Biological effects of radiation
                
                Most people know that radiation is potentially harmful to living 
                systems, unfortunately there are a number of misconceptions 
                about radiation biology which are perpetuated in popular 
                culture. 
                
Radiation Biology History 
                 1895-Roentgen announces 
                discovery of X-rays 
                1896-(4 
                months later) Reports of skin effects in x-ray researchers
                
                1902-First cases of 
                radiation induced skin cancer reported 
                1906-Pattern for 
                differential radiosensitivity of tissues was discovered.
                
                Relative Radiosensitivity of 
                Tissue  
                The relative 
                radiosensitivity (sensitivity to radiation exposure) of a 
                variety of tissue is shown in Figure 2-1 below: 
                Figure 2-1: Increasing 
                Sensitivity to Radiation 
                Alan Jackson, 2001 from 
                Seibert, 1996. 
                 
 
                By 1906 Bergonie and Tribondeau realized that cells were most 
                sensitive to radiation when they are: 
                
                  
- Rapidly dividing
- Undifferentiated
- Have a long mitotic future
Author Note: When DNA, which had not been 
                  discovered at this time,  has no backup (single strand).
                
Radiation sensitivity
                Radiosensitivity is a function of the cell cycle with late S 
                phase being the most radioresistant and G1, G2, and especially 
                mitosis being more radiosensitive.  
                
Mechanisms of Radiation Injury 
                Radiation can directly interact with a molecule and damage it 
                directly. Because of the abundance of water in the body, 
                radiation is more likely to interact with water.  When radiation 
                interacts with water, it produces labile chemical species (free 
                radicals) such as  hydronium (H
.) and hydroyxls (
.OH).  
                Free radicals can produce compounds such as hydrogen peroxide (H
2O
2) 
                which subsequently exert chemical toxicity.  The body has 
                sophisticated protections against this type of chemical damage.  
                For example, this is why hydrogen peroxide foams when it is 
                poured on a cut.  The hydrogen peroxide is being destroyed by an 
                extremely rapid enzyme, hydrogen peroxidase.   
                Nonetheless, while DNA and other repair methods are 
                extremely capable of protecting the body, some fraction of 
                the damage is not repaired or may be repaired incorrectly.  In 
                either case, if the DNA is damaged, several things can happen. 
                The most likely is that the damage will be repaired before the 
                end of the cell’s growth cycle. If not, the cell will probably 
                die. There is some chance that the cell will survive and behave 
                differently because of the damaged DNA.   
                
Radiation Damage to DNA 
                Radiation-induced structural changes to DNA can be readily 
                observed (Figure 2-2). 
                Figure 2.2: Radiation-Induced DNA Damage 
                
Photomicrograph showing examples of 
                radiation-induced chromosome damage in cancer cells following 
                radiotherapy treatment (Bushong 1980). Courtesy of Scott 
                Sorenson. 
                 
 
                When DNA is damaged, the harm can be magnified by the 
                cellular machinery.  One example of a possible consequence is a 
                cell which loses control over replication-this mutation is 
                better known as cancer. Ionizing radiation is thought to 
                initiate (start), but not promote (help grow) mutations. 
                
Types of Radiation Effects 
                Acute Effects: Short term effects 
                
Very large radiation exposures can kill humans.  The 
                lethal dose(LD) for half the population (50%) within 60 days is 
                termed the LD
50/60d.  The LD
50/60d in 
                humans from acute, whole body radiation exposure is 
                approximately 400 to 500 rads (4-5 Gy). The temperature 
                elevation in tissue caused by the energy imparted is much less 
                than 1° C. The severe biological response is due to ionizing 
                nature of X-ray radiation, causing the removal of electrons, and 
                therby chemical changes in molecular structures.  
                
Deterministic Radiation Effects
                
                A number of ionizing radiation effects occur at high doses. 
                These all seem to appear only above a 
threshold dose. 
                While the threshold may vary from one person to another, these 
                effects can be eliminated by keeping doses below 100 rad. The 
                severity of these effects increases with increasing dose above 
                the threshold. These so-called deterministic (non-stochastic) 
                effects are usually divided into tissue-specific local changes 
                and whole body effects, which lead to acute radiation syndrome 
                (Table 2-
                
Acute Whole Body Radiation Effects 
                Table 2-1: Acute Radiation Syndrome 
Sorenson, 
                2000
                
                  
                    | Syndrome | Symptoms | Dose (rad) | 
                    | Radiation sickness | Nausea, vomiting | > 100 rad | 
                    | Hemopoietic | Significant disruption of 
                    ability to produce blood products) | > 250 rad | 
                    | LD50/60d | Death in half the population | > 250 - 450 rad | 
                    | GI | Failure of GI tract lining, 
                    loss of fluids, infections | > 500 rad | 
                    | CNS | Brain death | > 2,000 rad | 
These whole body (to entire body) doses are 
                very unlikely for patients and staff from fluoroscopy or any 
                diagnostic radiology study. 
                Several factors, such as total dose, dose rate, fractionation 
                scheme, volume of irradiated tissue and radiation sensitivity 
                all affect a given organ’s response to radiation. Radiation is 
                more effective at causing damage when the dose is higher and 
                delivered over a short period of time.  Fractionating the dose 
                (i.e. spreading the dose out over time)  reduces the total 
                damage since it allows the body time for repair.  Patient 
                exposures are higher than attending staff but they occur over 
                short periods of time whereas staff exposures are normally low 
                and occur over several years. 
                
Acute Localized Radiation Effects  
                The Table 2-2 provides examples of possible radiation effects to 
                skin caused by typical fluoroscopy exposures. Note that patient 
                and technique factors can substantially increase exposure rates, 
                significantly reducing the time necessary for the subsequent 
                effect.  
                Table 2-2: Dose and Time to Initiate Localized Radiation 
                Effects 
                
[Specific case studies of radiation-induced 
                skin injury are presented in the next section] 
                Please note these localized effects will not be seen 
                immediately (in the clinic).  These effects take time to develop 
                and the minor effects may not be noticed and are often 
                attributed to other causes.  This effectively results in a lack 
                of warning for serious effects such as dermal necrosis. This 
                lack of warning has led the FDA, HFH Radiation Safety Committee, 
                and HFH Hospital Medical Executive Committee (HMEC) to have 
                concerns about fluoroscopy utilization.  Consequently, 
                fluoroscopy safety training and monitoring of fluoroscopy times 
                were mandated. 
                
Chronic Radiation Effects 
                Cataractogenesis 
                Cataract induction is of special interest to fluoroscopy 
                operators since the lens of eye often receives the most 
                significant levels of radiation (provided lead aprons are used). 
                Radiation is known to induce cataracts in humans from single 
                dose of 200 rad. Higher total exposures can be tolerated when 
                accumulated over time. Personnel exposed to the maximum levels 
                each year in the State of Michigan should accumulate no more 
                than 150 rem to the lens of the eye over 30 years. As such, the 
                risk for cataracts is likely to be small.  Nonetheless, it is 
                imperative that individuals who approach the State of Michigan 
                dose limit (1,250 mrem per quarter) wear leaded eyewear which 
                can reduce the radiation dose to the eye by 85%.  Leaded eyewear 
                will be provided, by Henry Ford Health System, to individuals 
                with high eye doses. Once leaded eyewear is issued, this 
must 
                be worn for all tableside X-ray procedures. 
                
Stochastic (Probabilistic) Effects 
                Since the discovery of radiation by Roentgen, there have been 
                many groups in which radiation effects have been studied (Bushong 
                1980) (Table 2-3):  
                Table 2-3: Groups Studied for Radiation Effects
                
Scott Sorenson, 2000. 
                
                  
                    | Groups Studied for Health 
                    Effects | 
                    | American Radiologists | 
                    | Nuclear weapon survivors | 
                    | Radiation-accident victims | 
                    | Radiation-accident victims | 
                    | Marshall Islanders (Atomic 
                    bomb fallout) | 
                    | Residents with high levels 
                    of environmental radiation | 
                    | Uranium miners | 
                    | Radium watch-dial painters | 
                    | Radioiodine patients | 
                    | Ankylosing spondylitis 
                    patients (radiation therapy) | 
                    | Thorotrast patients 
                    (radioactive contrast material) | 
                    | Diagnostic irradiation in-utero | 
                    | Cyclotron workers | 
Radiation Induced Cancer 
                These experiments have repeatedly shown that exposure to large 
                radiation doses results in an elevated risk of cancer.  
Thus, 
                radiation is considered a known human carcinogen.  The 
                experimental data suggest a non threshold dose response 
                relationship (Figure 2-3). 
                Figure 2-3: Stochastic Radiation Effects 
                Courtesy of Alan Jackson, 2001
                 
 
                Extrapolation of effects at higher doses using a straight 
                line, predict that very small radiation doses have corresponding 
                small risk of causing a cancer.  This straight line assumption, 
                called the 
linear, no threshold, dose response relationship (LNT), 
                involves the least amount of mathematical assumptions and is 
                thereby consistent with the ancient principle of scientific 
                philosophy known as Okam's razor (the simplest explanation which 
                describes a phenomenon is the best). There are also some 
                reasonable models which predict this relationship.  The slope of 
                this straight line can be used as a risk coefficient to compare 
                radiation risks with other hazards. 
                The LNT hypothesis implies that any amount of radiation 
                exposure will increase an individual's risk of cancer.  Thus, 
                all radiation doses should be mimimized or kept 
As 
Low
                
As 
Reasonably 
Achievable (
ALARA). 
                
                Due to statistical considerations, such as the normal 
                incidence of cancer (~30%), the ineffectiveness of the 
                production of cancer by radiation,  stochastic effects can only 
                be shown at doses much higher than that received by occupational 
                workers.  The effects from lower radiation exposures (such as 
                those encountered occupationally) are extrapolated from 
                observations made at high doses (Upton 1999). In any case, this 
                linear assumption is expected to provide the most conservative, 
                or highest, risk estimates. The slope of the line is the risk 
                coefficient.  
                
Radiation Risk 
                The cancer risk coefficient derived from the LNT model for 
                radiation exposure is approximately 4.8 * 10
-4 per 
                rem.  To put this number into perspective, imagine that you have 
                two similar groups of 10,000 people; exposed and not exposed.  
                Each member of the exposed group receive 1 rem 1,000 mrem) of 
                radiation exposure.  The control group does not recieve any 
                additional radiation exposure beyond that received by natural 
                sources.  Since the natural incidence of cancer is about 30%, 
                the control group would expect about 3000 people to die from 
                cancer. In comparison, the exposed group would expect that about 
                3005 people would die from cancer.  Thus, the exposed group 
                should expect about 5 additional cancers from the 1 rem 
                exposure. 
                One way better understand radiation risks is to compare 
                radiation risks with other commonly accepted risks (Figures 2-4 
                and 2-5). 
                Figure 2-4: One in Million Risks 
Alan Jackson, 
                2001
                 
 
                Figure 2-5: One in Million Risks 
Alan Jackson, 
                2001 
                 Radiation Induced Genetic Damage
 
                Radiation Induced Genetic Damage 
                Since radiation causes damage to DNA, genetic effects in human 
                populations have long been suspected. Unrepaired or incorrectly 
                repaired chromosonal damage can be passed on to subsequent 
                generations. To date, there have been 
no studies which show 
                an increase in genetic disorders in human populations. 
                Nonetheless, animal studies have shown a relationship between 
                radiation exposure and genetic defects which suggest a linear, 
                no threshold, dose response relationship (LNT) much like that 
                seen with cancer.  
                The 7 million mice, "Megamouse" project revealed the 
                following conclusions (Lam 1992):
                
- Different mutations differ significantly in the rate at 
                  which they are produced by a given dose. 
- There is a substantial dose rate effect with no threshold 
                  for mutation production.
-  The male was more radiosensitive than the female. The 
                  males carried most of the radiation induced genetic burden. 
- The genetic consequences of a radiation dose can be 
                  greatly reduced by extending the time interval between 
                  irradiation and conception. Six months to a year is
 recommended.
- The amount of radiation required to double the natural and 
                  spontaneous mutation rate is between 20 to 200 rads. 
Radiation apparently does not cause unique types of 
                mutations, but simply increases the mutations rate above their 
                natural rate of occurrence. Controlled studies of genetic 
                effects are only available from animal models. The risk 
                coefficient for serious genetic disorders from radiation 
                exposure is approximately 8 * 10
-5 per rem (NCRP 
                116).  This is less than the cancer risk coefficient (4.8 * 10
-4 
                per rem). Thus, if you protect against cancer, you are 
                simultaneously protecting against genetic effects.   
                
Radiation Induced Premature Aging
                In animal populations, radiation was correlated with 
                premature aging .
                
In-utero Radiation Health Effects
                Once conception has occurred (mother is pregnant), the 
                unborn child (fetus) can be harmed by radiation.  Certainly, the 
                unborn child can have the same health problems that an adult 
                might have such as cancer and genetic defects.  The Law of 
                Bergonie and Tribondeau predicts that a fetus would be 
                exquisitely sensitive to radiation since they are:
                1. Rapidly dividing;
                2. Undifferentiated; and
                3. Have a long mitotic future.
                Studies of children exposed to x-rays 
in-utero support 
                that prediction.  Thus, based on a concern for cancer induction, 
                X-ray examination of pregnant patients has transformed from a 
                standard health screening study to an extremely rare study.  
                Nonetheless, some X-rays of pregnant patients, particularly 
                those to protect the life of the mother, are performed when 
                necessary to protect the life of the mother typically under the 
                guidance of a Radiologist.
                In addition to the health effects which are a concern for an 
                adult, there is also a serious concern about the possibility of 
                developmental errors (teratogenesis) which can occur.  There are 
                three general prenatal effects which have been observed:
                
- Lethality;  
- Congenital abnormalities at birth; and 
- Delayed effects, not visible at birth, but manifested 
                  later in life.  
The expression of effects are dependent upon the dose and 
                stage of fetal development (Figure 2-6): 
                Figure 2-6: Fetal Developmental Radiation Risks 
                
Courtesy of Scott Sorenson, 2000 
                