RAB: ch.20 Radiation Biology Flashcards
Adverse biological effects from ionizing radiation were observed shortly after __________’s discovery of x-rays in year ____ and _________’s discovery of __________ in ____.
Wilhelm Conrad Roentgen, 1895
Becquerel, 1896
The study of the action of ionizing radiation on healthy and diseased tissue is the scientific discipline known as _________?
radiation biology
[Determinants of biologic effects of radiation]
What are the 3 radiation-related factors?
- absorbed dose (quantity)
- dose rate
- type and energy (quality) of radiation
The radiosensitivity of a complex biologic system is determined by a num
How do you classify the Biologic Effects of radiation exposure?
- Stochastic effect
- Deterministic effect
One in which the probability of the effect occurring, (rather than its severity), increases with dose.
Stochastic effect
Radiation-induced cancer and hereditary effects are stochastic in nature. For example, the probability of radiation-induced leukemia is substantially greater after an exposure to 1 Gy than to 10 mGy, but there will be no difference in the severity of the disease if it occurs
Regarded as the principal health risk from low-dose radiation, including exposures of patients and staff to radiation from diagnostic imaging procedures?
Stochastic effect
T or F?
Stochastic effects are believed not to have a dose threshold, because damage to a few cells or even a single cell could theoretically result in production of the disease.
True
It is this basic, but unproven, assumption that risk increases with dose and there is no threshold dose below which the magnitude of the risk goes to zero, that is the basis of modern radiation protection programs, the goal of which is to keep exposures as low as reasonably achievable
If a radiation exposure is very high, the predominant biologic effect is _____, which presents clinically as degenerative changes in the exposed tissue.
cell killing
The severity of the injury, (rather than its probability of occurrence), increases with dose.
Deterministic effect
T or F:
Deterministic effects (also referred to as tissue reactions) differ from stochastic effects in that they require much higher doses to produce a clinically observable effect and there is a threshold dose below which the effect does not occur or is subclinical.
True
What are examples of deterministic effects that can result from large radiation exposures?
- Skin erythema
- fibrosis
- hematopoietic damage
___ effects can be caused by severe radiation accidents and can be observed in healthy tissue that is unavoidably irradiated during radiation therapy.
Deterministic
T or F:
In the context of diagnostic x-ray exposure, cell death does not mean the acute physical destruction of the cell by radiation but rather a radiation-induced loss of mitotic capacity (i.e., reproductive death) or premature activation of apoptotic pathways (i.e., programmed cell death). There is considerable evidence that damage to DNA is the primary cause of radiation-induced cell death.
True
Spectrum of DNA Damage The deposition of energy (directly or indirectly) by ionizing radiation induces chemical changes in large molecules that may then undergo a variety of structural changes. These structural changes include ___?
- hydrogen bond breakage
- molecular degradation or breakage
- intermolecular and intramolecular cross-linking.
True or False:
Molecular breakages also may involve the sugar-phosphate polymers that comprise the backbones of the two helical DNA strands. They may occur as single-strand breaks (SSBs), double-strand breaks (DSBs) (in which both strands of the double helix break simultaneously at approximately the same nucleotide pair), base loss, base changes, or cross-links between DNA strands or between DNA and proteins.
True
A type of molecular breakage where the sugar and phosphate can rejoin, provided there is no opportunity for the broken portion of strands to separate.
SSB (single-strand breaks)
___ can occur if two SSBs are juxtaposed or when a single, densely ionizing particle (e.g., an alpha particle) produces a break in both strands. DNA DSBs are very genotoxic lesions that can result in chromosome aberrations.
Double strand breaks (DSB)
Regardless of its severity or consequences, the loss or change of a base is considered a type of ____
mutation
chromosome breaks produced by radiation do occur and can be observed microscopically during ___and ___, when chromosomes are condensed.
anaphase, metaphase
In DNA repair, the cell may activate _ checkpoint (which arrests cell cycle progression), to allow for repair of damaged or incompletely replicated chromosomes.
G1/S checkpoint
___ is a form of cell death that is characteristically different from cell necrosis in morphology and biochemistry, leading to the elimination of cells without releasing inflammatory substances into the surrounding area. Apoptosis results in cell shrinkage via nuclear condensation and extensive membrane blebbing ultimately resulting in the fragmentation of the cell into membrane bound apoptotic bodies composed of cytoplasm and tightly packed organelles that are eliminated by phagocytosis.
Apoptosis (programmed cell death)
What are the types of DNA reparie mechanisms
- direct repair of a damaged nucleotide
- short and long patch base excision repair (SP BER, LP BER)
- nucleotide excision repair (NER)
- SSB and DSB repair
- cross-link repair
Most DNA base damage and SSBs are repaired by the ___?
base excision repair pathway
___ is the major pathway for the repair of bulky, helix-distorting lesions such as thymine dimers produced by exposure to ultraviolet radiation.
nucleotide excision repair (NER)
True or False:
DNA repair occurs rapidly, and approximately 90% of SSB and base damage is repaired within an hour after the initial damage. Even with DSBs, DNA rejoining is virtually complete with 24 hours
True
How do you classify factors affecting cellular radiosensitivity?
- Conditional factors
- Inherent factors
___ includes those biologic factors that are characteristics of the cells themselves, such as the mitotic rate, the degree of differentiation, and the stage of the cell cycle
Inherent radiosensitivity
___ are those physical or chemical factors that exist before and/or at the time of irradiation. Some of the more important ___ factors affecting dose-response relationships include dose rate, LET, and the presence of oxygen.
Conditional radiosensitivities
In general, high dose rates are more effective at producing biologic damage than low dose rates. This dose-rate effect is diminished or not seen with ___-LET radiation primarily because the dense ionization tracks typically produce more complex, clustered DNA damage that cannot be repaired correctly. However, for a given dose rate, ___-LET radiation is considerably more effective in producing cell damage than low-LET radiation
high-LET radiation
The presence of this molecule increases the damage caused by low-LET radiation by inhibiting the recombination of free radicals to form harmless chemical species and by inhibiting the chemical repair of damage caused by free radicals
Oxygen
In 1906, these two French scientists experimented the relative radiosensitivity of rodent germ cells at different stages of spermatogenesis.
- J. Bergonie
- L. Tribondeau
This law states that radiosensitivity is greatest for thos cells that (1) have a high mitotic rate, (2) have a long mitotic future, and (3) are undifferentiated.
The Law of Bergonie and Tribondeau
For example, the pluripotential stem cells in the bone marrow have a high mitotic rate, a long mitotic future, are poorly differentiated, and are extremely radiosensitive compared with other cells in the body. On the other end of the spectrum, the fixed postmitotic cells that comprise the central nervous system (CNS) are relatively radioresistant
Arrange in order: most to least sensitive.
sperm, lymphocyte, hematopoeietic stem cells, small intestine crypt cells, hair follicles, colon and stomach, skin, kidney, CNS (Neurons), muscle, bone
This classification scheme was refined in 1968 by Rubin and Casarett, who defined five cell types according to characteristics that affect their radiosensitivity
Arrange in order: most to least sensitive to radiation
A. “gap” between S phase and Mitosis (G2)
B. Mitosis (M phase)
C. late DNA synthesis (S phase)
D. preperatory period for DNA synthesis (G1)
B. Mitosis (M phase)
A. “gap” between S phase and Mitosis (G2)
D. preperatory period for DNA synthesis (G1)
C. late DNA synthesis (S phase)
An initial exposure or “priming dose” reduced the effectiveness of a subsequent exposure
Adaptive Response to radiation
A fascinating phenomenon in which irradiated cells or tissues can produce deleterious effects on nonirradiated cells or tissues.
Bystander effect
While the vast majority of unrepaired and misrepaired radiation-induced lesions are expressed as chromosomal damage at the first division, a certain fraction of cells can express chromosomal damage such as chromosomal rearrangements, chromatid breaks and gaps, and micronuclei over many cell cycles after they are irradiated. demonstrated in vitro as delayed lethality in which cell cloning efficiency is reduced several generations after irradiation.
Genomic Instability
Concept
The response of an organ system to radiation depends not only on the dose, dose rate, and LET of the radiation but also on the relative radiosensitivities of the cells that comprise both the functional parenchyma and the supportive stroma.
Organ system response to Radiation
The response is measured in terms of morphologic and functional changes of the organ system as a whole rather than simply changes in cell survival and kinetics. The response of an organ system after irradiation occurs over a period of time. The higher the dose, the shorter the interval before the physiologic manifestations of the damage become apparent (latent period) and the shorter the period of expression during which the full extent of the radiation-induced damage is evidenced. There are practical threshold doses below which no significant changes are apparent. In most cases, the pathology induced by radiation is undistinguishable from naturally occurring pathology.
This refers to replacement of the damaged cells in the organ by cells of the same type, thus replacing the lost functional capacity.
Regeneration
Refers to the replacement of the damaged cells by fibrotic scar tissue, in which case the functionality of the organ system is compromised.
Repair
True or False
The types of response and the degree to which they occur are functions of the dose, the volume of tissue irradiated, and the relative radiosensitivity and regenerative capacity of the cells that comprise the organ system.
True
True or False
In radiation therapy, fractionation increases the effectiveness of the radiation by allowing for reoxygenation of the tumor cells and reassortment (redistribution) of the irradiated cells into more radiosensitive phases of the cell cycle.
True
Although a relateive rare event, it is still the MOST COMMONLY encountered tisse reaction (deterministic effect) following high-dose image guided interventional procedures
Radiation-induced SKIN damage
Skin reactions to radiation exposure are deterministic and have a threshold of approximately ___ Gy below which no effects are seen.
1 Gy
There are often no immediate clinical symptoms from a high skin dose and when initial symptoms do develop, they are often delayed by weeks or even months. What are the symptoms?
erythema, xerosis, pruritus
The reaction of skin to ionizing radiation
cutaneous radiation syndrome
This inflammatory response is largely caused by increased capillary dilatation and permeability secondary to the release of vasoactive amines (e.g., histamine)
early transient erythema
This is believed to be an inflammatory reaction secondary to release of proteolytic enzymes from damaged epithelial basal cells as well as reflecting loss of those epithelial cells.
Secondary or main erythema
This may also be seen between between 8 and 52 weeks after exposure. The dermal ischemia present at this stage produces an erythema with a bluish or mauve tinge. Temporary hair los
third or late erythema
___ can occur in approximately 3 weeks after exposure to 3 to 6 Gy, with regrowth beginning approximately 2 months later and complete within 6 to 12 months. After moderately large doses—40 Gy over a period of 4 weeks or 20 Gy in a single dose—intense erythema followed by an acute radiation dermatitis and moist desquamation occurs and is characterized by edema, dermal hypoplasia, inflammatory cell infiltration, damage to vascular structures, and permanent hair loss.
Epilation (temporary hair loss)
___, which implies a total destruction of the epidermis, is a clear predictor of late delayed injuries, particularly telangiectasia.
Moist desquamation
___ can also be produced by repeated low-level exposures (10 to 20 mGy/d) where the total dose approaches 20 Gy or more. In these cases the skin may become hypertrophic or atrophic and is at increased risk for development of skin neoplasms (especially squamous cell carcinoma). Erythema will not result from chronic exposures in which the total dose is less than 6 Gy.
Chronic radiation dermatitis
Radionuclides with high specific activity and high-energy beta particle emissions such as ___ are more likely to illicit skin reactions
F-18 radionuclide
most radiosensitive: ___
Intermediate:___
most radioresistant:___
- most radiosensitive: spermatogonia
- Intermediate: 1 & 2 spermatocytes and spermatids
- most radioresistant: mature spermatozoa
Temporary sterility can occur after acute doses of approx ___ mGy
The duration of temporary sterility is dose dependent with recovery beginning at 1 and as long as 3.5 years after doses of 1 and 2 Gy, respectively. However, following exposure (and provided the dose is not excessive), there will be a window of fertility before the onset of sterility, as long as mature sperms are available.
500 mGy
Permanent sterility can occur after acute doses of approx ___ Gy
6 Gy
Chronic exposures of ___ mGy/wk can result in permanent sterility when total dose exceeds ___ Gy
Chronic exposures of 20 to 50 mGy/wk can result in permanent sterility when total dose exceeds 2.5 to 3 Gy
Reduced fertility due to decreased sperm count (oligospermia) and motility (asthenozoospermia) can occur 6 weeks after a dose of ___ mGy
150 mGy
The ova within ovarian follicles are sensitive to radiation. Arrange the following in order of most to least radiosensitive: small, intermediate, large follicles.
Intermediate follicles -> large (mature) follicles -> small follicles
In women, permanent sterility is age dependent.
prior to puberty: 10 Gy
premenopausal: (over 40 yo): 2 to 3 Gy
prior to puberty: 10 Gy
premenopausal: (over 40 yo): 2 to 3 Gy
The ___ of the eye contains a population of radiosensitive cells that can be damaged or destroyed by radiation.
Lens
A unique aspect of cataract formation is that, unlike senile cataracts, which typically develop in the ___ pole of the lens, radiation-induced cataracts are caused by abnormal differentiation of damaged epithelial cells that begin as a small opacities (abnormal lens fibers) in the ___ ___region and migrate posteriorly.
Senile cataract : anterior pole of lens
Radiation induced cataracts: anterior subcapsular region and migrate posteriorly
Dose thresholds for detectable opacities?
acute exposure: 2 Gy
chronic exposure: 5 Gy
Occupational equivalent dose limit for the lens of the eye
(20 mSv/y averaged over 5 years, with no single year exceeding 50 mSv)
When the whole body (or large portion of the body) is subjected to a high acute radiation dose, there are a series of characteristic clinical responses known collectively as the ___ ?
The ARS refers to a group of subsyndromes occurring in stages over a period of hours to weeks after the exposure as the injury to various tissues and organ systems is expressed. These subsyndromes result from the differing radiosensitivities of these organ systems
acute radiation syndrome (ARS)
How do you divide (in order of occurence with increasing radiation dose ARS?
Hematopoietic
Gastrointetinal
Neurovascular
ARS can occur when a high radiation dose is ___, ___ and ___.
- delivered acutely
- involves exposure to the whole body (or at least a large portion of it)
- is from external penetrating radiation (xray, gamma ray, neutron)
What is the sequence of events in ARS?
prodromal, latent, manifest illness, recovery/death
As the whole-body exposure increases above a threshold of approximately ___ Gy, the prodromal symptoms, which (depending on dose) can include anorexia, nausea, lethargy, fever, vomiting, headache, diarrhea and altered mental status, begin earlier and are more severe.
0.5 to 1 Gy
The prodromal symptoms subside during the ___, whose duration is shorter for higher doses and may last for up to 4 weeks for modest exposures less than 1 Gy. The latent period can be thought of as an “incubation period” during which the organ system damage is progressing.
Latent period
The latent period ends with the onset of the clinical expression of organ system damage, called the ___, which can last for approximately 2 to 4 weeks or in some cases even longer. This stage is the most difficult to manage from a therapeutic standpoint, because of the overlying immunoincompetence that results from damage to the hematopoietic system.
manifest illness stage
Therefore, treatment during the first 6 to 8 weeks after the exposure is essential to optimize the chances for recovery. If the patient survives the manifest illness stage, recovery is likely;
The hematopoietic syndrome is the primary acute clinical consequence of an acute radiation dose between ___ and ___ Gy. Healthy adults with proper medical care almost always recover from doses lower than ___ Gy, whereas doses greater than ___ Gy are almost always fatal
between 0.5 and 10 Gy
lower than 2 Gy
greater than 8 Gy
____ radiation exposure maximizes damage because the majority of the active bone marrow is located in the spine and posterior region of the ribs and pelvis.
Posterior
Even with effective stem cells therapy, however, it is unlikely that patients will survive doses in excess of ___ Gy because of irreversible damage to the gastrointestinal tract and the vasculature.
12 Gy
In the absence of medical care, the human LD50/60 (the dose that would be expected to kill 50% of an exposed population within 60 days) is approximately ___ Gy to the bone marrow.
3.5 to 4.5 Gy
The decline in the ___ count occurs within hours after exposure and is a crude early biologic marker of the magnitude of exposure. The threshold for a measurable depression in the blood lymphocyte count is approximately ___ Gy; an absolute lymphocyte count lower than 1,000/mm3 in the first 48 hours indicates a severe exposure.
lymphocyte count
0.25 Gy
The clinical manifestation of bone marrow depletion peak ___ weeks after the exposure as the number of cells in circulation reaches its nadir.
3 to 4 weeks
Lethal consequences of severe hematopoietic compromise?
Hemorrhage from plt loss and opportunistic infection due to severe neutropenia
At higher doses, this becomes the dominant expression of radiation response with more immediate, severe consequences that overlap with hematopoietic syndrome. At doses higher than ___ Gy, is primarily responsible for lethality.
Gastrointestinal syndrome; 12 Gy
Its prodromal stage includes severe nausea, vomiting, watery diarrhea, and cramps occurring within hours after the exposure, followed by a much shorter latent period (5 to 7 days). The manifest illness stage begins with the return of the prodromal symptoms that are often more intense than during their initial presentation. The intestinal dysfunction is the result of the severe damage to the intestinal mucosa.
Gastrointestinal syndrome
Its most potentially serious effect is the severe decrease in circulating white cells at a time when bacteria are invading the bloodstream from the gastrointestinal tract.
Gastrointestinal syndrome
Systemic effects of acute radiation enteropathy
- malnutrition resulting from malabsorption; vomiting and abdominal distention from paralytic ileus; anemia from gastrointestinal bleeding; sepsis resulting from invasion of intestinal bacteria into the systemic circulation; and dehydration and acute renal failure from fluid and electrolyte imbalance.
Lethality from the gastrointestinal syndrome is essentially ___%. Death occurs within 3 to 10 days after the exposure if no medical care is given or as long as 2 weeks afterward with intensive medical support.
100%
It is important to appreciate that even at doses within the hematopoietic syndrome dose range (2 to 10 Gy), damage to the gastrointestinal tract is occurring. It is responsible for many of the prodromal symptoms and contributes to the toxicity of the radiation-induced myelosuppression that is the signature of the hematopoietic component of the ARS. While a whole body dose of 6 Gy does not result in the full gastrointestinal sequelae described above, damage to the mucosal barrier causes cytokines and other inflammatory mediators to be released into the circulation.
In this syndrome, death occurs within 2 to 3 days after supralethal doses in excess of ___ Gy.
Neurovascular syndrome; 50 Gy
In this syndrome, period may include a burning sensation of the skin that occurs within minutes, followed by nausea, vomiting, confusion, ataxia, and disorientation within 1 hour. There is an abbreviated latent period (4 to 6 hours), during which some improvement is noted, followed by a severe manifest illness stage. The prodromal symptoms return with even greater severity, coupled with respiratory distress and gross neurologic changes (including tremors and convulsions) that inevitably lead to coma and death.
Neurovascular syndrome
What are the three stages of gestational period?
- Preimplantation
- Organogenesis
- Fetal growth stage
This stage begins with the union of the sperm and egg and continues through day 9 in humans, when the zygote becomes embedded in the uterine wall The conceptus is very sensitive during the preimplantation stage and susceptibility to the lethal effects of irradiation is a concern. However, for doses less than ___ mGy, the risks are very low.
Preimplantation stage; less than 100 mGy (low risk)
In preimplantation period, embryos exhibit this response to radiation exposure in which if the exposure is not lethal, the damaged cells are repaired or replaced to the extent that there is unlikely to be any additional radiation-induced risk of congenital abnormalities beyond that which would occur for other reasons
All-or-nothing response
The most sensitive times of exposure in humans are at ___ hours after conception, when the two pronuclei fuse to the one-cell stage, and again at 30 and 60 hours when the first two divisions occur.
12 hours after conception
After implantation doses in excess of ___ mGy are required to induce prenatal death.
250 mGy
Embryonic malformations occur more frequently during the period of major organogenesis (___ to ___ week after conception).
2nd to 8th week after conception
The initial differentiation of cells to form certain organ systems typically occurs on a specific gestational day.
neuroblasts: ___ gestational day
forebrain and eyes: ___ day
primitive germ cells: ___ day
neuroblasts: 18th gestational day
forebrain and eyes: 20th day
primitive germ cells: 21st day
This the greatest probability of a malformation in a specific organ system to exist when radiation exposure is received during period of peak differentiation
Critical period
The only organ system (in humans or laboratory rodents) that has shown an association between malformations and low-LET radiation doses less than 250 mGy
CNS
Embryos exposed early in organogenesis exhibit the greatest intrauterine growth retardation, presumably because of cell depletion. In utero exposure to doses greater than 100–200 mGy of mixed neutron and gamma radiation from the Hiroshima atomic bomb resulted in a significant increase in the occurrence of microcephaly.
true or false
Radiation exposure of the embryo at the preimplantation stage usually leads to an allor-nothing phenomenon (i.e., either fetal death and resorption or normal fetal risk).
True
True or false
During the period of organogenesis, the risk of fetal death decreases substantially, whereas the risk of congenital malformation coincides with the peak developmental periods of various organ systems. Exposures in excess of 1 Gy are associated with a high incidence of CNS abnormalities. During the fetal growth stage in utero, exposure poses little risk of congenital malformations; however, growth retardation, abnormalities of the nervous system, and the risk of childhood cancer can be increased depending on fetal dose.
True
True or false
The ACR policy states “The interruption of pregnancy is rarely justified because of radiation risk to the embryo or fetus from a radiologic examination.” (ACR, 2005). The ACOG policy, which was revised in 2004, states “Women should be counseled that x-ray exposure from a single diagnostic procedure does not result in harmful fetal effects. Specifically, exposure to less than 5 rad [50 mGy] has not been associated with an increase in fetal anomalies or pregnancy loss.” (ACOG, 2004).
True
