mechanisms and concepts in toxicology

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Mechanisms and Concepts in Toxicology

Mechanisms and Concepts inToxicology

WNORMAN ALDRIDGERobens Institute of Health and Safety

University of Surrey

UK Taylor amp Francis Ltd 1 Gunpowder Square London EC4A 3DE

USA Taylor amp Francis Inc 1900 Frost Road Suite 101 Bristol PA 19007

This edition published in the Taylor amp Francis e-Library 2005

ldquoTo purchase your own copy of this or any of Taylor amp Francis or Routledgersquos collection of thousands of eBooks please go towwweBookstoretandfcoukrdquo

Copyright copy WNorman Aldridge 1996

All rights reserved No part of this publication may be reproduced stored in a retrievalsystem or transmitted in any form or by any means electronic electrostatic magnetic

tape mechanical photocopying recording or otherwise without the prior permission ofthe copyright owner

British Library Cataloguing in Publication DataA catalogue record for this book is available from the British Library

ISBN Master e-book ISBN

ISBN (Adobe eReader Format)ISBN 0-7484-0413-9 (cased)

ISBN 0-7484-0414-7 (paperback)

Library of Congress Cataloguing Publication Data are available

Cover design by Youngs Design in Production

Contents

Preface ix

Acknowledgements xi

1 Scope of Toxicology 1

11 Toxicology and mechanisms of toxicity 1

12 Definition of toxicology and toxicity 3

13 Origin and types of exposure 7

14 Discussion 8

15 Summary 9

2 Stages in the Induction of Toxicity 10

21 Introduction 10

22 Five stages in toxicity 11

23 Exposure and entry of chemicals 11

24 Delivery of intoxicant 12

25 Interactions with targets 13

26 Early changes and clinical consequences 13

27 Discussion 14

28 Summary 15

3 Kinetics and End-points 16

31 Introduction 16

32 Reversible interactions 17

33 Covalent interactions 19

34 Michaelis constants 22

35 Criteria to distinguish reversible from covalent interactions 23

36 In vivo kinetics 24

37 Discussion 25

38 Summary 26

4 Acute and Chronic Intoxication 28

41 Introduction 28

42 Single exposure rapid biological effect rapid recovery 28

43 Continuous exposure rapid biological effect slow but complete recovery 30

44 Single exposure rapid biological effect slow but complete recovery 30

45 Single exposure latent intoxication little or no recovery 31

46 Single or repeated exposure rapid intoxication irreversible secondary changes 32

47 Single exposure latent intoxication no recovery 32

48 Discussion 33

49 Summary 34

5 Delivery of Intoxicant Decrease in delivery to the target 35

51 Introduction 35

52 Delivery (entry and distribution) 38

53 Movement across membranes 39

54 Distribution 45

55 Factors which reduce the concentration of free intoxicant 45

56 Discussion 53

57 Summary 54

6 Delivery of Intoxicant Bioactivation and increase in delivery to the target 56

61 Introduction 56

62 Bioactivation 58

63 Delivery of bioactivated intoxicants 58

64 Cytochrome P450s 63

65 Active transport of intoxicants 65

66 Biliary excretion and enterohepatic circulation 69

67 Methods to establish if in vivo bioactivation occurs 69

68 Discussion 71

69 Summary 72

7 Initiating Reactions with Targets 74

71 Introduction 74

72 Intoxicants which affect oxidative energy conservation (many tissues) 76

73 Pyrethroids (nervous system) 78

v

74 Paraquat (lung) 80

75 Organophosphorus compounds and carbamates (nervous system) 81

76 Organophosphorus compounds (delayed neuropathy axonopathy) 86

77 Acrylamide (nervous system axonopathy) 88

78 2 5-Hexanedione (nervous system peripheral and central axonopathy) 91

79 Trichlorethylene (liver peroxisome proliferation) 94

710 Glycol ethers (testis embryonic and foetal development) 95

711 Beryllium and rare earths (liver reticulo-endothelial system) 98

712 Triorganotins (nervous system intramyelinic vacuoles and neuronal necrosis) 99

713 Cell death (necrosis and apoptosis) 101

714 Mutation and carcinogenesis 102

715 Immunotoxicity 105

716 Discussion 108

717 Summary 110

8 Biological Consequences of Initiating Reactions with Targets 111

81 Introduction 111

82 Functional without morphological change perturbation of the cellular utilisation ofoxygen

112

83 Functional without morphological change perturbation of the cholinergic transmittersystem

113

84 Functional without morphological change perturbation of voltage-dependent sodiumchannels

115

85 Cell death liver and lung damage and fibrosis 117

86 Cell death neuronal necrosis in specific areas of the brain 118

87 Cell death external stimuli and neuronal cell necrosis 119

88 Axonopathy primary effects on the nerve axon 120

89 Chemical carcinogenesis DNA adduct to tumour 123

810 Inflammatory response toxic oil syndrome 125

811 Discussion 128

812 Summary 130

9 Exposure Dose and Chemical Structure Response and Activity andThresholds

131

91 Introduction 131

vi

92 Essential and toxic compounds 132

93 Exposure-response for bioassay the malathion episode in Pakistan 133

94 Exposure-response chemical carcinogens 134

95 Structure- and dose-response -diketones and acrylamide 136

96 Structure-response triorganotins phenols and phenylimino compounds 139

97 Thresholds 142

98 Discussion 145

99 Summary 146

10 Selective Toxicity Animal Experimentation and In Vitro Methods 148

101 Introduction 148

102 Differences in metabolism methanol 151

103 Differences in detoxification and reaction with target chlorfenvinphos 153

104 Species difference in induction of peroxisomes in liver 155

105 Human chemical-induced disease with no animal model 155

106 The Ames test 156

107 In vitro techniques and the use of animals 157

108 Discussion 158

109 Summary 160

11 Biomonitoring 161


112 Genetically determined susceptibility 163

113 Succinyldicholine 163

114 Exposure dose and effect monitoring in humans 164

115 Dose monitoring in humans methylmercury (epidemic in Iraq) 165

116 Dose monitoring in humans ethylene oxide 167

117 Dose and effect monitoring in humans anticholinesterases 169

118 Dose and effect monitoring in humans dichlorvos 170

119 Dose monitoring in experimental animals 171

1110 Effect monitoring 171

1111 Discussion 172

1112 Summary 173

12 Epidemiology 174

vii


122 General methodological approaches 176

123 Epidemiological methods used in occupational exposures 178

124 Smoking and lung cancer 179

125 Toxic oil syndrome in Spain 181

126 Health effects of environmental exposure to cadmium 184

127 Discussion 187

128 Summary 188

13 Environmental and Ecotoxicology 189


132 Polychlorinated biphenyls 190

133 Toxic chemicals produced by cyanobacteria (algae) 193

134 Methylmercury Minamata and Niigata episodes 194

135 Chlorinated mutagenic agents in drinking water 196

136 Discussion 199

137 Summary 200

14 Reflections Research and Risk 201

141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface

Toxicology is the science of poisoning by chemicals natural or man-made small or large molecular weightHistorical studies have often been in essence descriptive but now we can define the early reactions and adverseconsequences of the interaction of chemicals with biological systems in chemical terms This chemicalapproach also requires a redefinition of some of the basic toxicological terms

Biology is rapidly absorbing information from molecular biology and the control of biological processesis being defined in molecular terms Research in toxicology aims to define the specific interactions of anintoxicant with molecular control points in living organisms In biochemistry and physiology the control ofbiological systems by hormone and transmitters and in pharmacology their modification by drugs etc isnow being described in terms of specific interactions with macromolecules (receptors) Although toxicitymay be initiated by interactions with these same receptors there are other macromolecular components of cells(targets) whose physiological biochemical andor structural function is as yet unknown in detail but whosemodification by a chemical causes toxicity

Many advances in biology have resulted from the experimental and controlled manipulation of biologicalsystems Claude Bernardrsquos famous quotation made in 1875 is explicit about the value to basic science of theunderstanding of the consequences of the perturbation of biological systems by intoxicants

Poisons can be employed as means for the destruction of life or as agents for the treatment of the sickbut in addition there is a third of particular interest to the physiologist For him the poison becomes aninstrument which dissociates and analyses the most delicate phenomena of living structures and byattending carefully to their mechanism in causing death he can learn indirectly much about thephysiological processes of lifehellip

Research in toxicology thus serves a dual purposemdashit defines the factors determining the degree ofinteraction with the primary target and also illuminates the molecular aspects of the biological processesinvolved

The focus of this book is research and not test procedures Test procedures are to provide data on specificquestions In research described by Medawar (1986) as lsquothat restless endeavour to make sense of thingsrsquoexperimental procedures are continually modified so that the results may prove or disprove a hypothesisMechanisms and concepts are illustrated as well as the research route by which they were establishedOccasionally unproven mechanisms are presented which because of our state of knowledge stimulateworking hypotheses leading to new research The concepts of the lsquobiochemical lesionrsquo and lsquolethal synthesisrsquodeveloped by Peters (1963) are milestones in toxicological research Research on mechanisms in toxicologyleads not only to greater understanding of the biology involved but also to the means to design substances with

selectivity among species for example pesticides with large differences between their toxicity to the pestand to humans

Society now demands that reassurance be given prior to the introduction of a chemical that that chemicalwill not cause illness in those unavoidably exposed Exposure can occur during medical treatment at workor in the general environment Governments have responded by increasing the extent of toxicity testing bothin vitro and in vivo However the interpretation of the results of these tests in terms of the risk to humansmay be difficult and often depends on other background information Rational decisions on how a toxicchemical may be used safely development of objective biological monitoring procedures design of saferdrugs and chemicals development of quicker and more precise predictive tests (in vitro and using animals)for particular types of toxicity require more understanding of mechanisms in toxicity A better definition ofthe factors which influence chemico-biological interactions and a greater knowledge of dose-response andstructure-activity relationships enhance the intellectual climate necessary for the rational prediction of thehazards and risks of exposure

Toxicologists in the future will have to utilise an increasing amount of information arising fromexpanding knowledge of the molecular complexity of biological phenomena Experience gained in teachingpostgraduate students with primary degrees in medicine pathology physiology biochemistry chemistry orphysics (and more mature students wishing to gain a general view of principles and approaches) has shownthat a conceptual framework helps in the assimilation of information from diverse disciplines This bookprovides such a framework for interactions of any chemical with any biological system

Although this book presents a chemistrsquos view of mechanistic toxicology other disciplines play animportant role Contributions from many disciplines are brought together and focused on the importance ofunderstanding the molecular science of chemical-induced perturbations in complex biological systems forboth practical and basic toxicology

Norman Aldridge

x

Acknowledgements

The subject of toxicology is so wide and needs the expertise of so many disciplines that it is obvious that theauthor before writing this book has received help during his career from many colleagues including thestaff of the Medical Research Council Toxicology Unit UK and many others from home and abroad whohave taken part in discussions whenever we met

For more immediate help I wish to acknowledge the following friends and colleagues who have given theirtime to read all or parts of the manuscriptmdashmany improvements have resulted

Professor Ernst Cohen formerly at the Department of Pharmacology Leiden University and head of theMedico-Biological Laboratory Rijswick Professor Lewis Smith Director of the Medical Research CouncilToxicology Unit University of Leicester and Dr Shirley Price Pathologist at the Robens Institute of Healthand Safety University of Surrey who have acted as general readers

The following have read specific chapters Professor Gordon Gibson School of Biological SciencesUniversity of Surrey (Chapters 5 and 6 delivery of intoxicant) Dr Peter Farmer Medical Research CouncilToxicology Unit University of Leicester (Chapter 11 biomonitoring) Professor Sir Richard Doll ICRFCancer Studies Unit Radcliffe Infirmary University of Oxford and Professor Benedetto TerraciniDepartment of Biological Sciences and Human Oncology University of Turin (Chapter 12 epidemiology)

To all I am extremely grateful

1Scope of Toxicology

11Toxicology and Mechanisms of Toxicity

Toxic substances have always been used by many species of animal including humans for defensive andoffensive purposes Textbooks of pharmacology are full of examples of such agents used by man egarrowhead poisons such as digitalis from Strophanthus and curare from Strychnos and ChondrodendronAlthough there are many examples of man using natural toxins for his own purposes there are probablymany more of one animal species using toxins to control another to deter an attack by another toimmobilise a food source either for immediate or later consumption Pharmacology has a rather positiveimage being concerned with the treatment of disease by natural products structural modifications of naturalproducts and by synthetic drugs designed for treatment of a particular disease In contrast toxicology issometimes regarded in a negative way This is a misconception for in its wider context natural toxins havea respectable position in evolutionary development which has allowed the equilibrium between species tobe attained and maintained Man-made chemicals also have provided and will continue to provideprotection by the control of disease vectors (in many species) and also enhanced comfort convenience andsecurity in modern society Toxicology and pharmacology are complementary and the thought processesinvolved in mechanisms of toxicity are similar to those in pharmacology

Novel therapeutic agents follow from new basic knowledge of disease processes and are now positivelydesigned to interfere with a particular receptor Even though it may be possible to design a chemical with ahigh affinity for a particular receptor it will not always result in an acceptable therapeutic agent During thedevelopment of new chemical structures (drugs) undesirable and novel side-effects may appear in tests onexperimental animals Sometimes even when a potential drug passes all safety checks side-effects mayappear during clinical trials or even after the drugrsquos release for general use Such side-effects highlight areasof biological activity about which little is known and new biological research is required

The meaning of mechanistic and mechanisms when applied to toxicology is not always clear It is oftenlimited as if it were only research which established the primary interaction of a chemical with amacromolecule as the initiating event for the disease This is an unhelpful and unnecessarily narrow viewStudies in the area of mechanisms are those whose purpose and intention is to provide a holistic view of theprocess of toxicity there are many levels of biological complexity which when combined allow a reasonablehypothesis of each mechanism of toxicity to be stated

In a historical context mechanistic toxicology could not begin before a certain knowledge in basicbiology Research in the seventeenth and eighteenth centuries largely on plants by Hooke and voslashn

Leeuwenhoek led to the view that tissues consisted of many small entities ie cells The importance of thenucleus as a feature of all cells was promoted by Schwann Purkinje Brown and Schleiden followed byVirchowrsquos clear statements

1 All living organisms are composed of nucleated cells2 Cells are the functional units of life3 Cells arise only from pre-existing cells by dividing

The foundation on which scientific toxicology developed probably derives from the work of Orfila wholived in times of great advancement in chemistry physiology and pathology In the early nineteenthcentury Orfila was the first to treat toxicology as a separate scientific subject and introduced chemicalanalysis as an essential component His first textbook on general toxicology laid the foundation ofexperimental and particularly forensic toxicology During the same period Magendie was making manydiscoveries which became the basis for the experimental analysis of the site of action of poisons (for anextensive discussion of the contributions of Orfila and Magendie see Holmstedt amp Liljestrand 1963) Laterin the nineteenth century it became clear that toxic substances could be useful as tools for the dissection ofliving tissues and thus to learn about the way they are organised in a functional sense (see Preface Bernard1875)

Following such work and the ability to identify by histopathological techniques the tissue and cellsattacked by a toxic substance advances in many relevant sciences took place eg methods for theseparation of the active principles of plants morphological detail of the structural arrangement of cells therelationship between organ and cell function and the biochemical reactions occurring in them Thedevelopment of the electron microscope has led to understanding of intracellular organisation egsubcellular organelles and the existence of other compartments Methods for the separation by fractionationof tissues and of cells in a functioning state are now being devised so that reactions can be studied in vitrounder controlled conditions separate from the controlling influences the whole organism Analytical methodsof great finesse are now available for the separation and identification of small and large molecules

These advances in the biological sciences signalled that there was a reasonable expectation thatmechanisms of toxicity should be able to be identified at the cell level and often down to changes inreactions occurring within cells and sometimes to a specific interaction with a macromolecule The latter isan early event in contrast to changes in morphology which indeed may be a rather late consequence of theprimary chemical event The concept of a lsquobiochemical lesionrsquo was first proposed by Rudolf Peters as aresult of research on the effects of vitamin B (thiamine) deficiency (Gavrilescu amp Peters 1931) and waslater used following research on the toxicity of vesicants such as the arsenical lewisite (Peters et al 1945)and on the intoxicant fluoroacetate (Peters 1963) in the latter the concept of lsquolethal synthesisrsquo was alsointroduced Lethal synthesis is when the toxicity of a chemical is changed and increased by biologicalconversion of one chemical to another

Thus understanding in toxicology depends on information derived from many other disciplines ietoxicology is an interdisciplinary subject (Figure 11) This is not exceptional for biological disciplines egpharmacology physiology microbiology and so on As in other areas of biology in addition to theimportance of the acquisition of new information mechanisms of toxicity provide the intellectual climate forthe solution of practical problems in toxicology and the subject moves from a descriptive to a predictivescience

2 MECHANISMS AND CONCEPTS IN TOXICOLOGY

12Definition of Toxicology and Toxicity

1 Toxicity by chemicals is changes from the normal in either the structure or function of living organismsor both

2 Chemicals causing toxicity are intoxicants or poisons3 Toxicology is the science of poisons

These definitions are wide and open-ended with respect to organisms responses and toxic chemicals

121Organisms

The aim of most studies is to provide safety for human beings In the past half century there has been aradical change in public attitudes about exposure to chemicals Prior to 1940 few chemicals weresynthesised in large amounts and exposure often occurred during the mining of metals and their subsequentpurification and fabrication If illness resulted then following medical advice conditions were improved Fora variety of reasons attitudes have changed these include the advance of chemistry the increased longevitydue to treatment of infectious diseases and better nutrition and an awareness through education of thepossibilities of toxicity It is now generally accepted that before (not after) a chemical (pesticide drug etc)is used industry and governmental authorities take responsibility for ensuring that sufficient informationabout potential hazard is available to protect the public This has resulted in a huge increase in the use ofexperimental animals for toxicity testing and for research

Veterinary practice has always been faced with toxicological problems Some are accidental as in thefeeding to livestock of feed supplement containing polybrominated biphenyls instead of magnesium oxide(Dunckel 1975) Other examples are the fatal exposure of animals in the Seveso episode (Holmstedt1980) drinking water contaminated by toxic cyanobacteria (Carmichael et al 1985) and consumption of

Figure 11 Areas of scientific study relevant to toxicology These relationships imply that crucial steps catalytic forprogress in mechanisms of toxicity may arise from research not only in departments or institutes of toxicology but alsoin many other areas

SCOPE OF TOXICOLOGY 3

feed on which organisms have grown and produced toxic metabolites as in the initial poisoning of turkeys withaflatoxin (Stoloff 1977) Toxic plants in fields and pastures have always been a cause of poisoning inanimals eg consumption of ragwort containing the toxic Senecio alkaloids (WHO 1988 Mattocks 1986)

While the egocentric attitudes of humans have provided the main driving force for the evaluation of thetoxicity of new chemicals in recent years there has been a growing view that the ecological balance innature should be preserved This view may be challenged and debated in extenso it has resulted in greaterattention being given to effects of chemicals on species other than the usual experimental and farm animalsFor example fish toxicity is now considered necessary before the introduction of most pesticides and thetoxicity of effluent resulting from their manufacture is more carefully evaluated The range of organismswhich can be studied from a toxicological point of view is potentially very large In many cases whereexposure to chemicals is postulated to be the cause of the change in the population of particular organismsproof that this is so often necessitates much more information and research (see Chapter 13)

The increase in the use of animals for experimental purposes has resulted in demands from somemembers of the public for the introduction of in vitro techniques to replace them or at least to diminish theirnumbers they might utilise a pure enzyme isolated animal tissues and in some cases model bacterialsystems (see Chapter 10)

As a consequence of all the above demands the range of species of organism and biological systems tobe considered in a toxicological context is now very large and is increasing This expanding range is mainlybeing driven by questions of a practical nature but in another context researchers in biological science havealways been prepared to widen their studies to other species in order to solve particular academic problems(eg when an animal model is not available within the usual range of experimental animals see Chapter 10)

122Responses

Current perception is that the range of responses is almost infinite any attempt to produce a useful list forthe huge range of potentially affected organisms would fail Sometimes the site of toxicity is decided by theroute of exposure eg through the skin by inhalation or by absorption from the gastro-intestinal tract whenthe toxicity evinced may be to the skin to the lung etc However all responses are not of equal practicalimportance In most cases tissue damage (eg loss of cells) can be repaired by mitosis from remaining cellsThus ingestion of the commonly consumed chemical ethyl alcohol no doubt from time to time causes thedeath of some hepatocytes but provokes few long-term consequences due to efficient repair processesHowever neuronal loss is permanent and although this may not be clinically significant owing to a largereserve capacity a permanent change has taken place Damage to long axons in the central (spinal cord) andperipheral (sciatic nerves) has different long-term consequences peripheral nerves can be repaired andreach the end organ while axons of central nerves do not reconnect Secondary consequences in the wholeorganism such as scar tissue formation or long lasting inflammatory processes clinical signs or symptomswhich after a short exposure take a long time to appear or which require a long exposure continue to presentchallenges to our current understanding in biology and toxicology (see Chapter 8)

Some chemicals cause toxicity following a reversible interaction with a tissue component whereas othersinteract to yield a covalently bonded and modified tissue component Biological consequences of suchinteractions can be very different but much remains to be explored particularly in relation to chronic andlong lasting toxicity (see Chapter 7)

Clinical responses are obviously emphasised but one of the most important tasks in toxicology is toidentify early interactions which result in changes which are part of a chain of events leading to toxicity (a


biological cascade) The identification of early changes may provide the basis for rational biomonitoring ofhuman populations The definition of such early changes their dose-response relationships and theidentification of longer-term consequences require a rather profound understanding of the biology involvedSometimes current basic biology is inadequate for the task thus the nature of a large human poisoningknown as toxic oil syndrome which in 1981 involved thousands of victims (Sections 810 and 125) is notyet fully understood at a biological level and the aetiological agent has not been identified

123Toxic Chemicals

Traditionally material which causes toxicity has been divided into toxic chemicals and toxins This divisionis arbitrary and is often based on molecular weight sometimes it is based on whether toxicity is caused by asynthetic chemical or a natural product Such a division is almost impossible to sustain when for instancean effluent is released into a river and then reacts with a natural constituent to produce a toxic entityBotulinum toxin is not usually considered to be within the province of toxicology but plant lectinssometimes are With few exceptions the toxic chemicals used in this book as examples of particularmechanisms have a molecular weight of less than 1000 no distinction is made between those chemicalssynthesised in chemical industry mined produced naturally by organisms in the environment or resultingfrom the release of synthesised chemicals or by-products into the environment

There is a popular misconception that chemicals synthesised by chemical industry are dangerous andnatural chemicals are not This is untrue for some of the most toxic agents occur in the natural worldTable 11 lists examples of both natural and synthesised chemicals All have a molecular weight of less than1000 A wide range of toxicity is shown for both natural and synthetic chemicals and extremely toxicchemicals occur in each group eg with a toxicity of less than 01 micromolkg This selection of chemicalscauses many types of toxicity by different mechanisms and illustrate a central fact in toxicology chemicalsare selective and specific in the toxicity they cause In one example a natural product has been structurallymodified to give a synthetic chemical with enhanced toxicity and properties Natural pyrethrins derived fromthe Pyrethrum plant is an effective knock-down pesticide but is very unstable to light Many pyrethroid

Table 11 Examples of natural and synthetic toxic chemicals

Toxic chemical (source) Molecular weight Tissue affected Ref

NATURAL TOXICANTS

Aflatoxin B1(Aspergillus flavus growthon nuts)

312 Liver necrosis andcarcinogenesis

1

α -Amanitin(Mushroom amanitaphalloides)

902 Gastro-intestinal tractlivernecrosis

2

Anatoxin-a(S)(organophosphorusproduced by cyanobacteria)

252 Nervous system(anticholinesterase)

28 29

Fluoroacetate Na(Plant dichapetalumcymosum)

100 Heartskeletal musclenervous system

3 4

Monocrotaline(Crotalaria spectabilis)

325 Liverlung 5 6



Ochratoxin A(Aspergillus ochraceusgrowth on nutsseeds)

403 Kidney 7 8

Pyrethrin I(Plant pyrethrumcinariaefolium)

328 Nervous system (nerveconduction)

9

Tetrodotoxin(Puffer fish)


10 11

SYNTHETIC TOXICANTS

Deltamethrin(pyrethroid insecticide)


12 13

Ethylene glycolmonomethyl ether (solvent)

76 Testis 14

Hexachloro-13-butadiene(intermediate)

267 Kidney 15

2 5-Hexane dione(bioactivated product fromhexane)

114 Nervous system (longaxons)

16 17

Methyl isocyanate(intermediate in synthesis ofcarbamates)

57 Lungeye 1819

Methylmercuricdicyandiamide(fungicide)

298 Nervous system(cerebellum)

20 21

MTTP 1-methyl-4-phenyl-1 236-tetrahydropyridine(impurity in pethidenederivative)

173 Nervous system (substantianigra)

22 23

Paraquat (bipyridiniumherbicide)

186 Lung 24 25

Pentachlorophenol(fungicide)

266 General metabolic poison 26

Soman pinacolylmethylphosphonofluoridate(nerve gas)


27

References (1) Stoloff 1977 (2) Weiland amp Faulstich 1978 (3) Peters 1963 (4) Hayes 1982 (5) McLean 1970 (6)Mattocks 1986 (7) Purchase amp Theron 1968 (8) Chu 1974 (9) Elliot 1971 (10) Kao 1966 (11)Narahashi 1990 (12) Elliott 1979 (13) Verschoyle amp Aldridge 1980 (14) Thomas amp Thomas 1984 (15)Hook et al 1983 (16) Divincenzo et al 1980 (17) Cavanagh 1982a (18) Nemery et al 1985 (19)Ferguson amp Alarie 1991 (20) Tsubaki amp Irukayama 1977 (21) Aldridge 1987 (22) Jenner amp Marsden1987 (23) Langston et al 1984 (24) Conning et al 1969 (25) Smith amp Nemery 1986 (26) Gaines (1969)(27) Black amp Upshall 1988 (28) Cook et al 1989 (29) Hyde amp Carmichael 1991

structures have now been synthesised with high biological activity and stability to light (Elliott 1979Hassall 1990)


13Origin and Types of Exposure

Exposure and toxicity occurs in different circumstances

1 Medical and veterinary practice2 At work (occupational)3 In the general environment (environmental)4 Accidental or intentional (including forensic)

Other subdivisions have been used environmental toxicity for incidental or occupational hazards economictoxicology for intentional administration to living organisms eg therapeutic agents for human and veterinaryuse chemicals used as food additives or cosmetics and chemicals used by humans selectively to eliminateanother species and forensic toxicology including both intentional and accidental exposure

131Medical and Veterinary Practice

Modern-day therapeutics are often designed from knowledge of the way particular physiological functionsare controlled and are thus intended to be specific in their action Many are intended to rectify defects innormal control or to modify normal physiology and thus are also often prescribed for use for many yearseg treatment of hypertension or the contraceptive pill Extensive animal studies are carried out so as todiscard undesirable side-effects but in practice others sometimes emerge after the pre-marketing clinicaltrials or when the drug has been released for general use and the side-effect is recognised during post-marketing monitoring Thus experience indicates that drug side-effects continue to be a problem as statedby Fingl and Woodbury (1966)

Drug toxicity is as old as drug therapy and clinicians have long warned of drug-induced diseasesHowever with the introduction into therapeutic practice of drugs of greater and broader efficacy theproblem of drug toxicity has increased and it is now considered the most critical aspect of moderntherapeutics Not only is a greater variety of drug toxicity being uncovered but the average incidenceof adverse effects of medication is increasing and unexpected toxic effects occur relatively frequentlyThere is an urgent need for the development of methods in animals that accurately predict the potentialharmful effects of drugs in man

Although improvements have been made since 1966 problems remain Side-effects which are novel formsof toxicity quite different from their therapeutic action may appear Also control of the dose necessary forthe drugrsquos therapeutic action is vital this is the province of the pharmacologist and the clinician

132Exposure at Work

Exposure at work takes place during the development period production on a pilot plant scale full-scaleproduction formulation and use In recent years there has been an irresistible centralising tendency inindustry so that fewer places synthesise a particular product or an intermediate for a future manufactureThis is beneficial for working conditions but the product then has to be transported in large quantities over


great distances with a potentiality for accidents In practice the environments of formulation plants areoften less controlled and exposure may be greater It is difficult to generalise about the extent of the dangerof exposure at work however during the dissemination of pesticides for agricultural pest control or vectorcontrol for public health purposes in developing countries long hours of work under poor conditionsproblems of diluting the concentrates and of disposal of empty containers often lead to high exposure

133Environmental Exposure

A major problem in environmental exposure is to reassure the public that long and perhaps life-timeexposure to low residues of compounds in food and water eg pesticides food additives fluoride indrinking water will not cause undesirable effects Neglecting the obvious problem of proving a negativethe potential for such a consequence can more confidently be predicted if a sound basis for mechanism ofaction is known and the scientific basis of threshold is established From the results of basic research dose-and biomonitoring techniques may be devised to follow up those people who are during their workexposed to a relatively higher concentration for a long timemdashsuch studies can be very useful for riskassessment

134Accidental and Intentional Exposure

As mentioned above there is always a potential hazard in the transport of the final product or the chemicallyactive intermediates used in its synthesis The use of a chemical for purposes for which it was not intendedfailing to follow the recommended procedure for its use the re-use of containers and the storage of achemical in unsuitable and often unlabelled bottles has led to many fatalities by accidental poisoningExperience shows that when a toxic chemical becomes available it will be used in suicide attempts andeven in the best regulated circumstances accidents will happen Although such accidents are regretted whenthey happen they provide a source of information about the susceptibility of humans to poisoning by particularchemicals Systems need to be available to collect and utilise this potential information (Aldridge ampConnors 1985) Expertise is required as an immediate need to care for those exposed and to contain theaccident However others trained in epidemiology analytical chemistry and experimental toxicology areneeded at an early stage to ensure the conditions for the collection of relevant information and samples foranalysis

14Discussion

The purpose of this chapter has been to outline the potential scope of toxicology both in the natural andindustrialised environments It is not intended to suggest demarcation disputes about what is and what is nottoxicology Perhaps more than other scientists those who are engaged in studies on toxicity rely oninformation from many other scientific areas Those engaged in research on mechanisms of toxicity areengaged in basic research in the biological sciences While it is possible to limit research to projects with apredictable practical benefit it is equally valid to choose an unsolved problem in mechanisms of toxicitywhich will throw light on some area of biology


We have to recognise the danger of being preoccupied with benefit rather than knowledgeKnowledge has a kind of inevitable priority and our confidence in the expected benefit depends onthe soundness of the knowledge (Paton 1984)

Over the past forty years due to inappropriate waste disposal and accidents involving chemicals ever morestringent regulations have been formulated to control the introduction of new chemicals to the market and tore-examine the safety of those materials already in use and a potential source for exposure of the public Whilethese regulations prescribe the quality and design of testing protocols their execution is in essence a routinematter However the design of such tests and the interpretation of the results should be based on scientificprinciples Regulation tends to be a national prerogative whereas the scientific aspects and particularlymechanisms and concepts are universal The move forward in such basic science draws together researchacross the whole spectrum of physiological and biomedical sciences The intention in this book is to providefor students a framework and mode of thought which will be useful to those who assess and apply the newhypotheses for those who will be the future creators of new mechanisms and concepts and also for thosewho wish to learn more about the structure of toxicological science

Because of advances in biological sciences the unfolding specificity in molecular terms of all biologicalprocesses leads to endless possibilities of interference in individual steps by chemicals (both low and highmolecular weight) Biological science and toxicology should advance in tandem sometimes an unexpectedtoxic response begins the search for an unknown biological process and its control mechanisms andsometimes the advance in biological science comes first Although many disciplines contribute to thesolution of mechanisms of toxicity an emphasis on the chemistry of the event is essential

15Summary

1 Toxicology is an interdisciplinary subject2 There is no fundamental distinction between natural and synthetic chemicals3 Studies in mechanisms of toxicity are research in basic biological science4 Exposure of humans andor animals to chemicals occurs during medical and veterinary treatment at

work in the environment and by accidental and intentional poisoning5 Organisms are targets for toxic chemicals in the environment6 Research on mechanisms of toxicity will produce new concepts and assist in the solution of practical

problems


References

ADAMSON IYR BOWDEN DH COcircTEacute MG amp WITSCHI HP (1977) Lung injury induced by butylatedhydroxytoluene cytodynamic and biochemical studies in mice Laboratory Investigations 36 26ndash32

AHLSTEDT S EKSTROM B SVARD PO et al (1980) New aspects on antigens in penicillin allergy CRCCritical Reviews in Toxicology 7 219ndash277

ALAJOUANINE T DEROBERT L amp THIEFFRY S (1958) Etude clinique drsquoensemble de 210 cas drsquointoxicationpar les sels organiques drsquoetain Revues neurologique 98 85ndash96

ALBERT A (1985) Selective Toxicity The Physicochemical Basis of Therapy Chapman and Hall LondonALDERSON M (1983) An Introduction to Epidemiology Macmillan BasingstokeALDRIDGE WN (1953) The inhibition of erythrocyte cholinesterase by triesters of phosphoric acid 3 The nature of

the inhibitory process Biochemical Journal 54 442ndash448(1954) Tricresyl phosphates and cholinesterase Biochemical Journal 56 185ndash189(1976a) Chronic toxicity as an acute phenomena In The Prediction of Chronic Toxicity from Short-term Studies (eds

WAMDuncan BJLeonard amp BBrunaud) Proceedings of the European Society of Toxicology Vol 17pp 5ndash6 Excerpta Medica Amsterdam

(1976b) The influence of organotin compounds on mitochondrial functions Advances in Chemistry Series 157186ndash196

(1980) Acetyl cholinesterase and other esterase inhibitors In Enzyme Inhibitors as Drugs (ed MSandler) pp 115ndash125Macmillan Basingstoke

(1981) Mechanisms of toxicity new concepts are required in toxicology Trends in Pharmacology 2 228ndash231(1986) The biological basis and measurement of thresholds Annual Reviews in Pharmacology and Toxicology 26

39ndash58(1987) Toxic disasters with food contaminants In Attitudes to Toxicology in the European Economic Community (ed

PL Chambers) pp 57ndash71 Wiley Chichester(1989a) Cholinesterase and esterase inhibitors and reactivators of organophosphorus inhibited esterases In Design of

Enzyme Inhibitors as Drugs (eds MSandler amp HJSmith) pp 294ndash313 Oxford University Press Oxford(1989b) The advisory subgroup in toxicology of the European Medical Research Councils Archives of Toxicology 63

253ndash256(1990) An assessment of the toxicological properties of pyrethroids and their neurotoxicity CRC Critical Reviews in

Toxicology 21 89ndash104 (1992a) Chemistry in relation to toxicity and to risks of exposure to organotin compounds In Chemistry and

Technology of Silicon and Tin (eds VGKumar Das NGSeik Weng amp MGeilen) pp 78ndash92 Oxford UniversityPress Oxford

(1992b) Selective neurotoxicity problems in establishing the relevance of in vitro data to the in vivo situation In Tissue-specific Toxicity Biochemical Mechanisms (eds WDekant amp HG Neumann) pp 15ndash31 Academic PressLondon

(1992c) The toxic oil syndrome (TOS 1981) from the disease towards a toxicological understanding of its chemicalaetiology and mechanism Toxicology Letters 6465 59ndash70

(1993) Postscript to the symposium on organophosphorus compound induced delayed neuropathy Chemico-BiologicalInteractions 87 463ndash66

(1995a) Aspects of selectivity and mechanisms in neurotoxicity In Molecular Mechanisms of Toxicity (edsFDeMatteis and LLSmith) pp 3ndash17 CRC Press Boca Raton Florida

(1995b) Defining thresholds in occupational and environmental toxicology Toxicology Letters 77 109ndash118ALDRIDGE WN amp BARNES JM (1961) Neurotoxic and biochemical properties of some triaryl phosphates

Biochemical Pharmacology 6 177ndash188ALDRIDGE WN amp BROWN AW (1988) The biological properties of methyl and ethyl derivatives of tin and lead

In The Biological Alkylation of Heavy Metals (eds PJCraig amp F Glockling) pp 147ndash163 Special PublicationNo 66 Royal Society of Chemistry London

ALDRIDGE WN amp CONNORS TA (1985) Chemical accidents and toxicology Human Toxicology 4 477ndash479ALDRIDGE WN amp LOVATT EVANS C (1946) The physiological effects and fate of cyanogen chloride Quarterly

Journal of Experimental Physiology 33 241ndash266ALDRIDGE WN amp REINER E (1972) Enzyme Inhibitors as Substrates Interaction of Esterases with Esters of

Organophosphorus and Carbamic Acids North-Holland AmsterdamALDRIDGE WN amp STREET BW (1970) Oxidative phosphorylation the specific binding of trimethyltin and

triethyltin to rat liver mitochondria Biochemical Journal 118 171ndash179ALDRIDGE WN MILES JW MOUNT DL amp VERSCHOYLE RD (1979) The toxicological properties of

impurities in malathion Archives of Toxicology 42 95ndash106ALDRIDGE WN DINSDALE D NEMERY B amp VERSCHOYLE RD (1987) Toxicology of impurities in

malathion potentiation of malathion toxicity and lung toxicity caused by trialkyl phosphorothioates In Selectivityand Molecular Mechanisms of Toxicity (eds FDe Matteis amp EALock) pp 265ndash294 Macmillan Basingstoke

ALDRIDGE WN STREET BW amp SKILLETER DN (1977) Halide-dependent and halide-independent effects oftriorganotin and triorganolead compounds on mitochondrial functions Biochemical Journal 168 353ndash364

ALDRIDGE WN STREET BW amp NOLTES JG (1981) The action of 5-coordinate triorganotin compounds on ratliver mitochondria Chemico-Biohgical Interactions 34 223ndash232

AMES BN DURSTAN WE YAMASAKI E amp LEE FD (1975a) Carcinogens are mutagens a simple test systemcombining liver homogenates for activation and bacteria for detection Proceedings of the National Academy ofSciences 70 2281ndash2285

AMES BN MCCANN J amp YAMASAKI E (1975b) Methods for detecting carcinogens and mutagens with theSalmonellamammalian-microsome mutagenicity test Mutation Research 31 347ndash364

AMOS HE BRIGDEN WD amp MCKERRON RA (1975) Untoward effects associated with practololdemonstration of antibody binding to epithelial tissue British Medical Journal 1 598ndash600

ANDERS MW ed (1985) Bioactivation of Foreign Compounds Academic Press OrlandoANDERSEN ME CLEWELL HJ III GARGAS ML SMITH FA amp REITZ RH (1987) Physiologically based

pharmacokinetics and the risk assessment process for methylene chloride Toxicology and Applied Pharmacology87 185ndash205

ANDERSON D ed (1990) Male-mediated F1 abnormalities Mutation Research 103ndash247ANDERSON DM (1994) Red tides Scientific American 271 52ndash58 APOSHIAN HV amp APOSHIAN MM (1990) Meso-23-dimercaptosuccinic acid chemical pharmacological and

toxicological properties of an orally effective metal chelating agent Annual Reviews of Pharmacology andToxicology 30 279ndash306

ASHBY J amp PATON D (1993) The influence of chemical structure on the extent and sites of carcinogenesis for 522rodent carcinogens and 55 different human carcinogen exposures Mutation Research 3ndash74

ASHBY J et al (1994) Mechanistically-based human hazard assessment of peroxisome proliferator-inducedhepatocarcinogenesis Human and Experimental Toxicology 13 (suppl) S1ndashS117

AXELSON O ANDERSSON K HUYSTEDT C et al (1978) A cohort study on trichlorethylene exposure andcancer mortality Journal of Occupational Medicine 20 194ndash196

BACKLUND P KROMBERG L PENSAR G amp TIKKANEN L (1985) Mutagenic activity in humic water andalum flocculated humic water treated with alternative disinfectants The Science of the Total Environment 47257ndash264

210 REFERENCES

BAER RL RAMSEY DL amp BONDI E (1973) The most common contact allergens Archives of Dermatology108 74ndash78

BAILEY E FARMER PB BIRD I LAMB JH amp PEAL JA (1986) Monitoring exposure to acrylamide by thedetermination of S-(2-carboxyethyl) cysteine in hydrolysed haemoglobin by gas chromatography-massspectrometry Analytical Biochemistry 157 241ndash248

BAKER EL ZACK M MILES JW et al (1978) Epidemic malathion poisoning in Pakistan malaria workersLancet 1 31ndash33

BAKIR F DAMLIJI SF AMIN-ZAKI L et al (1973) Methylmercury poisoning in Iraq Science 181 230ndash241BALDWIN RC PASI A MACGREGOR JC amp HINE GH (1975) The rates of radical formation from

dipyridilium herbicides paraquat diquat and morphamquat in homogenates of lung kidney and liver an inhibitoryeffect of carbon monoxide Toxicology and Applied Pharmacology 32 298ndash304

BALLANTYNE B amp MARRS TC eds (1992) Clinical and Experimental Toxicology of Organophosphates andCarbamates pp 1ndash641 ButterworthHeinemann Oxford

BARNES JM (1970) Observations on the effects on rats of compounds related to acrylamide British Journal ofIndustrial Medicine 27 147ndash149

BARNES JM amp DENZ FA (1953) Experimental demyelination with organophosphorus compounds Journal ofPathology and Bacteriology 65 597ndash605

BARTSCH H CASTEGNARO M ROJAS M et al (1992) Expression of pulmonary p4501A1 and carcinogenDNA adduct formation in high risk subjects for tobacco-related lung cancer Toxicology Letters 6465 477ndash483

BAYLISS WM (1920) Principles of General Physiology (Preface) Longman Green amp Co LondonBEAUMONT JJ amp BRESLOW NE (1981) Power considerations in epidemic studies of vinyl chloride workers

American Journal of Epidemiology 114 725ndash734BELAND FA amp POIRIER FC (1993) Significance of DNA adduct studies in animal models for cancer molecular

dosimetry and risk assessment Environmental Health Perspectives 99 5ndash10BERENBLUM I (1974) Carcinogenesis as a Biological Problem pp 1ndash376 North-Holland AmsterdamBERGMARK E CALLEMAN CJ amp COSTA LG (1991) Formation of haemoglobin adducts of acrylamide and its

epoxide metabolite glycidamide in the rat Toxicology and Applied Pharmacology 111 352ndash363BERGMARK E CALLEMAN CJ HE F amp COSTA LG (1993) Determination of haemoglobin adducts in

humans occupationally exposed to acrylamide Toxicology and Applied Pharmacology 120 45ndash54BERNARD C (1875) La Science Experimentale Bailliegravere ParisBERNARD A amp LAUWERYS R (1981) Retinol-binding protein in urine a more practical index than urinary 2-

microglobulin for the screening of renal tubular function Clinical Chemistry 27 1781ndash1782 BERNARD A BUCHET JP ROELS H et al (1979) Renal excretion of proteins and enzymes in workers exposed

to cadmium European Journal of Clinical Investigation 9 11ndash22BERNARD A ROELS H BUCHET JP amp LAUWERYS R (1992) Decrease in serum Clara cell protein in

smokers Lancet 339(1) 1620BERNDT WO amp MEHENDALE HM (1979) Effects of hexachlorobutadiene (HCBD) on renal function and renal

organic ion transport in the rat Toxicology 14 55ndash65BIBBO M GILL W AZIZI F et al (1977) Follow-up study of male and female offspring of DES-exposed

mothers Obstetrics and Gynaecology 49 1ndash8BIDSTRUP PL BONNELL JA amp BECKETT AG (1953) Paralysis following poisoning by a new

organophosphorus insecticide British Medical Journal 1 1068ndash1072BIGGAR JW DUTT GR amp RIGGS RL (1967) Predicting and measuring the solubility of pprsquoDDT in water

Bulletin of Environmental and Contaminant Toxicology 2 90ndash100BISCHOFF KB amp BROWN RH (1966) Drug distribution in mammals Chemical Engineering Progress Symposium

Series 62 33ndash5BISHOP JM (1991) Molecular themes in oncogenesis Cell 64 235ndash248BLACK RM amp UPSHALL DG (1988) Assessing the danger Chemistry in Britain (special issue) Chemical

Defence 659ndash662

REFERENCES 211

BLACKBURN DM GRAY AJ LLOYD SC SHEARD CM amp FOSTER PDM (1988) A comparison of theeffects of the three isomers of dinitrobenzene on the testis of the rat Toxicology and Applied Pharmacology 9254ndash64

BOEKELHEIDE K (1987) 25-Hexanedione alters microtubule assembly 1 Testicular atrophy not nervous systemtoxicity correlates with enhanced tubulin polymerisation Toxicology and Applied Pharmacology 88 370ndash382

(1988) Rat testis during 25-hexanedione intoxication and recovery 1 Dose-response and the reversibility of germ cellloss Toxicology and Applied Pharmacology 92 18ndash27

BOEKELHEIDE K amp EVELETH J (1988) The rate of 25-hexanedione intoxication not total dose determines theextent of testicular injury and altered microtubule assembly in the rat Toxicology and Applied Pharmacology 9476ndash83

BOTES DP TUINMAN AA WESSELS PL et al (1984) The structure of cyanoginosin-LA a cyclic heptapeptidefrom the cyanobacterium Microcystis aeruginosa Journal of the Chemical Society Perkins Transactions 12311ndash2318

BOULDIN TW and CAVANAGH JB (1979a) Organophosphorus neuropathy 1 A teased fiber study of the spatio-temporal shred of axonal degeneration American Journal of Pathology 94 241ndash252

(1979b) Organophosphorus neuropathy 2 A fine structural study of the early stages of axonal degeneration AmericanJournal of Pathology 94 253ndash270

BOULDIN BW GOINES ND BAGNELL CR amp KRIGMAN MR (1981) Pathogenesis of trimethyltin neuronaltoxicity ultrastructural and cytochemical observations American Journal of Pathology 104 237ndash249

BOUMA JMW amp SMIT MJ (1989) Gadolinium chloride selectively blocks endocytosis by Kupffer cells In Cells ofthe Hepatic Sinusoid (eds EWisse DLKnook and KDecker) pp 132ndash133 Kupffer Cell Foundation RijswijkThe Netherlands

BREMNER I (1979) Mammalian absorption transport and excretion of cadmium In The Chemistry Biochemistry andBiology of Cadmium (ed MWebb) pp 175ndash193 Elsevier North-Holland Amsterdam

BRENNER BB amp RECTOR FC Jr eds (1976) The Kidney Vols 1 and 2 (3rd edn) WB Saunders PhiladelphiaBRIDGES JW DAVIES DS amp WILLIAMS RT (1967) The fate of ethyltin and diethyltin derivatives in the rat

Biochemical Journal 105 1261ndash1267BRITISH MEDICAL ASSOCIATION (1987) Living with Risk Wiley ChichesterBRODIE ME amp ALDRIDGE WN (1982) Elevated cerebellar cyclic GMP levels during the deltamethrin-induced

syndrome Neurobehavioural Toxicology and Teratology 4 109ndash111BRODIE ME OPACKA-JUFFRY J PETERSEN DW amp BROWN AW (1990) Neurochemical changes in

hippocampal and caudate dialysates associated with early trimethyltin neuro toxicity in rats Neurotoxicology 1135ndash46

BROUWER A (1991) Role of biotransformation in PCB-induced alterations in vitamin A and thyroid hormonemetabolism in laboratory and wildlife species Biochemical Society Transactions 19 731ndash737

BROUWER A BLANER WS KUKLER A amp VAN DEN BERG KJ (1988) Study on the mechanism ofinterference of 343rsquo4rsquo-tetrachlorobiphenyl with the plasma retinol-binding proteins in rodents Chemico-Biological Interactions 68 203ndash217

BROUWER A REIJNDERS PJH amp KOEMAN JH (1989) Polychlorinated biphenyl (PCB)-contaminated fishinduces vitamin A and thyroid hormone deficiency in the common seal (Phoca vitulina) Aquatic Toxicology 1599ndash106

BROUWER A KLASSEN-WEHLER E BOKDAM M MORSE DC amp TRAAG WA (1990) Competitiveinhibition of thyroxine binding to transthyretin by monohydroxy metabolites of 343rsquo4rsquo-tetrachlorobiphenyl Chemosphere 20 1257ndash1262

BROWN AW ALDRIDGE WN amp VERSCHOYLE RD (1979) The behavioural and neuropathologic sequelae ofintoxication by trimethyltin compounds in the rat American Journal of Pathology 97 59ndash81

BROWN AW CAVANAGH JB VERSCHOYLE RD et al (1984) Evolution of the intracellular changes inneurons caused by trimethyltin Neuropathology and Applied Neurobiology 10 267ndash283

212 REFERENCES

BRUGGEMAN IM TEMMINK JHM amp VAN BLADEREN PJ (1986) Glutathione and cysteine mediatedcytotoxicity of allyl and benzyl isothiocyanate Toxicology and Applied Pharmacology 83 349ndash359

BUCHET JP LAUWERYS R ROELS H et al (1990) Renal effects of cadmium body burden of the generalpopulation Lancet 336 699ndash702

BUMPUS JA TIEN M WRIGHT D amp AUST D (1985) Oxidation of persistent environmental pollutants bywhite rot fungus Science 228 1434ndash1436

Bus JS CAGEN SZ OLGAARD M amp GIBSON JE (1976) A mechanism of paraquat toxicity in mice and ratsToxicology and Applied Pharmacology 35 501ndash513

CAPORASO NE TUCKER MA HOOVER RN et al (1990) Lung cancer and the debrisoquine metabolicphenotype Journal of the National Cancer Institute 82 1264ndash1272

CARAFOLI E (1987) Intracellular Ca2+ homeostasis Annual Reviews of Biochemistry 56 395ndash433CAROLDI S LOTTI M amp MASUTTI A (1984) Intraarterial injection of diisopropylfluo-rophosphate or

phenylmethanesulphonyl fluoride produces unilateral neuropathy or protection respectively in hens BiochemicalPharmacology 33 3213ndash3217

CARMICHAEL WW (1992) Cyanobacteria secondary metabolitesmdashthe cyanotoxins Journal of AppliedBacteriology 72 445ndash59

CARMICHAEL WW JONES CLA MAHMOOD NA amp THEISS WC (1985) Algal toxins and water baseddiseases Critical Reviews in Environmental Control 15 275ndash313

CARSON R (1962) Silent Spring Houghton Mifflin BostonCASIDA JE KIMMEL EC HOLM B amp WIDMARK G (1971) Oxidative dealkylation of tetra tri and di-

alkyltins and tetra and trialkyllead by liver microsomes Acta Chemical Scandinavica 25 1497ndash1499CAVANAGH JB (1964) The significance of the lsquodying-backrsquo process in experimental and human neurological

disease International Reviews and Experimental Pathology 3 219ndash267(1973) Peripheral neuropathy caused by toxic agents CRC Critical Reviews in Toxicology 2 365ndash417(1982a) Mechanisms of axon degeneration in three toxic lsquoneuropathiesrsquo organophosphorus acrylamide and hexacarbon

compared Recent Advances in Neuropathology 2 213ndash242(1982b) The pathokinetics of acrylamide intoxication a reassessment of the problem Neuropathology and Applied

Neurobiology 8 315ndash336CHANG LW TIEMEYER TM WENGER GR MCMILLAN DE amp REULL KR (1982) Neuropathology of

trimethyltin intoxication II Electron microscopic study on the hippocampus Environmental Research 29 445ndash58CHANG LW TIERMEYER TM WENGER GR amp MCMILLAN DE (1983) Neuropathology of trimethyltin

intoxication III Changes in brainstem neurones Environmental Research 30 399ndash411CHAPIN RE DUTTON SL Ross MD SUMRELL BM amp LAMB JC (1984) The effects of ethylene glycol

monomethylether on testicular histology in F344 rats Journal of lsquoAndrology 5 369ndash380CHAPIN RE DUTTON SL Ross MD amp LAMB JC (1985) Effects of ethylene glycol monomethyl ether

(EGME) on mating performance and epididymal sperm parameters in F344 rats Fundamental and AppliedToxicology 5 182ndash189

CHENG KK (1956) Experimental studies on the mechanism of zonal distribution of beryllium liver necrosis Journalof Pathology and Bacteriology 71 265ndash276

CHOLERTON S DALY AK amp IDLE JR (1992) The role of individual human cytochromes P-450 in drugmetabolism and clinical response Trends in Pharmacological Sciences 13 434ndash439

CHRISTIAN MS ed (1985) Cancer and the environment possible mechanisms for thresholds for carcinogens andother toxic substances Journal of the American College of Toxicology 2 1ndash321

CHU FS (1974) Studies on ochratoxins Critical Reviews in Toxicology 2 499ndash524CHYTIL F amp ONG DE (1978) Cellular vitamin A binding proteins Vitamin and Hormones 36 1ndash32CICERO TJ COWAN W MOORE BW amp SUNTZEFF V (1970) The cellular localisation of the two brain

specific proteins S-100 and 14-3-2 Brain Research 18 25ndash31CLARK DG MCELLIGOTT TF amp HURST EW (1966) The toxicity of paraquat British Journal of Industrial

Medicine 23 126ndash132

REFERENCES 213

CLARKE DO ELSWICK BA WELSCH F amp CONOLLY RB (1993) Pharmacokinetics of 2-methoxyethanoland 2-methoxyacetic acid in the pregnant mouse a physiologically based mathematical model Toxicology andApplied Pharmacology 121 239ndash252

CLARKSON TW AMIN-ZAKI L amp AL-TIKRITI SK (1976) An outbreak of methylmercury poisoning due toconsumption of contaminated grain Federated Proceedings 35 2395ndash2399

CLARKSON TW MAGOS L COX C et al (1981) Tests of efficacy of antidotes for removal of methylmercury inhuman poisoning during the Iraq outbreak Journal of Pharmacology and Experimental Therapeutics 218 74ndash83

CLEMMESEN J FUGLSANG-FREDERIKSEN V amp PLUM CM (1974) Phenobarbitone liver tumours andthorotrast Lancet 1 37ndash38

CLEWELL HJ III amp ANDERSEN ME (1989) Improving toxicity testing protocols using computer simulationToxicology Letters 49 139ndash158

CODD GA (1984) Toxins of freshwater cyanobacteria Microbiological Science 1 48ndash52COHEN AJ amp GRASSO P (1981) Review of the hepatic response to hypolipidaemic drugs in rodents and assessment

of its toxicological significance to man Food and Cosmetic Toxicology 19 585ndash605COHEN GM MACFARLANE M FEARNHEAD HO SUN XM amp DINSDALE D (1995) Mechanisms of cell

death with particular reference to apoptosis In Molecular Mechanisms of Toxicity (eds FDeMatteis ampLLSmith) pp 185ndash205 CRC Press Boca Raton Florida USA

COHEN JJ amp DUKE RC (1984) Glucocorticoid activation of a calcium dependent endonuclease in thymocyte nucleileads to cell death Journal of Immunology 132 38ndash42

COHEN SM amp ELLWEIN LB (1991) Genetic errors cell proliferation and carcinogenesis Cancer Research 516493ndash6505

COLLINS MKL amp RIVAS AL (1993) The control of apoptosis in mammalian cells Trends in BiochemicalSciences 18 307ndash309

COLLINS RC KIRKPATRICK JB amp MCDOUGAL DB (1970) Some regional and metabolic consequences inmouse brain of pyrithiamine-induced thiamine deficiency Journal of Neuropathology and ExperimentalNeurology 29 57ndash69

CONNING DM FLETCHER K amp SWAN AAB (1969) Paraquat and related bipyridyls British Medical Bulletin25 245ndash249

CONOLLY RB amp ANDERSEN ME (1991) Biologically based pharmacodynamic models tools for toxicologicalresearch and risk assessment Annual Reviews of Pharmacology and Toxicology 31 503ndash523

COOK WO DELLINGER JA SINGH SS et al (1989) Regional brain cholinesterase activity in rats injectedintraperitoneally with anatoxin-a(S) or paraoxon Toxicology Letters 49 29ndash34

COOPER AJL amp ANDERS MW (1990) Glutamine transaminase K and cysteine conjugate -lyase Annals of the NewYork Academy of Sciences 585 118ndash127

CORCORAN GB FIX L JONES DP et al (1994) Apoptosis molecular control point in toxicity Toxicology andApplied Pharmacology 128 169ndash181

COURI D amp MILKS M (1982) Toxicity and metabolism of the neurotoxic hexacarbons n-hexane 2-hexanone and 25-hexanedione Annual Review of Pharmacology and Toxicology 22 145ndash166

CRAIG PJ amp GLOCKLING F eds (1988) The Biological Alkylation of Heavy Metals pp 1ndash298 SpecialPublication No 66 Royal Society of Chemistry London

CREASEY DM amp FOSTER PMD (1984) The morphological development of glycol etherinduced testicularatrophy in the rat Fundamental and Molecular Pathology 40 169ndash176

CREECH JL amp JOHNSON MN (1974) Angiosarcoma of the liver in the manufacture of PVC Journal ofOccupational Medicine 16 150ndash151

CREMER JE (1958) The biochemistry of organotin compounds the conversion of tetraethyltin into triethyltinBiochemical Journal 68 685ndash692

(1959) Biochemical studies on the toxicity of tetraethyllead and other organolead compounds British Journal ofIndustrial Medicine 16 191ndash199

214 REFERENCES

CREMER JE amp CALLAWAY S (1961) Furthur studies on the toxicity of some tetra- and tri-alkyllead compoundsBritish Journal of Industrial Medicine 18 277ndash282

CREMER JE CUNNINGHAM VJ RAY DE amp GURCHURAN S (1980) Regional changes in brain glucoseutilisation in rats given a pyrethroid insecticide Brain Research 194 278ndash282

CRUICKSHANK JM amp PRICHARD T (1988) Beta-blockers in Clinical Practice Churchill Livingstone EdinburghCRUMP KS HOEL DG LANGLEY CH amp PETO R (1976) Fundamental carcinogenic processes and their

implications for low-dose risk assessment Cancer Research 36 2973ndash2979CUNNINGHAM VJ amp CREMER JE (1985) Current assumptions behind the use of PET for measuring glucose

utilisation in brain Trends in Neurosciences 8 96ndash99DAHL AR amp HADLEY WH (1991) Nasal cavity enzymes involved in xenobiotic metabolism effects on the

toxicity on inhalants Critical Reviews in Toxicology 21 345ndash372DAVIS A amp BAILEY DR (1969) Metrifonate in urinary schistosomiasis Bulletin of the World Health Organization

41 209ndash224DEAN JH MURRAY MJ amp WARD EC (1986) Toxic responses of the immune system In Toxicology The Basic

Science of Poisons (eds CDKlassen MOAmdur amp JDoull) pp 245ndash285 Macmillan New YorkDEANGELO AB DANIEL FB MCMILLAN L WERNSING P amp SAVAGE RE (1989) Species and strain

sensitivity to the induction of peroxisome proliferation by chloracetic acids Toxicology and AppliedPharmacology 101 285ndash298

DEARFIELD KL ABERNATHY CO OTTLEY MS BRANSTON JH amp HAYES PF (1988) Acrylamide itsmetabolism developmental and reproductive effects genotoxicity and carcinogenicity Mutation Research 19545ndash77

DECAPRIO AP (1985) Molecular mechanisms of diketone neurotoxicity Chemico-Biological Interactions 54257ndash270

(1987) Hexane neuropathy studies in experimental animals and man In Selectivity and Molecular Mechanisms ofToxicity (eds FDe Matteis amp EALock) pp 249ndash263 Macmillan Basingstoke

DECAPRIO AP amp OrsquoNEILL EA (1985) Alterations in rat axonal cytoskeletal proteins induced by in vitro and invivo 25-hexanedione exposure Toxicology and Applied Pharmacology 78 235ndash247

DEDUVE C amp BAUDHUIN P (1966) Peroxisomes (microbodies and related particles) Physiological Reviews 46319ndash375

DEKANT W BERTHOLD K VAMVAKAS S amp HENSCHLER D (1988) Thioacylating agents as ultimateintermediates in the -lyase catalysed metabolism of S-(pentachlorobutadienyl)1-cysteine Chemico-BiologicalInteractions 67 139ndash148

DEKANT W VAMVAKAS S amp ANDERS MW (1992) The kidney as a target organ for xenobiotics bioactivatedby glutathione conjugation In Tissue Specific Toxicity Biochemical Mechanisms (eds WDekant amp H-GNeumann)pp 163ndash194 Academic Press London

DE MATTEIS F amp ALDRIDGE WN eds (1978) Heme and Hemoproteins Springer-Verlag BerlinDEVONSHIRE AL amp MOORE GD (1984) Different forms of insensitive acetylcholinesterase in insect-resistant

house flies (Musca domestica) Pesticide Biochemistry and Physiology 21 336ndash340DEWAR AJ amp MOFFETT BJ (1979) Biochemical methods for detecting neurotoxicitymdashshort review

Pharmacology and Therapeutics 5 545ndash562DINSDALE D SKILLETER DN amp SEAWRIGHT AA (1981) Selective injury to rat liver Kupffer cells caused by

beryllium phosphate an explanation of reticuloendothelial blockade British Journal of Experimental Pathology62 383

DIVINCENZO GD KAPLAN CJ amp DEDINAS J (1976) Characterisation of the metabolites of methyl n-butylketone methyl iso-butyl ketone and methyl ethyl ketone in guinea pig serum and their clearance Toxicology andApplied Pharmacology 36 511ndash522

DIVINCENZO GD KRASAVAGE WJ amp OrsquoDONOGHUE JL (1980) Role of metabolism in hexacarbonneuropathy In The Scientific Basis of Toxicity Assessment (ed HPWitschi) pp 183ndash200 ElsvierNorth-HollandAmsterdam

REFERENCES 215

DIXON M amp WEBB EC (1966) Enzymes Longman Green amp Co LondonDODDS PF (1991) Incorporation of xenobiotic carboxylic acids into lipids Life Sciences 49 629ndash649DOEGLAS HMG HERMANS EH amp HUISMAN J (1961) The margarine disease American Medical Association

Archives of Dermatology 83 837ndash843DOLL R amp HILL AB (1950) Smoking and carcinoma of the lung British Medical Journal 2 739ndash748(1952) A study of the aetiology of carcinoma of the lung British Medical Journal 2 1271ndash1286(1953) Smoking and lung cancer British Medical Journal 1 505ndash506(1954) Mortality of doctors in relation to their smoking habits British Medical Journal 1 1451ndash1455(1964) Mortality in relation to smoking ten years observations of British doctors British Medical Journal 1

1399ndash1410 amp 1460ndash1467DOLL R amp PETO R (1976) Mortality in relation to smoking 20 years observation of male British doctors British

Medical Journal 1 1525ndash1536(1978) Cigarette smoking and bronchial carcinoma dose and time relationships among regular smokers and life long

non-smokers Journal of Epidemiology and Community Health 32 303ndash313(1981) The causes of cancer quantitative estimates of avoidable risks of cancer in the United States today Journal of

the National Cancer Institute 66 1191ndash1308DOLL R HILL AB GRAY PG amp PARR EA (1959) Lung cancer mortality and length of cigarette ends British

Medical Journal 1 3233ndash3232 DONNINGER C (1971) Species specificity of phosphate triester anticholinesterases Bulletin of the World Health

Organization 44 265ndash268DORMAN DC DYE JC NASSISE MP et al (1993) Acute methanol toxicity in the minipig Fundamental and

Applied Toxicology 20 341ndash347DRIVER HE WHITE INH amp BUTLER WH (1987) Dose-response relationships in chemical carcinogenesis

renal mesenchymal tumours induced in the rat by single dose dimethylnitrosamine British Journal ofExperimental Pathology 68 133ndash143

DUNCKEL AE (1975) An updating on the polybrominated biphenyl disaster in Michigan Journal of the AmericanVeterinary Medical Association 167 838ndash848

EDSALL JT amp WYMAN J (1958) Biophysical Chemistry Vol 1 Academic Press New YorkEDWARDS MJ KELLER BJ KAUFFMAN FC amp THURMAN RG (1993) The involvement of Kupffer cells in

carbon tetrachloride toxicity Toxicology and Applied Pharmacology 119 275ndash279EDWARDS PM (1975) Neurotoxicity of acrylamide and its analogues and the effects of these analogues and other

agents on acrylamide neuropathy British Journal of Industrial Medicine 32 31ndash38EHRENBERG L amp TORNQVIST M (1992) Use of biomarkers in epidemiology quantitative aspects Toxicology

Letters 6465 485ndash492EHRENBERG L HIESCHE KD OSTERMAN-GOLKAR S and WENNBERG I (1974) Evaluation of genetic

risks of alkylating agents tissue doses in the mouse from air contaminated with ethylene oxide Mutation Research24 83ndash103

ELCOMBE CR (1985) Species differences in carcinogenicity and peroxisome proliferation due to trichlor ethylene abiochemical human hazard assessment Archives of Toxicology suppl 8 6ndash17

ELDER GH (1978) Porphyria caused by hexachlorobenzene and other polyhalogenated aromatic hydrocarbons InHeme and Hemoproteins (eds FDe Matteis amp WNAldridge) pp 157ndash200 Springer-Verlag Berlin

ELFARRA AA amp ANDERS MW (1984) Renal processing of glutathione conjugates role in nephrotoxicityBiochemical Pharmacology 33 3729ndash3732

ELING TE THOMPSON DC FOUREMAN GL CURTIS JF amp HUGHES MF (1990) Prostaglandin Hsynthase and xenobiotic oxidation Annual Reviews of Pharmacology and Toxicology 30 1ndash5

ELLIOTT BM amp ALDRIDGE WN (1977) Binding of triethyltin to cat haemoglobin and modification of the bindingsites by diethylpyrocarbonate Biochemical Journal 163 583ndash589

216 REFERENCES

ELLIOTT BM ALDRIDGE WN amp BRIDGES JM (1979) Triethyltin binding to cat haemoglobin evidence fortwo chemically distinct sites and a role for both histidine and cysteine residues Biochemical Journal 177461ndash470

ELLIOTT M (1971) The relationships between the structure and the activity of pyrethroids In Alternative Insecticidesfor Vector Control pp 315ndash324 World Health Organization Geneva

(1979) Progress in the design of pesticides Chemistry and Industry pp 757ndash768ERIKSSON JE HAGERSTRAND H amp ISOMAA B (1987) Cell selective toxicity of a peptide toxin from the

cyanobacterium Microcystis aeruginosa Biochimica et Biophysica Acta 930 304ndash310ERIKSSON JE TOIVOLA D MERILNOTO JA et al (1990) Hepatocyte deformation induced by cyanobacterial

toxins reflects inhibition of protein phosphatase Biochemical and Biophysical Research Communications 1731347ndash1353

ETO M CASIDA JE amp ETO T (1962) Hydroxylation and cyclisation reaction involved in the metabolism of tri o-cresyl phosphate Biochemical Pharmacology 11 337ndash352

ETO M ABE M amp TAKAHARA H (1971) Metabolism of tri p-ethylphenyl phosphate and neurotoxicity of themetabolites Agricultural and Biological Chemistry 35 929ndash940

EVANS CH (1990) Biochemistry of the Lanthanides pp 1ndash444 Plenum New YorkEVANS DAP MANLEY KA amp MCKUSICK VA (1960) Genetic control of isoniazid metabolism in man British

Medical Journal 2 485ndash491 EXON JH MATHER GG BUSSIERE JL OLSON DP amp TALCOTT PA (1991) Effects of subchronic

exposure of rats to 2-methoxyethanol or 2-butoxyethanol thymic atrophy and immunotoxicity Fundamental andApplied Toxicology 16 830ndash840

FALCONER IR BERESFORD AM amp RUNNEGAR MTC (1983) Evidence for liver damage by toxin from abloom of the blue-green alga Microcystis aeruginosa Medical Journal of Australia 1 511ndash514

FARBER E (1971) Biochemical pathology Annual Review of Pharmacology 11 71ndash96FARMER PB (1994) Carcinogen adducts use in diagnosis and risk assessment Clinical Chemistry 40 1438ndash1443FARMER PB BAILEY E GORF SM et al (1986) Monitoring human exposure to ethylene oxide by

determination of haemoglobin adducts using gas chromatography-mass spectrometry Carcinogenesis 7 637ndash640FARMER PB NEUMANN HG amp HENSCHLER D (1987) Estimation of exposure of man to substances reacting

covalently with macromolecules Archives of Toxicology 60 251ndash260FARMER PB BAILEY E NAYLOR S et al (1993) Identification of endogenous electrophiles by means of mass

spectrometric determination of protein and DNA adducts Environmental Health Perspectives 99 19ndash24FARRINGTON JA EBERT M LAND EJ amp FLETCHER K (1973) Bipyridilium quaternary salts and related

compounds V Pulse radiolysis studies on the reaction of paraquat radical with oxygen Implications for the modeof action of bipyridilium herbicides Biochimica et Biophysica Acta 314 372ndash381

FARRIS FF DEDRICK RL ALLEN PV amp SMITH JC (1993) Physiological model for the pharmacokinetics ofmethylmercury in the growing rat Toxicology and Applied Pharmacology 119 74ndash90

FEARS R (1985) Lipophilic xenobiotic conjugates the pharmacological and toxicological consequences of theparticipation of drugs and other foreign compounds as substrates in lipid biosynthesis Progress in Lipid Research24 177ndash195

FELIX RH IVE FA amp DAHL MDC (1974) Skin reaction to practolol British Medical Journal 2 321ndash324FENWICK GR HEANEY RK amp MULLIN WJ (1983) Glucosinolates and their breakdown products in food and

food plants Critical Reviews in Food Science and Nutrition 18 123ndash201FERGUSON JS amp ALARIE Y (1991) Long term pulmonary impairment following a single exposure to methyl

isocyanate Toxicology and Applied Pharmacology 107 253ndash268FIELD EA PRICE CJ SLEET RB et al (1990) Developmental toxicity evaluation of acrylamide in rats and

mice Fundamental and Applied Pharmacology 14 502ndash512FINGL E amp WOODBURY DM (1966) General principles In Pharmacological Basis of Therapeutics (ed

LSGoodman amp AGilman) pp 1ndash36 Macmillan New York

REFERENCES 217

FISH RH KIMMEL EG amp CASIDA JE (1976a) Bioorganotin chemistry biological oxidation of organotincompounds In Organotin Compounds New Chemistry and Applications pp 197ndash203 Advances in ChemistrySeries No 157 American Chemical Society Washington DC

(1976b) Bioorganotin chemistry reactions of tributyltin derivatives with a cytochrome P-450 dependentmonooxygenase enzyme system Journal of Organometal Chemistry 118 41ndash54

FLEISCHNER G ROBBINS J amp ARIAS IM (1972) Immunological studies of Y-proteinmdasha major cytoplasmicorganic anion binding protein in rat liver Journal of Clinical Investigation 51 677ndash684

FORASTIERE F PERUCCI CA ARCAgrave M amp AXELSON O (1993) Indirect estimates of lung cancer death ratesin Italy not attributable to active smoking Epidemiology 4 489ndash92 amp 502ndash510

FORSHAW PJ LISTER T amp RAY DE (1993) Inhibition of a neuronal voltage dependent chloride channel by thetype II pyrethroid deltamethrin Neuropharmacology 32 105ndash111

FRIBERG L (1959) Studies on the metabolism of mercuric chloride and methyl mercury dicyandiamide Archives ofIndustrial Health 20 42ndash9

FRIBERG L ELINDER CG LJELLSTROM T amp NORDBERG GF (1986) Cadmium and Health AToxicological and Epidemiological Appraisal volume 2 CRC Press Boca Raton Florida

FRIEDBERG T SIEGERT P GRASSOW MA BARTLOMOWICZ B amp OESCH F (1990) Studies on theexpression of the cytochrome P450IA P450IIB and P450IIC gene family in extrahepatic and hepatic tissuesEnvironmental Health Perspectives 88 67ndash70

FULLERTON PM amp BARNES JM (1966) Peripheral neuropathy in rats produced by acrylamide British Journal ofIndustrial Medicine 23 210ndash221

GAGE JC (1953) A cholinesterase inhibitor derived from OO-diethyl-O-p-nitrophenyl thiophosphate in vivoBiochemical Journal 54 426ndash30

(1964) Distribution and excretion of methyl and phenyl mercury salts British Journal of Industrial Health 21197ndash202

(1968) The action of paraquat and diquat on the respiration of liver cell fractions Biochemical Journal 109 757ndash761GAINES B (1969) Acute toxicity of pesticides Toxicology and Applied Pharmacology 14 515ndash534GALJAARD H (1986) Biochemical diagnosis of genetic disease Experientia 42 1075ndash1085GARABANT DH HELD J LANGHOLZ B PETERS JM amp MACK TM (1992) DDT and related compounds

and risk of pancreatic cancer Journal of the National Cancer Institute 84 764ndash771GARABANT DH HELD J amp HOMA D (1993) Response to lsquoDDT and pancreatic cancerrsquo Journal of the National

Cancer Institute 85 328ndash329GAVRILESCU N amp PETERS RA (1931) Biochemical lesions in vitamin B deficiency Biochemical Journal 25

1397ndash1409GEHRING PJ WATANABE PG amp PARK CN (1978) Resolution of dose-response toxicity data for chemicals

requiring metabolic activation example vinyl chloride Toxicology and Applied Pharmacology 44 581ndash591GENTER ST CLAIR MB AMARNATH V MOODY MA et al (1988) Chemical Research in Toxicology 1

179ndash185GHIORSE WC amp WILSON JT (1988) Microbial ecology of the terrestrial subsurface Advances in Applied

Microbiology 33 107ndash172GIBSON GG amp SKETT P (1994) Introduction to Drug Metabolism Chapman and Hall LondonGILGER AP amp POTTS AM (1955) Studies on the visual toxicity of methanol V The role of acidosis in methanol

poisoning American Journal of Opthamology 39 63ndash86GILLETTE JR (1982) The problem of chemically reactive metabolites Drug Metabolism Reviews 13 941ndash961GLEICHMANN E KIMBER I amp PURCHASE IFH (1989) Immunotoxicology suppressive and stimulatory

effects of drugs and environmental chemicals on the immune system Archives of Toxicology 63 257ndash273GLOWAZ SL MICHNIKA M amp HUXTABLE RJ (1992) Detection of a reactive pyrrole in the hepatic

metabolism of the pyrollizidine alkaloid monocrotaline Toxicology and Applied Pharmacology 115 168ndash173GOMPERTZ D FLETCHER JG PERKINS J et al (1983) Renal dysfunction in cadmium smelters relation to in

vivo liver and kidney cadmium concentrations Lancet 1 1185ndash1187

218 REFERENCES

GONZALEZ FJ (1989) The molecular biology of cytochrome P450rsquos Pharmacological Reviews 40 243ndash288(1992) Human cytochromes P-450 problems and prospects Trends in Pharmacological Sciences 13 346ndash352GOODMAN DS (1980) Plasma retinol-binding protein in lipoprotein structure Annals of the New York Academy of

Sciences 348 378ndash390GOTTSCHALK CW (1964) Osmotic concentration and dilution of urine American Journal of Medicine 36

670ndash685GRAHAM DG (1980) Hexane polyneuropathy a proposal for the pathogenesis of a hazard of occupational exposure

and inhalant abuse Chemico-Biological Interactions 32 339ndash345GRAHAM DG SZAKAL-QUIN G PRIEST JW amp ANTHONY DG (1984) In vitro evidence that covalent

crosslinking of neurofilaments occurs in -diketone neuropathy Proceedings of the National Academy of Sciences81 4979ndash4982

GRASSO P SHARRATT M amp COHEN AJ (1991) Role of persistent non-genotoxic tissue damage in rodentcancer and relevance to humans Annual Reviews of Pharmacology and Toxicology 31 253ndash287

GRAY TJB (1986) Testicular toxicity in vitro sertoli-germ cell co-cultures as a model system Food and ChemicalToxicology 67 601ndash605

GRAY TJB Moss EJ CREASEY DM amp GANGOLLI SD (1985) Studies on the toxicity of some glycol ethersand alkoxyacetic acids in primary testicular cell cultures Toxicology and Applied Pharmacology 79 490ndash501

GREEN S TUGWOOD JD amp ISSEMANN I (1992) The molecular mechanism of peroxisome proliferator action amodel for species differences and mechanistic risk assessment Toxicology Letters 6465 131ndash139

GRIEG-SMITH PW (1993) Killing with caremdashcan pesticides be environmentally friendly Biologist 40 132ndash136GRIFFIN JW PRICE DL KUETHE D amp GOLDBERG AM (1980) Neurotoxicity of misonidazole in rats

Neurotoxicology 1 653ndash666GRIMMER H amp JOSEPH A (1959) An epidemic of infectious erythema in Germany American Medical Association

Archives of Dermatology 80 283ndash285GUENGERICH PP (1990) Enzymic oxidation of xenobiotic chemicals Critical Reviews in Biochemistry and

Molecular Biology 25 97ndash153(1991) Reactions and significance of cytochrome P450 enzymes Journal of Biological Chemistry 266 10019ndash10022GUPTA RC (1985) Enhanced sensitivity of the [32p]-post labelling assay for aromatic carcinogen-DNA adducts

Cancer Research 51 6470ndash6491GURTNER HP (1979) Pulmonary hypertension lsquoPlexogenic Pulmonary Arteriopathyrsquo and the appetite depressant

drug aminorex post or propter Bulletin Europien Physiopathologique Respiratoire 15 897ndash923GUTFREUND H (1965) An Introduction to the Study of Enzymes Blackwell Scientific OxfordHABIG WH PABST MJ FLEISCHNER G et al (1974) The identity of glutathione S-transferase B with ligandin

a major binding protein of the liver Proceedings of the National Academy of Science USA 71 3879ndash3882HALL ES HALL SJ amp BOEKELHEIDE K (1992) Sertoli cells isolated from adult 2 5-hexanedione exposed rats

exhibit atypical morphology and actin distribution Toxicology and Applied Toxicology 117 9ndash18HANNA PE amp BANKS RB (1985) Arylhydroxylamines and arylhydroxamic acids conjugation reactions In

Bioactivation of foreign compounds (ed MWAnders) pp 375ndash402 Academic Press OrlandoHARD GC amp BUTLER WH (1970a) Cellular analysis of renal neoplasia induction of renal tumours in dietary

conditioned rats by dimethylnitrosamine with a reappraisal of morphological characteristics Cancer Research 302796ndash2805

(1970b) Cellular analysis of renal neoplasia light microscopic study of the development of interstitial lesions induced inthe rat kidney by a single carcinogenic dose of dimethylnitrosamine Cancer Research 30 2806ndash2815

(1971a) Ultrastructural study of the development of interstitial lesions leading to mesenchymal neoplasia induced in therat renal cortex by dimethylnitrosamine Cancer Research 31 337ndash347

(1971b) Ultrastructural analysis of renal mesenchymal tumour induced in the rat by dimethylnitrosamine CancerResearch 31 348ndash365

(1971c) Ultrastructural aspects of renal adenocarcinoma induced in the rat by dimethylnitrosamine Cancer Research31 366ndash372

REFERENCES 219

HASCHEK WM amp WITSCHI H (1979) Pulmonary fibrosismdasha possible mechanism Toxicology and AppliedPharmacology 51 475ndash487

HASHIMOTO K amp ALDRIDGE WN (1970) Biochemical studies on acrylamide a neurotoxic agent BiochemicalPharmacology 19 2591ndash2604

HASHIMOTO K HAYASHI M TANTI H amp SAKAMOTO J (1988) Toxicological aspects of acrylamideneuropathy Journal of the Union of Occupational and Environmental Hygiene 10 209ndash218

HASSALL KA(1990) The Biochemistry and Uses of Pesticides Macmillan BasingstokeHATEFI Y (1985) The mitochondrial electron transport and oxidative phosphorylation system Annual Reviews in

Biochemistry 54 1015ndash1069HAWKINS JM JONES WE BONNER FW amp GIBSON GG (1987) The effect of peroxisome proliferators on

microsomal and mitochondrial enzyme activities in the liver and kidney Drug Metabolism Reviews 18 441ndash515HAYES WJ Jr (1982) Pesticides Studied in Man Williams amp Wilkins BaltimoreHE F WANG S Liu L CHEN S ZHANG Z amp SUN J (1989) Clinical manifestations and diagnosis of acute

pyrethroid poisoning Archives of Toxicology 63 54ndash58HEIN DW RUSTAN TD DOLL MA et al (1992) Acetyltransferases and susceptibility to chemicals Toxicology

Letters 6465 123ndash130HEINDEL JJ GULATI DK MOUNCE RC RUSSELL SR amp LAMB JC (1989) Reproductive toxicity of

three phthalic esters in a continuous breeding protocol Fundamental and Applied Toxicology 12 508ndash518HENSCHLER D (1987) Mechanisms of genotoxicity of chlorinated aliphatic hydrocarbons In Selectivity and

Molecular Mechanisms of Toxicity (eds FDe Matteis amp EALock) pp 153ndash181 Macmillan BasingstokeHERBST AL COLE P COLTON T ROBBOY S amp SCULLY R (1977) Age-incidence and risk of

diethylstilboestrol-related clear cell adenocarcinoma of the vagina and cervix American Journal of Obstetrics andGynaecology 128 43ndash50

HERNBERG S (1980) Evaluation of epidemiological studies in assessing the long-term effects of occupational noxiousagents Scandinavian Journal of Work and Environmental Health 6 163ndash169

HEYLINGS JR (1991) Gastro-intestinal absorption of paraquat in the isolated mucosa of the rat Toxicology andApplied Pharmacology 107 482ndash493

HIGGINSON J amp MUIR CS (1979) Environmental carcinogenesis misconception and limitations to cancer controlJournal of the National Cancer Institute 63 1291ndash1298

HILL AB (1962) Statistical Methods in Clinical and Preventative Medicine Oxford University Press Oxford(1965) The environment and disease Proceedings of the Royal Society of Medicine 58 295ndash300HILL RH SCHURZ HH POSADA M et al (1995) Possible etiological agents for Toxic Oil Syndrome fatty acid

esters of 3-(N-phenylamino)-12-propanediol Archives of Environmental Contamination amp Toxicology 28259ndash264

HIMSWORTH II (1970) The Development of Organisation of Scientific Knowledge Heinemann LondonHINSEN JA (1980) Biochemical toxicology of acetaminophen Reviews in Biochemical Toxciology 2 103ndash129HIRANO S KODAMA N SHIBATA K amp SUZUKI KT (1993) Metabolism and toxicity of injected yttrium

chloride in rats Toxicology and Applied Pharmacology 121 224ndash232HODGKIN AL amp HUXLEY AF (1952) A quantitative description of membrane current and its application to

conduction and excitation in nerve Journal of Physiology 117 500ndash544HOFER W (1981) Chemistry of Metrifonate and Dichlorvos Acta Pharmacologica et Toxicologica 49 (suppl V)

7ndash14HOLAN G (1971) Rational design of insecticides Bulletin of the World Health Organization 44 355ndash362HOLMBOM B VOSS RH MORTIMER RD amp WONG A (1984) Fractionation isolation and characterisation of

Ames mutagenic compounds in kraft chlorination effluents Environmental Science and Technology 18 333ndash337 HOLMSTEDT B (1980) Prolegomena to Seveso Archives of Toxicology 44 211ndash230HOLMSTEDT B amp LILJESTRAND G (1963) Readings in Pharmacology Pergamon OxfordHOLMSTEDT B NORDGREN I SANDOZ M amp SUNDWALL A (1978) Metrifonate summary of toxicological

and pharmacological information available Archives of Toxicology 41 3ndash29

220 REFERENCES

HOOK JB amp HEWITT WR (1986) Toxic responses of the kidney In Toxicology The Basic Science of Poisons (edsCDKlaasson MOAmdur amp JDoull) pp 310ndash329 Macmillan New York

HOOK JB ROSE MS amp LOCK EA (1982) The nephrotoxicity of hexachloro-1 3-butadiene in the rat studies oforganic anion and cation transport in renal slices and the effect of monooxygenase inducers Toxicology andApplied Pharmacology 65 373ndash382

HOOK JB ISHMAEL J amp LOCK EA (1983) Nephrotoxicity of hexachloro-13-butadiene in the rat the effect ofage sex and strain Toxicology and Applied Pharmacology 67 121ndash131

HOOSER SB BEASLEY BR WATTE LL et al (1991) Actin filament alterations in rat hepatocytes induced invivo and in vitro by microcystin-LR a hepatotoxin from the blue green algae Microcystis aeruginosa VeterinaryPathology 28 259ndash266

HORTON VL SLEET RB JOHN-GREEN JA amp WELSCH F (1984) Developmental stage-specific and dose-related teratogenic effects of ethylene glycol monomethyl ether in CD-1 mice Toxicology and AppliedPharmacology 80 108ndash118

HORVATH JJ WITMER CM amp WITZ G (1992) Nephrotoxicity of the 11 acrolein-glutathione adduct in the ratToxicology and Applied Pharmacology 117 200ndash207

HUANG J SHIBATA E KATO K ASEADA N amp TAKEUCHI Y (1992) Chronic exposure to a n-hexaneinduces changes in nerve-specific marker proteins in the distal peripheral nerve of the rat Human andExperimental Toxicology 11 323ndash327

HUTSON DH (1982) Formation of lipophilic conjugates of pesticides and other xenobiotic compounds Progress inPesticide Biochemistry 2 171ndash184

HUTSON DH amp HATHWAY DE (1967) Toxic effects of chlorfenvinphos in dogs and rats BiochemicalPharmacology 16 949ndash962

HUTSON DH amp MILLBURN P (1991) Enzyme-mediated selective toxicity of an organophosphate and apyrethroid some examples from a range of animals Biochemical Society Transactions 19 737ndash740

HUTSON DH amp WRIGHT AS (1980) The effect of hepatic microsomal monooxygenase induction on themetabolism and toxicity of the organophosphorus insecticide chlorfenvinphos Chemico-Biological Interactions31 93ndash101

HUXTABLE RJ (1990) Activation and pulmonary toxicity of pyrrolizidine alkaloids Pharmacology andTherapeutics 47 371ndash389

HYDE EG amp CARMICHAEL WW (1991) Anatoxin-a(S) a naturally occurring organophosphate is an irreversibleactive site-directed inhibitor of acetylcholinesterase (EC 3117) Journal of Biochemical Toxicology 6 195ndash201

IARC (1982) Some industrial chemicals and dyestuffs IARC Monograph on the Evaluation of Carcinogenic Risk ofChemicals to Humans International Agency for Cancer Research Lyon France

INGRAM AJ amp GRASSO P (1985) Nuclear enlargement an early change produced in mouse epidermis bycarcinogenic chemicals applied topically in the presence of a promoter Journal of Applied Toxicology 5 53ndash60

(1987) Nuclear enlargement produced in mouse skin by carcinogenic mineral oils Journal of Applied Toxicology 7289ndash295

INSTITUTE OF MEDICAL ETHICS (1991) Lives in the Balance The Ethics of Using Animals in BiomedicalResearch (eds JASmith amp KMBoyd) Oxford University Press Oxford

IOANNIDES C amp PARKE DV (1990) Cytochrome P450 I family of microsomal haemoproteins and their role in themetabolic activation of chemicals Drug Metabolism Reviews 22 1ndash85

ISHIKAWA T (1992) The ATP-dependent glutathione S-conjugate export pump Trends in Biochemical Sciences 17463ndash468

JACOBS JM amp FORD WCL (1981) The neurotoxicity and antifertility properties of 6-chloro6-deoxyglucose in themouse Neurotoxicology 2 405ndash417

JAFFE DR HASSEL CD BRENDEL K amp GANDOLFI AJ (1983) In vivo and in vitro nephrotoxicity of thecysteine conjugate of hexachlorobutadiene Journal of Toxicology and Environmental Health 11 857ndash867

JAKOBY WR (1978) The glutathione-S-transferases a group of multifunctional detoxification proteins Advances inEnzymology 46 383ndash414

REFERENCES 221

JAKOBY WB amp ZIEGLER DM (1990) The enzymes of detoxification Journal of Biological Chemistry 26520715ndash20718

JAKOBY WB KETTERER B amp MANNERVIK B (1984) Glutathione transferase nomenclature BiochemicalPharmacology 33 2539ndash2540

JANSSON K MAKI-PAAKKANEN J VAITTINEN S-L et al (1993) Cytogenetic effects of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in rat peripheral lymphocytes in vitro and in vivo MutationResearch 229 25ndash28

JENCKS WP (1969) Catalysis in Chemistry and Enzymology McGraw-Hill New YorkJENNER P amp MARSDEN CD (1987) Parkinsonian syndrome caused by 1-methyl-4-phenyl1236-

tertahydropyridine (MPTP) in man and animals In Selectivity and Molecular Mechanisms of Toxicity (eds FDeMatteis and EALock) pp 213ndash248 Macmillan Basingstoke

JOHNSON MK (1975a) The delayed neuropathy caused by some organophosphorus esters mechanism and challengeCRC Critical Reviews in Toxicology 3 289ndash316

(1975b) Organophosphorus esters causing delayed neurotoxic effects mechanism of action and structureactivitystudies Archives of Toxicology 34 259ndash288

(1982) The target for initiation of delayed neurotoxicity by organophosphorus esters biochemical studies andtoxicological applications Reviews in Biochemical Toxicology 4 141ndash212

(1993) Symposium introduction retrospect and prospects for neuropathy target esterase (NTE) and the delayedpolyneuropathy (OPIDP) induced by some organophosphorus esters Chemico-Biological Interactions 87339ndash346

JOHNSON MK amp SAFI JM (1993) The Rminus(+) isomer of O-n-hexyl S-methyl phosphorothioamidate causes delayedneuropathy in hens after generation of a form of inhibited neuropathy target esterase (NTE) which can bereactivated ex vivo Chemico- Biological Interactions 87 443ndash48

JONES HB amp CAVANAGH JB (1983a) Distortions of the nodes of Ranvier from axonal distension by filamentousmasses in hexacarbon intoxication Journal of Neurocytology 12 439ndash458

(1983b) Cytochemical staining characteristics of peripheral nodes of Ranvier in hexacarbon intoxication Journal ofNeurocytology 12 459ndash473

JUKES JH (1983) Chasing a receeding zero impact of the zero threshold concept on action of the regulatory officialsJournal of the American College of Toxicology 2 147ndash160

KADAR T COHEN G SAHAR R ALKALIE D amp SHAPIRA S (1992) Long term study of brain lesionsfollowing Soman in comparison to DFP and Metrazol poisoning Human and Experimental Toxicology 11517ndash523

KAGI JHR amp VALLEE BL (1960) Metallothionein a cadmium and zinc-containing protein from equine renalcortex Journal of Biological Chemistry 235 3460ndash3465

KAGI JHR HIMMELHOCH SR WHANGER PD BETHUNE JL amp VALLEE BE (1974) Equine hepaticand renal metallothioneins Journal of Biological Chemistry 249 3537ndash3542

KALOW W (1962) Pharmacogenetics Heredity and the Response to Drugs WBSaunders PhiladelphiaKAMAT SR MAHASHUR AA TIWARI AKB et al (1985a) Early observations on pulmonary changes and

clinical morbidity due to the isocyanate gas leak in Bhopal Journal of Post-graduate Medicine 31 63ndash72KAMAT SR PATEL MH KOLHATHKAR VP DAVE AA amp MAHASHUR AA (1985b) Sequential

respiratory changes in those exposed to the gas leak in Bhopal Indian Journal of Medical Research 82(suppl)20ndash38

KAMATAKI T LIN MCML BELCHER DH amp NEAL RA (1976) Studies of the metabolism of parathion withan apparently homogeneous preparation of rabbit liver cytochrome P450 Drug Metabolism and Disposition 4180ndash189

KAMINSKY LS (1985) Benzene and substituted benzenes In Bioactivation of Foreign Compounds (edMWAnders) pp 157ndash175 Academic Press Orlando

KAMINSKY LS amp FASCO MJ (1992) Small intestinal cytochrome P450 Critical Reviews in Toxicology 21407ndash422

222 REFERENCES

KAO CY (1966) Tetrodotoxin saxitoxin and their significance in the study of excitation phenomenaPharmacological Reviews 18 997ndash1049

KAVET R amp NAUSS KM (1990) The toxicity of inhaled methanol vapors CRC Critical Reviews in Toxicology 2121ndash50

KAWADA T KOYAMA H amp SUZUKI S (1989) Cadmium NAG activity and 2-microglobulin in the urine ofcadmium pigment workers British Journal of Industrial Medicine 46 52ndash55

KEAYS R HARRISON PM WENDON JA et al (1991) Intravenous acetylcysteine in paracetamol-inducedfulminant hepatic failure a prospective controlled trial British Medical Journal 303 1026ndash1029

KEDDERIS LB MILLS JJ ANDERSEN ME amp BIRNBAUM LS (1993) A physiologically basedpharmacokinetic model for 2378-tetrabromodibenzo-p-dioxin (TBDD) in the rat tissue distribution and CYP1Ainduction Toxicology and Applied Pharmacology 121 87ndash98

KEELING AK PRATT IS ALDRIDGE WN amp SMITH LL (1981) The enhancement of paraquat toxicity inrats by 85 oxygen lethality and cell-specific lung damage British Journal of Experimental Pathology 62643ndash654

KEELING PL SMITH LL amp ALDRIDGE WN (1982) The formation of mixed disulphides in rat lung followingparaquat administration correlation with changes in intermediary metabolism Biochimica Biophysica Acta 716249ndash257

KENNEDY AL SINGH G ALARIE Y amp BROWN WE (1993) Autoradiographic analyses of guinea pig airwaytissue following inhalation exposure to 14C-labelled methyl isocyanate Fundamental and Applied Pharmacology20 57ndash67

KETLEY JN HABIG WH amp JAKOBY WB (1975) Binding of non-substrates ligands to the glutathionetransferases Journal of Biological Chemistry 250 8670ndash8673

KILBOURNE EM BERNERT JT POSADA DE LA PAZ M et al (1988) Chemical correlates of pathogenicityof oils related to the toxic oil syndrome epidemic in Spain American Journal of Epidemiology 127 1210ndash1227

KILBOURNE EM POSADA DE LA PAZ M ABAITUA BORDA I et al (1991) Toxic Oil Syndrome a currentclinical and epidemiological summary including comparisons with the eosinophilia-myalgia syndrome Journal ofthe American College of Cardiology 18 711ndash717

KIMBROUGH R D (1980) Occupational exposure In Halogenated Biphenyls Terphenyls NaphthalenesDibenzodioxins and Related Compounds (ed RDKimbrough) pp 373ndash397 ElsevierNorth-Holland Amsterdam

KIMBROUGH RD and GAINES TB (1971) Hexachlorophene effects on the rat brain Archives of EnvironmentalHealth 23 114ndash118

KIMMEL EG FISH RH amp CASIDA JE (1976) Bioorganotin chemistry metabolism of organotin compounds inmicrosomal monooxygenase systems and in mammals Journal of Agricultural and Food Chemistry 25 1ndash9

KLAASSEN CD (1986) Distribution excretion and absorption of toxicants In Casarett and Doullrsquos Toxicology TheBasic Science of Poisons (eds CDKlaassen MOAmdur amp JDoull) pp 33ndash63 Macmillan New York

KLAASSEN CD amp WATKINS JB (1984) Mechanisms of bile formation hepatic uptake and biliary secretionPharmacological Reviews 36 1ndash67

KLAASSEN CD EATON DL amp CAGEN SZ (1981) Hepatobiliary disposition of xenobiotics In Progress inDrug Metabolism (eds JWBridges amp LFChasseaud) Vol 6 pp 1ndash75 Wiley Chichester

KOELLE GB ed (1963) Cholinesterases and Anticholinesterase Agents Springer-Verlag BerlinKOIVUSALO M JAAKKOLA JJK VARTIAINEN T et al (1994) Drinking water mutagenicity and

gastrointestinal and urinary tract cancers an ecological study in Finland American Journal of Public Health 81233ndash1228 See also 8 1211ndash1213

KOMULAINEN H amp BONDY SC (1988) Increased free intracellular Ca2+ by toxic agents an index of potentialneurotoxicity Trends in Pharmacological Sciences 9 154ndash156

KOPELMAN H ROBERTSON MH SANDERS P G amp ASH I (1966) The Epping jaundice British MedicalJournal 1 514ndash516

KRAGH-HANSEN U (1981) Molecular aspects of ligand binding to serum albumin Pharmacological Reviews 3317ndash53

REFERENCES 223

KRASAVAGE WJ OrsquoDONOGHUE JL DIVINCENZO GD amp TERHAAR CJ (1980) The relativeneurotoxicity of methyl-n-butyl ketone n-hexane and their metabolites Toxicology and Applied Pharmacology 52433ndash41

KRONBERG L amp VARTIAINEN T (1988) Ames mutagenicity and concentration of the strong mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone and its geometric isomer E-2-chloro-3-(dichloromethyl)-4-oxo-butenoic acid in chlorine treated tap waters Mutation Research 206 177ndash182

KUPERMAN AG (1958) Effects of acrylamide on the central nervous system of the cat Journal of Pharmacologyand Experimental Therapeutics 123 180ndash192

LADU BN (1972) Pharmacogenetics defective enzymes in relation to reaction to drugs Annual Review of Medicine23 453ndash468

LAIDLER KJ (1958) The Chemical Kinetics of Enzyme Action Oxford University Press OxfordLAKE BG GRAY TJB PELS RIJCKEN WR BEAMAND JA amp GANGOLLI SD (1984) The effect of

hypolipidaemic agents of peroxisomal mdashoxidation and MFO activities in primary cultures of rat hepatocytesrelationship between induction of palmitoyl-CoA oxidation and lauric acid hydroxylation Xenobiotica 14269ndash276

LANARUS T COOK CM ERIKSSON JE MERILNOTO JA amp HOTOKKA M (1991) Computer modellingof the 3-dimensional structure of the cyanobacterial hepatotoxin microcystin-LR and nodularin Toxicon 29901ndash906

LANGSTONE JW FORNO LS REBERT CS amp IRWIN I (1984) Selective nigral toxicity after systemicadministration of 1-methyl-4-phenyl-1236-tetrahydropyridine (MPTP) in the squirrel monkey Brain Research292 390ndash394

LARSON JL amp BULL RJ (1992) Species differences in the metabolism of trichloroethylene to the carcinogenicmetabolites trichloroacetate and dichloroacetate Toxicology and Applied Pharmacology 115 278ndash285

LARSSON A ORRENIUS S HOLMGREN A amp MANNERVIK B (1983) Functions of GlutathioneBiochemical Physiological Toxicological and Clinical Aspects Raven New York

LAUWERYS RR (1986) Occupational toxicology In Toxicology The Basic Science of Poisons (eds CDKlaassenMOAmdur amp JDoull) pp 902ndash915 Macmillan New York

(1989) Metalsmdashepidemiological and experimental evidence for carcinogenicity Archives of Toxicology 13 (suppl)21ndash27

LAUWERYS R amp LOIS-FERDINAND (1984) The need for closer collaboration between clinical and experimentaltoxicologists Human Toxicology 3 61ndash62

LAUWERYS R AMERY A BERNARD A et al (1990) Health effects of environmental exposure to cadmiumobjectives design and organisation of the Cadmibel study a cross sectional morbidity study carried out in Belgiumfrom 1985ndash1989 Environmental Health Perspectives 87 283ndash289

LAUWERYS R BERNARD A BUCKET JP et al (1991) Does environmental exposure to cadmium represent ahealth risk Conclusions from the Cadmibel study Acta Clinica Belgica 46 219ndash225

LAZARO WP (1978) Rat liver peroxisomes catalyse the -oxidation of fatty acids Journal of Biological Chemistry253 1522ndash1528

LAZARO WPL amp FUJIKI Y (1985) Biogenesis of peroxisomes Annual Reviews of Cell Biology 1 489ndash530LEADBEATER L (1988) When all else fails (Chemical Defence) Chemistry in Britain 24 683ndash688LEBLOND CP amp CLERMONT Y (1952) Definition of the stages of the cycle of the seminiferous epithelium in the

rat Annals of the New York Academy of Science 55 548ndash573LEVINE RR amp STEINBERG GM (1966) Intestinal absorption of pralidoxime and other aldoximes Nature

(London) 209 269ndash271LIEBER CS (1990) Mechanism of ethanol-induced hepatic injury Pharmacology and Therapeutics 46 1ndash41LIEBERMAN MW VERBIN RS LANDAY M et al (1970) A probable role for protein synthesis in intestinal

epithelial cell damage induced in vivo by cytosine arabinoside nitrogen mustard or X-irradiation Cancer Research30 942ndash951

224 REFERENCES

LIJINSKY W Loo J amp ROSS AE (1968) Mechanism of alkylation of nucleic acids by nitrosodimethylamineNature (London) 218 1174ndash1175

LILLIE RD amp SMITH MI (1932) The histopathology of some neurotoxic phenyl esters USA Public Health Reports47 54ndash64

LINDAMOOD G (1991) Xenobiotic transformation In Hepatotoxicity (eds RG Meeks SD Harrison amp RJBull)pp 139ndash180 CRC Press Boca Raton Florida

LITWACK G KETTERER B amp ARIAS IM (1971) Ligandin a hepatic protein which binds steroids bilirubincarcinogens and a number of exogenous organic anions Nature (London) 234 466ndash467

LOCK EA amp ISHMAEL J (1979) The acute toxic effects of hexachloro-13-butadiene on the rat kidney Archives ofToxicology 43 47ndash57

LOCK EA MITCHELL AM amp ELCOMBE CR (1989) Biochemical mechanisms of induction of hepaticperoxisome proliferation Annual Reviews in Pharmacology and Toxicology 29 145ndash163

LOTTI M (1987) Organophosphorus-induced delayed neuropathy in man and perspectives for biomonitoring Trendsin Pharmacological Sciences 8 176ndash177

(1992) The pathogenesis of organophosphorus polyneuropathy Critical Reviews in Toxicology 21 465ndash488LOTTI M amp JOHNSON MK (1980) Repeated small doses of a neurotoxic organophosphate monitoring of

neurotoxic esterase in brain and spinal cord Archives of Toxicology 45 263ndash271LOTTI M BECKER CE amp AMINOFF MJ (1984) Organophosphate polyneuropathy pathogenesis and

prevention Neurology 34 658ndash662LOTTI M CAROLDI S CAPODICASA E amp MORETTO A (1991) Promotion of organophosphorus-induced

delayed polyneuropathy by phenylmethanesulfonyl fluoride Toxicology and Applied Pharmacology 108234ndash241

LOTTI M MORETTO A CAPODICASA E et al (1993) Interactions between neuropathy target esterase and itsinhibitors and the development of polyneuropathy Toxicology and Applied Pharmacology 122 165ndash171

LUSTER MI amp DEAN JH (1982) Immunological hypersensitivity resulting from environmental or occupationalexposure to chemicals a state-of-the-art workshop summary Fundamental and Applied Toxicology 2 327ndash330

LUSTER MI BLANK JA amp DEAN JH (1987) Molecular and cellular basis of chemically inducedimmunotoxicity Annual Review of Pharmacology and Toxicology 27 23ndash49

MAGEE PN (1956) Toxic liver injury the metabolism of dimethylnitrosamine Biochemical Journal 64 676ndash682MAGEE PN amp BARNES JM (1956) The production of malignant primary hepatic tumours in the rat by feeding

dimethylnitrosamine British Journal of Cancer 10 114ndash122(1967) Carcinogenic nitroso compounds Advances in Cancer Research 10 163ndash246MAGEE PN amp FARBER E (1962) Toxic liver injury and carcinogenicity methylation of rat liver nucleic acids by

dimethylnitrosamine Biochemical Journal 83 114ndash124 MAGOS L (1976) The effects of dimercaptosuccinic acid on the excretion and distribution of mercury in rats and mice

treated with mercuric chloride and methylmercury chloride British Journal of Pharmacology 56 479ndash84(1981) Metabolic factors in the distribution and half time of mercury after exposure to different mercurials In

Industrial and Environmental Xenobiotics (eds IGut MCikrt amp GLPlaa) pp 1ndash15 Springer-Verlag BerlinMAKAR AB TEPHLY TR SAHIN G amp OSWEILER G (1990) Formate metabolism in young swine

Toxicology and Applied Pharmacology 105 315ndash320MALATS N REAL FX amp PORTA M (1993) DDT and pancreatic cancer Journal of the National Cancer

Institute 85 328MALI JWH amp MALTEN KE (1966) An epidemic of polymorph toxic erythema in the Netherlands in 1960 Acta

Dermatol-Venereol 46 123ndash135MANNERVIK B AWASHTHI IC BOARD PG et al (1992) Nomenclature for human glutathione transferases

Biochemical Journal 282 305ndash308MARGOSHES M amp VALLEE BL (1957) A cadmium protein from equine kidney cortex Journal of the American

Chemical Society 79 4813ndash4814

REFERENCES 225

MARON DM amp AMES BN (1983) Revised methods for the Salmonella mutagenicity test Mutation Research 113173ndash215

MARSELOS M amp TOMATIS L (1992) I Pharmacology toxicology and carcinogenicity in humans EuropeanJournal of Cancer 28A 1182ndash1189

MARTIN CN and GARNER RC (1977) Aflatoxin B1-oxide generated by chemical or enzymic oxidation ofaflatoxin B1 causes guanine substitution in nucleic acids Nature (London) 267 863ndash865

MARTIN-AMAT G MCMARTIN KE HAYREH SS HAYREH MS amp TEPHLY TR (1978) Methanolpoisoning ocular toxicity produced by formate Toxicology and Applied Pharmacology 45 201ndash208

MARTINEacuteZ-TELLO FJ NAVAS-PALACIOS JJ RICOY JR et al (1982) Pathology of a new toxic syndromecaused by ingestion of adulterated oil in Spain Virchows Archives (A) 397 261ndash285

MATSUNAGA S MOORE RE NIEMCZURA WP amp CARMICHAEL WW (1989) Anatoxin-a(S) a potentanticholinesterase from Anabaena flos-aquae Journal of the American Chemical Society 111 8021ndash8023

MATTOCKS AR (1968) Toxicity of pyrollizidine alkaloids Nature (London) 217 723ndash728(1986) Chemistry and Toxicology of Pyrrolizidine Alkaloids Academic Press LondonMATTOCKS AR LEGG RF amp JUKES R (1990) Trapping of short-lived electrophilic metabolites of pyrrolizidine

alkaloids escaping from perfused rat liver Toxicology Letters 54 93ndash99MCCONKEY DJ HARTZELL P DUDDY SK HAKANSSON H amp ORRENIUS S (1988) 2378-

Tetrachlorodibenzo-p-dioxin kills immature thymocytes by Ca2+-mediated endonuclease activation Science 242256ndash259

MCONKEY DJ amp ORRENIUS S (1989) 2378-Tetrachlorodibenzo-p-dioxin (TCDD) kills glucocorticoid-sensitivethymocytes in vivo Biochemical and Biophysical Research Communications 160 1003ndash1008

MCLAREN DS (1978) Nutritional deficiencies in animals and man vitamin A In Effect of Nutrient Deficiencies inMan Handbook Series in Nutrition and Food (ed MRecheigl) Vol 3 pp 107ndash116 CRC Press Boca RatonFlorida

MCLEAN EK (1970) The toxic action of pyrrolizidine (Senecio) alkaloids Pharmacological Reviews 22 429ndash83MCLEMORE TL ADELBERG S LIU MC et al (1990) Expression of CYP1A1 gene in patients with lung

cancer evidence for cigarette smoke-induced expression in normal lung tissue and for altered gene regulation inprimary pulmonary carcinomas Journal of the National Cancer Institute 82 1333ndash1339

MEBUS CA CLARKE DA STEDMAN DB amp WELSCH F (1992) 2-Methoxyethanol metabolism in pregnantCD-1 mice and embryos Toxicology and Applied Pharmacology 112 87ndash94

MEDAWAR P (1986) Memoir of a Thinking RadishmdashAn Autobiography Oxford University Press OxfordMEEHAN AP (1984) Rats and Mice Their Biology and Control pp 1ndash383 Rentokil Ltd East Grinstead UKMEIER JR (1988) Genotoxicity activity of organic chemicals in drinking water Mutation Research 196 211ndash245MEISTER A amp ANDERSON ME (1983) Glutathione Annual Review of Biochemistry 52 432ndash435MEREDITH C amp JOHNSON MK (1988) Neuropathy target esterase rates of turnover in vivo following covalent

inhibition with phenyl di n-pentylphosphinate Journal of Neurochemistry 51 1097ndash1101MESNIL RT TESTA B amp JENNER P (1985) Arylhydrocarbon hydroxylase in rat brain microsomes Biochemical

Pharmacology 34 435ndash436MILATOVIC D amp JOHNSON MK (1993) Reactivation of phosphorodiamidated acetylcholinesterase (AChE) and

neuropathy target esterase (NTE) by treatment of inhibited enzyme with potassium fluoride Chemico-BiologicalInteractions 87 425ndash430

MILLER MS amp SPENCER PS (1985) The mechanisms of acrylamide axonopathy Annual Reviews inPharmacology and Toxicology 25 643ndash666

MILLER RR HERMANN EA LANGVARDT PW MCKENNA MJ amp SCHWETZ BA (1983) Comparativemetabolism and disposition of ethylene glycol monomethyl ether and propylene glycol monomethyl ether in malerats Toxicology and Applied Pharmacology 67 229ndash237

MINCHIN RF amp BOYD MR (1983) Localisation of metabolic activation and deactivation systems in the lungsignificance to the pulmonary toxicity of xenobiotics Annual Reviews of Pharmacology and Toxicology 23217ndash238

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MORETTO A CAPODICASA E PERIACA M amp LOTTI M (1991) Age sensitivity to organophosphate-induceddelayed polyneuropathy Biochemical Pharmacology 41 1497ndash1504

MORETTO A CAPODICASA E amp LOTTI M (1992) Clinical expression of organophosphateinduced delayedpolyneuropathy in rats Toxicology Letters 63 97ndash102

MORGAN KT GROSS EA LYGHT O amp BOND JA (1985) Methodological and biochemical studies of anitrobenzene-induced encephalopathy in rats Neurotoxicology 6 105ndash116

MOORHOUSE KG LOGAN CJ HUTSON DH amp DODDS PP (1990) The incorporation of 3-phenoxybenzoicacid and other xenobiotic acids into xenobiotic lipids by enzymes of the monoacylglycerol pathway in microsomesfrom adult and neonatal tissues Biochemical Pharmacology 39 1529ndash1536

MOORHOUSE KG DODDS PP amp HUTSON DH (1991) Xenobiotic triacylglycerol formation in isolatedhepatocytes Biochemical Pharmacology 41 1179ndash1185

MOSS EJ THOMAS LV COOK MW et al (1985) The role of metabolism in methoxyethanolinduced testiculartoxicity Toxicology and Applied Pharmacology 79 480ndash89

MULDER GJ (1992) Pharmacological aspects of drug conjugates is morphine 6-glucuronide an exception Trends inPharmacological Sciences 13 302ndash304

MURRAY RE amp GIBSON JE (1972) A comparative study of paraquat intoxication in rats guinea pigs andmonkeys Experimental and Molecular Pathology 17 317ndash325

NARAHASHI T (1990) Occurrence and mechanism of action of marine neurotoxins In Basic Science in Toxicology(eds GNVolans JSims PMSullivan amp PTurner) pp 580ndash595 Taylor amp Francis London

(1992) Nerve membrane Na+ channels as targets of insecticides Trends in Pharmacological Sciences 13 236ndash241 NASH JA KING LJ LOCK EA amp GREEN T (1984) The metabolism and disposition of hexachloro-13-

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gene mapping accession numbers early trivial names of enzymes and nomenclature DNA and Cell Biology 121ndash51

NEMERY B amp ALDRIDGE WN (1988a) Studies on the metabolism of the pneumotoxin OSS-trimethylphosphorodithioate 1 Lung and liver microsomes Biochemical Pharmacology 37 3709ndash3715

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NEMERY B DINSDALE D SPARROW S amp RAY DE (1985) Effects of methylisocyanate on the respiratorytract of rats British Journal of Industrial Medicine 42 799ndash805

NEUMANN HG (1980) Dose-response relationship in the primary lesion of strong electrophilic carcinogensArchives of Toxicology (Suppl 3) 69ndash77

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NORDGREN I BERGSTROM M HOLMSTEDT B amp SANDOZ M (1978) Transformation and action ofmetrifonate Archives of Toxicology 41 31ndash41

NUYTS GD ROELS HA VERPOOTEN GF et al (1992) Intestinal-type alkaline phosphatase in urine as anindicator of mercury induced effects on the S3 segment of the proximal tubule Nephrology Dialysis andTransplantation 7 225ndash229

OrsquoBRIEN RD TRIPATHI RK amp HOWELL LL (1978) Substrate preferences of wild mutant houseflyacetylcholinesterase and a comparison with bovine erythrocyte enzyme Biochimica Biologica Acta 526 129ndash134

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ORRENIUS S amp MOLDEUS P (1984) The multiple role of glutathione in drug metabolism Trends inPharmacological Sciences 5 432ndash435

ORWELL G (1944) Essay No 68 Arthur Koestler In The Collected Essays Journalism and Letters of GeorgeOrwell Volume 3 1943ndash1945 pp 270ndash282 Penguin London

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PADDLE GM (1983) Incidence of liver cancer and trichloroethylene manufacture joint study by industry and acancer registry British Medical Journal 286 846ndash847

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Journal 67 280ndash286PETERS RA STOCKEN LA amp THOMPSON RHS (1945) British anti-lewisite (BAL) Nature (London) 156

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PHILBERT MA NOLAN CC CREMER JE TUCKER D amp BROWN AW (1987) 13-Dinitrobenzene-induced encephalopathy in rats Neuropathology and Applied Neurobiology 13 371ndash389

PIETERS RHH BOL M SEINEN W amp PENNINKS AH (1992) The organotin-induced thymus atrophycharacterised by depletion of CD4+CD8+ thymocytes is preceded by a reduction of the immature CD4minusCD8+

TcR minuslowCD2high thymoblast subset Immunology 76 203ndash208PLAA GL (1986) Toxic responses in the liver In Toxicology The Basic Science of Poisons (eds CDKlaassen

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and Bacteriology 106 235ndash249PLESTINA R DAVIS A amp BAILEY DR (1972) Effect of metrifonate on blood cholinesterases in children during

treatment of Schistosomiasis Bulletin of the World Health Organization 46 747ndash759POHJANVIRTA R KULJU T MORSELT AFW et al (1989) Target tissue morphology and serum biochemistry

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POLAND A amp KNUTSON JC (1982) 2378-Tetrachlorodibenzo-p-dioxin and related halogenated aromatichydrocarbons examination of the mechanisms of toxicity Annual Review of Pharmacology and Toxicology 22517ndash554

POPPER KR (1974) Conjectures and Refutations The Growth of Scientific Knowledge Routledge amp Kegan PaulLondon

PORTER TD amp COON MJ (1991) Cytochrome P450 multiplicity of isoforms substrates and catalytic andregulatory mechanisms Journal of Biological Chemistry 266 13469ndash13472

POSKANZER D amp HERBST A (1977) Epidemiology of vaginal adenosis and adenocarcinoma associated withexposure to stilboestrol in utero Cancer 39 1892ndash1895

POTTS AM PRAGLIN J FARKAS I ORBISON L amp CHICKERING D (1955) Studies on the visual toxicityof methanol VIII Additional observation on methanol poisoning in the primate test object American Journal ofOpthamology 40 76ndash82

PRICE SC HALL DE amp HINTON RH (1985) Lipid accumulation in the livers of chlorpromazine-treated ratsdoes not induce peroxisome proliferation Toxicology Letters 25 11ndash18

PRINEAS J (1969) The pathogenesis of dying back polyneuropathies 2 An ultrastructural study of experimentalacrylamide intoxication in the cat Journal of Neuropathology and Experimental Neurology 28 598ndash621

PROUT MS PROVAN WM amp GREEN T (1985) Species differences in response to trichloroethylene IPharacokinetics in rats and mice Toxicology and Applied Pharmacology 79 389ndash400

PULIDO P KAGI JHR amp VALLEE BL (1966) Isolation and some properties of human metallothioneinBiochemistry 5 1768ndash1777

PURCHASE IFH (1994) Current knowledge of mechanisms of carcinogenicity genotoxins versus non-genotoxinsHuman and Experimental Toxicology 13 17ndash28

PURCHASE IFH amp THERON JJ (1968) The acute toxiciry of ochratoxin A to rats Food and CosmeticToxicology 6 479ndash483

PURCHASE IFH STAFFORD J amp PADDLE GM (1987) Vinyl chloride an assessment of the risk ofoccupational exposure Food and Chemical Toxicology 25 187ndash202

RAAG R amp POULOS T (1991) Crystal structures of cytochrome P450CAM complexed with camphane thiocamphorand adamantane factors controlling P450 substrate hydroxylation Biochemistry 30 2674ndash2684

RAFFRAY M MCCARTHY D SNOWDEN RT amp COHEN GM (1993) Apoptosis as a mechanism of tributyltincytotoxicity relationship of apoptotic markers to biochemical and cellular effects Toxicology and AppliedPharmacology 119 122ndash130

RANDERATH K REDDY MF amp GUPTA RC (1981) 32P-Labelling test for DNA damage Proceedings of theNational Academy of Sciences 78 6126ndash6129

RANDERATH K RANDERATH E AGRAWAL HP et al (1985) Postlabelling methods for carcinogen-DNAadduct analysis Environmental Health Perspectives 62 57ndash65

RAG MS amp REDDY JKB (1987) Peroxisome proliferation and hepatocarcinogenesis Carcinogenesis 8 631ndash636RAO MS THORGEIRSSON S REDDY MK et al (1986) Induction of peroxisome proliferation in hepatocytes

transplanted into the anterior chamber of the eye American Journal of Pathology 124 519ndash527RAWLINGS SJ SHUKER DFG WEBB M amp BROWN NA (1985) The teratogenic potential of alkoxy acids in

post-implantation rat embryo culture structure-activity relationships Toxicology Letters 28 49ndash58RAY DE BROWN AW CAVANAGH JB et al (1992) Functionalmetabolic modulation of the brain stem

lesions caused by 13-dinitrobenzene in the rat Neurotoxicology 13 379ndash388REDDY BS COHEN LA MCCOY GD et al (1980) Nutrition and its relationship to cancer Advances in Cancer

Research 32 237ndash345REDDY JK amp KUMAR NS (1977) The peroxisome proliferation associated polypeptide in rat liver Biochemical

and Biophysical Research Communications 77 824ndash829

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REDDY JK amp LALWANI ND (1983) Carcinogenesis by hepatic peroxisome proliferators evaluation of the risk ofhypolipidaemic drugs and industrial plasticisers to humans Critical Reviews in Toxicology 12 1ndash58

REDDY JK LALWANI ND QURESHI SA REDDY MK amp MOEHLE CM (1984a) Induction of hepaticperoxisome proliferation in non-rodent species including primates American Journal of Pathology 114 171ndash183

REDDY JK RAO MS QURESHI SA et al (1984b) Induction and origin of hepatocytes in rat pancreas Journalof Cell Biology 98 2081ndash2090

REDDY JK JIRTLE RL WATANABE TK et al (1984c) Response of hepatocytes transplanted into syngeneichosts and heteroplanted into athymic mice to peroxisomal proliferators Cancer Research 44 2582ndash2589

REED DJ (1990) Glutathione toxicological implications Annual Reviews of Pharmacology and Toxicology 30603ndash631

REEVES PR CASE DE JEPSON HT et al (1978) Practolol metabolism II Metabolism in human subjectsJournal of Pharmacology and Experimental Therapeutics 205 489ndash498

REGAN T (1983) The Case for Animal Rights Routledge amp Kegan Paul LondonREGGIANI G (1983) An overview on the health effects of halogenated dioxins and related compounds the Yusho and

Taiwan episodes In Accidental Exposure to Dioxins (eds FCoulston amp FPocchiari) pp 39ndash67 Academic PressNew York

REID WD (1972) Mechanism of allyl alcohol-induced hepatic necrosis Experientia 28 1058ndash1061REINER E KRAUTHACKER B SIMEON V amp SKRINJARIC-SPOLJAR M (1975) Mechanism of inhibition in

vitro of mammalian acetylcholinesterase and cholinesterase in solution of OO-dimethyl 222-trichloro-1-hydroxyethyl phosphate (trichlorphon) Biochemical Pharmacology 24 717ndash722

RICKARD J amp BRODIE ME (1985) Correlation of blood and brain levels of the neurotoxic pyrethroid deltamethrinwith the onset of symptoms in rats Pesticide Biochemistry and Physiology 23 143ndash156

ROumlE O (1982) Species differences in methanol toxicity Critical Reviews in Toxicology 10 275ndash287ROELS HA LAUWERYS RR BUCHET JP et al (1989) Health significance of cadmium induced renal

dysfunction a five year follow up British Journal of Industrial Medicine 46 755ndash764ROGULJA PV KOVAC W amp SCHMID H (1973) Metronidazol-encephalopathie der ratte Acta Neuropathologica

(Berlin) 25 36ndash45ROITT IM BROSTOFF J amp MALE DK (1989) Immunology Gower Medical Publishing LondonROMERO I BROWN AWCAVANAGH JB et al (1991) Vascular factors in the neurotoxic damage caused by 1

3-dinitrobenzene in the rat Neuropathology and Applied Neurobiology 17 495ndash508ROSE OP amp DEWAR AJ (1983) Intoxication with four synthetic pyrethroids fails to show any correlation between

neuromuscular dysfunction and neurobiochemical abnormalities in rats Archives of Toxicology 53 297ndash316ROSE GP DEWAR AJ amp STRATFORD IJ (1980) A biochemical method for assessing the neurotoxic effects of

misonidazole in the rat British Journal of Cancer 42 890ndash899ROSE MS amp ALDRIDGE WN (1968) The interaction of triethyltin with components of animal tissues

Biochemical Journal 106 821ndash828ROSE MS SMITH LL amp WYATT I (1974) Evidence for energy-dependent accumulation of paraquat in rat lung

Nature (London) 252 314ndash315ROSE MS LOCK EA SMITH LL amp WYATT I (1976) Paraquat accumulation tissue and species specificity

Biochemical Pharmacology 25 419ndash423ROUGHTON FJW amp DARLING RC (1944) The effect of carbon dioxide on the oxygen dissociation curve

American Journal of Physiology 141 17ndash31ROWLAND IR MALLETT AK amp WISE A (1985) The effect of diet on the mammalian gut flora and its

metabolic activity CRC Critical Reviews in Toxicology 16 31ndash103ROYAL SOCIETY STUDY GROUP (1992) Risk Analysis Perception and Management Royal Society LondonRUSSELL LD (1980) Sertoli-germ cell interactions a review Gamete Research 3 179ndash202SAFE S (1984) Polychlorinated biphenyls (PCBrsquos) and polybrominated biphenyls (PBBrsquos) biochemistry toxicology

and mechanism of action CRC Critical Reviews in Toxicology 13 319ndash396

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(1990) Polychlorinated biphenyls (PCBs) dibenzo-p-dioxins (PCDDs) dibenzofurans (PCDFs) and related compoundsenvironmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs)CRC Critical Reviews in Toxicology 21 51ndash88

SAKAMOTO J KUROSAKA Y amp HASHIMOTO K (1988) Histological changes of acrylamideinduced testicularlesions in mice Experimental and Molecular Pathology 48 324ndash334

SANDERMAN H (1992) Plant metabolism of xenobiotics Trends in Biochemical Sciences 17 82ndash84SANDLER M ed (1980) Enzyme Inhibitors as Drugs Macmillan BasingstokeSANDLER M amp SMITH HJ eds (1989) Design of Enzyme Inhibitors as Drugs Oxford University Press Oxford SAYRE LM SHEARSON CM WONGRONGKOLRIT T MEDORI R amp GAMBETTI P (1986) Structural

basis of -diketone neurotoxicity non-neurotoxicity of 33-dimethyl-25-hexanedione a -diketone incapable ofpyrrole formation Toxicology and Applied Pharmacology 84 36ndash44

SCATCHARD G (1949) The attractions of proteins for small molecules Annals of the New York Academy ofSciences 51 660ndash672

SCHANNE FAX KANE AB YOUNG EE amp FARBER JL (1979) Calcium dependence of toxic cell death afinal common pathway Science 206 700ndash702

SCHAUMBURG HH WISMEWSKI HM amp SPENCER PS (1974) Ultrastructural studies of the dying backprocess I peripheral nerve terminal and axonal degeneration in synthetic acrylamide intoxication Journal ofNeuropathology and Experimental Neurology 33 260ndash284

SCHELINE RR (1973) Metabolism of foreign compounds by gastrointestinal micro-organisms PharmacologicalReviews 25 451ndash523

SCHMAHL D (1979) Problems of dose-response studies in chemical carcinogenesis with special reference to N-nitroso compounds CRC Critical Reviews in Toxicology 6 257ndash281

SCHMECHEL D MARANGOS PJ ZIS AR BRIGHTMAN M amp GOODWIN FK (1978) Brain enolases asspecific markers of neuronal and glial cells Science 199 313ndash315

SCHNEIDER H amp CERVOacuteS-NAVARRO J (1974) Acute gliopathy in spinal cord and brain stem induced by 6-aminonicotinamide Acta Neuropathologica (Berlin) 27 11ndash23

SCOTT JK NEUMAN WF amp ALLEN R (1950) The effect of added carrier on the distribution and excretion ofsoluble Be7 Journal of Biological Chemistry 182 291ndash298

SEINEN W Vos JG VAN SPANJE I et al (1977a) Toxicity of organotin compounds 2 Comparative in vivo andin vitro studies with various organotin and organolead compounds in different animal species with specialemphasis on lymphocyte cytotoxicity Toxicology and Applied Pharmacology 42 197ndash212

SEINEN W Vos JG VAN KRIEKEN R et al (1977b) Toxicity of organotin compounds 3 Suppression ofthymus dependent immunity in rats by di-n-butyltin dichloride and di-n-octyltin dichloride Toxicology andApplied Pharmacology 42 213ndash224

SEINEN W amp WILLEMS MI (1976) Toxicity of organotin compounds 1 Atrophy of thymus and thymusdependent lymphoid tissue in rats fed di-n-octyltin dichloride Toxicology and Applied Pharmacology 35 63ndash75

SELWYN MJ (1976) Triorganotin compounds as ionophores and inhibitors of ion translocating ATPases InOrganotin Compounds New Chemistry and Applications (ed JJZuckerman) pp 204ndash226 Advances inChemistry Series No 157 American Chemical Society Washington DC

SENIOR AE (1988) ATP synthesis by oxidative phosphorylatlon Physiological Reviews 68 177ndash231SHARMA R LAKE BG amp GIBSON GG (1988) Co-induction of microsomal cytochrome P-452 and peroxisomal

fatty acid -oxidation pathway in the rat by clofibrate and di(2-ethylhexyl)-phthalate Biochemical Pharmacology37 1203ndash1206

SHEN W KAMENDULLS LM RAY SD amp CORCORAN GB (1992) Acetaminophen-induced cytotoxicity incultured mouse hepatocytes effects of Ca2+ endonuclease DNA repair and glutathione depletion inhibitors onDNA fragmentation and cell death Toxicology and Applied Pharmacology 112 32ndash40

SHERRATT HSA amp OSMUNDSEN H (1976) On the mechanism of some pharmacological actions of thehypoglycaemic toxins hypoglycin and pent-4-enoic acid a way out of the present confusion BiochemicalPharmacology 25 743ndash750

REFERENCES 231

SHIMADA T YUN C-H YAMAZAKI H et al (1992) Characterisation of human lung microsomal P4501A1 andits role in the oxidation of chemical carcinogens Molecular Pharmacology 41 856ndash864

SIEBENLIST KR amp TAKETA F (1983) Inactivation of yeast hexokinase B by triethyltin bromide Biochemistry22 4229ndash4234

SIMEON V REINER E amp VERNON CA (1972) Effect of temperature and pH on carbamoylation andphosphorylation of serum cholinesterases theoretical interpretation of activation energies in complex reactionsBiochemical Journal 130 515ndash524

SINGER P (1983) Animal Liberation Thorsons Wellingborough UKSIPES IG amp GANDOLFI AJ (1986) Biotransformation of toxicants In Toxicology The Basic Science of Poisons

(eds CDKlaassen MOAmdur amp JDoull) pp 64ndash98 Macmillan New YorkSIVONEN K NAMIKOSHI M EVANS WR et al (1992) Isolation and characterisation of a variety of

microcystins from seven strains of the cyanobacterial genus Anabaena Applied Environmental Microbiology 582495ndash2500

SKERFVING S amp VOSTAL J (1972) Symptoms and signs of intoxication In Mercury in the Environment AnEpidemiological and Toxicological Appraisal (eds LFriberg amp JVostal) pp 93ndash108 CRC Press Clevedon Ohio

SKILLETER DN (1989) Molecular mechanisms of beryllium toxicity Life Science Reports 7 245ndash283SKILLETER DN amp PRICE RJ (1978) The uptake and subsequent loss of beryllium by rat liver parenchymal and

non-parenchymal cells after the intravenous administration of particulate and soluble forms Chemico-BiologicalInteractions 20 383ndash396

(1979) The role of lysosomes in the hepatic accumulation and release of beryllium Biochemical Pharmacology 283595ndash3599

(1981) Effects of beryllium compounds on rat liver Kupffer cells in culture Toxicology and Applied Pharmacology 59279ndash286

SKRINJARIC-SPOLJAR M SIMEON V amp REINER E (1973) Spontaneous reactivation and aging ofdimethylphosphorylated acetylcholinesterase and cholinesterase Biochimica et Biophysica Acta 315 363ndash369

SLUTSKER L HOESLY FC MILLER L et al (1990) Eosinophilia-myalgia syndrome associated with exposureto tryptophan from a single manufacturer Journal of the American Medical Association 264 213ndash217

SMIALOWICZ RJ RIDDLE MM ROGERS RR et al (1991) Evaluation of the immunotoxicity of orallyadministered 2-methoxyacetic acid in Fischer 344 rats Fundamental and Applied Toxicology 17 771ndash781

SMIALOWICZ RJ RIDDLE MM amp WILLIAMS WC (1993) Methoxyacetaldehyde an intermediate metaboliteof 2-methoxyethanol is immunosuppressive in the rat Fundamental and Applied Toxicology 21 1ndash7

SMITH HV amp SPALDING JMK (1959) Outbreak of paralysis in Morocco due to ortho cresyl phosphatepoisoning Lancet 2 1019ndash1021

SMITH LL amp NEMERY B (1986) The lung as a target organ for toxicity In Target Organ Toxicity (edGMCohen) Vol 2 pp 45ndash80 CRC Press Boca Raton Florida

SMITH LL amp WYATT I (1981) The accummulation of putrescine into slices of rat lung and brain and itsrelationship to the accummulation of paraquat Biochemical Pharmacology 30 1053ndash1058

SMITH LL COHEN GM amp ALDRIDGE WN (1986) Morphological and bio-chemical correlates of chemicalinduced injury in the lung Archives of Toxicology 58 214ndash218

SMITH LW and CULVENOR CC (1981) Plant sources of hepatotoxic pyrrolizidine alkaloids Journal of NaturalProducts 44 129ndash152

SMITH MI amp ELVOVE E (1930) Pharmacological and chemical studies of the so-called ginger paralysis USAPublic Health Reports 45 1703ndash1716

SMITH MI ELVOVE E amp FRAZIER WH (1930) Pharmacological action of certain phenol esters with specialreferences to the etiology of so-called ginger paralysis USA Public Health Reports 45 2509ndash2524

SMITH MI ENGEL EW amp STOHLMAN EF (1932) Further studies on the pharmacology of certain phenol esterswith special reference to the relation of chemical constitution and physiologic action USA Public Health Reports47 1ndash53

SMITH P amp HEATH D (1976) Paraquat Critical Reviews in Toxicology 4 411ndash445

232 REFERENCES

SMITH RP (1986) Toxic responses of the blood In Toxicology The Basic Science of Poisons (eds CDKlaassonMOAnadur amp JDoull) pp 223ndash244 Macmillan New York

SNOEIJ NJ PENNINKS AH amp SEINEN W (1988) Dibutyltin and tributyltin compounds induce thymus atrophyin rats due to a selective action on thymic lymphoblasts International Journal of Immunopharmacology 10891ndash899

SONES K HEANEY RK amp FENWICK GR (1984) The glucosinolate content of UK vegetablesmdashcabbage(Brassicae oleracea) swede (Bnapus) and turnip (Bcampestris) Food Additives and Contaminants 1 289ndash296

SPENCER PS amp SCHAUMBURG HH (1975) Experimental neuropathy produced by 25-hexanedionemdasha majormetabolite of the neurotoxic industrial solvent methyl n-butyl ketone Journal of Neurology Neurosurgery andPsychiatry 38 771ndash775

SPENCER PS amp SCHAUMBURG HH (1976) Central-peripheral distal axonopathymdashthe pathology of dying-backpolyneuropathies Progress in Neuropathology 3 253ndash295

STANBURY JB WYNGAARDEN JB FREDRICKSON DS GOLSTEIN JL amp BROWN MS eds (1983) TheMetabolic Basis for Inherited Disease McGraw-Hill New York

STOLOFF L (1977) Aflatoxinmdashan overview In Mycotoxins in Human and Animal Health (eds JWRodrickCWHeseltine amp MAMehlman) Pathotox Publishers Park Forest South Illinois

STONER HB (1961) Studies on the mechanism of shock the activity of the reticuloendothelial system after limbischaemia in the rat British Journal of Experimental Pathology 42 523ndash538

STUBBS GW SAARI JC amp FUTTERMAN S (1979) 11-cis-Retinol-binding proteins from bovine retina Journalof Biological Chemistry 254 8529ndash8533

SUGIMURA T amp WAKABAYASHI K (1991) Heterocyclic amines new mutagens and carcinogens in cooked foodAdvances in Experimental Biology and Medicine 283 569ndash578

SUSSMAN JL HAVEL M FROLOW F et al (1991) Atomic structure of acetylcholinesterase from Torpedocalifornica a prototype acetylcholine-binding protein Science 253 872ndash879

SWANN PP amp MCLEAN AEM (1968) The effect of diet on the toxic and carcinogenic action ofdimethylnitrosamine Biochemical Journal 107 14ndash15P

SWENBERG JA HOEL DG amp MAGEE PN (1991) Mechanistic and statistical insight into large carcinogenesisbioassays on N-nitrosodiethylamine and N-nitrosodimethylamine Cancer Research 51 6409ndash6414

SWENSEN DH MILLER EG amp MILLER JA (1974) Aflatoxin B1-2-oxide evidence for its formation in ratliver in vivo and by human liver microsomes in vitro Biochemical and Biophysical Research Communications 601036ndash1043

SWYGERT LA MAES EF SEWELL LE et al (1990) Eosinophilia-myalgia syndrome results of nationalsurveillance Journal of the American Medical Association 264 1698ndash1703

TABUENCA JM (1981) Toxic allergic syndrome caused by the ingestion of rape seed oil denatured with anilineLancet 2 567ndash568

TAKETA F SIEBENLIST K KASTEN-JOLLY J amp PALOSARRI N (1980) Interaction of triethyltin with cathemoglobin identification of binding sites and effects on haemoglobin function Archives of Biochemistry andBiophysics 203 466ndash472

TARDIF R LAPARE S KRISHNAN K amp BRODEUR J (1993) Physiologically based modelling of thetoxicokinetic interaction between toluene and m-xylene in the rat Toxicology and Applied Pharmacology 120266ndash273

TATES AD GRIMMT T TORNQVIST M et al (1991) Biological and chemical monitoring of occupationalexposure to ethylene oxide Mutation Research 250 483ndash497

TATUM EL (1959) A case history in biological research Science 129 1711ndash1715TENNANT RW amp ASHBY J (1991) Classification according to chemical structure mutagenicity to Salmonella and

level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the US NTP Mutation Research257 209ndash227

TEPHLY TR (1977) Introduction factors in responses to the environment Federated Proceedings 36 1627ndash1628 (1991) The toxicity of methanol Life Sciences 48 1031ndash1041

REFERENCES 233

TEPHLY TR PARKE RE Jr amp MANNERING GT (1964) Methanol metabolism in the rat Journal ofPharmacology and Experimental Therapeutics 143 292ndash300

THOMAS JA amp THOMAS MJ (1984) Biological effects of di-(2-ethylhexyl) phthalate and other phthalic estersCritical Reviews in Toxicology 13 283ndash317

TIBS (1994) Protein phosphorylation Trends in Biochemical Sciences special issue 19 439ndash513TIMBRELL JA (1982) Principles of Biochemical Toxicology Taylor amp Francis LondonTIPPING E KETTERER B CHRISTODOULIDES L amp ENDERBY G (1976) The non-covalent binding of small

molecules to ligandin interaction with steroids and their conjugates fatty acids bromsulphophthalein carcinogensglutathione and related compounds European Journal of Biochemistry 67 583ndash590

TIPPING E KETTERER B CHRISTODOULIDES C et al (1979) Interactions of triethyltin with rat glutathione-S-transferases A B and C enzyme inhibition and equilibrium dialysis studies Chemical Biological Interactions24 317ndash327

TIPTON KF (1980) Kinetics and enzyme inhibitor studies In Enzyme Inhibitors as Drugs (ed MSandler) pp 1ndash23Macmillan London

TOGGAS SM KRADY JK amp BILLINGSLEY ML (1992) Molecular neurotoxicity of trimethyltin identificationof stannin a novel protein expressed in trimethyltin sensitive cells Molecular Pharmacology 432 44ndash56

TOLBERT NE (1981) Metabolic pathways in peroxisomes and glyoxisomes Annual Reviews of Biochemistry 50133ndash157

TORKELSON TR SADEK SE ROWE DK et al (1961) Toxicologic investigations of 12-dibromo-3-chloropropane Toxicology and Applied Pharmacology 3 545ndash559

TORNQVIST M amp KANTIAINEN A (1993) Adducted proteins in the identification of endogenous electrophilesEnvironmental Health Perspectives 99 39ndash44

TORNQVIST M OSTERMAN-GOLKAR S KAUTIAINEN A et al (1986) Tissue doses of ethylene oxide incigarette smokers determined from adduct levels in haemoglobin Carcinogenesis 7 1519ndash1521

TORNQVIST M SVARTENGREN M amp ERICSSON CH (1992) Methylations of haemoglobin from twinsdiscordant for cigarette smoking hereditary and tobacco related factors Chemico-Biological Interactions 8291ndash98

TRIPATHI RK (1976) Relation of acetylcholinesterase sensitivity to cross resistance of a house fly strain toorganophosphates and carbamates Pesticide Biochemistry and Physiology 6 30ndash34

TRIPATHI RK amp OrsquoBRIEN RD (1973) Insensitivity of acetylcholinesterase as a factor in resistance of houseflies tothe organophosphate Rabon Pesticide Biochemistry and Physiology 3 495ndash498

TSUBAKI T amp IRUKAYAMA K eds (1977) Minamata disease Elsevier AmsterdamVAHTER M MOTTETT NK FRIBERG L et al (1994) Speciation of mercury in the primate blood and brain

following long-term exposure to methylmercury Toxicology and Applied Pharmacology 124 221ndash229VAINIO H COLEMAN M amp WILBOURN J (1991) Carcinogenicity evaluation and ongoing studies the IARC

databases Environmental Health Perspective 96 5ndash9VAN BLADEREN PJ (1988) Formation of toxic metabolites from drugs and other xenobiotics by glutathione

conjugation Trends in Pharmacological Sciences 9 295ndash299VANDEKAR M (1980) Minimising occupational exposure to pesticides cholinesterase determination and

organophosphorus poisoning Residue Reviews 75 68ndash79VARTIAINEN T amp LIIMATAINEN A (1986) High levels of mutagenic activity in chlorinated drinking water in

Finland Mutation Research 169 29ndash34VARTIAINEN T LIIMATAINEN A JAASKELAINEN S and KAURANEN P (1987) Comparison of solvent

extractions and resin absorption for isolation of mutagenic compounds from chlorinated drinking water with highhumus content Water Research 21 773ndash779

VARTIAINEN T LIIMATAINEN A KAURANEN P amp HIISVIRTA L (1988) Relations between drinking watermutagenicity and water quality parameters Chemosphere 17 189ndash202

VERMEULEN NPE BESSENS JGM amp VAN DER STRAAT R (1992) Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism-based prevention Drug Metabolism Reviews 24 367ndash407

234 REFERENCES

VERSCHOYLE RD amp ALDRIDGE WN (1980) Structure-activity relationships of some pyrethroids in ratsArchives of Toxicology 45 325ndash329

(1987) The interaction between phosphorothionate insecticides pneumotoxic trialkyl phosphorothiolates and effects onlung 7-ethoxycoumarin O-deethylase activity Archives of Toxicology 60 311ndash318

VERSCHOYLE RD amp LITTLE RA (1981) The acute toxicity of some organolead and organotin compounds in therat with particular reference to the gastric lesion Journal of Applied Toxicology 1 270ndash277

VIJVERBERG HPM amp VAN DEN BERCKEN J (1990) Neurotoxicological effects and the mode of action ofpyrethroid insecticides CRC Critical Reviews in Toxicology 21 105ndash126

VINEIS P CAPOROSO N TANNENBAUM SR et al (1990) Acetylation phenotype carcinogen-haemoglobinadducts and cigarette smoking Cancer Research 50 3002ndash3004

VOLK B HETTMANNSPERGER U PAPP T et al (1991) Mapping of phenytoin inducible cytochrome P450immunoreactivity in the mouse central nervous system Neuroscience 42 215ndash235

WAINIO WW amp GREENLEES J (1960) Complexes of cytochrome C oxidase with cyanide and carbon monoxideArchives of Biochemistry and Biophysics 90 18ndash21

WATANABE I IWASAKI Y SATOYOSHI E amp DAVIS JW (1981) Haemorrhage in thiamine-deficientencephalopathy Journal of Neuropathology and Experimental Neurology 40 566ndash580

WATANABE T LALWANI ND amp REDDY JK (1985) Specific changes in the protein composition of rat liver inresponse to the peroxisome proliferators ciprofibrate Wy-14 643 and Di(2-ethylhexyl)phthalate BiochemicalJournal 227 767ndash775

WEBB M ed (1979) The Chemistry Biochemistry and Biology of Cadmium Elsvier North-Holland AmsterdamWEIL CS (1952) Tables for convenient calculation of median-effective dose (LD50 or ED50) and instructions in their

use Biometrics 8 249ndash263WESER U amp RUPP H (1979) Physicochemical properties of metallothioneins In The Chemistry Biochemistry and

Biology of Cadmium (ed MWebb) pp 267ndash283 Elsevier North Holland Biomedical Press AmsterdamWEST IC (1990) What determines the specificity of the multi-drug resistence pump Trends in Biochemical Sciences

15 42ndash46WHO (1976) Conference on intoxication due to alkylmercury treated seed Baghdad Iraq 9ndash13 September 1974

Bulletin of the World Health Organization 53 (suppl)(1984) Toxic Oil Syndrome Mass Food Poisoning in Spain Report on a meeting in Madrid 21ndash25 March 1983 WHO

Copenhagen(1988) Pyrollizidine alkaloids International Programme of Chemical Safety Geneva Environmental Health Criteria

Document No 80(1991) Toxic Oil Syndrome and Eosinophilia-Myalgia Syndrome Pursuing Parallels in Pathogenesis WHO

Copenhagen(1992) Toxic Oil Syndrome Current Knowledge and Future Perspectives WHO Copenhagen(1993) Toxic Oil Syndrome and Eosinophilia-Myalgia Syndrome Clinical Aspects WHO CopenhagenWIELAND T amp FAULSTICH H (1978) Amatoxins phallotoxins phallolysin and antamanide the biologically active

components of poisonous Amanita mushrooms CRC Critical Review in Toxicology 5 185ndash260WILKINSON GN (1961) Statistical estimations in enzyme kinetics Biochemical Journal 80 324ndash332WILLIAMS GM amp WEISBURGER JH (1986) Chemical carcinogens In Toxicology The Basic Science of Poisons

(eds CDKlaassen MOAmdur amp JDoull) pp 99ndash173 Macmillan New York WITSCHI HP amp ALDRIDGE WN (1968) Uptake distribution and binding of beryllium to organelles of the rat

liver cell Biochemical Journal 106 811ndash820WOLFF M S TONIOLO PG LEE EW RIVERA M amp DUBIN N (1993) Blood levels of organochlorine

residues and risk of breast cancer Journal of the National Cancer Institute 85 648ndash652WOOD CA amp BULLER F (1904) Poisoning by wood alcohol cases of death and blindness from Columbian spirits

and other methylated preparations Journal of the American Medical Association 43 972ndash977 1058ndash10621117ndash1123 1213ndash1221 1289ndash1296

REFERENCES 235

WRIGHT P (1975) Untoward effects associated with practolol administration oculomucocutaneous syndrome BritishMedical Journal 1 595ndash598

WYLLIE AH (1992) Apoptosis and the regulation of cell numbers in normal and neoplastic tissues an overviewCancer and Metastasis Reviews 11 95ndash103

WYLLIE AH KERR JFR amp CURRIE AR (1980) Cell death the significance of apoptosis International Reviewsof Cytology 68 251ndash306

WYLLIE AH MOORS RG SMITH AL amp DUNLOP D (1984) Chromatin cleavage in apoptosis associationwith condensed chromatin morphology and dependence on macromolecular synthesis Journal of Pathology 14267ndash77

WYSYNSKI AM BALDWIN LA LEONARD DA amp CALABRESE EJ (1993) Interactive potential of omega-3fatty acids with clofibrate and DEHP on hepatic peroxisome proliferation in male Wistar rats Human andExperimental Toxicology 12 337ndash340

YONEMOTO J BROWN NA amp WEBB M (1984) Effects of dimethoxyethylphthalate monoethoxyethylphthalate2-methoxyethanol and methoxyacetic acid on post-implantation rat embryos in culture Toxicology Letters 2197ndash102

ZIEGLER BM (1993) Recent studies on the structure and function of multisubstrate flavincontainingmonooxygensises Annual Reviews of Pharmacology and Toxicology 33 179ndash199

ZELIKOFF JT SMIALOWICZ R BIGAZZI PE et al (1994) Immunomodulation by metals Fundamental andApplied Toxicology 22 1ndash7

236 REFERENCES

Book Cover

Half-Title

Title

Copyright

Contents

Preface

Acknowledgements

1 Scope of Toxicology

References

Mechanisms and Concepts in Toxicology

















Contents

Preface ix

Acknowledgements xi





14 Discussion 8

15 Summary 9


21 Introduction 10






27 Discussion 14

28 Summary 15


31 Introduction 16






37 Discussion 25

38 Summary 26


41 Introduction 28







48 Discussion 33

49 Summary 34


51 Introduction 35



54 Distribution 45


56 Discussion 53

57 Summary 54


61 Introduction 56

62 Bioactivation 58






68 Discussion 71

69 Summary 72


71 Introduction 74



v













716 Discussion 108

717 Summary 110


81 Introduction 111


112


113


115







811 Discussion 128

812 Summary 130


131

91 Introduction 131

vi






97 Thresholds 142

98 Discussion 145

99 Summary 146









108 Discussion 158

109 Summary 160












1111 Discussion 172

1112 Summary 173

12 Epidemiology 174

vii







127 Discussion 187

128 Summary 188







136 Discussion 199

137 Summary 200


141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface











Norman Aldridge

x

Acknowledgements























121Organisms









122Responses






123Toxic Chemicals





NATURAL TOXICANTS



1



2



28 29



3 4


325 Liverlung 5 6




403 Kidney 7 8



9



10 11

SYNTHETIC TOXICANTS



12 13


76 Testis 14


267 Kidney 15



16 17


57 Lungeye 1819



20 21



22 23


186 Lung 24 25





27












132Exposure at Work








14Discussion






15Summary



problems


References










































210 REFERENCES























Defence 659ndash662

REFERENCES 211





















212 REFERENCES

























REFERENCES 213
























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228 REFERENCES
























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REFERENCES 235









236 REFERENCES

Book Cover

Half-Title

Title

Copyright

Contents

Preface

Acknowledgements


References

















Contents

Preface ix

Acknowledgements xi





14 Discussion 8

15 Summary 9


21 Introduction 10






27 Discussion 14

28 Summary 15


31 Introduction 16






37 Discussion 25

38 Summary 26


41 Introduction 28







48 Discussion 33

49 Summary 34


51 Introduction 35



54 Distribution 45


56 Discussion 53

57 Summary 54


61 Introduction 56

62 Bioactivation 58






68 Discussion 71

69 Summary 72


71 Introduction 74



v













716 Discussion 108

717 Summary 110


81 Introduction 111


112


113


115







811 Discussion 128

812 Summary 130


131

91 Introduction 131

vi






97 Thresholds 142

98 Discussion 145

99 Summary 146









108 Discussion 158

109 Summary 160












1111 Discussion 172

1112 Summary 173

12 Epidemiology 174

vii







127 Discussion 187

128 Summary 188







136 Discussion 199

137 Summary 200


141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface











Norman Aldridge

x

Acknowledgements























121Organisms









122Responses






123Toxic Chemicals





NATURAL TOXICANTS



1



2



28 29



3 4


325 Liverlung 5 6




403 Kidney 7 8



9



10 11

SYNTHETIC TOXICANTS



12 13


76 Testis 14


267 Kidney 15



16 17


57 Lungeye 1819



20 21



22 23


186 Lung 24 25





27












132Exposure at Work








14Discussion






15Summary



problems


References










































210 REFERENCES























Defence 659ndash662

REFERENCES 211





















212 REFERENCES

























REFERENCES 213
























214 REFERENCES























REFERENCES 215






















216 REFERENCES
























REFERENCES 217























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REFERENCES 219























220 REFERENCES























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222 REFERENCES























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224 REFERENCES

























REFERENCES 225






















226 REFERENCES
























REFERENCES 227
























228 REFERENCES
























REFERENCES 229
























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REFERENCES 231

























232 REFERENCES























REFERENCES 233
























234 REFERENCES























REFERENCES 235









236 REFERENCES

Book Cover

Half-Title

Title

Copyright

Contents

Preface

Acknowledgements


References


41 Introduction 28







48 Discussion 33

49 Summary 34


51 Introduction 35



54 Distribution 45


56 Discussion 53

57 Summary 54


61 Introduction 56

62 Bioactivation 58






68 Discussion 71

69 Summary 72


71 Introduction 74



v













716 Discussion 108

717 Summary 110


81 Introduction 111


112


113


115







811 Discussion 128

812 Summary 130


131

91 Introduction 131

vi






97 Thresholds 142

98 Discussion 145

99 Summary 146









108 Discussion 158

109 Summary 160












1111 Discussion 172

1112 Summary 173

12 Epidemiology 174

vii







127 Discussion 187

128 Summary 188







136 Discussion 199

137 Summary 200


141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface











Norman Aldridge

x

Acknowledgements























121Organisms









122Responses






123Toxic Chemicals





NATURAL TOXICANTS



1



2



28 29



3 4


325 Liverlung 5 6




403 Kidney 7 8



9



10 11

SYNTHETIC TOXICANTS



12 13


76 Testis 14


267 Kidney 15



16 17


57 Lungeye 1819



20 21



22 23


186 Lung 24 25





27












132Exposure at Work








14Discussion






15Summary



problems


References










































210 REFERENCES























Defence 659ndash662

REFERENCES 211





















212 REFERENCES

























REFERENCES 213
























214 REFERENCES























REFERENCES 215






















216 REFERENCES
























REFERENCES 217























218 REFERENCES
























REFERENCES 219























220 REFERENCES























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222 REFERENCES























REFERENCES 223





















224 REFERENCES

























REFERENCES 225






















226 REFERENCES
























REFERENCES 227
























228 REFERENCES
























REFERENCES 229
























230 REFERENCES





















REFERENCES 231

























232 REFERENCES























REFERENCES 233
























234 REFERENCES























REFERENCES 235









236 REFERENCES

Book Cover

Half-Title

Title

Copyright

Contents

Preface

Acknowledgements


References













716 Discussion 108

717 Summary 110


81 Introduction 111


112


113


115







811 Discussion 128

812 Summary 130


131

91 Introduction 131

vi






97 Thresholds 142

98 Discussion 145

99 Summary 146









108 Discussion 158

109 Summary 160












1111 Discussion 172

1112 Summary 173

12 Epidemiology 174

vii







127 Discussion 187

128 Summary 188







136 Discussion 199

137 Summary 200


141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface











Norman Aldridge

x

Acknowledgements























121Organisms









122Responses






123Toxic Chemicals





NATURAL TOXICANTS



1



2



28 29



3 4


325 Liverlung 5 6




403 Kidney 7 8



9



10 11

SYNTHETIC TOXICANTS



12 13


76 Testis 14


267 Kidney 15



16 17


57 Lungeye 1819



20 21



22 23


186 Lung 24 25





27












132Exposure at Work








14Discussion






15Summary



problems


References










































210 REFERENCES























Defence 659ndash662

REFERENCES 211





















212 REFERENCES

























REFERENCES 213
























214 REFERENCES























REFERENCES 215






















216 REFERENCES
























REFERENCES 217























218 REFERENCES
























REFERENCES 219























220 REFERENCES























REFERENCES 221























222 REFERENCES























REFERENCES 223





















224 REFERENCES

























REFERENCES 225






















226 REFERENCES
























REFERENCES 227
























228 REFERENCES
























REFERENCES 229
























230 REFERENCES





















REFERENCES 231

























232 REFERENCES























REFERENCES 233
























234 REFERENCES























REFERENCES 235









236 REFERENCES

Book Cover

Half-Title

Title

Copyright

Contents

Preface

Acknowledgements


References






97 Thresholds 142

98 Discussion 145

99 Summary 146









108 Discussion 158

109 Summary 160












1111 Discussion 172

1112 Summary 173

12 Epidemiology 174

vii







127 Discussion 187

128 Summary 188







136 Discussion 199

137 Summary 200


141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface











Norman Aldridge

x

Acknowledgements























121Organisms









122Responses






123Toxic Chemicals





NATURAL TOXICANTS



1



2



28 29



3 4


325 Liverlung 5 6




403 Kidney 7 8



9



10 11

SYNTHETIC TOXICANTS



12 13


76 Testis 14


267 Kidney 15



16 17


57 Lungeye 1819



20 21



22 23


186 Lung 24 25





27












132Exposure at Work








14Discussion






15Summary



problems


References










































210 REFERENCES























Defence 659ndash662

REFERENCES 211





















212 REFERENCES

























REFERENCES 213
























214 REFERENCES























REFERENCES 215






















216 REFERENCES
























REFERENCES 217























218 REFERENCES
























REFERENCES 219























220 REFERENCES























REFERENCES 221























222 REFERENCES























REFERENCES 223





















224 REFERENCES

























REFERENCES 225






















226 REFERENCES
























REFERENCES 227
























228 REFERENCES
























REFERENCES 229
























230 REFERENCES





















REFERENCES 231

























232 REFERENCES























REFERENCES 233
























234 REFERENCES























REFERENCES 235









236 REFERENCES

Book Cover

Half-Title

Title

Copyright

Contents

Preface

Acknowledgements


References







127 Discussion 187

128 Summary 188







136 Discussion 199

137 Summary 200


141 Reflections 201

142 Research 202

143 Risk 205

144 Summary 208

References 209

Index

viii

237

Preface











Norman Aldridge

x

Acknowledgements























121Organisms









122Responses






123Toxic Chemicals





NATURAL TOXICANTS



1



2



28 29



3 4


325 Liverlung 5 6




403 Kidney 7 8



9



10 11

SYNTHETIC TOXICANTS



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mechanisms and concepts in toxicology

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