摘要:

Proceedingsof the Analytical Division ofThe Chemical SocietyCONTENTS275 Summaries of Papers275 'Topics in Envi:onmental and MarineChemistry'284 'Radiochemistry in Medicine'300 Obituary300 Publications Received301 Conferences and Meetings304 Analytical Division DiaryVolume 15 No 10 Pages 275-304 October 197PADSDZ 15(10)275-304(1978)ISSN 0306-1 396October 1978PROCEEDINGSOF THEANALYTICAL DIVISION OF THE CHEMICAL SOCIETYOfficers of the Analytical Divisionof The Chemical SocietyFresidentR. BelchsrHon. SecretaryP. G . W. CobbSecretar yMiss P. E. HutchinsonHon. Treasurer Hon. Assistant SecretariesJ. K. Foreman D. I. Coomber, O.B.E.; D. C. M. Squirrel1Editor, ProceedingsP. C. WestonProceedings is published by The Chemical Society.Editorial: The Director of Publications, The Chemical Society, Burlington House, London, W1 V OBN.Telephone 01 -734 9864.Telex 268001.Subscriptions (non-members) : The Chemical Society, Distribution Centre, Blackhorse Road,Letchworth, Herts., SG6 1 HN.Non-members can only be supplied with Proceedings as part of a combined subscription with The Analysrand Analytical Abstracts.@ The Chemical Society 1978Official,Standardised andRecommendedMethods of AnalysisSECOND EDITION (1973)Compiled and Edited forTHE ANALYTICAL METHODS COMMITTEEofb yThe Society for Analytical ChemistryN. W. Hanson, BSc, PhD, FRICPp. xxiv + 897 f17.00; U.S. $42.50ISBN 0 85990 704 XObtainable from The Chemical Society,Distribution Centre, Blackhorse Road, Letchworth, Herts., SG6 1 HNMembers of the Chemical Society are entitled to buy one COPY fortheir own personal use at the special price of f 14.50 (U.S. $36.50)provided they order direct and enclose remittance

ISSN:0306-1396    

DOI:10.1039/AD97815FX038

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

302 CONFERENCES AND MEETINGS Proc. Anal’yt. Div. Chem. SOC.Analytical Division Diary, continuedNovember, continuedFriday, 24th, 10 a.m.: HarrowElectroanalytical Group, jointly with theAssociation of Clinical Biochemists, on“Ion-selective Electrodes in Clinical Bio-chemistry.’ ’Plenary Lecture : “The Role of Ion-selectiveElectrodes in Clinical Science,” by J . A. W.Dalziel.“Newer Applications in Electrochemistry :Peak Integrated High Speed AnodicStripping Voltametry (PIHSASV) forMeasurement of Urinary Cadmium andBlood Lead,” by A. A. Cernik.“Graphite Electrode Coulometry for Measure-ment of Serum Iron and Total Iron BindingCapacity,” by W. Matson.Paper by J . Barclay.Seminar on “Ion-selective Electrodes inIntensive Care.” Contributors : J .Barclay,J. C. Stuart, K. Maring, R. K. Medd, J. F.Nunn and Mrs. B. Minty.“Clinical Applications of Ion-selective Elec-trodes : Measurement of Serum IonisedCalcium,” by Professor D. N. S. Kerr.“Ion-selective Electrodes for Screening forCystic Fibrosis,” by J . D. R. Thomas.“Fluoride Ion Determinations in the Diag-nosis and Management of Osteoporosis,”by D. C. Cowell and W. H. Taylor.Vickers Award and Lecture.Himsworth Hall, Clinical Research Centre,Harrow, Middlesex.Tuesday, 28th, 10.30 a.m.: LondonMicrochemical Methods and Special Tech-niques Groups : Annual General Meetingsand Meeting on “How to Attack YourSample ! Sample Preparation/Wet Diges-tion. ”Speakers to include: T. T. Gorsuch, D. A.Pantony and R. C. Rooney.Scientific Societies Lecture Theatre, 23 SavileRow, London, W.l.Thursday, 30th, 6.30 p.m.: LondonBiological Methods Group : Annual GeneralMeeting, followed by a Discussion Meetingintroduced by D.Jack.The Chemical Society, Burlington House,Piccadilly, London, W. 1.Thursday, 30th, 2 p.m.: LondonJoint Pharmaceutical Analysis Group :Meeting on “The Use of the Microscope.”Pharmaceutical Society of Great Britain,1 Lambeth High Street, London, S.E.lOctober, 1978 ANALYTICAL DIVISION DIARY 303Analytical Division Diary, continuedNovember, continuedWednesday, 8th, 2 p.m.: LondonSpecial Techniques and Education and Train-ing Groups: Meeting on “The InterfaceBetween Industry and Akadeniia-How DoYou Introduce Specialised AnalyticalTechniques to Students ? ’’Opening remarks by Professor D.ThorburnBurns and Dr. T. B. Pierce.“Construction of an Analytical ChemistryCourse,” by J . A. W. Dalziel.“Analytical Techniques Currently Used inIndustry,” by G. A. Newman.“Electronics in the Service of AnalyticalChemistry,” by J . P. Leppard.“Analytical Chemistry of Surfaces,” by D.Betteridge.“The Handling of Analytical ChemicalData,” by P. G. Barker.Lecture Theatre 201, North East LondonPolytechnic, Romford Road, Stratford,London, E.15.Tuesday, 14th, 2 p.m.: Stockton-on-TeesNorth East Region: Meeting on “Mass Spectro-metry for Trace Element Analysis.”“Introductory Review of Recent Develop-ments in Inorganic Mass Spectrometry,”by D. Hazelby.“Spark Source Mass Spectrometry of Semi-conducting Materials,” by C.Whiteheadand D. C. Newton.“Stable Isotope Dilution Analysis,” by E.Foster.“Ion Microprobe Analysis-Elements andIsotopes,” by J . V. P. Long.“Analytical Opportunities of Electrical Detec-tion Spark Source Mass Spectrometry,”by B. R. Harvey.Central Laboratories, Tioxide InternationalLtd., Portrack Lane, Stockton-on-Tees,Cleveland.Wednesday, 15th, 10 a.m. : ManchesterRadiochemical Methods Group : AnnualGeneral Meeting and Meeting on “Isotopesin Medicine: Production of lZsI and “‘Inand Their Potential in Medical Diagnosis.”Introduction by G. W. A. Newton.“Production of 1231,’’ by J . G. Cuninghame.“Synthesis of 1231 Labelled Compounds,” by“Clinical Aspects of 1231 Labelled Com-“Production of lllIn,” bv M.Finlan.H. L. Sharma.pounds,” by H. J. Testa.“111In Lymphocyte Labelling,” by W. L.Ford.“Clinical Aspects of Labelled Com-pounds,” by D. Crowther.Discussion on “Cyclotron CharacteristicsRequired for This and Future Work,”introduced by R. A. Shields.Department of Chemistry, The University,Manchester.Thursday, 16th, 2.30 p.m.: LondonElectroanalytical Group : Meeting on “StudentResearch Papers.” Chelsea College,Manresa Road, London, S.W.3.Wednesday, 22nd, 6.15 p.m. : BirminghamMidlands Region : Annual General Meeting,followed a t 6.30 p.m. by a Meeting on“Low Cost Computing.”Speakers: D. Danson and H. G. Woodsend,who will discuss and demonstrate theapplication of computers in the analyticalchemistry laboratory.Lecture Theatre 203, Haworth Building, TheUniversity, Birmingham.Thursday, 23rd, 2 p.m.: HuntingdonEast Anglia Region : Annual General Meeting,followed a t 2.15 p.m. by a Meeting on“Pesticides and Metabolism.”“Metabolism in Animals,” by R. Hemingway.“Metabolism in Plants and Soil,” by D.The meeting will be followed by a tour of theHuntingdon Research Centre, HuntingdonHawkins.laboratories.(on A1 near Alconbury).Thursday, 23rd, 4 p.m. : GlasgowScottish Region, jointly with the Glasgow andWest of Scotland Section of the CS/RICand the Andersonian Chemical Society.“Laser Remote Sensing of AtmosphericPollutants,” by B. L. Sharp.Room C133, Chemistry Department, Uni-versity of Strathclyde, Cathedral Street,Glasgow .Thursday and Friday, 23rd and 24th:SloughThermal Methods Group : Annual GeneralMeeting and Meeting on “Fundamentalsand Applications of Thermogravimetry.”Speakers : J.Dunn, E. J. Charsley, P. Barnes,C. J. Keattch, J. H. Sharp, A. W. Benbow,N. Scott and W. W. Wright.Fulmer Grange, Slough., _ I [continued on p. 30OCTOBERTuesday, 17th, 4.30 p.m. : EdinburghScottish Region, jointly with the Edinburghand East of Scotland Section of the CS andthe Edinburgh University ChemicalSociety.‘Strategy for Chromatography,” by ProfessorJ. H. Purnell.Chemistry Department, The University,Kings Buildings, West Mains Road, Edin-burgh.Wednesday, lSth, 4 p.m. : LoughboroughMidlands Region.“An Infrared Interferometer for GC - I RTechniques,” by Miss A.Saunders.“Differential Pulse Polarographic Determina-tion of Disodium Cromoglycate in Urine,”by N. Fayad.“Electroanalytical Determination of Drugs inBiological Fluids,” by W. F. Smyth.Main Lecture Theatre, Fisons Pharma-ceuticals Division, Research and Develop-ment Laboratories, Bakewell Road,Loughborough.Wednesday, lSth, 2 p.m. : LoughboroughEducation and Training Group on “SomeAspects of the Teaching of NMR Spectro-“Lanthanide Shift Reagents-Basic Prin-ciples, Implications and Applications,” byB. D. Flockhart.“Quantitative NMR in the PharmaceuticalIndustry,” by G. Harron and B. Peutrell.“A Definition of the Minimal Amount ofTheory for Practical Comprehension andUse,” by G. Briggs.Fisons Pharmaceuticals Ltd., Bishop MeadowRoad, Loughborough.scopy. ’ ’Thursday, 19th, 4 p.m.: BelfastNorthern Ireland Sub-Committee, j ointly withthe Andrews Club.“Thermometric and Enthalpimetric Methodsfor Rapid Assays of Fertilisers and Pharma-ceuticals,” by Professor L.S. Bark.5.30 p.m.: Annual General Meeting of theNorthern Ireland Sub-Committee of theScottish Region.Chemistry Department, Queen’s University,Belfast.Wednesday, 25th, 2.30 p.m. : LondonAnalytical Division“Strategy for Chromatography,” by ProfessorJ. H. Purnell.Analytical Division DiaryPrinted by Heffers Printers Ltd Cambridge EnglandFollowed by Demonstration and Discussionby Professor Purnell and S. Williams.Lecture Theatre B, Chemistry Department,Imperial College, South Kensington, Lon-don, S.W.7.Wednesday, 25th, 10 a.m.: GatesheadNorth East Region and Atomic SpectroscopyGroup on “Problem Areas in AtomicAbsorpt im.”“Sample Preparation for Determination of theVolatile Elements by the Hydride Genera-tion Technique,” by C. A. Watson.“Some Experiences with Background Correc-tion in Electrothermal Atomisation ,” byB. Fish.“Determination of Phosphorus and the Use ofElectrodeless Discharge Lamps,” by P.Whiteside.“Difficulties in the Analysis of EdibleMaterials,” by W. H. Hill.“The Use of the Graphite Furnace in EmissionAnalysis,” by R. C. Hutton.“Some Observations on the HSE 21-PointGuide on the Use of Acetylene,” by C. P.Cole.Discussion led by J . B. Dawson.Ravensworth Suite, Five Bridges Hotel,Gateshead, Tyne & Wear.NOVEMBERFriday, 3rd, 6.30 p.m.: ChepstowWestern Region : Discussion on “A PolishView of Analytical Chemistry,” introducedby Professor A. Hulanicki.The George Hotel, Chepstow.Friday, 3rd, 5 p.m. : EdinburghScottish Region : Annual General Meeting,followed a t 5.30 p.m. by an OrdinaryMeeting.“Endogenous Opiate Peptides : Biosynthesis,Release and Receptors,” by Professor W.Kosterlitz, F.R.S.Court Room, Heriot-Watt University,Chambers Street, Edinburgh.Wednesday, Sth, 6.30 p.m. : PrestonNorth West Region, jointly with the Lancasterand District Section of CS/RIC and thePreston Polytechnic Chemical Society.“Radiochemical Analysis a t Windscale, ” byJ . C. Dalton.The Polytechnic, Preston.[continued inside back cove

ISSN:0306-1396    

DOI:10.1039/AD97815BX040

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

Vol. 15 No. 10 Proceedings October 1978 of the Analytical Division of the Chemical Society Topics in Environmental and Marine Chemistry The following is a summary of one of the papers presented at a meeting of the Analytical Division held on October 13,1977, in London. A summary of one of the other papers presented at the meeting appeared in the April issue of Proceedings (p. 117). Studies on Toxic Trace Metals in the Environment by Advanced Polarographic Methods H.W. Nurnberg Institute of Chemistry, Institute 4 Applied Physical Chemistry, Nuclear Research Centre (KFA), Julich, Federal Republic of Germany General Environmental and Toxicological Aspects Most of the heavy and less common metals and certain metalloids (arsenic, antimony, selen- ium, etc.) occur in all parts of the environment at trace levels (the mg kg-l to ng kg-I levels).They reach man via the terrestrial and marine food chains and, bound to small dust particles, by respiration (Fig. 1). Although various metals have essential functions ( e g . , copper, zinc, se- lenium, vanadium, etc.) they display, above certain threshold levels, progressively toxic actions on man and other organisms. Thus, local or regional pollution may cause ecological disorder in the afflicted biota and hazards for mammals, including man.Of particular concern are the three toxic metals mercury, cadmium and lead and, in certain locations, also arsenic, thallium and others. The toxicity of metals stems from the fact that they are biologically non-degrad- able and have the tendency to accumulate in vital organs of man, where they act with pro- gressive toxicity over long periods of time.1-3 Marine Terrestrial Fig.1. Scheme of biogeochemical cycle for toxic metals: -, terrestrial and marine food chain; -.---.- , respiration ; _ _ _ - -, other pathways. Therefore, the trace analysis and trace chemistry of toxic metals in the environment have become subjects of high priority and special importance.The obtaining of reliable data on the toxic metal contents of the major sections of the environment (e.g., air, sea and inland waters and food) and of representative sample groups of the human population in polluted and 275276 ENVIRONMENTAL AND MARINE CHEMISTRY PYOC. Anzalyt. Div. Chem. SOC. unpolluted geographical regions, the elucidation of the predominantly occurring chemical species of toxic metals (speciation) in the various sections of the environment and the study of the kinetics and mechanisms of uptake and release by sediments and organisms are urgent tasks.Hitherto, reliable data on these significant topics of environmental trace chemistry have been obtained only to a small extent. Methodological Aspects A critical and comprehensive inspection of the wide spectrum of methods of modern trace analytical chemistryf,2 reveals that for a number of reasons only a few of them are particularly suitable for those problems which involve the necessity of analysing large series of samples and performing extended monitoring programmes.These tasks require efficient analytical methods with favourable cost - benefit ratios.Because of their general properties suitable modes of voltammetry and polarography have gained a prominent position in environmental trace metal chemistry.l-3 This electrochemical approach combines extreme sensitivity with good precision and an inherently high degree of accuracy. This fortunate combination of three basic prerequisites for efficient and reliable trace analyses stems from a foundation on Faraday’s law.One mole of substance is equivalent to the enormous electric charge of n x 96 500 C, where n is 1 to 3 for metals. Reliable commercial multi-mode instruments with high per- formance are available now for a relatively low cost, rendering voltammetry one of the most inexpensive methods of all the instrumental alternatives in trace-metal analysis (see Table I).For all metals of particular toxicological interest, e.g., cadmium, lead, mercury, arsenic, bismuth, selenium, copper, zinc, etc., the sensitivity is excellent and is not bettered by any non-electrochemical method. The highest sensitivity is achieved by diff erential-pulse anodic stripping voltammetry (DPASV) at a mercury-film electrode (MFE).3-5 This electrode consists of a thin film of mercury (10.0 to 120 nm thick).It is formed by cathodic deposition of mercury on a specially polished glassy carbon disc simultaneously with the deposition of the trace metals (in situ mercury-film formation). The solution is spiked beforehand with 10-5 M mercury(I1) nitrate solution. The rigorous application of the approved polishing procedure4 for the glassy carbon carrier is critical for the production of a high-performance MFE.After each analysis the film of mercury is wiped off with wet filter-paper. A properly treated glassy carbon carrier can be used many times over long periods (1 year or more). Up to four or five trace metals can be determined simultaneously in one run by the various methods listed in Table I.Nevertheless, voltammetry has, at present, a lower speed of determination compared with other non-electrochemical alternatives, such as atomic-absorption spectrophotometry,6-8 particularly if interest is focused on just one metal. Even then it remains a single element method which can only be applied sequentially to different metals in a given sample.Owing to the low levels of toxic metals in environmental samples, sensitivity reasons require the application of electrothermal atomic-absorption spectrophotometry with a graphite tube. Unfortunately, this popular approach in trace-metal analysis suffers from a much higher risk of deficiencies in accuracy than voltammetry for a number of reasons (instrumental bias and greater instrumental delicacy, non-specific absorption, losses due to volatilisation and mole- cular distillation, signal suppression by matrix interferences, various not always reproducible interactions with the graphite tube wall, carbide formation and much higher sensitivity to contamination because of the microlitre-range samples used). Thus, contrary to widespread belief induced by overoptimistic commercial advertisements, significant results by use of atomic absorption require very critical work and great expertise in the judgement of theresults.Moreover, test measurements of the same sample type by an independent analytical approach, e.g., voltammetry, become indispensable to establishing accuracy.6-8 These problems of electrothermal atomic-absorption spectrophotometry counterbalance, to a certain extent, its usual rapidity and convenience.In this context it should be added that for metals (mercury, arsenic, antimony, etc.) for which the cold vapour technique can be applied the risk to accuracy is significantly lower. In general, it should be emphasised that despite the foregoing warn- ings atomic-absorption spectrophotometry and voltammetry are not really competitors but essentially support each other in trace-metal analysis, if applied with the appropriate expertise and criticism.With respect to the speed of determination of voltammetry it has to be added Thus, voltammetry is essentially an oligo-substance method.October, 1978 ENVIRONMENTAL AND MARINE CHEMISTRY I w e A 0 V w , n w b Pis c,c, c d c d e 2 X c.l A\ 0 rl I 277278 ENVIRONMENTAL AND MARINE CHEMISTRY Proc.Anzalyt. Div. Chem. SOC. that automation and computerisation, now just being introduced in this method, will lead to very significant improvements during the coming years. It is, in principle, sensitive to the dissolved chemical species of trace metals rather than just to their elemental nature, as most of the other methods used in trace chemistry are.This particular property opens to voltammetry the important field of trace-metal speciation in natural waters. In another direction voltammetry has rather unique potential. Applications The following examples, selected from various areas of the research programme on environ- mental trace metal chemistry continuing at the author's institute, will illustrate and underline the foregoing general points. A very reliable simultaneous determination of cadmium, lead and copper in human whole blood by use of DPASV after prior low temperature ashing (LTA) in an oxygen plasma pro- duced by microwave excitation has been developed (1-ml blood sample, 170 "C, 8 h).9 This voltammetric approach (see Fig.2 ) has been applied to the determination of the trace-metal levels in blood samples from non-exposed and occupationally exposed subjects and has been used to check the accuracy of extended measurements by atomic absorptionl0yll following prior rapid digestion with 2 M nitric acid.General findings are that in Western Europe the average values of the lead (120 pg 1-l) and cadmium (0.78 pg 1-l) levels in the blood of non-exposed subjects are lower by about factors of 1.5 and 3, respectively, than the hitherto reported literature average values, which are usually based on measurements performed only with the use of electrothermal atomic-absorption spectrophotometry.Moreover, it became evident that the average cadmium content was twice as high for heavy cigarette smokers (> 20 cigarettes d-1) than for non-smokers.ll The procedure consisting of ashing by LTA (overnight, up to 24 samples simultaneously) and subse- quent DPASV has also been applied successfully to other biomatrices (marine organisms, fish, plant material, organs, hair and food) .1-3 Recently, a high-performance procedure, with respect to reliability and sensitivity, for the simultaneous dztermination of cadmium and lead in urine has been developed.12 After freeze drying 1 ml for 6-8 h (20 samples simultaneously) overnight rapidly digest it for 15 min with a 2 + 1 mixture of concentrated perchloric and nitric acids (0.2 + 0.1 ml). The solution is now adjusted to pH 5 with acetate buffer.The quartz crucible used for this stage is also used as the voltammetric cell and the metals are determined by DPASV at the MFE.This pro- cedure can be extended to other trace metals with slight modifications. It has also been successfully applied to trace-metal determinations in a variety of wines. JOnssonl3 has recently demonstrated the good reliability and superiority of DPASV for trace-metal deter- minations in digested milk. In summary, one can state that reliable and powerful voltammetric procedures now exist, or can be worked out by adaptation of the aforementioned approaches, for toxic trace metals in important environmental biomatrices, including from man and cattle and most easily attainable sample types, i.e., body fluids, such as blood and urine, and hair.While voltammetry shares its position as one of the attractive methods with significant application potential for the investigation of biological materials with various non-electro- chemical approaches, such as atomic-absorption spectrophotometry, trace-metal determina- tion in natural waters (rivers, lakes, estuaries and the sea) is rapidly becoming the domain of the voltammetric methods.In aqueous samples voltammetry can fully display all of its f avourable properties and potentialities as only a minimum of simple chemical pre-treatment of the sample, which always involves an increase of contamination risks, is required before making volt ammetric measurements.A simple, but very important, matrix is drinking water. A fully automated (including dosage) special voltammetric device coupled to the mains supply from a water works for the on-line monitoring of toxic trace metals has been intr0d~ced.l~ Cadmium, lead, copper and zinc are determined simultaneously by DPASV at the HMDE down to 50 ng 1-1 with a relative standard deviation of &20% at the limit of detection (see Fig.3). If the soil environment of water springs requires thallium monitoring this can be included. Extensions of the technique to selenium and arsenic are in progress.The great potential of the direct pulse-polarographic determination of lead and arsenic(II1)October, 1978 C 0.4 0.3 \ 5 + (I g 0.2 Y 0 0.1 0 ENVIRONMENTAL AND MARINE CHEMISTRY 279 8 0 - (a) 6.81 p.p.b. Pb 60 - 0 8 I L I I I d -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 +O.I Potential versus S.C.E./V Fig. 2. I 0.1 1 p.p.b. Cd Concentration of cadmium, p.p.b.I 6.81 p.p.b. Pb I 1 I I I I I I -8 -4 0 4 8 12 16 20 Concentration of lead, p.p.b. Simultaneous determination of cadmium, lead and copper in h;man whole blood after prior low temperature ashing in aqueous solution (pH 2, acidified with hydrochloric acid) by DPASV a t a HMDE with polarograph PAR 174A. ( a ) , Voltammogram, cathodic deposition potential -0.8 V (S.C.E.), deposition time 5 min (900 rev min-l, scan rate 2 mV s-l, pulse height 50 mV, pulse duration 56.7 ms, clock time of pulses 0.5 s.( b ) , Regression lines with 2 standard additions: 0, Cd; 0, Pb. (down to 20 ,ug 1-l) in run-off water from metallurgical waste disposal has been shown by us previ0us1y.l~ An important future application in the field of atmospheric pollution studies will be trace- metal chemistry in rain water, a topic which is currently being investigated in detail by us.16 DPASV at the MFE and also other modes of voltammetry have opened up new dimensions in marine c h e m i ~ t r y , ~ , ~ ~ , ~ ~ as in seawater the important trace metals are dissolved at ultra-trace levels, typically between 1 000 and 1 ng 1-1, levels that were hitherto hardly attainable.Sea- water is, of course, a very favourable matrix for voltammetry as nature has already added, via the salinity, the necessary supporting electrolyte. On the other hand, atomic absorption faces particular difficulties in this medium as the salinity components, e g . , magnesium and calcium,280 ENVIRONMENTAL AND MARINE CHEMISTRY Proc. AnaZyt. Div.Chem. Soc. suppress completely the signal of most toxic trace metals except those which are determinable by the cold-vapour technique (mercury, arsenic, etc.) .19 Thus, the direct application of atomic-absorption spectrophotometry is largely prohibited and prior solvent extraction of the trace metals, involving severe contamination risks, becomes mandatory. Fig. 3. Example of drinking water monitoring with automated voltam- metric device in DPASV mode a t a HMDE (see reference 14).Great care in sampling and rigorous cleaning of all used containers and laboratory ware are vital prerequisites if good results are to be obtained. The seawater samples (0.5-1 1) are separated from suspended particulate matter by filtration on a 0.45-pm filter. Each filtrate is then left to stand, after acidification to pH 2 (1 ml of concentrated hydrochloric acid per litre), for several hours to ensure decomposition of the chelates.If noticeable amounts of organic matter are present a certain percentage of the dissolved trace metals (up to 20y0) can be bound so strongly, for example as metallothionines, metalloproteins and by organophos- phates, that ultraviolet photolysis is required.This technique is performed in a new irradia- tion device that excludes all hitherto existing contamination risks.20 Particularly for water from large polluted rivers also used as waterways, such as the Rhine, ultraviolet irradiation is essential in order to obtain the total dissolved content of trace metals. Cadmium, lead and copper are determined simultaneously by DPASV at the MFE (determination limit 1 ng 1-1 with a relative standard deviation of not more than & 20% ; for levels of 20 ng 1-1 the relative standard deviation decreases to not more than 5y0).4 The filters with the particulate matter are digested by LTA (150 "C for 4 h).This ashing makes the trace metals contained in biological material, organic detritus, in the organic films on the surface of tiny sand grains and in carbonates available for voltammetry.These amounts are in addition to the dissolved amounts of trace metals that may be taken up by fishes and filter feeders (mussels and other molluscs) and can thus also enter the marine food webs. By analysing the results from a dense network of 500 sampling stations the contours of the cadmium, lead and copper contents of coastal waters along the North Sea coast (Oostende to Isle of Sylt, German Bight) and along the Ligurian and Tyrrhenian coast (Ventimiglia to Cape Anzio) have been established as functions of the operative hydrographic and oceanographic parameters.The special situations occurring in estuaries of major rivers and in big port areas have been also eluci- dated18,20,21 (see Fig.4). The high toxicity of mercury prompted us to develop a reliable voltammetric method for the ultra-trace range.22 By use of a twin-disc gold electrode, consisting of two halves separated by an insulating epoxy layer, programmed polarisation during the cathodic deposition stage (to purge the excess of copper) and DPASV in the subtractive mode during the stripping stage, determination limits of 1 ng 1-1 with a relative standard deviation of &30% (above 10 ng 1-1 the relative standard deviation was only *loyo) could be attained (see Fig.5). A unique feature of the voltammetric approach is its potentiality for yielding results on which generalisations can be based on trace-metal speciation in natural waters. Owing toOctober, 1978 c I m Y m a ' 0.200 ENVIRONMENTAL AND MARINE CHEMISTRY _ _ _ ~ - 2.00 4) - 1.0 ,2-0.316 \ L 4D Y U J 3.- 281 Fig. 4. Profile of dissolved lead level in Ligurian and Tyrrhenian coastal Each point corresponds to the average value a t waters, April-June, 1976. sampling stations within 4 km distance (see references 20 and 21). the high sensitivity of voltammetric methods measurements can be performed under realistic conditions that are at least close to the actual ultra-trace levels of dissolved toxic metals. One topic of significance is the stability of metal complex species in various types of natural water.The voltammetric approach selected depends on the degree of stability of the complex type formed. Organic ligands with chelating groups tend to form rather strong and inert chelates with metals, particularly with heavy metals such as cadmium, lead and zinc.Here, use is made of the fact that a considerable overvoltage is required to reduce (in an irreversible electrode reaction) a trace metal existing as a chelated species [MeL], while the unchelated metal dis- solved as the hydrated cation Me2+, or in the form of labile complexes [MeX] where X is carbonate, chloride, hydroxyl, etc., is reversibly reduced at a potential several hundred milli- volts more positive.Thus, the amount of chelation as a function of the adjusted ligand 80 60 E E > 40 .\ 2c C 1 1 I 0.4 0.6 0.8 Potential versus S.C.E./V 40 30 E E \ 20 10 0 Amount of mercury/ng I-' 2.1 Fig. 5. Determination of dissolved mercury(I1) in filtered sea water (0.45-pm filter), acidified to pH 2, by subtractive DPASV at twin gold-disc electrode.A, Sample; B and C, first and second standard additions. At these low levels of mercury (20 ng 1-l) the elimination of interference from copper is required in addition to the procedure described in the text. After the cathodic deposition stage the medium is changed to 0.1 M perchloric acid plus 3 x M sodium chloride solution before performing subtractive anodic stripping in the differ- ential pulse mode.Deposition time, 10 min; deposition potential, 0.2 V veysus S.C.E.282 ENVIRONMENTAL AND MARINE CHEMISTRY Proc. Analyt. Div. Chem. SOC. concentration can be followed from the decrease of the reversible response corresponding to the respective percentage of unchelated trace metal.In this manner results of general validity have been obtained concerning the problem of how, in seawater, the major com- ponents of salinity affect specifically the stability of trace-metal ~ h e l a t e s . ~ , ~ ~ Measurements have been made that are close to the actual trace levels of cadmium, lead and zinc dissolved in seawat:r with DPSAV.24 As a typical chelating organic ligand with defined properties nitrilotriacetic acid (NTA) was selected. One further aspect in this context is that NTA might appear a t least in coastal waters as it has been considered, and in certain countries already used on a large scale, as a substitute for the eutrophication-inducing phosphates in detergents.It appeared that predominantly due to the competition between the salinity components Ca2+ M) and Mg2+ (5.36 x lou2 M) for the chelation of 50% of the typical trace metals cadmium, lead and zinc a 300 to 2 000-fold higher concentration of NTA was required in seawater compared with a sodium perchlorate model solution having the same ionic strength ( I = 0.7) and a pH of about 8 (see Fig.6). Thus, fairly high concentrations of chelating organic matter of considerable chelating power, with a typical stability constant order of 109-1011, need to be present in seawater in order to chelate a considerable amount of most of the trace metals.The concentrations of these chelating organic ligands required should be rarely encountered in open oceans. Similar results have been obtained for inland waters je.g., Lake Ontario).Also, the kinetics and the mechanism of the formation of trace- metal chelates in seawater have been elucidated by DPASV measurements on the time dependence of trace-metal chelation subsequent to the addition of a chelating organic ligand (EDTA) . Virtually the only operative mechanism of trace-metal chelation is ligand exchange with the immediately formed alkaline earth ~ h e l a t e s .~ ~ , ~ ~ 50 0” I = 0.7 M pH = 9.0 pH = 7.91 - I I I I -7 -6 -5 -4 Log concentration of NTA/M Fig. 6. Dependence of unchelated cadmium(I1) percentage on the logarithm of chelating ligand (NTA) concentration in a model solution of 0.59 M sodium loride and n natural Adriatic seawater. Total cadmium(I1) concentration (100%) was 3 x M.The points represent determinations of unchelated cadmium(I1) by DPASV at an HMDE. 3 The investigation of labile trace metal complexes (MeX) requires a different methodological approach. The usual procedure is to measure the shift of the reversible half-wave potential AE, as a function of the concentration of the labile complex forming ligand X. This is, in principle, also possible at the ultra-trace level although in a somewhat more elaborate way.Because of sensitivity requirements anodic stripping voltamnietry (ASV) has to be applied and therefore, for a range of adjusted ligand concentrations, the respective half-wave potential values have to be determined from the experimentally obtained dependences of the ASV peak heights on a series of plating potentials in the reduction potential range.This laborious experimental step has been automated in this I n s t i t ~ t e . ~ By use of this sensitive and efficient experimental approach we have been able to elucidate, for the first time, the speci- ation of lead and cadmium in seawater with the carbonate i ~ n . ~ ~ ~ ~ I t has been established that lead in the sea forms predominantly carbonato complexes, i.e., [PbCOJO and [Pb(C0,),12-.For cadmium, both carbonato complexes are also formed but chloro complexation prevails in ~eawater,~’ Based on our experimental results for lead - carbonato complex formation, the experimentalOctober, 1978 ENVIRONMENTAL AND MARINE CHEMISTRY 283 data of Branica et aZ.28 on lead chloro complexes and on literature dataz9 extrapolated for sea- water conditions for lead hydroxy complexes, we have been able to evaluate (for seawater) the distribution of the total dissolved-lead content over the major inorganic complex species.27 The most abundant species are carbonato complexes. In conjunction with the aforementioned general findings on chelation by organic ligands it is concluded that in open ocean waters this lead distribution is probably not greatly affected by chelation with organic ligands.Conclusions The above examples demonstrate in an impressive way the great potential of suitably ad- vanced modes of polarography for the determination and speciation of toxic trace metals in environmental matrices. This is immediately relevant to samples from natural waters, which represent, particularly with respect to the sea, one of the most significant stages in the biogeo- chemical cycle of toxic trace metals.The very favourable basic properties of voltammetry also provide attractive opportunities for the voltammetric investigation of toxic trace metals in various other stages of the food chains leading to man. This includes the elucidation of speciation problems in those matrix types30 in conjunction with chromatographic methods.1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. References Nurnberg, H. W., Sci. Tot. Envir., in the press. Stoeppler, M., and Nurnberg, H. W., CEC-WHO-EPA, “Proceedings of the International Workshop on Biological Specimen Collection, Luxembourg, 1977,” Commission of the European Community, Luxembourg, 1977.Nurnberg, H. W., Electrochim. Acta, 1977, 22, 935. Niirnberg, H. W., Valenta, P., Mart, L., Raspor, B., and Sipos, L., 2. Analyt. Chem., 1976, 282, 357. Valenta, P., Mart, L., and Riitzel, H., J . Electroanalyt. Chem., 1977, 82, 327. Niirnberg, H. W., Stoeppler, M., and Valenta, P., Thalassia Jugosl., 1975, 11, 85. Stoeppler, M., Backhaus, F., Dahl, R., Dumont, M., Hagedorn-Gotz, H., Hilpert, K., Klahre, P., Riitzel, H., Valenta, P., and Niirnberg, H.W., “Proceedings of the International Symposium on Recent Advances in Assessment of Health Effects of Environmental Pollution, Paris, 1974,” Volume IV, Commission of the European Community, Luxembourg, 1975, p. 2231. Stoeppler, M., in Branica, M., Editor, “Proceedings of the International Expert Discussions on Lead Occurrence, Fate and Pollution in the Marine Environment, Rovinj, 1977,” Pergamon Press, Oxford, 1978.Valenta, P., Rutzel, H., Nurnberg, H. W., and Stoeppler, M., 2. Analyt. Chem., 1977, 285, 25. Stoeppler, M., Brandt, K., and Rains, T. C., Analyst, 1978, 103, 714. Stoeppler, M., and Brandt, K., “Proceedings of the International Symposium on Clinical Biochemistry, Golimowski, J., Valenta, P., Niirnberg, H.W., and Stoeppler, M., 2. Analyt. Chem., 1978, 290, 107. Jonsson, H., 2. Lebensmittelunters. u. -Forsch., 1976, 160, 1. Valenta, P., Riitzel, H., Krumpen, P., Salgert, K. H., and Klahre, P., 2. Analyt. Chern., in the press. Heckner, H. N., 2. Analyt. Chem., 1972, 261, 29. Nguyen, V.D., Valenta, P., and Nurnberg, H. W., Sci. Tot. Envir., in the press. Nurnberg, H. W., and Valenta, P., in Goldberg, E. D., Editor, “The Nature of Sea Water,” Dahlem- Konferenzen, Berlin, 1975, p. 87. Niirnberg, H. W., “Proceedings of the International Symposium on the 500th Anniversary of Uppsala University; Structure and Dynamics in Chemistry,” in the press. Stoeppler, M., and Matthes, W., Analytica Chirn. Acta, 1978, 98, 389. Mart, L., Doctoral thesis, RWTH, Aachen, 1978. Nurnberg, H. W., Mart, L., and Valenta, P., in Branica, M., Editor, “Proceedings of the International Expert Discussions on Lead Occurrence, Fate and Pollution in the Marine Environment, Rovinj, 1977,” Pergamon Press, Oxford, 1978. Marburg 1977,” Springer, Berlin, 1977. Sipos, L., Valenta, P., Niirnberg, H. W., and Branica, M., J . Electroanalyt. Chern., 1977, 77, 263. Raspor, B., Valenta, P., Niirnberg, H. W., and Branica, M., Sci. Tot. Envir., 1978, 9, 87. Raspor, B., Valenta, P., Niirnberg, H. W., and Branica, M., in Branica, M., Editor, “Proceedings of the International Expert Discussions on Lead Occurrence, Fate and Pollution in the Marine Environment, Rovinj, 1977,” Pergamon Press, Oxford, 1978. Raspor, B., Valenta, P., Nurnberg, H. W., and Branica, M., Thalassia Jugosl., submitted for publica- tion. Sipos, L., Valenta, P., Nurnberg, H. W., and Branica, M., in Branica, M., Editor, “Proceedings of the International Expert Discussions on Lead Occurrence, Fate and Pollution in the Marine Environment, Rovinj, 1977,” Pergamon Press, Oxford, 1978. Sipos, L., Raspor, B., Pytkowicz, R., and Nurnberg, H. W., Marine Chem., submitted for publication. Branica, M., Novak, D. M., and BubiC, S., Croat. Chem. Acta, 1978, 49, 539. Bilinski, H., Huston, R., and Stumm, W., Analytica Chivtz. Acta, 1976, 84, 157. MacCrehan, W. A., Durst, R. A., and Bellama, J. M., Analyt. Lett., 1977, 10, 1175.

ISSN:0306-1396    

DOI:10.1039/AD9781500275

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

284 RADIOCHEMISTRY IN MEDICINE Proc. AnaZyt. Div. Chem. SOC. Radiochemistry in Medicine The following are summaries of the seven papers presented at a Meeting of the Radiochemical Methods Group held on May 17th, 1978, in Sutton, Surrey. Value of /n Vivo Radionuclide Methods in Clinical Diagnosis D. 0. Cosgrove Department of Nuclear Medicine, Royal Marsden Hospital, SuttoPz, Surrey, SM2 5PT Central to the use of radionuclides in diagnostics is the well tried tracer concept with its implication that the nuclide used is not discriminated by the body mechanisms.The choice of radionuclides for in vivo use is greatly influenced by dosimetric considerations, especially the biological T& and, for external counting, the degree to which the disintegration pattern approximates to the ideal of a pure y emitter of medium energy (too low and the tissue dose rises, too high and capture by the sodium iodide crystal falls off).For imaging, the metastable nuclides, especially99Tcm, have proved physically ideal (although not without difficulty for the radiochemist) and have allowed the use of larger doses than were acceptable with, for example, 1311, with great improvements in image clarity and with the potential for dynamic imaging.Dynamic imaging, well established and invaluable in renal work, has become increasingly more important in cardiology. It is much simpler than X-ray angiocardiography and there- fore more readily repeatable. Information on the passage of a blood pool agent is collected through several cardiac cycles and displayed in slow motion in order to give a good visual impression of the heart's contractions. Numerical information can be extracted and promises to be useful in providing cardiac output measurements, etc.Static imaging has improved considerably over the past decade, owing to a combination of better y-ray cameras and more suitable radiopharmaceuticals. The images are two-dimensional representations of the distribution of the nuclide in the body, but it must be emphasised that they are not simple anatomical images, but show anatomy as revealed by selective organ function.Some specific clinically valuable applications are mentioned and a classification by tracer type is informative. Chemical Identity Its action depends upon selective concentration of iodide by functioning thyroid tissue and may be thought of as giving a positive image.In the brain an intact blood - brain barrier excludes most solutes but becomes permeable when damaged. Many tracers are available but the most useful are anionic forms of 99Tcm pertechnetate. The normal brain scan thus shows no brain at all; regions of increased activity are abnormalities. Many other examples of this group are less commonly used, e.g., 57Fe for the bone marrow and tagged damaged red cells for the spleen.The classic imaging nuclide is 1311 for the thyroid, and it is still one of the most valuable. Chemical Similarity In this application the tracer is sufficiently similar to a chemical present in the tissue under examination, although the lack of identity can lead to difficulties in interpretation. The use of l8F as a substitute for chloride as a bone scanning agent is a now superseded example, and one of current interest is the substitution of 201Tl for potassium as a cardiac muscle imaging agent.Selenium-75 can be substituted for sulphur in amino acids used to reveal sites of pro- tein synthesis. Selenomethionine is a useful agent for imaging the pancreas.Tracers Linked to Metabolites In this application the nuclide is bonded to a metabolite with a minimum of disturbance of behaviour. Iodoalbumin is the classic example, used for blood pool imaging or volume estimation and iodo- or selenocholesterol are similar substances that are useful in imaging the adrenals. The most valuable example is the use of phosphate-like substances, tagged with 99Tcm, for bone scanning. A number of similar compounds are available, and these rely on the fact that increased laying down of calcium phosphate occurs whenever boneis diseased so that a hot spot is produced.Thus the scans are non-specific for pathology but they areOctober, 1978 RADIOCHEMISTRY I N MEDICINE 285 extremely sensitive, becoming positive in malignancy for example, before conventional radiography reveals changes.Labelled Particles Large particles embolise in the first capillary bed encountered, and in this way 99Tcm-tagged albumen microspheres injected in vivo will produce a scan of patent pulmonary capillaries. Occluded vessels show as cold zones. Smaller particles are taken up by the macrophage cell system, and this procedure can be made selective if the particle size is carefully chosen.Colloidal sulphur, labelled with 99Tcm, is useful in this way as a liver scanning agent, lesions showing as cold defects. Tumour Seeking Agents This group is currently unclassifiable as the mode of uptake is not known. The most valu- able has been 67Ga citrate, which although erratic in its behaviour, does concentrate strongly in certain tumour types, especially seminoma, lymphoma and bronchial tumours.Because of gut excretion interpretation of the abdominal images is difficult and this agent is most useful for examination of the chest. When viewing the place of radionuclides in diagnosis in a clinical context, it seems clear that their most obvious advantage over the other imaging systems under development (especially computer X-ray tomography and ultrasound tomography) is the unique information on tissue function that is not available from the purely anatomical techniques.This distinction leads one to suspect that advances are likely to come from new radiopharmaceuticals allowing new applications in physiology and pathophysiology rather than from instrumentation advances designed to improve spatial resolution.It also collects strongly in abscesses. Technetium-99m Radiopharmaceuticals D. M. Taylor Radiopharmacology Department, Institute of Cancer Research, Sutton, Surrey, SM2 5PX Why should a rare element like technetium that possesses no known biological effects be of interest in medical diagnosis? The answer to this question lies in the basic characteristics that are required by the ideal radiopharmaceutical for the in vivo visualisation of human organs by scintillation scanning.For physical reasons modern gamma-ray cameras and other imaging devices yield the most satisfactory results with gamma-ray emissions in the range of 150-200 keV. Technetium-99m, which emits 140 keV gamma-rays, lies close to this ideal range. Further, the chemical proper- ties of the element permit the simple and rapid preparation of a wide range of radiopharma- ceuticals that exhibit useful biological characteristics, while the 6-h half-life of 99Tcm helps to limit the radiation dose received by the patient.These factors, together with the ready availability of 99Tcm from a simple generator system have made this the most widely used nuclide in modern nuclear medicine.Most of the 99Tcm that is used today is produced by the neutron bombardment of molyb- denum in a nuclear reactor utilising the following reaction sequence 3 99Ru P- Y P- 98M0 (n, y ) 99Mo - 99Tcm ---+ 99Tc 66 h 6 h 2.1 x lo5 year The 9 9 M ~ - 99Tcm pair can be utilised readily as a radionuclide generator system from which 99Tcm can be separated more or less on demand.Following separation of 99Tcm from 99Mo, the activity of the daughter nuclide grows rapidly to achieve virtual equilibrium with the parent after four half-lives (24 h). Thus a ready supply of 99Tcm can be made available.286 RADIOCHEMISTRY IN MEDICINE Proc. AnaZyt. Div. Chem. SOC. Although solvent extraction, distillation and ion-exchange methods have been used to separate 99Tcm from its parent nuclide, all modern generators for clinical use involve a simple ion-exchange system.Molybdenum-99, as molybdate, is absorbed on to a short column of alumina from which the 99Tcm can be eluted as pertechnetate with physiological saline. Modern generators are supplied as sealed sterile units that, if used correctly, will yield a sterile, pyrogen-free solution of 99Tcm as pertechnetate, which can be administered directly to patients or used for the preparation of other radiopharmaceuticals.The ggMo used in most of the generators is produced by neutron bombardment of molyb- denum but there is currently considerable interest in the exploitation of ggMo that has been produced as a fission product for use in 99Tcm generators.The eluate from the generator contains 99Tcm plus varying amounts of 99Tc depending on the period that has elapsed since the generator was last eluted. In general, the total concentration of pertechnetate ions in the eluate is less than 1 0 - 9 ~ . The general chemical properties of technetium show many similarities to those of manganese and, more especially, rhenium.Although compounds of technetium with oxidation states ranging from +7 to - 1 have been identified, in aqueous solution the most stable forms are the pertechnetate ion, Tc0,- (+7), and the insoluble dioxide, TcO, (+4). The lower oxidation states produced by reduction of pertechnetate ions show marked tendencies to form complexes with a wide variety of ligands.It is this property that makes technetium so useful in the radiopharmaceutical field. The reductants used in radiopharmaceutical preparations must be relatively non-toxic, as in general they cannot be removed from the final product. At the present time, tin(I1) ions are the most commonly used reductant. However, metallic reductants can cause consider- able problems in the preparation of radiopharmaceuticals based on the complexing of reduced 99Tcm, owing to interference with complex formation or the possible formation of mixed metal complexes.There is now considerable interest in the development of non-toxic organic reducing agents and of insolubilised reductants. A wide variety of 99Tcm labelled radiopharmaceuticals have been described over the past ten years and about 20 of these have found a place in routine clinical use.Some of the preparations that are in clinical use or are currently of investigational interest are listed in Table I. All of these radiopharmaceuticals are administered to the patient by intravenous injection, conse- quently their preparation must comply with all of the pharmaceutical and legislative require- ments relating to injectable products.This poses a number of practical difficulties as, because of the short half-life, all g9Tcm radiopharmaceuticals must be prepared in hospital radiopharma- cies and administered within an hour or two of preparati0n.l In order to overcome some of these problems, most of the commonly used 99Tcm radiopharmaceutical preparations have been designed to require only a simple one- or two-stage procedure involving the aseptic transfer of a sterile 99Tcm pertechnetate solution to a vial containing a pre-tested, sterile kit of reagents.Although the development of new 99Tcm radiopharmaceuticals has been a major growth area in nuclear medicine for more than a decade, there is an incomplete understanding of the fundamental chemistry of most of the various agents that are now in common use.This situation stems in part from the great difficulty of identifying with certainty the molecular species formed in radiopharmaceutical reactions involving picomoles of technetium and micromoles of tin, or other reductant, and complexing agents. Some studies of radiopharmaceutical reactions have been carried out using the long-lived nuclide 99Tc, or even rhenium, but the interpretation of such work imposes the uncertainties of extrapolating results from millimolar to picomolar concentrations. Currently there is considerable interest in the development of quantitative methods for the study of technetium reactions at picomolar concentrations. Owunwanne et aL2 have utilised ion-exchange methods in order to determine the technetium species produced by the reduction of 99Tcm present as pertechnetate with tin(I1) ions.The results suggest that the species produced are either dihydroxytechnetate, Tc(OH),,f, or oxotechnetate, Tc02+. Above pH 2, in the absence of complexing ions, these species hydrolyse to technetium dioxide dihydrate, Tc0,.2H20. These hydrolytic reactions can cause problems in some radiopharmaceutical preparations.However, on occasion they can be turned to advantage; for example, the reduction of 99Tcm as pertechnetate with about 1 mg of tin(I1) fluoride yields a mixed colloidal preparation of hydrolysed tin and 99Tcm that has excellent properties as a liver scanning agent.October, 1978 RADIOCHEMISTRY I N MEDICINE 287 TABLE I SOME TECHNETIUM-9h RADIOPHARMACEUTICALS Preparation Organ visualised Pertechnetate Brain, thyroid S9Tcm - sulphur colloid 99Tcm - hydrolysed tin colloid 99Tcm - bromomercurihydroxypropane sgTcm - dimercaptosuccinate 99Tcm - glucoheptonate 99Tcm - methylenediphosphonate 99Tcm - imidodiphosphonate Heart 99Tcm - diethylacetanilidoiminodiacetate 99Tcm - dimethylacetanilidoiminodiacetate 99Tcm - pyridoxylidineglutamate g9Tcm - human serum albumin-native Liver 1 Kidney Kidney, brain :ladder Blood pool microspheres Blood pool macroaggregates Lungs i ” T c ~ - DTPA Blood clot detection Spleen 1 g9Tcm - fibrinogen 99Tcm - plasmin 99Tcm - streptokinase 99Tcm - urokinase ggTcm - labelled cells- red blood cells (heat damaged) leucocytes platelets The oxidation states of 99Tcm in some of the commonly used radiopharmaceuticals have been studied and the evidence suggests3 that the diethylenetriamine-NNN’N‘’N”-pentaacetic acid (DTPA) complex contains Tc(II1) and the human serum albumin complex Tc(V).In the development of new 99Tc~radiopharmaceuticals not only is the chemistry of technetium important but so is the choice of the complexing ligand, which must be based on known or predicted biological behaviour. In relation to radiopharmaceuticals based on complex and chelate formation a point that is often unrecognised, or forgotten, is that the formation of the complex can itself change the biological properties of the ligand.This change can result from complexing with groups essential for biological activity, or from changes in lipophilicity or molecular charge.These changes usually lead to radiopharmaceuticals which do not fulfil the intended aim. Occasionally however, alteration in properties may be advantageous. For example, dimethylacetanilidoiminodiacetic acid is a derivative of the drug lidocaine. The parent compound is excreted mainly in the urine whereas the 9 9 T ~ m complex is excreted almost exclusively in the bile, making it a useful agent for imaging the gall bladder.4 To conclude, 99Tcm is not only the most widely used radionuclide in contemporary nuclear medicine, but it retains great potential for further exploitation. To the chemist the develop- ment of new 99Tcm radiopharmaceuticals provides many fascinating challenges, from the basic chemistry of technetium at picomolar concentrations, through the chemistry, biochemistry and pharmacology of 99Tcm complexes, to the problems of developing rapid and reliable methods of preparation and of quality control.References 1. 2. 3. 4. “Guidelines for the Preparation of Radiopharmaceuticals in Hospitals,” British Institute of Radiology Owunwanne, A., Marinsky, J., and Blau, M., J .Nucl. Med., 1977, 18, 1099. Richards, P., and Steigman, J., in Subramanian, G., Rhodes, B. A., Cooper, J . F., and Sodd, V. J., Editors, “Radiopharmaceuticals,” Society of Nuclear Medicine, New York, 1975, p. 23. Ryan, J., Cooper, M., Loberg, M., Harvey, E., and Sikorski, S., J . Nzrcl. Med., 1977, 18, 997. Special Report No. 11, British Institute of Radiology, London, 1975.Radioactive Gases of Short Half-life for Brain, Heart and Lung Studies John C. Clark Medical Research Council, Cyclotron Unit, Hammersmith Hospital, Ducane Road, London, W12 OHS The application of radioisotopes as in vivo probes in order to study organ morphology and function and the measurement of body spaces by radioisotope dilution analysis has been sum-288 RADIOCHEMISTRY IN MEDICINE Proc.Autalyt. Div. Chem. SOC. marked in the preceeding papers. This paper discusses the clinical applications of gaseous species containing radionuclides with short half-lives. It is ob- tained from a radionuclide generator, the parent radionuclide 8lRb having a half-life of 4.58 h. The chemical separation is simple, the daughter being an inert gas. 81Krm decays to SlKrg, which has a half-life of 2.1 x lo5 year and thus poses no further hazard.The krypton generator can be coupled on-line to the patient and after the study a very rapid decay occurs when the generator is switched off. In this respect the almost instant disappearance of radiation resembles the conventional X-ray technique. The use of a short half-life radio- isotope provides a new approach to dynamic studies in nuclear medicine. The krypton generators can be shipped readily by air and by using Concorde can reach America, where until recently they were unobtainable, in a usable state. An ultra-safe generator design is essential as the direct coupling to patients precludes intermediate testing.8lRb is prepared by either the (p,2n) or (d,3n) reactions on 82Kr or, as at Hammersmith, the alternative reaction 79Br(a,2n)81Rb using sodium or copper bromides as targets.The gas- phase reaction with a krypton target is the preferred production method. The bombardment of natural krypton with 30 MeV protons yields approximately 10 mCi of 8lRb PA-1 h-l. The 8lRb collects on the walls of the gas target pressure vessel. The best 81Rb recovery method reported is the use of a target vessel whose cylindrical stainless-steel walls can be rotated.When water is introduced into the rotating liner an epicyclic rod acts as a squeegee, ensuring good contact with the walls and an S0-90~0 recovery of BlRb, which can be absorbed on to a very small cation-exchange column. With sodium bromide targets it is found that a zir- conium phosphate inorganic ion exchanger has a high affinity for rubidium even in the presence of a gross excess of sodium ions.At Hammersmith Hospital there is a hot cell where six generators can be made and tested in parallel from one irradiation, all chemistry and target handling being carried out by remote control. Irradiations are carried out between 05.00 and 07.00 hrs, shipment throughout the UK and continental Europe being by road, rail or air.In operation the column is eluted with humidified air for use in pulmonary ventilation studies. When 81Krm is required in solution a specially prepared column is eluted with 5% dextrose in water. The eluate is passed through a small column of AG50 resin to ensure low 81Rb contamination. Terminal sterilisation is carried out on-line using a Millipore 0.22 pm Swinnex disposable filter unit.99Tcm microspheres (Ey 140 keV) can be monitored along with 81Krm (Ey 190 keV) as a differential test of lung function. The 99T~m microspheres test the blood supply and 8lKrm tests the ventilation as this isotope decays so rapidly that a significant decay occurs before a volume distribution can be achieved.Gross mismatching of the two isotopes (monitored at 140 and 190 keV, respectively) indicates abnormal lung function. Continuous infusion of 81Krm solution by a specially designed aortic root catheter whose tip is placed just above the aortic valve (the region from where the coronary arteries draw their blood supply) allows studies of the blood flow to the myocardium. This technique can give a semi-quantitative estimate of flow on a minute to minute basis.In contrast only one flow estimation can be carried out using 99Tcm microspheres. Similarly, arterial infusion of 8lKrm enables studies of brain blood flow during drug stimulation. Radioactive oxygen, 150, has been available for many years. I t has a 2 min half-life and is available as C150, C1502, 1502 and H2150.Nitrogen is irradiated with deuterons at about 7 MeV. Oxygen-15 atoms are produced by the 14N(d,n)150 reaction and react with selected substrates in radiolytic reactions in the target to form, for example, 1502 and C1502 at radio- chemical purities of around 99%. One recent application of 1502 and C1502 is in the study of regional brain oxygen consumption and blood flow.If a subject breathes 1502 until a steady-state equilibrium is obtained the body tissues become labelled with H2150 generated by metabolism of 1502. Some background is inevitably present due to the 1502 bound to haemoglobin in the blood but in practice this effect is small. If on the other hand C1502 is administered under similar conditions the body tissues become labelled with H25O by the exchange process C1502 + H20+C02 + H2150 (catalysed by carbonic anhydrase) and in this instance the labelled water content of the Of the radioisotopes in current practice 81Krm at 13 s has the shortest half-life.October, 1978 RADIOCHEMISTRY IN MEDICINE 289 tissue can be related to blood flow.Thus, by use of a suitable imaging device distributions of water of metabolism and flow can be studied and compared.Initial studies are being carried out in the brain where mismatching between metabolism and flow can be seen clearly in a variety of disorders. During radiotherapy of brain tumours, for example, brain metabolism and blood flow can be monitored non-invasively, the only co- operation required from the patient is to breath the labelled gas whilst being located in front of the imaging device (y-ray camera).Small cyclotrons (7-8 MeV deuterons) suitable for dedicated 150 production may at l250000 become a useful addition to the technological arsenal of the clinical scientist. Radioactive nitrogen 13N with its 10 min half-life can be produced by the 12C(d,n)13N or lsO(p,a)13N reactions. If carbon dioxide or methane are irradiated with deuterons 13N2 and 13NH3 are the major products, respectively.If water is irradiated with protons of 10 MeV or more 13N-labelled nitrate and nitrite are formed which can be reduced readily to 13NH,. 13N2 is used in the solution and gas phase for pulmonary function studies whereas 13NH3 has found application as a cerebral blood flow marker and in myocardial metabolism studies.Radioactive carbon-11 is commonly produced by the 14N(p,a)11C reaction to yield 11C02, which can be reduced to llC0 by zinc at 400 "C. llC0 can be used to label red blood cells as llC carboxyhaemoglobin and used to define blood pools, e.g. the heart chamber volumes in vivo. If approximately 5% H, is present during the proton irradiation of nitrogen llCH, is produced; this can be chemically converted into the useful synthetic precursor HllCN with ammonia by passing over platinum catalyst at 1 000 "C.Several natural and synthetic amino acids have been prepared using HlTN and a modified Strecker synthesis for use in in vivo protein metabolism studies, e.g., in the pancreas and tumours. These positrons, on annihilation, give rise to a 180" correlated coincidence pair of 511 keV photons.These photons can, with the aid of recently developed multi-crystal ring detectors using 66 or more sodium iodide (thallium) crystals, be used to generate a quantitative image similar to an in vivo autoradiograph using computer assisted reconstructed emission tomography, a technique akin to that used by the now familiar EM1 scanner.The positron and EM1 studies can be considered as complementary. With suitable labelled radiopharmaceuticals the former provides func- tional information whereas the latter provides morphological information. In conclusion, the application of radioactive gases of short half-life is now providing the clinician with useful information previously unobtainable both in the routine and research areas.The transition to the preparation and use of more complex molecules, based on simple gases as precursors has begun, and a challenging but interesting future seems to lie ahead. The radionuclides 150, 13N and llC all decay by the emission of positrons. Radiopharmaceuticals Containing Fluorine-I 8 A. J. Palmer Medical Research Council, Cyclotron Unit, Hammevsmith Hospital, Ducane Road, London, W12 OHS Fluorine-18 (half-life 110 min /3+) found a place in nuclear medicine in the late sixties and early seventies when it was extensively used (in the form of a simple aqueous solution of fluoride) for bone scanning.l Since that time it has been largely superseded for this purpose by 99Tcm labelled polyphosphate complexes but its use on a smaller scale for dental studies continues2 Interest has also continued in the preparation and applications of organic radiopharmaceuticals labelled with this radionuclide.Fluorine-1 8 labelled organic radiopharmaceuticals would appear to have several potential advantages. In fluorinated analogues the fluorine can replace either a hydrogen atom or a hydroxyl group in a normal organic compound, while a third possibility is the introduction of a trifluoromethyl group.In analogues of the first type the Van der Waals radii of the two ele- ments are very similar (rF = approximately 0.135 nm, rH = approximately 0.110 nm) and fluorine is the only element that can replace hydrogen without notable steric conseq~ences.~ The carbon - fluorine bond has a very high dissociation energy and consequently improved in vivo stability would be expected for these compounds when compared with, for example, the equivalent iodine-labelled material.Fluorine and hydrogen are however very different in their reactivities. Owing to the very strong electron withdrawing inductive effect of290 RADIOCHEMISTRY IN MEDICINE Proc. AnaZyt. Div. Chem. SOC. fluorine it may alter reaction rates substantially when placed in the vicinity of a reaction centre.Consequently, in the preparation of an lsF-labelled radiopharmaceutical that is an analogue of a natural compound (F replacing H) the fluorine atom should be placed in a site remote from functional groups. Replacement of a hydroxyl group by fluorine has mainly been applied to polyhydroxy compounds, while no [18F] trifluoromethyl radiopharmaceuticals have yet been reported.Production of the Radionuclide Fluorine-18 can be produced by a variety of nuclear reactions using either a cyclotron or reactor.4 Where aqueous solutions of fluoride ion are required the bombardment of water with either alpha or 3He particles has proved to be the most convenient r o ~ t e . ~ ? ~ For the prepara- tion of lsF-labelled compounds it is often necessary to prepare labelled, anhydrous, highly reactive fluorinating agents and the 20Ne(d,cc)1sF reaction is nearly always used for this pur- pose by virtue of its high yield and the inert nature of the target n u ~ l i d e .~ ~ ~ Radiopharmaceuticals containing 18F that have been prepared up to the present time are listed in Table I together with their proposed applications.Only biologically important com- pounds have been included. TABLE I l s F - L ~ ~ ~ ~ ~ ~ ~ RADIOPHARMACEUTICALS Radiopharmaceutical product Preparative method or reagent Application (proposed) Reference Fluoride - omp-Fluorophenylalanine (L,DL) Balz - Schiemann reaction 3-Fluorotyrosine (DL) Balz - Schiemann reaction 5,6-Fluorotryptophan (L,DL) Balz - Schiemann reaction 5-Fluoro-DOPA (DL) Balz - Schiemann reaction 6-Fluorodopamine Balz - Schiemann reaction 4-Fluoroestradiol Balz - Schiemann reaction p-Fluorohippuric acid 2-Deoxy-2-fluoro-~-glucose F2 3-Deoxy-3-fluoro-~-glucose CsF 6-Deoxy-6-fluoro-~-galactose (CH,),N+F- 5-Hydroxy-6-fluorocholestane- 21-Fluoropregnenolone-3-acetate K F 2 l-Fluoroprogesterone KF Balz - Schiemann reaction 3-Fluorocholestene AgF 3-acetate BF, - (C,H,),O 6-Fluoro-g-benz ylpurine AgF 5-Fluorouracil F 2 Fluorocarboxylic acids and 1 esters.2-Fluoroethanol J Sulphur hexafluoride F- ion-exchange resin In- targe t labelling Bone scanning 1 Bone blood flow measurement 31 Dental studies 2 (Pancreas scanning) 9-12 (Pancreas scanning) 9, 14 (Pancreas scanning) 9, 13 Brain scanning 15, 16 (Adrenal scanning) 17 (Localisation of oestrogen- dependant tumours) 19 (Renal scanning) 18 I n vivo metabolic studies 22.23 I n vivo metabolic studies 24, 25 ( I n vivo metabolic studies) 28 (Adrenal scanning) 18 (Adrenal scanning) 18 (Adrenal scanning) 33 (Brain scanning) 18 (Adrenal scanning) 32 (Tumour localisation) 29 (Study of brain perfusion and (Study of regional pulmonary morphology, myocardial imaging) 34-36 diffusion) 37 Fluoroaryl Compounds These derivatives have been prepared by the Balz - Schiemann reaction (thermal decomposi- tion of a diazonium tetrafluoroborate derivative to produce a fluoroaryl compound).The usefulness of this reaction rests on the fact that diazonium tetrafluoroborates can be labelled by exchange either in solution or by a heterogeneous gas phase m e t h ~ d .~ Generally, it is necessary to protect functional groups on the diazonium tetrafluoroborate (I), which are then deprotected after labelling and generation of the fluoroaryl compound (11) Deprotection X'ArN2B18F4 A X'q;"F reaction + X Ar'*F I (+ N 2 + B18F3) X' = protected group(s) X = functional group(s) The reaction has the disadvantage that it gives low radiochemical yields (approximately Fluoro derivatives of several aromatic amino 10%) and comparatively low specific activities.October, 1978 RADIOCHEMISTRY I N MEDICINE 291 acids have been prepared in both DL and L f ~ r m , ~ - l ~ and in addition [1sF]6-fluorodopamine,17 [1sF]p-fluorohippuric acidls and [1sF]4-fluoroestradio11g have been prepared by this method.Kook et al. have also labelled 4- [4-(~-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyro- phenone (the neuroleptic drug haloperidol) in order to study its pharmacokinetics.20 Fluorocarbohydrates Fluorine-18-labelled fluorocarbohydrates have recently become available as a result of the development of some interesting and rapid synthetic procedures.2-Deoxy-D-glucose is used as an analogue of glucose to study carbohydrate metabolism. This compound is used rather than glucose itself because substitution of the hydroxyl group on C2 by hydrogen results in a molecule that isolates the hexokinase reaction and thus makes it possible to study the first stage of glucose metabolism in the presence of other enzymes. It has also been shown that the hexokinase reaction is relatively insensitive to structural modification at C221 and conse- quently Ido et al.have developed ~1SF]2-deoxy-2-fluoro-~-glucose for the measurement of regional glucose metabolism in This compound (V) is prepared by addition of labelled elemental fluorine (0.1 yo in neon) to 3,4,6-tri-0-acetyl-~-glucal (111) followed by separation and hydrolysis of the resultant 3,4,6-tr~-~-acety~-2-deoxy-2-fluoro-a-~-g~ucopyra- nosy1 fluoride (IV).?->H OAc +~~F~-~CY OAc H + t-8 OAc 18F AcO AcO 18 AcO F H H H 18F H H Ill IV OH H H '8F HO v Fig. 1. Preparation of [1sF]2-deoxy-2-fluoro-~-glucose.23~23 The synthesis has necessitated the development of specialised targetry to produce and extract the labelled fluorine that is prepared by the deuteron bombardment of 0.1 yo fluorine in neon in a nickel target C2ONe(d,a)l8F reaction].As the addition reaction proceeds in high radio- chemical yield and the deprotection step is rapid 5-10 mCi batches of (V) can be made available (specific activity 2-5 mCi mg-l) . Several other regioselective fluorinations have been reported using dilute elemental fluorine (inactive) and this technique will doubtless find application to the preparation of other l8F-labelled radiopharmaceuticals.An alternative approach is the preparation of [1sF]3-deoxy-3-fluoro-~-g~ucose (VII) by Tewson and a compound that has also been reported to have favourable biological properties. 26 1,2 : 5,6-Di-O-isopropylidene-3-0-trifluoromethanesulphonyl-~-~-allofuranose (VI) is made to react with caesium [18F]fluoride followed by cleavage of the protecting groups with boron trichloride.The caesium [lsFIfluoride is produced in high specific activity by passing labelled hydrogen fluoride over caesium hydroxide or caesium fluoride. Deuteron bombardment of neon containing 16% hydrogen produces hydrogen [lsF]fl~oride.~~ Up to 5 mCi of (VII) are available for use.The only other lsF-labelled fluorocarbohydrate that has been reported is [lSF]6-deoxy- 6- fluoro-D-galactose, which has been prepared by Christman et al. by treating 1,2 : 3,4-di-0 - isopropylidine-6-tosyl-a-~-galact opyranose with t etraethylammonium [lsF]fluoride (nucleo - philic displacement), followed by hydrolysis. 28292 RADIOCHEMISTRY IN MEDICINE Proc.AnaZyt. Div. Chem. Soc. OSO2CF3 0-C-CH3 I CH3 V I (i) BCl3 (ii) H20 CH20H VII Fig. 2. Preparation of ["W] 3-deoxy-3-fluoro-~-glucose.~~~~~ Miscellaneous Compounds Other lsF-labelled organic radiopharmaceuticals that have been reported are listed in Table I. These have mainly been prepared by nucleophilic displacement reactions, which frequently give low radiochemical yields as an excess of the fluorinating agent is necessary.The direct fluorination method has, however, been applied to 5-fluoro~raci1,~~ a compound that has also been reported in low activity using an in-target labelling technique.30 Labelled Gases Some years ago [lsF] trichlorofluoromethane was prepared for pharmacodynamic studies by treating carbon tetrachloride with labelled silver fluoride.3* Recently this and other com- pounds in the series CCl,.,F, (n = 1-4) have been prepared more conveniently by an in-target labelling technique.39 Similarly, sulphur [lSF] hexafluoride has been prepared by the deuteron bombardment of 0.3-1.0% mixtures of sulphur hexafluoride in neon in a target with an internal surface of silver.37 Traces of labelled thionyl fluoride, sulphuryl fluoride and other impurities are also produced. These impurities can be removed by an on-line purification system when the gas is vented from the target, yielding approximately 25 mCi of pure sulphur [lsF]hexa- fluoride.This compound is of interest for the study of regional pulmonary diffusion. Conclusion Owing to the limited availability of the radionuclide, its short half-life, and the specialised expertise and equipment necessary to prepare complex organofluorine compounds, it appears to be unlikely that l*F-labelled radiopharmaceuticals will be used on a large scale in nuclear medicine.However, owing to the vast range of chemical syntheses described in the literature that can be applied to the preparation of compounds with many different biological properties, prospects for their application in more specialised research studies are good.This is particu- larly apparent now that positron imaging devices, which can give more detailed positional information than can be obtained from y-ray emitters, are becoming available in some large medical centres. References 1. 2. 3. 4. 5. 6. Barrett, J . J . , and Smith, P. H. S., B r .J . Radiol., 1974, 47, 387. Joystonbechal, S., Duckworth, R., and Braden, M., Archs Oral Biol., 1976, 21, 73. Schlosser, M., Tetrahedron, 1978, 34, 3. Nozaki, T., Iwamoto, M., and Ido, T., I n t . J . A$$. Radiat. Isotopes, 1974, 25, 393. Clark, J. C., and Silvester, D. J., I n t . Appl. Radiat. Isotopes, 1966, 17, 151. Tilbury, R. S., Dahl, R., Mamacos, J . P., and Laughlin, J.S., I n t . J . AppZ. Radiat. Isotopes, 1970, 21, 277.October, 1978 RADIOCHEMISTRY I N MEDICINE 293 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. Lambrecht, R . M., Nierinckx, R., and Wolf, A. P., I n t . J . Appl. Radiat. Isotopes, 1978, 29, 175. Casella, V. R., Ido, T., and Wolf, A. P., J . Labell. Compounds Radiopharm., 1977, 13, 209.Abstract. Clark, J. C., Goulding, R. W., Roman, M., and Palmer,A. J., Radiochem. Radionalyt. Lett., 1973,14, 101. Goulding, R. W., and Palmer, A. J., I n t . J . Appl. Radiat. Isotopes, 1972, 23, 137. Goulding, R. W., and Gunasekera, S. W., I n t . J . Appl. Radiat. Isotopes, 1975, 26, 561. Hoyte, R. M., Christman, D. R., Atkins, H. L., Hauser, W., and Wolf, A.P., J . Nucl. Med., 1971, Lin, S. S., Atkins, H. L., Christman, D. R., Fowler, J . S., Hauser, W., Hoyte, R. M., Klopper, J. F., Palmer, A. J., Clark, J. C., Goulding, R. W., and Roman, M., “Radiopharmaceuticals and Labelled Firnau, G., Nahmias, C., and Garnett, S., I n t . J . Appl. Radiat. Isotopes, 1973,24, 182. Firnau, G., Nahmias, C., and Garnett, S., J .Med. Chem., 1973, 16, 416. MacGregor, R. R., Ansari, A. N., Atkins, H. I,., Christman, D. R., Fowler, J . S., and Wolf, A. P. Ido, T., “Proceedings of the First World Congress of Nuclear Medicine, Tokyo and Kyoto,” World Palmer, A. J., and Widdowson, D. A., J . Labell. Compounds, Radiopharm., in the press. Abstract. Kook, C. S., Reed, M. F., and Digenis, G. A., J . Med. Chem., 1975, 18, 533.Bessell, E. M., Foster, A. B., and Westwood, J . H., Biochem. J . , 1972, 128, 199. Ido, T., Wan, C. N., Flower, J. S., and Wolf, A. P., J . Org. Chem., 1977, 42, 2341. Ido, T., Wan, C. N., Casella, V., Fowler, J. S., Wolf, A. P., Reivich, M., and Kuhl, D., J . Labell. Tewson, T. J., and Welch, M. J., J . Org. Chem., 1978, 43, 1090. Tewson, T. J., and Welch, M. J., J .Nucl. Med., in the press. Taylor, N. F., Romaschin, A., and Smith, D., American Chemical Society, Symposium Series, Volume Straatman, M. G., and Welch, M. J., J . Nucl. Med., 1977, 18, 151. Christman, D. R., Orchanovic, Z., Shreeve, W. W., and Wolf, A. P., J . Labell. Compounds., Radiopharm., Fowler, J . S., Finn, R. D., Lambrecht, R. M., and Wolf, A. P., J . Nucl. Med., 1973, 14, 63.Lebowitz, E., Richards, P., and Baranowsky, J., I n t . J . Appl. Radiat. Isotopes, 1972, 23, 392. Wootton, R., BY. J . Radiol., 1975, 48, 70. Eng, R., Hinn, G., and Spitznagle, L. A., J . Nucl. Med., 1975, 16, 526. Spitznagle, L. A., and Marino, C. A., J . Nucl. Med., 1977, 18, 618. Robinson, G. D., J . Nucl. Med., 1973, 14, 446. Robinson, G. D., J . Nucl. Med., 1975, 16, 561.Karin, H. M. A., and Stocklin, G., J . Labell. Compounds, Radiopharm., 1977, 13, 519. Palmer, A. J., Clark, J . C., Horlock, P. L., and Buckingham, P. D., J . Labell. Compounds, Radiopharm., Williams, F. M., Draffan, G. H., Dollery, C. T., Clark, J . C., Palmer, A. J., and Vernon, P., Thorax, Palmer, A. J., I n t . J . A p p l . Radiat. Isotopes, in the press. 12, 280. Lin, S.S., and Wolf, A. P., J . Nucl. Med., 1972, 13, 713. Compounds,” Volume 1, International Atomic Energy Agency, Vienna, 1973, pp. 291-302. J . Nucl. Med., 1974, 15, 513. Federation of Nuclear Medicine and Biology, 1974, pp. 901-903. Abstract. Compounds, Radiopharm., 1978, 14, 175. 28, American Chemical Society, Washington D.C., 1976, pp. 99-1 16. 1977, 13, 555. Abstract. Abstract.Abstract. Abstract. in the press. Abstract. 1974, 29, 99. Pharmaceutical Problems in the Manufacture of Radiopharmaceuticals Containing Radionuclides of Very Short Half-life A. E. Theobald Radiopharmacy Section, Defiavtvnent of Pharmacy, Chelsea College, 27 1 King Street, Hammersmith, London, W.6 A radiopharmaceutical is not the same as a radiochemical. Radiopharmaceuticals are radio- active materials that are administered to humans or animals for diagnostic or therapeutic purposes and they must comply with more stringent standards than radiochemicals.The half-lives of most radionuclides used in radiopharmaceuticals are measured in hours, which may be regarded as very short half-lives. Recent developments in nuclear medicine and radiopharmacy have changed the traditional pattern of manufacture, distribution and use of radioactive materials for diagnostic purposes.In earlier days, radionuclides for medical use were selected mainly on the basis of their avail- ability and biological distribution and excretion. Their half-lives, measured in days or weeks, were long enough to allow all manufacturing and quality control checks to be completed by the responsible government agency or commercial manufacturer before the radiopharmaceuticals were released to the user.The development and availability of radionuclide generators soon led to a shift of manu- facture away from commercial laboratories to hospital radiopharmaceutical laboratories, which294 RADIOCHEMISTRY IN MEDICINE Proc. Analyt. Div. Chem. SOC.now have a ready supply of short-lived radionuclides such as iodine-132, indium-l13rn, and technetium-99m. These radionuclides offer considerable advantages : the radiation dose to the patient is reduced considerably and the physical characteristics of the emitted radiation are more suitable for modern imaging equipment. The radio- pharmaceutical manufacturing process has moved from a small number of specialist laboratories to a much larger number of not so specialist laboratories scattered throughout the country.The second major problem arises from the short half-lives of the radionuclides employed. All of the manufacturing and quality control tests must be completed, wherever possible, in the short space of time between manufacture and administration, usually not more than a few hours, often less.These radiopharmaceuticals are nearly always prepared by adding a radioactive material to a non-radioactive “kit” vial that contains all of the other ingredients and reagents required to form the radiopharmaceutical. The use of non-radioactive kits greatly simplifies the manufacture of diagnostic radiopharmaceuticals. A common feature of all diagnostic radiopharmaceuticals is the small amount of chemical substance administered.Most drugs and pharmaceuticals are administered for their thera- peutic effects, but diagnostic amounts of radiopharmaceuticals do not disturb the steady-state physiology and metabolism in the patient and do not produce pharmacological, toxic, aller- genic, or immunological reactions.Any adverse reactions which do appear are invariably caused by other materials present in the formulated radiopharmaceutical. These developments have encouraged an active participation by the hospital pharmacist with medical physicists and clinicians in the routine manufacture and use of radiopharma- ceuticals. The prime concern of the pharmacist is the radiopharmaceutical product : how it is formulated, manufactured, tested and released for use.With ordinary non-radioactive pharmaceuticals, this concern can be sub-divided into a number of well defined procedures and tests which must be completed before the product is released for use. Full documentation at each stage of the manufacturing process and quality control programme is essential as it is the only way of obtaining a complete history of the product in the event of any inquiry.Diagnostic radiopharmaceuticals cannot be treated in the same way and may present additional problems to the pharmacist. Radiation hazards do not allow the use of many standard pharmaceutical methods and operations and these may have to be modified or dis- carded in favour of, perhaps, pharmaceutically less suitable methods that offer a greater degree of radiation protection to the operator.As most diagnostic radiopharmaceuticals are administered by intravenous injection, the pharmaceutical requirements of these products can be summarised by the following statement: the right dose of the right radionuclide in the required chemical state as a correct formulation in a sterile, apyrogenic injection.There are, then, six different requirements that must be satisfied before the radiopharmaceutical can be released for use. However, these developments have brought problems as well as benefits. Radioactive Dose The amount of radioactivity can be measured easily with modern isotope dose calibrators and ionisation chambers, which can give a direct reading in millicuries.Any measuring device is only as good as its calibration and maintenance, and the hospital physicist has a very important role in checking the performance and accuracy of these instruments in order to ensure that measured radioactivities are meaningful. Radionuclide Identity and Purity The requirements of radionuclide identity and radionuclidic purity can also be checked readily with modern nucleonic eqcipment and the hospital physicist is actively concerned in carrying out these tests and checking the equipment.Most of the tests on radionuclide identity and purity are carried out by the supplier of the radionuclide generator, but local radiopharmaceutical centres usually perform these tests as a safety measure. Chemical State, or Radiochemical Purity Everyone involved in radiopharmaceutical manufacture is concerned with the radiochemical Radiochemical impurities are usually present in small amounts, but purity of the product.October, 1978 RADIOCHEMISTRY IN MEDICINE 295 they can distort or degrade the quality of detection and imaging.They can also increase the radiation dose absorbed by the patient, or localise its effect in organs or tissues other than those intended.They can increase the likelihood of incomplete, or even incorrect diagnosis by the physician, who must be told if any such impurities are present and their approximate levels. Regular testing for radiochemical impurities in the final radiopharmaceutical product is obviously essential. The tests employed use some form of separation technique in order to isolate the desired radiochemical from the impurities.Chromatographic methods are widely used for this purpose, especially paper and thin-layer chromatography, which enable separa- tions and activity measurements to be carried out rapidly. Whichever technique is used, the radiochemical purity figures must be assessed in relation to the clinical use of the radio- pharmaceutical. For example, a technetium-labelled colloid can be used both for liver func- tion tests and for liver imaging, and the amount of free pertechnetate that can be tolerated is different in each use, being 1-2% for function tests and possibly 10% for imaging.Any comparison of radiochemical purity figures for different batches of the same radiopharma- ceutical can only be valid if each batch is prepared exactly according to the written instruc- tions provided.Simple deviations from standard procedures, such as excessive dilution with isotonic saline, can cause a considerable increase in radiochemical impurities. Formulation of Radiopharmaceuticals The majority of diagnostic radiopharmaceuticals contain technetium-99m as the radioactive element, which is usually obtained as a sterile isotonic solution of sodium pertechnetate from a generator.If the generator is properly made and properly eluted, the product is obtained as a sterile, non-pyrogenic injection that can be used directly, or as the raw material for manu- facture of other technetium-labelled radiopharmaceuticals. These diagnostic agents are nearly always prepared by adding the radioactive solution to a vial containing all the ingredients necessary to produce the radiopharmaceutical in a sterile, non-pyrogenic form.The product can be considered as being manufactured from the sterile generator eluate and the non- radioactive kit vial, and most of the pharmaceutical formulation effort goes into the manu- facture of the non-radioactive kit vial.Such vials are very similar to ordinary pharmaceutical injections and standard methods can be used to evaluate the quality and stability of these products. The usual ingredients of a kit vial are the substance to be labelled, e.g., human serum albumin or chelating agents, a reducing agent such as tin(I1) chloride or other tin(I1) salts, inactive salts for buffering and isotonicity and suspending and protective agents (for particulate and colloidal products).Each ingredient must be selected carefully and tested for its suitability in radio- pharmaceutical kits. Small amounts of chemical impurities such as antioxidants and chelating agents are frequently deliberately introduced into ordinary pharmaceuticals in order to improve their stability and shelf-life characteristics.Such impurities can rarely be toler- ated in formulations intended for radiopharmaceutical kits. The total physical mass of radionuclide added to a kit vial is incredibly small. For example, the mass of 1 mCi of technetium-99m is only about 10-lo g and even trace amounts of chemical impurities will be present in much larger amounts than the radionuclide and may react with it, producing un- wanted and undesirable radiochemical impurities.Each ingredient of the formulation must also be tested carefully for low levels of chemical impurities that are found to affect the quality and performance of the final radiopharmaceutical. Having established the quality of ingredients to be used in a kit, the pharmacist must satisfy himself that the manufacturing and compounding methods produce batches of consistent composition and quality, and that the completed kit vials have a reasonable shelf-life, usually several months.Naturally, radiopharmaceutical kits must be sterile and non-pyrogenic. Kit stability is always good enough to allow all quality assurance checks, including sterility and pyrogenicity, to be completed before the material is released for use.When the non- radioactive kit has been produced the more difficult problems of producing the final sterile and non-pyrogenic radiopharmaceutical can be examined. The manufacturing process appears to be simple. A sterile solution of a radionuclide is added to a sterile vial containing sterile, non-pyrogenic ingredients, which is shaken or heated to complete the labelling reaction.The chemistry of radioactive labelling is not yet well established and the processes used have some of the But practice is never as simple as theory.296 RADIOCHEMISTRY IN MEDICINE Proc. AnaZyt. Div. Chem. SOC. qualities of magic or witchcraft. Any deviation from the specified order of addition of re- agents, or change in technique, often breaks the spell and gives an unsuitable product.Thor- ough training of operators and strict attention to details are two important factors in good radiopharmaceutical manufacture. Another equally important factor is the manufacturing environment, which should not give rise to microbial contamination of the final product. Radiopharmaceuticals are not self-sterilising by virtue of their radioactivity. Sterility Diagnostic radiopharmaceuticals are no different from other injectable pharmaceuticals in regard to sterility and non-pyrogenicity.They are very different, however, in the way in which they can be sterilised and the time available for the sterilisation process. The most satisfactory sterilisation method is always autoclaving with steam under elevated temperatures and pressures. But most radiopharmaceuticals are delicate materials that cannot withstand such conditions.The only alternative would be to pass the injection through a bacteria-proof filter when filling the final container. Many radiopharmaceuticals are deliberately formulated as colloids, suspensions, or aggregates, and this treatment would remove the active principle in the formulation.Diagnostic radiopharmaceuticals are also different from other injectable pharmaceuticals in the time available for completion of sterility and pyrogenicity tests. The usual pharma- copoeial sterility tests require inoculation of a nutrient medium, incubation for 7 d and exam- ination for signs of bacterial or fungal growth. Diagnostic radiopharmaceuticals are useless clinically unless they are administered soon after manufacture and cannot be submitted to the usual sterility test before release.The problem has been recognised for a long time and the Pharmacopoeias allow these materials to be released for use before the results of a sterility test are known. Nevertheless, they insist that the sterility test be completed as a check on manu- facturing conditions.This is good advice but just what conditions will exclude this type of contamination are debatable. Some experts recommend full aseptic dispensing conditions, using procedures and operations carried out in specially designed cabinets provided with a sterile laminar air flow, contained in bacteriologically clean rooms, provided with fully condi- tioned sterile air supplies, and dispensed by operators dressed in sterile overalls, masks, hats, boots and gloves.On the other hand, equally eminent experts insist that a sterile product can be manufactured in an ordinary domestically clean room, using the minimum of sterile clothing and equipment, by employing trained, highly skilled operators who pay very close attention to the details of the manufacturing operation.It is tempting to state that the best manufacturing methods and conditions lie halfway between these two extremes. This temptation should be resisted because the quality of the final pro- duct is not controlled simply by the manufacturing environment. It depends on a number of other factors such as the training and experience of operators, the intended purpose of the radiopharmaceutical and, most important, the radiation hazards associated with a particular radionuclide or manufacturing operation.What can be done is to check whether existing conditions are adequate by applying a few relatively simple tests on each radiopharmaceutical. Firstly, a check for microbial contamina- tion can be made by simulated manufacture using a nutrient broth in place of the radioactive material.If this test is repeated a number of times on each radiopharmaceutical, a fair assessment of the suitability of the manufacturing environment for each radiopharmaceutical can be obtained. Secondly, the manufacturing area must be monitored for its environmental quality. Microbial contamination can be assessed from regular exposure and incubation of culture plates, and by measuring the particulate content of the air.Any tests on manufacturing conditions can only be valid if the area is systematically main- tained and cleaned according to some definite plan. A combination of planned quality control tests and dispensing and cleaning programme will ensure that the manufacturing environment and processes are satisfactory.Pyrogens Pyro- gen levels in generator eluates and radiopharmaceutical kits are controlled by their manu- Both opinions are right under some circumstances, and both are wrong under others. Pyrogens are water-soluble fever-producing substances formed by micro-organisms.October, 1978 RADIOCHEMISTRY IN MEDICINE 297 facturers by careful selection of raw materials and their storage, and they should present few problems in routine radiopharmaceutical manufacture.Any materials or equipment used in the manufacturing process should be cleaned carefully and rinsed in pyrogen free water, then heated at 250 “C for 40 min, whenever possible. The severity of pyrogenic reactions will depend on the route of administration and the volume administered.The reaction is most severe with injections directly into the cerebrospinal fluid, and any radiopharmaceuticals intended for administration by this route must be prepared under full aseptic conditions with full precautions against pyrogens. Small volume intra- venous radiopharmaceutical injections rarely cause pyrogenic reactions and excessive pre- cautions are not necessary in their manufacture.Conclusions Radiopharmaceutical manufacturing and quality control are too complicated to be left entirely with the pharmacist. They involve a broad spectrum of skills ranging from know- ledge of the physical characteristics and radiation hazards associated with particular radionu- clides, through analytical radiochemistry, sterile manufacturing, to the biological characteris- tics of the radiopharmaceutical after administration.In the final analysis it is these biological characteristics that are most important and all manufacturing and testing effort must be designed to achieve day to day reproducibility in this respect. Radioimmunoassay Techniques in Cancer Medicine D. J. R. Laurence Unit of Human Cancer Biology, Ludwig Institute for Cancev Reseavch (Lovzdon Branch), in conjunction with Royal Mavsden Hospital, Sutton, Surrey The principle of radioimmunoassay (RIA) is that the substance to be analysed competes with a radiolabel-tagged sample of the same substance at the binding sites of a suitable antibody. The number of antibody sites is limited so that significant displacement of the label occurs over the range of concentrations available in the samples. The antibody must have a corre- spondingly high affinity for the substance to be analysed but a low affinity for related sub- stances in order to ensure sensitivity and specificity.Read-out of the assay requires a separation between free label and label bound to the anti- body. The methods used in labelling, antibody production and separation of free and bound label are semi-empirical procedures that must be adapted to the substance under investigation.Tumours produce a variety of substances : proteins, glycoproteins, peptides and other small mo1ecules.l The immune response of the tumour-bearing host is of considerable interest in immunotherapy but, for RIA, human materials are used as immunogens in other species in order to develop antibodies of suitable affinity. There are methods by which most organic molecules can be rendered immunogenic in animals.Much effort has been devoted to the identification of products that are tumour-specific, i.e., are not produced by the normal tissues of the body. Evidence from animal tumours suggests that some antigens are individual-tumour-specific. Assays for such substances, if they could be identified in patients, would need a different assay for each patient.However, practical studies of human tumours have mainly been concerned with substances that are known to be normal products of metabolism or are recognised as such in retrospect. The monitoring of tumours in patients by means of estimation of such substances in the body fluids must rely on some degree of abnormality (“inappropriateness”) in the concentrations (“levels”).The abnormality can derive from a number of processes, e.g., lack of normal feed back control, a large mass of tumour relative to the tissue of origin, abnormal access to the blood stream or time defects, such as the presence of foetal or placental proteins in the adult, non-pregnant individual.In early work the substance of interest was recognised either by peripheral (hormone) effects in the patient, for example the production of adrenocorticotrophic hormone (ACTH) by lung tumours,2 or by cross-referencing the tumour and normal tissue by immunological tests, for example the discovery of carcinoembryonic antigen (CAE) by Ouchterlony pre~ipitation.~ More recently it has been found useful to test antibodies to the tumour, its normal tissue of298 RADIOCHEMISTRY IN MEDICINE Proc.Analyt. Div. Chem. SOC. origin or to normal secretions by the immunoperoxidase m e t h ~ d . ~ In this way it is possible to see whether the tumour has retained its ability to synthesise a potential tumour marker and to study tissue specificity.Complete assay procedures commonly use 1251 as the radiolabel for the substance to be analysed. However, use of a second label for the antibody (1311) and another as a volume marker (22Na or 57Co)5 can help to correct for shortcomings of the assay. The history of the CEA plasma assay illustrates some features in the evolution of a clinical test for cancer. Originally, this appeared to be a reliable indicator for the presence of digestive tract tumours, giving almost 100% detection of the tumours and discriminating against tumours at other sites or non-malignant pathology.6 Further work showed that CEA is also present at low levels in healthy adults but is elevated both in the presence of other common tumours and in patients with inflammatory disorders.It was mainly the patients with wide- spread metastases that could be easily discriminated by the test. Thus, the application of the test was not, as was originally suggested, to detect early lesions, but to detect any recurrence due to failure of surgical intervention. Although the “lead time” warning of recurrence by the test may be months or years,7 the disease of this type of patient is often resistent to treat- ment.A much better result is obtained for choriocarcinoma,8 where the human chorionic gonadotrophin (HCG) test is very sensitive to small tumour loads and the results of chemo- therapy are often beneficial if the tumour is detected early enough. A benefit may also be obtained with some teratomas, where the alphafoetoprotein (AFP) test can be helpful.With localised breast cancer no single marker has been identified that by itself can give information on this conditi~n.~ At present a variety of parameters are being studied and a multivariate discriminant is being obtained to evaluate these patients in order to detect residual tumour after surgery. The statistics used in monitoring studies need further clarifica- tion.1° The analytical problem of detecting tumour products from small amounts of residual tumour is not yet solved for the commoner tumours, e g ., lung, digestive tract and breast. It may be possible to make use of the natural packaging of tumour products into cells or cell clusters and to attempt to detect tumour cells within the body spaces. It is not clear whether nuclide analysis can assist in this or whether some other physical property, such as fluorescence, would provide a more sensitive tag to the antibodies. At least the scintillation methods familiar to nuclear chemists could be used to enhance signal to noise ratios in such a system.1. 2. 3. 4. 5. 6. 7. 8. 9. 10. References Ellison, M. L., and Neville, A. M., i n Rosen, R. W., Editor, “Modern Trends in Oncology-1,” Part 1, Orth, D.N., Nicholson, W. E., Mitchell, W. M., Island, D. Y., andLiddle, G. W., J . Clin. Invest., 1973, Gold, P., and Freedman, S. O., J . Exp. Med., 1965, 121, 439. Heyderman, E., and Neville, A. M., J . Clin. Path., 1977, 30, 138. Egan, M. L., Todd, C. W., and Knight, W. S., Immunochemistry, 1977, 14, 611. Thomson, D. M. P., ECrupey, J . , Freedman, S.O., and Gold, P., PYOC. Natn. Acad. Sci. U.S.A., 1969, Laurence, D. J . R., and Neville, A. M., Bull. Cancer, 1976, 63, 473, Bagshawe, K. D., Br. Med. Bull., 1974, 30, 68. Coombes, R. C., Powles, T. J., Gazet, J . C., Ford, H. T., Sloane, J . Y., Laurence, D. J . R., and Neville, Cooper, E. M., and Kenny, T. E., Proc. R . SOC. Med., 1977, 70, 840. Butterworths, London, 1973, p.163. 52, 1756. 64, 161. A. M., Lancet, 1977, 1, 132. Applications of Low Level Whole Body Counting to Metabolic Turnover Studies in Man N. G. Trott Physics Depavtment, Institute of Cancer Research, Royal Marsden Hospital, Sutton, Surrey The technique of whole body radioactivity measurement has now been under development for over 40 years.l The role of such measurements in clinical work can be broadly classified under three headings, namely radiation protection of patients and staff, dosimetry of therapeutic applications and clinical investigations of the biological turnover of particular radionuclides.Equipment now widely used consists either of a set of static scintillation detectors, mounted above and below a couch inside a room shielded with material of low natural radioactivityOctober, 1978 RADIOCHEMISTRY I N MEDICINE 299 against external radiation,2 or of a pair of heavily shielded detectors mounted in opposition, with a couch traversing between the detector^.^ An early clinical application, during the 1950s, was the measurement of the radioactivity due to natural 40K in the body and hence the determination of the total mass of potassium, norm- ally about 150 g in the adult male.4 The specific activity of 40K in natural potassium is ap- proximately 32 kBq kg-l (0.86 pCi kg-l), with a 1.46-MeV photon emitted in 10% of all nuclear transformations.Such measurements were at first used in studies of populations, but they have also proved to have useful direct clinical applications in, for example, assessing the effectiveness of treatment for potassium defi~iency.~~~ In this hospital we have, for many years, used the technique of whole body radioactivity counting as an alternative to the cumulative collection of total excretion in determining the pattern of retention in the body of directly administered radioactive tracers.In such measure- ments it is important to use a counting system with a sensitivity that is affected as little as is practicable by the redistribution of a radionuclide in the body, and this facility is provided by the types of systems referred to above.The earliest studies here, in collaboration with the then Radiological Protection Service, consisted of simultaneous measure-ments of the retention of 47Ca (T4 4.7 d) and 85Sr (Tg 65 d) in patients having breast cancer both with and without metastatic spread; it was found that retention over 15 d could be represented satisfactorily as power functions, and that in patients with metastases both radioactive nuclides tended to be excreted more rapidly.7 Administered activities were approximately 0.5 pCi.In recent years, our attention has shifted to applications in haematology, and at the same time we have developed a whole body rectilinear scanner with digital output, which provides data on the distribution as well as the total body retention of radionuclides.8 Developments of the technique have enabled us to follow, over extended periods, the retention not only in the whole body but also in selected regions or organs; it has also been possible to derive from the results recorded and suitable calibrations with phantoms estimates of the fraction of the administered activity retained at these sites.In this way 59Fe (Ti 47 d) has been used in studies of the kinetics of iron in patients with various blood dyscrasiasg and, more recently, 52Fe (Tg 8 h) in determining the distribution of bone marrow in patients whose marrow has been depleted through treatment or disease.1° Similar work with 51Cr-labelled erythrocytes provides information on sites of destruction of red cells and associated indications for splenec- tomy.A well established application of total body radioactivity measurement is the determination of the absorption of orally administered tracers, such as 59Fe in ionic form or 58Co-labelled vitamin B,,, using activities of about 1 pCi. Such studies can prove to be of direct value in the clinical management of individual patient+; in addition, they have proved to be of particular interest in providing answers to specific questions, such as establishing the most effective way of maintaining iron levels in patients on dialysis.12 The scope of whole body counting techniques, using quite simple designs of measuring systems, is well illustrated by studies of exchangeable sodium carried out by Veal1 et aZ.13 Interesting applications have been made over the past few years of whole body counting to in vivo activation analysis for the determination of the body content of particular elements, including calcium, sodium, iron and nitrogen .14 In summary, in addition to their long established role in radiation protection, whole body counting techniques have proved to have a definite place in clinical work, both in the manage- ment of individual patients and in general clinical investigations. A recent meeting held at the British Institute of Radiology provided a useful survey of the work now in progress in the United Kingdom.6 References Activities used in such tests are typically 10 pCi 59Fe, 70 pCi 52Fe and 100 pCi 51Cr. 1. 2. 3. 4. 5. 6. 7. Evans, R. D., Am. J . Roentg., 1937, 37, 368. Trott, N. G., and Cottrall, M. F., “Multiple Crystal Systems for Whole Body Counting” in “Clinical Uses of Whole Body Counting,” IAEA, Vienna, 1966, p. 131. Warner, G. T., and Oliver, R., Physics Med. Biol., 1966, 11, 83. Anderson, E. C., Ann. N.Y. Acad. Sci., 1963, 110, 189. Burrows, B. A., Tyson, I., Dukstein, W. G., and Genna, S., Trans. Am. Clin. Clivn. Ass., 1965, 77, 25, “Whole Body Counting and Scanning,” Abstracts of papers read a t a meeting a t The British Institute Taylor, D. M., Trott, N. G., Rinsler, M. G., and Vennart, J., BY. J . Radiol., 1963, 36, 732. of Radiology, November, 1976, BY. J. Radiol., 1977, 50, 451.300 8. 9. 10. 11. 12. 13. 14. PUBLICATIONS RECEIVED Proc. AnaZyt. Div. Chem. SOC. Trott, N. G., Cottrall, M. F., McCready, V. R., and Wells, D. G., “Investigations of Sequential Distri- butions Using a Low Background Whole Body Scanner with Digital Output” in “Medical Radio- isotope Scintigraphy,” Volume 1, IAEA, Vienna, 1973, p. 61. Cottrall, M. F., Hodt, H. J., Kent, R. W., and Trott, N. G., in “Fellinger, K., and Hofer, R., Editors, “Radioacktive Isotope in Klinik und Forschung,” Urban and Schwarzenberg, Munich, 1972, Lillicrap, S. C., Steere, H. A., and Clink, H. M., in Hofer, R., Editor, “Radioacktive Isotope in Klinik Cottrall, M. F., Wells, D. G., Trott, N. G., and Richardson, N. E . G., Blood, 1971, 38, 604. Brozovich, B., Cattell, W. R., Cottrall, M. F., Gwyther, M. M., McMillan, J . M., Malpas, J. G., Salsbury, Veall, N., Fisher, H. J., Browne, J . C. M., and Bradley, J . E. S., Lancet, 1955, 9, 419. Chamberlain, M. J., I n t . J . A p p l . Radiat. Isotopes, 1970, 21, 725. p. 45. und Forschung,” H. Egermann, Vienna, 1976, p. 79. A., and Trott, N. G., BY. M e d . J . , 1971, i, 695. Obituary Dr. D. W. Kent- Jones We deeply regret to announce the death, on August 31st, of Dr. D. W. Kent-Jones, who had been a member of the Society for Analytical Chemistry since 1923 and who served as President of the SAC in 1953-1954.

ISSN:0306-1396    

DOI:10.1039/AD9781500284

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

300 PUBLICATIONS RECEIVED Proc. AnaZyt. Div. Chem. SOC. Publications Received Atmospheric Pollution 1978. Proceedings of the 13th International Colloquium, UNESCO Building, Paris, France, April Edited by Michel M. Benarie. Studies in Environmental Science 1. Pp. xii + 291. Amsterdam, Oxford and New York : Elsevier. 1978. Price $47.75; Dfl105. 25-28, 1978. Compendium of Analytical Nomenclature. Definitive Rules 1977.International Union of Pure and Applied Chem- istry Analytical Chemistry Division (prepared for publication by H. M. N. H. Irving, H. Freiser and T. S. West). Pp. viii + 223. Oxford, New York, Toronto, Sydney, Paris and Frankfurt: Pergamon Press. 1978. Price $25. Chemistry : A Modern Introduction. Sec- ond Edition. Frank Brescia, Stanley Mehlman, Frank C.Pellegrini and Seymour Stambler. Pp. Lviii + 761. Philadelphia, London and Toronto: W. B. Saunders Company. 1978. Price A12. Environmental Pollution Analysis. P. D. Goulden. Heyden International Topics in Science. Pp. xii + 209. London, Philadelphia and Rheine: Heyden. 1978. Price $16.50; k8.30; DM53. High Performance Mass Spectrometry : Chemical Applications. Michael L. Gross.A symposium co-sponsored by the University of Nebraska-Lincoln, the National Science Foundation, A EI Scienti’,fic, and I N C O S Corp., Lincoln, November 3-5, 1976. ACS Symposizkm Series 70. Pp. x + 358. Washington, D.C. : American Chemical Society. 1978. Price $28. Handbuch der Analytischen Chemie. Dritter Teil. Quantitative Bestimmungs- und Trennungsmethoden. Band 6by. Elemente der Sechsten Nebmgruppe. Wolfram.G. Wunsch. Pp. xiv + 286. Berlin, Heidel- berg and New York: Springer-Verlag. 1978. Price DM146; $73. Trace Metals in the Environment. Volume 1. Thallium. Ivan C. Smith and Bonnie L. Carson. Pp. xii + 394. Ann Arbor, Mich.: Ann Arbor Science Publishers. Distributed by John Wiley, Chichester. 1977. Price A15.15. Emission Spectrochemical Analysis.Tibor Torok, J6zsef Mika and Ern0 Gegus. Pp. 692. Bristol: Adam Hilger. Budapest: Akadbmiai Kiad6. 1978. Price A31.50. Ion- Selective Electrodes. Conference held at Budapest, Hungary, 5-9 September, 1977. Edited by E. Pungor and I. BuzAs. Pp. x + 613. Amsterdam, Oxford and New York: Elsevier. Budapest : Akadkmiai Kiad6. 1978. Price $75; Dfl180. Manual on Hydrocarbon Analysis. (formerly STP 332 A).Third Edition. Sponsored by ASTM Committee D-2 on Petroleum Products and Lubricants. Pp. xx + 620. Philadelphia : American Society for Test- ing and Materials. 1977. Price $26 (softback).October, 1978 CONFERENCES AND MEETINGS 301 Treatise on Analytical Chemistry. Part 11. Analytical Chemistry of Inorganic and Organic Compounds. Section A. Syste- matic Analytical Chemistry of the Elements.Volume 10. Antimony, Arsenic, Boron, Carbon, Molybdenum and Tungsten. Edited by I. M. Kolthoff and Philip J. Elving, with the assistance of Ernest B. Sandell. New York, Chichester, Brisbane and Toronto : John Wiley. 1978. Price j524.40; $43.85. Equilibrium Constants of Liquid - Liquid Distribution Reactions. Part IV : Chelat- ing Extractants. Prepared for publication by J .Star9 and H. Freiser for the International Union of Pure and Applied Chemistry, Applied Chemistry Division Commission on Equilibrium Data. I U P A C Chemical Data Series-No. 18. Pp. xii + 228. Oxford, New York, Toronto, Sydney, Paris and Frankfurt: Pergamon Press. 1978. Price $37; jtj20.50. Calcium in Waters and Sewage Effluents by Atomic Absorption Spectrophotometry 1977.Tentative Method. Department of the Environment/National Water Council. Methods for the Examination of Waters and Associated Materials. Pp. 12. London: HM Stationery Office. 1978. Price Radiochromatography. The Chromato- graphy and Electrophoresis of Radio- labelled Compounds. T. R. Roberts. Journal of Chromatography Library, Volume 14. Pp. x + 174. Amster- dam, Oxford and New York: Elsevier.Distri- buted by Elsevier North-Holland in the USA and Canada. 1978. Price $39.95; Dfl90. Laboratory Handbook of Paper and Thin- Layer Chromatography. JiTi GaspariC and J aroslav ChurACek. Transla- tion Editor, R. A. Chalmers. Ellis Horwood Series in Analytical Chemistry. Pp. 362. Chichester : Ellis Horwood. New York, Lon- don, Sydney and Toronto : John Wiley.Distri- buted by John Wiley in Australia, New Zealand, South-east Asia, Europe and Africa and by Halsted Press in North and South America and the rest of the world. 1978. Price j518. Durability of Adhesive Bonded Structures. Edited by M. J . Bodnar. Journal of Applied Polymer Science, Applied Polymer Syvnposium 32, held at Picatinny Arsenal, Dover, N . J . , U S A , October 27-29, 1976.Pp. vi + 443. New York, London, Sydney and Toronto: John Wiley. 1977. Price j513.40; $24.15 (softback). fj0.80. Inelastic Electron Tunnelling Spectroscopy. Proceedings of the International Conference and Symposium on Electron Tunnelling, University of Missouri-Columbia, USA, May 25-27, 1977. Edited by T. Wolfram. Springer Series in Solid-State Sciences. Pp. viii + 242.Berlin, Heidelberg and New York : Springer-Verlag. 1978. Price DM58; $29. Remote Surveillance by Electromagnetic Waves for Air - Water - Land. Dag T. Gjessing. Pp. viii + 152. Ann Arbor, Mich. : Ann Arbor Science Publishers. Distri- buted by John Wiley, Chichester. 1978. Price fj9.45. Dosages Absorptiomktriques des Elkments Minbraux. Troisihme 6dition. G. Charlot. Pp. x + 444. Paris, New York, Barcelona and Milan: Masson. 1978. Price 260F. Handbuch der analytischen Chemie. Dritter Teil. Quantitative Bestimmungs - und Trennungsmethoden. Band 4ay. Element der vierten Hauptgruppe. Zinn. (In English.) J . W. Price and R. Smith. Pp. xvi + 262. Berlin, Heidelberg and New York : Springer- Verlag. 1978. Price DM146; $73.

ISSN:0306-1396    

DOI:10.1039/AD9781500300

出版商:RSC    

年代:1978

数据来源: RSC

摘要:

October, 1978 CONFERENCES AND MEETINGS 301 Conferences and Meetings 8th Technicon International Congress December 12-14, 1978, London This congress, on the theme “Laboratory Management and Automation,” will be held at the Wembley Conference Centre and will be organised by Technicon Instruments Co. Ltd. The ten sessions comprising the Scientific Pro- gramme are as follows. Laboratory Data Management, Current Trends in Clinical Chem- istry, Automated Investigations in Blood Bank- ing, Developments in Automated Haematology, New Windows in Clinical Haematology, Autom- ation in Water Monitoring and Sewage Control, Automation and Applications of Immunoassay, Automated Analysis for Intensive Care, Pharmaceutical Quality Control and Economics of Analysis in Commodity Trading and Food302 CONFERENCES AND MEETINGS Proc.Anal'yt. Div. Chem. SOC. Processing. There will also be workshop sessions and an exhibition. For further details contact the Technicon Congress Secretariat, Technicon Instruments Co. Ltd., Evans House, Hamilton Close, Hound- mills, Basingstoke, Hampshire, RG21 1BZ. Thermal Characteristics of Tumours : Applications in Detection and Treatment March 14-16, 1979, New York, U S A This conference is to be sponsored by the New York Academy of Sciences and will take place at the Barbizon-Plaza Hotel. New material covered will include : critical examination of the bio-heat transfer equation ; determination of thermal conductivity and diffusivity of normal and neoplastic tissues (in vivo and in vitro); measurement of temperature distributions in the viable and necrotic zones of tumours; effects of oxygen and glucose consumptions on the tem- perature distributions in tumours ; the inter- relationship between the blood flow distribu- tions and temperature field in tumours; temperature reached in various parts of tumours during hyperthermia ; precise characterisation of a narrow temperature range for the optimum use of heat; quantitative comparison of the various newly developed and old methods including hyperthermia ; and critical and quanti- tative evaluation of thermography as a diagnos- tic tool for cancer.For further information contact : Conference Department, The New York Academy of Sciences, 2 East 63rd Street, New York, N.Y. 10021, USA. Selective GC Detectors Novevnbev 17th, 1978, Livevfiool The meeting will be held in the Main Lecture Theatre R 137, Phase 111, of the Faculties of Science and Engineering of Liverpool Poly- technic.I t will form the Autumn Symposium of the Chromatography Discussion Group. The following have agreed to speak: Dr. M. J. Saxby, Food Research Laboratory, Leather- head; Dr. C. I . M. Beenakker, Philips Research, Eindhoven; Dr. D. A. Ferguson, BP Research, Sunbury on Thames; Dr. T. A. Gough, Labor- atory of the Government Chemist, London; and Mr. G. Steel, Thornton Research Centre, Chester. The final programme will be sent to all registered participants. For further details contact The Executive Secretary, Chromato- graphy Discussion Group, Trent Polytechnic, Burton Street, Nottingham, NG1 4BU.

ISSN:0306-1396    

DOI:10.1039/AD9781500301

出版商:RSC    

年代:1978

数据来源: RSC