Biologically Based Methods for Cancer Risk Assessment

352 Pages·1989·32.75 MB·English

by  Curtis C. Travis (auth.)

Biologically Based
Methods for Cancer
Risk Assessment
NATO ASI Series
Advanced Science Institutes Series
A series presenting the results of activities sponsored by the NA TO Science Committee,
which alms at the dissemination of advanced scientific and technological knowledge,
with a view to strengthening links between scientific communities.
The series is published by an international board of publishers in conjunction with the
NATO Scientific Affairs Division
A Life Sciences Plenum Publishing Corporation
B Physics New York and London
C Mathematical Kluwer Academic Publishers
and Physical Sciences Dordrecht, Boston, and London
o Behavioral and Social Sciences
E Applied Sciences
F Computer and Systems Sciences Springer· Verlag
G Ecological Sciences Berlin, Heidelberg, New York, London,
H Cell Biology Paris, and Tokyo
Recent Volumes in this Series
Volume 156-Anirnal Sonar: Processes and Performance
edited by Paul E. Nachtigall and Patrick W. B. Moore
Volume 157-Plasma Membrane Oxidoreductases in Control of
Animal and Plant Growth
edited by Frederick L. Crane, D. James Morre, and Hans LOw
Volume 158-Biocompatibility of Co-Cr-Ni Alloys
edited by Hartmut F. Hildebrand and Maxime Champy
Volume 159-Blologlcally Based Methods for Cancer Risk Assessment
edited by Curtis C. Travis
Volume 160-Early Influences Shaping the Individual
edited by Spyros Doxiadis
Volume 161-Research in Congenital Hypothyroidism
edited by F. Delange, D. A. Fisher, and D. Glinoer
Volume 162-Nematode Identification and Expert System Technology
edited by Renaud Fortuner
Series A: Life Sciences
Biologically Based
Methods for Cancer
Risk Assessment
Edited by
Curtis C. Travis
Oak Ridge National Laboratory
Oak Ridge, Tennessee
Plenum Press
New York and London
Published in cooperation with NATO Scientific Affairs Division
Proceedings of a NATO Advanced Research Workshop on
Biologically Based Methods for Cancer Risk Assessment,
held June 11-16,1988,
in Corfu, Greece
Library of Congress Cataloging in Publication Data
NATO Advanced Research Workshop on Biologically Based Methods for Cancer
Risk Assessment (1988: Kerkyra, Greece)
Biologically based methods for cancer risk assessment.
(NATO ASI series. Series A, Life sciences; vol. 159)
'Proceedings of a NATO Advanced Research Workshop on Biologically Based
Methods for Cancer Risk Assessment, held June 11-16, 1988, in Corfu, Greece
T.p. verso.
"Published in cooperation with NATO Scientific Affairs Division."
Includes bibliographies and index.
1. Carcinogenicity testing-Congresses. 2. Health risk assessment-Con
gresses. I. Travis, C. C. II. North Atlantic Treaty Organization. Scientific Affairs
Division. III. Title. IV. Series: NATO advanced science institutes series. Series A,
Life sciences; v. 159. [DNLM: 1. CarCinogens-congresses. 2. Neoplasms
chemically induced-congresses. 3. Risk Factors-congresses. QZ 202 N2784b
1988]
RC268.65.N36 1988 616.99'4075 88-35675
ISBN-13: 978-1-4684-5627-1 e-ISBN-13: 978-1-4684-5625-7
DOl: 10.1007/978-1-4684-5625-7
© 1989 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1 989
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
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, microfilming,
recording, or otherwise, without written permission from the Publisher
PREFACE
"Biologically Based Methods for Cancer Risk Assessment",
an Advanced Research Workshop, (ARW) sponsored by the North
Atlantic Treaty Organization (NATO) was held in Corfu, Greece
in June, 1989. The intent of the workshop was to survey
available pharmacokinetic and pharmacodynamic methods in
cancer risk assessment and identify methodological gaps and
research needs for biologically based methods in cancer risk
assessment. Incorporation of such methods represents one of
the most challenging areas for risk assessment. The workshop
included an international group of invited experts in the
field and provided for a dynamic exchange of ideas and
accomplishments.
Some of the major topics discussed were:
*
Inventory of available pharmacokinetic and
pharmacodynamic methods for cancer risk assessment.
*
Identification of methodology gaps and research needs
in biologically based methods in cancer risk
assessment.
*
Development of a general framework to guide future
cancer risk assessment research.
This book is a compilation of the papers presented at
the workshop and is intended to provide guidance for future
research to reduce uncertainties in the cancer risk
assessment process.
The primary sponsorship of this ARW by NATO and the
advice and cooperation of Dr. C. Sinclair of the Scientific
affairs Division are gratefully acknowledged.
Acknowledgement is also given to the National Science
Foundation for its support.
The organization of the ARW and the preparation of this
book have required considerable help from many other sources.
I owe special gratitude to the co-director, Dr. Vincent
Covello, and to the many lecturers and participants who
shared their knowledge and expertise to help make the ARW a
scientifically stimulating and socially enjoyable workshop
and last but not least to my assistant, Mary Oran.
Curtis C. Travis
v
CONTENTS
INTRODUCTION
Research Needs for Biologically Based Risk Assessment.... 1
C. C. Travis
BIOLOGICAL BASES FOR CANCER MODELS
Multistage Models for Cancer Risk Assessment ..... . 9
S. H. Moolgavkar
Understanding Multi-Stage Carcinogenesis at the
Molecular Level: Notes on Recent Progress .......... 21
M. Hollstein and H. Yamaskai
The Use of Enzyme-Altered Foci for Risk Assessment
of Hepatocarcinogens ...................... . 31
M. Schwarz, D. Pearson, A. Buchmann and
W. Kunz
Pathogenic Interrelationship of Focal Lesions,
Nodules, Adenomas and Carcinomas in the
Multistage Evolution of Azaserine-Induced
Rat Pancreas Carcinogenesis ......................... 41
E. Scherer, J. Bax and R. A. Woutersen
Phenotypic Cellular Changes in Multistage Carcinogenesis. 55
P. Bannasch
INTERSPECIES EXTRAPOLATION OF PHARMACOKINETICS
Interspecies Extrapolation ... 63
C. C. Travis
Comparative Carcinogenesis: Is There a Theoretical
Approach to Inter-Species Similarity ................ 79
P. Tautu
Biological Basis for Interspecies Extrapolations of
Halogenated Solvents and of 1,3-Butadiene ........... 111
H. M. Bolt and R. J. Laib
Species-Specific Inhalation Pharmacokinetics of 2-
Nitropropane, Methyl Ethyl Ketone, and n-Hexane ..... 123
W. Kessler, B. Denk, and J. G. Filser
PROMOTION AS A FACTOR IN CARCINOGENESIS
Overview of Promotion as a Mechanism in Carcinogenesis ... 141
M. Castagna and I. Marte11y
Hepatocarcinogenesis by Non-Genotoxic Compounds .......... 155
R. Schulte-Hermann, W. Parzefa11, W. Bursch,
I. Timmermann-Trosiener
The Role of Inhibited Intercellular Communication in
Carcinogenesis: Implications for Risk Assessment
From Exposure to Chemicals .......................... 165
J. E. Trosko and C. C. Chang
Comparative Analyses of the Timing and Magnitude of
Genotoxic and Nongenotoxic Cellular Effects
in Urinary Bladder Carcinogenesis ................... 181
L. B. E11wein and S. M. Cohen
Alterations in Gene Expression in Mouse
Hepatocarcinogenesis............. . .......... 193
T. A. Dragani, G. Manenti, M. R. M. Sacchi,
B. Colombo and G. D. Porta
SCREENING FOR CARCINOGENESIS
Medium-Term Bioassay Models for Environmental
Carcinogens - Two - Step Liver and Mu1ti-
Organ Carcinogenesis Protocols ...................... 209
N. Ito, H. Tsuda, R. Hasegawa, M. Tatematsu,
K. Imaida and M. Asamoto
The Use of A1dh Induction as a Carcinogenic Risk Marker
in Comparison With Typical in Vitro Mutagenicity
System .............................................. 231
V. Vasi1iou, K. Athanasiou and M. Marse10s
Expression of Inducible Cytochrome P-450 mRNAs During
Promotion of Expermentia1 Chemical
Hepatocarcinogenesis ................................ 241
M. C. Lechner
An In Vitro Approach for Interspecies Extrapolation
Using Animal and Human Airway Epithelial Cell
Culture ............................................. 255
M. Emura, M. Riebe, U. Mohr, J. Jacob, G. Grimmer,
J. Wen and M. Straub
CANCER RISK ASSESSMENT
Assement of Low-Exposure Risk from Carcinogens:
Implications of the Knudson-Moo1gavkar
Two-Critical Mutation Theory ........................ 275
J. D. Wilson
A Biological Data Base for Methylene Chloride Risk
Assessment .......................................... 289
T. Green
viii
Computer Simulation of Chemical Carcinogenesis ........... 301
R. B. Conolly, R. H. Reitz, H. J. Clewell, III,
and M. E. Andersen
Determination of Carcinogen Exposure by Immunological
Techniques .......................................... 319
L. O. Dragsted
Risk Estimation for Leukemogenic Drugs ................... 339
J. M. Ka1dor and D. E. G. Shuker
Contributors ....... . .349
Index .............. . .353
RESEARCH NEEDS FOR BIOLOGICALLY BASED RISK ASSESSMENT
Curtis C. Travis
Office of Risk Analysis
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37831-6109
INTRODUCTION
Because of gaps in our current scientific understanding of
the cancer-causing process, human risk assessment for
chemicals which have demonstrated carcinogenicity in rodents
requires the use of a series of judgmental decisions on
numerous unresolved scientific issues. Major assumptions are
based on the necessity to extrapolate experimental results (1)
across species from mice or rats to humans, (2) from the high
dose regions to which animals are exposed in the laboratory to
the low-dose regions to which humans are exposed in the
environment, and (3) across routes of administration.
Development of tools and methodologies which can help
evaluate the scientific bases of these assumptions will reduce
the uncertainties in the risk assessment process. A recent
development in the cancer risk area is the advent of
biologically based pharmacokinetic and pharmacodynamic models.
Pharmacokinetic models relate applied dose to effective dose
at target tissue, while pharmacodynamic models relate
effective dose with biological effect. We will look at each
of these areas in turn.
PHARMACOKINETIC MODELING
Pharmacokinetics is the study of the absorption,
distribution, metabolism, and elimination of chemicals in man
and animals. Predictive, biologically based pharmacokinetic
models provide an effective approach for interpreting
empirical data relating to pharmacokinetics (Ramsey and
Andersen, 1984; Andersen et a!., 1987; Reitz et a!., 1987;
Travis, 1987; Paustenbach et a!., 1988; Reitz et a!., 1988;
Ward et a1., 1988). These models utilize actual physiological
parameters of the experimental animals such as breathing
rates, blood flow rates, tissue volumes, etc., to describe the
metabolic process. These models can often quantitatively
relate exposure concentrations (in air, water, or food) to
concentrations of parent compound or metabolite in various
tissues of the body, allowing prediction of the relationship
between applied dose of a chemical and effective dose at the
target tissue(s). A chief advantage of the pharmacokinetic
model is that by simply using the appropriate physiological,
biochemical, and metabolic parameters, the same model can
describe the dynamics of chemical transport and metabolism in
mice, rats, and humans.
PHARMACODYNAMIC MODELING
Biologically based pharmacodynamic models relate
fundamental cellular processes to the epidemiology of cancer
in animal and human populations. Several authors have
developed pharmacodynamic models based on the assumption that
normal cells require two genetic alterations to become cancer
cells (Moo1gavkar et a1., 1980; Moo1gavkar et a1., 1981; Cohen
et a1., 1983; E11wein and Cohen, 1986; Moo1gavkar, 1986;
Thorslund et a1. 1987; E11wein and Cohen, 1988). These
genetic alterations are rare and result from a mutation,
translocation, or other event on a specific gene. (It is
estimated that the background rate of such genetic events in
Fischer rat liver is about 1 per 10 million cell divisions.)
A cell which has undergone a single genetic alteration is
termed initiated. An initiated cell is not malignant, nor
will it necessarily progress to malignancy. Initiated cells
expand through clonal proliferation to form islands (foci) of
initiated cells. When one of these initiated cells undergoes
a second genetic alteration, a cancer cell is formed. The
vast majority of initiated cells never undergo a second
genetic alteration to become cancerous.
This process is most clearly seen in rat liver (Scherer and
Emme10t, 1976). Initiated cells are arranged in foci of
hepatocytes displaying alterations in phenotype which can be
identified by histochemical staining. Ini tiated ce 11s have
higher rates of proliferation than normal hepatocytes. (In
control Fischer rats, initiated cells can proliferate at up to
80 times faster than normal hepatocytes). Consider the case
of the carcinogen diethy1nitrosamine (DEN). A single dose of
DEN to rats produces a reproducible number of foci in the
liver (each island representing one originally initiated
cell). Figure 1 shows the number of foci in rat liver as a
function of time after induction by a single dose of 10 mg
DEN/kg in rats partially hepatectomized 24 hours previously.
The partial hepatectomy is performed to induce cellular
proliferation so that all initiated cells will be c10na11y
expanded into visible foci. The number of foci remains
2