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

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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