Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays
Anthraquinones, both naturally occurring and synthetic, are widely distributed in the environment. Recent years, human exposure to 9,10-anthraquinone (9,10-AQ) through contaminated food has been raising significant health concerns due to its potential toxicity upon chronic exposure. Among these, 9,1...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-07-01
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| Series: | Environment International |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412025003058 |
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| Summary: | Anthraquinones, both naturally occurring and synthetic, are widely distributed in the environment. Recent years, human exposure to 9,10-anthraquinone (9,10-AQ) through contaminated food has been raising significant health concerns due to its potential toxicity upon chronic exposure. Among these, 9,10-AQ has been studied in traditional toxicology, with few of established Points of Departure (PoDs) and Health-Based Guidance Values (HBGV). However, toxicological data for other anthraquinones remain severely limited. Traditional animal experiments are resource-intensive and time-consuming, restricting the feasibility of deriving PoDs and HBGVs for a larger set of compounds and exposures, especially for risk assessment purposes. To address these challenges, New Approach Methodologies (NAMs) were employed and validated by using 9,10-AQ as a reference and representative compound in current study. Hepatocyte hypertrophy via lipid metabolism pathway induced by 9,10-AQ was predicted with applying network toxicology, which was validated using HepG2 cell (0.625-10 μM, for 48 h) combined with high-content imaging showing lipid accumulation induced by 9,10-AQ. The physiologically based toxicokinetic (PBTK) model for rat of 9,10-AQ was developed using in vitro and in silicodata, which was further extrapolated to humans PBTK model, enabling the translation of in vitro concentration–response relationships into in vivo dose–response predictions through PBTK modeling-based reverse dosimetry. From this, a PoD value was derived and converted to a HBGV of 0.0105 mg/kg BW, accounting for uncertainty factors of 100. The NAMs-based HBGV of 9,10-AQ matched well with values derived from animal studies, providing a proof-of-principle of using in vitro-in silicoapproach to predict hepatic lipid metabolic disorder in humans and indicating a good performance of the NAMs. This approach has the potential to be extended to other anthraquinones and derivatives, offering more accurate and reliable human-relevant value (i.e. PoDs, HBGVs), to support Next Generation Risk Assessment (NGRA) of 9,10-AQ and related compounds. |
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| ISSN: | 0160-4120 |