Table Of ContentGENETIC
TOXICOLOGY OF
COMPLEX MIXTURES
ENVIRONMENTAL SCIENCE RESEARCH
Series Editor:
Herbert S. Rosenkranz
Department of Environmental and Occupational Health
Graduate School of Public Health
University of Pittsburgh
130 DeSoto Street
Pittsburgh, Pennsylvania
Founding Editor:
Alexander Hollaender
Recent Volumes in this Series
Volume 32-SHORT-TERM BIOASSAYS IN THE ANALYSIS OF COMPLEX
ENVIRONMENTAL MIXTURES IV
Edited by Michael D. Waters, Shahbeg S. Sandhu, Joellen Lewtas,
Larry Claxton, Gary Strauss, and Stephen Nesnow
Volume 33-ACID RAIN: Economic Assessment
Edited by Paulette Mandelbaum
Volume 34-ARCTIC AND ALPINE MYCOLOGY II
Edited by Gary A. Laursen, Joseph R. Ammirati, and
Scott A. Redhead
Volume 35-ENVIRONMENTAL RADON
Edited by C. Richard Cothern and James E. Smith, Jr.
Volume 36-SHORT-TERM BIOASSAYS IN THE ANALYSIS OF COMPLEX
ENVIRONMENTAL MIXTURES V
Edited by Shahbeg S. Sandhu, David M. DeMarini, Marc J. Mass,
Martha M. Moore, and Judy L. Mumford
Volume 37 -HAZARDS, DECONTAMINATION, AND REPLACEMENT OF PCB:
A Comprehensive Guide
Edited by Jean-Pierre Crine
Volu~e 38-IN SITU EVALUATION OF BIOLOGICAL HAZARDS OF
ENVIRONMENTAL POLLUTANTS
Edited by Shahbeg S. Sandhu, William R. Lower, Frederick J. de Serres,
William A. Suk, and Raymond R. Tice
Volume 39-GENETIC TOXICOLOGY OF COMPLEX MIXTURES
Edited by Michael D. Waters, F. Bernard Daniel, loellen Lewtas,
Martha M. Moore, and Stephen Nesnow
Volume 40-NITROARENES: Occurrence, Metabolism, and Biological Impact
Edited by Paul C. Howard, Stephen S. Hecht, and Frederick A. Beland
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GENETIC
TOXICOLOGY OF
COMPLEX MIXTURES
Edited by
Michael D . Waters
US Environmental Protection Agent:)'
Research Triangle Park, North Carolina
F. Bernard Daniel
US Environmental Protection Agent:)'
Cincinnati, Ohio
Jo ellen Lewtas
Martha M. Moore
and
Stephen Nesnow
US Environmental Protection Agent:)'
Research Triangle Park, North Carolina
Technical Editor
Claire Wilson & Associates
Washington, D. C.
PLENUM PRESS. NEW YORK AND LONDON
Library of Congress Cataloglng-In-Publlcatlon Data
International Conference on Genetic Toxicology of Complex Mixtures
(1989 : Washington, D.C.)
Genetic toxicology of complex mixtures I edited by Michael D.
Waters ... [et al.l.
p. cm. -- (Environmental science research: v. 39)
"Proceedings of the International Conference on Genetic Toxicology
of Complex Mixtures, held July 4-7, 1989, in Washington, D.C., a
satellite symposium of the Fifth International Conference on
Environmental Mutagens"--T.p. verso.
Includes bibliographical references.
Inc 1u des index.
ISBN-13:978-1-4684-5852-7 e-ISBN-13: 978-1-4684-5850-3
001: 10.1007/978-1-4684-5850-3
1. Genetic toxlcology--Congresses. 2. Mixtures--Toxicology-
-Congresses. I. Waters, Michael D. II. lnternational Conference
on EnvironMental Mutagens (5th: 1989 , Cleveland, Ohio)
III. Title. IV. Title, Complex mixtures. V. Series.
[DNLM: 1. Carcinogens, EnvironNental--adverse effects--congresses.
2. Genes--drug effects--congresses. 3. Environmental Pollutants-
-adverse effects--congresses. 4. Mutagens--adverse effects-
-congresses. W1 EN986F v. 39 I WA 671 16025G 19891
RA1224.3.1574 1989
615.9'02--dc20
DNLM/DLC
for Library of Congress 90-7812
CIP
The research described in this volume has been reviewed by the Health Effects
Research Laboratory, U.S. Environmental Protection Agency, and approved for
publication. Approval does not signify that the contents necessarily reflect the views
and policies of the U. S. Environmental Protection Agency, nor does mention of trade
names or commerical products constitute endorsement or recommendation for use
Proceedings of the International Conference on Genetic Toxicology of Complex
Mixtures, held July 4-7, 1989, in Washington, D.C., a Satellite Symposium of the
Fifth International Conference on Environmental Mutagens
© 1990 Plenum Press, New York
Sof'tcover reprint of the hardcover 1st edition 1990
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
FOREWORD
Contained in this volume are the proceedings of the international
conference on the "Genetic Toxicology of Complex Mixtures," held from
July 4-7, 1989, in Washington, DC. This meeting was a satellite of the
"Fifth International Conference on Environmental Mutagens" and the
seventh in a biennial series of conferences on "Short-term Bioassays in
the Analysis of Complex Environmental Mixtures."
Our central objective in calling together key researchers from around
the world was to extend our knowledge of the application of the methods
of genetic toxicology and analytical chemistry in the evaluation of chemical
mixtures as they exist in the environment. This conference emphasized
the study of genotoxicants in air and water, and the assessment of human
exposure and cancer risk. The latest strategies and methodologies for
biomonitoring of genotoxicants (including transformation products) were
described in the context of the ambient environment. Source character-
ization and source apportionment were discussed as an aid to understand-
ing the origin and relative contribution of various kinds of complex mix-
tures to the ambient environment. Similarly, investigations of genotoxi-
cants found in the indoor environment (sidestream cigarette smoke) and in
drinking water (chlorohydroxyfuranones) were given special attention in
terms of their potential health impacts. New molecular techniques were
described to enable more precise quantitation of internal dose and dose-
to-target tissues. The emphasis of presentations on exposures/effects
assessment was on integrated quantitative evaluation of human exposure
and potential health effects. It is clear that the sophistication of complex
mixture research technologies has increased dramatically since the first
conference in 1978 with the application of state-of-the-art genetic and
molecular methods. It is now apparent that interdisciplinary approaches
are essential in order to assess the contribution of mixtures of genotoxic
agents in the environment to total human exposure and potential cancer
risk.
We are indebted to the speakers and chairpersons who presented
their data at the meeting and in the excellent chapters that follow.
A conference of this type requires the cooperative efforts of many
individuals. The organizing committee is grateful for the generous sup-
port of Dr. Don Hughes of Procter & Gamble, Cincinnati, Ohio, and Dr.
Steve Haworth of Hazelton Laboratories, Kensington, Maryland, who con-
tributed to these proceedings. I would like to acknowledge Dr. Bruce
Casto of the Environmental Health Research and Testing, Inc., who
v
vi FOREWORD
helped to organize the meeting, and his associates, Dale Churchill and
Kathy Rous, who helped on-site in Washington, DC. Special thanks to
Claire Wilson &; Associates, Washington, DC, for conference management
and technical editing of these proceedings.
Michael D. Waters, Ph.D.
Senior Editor
CONTENTS
Development and Application of New Methodologies
Applicable to Research on Complex Environmental
Mixtures ••.•.•...•...••••.•••..•••..••.•••.•.•• 1
P.H.M. Lohman, E.W. Vogel, B. Morolli,
A.A. v. Zeeland, and H. Vrieling
Complex Mixtures of Genotoxicants in Air
Identification of Genotoxic Agents in Complex Mixtures
of Air Pollutants •••..•.•..•..•.•.•.....•.••..• 11
Dennis Schuetzle and Joan M. Daisey
Human Exposure to Airborne Mutagens Indoors and
Outdoors Using Mutagenesis and Chemical
Analysis Methods ..••••.•••...•.......••..•..••• 33
Hidetsuru Matsushita, Sumio Goto, Yukihiko Takagi,
Osamu Endo, and Kiyoshi Tanabe
Genetic Toxicology of Airborne Particulate Matter
Using Cytogenetic Assays and Microbial Mutagen-
icity Assays................................... 57
Roberto Barale, Lucia Migliore, Bettina Cellini,
Lucia Francioni, Francesco Giorgelli,
Italo Barrai, and Nicola Loprieno
Indoor and Outdoor Sources of Airborne Mutagens in
Nonurban Areas •..•••••••••.•.••..•..•••••.•••.. 73
J.J. van Houdt and G.M. Alink
Characterization of Mutagen Sources in Urban
Particulate Matter in Gothenburg, Sweden 89
Goran LClfroth
Assessment of the Mutagenicity of Volatile Organic Air
Pollutants Before and After Atmospheric
Transformation ...••..••...••..•••..••••••••.•• 103
Larry D. Claxton, T.E. Kleindienst, Erica Perry,
and Larry T. Cupitt
Carcinogenicity of Complex Mixtures in Air Using
In Vitro and In Vivo Assays .•.•••.......••••.•. 113
I. Chouroulinkov
vii
viii CONTENTS
Contribution of Polycyclic Aromatic Hydrocarbons and
Other. Polycyclic Aromatic Compounds to the
Carcinogenicity of Combustion Sources and Air
Pollution ..................................... 127
G. Grimmer, H. Brune, G. Dettbarn, J. Jacob,
J. Misfeld, U. Mohr, K.-W. Naujack, J. Timm,
and R. Wenzel-Hartung
Old and New Carcinogens ••••••••••••••••••••••••••••••• 141
Lorenzo Tomatis
Experimental and Epidemiologic Applications to Cancer
Risk Assessment of Complex Mixtures ••••••••••• 149
Marja Sorsa, Harri Vainio, and Anthony J. McMichael
Mutagenicity, Carcinogenicity, and Human Cancer Risk
from Indoor Exposure to Coal and Wood Combustion
in Xuan Wei, China ............................ 157
Judy L. Mumford, Robert S. Chapman, Stephen Nesnow,
C. Tucker Helmes, and Xueming Li
The Role of Nitroarenes in the Mutagenicity of Airborne
Particles Indoors and Outdoors •••••••••••••••• 165
Hiroshi Tokiwa, Nobuyuki Sera, Mamiko Kai,
Kazumi Horikawa, and Yoshinari Ohnishi
Complex Mixtures of Genotoxicants in Wa.ters
Characterization of Mutagenic Compounds Formed During
Disinfection of Drinking Water •••••••••••••••• 173
Leif Kronberg
Genotoxic and Carcinogenic Properties of Chlorinated
Furanones: Important By-products of Water
Chlorination .................................. 185
J.R. Meier, A.B. DeAngelo, F.B. Daniel, K.M. Schenck,
J.U. Doerger, L.W. Chang, F.C. Kopfler,
M. Robinson, and H.P. Ringhand
Assessment and Identification of Genotoxic Compounds
in water ...................................... 197
J.K. Fawell and H. Horth
Methods to Measure Genotoxins in Wastewater: Evaluation
with In Vivo and In Vitro Tests ••••••••••••••• 215
Martin A. van der Gaag, Laury Gauthier,
Arie Noordsij, Yves Levi, and M. Nicoline
Wrisberg
Detection of Genotoxicity in Chlorinated or Ozonated
Drinking Water Using an Amphibian Micronucleus
Test •••••••••••••••••••••••••••••••••••••••••• 233
Andr~ Jaylet, Laury Gauthier, and Yves L~vi
CONTENTS ix
Exposure/Effects Assessment
The Significance of Mutagenicity as a Criterion in
'Ecotoxicological Evaluations •••••••••••••••••• 249
W.K. de Raat, G.J. Vink, and A.O. Hanstveit
DNA Adducts and Related Biomarkers in Assessing the
Risk of Complex Mixtures •••••••••••••••••••••• 271
F.P. Perera, P. Schulte, R.M. Santella, and
D. Brenner
Immunological Methods for the Detection of Polycyclic
Aromatic Hydrocarbon-DNA and Protein Adducts.. 291
Regina M. Santella, You Li, Yu Jing Zhang,
Tie Lan Xoung, Marina Stefanidis, Xiao Qing Lu,
Byung Mu Lee, Maria Gomes, and Frederica P. Perera
32P-Postlabeling DNA Adduct Assay: Cigarette Smoke-
induced DNA Adducts in the Respiratory and
Nonrespiratory Rat Tissues 303
R.C. Gupta and C.G. Gairola
Postlabeling Analysis of Polycyclic Aromatic
Hydrocarbon: DNA Adducts in White Blood Cells
of Foundry Workers •••••••••••••••••••••••••••• 313
K. Hemminki, K. Randerath, and M.V. Reddy
Protein Adducts as Biomarkers for Chemical
Carcinogens ................................... 323
Paul L. Skipper and Steven R. Tannenbaum
Evaluation of DNA Binding In Vivo for Low-Dose
Extrapolation in Chemical Carcinogenesis •••••• 331
Werner K. Lutz, P. Buss, A. Baertsch, and M. Caiezel
Cancer Risks Due to Occupational Exposure to Polycyclic
Aromatic Hydrocarbons: A Preliminary Report 343
D. Krewski, J. Siemiatycki, L. Nadon, R. Dewar,
and M. Ge'rin
Future Directions in Research on the Genetic Toxicology
of Complex Mixtures ••••••••••••••••••••••••••• 353
Joellen Lewtas
Index .............................................•... 363
DEVELOPMENT AND APPLICATION OF NEW METHODOLOGIES APPLICABLE
TO RESEARCH ON COMPLEX ENVIRONMENTAL MIXTURES
P.H.M. Lohman, E.W. Vogel, B. Morolli, A.A. v. Zeeland,
and H. ,Vrieling
MGC-Department of Radiation Genetics and
Chemical Mutagenesis
University of Leiden
Wassenaarseweg 72, 2333 AL Leiden, The Netherlands
Although the induction of cancer in man and in experimental animals
by exposure to ionizing radiation or chemicals has been known for a long
time, major insights into the mechanisms that underlie naturally occurring
and induced cancers began to emerge only since the early 1970s. There
is now persuasive evidence which documents that (i) many carcinogens
are mutagens; (ii) most forms of cancer are due, at least in part, to
changes (mutations) in the DNA (genetic material) contained in cells; and
(iii) such genetic changes playa pivotal role in the initiation of cancer at
the cellular level. A wide variety of test systems developed during the
last 20 years--ranging from bacteria and mammalian cells including human
cells in culture to whole mammals--is now available to examine the "muta-
genic potential" of different chemicals, but they are only suitable for a
qualitative determination of the level of cancer risk resulting from expo-
sure of man to such agents. Agents that are capable of damaging the
DNA are called "genotoxic" and a general characteristic of these is their
electrophilic reactivity towards DNA and other cellular macromolecules.
Interaction of chemicals with DNA has been considered as the initial step
in the formation of cancer and hereditary effects in mammals, in spite of
the (often spectacularly efficient) DNA repair processes in the individual
cells of the organism (Fig. 1). The assumption is made that DNA lesions
may escape correction by DNA repair processes, otpers may be errone-
ously repaired or not repaired at all. Moreover, the spectrum of lesions
in the DNA of exposed cells is often complex and strongly dependent on
the agent involved. Furthermore, DNA repair processes are found to be
dependent on organ and cell type, chromosomal structure, and whether
genes are active or inactive.
Mutation induction is only considered a first step (initiation) in the
long chain of events leading to malignant transformation of cells. Still
many other, mostly unknown, steps are involved in the complicated path-
way leading from an initiated cell to an established tumor. Especially
noticeable among unknown factors are those that influence the progression
Genetic Toxicology of Complex Mixtures
Edited by M. D. Waters el al.
Plenum Press, New York, 1990
