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1 Background Information and Scientific Principles PHYSICS AND DOSIMETRY OF IONIZING RADIATION All living matter is composed of atoms joined into molecules by elec- tron bonds. Ionizing radiation is energetic enough to displace atomic electrons and thus break the bonds that hold a molecule together. As described below, this produces a number of chemical changes that, in the case of living cells, can lead to cell death or other harmful effects. Ion- izing radiations fall into two broad groups: 1) particulate radiations, such as high energy electrons, neutrons, and protons which ionize matter by direct atomic collisions, and 2) electromagnetic radiations or photons such as x rays and gamma rays which ionize matter by other types of atomic interactions, as described below. Absorption and Scattering of Photons Photons ionize atoms through three important energy transfer proc- esses: the photoelectric process, Compton scattering, and pair production. For photons with low energies (<0.05 megaelectron volt iMeVi) the pho- toelectric process dominates in tissue. The photoelectric process occurs when an incoming photon interacts with a tightly bound electron from one of the inner shells of the atom, and causes the electron to be ejected with sufficient energy to escape the atom. Characteristic x rays and Auger electrons follow from this process, but the biological effects are due mainly to excitations and ionizations in molecules of tissue caused by the ejected electron. The probability of the photoelectric process occurring is strongly 9

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10 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING EDITION dependent on the average atomic number of the tissue with an equally strong inverse dependence on the photon energy. At higher photon energies (0.1-10 MeV), Compton scattering is the most probable process that takes place in irradiated tissue. It occurs when the photon energy greatly exceeds the electron binding energy, so that an orbital electron appears to the photon as a free electron. The photon scatters off the electron, giving up part of its energy to the electron, which proceeds to ionize and excite tissue molecules. The scattered photon with reduced energy continues to interact with other electrons and repeats the above process many times until the photon either escapes the absorbing material or its energy is sufficiently degraded for the photoelectric process to occur. Within the energy range of 0.1-10 MeV, the Compton process has a modest dependence on energy and is almost independent of atomic number. Above a threshold energy of 1.02 MeV, the pair-production process is possible. Here a photon converts its energy in the presence of an atomic nucleus to a positron-electron pair, which, in turn, proceeds to interact with tissue atoms and molecules, leading to eventual biological effects. When the positron slows down it is almost always annihilated with an electron, producing two 0.511 MeV photons. The probability of pair-production in tissue increases slowly with photon energy but does not outweigh that of the Compton process until the photon energy reaches 20 MeV The process depends upon the average atomic number of the tissue. Photon Spectral Distr~bui'ons As seen from the description presented above, the absorption and scattering of photons depend critically on photon energy. The initial photon energy depends on the source of the radiation. Gamma rays resulting from radioactive decay consist of monoenergetic photons with energies that do not exceed several MeV in energy. Because of scattering and absorption within the radioactive source itself and in the encapsulating material, the photons that are emitted do have a spectrum of energies but it is fairly narrow. Relatively broad energy distributions are the rule for x-ray photons produced from electrical devices. X rays are effectively produced by the rapid deceleration of charged particles (usually electrons) by a material of high atomic number. This results in a continuous distribution of energies with a maximum at an energy about one third that of the most energetic electron. As photons interact with matter, their spectral distribution is further altered in a complex manner as the photons transfer energy to the absorbing medium by the processes described above.

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BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES Electron Spectral Distributions and LET 11 When monoenergetic photons interact with a tissue medium, the elec- trons that are set in motion, particularly from the Compton process, pro- ceed to interact with the atoms and molecules of the medium, losing energr through collisions and excitations, and are scattered in the process. The result is a complex shower of electrons, the energy distribution of which is continuously degraded as the electrons give up their energy to the medium at a rate defined by the electron stopping power of the medium. As the electron proceeds through tissue, it creates a track of excited and ionized molecules that, for energetic electrons, are relatively far apart. For exam- ple, the dimension of this spacing is such that there is a finite probability that the energetic electron can pass through a DNA molecule, with about 3 rim separating the two strands, without releasing any of its energy and therefore without causing damage. The spatial energy distribution, stated in terms of the amount of energy deposited per unit length of particle track, is defined as the linear energy transfer (LET) of the radiation. X rays and gamma rays set in motion electrons with a relatively low spatial rate of energy loss and thus are considered low LET radiations. The photon and electron energy degradation processes described above result in a broad distribution of LET values occurring in irradiated tissue. A typical value of LET for the electrons set in motion by cobalt-60 gamma rays (average energy 1.25 MeV) would be about 0.25 keV/pm. This can be contrasted with a densely ionizing 2 MeV alpha particle which produces about 1000 times more ionization per unit distance, 250 keV/pm. Such particles are characterized as high LET radiation. Knowledge of LET is important when considering the relative biological effectiveness (RBE) of a given radiation; LET is commonly used as a measure of radiation quality, as discussed below. Microdosimetry Various limitations in the concept of LET and absorbed dose in sub- cellular tissue volumes led to the introduction of microdosimetry. Mi- crodosimetry takes account of the fact that energy deposition by ionizing radiations is a stochastic (random) process. Identical particles of the same energy interacting in a small volume of material deposit differing amounts of energy due to chance alone. The specific energy, z, is defined as the ratio c/m where ~ is the energy imparted by a single ionizing particle in a volume element of mass m. The mean value of z for a large number of particles is equal to the absorbed dose. The microdosimetric analogue to LET is the quantity lineal energy, defined as c/d, where d is the mean chord length in the volume occupied by mass m. Distributions of absorbed dose in terms of lineal energy can be measured by proportional counters

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12 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION filled with tissue-equivalent gas at pressure levels appropriate for simulating spheres of tissue with diameters on the order of 1 ~m. The principles of microdosimetry are extensively discussed in the BEIR IV report (NRC88) and ICRU report 36 (ICRU83~. Energy wander Kerma and Absorbed Dose The transfer of energy from photons to tissue takes place in two stages: (1) the interaction of the photon with an atom, causing an electron to be set In motion, and then (2) the subsequent absorption by the medium of kinetic energy from the high energy electron through excitation and ionization. The first stage can be identified with the quantity called henna, K, which stands for kinetic energy released in the material. IT = dE~r/dm, where dE~r is the kinetic energy transferred from pho- tons to electrons in a volume element of mass dm. lithe second stage, energy absorption, is more important for under- standing radiobiological effects. The absorbed dose, the energy absorbed per unit mass, differs from kerma in that the dose may be smaller due to lack of charged particle equilibrium, bremsstrahlung escaping from the medium, etc. Another difference is that the kerma refers to energy trans- fer at a point, whereas the energy is absorbed over a distance equal to the electron range. Of the two quantities, absorbed dose is the easier one to approach experimentally and can be determined by a number of well-defined techniques, including gas ionization methods, calorimetry, and thermoluminescent techniques. On the other hand, kerma is often more easily calculated. Radiation Chemical EHects Following Energy Absorption After the electron produced by a photon interaction passes through tissue, exciting and ionizing atoms and molecules, a number of important chemical events that precede the biological effects take place. Most of the energy absorption takes place in water, since cells are made up of more then 70% water. When an ionizing particle passes through a water molecule, it may ionize it to yield an ionized water molecule, H2O+, and an electron by the reaction: H O radiation H O+ + The electron can be trapped, polarizing water molecules to produce the so-called hydrated electron, eaq. On the other hand, the ionized water molecule, H2O+, reacts at the first collision with another water molecule to produce an hydroxyl radical, OH' according to the reaction:

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BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES H2O+ + H2O ) OH' + H3O+ . 13 The free radical OH' has an unpaired electron and is therefore highly reactive as it seeks to pair its electron to reach stability. At the high initial concentrations, certain back reactions occur producing hydrogen molecules, hydrogen peroxide and water. The initial species produced in water radiolysis can then be written as: H2O , eat, H', H2O2, H2. Instead of being ionized, the water molecule may simply be excited according to the reaction: H `' radiation H O* where H2O* is the excited molecule. But H2O* soon breaks up into the H' radical and the OH' radical according to: H2O* ~ H' + OH' . As a result of the above processes, three important reactive species are produced: the aqueous electron, OH', and H', with initial relative yields of about 45%, 45%, and 10%, respectively. These reactive species attack molecules in the cell leading to the production of biological damage. The OH' radical is believed to be the most effective of the three species in causing damage. Because it is an oxidizing agent, it can abstract a hydrogen atom from the deoxyribose moiety of DNA, for example, yielding a highly reactive site on DNA in the form of a DNA radical. Since this process arises from the irradiation of a water molecule rather than the DNA itself, the process is known as the indirect effect. Electrons set in motion by photons can, of course, directly excite or ionize cell macromolecules by direct interaction with the critical molecule. This is called the direct elect. Both mechanisms can produce cellular damage. There is strong evidence that the DNA is the most critical site for lethal damage, but other sites such as the nuclear membrane or the DNA-membrane complex may also be important. Ward (Wa88) has derived an approximation of the damage yields expected in various moieties of DNA within an irradiated cell, in which consideration is given to the direct deposition of energy in DNA and other molecules. Able 1-1 shows the amount of energy deposited per Gray in each moiety of DNA within a cell that is assumed to contain 6 pg of DNA.

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14 EFFECTS OF EXPOSURE TO LOW LEVELS OF IONIZING RADIATION TABLE 1-1 Amount of Energy Deposited in DNA per Cell per Gray Mass per Cell eV Number of Constituent (pa) Deposited 60-eV Events Deoxyribose 2.3 14,000 235 Bases 2.4 14,700 245 Phosphate 1.2 7,300 120 Bound water 3.1 19,000 315 Inner hydration 4.2 25,000 415 SOURCE: J. F. Ward, C. L. Limoli, P. Calabro-Jones, and J. W. Evans (Wages. Calculated from this is the number of events since 60 eV is the average amount of energy deposited per event. The yields of DNA damage necessary to kill 63% of mammalian cells (63% of cells killed means that, on average, each cell has sustained one lethal event) can be assessed for various lethal agents (Wa88), as shown in Table 1-2. The high efficiency with which ionizing radiation (and bleomycin) kill cells is not simply due to individual OH radical-induced lesions, as witnessed by the large-scale production of single-strand breaks with hydrogen peroxide. Ward et al. (WA87) suggest that the efficiency of cell killing by ionizing radiation at relatively low levels of DNA damage is due to the production of damage in more than one moiety in a localized region, i.e., lesions resulting from multiply damaged sites in a single location or locally multiply damaged sites (LMDS). Recent studies (Wi85, Gr85, Ei81), as analyzed by Ward (Wage), sup- port the importance of indirect effects of ionizing radiation in producing damage to intracellular DNA. This is of particular significance in view of the suggestion that most intracellular DNA damage is caused by direct ionization and that radicals produced in water cannot access the macro- molecule. It appears from the above analysis (Wa88) that the volume of water in the DNA-histone complex (nucleosome) is at least equal to the DNA volume and that radiation-produced OH radicals in the water volume have ready access to the DNA molecule. Some of the current assessments of DNA damage caused by ionizing radiation in mammalian cells (Wa~) are as follows: (1) direct and indirect effects are both important; (2) the quantity of damage produced by ionizing radiation is orders of magnitude lower than for most other agents for equal cell-killing efficiency; (3) individual damage moieties are not biologically significant since they can be repaired readily by using the undamaged DNA strand as a template; (4) LMDS are more likely the lethal lesion in cellular

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BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES TABLE 1-2 Yields of DNA Damage Necessary to Kill 63% of the Cells Exposed 15 Agent Number of Lesions DNA Lesion per Cell per D37a 1,000 40 440 150 150 30 400,000 100 Ionizing radiation Bleomycin A2 UV light Hydrogen peroxide go 37C Benzotaipyrene 4,5-oxide Aflatoxin 1-Nitropyrene Methylnitrosourea ssB dsB Total LMDSb Dpcc ssB dsB TT dimer ssB ssB ? Adduct 100,000 Adduct 10,000 Adduct 400,000 7-Methylguanine 800,0004 O6-Methylguanine 130,0004 3-Methyladenine 30,0004 2-(N-Acetoxy-N-acetyl~amino-fluorene Adduct 700,000 Other similar aromatic amides produce about the same number of adducts per lethal event aD37 = dose of agent required to reduce survival of cells to 37% of the number exposed. b Calculated, LMDS = locally multiply damaged sites. c DPC = DNA-protein cross-links. D37 calculated from individual exposures; no survival curves available. SOURCE: J. F. Ward, C. L. Limoli, P. Calabro-Jones, and J. W. Evans (Wa884. <2,600,000 DNA; these result from a high local energy deposition in the DNA (in such a volume, multiple radicals cause multiple lesions locally); (5) the individual lesions making up an LMDS can be widely separated on the opposite strands of the DNA; if they are separated too much, they could be repaired as individual lesions. Physics and Dosimetry of High-LET Radiation (Neutrons) Interactions of Neutrons with Tissue Elements When neutrons impinge on a tissue medium, they will either penetrate it without interacting with its constituent atoms or they will interact with its atoms in one or more of the following ways: (1) elastically, (2) inelasti- cally, (3) nonelastically, (4) by capture reactions, or (5) through spallation processes.

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16 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING EDITION Elastic scattering is the most important interaction in tissue irradiated with neutrons at energies below 20 MeV. This would include the energy range for fission neutrons (~10 MeV), neutrons produced with 16 MeV deuterons bombarding a beryllium target (<20 MeV), and neutrons pro- duced with 150 keV deuterons on tritium (<20 MeV). The neutron, an uncharged particle, interacts primarily by collisions with nuclei in the ab- sorbing medium. If the total kinetic energy of the neutron and the nucleus remains unchanged by the collision, the collision is termed elastic. During an elastic collision, the maximum energy is transferred from the neutron to the nucleus if the two masses are equal. In soft tissue, the most important neutron interaction is with hydrogen. There are three reasons for this: (1) Nearly two-thirds of the nuclei in tissue are protons, (2) the energy transfer with protons is maximal (about one-half), and (3) the interaction probability (cross-section) for hydrogen is larger than that for any other element. The result is that about 90% of the energy absorbed in tissue from neutrons with energy of less than 20 MeV comes from protons that are recoiling from elastic collisions. The remaining energy is absorbed by other recoiling tissue nuclei in the following decreasing order of importance: oxygen, carbon, and nitrogen. Inelastic scattering refers to reactions in which the neutron interacts with the nucleus but is promptly reemitted with reduced energy and usually with a changed direction. The scattering nucleus, which is left in an excited state, then emits a nuclear deexcitation gamma ray. For neutrons with kinetic energies of greater than 10 MeV, inelastic scattering contributes to energy loss in tissue; about 30% of the energy deposited in tissue by 14-MeV neutrons, for example, comes from inelastic interactions. The important inelastic interactions of neutrons in soft tissue are not with hydrogen but with carbon, nitrogen, and oxygen. Nonelastic scattering defines reactions in which the neutron-nucleus interaction results in the emission of particles other than a single neutron such as alpha particles and protons [e.g., i60(n,c~3C, i4N(n,p)~4C]. The cross-sections for nonelastic scattering in tissue become significant at en- ergies greater than S MeV and increase as the neutron energy approaches 15 MeV. These reactions are usually accompanied by deexcitation gamma rays, but their importance is due to the high LET of the charged particles emitted, especially alpha particles. At neutron energies greater than 20 MeV, even though nonelastic cross-sections do not increase appreciably, nonelastic processes become increasingly important contributors to the to- tal dose because of the increased average energy of the charged particles resulting from the interaction. The capture of low-energy neutrons in the thermal and near-thermal regions provides a significant contribution to tissue dose. The reactions of importance are i4N(n,p)~4C and ~H(n,~y)2H. The former reaction produces

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BACKGROUND INFORMATION AD SCIENTIFIC PRINCIPLES 17 locally absorbed energy of 0.62 MeV from the proton and the recoil nucleus. The latter reaction yields a 2.2-MeV gamma ray that, in general, deposits energy at a distance from the capture site and that has a reasonable probability of escaping altogether from a mass as large as a rodent. For thermal neutrons the i4N(n,p)~4C reaction is the major contributor of absorbed energy in tissue samples with a dimension of less than 1 cm because of the short range (<10 ~m) of the 0.58-MeV proton. However, for larger masses of tissue (e.g., the human body), the 2.2-MeV gamma rays from the ~H(n,:~2H reaction are a significant dose contributor. In the spallation process the neutron-nucleus interaction results in the fragmentation of the nucleus with the emission of several particles and nuclear fragments. The latter are heavily ionizing, so the local energy deposition can be high. Several neutrons and deexcitation gamma rays also can be emitted, yielding energy carriers that escape local energy deposition. The spallation process does not become significant until neutron energies are much greater than 20 MeV In summary, elastic and nonelastic scattering and the capture process are by far the most important reactions in tissue for neutrons in the fission energy range. Inelastic and nonelastic scattering begin at about 2.5 and 5 MeV, respectively, and become important at an energy of about 10 MeV As the neutron energy goes higher, nonelastic scattering and spallation reactions increase in importance, and elastic scattering becomes of less importance for energies greater than 20 MeV. POPULATION EXPOSURE TO IONIZING RADIATION IN THE UNITED STATES A new assessment of the average exposure of the U.S. population to ionizing radiation has recently been made by the National Council on Radiation Protection and Measurements (NCRP87b). Six main radiation sources were considered: natural radiation and radiation from the following five man-made sources: occupational activities (radiation workers), nuclear fuel production (power), consumer products, miscellaneous environmental sources, and medical uses. For each source category, the collective effective dose equivalent was obtained from the product of the average per capita effective dose equiv- alent received from that source and the estimated number of people so exposed. The average effective dose equivalent for a member of the U.S. population was then calculated by dividing the collective effective dose equivalent value by the number of the U.S. population (230 million in 1980~. As discussed below, the dose equivalent is defined as the product of the absorbed dose, D, and the quality factor Q. which accounts for

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18 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING ORATION TABLE 1-3 Average Annual Effective Dose Equivalent of Ionizing Radiations to a Member of the U.S. Population Dose Equivalenta Effective Dose Equivalent Source mSvmrem mSv % Natural Radonb 242,400 2.0 55 Cosmic 0.2727 0.27 8.0 Terrestrial 0.2828 0.28 8.0 Internal 0.3939 0.39 11 Total natural 3.0 82 Artificial Medical x-ray diagnosis 0.3939 0.39 11 Nuclear medicine 0.1414 0.14 4.0 Consumer products 0.1010 0.10 3.0 Other Occupational 0.0090.9 <0.01 <0.3 Nuclear fuel cycle <0.01<1.0 <0.01 <0.03 Fallout <0.01<1.0 <0.01 <0.03 MiscellaneousC <0.01< 1.0 <0.01 <0.03 Total artificial 0.63 18 Total natural and artificial 3.6 100 aTo soft tissues. b Dose equivalent to bronchi from radon daughter products. The assumed weighting factor for the effective dose equivalent relative to whole-body exposure is 0.08. c Department of Energy facilities, smelters, transportation, etc SOURCE: National Council on Radiation Protection and Measurements (NCRP87b). differences in the relative biological eRectiveness of different types of ra- diation. The effective dose equivalent relates the dose-equivalent to risk. For the case of partial body irradiation, the effective dose equivalent is the risk-weighted sum of the dose equivalents to the individually irradiated tissues. As seen in Bible 1-3 and Figure 1-1, three of the six radiation sources, namely radiation from occupational activities, nuclear power production (the fuel cycle), and miscellaneous environmental sources (including nuclear weapons testing fallout), contribute negligibly to the average effective dose equivalent, i.e., less than 0.01 millisievert (mSv)/year (1 mrem/year). A total average annual effective dose equivalent of 3.6 mSv (360 mrem)/year to members of the U.S. population is contributed by the other three sources: naturally occurring radiation, medical uses of radiation, and radiation from consumer products. By far the largest contribution (82%) is made by natural sources, two-thirds of which is caused by radon and its

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BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES TERRESTRIAL 8% INTERNAL 1 1% (Inside Human Body) Stocks COSMIC 8% (Outer Space)/ / _ a\ if\ - _ - RADON 55% \ \ \ ~ \ Strays 1 1% NUCLEAR MEDIC CONSUMER PRODUCTS 3% OTHER c 1% Occupational Fallout Nuclear Fuel Cycle Miscellaneous FIGURE 1-1 Sources of radiation exposure to the U.S. population (NCRP87b). 19 4% 0.3% <0.3% 0.1% 0.1% decay products. Approximately equal contributions to the other one-third come from cosmic radiation, terrestrial radiation, and internally deposited radionuclides. The importance of environmental radon as the largest source of human exposure has only recently been recognized. The remaining 18% of the average annual effective dose equivalent consists of radiation from medical procedures (x-ray diagnosis, 11% and nuclear medicine, 4%) and from consumer products (3%~. The contribution by medical procedures is smaller than previously estimated. For consumer products, the chief contributor is, again, radon in domestic water supplies, although building materials, mining, and agricultural products as well as coal burning also contribute. Smokers are additionally exposed to the natural radionuclide polonium-210 in tobacco, resulting in the irradiation of a small region of the bronchial epithelium to a relatively high dose (up to 0.2 Sv per year) that may cause an increased risk of lung cancer (NCRP84~. Uncertainties exist in the data shown in Table 1-3. Uncertainties for exposures from some consumer products are greater than those for exposures from cosmic and terrestrial radiation sources. The estimates for the most important exposure, that of lung tissue to radon and its decay products, have many associated uncertainties. Current knowledge

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54 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION to be too sparse to merit further modeling by incorporating age. Good human data on the Interaction between radiation and other exposures do not appear to exist. The present Committee has therefore decided not to pursue analysis of interaction effects further at this time. Approaches to Model Fitting The approach that is taken to fitting risk models to epidemiologic data depends on the form in which the data are available. Some of the more complex models require access to the raw data on individual subjects and their entire history of exposures. However, most models can be fitted with very little loss of information by placing the subjects into subgroups with similar values of the relevant characteristics, particularly dose and age at exposure, and then tabulating their person-years at risk and the numbers of cases of each type of cancer as a function of age and time since exposure. The study data can then be summarized by two arrays, one of person-years, Yield, for dose group i, age at exposure group j, attained age group k, and time since exposure interval 1, and one of numbers of cancers, Nijk~m, in each subgroup ijkl from each type of cancer m. Admittedly, the numbers of cases in most of the cells will be small, but this does not pose a problem for the method of analysis to be used. Next, one assumes that the numbers of cases in each cell follows a Poisson distribution, with the expected value given by the product of the rate predicted by the model and the person-years for that cell. The data can then be fitted by the technique of maximum likelihood. The likelihood is the probability of the observed data given a particular choice of model parameters, which, in this circumstance, is obtained from the product of the Poisson probabilities for each cell of the cross-tabulation. A Newton-Raphson search is used to find the parameter values which maximize this likelihood. Confidence limits and significance tests can be derived from large sample theory (Comb. The committee used a computer program known as AMFIT for fitting a general class of regression models for the Poisson data. Further details of the fitting program can be found in Annex 4C to Chapter 4. In any model fitting analysis, it is important to know how well the model describes the data. There are several aspects to this question. First, one would like an overall assessment of whether the model fits; such an assessment is known as a goodness-of-fit test. A poor fit might be an indication either that the chosen model is incorrect or that there is some problem with the data; a good fit does not prove that the model is correct- it simply means that there is insufficient evidence that the model is wrong. Next, assuming that the model fits, one would like to know the range of parameter values that is also consistent with the data; this range is known as a confidence interval and is important in evaluating the uncertainty in

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BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES 55 the fitted model. Next, one would like to be assured that the model is not unduly influenced by a few observations at the expense of the bunk of the data or by the inclusion of variables that are too highly correlated to be separated. Techniques to identify these types of problems are known as diagnostics and were used by the Committee throughout these analyses, as discussed in Annex 4F. Special Problems Pooling Data From Multiple Studies For many cancer sites, information was available from more than one epidemiologic study, raising the issue of how these data should be combined for risk assessment purposes. Because the studies generally differed in the nature of the exposures, the populations, and numerous methodological details, it was considered inappropriate to simply combine all of the raw data into a single data set. Instead, each of the studies for which original data were available to the committee were analyzed separately to obtain an estimate of the relevant parameters and their uncertainties. Formal tests of homogeneity were carried out to assess whether any differences in results could reasonably be ascribed to chance. If the results appeared to be consistent, an overall estimate could be obtained by a matrix weighted average and an estimate of the uncertainty of the pooled estimate could easily be derived. On the other hand, if the results appeared to be discrepant, the committee had to make a subjective judgment as to the quality and relevance of each of the studies. Use of Animal Data The committee felt strongly that its risk assess- ments should be based on human data to the extent that they were available and that animal data should be used only to address questions for which human data were unavailable or inadequate. Questions in the latter cate- gory included the RBE of neutrons and gamma rays and the effect of dose rate. Treatment of the RBE One of the problems for which the human data are inadequate is that of estimating the RBE for neutrons. The BEIR III Committee (NRC~) attempted to estimate the RBE for leukemia from the data from Japanese atomic-bomb survivors and then applied their estimate to the data on solid tumors. Aside from the inappropriateness of treating this point estimate as if it were known with certainty, the approach is no longer valid because reassessment of the atomic-bomb dosimetry has largely eliminated the differences in responses between Hiroshima and Nagasaki on which the previous estimate of the RBE was based. It therefore became necessary for the present Committee to rely on animal data for this purpose. For all analyses of the Radiation Effects Research Foundation

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56 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION (RERF) data, a value of 20 for the RBE for neutrons was assumed as a fixed constant. The justification for this choice is given in Chapter 4. Projection of Lifetime Risk Estimates Once the epidemiologic and animal data are summarized in the form of an exposure-time-response model, the final stage of risk assessment involves the calculation of lifetime risk for patterns of exposure of particular interest. This is done with standard life table (mortality table) techniques (Bugle. Consider the case of lifetime exposure at a constant annual rate. A life table analysis would proceed as follows. Starting with a hypothetical population of 1 million newborn infants, the first column in the life table gives the number of infants that are expected to survive to each age. The second column gives the cancer rate predicted by the exposure-time- response model, and the third column gives the number of cases of cancers that would result; this is given by the product of the first two columns. The fourth column gives the number of deaths from other causes, based on current mortality rates, which are not assumed to depend on radiation. The number of survivors at the beginning of the next age interval is therefore the number at the start of the interval minus the number of radiogenic and nonradiogenic deaths, and the process continues until the entire cohort is dead (although, in practice, the calculations are usually terminated at age 100~. The total number of excess cases of cancer is estimated by subtracting the number of deaths obtained from a similar life table for persons with no radiation exposure. For protracted exposures, these calculations assume that each incre- ment of exposure contributed independently to the cancer rates. Thus, the risk at age T is given by the background rate plus the sum over the entire exposure history of the excess rate attributable to each exposure increment; that is, if D(t) represents the history of radiation doses at each age t and [T~(t)] represents the postulated dependence of cancer rates on age and each increment of exposure then the risk from the the entire history of . . exposure Is given fly: rT A[T, D] = Ao(T) + J {[I, D(t)]-Ao(t)}dt (1-7) o This implies that the rate is a function of cumulative exposure (possibly weighted by a function of age at exposure or time since exposure). There is evidence, however, that the contributions of extended exposures are not simply additive: for low-LET radiation, protracted exposures appear to be less hazardous than instantaneous exposures of the same total dose, possibly because sublesions caused by the first event can be repaired before additional events occur; for high-LET radiation, the effect may simply be additive, or protracted exposures may even be more hazardous, possibly

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BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES 57 because subsequent radiation exposure can promote already initiated cells. The committee acknowledges this problem but, as explained earlier in this chapter, it does not believe that sufficient information is available to deal with this question in a definitive manner. The committee therefore chose to retain the assumption of independence for the calculations but to present the results in such a way that the reader can make adjustments for protracted exposure when warranted. Uncertainty of the Risk Estimates Unlike the BEIR III Committee (NRC80) which presented a range of lifetime risks based on relative and absolute risk models for several choices of dose-response functions, the present committee has chosen to assess the uncertainty of the projected lifetime risks by using a Monte Carlo simulation approach. The committee's preferred exposure-time-response model for a particular site of cancer or group of sites was characterized by a vector of parameter estimates and a covariance matrix which describes the uncertainty in each parameter. By repeated sampling from the set of possible parameter values, with sampling probabilities determined by their covariance matrices, 1,000 sets of possible parameters were obtained. Each combination was then applied to the life table calculation described above to obtain a set of predicted lifetime risks. The resulting distribution, presented in Chapter 4, gives a measure of the statistical uncertainty in the committee's risk estimates under the preferred model. Other sources of uncertainty, external to the preferred model and its statistical uncertainty, are discussed in Annex 4F. A number of other models fit the data nearly as well. The Monte Carlo simulation could, in principle, have been extended to include sampling over alternative models. However the committee invoked a number of non- statistical criteria, e.g., biological plausibility, to chose between alternative models, and felt that using a simple goodness-of-fit criteria as weights in the Monte Carlo simulation would not adequately reflect this process. Life table results are presented in Annex 4D for a number of alternative models. It is of interest that the range of life table risks estimated under these al- ternative models is less than the uncertainty estimated by the Monte Carlo simulation. REFERENCES Ad87 Adams, L. M., S. P. Ethier, and R. L. Ullrich. 1987. Enhanced in vitro prolifer- ation and in vivo tumorigenic potential of mammary epithelium from BALB/c mice exposed in vivo to gamma-radiation and/or 7,12-dimethylbenz~ajanthra- cene. Cancer Res. 47:4425-4431.

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