Unit 1. Biological Effects of Ionizing Radiations

Dominion Dental Journal, 1897 Excerpts: “Danger in X-rays”“So as to better diagnose the dental troubles of

which Miss Josie McDonald of New York complained, Drs. Nelson T. Shields and George F. Jernignan a month ago decided to have an X-ray photograph taken of the young woman’s face.

The picture was taken by Mr. J. O’Connor, and as a result of the exposure to the strong mysterious light, Ms. McDonald is now suffering from burns.

A few days after being photographed. The skin on the young woman’s face, neck, shoulder, left arm and breast became blistered and finally peeled off.

One ear swelled to three times its natural size and it is said there has been no hearing in it since.

The first picture taken of the young woman, O’Connor admits, was unsatisfactory, and a second and successful attempt was made. The first exposure lasted eight minutes and the last one thirteen minutes. Besides the burns, large patches of Miss McDonald’s hair have fallen out”

Biological Effects First case of radiation-induced human injury

was reported in the literature in 1896. Who discovered X rays and when? First case of X-ray induced cancer was

reported in 1902

Biological Effects X-radiation energy is transferred to the

irradiated tissues primarily by Photoelectric and Compton’s processes which produce ionizations and excitations of essential cell molecules such as DNA, enzymes, ATP, coenzymes, etc.

The functions of these molecules are altered. The cells with damaged molecules can not

function normally.

Biological Effects The severity of biological effect is related to

the type of molecule absorbing radiation. Effect on DNA molecule is more harmful

than on cytoplasmic organelles

Mechanism of Action Two mechanisms of radiation damage, mostly on

DNA: Direct action: Damage or mutation occurs at the site

where the radiation energy is deposited. Indirect action: The radiation initially acts on water

molecules to cause ionization. The water is abundantly present in the body (approx. 70 % by weight)

Indirect effect accounts for 2/3rd of the damage, direct effect is responsible for the remainder.

Indirect Action

The ions, H2O+ and H2O-, are very unstable and break up into free radicals.

Indirect Action Free radicals:

highly reactive atoms and molecules react with and alter essential molecules

that come in contact with them. These altered molecules have different

chemical and biologic properties from the original molecules. This translates to biologic damage.

Indirect Action Free radicals may also combine with each

other to produce hydrogen peroxide OH• + OH•-------> H2O2

Hydrogen peroxide is a cell poison which may contribute to biological damage

Radiation Effects at Cellular Level

Point mutations: Effect of radiation on individual genes is referred to as point mutation.

The effect can be loss or mutation in a gene or a set of genes.

The implication of such a change is that the cell may now exhibit an abnormal pattern of behavior.

Radiation Effects at Cellular Level

Chromosome alterations: Several kinds of alterations in the chromosomes have been described. Most of these are clearly visible under the microscope.

The effect upon chromosomes can result in the breaking of one or more chromosomes. The broken ends of the chromosome seem to possess the ability to join together again after separation.

Chromosome Breaks

Chromosome Breaks Such damage may be repaired rapidly in an

error-free fashion by cellular repair processes (restitution) using the intact second strand as a template.

However, if the separation between broken fragments is great, the chromosome may lose part of its structure (deletion).

Chromosome Breaks If more than one break, the broken fragments

may join in different combinations. inversion of the middle segment followed by

recombination

Chromosome Breaks Double-strand breakage: when both strands

of a DNA molecule are damaged. Sections of one broken chromosome may join sections of another, broken chromosome.

Chromosome Breaks A large proportion of damage will result in

misrepair which can result in the formation of gene and chromosomal mutations that may cause malignant development.

Arrested Mitosis Ionizing radiations also affect cell division,

resulting in arrested mitosis and, consequently, in retardation of growth. This phenomenon is the basis of radiotherapy of neoplasms.

The extent of arrested mitosis varies with the phase of the mitotic cycle that a cell is in at the time of irradiation. Cells are most sensitive to radiation during the last part of resting phase and the early part of prophase.

Cytoplasmic Changes Cytoplasmic changes probably play a minor

role in arrested mitosis and cell death. Swelling of mitochondria and changes in cell

wall permeability have been observed.

Radiation Effects at Tissue Level

Two types of biological effects may appear in tissues after exposure to ionizing radiation.

Somatic effects Genetic effects

Radiation Effects at Tissue Level

Somatic effects include responses of all irradiated body cells except the germ cells of the reproductive system.

Somatic effects are deleterious to the person irradiated.

Somatic effects may be stochastic or deterministic.

Radiation Effects at Tissue Level

Genetic effects. Include responses of irradiated reproductive cells.

Genetic effects become primarily important when they are passed on to future generations.

Genetic effects are of no consequence in persons who do not procreate or who are in the post-reproductive period of life.

Somatic Effects Somatic tissues do not always react to doses

of ionizing radiation so as to give immediate clinically observable effects. There may be a time-lapse before any effects are seen.

Basically, somatic effects are classified in two categories: Acute or immediate effects Delayed or chronic (latent) effects

Acute Somatic Effects Appear rather soon after exposure to a

single massive dose of radiation or after several smaller doses of radiation delivered within a relatively short period of time.

In general, effects which appear within 60 days of exposure to radiation are classified as acute effects.

Delayed Somatic Effects Delayed effects may occur anywhere from

two months to as late as 20 years or more after exposure to radiation. The time lapse between the exposure to radiation and the appearance of effects is referred to as the "latent period."

In radiobiology, the term “latent period” is usually used only in relation to stochastic effects (malignancy)

Variables in Somatic Effects The magnitude of somatic effects depend

on the following variables: IndividualSpeciesCellular and tissueExtent of exposure (full or partial body)Total doseDose rate

Variables in Somatic Effects Individual Variability. Certain individuals

are more sensitive or resistant than others in their response to radiation.

The expression, “LD50 (30 days)”, is frequently used in radiobiology which means that a certain dose kills 50% of the exposed animals within 30 days.

The 50% who survive are due to the individual variability.

Variables in Somatic Effects Species variability. The phenomenon of

species variability is well known. The reason is not well-understood.

Variables in Somatic Effects Cellular and tissue variability. In 1907

Bergonie and Tribondeu advanced the first generalization in radiobiology by stating that "cells are sensitive to radiation in proportion to their proliferative activity and in inverse proportion to their degree of differentiation.“

Simply stated, it means that the rapidly dividing cells are more sensitive to radiation than more differentiated, slowly dividing cells.

Bergonie and Tribondeu’s Axiom One of the most notable exceptions to this

generalization is the lymphocyte, not capable of proliferative activity, is a differentiated cell, and is one of the most radiosensitive cells in the body.

Variables in Somatic Effects Total-body vs localized-area exposure. A

single radiation dose of 4.5-5.0 Gy may produce only erythema of the skin if given to a localized part of the body.

However, if the same dose is given to the entire body, it will cause the death of 50 percent of the people exposed.

This quantity of radiation is identified as LD50, the lethal dose for 50 percent of the people thus exposed

Variables in Somatic Effects Specific area protection

Variables in Somatic Effects Total dose: The higher the dose of radiation,

the greater is the probability and severity of occurrence of biological effects.

Variables in Somatic Effects Dose rate dependence: radiation dose that would

be lethal if given in a short time, such as a few hours, may result in no detectable effects if given in small increments during a period of several years.

This is due to the ability of somatic cells to repair damage caused by exposure to radiation. However, tissues do not return to their original state following radiation damage, as there are some irreparable alterations produced.

Variables-Dose Rate In general, it may be stated that four-fifths of

somatic damage is repaired. But the irreparable damage is cumulative. When this cumulative damage reaches a high level, clinical manifestations may appear.

Variables-Dose Rate Local somatic effect (Alexander, p.149

Revised Edition)

Dose-effect Relationships Threshold response: An increase in radiation

dose may not produce an observable effect until the tissue has received a minimal level of exposure called the threshold dose.

Once the threshold dose has been exceeded, increasing dose will demonstrate exceeding observable tissue damage.

Cataract and erythema of skin are well-known threshold responses

Dose-effect Relationships Linear response: A linear dose-response

suggests that all exposure carries a certain probability of harm and that the effects of multiple small doses are additive.

The dose response curve for most radiation-induced tumors is linear which implies that there is no "safe" dose, i.e., no dose below which there is absolutely zero risk.

Every exposure carries some risk.

Dose-effect Relationships Linear-quadratic response (curve) A linear-quadratic response implies lesser

risk at lower dose rate than linear response or when the exposure is fractionated. However, there is no safe dose.

Variables in Somatic Effects Age. "The radiosensitivity is very high in new-born

mammals; it decreases until full adulthood is reached and then remains constant; old mice (about 600 days) are again more radiosensitive." (Bacq and Alexander, P.299)

"The embryo is . . . most sensitive during the period of most active organ development, which lasts from the second to the sixth week after conception." (Alexander, p. 156 Revised Edition)

Variables in Somatic Effects Sex The female is more radioresistant in some

species possibly due to high levels of estrogens, some of which have radioprotective properties. (Arena, p. 463)

Variables in Somatic Effects Metabolism. The lower the metabolic rate

and the lower the state of nutrition, the higher the resistance of the organism to the effects of radiation. Higher metabolic rate seems to magnify the radiation effect.

Variables in Somatic Effects Linear Energy Transfer (LET) The dose required to produce a certain

biological effect is reduced as the LET of the radiation increases. Thus alpha particles are more efficient in causing biological damage than low LET radiations.

Variables in Somatic Effects Oxygen effect The radioresistance of many biological tissues

increases 2 to 3 times when irradiation is conducted with reduced oxygen (hypoxia).

Types of Biological Responses Chronic deterministic effects: These effects are observed after large

absorbed doses of radiation. Doses required to produce deterministic effects are, in most cases, in excess of 1-2 Gy.

There is usually a threshold dose below which the effects are not manifested.

With increasing dose the severity of the effect increases.

Deterministic Effects Skin. Excessive exposure of the skin to ionizing

radiation may result in erythema or reddening of the skin, which is produced by dilatation of small blood vessels beneath the skin.

The dose of radiation required to produce erythema of the skin is between 1.65-3.5 Gy.

Higher doses are associated with dermatitis.

Deterministic Effects Hair. Epilation, or loss of hair, results from

exposure of the skin to 2.0-6.0 Gy. A latent period of about 3 weeks ensues before the hair is lost.

The hair usually grows back in a few weeks. For permanent epilation, considerably

higher doses are required.

Deterministic Effects Sterility. Sterility results from destruction by X-radiation

of gonadal tissues which produce mature sperm or ova.

A single dose of 4.0 Gy to the male gonads is necessary to produce permanent sterility.

The dose required to produce permanent sterility in the female may be 6.25 Gy or more.

Deterministic Effects Cataract. Exposure of the lens of the eye to

radiation can cause cataract (opacification of the lens).

The threshold for cataract induction is 2.0-5.0 Gy for a single exposure and approximately 10.0 Gy or more for exposures protracted over a period of months or years.

Therapeutic Radiation to Oral Tissues Standard therapeutic radiation dose for

treating cancer is approximately 50 to 60 Gy. Administered over a period of 10 to 14 weeks

at the rate of approximately 2.5 Gy twice weekly.

Radiation Effect on Oral Tissues : Teeth Adult teeth:

very resistant to the direct effect of radiation exposure.

no effect on the crystalline structure of enamel, dentin and cementum.

Radiation caries: in individuals whose salivary glands have been damaged resulting in xerostomia. Secondary to changes in saliva; i.e., reduced flow, pH and buffering capacity and increased viscosity.

Radiation Effect on Oral Tissues : Developing teeth

<10 Gy has very little or no visible effect. Effects to an infant may include: destruction

of tooth bud, tooth malformation and delay in eruption.

Radiation Effect on Oral Tissues : Bone The most serious complication: jaw

osteoradionecrosis. This is primarily due to damage to the blood

vessels of the jaw and consequent decreased capacity of the bone to resist infection.

Tooth extraction or other injury: possibility of bone infection and necrosis becomes very high.

More common in the mandible than in maxilla.

Radiation Effect on Oral Tissues : Salivary glands

Xerostomia: marked and progressive loss of salivary secretion.

The mouth becomes dry (xerostomia) and tender. The pH of saliva falls below normal (5.5 as

compared to 6.5 in normal saliva). The salivary changes influence oral microflora, and,

secondarily contribute to the formation of radiation caries.

Whether xerostomia is temporary or permanent depends upon the volume of glands exposed.

Radiation Effect on Oral Tissues : Mucosa Mucositis. At 3rd or 4th week, oral mucosa becomes

red and inflamed (mucositis). As the therapy continues, mucosa forms yellow pseudomembrane.

Secondary infection by Candida albicans is a common complication. Mucositis is most severe at the end of the treatment period.

Healing begins soon after treatment and is usually complete in about two months after therapy. The mucosa tends to become atrophic, thin and relatively avascular permanently. Dentures may frequently cause oral ulceration.

Radiation Effect on Oral Tissues: Taste buds Taste acuity is reduced or lost in about 4 weeks

into the radiation treatment. In general, bitter and acid flavors are more

severely affected when posterior third of the tongue is irradiated and salt and sweet when anterior third is irradiated.

Complete recovery of taste usually occurs in two to four months following treatment completion.

Deterministic Effects Life span shortening. Life span of small

laboratory animals can be shortened by exposure to repeated large doses of radiation.

If this phenomenon occurs among the human beings is inconclusive.

Deterministic Effects Embryological and developmental effects.

therapeutic doses of radiation delivered to the pelvic region of a pregnant woman can result in the death of the fetus or in the birth of an abnormal child.

The developmental effects on the embryo are strongly related to the stage at which the exposure occurs.

Embryological and developmental The first 2 weeks of pregnancy: most critical

period. If the dose is high, the fetus will die. The congenital anomalies are rare at this stage.

The highest incidence of malformations is the period of organogenesis (3-8 weeks of pregnancy).

The threshold doses are relatively low: 100-200 mGy for most malformations and 200 mGy for brain damage.

Embryological and developmental After organogenesis, effect is at the tissue and

cellular level rather, than at the organ level; so that gross, congenital anomalies are not to be expected.

In general, a dose as small as 100 mGy may cause gross defects. In Denmark, a therapeutic abortion is recommended once it is determined that the fetus has received 100 mGy (or 100 mSv) of radiation.

Acute Radiation Syndrome Radiation Sickness. Symptom complex that occurs after the

exposure of the entire body, or a major portion of the body to a large dose of radiation (above 1.0 Sv) within a short period of time. The effect may vary from a transient illness to death.

A radiation dose of this magnitude is not expected in any diagnostic procedure, especially in dentistry.

Acute Radiation Syndrome

Acute Radiation Syndrome Prodromal Syndrome. 1.0 - 2.0 Gy exposure. Individual usually develops G.I. symptoms

such as nausea, vomiting, weakness, fatigue, and anorexia. These symptoms usually disappear soon.

Acute Radiation Syndrome Hematopoietic Syndrome. 2.0 - 7.0 Gy. Severe injury to hematopoietic system of

the bone marrow, irreversible damage to the proliferative capacity of the of the spleen and bone marrow.

Rapid fall in the number of circulating granulocytes, platelets and erythrocytes

Rampant infection, due in part from lymphopenia, granulopenia, and anemia. The death occurs in 10 to 30 days.

Acute Radiation Syndrome Gastrointestinal syndrome. 7.0 to 15.0 Gy. Extensive damage to GI system: anorexia, nausea,

vomiting, severe diarrhea and malaise in a few hours after exposure. Basal epithelial cells of the intestinal villi are destroyed.

Loss of plasma and electrolytes into the intestines, hemorrhages and ulcerations. Results in dehydration and loss of weight. The denuded surface gets rapidly infected; septicemia and death is an invariable consequence.

Acute Radiation Syndrome Cardiovascular and CNS syndrome. Excess of

50 Gy. Death occurs within 1 or 2 days. Common

symptoms are: uncoordination, disorientation and convulsions. This is due to damage to the neurons and brain vasculature.

Stochastic Effects The most important effect of ionizing radiation on

human mortality is judged to be neoplasia and leukemia . Radiation in this regard is considered a two-edged sword. It cures cancer and it also causes cancer.

The probability of carcinogenic effect increases with dose.

It is currently judged that there is NO THRESHOLD below which the effect will not occur. Severity of the effect is independent of the radiation dose.

Stochastic Effects There is no controversy relative to relationship of

ionizing radiation exposure and neoplasia production.

It is universally accepted that such exposure increases incidence of tumors in a great variety of tissues and organs.

It is important to appreciate that in the U.S., almost 20 percent of deaths are attributable to cancer (400,000 annually) and a very small fraction of this total number is due to radiation exposure.

Stochastic Effects A statistically significant increase in cancer

has not been detected in populations exposed to doses less than 50 mSv.

Stochastic Effects- Evidence The largest group of individuals studied are the

Japanese atomic bomb survivors. In the cohort of 86,572, there were 9,335

deaths from solid cancer between 1950 and 1997. Only 440 deaths were estimated to be excess over spontaneous incidence and were considered radiation-induced cancer deaths (NCRP Report # 145).

During the same period, 87 leukemia deaths can be attributed to radiation exposure.

Stochastic Effects- Evidence Other studies have followed over 14,000

British patients who received spinal irradiations for ankylosing spondylitis between 1935-1954.

36 cases of leukemia and 563 cases of cancer of other types have been reported in these patients.

Stochastic Effects- Evidence Patients receiving repeated fluoroscopic

examinations during treatment of tuberculosis and women treated with radiation for postpartum mastitis between 1930-1956 demonstrated a higher risk of breast cancer.

Stochastic Effects- Evidence Increased incidence of thyroid cancer has

been observed in children who received radiation therapy for enlarged thymus. Breast cancer was also elevated in these individuals.

Stochastic Effects- Evidence Until the 1950’s, X rays were used to

epilate children with tinia capitis (ringworm infection of the scalp) in Israel. Over 10, 000 children were exposed.

These children showed a higher incidence of thyroid cancer as well as brain tumors, salivary gland tumors, skin cancer and leukemia.

Stochastic Effects- Evidence Increased incidence of leukemia in

radiologists (as compared to non- radiologic physicians) who practiced before the radiation protection methods were established.

Bone tumors in radium dial painters.

Stochastic Effects- Evidence Higher incidence of lung cancer in miners in

Saxony who dug out the ore from which the radium was extracted.

Higher incidence of lung cancer was also reported in uranium miners in central Colorado

Stochastic Effects- Evidence All patients in above studies received

exposures well above diagnostic range. The probability of diagnostic-dose radiation-

induced cancer occurrence can only be estimated by extrapolating from cancer rates observed following exposures to larger doses.

Stochastic Effects- Generalizations

Cancers other than leukemia typically start to appear 10 years following exposure (5 years for leukemia) and the increased risk remains for the lifetime of the exposed individuals.

The risk from exposure during fetal life, childhood and adolescence is estimated to be about 2-3 times as large as the risk during adulthood.

Stochastic Effects

Leukemia: The incidence of leukemia (other than chronic lymphocytic) rises following exposure of red marrow. Wave of leukemia appear within 5 years of exposure, and return to base line rates within 40 years.

Children under 20 are more at risk than adults. The mortality data for leukemia are compatible

with a linear quadratic dose response relationship.

Stochastic Effects

Thyroid cancer: The incidence of thyroid carcinoma increases following radiation exposure.

The susceptibility is greater early in childhood that later in life.

Females are 3 times more susceptible than males to both radiation induced and spontaneous thyroid cancer.

Stochastic Effects Bone cancer: Patients treated for childhood

cancer demonstrate an increasing risk of bone sarcomas.

Brain and nervous system cancer: Ionizing radiation exposure can induce tumors of the CNS. Most tumors are benign such as neurilemommas and meningiomas (average mid-brain dose of 1 Gy). Malignant brain tumors have also been demonstrated, but only at radiation therapy doses.

Stochastic Effects Esophageal cancer: The data regarding

esophageal cancer is sparse. Excess cancers are found in the Japanese A-bomb survivors as well as in patients treated with X-rays for ankylosing spondylitis.

Stochastic Effects Salivary-gland cancer: An increased

incidence of salivary gland tumors has been demonstrated in patients therapeutically irradiated for the diseases of head and neck, in the Japanese A-bomb survivors and in persons exposed to diagnostic levels of x-radiation (cumulative parotid dose of 0.5 Gy or more).

Stochastic Effects Skin: Association between ionizing radiation

exposure and development of basal cell carcinoma is well documented in the literature. There is minimal indication of association with malignant melanoma.

Other organs: Excess cases of multiple myeloma as well as malignancy of paranasal sinuses have also been demonstrated in patients receiving radiation doses.

Risk Estimation Four agencies or bodies comprehensively

review, assess, or estimate the radiation risk to humans from exposure to ionizing radiation and periodically publish their findings in the form of reports. These agencies are:

Risk Estimation1. The Biological Effects of Ionizing Radiations

(BEIR) Committee of the U.S. National Research Council

2. International Commission on Radiological Protection (ICRP)

3. National Council on Radiation Protection and Measurements (NCRP)

4. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR).

Risk Estimation Radiation induced tumors are clinically, morphologically

and biochemically indistinguishable from those which occur spontaneously.

This implies that carcinogenic effects of radiation may be demonstrated on statistical basis only; that is, one may infer such action by the demonstration of an excess in the number of cancers in the irradiated population over the natural incidence.

Alternately, the probability of the cancer incidence from a small dose is estimated by extrapolating from cancer rates observed following exposure to large doses.

Risk vs benefit