Health Effects of Exposure to Radon Time for Reassessment? (1994) / Chapter Skim
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2 Radiation Biology and Carcinogenesis
2 Radiation Biology and Carcinogenesis
Pages 17-42
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From page 17... ...
ShIl, the data available for this purpose are limited and risk estimates are subject to major uncertainties. In Be dosimetnc approach, doses to the bronchial epithelium are estimated, arid the long-term risks of lung cancer in Japanese atom~c-bomb survivors are used to estimate lung-cancer risks from radon exposure.
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From page 18... ...
This section on Me radiation biology of a particles summarizes basic concepts In the field, focusing on how radiation biology can contribute to the assessment of radon risks, namely by using doserate corrections and the radiation quality factor for radon-progeny ~ particles. It also presents selected examples where recent informadon on mecharusms, oncogenes and tumor-suppressor genes, and possible biologic markers of a-particle exposures will be reviewed in depth in a Phase ~ study.
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From page 19... ...
Ranges of two a particles emitted by radon progeny deposited on lung surface and average depths of serous and basal cells in h Amen lung, according to study of several hundred nnormaln lung sections from Pathology Department at Columbia Presbyterian Medical Center. (Based on data collected by Charles Geard and David Brenner; reproduced from Hall, 1992, with permission of the publisher ~ 19
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From page 20... ...
0.01 FIGURE 2. Change in dose and dose-averaged lineal energy ED (1-,Um site sized win depth for a particles simulating those emitted by radon progeny.
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From page 21... ...
of a particles, compared with x rays or gamma rays, in HIling cells is due to the a particles' ability to induce irreparable DNA damage, inasmuch as these densely ionizing particles deposit a large amount of energy and efficiently induce localized multiple lesions (Ward, 1985; Goodhead, 19891. MumHons In Cultured CeNs The mutagenic potential of a particles with energies similar to those charactenshc of radon progeny has been measured at several 21
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From page 22... ...
In general, the mutagenicity of a particles depends on both dose and LET. Figure 4 shows mutation induction at the HGPRT locus.
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From page 23... ...
FIGURE 4. Mutation induction at HGPRT locus in primaly hunter fibroblasts irradiated with gamma rays and charged particles of venous LET.
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From page 24... ...
. Closed symbols represent cell ledulit~r; open symbols, mutation at HGPRT locus.
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From page 25... ...
~ content win rodent ceils, which are readily transformable by a particles, human cells In culture are refractory to malignant transformation by either radiation or chemicals. Also, unlike rodent celIs, normal human ceils in culture rarely undergo spontaneous transformation (Harris, 1987; Rhim, 19921.
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From page 26... ...
0 1 0 475 keV/~m ,:____ -- ' l 2 FIGURE 6. Transformation data for C3HlOTl/2 cells as a function of dose for x rays (open circles)
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From page 28... ...
Comparison of Effects In Vivo and In Vibro An important step in the dosimetnc approach to risk assessment is to convert exposure to radon progeny in working-level months ~M) to absorbed dose in the bronchial epi~elium.
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From page 29... ...
Since the BEIR IV committee completed its work, additional analyses of data from experiments performed at Battelle, Pacific Northwest Laboratories, have taken account of competing risks and confirmed that, after exposures above 600 WLM, lung cancer in rats shows a significant inverse dose-rate effect. A dose-rate effect is termed inverse if higher dose rates produce less effect per unit dose Earl lower dose rates.
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From page 30... ...
Data from additional experiments conducted at Battelle, Pacific Northwest Laboratories, might also be avmiable for consideration by a Phase ~ committee. These include results of experiments with lower total exposures and lower exposure rates than those used previously and results of ~n~dabon-promodon-initiation OPl)
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From page 31... ...
Numerous past studies, win a variety of biologic systems from cell lethality to mutation to oncogenic transformation, have confirmed the general shape of the ABE-LET cube, namely, an increase of RBE wad increasing LET up to a maximum at an LET of about 100 200 keV/pm, followed by a sharp decline at higher LET (as shown in Figure 5) e Inasmuch as survival after a-particle irradiation generally varies exponentially with dose (whereas the curves for survival after exposure to x rays or y rays have a shape at low doses that is not exponendal)
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From page 32... ...
The transformation data imply a much-reduced effectiveness of a particles near He end of their range and a lower overall effective Q over the range of the a particles compared with those reported previously ~nternai~onal Commission on Radiation Units and Measurements, 19864. DOSE RATE THETIS AND IMPLICATIONS FOR RISK ESTIMATES For low-LET radiation, a unit of dose is usually more biologically effective at a high dose rate than at a low dose rate.
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From page 33... ...
oncogenic transformation in C3HIOTI/2 cells as an end point, an inverse dose-rate effect is apparent for high-LET radiation such as fission-spectrum neutrons. The effect appears to be confined to particular radiobiologic end points; e.g., for clonogenic survival, the biologic effectiveness at medium or high LET is virtually independent of dose rate.
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From page 34... ...
That argument is relevant to the relationship of radon progeny exposure and lung cancer; epidemiologic studies have shown that lung-cancer risk from radon-progeny exposure depends on He exposure rate and Horses as He exposure rate decreases. Figure 9 shows the result of c~culadons from the biophysical model referred to above surface that describes He enhancement in risk (relative to an acute exposure)
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From page 35... ...
In the context of radon risk esi~mates, it is a tar~talizing possibility that the densely ionizing a particles released by radon progeny produce charactenshc genetic changes that can be recognized at the molecular level and would therefore constitute a "signature" or "footpnnt" of radon exposure. The possibility is being explored through the study of oncogenes and tumor-suppressor genes in tumors from uranium miners and in a particle-~nduced tumors in experimental animals.
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From page 37... ...
· ~ ~ ~ ·= ~ ~ ~ ~ to .~ ~ .9 .s ~ o o .E E -& ~ ~ ~ E D ~ 9 ~ ~ .
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From page 38... ...
The putative tumor suppressor genes have been mapped to specific chromosomes, such as chromosome Il in the example quoted, by analyzing which chromosomes were lost from the hybnds that re-express tumor~genicity (Stanbndge, 19761. The importance of tumor-suppressor genes became evident in the work of Knudson (1971)
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From page 39... ...
A tumor suppressor gene acts in a recessive way, so the deletion would have to occur in both chromosomes of a pair, an event of very low frequency. In practice, it is often found that the loss of a pair of suppressor genes occurs by the process of somatic homozygosity (Cavanee, 19891: one chromosome of a pair is lost, a deletion occurs in the other, and then the chromosome with the deletion is replicated.
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From page 40... ...
The mutation spectra of pS3 and K-ras in lung cancers of uranium miners exposed to radon at high levels have been studied. The results In 19 miners, IS of whom also smoked, showed no codon 12-13 mutations ~ K-ras (K-ras mutations are very common in lung cancers of cigarette smokers)
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From page 41... ...
appears to be consistent with the dose-rate effect observed in studies of experimental animals and underground uranium miners and has implications for the extrapolation of data from radon exposures in mines to exposures in residences. That is an important development since the publication of BEIR IV and needs to be con sizers and evaluated by Phase ~ (BEIR VI)
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From page 42... ...
RADON: TIME FOR REASSESSMENT, biology, hansformadon, and carcinogenesis, as well as some useful data from studies of neutron-radiation biology, He committee recommends that a Phase ~ Research Council committee · Evaluate biophysical models of the inverse dose-rate effect and Weir implications for risks associated with indoor radon exposure. · Compare risks and pathology of lung tumors induced by exposure to radon win risks and pathology of those induced by external exposures to low-LET radiation.
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