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LOOMIS'S ESSENTIALS of TOXICOLOGY
FOURTH EDITION

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LOOMIS'S ESSENTIALS of TOXICOLOGY
FOURTH EDITION

Ted A. Loomis, M.D., Ph.D.
University of Washington School of Medicine Seattle, Washington

A. Wallace Hayes, Ph.D.
Corporate Product Integrity The Gillette Company Boston, Massachusetts

ACADEMIC PRESS
San Diego New York Boston London SydneyTokyo Toronto

This book is printed on acid-free paper.

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Copyright © 1996 by Ted A. Loomis and A. Wallace Hayes Copyright © 1978, 1974, 1968 by Ted A. Loomis All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, withoutpermission in v^riting from the publisher.

Academic Press, Inc.

A Division of Harcourt Brace & Company 525 B Street, Suite 1900, San Diego, California 92101-4495

United Kingdom Edition published by Academic Press Limited 24-28 Oval Road, London NWl 7DX Library of Congress Cataloging-in-Publication Data Loomis, Ted A. Essentials of toxicology / by Ted A. Loomis, A. Wallace Hayes. ~ 4th ed. p. cm.Includes index. ISBN 0-12-455625-6 (alk. paper) 1. Toxicology. I. Hayes, A. Wallace (Andrew Wallace), date. II. Title. RA1211.L6 1996 615.9-dc20 95-41426 CI? PRINTED IN THE UNITED STATES OF AMERICA 96 97 98 99 00 01 MM 9 8 7 6 5

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CONTENTS
Preface xi Chapter 1 INTRODUCTION, SCOPE, AND PRINCIPLES History 3 Scope of Modern Toxicology 4 Environmental Toxicology 6 Economic Toxicology8 Medical Toxicology 10 Fundamental Principles in Toxicology 12 Chapter 2 NUMBERS IN TOXICOLOGY Dose 17 Dose-Response Relationships 19 Statistical Concepts and LDsos 22 Potency versus Toxicity 23 Safety versus Toxicity 26 Hypersensitivity and Hyposensitivity 29 Response Concepts for Compounds Essential to the Biologic System 30 Chapter 3 BIOLOGIC FACTORS THAT INFLUENCE TOXICITY Absorption andTranslocation of Chemicals 34 Reserve Functional Capacity 40 Accumulation and Storage of Chemicals in the Organism 41 Tolerance 44

vi Chapter 4 CHEMICAL FACTORS THAT INFLUENCE TOXICITY Nonspecific Chemical Action 48 Selective Chemical Action 48 Effect of Ionization and Lipid Solubility on Translocation of Chemicals 50 Biotransformation Mechanisms 55 Chapter 5

Contents

INFLUENCE OF ROUTE OFADMINISTRATION ON SYSTEMIC TOXICITY Percutaneous Route 72 Inhalation Route 74 Oral Route 76 Parenteral Routes 79

Chapter 6

GENETIC FACTORS THAT INFLUENCE TOXICITY The Genetic Mechanism 85 Chemicals as Mutagens 87 Principles of Genetic-Induced Chemical Toxicity 8{ Discovery and Classification of Genetic-Induced Chemical Toxicity 89 Genetic Factors in Accumulation of Chemicals 94 GeneticFactors in Prolongation of Action of Chemicals 95 Genetic Factors in Increased Sensitivity to Chemicals 96 Drug-Sensitive Hemoglobins 97 Genetic Factors in Species and Strain Resistance to Toxicity 99

Chapter 7

CLASSIFICATION OF HARMFUL EFFECTS OF CHEMICALS Drug-Induced Toxicity 101 Chemicals Intentionally Administered to Biologic Specimens 103 Chemicals Not Intended for Administration to BiologicSpecimens 103

Contents

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Expected or Normal Effects of Chemicals 103 Unexpected or Abnormal Effects of Chemicals 104 Chapter 8 NORMAL TOXIC EFFECTS OF CHEMICALS Harmful Effects of Chemicals Not Intended for Introduction into Biologic Systems 107 Harmful Effects of Chemicals Intended for Introduction into Biologic Systems 112 Chapter 9 ABNORMAL RESPONSE TO CHEMICALS The ImmuneMechanism 122 Initial Exposure to Haptens—The Sensitizing Systems 123 Subsequent Exposure to Haptens—The Allergic Reaction 125 The Immune Mechanism in Toxicology 125 Immune Mechanisms in Clinical Toxicology 130 Activation and Suppression of the Immune System 133 Chapter 10 THE BASIS OF SELECTIVE TOXICITY Selective Toxicity Due to Translocation Mechanisms 138 Selective Toxicity Due to Biotransformation...
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