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Health Risks of Radon and Other Internally Deposited Alpha-Emitters: BEIR IV (1988)
Commission on Life Sciences (CLS)

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APPENDIX ~{ Cellular Radiobiology INTRODUCTION Cellular radiobiology is a well-developed discipline, dating to almost 90 yr ago, when it was first recognized that exposure to ionizing radiation had biological consequences. Much information has since been accumulated from studies with irradiated animals and plants and, over the last 50 yr in particular, from studies of effects at the cellular, physical, and chemical levels. Molecular and cellular radiobiology have contributed greatly both to our understanding of the physical and chemical processes involved in the induction of radiation effects and to our understanding of the responses observed in whole organisms. Mom the vast store of radiobiological in- formation, it is possible to draw a number of general principles.26 28~35~36 These principles sometune constitute our only rational basis for making human risk assessments, for example, when direct empirical observations on which to base such assessments are not available. DOS~RESPONSE CURVES Many models have been developed to describe radiabiological re- sponses, but one broad generalization is that empirical dose-response curves for cellular radiobiological effects, whether in viva or in vitro, take the general form: Y = (a + ID + ABODE) expt—ID—,B2D2), (II-1) where Y is the response observed in a population, a is the spontaneous incidence, axe and ,6~ are the coefficients for the induction of the observed 415

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416 HEALTH RISKS OF RADON AND OTHER ALPHA fITTERS effect, D is the dose, and the exponential is a term expressing the loss of observed response due to competing effects, such as cell killing, with 2 and p2 as the coefficients for cell kiBing. For doses well below that at which competing effects are important, the simpler expression, Y = a + cad + pD2, suffices. The relationship is often referred to as mixed quadratic or linear-quadratic, although the expression is simply quadratic. Such an expression adequately describes the dose-response relationship at low to moderate doses of low linear energy transfer (LET) radiation for a wide variety of cellular radiobiological endpoints, including induction of mutations and induction of the various classes of chromosomal aberrations. As described in more detail below, the quadratic expression also describes adequately the responses of such systems to high-LET radiation. Cell killing is often analyzed according to the following expression for survival: S = 1—(1—e ), (II-2) where k is the coefficient for killing, and n is an exponent often called the hit number or extrapolation number. The survival fraction can also be expressed by an c'D + pD2 model of the form: S = expt—aD—,BD2), (II-3) the same as the last term in the complete quadratic with saturation model given above in Equation II-1. Although the quadratic model can be derived entirely empirically from response data, there appears to be a rational biophysical basis. What such dose-effect curves imply is that some of the effects of radiation of any given class are induced by single ionizing events (i.e., the passage of a single photon or of a single particle), whereas others result from the interaction of two or more statistically independent ionizing events. The dose-squared term can be understood in another way: If P is the probability of hitting a target and causing a sublethal amount of damage, then the probability that target will be hit twice (or more), to give an effective hit, is (P)(P), or p2. The quadratic expression can yield curves ranging from linear (or nearly linear), in the case where l] is so small in relation to ax that the aD dominates, to essentially dose-squared, in the case where ~ is negligibly small in relation to ,0. Mutation induction in simple prokaryotic cells is an example of linear response, and the induction of two-break chromosomal aberrations of the exchange type in higher eukaryotic cells exposed to acute doses of low-LET radiation is an example of quadratic response. Many dose-response curves, however, are somewhere in between.

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CELLULAR RADIOBIOLOGY EFFECT OF DOSE RATE AND FRACTIONATION 417 The expressions presented above apply specifically to low-LET radi- ation, such as x or gamma rays, delivered at a high (acute) rate. It was noticed early, however, that when low-LET doses were protracted or appre- ciable periods passed between successive dose fractions, the effectiveness of the total dose was likely to diminish. In fact, as dose rate decreased, the radiobiological endpoints that at higher dose rates had response curves with an appreciable ,BD2 term began to lose that term. Eventually, little was left of the pD2 term, and the dose-response curve was essentially linear, represented simply by aD. With increasing interfraction time, much the same thing happened, with the ,BD2 term for the total dose decreasing until, instead of what is often called complete interaction ti.e., p(D, + D2 + D3 . . .121, one observed the sum of pD2 terms for the individual fractions (i.e., ,CD,2 + ~BD22 + ,BD32 . . A. This implied that somehow the subeffective partial lesions left at the end of the first dose fraction were becoming unavailable, or repaired, with time; thus, if enough time elapsed between fractions (a few hours), none were left from the first dose fraction to interact with those from the second. Loss of subeffective partial lesions also accounts for the sunple dose-rate effect. Lea35 understood this early and created a correction factor that he called the G factor to correct for dose-rate effects: G = 2~/T)2(T/r—1 + e-/, (II-4) where ~ Is the average time between breakage and restitution, and T is the duration of treatment. EFFECT OF LET As the LET of radiation (usually calculated as track-average LET) increases, two things happen. First, for radiobiological endpoints that have a substantial ,BD2 term with acute doses of low-LET radiation, the curves begin to straighten, losing the D2 component and tending toward linearity. Second, the effectiveness of the c'D component also increases, indicating that this is not the same phenomenon as that observed for dose rate or fractionation with low-LET radiation. In sum, the higher-LET radiation seems to be capable, if it deposits energy in a target at all, of causing fully effective events. In other words, the production of subeffective lesions becomes less and less likely, while the production of fully effective lesions becomes more likely as LET increases. This makes sense, because as the ionization per unit track length increases, a target becomes more likely to suffer substantial damage, if it is affected at all. In fact, one might expect that if the LET of radiation becomes high enough, the effectiveness with

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418 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS increasing LET would saturate at some point and then fall off as the LET continued to increase. That is what is observed, particularly in prokaryotic systems. For the induction of radiobiological effects in mammalian cells, the target volume appears to be large enough for the effect to occur at a higher LET, with the maximally eRective LET being around 100 keV/,um. MICROSCOPIC DOSE DISTRIBUTION With energetic photon irradiation, the quantity dose, used in calcu- lating a dose-effect model, has an easily understood meaning and is easy to measure empirically. However, the situation often is not so simple for particle irradiation from internally deposited radionuclides, particularly when the mean path length of the charged particle is small in relation to the diameter of the average cell or subcellular structure of interest and when the distribution of the radionuclide is very nonuniform. The problem is particularly acute when, as in the case of tritium incorporated into the DNA of a cell in the form of tritiated purines or pyrimidines, only parts of cells have incorporated the radionuclide and only some of the potential target cells have incorporated any radionuclide at all. In such cases, dose expressed in the usual terms of the average amount of energy deposited per unit of tissue mass over the mass of the organs (or parts of organs) becomes meaningless, if not actually misleading. Here it is important to consider the microscopic distribution of dose and the doses accumulated by individual targets (usually taken to be individual cell nuclei). In the case of the alpha-emitting radionuclides of interest here, we must consider the problem presented by the inadequacy of simply measuring body or even organ burdens of a radionuclide, and try instead to identify the target cells at risk for a particular possible health impact and then to determine the average dose to the nuclei of all these cells. The distribution factor will otherwise be confounded with the relative biological effectiveness (RBE) factor, and that can lead to large uncertainties and ambiguities. In fact, if the RBE for a given particle seems to be reasonably well established, deviations from that RBE can be used to infer the magnitude that must be attributed to the microscopic dose-distribution factor. MODELS OTHER THAN THE QUADRATIC Models designed to describe and, thus, to permit prediction of the response of cell populations to radiation with different LETs can be di- vided broadly into two categories: those derived empirically from observed cellular dose-response curves (observation obviates assumptions about or dependence on underlying molecular or subcellular biological ejects or mechanisms), and those built on assumptions about underlying subcellular

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CELLULAR RADIOBIOLOGY 419 mechanisms (which might or might not be shown to be applicable). A1- though the two approaches must ultimately converge, there can be little confidence that this will occur soon. The first category includes two models that are related to the original target theory:35 the quadratic model and the model of Bond et al.8 As noted above, the former is applicable to a wide variety of endpoints in many systems, particularly with low-level exposure to radiation ti.e., either small doses at any dose rate or larger doses at very low dose rates). It also adequately accommodates dose-rate and protraction effects and accurately describes most responses as a function of LET in tissue in terms of an increasing ED component and a decreasing ,BD2 contribution as the LET increases. Thus, with very low doses, the mean absorbed dose to the population of cells increases only because the fraction of cells hit increases; the mean dose (specific energy) delivered stochastically to the hit cells remains constant. However, as the fraction of cells hit approaches unity, the absorbed dose to the cell population can increase only if the number of hits per cell increases.8 At high doses and high dose rates, where each cell has received many hits, the variance of the mean decreases; so the dose to each cell, the mean dose to the cell population, and the mean dose to the organ or other medium approach equality. The other model that belongs in this category and that combines some elements of hit theory with those of microdosimetry is under development.8 The unique addition is an empirically derived hit size effectiveness factor. This factor gives the probability that a cell with a certain amount of energy deposited within it will respond as a function of the energy deposited. Ad- ditional testing with different endpoints and biological systems is necessary before the degree of applicability of the model can be ascertained. The second category includes several models that cover a wide vari- ety of assumptions, some of which are commented on below. The early dual-action model33 combines microdosimetry with assumptions about the stochastic interactions of microdosimetric events to derive the basic for- mulation: E = K(§D + D2), (II-5) where S. is a physical quantity equal to the average specific energy (dose to a subcellular target volume in single events), and K is the sensitivity coefficient. This expression is equivalent to the more general aD ~ ,BD2 formulation, with K: equivalent to ~ and K equivalent to §. A recently developed thesis is the lethal and potentially lethal model,24 which, with the earlier repair-nonrepair model of cell survival46 and other models, is built on the added assumptions of irreparable lethal lesions,

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420 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITS repairable potentially lethal lesions, first-order kinetics for correct repair, and second-order kinetics for misrepair. Although the models have been applied only to cell lethality in plateau-phase tstationary-phase) cells in culture, they do take LET and dose rate into account. The principal mathematical formulation is complex and embraces a power expansion, but the first two terms also yield the aD + ,BD2 expression. Such models constitute valuable contributions in attempting to unify the most attractive features of a number of others; the extent of their universality remains to be determined. Other models have also been developed, for example, the molecular theory of Chadwick and Leenhouts,2t the kinetic model of Dienes,25 the cybernetic model of Kappos and Pohlit,32 the incomplete-repair model of Thames,45 and the repair model of Braby and Roesch.~9 Many are limited, in that they deal either with only a small fraction of the many radiobiological factors that must be taken into account (e.g., some are limited to high dose rates and others to the question of repair, possible misrepair, and dose rate), or in encompassing only particular endpoints (e.g., some deal only with cell lethality, and others exclude it). There is evidence that the various models can be reconciled, but it seems unlikely that there will be general agreement or that the mechanistic assumptions behind any of them will soon be proved. None of the models in this category has the simplicity or the generality of application of the quadratic model, and none is at the point of applica- bility to the problems of predicting either genetic or carcinogenic responses in mammalian systems. Thus, although they contribute to our general understanding and appreciation of problems remaining to be solved, they cannot yet be applied in practical exercises that require the prediction of risk associated with exposure to principally low-level radiation. Therefore, it appears reasonable that the quadratic model be used. APPLICATION TO RISK ESTIMATION FOR INCORPORATED ALPHA-EMITTING RADIONUCLIDES With some notable exceptions such as Thorotrast-exposed patients, radium-dial painters, or uranium miners there is generally little direct information on the human health effects of the internally incorporated alpha-emitting radionuclides. However, we can derive several generaliza- tions that can be applied to the problem of extrapolating available empirical evidence of the induction of human health effects by low-LET radiation. First, even though the question of whether the low-LET effects best fit a simple linear dose-response model or a dose-squared model is unsettled, as far as the epidemiological data on radiation carcinogenesis are concerned (see Committee on the Biological Effects of Ionizing Radiations WEIR

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C~.rr.l~AR RADIOBIOLOGY 421 IIIi38), we can be reasonably sure that the dose-effect curves of alpha particles are linear (or essentially linear), at least for the low to moderate doses of interest, for which saturation effects can be ignored. Second, the evidence is that there are no dose-rate effects for high-LET alpha particles (with the one possible exception of in vitro cell transformation as discussed below). Third, we can be sure that the yields of effects per unit dose of alpha particles are greater than those per unit dose for low-LET x or gamma rays, that is, that the RBE for alpha particles is greater than unity. Although the appropriate RBE for a given alpha particle might not have been empirically measured in an appropriate target-cell system, generalizations on the basis of LET seem reasonable, provided that they are based on RBEs determined in cells likely to have similar cell nucleus and target volumes and based on doses that produce similar hit fractions per red. Thus, in considering the hazard of induction of a malignancy of, say, the liver by deposition of plutonium, it seems reasonable to multiply the low-dose risk coefficients for low-LET radiation available in the BEIR III report38 by an appropriate RBE factor to derive a new estimate that can be useful in the absence of empirical information on the overall risk associated with the radionuclide of interest. We present below the empirical evidence from cellular Idiobiology on RBE for alpha particles, with necessary background information, on which to base estimates of expected effects of exposure of human populations to alpha-emitting radionuclides. MAMMALIAN CELL SURVIVAL Although much work had been done earlier with prokaryotes and unicellular eukaryotes, mammalian cell survival studies became possible only with the development by Puck et al.39 of a practical clonal assay for the survival of single mammalian cells in culture. The general principles already discussed in this appendix were elucidated mainly with low-LET x and gamma rays and have been reviewed elsewhere. Much work has been done with high-LET irradiation, particularly with neutrons, protons, and beams of heavy ions, largely because of interest in their potential application to radiation oncology. Much less has been done on cell killing by alpha particles from the radionuclides of interest here. Therefore, it is necessary to consider the larger body of data from other high-LET radiation. Extensive studies with fast neutrons of various energies have been done by Broerse et al.,20 Be~Ty,6 and by the Radiological Research Labora- tory group at Columbia University.30~34 The last studies are of particular interest because of the essentially monoenergetic neutron beams that the group at Columbia University was able to use. Survival curves for Chinese

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422 HEALTH RISKS OF RADON AND OTHER ALPNA-EMITTERS hamster cells irradiated with neutrons of 0.1-50 MeV have been obtained. As expected, neutron energies below a few million electron volts produced exponential survival curves without the shoulder characteristic of low-LET survival curves. At energies above a few million electron volts, the LET is lower and a small shoulder becomes evident. RBE varied with neutron energy, exhibiting a rather broad peak at approximately 0.4 MeV. Because of the difference in survival-curve shapes, RBE was a function of the survival fraction at which the comparison was made with the reference curve, in this case for 25~kV x rays, peaking at about 9 for 80% survival and falling to approximately 3 at 0.001% survival. Blakely et al.7 recently reviewed extensive mammalian cell-survival studies with heavy ions, t2C to 40Ar, which used a variety of tissue-culture cell types. RBE was found to increase from about 1.0 at a track-average LET of 10 keV/pm to about 2.5 at a track-average LET of around 100 keV/pm. Survival curves lost their shoulders as LET increased, becoming simple exponentials for a higher LET. Thus, the results of both the fast- neutron and the heavy-ion experiments are in general agreement as to the modification of curve shape and increase in RBE with increasing LET. The maximal RBE observed in the neutron experiments, about 5 for 5%o survival, is somewhat higher than the maximum observed in the heavy-ion experiments, probably because the heavy ions, with their high velocities, deposit a larger fraction of their energy via lower-LET secondary electrons and are thus less monochromatic with respect to LET.43 The results of the heavy-ion experiments clearly demonstrate the falloff in efficiency (dose wastage) at average LETs greater than approximately 100 keV/,um. Barendsen and coworkersi-4 have studied mammalian cell-survival curves for cyclotron-accelerated alpha particles (and deuterons) and for Echo alpha particles. Polonium-210 alpha particles induced simple expo- nential survival curves with an RBE ranging from 2.5 (at high acute doses) to around 6.0 (at low doses). With cyclotron-accelerated alpha particles at LETs of 25-86 keV/pm, survival curves for the higher-LET alpha particles were again simple exponentials, although that for 25-keV/,um, alpha parti- cles did show some evidence of a shoulder. The RBE, in comparison with the curve for 200-kV x rays, was dose dependent but was in the range of 3-5 for survival below about 20%, with the peak for any degree of survival at about 100 keV/,um. Lloyd et al.36 also determined mammalian cell-survival curves for accelerator-produced alpha particles. Essentially exponential survival curves were found for alpha particles with LETs of about 85 keV/,um; the slope agreed well with that determined by Barendsen and coworkers.~~4 Barnhart and Cox5 and Thacker et al.43 have determined survival curves for Chinese hamster cells in tissue culture exposed to alpha parti- cles from 238 Pu. Again, the survival curves were exponential. With the

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C.h~l T. ULAR RADIOBIOLOGY 423 irradiation geometry used, the ranges of LET through the cells were 127- 165 keV/,um and 10~135 keV/pm, respectively, in the two studies. RBE values of 7-10 were observed for high survival fractions. Thus, there Is general agreement that cell-survival curves for alpha particles, as well as other high-LET irradiation, are exponential with high RBE, peaking at around 100 keV/,um; are dose dependent; and reach maximal calculated values of about 5-10 at low doses. Low-dose-rate, low- LET ionizing radiation seems appropriate for comparison for the purposes of this report (i.e., comparison of the a terms of the quadratic relationship seems appropriate). Therefore, the lowest dose and, consequently, the highest RBE observed seem appropriate as a basis for extrapolating from the BEIR III report38 and similar risk estimates to alpha-particle estimates when direct human data are not available. MUTATION IN VITRO Mutation induction at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus can be studied in vitro in Chinese hamster or human cells by using selection in a thioguanine-containing medium. Dose-effect curves have been determined in this way for both high- and low-LET radiations. Thacker et al.43 and Cox and Masson22 determined HGPRT mutation by henry ions in Chinese hamster cells and human diploid fibroblasts, respectively. Helium, nitrogen, and boron ions with LETs of 28-470 keV/pm in the irradiated cells were used. Mutation- induction curves were essentially linear, giving maximal RBEs of about 6 at 9~200 keV/pm when calculated in terms of mutants per survivor and compared with the initial slope of the curve for gamma rays. Both Barnhart and Cox5 and Thacker et al.43 have reported on the mutagenicity of alpha particles from 238 Pu in Chinese hamster cells. The study by Barnhart and Cox,5 however, appears to have suffered from technical difficulties; as noted by Thacker et al., the latter found an RBE of about 2 for the alpha particles, which had an LET range of 127-165 keV/pm as they traversed the cells, compared with acute exposure to 25~kV x rays. TRANSFORMATION IN VITRO A few types of mammalian cells growing in tissue culture can be transformed in vitro from the growth patterns that characterize fairly normal cultured cells to a new phenotype that more closely resembles that of cancer cells. The basic change is from an orderly growth pattern exhibiting contact inhibition on the culture vessel surface to a pattern resulting from the loss of contact inhibition. That loss causes the cells

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424 HEALl,H RISKS OF RADON AND OTHER ALPHA-EAlITTERS to pile up and overgrow each other and to produce foci of a distinct and recognizable morphology. Examples are shown in Figure II-1. The development of cell-culture systems has made it possible to study the cellular and molecular mechanisms involved in radiation transformation under defined conditions devoid of host-mediated homeostatic modulating factors, and to assess the underlying mechanisms qualitatively and quan- titatively. These systems afford the opportunity to study dose-related and time-dependent interactions of radiation with single cells and to identify factors and conditions that can prevent or increase cellular transformation by radiation. Because such cells transformed in vitro give rise to tumors when injected into hamsters, whereas untreated cells show no spontaneous transformation,~4~5 the system has obvious implications with respect to in viva carcinogenesis. The details of the system and its utility in cellular radiation biology were recently reviewed by Bore. The role of DNA as a target in radiation transformation was suggested early by the requirement of DNA metabolism for fixation of the transformed state.~5 The ability of genomic high-molecula~-weight DNA purified from cells transformed In vitro to transmit the transformed phenotype to normal cells constitutes an important criterion for the neoplastic state of the cells transformed after exposure to a carcinogen, ~ 3~7~8~4t indicating that the transformed phenotype of the cells exposed to the carcinogen in vitro is encoded in the DNA. This criterion aids in mechanistic studies of transformation that attempt to analyze the specific transforming genes activated as a result of exposure to the carcinogen and to elucidate genetic changes.~7~'~ For both low- and high-LET radiation, transformants are produced as a function of increasing dose up to approximately 1-S surviving cells/100 exposed cells, at which point the curves saturate. ~ansformants are produced more efficiently by fission neutrons than by 250-kVp x rays, with an RBE of approximately 10 in the region below saturations 3i Figure II-2 shows an example for 43~keV neutrons. Data on alpha-particle-induced in vitro transformation are sparse and often incomplete (there are no data on the tumorigenicity of the transformed cells). The eRect of low-energy alpha particles in transforming the C3H/lOT-1/2 cells was evaluated by Lloyd et al.37 Transformation frequency per surviving cell increased as the cube of the dose, peaking at a fluence of 1.5 x 107-2.5 x 107 alpha particles/cm2 (205-342 red). Maximal transformation frequency reached 4%. No parallel experiments were carried out with x rays; thus, no RBE for alpha radiation was determined. By taking the dose required to reach the peak transformation region and comparing it with x-ray data determined for the same cell line by Terzaghi and Little,42 an RBE of approximately 2 is obtained. A study carried out by Robertson et al.40 evaluated the eRects of 238 Pu alpha particles in mouse BALB/3T3 cells. The A31-11 mouse BALB/3T3

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CF~UlAR RADIOBIOLOGY (A) it: . . 425 :' 5~ ~ ~ 4 ~ I: ~ j . ~ it,: ~ if ~ ~ A:-. ~ f ~ it: ~ :< I: ~ ~ ~ -. . ~ ~ .~ -I : : ~ .~ ' . ~ . . ~ . _4 ;. :.. FIGURE II-1 (A) Normal colony of hamster embryo cells. (B) Colony of x-ray- transformed hamster embryo cells. (C) Focus of C3H/lOT-1/2 cells transformed by x rays growing over normal cells. Morphology of transformed cells is the same as that after exposure to high-LET radiation. SOURCE: Borek.l2

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426 too lo - ·s 10 HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS ~ 430 keV neutrons 250kVp x-ra~ i 10 HAMSTER EMBRYO CELLS . , ,~,,,] ~ --,,, , · ....,,, ,, ...— HAMSTER EMBYRO CELLS ,' O ~ ~ 10-2 ,>10-3 .. -2~ 30 keV neutrons \ 10 ~o~6 0 2 4 6 8 10 0~3 ~o~2 10-' too i' (A) D O S E / Gy (B) DOSE/Cy FIGURE II-2 (A) Pooled data on sur~ri~ral of hamster embryo cells uTadiated with 250-kVp x rays (solid circles) or 43~keV monoenergetic neutrons (open circles). Error bare show estunated standard deviation. 1 Gy = 100 red. (B) Pooled data for hamster embryo cells on number of transformants per surprising cell after irradiation with 25~kVp x rays (solid circles) or 430~keV monoenergetic neutrons (open circles) at the Radiological Research Accelerator Facility. Error bare show 9596 confidence intermurals for estimates. SOURCE: Borek et al.l6 1 1 1 1 1 1 1 1 430 keV neutrons S_. He 10 1/ /e 95'. confidence limits ... 1 . , 1 . 1 . cell system was used, and in vitro transformation was induced by 5.~MeV alpha particles from a specially constructed 238 Pu source. The biological effects were compared with those of 22~kVp x rays. The alpha-radiation survival curve gave an RBE of 3.5 at 50% survival. The transformation frequency increased exponentially with dose in the range examined (25-250 red); the maximal RBE for the induction of transformation in growing cells wan approximately 3. However, the RBE for alpha transformation in nonproliferating cells appeared to be much higher; the yield of transformants among x-irradiated cells that were held in the stationary phase of growth for 0220 h after irradiation declined by a factor of nearly 50, whereas no decrease occurred in alpha-irradiated cells. The findings suggest that carcinogenic damage induced by high-LET radiation in mammalian cells is very inefficiently repaired, compared with that induced by x rays, and that the intracellular carcinogenic effect of exposures to high-LET radiation can be cumulative. They also suggest that the eBective RBE for alpha radiation in nonpro- liferating cell populations in viva might be much higher than one would predict on the basis of measurements in dividing cells. Work by Hall and Hei29 with C3H/lOT-1/2 cells compared the trans- forming action of radiation, from a source of 24tAm, delivered at 10 rad/min with that of gamma rays from a i37Cs source with an absorbed dose rate of 137 rad/min at equivalent doses. Alpha particles were sum stantially more cytotoxic and more efficient than gamma rays in inducing oncogenic transformation. The calculated RBE ranged from 2.3 to 9 for the transformation frequencies examined.

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Representative terms from entire chapter:

mammalian cells