Analytical Methods in Human Toxicology: Part 2 PDF
Preview Analytical Methods in Human Toxicology: Part 2
ANALYTICAL METHODS IN HUMAN TOXICOLOGY ANALYTICAL METHODS IN HUMAN TOXICOLOGY Part 2 Edited by A. S. CURRY M MACMILLAN ©The contributors 1986 Softcoverreprintofthehardcover1stedition1986 Allrights reserved. Noreproduction,copy or transmission of this publicationmay bemade withoutwritten permission. No paragraphofthis publication may be reproduced,copied or transmitted savewithwritten permission orin accordance with the provisions ofthe Copyright Act 1956 (asamended). Any person who does any unauthorised act in relation to this publication may beliable to criminal prosecution and civilclaims for damages. First published 1986 Published by THE MACMILLANPRESS LTD Houndmills,Basingstoke,Hampshire RG21 2XS and London Companies and representatives throughout the world Typeset by TecSet Ltd, Wallington,Surrey British Library Cataloguing inPublication Data Analyticalmethodsinhuman toxicology. Part 2. 1.Toxicology - Technique I. Curry,A.S. 615.9'0028 RA1211 ISBN978-1-349-07246-0 ISBN978-1-349-07244-6(eBook) DOI 10.1007/978-1-349-07244-6 Contents TheContributors vi Introduction ix AREVIEW OFANALYTICALMETHODS D.Stevenson andJ. W.Bridges 2 THEUSEOFHIGH PRESSURE LIQUIDCHROMATOGRAPHY INHUMANTOXICOLOGY M.D. Osselton 35 3 FLUORESCENCE ANALYSIS L. A. KingandJ.N Miller 71 4 RADIOIMMUNOASSAYSINANALYTICALMETHODS IN HUMANTOXICOLOGY G. W.Aherne 115 5 PHARMACOKINETICSANDPATIENT CARE G.P.Mould 131 6 DRUGANALYSES INADEPARTMENTOFFORENSIC MEDICINE ANDTOXICOLOGY P.S.B.Minty 161 7 THEANALYSISOFNARCOTICS A. T.Holder 241 8 FIREGASES R.A.Anderson 289 9 THERAPEUTIC DRUGMONITORING P.A. Toseland, D.J.BerryandJ. Williams 319 Index 345 The contributors G.W.Aherne J. N.Miller DepartmentofBiochemistry andRobens DepartmentofChemistry InstituteofIndustrialandEnvironmental University ofTechnology Health and Safety Loughborough University ofSurrey LeicsLEll 3TU Guildford Surrey GU25XH P.S.B.Minty R.A.Anderson Departmentof Forensic Medicineand DepartmentofForensicMedicineandScience Toxicology TheUniversity ofGlasgow CharingCrossHospital MedicalSchool GlasgowGl28QQ Fulham PalaceRoad LondonW68RF D.J. Berry PoisonsUnit Guy'sHospital G.P.Mould LondonSEI 9RT ClinicalPharmacy Section DepartmentofClinicalBiochemistry J.W.Bridges St Luke'sHospital Robens Instituteof Industrialand WarrenRoad EnvironmentalHealth and Safety Guildford University of Surrey Surrey GUI 3NT Guildford Surrey GU25XH M.D.Osselton Toxicology Division A.T.Holder Central Research Establishment School ofChemistry HomeOfficeForensicScienceService Thames Polytechnic Aldermaston Woolwich Reading LondonSE18 6PF BerksRG74PN L.A.King OperationalServicesDivision D.Stevenson Central Research Establishment Robens Instituteof Industrialand HomeOffice ForensicScienceService EnvironmentalHealth and Safety Aldermaston University ofSurrey Reading Guildford BerksRG74PN Surrey GU25XH The Contributors vii P.A.Toseland J.Williams DepartmentofClinicalChemistry DepartmentofPharmacology and Guy'sHospital Therapeutics LondonSEI 9RT WelshNational School ofMedicine Cardiff Introduction In these two volumes on analytical methods in human toxicology twenty-six authors have presented the latest experimental techniques and their application to practical problems. The individual chapters have been written by scientists who are in the fore front of their science. They have not forgotten that the analyses have conse quencesand many havecommentedon how vitalit isthat the results beaccurate and precise. The social scene today revolves very much around drugs and their use and abuse,and there is a heavy responsibility on toxicologists to showwhere inthe body a drug is localised and,if possible, how it isacting. Onlyby knowing such fundamental facts canadvancesbemade in the future on arational basis. Much of the work in these two volumes describes analytical methods using 'black boxes' - machines of high complexity and high cost but involvingvery simple physicochemical principles. It isvital that the operator understands the underlying principles if mistakes are not to be made,and it is refreshing to see how many authors haverecognisedthis fact. Unfortunately international quality control programs have demonstrated a very poor performance when samples have been circulated on a 'known' basis (let alone in 'blind trials'). The best equipment will only givethe best possible results if it isoperated byscientists who areextremelyselfcritical,and although this book (along with the previous volume) describes a host of experimental techniques, it has to be read with care and should be used by experienced personnel. Human toxicology is not only a fascinating subject, but it also has a vast potential for unravelling the solutions to diseases. To use an analogy, Erlich's silver bullet has now to be fired and its position in tissue discovered to within a few microns. The unlocking of molecular structure using monoclonal anti- x Introduction bodies coupled with advanced chemistry means that the key can now be made with the knowledge of how the lock will respond. Medicalscienceis not only knocking onthe door - it hasone foot insideaswell. The editor has been mainly involvedwith forensic problems but it has been refreshing for him to be able to have an overviewofthe wholesceneand to see how many analytical techniques haveevolvedbecauseforensictoxicologistshave required even more sensitivemethods of detection.Their criticalevaluationhas added agreat dealto these two volumes. It ishoped that these two volumeswillprovideknowledgethat willbeshared and that willleadto evenfurther advances. Reading,1986 A.S.C. 1 A Review of Analytical Methods D. STEVENSON and J. W. BRIDGES 1.1 INTRODUCTION For xenobiotics and their metabolites which form readily reversibleinteractions with target sites for toxicity (e.g. receptors), the peak level of unbound com pound present in the immediate vicinity of the target site should be directly related to the biological response over a considerable concentration range. In contrast, for chemicalswhich form ratherstable ligandsto their target, including veryreactivexenobioticsandtheir metabolites,the amount ofcompound present over a period of time isoftenmore important than the peak level.For anumber of compounds, a direct correlation between total covalent binding to cellular proteinsand theextentofhepatocellularnecrosishas been established.Similarly, for several carcinogens, DNAalkylation has-been shown to bedirectly related to their carcinogenic potency, although in some cases (e.g. dimethyl-nitrosamine) such a correlation is not observed with total binding but rather with specific adducts. There are a number of additional reasons why the concentration of a xenobiotic and/or its metabolites that is achieved in a tissue may not correlate with the biological response observed.Commoncausesare asfollows. (a) The xenobiotic and/or its metabolites may be strongly bound to cellular macromolecules which are not involved in the expression of biological activity. For example, cadmium is very strongly bound in both liver and kidney to the protein metallothionein;therefore, the measurement of total cadmium levels does not correlate well with the extent of adverse change. Organic compounds may also bind strongly but non-covalently to cellular macromolecules, e.g. quinacrine is strongly boundin the liver,gentamicin is slowly but strongly boundin the kidney. (b) The toxic effect on the tissue may be mediated indirectly, e.g. at a site which is distant from the observed site of biological activity, for example the primary target may bethe nervous orendocrine system.
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