Environmental Toxin Series 3 Editors-in-Chief: S. Safe and O. Hutzinger Environmental Toxin Series Editors-in-Chief: S. Safe and O. Hutzinger Volume 1 Polychlorinated Biphenyls (PCBs): Mammalian and Environmental Toxicology S. Safe (Ed.) Volume 2 Cadmium M. Stoeppler and M. Piscator (Eds.) Contents: I. Toxicity, Carcinogenicity, Animal Experiments H. Epidemiology IH. Cadmium in the Environment IV. Methodology and Quality Assessment S. Safe, O. Hutzinger, T. A. Hill (Eds.) Polychlorinated Dibenzo-p-dioxms and -furans (PCDDs/PCDFs): Sources and Environmental Impact, Epidemiology, Mechanisms of Action, Health Risks With 8 Figures and 32 Tables Springer-Verlag Berlin Heidelberg NewY ork London Paris Tokyo Hong Kong Barcelona Volume Editors Prof. Dr. S. Safe Texas A&M University, College of Veterinary Physiology and Pharmacology, College Station, TX 77843-4466, USA Prof. Dr. O. Hutzinger Institute of Ecological Chemistry and Geochemistry, University of Bayreuth, P.O. Box 101251, 8580 Bayreuth, FRG T.A. Hill Consultants in Epidemiology and Occupational Health, 2428 Wisconsin Avenue, NW Washington, DC 20007, USA ISBN-13: 978-3-642-70558-8 e-ISBN-13: 978-3-642-70556-4 DOl: 10.1007/978-3-642-70556-4 Library of Congress Cataloging-in-Publication Data Polychlorinated dibenzo-p-dioxins and -furans (pCDDs/pCDFs): sources and environ mental impact, epidemiology, mechanisms of action, health risks/So Safe, O. Hutz inger, T.A. Hill (eds.). (Environmental toxin series; 3) ISBN-13: 978-3-642-70558-8 1. Polychlorinated dibenzodioxins - Toxicology. 2. Polychlorinated dibenzodioxins Environmental aspects. 3. Polychlorinated dibenzofurans - Toxicology. 4. Polychlor inated dibenzofurans - Environmental aspects. I. Safe, S. 11. Hutzinger, O. Ill. Hill, Thomas A. IV. Series: Environmental toxin series; v.3. RAI242.P72P65 1990 615.9'511-dc20 90-9703 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its current version, and a copyright fee must always be paid. © Springer-Verlag Berlin Heidelberg 1990 Softcover reprint of the hardcover I st edition 1990 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Typesetting: Macmillan India Ltd., Bangalore-25 Offsetprinting: Mercedes-Druck, Berlin; Bookbinding: B. Helm, Berlin 2152/3020- 543210 - Printed on acid-free paper Editorial The concern about environmental toxins is constantly increasing, as is the need for sound scientific information. The Environmental Toxin Series is dedicated to the publication of comprehensive reviews and monographs on compounds or classes of chemicals which are of importance in environmental toxicology. The series is designed to serve as a background of information for scientific investigation as well as risk analysis and political decision making. The main aim of the series is to describe in as complete a way as possible all potentially hazardous chemicals from the point of view of chemistry, ecology, toxicology, risk analysis and regulatory implications. From time to time conference proceedings on important and urgent topics will be included in the series. We thank the members of the editorial board for their enthusiastic support. S. Safe and O. Hutzinger Editorial Board Editors-in-Chief Prof. Dr. S. Safe Texas A&M University, College of Veterinary Physiology and Pharmacology, College Station, TX 77843-4466, USA Prof. Dr. O. Hutzinger Institute of Ecological Chemistry and Geochemistry, University of Bayreuth, P.O. Box 101251, 8580 Bayreuth, FRG Volume Editors Prof. Dr. S. Safe Texas A&M University, College of Veterinary Physiology and Pharmacology, College Station, TX 77843-4466, USA Prof. Dr. O. Hutzinger Institute of Ecological Chemistry and Geochemistry, University of Bayreuth, P.O. Box 101251, 8580 Bayreuth, FRG T.A. Hill Consultants in Epidemiology and Occupational Health, 2428 Wis consin Avenue, NW Washington, DC 20007, USA Editors Prof. Dr. M.W. Anders Department of Pharmacology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA Prof. Dr. J. DiGiovanni University of Texas System Cancer Center Research Division, Science Park, P.O. Box 389, Smithville, TX 78957, USA Dr. P.S. Guzelian Division of Clinical Toxicology and Environmental Medicine, Vir- ginia College of Medicine, P.O.Box 267, Richmond, V A 23298-0001, USA Dr. A.W. Hayes RIR Nabisco, Inc., Bowman Gray Technical Center, Winston Salem, NC 27109, USA Prof. Dr. M.A. Hayes Department of Pathology, University of Guelph, Guelph, Ontario NIG 2Wl, CND Or. G.W. Ivie Agricultural Research Service, U.S. Department of Agriculture, College Station, TX 77841, USA Or. R. Koch Academy of Sciences, Institute of Geography and Geo-Ecology, Rudower Chaussee 5, 1199 Berlin, GDR Or. HJ. Lewerenz Academy of Sciences of the GDR, Central Institute of Nutrition, Artur-Scheunert-Allee, 1505 Bergholz-Rehbriicke, GDR Dr. E. Loser Bayer AG, Institute ofIndustrial Toxicology, P.O. Box 101709,6500 Wuppertal 1, FRG Or. 1.0. McKinney Division of Molecular Biophysics N.I.E.H.S., P.O. Box 12233, Re search Triangle Park, NC 27709, USA Prof. Dr. A. Parkinson Department of Pharmacology, Toxicology and Therapeutics, Uni versity of Kansas, Medical Center, 39th St., Kansas City, KS 66103, USA Or. T.D. Phillips Texas A&M University, Department of Public Health, College of Veterinary Medicine, College Station, TX 77843, USA Or. I.G. Sipes Department of Pharmacology and Toxicology, University of Ariz ona, College of Pharmacy, Tucson, AZ 85721, USA Or. 1. Thies Bayer AG, Analytical Laboratory Center, OAL, 5090 Leverkusen, FRG Dr. H.R. Witschi Oak Ridge National Laboratory, Biology Division, P.O. Box Y, Oak Ridge, TN 37831, USA Contents 1 PCDDs and PCDFs: Sources and Environmental Impact S. Safe and O. Hutzinger ................... 1 2 UAREP-Report on Health Aspects of Polychlorinated Dibenzo-p-dioxins (PCDDs) and Polychlorinated Diben- zofurans (PCDFs) ..................... 23 2.1 Epidemiology A.H. Smith, L.T. Kurland and S. Shindell .. 27 2.2 Mechanism of Action S.H. Safe, T. Gasiewicz and J.P. Whitlock, Jr. 61 2.3 Characterization of Human Health Risks e.O. Schulz, D.R. Brown and le. Munro ...... 93 3 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . .. 141 1 PCDDs and PCDFs: Sources and Environmental Impact o. S. Safel and Hutzinger2 1 Introduction............................................ 1 2 Sources of PCDDs and PCDFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1 Chemical Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2 Pulp and Paper Mills and Paper/Board Products . . . . . . . . . . . . . . . . . . . . . . 7 2.3 Combustion Sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3 PCDDs and PCDFs-Environmental Impact. . . . . . . . . . . . . . . . . . . . . . . . . 11 3.1 Atmospheric Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2 Sediments, Sludge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.3 Environmental Levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 2 3.4 Yusho and Yu-Cheng Incidents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 4 References.............................................. 17 1 Introduction Polychlorinated dibenzo-p-dioxins (PCDDs or polyCDDs) and polychlorinated dibenzofurans (PCDFs or polyCDFs) are members of the family of halogenated aromatic chemicals which includes the polychlorinated biphenyls (PCBs), naph thalenes, terphenyls, azo and azoxybenzenes, quaterphenyls and their bromina ted and mixed chlorojbromo analogs. The PCDDs and PCDFs can be substi tuted with 1-8 chlorine atoms and there are 75 and 135 possible isomers and congeners. With the exception of the fully chlorinated octaCDD and octaCDF, there are multiple isomers within each group as illustrated in Fig. 1. The PCDFs, PCDDs and structurally-related halogenated aryl hydrocar bons exhibit a number of common properties. For example, the PCDDs and PCDFs are hi_ghly lipophilic molecules and are generally resistant to chemical breakdown by acids, bases or by oxidation, reduction and hydrolysis. These physicochemical properties were important properties which contributed to the diverse number of industrial applications of PCBs. In addition, the degree of 1 Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843, USA 2 Department of Ecological Chemistry & Geochemistry, University of Bayreuth, Postfach 3008, D-8580, Bayreuth, FRG Environmental Toxin Series, Vol. 3 © Springer-Verlag Berlin Heidelberg 1990 2 Introduction Clx 0 Cy "~" 't§roX§J No. of No. of No. of Cl groups Isomers Isomers 4 1 2 16 2 10 3 14 28 4 22 38 5 14 28 6 10 16 7 2 4 8 1 TOTAL 75 135 Fig. 1. PCDDs and PCDFs - multiplicity of isomers and congeners lipophilicity and stability of PCDDs and PCDFs also increases with increasing ring chlorination. Not surprisingly, these physicochemical properties contribute to the environmental stability of these compounds which have been detected in almost every component of the global ecosystem. Moreover, the lipophilic nature of these hydrocarbons has resulted in their bioaccumulation in the food chain and PCDDs and PCDFs have been reported in fish, wildlife and human adipose tissue, milk and serum. The widespread identification of trace levels of PCDDs and PCDFs in human populations has engendered considerable public and regulatory concern over the potential adverse human health impacts of these pollutants. In addi tion, this concern has been heightened by several accidental and occupational exposures to PCDDs and PCDFs. These incidents have been thoroughly documented and are summarized in this book. Figure 1 shows that there are a large number of PCDD and PCDF congeners, and humans are exposed to complex mixtures of these compounds. However, in exposures associated with 2,4,5-trichlorophenol and its derived products [e.g. 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or Agent Orange], the major contaminant has been identified as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 2,3,7,8-TCDD is the most toxic halogenated aromatic compound and has been utilized as a prototype for investigating the toxicity, carcinogenicity and mechanisms of action of halo genated aryl hydrocarbons. 2,3,7,8-TCDD exhibits exquisitely high toxicity in some laboratory animal species (e.g. LDso guinea pigs - < 2 Ilgfkg) and is a potent rodent carcinogen. For example, hyperplastic liver nodules were observed in female Sprague Dawley rats fed 2,3,7,8-TCDD at a dose of 0.01 Ilgfkg/day. Thus early studies on the sources and environmental impact of PCDDs and PCDFs primarily focused on the specific detection and quantitation of 2,3,7,8-TCDD. However, it is now