- Challenges in the Development of In Vitro-In Vivo Extrapolation Models for Next-Generation Risk Assessment
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Chair:John Wambaugh, US EPA
Co-Chair:Mathieu Vinken, Vrije Universiteit Brussel, Belgium
Primary Endorser: In Vitro and Alternative Methods Specialty Section
Endorser(s): Biological Modeling Specialty Section
Endorser(s): Regulatory and Safety Evaluation Specialty SectionNext-generation risk assessments (NGRA) are expected to rely on new approach methods (NAMs), which include human in vitro and in silico approaches for hazard identification and characterization. One key aspect for risk assessment is the derivation of a point of departure (PoD), which for NGRA might be derived by in vitro to in vivo extrapolation (IVIVE) from an in vitro benchmark concentration. Programs are working to advance NGRA methods in both the EU and the US. In the EU, the newly launched ONTOX program is developing a strategy to create innovative NAMs to predict systemic repeated dose toxicity effects, while the new program RISK-HUNT3R (short for Risk Assessment of Chemicals Integrating Human-Centric Next-Generation Testing Strategies Promoting the 3Rs) will develop, validate, and implement integrated approaches to lead the way toward NGRA. In the US, the Federal Tox21 and US EPA ToxCast and ExpoCast programs have similarly been working to develop a working NGRA to inform chemical safety decision-making. This session will begin with an overview of the NGRA framework recently developed for cosmetic ingredients and identify research gaps for greater implementation of NGRA with respect to IVIVE. The following presentations will address these IVIVE gaps. The IVIVE approach relies on two different types of information. Firstly, in vitro biokinetics modeling is used to define the free intracellular concentration of test substances in the in vitro test conditions. Different approaches to defining this concentration are under development in the EU and US. Second, this session will discuss generic physiologically based kinetic (PBK, also known by PBTK and PBPK) models parameterized using human in vitro inputs (e.g., for clearance, absorption, and binding) as part of NGRA. In this session, we will dicuss this particular type of PBK model that has been widely used in the pharmaceutical industry and its application in chemical risk assessment. Other specific topics covered will include PBK modeling for different barrier organs, such as lung, skin, and GI tract, and approaches to account for the disposition of metabolites within the PBK models. The overall integration of NAM data into risk assessment is one of the most challenging aspects of NGRA. This session will also examine the current status of IVIVE for NAM integration.
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