Small Animal Toxicology, Second Edition

11830 Westline Industrial Drive St. Louis, Missouri 63146

SMALL ANIMAL TOXICOLOGY

ISBN 13: 978-0-7216-0639-2 ISBN 10: 0-7216-0639-3

Copyright © 2006, 2001 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions’.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Authors assume any liability for any injury and/or damage to persons or property arising out or related to any use of the material contained in this book. The Publisher ISBN 13: 978-0-7216-0639-2 ISBN 10: 0-7216-0639-3 Publishing Director: Linda Duncan Acquisitions Editor: Anthony J. Winkel Developmental Editor: Shelly Stringer Publishing Services Manager: Patricia Tannian Project Manager: Sarah Wunderly Design Direction: Amy Buxton Editorial Assistant: Jennifer Hong Printed in United States Last digit is the print number:

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I would like to dedicate this edition to my wife Kate and my children Greyson, Rosie, Rube, and Cory. I would also like to express my gratitude to Tim Reid and the staff at Reid Veterinary Hospital for their support in my academic endeavors. I am also grateful for Dr. Talcott's insights and "efforts; I could not have a better co-author.

Michael E. Peterson

I would like to dedicate this book to all my past and present students who continually challenge me to do my best in the classroom, and who keep my passion in toxicology alive through their interest, support, and humor. I also wish to thank my husband Glenn, daughter Haley, and son Billy, for being supportive and patient in my attempts to balance a career and family. Patricia A. Talcott

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CONTRIBUTORS

Janet Aldrich, DVM

Clinical Veterinarian Veterinary Medical Teaching Hospital School of Veterinary Medicine University of California, Davis Davis, California, USA

Initial Management of the Acutely Poisoned Patient Rodney S. Bagley, DVM, DACVIM (Neurology)

Professor, Neurology and Neurosurgery Department of Clinical Sciences College of Veterinary Medicine Washington State University Pullman, Washington, USA

Anticonvulsants E. Murl Bailey, Jr., DVM, PhD, DABVT

Professor of Toxicology Department of Veterinary Physiology and Pharmacology College of Veterinary Medicine Texas A&M University College Station, Texas, USA

Botulism Ricin A. Catherine Barr, PhD, DABT

Veterinary Toxicologist Texas Veterinary Medical Diagnostic Laboratory College Station, Texas, USA

Household and Garden Plants

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viii Contributors Karyn Bischoff, DVM, MS, DABVT

Resident Pathobiology University of Florida Gainesville, Florida, USA

Diethylene Glycol Methanol Propylene Glycol Dennis J. Blodgett, DVM, PhD, DABVT

Veterinary Toxicologist Biomedical Sciences and Pathobiology Virginia Polytechnic Institute and State University Blacksburg, Virginia, USA

Organophosphate and Carbamate Insecticides Keith Boesen, PharmD, CSPI

Certified Specialist in Poison Information Arizona Poison and Drug Information Center College of Pharmacy University of Arizona Tucson, Arizona, USA

Toxicological Information Resources Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP

Professor Anatomy, Physiology and Pharmacology Auburn University Auburn, Alabama, USA

Considerations in Pediatric and Geriatric Poisoned Patients Thomas L. Carson, DVM, PhD, DABVT

Veterinary Toxicologist Department of Veterinary Diagnostic and Production Animal Medicine College of Veterinary Medicine Iowa State University Ames, Iowa, USA

Methylxanthines

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Contributors ix

Stan W. Casteel, DVM, PhD, DABVT

Professor of Toxicology Veterinary Pathobiology College of Veterinary Medicine University of Missouri Columbia, Missouri, USA

Lead Heather E. Connally, DVM, MS

Resident Small Animal Emergency and Critical Care Medicine Department of Clinical Sciences Colorado State University Fort Collins, Colorado, USA

Ethylene Glycol Alastair E. Cribb, DVM, PhD

Professor, Clinical Pharmacology Canada Research Chair in Comparative Pharmacology and Toxicology Department of Biomedical Sciences Atlantic Veterinary College University of Prince Edward Island Charlottetown, Prince Edward Island, Canada

Adverse Drug Reactions Rebecca N. Dailey, BS Biology

Graduate Research Assistant Animal and Veterinary Science University of Wyoming Laramie, Wyoming, USA

Petroleum Hydrocarbons Rosalind R. Dalefield, BVSc, PhD, DABVT, DABT

Senior Study Director Gene Logic Inc. Gaithersburg, Maryland, USA

Antidotes for Specific Poisons David C. Dorman, DVM, PhD, DABVT

Director of Biological Sciences CIIT Centers for Health Research Research Triangle Park, North Carolina, USA

Bromethalin

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x Contributors Sharon Drellich, DVM, DACVECC

Staff Veterinarian Emergency and Critical Care Service Angell Animal Medical Center—Boston Boston, Massachusetts, USA

Initial Management of the Acutely Poisoned Patient Joanna E. Ellington, DVM, PhD, DACT

Associate Professor Adjunct Pharmacotherapy Washington State University Spokane, Washington, USA CEO INGFertility Valleyford, Washington, USA

Reproductive Toxicology of the Female Companion Animal Reproductive Toxicology of the Male Companion Animal Tim J. Evans, DVM, MS, PhD, DACT, DABVT

Toxicology Section Head/Assistant Professor Veterinary Medical Diagnostic Laboratory/Veterinary Pathobiology University of Missouri—Columbia Columbia, Missouri, USA

Toxicokinetics and Toxicodynamics Kevin T. Fitzgerald, PhD, DVM, DABVP (Canine/Feline)

Staff Veterinarian Alameda East Veterinary Hospital Denver, Colorado, USA

Taking a Toxicological History Establishing a Minimum Database in Small Animal Poisonings Smoke Inhalation Poisonings in the Captive Reptile Carbon Monoxide Cyanide Insects—Hymenoptera Metronidazole

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Contributors xi

Francis D. Galey, DVM, PhD, DABVT

Dean College of Agriculture University of Wyoming Laramie, Wyoming, USA

Approach to Diagnosis and Initial Treatment of the Toxicology Case Effective Use of a Diagnostic Laboratory Tam Garland, DVM, PhD

Research Veterinarian Interventional Radiology Research Laboratory School of Medicine Indiana University Indianapolis, Indiana, USA Director of Cattle and Ruminants Ruminant Division Indiana Board of Animal Health Indianapolis, Indiana, USA

Disaster Management Gregory F. Grauer, DVM, MS, DACVIM

Professor and Head Department of Clinical Sciences Kansas State University Manhattan, Kansas, USA Veterinary Medical Teaching Hospital Kansas State University Manhattan, Kansas, USA

Ethylene Glycol Sharon M. Gwaltney-Brant, DVM, PhD, DABVT, DABT

Medical Director ASPCA Animal Poison Control Center Urbana, Illinois, USA

Christmastime Plants Macadamia Nuts Oxalate-Containing Plants

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xii Contributors Jeffery O. Hall, DVM, PhD, DABVT

Associate Professor Department of Animal, Dairy, and Veterinary Sciences Utah State University Logan, Utah, USA Head of Diagnostic Toxicology Utah Veterinary Diagnostic Laboratory Logan, Utah, USA

Ionophores Iron Lilies Dwayne Hamar, PhD

Diagnostic Laboratory College of Veterinary Medicine and Biomedical Sciences Colorado State University Fort Collins, Colorado, USA

Ethylene Glycol Steven R. Hansen, DVM, MS, DABT, DABVT

Assistant Instructor Veterinary Biosciences University of Illinois Urbana, Illinois, USA Senior Vice President Animal Poison Control Center ASPCA Urbana, Illinois, USA

Pyrethrins and Pyrethroids Steve C. Haskins, DVM, MS, DACVA, DACVECC

Professor Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California Davis, California, USA Director Small Animal Intensive Care Unit Veterinary Medical Teaching Hospital University of California Davis, California, USA

Supportive Care of the Poisoned Patient

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Contributors xiii

Stephen B. Hooser, DVM, PhD, DABVT

Head of Toxicology and Assistant Director Animal Disease Diagnostic Laboratory Purdue University West Lafayette, Indiana, USA Associate Professor Department of Veterinary Pathobiology Purdue University West Lafayette, Indiana, USA

Cyanobacteria Mycotoxins Carl S. Hornfeldt, PhD, RPh

Director, Medical Information and Drug Safety Orphan Medical, Inc. Minnetonka, Minnesota, USA

Summary of Small Animal Poison Exposures Michael W. Knight, DVM, DABVT, DABT ASPCA Animal Poison Control Center Urbana, Illinois, USA

Zinc Phosphide Anita M. Kore, DVM, PhD, DABVT

Senior Toxicology Specialist 3M Medical Department 3M St. Paul, Minnesota, USA

Miscellaneous Indoor Toxicants Gary R. Krieger, MD, MPH

Associate Professor (Adjunct) Department of Toxicology School of Pharmacy Department of Pharmaceutical Science University of Colorado Denver, Colorado, USA Partner NewFields, LLC Denver, Colorado, USA

Indoor Environmental Quality and Health

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xiv Contributors Michelle Anne Kutzler, DVM, PhD, DACT

Assistant Professor Department of Clinical Sciences College of Veterinary Medicine Oregon State University Corvallis, Oregon, USA

Considerations in Pregnant or Lactating Patients Shajan Mannala, BSc, BVSc, MS, PGD (Toxicology)

Manager Virbac Corporation Fort Worth, Texas, USA

Paraquat Jude McNally, RPh, DABAT

Managing Director Arizona Poison and Drug Information Center College of Pharmacy University of Arizona Tucson, Arizona, USA

Toxicological Information Resources Spider Envenomation: Black Widow Spider Envenomation: Brown Recluse Katrina L. Mealey, DVM, PhD, DACVIM, DACVCP

Associate Professor Veterinary Clinical Sciences Washington State University Pullman, Washington, USA

Ivermectin: Macrolide Antiparasitic Agents Matthew S. Mellema, DVM

Fellow Physiology Program School of Public Health Harvard University Boston, Massachusetts, USA

Supportive Care of the Poisoned Patient

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Contributors xv

Michelle S. Mostrom, DVM, MS, PhD, DABVT

Veterinary Toxicologist Veterinary Diagnostic Services North Dakota State University Fargo, North Dakota, USA

Grapes and Raisins Michael J. Murphy, DVM, PhD, JD, DABVT

Professor of Toxicology Department of Veterinary Population Medicine College of Veterinary Medicine University of Minnesota St. Paul, Minnesota, USA

Summary of Small Animal Poison Exposures Anticoagulant Rodenticides Regg D. Neiger, DVM, PhD

Professor Department of Veterinary Science South Dakota State University Brookings, South Dakota, USA

Arsenic Frederick W. Oehme, DVM, PhD, DABVT

Professor of Toxicology, Pathobiology, Medicine, and Physiology College of Veterinary Medicine Kansas State University Manhattan, Kansas, USA Director Comparative Toxicology Laboratories Kansas State University Manhattan, Kansas, USA

Miscellaneous Indoor Toxicants Antidotes for Specific Poisons Paraquat

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xvi Contributors Gary D. Osweiler, DVM, MS, PhD, DABVT

Professor Veterinary Diagnostic and Production Animal Medicine Iowa State University Ames, Iowa, USA Veterinary Diagnostic Laboratory Veterinary Diagnostic and Production Animal Medicine Iowa State University Ames, Iowa, USA

General Toxicological Principles Kathy Parton, DVM, MS

Senior Lecturer in Pharmacology and Toxicology Institute of Veterinary, Animal and Biomedical Sciences Massey University Palmerston North, New Zealand

Sodium Monofluoroacetate (1080) Michael E. Peterson, DVM, MS

Reid Veterinary Hospital Albany, Oregon, USA

Toxicological Decontamination Considerations in Pediatric and Geriatric Poisoned Patients Indoor Environmental Quality and Health Poisonous Lizards Snake Bite: North American Pit Vipers Snake Bite: Coral Snakes Spider Envenomation: Black Widow Spider Envenomation: Brown Recluse Toads Mathieu Peyrou, DVM, MSc

Postdoctoral Fellow Biomedical Sciences Atlantic Veterinary College University of Prince Edward Island Charlottetown, Prince Edward Island, Canada

Adverse Drug Reactions

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Contributors xvii

Konnie H. Plumlee, DVM, MS, DABVT, DACVIM

Laboratory Director Veterinary Diagnostic Laboratory Arkansas Livestock and Poultry Commission Little Rock, Arkansas, USA

Citrus Oils DEET Nicotine Robert H. Poppenga, DVM, PhD, DABVT California Animal Health and Food Safety Toxicology Laboratory School of Veterinary Medicine University of California Davis, California, USA

Hazards Associated with the Use of Herbal and Other Natural Products Birgit Puschner, DVM, PhD, DABVT

Associate Professor of Clinical Toxicology California Animal Health and Food Safety Laboratory System School of Veterinary Medicine University of California, Davis Davis, California, USA

Approach to Diagnosis and Initial Treatment of the Toxicology Case Metaldehyde Merl F. Raisbeck, DVM, MS, PhD, DABVT

Professor, Veterinary Toxicology Department of Veterinary Sciences University of Wyoming Laramie, Wyoming, USA

Organochlorine Pesticides Petroleum Hydrocarbons Jill A. Richardson, DVM

Associate Director of Technical Services The Hartz Mountain Corporation Technical Services Secaucus, New Jersey, USA

Amitraz Ethanol Atypical Topical Spot-On Products

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xviii Contributors Brian K. Roberts, DVM, DACVECC

Director of Emergency and Critical Care ER/Critical Care Veterinary Specialists of South Florida Cooper City, Florida, USA

Toads William O. Robertson, MD

Professor of Pediatrics Pediatrics University of Washington School of Medicine Seattle, Washington, USA Attending Staff Member Pediatrics Children’s Hospital and Regional Medical Center Seattle, Washington, USA Attending Staff Member Pediatrics University of Washington Academic Medical Center Seattle, Washington, USA Attending Staff Member Pediatrics Harborview Medical Center Seattle, Washington, USA

Use of Human Poison Centers in the Veterinary Setting Wilson K. Rumbeiha, BVM, PhD, DABT, DABVT

Associate Professor Pathobiology and Diagnostic Investigation Michigan State University East Lansing, Michigan, USA

Cholecalciferol—Vitamin D Rance K. Sellon, DVM, PhD, DACVIM Associate Professor Veterinary Clinical Sciences Washington State University Pullman, Washington, USA

Acetaminophen

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Contributors xix

David Spoerke, MS, RPh

Triage Officer Administration Mountainland Pediatrics, P.C. Denver, Colorado, USA

Mushrooms John B. Sullivan, Jr., MD, MBA

Associate Professor of Surgery Adjunct Assistant Professor of Pharmacology Acting Medical Director of Poison Control University of Arizona Health Sciences Center Tucson, Arizona, USA Active Medical Staff Toxicology University Medical Center Tucson, Arizona, USA

Indoor Environmental Quality and Health Patricia A. Talcott, MS, DVM, PhD, DAVBT

Associate Professor Department of Food Science and Toxicology Veterinary Diagnostic Toxicologist Analytical Sciences Laboratory University of Idaho Moscow, Idaho, USA Veterinary Diagnostic Toxicologist Washington Animal Disease Diagnostic Laboratory Washington State University Pullman, Washington, USA

Anticoagulant Rodenticides Copper Cyanobacteria Effective Use of a Diagnostic Laboratory Mycotoxins Nonsteroidal Antiinflammatories Strychnine Zinc

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xx Contributors John H. Tegzes, VMD, MA, DABVT

Associate Professor, Toxicology College of Veterinary Medicine Western University of Health Sciences Pomona, California, USA

Mercury Sodium Mary Anna Thrall, DVM, MS, DACVP

Professor Microbiology, Immunology and Pathology Colorado State University Fort Collins, Colorado, USA Clinical Pathology Colorado State University Veterinary Teaching Hospital Colorado State University Fort Collins, Colorado, USA

Ethylene Glycol Theodore G. Tong, PharmD, DABAT, FAACT

Professor and Associate Dean Pharmacy Practice, Pharmacology, Toxicology and Public Health College of Pharmacy University of Arizona Tucson, Arizona, USA

Toxicological Information Resources Mark D. Van Ert, PhD, CIH

Adjunct Associate Professor Division of Environmental and Community Health Environmental and Occupational Health Concentration College of Public Health University of Arizona Tucson, Arizona, USA

Indoor Environmental Quality and Health Rebecca Vera, AAS, CVT

Intensive Care Nurse Alameda East Veterinary Hospital Denver, Colorado, USA

Smoke Inhalation Poisonings in the Captive Reptile Insects—Hymenoptera

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Contributors xxi

Petra A. Volmer, DVM, MS, DABVT, DABT

Assistant Professor Veterinary Biosciences University of Illinois Urbana, Illinois, USA

“Recreational” Drugs Katie Von Derau, RN, CPN, CSPI

Supervisor Washington Poison Center Seattle, Washington, USA

Use of Human Poison Centers in the Veterinary Setting Gary Vroegindewey, DVM, MSS

Assistant Chief U.S. Army Veterinary Corps U.S. Army Medical Department Fort Sam Houston, Texas, USA

Toxicological Disasters Clynn E. Wilker, DVM, PhD, DACT

Director Preclinical Safety Assessment NPS Pharmaceuticals, Inc. Salt Lake City, Utah, USA

Reproductive Toxicology of the Female Companion Animal Reproductive Toxicology of the Male Companion Animal Roger A. Yeary, DVM, DABVT

Professor Emeritus Veterinary Bioscience The Ohio State University Columbus, Ohio, USA

Miscellaneous Herbicides, Fungicides, and Nematocides

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PREFACE

This book was originally written with two goals in mind: to provide a textbook for veterinary students that would supplement their classroom instruction and to supply a valuable aid for the practicing small animal clinician. Dr. Peterson approached the textbook from the viewpoint of an active practicing small animal clinician with an academic background in toxicology and public health. He is also an authority on clinical management of animals envenomated by a variety of zootoxins. Dr. Talcott is a veterinary toxicologist at the Washington Animal Disease Diagnostic Laboratory and is a diplomate of the American Board of Veterinary Toxicology who brings to the text the experience of a practicing veterinary diagnostic toxicologist and of an instructor of veterinary students. The book, similar to the first edition with an additional 25 new chapters, is divided into three sections. The first includes chapters on toxicological principles. The second section is devoted to general toxicology exposures with an overview of major complex topics. The final section, arranged alphabetically, concentrates on commonly encountered specific toxins, with a brief outline containing critical pieces of information located at the beginning of each chapter. In addition to the added chapters and updated information, an index in the front of the book listing toxins by systems, along with an upgraded index at the end, will aid the clinician in finding information quickly. We hope that this textbook will be of assistance to those students and veterinarians looking for an updated resource on small animal toxicology. Michael E. Peterson Patricia A. Talcott

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INDEX OF TOXINS BY SYSTEM (refer to Chapter 19 for a complete list of toxic plants by system)

Substances Potentially Associated with Blindness

Ethylene glycol, ivermectin and ivermectin-like parasiticides (e.g., moxydectin, eprinomectin, selamectin, abamectin), lead, metaldehyde, paintballs, salt (e.g., homemade play dough, ice melts, water deprivation). Substances Potentially Associated with Cardiac Abnormalities

Acetylcholinesterase-inhibiting compounds (e.g., organophosphate and carbamate insecticides), Aconitum (monkshood), amitraz, amphetamines, antidepressants, Apocynum (dogbane), Asclepias (milkweed, pleurisy root), Bufo sp. (toads), caffeine, calcipotriene or calcipotriol, cantharidin, cholecalciferol (and related products), Cassia (senna), cobalt, cocaine, Convallaria (lily-of-the-valley), cyanide, Digitalis (foxglove), digitoxin, digoxin, Eupatorium (white snakeroot), fluoroacetate and fluoroacetamide (Compounds 1080 and 1081), gossypol (Gossypium—cottonseed), ice melts (e.g., magnesium chloride, potassium chloride), ionophores (e.g., laidlomycin, lasalocid, lizard (Heloderma), monensin, narasin, salinomycin) Kalmia (laurel), minoxidil, mushrooms, Nerium (oleander), Persea (avocado), petroleum hydrocarbons (e.g., diesel fuel, gasoline, kerosene), Phoradendron (mistletoe), Pieris (Japanese pieris), pit viper venom, Rhododendron (rhododendron, azalea), Sassafras (sassafras), selenium, Taxus (yew), theobromine, tricyclic antidepressants, Urginea (red squill), Veratrum (false hellebore), Vicia (vetch), xylazine, Zigadenus (death camas). Substances Potentially Associated with Gastrointestinal Abnormalities

Abrus (precatory bean), acetylcholinesterase-inhibiting organophosphate and carbamate pesticides, aluminum/zinc/magnesium phosphide, antimony, arsenic, Asclepias (milkweed, pleurisy root), cadmium, caffeine, cantharidin, cationic detergents, cholecalciferol (and related products), chromium, Colchicum (Autumn crocus), copper, corrosives, 2,4-D (2,4dichlorophenoxyacetic acid), diethylene glycol, Digitalis (foxglove), diethylene glycol, digitoxin, digoxin, diquat, ethanol, ethylene glycol, Euphorbia family, fireworks, flares, fluoroacetate and fluoroacetamide (Compounds xxxi

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xxxii Index of Toxins by System

1080 and 1081), gorilla glue, grapes, Hedera helix (English ivy), Helleborus (Christmas rose), Hyacinthus (hyacinth), Hydrangea (hydrangea), ice melts (e.g., urea, calcium carbonate, calcium magnesium acetate, sodium chloride, magnesium chloride, potassium chloride), Ilex (holly), iron, Kalmia (laurel), lead, Ligustrum (privet), mace, matches, mercury, mothballs, mushrooms, Narcissus (daffodil, jonquil), nicotine, nitrate, nonionic detergents, nonsteroidal antiinflammatory agents, nutmeg, oil of wintergreen, paintballs, paraquat, phenol, phenoxy herbicides (e.g., 2,4-dichlorophenoxyacetic acid), phosphorus, Phoradendron (mistletoe), Phytolacca (pokeweed), play dough (homemade), raisins, Rhododendron (rhododendron, azalea), Ricinus (castor bean—ricin), Robinia (black locust), Sassafras (sassafras), soaps, thallium, theobromine, trichothecene mycotoxins (e.g., deoxynivalenol—vomitoxin or DON), Viscum (mistletoe), zinc. Substances Potentially Associated with Heinz Bodies and/or Hemolysis (see also Substances Potentially Associated with Methemoglobin Production)

Acetaminophen, Allium (e.g., onions, garlic, chives), chlorate, copper, coral snake venom, Cruciferae family (e.g., kale, broccoli, cauliflower, rapeseed, mustard), drugs (e.g., acepromazine, benzocaine, bupivacaine, chloramphenicol, griseofulvin, lidocaine, prilocaine, tetracaine, trimethoprim sulfa), fireworks, flares, insect stings, matches, methylene blue, mothballs (naphthalene), mushrooms, nonionic detergents, overhydration, paracetamol, pit viper venoms, propylene glycol, skunk spray, spider venom (Loxosceles—brown recluse), zinc. Substances Potentially Associated with Hemostasis Abnormalities

Anticoagulant rodenticides (e.g., brodifacoum, bromadiolone, chlorophacinone, coumafuryl, difenacoum, difethialone, diphacinone, phenindione, pindone, valone, warfarin), nonsteroidal anti-inflammatories, pit viper venom, sulfaquinoxaline, toxins associated with liver failure (e.g., aflatoxin, acetaminophen, copper, cyanobacteria, mushrooms, zinc), toxins associated with thrombocytopenia (e.g., antibiotics—cephalosporins, diuretics, heparin, phenol, quinidine, quinine). Substances Potentially Associated with Hepatic Abnormalities

Acetaminophen, aflatoxin, carbon tetrachloride, carprofen, coal tar, copper, cyanobacteria (i.e., blue-green algae), diazepam (cat), germander, iron, lead, mebendazole, melarsomine, mothballs, mushrooms, nitrosamines, nonsteroidal antiinflammatory agents, paracetamol, pennyroyal oil, petroleum hydrocarbons (e.g., diesel fuel, gasoline, kerosene),

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Index of Toxins by System xxxiii

phenacetin, phenobarbital, phenol, phenytoin, primidone, pyrrolizidine alkaloids, sulfonamides, phenol, phosphorus, quinine, Sassafras (sassafras), stanozolol, tannic acid, thiacetarsamide, toluene, trimethoprim sulfas, valium, vitamin A, zinc. Substances Potentially Associated with Hyperthermia

Bromethalin, cocaine, dinitrophenol, disophenol, halothane, hops, pentachlorphenol, seizures (or muscle tremors). Substances Potentially Associated with Methemoglobin Production (see Substances Potentially Associated with Heinz Bodies and/or Hemolysis)

Acetaminophen, aniline dyes, benzocaine, chlorate, chloroquine, copper, dibucaine hydrochloride, gallic acid, lidocaine, naphthalene (mothballs), nitric and nitrous oxide, nitrite (nitrate), nitrobenzene, nitroglycerin, nitroprusside, phenacetin, phenazopyridine, phenol, prilocaine, primaquine, propitocaine, pyridium, pyrogallol, resorcinol, silver nitrate, sulfonamides, sulfone, tannic acid. Substances Potentially Associated with Nervous System— Depression

Acetone, amitraz, barbiturates, benzodiazepine, cholecalciferol (and related products), citrus oils, diethylene glycol, ethanol, ethylene glycol, ice melts (e.g., potassium chloride, magnesium chloride), isopropanolol, ivermectin and ivermectin-like parasiticides (e.g. moxydectin, eprinomectin, selamectin, abamectin), lizard (Heloderma), marijuana (Cannabis), methanol, mushrooms, nicotine, opioids, phenothiazines, pine oil, piperazine, pit viper venom, propylene glycol, tranquilizers, turpentine, xylitol. Substances Potentially Associated with Nervous System— Excitation

Acetylcholinesterase-inhibiting organophosphate and carbamate pesticides, 4-aminopyridine, amitraz, amphetamines, antidepressants, Asclepias (milkweed), Atropa (belladonna), atropine, bromethalin, Bufo sp. (toad) caffeine, camphor, chlorinated hydrocarbons (e.g., aldrin, chlordane, endosulfan, heptachlor), cholecalciferol, Cicuta (water hemlock), citrus oils, cocaine, cyanide, cyanobacteria (i.e., blue-green algae), Datura (jimsonweed), DEET, Dicentra (bleedingheart, Dutchman’s breeches), dichloromethane, ethylene glycol, 5-fluorouracil, Hyoscyamus (henbane), ice melts (e.g., sodium chloride), Ipomea (morning glory), imidacloprid, ivermectin and ivermectinlike parasiticides (e.g., moxydectin, eprinomectin, selamectin, abamectin), khat, Latrodectus spider venom, lead, Lobelia (lobelia), LSD, mace, ma huang,

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xxxiv Index of Toxins by System

melaleuca oil, mercury, metaldehyde, metronidazole, mushrooms, nicotine, nutmeg, opioids (cat), paintballs, pemoline, penitrem A, phencyclidine, play dough (homemade), potassium bromide, propylene glycol, pyrethrin, pyrethrum, pyrethroids (e.g., allethrin, tetramethrin, resmethrin, permethrin), roquefortine, rotenone, ricin (Ricinus—castor bean), salt (e.g., homemade bread dough, ice melts, water deprivation), Sassafras (sassafras), scopolamine, sodium fluoroacetate and fluoroacetamide (Compounds 1080 and 1081), Sophora (mescal bean), strychnine, Taxus (yew), theobromine (chocolate), theophylline, tricyclic antidepressants, valproic acid, xylitol, yohimbe, zinc/magnesium/aluminum phosphide. Substances Potentially Interfering with Oxygen Transport and/or Hemoglobin Binding

Carbon monoxide, cyanide (e.g., mining activity, plants), hydrogen sulfide. Substances Potentially Associated with Renal Abnormalities

Acetaminophen, antibiotics (e.g., amphotericin B, bacitracin, gentamycin, neomycin, oxytetracycline, paromomycin, polymixin-B, sulfonamides), Aristolochia (birthwort), bismuth, boric acid, 2-butoxyethanol, cadmium, calcipotriene or calcipotriol, cantharidin, carbamate fungicides, carbon tetrachloride, cholecalciferol, chromium, citrinin, copper, diethylene glycol, diquat, ethylene glycol, grapes, lead, lilies (Hemerocallis, Lilium), mercury, mothballs, mushrooms, nonsteroidal antiinflammatory agents, ochratoxin, oxalic acid (e.g., Oxalis, Rheum, Rumex), paraquat, petroleum hydrocarbons (e.g., diesel fuel, gasoline, kerosene), phenol, raisins, toluene, uranium, vitamin D–containing plants (e.g., Cestrum diurnum, Solanum malacoxylon), zinc. Substances Potentially Associated with Respiratory System

Acetylcholinesterase-inhibiting organophosphate and carbamate pesticides, α-napthyl thiourea, ammonia, chlorinated hydrocarbons (e.g., aldrin, chlordane, endosulfan, heptachlor), formaldehyde, freon, hydrochloric acid, hydrofluoric acid, hydrogen sulfide, iodine, mercury, nitrogen oxide, opioids, overheated Teflon, paraquat, pennyroyal oil, petroleum hydrocarbons (e.g., diesel fuel, gasoline, kerosene), pine oils, selenium, turpentine, zinc/magnesium/aluminum phosphide. Substances Potentially Associated with Skeletal Muscle Abnormalities/Paralysis

Acetylcholinesterase-inhibiting organophosphates, arsenic, botulism, coral snake venom, ciquatera, cyanobacteria, curare, ionophores (e.g., laidlomycin, lasalocid, monensin, narasin, salinomycin), macadamia nuts,

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Index of Toxins by System xxxv

phenoxy herbicides (e.g., 2,4-dichlorophenoxyacetic acid), saxitoxin, spider (Latrodectus—black widow), succinylcholine. Substances Potentially Associated with Excessive Salivation/Oral Irritation

Acetylcholinesterase-inhibiting compounds (e.g., organophosphate and carbamate insecticides), acids and alkalis (e.g., detergents, disinfectants, soaps), batteries, bleaches, Bufo (toads), cationic detergents, citrus oils, corrosives, cyanobacteria (i.e., blue-green algae), DEET, formaldehyde, glow jewelry (dibutyl phthalate), ivermectin and other macrolide antiparasitic agents (e.g., selamectin, moxidectin, doramectin, eprinomectin, abamectin, milbemycin), lizards, metaldehyde, mushrooms, nonionic detergents, insoluble oxalate-containing plants (e.g., Alocasia [alocasia], Arisaema [ Jack-in-thepulpit], Calla [calla], Colocasia [elephant’s ear], Dieffenbachia [dumbcane], Monstera [split leaf philodendron], Philodendron [ philodendron]), phenol, pine oil, pyrethrins, pyrethroids, spider (Latrodectus—black widow), strychnine, superglue, tremorgenic mycotoxins (e.g., penitrem A, roquefortine), turpentine.

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General Toxicological Principles Gary D. Osweiler, DVM, MS, PhD

• Toxicology is the science and study of how poisons affect organisms. • Dosage is the most important factor that determines response to poisons. • Toxicity is the quantitative amount of toxicant required to produce a defined effect. • Hazard or risk of toxicosis depends on toxicity of the agent, and probability of exposure to the toxicant under conditions of use. • Acute, subacute, and chronic toxicity are different chronological quantitations of chemical toxicity and are determined by relative dosage and time of exposure. • LD50 values are useful for comparison of toxicity among chemicals but do not define the nature of toxicosis or the safe dosage for a majority of animals. • The lowest known clinical toxic dosage is of greatest value for clinical toxicology. • Many factors can alter an animal’s response to toxicants, including those inherent in the toxicant, the animal, the environment, and the combinations of these major factors. • Clinical toxicology evaluation depends heavily on determination of exposure and evidence for the contribution of interacting factors that can alter toxicity. • Common quantitative expressions of dosage and concentration are essential for thorough toxicological evaluation and prognosis.

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Toxicology is the study of poisons and their effects on living organisms. In veterinary medicine, this has come to mean an understanding of sources of poisons, circumstances of exposure, diagnosis of the type of poisoning, treatment, and application of management or educational strategies to prevent poisoning.1-3 More so than many of the specialties in veterinary medicine, toxicology is based on the important principle of dose and response. That is, there is a graded and possibly predictable response based on increasing exposure to the toxicant. In the words of Philipus Aureolus Theophrastus Bombastus von Hohenheim-Paracelsus, a physicianalchemist of the sixteenth century, “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.”2 Although alchemy has long since been abandoned, Paracelsus’ principle of what makes a poison is still true and relevant in the daily practice of nutrition, therapeutics, and toxicology. Today, with emphasis on synthetic drugs, natural or alternative therapies, and the rapidly growing field of nutraceuticals, there is increasing need to be aware of the dosage and response principle for both beneficial and detrimental effects in the daily practice of veterinary medicine. Many of the toxicants discussed in this book will provide examples of the point at which the dosage determines whether the agent is a nutrient, a remedy, or a poison. Determinants of exposure that affect dosage may be more than simply the gross amount of material ingested or applied to the skin. Rather, the effective dosage at a susceptible receptor site determines the ultimate response. Thus species differences in metabolism, vehicle differences that promote skin penetration, specific drug or chemical interactions that potentiate response, and organ dysfunction that limits elimination can all influence the ultimate dosage.2-4 Clinicians must consider all of these possibilities when working to diagnose a potential toxicosis or apply therapeutic agents to their patients. Toxicology involves the knowledge of poisons, including their chemical properties, identification, and biologic effects, and the treatment of disease conditions caused by poisons. Toxicology shares many principles with pharmacology, including the dynamics of absorption, distribution, storage, metabolism, and elimination; mechanisms of action; principles of treatment; and dose-response relationships. Although some of these important principles will be mentioned, a full discussion of such factors is beyond the scope of this chapter. Toxicology literature is best understood if some basic terminology is remembered. A poison or toxicant is usually considered any solid, liquid, or gas that when introduced into or applied to the body can interfere with homeostasis of the organism or life processes of its cells by its own inherent qualities, without acting mechanically and irrespective of temperature.

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The term toxin is used to describe poisons that originate from biological sources and are generally classified as biotoxins. Biotoxins are further classified according to origin as zootoxins (animal origin), bacterial toxins (which include endotoxins and exotoxins), phytotoxins (plant origin), and mycotoxins (fungal origin).2-4 Poisons may be categorized as organic, inorganic, metallic, or biological. A further distinction is made by some between synthetic and natural agents. Synthetic agents may have been designed specifically as toxicants that may have a very broad or very narrow range of toxicity and/or may produce effects in very specific targets. Natural products used in nutrition, medicine, or commerce are sometimes believed to be less hazardous than synthetic products. However, natural products are not inherently more or less toxic than synthetic molecules. Indeed, some of the most toxic agents known (e.g., botulinum toxin, tetrodotoxin) are of natural origin. Knowledge of the chemical nature and specific effects of toxicants is the only certain way to assess hazard from exposure. The terms toxic, toxicity, and toxicosis are often misunderstood or misused.3,4 The word toxic is used to describe the effects of a toxicant (e.g., the “toxic” effects of organophosphate insecticides may be described as cholinesterase inhibition; vomiting, salivation, dyspnea, and diarrhea). However, toxicity is used to describe the quantitative amount or dosage of a poison that will produce a defined effect. For example, the acute lethal dosage to cats of ethylene glycol would be described as 2 to 5 mL/kg body weight. The toxic effects of ethylene glycol are acidosis and oxalate nephrosis. Finally the state of being poisoned by a toxicant, such as ethylene glycol, is toxicosis. Mammalian and other vertebrate toxicities are usually expressed as the amount of toxicant per unit of body weight required to produce toxicosis. Dosage is the correct terminology for toxicity expressed as amount of toxicant per unit of body weight.2-4 The commonly accepted dosage units for veterinary medicine are milligrams per kilogram (mg/kg) body weight. However, toxicity can also be expressed as moles or micromoles of agent per kilogram body weight. In some experimental studies, comparisons of large and small animals relate dosage to the body surface area, which is approximately equal to body weight.2-4 The use of body surface area dosages is advocated by some as a more accurate way to account for very different body sizes in veterinary medicine. For clinical toxicology, the examples in Table 1-1 generally show that as animals increase in weight, the body surface area increases proportionally less, and this may affect the rate of metabolism, excretion, and receptor interaction with toxicants.3 For many toxicants, larger animals can be poisoned by relatively lower body weight dosages than can smaller mammals.4 However, other factors, such as species differences in metabolism or excretion or specific differences in receptor sites can alter this generalization. Dose is a term for the total

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Table 1–1

Comparison of Body Weight to Surface Area for Animals of Representative Sizes Body Weight (kg)

Body Surface (m2)

0.5 1.0 5.0 10.0 20.0 40.0

0.06 0.10 0.29 0.46 0.74 1.17

amount of a drug or toxicant given to an individual organism. In veterinary medicine, the extreme ranges of body weight and surface area, even within some species, generally make the “dose” approach of little practical value. A commonly used means to compare the toxicity of compounds with one another is the median lethal dosage, also known as the acute oral LD50 in a standard animal, such as the laboratory rat. The LD50 value is usually based on the effects of a single oral exposure with observation for several days after the chemical is administered to determine an end point for total deaths. The LD50 is a standardized toxicity test that depends on a quantal (i.e., all-or-none) response to a range of regularly increasing dosages. In some cases a multiple-dosage LD50 is used to show the acute effects (typically up to 7 days) produced by multiple dosages in the same animals. Increasing dosage levels are usually spaced at logarithmic or geometric intervals. When cumulative deaths are plotted on linear graph paper, the dose-response curve is sigmoid, and the most predictable value is usually around either side of the LD50 (Figure 1-1). 12 10

Deaths

8 6 4 2 0 1

3

5

7

9

11 13 15 Dosage (mg/kg)

17

19

Figure 1–1. Dose-response curve for a typical LD50 study.

21

23

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6 Toxicological Concepts

The end point of an LD50 study is death, and the published LD50 value says nothing about the severity of clinical signs observed in the surviving animals or the nature of the clinical effects.2-4 Twenty or more animals may be used to arrive at a good estimate of the LD50, which limits the use of LD50 values in most animals of economic significance. In some species, such as birds and fish, the oral toxicity is often expressed on the basis of the concentration of the substance in the feed or water. The acute oral toxicity for birds is often expressed as the LC50, meaning the milligrams of compound per kilogram of feed. For fish, the LC50 refers to the concentration of toxicant in the water. Other terms are used in the literature to define toxicity of compounds. The highest nontoxic dose (HNTD) is the largest dose that does not result in hematological, chemical, clinical, or pathological drug-induced alterations. The toxic dose low (TDL) is the lowest dose to produce drug-induced alterations; twice this dose will not be lethal. The toxic dose high (TDH) is the dose that will produce drug-induced alterations; administering twice this dose will cause death. The lethal dose (LD) is the lowest dose that causes toxicant-induced deaths in any animal during the period of observation. Various percentages can be attached to the LD value to indicate doses required to kill 1% (LD1), 50% (LD50), or 100% (LD100) of the test animals. Another acronym occasionally used is MTD. It has been used to note the “maximum tolerated dose” in some situations or “minimal toxic dose.” Thus one should read such abbreviations carefully and look for the specific term defined. Acute toxicity is a term usually reserved to mean the effects of a single dose or multiple doses measured during a 24-hour period. If toxic effects become apparent over a period of several days or weeks, the terms subacute or chronic toxicity may be used. Subacute may refer to any effects seen between 1 week and 1 month, whereas chronic often refers to effects produced by prolonged exposure of 3 months or longer. These definitions obviously leave a large gap between 30 days and 90 days. The term subchronic is sometimes used to define this time period, although others avoid the problem in semantics by stating the time period involved. For example, a study could refer to a 14-day toxicity trial with the toxic dosage being 5 mg/kg. Duration of exposure can greatly affect the toxicity. The single-dose LD50 of warfarin in dogs is approximately 50 mg/kg, whereas 5 mg/kg for 5 to 15 days may be lethal. In rats the single-dose LD50 of warfarin is 1.6 mg/kg, whereas the 90-day LD50 is only 0.077 mg/kg. On the other hand, rapidly inactivated or excreted compounds may have almost the same 90-day LD50 as the single dose LD50. For example, the single-dose LD50 for caffeine in rats is 192 mg/kg and the 90-day LD50 is slightly lower

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at 150 mg/kg. Conversely, animals may develop tolerance for a compound such that repeated exposure serves to increase the size of the dose required to produce lethality. The single-dose LD50 of potassium cyanide in rats is 10 mg/kg, whereas rats given potassium cyanide for 90 days are able to tolerate a dosage of 250 mg/kg without mortality. The ratio of the acute to chronic LD50 dosage is called the chronicity factor.3 Compounds that have strong cumulative effects have larger chronicity factors. In the foregoing examples the chronicity factors are as follows: warfarin, 20; caffeine, 1.3; and potassium cyanide, 0.04. From a public health and diagnostic toxicology perspective, it is essential to know the exposure level that will not cause any adverse health effect. This level is usually referred to as the no observed adverse effect level (NOAEL).2 It can also be thought of as the maximum nontoxic level. This is the amount that can be ingested without any deaths, illness, or pathophysiological alterations occurring in animals fed the toxicant for the stated period of time. Usually a NOAEL in laboratory animals is based on chronic exposures ranging from 90 days to 2 or more years, depending on the species. The no-effect level is the largest dosage that does not result in detrimental effects. The concept of risk or hazard is important to clinical toxicology. Although toxicity defines the amount of a toxicant that produces specific effects at a known dosage, hazard or risk is the probability of poisoning under the conditions of expected exposure or usage. Compounds of high toxicity may still present low hazard or risk if animals are never exposed to the toxicant. For example, ethylene glycol antifreeze would be defined as low toxicity (2 to 5 mL/kg body weight), but because it is often readily available in homes, is voluntarily consumed by cats, and is difficult to reverse once clinical signs have developed, it is seen as a high-risk or highhazard toxicant. Another way to define risk is to compare the ratio of the lowest toxic or lethal dosage (e.g., the LD1) with the highest effective dosage, which could be defined as the ED99. The ratio of LD1/ED99 is defined as the standard safety margin, and it is useful for comparing the relative risk of therapeutic drugs, insecticides, anthelmintics, and other agents applied to animals for their beneficial effects.2,4 If all animals in an LD50 study were the same, then the LD50 would actually be a standard toxic dosage for all animals. However, at the same LD50 dosage, not exactly 50% of animals will die each time. This biological variation can be due to many factors and is the reason that veterinary clinicians must exercise judgment about the response of animals to a given toxicant. Even more variability is expected because of the differences in species, age, body size, route of exposure, inherent differences in metabolism, and pregnancy and lactation effects. Remember also that the slope of the LD50

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curve is important and is not revealed from the LD50 value alone. An LD50 with a very steep dose-response slope indicates a toxicant or drug has a very narrow margin between no effects and maximal lethal effects.3,4 Although such compounds may be dangerous to use as therapeutics, they could be very effective pesticides because of lower probability of survival of target animals.

FACTORS THAT INFLUENCE TOXICITY Many factors inherent in the toxicant, the animal, or the environment can alter a toxicity value determined under defined experimental conditions. The toxicity of a compound will vary with the route of exposure. Usual routes of exposure are oral, dermal, inhalation, intravenous, intraperitoneal, and subcutaneous. In addition, the most potent routes of exposure are usually the intravenous, intrapulmonary, and intraperitoneal routes. In clinical veterinary toxicology, oral and dermal routes of exposure are the most common, and these routes generally delay the absorption and diffuse exposure over a longer period of time. A daily dosage of toxicant mixed in food and consumed over a 24-hour period may cause much less effect than that same dosage given as a bolus at one specific time. However, retention in the gastrointestinal tract, including enterohepatic cycling, and dermal or hair retention of poisons can significantly prolong the exposure or exposures.2-4 Another factor that can accentuate the toxic effects of a compound is concurrent organ damage as a result of other causes. This is most important for diseases that alter liver or kidney function, leaving the animal with insufficient resources to metabolize and excrete toxicants. Species and breed differences exert important influences on toxicity. The familiar example of cats and their intolerance to phenolic compounds results directly from their lack of glucuronyl transferase, which is necessary to produce glucuronides for the excretion of phenolic metabolites. A common example is acetaminophen, which is quite toxic to cats partly as a result of ineffective excretion of the toxic metabolite. In addition, the amino acid and sulfhydryl content of feline hemoglobin and a relative lack of methemoglobin reductase in erythrocytes makes it more susceptible to oxidant damage. As a result, the cat is more likely to be poisoned by agents that induce methemoglobinemia.4 Occasional differences within a species can increase the probability of toxicosis. The anthelmintic ivermectin provides an example of breed susceptibility differences, with collies and individuals in other herding breeds being more susceptible. Many environmental and physiological factors can influence the toxicity of compounds, and one should remember that such factors, or others

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possibly unknown, can substantially influence an individual’s response to toxicants. Entire publications are devoted to drug and chemical interactions, and the reader is encouraged to be aware of toxicological interactions that are illustrated throughout this text. Some examples of factors that alter response to toxicants are presented in Table 1-2. Table 1–2

Factors that May Alter Response to Toxicants Alteration or Change Impurities or contaminants

Changes in chemical composition or salts of inorganic agents

Instability or decomposition of chemical Ionization Vehicle effects

Protein binding

Chemical or drug interactions

Biotransformation

Mechanism or Example Some older phenoxy herbicides were contaminated with a highly toxic dioxin byproduct of manufacturing, leading to chronic toxicosis from the dioxin. Toxicity of metals may be altered by valence state. Trivalent arsenicals are much more toxic than pentavalent arsenic. Specific salts also alter toxicity (e.g., barium carbonate is cardiotoxic, whereas barium sulfate is insoluble and nearly nontoxic). Some organophosphate insecticides under adverse storage conditions can decompose to form more toxic degradation products. Generally, compounds that are highly ionized are poorly absorbed and thus less toxic. Nonpolar and lipid-soluble vehicles usually increase toxicity of toxicants by promoting absorption and membrane penetration. Binding to serum albumin is common for many drugs and toxicants, limiting the bioavailability of the agent and reducing toxicity. Chemicals may directly bind, inactivate, or potentiate one another. One chemical may also induce microsomal enzymes to influence the metabolism of another. Prior exposure to the same or similar chemical may induce increased metabolic activity of microsomal mixed function oxidases (MFOs). Foreign compounds activated by MFOs can then be conjugated by phase II metabolism and excreted. If toxicants are activated by MFO activity, toxicity may be Continued

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Table 1–2

Factors that May Alter Response to Toxicants—cont’d Alteration or Change

Liver disease

Nutrition and diet

Mechanism or Example increased. Liver disease, very young or very old animals, and specific breeds or strains of animal can alter ability of MFO to begin metabolism followed by phase II detoxification of foreign compounds. Reduced synthesis of glutathione, metallothioneine, and coagulation factors may alter response to acetaminophen, cadmium, and anticoagulant rodenticides, respectively. Natural dietary compounds, such as calcium and zinc, may affect absorption and response to lead. Vitamin C and vitamin E can aid in scavenging of free radicals and repair of cellular protective mechanisms.

BIOLOGICAL VARIATION AND TOXICITY DATA IN VETERINARY PRACTICE Biological variation is a significant factor in interpretation of clinical and diagnostic data used in toxicology. A single toxicity figure will not define the range of toxicity and effects in a given population. Because LD50 or other values are usually defined in very similar animals (e.g., laboratory rats and laboratory beagles), the laboratory toxicity figure does not reflect the biological variation and differences in toxicity that may occur in a diverse group of breeds within the canine or any other species. For animals of veterinary importance there is usually insufficient information on the variability of effects from low or moderate exposures. Furthermore, individual environmental and husbandry conditions vary widely and can affect the severity of response in any particular group of animals for a specific toxicant and dosage. Therefore, thorough clinical and environmental investigation and good laboratory diagnostic procedures are essential to toxicological evaluation in a suspected exposure.

CALCULATIONS FOR TOXICOLOGY As indicated earlier, the basis for toxicological effects is the dose versus response relationship. In a practical clinical situation, the dosage is often

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not defined. Rather, an animal is ill with clinical signs that suggest toxicosis, and there is potential exposure to a known or suspected amount of poison that is probably at some concentration less than 100% in a commercial product or natural source. Alternatively, the animal owner may have seen an exposure, such as an animal consuming some tablets or a potential toxicant such as chocolate. Sometimes, animals with subacute or chronic signs are suspected of consuming some toxicant in the food. Analysis of a food may reveal a concentration in parts per million (ppm), mg/kg, µg/g, or percentage, and the concentration in the food must be related to a known toxicity based on milligram per kilogram of body weight. In all these circumstances, the veterinary clinician must first relate a probable amount of toxicant to a body weight dosage and then decide if detoxification therapy or antidotal treatment is necessary. If dosage is low, careful observation with no treatment may be a valid option. Thus the clinician should investigate the probable dosage as part of the decision process on whether therapy or observation is more appropriate. The ability to accurately convert numbers relating to concentration and dosage and to convert different expressions of exposure or concentration is essential to the practice of medicine, and is equally important in clinical toxicology. The principles of dosage and calculations practiced in pharmacology and therapeutics are similar to those used in toxicology. Of particular importance in toxicology is the need to differentiate between and convert different expressions of concentration as stated on labels or obtained from laboratory analysis. The toxicologist is further challenged to correlate the level of contamination in a feed to the clinical signs observed in a suspected poisoning. The following examples are intended to clarify some of these calculations and to show how they are used in clinical toxicology.

EXPRESSING CONCENTRATION AND DOSAGE IN VETERINARY TOXICOLOGY The amount of a toxic agent in feed, water, baits, and solutions is often expressed as a weight/weight relationship (e.g., g/ton, mg/kg, µg/g), as a weight/volume relationship (e.g., mg/mL, mg/dL, mg/L), or as a proportion of the toxicant to the total medium in which it is held, such as percentage, parts per million (ppm), parts per billion (ppb), and parts per trillion (ppt). For correct toxicological evaluation, one must understand the relationships among these expressions. Relationships and equivalencies of common expressions of concentration useful in calculations and interpretation for veterinary toxicology are shown in Table 1-3. In addition, the clinician may find toxicity data expressed as milligram per kilogram body weight of animal, but may receive a label or statement

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Table 1–3

Common Comparative and Equivalent Values in Veterinary Toxicology Expression or Measurement

Equivalent Value

1 ppm 1 mg/kg or 1 mg/L 1 ppm 1 µg/g or 1 µg/mL 1 ppm 0.0001% 1 ppm 1000 ppb 1 ppm 1,000,000 ppt 1 ppb 0.000001% 1 ppb 1 ng/g 1 ppb 1 µg/kg 1% 10,000 ppm (Convert % to ppm by moving decimal point 4 places to the right) 1 mg/dL 10 ppm or 10 mg/L 1 ounce 28.35 g 1 pound 453.6 g 1 kg 2.205 lbs 1 liter 0.908 quarts 1 gallon 3.785 liters 1 teaspoon 5 milliliters 1 tablespoon 15 milliliters 1 cup 8 ounces or 227 milliliters 1 quart 32 ounces or 946 milliliters

of analysis that expresses the feed, water, or bait concentration as proportional or weight/weight relationships. The accurate assessment of toxicological risk depends on the ability to convert different toxicological expressions to an equivalent common denominator. One common clinical situation is the need to convert a feed or bait concentration to body weight basis toxicity. The following clinical problem illustrates this calculation.

Clinical Problem 1

If the toxicity of cholecalciferol rodenticide is 2 mg/kg of body weight and the bait concentration is 0.075%, is a 2-oz package of bait likely to be toxic to a 35-lb dog that consumes the entire package at one time? Solution:

To evaluate this risk, one must know or assume the following: • Amount of food or bait consumed • Weight of the animal at risk • Concentration of toxicant in the food or bait

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In this case, first convert as much as possible to the metric system: • 35-lb dog/(2.2 lb/kg) = 15.9 kg • 0.075% is 750 mg cholecalciferol/kg or 0.75 mg cholecalciferol/g of bait • Two ounces of bait × 28.35 g/ounce = 56.7 g bait Thus total consumption of cholecalciferol is expressed as: • 56.7 g bait × (0.75 mg cholecalciferol/g bait) = 42.5 mg cholecalciferol consumed • 42.5 mg cholecalciferol/15.9-kg dog = 2.67 mg/kg

From the calculations, it is apparent that this exposure could cause a high risk of toxicosis from cholecalciferol. If the concentration of vitamin D in a complete pet food is known or assumed, one may also need to calculate the potential for toxicosis based on feed contamination.

Clinical Problem 2

Continuing the bait example to another scenario, assume that vitamin D at 2000 IU/kg/day for 1 to 2 weeks can cause subacute toxicosis to dogs. If a dog food were accidentally fortified with a concentration of 1000 IU/lb, would long-term consumption likely result in toxicosis? Solution:

In this case, the needed information is expanded from problem 1, because we do not know the amount of contaminated material consumed. • From current knowledge: food intake for a 35-lb dog would be 2.5% of body weight • Recall from problem 1 that a 35-lb dog is 15.9 kg: 15.9 kg × 0.025 = 0.3975 kg (amount ingested in one day) • Vitamin D in feed at 1000 IU/lb: 1000 IU/lb × 2.2 lb/kg = 2200 IU/kg of feed • Daily total vitamin D intake = 0.3975 kg/day × (2200 IU/kg feed) = 874.5 IU/day • Dosage to the 15.9-kg dog = 874.5 IU/day/15.9 kg = 55 IU/kg/day

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In this clinical example, the daily dosage of 55 IU/kg on a body weight basis is about twice the recommended requirement but far below the known toxicity of 2000 IU/kg. Small animal toxicants may sometimes be expressed in blood or body fluids by different units. Most common are parts per million (ppm), milligrams per deciliter (mg/dL), and milliequivalents per liter (mEq/L). If laboratory results are given in one of these units, but toxicity information is available to the clinician in different units, the ability to convert to comparable units is essential to interpretation. Clinical problem 3 illustrates this conversion.

Clinical Problem 3

In a dog having neurological signs and a suspected salt toxicosis, toxicology laboratory results are returned indicating a serum sodium value of 3600 ppm. Expected normal values in your practice are 135 to 145 mEq/L. Is the laboratory analysis indicative of hypernatremia suggesting salt toxicosis? Solution:

In this case, it will be necessary to convert the laboratory analysis results to mEq/L for interpretation. There is a common formula for converting mg/dL to mEq/L. To use this formula, do the following: • Convert ppm to mg/dL • Since 1 ppm = 1 mg/L, and 1 mg/dL = 10 mg/L, then dividing ppm by 10 = mg/dL (3600 ppm divided by 10 = 360 mg/dL) • mEq/L = mg/dL × valence × 10/atomic weight = 360 × 1 × 10/23 = 156.5 mEq/L

Clinical problem 3 illustrates the tenfold difference between ppm and mg/dL (1 mg/dL = 10 ppm) and shows that to convert from mg/dL to mEq/L one must know the valence and atomic weight of specific toxicants or metals. Toxicoses, although difficult clinical problems, can best be managed by using basic principles and calculations to estimate probable exposure to toxicants and the factors that may alter those responses. Adding to this knowledge of the systemic and medical effects of toxicants and the principles of antidotal and detoxification therapy should result in the best possible outcome in response to small animal toxicoses.

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Clinical Problem 4

A reported LD50 for aflatoxin in dogs is 0.80 mg/kg of body weight. If a beagle dog is exposed to aflatoxin at 2000 parts per billion (ppb) on a continuing basis, will the toxic dosage be exceeded on a daily basis? Solution:

In this scenario, the toxic body weight dosage must be compared against risk from a known or presumed concentration in the diet. The body weight dosage must be converted to a dietary concentration. In addition, remember the principle that dietary dosage is affected by the amount of food consumed. No weight was given for the dog, but it is a beagle, so one can assume a weight of 22 lb for purposes of calculation. • First, convert all weights to the metric system. A 22-lb beagle can reasonably be assumed to weigh 10 kg (22 lb/2.2 kg) • Next, estimate the food intake of the beagle. As in problem 2, a reasonable intake would be 2.5% of body weight daily • Calculate food ingested daily: 10 kg × 0.025 = 0.25 kg food • Calculate the amount of aflatoxin in 0.25 kg food: 2000 ppb = 2000 µg/kg = 2 mg/kg or 2 ppm; at 2 mg/kg × 0.25 kg the food consumed contains 0.5 mg aflatoxin • Calculate the dosage of aflatoxin in mg/kg of body weight: 0.5 mg/10 kg BW = 0.05 mg/kg Alternatively a formula to convert ppm to mg/kg of body weight is: mg/kg BW = ppm in feed × kg feed eaten body wt in kg 2 mg/kg × 0.25 kg feed = 0.05 mg/kg of body weight 10 kg Conclusion: 2000 ppb (2 ppm) dietary aflatoxin is not an LD50 dosage of aflatoxin in the dog. To quickly convert mg/kg of body weight dosage to dietary ppm, use the following formula: Dietary ppm =

mg/kg body weight % of body weight eaten daily

e.g., 0.5 mg/kg BW = 2 ppm = 2000 ppb 0.025 Continued

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Quick Guide: Figure 1-2 provides a range of body weight dosages and food consumption for quick reference in estimating equivalent ppm concentrations in the diet without using calculations. Remember that as a higher proportion of food is consumed relative to body weight, then the same dietary concentration will cause increasing dosage of the toxicant per unit of body weight.

% BW Consumed

ppm toxicant in diet 1

10

50

100

1

0.01

0.1

0.5

2

0.02

0.2

1

3

0.03

0.3

4

0.04

0.4

5

0.05

0.5

10

0.1

1

500

1000

1

5

10

2

10

20

1.5

3

15

30

2

4

20

40

2.5

5

25

50

5

10

50

100

Equivalent body weight dosage (mg/kg)

100 90 1

70

2 60

3

50

4

40

5

30

10

20 5

10 3

% Body weight consumed

1000

500

1 100

50

10

0 1

Dosage in mg/kg BW

80

ppm in diet Figure 1–2. Relationships of food intake and body weight dosage.

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REFERENCES 1. Beasley VR, Dorman DC, Fikes JD, Diana SG, Woshner V: A Systems Affected Approach to Veterinary Toxicology, Urbana, Ill, 1999, University of Illinois. 2. Eaton DL, Klassen CD: Casarette and Doull’s Toxicology: The Basic Science of Poisons, ed 6, 2001, New York, McGraw-Hill. 3. Osweiler GD, Carson TL, Buck WB, Van Gelder GA: Clinical and Diagnostic Veterinary Toxicology, ed 3, Dubuque, Iowa, 1985, Kendall Hunt. 4. Osweiler GD: Toxicology. The National Veterinary Medical Series, Philadelphia, 1996, Williams & Wilkins. 5. Spoo W: Concepts and Terminology. In Plumlee KH, editor: Clinical Veterinary Toxicology, St Louis, 2004, Mosby.

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Toxicokinetics and Toxicodynamics Tim J. Evans, DVM, MS, PhD

DEFINITIONS The basic concepts regarding the toxicokinetics and toxicodynamics of xenobiotics are clinically relevant to veterinary toxicology and need to be understood by veterinary practitioners, professional students, and other personnel who will be participating in the diagnosis and treatment of small animal intoxications. In discussing the aspects of toxicokinetics and toxicodynamics most pertinent to small animal toxicoses, it is first necessary to define several terms. “Xenobiotic” is a general term referring to any chemical foreign to an organism or, in other words, any compound not occurring within the normal metabolic pathways of a biological system.1,2 Depending on the compound and the level of exposure, interactions between xenobiotics and animals can be benign, therapeutic, or toxic in nature. The pharmacokinetics and pharmacodynamics of a therapeutic xenobiotic influence the time course and efficacy of that compound in a pharmacological setting. Likewise, the toxicokinetics and toxicodynamics of a toxic xenobiotic determine the “when,” “how long,” “what,” and “why” for the adverse effects of that toxicant.2 The “disposition” of a xenobiotic is what the animal’s body does to that compound following exposure. The disposition or fate of a xenobiotic within the body consists of the chemical’s absorption, distribution, metabolism (biotransformation), and excretion characteristics, which are collectively abbreviated as ADME.2,3 “Toxicokinetics” refers to the quantitation and determination of the time course of the disposition or ADME for a given toxic xenobiotic.3 There are a variety of specialized toxicokinetic terms, including bioavailability, volume of distribution, clearance, half-life, one-compartment model and first- and zero-order kinetics, which will be discussed later in this chapter under the separate components of ADME. The term “toxicodynamics” describes what a toxicant does physiologically, biochemically, and molecularly to an animal’s body following exposure. 18

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The toxicodynamics of a given toxic xenobiotic are dependent on the mechanism of action of that toxicant and the relationship between toxicant concentration and the observed effects of the toxicant on biological processes in the animal (i.e., the dose-response relationship).1 The disposition and/or toxicokinetics of a particular xenobiotic also play a role in determining the organs or tissues affected by a toxicant, and the clinical presentation and time course of a toxicosis resulting from excessive exposure to that compound.1,2

TOXICOKINETICS/DISPOSITION Xenobiotic absorption With the exception of caustic and corrosive toxicants that cause adverse effects at the site of exposure, a toxic xenobiotic is generally first “absorbed” or taken up into the body.3 Absorption involves crossing cellular membranes, which are typically composed of phospholipid bilayers containing various sized pores and embedded proteins.2 The route of exposure and physiochemical properties of a toxicant, such as its resemblance to endogenous compounds, its molecular size and relative lipid and water solubilities, the magnitude of a molecule’s association constant, and whether a compound can be classified as a weak acid or as a weak base, all determine the manner and quantities in which a xenobiotic is absorbed across cell membranes.

Routes of xenobiotic exposure and xenobiotic bioavailability The most common routes of exposure for xenobiotics in small animal toxicology are oral (gastrointestinal), dermal (percutaneous), and inhalation (pulmonary). In rare instances of iatrogenic intoxications, xenobiotics can be injected subcutaneously, intramuscularly, intraperitoneally, or even intravenously.3 There are unique aspects to the absorption of xenobiotics associated with each route of exposure, especially with regard to the bioavailability of potential toxicants. “Bioavailability” (often represented by “F” in toxicokinetic equations) represents the fraction of the total dose of a toxic xenobiotic that is actually absorbed by an animal.2 In intravenous exposures, the bioavailability of a toxic xenobiotic is 100% since the entire dose of the toxicant reaches the peripheral circulation. The absorption of gases and vapors in the

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respiratory tract is largely dependent on the ratio (blood-to-gas partition coefficient) between the equilibrium concentrations of the toxicant dissolved in the blood and the gaseous phase of the toxicant in the alveolar spaces.2,3 The size of aerosolized particles will determine to a large degree whether a xenobiotic is deposited in the nasopharyngeal region (particles > 5 µm) or within the alveoli of the lungs (45 mm Hg) with acidosis (pH 50 mm Hg can be tolerated if the pH remains above 7.25 and cardiovascular function is adequate.5 Hypoventilation is usually secondary to central nervous system and neuromuscular abnormalities. If pulmonary function in dogs and cats is normal, ventilation at normal minute volumes (100 to 200 mL/kg) with room air or a slightly increased FiO2 should return the blood gases to normal. Permissive hypercapnia is contraindicated in patients with CNS disease or cerebral edema because the resulting cerebral acidosis will cause cerebral vasodilation and can increase cerebral morbidity. Hypoxemia (PaO2 < 65 mm Hg) should be treated with enriched oxygen of 40% or more as necessary to maintain the PaO2 at >65 mm Hg. If continued increases in the inspired oxygen concentration do not improve the PaO2, or if the effort required to maintain the PaO2 at that level is excessive and exhausting, assisted ventilation is required. If the toxin was not inhaled, a reason for the hypoxemia must be sought. Aspiration pneumonia or preexisting respiratory disease should be considered, and a work-up should be performed when the patient is stabilized. The management of patients on mechanical ventilation is beyond the scope of this chapter, and the reader is referred to the references at the end of the chapter.6,7

Circulation (oxygen delivery) Adequate oxygen delivery (circulation) is dependent on the volume of blood in the vessels, the pumping function of the heart, the integrity of the

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blood vessels, and the oxygen content of the blood. An early assessment of the electrocardiogram (ECG) will aid in determining the function of the pump. Toxins such as oleander, foxglove, and other cardiotoxic plants, organophosphates, and overdoses of therapeutic drugs for cardiac disease directly affect the heart. Many hydrocarbons and industrial chemicals have arrhythmogenic properties as well.8 The vascular volume status of any intoxicated patient varies greatly among individuals. The presence of a deficit in interstitial or vascular volume depends on whether the animal has been able to eat and drink or has had vomiting or diarrhea, the type of toxin and whether it induces a diuresis, and the presence of preexisting medical conditions. As in any emergency situation, tachycardia, cold extremities, pale mucous membranes, and slow capillary refill time indicate a vascular volume deficit and perhaps hypovolemic shock. A patient with these signs should be resuscitated quickly with isotonic crystalloid solutions (60 to 90 mL/kg in dogs and 40 to 50 mL/kg in cats), colloid solutions (10 to 20 mL/kg in dogs and 5 to 10 mL/kg in cats), or a combination of these. If the poison was a vitamin K antagonist, the preferred fluid may be frozen plasma and packed red blood cells. The source of hemorrhage should be located and vitamin K1 therapy begun immediately. Interstitial deficits are identified by decreased skin turgor, dry or tacky mucous membranes, and perhaps mild azotemia. The serum sodium concentration may be high if the patient has had free water losses, or low if the patient has had losses from vomiting and/or diarrhea, but is continuing to drink water. The percentage of deficit should be estimated and the deficit volume calculated. For example, a 10-kg dog who is estimated to be 7% dehydrated has a fluid volume deficit of 10 kg × 0.07 or 0.700 kg (700 mL). The deficit can be replaced over 8 to 12 hours using an isotonic crystalloid solution. A continuing maintenance fluid should be administered at the same time to keep up with insensible losses. Ongoing fluid losses (caused by diarrhea, vomiting, or polyuria) should also be assessed and a replacement fluid added to the fluid plan. Nonsteroidal antiinflammatory agents (NSAIDs) are known to be nephrotoxic.9 If a patient has ingested toxic amounts of NSAIDs, fluid therapy planning should maximize renal perfusion. Blood urea nitrogen and creatinine levels and urinalysis should be monitored closely. If fluid therapy does not restore adequate circulation, the heart may be unable to provide adequate cardiac output because of intrinsic damage to or disease of the myocardium. Inotropic drugs, such as dobutamine, may be justified in this setting if adequate monitoring is available. Dobutamine is delivered as a continuous IV infusion at 5 to 15 µg/kg/minute. Dopamine is an effective first line vasopressor at an initial IV dose of

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3 µg/kg/minute. The dose can be titrated up to 15 µg/kg/minute. Higher doses cause dangerous tachycardia and vasoconstriction with no further improvement in cardiac output and blood pressure. Epinephrine can be used if dopamine is unsuccessful at improving blood pressure. Epinephrine is a potent alpha and beta agonist that increases cardiac output and can improve blood pressure. Higher doses increase vasoconstriction and heart rate without leading to further improvement in cardiac output. The IV dosage of epinephrine is 0.05 to 0.30 µg/kg/minute. Higher dosages of epinephrine should be avoided because they predispose the patient to ventricular fibrillation. Norepinephrine is indicated if the previously mentioned agents do not improve blood pressure. Norepinephrine is an extremely potent vasoconstrictor and may impair perfusion to the viscera and periphery. The infusion is begun at a dosage of 0.5 µg/kg/minute and can be titrated up to 1 µg/kg/minute. Toxins may affect the blood vessels by altering the function of the smooth muscle in the vessel walls or by poisoning the endothelial cells directly. Vascular endothelium is exposed to any blood-borne toxin, and accumulation of toxin in endothelial cells can occur. Toxins can also induce the activation of inflammatory mediators produced by the endothelium, which can greatly affect vascular tone and incite the cascades responsible for the systemic inflammatory response.8 Blood pressure should be measured and maintained above a mean of 60 mm Hg. Volume replacement is the initial means of restoring blood pressure. When maximum safe volumes have been administered without satisfactory effect, vasopressor medications may have to be given. If the blood pressure stays persistently elevated (>140 mm Hg mean arterial pressure) after adequate fluid restoration and there is evidence of increased peripheral vascular resistance, hydralazine or nitroprusside can be used to reduce the blood pressure. The use of these agents requires adequate myocardial contractility. Hydralazine is primarily an arteriolar vasodilator. It works by decreasing cytosolic calcium. Hydralazine can be administered enterally or parenterally at a dose of 0.5 to 3 mg/kg every 8 to 12 hours. In the acute care setting, a test dose can be given intravenously. Onset of action occurs in 10 to 30 minutes, and the effect lasts up to a few hours. Because of the decrease in systemic vascular resistance induced by this drug, heart rate can increase significantly and should be monitored closely. Nitroprusside is a venous and arteriolar vasodilator. It is given intravenously and its onset of action is immediate. The dosage of nitroprusside is 0.5 to 1 µg/kg/minute. This drug should not be used in patients with preexisting renal or hepatic disease. Administration of any vasoactive agent requires close monitoring of the ECG, blood pressure, and volume status of the patient. These drugs are all potentially

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arrhythmogenic and can dangerously elevate or reduce systemic blood pressure. Their use should not be considered if adequate monitoring is not available. The oxygen-carrying capability of the blood is affected by several toxins. The blood oxygen content is a product of oxygen bound to hemoglobin and oxygen dissolved in the blood. These can be maximized by instituting transfusions of red blood cells, when anemia is present, and by increasing the inspired oxygen concentration. Carbon monoxide (CO) and acetaminophen are two toxins that inhibit the ability of hemoglobin to transport oxygen. Initial management in poisoning with either of these toxins is to increase the inspired oxygen concentration and support ventilation if necessary. In CO poisoning, hyperbaric oxygen therapy may be required. Acetaminophen toxicosis is treated with acetylcysteine at an initial dose of 150 mg/kg PO or IV in dogs and cats followed by three to five additional treatments at 70 mg/kg every 4 hours. Blood transfusions may be indicated based on the clinical picture. Parameters, such as heart rate, mucous membrane color, distal extremity temperature, and color and mentation, should be monitored along with clinical laboratory indicators to aid in adjustment of the fluid plan as the patient’s condition changes. Urine output is an important indicator of vascular volume and blood pressure adequacy. Monitoring urine output accurately requires placement of a urethral catheter and a closed collection system. A urine output of less than 1 mL/kg/hour suggests a volume deficit, decreased blood pressure, or a change in renal function and should be evaluated and treated promptly.

CONTROLLING SEIZURES AND TREMORS Animals who are suffering seizures or are trembling are given anticonvulsants and sedatives to relieve the problem. Initially 0.5 mg/kg of diazepam is administered intravenously. If the neuromuscular activity is not controlled, or if the effect is short lived, the dose can be repeated. In general, if diazepam needs to be repeated more than twice for seizure control, constant rate infusion should be instituted or a different drug should be tried. Pentobarbital at 5 to 20 mg/kg IV, titrated to effect, will anesthetize the patient and reduce the visible seizure activity. If seizure breakthrough occurs again, a continuous infusion of pentobarbital can be given at 1 to 6 mg/kg/hour. If an anesthetic plane is reached and must be maintained, the patient must be intubated. As mentioned earlier, blood gases should be monitored for evidence of hypoventilation or hypoxemia. If blood gases are not available, an end-tidal CO2 monitor is useful for

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monitoring the presence of hypercapnia. The end-tidal CO2 is well correlated with the PaCO2 and is therefore a marker of ventilation. If hypoventilation develops, the pentobarbital infusion should be discontinued. If the animal again requires anesthesia for seizure control, a lower infusion dose should be used. A patient that has been having seizures continually or in clusters is prone to develop cerebral edema and increased intracranial pressure. The brain has an obligate requirement for glucose as an energy source for aerobic metabolism. The increased metabolic requirements of the brain cells coupled with the reduced perfusion of the brain lead quickly to a depletion of energy for the cells and increased amounts of carbon dioxide and lactate. Ionic channel alterations secondary to the seizures and energy depletion lead to intracellular hypercalcemia and hyperosmolality. These in turn lead to swelling of the neurons and may induce increased blood flow overall.10 Because the brain is encased within the rigid structure of the calvarium, there is little room for swelling, and the pressure within the brain increases quickly. By creating a brief increase in serum osmolality relative to the tissues, mannitol can draw brain water into the blood vessels. Mannitol infused IV at 0.5 to 1 g/kg over 20 minutes increases serum osmolality and can be very effective at reducing intracranial pressure.11 A rapidly deteriorating neurological status, including the onset of anisocoria and depression of brainstem responses (e.g., physiological nystagmus, heart rate, and respiratory rate), indicates an increase in intracranial pressure. An animal poisoned by a tremorgenic toxin may need only diazepam, diazepam combined with muscle relaxants, or diazepam and some degree of barbiturate anesthesia to control the tremors and relax the muscles. Methocarbamol is a centrally acting muscle relaxant. It is a central nervous system depressant and can itself cause salivation, emesis, ataxia, and sedation, making it difficult to assess these monitored parameters. The manufacturer’s recommended dose in dogs and cats is 44 to 220 mg/kg IV, generally not to exceed 330 mg/kg/day. The lower end of the dose range is usually effective. As with seizures, intubation and monitoring of blood gases or end-tidal CO2 is necessary after the patient has been anesthetized. During this period the body temperature can undergo wide fluctuations. Temperatures of >106° F secondary to seizures or trembling are not uncommon. The high temperature need not be treated per se because it will come down when the excessive muscle activity is stopped. Sedatives, anesthetics, and muscle relaxants may cause the body temperature to drop quickly and steeply, making the animal hypothermic. Monitoring for temperature fluctuations and heating or cooling as necessary is very important. Rectal temperature probes can be placed for continuous monitoring.

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ASSESSMENT OF METABOLIC STATUS The availability of inexpensive rapid tests for blood chemistry and blood gases has made it much easier to provide optimal care for critically ill and poisoned patients. The poisons themselves and the secondary consequences of their ingestion (e.g., vomiting, diarrhea, seizures, and tremors) can induce varied derangements in acid-base and electrolyte values as well as azotemia, and, in some cases, specific organ failure. Mild metabolic acidosis or alkalosis can often be corrected by instituting fluid therapy and treating the underlying disease. For instance, the metabolic acidosis present in a patient having seizures is in large part caused by increased lactic acid production. Lactic acid is produced in large amounts in the muscle in response to the excessive muscle activity and the relative deficit of energy during the seizure. Lactic acidosis quickly resolves once the seizures have ceased. Mild changes in bicarbonate and pH usually resolve with fluid therapy and treatment of the underlying disease. Metabolic acidosis with a pH of 10 mg/kg weakness, diarrhea, Subacutely toxic: ataxia, hypoactivity, >2 mg/kg/day depression, salivation, Chronically toxic: labored breathing, >1 mg/kg/day recumbency, weight loss

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Table 49–1

Toxicity of Various Ionophores and Resultant Clinical Signs—cont’d Ionophore

Species Toxic Dose Rabbit

Rabbit

Salinomycin3

Feline

Clinical Signs

Acute oral LD50: 15.5 mg/kg Subacutely toxic: >1 mg/kg/day

Anorexia, leg weakness, ataxia, incoordination, incoordination, hypoactivity Field cases: Anorexia, 140-150 mg/kg in feed; incoordination, 30 mg/kg in feed weakness, paralysis, recumbency, diarrhea, opisthotonus, labored breathing Field case: 440 mg/kg Dyspnea, weakness, in cat food hyporeflexia, paresis, paralysis, recumbency

of clinical signs can be either acute or somewhat delayed. With acutely toxic concentrations of ionophores, the onset of clinical signs generally occurs within 6 to 24 hours.4,5,7,14 However, with lower concentrations, clinical signs may not occur for 2 weeks or more.13,14 Thus the onset of toxic effects is dose dependent. As with the onset of clinical effects, the duration of effects is quite varied. Once ionophore exposure stops, clinical signs may continue for as little as a few days or as long as 3 months.4,5,7,13,14 The duration of clinical signs is thought to correlate with the severity of the clinical signs at the time exposure was terminated. Because ionophores are lipid soluble and clinical severity is dose-related, it is likely that there is either a long terminal elimination phase from the tissue compartments or a longer period of tissue repair in the more severely affected animals. Ionophores appear to be extensively metabolized and are primarily eliminated in the feces in dogs.10 Less than 2% of a dose of laidlomycin propionate was eliminated in the urine as either the parent drug or its metabolites. Dogs metabolize laidlomycin propionate to at least 11 different metabolites.10 However, it is not known whether the ionophore metabolites retain any of their ionophore transport capability.

MECHANISM OF TOXICITY Translocation of ions and disruption of ion gradients are responsible for the therapeutic and toxic effects of ionophores.15,16 Translocation of ions

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across the mitochondria disrupts mitochondrial energy production and causes mitochondrial swelling and fragmentation.17-19 This loss of energy production is at least partially responsible for the cell death and tissue necrosis associated with ionophore poisoning. The translocation of ions across the plasma membrane by ionophores also inhibits the activity of excitable tissues. The disruption of potassium, hydrogen, calcium, and sodium concentrations in excitable cells alters resting potentials, action potentials, and contractility.20-26 In rat neuronal cell cultures, lasalocid causes neuronal cell damage and death, but spares the nonneuronal cells.27 The alteration in excitable tissues can decrease or halt neurological, cardiac, and skeletal muscle functions.

CLINICAL SIGNS Presenting clinical signs are suggestive of a neurological or neuromuscular disorder (Table 49-1). Feed refusal, a common finding in ionophorepoisoned livestock, has not been consistently reported in companion animal poisonings. In acutely toxic ionophore exposures, there is generally a history of a sudden onset of depression, weakness, and incoordination, with some animals exhibiting hypersalivation.3-7,10,12 The weakness and incoordination begin in the hindlimbs and progress to include the frontlimbs. With more chronic lower exposure rates there can be a more gradual onset of signs.10-14 Both the acute and chronic syndromes progress to include recumbency, paresis, paralysis, loss of reflexes, dyspnea, and apnea. Even in the presence of quadriplegia, cutaneous sensitivity remains intact.5 Some quadriplegic dogs retain the ability to wag their tails and follow movement with their eyes. Respiratory paralysis is the life-threatening sequela. Although myocardial necrosis can be found in ionophore-poisoned animals, electrocardiographic (ECG) abnormalities were absent in salinomycin-poisoned cats3 and monensin-poisoned dogs.7 However, one must remember that ECG changes may occur in ionophore-poisoned animals that develop myocardial necrosis. In addition, the extent and type of ECG changes are directly related to the location and severity of the myocardial necrosis.

MINIMUM DATABASE Clinicopathologic changes have been found to be inconsistent between animals and across time. Changes associated with ionophore-poisoned

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dogs include increased creatine phosphokinase, lactate dehydrogenase, and aspartate transaminase levels, proteinuria, and myoglobinuria.4,5,7,13,14 However, these changes occurred in only some of the animals and only periodically during the evaluations. Although it is inconsistent, increased creatine phosphokinase appears to be the most common alteration identified in dogs. In a field case of salinomycin poisoning in cats, one of the seven affected cats had a slight hypokalemia and leukocytosis,3 but no clinicopathologic abnormalities were noted in the other cats. Thus clinicopathologic changes are quite inconsistent, and their absence does not rule out ionophore toxicosis.

CONFIRMATORY TESTS Analytic verification of the presence of an ionophore drug is currently the most valid confirmatory test. The most diagnostic analytical test would be serum analysis to verify that the drug is in the body, but currently analytic sensitivities and diagnostic laboratory capabilities do not permit this type of testing on a routine basis. Thus analytic verification of the presence of ionophores in the food or stomach contents of live animals and in the food or tissues (e.g., gastrointestinal contents, feces, bile, liver) of dead animals is the next best option.

TREATMENT In cases of known recent exposure, general decontamination procedures should be implemented. These procedures include evacuation of the gastric contents by induction of emesis and administration of activated charcoal along with a cathartic. However, this may be contraindicated in animals with severe clinical signs, since emesis and/or administration of adsorbents could result in aspiration in animals exhibiting the paralytic effects. When implemented early after exposure, decontamination procedures will minimize the absorption of the drug and thus the potential for clinical effects. In animals with clinical signs of ionophore poisoning, good general supportive care is the only effective treatment. Nutritional intake must be maintained, and the animal must be kept warm and hydrated. Recovery has even occurred in animals that developed respiratory paralysis by maintaining them on positive pressure ventilation. In lasalocid-poisoned dogs that developed apnea, spontaneous respiration returned after 6 to 12 hours.4 Recovery time was reported to be as long as 50 days in

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severely affected lasalocid-poisoned dogs. In contrast, some salinomycinpoisoned animals exhibited clinical signs as long as 7 weeks after the intoxication.3

PROGNOSIS Although recovery occurs with good supportive care, in severely affected animals a fair to guarded prognosis is advised. For mildly affected animals, a fair to good prognosis is warranted. However, owners must be advised that the recovery process may be an extended one, and if severe cardiac or skeletal muscle damage has occurred, the animal may experience some permanent deficits.3

GROSS AND HISTOLOGICAL LESIONS Gross lesions may or may not be present in animals that die from ionophore poisoning. The gross lesion that is most commonly found is a paling or pale spotting of the heart.3,6 Similar gross lesions have been observed in the skeletal musculature in several ionophore-poisoned food animal species,6,28 but this finding has not been reported in dogs or cats. Ionophore-induced microscopic pathological lesions generally involve the cardiac musculature, skeletal musculature, and peripheral nerves, but in some animals it may be absent. Although there are limited numbers of reports, dogs tend to have more necrosis of the skeletal muscles than of cardiac muscle.7,10,12-14 Cats, on the other hand, have more cardiac lesions.3 In contrast, rabbits more commonly have histological lesions in both the skeletal and cardiac musculature. In both skeletal and cardiac muscle, lesions comprise fibrillar degeneration and necrosis.6-8,10,12-14 In animals that live long enough, there may be evidence of cellular repair and fibrosis. In addition to the muscular lesions, vacuolization and degeneration of peripheral sensory and motor nerves have been identified.3,10,14

DIFFERENTIAL DIAGNOSES Most clinical conditions that would be included in a differential with ionophore toxicosis can be ruled out based on the history and a clinical examination. Absence of ticks and wounds can aid in ruling out tick paralysis and polyradiculoneuritis. Normal serum mineral concentrations can be used to rule out calcium and magnesium abnormalities. Rearlimb to

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frontlimb progression and rapid onset can be used to rule out myasthenia gravis. Macrolide parasiticides (i.e., ivermectin) and amitraz poisoning can present as a severe CNS depression, recumbency, or a paralytic syndrome and must be ruled out by lack of previous exposure. The most difficult differential that must be ruled out is botulism. Botulism is not common in dogs and cats, but mimics ionophore poisoning in many ways. Laboratory analysis that is negative for the organism and/or toxin would serve to rule out botulism. Other differential diagnoses may include macadamia nut ingestion in dogs, bromethalin poisoning, and organophosphate-induced delayed neuropathy. REFERENCES 1. Bennett K: Compendium of veterinary products, ed 3, Port Huron, Mich, 1995, North American Compendiums. 2. McDougald LR, Roberson EL: Antiprotozoan drugs. In Booth NH, McDonald LE, editors: Veterinary pharmacology and therapeutics, ed 6, Ames, Iowa, 1988, Iowa State University Press. 3. Van Der Linde-Sipman JS, VanDen Ingh TSGAM, Van Nes JJ et al: Salinomycininduced polyneuropathy in cats: morphologic and epidemiologic data, Vet Pathol 36:152-156, 1999. 4. Safran N, Aizenberg I, Bark H: Paralytic syndrome attributed to lasalocid residues in a commercial ration fed to dog, J Am Vet Med Assoc 202:1273-1275, 1993. 5. Segev G, Baneth G, Levitin B et al: Accidental poisoning of 17 dogs with lasalocid, Vet Rec 155:174-176, 2004. 6. Salles MS, Lombardo de Barros CS, Barros SS: Ionophore antibiotic (narasin) poisoning in rabbits, Vet Hum Toxicol 36(5):437-444, 1994. 7. Wilson JS: Toxic myopathy in a dog associated with the presence of monensin in dry food, Can Vet J 21:30-31, 1980 8. Osz M, Salyi G, Malik G et al: Narasin poisoning in rabbits, Vet Bull 59:416, 1989, (Abstract 2985). 9. Syntex. Material safety data sheet, Palo Alto, Calif, July 1991, Syntex Inc. 10. Food and Drug Administration: Laidlomycin propionate, NADA Number 141-025, Rockville, Md, Freedom of Information Office, Center for Veterinary Medicine, 1994. 11. Galitzer SJ, Oehme FW: A literature review on the toxicity of lasalocid, a polyether antibiotic, Vet Hum Toxicol 26:322-326, 1984. 12. Food and Drug Administration: Maduramicin ammonium, NADA Number 139075, Rockville, Md, Freedom of Information Office, Center for Veterinary Medicine, 1989. 13. Todd GC, Novilla MN, Howard LC: Comparative toxicology of monensin sodium in laboratory animals, J Anim Sci 58:1512-1517, 1984. 14. Novilla MN, Owen NV, Todd GC: The comparative toxicology of narasin in laboratory animals, Vet Hum Toxicol 36(4):318-323, 1994. 15. Pressman BC: Induced active transport of ions in mitochondria, Proc Nat Acad Sci 53:1076-1083, 1965. 16. Pressman BC: Ionophorous antibiotics as models for biological transport, Fed Proc 27: 1283-1288, 1968. 17. Estrada OS, Celis H, Calderon E et al: Model translocators for divalent and monovalent ion transport in phospholipid membranes: the effects of ion translocator X-537A on the energy-conserving properties of mitochondrial membranes, J Membr Biol 18:201-218, 1974. 18. Mitani M, Yamanishi T, Miyazaki Y et al: Salinomycin effects on mitochondrial ion translocation and respiration, Antimicrob Ag Chem 9:655-660, 1976.

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776 Specific Toxicants 19. Wong DT, Berg DH, Hamill RH et al: Ionophorous properties of narasin, a new polyether monocarboxylic acid antibiotic, in rat liver mitochondria, Biochem Pharmacol 26:1373-1376, 1977. 20. Haeusler G: The effects of the ionophore X-537A (lasalocid) on the heart and on vascular smooth muscle, Experientia 32:779 (Abstract), 1976. 21. Levy JV, Cohen JA, Inesi G: Contractile effects of a calcium ionophore, Nature 242:461-463, 1973. 22. Lattanzio FA Jr, Pressman BC: Alterations in intracellular calcium activity and contractility of isolated perfused rabbit hearts by ionophores and adrenergic agents, Biochem Biophys Res Commun 139:816-821, 1986. 23. Satoh H, Uchida T: Morphological and electrophysiological changes induced by calcium ionophores (A23187 and X-537A) in spontaneously beating rabbit sino-atrial node cells, Gen Pharmacol 24:49-57, 1993. 24. Devore DI, Nastuk WL: Effects of “calcium ionophore” X537A on frog skeletal muscle, Nature 253:644-646, 1975 25. Murakami K, Karaki H, Nakagawa H et al: The inhibitory effect of X537A on vascular smooth muscle contraction, Naunyn-Schmiedeberg’s Arch Pharmacol 325:80-84, 1984. 26. Levy JV, Cohen JA, Inesi G: Contractile effects of a calcium ionophore, Nature 242:461-463, 1973. 27. Safran N, Haring R, Gurwitz D et al: Selective neurotoxicity induced by the ionophore lasalocid in rat dissociated cerebral cultures, involvement on the NMDA receptor/channel, Neurotox 17:883-895, 1996. 28. Novilla MN: The veterinary importance of the toxic syndrome induced by ionophores, Vet Hum Toxicol 34:66-70, 1992. 29. Food and Drug Administration: Lasalocid, NADA Number 096-298, Rockville, Md, Freedom of Information Office, Center for Veterinary Medicine, 1982.

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Iron

50

Jeffery O. Hall, DVM, PhD

• Sources include gestational supplements, multivitamins or minerals, and fertilizers. • Toxic dose: less than 20 mg/kg elemental iron is generally not systemically toxic; 20 to 60 mg/kg elemental iron can be mildly to moderately toxic; more than 60 mg/kg elemental iron can cause severe intoxication. • Iron is a highly reactive metal, when not protein bound, that induces free radical production and lipid peroxidation. • Clinical signs include gastrointestinal distress, shock, and cardiovascular collapse. • Confirmatory tests include analytical confirmation of serum iron concentrations that surpass the iron binding capacity. • Treatment should include early gastric decontamination, good supportive care (fluids, electrolytes, acid-base correction), and chelation therapy. • Prognosis is fair to good depending on the severity of clinical signs. • Gross and histological lesions include gross erythema or necrosis of the gastrointestinal mucosa, hepatic swelling, systemic edema or hemorrhage, and damage to hepatocytes or vascular epithelium. • Differential diagnoses are garbage intoxication, gastric torsion, caustic or corrosive intoxication, snake bite, heat prostration, and bacterial and viral enteritis.

Iron is an essential mineral, but when a large amount is ingested, it also can be lethal. This type of acute poisoning occurs primarily in dogs because of their often indiscriminate eating habits. Although cats are also susceptible to the toxic effects of large doses of iron, there are no reported cases in the literature. Ingestion of large doses of soluble iron overwhelms the body’s protective defense mechanisms and results in free circulating iron, which causes severe tissue damage. 777

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SOURCES Numerous products contain iron in some form, but the more soluble salt forms of iron pose the greatest risk of toxicosis. This type of soluble iron is commonly found in numerous over-the-counter multivitamin-mineral preparations, gestational iron supplements, and some fortified lawn and garden fertilizers. Because dietary or nutritional supplements are often sugar coated, dogs may eat large numbers of tablets. In addition, pet owners frequently think that vitamin or mineral supplements are not dangerous and leave this type of material in locations where animals can gain easy access. Although many other products contain iron in some form, its solubility is often so low that toxicosis would not occur. For example, metallic iron and ferric oxide (rust) are so poorly soluble that they are not considered a threat for a toxic ingestion. This type of insoluble iron may be the type found in some fertilizers, so identification of the iron form is important.

TOXIC DOSE The dose of iron necessary to induce an iron toxicosis in the dog follows that reported for humans.1 Ingestion of less than 20 mg/kg is generally not a threat for systemic intoxication, although a mild gastric upset may occur. With ingestion of 20 to 60 mg/kg, a mild to moderate intoxication can be expected. Ingestion of more than 60 mg/kg is a serious threat for severe intoxication. Without early intervention, ingestion of greater than 100 mg/kg is potentially fatal. However, these toxic doses are based on soluble, bioavailable forms of iron and would greatly overestimate the toxicity of an insoluble iron form. In evaluating the potential for toxicosis, one must calculate the amount of elemental iron ingested. This is accomplished by multiplying the amount of the iron salt (mg) by the percentage of elemental iron (0.10 for 10%). Table 50-1 lists the more common salt forms of iron and their relative percentages of elemental iron. For tablet ingestions, this information will provide the amount of elemental iron per tablet because most tablets are labeled with the amount of iron salt per tablet. Because iron ingestion can be underestimated if the label lists elemental iron instead of iron salt, one must be certain about whether the amount of iron is listed as the elemental or salt form. In addition, the ferrous salt forms of iron are more bioactive and more rapidly absorbed, but their overall toxicity is more dependent on the total soluble concentration of elemental iron.

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Table 50–1

Percentage of Elemental Iron in Common Soluble Iron Salts Salt Iron (as ferric salt) Iron (as ferrous salt) Ferric ammonium citrate Ferric chloride Ferric hydroxide Ferric phosphate Ferric pyrophosphate Ferriglycine sulfate Ferrous fumarate Ferrous carbonate Ferrous gluconate Ferrous lactate Ferrous sulfate (anhydrous) Ferrous sulfate (hydrate) Peptonized iron

Percentage of Elemental Iron 100 100 15 34 63 37 30 16 33 48 12 24 37 20 16

TOXICOKINETICS Because free elemental iron is deleterious to tissue, mammals have mechanisms to bind and store iron. As iron enters the systemic circulation, it is rapidly bound to transferrin, the primary iron transport protein.2 This protein transports iron to the peripheral tissue where iron is needed. Serum transferrin concentrations greatly exceed those necessary to bind iron under normal physiological conditions. This reserve binding capacity provides protection against iron becoming free in systemic circulation. In cases of intoxication, this protein-binding capacity becomes saturated, thus allowing nonbound iron to interact with cellular constituents. Cellular iron that is not necessary for production of proteins is bound into ferritin, an iron-storage protein of the tissues.3 Chronic exposure to excess iron induces the production of additional transferrin and ferritin, but in acute exposures iron can overwhelm the binding capacity of these proteins.4 The kinetics of iron absorption are quite complex and do not follow the normal pattern for most nutrients. The overall body load of iron is regulated at the point of absorption because there is no mechanism for actively eliminating excess iron. The absorption of iron from the gastric lumen into the systemic circulation involves a two-step regulation. First, the iron must be transferred into the gastric mucosal cells. It is thought that this involves a carrier-mediated process, but the exact mechanism is still not clear.5 Next the iron is either transferred from the mucosal cell into the circulation, or it is lost when the cells are sloughed through normal

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cellular turnover.6 It is interesting that much more iron is absorbed into the gastric mucosal cells than is eventually transferred into the systemic circulation. This retained cellular iron is bound in ferritin. In animals with large acute exposures, the gastric mucosal cells’ ability to sequester the iron into ferritin probably becomes saturated, allowing nonbound iron to damage the cells and enter systemic circulation, where it is bound to transferrin until that also becomes saturated. In nonlethal exposures, the excess iron is sequestered into tissue. Iron elimination from the body occurs at a fairly constant rate. Even with large doses of iron, there is no increase in the rate of elimination.7 Thus the excess is stored in the body in ferritin or hemosiderin, a mineralized iron deposit in tissue.

MECHANISM OF TOXICITY Iron is a very reactive transition metal that can change valence states, from ferrous to ferric and then back to the ferrous form, very rapidly. This is one reason why iron plays a major role in biological redox reactions. This same characteristic is responsible for the toxic nature of nonbound iron. Iron toxicity centers on its ability to act as and produce free radicals, molecules with one or more unpaired electrons.3 Free radicals seek to scavenge electrons and in doing so produce additional free radicals. These free radicals can initiate autooxidation of polyunsaturated fatty acids (lipid peroxidation).8 Thus free iron can either directly or indirectly result in tissue damage and necrosis. Because free iron is so reactive, the primary tissues that are damaged are those that have first contact with absorbed free iron: the gastrointestinal, vascular, hepatic, and cardiac tissues. However, all tissues are susceptible to the toxic effects of free iron. In addition to direct cellular damage, metabolic disorders can also occur. With severe systemic tissue damage, coagulopathies can appear. Severe metabolic acidosis is common because of fluid and electrolyte loss resulting from vascular and gastrointestinal damage, and from direct mitochondrial damage. The mitochondrial damage, along with decreased tissue perfusion, causes increases in lactic acid. The direct tissue damage and resultant metabolic disruption combine to result in gastrointestinal distress, hepatic necrosis, cardiovascular collapse, and occasionally death.

CLINICAL SIGNS Clinical signs that are commonly reported are associated with gastrointestinal damage, cardiovascular damage, and neurological effects. These signs

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can include depression, vomiting, hematemesis, diarrhea, bloody stools, abdominal pain, muscle tremors, shock, and death. The progression of clinical effects in domestic animals closely follows the four stages described in humans. The first stage, 0 to 6 hours after ingestion, primarily involves gastrointestinal upset and depression resulting from damage to the gastrointestinal mucosa. Bloody vomitus or stool can occur in this stage. The second stage, 6 to 24 hours postingestion, is one of apparent recovery. The gastrointestinal effects subside, and the animal becomes more alert. This stage can lead to a false sense of security that the animal is out of danger. The third stage, 12 to 96 hours following ingestion, involves a return of the gastrointestinal effects plus metabolic acidosis, shock, hepatic failure, cardiovascular collapse, coagulation disorders, and in some cases, death. The fourth stage, which occurs at 2 to 6 weeks postexposure, is one of gastrointestinal obstruction secondary to the fibrosing repair of the gastrointestinal damage. This stage is not seen as commonly as the other stages, but can occur.

MINIMUM DATABASE The database necessary to evaluate an exposure or clinical condition includes estimating the potential iron exposure and performing a thorough clinical evaluation. However, estimation of exposure is often difficult because numbers of tablets or amounts can often only be estimated. When pets are symptomatic or exposures are potentially large, one should evaluate the total serum iron concentration and serum iron binding capacity (these tests are available at most human hospitals), and the complete blood count, serum chemistry profile, and abdominal radiographs. On abdominal radiographs, tablets remaining to be dissolved and absorbed can often be observed, and it is not uncommon for the tablets to adhere to the gastric mucosa or form a mass that will slowly dissolve and be absorbed over time.

CONFIRMATORY TESTS Measurements of total serum iron concentration and serum iron binding capacity are the most reliable tests for the presence of iron poisoning. Systemic poisoning does not occur until the serum iron binding capacity has been exceeded. Because iron binding capacity varies greatly among dogs, it is recommended that both serum iron concentration and serum iron binding capacity be measured. Caution must be observed in the timing of sample collection because the rate of tablet dissolution can vary and iron

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has multicompartmental kinetics of disposition. Thus the serum iron concentration can vary greatly in the first few hours. It is therefore recommended that serum iron concentration and iron binding capacity be measured 4 to 6 hours after ingestion. These tests should be repeated in 2 to 4 hours if the results show serum iron concentration below but near the total iron binding capacity. If there has been a large ingestion or if the patient is clinically symptomatic, earlier measurements may be indicated.

TREATMENT With acute ingestions in asymptomatic animals, gastric decontamination is recommended by means of induction of emesis. Ingestion of a large quantity of tablets, adverse clinical signs, or failure of tablets to be removed by induction of emesis, as indicated by densities on abdominal radiographs, are indications for gastric lavage under anesthestic, with an endotracheal tube in place. A gastrotomy is indicated when radiographic observation indicates a tablet bezoar or adherent tablets. Activated charcoal is not indicated because it does not bind iron. In addition, gastric administration of salt solutions to precipitate the iron and render it nonbioavailable has not been successful. Careful management of fluid load, electrolytes, and acid-base status, along with symptomatic care, is necessary in the care of an iron-poisoned animal. Fluid replacement is necessary to combat circulatory shock and fluid loss. The amount of replacement fluids should be based on replacement of the fluid deficit plus fluids necessary for maintenance. Electrolytes should be monitored and added to the fluids as necessary to correct deficits. Blood gas analysis aids in determining whether treatment is necessary for the correction of a metabolic acidosis. The use of gastrointestinal protectants, such as sucralfate, may also be indicated. In animals that are experiencing severe toxicosis, chelation therapy is indicated. Using a regimen originally based on human treatment protocols, the Animal Poison Control Center has successfully used deferoxamine (Desferal) to chelate iron. This chelation agent has a very high binding affinity for iron. Chelation therapy should be started early in the clinical course of the intoxication because it usually has little benefit when started more than 12 hours after ingestion. Deferoxamine should be given by continuous intravenous (IV) infusion at a rate of 15 mg/kg/hour. Faster rates of infusion are associated with arrhythmias and a worsening of existing hypotension. If continuous infusion is not possible, intramuscular administration of 40 mg/kg every 4 to 8 hours is recommended. However, this method is not as effective as the IV infusion. Chelation therapy should be

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continued until the serum iron concentration is below either 300 µg/dL or the measured serum iron binding capacity, whichever is lower.

PROGNOSIS For most asymptomatic patients that receive early decontamination, the prognosis is good. However, in animals that are symptomatic the prognosis can range from guarded to good depending on the severity of the clinical effects, the amount of iron ingested, and how early chelation and supportive therapies were started.

GROSS AND HISTOLOGICAL LESIONS Gross and histological lesions are primarily the result of damage to the gastrointestinal tract, vascular system, and liver. Gastrointestinal damage can range from mild erythema to severe necrosis and sloughing of the mucosal epithelium with severe hemorrhage. Damaged vascular epithelium leads to the development of edema, which can occur at any site. In animals with a coagulopathy, hemorrhage can be observed in any organ. Gross hepatic lesions can range from mild capsular swelling to severe friability and hemorrhage. Histological lesions follow the gross lesions and can include cellular swelling and/or necrosis of the mucosal epithelial cells, myocardial cells, vascular epithelium, and hepatocytes. Vascular leaking and hemorrhage are also observed.

DIFFERENTIAL DIAGNOSES There are not many differential diagnoses to consider if an iron-poisoned dog develops the full spectrum of clinical effects, but as with most clinical conditions, this spectrum is not often encountered. Primary considerations include any cause of gastrointestinal distress that also causes shock, such as garbage intoxication, gastric torsion, caustic or corrosive intoxication, snake bite, heat prostration, bacterial enteritis, or viral enteritis. REFERENCES 1. Greentree WF, Hall JO: Iron toxicosis. In Bonagura JD, editor: Kirk’s current veterinary therapy small animal practice, ed 12, Philadelphia, 1995, WB Saunders. 2. Adrian GS, Korinek BW, Bowman, BH et al: The human transferrin gene: 5th region contains conserved sequences which match the control elements regulated by heavy metals, glucocorticoids, and acute phase reaction, Gene 49:167-175, 1986.

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784 Specific Toxicants 3. Ponka P, Schulman HM, Woodworth RC: Iron transport and storage, Boca Raton, 1990, CRC Press. 4. McKnight GS, Lee DC, Hemmaplardh D et al: Transferrin gene expression: effects of nutritional iron deficiency, J Biol Chem 255(1):144-147, 1979. 5. Raja KB, Simpson RJ, Peters TJ: Membrane potential dependence of Fe(III) uptake by mouse duodenum, Biochem Biophys Acta 984:262-266, 1989. 6. Whebey MS, Cosby WH: The gastrointestinal tract and iron absorption, Blood 22(4):416-428, 1963. 7. Smith A, Morgan WT: Haem transport to the liver by haemopexin, Biochem J 1983: 47-54, 1979. 8. O’Connell MJ, Ward RJ, Baum H et al: The role of iron in ferritin- and hemosiderin-mediated lipid peroxidation in liposomes, Biochem J 229:135-139, 1985.

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Ivermectin: Macrolide Antiparasitic Agents

51

Katrina L. Mealey, DVM, PhD

• Ivermectin, selamectin, moxidectin, doramectin, eprinomectin, abamectin, and milbemycin are potential sources of toxicity caused by accidental overdose or access or when used in susceptible breeds. • Some collies and other herding breeds lack a functional P-glycoprotein that renders them more susceptible to the neurotoxic effects of these drugs. • Clinical signs typically include disorientation, ataxia, hyperesthesia, hypersalivation, vocalization, recumbency and coma. • Most animals will recover following appropriate supportive care, but recovery may take hours, days, or even weeks.

Ivermectin, selamectin, moxidectin, and milbemycin are macrolides (or macrocyclic lactones) that are used to treat a variety of parasitic diseases in dogs and cats.1 In the United States, each of these agents is licensed for use as a heartworm preventive in dogs. In cats, macrolide antiparasitic agents are licensed for use as heartworm preventives, and some are licensed for the treatment of otodectes and hookworms, Ancylostoma braziliense and Ancylostoma tubaeforme. In an extralabel manner, and at doses greatly exceeding the recommended label dose, macrolide antiparasitic agents are also used to treat scabies, lice, cheyletiella, demodecosis, gastrointestinal nematodes, and the microfilaria of Dirofilaria immitis.1 Macrolide antiparasitic agents are generally considered to have a wide margin of safety.2 However, a percentage of collies and other herding breeds harbor a mutation in the MDR1 (ABCB1) gene that renders them exceptionally susceptible to toxicity from most, if not all, of these agents.3 It is important to note that at the labeled doses for heartworm prevention, the macrolide antiparasitic agents are safe for use in herding breeds, even those dogs with the mutant MDR1 genotype. While toxicosis in nonherding 785

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dog breeds and cats generally results from an extreme overdose (i.e., when a product marketed for livestock is used off-label in small animals), the author is aware of reports of suspected toxicosis in a dog (moxidectin) and cat (topical ivermectin) receiving the approved label dose of the particular macrolide. Doramectin and eprinomectin are macrolides approved for use in cattle only.4 The manufacturers of these agents do not recommend their use in other species. Clinical signs associated with macrolide toxicity reflect the actions of these drugs on the central nervous system.1 A specific antidote is not available, but most animals experiencing toxicosis from exposure to these drugs will have a complete recovery if appropriate supportive care is provided.

SOURCES Ivermectin (Heartguard, others) is a mixture of 22,23-dihydroavermectin B1a (>80%) and B1b (55 mg/kg), animals survive less than 4 days and die of cardiogenic shock. Acidosis develops in such cases. Alveolitis is also observed, with clinical signs of acute noncardiogenic pulmonary edema. At necropsy, lesions are often seen in the gastrointestinal tract, adrenal glands, renal tubules, and hepatocytes.7

MINIMUM DATABASE AND CONFIRMATORY TESTS Paraquat poisoning of companion animals can present as acute or chronic pulmonary disease. Since treatment is not effective in the chronic stages of the disease, successful management of paraquat toxicosis requires institution of treatment within hours of the exposure. Therefore rapid diagnosis is vital for the successful outcome of therapy. Clinical signs of acute paraquat poisoning include diarrhea, vomiting, and ulceration of the oral and gastrointestinal tracts. In all cases of acute poisoning, acute respiratory distress develops because of pulmonary edema. Days to weeks after exposure, progressive respiratory insufficiency occurs because of severe pulmonary fibrosis. Radiographic changes are often minimal and frequently do not correlate with the severity of clinical signs.7 One of the earliest changes reported in paraquat-poisoned dogs is pneumomediastinum. Dogs that enter the chronic stage of the disease do not respond to treatment and eventually die from respiratory failure. All these factors point to the importance of early diagnosis and treatment of paraquat poisoning.9

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Measurement of plasma paraquat concentrations is the most reliable method of assessing the severity and predicting the outcome of paraquat poisoning. However, measurement of plasma paraquat is not available in most veterinary practices and is rarely performed even in teaching institutions. Therefore other reliable methods of detection of paraquat must be employed.7 The dithionate spot test may detect paraquat in tissue or bait samples. Methods for the quantification of paraquat have been developed using visible light spectrophotometry5 and liquid chromatography-mass spectrometry. In acute poisoning cases, stomach contents, vomit, or suspected bait are the samples of choice, and lung and kidney tissue are the organs of choice for paraquat testing. Urine samples may contain paraquat up to 48 hours after ingestion. In chronic poisoning cases, the lung is the sample of choice, but the liver and kidney may also contain sufficient quantities of the compound for testing to be valuable. Within 30 hours of oral ingestion, lung tissue contains the highest concentration of the compound.8 The half-life of paraquat in lung tissue is about 30 hours.10 In rats exposed to paraquat, the compound could be detected only in the lung tissue after 4 days.11 Because of its rapid excretion and tissue storage, paraquat concentrations in body fluids and tissues may be below the limit of detection in animals that die from pulmonary fibrosis.

TREATMENT Treatment of paraquat-poisoned patients must be instituted as early as possible because delaying treatment often results in fatal outcomes. Although various treatment approaches have been described by various authors, most of these were designed for human patients. The validity and relevance of these treatments in companion animals are not well established. One promising aspect of these treatments is that they all were developed by studying the effect in experimental animals. There is no specific and effective antidote for paraquat poisoning, and measures designed to enhance the elimination of paraquat from the body have not altered mortality significantly in human patients. The prognosis is extremely guarded, especially in companion animal practice, where treatment is frequently delayed.7 Attention has been given to gastrointestinal decontamination in an attempt to reduce the absorption of ingested paraquat. Gastric emesis followed by gastric lavage and activated charcoal administration is mandatory in all cases of acute paraquat exposure. Paraquat absorption from the gut is often incomplete, but is rapid, as evidenced by the early development of

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peak plasma concentrations. Energy-dependent accumulation of paraquat in lung tissue and subsequent development of toxicity occur once a crucial plasma concentration has been reached. This accumulation is time dependent. Therefore every early intervention procedure available that will reduce adsorption must be employed to prevent the rapid rise in plasma concentration to the critical level. In 1977, the manufacturer of paraquat (Imperial Chemical Industries, Fernhurst, Haslemere, Surrey, England) added a potent emetic to its liquid and solid preparations because experiments conducted in primates demonstrated a fivefold decrease in toxicity following emesis. A significant reduction in mortality from paraquat poisoning after the introduction of this emetic-containing formulation has not yet been reported for human paraquat exposure cases. There is little experimental information about the use of gastric lavage alone for the treatment of paraquat poisoning. However, studies have demonstrated that reduced blood levels of paraquat occur in the cat following gastric lavage.12 Whether these low plasma paraquat levels have any beneficial influence on the outcome of toxicosis is still questionable. There are obvious drawbacks to the use of these procedures. Ulceration of oropharyngeal and esophagogastric mucosal surfaces because of contact with the concentrated paraquat is likely to make these procedures hazardous. In addition, unnecessary waste of valuable time may go into the efforts, delaying deployment of alternative forms of treatment that may have greater value. There is no definite evidence that gastric lavage has any value in paraquat poisoning in humans.12 It may also be of limited value in companion animal practice unless initiated in the first few hours following exposure. Whole bowel lavage can also be used soon following ingestion to reduce the amount of paraquat absorbed from the gut. Administration of oral adsorbents followed by cathartics may reduce the severity of the disease. The common oral adsorbents used are bentonite, Fuller’s earth, and activated charcoal. Of these, activated charcoal is preferred because it is more effective in reducing mortality than is either Fuller’s earth or bentonite. In vitro adsorption of paraquat to the different activated charcoals occurs to a greater degree in the presence of sodium chloride, suggesting that saline should be used as the carrier vehicle for the activated charcoal.13 In general, published reports in human cases of paraquat ingestion do not support the efficacy of gastrointestinal decontamination. The relevance of this observation to companion animal practices is difficult to confirm. Once gastrointestinal decontamination has been performed, two other possible treatment modalities are still available. The first is to alter the distribution of paraquat in the body, and the second is to modify the herbicide’s effect on various biological target organs.

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Paraquat is poorly absorbed from the intestinal tract in all animal species. It is not metabolized, but is excreted unchanged in the urine. Paraquat reaches higher concentrations in body tissue than in plasma. This has led to therapeutic interventions aimed at removing paraquat from blood by increasing its renal clearance or by using extracorporeal elimination routes. Administration of large volumes of fluids to establish and maintain a diuretic urine flow is beneficial because the kidney is the major route of paraquat elimination. The increased urine flow in diuresis will increase the glomerular filtration and tubular secretion of paraquat. Fluid administration has additional benefits in paraquat poisoning cases because most clinically affected animals are severely dehydrated because of the gastrointestinal loss of fluids. Paraquat also causes vasodilatation apart from the fluid losses described earlier. Both of these mechanisms can account for a functional adverse component in the early stages of paraquat-induced acute renal failure. This functional impairment can be corrected by administering sufficient fluids to cause plasma volume expansion and maintain adequate renal perfusion, thus allowing maximal clearance of the systemically absorbed and circulating paraquat. Diuretics can also be administered to increase urinary flow; however, renal excretion of paraquat is often not accelerated by diuretics because tubular reabsorption is very limited. Experimental therapies have been proposed to protect renal tubular cells from the direct effects of absorbed paraquat. A combination of free superoxide dismutase (SOD), liposomal SOD, and glutathione peroxidase is being evaluated for this purpose.13 Peritoneal dialysis is of little value in paraquat poisoning because it dialyses paraquat very poorly, even in the presence of elevated paraquat plasma concentrations. Substantial amounts of paraquat can be cleared by hemodialysis, with as much as 150 mL cleared per minute.13 However, since plasma concentrations in animals with paraquat poisoning tend to be low compared with the concentrations in tissue compartments, the actual amount of paraquat removed by this procedure is clinically insignificant. Another drawback of this procedure is that paraquat clearance with hemodialysis drops considerably when plasma concentrations fall below 0.5 mg/L.13 Charcoal hemoperfusion is considered the most efficient extracorporeal procedure for removing paraquat, offering plasma clearances as high as 170 mL/min. One study using Hemocol cartridges reported paraquat clearance from plasma at rates between 113 and 156 mL plasma/min, even when the plasma concentration was only 0.2 mg/L. Hemodialysis and hemoperfusion have also been used in series to increase total paraquat removal.13

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The aim of all these procedures is to increase the elimination of paraquat from the circulation and to prevent its uptake by pneumocytes. Studies conducted in dogs showed that survival time of exposed animals was longer when the animals underwent charcoal hemoperfusion for 4 hours, beginning 12 hours after ingestion.13 The poor total paraquat body clearance by these methods and the rise in plasma concentrations for several hours following the cessation of such therapy can be explained by the extensive paraquat tissue distribution and its slow and sustained redistribution back into the circulation following the termination of extracorporeal procedures. One way to overcome this is to institute continuous hemoperfusion. This procedure is reported to be successful in paraquat poisoning cases where lethal concentrations of the compound have been ingested. The exact clinical value of this procedure has not been convincingly demonstrated, although animal studies have shown improved survival rates with this technique. Continuous arteriovenous hemofiltration is a procedure more easily instituted than hemodialysis or hemoperfusion. Unfortunately, definitive clinical data on the clinical benefits in humans and animals are lacking. Supportive care has improved the prognosis of paraquat-poisoned human patients and holds the same unfulfilled promise in veterinary practice.7 The most useful management techniques still include protection of the airway, maintenance of cardiovascular circulation, frequent monitoring of vital signs and blood gases, prompt and timely treatment of secondary infections, adequate pain relief, prevention and management of renal failure, replacement of blood losses, and treatment of cardiac complications and neurological signs. Supplemental oxygen is contraindicated, even when the animal shows signs of respiratory difficulty. Reduction of the oxygen supply has even been attempted because there is evidence that a positive relationship exists between the inspired oxygen concentration in inspired air and the severity of pulmonary damage. Mechanical ventilation may therefore not be a treatment option to a patient who is in impending respiratory failure due to pulmonary fibrosis. There is no effective antidote available for paraquat poisoning. Research into the mechanisms of paraquat toxicity and the development of antidotes have yielded mixed results. Although efforts to understand the mechanisms of free radical generation, lipid peroxidation, and polyamine-mediated uptake of the compound into tissue have generated productive information, the development of an effective antidote remains as elusive today as it was a decade ago. Certain compounds have shown promising results in animal studies if they are administered prophylactically or immediately upon intoxication.

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Their relevance to a clinical setting is not established because of the heterogeneity of poisoning cases and the fact that most of the clinical data is derived from human patients. The traditional approach to antidote development is to find compounds that detoxify either the superoxide radical or the subsequently formed toxic intermediates. Compounds studied so far are superoxide dismutase or the mimetic enzymes and antioxidants, such as vitamin E, ascorbic acid, deferoxamine, selenium, clofibrate, N-acetylcysteine, riboflavin, and niacin. Another approach has been to decrease the reduction-oxidation cycling of paraquat by providing alternative substrates, such as methylene blue, which compete with paraquat for reduction by NADPH. Another approach has been to inhibit the uptake of paraquat into alveolar tissue through polyamine uptake pathways. In vitro studies using the uptake inhibitors putrescine and valinomycin have been successful, but in vivo studies have failed to show antidotal activity. Other methods employed to reduce the toxic effects of paraquat have included the reduction of pulmonary inflammation and fibrosis through radiotherapy, and the use of various immunosuppressant and cytotoxic drugs, such as cyclophosphamide and steroids. These techniques have thus far failed to produce beneficial effects to the patients. Lung transplantation for replacement of a fibrotic lung has been done in humans with moderate success when it is performed after paraquat has been completely eliminated from the body. The practicality of this procedure in veterinary medicine is questionable.

PROGNOSIS The prognosis for animals presented with suspected paraquat poisoning can be determined from the plasma concentration of the compound relative to the time of ingestion. In human medicine, a nonogram is used that relates plasma paraquat levels to prognosis. Initial plasma concentrations give an indication of prognosis. The urinary concentration of paraquat in the first 24 hours of intoxication also can be used to arrive at a prognosis. Unfortunately, such basal values are not available in animals and have to be extrapolated from humans. In human patients, a urinary paraquat concentration of less than 1 mg/L within the first 24 hours indicates a good prognosis. In patients that die within the first 24-hour period, urine concentrations ranged from 10 to 10,000 mg/L, and in those who died later from pulmonary fibrosis the urine paraquat concentrations ranged from 1 to 1000 mg/L.1

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In animal patients, as in human paraquat ingestions,7 the presence of gastric and esophageal ulcers indicates a grave prognosis. Early development of renal failure and concurrent acid-base disturbances suggest a poor outlook.9 The ability of the animal to excrete paraquat depends to a large extent on normal renal function. Various studies have pointed out that the ability of healthy kidneys to excrete paraquat (a polar compound) is so remarkable that toxic concentrations can be attained in the lungs only if there is concomitant renal failure. When such large amounts of paraquat are ingested, however, concurrent multiorgan failure is likely.9

GROSS AND HISTOLOGICAL LESIONS Visible lesions are generally confined to the gastrointestinal tract and lung. Erosive stomatitis and esophagitis are often seen because of the irritating nature of paraquat. Paraquat produces its characteristic, but nonspecific, acute to subacute interstitial pneumonia with fulminating pulmonary edema and hemorrhage. In animals chronically affected, the lungs may be shrunken and fibrotic because of hyperplasia of the alveolar type II cells and the fibroplasia superimposed on the earlier exudative changes. Paraquat also causes proximal renal tubular degeneration and focal centrizonal hepatic degeneration. Diquat, in contrast, causes cerebral hemorrhage and infarcts and renal tubular degeneration and necrosis in addition to ulcerative effects in the gastrointestinal tract.

DIFFERENTIAL DIAGNOSES In the initial phase, paraquat must be differentiated from other gastrointestinal irritant syndromes marked by abdominal pain, vomiting, and diarrhea; causes of these are caustic agents (e.g., strong acids or alkalis), zinc phosphide, inorganic arsenic or mercury, lead, zinc, pancreatitis, and many viral or bacterial agents.3 Because the acute and chronic phases of paraquat poisoning include some degree of interstitial pneumonia and fibrosis, this clinical syndrome mimics the signs of many infectious diseases and α-naphthyl-thiourea poisoning (rarely reported).

CURRENT TOXICOLOGICAL STATUS The severe consequences of paraquat exposure and its resulting toxic effects mandate that early diagnosis and aggressive treatment, coupled

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with intensive management, are required if the prognosis for the severely poisoned paraquat patient is to be improved. With the current limited effectiveness of treatment protocols for animal paraquat exposures, a focus on exposure prevention is paramount to prevent continuing companion animal losses from this highly toxic herbicide.7 REFERENCES 1. Pond MS: Manifestations and management of paraquat poisoning, Med J Aust 152:256-259, 1990. 2. Onyema HP, Oehme FW: A literature review of paraquat toxicity, Vet Hum Toxicol 26:494-502, 1984. 3. Cope RB, Bildfell RJ, Valentine BA et al: Seven cases of fatal paraquat poisoning in Portland, Oregon dogs, Vet Hum Toxicol 46:258-264, 2004. 4. Merck veterinary manual, ed 8, Whitehouse Station, NJ, 1998, Merck & Co. 5. Slade P: Photochemical degradation of paraquat, Nature (London) 207:515, 1965. 6. World Health Organization: Environmental health criteria 39: paraquat and diquat, Geneva, 1984, World Health Organization. 7. Cope RB: Helping animals exposed to the herbicide paraquat, Vet Med 99: 755-762, 2004. 8. Bischoff K, Brizze-Buxton B, Gatto N et al: Malicious paraquat poisoning in Oklahoma dogs, Vet Hum Toxicol 40:151-153, 1998. 9. Shuler CM, DeBess EE, Scott M et al: Retrospective case series of suspected intentional paraquat poisonings: diagnostic findings and risk factors for death, Vet Hum Toxicol 46:313-314, 2004. 10. Smith LL: The mechanism of paraquat toxicity in the lung, Rev Biochem Toxicol 26: 494-502, 1984. 11. Smith P, Heath D: Paraquat, CRC Crit Rev Toxicol 4:411-445, 1987. 12. Meredith T, Vale JA: Treatment of paraquat poisoning: gastrointestinal decontamination. In Bismuth C, Hall A, editors: Paraquat poisoning, New York, 1995, Marcel Dekker Inc. 13. Pond MS: Treatment of paraquat poisoning. In Bismuth C, Hall A, editors: Paraquat poisoning, New York, 1995, Marcel Dekker Inc. 14. Lewis CPL, Nemery B: Pathophysiology and biochemical mechanisms of the pulmonary toxicant of paraquat. In Bismuth C, Hall A, editors: Paraquat poisoning, New York, 1995 Marcel Dekker Inc.

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Atypical Topical Spot-On Products Jill A. Richardson, DVM

• Topical spot-on products are the newest method of insect control for pets. • Most products are applied between the shoulder blade or striped down the animal’s back. • Most products are labeled for application every 30 days. • Topical spot-on products may repel or kill fleas, ticks, and/or mosquitoes. • Some products prevent flea egg development. • Most of these products, when used appropriately, present little risk of toxicity to the pet.

IMIDACLOPRID Sources Imidacloprid (1-[(6-chloro-3-pyridinyl) methyl]-N-nitro-2-imidazolidinimine) is a chloronicotinyl nitroguanidine insecticidal agent.1 Imidacloprid spot on products are labeled to kill adult fleas and their larvae in dogs and cats.1 The manufacturer states that these products should be used with caution in debilitated, aged, pregnant, or nursing animals, and kittens or puppies less than 4 months of age.1 Imidacloprid is also found in combination with permethrin in dog-only products that also kill ticks.1 In addition to its use in veterinary medicine, imidacloprid is also used in agriculture2 (Box 69-1).

Toxic dose Dermal median lethal dose (LD50) for rats is >2000 mg/kg.3 Dogs fed up to 41 mg/kg for a year showed only increased cholesterol levels and increased concentration of cytochrome P450.3 978

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Box 69–1

Veterinary Products Containing Imidacloprid Only Advantage (Bayer); (OTC) Approved for use in dogs and cats. Imidacloprid topical solution 9.1% 0.4 ml (Cats/kittens: under 9 lb; orange vial) 0.8 ml (cats/kittens: over 9 lb; purple vial) 0.4 ml (dogs/puppies: under 10 lb; green vial) 1.0 ml (dogs/puppies: 11-20 lb; teal) 2.5 ml (dogs/puppies: 21-55 lb; red) 4.0 ml (dogs/puppies: over 55 lb; blue)

Toxicokinetics According to the technical profile, topically applied Advantage spreads rapidly over the skin by translocation.3 The product is not systemically absorbed, but goes to the hair follicles and glands where is it shed with sebum.3 Ingested imidacloprid is quickly absorbed from the gastrointestinal tract.2,3 Within 48 hours, 96% is eliminated via urine (70% to 80%) and feces (20% to 30%).3

Mechanism of toxicity Imidacloprid blocks nicotinergic pathways, which results in a build up of acetylcholine at the neuromuscular junction.1,3 Acetylcholine buildup results in insect hyperactivity, then paralysis, and later death.1-3

Clinical signs There is limited published information detailing adverse effects of imidacloprid in dogs or cats; however, clinical effects from the veterinary product would be expected to be mild. Because the drug is bitter tasting, oral contact may cause excessive salivation.1,3 Signs and symptoms of poisoning from imidacloprid would be expected to be similar to nicotinic signs and symptoms, including fatigue, twitching, cramps, and muscle weakness.4

Minimum database Assessment of the hydration status and urinary function may be required since the kidneys are the primary sites of elimination of imidacloprid.

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Confirmatory tests Some laboratories can test for imidacloprid in hair and skin samples. However, these results can only confirm the exposure since toxic levels in tissues have not been determined.

Treatment There is no specific antidote for imidacloprid; treatment for adverse effects would be symptomatic and supportive. If the exposure is dermal, the treatment would include initial stabilization and bathing with a mild dishwashing detergent. Treatment of ingestion of a topically applied veterinary imidacloprid product should consist of dilution with milk or water. Hypersensitivity skin reactions could occur with any topical product. In those instances, a bath with a noninsecticidal shampoo and symptomatic care, such as hydrocortisone, antibiotics, or antihistamines, would be recommended.

Prognosis Although published reports of adverse effects of imidacloprid are limited, in most situations, animals would be expected to recover in 24 to 72 hours with veterinary care.

Differential diagnoses Other toxicants with similar clinical presentation could include pyrethrum and pyrethrins, and acetylcholinesterase-inhibiting organophosphorus and carbamate insecticides.

FIPRONIL Sources Fipronil is a phenylpyrazole antiparasitic agent used for fleas and ticks in dogs and cats.1,5 Fipronil is available as a topical product for flea and tick control and in combination with methoprene for additional control of immature flea stages.1 In addition to being used as a topical spot-on for

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Box 69–2

Veterinary Spot-On Products Containing Fipronil Only Frontline Top Spot (Merial) Fipronil Topical Solution 9.7% (OTC) Approved for use in dogs and cats 0.5 ml (cats/kittens; green vial) 0.67 ml (dogs up to 22 lb; yellow vial) 1.3 ml (dogs 23-44 lb; blue vial) 2.68 ml (dogs 45-88 lb; purple vial) 4.02 ml (dogs 89-132 lb; red vial)

dogs and cats, it is also available in a veterinary formulation as a 0.29% topical spray.1 Fipronil has other uses in agriculture2,3 (Box 69-2).

Toxic dose Reported oral median lethal dose (LD50) in rats for veterinary product formulations is greater than 5000 mg/kg.3 In chronic feeding studies, no signs were seen when dogs were fed 0.5 mg/kg/day for 13 weeks.2

Toxicokinetics The manufacturer states that fipronil collects in the oils of the skin and hair follicles and continues to be released over a period of time resulting in long residual activity.3,6 Topically applied, the drug apparently spreads over the body in approximately 24 hours via translocation.3,6 In oral rat studies, 5% to 25% of the parent compound and metabolites is excreted in the urine, and 45% to 75% is excreted in the feces.3

Mechanism of toxicity Fipronil is a γ-aminobutyric acid (GABA) agonist.2 Its mechanism of action in invertebrates is to interfere with the passage of chloride ions in GABA regulated chloride channels, thereby disrupting CNS activity.1,3,5 Blockade of the GABA receptors by fipronil results in neural excitation.1,3

Clinical signs There is limited published information detailing adverse effects of fipronil in dogs or cats; however, clinical effects from the veterinary product would

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be expected to be mild. Ingestion of any topical products may cause a taste reaction as a result of the inert ingredients. Also, topical hypersensitivity reactions could occur with any dermal product. Extra label use in rabbits has been reported to cause anorexia, lethargy, convulsion, and death.1,7

Minimum database Assessment of the hepatic function may be required since the liver is the primary site of metabolism of fipronil.

Confirmatory tests Some laboratories can test for fipronil in hair and skin samples. These results can only confirm the exposure since toxic levels in tissues have not been determined.

Treatment There is no specific antidote for fipronil; treatment for adverse effects would be symptomatic and supportive. If the exposure is dermal, the treatment would include initial stabilization and bathing with a mild dishwashing detergent. Treatment of ingestion of a topically applied veterinary fipronil product should consist of dilution with milk or water. Hypersensitivity skin reactions could occur with any topical product. In those instances, a bath with a noninsecticidal shampoo and symptomatic care, such as hydrocortisone, antibiotics, or antihistamines, would be recommended.

Prognosis Although published reports of adverse effects of fipronil are limited, in most situations animals would be expected to recover in 24 to 72 hours with veterinary care.

Differential diagnoses Other toxicants that interfere with GABA transmission, such as the macrolide antiparasitic agents.

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METHOPRENE Sources Methoprene is a synthetic insect growth regulator and is classified as a terpenoid.8 It is used in topical flea control products to help break the flea life cycle alone or in combination with adulticide products. Methoprene does not kill adult fleas (Box 69-3).

Toxic dose In dogs the acute oral median lethal dose (LD50) is 5000 to 10,000 mg/kg.8 The World Health Organization (WHO) has approved methoprene safe for use in drinking water to control mosquitoes because of minimal or no risk to humans, animals, or the environment.8

Toxicokinetics In mammals, methoprene is rapidly and completely broken down and excreted, mostly in the urine and feces.8

Mechanism of toxicity Methoprene is a compound, which mimics the action of an insect growth regulation hormone. It is used as an insecticide because it interferes with the normal maturation process. In a normal life cycle, an insect goes from egg to larva, to pupa, and eventually to adult. Methoprene artificially stunts the insects’ development, making it impossible for insects to mature to the adult stages, and thus preventing them from reproducing.8

Box 69–3

Veterinary Topical Spot-On Products Containing Methoprene Frontline Plus—fipronil and methoprene Hartz Advanced Care Plus for Dogs and Cats—phenothrin and methoprene Zodiac Spot on for Dogs—permethrin and methoprene Zodiac Spot on for Cats—methoprene only Various other brands

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Juvenile hormones maintain the larval stage in the insect or prevent metamorphosis; when the level of juvenile hormone drops, pupal and adult developmental stages begin.8

Clinical signs There is limited published information detailing adverse effects of methoprene in dogs or cats; however, given the mechanism of action, clinical effects would be expected to be mild. Ingestion of any topical products may cause a taste reaction as a result of the inert ingredients. Also, topical hypersensitivity reactions could occur with any dermal product.

Minimum database Assessment of renal and hepatic function may be helpful since the liver and kidney are the sites of metabolism and elimination of methoprene.

Confirmatory tests Some laboratories can test for methoprene in hair and skin samples. However, these results can only confirm the exposure since toxic levels in tissues have not been determined.

Treatment If the exposure is dermal, the treatment would include initial stabilization and bathing with a mild dishwashing detergent. Treatment of ingestion should consist of dilution with milk or water. Hypersensitivity skin reactions could occur with any topical product. In those instances, a bath with a noninsecticidal shampoo and symptomatic care, such as hydrocortisone, antibiotics, or antihistamines, would be recommended.

Prognosis Given the mechanism of action, prognosis would be expected to be good in most cases.

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Differential diagnoses Potential toxicants that could mimic these signs include ingestion of caustic or corrosive agents, pyrethrum or pyrethrins, and acetylcholinesterase-inhibiting carbamate and organophosphorus insecticides. REFERENCES 1. Plumb DC: Veterinary drug handbook, ed 4, Ames, Iowa, 2002, Iowa State University Press. 2. Wismer TA: Novel insecticides. In KH Plumlee, editor: Clinical veterinary toxicology, St Louis, 2003, Mosby. 3. Hovda LR, Hooser SB: Toxicology of newer pesticides for use in dogs and cats, Vet Clin Small Anim 32:455-467, 2002. 4. Doull, J, CD Klassen, MO Amdur, editors: Cassarett and Doull’s toxicology. The basic science of poisons, ed 4, Elmsford, NY, 1991, Pergamon Press. 5. Hainzl D, Cole LM, Casida JE: Mechanisms for selective toxicity of fipronil insecticide and its sulfone metabolite and desulfinyl photoproduct, Chem Res Toxicol 11(12): 1529-1535, 1998. 6. Birckel P, Cochet P, Benard P et al: Cutaneous distribution of C-fipronil in the dog and cat following a spot on administration. Proceedings from the Third World Congress of Veterinary Dermatology. September, 1996, Edinburgh, Scotland. 7. Webster M: Product warning, Frontline, Aust Vet J 77:202, 1999. 8. Ramesh C et al: Pharmacologic profile of methoprene, an insect growth regulator, in cattle, dogs, and cats, J Am Vet Med Assoc,194[3]:410-412, Feb 1, 1989.

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Petroleum Hydrocarbons Merl F. Raisbeck, DVM, MS, PhD Rebecca N. Dailey, BS

• The most important toxic effect associated with the petroleum products commonly ingested by small animals is aspiration pneumonia. • Low boiling point (i.e., volatile) products are more likely to produce aspiration pneumonia. • Systemic toxic effects to the CNS and to a lesser extent the liver, heart, and kidneys are more likely with aromatic or very volatile aliphatic compounds. • Gastric decontamination, especially with emetics, is contraindicated unless there is a strong probability of some other, systemic toxicant in the GI tract.

SOURCES Petroleum is a highly complex mixture of hydrocarbons. “Petroleum poisoning” is actually the sum of the toxic effects and interactions of a mixture of disparate compounds. Although crude oil intoxication occurs in large animals and is a serious environmental problem, pets are most frequently exposed to more refined petroleum products. These include fuels such as propane, gasoline, kerosene, or diesel oil; solvents, such as paint thinner, engine degreaser, or laboratory chemicals; and lubricants, such as motor oil, waxes, or asphalt. Petroleum-based solvents are often used as “inert” carriers for a number of pesticides, paints, and medications. Petroleum-based chemicals are also the basic feedstock for products as diverse as plastics and pharmaceuticals. In other words, petroleum products represent a very diverse group of chemicals and are very widespread throughout the modern environment. The precise composition of any specific petroleum product varies with its intended use and the characteristic process or processes used to produce it. 986

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For most of the simpler products like gasoline, the refining process consists largely of differential distillation and cracking. The product itself is defined in terms of boiling point rather than any specific composition. Thus, volatility provides one convenient index with which to broadly classify petroleum products. Some products, notably fuels with a high boiling point such as fuel oil, receive little further processing. Others, such as gasoline, are modified with a considerable number of additives, such as methanol or methyl tertbutyl ether, which possess significant toxic properties of their own. Finally, some products, such as the thermoplastics, are chemically modified to such an extent that their physical, chemical, and toxic properties are quite distinct from petroleum hydrocarbons as a whole. This last group is not included in this chapter. Conversely, some hydrocarbons of nonpetroleum origin, such as turpentine or linseed oil, are similar enough to be considered with petroleum-based solvents of similar molecular weight. In people, the most frequent cause of petroleum poisoning involves substance abuse (e.g., using petroleum products to get “high”). Animals usually exhibit a little more common sense, but may still sample motor oil or gasoline out of curiosity if it is available. Inappropriate containers and failure to clean up spills are common sources of exposure to pets. Pets, especially cats, may ingest significant amounts of gasoline or other petroleum products via grooming and transdermally after topical exposure. Gasoline or kerosene are sometimes used in an attempt to remove sticky material, such as tar, from an animal’s coat. Many folk remedies contain inappropriate types and amounts of petroleum products. For example, a Doberman Pinscher came to a diagnostic laboratory after having been force-fed a mixture of gasoline and smokeless powder to make it more aggressive (the treatment was not successful).

TOXIC DOSE The toxicity of a specific petroleum product theoretically varies with its composition. Given the huge number of distinct petroleum products in common use, it is impossible to track the toxicity of each individually. Fortunately, however, it is possible to make some broad generalizations about the toxicity of petroleum hydrocarbons on the basis of simple physical and chemical properties such as boiling point. Products with very high boiling points, such as asphalt, mineral oil, or waxes, are relatively nontoxic. In general the more volatile the compound, the more readily it is absorbed and thus the greater possibility for systemic toxicity. Very volatile compounds, such as benzene, also tend to be more readily

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Table 70–1

Acute Toxicity of Some Commonly Encountered Hydrocarbons Compound

Dose

Clinical Signs

Acetone

Oral LD50: 5-10 mg/kg

Benzene

Oral LD50: 4 mL/kg

Carbon disulfide Cyclohexane

Oral LD50: 5-10 mg/kg Inhalation LC50: 15 mg/L Oral LD50: >8 mL/kg

Diesel fuel

Oral LD50: 9 mL/kg

Gasoline

Oral LD50: 18 mL/kg

Home heating oil

Oral LD50: 18 mL/kg

Isopropanol

Oral LD50: 6-13 g/kg

Jet fuel A

Oral LD50: >20 mL/kg

Motor oil

Oral LD50: >22 mL/kg

Toluene

Oral LD50: 6-8 mL/kg

Turpentine

Minimum lethal dose (children): 15 mL/kg

Xylene

Oral LD50: 4 mL/kg

CNS depression, narcosis, coma CNS depression, narcosis, bone marrow suppression Tremor, cyanosis, vascular collapse, coma CNS depression, ataxia, narcosis, coma Relatively nontoxic; diarrhea, GI upset Moderate topical and GI irritant, aspiration pneumonia Relatively nontoxic; diarrhea, GI upset if dose is sufficient CNS depression, ataxia, acidosis, coma Relatively nontoxic; diarrhea, GI upset if dose is sufficient Relatively nontoxic; diarrhea, GI upset if dose is sufficient CNS depression, ataxia, liver and kidney damage Strong irritant, readily absorbed through skin and by inhalation Strong topical irritant, CNS depression, tremors, coma

aspirated and thus are more likely to cause chemical pneumonitis (Table 70-1). The likelihood of pneumotoxicity is also determined by viscosity and surface tension. Lower viscosity enhances the penetration of the product into smaller and therefore more numerous airways. Low surface tension facilitates the spread of hydrocarbons over larger areas of pulmonary tissues. As little as 0.1 mL of a low-viscosity hydrocarbon-like mineral spirits, when aspirated directly into the trachea of dogs, may produce severe pneumonitis. In contrast, products with a high viscosity, such as motor oil, have a much more limited pneumotoxic potential (Box 70-1). Hydrocarbon solvents, including petroleum distillates, turpentine, etc., are skin and eye irritants by virtue of their lipid solvent properties and are

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Box 70–1

Petroleum Products Listed in Order of Decreasing Viscosity Tar (most viscous) Paraffin wax Motor oil Fuel oil Kerosene Mineral spirits Gasoline Naphtha Hexane (least viscous)

capable of producing erythema, dermatitis, and epithelial necrosis. Systemic toxicity should be considered following heavy dermal exposure, especially with strong solvents such as gasoline. This is especially important in small animals (e.g., pups or kittens), which have a relatively high body surface area to mass ratio. Again the relative toxicity of various products by this route of exposure seems to be inversely proportional to molecular weight and volatility. Toxicity is further enhanced by other factors such as long or matted hair that trap the hydrocarbon against the skin.

TOXICOKINETICS Contrary to some older texts, many hydrocarbons are readily absorbed after ingestion. Studies with a number of different radiolabeled hydrocarbons have demonstrated both gastrointestinal and percutaneous absorption and subsequent distribution to all major organ systems. The degree of such absorption was inversely proportional to the molecular weight of the hydrocarbon involved. High-molecular-weight hydrocarbons, such as grease or motor oil, are not absorbed to any significant extent, whereas lower-molecular-weight products, such as gasoline or hexane, are more readily absorbed. Aromatic compounds are more readily absorbed than aliphatic hydrocarbons of similar molecular weight and thus more likely to cause systemic toxicity. Regardless of the class of compound or route of exposure, respiration is an important route of elimination for volatile hydrocarbons. Volatile compounds, such as petroleum ether, are largely cleared within 24 hours; less volatile compounds, such as motor oil, may remain in the gastrointestinal tract for a considerably longer time. Most aliphatic hydrocarbons are degraded to some extent by the liver. Metabolism usually involves

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oxidation, rendering the compound more polar and thus more readily excreted, but may also contribute to the pathogenesis of chronic toxic effects. Aromatic hydrocarbons are metabolized to phenols or carboxylic acids; conjugated with sulfates, glucuronides, or glycine; and excreted through urine or bile.

MECHANISM OF TOXICITY As a general rule, the most acute life-threatening effects of petroleum intoxication result from aspiration pneumonia. Experimental data suggest that the pulmonary injury in aspiration pneumonia results primarily from aspiration and not from gastrointestinal or dermal absorption. Dogs given 250 mL of kerosene by gavage showed no radiographic evidence of pulmonary damage, but substantially smaller volumes (less than 1 mL) given intratracheally caused rapid progression of depression, dyspnea, and death. Vomiting often precedes aspiration; it is not a prerequisite, however, because aspiration can also occur when the hydrocarbon is initially ingested. Thus the lack of emesis in the history does not preclude the possibility of aspiration. Pulmonary function should be monitored carefully following any oral hydrocarbon exposure. The pneumotoxic potential of any particular hydrocarbon mixture is determined by its volatility, viscosity, and surface tension. Compounds with viscosities of less than 35 Saybolt units (SSU) are very likely to be aspirated, whereas compounds with viscosities of greater than 60 SSU are less likely to cause pneumonia. Gasoline, kerosene, and lighter fluid have viscosities in the 30 to 35 SSU range and are easily aspirated. Mineral oil (150 SSU), motor oil (60 to 500 SSU), and paraffin wax almost never cause pulmonary damage. At a tissue level, pneumotoxic effects of petroleum hydrocarbons are mediated by the dissolution of the lipid component of cellular membranes in contact with the hydrocarbon. This results in swelling and/or necrosis of the cell that in turn provokes inflammation. In the lung, the end result is edema, bronchospasm, and necrosis of the terminal airways and alveoli within a few minutes to an hour of exposure. There may be hemorrhage into the airways that also compromises respiration. Alteration of pulmonary surfactant is another result of the lipophilicity of petroleum products. Loss of pulmonary surfactant increases the surface tension of the fluid lining of the alveoli and destabilizes the alveoli, resulting in atelectasis and collapse of distal airways. Finally, volatile hydrocarbons may displace sufficient alveolar oxygen to produce acute cyanosis even before pneumonitis becomes apparent.

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Later, inflammation, thrombosis, and emphysema extend the functional damage beyond tissues in immediate contact with the hydrocarbon. Bacteria may colonize damaged areas, resulting in further tissue destruction and pneumonia. Uncomplicated lesions typically heal within 2 weeks of the initial crisis, but there is some evidence that subclinical effects remain for months or years. A retrospective epidemiologic study in human patients demonstrated an increased incidence of respiratory infections several years following hydrocarbon pneumonitis, and (in a separate study) asymptomatic patients who had experienced hydrocarbon pneumonitis more than 8 years earlier still had detectable functional abnormalities typical of small airway disease. Systemic effects of the petroleum hydrocarbons involve the central nervous system (CNS) and, to a lesser extent, the liver, kidneys, and heart. Again, the more volatile, lower-molecular-weight hydrocarbons, such as hexane, are more likely to be involved because they are more readily absorbed than heavier products, such as kerosene. For the same reason, aromatic compounds, such as toluene or benzene, are more toxic systemically than naphthalenes, which are in turn more toxic than aliphatics of similar molecular weight. Absorption and subsequent systemic toxicity are also greater when hydrocarbons are inhaled as a vapor rather than ingested. The principal systemic effect of hydrocarbon intoxication is usually CNS depression. The acute neurotoxic effects of petroleum hydrocarbons apparently result from a direct physicochemical interaction between the hydrocarbon and the neuronal membranes of the CNS. Since this is largely a physical process, clinical signs can become apparent within minutes of toxic exposure and for the most part disappear as soon as the hydrocarbon is cleared from the system. Exceptions to this rule, such as hexane neuropathy, usually require prolonged exposure and are beyond the scope of this discussion. Hepatic and renal damage have been reported from a percentage of both experimental and field cases of hydrocarbon poisoning. The mechanism is not clear, but probably involves metabolism by the target organ to a toxic intermediate. Some hydrocarbons are also apparently capable of sensitizing the myocardium to endogenous catecholamines, resulting in arrhythmias and even complete cardiovascular collapse.

CLINICAL SIGNS Human patients report a burning sensation in the mouth and pharynx immediately after ingestion of petroleum products such as gasoline. Animals appear to experience much the same sensations: slobbering, champing their jaws, shaking their head, and pawing at their muzzle. This is usually

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followed by signs of aspiration: choking, coughing, gagging, and varying degrees of dyspnea. Direct damage to the airway components and bronchospasm may result in hypoxia. Cyanosis may also develop immediately as alveolar oxygen is displaced by hydrocarbon vapor. Astute observers may note an odor of the hydrocarbon on the animal’s breath. Fever usually occurs in 3 to 4 hours, but may occur in less than 1 hour or as late as 24 hours after exposure. Pneumonitis is the most common complication following ingestion of volatile, low-viscosity, aliphatic petroleum hydrocarbons (e.g., gasoline). The central nervous and gastrointestinal systems may also be affected, but death, if it occurs, usually results from the pulmonary effects. Respiratory involvement, when present, is progressive over the first 24 to 48 hours and then gradually resolves 3 to 10 days following exposure. Signs referable to the respiratory system usually occur within a few minutes to 1 or 2 hours. Animals that remain asymptomatic for 6 to 12 hours after ingestion are unlikely to develop respiratory illness. Radiographic abnormalities may lead or lag behind the clinical signs slightly, but animals that eventually develop clinical pneumonitis show readily observable radiographic changes within a few hours of ingestion. Radiographic findings are typical of aspiration pneumonia and consist of fine, perihilar densities and extensive infiltrates in ventral portions of the lungs. These changes are worse at 3 to 4 days and then clear over an additional few days. Not all animals with radiographic signs of hydrocarbon aspiration develop respiratory signs, and radiographic changes usually persist past the resolution of clinical signs. The irritant properties of petroleum products produce gastroenteritis, vomiting, colic, and diarrhea after oral exposure. The severity, and indeed even the presence, of such signs is a function of the dose and the individual hydrocarbon. Heavier, aliphatic hydrocarbons, such as mineral oil, may produce diarrhea and altered gastrointestinal motility but little else. Lighter hydrocarbons, such as gasoline, are more likely to produce colic and vomiting. The CNS signs of acute hydrocarbon toxicity are similar to those of ethanol inebriation. Intoxicated animals exhibit vertigo, ataxia, and mental confusion. Hydrocarbons produce depression and narcosis in most cases, but tremors and convulsions have also been reported. If the dose is high enough, the animal becomes comatose, and coma may proceed to death without any accompanying respiratory signs. The heartbeat may be irregular as a result of myocardial sensitization, or complete cardiac collapse may occur if the animal is stressed. Myocardial sensitization may persist for 24 to 48 hours after apparent recovery from the neurological effects of intoxication.

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MINIMUM DATABASE A minimum evaluation of possible petroleum hydrocarbon ingestion includes determination of vital signs, careful evaluation of respiratory status, auscultation of the chest, and a chest radiograph. The clinical signs and radiographic changes associated with aspiration of petroleum products are indistinguishable from the signs and radiographic changes seen with other forms of aspiration pneumonia. Thus some means of confirming petroleum hydrocarbon exposure is essential to confirm the diagnosis. It is also desirable to identify the particular product involved because its volatility and viscosity affect the prognosis and treatment. This information is most readily available from the history. The owner should be instructed to bring the container or label to the clinic with the animal if the product is not a relatively common one like gasoline. It may also be possible to detect the characteristic odor of petroleum hydrocarbons on the animal’s breath, a test often overlooked by clinicians. An inflammatory profile is commonly observed on a complete blood count analysis.

CONFIRMATORY TESTS A simple spot test involves mixing vomitus vigorously with warm water. If gasoline or other petroleum distillates are present they will float to the surface. Care must be taken to distinguish between petroleum products and dietary lipids. Most petroleum products lighter than kerosene, if isolated and absorbed onto a paper towel, evaporate relatively quickly and have a characteristic odor. Chemical analysis of ingesta or postmortem tissues is useful forensically but is seldom practical for evaluating the clinical case. If chemical analysis is to be conducted, samples should be taken as quickly as practical and frozen in airtight, glass containers to prevent loss as a result of volatilization.

TREATMENT In all cases of uncomplicated (i.e., not contaminated by some other, more toxic substance) petroleum hydrocarbon ingestion, the primary goal should be to minimize the risk of aspiration. If the amount ingested was small, and especially if the hydrocarbon ingested was known to be one of the less volatile, more viscous products, such as motor oil or grease, cage rest and observation may be all that are required. If the volume ingested was substantial and the product involved was one known to cause systemic

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toxicity (e.g., hexane, toluene, or xylene), activated charcoal or gastric lavage is indicated within the first 4 to 6 hours post exposure. Gastric decontamination may also be indicated, despite the risk of aspiration, if the product was contaminated with a highly toxic substance such as a pesticide. If lavage is to be attempted, it is essential to take precautions to prevent possible aspiration of stomach contents. Emetics are contraindicated except as a last resort to clear some other highly toxic constituent, such as a pesticide from the gastrointestinal tract. In the past, mineral oil or vegetable oil was recommended to increase the viscosity of petroleum hydrocarbons and thus decrease the risk of aspiration. Oils also produce a mild catharsis, decreasing the period during which the petroleum product might be absorbed. However, retrospective studies in children suggest that such treatment actually increases the likelihood of aspiration pneumonia, and the use of such oils is no longer recommended. Respiratory effects should be treated symptomatically. The routine use of antibiotics and corticosteroids has been questioned. Hydrocarbon pneumonitis is reported to be largely nonbacterial in origin. In one experimental study in which dogs were given an intratracheal dose of kerosene, parenteral ampicillin and dexamethasone did not reduce either the respiratory rate or the presence of radiographic, gross, or microscopic pulmonary lesions. Corticosteroid use, in another experiment, was associated with increased numbers of positive lung cultures. Corticosteroids are thus considered contraindicated. However, given the potentially severe consequences of bacterial complications and the relatively small downside of antibiotic use, it seems prudent to use some form of antimicrobial prophylaxis. Supplemental oxygen, continuous positive airway pressure, and mechanical ventilation should be used as needed. However, because pneumomediastinum, pneumatoceles, and pneumothorax are common complications of hydrocarbon pneumonitis, positive pressure systems must be used with caution. Also, since the lungs are the major route of elimination for many hydrocarbons, closed or semiclosed systems should be purged frequently. Cage rest is indicated, both for its beneficial effects on the healing process and to minimize the effects of excitement-induced catecholamines on hydrocarbon-sensitized myocardium. Likewise, bronchospasm may be treated with β-2 agonists if the myocardium has been unduly sensitized. Topical exposures may be treated by gently bathing the animal with warm water and a mild detergent shampoo. If the hair coat is especially heavy or matted, it may be necessary to clip the contaminated areas to prevent systemic absorption and minimize skin damage. Symptomatic treatment of petroleum burns may involve the use of topical antibacterial agents as necessary. Highly viscous hydrocarbons (e.g., tar and waxes) may also be removed with mild detergents. Because they are not readily

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absorbed they pose only a cosmetic problem or a risk of mechanical irritation and are not as critical to remove. Lipophilic materials (butter, lard, mechanics’ hand cleaner) may also be useful in such cases, but the use of hydrocarbon solvents is not recommended.

PROGNOSIS The prognosis depends on the extent and severity of tissue damage. Animals that remain asymptomatic for 12 to 24 hours require no further follow up or treatment. If pulmonary lesions are extensive or if the animal is comatose when presented, the prognosis is guarded to poor.

GROSS AND HISTOLOGICAL LESIONS Systemic toxicity may result in centrilobular hepatic, myocardial, or renal tubular necrosis if the animal survives more than 24 hours after exposure. However, these lesions are not that common, and animals that survive the acute neurotoxic effects long enough to develop recognizable lesions usually recover. If aspiration has occurred, the principal lesions will be found in the respiratory tract. There may be ulcerations in the ventral mucosa of the trachea and larger airways. Pulmonary lesions are bilateral and involve primarily the caudoventral portion. Early lesions include hyperemia, edema, and hemorrhage into the airways. Oil may be grossly visible in the smaller airways. Later, bronchospasm, emphysema, and atelectasis occur. Pneumatoceles, pneumothorax, and subcutaneous emphysema result from airway collapse. Bacterial pneumonia occasionally supervenes and may result in abscesses.

DIFFERENTIAL DIAGNOSES A large number of infectious diseases and toxins may result in respiratory signs similar to those associated with hydrocarbon aspiration. However, only very acute processes, such as trauma or chylothorax, exhibit a similar rapidity of onset. SUGGESTED READINGS Fukunaga T, Yamamoto H, Tanegashima A et al: Liquefied petroleum gas (LPG) poisoning: report of two cases and review of the literature, Forensic Sci Int, 82:193-200, 1996. Kimbrough RD, Reese E: Acute toxicity of gasoline and some additives, Environ Health Perspect, Suppl 6:115-131, 1993.

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Propylene Glycol Karyn Bischoff, DVM, MS

• Propylene glycol (PG) is used as automotive antifreeze, hydraulic fluid, an industrial and pharmaceutical solvent, an ingredient in cosmetics, and an additive in processed foods. • Clinical signs following oral exposure are related to propylene glycol’s narcotic effects and lactic acidosis-depression, ataxia, muscle twitching, and seizures. • Increased numbers of Heinz bodies and reticulocytes and lower packed cell volumes occur in animals, particularly felines, exposed to propylene glycol.

Small animals may occasionally have access to automotive solvents. Dogs and cats may obtain access to a garage where there are open containers, or solvents may be found in an outdoor setting when automobile radiators are drained or fluids leak. The most toxic radiator fluid is ethylene glycol (Ethylene Glycol—Chapter 45). Animals frequently have access to this solvent, and it presents a significant problem to the small animal practitioner. Propylene glycol is commonly used as a relatively “safe” alternative to ethylene glycol as antifreeze. Propylene glycol has other uses ranging from an industrial solvent to a food additive. Until recently, it was used in semimoist cat foods, some of which used to contain more than 10% propylene glycol. Propylene glycol is no longer used in cat foods since cats have been found to be particularly susceptible to adverse effects from the compound. Toxicosis due to large doses of propylene glycol has been reported in various species. Cats may be more susceptible than other species.

SOURCES Propylene glycol, or 1,2-propanediol, is a stable, colorless, odorless, viscous liquid with a specific gravity of 1.036. It is an excellent solvent because it is freely miscible with water yet dissolves hydrophobic substances. Among the glycols, propylene glycol has the lowest toxicity.1 Unlike ethylene glycol, propylene glycol does not cause oxalate nephrosis. Propylene glycol 996

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is classified by the Food and Drug Administration (FDA) as “generally recognized as safe” (GRAS) except for use in cat foods. Because of these properties, it is used not only as automotive antifreeze, hydraulic fluid, and an industrial solvent, but also as a pharmaceutical solvent for oral, topical, and injectable preparations, an ingredient in cosmetics, and an additive in processed foods for human and animal consumption.

TOXIC DOSE The oral median lethal dose (LD50) for propylene glycol in dogs is reported to be as low as 9 mL/kg, though that for most laboratory animal species is approximately 20 mL/kg.5,8,16,17

TOXICOKINETICS Acute propylene glycol toxicosis has occurred in humans, horses, and cattle due to ingestion, parenteral administration, and topical treatment for burns.2-13 The condition has also been experimentally produced in cats, dogs, laboratory animals, goats, and chickens.1,8,14-19 Propylene glycol is palatable to dogs.20 It is absorbed rapidly in the digestive system.2 Toxic doses may also be absorbed through damaged skin, and toxicosis has been reported in burn patients.1,12,21,22 Oral absorption of propylene glycol is rapid and the volume of distribution is 0.5 L/kg in humans.23 Like other glycols and alcohols, propylene glycol is oxidized by two saturable enzymes, hepatic alcohol dehydrogenase and aldehyde dehydrogenase, to D and L isomers of lactic acid.2 Nonmetabolized propylene glycol is excreted in the urine.2,23-26 L-lactic acid enters the citric acid cycle and is metabolized rapidly.4 However, D-lactic acid is not readily metabolized and accumulates in plasma.4,27 Because of this, intoxicated animals succumb to lactic acidosis. Propylene glycol concentrates in the central nervous system in humans.11 Propylene glycol has narcotic effects similar to those of ethanol, although it is only about one third as potent.1,4,5,12,21 Dogs eliminate propylene glycol almost completely within 24 hours.14 The elimination half-life in humans is 1.4 to 3.3 hours.23 Heinz body formation occurs through the interaction of propylene glycol or its metabolite with the sulfhydryl groups on the hemoglobin molecule.1,27,.28 Cats may be particularly sensitive because their hemoglobin contains eight sulfhydryl groups. The hemoglobin molecule becomes denatured and adheres to the cell membrane. Heinz body numbers decrease to normal levels within 8 weeks of cessation of exposure.29,30

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CLINICAL SIGNS Clinical signs of acute propylene glycol poisoning in small animals are related to its narcotic effects and lactic acidosis. Most patients present with central nervous system (CNS) depression and ataxia after they have ingested large quantities of propylene glycol.2,23,24,31-34 Seizures have also been reported in human cases of propylene glycol poisoning.2-5 Muscle twitching may be evident in cats.19 The author is familiar with a case of malicious poisoning with propylene glycol where three dogs were found dead. A foul or garlic-like odor to gastrointestinal contents has been reported in horses and a llama.34,35 Parenteral overdosing with propylene glycol has been associated with hypotension in cats and circulatory collapse in dogs and other species.2,4,14,18,25 Intravenous infusion of undiluted propylene glycol is associated with hemolysis because of the hyperosmolarity of the compound.2 Osmotic diuresis and dehydration are also commonly seen with oral and parenteral exposure to propylene glycol.1,13,17,20 Contact dermatitis because of hypersensitivity to propylene glycol has been reported in humans.10

MINIMUM DATABASE Clinical pathological findings in animals with propylene glycol toxicosis are consistent with metabolic acidosis and hyperosmolarity. Carbon dioxide and carbonic acid levels are low.4 Animals have an increased ion gap, which correlates with elevated blood levels of lactic acid.2-4,6,7 Intoxicated animals may be hypoglycemic.1 Urine from dogs with osmotic diuresis has a low specific gravity and casts may be observed.6,11 Blood urea nitrogen (BUN) may be elevated.6 If the animals were exposed intravenously, the serum is hyperosmolar.2 Hemoglobinuria caused by hemolysis has been reported in dogs and other species as a result of high intravenous doses of propylene glycol.7,18,24 Heinz body formation has been reported in cats and horses secondary to ingestion of propylene glycol.1,13,27-30,34 Heinz bodies were present in up to 18% of erythrocytes in adult cats and 36% in kittens as a result of dietary exposure to propylene glycol.13,15,27,29 There have been no reports of clinical anemia or methemoglobinemia in cats because of chronic dietary exposure to propylene glycol, though PCVs may be mildly reduced.27,32,36 However, such exposure may predispose feline red cells to oxidative damage by other agents, such as acetaminophen.27 Experimental dogs fed diets containing 20% propylene glycol had decreased PCVs, increased reticulocyte counts, increased nucleated erythrocyte counts, and evidence of hemolysis.1,37

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CONFIRMATORY TESTS Diagnosis of propylene glycol toxicosis is usually based on a history of exposure. PG can be detected in urine and serum by gas chromatography.3,8,21 Poisoning was confirmed using gas chromatography to detect residue in a container found near the three dogs in the terminal case, which was mentioned previously. An important note to add is that propylene glycol will give a false positive in some commercially available ethylene glycol test kits (refer to Chapter 45—Ethylene Glycol).

TREATMENT Treatment of acute propylene glycol toxicosis is supportive. Intravenous fluids containing sodium bicarbonate should be administered as needed to correct dehydration and acidosis. A horse with propylene glycol toxicosis was treated by gastric lavage to remove remaining material in the stomach and activated charcoal to adsorb propylene glycol. Isotonic sodium bicarbonate and dexamethasone were administered IV. Blood gas was monitored on an hourly basis.34 Hypoglycemia should be corrected if present. Vitamin C was administered to diminish oxidative damage to erythrocytes in an intoxicated horse.34 However, experimental administration of vitamin C and vitamin E failed to significantly decrease Heinz body formation in cats fed a diet containing propylene glycol and N-acetylcysteine was only slightly beneficial.36

PROGNOSIS The prognosis is highly variable depending on the exposure dose and time interval between exposure and initiation of treatment. In general, it would be considered guarded to fair.

GROSS AND HISTOLOGICAL LESIONS There may be no gross or microscopic lesions in animals poisoned with propylene glycol.14 Reported kidney lesions include congestion and tubular necrosis.8,16,31 Liver lesions have been reported in horses.8,31

DIFFERENTIAL DIAGNOSES Some toxicants that could mimic this clinical presentation include ivermectin and other macrolide antiparasitic agents, ethylene glycol, methanol,

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diethylene glycol, 2-butoxyethanol, sedatives and tranquilizers, isopropanol and amitraz. Others causes of a hemolytic anemia are zinc, naphthalene containing mothballs, onions, acetaminophen, copper and pit viper snakebites. REFERENCES 1. Christopher MM, Perman V, Eaton JW: Contribution of propylene glycol-induced Heinz body formation to anemia in cats, J Am Vet MedAssoc 194(8):1045-1056, 1989. 2. Pastemak G: Ethylene/propylene glycol toxicity. In Goldfrank L, editor: Case studies in environmental medicine 30, San Rafael, Calif, 1993, DeLima Associates. 3. Cate JC, Hedrick R: Propylene glycol intoxication and lactic acidosis, N Engl JMed 303(21):1237, 1980. 4. Christopher MM, Eckfeldt H, Eaton JW: Propylene glycol ingestion causes D-lactic acidosis, Lab Invest 60(1):114, 1990. 5. Yu DK, Elmquist WF, Sawchuck RJ: Pharmacokinetics of propylene glycol in humans during multiple dosing regimens, J Pharmacol Sci 74(8):876-879, 1985. 6. Van de Wiele B, Rubinstein E et al: Propylene glycol toxicity caused by prolonged infusion of etomidate, J Neurosurg Anesthesiol 7(4):259-262, 1995. 7. Dorman DC, Hascheck WM: Fatal propylene glycol toxicosis in a horse, J Am Vet Med Assoc 198(9):1643-1644, 1991. 8. McConnel JR, McAllister JL, Gross GG: Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema, Neurosurgery 38(1):232-233, 1996. 9. Levy ML, Aranda M, Zelman V et al: Propylene glycol toxicity following continuous etomidate infusion for the control of refractory cerebral edema, Neurosurgery 37(2): 363-371, 1995. 10. Angelini G, Meneghini CL: Contact allergy from propylene glycol, Contact Dermatitis 7(4):197-198, 1981. 11. Fligner CL, Jack R, Twiggs GA et al: Hyperosmolality induced by propylene glycol, JAMA 253(11):1606-1609, 1985. 12. MacDonald MG, Getson PR, Glasgow AM et al: Propylene glycol: increased incidence of seizures in low birth weight infants, Pediatrics 79(4):622-625, 1987. 13. Bauer MC, Weiss DJ, Perman V: Hematological alterations in kittens induced by 6% and 12% dietary propylene glycol, Vet Hum Toxicol 34(2):127-131, 1992. 14. Hanzlik PH, Newman HW, Van Winkle W Jr et al: Toxicity, fate and excretion of propylene glycol and some other glycols, J Pharmacol Exp Ther 67(12):101-113, 1939. 15. Ruddick JA: Toxicology, metabolism, and biochemistry of 1,2-propanediol, Toxicol Appl Pharmacol 21(1):102-111, 1972. 16. Gaunt IF, Carpanini FMB: Long-term toxicity of propylene glycol in rats, Food Cosmet Toxicol 10(5):151-162, 1972. 17. Moon PF: Acute toxicosis in two dogs associated with etomidate-propylene glycol infusion, Lab An Sci 44(6):590-594, 1994. 18. Seidenfeld MA, Hanzlik PJ: The general properties, actions and toxicity of propylene glycol, J Pharmacol Exp Ther 44:109-121, 1932. 19. Marshall DA, Doty RL: Taste responses of dogs to ethylene glycol, propylene glycol, and ethylene glycol-based antifreeze, J Am Vet Med Assoc 197(12):1599-1602, 1990. 20. Glasgow AM, Boeckx RL, Miller MK et al: Hyperosmolality in small infants due to propylene glycol, Pediatrics 72(3):353-355, 1983. 21. Kelner MJ, Bailey DN: Propylene glycol as a cause of lactic acidosis, J Anal Toxicol 9(1):40-42, 1985. 22. Lehman AJ, Newman HW: Propylene glycol: rate of metabolism, absorption, and excretion with a method for estimation in body fluids, J Pharmacol Exp Ther 60: 312-322, 1937.

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23. Brooks DE, Wallace KL: Acute propylene glycol ingestion, Clin Toxicol 40(4):513-516, 2002. 24. Arulanantham K, Genel M: Central nervous system toxicity associated with ingestion of propylene glycol, J Pediatr 1978; 93(3):515-516, 1978. 25. Yu DK, Sawchuk RJ: Pharmacokinetics of propylene glycol in the rabbit, J Pharmacokinet Biopharm 15(5):453-471, 1987. 26. Pintchuk PA, Galey FD, George LW: Propylene glycol toxicity in adult dairy cows, J Vet Intern Med 7(3):150, 1993. 27. Weiss D, McClay CB, Christopher MM et al: Effects of propylene glycol containing diets on acetominophen-induced methemoglobinemia in cats, J AmVet Med Assoc 196(11):1816-1819, 1990. 28. Bauer MC, Weiss DJ, Perman V: Hematologic alterations in adult cats fed 6% or 12% propylene glycol, Am J Vet Res 53(1):69-72, 1992. 29. Dzanis DA: Propylene glycol unsafe for use in cat foods, FDA Vet 9(1):1-3, 1994. 30. Hickman MA, Rodgers QR, Morris JG: Effects of diet on Heinz body formation in kittens, Am J Vet Res 50(3):475-478, 1990. 31. Myers VS, Usenik EA: Propylene glycol intoxication of horses, J Am Vet Med Assoc 155(12):1841, 1969. 32. Gross DR, Kitzman JV, Adams HR: Cardiovascular effects of intravenous administration of propylene glycol and oxytetracycline and propylene glycol in calves, Am J Vet Res 40(6):783-791, 1979. 33. Martin G, Finberg L: Propylene glycol: a potentially toxic vehicle in liquid dosage form, J Pediatr 77(5):877-878, 1970. 34. McLanahan S, Hunter J, Murphy M et al: Propylene glycol toxocosis in a mare, Vet Hum Toxicol 40(5):294-296, 1998. 35. Ivany JM, Anderson DE: Propylene glycol toxicosis in a llama, J Am Vet Med Assoc 218(2):243-244, 2001. 36. Hill AS, O’Niell S, Rogers QR et al: Antioxidant prevention of Heinz body formation and oxidative injury in cats, Am J Vet Res 62(3):370-374, 2001. 37. Weil CS, Woodside MD, Smyth HF Jr et al: Results of feeding propylene glycol in the diet to dogs for two years, Food Cosmet Toxicol 9(4):479-490, 1971.

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Pyrethrins and Pyrethroids Steven R. Hansen, DVM, MS

• Natural pyrethrins are derived from Chrysanthemum cinerariaefolium and related species. • Synthetic pyrethroid insecticides demonstrate enhanced stability and potency. • Most products with EPA-approved labels for use on dogs and/or cats represent a relatively low hazard when used as directed in healthy animals. • Cats are more sensitive than most other species to pyrethrins and pyrethroids. • Pyrethrin and pyrethroid insecticides reversibly alter the activity of sodium ion channels of nerves. • Clinical signs result from allergic, idiosyncratic, and neurotoxic reactions. • Treatment is based on preventing further systemic absorption and topical contact while providing supportive care, and, in serious cases, controlling tremors or seizures. • Veterinarians should educate clients on the safe use of pesticides.

SOURCES Natural pyrethrum extract contains a mixture of similar compounds and isomers derived from Chrysanthemum cinerariaefolium and related species. The insecticidal activity of pyrethrum has been known since at least the mid-1800s. Today, most agricultural production of pyrethrum extract intended for formulation into insecticidal products occurs in East Africa.1 Pyrethrin-containing flea and tick control products for dogs and cats have been popular for many years because they can rapidly knock down and kill insects and have a reasonable safety profile. Pyrethroid insecticides are synthetic compounds that have been, and continue to be, developed and formulated to provide enhanced stability and potency on pets and in the environment. Pyrethroids represent a diverse 1002

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and growing collection of synthetic compounds that have a structure and/ or mechanism similar to that of natural pyrethrins. Examples of synthetic pyrethroid compounds include allethrin, deltamethrin, fenvalerate, fluvalinate, cypermethrin, cyfluthrin, phenothrin, permethrin, resmethrin, tetramethrin, and tralomethrin. The United States Environmental Protection Agency (EPA) approves product labels and regulates all insecticidal products. Many pyrethrin and pyrethroid formulations are registered for topical and household use on or around dogs and/or cats for flea and tick control. Other products are registered for environmental and agricultural use for a host of economic and annoyance pests. Products containing pyrethrin or pyrethroid insecticides are readily available through grocery, discount, home improvement, and veterinary locations. Spot-on formulations represent the most popular consumer product form, although some dip, shampoo, spray, mousse, premise, and other formulations remain available. Consumer confusion regarding which products are appropriate for use on dogs, cats, or both results in misuse of dog products on cats with potentially life-threatening consequences.

TOXIC DOSE Toxic doses for pyrethrin and pyrethroid compounds vary substantially and in most cases are not known in dogs or cats. The rat acute oral median lethal dose (LD50) for technical grade pyrethrin isomers is reported to be 260 to more than 600 mg/kg.2 Acute dermal LD50 values for pyrethrins are more than 1350 mg/kg in the rat and more than 4500 mg/kg in the rabbit.3 Toxicity of pyrethroids varies similarly; for example, the rat oral LD50 for tefluthrin is 22 mg/kg, whereas that for phenothrin is 10,000 mg/kg.4 Although the toxic dose for permethrin in the cat is unknown, clinical evidence clearly demonstrates a marked sensitivity in this species. This sensitivity likely also occurs in response to other pyrethroids as well. Although valuable information can be gained from insecticide LD50 data when considered in the context of a diluted final product, the actual toxicity of the complete formulation in the target species is what is most important. Inert or synergist activity may enhance the toxicity of a formula. Inert ingredients in insecticidal formulations include solvents, such as aromatic and aliphatic hydrocarbons, glycols, and alcohols. Synergists, which are formulated to slow an insect’s metabolic processes by inhibiting microsomal enzyme activity, include piperonyl butoxide and N-octyl bicycloheptene dicarboximide (MGK-264).

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Generally, most products registered for use on dogs and cats represent a relatively low hazard when used according to label directions in healthy pets. The EPA requires standardized product toxicity testing to determine which signal word must appear on the label. Signal words, representing the least to the most hazardous compounds, include the terms: Caution, Warning, and Danger. The signal word is determined based on six acute toxicity studies and product composition. These studies include tests for acute oral, acute dermal, and acute inhalation toxicity, eye irritation, skin irritation, and skin sensitization. Skin sensitization determines whether a product is capable of causing an allergic reaction and is not considered when determining the signal word. The standard battery of acute toxicity tests is based on rat, rabbit, and guinea pig protocols (not dog or cat protocols). Ultimately the signal word on the label is based on the most sensitive test. Previously defined precautionary statements are determined by the toxic effects noted on each individual test. For example, “Causes eye injury” is an EPA required statement based on the severity of the eye irritation noted in a study in rabbits. Most animal-registered products display the signal word Caution, which means that the final product formulation exhibited an acute rat oral LD50 of less than 500 mg/kg, thereby also requiring the statement “harmful if swallowed.” A target animal safety study is conducted in each approved species, which also may trigger specific label requirements.5 One specific toxicosis warrants special comment. Based on the public database of the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center, “spot-on” products that contain the pyrethroid permethrin, which are labeled clearly for use on dogs only, can result in serious toxicosis when used inappropriately on cats. Significant adverse reactions in dogs are rare. Based on these cases, dermal application of 100 mg/kg permethrin (1 mL of 45% permethrin applied dermally to a 4.5-kg cat), if untreated, can result in life-threatening toxicosis. The minimum toxic dose is unknown, but would be expected to be significantly lower. Similarly, case data suggest that some cats that closely cohabitate (direct contact while sleeping or grooming) with dogs are at risk for permethrin toxicosis when the dog alone was treated appropriately with a permethrin-containing product. Based on data from these and other cases, cats should be considered exceptionally sensitive to permethrin compared with dogs, rats, or humans. Permethrin-based products formulated for dogs can contain anywhere from 0.054% to 65% permethrin. Products formulated for cats should contain less than 0.20% permethrin. Based on a similar review of recent 2005 public database cases, some cats appear sensitive to properly applied EPA approved spot-on formulations containing 85.7% phenothrin. Clinical signs are generally, but not always, less severe with shorter duration than effects reported following

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permethrin exposure. Clinical signs reported from most to least frequent include tremors, ear twitching, ataxia, pruritis, vomiting, facial twitching, and agitation. According to the EPA, production of 85.7% spot-on feline phenothrin formulations is scheduled to end September 30, 2005, with sales to be discontinued by March 31, 2006. Veterinarians should take every opportunity to educate clients on the safe use of pesticides in compliance with label directions. Many pesticide regulatory documents and other information on pesticides are available on the Internet at www.epa.gov/pesticides.

TOXICOKINETICS Pyrethrin insecticides are fat-soluble compounds that undergo rapid metabolism and excretion following oral or dermal exposure. Pyrethroid insecticides have enhanced stability and potency. Carriers, solvents, and synergists can greatly influence the effect of excess exposure to insecticidal products. For example, some formulations contain large percentages of alcohols and other solvents, which can result in profound depression, especially when applied excessively to cats or small dogs. Synergists, such as piperonyl butoxide and N-octyl bicycloheptene dicarboximide (MGK-264), are included in older formulations to enhance insecticidal activity. It is unclear what impact these compounds have on the metabolism of xenobiotics in dogs and cats, especially in situations of overdose.

MECHANISM OF TOXICITY The basic mechanism of action of pyrethrin and pyrethroid insecticides is essentially the same. These compounds affect insects and animals by altering the activity of the sodium ion channels of nerves. Under conditions of normal membrane depolarization, the sodium channels of nerve fibers allow an influx of sodium ions into the nerve axon. Inactivation of the action potential occurs as sodium ion influx decreases. During the peak of the action potential potassium channels open, allowing potassium to move out of the cell. The cell membrane returns to its normal resting state through the action of energy-dependent sodium and potassium pumps. Exposure to pyrethrin or pyrethroid compounds prolongs the period of sodium conductance, which increases the length of the depolarizing action potential, resulting in repetitive nerve firing. Sensory nerve fibers are more susceptible to stimulation because of differences in sodium channel kinetics.6

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CLINICAL SIGNS Based on the experience of the ASPCA Animal Poison Control Center, clinical signs can result from both appropriate and inappropriate exposure of pets to pyrethrin or pyrethroid insecticides. Such exposures can result in either minor or major clinical signs. Clinical signs result from immune-mediated hypersensitivity reactions, genetic-based idiosyncratic reactions, and neurotoxic reactions. Although an understanding of the mechanism of the reaction is important when considering a treatment plan, the treatment plan itself is ultimately designed to meet the specific needs of the patient. This concept can be summarized simply as “treat the patient and not the poison.” Minor, usually self-limiting, clinical signs include hypersalivation, paw flicking, ear twitching, hyperesthesia, reduced activity, and single-episode vomiting or diarrhea. Hypersalivation, paw flicking, ear twitching, and hyperesthesia are commonly reported and are caused by topical and oral stimulation of sensory nerves. Vomiting and diarrhea are nonspecific signs. These clinical signs are considered side effects but not adverse, deleterious, or toxic effects. Although these clinical effects are often self-limiting, pet owners can often be greatly alarmed and may describe hyperesthesia as seizure activity. Topical allergic reactions are relatively common and can be manifested as generalized dermal urticaria, hyperemia, pruritus, and alopecia. Systemic anaphylactic reactions are a much less common but potentially very serious complication and are expressed as circulatory collapse, respiratory distress, and sudden death. Allergic reactions are often the result of minimal or appropriate exposure. Dermal reactions are the most common allergic manifestation and are not considered serious. Anaphylactic reactions are life threatening. Future avoidance of products containing pyrethrin or pyrethroid compounds is recommended for the animal affected. Idiosyncratic reactions are considered the direct result of pyrethrin or pyrethroid neurotoxic effects, which occur at much lower doses than expected. Typically, these sensitive animals represent a small percentage of a normally distributed population. Standard descriptive toxicology tests use exaggerated doses in an attempt to reveal the likelihood of such occurrences. Future avoidance of pyrethrin or pyrethroid formulations in these animals is important. True toxic reactions are the result of overdose or repeated overapplication of insecticides. Protracted vomiting and diarrhea, marked depression, ataxia, or muscle tremors warrant immediate veterinary examination and treatment. If untreated, marked dermal or oral overdose may result in tremors and, rarely, seizures or death. Cats are especially

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sensitive to concentrated permethrin-containing products labeled for use on dogs and can develop muscle tremors, ataxia, seizures, and death within hours. Seizure activity is unusual following pyrethrin exposure even at exaggerated doses. Future use of these products in accordance with label instructions would not be expected to lead to a recurrence. Exceptions would include the situation in which a very sensitive animal received an exaggerated dose.

MINIMUM DATABASE The minimum database includes baseline serum chemistries, complete blood count, and urinalysis. These minimal data help to uncover preexisting conditions that can affect the treatment plan and prognosis. Often a suspected poisoning case is actually the result of a preexisting disease process. Sick, debilitated, or stressed animals may be predisposed to toxicosis. Heavy flea or tick infestation or other parasitic diseases may also increase individual risk.

TREATMENT Minor side effects, such as hypersalivation, paw flicking, ear twitching, hyperesthesia, reduced activity, and single-episode vomiting or diarrhea, are usually self-limiting and require no treatment. If the pet is wet from application of a product, a towel that has been warmed in a dryer works nicely to warm up and dry a small cat or dog. Consumption of water or milk may help dilute and rinse product from the mouth, thereby reducing salivation. Thorough brushing may remove loose hair and reduce grooming in cats. Allergic reactions most commonly become manifest as hyperemic and pruritic skin. In these cases, a detergent bath (hand dishwashing product) with copious rinsing in cool water is usually adequate. Topical vitamin E applied to the affected area of skin may reduce inflammation and pruritis. Diphenhydramine may prove beneficial when topical vitamin E does not yield positive results or systemic antiinflammatory drugs may be required to stop self-inflicted trauma. Anaphylactic reactions should be managed aggressively using routine protocols. After bathing, pets must be dried completely to avoid chilling. Activated charcoal administration is not routinely recommended because benefits often do not outweigh the stress or need for sedation in cats. An exception would be when a topical spot-on product was administered

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orally to a cat. In this case activated charcoal should be administered orally at 2 gm/kg bw. Overuse of activated charcoal in very small or dehydrated animals should be avoided because of potential adverse effects on sodium homeostasis resulting in hypernatremia. In cases where prolonged seizure activity has occurred without early veterinary intervention, achieving adequate seizure control can be challenging and is often the determining prognostic indicator. In most cases, control of marked tremor or seizure activity can be achieved with Robaxin-V (methocarbamol) administered intravenously at a rate of 0.25 to 1 mL/lb (55 to 220 mg/kg). Administer half the dose rapidly without exceeding a rate of 2 mL/min, then pause until the pet begins to relax, and then administer the remainder to effect. A maximum dose of 330 mg/kg/day should not be exceeded. In serious cases, diazepam will not produce acceptable seizure control. Other agents successfully used to control seizures include barbiturates, isoflurane following mask induction, and propofol. Care should be used to avoid oversedation because complete elimination of random muscle trembling is not required or likely.7,8 Once seizure or tremor activity is controlled, topically exposed animals must be thoroughly bathed with a liquid hand dishwashing detergent and rinsed with copious amounts of water at body temperature. Maintenance of a normal body temperature is extremely important. Severe hyperthermia often results during prolonged tremor or seizure activity. In contrast, hypothermia often results following bathing or sedative administration. Hypothermia is as dangerous as hyperthermia because reduced body temperature enhances nervous activity by slowing sodium channel kinetics. Adequate nutritional and fluid support also hastens recovery. Administration of atropine should be strictly avoided because atropine is not antidotal and can produce CNS stimulation in excessive doses.

PROGNOSIS Early, aggressive treatment often results in a full recovery within 24 to 72 hours. Nervous system effects are completely reversible on recovery. Unfortunately, pets not receiving early aggressive care may die.

GROSS AND HISTOLOGICAL LESIONS Pyrethrin and pyrethroid insecticides do not produce identifiable lesions.

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Pyrethrins and Pyrethroids 1009

DIFFERENTIAL DIAGNOSES Analysis of hair samples can confirm exposure to specific pyrethroids, especially permethrin. In cats, hair analysis can confirm permethrin exposure when no exposure to permethrin was known or when exposure was reported to be to a feline-approved flea and tick product that contains other insecticides not expected to cause severe neurological effects. Pyrethrin or pyrethroid toxicosis must be differentiated from other neurotoxicant exposures, including strychnine, metaldehyde, fluoroacetate (1080), 5-fluorouracil, 4-aminopyridine, caffeine, theobromine, amphetamine, cocaine, tremorgenic mycotoxins, and organophosphate, carbamate, or organochlorine insecticides. Trauma, endocrine abnormalities, and neoplasia also warrant consideration. Animals found dead must be presented to a veterinary clinic or veterinary diagnostic laboratory for necropsy. Sudden death in cats following exposure to a stressful situation, such as a bath, can result from decompensated cardiomyopathy or cardiac failure secondary to thyroid neoplasia. Other disease processes can similarly complicate diagnosis and treatment.

Case report 1 A 1-year-old 4.5-kg castrated male domestic shorthair cat was presented to an emergency clinician for treatment. The cat owner had applied a 1-mL 45% permethrin, 5% pyriproxyfen spot-on product EPA registered for use only on dogs. The product had been applied on the cat 4 hours earlier to the dorsal scapular area, where it was thought that the cat could not groom. Within 4 hours of exposure, the cat developed hypersalivation, severe tremors, and seizures. At the time of the call to the ASPCA Animal Poison Control Center, the cat had already been bathed with a hand dishwashing detergent to remove residual permethrin. Subsequently, diazepam, pentobarbital, and methocarbamol were ineffective in controlling seizure activity. The pet owner elected to have the cat euthanized. The cat in this case report was exposed to a known permethrin dose of 100 mg/kg. The second active ingredient was pyriproxyfen, 11 mg/kg, which is an insect growth regulator of low toxicity. Delayed treatment resulting in progression to intractable seizure activity is the primary reason permethrin-exposed cats die or are euthanized.

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Case report 2 A 5-year-old, 6.8-kg castrated male domestic shorthair cat was presented to a veterinarian for treatment. The cat owner had applied a 2.5-mL 44% permethrin, 8.8% imidacloprid spot-on product EPA registered for use only on dogs. Within 2.5 hrs the cat was exhibiting muscle tremors, had a body temperature of 103° F and vomited once. Within 4 hours of exposure, the cat had been bathed in a hand liquid dishwashing detergent and was administered methocarbamol. The cat fully recovered. In this case the cat was topically exposed to 162 mg/kg permethrin and 32 mg/kg imidacloprid. Topical application of imidacloprid alone at this dose would not be expected to cause adverse effects in cats. Topical decontamination and use of methocarbamol resulted in a successful outcome. REFERENCES 1. Ray D: Pesticides derived from plants and other organisms. In Hayes WJ Jr, Laws ER Jr, editors: Handbook of pesticide toxicology, San Diego, 1991, Academic Press. 2. Casida JE, Kimmel EC, Elliott M et al: Oxidative metabolism of pyrethrins in mammals, Nature 230:326-327, 1971. 3. Malone JC, Brown NC: Toxicity of various grades of pyrethrum to laboratory animals, Pyrethrum Post 9:3-8, 1968. 4. Thomson WT: Agricultural chemicals, vol 1. Insecticides, Fresno, Calif, 1992, Thomson Publications. 5. Environmental Protection Agency: Label review manual, Washington, DC, 1996, EPA Registration Division, Office of Pesticide Programs. 6. Hansen S, Villar D, Buck W et al: Pyrethrins and pyrethroids in dogs and cats, Compend Cont Educ Pract Vet 16(6):707-713, 1994. 7. Volmer P, Khan S, Knight M et al: Warning against use of some permethrin products in cats (letter to editor), J Am Vet Med Assoc 213(6):800, 1998. 8. Richardson J: Permethrin spot-on toxicoses in cats, JVECCS 10(2):103-106, 2000.

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Ricin

73

E. Murl Bailey, Jr., DVM, PhD

• Ricin is the toxic principle isolated from the castor bean plant, Ricinus communis. • The median oral lethal dose is thought to be 20 mg/kg (LD50) in dogs and cats. • Clinical signs may be delayed 8 to 24 hours postexposure. Initial signs postinhalation include anorexia and respiratory distress, developing into pulmonary edema. Oral exposures lead to gastrointestinal signs, including diarrhea, abdominal pain, anorexia, and vomiting with or without blood. Seizures are possible. • Diagnosis is based upon history, physical examination findings, and biochemical alterations, with increases in ALT, AST, BUN, and creatinine. • There are no antidotes, and treatment is largely supportive. Patients exposed orally should be decontaminated with emesis induction and dosed with activated charcoal. • Lesions after oral or intramuscular exposure include hemorrhagic gastroenteritis and hepatic, renal, and splenic necrosis. Fibrinopurulent pneumonia, diffuse necrosis and acute inflammation of airways, alveolar flooding with peribronchial vascular edema, and purulent mediastinal lymphadenitis are seen following inhalation exposures.

SOURCES Ricin is a naturally occurring toxin isolated from the castor bean plant (Ricinus communis).1 The ricin concentration in the plant is approximately 1% to 5% by weight. Approximately 1 million tons of castor beans are processed annually in the production of castor oil for lubrication and medicinal purposes.2 Ricin is a large glycoprotein, which is a water soluble, white powder in pure form, stable under ambient temperature conditions, but is heat labile.1 Heating the compound to 80° C for 10 minutes or 50° C for 1011

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50 minutes effectively inactivates the protein. Ricin has a molecular weight of 66 kDa, which is slightly smaller than albumin, and consists of two chains, A and B.3 Two hemagglutinins are associated with ricin, but their significance is unknown.2 Ricin is easily obtained in small or large quantities throughout the world. It is a potential terrorist weapon, but not likely a chemical warfare agent because large quantities would be required in an aerosol form.4 It could be used to contaminate food or small bodies of water, but aerosolization would be required in most potential terrorist or weapons of mass destruction activities.2 Ricin has been used for assassination and suicidal activities in humans.5 Toxicities have been associated with accidental ingestions of castor beans in humans, dogs, and horses.1,6-10 Ricin occurs as a residual product from the plant material after oil extraction, which would require additional purification before use.1,8,9 The residual “cake” is used in some parts of the world for fertilizer and cattle feed, but the latter is used only after heat treatment.1,9 Castor oil does not contain ricin and is used for lubricants and as an irritant laxative and rodent repellent.3,9

TOXIC DOSE The toxic or lethal dose of ricin depends upon the species exposed and the route of exposure.3 There is greater than a 100-fold difference between susceptibility of various species.10 The oral lethal dose of seed material (assuming 1% to 5% ricin concentration) has been reported for the following species: chicken = 14 g/kg (140 to 170 mg ricin/kg); swine = 1.3 g/kg (13 to 65 mg ricin/kg); rabbit = 0.9 g/kg (9 to 45 mg ricin/kg); and horse = 0.1 g/kg (1 to 5 mg ricin/kg).1,3 The reported toxic oral doses of pure ricin are: mice = 20 mg/kg (LD50); horse = 1 to 5 mg/kg; dog = unknown, but probably similar to mice; and in humans it is speculated that the lethal dose is 1.0 mg/kg, but some authors question if ricin is that toxic to humans.1,3 The intravenous toxic doses of ricin have been reported as being 5 µg/kg (LD50) for mice, with the minimum lethal dose varying from 0.7 to 2.7 µg/kg; in humans it is unknown, but 1 to 10 µg/kg is the suggested toxic dose, and the MLD in the dog is 1.6 to 1.75 µg/kg.1,3,14 The inhalation toxic doses are 3 to 5 µg/kg (LD50) in mice, and 21 to 42 µg/kg is the reported lethal dose in monkeys.3,15 The intraperitoneal LD50 in mice is 22 µg/kg.3 Subcutaneous or intramuscular toxicity of ricin ranges from 24 µg/kg (LD50) in mice, 33 to 50 µg/kg in rats (lethal dose), and 70 µg/kg is apparently a lethal dose in humans, but an individual receiving an estimated 140 µg/kg survived with hospitalization.1,3

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TOXICOKINETICS Ricin is a large protein molecule, which is poorly absorbed from the gastrointestinal tract.3 After an oral exposure, most of the ricin is found in the large intestine 24 hours after ingestion, illustrating the limited systemic uptake of the protein.1 Based on mouse toxicity (LD50) data, approximately 0.025% of the ingested ricin is absorbed following oral administration, but other work has shown that up to 0.27% of the ingested ricin may be absorbed. Once absorbed, ricin most likely distributes throughout the extracellular fluid space in the body.1,3,16 Ricin appears to be readily absorbed via the inhalation route, but dermal absorption is unlikely to occur through intact skin.1,3 Intravenously administered ricin distributes primarily to spleen, kidneys, heart, and liver, and intramuscularly administered ricin distributes to draining lymph nodes.1

MECHANISM OF TOXICITY The B chain of ricin binds to galactoside-containing proteins on cell surfaces, which allows for the internalization of the A chain by triggering an endocytotic uptake.1,3 This is the probable cause of the 8- to 24-hour latent period associated with ricin and/or castor bean intoxication because the transport may be slow in some instances.3 The A-chain binds with the 28S RNA subunit of eukaryotic cells, killing the cell through the inhibition of protein synthesis.3 Ricin has also been shown to disturb calcium homeostasis in the heart, leading to myocardial necrosis and cardiac hemorrhage. Ricin may target Kupffer cells, which gives rise to the hepatotoxicity that is often reported.1,6 It has been speculated that the lesions seen in ricin and/or castor bean intoxications may be due to effects on endothelial cells, causing fluid and protein leakage along with tissue edema.1 Inhaled ricin binds to ciliated bronchiolar lining cells, alveolar macrophages, and alveolar lining cells.3 It is of note that castor beans and leaves also contain a pyridine compound, ricinin, which may cause neuromuscular weakness as a result of an interference with acetylcholine binding at nicotinic receptor sites.11

CLINICAL SIGNS The clinical signs associated with ricin exposure vary with the dose and route of exposure. With respiratory and/or inhalation exposures, there may be a preclinical dose-dependent delay of 8 to 24 hours (reported in

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rats and primates) before the onset of the clinical syndrome.3 Anorexia subsequently develops, and there is a progressive decrease in physical activity, probably caused by developing hypoxemia and the generalized toxic cellular effects of ricin.3 Respiratory distress starts developing, and there are increased inflammatory cell counts and increased protein from bronchiolar lavage at 12 hours postexposure. At 18 hours postexposure, alveolar flooding and pulmonary edema develop, and at 30 hours postexposure, severe arterial hypoxemia and acidosis are present. In humans a primary allergic syndrome has been reported in workers exposed to castor bean dust, but this type of syndrome has not been reported in animals.1,3 Postmortem airway and pulmonary lesions associated with inhalation exposure to ricin include marked to severe fibrinopurulent pneumonia, diffuse necrosis and acute inflammation of airways, alveolar flooding and peribronchial vascular edema, acute tracheitis, and marked to severe purulent mediastinal lymphadenitis. The lung lesions are sufficiently severe to cause death. Adrenalitis and hepatic lesions may or may not be present. Oral exposure to castor beans have been reported in dogs and humans.6-8 It should be noted that the beans must be broken or masticated for the ricin to be released.7,8 There may be a latent period of 8 to 24 hours following oral exposures to either ricin or castor beans. The gastrointestinal signs, which typically develop, include vomiting with or without blood, depression, diarrhea (with or without blood), abdominal pain, and anorexia.6-8 In humans there have been cases of intramuscular exposure to ricin and castor beans.3,5 The initial signs have included localized pain and muscular weakness within 5 hours of exposure. Fifteen to 24 hours after exposure, high body temperatures, nausea and vomiting, tachycardia with normal blood pressures, swollen regional lymph nodes, induration at the injection site, and a leukocytosis (26,000/mm3) have developed in these individuals. Forty-eight hours after exposure, hypotension, tachycardia, and vascular collapse developed in these individuals. At 72 hours, anuria, vomiting blood, complete AV conduction block, and a white blood cell count of 33,200 /mm3 developed in these individuals. Death occurred very rapidly in spite of heroic resuscitation efforts.

MINIMUM DATABASE The development of abnormal organ-specific biochemical values may not occur for 12 to 24 hours after exposure. The minimum database to be developed in cases of suspected exposure to ricin or castor beans should

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include serum alanine transaminase (ALT), serum aspartate transaminase (AST), blood urea nitrogen (BUN), serum creatinine, CBC, PCV, and total serum protein.

CONFIRMATORY TESTS Analytical methods exist for ricin, but they are not readily available at veterinary diagnostic toxicology laboratories.

TREATMENT There are no postingestion antidotes for ricin. Normal therapy for oral exposures should include induction of emesis if indicated, administration of activated charcoal (1 to 5 g/kg in a slurry), a cathartic (magnesium sulfate [250 mg/kg, PO ] or sorbitol [70%, 3 mL/kg, PO]) unless the animal already has diarrhea, and the placement of at least one indwelling catheter for fluid therapy and other supportive medications. The hypotension, which normally develops, should be treated vigorously as in any emergency situation. Any seizures should be treated with diazepam (0.5 to 1 mg/kg, IV). Sucralfate (0.25 to 2 g, PO, tid) should be used as needed. The affected animals should be fed a soft, bland diet.

PROGNOSIS It is interesting to note that in 98 dog cases reported over an 11-year period, clinical signs developed in 76% of the cases, but only seven died or 7.1% of total cases or 9% of those cases in which signs developed (three were euthanized for a true case fatality rate of 5%).8 In more than 751 human cases of castor bean ingestion, 14 died for a 1.8% fatality rate.7

GROSS AND HISTOLOGICAL LESIONS Lesions caused by ingested ricin or castor beans include hepatic necrosis, splenic necrosis, and renal necrosis, along with hemorrhagic gastroenteritis.3,9 The lesions reported following intramuscular ricin exposure in humans include severe local lymphoid necrosis, gastrointestinal hemorrhage, hepatic necrosis, diffuse splenitis, and mild to moderate pulmonary edema. Similar lesions have been reported in experimental animals.2

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DIFFERENTIAL DIAGNOSES The differential diagnoses could be many, depending upon the locale. Those which should be included are garbage poisoning, any other intoxications resulting in gastrointestinal distress (e.g., zinc phosphide, Abrus precatorius—precatory bean, inorganic arsenic, lead, inorganic mercury, thallium, and deoxynivalenol [DON, vomitoxin], and numerous bacterial, viral, neoplastic, and inflammatory gastrointestinal insults. REFERENCES 1. Bradberry SM, Dickers KJ, Rice P et al: Ricin poisoning, Toxicol Rev 22:65, 2003. 2. Franz DR, Jaax NK, Ricin Toxin: In Sidell FR, Takafuji ET, Franz DR, editors: Medical aspects of chemical and biological warfare, 1997, Washington, DC, Office of The Surgeon General at TMM Publications, Borden Institute, Walter Reed Army Medical Center. 3. Greenfield RA, Brown BR, Hutchins JB et al: Microbiological, biological and chemical weapons of warfare and terrorism, Am J Med Sci 323:326, 2002. 4. Rosenbloom M, Leikin JB, Vogel SN et al: Biological and chemical agents: a brief synopsis, Am J Therap 9:5, 2002. 5. Passeron T, Mantoux F, Lacour JP et al: Infectious and toxic cellulitis due to suicide attempt by subcutaneous injection of ricin, Brit J Derm 150:154, 2004. 6. Palatnick W, Tenenbein M: Hepatotoxicity from castor bean ingestion in a child, Clin Tox 38:67, 2000. 7. Rauber A, Heard J: Castor bean toxicity re-examined: a new perspective, Vet Hum Toxicol 27:498, 1985. 8. Albretsen JC, Gwaltney-Brant SM, Khan SA: Evaluation of castor bean toxicosis in dogs: 98 cases, JAAHA 35:229, 2000. 9. Soto-Blanco B, Sinhorini IL, Gorniak SL et al: Ricinus communis poisoning in a dog, Vet Hum Toxicol 44:155, 2002. 10. Balint GA: Ricin: the toxic protein of castor oil seeds, Toxicol 2:77, 1974. 11. Burrows GE, Tyrl RJ: Toxic plants of North America, Ames, 2001, Iowa State University Press. 12. Olsnes S, Kozlov JV: Ricin, Toxicon 39:1723, 2001. 13. Lianmin MA, Chia-Hsuh H, Patterson, E et al.: Ricin depresses cardiac function in the rabbit heart, Toxico.l Appl. Pharmacol 138:72, 1996. 14. Fodstad O, Johannessen JV, Schjerven L et al: Toxicity of abrin and ricin in mice & dogs, J Tox Env Health 5:1073-1084, 1979. 15. Wilhelmsen C, Pitt M: Lesions of acute inhaled lethal ricin intoxication in Rhesus monkeys, (Abstract) Vet Pathol 30(5):482, 1993. 16. Ishiguro M, Tanabe S, Matori Y et al: Biochemical studies on oral toxicity or ricin. IV. A fate of arally administered ricin in rats, J Pharmacobio-Dyn 15:147-156, 1992. 17. Jergens AE: Acute Diarrhea. In Bonagura JD, editor: Kirk’s current veterinary therapy xii. small animal practice, Philadelphia, 1995, WB Saunders Co.

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Snake Bite: North American Pit Vipers

74

Michael E. Peterson, DVM, MS

• Pit viper venoms are a complex combination of enzymatic and nonenzymatic proteins that elicit a wide array of physiological problems. • Clinical signs can be quite varied and can range from mild to severe localized tissue reactions at the bite site to severe systemic problems. • A minimum database should include complete blood count, serum chemistry panel, urinalysis, and coagulation profile. • Treatment options, depending on the clinical presentation, may include hospitalization (minimum of 8 hours), IV fluid therapy, antihistamines, antibiotics, and antivenin. • Prognosis is highly variable; dependent on the toxicity of the venom dose, bite site, and victim’s response.

SOURCES Two families of poisonous snakes, the Elapidae and Crotalidae, populate many portions of the United States. The crotalids are represented by the pit vipers and are found throughout most of the United States. Every state except Maine, Alaska, and Hawaii is home to at least one species of venomous snake. Pit vipers are the largest group of venomous snakes in the United States and are involved in an estimated 150,000 bites annually of dogs and cats.1 Approximately 99% of all venomous snake bites in the United States are inflicted by pit vipers. In North America, members of the family Crotalidae belong to three genera: the rattlesnakes (Crotalus and Sistrurus spp.) and the copperheads and cottonmouth water moccasins (Agkistrodon spp.). 1017

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Pit vipers can be identified by their characteristic retractable front fangs, bilateral heat-sensing “pits” between the nostrils and eyes, elliptical pupils, a single row of subcaudal scales distal to the anal plate, and triangular shaped heads (Figure 74-1). Those members of the Crotalus and Sistrurus genera (the rattlesnakes) have special keratin rattles on the ends of their tails, with the exception of one subspecies (C. catalinensis). Agkistrodon species, the copperheads and water moccasins, are found throughout the Eastern and Central United States. Copperheads are responsible for the majority of venomous snake bites to humans in North America because of their proclivity for living next to human habitation. Water moccasins can be pugnacious and have a greater tendency to deliver venom when they bite. Rattlesnakes (Crotalus spp, Sistrurus spp) are found throughout the continental United States and account for the majority of deaths in both human and animal victims. Clinicians should become familiar with their regional indigenous poisonous snake species.

Heat-sensing "pit" Nostril

Elliptical pupil

Retractable front fang

Fang sheath

Figure 74–1. Anatomy of a pit viper.

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Ninety percent of venomous snake bites occur during the months of April through October. Two thirds of the bites are inflicted by snakes less than 20 inches in length. The heat-sensing pit located between the eye and the nostril can differentiate a temperature gradient of 0.003° C at a distance of 14 inches. These snakes can strike approximately one half of their body length at a speed of 8 ft/sec. The number of puncture wounds from a single bite can be one to six because several ancillary fangs can rotate forward with the strike. Rattlesnakes do not always rattle before striking. Based on clinical observations, it was once thought that pit viper venom was more toxic in the hotter months of the year. However, when individual snake venoms were analyzed, no seasonal variation in patterns of venom proteins was evident over any period of time. The venom is not considered more toxic in the summer months; however, snakes show increased aggression and venom yield with environmental warming and an increased photoperiod (as in the spring and summer).2 The maximum venom yields occur during the hottest months of summer. Pit vipers control the amount of venom that they inject during a bite. The amount of venom injected depends on the snake’s perception of the situation. Initial defensive strikes are often nonenvenomating. Offensive bites meter a given amount of venom into the victim, and agonal bites deliver the entire venom load and are therefore the most dangerous. A decapitated snake head can bite reflexively for up to an hour after decapitation.

TOXIC DOSE The severity of any pit viper bite is related to the volume and toxicity of the venom injected and to the location of the bite, which may influence the rate of venom uptake. As a generalization, the toxicity of pit viper venoms ranges in descending order from the rattlesnakes to the water moccasins and then to the copperheads (Table 74-1). The toxicity of Table 74–1

Venom Yields of North American Snakes Snake Species Eastern diamondback (Crotalus adamanteus) Western diamondback (Crotalus atrox) Mojave rattlesnake (Crotalus scutulatus) Eastern coral (Micrurus fulvius) Copperhead (Agkistrodon contortrix) Cottonmouth (Agkistrodon piscivorus)

Dry Weight (mg venom)

LD50 IV (mice)

200-850 175-800 75-150 2-20 40-75 90-170

1.68 2.18 0.23 0.28 10.92 4.19

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rattlesnake venom varies widely. Nine species and 12 subspecies of rattlesnakes have populations with venoms containing proteins that are immunologically similar to the potent neurotoxin, Mojave toxin. It is possible for pit viper venom to be strictly neurotoxic with virtually no local signs of envenomation. Examples of these venom types are certain subpopulations of rattlesnakes: Mojave rattlesnakes (C. scutulatus) canebrake rattlesnakes (C. horridus atricaudatus), and tiger rattlesnakes (C. tigris).3-5

TOXICOKINETICS It may take weeks for all venom fractions to be cleared by the body. Because of the complexity of the venom, the victim’s metabolic response to the venom components varies with the species of snake, the volume of venom injected, and the species of the bite recipient.

MECHANISM OF TOXICITY Pit viper venoms are a complex combination of enzymatic and nonenzymatic proteins (Box 74-1). The primary purpose of the venom is not to kill, but rather to immobilize the prey and predigest its tissue. The venom is derived from modified salivary glands. The venom is 90% water and has a minimum of 10 enzymes and 3 to 12 nonenzymatic proteins and peptides in any individual snake. The nonenzymatic components, called the “killing fraction,” have a median lethal dose (LD50) more than 50 times smaller than that of the crude venom. More than 60 purified polypeptides have been identified in crotalid venoms. Approximately 50 enzymatic crotalid venom fractions have been characterized. Proteolytic trypsin-like enzymes, which are catalyzed by Box 74–1

Examples of Enzymes from Pit Viper Venoms Arginine ester hydrolase Proteolytic enzymes Thrombin-like enzyme Collagenase Hyaluronidase Phospholipase A2 Phospholipase B Phosphomonoesterase

Phosphodiesterase Acetylcholinesterase RNAse DNAse 5’-Nucleotidase NAD-nucleotidase Lactate dehydrogenase L-Amino acid oxidase

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metals (e.g., calcium, magnesium, and zinc), are common constituents of pit viper venom and cause marked tissue destruction. Arginine ester hydrolase is a bradykinin-releasing agent that may adversely affect clotting activity. Thrombin-like enzymes also can mediate increased clotting activity. The eastern diamondback rattlesnake (C. adamanteus) venom enzyme, protease H, induces systemic hemorrhage.6 Five proteolytic toxins from western diamondback rattlesnake (C. atrox) venom induce hemorrhage by cleaving laminin and the basement membrane at band A.7,8 Crotavirin, found in prairie rattlesnake (C. viridis viridis) venom, is a potent platelet aggregation inhibitor and prevents platelet-collagen interaction by binding to collagen fibers. Interference with the platelet-collagen interaction has the net effect of blocking collagen-mediated platelet functions, such as adhesion, release reaction, thromboxane formation, and aggregation.9 The preponderant mechanism of afibrinogenemia seen in a patient after western diamondback rattlesnake (C. atrox) envenomation is a reflection of fibrinogenolysis and not a primary consumptive coagulopathy. The fibrinogenolysis results from indirect activation of plasminogen by vascular plasminogen activator.10 Differences in venom within a species induced by the age of the snake are highlighted by a study of northern Pacific rattlesnakes (Crotalus viridis organus) in which the adult venoms were shown to have approximately fivefold higher fibrinogenolytic protease activity. Two protease bands were identified in juvenile and subadult snakes, and four bands were identified in adult venom using gel filtration.11 Zinc metalloproteinase with fibrinolytic activity has been isolated from the venom of copperheads (Agkistrodon contortrix) and is called fibrolase. A specific fibrolase cleavage site is in the alpha chain of fibrin. The complexity of the issue of variation of venom components is highlighted by the differences found in fibrinolysis and complement inactivation of venoms from different Blacktail rattlesnakes (Crotalus molossus molossus). In a study of 72 individual Blacktail rattlesnake venoms, the following conclusion was made: there were no venom differences as a function of geographic distribution; however, individual venom variability was significant enough to be identified as an important clinical reality.12 Hyaluronidase, present in most venom, catalyzes the cleavage of internal glycoside bonds and mucopolysaccharides, leading to decreases in the viscosity of connective tissue. Hyaluronidase is commonly called the “spreading factor” since this breakdown facilitates the penetration of other venom components into the tissue. Collagenase is also found in venom, and its major function is to digest collagen, thereby breaking down connective tissue. The enzyme, phospholipase A, is distributed throughout pit viper venoms. This enzyme catalyzes the hydrolysis of fatty ester linkages in

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diacyl phosphatides, which form lysophosphatides and release unsaturated and saturated fatty acids. There are many antigenically different isoenzymes. Some controversy exists about the extent of any neurotoxic effects that these isoenzymes may possess. Many cellular substances may be released by this enzyme, including histamine, kinins, slow-reacting substance, serotonin, and acetylcholine. The extent of the release of these physiologically active compounds most likely depends on the ability of phospholipase A to degrade membranes. The enzyme, phospholipase B, may also be present and is responsible for hydrolyzing lysophosphatides. The phosphodiesterases, such as diester phosphohydrolase, break free the 5-mononucleotide, thereby attacking DNA and RNA and derivatives of arabinose. L-Amino acid oxidase catalyzes oxidation of L-alpha-amino acids and L-alpha-hydroxy acids. This is the most active of the known amino acid oxidases and has been found in all pit viper venoms studied; it is responsible for the yellow color of the venom. Nicotinamide adenine dinucleotide (NAD)-nucleotidase is found in Agkistrodon but not Crotalus venom. The enzyme catalyzes hydrolysis of nicotinamide N-ribosidic linkages of NAD, forming adenosine diphosphate riboside and nicotinamide. Other enzymes that are possibly present in viper venom include RNAse, DNAse, 5′-nucleotidase, and lactate dehydrogenase. Direct cardiotoxic effects of venom proteins have been exhibited in some pit viper venoms, particularly the diamondback rattlesnakes. A key point is that the envenomation syndrome reflects the complexity of the venom. The body has to respond to the effects of multiple venom fractions, metabolize each, and deal with the resultant myriad of metabolites. In addition to the individual pharmacological properties of these proteins and their metabolites, it has been demonstrated that some components act synergistically in producing specific effects or reactions. The net effect of this interaction of venom with the victim’s response is a metabolic stew of toxic peptides and digestive enzymes. Additionally the traditional categorization of pit vipers as having only hematotoxic venoms should be reevaluated because some subpopulations of rattlesnakes possess only neurotoxic venom. The average rattlesnake needs 21 days to replenish expended venom. The “lethal fraction” peptides are the first to regenerate. This adds yet another variable to any given envenomation.

CLINICAL SIGNS The onset of clinical signs after a snake bite may be delayed for several hours (Box 74-2). In humans it is estimated that 20% of all pit viper bites

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Box 74–2

Common Signs of Envenomation Pain Swelling Ecchymosis Weakness

Sloughing tissue Shock Puncture(s) Nausea

are nonenvenomating (i.e., dry), with an additional 25% classified as mild envenomations. It is for this reason that so many antidotal treatments are championed, and it also emphasizes the necessity to rely on scientific evaluation for the various treatment modalities proposed. Every pit viper envenomation is different for many reasons (Box 74-3). The severity of an envenomation is additionally altered by factors, such as species of victim, body mass, location of bite, postbite excitability, and use of premedications (e.g., nonsteroidal antiinflammatory drugs in older dogs that may make the dog more susceptible to clotting defects). The snake affects the severity of the envenomation by species and size of snake, age of snake, motivation of snake, and degree of venom regeneration since last use. Cats are more resistant, on the basis of milligram of venom per kilogram body mass, to pit viper venom than dogs. However, cats are generally presented to veterinary care facilities in a more advanced clinical condition. This is probably caused by the cat’s smaller body size and the proclivity of cats to play with the snake, thereby antagonizing it and inducing an offensive strike, often to the torso. Additionally, cats commonly run off and hide after being bitten before they return home to allow the owner to identify the injury, thus delaying the time from bite to veterinary care. Because dogs generally receive more defensive strikes, have a larger body mass, and more frequently seek immediate human companionship after injury, they are more likely to receive medical attention promptly.

Box 74–3

Variables Affecting the Severity of Envenomation Victim Body mass Bite location Time to medical facility Type of first aid applied Concurrent medications (Nonsteroidal antiinflammatory drugs, etc.)

Snake Species Size Age of snake Motivation for bite Time since last venom use Time of year

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It is possible that a life-threatening envenomation may occur with no local clinical signs other than the puncture wounds themselves. This seems particularly true of those snake species with primary neurotoxic venoms (Box 74-4). Local tissue reactions to pit viper envenomation include puncture wounds, one to six from a single bite, which may be bleeding. Occasionally these fang wounds appear as small lacerations. Rarely, local swelling can obscure puncture wounds from small snakes. Rapid onset of pain may ensue with development of progressive edema. Ecchymosis and petechiation may become manifest. Tissue necrosis may occur, particularly in envenomations to areas without a significant subcutaneous tissue mass. The presence of fang marks does not indicate that envenomation has occurred, only that a bite has taken place. It must be reiterated that the severity of local signs does not necessarily reflect the severity of the systemic envenomation. Systemic clinical manifestations encompass a wide variety of problems, including pain, weakness, dizziness, nausea, severe hypotension, thrombocytopenia, fasciculations, regional lymphadenopathy, alterations in respiratory rate, increased clotting times, decreased hemoglobin, abnormal electrocardiogram, increased salivation, echinocytosis of red cells, cyanosis, proteinuria, bleeding (e.g., melena, hematuria, and hematemesis), obtundation, and convulsions. Not all of these clinical manifestations are seen in each patient, and they are listed in descending order of frequency as seen in human victims. Severe hypotension results from pooling of blood within the shock organ of the species bitten (i.e., the hepatosplanchnic [dogs] or pulmonary

Box 74–4

Species of Rattlesnakes That Have Populations Containing Neurotoxin Crotalus durissus durissus Crotalus durissus terrificus var. cumanensis Crotalus durissus terrificus (Brazil) Crotalus horridus atricaudatus Crotalus lepidus klauberi Crotalus mitchellii mitchellii Crotalus tigris Crotalus vegrandis Crotalus viridis abyssus Crotalus viridis concolor Crotalus scutulatus scutulatus (venom A) Crotalus scutulatus salvini Sistrurus catenatus catenatus

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[cats] vascular bed) and fluid loss from the vascular compartment secondary to severe peripheral swelling. This swelling can be great. A 2-cm increase in the circumference of a human’s swelling thigh can incorporate one third of the patient’s circulating fluid volume.13 Often this swelling is not edema, but rather caused by extravascularized blood, resulting from damage to blood vessel walls as a result of swelling and rupturing of the endothelial cells of the microvasculature, leaving large gaps in the vessel walls. The victim’s clotting anomalies largely depend on the species of snake involved (Figure 74-2). Coagulopathies range from direct blockage or inactivation of various factors in the patient’s clotting cascade to the possible destruction of megakaryocytes in the circulating blood and bone marrow (Box 74-5). A coagulopathy, with prolonged clotting times, develops in approximately 60% of envenomated patients; by far the most common is hypofibrinogenemia. Venom induced thrombocytopenia occurs in approximately 30% of envenomations with an untreated nadir usually occurring between 72 and 96 hours. Some venom fractions inhibit platelet adhesion. Other pit viper venoms do not affect clotting per se, but rather destroy clots once they are formed by initiating aggressive fibrinolysis. Syndromes resembling diffuse intravascular coagulation (DIC) are possible with pit viper envenomations.

Factor X

Factor Xa

Factor V

Venom A Prothrombin Fibrinogen

Fibrin Venom B

(fibrinolysis) Venom C

Thrombin Fibrin split products

Venom A Crotalus horridus (timber rattlesnake) Crotalus viridis helleri (Southern Pacific Crotalus viridis helleri (Southern Pacific rattlesnake) rattlesnake) Venom C Venom B Crotalus atrox (Western diamondback Agkistrodon contortrix (copperhead) rattlesnake) Agkistrodon piscivorus (cottonmouth) Crotalus molossus molossus (Blacktail Crotalus adamanteus (Eastern diamondrattlesnake) back rattlesnake) Figure 74–2. Venom effects on clotting mechanisms.

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Box 74–5

Pit Viper Envenomations: Hemostatic Defects Consumption coagulopathy Diffuse vascular damage DIC-like syndrome Localized massive clotting Hyperfibrinolysis Thrombocytopenia (independent from consumption coagulopathy above) Blood vessel injury

Myokymia, a type of fasciculation of various muscle groups, is frequently reported in humans after bites received by timber rattlesnakes (Crotalus horridus horridus) and Western diamondback rattlesnakes (Crotalus atrox).14

MINIMUM DATABASE Monitoring the severity and progression of the clinical envenomation syndrome may be difficult. A tool that has proven useful is the envenomation severity score system (Box 74-6). Use of this system more accurately quantifies the severity of the patient’s condition over time and allows a more objective assessment of the patient.15 It is recommended that a severity score be assessed on entry, 6 hours, 12 hours, and 24 hours after initial hospitalization. A complete blood count with differential, including platelet counts, should be obtained; red blood cell morphology along with baseline serum chemistry with electrolytes should be collected. A coagulation profile should be obtained, including activated clotting times, prothrombin time (PT), activated partial thromboplastin time (PTT), fibrinogen, and fibrin degradation products. Urinalysis with macroscopic and microscopic evaluations, including free protein and hemoglobin and myoglobin, should be performed. An electrocardiogram may be indicated in animals with significant envenomations. These laboratory tests should be repeated periodically to monitor the progression of the syndrome and/or the effectiveness of therapy. Significant rhabdomyolysis may also be seen with large increases in creatine phosphokinase and urine myoglobin levels, particularly in envenomations by snakes with potent neurotoxins (e.g., Mojave, Canebreak, and Tiger rattlesnakes). Tiger rattlesnake venom (Crotalus tigris) has been characterized as having a low protease activity, no hemolytic activity, and toxins that have complete immunoidentity with the potent neurotoxins, crotoxin and Mojave toxin.3

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Box 74–6

Snakebite Severity Score System Pulmonary System

Signs within normal limits Minimal—slight dyspnea Moderate—respiratory compromise, tachypnea, use of accessory muscles Severe—cyanosis, air hunger, extreme tachypnea, respiratory insufficiency or respiratory arrest from any cause

0 1 2 3

Cardiovascular System

Signs within normal limits Minimal—tachycardia, general weakness, benign dysrhythmia, hypertension Moderate—tachycardia, hypotension (but tarsal pulse still palpable) Severe—extreme tachycardia, hypotension (nonpalpable tarsal pulse or systolic blood pressure < 80 mm Hg), malignant dysrhythmia or cardiac arrest

0 1 2 3

Local Wound

Signs within normal limits Minimal—pain, swelling, ecchymosis, erythema limited to bite site Moderate—pain, swelling, ecchymosis, erythema involves less than half of extremity and may be spreading slowly Severe—pain, swelling, ecchymosis, erythema involves most or all of one extremity and is spreading rapidly Very severe—pain, swelling, ecchymosis, erythema extends beyond affected extremity, or significant tissue slough

0 1 2 3 4

Gastrointestinal System

Signs within normal limits Minimal—abdominal pain, tenesmus Moderate—vomiting, diarrhea Severe—repetitive vomiting, diarrhea, or hematemesis

0 1 2 3

Hematological System

Signs within normal limits Minimal—coagulation values slightly abnormal, PT