DOSE-EFFECT CURVES; DETERMINISTIC AND STOCHASTIC EFFECTS OF RADIATION Module IX

DOSE-EFFECT CURVES;DOSE-EFFECT CURVES;DETERMINISTIC AND STOCHASTIC DETERMINISTIC AND STOCHASTIC

EFFECTS OF RADIATIONEFFECTS OF RADIATION

Module IX

Module Medical IX. 2

Biological effects of radiation Biological effects of radiation in time perspectivein time perspective

Time scale

Fractions of seconds

Seconds

Minutes

HoursDays

WeeksMonths

Years

Decades

Generations

Effects

Energy absorption

Changes in biomolecules(DNA, membranes)

Biological repair

Change of information in cell

Cell death

Organ Clinicaldeath changes

Mutations in a

Germ cell Somatic cell

Leukaemia

or Cancer

Hereditary effects


Radiation effectsRadiation effects

Early(deterministic only)

LocalRadiation injury ofindividual organs:functional and/or

morphologicalchanges withinhrs-days-weeks

Common

Acute radiation disease Acute radiation syndrome(LD50/60 ~ 3.5Sv LD ~ 5 Sv)

Late

Deterministic(Above DQ, cummul.) - Rad. Dermatitis- Rad. Cataracta - Teratogenic

(DQ,F~0,1Sv)

Stochastic(Probability increaseswith dose)- tumours, leukaemia- genetic effects


Det

Deterministic (a) and stochastic (b) effects of Deterministic (a) and stochastic (b) effects of radiationradiation


Sources of data on human effects of Sources of data on human effects of radiation overexposureradiation overexposure

Number x103

1 Occupational exposure 1.1 Early radiologist and medical physicists 1.2 Ra-dial painters 1.3 U-miners, nuclear industry workers

110 10 4 96

2 Medical overexposure 95

3 A-bomb victims 86.5

4 Overexposure due to nuclear weapons test4.1. Inhabitants of Marshall Islands

4.2 Personnel of nuclear weapon tests (NWT) 4.3 Inhabitants living around NWT sites

0.25 ~ 100* ~ 500*

5 Accidents – a) deterministic effects 5.1 Radiation accidents 5.2 Nuclear accidents (Chernobyl) -stochastic effects Registered thyroid cc.

3 2.8 0.2 ~600* 3 (~30M*)

6 Inhabitants of high natural background areas (~60M*)Total number of registered overexposures 300

Note: *Effects of radiation exposure are not proved in these population groups, but studied recently (M - million)


Typical dose-effect relationships for Typical dose-effect relationships for deterministic effects in populationdeterministic effects in population


Threshold doses for some deterministic Threshold doses for some deterministic effects in the most radiosensitive tissueseffects in the most radiosensitive tissues

Bone marrow Depression of 0.5 > 0.4 haematopoesis

Testes

Temporary sterility 0.3 0.4

Permanent sterility 3.5-6.0 2.0

Tissue and Tissue and Total dose Annual dose rate received Total dose Annual dose rate receivedeffects effects single brief single brief in highly fractionated or in highly fractionated or

exposure (Gy) exposure (Gy) protracted exposure protracted exposure for many years (Gy/y)for many years (Gy/y)


Tissue and Tissue and Total dose Annual dose rate Total dose Annual dose rate received in received in received yearly in received yearly in

effectseffects single brief single brief highly fractionated or highly fractionated or exposure exposure protracted exposure protracted exposure (Gy)(Gy) for for

many years (Gy/y) many years (Gy/y)

Threshold doses for some Threshold doses for some

deterministic effectsdeterministic effects

Ovaries

Sterility 2.5-6.0 > 0.2

Lens

Detectable opacities 2.0 > 0.1

Visual impairment 5.0 > 0.4

(cataract)


Time of onset of clinical signs Time of onset of clinical signs of skin injury depending onof skin injury depending on

dose receiveddose received

SymptomsSymptoms Dose range Dose range Time of onset Time of onset

(Gy) (Gy) (day) (day)

Erythema 3-10 14-21 Epilation >3 14-18 Dry desquamation 8-12 25-30 Moist desquamation 15-20 20-28 Blister formation 15-25 15-25 Ulceration >20 14-21 Necrosis >25 >21

Ref.: IAEA-WHO: Diagnosis and Treatment of Radiation Injuries.

IAEA Safety Reports Series, No. 2, Vienna, 1998


Acute radiation syndromeAcute radiation syndrome(ARS)(ARS)

ARS is the most notable ARS is the most notable deterministic effectdeterministic effect of ionizing radiation of ionizing radiation

Signs and symptoms are Signs and symptoms are not specificnot specific for radiation injury but for radiation injury but

collectively highly characteristiccollectively highly characteristic of ARS of ARS

Combination of symptomsCombination of symptoms appears in phases during hours to appears in phases during hours to

weeks after exposureweeks after exposure - prodromal phase- prodromal phase - latent phase- latent phase - manifest illness- manifest illness - recovery (or death)- recovery (or death) Extent and severityExtent and severity of symptoms determined by of symptoms determined by - total radiation dose received- total radiation dose received - how rapidly dose delivered (dose rate)- how rapidly dose delivered (dose rate) - how dose distributed in body (whole vs partial body irradiation) - how dose distributed in body (whole vs partial body irradiation)


Principle syndromes contributing toPrinciple syndromes contributing to death after acute whole body radiation death after acute whole body radiation

exposureexposure

Whole body dose, Gy

Syndrome Time of death after the exposure - days

3-10

bone marrow

30-60

10-30

gastrointestinal tract

10-20

>30

neurovascular system

1-5


Special Special deterministic effectsdeterministic effects

Teratogenic effects of radiationTeratogenic effects of radiation


Frequency of severe mental retardation in prenatally exposed survivors of

A-bombing in Hiroshima and Nagasaki

%

Sv


Microcephaly: Microcephaly: Hiroshima dataHiroshima data

0

5

10

15

20

25

30

35

40

45

0 10-90 100-190 200-290 300-490 500-1490 >1500

Foetal dose, mSv

%


Stochastic effectsStochastic effects

Cancer induction and genetic effects


Phases of cancer induction Phases of cancer induction and manifestationand manifestation

In itia tio n Mu ta te d C e lls

Elim ia tio n Re p a ra tio n

Pro g re ssio n

Pre -c a n c e r

No rm a l C e lls

Pro m o tio n

Min im a l C a n c e r

C lin ic a l C a n c e r

Sp re a d in g


Stochastic Effects of Stochastic Effects of Radiation ExposureRadiation Exposure

Frequency proportional to dose

No threshold dose

No method for identification of appearance of effect of ionizing radiation in individuals

Increase in occurrence of stochastic effects provable only by epidemiological method


Stochastic effects of Stochastic effects of radiation exposureradiation exposure

(continued)(continued)

Stochastic effects observed in animal experiments

Dose-effect relationship for humans can be studied only in human population groups

Dose-effect relationship in low dose range (below 100 mSv) not yet verified

Extrapolation down to zero excess dose accepted only for radiation protection and safety


Human data on Human data on radiation cancerogenesisradiation cancerogenesis

Type or localization of cancer

Populationgroups

Leukemia Thyroidgland

Lung Breast Bone Skin

A-bombsurvivors + + + +Ra-dial painters +Earlyradiologists + +U-miners +

Exposed in anuclearaccident

+


Latency periods for Latency periods for radiation-induced cancerradiation-induced cancer


Risk of leukaemia depending on Risk of leukaemia depending on age at exposure to A-bombage at exposure to A-bomb


1

10

100

1000

10000

10 20 30 40 50 60 70

AGE, years

Leuk

aem

ia

per

mill

ion/

yr

General Population Radiotherapy patients

Age dependency of incidence of leukaemia in British population and radiotherapy patients


Cancer deaths attributableCancer deaths attributable to A-bomb to A-bomb

In 86 572 survivors of Hiroshima and Nagasaki, 7827 persons died of cancer in 1950-90

Observed Expected Excess (%)

All tumours 7578 7244 334 (4.4)

Leukaemia 249 162 87 (35.0)

All cancers 7827 7406 421 (5.4)

Ref: Pierce et al, Rad.Res. 146: 1-27, 1996


DOSE DEPENDENCE OF LEUKAEMIA IN A-BOMB SURVIVORS

0

20

40

60

80

100

120

140

0 0.01-0.49 1.0-1.9 >4.0

ABSORBED DOSE, Gy

LEU

KA

EM

IA C

AS

ES

pe

r 100

,000

per

son

per y

ear

Hiroshima

Nagasaki


Cancer mortality of Cancer mortality of nuclear industry workersnuclear industry workers

Observed/Expected deaths Total Trend

Dose ranges, mSv number test

<10 10- 20- 50- 100- 200- 400- of deaths (p-value)

O/E number of deaths from cancers other than leukemia

2234/

2228.3

462/

465.4

445/

479.6

276/

254.3

196/

190.5

161/

147.6

56/

67.3

3830 -0.28

(0.609)

O/E number of deaths from leukemia other than CLL (chronic lymphocytic leukemia)

60/

62.0

19/

17.2

14/

17.2

8/

9.0

8/

6.4

4/

4.7

6/

2.3

119 1.85

(0.046)

The ERR (excess relative risk) per Sv among the 95,673 nuclear industry workers of Canada, UK and USA (having a mean cumulativedose of 36.6 mSv in the combined cohort for the total period of observation, ie. 34 yrs in the USA and UK, and 29 years in Canada ) is

–0.07 for all cancers excluding leukemia, and 2.18 for leukemia excluding CLL.

Ref.: Cardis, E. et al: Combined Analyses of Cancer Mortality Among Nuclear Industry Workers in Canada, the UK and the USA. IARCTechnical Report No.25, Lyon, 1995


Childhood leukaemia aroundChildhood leukaemia around UK nuclear facilities UK nuclear facilities

STUDY GROUP: 46 000 children (followed till the age of 25 yrs) born to parents working in nuclear industry

FINDINGS: 111 cases of acute leukaemia observed, i.e. fewer than expected in a group of this size and age

Study found 3 cases of leukaemia in children of male workers who had received a pre-conceptional exposure of 100 mSv or more

Two of these three cases had already been identified in the 1990 Gardner report (proposed theory that paternal pre-conception radiation leads to increased risk of leukaemia in offspring)

Conclusions No substantial evidence found to support Gardner’s theory Study did not confirm theory

Ref. ICRF, LSHTM & LRF: Nuclear Industry Family Study (NIFS). BMJ, 28-05-1999


Lifetime mortality in population of Lifetime mortality in population of

all ages from cancer all ages from cancer

after exposure to low dosesafter exposure to low doses

Organ or tissue Fatal Cancer Probability Coefficient (10-4 Sv-1)

Bladder Bone Marrow Bone Surface Breast Colon Liver Oesophagus Ovary Skin Stomach Thyroid Remainder1 Total

30 50 5 20 85 15 30 10 2 110 8 50 500*

* For general public (all age groups) only

Summary factor of cancer risk for working population taken to be 400x10-4 Sv-1

Reference ICRP, Publ. 60, 1991


Nominal probability coefficients Nominal probability coefficients

for stochastic radiation effectsfor stochastic radiation effects

Ref. ICRP, Publ. 60, 1991

Detriment (10- 2 Sv-1)

Exposed population

Fatal cancer

Non-fatal cancer

Severe hereditary

effects

Total

Adult workers only

4.0

0.8

0.8

5.6

Whole population (all age groups)

5.0

1.0

1.3

7.3

1 Rounded values 2 For fatal cancer, detriment coefficient is equal to probability coefficient


Genetic radiation damageGenetic radiation damage

Increase of chromosome aberrations in human spermatogonia following radiation exposure of testes has been detected

inheritance of radiation damage in human population (including A-bomb survivors) not yet detected


Review of topics discussedReview of topics discussed

Biological effects of radiation in time perspective Main characteristics of deterministic and stochastic effects Sources of data on human effects of radiation overexposure Threshold doses of deterministic effects in the most radiosensitive

tissues Teratogenic effects of radiation: severe mental retardation,

microcephaly Phases of cancer induction Sources of human data on radiation cancerogenesis (3 groups) Latency periods of radiation induced cancers (lag 2 & 10 yrs) Risk of cancer depending on age at exposure (reverse dependence) Cancer deaths attributable to A-bombs – 5.4% in 40-yr follow up Cancer mortality studies of nuclear industry workers and offspring –

leukaemia probable in workers Genetic effects of radiation – not proved in human population

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DOSE-EFFECT CURVES; DETERMINISTIC AND STOCHASTIC EFFECTS OF RADIATION Module IX