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However, to facilitate the shift in reliance on apical effects for risk assessment to predictive surrogate metrics having characterized linkages to chemical mechanisms of action, targeted in vivo testing is necessary to establish these predictive relationships. In this study, we demonstrate a means to predict thyroid-related metamorphic success in the model amphibian Xenopus laevis using relevant biochemical measurements during early prometamorphosis. The adverse outcome pathway for thyroperoxidase inhibition leading to altered amphibian metamorphosis was used to inform a pathway-based in vivo study design that generated response-response relationships. These causal relationships were used to develop Bayesian probabilistic network models that mathematically determine conditional dependencies between biochemical nodes and support the predictive capability of the biochemical profiles. Plasma thyroxine concentrations were the most predictive of metamorphic success with improved predictivity when thyroid gland sodium-iodide symporter gene expression levels (a compensatory response) were used in conjunction with plasma thyroxine as an additional regressor. Although thyroid-mediated amphibian metamorphosis has been studied for decades, this is the first time a predictive relationship has been characterized between plasma thyroxine and metamorphic success. Linking these types of biochemical surrogate metrics to apical outcomes is vital to facilitate the transition to the new paradigm of chemical safety assessments.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa036","type":"journal-article","created":{"date-parts":[[2020,3,12]],"date-time":"2020-03-12T20:32:03Z","timestamp":1584045123000},"page":"236-250","source":"Crossref","is-referenced-by-count":18,"title":["Targeted Pathway-based<i>In Vivo<\/i>Testing Using Thyroperoxidase Inhibition to Evaluate Plasma Thyroxine as a Surrogate Metric of Metamorphic Success in Model Amphibian<i>Xenopus laevis<\/i>"],"prefix":"10.1093","volume":"175","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9006-7625","authenticated-orcid":false,"given":"Jonathan T","family":"Haselman","sequence":"first","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7877-4773","authenticated-orcid":false,"given":"Jennifer H","family":"Olker","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A","family":"Kosian","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J","family":"Korte","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A","family":"Swintek","sequence":"additional","affiliation":[{"name":"Badger Technical Services, Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey S","family":"Denny","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W","family":"Nichols","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph E","family":"Tietge","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-0256","authenticated-orcid":false,"given":"Michael W","family":"Hornung","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigmund J","family":"Degitz","sequence":"additional","affiliation":[{"name":"Great Lakes Toxicology and Ecology Division, U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Duluth, Minnesota 55804"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,3,16]]},"reference":[{"key":"2021031600092814800_kfaa036-B1","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","article-title":"A new look at the statistical model identification","volume":"19","author":"Akaike","year":"1974","journal-title":"IEEE Trans. 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