Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry...

Area of Science:

• Environmental toxicology
• Computational toxicology
• Risk assessment

Background:

• Anthraquinones, including 9,10-anthraquinone (9,10-AQ), are environmental contaminants with potential chronic toxicity.
• Limited toxicological data and resource-intensive animal studies hinder the derivation of Points of Departure (PoDs) and Health-Based Guidance Values (HB GVs) for many anthraquinones.
• There is a need for efficient and reliable methods to assess the health risks of anthraquinones.

Purpose of the Study:

• To validate New Approach Methodologies (NAMs) for deriving toxicological guidance values for 9,10-AQ.
• To establish a human-relevant Health-Based Guidance Value (HBGV) for 9,10-AQ using NAMs.
• To demonstrate the potential of NAMs for the risk assessment of other anthraquinones.

Main Methods:

• Network toxicology was used to predict hepatocyte hypertrophy via lipid metabolism.
• HepG2 cells and high-content imaging validated 9,10-AQ-induced lipid accumulation.
• Physiologically Based Toxicokinetic (PBTK) models for rats and humans were developed and used for reverse dosimetry.

Main Results:

• NAMs accurately predicted 9,10-AQ-induced hepatic lipid metabolism disorder.
• A human-relevant HBGV of 0.0105 mg/kg BW was derived for 9,10-AQ.
• The NAMs-based HBGV aligned well with values from traditional animal studies.

Conclusions:

• NAMs provide a validated, efficient, and reliable in vitro-in silico approach for predicting chemical toxicity and deriving human-relevant guidance values.
• This NAMs-based approach supports the Next Generation Risk Assessment (NGRA) of 9,10-AQ and related compounds.
• The methodology can be extended to assess other anthraquinones, improving risk assessment capabilities.