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  • 1. DIOXINS AND HEALTH
  • 2. DIOXINS AND HEALTHSECOND EDITIONEdited byArnold SchecterProfessor of Environmental SciencesUniversity of Texas School of Public HealthDallas Campus, Dallas, TexasThomas A. GasiewiczProfessor and ChairDepartment of Environmental MedicineUniversity of Rochester School of MedicineRochester, New YorkA JOHN WILEY & SONS, INC., PUBLICATION
  • 3. Copyright 6 2003 by John Wiley & Sons, Inc. All rights reserved.Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.No part of this publication may be reproduced, stored in a retrieval system, or transmitted in anyform or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise,except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, withouteither the prior written permission of the Publisher, or authorization through payment of theappropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers,MA 01923, 978-750-8400, fax 978-750-4470, or on the web at www.copyright.com. Requests tothe Publisher for permission should be addressed to the Permissions Department, John Wiley &Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, e-mail:permreq@wiley.com.Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their beste¤orts in preparing this book, they make no representations or warranties with respect to theaccuracy or completeness of the contents of this book and specifically disclaim any impliedwarranties of merchantability or fitness for a particular purpose. No warranty may be created orextended by sales representatives or written sales materials. The advice and strategies containedherein may not be suitable for your situation. You should consult with a professional whereappropriate. Neither the publisher nor author shall be liable for any loss of profit or any othercommercial damages, including but not limited to special, incidental, consequential, or otherdamages.For general information on our other products and services please contact our Customer CareDepartment within the U.S. at 877-762-2974, outside the U.S. at 317-572-3993 or fax 317-572-4002.Wiley also publishes its books in a variety of electronic formats. Some content that appears inprint, however, may not be available in electronic format.Library of Congress Cataloging-in-Publication Data:Dioxins and health / [edited by] Arnold Schecter, Thomas A. Gasiewicz — 2nd ed. p. ; cm.Includes bibliographical references and index. ISBN 0-471-43355-1 (cloth : alk. paper) 1. Dioxins—Toxicology. [DNLM: 1. Dioxins—toxicity. WA 240 D5953 2003] I. Schecter,Arnold. II. Gasiewicz, Thomas A. RA1242.D55D58 2003 615.9 0 512—dc21 2003003817Printed in the United States of America10 9 8 7 6 5 4 3 2 1
  • 4. To our families
  • 5. CONTENTSContributors ixPreface xiii 1. Overview: The Dioxin Debate 1 Thomas F. Webster and Barry Commoner 2. Production, Distribution, and Fate of Polychlorinated Dibenzo-p- Dioxins, Dibenzofurans, and Related Organohalogens in the Environment 55 Roger K. Gilpin, Daniel J. Wagel, and Joseph G. Solch 3. Dioxins and Dioxinlike PCBs in Food 89 James R. Startin and Martin D. Rose 4. Toxicology of Dioxins and Dioxinlike Compounds 137 Jeanelle M. Martinez, Michael J. DeVito, Linda S. Birnbaum, and Nigel J. Walker 5. Health Risk Characterization of Dioxins and Related Compounds 159 Linda S. Birnbaum and William H. Farland 6. Pharmacokinetics of Dioxins and Related Chemicals 191 James R. Olson 7. Dose–Response Modeling for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin 247 Michael J. DeVito, Amy Kim, Nigel J. Walker, Fred Parham, and Christopher Portier 8. Immunotoxicology of Dioxins and Related Chemicals 299 Nancy I. Kerkvliet 9. Developmental and Reproductive Toxicity of Dioxins and Related Chemicals 329 H. Michael Theobald, Gary L. Kimmel, and Richard E. Peterson vii
  • 6. viii CONTENTS10. E¤ects of Polychlorinated Biphenyls on Neuronal Signaling 433 Richard F. Seegal11. Experimental Toxicology: Carcinogenesis 457 Justin G. Teeguarden and Nigel J. Walker12. Ah Receptor: Involvement in Toxic Responses 491 Thomas A. Gasiewicz and Sang-ki Park13. Biochemical Responses to Dioxins: Which Genes? Which Endpoints? 533 J. Kevin Kerzee, Ying Xia, and Alvaro Puga14. Evolutionary and Physiological Perspectives on Ah Receptor Function and Dioxin Toxicity 559 Mark E. Hahn15. Dioxin Toxicity and Aryl Hydrocarbon Receptor Signaling in Fish 603 Robert L. Tanguay, Eric A. Andreasen, Mary K. Walker, and Richard E. Peterson16. Exposure Assessment: Measurement of Dioxins and Related Chemicals in Human Tissues 629 Arnold Schecter, Olaf Papke, Marian Pavuk, and Rachel E. Tobey ¨17. Human Health E¤ects of Polychlorinated Biphenyls 679 Matthew P. Longnecker, Susan A. Korrick, and Kirsten B. Moysich18. Epidemiological Studies on Cancer and Exposure to Dioxins and Related Compounds 729 Lennart Hardell, Mikael Eriksson, Olav Axelson, and Dieter Flesch-Janys19. Reproductive and Developmental Epidemiology of Dioxins 765 Sherry G. Selevan, Anne Sweeney, and Marie Haring Sweeney20. Health Consequences of the Seveso, Italy, Accident 827 Pier Alberto Bertazzi and Alessandro di Domenico21. The Yusho Rice Oil Poisoning Incident 855 Yoshito Masuda22. The Yucheng Rice Oil Poisoning Incident 893 Yueliang Leon Guo, Mei-Lin Yu, and Chen-Chin HsuIndex 921
  • 7. CONTRIBUTORSEric A. Andreasen, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331Olav Axelson, Department of Health and Environment, Linkoping University, ¨ 581 85 Linkoping, Sweden ¨Pier Alberto Bertazzi, Department of Occupational and Environmental ` Health, Universita degli Studi, 20122 Milan, ItalyLinda S. Birnbaum, National Health and Evironmental E¤ects Research Lab- oratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711Barry Commoner, Center for the Biology of Natural Systems, Queens College, CUNY, Flushing, NY 11367Michael J. DeVito, National Health and Evironmental E¤ects Research Lab- oratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711Alessandro di Domenico, Laboratory of Comparative Toxicology and Ecotox- ´ `, icology, Istituto Superiore di Sanita 00161 Rome, ItalyMikael Eriksson, Department of Oncology, University Hospital, SE-221 85 Lund, SwedenWilliam H. Farland, O‰ce of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460Dieter Flesch-Janys, Working Group Epidemiology, Institute of Mathematics and Computational Sciences in Medicine, Winterhuder Weg 29, 22085 Hamburg, GermanyThomas A. Gasiewicz, Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642Roger K. Gilpin, Brehm Laboratories, Wright State University, Dayton, OH 45435Yueliang Leon Guo, Institute of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan 70428, Taiwan ix
  • 8. x CONTRIBUTORSMark E. Hahn, Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543Lennart Hardell, Department of Oncology, University Hospital, SE-701 85 ¨ ¨ Orebro, and Department of Natural Sciences, Orebro University, SE 701 82 O¨ rebro, SwedenChen-Chin Hsu, Department of Psychiatry, En Chu Kong Hospital, Taipei, TaiwanNancy I. Kerkvliet, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331J. Kevin Kerzee, Department of Environmental Health, University of Cincin- nati Medical Center, Cincinnati, OH 45267-00567Amy Kim, Curriculum in Toxicology, University of North Carolina–Chapel Hill, Chapel Hill, NC 27599Gary L. Kimmel, U.S. Environmental Protection Agency, Washington, DC 20460Susan A. Korrick, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115Matthew P. Longnecker, Epidemiology Branch, National Institute of Envi- ronmental Health Sciences, Research Triangle Park, NC 27709Jeanelle M. Martinez, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709Yoshito Masuda, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa- cho, Minami-ku, Fukuoka 815, JapanKirsten B. Moysich, Department of Cancer Prevention, Epidemiology, and Biostatistics, Roswell Park Cancer Institute, Bu¤alo, NY 14263James R. Olson, Department of Pharmacology and Toxicology, University at Bu¤alo, SUNY, Bu¤alo, NY 14214-3000Olaf Papke, ERGO, Forschungsgesellschaft mbH, Geierstrasse 1, D 22305 ¨ Hamburg, GermanyFred Parham, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709Sang-ki Park, Department of Environmental Medicine, University of Roches- ter School of Medicine, Rochester, NY 14642Marian Pavuk, University of Texas School of Public Health, Dallas Campus, Dallas, TX 75235-9128Richard E. Peterson, School of Pharmacy and Environmental Toxicology Center, University of Wisconsin, Madison, WI 53705-2222
  • 9. CONTRIBUTORS xiChristopher Portier, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709Alvaro Puga, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-00567Martin D. Rose, Central Science Laboratory, Sand Hutton, York YO41 1LZ, UKArnold Schecter, University of Texas School of Public Health, Dallas Campus, Dallas, TX 75390-9128Richard F. Seegal, New York State Department of Health and School of Public Health, University at Albany, SUNY, Albany, NY 12201-0509Sherry G. Selevan, U.S. Environmental Protection Agency, Washington, DC 20460Joseph G. Solch, Brehm Research Laboratories, Wright State University, Dayton, OH 45435James R. Startin, Central Science Laboratory, Sand Hutton, York YO41 1LZ, UKAnne Sweeney, University of Texas–Houston School of Public Health, Houston, TX 77030Marie Haring Sweeney, National Institute for Occupational Safety and Health, Cincinnati, OH 45226Robert L. Tanguay, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331Justin G. Teeguarden, Environ International, Ruston, LA 71270H. Michael Theobald, School of Pharmacy, University of Wisconsin, Madison, WI 53705Rachel E. Tobey, University of Texas School of Public Health, Dallas Cam- pus, Dallas, TX 75390-9128Daniel J. Wagel, Brehm Research Laboratories, Wright State University, Dayton, OH 45435Mary K. Walker, College of Pharmacy, Health Sciences Center, University of New Mexico, Albuquerque, NM 87131Nigel J. Walker, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709Thomas F. Webster, Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118-2526
  • 10. xii CONTRIBUTORSYing Xia, Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH 45267-00567Mei-Lin Yu, Department of Public Health, National Cheng Kung University Medical College, Tainan 70428, Taiwan
  • 11. PREFACEIt is sometimes said that there are at least two sides to every story, andthat the truth is often somewhere in between. In like manner, the literature onthe dioxins is most often dichotomized by interests either directly relevantto human health risks or very focused on the molecular mechanisms bywhich these chemicals act to a¤ect cellular functions. How we bring all of thisinformation together to actually determine, and not estimate, the true risksto human (and wildlife) populations exposed to these chemicals continues toremain a challenge. There is also a literature on the chemical aspects of dioxinsand related synthetic chemicals, and historical events where dioxin contamina-tion was noteworthy and of concern. On the social side there is extensiveliterature on legal aspects of environmental pollutants and on response of in-dividuals and organizations to incidents posing perceived or actual physical orpsychological risks. During the years since the first edition of this book in 1994, an extensiveamount of new policy and scientific literature has been published related todioxins and dioxin-like chemicals. For the purposes of this text these chemicalsinclude the halogenated dioxins and dibenzofurans, certain polychlorinatedbiphenyls (PCBs), and other compounds that are structurally and toxicologi-cally similar to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD, or justTCDD), the most extensively studied and most potent member of this group.Much of this literature has continued to refine our understanding of the e¤ectsof human exposures, possible e¤ects on human and wildlife populations, dose–e¤ect relationships, and the mechanisms whereby these chemicals work at themolecular level, in particular as mediated by a transcription factor the arylhydrocarbon receptor (AhR). In several cases, and in part due to new techno-logical advances, substantial new and striking strides have been made in ourability to detect sensitive endpoints of toxicity, to measure, evaluate, and pre-dict with greater accuracy e¤ects of low exposure levels, to examine on a cell-and tissue-specific basis the genes that may be altered following exposure,and to begin to understand the normal function of the AhR. Thus, it appearsthat the scientific community is at the brink of finally making some connectionsbetween the molecular actions of TCDD and those biological and toxic e¤ectsin animals and humans. Real issues such as What concentrations are toxic tohumans?, What e¤ects are more likely to be observed and at what doses?, andWhat subpopulations might be most sensitive?, are beginning to be addressed.This text was written to foster further these connections by o¤ering a perspec- xiii
  • 12. xiv PREFACEtive as to how recent scientific data may relate to very relevant issues in humanand environmental health. The chapter authors are scientists with international reputation in their par-ticular area of the dioxin arena. Many of these individuals have been responsi-ble for generating the original scientific data that they discuss. They have beenasked to address their chapters to an audience of well-educated and intelligentlay persons and professionals who may not necessarily be familiar with thedetails of the di¤erent specialties. As such, the authors have included high-lights of their respective fields with a sampling, without being encyclopedic, ofimportant references. Furthermore, each author has been asked to discuss therelevance of these scientific data to possible human exposures and health risks.Through this approach, the book gives a meaningful and accessible presenta-tion to the broadest range of health professionals and nonhealth professionalsinterested in dioxins, as well as policy makers and the general public. Since the middle of the 20th century, dioxins have been widespread andpersistent synthetic environmental contaminants in the United States and otherindustrial counties. Because of their ubiquity, persistence, and extreme toxicityin laboratory animals, considerable concern arose regarding their presence inthe food chain and in human tissue. The fact that these chemicals have beenshown to cause cancer, immune system disorders, reproductive and devel-opmental abnormalities, neurological and endocrine system alterations in lab-oratory animals at very low doses has further fueled this concern. While thereexists controversy regarding extrapolation of laboratory animal data to humanrisks, more and more data is available that may allow us within the next fewyears to draw better conclusions about the actual risks to human populations. In their introductory overview of the continuing dioxin debate, ThomasWebster and Barry Commoner provide a summary of some of the major cur-rent dioxin controversies. Chapters 2 and 3, by Roger Gilpin, Daniel Wagel,and Joseph Solch, and James Startin and Martin Rose, respectively, provide aperspective on the sources of the dioxins, how they move in the environment,and how and why humans are exposed predominantly by dietary intake. In separate chapters, several scientists present our current understanding ofthe information we have obtained, mainly from studies of experimental ani-mals, for the e¤ects of these chemicals on certain health outcomes. Chapter 4,by Jeanelle Martinez, Michael DeVito, Linda Birnbaum, and Nigel Walker,gives a brief overview of the toxicology of the dioxins and the predominantissues that bench scientists are attempting to address. More detailed considerations of the subdisciplines are presented in subse-quent chapters. Chapter 5, by Linda Birnbaum and William Farland, summa-rizes the approaches used to consider the available animal and human datafor possible human health risks. Here, while the good news is presented thathuman body burdens of these chemicals are, in general, declining in moreindustrialized countries, an analysis of the toxicity data may suggest that thesebody burdens are still at or near concentrations where some e¤ects might beexpected to occur. In Chapter 6, James Olson summarizes what is known about
  • 13. PREFACE xvthe fate of these chemicals in animal and human tissues. These data are partic-ularly important for defining body burdens at di¤erent life stages and exposureconditions. One of the major issues that remains to be better characterized isthe determination of what body burdens cause what toxic e¤ects. The discus-sion by Michael DeVito, Amy Kim, Nigel Walker, Fred Parham, and ChrisPortier in Chapter 7 indicates that most responses to these chemicals do nothave the same dose–response relationships and clearly some responses are moresensitive than others. Notably this conclusion is mirrored in a later chapterwhere gene responses are discussed. Chapters 8 through 11, by Nancy Ker-kvliet; Michael Theobald, Gary Kimmel, and Richard Peterson; Richard See-gal; Justin Teeguarden and Nigel Walker, respectively, discuss in greater detailsome of the most consistent and sensitive toxic responses to these chemicals inthe immune system, on developing and reproductive tissues, in the nervoussystem, and for carcinogenesis. Here, much of the focus is on defining the cel-lular and biochemical alterations that lead to these responses. Chapters 12, 13, and 14, by Tom Gasiewicz and Sang-ki Park; KevinKerzee, Ying Xia, and Alvaro Puga; and Mark Hahn, respectively, are newchapters in this edition. These have been written to summarize the most recentdata at the molecular level, indicating that the Ah receptor and its ability tomodulate the expression of genes is ultimately responsible for the toxic e¤ectsobserved. In particular, these studies open avenues to explore the possibility ofdeveloping molecular biomarkers of susceptibility and exposure. These chap-ters also present particularly exciting findings concerning possible normalfunctions of the receptor, our understanding of which could add much to de-termining how and at what concentrations the dioxins may be acting to causetoxicity, and why these chemicals elicit such tissue- and species-specific e¤ects.As Robert Tanguay, Eric Andreasen, Mary Walker, and Richard Petersonindicate in Chapter 15, fish have been found to be particularly sensitive to thee¤ects of these chemicals. The newest models using Zebra fish may also be ex-tremely useful in dissecting relationships between molecular actions and e¤ectsof the dioxins on several physiological systems. Since one cannot purposefully dose humans with the dioxins, it is more dif-ficult to come to conclusions on health consequences from studies on people.Yet, epidemiology, the study of human populations and health outcomes, hasthe advantage of dealing with the human species. A number of chapters discusswhat is known from epidemiology, including cancer epidemiology. In Chapter16 Arnold Schecter, Olaf Papke, Marian Pavuk, and Rachel Tobey review ex- ¨posure assessment of dioxins, with special emphasis on high resolution gaschromatography–high resolution mass spectroscopy, the current gold standardof exposure assessment. They note that only in the 1980s did this become pos-sible, and it was only in the 1980s that data showed that all humans carry abody burden of chlorinated dioxins and dibenzofurans. In Chapter 17 Matthew Longnecker, Susan Korrick, and Kirsten Moysichreview the epidemiology of polychlorinated biphenyls or PCBs. In Chapter 18Lennart Hardell, Mikael Eriksson, Olav Axelson, and Dieter Flesch-Janys
  • 14. xvi PREFACEreview the epidemiology of dioxins and cancer, including evidence of humancarcinogenicity. Chapter 19, by Sherry Selevan, Anne Sweeney, and Marie H.Sweeney, discuss the reproductive and developmental epidemiology of dioxins.In Chapter 20 a major dioxin incident that took place in Seveso, Italy in 1976 isdescribed by Pier Alberto Bertazzi and Alessandro di Domenico, who alsonoted the health consequences detected to date. Chapter 21 o¤ers a descriptionof the health consequences of Japan rice oil, or Yusho, poisoning with PCBs,dibenzofurans, and small amounts of other chemicals in 1968, by one of thekey scientists who studied the incident, Yoshito Masuda. In the last chapter,Chapter 22, Yueliang Leon Guo, Mei-Lin Yu, and Chen-Chin Hsu describe asimilar rice oil poisoning—the Yucheng incident—that occurred in Taiwan in1979 and its consequences on exposed persons. This book presents policy and science from the molecule to whole animals,and to human epidemiology in a selective fashion within one volume. Hope-fully, it will continue the e¤orts of the first edition in presenting a relativelylarge but not overwhelming amount of material useful to experts, policy mak-ers, and the general public. Arnold Schecter Thomas A. Gasiewicz
  • 15. CHAPTER 1Overview: The Dioxin DebateTHOMAS F. WEBSTERBoston University, Boston, MassachusettsBARRY COMMONERQueens College, CUNY, Flushing, New York1.1 INTRODUCTIONTo the general public, dioxin is the archetype of toxic chemicals, a substancethat in minute amounts causes cancer and birth defects. Raised to a high levelof visibility by the use of Agent Orange in Vietnam, it continues to generateenvironmental issues that capture public attention: Times Beach, Seveso, LoveCanal, herbicide spraying in the United States, waste incineration, and foodcontamination. Public fear engendered counter-reactions. Some claimed that dioxin causesno harm to humans other than chloracne, a disfiguring skin disease.1,2 Otherscompared the public attitude toward dioxin with witch hunts. Dioxin, theysaid, is a prime example of chemophobia, the irrational fear of chemicals.3,4U.S. Assistant Surgeon General Vernon Houk claimed that the evacuation ofTimes Beach, Missouri had been a mistake.5,6 Administrator William Reilly ofthe U.S. Environmental Protection Agency (USEPA) ordered a reassessmentof the toxicity of dioxin. He stated: ‘‘I don’t want to prejudge the issue, but weare seeing new information on dioxin that suggests a lower risk assessment fordioxin should be applied.’’6 In our opinion, the public fears are largely justified. The current scientificevidence argues not only that dioxin is a potent carcinogen, but also that thenoncancer health and environmental hazards of dioxin may be more seriousthan believed previously. Indeed, dioxin appears to act like an extremely per-sistent synthetic hormone, perturbing important physiological signaling sys-tems. Such toxic mimicry leads to a host of biological changes, especiallyaltered cell development, di¤erentiation, and regulation. Perhaps the mostDioxins and Health, Second Edition, Edited by Arnold Schecter and Thomas A. GasiewiczISBN 0-471-43355-1 6 2003 John Wiley & Sons, Inc. 1
  • 16. 2 OVERVIEW: THE DIOXIN DEBATEtroubling consequence is the possibility of reproductive, developmental, andimmunological e¤ects at the levels of dioxinlike compounds now present in thebodies of the average person. Observation of such phenomena in wildlife sug-gests that the environment is overburdened with these dangerous compounds. The pendulum of o‰cial opinion has swung back. Contradicting Houk,U.S. Assistant Surgeon General Barry Johnson testified in June 1992 that theevacuation of Times Beach was not a mistake.7 The USEPA’s reassessment,although still incomplete at this writing, indicates that the danger from dioxinmay be broader and more serious than thought previously.8 In this overview,we discuss the basis for this dramatic turnaround and its logical implication: apolicy directed toward exposure reduction and pollution prevention.1.2 DIOXIN AND DIOXINLIKE COMPOUNDSThe polychlorinated dibenzo-p-dioxins are a group of 75 structurally relatedcompounds (congeners), including the well-known 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD or, as we shall refer to it, TCDD). Based on toxicitysimilar to that of TCDD, a wider group of halogenated aromatic compoundshave been recognized as dioxinlike. These include certain polychlorinateddibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), polychlorinateddiphenyl ethers, polychlorinated naphthalenes, and others. Brominated andchloro–bromo versions of these compounds may be dioxinlike as well.9 Membership in the class is defined biologically: dioxinlike compounds pro-duce a similar spectrum of toxic e¤ects thought to be caused by a commonmechanism. The key step in the presumed mechanism is binding of the dioxin-like compound to a receptor protein, the Ah (aryl hydrocarbon) receptor(AhR). The molecule’s planar shape facilitates binding to the receptor, and itsrelative potency depends to a large degree on its persistence and how well it fitsthe receptor. TCDD binds the Ah receptor with a very high a‰nity and isextremely potent. Other planar molecules of about the same size and shape,including a number of the polyhalogenated dibenzo-p-dioxins and dibenzo-furans, fit almost as well and are also very active. Although certain types ofpolychlorinated biphenyls bind to the receptor only weakly, their relativeabundance in the environment nevertheless makes them biologically important.PCBs with chlorines in positions that prevent the molecule from assuming aplanar position do not bind to the Ah receptor and are not dioxinlike in theirbiological e¤ects. Some of these PCBs can exert toxicity through other mecha-nisms, however.101.3 SOURCESLarge-scale industrial production of the dioxinlike polychlorinated naph-thalenes began during World War I. Production of polychlorinated biphenyls
  • 17. SOURCES 3(PCBs) followed in the late 1920s (Table 1.1). The thermal and chemical sta-bility of PCBs, among other properties, led to their widespread use in trans-formers, capacitors, heat transfer and hydraulic fluids, as well as carbonlesscopy paper, plasticizers, and numerous other applications. Health and envi-ronmental problems led to curbs on their industrial production, but not untildecades later. In the meantime, about 650,000 metric tons were produced in theUnited States and about 1.5 million metric tons worldwide.11 It is estimatedthat about 20 to 30% of this amount has entered the environment. Much of theremainder is still in stock or in uses such as capacitors and transformers.12 In contrast, the polychlorinated dibenzo-p-dioxins (PCDDs) and poly-chlorinated dibenzofurans (PCDFs) are unwanted by-products. Knowledgeof their origins has increased considerably, beginning with the identifica-tion of TCDD as an unwanted by-product of the production of certaintrichlorophenols and herbicides,13 in particular, Agent Orange, a 1 : 1 mixtureof the n-butyl esters of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D). TCDD formation simply requires com-bining two molecules of 2,4,5-trichlorophenol under the right conditions.14More highly chlorinated PCDDs and PCDFs are formed during the productionof pentachlorophenol, a compound still used in the United States and elsewhereas a wood preservative. PCDFs also occur as low-level contaminants of PCBs.Much higher levels are generated by heating PCBs under the right conditions ofheat and oxygen.15 This phenomenon was a major contributor to the Yushoand Yucheng (oil disease) tragedies, where cooking oil was contaminated withPCBs.16,17 It also occurred in numerous incidents involving capacitor andtransformer fires18,19 and the contamination of Belgian food in 1999.20 It was thought for a while that the dioxin problem was limited to a fewreactions of closely related chemicals. Unfortunately, this is not the case.PCDD and PCDF were discovered in ash from trash-burning incinerators in1977 and later in their air emissions.21 It was not known at first whether theemissions were due to unburned PCDD and PCDF in the fuel, formation fromchlorinated organic precursors, or de novo synthesis.21,22 Based on the obser-vation of fly-ash-catalyzed chlorination of organic residues,23 it was hypothe-sized that PCDD and PCDF were synthesized as exhaust gases cooled down inthe boiler and air pollution control devices.24,25 This was soon confirmed bytests conducted at a Canadian incinerator. Little or no PCDD and PCDF werefound in the gases leaving the furnace, but these compounds were detected inthe cooler stack gases.26 Laboratory studies indicate significant formation atabout 300 C.27 A number of U.S. incinerators equipped with electrostatic pre-cipitators running at these temperatures were very large dioxin sources: twoemitted at rates of roughly 1 kg per year of TCDD equivalents (TEQs),28 anamount of dioxinlike compounds considered equivalent in toxicity to TCDD.9Various mechanisms have been postulated for the synthesis reactions, in whichmetals play an important role (e.g., Ref. 29). Both organic and inorganicsources of chlorine may contribute to the formation of PCDD and PCDF.30Although there undoubtedly exists a connection between total emissions of
  • 18. 4 OVERVIEW: THE DIOXIN DEBATETABLE 1.1 Selected History of Dioxin and Dioxinlike Compounds1897–1899 Chloracne characterized1918 Outbreaks of chloracne following exposure to chlorinated naphthalenes1920–1940 Dramatic increase of PCDD and PCDF levels in North American lake sediments (reported 1984)1929 U.S. commercial production of PCBs begins1947 X disease described in cattle in the United States1949–1953 Chemical accidents at Monsanto, Boehringer, and BASF1957 TCDD identified as unwanted contaminant in the manufacture of trichlorophenol1957 Chick edema disease outbreak in poultry in southeastern United States1962–1970 Agent Orange used in Southeast Asia1965–1966 Holmesburg prison experimentsMid 1960s Outbreaks of reproductive and developmental e¤ects in Great Lakes fish-eating birds1968 Yusho oil disease (Japan)1971 TCDD found to cause birth defects in mice Contamination of Times Beach and other Missouri sites1972–1976 Ah receptor hypothesis developed1973 Polybrominated biphenyls accidentally added to cattle feed in Michigan1974 TCDD detected in human breast milk from South Vietnam1976 Accident in Seveso, Italy1977 U.S. commercial production of PCBs halted TCDD found to cause cancer in rats Discovery of dioxin emissions from trash incinerators1978 Kociba et al. cancer study of rats exposed to TCDD1979 USEPA emergency suspension of some 2,4,5-T uses Yucheng oil disease (Taiwan) Association of soft tissue sarcoma with TCDD and phenoxyacetic acid herbicides1979– TCDD found to modulate hormones and their receptors1980 Evacuation of Love Canal1981 Transformer fire in Binghamton, New York state o‰ce building1983–1985 General public found to be contaminated with PCDD and PCDF1985 USEPA health assessment of TCDD1986 Production of dioxin by chlorine-bleached paper mills discovered, al- though proposed earlier1988 First USEPA reassessment of TCDD Die-o¤ of Baltic seals1990 Second Banbury conference on dioxins1991 NIOSH cancer mortality study of U.S. chemical workers Second USEPA