Оглавление
Robin Whelpton. Fundamentals of Analytical Toxicology
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
FUNDAMENTALS OF ANALYTICAL TOXICOLOGY. Clinical and Forensic
Preface
Notes
Health and Safety
Nomenclature, Symbols, and Conventions
Uniform Resource Locators
Amount Concentration and Mass Concentration
Acknowledgements
List of Abbreviations
1 Analytical Toxicology: Overview. 1.1 Introduction
1.2 Modern analytical toxicology
1.2.1 Analytical methods
Box 1.1 Opiates, opioids, and opium
1.2.2 Systematic toxicological analysis
1.2.3 Ethanol and other volatile substances
1.2.4 Trace elements and toxic metals
1.3 Provision of analytical toxicology services
1.3.1 Samples and sampling
1.3.2 Choice of analytical method
1.3.3 Method validation and implementation
1.3.4 Quality control and quality assessment
1.4 Applications of analytical toxicology
1.4.1 Clinical toxicology
1.4.2 Forensic toxicology
1.4.3 Testing for substance misuse
1.4.4 Therapeutic drug monitoring
1.4.5 Occupational and environmental toxicology
1.5 Summary
References
2 Sample Collection, Transport, and Storage. 2.1 Introduction
2.2 Clinical samples and sampling. 2.2.1 Health and safety
2.2.2 Clinical sample types
2.2.3 Blood and blood fractions. 2.2.3.1 Arterial blood
2.2.3.2 Venous blood
2.2.3.3 Serum
2.2.3.4 Plasma
Box 2.1 Calculating relative centrifugal force
2.2.3.5 Blood cells
Erythrocyte:plasma distribution
2.2.3.6 Dried blood spots
2.2.3.7 Volumetric microsampling
2.2.4 Urine
2.2.5 Stomach contents
2.2.6 Faeces
2.2.7 Tissues
2.3 Guidelines for sample collection for analytical toxicology
Box 2.2 Information that should accompany a request for general toxicological analysis
2.3.1 Sample collection and preservation
2.3.2 Blood
2.3.2.1 Collection of blood post-mortem
2.3.3 Urine
2.3.4 Stomach contents
2.3.5 Oral fluid
2.3.6 Sweat
2.3.7 Exhaled air
2.3.8 Cerebrospinal fluid
2.3.9 Vitreous humour
2.3.10 Synovial fluid
2.3.11 Pericardial fluid
2.3.12 Intraosseous fluid
2.3.13 Liver
2.3.14 Bile
2.3.15 Other tissues
2.3.16 Insect larvae
2.3.17 Keratinaceous tissues (hair and nail)
Box 2.3 Protocol for collection of head hair for testing for drug exposure
2.3.18 Bone
2.3.19 Injection sites
2.3.20 Scene residues
2.4 Sample transport, storage, and disposal
Box 2.4 Chain of custody documents
Box 2.5 Guidance on freezer storage of samples
2.5 Common interferences
2.6 Summary
References
3 Basic Laboratory Operations
3.1 Introduction
Box 3.1 Stages in analytical toxicology laboratory operation
3.1.1 Reagents and standard solutions
Box 3.2 Example of weights of morphine salts required to make 1 litre of a 100 μmol L−1 solution of morphine
3.1.2 Reference compounds
3.1.3 Preparation and storage of calibration solutions
3.2 Aspects of quantitative analysis. 3.2.1 Analytical error
3.2.1.1 Confidence intervals
3.2.2 Minimizing random errors
3.2.2.1 Preparation of a solution of known concentration
3.2.3 Accuracy and precision
3.2.3.1 Assessing precision and accuracy
3.2.3.2 Detecting systematic error (fixed bias)
3.2.3.3 Identifying sources of variation: analysis of variance
3.2.3.4 Measurement uncertainty
3.2.4 Calibration graphs
3.2.4.1 Linear regression
3.2.4.2 Testing for linearity
3.2.4.3 Weighted linear regression
3.2.4.4 Non-linear calibration
3.2.4.5 Residuals and standardized residuals
3.2.4.6 Blank samples and the intercept
3.2.4.7 Method of standard additions
3.2.4.8 Limits of detection and quantitation
3.2.4.9 Curve fitting and choice of equation
3.2.4.10 Single-point calibration
3.2.5 Batch analyses
3.2.6 Random access analysis
3.3 Use of internal standards
3.3.1 Advantages of internal standardization. 3.3.1.1 Reproducibility of injection volume
Box 3.3 Some requirements for an internal standard
3.3.1.2 Instability of the detection system
3.3.1.3 Pipetting errors and evaporation of extraction solvent
3.3.1.4 Extraction efficiency
3.3.1.5 Derivatization and non-stoichiometric reactions
3.3.2 Internal standard availability
3.3.3 External calibration
Box 3.4 Points to be considered when using external calibration
3.3.4 Potential disadvantages of internal standardization
3.3.5 Quantity of internal standard added
3.4 Method comparison
3.4.1 Bland–Altman plots
3.5 Non-parametric statistics
Box 3.5 Grubbs' test for outliers
3.5.1 Sign tests
3.5.1.1 Wilcoxon signed rank test
3.5.2 Runs test
3.5.3 Mann–Whitney U-test
Box 3.6 Procedure for calculating U-values
3.5.4 Spearman rank correlation
3.5.5 Non-parametric regression
Box 3.7 Steps for Theil's incomplete method for non-parametric calibration curves
3.6 Quality control and quality assessment
3.6.1 Quality control charts
3.6.1.1 Shewhart charts
3.6.1.2 Cusum charts
3.6.1.3 J-chart
3.6.2 External quality assessment
3.6.3 Toxicology external quality assessment schemes
3.7 Operational considerations. 3.7.1 Staff training
3.7.2 Recording and reporting results
3.8 Summary
References
4 Aspects of Sample Preparation. 4.1 Introduction
Box 4.1 Aims of sample preparation
Box 4.2 Modes of sample preparation
4.2 Modes of sample preparation
4.2.1 Protein precipitation
4.2.2 Liquid–liquid extraction
Box 4.3 Properties of the ‘ideal’ extraction solvent
4.2.2.1 pH-Controlled liquid–liquid extraction
4.2.2.2 Ion-pair extraction
4.2.2.3 Supported liquid extraction
Box 4.4 Use of Isolute columns to extract 12 drugs from whole blood prior to LC-MS/MS (Kristoffersen et al., 2018 – reproduced with permission of Elsevier)
4.2.2.4 Immobilized coating extraction
4.2.3 Solid phase extraction
Box 4.5 LC-MS assay of plasma clozapine and norclozapine using ICE (Couchman et al., 2016 – reproduced with permission of Wolters Kluwer Health, Inc.)
4.2.3.1 Types of stationary phase
4.2.4 Solid phase microextraction
4.2.5 Liquid phase microextraction
4.2.6 Supercritical fluid extraction
4.2.7 Accelerated solvent extraction
4.3 Plasma protein binding
Box 4.6 Considerations in the measurement of plasma protein binding
4.3.1 Ultrafiltration
4.3.2 Equilibrium dialysis
4.4 Hydrolysis of conjugated metabolites
4.5 Extraction of drugs from tissues
4.6 Summary
References
5 Colour Tests, and Spectrophotometric and Luminescence Techniques. 5.1 Introduction
5.2 Colour tests in toxicology
Box 5.1 Colour tests in toxicology
5.3 Colour tests for pharmaceuticals and illicit drugs
5.4 UV/Visible spectrophotometry
5.4.1 The Beer–Lambert law
Box 5.2 Beer–Lambert law: factors causing non-linearity
5.4.2 Instrumentation
Box 5.3 Operation of a single-beam spectrophotometer
5.4.2.1 Derivative spectrophotometry
5.4.3 Spectrophotometric assays
Box 5.4 Visible and UV spectrophotometry
5.4.3.1 Salicylates in plasma or urine
5.4.3.2 Carboxyhaemoglobin in whole blood
Box 5.5 Measurement of salicylates in plasma or urine
Box 5.6 Measurement of carboxyhaemoglobin
5.4.3.3 Cyanide in whole blood by microdiffusion
Box 5.7 Microdiffusion
Box 5.8 Cyanide measurement using microdiffusion
5.5 Fluorescence and phosphorescence
5.5.1 Intensity of fluorescence and quantum yield
5.5.2 Instrumentation
5.5.3 Fluorescence assays
5.5.3.1 Fluorescence measurement of quinine
Box 5.9 Fluorescence assay for plasma quinine
5.6 Chemiluminescence
5.6.1 Instrumentation
5.6.2 Chemiluminescence assays
5.7 Infrared and Raman spectroscopy
5.7.1 Instrumentation
5.7.2 Applications
5.8 Summary
References
6 Immunoassays and Related Assays. 6.1 Introduction
6.2 Basic principles of competitive binding assays
Box 6.1 Immunoassays: practicalities
6.2.1 Antibody formation
6.2.2 Selectivity
6.2.3 Performing the assay
6.2.3.1 Classical radioimmunoassay
6.2.3.2 Modern radioimmunoassay
Box 6.2 Radioimmunoassay
6.2.4 Non-isotopic immunoassay
Box 6.3 Non-isotopic immunoassays in analytical toxicology
6.2.5 Assay sensitivity and selectivity
6.2.6 Immunoassay development
6.3 Heterogeneous immunoassays
6.3.1 Tetramethylbenzidine reporter system
6.3.2 Antigen-labelled competitive ELISA
6.3.3 Antibody-labelled competitive ELISA
Box 6.4 Enzyme linked immunosorbent assay
6.3.4 Sandwich ELISA
6.3.5 Lateral flow competitive ELISA
6.3.6 Chemiluminescent immunoassay
6.4 Homogenous immunoassays
6.4.1 Enzyme-multiplied immunoassay technique
Box 6.5 Enzyme-multiplied immunoassay technique
6.4.2 Fluorescence polarization immunoassay (FPIA)
Box 6.6 Fluorescence polarization immunoassay
6.4.3 Cloned enzyme donor immunoassay
Box 6.7 Cloned enzyme donor immunoassay
6.5 Microparticulate and turbidimetric immunoassays
6.5.1 Microparticle enzyme immunoassay (MEIA)
6.5.2 Chemiluminescent magnetic immunoassay (CMIA)
6.6 Assay calibration, quality control, and quality assessment
6.6.1 Immunoassay calibration
6.6.2 Drug screening
6.7 Interferences and assay failures
6.7.1 Measurement of plasma digoxin after Fab antibody fragment administration
6.8 Aptamer-based assays
6.9 Enzyme-based assays
6.9.1 Paracetamol
6.9.2 Ethanol
6.9.3 Anticholinesterases
6.10 Summary
References
7 Separation Science: Theoretical Aspects. 7.1 General introduction
7.2 Theoretical aspects of chromatography
7.2.1 Analyte phase distribution
7.2.2 Column efficiency
7.2.3 Zone broadening
7.2.3.1 Multiple path and eddy diffusion
7.2.3.2 Longitudinal diffusion
7.2.3.3 Resistance to mass transfer
7.2.4 Kinetic plots
7.2.5 Extra-column contributions to zone broadening
7.2.6 Temperature programming and gradient elution
7.2.7 Selectivity
7.2.8 Peak asymmetry
7.3 Measurement of analyte retention. 7.3.1 Planar chromatography
Box 7.1 Calculation of corrected hRf values
7.3.2 Elution chromatography
7.4 Summary
References
8 Planar Chromatography. 8.1 Introduction
Box 8.1 Application of TLC in analytical toxicology
8.2 Qualitative thin-layer chromatography
Box 8.2 Practical aspects of TLC in analytical toxicology
8.2.1 Thin-layer plates
8.2.2 Sample application
8.2.3 Developing the chromatogram
8.2.4 Visualizing the chromatogram
Box 8.3 Visualizing reagents for acidic and basic extracts (see Figure 8.3)
8.2.5 Interpretation of thin-layer chromatograms
Box 8.4 Analytical toxicology: interpretation and storage of TLC data
8.2.6 TIAFT-DFG Rf data compilation
8.2.7 Toxi-Lab
8.3 Quantitative thin-layer chromatography
8.3.1 Forced-flow planar chromatography
8.3.2 Quantitative high-performance thin-layer chromatography
8.4 Summary
References
9 Gas Chromatography. 9.1 Introduction
Box 9.1 Advantages of GC in analytical toxicology
Box 9.2 Limitations of GC in analytical toxicology
9.2 Instrumentation
9.2.1 Injectors and injection technique
9.2.1.1 Cryofocusing/thermal desorption
9.2.2 Detectors for gas chromatography
9.2.2.1 Thermal conductivity detection
9.2.2.2 Flame ionization detection
9.2.2.3 Nitrogen/phosphorus detection
9.2.2.4 Electron capture detection
9.2.2.5 Pulsed discharge detection
Box 9.3 Disadvantages of 63Ni electron-capture detectors
9.2.2.6 Flame photometric detection
9.2.2.7 Atomic emission detection
9.2.2.8 Chemiluminescent nitrogen detection
9.2.2.9 Fourier transform infra-red detection
9.2.2.10 Vacuum UV detection
9.3 Columns and column packings
9.3.1 Stationary phases
9.3.2 Packed columns
9.3.3 Capillary columns
Box 9.4 GC capillary column selection
9.3.4 Multidimensional gas chromatography
9.4 Headspace and ‘purge and trap’ analysis
9.5 Formation of artefacts in gas chromatography
9.6 Derivatization for gas chromatography
Box 9.5 Summary of reasons for derivatization in gas chromatography
9.7 Chiral separations
9.8 Summary
Box 9.6 Summary of the use of GC in analytical toxicology
References
10 Liquid Chromatography. 10.1 Introduction
Box 10.1 Advantages of liquid chromatography in analytical toxicology
Box 10.2 Limitations of liquid chromatography in analytical toxicology
10.2 General considerations
10.2.1 The column
10.2.2 Column configuration
10.2.3 Column oven
10.2.4 The eluent
10.2.5 The pump
10.2.6 Sample introduction
10.2.7 System operation
10.3 Detection in liquid chromatography
10.3.1 UV/Visible absorption detection
10.3.2 Fluorescence detection
10.3.3 Chemiluminescence detection
10.3.4 Electrochemical detection
10.3.5 Chemiluminescent nitrogen detection
10.3.6 Aerosol-based detectors
10.3.6.1 Evaporative light scattering detection
10.3.6.2 Condensation nucleation light scattering detection
10.3.6.3 Charged aerosol detection
10.3.7 Radioactivity detection
Box 10.3 Practical considerations in the use of radioactivity detectors
10.3.8 Chiral detection
10.3.9 Post-column modification
10.3.10 Immunoassay detection
10.4 Columns and column packings
10.4.1 Column packings
10.4.1.1 Chemical modification of silica
10.4.1.2 Bonded-phase selection
10.4.1.3 Stability of silica packings
10.4.1.4 Monolithic columns
10.4.1.5 Surface porous particles
10.4.1.6 Hybrid particle columns
10.4.1.7 Restricted access media
10.5 Modes of liquid chromatography
10.5.1 Normal-phase chromatography
10.5.2 Hydrophilic interaction liquid chromatography
10.5.3 Reverse-phase chromatography
10.5.4 Ion-exchange chromatography
10.5.5 Ion-pair chromatography
10.5.6 Affinity chromatography
10.5.7 Size exclusion chromatography
10.5.8 Semi-preparative and preparative chromatography
10.6 Chiral separations
10.6.1 Chiral stationary phases. 10.6.1.1 Amylose and cellulose polymers
10.6.1.2 Crown ethers
10.6.1.3 Cyclodextrins
10.6.1.4 Ligand exchange chromatography
10.6.1.5 Macrocyclic glycopeptides
10.6.1.6 Pirkle brush-type phases
10.6.1.7 Protein-based phases
10.6.2 Chiral eluent additives
Box 10.4 Advantages and disadvantages of eluent additives in chiral LC
10.7 Derivatives for liquid chromatography
10.7.1 Fluorescent derivatives
10.7.2 Chiral derivatives
Box 10.5 Requirements for an ideal chiral derivatization reagent
10.8 Use of liquid chromatography in analytical toxicology
Box 10.6 Summary of the use of liquid chromatography in analytical toxicology
10.8.1 Acidic and neutral compounds
Box 10.7 Considerations in the liquid chromatography of acidic and neutral compounds
10.8.2 Basic drugs and quaternary ammonium compounds
Box 10.8 Liquid chromatography of basic compounds
10.8.2.1 Non-aqueous ionic eluent systems
10.8.3 Chiral analysis
10.9 Summary
References
11 Supercritical Fluid Chromatography. 11.1 Introduction
Box 11.1 Supercritical fluid chromatography
Box 11.2 Supercritical fluid chromatography versus gas chromatography
Box 11.3 Supercritical fluid chromatography versus liquid chromatography
11.2 General considerations
11.2.1 The pump
11.2.2 The eluent
11.3 Detection in supercritical fluid chromatography
11.4 Columns and column packings
11.5 Chiral separations
11.6 Toxicological and forensic applications
11.7 Summary
References
12 Capillary Electrophoretic Techniques. 12.1 Introduction
Box 12.1 Preparation, conditioning, and storage of capillaries for electrophoresis
12.2 Theoretical aspects. 12.2.1 Electrophoretic mobility
12.2.2 Efficiency and zone broadening
12.2.3 Joule heating
12.2.4 Electrodispersion
12.2.5 Adsorption of analyte onto the capillary wall
12.2.6 Reproducibility of migration time
12.3 Sample injection in capillary electrophoresis
12.3.1 Hydrodynamic injection
12.3.2 Electrokinetic injection
12.3.3 Sample ‘stacking’
12.4 Detection in capillary electrophoresis
12.5 Other capillary electrokinetic modes
12.5.1 Micellar electrokinetic capillary chromatography
12.5.2 Capillary electrochromatography
12.6 Capillary electrophoretic techniques in analytical toxicology
12.6.1 Chiral separations
12.7 Summary
References
13 Mass Spectrometry. 13.1 Introduction
Box 13.1 Mass spectrometry in analytical toxicology
13.2 Instrumentation
Box 13.2 Mass spectrometry: types of mass analyzers
Box 13.3 Mass spectrometry: resolving power and mass error
13.2.1 Sector instruments
13.2.2 Quadrupole instruments
13.2.3 Ion trap quadrupole instruments
13.2.4 Controlled fragmentation
13.2.5 Quadrupole ion trap
13.2.6 Time-of-flight instruments
13.2.7 Ion cyclotron resonance
13.2.8 Orbitrap mass analyzer
13.3 Gas chromatography-mass spectrometry
13.3.1 Analyte ionization in gas chromatography-mass spectrometry
13.3.1.1 Electron ionization
Box 13.4 Modes of ionization in gas chromatography-mass spectrometry
13.3.1.2 Chemical ionization
13.3.2 Gas chromatography-combustion-isotope ratio mass spectrometry
13.4 Liquid chromatography-mass spectrometry
Box 13.5 Some advantages and potential disadvantages of LC-MS
13.4.1 Analyte ionization in liquid chromatography-mass spectrometry
Box 13.6 Some modes of ionization in liquid chromatography-mass spectrometry
13.4.1.1 Electrospray and ionspray ionization
13.4.1.2 Atmospheric pressure chemical ionization
13.4.1.3 Atmospheric pressure photoionization
13.5 Supercritical fluid chromatography-mass spectrometry
13.6 Capillary electrophoresis-mass spectrometry
13.7 Direct introduction mass spectrometry
13.7.1 Flow injection analysis-mass spectrometry
13.7.2 High-performance thin-layer chromatography-mass spectrometry
13.7.2.1 Elution-based approaches
13.7.2.2 Desorption-based approaches
13.7.3 Desorption electrospray ionization mass spectrometry
13.7.4 Paperspray ionization-mass spectrometry
13.7.5 Laser diode thermal desorption mass spectrometry
13.7.6 Matrix assisted laser desorption ionization mass spectrometry
13.8 Presentation of mass spectral data
13.9 Interpretation of mass spectra
13.10 Quantitative mass spectrometry
13.10.1 Stable isotope-labelled internal standards
13.10.2 Assay calibration
13.10.3 Isotopic internal calibration
13.11 Mass spectrometry imaging
13.12 Summary
References
14 Ion Mobility Spectrometry. 14.1 Introduction
Box 14.1 Advantages of ion mobility spectrometry
14.1.1 Interactions with buffer gas
14.2 Theoretical aspects
14.3 Types of ion mobility spectrometry
14.3.1 Drift time ion mobility spectroscopy
14.3.2 High field asymmetric waveform ion mobility spectroscopy
14.3.3 Travelling wave ion mobility spectrometry
14.3.4 Trapped ion mobility spectrometry
Box 14.2 Advantages of trapped ion mobility spectrometry
14.4 Resolving power
14.5 Interfacing ion mobility spectrometry
14.5.1 Selected ion flow tube mass spectrometry
14.6 Applications of ion mobility spectrometry in analytical toxicology. 14.6.1 Direct analysis
14.6.2 Interfaced techniques
14.6.3 Chiral separations
14.7 Summary
References
15 Absorption, Distribution, Metabolism, and Excretion of Xenobiotics. 15.1 Introduction
15.2 Movement of drugs and other xenobiotics around the body
15.2.1 Passive diffusion
15.2.1.1 pH-Partition relationship
15.2.1.2 Other physiochemical properties
15.2.2 Carrier-mediated transport
15.3 Routes of administration. 15.3.1 Oral dosage
15.3.1.1 Pre-systemic metabolism
15.3.2 Intravenous injection
15.3.3 Intramuscular and subcutaneous injection
15.3.4 Sublingual and rectal administration
15.3.5 Intranasal administration
15.3.6 Transdermal administration
15.3.7 Inhalation
15.3.8 Other routes of administration
15.4 Distribution
15.4.1 Ion-trapping
15.4.2 Binding to macromolecules
15.4.2.1 Plasma protein binding
15.4.3 Carrier-mediated transport
15.5 Metabolism
15.5.1 Phase 1 metabolism
15.5.1.1 The cytochrome P450 family
15.5.1.2 Other phase 1 oxidases
15.5.1.3 Enzymatic reductions
15.5.1.4 Hydrolysis
15.5.2 Phase 2 reactions
15.5.2.1 D-Glucuronidation
15.5.2.2 O-Sulfation and N-acetylation
15.5.2.3 O-, N- and S-Methylation
15.5.2.4 Conjugation with glutathione
15.5.2.5 Amino acid conjugation
15.5.3 Stereoselective metabolism
15.5.4 Metabolic reactions of toxicological importance. 15.5.4.1 Oxidative dealkylation
15.5.4.2 Hydroxylation
15.5.4.3 S- and N-oxidation
15.5.4.4 Oxidative dehalogenation
15.5.4.5 Desulfuration
15.5.4.6 Trans-sulfuration and trans-esterification
15.5.5 Enzyme induction and inhibition. 15.5.5.1 Enzyme induction
15.5.5.2 Enzyme inhibition
15.6 Excretion
15.6.1 The kidney
15.6.1.1 Tubular secretion
15.6.1.2 Renal excretion of metabolites
15.6.2 Biliary excretion
15.6.2.1 Recycling of xenobiotics
15.7 Pharmacogenetics and pharmacogenomics
15.7.1 Cytochrome P450
15.7.2 Atypical pseudocholinesterase
15.7.3 Alcohol dehydrogenase and aldehyde dehydrogenase
15.7.4 Thiopurine methyltransferase
15.7.5 N-Acetyltransferase
15.7.6 UDP-Glucuronosyltransferases
15.8 Summary
References
16 Pharmacokinetics. 16.1 Introduction
16.2 Fundamental concepts
16.2.1 Rates, rate constants, and orders of reaction
16.2.1.1 First-order elimination
16.2.1.2 Zero-order elimination
16.2.2 Dependence of plasma half-life on volume of distribution and clearance
16.2.2.1 Apparent volume of distribution
16.2.2.2 Clearance
16.3 Absorption and elimination. 16.3.1 First-order absorption
16.3.2 Quantification of F
16.3.3 Maximum concentration (Cmax)
16.4 Drug accumulation
16.4.1 Intravenous infusion
16.4.1.1 Loading doses
16.4.2 Multiple dosage
16.5 Sustained-release preparations
16.6 Non-linear pharmacokinetics
16.6.1 Example of non-linear kinetics in overdose
16.7 Multi-compartment models
16.7.1 Calculation of rate constants and volumes of distribution
16.7.2 Multiple-compartment models in analytical toxicology
16.8 Non-compartmental methods
16.9 Factors affecting pharmacokinetic parameters
16.9.1 Gastrointestinal contents and gastrointestinal motility
16.9.2 Age
16.9.2.1 Effect of age on renal function
16.9.3 Sex
16.10 Disease
16.11 Pharmacokinetics and the interpretation of results. 16.11.1 Back-calculation of dose or time of dose
16.11.1.1 How much substance was administered?
16.11.1.2 When was the substance administered?
16.11.1.3 Prediction of ethanol concentrations
16.12 Summary
References
17 Toxicology Testing at the Point of Contact. 17.1 Introduction
17.2 Use of point of contact testing
Box 17.1 Questions when deciding to implement point of contact testing
17.2.1 Samples and sample collection
Box 17.2 Advantages and disadvantages of using oral fluid to detect substance misuse
17.3 Toxicology testing at the point of contact. 17.3.1 Ethanol
17.3.1.1 Breath ethanol
17.3.1.2 Oral fluid ethanol
17.3.2 Substance misuse
17.3.2.1 Oral fluid testing
17.3.2.2 Autopsy specimens
17.4 Interferences and adulterants
17.5 Quality assessment
17.6 Summary
References
18 Laboratory Testing for Substance Misuse. 18.1 Introduction
18.1.1 Matrix and sampling. 18.1.1.1 Urine
18.1.1.2 Oral fluid
18.1.1.3 Hair
18.1.1.4 Blood
18.1.1.5 Exhaled air
18.1.1.6 Sweat
18.1.2 ‘Cut-off’ concentrations
18.2 Urine testing
Box 18.1 Urine testing for substance misuse: summary
18.2.1 Sample adulteration
18.2.2 Analytical methods
18.2.2.1 Immunoassay
18.2.2.2 Chromatographic methods
18.2.2.3 Assay calibration and acceptance criteria
18.2.3 ‘Cut-off’ concentrations
18.3 Oral fluid testing
18.3.1 Sample collection and storage
18.3.1.1 Oral fluid collection devices
18.3.2 Road-side testing procedures and ‘cut-off’ concentrations
18.3.3 Analytical methods
Box 18.2 Steps in the analysis of drugs and metabolites in oral fluid
18.3.4 ‘Cut-off’ concentrations
18.4 Blood testing. 18.4.1 Legislative limits drugs and driving
18.4.2 Analytical methods
Box 18.3 Steps in the analysis of drugs in whole blood
18.5 Hair testing
18.5.1 Surface contamination
Box 18.4 Steps in the analysis of drugs and metabolites in hair
18.5.2 Analytical methods
18.5.3 Assay calibration and quality assessment
Box 18.5 SoHT assay validation, IQC and EQA recommendations
18.5.4 ‘Cut-off’ concentrations
18.5.5 Ethanol markers
18.5.5.1 Ethyl glucuronide
18.5.5.2 Fatty acid ethyl esters
18.5.6 Children
18.6 Breath testing
Box 18.6 Sample preparation of exhaled air condensate on an Empore disc C18 for methadone detection
18.6.1 Collection devices
18.7 Sweat testing
18.8 Summary
References
19 General Analytical Toxicology. 19.1 Introduction
19.2 Gas chromatography
19.2.1 Qualitative analyses
19.2.2 Quantitative analyses
19.2.2.1 Ethanol and other volatiles
Box 19.1 HS-GC-FID of blood volatiles (Flanagan & Fisher, 2013–reproduced with permission of Elsevier)
19.2.2.2 Carbon monoxide and cyanide
19.3 Gas chromatography-mass spectrometry
19.3.1 Qualitative analysis. 19.3.1.1 Targeted analysis
19.3.1.2 Systematic toxicological analysis
Box 19.2 STA of urine by GC-MS: sample preparation
19.3.2 Quantitative analysis
Box 19.3 LLE for quantification in plasma by GC-MS or LC-MS
Box 19.4 SPE for quantification in plasma by GC-MS or LC-MS
19.4 Liquid chromatography
19.4.1 Qualitative analysis
19.5 Liquid chromatography-mass spectrometry
19.5.1 Qualitative analysis. 19.5.1.1 Targeted analysis
19.5.1.2 Systematic toxicological analysis
Box 19.5 Sample preparation for LC-MS
19.5.2 Quantitative analysis
19.5.2.1 Batch analysis
19.5.2.2 Emergency toxicology
19.6 Liquid chromatography-high resolution mass spectrometry
19.6.1 Qualitative analysis
19.6.1.1 Targeted analysis
19.6.1.2 Systematic toxicological analysis
19.6.2 Quantitative analysis
Box 19.6 Assay of apixaban, dabigatran, edoxaban, and rivaroxaban in plasma
19.7 Summary
References
20 Therapeutic Drug Monitoring. 20.1 Introduction
Box 20.1 Indications for therapeutic drug monitoring
Box 20.2 Biological effect monitoring
20.2 Sample collection
20.3 Sample types. 20.3.1 Blood and blood fractions
20.3.1.1 Dried blood spots
20.3.1.2 Volumetric microsampling devices
20.3.2 Urine
20.3.3 Oral fluid
20.3.4 Keratinaceous samples
20.3.5 Other alternative matrices
20.4 Analytical methods
20.5 Factors affecting interpretation of results
20.6 Gazetteer
20.6.1 Antiasthmatics
20.6.2 Anticoagulants
20.6.3 Antiepileptic drugs
20.6.4 Anti-infectives. 20.6.4.1 Antibiotics
20.6.4.2 Antifungal drugs
20.6.4.3 Antimalarials
20.6.4.4 Antiretroviral drugs
20.6.5 Anti-inflammatory drugs
20.6.5.1 Therapeutic antibodies
20.6.6 Antineoplastic drugs
20.6.6.1 Chemotherapeutic agents
20.6.6.2 Protein kinase inhibitors
20.6.6.3 Therapeutic antibodies
20.6.7 Cardioactive drugs
20.6.7.1 Digoxin
20.6.7.2 Other cardioactive drugs
20.6.8 Immunosuppressants
20.6.9 Psychoactive drugs
20.6.9.1 Lithium
20.6.9.2 Antidepressants
20.6.9.3 Antipsychotics
20.7 Summary
References
21 Trace Elements and Toxic Metals. 21.1 Introduction
21.2 Sample collection and storage
21.3 Sample preparation
21.3.1 Analysis of tissues
21.3.2 Analyte enrichment
21.4 Atomic spectrometry
21.4.1 General principles of optical emission spectroscopy
21.4.2 Atomic absorption spectrometry
21.4.2.1 Flame atomization
Box 21.1 Advantages and disadvantages of pneumatic nebulization
21.4.2.2 Electrothermal atomization
21.4.2.3 Sources of error
Box 21.2 Actions to match sample and calibrator viscosity in the measurement of serum copper and zinc by FAAS
Box 21.3 Measurement of lead in blood by ETAAS
21.4.3 Atomic emission and atomic fluorescence spectrometry. 21.4.3.1 Optical emission spectrometry
21.4.3.2 Atomic fluorescence spectrometry
21.4.4 Inductively coupled plasma-mass spectrometry
21.4.4.1 Ion sources
21.4.4.2 Mass analyzers
21.4.4.3 Interferences
21.4.5 Vapour generation approaches
21.4.5.1 Hydride generation
21.4.5.2 Mercury vapour generation
Box 21.4 Measurement of mercury in urine by cold vapour generation AAS
21.4.6 X-Ray fluorescence
21.5 Colorimetry and fluorimetry
21.6 Electrochemical methods. 21.6.1 Anodic stripping voltammetry
21.6.2 Ion-selective electrodes
21.7 Catalytic methods
21.8 Neutron activation analysis
21.9 Chromatographic methods
21.9.1 Chromatography
21.9.2 Speciation
21.10 Quality assessment
21.11 Summary
References
22 Clinical Interpretation of Analytical Results. 22.1 Introduction
22.2 Clinical toxicology
22.2.1 Pharmacokinetics and the interpretation of results
22.3 Forensic toxicology
22.3.1 Drug-facilitated assault
22.3.2 Fabricated illness
22.3.3 Post-mortem toxicology
22.4 Gazetteer
22.4.1 Alcohols
22.4.1.1 Ethanol
22.4.1.2 Ethylene glycol and methanol
22.4.2 Anabolic steroids
22.4.3 Antidepressants
22.4.4 Antidiabetic drugs
22.4.4.1 Insulin and C-peptide
22.4.4.2 Insulin analogues
22.4.4.3 LC-MS of insulin and insulin analogues
22.4.5 Antiepileptics
22.4.6 Antipsychotics
22.4.7 Barbiturates
22.4.8 Benzodiazepines
22.4.9 Carbon monoxide
22.4.10 Cannabinoids
22.4.10.1 Synthetic cannabinoids
22.4.11 Cardioactive drugs
22.4.12 Diuretics and laxatives
22.4.13 Hallucinogens
22.4.13.1 N-Benzylphenethylamines
22.4.13.2 2,5-Dimethoxy-substituted phenethylamines
22.4.13.3 Mescaline and psilocybin
22.4.14 γ-Hydroxybutyrate and γ-butyrylactone
22.4.15 Inorganic anions
22.4.15.1 Azide
22.4.15.2 Cyanide and thiocyanate
22.4.15.3 Nitrite
22.4.15.4 Phosphide
22.4.15.5 Sulfide
22.4.16 Ketamine
22.4.17 Non-opioid analgesics
22.4.18 Opioids
22.4.18.1 Buprenorphine
22.4.18.2 Codeine/codeine analogues
22.4.18.3 Diamorphine/morphine
22.4.18.4 Fentanyl
22.4.18.5 Methadone
22.4.18.6 Novel synthetic opioids
22.4.18.7 Tramadol
22.4.19 Organophosphorus compounds
22.4.20 Phosphodiesterase 5 inhibitors
22.4.21 Stimulants and related compounds
22.4.21.1 Amfetamine and metamfetamine
22.4.21.2 Cocaine
22.4.21.3 MDMA and related compounds
22.4.22 Trace elements/toxic metals
22.4.23 Volatile substances
22.5 Sources of further information
22.6 Summary
References
Index
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