Molecular and Cellular Toxicology - An Introduction

Toxicology is the study of the adverse effects of chemical, physical, or biological agents on people, animals, and the environment. Toxicologists are trained to investigate, interpret, and communicate the nature of those effects.
 
Over the last ten years the subject of toxicology has changed dramatically, moving from a discipline which was once firmly wedded to traditional methods to one which is keen to embrace the innovative techniques emerging from the developing fields of cell culture and molecular biology. There is an acute need for this to be reflected in a paradigm shift which takes advantage of the opportunities offered by modern developments in the life sciences, including new in vitro and in silico approaches, alternative whole organism (non-mammalian) models and the exploitation of 'omics methods, high throughput screening (HTS) techniques and molecular imaging technologies.
 
This concise, accessible introduction to the field includes the very latest concepts and methodologies. It provides MSc, PhD and final year undergraduate students in pharmacy, biomedical and life sciences, as well as individuals starting out in the cosmetics, consumer products, pharmaceutical and testing industries, with everything they need to know to get to grips with the fast moving field of toxicology and the current approaches used in the risk assessment of drugs and chemicals.

List of contents

Foreword xiii
 
Preface xv
 
Acknowledgements xvii
 
Abbreviations xix
 
About the Companion Website xxiii
 
1 Background to Molecular and Cellular Toxicology 1
 
1.1 What do we mean by molecular and cellular toxicology? 1
 
1.2 Tissues and their maintenance 2
 
1.2.1 Stem cells 3
 
1.3 Tissue damage 4
 
1.3.1 Consequences of tissue injury 4
 
1.3.2 Reversible changes in cells and tissues 6
 
1.3.3 Irreversible changes in cells and tissues 7
 
1.4 Tissue responses to injury 7
 
1.4.1 Oxidative stress 7
 
1.4.2 Necrosis and apoptosis 10
 
1.4.3 Neoplasia 13
 
1.4.4 The initiation-promotion paradigm 13
 
1.5 Key concepts in toxicology 23
 
1.5.1 Risk and hazard 23
 
1.5.2 Variability and uncertainty 25
 
1.5.3 Threshold and non-threshold dose responses 26
 
1.5.4 The regulatory context 28
 
1.5.5 Limitations of whole animal studies 29
 
1.5.6 Use of human tissues in toxicology 31
 
1.6 Summing up 33
 
Self-assessment questions 33
 
Background Reading 34
 
References 34
 
2 Individual Susceptibility to Toxic Chemicals 37
 
2.1 Introduction 37
 
2.2 Toxicogenetics and toxicogenomics 38
 
2.3 Genotyping and phenotyping 39
 
2.3.1 Genotyping 40
 
2.3.2 Phenotyping 43
 
2.3.3 Correlating genotype and phenotype 44
 
2.4 Polymorphic xenobiotic metabolism 45
 
2.4.1 Polymorphic xenobiotic metabolising enzymes 49
 
2.4.2 The role of xenobiotic metabolising polymorphisms in susceptibility to toxic agents 50
 
2.5 Study numbers and effect size 60
 
2.6 Recent developments 62
 
2.6.1 Genome-wide association studies 62
 
2.6.2 Collaborative programmes 64
 
2.7 The UK Biobank 69
 
2.8 Conclusions 71
 
Self-assessment questions 72
 
Background Reading 72
 
References 73
 
3 'Omics Techniques 79
 
3.1 'Omics and bioinformatics 79
 
3.2 Transcriptomics 80
 
3.2.1 Methodology 80
 
3.2.2 Proof of principle 89
 
3.2.3 Hepatotoxicity 91
 
3.2.4 Extrahepatic toxicity 96
 
3.3 Proteomics 97
 
3.3.1 Methodology 98
 
3.4 Metabolomics/metabonomics 101
 
3.4.1 MS-based metabolomics 102
 
3.4.2 NMR-based metabolomics 106
 
3.5 Integrating different types of 'omics data 107
 
3.5.1 'Omics in drug discovery 108
 
3.5.2 'Omics profiles as biomarkers of toxicity 109
 
3.6 Remaining issues with 'omics approaches 111
 
3.7 Conclusions 112
 
Self-assessment questions 113
 
Background Reading 113
 
References 113
 
4 In Vitro Methods for Predicting In Vivo Toxicity 117
 
4.1 In vitro toxicology 117
 
4.2 Tissue culture 117
 
4.2.1 Primary cell cultures 122
 
4.2.2 Established cell lines 125
 
4.3 Acute toxicity in vitro 127
 
4.3.1 Cytotoxicity testing 127
 
4.3.2 Choice of cell line 129
 
4.3.3 Liver 131
 
4.3.4 Skin 133
 
4.3.5 Eye 141
 
4.4 Repeated dose toxicity 144
 
4.5 Reproductive toxicity 147
 
4.6 Stem cell-derived systems 149
 
4.7 Conclusions 151
 
Self-assessment questions 151
 
Background Reading 152
 
References 152
 
5 In Vitro Methods for Absorption, Distribution, Metabolism and Excretion 159
 
5.1 Why study ADME in vitro? 159
 
5.2 Absorption 160
 
5.2.1 Dermal penetration 160
 

About the author

Dr Lesley Stanley is a toxicologist with over 20 years experience in assessing the effects of chemicals on human health. Her fi rst degree was in Biochemistry from the University of Oxford and she obtained her PhD from the University of Edinburgh. Since May 2005 she has been a freelance consultant in Investigative Toxicology, while her previous experience includes three years as Head of Operations at CXR Biosciences Ltd, Dundee, and six years lecturing in Biomedical Science at De Montfort University, Leicester, as well as spells at the MRC Toxicology Unit and the National Institute of Environmental Health Sciences, North Carolina, USA. Dr Stanley was a member of the Committee on Toxicity from 2001- to 2007 and has been a member of the Hazardous Substances Advisory Committee (previously the Advisory Committee on Hazardous Substances) since 2007. She is also Deputy Chair of the Panel of the UK Register of Toxicologists.

Summary

Over the last ten years the subject of toxicology has changed dramatically, moving from a discipline which was once firmly wedded to traditional (some might say old-fashioned) methods to one which is keen to embrace the innovative techniques emerging from the developing fields of cell culture and molecular biology.

Report

"Overall, we consider that this book is a useful summary of current and emerging techniques in molecular toxicology." ( BTS Newsletter , 1 March 2015)

Product details

• Authors: Lesley Stanley, Lesley (Consultant in Investigative Toxic Stanley, Stanley Lesley
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Paperback / Softback
• Released: 23.05.2014
• EAN: 9781119952060
• ISBN: 978-1-119-95206-0
• No. of pages: 448
• Subjects: Natural sciences, medicine, IT, technology > Biology > General, dictionaries; Chemie, Maschinenbau, Medizin, Molekularbiologie, Toxikologie, Life Sciences, ZELLBIOLOGIE, Biowissenschaften, chemistry, Zell- u. Molekularbiologie, Pharmacology & Pharmaceutical Medicine, Cell & Molecular Biology, Pharmakologie u. Pharmazeutische Medizin, Medical Science, Toxicology