A workflow to practically apply true dose considerations to in vitro testing for next generation risk assessment

Area of Science:

• Toxicology and Chemical Safety
• In Vitro and In Silico Modeling
• Regulatory Science

Background:

• The scientific community is moving away from animal testing towards Next Generation Risk Assessment (NGRA).
• NGRA relies on in silico and in vitro data, introducing uncertainties in determining the actual dose at the target site.
• Surrogate dose metrics like nominal concentration are used, but their accuracy in reflecting biologically effective doses is critical for reliable risk assessment.

Purpose of the Study:

• To illustrate how in vitro dose considerations can characterize the
• true dose
• for NGRA.
• To build confidence in understanding biologically effective doses in in vitro systems for determining points of departure (PoDs).
• To propose and apply a workflow for assessing nominal test concentrations as conservative dose metrics in NGRA.

Main Methods:

• Utilized 40 case study chemicals to evaluate in vitro dose metrics.
• Developed a workflow examining chemical properties: volatility, stability, hydrophobicity, binding to plastic and serum, and solubility.
• Incorporated in silico models to predict certain chemical parameters.

Main Results:

• For most chemicals, nominal concentrations provide conservative dose metrics in risk assessment.
• Identified several chemicals where nominal concentrations may underestimate in vivo human risk.
• Proposed methods for refining risk assessment by characterizing actual effect concentrations.

Conclusions:

• The proposed workflow helps assess the suitability of nominal concentrations for NGRA.
• While often conservative, nominal concentrations require careful evaluation for specific chemicals.
• Characterizing actual effect concentrations is crucial for accurate risk assessment and refining NGRA.