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Developing non-testing IATA informed by mechanistic insights: Case studies in building scientific confidence (ASCCT meeting)
Citation:
Tier, G. Developing non-testing IATA informed by mechanistic insights: Case studies in building scientific confidence (ASCCT meeting). Presented at ASCCT, RTP, NC, October 01 - 02, 2015. https://doi.org/10.23645/epacomptox.5063293
Impact/Purpose:
This is an invited presentation at the forthcoming ASCCT meeting being held at EPA, RTP to highlight some of the thinking in terms of how non testing approaches including (Q)SARs and read-across should be developed going forward exploiting the AOP structure.
Description:
Non-testing approaches encompassing (Q)SARs, chemical categories and read-across have enjoyed a revival in recent years following changes in the global regulatory landscape. Whilst the uptake of these non-testing approaches for regulatory purposes is very encouraging, their practical application suffers from certain shortcomings. Some regulatory endpoints lend themselves to robust (Q)SAR development, whilst others such as repeated dose toxicity are too complex to be modelled in this way and despite the role that read-across can play, acceptance is still in part thwarted by the difficulty in addressing uncertainties.Adverse Outcome Pathways (AOPs) which are useful constructs for representing existing knowledge concerning the causal linkages between a molecular initiating event and an adverse outcome could offer some practical solutions in addressing at least some of these difficulties. AOPs themselves provide the mechanistic basis for generating, integrating and interpret non-standard information for key events (KEs) in a manner that can be applied in decision making. The framework for this is Integrated Approaches to Testing and Assessment (IATA). Indeed an IATA focused on existing data and other non-testing approaches marks a significant change in how read-across and (Q)SAR approaches could be developed and applied in the future. Instead of predicting the adverse outcome, future (Q)SARs could be developed to model individual KEs – thus providing some information on the chemical applicability domain. Uptake and acceptance of AOP-informed IATA and their associated elements will still necessitate some level of validation to demonstrate scientific confidence for specific purposes. Here we describe a scientific confidence framework for Tox21 approaches anchored in AOPs and illustrate how this can be used to direct the development of non-testing approaches and their application as part of IATA. Case study examples will illustrate insights derived from various endpoints that are informed by mechanistic information including that arising from AOPs.
URLs/Downloads:
DOI: Developing non-testing IATA informed by mechanistic insights: Case studies in building scientific confidence (ASCCT meeting)
ASCCT_Patlewicz_051015_presentation (PDF, NA pp, 4684 KB, about PDF)