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1 Background Information and Scientific Principles
Pages 9-64

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From page 9...
... 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.
From page 10...
... X rays are effectively produced by the rapid deceleration of charged particles (usually electrons) by a material of high atomic number.
From page 11...
... 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.
From page 12...
... 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.
From page 13...
... 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.
From page 14...
... 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)
From page 15...
... 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 37°C Benzotaipyrene 4,5-oxide Aflatoxin 1-Nitropyrene Methylnitrosourea ssB dsB Total LMDSb Dpcc ssB dsB T<>T 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.
From page 16...
... 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 total dose because of the increased average energy of the charged particles resulting from the interaction.
From page 17...
... 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)
From page 18...
... c Department of Energy facilities, smelters, transportation, etc SOURCE: National Council on Radiation Protection and Measurements (NCRP87b)
From page 19...
... / / _ 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)
From page 20...
... In the case of sparsely ionizing radiations, such as x rays and gamma rays, about two-thirds of the biological effects are produced by this indirect action, and this component of the radiation damage is amenable to modification by a variety of physical and chemical factors. As the quality of the radiation changes from low to high LET, the balance shifts from the indirect action to the direct action.
From page 21...
... Thus, the interpretation of the linear-quadratic formulation is that the characteristic shape of the dose-response curve reflects a predominance of single-track events, which are proportional to the dose at low doses and low dose rates, and of two-track events which are proportional to the square of the dose and result in the upward bending of the cancer induction curve at high doses received at high dose rates. This biophysical model has been challenged in recent years, largely on the basis of data with soft x rays, which are highly effective biologically even though the length of the secondary tracks they produce is too short to enable a single track to break two independent chromosomes (Them.
From page 22...
... is assumed to reflect a linear quadratic relationship between the incidence and the dose, the contribution of the quadratic dose term can be expected to be reduced at low doses and low dose rates. According to this interpretation, fitting linear and
From page 23...
... This compares with the estimate of 2.25 made by the BEIR III Committee, based on essentially the same data set but with the obsolete T65D dose estimates (see Annex 4B)
From page 24...
... In the 1963 "Report of the RBE Committee to the International Commission on Radiological Protection and the International Commission on Radiological Units and Measurements" (ICRP63) , the comparison of low-LET or standard radiation was designated as x rays, gamma rays, electrons, or positrons of any specific ionization; and an RBE of uniter was assigned to any radiation with an average LET in water of 3.5 keV/pm or less.
From page 25...
... In dealing with the limited data on RBE then available, particularly on the more relevant endpoints of mutagenesis and carcinogenesis, it was assumed that the dose-response curve for high-LET radiation generally tended to be linear, at least at low doses. For the low-LET standard radiation, discussion oriented largely around the linear quadratic dose-response curve, with an initial linear component dominating at low doses and dose rates.
From page 26...
... x rays are twice as effective as Cobalt60 gamma rays for low doses on the order of 1 red, at least for some endpoints such as oncogenic transformation and chromosome aberrations (Bo83, Un76, Scoff. Microdosimetric measurements lead to similar conclusions (Elms.
From page 27...
... . Vanation of RBE with LET For charged particles of defined LET in the track segment mode, RBE has been determined as a function of LET, by using monolayers of mammalian cells and scoring cell lethality, mutation, and oncogenic transformation as biological endpoints.
From page 28...
... In a few important instances, including neoplastic transformation in vitro, carcinogenesis in experimental animals, and mutagenesis, dose protraction by use of a low dose rate or by fractionation actually enhances the biological effectiveness of a given dose (Figures 1-4, 1-5~. The overall conclusion is that the RBE of high-LET radiations compared with that of low-LET radiations may be larger for a low dose rate than for a single acute exposure at a high dose rate.
From page 29...
... For lower doses and dose rates and with mutation, neoplastic transformation, or carcinogenesis in viva as an endpoint, a wide range of RBEm values has been reported. Values have ranged from less than 10 to greater than 100.
From page 30...
... In general, the biological effects of x rays or gamma rays decrease with fractionation or reduction in the dose rate, whereas with neutrons the effectiveness per red remains the same or even increases as the dose rate is reduced or the time over which the dose is delivered is protracted. For this reason, the RBE is usually quite different for a protracted exposure from that for a single acute exposure.
From page 31...
... The limiting value of the RBE also varies by a factor of about 2, depending on whether x rays or gamma rays are used as the low-LET radiation (Bomb. This is consistent with the difference in microdosimetric spectra that are characteristic of 250-keV x rays, as compared with those which are characteristic of high-energy gamma-rays (E172~.
From page 32...
... 32 EFFECTS OF EXPOSURE TO LOW LE^LS OF IONIZING MOTION pairs of DNA bases (3 x 109 per haploid set of chromosomes) and each chromosome includes a single supercoiled molecule of DNA associated with chromosomal proteins.
From page 33...
... At low doses, neutrons are much more biologically effective; i.e., the RBE of neutrons relative to that of x rays is significantly greater than unity. The frequency of two-break aberrations in human lymphocytes irradiated in culture approximates 0.1 aberration per cell per Sv in the low-to-intermediate dose range (L181~.
From page 34...
... 4 5 FIGURE 1-6 Frequengy of dicentr~c chromosome aberrations in human lymphocytes irradiated in vitro in relation to dose, dose rate, and quality of radiation (Ll81~. Although chromosome aberrations can be induced by relatively low doses of radiation, only a small percentage of them Is attributable to natural background radiation.
From page 35...
... BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES 35 conditions, such as folate deficiency (Hemp. In addition, there are three recessively inherited conditions in which chromosomal breakage and rearrangement occur, namely, ataxia telangiectasia (AT)
From page 36...
... 36 EFFECTS OF EXPOSURE TO LOW LE~LS OF IONIZING MOTION DNA Abnormalities Abnormalities in chromosome number are not necessarily associated with structural changes in DNA, but chromosomal breaks and aberrations involve such changes, as do the many mutations that are not visible microscopically. The mechanisms by which mutations are caused have of course, been of considerable interest.
From page 37...
... The dose-response curves for single-strand and double-strand breaks may both be linear with x rays, apparently because the former are caused by single ionizations and the latter are caused by the dense tails of ionization tracks. Most chain breaks are repaired following modification of the break termini, filling the defect with polymerase activity and ligation.
From page 38...
... Thus, the radiation is delivered to various organs gradually, at changing dose rates, over what may be an extended range of ages. An internally deposited radionuclide also frequently produces nonuniform irradiation to the organs and tissues in which or near which it is incorporated, depending on its radioactive emissions and metabolic characteristics.
From page 39...
... BACKGROUND INFORMATION AND SCIENTIFIC PRINCIPLES External Irradiation Exposure and Dose Occur at Same Time Dose - Relatively Uniform Majority of Data on Exposed People LL LL oh o c, lo: cr LL oh o cat Radionuclides .
From page 40...
... and the National Council on Radiation Protection and Measurements (NCRP85~. The methodology and values given by ICRP were assembled for radiological protection planning purposes.
From page 41...
... Other factors that need to be considered when determining the dose received by critical cells include an identification of the target cells of concern and how the patterns of cellular irradiation are influenced by nonuniform radionuclide deposition or clearance, age, and health status (Sm84, Fight. Radionuclide Response-Modify~ng Factors There are only a few groups of human subjects with radionuclide burdens of sufficient magnitude to produce long-term biological effects.
From page 42...
... USE OF ANIMAL STUDIES Observations on the biological effects of ionizing radiation began to be made soon after the discovery of x rays in 1895. Already in 1896, there were reports of dermatitis and alopecia in those experimenting with x-ray generators (Fume.
From page 43...
... prediction of the effects of low or varying dose rates and of various patterns of fractionation of exposure to low-LET radiations, high-LET radiations, or both; 3. clarification of the mechanisms of radiogenic damage including mutagenesis, carcinogenesis, and developmental effects; this is crucial to the development of appropriate interpretations and mathematical models of radiation effects in humans; and 4.
From page 44...
... Interspecies extrapolation of experience with dosemutation effects can therefore be done with somewhat greater confidence than can comparable extrapolations of effects on multistage prolonged processes such as carcinogenesis and lifeshortening. There are extensive experimental data concerning radiation effects on embryogenesis with specific reference to the development of gross abnormalities of the central nervous system and disruption of neuroblast proliferation, migration, differentiation, and establishment of neural pathways.
From page 45...
... Misclassification of exposure is likely to be a major potential source of error in making risk estimates. Nondifferential misclassification with respect to exposure level leads to an underestimation of risk and tends to reduce any upward curvature in the dose-response relationship.
From page 46...
... The rationale for this approach is that only these studies provide sufficiently precise estimates of risk at any dose. Risk estimates for low doses and protracted exposure could therefore be in error because of (1)
From page 47...
... Thus, suppose the relative risk in the high-dose population was 11 with 95% confidence intervals of 5.5 and 22 and the relative risk in the low-dose population was 1.1 with confidence intervals of 0.55 and 2.2. The point estimates on the relative risk coefficient from the two studies would be identical at 10/Gy, but the confidence intervals on the high-dose estimate are 4.5 and 21 and on the low dose estimate are-4.5 and 12.0.
From page 48...
... Epidemiologists are more likely to report and journal editors are more likely to accept positive findings than null findings. Thus, information in the literature on populations exposed to low doses of radiation may be slanted in favor of those studies that show higher risks than the conventional estimates, since those that show estimates consistent with the
From page 49...
... For example, the BEIR III report estimated that a single exposure to 0.1 Gy (10 reds) of low-LET radiation might cause, at most, about 6,000 excess cases of cancer (other than leukemia and bone cancer)
From page 50...
... Epidemiologists generally agree that excess risks of less than 50% are difficult to interpret causally (Bract. In practice, therefore, it is necessary to obtain risk estimates by extrapolation from smaller and less homogeneous groups who have been exposed to larger doses by using statistical dose-response models.
From page 51...
... Thus, while they are useful for describing patterns and testing associations in which there is relatively little prior knowledge or biological theory, more reliable predictions can be made by using models that exploit such prior knowledge. The Committee has chosen, instead, to base its reanalyses of original epidemiologic data and risk assessments on the radiobiological principles and theories of the carcinogenesis process that are described elsewhere in this report.
From page 52...
... Numerous mathematical theories of carcinogenesis have been devised to predict the dependence of incidence rates on exposure, age, and other time-related factors, but so far none has won universal acceptance and there have been few attempts to fit these models to epidemiologic data. Although the committee felt that stronger inferences about lifetime risk might be possible by exploiting these biomathematical models, it was unable to arrive at a consensus as to the particular models to use.
From page 53...
... and much of the radioepidemiologic literature has relied on two simple models for projecting risks of these cancers: absolute risk and relative risk models. Letting )
From page 54...
... 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.
From page 55...
... 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 assessments 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.
From page 56...
... 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 increment of exposure contributed independently to the cancer rates.
From page 57...
... 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.
From page 58...
... 1972. The Microdosimet~y of 250 kVp and 65 kVp X Rays, 60Co Gamma Rays, and llitium Beta Particles.
From page 59...
... 1980. Thyroid hormone modulation of x ray induced in vitro neoplastic transformation.
From page 60...
... 1984. F~ssion-spectrum neutrons at a low dose rate enhance neoplastic transformation in the linear, low dose region (0-10 coy)
From page 61...
... NCRP84 National Council for Radiation Protection and Measurements (NCRP)
From page 62...
... 91. Bethesda, Md.: National Council on Radiation Protection and Measurements.
From page 63...
... 1984. Lung modelling for inhalation of radioactive materials, Proceedings of a meeting jointly organized tar the Commission of the European Communities and the National Radiological Protection Board, Oxford, March 26-28, 1984.
From page 64...
... Pp. 32-52 in Life-Span Radiation Effects Studies in Experimental Animals: What Can They Tell Us?


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