{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T12:31:01Z","timestamp":1781613061008,"version":"3.54.5"},"reference-count":48,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T00:00:00Z","timestamp":1652054400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/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"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The developmental toxicity potential (dTP) concentration from the devTOX <jats:italic>quick<\/jats:italic>Predict (devTOX<jats:sup><jats:italic>qP<\/jats:italic><\/jats:sup>) assay, a metabolomics\u2010based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOX<jats:sup><jats:italic>qP<\/jats:italic><\/jats:sup> assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>VPA and a series of structural analogues were tested with the devTOX<jats:sup><jats:italic>qP<\/jats:italic><\/jats:sup> assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations. The EADs were compared to the LELs in rat developmental toxicity studies, human clinical doses, and EADs reported using other in vitro assays. To evaluate the impact of different pharmacokinetic (PK) models on IVIVE outcomes, we compared EADs predicted using various open\u2010source and commercially available PK and physiologically based PK (PBPK) models. To evaluate the effect of in vitro kinetics, an equilibrium distribution model was applied to translate dTP concentrations to free medium concentrations before subsequent IVIVE analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The EAD estimates for the VPA analogues based on different PK\/PBPK models were quantitatively similar to in vivo data from both rats and humans, where available, and the derived rank order of the chemicals was consistent with observed in vivo developmental toxicity. Different models were identified that provided accurate predictions for rat prenatal LELs and conservative estimates of human safe exposure. The impact of in vitro kinetics on EAD estimates is chemical\u2010dependent. EADs from this study were within range of predicted doses from other in vitro and model organism data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study highlights the importance of pharmacokinetic considerations when using in vitro assays and demonstrates the utility of the devTOX<jats:sup><jats:italic>qP<\/jats:italic><\/jats:sup> human stem cell\u2010based platform to quantitatively assess a chemical's developmental toxicity potency.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2019","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T15:29:23Z","timestamp":1652110163000},"page":"1037-1055","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues"],"prefix":"10.1002","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0752-1848","authenticated-orcid":false,"given":"Xiaoqing","family":"Chang","sequence":"first","affiliation":[{"name":"Inotiv\u2010RTP  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7373-4118","authenticated-orcid":false,"given":"Jessica","family":"Palmer","sequence":"additional","affiliation":[{"name":"Stemina Biomarker Discovery, Inc.  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9939-4035","authenticated-orcid":false,"given":"Annie","family":"Lumen","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research U.S. Food and Drug Administration  Jefferson Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6097-6414","authenticated-orcid":false,"given":"Un Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research U.S. Food and Drug Administration  Jefferson Arkansas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5167-9928","authenticated-orcid":false,"given":"Patricia","family":"Ceger","sequence":"additional","affiliation":[{"name":"Inotiv\u2010RTP  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6426-8036","authenticated-orcid":false,"given":"Kamel","family":"Mansouri","sequence":"additional","affiliation":[{"name":"National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods National Institute of Environmental Health Sciences  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9436-5673","authenticated-orcid":false,"given":"Catherine","family":"Sprankle","sequence":"additional","affiliation":[{"name":"Inotiv\u2010RTP  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Donley","sequence":"additional","affiliation":[{"name":"Stemina Biomarker Discovery, Inc.  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5754-6085","authenticated-orcid":false,"given":"Shannon","family":"Bell","sequence":"additional","affiliation":[{"name":"Inotiv\u2010RTP  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Knudsen","sequence":"additional","affiliation":[{"name":"Center for Computational Toxicology and Exposure Environmental Protection Agency  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4024-534X","authenticated-orcid":false,"given":"John","family":"Wambaugh","sequence":"additional","affiliation":[{"name":"Center for Computational Toxicology and Exposure Environmental Protection Agency  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2279-8485","authenticated-orcid":false,"given":"Bethany","family":"Cook","sequence":"additional","affiliation":[{"name":"Inotiv\u2010RTP  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8575-9547","authenticated-orcid":false,"given":"David","family":"Allen","sequence":"additional","affiliation":[{"name":"Inotiv\u2010RTP  Morrisville North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7914-3682","authenticated-orcid":false,"given":"Nicole","family":"Kleinstreuer","sequence":"additional","affiliation":[{"name":"National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods National Institute of Environmental Health Sciences  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.comtox.2021.100184"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0378-4274(02)00375-2"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/es501955g"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2017.11.016"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0272-0590(88)90112-1"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1289\/EHP1655"},{"key":"e_1_2_10_8_1","unstructured":"CDC.2020.Data & statistics on birth defects | CDC. Centers for Disease Control and Prevention. January 23 2020.https:\/\/www.cdc.gov\/ncbddd\/birthdefects\/data.html"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm4004285"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03261.x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2015.04.009"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx0502241"},{"key":"e_1_2_10_13_1","unstructured":"Elsevier Amsterdam Netherlands.2021.PharmaPendium.2021.https:\/\/www.pharmapendium.com\/"},{"key":"e_1_2_10_14_1","unstructured":"EU\u2010ToxRisk.2020.EU\u2010ToxRisk. 2020.https:\/\/www.eu-toxrisk.eu\/"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2013.08.012"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(90)90007-e"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/20.2.199"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41370-018-0046-9"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1975"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.41"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0215906"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2011.08.025"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420350319"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199120060-00001"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfy174"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-018-0263-1"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/faat.1994.1029"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1991.tb01303.x"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0272-0590(86)90180-6"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(81)90541-5"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-016-0148-0"},{"key":"e_1_2_10_32_1","unstructured":"OECD.2020.ENVIRONMENT DIRECTORATE JOINT MEETING OF THE CHEMICALS COMMITTEE AND THE WORKING PARTY ON CHEMICALS PESTICIDES AND BIOTECHNOLOGY Case Study on the Use of Integrated Approaches to Testing and Assessment for READ\u2010ACROSS BASED FILLING OF DEVELOPMENTAL TOXICITY DATA GAP FOR METHYL HEXANOIC ACID. Series on Testing and Assessment No. 325.https:\/\/www.oecd.org\/officialdocuments\/publicdisplaydocumentpdf\/?cote=ENV%2fJM%2fMONO(2020)21&docLanguage=en&msclkid=cce48a99a62111ecb8a11d0da24f83ae"},{"key":"e_1_2_10_33_1","unstructured":"OECD.2021.Guidance Document on the Characterisation Validation and Reporting of Physiologically Based Kinetic (PBK) Models for Regulatory Purposes. Series on Testing and Assessment No. 331.https:\/\/www.oecd.org\/chemicalsafety\/risk-assessment\/guidance-document-on-the-characterisation-validation-and-reporting-of-physiologically-based-kinetic-models-for-regulatory-purposes.pdf"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2009.02.014"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2017.07.011"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.21078"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v079.i04"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/0272-0590(92)90088-Y"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.0c00264"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2007.09.010"},{"key":"e_1_2_10_41_1","unstructured":"Sfeir M.(2020). Evaluation of a rapid multi\u2010chemical human gestational physiologically based toxicokinetic model (conference abstract). Conference abstract presented at the Society of Toxicology 59th Annual Meeting 2939 March 14.https:\/\/eventpilotadmin.com\/web\/page.php?page=IntHtml&amp;project=SOT20&amp;id=688"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2010.07.007"},{"key":"e_1_2_10_43_1","unstructured":"Simulations Plus Inc.2020.GastroPlus Software.http:\/\/www.simulations-plus.com"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12316"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.117-a440"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/ci00057a005"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfr254"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1080\/00984109708984072"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaa014"}],"container-title":["Birth Defects Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdr2.2019","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bdr2.2019","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdr2.2019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T22:06:43Z","timestamp":1692655603000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdr2.2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,9]]},"references-count":48,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.1002\/bdr2.2019"],"URL":"https:\/\/doi.org\/10.1002\/bdr2.2019","archive":["Portico"],"relation":{},"ISSN":["2472-1727","2472-1727"],"issn-type":[{"value":"2472-1727","type":"print"},{"value":"2472-1727","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,9]]},"assertion":[{"value":"2022-02-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}