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Sensitivity Analysis of the Inputs for Bioactivity-Exposure Ratio Calculations in a NAM-Based Systemic Safety Toolbox
Hsing-Chieh Lin1, Maria Teresa Baltazar2, Sophie Cable2
1Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA.
Next-Generation Risk Assessment (NGRA) using New Approach Methodologies (NAM) can be robust. Human-relevant in vitro data and accessible modeling tools improve regulatory decision-making without animal testing.
Area of Science:
- Toxicology
- Risk Assessment
- Computational Chemistry
Background:
- Next-Generation Risk Assessment (NGRA) utilizes New Approach Methodologies (NAM) to reduce animal testing for regulatory decisions.
- Bioactivity-Exposure Ratios (BERs) are key in NGRA, comparing NAM assay data with human exposure estimates.
- Methodological choices in NGRA, including toxicokinetic modeling and data sources, introduce uncertainty.
Purpose of the Study:
- To assess the sensitivity of NGRA workflows to key methodological variables.
- To evaluate the robustness of a previously reported NGRA workflow for 35 diverse chemicals.
- To determine the impact of different physiologically based kinetic (PBK) modeling approaches and data sources on risk classification.
Main Methods:
- Conducted a sensitivity analysis on variables including PBK modeling software (GastroPlus, httk), parameterization levels, and POD sources (in vitro assays, ToxCast, iTTCs).
- Calculated BERs using Cmax estimates from PBK models and various PODs, with and without adjustments for free concentrations.
- Compared risk classifications derived from different NGRA methodological choices.
Main Results:
- The open-source httk model yielded Cmax estimates comparable to commercial GastroPlus when parameters were aligned.
- BERs derived from human-relevant cell-based PODs and nominal concentrations showed the best alignment with risk classifications.
- Adjustments for free concentrations and consideration of population variability in PBK modeling had limited impact on risk prediction accuracy.
Conclusions:
- Human-relevant in vitro PODs and nominal dose metrics are suitable for NGRA, supporting regulatory decision-making.
- Accessible and well-parameterized PBK tools like httk enhance the efficiency and reproducibility of NGRA.
- The study validates the potential of NAM-based approaches for reducing reliance on animal testing in chemical risk assessment.
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