RADIATION PROTECTION IN NUCLEAR MEDICINE

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RADIATION PROTECTION IN NUCLEAR MEDICINE

• Part 1 Biological effects of
• ionizing radiation

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OBJECTIVE
To become familiar with the mechanisms of
different types of biological effects following
exposure to ionizing radiation and results of
epidemiological studies of exposed population to
ionizing radiation. To be aware of the models
used to derive risk coefficients for estimating
the detriment
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CONTENT

• Basic concepts, cellular effects
• Deterministic effects
• Stochastic effects
• Effects on embryo and fetus
• Risk estimates

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Part 1. Biological effects

• Module 1.1. Basic concepts

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Early Observations of the Effects of Ionizing
Radiation

• 1895 X-rays discovered by Roentgen
• 1896 First skin burns reported
• 1896 First use of x-rays in the treatment of
  cancer
• 1896 Becquerel Discovery of radioactivity
• 1897 First cases of skin damage reported
• 1902 First report of x-ray induced cancer
• 1911 First report of leukaemia in humans and
  lung cancer from occupational exposure
• 1911 94 cases of tumour reported in Germany
  (50 being radiologists)

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Effects of Radiation Exposure

• Information comes from
• studies of humans (epidemiology)
• studies of animals and plants (experimental
  radiobiology)
• fundamental studies of cells and their
  components (cellular and molecular biology)
• The key to understanding the health effects of
  radiation is the interaction between these
  sources of information.

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Radiation exposure affects the center of life
the cell
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The critical target DNA
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Interaction of ionizing radiation with DNA
DIRECT ACTION
INDIRECT ACTION
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Damage to DNA
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Exposure of the cell
No change
radiation hit cell nucleus!
DNA mutation
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Outcomes after cell exposure
Viable Cell
Mutation repaired
Unviable Cell
Cell death
Cancer?
DNA Mutation
Cell survives but mutated
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How is DNA repaired?
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Altered base
Enzyme Glycosylases recognizes lesion and
releases damaged base
AP-endunuclease makes incision and releases
remaining sugar
DNA-polymerase fills resulting gap but nick
remains
DNA ligase seals the nick. Repair completed.
DNA has been repaired with no loss of genetic
information
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Repair
The human body contains about 1014 cells. An
absorbed dose of 1 mGy per year (natural sources)
will produce about 1016 ionizations, which means
100 per cell in the body. If we assume that the
mass of DNA is 1 of the mass of the cell, the
result will be one ionization in the DNA-molecule
in every cell in the body each year.
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order of magnitudes

• 999 of 1000 lesions are repaired
• 999 of 1000 damaged cells die (not a major
  problem as millions of cells die every day in
  every person)
• many cells may live with damage (could be mutated)

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Cell killingRadiosensitivity

• RS Probability of a cell, tissue or organ of
  suffering an effect per unit of dose.
• Bergonie and Tribondeau (1906) RS LAWS RS
  will be greater if the cell
• Is highly mitotic.
• Is undifferentiated.

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RADIOSENSITIVITY
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Biological effects at cellular level

• Possible mechanisms of cell death
• Physical death
• Functional death
• Death during interphase
• Mitotic delay
• Reproductive failure

Cellular effects of ionizing radiation are
studied by cell survival curves
Exponential
n targets
survival cells (semi logarithmic)
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Dq
(threshold)
D0
(radiosensitivity)
Dose
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Factors affecting radiosensitivity

• Physical
• LET (linear energy transfer) ? RS
• Dose rate ? RS
• Temperature ? RS
• Chemical
• Increase RS OXYGEN, cytotoxic drugs.
• Decrease RS SULFURE (cys, cysteamine)
• Biological
• Cycle status
• ? RS G2, M
• ? RS S
• Repair of damage (sub-lethal damage may be
  repaired e.g. fractionated dose)

survivor cells
? LET
? LET
G0
M
G1
G2
S
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CELL SURVIVALRadiation quality
low LET
Surviving fraction
low LET
high LET
high LET
Absorbed dose
LET (linear energy transfer) is the amount of
energy (MeV) a particle will loose in
traversing a certain distance (m) of a material.
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IONIZATION PATTERN
Adapted from Marco Zaider (2000)
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BIOLOGICAL EFFECTS
Direct effects
Indirect effects
Repair
Primary damage
Cell death
Modified cell
Damage to organ
Somatic cells
Germ cells
Hereditary effects
Cancer Leukemia
Death of organism
Deterministic effects
Stochastic effects
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Timing of events leading to radiation effects
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Part 1. Biological effects

• Module 1.2. Deterministic effects

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EFFECTS OF CELL DEATH
Probability of death
100
Dose (mSv)
D
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Deterministic effects


SEVERITY
Most radiosensitive
Most radioresistant


individual
individual
Diagnostic


threshold


FREQUENCY
Threshold


ABSORBED DOSE


dose
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Threshold Doses for Deterministic Effects

• Cataracts of the lens of the eye 2-10 Gy
• Permanent sterility
• males 3.5-6 Gy
  
• females 2.5-6 Gy
• Temporary sterility
• males 0.15 Gy
• females 0.6 Gy

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Note on threshold values

• Depend on dose delivery mode
• single high dose most effective
• fractionation increases threshold dose in most
  cases significantly
• decreasing the dose rate increases threshold in
  most cases
• Threshold may differ in different persons

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Systemic effects

• Effects may be morphological and/or functional
• Factors
• Which Organ
• Which Dose
• Effects
• Immediate (usually reversible) lt 6 months e.g.
  inflammation, bleeding.
• Delayed (usually irreversible) gt 6 months e.g.
  atrophy, sclerosis, fibrosis.
• Criteria of dose
• lt 1 Gy LOW DOSE
• 1-10 Gy MODERATE DOSE
• gt 10 Gy HIGH DOSE
• Regeneration means replacement by the original
  tissue while Repair means replacement by
  connective tissue.

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Skin effects

• Following the RS laws (Bergonie and Tribondeau),
  the most RS cells are those from the basal
  stratum of the epidermis.
• Effects are
• Erythema 1-24 hours after irradiation of about
  3-5 Gy
• Alopecia 5 Gy is reversible 20 Gy is
  irreversible.
• Pigmentation Reversible, appears 8 days after
  irradiation.
• Dry or moist desquamation traduces epidermal
  hypoplasia (dose about 20 Gy).
• Delayed effects teleangiectasia, fibrosis.

Histologic view of the skin
From Atlas de Histologia.... J. Boya
Basal stratum cells, highly mitotic, some of them
with melanin, responsible of pigmentation.
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Skin effects
Skin damage from prolonged fluoroscopic exposure
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SKIN EFFECTS
By handling unshielded syringes and vials
containing radioactive material the threshold
dose of skin erythema will be reached in a short
time. Example The dose rate at the surface of a
vial containing 30 GBq Tc99m is of the order of 2
Gy/h meaning that the threshold dose will be
reached after 2 h of exposure. This corresponds
to 36 s per working day in a year
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SKIN EFFECTS
Example After an extravascular injection of 500
MBq of a Tc99m radiopharmaceutical, the locally
absorbed dose at the injection site might be as
high as 5-20 Gy!
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Effects in eye

• Eye lens is highly RS.
• Coagulation of proteins occur with doses greater
  than 2 Gy.
• There are 2 basic effects

Histologic view of eye
Sv/year for many years
Sv single brief exposure
Effect
gt 0.1
0.5-2.0
Detectable opacities
gt 0.15
5.0
Visual impairment (cataract)
From Atlas de Histologia.... J. Boya
Eye lens is highly RS, moreover, it is surrounded
by highly RS cuboid cells.
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Eye injuries
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Whole body response adult
Chronic irradiation syndrome

• Acute irradiation syndrome

1-10 Gy

• Whole body clinic of a partial-body irradiation
• Mechanism Neurovegetative disorder
• Similar to a sick feeling
• Quite frequent in fractionated radiotherapy

10-50 Gy
gt 50 Gy
Survival time
BMS(bonemarrow)
GIS(gastrointestinal)
Lethal dose 50 / 30
CNS
(central nervous system)
Dose
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Lethal dose 50 / 30

• It is an expression of the per cent lethal dose
  as a function of time.
• It means Dose which would cause death to 50 of
  the population in 30 days.
• Its value is about 2-3 Gy for humans for whole
  body irradiation.

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Whole body exposure
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Whole body exposure
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Part 1. Biological effects

• Module 1.3. Stochastic effects

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STOCHASTIC EFFECTS OF IONIZING RADIATION
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STOCHASTIC EFFECTS OF IONIZING RADIATION

• Health consequences of Chernobyl accident
• 1800 children diagnosed with thyroid cancer (1998)

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STOCHASTIC EFFECTS OF IONIZING RADIATION
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Genetic effects
Frequency ()
10 5 0
10 20 30 40
Absorbed dose (Gy)
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Genetic Effects

• Ionising radiation is known to cause heritable
  mutations in many plants and animals
• BUT
• intensive studies of 70,000 offspring of the
  atomic bomb survivors have failed to identify an
  increase in congenital anomalies, cancer,
  chromosome aberrations in circulating lymphocytes
  or mutational blood protein changes.

Neel et al. Am. J. Hum. Genet. 1990, 461053-1072
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Part 1. Biological effects

• Module 1.4. Effects on embryo and fetus

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Sensitivity of the early conceptus

• Till early 1980s, early conceptus was considered
  to be very sensitive to radiation - although no
  one knew how sensitive?
• Realization that
• organogenesis starts 3-5 weeks after conception
• In the period before organogenesis high radiation
  exposure may lead to failure to implant. Low dose
  may not have any observable effect.

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Incidence of Prenatal Neonatal Death and
Abnormalities

• Hall, Radiobiology for the Radiologist pg 365

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PRE-IMPLANTATION
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Pre-implant stage (up to 10 days)

• Only lethal effect, all or none
• Embryo contains only few cells which are not
  specialized
• If too many cell are damaged-embryo is resorbed
• If only few killed-remaining pluripotent cells
  replace the cells loss within few cell divisions
• Atomic Bomb survivors - high incidence of both -
  normal birth and spontaneous abortion

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Fetal Radiation Risk

• There are radiation-related risks throughout
  pregnancy which are related to the stage of
  pregnancy and absorbed dose
• Radiation risks are most significant during
  organogenesis and in the early fetal period
  somewhat less in the 2nd trimester and least in
  the third trimester

Most risk
Less
Least
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Radiation-Induced Malformations

• Malformations have a threshold of 100-200 mGy or
  higher and are typically associated with central
  nervous system problems
• Fetal doses of 100 mGy are not reached even with
  3 pelvic CT scans or 20 conventional diagnostic
  x-ray examinations
• These levels can be reached with fluoroscopically
  guided interventional procedures of the pelvis
  and with radiotherapy

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Central Nervous System Effects

• During 8-25 weeks post-conception the CNS is
  particularly sensitive to radiation
• Fetal doses in excess of 100 mGy can result in
  some reduction of IQ (intelligence quotient)
• Fetal doses in the range of 1000 mGy can result
  in severe mental retardation particularly during
  8-15 weeks and to a lesser extent at 16-25 weeks

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Heterotopic gray matter (arrows) near the
ventricles in a mentally retarded individual
occurring as a result of high dose in-utero
radiation exposure
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Effects on embryo and fetus
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Effects on embryo and fetus
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Leukemia and Cancer

• Radiation has been shown to increase the risk for
  leukemia and many types of cancer in adults and
  children
• Throughout most of pregnancy, the embryo/fetus is
  assumed to be at about the same risk for
  carcinogenic effects as children

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Leukemia and Cancer

• The relative risk may be as high as 1.4 (40
  increase over normal incidence) due to a fetal
  dose of 10 mGy
• Individual risk, however, is small with the risk
  of cancer at ages 0-15 being about 1 excess
  cancer death per 1,700 children exposed in
  utero to 10 mGy

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Part 1. Biological effects

• Module 1.5. Risk estimates

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Risk Estimates

• Risk probability of effect
• Different effects can be looked at - one needs to
  carefully look at what effect is considered E.g.
  Thyroid cancer mortality is NOT identical to
  thyroid cancer incidence!!!!
• Risk estimates usually obtained from high doses
  and extrapolated to low doses

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EPIDEMIOLOGICAL DATA FROM Hiroshima-Nagasaki
Patients with ancylosing spondylitis cervical
cancer tuberculosis mastitis tinea
capitis thymus enlargement thyrotoxicosis he
mangiomas and more may come Chernobyl Techa
river Semiplatinsk Nevada ..
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Populations used in the UNSCEAR Reports
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How to use epidemiological data to estimate
radiation risks at low doses?
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Dose-response curve
Frequency of leukemia (cases/1 miljon)
Equivalent dose (mSv)
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Mortality of the Atomic Bomb Survivors

• Dose response curve for Solid Cancer
• The dose response is linear up to about 3 Sv with
  a slope of 0.37 ERR/Sv
• The excess lifetime risk per Sv for those exposed
  at age 30 is estimated at 0.10 and 0.14 for males
  and females respectively
• The lowest dose at which there is a
  statistically significant excess risk is shown
  to be 50 mSv

Pierce DA et al, Rad Res 1996 1461-27
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Latest news from the Hiroshima-Nagasaki
cohortExtra years 1986-1990There are now 10
500 survivors with DS86-dosimetry out of a total
population of 86 572, who were irradiated44
had died by the end of 1990. The data is
incomplete in that deaths in the first five years
are not included. 7 827 have died from cancer,
there being 420 excess cancer deaths. 1945-1950
1950-90 (1986-90)Leukemia ? 87
(3)Solid cancer ? 335
(88)---------------------------------------------
---------------------- 420Risk for
children/Risk for adults 1.4 - 1.7
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RADIATION RISKS
Linear-quadratic model
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What happens at the low-dose end of the graph?

• Linear extrapolation
• Threshold dose
• Lower risk per dose for low doses
• Higher risk per dosefor for low doses

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P AD BD2 P is the probability of cancer
induction
The quotient A/B is called DDREF (Dose and Dose
Rate Effectiveness Factor) and has been assigned
by ICRP the value 2 for low LET radiation, low
doses and low dose rates.
Low doses lt0.2 Gy(Sv) Low dose rates lt 0.1
Gy(Sv)/hour (ICRP) 0.1 Gy(Sv)/day (NCRP)
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Epidemiological Evidence
Linear No-Threshold (LNT) Hypothesis reduced at
low dose and dose rate by a factor of 2 - in
general agreement with data
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CANCER
initiation pre-cancer stage promotion growth
detection metastasis
Elimination and repair
latency period period of suffering death life
time loss
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Carcinogenic Effects

• An assessment of the atomic bomb survivors
  showed
• the leukaemia risk peaked at 10 years after
  exposure
• thyroid cancer was the first solid cancer
  reported
• the incidence of breast cancer was higher in
  young women than older women
• other cancer, with a latent period of up to 30
  years, included lung, stomach, colon, bladder and
  oesophagus

Shimizu et al JAMA 1990, 264601-604
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Variation of Cancer Incidence with time following
the Atomic Bombs
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Variation of Cancer Incidence with time
following the Atomic Bombs
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Time projection models
Lifetime Expression, Comparison ofAbsolute and
Relative Risk Models
Incidence
Incidence
Absolute Risk
Relative Risk
Incidence afterirradiation
Spontaneousincidence
0 xo xol
90 0 xo xol
90
ICRP 60
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RADIATION RISKS
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Risk (/ Sv) for Cancer induction by Age at
exposure and Sex
20 15 10 5 0
Male Female
0 10 20 30 40 50 60
70 80 (age at
exposure)
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Life-time risk of dying from radiation induced
cancer 5 per sievert
UNSCEAR has recently (2000) further assessed the
cancer risk from radiation exposures. For a
population of all ages and both genders, the
life-time risk of dying from radiation induced
cancer after an acute dose of 1000 mSv is about
9 for men and 13 for women or 11 as a mean.
Applying a DDREF of 2, these data confirm the 10
years old ICRP estimate.
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EFFECTS AT LOW DOSES
In the latest Hiroshima-Nagasaki Life Span Study
(1986-1990), LSS Report 12, (Pierce et al., 1996)
find the nominal estimates of risk (5 per Sv) to
apply down to a dose of about 50 mSv. For
childhood cancer following fetal irradiation,
very similar risk estimates (6 per Sv) are found
to apply to doses of 10 mSv (Doll and Wakeford,
1997). The risk estimates and the uncertainties
associated with them are expected to apply at low
doses.
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Uncertainties in fatal cancer risk estimate (5
per Sv)
Frequency chart 100 000 Trials
Shown
Probability
0.027
0.020
0.013
0.007
0.000
0.00
2.75
5.50
8.25
11.0
8.84
1.20
Lifetime Risk Coefficient (/Sv)
Probability distribution of lifetime risk
coefficient. The 90 confidence interval is shown
by the arrows (5 should be read as 1 - 9).
NCRP, 1997
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Uncertainties in fatal cancer risk estimates
Sensitivity chart of uncertainty component
influence (population of all ages) From NCRP, 1997
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Radiation risks - embryo and fetus
Threshold dose deterministic effects 50-100
mSv Mental retardation 40 / Sv Cancer and
leukemia before 10 y of age 2 /
Sv lifetime 15 / Sv Hereditary effects
1 / Sv
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TYPES OF EFFECTS FOLLOWING IRRADIATION IN UTERO
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Radiation risksembryo and fetus
Other reasons 310-3 410-2
710-3 110-3
0.2
Data from
Sweden 1992
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Risks in a pregnant population not exposed to
medical radiation

• Spontaneous abortion gt 15
• incidence of genetic abnormalities 4-10
• intrauterine growth retardation 4
• incidence of major malformation 2-4

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Probability of bearing healthy children as a
function of radiation dose
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Approximate fetal whole body dose (mGy) from
common nuclear medicine procedures done in early
and late pregnancy
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Doses and Risks for in Utero Radiodiagnostics
Exposure Mean foetal dose Hered. Disease
Fatal cancer
(mGy)
to age 14 y X-ray
Abdomen 2.6 6.2 10-5 7.7 10-5 Barium enema
16 3.9 10-4 4.8 10-4 Barium meal 2.8 6.7
10-5 8.4 10-5 IV urography 3.2 7.7 10-5 9.6
10-5 Lumbar spine 3.2 7.6 10-5 9.5
10-5 Pelvis 1.7 4.0 10-5 5.1 10-5 Computed
tomography Abdomen 8.0 1.9 10-4 2.4 10-4 Lumbar
spine 2.4 5.7 10-5 7.1 10-5 Pelvis 25 6.1
10-4 7.7 10-4 Nuclear medicine Tc bone
scan 3.3 7.9 10-4 1.0 10-4 Tc brain
scan 4.3 1.0 10-5 1.3 10-4
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Comment on Fetus/Embryo

• Fetus/embryo is more sensitive to ionizing
  radiation than the adult human
• Increased incidence of spontaneous abortion a few
  days after conception
• Increased incidence
• Mental retardation
• Microcephaly (small head size) especially 8-15
  weeks after conception
• Malformations skeletal, stunted growth, genital
• Higher risk of cancer (esp. leukemia)
• Both in childhood and later life

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Scale of Radiation Exposures
Typical Radiotherapy Fraction
Bone scan
CT scan
Annual Background
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Example for Risk Calculation

• Assume
• Risk of 0.05 per Sv
• 1,000 people are exposed to 5 mSv/y for 20 y
• Expected additional cancer deaths is
• 0.05 cancers/Svx0.005Sv/yx20yx1,000people
• 5 additional cancer deaths due to radiation
  (5/1000)
• General population 23 (230/1000) of all deaths
  due to cancer (difficult to ascertain 5
  additional ones caused by radiation)
• Calculations become more complex for individual
  tissue exposures vs. whole body exposures

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RADIATION RISKS IN X-RAY EXAMINATIONS
Examination Skin dose Effective dose
Risk (mGy)
(mGy) () Urography
30 8 0.04 Lumbar
spine 40 5
0.025 Abdomen 10
2.5 0.013 Chest
2 0.25 0.0013 Extremities
3 0.025
0.00013
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RADIATION RISKS IN NUCLEAR MEDICINE
Examination Radiopharmaceutical
Effective dose Risk
(mSv)
() Myocardium Tl-201
chloride 23
0.12 Bone Tc-99m MDP 3.6
0.018 Thyroid Tc-99m
pertechnetate 1.1
0.006 Lungs Tc-99m MAA 0.9
0.005 Kidney clearance Cr-51
EDTA 0.01 0.00005
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Average Annual Risk of Death in the UK from
Industrial Accidents and from Cancers due to
Radiation Work

These figures can be compared to an estimate of 1
in 17000 for 1.5 mSv/year received byradiation
workers
From L Collins 2000
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Comparison of Radiation Worker Risks to Other
Workers

• Mean death rate 1989
• (10-6/y)
• Trade 40
• Manufacture 60
• Service 40
• Government 90
• Transport/utilities 240
• Construction 320
• Agriculture 400
• Mines/quarries 430

Safe industries ? 2 mSv/y (100 mSv overa
lifetime)

• ? max permissible exposure(20 mSv/year or 1000
  mSvover a lifetime

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RISKS
The following activities are associated with a
risk of death that is 1/1000000

• 10 days work in a nuclear medicine department
• smoking 1.4 cigarette
• living 2 days in a polluted city
• traveling 6 min in a canoe
• 1.5 min mountaineering
• traveling 480 km in a car
• traveling 1600 km in an airplane
• living 2 months together with a smoker
• drinking 30 cans of diet soda

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RISKS
Expected reduction of life
Unmarried man 3500 days Smoking man 2250
days Unmarried woman 1600 days 30
overweight 1300 days Cancer 980
days Construction work 300 days Car
accident 207 days Accident at home 95
days Administrative work 30 days Radiological
examination 6 days
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Questions??
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DISCUSSION

• A woman was referred to a bone scan. After the
  examination she turned out to be pregnant at a
  very early stage. She is extremely worried and
  wants to have an abortion. Discuss how to act.

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DISCUSSION

• Dose fractionation results in
• increased radiation sensitivity for photons?
• decreased radiation sensitivity for photons?
• decreased radiation sensitivity for heavy charged
  particles?
• increased radiation sensitivity for heavy charged
  particles?

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DISCUSSION

• A patient (radiobiologist) wants to know the
  radiation risk he will suffer in an examination
  of the cerebral blood flow (1000 MBq 99mTc).
• What to answer?

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Where to Get More Information

• Other sessions
• Part 2 Radiation Physics
• Further readings
• WHO/IAEA. Manual on Radiation Protection in
  Hospital and General Practice. Volume 1. Basic
  requirements (draft manuscript)
• ICRP publications (41, 60, 84)
• UNSCEAR reports
• ALPEN E.L Radiation Biophysics. Academic Press,
  1998
• RUSSEL, J.G.B., Diagnostic radiation, pregnancy
  and termination, Br. J. Radiol. 62 733 (1989)
  92-3.