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Regulatory Toxicology
Franz-Xaver Reichl • Michael SchwenkEditors
Regulatory Toxicology
With 144 Figures and 105 Tables
EditorsFranz-Xaver ReichlLMU Munich, Munich, Germany
Michael SchwenkFormerly Medical SchoolHannover, Germany
ISBN 978-3-642-35373-4 ISBN 978-3-642-35374-1 (eBook)ISBN 978-3-642-35375-8 (print and electronic bundle)DOI 10.1007/ 978-3-642-35374-1Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014932168
# Springer-Verlag Berlin Heidelberg 2014This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part ofthe material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformation storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodology now known or hereafter developed. Exempted from this legal reservation are brief excerptsin connection with reviews or scholarly analysis or material supplied specifically for the purpose of beingentered and executed on a computer system, for exclusive use by the purchaser of the work. Duplicationof this publication or parts thereof is permitted only under the provisions of the Copyright Law of thePublisher’s location, in its current version, and permission for use must always be obtained fromSpringer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center.Violations are liable to prosecution under the respective Copyright Law.The use of general descriptive names, registered names, trademarks, service marks, etc. in thispublication does not imply, even in the absence of a specific statement, that such names are exemptfrom the relevant protective laws and regulations and therefore free for general use.While the advice and information in this book are believed to be true and accurate at the date ofpublication, neither the authors nor the editors nor the publisher can accept any legal responsibility forany errors or omissions that may be made. The publisher makes no warranty, express or implied, withrespect to the material contained herein.
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Foreword
Regulatory toxicology requires knowledge of aspects related to a number of
disciplines of natural and social sciences, including chemistry, biology, bioinfor-
matics, toxicology, epidemiology, exposure assessment and nutrition, as well as
sociology, psychology and communication, to name a few. It builds a bridge
between science and decision-making. In fact, risk analysis, the centrepiece of
regulatory toxicology, is often seen as an art, in addition to its being a science.
This explains why standard textbooks on regulatory toxicology are rare.
Ten years after the publication of the first standard work on regulatory toxicol-
ogy in German, an updated, expanded version is now at hand in English language.
This major publication addresses questions covering various aspects of risk assess-
ment and risk management in general, paying attention to a number of fields
including health protection, occupational health, environmental health and con-
sumer protection. 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 transparency and with full involvement of all stakeholders, issues
of risk perception and risk communication are addressed.
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
policymakers and their advisors, and also to informed consumers.
A welcome and timely publication, indeed.
Madged Younes, WHO, Geneva, Switzerland
Herman Autrup, IUTOX-president, Aarhus, Denmark
v
About the Editors
Univ.-Prof. Dr. Dr. Franz-Xaver Reichl Department of Operative/Restorative
Dentistry, Periodontology and Pedodontics, LMU Munich and Walther-Straub-
Institute of Pharmacology andToxicology, LMUMunich, Nussbaumstr. 26, Germany
Univ.-Prof. Dr. Dr. Franz-Xaver Reichl studied microbiology and medicine in
Munich, Germany. He then qualified as a toxicologist/pharmacologist and works
at the Ludwig Maximilains University of Munich (LMU) as a dental-toxicologist at
the Dental Clinic and at the Walther-Straub-Institute of Pharmacology and Toxi-
cology at the LMU. His research was mainly related to molecular, cellular, and
analytical (dental) toxicology. F.-X. Reichl consulted health agencies in toxicolog-
ical risk management and is member of toxicological/pharmacological committees.
He is head of the “International Advisory Board for the Biocompatibility/Toxicol-
ogy of Dental Materials” at the LMU.
vii
Prof. Dr. Michael Schwenk Formerly Medical School, Hannover, Germany
Prof. Dr. Michael Schwenk studied Biochemistry and Medicine in T€uebingen,Germany. He then qualified as a toxicologist/pharmacologist; worked in universi-
ties, industry, and research institutions; and later became head of the environmental
health department of a state health agency. His research was mainly related to
molecular and cellular toxicology, but he was also involved in human trials
with volunteers and in epidemiological studies on exposure–response relationships.
M. Schwenk consulted health agencies in toxicological risk management and is
member of regulatory committees.
viii About the Editors
Contents
Volume 1
Part I The “Modus Operandi” of Regulatory Toxicology . . . . . . . . 1
Aims and Mission of Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . . 3
Helmut Greim
Working Areas of Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . . . . 21
Michael Schwenk and H. Paul A. Illing
National and International Collaboration in RegulatoryToxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Klaus E. Appel
The Regulatory Process in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Dietrich Henschler and Wolfgang Dekant
Quality Assurance in Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . 57
Werner Lilienblum and Stephen Harston
Toxicological Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Maged Younes
Part II Approaches Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Characterization of Physicochemical Parameters inToxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Mathias Locher
Examination of Acute and Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . 81
Karl Georg Heimann and Kevin Doughty
Examination of Organ Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Wolfgang Kaufmann and Matt C. Jacobsen
Specific Toxicity Tests for Neurotoxicity, Immunotoxicity,Allergy, Irritation, Reprotoxicity, and Carcinogenicity . . . . . . . . . . . . 99
Eckhard von Keutz
ix
Toxicity Testing In Vitro. Regulatory Aspects . . . . . . . . . . . . . . . . . . . 107
Eckhard von Keutz
New and Future Toxicological Assays and Their Regulation . . . . . . . . 115
Horst Spielmann
Computer-Based Prediction Models in Regulatory Toxicology . . . . . . 123
Thomas Steger-Hartmann and Scott Boyer
Metabolism Tests in Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . . 133
Gert Ulrich Kuerzel and Christine Mauriac
Toxicokinetic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
J€urgen Pauluhn
Toxicodynamic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Dieter Schrenk
Omics in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Heidrun Ellinger-Ziegelbauer and Hans-Juergen Ahr
International Regulation of Toxicological Test Systems . . . . . . . . . . . . 181
Horst Spielmann
Epidemiological Methods in Regulatory Toxicology . . . . . . . . . . . . . . . 191
Ulrich Ranft and Gregory A. Wellenius
Studies in Volunteers and Its Regulation . . . . . . . . . . . . . . . . . . . . . . . . 207
Klaus Morike
Statistical Evaluation Methods in Toxicology . . . . . . . . . . . . . . . . . . . . 213
Ludwig A. Hothorn
Dose-Response Analysis, Identification of Threshold Levelsfor Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Hans-Karl Heim and Peter Mayer
Extrapolation-Procedures for Carcinogenic and NoncarcinogenicCompounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Lutz Edler
Probabilistic Methods in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Odile Mekel and Rainer Fehr
Toxicodynamic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Lutz Edler and Angelika Tritscher
Toxicokinetic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Johannes Georg Filser
Exposure Analysis for Indoor Contaminants . . . . . . . . . . . . . . . . . . . . 277
Gerhard Volland
x Contents
Exposure Scenarios in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Gerhard Heinemeyer
Quality Criteria for Primary Literature in Toxicology . . . . . . . . . . . . 305
Klaus Schneider, Agnieszka Kinsner-Ovaskainen, and
Martin Hassauer
Data-Mining in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Inge Mangelsdorf
Principles of Analytical Chemistry for Toxicology . . . . . . . . . . . . . . . . 321
J€urgen Durner and David C. Watts
Benchmark Dose in Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . . 359
Lutz Edler
Uncertainty Analysis in Exposure Assessment. Relevance forRegulatory Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Michael Sch€umann, Ozkaynak Haluk, and Alexandre Zenie
Part III Paradigms used in Risk Evaluation . . . . . . . . . . . . . . . . . . 395
Do Carcinogens Have a Threshold Dose? Pro and Contra . . . . . . . . . . 397
Bernd Kaina, Adam D. Thomas, and Jan G. Hengstler
Single Compounds Versus Combination Effects in Toxicology . . . . . . 407
Thomas R. H. B€uch, Eva A. M. Sch€afer, John H. Duffus, and
Thomas Gudermann
Biomolecules Versus Smaller Chemicals in Toxicology . . . . . . . . . . . . 413
Manfred Ruthsatz, Carlo Chiavaroli, and Emmanuelle Voisin
Sensitive Humans Versus Average Persons in Toxicology . . . . . . . . . . 423
Alexander Eckhardt
Extrapolation Factors and Safety Factors in Toxicology . . . . . . . . . . . 431
Rainer Konietzka, Klaus Schneider, and Leonard Ritter
Background Exposure Versus Additional Exposure inHuman Biomonitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Hans-G€unter Neumann
Adverse Effects Versus Non-adverse Effects in Toxicology . . . . . . . . . 449
Norbert Englert and Robert L. Maynard
Health-Based Threshold ADI Versus MOS in Toxicology . . . . . . . . . . 457
Ursula Gundert-Remy
Precaution Principle Versus Danger Prevention inToxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Ludwig M€uller and Neill H. Stacey
Contents xi
Hygienic Versus Toxicological Approaches in Regulation . . . . . . . . . . 469
Roland Suchenwirth
Protected Property and Protection Level in RegulatoryToxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Bernhard Liebl and Ines Liebl
Ethical Issues in Science. Focus on Regulatory Toxicology . . . . . . . . . 481
Beate Henrikus and Wolfgang Eisenmenger
Volume 2
Part IV Risk Assessment and Evaluation . . . . . . . . . . . . . . . . . . . . 491
Current Role of the Risk Concept in Regulatory Toxicology . . . . . . . . 493
Rolf Hertel, Michael Schwenk, and H. Paul A. Illing
Risk Cycles in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
H. Paul A. Illing and Michael Schwenk
Risk Minimization in Drug Development. Regulatory Aspects . . . . . . . 509
Elke Roehrdanz and Klaus Olejniczak
Importance of Physical-Chemical Properties for ToxicologicalRisk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Hans-Uwe Wolf and Michael Schwenk
Importance of Intrinsic Toxic Properties for Risk Assessment . . . . . . 525
Hermann Kappus and Michael Schwenk
Importance of Metabolism. Mechanistic Considerations Relevantfor Toxicological Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Franz Oesch and Jan G. Hengstler
Dose–Response Relationship and Extrapolationin Toxicology. Mechanistic and Statistical Considerations . . . . . . . . . . 547
Werner K. Lutz, Roman W. Lutz, David W. Gaylor, and
Rory B. Conolly
Importance of Exposure Level for Risk Toxicological Assessment . . . . 569
Hans Drexler and Anuradha Shukla
Risk Characterization in Regulatory Toxicology . . . . . . . . . . . . . . . . . 577
Maged Younes
Risk Evaluation in Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . . . 583
Maged Younes
Risk Comparison in Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Franz-Xaver Reichl
xii Contents
Risk-Benefit Considerations in Toxicology . . . . . . . . . . . . . . . . . . . . . . 601
Rolf Hertel, Michael Schwenk, and H. Paul A. Illing
Toxicological Risk Assessment in Different Jurisdictions . . . . . . . . . . . 607
Dietrich Henschler and Wolfgang Dekant
Part V Risk Management and Risk Communication . . . . . . . . . . . 615
Purpose of Risk Management in Regulatory Toxicology . . . . . . . . . . . 617
Rolf Hertel, Michael Schwenk, and H. Paul A. Illing
Assessment of Limit Values in Regulatory Toxicology . . . . . . . . . . . . . 627
Hermann H. Dieter
Limit Value Setting in Different Areas of Regulatory Toxicology . . . . 649
Klaus-Michael Wollin and Paul Illing
Registration and Approval in Regulatory Toxicology . . . . . . . . . . . . . . 661
Thomas Wallenhorst
Health Hazards Classification and Labeling . . . . . . . . . . . . . . . . . . . . . 677
Herbert Desel, Pieter Brekelmans, and Ronald de Groot
Human Biomonitoring. Its Importance in ToxicologicalRegulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Michael Wilhelm
Restrictions and Prohibitions as Tools in Regulatory Toxicology . . . . 703
Ullrich Kleeberg, Hans Jochen Kittel, and
Alfred Georg Hildebrandt
Observance of Susceptible Population Groupsin Regulatory Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
Ursula Gundert-Remy
Toxicological Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
Thomas Gudermann, Harald M€uckter, John H. Duffus, and
Hermann M. Bolt
Risk Management in Toxicological Disasters . . . . . . . . . . . . . . . . . . . . 739
Kai Kehe and John H. Duffus
Institutionalized Participation in Regulatory Toxicology . . . . . . . . . . . 747
Andreas D. Kappos
Risk Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
Werner Lilienblum and Marianne Lilienblum
Dealing with Diseases That Have Been Attributedto Chemical Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Thomas Zilker
Contents xiii
Reach (and CLP). Its Role in Regulatory Toxicology . . . . . . . . . . . . . . 779
Walter Aulmann and Nathan Pechacek
Bridging. The Regulation of Toxic Mixtures . . . . . . . . . . . . . . . . . . . . . 797
Walter Aulmann and Nathan Pechacek
Risk Assessment of Food Additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
Rainer G€urtler
Risk Assessment of Food Components with Botanical Origin . . . . . . . 813
Birgit Dusemund
Risk Assessment of Novel Food and Genetically ModifiedFood and Feed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
Annette Poting, Marianna Schauzu, Birgit Niemann, and
Regina Schumann
Notification of Cosmetic Products and Dangerous Mixtures inRegulatory Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
Herbert Desel, Pieter Brekelmans, and Ronald de Groot
Chemical and Biological Weapons and Their Regulation . . . . . . . . . . . 855
Horst Thiermann, Kai Kehe, Julia Riehm, and Lothar Zoller
Part VI Addendum: Tables and Lists . . . . . . . . . . . . . . . . . . . . . . . 869
Checklist: Toxicological Risk Assessment in Practice . . . . . . . . . . . . . . 871
Michael Schwenk and H. Paul A. Illing
Limit Values and Guideline Values in Regulatory Toxicology . . . . . . . 875
Karin Heine and Alexander Eckhardt
Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
Regulatory Toxicology: Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
Franz-Xaver Reichl and Gisela Degen
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
xiv Contents
Contributors
Hans-Juergen Ahr Investigational Toxicology, Bayer Pharma AG, Wuppertal,
Germany
Klaus E. Appel Federal Institute for Risk Assessment, Berlin, Germany
Walter Aulmann Ecolab Deutschland GmbH, Monheim, Germany
Hermann M. Bolt Leibniz Research Centre for Working Environment and
Human Factors, Dortmund, Germany
Scott Boyer Global Head of Molecular and Investigational Toxicology, Global
Safety Assessment, AstraZeneca R&D, Molndal, Sweden
Pieter Brekelmans National Poisons Information Center (NVIC), University
Medical Center Utrecht, Utrecht, GA, The Netherlands
Thomas R. H. B€uch Rudolf-Boehm Institute of Pharmacology and Toxicology,
Clinical Pharmacology, University of Leipzig, Leipzig, Germany
Carlo Chiavaroli Voisin Consulting Life Sciences, Lausanne, Switzerland
Rory B. Conolly Integrated Systems Toxicology Division, NHEERL/ORD,
U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
Ronald de Groot National Poisons Information Center (NVIC), University
Medical Center Utrecht, Utrecht, GA, The Netherlands
Gisela Degen Leibniz Research Centre for Working Environment and Human
Factors, Dortmund, Germany
Wolfgang Dekant Institute for Toxicology, University of Wurzburg, W€urzburg,Germany
Herbert Desel GIZ-Nord Poisons Center, University Medical Center Gottingen -
Georg-August-Universit€at, Gottingen, Lower Saxony, Germany
Hermann H. Dieter Department of Toxicology of Drinking-Water, Federal
Environment Agency of Germany/Umweltbundesamt (UBA), Dessau-Roßlau,
Germany
xv
Kevin Doughty Product Stewardship Manager, Bayer CropScience, Registration
Department, Monheim, Germany
Hans Drexler Institute and Outpatient Clinic for Occupational, Social and
Environmental Medicine, University of Erlangen-Nuremberg, FAU, Erlangen,
Germany
John H. Duffus The Edinburgh Centre of Toxicology, Edinburgh, Scotland, UK
J€urgen Durner Walther-Straub-Institute of Pharmacology and Toxicology,
Ludwig-Maximilians-University of Munich, Munich, Germany
Birgit Dusemund Department of Food Safety, Federal Institute for Risk
Assessment (BfR), Berlin, Germany
Alexander Eckhardt Toxicology of Drinking Water and Swimming Pool Water,
Federal Environment Agency, Bad Elster, Germany
Lutz Edler Department of Biostatistics –C060, German Cancer Research Center
(DKFZ), Heidelberg, Germany
Wolfgang Eisenmenger Ethics Committee Ludwig-Maximilians-University
Munich, Munich, Germany
Heidrun Ellinger-Ziegelbauer Investigational Toxicology, Bayer Pharma AG,
Wuppertal, Germany
Norbert Englert Formerly: Federal Environmental Agency, Berlin, Germany
Rainer Fehr Department of Public Health, University of Bielefeld, Bielefeld,
Germany
Johannes Georg Filser Institute for Toxicology and Environmental Hygiene,
Technical University of Munich, Munich, Germany
David W. Gaylor Formerly: National Center for Toxicological Research, Food
and Drug Administration, Jefferson, AR, USA
Helmut Greim Institute for Toxicology and Environmental Hygiene, Technical
University Munich, Freising-Weihenstephan, Bavaria, Germany
Thomas Gudermann Walther-Straub-Institute of Pharmacology and Toxicology,
Ludwig-Maximilians-Universit€at M€unchen, Munich, Germany
Ursula Gundert-Remy Institute for Clinical Pharmacology and Toxicology/
Institut f€ur Klinische Pharmakologie und Toxikologie, Charite
Universit€atsmedizin Berlin, Berlin, Germany
Rainer G€urtler Department of Food Safety, Federal Institute for Risk Assessment
(BfR), Berlin, Germany
Ozkaynak Haluk U.S. Environmental Protection Agency (EPA), Durham, NC, USA
xvi Contributors
Stephen Harston Hofheim am Taunus, Germany
Martin Hassauer Research and Advisory Institute for Hazardous Substances,
FoBiG, Freiburg, Germany
Hans-Karl Heim Federal Institute for Drugs and Medical Devices, Bonn,
Germany
Karl Georg Heimann Expert Regulatory Toxicology, Koln, Germany
Karin Heine Research and Advisory Institute of Hazardous Substances, FoBiG -
Forschungs- und Beratungsinstitut Gefahrstoffe GmbH, Freiburg, Germany
Gerhard Heinemeyer Federal Institute for Risk Assessment, Berlin, Germany
Jan G. Hengstler Leibniz Research Centre for Working Environment and Human
Factors at the Technical University of Dortmund (IfADo), Dortmund, Germany
Beate Henrikus Ethics Committee Ludwig-Maximilians-University Munich,
Munich, Germany
Dietrich Henschler Institute for Toxicology, University of Wurzburg, W€urzburg,Germany
Rolf Hertel Formerly Federal Institute of Risk Assessment, Berlin, Germany
Alfred Georg Hildebrandt (former) Head of Federal Institute of Drugs and
Medicinal Products, Bonn, Germany
Ludwig A. Hothorn Leibniz University Hannover, Hannover, Germany
H. Paul A. Illing Centre for Occupational and Environmental Health, University
of Manchester, Manchester, UK
Paul Illing Consultancy Services Ltd, Heswall, Wirral, UK
Matt C. Jacobsen AstraZeneca, R&D Innovative Medicines, Global Safety
Assessment, Macclesfield, Cheshire, UK
Bernd Kaina Department of Toxicology, University Medical Center, Mainz,
Germany
Andreas D. Kappos Former Head of Department of Health and Environment,
Hamburg Health Authority, Frankfurt, Germany
Hermann Kappus Formerly MAK-Commission, Freising-Weihenstephan,
Germany
Wolfgang Kaufmann Merck KGaA, Non-Clinical Safety, Global Pathology and
Reproduction Toxicology, Darmstadt, Germany
Kai Kehe Bundeswehr Medical Academy, Military Medical Research and
Development, Munich, Germany
Contributors xvii
Agnieszka Kinsner-Ovaskainen European Commission DG Joint Research
Centre, Institute for Health and Consumer Protection, Ispra (Varese), Italy
Hans Jochen Kittel Institute for European Projects/Institut f€ur Europaprojekte
e.V, Berlin, Germany
Ullrich Kleeberg Berlin Medical Association – Berliner Medizinische
Gesellschaft, Berlin, Germany
Rainer Konietzka Federal Environment Agency, Dessau-Roßlau, Germany
Gert Ulrich Kuerzel Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst,
Frankfurt am Main, Germany
Bernhard Liebl Bavarian Health and Food Safety Agency, Oberschleissheim,
Germany
Ines Liebl Bavarian State Ministry for the Environment and Public Health,
Munich, Germany
Marianne Lilienblum Faculty of Social and Behavioural Sciences, University of
Amsterdam, Amsterdam, The Netherlands
Werner Lilienblum Formerly: Governmental Institute of Public Health,
Hannover, Germany
Mathias Locher Covagen, Zurich, Schlieren, Switzerland
Roman W. Lutz Formerly: Seminar for Statistics, Swiss Federal Institute of
Technology, Z€urich, Switzerland
Werner K. Lutz Institute of Pharmacology and Toxicology, University of
W€urzburg, W€urzburg, Germany
Inge Mangelsdorf Department Chemical Risk Assessment, Fraunhofer Institute
of Toxicology and Experimental Medicine, Hannover, Germany
Christine Mauriac Sanofi R&D, Chilly-Mazarin, France
Peter Mayer Federal Institute for Drugs and Medical Devices, Bonn, Germany
Robert L. Maynard Bideford, Devon, UK
Odile Mekel Department of Prevention and Innovation, Innovation in Health,
NRW Centre for Health, Bielefeld, Germany
Klaus Morike Division of Clinical Pharmacology, Eberhard Karls University
T€ubingen, T€ubingen, Germany
Harald M€uckter Walther-Straub-Institute of Pharmacology and Toxicology,
Ludwig-Maximilians-Universit€at M€unchen, Munich, Germany
xviii Contributors
Ludwig M€uller State Health Administration, unit 44 (Pharmaceutics, Toxicology,
Genetic Engeneering), Bremen, Germany
Hans-G€unter Neumann Department of Toxicology, University of W€urzburg,W€urzburg, Germany
Birgit Niemann Department of Food Safety, Federal Institute for Risk
Assessment (BfR), Berlin, Germany
Franz Oesch Oesch-Tox Toxicological Consulting and Expert Opinions
GmbH&Co.KG, Wackernheim, Germany
Klaus Olejniczak Non-clinical Regulatory Consultant, Berlin, Germany
J€urgen Pauluhn Experimental Toxicology, Bayer HealthCare, Wuppertal,
Germany
Nathan Pechacek Ecolab Inc, St. Paul, MN, USA
Annette Poting Department of Food Safety, Federal Institute for Risk Assessment
(BfR), Berlin, Germany
Ulrich Ranft IUF - Leibniz Research Institute for Environmental Medicine,
D€usseldorf, Germany
Franz-Xaver Reichl LMU Munich, Munich, Germany
Julia Riehm Bundeswehr Institute of Microbiology, Munich, Germany
Leonard Ritter School of Environmental Sciences, University of Guelph, Bovey
Bldg, Canada
Elke Roehrdanz Federal Institute for Drugs and Medical Devices, Bonn,
Germany
Manfred Ruthsatz Nestle Health Science, Vevey, Switzerland
Eva A. M. Sch€afer Walther-Straub Institute of Pharmacology and Toxicology,
Ludwig-Maximilian University Munich, Munich, Germany
Marianna Schauzu Department of Food Safety, Federal Institute for Risk
Assessment (BfR), Berlin, Germany
Klaus Schneider Research and Advisory Institute for Hazardous Substances,
FoBiG, Freiburg, Germany
Dieter Schrenk Food Chemistry and Toxicology, Technical University of
Kaiserslautern, Kaiserslautern, Germany
Michael Sch€umann Department of Health and Consumer Protection, Hamburg,
Germany
Contributors xix
Regina Schumann Department of Food Safety, Federal Institute for Risk
Assessment (BfR), Berlin, Germany
Michael Schwenk Formerly Medical School, Hannover, Germany
Anuradha Shukla Institute and Outpatient Clinic for Occupational, Social and
Environmental Medicine, University of Erlangen-Nuremberg, FAU, Erlangen,
Germany
Horst Spielmann Institute of Pharmacy, Freie Universit€at Berlin, Berlin, Germany
Neill H. Stacey Southern Cross Pharma Pty Ltd, Malua Bay, NSW, Australia
Thomas Steger-Hartmann Head of Investigational Toxicology, Global Early
Development, Bayer Healthcare, Berlin, Germany
Roland Suchenwirth Head of Department of Environmental Medicine,
Governmental Institute of Public Health of Lower Saxony, Hannover, Germany
Horst Thiermann Bundeswehr Institute of Pharmacology and Toxicology,
Munich, Germany
Adam D. Thomas Department of Toxicology, University Medical Center, Mainz,
Germany
Angelika Tritscher Department of Food Safety and Zoonoses, World Health
Organization, Geneva 27, Switzerland
Emmanuelle Voisin Voisin Consulting Life Sciences, Boulogne, France
Gerhard Volland Schwabisch Gmund, Germany
Eckhard von Keutz Bayer HealthCare, Global Early Development, Wuppertal,
Germany
Thomas Wallenhorst Sanitized AG, Burgdorf, Switzerland
David C. Watts School of Dentistry and Photon Science Institute, University of
Manchester, Manchester, UK
Gregory A. Wellenius Department of Epidemiology, Brown University,
Providence, RI, USA
Michael Wilhelm Department of Hygiene, Social and Environmental Medicine,
Ruhr-University Bochum, Bochum, Germany
Hans-Uwe Wolf Department of Pharmacology and Toxicology, University of
Ulm, Ulm, Germany
Klaus-Michael Wollin Lower Saxony Governmental Institute of Public Health,
Hannover, Germany
Maged Younes Former Director, Food Safety and Zoonoses, World Health
Organization (WHO), Mies, Switzerland
xx Contributors
Alexandre Zenie Joint Research Centre, European Commission, Ispra, Italy
Thomas Zilker Formerly head of the Department for Clinical Toxicology,
Medizinische Klinik Klinikum rechts der Isar Technical University M€unchen,Munich, Germany
Lothar Zoller Bundeswehr Institute of Microbiology, Munich, Germany
Contributors xxi
Introduction
“All things are poisonous, there is nothing that is not poisonous; it is the dose that
makes the poison.” This saying was coined 500 years ago by Paracelsus (Phillipus
Aureolus Theophrastus Bombastus von Hohenheim, 1493–1541). It still serves as
a maxim for toxicological risk assessment, although what constitutes a poison
(or harmful chemical or biological agent) has changed dramatically.
New chemical entities are synthesized in increasing numbers and new uses are
found for existing chemical entities. These new chemicals and new uses mean that
chemicals have to be tested for their toxic properties. Only then can it be decided
whether the intended applications pose a toxicological risk to humans or the
environment.
Regulatory toxicology has become increasingly complex and fragmented in
recent years, and the number of regulated areas continues to increase. New
computer-based methods help to make predictions of structure–activity relation-
ships more reliable and effective. At the same time, new cell biological and
molecular biological methods are introduced into toxicology, partly to replace
animal experiments and partly to augment them. The actual significance of some
of these tests for risk assessment may be unclear at first, but becomes clear with
experience. Finally, an increasing number of risk extrapolation models are evalu-
ated and used.
Nevertheless, one can consider regulatory toxicology as a uniform discipline, for
it pursues a common goal, to protect human health and the environment, and uses
a specific methodology for testing and evaluating. Thus, regulatory toxicologists in
industry, government, universities, and other institutions have a common basis for
action, even though the interest of each of the institutions may differ.
The present International edition is based on a book that was published in
German by Springer in 2004. Toxicologists from the various working areas con-
sidered it necessary to collect all the aspects of regulatory toxicology in a single
book. The present edition was thoroughly revised and updated by the authors and
their international coauthors. This English edition makes the book and its chapters
accessible to toxicologists worldwide. It is hoped that this will contribute to an
improvement of the understanding between countries and between regulated areas.
It is for professional toxicologists, but also should be of interest to other pro-
fessionals who are involved in the protection of the environment and human health.
xxiii
Opinions expressed are those of the individual authors and do not necessarily
represent the views of their institutions.
The editors have sought to bring consistency to the diversity of opinions
concerning toxicological risk assessment. We thank all the authors for their valu-
able input. We also thank Britta M€uller, Susanne Friedrichsen and their colleagues
Barbara Wolf, Ingrid Fischer and Ariane Israel at Springer for their excellent
continuing support during the writing of this book. Finally, we thank Dr. Paul Illing
for his help in translating the linking text.
F.-X. Reichl, Munich
M. Schwenk, T€ubingen
xxiv Introduction
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