Radiobiology 6

Deterministic effects
• Most organs or tissues of the body are unaffected by the loss of a few
cells; but if the number of cells lost is sufficiently large, there is
observable harm, reflecting the loss of tissue function.
• The probability of such harm is zero at small radiation doses, but
above some level of dose, called the threshold dose, the probability
increases rapidly with dose to 100%.
• Above the threshold, the severity of harm also increases with dose
• To produce a radiation response in humans within a few days to
months, the dose must be substantial
Deterministic radiation responses are those that exhibit increasing
severity with increasing radiation dose. Furthermore, there is a dose
threshold, and the dose-response relationship is nonlinear
ACUTE RADIATION LETHALITY
• 1. Prodromal Period - At radiation doses above approximately 1 Gyt
(100 rad) delivered to the total body, signs and symptoms of radiation
sickness may appear within minutes to hours
• The symptoms of early radiation sickness most often take the form of
nausea, vomiting, diarrhea, and a reduction in the white blood cells of
the peripheral blood (leukopenia).
• The prodromal period may last from a few hours to a couple of days.
The severity of the symptoms is dose related
• at doses in excess of 10 Gyt (1000 rad), symptoms can be violent.
• At still higher doses, the duration of the prodromal syndrome becomes shorter until
it is difficult to separate the prodromal syndrome from the period of manifest illness
• 2. Latent Period - After the period of initial radiation sickness, a period of apparent
well-being occurs, which is called the latent period.
• The latent period extends from hours or less (at doses in excess of 50 Gyt) to weeks
(at doses from 1 to 5 Gyt).
• The latent period is sometimes mistakenly thought to indicate an early recovery from
a moderate radiation dose.
• It may be misleading, however, because it gives no indication of the extensive
radiation response yet to follow
Acute Radiation Syndrome (Manifest
Illness )
• The dose necessary to produce a given syndrome and the mean
survival time are the principal quantitative measures of human
radiation lethality
Hematologic Syndrome
• Radiation doses in the range of approximately 2 to 10 Gyt (200–1000
rad)
• patient initially experiences mild symptoms of the prodromal
syndrome, which appear in a matter of a few hours and may persist
for several days
• The latent period that follows can extend as long as 4 weeks and is
characterized by a general feeling of wellness.
• There are no obvious signs of illness, although the number of cells in
the peripheral blood declines during this time
• The period of manifest illness is characterized by possible vomiting, mild
diarrhea, malaise, lethargy, and fever.
• Each of the types of blood cells follows a rather characteristic pattern of cell
depletion.
• If the dose is not lethal, recovery begins in 2 to 4 weeks, but as long as 6 months
may be required for full recovery
• If the radiation injury is severe enough, the reduction in blood cells continues
unchecked until the body’s defense against infection is nil.
• Just before death, hemorrhage and dehydration may be pronounced.
• Death occurs because of generalized infection, electrolyte imbalance, and
dehydration
Gastrointestinal Syndrome
• Radiation doses of approximately 10 to 50 Gyt (1000–5000 rad)
• The prodromal symptoms of vomiting and diarrhea occur within hours of exposure
and persist for hours to as long as a day.
• A latent period of 3 to 5 days follows, during which no symptoms are present
• manifest illness period begins with a second wave of nausea and vomiting followed
by diarrhea.
• The victim experiences a loss of appetite (anorexia) and may become lethargic.
• The diarrhea persists and becomes more severe, leading to loose and then watery
and bloody stools.
• Supportive therapy cannot prevent the rapid progression of symptoms that
ultimately leads to death within 4 to 10 days of exposure
• Intestinal cells are normally in a rapid state of proliferation and are
continuously being replaced by new cells. The turnover time for this
cell renewal system is normally 3 to 5 days.
• Radiation exposure kills the most sensitive cells— stem cells; this
controls the length of time until death.
• When the intestinal lining is completely denuded of functional cells,
fluids pass uncontrollably across the intestinal membrane, electrolyte
balance is destroyed, and conditions promote infection.
• At doses consistent with GI syndrome, measurable and even severe
hematologic changes occur.
• It takes a longer time for the cell renewal system of the blood to
develop mature cells from the stem cell population; therefore, there
is not enough time for maximum hematologic effects to occur
Central Nervous System Syndrome
• radiation dose in excess of approximately 50 Gyt (5000 rad) or higher is
received
• lead to death within a matter of hours to days
• severe nausea and vomiting begins, usually within a few minutes of
exposure.
• During this initial onset, the patient may become extremely nervous
and confused, may describe a burning sensation in the skin, may lose
vision, and can even lose consciousness within the first hour.
• This may be followed by a latent period that lasts up to 12 hours,
during which earlier symptoms subside or disappear
• The latent period is followed by the period of manifest illness, during
which symptoms of the prodromal stage return but are more severe.
• The person becomes disoriented; loses muscle coordination; has
difficulty breathing; may go into convulsive seizures; experiences loss
of equilibrium, ataxia, and lethargy; lapses into a coma; and dies
• Regardless of the medical attention given the patient, the symptoms
of manifest illness appear rather suddenly and always with extreme
severity.
• At radiation doses high enough to produce CNS effects, the outcome
is always death within a few days of exposure
• CNS syndrome is characterized by increased intracranial pressure,
inflammatory changes in the blood vessels of the brain (vasculitis),
and inflammation of the meninges (meningitis).
• At doses sufficient to produce CNS damage, damage to all other
organs of the body is equally severe.
• The classic radiation-induced changes in the GI tract and the
hematologic system cannot occur, because there is insufficient time
between exposure and death for them to appear
LD50/60
• The LD50/60 is the whole body radiation dose that causes 50% of
irradiated subjects to die within 60 days
Mean Survival Time
• the average time between exposure and death
LOCAL TISSUE DAMAGE
• Effects on the Skin - The basal cell layer is most radiosensitive. The
resultant skin damage was seen as erythema (a sunburn-like
reddening of the skin) followed by desquamation (ulceration and
denudation of the skin). At higher doses, this second wave of
erythema is followed by a moist desquamation, which in turn may
lead to a dry desquamation. Moist desquamation is known as clinical
tolerance for radiation therapy. Contemporary radiation oncology
uses high-energy x-radiation from linear accelerators; this protects the
skin from radiation damage. the skin erythema dose required to affect
50% of those irradiated (SED50) is about 5 Gyt (500 rad).
• Another response of the skin to radiation exposure is epilation, or loss
of hair. For many years, soft x-rays (10–20 kVp), called grenz rays,
were used as the treatment of choice for persons with skin diseases,
such as tinea capitis (ringworm)
• High-dose fluoroscopy has focused more attention on the response of
the skin to x-rays
• Longer fluoroscopy times required for cardiovascular and
interventional procedures, coupled with allowed exposure rates twice
the previous normal, are of great concern
Effects on the Gonads
• Human gonads are critically important target organs.
• As an example of local tissue effects, they are particularly sensitive to
radiation.
• Responses to doses as low as 100 mGyt (10 rad) have been observed.
• Because these organs produce the germ cells that control fertility and
heredity, their response to radiation has been studied extensively
• The cells of the testes (the male gonads) and the ovaries (the female
gonads) respond differently to radiation because of differences in
progression from the stem cell to the mature cell
• at puberty, the follicles rupture with regularity, ejecting a mature
germ cell, the ovum. Only 400 to 500 such ova are available for
fertilization (number of years of menstruation times 13 per year)
• The maturation process from stem cell to spermatozoa requires 3 to 5
weeks
• Irradiation of the ovaries early in life reduces their size (atrophy)
through germ cell death.
• After puberty, such irradiation also causes suppression and delay of
menstruation.
• The most radiosensitive cell during female germ cell development is
the oocyte in the mature follicle.
• male stem cell is the spermatogonia is the most radiosensitive
• Radiation effects on the ovaries depend somewhat on age.
• At fetal life and in early childhood, the ovaries are especially
radiosensitive.
• They decline in radiosensitivity, reaching a minimum in the age range
of 20 to 30 years, and then increase continually with age
• Doses as low as 100 mGyt (10 rad) may delay or suppress menstruation in
a mature female.
• A dose of approximately 2 Gyt (200 rad) produces temporary infertility;
approximately 5 Gyt (500 rad) to the ovaries results in permanent sterility
• irradiation of the ovaries of experimental animals has been shown to
produce genetic mutations.
• Even moderate doses, such as 250 to 500 mGyt (25–50 rad), have been
associated with measurable increases in genetic mutations.
• Evidence also indicates that oocytes that survive such a modest dose can
repair some genetic damage as they mature into ova
• The testes, similar to the ovaries, atrophy after high doses of
radiation.
• Two gray (200 rad) produces temporary infertility, which commences
approximately 2 months after irradiation and persists for up to 12
months.
• Five gray (500 rad) to the testes produces permanent sterility.
• Even after doses sufficient to produce permanent sterility, the male
patient normally retains his ability to engage in sexual intercourse
• Male gametogenesis is a self-renewing system
Hemopoietic System
• The hemopoietic system consists of bone marrow, circulating blood,
and lymphoid tissue
• Lymphoid tissues are the lymph nodes, spleen, and thymus
• the principal effect of radiation is a depressed number of blood cells
in the peripheral circulation
• Time- and dose-related effects on the various types of circulating
blood cells are determined by the normal growth and maturation of
these cells
• Developing granulocytes and erythrocytes spend about 8 to 10 days in the
bone marrow.
• Thrombocytes have a lifetime of approximately 5 days in the bone marrow
• Lymphocytes are produced over varying times and have varying lifetimes in
the peripheral blood.
• Some are thought to have lives measured in terms of hours and others in
terms of years.
• In the peripheral blood, granulocytes have a lifetime of only a couple of days.
• Thrombocytes have a lifetime of approximately 1 week and erythrocytes a
lifetime of nearly 4 months
Hemopoietic Cell Survival
• The principal response of the hemopoietic system to radiation
exposure is a decrease in the numbers of all types of blood cells in the
circulating peripheral blood.
• Lethal injury to the stem cells causes depletion of these mature
circulating cells
• After exposure, the first cells to become affected are the
lymphocytes.
• These cells are reduced in number (lymphopenia) within minutes or
hours after exposure, and they are very slow to recover.
• Because the response is so immediate, the radiation effect is apparently a
direct one on the lymphocytes themselves rather than on the stem cells
• The lymphocytes and the spermatogonia are the most radiosensitive cells in
the body
• Granulocytes experience a rapid rise in number (granulocytosis) followed first
by a rapid decrease and then a slower decrease in number
(granulocytopenia).
• If the radiation dose is moderate, then an abortive rise in granulocyte count
may occur 15 to 20 days after irradiation.
• Minimum granulocyte levels are reached approximately 30 days after
irradiation. Recovery, if it is to occur, takes approximately 2 months
• The depletion of platelets (thrombocytopenia) after irradiation
develops more slowly, again because of the longer time required for
the more sensitive precursor cells to reach maturity.
• Thrombocytes reach a minimum in about 30 days and recover in
approximately 2 months, similar to the response of granulocytes
• Erythrocytes are less sensitive than the other blood cells, apparently
because of their very long lifetime in the peripheral blood.
• Injury to these cells is not apparent for a matter of weeks.
• Total recovery may take 6 months to a year
CYTOGENETIC EFFECTS
• Cytogenetics is the study of the genetics of cells, particularly cell
chromosomes
• Radiation cytogenetic studies have shown that nearly every type of
chromosome aberration can be radiation induced and that some aberrations
may be specific to radiation
• Radiation-induced chromosome aberrations follow a nonthreshold dose-
response relationship
• When the body is irradiated, all cells can sustain cytogenetic damage. Such
damage is classified here as an early response to radiation because, if the
cell survives, the damage is manifested during the next mitosis after the
radiation exposure
• Cytogenetic damage to the stem cells is sustained immediately but
may not be manifested for the considerable time required for that
stem cell to reach maturity as a circulating lymphocyte.
• Although chromosome damage occurs at the time of irradiation, it
can be months and even years before the damage is measured.
• For this reason, chromosome abnormalities in circulating lymphocytes
persist in some workers who were irradiated in industrial accidents 20
years ago
Single-Hit Chromosome Aberrations
• radiation interacts with chromosomes, the interaction can occur through
direct or indirect effect.
• In either mode, these interactions result in a hit.
• The hit, however, is somewhat different from the hit described previously
in radiation interaction with DNA.
• A chromosome hit, on the other hand, produces a visible derangement of
the chromosome.
• Because the chromosomes contain DNA, this indicates that such a hit has
disrupted many molecular bonds and has severed many chains of DNA
• A chromosome hit represents severe damage to the DNA.
• Single-hit effects produced by radiation during the G1 phase of the
cell cycle
• chromatid deletion- breakage of a chromatid
Multi-Hit Chromosome Aberrations
• In the G1 phase of the cell cycle, ring chromosomes are produced if the two
hits occur on the same chromosome.
• Dicentrics are produced when adjacent chromosomes each sustain one hit
and recombine.
• The mechanism for the joining of chromatids depends on a condition called
stickiness that is radiation-induced and appears at the site of the severed
chromosome
• Similar aberrations can be produced in the G2 phase of the cell cycle;
however, such aberrations again require that (1) either the same
chromosome be hit two or more times or (2) adjacent chromosomes be hit
and joined together
• Reciprocal translocations are multi-hit chromosome aberrations that
require karyotypic analysis for detection.
• Radiation-induced reciprocal translocations result in no loss of genetic
material, simply a rearrangement of the genes.
• Consequently, all or nearly all genetic codes are available; they simply
may be organized in an incorrect sequence
Kinetics of Chromosome Aberration
• At very low doses of radiation, only single-hit aberrations occur. When the
radiation dose exceeds approximately 1 Gyt (100 rad), the frequency of multi-hit
aberrations increases more rapidly
• Single-hit aberrations are produced with a linear, nonthreshold dose-response
relationship.
• Multi-hit aberrations are produced following a nonlinear, non-threshold
relationship
• Multi-hit aberrations are considered to be the most significant in terms of latent
human damage. If the radiation dose is unknown yet is not life threatening, the
approximate chromosome aberration frequency is two single-hit aberrations per
10 mGyt per 1000 cells and one multi-hit aberration per 100 mGyt per 1000 cells