A Radiobiology Primer

A Radiation biology primer

Before we look at the actual effects of radiation on humans, we have to know a few specific details about the exposure. Not all exposures are the same. A day of sun tanning on the beach in Mexico is different from working a shift near the core of a nuclear reactor. Given the protection systems in place, the worker is safer.

We need to know the type of radiation, is it electromagnetic or particle, and its energy level. The dose rate, how much radiation per minute or hour, and the time frame such as daily, weekly, etc. are important. The age of the person being exposed is also critical, as children are more sensitive to radiation than adults. The method of exposure, i.e. swallowed, external or inhaled, matters as well. Let’s look at each factor in a little more detail

Type and strength

In chapter 1 we looked at the large spectrum of radiation, both electromagnetic and particle radiation. Electromagnetic radiation can be broken down into groups based on frequency and wavelength. At one end of the spectrum are radio waves with long wavelengths and low frequency. Gamma rays are at the opposite extreme. Almost any radiation can have biologic effects, but it is useful to separate radiation into two groups based on how they produce those effects.

Figure 1

Figure 1 again shows the spectrum of electromagnetic radiation. Notice that the higher frequencies, above the range of Ultra violet (UV) radiation are labeled“ionizing radiation.” When ionizing radiation strikes the molecules in living tissue, it has enough energy to dislodge electrons from the atoms in those molecules. This changes the atoms, and mightdisrupt the molecules enough to permanently injure the molecule, the cell, the tissue and the person involved. Particle radiation, being stronger than any of the electromagnetic spectrum, is also ionizing.

Lower frequency radiation, also called non-ionizing radiation, does not carry enough energy to disrupt our molecular structure directly. What it can do is physically excite our molecules, and heat them up. When radar using microwaves was first introduced on navy ships, sailors noticed they could warm themselves by standing in front of the generator. Now, we all warm things everyday in a microwave oven. UV radiation, the strongest level of non-ionizing radiation, heats up our surfaces, affecting primarily our skin, the tissues just under the skin, and our eyes. Magnetic Resonance Imaging uses a combination of magnetic fields and radio waves to make amazing images of human structures. Prolonged MRI scanning has no know effect, except slight warming from the radio waves.

When people talk about radiation, and their fear of radiation, 99% of the time they are referring to ionizing radiation. Although UV radiation from the sun causes far more death and cancer in America than ionizing radiation, I have not seen a lot of evidence of “sun phobia” in my life time.

Dose Rate

If your house catches on fire, you should run outside. If someone lights a match in the room where you’re standing, everyone doesn’t immediately leave or don protective clothing. The fire is the same; the difference is the dose rate. Flicking your Bic slowly releases a small amount of heat, i.e. a low dose rate. Forest fires have very high dose rates, quite lethal in fact.

On earth, high dose rates of radiation are quite rare. Radiation therapy often uses high dose rates, but they are usually tightly focused on the tumor being treated. If someone drops an atom bomb on you, that is a high dose rate. The unfortunate people of Hiroshima and Nagasaki within a 2 mile radius received high dose rates, although most of the deaths and injuries were from explosive forces, not radiation. Of the 80,000 survivors of Hiroshima who received high dose rates, 50,000 mRem and up, scientists estimate around 500 have developed cancer attributed to their exposure.

Low dose rate radiation exposure is not just common on earth, it is universal. We all receive low dose rate radiation every day from cosmic radiation, the earth, the air we breathe and the water we drink. All authorities agree that this background radiation is low dose rate.

Between the obviously high rates of an atomic explosion, and our low natural background rate is a large grey area. Our background rate is clearly safe. Man evolved in it, and it has always been there. Without it, the earth would be cold and sterile, and man would not exist.

There is disagreement on how high a dose rate and total dose humans can receive, and still consider it safe. Traditional thinking, and most government regulations, assume anything above background is unsafe. We’ll come back to this.

Method or mode of exposure

How you receive radiation can be an important determinant of its potential effect. X-rays are produced outside the body, and we are exposed externally to them. Radioactive material can be outside or inside our body. How it gets inside, and where it ultimately ends up, has definite consequences for the ultimate effect.

A typical x-ray exposure, such as a chest X-ray strikes you externally, but passes through your body, affecting everything in its path just a little. The biggest dose is usually the skin entrance dose, but everything in the path of the x-ray gets a small dose. The typical dose is around 10mRem, or the amount of natural radiation you would receive in 10 days.

As we said before, big alpha particles carry lots of energy, but penetrate very little. Cosmic radiation contains alpha particles, but they do us little damage because they can’t penetrate past the layer of dead cells on our skin. Radon gas emits similar alpha particles. Uranium miners used to inhale large quantities of radon in the mines. The lining of your lung has no dead cell layer, and alphas released in the miners’lungs struck living cells constantly, often producing lung cancer.

Iodine we eat is concentrated in our thyroid glands. I give people with hyperthyroidism radioactive Iodine 131 in a capsule to treat their disease. Iodine 131 is a beta emitter. Remember Beta particles, they penetrate about one half inch and then they’re gone. Because ingested iodine(radioactive or not) is concentrated in the thyroid, the effect of the beta radiation is confined there too. The right dose of oral Iodine 131 will kill most or all of the cells in a sick thyroid, with no significant effect elsewhere in the body.

Age at exposure

Children are generally more sensitive than adults, and this is true for radiation. Based on the data from Hiroshima, we know that growing children respond more and faster to a high dose of radiation than an adult, given the same dose. Although never directly measured, we all assume the same is true for low doses. It would be foolish to think otherwise.

In summary, what kind of radiation and how strong of radiation is important. How you receive the radiation, your age and the timing of your exposure are just as important. Unless you are undergoing radiation therapy: high energy, high dose rate radiation should be avoided. It kills cells and causes problems.

Low levels of radiation, things like medical X-rays, nuclear waste, radon and nuclear power plants, are different. Their effects on humans are too small to be measured. We can observe low dose effects on cells and smaller animals in a lab, and we can guesstimate their effects from people who received high dose rates, but no study has ever shown a direct effect of low dose radiation on humans. Unless specifically stated, the rest of this chapter deals with low dose radiation, the kind we will all encounter, and most people fear.

Biologic effects, starting at the cellular level

Free Radicals (Physical, not political) : cellular effects

When Ionizing radiation hits you, most of it just passes right through. That is how we can take x-ray images. The x-rays pass through your body and create an image by striking a plate on the other side. Denser tissue, like bone, tends to stop the X-rays, so this allows us to make an image. For a century the plate contained film. Now most receptor plates are digital.

When Ionizing radiation is absorbed in the human cell, it will most likely cause a chemical reaction called free-radical formation. A free radical is an atom or molecule with an unpaired electron in orbit around the nucleus. Happy, stable atoms and molecules usually have paired electrons orbiting the nucleus. Ionizing radiation is called “ionizing” precisely because it has the energy to knock an electron out of its orbit. Because we are primarily made up of water, the major free radical produced is the hydroxyl radical. This is the radical produced when you knock an electron out of an H20 molecule. Free radicals are a very reactive chemical species. Most hydroxyl radicals recombine with water almost instantly, with no biologic effect. If a free radical reacts with something other than water, such as an adjacent cell structure, or a nearby molecule of DNA, there may be a biologic effect.

The other possibility, which is a thousand of fold less likely, is the ionizing radiation going through your body may strike a DNA molecule or other important structure directly. Either form of injury, free radical or direct hit, can result in a DNA strand break, which is generally considered the worst kind of cellular injury. Unrepaired DNA strand breaks can lead to cell death and/or cell mutations.

It is important to keep radiation induced cellular injuries in perspective. As mentioned before, everything around us, including human bodies, has some radioactivity. This background radiation varies widely throughout the world and throughout the United States, but 300 mRem is considered an average annual dose in the US. If you average this dose over the trillion or so cells in our bodies, each cell will experience about 3 “hits” or free-radical formations a year from this 300mRem dose. Which means for every 100 mRem of radiation, each cell may have one free-radical form. This is in contrast to normal energy metabolism in human cells, which produces thousands of free radicals and“hits” in every cell, every day. Fortunately, cells have very good repair systems. The presence of these repair systems is why dose rate is so important. Unless the dose rate exceeds the repair rate, the odds of permanent injury are very small.

This is a very important point. One worth repeating. Every cell in your body undergoes thousands of free radical hits every day during the course of normal energy metabolism. These free radicals strike everything in the cell, including your DNA. But, we repair them. Day in and day out we are repairing the damage from this constant barrage. The repair system is a massive, sophisticated part of our existence. Government regulations, the medical field and anti-nuclear groups ignore this system. They assume that for radiation hits (which are indistinguishable from every other free radical hit) every small dose is potentially lethal, and every small dose is cumulative. When radiation is the concern, the assumption is your body has no repair system, which of course is total nonsense. The technical name for this assumption is the Linear No Threshold theory (LNT).

Linear No Threshold

Development of equipment to monitor radiation lagged behind the production of radiation. Adverse effects were soon noticed, and ways to limit exposure and quantify exposure have been evolving ever since. Early users spoke of the skin erythema dose. The amount of radiation it takes to turn your skin red, or erythematous, in medical terminology. It was the best they could do, but it is like counting your cows to see if the gate to the field is open. Not exactly a great early warning system. Up to around 1930, exposure limits (the amount of exposure considered safe) were given as a fraction of the erythema dose, initially one tenth, and later one hundredth.

Delayed effects of high dose radiation, such as cancer development, were proven in the 20s. Radium dial painters were one of the earliest demonstrated. Radium is fluorescent, giving off a light glow in the dark. Watch makers learned they could paint their watches with radium and people could read the time in the dark. We still do this, but not with radium. The dial painters would frequently lick their brush to form the fine point necessary to paint small dial marks. The ingested radium, a strong particle emitter, was absorbed and concentrated in bone, producing high doses of radiation concentrated in the bones, and leading to bone cancers in experienced painters.

In 1934 the first formal standards for external radiation protection were issued by the U.S. Advisory Committee on X-ray and Radium Protection (now the NCRP, National Council on Radiation Protection.) They limited occupational exposure to 25,000 mRem per year, and said nothing about exposure of the general public. The NCRP revised their recommendations downward in 1954, setting the annual occupational exposure at 15,000 mRem. The primary concerns for limiting exposure up to this time were the immediate effects of radiation, and the possible latent effect of cancer induction, especially leukemia.

Following Hiroshima, the public perception of radiation and its risks changed. For political reasons, limiting public exposure, not just occupational exposure, grew in importance. Possible genetic risks of radiation, based on studies of irradiated fruit flies and other small species, as well as initial erroneous reports of genetic effects in Hiroshima survivors, prompted the 1956 Committee on the Biological Effects of Atomic Radiation to recommend limits on public exposure to radiation. The subsequent NCRP revision in 1958 reduces the occupational limit to 5,000 mRem annually, and the public to one tenth of this dose (500 mRem). In 1959 yet another group, the International Commission on Radiological Protection(ICRP) was formed, issuing its first recommendations in 1960.

This alphabet soup of radiation expert panels, arising in the wake of Hiroshima and the midst of the Cold War nuclear arms race, embraced as their fundamental basis the Linear No Threshold theory. The LNT assumes that all radiation is dangerous. There is no threshold dose, below which the dose is safe. All doses a person receives in their life time are cumulative. We have no repair system for radiation damage, even though everyone agrees the damage is just the same as normal free radical formation occurring thousands of times a day in every cell of your body. Standing two miles from Hiroshima and getting one large dose in a millisecond is equivalent to getting the same total dose in small quantities spread over your lifetime. At the time, with public anxiety high, and actual knowledge limited, it was an acceptable, conservative basis for setting standards. Accepting the LNT for these standards was a political and administrative decision. It was not scientific confirmation or acceptance that the LNT was true. In this same time frame a national policy of segregation seemed sensible, since black people were clearly different from white people. Some political decisions are harder to change than others.

Everything we know about human physiology and human experience says this assumption is false. When I lecture on this topic, I often ask for a volunteer from the crowd, someone with heart disease. I want them to come up to the podium and consume my jar of 500 aspirin tablets. There are seldom any takers. The nice folks at Bayer make sure we all know taking one aspirin a day is good for our hearts, but taking 500 at once will kill you. We have a threshold for Aspirin, well over 10 or 20 per day. Large bodies of data now exist which support the concept of a threshold for radiation injury, a level below which radiation is safe. No evidence exists to prove there is no threshold.

Effects we can see without a microscope.

When cells are injured, and not repaired, there are three main clinical outcomes which worry most of us:

1. The cells may die, causing the organ or organs involved to fail. Iodine 131 by mouth can do this to an adult thyroid.

2. If the cells don't die, they might mutate and becomemalignant, going on to produce cancer. This is what happened to the Uranium miners and their high rate of lung cancer.

3. The third possibility is the cell may mutate, but not die or become malignant. This non-lethal genetic mutation might be passed on to future generations, with unknown consequences.

Radiation induced cell death, organ failure and human death have never been demonstrated with low doses of radiation. At high doses, 50,000 to 500,000 mRem, directly radiated mammalian cell cultures do show cell death. These cultures, which normally just keep replicating themselves indefinitely, will stop replicating and the culture will die. In our bodies, different cell types replicate at different rates. Adult central nervous system cells rarely replicate, which explains the finality of spinal cord and brain injuries. Skin and mucous membrane cells replicate rapidly, and therefore heal quickly. In cell cultures, and in the human body, cells which replicate rapidly are more sensitive to radiation than slower replicating cell types. Cultures of rapidly replicating cells take lower doses of radiation to induce cell death than their slower growing neighbors. At very high total body doses(450,000 mRem and up), given in a single dose, human death within 30 days is likely. Fortunately, death from radiation is exceedingly rare. In the US, there have been only 7 reported deaths from acute radiation syndrome in the last 50 years, and all were industrial

In my 30 years of practice, I have never met anyone concerned about dying or direct injury from radiation. What they worry about is cancer. Carcinogenesis, the induction of cancer, is the number one fear. The number two fear, which we’ll deal with later, are genetic malformations and teratogenesis. Radiation induced cancer from higher doses is an accepted fact. Traditional practices, regulations, public policy and warnings to the public about radiation usually focus primarily on this risk, and they are usually based on the LNT, i.e. any dose might induce cancer, and small doses are cumulative.

Figuring out the exact risk of low dose radiation in cancer induction is very difficult, primarily because the risk is so small. Also, cancer induction takes a long time, which is called the latent period between the radiation and the cancer. This latent period is years or decades, which makes directly measuring the effects of large doses hard, and low doses impossible. Once a cancer arises, it is indistinguishable from other similar cancers. There is no way of analyzing a tumor and saying “this one was caused by radiation,”or any other suspected agent. Almost all the data we have on radiation carcinogenesis is from long term follow-up of groups of people who received large doses of radiation in the past, such as atomic bomb survivors and people treated with radiation therapies.

Since the 50s, a lot has been learned about carcinogenesis, and what might induce it. Generally, an injury to cellular DNA, our genes, must occur. This injury must be capable of being passed on to subsequent cells. Normal cell replication is under both positive and negative controls. Cancer is essentially uncontrolled cell replication.

Tumor induction may occur from activation of an oncogen (an already present but inactive malignant gene), destruction of a suppressor gene(which has been holding malignant growth in check) or the combination of the two. A large number of carcinogens have been studied, both natural and manmade. Radiation is a weak carcinogen. The probability of carcinogenesis increases with dose. The effect on humans at low dose is too small to measure directly, it must be calculated based on groups exposed to higher doses, a method with known flaws.

There is good evidence that low doses of radiation at low dose rates are not carcinogenic. The average dose from natural background sources of radiation in the US is 300mRem per year. Some areas, like Denver, receive much higher doses related to their altitude. In other countries there are regions with average background doses over 15000 mRem per year. None of these areas has a measurable difference in their cancer rates. If low doses given constantly were carcinogenic, these areas should have many more cancers. The survivors of Hiroshima and Nagasaki who received an instantaneous dose less than 10,000 mRem have not shown significant cancer induction. The survivors who received very high doses, and remember these are instantaneous doses easily capable of overwhelming our cellular repair mechanisms, only show a 5 to 7% increase in cancers in their lifetime. Low doses at low dose rates have never been shown to induce cancer.

At least once a week a pregnant woman comes to our hospital with symptoms suspicious for a blood clot in her lung, a condition which left untreated is often fatal for her and her baby. The treatment involves long term blood thinners, which carry a risk for both mother and fetus. Therefore, it is important to make this diagnosis correctly. The best test is a CT scan, a computerized X-ray exam of the chest. Pregnant women seldom come to the ER alone, so we usually have the patient and her extended family, all concerned about the risk of radiation to the fetus. They are concerned about malformations and genetic effects.

Earlier in this chapter I mentioned that radiation has the most effect on cells which are rapidly dividing. In early pregnancy, the fetus is one big mass of rapidly dividing and differentiating cells. From conception to our death, low dose radiation has little effect, but in utero is clearly when it has the most. It makes sense to be careful about exposure of a fetus to radiation, and we always take such exposure, and the family anxiety associated with it, quite seriously.

When the family starts asking questions it all boils down to one, “what is the chance this will harm my baby?” I answer quite honestly, “I believe there is none, but I can’t prove it. No one has ever shown an actual malformation or genetic defect from medical doses of radiation. Even the pregnant survivors of Hiroshima, who received near lethal doses of radiation in one blast, have shown no malformations or genetic defects in their offspring or their descendents. High doses of radiation during the first half of pregnancy are associated with a slight increase in the risk your child may get leukemia or be mentally retarded, but these effects have not been shown at low doses. I see you smoke. You and I both know that can hurt your baby. You drove here in a car. Cars kill 60,000 people a year. You have symptoms of a disease that could quickly kill you and your baby if untreated. We will do everything we can to keep the radiation dose to you and your baby as low as possible. The dose to your baby will be miniscule. The CT scan and the radiation are the least of your worries.”

In addition to radiation in utero, there is another specific situation which requires attention, radiation of children. Because they are growing, children’s cells are replicating faster than adults, which makes children more susceptible to most carcinogens, including radiation. It does not make them “very” susceptible, just a little “more” susceptible. This distinction is important to remember, because even in children, low doses have never been shown to have an effect. The effects of low doses can only be estimated from higher doses. Higher doses in children, like high doses in early pregnancy, are associated with slightly higher rates of later developing childhood leukemia. The latent period is 2 to 10 years, with a decline in the risk 15 years after the exposure. Fortunately, leukemia is a rare disease. The incidence in the US is around 4.3 cases per 100,000 children. High doses of radiation may increase this rate to 6-8 cases per 100,000.

Over the years many studies have tried to relate the variations in the incidence of leukemia in a region to the variations in the natural radiation by region. This would imply that low dose radiation is a factor. None of the studies has confirmed such a link. The bottom line: if your child needs a medically indicated X-ray procedure, the risk of not doing it far outweighs the radiation risk.

I believe the effects of low dose radiation are trivial when compared to all the other risks we encounter in modern life, but I can’t prove there is no risk. No one can prove something is safe. That is not how science works. I can say the effect is too small to measure directly. I can say there is a lot of evidence suggesting it is safe. But, I cannot prove it any more than I can prove coffee is safe. People drink a lot of coffee. It contains many known carcinogens. Science cannot prove there is no risks from coffee or radiation, only that there is less risk when compared with things you do every day without giving them a thought. This concept of relative risks is the topic of my next page.

I will be links to radiobiology articles and sites:

Good article on low dose rate radiation in mice