Transcript Biological Dosimetry in Radiation Accidents.

Biological Dosimetry in Radiation Accidents
Andrzej Wojcik
Department of Radiobiology and Health Protection
Institute for Nuclear Chemistry and Technology
Warszawa
Department of Radiobiology and Immunology
Insitute of Biology
Swietokrzyska Academy
Kielce
Why is it important to perform biological dosimetry
in case of a radiation accident?
Phases of the Acute Radiation Syndrome
P. Gourmelon et al. 2004
The principle of biological dosimetry
Biological dosimetry is a method of dose assessment on the
basis of radiation-induced damage in the body
The methods
• Chromosomal Aberrations and Micronuclei in peripheral blood
lymphocytes. Application: whole- and partial-body exposure
• Electron paramagnetic resonance (EPR)
Application: teeth, bones – partial body exposure
Both methods rely on comparing the results of a measurement
with a calibration curve that is generated under in vitro conditions
The material of choice for biological dosimetry
is the human peripheral blood lymphocyte
 Lymphocytes circulate around the body, so some of them are always
exposed even in cases of partial-body exposure
 Lymphocytes can be collected easily
 Lymphocytes are to over 95% in the resting phase G0
The principle of blood lymphocyte culture
Phytohaemaglutinine
Colcemid
culture time = 48h
culture time = 72h
Analysis of micronuclei
Cytochalasin B
harvest
slide praparation
staining
Analysis of chromosomal aberrations
A mitotic cell with chromosomal aberrations
ace
dic
?
Analysis of chromosomal aberrations by
fluorescence in situ hybridization (FISH)
reciprocal
translocation
chromosome 14
chromosome 2
chromosome 8
The frequency of radiation-induced aberrations
is the same in lymphocytes exposed under
in vivo and in vitro conditions
0 – 3 Gy
A calibration curve
0 – 3 Gy
Dose (Gy)
Is it better to analyse unstable aberrations like
dicentrics or stable aberrations like translocations?
initial damage
Dicentric
Translocation
Dicentric
restitution
Micronucleus
Translocation
How stable with time are dicentrics and
translocations?
Frequencies of aberrations as function of time post exposure
K. Buckton et al., 1983
Aberrations in Lymphocytes of patients with Morbus Bechterew
who were treated with radiotherapy
Percent
cells with dicentrics
cells with translocations
t1/2 = 3 years
Years after exposure
Frequency of dicentrics remains stable for several weeks
that of translocations – for several years
How to detect partial-body exposure
Distribution of radiation-induced dicentrics
Whole body
exposure
Example of a distribution
Number of
aberrations
0
1
2
3
4
5
Partial body
exposure
Number
of cells
70
24
5
0
0
0
m = 0,34 ab/cell
Poisson distribution
var
m =1
(dispersion index, relative variance)
Overdispersed distribution
var
m >1
The degree of deviation from a Poisson distribution allows
to assess the size of the exposed part of the body
11 young frontier guards were exposed to one or
several sources of Cs-137 not exceeding 150 GBq
at the Lilo military training center 20 km
to the east of Tbilisi, from mid 1996 - mid 1997.
Autumn 1997:
7 soldiers were treated in Ulm, Germany
4 soldiers were treated inParis, France
Problem 1: partial body exposure, Problem 2: chronic exposure
ad 1. Dolphin or Qdr methods: allow the reconstruction of dose received by
blood which was exposed and the part of the body which was exposed.
ad 2. G-function: Dose response relationship: Y = aD + bD2
A coefficient G is added to the parameter b, reducing it to 0, when the DNA repair time exceeds the
irradiation time (> 6 hours). The dose-effect curve becomes Y = aD + (Gx)bD2 , where x = t/t0
with t being the time over which the radiation occurred and t0 the mean lifetime of breaks
Patient
Acute dose
(Gy)
Dolphin
(Gy)
Percent of
lymphocytes
irradiated
Qdr
(Gy)
Function G
(Gy)
AN
1.2 ± 0.2
2.3
0.40
2.8
3.1 ± 0.8
EP
1.6 ± 0.3
2.5
0.50
3.4
4.3 ± 1.0
4.5  0.3
CG
0.7 ± 0.2
-
-
-
1.0 ± 0.5
1.4  0.4
TK
0.5 ± 0.2
-
-
-
0.7 ± 0.4
1.5  0.2
EPR
-
The Tokaimura criticality accident
September 30, 1999, uranium conversion test plant of JCO Co. Ltd. in Tokai-mura, 115 km northeast
from the center of Tokyo. Three workers (A, B and C) were involved in the process of enriching U-235.
The criticality chain reaction started when B was pouring uranyl nitrate solution into a tank
through a peephole, while A who was standing beside the tank supported the funnel that
was inserted into that hole. C, the supervisor, was in the next room.
The problem: extremely high dose, causing mitotic delay of lymphocytes
solution: Premature Chromosome Condensation - PCC
Phytohaemaglutinine
okadaic acid
calyculin A
culture time = 48h
harvest
slide praparation
staining
G2 PCC
S PCC
Frequencies of PCC-aberrations in lymphocytes of Tokaimura victims
14
Aberrations per cell
12
24.5 GyEq
(16 - 30)
Caclulated doses
10
8
6
8.3 GyEq
(6.9 - 10)
4
3.0 GyEq
(2.8 - 3.2)
2
0
worker A
worker B
worker C
Doses confirmed by measurement of 24Na (22Na → 24Na)
Worker A died after 81 days, worker B after 210 days. Patient C is alive.
Biological dosimetry in accidents during radiotherapy
Problem:
• Extreme partial-body exposure
• Effect of fractionated doses before accidental exposure
In none of the accidents that occurred since the 70-ties until
the Bialystok accident was it necessary to apply biological
dosimetry for dose reconstruction
The radiological accident at the Białystok Oncology Center
27th February 2001
5 patients treated
for mamma Ca
(post-operative RT)
were exposed to
a single dose of
8 MeV electrons
patient
number
Dose measured by the physicist immediately
after the accident: 103 Gy
Validity of measurement questioned by the
manufacturer of the accelerator
1
2
3
4
5
number
of fractions
received
before
accident
1
24
10
21
2
Problem 1: no appropriate calibration curve available
Dose effect curves for aberrations and micronuclei in lymphocytes irradiated
in vivo (radiotherapy patients) and in vitro
Venkatachalam et al. Mutat. Res. 1999
100
in vitro dicentrics - dashed line
in vitro micronuclei - solid line
Frequency per 100 cells
80
in vivo dicentrics - dashed line
in vivo micronuclei - solid line
60
40
20
0
0
1
2
3
4
Dose (Gy)
Solution:
Analysis of aberrations in lymphocytes
of5 breast 6cancer patients
undergoing
a
7
8
correct radiotherapy
Problem 2: how to bring the doses absorbed during
therapy to a common denominator
Absorbed Dose vs Equivalent Whole Body Dose
Absorbed dose =
absorbed energy (J)
mass (kg)
Ein
Eex
1 Gy = 1 Joul / kg
Equivalent whole body dose (EBWD)
EWBD =
absorbed energy (J)
body mass (kg)
1 Gy EWBD = Σ J / body mass
Ein
Eex
Frequency of aberrations
The idea behind the strategy of comparing the aberration frequencies
found in lymphocytes of accident patients with the dose-response
curve plotted on the basis of data from properly treated
breast cancer patients
Accident dose
EWBD
Dose-response curves for accident patients and
for control (properly treated) breast cancer patients
50
Accident patients
Control patients
A2
Dicentrics per 100 cells
40
A4
30
C7
20
A3
10
A1 A5
0
0
1
2
3
4
5
EWBD (Gy)
Wojcik et al. Radiation Research 160: 677-683, 2004
The principle of Electron Paramagnetic Resonance EPR
Bone = hydroxyapatite crystals Ca10(PO4)6(OH)2 bound by collagen
The paramagnetic centres occur in carbonated apatites
= hydroxyapatite crystals where some of the OH- or PO43- have been replaced
by carbonate ions CO32-
Bone tissue can contain up to 8% of these. Tooth enamel - more.
t ½ = 160 000a
CO2-
EPR: Electron Paramagnetic Resonance
example of an extrapolation curve
Dose estimation by EPR
Accident doses received by Patients 3, 4 and 5 estimated at a tissue depth
of 1.9 cm (dmax of 8 MeV electrons). The bottom line values were derived from the
physical measurement perfomed by the local medical phisics team immediatelly
after the accident.
Patient 3
frontal position
distal position
59  7
67  8
calculation based
on physical
measurement
103  9
Patient 4
Patient 5
64  11
84  19
71  3
78  5
83  9
103  9
Bialystok accident: frequencies of chromosomal
aberrations and doses estimated by EPR
Patient 3
EPR analysis
52 - 76 Gy
Patient 5
EPR analysis
68 - 83 Gy
Patient 2
?
50
Accident patients
Control patients
A2
Dicentrics per 100 cells
40
A4
Patient 4
EPR analysis
53 - 103 Gy
30
C7
20
A3
10
A1 A5
Patient 1
??
0
0
1
2
3
4
5
EWBD (Gy)
Wojcik et al. Radiation Research 160: 677-683, 2004