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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Elsevier
2025-07-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412025003058 |
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| author | Da Zhang Miaoying Shi Junyu Ning Shan Zheng Yi Yang Xudong Jia Yaru Tian Zinan Li Nan Zhang Ying Feng Shan Gao Zhuangsheng Tan Jau-Shyong Hong Ru-Band Lu Jiaxue Wang Haiming Jing Guojun Li |
| author_facet | Da Zhang Miaoying Shi Junyu Ning Shan Zheng Yi Yang Xudong Jia Yaru Tian Zinan Li Nan Zhang Ying Feng Shan Gao Zhuangsheng Tan Jau-Shyong Hong Ru-Band Lu Jiaxue Wang Haiming Jing Guojun Li |
| author_sort | Da Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6b293d2a321b48fb8a3dd7d63dc9cc7b |
| institution | Kabale University |
| issn | 0160-4120 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj-art-6b293d2a321b48fb8a3dd7d63dc9cc7b2025-08-20T03:30:44ZengElsevierEnvironment International0160-41202025-07-0120110955410.1016/j.envint.2025.109554Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassaysDa Zhang0Miaoying Shi1Junyu Ning2Shan Zheng3Yi Yang4Xudong Jia5Yaru Tian6Zinan Li7Nan Zhang8Ying Feng9Shan Gao10Zhuangsheng Tan11Jau-Shyong Hong12Ru-Band Lu13Jiaxue Wang14Haiming Jing15Guojun Li16School of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaNHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, ChinaSchool of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaBeijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaSchool of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaNHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100021, ChinaCollege of Urban and Environmental Sciences, Peking University, Beijing, 100871, ChinaSchool of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaBeijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaBeijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaBeijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaBeijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, ChinaNeurobiology Laboratory, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, USAColumbia International University, Monticello Road, Columbia, 29203, USABeijing YiNing Hospital, No. 9 Minzhuang Road, Haidian District, Beijing, 100195, ChinaSchool of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, China; Corresponding author.School of Public Health, Capital Medical University, Beijing, 100069, China; Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, China; Corresponding author at: Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing, 100013, China.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.http://www.sciencedirect.com/science/article/pii/S01604120250030589,10-anthraquinone (9,10-AQ)Physiologically based toxicokinetic (PBTK) modelQuantitative in vitro to in vivo extrapolation (QIVIVE)Benchmark dose (BMD)Health-based guidance value (HBGV) |
| spellingShingle | Da Zhang Miaoying Shi Junyu Ning Shan Zheng Yi Yang Xudong Jia Yaru Tian Zinan Li Nan Zhang Ying Feng Shan Gao Zhuangsheng Tan Jau-Shyong Hong Ru-Band Lu Jiaxue Wang Haiming Jing Guojun Li Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays Environment International 9,10-anthraquinone (9,10-AQ) Physiologically based toxicokinetic (PBTK) model Quantitative in vitro to in vivo extrapolation (QIVIVE) Benchmark dose (BMD) Health-based guidance value (HBGV) |
| title | Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays |
| title_full | Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays |
| title_fullStr | Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays |
| title_full_unstemmed | Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays |
| title_short | Deriving a Health-Based Guidance Value for 9,10-Anthraquinone via integrating PBTK modeling-based reverse dosimetry and In Vitro bioassays |
| title_sort | deriving a health based guidance value for 9 10 anthraquinone via integrating pbtk modeling based reverse dosimetry and in vitro bioassays |
| topic | 9,10-anthraquinone (9,10-AQ) Physiologically based toxicokinetic (PBTK) model Quantitative in vitro to in vivo extrapolation (QIVIVE) Benchmark dose (BMD) Health-based guidance value (HBGV) |
| url | http://www.sciencedirect.com/science/article/pii/S0160412025003058 |
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