Auger Cascades and Nuclear Medicine
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533 Auger Cascades and Nuclear Medicine THE technique of administering short-lived radioactive nuclides into the body and examining their distribution with time is a diagnostic and investigative procedure with considerable potential for further development. For use in nuclear medicine the ideal nuclide will have high specificity for the tissue under examination; its biological half-life will be long enough for it to be retained in the organ during measurement; its radioactive half-life will be such that it can be measured easily over the time-scale of the investigation but that it will not, if biologically retained over longer periods, continue to deliver a substantial dose to the body; and its primary radiations will be sufficiently penetrating to be measurable outside the body. It transpires that several of the most suitable nuclides for these purposes, including the widely used technetium-99m, have, as an incidental part of their decays, the production of electron vacancies in the inner shells of the atom. These vacancies trigger a cascade of very low energy electrons (Auger electrons), many of which have ranges less than the diameter of the nucleus of a cell which is typically about 10 /-lm. (For example,3 the Auger cascade electrons from the decay of thallium-201 have average energies from 0*02 to 61 keV and ranges in tissue from <1 nm to about 65 jum.) The combined energy of these electrons may be only a small fraction of the total energy released by the decay, but since this energy is concentrated in a very small volume it produces a very local high dose in addition to the overall irradiation of the organ by the longer ranged emissions. Conventional dosimetry,’ and consequent assessment of radiation risk, follows the methods developed by the Medical Internal Radiation Dose Committee (mind).2 These consider only the average dose to the organ and ignore the localised cellular and subcellular concentrations. There is now evidence, from work in animals and cell systems,3-6 that Auger electrons may be an important determinant of the biological effects of some radionuclides. 1. International Commission on Radiation Units and Measurements. Methods of assessment of absorbed dose in clinical use of radionuclides, report 32. Washington: ICRU, 1979 2. Loevinger R, Berman M. A revised schema for calculating the absorbed dose from biologically distributed radionuclides, MIRD pamphlet No. 1 revised. New York: Society of Nuclear Medicine, 1976. 3 Rao DV, Govelitz GF, Sastry KSR Radiotoxicity of thallium-201 in mouse testes: inadequacy of conventional dosimetry. J Nucl Med 1983; 24: 145-53. 4. Kassis AI, Adelstein SJ, Haydock C, Sastry KSR. Thallium-201: an experimental and theoretical radiobiological approach to dosimetry. J Nucl Med 1983; 24: 1164-75. 5 Kassis AI, Sastry KSR, Adelstein SJ. Intracellular distribution of radiotoxicity of chromium-51 in mammalian cells: Auger-electron dosimetry. J Nucl Med 1985, 26: 59-67 6. Rao DV, Sastry KSR, Govelitz GF, Grimmond HE, Hill HZ. Radiobiological effects of Auger electron emitters in vivo: spermatogenesis in mice as an experimental model (Proceedings of Ninth Symposium on Microdosimetry, Toulouse, May, 1985 ) Radiat Prot Dosim (in press) The biological structures that are critical for delayed somatic effects are very small and probably located in the cell nucleus. Thus if the Auger cascade energy is preferentially deposited within, or outside, the cell nucleus the biological effect may be respectively more, or less, than indicated by the "macroscopic" dose which is calculated as if the distribution was even. Auger cascades originating in intercellular fluids will not be a hazard whereas decays in the cell nucleus, near the DNA, may well be. Furthermore, it is now becoming clear that the biological effects of radiation depend critically on the density of energy deposition in small volumes. We know that densely ionising (high LET) radiation such as neutrons and alpha-particles can be considerably more effective biologically than X or y rays for the same energy deposited. The increased biological damage at high LET may be related to the more probable occurrence of substantial energy deposition in very small subcellular volumes. It is therefore possible that Auger decays can produce events characteristic of high LET radiations, thus introducing an additional factor for enhanced biological hazard under certain circumstances. This is particularly evident when the decay takes place in the DNA itself, as in the well-studied case of DNA- incorporated iodine-12 5.’" To evaluate adequately the biological effect of the very local dose from the short-ranged Auger cascade electrons, detailed knowl- edge is required of the distribution of the radionuclide within the cell and its nucleus. There is, however, scant information on the microscopic distribution of relevant nuclides and pharmaceuticals. Such information would be a prerequisite for assessment of risks from these low-energy-electron emitting isotopes in a particular diagnostic procedure. Physical aspects of the matter could then be accurately addressed by means of modern computer methods to simulate radionuclide decays and detailed electron track structures; but additional radiobiological information would be 7 Hofer KG, Hughes WL. Radiotoxicity of intracellular tritium, 125iodine and 131iodine Radiat Res 1971; 47: 94-109. 8. Burki HF, Roots R, Feinendegen LE, Bond VP. Inactivation of mammalian cells after disintegration of 3H or 125I in cell DNA at -196°C. Int J Radiat Biol 1973; 24: 363-75. 9 Bradley EW, Chan PC, Adelstein SJ The radiotoxicity of iodine-125 in mammalian cells. I Effects on the survival curve of radioiodine incorporated in DNA. Radiat Res 1975, 64: 555-63 10. Hofer KG, Harris CR, Smith JM. Radiotoxicity of intracellular 67Ga, 125I and 3H Nuclear versus cytoplasmic radiation effects in murine L1210 leukaemia Int J Radial Biol 1975, 28: 225-41. 11. Chan PC, Lisco E, Lisco H, Adelstein SJ The radiotoxicity of iodine-125 in mammalian cells. II. A comparative study on cell survival and cytogenetic response to 125IU dR, 131IU dR and 3HT dR Radiat Res 1976; 67: 332-42. 12. Warters RL, Hofer KG, Harris CR, Smith JM. Radionuclide toxicity in cultured mammalian cells. elucidation of primary site of radiation damage. Curr Top Radiat Res Q 1978; 12: 389-407. 13 Bloomer WD, McLaughlin WH, Weichselbaum RR, Hanson RN, Adelstein SJ, Seitz DE. The role of sub-cellular localization in assessing the cytotoxicity of iodine-125 labelled iododeoxyuridine, iodotamoxifen, and iodoantipyrene. J Radioanal Chem 1981, 65: 209-21. 14. Miyazaki N, Fujiwara Y. Mutagenic and lethal effects of [5-125 I] iodo-2’-deoxyuridine incorporated into DNA of mammalian cells, and their RBEs. Radiat Res 1981; 88: 456-65. 15 Le Motte PK, Adelstein SJ, Little JB. Malignant transformation induced by incorporated radionuclides in BALB/3T3 mouse embryo fibroblasts. Proc Natl Acad Sci USA 1982; 79: 7763-67. 16. Liber HL, Le Motte PK, Little JB. Toxicity and mutagenicity of X-rays and [125I]dUrd or [3H] TdR incorporated in the DNA of human lymphoblast cells. Mut Res 1983; 111: 387-404.
Transcript of Auger Cascades and Nuclear Medicine
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Auger Cascades and Nuclear MedicineTHE technique of administering short-lived
radioactive nuclides into the body and examining theirdistribution with time is a diagnostic and investigativeprocedure with considerable potential for further
development. For use in nuclear medicine the idealnuclide will have high specificity for the tissue underexamination; its biological half-life will be long enoughfor it to be retained in the organ during measurement;its radioactive half-life will be such that it can bemeasured easily over the time-scale of the investigationbut that it will not, if biologically retained over longerperiods, continue to deliver a substantial dose to thebody; and its primary radiations will be sufficientlypenetrating to be measurable outside the body.
It transpires that several of the most suitable nuclidesfor these purposes, including the widely used
technetium-99m, have, as an incidental part of theirdecays, the production of electron vacancies in theinner shells of the atom. These vacancies trigger acascade of very low energy electrons (Auger electrons),many of which have ranges less than the diameter of thenucleus of a cell which is typically about 10 /-lm. (Forexample,3 the Auger cascade electrons from the decayof thallium-201 have average energies from 0*02 to 61keV and ranges in tissue from <1 nm to about 65 jum.)The combined energy of these electrons may be only asmall fraction of the total energy released by the decay,but since this energy is concentrated in a very smallvolume it produces a very local high dose in addition tothe overall irradiation of the organ by the longer rangedemissions. Conventional dosimetry,’ and consequentassessment of radiation risk, follows the methods
developed by the Medical Internal Radiation DoseCommittee (mind).2 These consider only the averagedose to the organ and ignore the localised cellular andsubcellular concentrations. There is now evidence,from work in animals and cell systems,3-6 that Augerelectrons may be an important determinant of thebiological effects of some radionuclides.
1. International Commission on Radiation Units and Measurements. Methods ofassessment of absorbed dose in clinical use of radionuclides, report 32. Washington:ICRU, 1979
2. Loevinger R, Berman M. A revised schema for calculating the absorbed dose frombiologically distributed radionuclides, MIRD pamphlet No. 1 revised. New York:Society of Nuclear Medicine, 1976.
3 Rao DV, Govelitz GF, Sastry KSR Radiotoxicity of thallium-201 in mouse testes:inadequacy of conventional dosimetry. J Nucl Med 1983; 24: 145-53.
4. Kassis AI, Adelstein SJ, Haydock C, Sastry KSR. Thallium-201: an experimental andtheoretical radiobiological approach to dosimetry. J Nucl Med 1983; 24: 1164-75.
5 Kassis AI, Sastry KSR, Adelstein SJ. Intracellular distribution of radiotoxicity ofchromium-51 in mammalian cells: Auger-electron dosimetry. J Nucl Med 1985, 26:59-67
6. Rao DV, Sastry KSR, Govelitz GF, Grimmond HE, Hill HZ. Radiobiological effectsof Auger electron emitters in vivo: spermatogenesis in mice as an experimentalmodel (Proceedings of Ninth Symposium on Microdosimetry, Toulouse, May,1985 ) Radiat Prot Dosim (in press)
The biological structures that are critical for delayedsomatic effects are very small and probably located inthe cell nucleus. Thus if the Auger cascade energy ispreferentially deposited within, or outside, the cellnucleus the biological effect may be respectively more,or less, than indicated by the "macroscopic" dosewhich is calculated as if the distribution was even.
Auger cascades originating in intercellular fluids willnot be a hazard whereas decays in the cell nucleus, nearthe DNA, may well be. Furthermore, it is now
becoming clear that the biological effects of radiationdepend critically on the density of energy deposition insmall volumes. We know that densely ionising (highLET) radiation such as neutrons and alpha-particlescan be considerably more effective biologically than Xor y rays for the same energy deposited. The increasedbiological damage at high LET may be related to themore probable occurrence of substantial energydeposition in very small subcellular volumes. It istherefore possible that Auger decays can produceevents characteristic of high LET radiations, thusintroducing an additional factor for enhanced
biological hazard under certain circumstances. This isparticularly evident when the decay takes place in theDNA itself, as in the well-studied case of DNA-
incorporated iodine-12 5.’" To evaluate adequatelythe biological effect of the very local dose from theshort-ranged Auger cascade electrons, detailed knowl-edge is required of the distribution of the radionuclidewithin the cell and its nucleus. There is, however, scantinformation on the microscopic distribution of relevantnuclides and pharmaceuticals. Such informationwould be a prerequisite for assessment of risks fromthese low-energy-electron emitting isotopes in a
particular diagnostic procedure. Physical aspects of thematter could then be accurately addressed by means ofmodern computer methods to simulate radionuclide
decays and detailed electron track structures; butadditional radiobiological information would be
7 Hofer KG, Hughes WL. Radiotoxicity of intracellular tritium, 125iodine and131iodine Radiat Res 1971; 47: 94-109.
8. Burki HF, Roots R, Feinendegen LE, Bond VP. Inactivation of mammalian cells afterdisintegration of 3H or 125I in cell DNA at -196°C. Int J Radiat Biol 1973; 24:363-75.
9 Bradley EW, Chan PC, Adelstein SJ The radiotoxicity of iodine-125 in mammaliancells. I Effects on the survival curve of radioiodine incorporated in DNA. RadiatRes 1975, 64: 555-63
10. Hofer KG, Harris CR, Smith JM. Radiotoxicity of intracellular 67Ga, 125I and 3H Nuclear versus cytoplasmic radiation effects in murine L1210 leukaemia Int JRadial Biol 1975, 28: 225-41.
11. Chan PC, Lisco E, Lisco H, Adelstein SJ The radiotoxicity of iodine-125 in
mammalian cells. II. A comparative study on cell survival and cytogenetic responseto 125IU dR, 131IU dR and 3HT dR Radiat Res 1976; 67: 332-42.
12. Warters RL, Hofer KG, Harris CR, Smith JM. Radionuclide toxicity in culturedmammalian cells. elucidation of primary site of radiation damage. Curr Top RadiatRes Q 1978; 12: 389-407.
13 Bloomer WD, McLaughlin WH, Weichselbaum RR, Hanson RN, Adelstein SJ, SeitzDE. The role of sub-cellular localization in assessing the cytotoxicity of iodine-125labelled iododeoxyuridine, iodotamoxifen, and iodoantipyrene. J Radioanal Chem1981, 65: 209-21.
14. Miyazaki N, Fujiwara Y. Mutagenic and lethal effects of [5-125 I] iodo-2’-deoxyuridineincorporated into DNA of mammalian cells, and their RBEs. Radiat Res 1981; 88:456-65.
15 Le Motte PK, Adelstein SJ, Little JB. Malignant transformation induced byincorporated radionuclides in BALB/3T3 mouse embryo fibroblasts. Proc NatlAcad Sci USA 1982; 79: 7763-67.
16. Liber HL, Le Motte PK, Little JB. Toxicity and mutagenicity of X-rays and[125I]dUrd or [3H] TdR incorporated in the DNA of human lymphoblast cells. MutRes 1983; 111: 387-404.
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needed as to the critical subcellular components."These theoretical considerations have been current
for some time; what has stimulated recent interest18 is °
in-vivo findings by workers in the USA3 that, wheninjected into the testis of a mouse, thallium-201, aradionuclide widely used in investigations of the heart,produces a biological effect (killing of spermatogonialcells) greater than that expected on the basis ofconventional macroscopic dosimetry and comparisonwith external X rays. Similar effects have been seenwith iron-556 and indium-Ill. The importance ofthese results does not lie so much in their direct
extrapolation to the effects of these Auger-emittingradionuclides in the testis of man but rather in thedemonstration that Auger electrons have biologicaleffects in vivo, and that these actions cannot beaccounted for by the conventional macroscopicdosimetry of MIRD. These observations were
strikingly confirmed in vitro when thallium-201 andother Auger-emitting radionuclides were shown to killestablished Chinese hamster V79 lung fibroblasts. 4,5,19The in-vitro intracellular concentration of thalliumions may rise to 130 times their concentration in theexternal medium, possibly because of their chemicalsimilarity to potassium ions.4 Thus two factors maycontribute to the biological consequences of Auger-emitting radionuclides-namely, one due to thedistribution of the radionuclides in relation to the cell
nucleus, and the other due to the high LET nature ofsome energy depositions from Auger cascades inrelation to the critical subcellular macromolecules.In view of the enormous beneficial value of
diagnostic nuclear medicine, its potential for furtherdevelopment, and its possible extension to therapeuticuse it is clearly important to find a way of assessing therisk associated with the use of Auger-emittingradiopharmaceuticals. A meeting held lately underthe auspices of the Medical Research Council’sCommittee on the Effects of Ionizing Radiation
brought together people who use the techniques andpeople whose interest is in the fundamental
radiobiology and physics underlying nuclear medicine.It was soon apparent that we know little about thesubcellular physiology of commonly used
radiopharmaceuticals-an aspect of the subjectessential to any rational assessment of the likely extentof biological impact of the Auger decays. Although thefactors by which effective doses are under or overestimated by macroscopic dosimetry are unlikely toexceed one order of magnitude, realistic dosimetry isessential for an assessment of risk of harm againstwhich the benefits of a clinical investigation should beweighed.Similar difficulties may be encountered in assessing
the risk to human beings exposed to environmentalAuger-emitting radionuclides. Information on the
17 Goodhead DT, Charlton DE. Analysis of high-LET radiation effects in terms of localenergy deposition. (Proceedings of Ninth Symposium on Microdosimetry,Toulouse, May, 1985.) Radiat Prot Dosim (in press).
18 Gaulden ME "Biological dosimetry" of radionuclides and radiation hazards. J NuclMed 1983; 24: 160-64.
19. Kassis AI, Adelstein SJ, Haydock C, Sastry KSR. Radiotoxicity of 7 5Se and 3 5S:theory and application to a cellular model Radiat Res 1980; 84: 407-25.
cellular and subcellular physiology of an ingestedradionuclide may be a prerequisite for accurate
assessment of the possible additional hazard due to theAuger cascade electrons.
Haemorrhagic Shock andEncephalopathy
IT is now two years since workers at the Hospital forSick Children, Great Ormond Street, London,reported in The Lancet what seemed to be a newdisorder-" haemorrhagic shock and encephalo-pathy".’ Ten infants had presented with a suddenonset of shock, coma and convulsions, bleeding,disseminated intravascular coagulation, watery diar-rhoea, and impaired hepatic and renal function.
Despite intensive treatment, seven of the ten died andthe survivors were all neurologically damaged. Post-mortem studies revealed haemorrhages and petechiaein several organs, and severe cerebral oedema. A searchfor the cause revealed no specific microbial agent,toxin, or metabolic disorder, but the infants did showan unusual pattern of plasma proteins with reducedalpha-1-antitrypsin and increased trypsin. This obser-vation led to the suggestion that the pathogenesis mighthave involved massive release of proteolytic enzymesinto the circulation, overwhelming the natural proteaseinhibitors. While the disorder in these ten cases hadindividual features in common with other acute
illnesses, such as Reye’s syndrome, the staphylococcaltoxic shock syndrome, septicaemia, and heatstroke, theGreat Ormond Street workers felt that it could be
distinguished from them on clinical or laboratorygrounds.
Other cases were soon reported from the UK,2-4 theNetherlands,5 and the United States,b’ and hypothesesto explain the disorder included suggestions that it wasdue to a bacterial toxin produced by abnormal gutflora,8 that it was related to the syndrome of idiopathicacute pancreatitis in children,9’lO and that it was due toheatstroke."-’4 Five infants with an illness similar to
haemorrhagic shock and encephalopathy had beenreported in 1979 by Bacon and co-workersl5 in
1 Levin M, Kay JDS, Gould JD, et al Haemorrhagic shock and encephalopathy. A newsyndrome with a high mortality in young children. Lancet 1983, ii: 64-67.
2. Morris JA, Matthews TS Haemorrhagic shock and encephalopathy syndrome: A newsyndrome in young children. Lancet 1983; n: 278.
3. McGucken RB Haemorrhagic shock and encephalopathy syndrome. Lancet 1983; ii:1087.
4. David TJ, Mughal MZ. Haemorrhagic shock and encephalopathy syndrome:Epidemic of a new disease. J R Soc Med 1984; 77: 721-22
5 Lafeber HN, van der Voort E, De Groot R. Haemorrhagic shock and encephalopathysyndrome. Lancet 1983, n: 795.
6 Schrager GO, Shah A. Haemorrhagic shock/encephalopathy syndrome in infancy.Lancet 1983; n: 396.
7. Whittington LK, Roscelli JD, Parry WH. Haemorrhagic shock and encephalopathyFurther description of a new syndrome. J Pediatr 1985; 106: 599-602.
8. Morris JA Haemorrhagic shock and encephalopathy. Lancet 1983; ii: 686.9 Morens DM. Haemorrhagic shock, encephalopathy and the pancreas. Lancet 1983; ii:
967
10. Morens DM, Hammar SL, Heicher DA. Idiopathic acute pancreatitis in childrenassociation with a clinical picture resembling Reye’s syndrome. Am J Dis Child1974, 128: 401-04.
11. Bacon CJ. Haemorrhagic shock and encephalopathy a new syndrome in youngchildren. Lancet 1983; n: 278.
12 Beaufils F, Aujard Y Haemorrhagic shock and encephalopathy syndrome. Lancet1983, ii: 1086
13 Bacon CJ Over heating in infancy Arch Dis Child 1983; 58: 673-74.14. Bacon CJ, Bellman MH. Heatstroke as a possible cause of encephalopathy in infants. Br
Med J 1983; 287: 328.15 Bacon C, Scott D, Jones P Heatstroke in well-wrapped infants. Lancet 1979; i: 422-25
