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4 Basic Principles of Radiation Biology To understand how ionizing radiation can damage biologic systems, it is necessary to understand what ionizing radiation is and how it interacts with tis- sues in the body. There are two types of ionizing radiation: nonparticulate (gamma and X rays) and particulate (alpha and beta particles, neutrons and pro- tons). Both forms can transfer energy into a substance. If the energy is high enough, the incoming radiation may eject electrons from atoms along its path through the material. This process is called ionization. The composition of ionizing radiation determines how it interacts with the matter surrounding it. Electromagnetic radiation is a form of light energy. The electromagnetic spectrum extends from very long wavelengths, which include electric power, television and radio, to those in the middle, which include visible and ultraviolet light. Approaching the other end of the spectrum, those with the shorter wavelengths include microwaves, radar, and infrared radiation, and as the wavelength becomes very short, the spectrum contains the highly energetic waves of ionizing radiation. The particulate types of radiation consist of suba- tomic particles that may be either charged or neutral and can vary considerably . . n size anc mass. Not all types of radiation are equally penetrating, and the depth that a par- ticular radiation penetrates into material depends on the energy and the type of radiation. Almost all types of ionizing radiation are much more easily stopped by dense material (such as lead) than by water or tissue in the human body. In 21

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22 ADVERSE REPRODUCTIVE OUTCOMES general, X rays and gamma rays are more penetrating than the particulate types of radiation such as beta and alpha particles. Beta particles are electrons and typically penetrate into the tissue only a centimeter or so. Their limited range means that they can damage internal or- gans only when ingested or inhaled, but they can be an external hazard to ex- posed skin if they are present in sufficient concentrations. Alpha particles are much larger and heavier than beta particles and have a greater electrical charge. This makes it even more difficult for them to penetrate tissue. A typical alpha particle from radioactive materials, such as plutonium, will not even penetrate the external dead layer of skin tissue. Radioactive materials that emit alpha par- ticles are a hazard only if they are inhaled or ingested and get into the cells of the body in sufficiently large concentrations. Because X rays and gamma rays travel as very-high-energy electromagnetic waves, they can penetrate the human body quite easily. Either external or internal sources of gamma radiation can be haz- ardous to the whole body because of the extraordinary penetrating ability of the radiation that they emit. Radiation damage to genetic material can occur directly or indirectly when ionizing radiation passes through the nucleus of a cell. For direct damage to occur the radiation must hit genetic material. Since the volume of the sensitive material is so very small compared with the total volume of the cell and its sur- rounding tissue, the probability of that happening is remote. If the radiation in- teracts in close proximity to the genetic material, the interaction can create a free radical that can then drift close enough to the DNA to damage it. The vast majority of those types of radiations that do interact produce ioni- zation and, subsequently, free radicals. These free radicals generally will re- combine in microseconds with no biologic effect. Even if they do not recom- bine, it must be remembered that only a very small portion of the cell is represented by genetic material and that the diffusion distance of free radicals is very short. Thus, most free radicals are not able to interact with genetic material. Furthermore, it is common for electromagnetic radiation to pass through a cell without interacting with the cell or its contents. It is also clear from radiobiological research that even if there is an interac- tion with a segment of genetic material as a result of the presence of ionizing radiation, the cell possesses many repair mechanisms. These ensure that few of the genetic interactions will result in an adverse health outcome. This can be understood more easily if one thinks about the number of ionizing events that occur in each person daily as a result of natural background radiation. Approxi- mately 25 million ionizing events occur within the body of each person each hour of each day. Since people are usually healthy, these ionizing events rarely lead to mutations or obvious harm. Radiation is measured and described in a number of ways. One can use a meter or other device to measure radiation in air, that is, exposure. The units used to express exposure are either roentgens or coulombs per kilogram. This

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RADIA TION BIOLOGY Jo measurement method applies only to ionizing electromagnetic radiation, such as gamma ray and X rays, not to particulate radiation. Also, since there are differ- ences between the levels of penetration of different types of radiation in tissue as well as differences in the distribution of energy along the path of the ionization, a more useful expression is the energy actually deposited in a certain amount of tissue. This measurement is referred to as absorbed dose. The unit of absorbed dose is either the gray or the red. One gray equals 100 reds. However, meas- urement of the energy deposited in tissue does not account for all of the differ- ences in biologic effects between different radiation types. This fact is important because the spatial distributions of ionization in ma- terial for gamma rays, beta particles, and alpha particles are different. Alpha particles interact very readily with the matter that they penetrate. They are called high-linear-energy-transfer (high-LET) radiation because they dissipate their energy rapidly, producing very short, dense tracks of ionization. Because of their high-LET characteristics alpha particles can be much more damaging, for a given absorbed dose, than low-LET radiations such as beta particles and gamma rays. Low-LET radiations ionize the atoms in their paths much less frequently and produce tracks that are much less densely ionized. It is possible to compare the biologic effects from different types of radia- tion by using radiation weighting factors. The factor for alpha particles is about 20 and that for gamma and beta radiation is approximately 1, indicating that it takes about 20 times more gamma or beta radiation than alpha radiation to cause a given effect. The dosimetry measurement that allows the differences in bio- logic effectiveness of various types of radiation to be combined is called the equivalent dose. It is calculated by multiplying the absorbed dose by the radia- tion weighting factors. The unit of equivalent dose is the sievert or the rem. One sievert (Sv) equals 100 rem. BIOLOGICAL EFFECTS There are two general types of biological effects from ionizing radiation: deterministic effects and stochastic effects. Stochastic effects are those effects whose frequency in the exposed population is a direct function of dose, no matter how low the dose is; these effects are commonly regarded as having no thresh- old. Deterministic effects are those effects whose severity in the exposed indi vidual is dependent on dose; these effects are commonly regarded as having a threshold. Deterministic effects are often the result of cell killing. Since in most organs and tissues there is a continuous process of loss and replacement of cells, a slight increase in the rate of loss due to cell killing can be compensated for by an increase in the replacement rate. If the radiation exposure is higher, there may be some reduction in function of that particular tissue. For most healthy individuals, the probability of causing harm because of deterministic effects will be close to zero at absorbed doses of less than 100 mSv

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24 AD VERSE REPRODUCTIVE OUTCOMES (10 rem) (NRC, 1990~. Some tissues are much more resistant than others to cell killing, and no effects are demonstrated until absorbed doses are in the range of several sieverts (several hundred rem). A notable exception is the sensitivity of the testes during germ cell formation. For deterministic effects, there is a practi- cal threshold below which the body is able to compensate with cellular replace- ment. If doses are high enough and involve exposure to the entire body, then death will occur. In the absence of medical treatment, an acute (brief) whole- body dose of 3,500 mSv (350 rem) will result in the deaths of approximately half of the exposed individuals. At small increments of dose above the level of background radiation, the probability of inducing either an additional cancer or a genetic defect is negligi- ble, and the number of cases of cancer or genetic effects attributable to a small increase in dose in a very large exposed group may well be less than one. A1- though there may be no definable threshold, epidemiologic studies show that, as the radiation exposure becomes lower, the magnitude of any effect in a popula- tion is so small that it cannot be identified against the background of spontane- ously occurring cancer or genetic effects. Scientific studies of the 86,000 atomic bomb survivors from Hiroshima and Nagasaki showed that 37,800 individuals died from all causes. About 8,000 persons died from cancer but the excess can- cer cases due to radiation were estimated to be fewer than 450 during the entire 40-year follow-up period (Mettler and Upton, 1995~. The incidence and severity of many radiation-induced biologic effects are a function not only of the level of dose but also of the rate at which the radiation is received. A simple explanation for this is that a given radiation dose that is spread over time allows the body to use repair mechanisms, whereas very high doses given in a very short time may overcome the body's ability to use repair mechanisms. The human data that contribute to current estimates of radiation effects are based on high-dose and high-dose-rate exposures. In general, a dose and/or a dose rate effectiveness factor (DDREF) is applied to high-dose/high- dose-rate estimates to assess biologic effects in those receiving low dose rates or low doses. A DDREF between 2 and 10 is found in experiments in animals. However, for most radiation protection purposes, a conservative factor of 2 in reducing the expected effect is used. For most of the Atomic Veterans exposed to fallout, the dose rate would generally be low, whereas for those exposed di- rectly to a weapon at the time of explosion, the dose rate would be high. Given the dose information, presented in Chapter 9, it would appear that almost all of the Atomic Veterans have what would be classified as a low dose, and therefore, a reduction factor of 2 for potential biologic effects could be assumed, that is, half that expected at a high dose and a high dose rate.

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RADIA TION BIOLOGY 25 SOURCES OF RADIATION EXPOSURE It is important to place the magnitude of exposure received by the Atomic Veterans in perspective. Exposure to ionizing radiation comes from two major sources: natural (background) radiation and technology-induced radiation, often referred to as manmade radiation. In most, if not all, countries, natural sources of radiation constitute the major source of radiation exposure for the population, with the next largest source being medical applications. In the United States the average annual effective dose of naturally occurring background radiation is about 3 mSv (0.30 rem) per year (NCRP, 1987~. Of this, about 2 mSv (0.20 rem) comes from exposure to radon, 0.28 mSv (0.028 rem) from cosmic rays, 0.39 mSv (0.039 rem) comes from naturally occurring nuclides in the human body, and finally, 0.28 mSv (0.028 rem) comes from natu- rally occurring radioactive materials within the ground. There can be significant variations in the levels of background radiation even within the United States. For example, the natural background radiation from cosmic rays and terrestrial sources in Denver, Colorado, is 50 percent higher than the national average (NCRP, 19873. Natural background exposure during 70 years of a lifetime is an effective dose of approximately 200 mSv (20 rem). If one lived in Denver or in an area of equivalent altitude, one's lifetime effective dose would be approximately 20 mSv (2 rem) higher than the national average. An inspection of the doses received by the Atomic Veterans indicates that the majority received less than 5 mSv (0.5 rem). Only 10 percent of the Atomic Veterans appear to have received doses that would exceed the naturally occurring difference in radiation resulting from living in Denver compared with that from living in an area in the United States with a more typical level of back- ground radiation. Medical exposure to ionizing radiation is very common in the United States. Typical effective doses (NCRP, 1987) from a chest X ray are approximately 0.06 mSv (0.006 rem) but other procedures such as an upper gastrointestinal examination (2.45 mSv; 0.245 rem), barium enema (4.05 mSv; 0.405 rem), or computed tomography (CT) scan (1.1 mSv; 0.11 rem) result in significantly higher doses. Medical radiation procedures avoid unnecessary exposure to the gonads, which keeps doses of genetic importance below the doses given above. The National Council on Radiation Protection and Measurements (NCRP) esti- mates that the annual genetically significant dose (GSD) from medical exposures received by the general population is in the range of 0.2-0.3 mSv (0.02-0.03 rem) (NCRP, 1987~. Thus, the majority of Atomic Veterans would have re- ceived exposures to some tissues very similar to those that occur as a result of standard medical examinations, and in the absence of detailed information on diagnostic irradiation this, too, poses a possible source of error in the estimation of their possible doses.

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26 AD VERSE REPRODUCTIVE OUTCOMES POTENTIALLY SENSITIVE SUBGROUPS The committee has reviewed the scientific literature for evidence of sub- groups of the population potentially sensitive to ionizing radiation. Two groups of individuals are known to have genetic or chromosomal defects and have in- creased sensitivities to various types of ionizing radiation. The most notable are individuals with ataxia-telangiectasia (AT), a rare inherited disorder (2 or 3 per 100,000 live births) in which children have a staggering gait (ataxia), bloodshot eyes (conjunctival telangiectasia), chromosomal breakage on culture of their fibroblasts, and a high risk of lymphoma. When the lymphoma is treated with conventional doses of X rays, a severe, often lethal acute radiation reaction oc- curs. The abnormality in patients with AT is a result of cell killing because of their inability to repair DNA damaged by ionizing radiation. An extensive search has been made of other diseases with a defect in DNA repair capacity that might influence radiosensitivity. In five rare single-gene disorders, some im- pairment of survival of fibroblasts was found in culture after gamma irradiation, but not to the same degree as that found in AT homozygotes. The AT heterozy- gotes have normal test results (Paterson et al., 19841.