Introduction to Radiation Health: Late Effects - Cancer Dr. Niel Wald.
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Transcript of Introduction to Radiation Health: Late Effects - Cancer Dr. Niel Wald.
Introduction to Radiation Health: Late Effects - Cancer
Dr. Niel Wald
Radiobiological Effects
• Non-Stochastic – Severity varies with dose – May have threshold (cataract, dermatitis)
• Stochastic– Probability of occurrence in population varies
with dose– No threshold (cancer, genetic damage)
227-4
Intracellular Effects of Radiation
138-A
Classification of NeoplasmsTissue Origin Benign Malignant Examples
Epithelial
Glandular Adenoma Adenocarcinoma Thyroid follicular adenomaAdenocarcinoma of lung
Squamous and Transitional
Polyp, papilloma
Squamous cell carcinomaTransitional cell carcinoma
Squamous papiloma of skinSquam. cell carcinoma skin
Connective tissue Tissue type + suffix (-oma)
Sarcoma Osteoma, Osteosarcoma, Hemangioma, Hemangiosarcoma
Hematopoietic & lymphoreticular
LymphomaLeukemia
Large cell lymphomaHodgkin’s diseaseMylocytic leukemia
Neural tissue NeuromaNeurofibroma
SarcomaBlastoma
Glioblastoma multiformeNeurofibrosarcoma
Mixed tissues of origin
Teratoma Teratocarcinoma Teratoma of ovaryTeratocarcinoma of testis
395-4
Basis for Tumor Dose:Response Estimates
175-3
Tumor Growth Curve
395-6
Scheme for Induction of Cancer by Environmental Carcinogens
Chemical or Radiation
Carcinogen
Initiator(s) (electrophilic, mutagenic)
Promoter(s)
Inactive Metabolites
Normal Cells
Initiated Cells
Tumor Cells
Clones
Gross Tumors
Courtesy of Miller and Miller 395-11
395-1
395-2
395-3
Three germ layers and the tissues derived from themEmbryonic origin Adult derivative
Ectoderm Skin Brain Breast Sweat glands etc.
Mesoderm
Fibrous tissue (connective) Cartilage Bone Muscle etc.
Endoderm Gut Liver Lung Pancreas etc.
666-1
Histogenetic classification of benign tumors
Normal tissue Resultant Benign tumorGlandular epitheliumSurface epitheliumFibroblastsCartilageStriated MuscleSmooth MuscleBlood VesselsFatBoneLiver
AdenomaPapillomaFibromaChondromaRhabdomyomaLeiomyomaHemangiomaLipomaOsteomaHepatoma
642-1
Histogenetic classification of malignant tumorsNormal tissue Resultant Malignant tumorEpitheliumConnective tissueBone Marrow
CarcinomaSarcomaLeukemia
More Specifically:Glandular epitheliumSquamous epitheliumFibroblastsCartilageStriated MuscleSmooth MuscleEndotheliumFatBoneLiver
AdenocarcinomaSquamous carcinomaFibrosarcomaChondrosarcomaRhabdomyosarcomaLeiomyosarcomaAngiosarcomaLiposarcomaOsteosarcomaHepatocellular carcinoma642-2(1)
Histogenetic Classification of Malignant Tumors with Atypical Nomenclature:
Normal tissue Resultant Malignant tumorSkin- melanocytesFibroblast/histiocyte
Myeloid stem cellsPlasma cellsLymphoid tissueSympathetic neurones (neuroblasts)? EndotheliumEmbryonal kidneyEmbryonal retinaGonad (male germ cells)Gonad (female germ cells)Germ cells
Malignant melanomaMalignant fibrous histiocytomaMyeloid leukemiaMultiple myelomaLymphoma/Hodgkin’s Dis.NeuroblastomaKaposi’s sarcomaNephroblastomaRetinoblastomaSeminomaDysgerminomaMalignant teratoma
642-2(2)
Mechanisms of Cell Death
642-3
Cell Death (necrosis and apoptosis)
642-4
Maturation Arrest
642-6
Metastasis Formation
666-2
Metastasis Formation
666-3
Cancer Development
395-16
General Properties of Initiating Agents & Promoting Agents
Initiating Agents* Promoting Agents1. Carcinogenic by themselves.2. Activity strictly determined by
molecular structure.3. Generally active in more than one
tissue.4. No detectable threshold dose;
action is cumulative and irreversible.
5. Most require metabolic activation and covalently bind to macromolecules.
6. Most are mutagens.7. More active in proliferating
tissues.8. Induce rapid shift in the
biological potential of the cells (a single exposure is often sufficient to initiate).
1. Not carcinogenic alone; must be given after initiating agent to exert effect.
2. Activity strictly determined by molecular structure.
3. Action of individual exposures is reversible and not cumulative. Repeated exposures are required.
4. Metabolism or macromolecular binding may not be required.
5. Not mutagenic but may enhance the expression of induced mutations.
6. Usually induce proliferation in target tissue (although proliferation alone is not a sufficient promoting stimulus).
7. Induced changes are progressive; stable intermediate stages may be observed prior to overt malignancy.
*defined in a broad sense as agents that can both initiate cancer in limited dosages and induce cancer in higher dosages or in states of increased host susceptibility 395-15
Properties of Oncogenes and Tumor Supressor Genes
Property Oncogenes Tumor Supressor Genes
Mutational events involved in cancer
One Two
Function of mutation Gain of function (“dominant”) Loss of function (“recessive”)
Germline inheritance No Yes
Somatic mutations Yes Yes
Effects on growth control
Activate cell proliferation Negatively regulate growth-promoting genes
Effects of gene transfection
Transform partly abnormal fibroblasts (e.g., NIH3T3)
Supress malignant phenotype in malignant cells
Genetic alterations Point mutations, gene rearrangements, amplification
Deletions, point mutations
* From Rudden, 1995b, with permission. 666-9
International Leukemia Incidence
666-4
Alternative Radiation Dose-Response Curves
227-5
Cancer Summary• Tissues vary considerably with respect to their sensitivity to
cancer induction.• The major sites of solid tumors induced by whole-body exposure
to radiation are the breast, thyroid, lung and digestive organs.• Age, both at the time of exposure and diagnosis, is a very
important variable relating to cancer induction.• The latency period (time from exposure to tumor detection) is
frequently very long, i.e. years to decades.• Interaction between host and environmental factors (i.e.,
hormonal influences, exposure to other carcinogenic agents) may play a significant role in tumor induction.
• Nearly all the tissues in the body are susceptible to tumor induction.
• The dose-response relationships for many animal model systems are qualitatively similar to those for human tumor induction. However, direct quantitative risk extrapolation from animals to man would be inappropriate
395-28
Radiation Cancer Risk Estimation
341-2
Radiation-induced Cancer Risk
227-6
Absolute Risk Model
220-4
Relative Risk Model
220-5
Dose-response Interpolation Curves
227-1
Radiation Dose:Slope Relationships
Dose Range Rads
Low LET D:R Curve Range
Low
Intermediate
High
Very High
0 to ~ 20
~ 20 to 250
~ 250 to 400
> ~ 400
Straight
Increasing Slope
Max. to 0 Slope
Remainder
227-2
Radiation Dose Rate Ranges
Dose-Rate Range Rads
Low
Intermediate
High
5 per year or less
Between low and high
~ 200 - 250 in minutes
to 12 hours
227-3
Hiroshima Dose:Distance Relationship
92-I
ABCC Shielding History Floor Plan
93-C
A-Bomb Leukemia Cases by Year
100-C
A-Bomb Leukemia by Type and Dose
96-B
A-Bomb Leukemia Dose-Response Curves
302-5
A-Bomb Exposure Age vs.Leukemia Risk
220-2
The quadratic risk coefficient () has increased, whereas the linear low-dose risk coefficient () has decreased, suggesting that currently accepted standards for low-level gamma exposures are not in need of revision on the basis of changes in data from Japan.
Induced Effect “New” BEIR (1980) “New” BEIR (1980)
Leukemia 0.8 0.98 2.7 1.8
Risk Coefficient 10 rad
(Cases/106/year/rad)100 rad
Risk Coefficients for Leukemia Mortality
Source: Adapted from Straume and Dobson (1981). Reproduced from Health Physics, Vol. 44 by permission of the Health Physics Society 303-4
The observed and expected numbers of Ankylosing Spondylitis deaths due to leukemia and aplastic anemia, 1935 - 54 study series
Disease Group Sex Minimum expected
Maximum expected
Observed
Leukemia (International List
Code no. 204)
M.
F.
M. And F.
1.25
0.19
1.44
2.06
0.34
2.40
22
0
22
Aplastic anemia (International List
Code no. 292-4)
M.
F.
M. And F.
0.12
0.03
0.15
0.20
0.05
0.25
10
1
11
Number of Deaths
Significance of difference between observed and maximum expected number of deaths:
Leukemia: P < 0.000001
Aplastic anemia: P < 0.000001 104-E
Spondylitis: Leukemia Dose-Response
104-G
Spondylitis: Leukemia Latency Postexposure
104-F
Incidence of Death from Leukemia in PhysiciansOccupation Time Place Total
DeathsLeukemia
DeathsIncidenc
e
Ratio of Incidences
Radiologists: All Physicians
General Population Incidence
Reference
Radiologist
Non-radiologist
All Physicians
Radiologist
All Specialists
All Physicians
Radiologist
Non-radiologist
All Physicians
Radiologist
All Physicians
Radiologist
Radiologist
Non-radiologist
Radiologist
Non-radiologist
Radiologist
Non-radiologist with X-ray
Non-radiologist without
X-ray
1929-43
1929-43
1933-42
1938-42
1938-42
1938-42
1944-48
1944-48
1947-51
1949-58
1949-58
1897-56
1938-42
1938-42
1952-55
1952-55
1930-54
1930-54
1930-54
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
USA
G. Brit.
Eire
USA
USA
USA
USA
USA
USA
USA
175
50,160
26,788
95
2,029
12,419
124
15,637
11,481
296
23,393
463
205
34,626
8
221
143
5
19
62
6
113
133
11
221
3
8
158
4.57%
0.44%
0.53 %
5.3 %
0.94 %
0.50 %
4.84 %
0.72 %
1.2 %
3.71 %
0.77 %
0.65 %
3.9 %
0.44 %
3.57 %
1.00 %
3.65 %
2.33 %
0.63 %
10.3:1
10.6:1
6.7:1
4.8:1
3.6:1
0.39%
0.52%
0.39%
(1950)
March
Henshaw and
Hawkins
Dublin and
Spiegelman
March
Peller and Pick
Cronkite
Court-Brown
Ulrich
Melville in Schwartz and
Upton
Warren
104-D
Risk of Leukemia in various Diseases and Conditionsa,b
Group
Approximate Risk
Increased Risk Over
Control Population
Occurrence
Identical twin of leukemic twin
Irradiation-treated polycythemia vera
Blood syndrome
Hiroshima survivors who were within 1,000 meters of the hypocenterc
Down’s Syndrome
Irradiation-treated patients with ankylosing spondylitis
Siblings of leukemic children
Children exposedd to pelvimetry in utero (gestational exposure)
U.S. white children < 15 years of age
1/3
1/6
1/8
1/60 1/95
1/270 1/720
1/2,000 1/2,800
1,000
500
375
50 30
10 4
1.5 1
Weeks to months
10-15 years
< 30 years of age
Average 12 years < 10 years of age
15 years To 10 years
< 10 years To 10 years
a Risk of leukemia in various groups with specific epidemiologic and pathologic characteristics in populations followed for 10-30 years.
b Leukemia risk (lifetime): Mortality increment from single exposure to 1 rad is 15-25 cases/106 persons or ~ 1/50,000.
c Free in air doses (rads): gamma rays > 500 rads; neutrons > 60 rads
Source: Modified from Miller (1970; from Brent (1980)303-5
Leukemia Risk
Adults Children
Percent increase in risk/ rem 2 to 3 5 to 10
Absolute risk (cases/ 106/ rad) 1 to 2 2 to 3
96-I
A-Bomb: Mortality Relative Risks
173-1
A-Bomb: Cancer Relative Risks
173-2
A-Bomb: Cancer Dose-Response
173-3
668-29
Thyroid Cancer Risk Associated with I-131 Exposure from Chernobyl
< 0.30 0.30-0.99 1.0+ RR
Cases
Population Controls
64
88
26
15
17
4
2.1
(1.7-5.8)
Cases
Medical Controls
64
84
26
19
17
4
2.6
(1.4-4.8)
Estimated Thyroid Dose from I-131 (Gy)
Adapted from Astakhova et al., 1998
668-5
Observed and Expected Neoplasms by Site in Hiroshima and Nagasaki Residents Exposed to 1-9 rad (1950-1974)
SITES OBS. EXP. OBS / EXP
OBS. EXP. OBS / EXP
Leukemia
Thyroid
Female Breast
Trachea, Bronchus, Lung
Digestive Organs, Peritonium
Stomach
Esophagus
Cervix Uteri, Uterus
Overy, Tube, Ligament
Bladder, Urinary
Prostate
4
17
22
49
318
197
9
66
3
9
7
10.1
21.4
28.8
52.2
319.5
204.2
15.5
60.9
6.9
16.2
11.1
0.4
0.8
0.8
0.9
1.0
1.0
0.6
1.1
0.4
0.6
0.6
5
12
9
20
125
75
5
34
1
3
3
5.8
13.1
12.7
19.8
125.7
75.2
7.9
29.0
1.5
4.7
3.4
0.9
0.9
0.7
1.0
1.0
1.0
0.6
1.2
0.7
0.6
0.9
Hiroshima Nagasaki
175-16
Radiation Field for Newborn Thymus Therapy
108-E
Observed Expected Observed Expected
Malignant
Thyroid carcinoma
Leukemia
Hodgkin’s disease
Salivary gland tumor
Breast carcinoma
Brain tumor
Benign
Thyroid adenoma
Osteochondroma
Breast adenoma
23
14
3
0
3
0
1
31
15
9
1
2.21
0.06
0.43
0.16
0.03
0.05
0.28
---
0.60
1.26
---
14
0
2
1
1
0
2
32
3
3
7
14.50
0.31
3.21
0.80
0.15
0.40
2.48
---
3.10
7.22
---
Type of Neoplasm Anterior + Posterior
Tumors After Newborn Thymus Irradiation
Untreated Siblings
108-I
Bikini A-BombTest Fallout
109-G
Thyroid Nodules (1981)* After Bikini A-BOMB testGroup
age 1954 No.
Est. thyroid
Dose (rads) No. % No. %
Rongelap
1 yr
2-10
> 10
6
16
45
> 1,500 (?)
800-1500
387
4
13
6
66.7
81.2
13.3
0
1
3
0
6.2
6.6
Ailingnae
< 10
> 10
7
12
275-450
140
2
4
28.6
33.3
0
0
0
0
Utirik
< 10
> 10
64
100
60-90
53
5
12
7.8
12.0
1
2
1.6
2.0
Matched Controls
< 10
> 10
229
371
6
29
2.6
7.8
2
3
0.9
0.8
Total Nodules Carcinoma
* Prevalence has not been corrected for control levels. The carcinoma prevalence is probably low, since all unoperated nodule cases were considered benign for this table. Occult carcinomas were not included as carcinomas. 109-
H
Post-Chernobyl Accident Fallout
668-4
Thyroid Cancer Post-Chernobyl Accident
668-10
Thyroid Nodules Post-Bikini Test Fallout
258-4
Absolute Risk of Thyroid Abnormalities After Exposure to Radiation
Thyroid nodularity
Children
Adults
Thyroid cancer
Children
Adults
9,000
8,755
9,000
8,755
0.23
0.11
0.06
0.05
0 to 0.52
0.06 to 0.15
0 to 0.16
0.038 to 0.066
Hypothyroidism
“Low dose” - children
“High dose” - adults
< 10 to 1,900
2,500 to 20,000
4.9
4.4
3.9 to 22.9
2.8 to 7.6
Type of Abnormality and Population Surveyed
Mean Dose or Dose Range (rem) for which Data Were Available
Thyroid nodularity in children
Thyroid cancer in children
Hypothyroidism in adults
0 to 1,500
0 to 1,500
1,640
12.3
4.2
10.2
4 to 45
0.9 to 17.3
0 to 25
Absolute Risk
Statistical Risk Range
Internal Irradiation (131I)
External Irradiation
221-3
Thyroid Cancer Dose-Response
304-5
Thyroid Cancer after External Irradiation
Series
No. persons
Type of control groupa
Mean dose
(rads) Obs. Exp.
Abs. riskb
A-bomb, age < 30c
(> 50 rads)
A-Bomb, age > 30c
(> 50 rads)
Thymus x-ray (Rochester)
Tonsil x-ray (M. Reese)
Head/ Neck x-ray (Cinn.)
Tinea (Israel, NYC)
4,377
2,782
2,651
2,578
1,266
13,060
U
U
S,P
---
D
D,S,U
~ 130
~ 130
138
~ 780
~ 290
~ 9
26
6
30
181
16
23
2,8
2.6
0.7
~ 2
~ 0,4
6,8
3.4
0.3
3.5
~ 3.6
~ 1.7
~ 6.3
a U, unexposed group; S, siblings; D, same-disease control; P, general population control
b Absolute risk = excess cancers/ 106 PY-rad
c From Prentice et al., with permission
304-6
Breast Cancer Post-TB Fluoroscopy
305-7
Post-A-Bomb Breast Cancer
305-4
Breast Cancer after TB Fluoroscopy
305-6
Lung Cancer: Czech Miners
306-7
Lung Cancer: US Uranium Miners
113-F
Histologic Classification of Lung Cancer
I. Squamous cell carcinomas
II. Small cell carcinomas1. Fusiform cell type (intermediate)
2. Polygonal cell type “ “
3. Lymphocyte-like type (oat cell)
III. Adenocarcinomas
IV. Large cell carcinomas
Intermediate
260-2
Lung Cancer and Age in Miners
Age at Start of Mining
Excess Rate and 95% Confidence Limits
(10-6 WLM-1)
Under 30 140 (100 - 180)
30 to 39 230 (160 - 300)
Over 40 370 (280 - 460)
All 230 (155 - 305)
145-10
Thorotrast Distribution 23 yrs. Post-injection
110- I
Liver Cancer in Thorotrast Patients Surviving at least 10 years After Intravascular Injection
Country and Year of
Last Followup
No. Cases
Liver Cancer
Traced Patients
Surviving at
Least 10 Yr
Person-Years at Risk
from 10 Yr After
Injection to Death or
Last Contact
Germany, 1977
Denmark, 1977
Portugal, 1974
Total
176
50
75
301
1,733
646
667
3,046
28,424
12,274
12,673a
53,371
a The fraction of the Portuguese patients surviving at least 10 yr and their average time to death or last contact were considered similar to those documented for the Danish patients. In both countries, suspected brain diseases were the main reason for the intravascular injection of Thorotrast (80% in Portugal and nearly 100% in Denmark). 223-1
Causes of Death Among the 1,120 Traced Individuals Who Received Thorotrast and were Followed-up Until March 30, 1966
Causes of Death (Only the Basic Cause of Death
Was Considered)Number Total Percent
Usual Time Interval Between Administration &
Death (in Yrs.)
Total number of deaths which could
have been due to a possible thorotrast
side-effect
A. Local Granulomata
B. Hemangioendotheliomata
C. Malignant tumor on the edge of
granulomata
D. Other malignant tumors
E. Leukemias
F. Aplastic anemias
G. “Purpuras”
H. Liver fibrosis
I. Other possible fatal ‘consequences”
Deaths, due to causes which could not be
due to thorotrast
Unknown cause of death
Total deaths during the period
9
27
5
23
9
6
2
17
3
101
591
41*
733
13.77%
80.63%
5.59%
---
15 y. or more
25 y. or more
15 - 20 y.
20 y. or more
17 y.
18 y.
19 y.
15 - 20 y. or more
---
---
---
---
Number of Deaths
* Some of these cases are still under investigation and will probably be classified eventually in other diagnoses 110-C
Thorotrast Patients: Liver Tumors and Dose Rate
307-4
Liver Cancer Summary
Excess Risk Cases/ 106/ Yr/ RAD
High LET
Low LET
13.0
0.7
223-3
Cancer in Radium Dial Painters
308-8
Dial Painters’ Radium Burden and Cancer
115-E
Dial Painters’ Skeletal Dose and Bone Cancer
224-1
Cancer Rate Per Million Persons Per RAD of Exposure
Incidence
(Unscear ‘77)
Fatalities
(ICRP ‘77)
Thyroid
Breast (F)
Leukemia
Lung
Bone
Other
100
100
20-50
20-50
2-5
2-15
5
50
20
20
5
50
175-17
492-3
Comparison of Lifetime Excess Cancer risk Estimates from BEIR III and BIER V Reports
Males Females Males Females
Leukemia
BIER IIIa
BIER V
Ratio BIER V /
BIER III
15.9
70
4.4
12.1
60
5.0
27.4
110
4.0
18.6
80
4.3
Nonleukemia
BIER III
Additive risk
model
Relative risk
model
BIERV
Ratio BIER V /
BIER III
24.6
92.9
450
4.8 - 18.3
42.4
118.5
540
4.6 - 12.7
42.1
192
660
3.4 - 15.7
65.2
213
730
3.4 - 11.2
Continuous Lifetime Exposure, 1 mGy/y (deaths per 100,000)
Instantaneous Exposure, 0.1 Gy (deaths per 100,000)
492-4a based on Table V-16, page 203 and Table V-19, page 206