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
]. 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 [4
], 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
] and plateout on the skin [14
] 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 [17
]. 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 [18
]. 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
]. 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 [24
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 [31
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
], 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
]. 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
] and gastrointestinal malignancies [43
], although any evidence of a cause-effect relationship remains conjectural [10
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.
3. Chromosome Aberrations
Disruptions to normal chromosomal arrangement represent a major contribution to cellular mutagenicity [126
]. 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 [132
] and various types of radiation, including both low and high-LET exposures [135
], in addition to data from atomic bomb survivors [139
], radiotherapy patients [141
] and even underground water-well workers [144
]. Attempts have also been made to estimate prior exposure through CA analysis [145
]. 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.
] and Bender et al.
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
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
]. 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
], 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.
] 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
]. 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 [180
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
]. 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 [186
]. 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
]. 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 [202
]. 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.
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
] and non-melanoma skin cancer [21
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
]. 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
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