TOXICOLOGY A Case-Oriented Approach CRC PRESS Boca Raton London New York Washington, D.C. John Joseph Fenton TOXICOLOGY A Case-Oriented Approach This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. Visit the CRC Press Web site at www.crcpress.com © 2002 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-0371-0 Library of Congress Card Number 2001035682 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper Library of Congress Cataloging-in-Publication Data Fenton, John Ph.D. Toxicology : a case-oriented approach / John Fenton. p. cm. Includes bibliographical references and index. ISBN 0-8493-0371-0 (alk. paper) 1. Toxicology Case studies. I. Title. [DNLM: 1. Toxicology Case Report. Poisons Case Report. QV 600 F342t 2001] RA1219 .F46 2001 615.9 ′ 07—dc21 2001035682 CIP 0371 fm frame Page 4 Wednesday, August 29, 2001 11:20 AM Preface This book is an outgrowth of the author’s experience teaching a toxicology course for 12 years at West Chester University and his interactions with physicans and laboratory toxicologists for 24 years in the Crozer Keystone Health System. These experiences provided valuable insights into the needs both groups have for an enhanced understanding of toxicology in the laboratory and in the emergency depart- ment. Accordingly, the present volume was written in hopes of meeting the require- ments of both physicians and laboratory toxicologists by presenting the analytic and clinical aspects of toxicology. Many excellent books are available that address the diagnosis and treatment of the overdose patient. Other fine volumes, intended for a scientific audience, have been written that provide test methods and explanations of instrumental modalities for toxicology testing. The present book is the only one, to the author’s knowledge, that speaks equally to both audiences, the caregiver and the analytical scientist. The reader will find that this book, although less clinical than medical toxicology texts, and less chemical than analytical works, is, nevertheless, heavily vested in both clinical and analytical aspects of toxicology. Scientists can provide better test results if they understand the problems of the clinician. Physicians can employ the labora- tory more effectively if they understand the nature, power, and limitations of toxi- cology testing. We hope that this book will meet these needs. Case studies are a popular and effective means of teaching concepts. Pedagogic research has shown that people tend to remember information that is presented in the form of case studies. Students also enjoy the narrative approach characteristic of such studies. Accordingly, the present volume features a very large number of case studies, all of which are cross-referenced to the clinical literature. They were selected for their interest and their ability to teach important aspects of toxicology. The reader is challenged in each case to identify an unknown toxin and may, in fact, make the identification on the basis of his/her knowledge of symptoms, physical properties of toxins, and so on. The level of medical knowledge required to fully understand each case presented here is not insignificant. Some students who have very little clinical experience will find them very challenging. It is the author’s belief, however, that even without a complete understanding of every aspect of each clinical history presented here, one can derive a great deal of benefit by reading the case studies and trying to answer the questions and problems. The author has endeavored to maintain the reader’s interest in other ways as well. For example, many interesting anecdotes from the history of toxicology are found throughout the text. The alleged arsenical poisonings of Napoleon and of President Taylor, the probable mercury overdose of Isaac Newton, and the hemlock ingestion of Socrates are just a few examples of the many famous facts or fiction 0371 fm frame Page 5 Monday, August 27, 2001 1:35 PM that are part of the history of toxicology. Such events teach us about the nature of life in the past and the specific dangers that toxins presented to our ancestors. The author wishes to thank the many who have contributed to his teaching and toxicology experiences. It has always been a pleasure working with young people as they start their careers in science. I have also been continuously impressed by the dedication and effort that the toxicology staff at Crozer Keystone Health System brought to their jobs everyday. In their company and that of many other members of the hospital staff we learned toxicology in the “real world.” John Fenton, Ph.D. Philadelphia 0371 fm frame Page 6 Monday, August 27, 2001 1:35 PM Dedication to Marjorie 0371 fm frame Page 7 Monday, August 27, 2001 1:35 PM Table of Contents Chapter 1 History of Toxicology Chapter 2 Measuring Toxicity Chapter 3 Therapy Chapter 4 The Role of the Laboratory in Diagnosis and Treatment of Poisoning Chapter 5 Introductory Toxicokinetics Chapter 6 Biotransformation Chapter 7 Hepatic Toxicity Chapter 8 Renal Toxicology Chapter 9 Cardiac Toxicity Chapter 10 Neurological Toxicity Chapter 11 Pulmonary Toxicology Chapter 12 Drug Testing: Screening 0371 fm frame Page 9 Monday, August 27, 2001 1:35 PM Chapter 13 Confirmatory Tests in Toxicology Chapter 14 Metal Analysis (Assay of Toxic Metals) Chapter 15 Alcohols Chapter 16 Toxic Gases Chapter 17 Insecticides Chapter 18 Metals Chapter 19 Over-the-Counter Analgesics Chapter 20 Drugs of Abuse Chapter 21 Sedatives and Hypnotics Chapter 22 Stimulants Chapter 23 Anticholinergic Drugs Chapter 24 Psychedelic Drugs Chapter 25 Plants Chapter 26 Snake Venoms 0371 fm frame Page 10 Monday, August 27, 2001 1:35 PM © 2002 by CRC Press LLC History of Toxicology CONTENTS Ancient Times Antidotes Middle Ages Poisoners Advances in Toxicology Therapy Modern Toxicology The Problem of Poisoning Poison Control Centers Interpretation of PCC Data References Questions and Exercises ANCIENT TIMES The history of poisons dates to earliest times. Ancient man undoubtedly observed toxic effects in nature partly on a serendipitous basis as, for example, when he noted a harmful or fatal effect follow the casual ingestion of some plant or animal product by one of his fellow tribesmen. But serendipity was not the only mechanism of discovery. Assuredly, man experimented with natural products in an effort to improve his arsenal of weapons, the better to achieve success when waging war with his enemies. Modern toxicology is characterized by extremely sophisticated scientific inves- tigation and evaluation of toxic exposures of all kinds. To a large degree this has been made possible by the widespread application of computers to analytical equip - ment. Coupled with other chemical and electronic innovations modern instruments can detect quantities of toxins that are much smaller than those that could be measured in the past. Analytic methods are not only highly sensitive but they are also capable of extreme specificity so that compounds can be implicated in poisoning episodes to the near certain exclusion of other highly similar compounds. In the course of this text the reader will learn to appreciate the sophistication and applica - tion of technologies such as chromatography-mass spectrometry, inductively coupled plasmas, and many of the novel ways that antibodies have been employed to allow rapid and sensitive drug detection. In modern times most poisoning episodes relate to synthetic products. Obviously, at an earlier and simpler time before technology permitted us to make better toxins, 1 © 2002 by CRC Press LLC Measuring Toxicity CONTENTS Qualitative Descriptions of Toxicity Exposure Limits Determination of LD 50 and Graphical Representations ED 50 and LD 50 Units in Toxicology Problems QUALITATIVE DESCRIPTIONS OF TOXICITY There are many ways to express the relative toxicity of a substance. In one of the simplest methods, toxins have been divided into six groups (Table 2.1). There are several shortcomings in the above qualitative description of relative toxicity. One such weakness is the width of each category. A second problem is the imprecision of the terminology. The term supertoxin, for example, is not clear. An alternative semi-quantitative description which has the advantage of showing the extremes of toxicity is depicted in Table 2.2. This shows that the lethality of known substances can vary over an incredibly wide range of 10 orders of magnitude, extending from ethyl alcohol (which is not entirely innocuous) to botulinus toxin. These categorizations are helpful only in providing an approximate idea of relative toxicity. While they allow one to appreciate relative magnitudes of toxicity, they avoid the inherent complexity of the subject. The LD 50 is the main statistic used in most toxicology studies. It is described in greater depth below. For now, it is sufficient to state that it represents the dose of a toxin which will kill 50% of a group of test subjects. While this is a valuable quantity to be aware of it is inadequate in terms of fully understanding the inherent danger present in certain substances. For one thing, the LD 50 describes only one end-point, death. Organ damage, cancer induction, and other dangers present in substances, while they are less serious outcomes than death are, nevertheless, extremely undesirable. If a substance has a low LD 50 , we suspect that it is also dangerous to health in exposures below the LD 50 . While this is usually true, it does not clearly define the problem. In other words, there are many substances to which we are exposed in amounts well below the LD 50 . If the exposure is several orders of magnitude less than the LD 50 we might, perhaps, feel entirely safe. This is inappropriate because the potential for health damage to a degree which falls short of killing a subject cannot be predicted on the basis of the LD 50 . A second problem with the LD 50 is that it has a large uncertainty associated with it even in the prediction 2 [...]... Therapy CONTENTS Approach to Treatment History and Physical Examination Management Decontamination Emesis (Vomiting) Orogastric Lavage Activated Charcoal Whole Bowel Irrigation Enhanced Elimination Dialysis and Hemoperfusion Antidotes Questions and Exercises Reference The primary goal of this book is to understand toxicology from a scientific perspective It is not intended to be a guide toward treatment,... an area which is covered in much greater detail in other fine texts Therefore, this chapter deals with treatment in a brief manner with the emphasis on the scientific aspects of the therapy of poisoning Stages in Work-Up of Suspected Poisoning Evaluation Stabilization History and physical Toxidrome? Laboratory testing Management Decontamination Enhanced elimination Administration of antidote APPROACH. .. antidote APPROACH TO TREATMENT The first step in the treatment of a potential poisoning is the stabilization of the patient The attending physician must assure that the patient’s vital functions are © 2002 by CRC Press LLC 4 The Role of the Laboratory in Diagnosis and Treatment of Poisoning CONTENTS Current Practices Value and Limitations of Laboratory Testing Laboratory Accuracy or Error Outcome Studies... very common or a part of routine medical practice This latter group of laboratories would test, for example, for digoxin, a cardioactive drug that is often involved in overdoses Such labs might also test for the most common drugs of abuse These tests would be urine-based, qualitative, and usually less than 10 0% specific Why is there little uniformity among healthcare institutions in regard to the extent... extent, a function of the specific mission of the medical center For example, an urban institution located where drug abuse is a severe problem would be more likely to develop elaborate toxicology laboratory facilities Further, the directors of laboratory facilities do not always agree on what the precise role of drug testing should be Opinions differ Some pathologists and laboratory scientists have great... of Clinical Toxicology Testing Questions References CURRENT PRACTICES There is a wide disparity in the emphasis placed on toxicology testing in modern hospitals Some hospitals have extensive toxicology testing with relatively sophisticated instruments that are dedicated to the detection and measurement of poisons Many others do little or no testing for poisons except for those toxins that are very... precise role of drug testing should be Opinions differ Some pathologists and laboratory scientists have great faith in the ability of the toxicology laboratory to help the attending physician Other laboratory directors are of the opinion that limited medical resources are better directed at other areas © 2002 by CRC Press LLC . 03 71 fm frame Page 9 Monday, August 27, 20 01 1:35 PM Chapter 13 Confirmatory Tests in Toxicology Chapter 14 Metal Analysis (Assay of Toxic Metals) Chapter 15 Alcohols Chapter 16 . the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper Library of Congress Cataloging-in-Publication Data Fenton, John Ph.D. Toxicology : a case-oriented approach / John. LLC Therapy CONTENTS Approach to Treatment History and Physical Examination Management Decontamination Emesis (Vomiting) Orogastric Lavage Activated Charcoal Whole Bowel Irrigation Enhanced Elimination Dialysis