New approach methodologies: A quantitative in vitro to in vivo extrapolation case study with PFASs
Styliani Fragki1, Jochem Louisse2, Bas Bokkers3
1Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
Summary
Polyfluoroalkyl substances (PFASs) exposure may disrupt human lipid metabolism and liver function. This study used in vitro and in silico methods to calculate effect doses, finding current dietary PFASs exposure levels overlap with concerning thresholds.
Area of Science:
- Environmental Toxicology
- In Vitro and In Silico Toxicology
- Human Health Risk Assessment
Background:
- Polyfluoroalkyl substances (PFASs) are linked to adverse health outcomes, including elevated blood lipids and liver enzyme levels (e.g., ALT).
- The liver is a primary target organ for many PFASs, necessitating investigation into their hepatotoxic and metabolic effects.
- New Approach Methodologies (NAMs) offer alternatives to traditional animal testing for assessing chemical risks.
Purpose of the Study:
- To calculate chronic oral equivalent effect doses for key PFASs (PFOA, PFNA, PFHxS, PFOS) using in vitro data.
- To assess potential interference with lipid metabolism and hepatotoxicity biomarkers in human liver cells (HepaRG).
- To establish an in vitro-in silico framework for prioritizing PFASs for further hazard characterization.
Main Methods:
- Utilized HepaRG cell line to measure in vitro effects of PFASs on triglyceride accumulation and gene expression.
- Employed physiologically based kinetic (PBK) model-facilitated reverse dosimetry to convert in vitro data to human equivalent doses.
- Investigated PFAS biokinetics within the cell system to inform dose-response relationships.
Main Results:
- Calculated oral equivalent effect doses for PFOA, PFNA, PFHxS, and PFOS based on HepaRG cell responses.
- Identified overlaps between current European dietary PFASs exposure levels and calculated effect doses.
- Demonstrated potential for PFASs to interfere with hepatic gene expression and lipid metabolism at current exposure levels.
Conclusions:
- The developed in vitro-in silico methodology provides a robust approach for assessing PFASs' potential health risks.
- Current dietary exposure to PFASs may pose a risk to human liver function and lipid homeostasis.
- This approach can guide regulatory efforts by prioritizing PFASs for comprehensive hazard assessment.
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