Tarsheen K. Sethi, MD, Moataz N. El-Ghamry, MD, and Goetz H. Kloecker, MD, MSPH
Dr. Sethi is a Resident in the Department of Internal Medicine, Dr. El-Ghamry is an Assistant Professor in the Department of Radiation Oncology, and Dr. Kloecker is an Associate Professor in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Louisville in Louisville, Kentucky.
Address correspondence to: Goetz Kloecker, MD, MSPH, Department of Internal Medicine, Division of Hematology/Oncology, James Graham Brown Cancer Center, 529 S. Jackson St., Louisville, KY 40202; Phone: 502-562-4358; E-mail: firstname.lastname@example.org
Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide. Radon exposure is the second leading cause of lung cancer, following tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers. Numerous cohort, case-control, and experimental studies have established the carcinogenic potential of radon. The possibility of radon having a causative effect on other cancers has been explored but not yet proven. One of the postulated mechanisms of carcinogenesis is DNA damage by alpha particles mediated by the production of reactive oxygen species. The latter are also thought to constitute one of the common mechanisms underlying the synergistic effect of radon and tobacco smoke. With an estimated 21,000 lung cancer deaths attributable to radon in the United States annually, the need for radon mitigation is well acknowledged. The Environmental Protection Agency (EPA) has established an indoor limit of 4 picocuries (pCi)/L, and various methods are available for indoor radon reduction when testing shows higher levels. Radon mitigation should accompany smoking cessation measures in lung cancer prevention efforts.
Lung cancer is the leading cause of cancer-related deaths worldwide. The role of limiting tobacco exposure for lung cancer prevention is well recognized. Nonetheless, it is important to be aware of other risk factors implicated in its pathogenesis (Table 1). Radon exposure is the second leading cause of lung cancer following smoking, and it has caught the attention of policy makers and scientists across the globe.1 Even in smokers, the risk of lung cancer is greater among those exposed to radon. Although the initial evidence supporting the association of radon and lung cancer came from studies involving mine workers, research in recent years has focused on indoor radon exposure and its risk to the general population.
Radon finds its place among the top 4 environmental risks to public health in the United States.2 It is believed to cause approximately 10% of lung cancer cases in the United States each year.3 Aside from increasing the risk of lung cancer in smokers, radon is an independent risk factor in nonsmokers. Recognition of the carcinogenic potential of radon in studies of miners led to numerous case-control studies that evaluated the risk of indoor radon exposure. These studies have successfully demonstrated that not only is the risk of radon a very real concern, but it is a universal issue as well. This review focuses on recent advances in the understanding of the mechanisms of radon-induced injury, the epidemiologic evidence implicating indoor radon exposure in lung cancer causation, and the important preventive measures that are available.
Radon is known to accumulate in closed spaces. An increased level is seen in underground rock mines, especially those containing uranium. This concentration is mainly caused by gas entering directly from the ore, but radon can also be brought into the mine when it is dissolved in water. For indoor radon, diffusion from subsoil remains the most important source. Other additional, less significant sources include building materials and radon dissolved in water. Within the structure of a building, radon concentrations are highest in the basement, due to the proximity to the subsoil.4 People residing near uranium mines have a higher radon exposure. Indoor radon levels vary throughout the United States, depending on local conditions (Figure 1).5
Pathophysiology: Mechanisms of Radon-Induced Injury
Radon-222 is a radioactive gas that forms from the decay of naturally occurring uranium-238. Uranium-238 is present throughout the earth’s crust; as such, the presence of radon is also universal. As a gas, radon is relatively harmless, and only a small fraction of the inhaled gas is absorbed. In contrast, radon decay results in solid particles that readily settle within the airways. These decay products, including polonium-218 and polonium-214, mediate injury by emitting alpha radiation. Alpha radiation is classified as high linear energy transfer (LET) radiation, which means that although it has a low penetration distance, it transfers more energy to the target, thus causing a greater number of ionizing events. This process leads to more severe cell damage.6 Becquerel (1 Bcq=1 disintegration per second) and Curie (1 Ci=3.7 x 1010 disintegrations per second) are the 2 commonly used measurement units of radioactivity; the former is part of the International System of Units (SI).
Alpha particles are capable of causing severe DNA damage by a direct hit on the DNA. Evidence also suggests that DNA injury may be mediated by reactive oxygen species (ROS) that are produced in the cytoplasm and subsequently reach the nucleus.7 The effect of radon and the alpha particle is highly complex, and it is suspected that the extent of damage may exceed what has been predicted based on alpha particle physics at low doses.8 The radiation damage by alpha particles is seen to extend beyond the directly irradiated cells. This finding is explained by the bystander effect of alpha radiation, which implies that the directly hit cell sends out signals to surrounding cells, resulting in damage and contributing to tumor genesis.9 This effect has been observed to be more prominent at low doses.10,11 Again, ROS are suspected to be the mediators of this effect.12 In 2006, Breier and colleagues tested this model for the prediction of risk due to indoor radon exposure, and found it to be suitable in this setting.13
Experimental studies on animals have clearly demonstrated an increased risk of lung cancer with inhalation of radon.14 In addition, nonspecific effects on the lungs have also been reported. Radon-induced cytogenetic damage involves various mechanisms, including base mutations and chromosomal breaks. This has been supported by multiple animal and human cell line studies, including one that found gene deletion to be the most common effect at this location.8 A recent study conducted on human lymphocytes in vitro also demonstrated the cytogenetic effect of radon.15
There has been a keen interest in identifying the loci for radon-induced carcinogenesis. Like most cancers, the pathogenesis of lung cancer involves many pathways and mutations. Various studies have examined the role of mutations of the p53 and p16 tumor suppressor loci, but no particular locus has thus far been proven to be predominant.16-19 In addition, there is evidence that certain proteins mediate radon-induced inflammation, fibrosis, and carcinogenesis. Of these proteins, RAGE and S100A6 were found to be upregulated in response to radon exposure, and have been proposed as potential biomarkers of radon-induced injury.20
Radon and Cancer: The Epidemiologic Evidence
Radon is classified as a human carcinogen by various US agencies, including the National Toxicology Program (NTP), the International Agency for Research on Cancer (IARC), and the Agency for Toxic Substances and Disease Registry (ATSDR).14,21,22 In addition to the scientific evidence described above, there is strong epidemiologic evidence to support the causal association between radon and lung cancer. The initial evidence emerged from the observation that many underground miners died of lung cancer. This finding led to the detailed study of various cohorts in miners across many countries, including Czechoslovakia, France, Australia, the United States, Canada, Sweden, and China.23-25 Although most of these were in uranium mines, the studies from the last 3 countries involved other metal mines. An increased risk of lung cancer from radon exposure was demonstrated among these cohorts. The relative risk (RR) was found to be time-dependent, and decreased when more time had elapsed since last exposure. Long-term exposure yielded a greater risk than did short-term exposure, irrespective of the rate of exposure.23 Data from these miner studies led to an interest in the risks associated with indoor radon exposure, and triggered a number of case-control studies that evaluated residential radon exposure. These studies enrolled people from the general population who had been exposed to indoor radon, and compared patients with lung cancer to lung cancer–free controls. Table 2 shows the radon exposure levels in mines and indoors, and demonstrates the risk of lung cancer attributable to radon in smokers compared with nonsmokers.
Indoor Radon Risk: The Case-Control Studies
Pooled results from case-control studies conducted in North America,26,27 Europe,28,29 and China30 demonstrated increased incidence rates of lung cancer related to residential radon exposure at levels of 2.7 picocuries per liter (pCi/L) (100 Bq/m3). One of the early indoor radon case-control studies corroborating the projected risk from miner data was based on lung cancer cases diagnosed between 1980 and 1984 in Sweden.31 The relative risk estimates for levels 3.8–10.8 pCi/L and those above 10.8 pCi/L were 1.3 and 1.8, respectively. Another case-control study conducted in Iowa from 1993–1997 found an excess odds ratio (OR) of 0.5–0.83 with an indoor radon exposure cut-off of 4 pCi/L (148 Bq/m3).32 After the Biological Effects Of Ionizing Radiation (BEIR VI) report3 in 1999, there have been 2 major meta-analyses, both published in 2006, combining 7 studies from North America and 13 studies from Europe. The North American meta-analysis27 showed an increase in lung cancer risk by about 10% per 100 Bq/m3 increase in radon while the European meta-analysis28 estimated this risk to be 8.4% (16% after adjusting for uncertainties) per 100 Bq/m3 rise in radon levels. The pooled results of 2 studies in China revealed similar outcomes,30 with an increased risk of 13.3% per 100 Bq/m3 of measured radon. Following these meta-analyses, there have been recent studies conducted in the United States, specifically in New Jersey and Massachusetts.33,34 The New Jersey study revealed an increased risk for exposure greater than 75 Bq/m3, but the results were not statistically significant.34
The major limitation of case-control studies is an underestimation of risk. It arises from various uncertainties,3 and is primarily due to dosimetry errors concerning the actual estimation of exposure. The use of recent indoor radon exposure as a surrogate for past radon exposure is one such problem. Krewsky and coworkers tried to obviate this concern by using long-term alpha detectors for estimation of exposure as an inclusion criterion for study in their meta-analysis.27 Measurement of surface activity of radon on glass objects present in the subjects’ homes for the entire duration of the study period can also help estimate average past exposure.35
Another source of uncertainty is that risk is estimated based on the residential radon levels rather than the actual bronchial radon dose, which varies among individuals and is dependent on a number of other factors, including time spent at and away from home, exposure at other sites, and the variation of radon levels in the home. There is evidence that indoor radon concentrations vary from day-to-day and season-to-season, being more in winter and less in summer.36 Despite the known limitations of case-control studies, direct observational data in the residential setting is of import as it has obviated the need for data extrapolation from miner studies and the errors that arise thereof.
Based on these studies, an important aspect in predicting lung cancer risk is the relationship between radon exposure and lung cancer incidence. Knowledge of this relationship is important when predicting risk at lower levels of radon exposure, such as that which occurs indoors.
The BEIR IV report constructed various theories for the possible exposure/response relationship, suggesting it can be linear, quadratic, curved, threshold, or hormetic. A linear, non–threshold curve (Figure 2, Curve A) was selected, based on data encompassing properties of alpha particle–induced carcinogenesis, extrapolation from miner data, and evidence from case-control studies available at the time.3 Although this theory has since been corroborated by most studies, researchers agree that the existence of a threshold level—below which cancer risk is negligible—cannot be ruled out entirely.28 Recently, much interest has been generated by the theory of hormesis (Figure 2, Curve E), which posits that low levels of radiation exposure are thought to have a protective effect. In the case of radon, this theory refers to a protective effect of low-level radon exposure against lung cancer in smokers. A possible explanation is that this low-dose exposure may eliminate the smoke-injured cells by stimulation of apoptosis and immunity.37 Figure 2 illustrates the possible exposure/effect relationships discussed above.38
Histopathology of Radon-Associated Lung Cancer
The histopathology of lung cancer associated with radon exposure has produced great interest among epidemiologists. Unfortunately, a prototypical histologic subtype association has not been found.3 Various studies, including both miner and indoor radon studies, have suggested a preponderance of small cell subtypes.27,28,39-41 One possible explanation for this association is that radon and its decay products deliver the maximum radiation dose to the central zone of the lung.3 Nevertheless, it is important to acknowledge that all histologic subtypes have been described in association with radon, including squamous cell carcinoma and adenocarcinoma.39,41,42
Synergistic Effects of Radon and Smoking
More radon-related lung cancers occur in individuals who smoke. This association has been described as submultiplicative.3 Following exposure to 4 pCi/L (148 Bq/m3) of radon over a lifetime, 7 out of every 1,000 nonsmokers would develop lung cancer, compared with 62 out of every 1,000 smokers.43 Moreover, this relationship may not be limited to active smokers alone, as a synergism between second-hand smoke and radon exposure is also suspected to increase lung cancer risk.44 This combined effect may be due to the fact that the radon dose required for injury is modified by changes in morphologic and physiologic parameters in smokers.3 In support of this theory, a recently published study found that the effective dose of inhaled radon progeny was amplified 2 times in heavy, long-term smokers, a result of impaired mucociliary clearance and changes in ventilation.45 In addition, particulate matter from tobacco smoke may increase the amount of attached radon progeny, impacting the dose of alpha energy delivered to the cells.
Another explanation for this synergism is that carcinogens from tobacco smoke and radioactive alpha particles may act together or at different stages in the carcinogenic pathway.3 Although many common mechanisms may exist, inflammation is one such process, as both of these carcinogens are known to cause lung inflammation.46 Another mechanism is ROS-mediated injury. Although it is well known that tobacco smoke produces ROS, recent evidence suggests the possibility of ROS generation by alpha particles, as discussed above. In a related study, Bonner and associates found an increased frequency in lung cancer occurrence in a population subset that lacked both genes for the GSTM1 subtype of the enzyme glutathione S-transferases (GST) and were exposed to either radon or second-hand smoke. Since GST is an important enzyme in the body’s defense against oxidative stress, this finding supports oxidative injury as a common mechanism for these 2 carcinogens.47 An important implication of the synergism between smoking and radon in the occurrence of lung cancer is that many radon-related deaths can be prevented by quitting smoking.
Risk Beyond Lung Cancer
Most clinical studies have failed to find a causal association between inhaled radon and diseases other than lung cancer; dosimetric studies have shown that the dose of radon received by the lungs far exceeds that received by any other organ. Some miner studies have suggested an association with benign lung disease, especially pulmonary fibrosis.48 Although it was suspected that radon exposure might be linked to other malignancies (Table 3), no causal association was demonstrated in these miner studies. The discovery of higher incidences of childhood acute lymphoblastic leukemia in areas with higher indoor radon exposure has raised the possibility of a weak association (RR <2). Studies with more statistical power are needed for confirmation.49,50
The EPA estimates that 21,000 lung cancer–related deaths in the United States every year are attributable to radon.43 As a guidance tool for initiating mitigation measures, it has set an action level for homes and schools of 4 pCi/L (148 Bq/m3), as averaged over a year. The average radon exposure in occupied living areas is 48 Bq/m3. However, in 2005, 7 million housing units had radon levels greater than 4 pCi/L (148 Bq/m3).51 In addition, it has been determined that decreasing residential radon levels to below 4 pCi/L (148 Bq/m3) would eliminate merely one-third of the lung cancer cases attributable to radon annually.3 Thus, there has been a drive to lower the intervention level. The World Health Organization recently decreased its recommended maximum residential radon level to 2.7 pCi/L (100 Bq/m3).52 The most recent President’s Cancer Panel report recommends decreasing the current EPA action level to below 4 pCi/L.53
Radon mitigation protocols begin with the measurement of radon concentration in buildings. It is recommended that all occupied spaces below the third floor undergo radon measurement. Those areas with a radon level exceeding the cut-off (action level) warrant reduction measures. Radon testing devices include both passive tools that do not need electrical power to function and active devices. Further, the testing may be done over a short-term period within 90 days or over a long-term period greater than 90 days. Long-term detectors are recommended because they provide a value close to the annual average of radon concentration, while taking into account the day-to-day and seasonal concentration variations in indoor air. In general, radon reduction measures encompass techniques that help prevent indoor radon entry and remove any radon that has already entered indoor air.54 These methods are further classified as passive or active, based on the use of a mechanical assist device in the latter. In order to be considered effective, a radon reduction measure should decrease levels by more than 50%. A combination of techniques may be effective in decreasing levels by up to 90%. Active soil depressurization is the most commonly used technique in the United States, and has been found to be the most effective radon reduction measure by the EPA. Furthermore, the efficacy of any measure also depends on the individual characteristics of the building to which it is applied. Table 4 compares radon reduction methods in new construction, as compiled by the EPA.55
Based on their review of the existing mitigation measures in various countries, Rahman and colleagues recommended that radon reduction efforts begin with passive measures to reduce radon entry from the soil. If such methods fail, sub-slab depressurization would be effective and economical for smaller buildings. For larger buildings, increased ventilation in combination with heat exchange methods would be a viable alternative.56
Various studies have analyzed cost-effective detection and prevention strategies.57,58 In a review of measures in the United Kingdom, Gray and coworkers concluded that, since even low to moderate concentrations of radon can cause lung cancer, the most cost-effective policy is to apply basic anti-radon measures in all new dwellings, instead of the 2-step strategy of detection and mitigation.59 The cost of radon mitigation in existing dwellings clearly exceeds that of using radon-resistant construction for new dwellings. The EPA’s guidelines for radon reduction include promotion of radon awareness, use of testing and mitigation measures in existing dwellings, and construction of radon-resistant new dwellings. Cessation of smoking is another important, cost-effective measure to reduce a fraction of radon-related deaths. A recent analysis by Mendez and associates revealed that quitting smoking will decrease the radon-related risk of lung cancer by a factor of 2.60 This reduction will still leave approximately 10,000 lung cancer deaths per year that are solely attributable to radon, hence the importance of radon mitigation measures.
Guidance for Health Care Providers
Although there is overwhelming evidence that supports the carcinogenic potential of radon, lack of awareness in the general population is a major deterrent in the effective implementation of radon mitigation measures. Education guidance for health care providers should include the following:
Because radon is the second-leading cause of lung cancer (after tobacco exposure), it deserves a mention in cancer prevention strategies discussed during office visits.
Most radon-related lung cancer cases occur in smokers; thus, discussions should begin with tobacco cessation advice.
Once high levels of radon are detected, corrective measures should be implemented as soon as possible.
Further information regarding the availability of detectors and correction measures in the United States can be found at the EPA website, at http://www.epa.gov/radon/pubs/citguide.html.43
The WHO Handbook on Indoor Radon is a product of the WHO International Radon Project and describes residential radon exposure from a public health perspective.52 It can be downloaded at http://whqlibdoc.who.int/publications/2009/9789241547673_eng.pdf.
In the absence of a clear association between radon and other malignancies, protection standards continue to be based on lung cancer risk.
Radon is a naturally occurring carcinogen associated with lung cancer. An estimated 21,000 lung cancer deaths per year in the United States are attributable to radon. Initially, radon was thought to be a hazard only to miners, but the risk to the general population due to indoor radon exposure is now well recognized. There is strong experimental and epidemiologic evidence to support this risk. However, predictive measures for risk at low levels of exposure, such as that associated with indoor radon, are still based on a presumed exposure/response relationship. There is some scientific and epidemiologic evidence supporting a linear non-threshold exposure/response relationship, but it remains to be proven beyond doubt. Much advancement has been made in the understanding of the mechanisms of radon-induced injury over the years, and it will continue to be an area of future research. US public policy for radon control as recommended by the EPA encompasses measures to improve radon awareness, detection, and mitigation. A systematic approach toward radon mitigation using existing measures can be strengthened by continued research for more cost-effective measures that would ensure a more universal application. Furthermore, ongoing analysis of the existing methods for efficacy, longevity, and cost will help improve and sustain the quality of life measures in the future. Given that lung cancer continues to be the leading cause of cancer-related deaths globally, efforts for radon mitigation should go hand-in-hand with implementation of smoking cessation strategies.
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Authors: Tarsheen K. Sethi, MD, Moataz N. El-Ghamry, MD, and Goetz H. Kloecker, MD, MSPH