BIOMARKERS IN TOXICOLOGY BIOMARKERS IN TOXICOLOGY Edited by R C. G , DVM, MVS , P D, DABT, FACT, FACN, FATS AMESH UPTA C H ProfessorandHead,ToxicologyDepartment BreathittVeterinaryCenter MurrayStateUniversity Hopkinsville,Kentucky USA AMSTERDAM(cid:1)BOSTON(cid:1)HEIDELBERG(cid:1)LONDON NEWYORK(cid:1)OXFORD(cid:1)PARIS(cid:1)SANDIEGO SANFRANCISCO(cid:1)SINGAPORE(cid:1)SYDNEY(cid:1)TOKYO AcademicPressisanimprintofElsevier AcademicPressisanimprintofElsevier 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 32JamestownRoad,LondonNW17BY,UK 225WymanStreet,Waltham,MA02451,USA Copyrightr2014ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformor byanymeanselectronic,mechanical,photocopying,recordingorotherwisewithoutthepriorwritten permissionofthepublisher. PermissionsmaybesoughtdirectlyfromElsevier’sScience&TechnologyRightsDepartmentinOxford, UK:phone(144)(0)1865843830;fax(144)(0)1865853333;email:[email protected], visittheScienceandTechnologyBookswebsiteatwww.elsevierdirect.com/rightsforfurtherinformation. Notice Noresponsibilityisassumedbythepublisherforanyinjuryand/ordamagetopersonsorpropertyasa matterofproductsliability,negligenceorotherwise,orfromanyuseoroperationofanymethods,products, instructionsorideascontainedinthematerialherein.Becauseofrapidadvancesinthemedicalsciences, inparticular,independentverificationofdiagnosesanddrugdosagesshouldbemade. BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-404630-6 ForinformationonallAcademicPresspublications visitourwebsiteatelsevierdirect.com TypesetbyMPSLimited,Chennai,India www.adi-mps.com PrintedandboundintheUnitedStatesofAmerica 14 15 16 17 18 10 9 8 7 6 5 4 3 2 1 This book is dedicated to my daughter Rekha, wife Denise, and parents the late Chandra and Triveni Gupta. Foreword Merriam-Webster defines a biomarker as a distinctive toxicology and are also widely used in regulation of biologicalor biologicallyderivedindicator (asametab- chemicalsinanimaland,lesscommonly,humanexperi- olite) of a process, event, or condition (as, for example, mental studies. Toxicological biomarkers are also used aging, disease, or oil formation). The subject of the in allied disciplines (cid:1) for example epidemiology (cid:1) and present book is biomarkers in toxicology, but it should maybeusedtoestimatepopulationloadsofexposure. be remembered that biomarkers include substances In toxicology, biomarkers are often divided into used in the detection of numerous diseases, including biomarkers of exposure, of effect, and of susceptibility the autoimmune diseases, which are not generally and all of these are dealt with in this extremely wide- thoughtofastoxicologicalinorigin. ranging book. The book has an initial introductory sec- The earliest biomarkers of toxicological exposure date tion, including discussion of rodent, minipig, primate, from a time before precise analytical techniques were zebrafish, Caenorhabditis elegans, and alternative animal available and include the Kayser-Fleischer ring, usually models for toxicological testing and biomarkers and indicative of copper accumulation in the cornea in cases pharmacokinetics, PBPK modeling, and toxicological of Wilson’s disease, as well as lead lines in the gums biomarkers. Part II, Systems Toxicity Biomarkers, com- associatedwithleadtoxicity.Thecherry-redcolornoted prises chapters on biomarkers of toxicity in relation to as a (rather unreliable) clinical sign in carbon monoxide all important organs and organ systems. Part III deals poisoningmayalsobedescribedasabiomarker. with biomarkers in relation to the toxicity of specific One of the earliest biomarkers relying on biochemi- groups of compounds, and includes chapters on pesti- cal analytical techniques was cholinesterase, initially cides, as well as polychlorinated biphenyls (PCBs), whole blood cholinesterase and later plasma pseudo- polybrominated biphenyls (PBBs), and brominated cholinesterase (butyrylcholinesterase) and red blood flame retardants, polycyclicaromatic hydrocarbons cell acetylcholinesterase. Cholinesterase measurements (PAHs), bisphenol A, melamine, metals, chemical and were introduced at defense laboratories after World biological warfare agents, mycotoxins, and poisonous War II as a screening test for excessive exposure to plants. Part IV covers pharmaceuticals and nutraceuti- organophosphate compounds: a 20% depression in cals, with chapters on drug toxicity biomarkers, and activity was considered a mandate for cessation of toxicological testing, and biomarkers in the regulation exposure of individuals to organophosphate nerve ofdietarysupplementsandnutriphenomicbiomarkers. agents. Pseudocholinesterase and red blood cell acetyl- Part V covers biomarkers of petroleum products toxic- cholinesterase measurements now have numerous uses ity and chemical mixtures toxicity. Part VI is devoted in worker protection, clinical diagnosis of poisoning, to biomarkers of radiation, nanoparticles, carcinogens, and human and experimental animal studies (including and carcinogenesis, while Part VII deals with chapters regulatory studies) in relation to the use of organophos- on miscellaneous topics, including biomarkers of phate and other anticholinesterase pesticides. Since neurodegenerative diseases, such as Alzheimer’s World War II, biomarkers of toxicity have ballooned in and Parkinson’s. In addition, this section includes importance and number in worker and consumer chapters on cytoskeletal disruption as a biomarker protection and in clinical toxicology and experimental of developmental neurotoxicity, biomarkers of xi xii FOREWORD mitochondrial dysfunction and toxicity, and biomar- Greece, Hungary, India, Italy, Japan, Portugal, South kers of oxidative and nitrosative stress. There are also Africa, and Spain. Professor Gupta deserves our chapters on citrulline as a biomarker of diseases and gratitude for assembling such a distinguished group of toxicities and pathological biomarkers in toxicology. experts to produce a comprehensive book on this Part VIII is devoted to applications of biomarkers in rapidlygrowingandveryimportantfield. toxicologywithtenextremelycomprehensivechapters. TimothyCMarrs The 64-chapter book has an outstanding array of Edenbridge,UK authors from the USA, Canada, Denmark, Finland, List of Contributors AngelaAliberti FrankA.Barile St. John’s University, College of Pharmacy and CollegeofPharmacyandHealthSciences,Department Health Sciences, Department of Pharmaceutical ofPharmaceuticalSciences,ToxicologyDivision, Sciences, Toxicology Division, Queens, NY, USA St.John’sUniversity,Queens,NY,USA PatrickAllard SudheerR.Beedanagari DepartmentofEnvironmentalHealthSciencesand BristolMyersSquibb,NewBrunswick,NJ,USA InstituteforSociety&Genetics,Universityof California,LosAngeles,LosAngeles,CA,USA EnricoBergamaschi DepartmentofClinicalandExperimentalMedicine, ArturoAnado´n OccupationalandEnvironmentalMedicineUnit, DepartmentofToxicologyandPharmacology,Faculty UniversityofParma,Parma,Italy ofVeterinaryMedicine,UniversidadComplutense deMadrid,Madrid,Spain SnehaP.Bhatia ResearchInstituteforFragranceMaterials,NJ,USA VellareddyAnantharam Parkinson’sDisorderResearchLaboratory, KarynBischoff IowaCenterforAdvancedNeurotoxicology, SeniorExtensionAssociate,DiagnosticToxicologist, DepartmentofBiomedicalSciences,IowaState CornellUniversity,NewYorkStateAnimalHealth University,Ames,IA,USA DiagnosticCenter,Ithaca,NY,USA AnthonyE.Archibong Vı´ctorCastellano DepartmentofPhysiology,MeharryMedicalCollege, DepartmentofToxicologyandPharmacology, Nashville,TN,USA FacultyofVeterinaryMedicine,Universidad ComplutensedeMadrid,Madrid,Spain AdamD.Aulbach MPIResearch,Mattawan,MI,USA DanielT.Chang USEnvironmentalProtectionAgency,National AryamitraBanerjee ExposureResearchLaboratory,ResearchTrianglePark, ToxicologyResearchLaboratory,UniversityofIllinois NC,USA atChicago,Chicago,IL,USA JamesJ.Chen LeahD.Banks DirectorofBiostatisticsBranch,Divisionof DepartmentofBiochemistry&CancerBiology,Meharry BioinformaticsandBiostatistics,NationalCenterfor MedicalCollege,Nashville,TN,USA ToxicologicalResearch,USFoodandDrug Administration,Jefferson,AR,USA xiii xiv LISTOFCONTRIBUTORS DeborahCitrin JorgeEste´vez Investigator,RadiationOncologyBranch, InstitutodeBioingenier´ıa,UniversidadMiguel CenterforCancerResearch,NationalCancerInstitute, Herna´ndezdeElche,Spain Bethesda,MD,USA DanielS.Fabricant RoryConolly Director,DivisionofDietarySupplementPrograms,Center USEnvironmentalProtectionAgency,National forFoodSafetyandAppliedNutrition,USFoodandDrug HealthandEnvironmentalEffectsResearchLaboratory, Administration,CollegePark,MD,USA ResearchTrianglePark,NC,USA AnnaM.Fan Chief,PesticideandEnvironmentalToxicologyBranch, R.W.Coppock OfficeofEnvironmentalHealthHazardAssessment, AdjunctProfessor,DepartmentofPublicHealth CaliforniaEnvironmentalProtectionAgency, Sciences,SchoolofPublicHealthUniversityofAlberta, Oakland,CA,USA AdjunctProfessor,EnvironmentalHealth,Concordia UniversityCollegeofAlberta,Edmonton,AB,Canada; AliFaqi PresidentandCEO,RobertW.Coppock,Toxicologist SeniorDirectorofDevelopmentalandReproductive andAssociatesLtd,Vegreville,AB,Canada Toxicology,MPIResearch,Mattawan,MI,USA LucioG.Costa SuzanneE.Fenton DepartmentofEnvironmentalandOccupationalHealth NationalToxicologyProgram(NTP)Laboratories Sciences,UniversityofWashington,Seattle,WA,USA Branch,DivisionoftheNTP,NationalInstituteof EnvironmentalHealthSciences,NationalInstitutes T.V.Damodaran ofHealth,DepartmentofHealthandHumanServices, DepartmentofBiology,NorthCarolinaCentral ResearchTrianglePark,NC,USA University,Durham,NC,USA VanessaAFitsanakis KellyeK.Daniels KingUniversity,DepartmentofBiology,Bristol, Director,ToxicologyandPathology,SouthernResearch TN,USA Institute,Birmingham,AL,USA JohnFlaskos CurtisC.Dary LaboratoryofBiochemistryandToxicology, USEnvironmentalProtectionAgency,National FacultyofVeterinaryMedicine,AristotleUniversity ExposureResearchLaboratory,LasVegas,NV,USA ofThessaloniki,Thessaloniki,Greece RobinB.Doss SwaranJ.S.Flora MurrayStateUniversity,ToxicologyDepartment, DivisionofRegulatoryToxicology,DefenceResearch BreathittVeterinaryCenter,Hopkinsville,KY,USA andDevelopment,Gwalior,MP,India FilipeV.Duarte SueM.Ford DepartmentofLifeSciences,CenterforNeurosciences St.John’sUniversity,CollegeofPharmacy&Health andCellBiology,UniversityofCoimbra,Portugal Sciences,PharmaceuticalSciencesDepartment, ToxicologyProgram,Jamaica,NY,USA MargittaM.Dziwenka AssistantDirectorofOperations,HealthSciences DomnikiFragou LaboratoryAnimalServices,FacultyofMedicineand LaboratoryofForensicMedicineandToxicology,School Dentistry,UniversityofAlberta,Edmonton,AB, ofMedicine,AristotleUniversityofThessaloniki,Greece Canada;PresidentandCEO,ToxaltaConsultingLtd. Vegreville,AB,Canada ShayneC.Gad GadConsultingServices,Cary,NC,USA StephenEdwards USEnvironmentalProtectionAgency,NationalHealth Niels-ChristianGanderup andEnvironmentalEffectsResearchLaboratory, ChiefScientificOfficer,EllegaardGo¨ttingenMinipigs ResearchTrianglePark,NC,USA A/S,Dalmose,Denmark LISTOFCONTRIBUTORS xv DaleR.Gardner AlanJHargreaves UnitedStatesDepartmentofAgriculture,Agricultural SchoolofScienceandTechnology,NottinghamTrent ResearchService,PoisonousPlantResearchLaboratory, University,Nottingham,UK Logan,UT,USA KellyL.Harris RonetteGehring DepartmentofBiochemistry&CancerBiology,Meharry DepartmentofAnatomyandPhysiology,Collegeof MedicalCollege,Nashville,TN,USA VeterinaryMedicine,KansasStateUniversity, HollyE.Hatfield Manhattan,KS,USA DepartmentofBiochemistry,UniversityofCincinatti MedicalSchool,Cincinnati,OH,USA FernandoGil DepartmentofLegalMedicineandToxicology, DianeE.Heck UniversityofGranadaSchoolofMedicine, DepartmentofEnvironmentalHealthScience, Granada,Spain SchoolofHealthSciencesandPractice,NewYork MedicalCollege,Valhalla,NY,USA SaryuGoel AssociateDirector&ProjectLeader,Preclinical& AntonioF.Herna´ndez CompetitiveIntelligence,SupernusPharmaceuticals, DepartmentofLegalMedicineandToxicology, Inc.Rockville,MD,USA UniversityofGranadaSchoolofMedicine, Granada,Spain Michael-RockGoldsmith USEnvironmentalProtectionAgency,National CoreyJ.Hilmas ExposureResearchLaboratory,ResearchTrianglePark, Chief,DietarySupplementsRegulationImplementation NC,USA Branch,DivisionofDietarySupplementPrograms, CenterforFoodSafetyandAppliedNutrition,USFood ChristopherM.Grulke andDrugAdministration,CollegePark,MD,USA USEnvironmentalProtectionAgency,National ExposureResearchLaboratory,ResearchTrianglePark, EvangeliaHondroulis NC,USA Nanobioengineering/BioelectronicsLaboratory, DepartmentofBiomedicalEngineering,Florida MaryGulumian InternationalUniversity,Miami,FL,USA ToxicologyDepartment,NationalInstitute forOccupationalHealth,Hematology DarrylB.Hood andMolecularDepartmentofToxicology, DivisionofEnvironmentalHealthScience,College NationalInstituteofOccupationalHealth, ofPublicHealth,DepartmentofNeuroscience,College Johannesburg,SouthAfrica ofMedicine,TheOhioStateUniversity,Columbus, OH,USA P.K.Gupta PatronandFounder,President,SocietyofToxicology KathrynHudak Founder,Editor-in-Chief,ToxicologyInternational ResearchFellow,RadiationOncologyBranch,Centerfor President,AcademyofSciencesforAnimalWelfare, CancerResearch,NationalCancerInstitute,Bethesda, FormerHeadofDiv.Pharmacology&Toxicology, MD,USA IVRIandAdvisortoWHO,C-44,RajendraNagar, Bareilly,UP,India PasiHuuskonen SchoolofPharmacy/Toxicology,FacultyofHealth RameshC.Gupta Sciences,UniversityofEasternFinland,Kuopio,Finland ProfessorandHead,MurrayStateUniversity, ToxicologyDepartment,BreathittVeterinaryCenter, StewartB.Jacobson Hopkinsville,KY,USA ShinNipponBiomedicalLaboratoriesUSA,Ltd, Everett,WA,USA SharonGwaltney-Brant Consultant,VeterinaryInformationNetwork, HuajunJin AdjunctFaculty,DepartmentofComparative Parkinson’sDisorderResearchLaboratory,IowaCenter Biosciences,CollegeofVeterinaryMedicine,University forAdvancedNeurotoxicology,DepartmentofBiomedical ofIllinoisatUrbana-Champaign,IL,USA Sciences,IowaStateUniversity,Ames,IA,USA xvi LISTOFCONTRIBUTORS LaurieB.Joseph PrasadaRaoS.Kodavanti DepartmentofPharmacologyandToxicology, NeurotoxicologyBranch,ToxicityAssessmentDivision, RutgersUniversity,ErnestMarioSchoolofPharmacy, NHEERL/ORD,USEnvironmentalProtectionAgency, Piscataway,NJ,USA ResearchTrianglePark,NC,USA JunKanno UrmilaP.Kodavanti DivisionofCellularandMolecularToxicology, EnvironmentalPublicHealthDivision,National BiologicalSafetyResearchCenter,NationalInstitute HealthandEnvironmentalEffectsResearchLaboratory, ofHealthSciences,Tokyo,Japan OfficeofResearchandDevelopment,USEnvironmental ProtectionAgency,ResearchTrianglePark,NC,USA AnumanthaG.Kanthasamy Parkinson’sDisorderResearchLaboratory, GeorgeA.Kontadakis IowaCenterforAdvancedNeurotoxicology, DepartmentofOphthalmology,FacultyofMedicine, DepartmentofBiomedicalSciences,IowaState UniversityofCrete,Heraklion,Greece University,Ames,IA,USA Pe´terKrajcsi ArthiKanthasamy SOLVOBiotechnology,Budao¨rs,Hungary Parkinson’sDisorderResearchLaboratory, IowaCenterforAdvancedNeurotoxicology, GopalaKrishna DepartmentofBiomedicalSciences,IowaState ExecutiveDirector,Preclinical&Competitive University,Ames,IA,USA Intelligence,SupernusPharmaceuticals,Inc.,Rockville, MD,USA NavinchandraM.Kaore DepartmentofMicrobiology,People’sCollege KavyaA.Krishna ofMedicalSciences&ResearchCenter,Bhopal,MP, SupernusPharmaceuticals,Inc.Rockville,MD,USA India MariaKummu ShilpaN.Kaore DepartmentofPharmacologyandToxicology, DepartmentofPharmacology,People’sCollege InstituteofBiomedicine,andCenterforArctic ofMedicalSciences&ResearchCenter,Bhopal, Medicine,ThuleInstituteofOulu,UniversityofOulu, MP,India Oulu,Finland BhupendraS.Kaphalia GeorgeD.Kymionis DepartmentofPathology,UniversityofTexasMedical DepartmentofOphthalmology,FacultyofMedicine, Branch,Galveston,TX,USA UniversityofCrete,Heraklion,Greece VesaKarttunen MichelleA.Lasher SchoolofPharmacy/Toxicology,Facultyof MurrayStateUniversity,ToxicologyDepartment, HealthSciences,UniversityofEasternFinland, BreathittVeterinaryCenter,Hopkinsville,KY,USA Kuopio,Finland Chen-zhongLi GreerE.Kaufman Nanobioengineering/BioelectronicsLaboratory, DepartmentofBioanalysis,SouthernResearchInstitute, DepartmentofBiomedicalEngineering,Florida Birmingham,AL,USA InternationalUniversity,Miami,FL,USA RavneetKaur Wei-JiunLin Aveley,WesternAustralia AssistantProfessor,DepartmentofApplied Mathematics,FengChiaUniversity,Taiwan HongDuckKim DepartmentofEnvironmentalHealthScience,Schoolof BommannaG.Loganathan HealthSciencesandPractice,NewYorkMedical DepartmentofChemistryandWatershedStudies College,ValhallaNY,USA Institute,MurrayStateUniversity,Murray,KY,USA