Effects of Long-Term Exposure to Radiation...•MIIWIIQI: Effects of Long Term Exposure to Radiation •45 Hr PET Registry Review Course •Reference Number: 028613 •1.5 CEH’s

Effects of Long-Term

Exposure to Radiation

Tim Marshel R.T. (R)(N)(CT)(MR)(NCT)(PET)(CNMT)

SNMTS Approved

• MIIWIIQI: Effects of Long Term Exposure to Radiation

• 45 Hr PET Registry Review Course

• Reference Number: 028613

• 1.5 CEH’s

Program ObjectivesDiscuss and describe epidemiology

Discuss population used as sources

Describe limitations on epidemiologic studies

Discuss Hiroshima-Nagasaki atomic bombings and radiation induced malignancies

Discuss and explain different risk models

Review the genetic effects of radiation

Discuss Life Span Shortening

Discuss the effects of radiation to the fetus

Review stochastic and nonstochastic effects

Discuss Radiation Hormesis

EPIDEMIOLOGYEpidemiology is the study of diseases in

populations of humans or other animals, specifically how, when and where they occur.

The science of epidemiology was first developed to discover and understand possible causes of contagious diseases such as:▫ Small pox

▫ Thyroid

▫ polio

EPIDEMIOLOGYFirst documented case of radiation-induced

carcinoma (growth or tumor)

In 1902, it was determined that radiation is carcinogenic (cancer causing)

Incidence rates for radiation-induced cancer are determined by Expected occurrence in a control group (general

population)

Occurrence in experimental group (the irradiated population)

EPIDEMIOLOGYPopulation used as sources of data (cancer)Atomic bomb survivors

Medically exposed patients

Occupationally exposed personnel

Populations who receive high natural background exposure

EPIDEMIOLOGYLimitations on epidemiologic studies include:Failure to control experimental group for other known carcinogens

Insufficient observation periods which permit full demonstration of cancers with long latent periods

Using improper control groups

Deficient or incorrect health records

Studies can be divided into two basic types Whether the events have already happened (retrospective)

Whether events may happen in the future (prospective)

ATOMIC BOMB SURVIVORS

The two A-bombs dropped in August 1945 killed between 150,000 and 200,000 of a total population. Around 93,000 were exposure at the time of the bombing. Approximately 20,000 received doses between 1-5 cGy while ~1,1000 received doses in excess of 2 Gy

A-BOMB SURVIVORS' OBSERVED AND EXPECTED

DEATHS FROM SOLID CANCERS (1950-1990)

Radiation induced cancer deaths in the Japanese

A-Bomb survivor cohort (1950-1990)% Ca’s Radiation

Total CA Deathsb Radiation Induced Induced

_____________________________________________________

Solid Tumors

7,578 334 4.4%

Leukemia

249 87 35%

Combined

7,827b 421 5.4%

_____________________________________________________

a. 86,572 individuals are included in the Life Span Study of survivors (whole

body dose received by this group was >10 rads with an average dose of 28

rads).

b. By 1991, approximately 38,600 had died; approximately 20% from cancer.

Calculations estimate that 1.1% of the deaths in this population resulted from

the radiation exposure

Earlier Epidemiology Studies

―[most] of these studies was considered by the Committee to constitute reliable evidence at present for use in risk estimation, for various reasons, including inadequate sample size in some instances, inadequate statistical analysis, and unconfirmed results.‖

BEIR 1980, p. 138

Populations exposed to very low levels

of irradiation• DOE’s Hanford Facility

• Portsmouth Naval Nuclear Shipyard

• Tri-state study of leukemia deaths

• Utah residents exposed to fallout

• Project Smoky

• Three-Mile Island

Project “Smoky”

• 1957 Nevada atmospheric A-bomb test

• 3,153 Military personnel

Dose estimate – Most under 5 rem

Leukemia – Observed 8 cases

expected 2-4 cases

Effects for Which No Relationship with

A-Bomb Exposure Has Been Shown1. Increased birth defects in the F1 generation.

2. Increased F1 mortality.

3. Infertility.

4. Accelerated aging.

5. Altered immune function.

6. Diseases other than neoplasm.

BEIR V

… the possibility that there may be no risks from exposure comparable to external natural

background radiation cannot be ruled out.

Estimation of Risk

“Low Level” Radiation Exposure

• Single exposure of 10 rad or less

• Larger exposures delivered over periods of days or longer (low dose rates)

Risk modelThe relative or multiplicative risk model Explains how age at the time of radiation exposure may

influence the cancer risk estimate

The absolute or additive risk modelEstimates continual increase in risk that is independent

of the spontaneous age specific cancer risk at the time of exposure

Excess riskIs another way to express risk. Expressed as number of

excess cases observed compared with the expected spontaneous occurrence

Risk model

Absolute risk states risk in terms of number of cases

10⁶ persons/rad/year

Excess risk

Observed cases–expected cases

Relative risk

Observed cases/ expected cases

Risk• Risk from a radiation dose is typically based on

calculations of the ―real‖ effect of the radiation dose that is absorbed.

• These calculations are based on:

▫ The type of radiation. Each type of radiation is different and affects tissues differently.

▫ The energy that it leaves in the body. More energy means a higher probability of an effect.

▫ Where in the body the energy remains. Radiation exposure to a nonsensitive area of the body (i.e., wrist)

really has no actual effect. Radiation exposure to a sensitive area of the body (i.e., blood-forming organs) can have an effect if the amount of energy left is high enough.

Cancer• The average natural lifetime incidence of cancer in the

United States is 42 percent—42 out of 100 people will get cancer in their lifetime.1

• Diagnostic medical radiation exposures typically will not increase this risk appreciably.

• Radiation exposure does not create a unique cancer risk situation, nor is the risk directly measurable or distinguishable from the cancer risk caused by other

sources (environmental, chemical, biological, etc.).

Cancer

• Radiation-induced cancers do not appear until at least 10 years after exposure (for tumors) or 2 years after exposure (for leukemia).

• The time after exposure until possible cancer formation is called the ―latent period.‖

• The risk of cancer after exposure can extend beyond this latent period for the rest of a person’s life for tumors or about 30 years for leukemia.

Cancer Risk Estimates

• We lack scientific data to determine a precise risk of cancer in the future from radiation exposure today.

• We estimate the increase in the cancer incidence rate is about 0.17 percent per rem of radiation dose1; this is based on effects seen at high doses.

• However, it may be impossible to demonstrate that additional cancers occur at low levels of radiation exposure since the normal incidence rate of cancer is plus or minus some natural variation.

Cancer Risk Estimates (cont.)

• This means that, of a group of 100 people, it is estimated that about 42 will get a cancer in their lifetime. If we expose each to one rem of radiation, still about 42 will get a cancer in their lifetime. If we expose each to five rem of radiation, we estimate that about 43 will get a cancer in their lifetime.

• What we cannot tell, though, is whether the estimated one additional cancer is just a natural variation or whether it is due to the radiation exposure.

STOCHASTIC EFFECTS:

In low dose ranges—hereditary

effects, carcinogenesis.

NON-STOCHASTIC EFFECTS:

Various somatic effects,

including erythema,

epilation, cataracts,

impaired fertility, etc.

RISKS OF LOW-LEVEL RADIATION

EXPOSURE• Genetic Effects

• Induction of Cancer

• Effects on the embryo

GENERAL CONCEPTS

Considerable time may elapse between radiation exposure and cancer development. In human beings the length of this latent period may be 10, 20, 30 or even 40 years.

Variable Radiation Sensitivity

Cancer can be induced in almost all body tissues but they vary considerably in their sensitivity.

Latent Effects

4. Whole body exposure produces more solid tumors than leukemias. Solid tumors also have longer latent periods and periods of expression.

Radiation Induced Cancers

Cancers induced by radiation are indistinguishable from those that occur spontaneously, hence their existence must be inferred on the basis of statistical excess.

Radiation cancer is difficult to

demonstrate at high doses and

essentially impossible to quantify at

low doses even with large populations.

High Background of “Spontaneous”

Cancers

Reason: The observed number of cancers in the control population is so large with respect to the number of cancers induced by radiation that the radiation effects become undetectable.

DOSE RATE EFFECTS

Thyroid and Breast Cancers

The incidence of radiation-induced human breast and thyroid cancer is such that the total cancer risk is greater for women than for men. For other cancers, the risks are about equal.

Example of Linear-, Non-Threshold

Estimation of Risks at Low Doses100 rad to breast 1000 women

Observed = 40 cancers

Expected [Background] = 22

Excess = 18

Linear Extrapolation of Risk

Estimation

100 rad 1000 women 18 cancers

1 rad 100,000 women 18 cancers

LINEAR EXTRAPOLATION OF RISK ESTIMATION

100 rad 1000 women 1 rad 100,000

women

Expected = 22 Expected = 2,200

Exces = 18 Excess = 18

22 vs. 40 2200 vs. 2218 vs. 22

Age Dependency

Age is a major factor in the risk of radiation-induced cancer (breast, lung, and leukemia in A-bomb survivors; in utero irradiation).

R.J. Hall, Radiobiology for the Radiologist

5th ed. Lippincott Williams & Williams, Philadelphia, PA 2000, p. 150

Treatment of Hyperthyroid

Disease in Humans with 131I

Radioiodine (Na131I)

• Thyroid Gland Dose ~ 50-100 Gy

• No significant increase in thyroid cancer or leukemia compared to ―hyperthyroid‖ control cohort.

EXPRESSION OF RADIOSENSITIVITY

Absolute Risk

• Breast and thyroid are well ahead of bone marrow and lung

Relative Risk

• The sequence is probably: Thyroid, bone marrow, lung, and breast.

Somatic Effects

• Approximately 450 cancer deaths/million/rem

• Natural incidence of cancer deaths is 200,000/million

Health Effects of Exposure to Low Levels of Ionizing Radiation – BEIR V

National Research Council. National Academy Press, Washington D.C.,

1990, P. 357.

GENETIC EFFECTS

Genetic Effects

Must be estimated on

the basis of data from

animal experiments

because NO Conclusive

Human Data Exists.

Genetic Effects

• Genetic mutations occur from incorrect repair of damaged chromosomes in egg or sperm cells.

• Ovaries can repair mild radiation damage.

• Genetic mutations may show up in future generations.

• Radiation-caused genetic mutations have been shown in animal studies at very high radiation doses (>25 rem).

• Radiation-caused genetic mutations have notbeen seen in exposed human populations.

Radiation Damage to

Chromosomes

• Indirect damage▫ Water molecule is ionized, breaks apart, and

forms OH free radical.

▫ OH free radical contains an unpaired electron in the outer shell and is highly reactive: Reacts with DNA.

▫ 75 percent of radiation-caused DNA damage is due to OH free radical.

• Direct damage▫ DNA molecule is struck by radiation,

ionized, resulting in damage.

Chromosome Damage

Formation of a ring and fragments followed

by replication of chromosomes.

Chromosome Damage

Interchange between two chromosomes

forms a chromosome with two centromeres

and fragment, followed by replication.

What Follows Chromosome Damage?

• The cell might:▫ Repair mild damage. ▫ Have some mild damage that sits inactive until

another agent interacts with the same cell. ▫ (If it is a reproductive cell like sperm or egg cells)

have damage to the genetic code that doesn’t show up until future generations (your children, their children, etc.).

▫ Have some damage, causing it to become a cancer.

▫ Stop functioning. ▫ Be killed.

Estimation of Genetic Effects

• Conclusions are largely ―mousebound‖.

• How are mouse numbers converted to human numbers?

• Some evidence of similarity from in vitro studies of imitation and chromosome changes.

EFFECTS ON THE EMBRYO

Justification• A medical procedure involving radiation should be done

only when there is a question to be answered–is something broken, why the pounding headaches, could there be cancer?

• This is justification; i.e., there should be an appropriate medical reason for the x ray to be performed.

• The issue of medical radiation exposure is not only a matter of safety; it’s a matter of benefit compared with risk.

• For properly performed common medical radiation procedures that are necessary in light of the patient’s medical condition, safety alone is not the issue.

Radiation Effects on the Embryo

Depends on….

Radiation dose

Dose-rateStage of gestation

Classical Triad of Effects of Radiation

on the Embryo• Growth retardation

• Embryonic, fetal or neonatal death

• Congenital malformation

Hall, R.J., Radiobiology for the Radiologist

5th Ed. Lippincott Williams & Williams, Philadelphia, PA 2000, p. 187

Embryo is Radiosensitive

• Embryonic cells have high rates of cell division and cell differentiation.

• Composed of relatively few cells.

NCRP Report 54, page 6

Animal experiments have shown that irradiation during the pre-implantation period generally produces an all-or-none effect, i.e., either very early embryonic death (pre- or immediately post-implantation) is caused, or there is apparent normalcy (including growth rate, fertility, and longevity) of survivors.

Radiation and Congenital

Malformations• Radiation produces no unique abnormalities.

• High rate of spontaneous abnormality

(4-6%).

NCRP Report 54, page 7

Noting that the excess risk of adverse effects arising from doses below 10 rad probably is not statistically detectable in experiments involving manageable numbers of animals, one must decide on a level above which scheduling is indicated. Doses below 5 rad to the human embryo-fetus are considered by many to represent an acceptable risk when compared to the potential medical benefit of the examination to the patient.

10 Day RuleIt must be emphasized that both the ICRP and NCRP recommended application of the 10-day rule only to those studies that do not contribute to management of current disease. It, therefore, follows that studies which do contribute to diagnosis or treatment of current disease should be performed in fertile women without regard to stage of the menstrual cycle. The ACR supports the American College of Obstetricians and Gynecologists’ 1977 Guidelines for Diagnostic X-ray Examinations of Fertile Women.

Fetal Irradiation

Therefore, one concludes that frompreconception to birth there is no period during which a radiological examination of the lower abdomen and pelvis of a woman of reproductive capacity can be conducted with no risk.

Linear No-Threshold Hypothesis (LNT)

• As early as the 1950s, when scientific groups were creating radiation protection guidelines:▫ No one really knew what the effects of radiation at low doses were or if there were

any.

▫ It was decided to assume that the radiation dose and the effect of the dose were linear and proportional.

This means for a given dose of radiation to a person, that person has some possibility of a radiation effect; if the dose of radiation is doubled, that person has twice the possibility and so on.

▫ It was also decided that at any dose, no matter how small, there could be an effect (no threshold).

• Setting radiation protection standards required ―erring‖ on the ―safe‖ side—setting a standard lower than it may have to be if the real level of hazard were known. This was and still is the basis for the LNT.

• LNT was intended for scientists to set radiation protection standards and not for general use; because it was easy to use and explain, most people quickly presented it as fact rather than saying we do not know the effects of low doses of radiation or that low doses of radiation are safe.

Life Span Shortening

• Animals that received acute and chronic radiation indicate that animals that were chronically irradiated died younger than animals that were not

• Examinations of the dead animals showed a decreased number of Parenchymal (essential life sustaining) cells and blood vessels along with increased in connective tissue organs

Con’t

• The correlation between life span shortening and dose is linear nonthreshold relationship.

Stochastic (random)

• Stochastic effect are thought to be non threshold as damage to a few cells or even a single cell could theoretically produce the disease

• They are associated with the linear and linear quadratic dose response curve

▫ Examples: include radiation induced cancer and radiation induced genetic effects

Nonstochastic (not random)

Nonstochastic or deterministic effect are thought to be threshold as these are doses below which the effect is not observed

These nonstochatic or deterministic effects are different from stochastic effects in that they need much higher dose to occur› Examples: ionizing radiation, cataracts,

erythema, fibrosis, and hematopoietic damage

Nonstochastic or deterministic affect increase in severity with dose and therefore are considered to be threshold

Hormesis• By definition, hormesis is a generally favorable biological response to low

exposures to toxins or stressors that would give an unfavorable response at high exposures.

• Some studies of worker populations, plants, animals, and cells have shown favorable health outcomes at low exposures of radiation as compared to adverse outcomes at high exposures. However, these studies have not been accepted as proof of a hormetic effect from radiation.

• There are some studies in which the authors report that cells exposed to a small amount of radiation (called a conditioning dose) can actually produce what they refer to as an adaptive response that makes cells more resistant to another dose of radiation.

• Some potential issues:

▫ Many of the results cannot be reproduced (meaning that other scientists have tried to do the same testing and get the same results, but haven’t been able to; this suggests that the initial results might have been just due to chance).

▫ Not every type of cell has this capacity for an adaptive response.

▫ The adaptive response does not appear to last long (so the second radiation dose would have to occur soon after the conditioning dose).

Effects of Long-Term Exposure to Radiation...•MIIWIIQI: Effects of Long Term Exposure to Radiation •45 Hr PET Registry Review Course •Reference Number: 028613 •1.5 CEH’s

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