GENETIC 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 A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher. 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