Clinical 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 Butterworth-Heinemann Ltd Linacre House, Jordan Hill, Oxford OX2 8DP {& PART OF REED INTERNATIONAL BOOKS OXFORD LONDON BOSTON MUNICH NEW DELHI SINGAPORE SYDNEY TOKYO TORONTO WELLINGTON First published 1992 © Butterworth-Heinemann Ltd 1992 All rights reserved. No part of this publication may be reproduced in any material form (including photocopying or storing in any medium by electronic means and whether or not transiently or incidentally to some other use of this publication) without the written permission of the copyright holder except in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London, England W1P 9HE. Applications for the copyright holder's written permission to reproduce any part of this publication should be addressed to the publishers 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