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New Approach Methods for Hazard Identification: A Case Study with Azole Fungicides Affecting Molecular Targets
Constanze Knebel1, Roderich D Süssmuth2, Helen S Hammer3
1Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Street 8-10, 10589 Berlin, Germany.
Cells
|October 27, 2022
Summary
Triazole fungicides like propiconazole and tebuconazole can affect liver cells. While they show potential for cholestasis in vitro, in vivo studies indicate no significant risk at relevant concentrations.
Area of Science:
- Toxicology
- Hepatotoxicity
- Environmental Health
Background:
- Triazole fungicides, including propiconazole (Pi) and tebuconazole (Te), are known to cause liver toxicity (hepatotoxicity) in vivo.
- Hepatotoxicity is linked to interactions with nuclear receptors like PXR and CAR, affecting gene expression and potentially leading to liver cholestasis.
Purpose of the Study:
- To investigate the potential of propiconazole (Pi) and tebuconazole (Te) to induce cholestasis using an adverse outcome pathway (AOP)-driven approach in human hepatic cells in vitro.
- To reconcile in vitro findings with existing in vivo data regarding the cholestatic potential of these azole fungicides.
Main Methods:
- Utilized human liver cells in vitro for toxicogenomic analysis.
- Performed bile salt export pump (BSEP) activity assays.
- Assessed expression of cholestasis-associated genes and proteins.
- Evaluated mitochondrial membrane function.
Main Results:
- Propiconazole and tebuconazole were identified as weak inhibitors of BSEP.
- These azoles altered the expression of cholestasis-related genes and proteins and affected mitochondrial membrane potential.
- In vivo studies in rodents did not show evidence of cholestasis for either fungicide.
Conclusions:
- The discrepancy between in vitro and in vivo results for cholestasis is attributed to in vivo concentrations being below the EC50 for BSEP inhibition.
- Toxicogenomics and human in vitro models are valuable for identifying potential toxicity.
- Regulatory assessment requires a weight-of-evidence approach, integrating toxicokinetics and in vivo data for a comprehensive conclusion on in vivo relevance.
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