My name is Martin Meltz, and I'm the organizer of this symposium which is entitled Ionizing
Radiation and its Biological and Human Health Effects.
The sponsors are the Department of Radiation/Oncology, The University of Texas Health Science Center at San Antonio, the Regional Emergency Medical Preparedness Steering Committee (REMPSC) San Antonio and Bexar County, the Bexar County Medical Society and the Greater San Antonio Hospital Council.
The speakers include, in the area of radiation physics, John Hagman, who is the radiation safety officer at Southwest Research Institute; myself, I'm a professor and chief of the radiobiology group here at the Department of Radiation/Oncology at The UT Health Science Center San Antonio; and clinical radiobiology will be covered by Dr. Sam Morale who's in the division of emergency medicine Department of Surgery at The Health Science Center and on the staff at University Hospital.
Just to mention, all of the speakers are contributing their time as a true community service. The schedule is this welcome and introduction, then a 30-minute presentation on radiation physics, five minutes for pressing questions-but I urge you to write down questions which you could ask later at the end of the session, then a presentation on basic radiobiology-also, a question or two, then a 10-minute break, then a presentation by Dr. Morale on clinical radiobiology. Then, we want to have a question-and-answer period. We'll do the best we can in answering your questions. One thing I would ask you to do, is during the session, on your evaluation form, you only need the first three lines or so for the speakers, but if you have issues you would like us to move towards or address, please make note of that as an issue to be addressed and we'll look to do that in future, more directed symposiums.
This session is being videotaped and it would become available to you as a URL through the UT Health Science Center Web site. Each speaker will initially mention objectives or topics to be covered in his talk. I need to mention that this is an introduction to the biology and human health effects and we won't be providing you with guidance on how to respond to a radiological terrorism attack.
Under the offices of REMPSC here in San Antonio, REMPSC being one of our co-sponsors, a working group is being formed of radiation physicists and medical professionals to review already available guidances for dealing with a radiological terrorism event and to see if we can bring that to our local and regional community. We will be reporting back to REMPSC and REMPSC will decide how that is to be communicated locally.
Separately, but related to this issue, the South Texas Chapter of Health Physics Society as well as the National Health Physics Society are both developing ways in which they can help. One way is through participation in what's called the HDER the Homeland Defense Equipment Reuse Program, and we're hoping that through attendance of chapter members, we'll be able to bring some of this reusable, reconditioned equipment to the San Antonio region. That will possibly be in April 2003. At the moment, only Houston and Dallas, Texas have become eligible for access to that equipment.
Finally, dealing with some immediate practical matters, there are men's and women's rooms on this floor. There's an operational water fountain towards the left. There are additional bathrooms one floor below, if you go to the stairwell and walk downstairs. And there is a soda machine for during the 10-minute break that's on our schedule.
Now I'd like to introduce our first speaker Dr. John Hagman who will address the issue of the radiation physics.
John Hagman speaks
I want to thank Dr. Meltz for the field promotion, but don't call me doctor. Let's go to slide show. That's me and that's where I work-Southwest Research Institute.
The topics that I want to address today is what is radiation? When we refer to radiation, we're using the generic term that refers to ionizing radiation. Ionization means that you can strip electrons off an atom. The radiation has enough energy, not like light or heat or infrared where the electrons can't be stripped off the atom. But with ionizing radiation, that we just call radiation, can do that. In introducing what ionizing radiation is versus regular radiation or nonionizing, we'll talk about the electromagnetic spectrum and how they're different from each other. When you go into ionizing radiation you have electromagnetic or the waves that can ionize the material and you also have particulate radiation. These are basically neutrons, betas and gammas and alphas, and we'll talk about those too. We'll talk about sources of radiation. If you're going to have a terrorist that's going to try to spread some radioactive material around, a dirty bomb, you need to know what some of the sources of radiation are. Radioactive decay-we'll talk about that. Basically, the half life. This may be a review for a lot you, but I'm going to go through this quickly. And if it is not a review, then you can talk to me afterwards.
Units of radioactive material. Anytime you're dealing with something, you need to know the names of the parts. If you're going to take apart an engine you need to know what a camshaft is and a piston is. In radiation, you need to know what a curie, Becquerel, etc., we'll talk about those terms when you're dealing with radioactive materials so you know how much there and how to work with it.
Stopping ionizing radiation. How do you shield against these three major types of ionizing radiation: alphas, the betas and the gammas or X-ray.
Atomic weapons. I'll just briefly introduce you to that. Dirty bombs, what they are. Units of does, again, you need to know the terminology and if someone says I'm walking into a 10R field or a .1 gray per hour field, you need to know what does that mean? How dangerous is it? You need to know the difference in what it is and how it's going to affect you.
We'll talk about equipment. I have some equipment that I brought with me. We'll have that available at the end of the session. And we can talk about on a one-to-one basis how this equipment works, how effective it is and how you can use it to determine what you have.
What is radiation? Radiation in general is the emission of energy in the form of waves or rays. These are definitions right out of the dictionary; energy radiated in rays or waves or in the form of particles. And basically, we're talking about a stream of particles per electromagnetic wave emitted by the atom and molecules of a radioactive substance during nuclear decay. Nuclear means it comes from the nucleus. Don't worry about nuclear being anything besides it comes from the nucleus of the atom.
The electromagnetic spectrum. You could see the light portion there, the infrared. Down to the long wavelengths you get AM radios and then above this you get ultraviolet in the X-rays and gamma rays. Those are the ones that have enough energy that they can ionize or strip electrons off of an atom.
Ionizing radiation. Another one, this is from the EPA. I'm not plagiarizing, I have it referenced right there. So don't fire me for my weatherman's job. Beyond this point, you have again, ionizing radiation.
Energy. Associated radiation can transfer to matter. It removes the electrons. I've said that about three times so you know it's going to be on your test right?
Types of radiation capable of producing ions are collectively referred to as ionizing radiation. Ions can be positively charged, have too few electrons or negatively charged have too many electrons. So creating ionized atoms, they have plus or minus charge, unbalanced from what's normally there.
Electromagnetic vs. particulate radiation. There's two types of ionizing radiation: the rays, and those are X-rays and gamma rays; and then you have particles or particulate radiation that come from the nucleus of an atom and they can be alpha particles, beta particles and neutrons. You won't ever see neutrons unless there's a nuclear blast. And then you'll only see them for a few seconds and that's during the blast itself. But even after the blast itself, there will be no neutron sources of radiation. You have to have an operating reactor basically to get neutrons with a few exceptions.
What's an X-ray? It's a wave that comes from the anode of an X-ray machine. You accelerate the electrons in the vacuum tube. Put about 50,000 to 300,000 volts across the cathode to the anode. These things accelerate and get going rather fast and then they're stopped in the anode usually tungsten or some other material at the high melting point. And when the electrons are stopped, they can emit, heat, light and then X-rays. That's what you see in the doctor's and dentist's office to get your X-rays. Gamma Radiation. It's electromagnetic waves too just like an X-ray, but the big difference is it comes from the nucleus of the atom. It's nuclear radiation. So that's the two types of electromagnetic radiation.
So then you have alpha particles. A particle radiation. A nucleus like thorium or uranium or plutonium. These emit alpha particles spontaneously. An alpha particle is simply two neutrons and two protons, I hope I got them right-usually the neutrons are white and the protons are black. When this is stopped, these alpha particles becomes a helium atom. Do you all ever wonder where we got our helium from for our helium balloons? You'd think all that stuff would escape from the earth and go up into the atmosphere. What comes from alpha particle decay, from the heavy elements in the ground, the alpha particles are stopped in stuff like oil. They refine the oil and we get the helium. Helium is one of the byproducts of oil refining. So that's where the helium is coming from. It's dead alpha particles from the heavy metals in the earth.
Beta particles. It's basically a high-energy electron. And when you convert one of the neutrons in the atom, it converts into a proton and releases an electron. Fast-moving, can zip along an ionized material. We won't go into the physics of it, but there's the beta particle. And when it's slowed down or stopped or shielded, it becomes just like any other electron. If you want a few electrons, go find a wall outlet, you'll get a few electrons out of it.
Sources of radiation. X-ray machines. Accelerators that they use in radiation therapy. You can get electromagnetic radiation and you can also get high-energy electrons or beta particles essentially. And radioactive material: radionuclides can emit electromagnetic radiation and particles.
When we talk about radioactive material, we're going to ignore the X-ray machines now because you can't use those to make a dirty bomb. We're going to focus on the particles. The radioactive material always decays with a given half life cobalt 60 has about 5.26 years half life. Tritium has about a 12 year. And other things decay at different rates. It's always going in half over a certain half-life time. This is one half-life and it goes to about 1,000 to 100, from 500 to 250, down to 125 and so on. So that's the half life of radioactive material. Does it ever all go away? If you're a scientist, no. If you're an engineer, it goes away in about 10 half lives and it's close enough to be effective. It's the way engineers look at it.
Measure of radioactive material. There are two primary ways of measuring radioactive material. One is a curie and the new metric or system international unit is the Becquerel. When a nucleus decays, it gives off its radiation, it disintegrates, decays, that's the D. And you have one disintegration per second, one dps. You have a Becquerel. That's a unit of radiation. So you have a lump of radioactive material and it's decaying at 2,000 dps, you've got 2,000 Becquerels. A curie, the common unit that we've used, it's extremely large compared to a Becquerel, 3.7 times 10 to the tenth times larger. That's 10 with 10 zeros behind it. So often we talk about a millicurie, which is one-one thousands of that, that's like a millimeter being one-one thousands of a meter. So then you have a microcurie which is 10 to the minus sixth curies, a millionth of a curie. You get down small enough and eventually you get down to a Becquerel. In stopping these particles of radiation and the electromagnetic waves (the gamma rays or X-rays). Alpha particles, lucky us, they're high energy, high charged plus two charged for the two neutrons and extremely massive. You can stop them all with a piece of paper. I brought some radioactive sources I can demonstrate this with at the end of the class. Alpha particles stop with a piece of paper. So if you have on clothing to protect you from an alpha emitter that's been spread around, it's not going to affect you. But guess what happens if you inhale that alpha emitting particle, the piece of paper that stops them is going to be your lung tissue, so it's an extreme internal hazard because all its energy is hammered right into the tissue and causes tissue damage, but as long as it's outside your body it's really a non-issue. Beta particles take a big piece of plastic, about a quarter-inch at the worst, or a thin piece of aluminum to stop all the beta particles. Some beta particles you can stop with a piece of paper, some you can't. And then gamma rays and X-rays-what are you going to use to stop it? Lead. You need something thick and dense to stop the X-rays. They go through and can cause damage. So if you have two sources outside your body, one's an alpha, don't worry about it. One's a gamma ray emitter like Cobalt 60, you want to worry about it and have some shielding to protect you from the radiation.
Atomic weapons. Prompt, gamma and neutron radiation , when a nuclear blast occurs. And then you're going to have fallout. And the fallout is the radioactive material that's emitting alphas, betas and gammas, no more neutrons.
The effects of an atomic weapon. I won't go deeply into this, but they're severe, and prompt death within a relatively small area. Most of the small weapons-they could be the suitcase type you hear about like in movies like Sum of All Fears, would have a very small footprint of immediate deaths. A larger weapon may have up to a mile in diameter of total devastation. I got that from one of our audience members here (Roger). But it is a relatively small area. Your aren't going to have a nuclear weapon go off in the middle of San Antonio and everybody in Bexar County die. Actually, the building would remain in tact, and there would be quite a few, are going to shield and protect quite a few people. You're going to have deaths within a very small area. If you saw the Sum of All Fears, you might have noticed that there was a football player at the emergency room, when he was right there in the field where the weapon went off. And that's a very realistic scenario if he was standing behind some concrete or out in the locker room when the weapon went off.
Dirty bombs. Well, you have to have some radioactive waste and you got to have something to disperse it. What is a dirty bomb? It's a weapon made by combining radioactive material such as spent nuclear fuel rods. Who's going to get a hold of those? Not very many people. If you heard about the security measures around a nuclear power plant and while they're transporting spent fuel, no one's going to get there hands on spent nuclear fuel. A dirty bomb can spread intense radiation over a wide area. You may think that's bad, but in one sense it's good. The more you disperse it, you dilute the radioactive material and it's going to have less effect on the population as far as immediate concerns. But long term effects need to be considered when you disperse it around. The biggest effect of a dirty bomb is the psychological effect. The cleanup will be costly and time consuming, but the only thing that's going to cause immediate deaths is going to be the explosive materials not the radioactive material.
Units of dose. I took this right out of the Nuclear Regulatory Commission's definitions. You have the gray and you have the red. These are units of absorbed dose. The SI unit is gray and the absorption of one joule per kg, well that's nice. The old unit is the rad. And one gray is equal to 100 rads. Or another way to say it is a centigray is one rad. The rad, that's a traditional term that's still used extensively in the United States, but not as much in hospitals, but elsewhere. The rad is also a unit of absorbed dose and it's the absorption of 100 ergs per gram of whatever it is. It could be aluminum or whatever. I always like to ask the question when I give this class at work, what's an erg? And nobody knows what an erg is. An erg is about the energy it takes a mosquito to do a pushup. And so, 100 ergs per gram of material.
Now, when we talk about biological damage-damage to your body-we have two new terms, different, slightly different. The Seivert and the Rem. The Seivert is the new SI unit and it's equal to 100 grams and this is damage to your body. That's the main thing you need to know. But lucky us, for beta particles, which is mostly what we're going to encounter if we run into radioactive material, gamma rays and X-rays, for all practical purposes, a Rem and Rad are the same and a Sievert and a gray are the same. So if somebody says I've been exposed to 10 rads, you say oh, you got 10 rems as long as it's X-rays and betas. And so those are the terms that you will need to know if you're working with radiation.
Equipment used to detect different kinds of radioactive material. We'll talk about these. Many different kinds of devices, and we'll show you some pictures of those and I brought some with me if you want to see those at the end of the class. Personal dosimeters, handheld detectors, and air sampling. I brought two personal dosimeter, the TLD and also a ring badge. I'll be glad to demonstrate those at a show and tell later, and we'll show some pictures right now. Also, you have a pocket dosimeter that you can get an instant read out of your dose while you're working with your radiation. It's great for gamma rays and X-rays, but it will not detect betas because of that thick plastic or aluminum casing that it's in. There's the TLD badge and the ring badge just like I have. Gieger counters, you've got one that measures, this one is in millirems per hour, the other one measures in counts per minute. This one has a thin window. I have a similar detector just a different configuration. It detects alphas and betas and gammas. The window there is so thin, it's thinner than a piece of paper and the alphas will go through it and it can be detected. I would call any kind of thin window pancake detector, kind of the workhorse of what you need in the field if you're working around a dirty bomb. It's going to tell you right away if you've got alphas or betas or gamma or all three combined. And using the trick of putting a piece of paper between it and the source to determine if there's alphas there or not then the count drops dramatically. You can have a response kit with your millirems per hour or milliseiverts per hour, whatever unit you want it in. You can also have air sampling monitors.
But since I have two minutes, I will show you some radioactive sources. These are contributed by the International Atomic Energy Agency. This is an old radium source. You'll never see those. They discontinued those back in the 1930s and 40s. This is off a radiographers camera, highly radioactive for a short period of time. They cut the pigtail off. It comes with a long, long cable, so the guy can get far away to use it. But it's really about the size of a pencil or smaller. You may see a cobalt therapy source. These are the holders. And that's a picture of a dummy cobalt therapy source. This is a radium needle, probably won't see much of those anymore. The radium night light. They put that on their helmets to see at night. You might see something like this-an old radioactive source cast, lead shielding to protect whoever's working with it. And the source would be tucked away inside. These are some old casts. They're painted gray instead of yellow.
We'll answer questions at the end of this.
Martin Meltz speaks.
We're going to switch gears and take you to basic radiation biology. I'm not going to be addressing human issues, but I'm going to take you down to the level where we're dealing with the basic cellular effects and what happens to DNA when the ionizing radiation enters your body.
My objectives are for you to know that the cells and tissues are the primary element for the radiation exposure leading to physiological harm, could be clinically detected. Dr. Morali will be addressing those issues. Because of extensive cell death, physiological harm, mutation and/or cancer if the cell survives, that the initial event after the physical deposition of energy is the generation of what are called free radicals, that damage to the DNA is either direct by interaction of the electromagnetic radiation or the particle with atoms in the DNA molecules or through the indirect action of free radicals. Radioprotectors can work to protect against that. Ours cells actually have some natural radioprotective chemicals in them. That cell-killing, mutation or cancer are all dose dependent, whether the source of radiation is internal, inside our body or external. That cell killing has a measurable threshold. The extent of cell killing increases with increasing dose and that's called a deterministic effect. That it is the risk of inherited mutation or cancer that increases with dose. When it happens it happens and it doesn't increase with severity, it simply happens, will occur to some but not everyone in the exposed population as the dose to the population increases.
Now the time frame for radiobiology is very rapid. The physical actions occur in 10 to the minus 19 to a millionth of a millionth of a second. The end result after the interaction with water and production of free radicals and the indirect effect, the chemical interactions and the free radical life times and interactions occur at about one-one hundredth thousandth of a second. The observable biological responses, depending on what you're looking for can occur in seconds or minutes or hours or days or weeks or months, for years, or in fact over a whole life time of the individual. So that depends on the biological endpoint. When we are exposed to radiation, again whether it's internal or external, because we're about 85 percent water, the most likely random interaction with the electromagnetic or particulate radiation is going to be with water. And when that occurs, there are three dangerous chemical reactive species which are produced. They're called the hydroxyl radical, the hydrogen free radical and something called the aqueous electron, which is simply those electrons which are ionized which slow down. They become thermalized, they are moving very slowly and they're surrounded by polar water molecules. And the reason these are important is if the water near the DNA is altered to become these chemical reactive species by the ionizations, there's enough time for them to move over and damage the genetic material of the cell of the DNA. There are other products because of secondary reactions, but these are essentially the chemical bad reactors. So what we're really talking about is a chemical process. As I mentioned there are natural radioprotectors like the amino acids and glutathione in our cells which will scavenge some of these. And if radioprotectors were generally available, which they're not, they could be used to inactivate these free radicals.
This is a model of the DNA and I'll give you some more information about that in a moment. The slide is put up to show you that if the photon causes the ejection of an electron, and that electron gives you free radicals to move over to the beginning of the cell, that's called indirect action. And again, this has to happen in very close proximity to the DNA in the nucleus. It's not that it's not going on in other parts of the cell, but as you'll see, the major target of concern for us as individuals in the communities we serve is going to be damage to the DNA. The free radical would migrate over and damage the DNA. But there's also the possibility of a direct interaction of a photon with the DNA itself, because it's a very large molecule. But there's approximately 10 to the 12 water molecules for every DNA molecule, so again the greatest likelihood is of indirect action and 60 percent of mammalian cell killing is attributed to indirect action.
This is put up basically to remind us that what we're really talking about is we're made up of body parts. There are organs which are structural and functional. They're comprised of tissue and again, structural such as bone and cartilage and our functional tissue. This slide just shows in the image where background radiation can enter our body. Basically, 55 percent of the average annual exposure of the American population is attributed to radon, but that's only if you live in a radon area. But averaged over the whole population it's about 55 percent. The contribution for man is only about 18 percent. Our body parts are made up of the cells in our body. So again, when radiation enters our body, it's going to be random in terms of where it enters, it's going to be random in terms of its interaction with the cells. One gram of tissue might have a thousand million cells in it, and just to give you a perspective of what has to happen.
Different cells have different kinds of sensitivities. Those cells which are fully differentiated, functional and non-dividing, such as our nerve cells and muscle cells are known to be radioresistant. Those which are partially differentiated cells that continue to divide are less resistant, such as liver cells and glandular cells, and when people have liver damage, the cells can be called upon to divide again so they're not fully differentiated. And that's the kind of tissue repair that can occur. So they're resistant but less resistant than the fully differentiated cells. Now cells that can divide but lend support to the other cells and tissue such as the endothelial cells lining the blood vessels and the fiberglass of the connective tissue are intermediate in radiosensitivity. And the point is if our body was exposed to the whole body, the nervous cells would not be damaged as much as the cells of the blood vessels lining the blood vessels. And this comes into play when Dr. Morale talks about the radiation syndromes and which syndromes occur at lower doses and which occur at higher doses. There are dividing cells which start to differentiate which are not the primary stem cells. There are also cells, for instance, that are moving up along villi that are like little mountains that stick out into the lumen of our intestine. The most sensitive cells which are the stem cells are the cells at the bottom of these villi which are rapidly dividing which move up along the villi become a little more differentiated then fully differentiated. The one's which are more radioresistant are the ones that are fully differentiated ones. But the cells which are constantly dividing are very radiosensitive. They're found in the bone marrow, which is why there's a great attention after radiation exposure to looking at the blood, the intestine, the skin and the rapidly dividing cells in the testis.
Because these cells are rapidly dividing, at low doses, they can rapidly allow the organ to recover. But since they're radiosensitive, if the dose is too high, you kill too high a proportion of them and then the organ cannot recover. So there's a little race going on here between dose and recovery.
Now there are two cell types not in that category, but which are very radiosensitive. The ocyte and the very important cell type the small lymphocyte because it's functional in the immune system and again, Dr. Morale will address this when he talks about human clinical effects.
Now this is a cell. I didn't put it up to describe all the components of the cell. Remember, radiation can react anywhere in this, cytoplasm or nucleoplasm. But it turns out that the main target is going to be in the nucleus where the chromosomes are located. The chromosomes are comprised of DNA and proteins. The only time we can see them is when the cell actually divides, but they're basically the target for cell killing; they're the target for mutation; and they're the target for cancer with respect to ionizing radiation exposure.
This is a description of the DNA molecule, but with all of the cell components present, the main and most important molecule in the cell through either indirect or direct action is going to be through free radical generation, is going to be the DNA molecule. The DNA is a very large molecule. It's comprised of a backbone of two intertwined strands. There are sugar phosphate groups which line the strands and make up the strands. And there are bases which stick out into the middle of this molecule. Those bases are thymine, guanine, adenine and cytosine. And the sequence of units of three, are what defines the genetic code. This is what the free radical or radiation can live. Basically, everything in here can be damaged.
This is a list of the kinds of damage that can occur. You can have single strand breaks where you break just one of the strands, because you damage the sugar phosphate linkage. You can have a DNA double strand break which is much slower in being repaired which could lead to either death of the cell if it's not repaired or possibly lead to cancer. You can have sugar damage, because there is sugar molecules in the backbone. You can have base damage which can lead to mutation. This would be damage to the thymine, guanine, adenine and cytosine. You could have separation of the two strands which occurs if the bases are damaged. The bases attract one another to keep the strands lined up. You can have DNA-DNA crosslinks which are liable to be lethal, because the strands can't pull apart for the cells to divide. And you can have DNA protein crosslinks which may not kill the cell if it doesn't divide. It could stop some of the metabolism of the cell by stopping synthesis of RNAs that turn out to be proteins. So this is a unique molecule of what we call some redundancy of genes, but it has the genes which have to be conserved and passed on to the daughter cells.
What happens if the DNA is damaged? There'd be a slow down in the cells synthesizing copies of its DNA so that there's a delay of one cell dividing into two which could be a problem if we're depending on an immune response. The delay to allow for repair to occur, because our cells fortunately can repair their DNA, could stop the cell progression towards its next cell division. So that's called a delay in cell cycle progression. But it doesn't have to be lethal, because repair is a good thing to occur.
Decrease in the overall rate of cell proliferation, increase in cell number therefore occurs, because we've delayed the progress of the individual cells in that population. But then we could have death of a cell, if there is too much damage to the DNA, and it can't be repaired. The cell tries to synthesize the DNA. There could be a mutation of the cell, which is passed on to the daughter cells which could be a problem in the testis or ocytes for inherited mutations. Or, it could become a problem if the cell survives in terms of cancer risk. And then, there are changes in the cell which will make it cancerlike called cell transformation. But that doesn't mean that cell with those changes is going to become a cancer cell, but it's one of the early steps. Now, in respect to cell death, there are two general descriptions: interphase death, which is for those cells which are dividing where the cell dies before it goes into division. Or, reproductive death, where the cell may divide a few times and then die. There are specific descriptions of the kinds of cell deaths. One is necrosis, where the cells are all in contact to one another and the field of cells is dead. That can happen if there is trauma to the tissue as well as radiation to the tissue. Another would be the cell basically bursts open, because there has been damage. But of greater renown today, is this phenomenon called apoptosis or programmed cell death. It actually is something that's naturally supposed to happen in our bodies. In fact, it has to happen in the developing embryo in order to get a fetus developing, and so it's required. It requires energy and when the cells die, the DNA fragments are of discrete sizes, it's under genetic control. It's supposed to happen. The problem is if we had radiation, more of it will happen than we want. But the end result is dead cells, depletion of the cells and if too many cells in the tissue are affected then we have organ affects and then we have the clinical human affects that you'll hear about in a little while.
Now this is the overview of the radiobiology. We described the physical interaction which happens in the very rapid time frame. The free radical interactions, which will then occur. Then, after the DNA is damaged, most of us have DNA repair enzymes which basically keep us alive, because there are free radicals generated by our own cell metabolism. That's why people go to the food store to buy antioxidants. The antioxidants work against free radicals. And so, the DNA is repaired except in people with genetically inherited diseases. Repair can be error prone or error free. If it's error free, the cell doesn't ever know it had a problem. If the repair is error prone, there can be inherited mutations and there can be cancer. These are low dose effects, because the cell has to live. High dose effects involve cell killing, tissue damage and organ toxicity. I wanted to put in here effects on the embryo fetus, because low dose effects in my way of thinking, are doses below one centigray. That's how I tend to think about it. Much higher doses, you're going to start to get measurable cell killing. At about 10 centigrays to 25 centigray you could have effects on the embryo or fetus. Those are my arbitrary ways of thinking about it. A chest X-ray might only give you .02 centigray.
Measurable fraction of radiotherapy is 250 centigray. Acute whole body radiation that can start to kill you is around 250 centigray. So I just began arguing for a low doses being something that the population can be exposed to from radioactive contamination. Most people would not be exposed to the acute high doses in even a dirty bomb incident. And that's something that John Hagman mentioned.
This is now about cell survival. This shows that there is a survival curve for what we call low LET radiation, X-rays or gamma rays. In the initial low dose region, and this is in centigray there's not very efficient killing. But as you go pass this shoulder where you accumulate lethal damage you have a more rapid cell killing, and the inverse of this slope is called the D-zero dose. It's the dose which would reduce survival to .37 of what it was before you gave it. Several D-zero doses can be very damaging to a population of cells. Fortuitously, at lower dose rates for X-rays and gamma rays, but not necessarily for alpha particles, at lower dose rates for the same total dose, you have less killing efficiency. Which is why putting distance between you and a source using shielding, reducing your time of exposure, and lower the dose rate and therefore, be protective of the person being exposed. And so, lower dose rate is a benefit.
Fractionation. If you're exposed today, and then you're exposed tomorrow, and then you're exposed the next day, in terms of cell killing, and I'm only talking about cell killing right now, fractionation where you have a shoulder region on the curve where you accumulate what's called sublethal damage. You wind up for each dose with less of an effect. In a way, it's like a low dose rate effect. So again, fractionation is protected of the individual who's exposed in terms of the cell survival.
This shows you what happens when you have X-rays or gamma rays vs. high LET radiation. Now I should mention that for things like bone marrow cells, there's very little shoulder. So even for X-rays and gamma rays, the curve is going to have a very short region where you're short of wasting the radiation, but then it's a very severe killing. Bone marrow cells are very radiosensitive. Chromosome aberrations. It results in many different types of aberrations with the type depending on where the cell is in relation to its next cell division. The most commonly observed types of aberrations are what are called ring or dicentric aberrations. In radiation events the clinicians probably will take a blood sample so that that could be sent off to see if they can get biological dosimetry performed by measuring dicentrics and ring aberrations against historical controls. There are many other aberrations which can be measured. If you really see one of these gross structural aberrations, chances are the cell would have died anyway. We have to be concerned about in terms of cancer risk are something called reciprocal translocations where the cell doesn't lose the genetic content and survives and that could lead to a cancer event, but it doesn't have to lead to a cancer event.
Another thing that could happen is also genetic mutations in the DNA which would be base damages, because they're part of the process of cancer formation ultimately also in a surviving cell could lead to a cancerlike change.
From mutations. What we're concerned about is exposure of the spermarocytes, and the outcome is either yes or no and there is no threshold of dose below which ionizing radiation can induce mutations. For both mutations and cancer, it's different than cell killing. The deterministic effect say that if I expose all of you to a dose where I could measure killing of cells, if I increase the dose to all of you, I'd see more of that effect in all of you. For mutation and cancer, if there are 10,000 people here and 10,000 people here, and there is a risk of one in 10,000 getting cancer or inherited mutation, if I gave everyone that dose which was going to be an increase of one in 10,000, I could have two in 10,000 here and two in 10,000 here. Or, I could have one in 10,000 here and three in 10,000 here. Or, I could have one in 10,000, one in 10,000 and four in another 10,000 that wasn't even part of my exposed population. Because, it's a probability event. We can never predict who is going to get the inherited mutation, or who is going to get the cancer. We just know that there would be an increase in risk to the population above what's there already. At low doses and low dose rates the risk of mutation is very low and it is lower for low dose rates at all doses. So again, low dose rates is protective of the people who are going to be exposed. The relationship can either be linearly increasing with dose or a linear quadratic relationship, and I'll come back to that in a moment.
Radiation and cancer. Cancer results from exposure of cells to ionizing radiation and it's a stochastic event, and it's a probability event as I just said. The outcome is either yes or no. The severity of cancer has not changed-you either have it or you don't. They types of cancers due to the exposure are either blood cancers or solid tumors. In the blood cancers, there's acute myeloid and chronic myeloid leukemia and acute lymphocytic leukemia, but for some reason, there's never any chronic lymphocytic leukemia. And for solid tumors, over time, it's been discovered from radiating a population, there are far more solid tumors than there are blood cancers and the ratio is something like six to one. The solid tumors are more likely to occur in organs such as the lung and the thyroid and the bone. There is another unit of measure which I'm just going to mention briefly, for low level radiation exposures where you're interested in the risk of cancer or the risk of mutation and that's called the effective dose. It's different from the dose equivalent as John Hagman mentioned, because scientists on an expert committee have assigned tissue waiting factors which ultimately add up to one so that if you knew what a dose equivalent was to a tissue, you would multiply that by the waiting factor for that tissue, and you get an effective dose. Then you add up all the effective doses for all the organs from that kind of exposure, and you have the effective dose, which is an indication of the risk of cancer or mutation from that particular exposure. Now, the reason that's important is the guidelines, the annual occupational exposure guidelines, are based on the effective dose and not on the dose equivalent. So you just need to be aware of that.
This shows some of the relationships. If you had an actual relationship which was linear, it would look something like this. For solid tumors, it's believed there's a linear relationship of increased risk or incidents with increasing dose. Most of the data is of high doses. So there's a lot of guesswork which goes on with low doses.
If you have something like blood cancer, the risk is likely to be linear quadratic where at low doses it's linear, but at high doses it becomes related to dose by the square of the dose. So a dose of two becomes four, a dose of three becomes nine. When you get to higher doses, the curves tend to flatten out. The reason they tend to flatten out at higher doses, you're actually killing the very cells that could become the cancer cells. But when you get out where these are beginning to flatten out, you're also starting to kill people. So at that point, that's not going to be the issue.
For anyone who's exposed to a radiation, external or internal, we're going to be dealing with either a linear relationship or a linear quadratic relationship. If there is a low dose rate, the dose reduction factor for the risk is essentially two for both solid tumors and for blood cancers.
The summary for my part of the talk is that exposure of cells to high doses of ionizing radiation can be expected to be harmful to the cells, and therefore to the body either immediately or at later times after the exposure. And some protection is afforded by low dose rates. The exposure of cells to low doses, and especially at low dose rates is unlikely to result in obvious cell harm. However, continued exposure at even low dose rates to large numbers of people will increase the risk of such stochastic hazardous events as cancer or inherited mutation.
Ten minute break
Meltz introduces Dr. Sam Morale: I'd like to introduce Dr. Sam Morale who is one of our limited number of clinicians in Bexar County who has given attention to radiation effects in terms of clinical manifestations, and we're very pleased with that. He's been instrumental already in identifying clinicians and hospital personnel who will be part of a working group that's formed under REMPSC here in San Antonio to look to bring together radiation physicists and medical personnel to move forward to trying to get our hospitals and medical community prepared to deal with radiation. And again, that committee with report back to REMPSC.
Sam Morale speaks
We have certain objectives which we'd like to cover. There's certainly going to be more things introduced than what we've identified here. But first of all, we'd like to be able to recognize radiation prodromal symptoms, the symptoms one would experience or that you would observe in terms of signs of an individual who hadn't been exposed to a substantial amount of ionizing radiation. We'd also like to be able to identify at least three acute radiation syndromes. There are three principle ones identified at this point in time. We'd like to be able to understand the basic concepts of exposure and contamination. There's an important distinction between those two. And also appreciate there are indeed a variety of injury patterns which are possible as opposed to the simplified model of an individual directly exposed to some source.
We'd also like to be able to identify two assessment methods to objectively quantitate the degree of an individual's radiation exposure. Just knowing that someone's been exposed is one thing which may not be too complex. However, to quantitate the magnitude and characterize the type of exposure is an entirely different matter. We'd also like to become familiar with the general treatment approaches. There are a variety of treatment approaches which have been developed. From principally industry where misadventures have occurred and accidents of criticality in the like which we'll go into at least to some degree. We' also like to identify at least three clearly identifiable delayed effects of ionizing radiation.
There are many ways in which an individual might become exposed to radioactive material. We've certainly discussed the thermal nuclear detonation-the devastation associated with that, as well as the dirty bomb. However, the consideration of contamination of food or water, aerosolization of substances with a specific ionizing radiation activity as well as source exposure-a source being that little pellet for example that was at the end of the industrial radiography device that was shown earlier, as well as other types of exposure. Of course individuals are exposed to radiation all the time. From low level sources in our soil such as uranium and a variety of different isotopes, the cosmic rays particularly when a individual goes on a space flight for example. It's a serious concern. There's been many people in many different arenas which have been investigating the potential harm which might occur from radiation, as well as what can be done about it. There's another group of people who have been working to figure out ways in which radiation can be used in a practical and helpful way. And some of these people possess substantial amounts of radioactive material which could indeed be utilized by an evildoer to sort of wreak havoc. For example, there's individuals who possess rather substantial amounts of solid sources that are used to sterilize food and medical materials. This is not just in the U.S., this has been worldwide. There have been accidents with these devices which has kind of brought the attention of radiation disaster people. We'll go into these things. As we're talking about the types of exposures and individual might be faced with, there are these substantial amounts of materials which are not stored at a nuclear reactor site. Materials that are a product of the nuclear reactions in our reactor facilities-those materials have separated out, and a variety of them, like cesium for example and strontium, these materials are separated out and they're provided to the medical treatment community, like cobalt and the like, to eradiate tumors and the industry for industrial radiography. They're also supplied to individuals that manufacture these radiation/sterilization devices. This has been going on for quite some time. There are a very large number of these very sources distributed worldwide. This type of material could be groundup or fashioned in some way to create harm to a fairly large number of people in a fairly confined place. That's why I bring up the point of aerosolization in food and water contamination.
Complicating factors. If an individual is exposed to ionizing radiation where they to be exposed to chemical agents, vesicants and the like, infectious agents such as our anthrax for example, or any number of less virulent organisms, or to trauma that can certainly complicate the situation and exacerbate the toxicity of the ionizing radiation source. Fear is a big factor.
We need to consider the acute radiation syndromes and their management. When we do that, we need to consider, the key underlying pathophysiology at both the cellular and organ level. We're going to describe those syndromes. We're going to discuss diagnostic procedures and some aspects of clinical care.
Various tissues in your body are more or less sensitive to radiation. Interestingly enough the human lymphocyte is extremely sensitive. As you can see at the lower end of our chart here, nerve cells and muscle cells are relatively resistant. The other tissues are in some intermediate category, for example, the testis and ovary. We're not going to go into those here but those are issue that addressed at a later time. The prodromal signs and symptoms that I alluded to in the objectives consist of anorexia, nausea, vomiting, diarrhea, fever, conjunctivitis and skin erythema. These are certainly symptoms which could be associated with any one of a number of other ailments and infections, toxicities from various substances, which could certainly cloud a picture.
This diagram here illustrates the likelihood of experiencing prodromal symptoms if an individual were exposed to a variety of different ionizing radiation levels. As you can see on the highest line on the diagram. If an individual were to be exposed to 300 rads or 3 gray in the international system. You would see that essentially, everyone would experience the prodromal symptoms. The appearance of them would increase over time. The wouldn't be occurring right at the very outset but they would gradually develop more and more people would demonstrate these. You can see at low level exposures down here, perhaps 150 or 100 rads, or 1 or 1.5 gray, that a relatively small number of people would actually experience these. Of course, if you had someone exposed to a real high level, things would be rather markedly accentuated. We could divide individuals into groups basically based upon this.
Dr. Wald, a rather known physician who has treated individuals with radiation exposure, describes basically five groups:
-Your first groups, as you can see, we're looking at an individual with a pretty low level exposure. Any manifestations would be basically latent. The individual probably wouldn't show any signs or symptoms. But if you were to do testing on them at a subsequent date, you can identify that they had indeed been exposed.
-Then we have our mild form with a hematologic effect, which could progress on to severe as the radiation dose goes on higher and higher. We can see the different types of manifestations and the different syndromes begin to appear. The blood-forming organs are affected earliest.
- And then we proceed on to a gastrointestinal syndrome where the GI system becomes affected.
-And finally, the nervous system, as we progress to an escalating dose. The symptoms associated with these.
The cardiovascular collapse with an extremely high dose where the nervous system and cerebral edema occur.
The gastrointestinal complications where the cells lining the GI tract are directly affected by the radiation. In the lower ranges, we're looking at the hematologic system taking the brunt of the injury.
Now taking each of these areas individually we can see when the hematopoietic system insulted by a significant dose of ionizing radiation we obviously have an impairment of the immune system, immune dysfunction, which can lead to infectious complications. Ultimately, platelets can be damaged, and the platelet count drop and the individual can hemorrhage which could lead to anemia or the individual could simply have their red cell precursors injured and over time, they could develop anemia. And certainly, impaired wound healing.
The gastrointestinal syndrome. Now notice that we're talking about GI symptoms, but this in counter distinction as to the effects of the prodromal symptoms which we see. This is direct toxicity to the GI tract. It's not a vaguely mediated mechanism as we see with many of the symptoms from the prodromal phase. We're looking at devastating effects which could lead to GI bleeding. There could be subsets, basically which is a severe systemic infection from bacteria which make their way into the blood stream and the barrier of the GI tract is insulted and degraded.
However, if you notice here, there could be a latent period, which can occur from four to five days on up to weeks before this syndrome actually manifests itself. All of these things are dose dependent. You'll notice the 6 to 8 gray exposure, which would be 600 to 800 rads, would be sort of the minimum needed to produce a significant and probably fatal gastrointestinal syndrome.
You might wonder where all these numbers come from. These numbers come from an accumulation of data and from many, many scenarios involving all sorts of accidents combined with individuals who have received treatment with radiotherapy. Obviously, we're not eradiating people's guts with these kinds of numbers deliberately, but an inadvertent accident or two has also occurred historically.
The neurovascular syndrome. We looking at vomiting and diarrhea which can occur within minutes, it doesn't have to. If a person receives a high dose radiation to the head. There have been case reports of individuals actually wearing a personal dosimeters and inadvertently exposed to high doses of radiation that have ultimately have gone on to experience this neurovascular syndrome, but it has perhaps taken several hours for it to manifest itself. Hyperpyrexia, which is fever, hypertension, the person becomes confused and disoriented, cerebral edema, convulsions and coma follow. This is obviously just like the GI syndrome. It's a fatal syndrome. If these types of syndromes manifest themselves in a patient early on, they're terminal.
As I alluded to earlier, we need to learn ways where we can assess how an individual has been affected by the radiation-what magnitude of exposure they sustained.
This diagram here, reveals the time, course of events of a typical, 450 gray, we're looking at a lethal level without treatment. We can see that our platelets or the thrombocytes drop off gradually, and then around 15 days fall somewhat precipitously. You'll notice that our lymphocytes plummet. Lymphocytes as you recall from the earlier chart are the most radiosensitive of our cell types. They actually wind up being a pretty good indicator of the magnitude of radiation exposure in a patient.
Peripheral blood lymphocytes are what I'd like to talk about at this point. If an individual were to be exposed to an acute dose of ionizing radiation, a 50 percent drop in your peripheral lymphocyte count would indicate a rather significant exposure. Potential lethal case of bone marrow suppression may begin from three weeks after an exposure or not occur until seven or eight weeks out. All these time courses are all dose dependent. So, just because someone looks pretty well early on, doesn't mean some fatal outcome may not ensue. That's where our blood count would come in.
This chart depicts kind of the same basic principle. It shows the lymphocytes dropping. As you can see with the lower dose, the rate of decline and the absolute decline are both influenced by the dose an individual sustains. So an individual who's exposed to a very high dose, you'd expect their lymphocyte count to fall very rapidly and to plummet. People who survive typically, there's drops off and begins to show a plateau as opposed to continuing to decline. A plateau is not a serious prognostic indicator. The lymphocytes are one mechanism for assessing the magnitude of exposure of an individual. However, as Dr. Meltz alluded to cytogenetics can be applied and has been in a number of cases to ascertain the magnitude of an individual's exposure. It's been found there's a relationship between the disentromeric chromosome. An individual's lymphocytes are separated out by a variety of means. They're exposed to a stimulant which would stimulate their proliferation. There's a variety of agents. Phytohemagglutin is a common one. They begin to proliferate and then they're arrested and they're stained, and the number of dissentromeric and other types of chromosomes, can be counted. The number of dissentromeric chromosomes goes up as the dose of radiation goes up. Perhaps a week or two after an exposure this assay can be performed, and you could get a very good idea about the prognosis and what you need to do with the patient.
Treatment of the acute, noncontaminated radiation exposure victim. That's somewhat straightforward than other issues we're going to be talking about in a little bit having to do with contamination and the like. Classically, an LD 50/60, as you can see here, would be the dose of radiation which would kill 50 percent of the patients in 60 days. It's sort of a benchmark that's been established in the literature regarding radiation exposures. Approximately, 3.5 grays has been established as that dose provided an individual wasn't treated.
Speaking of treatment. Conventional therapy obviously for any individual who's immune is suppressed and has other types of toxicity. Cytokines have been found to be very, very effective in treating individuals. We're talking about the colony stimulating factors, granulocyte, monocyte, granulocyte stimulating factors as well as other agents that have been used to stimulate platelet production in a similar vein. Even epigen for the red cells. This effectiveness just incidentally, I'd like to pass on to you, is very time dependent. So, if we had someone who needed this treatment, the earlier the better. If an individual's tissue has been exposed to ionizing radiation of a significant magnitude, it'd be very important to close the wound early, because wound healing would be significantly impaired at a later time. If an individual needed surgery, the intervention should take place at the earliest possible time.
We'll move into the subject of external contamination. Were an individual be exposed to a dirty bomb from aerosol from some type of particulate which was ground up from some industrial radiography source, the materials on the surface of the persons skin or hair or clothing, would really represent a fairly negligible health risk to the individual treating them. It's unless they had a really large amount, that could kind of be suspended in the air. Beta emitters when left on the skin, would cause significant burns and scarring. Alpha radiation does not penetrate the epithelium.
Radiation dermatitis is an important consideration in an individual who has a substance capable of producing this in their skin-the material just directly on the skin. And perhaps you will recall, I'm not sure if we mentioned the inverse square rule, but as you move a radiation source away from the individual, as you double the distance the magnitude of the radiation exposure is decreased by a fourth squared. So if you move a substance closer and closer to an individual, the radiation does increase in that same fashion. Six hundred to 2,000 rem would cause erythema. That would be a dose. If you recall, a dose, depending upon not only the isotope, but how long it's present, but how close it is to you. So removing the material promptly could prevent the sequoia from the 2,000 to 4,000 dose of skin break down which could be seen perhaps in two weeks. When you get over 3,000 rem, you start seeing immediate skin blistering. Chronic radiodermatitis is associated with exposure about 20,000 centiseivert and that would be perhaps spread out over longer periods of time-lower dose more prolonged exposure. Internal contamination. That's probably the one thing most people don't spend a lot of time thinking about in the introductory kind of materials you might have encountered. However, an inhalation of any type of particle is going to be size dependent depending on the deposition characteristics.
Ingestion. This could include inhaled substances which are perhaps substances that were inhaled. They weren't straightly absorbed. They followed the mucociliary path, they get swallowed and they wind up in the stomach.
Wound contamination. Of course the possibility of skin absorption. Interestingly enough, the distribution metabolism of radioactive substances is another issue that hasn't received a lot of attention. However, substances are handled according to their physiochemical makeup or properties. For example, radioiodine, cesium and strontium are rapidly absorbed-strontium particularly in the GI tract. Iodine would seek the thyroid gland, of course that's where iodine goes in the body. Cesium, which is chemically most like potassium, would be concentrated in the kidneys, because if you have excessive amounts of potassium, it goes to the kidneys and it's excreted and that could be quite toxic to the kidneys. Strontium behaves like calcium and is deposited in the primary target-the bone. Strontium is used in medical research to ablate the bone marrow of animals in order to repopulate them in graftments. This is a well known effect. A small amount of strontium stays in the bone for a long period of time-you have a large dose. For example, plutonium, the metal itself is actually poorly absorbed. It's like a local radiation source, and that would pose a threat to the pulmonary tissue in addition to its own natural toxicity. Plutonium salts on the other hand, behave very differently. They're soluble and would require different treatment modality.
When we consider the assessment and treatment of an individual who has been exposed, obviously as I alluded to earlier, the contaminants in their skin really represent a very small threat. Just simply removing the clothing from the individual would take away the vast majority of the problem we'd be dealing with. We need to decontaminate the individual with practical consideration. If we have a large number of individuals, the decontamination can't be the same as a single individual. Most of the treatment paradigms and treatment programs revolve around treating one or two people, because those are the types of accidents that typically occur at reactor sites or the research laboratories. They go through exhaustive degrees to decontaminate and do everything to a level of perfection which would not be practical in a mass casualty incident. We need to consider the collection of the appropriate blood and body fluids for analysis. The blood count as you can see, because of the lymphocytes. However, if we believe an individual were exposed to some type or aerosol or something that could have been inhaled or ingested, we'd need to consider the collection of other body fluids. Nasal swabs can be invaluable if we think someone might have inhaled some particulate matter.
Internal decontamination. People that deal with these types of things on a regular basis have worked out many, many different interesting treatments. Some of the characteristic things which sort of illustrate these points very well, would be the consideration of displacement of iodine, of radioiodine and strontium with co iodine or calcium, for example. There's other treatments for this too, but calcium really illustrates that point really well. Strontium behaves like calcium. We use calcium. Delusion has been found with tritium, which is basically a water molecule. It's got hydrogen that's radioactive-would typically be treated with delusion.
Uptake inhibitors like pression blue have been found to be useful for cesium. And kilation therapy with a substance called DTPA, which is a very long name, has been used successfully for plutonium at research facilities and reactor sites.
As you can see with all these complex possibilities of an individual's exposure, it would be very essential if you'd discover someone had been exposed in this fashion, to get a radiation health physicist involved-someone with the hardware and the wherewithal to be able to assess a patient and using their instrumentation and the knowledge of the characteristic patterns of different isotopes to figure out what an individual might have been exposed to-if it was a beta, alpha, met gamma, what proportions, the frequency of the energy source being recognized by the monitoring equipment.
Then after all this is said and done, we need to consider what might occur down the road with some delayed effects. There's been a lot of information from various accidents as well, Hiroshima, Nagasaki, the unfortunate incident in Russia with Chernobyl, has given us a lot of information on this. It's been determined in utero exposure leads to a dose dependent increase, actually, a mental retardation, which you see in the eight to 15 week period and less so in the 16 to 25 week period. It's not really seen below eight and above 25 by and large. Below eight is probably fatal, because of the level of development. Parental exposure, does not reveal an overeffect on offspring. However, when an individual is exposed to ionizing radiation, the gonads, particularly the male, are really, really radiosensitive, and the sperm count just drops like a rock. It appears the cell's defense mechanism prevents this effect from being noticed.
Acute exposure to as little as two sieverts, can lead to cataract formation. This is another common thing found in the literature and is something to keep in mind. Characteristically between six months and several years, this is noted. The type of effect is a deterministic effect, and it's a direct toxicity to the whole entire population would be exposed to it as opposed to the incidents of leukemia and thyroid cancer particularly in children which has been noted. This is what we'd refer to as a stochastic effect. You either have leukemia or you don't. There's no shades of gray in the matter.
In summary, we'd consider dealing with a life threatening condition promptly and use our standard universal precautions which could be quite adequate, that when you balance the minimal health risks to an individual treating someone with a potential devastation that could occur if those materials aren't removed from the body, and the individual is not assessed and treated promptly. Simple clothing removal can make a tremendous difference. If screening were to reveal a radioisotope involvement, it would be very important to get your health physicist out and do some quantitation and assessment very promptly. Recognize the importance of important specimen collection and the role it would play in objective assessment in terms to determine what would we need to do with these people down the road. And finally of course, going over all these complex issues, we realize that we need to acquire more knowledge so that we'd be prepared to deal with the community, the health officials and provide accurate information to our patients God forbid some catastrophic event occur.