The Future of Uncertainty Factors With In Vitro Studies Using Human Cells.

Area of Science:

• Toxicology
• Risk Assessment
• In Vitro Methods

Background:

• New Approach Methodologies (NAMs), including in vitro human cell models, are transforming regulatory risk assessments.
• Traditional risk assessments rely on Uncertainty Factors (UFs) to address data gaps.
• The increasing use of human cell-based NAMs raises questions about the necessity of UFs.

Purpose of the Study:

• To debate the necessity of Uncertainty Factors when using in vitro human cell models in regulatory risk assessment.
• To explore the implications of organ-on-a-chip technology for reducing UFs.
• To identify future directions for integrating NAMs into regulatory frameworks.

Main Methods:

• Debate between experts on Uncertainty Factors and NAMs.
• Analysis of the applicability of interspecies and intraspecies UFs with in vitro human cell data.
• Consideration of other UFs, such as LOAEL-to-NOAEL and exposure duration extrapolation.

Main Results:

• The interspecies uncertainty factor (animal-to-human) can potentially be eliminated when using in vitro human cells on a chip.
• The intraspecies uncertainty factor (average-to-sensitive human) likely requires additional toxicokinetic/toxicodynamic data.
• Other uncertainty factors may still necessitate further data even with in vitro human cell models.

Conclusions:

• Collaboration between traditional and modern risk assessors is crucial for advancing 21st-century risk assessment.
• Organ-on-a-chip models show promise in reducing reliance on certain Uncertainty Factors.
• Further research and data are needed to refine the application of Uncertainty Factors with NAMs.