Radiation Toxicology: Bone Marrow and Leukaemia

Book Cover......Page 1
Half-Title......Page 2
Title......Page 3
Copyright......Page 4
Dedication......Page 5
Contents......Page 6
Preface......Page 8
Contributors......Page 9
1 Radiation Toxicology: Bone marrow and leukaemia......Page 11
1.1  Introduction......Page 12
1.2  Bone Marrow......Page 14
1.3  Human Radiation Exposure......Page 16
1.4  The Response of Bone Marrow to Low LET Irradiation......Page 17
1.5  High LET Irradiation......Page 18
1.6  Experimental Approaches for Therapeutic Treatment of Radiation-induced Haemopoietic Injury......Page 20
1.7  Clinical Approaches to Treatment of Radiation-induced Haemopoietic Injury......Page 21
1.8  The Pathogenesis of Leukaemia......Page 23
1.9  Genetic Effects of Ionising Radiation with respect to Leukaemia......Page 24
1.10  Experimental Radiation Leukaemogenesis......Page 25
1.11  Human Studies in Radiation Leukaemogenesis......Page 27
1.12  Conclusion......Page 28
References......Page 29
2 Haemopoiesis......Page 30
2.1  Introduction......Page 31
2.2  The Cellular Hierarchy......Page 32
2.2.1  Stem Cells......Page 34
2.2.2  Committed Progenitors......Page 35
2.3  Developmental Haemopoiesis......Page 37
2.4  Microanatomy of the Haemopoietic Bone Marrow......Page 38
2.6  The Haemopoietic Microenvironment......Page 40
2.6.1  Lodgement......Page 41
2.6.2  Commitment and Proliferation......Page 42
2.8  What Can Go Wrong?......Page 43
References......Page 44
3 Human Radiation Exposure......Page 47
3.1  General Introduction......Page 49
3.1.1  Definitions......Page 52
3.2.2  Terrestrial Gamma-rays......Page 53
3.3.1  Introduction......Page 55
3.3.2  Polonium-210 in Bone......Page 57
3.3.3  Radium-226 in Bone......Page 59
3.3.5  Discharge and Fallout Sources......Page 60
3.3.6  Bone Surface Retention of Alpha-radionuclides......Page 61
3.3.7  Alpha-radionuclides in Teeth......Page 63
3.3.9  Distribution of Cells at Risk in the Foetus......Page 67
3.3.10  Environmental and Geographical Features of Long-lived Alpha-radionuclides in Bones and Teeth......Page 72
3.4.1  Introduction......Page 74
3.4.2  Radon- and Thoron-derived Dose to Bone Marrow......Page 75
3.4.3  Radon and Thoron Dose to the Foetus......Page 76
3.4.4  Spatial and Number Distribution of Fat Cells in Bone Marrow......Page 77
3.4.5  Distribution of Cells at Risk in Bone Marrow......Page 79
3.4.6  Radon and Leukaemia......Page 80
3.5.3  Radium Dial Painters......Page 81
3.5.4  Thorotrast Patients......Page 82
3.6.1  Various Groups Monitored for Exposure to Ionising Radiation......Page 83
3.7.1  Diagnostic X-Rays......Page 84
3.7.3  Radiation Therapy......Page 85
3.7.4  Obstetric X-rays and Childhood Cancers......Page 86
References......Page 87
4 Response of Bone Marrow to Low LET Irradiation......Page 92
4.1.1  Haemopoietic Responses......Page 93
4.1.2  LD50/30......Page 94
4.1.3  Haemopoietic Progenitor Cell Radiosensitivity......Page 97
4.1.4  Marrow Stromal Radiosensitivity......Page 101
4.1.5  Cell Population Recovery......Page 102
4.2.2  Fractionated Doses......Page 103
4.3.2  Partial Body Irradiation......Page 104
4.3.4  Radionuclides......Page 105
4.4  Residual Injury......Page 107
References......Page 109
5  Effects of High LET Irradiation on Haemopoiesis......Page 115
5.1  Introduction......Page 116
5.2  High LET Dose Distribution and its Relationship to Bone Marrow Cell Distribution......Page 117
5.2.1  Bone Marrow Cell Populations......Page 118
5.2.2.1  Haemopoietic tissue......Page 119
5.2.2.2  Stromal tissue......Page 124
5.3.1  Uptake, Transfer and Retention of 239Pu......Page 125
5.3.2  Effects on Haemopoiesis......Page 126
5.5   Preconceptual Paternal Contamination......Page 127
5.6  Radiation Dose Effectiveness of Alpha-particle Emitters......Page 128
5.8.1  Neutrons......Page 129
5.9  Implications for Leukaemia (and Osteosarcoma)......Page 130
References......Page 131
6 Experimental Approaches for Therapeutic Treatment of Radiation-induced Haemopoietic Injury......Page 136
6.1.1  Critical Factors in Survival......Page 137
6.1.2  Stem Cell Heterogeneity......Page 138
6.2.1  Modification of Morbidity and Mortality through the use of Antibiotics, Platelet and Whole-blood Transfusions......Page 139
6.3.1  Current Generation: Single Cytokine Protocols......Page 141
6.3.1.1  Cell viability and survival......Page 142
6.3.1.2  Granulopoiesis: G-CSF, GM-CSF......Page 143
6.3.1.3  Megakaryocytopoiesis and thrombocytopoiesis: IL-3, IL-6, IL-11, LIF, OSM......Page 147
6.3.2  Current Generation: Combined Cytokine Protocols......Page 151
6.3.2.1  IL-3 plus GM-CSF......Page 152
6.3.2.2  IL-6 plus IL-3......Page 153
6.3.2.3  IL-6 plus GM-CSF, G-CSF......Page 154
6.3.2.5  Fusion proteins......Page 155
6.3.3.1  MGDF/TPO......Page 156
6.3.3.3  Synthokines......Page 158
6.4.1  Peripheral Blood-derived Stem Cells......Page 159
6.4.2  Ex vivo Expansion of Haemopoietic Cells......Page 162
6.4.3  Cord Blood-derived Stem Cells......Page 164
6.5  Conclusions......Page 165
References......Page 166
7 Clinical Approaches to Treatment of Radiation-induced Haemopoietic Injury......Page 183
7.1.1  Introduction......Page 185
7.1.2  High-dose Total-body Medical Irradiation......Page 186
7.1.3  Total-body Accidental Irradiation......Page 187
7.1.3.1  Bone marrow transplantation for treatment of accidental radiation-induced aplasia......Page 188
7.1.3.2  Growth factor therapy for treatment of accidental radiation-induced aplasia......Page 190
7.1.3.3  Transfusion therapy for treatment of accidental radiation-induced aplasia......Page 191
7.1.4  Comparison of Medically Irradiated Patients and Accidentally Overexposed Individuals......Page 192
7.1.5  Main Medical Issues......Page 194
7.2.1  Clinical and Biological Features......Page 196
7.2.2.2  Nature, type and size of the source......Page 198
7.2.3.1  Physical dosimetry......Page 199
7.2.3.2  Biological dosimetry......Page 200
7.2.4  Practical Consideration for Triage......Page 204
7.3.1  Prevention and Treatment of Infection......Page 205
7.3.3  Blood Products......Page 206
7.3.4  Associated Local Radiation Injury......Page 207
7.4.2.1  General background......Page 208
7.4.2.2  Complications......Page 209
7.4.2.3  New trends......Page 211
7.4.3.1  General......Page 212
7.4.3.2  Current situation......Page 213
7.4.3.3  New trends......Page 216
7.5  Combined Injury Complications......Page 217
7.6.1  Prolonged Hypoplasia......Page 219
7.6.2  Radiation-induced Leukaemia......Page 220
7.6.4  New Trends......Page 221
References......Page 222
8  The Pathogenesis of Leukaemia......Page 228
8.2  Haemopoietic Malignancies......Page 229
8.3  The Leukaemias......Page 230
8.4  Clonality and Lineage Studies......Page 233
8.5  The Emergence of a Dominant Leukaemic Clone......Page 234
8.6  Biology of Chronic Myeloid Leukaemia......Page 235
8.7  Biology of Acute Leukaemias......Page 238
8.8  Experimental Radiation Leukaemogenesis......Page 241
8.9  Radiation-induced Genomic Instability......Page 244
References......Page 246
9 Genetic Effects of Ionising Radiation with respect to Leukaemia......Page 254
9.1  Introduction......Page 256
9.3  Mechanisms of Leukaemogenesis......Page 258
9.3.1  Initiation, Promotion and Progression......Page 259
9.3.3  Mutations......Page 260
9.4  Radiation-induced Leukaemia......Page 262
9.5  Heredity and Heritability......Page 264
9.5.2  Dominant, Recessive and X-linked Disorders......Page 265
9.5.3  Heredity and Radiation-induced Leukaemia......Page 266
9.5.4  Germ Cell Mutation and Leukaemia......Page 267
9.6.1  Imprinting......Page 268
9.6.2  Fragile Sites and Dynamic Mutation......Page 269
9.7  Multifactorial Inheritance—Quantitative Traits......Page 270
9.8  Predisposition and Susceptibility......Page 271
9.9.1  Family Studies......Page 272
9.9.3  Consanguinuity......Page 273
9.10  Chromosomal and Congenital Abnormalities......Page 274
9.11.1  Bone Marrow Failure, Genetic Instability and Primary Immunodeficiency......Page 275
9.11.2  Inherited Cancer......Page 277
9.12  Conclusions......Page 278
References......Page 279
10  Experimental Radiation Leukaemogenesis......Page 286
10.1  Early Studies on Radiation Leukaemogenesis......Page 287
10.2  Morphological Appearances and Properties of Experimental Radiation-induced Leukaemias......Page 288
10.3  Radiation Dose-Response Relationships for Different Leukaemias......Page 290
10.4  Influence of Age at Exposure on Leukaemia Incidence......Page 293
10.5  Radiation-induced Leukaemia following Exposure to High LET Radiations......Page 294
10.6  Radionuclide Induction of Leukaemias......Page 295
10.7  Effects of Fractionation and Dose Rate of Exposure......Page 296
10.8  Treatments which Modify Leukaemia Induction......Page 297
10.10  Leukaemia Induction in vitro......Page 299
10.11  Potential Leukaemic Cells in Experimental Leukaemias......Page 300
10.12  Summary......Page 302
References......Page 303
11  Human Studies in Radiation Leukaemogenesis......Page 307
11.2  The Life Span Study of Atomic Bomb Survivors......Page 308
11.3  Studies of Medically Irradiated Populations......Page 312
11.4  Occupational Exposures......Page 317
11.5  Studies of Diagnostic X-rays......Page 318
11.6  Leukaemia Risks following Exposure to High LET Radiation......Page 319
11.7  Effects of Environmental Exposures......Page 320
References......Page 321
Index......Page 323