The direct effect theory or target theory proposes that ionizing radiation acts by direct hits on target atoms. All atoms or molecules within the cells, such as enzymatic and structural proteins and RNA, are vulnerable to radiation injury. DNA, however, is the principle target, in which ionizing radiation produces single- or double-stranded chromosomal breaks.

The direct mechanism theory was found to be inadequate in explaining cellular radiation injuries. The indirect theory proposes that ionizing radiation exerts its effect via radiolysis of cellular water, forming free radicals. These free radicals interact with atoms and molecules within the cells, particularly DNA, to produce chemical modifications and consequently harmful effects. When X-rays interact with water, two types of free radicals are formed:

The presence of an excess of oxygen during irradiation of cells allows the formation of additional free radicals:

It is worth noting that antioxidants block hydroxyperoxy free radical combination into the highly unstable hydrogen peroxide.

It has been estimated that about two thirds of biological damage caused by low linear energy transfer (LET) radiation is due to indirect action [3]. Biological damage by high LET is primarily by direct ionization action. Figure 21.3 illustrates how radiation leads to tissue damage.

Radiation effects have been observed in extents beyond that explained by effects exerted on directly irradiated cells. Cells in temporal or spatial distance from the initial radiation insult have been shown to have delayed effects of radiation. Two phenomenons are described: the bystander effect and genomic instability.

Certain factors related to radiation itself determine the various effects for the same radiation dose to biological organs.

Type of Radiation. Various types of radiation differ in penetrability based on LET, which expresses energy loss per unit distance traveled (kiloelectron volts per micrometer). This value is high for alpha particles, lower for beta particles, and even less for gamma rays and X-rays. Thus, alpha particles penetrate a short distance but induce heavy damage, and beta particles travel a longer distance but much shorter than gamma rays.

Mode of Administration. The radiation dose is obviously an important factor. In addition, a single dose of radiation causes more damage than the same dose being divided (fractionated). Collectively these two factors are expressed as dose per fraction.

Dose Rate. Dose rate expresses the time for which dose is administered. The longer the duration for the same total dose, the better the chance of cellular repair and the smaller the damage.

Certain properties of tissues and cells can significantly modify the biological effects of ionizing radiation.

Radiosensitivity. Although all cells can be affected by ionizing radiation, normal cells and their tumors vary in their sensitivity to radiation. Slowly and rapidly growing cells have different radiosensitivity in relation to their movement through the cell cycle. Radiosensitivity varies with the rate of mitosis and cellular maturity. Blood-forming cells are very sensitive to radiation, while neurons, muscles, and parathyroid cells are highly radioresistant. Within a given cell, the nucleus in general is relatively more radiosensitive than the cytoplasm. When cells in G₀\G₁ phase of the cell cycle are exposed to radiation they tend to halt their progression into G₂\M phase. G₂ synchronization produces a cluster of radiosensitive cells. A second hit within a time frame of 5–12 h leads to higher proportion of deleterious effects. This is expected for radioisotopes with sequential alpha or beta decay as in ⁹⁰Sr\⁹⁰Y [9].

Repair Capacity of Cells. Some cells are known to have a higher capacity than others to repair the damage caused by ionizing radiation; consequently, the biological effects of the same radiation dose are different. Significant repair is known to occur quickly, within 3 h.

Cell-Cycle Phase. The life cycle of the cell includes several phases: the pre-DNA synthetic phase (G₁), the DNA synthetic phase (S), the post-DNA synthetic phase (G₂), mitosis (M), and the more recently identified phase of no growth (0), which represents the time after mitosis to the start of the G₁ phase. All phases of the cell cycle can be affected by ionizing radiation. The radiosensitivity of a given cell varies from one cell-cycle phase to another. Overall, sensitivity appears to be greatest in G₂ phase; irradiation during this phase retards the onset of cell division. Irradiation during mitosis induces chromosomal aberrations, i.e., breaks, deletions, translocations, and others. The sensitivity of a given cell-cycle phase also differs from one cell type to another and by alteration of radiation injury [3]. For example, the reproductive cells are most sensitive during the M phase, while damage to DNA synthesis and chromosomes occurs mostly when the cell is in the G₂ phase. Recovery from sublethal damage occurs in all phases of the cell cycle. However, this is most pronounced in the S phase, which is also the most radioresistant phase [3].

Degree of Tissue Oxygenation. Molecular oxygen is known to have the ability to potentiate the response to radiation; this is known as the oxygen effect. The amount of molecular oxygen rather than the rate of oxygen utilization by the cells is the most important factor for increasing the sensitivity of cells to radiation. The probable mechanism is the allowance of additional free radicals, which enhance the damage of cells [10].

There are many models predicting relationships between the radiation dose and the effect of such an exposure to a biological target. The differences between these models arise from different underlying assumptions. Figure 21.4 illustrates three models describing the response of a biological system to various radiation doses.