2721 Stochastic Effects and Late Tissue Reactions

Late Effects

• Long term results of radiation exposure

• Measurable delayed biologic damage are

  • Cataracts

  • Leukemia

  • Genetic Mutations

• Cataracts are considered to be a late tissue reaction that is non random; whereas leukemia and genetic mutations are viewed as stochastic or random consequences that if they appear do not do so for extended periods

Epidemiology

• Defined as a “Science that deals with the incidence, distribution, and control of disease in a population”

• The incident rates at which these irradiation related malignancies occur are determined by comparing the natural incidence of cancer occurring in a human population with the incidence of cancer occurring in an irradiated population

• Epidemiologic studies are of significant value to radiobiologist who use the information from these studies to formulate dose response estimates for making predictions of the risk of cancer in human populations exposed to low doses of ionizing radiation

Radiation Dose Response Relationship

• Demonstrated graphically through a curve (the DR curve) that maps the observed effects of radiation exposure in relation to the dose of radiation received

• The DR curve is either linear (straight line) or nonlinear (curved to some degree) and it depicts either a threshold dose or a non threshold dose

Threshold and Non Threshold Relationships

• Threshold may be defined as a point or level at which a response or reaction to an increasing stimulation first occurs

• With reference to ionizing radiation, this means that below a certain absorbed radiation dose no biologic effects are observed

• Non threshold indicated that a radiation absorbed dose of any magnitude has the capability of producing a biologic effect

• Biologic effect responses will be caused by ionizing radiation in living organisms in a directly proportional manner all the way down to dose levels approaching zero

• This behavior is referred to as a linear nonthreshold (LNT) relationship

• The sigmoid or S shaped (nonlinear) threshold curve of the radiation dose response relationship is generally employed in radiation therapy to demonstrate high dose cellular response to the radiation absorbed doses within specific tissues such as the skin, lens of the eye, and various types of blood cells

• Different effects require different minimal doses

Risk Models Used to Predict Cancer Risk and Genetic Damage in Human Populations

• Committee of the Biologic Effects of Ionizing Radiation (BEIR) (1990)

• Revised risk estimates indicated that the risk of radiation exposure was about three to four times greater than previously projected

• Currently recommends the use of the linear non threshold curve of radiation dose response for most types of cancer

• Curve implies that the biologic response to ionizing radiation is directly proportional to dose

Risk Models Used to Predict Leukemia, Breast Cancer, and Heritable Damage

• Some experts theorize that all radiation exposure levels possess the potential to cause biologic damage radiographer must employ thoughtful radiation safety measures whenever humans are exposed to radiation during diagnostic imaging procedures

• BEIR Committee believes that the linear nonthreshold curve is a more accurate reflection of stochastic somatic and genetic effects at low dose levels from low LET radiation

• Leukemia, breast cancer, and heritable damage are presumed to follow the curve

• For leukemia, the linear non threshold curve is supported by an analysis of the leukemia occurrence in Nagasaki and Hiroshima using a recent reevaluation of the radiation dose distribution in these two cities

Late Somatic Effects

• Consequences of radiation exposure that appear months or years afterwards

• They can be either stochastic or tissue reactions

• Stochastic effects, such as the incidence of cancers in a population, usually require years to be noticeable in a population

• Tissue reactions, such as skin effects, may be noticeable sooner in individuals, although months or more may be required for their full expression

• Tissue reactions are the result of slowly developing changes to body tissues that may be modified by other factors, such as medical intervention, after the exposure

• Stochastic effects, such as the incidence of cancer, are generally determined at the time or irradiation

Major Types of Late Effects

• Three major types of late effects are

  • Carcinogenesis

  • Cataractogenesis

  • Embryologic effects (birth defects)

• Carcinogenesis and embryologic effects are considered stochastic events

• Cataractogenesis is regarded as a late tissue reaction

Carcinogenesis

• Cancer is the most important late stochastic effect caused by exposure to ionizing radiation

• Cancer caused by low level radiation is extremely difficult to identify

• Evidence of radiation induced carcinogenesis in humans comes from the observation of irradiated human and from epidemiologic studies conducted many years after subjects were exposed to high doses of ionizing radiation

Human Evidence for Radiation Carcinogenesis

• Radium watch dial painters (1920s-1930s)

• Uranium miners (early years, and Navajo people of Arizona and New Mexico during the 1950s and 1960s)

• Early medical radiation workers (radiologists, dentists, technologists) (1896-1910)

• Patients injected with the contrast agent Thorotrast (1925-1945)

• Infants treated with x-radiation to reduce the enlarged thymus gland (1940s-1950s)

• Children of the Marshall Islanders inadvertently subjected to high levels of fallout during an atomic bomb test in 1954

• Japanese atomic bomb survivors (1945)

• Patients with benign postpartum mastitis who were given radiation therapy treatments (mid 1900s)

• Evacuees from the Chernobyl nuclear power station disaster in 1986

Cataractogenesis

• The probability that a single dose of ionizing radiation of approximately 2Gy will induce the formation of cataracts (Opacity of the eye lens) is high

• Cataracts result in partial or complete loss of vision

• Highly ionizing neutron radiation is extremely efficient in inducing cataracts

• Radiation induced cataracts in humans follow a threshold nonlinear dose response relationship

• Recent data to show that the threshold for cataract induction is lower than was previously thought. The threshold for single exposure is therefore now considered to be 0.5 Gy (50 cGy)

Embryologic Effects (Birth Defects)

• Stages of Gestation in Humans

  • All life forms seem to be most vulnerable to radiation during the embryonic stage of development

  • The period of gestation during which the embryo-fetus is exposed to radiation governs the effects (death or congenital abnormality) of the radiation

• Gestation in humans is divided into three stages

  • Preimplantation which corresponds to 0-9 days after conception

  • Organogenesis which lasts approximately from 10 days post conception to 12 weeks after conception

  • The fetal stage, which extends from the twelfth week to term

Embryonic Cell Radiosensitivity During the First Trimester of Pregnancy

• Embryonic cells are extremely radiosensitive and hence may easily be damaged by exposure to ionizing radiation

• The first trimester of pregnancy is the most crucial period with respect to harmful consequences from irradiation because the developing central nervous system and related sensory organs of the embryo fetus contain a large number of stem cells during this period of gestation

• When a high dose of radiation is received by the embryo within approximately 2 weeks of fertilization (before the start of organogenesis) prenatal death is the most obvious adverse consequence of such and exposure and manifest as a spontaneous abortion

• Abnormalities occurring as a consequence of irradiation during the period of organogenesis may include

  • Growth inhibition

  • Intellectual disability

  • Microcephaly pertains to head growth

  • Genital deformities

  • Sensory organ damage

Embryonic Cell Radiosensitivity During the Second and Third Trimesters of Pregnancy

• Fetal radiosensitivity decreases as gestation progresses

• Congenital abnormalities and functional disorders such as sterility may be caused by radiation exposure

• Leukemia also may be brought on by exposure to radiation during the second and third trimesters

Genetic (Hereditary Effects)

• Cause of genetic mutations

• Biologic effects of ionizing radiation on future generation are termed genetic or hereditary effects

• They can occur as a result of radiation induced damage to the DNA molecule in the sperm or ova of an adult, leading to germ cell mutations

• These cause faulty genetic information to be transmitted to the offspring

• This altered hereditary information may manifest as various diseases or malformations

Natural Spontaneous Mutations

• Some mutations in genetic material occur spontaneously, without a known cause

• Randomly occurring mutation in genes and DNA are called spontaneous mutations

• These mutation can be transmitted from one generation to the next and can cause a wide variety of disorders or diseases

  • Hemophilia: Lack of blood clotting

  • Huntingtons Chorea: uncontrolled body movements

  • Down Syndrome

  • Duchenne’s muscular Dystrophy: most severe form

  • Sickle cell anemia: mis shaped red blood cells

  • Cystic Fibrosis: damaged lungs GI, other organs

  • Hydrocephalus: cerebrospinal fluid build up in brain

Metagens Capable of Inducing Genetic Mutations

• Certain agents can increase the frequency of mutations. Some of these include

  • Ionizing radiation

  • Viruses

  • Specific chemicals

• These agents are called mutagens and ionizing radiation is one of the more effective mutagens known

• Any nonlethal radiation dose received by the germ cells can cause chromosome mutations that may be transmitted to successive generations

• When radiation interacts with DNA macromolecules, it can modify the structure of these molecules by causing breaks in the chromosomes or by causing a deletion or an alteration in the sequence of nitrogen bases

• Such modifications change the cell’s hereditary information. A mutation of this type could eventually lead to genetic disease in subsequent generations

Incapacities of Mutant Genes

• Mutant genes cannot properly govern the cell’s normal chemical reactions or properly control the sequence of amino acids in the formation of specific proteins

• These incapacities result in various genetic diseases

Dominant or Recessive Point Mutations

• Point mutations (genetic mutations at the molecular level) may be either dominant (probably expressed in the offspring) or recessive (probably not expressed for several generations)

• Radiation is though to cause primarily recessive mutations

• For a recessive mutation to appear in the offspring, both parent must have the same genetic defect

• Damage from recessive mutation sometimes manifests more subtly and may play a role in many commonly encountered disorders related to metabolism or the immune system

Ionizing Radiation as a Possible Cause of Genetic (Hereditary) Effects

• In 2001 an UNSCEAR study on the hereditary effects of radiation concluded that no radiation induced genetic diseases had so far been demonstrated in human populations exposed to ionizing radiation

• Evidence of radiation induce hereditary effects has not been observed in persons employed in diagnostic imaging or in patients undergoing radiologic examinations

• Even with this information, it is still recommended that gonadal shielding be effectively used and all radiation exposure be maintained as low as reasonably achievable (ALARA)