Health Effects of Exposure to Radon BEIR VI (1999) / Chapter Skim
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2 The Mechanistic Basis of Radon-Induced Lung Cancer
2 The Mechanistic Basis of Radon-Induced Lung Cancer
Pages 36-68
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From page 36... ...
is at least semiquantitative, our knowledge of the various steps in the carcinogenic process (particularly at the genetic level) is at best qualitative in spite of important research findings since the publication of the report of the 4th Committee on the Biological Effects of Ionizing Radiations, BEIR IV (NRC 1988)
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From page 37... ...
However, the role and progression of these cellular and molecular changes in the development of disease also can be addressed with experimental-animal studies. It should be noted that although many of the studies discussed in this chapter used interactions of bronchial tissue with alpha particles as the experimental model, there is a much greater base of information on interactions of x rays with other target tissues.
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From page 38... ...
Consequently, in assessment of the predominant initial radiation damage the first of the many steps by which alpha particles can induce cancer deletions or translocations seem to be the most likely candidates for the first changes. Numerous experimental and epidemiologic studies have demonstrated that radiation can cause cancer (Martland 1931; Court-Brown and Doll 1958; Beebe and others 1962~.
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From page 39... ...
showed that a single small dose of alpha particles (30 cGy of absorbed dose) , corresponding to an average of a few particles per cell nucleus, can cause human bronchoepithelial cells to become tumorigenic.
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Alpha particles are particularly efficient at producing large deletions (for example, Melting and others 1992~. Two radiation-induced breaks in the same arm of a chromosome can readily result in a deletion.
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From page 41... ...
The multiple mutations and chromosomal changes follow as a cascade because of the induced instability as described below. Both densely ionizing and sparsely ionizing radiation have been shown to induce chromosomal and mutational changes that appear in the progeny of exposed cells many generations after the initial exposure (Morgan and others 1996~.
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From page 42... ...
that ionizing radiation might interact with the genetic predisposition to increase the frequency of radiation-induced cancer. The current evidence for that hypothesis is still relatively weak (for example, Hall and others 1992)
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From page 43... ...
As genes such as the ATM gene for ataxia telangectasia are identified and sequenced, much attention will be focused on the possibility that some persons have a genetically based susceptibility to radiationinduced cancer (Sankaranarayanan and Chakraborty 1995) , possibly including lung cancer induced by alpha particles.
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From page 44... ...
Combining research on cellular and molecular changes with whole-animal exposures could provide some understanding of the basis of species and strain differences; these differences eventually might be related to individual changes in sensitivity for the induction of cancer. CELL-CYCLE EFFECTS It is well established that ionizing radiation in general and alpha particles in particular produce a dose-dependent delay in progression through both the G2 and the Go stages of the cell cycle (for example, Lucke-Huhle and others 1982; Kasten and others 1991~.
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From page 45... ...
In addition, the efficiency of cell killing by alpha particles might also decrease the relevance of cell-cycle delay to a risk assessment model. Those considerations make it likely, although not certain, that cellcycle delay produced by environmental radon exposure plays a minor role in changing potential response or risk.
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From page 46... ...
Cell proliferation is a required step during cancer induction without which cancer cannot form, thus, enhanced cell proliferation can be viewed as a mechanism of either tissue repair or promotion of the cancer process. CELLS AT RISK To determine the dose, energy distribution, and cellular processes essential for radon-induced carcinogenesis, it is important to identify the respiratory tract cells at risk from radon exposure.
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From page 47... ...
Other lines of research have suggested that the major airway epithelial cell type at risk for radon-induced cancer is the secretory cell (Johnson and Hubbs 1990; Johnson 1995~. It has been demonstrated that in rat trachea, secretory cells constitute a major progenitor cell compartment.
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From page 48... ...
Those findings suggest that secretory cells can differentiate to form all the cell types in the trachea, whereas basal cells have more-limited capacity to differentiate. The observations that both cell types can divide and differentiate, point to the potential role of the secretory cell in radon-induced cancer induction.
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From page 49... ...
have demonstrated that when cells were exposed simultaneously to very low doses of alpha particles (6 cGy) and x rays, the response to the x rays with respect to both cell killing and induction of micronuclei was markedly increased.
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From page 50... ...
For any radon exposures of practical relevance, a given cell in the lung is likely either to be unirradiated, to receive an instantaneous large energy deposition from a single alpha particle, or to receive a small number of such large energy depositions, each well separated in time by months or years. For example, even for a miner in the highest-exposure cohort receiving 2.8 Jhm-3 (800 WLM)
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From page 51... ...
BASIS OF RADON-INDUCED LUNG CANCER Low-LET tracks ~ ~_ in cell nucleus / \ , ~ e.~; /= ~ 51 A dose of ~ Gy ~_:_ corresponds to ~ ~1000 tracks ~ / all,,\ //~_ High-LET tracks in cell nucleus e.g., alpha-particles / A dose of ~ Gy corresponds to -4 tracks \\ ~1 him FIGURE 2-1 Illustration of the differences in ionization-track densities in a cell nucleus between low-LET and high-LET radiations.
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From page 52... ...
52 sit ca ~ A ~ ~ ~ ;^ ca I ~ ;^ ~ o To To ~ ~ .
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From page 53... ...
Therefore, it is possible that biologic consequences of alpha-particle exposure differ from those of low-LET irradiation in both qualitative and quantitative respects (Goodhead 1988~. Low-dose alpha-particle induced radiation damage differs from damage caused by x rays in that the potential to transmit viable mutations or aberrations can be substantially reduced by cell death induced by the same single alpha particle.
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From page 54... ...
Dose fractionation or dose protraction had little effect on the induction of chromosomal aberrations following exposure to high-LET radiation (Brooks 1975; Bender and others 1989~. At the chromosomal level, alpha particles produce initial DNA breaks that are more closely associated with each other than those produced by x rays.
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From page 55... ...
Several studies have suggested that densely ionizing radiations produce a higher proportion of gene mutations involving large deletions than do x rays (Chen and others 1990; Evans 1991; Hei and others 1994c; Schwartz and others 1994; Bao and others 1995; Kronenberg and others 1995; Zhu and others 1996~. It has also been suggested that the frequency of large deletions increases as a function of dose for high-LET radiation (Hei and others 1993; Zhu and others 1996~.
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From page 56... ...
Other studies also have proposed signatures for alpha-particle-induced biologic damage in the form of the induction of specific point mutations in the tumors of uranium miners (Taylor and others 1994; Vahakangas and others 1992~; however, the results are not consistent, nor have they been confirmed by larger-scale animal studies (McDonald and others 1995; Kelly and others 1995~. BIOLOGIC EFFECTS OF LOW EXPOSURE LEVELS TO ALPHA PARTICLES The primary approach to radon risk estimation involves epidemiologic studies of underground miners whose mean exposure was typically much larger than average residential exposures.
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From page 57... ...
In chapter 3 we attempt to avoid that problem by focusing on the low-exposure miners. However, the prima facie approach of performing alpha-particle experiments at both high and low doses to guide the extrapolation does not allow for a direct assessment of the effects of a single alpha particle.
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From page 58... ...
BIOLOGIC EFFECTS OF ALPHA PARTICLES AT LOW EXPOSURE RATES In the last few years, it has become increasingly clear that densely ionizing radiation such as alpha particles can exhibit an inverse dose-rate effect for carcinogenesis (for example, Miller and others 1993~; that is, for a given dose or cumulative exposure, as the dose rate is lowered, the probability of carcinogenesis increases. The phenomenon has come to be known as the inverse dose-rate effect because it is in marked contrast to the situation for sparsely ionizing radiation, which with protraction in delivery of a given dose, either by fractionation or by low dose rate, usually results in a decreased biologic effect.
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From page 59... ...
· Enhancement of cellular repair (Burch and Chesters 1986~. · A correlation across the cell cycle between cell killing and oncogenic transformation induction (Elkind 1994; Brenner and others 1996~.
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From page 60... ...
, which is about 4 times the average indoor exposure, would result in on average about 1 alpha-particle traversal per bronchial epithelial cell nucleus location (0.6 for the location associated with the bronchial basal nuclei or 2-4 for the location of bronchial secretory cell nuclei; see Table 2-1~. In most indoor-exposure situations, protraction would be expected to have little effect on risk unless there are large additional spatial and temporal factors, such as persisting long-range cell signaling or clonal expansion.
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From page 61... ...
61 cd ~ ~ ,~ D +, `_ ~t!
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From page 62... ...
reviewed the animal studies that included exposure to both radon progeny and cigarette smoke. The relevant studies included experiments involving rats conducted by the Compagnie Generate des Matieres Nucleaires (COGEMA)
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From page 63... ...
A different, and possibly complementary, approach is to estimate radon risks on the basis of people exposed primarily to sparsely ionizing radiation largely the Japanese atomic-bomb survivor cohorts. This so-called dosimetric approach to radon risk assessment using ICRP quantities (ICRP 1991)
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From page 64... ...
Essentially, the rationale, other than the pragmatic issue of quantifiability, is that the radiation weighting factor is used for predicting only relative risks (compared with risks associated with gamma rays or x rays) of one kind of radiation relative to another, rather than absolute risks.
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From page 65... ...
Extrapolation from High to Low Radon-Progeny Exposures The challenge is to guide the extrapolation of risks from radon-progeny exposures at which effects can readily be observed and risks quantified down to lower exposures at which events might occur with probabilities too small to measure with sufficient precision in any human population. Low exposures and doses correspond to the traversal of cells by single alpha particles.
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From page 66... ...
It is important to note that we have considered only low-dose extrapolation of the effects of alpha particles, and these arguments do not necessarily apply to the effects of sparsely ionizing radiation, such as x or gamma rays. At higher doses of densely ionizing radiation, various processes can, in principle, result in a nonlinear relation, as has often been observed (for example, Ullrich and others 1976; Ullrich 1983; Fry and others 1985; Chmelevsky and others 1984; NRC 1988; Furuse and others 1992~.
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From page 67... ...
Specifically, protracting a given total dose (experimentally, at least 0.10 Gy) of densely ionizing radiation, such as alpha particles, can increase oncogenic transformation in vitro or carcinogenesis in vivo.
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From page 68... ...
In addition, within a given species, different inbred strains show variations in susceptibility to ionizing radiation or chemical carcinogens. Cell lines or animals with specific repair deficiencies also show increased susceptibility to radiation-induced malignant or premalignant changes, although there have been few experiments specifically with alpha particles from radon progeny.
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