Perspectives on Biologically Based Cancer Risk Assessment

328 Pages·1999·21.49 MB·English

by  V. J. Cogliano, E. D. Kroese, G. A. Zapponi (auth.), Vincent James Cogliano, E. Georg Luebeck, Giovanni A. Zapponi (eds.)

Perspectives on
Biologically Based
Cancer Risk Assessment
NATO • Challenges of Modern Society
A series of volumes comprising multifaceted studies of contemporary problems
facing our society, assembled in cooperation with NATO Committee on the
Challenges of Modern Society.
Recent volumes in this series:
Volume 7 AIR POLLUTION MODELING AND ITS APPLICATION IV
Edited by C. De Wispelaere
Volume 8 CONTAMINATED LAND: Reclamation and Treatment
Edited by Michael A. Smith
Volume 9 INTERREGIONAL AIR POLLUTION MODELING: The State of the Art
Edited by S. Zwerver and J. van Ham
Volume 10 AIR POLLUTION MODELING AND ITS APPLICATION V
Edited by C. De Wispelaere, Francis A. Schierm eier,
and Noor V. Gillani
Volume 11 AIR POLLUTION MODELING AND ITS APPLICATION VI
Edited by Han van Dop
Volume 12 RISK MANAGEMENT OF CHEMICALS IN THE ENVIRONMENT
Edited by Hans M. Seip and Anders B. Heiberg
Volume 13 AIR POLLUTION MODELING AND ITS APPLICATION VII
Edited by Han van Dop
Volume 14 HEALTH AND MEDICAL ASPECTS OF DISASTER PREPAREDNESS
Edited by John C. Duffy
Volume 15 AIR POLLUTION MODELING AND ITS APPLICATION VIII
Edited by Han van Dop and Douw G. Steyn
Volume 16 DIOXIN PERSPECTIVES: A Pilot Study on International Information
Exchange on Dioxins and Related Compounds
Edited by Erich W. Bretthauer, Heinrich W. Kraus,
and Alessandro di Domenico
Volume 17 AIR POLLUTION MODELING AND ITS APPLICATION IX
Edited by Han van Dop and George Kallos
Volume 18 AIR POLLUTION MODELING AND ITS APPLICATION X
Edited by Sven-Eric Gryning and Millan M. Millan
Volume 19 METHODS OF PESTICIDE EXPOSURE ASSESSMENT
Edited by Patricia B. Curry, Sesh Iyengar, Pamela A. Maloney,
and Marco Maroni
Volume 20 PLANNING ESTUARIES
Cees-Jan van Westen and Reinier Jan Scheele
Volume 21 AIR POLLUTION MODELING AND ITS APPLICATION XI
Edited by Sven-Eric Gryning and Francis A. Schiermeier
Volume 22 AIR POLLUTION MODELING AND ITS APPLICATION XII
Edited by Sven-Eric Gryning and Nadine Chaumerliac
Volume 23 PERSPECTIVES ON BIOLOGICALLY BASED CANCER RISK
ASSESSMENT
Edited by Vincent James Cogliano, E. Georg Luebeck,
and Giovanni A. Zapponi
Perspectives on
Biologically Based
Cancer Risk
Assessment
Edited by
Vincent James Cogliano
United States Environmental Protection Agency
Washington, DC
E. Georg Luebeck
Fred Hutchinson Cancer Research Center
Seattle, Washington
and
Giovanni A. Zapponi
National Institute of Health
Rome, Italy
Published in cooperation with
NATO Committee on the Challenges of Modern Society
Springer Science+Busineas Media. LLC
Llbrary of Congress Cataloglng-ln-Publlcatlon Data
Perspectlves on blologlcally based cancer rlsk assessment I edlted by
Vlncent James Cogllano, E. Georg Luebeck, and Glovann~ A. Zapponl.
p. cm. -- (NATO challenges of modern soclety ; v. 23)
"Publlshedln cooperat Ion wlth NATO Conlttee on the Challenges of
Modern Soclety."
Includes blbllographlcal references and Index.
ISBN 978-1-4613-7149-6 ISBN 978-1-4615-4741-9 (eBook)
DOI 10.1007/978-1-4615-4741-9
1. Carc1nogens--Dose-response relatlonshlp. 2. Cancer--Rtsk
factors. 3. Health rlsk assessment. 4. Tumor markers.
1. Cogliano, Vincent James. II. Luebeck, E. Georg. III. Zapponl,
Gtovanni A. IV. Ser ies.
[DNLM: 1. Neop 1a sms--et 1o 1o gy. 2. Ri sk Assessment. az 202 P467
19991
RC268.65.P47 1997
616.99'4071--dc21
DNLM/DLC
for Llbrary of Congress 99-30081
CIP
Proceedings of the Final Report of the NATO CCMS Pilot Study on Dose Response Analysis
and Biologically-Based Risk Assessment of Initiator and Promoter Carcinogens
ISBN 978-1-4613-7149-6
© 1999 Springer Science+Business Media New York
Originally published by Kluwer AcademicjPlenum Publishers in 1999
Softcover reprint of the hardcover 1s t edition 1999
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any
form or by any means, electronic, mechanical. photocopying, microlilming, record ing, or
otherwise, without written permission from the Publisher
Preface
The first meeting of the NATO/CCMS Pilot Study "Dose-Response Analysis and
Biologically-Based Risk assessment for Initiator and Promoter Carcinogens" was held
in Rome, Italy, in the spring of 1991, and was followed by annual or bi-annual meetings
held in Germany, Greece, Netherlands, Portugal, USA, up to the end of 1995; in large
part supported by NATO/CCMS grants or fellowships, and organized by Pilot Study
participants. The Pilot Study activity has been characterized by a higly collaborative
atmosphere, which was essential for a deep and detailed analysis of a problem on which
different points of view, methodological approaches and regulations exist in the various
member countries.
The Pilot Study was aimed at proposing a carcinogenic risk assessment procedure
which is based on a detailed analysis of the relevant biological processes, and may also
consent the verification of hypotheses. The specific form of theoretical and mathe-
matical models is identified by considering and using the whole set of objective data
available. The multidisciplinary approach of the pilot study is reflected by the struc-
ture of this book. Each chapter is the result of the cooperation of several authors from
different countries; its objective was to produce a comprehensive manual that includes
both theoretical and practical information.
The main topics treated are:
• Basic Assumptions in Carcinogenic Risk Assessment
• The Biological Basis
• Data Sources
• The Use of Biomarkers in Risk Assessment
• Multistage Models
• Biologically-Based Modelling
• Statistical Considerations
• Case Studies and Practical Applications
v
vi PREFACE
The theoretical, mathematical and statistical basis of advanced carcinogenic risk
assessment, together with its biological basis, are discussed in detail, keeping in mind the
possible interests of readers specialized in this field as well as readers simply interested
in the general aspects of carcinogenic risk assessment.
We are greatly indebted to the NATO/CCMS programme direction in Bruxelles
and to our National CCMS Coordinators for the fundamental help they have provided
to our work, as well as to all the institutes which have hosted and given support to the
meetings.
The authors wish to express their appreciation to Ms. Lynn Schoolfield of the
U.S. Environmental Protection Agency for her extra efforts to host three Pilot Study
meetings in Washington and her devoted support of NATO-CCMS.
Contents
1. INTRODUCTION 1
V.J. Cogliano, E.D. Kroese, G.A. Zapponi, L. Attias, and I. Marcello
1.1. DOSE-RESPONSE ASSESSMENT IN NATO COUNTRIES 1
1.1.1. European Community .. 1
1.1.1.1. European Union 2
1.1.1.2. The Netherlands 2
1.1.1.3. United Kingdom 3
1.1.1.4. Germany 4
1.1.1.5. Denmark 4
1.1.1.6. Norway 5
1.1.1. 7. Other countries . 5
1.1.1.8. Concluding remarks 6
1.1.2. United States ........ . 6
1.1.2.1. Use of Dose-Response Assessment. 6
1.1.2.2. Evolution of Dose-Response Assessment 8
1.1.3. Differences between the United States and European Countries 9
1.2. FUTURE DIRECTIONS IN DOSE-RESPONSE ASSESSMENT. 10
1.3. BRIEF CONSIDERATIONS ON SOME COMMONLY USED
PARAMETERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.1. Variation in Carcinogenic Potency and in Parameters Adopted
for Carcinogen Regulation . . . . . . . . . . . . . . . . . . . .. 11
1.3.2. Toxicity Data and Carcinogenic Potencies: Correlation between
Parameters Adopted for Risk Assessment . . . . . . . . . . . . 13
1.3.3. The Linearized Multistage Model and Benchmark Dose (BD)
Approaches: Dose-Response Analysis May Provide a Unique
Framework for Both the Carcinogenic and Noncarcinogenic
Procedures ......... . 15
1.4. STRUCTURE OF THIS REPORT 17
1.5. REFERENCES .......... . 17
vii
VIlI CONTENTS
2. THE BIOLOGICAL BASIS OF CANCER 21
V.J. Cogliano, A. Kappas, G. Voutsinas, and G.A. Zapponi
2.1. INTRODUCTION .............. . 21
2.2. CELL PROLIFERATION . . . . . . . . . . . 23
2.3. CELL PROLIFERATION AND MUTATION 26
2.4. DIFFERENCES IN SUSCEPTIBILITY .,. 27
2.5. MECHANISMS OF INHIBITION IN MUTAGENESIS AND
CARCINOGENESIS . . . . . . . . . . . . . . . . . . 29
2.5.1. Introduction. . . . . . . . . . . . . . . . . . . 29
2.5.2. Inhibition in Mutagenesis and Carcinogenesis 30
2.5.3. Extracellular Inhibition. . . . . 30
2.5.4. Intracellular Inhibition . . . . . . . . . . . . . 32
2.5.5. Inhibitors of Cancer Initiation . . . . . . . . . 33
2.5.6. Inhibitors of Tumor Promotion and Progression 37
2.5.7. Dual Effects of Inhibitors. 38
2.6. REFERENCES . . . . . . . . . . . . . . . . . . . . . . 39
3. SOURCES OF DATA FOR CANCER RISK ASSESSMENT 49
A. Kappas, V.J. Cogliano, K. Watanabe, and G.A. Zapponi
3.1. INTRODUCTION ................. . 49
3.2. IN VITRO AND SHORT TERM TESTING ... . 49
3.3. TRENDS IN ANIMAL TOXICOLOGY TESTING 53
~~.4. CELL PROLIFERATION ............. . 56
3.4.1. Quantitative Methods and Data Sources .. 57
3.4.1.1. Direct Measurements of Cell Division. 58
3.4.1.2. Serum Biomarkers of Cellular Proliferation. 59
3.4.1.3. Cell kinetics of EAF ... 60
3.5. SOURCES OF TOXICOKINETIC DATA 60
3.5.1. Introduction. . . . . 60
3.5.2. Model Parameters .. 61
3.5.2.1. Physiologic . 61
3.5.2.2. Biochemical. 61
3.5.3. Toxicokinetic Data .. 62
3.6. INTER- AND INTRA-SPECIES VARIABILITY 62
3.6.1. Variability in Genetic Damage . 62
3.6.2. The Parallelogram Model 68
3.7. REFERENCES ............ . 68
CONTENTS ix
4. USE OF BIOCHEMICAL AND MOLECULAR BIOMARKERS
FOR CANCER RISK ASSESSMENT IN HUMANS 81
J.J. Amaral-Mendes and E. Pluygers
4.1. INTRODUCTION ...................... . 81
4.2. THE INITIATORY COMPLEX AND ITS MODULATORS 88
4.2.1. Biomarkers of Exposure .. 88
4.2.1.1. The External Dose ...... . 88
4.2.1.2. The Internal Dose ...... . 88
4.2.1.3. The Biologically Effective Dose 89
4.2.1.4. Interaction with Relevant Macromolecules 89
4.2.1.5. Cytogenetic Biomarkers of Early Effects 93
4.2.1.6. Discussion about the Biomarkers of Exposure 97
4.2.2. Biomarkers of Individual Susceptibility . . . . . 98
4.2.2.1. Phase I Enzymes and Related Markers 98
4.2.2.2. Phase II Enzymes ..... 101
4.2.3. DNA Repair and its Variability . . . . . . . . . 102
4.2.3.1. Assessment of DNA Repair . . . . . . 103
4.2.3.2. Mismatch Repair, Microsatellite Instability and
Mutator Phenotype ............ 107
4.2.3.3. Other Genetic Instability Syndromes . . . 110
4.2.3.4. Restatement of the DNA Repair Problem 110
4.2.4. Exogenous Nutritional Factors. . . . . . . . . . . . 111
4.3. THE DETERMINANTS OF THE CLONAL EXPANSION OF THE
INITIATED CELLS .......... 112
4.3.1. Basic Mechanisms. . . . . . . . 112
4.3.2. Cell Cycle Control Mechanisms 114
4.3.2.1. p53 .......... 114
4.3.2.2. The Rb tumour suppressor gene. 117
4.3.2.3. The myc Oncogene . . . . . . . . 117
4.3.2.4. Low Molecular Weight Regulatory Proteins 118
4.3.3. Growth Factors, Growth Factor Receptors and
Signal Transduction Pathways . . . . . . 120
4.3.3.1. Growth Factors and Receptors 120
4.3.3.2. Growth Factor Receptors ... 125
4.3.4. Signal Transduction Pathways . . . . . . 128
4.3.4.1. Transmembrane Receptors with Intrinsic TRK Activity 129
4.3.4.2. Receptors with Seven Transmembrane-spanning Domains131
4.3.4.3. Cytoskeletal Signal Transduction Pathways .... 132
4.3.5. The Outcome: The Clonal Expansion of the Initiated Cells . 132
4.3.5.1. Proliferation ..................... 132
4.3.5.2. Apoptosis....................... 136
4.4. ADJUVANT DETERMINANTS OF THE CLONAL EXPANSION 137
4.4.1. Oxidative Damage and its Repair . . . . . . . . . . . . . . . 137
x CONTENTS
4.4.1.1. Identification of Oxidative Damage . . . . . . . 138
4.4.1.2. Thymine Glycol and Thymidine Glycol. . . . . 138
4.4.1.3. 8-Hydroxydeoxyguanosine (80HdG) ...... 139
4.4.1.4. ADPRT...................... 139
4.4.1.5. Others....................... 139
4.4.2. Intercellular Communication ........ . 139
4.4.3. Intercellular Adhesion ........... . 140
4.4.4. Cell-Surface Structures ........... . 142
4.4.5. Miscellaneous Determinants 145
4.4.5.1. Immune Status .. 145
4.4.5.2. Nutritional Status 146
4.5. CONCLUSION .......... . 150
4.6. ACKNOWLEDGMENTS ...................... 151
4.7. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 152
5. THE MULTISTAGE MODEL OF CARCINOGENESIS:
A CRITICAL REVIEW OF ITS USE 183
V.J. Cogliano, E.G. Luebeck, and G.A. Zapponi
5.1. INTRODUCTION .............. . 183
5.2. HISTORICAL ANTECEDENTS OF THE MULTISTAGE MODEL ., 184
5.3. THE ARMITAGE-DOLL MULTISTAGE MODEL ........... 186
5.4. DERIVATION, RATIONALE AND MATHEMATICAL FORM OF THE
MODEL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187
5.5. THE "LINEARIZED MULTISTAGE MODEL" ............ 191
5.6. TIME-DEPENDENT NON-CONSTANT EXPOSURE PATTERNS:
THEIR INFLUENCE ON MULTISTAGE-DERIVED
RISK ESTIMATES . . . . . . . . . . . . . . . . . . . . . . . . . . .. 194
5.7. CONSIDERATION OF PHARMAKOKINETICS IN MULTISTAGE
MODELING. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
5.8. THE PROBLEM OF MULTIPLE EXPOSURE: MULTISTAGE
CARCINOGENESIS THEORY AND ADDITIVE AND
MULTIPLICATIVE MODELS. . . . . . . . . . . . . . . . . . . . 198
5.9. CRITICAL REVIEvV OF THE MODEL . . . . . . . . . . . . . . . .. 198
5.10. DISCUSSION . . .. ....... . . . . . . . . . . . . 201
5.11. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201
6. BIOLOGICALLY BASED MODELS OF CARCINOGENESIS 205
E.G. Luebeck, K. Watanabe, and C. Travis
6.1. INTRODUCTION .......................... 205
6.2. A BRIEF HISTORY OF BIOLOGICALLY-BASED CANCER
MODELS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
6.3. TWO-MUTATION CLONAL EXPANSION MODEL . . . . . . . . .. 208