Table Of ContentClinical and Experimental Toxicology of
Organophosphates and Carbamates
Bryan Ballantyne MD, DSC, PhD, MFOM, FACOM, FAACT, FATS, FRCPath, FIBÎOI
Director of Applied Toxicology, Union Carbide Corporation, USA
Adjunct Professor of Toxicology and Pharmacology, University of West Virginia, USA
Timothy C. MarrS MD, MSC, FRCPath, FIBiol, DipRCPath(Tox)
Senior Medical Officer, Department of Health, London, UK
Foreword by:
W.N. Aldridge OBE, PhD, FIBiol
The Robens Institute for Health and Safety, University of Surrey, UK
U T T E R W O R TH
E I N E M A N N
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First published 1992
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British Library Cataloguing in Publication Data
Clinical and experimental toxicology of
organophosphates and carbamates.
I. Ballantyne, Brian II. Marrs, Timothy C.
615.9
ISBN 0 7506 0271 6
Library of Congress Cataloguing in Publication Data
Clinical and experimental toxicology of organophosphates and
carbamates/[edited by] Bryan Ballantyne, Timothy C. Marrs;
foreword by W. N. Aldridge.
p. cm.
Includes bibliographical references and index.
ISBN 0 7506 0271 6
1. Organophosphorous compounds - Toxicology. 2. Carbamates -
Toxicology. 3. Cholinesterase inhibitors - Toxicology.
4. Insecticides - Toxicology. I. Ballantyne, Bryan. II. Marrs,
Timothy C.
[DNLM: 1. Carbamates - toxicity. 2. Organophosophorus Compounds -
toxicity. QV627C641]
RA1242.P56C57
615.9'517-dc20
DNLM/DLC 91-29191
for Library of Congress CIP
Composition by Scribe Design, Gillingham, Kent
Printed and bound in Great Britain by The Bath Press, Avon
Foreword
A knowledge of the type of chemical struc- catalytic centre of enzymes or receptors. It is
tures which possess anticholinesterase actions difficult to remember the days when it was
began with the determination by Stedman not always appreciated that the mechanisms
and Barger in 1925 of the structure of the car- of enzymes followed the normal laws of chem-
bamate, physostigmine, isolated from the istry.
Calabar bean and with the synthesis of Along with an increasing use of anti-
organophosphorus compounds by Lange and cholinesterases, the firm chemical basis for
Schrader in the 1930s. Although the latter their action has allowed many practical prob-
compounds first became known as chemical lems to be solved, e.g. biomonitoring tech-
warfare agents the synthesis of many modifi- niques in human and other species after
cations of the basic completely substituted exposure and the development of rational
oxyacids of phosphorus has lead to com- therapeutic agents for poisoning by them.
pounds effective and safe to use as pesticides. The number of possible chemical structures
Although the lock and key principle for drugs around the phosphorus atom or derivatives of
was known long before the structure of these carbamic acid is almost limitless. It is not sur-
anticholinesterases was established, toxico- prising that it has been found that some struc-
logical research on their mode of action was tures cause other forms of selective toxicity,
one of the earliest to establish the initiating e.g. delayed neuropathy and lung damage.
reaction in precise chemical terms and to link Similar studies in depth of the mechanisms of
this with the many derangements produced in these forms of toxic reactions has established
whole animals, including humans. how to avoid these undesirable chronic toxici-
The acute and selective toxicity of many of ties during the development of new pesticides.
the anticholinesterases can be very high (e.g. Thus the anticholinesterases are classic exam-
μg/kg) and is the result of inhibition of the ples of the value of basic research for the solu-
enzymic hydrolysis of acetylcholine. The tion of practical problems; progress can be
enzyme responsible is acylated by both the slow but the dividends are great.
organophosphorus compounds and the carba- In 1963 a textbook appeared with the title
mates in a reaction in which they take the Cholinesterases and Anticholinesterases, with
place of the normal substrate, acetylcholine. chapters by many experts and the whole edit-
The phosphylated and carbamylated acetyl- ed by G.B. Koelle. This has been the source
cholinesterases are stable, unlike the acylated book on the subject for over 25 years.
intermediates formed in the hydrolysis of nor- However, with the increasing use of the anti-
mal substrates. The reaction sequence for cholinesterases during this period much
inhibition of esterases is now known to be research has been published. Organo-
general; its elucidation laid the theoretical phosphorus compounds and/or the carba-
groundwork for the development of many mates have been used as pesticides, in
biologically active molecules through their industry, as therapeutic agents and as tools
chemical affinity for and reactivity with the for the study and elucidation of complex
ix
x Foreword
physiological systems (as recommended by look at the Contents page of the present vol-
Claude Bernard in 1875). The literature is ume indicates its enormous scope; it provides
vast and the time is ripe for another textbook a reference book with a sound appreciation of
which embraces these new developments. A past research and a look ahead to the future.
Professor W.N. Aldridge
The Robens Institute for Health and Safety,
University of Surrey, UK
Preface
The organophosphates and carbamates have viewpoints as globally representative as possi-
important, sometimes unique, applications for ble from East and West, contributors have
the benefit of mankind. Principal uses in this been drawn from 17 countries. We are particu-
respect are in agriculture, general commerce, larly pleased and grateful to have as one of the
therapeutic medicine and as insecticides in authors Dr George B. Koelle, who 27 years
domestic and public health applications. ago edited Chohnesterase and Anti-
Additionally, and perhaps to the detriment of cholinesterase Agents, for long widely recog-
mankind, the organophosphates are of poten- nized as the leading text in this field.
tial usefulness in chemical warfare operations. In view of the varied, extensive and global
In most circumstances, when organophos- uses of organophosphates and carbamates, it is
phates and carbamates are handled correctly hoped that this volume will be of value to a
and with appropriate protective, precautionary wide spectrum of professionals and organiza-
and guidance measures, they may be used safe- tions. Particularly, we believe that this text will
ly. However, because of their wide usage, be a reference source to biochemists, pharma-
potential for misuse and often high biological cologists, general physicians, general and clini-
activity, the likelihood for adverse effects cal toxicologists, emergency room and
developing by accident or intent is high. Also, occupational health physicians, poison control
the possibility for environmental contamina- centres, pesticide scientists, ecotoxicologists,
tion, with severe ecological consequences, is industrial hygienists, and forensic toxicologists
well appreciated. Therefore, a considerable and pathologists. Additionally, the book
wealth of experience and source of information should be useful to those reading for under-
has developed about the biological activities of graduate and postgraduate degrees in subjects
organophosphates and carbamates, their gen- with a toxicological facet, or for those working
eral and mammalian toxicology, ecotoxicology, towards various toxicology certifying examina-
human and veterinary poisoning, management tions.
of poisoning, prophylaxis and prevention We are grateful to Dr W.N. Aldridge, OBE,
against intoxication and industrial hygiene. for writing a Foreword to this volume. His
Although the central biological activity that name is universally synonymous with anti-
underlies the mechanistic basis for the use of cholinesterase toxicology. Finally we are
carbamates and organophosphates, namely acutely aware of the tolerance and unfailing
inhibition of the chohnesterase group of help provided by Ms Sue Deeley, Managing
enzymes, also mediates some of their toxicity, Editor and Ms Cathie Staves of Butterworth-
the potential for a wide spectrum of differing Heinemann.
toxicity by other mechanisms is well appreciat-
ed. The intentions of this volume are to present Bryan Ballantyne
both a review of the more important aspects of Union Carbide Corporation, USA
the basic and applied toxicology of anti- Timothy C. Marrs
cholinesterase organophosphates and carba- Edenbridge, UK
mates, and also to allow the reader the benefit July 1991
of unpublished information and experience
from a number of experts in this area. To allow
xi
Contributors
Michael Adler, BS, PhD
Neurotoxicology Branch, Pathophysiology Division, US Army Medical Research Institute of
Chemical Defense, Aberdeen Proving Ground, Maryland, USA
Alvito P. Alvares, PhD
School of Medicine, Uniformed Services University, Bethesda, Maryland, USA
Bryan Ballantyne, MD, DSc, PhD, MFOM, FACOM, FAACT, FATS, FRCPath, FIBiol
Union Carbide Corporation, Danbury, Connecticut, USA
Steven I. Baskin, PharmD, PhD, FCP, FACC, DABT
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen
Proving Ground, Maryland, USA
F.M. Belpaire
Heymans Institute of Pharmacology, University of Ghent Medical School, Ghent, Belgium
Francis W. Beswick, MB, BCh, PhD, OStJ
Chemical Defence Establishment, Porton Down, UK
C. Bismuth, MD
Hôpital Fernand Widal, University of Paris VII, Paris, France
John E. Bright, CBiol, FIBiol
Medical Division, Chemical Defence Establishment, Porton Down, UK
R.B. Carrington da Costa, MD, PhD
Intensive Care Unit, Coimbra University Hospital, Coimbra, Portugal
Blés Dési, MD, PhD, DSc, MSc
Department of Hygiene and Epidemiology, Albert Szent-Györgyi University Medical School,
Hungary
Wolfe-D. Dettbarn, MD
Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee,
USA
B.H. Devens, PhD
Livingston Research Center, School of Medicine, University of Southern California, Los
Angeles, USA
David Dinsdale, BSc, DPhil
Medical Research Council Toxicology Unit, Carshalton, UK
Darol E. Dodd, PhD, DABT
Bushy Run Research Center, Export, Pennsylvania, USA Present address: ManTech
Environmental Technology Ltd, Dayton, Ohio, USA
Glenville, D. D'Mello, PhD
Biology Division, Chemical Defence Establishment, Porton Down, UK
Kenneth L. Dretchen, PhD
Department of Pharmacology, School of Medicine, Georgetown University, Washington DC,
USA
Robert C. Duncan, PhD
Department of Oncology, School of Medicine, University of Miami, Miami, Florida, USA
Xlll
xiv Contributors
Essam Enan, BSc, MSc, DipPHSc, PhD
High Institute of Public Health, University of Alexandria, Alexandria, Egypt. Present address:
Department of Environmental Toxicology, University of California, Davis, California, USA
Kristine Erickson-Lamy, PhD
Howe Laboratory of Ophthalmology, Harvard Medical School, Boston, USA
Claire A. Franklin, PhD
Environmental and Occupational Toxicology Division, Environmental Health Directorate,
Department of National Health and Welfare, Ottawa, Ontario, Canada
Margaret G. Filbert, PhD
Neurotoxicology Branch, Pathophysiology Division, US Army Medical Research Institute of
Chemical Defense, Aberdeen Proving Ground, Maryland, USA
Neil E. Garrett, PhD
Orion Medical and Research Services Inc., Chapel Hill, North Carolina, USA
W. Morton Grant, MD
Howe Laboratory of Ophthalmology, Harvard Medical School, Boston, USA
Peter W. Greig-Smith, BSc, DPhil
Ministry of Agriculture, Fisheries and Food, Agricultural Development and Advisory Service,
Tolworth Laboratory, Surbiton, UK
Jack Griffith, PhD, MS
Health Effects Research Laboratory, US Environmental Protection Agency, North Carolina,
USA
R.E. Grissom, Jr., PhD
Agency for Toxic Substances and Disease Registry, Atlanta, Georgia, USA
Alan H. Hall, MD, FACEP
Rocky Mountain Poison and Drug Center, and Department of Pediatrics, Denver, Colarado, USA
Andrew J.W. Heath, MD, PhD
Hässler Lakemedel, Mölndal, Sweden
Theresa R. Henderson, MS
Department of Pharmacology, School of Medicine and Dentistry, Georgetown University,
Washington DC, USA
Elwood F. Hill, PhD
US Fish and Wildlife Service, Patuxent Wildlife Research Center, Laurel, Maryland, USA
Michael J. Hodgson, MD, MPH
Occupational and Environmental Medicine Program, Department of Medicine, University of
Pittsburgh, Pennsylvania, USA
T. Imamura, PhD
Livingston Research Center, School of Medicine, University of Southern California, Los
Angeles, USA
Robert H. Inns, CBiol, MIBiol
Medical Division, Chemical Defence Establishment, Porton Down, UK
Marcus A. Jackson, PhD
Environmental Health Research and Testing, Research Triangle Park, North Carolina, USA
Frank Samsoe Jensen, MD
Department of Anaesthesia, Herlev Hospital, University of Copenhagen, Herlev, Denmark
Martin K. Johnson, BSc, ARCS, PhD
Medical Research Council Toxicology Unit, Carshalton, UK
Y. S. Kagan, DrScMed
All-Union Scientific Research Institute of Hygiene, Kiev, Ukraine
Lakshman Karalliedde, MB, BS, DA, FFARCS
Department of Anaesthesia, School of Medicine, University of Peradeniya, Sri Lanka
George B. Koelle, MD, PhD
Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia,
Pennsylvania, USA
Contributors xv
Edward P. Krenzelok, PharmD, DABAT
Pittsburgh Poison Center, Children's Hospital of Pittsburgh, Pennsylvania, USA
Y. I. Kundiev, DrScMed
Research Institute of Labour Hygiene and Occupational Diseases, Saksagans Kogo, Kiev,
Ukraine
David E. Lenz, PhD
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground,
Maryland, USA
Hilton C. Lewinsohn, MB, BCh, FCCP, FFOM, FACOM, DIH
Union Carbide Corporation, Danbury, Connecticut, USA
Marcello Lotti, MD
Istituto di Medicina del Lavoro, Université di Padova, via J. Facciolati 71, Padova, Italy
Timothy C. Marrs, MD, MSc, FRCPath, FIBiol, DipRCPath
Chemical Defence Establishment, Porton Down, UK. Present address: Department of Health,
London, UK
Donald M. Maxwell, MSc
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground,
Maryland, USA
R.L. Maynard, BSc, MB, BCh, MRCPath, FIBiol
Department of Health, London, UK
Tim Meredith, MA, MD, MRCP
Department of Health, London, UK
Neil Minton, MB, BS, MRCP
National Poisons Unit, Guy's Hospital, London, UK
U.K. Misra, MD, DM, MNAMS
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar
Pradesh, India
David H. Moore, DVM, PhD
Neurotoxicology Branch, Pathophysiology Division, US Army Medical Research Institute of
Chemical Defense, Aberdeen Proving Ground, Maryland, USA
Virginia Murray, MB, BS, MSc, MFOM
National Poisons Unit, Guy's Hospital, London, UK
William J. Murray, MSc
Chemical Evaluation Division, Food Directorate, Health and Welfare Canada, Ottawa, Ontario,
Canada
A.S. Murty, MSc, PhD
School of Life Sciences, University of Hyderabad, India
Lâszlo Nagymajtényi, MD, PhD
Department of Hygiene and Epidemiology, Albert Szent-Györgyi University Medical School,
Szeged, Hungary
Maria Nehéz, MD
Department of Hygiene and Epidemiology, Albert Szent-Györgyi University Medical School,
Szeged, Hungary
Frederick W. Oehme, BS, DVM, MS, Drmedvet, PhD
Comparative Toxicology Laboratories, Kansas State University, Manhattan, Kansas, USA
Doris 0stergaard, MD
Danish Cholinesterase Research Unit, Department of Anaesthesia, Herlev Hospital, Herlev,
Denmark
W-O. Phoon, AM, MB, BS, FFCM, FRCP, FRCPE, FRCPG, FFOM, FACOM, FRFPSG, DIH,
DIHSA, DCH
National Institute of Occupational Health and Safety, Sydney, Australia
David W. Pike, LIBiol
Military Division, Racal Panorama, Beresford Avenue, Wembley, UK
xvi Contributors
J. M. Pimentel, MD
Intensive Care Unit, Coimbra University Hospital, Coimbra, Portugal
David A. Purser, BSc, PhD, DipRCPath(Tox)
Huntingdon Research Centre, Huntingdon, UK. Present address: Fire Research Station,
Borehamwood, UK
Arthur Raines, BS, MS, PhD
Department of Pharmacology, School of Medicine, Georgetown University, Washington DC,
USA
A.V. Ramani, MSc, MPhil
Department of Zoology, BHHG College, Guntur, South India
Elihu D. Richter, MD, MPH
Hadassah University Medical School, Jerusalem, Israel
Kathleen E. Rodgers, PhD
Livingston Research Center, School of Medicine, University of Southern California, Los
Angeles, USA
George E. Rottinghaus, PhD
Department of Veterinary Biomédical Sciences, College of Veterinary Medicine, University of
Missouri, Columbia, USA
Barry H. Rumack, MD
Rocky Mountain Poison and Drug Center, and Department of Pediatrics, University of
Colorado Health Sciences Center, Denver, Colorado, USA
Âke Sellström, PhD
Swedish Defence Research Establishment, Umeâ, Sweden
Nimal Senanayake, MD, FRCP
Department of Medicine, Faculty of Medicine, University of Peradeniya, Sri Lanka
P.V. Shah, PhD
Hoffman-LaRoche, Nutley, New Jersey, USA
Raghubir P. Sharma, PhD
Utah State University, Logan, Utah, USA
Angela D. Smith
School of Medicine, University of Pittsburgh, Pennsylvania, USA
H. Frank Stack, PhD
Environmental Health Research and Testing, Research Triangle Park, North Carolina, USA
Vincent E.V. St Omer, PhD, DVM
Department of Veterinary Biomédical Sciences, College of Veterinary Medicine, University of
Missouri, Columbia, USA
Helen M. Thompson, BSc, PhD
Ministry of Agriculture, Fisheries and Food, Agricultural Development and Advisory Service,
Surbiton, UK
Rajpal S. Tomar, PhD
Department of Entomology, University of California, California, USA
Rochelle W. Tyl, PhD, DABT
Research Triangle Institute, Research Triangle Park, North Carolina, USA
J.A. Vale, MD, FRCP
West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, UK
Bellina Veronesi, PhD
US Environmental Protection Agency, Neurotoxicology Division, Health Effects Research
Laboratory, North Carolina, USA
Gabor Vetro, MD
Department of Hygiene and Epidemiology, Albert Szent-Györgyi University Medical School,
Szeged, Hungary
Jörgen Viby-Mogensen, MD, PhD
Department of Anaesthesia, Righospitalet, Copenhagen, Denmark
Contributors xvii
Colin H. Walker, BSc, MSc, DSc
School of Animal and Microbial Sciences, University of Reading, Reading, UK
Michael D. Waters, PhD
US Environmental Protection Agency, Genetic Toxicology Division, Health Effects Research
Laboratory, North Carolina, USA
Gregory Paul Wedin, PharmD
West Virginia Poison Center, School of Pharmacy, West Virginia University Health Sciences
Center, Charleston Division, Charleston, West Virginia, USA
Sarah Weir, BSc
National Poisons Unit, Guy's Hospital, London, UK
Michael P. Whitmer, BS
Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen
Proving Ground, Maryland, USA
Jan L. Willems, MD, PhD
Royal School of the Medical Services, Leopoldskazerne, Ghent, Belgium
Alan David Wolfe, PhD
Department of Applied Biochemistry, Division of Biochemistry, Walter Reed Army Institute of
Research, Washington DC, USA
K.N. Woodward, BA, BSc, MSc, PhD
Veterinary Medicines Directorate, New Haw, Weybridge, UK
Xue Shou-Zheng, MD
Department of Occupational Health, School of Public Health, Shanghai Medical University,
Shanghai, China
