Toxicology A Case-Oriented Approach - part 1 pdf

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 toxic

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TOXICOLOGY A Case-Oriented

Approach

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C RC PR E S S

Boca Raton London New York Washington, D.C

John Joseph Fenton

Approach

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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.

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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

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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

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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

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to Marjorie

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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

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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

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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,

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Measuring Toxicity

CONTENTS

Qualitative Descriptions of Toxicity

Exposure Limits

Determination of LD50 and Graphical Representations

ED50 and LD50

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 LD50 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 LD50 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 LD50, we suspect that it is also dangerous to health in exposures below the LD50 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 LD50 If the exposure is several orders

of magnitude less than the LD50 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 LD50 A second problem with the LD50 is that it has a large uncertainty associated with it even in the prediction

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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

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

Stages in Work-Up of Suspected Poisoning

Evaluation Stabilization History and physical Toxidrome?

Laboratory testing Management Decontamination Enhanced elimination Administration of antidote

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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

The Structure 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 sophis-ticated 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 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 100% specific Why is there little uniformity among healthcare institutions in regard to the extent of their test menus? This is, to some 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 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

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