Radiation Biology Illustrated Introduction [ionization DNA breaks, LD50, stochastic vs deterministic] for Radiologic Technologists

The body is composed of individual cells wherein the genetic information is stored in DNA (deoxyribose nucleic acid). This DNA can be damaged by ionizing radiation, i.e. radiation which has sufficient energy to remove electrons from atoms. The DNA damage can be either direct (i.e. the electron hits the DNA directly) or indirect (i.e. the electron creates a free radical which damages the DNA).

Depending upon the radiation dose level the response to radiation can be either deterministic (i.e. repeatable across multiple members of the population) or stochastic (i.e. there is some level of random chance in the outcome). The higher level dose responses which are deterministic are typically characterized by the dose response survival curve and the LD50 (i.e. the lethal dose to 50% of the population).

Table Of Contents

In this post we provide an overview of Radiation Biology that is of interest to a Radiologic Technologist. We start with a high-level description of the tissues in the body and focus on DNA as this is where the majority of the concerns with radiation damage occur.

Biological Overview

The human body is composed of multiple functional systems each of which is in tern composed of organs. These organs themselves are made up of matrices of cells. In this figure you can see that within each cell there is a small region, the nucleus, where the genetic material resides.

Specifically, within the nucleus the genetic code is stored in our DNA (deoxyribonucleic acid). This DNA is what differentiates each of us; except identical twins, who have the same genetic material. When the body is exposed to radiation it is this DNA which is most affected.

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Rad Take-home Point: The radiation which interacts induces most of the negative effects by damage of DNA.  

DNA

An average human body with weight of 80 kg has DNA which is not more than 20 grams, or DNA is only 0.25% percent of the whole human body. When x-rays interact with the body, they deposit energetic electrons. These electrons can cause direct or indirect damage to the DNA.

DNA Damage Radiation Biology 1

DNA has four pairs on a sugar backbone, and these same base pairs make up a double helix in all plants and animals. The base pairs are adenine, thymine, cytosine, and guanine, called A, T, C, and G. We know that the A and T are always paired together, and the C and G are always paired together as well.

As we discussed DNA is composed of four base pairs, two sets of two. If one of the base pairs is damaged by a fast moving particle for instance, this is referred to as a single strand break.

Single strand breaks can be repaired fairly easily using the other strand as a template. So if there was an A-T pairing and the A was destroyed it is clear that since there is a T present that the A should be replaced in the missing strand.

However, if there is a double strand break this is more difficult to repair as not a template to use in the repair. Therefore, double strand breaks are more problematic.

During replication if there is sufficient damage to the DNA this can lead to a global response for enzyme repair mechanisms that are at the chromosomal level, not just the base pair level (chemical repair). And if these mechanisms fail a global response of apoptosis or programmed cell death can be triggered, in order to preserve the larger organism.

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Rad Take-home Point: In animals the genetic material is encoded in DNA, which has some inherent redundancy as the base pairs A-T are always paired together and C-G are also always paired together.

Radiation Damage Pathways

X-ray Interactions

In the post on interaction of x-rays with the body we discussed the Compton and Photoelectric effect which dominate the interactions for diagnostic x-rays with the body. In that post we focused on the physical interactions and how the image signal is generated in x-ray imaging.

Here we focus on the local damage from the x-rays with matter. As we discussed in that post both Compton and Photoelectric effect result in energetic (i.e. fast) electrons being generated locally in the body. These electrons deposit their energy locally so they do not affect the image signal generated in x-ray imaging, but they do lead to tissue damage.

Radiation Biology 1

This figure on radiation damage pathways gives a good overview of how the x-ray photons lead to different damage in the body. The green end points are the positive end points and the red endpoints are the negative endpoints. For the next several paragraphs we will be referring to this figure to describe the pathways of radiation damage.

When x-ray photons interact with the body, they excite atoms. If energy of photon isn’t enough to free an electron, dissipation of heat occurs.

When the x-rays have sufficient energy the most common interactions of x-rays with matter are Compton Effect and Photoelectric Effect.

Both Compton and Photoelectric Effects lead to the generation of energetic electrons.

Direct Damage (Energetic Electrons)

These energetic electrons can interact with DNA that is within a few nanometers (10-9m). This is referred to as direct action since it is the energetic electrons that are directly causing the damage to the DNA.

Indirect Damage (Free Radicals)

There is an alternative pathway for DNA damage where the electrons cause the DNA damage indirectly.

As you can see in the figure above the energetic electrons hit stable molecules and generate Ion Radicals which are charged ions. These charged ions then undergo a chemical reaction with other molecules to generate Free Radicals.

These Free Radicals while not charged are chemically unstable.

Free radicals that remain within a few nanometers away from the DNA can damage the DNA. We refer to this as indirect action since it was not the electrons directly causing the damage, but rather the energetic electrons generate chemically unstable molecules (Free Radicals) which cause this DNA damage.

Indirect action is responsible for more of the DNA damage than direct action.

In some instances the DNA damage can be repaired. In this case long term damage can be avoided.

However, if there is damage that cannot be repaired, this can lead to DNA mutations or cell death.

In the case of cell death, the resulting outcome will be dependent on the radiation dose and the tissue being irradiated. Possible consequences of cell death at large scale include– acute radiation sickness and fetal developmental effects.

If it’s an embryo/fetus that is receiving the radiation there are specific concerns which a very dependent on the stage of gestational development.

The other option that can happen and has longer-term consequences is DNA mutation. DNA mutations can cause cancer (Radiation Carcinogenesis ) in a process that takes many years. If the DNA mutation occurs in a germline cell such as a sperm or an ovum (i.e. a human egg), this can potentially lead to Inherited Radiation Effects.

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Rad Take-home Point: There are multiple radiation damage pathways including both long term and short-term effects (see Figure above). The damage is primarily done by energetic electrons generated by Compton and photo-electric effect.

Single vs Double Strand Breaks

Radiation Biology 19

As we discussed above in the biological background section single strand breaks can be more easily repaired than double strand breaks. In terms of the damage from x-rays this can be caused by both direct interaction with the electrons or by indirect interaction via free radicals which can cause damage to the DNA.

If the electron damages to the DNA directly, it’s what’s called direct damage. Alternatively, indirect damage is when the energetic electrons generate Free Radicals that then do the damage. About two-thirds of the damage is caused by the free radicals. And if the damage occurs in a double strand break, it’s much more damaging because it’s much more difficult to repair.

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Rad Take-home Point: Damage to DNA can be direct or indirect. If there’s a double strand break, it’s significantly more damaging to the DNA.

Dose Response Relationships

Survival Curves, LD50

Particularly, when describing deterministic effects caused by cell death inflicted by radiation damage Dose Response Survival Curves are frequently used. These curves can either represent survival of: individuals in a population, individual animals in a controlled experiment, or individual cells in a laboratory experiment.

For instance, in the case of a laboratory experiment cells are:

  1. Cells grown on a petri dish
  2. Cells exposed to radiation
  3. Cells are then counted.
LD 50

A control is also made that can be counted as well. For each dose level the control that is not irradiated is compared with the samples that are irradiated. This is how a survival curve can be generated as shown in the figure.

Sometimes the survival curve is plotted in terms of mortality (i.e. those that died) and sometimes in terms of survival fraction (i.e. those that lived).

These are the same thing but just flipped upside down as we are plotted either those that survived or those that did not.

Finally, we note that rather than looking at plots of the survival curve it can be useful to have one or two numbers that summarize the curve.

For dose response curves it is common to use the lethal dose to 50% of the population (LD-50) as one number to summarize how the population responds to radiation. To estimate the LD50 simply draw a line from 50% and where the line intersects the curve is the LD50.

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Rad Take-home Point: The Lethal Dose for 50% of the population (LD-50) is a common descriptor of radiation damage.

Stochastic vs Deterministic

The effects of radiation can be separated into two major categories that are modeled differently. We will compare these two types of damage here.

In general radiation damage occurs to either germline cells (sperm and ova) or to somatic non-germline cells. In the hereditary section we describe the impact to germline cells. In this section the description will focus primarily on Somatic or non-germline cells.

stocastic vs deterministic 800 1600

Deterministic

A deterministic process is one that happens the same way every time if the inputs are the same. A process is termed deterministic if it is repeatable.

This differs from stochastic processes that we will describe below where there is some degree of chance involved in what outcome will occur given the same inputs (i.e. the same radiation dose and the same cells).

For deterministic processes if the dose is below a certain threshold the effect will not occur. In the classical description of radiation damage pathways, the deterministic effects are due to cell death.

These deterministic processes are driven by cell death occur typically at higher radiation doses.

In the figure below you can see that for low radiation doses (below a given threshold) the deterministic effect will not occur.

Radiation Biology 26

Then in the intermediate range of doses as the dose is increased the severity of the deterministic effect is increased. In case of higher doses, in deterministic process, more severe damage take place with increased amounts of radiation.  

Finally, above another high threshold dose the effects will not be increased as the radiation dose is increased. This is the plateau or flat region of the plot. After reaching this dose the severity of impact is not increased.

Examples of deterministic effects from radiation exposure include:

  • Acute Radiation Syndromes
  • Cataracts
  • Skin Burns

Stochastic

Stochastic processes involve some level of chance or randomness in the outcome. In the classic model these are effects are due to DNA mutation. In stochastic processes we are talking about higher probabilities of events happening, but the severity is the same.

For instance, in the case when radiation dose leads to carcinogenesis (cancer induction) the chance of getter cancer may be dose dependent, but the level of illness due to cancer is not dose dependent.

Radiation Biology 27

Therefore, in this figure we show a plot of the probability of harm plotted as a function of dose. As we discuss below in the case of some stochastic processes such as carcinogenesis there is debate in the community about the best model to use. However, the most accepted model remains a straight line (termed the Linear No Threshold (LNT) extrapolation approach).

Summary

Stochastic processes are probabilistic in nature. In deterministic process, for radiation doses above a minimum threshold and below a maximum threshold higher doses lead to increased harm or increased severity.

StochasticDeterministic
Probabilistic EffectAbove a threshold, there will certainly be an effect.
Higher doses, Increased chance of harmful effectHigher doses, Above threshold Increased Severity
Caused by: DNA MutationCaused by: Cell Death
Examples: Cancer Induction, Hereditary EffectsExamples: Acute Radiation Sickness, Hair Loss, Cataracts, Reduced Fertility 

Stochastic radiation damage is caused by DNA mutation, whereas deterministic are principally caused by cell death. Examples are cancer induction for stochastic processes or hereditary effects. For deterministic processes, examples are hair loss, cataracts, acute radiation sickness, and reduced fertility.

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