Flashcards RADSCI 4670 - exam 2

law of bergonie and tribondeau

- radiosensitivity increases with increased rate of cell division, low degree of differentiation, ability to divide multiple times for a long period of time

- increased rate of cell division: more frequent DNA replication events --> more chances for mis-repair

- low degree of specialization: primitive, undifferentiated cells divide rapidly (stem cells)

- ability to divide multiple times for a long time period: long mitotic future --> cell lineage has many mitosis rounds (high reproductive potential)

- 3 factors = unspecialized / undifferentiated, high reproductive rate, high reproductive potential

-Stem cells carry the burden of renewing tissues, if radiation kills these cells,

the tissues lose capacity to regenerate - radiosensitivity is DIRECTLY proportional to reproductive rate and INVERSELY proportional to differentiation; 1906, rodent testicle experiments; considered a "rule of thumb"

exceptions to the law of bergonie and tribondeau

- lymphocytes (white blood cells) = mature BUT radiosensitive (due to nuclear structure / having robust apoptotic pathways)

- oxygen = oxygen modifies sensitivity

- tissues & organs = studied individual cells rather than whole organs (tissues have multiple populations with different radiosensitivities heterogenious)

law of ancel & vitemberger

- cells are susceptible to radiation damage to the same degree, but the damage will only be expressed if and when the cell divides

- cells divide faster = display damage faster - proposed in 1925

differentiation

- process of maturation from non-specific cell type to a specialized cell (ex: stem cell in bone marrow matures into RBC)

- well differentiated = mature and specialized (RBC, lung cells)

- undifferentiated = immature and not specialized (primary function is to divide) --> stem cells

cell classification order (high --> low sensitivity)

1. vegetative intermitotic cell (VIM)

2. differentiating intermitotic cell (DIM)

3. multipotential connective tissue

4. reverting postmitotic cell (RPM)

5. fixed postmitotic cell (FPM)

vegetative intermitotic cell (VIM)

- rapidly dividing continuously

- undifferentiated

- short lifetime

- most sensitive cells in the body (stem cells)

-ex: Basal cells of epidermis, crypt cells of the intestines, type A spermatogonia and erythroblasts

• High dose radiation damage to the gut lining and bone marrow so severely

differentiating intermitotic cell (DIM)

- produced by division of VIM cells

- actively mitotic

- more differentiated than VIM cells

- divide regularly (undergo some maturation & differentiation between divisions)

-ex: • Type B spermatogonia, myelocytes (cells of the bone marrow)

• Radiosensitivity is moderate to high, but lower than VIM

multipotential connective tissue

- capacity for limited mitosis (divide irregularly)

- can differentiate into various connective tissue cell types (fibroblasts, chondrocytes, osteoblasts, etc.)

- stem-like cells in the in the stromal compartment or connective tissue

- radiation damage contributes to late effects (slower turnover makes early effects less dramatic)

-Their slow turnover makes early effects less dramatic than with VIM/DIMs - more differentiated than VIM/DIM; late effects = fibrosis, poor wound healing, osteoradionecrosis; ex: endothelial cells, fibroblasts

reverting postmitotic cell (RPM)

- don't normally undergo mitosis but have the capability of division under certain circumstances

- long lifespan

- more differentiated

- moderately radioresistant --> radiosensitivity depends on their ability to re-enter the cell cycle - ex: liver (parenchymal) cells, mature lymphocytes; if radiation prevents re-entry into the cell cycle, regeneration is impaired; long-term repair is compromised if stem pools AND RPMs are damaged

fixed postmitotic cell (FPM)

- fully differentiated & specialized cells that have permanently exited the cell cycle (cannot divide again = no capacity to revert to mitosis)

- long, functional lifespan

- most radioresistant (damage doesn't cause mitotic death but can impair function) ex:Nerve cells, muscle cells, erythrocytes (RBC's), spermatozoaand granulocytes

- loss of FPM produce late functional effects (cannot be replaced if destroyed) --> only replaceable by active stem cells - neurons have no stem cell pool to replace them

tissues & organ compartments

1. parenchymal compartment

2. stromal compartment

parenchymal compartment

- performs the function of the tissue / organ

- contains VIM, DIM, RPM, FPM --> composed of 1+ of these types of cells

- supported & held in place by the stromal compartment

stromal compartment

- supports the parenchymal compartment (supporting structure of the organ)

- composed of connective tissue & blood vessels - blood vessels supply cells with oxygen & nutrients

- intermediate in sensitivity

early / acute effects

- result from death of a large number of cells that occur within a few days / weeks of irradiation in tissues with a rapid turnover rate

-The type of cells include epithelial, gastrointestinal, and hematopoietic.

- side effects of treatment

- repair quickly due to rapid regeneration / proliferation

- larger field = more acute damage

- increases with dose & field size -characterized by the different a/b ratio

- ex: skin burns

late effects

- appear after a delay of months / years

- will affect the slowly proliferating cells ex:such as the lung, kidney, heart, liver and CNS

- may never be completely repaired

- cells that survived but maintained radiation exposure

- more sensitive to changes in fractionation

- ex: cancer

probability of late effects

- increases with dose, dose rate, LET

- late effects have long latent periods

- late effects seen in aging populations

carcinogensis

- process that leads to the formation of cancer

- cellular damage that doesn't repair may prevent the cell from surviving / reproducing OR result in a viable cells that has been modified (retains the damage from the exposure = mutation)

- radiation induced cancers & spontaneously occurs cancers are identical

- leukemia, thyroid, breast cancer

- risk is higher at younger ages (decrease risk with age)

cancer latent period

- time elapsed between radiation exposure & appearance of cancer

- radiation induced tumors = long latent period

- leukemia = shortest latent period (2 - 12yr)

- solid tumors = average 25yr (10 - 60yr)

consequential late effect

late effect that evolved from a persistent early effect (ex: multiple skin burns cause permanent issues)

factors affecting tissue / organ sensitivity

- field size

- fractionation (dose rate effect)

- time between doses of radiation (fractions)

field size

- more irradiated = more sensitive

- the more tissue destroyed = the more structural / functional deficit (less ability to repair)

fractionation (dose rate effect)

more a total dose is divided = less damage is done (repair of sublethal damage)

time between doses of radiation (fractions)

more prolonged a dose = less damage (proliferation & repair) - proliferating tissues show this effect the most

TD 5/5

5% risk within 5 years

what type of cell is not sensitive to radiation?

well differentiated

true or false: the cell classification is a determining factor as to if the tissue is sensitive or resistant to radiation

true

what are tissues composed of RPM and FPM cells considered?

well differentiated

free radicals

- atoms, molecules, ions with an unpaired electron

- highly reactive and short-lived

- Can propagate a chain reaction

• Becomes stable when electrons pair or a covalent bond forms

radiolysis

- ionization of water

- most common free radical produced = hydroxyl (OH-)

-Radiation deposits energy first and chemistry determines whether the initial damage is repaired or fixed

hypoxic

reduced oxygen - all anoxic conditions are severely hypoxic, but most hypoxic conditions are not anoxic

anoxic

no oxygen

radiolysis & oxygen

- oxygen increases sensitivity (anoxic = less sensitive)

- radicals / free electrons interact with oxygen --> creates more reactive oxygen species

- DNA is damaged --> becomes reactive & triggers self-healing

- oxygen can interact with the damaged spot to chemically change is (make it unrepairable =fixed) DNA radical-> O2 reacts -> damage becomes difficult to reverse

- oxygen makes the DNA damage "fixed" (permanent)

- presence of oxygen enhances radiation damage through generation of a second crop of radicals AND damage fixation

-Both mechanisms increase biologic effect without increasing the delivered physical dose.

oxygen enhancement ratio (OER)

-OER compares doses that produce the same biologic effect

- For x-rays and γ-rays, OER is commonly about 2.5-3.0. A hypoxic cell population may therefore require roughly 2.5-3× the dose for the same effect.

-high survical= low dose =curves closer near the shoulder = OER may appear smaller

-low survival = high dose =curves separate more = OER may be larger

-Oxygen fixes (makes permanent) a greater fraction of radiation-induced damage. As dose increases, aerated cells accumulate lethal damage faster than hypoxic cells, so the horizontal separation can

increase.

-resistant cells: a larger oxygen effect may remain visible because hypoxia adds resistance to an already shallow response.

-more sensitive cells: The difference between oxygen states may be smaller at some endpoints

because survival falls rapidly in both conditions.

-Do not use OER as a stand-alone measure of 'how radiosensitive' a cell is.

-Cell cycle: S phase: most resistant, OER may be lower (about 2-2.5) : OER remains unchanged—or decreases—as cells move through the cycle; it is not simply proportional to radiosensitivity.

OER formula

OER = Do in absence of oxygen (hypoxia) / Do in presence of oxygen (aerated conditions)

oxygen on the cell survival curve

- presence of oxygen creates a steeper slope on the cell survival curve

- lower Do = more sensitive (curve drops faster)

- aerated curve = steeper; hypoxic curve = shallower- OER = the horizontal gap between the two curves at the same survival level (not the steepness of one curve)

- more separation = higher OER (bottom of the graph)

- less separation = lower OER (top of the graph)

- steep curve = oxygenated

radiosensitivity: oxygen effect

- oxygen will only increase the response to radiation up to a point

- response to oxygen occurs between 0 - 20 mmHg

- oxygen has to be present within milliseconds after radiation

- saturation effect = above 20 mmHG (flattens out to 100%) - radiobiologic hypoxia = pO₂ < 20 mmHg; normal tissues ≈ 20-100 mmHg

- greatest change in radiation oxygen sensitization = 0 - 10 mmHg

-Small changes in a very hypoxic environment can produce large changes in radiosensitivity.

-clinical meaning: at the same low-LET radiation dose, hypoxic tumor cells are more likely to survive than well-oxygenated tumor cells.

tomlinson & gray

- tumor cells grow more rapidly when in close proximity to a blood supply (exchange O2)

- oxygen from the capillaries can only reach 160-180 um

- cells beyond 200 um = hypoxic

- hypoxic centers increase in size, but the outer thickness of aerated tissue remains below 200 um

- tumors grow actively only if close to oxygen

- hypoxic cells can become oxygenated through reoxygenation

-hypoxic cells: more resistant

-radiation resistance: low-LET photons rely strongly on oxygen-mediated radical chemistry, so hypoxia reduces damage fixation

-selection pressure: survival of cells adapted to low oxygen

-genomic instability: stress responses and impaired repair regulation

-angiogenesis: new vessels are abnormal and inefficient, sustaining uneven perfusion and hypoxia while supporting tumor growth

-The oxygen effect is one part of a broader hypoxic tumor phenotype. - tumor cords form around vessels; necrosis appears beyond the viable rim; the viable rim can still contain hypoxic cells

reoxygenation

- tumors contain a mixture of aerated & hypoxic cells

- tumor irradiated —> oxygenated cells die & hypoxic cells survive

- tumor shrinks —> hypoxic cells get closer to blood vessels & become oxygenated

- tumor irradiated again (cycle repeats)

- - after 10 Gy, anoxic fraction drops sharply in the first few hours, then plateaus near 20% → reoxygenation may be incomplete even after 6-12 hr

- complete reoxygenation = 6hr

-An increase in oxygenation of surviving tumor cells between fractions, which can increase their response to a later low-LET radiation dose.

tumor hypoxia

- hypoxic = harder to kill

- chronic = results of the limited diffusion range of oxygen through tissue

- acute = results of the temporary closing of tumor blood vessels (transient = swapping from hypoxia to aerated)

-strategies for overcoming tumor hypoxia:

1. Radiation fractionation Allows time for reoxygenation between doses

2. Improve oxygenation Increase oxygen delivery or perfusion: supplemental/hyperbaric oxygen, correct anemia or use oxygen carriers

3. Hypoxic-cell sensitizers Increase response of poorly oxygenated cells

4.Hypoxia-selective cytotoxins Preferentially target hypoxic cells - drug examples: misonidazole, etanidazole, tirapazamine, mitomycin C

true or false: an anoxic cell will show greater sensitivity than a hypoxic cell?

false

what would produce a smaller Do on the cell survival curve?

aerated cells

what will happen if oxygen is present at the time of radiation / within a millisecond after radiation?

(1) more reactive species (free radicals) are produced AND (2) damage is fixed (made permanent)

at which level of oxygen is the oxygen effect the most prevalent?

0-10 mmHg

oxygen effect with different radiation

- low LET =sparsely ionizing radiation = high oxygen effect (high OER) - low LET: OER often 2.5-3

- high LET =densely ionizing radiation = low oxygen effect (low OER)

-Oxygen makes low-LET radiation damage harder to reverse

- High-LET radiation already creates dense, complex damage, so oxygen adds little. OER approaches 1

-RBE: Rises with LET (100kev/um), then falls because of overkill: OER and RBE move in opposite directions over much of the LET range: OER falls while RBE rises toward its maximum

GRAPHICALLY:

- less space between lines on the graph = low OER

- alpha particles have high LET = low OER

parameters affecting OER

1. nature of cellular sensitivity (tissue type)

2. nature of radiation / LET (high LET=Low OER)

3. pO2 (oxygen tension)

4. time of oxygen presence (milliseconds after radiation due to short life of free radicals)

5. cell cycle (S phase is more resistant )

oxygen "fixing" damge

- - DNA radical forms → O₂ reacts with it → damage becomes difficult to reverse

- oxygen makes the damage permanent

- more effective with radio resistant cells

- - high LET already causes dense, complex damage, so oxygen adds little (OER approaches 1)

somatic effects

- effects upon the body that was irradiated

- occurs in the person exposed to the radiation

- early vs late effects

genetic effects

effects upon future generations due to the irradiation of germ cells in previous irradiations

response to damage depends on:

1. nature of the cellular radiosensitivity (tissue type)

2. kinetics of the tissue (metabolic activity of the tissue)

3. organization of the cells in the tissue

normal tissue tolerance

- amount of radiation a tissue can handle

- risk of damage to normal tissue increases with an increase in radiation dose AND the volume of tissue irradiated (AKA increases with dose & field size) and the probability of tumor control

tolerance dose

dose that produces an acceptable probability of a treatment complication

tolerance

- derived from TD 5/5

- the normal surrounding tissues & the relation to the specific end point

diagnostic doses

- large doses = fluoro (dose rate is greatest at the skin)

- high doses from IR, cardiac catheterization, CT scans: CT scanners provide a considerable amount of radiation to each organ: Avg dose of 40 - 60 mGy for head CT's and 10 - 40 mGy for body scans

- effective dose = "whole body dose"

- IMPORTANT TO NOTE: still receiving doses in sensitive areas even if they're not close to the area being images (ex: eyes get doses of radiation when the spine is being imaged)

radiation therapy doses

- doses delivered to various tissues & organs

- can range from 400cGy to 9-5,000cGy

- no more than 150-400cGy in a single dose if not stereotactic

hemopoietic system

- bone marrow (very sensitive)(RBC, WBC, platelets, stem cells), circulating blood, lymph nodes, spleen, thymus

- lymphocytes = MOST radio sensitive

- RBC = LEAST radio sensitive

- (most) lymphocytes —> granulocytes —> platelets —> RBC (least)

- smaller doses = regeneration may start before all the dead cells have been removed from the node(repair)

- large doses = permanently inhibit regeneration (fibrous) -Most stem cell tissue is located in the bone marrow - 60% located in

the pelvis and vertebrae, and the remainder in the ribs, skull, sternum,

scapula, and proximal sections of the femur and humorous. -Diagnostic imaging procedures with appropriate radiation protection for

patients and personnel result in negligible damage to the blood and blood

forming organ

digestive system

- mouth, esophagus, stomach, small & Large intestines and rectum

- small intestine = most radio sensitive part of the GI tract

- large doses may cause ulceration

-Early effects - anorexia, nausea, vomiting & diarrhea

- Late effects - esophagitis and mucositis

skin

- germinal (basal) layer = MOST radio sensitive

- superficial layers = LEAST radio sensitive

- erythema: changes in demis(moderate dose) --> epilation (hair loss; temporary loss after 300 cGy within 1-3 weeks) --> dry desquamation. (large dose) --> moist desquamation (massive dose- possible necrosis) --> ulceration --> necrosis

-erythemia (redness) 2-6 Gy

what type of radiation will have the greatest oxygen effect?

x-ray

- low LET = more single strand breaks

what is true regarding acute radiation effects?

larger fields will be more likely to cause acute damage to tissues

true or false: RBCs are more sensitive to radiation than platelets?

false

- RBC = LEAST radio sensitive

true or false: bone marrow in children is more sensitive to radiation than adult bone marrow?

true

true or false: CT imaging will produce erythema effects more than doses from IR?

false

male reproductive system

- Testes, epididymis, ducts, seminal vesicles, vas deferens & Prostate -tissue is radio-resistant EXCEPT for testes (young sperm = undifferentiated = radiosensitive)

-Primary effect - damage & depopulation (as low as 0.1 Gy) of the spermatogonia, eventually results in depletion of mature sperm. Possibly sterility & mutations.

- - 2 Gy = temporary sterility

- 5 - 6 Gy = permanent sterilization

- wait 30-60 days to conceive after irradiation

female reproductive system

- radio sensitive vs resistant based on cell maturity

- undifferentiated cells decrease with age —> dose necessary to cause sterilization decreases with age

- young children = large # of stem & immature cells (# decreases after puberty with mature cells up to 30y/o)

-- approximately 5 Gy = permanent sterility

eyes

- contains actively diving cells prior to puberty that may cause damage / destroy cells —> cataracts later in life

- doses as low as 50 cGy may produce cataracts (lens TD 5/5 = 10 Gy)

-Latent period for cataracts

• 250 - 650 cGy - 8 years

• 651 - 1150 cGy - 4 years

cardiovascular system

- vascular: could cause occlusion of blood vessel —> necrosis

- smaller vessels = more radiosensitive

- heart: high doses can produce pericarditis

- TD 5/5 of the whole heart is 4000 cGy

bone & cartilage

- mature bone & cartilage = radio resistant

- growing bone & cartilage = moderately radioresistant

- radiation exposure may produce bone abnormalities in children (scoliosis)

CNS

- relatively radioresistant

- early changes = inflammation progressing to necrosis / fibrosis -TD 5/5

• 1/3 is 6000 cGy, 3/3 is 4500 cGy

LD 50/30

- dose lethal to 50% of the human population in 30 days of exporsure

- humans = 3-4 Gy

stages of syndromes

1. prodromal

2. latent

3. manifest illness

4. recovery or death

**larger the dose = shorter the stages**

prodromal stage

- body's initial reaction to high dose exposure

- symptoms occur in minutes to days (subside in a few days)

- 50% lethal dose = anorexia, nausea, vomiting, easy fatiguability

- supralethal dose = immediate diarrhea, fever, hypotension (anorexia, nausea, vomiting, easy fatiguability)

latent stage

- initial illness appears to resolve (patient feels better)

- stage length is inversely related to dose (high doses = less time in latent stage) hours to weeks

- delay between the time of irradiation & onset of ARS is dictated by the normal life span of the mature functioning cells

- symptom free

manifest illness

- full onset of systemic illness

- stage length is directly related to dose (high doses = high severity & length in stage)

- symptoms = ARS symptoms

what is the most fundamental event following irradiation?

cell death

4 systems involved with ARS

1. cutaneous

2. hematopoietic

3. gastrointestinal

4. CNS

cutaneous syndrome

- duration = 1-2 days

- critical/target cells = epidermis, dermis, hair follicles, subcutaneous tissue //

- symptoms = blisters, hair loss, moist desquamation, erythema, epilation=10-20 days after >3-4 Gy

hematopoietic syndrome

- occurs between 1-10 Gy

- critical cells = hematopoietic precursor cells

- destruction of bone marrow & inadequate blood cell production

- lymphocytes (drops in 24hr) —> granulocytes (drops in 24-72hr) —> platelets (drops in 120hr) —> RBC (drops in 120 days)

- peak mortality at 30 days (up to 60 days) --> final symptoms take the longest time to see

- death due to infection

- symptoms = chills, fatigue, hemorrhage in skin, mouth ulcerations

- treatment = decontamination, whole blood replacement, antibiotics

gastrointestinal syndrome

- occurs between 8-12 Gy//whole body 10-100

- critical cells = epithelial lining of the GI tract (crypt cells & villi destroyed)

- death within 3-10 days (no treatment)

- death from change in fluid & electrolyte balance (loss of absorption)

- no crypt cells = can't absorb

CNS syndrome

- occurs at 100 Gy+

- death within a matter of minutes / hours --> final symptoms take the shortest time to see

- symptoms = nervousness, confusion, LOC

- within hours = respiratory distress, convulsions, shock

- death from increased brain fluid content due to small vessel leakage

oxygen with different radiation types

- oxygen & x-ray = increases cell sensitivity

- oxygen & alpha particles = NO CHANGE in sensitivity (double strand breaks occur, so oxygen has no effect)

acute radiation syndrome (ARS)

- symptoms of short term radiation effects after a large dose of ionizing radiation

- whole body exposed

- deterministic = symptoms occur at specific (high) threshold

- early effect = symptoms occur soon after exposure

types of damaging effects on radiation

stochastic & deterministic

stochastic effect

- cancer

- no threshold dose (can occur at any dose)

- outcome of irradiated cells that are functional but modified

- probability of effect will increase with dose (NOT severity)

deterministic effect

- only occur at specific threshold doses

- above the threshold, the severity of harm increases with dose (hit threshold = increases linearly with dose)

- severity of harm is dose dependent

- threshold doses are tissue dependent

- skin erythema, decreased sperm count, cataracts, epilation

threshold values

depend on dose delivery method:

- single high dose = most effective for cell killing

- fractionation increases threshold dose significantly

- decreasing dose rate increases threshold

true or false: all reproductive cells are sensitive to radiation?

false

3 principles of hereditary diseases

1. mendelian

2. chromosomal

3. multifactorial

mendelian

- caused by mutations in single genes located on autosomes or sex chromosomes

- divided into autosomal dominant, recessive, X-linked

- ex: cystic fibrosis

chromosomal

- caused by gross abnormalities in structure or number of chromosomes

- ex: down syndrome

multifactorial

- caused by genetic component not described by mendelian genetics

- ex: Alzheimer's

pregnant atomic bomb survivors

- growth retardation is seen with increasing radiation dose / exposure (microcephaly, weight less, shorter)

- no mental retardation risk for survivors exposed during 0-8 weeks

- significant increase in mental retardation for those exposed during 8-15 weeks

- no significant risk during 15+ weeks

- mental retardation NOT observed in less than 8 weeks & greater than 25 weeks

radiation effects on embryos

- depend on stage of gestation, dose rate, dose

- exposed early = lethal effects (induced by radiation before or immediately after implantation)

- exposed halfway = malformations (induced by radiation when main body structures are being formed)

- exposed late = growth disturbances without malformations (induced by radiation late in pregnancy)

- 5-10% of kids are born with abnormalities (may not be due to radiation)

genetic vs congenital effects of radiation

- genetic = mutations produced in the fetus when the ovum / sperm is irradiated

- congenital = mutations due to direct exposure to the fetus

3 stages of fetal development

1. pre-implantation (0-2 weeks)

2. organogenesis (2-8 weeks)

3. fetal stage (8-40 weeks)

pre-implantation stage

- embryo attempts to implant into the uterine wall & begin dividing

- all or nothing (no implantation = no baby)

radiation effects during pre-implantation stage

- most sensitive stage (cells rapidly divide & are highly undifferentiated)

- few # of cells = larger population dies

- radiation frequently prevents implantation (NO BABY)

- greater incidence of prenatal death (70% death rate at 2 Gy)

- all or nothing = if the embryo survives, it will continue to grow normally without abnormalities

- 5-15 cGy can kill the fertilized egg

organogenesis stage

- embryo has already implanted & initial division has occurred

- basic organ systems begin to form & differentiate

- stage extends to 14-15 weeks

radiation effects during organogenesis stage

- radiation exposure prevents formal organ development = birth defects & risk of NEONATAL death

- congenital abnormalities at birth

- majority of effects are CNS & sense organ related

- smaller size & low birth weight

fetal stage

- major organ systems have formed (are now maturing) --> contains differentiated & undifferentiated cells

- final alterations are made

radiation effects during fetal stage

- radiation delays growth process (growth retardation)

- fewer abnormalities (require higher doses to cause problems)

- requires higher doses to kill a fetus

- mental retardation between 8-15 weeks

- some effects may not appear until years later (CANCER)