{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T14:35:56Z","timestamp":1786631756767,"version":"build-2736575974"},"reference-count":22,"publisher":"American Chemical Society (ACS)","issue":"5","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":1417,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, interindividual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.<\/jats:p>\n                  <jats:p>Objectives: We evaluated the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study.<\/jats:p>\n                  <jats:p>Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and 1 hybrid mouse strains to calibrate and extend existing physiologically based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). We used a Bayesian population analysis of interstrain variability to quantify variability in TCE metabolism.<\/jats:p>\n                  <jats:p>Results: Concentration\u2013time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation were less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production were less variable (2-fold range) than DCA production (5-fold range), although the uncertainty bounds for DCA exceeded the predicted variability.<\/jats:p>\n                  <jats:p>Conclusions: Population PBPK modeling of genetically diverse mouse strains can provide useful quantitative estimates of toxicokinetic population variability. When extrapolated to lower doses more relevant to environmental exposures, mouse population-derived variability estimates for TCE metabolism closely matched population variability estimates previously derived from human toxicokinetic studies with TCE, highlighting the utility of mouse interstrain metabolism studies for addressing toxicokinetic variability.<\/jats:p>\n                  <jats:p>Citation: Chiu WA, Campbell JL Jr, Clewell HJ III, Zhou YH, Wright FA, Guyton KZ, Rusyn I. 2014. Physiologically based pharmacokinetic (PBPK) modeling of interstrain variability in trichloroethylene metabolism in the mouse. Environ Health Perspect 122:456\u2013463;\u2002http:\/\/dx.doi.org\/10.1289\/ehp.1307623<\/jats:p>","DOI":"10.1289\/ehp.1307623","type":"journal-article","created":{"date-parts":[[2014,2,11]],"date-time":"2014-02-11T12:14:06Z","timestamp":1392120846000},"page":"456-463","source":"Crossref","is-referenced-by-count":41,"title":["Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse"],"prefix":"10.1021","volume":"122","author":[{"given":"Weihsueh A.","family":"Chiu","sequence":"first","affiliation":[{"name":"National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Jerry L.","family":"Campbell","sequence":"additional","affiliation":[{"name":"The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Harvey J.","family":"Clewell","sequence":"additional","affiliation":[{"name":"The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Statistics and Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred A.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Statistics and Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn Z.","family":"Guyton","sequence":"additional","affiliation":[{"name":"National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,2,11]]},"reference":[{"issue":"suppl 2","key":"2026080603014695500_micit1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1289\/ehp.00108s2307","article-title":"Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.","volume":"108","author":"Bois","year":"2000","journal-title":"Environ Health Perspect"},{"issue":"1","key":"2026080603014695500_micit2","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1093\/toxsci\/kfq362","article-title":"Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice.","volume":"120","author":"Bradford","year":"2011","journal-title":"Toxicol Sci"},{"key":"2026080603014695500_micit3","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1289\/ehp.1205879","article-title":"Human health effects of trichloroethylene: key findings and scientific issues.","volume":"121","author":"Chiu","year":"2013","journal-title":"Environ Health Perspect"},{"issue":"1","key":"2026080603014695500_micit4","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.taap.2009.07.032","article-title":"Characterizing uncertainty and population variability in the toxicokinetics of 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model of trichloroethylene and its metabolites.","volume":"46","author":"Hack","year":"2006","journal-title":"Regul Toxicol Pharmacol"},{"key":"2026080603014695500_micit10","article-title":"Empirically observed distributions of pharmacokinetic and pharmacodynamic variability in humans-Implications for the derivation of single point component uncertainty factors providing equivalent protection as existing RfDs","author":"Hattis D, Lynch MK.","year":"2007"},{"issue":"3","key":"2026080603014695500_micit11","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.tox.2009.06.013","article-title":"Liquid chromatography electrospray ionization tandem mass spectrometry analysis method for simultaneous detection of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and 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Washington, DC:U.S. EPA.Available: http:\/\/www.epa.gov\/iris\/toxreviews\/0199tr\/0199tr.pdf [accessed: 13 March 2014]."},{"issue":"2","key":"2026080603014695500_micit21","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/toxsci\/kft012","article-title":"Relative impact of incorporating pharmacokinetics on predicting in vivo hazard and mode of action from high-throughput in vitro toxicity assays.","volume":"132","author":"Wetmore","year":"2013","journal-title":"Toxicol Sci"},{"key":"2026080603014695500_micit22","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1289\/ehp.1205687","article-title":"Addressing human variability in next-generation human health risk assessments of environmental chemicals.","volume":"121","author":"Zeise","year":"2013","journal-title":"Environ Health Perspect"}],"container-title":["Environmental Health Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/122\/5\/456\/66429177\/ehp.1307623.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/122\/5\/456\/66429177\/ehp.1307623.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:47:18Z","timestamp":1786628838000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-lookup\/doi\/10.1289\/ehp.1307623"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,11]]},"references-count":22,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2014,2,11]]},"published-print":{"date-parts":[[2014,5,1]]}},"URL":"https:\/\/doi.org\/10.1289\/ehp.1307623","relation":{},"ISSN":["0091-6765","1552-9924"],"issn-type":[{"value":"0091-6765","type":"print"},{"value":"1552-9924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,11]]}}}