Lu’s Basic Toxicology Lu’s Basic Toxicology Fourth Edition Fundamentals, target organs and risk assessment Frank C. Lu Consultant in Toxicology Miami, Florida U.S.A. Sam Kacew Professor of Pharmacology University of Ottawa, Ontario Canada London and New York First published 2002 by Taylor & Francis 11 New Fetter Lane, London EC4P 4EE Simultaneously published in the USA and Canada by Taylor & Francis Inc, 29 West 35th Street, New York, NY 10001 Taylor & Francis is an imprint of the Taylor & Francis Group This edition published in the Taylor & Francis e-Library, 2003. © 2002 Frank C. Lu and Sam Kacew All rights reserved. No part of this book may be reprinted or reproduced or utilized in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Every effort has been made to ensure that the advice and information in this book is true and accurate at the time of going to press. However, neither the publisher nor the authors can accept any legal responsibility or liability for any errors or omissions that may be made. In the case of drug administration, any medical procedure or the use of technical equipment mentioned within this book, you are strongly advised to consult the manufacturer’s guidelines. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record has been requested ISBN 0-203-36143-1 Master e-book ISBN ISBN 0-203-37399-5 (Adobe eReader Format) ISBN 0-415-24856-6 (PB) ISBN 0-415-24855-8 (HB) Contents About the authors xiii Preface xv PART I General principles of toxicology 1 1 General considerations 3 Definition and purpose of toxicology 3 Scope and subdisciplines 4 Early developments 5 Recent developments 5 Some challenges and successes 7 Toxicity vs. other considerations 8 Future prospects 9 References 11 Appendix 1.1 U.S. laws that have a basis in toxicology 11 Appendix 1.2 Examples of outbreaks of mass poisoning 12 2 Absorption, distribution, and excretion of toxicants 13 Introduction 13 Absorption 17 Distribution 19 Excretion 21 Levels of toxicants in the body 23 References 25 3 Biotransformation of toxicants 26 General considerations 26 vi Contents Phase I (degradation) reactions 27 Phase II (conjugation) reactions 29 Bioactivation 32 Complex nature of biotransformation 35 References 37 Appendix 3.1 Examples of bioactivation 38 4 Toxic effects 39 General considerations 40 Spectrum of toxic effects 40 Target organs 43 Mechanisms of action 45 Molecular targets: chemical nature 47 Receptors 50 References 54 5 Modifying factors of toxic effects 56 General considerations 56 Host factors 57 Environmental factors 64 Chemical interaction 65 References 67 Appendix 5.1 Mechanisms underlying certain modifying factors 69 Appendix 5.2 Strain-related differences in drug-induced responses 70 PART II Testing procedures for conventional and nontarget organ toxicities 71 6 Conventional toxicity studies 73 Introduction 74 Acute toxicity studies 75 Short-term and long-term toxicity studies 81 Good laboratory practice 85 References 86 Additional reading 87 Appendix 6.1 General observations, clinical laboratory tests, and pathology examinations that may be used in short- and long-term toxicity studies 88 Contents vii 7 Carcinogenesis 89 Introduction 90 Mode of action 92 Categories of carcinogens 95 Some human carcinogens/target organs 100 Tests for carcinogenicity 101 Evaluation 105 References 108 Additional reading 110 Appendix 7.1 Probable carcinogenic chemicals 110 Appendix 7.2 Biomarkers of carcinogenesis/human cancers 111 8 Mutagenesis 113 Introduction 114 Gene mutation 116 Chromosomal effects 121 DNA repair and recombination 124 Other tests 125 Evaluation 125 References 127 9 Developmental toxicology130 Introduction 131 Teratogens (developmental toxicants) and their effects 133 Mode of action 134 Teratogens of special interest 136 Testing procedures 137 Evaluation of teratogenic effects 138 References 139 Appendix 9.1 Teratogens in animal models 140 10 Lactation 142 General remarks 142 Benefits of breast-feeding 143 Toxicants 146 References 150 viii Contents PART III Target organs and systems 153 11 Toxicology of the immune system 155 General considerations 155 Components of the system 156 Immunotoxicants 159 Immunotoxicities: testing procedures 162 Evaluation 165 References 166 Additional reading 167 12 Respiratory system: inhalation toxicology 168 Introduction 169 Toxicants and their effects 170 Testing procedures 174 Evaluation 177 References 178 Appendix 12.1 Site of action and pulmonary disease produced by selected occupationally inhaled toxicants 180 Appendix 12.2 Mechanisms underlying the oxidative stress induced by cigarette smoke 181 13 Toxicology of the liver 182 General considerations 183 Types of liver injury 184 Hepatotoxicants 188 Testing procedures 189 Evaluation 191 References 192 Appendix 13.1 Examples of hepatotoxic agents and associated liver injury 195 14 Toxicology of the kidney 196 Introduction 197 Nephrotoxicants: mechanism and site of action 200 Testing procedure 202 Evaluation 206 References 207 Additional reading 208 Contents ix 15 Toxicology of the skin 209 General considerations 209 Types of toxic effects and dermatotoxicants 211 Testing procedures 215 Evaluation 217 In vitro tests 217 References 218 Appendix 15.1 Primary irritation 219 16 Toxicology of the eye 221 General considerations 221 Toxicants and site of their effects 223 Testing procedures 227 Evaluation 229 References 230 Appendix 16.1 Cataractogenic chemicals 231 Appendix 16.2 Grading of eye irritation 232 17 Toxicology of the nervous system 233 Introduction 234 Neurotoxic effects and neurotoxicants 236 Testing procedures 243 Behavioral studies: testing procedures 245 Evaluation 247 References 247 Appendix 17.1 Select neurotoxicants described in text 249 18 Reproductive and cardiovascular systems 251 Reproductive system 252 Introduction 252 Toxicants and their effects 254 Routine testing: multigeneration reproduction studies 256 Other tests 258 Cardiovascular system 258 General considerations 258 Toxic effects on the heart 260 Toxic effects on blood vessels 262 Testing procedures 263 References 265 x Contents PART IV Toxic substances and risk assessment 267 19 Food additives and contaminants 269 Introduction 270 Toxicological testing and evaluation 272 Additives of toxicological concern 274 Indirect additives and contaminants 276 Contaminants 278 References 281 Appendix 19.1 Major functional groups of direct food additives 283 20 Toxicity of pesticides 285 Introduction 286 Categories of pesticides 287 Toxicological properties 291 Testing, evaluation, and control 295 Gulf War Syndrome 297 References 299 Appendix 20.1 Toxicological findings and evaluation on certain insecticides 301 21 Toxicity of metals 302 Introduction 303 Certain common features 304 Common toxic effects 308 Metals of major toxicological concern 310 Risk/benefit considerations 317 References 321 22 Over-the-counter preparations 324 General remarks 324 Prevalence in society 325 Adverse consequences 326 References 330 Contents xi 23 Environmental pollutants 333 General remarks 334 Air pollutants 335 Water and soil pollutants 339 References 343 24 Occupational toxicology346 General remarks 347 Exposure limits 348 Occupational toxicants 350 Monitoring 356 References 357 Appendix 24.1 Acute pesticide toxicity, general signs and symptoms in humans 359 25 Toxicologic evaluation: assessment of safety/risk 361 Introduction 362 Major approaches 363 Acceptable daily intake (ADI/RfD)/safety assessment 364 Mathematical models/risk assessment 368 Other procedures 373 International activities in toxicological evaluation 374 References 376 Chemical index 380 Subject index 386 About the authors Frank C. Lu, MD, is a Consulting Toxicologist in Food Additives, Pesti- cides, and Environmental Chemicals, and the Managing Editor of the journal Biomedical and Environmental Sciences. He is also an Honorary Professor at the Chinese Academy of Preventive Medicine. His previous positions include Professor of Pharmacology at the University of Miami, Chief of the Food Additives Unit of the World Health Organization (WHO), and Head of the Pharmacology and Toxicology Section of the Canadian Food and Drug Directorate (FDD). At FDD, he conducted and participated in testing the toxicity of a variety of food additives, contami- nants, pesticides, and drugs, and was in charge of assessing their safety. In addition, he was responsible for drafting new sets of Toxicological Requirements for New Drugs and for Food Additives and Pesticides. At WHO, he was the Scientific Secretary to the Joint FAO/WHO Expert Committee on Food Additives and Contaminants, and to the Joint FAO/WHO Meeting on Pesticide Residues. These expert bodies were responsible for assessing the safety of these chemicals on the basis of all available data. He was also the Chief Liaison Officer for WHO to the inter-governmental body, the Codex Alimentarius Commission. A Charter Member of the Society of Toxicology, he is a recipient of the International Achievement Award from the International Society of Pharmacology and Toxicology. In 1994 the Frank C. Lu Foundation for Advancement of Pre- ventive Medicine was established in China to honor him and his work. He received the Magnolia Award in 2000 from the Shanghai Municipal Government for his assistance