{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T05:08:42Z","timestamp":1792559322719,"version":"4.5.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K25ES030402"],"award-info":[{"award-number":["K25ES030402"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A main function of dose-response assessment is to estimate a \u201csafe\u201d dose in the target population to support chemical risk assessment. Typically, a \u201csafe\u201d dose is developed differently for cancer and noncancer effects based on a 2-step procedure, ie, point of departure (POD) derivation and low-dose extrapolation. However, the current dose-response assessment framework is criticized for its dichotomized strategy without integrating the mode of action (MOA) information. The objective of this study was, based on our previous work, to develop a MOA-based probabilistic dose-response framework that quantitatively synthesizes a biological pathway in a dose-response modeling process to estimate the risk of chemicals that have carcinogenic potential. 3,3\u2032,4,4\u2032,5-Pentachlorobiphenyl (PCB-126) was exemplified to demonstrate our proposed approach. There were 4 major steps in the new modeling framework, including (1) key quantifiable events (KQEs) identification and extraction, (2) essential dose calculation, (3) MOA-based POD derivation, and (4) MOA-based probabilistic reference dose (RfD) estimation. Compared with reported PODs and traditional RfDs, the MOA-based estimates derived from our approach were comparable and plausible. One key feature of our approach was the use of overall MOA information to build the dose-response relationship on the entire dose continuum including the low-dose region. On the other hand, by adjusting uncertainty and variability in a probabilistic manner, the MOA-based probabilistic RfDs can provide useful insights of health protection for the specific proportion of population. Moreover, the proposed framework had important potential to be generalized to assess different types of chemicals other than nonmutagenic carcinogens, highlighting its utility to improve current chemical risk assessment.<\/jats:p>","DOI":"10.1093\/toxsci\/kfad091","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T22:54:48Z","timestamp":1693349688000},"page":"250-260","source":"Crossref","is-referenced-by-count":2,"title":["A mode of action-based probabilistic framework of dose-response assessment for nonmutagenic liver carcinogens: a case study of PCB-126"],"prefix":"10.1093","volume":"196","author":[{"given":"Yun","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health\u2014Bloomington, Indiana University , Bloomington, Indiana 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiran","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida , Gainesville, Florida 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E","family":"Klaunig","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health\u2014Bloomington, Indiana University , Bloomington, Indiana 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health\u2014Bloomington, Indiana University , Bloomington, Indiana 47405, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"2023112810361221100_kfad091-B1","volume-title":"Toxicological Profile for Chlorinated Dibenzo-p-Dioxins (CDDs)","author":"ATSDR","year":"1998"},{"key":"2023112810361221100_kfad091-B2","volume-title":"Toxicological Profile for Polychlorinated Biphenyls (PCBs)","author":"ATSDR","year":"2000"},{"key":"2023112810361221100_kfad091-B3","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.yrtph.2015.06.015","article-title":"The adverse outcome pathway for rodent liver tumor promotion by sustained activation of the aryl hydrocarbon receptor","volume":"73","author":"Becker","year":"2015","journal-title":"Regul. 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