radiation biology robert metzger, ph.d.. biologic effects many factors determine the biologic...

Radiation Biology

Robert Metzger, Ph.D.

Biologic Effects Many factors determine the biologic response to radiation exposure Many factors determine the biologic response to radiation exposure Radiosensitivity and complexity of the biologic system determine the Radiosensitivity and complexity of the biologic system determine the

type of response from a given exposure type of response from a given exposure Usually complex organisms exhibit more sophisticated repair Usually complex organisms exhibit more sophisticated repair

mechanisms mechanisms Some responses appear instantaneously, others weeks to decadesSome responses appear instantaneously, others weeks to decades

c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2ndnd ed., p. 814. ed., p. 814.

Classification of Bio Effects

Biologic effects of radiation exposure can be classified Biologic effects of radiation exposure can be classified as either stochastic or deterministic (non-stochastic) as either stochastic or deterministic (non-stochastic)

Stochastic Effect Stochastic Effect The probability of the effect, rather than its severity, ↑ with dose The probability of the effect, rather than its severity, ↑ with dose Radiation-induced cancer and genetic effects Radiation-induced cancer and genetic effects Basic assumption: risk ↑ with dose and no threshold Basic assumption: risk ↑ with dose and no threshold Injury to a few cells or even a single cell can theoretically result Injury to a few cells or even a single cell can theoretically result

in manifestation of disease in manifestation of disease The principal health risk from low-dose radiationThe principal health risk from low-dose radiation

Classification of Bio Effects

Deterministic or Non-stochastic Effect Deterministic or Non-stochastic Effect Predominant biologic effect is cell killing resulting in Predominant biologic effect is cell killing resulting in

degenerative changes to the exposed tissue degenerative changes to the exposed tissue Severity of the effect, rather than its probability, ↑ with dose Severity of the effect, rather than its probability, ↑ with dose Require much higher dose to produce an effect Require much higher dose to produce an effect Threshold dose below which the effect is not seen Threshold dose below which the effect is not seen Cataracts, erythyma, fibrosis, and hematopoietic damage are Cataracts, erythyma, fibrosis, and hematopoietic damage are

some deterministic effects some deterministic effects Dx radiology: only observed in some lengthy, fluoroscopically Dx radiology: only observed in some lengthy, fluoroscopically

guided interventional proceduresguided interventional procedures

Interaction of Radiation with Tissue

Ionizing radiation energy deposited randomly and rapidly Ionizing radiation energy deposited randomly and rapidly (< 10(< 10-10-10 sec) via excitation, ionization & thermal heating sec) via excitation, ionization & thermal heating

Interactions producing biologic changes classified as Interactions producing biologic changes classified as either direct or indirect either direct or indirect

Direct Direct Critical targets (e.g., DNA, RNA or protein) directly ionized or Critical targets (e.g., DNA, RNA or protein) directly ionized or

excited excited

Indirect Indirect Radiation interacts within the medium (e.g., cytoplasm) creating Radiation interacts within the medium (e.g., cytoplasm) creating

reactive chemical species (free radicals) which in turn interact reactive chemical species (free radicals) which in turn interact with the a critical target macromoleculewith the a critical target macromolecule


Vast majority of interactions are indirect (body 70% - Vast majority of interactions are indirect (body 70% - 85% water) 85% water) Results in an unstable ion pair, HResults in an unstable ion pair, H22OO++, H, H22OO- -

Dissociate into another ion and a free radical (lifetime is less Dissociate into another ion and a free radical (lifetime is less than 10than 10-5-5) )

HH22OO++ H H++ + OH• + OH•

HH22OO- - H• + OH H• + OH- -

Combine w/ other free radicals to form molecules such Combine w/ other free radicals to form molecules such as hydrogen peroxide (Has hydrogen peroxide (H22OO22) → highly toxic to cell ) → highly toxic to cell

Oxygen enhances free radical damage via production of Oxygen enhances free radical damage via production of reactive oxygen species (e.g., H• + Oreactive oxygen species (e.g., H• + O22 → HO → HO22•)•)

Linear Energy Transfer Biological effect dependent on the dose, dose rate, Biological effect dependent on the dose, dose rate,

environmental conditions, radiosensitivity and the spatial environmental conditions, radiosensitivity and the spatial distribution of energy deposition distribution of energy deposition

Linear Energy Transfer (LET) Linear Energy Transfer (LET) Amount of energy deposited per unit length (eV/cm) Amount of energy deposited per unit length (eV/cm) LET LET q q22/KE /KE Describes the energy deposition density which largely Describes the energy deposition density which largely

determines the biologic consequence of radiation exposure determines the biologic consequence of radiation exposure High LET radiation: High LET radiation: αα2+2+, p, p++, and other heavy ions , and other heavy ions Low LET radiation: Low LET radiation:

Electrons (eElectrons (e--, , ββ-- and and ββ++) ) EM radiation (x-rays or EM radiation (x-rays or -rays) -rays)

High LET >> damaging than low LET radiationHigh LET >> damaging than low LET radiation

Relative Biological Effectiveness (RBE)

Although all ionizing radiation capable of producing a Although all ionizing radiation capable of producing a specific biological effect, the magnitude/dose differs specific biological effect, the magnitude/dose differs

Compare dose required to produce the same specific Compare dose required to produce the same specific biologic response as a reference radiation dose (typically biologic response as a reference radiation dose (typically 250 kVp x-rays): Relative Biological Effectiveness (RBE) 250 kVp x-rays): Relative Biological Effectiveness (RBE)

Essential in establishing radiation weighting factors (wEssential in establishing radiation weighting factors (wRR) ) X-rays/gamma rays/electrons: LET ≈ 2 keV/X-rays/gamma rays/electrons: LET ≈ 2 keV/μμm; wm; wRR = 1 = 1

Protons (< 2MeV): LET ≈ 20 keV/Protons (< 2MeV): LET ≈ 20 keV/μμm; wm; wRR = 5-10 = 5-10

Neutrons (E dep.): LET ≈ 4-20 keV/Neutrons (E dep.): LET ≈ 4-20 keV/μμm; wm; wRR = 5-20 = 5-20

Alpha Particle: LET ≈ 40 keV/Alpha Particle: LET ≈ 40 keV/μμm; wm; wRR = 20 = 20

H (equivalent dose, Sv) = D (absorbed dose, Gy) ∙ wH (equivalent dose, Sv) = D (absorbed dose, Gy) ∙ wRR

LET vs. RBE


Cellular Targets Radiation-sensitive targets are located in the nucleus Radiation-sensitive targets are located in the nucleus

and not the cytoplasm of the cell and not the cytoplasm of the cell Cell death may occur if key macromolecules (e.g., DNA) Cell death may occur if key macromolecules (e.g., DNA)

which have no replacement are damaged or destroyed which have no replacement are damaged or destroyed Considerable evidence that damage to DNA is the Considerable evidence that damage to DNA is the

primary cause of radiation-induced cell death primary cause of radiation-induced cell death Concept of key or critical targets has led to a model of Concept of key or critical targets has led to a model of

radiation-induced cellular damage termed radiation-induced cellular damage termed target theorytarget theory in which critical targets may be inactivated by one or in which critical targets may be inactivated by one or more ionization events (hits)more ionization events (hits)

Radiation Effects on DNA


Cellular Radiosensitivity Studied through radiation-Studied through radiation-

induced cell death (loss of induced cell death (loss of reproductive integrity) reproductive integrity)

Useful in assessing the relative Useful in assessing the relative biologic impact of various biologic impact of various types of radiation and types of radiation and exposure conditions exposure conditions

Cellular inability to form Cellular inability to form colonies as a function of colonies as a function of radiation exposure → cell radiation exposure → cell survival curves survival curves

Three parameters defining Three parameters defining response to radiation: n, Dresponse to radiation: n, Dqq and Dand D00 c.f. Bushberg, et al. The Essential Physics of Medical c.f. Bushberg, et al. The Essential Physics of Medical

Imaging, 2Imaging, 2ndnd ed., p. 822. ed., p. 822.

Cell Survival Cures: n n: Extrapolation number - n: Extrapolation number -

found by extrapolating the found by extrapolating the linear portion of the curve back linear portion of the curve back through the y-axis Represents through the y-axis Represents either the number of targets in either the number of targets in a cell that must be a cell that must be “hit” once by a radiation event “hit” once by a radiation event to inactivate the cell or the to inactivate the cell or the number of “hits” required on a number of “hits” required on a single critical target to single critical target to inactivate the cell inactivate the cell

For mammalian cells: [2,10]For mammalian cells: [2,10]

c.f. Bushberg, et al. The Essential Physics of Medical c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2Imaging, 2ndnd ed., p. 822. ed., p. 822.

Cell Survival Curves: D0

DD00: Mean lethal dose : Mean lethal dose

Radiosensitivity of the cell Radiosensitivity of the cell population under study population under study

Dose producing a Dose producing a 63%63% (1-e (1-e-1-1) ) reduction in viable cell number: reduction in viable cell number: slope = slope = ΔΔy/y/ΔΔx = .63/Dx = .63/D0 0 (e (e

≈ 2.72; e≈ 2.72; e-1-1 = 0.37) = 0.37) reciprocal linear region slope reciprocal linear region slope Radioresistant cell DRadioresistant cell D00 > >

radiosensitive cell Dradiosensitive cell D00

↓ ↓ DD00 → lesser survival/dose → lesser survival/dose

Mammalian cells: [1Gy,2Gy]Mammalian cells: [1Gy,2Gy]c.f. Bushberg, et al. The Essential Physics of Medical c.f. Bushberg, et al. The Essential Physics of Medical


Cell Survival Curves: Dq

DDqq: Quasithreshold dose (D: Quasithreshold dose (Dqq

= D= D00 · log · logeen) n)

Width of the shoulder region Width of the shoulder region and a measure of sublethal and a measure of sublethal damage damage

Irradiated cells remain viable Irradiated cells remain viable until enough hits received to until enough hits received to inactivate the critical target or inactivate the critical target or targets targets

Clear evidence that for low-LET Clear evidence that for low-LET radiation, damage produced by radiation, damage produced by a single radiation interaction a single radiation interaction with cellular critical target(s) is with cellular critical target(s) is insufficient to produce insufficient to produce reproductive deathreproductive death c.f. Bushberg, et al. The Essential Physics of Medical c.f. Bushberg, et al. The Essential Physics of Medical


Factors Affecting Cellular Radiosensitivity

Conditional factors - physical or chemicals factors that Conditional factors - physical or chemicals factors that exist previous to and/or at irradiation exist previous to and/or at irradiation Dose rate Dose rate LET LET Fractionation Fractionation Presence of oxygen Presence of oxygen

Inherent factors - biologic factors characteristic of the cell Inherent factors - biologic factors characteristic of the cell Mitotic rate Mitotic rate Degree of differentiation Degree of differentiation Cell cycle phaseCell cycle phase

Conditional Factors-Dose Rate


Which has highest D0?

Which has highest n?

Which has highest DDqq??

Conditional Factors-LET


Conditional Factors-Fractionation


Conditional Factors-Presence of Oxygen

Increases cell damage by inhibiting Increases cell damage by inhibiting Free radical recombination to form harmless chemical species Free radical recombination to form harmless chemical species Repair of damage caused by free radicals Repair of damage caused by free radicals

Oxygen enhancement ratio (OER): ratio of dose Oxygen enhancement ratio (OER): ratio of dose producing a given biologic response in the absence of producing a given biologic response in the absence of oxygen to that in the presence of oxygen oxygen to that in the presence of oxygen

Mammalian cells Mammalian cells Low-LET: [2,3] Low-LET: [2,3] High-LET: [1,2]High-LET: [1,2]

Conditional Factors- Oxygen

Conditional Factors - OxygenConditional Factors - Oxygen

c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2ndnd ed., p. ed., p.

Inherent Factors: Inherent Factors: Law of Bergonie & TribondeauLaw of Bergonie & Tribondeau

Radiosensitivity Radiosensitivity greatest for cells with greatest for cells with High mitotic rate High mitotic rate Long mitotic future Long mitotic future UndifferentiatedUndifferentiated


Inherent Factors-Cell Cycle Phase

Cells are most sensitive to Cells are most sensitive to radiation during mitosis (M radiation during mitosis (M phase) and RNA synthesis phase) and RNA synthesis (G2 phase) (G2 phase)

Less sensitive during the Less sensitive during the preparatory period for DNA preparatory period for DNA synthesis (G1 phase) synthesis (G1 phase)

Least sensitive during DNA Least sensitive during DNA synthesis (S phase) synthesis (S phase)

During mitosis (M), the During mitosis (M), the metaphase is the most metaphase is the most sensitivesensitive


Davis Notes-Radiation Biology

4. The quasi-threshold dose (Dq) for cell line C is:

A. 500 B. 700 C. 1,000 D. 1,500 E. impossible to

determine from this data

Huda 2nd Edition-Chapter 10-Radiation Biology

1. Radiological LD50 is the radiation dose that kills:

(A) 50% of exposed cells (B) 50 exposed cells (C) All exposed cells within 50 days (D) e-50 of exposed cells (E) e/50 of exposed cells


10. Stochastic effects of radiation (A) Can be recognized as caused by radiation (B) Have a dose-dependent severity (C) Have a threshold of 50 mSv/year (D) Include carcinogenesis (E) Involve cell killing


5. The LET of x-rays is: (A) Between 0.3 and 3 keV/μm (B) Cannot be defined for energies greater than 2

MeV (C) Greater than the LET for alpha particles (E) Low energy threshold (D) Independent of relative biological effectiveness

(RBE)


4. Which is not true of the interaction of ionizing radiation with tissues?

(A) Cellular DNA is a key target (B) Direct action is more frequent than indirect action (D) Ions can dissociate into free radicals (E) It can produce chromosome aberrations

(C) Indirect action causes most of the biological damage


3. Which cells are considered to be the least radiosensitive?

(A) Bone marrow cells (B) Lymphoid tissues (C) Neuronal cells (D) Skin cells (E) Spermatids


2. The cell division stage most sensitive to radiation is:

(A) Anaphase (B) Interphase (C) Metaphase (D) Prophase (E) Telophase

Organ Systems Response: Regenerization and Repair


Organ Organ Systems Systems Response: Response:

SkinSkin

c.f. Bushberg, et al. The c.f. Bushberg, et al. The Essential Physics of Medical Essential Physics of Medical Imaging, 2Imaging, 2ndnd ed., p. 830. ed., p. 830.

Organ Systems Response: Reproductive System

Gonads are very radiosensitive Gonads are very radiosensitive Females Females

Temporary sterility: 1.5 Gy (150 rad) acute dose Temporary sterility: 1.5 Gy (150 rad) acute dose Permanent sterility: 6.0 Gy (600 rad) acute dose* Permanent sterility: 6.0 Gy (600 rad) acute dose*

*reported for doses as low as 3.2 Gy *reported for doses as low as 3.2 Gy

Males Males Temporary sterility: 2.5 Gy (250 rad) acute dose* Temporary sterility: 2.5 Gy (250 rad) acute dose*

*reported for doses as low as 1.5 Gy *reported for doses as low as 1.5 Gy Permanent sterility: 5.0 Gy (500 rad) acute dose Permanent sterility: 5.0 Gy (500 rad) acute dose Reduced fertility 20-50 mGy/wk (2-5 rad/wk) when total dose > Reduced fertility 20-50 mGy/wk (2-5 rad/wk) when total dose >

2.5 Gy2.5 Gy

Organ Systems Response: Ocular Effects

Eye lens contains a population of radiosensitive cells Eye lens contains a population of radiosensitive cells Cataract magnitude and probability of occurrence Cataract magnitude and probability of occurrence to the dose to the dose Acute doses Acute doses

= 2 Gy (200 rad) cataracts in a small percentage of people exposed = 2 Gy (200 rad) cataracts in a small percentage of people exposed > 7 Gy (700 rad = 700 cGy) always produce cataracts > 7 Gy (700 rad = 700 cGy) always produce cataracts

Protracted exposure Protracted exposure 2 months: 4 Gy threshold 2 months: 4 Gy threshold 4 months: 5.5 Gy threshold 4 months: 5.5 Gy threshold

Unlike senile cataracts that typically develop in the anterior pole of Unlike senile cataracts that typically develop in the anterior pole of the lens radiation-induced cataracts begin with a small opacity in the the lens radiation-induced cataracts begin with a small opacity in the posterior pole and migrate anteriorly posterior pole and migrate anteriorly

Acute Radiation Syndrome Characteristic clinical response when whole body (or Characteristic clinical response when whole body (or

large part thereof) is subjected to a large acute external large part thereof) is subjected to a large acute external radiation exposure radiation exposure

Organism response quite distinct from isolated local Organism response quite distinct from isolated local radiation injuries such as epilation or skin ulcerations radiation injuries such as epilation or skin ulcerations

Combination of subsyndromes occurring in stages over Combination of subsyndromes occurring in stages over hours to weeks as the injury to various tissues and hours to weeks as the injury to various tissues and organs is expressed organs is expressed

In order of their occurrence with increasing radiation In order of their occurrence with increasing radiation dose: dose: Hematopoietic syndrome Hematopoietic syndrome Gastrointestinal syndrome Gastrointestinal syndrome Neurovascular syndromeNeurovascular syndrome

ARS Sequence of Events ProdromalProdromal symptoms typically symptoms typically

begin within 6 hours of exposure begin within 6 hours of exposure No symptoms during the No symptoms during the latentlatent

period, which may last up to 6 period, which may last up to 6 weeks for dose < 1 Gy weeks for dose < 1 Gy

Manifest illnessManifest illness stage: onset of stage: onset of organ system damage clinical organ system damage clinical expression which can last 2-3 wks expression which can last 2-3 wks

Most difficult to manage from a Most difficult to manage from a therapeutic standpoint therapeutic standpoint

Treatment during the first 6-8 wks Treatment during the first 6-8 wks essential to optimize recovery essential to optimize recovery

Higher risk of cancer and genetic Higher risk of cancer and genetic abnormalities in future progeny if abnormalities in future progeny if patient survivespatient survives

c.f. Bushberg, et al. The Essential Physics of Medical c.f. Bushberg, et al. The Essential Physics of Medical Imaging, 2Imaging, 2ndnd ed., pp. 832-3. ed., pp. 832-3.

Acute Radiation Syndrome Interrelationships

c.f. Bushberg, et al. c.f. Bushberg, et al. The Essential The Essential Physics of Medical Physics of Medical Imaging, 2Imaging, 2ndnd ed., p. ed., p. 836.836.

Epidemiologic Investigations of Radiation Induced Cancer

Dose-response relationships for cancer induction at high Dose-response relationships for cancer induction at high dose and dose rate have been well established dose and dose rate have been well established

Not so for low dose exposures like those resulting from Not so for low dose exposures like those resulting from diagnostic and occupational exposures diagnostic and occupational exposures

Very difficult to detect a small increase in the cancer rate Very difficult to detect a small increase in the cancer rate due to radiation due to radiation Natural incidence of many forms of cancer is high Natural incidence of many forms of cancer is high Latent period for most cancers is long Latent period for most cancers is long

To rule out simple statistical fluctuations, a very large To rule out simple statistical fluctuations, a very large irradiated population is requiredirradiated population is required

Difficulties in Quantifying Low Dose Risk

If excess risk proportional to dose, If excess risk proportional to dose, then large studies are required for then large studies are required for low absorbed dose to maintain low absorbed dose to maintain statistical precision and power; the statistical precision and power; the necessary sample power necessary sample power increases approximately as the increases approximately as the inverse square of dose inverse square of dose

This relationship reflects a decline This relationship reflects a decline in the signal (radiation risk) to in the signal (radiation risk) to noise (natural background risk) noise (natural background risk) ratio as dose decreases. ratio as dose decreases.

500 persons needed to quantify 500 persons needed to quantify the effect of a 1,000 mSv dose the effect of a 1,000 mSv dose

50,000 for a 100 mSv dose 50,000 for a 100 mSv dose 5 million for a 10 mSv dose (a 5 million for a 10 mSv dose (a

single body CT = 7.5 mSv)single body CT = 7.5 mSv)

National Research Council (1995) Radiation Dose Reconstruction for Epidemiologic Uses. Natl. Acad. Press

SS = c/D2

What is the Evidence?

Major epidemiological investigations that form the basis Major epidemiological investigations that form the basis of current cancer dose-response estimates in human of current cancer dose-response estimates in human populations: populations: Atomic-bomb survivors (Japan) life span study (LSS) Atomic-bomb survivors (Japan) life span study (LSS) Anklyosing spondylitis (UK) Anklyosing spondylitis (UK) Postpartum mastitis study (New York) Postpartum mastitis study (New York) Radium dial painters (Tritium) Radium dial painters (Tritium) Thorotrast (radioactive Thorium x-ray contrast agent) Thorotrast (radioactive Thorium x-ray contrast agent) Massachusetts tuberculosis patients (multiple chest fluoroscopy) Massachusetts tuberculosis patients (multiple chest fluoroscopy) Stanford University Hodgkin’s disease patients (x-ray therapy)Stanford University Hodgkin’s disease patients (x-ray therapy)

Risk Estimation Models Dose-Response Curves

Dose-response models predict Dose-response models predict cancer risk from exposure to cancer risk from exposure to low levels of ionizing radiation low levels of ionizing radiation → dose-response curves → dose-response curves

Linear, non-threshold (LNT) Linear, non-threshold (LNT) Effect = Effect = α∙α∙DoseDose

Linear-quadratic, non-Linear-quadratic, non-threshold threshold Effect = Effect = α∙α∙Dose + Dose + β∙β∙DoseDose22 αα//ββ: [1Gy-10Gy] : [1Gy-10Gy] appears linear for low dose appears linear for low dose appears quadratic (non-linear) appears quadratic (non-linear)

for higher dosefor higher dose


Risk Estimation Models-Risk Models

Multiplicative risk model: after Multiplicative risk model: after a latent period, the excess risk a latent period, the excess risk is a multiple of the natural age-is a multiple of the natural age-specific cancer risk for the specific cancer risk for the population in question population in question

Additive risk model: fixed or Additive risk model: fixed or constant increase in risk constant increase in risk unrelated to the spontaneous unrelated to the spontaneous age-specific cancer risk at the age-specific cancer risk at the time of exposure time of exposure

Latency periods: Latency periods: Leukemia 10 yrs average Leukemia 10 yrs average Solid tumors 25 yrs averageSolid tumors 25 yrs average


Risk Estimation Models-Risk Expression

Relative Risk Relative Risk Ratio of the cancer incidence in the exposed population to that in the Ratio of the cancer incidence in the exposed population to that in the

general (unexposed) population general (unexposed) population RR of 1.2 would indicate 20% increase over the spontaneous rate RR of 1.2 would indicate 20% increase over the spontaneous rate Excess relative risk is simply RR - 1 Excess relative risk is simply RR - 1

Absolute Risk Absolute Risk Expressed as the number of excess radiation-induced cancers per 10Expressed as the number of excess radiation-induced cancers per 1044

people/Sv-yr people/Sv-yr For a cancer with a radiation-induced risk of 4 per 10,000 person/Sv-yr For a cancer with a radiation-induced risk of 4 per 10,000 person/Sv-yr

and a latency period of 20 years, the risk of developing cancer from a and a latency period of 20 years, the risk of developing cancer from a dose of 0.1 Sv (~13x body CT dose) within the next 40 years would be: dose of 0.1 Sv (~13x body CT dose) within the next 40 years would be:

(40-20) or 20 years x 0.1 Sv x 4 per 10,000 person/Sv-yr (40-20) or 20 years x 0.1 Sv x 4 per 10,000 person/Sv-yr = 8 per 10,000 or 0.08%= 8 per 10,000 or 0.08%

Radiation Standards Organizations

Independent bodies of experts Independent bodies of experts evaluate informationevaluate information on radiation on radiation health effects health effects BIER - National Academy of Sciences/National Research Council BIER - National Academy of Sciences/National Research Council

Committee on the Biological Effects of Ionizing Radiation Committee on the Biological Effects of Ionizing Radiation UNSCEAR - United Nations Scientific Committee on the Effects of UNSCEAR - United Nations Scientific Committee on the Effects of

Radiation Radiation RERF - Radiation Effects Research Foundation RERF - Radiation Effects Research Foundation

Experts draw upon this collective knowledge to Experts draw upon this collective knowledge to develop develop recommendationsrecommendations for systems of radiation protection for systems of radiation protection NCRP – National Council on Radiation Protection and Measurements NCRP – National Council on Radiation Protection and Measurements ICRP – International Commission on Radiological Protection ICRP – International Commission on Radiological Protection

Radiation protection Radiation protection regulatory framework regulatory framework NRC – Nuclear Regulatory Commission NRC – Nuclear Regulatory Commission EPA - Environmental Protection AgencyEPA - Environmental Protection Agency

BEIR V Risk Estimates

BEIR published a report in 1990 entitled, “The Health Effects of BEIR published a report in 1990 entitled, “The Health Effects of Exposure to Low Levels of Ionizing Radiation” or the BEIR V report Exposure to Low Levels of Ionizing Radiation” or the BEIR V report

Single best estimate of radiation-induced mortality at low exposure Single best estimate of radiation-induced mortality at low exposure levels is 4% per Sv (0.04% per rem) for a working population (ICRP levels is 4% per Sv (0.04% per rem) for a working population (ICRP - 5% per Sv for the whole population - takes children into account) - 5% per Sv for the whole population - takes children into account)

The single best estimate of radiation-induced mortality at high doses The single best estimate of radiation-induced mortality at high doses applied at high dose rate is 8% per Sv (0.08% per rem) applied at high dose rate is 8% per Sv (0.08% per rem)

The BEIR V Committee believed that the LNT dose-response model The BEIR V Committee believed that the LNT dose-response model was best for all cancers except leukemia and bone cancer; for those was best for all cancers except leukemia and bone cancer; for those malignancies, a linear-quadratic model was recommended malignancies, a linear-quadratic model was recommended

According to the LNT model, an exposure of 10,000 people to 10 According to the LNT model, an exposure of 10,000 people to 10 mSv would result in approximately 4 cancer deaths in addition to the mSv would result in approximately 4 cancer deaths in addition to the 2,200 (22%) normally expected in the general population2,200 (22%) normally expected in the general population

ACRP 60 Risk Estimates


Specific Cancer Risk Estimates: Leukemia

Natural incidence in US Natural incidence in US population: 1 in 10population: 1 in 1044 (0.01%) (0.01%)

17% of total mortality from 17% of total mortality from radiocarcinogenesis radiocarcinogenesis

The incidence of leukemia The incidence of leukemia greatly influenced by age at greatly influenced by age at the time of exposure the time of exposure

BEIR V: nonlinear dose-BEIR V: nonlinear dose-response model predicting response model predicting excess life-time risk of 10 in excess life-time risk of 10 in 101044 (0.1%) after exposure to (0.1%) after exposure to 0.1 Gy (10 rad) 0.1 Gy (10 rad)

Average latent period = 10 yrsAverage latent period = 10 yrsc.f. Bushberg, et al. The Essential Physics of Medical c.f. Bushberg, et al. The Essential Physics of Medical


Specific Cancer Risk Estimates: Thyroid Cancer

6-12% of total mortality from radiocarcinogenesis 6-12% of total mortality from radiocarcinogenesis Females 3-5x greater risk than males Females 3-5x greater risk than males Latency period Latency period

Benign nodules: 5-35 yrs Benign nodules: 5-35 yrs Thyroid malignancies: 10-35 yrs Thyroid malignancies: 10-35 yrs

Dose-response curve: LNT Dose-response curve: LNT Associated mortality rate: 5% Associated mortality rate: 5% However, other responses such as hypothyroidism and However, other responses such as hypothyroidism and

thyroiditis with thresholds: thyroiditis with thresholds: 2 Gy for external irradiation 2 Gy for external irradiation 50 Gy for internal radiation (radioactive materials like 50 Gy for internal radiation (radioactive materials like 131131I)I)

Specific Cancer Risk Estimates: Breast Cancer

One of 8 US women at risk of developing breast cancer One of 8 US women at risk of developing breast cancer 180,000 new cases/yr 180,000 new cases/yr 1 in 30 women die of breast cancer 1 in 30 women die of breast cancer Low LET radiation risk age dependent, ≈ 50 times greater for the 15 Low LET radiation risk age dependent, ≈ 50 times greater for the 15

yo age group (≈ 0.3% per year) after exposure of 0.1 Gy than those yo age group (≈ 0.3% per year) after exposure of 0.1 Gy than those > 55 yo > 55 yo

The risk estimates for women in the 25, 35 and 45 yo age groups The risk estimates for women in the 25, 35 and 45 yo age groups are 0.05%, 0.04% to 0.02% respectively (BEIR V) are 0.05%, 0.04% to 0.02% respectively (BEIR V)

Dose-response curve: LNT w/ dose of ≈ 0.8 Gy doubling the natural Dose-response curve: LNT w/ dose of ≈ 0.8 Gy doubling the natural incidence incidence

Latent period [10yrs,40yrs]; longer latencies with younger womenLatent period [10yrs,40yrs]; longer latencies with younger women

Increased Risk of Induced Breast Cancer Before 65 Years of Age per 25 mSv Breast Organ Dose for Age at Exposure

0.000%

0.020%

0.040%

0.060%

0.080%

0.100%

0.120%

0.140%

0.160%

10 20 30 40 50 60

Years of Age at Exposure

Incr

ease

d R

isk/

25 m

Sv

Comparisons of the Risks of Some Medical Exams

Davis Notes- Radiation Biology

9. The overall fatal cancer risk per rad of whole body low LET radiation of a population selected at random would be on the order of:

A. 104

B. 102

C. 10-4

D. 10-6

E. 106

Risk ≈ 1 cSv (1 rad) · 0.04/Sv = 0.0004 = 4x10-4

Genetic Effects in Humans

Genetic effects the result of radiation exposure to the Genetic effects the result of radiation exposure to the gonads gonads

Epidemiological investigations have failed to Epidemiological investigations have failed to demonstrate radiation-induced genetic effects demonstrate radiation-induced genetic effects

Current risk estimates are based on animal experiments Current risk estimates are based on animal experiments For workers, the risk of severe hereditary effects is 0.8% For workers, the risk of severe hereditary effects is 0.8%

per Sv of gonadal radiation according to the ICRP per Sv of gonadal radiation according to the ICRP For a whole population, the risk of severe hereditary For a whole population, the risk of severe hereditary

effects is 1.3% per Sv which is higher because of the effects is 1.3% per Sv which is higher because of the inclusion of childreninclusion of children

Radiation Effects In Utero

Gestational period divided into 3 stages: Gestational period divided into 3 stages: Relatively short preimplantation stage (day 0-9) Relatively short preimplantation stage (day 0-9) Extended period of major organogenesis (day 9-56) Extended period of major organogenesis (day 9-56) Fetal growth stage (day 45 to term) Fetal growth stage (day 45 to term)

Preimplantation: conceptus extremely sensitive and Preimplantation: conceptus extremely sensitive and radiation damage can result in prenatal death: “All-or-radiation damage can result in prenatal death: “All-or-nothing response” nothing response”

Animal experiments have demonstrated an increase in Animal experiments have demonstrated an increase in the spontaneous abortion rate after doses as low as 50 the spontaneous abortion rate after doses as low as 50 to 100 mGy (5 to 10 rad)to 100 mGy (5 to 10 rad)

Critical Periods for Radiation-Induced Birth Defects


major organogenesis

fetal growth

pre-implantation

Relative Incidence of Radiation-Induced Health Effects at Various Stages in Fetal Development


Radiation Effects In Utero (2)

Exposures > 1 Gy associated with a high incidence of Exposures > 1 Gy associated with a high incidence of CNS abnormalities CNS abnormalities

Growth retardation after in utero exposure ≥ 100 mGy Growth retardation after in utero exposure ≥ 100 mGy demonstrated demonstrated

Fetal doses generally are much less than 100 mGy in Fetal doses generally are much less than 100 mGy in most diagnostic and nuclear medicine procedures and most diagnostic and nuclear medicine procedures and thought to carry negligible risk compared with the thought to carry negligible risk compared with the spontaneous incidence of congenital abnormalities (4%-spontaneous incidence of congenital abnormalities (4%-6%) 6%)

A conservative estimate of the excess risk of childhood A conservative estimate of the excess risk of childhood cancer from cancer from in uteroin utero irradiation is ≈ 6% per Gy (0.06% per irradiation is ≈ 6% per Gy (0.06% per rad)rad)


Recommendations from Wagner* are: Recommendations from Wagner* are: If radiation dose received during or prior to the first two If radiation dose received during or prior to the first two

weeks post conception (< 14 days) weeks post conception (< 14 days) Exposure to diagnostic radiation is not an indication for Exposure to diagnostic radiation is not an indication for

therapeutic abortion therapeutic abortion For patients exposed to radiation between the 2nd and For patients exposed to radiation between the 2nd and

8th weeks post-conception (days 14-56): 8th weeks post-conception (days 14-56): Therapeutic abortion based solely on radiation exposure is not Therapeutic abortion based solely on radiation exposure is not

advised for dose less than 150 mGy (15 rad) advised for dose less than 150 mGy (15 rad) Dose exceeding 150 mGy (15 rad) may be an indication for Dose exceeding 150 mGy (15 rad) may be an indication for

therapeutic abortion in the presence of less severely therapeutic abortion in the presence of less severely compromising factors. However, diagnostic studies rarely result compromising factors. However, diagnostic studies rarely result in such dose levels.in such dose levels.

* Wagner, et al. Exposure of the Pregnant Patient to Diagnostic Radiation, pp. 166-* Wagner, et al. Exposure of the Pregnant Patient to Diagnostic Radiation, pp. 166-7.7.


For a conceptus exposed between the 8th and 15th For a conceptus exposed between the 8th and 15th week post-conception (days 56-105): week post-conception (days 56-105): Fetal dose below 50 mGy (5 rad) Fetal dose below 50 mGy (5 rad)

Radiation not a sufficient risk to justify therapeutic abortion Radiation not a sufficient risk to justify therapeutic abortion Fetal dose between 50-150 mGy (5-15 rad) Fetal dose between 50-150 mGy (5-15 rad)

therapeutic abortion is not advisable on the basis of the radiation therapeutic abortion is not advisable on the basis of the radiation risk alone risk alone

Fetal dose above 150 mGy (15 rad) Fetal dose above 150 mGy (15 rad) In this time interval there is scientific evidence that may support a In this time interval there is scientific evidence that may support a

recommendation for therapeutic abortion based on the radiation recommendation for therapeutic abortion based on the radiation exposure. However, this does not mean an abortion is necessarily exposure. However, this does not mean an abortion is necessarily recommended. Diagnostic studies rarely result in such dose levels.recommended. Diagnostic studies rarely result in such dose levels.



Fetal dose at 150 mGy: Fetal dose at 150 mGy: Up to a 6% probability the child could be mentally retarded Up to a 6% probability the child could be mentally retarded

Natural incidence = 0.4% Natural incidence = 0.4% Probability the child will develop cancer < 3% Probability the child will develop cancer < 3%

Natural incidence = 1.4% Natural incidence = 1.4% Probability of small head size ≈ 15% (but does not necessarily Probability of small head size ≈ 15% (but does not necessarily

affect normal mental function) affect normal mental function) Natural incidence = 4% Natural incidence = 4%

IQ may fall a few points short of its full potential IQ may fall a few points short of its full potential Except for possible effects to individual organs from radionuclide Except for possible effects to individual organs from radionuclide

studies, no other risks have been demonstrated. However, studies, no other risks have been demonstrated. However, always practice ALARA!always practice ALARA!


Effect of In Utero Risk Factors on Outcome


In Utero Irradiation Summary



15. When is gross malformation most likely to occur? (A) Early fetal period (B) Early organogenesis (C) Late fetal period (D) Late organogenesis (E) Preimplantation


16. What “threshold” embryo/fetal dose corresponds to a radiation risk smaller than those normally encountered during pregnancy?

(A) Less than 10 mGy (1 rad) (B) 10 mGy (1 rad) (C) 30 mGy (3 rad) (D) 100 mGy (10 rad) (E) More than 100 mGy (10 rad)

Davis Notes-Radiation Biology 6. A barium enema was performed on a 25 year-old female who was

determined to be three weeks pregnant at the time of examination. As the consulting radiologist, you should:

A. Recommend a therapeutic abortion. B. Counsel the patient that the embryo is at a significantly high risk for gross

malformations as a result of the radiation exposure; however, an abortion is not

necessarily warranted. C. Discuss the implications of the radiation exposure with the hospital’s legal

department. D. Do not discuss any potential effects of the radiation exposure on the

embryo because very little is known about in utero radiation exposure and your

comment would be totally speculative and unsubstantiated. E. Explain to the referring physician and patient that the radiation received by

the embryo by this diagnostic procedure is relatively small and that the increase in

risk is negligible compared to the spontaneous incidence of congenital

abnormalities.

radiation biology robert metzger, ph.d.. biologic effects many factors determine the biologic...

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