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