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研究生：	李艷林 Lee, Yen-Ling
論文名稱：	使用魚類胚胎毒性測試與整合測試策略進行生態毒性評估 Utilizing Fish Embryo Toxicity (FET) Test and Integrated Testing Strategy (ITS) for the Assessment of Ecotoxicity
指導教授：	王應然 Wang, Ying-Jan
學位類別：	博士 Doctor
系所名稱：	醫學院 - 環境醫學研究所 Department of Environmental and Occupational Health
論文出版年：	2025
畢業學年度：	113
語文別：	英文
論文頁數：	137
中文關鍵詞：	奈米粒子、斑馬魚胚胎、魚類胚胎急毒性、自體吞噬、3R原則、電腦模擬、整合測試策略
外文關鍵詞：	nanoparticles, zebrafish embryos, fish embryo acute toxicity, autophagy, 3Rs principle, in silico, integrated testing strategy
相關次數：	點閱：8 下載：0
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隨著奈米銀粒子（AgNPs）與奈米氧化鋅粒子（ZnONPs）等工程奈米材料（ENPs）在環境中的暴露日益增加，其可能對生態產生的毒理效應引發了高度關注。本研究利用斑馬魚胚胎作為模型，評估AgNPs與ZnONPs在Milli-Q水與天然水體中的發育毒性與作用機制。結果顯示，奈米粒子暴露會造成孵化延遲、存活率下降、氧化壓力上升，以及細胞凋亡與自體吞噬等毒性反應。當奈米粒子存在於天然水體時，這些毒性效應有所減緩，推測可能與其在自然環境中發生聚集，並與有機物、硫與氯離子等成分發生作用有關。本研究強調奈米粒子在真實環境中的複雜行為，並指出氧化壓力與溶酶體活性等機轉性指標可作為奈米毒性早期偵測的關鍵指標。
同時，為降低對傳統活體魚類毒性試驗的依賴，並配合全球朝向動物福利與3R原則（替代、減量、優化）轉向的趨勢，本研究亦開發出一套創新的整合測試策略（Integrated Testing Strategy, ITS），用於急性魚類毒性評估。該ITS結合了電腦模擬（QSAR Toolbox）、體外細胞測試（RTgill-W1細胞株）與體內斑馬魚胚胎毒性試驗三種方法，可進行化學物質毒性之篩選與預測。此策略與傳統魚類急毒試驗（LC₅₀）的結果具有高度相關性，預測準確率超過73%。研究中提出多種ITS應用方式，如偏好導向、階段性測試與敏感度導向策略，以滿足不同法規與倫理需求。其中，階段性策略在預測準確性與動物福利之間取得良好平衡。此外，ITS透過整合機轉性與定量資料，克服單一方法的限制，提供更具效率與倫理兼顧的決策支持。綜合這兩項研究，顯示出將斑馬魚胚胎模型的毒性機轉洞察與多層次ITS架構結合之重要性，為化學物質與奈米材料在水生環境中的危害評估提供了一個嚴謹科學、彈性高且更人道的評估平台。

The increasing environmental presence of engineered nanoparticles (ENPs), such as silver nanoparticles (AgNPs) and zinc oxide nanoparticles (ZnONPs), has raised urgent concerns about their ecotoxicologicalal impact. In this study, zebrafish embryos were employed to assess the developmental and mechanistic toxicity of AgNPs and ZnONPs in both Milli-Q and natural aquatic environments. Results revealed significant nanoparticle-induced effects, including delayed hatching, reduced survival, increased oxidative stress, apoptosis, and autophagy. These effects were attenuated in natural waters, likely due to nanoparticle aggregation and interactions with environmental components such as organic matter, sulfur, and chloride ions. The study underscores the complexity of nanoparticle behavior in real-world ecosystems and highlights the importance of mechanistic endpoints such as reactive oxygen species (ROS) generation and lysosomal activity for early detection of nanotoxicity.
In parallel, to reduce reliance on traditional in vivo fish testing and align with global regulatory shifts favoring animal welfare and the 3Rs principle, a novel Integrated Testing Strategy (ITS) was developed for acute fish toxicity assessment. This ITS combines in silico (QSAR Toolbox), in vitro (RTgill-W1 cell line), and in vivo (zebrafish embryo toxicity test) methodologies to screen and predict chemical toxicity. The ITS demonstrated strong correlations with standard acute fish toxicity outcomes (LC₅₀), with predictive accuracies exceeding 73%. Various ITS approaches — preference-dependent, sequential, and sensitivity-based — were proposed to accommodate different regulatory and ethical needs. The ITS also effectively addressed limitations of individual methods by integrating mechanistic and quantitative data, supporting regulatory decision-making with enhanced efficiency and ethical compliance. Together, these complementary studies demonstrate the value of integrating mechanistic toxicity insights from zebrafish embryo models with multi-tiered ITS frameworks. This approach provides a scientifically robust flexible, and humane platform for evaluating chemical and nanomaterial hazards in aquatic environments.

1.Introduction  6
1.1 Current Status of Alternative Testing Methods in International Regulations 7
1.1.1 European Union (EU) 7
1.1.2 United States (US) 9
1.1.3 Organization for Economic Co-operation and Development (OECD) 12
1.1.4 Taiwan 14
1.2Alternative Tests 17
1.2.1The Zebrafish Test in Ecotoxicity  18
1.2.2Quantitative Structure Activity Relationship (QSAR) 20
1.2.3 New Approach Methodologies (NAMs) 21
1.2.4Integrated Testing Strategy (ITS) 23
1.3 Application of Alternative Testing in Nanomaterial Toxicity 25
1.3.1 Nanomaterials 25
1.3.2 Potential Ecological Hazards Caused by Nanoparticles 26
1.3.3 Regulation of Nanomaterials 26
1.3.4 Alternative Testing for Nanomaterials  31
1.4 Hypothesis and Rationale  32
Part A. Use Zebrafish Embryo to Evaluate Toxic Effects of Nanoparticles (AgNPs andZnONPs) in Aquatic Ecosystems 32
Part B. Use ITS for the Assessment of Ecotoxicity 33
2.Materials and Methods            35
Part A. Toxic Effects of AgNPs and ZnONPs on Zebrafish Embryos in Aquatic Ecosystem            35
A.2.1 Natural Water Preparation         35
A.2.2 Preparation of AgNPs and ZnONPs     36
A.2.3 The acute toxicity on zebrafish embryos     38
A.2.4 Toxicity Analyses         39
A.2.5 Statistics         41
B.2.1 Dara Resources          41
B.2.2 OECD QSAR Toolbox         42
B.2.3 Fish Husbandry          43
B.2.4 Fish Embryo Toxicity (FET) Test        43
B.2.5 Fish Cell Line Toxicity (FCT) Test       44
B.2.6 Statistics         45
3.Results              46
Part A. Toxic Effects of AgNPs and ZnONPs on Zebrafish Embryos in Aquatic Ecosystem            46
A.3.1 Characteristics of AgNPs and ZnONPs      46
A.3.2 Deposition of AgNPs and ZnONPs in Natural Water    47
A.3.3 Elemental Mapping of Natural Water    48
A.3.4 Embryo Mortality Induced by AgNPs and ZnONPs in Natural Water 49
A.3.5 Developmental Toxicity Induced by ZnONPs     50
A.3.6 Apoptotic Effects Induced by AgNPsand ZnONPs    51
A.3.7 Induction of Oxidative Stress by AgNPs and ZnONPs  51
A.3.8 Induction of Autophagy by AgNPs and ZnONPs   52
Part B. An Innovative Integrated Testing Strategy (ITS) for Evaluating Acute Fish Toxicity with New Approach Methodologies (NAMs)    53
B.3.1 Application of the ITS Framework       53
B.3.2 Correlation of Individual NAMs with AFT     54
B.3.3 Flowchart of Integrated Testing Strategy     55
B.3.4 Assessment of ITS Performance: Efficiency, Sensitivity, and Predictive Accuracy        57
B.3.5 Performance of ITS in Relation to GHS-Based Fish Acute Toxicity Classifications         58
B.3.6 External Validation of ITS-Based Toxicity Predictions Using Priority Chemicals Registered in Taiwan         59
4.Discussion           61
Part A. Toxic Effects of AgNPs and ZnONPs on Zebrafish Embryos in Aquatic Ecosystem            61
A.4.1 Engineered Nanoparticles in the Environment: Behavior and Toxicity in Natural Waters       61
A.4.2 Physicochemical Alterations and Sedimentation Behavior of Nanoparticles         61
A.4.3 Surface Chemistry and Environmental Transformation of AgNPs and ZnONPs          62
A.4.4 Zebrafish Embryotoxicity in Natural Waters Containing ENPs 62
A.4.5 Hatching Delays and Oxidative Stress from ZnONPs  63
A.4.6 ROS, Autophagy, and Cell Death Mechanisms Induced by ENPs 64
A.4.7 Implications for Future Monitoring and Risk Assessment   64
Part B. An Innovative Integrated Testing Strategy (ITS) for Evaluating Acute Fish Toxicity with New Approach Methodologies (NAMs)    64
B.4.1 Challenges in Traditional AFT Testing and the Need for NAMs 65
B.4.2 Advancing Fish Cell Line Approaches in Ecotoxicology 65
B.4.3 OECD’s IATA Framework and Gaps in NAMs Integration   65
B.4.4 Addressing FET and FCT Limitations through ITS     66
B.4.5 FET and FCT Correlation with AFT Performance  66
B.4.6 QSAR Toolbox Screening Limitations    67
B.4.7 Chemical Dataset and Scope of Application      67
B.4.8 GHS Classification Using ITS and NAMs    68
B.4.9 External Validation with Taiwan Priority Substances   68
5.Conclusion           68
6.Reference            71
7.Table Lists           84
Table 1: Definitions of Nanoparticles by Different International Organizations and Countries             84
Table 2. The Characteristics of AgNPs and ZnONPs    85
8.Figure Lists              86
Figure 1. Graphical Abstract of Part A: Toxic Effects of AgNPs and ZnONPs on Zebrafish Embryos in Aquatic Ecosystem         86
Figure 2. Graphical Abstract of part B: An Innovative Integrated Testing Strategy (ITS) for Evaluating Acute Fish Toxicity with New Approach Methodologies (NAMs)         .87
Figure 3. Physical and Chemical Properties of AgNPs and ZnONPs  88
Figure 4. Spiked AgNPs and ZnONPs in Natural Water     89
Figure 5. Elemental Mapping of AgNPs and ZnONPs in natural aquatic matrices              90
Figure 6. Lethality of AgNPs and ZnONPs Spiked in Natural Water   91
Figure 7. Developmental Toxicity of ZnONPs      92
Figure 9. Detection of ROS Production in Zebrafish Embryos Following Exposure to AgNPs and ZnONPs        94
Figure 10. Scheme of the Novel ITS for Acute Fish Toxicity      95
Figure 11. Correlation of NAMs Results with AFT       96
Figure 12. Evaluation of NAMs for Chemical Hazard Screening and Toxicity Prediction            97
Figure 13. Efficiency and Various Capacities of ITS     98
Figure 14. ITS Identification of Hazard Risk Compared to GHS Classification              99
Figure 15. External Validation of ITS Models through Prediction Accuracy on Selected Priority Substances          100
9.Abbreviations           101
10.Supplemental Figure          102
Figure S1. Zebrafish Embryo Viability Following Exposure to Natural Water Samples            103
Figure S2. Measurement of Zebrafish Embryo Body Length in Original Water                104
11.Appendices 104
                                    

1. ECHA, Guidance on Information Requirements and Chemical Safety Assessment. 2020.
2. Anon., Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals. 2006.
3. How to use alternatives to animal testing to fulfil your information requirements for REACH registration. European Chemicals Agency, 2016. Version 2.0 – July 2016.
4. Balls M. et al., The three Rs: the way forward: the report and recommendations of ECVAM Workshop 11. Altern Lab Anim, 1995. 23(6): p. 838-66.
5. Russell, W.M., The development of the three Rs concept. Altern Lab Anim, 1995. 23(3): p. 298-304.
6. De Wever, B., Fuchs, H.W., et al., Implementation challenges for designing integrated in vitro testing strategies (ITS) aiming at reducing and replacing animal experimentation . Toxicol. In Vitro, 2012. 26, 526–534.
7. ECHA, Practical guide How to use alternatives to animal testing to fulfil your information requirements for REACH registration. 2016. EPA 10.2823/194297.
8. Stefan Scholz et al. , A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment. Regul Toxicol Pharmacol 2013. 67:506-530.
9. Marcel Leist et al. , Consensus report on the future of animal-free systemic toxicity testing. . Altex 2014. 31:341-356.
10. Adam Lillicrap et al. , Alternative approaches to vertebrate ecotoxicity tests in the 21st century: A review of developments over the last 2 decades and current status. Environ Toxicol Chem 2016. 35:2637-2646.
11. Norberg-King, T.J.E., M.R., et al., An International Perspective on the Tools and Concepts for Effluent Toxicity Assessments in the Context of Animal Alternatives: Reduction in Vertebrate Use. . Environ Toxicol Chem 2018. 37:2745-2757.
12. ECHA, Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC. . OJEU 2006:L396/391-L396/849., 2006.
13. ECHA, Practical guide How to use alternatives to animal testing to fulfil your information requirements for REACH registration. EPA. doi: 10.2823/194297. 2016.
14. ECHA, The use of alternatives to testing on animals for the REACH Regulation. 2023.
15. ZUANG Valerie et al., EURL ECVAM progress report on the development, validation and regulatory acceptance of alternative methods (2010-2013). Joint Research Centre Scientific and Policy Reports 2013. Prepared in the framework of Directive 76/768/EEC and Regulation (EC) No 1223/2009 on cosmetic products.
16. Wax PM. Elixirs, d., and the passage of the 1938 Federal Food, Drug and Cosmetic Act. , Ann Intern Med., 1995 Mar 15;122(6):456-61. .
17. Daniel Krewski et al., TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY. J Toxicol Environ Health B Crit Rev. 2010 February, 2010. 13(0): 51–138. doi: 10.1080/10937404.2010.483176.
18. Lucie A Low, Danilo A Tagle, Organs-on-chips: Progress, challenges, and future directions. Experimental Biology and Medicine, 2017. 242: 1573–1578. DOI: 10.1177/1535370217700523.
19. ADMINISTRATION, U.S.F.D., FDA PREDICTIVE TOXICOLOGY ROADMAP. 2017.
20. Doortje Swaters et al., A History of Regulatory Animal Testing: What Can We Learn? Alternatives to Laboratory Animals, 2022. Volume 50, Issue 5, September 2022, Pages 322-329.
21. Syed Mukhtar Ahmed, Rabindra V Shivnaraine, Joseph C Wu, FDA Modernization Act 2.0 Paves the Way to Computational Biology and Clinical Trials in a Dish. Circulation, 2023. 2023 July 25; 148(4): 309–311. doi:10.1161/CIRCULATIONAHA.123.065585.
22. Commerce, H.-E.a., H.R.7248 - FDA Modernization Act 3.0. 2024. H.R.7248 — 118th Congress (2023-2024).
23. ICCVAM, Validation, Qualification, and Regulatory Acceptance of New Approach Methodologies (NAMs). A Report of the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Validation Workgroup, 2024.
24. Agency, U.S.E.P., EPA New Approach Methods Work Plan. 2021. EPA/600/X-21/209.
25. Buschmann, J., The OECD guidelines for the testing of chemicals and pesticides. Methods Mol Biol. , 2013. 2013:947:37-56. doi: 10.1007/978-1-62703-131-8_4.
26. Atici C., Low Levels of Genetically Modified Crops in International Food and Feed Trade: FAO International Survey and Economic Analysis. Food and Agriculture Organization of the United Nations, 2014.
27. OECD, Guidance Document on the Validation of (Quantitative) Structure-Activity Relationship [(Q)SAR] Models. OECD Series on Testing and Assessment, 2014.
28. P Marx-Stoelting et al., A walk in the PARC: developing and implementing 21st century chemical risk assessment in Europe. Archives of Toxicology 2023. 97, pages 893–908.
29. McNamee, P. et al., A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: eye irritation. Regul. Toxicol. Pharmacol., 2009. 54: 197-209.
30. 中華實驗動物學會, 我國導入歐盟替代方法之能量及時程評估研究報告. 民國109年12月.
31. 化學物質管理/毒性及關注化學物質管理, 新化學物質及既有化學物質資料登錄辦法. 民國103年, 民國 110 年 11 月 23 日修正. 環署化字第1108201465號令.
32. 化學物質管理/毒性及關注化學物質管理, 毒性及關注化學物質管理法. 公發布日: 民國 75 年 11 月 26 日, 修正日期: 民國 108 年 01 月 16 日. 華總一義字第10800005221號令.
33. 中華實驗動物學會, 產品上市前動物測試替代方法研究報告。. 行政院農業委員會。臺北, 民國107年. 145 頁。.
34. 衛生福利部, 化粧品衛生安全管理法. 民國108年. 院臺衛字第 1080011912 號.
35. 行政院衛生福利部,食品藥物管理目, 健康食品管理法. 修正日期：民國109年01月15 日.
36. 經濟部產業發展組, 2018生技產業白皮書. 民國107年.
37. 經濟合作暨發展組織, 經濟合作暨發展組織優良實驗室操作規範 OECD Principles of Good Laboratory Practice. 優良實驗室操作規範與依從監督專輯經濟合作暨發展組織環境健康與安全刊物, 民國86年年修訂版.
38. 衛生福利部食品藥物管理署, 人體細胞組織優良操作規範. 91.12.13衛署醫字第0910078677號公告, 民國91年.
39. 衛生福利部食品藥物管理署, 國際醫藥法規協和會(ICH)指引採認清單. 民國112年.
40. 衛生福利部食品藥物管理署, 藥品非臨床試驗安全性規範(第五版). 發文文號：FDA藥字第1031405812號, 發文日期：103年7月7日.
41. Sapna Kumari Pandey, P.K.O., Kunal Roy, Exploring QSAR models for assessment of acute fish toxicity of environmental transformation products of pesticides (ETPPs). Chemosphere, 2020. Volume 252, August
42. Burden, N., Benstead, R., et al., Key opportunities to replace, reduce, and refine regulatory fish acute toxicity tests. Environ. Toxicol. Chem. , 2020. 39, 2076–2089.
43. Busquet, F., Strecker, R., et al., OECD validation study to assess intra- and interlaboratory reproducibility of the zebrafish embryo toxicity test for acute aquatic toxicity testing. . Regul. Toxicol., 2014. Pharm. 69, 496–511.
44. OECD, Fish testing framework. In: OECD Series of Testing and Assessment. OECD Publishing 2012 2012. No. 177. ) 2016/en/pdf.
45. Paparella, M., Scholz, S., et al., Limitations and uncertainties of acute fish toxicity assessments can be reduced using alternative methods. ALTEX 2021. 38, 20–32.
46. Coors, A., Brown, A.R., et al., Minimizing experimental testing on fish for legacy pharmaceuticals. . Environ. Sci. Tech. , 2023. 57, 1721–1730.
47. OECD, Test No. 203: Fish, Acute Toxicity Test." OECD Guidelines for the Testing of Chemicals. 2019.
48. OECD, Test No. 236: Fish Embryo Toxicity (FET) Test." OECD Guidelines for the Testing of Chemicals. 2013.
49. Kamelia, L., Brugman, S., et al., Prenatal developmental toxicity testing of petroleum substances using the zebrafish embryotoxicity test. . ALTEX 2019. 36, 245–260.
50. Krzykwa, J.C., King, S.M., et al., Investigating the predictive power of three potential sublethal endpoints for the fathead minnow fish embryo toxicity test: snoutvent length, eye size, and pericardial edema. Environ. Sci. Tech., 2021. 55, 6907–6916.
51. Rodrigues de Souza, I., de Oliveira, J.B.V., et al., Prediction of acute fish toxicity (AFT) and fish embryo toxicity (FET) tests by cytotoxicity assays using liver and embryo zebrafish cell lines (ZFL and ZEM2S). Chemosphere, 2024. 346, 140592.
52. Hutchinson, T.H., Wheeler, J.R., et al., Promoting the 3Rs to enhance the OECD fish toxicity testing framework. . Regul. Toxicol. Pharm. , 2016. 76, 231–233.
53. Jimeno-Romero, A., Gwinner, F., et al., Sea Bass Primary Cultures versus RTgill-W1 Cell Line: Influence of Cell Model on the Sensitivity to Nanoparticles. Nanomaterials, 2021. (Basel, Switzerland) 11.
54. Scott, J., Grewe, R., et al., Fish embryo acute toxicity testing and the RTgill-W1 cell line as in vitro models for whole-effluent toxicity (WET) testing: an in vitro/in vivo comparison of chemicals relevant for WET testing. . Environ. Toxicol. Chem. , 2022. 41, 2721–2731.
55. Scott, J., Mortensen, S., et al., Alternatives to fish acute whole effluent toxicity (WET) testing: predictability of RTgill-W1 cells and fathead minnow embryos with actual wastewater samples. Environ. Sci. Tech. , 2023. 57, 13721–13731.
56. Tanneberger, K., Knöbel, M., et al., Predicting fish acute toxicity using a fish gill cell line-based toxicity assay Environ. Sci. Tech., 2013. 47, 1110–1119.
57. OECD, Test No. 249: Fish Cell Line Acute Toxicity - The RTgill-W1 cell line assay. OECD Publishing., 2021.
58. López, E., et al., Characterization of RTgill-W1 cell line for ecotoxicologicalal studies Cell Biology and Toxicology, 2019. 35(1), 1-12.
59. Thao V. Nguyen, A.K., Phan Nguyen Trang The use of fish cell lines as in-vitro ecotoxicologicalal tools: A cellular solution to aquaculture sustainability. Aquaculture, 2024. Volume 593, 15 December 2024, 741302.
60. Justin Scott, M.M., Characterization of RTgill-W1 cells epithelial development on transwell inserts: Evaluation of osmotic and toxic challenges. Comparative Biochemistry and Physiology 2023. Part C: Toxicology & Pharmacology, Volume 270, 109638.
61. Barun Bhhatarai et al., Evaluation of OASIS QSAR Models Using ToxCast™ in Vitro Estrogen and Androgen Receptor Binding Data and Application in an Integrated Endocrine Screening Approach. Environ Health Perspect, 2016. May 6;124(9):1453–1461.
62. Worth et al., Review of QSAR Models and Software Tools for predicting Developmental and Reproductive Toxicity. Joint Research Centre, 2010. EUR 24522 EN
63. Moritz Walter et al., Analysis of the benefits of imputation models over traditional QSAR models for toxicity prediction. Journal of Cheminformatics 2022. 14:32.
64. Hedvig Norlén et al., An investigation into the use of computational and in vitro methods for acute systemic toxicity prediction. Joint Research Centre 2012.
65. Meyer, J.N., et al., QSAR model for predicting pesticide aquatic toxicity. J Chem Inf Model., 2005. Nov-Dec;45(6).
66. Fotios Tsopelas et al., The QSAR Paradigm to Explore and Predict Aquatic Toxicity. Chemometrics and Cheminformatics in Aquatic Toxicology, 2021. 13 October.
67. Mikael Gustavsson et al., Transformers enable accurate prediction of acute and chronic chemical toxicity in aquatic organisms. Science Advances, 2024. Vol 10, Issue 10.
68. Thomas Y. Sheffield, R.S.J., Ensemble QSAR Modeling to Predict Multispecies Fish Toxicity Lethal Concentrations and Points of Departure. Environmental Science & Technology, 2019. Vol 53/Issue 21.
69. Kabiruddin Khan et al., QSAR modeling of Daphnia magna and fish toxicities of biocides using 2D descriptors. Chemosphere, 2019. Aug:229:8-17.
70. Monika Nendza, M.M., Andrea Wenzel, Classification of baseline toxicants for QSAR predictions to replace fish acute toxicity studies. Environmental Science: Processes & Impacts, 2017. Issue 3.
71. Kazue Chinen, T.M., QSAR Use in REACH Analyses of Alternatives to Predict Human Health and Environmental Toxicity of Alternative Chemical Substances. Integr Environ Assess Manag., 2020. Sep;16(5):745-760.
72. M Zeeman, C.M.A., R G Clements, J V Nabholz, R S Boethling, U.S. EPA regulatory perspectives on the use of QSAR for new and existing chemical evaluations. SAR QSAR Environ Res, 1995. 1995;3(3):179-201.
73. Walker, J.D., Applications of QSARs in toxicology: a US Government perspective. Journal of Molecular Structure: THEOCHEM, 2003. Volume 622, Issues 1–2, 7 March, Pages 167-184.
74. Fiona Sewell, C.A.-W., et al., New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption. Toxicology Research, 2024. 13, 1–9.
75. Council., N.R., Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. 2014.
76. Hartung, T., Toxicology for the Twenty-First Century . Nature, 2010. 460(7252), 208-212.
77. Judson, R.S., et al., In Vitro Screening of Environmental Chemicals: The Tox21 Approach. . Environmental Health Perspectives, 2010. 118(4), 485-492.
78. Jaleh Abedini et al., Application of new approach methodologies: ICE tools to support chemical evaluations. Computational Toxicology, 2021. 20, November 2021, 100184.
79. EPA, U., Freshwater and saltwater fish acue toxicity test. In: Ecological Effects Test Guidelines. . 2016a.
80. ISO, Water quality — Determination of the acute lethal toxicity of substances to a freshwater fish. ISO 7346-1:1996. 1996.
81. Ottofuelling et al., Commercial titanium dioxide nanoparticles in both natural and synthet-ic water: Comprehensive multidimensional testing and prediction of aggregation behavior. Environ. Sci. Technol. , 2011. 45, 10045–10052, doi:10.1021/es2023225.
82. Espinasse B.P. et al., Comparative Persistence of Engineered Nanoparticles in a Complex Aquatic Ecosystem. Environ. Sci. Technol. , 2018. 52, 4072–4078, doi:10.1021/acs.est.7b06142.
83. Bind V.K. et al., Current issue on nanoparticle toxicity to aquatic organism. MOJ Toxicol., 2019. 5, 66–67, doi:10.15406/mojt.2019.05.00155.
84. Liu, R., et al, Ecological risks of engineered nanoparticles. Environmental Pollution, 2016. 218, 533-541.
85. Chen, Z.Y.W., Y.J. et al. , The Effect of the Chorion on Size-Dependent Acute Toxicity and Underlying Mechanisms of Amine-Modified Silver Nanoparticles in Zebrafish Embryos. Int. J. Mol. Sci. , 2020. 21, 2864, doi:10.3390/ijms21082864. .
86. Jahan, S et al., Reviews of the toxicity behavior of five potential engineered nanomaterials (ENMs) into the aquatic ecosystem. Toxicol. Rep., 2017. 4, 211–220, doi:10.1016/j.toxrep.2017.04.001.
87. Union, E., COMMISSION RECOMMENDATION of 10 June 2022 on the definition of nanomaterial 2022. (2022/C 229/01).
88. EU, Commission Regulation (EU) 2022/477 of 24 March 2022 amending Annexes VI to X to Regulation (EC) No 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). 2022. C/2022/1721.
89. ECHA, Guidance on Information Requirements and Chemical Safety Assessment: Appendix R7-1 for Nanomaterials Applicable to Chapter R7a Endpoint Specific Guidance (ECHA). 2022.
90. ECHA, Study on (bio)degradation, persistence and safe by design of nanomaterials. 2022.
91. OECD, In Vitro Immunotoxicity: Il-2 Luc Assay. Test Guideline No. 444A, 2023.
92. OECD, Determination of the Hydrophobicity Index of Nanomaterials Through an Affinity Measurement. Test Guideline No. 126, 2023.
93. ISO, Nanotechnologies - Measurements of particle size and shape distributions by transmission electron microscopy (ISO 21363:2020). 2020. Swedish standard · SS-EN ISO 21363:2022.
94. ISO, Nanotechnologies — Measurements of particle size and shape distributions by scanning electron microscopy. 2021. ISO 19749:2021.
95. Caterina Minelli, M.W. et al., Versailles project on advanced materials and standards (VAMAS) interlaboratory study on measuring the number concentration of colloidal gold nanoparticles. Nanoscale, 2022. 14, 4690.
96. OECD, Testing of Chemicals Particle Size and Particle Size Distribution of Nanomaterials. OECD GUIDELINE FOR THE TESTING OF CHEMICALS, 2023.
97. 勞動部, 行政院, 職業安全衛生法. 民國102年.
98. 勞動及職業安全衛生研究所, 勞動部, 奈米物質危害分級手冊. 民國105年5月11日.
99. 勞動及職業安全衛生研究所, 勞動部, 奈米物質安全衛生管理技術手冊. 民國105年.
100. 衛生福利部食品藥物管理署, 含奈米物質食品器具容器包裝申請作業指引. 民國106年.
101. 環保署, 奈米材料安全性評估指引. 民國107年.
102. 化學物質管理署, 既有化學物質標準登錄資料撰寫指引. 民國109年.
103. 食品藥物管理署, 含奈米成分化粧品風險評估指引. 民國113年.
104. SCCS, GUIDANCE ON THE SAFETY ASSESSMENT OF NANOMATERIALS IN COSMETICS. Scientific Committee on Consumer Safety 2019.
105. Rovida, C., Alépée, N., et al., Integrated Testing Strategies (ITS) for safety assessment. ALTEX 32, 25–40., 2015.
106. Ahlers, J., Stock, F., et al., Integrated testing and intelligent assessment-new challenges under REACH. Environ. Sci. Pollut. Res. Int. , 2008. 15, 565–572.
107. Bradbury, S.P., Feijtel, T.C., et al., Meeting the scientific needs of ecological risk assessment in a regulatory context. Environ. Sci. Tech. , 2004. 38, 463a–463a470a.
108. Hartung, T., Luechtefeld, T., et al., Integrated testing strategies for safety assessments. ALTEX, 2013. 30, 3–18.
109. OECD, Guidance Document on the Reporting of Defined Approaches and Individual Information Sources to be Used within Integrated Approaches to Testing and Assessment (IATA) for Skin Sensitisation. . OECD Publishing, 2017. No. 256.
110. Lammer, E., Carr, G.J., et al., Is the fish embryo toxicity test (FET) with the zebrafish (Danio rerio) a potential alternative for the fish acute toxicity test? . Comp. Biochem. Physiol. C: Toxicol. Pharmacol, 2009. 149, 196–209.
111. Natsch, A., Laue, H., et al., Accurate prediction of acute fish toxicity of fragrance chemicals with the RTgill-W1 cell assay. Environ. Toxicol. Chem. 37, 931–941., 2018.
112. Abbas, Q.Y. et al., Transformation pathways and fate of engineered nanoparticles (ENPs) in distinct interactive environmental compartments: A review. Environ. Int. , 2020. 138, 105646.
113. Kansara, K.K., A.; Karakoti, A.S., Combination of humic acid and clay reduce the ecotoxicological effect of TiO(2) NPs: A combined physico-chemical and genetic study using zebrafish embryo. Sci. Total Environ. , 2020. 2020, 698, 134133.
114. Mao, B.H.C., Z.Y.;Wang, Y.J.; Yan, S.J. , Silver nanoparticles have lethal and sublethal adverse effects on development and longevity by inducing ROS-mediated stress responses. Sci. Rep. , 2018. 8, 2445.
115. Attia, H.N., H.; Shalaby, M. Zinc Oxide Nanoparticles Induced Oxidative DNA Damage, Inflammation and Apoptosis in, Zinc Oxide Nanoparticles Induced Oxidative DNA Damage, Inflammation and Apoptosis in Rat’s Brain after Oral Exposure. Toxics, 2018. 6, 29.
116. Kang, K.J., H.; Lim, J.S. , Cell Death by Polyvinylpyrrolidine-Coated Silver Nanoparticles is Mediated by ROS-Dependent Signaling. Biomol. Ther., 2012. 20, 399–405.
117. Akter, M.S., M.T.; Rahman, M.M.; Ullah, A.; Hossain, K.F.B.; Banik, S.; Hosokawa, T.; Saito, T.; Kurasaki, M. , A systematic review on silver nanoparticles-induced cytotoxicity: Physicochemical properties and perspectives. J. Adv. Res. , 2018. 2018, 9, 1–16.
118. Zhang, J.Q., X.;Wang, B.; Xu, G.; Qin, Z.;Wang, J.;Wu, L.; Ju, X.; Bose, D.D.; Qiu, F.; et al. , Zinc oxide nanoparticles harness autophagy to induce cell death in lung epithelial cells. Cell Death Dis. , 2017. 8, e2954.
119. Ahlers, J., Stock, F., et al., Integrated testing and intelligent assessment-new challenges under REACH. Environ. Sci. Pollut. Res. Int., 2008. 15, 565–572.
120. Cavasotto, C.N., Scardino, V., Machine learning toxicity prediction: latest advances by toxicity end point. ACS Omega, 2022. 7, 47536–47546.
121. Crofton, K.M., Bassan, A., et al., Current status and future directions for a neurotoxicity hazard assessment framework that integrates in silico approaches. Comput. Toxicol., 2022. 22.
122. Worth, A., Gatnik, M., et al., Applicability of QSAR analysis in the evaluation of developmental and neurotoxicity effects for the assessment of the toxicologicalal relevance of metabolites and degradates of pesticide active substances for dietary risk assessment EFSA, 2011.
123. Wang, Z., Walker, G.W., et al., Toward a global understanding of chemical pollution: a first comprehensive analysis of national and regional chemical inventories. Environ. Sci. Tech. , 2020. 54, 2575–2584.
124. Sutton, P., Woodruff, T.J., et al., Toxic environmental chemicals: the role of reproductive health professionals in preventing harmful exposures. Am. J. Obstet. Gynecol., 2012. 207, 164–173.
125. Keller, A.A.M., S.; Lazareva, A.; Suh, S. , Global life cycle releases of engineered nanomaterials. J. Nanopart. Res. , 2013. 15, 1692.
126. Giese, B.K., F.; Park, B.; Kaegi, R.; Steinfeldt, M.;Wigger, H.; von Gleich, A.; Gottschalk, F. , Risks, Release and Concentrations of Engineered Nanomaterial in the Environment. Sci. Rep. , 2018. 8, 1565.
127. Bathi, J.R. et al., Behavior of engineered nanoparticles in aquatic environmental samples: Current status and challenges. Sci. Total Environ., 2021. 793, 148560.
128. Wang, Z.Z., L.; Zhao, J.; Xing, B. , Environmental processes and toxicity of metallic nanoparticles in aquatic systems as affected by natural organic matter. Environ. Sci. Nano 2016. 3, 240–255.
129. Bundschuh, M.F., J.; Lüderwald, S.; McKee, M.S.; Metreveli, G.; Schaumann, G.E.; Schulz, R.; Wagner, S. , Nanoparticles in the environment: Where do we come from, where do we go to? . Environ. Sci. Eur. , 2018. 30, 6.
130. Li, X.L. et al. , Aggregation and Dissolution of Silver Nanoparticles in Natural SurfaceWater. Environ. Sci. Technol. , 2012. 46, 5378–5386.
131. Slomberg, D.L.O., P.; Miche, H.; Angeletti, B.; Bruchet, A.; Philibert, M.; Brant, J.; Labille, J. , Nanoparticle stability in lake water shaped by natural organic matter properties and presence of particulate matter. Sci. Total Environ., 2019. 656, 338–346.
132. Dal, N.K.K., A.;Wohlmann, J.; Van Herck, S.; Bauer, T.A.; Resseguier, J.; Bagherifam, S.; Hyldmo, H.; Barz, M.; De Geest, and B.G.e. al., Zebrafish Embryos Allow Prediction of Nanoparticle Circulation Times in Mice and Facilitate Quantification of Nanoparticle–Cell Interactions. Small, 2020. 2020, 16, 1906719.
133. Chakraborty, C.S., A.R.; Sharma, G.; Lee, S.S. , Zebrafish: A complete animal model to enumerate the nanoparticle toxicity. J. Nanobiotechnol, 2016. 14, 1–13.
134. Pereira, A.C.G., T.; Ferreira Machado, M.R.; Rocha, T.L. , The zebrafish embryotoxicity test (ZET) for nanotoxicity assessment: From morphological to molecular approach. Environ. Pollut., 2019. 252, 1841–1853.
135. Chen, T.H.L., C.C.; Meng, P.J. , Zinc oxide nanoparticles alter hatching and larval locomotor activity in zebrafish (Danio rerio). J. Hazard. Mater, 2014. 277, 134–140.
136. Wu, W.B., P.A.; Samet, J.M., Zinc ions as effectors of environmental oxidative lung injury. Free Radic. Biol. Med. , 2013. 65, 57–69.
137. Hansjosten, I.T. et al., Surface functionalisation-dependent adverse effects of metal nanoparticles and nanoplastics in zebrafish embryos. Environ. Sci. Nano, 2021. 9, 375–392.
138. Lin, S.Z., Y.; Ji, Z.; Ear, J.; Chang, C.H.; Zhang, H.; Low-Kam, C.; Yamada, K.; Meng, H.; Wang, X.; et al. , Zebrafish highthroughput screening to study the impact of dissolvable metal oxide nanoparticles on the hatching enzyme, ZHE1. Small 2013. 9, 1776–1785.
139. Osborne, O.J.J., B.D.; Moger, J.; Balousha, M.; Lead, J.R.; Kudoh, T.; Tyler, C.R. , Effects of particle size and coating on nanoscale Ag and TiO2 exposure in zebrafish (Danio rerio) embryos. Nanotoxicology, 2013. 7, 1315–1324.
140. Lee, Y.H.C., F.Y.; Chiu, H.W.; Tsai, J.C.; Fang, C.Y.; Chen, C.W.; Wang, Y.J. , Cytotoxicity, oxidative stress, apoptosis and the autophagic effects of silver nanoparticles in mouse embryonic fibroblasts. Biomaterials, 2014. 35, 4706–4715.
141. Wu, Y.H.; Wang, B.J.; Wang, Y.J. et al., The Recent Progress in Nanotoxicology and Nanosafety from the Point of View of Both Toxicology and Ecotoxicology. Int. J. Mol. Sci. , 2020. 21, 4209.
142. BH Mao et al., Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy. Nanotoxicology, 2016. 10, 1021–1040.
143. YH Lee et al., Endoplasmic Reticulum Stress-Triggered Autophagy and Lysosomal Dysfunction Contribute to the Cytotoxicity of Amine-Modified Silver Nanoparticles in NIH 3T3 Cells. J. Biomed. Nanotech, 2017. 13, 778–794.
144. BH Mao et al., Use of An In Silico Knowledge Discovery Approach To Translate Mechanistic Studies of Silver Nanoparticles-Induced Toxicity From In Vitro to In Vivo. Part. Fibre Toxicol., 2022. 19, 6.
145. Guo, L.H., N.; Zhao, Y.; Liu, T.; Deng, Y. , Autophagy Modulated by Inorganic Nanomaterials. Theranostics, 2020. 10, 3206–3222.
146. Pereira, A.C.G., T.; Ferreira Machado, M.R.; Rocha, T.L. , The zebrafish embryotoxicity test (ZET) for nanotoxicity assessment: From morphological to molecular approach. Environ. Pollut., 2019. 252, 1841–1853.
147. Chen, R.J.H., C.C.; Pranata, R.; Lee, Y.H.; Chen, Y.Y.;Wu, Y.H.; Wang, Y.J. , Modulation of Innate Immune Toxicity by Silver Nanoparticle Exposure and the Preventive Effects of Pterostilbene. Int. J. Mol. Sci. , 2021. 22, 2536.
148. Finlayson, K.A., Leusch, F.D.L., et al. , Review of ecologically relevant in vitro bioassays to supplement current in vivo tests for whole effluent toxicity testing - Part 1: Apical endpoints. Sci. Total Environ., 2022. 851, 157817.
149. Ribeiro, R.X. et al., Ecotoxicologicalal assessment of effluents from Brazilian wastewater treatment plants using zebrafish embryotoxicity test: A multibiomarker approach. Sci. Total Environ. , 2020. 735, 139036.
150. Jaworska, J., Integrated Testing Strategies for Skin Sensitization Hazard and Potency Assessment—State of the Art and Challenges. . Cosmetics, 2016. 3, 16.
151. Jaworska, J., Hoffmann, S., Integrated Testing Strategy (ITS) - Opportunities to better use existing data and guide future testing in toxicology. ALTEX, 2010. 27, 231–242.
152. Zhu, H., Zhang, J., et al., Big data in chemical toxicity research: the use of highthroughput screening assays to identify potential toxicants. Chem. Res. Toxicol. , 2014. 27, 1643–1651.
153. ISO, Nanotechnologies — Assessment of nanomaterial toxicity using dechorionated zebrafish embryo. ISO/TS 22082, 2020. . 2020.
154. (TSCA), T.S.C.A., Working Guidance on EPA’s Section 8(a) Information Gathering Rule on Nanomaterials in Commerce. 2017.
155. ISO, ISO/TS 80004-1:2015(en) Nanotechnologies — Vocabulary — Part 1: Core terms. 2015.
156. Glenn J Myatt et al., In silico toxicology protocols, Regul Toxicol Pharmacol. 2018 Jul:96:1-17.
157. Edwin J. Matthews et al., A comprehensive model for reproductive and developmental toxicity hazard identification: I. Development of a weight of evidence QSAR database, Regulatory Toxicology and Pharmacology, Volume 47, Issue 2, March 2007, Pages 115-135
158. Natalja Fjodorova et al., New public QSAR model for carcinogenicity, Chem Cent J. 2010 Jul 29;4

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