Table Of ContentFranz-Xaver Reichl
Michael Schwenk
Editors
Regulatory
Toxicology
Second Edition
Regulatory Toxicology
(cid:129)
Franz-Xaver Reichl Michael Schwenk
Editors
Regulatory Toxicology
Second Edition
With236Figuresand127Tables
Editors
Franz-XaverReichl MichaelSchwenk
DepartmentofOperative/Restorative Formerly:HannoverMedicalSchool
Dentistry Hannover,Germany
PeriodontologyandPedodontics
Tübingen,Germany
UniversityHospital,LMU
München,Germany
Walther-Straub-InstituteofPharmacology
andToxicology
LMUMunich
Munich,Germany
ISBN978-3-030-57498-7 ISBN978-3-030-57499-4(eBook)
ISBN978-3-030-57500-7(printandelectronicbundle)
https://doi.org/10.1007/978-3-030-57499-4
1stedition:©Springer-VerlagBerlinHeidelberg2014
2ndedition:©SpringerNatureSwitzerlandAG2021
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Foreword of the First Edition
Regulatory toxicology requires knowledge of aspects related to a number of disci-
plines of natural and social sciences, including chemistry, biology, bioinformatics,
toxicology, epidemiology,exposureassessmentandnutrition,aswell as sociology,
psychologyandcommunication, toname a few.It builds abridge between science
anddecision-making.Infact,riskanalysis,thecentrepieceofregulatorytoxicology,
isoftenseenasanart,inadditiontoitsbeingascience.Thisexplainswhystandard
textbooksonregulatorytoxicologyarerare.
Tenyearsafterthepublicationofthefirststandardworkonregulatorytoxicology
inGerman,anupdated,expandedversionisnowathandinEnglishlanguage.This
major publication addresses questions covering various aspects of risk assessment
and risk management in general, paying attention to a number of fields including
health protection, occupational health, environmental health and consumer protec-
tion. Basic principles are outlined, new developments described, and scientific,
social and philosophical questions discussed at length. In times of an increased
understanding that risk assessment and management need to be conducted in full
transparencyandwithfullinvolvementofallstakeholders,issuesofriskperception
andriskcommunicationareaddressed.
This breadth of information, complemented by a listing of the newest guidance
values, makes this book a standard reference to those involved in the field of
regulatory toxicology. It is of interest to risk scientists of various backgrounds, to
policymakersandtheiradvisors,andalsotoinformedconsumers.
Awelcomeandtimelypublication,indeed.
WHO,Geneva,Switzerland MagedYounes
IUTOX-president,Aarhus,Denmark HermanAutrup
v
Preface
Basedonthesuccessofthefirstedition(2014)ofthebookRegulatoryToxicology,
theeditorsdecidedtocompileasecondedition.Thoughthebasicsoftoxicological
risk assessment and risk management experienced only moderate changes, the
methodstostudyandevaluateadversechemico-biologicalinteractionswerefurther
refinedintheyearssincethefirstedition,notleastduetonumerousnovelinvitrotest
systems.Moreover,weexperiencedadecadeofmanyadvancesintheconsolidation
ofrulesandguidelinesonnationalandinternationallevels.
Thechaptersofthefirsteditionwereupdatedforthissecondedition.Moreover,
many new chapters were included, dealing with novel developments, such as
regulations of nanoparticles, designer drugs, tattoos, biopharmaceuticals and gene
therapy. The chapters were written by experts for all those who are involved in
toxicologicaldatagenerationanddecision-makingininstitutionsofpureandapplied
regulatorytoxicology.
In summary, this handbook deals comprehensively with the management of
chemical hazards and risks in regulatory toxicology, with a focus on test systems
andtheirinterpretation,andtheconceptsusedtoestimateacuteandchronictoxicity
to humans and the environment. Such information supports the work of those
involved in risk assessment in academia, industry, government or related agencies.
It also serves the superior aim of contributing to the protection of human health,
cleanenvironments,andasustainabledevelopmentonearth.
Theeditorshavesoughttobringconsistencytothediversityofapproachesandof
opinions concerning toxicological risk assessment. Guideline values, regulations
anddatamaychangewithtimeandamongjurisdictions.Howeverthebasicprinci-
ples and approaches discussed in this handbook will continue to provide a stable
basis for future decision finding. Opinions expressed are those of the individual
authorsanddonotnecessarilyrepresenttheviewsoftheirinstitutions.
September2021 Franz-XaverReichl
MichaelSchwenk
vii
Acknowledgments
Theeditorswishtothankallauthorsfortheirvaluablecontributionstothiseditionof
RegulatoryToxicology.TheyalsothankKerstinBeckertandBarbaraWolffromthe
EditorialteamofSpringerfortheexcellentcooperation.
ix
Contents
Volume 1
PartI The“ModusOperandi”ofRegulatoryToxicology ......... 1
1 AimsandMissionofRegulatoryToxicology ................. 3
HelmutGreim
2 WorkingAreasofRegulatoryToxicology .................... 23
MichaelSchwenkandH.PaulA.Illing
3 NationalandInternationalCollaborationinRegulatory
Toxicology ............................................ 35
AlfonsoLampenandKlausE.Appel
4 TheRegulatoryProcessinToxicology ...................... 51
DietrichHenschlerandWolfgangDekant
5 QualityAssuranceinToxicology .......................... 59
Klaus-MichaelWollin,StephenHarston,andWernerLilienblum
6 ToxicologicalRiskAssessment ............................ 69
MagedYounesandNikolaosGeorgiadis
PartII TestsandMethods ................................. 81
7 MonoclonalAntibodies:DiscoveryandProteinEngineering ..... 83
WibkeLembkeandMathiasLocher
8 CharacterizationofPhysicochemicalParametersin
Toxicology ............................................ 99
MathiasLocher
9 ExaminationofAcuteandRepeated-DoseToxicity ............ 107
VolkerMostert,KarlGeorgHeimann,andKevinDoughty
10 ExaminationofOrganToxicity ............................ 117
WolfgangKaufmannandMattC.Jacobsen
xi
xii Contents
11 SpecificToxicityTestsforNeurotoxicity,Immunotoxicity,
Allergy,Irritation,Reprotoxicity,andCarcinogenicity ......... 129
EckhardvonKeutz
12 ToxicityTestingInVitro:RegulatoryAspects ................ 139
EckhardvonKeutz
13 IntegrationofAdvancedTechnologiesintoRegulatory
Toxicology ............................................ 149
HorstSpielmannandHelenaKandarova
14 Computer-BasedPredictionModelsinRegulatoryToxicology ... 163
ThomasSteger-HartmannandScottBoyer
15 MetabolismInvestigationsinDrugDevelopment .............. 177
JensRiedelandAlainKrick
16 ToxicokineticTests ..................................... 189
JürgenPauluhn
17 ToxicodynamicTests .................................... 215
AlexanderCartusandDieterSchrenk
18 OmicsinToxicology .................................... 231
HeidrunEllinger-ZiegelbauerandHans-JuergenAhr
19 EpidemiologicalMethodsinRegulatoryToxicology ............ 245
UlrichRanftandGregoryA.Wellenius
20 EarlyClinicalTrials .................................... 261
SimonJägerandMatthiasSchwab
21 StatisticalEvaluationMethodsinToxicology ................. 273
LudwigA.Hothorn
22 Dose-ResponseAnalysis:IdentificationofThresholdLevels
forChemicals ......................................... 285
Hans-KarlHeimandPeterMayer
23 ExtrapolationProceduresforCarcinogenicand
NoncarcinogenicCompounds ............................. 299
LutzEdler
24 ProbabilisticMethodsinToxicology ........................ 317
OdileMekelandRainerFehr
25 ExposureAnalysisforIndoorContaminants ................. 325
GerhardVolland
26 BenchmarkDoseApproachinRegulatoryToxicology .......... 339
LutzEdler
Contents xiii
27 HumanBiomonitoring:ItsImportanceinToxicological
Regulation ............................................ 375
MichaelWilhelm
PartIII ApproachesUsed ................................. 395
28 ToxicodynamicModels .................................. 397
LutzEdler
29 ToxicokineticModels .................................... 407
JohannesGeorgFilser
30 ExposureScenariosinToxicology .......................... 419
GerhardHeinemeyer
31 QualityCriteriaforPrimaryLiteratureinToxicology ......... 439
KlausSchneider,SebastianHoffmann,and
AgnieszkaKinsner-Ovaskainen
32 DataMininginToxicology ............................... 445
PetraWiedemeierandIngeMangelsdorf
33 PrinciplesofAnalyticalChemistryforToxicology ............. 455
JürgenDurnerandDavidC.Watts
34 UncertaintyAnalysisinExposureAssessment-Relevancefor
ToxicologicalRiskAssessment ............................ 499
MichaelSchümann,HalukÖzkaynak,andAlexandreZenié
PartIV ParadigmsUsedinRiskEvaluation ................... 523
35 Read-AcrossMethodologyinToxicologicalRiskAssessment .... 525
S.E.EscherandA.Bitsch
36 GreenandSustainableChemistryasRegulatoryLevers ........ 539
MichaelSchwenk
37 DoCarcinogensHaveaThresholdDose?TheProsandCons .... 555
BerndKaina,AdamD.Thomas,HartwigVisser,JanG.Hengstler,and
RolandFrötschl
38 SingleSubstancesVersusCombinedEffects:Problemsin
MixtureToxicology ..................................... 575
ThomasR.H.Büch,EvaA.M.Büch,IngridBoekhoff,
JohnH.Duffus,andThomasGudermann
39 BiomoleculesVersusSmallerChemicalsinToxicology:
ICH,EU,andUSRecommendations ....................... 581
ManfredRuthsatz,CarloChiavaroli,M.A.Cassar,and
EmmanuelleM.Voisin
