Radiobiology and bioeffect-models CRISTER CEBERG

Transcription

1 Radiobiology and bioeffect-models CRISTER CEBERG

2 Radiobiology» Molecular and cellular level» Stochastic effects Hereditary effects Cancer» Deterministic effects» Effects on embryo and fetus

3 Radiobiology» Molecular and cellular level» Stochastic effects Hereditary effects Cancer» Deterministic effects» Effects on embryo and fetus

4 Large time scale

5 Physical interactions

6 Physical interactions

7 ICRU 85 (2011)

8 LET depends on type of radiation

9 LET depends on energy

10 Lineal energy

11 Comparison between photons and neutrons

12 Chemical interactions

13 Radiolysis of water

14 Radiation affects important biomolecules Levy et al., Crit Rev Oncol 85:278, 2013

15 Direct and indirect action

16 Double strand break (DSB)

17 Double strand break (DSB)

18 Double strand break (DSB) DSB Chromosome break

19 DNA damage and repair

20 DSB repair HRR: Homologous Recombination Repair NHEJ: Nonhomologous End Joining

21 Multiple DSBs 1 Gy produces about 50 DSB per cell

22 Multiple DSBs A B

23 Multiple DSBs A B

24 Cell cycle checkpoints

25 Cell cycle checkpoints Genetic mutations

26 Heritable effects» Heritable effects have only been observed in animal populations exposed to relatively high doses of radiation» However, ionizing radiation is known to be mutagenic, and experimental studies in plants and animals have clearly demonstrated that radiation can induce genetic effects» Heritable effects are also presumed to occur in humans

27 Cancer Crude incidence of leukaemia per 10,000 males per annum following radiotherapy for ankylosing spondylitis Derived from Radiation Physics with Applications in Medicine and Biology 2nd ed Norman Dyson Dose (Gy) d from Radiation Physics with Applications in Medicine and Biology, 2nd ed Norman Dyson 199

28 Cancer Breast Cancer (Hiroshima and Nagasaki) Health Physics Vol 41 No 4 October 1981 pp (100 rad = 1 Gy)

29 Cancer Thyroid cancer incidence rate in children exposed before the age of 14 years as a result of the Chernobyl accident (1986) UNSCEAR 2000

30 Cancer Doses where cancers have been observed Doses of relevance in radiation protection

31 Cell cycle checkpoints Genetic mutations Cell death

32 Cell death Mitotic catastrophe Apoptosis Resting state

33 The linear-quadratic (LQ) model A B

34 The linear-quadratic (LQ) model S e D D 2

35 Variation over the cell cycle

36 Dose-rate effect

37 LET effect

38 Relative biological effect (RBE) RBE=D x /D n

39 RBE and LET

40 The basis for fractionated radiotherapy

41 Oxygen effect OER=D hyp /D O2

42 Oxygen effect

43 Oxygen effect

44 Experimental cell survival curves

45 Low-dose sensitivity

46 From cells to tissue

47 Effect on a cell population» A cell population consists of N 0 clonogenic cells» Cell death is a binary process, i.e. the probability for exactly N surviving cells is given by the bionomial distribution: P(N) N! N!(N N)! N N0 S ( 1 S) 0 N 0 2 where S e D D

48 Effect on a cell population N/N 0 S

49 Tumour control probability» The binomial distribution can be approximated by a Poisson distribution For large N 0, which is applicable to a tumour For small S, which is relevant for tumour control P(N)» For tumour control, all clonogenic cells should be eradicated, i.e. N=0 P( 0) e e N 0 S N S (N0S) N! (N S) 0! N 0 0 D D 2 0 N0S N0e N0 e e e e nd( d)

50 Tumour control probability» Tumour Control Probability (TCP) TCP TCP( D) e N 0 e nd ( d ) D

51 Normal tissue response» The probability for normal tissue complication (NTCP) can be determined for a certain end-point Specified type and grade of damage Frequency as a function of dose NTCP D

52 From cells to tissue» Tissues and organs Consist of different cell populations Different effects in different parts» Cells with high sensitvity No differentiation Divide regularly» Cells with low sensitivity Highly differentiated Do not divide

53 Michalowski s tissue classification» Hierarchal tissue type (H-type)» Flexible tissue type (F-type)

54 Michalowski s tissue classification» Hierarchal tissue type (H-type) Stem cells: Constanctly dividing, a source of new undifferentiated cells Partially differentiated cells: Divides regularly, migrates from stem cell niche to final destination Functional cells: Fully differentiated, do not divide, dies after certain (varying) time» Erythrocytes: about 4 months» Epidermis: about 4 weeks» Intestinal epithelium: about 4 days» Display early (acute) radiation effects

55 Early (acute) effects» Stem cells are killed» Differentiated cells are not replaced» Appear after a few days or weeks» Recovery is possible if the stem cell population is repopulates» Example Bone marrow/blood Skin Intestines

56 Bone marrow/blood

57 Bone marrow/blood

58 Epidermis

59 Intestinal epithelium

60 Michalowski s tissue classification» Flexible tissue type (F-type) Contains functional cells without internal hierarchy Rarely divide Can be activated Extra cellular network (connective tissue) Contains vasculature» Display late radiation effects

61 Late effects» Killing of slowly dividing or resting cells» Damage on vasculature is important» Appears after months or years» Will not recover» Examples Lung Kidney Liver CNS

62 Vascular damage» Oxidative stress Initially through radiolysis Maintained by damaged cells» Inflammatory response Macrophages» Chronic inflammation Plaque Atherosclerosis» Consequences Atrophy Infarction

63 Vascular damage» Radiation induced Oxidative stress Chronic inflammation» Stimulates revascularisation Capillary malformation Telangiectasia Bleeding

64 Fibrosis» Radiation induced Oxidative stress Chronic inflammation» Stimulates fibroblasts Produces collagen Scar formation Fibrotic tissue

65 CNS» Slow turnover Differentiated neuron do not divide Glial cells divide very seldom Necrosis» Late effects may take many years to develop Vascular damage Cognitive consequences» Children can get cognitive damage to the growing brain Radiation sensitive stem cells

66 Cataract» Cataract is a natural part of ageing Epithelial stem cells divide all life Progenitors for lens fibers to the eye lens No system for destruction of damaged lens fibers Damaged lens fibers accumulate at the posterior pole This makes the lens increasingly opaque

67 Cataract» Radiation Radiation damages advance this process Latency time can be many years, depending on dose A treshold dose of about 5 Gy of acute exposure, >8 Gy in fractionated radiotherapy

68 Acute Radiation Syndrome (ARS)» In accidents with high doses acute effects dominate» Experience mainly from animal experiments» Human data are scarce, for instance Nuclear weapons tests Atomic bombs in Japan Accidents in nuclear power plants Radiotherapy» About 400 persons have died due to ARS

69 Increasing dose Prodromal phase» Initial symptoms occur at about D>0.1 Gy Decrease in circulating lymphocytes can be observed in blood samples Increased risk for infections» Gastrointestinal symptoms (several Gy) Anorexia, nausea, vomiting Diarrhea, dehydration» CNS symptoms Fatigue, apathy Low blood pressure, fever, headache

70 Prodromal phase» Prodromal symptoms occur shortly after exposure (min hours) and can last for a couple of days» Below ~1 Gy there are no further effects» At higher doses there will be a latency period before the onset of Hematopoietic syndrome (3-5 Gy) Gastrointestinal syndrome (5-15 Gy)» Above ~15 Gy, the prodromal syndrome may develop into the CNS syndrome without latency

71 Hematopoietic syndrome» Sensitivity Associated with doses between 3 5 Gy Latency period of about 1 3 weeks» Effect Sterilisation of blood stem cells (HSC) Loss of differentiated blood cells Recovery by repopulation of HSC

72 Hematopoietic syndrome» Symptoms Chills, fatigue Capillary bleeding, oral mucosa Hair loss» Mortality Bleeding due to loss of thrombocytes Infections due to supressed immune system LD 50 =4 Gy Death occurs between days

73 Hematopoietic syndrome» Chernobyl 203 workers were exposed at D>1 Gy 35 had severe hematopoietic syndrome 13 deceased, while the rest recovered

74 Gastrointestinal syndrome» Sensitivity Associated with doses between 5 15 Gy Latency period 6 9 days» Effect Sterilisation of stem cells in the intestinal epithelium Depletion of intestinal villi Recovery by repopulation of crypt cells

75 Gastrointestinal syndrome» Symptom Nauesa, vomtiting Diarrhea Early and persistant diarrhea indicates D>10 Gy» Mortality Dehydration Intestinal bleeding At D>10 Gy death occurs within 7-20 days

76 Gastrointestinal syndrome» Chernobyl Patients who received one marrow transplantation died due to gastrointestinal syndrome within 7-10 days

77 CNS syndrome» Sensitivity At D>15 Gy there is no latency period There is no time to develop neither hematopoietic nor gastrointestinal syndrome» Effects Damage to micro-vasculature in the brain Intracerebral bleedings

78 CNS syndrome» Symptoms Severe nausea, vomiting Diarrhea Dyspnea Disorientation Convulsions Coma» Mortality Only few cases are known Death occurs within less than 5 days

79 Skin damage» Skin damage can be dominating For non-penetrating radiation (e.g. electrons) For spatially limited exposure» Prodromal symptoms above 2 Gy Itch, pain, oedema Onset in hours to days, lasts for a couple of days Latency period of 1 5 weeks Above D>40 Gy there is not latency

80 Increasing dose Skin damage» Cutaneous Radiation Injury (CRI) Oedema, pain, heat sensation Increased pigmentation Skin desquamation, hair loss Moist desquamation, necrosis» Recovery possible at D<20 Gy» Remaining damage (apart from increased cancer risk) Chronic wounds Teleangiectasia Atrophy, fibrosis

81 Treatment of radiation damage» With adequate medical care LD 50 can be increases to about 7 Gy» Symptomatic treatment Pain relief Platelet transfusion Antibiotics» At about 8-10 Gy bone marrow transplantation can be indicated At lower dose the risk for immunologic rejection is too high At higher dose the risk for death due to GI is too high There may be a window at around 8 10 Gy

82 Effects on embryo and fetus» Three different types of effects Prenatal or neonatal death Malformations Growth and mental retardation» Three phases of pregnancy Pre-implantation Organogenesis Fetus

83 Effects on embryo and fetus» Animal experiments (mice)» Atomic bomb victims in Japan» Radiotherapy patients

84 Effects on embryo and fetus

85 Pre-implantation phase

86 Pre-implantation phase» Effect Cell death leads to» Implantation does not occur» Prenatal death With enough surviving cells, implantation occurs and the pregnacy proceeds normally» Risk for prenatal death Large risk at D>1 Gy In humans, the risk is very low below D<0.1 Gy

87 Organogenesis» Effect Malformations Type depends on exact time for exposure Temporary growth retardation at D>0.25 Gy Neonatal death at higher doses» Risk for malformation Threshold dose about Gy Reaching maximum levels at 2 Gy

88 Organogenesis

89 Fetus» Effects» Risk Radiation limits proliferation, differentiation and migration and may lead to growth retardation and/or mental retardation Threshold dose of about Gy Depends on time of exposure» Week 0-15 microcefali» Week 8-25 mental retardation» Also risk for ARS and cancer

90 Radiotherapy of pregnant women» Pregnant women may receive radiotherapy Acute illness Pregnancy is not known (kept secret?)» If the absorbed dose to the fetus is >0.1 Gy Damages are very probable Risk for both mother and fetus» Alternatives Wait until after birth (if known) Advanced delivery Abortion (if it is an option)

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