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Herein, an integrated approach combining adverse outcome pathways (AOPs) with in vitro-to-in vivo extrapolation (IVIVE) was established, enabling the systematic organization of mechanistic evidence and the quantitative translation of early molecular events into human health risk metrics. Using cadmium (Cd) as a case study, this framework incorporated toxicogenomic data, bioinformatics, and human-relevant in vitro cellular assays to elucidate the AOPs underlying Cd-induced bone toxicity. Two AOP frameworks were proposed, highlighting key events (KEs) involving the RANKL\/OPG, Wnt, BMP, and MAPK signaling pathways as well as osteogenic differentiation and cell apoptosis. Benchmark dose and physiologically based toxicokinetic modeling were further applied within IVIVE to derive human-equivalent doses (HEDs) for KEs in the proposed AOPs. Of these, the HED derived from Wnt and MAPK signaling pathways (both 0.03 \u03bcg\/kg bw\/day) was considered an appropriate metric for risk characterization, with its scientific validity further supported by existing epidemiological evidence. This study presents an AOP\u2013IVIVE integration strategy that advances mechanism-informed and human-relevant risk assessment, providing scientific evidence to support regulatory decision-making.<\/jats:p>","DOI":"10.1021\/acs.est.6c01142","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T16:26:09Z","timestamp":1784132769000},"page":"20226-20241","source":"Crossref","is-referenced-by-count":0,"title":["Integrating\nAdverse Outcome Pathways with\n                    <i>In Vitro<\/i>\n                    -to-\n                    <i>In Vivo<\/i>\n                    Extrapolation for Risk\nAssessment: A Case Study of Cadmium-Induced Bone Toxicity"],"prefix":"10.1021","volume":"60","author":[{"given":"Fei-Fei","family":"Xu","sequence":"first","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yi","family":"Li","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Yin","family":"Li","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Fen","family":"Mo","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yu","family":"Wan","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Ru","family":"Li","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6611-6925","authenticated-orcid":true,"given":"Wei-Liang","family":"Wu","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Song","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. China, 510515"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5806-4507","authenticated-orcid":true,"given":"Xing-Fen","family":"Yang","sequence":"additional","affiliation":[{"name":"Southern Medical University , , ,","place":["Guangzhou, P. R. 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