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The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review

Clinical Photobiology, European Centre for Environment and Human Health, University of Exeter Medical School, University of Exeter, Knowledge Spa, Royal Cornwall Hospital, Truro, Cornwall TR1 3HD, UK
Clinical Oncology, Sunrise Centre, Royal Cornwall Hospital, Truro, Cornwall TR1 3LJ, UK
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2013, 14(7), 14024-14063;
Original submission received: 8 May 2013 / Revised: 14 June 2013 / Accepted: 17 June 2013 / Published: 5 July 2013
(This article belongs to the Collection Radiation Toxicity in Cells)


Radon-222 is a naturally occurring radioactive gas that is responsible for approximately half of the human annual background radiation exposure globally. Chronic exposure to radon and its decay products is estimated to be the second leading cause of lung cancer behind smoking, and links to other forms of neoplasms have been postulated. Ionizing radiation emitted during the radioactive decay of radon and its progeny can induce a variety of cytogenetic effects that can be biologically damaging and result in an increased risk of carcinogenesis. Suggested effects produced as a result of alpha particle exposure from radon include mutations, chromosome aberrations, generation of reactive oxygen species, modification of the cell cycle, up or down regulation of cytokines and the increased production of proteins associated with cell-cycle regulation and carcinogenesis. A number of potential biomarkers of exposure, including translocations at codon 249 of TP53 in addition to HPRT mutations, have been suggested although, in conclusion, the evidence for such hotspots is insufficient. There is also substantial evidence of bystander effects, which may provide complications when calculating risk estimates as a result of exposure, particularly at low doses where cellular responses often appear to deviate from the linear, no-threshold hypothesis. At low doses, effects may also be dependent on cellular conditions as opposed to dose. The cellular and molecular carcinogenic effects of radon exposure have been observed to be both numerous and complex and the elevated chronic exposure of man may therefore pose a significant public health risk that may extend beyond the association with lung carcinogenesis.

Graphical Abstract

1. Introduction

Radon-222 (further referred to as radon) is a naturally occurring inert gas formed in the decay series of uranium-238 (Figure 1), which can be found in trace amounts in many rocks and soils. As radon decays, it produces radioactive progeny and emits significant levels of alpha radiation, along with lower levels of beta and gamma radiation, of various energies (Table 1), leading to biological damage that can be dangerous to human health [1,2]. Radon levels can vary greatly depending upon a number of factors, including geographical location, temperature and geology [3]. A link between radon and lung carcinogenesis has already been established and radon is thought to be the second leading cause of lung cancer in the UK after smoking [410], with evidence of a synergistic effect between radon and tobacco smoke [7]. Greater than 50% of the average annual background radiation dose is due to radon and its decay products [11], which, due to electrostatic forces, can attach to aerosols [12,13] and plateout on the skin [1416] significantly increasing the potential dose delivered to this organ.
Radioactive decay occurs in unstable atomic nuclei with the emission of ionizing particles resulting in a release of energy. With a half-life of 3.82 days, radon can accumulate in buildings before rapidly decaying into lead-210 with a half-life of 22 years. Other isotopes of radon, such as radon-219 (actinon) and radon-220 (thoron), are also present in the natural environment and a number of studies have suggested that thoron may also be detrimental to human health [1721]. Nevertheless, they are often left unacknowledged when investigating potential health effects in humans due to their shorter half-lives of 4 and 56 s, suggesting harmful accumulation is unlikely as a result of reduced exposure estimates [1820]. The lack of acknowledgement of thoron is of interest when considering Thorotrast. Thorotrast is a medically administered radioactive contrast agent that was used throughout the 1930s and 1940s and is strongly associated with liver carcinogenesis as a result of chronic internal radiation exposure [22,23]. Of particular intrigue is that Thorotrast treated patients are known to exhale elevated levels of thoron and there have been some investigations into the potential for patients to develop lung cancer although the studies remain inconclusive [2428].
Alpha particles represent the predominant form of radiation emitted as a result of the decay of radon. Despite their limited tissue penetration capability, alpha particles can cause significant biological damage in exposed tissue due to their high relative biological effectiveness (RBE) [29]. Beta and gamma-radiation are also emitted from the decay of radon progeny, however the RBE compared to alpha particle ionization is minimal [30] (Table 1). Alpha particles consist of a helium nucleus (two protons and two neutrons) and have the potential to deposit large amounts of energy as they traverse matter. In comparison to beta particles (electrons) and gamma radiation (photons) they are described as having a high linear energy transfer (LET). Mainly as a result of this high-LET classification, alpha particles are more biologically significant than either beta or gamma radiations, reacting much more readily with DNA and generating oxidative stress through radiolysis despite their reduced penetrating capability. Tissue regions and cell types that are within depths traversable by alpha particle exposure can be particularly susceptible to biological damage. The most substantial alpha emitters from radon decay are polonium-218 (6.0 MeV) and polonium-214 (7.69 MeV) and have penetration depths of 47 μm and 70 μm respectively [29], suggesting high levels of irradiation, particularly of the bronchial epithelium and at bifurcation sites, when inhaled into the lungs [3135].
It has previously been assumed that the depth of skin would be too thick for alpha particles to successfully penetrate and provide sufficient exposure to the sites vulnerable to mutagenesis. However, research now suggests that exposure to areas of the skin that are particularly thin, such as on the face where epidermal thickness has been measured to be 10–40 μm [36] could result in significant exposure of the basal layer to alpha radiation [21,3638], theoretically increasing the likelihood of the potential for biological damage. The South-West of England has both the highest rates of non-melanoma skin cancer (NMSC) and the highest average radon concentrations in the UK, with epidemiological evidence now suggesting that in Devon and Cornwall increased domestic residential radon exposure may be a risk factor for the development of squamous cell carcinoma of the skin [39,40]. It should be noted that a number of other cancers have also been suggested to have an increased risk with high radon concentrations including leukemia [41,42] and gastrointestinal malignancies [43,44], although any evidence of a cause-effect relationship remains conjectural [10,45,46].
Ionizing radiation in the form of alpha particles can cause DNA damage from chromosomal aberrations [47], double strand DNA breaks and generate reactive oxygen species (ROS) [48], resulting in cell cycle shortening, apoptosis and an increased potential for carcinogenesis.
Radon concentrations are typically tested using alpha track detectors usually placed in multiple sites throughout the home or workplace to obtain an applicable result that takes into account the variability between rooms. As a result of the heterogeneous distribution of uranium in rocks and soils around the world, radon concentrations can vary significantly between different locations. Not only can there be variation in concentrations but the levels that are deemed acceptable also vary between different countries. In the UK, the radon action level (the threshold whereby action should be taken to reduce radon concentrations) is deemed to be 200 Bq·m−3 (10 times the national average of 20 Bq·m−3) and in the US this figure is lower at 148 Bq·m−3 (4 pCi/L). If the concentrations of these figures are observed in domestic or work environments it is recommend that remedial action should be taken to reduce the risk (risk estimates for lung cancer are displayed in Table 2). However, there is an inherent difficult in accurately predicting or determining personal exposure dosimetry based upon values derived using alpha track detectors as often individuals can spend varying amounts of time in areas away from those that have been measured. In response, a number of studies have tried to derive a more accurate quantification of exposure through the use of plastics and other materials that a sensitive to tracks produced by alpha particles with examples including eye-glass lenses [49], passive personal dosimeters [50] and wrist watch detectors [51]. Nevertheless, accurate exposure estimates to the general population can often remain difficult to accurately obtain and the requirement for cheap, portable and reliable personal dosimeters has been acknowledged [51] and until such devices are routinely employed across multiple in vivo studies the effective comparison of exposures between laboratory based biological studies and those at physiological exposures will remain difficult to compare effectively.
The employment of radon spas, whereby radon exposure is used therapeutically for pain relief, has not only been conducted historically but has also persisted despite both the recognition of radon as a carcinogen and the continuing debate regarding safe levels of exposure [52]. Typical sources used by radon spas include natural springs, thermal pools or enclosed environments in the presence of radium-rich rocks for which all are located in areas with very high radon concentrations. Measured levels can reach thousands of Bq·m−3. These high exposures have raised a number of health issues not just for the individuals that are treated but also for workers at the spas [53]. Regardless of the potential carcinogenic risk of radon spa use, decreases in perceived pain relief and increases in joint mobility have been reported in rheumatoid arthritis sufferers following treatment [54].
Much of the evidence obtained relating to radon’s carcinogenicity has been from studies performed on cohorts of uranium miners that have historically received high levels of radon exposure. Concentrations of radiation in mines are often reported in terms of working levels whereby one working level (WL) is defined as the alpha particle emission of 1.3 × 105 MeV from radon and its daughters. One working level month (WLM) represents this value over the length of working time in a single month, averaged to 170 h, i.e., 1WL × 170 h. The miner cohorts have often contained incomplete data with regards to the lifestyle conditions of the miners, which has resulted in a difficulty in identifying implications at lower, more archetypal, exposures. However, a number of cytogenetic studies have revealed cellular and molecular mechanisms that play a crucial role in the elucidation of radon’s neoplastic potential and they can provide an approach to investigate any harmful effects that may affect mutation or cancer incidence as a result of environmental radon exposure. The aim of this review is to provide a summary of these developments and to investigate the evidence of a mutagenic effect of radon at low exposure levels. A significant proportion of the current literature employs alpha particle emitters as surrogates in place of radon and its daughter products and so the cellular and molecular effects of alpha emitters such as polonium-238 or americium-241 (that are often employed to imitate the effects of radon in vitro) are included alongside the effects produced by radon itself.

2. Genetic Effects

2.1. Environmental Investigations at the TP53 Locus

2.1.1. Hotspot Mutations of the TP53 Gene

The tumor suppressor gene TP53 (previously named p53), located in humans on chromosome 17p13.1, codes for the p53 protein and is part of a network that is integral to the effective maintenance of the cell cycle. TP53 mutations and deletions [56] have been frequently observed in various cancers, including those of the lung, and investigations have previously located unique mutations in regions referred to as hotspots that could result from radon exposure, although evidence remains conjectural. A number of TP53 mutations are associated with tobacco smoking-induced lung cancers and similar mutation hotspots have been identified that are not associated with other types of cancer, e.g., codon 157 [57]. These mutation spectra are also different between smokers and non-smokers [58,59]. If it was possible to identify hotspot regions for radon-induced lung cancers in a similar manner, this could help to provide a unique biomarker that contributes to the understanding of the aetiology of the disease and contribute to the elucidation of risk at typical exposure levels. A number of studies have explored this prospect (Table 3).

2.1.2. Investigations of TP53 Mutations in Uranium Miners

Vähäkangas et al. [60] studied 19 lung cancers from New Mexican uranium miners and identified 9 various TP53 mutations, of which none were the G:C to T:A transversions known to be associated with tobacco smoke exposure [61]. Furthermore, a study of 52 large and squamous cell carcinomas of the lung diagnosed in Colorado uranium miners, found that 31% possessed the matching AGG to ATG (Arg→Met) transversions, but at the second base pair region of codon 249 in exon 7. This was also observed in 3 of 5 cancers from non-smoking miners [62], leading the authors to highlight this region as a potential biomarker for radon associated lung cancer which, they suggest, is due to the rarity (0.4%) of this specific mutation occurring insmoking-associated lung cancers, although further studies have not been able to show a similar association. A follow up study on the same cohort of miners investigated adenocarcinomas as opposed to the original squamous cell carcinomas and failed to demonstrate the codon 249 transversion previously observed [63].
The analysis of archived tumors from 50 uranium miners from the German Wismut company archive cohort [64] found no evidence for the codon 249 hotspot in adenocarcinomas, squamous, large cell, small cell or mixed lung carcinomas [65]. A follow-up study providing an additional genetic analysis of the cohort of exposed uranium miners identified only 2% (1 of 50) of the studied tumors displayed the G to T mutation in codon 249 [66]. An additional study analysed a greater proportion of the squamous cell carcinomas from the same Wismut company cohort, exploring the speculation that the radon induced hotspot may only be an indicator of radon associated exposure in squamous cell carcinomas. Of the 29 squamous cell carcinomas studied, two demonstrated the G to T mutation leading the authors to conclude that the hotspot is not a likely marker for radon exposure in squamous cell carcinomas [67].
Popp et al. [68] studied the lung cancers of 16 uranium miners (12 squamous cell carcinomas, 3 adenocarcinomas and 1 small-cell carcinoma) in Germany and 13 non-mining patients who had lung cancer (4 squamous cell carcinomas, 8 adenocarcinomas and 1 large cell carcinoma) and were all from the same geographical region. In line with many of the previous studies, they found no codon 249 G to T transversion in any of investigated patients, with the exception of the only non-smoking uranium miner present in the study. However, they did identify a codon 213/3 polymorphism in 19% of the miners and 8% of the non-miners.
It could therefore be concluded that, to date, no clear radon-induced TP53 hotspot mutation has been identified (other than in the Colorado study [62]) in uranium miner cohorts.

2.1.3. Investigations of TP53 Mutations in Non-Mining Individuals

Lo et al. [72] analysed a total of 17 lung cancers of individuals from Devon and Cornwall, UK, with homes of known radon concentrations grouped into high radon exposure (greater than 200 Bq·m−3), low exposure (less than 20 Bq·m−3) or intermediate exposure. Three lifelong non-smokers were included, of which two were in the intermediate group and one was in the high exposure group. No evidence was found in any of the studied cases for the TP53 mutation hotspot at codon 249 from either the 14 smokers’ or 3 non-smokers’ lung cancers. The authors suggest that this may be due to a much lower radiation level compared to the Taylor et al., [62] study and that this may either represent a dose-response relationship or, along with other authors [73], may be the result of mycotoxins from the Colorado mines. A similar study of individuals from homes of known radon concentration, where at least 20% were greater than 148 Bq·m−3, in Galicia, Spain, analysed 72 lung cancers and found no correlation between variation in radon exposure and either TP53 mutations or p53 expression, although the number of sequenced samples for mutation analysis was small (n = 4) with a relatively low radon concentration of between 11.1 and 51.8 Bq·m−3[71].
A nationwide population-based study in Sweden including 83 non-smoking and 250 smoking-induced lung cancers investigated the association between TP53 mutations and time-weighted average radon concentrations of less than 50 Bq m−3 or greater than 140 Bq·m−3 adjusting for smoking status, age and gender [70]. A final analysis of 243 tumors determined a TP53 mutation rate of 23.9%, whereby a higher percentage of individuals with TP53 mutations were observed in the high residential radon exposure group (42.9%) compared to the lower exposure group (20.9%), particularly among non-smokers. It should be noted, however, that no specific difference in mutation pattern was observed between groups and while information on smoking habits was obtained from questionnaires, the authors drew attention to the uncertainties relating to the measurements and previous estimates of the individuals’ radon exposure.
In further work by Vähäkangas et al. [57], analysis of 126 lung cancers (including adeno, broncho-aleveolar, squamous, small cell and mixed carcinomas) from ex-smoking (n = 9) and non-smoking (n = 117) women, aged between 41 and 84 at the time of diagnosis, demonstrated a higher TP53 mutation frequency in ex-smokers (67%) than in non-smokers (19%), which, as the authors suggest, is due to the persistence of molecular damage even 15 years after smoking cessation. Non-smokers were defined as having neither smoked more than 100 cigarettes nor having used any tobacco products for longer than 6 months during their lifetime. Ex-smokers were defined as having stopped smoking at least 15 years before the study. Radon measurements were performed on the homes that each individual had occupied for at least 1 year during the preceding 30 years [74] and although the authors identified a TP53 mutation difference between lung cancers from smokers and non- or ex-smokers (most visibly a lower mutation frequency in non-smokers compared to smokers), they found no statistically significant relationship with TP53 mutations and radon exposure.
Again, it appears that, similarly to the mining cohorts, no consistent TP53 mutation pattern associated with radon exposure has been identified in non-mining cohorts.

2.2. TP53 Laboratory Investigations

In vitro exposure of cultured A549 cells to alpha particles produced by Pu-238 (with an activity of 2.7 Mbq) ensuring a dose of 0.6 Gy (with a rate of 1 Gy per minute) using a specially constructed 45 mm diameter culture dish with 1.5 μm mylar film bases resulted in a significant increase in the production of p53, and rats that have been exposed in vivo to radon exhibit an increase in the number of G1 phase cells with an accompanying decrease of those in S phase [75], suggesting an augmentation of cell cycle arrest. Normal human bronchial epithelial cells (NHBE), cultured from a single donor, exposed to 4 Gy (approximately equivalent to 1460 WLM in a uranium mine) of high-LET alpha radiation (using a Pu-238 source) demonstrated no G to T transversions at the TP53 hotspot, although there was evidence for G to A transitions at codon 249 and a C to A transversion at codon 250 [69]. The authors note that this is in agreement with the study by Vähäkangas et al. [60] and suggest the high frequency of the G to A transition is indicative of alpha particle exposure, although they underline the limitations of the single donor origin and propose that observations may exhibit different results from other donors.
Cellular exposure has also demonstrated a malignant transformation potential following a single exposure (0.6 Gy) to alpha particles [76]. Telomerase-immortalised human prostate epithelial (HBPE) cells retaining morphology, contact growth inhibition and anchorage dependency [77] were malignantly transformed following helium-4 exposure and insertion into SCID (severe combined immunodeficiency) mice. The resulting tumors were characterised as adenocarcinomas, with mutations and deletions of the TP53 gene including: G to T transversions at codon 314 (Pro→Leu) and 383 (Ala→Ser) and a C to T transition at codon 1090 (Pro→Leu) of exons 4–10 [76]. However, the study did not detect a codon 249 hotspot mutation.
Belinsky et al. [78] identified that exposure of F344 rats to the alpha emitter Pu-239 did not sufficiently suggest that the TP53 mutation underlies the aetiology of the genesis of rat lung tumors with just 7% (2/29) of rat squamous cell carcinomas representing alterations of the TP53 gene, both of which were G to A transitions at codons 280 and 283. In a similar study of tumors from radon progeny exposed F344 rats, direct sequencing revealed 14% (4/29) of the tumors had TP53 mutations or deletions, including two A to G transitions at codons 124 and 134, homologous to human codons 126 and 136, respectively [79]. No codon 249 hotspot was observed. The authors suggest that inactivation of the TP53 gene is rarely involved in radon-induced rat lung carcinogenesis due to the infrequent observation of mutations from this study.
It therefore seems evident that although some radon induced TP53 mutations have been observed in the environmental studies, they have been found on the whole to be infrequent and not associated with a potential codon 249 hotspot mutation.

2.3. Environmental Investigations at the HPRT locus

The X-linked hypoxanthine phosphoribosyl transferase (HPRT) gene encodes a transferase enzyme, found in all cells, which catalyses the conversions of both hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate, thus, affording a key role in the purine salvage pathway [80]. A deficiency of the enzyme can result in Lesch-Nyhan syndrome characterised by the overproduction of uric acid [81]. The HPRT gene has been widely used as an indicator of mutagenesis both in vivo and in vitro for a number of reasons. Firstly, as HPRT is X-linked, its hemizygosity implies that mutation of both alleles is not necessary to convert a wild type to a mutant and secondly, HPRT+/−cells are easily selectable in culture. In addition, the entire gene has been sequenced [82] and both a database and software have been produced for mutational analysis [8385].
Alpha particle-induced HPRT mutations from a number of sources, including radon exposure, have been demonstrated. Furthermore, there is evidence from atomic bomb survivors of a dose dependent increase in HPRT mutations [86] up to more than 40 years after exposure [87]. An eight-fold increase in HPRT mutant frequency has also been observed in cancer patients one week after radiotherapy [88]. It has therefore been proposed that analysis of mutations at the HPRT locus could provide a method to differentiate between genetic damage caused by low or high-LET radiation through the identification of a unique “fingerprint” of damage, or biomarker. As a result, the HPRT gene has been of substantial interest in radiation research. Although the combined analysis of a number of separate HPRT studies reveal mutations that are spread widely across the gene, there is still some evidence that some regions do appear as potential hotspot sites as found by a study investigating 271 different HPRT mutations [89].

2.3.1. Investigations of HPRT Mutations in Uranium Miners

A study of a mining cohort from the Radium Hill uranium mine in South Australia [90] found no evidence to suggest radon concentrations affect HPRT mutation frequencies compared to a control group of workers located above ground, although they did observe significance for glycophorin A mutation rates. This is of particular interest as a separate study of workers from the same mine concluded that lung cancer mortality of the underground workers was markedly increased compared to the control group [91] and that the difference was unlikely to be due to confounding factors such as smoking.

2.3.2. Investigation of HPRT and BCL-2 Mutations in Non Mining Individuals

The possibility of HPRT mutation as a result of domestic radon exposure has been investigated in peripheral T lymphocytes following prior suggestions of an increased risk of acute myeloid leukemia in regions with high radon concentrations [92]. Twenty non-smokers were selected from homes of known radon concentrations in the town of Street, Somerset, UK, where radon concentrations in the selected homes varied by a factor of more than 10. Radon measurements were initially performed for one month before a more detailed follow-up over three months was completed accounting for differences between living room and bedroom concentrations. Regular smokers were excluded from the study on the assumption that they would harbour increased mutation frequencies as a result of tobacco exposure, although three of the included participants did admit to occasional smoking during the previous year. The authors identified a significant association between radon concentrations and HPRT mutant frequency using both the first (p < 0.01) and second (p < 0.05) radon concentration analyses. However, in a follow up study that increased the sample size, blood samples were obtained from 66 of the occupants and analysed for both mutations at the HPRT locus and the leukemia and non-Hodgkin lymphoma associated(apoptotic regulator) B-cell lymphoma 2 (BCL-2) translocation t(14;18) [9395]. On this occasion, they observed no significant correlation between radon concentrations and either HPRT mutation frequencies or BCL-2 chromosome translocations [96]. Another investigation of T lymphocytes [97] collected from 120 individuals with varying exposures to radon and tobacco smoke identified a significant translocation frequency at the BCL-2 locus with a 4.9-fold larger variation in translocation frequency than HPRT mutation frequency leading the authors to suggest that BCL-2 translocations may be a more appropriate indication of cancer risk than HPRT mutations due to the dose-dependent increase of BCL-2 translocations with age [98,99], smoking [100] and because BCL-2 translocations are already directly associated with a number of cancers (e.g., non-Hodgkin lymphoma).
Despite these studies providing evidence both for and against increased HPRT mutant induction after exposure, another study [101] on a separate cohort of 11 individuals with dwellings of known radon concentrations found an inverse relationship between HPRT mutations and exposure level, providing a result in deviation from both the Bridges et al. [92] and the Liu et al. [97] study. In recognition of the small sample size, a follow-up study [102] of 116 different dwellings with concentrations ranging from 50 to 3300 Bq·m−3 was performed (all investigated individuals were from houses with a minimum concentration of 100 Bq·m−3). The same result was obtained, i.e., an inverse relationship between domestic residential radon exposure and HPRT mutation frequency. No association for sister chromatid exchanges (SCEs), chromosome aberrations (CAs) or micronuclei (MN) formation was observed. The authors suggested that exposures to low doses of radon may induce HPRT associated repair mechanisms.
A similar lack of a definitive in vivo observation of HPRT mutation frequencies has also been identified in a study of high school students from Colorado living in homes of known radon concentrations where no correlation between radon exposure and HPRT mutant frequency was observed [103]. A study of flight engineers (n = 28) exposed to cosmic radiation observed a non-statistically significant increase in HPRT mutations, MN formation and CAs [104], with the authors suggesting that the lack of statistical significance of the data may have been due to large individual variations. Although no significant increase was observed, it is interesting to note that the HPRT mutations were higher in those subjects with a shorter flight history, which may support the inverse relationship detected by Albering et al. [101]. An assessment of factory workers’ exposure to ionizing radiation revealed a correlation between exposure and increased HPRT mutant frequency in the lymphocytes of workers who wore dosimeters and were analysed over a 72-week period [105], although no correlation was observed across a shorter time of 36 weeks.
An analysis of Gulf War I veterans exposed to alpha particle emitting depleted uranium has also identified a significant 50% increase in HPRT mutant frequency compared to a low exposure group [106] and a number of other studies have also observed the mutagenic and clastogenic potential of depleted uranium exposure [107,108].
The only rat study that has investigated inhaled radon and Hprt mutations [109] identified significant increases in both MN formation and Hprt mutation frequency in a dose-dependent manner with exposures of 60–120 WLMs across eight hours a day, six days a week. The authors recommended investigating MN and Hprt investigations in future studies of the genetic effects of radon exposure.
In line with the previous inconsistencies of the TP53 environmental and laboratory investigations, it could also be concluded that, to date, no clear radon induced HPRT mutation hotspot has been identified and in some cases an inverse relationship between radon and HPRT mutation frequency has been observed.

2.4. HPRT Laboratory Investigations

In vitro experiments on T lymphoblasts exposed to alpha particles resulted in an increased HPRT mutation frequency along with increased cell death [47]. Alpha particle-induced mutation frequencies were higher when compared to those from X-radiation. Single-hit kinetics best explained the linear nature of the results and using dose, mutation frequency and an approximation of 50,000 genes per cell, they calculated that each alpha particle had the potential to induce approximately 16 mutations per DNA genome.
The exposure of Chinese hamster ovary (CHO) cells to radon and its daughters [110] using a gaseous exposure apparatus [111] of doses between 0.25 and 0.77 Gy identified a linear dose response relationship between dose and induced mutation frequency at the Hprt locus, with an induction frequency of 1 × 10−4 per viable cell per Gy. When the spectra of mutation types were investigated, there was no significant difference between radon-induced and X-radiation-induced mutants, although a difference was observed between radiation-induced and spontaneous mutations that were not exposed to radiation, with the principal spontaneous-induced mutation resembling a small event not detectable by Southern blot or PCR exon analysis. The principal radiation-induced mutations, which occurred in 48% of mutants, were gene deletions.
While some of these studies demonstrate a certain degree of similarity between low-LET (e.g., X- or gamma-radiation) and high-LET (e.g., alpha-radiation) HPRT mutation spectra, suggesting no difference between the two types of exposure, there are further studies that suggest otherwise. Americium-241 exposure of Chinese hamster lung fibroblasts produced a higher fraction of Hprt deletions from alpha particle exposure (80%) than X-radiation exposure (60%) [112]. A similar study on human B lymphoblastoid (TK6) cells [113], which employed a different radon dosing apparatus [114], also identified that the predominant HPRT mutation resembled a gene deletion with irradiation of 0.15–1.07 Gy producing deletions in 86% of mutants compared to 81% of X-radiation-induced (1.5 Gy) mutations.
Although not directly HPRT related, in a follow-up to the Bao et al. [113] study, assessment of thymidine kinase (TK) gene mutations in TK6 cells revealed 82% of radon exposed mutants possessed a complete gene deletion compared to 74% of those exposed to X-radiation [115], providing evidence in general agreement with the previous study. However, they also observed reduced growth rates in radon exposed mutants compared to X-radiation exposed mutants (an observation also identified in another study [116]) suggesting that radon-induced lesions may be more complex or harder to repair.
Despite the previous studies appearing to be in some agreement with regards to the types of induced damage between high and low-LET, it is evident that such a conclusion may be premature. Further analysis of CHO-K1 cells, following up from the study conducted by Hsie et al. [117], failed to detect a difference between Hprt mutation spectra [118] and again in a similar contrast to some previous studies, work in human T lymphocytes [119] demonstrated less than 2% total gene deletions at the HPRT locus after exposure to radon and its daughters, although partial deletions were still present. Furthermore, human T lymphocytes exposed to high-LET radon (using the same methodology as described by Jostes et al. [111]) and low-LET Caesium-137 found that the main marker of low-LET exposed lymphocytes were large deletions of the entire HPRT gene and high-LET exposure predominantly resulted in partial deletions and multiple single base changes [120]. Although not comparing high and low-LET exposures, other work in CHO cells using varying doses of Caesium-137 gamma-radiation has observed dose-dependent changes in mutation spectra [121] and a difference in mutation type between exposures of low (resulting mainly in point mutations) and high-dose (resulting in multibase deletion mutations). This suggests that the risks of exposure to low-dose radiation may not be well represented from extrapolations and interpretations of high-dose exposures.
Analyses of the mutation spectra of cells that are not directly irradiated with alpha particles but still receive damage signals from irradiated cells (i.e., “bystander” cells) have shown HPRT mutant induction [122], which mainly consist of point mutations compared to a high frequency of deletions in directly irradiated cells [123]. A follow-up study in DNA double-strand repair deficient cells [124] identified a larger bystander effect compared to the control cells, suggesting that an inability for effective DNA repair resulted in increased HPRT mutation induction in bystander cells.
Both in vitro and rodent studies have demonstrated both similarity and differences between low and high-LET exposures. However, radon is associated with the latter and in this case some deletions and bystander effects have been observed. The results from studies of HPRT have often been contradictory and data have been highly variable resulting in a long-running difficulty in elucidating effects of radiation at the HPRT locus and in identifying such hotspot regions. Although the in vivo studies of individuals living in homes with known radon concentrations coupled with in vitro investigations do seem to suggest an association between radon exposure and HPRT mutation frequency, it appears logical to conclude that they do not yet seem to have clearly identified a unique region, or hotspot, as a marker of high-LET compared to low-LET exposure. The large variability in reported mutant frequencies and general inconsistencies in reported findings have led some to suggest caution when interpreting the results [103,125] and that HPRT mutations may not represent an effective methodology when evaluating cancer risk.

3. Chromosome Aberrations

Disruptions to normal chromosomal arrangement represent a major contribution to cellular mutagenicity [126131]. Cytogenetic analysis has been used for many decades as a tool to determine mutagenic and carcinogenic risks in both domestic and occupational settings and the detection of chromosomal aberrations (CAs) has been associated with numerous chemicals [132134] and various types of radiation, including both low and high-LET exposures [135138], in addition to data from atomic bomb survivors [139,140], radiotherapy patients [141143] and even underground water-well workers [144]. Attempts have also been made to estimate prior exposure through CA analysis [145,146]. The focus here will be placed on reviewing the effects of radon exposure, along with its surrogates, on CAs (Table 4). The cardinal types of structural aberrations include insertions, deletions, translocations, SCEs, ring formation, duplications and inversions (Figure 2). Such structural abnormalities can contribute a significant mutagenic load resulting in a number of identifiable cellular effects (e.g., mitotic delay [147]). For a more complete classification on aberration structures and formations see Savage et al. [148] and Bender et al. [129].

3.1. Environmental Investigations of Chromosome Aberrations

3.1.1. Investigations of Chromosome Aberrations in Uranium Miners

With the progression of cytogenetic techniques, the feasibility of using CAs as a marker of exposure to environmental stressors and of increased cancer risk has been well established. One particular difficulty when using miner cohorts can be ascribing any observed biological effects to a particular exposure, as mining environments are known to contain a number of toxic agents (e.g., arsenic, lead and silica). Despite this limitation, a number of reports have identified an increase in CA frequencies among miners exposed to high radon concentrations, in addition to studies investigating uranium [159] or plutonium [160] compounds.
The analysis of almost 9000 cytogenetic tests from nearly 4000 subjects appeared to determine a significant association between human peripheral blood lymphocyte CA frequency and cancer incidence in radon exposed miners, with just a 1% increase in CAs resulting in a 64% increase in cancer incidence [161]. A follow-up study [162] of a further 1323 tests and 225 individuals provided additional data and found similar results confirming an association between aberration frequency and cancer incidence with a 1% increase in chromosomal aberrations resulting in an increase in cancer incidence of 62%. Of particular note was that an increased frequency of chromatid breaks in 1% of cells resulted in a 99% increase in cancer risk and the authors emphasised that the increased risk was not just limited to lung carcinogenesis.
Peripheral blood leukocytes obtained from 15 uranium miners with radon exposures ranging from 10 to 5400 WLMs have demonstrated a significant increase in a number of CAs including chromatid gaps and breaks, and the formation of dicentric rings in miners compared to controls [163]. Despite this, no consistency was observed between exposure and aberration frequency. An additional follow-up study [164], which also assessed peripheral blood lymphocytes, investigated five groups of radon exposed miners from <100 to >3000 WLMs (n = 100, including controls). In general, CAs increased with exposure with the exception of the highest studied concentrations (>3000 WLM) where there was a discernible decrease of deletion prevalence, which was independent of any confounding factors. Nevertheless, they do conclude that CAs represent a sensitive marker of radiation exposure.
Significant increases in CA frequency, MN formation and SCEs have been observed in miners exposed to high radon concentrations when compared to two control groups [165,166]. A cohort of German uranium miners [167] also exhibited increased CAs in their lymphocytes, along with increased MN formation in their lung macrophages and an increased prevalence of fibronectin and the cytokine tumor necrosis factor-alpha (TNF-α) in their bronchoalveolar fluid. Furthermore, two studies of radon exposed miners from the Czech Republic also found an increase in chromatid breaks and MN in miners from a number of different mines [168,169], although in one of the groups no significant difference was observed for increased dicentric ring formation between the miners and controls. A group of Namibian miners exposed to radon demonstrated a reduction in testosterone levels and neutrophil count, along with a three-fold increase in CAs [170].
Further investigations of blood samples from 165 active underground uranium miners exposed up to 600 WLMs between 1981 and 1985, along with 141 former miners from 1998 to 2002, were analysed for CAs and compared to a control group of 175 seemingly healthy subjects [171]. The data revealed a 7–12-fold increase in aberrations in the active mining group, particularly for acentric fragments. Interestingly, the values for the former miners were not significantly different from those of the active miners, suggesting aberrations can persist for many years after exposure, with even the largest decrease in observed aberrations in the form of acentric fragments still remaining 2–3 times higher than in the unexposed population.
There are therefore numerous examples of radon exposed miners exhibiting increased CAs and this is of concern because of the supposed association between elevated CA frequency and the risk of carcinogenesis.

3.1.2. Investigations of Chromosome Aberrations in Non Mining Individuals

Despite a clear association between increased CA frequencies in radon exposed miners, the risks of domestic radon exposures at lower doses have also been explored using CA analyses. Reports of increased frequencies in CAs have not just been reported for occupational exposures, such as among nuclear workers [172], but also, as discussed below, in large numbers of individuals exposed to background radiation in Brazilian, Austrian, Chinese, German, Russian and Slovenian populations, although some studies have not identified significant associations.
A continuation of the Costa-Ribeiro et al. [159] study investigated 202 subjects from a Brazilian population environmentally exposed to high background radiation concentrations [173]. An increase of chromosome breaks was identified in blood lymphocytes of subjects who had a local residency of at least eight-years when compared to a control group of 147 individuals from a region of similar socio-economic status but with normal background levels of radiation. A similar study of individuals from an Austrian population exposed to high levels of background radiation from radon [174] found results in agreement with this previous study, including evidence for a dose-response effect above low exposures, although they did observe a decrease in two-event aberrations in a select group of miners exposed to particularly high levels of radon.
A study of individuals living in high background radiation areas (with exposure levels 2.9-times those of the control areas) in Guangdong Province, China found higher levels of dicentric and ring formation aberrations in lymphocytes compared to controls [175]. A matching epidemiological study, however, found mortality from all types of cancer in the high background radiation areas was lower than in the control areas (including leukemia and breast and lung cancers) although the difference was not statistically significant. Dicentric and ring formations were also significantly increased in lymphocytes of 25 individuals, with known radon concentrations 4 to 60-times the German average of 50 Bq·m−3, when compared to controls from an assumed low-level radon area in South Germany [176]. No difference in CA frequency was identified between males and females suggesting the damage did not appear to be gender specific. Nevertheless, despite a clear trend with age, a Finnish study [177] found no correlation between domestic radon concentrations (<100 to >800 Bq·m−3) in 84 non-smokers and CAs.
A study that followed 6430 healthy people from across Central Europe [178], for whom chromosomal aberration surveys had been performed between 1978 and 2002, provided further evidence for an association between high CA frequencies in peripheral blood lymphocytes and an increased cancer risk. The study identified a significant increase in cancer risk assessed by the frequency of CAs, with a relative risk of cancer of 1.78 in the medium and 1.81 in the high frequency groups when compared to the low frequency group (relative risk = 1).
Eighty-five Slovenian pupils aged 9–12 years old attending an elementary school with high radon concentrations up to 7000 Bq·m−3 were identified as having significantly higher levels of CAs and MN compared to a control group of pupils that were the same age but attended a school with concentrations <400 Bq·m−3[179]. Mean CA frequencies in blood lymphocytes of residents, including children and teenagers, from high radon concentration areas in Gornaya Shoria, Russia, were significantly higher than those of controls in both home and school based environments [180182].
In addition, 38 cave tour guides exposed to an estimated annual dose of 40–60 mSv from background radiation from radon were also identified as having higher frequencies of CAs and MN [183] with the principal abnormality representing chromosomal breaks and acentric fragments.
From the environmental studies identified, such an association between increased radon exposure and higher frequencies of CAs appears to be apparent in non-mining as well as mining cohorts.

3.2. Laboratory Chromosome Aberration Investigations

Numerous in vitro studies have also considered radon and CA formation. Human peripheral lymphocytes have demonstrated an increase in CAs after in vitro exposure to 18 cGy of radon and its progeny [150] with 80% of the CAs being chromatid deletions and another 10%–15% chromatic exchanges. Cells were fixed 4, 11, 14 or 17 h after exposure but some dicentric and ring chromosomes were also observed at later harvest times. A linear increase in CAs was observed for cells exposed to increasing doses harvested at the same time. Interestingly, aberrations were approximately one-half lower at each harvest time if cells were pre-exposed to 2 cGy of X-radiation suggesting an adaptive effect.
Data from irradiated haemopoietic cells with environmentally relevant doses of Pu-238 demonstrated a higher frequency of CAs in clonal descendants [151], providing early evidence for transgene rational instability. In a subsequent study investigating chromosome abnormalities of bone marrow cells from four donors [42], CAs were observed in two of the four individuals and the authors highlighted the causal link between chromosome instability and leukemia.
Sister chromatid exchanges have also been observed in murine 10T1/2, 3T3 cells [152] and CHO cells exposed to a low dose of 0.31 mGy of alpha radiation [153]. An increased frequency of SCEs was observed in 30% of the CHO cells although the authors calculate only 1% of the cells were traversed by an alpha particle, suggesting further evidence of a bystander effect. Similar results have been noted in human lung fibroblast cells [31] with radon doses from 0.4 to 12.9 cGy and a dose-dependent increase was observed at low doses. It was noted that the numbers were larger than predicted, based upon predicted numbers of cellular alpha particle traversals, and suggested that alpha particle irradiation was associated with an extranuclear mechanism in inducing SCEs. A follow up study in the same cell type [32] noted an increase of SCEs in cells that were not directly exposed to alpha particles; instead, culture medium from exposed cells was transferred to the unexposed cells. The authors also noted that the extranuclear SCE-inducing factor, or factors, had to survive freeze-thawing and was heat labile, suggesting it may be a protein [184]. A later report identified an increased intracellular production of superoxide anions and hydrogen peroxide after alpha particle exposure even in cells not directly irradiated [48]. The transmission of effects to non-irradiated lung fibroblast cells after exposure to supernatant of irradiated cells was further confirmed by another study [154]. They also identified the transforming growth factor beta 1 (TGF-β1) cytokine as a mediator of the bystander response and, interestingly, a promitogenic effect with augmentation of cell growth. An increase in the production of the TP53 protein and cyclin-dependent kinase inhibitor 1A (CDKN1A) was detected by Western blotting, along with a decrease in cell division control protein 2 (CDC2). Interestingly, modulation of TP53, CDKN1A, CDC2, CCNB1 and RAD51 have also previously been reported after Pu-238 irradiation in non-traversed bystander cells [155].
Following exposure to bismuth-212, which had been chelated to diethlyenetriamine pentaacetic acid (DTPA) to prevent cell entry or attachment ensuring all exposure was external, CHO cells, along with the mutant derivative radiosensitive xrs-5 cell line that is incapable of repairing X-radiation-induced DNA double-strand breaks, displayed an increase in CAs [149].
CAs have also been observed in blood lymphocytes at very low doses (0.03–41.4 mGy) using polonium-214 derived from a gaseous radon dosing apparatus [156]. Aberration frequency rose by more than a factor of 10 between 0.03 and 0.10 mGy before reaching a plateau at exposures of 0.10–5 Gy. At higher doses a linear dose-effect was observed. This again suggests deviation from the linear-dose response relationship at low-dose exposures.
Increases in the frequency of dicentric and acentric fragments, along with centric ring formations and MN have been reported in irradiated blood samples taken from healthy non-smokers using low doses (0–127 mGy) of radon gas delivered in vitro [157]. Another in vitro study investigating the synergistic effect between radon and smoking examined CAs in blood lymphocytes of both smokers and non-smokers [158]. Blood samples were exposed to a wide range of concentrations from 0 to 35,643 kBq·m−3 using a portable irradiation assembly [185] providing doses between 0.9 and 5.2 mGy. Compared to the non-smokers, the smokers’ lymphocytes showed a significant increase in radon-induced dicentric fragments, acentric fragments and chromatid breaks and it was concluded that the study demonstrated lymphocytes of smokers were more unstable to radon exposure.
It is therefore clear that radon and its progeny can produce CAs of a number of different forms in a variety of cell types in vitro in addition to bystander effects. It is important to note however that the evidence of an increased CA frequency and detection of DNA damage in high background radiation regions has not necessarily resulted in an increased cancer incidence in some of the studies, suggesting that the correlation between CA frequency and cancer risk may be complicated by the time dependence of the cytogenetic test output.

3.3. Biomarker Chromosome Aberration Ratio Studies

With a consistent observation between increased radiation exposure and an increase in CAs, similar suggestions have been made with regards to the possibility of identifying a biomarker of previous exposure to radiation using CAs. Although many CAs are fatal to the cell, some are maintained past cell division [186188]. The concept of energy deposition from alpha particles occurring over a smaller area than lower LET radiation has resulted in a number of theoretical concepts to identify past exposure. One such suggestion has been that exposure to high-LET radiation results in a low ratio (F) between intra- (same chromosome), inter-chromosomal (separate chromosomes), and inter-arm exchange-type aberrations [189]. However, the authors state that the F value has not been adequately observed epidemiologically and suggest a theoretically more representational method, termed the H value, with a stronger differential ability, which represents the ratio of inter-CAs, including dicentric or translocations, to intra-arm chromosomal aberrations, including acentric inversions or interstitial deletions [190]. Nevertheless, aberration complexity is still reported as a noteworthy outcome of high-LET radiation [191] and some difficulties still remain in observing differences between intra and inter-chromosomal changes [192].

3.4. Experimental Investigations of Micronuclei

Another potential consequence of CAs is the formation of micronuclei (MN). MN result from genotoxic events and form following mitosis as cytoplasmic fragments of chromosomes that have not been incorporated into daughter nuclei [193,194]. A number of studies investigating MN formation following radon exposure have been conducted. Exposure to ionizing radiation can lead to an increase in MN formation [195] and there is some evidence that MN frequency can be used as a biomarker to help predict cancer risk [196] with significant increases in MN frequency having been observed following radiotherapy [88].
Comparisons of MN frequency in rats identified linear increases in frequency following in vivo exposure to 0, 115, 213 or 323 WLMs of radon gas or in vitro exposure using primary rat lung fibroblasts [197] with cell proliferation appearing to be unaffected as a result of MN induction. The authors calculate that in vivo exposure in rats of 1 WLM resulted in the equivalent level of damage induced by 0.79 mGy in vitro. Elevated levels of MN have also been observed in the alveolar macrophages of rats exposed to 120, 225, 440 or 990 WLMs, with peak frequencies occurring around 13 days after exposure [198].
CHO-K1 cells exposed to 3.2 MeV alpha particles producing 0–5 cellular traversals demonstrated a linear relationship between the number of hits and MN induction [199] although 72% of the cells contained no MN even after five alpha particle traversals, demonstrating a possible variation in cell population sensitivity and, in light of the strong relationship between MN formation and cell death, many cells without MN may survive despite the substantial number of traversals potentially resulting in an increased cancer risk. Similar conclusions have also been drawn from another study using exact alpha particle numbers in human-hamster hybrid cells [200].
Human bronchial epithelial cells have also been exposed to alpha particles from Pu-238 as a radon surrogate [201]. An increase in MN was detected following exposure to six equal fractionated doses (2–4 Gy, 730–1460 WLMs) comparable to exposures received by uranium miners. Deletions on chromosomes 7 and 9 were observed and mapped to regions containing the tumor suppressor genes CDKN2A (which encodes p16Ink4A) and TES that are often inactivated in some lung, prostate and skin tumors [202205]. Increases in MN frequency have also been identified in human A549 lung cells after exposure to Po-210 (acting as a radon surrogate) across a dose range of 0–2000 mGy [206].
Such evidence leads to the conclusion that radon exposure in vitro can consistently result in MN formation, which can be an indication of increased carcinogenic potential.

3.5. Genomic Studies

The data available for genomics studies are limited with reference to direct radon exposure and as a result they will not be elaborated on in detail here. However, a range of effects have been observed following low-LET irradiation including alterations in gene expression [207], microRNA modulation following chronic and acute exposures [208], differential gene expression between irradiation and bystander cells [209], transcriptional modification of mitochondrial genes [210] and a suggestion that relative levels in the expression of mRNA in blood lymphocytes may provide a biomarker of exposure [211], highlighting the importance of genomic investigations when studying the biological outcomes of radiation exposure.

4. Implications at Low Doses

4.1. Investigations of the Linear, No-Threshold Dose-Response Hypothesis

The current risk model as recommended by the National Research Council (NRC) in its Biological Effects of Ionizing Radiation Report VII (BEIR VII) [11] is to estimate risk at low exposures on the basis of a linear, no-threshold (LNT) dose-response relationship, whereby potential risk at low doses is calculated by extrapolation from medium and higher doses. The LNT model plays a central role in estimating risk as a result of radiation exposure and is routinely used by various protection agencies [212]. Even so, there is some evidence for a deviation from the LNT model at low doses and a number of alternative hypotheses have been suggested, including threshold, hormetic and supralinear (hypersensitive) biological responses (Figure 3).
There have been suggestions for both a potentially greater or lesser risk than what would currently be predicted based upon the LNT model. It may be possible that at lower doses a number of beneficial cellular mechanisms are induced yielding a protective or hormetic influence [213]. Similarly, hypersensitive responses could result in increased biological damage increasing the risk at low doses [214216].
Extrapolating risk linearly from medium and high doses implies an effect that is stochastic in its origin, whereby even at the smallest doses an effect would be observed and to decrease the dose would result in a reduction in the number of cells exposed without altering the condition of the insult. The foundations for this mechanism are constructed on the evidence that neoplasms can be of monoclonal origin as well as the observation that a single alpha particle traversal can induce significant cellular damage that can be both permanent and evident in further generations. This is opposed to an effect that would be deterministic in its basis, implying a multicellular foundation whereby a threshold dose may need to be achieved in order to initiate a response and below such a threshold no effect would be observed [217].

4.2. Investigations of Bystander Effects

Historically, it has been a widely held belief that any effect resulting from exposure to ionizing radiation is the consequence of nuclear DNA exposure, either by direct irradiation or through radiolysis [218]. However in recent years, some evidence has accumulated suggesting that a number of biological effects relevant to carcinogenesis, which have been credited to nuclear irradiation, can also be produced after cytoplasmic exposure [219,220]. Furthermore, there are now some studies that have reported the induction of biological effects in cells that have not been directly irradiated and where no direct traversal of a charged particle has occurred [221,222]. These effects are referred to as bystander effects and, although their exact mechanisms are yet to be elucidated, there is evidence across a number of studies, with disparate methodologies, for cellular signalling [155,223226]. Moreover, many bystander effects have been reported at low doses and a response that augments the effects of exposure across large numbers of cells could be a major contributor to the effects observed at low doses. If such bystander effects were also found to occur in vivo then the exactitude of the LNT dose-response hypothesis at low doses may have to be called into question.
Some of the identified outcomes that have been attributed to the bystander effect include CAs, including MN formation and SCEs; apoptotic progression and inhibition; modification of gene and protein expression; neoplastic transformation; mutagenesis; cytokine and growth factor production; and generation of γ-H2AX species, indicative of double strand DNA breaks [219,221,222,227229].
Interest in the bystander effect first occurred after initial investigations by Nagasawa & Little [153] identified SCE induction in CHO cells at alpha particle doses from plutonium-238 as low as 0.31 mGy. While only 1% of cell nuclei were identified as having been traversed, 30% of cells displayed an increased frequency of SCEs. The authors noted that the dose range used is within that expected from domestic radon exposure. Other reports of irradiation of just 10% of a cell population have identified mutant yields similar to when the entire population is irradiated [215].
Since the initial investigations, a number of studies have continued to report bystander effects in cells. Typically, these experiments either use microbeams, emitting single particles, or cell media are transferred from irradiated to nonirradiated cells. There is some debate with regards to the exact mechanisms these two techniques are investigating and a number of extensive reviews explore these [214,230233].
In contrast to some of the studies that have observed deleterious outcomes as a result of the bystander effect, protective and/or adaptive responses have also been observed in bystander cells including reduced radio-sensitivity [234,235] and increases in the elimination of abnormal cells reducing neoplastic potential [236], which could provide adaptation against future exposures and carcinogenic development in mutated cells [219]. The current mechanistic understanding of the potential for bystander effects to have both deleterious and beneficial effects following irradiation is evidently complex and further research into this area is vital.

4.3. Investigations of Adaptive Responses

Not to be confused with hormesis, a potentially beneficial adaptive response has been observed whereby the effects of larger doses of irradiation are minimised when preceded by a previous non-lethal dose [237,238]. The effect has been described in a variety of cell types and it has been suggested to account for the lack of expected cancer incidences in high background radiation areas.
An example of one study suggesting an adaptive response is from Ramsar, Iran, where many people receive very high doses of background radiation from radon of up to 260 mSv·y−1 and many individuals have lived in these conditions for generations [239]. A reduced CA frequency following in vitro exposure of lymphocytes from individuals living in the Ramsar area to 1.5 Gy of gamma radiation was observed when compared to lymphocytes from people in normal radiation exposure background areas, suggesting a possible adaptive response in these individuals. It is evident that such a response appears to contrast directly with many of the previously discussed miner and laboratory based studies, for which there are a much greater number, where CA frequency increases after exposure and the reasons for this remain unclear.
It is clear that the bystander effect and any potential deviations from the LNT dose-response hypothesis propose implications for risk estimates at low doses, whereby the primary factor affecting cellular response may not be principally defined by dose [240]. However, difficulty in identifying whether cancer risk is increased or decreased at low doses has lead to the decision of the BEIR VII Committee to maintain the LNT model. The report states that it is unclear if the influence of the bystander effect would result in an overall positive or negative health effect and they conclude that the linear, no-threshold dose-response relationship remains generally in line with the evidence available at this time [11]. It may, therefore, still represent the most accurate method to assume the level of risk currently available [217].

5. Discussion

There is substantial evidence that exposure to radon and its progeny is the second leading cause of lung cancer behind smoking [45] and concerns have been raised regarding its potential to induce other neoplasms including leukemia [41,241,242] and non-melanoma skin cancer [21,40,243].
Ionizing radiation from radon and its daughter products can induce a variety of cytotoxic and genotoxic effects that are known to be mutagenic and increase carcinogenic potential. Such effects can include genetic mutations, generation of reactive oxygen species, modification of cell cycle regulation (e.g., mitotic delay and inhibition of apoptosis), cytokine up and/or down regulation, CAs and MN formation and generation of γ-H2AX species (indicative of double-strand DNA breaks) [244,245]. These effects can vary depending upon a number of different factors including but not limited to dose, frequency of dose, cell type, cellular conditions (such as cell-cycle stage during exposure) and intra and inter signaling between neighbouring cells [10,246248].
Identification of a specific genetic response to radon exposure would provide significant assistance to the elucidation of radon-induced carcinogenesis and could act as both a useful biodosimeter and an identifier of risk at typical exposures. Despite promising early investigations [72], it now appears evident that such a mutation hotspot is not located at the codon 249 region of the TP53 gene. Other regions, such as at the HPRT locus, also demonstrate large variability in the current literature. This may best be explained as a result of the lack of knowledge with regards to exposures at low doses whereby expected outcomes appear to deviate from the LNT hypothesis recommended by the BEIR VII Committee. Many of the biomarker studies also appear to suffer from relatively small sample sizes, which may potentially explain why some of the results are inconsistent. Despite the current lack of experimental agreement for identifying a hotspot biomarker, the possibility of identifying such a unique marker should not be ruled out. More investigations into a consistent genetic modification as a result of radon exposure are therefore required. Nevertheless, it is clear that if potential molecular biomarkers can be identified despite variation at low doses, they should be used with caution when attempting to estimate exposure or risk.
CAs (including insertions, deletions, translocations, SCEs, ring formation, duplications, inversions and formation of MN) are thought to significantly increase the risk of neoplastic progression and to intensify carcinogenic capacity. Such cytogenetic markers of biological damage have been consistently observed both in vitro and in vivo in a large number of studies following exposure either to radon and its progeny or a surrogate alpha particle emitter used in its place for comparison.
Regardless of stochastic or deterministic foundations, it appears that the current evidence is too varied to conclude with certainty whether or not the LNT model holds true at low doses and this is particularly pertinent in light of implications proposed by intercellular communication such as those attributable to bystander effects. However, the possibility of underestimating the carcinogenic risk of radon exposure is likely to be increased when considering the additional influence of a “bystander” effect generated by inter and/or intra-cellular signaling mechanisms, the details of which remain largely unidentified. It is evident however that cytogenetic effects can be observed in non-irradiated cells and further research efforts are required to elucidate the details of these mechanisms of damage [249].

6. Conclusions

Exposure to radon and its progeny can induce a range of cellular and molecular cytogenetic effects both in vitro and in vivo. Data from animal, laboratory and miner studies, as well as residents of the domestic home and school environments, have all demonstrated the potential of radon exposure to induce biological damage. When taken together, these data suggest that exposure to radon and its progeny (when concentrations are elevated at medium and high doses, such as those that exceed the recommended action levels) can represent a significant public health risk. Future work, particularly in the low and ultra-low dose range where data for cellular responses are varied, is also vital to elucidate the full risk from the ionizing radiation experienced by the general population through natural environmental radon exposure.


The European Centre for Environment and Human Health (part of the University of Exeter Medical School) is part financed by the European Regional Development Fund Programme 2007 to 2013 and European Social Fund Convergence Programme for Cornwall and the Isles of Scilly. We would also like to thank three anonymous reviewers for their helpful comments.

Conflict of Interest

The authors declare no conflicts of interest.


  1. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), Report of the United Nations Scientific Committee on the Effects of Atomic Radiation to the General Assembly; United Nations: New York, NY, USA, 2000.
  2. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), Biological Mechanisms of Radiation Actions at Low Doses. A white paper to guide the Scientific Committee’s future programme of work; United Nations: New York, NY, USA, 2012.
  3. Sachs, H.; Hernandez, T.; Ring, J. Regional geology and radon variability in buildings. Environ. Int 1982, 8, 97–103. [Google Scholar]
  4. Lubin, J. Lung cancer risk from residential radon: Meta-analysis of eight epidemiologic studies. J. Natl. Cancer 1997, 89, 49–57. [Google Scholar]
  5. Pavia, M.; Bianco, A.; Pileggi, C.; Angelillo, I.F. Meta-analysis of residential exposure to radon gas and lung cancer. Bull. World Health Organ 2003, 81, 732–738. [Google Scholar]
  6. Sethi, T.; El-Ghamry, M.; Kloecker, G. Radon and lung cancer. Clin. Adv. Hematol. Oncol 2012, 10, 157–164. [Google Scholar]
  7. Darby, S.; Hill, D.; Auvinen, A.; Barros-Dios, J.M.; Baysson, H.; Bochicchio, F.; Deo, H.; Falk, R.; Forastiere, F.; Hakama, M.; et al. Radon in homes and risk of lung cancer: Collaborative analysis of individual data from 13 European case-control studies. Br. Med. J. 2005, 330. [Google Scholar] [CrossRef]
  8. Committee on Health Risks of Exposure to Radon, National Reseaerch Council, Health Effects of Exposure to Radon; The National Academies Press: Washington, DC, USA, 1999.
  9. Krewski, D.; Lubin, J.H.; Zielinski, J.M.; Alavanja, M.; Catalan, V.S.; Field, R.W.; Klotz, J.B.; Letourneau, E.G.; Lynch, C.F.; Lyon, J.I. Residential radon and risk of lung cancer: A combined analysis of 7 North American case-control studies. Epidemiology 2005, 16, 137. [Google Scholar]
  10. Al-Zoughool, M.; Krewski, D. Health effects of radon: A review of the literature. Int. J. Radiat. Biol 2009, 85, 57–69. [Google Scholar]
  11. Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, National Research Council, Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2; The National Academies Press: Washington, DC, USA, 2006.
  12. Morawska, L.; Phillips, C. Attachment of radon progeny to cigarette smoke aerosol. Aerosol Sci. Technol 1992, 17, 149–158. [Google Scholar]
  13. Biermann, A.H.; Sawyer, S.R. Attachment of radon progeny to cigarette-smoke aerosols. Lawrence Livermore Natl. Lab. 1995. [Google Scholar] [CrossRef]
  14. McLaughlin, J.; O’Byrne, F. The role of daughter product plateout in passive radon detection. Radiat. Prot. Dosim 1984, 7, 115–119. [Google Scholar]
  15. Porstendörfer, J. Behaviour of radon daughter products in indoor air. Radiat. Prot. Dosim 1984, 7, 107–113. [Google Scholar]
  16. Neman, R.; Hadler, N.J.C.; Iunes, P.J.; Paulo, S.R. On indoor radon daughters’ plate-out on material surfaces. Radiat. Meas 2005, 39, 653–655. [Google Scholar]
  17. Richardson, R.; Eatough, J.; Henshaw, D. Dose to red bone marrow from natural radon and thoron exposure. Br. J. Radiol 1991, 64, 608–624. [Google Scholar]
  18. Steinhausler, F.; Hofmann, W.; Lettner, H. Thoron exposure of man: A negligible issue? Radiat. Prot. Dosim 1994, 56, 127–131. [Google Scholar]
  19. Tokonami, S. Why is Rn-220 (thoron) measurement important? Radiat. Prot. Dosim 2010, 141, 335–339. [Google Scholar]
  20. Akiba, S.; Tokonami, S.; Bochicchio, F.; McLaughlin, J.; Tommasino, L.; Harley, N. Thoron: Its metrology, health effects and implications for radon epidemiology: A summary of roundtable discussions. Radiat. Prot. Dosim 2010, 141, 477–481. [Google Scholar]
  21. Eatough, J.; Henshaw, D. Radon and thoron associated dose to the basal layer of the skin. Phys. Med. Biol 1992, 37, 955–967. [Google Scholar]
  22. Reeves, D.; Stuck, R. Clinical and experimental results with thorotrast. Medicine 1938, 17, 37–74. [Google Scholar]
  23. Looney, W. An investigation of the late clinical findings following thorotrast (thorium dioxide) administration. J. Occup. Environ. Med 1960, 83, 163–185. [Google Scholar]
  24. Ishikawa, Y.; Mori, T.; Kato, Y.; Tsuchiya, E.; Machinami, R.; Sugano, H.; Kitagawa, T. Lung cancers associated with thorotrast exposure: High incidence of small-cell carcinoma and implications for estimation of radon risk. Int. J. Cancer 1992, 52, 570–574. [Google Scholar]
  25. Spiethoff, A.; Wesch, H.; Wegener, K.; Klimisch, H. The effects of Thorotrast and quartz on the induction of lung tumors in rats. Health Phys 1992, 63, 101–110. [Google Scholar]
  26. Hofmann, W.; Hornik, S. Lung dosimetry for thorotrast patients: Implications for inhalation of radon progeny. Radiat. Res 1999, 152, S93–S96. [Google Scholar]
  27. Dos Santos Silva, I.; Malveiro, F.; Jones, M.; Swerdlow, A. Mortality after radiological investigation with radioactive Thorotrast: A follow-up study of up to fifty years in Portugal. Radiat. Res 2003, 159, 521–534. [Google Scholar]
  28. Wang, L.; Liu, D.; Shimizu, T.; Fukumoto, M. Mechanisms of liver carcinogenesis by chronic exposure to alpha-particles form internally deposited Thorotrast. Int. Congr. Ser 2005, 1276, 192–194. [Google Scholar]
  29. Kendall, G.M.; Smith, T.J. Doses to organs and tissues from radon and its decay products. J. Radiol. Prot 2002, 22, 389. [Google Scholar]
  30. Axelson, O. Cancer risks from exposure to radon in homes. Environ. Health Perspect 1995, 103, 37–43. [Google Scholar]
  31. Deshpande, A.; Goodwin, E.; Bailey, S.; Marrone, B.; Lehnert, B. Alpha-particle-induced sister chromatid exchange in normal human lung fibroblasts: Evidence for an extranuclear target. Radiat. Res 1996, 145, 260–267. [Google Scholar]
  32. Lehnert, B.; Goodwin, E. Extracellular factor(s) following exposure to α particles can cause sister chromatid exchanges in normal human cells. Cancer Res 1997, 57, 2164–2171. [Google Scholar]
  33. Madas, B.G.; Balásházy, I. Mutation induction by inhaled radon progeny modeled at the tissue level. Radiat. Environ. Biophys 2011, 50, 553–570. [Google Scholar]
  34. Balásházy, I.; Farkas, A.; Madas, B.G.; Hofmann, W. Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies. J. Radiol. Prot 2009, 29, 147–162. [Google Scholar]
  35. Farkas, A.; Hofmann, W.; Balásházy, I.; Szoke, I.; Madas, B.G.; Moustafa, M. Effect of site-specific bronchial radon progeny deposition on the spatial and temporal distributions of cellular responses. Radiat. Environ. Biophys 2011, 50, 281–297. [Google Scholar]
  36. Konishi, E.; Yoshizawa, Y. Estimation of depth of basal cell layer of skin for radiation protection. Radiat. Prot. Dosim 1985, 11, 29–33. [Google Scholar]
  37. Eatough, J.P. Alpha-particle dosimetry for the basal layer of the skin and the radon progeny 218-Po and 214-Po. Phys. Med. Biol 1997, 42, 1899–1911. [Google Scholar]
  38. Charles, M. Radon exposure of the skin: I. Biological effects. J. Radiol. Prot 2007, 27, 231–252. [Google Scholar]
  39. Etherington, D.; Pheby, D.; Bray, F. An ecological study of cancer incidence and radon levels in South West England. Eur. J. Cancer 1996, 32A, 1189–1197. [Google Scholar]
  40. Wheeler, B.; Allen, J.; Depledge, M.; Curnow, A. Radon and skin cancer in Southwest England: An ecologic study. Epidemiology 2012, 23, 44–52. [Google Scholar]
  41. Henshaw, D.; Eatough, J.; Richardson, R. Radon as a causative factor in induction of myeloid leukaemia and other cancers. Lancet 1990, 335, 1008–1012. [Google Scholar]
  42. Kadhim, M.A.; Lorimore, S.A.; Goodhead, D.T.; Wright, E.G.; Hepburn, M.D.; Buckle, V.J. Alpha-particle-induced chromosomal instability in human bone marrow cells. Lancet 1994, 344, 987–988. [Google Scholar]
  43. Wilkinson, G. Gastric cancer in New Mexico counties with significant deposits of uranium. Arch. Environ. Health 1985, 40, 307–312. [Google Scholar]
  44. Kjellberg, S.; Wiseman, J. The relationship of radon to gastrointestinal malignancies. Am. Surg 1995, 61, 822–825. [Google Scholar]
  45. Darby, S.C.; Whitley, E.; Howe, G.R.; Hutchings, S.J.; Kusiak, R.A.; Lubin, J.H.; Morrison, H.I.; Tirmarche, M.; Tomasek, L.; Radford, E.; et al. Radon and cancers other than lung-cancer in underground miners: A collaborative analysis of 11 studies. J. Natl. Cancer Inst 1995, 87, 378–384. [Google Scholar]
  46. Auvinen, A.; Salonen, L.; Pekkanen, J.; Pukkala, E.; Ilus, T.; Kurttio, P. Radon and other natural radionuclides in drinking water and risk of stomach cancer: A case-cohort study in Finland. Int. J. Cancer 2005, 114, 109–113. [Google Scholar]
  47. Chen, D.J.; Strniste, G.F.; Tokita, N. The genotoxicity of alpha particles in human embryonic skin fibroblasts. Radiat. Res 1984, 100, 321–327. [Google Scholar]
  48. Narayanan, P.K.; Goodwin, E.H.; Lehnert, B.E. Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. Cancer Res 1997, 57, 3963–3971. [Google Scholar]
  49. Fleischer, R.; Meyer, N.; Hadley, S.; MacDonald, J.; Cavallo, A. Personal radon dosimetry from eyeglass lenses. Radiat. Prot. Dosim 2001, 97, 251–258. [Google Scholar]
  50. Bigu, J.; Raz, R. Passive radon/thoron personal dosimeter using an electrostatic collector and a diffused-junction detector. Rev. Sci. Instrum 1985, 56, 146. [Google Scholar]
  51. Eatough, J.; Worley, A.; Moss, G. Personal monitoring of 218Po and 214Po radionuclide deposition onto individuals under normal environmental exposure conditions. Phys. Med. Biol 1999, 44, 2227–2239. [Google Scholar]
  52. Erickson, B. The therapeutic use of radon: A biomedical treatment in Europe; an “alternative” remedy in the United States. Dose-Response 2007, 5, 48–62. [Google Scholar]
  53. Steinhäusler, F. Radon spas: Source term, doses and risk assessment. Radiat. Prot. Dosim 1988, 24, 257–259. [Google Scholar]
  54. Franke, A.; Reiner, L.; Pratzel, H.; Franke, T.; Resch, K. Long-term efficacy of radon spa therapy in rheumatoid arthritis-a randomized, sham-controlled study and follow-up. Rheumatology 2000, 39, 894–902. [Google Scholar]
  55. U.S. Environmental Protection Agency Office of Radiation and Indoor Air, EPA assessment of risks from radon in homes; United States Environmental Protection Agency: Washington, DC, USA, 2003.
  56. Wazer, D.E.; Chu, Q.; Liu, X.L.; Gao, Q.; Safaii, H.; Band, V. Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. Mol. Cell. Biol 1994, 14, 2468–2478. [Google Scholar]
  57. Vähäkangas, K.H.; Bennett, W.P.; Castrén, K.; Welsh, J.A.; Khan, M.A.; Blömeke, B.; Alavanja, M.C.; Harris, C.C. p53 and K-ras mutations in lung cancers from former and never-smoking women. Cancer Res. 2001, 61, 4350–4356. [Google Scholar]
  58. Hainaut, P.; Pfeifer, G.P. Patterns of p53 G→T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis 2001, 22, 367–374. [Google Scholar]
  59. Toh, C.; Lim, W. Lung cancer in never-smokers. J. Clin. Pathol 2007, 60, 337–340. [Google Scholar]
  60. Vähäkangas, K.H.; Samet, J.M.; Metcalf, R.A.; Welsh, J.A.; Bennett, W.P.; Lane, D.P.; Harris, C.C. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet 1992, 339, 576–580. [Google Scholar]
  61. Hollstein, M.; Sidransky, D.; Vogelstein, B.; Harris, C.C. p53 mutations in human cancers. Science 1991, 253, 49–53. [Google Scholar]
  62. Taylor, J.; Watson, M.; Michels, R.; Saccomanno, G.; Anderson, M. p53 mutation hotspot in radon-associated lung cancer. Lancet 1994, 343, 86–87. [Google Scholar]
  63. McDonald, J.W.; Taylor, J.A.; Watson, M.A.; Saccomanno, G.; Devereux, T.R. p53 and K-ras in radon-associated lung adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 1995, 4, 791–793. [Google Scholar]
  64. Wesch, H.; Wiethege, T.; Spiethoff, A.; Wegener, K.; Müller, K.M.; Mehlhorn, J. German uranium miner study: Historical background and available histopathological material. Radiat. Res 1999, 152, S48–S51. [Google Scholar]
  65. Hollstein, M.; Bartsch, H.; Wesch, H.; Kure, E.; Mustonen, R.; Muhlbauer, K.; Spiethoff, A.; Wegener, K.; Wiethege, T.; Muller, K. p53 gene mutation analysis in tumors of patients exposed to alpha-particles. Carcinogenesis 1997, 18, 511–516. [Google Scholar]
  66. Wiethege, T.; Wesch, H.; Wegener, K.; Muller, K.; Mehlhorn, J.; Spiethoff, A.; Schomig, D.; Hollstein, M.; Bartsch, H. German uranium miner study: Pathological and molecular genetic findings. J. Radiat. Res 1999, 152, S52–S55. [Google Scholar]
  67. Yang, Q.; Wesch, H.; Mueller, K.M.; Bartsch, H.; Wegener, K.; Hollstein, M. Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation. Br. J. Cancer 2000, 82, 763–766. [Google Scholar]
  68. Popp, W.; Vahrenholz, C.; Schuster, H.; Wiesner, B.; Bauer, P.; Täuscher, F.; Plogmann, H.; Morgenroth, K.; Konietzko, N.; Norpoth, K. P53 mutations and codon 213 polymorphism of p53 in lung cancers of former uranium miners. J. Cancer Res. Clin. Oncol 1999, 125, 309–312. [Google Scholar]
  69. Hussain, S.P.; Kennedy, C.H.; Amstad, P.; Lui, H.; Lechner, J.F.; Harris, C.C. Radon and lung carcinogenesis: Mutability of p53 codons 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells. Carcinogenesis 1997, 18, 121–125. [Google Scholar]
  70. Yngveson, A.; Williams, C.; Hjerpe, A.; Söderkvist, P.; Pershagen, G. p53 mutations in lung cancer associated with residential radon exposure. Cancer Epidemiol 1999, 8, 433–438. [Google Scholar]
  71. Ruano-Ravina, A.; Pérez-Becerra, R.; Fraga, M.; Kelsey, K.; Barros-Dios, J. Analysis of the relationship between p53 immunohistochemical expression and risk factors for lung cancer, with special emphasis on residential radon exposure. Ann. Oncol 2008, 19, 109–114. [Google Scholar]
  72. Lo, Y.; Darby, S.; Noakes, L.; Whitley, E.; Silcocks, P.; Fleming, K.; Bell, J. Screening for codon 249 p53 mutation in lung cancer associated with domestic radon exposure. Lancet 1995, 345, 60. [Google Scholar]
  73. Venitt, S.; Biggs, P.J. Radon, mycotoxins, p53, and uranium mining. Lancet 1994, 343, 795. [Google Scholar]
  74. Alavanja, M.; Brownson, R.; Lubin, J.; Berger, E.; Chang, J.; Boice, J.D. Residential radon exposure and lung cancer among nonsmoking women. J. Natl. Cancer Inst 1994, 86, 1829–1837. [Google Scholar]
  75. Johnson, N.; Carpenter, T.; Jaramillo, R.; Liberati, T. DNA damage-inducible genes as biomarkers for exposures to environmental agents. Environ. Health Perspect 1997, 105, 913–918. [Google Scholar]
  76. Li, H.; Gu, Y.; Miki, J.; Hukku, B.; McLeod, D.G.; Hei, T.K.; Rhim, J.S. Malignant transformation of human benign prostate epithelial cells by high linear energy transfer alpha-particles. Int. J. Oncol 2007, 31, 537–544. [Google Scholar]
  77. Gu, Y.; Li, H.; Miki, J.; Kim, K.-H.; Furusato, B.; Sesterhenn, I.A.; Chu, W.-S.; McLeod, D.G.; Srivastava, S.; Ewing, C.M.; et al. Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines. Exp. Cell Res 2006, 312, 831–843. [Google Scholar]
  78. Belinsky, S.A.; Swafford, D.S.; Finch, G.L.; Mitchell, C.E.; Kelly, G.; Hahn, F.F.; Anderson, M.W.; Nikula, K.J. Alterations in the K-ras and p53 genes in rat lung tumors. Environ. Health Perspect 1997, 105, 901–906. [Google Scholar]
  79. Bastide, K.; Guilly, M.-N.; Bernaudin, J.-F.; Joubert, C.; Lectard, B.; Levalois, C.; Malfoy, B.; Chevillard, S. Molecular analysis of the Ink4a/Rb1-Arf/Tp53 pathways in radon-induced rat lung tumors. Lung Cancer 2009, 63, 348–353. [Google Scholar]
  80. Stout, J.T.; Caskey, C.T. HPRT: Gene structure, expression, and mutation. Ann. Rev. Genet 1985, 19, 127–148. [Google Scholar]
  81. Lesch, M.; Nyhan, W.L. A familial disorder of uric acid metabolism and central nervous system function. Am. J. Med 1964, 36, 561–570. [Google Scholar]
  82. Edwards, A.; Voss, H.; Rice, P.; Civitello, A.; Stegemann, J.; Schwager, C.; Zimmermann, J.; Erfle, H.; Caskey, C.; Ansorge, W. Automated DNA sequencing of the human HPRT locus. Genomics 1990, 6, 593–608. [Google Scholar]
  83. Cariello, N.F.; Craft, T.R.; Vrieling, H.; van Zeeland, A.A.; Adams, T.; Skopek, T.R. Human HPRT mutant database: Software for data entry and retrieval. Environ. Mol. Mutagenes 1992, 20, 81–83. [Google Scholar]
  84. Cariello, N. Database and software for the analysis of mutations at the human hprt gene. Nucleic Acids Res 1994, 22, 3547–3548. [Google Scholar]
  85. Cariello, N.; Douglas, G.; Gorelick, N.; Hart, D.; Wilson, J.; Soussi, T. Databases and software for the analysis of mutations in the human p53 gene, human hprt gene and both the lacI and lacZ gene in transgenic rodents. Nucleic Acids Res 1998, 26, 198–199. [Google Scholar]
  86. Hakoda, M.; Hirai, Y.; Kyoizumi, S.; Akiyama, M. Molecular analyses of in vivo hprt mutant T cells from atomic bomb survivors. Environ. Mol. Mutagenes 1989, 13, 25–33. [Google Scholar]
  87. Hakoda, M.; Akiyama, M.; Kyoizumi, S.; Awa, A.; Yamakido, M.; Otake, M. Increased somatic cell mutant frequency in atomic bomb survivors. Mutat. Res 1988, 201, 39–48. [Google Scholar]
  88. Zwingmann, I.; Welle, I.; Engelen, J.; Schilderman, P.; de Jong, J.; Kleinjans, J. Analysis of oxidative DNA damage and HPRT mutant frequencies in cancer patients before and after radiotherapy. Mutat. Res 1999, 431, 361–369. [Google Scholar]
  89. Jinnah, H.; de Gregorio, L.; Harris, J.; Nyhan, W.; O’Neill, J. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat. Res 2000, 463, 309–326. [Google Scholar]
  90. Shanahan, E.M.; Peterson, D.; Roxby, D.; Quintana, J.; Morely, A.A.; Woodward, A. Mutation rates at the glycophorin A and HPRT loci in uranium miners exposed to radon progeny. Occup. Environ. Med 1996, 53, 439–444. [Google Scholar]
  91. Woodward, A.; Roder, D.; McMichael, A.J.; Crouch, P.; Mylvaganam, A. Radon daughter exposures at the Radium Hill uranium mine and lung cancer rates among former workers, 1952–87. Cancer Causes Control 1991, 2, 213–220. [Google Scholar]
  92. Bridges, B.; Cole, J.; Arlett, C.; Green, M.; Waugh, A.; Beare, D.; Henshaw, D.; Last, R. Possible association between mutant frequency in peripheral lymphocytes and domestic radon concentrations. Lancet 1991, 337, 1187–1189. [Google Scholar]
  93. Yunis, J.J.; Oken, M.M.; Kaplan, M.E.; Ensrud, K.M.; Howe, R.R.; Theologides, A. Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin’s lymphoma. N. Engl. J. Med 1982, 307, 1231–1236. [Google Scholar]
  94. Gribben, J.; Freedman, A.; Woo, S.; Blake, K.; Shu, R.; Freeman, G.; Longtine, J.; Pinkus, G.; Nadler, L. All advanced stage non-Hodgkin’s lymphomas with a polymerase chain reaction amplifiable breakpoint of bcl-2 have residual cells containing the bcl-2 rearrangement. Blood 1991, 78, 3275–3280. [Google Scholar]
  95. Cory, S.; Huang, D.; Adams, J. The Bcl-2 family: Roles in cell survival and oncogenesis. Oncogene 2003, 22, 8590–8607. [Google Scholar]
  96. Cole, J.; Green, M.; Bridges, B.; Waugh, A.; Beare, D.; Henshaw, D.; Last, R.; Liu, Y.; Cortopassi, G. Lack of evidence for an association between the frequency of mutants or translocations in circulating lymphocytes and exposure to radon gas in the home. Radiat. Res 1996, 145, 61–69. [Google Scholar]
  97. Liu, Y.; Cortopassi, G.; Steingrimsdottir, H.; Waugh, A.P.; Beare, D.M.; Green, M.H.; Robinson, D.R.; Cole, J. Correlated mutagenesis of bcl2 and hprt loci in blood lymphocytes. Environ. Mol. Mutagenes 1997, 29, 36–45. [Google Scholar]
  98. Liu, Y.; Hernandez, A.; Shibata, D.; Cortopassi, G. BCL2 translocation frequency rises with age in humans. Proc. Natl. Acad. Sci. USA 1994, 91, 8910–8914. [Google Scholar]
  99. Curry, J.; Karnaoukhova, L.; Guenette, G.; Glickman, B. Influence of sex, smoking and age on human hprt mutation frequencies and spectra. Genetics 1999, 152, 1065–1077. [Google Scholar]
  100. Bell, D.; Liu, Y.; Cortopassi, G. Occurrence of bcl-2 oncogene translocation with increased frequency in the peripheral blood of heavy smokers. J. Natl. Cancer Inst 1995, 87, 223–224. [Google Scholar]
  101. Albering, H.J.; Hageman, G.J.; Kleinjans, J.C.; Engelen, J.J.; Koulishcer, L.; Herens, C. Indoor radon exposure and cytogenetic damage. Lancet 1992, 340, 739. [Google Scholar]
  102. Albering, H.; Engelen, J.; Koulischer, L.; Welle, I.; Kleinjans, J. Indoor radon, an extrapulmonary genetic risk? Lancet 1994, 344, 750–751. [Google Scholar]
  103. Ruttenber, A.; Harrison, L.; Baron, A.; McClure, D.; Glanz, J.; Quillin, R.; O’Neill, J.; Sullivan, L.; Campbell, J.; Nicklas, J. hprt mutant frequencies, nonpulmonary malignancies, and domestic radon exposure: “Postmortem” analysis of an interesting hypothesis. Environ. Mol. Mutagenes 2001, 37, 7–16. [Google Scholar]
  104. Zwingmann, I.; Welle, I.; van Herwijnen, M.; Engelen, J.; Schilderman, P.; Smid, T.; Kleinjans, J. Oxidative DNA damage and cytogenetic effects in flight engineers exposed to cosmic radiation. Environ. Mol. Mutagenes 1998, 32, 121–129. [Google Scholar]
  105. Seifert, A.; Demers, C.; Dubeau, H.; Messing, K. HPRT-mutant frequency and lymphocyte characteristics of workers exposed to ionizing radiation on a sporadic basis: A comparison of two exposure indicators, job title and dose. Mutat. Res 1993, 319, 61–70. [Google Scholar]
  106. McDiarmid, M.; Albertini, R.; Tucker, J.; Vacek, P.; Carter, E.; Bakhmutsky, M.; Oliver, M.; Engelhardt, S.; Squibb, K. Measures of genotoxicity in Gulf war I veterans exposed to depleted uranium. Environ. Mol. Mutagenes 2011, 52, 569–581. [Google Scholar]
  107. Xie, H.; LaCerte, C.; Thompson, W.; Wise, J. Depleted uranium induces neoplastic transformation in human lung epithelial cells. Chem. Res. Toxicol 2010, 23, 373–378. [Google Scholar]
  108. Wise, S.S.; Thompson, W.D.; Aboueissa, A.-M.; Mason, M.D.; Wise, J.P. Particulate depleted uranium is cytotoxic and clastogenic to human lung cells. Chem. Res. Toxicol 2007, 20, 815–820. [Google Scholar]
  109. Cui, F.; Fan, S.; Hu, M.; Nie, J.; Li, H.; Tong, J. Micronuclei rate and hypoxanthine phosphoribosyl transferase mutation in radon-exposed rats. Prog. Nat. Sci 2008, 18, 1305–1308. [Google Scholar]
  110. Jostes, R.F.; Fleck, E.W.; Morgan, T.L.; Stiegler, G.L.; Cross, F.T. Southern blot and polymerase chain reaction exon analyses of HPRT-mutations induced by radon and radon progeny. Radiat. Res 1994, 137, 371–379. [Google Scholar]
  111. Jostes, R.; Hui, T.; James, A.; Cross, F.; Schwartz, J.; Rotmensch, J.; Atcher, R.; Evans, H.; Mencl, J.; Bakale, G.; et al. In vitro exposure of mammalian cells to radon: Dosimetric considerations. Radiat. Res 1991, 127, 211–219. [Google Scholar]
  112. Kiefer, J.; Schreiber, A.; Gutermuth, F.; Koch, S.; Schmidt, P. Mutation induction by different types of radiation at the Hprt locus. Mutat. Res 1999, 431, 429–448. [Google Scholar]
  113. Bao, C.Y.; Ma, A.; Evans, H.H.; Horng, M.F.; Mencl, J.; Hui, T.E.; Sedwick, W.D. Molecular analysis of hypoxanthine phosphoribosyltransferase gene deletions induced by alpha- and X-radiation in human lymphoblastoid cells. Mutat. Res 1994, 326, 1–15. [Google Scholar]
  114. Bakale, G.; Rao, P.S.; Mencl, J.; Adams, R.B.; Evans, H.H. A radon generator/delivery system. Radiat. Res 1993, 133, 277–281. [Google Scholar]
  115. Chaudhry, M.; Jiang, Q.; Ricanati, M.; Horng, M.; Evans, H. Characterization of multilocus lesions in human cells exposed to X radiation and radon. Radiat. Res 1996, 145, 31–38. [Google Scholar]
  116. Amundson, S.; Chen, D.; Okinaka, R. Alpha particle mutagenesis of human lymphoblastoid cell lines. Int. J. Radiat. Biol 1996, 70, 219–226. [Google Scholar]
  117. Hsie, A.; Porter, R.; Xu, Z.; Yu, Y.; Sun, J.; Meltz, M.; Schwartz, J. Molecular markers of ionizing radiation-induced gene mutations in mammalian cells. Environ. Health Perspect 1996, 104, 675–678. [Google Scholar]
  118. Schwartz, J.; Hsie, A. Genetic and cytogenetic markers of exposure to high-linear energy transfer radiation. Radiat. Res 1997, 148, S87–S92. [Google Scholar]
  119. Albertini, R.; Clark, L.; Nicklas, J.; O’Neill, J.; Hui, T.; Jostes, R. Radiation quality affects the efficiency of induction and the molecular spectrum of HPRT mutations in human T cells. Radiat. Res 1997, 148, S76–S86. [Google Scholar]
  120. O’Neill, P.; Nicklas, J.; Hirsch, B.; Jostes, R.; Hunter, T.; Sullivan, L.; Albertini, R. In vitro studies of the genotoxicity of ionizing radiation in human G(0) T lymphocytes. Environ. Mol. Mutagenes 2005, 46, 207–220. [Google Scholar]
  121. Schwartz, J.L.; Jordan, R.; Sun, J.; Ma, H.; Hsieb, A. Dose-dependent changes in the spectrum of mutations induced by ionizing radiation. Radiat. Res 2000, 153, 312–317. [Google Scholar]
  122. Nagasawa, H.; Little, J. Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: Evidence for a bystander effect. Radiat. Res 1999, 152, 552–557. [Google Scholar]
  123. Huo, L.; Nagasawa, H.; Little, J. HPRT mutants induced in bystander cells by very low fluences of alpha particles result primarily from point mutations. Radiat. Res 2001, 156, 521–525. [Google Scholar]
  124. Nagasawa, H.; Huo, L.; Little, J.B. Increased bystander mutagenic effect in DNA double-strand break repair-deficient mammalian cells. Int. J. Radiat. Biol 2003, 79, 35–41. [Google Scholar]
  125. Da Cruz, A.; Curry, J.; Curado, M.; Glickman, B. Monitoring hprt mutant frequency over time in T-lymphocytes of people accidentally exposed to high doses of ionizing radiation. Environ. Mol. Mutagenes 1996, 27, 165–175. [Google Scholar]
  126. Mitelman, F. Catalog of chromosome aberrations in cancer, 4th edition, in two parts. Am. J. Hum. Genet 1992, 50, 1354–1355. [Google Scholar]
  127. Solomon, E.; Borrow, J.; Goddard, A.D. Chromosome aberrations and cancer. Science 1991, 254, 1153–1160. [Google Scholar]
  128. Albertson, D.G.; Collins, C.; McCormick, F.; Gray, J.W. Chromosome aberrations in solid tumors. Nat. Genet 2003, 34, 369–376. [Google Scholar]
  129. Bender, M.; Griggs, H.; Bedford, J. Mechanisms of chromosomal aberration production III. Chemicals and ionizing radiation. Mutat. Res 1974, 23, 197–212. [Google Scholar]
  130. Sorsa, M.; Wilbourn, J.; Vainio, H. Human cytogenetic damage as a predictor of cancer risk. IARC Sci. Publ. 1992, 543–554. [Google Scholar]
  131. Norppa, H. Cytogenetic biomarkers and genetic polymorphisms. Toxicol. Lett 2004, 149, 309–334. [Google Scholar]
  132. Tucker, J.D.; Auletta, A.; Cimino, M.C.; Dearfield, K.L.; Jacobson-Kram, D.; Tice, R.R.; Carrano, A.V. Sister-chromatid exchange: Second report of the Gene-Tox program. Mutat. Res 1993, 297, 101–180. [Google Scholar]
  133. Anderson, B.E.; Zeiger, E.; Shelby, M.D.; Resnick, M.A.; Gulati, D.K.; Ivett, J.L.; Loveday, K.S. Chromosome aberration and sister chromatid exchange test results with 42 chemicals. Environ. Mol. Mutagenes 1990, 16, 55–137. [Google Scholar]
  134. Galloway, S.M.; Armstrong, M.J.; Reuben, C.; Colman, S.; Brown, B.; Cannon, C.; Bloom, A.D.; Nakamura, F.; Ahmed, M.; Duk, S. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ. Mol. Mutagenes 1987, 10, 1–35. [Google Scholar]
  135. Wald, N.; Koizumi, A.; Pan, S. A pilot study of the relationship between chromosome aberrations and occupational external and internal radiation exposure. Hum. Radiat. Cytogenet. 1968, 183–193. [Google Scholar]
  136. Boyd, J.; Brown, W.; Vennart, J.; Woodcock, G. Chromosome studies on women formerly employed as luminous-dial painters. Br. Med. J 1966, 1, 377–382. [Google Scholar]
  137. Sax, K. Chromosome aberrations induced by X-rays. Genetics 1938, 23, 494–516. [Google Scholar]
  138. Brown, J.; McNeill, J. Aberrations in leukocyte chromosomes of personnel occupationally exposed to low levels of radiation. Radiat. Res 1969, 40, 534–543. [Google Scholar]
  139. Ishihara, T.; Kumatori, T. Chromosome studies on japanese exposed to radiation resulting from nuclear bomb explosions. Hum. Radiat. Cytogenet. 1968, 144–166. [Google Scholar]
  140. Awa, A.; Honda, T.; Sofuni, T.; Neriishi, S. Chromosome-aberration frequency in cultured blood-cells in relation to radiation dose of A-bomb survivors. Lancet 1971, 298, 903–905. [Google Scholar]
  141. Müller, I.; Geinitz, H.; Braselmann, H.; Baumgartner, A.; Fasan, A.; Thamm, R.; Molls, M.; Meineke, V.; Zitzelsberger, H. Time-course of radiation-induced chromosomal aberrations in tumor patients after radiotherapy. Int. J. Radiat. Oncol. Biol. Phys 2005, 63, 1214–1220. [Google Scholar]
  142. Jones, L.A.; Scott, D.; Cowan, R.; Roberts, S.A. Abnormal radiosensitivity of lymphocytes from breast cancer patients with excessive normal tissue damage after radiotherapy: Chromosome aberrations after low dose-rate irradiation. Int. J. Radiat. Biol 1995, 67, 519–528. [Google Scholar]
  143. Barrios, L.; Miró, R.; Caballín, M.R.; Fuster, C.; Guedea, F.; Subias, A.; Egozcue, J. Cytogenetic effects of radiotherapy. Breakpoint distribution in induced chromosome aberrations. Cancer Genet. Cytogenet 1989, 41, 61–70. [Google Scholar]
  144. AlSuhaibani, E.S. Chromosomal aberration analysis among underground water well workers in Saudi Arabia. Radiat. Prot. Dosim 2011, 144, 651–654. [Google Scholar]
  145. Liu, Q.; Cao, J.; Wang, Z.; Bai, Y.; Lü, Y.; Huang, Q.; Zhao, W.; Li, J.; Jiang, L.; Tang, W.; et al. Dose estimation by chromosome aberration analysis and micronucleus assays in victims accidentally exposed to 60Co radiation. Br. J. Radiol 2009, 82, 1027–1032. [Google Scholar]
  146. Liu, Q.; Cao, J.; Liu, Y.; Lü, Y.; Qin, B.; Jiang, B.; Jiang, L.; Fu, B.; Zhao, F.; Jiang, E.; et al. Follow-up study by chromosome aberration analysis and micronucleus assays in victims accidentally exposed to 60Co radiation. Health Phys 2010, 98, 885–888. [Google Scholar]
  147. Heimers, A.; Brede, H.J.; Giesen, U.; Hoffmann, W. Chromosome aberration analysis and the influence of mitotic delay after simulated partial-body exposure with high doses of sparsely and densely ionising radiation. Radiat. Environ. Biophys 2006, 45, 45–54. [Google Scholar]
  148. Savage, J. Classification and relationships of induced chromosomal structual changes. J. Med. Genet 1976, 12, 103–122. [Google Scholar]
  149. Shadley, J.; Whitlock, J.; Rotmensch, J.; Atcher, R.; Tang, J.; Schwartz, J. The effects of radon daughter alpha-particle irradiation in K1 and xrs-5 CHO cell lines. Mutat. Res 1991, 248, 73–83. [Google Scholar]
  150. Wolff, S.; Jostes, R.; Cross, F.T.; Hui, T.E.; Afzal, V.; Wiencke, J.K. Adaptive response of human lymphocytes for the repair of radon-induced chromosomal damage. Mutat. Res 1991, 250, 299–306. [Google Scholar]
  151. Kadhim, M.; Macdonald, D.; Goodhead, D.; Lorimore, S.; Marsden, S.; Wright, E. Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 1992, 355, 738–740. [Google Scholar]
  152. Nagasawa, H.; Robertson, J.; Little, J. Induction of chromosomal aberrations and sister chromatid exchanges by alpha particles in density-inhibited cultures of mouse 10T1/2 and 3T3 cells. Int. J. Radiat. Biol 1990, 57, 35–44. [Google Scholar]
  153. Nagasawa, H.; Little, J.B. Induction of sister chromatid exchanges by extremely low doses of α-particles. Cancer Res 1992, 52, 6394–6396. [Google Scholar]
  154. Iyer, R.; Lehnert, B.E.; Svensson, R. Factors underlying the cell growth-related bystander responses to α particles. Cancer Res 2000, 60, 1290–1298. [Google Scholar]
  155. Azzam, E.; de Toledo, S.; Gooding, T.; Little, J. Intercellular communication is involved in the bystander regulation of gene expression in human cells exposed to very low fluences of alpha particles. Radiat. Res 1998, 150, 497–504. [Google Scholar]
  156. Pohl-Rüling, J.; Lettner, H.; Hofmann, W.; Eckl, P.; Haas, O.; Obe, G.; Grell-Büchtmann, I.; van Buul, P.; Schroeder-Kurth, T.; Atzmüller, C.; et al. Chromosomal aberrations of blood lymphocytes induced in vitro by radon-222 daughter alpha irradiation. Mutat. Res 2000, 449, 7–19. [Google Scholar]
  157. Hamza, V.Z.; Mohankumar, M.N. Cytogenetic damage in human blood lymphocytes exposed in vitro to radon. Mutat. Res 2009, 661, 1–9. [Google Scholar]
  158. Meenakshi, C.; Mohankumar, M. Radon-induced chromosome damage in blood lymphocytes of smokers. Res. J. Environ. Toxicol 2012, 6, 51–58. [Google Scholar]
  159. Costa-Ribeiro, C.; Barcinski, M.A.; Figueiredo, N.; Franca, E.P.; Lobão, N. Radiobiological aspects and radiation levels associated with the milling of monazite sand. Health Phys 1975, 28, 225–231. [Google Scholar]
  160. Livingston, G.K.; Falk, R.B.; Schmid, E. Effect of occupational radiation exposures on chromosome aberration workers rates in former plutonium workers. Radiat. Res 2006, 166, 89–97. [Google Scholar]
  161. Smerhovsky, Z.; Landa, K.; Rössner, P.; Brabec, M.; Zudova, Z.; Hola, N.; Pokorna, Z.; Mareckova, J.; Hurychova, D. Risk of cancer in an occupationally exposed cohort with increased level of chromosomal aberrations. Environ. Health Perspect 2001, 109, 41–45. [Google Scholar]
  162. Smerhovsky, Z.; Landa, K.; Rössner, P.; Juzova, D.; Brabec, M.; Zudova, Z.; Hola, N.; Zarska, H.; Nevsimalova, E. Increased risk of cancer in radon-exposed miners with elevated frequency of chromosomal aberrations. Mutat. Res 2002, 514, 165–176. [Google Scholar]
  163. Brandom, W.F.; Saccomanno, G.; Archer, V.E.; Archer, P.G.; Coors, M.E. Chromosome aberrations in uranium miners occupationally exposed to 222 Radon. Radiat. Res 1972, 52, 204–215. [Google Scholar]
  164. Brandom, W.F.; Saccomanno, G.; Archer, V.E.; Archer, P.G.; Bloom, A.D. Chromosome aberrations as a biological dose-response indicator of radiation exposure in uranium miners. Radiat. Res 1978, 76, 159–171. [Google Scholar]
  165. Bilban, M. Influence of the work environment in a Pb-Zn mine on the incidence of cytogenetic damage in miners. Am. J. Ind. Med 1998, 34, 455–463. [Google Scholar]
  166. Bilban, M.; Jakopin, C. Incidence of cytogenetic damage in lead-zinc mine workers exposed to radon. Mutagenesis 2005, 20, 187–191. [Google Scholar]
  167. Popp, W.; Plappert, U.; Müller, W.U.; Rehn, B.; Schneider, J.; Braun, A.; Bauer, P.C.; Vahrenholz, C.; Presek, P.; Brauksiepe, A.; et al. Biomarkers of genetic damage and inflammation in blood and bronchoalveolar lavage fluid among former German uranium miners: A pilot study. Radiat. Environ. Biophys 2000, 39, 275–282. [Google Scholar]
  168. Sram, R.; Binková, B. Monitoring genotoxic exposure in uranium miners. Environ. Health Perspect 1993, 99, 303–305. [Google Scholar]
  169. Zölzer, F.; Hon, Z.; Skalická, Z.F.; Havránková, R.; Navrátil, L.; Rosina, J.; Škopek, J. Micronuclei in lymphocytes from currently active uranium miners. Radiat. Environ. Biophys 2012, 51, 277–282. [Google Scholar]
  170. Zaire, R.; Notter, M.; Riedel, W.; Thiel, E. Unexpected rates of chromosomal instabilities and alterations of hormone levels in Namibian uranium miners. Radiat. Res 1997, 147, 579–584. [Google Scholar]
  171. Mészáros, G.; Bognár, G.; Köteles, G.J. Long-term persistence of chromosome aberrations in uranium miners. J. Occup. Health 2004, 46, 310–315. [Google Scholar]
  172. Tawn, E.; Whitehouse, C.; Tarone, R. FISH chromosome aberration analysis on retired radiation workers from the Sellafield nuclear facility. Radiat. Res 2004, 162, 249–256. [Google Scholar]
  173. Barcinski, M.; do Céu Abreu, M.; de Almeida, J.; Naya, J.; Fonseca, L.; Castro, L. Cytogenetic investigation in a Brazilian population living in an area of high natural radioactivity. Am. J. Hum. Genet 1975, 27, 802–806. [Google Scholar]
  174. Pohl-Rüling, J.; Fischer, P. The dose-effect relationship of chromosome aberrations to α and γ irradiation in a population subjected to an increased burden of natural radioactivity. Radiat. Res 1979, 80, 61–81. [Google Scholar]
  175. Chen, D.; Wei, L. Chromosome aberration, cancer mortality and hormetic phenomena among inhabitants in areas of high background radiation in china. J. Radiat. Res 1991, 32, 46–53. [Google Scholar]
  176. Bauchinger, M.; Schmid, E.; Braselmann, H.; Kulka, U. Chromosome aberrations in peripheral lymphocytes from occupants of houses with elevated indoor radon concentrations. Mutat. Res 1994, 310, 135–142. [Google Scholar]
  177. Lindholm, C.; Mäkeläinen, I.; Paile, W.; Koivistoinen, A.; Salomaa, S. Domestic radon exposure and the frequency of stable or unstable chromosomal aberrations in lymphocytes. Int. J. Radiat. Biol 1999, 75, 921–928. [Google Scholar]
  178. Boffetta, P.; van der Hel, O.; Norppa, H.; Fabianova, E.; Fucic, A.; Gundy, S.; Lazutka, J.; Cebulska-Wasilewska, A.; Puskailerova, D.; Znaor, A.; et al. Chromosomal aberrations and cancer risk: results of a cohort study from Central Europe. Am. J. Epidemiol 2007, 165, 36–43. [Google Scholar]
  179. Bilban, M.; Vaupoti, J. Chromosome aberrations study of pupils in high radon level elementary school. Health Phys 2001, 80, 157–163. [Google Scholar]
  180. Minina, V.I.; Druzhinin, V.G.; Golovina, T.A.; Larin, S.A.; Mun, S.A.; Akhmat’ianova, V.R.; Bakanova, M.L.; Glushkov, A.N. Spread of carcinogenic and mutagenic effects in the population of Gornaia Shoria. Gig. Sanit. 2011, 35–38. [Google Scholar]
  181. Druzhinin, V.G.; Akhmat’ianova, V.R.; Golovina, T.A.; Volkov, A.N.; Minina, V.I.; Larionov, A.V.; Makeeva, E.A. Genome sensitivity and genotoxic effects features in children-teenagers affected by radon radiation in living and educational environment. Radiats. Biol. Radioecol 2009, 49, 568–573. [Google Scholar]
  182. Minina, V.; Druzhinin, V.; Lunina, A.; Larionov, A.; Golovina, T.; Glushkov, A. Association of DNA repair gene polymorphism with chromosomal aberrations frequency in human lymphocytes. Russ. J. Genet 2012, 2, 171–176. [Google Scholar]
  183. Bilban, M.; Bilban-Jakopin, C.; Vrhovec, S. Incidence of chromosomal aberrations and micronuclei in cave tour guides. Neoplasma 2001, 48, 278–284. [Google Scholar]
  184. Lehnert, B.; Goodwin, E. A new mechanism for DNA alterations induced by alpha particles such as those emitted by radon and radon progeny. Environ. Health Perspect 1997, 105, 1095–1101. [Google Scholar]
  185. Hamza, V.Z.; Kumar, P.R.V.; Jeevanram, R.K.; Santanam, R.; Danalaksmi, B.; Mohankumar, M.N. A simple method to irradiate blood cells in vitro with radon gas. Radiat. Prot. Dosim 2008, 130, 343–350. [Google Scholar]
  186. Bender, M.; Gooch, P. Persistent chromosome aberrations in irradiated human subjects. II. Three and one-half year investigation. Radiat. Res 1963, 18, 389–396. [Google Scholar]
  187. Awa, A. Persistent chromosome aberrations in the somatic cells of A-bomb survivors, Hiroshima and Nagasaki. Radiat. Res 1991, 32, 265–274. [Google Scholar]
  188. Bender, M.; Gooch, P. Persistent chromosome aberrations in irradiated human subjects. Radiat. Res 1962, 16, 44–53. [Google Scholar]
  189. Brenner, D.; Sachs, R. Chromosomal “fingerprints” of prior exposure to densely ionizing radiation. Radiat. Res 1994, 140, 134–142. [Google Scholar]
  190. Brenner, D.; Okladnikova, N.; Hande, P.; Burak, L.; Geard, C.; Azizova, T. Biomarkers specific to densely-ionising (high LET) radiations. Radiat. Prot. Dosim 2001, 97, 69–73. [Google Scholar]
  191. Anderson, R.M.; Stevens, D.L.; Sumption, N.D.; Townsend, K.M.S.; Goodhead, D.T.; Hill, M.A. Effect of linear energy transfer (LET) on the complexity of alpha-particle-induced chromosome aberrations in human CD34+ cells. Radiat. Res 2007, 167, 541–550. [Google Scholar]
  192. Tawn, E.; Whitehouse, C. Chromosome intra- and inter-changes determined by G-banding in radiation workers with in vivo exposure to plutonium. J. Radiol. Prot 2005, 25, 83–88. [Google Scholar]
  193. Fenech, M.; Morley, A. Measurement of micronuclei in lymphocytes. Mutat. Res 1985, 147, 29–36. [Google Scholar]
  194. Heddle, J.A.; Carrano, A.V. The DNA content of micronuclei induced in mouse bone marrow by gamma-irradiation: Evidence that micronuclei arise from acentric chromosomal fragments. Mutat. Res 1977, 44, 63–69. [Google Scholar]
  195. Countryman, P.; Heddle, J. The production of micronuclei from chromosome aberrations in irradiated cultures of human lymphocytes. Mutat. Res 1976, 41, 321–331. [Google Scholar]
  196. Bonassi, S.; El-Zein, R.; Bolognesi, C.; Fenech, M. Micronuclei frequency in peripheral blood lymphocytes and cancer risk: Evidence from human studies. Mutagenesis 2011, 26, 93–100. [Google Scholar]
  197. Khan, M.A.; Cross, F.T.; Jostes, R.; Hui, E.; Morris, J.E.; Brooks, A.L. Micronuclei induced by radon and its progeny in deep-lung fibroblasts of rats in vivo and in vitro. Radiat. Res 1994, 139, 53–59. [Google Scholar]
  198. Taya, A.; Morgan, A.; Baker, S.; Humphreys, J.; Bisson, M.; Collier, C. Changes in the rat lung after exposure to radon and its progeny: Effects on incorporation of bromodeoxyuridine in epithelial cells and on the incidence of nuclear aberrations in alveolar macrophages. Radiat. Res 1994, 139, 170–177. [Google Scholar]
  199. Nelson, J.; Brooks, A.; Metting, N.; Khan, M.; Buschbom, R.; Duncan, A.; Miick, R.; Braby, L. Clastogenic effects of defined numbers of 3.2 MeV alpha particles on individual CHO-K1 cells. Radiat. Res 1996, 145, 568–574. [Google Scholar]
  200. Hei, T.K.; Wu, L.J.; Liu, S.X.; Vannais, D.; Waldren, C.A.; Randers-Pehrson, G. Mutagenic effects of a single and an exact number of alpha particles in mammalian cells. Proc. Natl. Acad. Sci. USA 1997, 94, 3765–3770. [Google Scholar]
  201. Kennedy, C.H.; Mitchell, C.E.; Fukushima, N.H.; Neft, R.E.; Lechner, J.F. Induction of genomic instability in normal human bronchial epithelial cells by 238Pu alpha-particles. Carcinogenesis 1996, 17, 1671–1676. [Google Scholar]
  202. Tobias, E.S.; Hurlstone, A.F.; MacKenzie, E.; McFarlane, R.; Black, D.M. The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein. Oncogene 2001, 20, 2844–2853. [Google Scholar]
  203. Chêne, L.; Giroud, C.; Desgrandchamps, F.; Boccon-Gibod, L.; Cussenot, O.; Berthon, P.; Latil, A. Extensive analysis of the 7q31 region in human prostate tumors supports TES as the best candidate tumor suppressor gene. Int. J. Cancer 2004, 111, 798–804. [Google Scholar]
  204. Zenklusen, J.C.; Thompson, J.C.; Klein-szanto, A.J.P.; Conti, C.J. Frequent loss of heterozygosity in human primary squamous cell and colon carcinomas at 7q31.1: Evidence for a broad range tumor suppressor gene. Cancer Res 1995, 55, 1347–1350. [Google Scholar]
  205. Ruas, M.; Peters, G. The p16 INK4a/CDKN2A tumor suppressor and its relatives. Biochim. Biophys. Acta 1998, 1378, F115–F177. [Google Scholar]
  206. Belchior, A.; Gil, O.M.; Almeida, P.; Vaz, P. Evaluation of the cytotoxicity and the genotoxicity induced by α radiation in an A549 cell line. Radiat. Meas 2011, 46, 958–961. [Google Scholar]
  207. Chaudhry, M.A. Analysis of gene expression in normal and cancer cells exposed to gamma-radiation. J. Biomed. Biotechnol 2008, 2008, 541678. [Google Scholar]
  208. Chaudhry, M.; Omaruddin, R.; Kreger, B.; de Toledo, S.; Azzam, E. Micro RNA responses to chronic or acute exposures to low dose ionizing radiation. Mol. Biol. Rep 2012, 39, 7549–7558. [Google Scholar]
  209. Chaudhry, M.; Omaruddin, R. Differential regulation of MicroRNA expression in irradiated and bystander cells. Mol. Biol 2012, 46, 569–578. [Google Scholar]
  210. Chaudhry, M.; Omaruddin, R. Transcriptional changes of mitochondrial genes in irradiated cells proficient or deficient in p53. J. Genet 2012, 91, 105–110. [Google Scholar]
  211. Amundson, S.; do, K.; Shahab, S.; Bittner, M.; Meltzer, P.; Trent, J.; Fornace, A. Identification of potential mRNA biomarkers in peripheral blood lymphocytes for human exposure to ionizing radiation. Radiat. Res 2000, 154, 342–346. [Google Scholar]
  212. Scott, B.R.; Walker, D.M.; Tesfaigzi, Y.; Schöllnberger, H.; Walker, V. Mechanistic basis for nonlinear dose-response relationships for low-dose radiation-induced stochastic effects. Nonlinearity Biol. Toxicol. Med 2003, 1, 93–122. [Google Scholar]
  213. Feinendegen, L.E. Evidence for beneficial low level radiation effects and radiation hormesis. Br. J. Radiol 2005, 78, 3–7. [Google Scholar]
  214. Baskar, R. Emerging role of radiation induced bystander effects: Cell communications and carcinogenesis. Genome Integr 2010, 1, 13. [Google Scholar]
  215. Zhou, H.; Suzuki, M.; Randers-Pehrson, G.; Vannais, D.; Chen, G.; Trosko, J.E.; Waldren, C.A.; Hei, T.K. Radiation risk to low fluences of alpha particles may be greater than we thought. Proc. Natl. Acad. Sci. USA 2001, 98, 14410–14415. [Google Scholar]
  216. Little, M.P.; Wakeford, R. The bystander effect in experimental systems and compatibility with radon-induced lung cancer in humans. J. Radiol. Prot 2002, 22, A27–A31. [Google Scholar]
  217. Little, M.; Wakeford, R.; Tawn, E.; Bouffler, S.; de Gonzalez, A. Risks associated with low doses and low dose rates of ionizing radiation: Why linearity may be (almost) the best we can do. Radiology 2009, 251, 6–12. [Google Scholar]
  218. Sawant, S.G.; Zheng, W.; Hopkins, K.M.; Randers-Pehrson, G.; Lieberman, H.B.; Hall, E.J. The radiation-induced bystander effect for clonogenic survival. Radiat. Res 2002, 157, 361–364. [Google Scholar]
  219. Goldberg, Z.; Lehnert, B.E. Radiation-induced effects in unirradiated cells: A review and implications in cancer. Int. J. Oncol 2002, 21, 337–349. [Google Scholar]
  220. Wu, L.J.; Randers-Pehrson, G.; Xu, A.; Waldren, C.A.; Geard, C.R.; Yu, Z.; Hei, T.K. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc. Natl. Acad. Sci. USA 1999, 96, 4959–4964. [Google Scholar]
  221. Prise, K.; O’Sullivan, J. Radiation-induced bystander signalling in cancer therapy. Nature Rev. Cancer 2009, 9, 351–360. [Google Scholar]
  222. Belyakov, O.V.; Mitchell, S.A.; Parikh, D.; Randers-Pehrson, G.; Marino, S.A.; Amundson, S.A.; Geard, C.R.; Brenner, D.J. Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away. Proc. Natl. Acad. Sci. USA 2005, 102, 14203–14208. [Google Scholar]
  223. Chen, S.; Zhao, Y.; Han, W.; Chiu, S.K.; Zhu, L.; Wu, L.; Yu, K.N. Rescue effects in radiobiology: Unirradiated bystander cells assist irradiated cells through intercellular signal feedback. Mutat. Res 2011, 706, 59–64. [Google Scholar]
  224. Zhou, H.; Ivanov, V.N.; Gillespie, J.; Geard, C.R.; Amundson, S.A.; Brenner, D.J.; Yu, Z.; Lieberman, H.B.; Hei, T.K. Mechanism of radiation-induced bystander effect: Role of the cyclooxygenase-2 signaling pathway. Proc. Natl. Acad. Sci. USA 2005, 102, 14641–14646. [Google Scholar]
  225. Nagasawa, H.; Cremesti, A.; Kolesnick, R.; Fuks, Z.; Little, J. Involvement of membrane signaling in the bystander effect in irradiated cells. Cancer Res 2002, 62, 2531–2534. [Google Scholar]
  226. Yu, H. Typical cell signaling response to ionizing radiation: DNA damage and extranuclear damage. Chin. J. Cancer Res 2012, 24, 83–89. [Google Scholar]
  227. Shao, C.; Folkard, M.; Michael, B.D.; Prise, K.M. Targeted cytoplasmic irradiation induces bystander responses. Proc. Natl. Acad. Sci. USA 2004, 101, 13495–13500. [Google Scholar]
  228. Burdak-Rothkamm, S.; Short, S.C.; Folkard, M.; Rothkamm, K.; Prise, K.M. ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 2007, 26, 993–1002. [Google Scholar]
  229. Schaue, D.; Kachikwu, E.L.; McBride, W.H. Cytokines in radiobiological responses: A review. Radiat. Res 2012, 178, 505–523. [Google Scholar]
  230. Hall, E.J. The bystander effect. Health Phys 2003, 85, 31–35. [Google Scholar]
  231. Morgan, W. Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation? Oncogene 2003, 22, 7094–7099. [Google Scholar]
  232. Morgan, W. Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation induced genomic instability and bystander effects in vitro. Radiat. Res 2003, 159, 567–580. [Google Scholar]
  233. Little, J.B. Radiation carcinogenesis. Carcinogenesis 2000, 21, 397–404. [Google Scholar]
  234. Iyer, R.; Lehnert, B. Low dose, low-LET ionizing radiation-induced radioadaptation and associated early responses in unirradiated cells. Mutat. Res 2002, 503, 1–9. [Google Scholar]
  235. Matsumoto, H.; Hayashi, S.; Hatashita, M.; Ohnishi, K.; Shioura, H.; Ohtsubo, T.; Kitai, R.; Ohnishi, T.; Kano, E. Induction of radioresistance by a nitric oxide-mediated bystander effect. Radiat. Res 2001, 155, 387–396. [Google Scholar]
  236. Barcellos-Hoff, M.; Brooks, A. Extracellular signaling through the microenvironment: A hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat. Res 2001, 156, 618–627. [Google Scholar]
  237. Wolff, S. The adaptive response in radiobiology: Evolving insights and implications. Environ. Health Perspect 1998, 106, 277–283. [Google Scholar]
  238. Bonner, W. Low-dose radiation: Thresholds, bystander effects, and adaptive responses. Proc. Natl. Acad. Sci 2003, 100, 4973–4975. [Google Scholar]
  239. Ghiassi-nejad, M.; Mortazavi, S.M.J.; Cameron, J.R.; Niroomand-rad, A.; Karam, P. A Very high background radiation areas of Ramsar, Iran: Preliminary biological studies. Health phys. 2002, 82, 87–93. [Google Scholar]
  240. Mothersill, C.; Seymour, C.B. Radiation-induced bystander effects and the DNA paradigm: An “out of field” perspective. Mutat. Res 2006, 597, 5–10. [Google Scholar]
  241. Forastiere, F.; Sperati, A.; Cherubini, G.; Miceli, M.; Biggeri, A.; Axelson, O. Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: A case control study in central Italy. Occup. Environ. Med 1998, 55, 106–110. [Google Scholar]
  242. Rechavi, G.; Berkowicz, M.; Rosner, E.; Neuman, Y.; Ben-Bassat, I.; Ramot, B. Chromosomal aberrations suggestive of mutagen-related leukemia after 21 years of “therapeutic” radon exposure. Cancer Genet. Cytogenet 1990, 48, 125–130. [Google Scholar]
  243. Eatough, J.; Henshaw, D. Radon dose to the skin and the possible induction of skin cancers. Radiat. Prot. Dosim 1991, 39, 33. [Google Scholar]
  244. Attar, M.; Kondolousy, Y.; Khansari, N. Effect of high dose natural ionizing radiation on the immune system of the exposed residents of Ramsar Town, Iran. Iran J. Allergy Asthma 2007, 6, 73–78. [Google Scholar]
  245. Chauhan, V.; Howland, M.; Kutzner, B.; McNamee, J.P.; Bellier, P.V.; Wilkins, R.C. Biological effects of alpha particle radiation exposure on human monocytic cells. Int. J. Hyg. Environ. Health 2012, 215, 339–344. [Google Scholar]
  246. Jostes, R.F. Genetic, cytogenetic, and carcinogenic effects of radon: a review. Mutat. Res 1996, 340, 125–139. [Google Scholar]
  247. Leonard, B.E.; Thompson, R.E.; Beecher, G.C. Human lung cancer risks from radon-Part II—Influence from combined adaptive response and bystander effects—A microdose analysis. Dose-Response 2011, 9, 502–553. [Google Scholar]
  248. Hall, E.J.; Hei, T.K. Genomic instability and bystander effects induced by high-LET radiation. Oncogene 2003, 22, 7034–7042. [Google Scholar]
  249. Schöllnberger, H.; Mitchel, R.; Redpath, J.; Crawford-Brown, D.; Hofmann, W. Detrimental and protective bystander effects: A model approach. Radiat. Res. Soc 2009, 168, 614–626. [Google Scholar]
Figure 1. The decay series of uranium-238 indicating its decay products, their half-lives and the electron configuration of radon-222 complete with each respective atomic number.
Figure 1. The decay series of uranium-238 indicating its decay products, their half-lives and the electron configuration of radon-222 complete with each respective atomic number.
Ijms 14 14024f1
Figure 2. Examples of (a) intra-chromosomal aberrations (including pericentric inversions and the formation of centric rings and acentric fragments); (b) Inter-chromosomal aberrations (including translocations and the formation of dicentric and acentric fragments); and (c) Sister chromatid exchange (whereby genetic material is exchanged between two sister chromatids).
Figure 2. Examples of (a) intra-chromosomal aberrations (including pericentric inversions and the formation of centric rings and acentric fragments); (b) Inter-chromosomal aberrations (including translocations and the formation of dicentric and acentric fragments); and (c) Sister chromatid exchange (whereby genetic material is exchanged between two sister chromatids).
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Figure 3. Graphical representation of some of the suggested hypotheses of dose-response functions at low doses, including hormetic, threshold, linear no threshold and supralinear (u-shaped) responses.
Figure 3. Graphical representation of some of the suggested hypotheses of dose-response functions at low doses, including hormetic, threshold, linear no threshold and supralinear (u-shaped) responses.
Ijms 14 14024f3
Table 1. Energy emissions (MeV) of the radon-222 decay series.
Table 1. Energy emissions (MeV) of the radon-222 decay series.
IsotopeEmission energy (MeV)Decay type


Lead-2140.67, 0.73β
0.35, 0.30, 0.24γ

Bismuth-2141.54, 1.51, 3.27β
0.61, 1.76, 1.12γ


Lead-2100.06, 0.02β

0.27, 0.30γ


Table 2. Estimated lifetime risk of lung cancer death by radon level for never smokers, current smokers and the general population assuming lifetime exposure (adapted from United States Environmental Protection Agency [55]).
Table 2. Estimated lifetime risk of lung cancer death by radon level for never smokers, current smokers and the general population assuming lifetime exposure (adapted from United States Environmental Protection Agency [55]).
Radon level Bq/m3Lifetime risk of lung cancer death from radon exposure in homes (%)

Never smokersCurrent smokersGeneral population
Table 3. Key human TP53 analyses of exposure to radon or its surrogates.
Table 3. Key human TP53 analyses of exposure to radon or its surrogates.
Exposure aCancer/cell typeG to T hotspot transversionNumber of observed mutations/number of cancers studiedExon(s) sequencedReference
-NSNot evident7/195–9[60]
1382 WLM11 LCC; 41 SCC(16/29)29/525–9[62]
-23 ACNot evident0/235–9[63]
4 Gy (~1460 WLM)NHBE cellsNot evident-7[69]
~1160 WLM (estimated mean)19 AC; 19 SmCC; 9 SCC; 2 Mixed; 1 ASCNot evident5/507[65]
<50 or >140 Bq·m−373 SmCC; 59 SCC; 86 AC; 25 OtherNot evident58/2435–8[70]
~1100 WLM19 AC; 19 SmCC; 9 SCC; 3 MixedNot evident5/507[66]
-16 SCC; 11 AC; 1 SmCC; 1 LCCRare (1/29)12/295–7[68]
-29 SCCRare (2/29)Not reported/297[67]
11.1–51.8 Bq·m−3NSNot evident0/4 (Only 4/16 could be analysed)4–8[71]
aExposures are based on presented values;
Abbreviations: NS (not specified); LCC (large cell carcinoma); SCC (squamous cell carcinoma); AC (adenocarcinoma); NHBE (normal human bronchial epithelial); ASC (adenosquamous carcinoma).
Table 4. Key cytogenetic analyses of exposure to radon or its surrogates in vitro with identified doses.
Table 4. Key cytogenetic analyses of exposure to radon or its surrogates in vitro with identified doses.
ExposureCell typeDose rangeDose rateEnergy (MeV)Investigated abnormalityReference
212BiCHO-K1; xrs-51–5 Gy0.125–0.5 Gy/hCellSurvival; CAs; HPRT mutations[149]
222RnBlood lymphocyte2–18 cGy15 cGy/hChromatid deletions[150]
238PuMultipotential murine marrow0.25–1 Gy-3.3CAs[151]
238PuMultipotential human marrow0.25–1 Gy-CAs[42]
238Pu10T1/2; 3T32.5–5 cGy-5.3CAs; SCEs[152]
238PuCHO0.16–4.9 mGy0.147 Gy/min3.7SCEs[153]
238PuHFL10.4–12.9 cGy3.65 cGy/s3.5SCEs[31]
238PuHFL11.8–12.9 cGy3.65 cGy/s3.5SCE[32]
238PuHFL10.4–19 cGy3.65 cGy/s3.5ROS generation[48]
238PuHFL11–19 cGy3.65 cGy/s3.5ROS, TP53, CDC2, CDKN1A and TGF-β1 generation; cell proliferation[154]
238PuAG1521; AG1522; GM5758; GM6419; GM83330.3–75 cGy9.9 cGy/min3.65TP53, CDC2, CDKN1A, RAD51 and CCNB1 generation[155]
214PoBlood lymphocyte0.03–41.4 mGy-7.68CA[156]
4HeHBPE0.6 Gy-4.0Colony formation; malignant transformation; TP53 mutations; CA; invasion ability[76]
222RnBlood lymphocyte0–127 mGy-5.5CA; CBMN[157]
222RnBlood lymphocyte0.9–5.2 mGy-5.5CA[158]
Abbreviations: CA (Chromosome/chromatid aberrations); SCE (Sister chromatid exchanges); ROS (Reactive oxygen species); CBMN (Cytokinesis blocked micronuclei).

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Robertson, A.; Allen, J.; Laney, R.; Curnow, A. The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review. Int. J. Mol. Sci. 2013, 14, 14024-14063.

AMA Style

Robertson A, Allen J, Laney R, Curnow A. The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review. International Journal of Molecular Sciences. 2013; 14(7):14024-14063.

Chicago/Turabian Style

Robertson, Aaron, James Allen, Robin Laney, and Alison Curnow. 2013. "The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review" International Journal of Molecular Sciences 14, no. 7: 14024-14063.

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