2020
Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids
Mallick P, Song G, Efremenko A, Pendse S, Creek M, Osimitz T, Hines R, Hinderliter P, Clewell H, Lake B, Yoon M, Moreau M. Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids. Toxicological Sciences 2020, 176: 460-469. PMID: 32421774, PMCID: PMC7416317, DOI: 10.1093/toxsci/kfaa070.Peer-Reviewed Original ResearchConceptsAge-related pharmacokinetic differencesPharmacokinetic differencesPBPK modelTarget tissue exposureAge-related sensitivityHuman PBPK modelAge-dependent changesAge-related differencesRat modelTissue exposureVivo rat dataPharmacokinetic modellingPharmacokinetic modelingInternal exposureRat dataRisk assessmentVivo extrapolationRisk assessment purposesExposureAdultsExternal exposureSensitive populationsChildrenMetabolic capacityAssessment
2019
Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans
Mallick P, Moreau M, Song G, Efremenko A, Pendse S, Creek M, Osimitz T, Hines R, Hinderliter P, Clewell H, Lake B, Yoon M. Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans. Toxicological Sciences 2019, 173: 86-99. PMID: 31593217, PMCID: PMC6944222, DOI: 10.1093/toxsci/kfz211.Peer-Reviewed Original ResearchConceptsTarget tissue exposureTissue exposurePharmacokinetic modelLiver blood flowLow internal exposureAge-related sensitivityAge-dependent changesEfficient metabolic clearanceIndividual cytochrome P450Human hepatic metabolismAge-related differencesCis-permethrinHepatic metabolismBlood flowMetabolic clearanceCES enzymesHepatic CLintInternal doseIntrinsic clearanceTarget tissuesInternal exposureClearanceCarboxylesterase enzymesCytochrome P450Vivo extrapolationA Time-Embedding Network Models the Ontogeny of 23 Hepatic Drug Metabolizing Enzymes
Matlock M, Tambe A, Elliott-Higgins J, Hines R, Miller G, Swamidass S. A Time-Embedding Network Models the Ontogeny of 23 Hepatic Drug Metabolizing Enzymes. Chemical Research In Toxicology 2019, 32: 1707-1721. PMID: 31304741, PMCID: PMC6933754, DOI: 10.1021/acs.chemrestox.9b00223.Peer-Reviewed Original ResearchConceptsAge-dependent changesHepatic Drug Metabolizing EnzymesAdverse drug reactionsValproic acid toxicityDrug metabolizing enzymesDrug metabolism enzymesElimination of drugsPediatric patientsPediatric populationMetabolite exposureDrug reactionsClinical dataElevated riskOverall clearanceDrug toxicityFunction of ageDrug safetyFetal periodMetabolizing enzymesDrug metabolismDrug toxicity risksPotential mechanismsAcid toxicityEnzyme expressionDemographic factorsDevelopmental Expression of the Cytosolic Sulfotransferases in Human Liver
Dubaisi S, Caruso J, Gaedigk R, Vyhlidal C, Smith P, Hines R, Kocarek T, Runge-Morris M. Developmental Expression of the Cytosolic Sulfotransferases in Human Liver. Drug Metabolism And Disposition 2019, 47: dmd.119.086363. PMID: 30885913, PMCID: PMC6505379, DOI: 10.1124/dmd.119.086363.Peer-Reviewed Original ResearchConceptsMRNA levelsLiver specimensHuman liverReverse transcription-quantitative polymerase chain reactionTranscription-quantitative polymerase chain reactionProtein levelsRT-qPCR analysisHuman liver cytosolHuman liver samplesQuantitative polymerase chain reactionCytosolic sulfotransferasesRNA sequencingHepatic sulfotransferasesPolymerase chain reactionDrug eliminationPredominant organInfant liverLiverLiver samplesChain reactionLiver cytosolForeign chemicalsImportant metabolic roleInfantsAdditional findings
2018
The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM)
Kenyon E, Lipscomb J, Pegram R, George B, Hines R. The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM). Toxicological Sciences 2018, 167: 347-359. PMID: 30252107, PMCID: PMC10448349, DOI: 10.1093/toxsci/kfy236.Peer-Reviewed Original ResearchConceptsPharmacokinetic outcomesPK outcomesYounger age groupsDose-response studyBDCM concentrationsLarge inter-individual differencesPediatric populationLiver massBody weightAge groupsMicrosomal contentOral exposure routePharmacokinetic modelDose metricsDrink of waterEnzyme ontogenyOutcome variationEarly childhoodAdult findingsInter-individual differencesOutcomesNeonatesExposure routes
2017
Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages
Song G, Sun X, Hines R, McCarver D, Lake B, Osimitz T, Creek M, Clewell H, Yoon M. Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages. Drug Metabolism And Disposition 2017, 45: dmd.116.074583. PMID: 28228413, DOI: 10.1124/dmd.116.074583.Peer-Reviewed Original ResearchConceptsCYP2C8 expressionOntogeny dataMonths postnatal ageProtein levelsLiver microsomal samplesAge-dependent expressionMultiple cytochrome P450Weeks' gestationPostnatal agePostnatal dayYoung infantsPostnatal samplesFetal samplesMicrosomal samplesCYP1A2 expressionQuantitative Western blottingPyrethroid metabolismCYP2C8Western blottingHealth risk assessmentHuman health risk assessmentRisk assessmentAgeCarboxylesterase enzymesCytochrome P450
2016
FutureTox III: Bridges for Translation
Juberg D, Knudsen T, Sander M, Beck N, Faustman E, Mendrick D, Fowle J, Hartung T, Tice R, Lemazurier E, Becker R, Fitzpatrick S, Daston G, Harrill A, Hines R, Keller D, Lipscomb J, Watson D, Bahadori T, Crofton K. FutureTox III: Bridges for Translation. Toxicological Sciences 2016, 155: 22-31. PMID: 27780885, PMCID: PMC6080854, DOI: 10.1093/toxsci/kfw194.Peer-Reviewed Original ResearchIntegration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards
El-Masri H, Kleinstreuer N, Hines R, Adams L, Tal T, Isaacs K, Wetmore B, Tan Y. Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards. Toxicological Sciences 2016, 152: 230-243. PMID: 27208077, PMCID: PMC5009469, DOI: 10.1093/toxsci/kfw082.Peer-Reviewed Original ResearchConceptsPutative adverse outcome pathwayExposure levelsPharmacokinetic modelAdverse outcome pathwaysPotential exposure levelsFetal blood levelsExternal exposure levelsMaternal exposureBlood levelsExposure modelHigh-throughput toxicity screeningVasculogenesis/angiogenesisOutcome pathwaysPBPK modelExposure estimatesChemical dispositionDevelopmental toxicityPotential exposureVivo extrapolationExposureAdulthood stagesToxicityAssaysEnvironmental exposure modelsPregnancyExpression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver
Thomson M, Hines R, Schuetz E, Meibohm B. Expression Patterns of Organic Anion Transporting Polypeptides 1B1 and 1B3 Protein in Human Pediatric Liver. Drug Metabolism And Disposition 2016, 44: 999-1004. PMID: 27098745, PMCID: PMC4931892, DOI: 10.1124/dmd.115.069252.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAgingChildChild, PreschoolFemaleGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicGlycosylationHumansInfantInfant, NewbornLiver-Specific Organic Anion Transporter 1MaleProtein Processing, Post-TranslationalSolute Carrier Organic Anion Transporter Family Member 1B3ConceptsYears of ageOrganic anion transporting polypeptide (OATP) 1B1Relative protein expressionAge groupsProtein expressionDrug disposition pathwaysMonths of ageDrug-metabolizing enzymesHigh interindividual variabilityStudied age groupsPolypeptide 1B1Appropriate pharmacotherapyPediatric liverChildren 6Children 2Liver specimensInterindividual variabilityFirst monthDrug transportersWestern blottingDisposition pathwaysPreadolescent periodHigh expressionAge rangeMonthsRole of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny
Giebel N, Shadley J, McCarver D, Dorko K, Gramignoli R, Strom S, Yan K, Simpson P, Hines R. Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny. Drug Metabolism And Disposition 2016, 44: 1027-1037. PMID: 26921389, PMCID: PMC4931893, DOI: 10.1124/dmd.116.069344.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsAgedAged, 80 and overBinding SitesChildChild, PreschoolChromatinChromatin Assembly and DisassemblyCytochrome P-450 CYP3AGene Expression Regulation, DevelopmentalGene Expression Regulation, EnzymologicGestational AgeHepatocytesHistonesHumansInfantLiverMiddle AgedNucleic Acid ConformationPromoter Regions, GeneticProtein ConformationStructure-Activity RelationshipTranscription, GeneticAge-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny
Hines R, Simpson P, McCarver D. Age-Dependent Human Hepatic Carboxylesterase 1 (CES1) and Carboxylesterase 2 (CES2) Postnatal Ontogeny. Drug Metabolism And Disposition 2016, 44: 959-966. PMID: 26825642, DOI: 10.1124/dmd.115.068957.Peer-Reviewed Original ResearchConceptsHepatic carboxylesterase 1Weeks of ageCarboxylesterase 1CES2 expressionAge groupsYounger age groupsCES1 expressionLiver diseaseAdverse outcomesMetabolic clearancePmol/Older groupOlder individualsWestern blottingLiver samplesWeeksEnvironmental chemicalsPostnatal ontogenyMicrosomal proteinMedian valueAgeCytosolic fractionGroupExpressionSubjects
2015
Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression
McCullough S, Bowers E, On D, Morgan D, Dailey L, Hines R, Devlin R, Diaz-Sanchez D. Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression. Toxicological Sciences 2015, 150: 216-224. PMID: 26719369, PMCID: PMC4838038, DOI: 10.1093/toxsci/kfv324.Peer-Reviewed Original ResearchConceptsChromatin modificationsH3 lysine 4 trimethylationSpecific chromatin modificationsChromatin modification statesLysine 4 trimethylationUnmodified H3Human bronchial epithelial cellsModification statesTotal H3H3K27 acetylationCellular signalsGene inductionPrimary human bronchial epithelial cellsKey regulatorGene expressionEpigenetic markersBronchial epithelial cellsTraditional toxicological paradigmModification levelsRelative abundanceAir-liquid interface modelTrimethylationEpithelial cellsH3Specific modificationsOxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells
Rudraiah S, Gu X, Hines R, Manautou J. Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells. Toxicology In Vitro 2015, 31: 54-59. PMID: 26616280, PMCID: PMC4695222, DOI: 10.1016/j.tiv.2015.11.016.Peer-Reviewed Original ResearchConceptsGene expressionFlavin-containing monooxygenasesStress-responsive transcription factor Nrf2Stress transcription factorsCytosolic regulatory proteinsHepG2 cellsPromoter-luciferase reporter constructsNrf2 target gene expressionGene regulation studiesCo-transfection studiesTarget gene expressionReporter gene activityHeme oxygenase-1Transcription factor Nrf2Luciferase reporter constructsTranscriptional regulationGene regulationKelch-like ECHGene activityTranscription factorsRegulatory proteinsRegulatory pathwaysReporter constructsExpression vectorRegulation studiesOntogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin
Sethi P, White C, Cummings B, Hines R, Muralidhara S, Bruckner J. Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin. Pediatric Research 2015, 79: 409-415. PMID: 26571224, DOI: 10.1038/pr.2015.237.Peer-Reviewed Original ResearchConceptsTotal proteinBinding of diazepamUnbound diazepamAlbumin levelsStandard dosesPlasma levelsDrugs/chemicalsPediatric databasePlasma bindingAge groupsMaturational changesAdult levelsCyclosporineDiazepamPlasma albuminThree- to fourfoldPlasma samplesFree drugNeonatesPlasma proteinsPyrethroid insecticidesAge bracketDrugsAlbuminRiskUse of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting
Doe J, Lander D, Doerrer N, Heard N, Hines R, Lowit A, Pastoor T, Phillips R, Sargent D, Sherman J, Tanir J, Embry M. Use of the RISK21 roadmap and matrix: human health risk assessment of the use of a pyrethroid in bed netting. Critical Reviews In Toxicology 2015, 46: 54-73. PMID: 26517449, PMCID: PMC4732465, DOI: 10.3109/10408444.2015.1082974.Peer-Reviewed Original ResearchCurrent Research and Opportunities to Address Environmental Asbestos Exposures
Carlin D, Larson T, Pfau J, Gavett S, Shukla A, Miller A, Hines R. Current Research and Opportunities to Address Environmental Asbestos Exposures. Environmental Health Perspectives 2015, 123: a194-a197. PMID: 26230287, PMCID: PMC4529018, DOI: 10.1289/ehp.1409662.Peer-Reviewed Original ResearchConceptsEnvironmental asbestos exposureAsbestos exposureAsbestos-related diseasesHealth effectsRisk factorsOccupational exposureBasic research findingsDisease RegistryEnvironmental Health SciencesToxicological findingsTumor developmentSociety of ToxicologyHazardous exposuresPotential health risksDose metricsNational InstituteSusceptible populationPublic healthHigh rateAsbestosHealth risksDiseaseExposureProper dose metricToxicity
2014
Human Hepatic UGT2B15 Developmental Expression
Divakaran K, Hines R, McCarver D. Human Hepatic UGT2B15 Developmental Expression. Toxicological Sciences 2014, 141: 292-299. PMID: 24980262, PMCID: PMC4271124, DOI: 10.1093/toxsci/kfu126.Peer-Reviewed Original ResearchConceptsUGT2B15 expressionAge groupsHuman hepatic microsomesLate fetal lifeFunctional single nucleotide polymorphismsFetal contentMale genderFetal lifeLate gestationPostnatal samplesLower clearanceOlder individualsWeeks ageHepatic microsomesProtein expressionSingle nucleotide polymorphismsLatter groupImportant drugsMature valuesBisphenol ADevelopmental expressionExpression changesNucleotide polymorphismsGreater rateGroupA 21st century roadmap for human health risk assessment
Pastoor T, Bachman A, Bell D, Cohen S, Dellarco M, Dewhurst I, Doe J, Doerrer N, Embry M, Hines R, Moretto A, Phillips R, Rowlands J, Tanir J, Wolf D, Boobis A. A 21st century roadmap for human health risk assessment. Critical Reviews In Toxicology 2014, 44: 1-5. PMID: 25070413, DOI: 10.3109/10408444.2014.931923.Peer-Reviewed Original ResearchRisk assessment in the 21st century: Roadmap and matrix
Embry M, Bachman A, Bell D, Boobis A, Cohen S, Dellarco M, Dewhurst I, Doerrer N, Hines R, Moretto A, Pastoor T, Phillips R, Rowlands J, Tanir J, Wolf D, Doe J. Risk assessment in the 21st century: Roadmap and matrix. Critical Reviews In Toxicology 2014, 44: 6-16. PMID: 25070414, DOI: 10.3109/10408444.2014.931924.Peer-Reviewed Original Research
2013
Toll-like receptor genetic variants are associated with Gram-negative infections in VLBW infants
Sampath V, Mulrooney N, Garland J, He J, Patel A, Cohen J, Simpson P, Hines R. Toll-like receptor genetic variants are associated with Gram-negative infections in VLBW infants. Journal Of Perinatology 2013, 33: 772-777. PMID: 23867959, PMCID: PMC4465440, DOI: 10.1038/jp.2013.80.Peer-Reviewed Original ResearchMeSH KeywordsBlack or African AmericanFemaleGenetic Predisposition to DiseaseGenetic VariationGram-Negative Bacterial InfectionsHumansImmunity, InnateInfant, NewbornInfant, PrematureInfant, Premature, DiseasesInfant, Very Low Birth WeightInterleukin-1 Receptor-Associated KinasesLeukocyte CountLogistic ModelsMalePolymorphism, Single NucleotideRisk FactorsToll-Like Receptor 4Toll-Like Receptor 5Toll-Like ReceptorsWhite PeopleConceptsWhite blood cellsToll-like receptorsGram-negative infectionsVLBW infantsBacterial infectionsSingle nucleotide polymorphismsLow birth weight infantsTLR single nucleotide polymorphismsBirth weight infantsElevated WBC countGenetic variantsWeight infantsMulticenter studyTLR4 variantsWBC countFemale infantImmune responseInfantsInfection rateInfectionAlters susceptibilityBlood cellsRegression modelsConfoundersCohort