Table Of ContentDioxins and Health
Dioxins and Health
Edited by
Arnold Schecter
State University ofN ew York
Health Science Center at Syracuse
Clinical Campus at Binghamton
Binghamton, New York
Springer Science +B usiness Media, LLC
Library of Congress Cataloging-in-Publication Data
Dioxins and health / edited by Arnold Schecter.
p. era.
Includes bibliographical references and index.
ISBN 978-1-4899-1464-4
1. Dioxins—Toxicology. I. Schecter, Arnold.
RA1242.D55D58 1994
615.9'512—dc20 94-40007
CIP
This limited facsimile edition has been issued
for the purpose of keeping this title available
to the scientific community.
10 98765432
ISBN 978-1-4899-1464-4 ISBN 978-1-4899-1462-0 (eBook)
DOI 10.1007/978-1-4899-1462-0
© 1994 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1994
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
Contributors
Olav Axelson • Department of Occupational Medicine, University Hospital,
S-581 85 Linkoping, Sweden
Pier Alberto Bertazzi • Institute of Occupational Health, Epidemiology Section,
University of Milan, 20122 Milan, Italy
Linda S. Birnbaum • Environmental Toxicology Division, Health Effects
Research Laboratory, United States Environmental Protection Agency, Research
Triangle Park, North Carolina 27711
Yung-Cheng Joseph Chen • Department of Psychiatry, National Cheng Kung
University Medical College, Tainan 70428, Taiwan, Republic of China
George C. Clark • National Institute of Environmental Health Sciences,
Laboratory of Biochemical Risk Analysis, Research Triangle Park, North Carolina
27709
Barry Commoner • Center for the Biology of Natural Systems, Queens College
CUNY, Flushing, New York 11367
Peter L. deFur • Environmental Defense Fund, Washington, D.C. 20009
Michael J. DeVito • Center for Environmental Medicine and Lung Biology,
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514
Alessandro di Domenico • Laboratory of Comparative Toxicology and
Ecotoxicology, Italian National Institute of Health, 00161 Rome, Italy
Mikael Eriksson • Department of Oncology, University Hospital, S-901 85
Umea, Sweden
John P. Giesy • Department of Fisheries and Wildlife, Pesticide Research Center
and Institute of Environmental Toxicology, Michigan State University, East Lansing,
Michigan 48824
Yue-Liang Leon Guo • Department of Environmental and Occupational Health,
National Cheng Kung University Medical College, Tainan 70428, Taiwan, Republic
of China
v
vi Contributors
Lennart Hardell • Department of Oncology, Orebro Medical Centre, S-701 85
Orebro, Sweden
Chen-Chin Hsu • Department of Psychiatry, National Cheng Kung University
Medical College, Tainan 70428, Taiwan, Republic of China
James Huff • Environmental Carcinogenesis Program, National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Nancy I. Kerkvliet • Department of Agricultural Chemistry and Environmental
Health Sciences Center, Oregon State University, Corvallis, Oregon 97331
Philip J. Landrigan • Department of Community Medicine, Mount Sinai School
of Medicine, New York, New York 10029
George W. Lucier • National Institute of Environmental Health Sciences,
Laboratory of Biochemical Risk Analysis, Research Triangle Park, North Carolina
27709
James P. Ludwig • The SERE Group, Ltd., Victoria, British Columbia, Canada
V8P 3C8
Yoshito Masuda • Daiichi College of Pharmaceutical Sciences, Fukuoka 815,
Japan
William 1. Nicholson • Department of Community Medicine, Mount Sinai
School of Medicine, New York, New York 10029
James R. Olson • Department of Pharmacology and Toxicology, State University
of New York at Buffalo, Buffalo, New York 14214
Richard E. Peterson • School of Pharmacy and Environmental Toxicology
Center, University of Wisconsin, Madison, Wisconsin 53706
Christoffer Rappe • Institute of Environmental Chemistry, University of Umea,
S-901 87 Umea, Sweden
Walter J. Rogan • Intramural Research Program, National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Susan L. Schantz • Institute for Environmental Studies, University of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
Arnold Schecter • Department of Preventive Medicine, University of New York
Health Science Center-Syracuse, Binghamton, New York 13903
Richard F. Seegal • New York State Department of Health, Wadsworth Center for
Laboratories and Research, Albany, New York 12201, and School of Public Health,
University at Albany, State University of New York, Albany, New York 12203
Ellen K. Silbergeld • Environmental Defense Fund, Washington, D.C., 20009,
and Department of Epidemiology and Preventive Medicine, University of Maryland
Medical School, Baltimore, Maryland 21201
Contributors vii
James R. Startin • Ministry of Agriculture, Fisheries and Food, Food Science
Laboratory, Norwich Research Park, Colney, Norwich NR4 7UQ, United Kingdom
Anne Sweeney • School of Public Health, University of Texas Health Science
Center at Houston, Houston, Texas 77025
H. Michael Theobald • School of Pharmacy, University of Wisconsin, Madison,
Wisconsin 53706
Donald E. Tillitt • National Fisheries Contaminant Research Center, U.S. Fish
and Wildlife Service, Columbia, Missouri 65201
Angelika M. Tritscher • National Institute of Environmental Health Sciences,
Laboratory of Biochemical Risk Analysis, Research Triangle Park, North Carolina
27709
Mary K. Walker • School of Pharmacy, University of Wisconsin, Madison,
Wisconsin 53706
Thomas Webster • Department of Environmental Health, Boston University
School of Public Health, Boston, Massachusetts 02118
Mei-Lin M. Yu • Department of Public Health, National Cheng Kung University
Medical College, Tainan 70428, Taiwan, Republic of China
Sheila Hoar Zahm • Occupational Studies Section, Environmental Epidemiology
Branch, Division of Cancer Etiology, National Cancer Institute, Rockville,
Maryland 20892
Douglas R. Zook • Institute of Environmental Chemistry, University of Umea,
S-901 87 Umea, Sweden. Present address: University of Groningen, Mass
Spectrometry Center, 9713 AW Groningen, The Netherlands
Preface
This book originated in a series of cross-disciplinary conversations in the years
1984-1990 between the editor, who is a physician-researcher involved in clinical and
laboratory research, and a dioxin toxicologist.
During the years in which the conversations took place, an extraordinary amount
of new scientific literature was published related to dioxins, defined for purposes of
this text as the chlorinated dibenzo-p-dioxins, dibenzofurans, polychlorinated biphe
nyls (PCB's) and other compounds that are structurally and toxicologically similar to
2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7 ,8-TCDD), the most extensively studied and
most toxic of this group of chemicals. Dioxins also began to interest not only chemists
and toxicologists, but also specialists from diverse disciplines such as wildlife and
environmental science, immunology, neuroscience,public health, epidemiology, med
icine, government, law, sociology, and journalism.
Specialists from such varied disciplines, while familiar with their own literature,
frequently did not have time to follow the dioxin literature outside their specialty area.
In addition, each specialty had unique knowledge, methods, and perspectives. Cross
disciplinary conversation was necessary, but all too frequently, specialists from the
various disciplines did not speak the same language, resulting in misunderstanding.
This text was written to help facilitate cross-disciplinary discourse in the dioxin field
both by providing a one volume summary of the new and cutting edge dioxin research
of the past few years and by offering a perspective as to how this data may relate to real
issues of human and environmental health. Most major scientific areas involving
dioxins have been included; however, the coverage has been somewhat condensed
deliberately in order not to overwhelm the reader.
The chapter authors are all scientists with international reputations in the dioxin
scientific arena. They have been asked to address their chapters to an audience of well
educated and intelligent professionals who may not be familiar with the authors'
specialties, and have included highlights of their fields with a representative, but not
necessarily encyclopedic, sampling of important references. Through this approach, the
book should be accessible to the broadest range of health professionals and non-health
professionals interested in dioxins, as well as to policy makers and the general public.
Since the middle of this century, dioxins have been wide-spread and persistent
environmental contaminants in the United States and other industrial countries. Be
cause of their ubiquity, persistence, and known toxicity in animal laboratory studies,
considerable concern arose regarding their presence in the food chain and in human
tissue, and in the multiple types of potential health consequences in humans and
ix
x Preface
animals, such as cancer, immune system compromise, reproductive and developmental
disorders, neurological damage and endocrine system alterations. Although consider
able controversy exists at the present time in many areas of dioxin research, with
increasing human as well as laboratory studies, the extent of dioxin toxicity has
become better characterized in many species, including humans.
In their introductory overview of the dioxin debate, Thomas Webster and Barry
Commoner provide a summary of some of the major current dioxin controversies. A
review of the current understandings and controversies in dioxin risk assessment is
presented in considerable depth by Ellen Silbergeld and Peter deFur. Douglas Zook and
Christoffer Rappe, in reviewing chemical aspects of dioxins, examine the question of
the environmental sources of dioxins, noting that the source of much (or most) dioxin
production and discharge is unknown at this time. James Startin provides a review of
what is currently known with respect to dioxins in the food chain, which is the imme
diate source of over 90% of the dioxin body burden in the general population in in
dustrial countries. He describes the challengesjnvolved in both analyzing the presence
of dioxin in foods and in interpreting existing studies.
In separate articles, Michael DeVito and Linda Birnbaum; James Olson; Nancy
Kerkvliet; and Angelika Tritscher, George Clark, and George Lucier, many of whom
were responsible for generating the original data presented in their chapters, discuss the
toxicology, pharmacokinetics, immunotoxicology, and dose-response of dioxins and
related chemicals at the cellular and molecular level, based on a variety of toxicologi
cal and biochemical studies. The discussion regarding the threshold level of dioxins,
below which there may be no serious health effects, is of particular importance in light
of the present research and debate in this area. John P. Giesy, James Ludwig, and
Donald Tillitt; and Mary Walker and Richard Peterson review the research on the
effects of dioxin and related chemicals on wildlife health in general, and in biota in
aquatic environments. The authors observe that many biological outcomes and mecha
nisms are similar between species; however, correlation between the effects of dioxins
on other animal species and humans is still not completely characterized.
Specific laboratory and related findings on the developmental and reproductive
toxicity of dioxins, dioxins and mammalian carcinogenesis, and the neurochemical and
behavioral sequelae of exposure to dioxins and PCB's are discussed respectively in
articles by H. Michael Theobald and Richard Peterson; James Huff; and Richard Seegal
and Susan Schantz. The findings of Theobald and Peterson that low level maternal
exposure of rats to dioxin at a sensitive time during pregnancy can lead to behavioral,
reproductive, and. endocrine alterations in male offspring are especially significant
when viewed in conjunction with the discussion of human epidemiological studies in
later chapters.
The final chapters in the text are devoted to more specific discussion of dioxins
and related chemicals and human health. The difficulties in measuring dioxins and
related chemicals in human tissue and the current "state of the art" are reviewed in a
chapter by the editor, followed by a comprehensive overview of the literature on the
human health effects of polychlorinated biphenyls provided by William J. Nicholson
and Phillip 1. Landrigan. The epidemiological studies of dioxins and cancer and dioxin
and reproduction are described in greater depth in respective articles by Lennart Har
dell, Mikael Eriksson, Olav Axelson and Sheila Hoar Zahm; and Anne Sweeney. The
Preface xi
work concludes with reviews and analyses of three major incidents of dioxin exposure
in humans by scientists who have been long involved in their study. Pier Bertazzi and
Alessandro di Domenico discuss the dioxin industrial incident in Seveso, Italy in 1976.
Yoshito Masuda describes the Japanese "Yusho" rice oil poisoning of 1968, and Chen
Chin Hsu, Mei-Lin M. Yu, Yung-Cheng Joseph Chen, Yue-Liang Leon Guo, and
Walter Rogan review and interpret the Taiwan Yu-cheng rice oil poisoning of 1979.
While differences of opinion are reflected in the text, the authors generally agree
that dioxins are highly dangerous and persistent synthetic chemicals which may cause a
large number of different types of health consequences, and which can initiate harmful
biological responses in a dose-dependent fashion. Dioxins appear to be causally linked
to cancers, adverse reproductive and developmental outcomes, and immune system
compromise. They have also been associated with endocrine, neurological, liver and
skin damage, which may occur at relatively low doses in genetically sensitive individu
als. The very long half lives of dioxins, especially 2,3,7,8-TCDD, the most toxic of
the dioxins, in the environment and in humans are cause for concern. It is not known,
however, whether all biological effects of dioxins are harmful, or whether some are
attempts to adapt. Also, there are sex differences in cancer response and other dioxin
toxic end points.
It is now relatively well established that dioxins interact with the cytoplasmic aryl
hydrocarbon, or aH receptor, to initiate a cascade of changes in signal transduction and
gene expression. Because the aH receptor may have some normal functions, action via
a transcription factor, and likely via altered cell differentiation and proliferation, may
well provide significant information about disease states. Dioxin may be toxic due to
the inappropriate movement of the dioxin receptor complex at an inappropriate time
and/or for an inappropriate period. One exciting recent development in the field of
dioxin research reviewed in these chapters is the research into the mechanisms for
dioxin activity and the consideration of the meaning of this knowledge for human
health and the possibilities of developing molecular biomarkers of susceptibility as
well as biomarkers of exposure.
The preparation of this book has taken several years. Each year has brought
important new developments. Both the chapter authors and the editor realize that,
although we have made every effort to make this text the most independent, compre
hensive, and current available reference on dioxin and health, supplements and new
editions will be necessary. Even as the text is delivered to the publisher, new discov
eries are being made, and a bi-yearly update is being planned. By the next edition, new
knowledge from laboratory and human research may have eliminated many of the
current controversies surrounding dioxin and health. Until then, both the authors and
editor hope that the reader derives as much enjoyment in reading this volume as we
have derived from performing the research and preparing the text.
Acknowledgments
I wish to acknowledge and thank the chapter authors for their extraordinary effort
and patience during editing. In addition, the chemists who helped generate the data of
very high quality which I reviewed in my chapter on exposure assessment are gratefully
