II.1.4 Kanzerogenität unter besonderer Berücksichtigung...

II.1.4

Kanzerogenität unter besonderer Berücksichtigung

immunhämatopoetischer Malignitäten

Version 25.03.2003

von

Prof. Dr. Horst Kuni

Klinische Nuklearmedizin

Medizinisches Zentrum für Radiologie

Philipps-Universität Marburg

D 35033 Marburg/Lahn

http://staff.uni-marburg.de/~kunih/

[email protected]

II.1.4 Kanzerogenität unter besonderer Berücksichtigung immunhämatopoetischer Malignitäten

II.1.4.0 Verzeichnisse

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II.1.4.0.1 Inhalt

II.1.4.0 Verzeichnisse........................................................................................................................2 II.1.4.0.1 Inhalt .....................................................................................................................2 II.1.4.0.2 Abbildungen..........................................................................................................4 II.1.4.0.3 Tabellen ................................................................................................................9 II.1.4.0.4 Abkürzungen.......................................................................................................10

II.1.4.1 Formale und inhaltliche Struktur des Beitrages..............................................................12

II.1.4.2 Die besondere Stellung der Leukämie unter den strahleninduzierten Tumoren .........14

II.1.4.3 Ergebnisse der RERF zur Leukämie.................................................................................17 II.1.4.3.1 Der Wert der Daten aus Hiroshima und Nagasaki .............................................17 II.1.4.3.2 Analyse der Leukämie-Inzidenz 1950 bis 1987 ..................................................18 II.1.4.3.3 Analyse der Leukämie-Mortalität 1950 bis 1990.................................................26 II.1.4.3.4 Analyse der Leukämie-Mortalität junger Kinder 1950 bis 1992 ..........................27 II.1.4.3.5 Klinische Ausprägung und chromosomale Veränderungen ...............................31 II.1.4.3.6 Einfluß zusätzlicher beruflicher Exposition und anderer Faktoren......................40 II.1.4.3.7 Medizinische Strahlenbelastung .........................................................................41 II.1.4.3.8 Pränatale Strahlenbelastung ..............................................................................41 II.1.4.3.9 Präkonzeptionelle Strahlenbelastung .................................................................44

II.1.4.4 Probleme bei der quantitativen Übertragung auf andere Populationen .......................47 II.1.4.4.1 Absolutes oder relatives Risikomodell ................................................................47 II.1.4.4.2 Time since exposure effect (TSE) Effekt............................................................49 II.1.4.4.3 Dosimetrie...........................................................................................................54 II.1.4.4.4 Selektierende Wirkung der Atombomben...........................................................62 II.1.4.4.5 Diagnose und Differentialdiagnose der Leukämie..............................................64 II.1.4.4.6 Spezifische Eigenschaften der Studienpopulation..............................................67

II.1.4.5 Die zeitliche Verteilung strahleninduzierter Leukämien.................................................76 II.1.4.5.1 Einleitung ............................................................................................................76 II.1.4.5.2 Der Time Since Exposure Effect bei den Atombombenopfern...........................78 II.1.4.5.3 Multidimensionale Analyse .................................................................................81

II.1.4.6 Auswertung mit unterschiedlicher RBW der Neutronen ................................................89 II.1.4.6.1 Einleitung ............................................................................................................89 II.1.4.6.2 Methodik der Kurvenanpassung.........................................................................90 II.1.4.6.3 Resultate.............................................................................................................91 II.1.4.6.4 Vergleich mit Beobachtungen nach einer Strahlentherapie..............................101

II.1.4.7 Leukämien nach Anwendung lockerionisierender Strahlen in der Medizin ...............108 II.1.4.7.1 Einleitung ..........................................................................................................108 II.1.4.7.2 Präkonzeptionelle Strahlenbelastung ...............................................................108 II.1.4.7.3 Pränatale Strahlenbelastung ............................................................................112 II.1.4.7.4 Strahlenbelastung im Säuglingsalter ................................................................119



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II.1.4.7.5 Strahlenbelastung im Kindesalter .....................................................................126 II.1.4.7.6 Strahlenbelastung im Erwachsenenalter ..........................................................129

II.1.4.8 Leukämien nach Exposition gegenüber dichtionisierender Strahlung ......................138 II.1.4.8.1 Alphateilchen ....................................................................................................138 II.1.4.8.2 Neutronen .........................................................................................................140

II.1.4.9 Leukämie als Zweittumor.................................................................................................141 II.1.4.9.1 Einleitung ..........................................................................................................141 II.1.4.9.2 Therapie des Ersttumors im Erwachsenenalter................................................141 II.1.4.9.3 Therapie des Ersttumors im Kindesalter ..........................................................144

II.1.4.10 Zusammenfassung...........................................................................................................146 II.1.4.10.1 Formale und inhaltliche Struktur des Beitrages................................................146 II.1.4.10.2 Die besondere Stellung der Leukämie unter den strahleninduzierten

Tumoren ...........................................................................................................146 II.1.4.10.3 Ergebnisse der RERF zur Leukämie ................................................................146 II.1.4.10.4 Probleme bei der quantitativen Übertragung auf andere Populationen............148 II.1.4.10.5 Die zeitliche Verteilung strahleninduzierter Leukämien ....................................151 II.1.4.10.6 Auswertung mit unterschiedlicher RBW der Neutronen ...................................151 II.1.4.10.7 Leukämien nach Anwendung lockerionisierender Strahlen in der Medizin ......152 II.1.4.10.8 Leukämien nach Exposition gegenüber dichtionisierender Strahlung..............152 II.1.4.10.9 Leukämie als Zweittumor..................................................................................153

II.1.4.11 Anmerkung........................................................................................................................154

II.1.4.12 Quellen...............................................................................................................................155

II.1.4.13 Index ..................................................................................................................................169



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II.1.4.0.2 Abbildungen

Abb. 1: Excess relative risk pro Sievert für eine Erkrankung an CML nach einer

Strahlenbelastung im Alter von 25 Jahren. ...........................................................................23

Abb. 2: Verdoppelungsdosis für eine Erkrankung an CML nach einer Strahlenbelastung im

Alter von 25 Jahren. ..............................................................................................................24

Abb. 3: Excess relative risk pro Sievert für eine Erkrankung an CML im 5. Jahr nach einer

Strahlenbelastung in Abhängigkeit vom Lebensalter bei Exposition.....................................25

Abb. 4: Verdoppelungsdosis für eine Erkrankung an CML im 5. Jahr nach einer

Strahlenbelastung in Abhängigkeit vom Lebensalter bei Exposition.....................................26

Abb. 5: Mortalität junger Kinder durch Leukämie in Abhängigkeit vom Alter ATB ............................28

Abb. 6: Mortalität junger Kinder durch Leukämie in Abhängigkeit von der Dosis..............................29

Abb. 7: Excess relative risk pro Sievert für Mortalität junger Kinder an Leukämie in

Abhängigkeit vom erreichten Lebensalter.............................................................................30

Abb. 8: Verdoppelungsdosis für Mortalität junger Kinder an Leukämie in Abhängigkeit vom

erreichten Lebensalter ..........................................................................................................31

Abb. 9: Häufigkeit der Untergruppen einer AML nach einer Dosis zwischen 0,01 und 0,99 Gy .......33

Abb. 10: Häufigkeit der Untergruppen einer AML nach einer Dosis von 1,0 Gy und mehr .................34

Abb. 11: Häufigkeit chromosomaler Aberrationen bei AML nach einer Dosis zwischen 0,01 und

0,99 Gy..................................................................................................................................35

Abb. 12: Häufigkeit chromosomaler Aberrationen bei AML nach einer Dosis von 1,0 Gy und

mehr ......................................................................................................................................36

Abb. 13: Häufigkeit einer Aneuploidie bei AML nach einer Dosis zwischen 0,01 und 0,99 Gy ...........37

Abb. 14: Häufigkeit einer Aneuploidie bei AML nach einer Dosis von 1,0 Gy und mehr.....................38

Abb. 15: Häufigkeit einer Aneuploidie bei AML in Abhängigkeit von der Dosis...................................39



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Abb. 16: Extrapolation des excess relative risk pro Sievert für eine Erkrankung an CML nach

einer Strahlenbelastung im 25. Lebensjahr in Bereiche kürzerer mittlerer Latenzzeit. .........50

Abb. 17: Extrapolation des excess relative risk pro Sievert für eine Erkrankung an CML nach

einer Strahlenbelastung im 25. Lebensjahr in Bereiche kürzerer mittlerer Latenzzeit. .........51

Abb. 19: Extrapolation der Verdoppelungsdosis für Mortalität junger Kinder an Leukämien in

Bereiche kürzerer mittlerer Latenzzeit...................................................................................53

Abb. 20: Relative biologische Wirksamkeit von Photonenstrahlung für stochastische Effekte in

Abhängigkeit von der Energie ...............................................................................................55

Abb. 21: Abhängigkeit der linear-quadratischen Parameter des relative risk-Modells von der

angesetzten RBW der Neutronen im Verhältnis zu den Gammastrahlen der

Atombombe...........................................................................................................................56

Abb. 22: Abhängigkeit der linearen Parameter des relative risk-Modells von der angesetzten

RBW der Neutronen im Verhältnis zu den Gammastrahlen der Atombombe ......................57

Abb. 23: Abhängigkeit von Steigung und relativer Standardabweichung der lineare Komponente

sowie Ausprägung der quadratischen Komponente vom Ausschluß hoher Dosen ..............61

Abb. 24: Inzidenz und Mortalität an Leukämie im japanisch-deutschen Vergleich..............................65

Abb. 25: Excess absolute risk für Leukämie israelischer Kinder in Abhängigkeit vom

Herkunftsland ........................................................................................................................68

Abb. 26: Relative Risk für Leukämie von Kindern bis 4 Jahre nach pränataler Strahlenbelastung

bei Anfälligkeit gegenüber Infektionen oder Allergie .............................................................69

Abb. 27: Relative Risk für Leukämie von Kindern nach pränataler Strahlenbelastung bei

Anfälligkeit gegenüber Allergie in Abhängigkeit vom Alter ....................................................70

Abb. 28: Excess relative risk für Sterblichkeit an Leukämie in Abhängigkeit von der

Knochenmarksdosis: Vergleich zwischen der Kohorte der Atombombenopfer (LSS)

und der Bevölkerung in der Region des Flusses Techa (TRC). ...........................................72

Abb. 29: Häufigkeit von Röntgenuntersuchungen in Japan und der russischen Sowjetrepublik ........74



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Abb. 30: Excess relative risk pro Gray für Sterblichkeit an Leukämie in Untergruppen der TRC-

Kohorte..................................................................................................................................75

Abb. 31: Abhängigkeit der mittleren Latenzzeit für verschiedene Typen der Leukämie von der

Knochenmarksdosis..............................................................................................................77

Abb. 32: Zeit in Jahren bis zum Ausbruch einer CGL (nach Ishimaru et al. [42]), eingestuft als

CML (FAB) ............................................................................................................................78

Abb. 33: Zeit in Jahren bis zum Ausbruch einer AGL, AML und erythroleukemia (nach Ishimaru

et al. [42]), eingestuft als AML (FAB) ....................................................................................79

Abb. 34: Zeit in Jahren bis zum Ausbruch einer AL und ASL (nach Ishimaru et al. [42]),

eingestuft als AL (FAB) .........................................................................................................80

Abb. 35: Zeit in Jahren bis zum Ausbruch einer ALL (nach Ishimaru et al. [42]), eingestuft als

ALL (FAB)..............................................................................................................................81

Abb. 36: Säulen vom Alter ATB bis zum Ausbruch einer CGL (nach Ishimaru et al. [42]),

eingestuft als CML (FAB), nach Dosis sortiert und angeordnet. ...........................................82

Abb. 37: Säulen vom Alter ATB bis zum Ausbruch einer CGL (nach Ishimaru et al. [42]),

eingestuft als CML (FAB), nach TSE sortiert und angeordnet. .............................................83

Abb. 38: Säulen vom Alter ATB bis zum Ausbruch einer AGL, AML und erythroleukemia (nach

Ishimaru et al. [42]), eingestuft als AML (FAB), nach Dosis sortiert und angeordnet. ..........84

Abb. 39: Säulen vom Alter ATB bis zum Ausbruch einer AGL, AML und erythroleukemia (nach

Ishimaru et al. [42]), eingestuft als AML (FAB), nach TSE sortiert und angeordnet .............85

Abb. 40: Säulen vom Alter ATB bis zum Ausbruch einer ALL (nach Ishimaru et al. [42]),

eingestuft als ALL (FAB), nach Dosis sortiert und angeordnet .............................................86

Abb. 41: Säulen vom Alter ATB bis zum Ausbruch einer ALL (nach Ishimaru et al. [42]),

eingestuft als ALL (FAB), nach TSE sortiert und angeordnet ...............................................87

Abb. 42: Zeit bis zum Ausbruch der Erkrankung für alle Typen einer Leukämie (CGL, AGL,

AML, AL, ALL ASL und erythroleukemia (nach Ishimaru et al. [42]).....................................88



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Abb. 43: Dosiswirkungsfläche für AML, relative risk-Modell, alle Altersgruppen.................................94

Abb. 44: Dosiswirkungskurve für die Gammastrahlung der Atombomben, relative risk-Modell,

alle Altersgruppen .................................................................................................................98

Abb. 45: Wie Abb. 44, S. 98, Bereich niedriger Dosen <100 mGy......................................................99

Abb. 46: Dosiswirkungskurve für die Gammastrahlung der Atombomben, relative risk-Modell,

Alter <15 Jahre....................................................................................................................100

Abb. 47: Berechnete Dosiswirkungskurve für Leukämie nach Strahlentherapie eines Cervix-

Krebses und Beobachtungen..............................................................................................102

Abb. 48: Berechnete Dosiswirkungskurve für Leukämie nach einer Strahlentherapie gutartiger

gynäkologischer Erkrankungen und Beobachtungen..........................................................104

Abb. 49: Vergleich wie Abb. 48, S. 104, jedoch nur für Brachytherapie ............................................105

Abb. 50: Berechnete Dosiswirkungskurve für Leukämie nach Strahlentherapie einer Spondylitis

ancylosans und Beobachtungen .........................................................................................106

Abb. 51: Inzidenz der Leukämie im Kindesalter nach den Daten des OSCC....................................112

Abb. 52: Lymphatische Leukämien im Kindesalter nach Röntgenuntersuchungen der Mutter

während der Schwangerschaft............................................................................................113

Abb. 53: Stammzell-Leukämien im Kindesalter nach Röntgenuntersuchungen der Mutter


Abb. 54: Myeloische Leukämien im Kindesalter nach Röntgenuntersuchungen der Mutter


Abb. 55: Relative risk für maligne Tumore im Kindesalter ................................................................117

Abb. 56: Malignome im Kindesalter nach Röntgenuntersuchung der Mutter in verschiedenen

Zeitabschnitten der Schwangerschaft .................................................................................118

Abb. 57: Häufigkeit kindlicher Leukämie in Abhängigkeit vom Alter bei Erkrankung nach einer

Strahlenbelastung im Säuglingsalter...................................................................................125



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Abb. 58: Leukämie-Mortalität nach Strahlenbehandlung eines Hämangioms im Säuglingsalter ......126

Abb. 59: Verschiedene Typen von Leukämie nach Strahlentherapie einer Spondylitis

ancylosans ..........................................................................................................................130

Abb. 60: Relative risk für Todesfälle durch verschiedene Typen von Leukämie in Abhängigkeit

von der Zeit nach Strahlentherapie einer Spondylitis ancylosans.......................................131

Abb. 61: Todesfälle durch verschiedene Typen von Leukämie nach Strahlentherapie gutartiger

gynäkologischer Erkrankungen...........................................................................................133

Abb. 62: Standardisierten Mortalitätsrate (SMR) für verschiedene Typen von Leukämie in

Abhängigkeit von der Zeit nach Strahlentherapie gutartiger gynäkologischer

Erkrankungen......................................................................................................................134

Abb. 63: Erkrankungen an verschiedenen Typen von Leukämie nach Strahlentherapie eines

Cervix-Karzinoms................................................................................................................135

Abb. 64: Relative risk (RR) für verschiedene Typen von Leukämie in Abhängigkeit von der Zeit

nach Strahlentherapie eines Cervix-Karzinoms ..................................................................136

Abb. 65: Excess relative risk für CML nach Röntgendiagnostik........................................................137

Abb. 66: Relative risk für Leukämie nach Strahlentherapie und/oder Chemotherapie......................143

Abb. 67: Zeit bis zur Erkrankung an einer Leukämie nach Chemotherapie ......................................145



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II.1.4.0.3 Tabellen

Tab. 1: Attributable risk, excess relative risk und absolute excess radiogener

Krebserkrankungen nach einer Ganzkörperexposition.........................................................15

Tab. 2: Parameters der Dosiswirkungskurve für ALL, AML und CML (alle Altersgruppen

gemeinsam). .........................................................................................................................92

Tab. 3: Parameter der Dosiswirkungskurven (ausschließlich für das relative risk-Modell) für

ALL, AML und CML (mittleres Alter bei Exposition unter 15 Jahre). ....................................93

Tab. 4: Parameter der Dosis-Wirkungsrelation für ALL, AML und CML, Frauen >35 Jahre.............95

Tab. 5: Parameter der Dosiswirkungskurve für ALL, AML und CML, 20-60Jahre ...........................96

Tab. 6: Präkonzeptionelle Röntgendiagnostik beim Vater und kindliche Leukämie........................110

Tab. 7: Präkonzeptionelle Röntgenuntersuchungen des Gastrointestinaltraktes und des

Thorax beim Vater und kindliche Leukämie........................................................................111

Tab. 8: Leukämie nach pränataler Exposition gegenüber Röntgenstrahlung .................................116

Tab. 9: Ergebnisse zweier Studien über Leukämie nach einer Strahlentherapie im

Säuglingsalter......................................................................................................................121

Tab. 10: Leukämietypen nach Strahlenbelastung im Säuglingsalter ................................................123

Tab. 11: Leukämietypen nach Strahlenbelastung im Säuglingsalter in Abhängigkeit vom

Sterbealter und der Dosis ...................................................................................................124

Tab. 12: Einfluß des Alters bei Strahlenbelastung auf die Mortalität an Leukämie ..........................128

Tab. 13: Leukämietypen nach Strahlenbelastung im Kindesalter .....................................................128

Tab. 14: Relative Risk für verschiedene Typen einer Leukämie als Zweittumor nach

Strahlentherapie oder Chemotherapie eines Mammakarzinoms........................................141

Tab. 15: Typ der Leukämie als Zweittumor in Abhängigkeit vom Alter bei Behandlung des

Ersttumors mit Strahlentherapie und Chemotherapie.........................................................144



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II.1.4.0.4 Abkürzungen

ABCC Atomic Bomb Casualty Commission, Vorläufer der RERF

AGL acute granulocytic leukaemia

AKW Atomkraftwerk

AL akute Leukämie

ALL akute lymphatische Leukämie

AML akute myeloische Leukämie

ANLL akute nichtlymphatische Leukämie

ASL acute stem cell undifferentiated leukaemia, akute undifferenzierte Stammzell-Leukämie

ATB at time of bombings; (Alter) zum Zeitpunkt der Atombombenexplosion

ATL Adult T-cell leukaemia, T-Zellen-Leukämie der Erwachsenen, hervorgerufen durch das HTLV-1-Virus

AU akute unspezifische Leukämie

BEIR Committee on the Biological Effects of Ionizing Radiations

CGL chronic granulocytic leukaemia

CL überwiegend chronische Leukämien der Erwachsenen (alle Formen ohne ANLL und CLL, einzelne ALL möglicherweise enthalten)

CLL chronisch lymphatische Leukämie

CML chronisch myeloische Leukämie

DS 86 Dosimetry System 1986

EAR excess absolute risk, Anzahl zusätzlicher Erkrankungen oder Sterbefälle, meist pro 104 oder 105 Personenjahre

ERR excess relative risk, Verhältnis der zusätzlichen Erkrankungen oder Sterbefälle zu den erwarteten, entspricht RR-1

FAB French American British classification of leukaemia

ICRP International Commission on Radiological Protection, Internationale Strahlenschutzkommission

LL lymphatische Leukämie



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LSS Life Span Study, Studienpopulation, aus Hiroshima 62.000, aus Nagasaki 32.000 exponierte, 20.000 bzw. 6.000 nicht exponierte Personen

MDS myelodysplastic syndrome; Bluterkrankung durch klonale Vermehrung einer mutierten Stammzelle, die häufig in eine AML übergeht; früher auch Präleukämie

ML myeloische Leukämie

NIC not in the cities; Einwohner von Hiroshima und Nagasaki, die zur Zeit der Atombombenexplosion sich nicht in der Stadt aufgehalten hatten

O/E Observed/expected; Verhältnis der beobachteten zu den erwarteten Fälle

OSCC Oxford Survey of Childhood Cancers, Kinderkrebsregister für Großbritannien in Oxford

PY Person years; Personenjahre

RBW Relative biologische Wirksamkeit

RERF Radiation Effects Research Foundation, eine japanische private Stiftung, seit April 1975 Nachfolgerin der ABCC

RR relative risk; Verhältnis der Häufigkeit von Erkrankungen oder der Sterblichkeit zwischen zwei Gruppen

SIR Standard incidence ratio; Verhältnis der Häufigkeit von Erkrankungen in einer Gruppe zur Bevölkerung unter Berücksichtigung soziodemographischer Merkmale, besonders Alter und Geschlecht

SLL subakute lymphatische Leukämie

SMR Standard mortality ratio; Verhältnis der Sterblichkeit in einer Gruppe zur Bevölkerung unter Berücksichtigung soziodemographischer Merkmale, besonders Alter und Geschlecht

T65D tentative 1965 dose, vorläufige Dosimetrie von 1965

TRC Techa River Cohort, Studienpopulation aus der Region des Flusses Techa im südlichen Ural, 26.485 Personen, belastet durch die Abwässer der Wiederaufarbeitungsanlage Mayak bei Tscheliabinsk

TSE time since exposure

VD Verdoppelungsdosis

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0

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0

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II.1.4 Kanzerogenität unter besonderer Berücksichtigung...

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