Toxicology and risk assessment: a comprehensive introduction

829 Pages·2019·13.1 MB·English

by  Greim

Toxicology and Risk Assessment
Toxicology and Risk
Assessment:
A Comprehensive
Introduction
Second Edition
EditedBy
HELMUTGREIM
TechnicalUniversityofMunich,Munich,Germany
ROBERTSNYDER
RutgersUniversityandEOHSI,USA
Thiseditionfirstpublished2019
©2019JohnWiley&SonsLtd
EditionHistory
ToxicologyandRiskAssessment:AComprehensiveIntroduction,FirstEdition,Wiley2008.
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LibraryofCongressCataloging-in-PublicationData:
Names:Greim,Helmut,editor.|Snyder,Robert,editor.
Title:Toxicologyandriskassessment:acomprehensiveintroduction/edited
byHelmutGreim,TechnicalUniversityofMunich,Munich,Germany,Robert
Snyder,RutgersUniversityandEOHSI,USA.
Description:Hoboken,NJ:Wiley,2019.|Originallypublished.2008.|
Includesbibliographicalreferencesandindex.|
Identifiers:LCCN2018009797(print)|LCCN2018010582(ebook)|ISBN
9781119135920(pdf)|ISBN9781119135937(epub)|ISBN9781119135913
(cloth)
Subjects:LCSH:Toxicology.|Healthriskassessment.
Classification:LCCRA1211(ebook)|LCCRA1211.T6352018(print)|DDC
615.9/02–dc23
LCrecordavailableathttps://lccn.loc.gov/2018009797
CoverDesign:Wiley
CoverImages:©zffoto/Shutterstock;
©chromatos/Shutterstsock;©Mopic/Shutterstock
Setin10/12ptTimesLTStdbySPiGlobal,Chennai,India
10 9 8 7 6 5 4 3 2 1
Contents
ListofContributors xv
ShortCVsofAuthors xix
Preface xxix
Dedication xxxi
ListofAbbreviations xxxiii
1 IntroductiontotheDisciplineofToxicology 1
HelmutGreimandRobertSnyder
1.1 Introduction 1
1.2 TheRiskAssessmentProcess 2
1.2.1 HazardIdentification 2
1.2.2 DoseResponseandToxicPotency 3
1.2.3 ExposureAssessment 4
1.2.4 RiskCharacterization 6
1.3 ToxicologicalEvaluationofNewandExistingChemicals 6
1.3.1 GeneralRequirementsforHazardIdentificationandRiskAssessment 7
1.3.2 GeneralApproachforHazardIdentificationandRiskAssessment
(fordetailsseeChapter2.1) 12
1.3.3 ToxicologicalIssuesrelatedtoSpecificChemicalClasses 13
1.3.4 ExistingChemicals 14
1.3.5 TestGuidelines(Chapter4.1) 14
1.3.6 AlternativestoAnimalExperiments(Chapter4.5) 15
1.3.7 EvaluationofMixtures(Chapter2.7) 15
1.3.8 EvaluationofUncertainties 16
1.3.9 ThePrecautionaryPrinciple 16
1.3.10 TheTTCConcept 17
1.3.11 ClassificationandLabelingofChemicals 17
1.4 Summary 18
2 PrinciplesinToxicology 21
2.1 GeneralConceptsofHumanHealthRiskAssessment 21
PaulT.C.Harrison,PhilipHolmes,andRuthBevan
2.1.1 Introduction 21
2.1.2 PrinciplesofRiskAssessment 21
2.1.3 ApplicationofRiskAssessmentinSettingExposureStandards
andLimits 30
vi Contents
2.1.4 TheWiderImportanceofRiskAssessment 32
2.1.5 Summary 32
2.2 Toxicokinetics 34
JohannesG.Filser
2.2.1 DefinitionandPurpose 34
2.2.2 Absorption,Distribution,andElimination 35
2.2.3 ToxicokineticModels 47
2.2.4 Summary 61
2.3 BiotransformationofXenobiotics 61
WolfgangDekant
2.3.1 Introduction 61
2.3.2 PhaseIReactions 64
2.3.3 PhaseIIReactions 74
2.3.4 FactorsthatInfluencetheBiotransformationofXenobiotics 80
2.3.5 RoleofBioactivationinToxicity 87
2.3.6 InteractionsofReactiveIntermediatesformedduringthe
Biotransformation 90
2.3.7 Summary 94
2.4 Cytotoxicity 98
DanielDietrich
2.4.1 Introduction 98
2.4.2 TheCell 102
2.4.3 CellularTargetsofToxins 106
2.4.4 MechanismsunderlyingCellDeath 115
2.4.5 Summary 120
2.5 Toxicogenetics 122
LesleyA.Stanley
2.5.1 Introduction 122
2.5.2 ToxicogeneticsandToxicogenomics 123
2.5.3 GenotypeandPhenotype 123
2.5.4 TheRoleofXenobiotic-metabolisingPolymorphismsin
SusceptibilitytoToxicAgents 127
2.5.5 StudyNumbersandEffectSize 135
2.5.6 Summary 139
2.6 Receptor-mediatedMechanisms 140
JensSchlossmannandFranzHofmann
2.6.1 Introduction 140
2.6.2 Ligand–ReceptorInteractions 141
2.6.3 BiologicalConsequencesofLigand–ReceptorInteractions 142
2.6.4 ReceptorSignalTransduction 144
2.6.5 Summary 147
2.7 MixturesandCombinationsofChemicals 148
HermannBolt
2.7.1 Introduction 148
2.7.2 TypesofMixedExposures 148
2.7.3 TypesofJointActionsandtheirRoleinSafetyEvaluation 149
2.7.4 RoleinSafetyEvaluation 151
2.7.5 Summary 158
Contents vii
2.8 ChemicalCarcinogenesis:GenotoxicandNon-GenotoxicMechanisms 159
ThomasEfferthandBerndKaina
2.8.1 Introduction 159
2.8.2 MechanismsofDNADamage,Repair,andCarcinogenesis 160
2.8.3 CancerDevelopment 171
2.8.4 Non-GenotoxicMechanismsofCarcinogenesis 181
2.8.5 ImplicationsofInitiationandPromotionforRiskAssessment 184
2.8.6 Summary 185
2.9 ThresholdEffectsforGenotoxicCarcinogens 186
HelmutGreim
2.9.1 Introduction 186
2.9.2 DevelopmentofCancerduetoGenotoxicCarcinogens 187
2.9.3 CellularReactiontoDNADamage 187
2.9.4 ExamplesofDose-dependentReactionsinCasesofGenotoxicity 193
2.9.5 Summary 193
2.10 ReproductiveToxicology 195
HorstSpielmann
2.10.1 Introduction 195
2.10.2 CharacteristicsofReproductiveToxicology 196
2.10.3 AdverseEffectsonFemaleandMaleFertility 197
2.10.4 InternationalTestMethodsintheFieldofReproductiveToxicology 199
2.10.5 Pre-andPostnatalToxicology 201
2.10.6 EffectsofDrugsandotherChemicalsonLactation 207
2.10.7 EndocrineDisrupters 208
2.10.8 Summary 208
2.11 Ecotoxicology:MorethanWildlifeToxicology 209
PeterCalowandValeryE.Forbes
2.11.1 Introduction 209
2.11.2 ProtectionTargets 210
2.11.3 NecessaryInformation 211
2.11.4 RiskAssessment 216
2.11.5 Fast-trackApproaches 217
2.11.6 Summary 218
3 OrganToxicology 221
3.1 TheGastrointestinalTract 221
MichaelSchwenk
3.1.1 Introduction 221
3.1.2 StructureandFunction 221
3.1.3 FateofXenobioticsintheGITract 223
3.1.4 Toxicology 226
3.1.5 Summary 231
3.2 TheLiver 231
JanG.Hengstler
3.2.1 Introduction 231
3.2.2 StructureandFunction 232
3.2.3 Toxicology 237
3.2.4 MythsoftheLiver 247
3.2.5 Summary 248
viii Contents
3.3 TheRespiratorySystem 248
FlorianSchulz
3.3.1 Introduction 248
3.3.2 Structure 249
3.3.3 Function 252
3.3.4 ProtectiveSystems 254
3.3.5 TheRespiratoryTractasaTargetforToxicity 256
3.3.6 RespiratoryAllergyandAsthma 261
3.3.7 LungCancer 262
3.3.8 TestSystemstoDetecttheToxicEffectsofInhaledMaterials 263
3.3.9 Summary 263
3.4 TheNervousSystem 264
GunterP.EckertandWalterE.Müller
3.4.1 StructureandFunctionoftheNervousSystem 264
3.4.2 TheNervousSystemSiteofAttackforToxins 273
3.4.3 ClinicalSignsandSymptomsinducedbyNeurotoxins 279
3.4.4 Summary 281
3.5 BehavioralNeurotoxicology 283
AndreasSeeber
3.5.1 Introduction 283
3.5.2 ExposureAssessment 283
3.5.3 Methods 284
3.5.4 NeurobehavioralEffectsinHumans 291
3.5.5 Summary 295
3.6 TheSkin 296
BrunhildeBlömeke
3.6.1 Structure 296
3.6.2 Function 298
3.6.3 ToxicologyoftheSkinandtheAnteriorSegmentoftheEye 300
3.6.4 Summary 309
3.7 KidneyandUrinaryTract 311
HelmutGreim
3.7.1 Introduction 311
3.7.2 AnatomyandFunction 311
3.7.3 Toxicology 313
3.7.4 Summary 319
3.8 TheHematopoieticSystem(BoneMarrowandBlood) 320
RobertSnyder
3.8.1 Introduction 320
3.8.2 Hematopoiesis 321
3.8.3 TheBoneMarrowNiche 323
3.8.4 ToxicologicalFeaturesofCirculatingBloodCells 323
3.8.5 Leucocytes(WhiteBloodCells) 326
3.8.6 Platelets(Thrombocytes) 328
3.8.7 ImpairmentofBoneMarrowFunction 328
3.8.8 MechanismsbywhichChemicalscanInduceLeukemia 330
3.8.9 Summary 330
Contents ix
3.9 TheImmuneSystem 331
PeterGriem
3.9.1 Introduction:theInnateandSpecificImmuneSystem 331
3.9.2 AntigenRecognition 333
3.9.3 ActivationofTandBlymphocytes 334
3.9.4 ImmunologicTolerance 336
3.9.5 SensitizationandAllergy 337
3.9.6 RiskAssessmentofImmunotoxicEffects 342
3.9.7 Chemical-inducedAutoimmunity 345
3.9.8 GeneralImmunostimulationbyChemicals 346
3.9.9 ChemicalImmunosuppression 348
3.9.10 Summary 350
3.10 TheEye 351
InesLanzl
3.10.1 Introduction 351
3.10.2 StructureandFunctionoftheEye 351
3.10.3 RoutesofDeliveryofXenobioticstotheEye 354
3.10.4 SpecificToxicologyoftheEye 355
3.10.5 Summary 363
3.11 TheCardiovascularSystem 364
HelmutGreim
3.11.1 StructureandFunction 364
3.11.2 Toxicology 366
3.11.3 Summary 371
3.12 TheEndocrineSystem 372
GerlindeSchriever-Schwemmer
3.12.1 Introduction 372
3.12.2 StructureandFunction 373
3.12.3 FoetalDevelopmentoftheHypothalamus–Pituitary–GonadAxis 381
3.12.4 TestingofSexualFunctioninToxicology 383
3.12.5 HazardIdentificationandRiskAssessmentofEndocrineDisruptors 386
3.12.6 Summary 386
4 MethodsinToxicology 389
4.1 OECDTestGuidelinesforToxicityTestsinvivo 389
RüdigerBartsch
4.1.1 Introduction 389
4.1.2 RequirementsforinvivoTests 390
4.1.3 AcuteToxicity 392
4.1.4 SkinandEyeIrritation 394
4.1.5 SkinSensitization 397
4.1.6 ToxicityafterRepeatedDosing 398
4.1.7 ReproductiveToxicity 401
4.1.8 OtherTestGuidelines 406
4.1.9 OtherRegulatoryBodies 407
4.1.10 Summary 407
x Contents
4.2 Genotoxicity 408
4.2A InvitroTestsforGenotoxicity 408
Hans-JörgMartus
4.2A.1 Introduction 408
4.2A.2 BacterialTestSystems 409
4.2A.3 TestSystemsemployingMammalianCells 411
4.2A.4 CellTransformationAssays 420
4.2A.5 XenobioticMetabolism 420
4.2A.6 Summary 421
4.2B Mutagenicitytestsinvivo 422
Ilse-DoreAdlerandGerlindeSchriever-Schwemmer
4.2B.1 Introduction 422
4.2B.2 ChromosomalMutationsinSomaticCells 424
4.2B.3 GeneMutationsinSomaticCells 427
4.2B.4 ChromosomeMutationsinGermCells 429
4.2B.5 GeneMutationsinGermCells 433
4.2B.6 Summary 435
4.3 AssessmentoftheIndividualExposuretoXenobiotics(Biomonitoring) 440
ThomasGöen
4.3.1 Introduction 440
4.3.2 PrerequisitesforCarryingOutBiomonitoring 442
4.3.3 ExamplesofBiomonitoringofSpecialSubstanceGroupsorSpecial
BiomonitoringParameters 447
4.3.4 Summary 449
4.4 Epidemiology 450
KurtUlm
4.4.1 Introduction 450
4.4.2 MeasurestoDescribetheRisk 450
4.4.3 Standardization 452
4.4.4 TypesofEpidemiologicalStudies 454
4.4.5 Statistics 456
4.4.6 Meta-analysis 457
4.4.7 Bias,Confounding,Chance,Causality 459
4.4.8 Summary 460
4.5 AlternativestoAnimalTesting 461
ThomasHartung
4.5.1 Introduction 461
4.5.2 TheBirthofDoubtinAnimalExperiments 461
4.5.3 EarlySuccessfulAlternatives 463
4.5.4 TheReplacementofAnimalTestsisPossible 463
4.5.5 ValidationofAlternativeMethods:AnimalWelfaremustnotTrump
PatientandConsumerSafety 466
4.5.6 HowReliableareAnimalTests? 467
4.5.7 TheAnimalTestBanforCosmeticsinEuropeasanEngineof
Change 467
4.5.8 “ToxicologicalIgnorance”:theEuropeanREACHProgramasa
DriverforAlternativeMethods 468
4.5.9 Outlook 469
4.5.10 Summary 471
Contents xi
4.6 OmicsinToxicology 472
LauraSuter-Dick
4.6.1 Introduction 472
4.6.2 ConceptofToxicogenomics 472
4.6.3 TechnologyPlatforms 475
4.6.4 BioinformaticsandBiostatistics 480
4.6.5 ApplicationsofToxicogenomics 481
4.6.6 Summary 484
4.7 IntroductiontotheStatisticalAnalysisofExperimentalData 486
GyörgyCsanády
4.7.1 Introduction 486
4.7.2 DescriptiveStatistics 488
4.7.3 ErrorPropagation 491
4.7.4 ProbabilityDistribution 492
4.7.5 InferentialStatistics 496
4.7.6 RegressionAnalysis 504
4.7.7 ProbitAnalysis 506
4.7.8 ExperimentalDesigns 507
4.7.9 StatisticalSoftware 508
4.7.10 Summary 509
4.8 MathematicalModelsforRiskExtrapolation 510
JürgenTimm
4.8.1 Introduction 510
4.8.2 BasicApproachofLinearExtrapolation 512
4.8.3 SomeSpecialMethodsofLinearExtrapolation 514
4.8.4 ConsiderationofTimeAspects 515
4.8.5 ModelsofCarcinogenesis 518
4.8.6 AssumptionsandLimitsofExtrapolationinMathematicalModels 521
4.8.7 Summary 523
5 RegulatoryToxicology 525
5.1 RegulationsonChemicalSubstancesintheEuropeanUnion 525
WernerLilienblumandKlaus-MichaelWollin
5.1.1 Introduction 525
5.1.2 CurrentLegislationintheEU 526
5.1.3 RiskIssuesandSomeDefinitionsinTermsofChemicalSubstances 528
5.1.4 InternationalCo-operationandHarmonizationSupportedand
ImplementedbytheEU 531
5.1.5 EULegislationonChemicalSubstancesandTheirUses 535
5.1.6 LegislationonChemicalSubstancesintheEnvironment 552
5.1.7 Summary 556
5.2 RegulationsRegardingChemicalsandRadionuclidesintheEnvironment,
Workplace,ConsumerProducts,Foods,andPharmaceuticalsin
theUnitedStates 557
DennisJ.Paustenbach
5.2.1 Introduction 557
5.2.2 OccupationalHealthRegulations 558
5.2.3 FoodandDrugRegulations 561
5.2.4 EnvironmentalRegulations 563