1. BIOLOGICAL BASIS FOR RADIATION SAFETY

2. Contrary to the popular belief that our experience with radiation bioeffects started with the nuclear weapons project during World War II, our experience actually goes back to the very earliest days of radiation use. As early as 1906, two French physiologists published the results of their studies on the sensitivity of various tissues and organs to radiation. They found that “the sensitivity of cells to irradiation is in direct proportion to their reproductive activity and inversely proportional to their degree of differentiation.” This observation is as valid today as it was then, and is one of the bases for cancer treatment with radiation.

3. Since then, an enormous database on radiation bioeffects has been built up from observations on the occupational exposure of workers including scientists, medical personnel, uranium miners, radium-dial painters, atomic-energy workers, and industrial radiographers. Patients who were exposed to radiation for diagnosis and therapy constitute a second source of information.

4. DOSE–RESPONSE CHARACTERISTICS
Observed radiation effects (or effects of other noxious agents) may be broadly classified into two categories, namely, stochastic (Effects that occur randomly, and whose probability of occurrence rather than the severity of the effect, depends on the size of the dose. Stochastic effects, such as cancer, are also seen among persons with no known exposure to the agent associated with that effect.) and nonstochastic, or deterministic effects. Most biological effects fall into the category of deterministic effects. Deterministic effects are characterized by the three qualities stated by the Swiss physician and scientist Paracelsus about 500 years ago when he wrote “the size of the dose determines the poison”.

5. ” (A corollary to this is the old adage that there are no harmful chemicals [or radiation], only harmful uses of chemicals [or radiation]):
1. A certain minimum dose must be exceeded before the particular effect is observed.
2. The magnitude of the effect increases with the size of the dose.
3. There is a clear, unambiguous causal relationship between exposure to the noxious agent and the observed effect.
For example, a person must exceed a certain amount of alcoholic intake before he or she shows signs of drinking.

6. After that, the effect of the alcohol depends on how much the person drank. Finally, if this individual exhibits drunken behavior, there is no doubt that the behavior is the result of drinking. For such nonstochastic effects, when the magnitude of the effect or the proportion of individuals who respond at a given dose is plotted as a function of dose in order to obtain a quantitative relationship between dose and effect, the dose–response curve A, shown in the following Figure, is obtained. Because of the minimum dose that must be exceeded before an individual shows the effect, nonstochastic effects are called “threshold effects”.

7. Deterministic or Nonstochastic
Effects
Stochastic
Effects
Dose–response curves. Curve A is the characteristic shape for a biological effect that
exhibits a threshold dose—point a. The spread of the curve from the threshold at point a until the 100% response is thought to be due to “biological variability” around the mean dose, point c, which is called the 50% dose. Curve B represents a zero-threshold, linear response. Point b represents the 50% dose for the zero-threshold biological effect being studied.

8. Threshold radiation doses for some clinically significant deterministic effects are shown in the following Table.
Estimated Threshold Doses for Several Clinically Significant Detrimental
Deterministic Effects

9. In an experiment to determine the dose–response curve, the 50% dose—that is, the dose to which 50% of those who are exposed respond—is statistically the most reliable. For this reason, the 50% dose is most frequently used as an index of relative effectiveness of a given agent in eliciting a particular response. When death is the biological end point, the 50% dose is called the LD50 dose. The time required for the noxious agent to act is important and is always specified with the dose. Thus, if 50% of a group of experimental animals die within 30 days, we refer to it as the LD50/30-day dose. This index, the LD50/30-day dose, is widely used by toxicologists to designate the relative toxicity of an agent.

10. When the frequency of occurrence of a stochastic effect is plotted against the size of the dose (curve B in the previous figure), a linear dose relationship is observed rather than the S-shaped curve that is characteristic of agents associated with a threshold response.
The biological model that is compatible with this linear dose–response relationship and with our knowledge of molecular biology postulates that “cancer can be initiated or a genetic change be wrought by scrambling the genetic information encoded in a single DNA molecule”.

11. According to this postulated model, “a cancer is initiated by damaging the information stored in the chromosomes of a somatic cell, whereas (heritable) genetic change results from damage to the information stored in the chromosomes of a germ cell (a sperm or an ovum)”.
This postulated model predicts a zero threshold for stochastic effects. That is, the model assumes that even the smallest amount of carcinogen or mutagen, a single molecule in the case of chemicals or a single photon in the case of X-rays, can produce the effect if the molecule or photon should happen to interact with the appropriate base pair in the DNA molecule. For these reasons, stochastic effects are assumed to lie on a linear, zero-threshold dose–response curve.

12. Initiating Mechanisms of Radiogenic Effects
Direct Action
The gross biological effects resulting from overexposure to radiation are the sequelae of a long and complex series of events that are initiated by ionization or excitation of relatively few molecules in the organism. For example, the LD50/30-day dose of gamma-rays for man is about 4 Gy (400 rads). Since 1 Gy corresponds to an energy absorption of 1 J/kg, or , and since about 34 eV I expended in producing a single ionization, the lethal dose produces, in tissue,

13. ionized atoms per gram tissue
ionized atoms per gram tissue. If we estimate that about nine other atoms are excited for each one ionized, we find that about of tissue are directly affected by a lethal radiation dose. In soft tissue, there are about The fraction of directly affected atoms therefore, is

14. or about 1 atom in 10 million.

15. Indirect Action
Direct effects of radiation, ionization, and excitation are nonspecific and may occur anywhere in the body. When the directly affected atom is in a protein molecule or in a molecule of nucleic acid, then certain specific effects due to the damaged molecule may ensue. However, most of the body is water, and most of the direct action of radiation is therefore on water. The result of this energy absorption by water is the production, in water, of highly reactive free radicals that are chemically toxic (a free radical is a fragment of a compound or an element that contains an unpaired electron) and which may exert their toxicity on other molecules. When pure water is irradiated, we have:

16. (1)
(2)
(3)
(4)

17. most probable fate is determined chiefly by the LET of the radiation
most probable fate is determined chiefly by the LET of the radiation. In the case of a high rate of LET, such as that which results from passage of an alpha particle or other particle of high specific ionization, the free OH radicals are formed close enough together to enable them to combine with each other before they can recombine with free H radicals, which leads to the production of hydrogen peroxide,

18. (5)
while the free H radicals combine to form gaseous hydrogen. Whereas the products of the primary reactions of Eqs. (1) through (4) have very short lifetimes, on the order of a microsecond, the hydrogen peroxide, being a relatively stable compound, persists long enough to diffuse to points quite remote from their point of origin. The hydrogen peroxide, which is a very powerful oxidizing agent, can thus affect molecules or cells that did not suffer radiation damage directly. If the irradiated water contains dissolved oxygen, the free hydrogen radical may combine with oxygen to form the hydroperoxyl radical as follows:

19. (6)
The hydroperoxyl radical is not as reactive as the free OH radical and therefore has a longer lifetime than it. This greater stability allows the hydroperoxyl radical to combine with a free hydrogen radical to form hydrogen peroxide, thereby further enhancing the toxicity of the radiation.
Radiation is thus seen to produce biological effects by two mechanisms, namely, directly by dissociating molecules following their excitation and ionization and indirectly by the production of free radicals and hydrogen peroxide in the water of the body fluids

20. THE PHYSIOLOGICAL BASIS FOR INTERNAL DOSIMETRY
The determination of radiation dose from radionuclides within the body and the calculation of amounts that may be safely inhaled or ingested depend on the knowledge of the fate of these radionuclides within the body. Physiologically based pharmacokinetic models are used to mathematically describe the kinetics of metabolism of a radionuclide. The processes by which the complex food molecules are disassembled and then reassembled into cellular material and specialized proteins, and by which energy that is stored in the food is converted into useful energy are collectively called metabolism. The biochemical and biophysical principles govern the physiological processes.

21. Biokinetic Processes
Physiological activity encompasses four vital processes:
transport of materials,
transport of information,
tissue building, and
energy conversion.
Physiological Transport
Transport of materials is accomplished by two different mechanisms:
bulk transport due to pressure differences and
diffusion due to concentration differences.

22. An example of bulk transport is the flow of air into and out of the lungs. This flow of air is passive and is due to pressure differences caused by the expansion and relaxation of the chest cavity. Inhalation occurs when the chest cavity is expanded and its volume increases. This leads to a decrease in the intrathoracic pressure of several millimeters of mercury, and air flows into the lungs. During exhalation, the muscles that control the volume of the chest cavity relax and the thoracic volume decreases, thereby increasing the intrathoracic pressure and forcing the air out of the lungs.

23. Metabolism: Tissue Building and Energy Conversion
Cells, from which all tissues and organs are made, go through life cycles of their own. They are born from relatively undifferentiated progenitor cells—such as the basal layer in the skin and the stem cells in the bone marrow—go through a period of maturation, grow old, die, and are sloughed off. The time for cellular death, called apoptosis, and the instructions for the synthesis of new tissue is contained in the information encoded in the DNA molecules within the cells.

24. The food and drink that we consume—proteins, carbohydrates, fats, and water— supply the materials for the manufacture of new tissue and for the synthesis of specialized molecules. In the process called metabolism, the foodstuffs are broken down into their constituent subunits—amino acids, sugars, fatty acids, and glycerols—and then these units are reassembled into the cellular constituents needed for building tissues and organs. Metabolic processes include a number of oxidation–reduction reactions that result in the transfer of energy stored in the intramolecular bonds of the foodstuffs into energy-consuming reactions that drive all the vital processes. Oxygen for these oxidation reactions is brought into the body through the respiratory system.