Next Article in Journal
Australian Mental Health Consumers’ Experiences of Service Engagement and Disengagement: A Descriptive Study
Previous Article in Journal
Consequences of the COVID-19 Lockdown in Germany: Effects of Changes in Daily Life on Musical Engagement and Functions of Music
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJERPH
Volume 18
Issue 19
10.3390/ijerph181910466
ijerph-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Environmental/Occupational Exposure to Radon and Non-Pulmonary Neoplasm Risk: A Review of Epidemiologic Evidence

by
Paola Mozzoni
1,2,
Silvana Pinelli
1,
Massimo Corradi
1,2,
Silvia Ranzieri
1,
Delia Cavallo
3 and
Diana Poli
3,*
1
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
2
Centre for Research in Toxicology (CERT), University of Parma, Via A. Gramsci 14, 43126 Parma, Italy
3
INAIL Research, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Via Fontana Candida 1, 00078 Monte Porzio Catone, Italy
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2021, 18(19), 10466; https://doi.org/10.3390/ijerph181910466
Submission received: 7 September 2021 / Revised: 29 September 2021 / Accepted: 29 September 2021 / Published: 5 October 2021
(This article belongs to the Section Environmental Health)
Browse Figure
Review Reports Versions Notes

Abstract

:
Although Radon (Rn) is a known agent for lung cancer, the link between Rn exposure and other non-pulmonary neoplasms remains unclear. The aim of this review is to investigate the role of Rn in the development of tumors other than lung cancer in both occupational and environmental exposure. Particularly, our attention has been focused on leukemia and tumors related to brain and central nervous system (CNS), skin, stomach, kidney, and breast. The epidemiologic literature has been systematically reviewed focusing on workers, general population, and pediatric population. A weak increase in leukemia risk due to Rn exposure was found, but bias and confounding factors cannot be ruled out. The results of studies conducted on stomach cancer are mixed, although with some prevalence for a positive association with Rn exposure. In the case of brain and CNS cancer and skin cancer, results are inconclusive, while no association was found for breast and kidney cancers. Overall, the available evidence does not support a conclusion that a causal association has been established between Rn exposure and the risk of other non-pulmonary neoplasms mainly due to the limited number and heterogeneity of existing studies. To confirm this result, a statistical analysis should be necessary, even if it is now not applicable for the few studies available.

1. Introduction

Radon (Rn), a colorless and odorless radioactive noble gas, originated from the decay of Uranium (U) and Thorium (Th), is found in rocks and soil. Soil is responsible for about 80% of the Rn in atmosphere, water contributes to 19%, and other sources for only 1% [1]. Rn concentration in air depends on the intensity of the source and on dilution factors, both strongly influenced by weather conditions, such as humidity, atmospheric pressure, and wind conditions. Therefore, Rn levels exhibit both daily and seasonal variations, which are often cyclical [2].
Three are the main naturally occurring isotopes of Rn: 219Rn (also known as thoron); 220Rn (also called actinon); and 222Rn, arising from the decay of 235U, 232Th, and 238U, respectively (Figure 1) [3]. The amount of 219Rn and 220Rn in air pollution is small due to their short half-life (3.96 s, and 55.6 s, respectively) that limits their diffusion in the atmosphere before decay. In addition, the scarcity of 235U makes the role of 219Rn negligible. Therefore, the lack of knowledge about 219Rn and 220Rn potential human health effects is due to their unlikely environmental accumulation with consequently reduced human exposure [4], even if their environmental evidence and detrimental effect on human health are described in literature [5]. Most of the radioactivity in the atmosphere attributable to 222Rn is due to its longer half-life (3.82 days) that allows its diffusion from environment to dwellings. 222Rn decays into more chemically reactive progeny such as 218Polonium (Po), 214Lead (Pb), 214Bismuth (Bi), and 214Po (half-life equal to 3,1 min; 26,8 min; 19,9 min; and 1664 µs, respectively), which are able to emit dangerous α and β radiation. Additionally, 218Po and 214Pb are solids that may spread out in the atmosphere by attaching themselves to air particulate and then settle in soil or water through mechanisms of deposition or the action of rain [6,7].
The concentration of Rn outdoors is typically low and, in any case, does not exceed a few tens of Bq/m3 (See Appendix A for Radon measurement units). In fact, Rn escaping from the ground is diluted in a very large volume of air and is rapidly degraded in the atmosphere. On the other hand, in closed places (e.g., homes, offices, schools, etc.) levels vary from a few tens to a few hundred Bq/m3, reaching sometimes thousands of Bq/m3 [8].
Human exposure occurs primarily through inhalation and ingestion, the latter given by Rn dissolved in groundwater. In the field of occupational exposure, high Rn concentrations can be detected in underground places with poor ventilation and in water treatment plants [9]. The highest concentrations to which workers might be frequently exposed occur in mines; in fact, the first studies related to the effects of Rn exposure have been conducted among miners of the underground mines of uranium [10]. As far as the general population is concerned, Rn exposure is mainly due to its presence in dwellings. Rn levels in building vary regionally and according to season and housing characteristics, with higher concentrations in colder months, in homes with poor ventilation, and on the lower floors of houses [11,12,13,14]. Rn enters buildings through various routes, such as cracks in solid floors, construction joints, cracks in walls above and below ground level, gaps in suspended floors, gaps around service pipes and cavities in the walls [15]. Another cause is the depression created between the various rooms and the ground, induced primarily by the temperature difference between the internal and external environment. The pressure difference determines an upward flow of air from the ground (movement from a high to a low-pressure area), causing the chimney effect [16]. In addition, Rn dissolved in groundwater can be released into indoor air during domestic water use, such as cooking, showering, clothes washing, or water boiling, thereby increasing the total inhalation risk [17,18,19].
Because of its presence in living and working environments and its effects on human health, specific laws and regulations have been produced in many countries. Most European States and many non-European countries recommended reference levels for dwellings and workplaces, and some embraced guidelines for construction techniques and for Rn risk management incorporated in the building codes. In Europe, the International Commission on Radiological Protection (ICRP) and The Council of the European Union (EU) have recommended the Member States to take action against Rn in homes and at workplaces. Several European Directives have been succeeded by lowering the limits required for Rn (e.g., 96/143, 96/29, 2013/59). Consequently, each Member State had to lay down the appropriate provisions, whether by legislation, regulation, or administrative action, to ensure compliance with the basic standards, which have been established. In particular, Council Directive 90/143/Euratom recommendation about indoor Rn in dwellings suggested an average concentration of 200 Bq/m3 for new dwellings and 400 Bq/m3 in existing dwellings as level for considering remedial action (90/143/Euratom) [20]. The European Council Directive 96/29/Euratom had stipulated that Member States should have required the carrying out of practices for monitoring work activities linked to a significant increase in worker’ exposure (96/29/Euratom) [21] Later, the Council Directive 2013/59/Euratom laying down basic safety standards for protection against the dangers arising from exposure to ionizing radiation repealed Directive 96/29/Euratom establishing 300 Bq/m3 as a concentration threshold for both dwellings and workplaces in all EU countries. (2013/59/Euratom) [22]. In the United States, where generally the Rn level is measured in pCi/L (i.e., Ci = Curie that represents the activity of one gram of Rn in radioactive equilibrium; pCi = equivalent to 10−12 Curie; 1pCi/l = 37 Bq/m3), a Rn level below 2 pCi/L (74 Bq/m3) is accepted as normal (Radon Zone 3), while an indoor level between 2 and 4 pCi/L (74–148 Bq/m3) is designated as Radon Zone 2 at which the USEPA suggests to perform mitigation. An indoor Rn level above 4 pCi/L (148 Bq/m3) (Action Level) is categorized as Radon Zone 1 where mitigation is deemed necessary because an increased risk for lung cancer has been observed at that exposure level [23]. In Western Australia, the management of radioactive materials is governed by the Radiation Safety Act (1975) [24], and the specific provisions relating to the management of naturally occurring radioactive materials in mining operations are included in the Mines Safety and Inspection Act (1994) [25] and Regulations (1995) [26] which specify the same dose limits for exposed workers. Specifically, the effective dose for workers must not exceed 50 mSv (i.e., Sv = Sievert: unit of measurement equal to the absorbed dose of any ionizing radiation having the same biological efficacy as 1 gray of X-rays) in a single year and 100 mSv over a period of five consecutive years. From this scenario, it is clear how Rn mitigation requirements in most states vary substantially. These discrepancies have public health implications. The influence of EU Directives on Rn exposure may have relevance as a model for standardized international regulations. This is why it would be important to harmonize limit value. A Rn assessment is essential because it allows to obtain information on indoor Rn concentration distribution which are useful for decision making (e.g., for establishing reference levels, for individuation of Rn priority areas).
The concern about occupational and environmental exposure arises from the fact that Rn and its short-lived decay products have been classified as a known pulmonary carcinogen in humans by the International Agency of Research on Cancer since 1988 [27].
Epidemiologic studies support a relationship between Rn exposure and cancer risk, in particular for lung cancer [28,29,30]. Although it is conceivable that Rn may have a role in other cancer diseases, the epidemiologic evidence is not so strong such as for lung cancer. One reason is that due to the bio-kinetics of Rn inhalation in the body, the effective radiation doses reaching specific organs is several times lower than that received by the lungs. Furthermore, there is a lower number of scientific publications studying the relationship between Rn and risks other than lung cancer. For the latter, the average of publications on the main databases such as Pubmed [31], Scopus [32], and Web of Sciences [33] is 18.1%, while for the only Rn lung cancer it reaches 81.9%. In addition, most of these studies evaluate the effect of Rn exposure on multiple organs focusing mostly on the lung and making the extrapolation of the results difficult.
The aim of this review is to analyze the epidemiologic evidence in order to investigate the role of Rn in the development of tumors other than lung cancer in both occupational and environmental exposure. Particularly, leukemia and tumors related to brain and central nervous system (CNS), skin, stomach, kidney, and breast have been investigated focusing on workers, general population, and pediatric population.

2. Materials and Methods

Published reviews of the epidemiology of Rn that formed the basis of our literature search were by the World Health Organization [28], United States Environmental Protection Agency (USEPA) [34], National Council on Radiation Protection and Measurements (NCRP) [35], National Research Council (NRC) [36], International Agency for Research on Cancer (IARC) [37], and National Institute for Occupational Safety and Health Technical Information Center (NIOSHTIC) [38].
Furthermore, a systematic literature search using PubMed, Scopus, and Web of Science databases was performed with the terms and phrases: “radon” and “cancer”, or “other than lung cancer”, or “brain and Central Nervous System (CNS) cancer”, or “leukemia”, or “skin cancer”, or “stomach cancer”, or “breast cancer”, or “occupational exposure”, or “environmental exposure”. We included original articles, reviews, and meta-analyses published in the English language until 2020. The literature was also searched for regulations related to Rn both in occupational and environmental exposure. We completed the search through consulting manually the references of the papers selected to be full-text read.

3. Results

Publications have been analyzed focusing on workers and general and pediatric populations.

3.1. Brain and Central Nervous System (CNS) Cancer

Results are summarized in Table 1a–c.

3.1.1. Workers

Almost all studies in working population were performed in miners. In 1995, Tirmarche et al. studied French uranium miners exposed to Rn concentrations range from 500 to 1000 Bq/m3 in order to calculate the number of expected deaths due to brain cancer. Combined malignant brain tumor, malignant tumors of other parts of the nervous system, and tumors of unspecified nature of the brain and other parts of the nervous system were investigated. A significant risk of death (p-value = 0.03) has been calculated only by excluding the last group (i.e., tumors of unspecified nature of the brain and other parts of the nervous system) [39]. Darby et al. examined mortality from non-lung cancer in an analysis of data from 11 cohorts of underground miners in which Rn-related excess of lung cancer had been established. The study included 64,209 men employed in the mines for 6.4 years on average, receiving average cumulative exposures of 155 working-level months (WLM), and were followed for 16.9 years on average. This study provides considerable evidence that high concentrations of Rn in air do not cause a risk of mortality from cancers other than lung cancer, including brain and CNS cancers [40]. Similarly, in a cohort of iron miners from northern Sweden occupationally exposed to elevated levels of Rn, the mortality was increased for all cancers other than lung cancer, but it was not significantly associated with cumulative exposure to Rn [41]. About ten years later, Vacquier and co-authors in a first study on a cohort of men employed as uranium miners between 1946 and 1990 highlighted a significant excess risk of cancer death for a lung (associated with levels of cumulated radon exposure) and kidney (not associated with radon exposure), but the brain and CNS cancer had not been included [42]. In a later paper, the same authors examined the mortality risks associated with exposure to Rn, external γ- rays, and long-lived radionuclides (LLR) in the French “post-55” sub-cohort, including uranium miners first employed between 1956 and 1990 for whom all three types of exposure were individually assessed. The study highlighted for the first time an increase of mortality for brain and CNS cancer (SMR: 2.00; 95% CI: 1.09–3.35) [45].
On the contrary, the cohort of uranium miners examined from Kreuzer et al., which included 58,987 men employed for at least 6 months from 1946 to 1989 in an uranium mining company in Eastern Germany, highlighted a statistically significant increase in mortality for other than lung cancers (stomach and liver), but not for brain and CNS [43,58]. Finally, in the Colorado Plateau cohort (3358 white miners and 779 miners of another race) a significant risk to develop some cancer types was found but not brain or CNS cancers [44].

3.1.2. General Population

In 1993, Hess et al. demonstrated significant correlation between Rn levels throughout the countries of the state of Maine, USA, and incidence of all cancers, including brain and nervous system cancer [59]. Similarly, twenty years later, a Danish study in a cohort of 57,053 persons observed a statistically significant association between residential Rn and brain cancers. The adjusted incidence rate-ratios (IRR) for primary brain tumor associated with each 100 Bq/m3 increment in average residential Rn levels was 1.96 (95% CI: 1.07–3.58). This association was not modified by air pollution [47]. Later, a paper from a Spanish group observed a significant correlation between residential Rn exposure and brain cancer mortality, with a higher correlation for females. These results were reinforced when the analysis was restricted to municipalities with more than five Rn measurements, showing Spearman’s Rho equal to 0.286 (p-value < 0.001) and 0.509 (p-value < 0.001) for males and females, respectively [48]. Again, another Spanish study highlighted that indoor Rn concentration in Galicia was statistically associated with higher lung, stomach, and brain cancer mortality only among women [49].
In contrast, Monastero et al. reported no relationship between mean Rn levels and CNS cancer incidence in five highly populated and Rn-enriched US states [50], as well as the Turner’s study performed in the American Cancer Society cohort [46].

3.1.3. Pediatric Population

In 1991, the association between groundwater Rn levels and childhood cancer mortality in North Carolina was explored. This study highlighted an increase of the relative risks for several cancers, included brain and CNS tumors [51]. Another study considered children suffering from leukemia and common solid tumors (nephroblastoma, neuroblastoma, rhabdomyosarcoma, and CNS tumors) diagnosed between 1988 and 1993 in Lower Saxony, Germany. Rn measurements were performed for one year in those homes where the children had been living for at least one year, with particular attention posed to those rooms where they had stayed most of the time. The risk estimates were high for solid tumors (OR: 2.61; 95% CI: 0.96–7.13) [52].
In contrast with these results, in a Danish children cohort, the cumulative Rn exposure was not associated with risk for CNS tumor [53], as well as in a Swiss study where a cohort of 997 childhood cancer cases was evaluated. Specifically, compared with children exposed to Rn concentration below the median (<77.7 Bq/m3), adjusted hazard ratios for children with exposure ≥ the 90th percentile (≥139.9 Bq/m3) were 0.93 (95% CI: 0.74–1.16) for all cancers and 1.05 (95% CI: 0.68–1.61) for CNS tumors [54]. Similarly, Kendal et al. reported how Rn exposure was not significant for brain and CNS childhood cancers in children born and diagnosed with cancer or nonmalignant brain tumor in Great Britain between 1980 and 2006, as recorded on the National Registry of Childhood Tumors [55]. Again, in a Norway cohort of 712,674 children with a total of 864 cancer cases 427 of them related to the CNS, an elevated non-significant risk for cancer was observed [56]. An ecological study related to a cohort of 5471 children with CNS tumors demonstrated that there was no association between Rn exposure and childhood CNS tumors incidence (IRR: 1.07; CI: 0.95–1.20 per 100 Bq/m3) [57]. Finally, the results of a review performed on 18 studies (8 on miners, 3 on the general population, and 7 on children) are inconclusive because the available studies are extremely heterogeneous in terms of design and populations [60].

3.2. Leukemia

The main results are described in Table 2a (Workers) and Table 2b (General and Pediatric Population).

3.2.1. Workers

A report of Tomasek et al. demonstrated an increased mortality trend from multiple myeloma with cumulative exposure to Rn and an increasing trend of leukemia mortality with long-lasting employment in uranium mines. Mortality from multiple myeloma, although not significantly increased overall, increased with cumulative exposure to Rn. Instead, mortality from leukemia was not increased overall and was not related to cumulative Rn exposure but did increase with increasing duration of employment in the mines [61]. In a pooled statistical analysis combining 11 epidemiological studies on underground uranium miners, Darby et al. established increased leukemia mortality only in the period of less than 10 years after beginning work at mine [40]. In a case-cohort study in Czech uranium miners, exposure to Rn and its progeny was associated with an increased risk of developing leukemia. Particularly, an increased incidence of all types of leukemia, along with chronic lymphocytic leukemia, in relation to cumulative Rn exposure has been observed. The relative risk (RR) comparing high Rn exposure (110 WLM; 80th percentile) to lower Rn exposure (3 WLM; 20th percentile) was equal to 1.75 (95% CI: 1.10–2.78; p-value = 0.014) for all leukemia subtypes combined and 1.98 (95% CI: 1.10–3.59; p-value = 0.016) for chronic lymphocytic leukemia (CLL) [62].
Kreuzer et al. analyzed a cohort including 58,987 men employed for at least 6 months from 1946 to 1989 at the former Wismut uranium mining company in Eastern Germany. The number of deaths observed for leukemia was close to that expected from national rates. No association between cumulative Rn exposure and leukemia was found, or with chronic lymphatic leukemia (CLL), non-CLL or acute myeloid leukemia (AML) [43].
Zabloska et al. analyzed radiation-related risks of hematologic cancers in the cohort of Eldorado uranium miners and processors first employed in 1932–1980 in relation to cumulative Rn decay products (RDP) exposures and γ-ray doses. The average cumulative RDP exposure was 100.2 working level months (WLM). No statistically significant association between RDP exposure or γ-ray doses, or a combination of both, and mortality or incidence of any hematologic cancer was found [63].
A cohort of 16,434 male underground miners from Czech Republic were exposed to low and moderate levels of Rn gas and other hazards. The SIR was elevated for all leukemias (SIR: 1.51; 95% CI: 1.08–2.07) and for lymphatic and hematopoietic cancers combined (SIR: 1.31; 95% CI: 1.05–1.61) [64].

3.2.2. General Population

With regard to environmental exposure, in 1989 Lucie suggested a relationship between Rn concentration and the incidence of leukemia in England and Wales [73]. Subsequently, significant correlations between Rn concentration and several leukemia subtypes in England and Wales have been observed [74]. Similarly, Eatough et al. observed a significant correlation between standardized registration ratio (SRR) for monocytic leukemia and the Rn concentration by county in England. The authors showed these results had been unlikely produced by regional variations in registration efficiency or by being confounded due to social class or to gamma radiation exposure [65]. In line with these data, Henshaw et al., suggested that for the world average Rn exposure of 50 Bq/m3, 13–25% of myeloid leukemia at all ages might be caused by Rn [70].

3.2.3. Pediatric Population

Between 1976 and 1985 in Britain, Thorne and colleagues evaluated the incidence of childhood malignancies compared to postcode sectors with a Rn exposure ≥ 100 Bq/m3 with sectors with a Rn exposure < 100 Bq/m3. No significant difference in the incidence rate as compared to all cancers and no association between Rn exposure and overall rate of childhood malignancy were found [66]. Steinbuch et al. evaluated the risk factors for childhood acute myeloid leukemia associated with indoor residential Rn level within a larger interview-based case–control study performed over 120 institutions in the USA and Canada. A total of 173 cases and 254 controls were analyzed and no association was observed between Rn exposure and risk of acute myeloid leukemia, with adjusted OR of 1.2 (95% CI 0.7–1.8) for 37–100 Bq/m3 and 1.1 (95% CI: 0.6–2.0) for >100 Bq/m3 compared with <37 Bq/m3 [67]. In another study, including 505 cases and 443 age matched controls, the association between the incidence of acute lymphatic leukemia (ALL) in children under age 15 years and indoor Rn exposure was investigated. Mean radon concentration was lower for case subjects (65.4 Bq/m3) than for control subjects (79.1 Bq/m3). Therefore, the results from this analytic study provide no evidence for an association between indoor Rn exposure and childhood ALL [68].
Kaletsch et al. conducted a case/control study on 82 cases of childhood leukemia in Lower Saxony. Long term Rn measurements were carried out in dwellings where the children had lived for at least one year. There was no association between higher radon levels and leukemia [OR: 1.30; 95% CI: 0.32–5.33)] [52].
One of the largest of the available case/control studies was conducted in the United Kingdom. The parents of 3838 children with cancer (1461 of which were of acute lymphoblastic leukemia) and of 7629 children without cancer were interviewed. The arithmetic mean Rn concentration measured in the homes was 24.0 Bq/m3, with the mean concentration being slightly lower in case homes than in control homes. No evidence to support an association between higher Rn concentrations and risk of any of the childhood cancers was then found [69].
In contrast, the analysis performed by Henshaw et al. for myeloid leukemia in UK children suggested that the 6–12% incidence might be attributed to Rn exposure, the figure becoming 23–43% in Cornwall, where Rn levels are higher [70]. In the same way, for data from throughout Britain, a significant correlation for childhood leukemia with Rn concentration by county was observed [75]. Gilman and Knox conducted a study about 8500 cases of childhood cancers diagnosed up to age 15 and born in Great Britain between 1953 and 1964. There was a significant positive trend of mortality with increasing Rn exposure for leukemias and lymphomas (RR. 1.06, CI 0.99–1.12), just failing to reach statistical significance [71].
In 2000, a Swedish study assessed 53,146 children, and among these, 90 developed hematologic malignancies. Standardized mortality ratios (SMR) for acute lymphatic leukemia among children born in high, normal, and low risk areas were 1.43, 1.17, and 0.25, respectively. The RR for normal risk group and high-risk group as compared with the low-risk group was 4.64 (95% CI: 1.29–28.26) and 5.67 (95% CI: 1.06–42.27). The association between acute lymphatic leukemia and continued residence in normal or high-risk areas showed a similar trend. No association between Rn risk levels and any other malignancy was seen. This study evidenced that children born in and continuously living in areas classified as high and normal risk for background radiation of Rn have a higher incidence of acute lymphatic leukemia [72]. Later in 2012, a meta-analysis of case-control studies was conducted to uncover the influence of Rn exposure on childhood leukemia. The combined OR for calculating the lowest exposure of Rn on the high incidence of childhood leukemia was 1.37 (95% CI: 1.02–1.82), suggesting a weak association. A major source of uncertainty was the Rn dose estimate [76]. However, in a 2016 review about environmental exposure and risk of childhood leukemia, Schüz concluded that radiation is not a contributor to the global childhood leukemia burden [77].

3.3. Skin Cancer

As regards Rn exposure and skin cancer, scientific works are mainly focused on the general population (See Table 3).

General Population

The American Cancer Prevention Study II (CPS-II), a large prospective study of nearly 1.2 million participants recruited in 1982 by the American Cancer Society, highlighted no association between residential Rn and any other mortality cause beyond lung cancer or chronic obstructive pulmonary disease. With regard to the relationship with skin cancer, the authors calculated HRs of 1.08 (95% CI: 0.88–1.33) and 0.70 (95% CI: 0.42–1.19) per 100 Bq/m3 in mean county-level residential Rn for malignant melanoma and non-melanoma skin cancer mortality, respectively [46]. In 1996, Etherington et al., studying the relationship between domestic Rn levels and cancer in southwest England, observed that only non-melanoma skin cancers showed a significant increase in incidence in the high-Rn sectors (≥100 Bq/m3) compared to the low-Rn sectors (<60 Bq/m3) [78]. Later, still in the southwest of England, the ecological epidemiology data provided no evidence for elevated skin cancer risks at Rn levels <100 Bq/m3 [84]. Wheeler et al. found an association between Rn levels in Southwest England and incidence of squamous cell carcinoma (SCC), but not for basal cell carcinoma (BCC) or malignant melanoma [79]. The same authors did not find an association with incidence of non-melanoma skin cancer (SCC and BCC combined) [80]. In a cohort study in Galicia performed on 2294 subjects, no association appeared for several tumors except for melanoma [82]. In a Danish cohort, Bräuner et al. found a statistically significant association between basal cell carcinoma and Rn (IRR: 1.14; 95% CI: 1.03–1.27) but not for squamous cell carcinoma (IRR: 0.90; 95% CI 0.70–1.37) and malignant melanoma (IRR: 1.08; 95% CI: 0.77–1.50) [81]. In contrast, in a study conducted in Switzerland, a significant positive association with malignant melanoma mortality and Rn exposure was observed with an HR of 1.16 (95% CI: 1.04–1.29) per 100 Bq/m3 [83]. Finally, Denman et al., considering the Rn levels in abandoned mines and the lung and skin dose received by visitors, highlighted the increased lifetime risk of skin cancer due to a 1 h exposure in each mine. The results indicated that if visitors ensure that their Rn exposure is below the National Radiological Protection Board (NRPB) guideline of 106 Bq/m3 h in 1 year, the skin dose and effective dose will both be below the annual limits for UK radiation workers and below the levels at which any acute skin effect will occur [85].

3.4. Stomach Cancer

Table 4 summarized the main results related to workers and general population.

3.4.1. Workers

Deaths from several cancer types, including stomach tumor, are elevated among the miners. In a collaborative analysis of data from 11 cohorts of underground miners in which Rn-related excesses of lung cancer had been established, Darby et al. examined the mortality from non-lung cancer. The study included 64,209 men who were employed in the mines for 6.4 years on average. Among 28 individual cancer categories, statistically significant increases in mortality for cancers of the stomach (O/E: 1.33; 95% CI: 1.16–1.52) were observed [40]. Similarly, a cohort of underground miners in the Czech Republic between 1977 and 1992 was selected from the registry Příbram Uranium Industry (UI) employees. There was a 52% increase in deaths from all malignant causes compared with expected rates (SMR: 1.52, 95% CI: 1.44–1.60). In addition to lung cancer, mortality was also higher for other cancer subtypes, particularly stomach cancer (SMR: 1.27; 95% CI: 1.02–1.51), as well as all cancer incidence, stomach cancer included (SIR: 1.37; 95% CI: 1.11–1.63) [64]. In Swedish iron miners occupationally exposed to elevated levels of the radioactive gas Rn, mortality was increased for all cancers other than lung cancer. With regard to stomach cancer, ratio of observed to expected deaths was 1.45, with a 95% C.I. of 1.04–1.98. However, the authors underlined that the increase in stomach cancer mortality might be due to the considerable number of Finns in the workforce, in which stomach cancer rates were considerably higher than in Swedish population. In addition, mortality was not significantly associated with cumulative Rn exposure [41]. Finally, in a cohort of 28,546 workers in Ontario uranium mines, no association was observed between increasing cumulative Rn exposure and other than lung cancer (e.g., stomach, leukemia, kidney, and extrathoracic airways) [86].

3.4.2. General Population

In a retrospective analysis that compared Rn levels for each county in Pennsylvania to the incidence and mortality of gastrointestinal cancer, a positive correlation was found for stomach cancer in females, and the mortality of stomach cancer for male, female, and total population [88]. Messier et al. provided epidemiological evidence of a positive association between groundwater Rn concentration and an increase in the probability of a stomach cancer [87]. Moreover, Lopez-Abente evaluated the cancer mortality in Galicia and residential Rn levels. For the whole study period (1999–2008), mortality data for each of the 313 Galician municipalities were drawn from the records of the National Statistics Institute. Expected cases were computed using Galician mortality rates for 14 types of malignant tumors as reference, with a total of 56,385 deaths due to the tumors analyzed. The effect estimates of indoor Rn (3371 sampling points) were adjusted for several parameters, such as sociodemographic variables, altitude, and arsenic topsoil levels. The results showed a statistical association between twofold increase in indoor Rn and several cancers in women, included stomach cancer (RR: 1.174; 95% CI: 1.022–1325) [49]. In contrast, an epidemiologic study conducted in Finland to evaluate the risk of developing stomach cancer due to the presence of Rn in drinking water showed no association (HR = 0.68, 95% CI: 0.29 –1.59 at 100 Bq/L water), even for Rn concentrations exceeding 300 Bq/L. This study was conducted for the very high concentrations of several naturally occurring radionuclides in the Finland ground. Only subjects using drilled wells as a source of drinking water were included in the study, and 1492 were the stomach cancers diagnosed during 1981–1995 from the Finnish Cancer Registry [89].

3.5. Kidney Cancer

Few scientific works studied Rn exposure and kidney cancer and they are mainly focused on workers (see Table 5).

Workers and General Population

In an extended follow-up study (1946–1990) performed on 4140 French miners exposed to Rn for at least 1 year with an average cumulative exposure of 36.6 WLM, a significant excess of kidney cancer deaths was observed (SMR: 2.0; 95% CI: 1.22–3.09). However, no association with cumulative Rn exposure was found [42]. Similarly, Navaranjan et al., evaluating an Ontario uranium miner cohort consisting of 28,546 male miners with a mean cumulative Rn exposure of 21.0 WLM, observed an association with Rn exposure only for lung cancer [86]. Similar results were obtained in French (n = 3377) and German (n = 58,986) cohorts of uranium miners where deaths from kidney cancer were analyzed. In detail, no significant excess of kidney cancer mortality had been observed neither in the French cohort (SMR: 1.49, 95% CI: 0.73–2.67) nor in the German cohort (SMR: 0.91; 95% CI: 0.77–1.06]). Moreover, no significant association between kidney cancer mortality and any type of occupational Rn exposure or kidney equivalent dose had been observed [90]. Finally, in a careful and precise meta-analysis, Chen et al. analyzed several studies carried out in order to verify the relationship between kidney cancer and Rn exposure. Authors concluded how it was not possible to affirm a clear correlation mainly for the lack of homogeneity in the exposure assessment, for the different sample sizes (from 779 to 28,546) and because in many cases kidney cancer mortality rather than incidence was evaluated, thus underestimating the carcinogenic effects of Rn on the kidney. In addition, most of the studies were carried out on mine workers with the possibility of co-exposure to other carcinogenic mineral products such as arsenic, silica dust, and gamma radiation [91].

3.6. Breast Cancer

Results, mainly focus on general population, are reported in Table 6.

Workers and General Population

Increased breast cancer incidence was observed among former female employees of a Missouri school with elevated Rn levels [93]. In contrast, ecologic studies in the U.S. showed no association between county-level Rn concentrations and breast cancer incidence [95]. Later, a perspective analysis carried out in the American Cancer Society cohort showed no association between Rn exposure and breast cancer-related mortality [46]. Recently, also in the USA, VoPham et al. examined the association between environmental Rn levels and breast cancer incidence in a prospective cohort of non-occupationally exposed of 112,639 females. Increasing Rn exposure was not associated with breast cancer risk overall. However, women in the highest quintile of exposure (≥74.9 Bq/m3) showed an elevated risk of ER−/PR- breast cancer compared to women in the lowest quintile (<27.0 Bq/m3). No association was observed for ER+/PR+ breast cancer [95]. Finally, breast cancer incidence in Iceland resulted higher among residents of high temperature geothermal areas and higher level of Rn in water compared to residents of non-geothermal areas [93].

4. Discussion

The possible etiologic relationship between Rn and tumor sites other than lung, as well as the pathogenic mechanism, are controversial. In this review, we analyzed the epidemiologic evidence in the development of tumors other than lung cancer in both occupational and environmental Rn exposure. Several large-scale studies were launched in an effort to investigate factors possibly affecting dose–response relationship and Rn exposure in other than lung cancer. As far as occupational exposure is concerned, literature data refer almost exclusively to miners, while for environmental exposure, the research work focuses on both inhalation and ingestion exposure due to the presence of Rn in water. For their greater risk of developing cancer diseases because of radiation exposure compared to adults, the outcomes of studies related to children were also analyzed.
Even if the mechanism whereby Rn initiates tumorigenesis is not completely known, literature data indicate that there are several tumor pathologies that can develop following occupational and environmental exposure. Lung cancer is certainly the most frequent disease for which the results of the literature largely confirm the etiological role of Rn and its products. However, their effect in reference to other organs is still rather elusive and sometimes contradictory. The risk depends on the concentration of Rn and its products as well as on the time spent in their presence [96], even if there is general agreement in the assumption that there is no exposure threshold value below which one can be considered protected. The probability of oncogenic phenomena, in fact, does not depend on the number of radiations that affect a single cell, but on the total number of interactions between cells and radiations, which is proportional to the exposure (International Commission on Radiation Units and Measurements, 1980.) [36].
Among other than lung cancers, we first considered brain and CNS cancer because they have been associated with ionizing radiation exposure [97,98]. The cumulative dose in brain could be a consequence to the transport of Rn and its progeny through the blood together with the fact that particles with aerodynamic diameter around 1 nm and a high extrathoracic deposition including the nasal cavity could reach the brain via the olfactory neuronal pathway [47]. Additionally, it has been proposed that macrophages might phagocyte small solid particles in the lungs that could reach the brain through the blood [99]. The weight of evidence from high-dose occupational studies suggests Rn’s potential role in brain and CNS cancer development. Nevertheless, very few studies have assessed the relationship between Rn levels and brain or CNS tumors. Most studies of mineworkers showed no relationship between occupational exposure and incidence or mortality for these cancers, while assessment of general population provided mixed results. Some papers have evaluated the impact of Rn not only in adults but also in children. In fact, CNS tumors are the second most common cancer worldwide in children aged 0–14 years, after leukemia. In addition, the United Nations Scientific Committee on the Effects of Atomic Radiation has suggested a greater risk for children compared to adults of radiation-induction of some cancer types, including CNS tumors [100]. Despite this, even in the case of children, results are inconclusive.
Similarly, risks of developing leukemia following protracted exposure to very low levels of radiation, such as those due to background radiation, are still in dispute. It has been clearly established that acute or repeated exposure to high dose ionizing radiation induces leukemia. Less is known about the effects of Rn decay alpha particles on the bone marrow. However, a recent study reported that the bronchial mucosa has an abundance of circulating lymphocytes, thus suggesting that Rn decay particles exposures could be associated with hematologic cancers originating from these cells [101]. Several studies evaluated leukemia related to occupational and environmental Rn exposure, suggesting a correlation between indoor levels and leukemia incidence at all ages [65,70,73,74,102]. With regard to childhood leukemia, the most common cancer diagnosed in children worldwide, Rn level in dwellings showed an increase in risk in numerous studies [70,71], but bias and confounding factors cannot be ruled out as possible explanations.
Environmental Rn is also relevant for skin exposure because it attaches to aerosol particles in the air, which adhere to the human skin via electrostatic attraction. Subsequently, the alpha particles from Rn decay irradiate the skin’s outer layer. Therefore, the skin receives the second-highest dose after the respiratory tract; an annual dose for the skin at 200 Bq/m3 is estimated to be 25 mSv [103]. The critical cells in the skin are located in the basal layer of the epidermis, and the emitted alpha particles must penetrate the outer layers to reach these cells. Eatough et al. estimated that, for nuclides attached to the actual skin surface, the dose to the basal layer is around 0.5 µSv decay-1 cm2 for 218Po, which emits a 6.0 MeV alpha particle, and 1 µSv decay-1 cm2 for 214Po, with a 7.69 MeV alpha [104]. Despite this, only scarce research on the association between skin cancer and Rn has been conducted with mixed results due to low numbers and heterogeneity of studies.
Stomach cancer has been considered because groundwater is a source of indoor air contamination due to Rn’ transfer from water to air during showers, laundry, and washing dishes. Rn dissolved in water might be riskier for stomach cells because the stomach is a storage organ and exposure might be prolonged [105]. Various models have been developed for estimating the radiation dose to different organs and tissues from ingested Rn, but there is no consensus about the doses. The NRC has proposed a conversion factor of 3.5 × 10−9 Sv/Bq for calculating the dose to the stomach due to Rn in drinking water [106]. The results of studies conducted to verify an association between exposure to Rn and stomach cancer are mixed, although with some prevalence for results with a positive association.
The hypothesis that Rn can cause kidney cancer is biologically plausible because the kidney filters Rn and its decay products from the blood. During this process, the radioactive alpha particles interact with renal cells directly and exert carcinogenic effects on the kidney [70]. Again, few studies have been reported about kidney cancers and Rn exposure, and these only referred to workers. Generally, no association has been found, even if a possible association cannot be definitively excluded.
Though the molecular mechanisms underlying the effects of Rn on breast cancer risk are not fully understood, Rn and its decay products have been suspected to deliver radiation doses to breast tissue [95]. In fact, based on its lipophilic properties, biokinetic models estimated the deliverable concentrations of Rn decay products detected in the breast at an annual dose of 1000 Bq/L (or 2.7 × 104 pCi/L) [99]. However, even in the case of breast cancer, few studies have been carried out about the association between Rn exposure and the development of neoplasia, and generally, increasing exposure was not associated with breast cancer risk overall.
Because of considerable experience gained by studying health effects in miners who worked in Rn-rich environments, the radioactive Rn and its progeny were identified as a cause of lung-cancer [36]. The lung is the main target organ, but it should not be considered the exclusive one. Rn enters the body principally through the respiratory system where further decay occurs, causing oxidative damage to DNA, proteins, and lipids (UNSCEAR, 2000). Rn and its progeny can settle in lungs, where they continue to undergo radioactive decay and give a radiation dose to tissues, potentially capable of irreversibly damaging the cells. Moreover, from the respiratory tree, they can pass the capillary- alveolus barrier and spread systemically to other organs. Alpha particles represent the predominant form of radiation emitted as a result of the decay of Rn (Figure 1). The most substantial alpha emitters from Rn decay are 218Po (6.0 MeV) and 214Po (7.69 MeV), and they have penetration depths of 47 µm and 70 µm, respectively [99], suggesting high levels of irradiation, particularly of the bronchial epithelium and at bifurcation sites, when inhaled into the lungs [3,107]. Inhaled decay products, largely attached to particulate matter always present in the air, settle on the walls of the respiratory system and from here irradiate, through alpha radiation, bronchial cells. Despite their limited tissue penetration capability, alpha particles can cause significant biological damage in exposed tissue due to their high relative biological effectiveness. In fact, they generate free radicals and oxidative stress, which can directly damage DNA in exposed cell nuclei. A variety of genetic lesions, including chromosomal damage, gene mutations, induction of micronuclei, and sister chromatid exchange (SCE), have been associated with the DNA damaging effects of alpha particles [108,109,110,111,112,113,114]. Rn exposure also correlates with tumor mutation burden (TMB), and subjects with a high exposure have almost twice as many mutations/Mb compared with those with low exposures. Apparently, this mutational signature is associated with defective DNA mismatch repair [115]. There is also evidence that adjacent cells may sustain damage via a “bystander effect”, phenomenon for which no irradiated cells respond to signals emitted by adjacent irradiated cells [116]. Brenner et al. suggests that the bystander effects can result in non-linear dose–response relations and inverse dose–rate effects [117]. Several identified outcomes have been attributed to the bystander effect including chromosome aberration (CAs), micronuclei formation (MN) and sister chromatid exchange (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 [112,118,119,120]. However, recently, much interest has been generated by the theory of hormesis according to which low levels of radiation exposure could have a protective effect. In the case of Rn, this theory refers to a protective effect of low-level Rn 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 [121,122,123,124].

5. Conclusions

Epidemiological data on Rn exposure and cancer risk confirm the lack of a clear prevalence of other than lung cancer. This is mainly due to the limited number of studies but also to the fact that they are heterogeneous with bias or several confounding factor, which makes the results less reliable. The study of Rn exposure and its health effects includes many aspects ranging from risk assessment to techniques for reduction, passing through the identification of areas with high concentrations, knowledge of the factors affecting concentrations, measurement techniques, remedial actions, and the definition of regulations. Each of these aspects requires considerable efforts and skills, and the investigation methods must always deal with the complexity of the phenomenon due to the multiplicity of sources that produce it.
The health risks associated with exposure to Rn appear to be high and require the definition of investigation plans at an international level, for further development of policies to prevent and reduce the risk. A careful evaluation and an in-depth study of the pathogenetic mechanisms that exist between exposure to Rn and the onset of pathological processes are required, in order to implement more effective primary prevention.

Author Contributions

Conceptualization, P.M. and D.P.; methodology, P.M. and D.P.; validation, P.M., D.P., S.P., M.C. and S.R.; formal analysis, P.M. and D.P.; investigation, P.M., D.P., S.R. and S.P.; data curation, S.P., D.C. and M.C.; writing—original draft preparation, P.M. and D.P.; writing—review and editing, M.C., S.R. and D.C.; supervision, P.M. and D.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Radon Measurement Units

  • Bequerel (Bq) = one radioactive disintegration per second. It is a measure of radioactivity;
  • Bq/m3 = number of decays of Rn per second in one cubic meter of air;
  • Curie (Ci) = the activity of one gram of Rn in radioactive equilibrium;
  • pCi = 10−12 Curie;
  • pCi/l = 37 Bq/m3;
  • Sievert (Sv) = absorbed dose of any ionizing radiation having the same biological efficacy as 1 gray of X-rays;
  • mSv = 10−3 Sv;
  • Working Level (WL) = any combination of short-lived radon daughters in 1 L of air with the potential of emitting 1.3 × 105 MeV of alpha particle energy during decay;
  • Working Level Month (WLM) = 1 WL exposure for 170 h.

References

  1. Polpong, P.; Bovornkitti, S. Indoor radon. J. Med. Assoc. Thai. 1998, 81, 47–57. [Google Scholar]
  2. Friedmann, H.; Baumgartner, A.; Bernreiter, M.; Gräser, J.; Gruber, V.; Kabrt, F.; Kaineder, H.; Maringer, F.J.; Ringer, W.; Seidel, C.; et al. Indoor radon, geogenic radon surrogates and geology—Investigations on their correlation. J. Environ. Radioact. 2017, 166, 382–389. [Google Scholar] [CrossRef]
  3. Robertson, A.; Allen, J.; Laney, R.; Curnow, A. The cellular and molecular carcinogenic effects of radon exposure: A review. Int. J. Mol. Sci. 2013, 5, 14024–14063. [Google Scholar] [CrossRef] [Green Version]
  4. 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] [CrossRef]
  5. Steinhausler, F.; Hofmann, W.; Lettner, H. Thoron exposure of man: A negligible issue? Radiat. Prot. Dosim. 1994, 56, 1–4. [Google Scholar] [CrossRef]
  6. Amrane, M.; Oufni, L.; Misdaq, M.A. Attached and unattached fractions of short-lived radon decay products in outdoor environments: Effect on the human respiratory system. Radiat. Prot. Dosim. 2014, 162, 400–409. [Google Scholar] [CrossRef] [PubMed]
  7. Porstendörfer, J.; Pagelkopf, P.; Gründel, M. Fraction of the positive 218Po and 214Pb clusters in indoor air. Radiat. Prot. Dosim. 2005, 113, 342–351. [Google Scholar] [CrossRef] [PubMed]
  8. Appleton, J.D. Radon: Sources, health risks, and hazard mapping. Ambio 2007, 36, 85–89. [Google Scholar] [CrossRef] [Green Version]
  9. Daniels, R.D.; Schubauer-Berigan, M.K. Radon in us workplaces: A review. Radiat. Prot. Dosim. 2017, 176, 278–286. [Google Scholar] [CrossRef]
  10. Craft, B.F.; Oser, J.L.; Norris, F.W. A method for determining relative amounts of combined and uncombined radon daughter activity in underground uranium mines. Am. Ind. Hyg. Assoc. J. 1966, 27, 154–159. [Google Scholar] [CrossRef]
  11. Jedrychowski, W.; Flak, E.; Wesolowski, J.; Liu, K.S. Relation between residential radon concentrations and housing characteristics. The Cracow Study. Cent. Eur. J. Public Health 1995, 3, 158–160. [Google Scholar]
  12. Stanley, F.K.; Zarezadeh, S.; Dumais, C.D.; Dumais, K.; MacQueen, R.; Clement, F.; Goodarzi, A.A. Comprehensive survey of household radon gas levels and risk factors in southern Alberta. CMAJ Open 2017, 28, E255–E264. [Google Scholar] [CrossRef] [Green Version]
  13. Lee, C.; Lee, D. Review of domestic and international methods of measuring radon in residential buildings. Ann. Occup. Environ. Med. 2016, 28, 14. [Google Scholar] [CrossRef] [Green Version]
  14. Noh, J.; Sohn, J.; Cho, J.; Kang, D.R.; Joo, S.; Kim, C.; Shin, D.C. Residential radon and environmental burden of disease among Non-smokers. Ann. Occup. Environ. Med. 2016, 28, 12. [Google Scholar] [CrossRef] [Green Version]
  15. Bard, D.; Tirmarche, M.; Pirard, P. Exposition au radon et risques pour la santé publique [Radon exposure and risks for public health]. Ann. Pharm. Fr. 2000, 58, 373–382. (In French) [Google Scholar]
  16. Nazaroff, W.M. Entry by pressure-driven flow or molecular diffusion? A reassessment of 222Rn concentrations measured in an energy-efficient house. Health Phys. 1988, 55, 1005–1011. [Google Scholar] [CrossRef]
  17. Villalba, L.; Colmenero Sujo, L.; Montero Cabrera, M.E.; Cano Jiménez, A.; Rentería Villalobos, M.; Delgado Mendoza, C.J.; Jurado Tenorio, L.A.; Dávila Rangel, I.; Herrera Peraza, E.F. Radon concentrations in ground and drinking water in the state of Chihuahua, Mexico. J. Environ. Radioact. 2005, 80, 139–151. [Google Scholar] [CrossRef]
  18. Chen, J. A discussion on issues with radon in drinking water. Radiat. Prot. Dosim. 2019, 185, 526–531. [Google Scholar] [CrossRef]
  19. Cho, B.W.; Kim, H.K.; Kim, M.S.; Hwang, J.H.; Yoon, U.; Cho, S.Y.; Choo, C.O. Radon concentrations in the community groundwater system of South Korea. Environ. Monit. Assess. 2019, 191, 189. [Google Scholar] [CrossRef]
  20. Official Journal on European Community, N° L 80/26, 27.3.90. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31990H0143&from=IT (accessed on 28 September 2021).
  21. Official Journal on European Community, N° L 159/1, 29.6.96. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31996L0029&from=EN (accessed on 28 September 2021).
  22. Official Journal on European Community, N° 13/1, 17.1.2014. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32013L0059&qid=1630058541624&from=EN (accessed on 28 September 2021).
  23. Gordon, K.; Terry, P.D.; Liu, X.; Harris, T.; Vowell, D.; Yard, B.; Chen, J. Radon in Schools: A Brief Review of State Laws and Regulations in the United States. Int. J. Environ. Res. Public Health 2018, 15, 2149. [Google Scholar] [CrossRef] [Green Version]
  24. Western Australian Legislation, Radiation Safety Act 1975. Available online: https://www.legislation.wa.gov.au/legislation/statutes.nsf/main_mrtitle_784_homepage.html (accessed on 28 September 2021).
  25. Western Australian Legislation, Mines Safety and Inspection Act 1994. Available online: https://www.legislation.wa.gov.au/legislation/statutes.nsf/main_mrtitle_599_homepage.html (accessed on 28 September 2021).
  26. Western Australian Legislation, Mines Safety and Inspection Regulations 1995. Available online: https://www.legislation.wa.gov.au/legislation/statutes.nsf/main_mrtitle_1819_homepage.html (accessed on 28 September 2021).
  27. Bolck, F. Man-Made Mineral Fibres and Radon IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans; IARC: Lyon, France, 1990; Volume 43. [Google Scholar]
  28. WHO. Indoor Radon a Public Health Perspective. A Public Health Perspective; WHO: Geneva, Switzerland, 2009. [Google Scholar]
  29. Puskin, J.S.; James, A.C. Radon exposure assessment and dosimetry applied to epidemiology and risk estimation. Radiat. Res. 2006, 166, 193–208. [Google Scholar] [CrossRef] [PubMed]
  30. Krewski, D.; Lubin, J.H.; Zielinski, J.M.; Alavanja, M.; Catalan, V.S.; Field, R.W.; Klotz, J.B.; Létourneau, E.G.; Lynch, C.F.; Lyon, J.L.; et al. A combined analysis of North American case-control studies of residential radon and lung cancer. J. Toxicol. Environ. Health Part A 2006, 69, 533–597. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. National Library of Medicine. Available online: https://pubmed.ncbi.nlm.nih.gov/ (accessed on 28 September 2021).
  32. Elsevier. Available online: https://scopus.com (accessed on 28 September 2021).
  33. Web of Science. Available online: https://webofscience.com (accessed on 28 September 2021).
  34. U.S. Environmental Protection Agency–Radon. Available online: https://www.epa.gov/radon (accessed on 28 September 2021).
  35. Cool, D.A.; Kase, K.R.; Boice, J.D. NCRP Report no.180-management of exposure to ionizing radiation: NCRP radiation protection guidance for the United States. J. Radiol. Prot. 2019, 39, 966–977. [Google Scholar] [CrossRef] [PubMed]
  36. Beir, V.I.; National Research Council. Committee on Health Risks of Exposure to Radon (BEIR VI). Health Effects of Exposure to Radon: BEIR VI; National Academies Press: Washington, DC, USA, 1999. [Google Scholar]
  37. IARC-WHO. Available online: https://www.iarc.who.int/ (accessed on 28 September 2021).
  38. Center for Disease Control and Prevention - The National Institute for Occupational Safety and Health (NIOSH). Available online: https://www.cdc.gov/niosh/ (accessed on 28 September 2021).
  39. Tirmarche, M.; Raphalen, A.; Allin, F.; Chameaud, J.; Bredon, P. Mortality of a cohort of French uranium miners exposed to relatively low radon concentrations. Br. J. Cancer 1993, 67, 1090–1097. [Google Scholar] [CrossRef] [Green Version]
  40. Darby, S.C.; Whitley, E.; Howe, G.R.; Hutchings, S.J.; Kusiak, R.A.; Lubin, J.H.; Morrison, H.I.; Tirmarche, M.; Tomásek, L.; Radford, E.P.; 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] [CrossRef]
  41. Darby, S.C.; Radford, E.P.; Whitley, E. Radon exposure and cancers other than lung cancer in Swedish iron miners. Environ. Health Perspect. 1995, 103 (Suppl. 2), 45–47. [Google Scholar] [CrossRef] [Green Version]
  42. Vacquier, B.; Caer, S.; Rogel, A.; Feurprier, M.; Tirmarche, M.; Luccioni, C.; Quesne, B.; Acker, A.; Laurier, D. Mortality risk in the French cohort of uranium miners: Extended follow-up 1946-1999. Occup. Environ. Med. 2008, 65, 597–604. [Google Scholar] [CrossRef]
  43. Kreuzer, M.; Walsh, L.; Schnelzer, M.; Tschense, A.; Grosche, B. Radon and risk of extrapulmonary cancers: Results of the German uranium miners’ cohort study, 1960–2003. Br. J. Cancer 2008, 99, 1946–1953. [Google Scholar] [CrossRef]
  44. Schubauer-Berigan, M.K.; Daniels, R.D.; Pinkerton, L.E. Radon exposure and mortality among white and American Indian uranium miners: An update of the Colorado Plateau cohort. Am. J. Epidemiol. 2009, 169, 718–730. [Google Scholar] [CrossRef] [Green Version]
  45. Vacquier, B.; Rage, E.; Leuraud, K.; Caër-Lorho, S.; Houot, J.; Acker, A.; Laurier, D. The influence of multiple types of occupational exposure to radon, gamma rays and long-lived radionuclides on mortality risk in the French “post-55” sub-cohort of uranium miners: 1956–1999. Radiat. Res. 2011, 176, 796–806. [Google Scholar] [CrossRef]
  46. Turner, M.C.; Krewski, D.; Chen, Y.; Pope, C.A., 3rd; Gapstur, S.M.; Thun, M.J. Radon and nonrespiratory mortality in the American Cancer Society cohort. Am. J. Epidemiol. 2012, 176, 808–814. [Google Scholar] [CrossRef] [Green Version]
  47. Bräuner, E.V.; Andersen, Z.J.; Andersen, C.E.; Pedersen, C.; Gravesen, P.; Ulbak, K.; Hertel, O.; Loft, S.; Raaschou-Nielsen, O. Residential radon and brain tumour incidence in a Danish cohort. PLoS ONE. 2013, 8, e74435. [Google Scholar] [CrossRef]
  48. Ruano-Ravina, A.; Aragonés, N.; Kelsey, K.T.; Pérez-Ríos, M.; Piñeiro-Lamas, M.; López-Abente, G.; Barros-Dios, J.M. Residential radon exposure and brain cancer: An ecological study in a radon prone area (Galicia, Spain). Sci. Rep. 2017, 7, 3595. [Google Scholar] [CrossRef] [Green Version]
  49. López-Abente, G.; Núñez, O.; Fernández-Navarro, P.; Barros-Dios, J.M.; Martín-Méndez, I.; Bel-Lan, A.; Locutura, J.; Quindós, L.; Sainz, C.; Ruano-Ravina, A. Residential radon and cancer mortality in Galicia, Spain. Sci. Total Environ. 2018, 610, 1125–1132. [Google Scholar] [CrossRef]
  50. Monastero, R.N.; Meliker, J.R. Incidence of brain and spinal cord cancer and county-level radon levels in New Jersey, Wisconsin, Minnesota, Pennsylvania, and Iowa, USA. Environ. Geochem. Health 2020, 42, 389–395. [Google Scholar] [CrossRef]
  51. Collman, G.W.; Loomis, D.P.; Sandler, D.P. Childhood cancer mortality and radon concentration in drinking water in North Carolina. Br. J. Cancer 1991, 63, 626–629. [Google Scholar] [CrossRef] [Green Version]
  52. Kaletsch, U.; Kaatsch, P.; Meinert, R.; Schüz, J.; Czarwinski, R.; Michaelis, J. Childhood cancer and residential radon exposure–results of a population-based case-control study in Lower Saxony (Germany). Radiat. Environ. Biophys. 1999, 38, 211–215. [Google Scholar] [CrossRef]
  53. Raaschou-Nielsen, O.; Andersen, C.E.; Andersen, H.P.; Gravesen, P.; Lind, M.; Schüz, J.; Ulbak, K. Domestic radon and childhood cancer in Denmark. Epidemiology 2008, 19, 536–543. [Google Scholar] [CrossRef]
  54. Hauri, D.; Spycher, B.; Huss, A.; Zimmermann, F.; Grotzer, M.; von der Weid, N.; Weber, D.; Spoerri, A.; Kuehni, C.E.; Röösli, M.; et al. Domestic radon exposure and risk of childhood cancer: A prospective census-based cohort study. Environ. Health Perspect. 2013, 121, 1239–1244. [Google Scholar] [CrossRef] [Green Version]
  55. Kendall, G.M.; Little, M.P.; Wakeford, R.; Bunch, K.J.; Miles, J.C.; Vincent, T.J.; Meara, J.R.; Murphy, M.F. A record-based case-control study of natural background radiation and the incidence of childhood leukaemia and other cancers in Great Britain during 1980–2006. Leukemia 2013, 27, 3–9. [Google Scholar] [CrossRef]
  56. Del Risco Kollerud, R.; Blaasaas, K.G.; Claussen, B. Risk of leukaemia or cancer in the central nervous system among children living in an area with high indoor radon concentrations: Results from a cohort study in Norway. Br. J. Cancer 2014, 111, 1413–1420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Berlivet, J.; Hémon, D.; Cléro, É.; Ielsch, G.; Laurier, D.; Guissou, S.; Lacour, B.; Clavel, J.; Goujon, S. Ecological association between residential natural background radiation exposure and the incidence rate of childhood central nervous system tumors in France, 2000–2012. J. Environ. Radioact. 2020, 211, 106071. [Google Scholar] [CrossRef] [PubMed]
  58. Walsh, L.; Dufey, F.; Tschense, A.; Schnelzer, M.; Grosche, B.; Kreuzer, M. Radon and the risk of cancer mortality—Internal Poisson models for the German uranium miners cohort. Health Phys. 2010, 99, 292–300. [Google Scholar] [CrossRef] [PubMed]
  59. Hess, C.T.; Weiffenbach, C.V.; Norton, S.A. Environmental radon and cancer correlations in Maine. Health Phys. 1983, 45, 339–348. [Google Scholar] [CrossRef]
  60. Ruano-Ravina, A.; Dacosta-Urbieta, A.; Barros-Dios, J.M.; Kelsey, K.T. Radon exposure and tumors of the central nervous system. Gac. Sanit. 2018, 32, 567–575. [Google Scholar] [CrossRef]
  61. Tomásek, L.; Darby, S.C.; Swerdlow, A.J.; Placek, V.; Kunz, E. Radon exposure and cancers other than lung cancer among uranium miners in West Bohemia. Lancet 1993, 341, 919–923. [Google Scholar] [CrossRef]
  62. Rericha, V.; Kulich, M.; Rericha, R.; Shore, D.L.; Sandler, D.P. Incidence of leukemia, lymphoma, and multiple myeloma in Czech uranium miners: A case-cohort study. Environ. Health Perspect. 2006, 114, 818–822. [Google Scholar] [CrossRef] [Green Version]
  63. Zablotska, L.B.; Lane, R.S.; Frost, S.E.; Thompson, P.A. Leukemia, lymphoma and multiple myeloma mortality (1950–1999) and incidence (1969–1999) in the Eldorado uranium workers cohort. Environ. Res. 2014, 130, 43–50. [Google Scholar] [CrossRef] [Green Version]
  64. Kelly-Reif, K.; Sandler, D.P.; Shore, D.; Schubauer-Berigan, M.; Troester, M.A.; Nylander-French, L.; Richardson, D.B. Mortality and cancer incidence among underground uranium miners in the Czech Republic 1977–1992. Occup. Environ. Med. 2019, 76, 511–518. [Google Scholar] [CrossRef]
  65. Eatough, J.P.; Henshaw, D.L. Radon and monocytic leukaemia in England. J. Epidemiol. Community Health 1993, 47, 506–507. [Google Scholar] [CrossRef] [Green Version]
  66. Thorne, R.; Foreman, N.K.; Mott, M.G. Radon in Devon and Cornwall and paediatric malignancies. Eur. J. Cancer. 1996, 32, 282–285. [Google Scholar] [CrossRef]
  67. Steinbuch, M.; Weinberg, C.R.; Buckley, J.D.; Robison, L.L.; Sandler, D.P. Indoor residential radon exposure and risk of childhood acute myeloid leukaemia. Br. J. Cancer 1999, 81, 900–906. [Google Scholar] [CrossRef] [Green Version]
  68. Lubin, J.H.; Linet, M.S.; Boice, J.D., Jr.; Buckley, J.; Conrath, S.M.; Hatch, E.E.; Kleinerman, R.A.; Tarone, R.E.; Wacholder, S.; Robison, L.L. Case-control study of childhood acute lymphoblastic leukemia and residential radon exposure. J. Natl. Cancer Inst. 1998, 90, 294–300. [Google Scholar] [CrossRef] [Green Version]
  69. UK Childhood Cancer Study Investigators. The United Kingdom Childhood Cancer Study of exposure to domestic sources of ionising radiation: 1: Radon gas. Br. J. Cancer 2002, 86, 1721–1726. [Google Scholar] [CrossRef] [Green Version]
  70. Henshaw, D.L.; Eatough, J.P.; Richardson, R.B. Radon as a causative factor in induction of myeloid leukaemia and other cancers. Lancet 1990, 335, 1008–1012. [Google Scholar] [CrossRef]
  71. Gilman, E.A.; Knox, E.G. Geographical distribution of birth places of children with cancer in the UK. Br. J. Cancer 1998, 77, 842–849. [Google Scholar] [CrossRef] [Green Version]
  72. Kohli, S.; Noorlind Brage, H.; Löfman, O. Childhood leukaemia in areas with different radon levels: A spatial and temporal analysis using GIS. J. Epidemiol. Community Health 2000, 54, 822–826. [Google Scholar] [CrossRef] [Green Version]
  73. Lucie, N.P. Radon exposure and leukaemia. Lancet 1989, 2, 99–100. [Google Scholar] [CrossRef]
  74. Alexander, F.E. Radon and leukaemia. Lancet 1990, 335, 1336–1340. [Google Scholar]
  75. Muirhead, C.R.; Butland, B.K.; Green, B.M.; Draper, G.J. Childhood leukaemia and natural radiation. Lancet 1991, 337, 503–504. [Google Scholar] [CrossRef]
  76. Tong, J.; Qin, L.; Cao, Y.; Li, J.; Zhang, J.; Nie, J.; An, Y. Environmental radon exposure and childhood leukemia. J. Toxicol. Environ. Health B Crit. Rev. 2012, 15, 332–347. [Google Scholar] [CrossRef] [PubMed]
  77. Schüz, J.; Erdmann, F. Environmental Exposure and Risk of Childhood Leukemia: An Overview. Arch. Med. Res. 2016, 47, 607–614. [Google Scholar] [CrossRef] [PubMed]
  78. Etherington, D.J.; Pheby, D.F.; Bray, F.I. An ecological study of cancer incidence and radon levels in South West England. Eur. J. Cancer 1996, 32, 1189–1197. [Google Scholar] [CrossRef]
  79. Wheeler, B.W.; Allen, J.; Depledge, M.H.; Curnow, A. Radon and skin cancer in southwest England: An ecologic study. Epidemiology 2012, 23, 44–52. [Google Scholar] [CrossRef] [Green Version]
  80. Wheeler, B.W.; Kothencz, G.; Pollard, A.S. Geography of non-melanoma skin cancer and ecological associations with environmental risk factors in England. Br. J. Cancer 2013, 109, 235–241. [Google Scholar] [CrossRef] [Green Version]
  81. Bräuner, E.V.; Loft, S.; Sørensen, M.; Jensen, A.; Andersen, C.E.; Ulbak, K.; Hertel, O.; Pedersen, C.; Tjønneland, A.; Krüger Kjær, S.; et al. Residential Radon Exposure and Skin Cancer Incidence in a Prospective Danish Cohort. PLoS ONE 2015, 10, e0135642. [Google Scholar] [CrossRef] [Green Version]
  82. Barbosa-Lorenzo, R.; Barros-Dios, J.M.; Raíces Aldrey, M.; Cerdeira Caramés, S.; Ruano-Ravina, A. Residential radon and cancers other than lung cancer: A cohort study in Galicia, a Spanish radon-prone area. Eur. J. Epidemiol. 2016, 31, 437–441. [Google Scholar] [CrossRef]
  83. Vienneau, D.; de Hoogh, K.; Hauri, D.; Vicedo-Cabrera, A.M.; Schindler, C.; Huss, A.; Röösli, M.; SNC Study Group. Effects of Radon and UV Exposure on Skin Cancer Mortality in Switzerland. Environ. Health Perspect. 2017, 125, 67009. [Google Scholar] [CrossRef] [Green Version]
  84. Charles, M.W. Radon exposure of the skin: II. Estimation of the attributable risk for skin cancer incidence. J. Radiol. Prot. 2007, 27, 253–274. [Google Scholar] [CrossRef]
  85. Denman, A.R.; Eatough, J.P.; Gillmore, G.; Phillips, P.S. Assessment of health risks to skin and lung of elevated radon levels in abandoned mines. Health Phys. 2003, 85, 733–739. [Google Scholar] [CrossRef]
  86. Navaranjan, G.; Berriault, C.; Do, M.; Villeneuve, P.J.; Demers, P.A. Cancer incidence and mortality from exposure to radon progeny among Ontario uranium miners. Occup. Environ. Med. 2016, 73, 838–845. [Google Scholar] [CrossRef]
  87. Messier, K.P.; Serre, M.L. Lung and stomach cancer associations with groundwater radon in North Carolina, USA. Int. J. Epidemiol. 2017, 46, 676–685. [Google Scholar] [CrossRef] [Green Version]
  88. Kjellberg, S.; Wiseman, J.S. The relationship of radon to gastrointestinal malignancies. Am. Surg. 1995, 61, 822–825. [Google Scholar]
  89. 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] [CrossRef]
  90. Drubay, D.; Ancelet, S.; Acker, A.; Kreuzer, M.; Laurier, D.; Rage, E. Kidney cancer mortality and ionizing radiation among French and German uranium miners. Radiat. Environ. Biophys. 2014, 53, 505–513. [Google Scholar] [CrossRef]
  91. Chen, B.; Yuan, T.W.; Wang, A.Q.; Zhang, H.; Fang, L.J.; Wu, Q.Q.; Zhang, H.B.; Tao, S.S.; Tian, H.L. Exposure to Radon and Kidney Cancer: A Systematic Review and Meta-analysis of Observational Epidemiological Studies. Biomed. Environ. Sci. 2018, 31, 805–815. [Google Scholar] [CrossRef]
  92. Neuberger, J.S.; Pierce, J.T.; Lai, S.M. Cancer cluster investigation in a school district. J. Sch. Health 1997, 67, 380–383. [Google Scholar] [CrossRef]
  93. Kristbjornsdottir, A.; Rafnsson, V. Incidence of cancer among residents of high temperature geothermal areas in Iceland: A census based study 1981 to 2010. Environ. Health 2012, 11, 73. [Google Scholar] [CrossRef] [Green Version]
  94. VoPham, T.; DuPré, N.; Tamimi, R.M.; James, P.; Bertrand, K.A.; Vieira, V.; Laden, F.; Hart, J.E. Environmental radon exposure and breast cancer risk in the Nurses’ Health Study II. Environ. Health 2017, 16, 97. [Google Scholar] [CrossRef]
  95. Cohen, B.L. Relationship between exposure to radon and various types of cancer. Health Phys. 1993, 65, 529–531. [Google Scholar] [CrossRef]
  96. ANPA, Agenzia Nazionale per la Protezione dell’Ambiente, ANPA-RT--00-009. Available online: https://inis.iaea.org/collection/NCLCollectionStore/_Public/32/007/32007841.pdf (accessed on 28 September 2021).
  97. McNeill, K.A. Epidemiology of Brain Tumors. Neurol. Clin. 2016, 34, 981–998. [Google Scholar] [CrossRef] [PubMed]
  98. Braganza, M.Z.; Kitahara, C.M.; Berrington de González, A.; Inskip, P.D.; Johnson, K.J.; Rajaraman, P. Ionizing radiation and the risk of brain and central nervous system tumors: A systematic review. Neuro. Oncol. 2012, 14, 1316–1324. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Kendall, G.M.; Smith, T.J. Doses to organs and tissues from radon and its decay products. J. Radiol. Prot. 2002, 22, 389–406. [Google Scholar] [CrossRef]
  100. United Nations Scientific Committee on the effects of atomic radiation. Available online: https://www.unscear.org/docs/publications/2013/UNSCEAR_2013_Report_Vol.II.pdf (accessed on 28 September 2021).
  101. Harley, N.H.; Robbins, E.S. Radon and leukemia in the Danish study: Another source of dose. Health Phys. 2009, 97, 343–347. [Google Scholar] [CrossRef] [PubMed]
  102. Laurier, D.; Valenty, M.; Tirmarche, M. Radon exposure and the risk of leukemia: A review of epidemiological studies. Health Phys. 2001, 81, 272–288. [Google Scholar] [CrossRef] [PubMed]
  103. Eatough, J.P.; Henshaw, D.L. Radon and thoron associated dose to the basal layer of the skin. Phys. Med. Biol. 1992, 37, 955–967. [Google Scholar] [CrossRef] [PubMed]
  104. 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] [CrossRef] [PubMed]
  105. Barbosa-Lorenzo, R.; Barros-Dios, J.M.; Ruano-Ravina, A. Radon and stomach cancer. Int. J. Epidemiol. 2017, 46, 767–768. [Google Scholar] [CrossRef]
  106. National Research Council. Risk Assessment of Radon in Drinking Water; National Academies Press: Washington, DC, USA, 1999. [Google Scholar]
  107. 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] [CrossRef]
  108. Bartsch, H.; Hollstein, M.; Mustonen, R.; Schmidt, J.; Spiethoff, A.; Wesch, H.; Wiethege, T.; Müller, K.M. Screening for putative radon-specific p53 mutation hotspot in German uranium miners. Lancet 1995, 346, 121. [Google Scholar] [CrossRef]
  109. 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] [CrossRef] [Green Version]
  110. Brooks, A.L.; Bao, S.; Harwood, P.W.; Wood, B.H.; Chrisler, W.B.; Khan, M.A.; Gies, R.A.; Cross, F.T. Induction of micronuclei in respiratory tract following radon inhalation. Int. J. Radiat. Biol. 1997, 72, 485–495. [Google Scholar] [CrossRef]
  111. Deshpande, A.; Goodwin, E.H.; Bailey, S.M.; Marrone, B.L.; Lehnert, B.E. Alpha-particle-induced sister chromatid exchange in normal human lung fibroblasts: Evidence for an extranuclear target. Radiat. Res. 1996, 145, 260–267. [Google Scholar] [CrossRef] [Green Version]
  112. Nagasawa, H.; Little, J.B. Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Res. 1992, 52, 6394–6396. [Google Scholar]
  113. 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] [CrossRef] [Green Version]
  114. Lorenzo-González, M.; Ruano-Ravina, A.; Torres-Durán, M.; Kelsey, K.T.; Provencio, M.; Parente-Lamelas, I.; Leiro-Fernández, V.; Vidal-García, I.; Castro-Añón, O.; Martínez, C.; et al. Residential radon, genetic polymorphisms in DNA damage and repair-related. Lung Cancer 2019, 135, 10–15. [Google Scholar] [CrossRef]
  115. Lim, S.M.; Choi, J.W.; Hong, M.H.; Jung, D.; Lee, C.Y.; Park, S.Y.; Shim, H.S.; Sheen, S.; Kwak, K.I.; Kang, D.R.; et al. Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma. Lung Cancer 2019, 131, 139–146. [Google Scholar] [CrossRef]
  116. Alavanja, M.C. Biologic damage resulting from exposure to tobacco smoke and from radon: Implication for preventive interventions. Oncogene 2002, 21, 7365–7375. [Google Scholar] [CrossRef] [Green Version]
  117. Brenner, D.J.; Sachs, R.K. Do low dose-rate bystander effects influence domestic radon risks? Int. J. Radiat. Biol. 2002, 78, 593–604. [Google Scholar] [CrossRef]
  118. Azzam, E.I.; De Toledo, S.M.; Spitz, D.R.; Little, J.B. Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res. 2002, 62, 5436–5442. [Google Scholar]
  119. Iyer, R.; Lehnert, B.E.; Svensson, R. Factors underlying the cell growth-related bystander responses to alpha particles. Cancer Res. 2000, 60, 1290–1298. [Google Scholar] [PubMed]
  120. Azzam, E.I.; Little, J.B. The radiation-induced bystander effect: Evidence and significance. Hum. Exp. Toxicol. 2004, 23, 61–65. [Google Scholar] [CrossRef] [PubMed]
  121. Sethi, T.K.; El-Ghamry, M.N.; Kloecker, G.H. Radon and lung cancer. Clin. Adv. Hematol. Oncol. 2012, 10, 157–164. [Google Scholar] [PubMed]
  122. Sanders, C.L.; Scott, B.R. Smoking and hormesis as confounding factors in radiation pulmonary carcinogenesis. Dose-Response 2006, 6, 53–79. [Google Scholar] [CrossRef] [PubMed]
  123. Brenner, D.J.; Doll, R.; Goodhead, D.T.; Hall, E.J.; Land, C.E.; Little, J.B.; Lubin, J.H.; Preston, D.L.; Preston, R.J.; Puskin, J.S.; et al. Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know. Proc. Natl. Acad. Sci. USA 2003, 100, 13761–13766. [Google Scholar] [CrossRef] [Green Version]
  124. Luckey, T.D. Radiation hormesis: The good, the bad, and the ugly. Dose-Response 2006, 4, 169–190. [Google Scholar] [CrossRef] [PubMed]
Ijerph 18 10466 g001 550
Figure 1. Decay series of Uranium, Thorium, and Actinium. Pa = Protactin, Ac = Actinium, Ra = Radium, Tl = Tallium.
Figure 1. Decay series of Uranium, Thorium, and Actinium. Pa = Protactin, Ac = Actinium, Ra = Radium, Tl = Tallium.
Ijerph 18 10466 g001
Table
Table 1. Brain and Central Nervous System (CNS) cancer.
Table 1. Brain and Central Nervous System (CNS) cancer.
a: Workers
Study DesignSample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Cohort mortality study178570.4 WLM 1SMR: 1.89; 95% CI: 0.78–3.89
Expected number of deaths 3: p-value = 0.03		Tirmarche et al. (1993) [39]
Cohort mortality study64,209155 WLM 1O/E deaths 4: 1.01; 95% CI: 0.95–1.07
No significant association		Darby et al.
(1995) [40]
Cohort mortality study129489 WLM 1O/E deaths 4:1.21; 95% CI 1.03–1.41
No significant association		Darby et al.
(1995) [41]
Cohort study5086 (4140 exposed to radon)36.6 WLM 1No significant associationVacquier et al.
(2008) [42]
Cohort study49,268 Ex-E
7931 NE		279.4 WLM 2O/E 4: 1.02; 95% CI: 0.98–1.05Kreuzer et al.
(2008) [43]
Cohort study4137794–808 WLMNo significant associationSchubauer-Berigan
et al.
(2009) [44]
Cohort study 337717.8 WLM 1SMR: 2.00; 95% CI: 1.09–3.35Vacquier et al.
(2011) [45]
b: General Population
Study DesignSample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Prospective study 811,961 mean ± s.d: 53.5 ± 38.0 Bq/m3 range: 6.3–265.7 HR: 0.98 per 100 Bq/m3;
95% CI: 0.83–1.15
No clear associations		Turner et al.
(2012) [46]
Cohort study57,05340.5 Bq/m3IRR: 1.96; 95% CI: 1.07–3.58Bräuner et al.
(2013) [47]
Ecological study251GM: 100–200 Bq/m3Spearman’s Rho:
0.286 (males; p-value: <0.001;)
0.509 (females; p-value: <0.001)		Ruano-Ravina et al.
(2017) [48]
Ecological study13153.9 Bq/m3RR: 1.28
Statistical association		López-Abente et al.
(2018) [49]
Ecological studyNew Jersey: 14,662;
Iowa: 8429;
Wisconsin: 8023;
Pennsylvania: 22,940; Minnesota: 5338		4.6–8.6 pCi/LNegative association: p-value <0.0001Monastero et al.
(2020) [50]
c: Pediatric Population
Study designSample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Ecological studyTotal death: 2706
Brain and CNS disease: 454		0–10,692 pCi/l 1Medium exposure
RR: 1.28; 95% CI: 1.00–1.62
High exposure
RR: 1.18; 95% CI: 0.90–1.54		Collman et al.
(1991) [51]
Case-control study 82 L; 82 ST; 209 Controls mean: 27 Bq/m3
range: 10–584 Bq/m3		 Solid Tumor
OR: 2.61; 95% CI: 0.96–7.13 		Kaletsch et al.
(1999) [52]
Case-control study Cases: 2400 Controls: 6697 mean: 48 Bq/m3
range: 4–254 Bq/m3		No significant associationRaaschou-Nielsen et al. (2008) [53]
Cohort studyChildhood cancer cases: 997median: 77.7 Bq/m3;
90th: 139.9 Bq/m3		All cancers
HR: 0.93; 95% CI: 0.74–1.16
CNS tumors
HR: 1.05; 95% CI: 0.68–1.61		Hauri D et al.
(2013) [54]
Case-control studyCases: 27,447 Controls: 36,793mean: 22 Bq/m3ERR: 3%; 95% CI: 4–11;
p-value: 0.35		Kendall et al.
(2013) [55]
CohortsTotal: 712,674
Cancer cases: 864		mean: 91 Bq/m3 median: 74 Bq/m3<50 Bq/m3 HR: 1.00 (Ref.)
50–100 Bq/m3 HR: 0.88; CI: (0.68–1.14)
>100 Bq/m3 HR: 1.15; CI: (0.87–1.50)
No significant association 		Del Risco Kollerud et al.
(2014) [56]
Ecological study5471 cases of CNST1 41.0 Bq/m3IRR: 1.07; CI: 0,95–1.20 per 100 Bq/m3
No significant association		Berlivet J et al.
(2020) [57]
a: 1 Average cumulative exposure; 2 accumulated exposure; 3 malignant brain tumor and malignant tumors of other parts of the nervous system; 4 for all other than lung cancer combined; WLM: Working Level Month; Ex-E: ex esposed; NE: never exposed; O/E: observed/expected cases; 95% CI: 95% confidence interval; SMR: Standardized Mortality Ratio. b: IRR: incidence rate-ratios; RR: Relative Risk; GM: geometric mean; 95% CI: 95% confidence interval; HR: Hazard Ratio. c: 1 drinking water; L: leukemias; ST: solid tumors; IRR: incidence rate-ratios; RR: Relative Risk; 95% CI: 95% confidence interval; HR: Hazard Ratio; OR: odds ratio; ERR: excess relative risk.
Table
Table 2. Radon exposure and leukemia.
Table 2. Radon exposure and leukemia.
a: Workers
Study
Design		Sample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Cohort mortality study4320196.8 WLM 1O/E deaths: 1.11; 95% CI: 0.98–1.24
No significant association		Tomàsek et al.
(1993) [61]
Cohort study 64,209 155 WLM 1O/E: 1.93; 95% CI: 1.19–2.95
No significant association		Darby et al.
(1995) [40]
Retrospective case–cohort study23,043mean ± sd:
64.1 ± 98 WLM		All leukemia
RR: 1.75; 95% CI: 1.10–2.78;
p-value = 0.014
CLL
RR: n.s.		Rericha et al.
(2006) [62]
Cohort study58,987279.4 WLMNo significant association
O/E: 0.89; 95% CI: 0.74–1.06		Kreuzer et al.
(2008) [43]
Cohort study17,660100.2 WLMAll leukemia
SMR: 0.69; 95% CI: 0.48–0.97;
p-value = 0.031
SIR: 0.79; 95% CI: 0.59–1.03;
p-value = 0.088		Zablotska et al.
(2014) [63]
Cohort study16,43453 WLMAll leukemias:
SIR: 1.51; 95% CI: 1.08–2.07
Lymphatic and hematopoietic cancers combined
SIR: 1.31; 95% CI: 1.05–1.61		Kelly-Reif et al.
(2019) [64]
b: General and Pediatric Population
Study
Design		Sample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Ecological study45<120 Bq/m3Lymphocytic leukemia
r = 0.40; p-value < 0.005,
ρ = 0.24; p-value < 0.1
Myeloid leukemia
r = 0.43; p-value < 0.005,
ρ = 0.22 p-value < 0 1		Eatough et al.
(1993) [65]
Ecological studyArea ≥ 100 Bq/m3
Cases: 35
Area < 100 Bq/m3
Cases: 73		Area ≥ 100 Bq/m3 (Mean: 183 Bq/m3)
Area < 100 Bq/m3 (Mean: 57 Bq/m3)		Area ≥ 100 Bq/m3:
Incidence = 106.7 per million child years
Area < 100 Bq/m3: Incidence = 121.7 per million child years
No significant difference between Area ≥ 100 Bq/m3 and Area < 100 Bq/m3 (p-value = 0.29).		Thorne et al.
(1996) [66]
Case-control study Cases: 173
Controls: 254 		1 Cases: 56.0 Bq/m3
1 Controls: 49.8 Bq/m3		37–100 Bq/m3
adjusted OR: 1.2; 95% CI: 0.7–1.8
>100 Bq/m3
adjusted OR: 1.1; 95% CI 0.6–2.0
No significant difference		Steinbuch et al.
(1999) [67]
Case-control studyCases: 505
Controls: 443 		1 Cases
65.4 Bq/m3
1 Controls
79.1 Bq/m3		Rn concentration < 37 Bq/m3
RR: 1; (Reference)
Rn concentration 37–73 Bq/m3
RR: 1.22; 95% CI: 0.8–1.9
Rn concentration 74–147 Bq/m3
RR: 0.82; 95% CI: 0.8–1.9
Rn concentration ≥ 148 Bq/m3
RR: 1.02; 95% CI: 0.5–2.0		Lubin et al.
(1998) [68]
Case-control studyCases: 82
Controls: 209 		Median:
27 Bq/m3
Range:
10–584 Bq/m3		OR: 1.30; 95% CI: 0.32–5.33Kaletsch et al.
(1999) [52]
Case-control studyCases: 3838 cases (1461 ALL)
Controls 7629 		1 24.0 Bq/m3OR: 0.80; 95% CI: 0.64–0.99UKCCS [69]
(2002)
Ecological studyData not providedUK: 20 Bq/m3;
Cornwall: 110 Bq/m3;
World: 50 Bq/m3		Country data alone
r = 0.65; p-value < 0.02;
Regional data
r = 0.62; p-value <0.02		Henshaw et al.
(1990) [70]
Ecological studyLeukemias and lymphomas: 4851 median: 21 Bq/m3,RR: 1.06; 95% CI: 0.99–1.12Gilman et al.
(1998) [71]
Ecological correlation study53,146High risk area:
50,000 Bq/m3;
Normal risk area:
10,000–50,000 Bq/m3;
Low risk area: <10,000 Bq/m3; 		ALL2:
RR (normal risk area): 4.64
95% CI: 1.29–28.26
RR (high risk area): 5.67
95% CI: 1.06–42.27		Kohli et al.
(2000) [72]
Cohort studyChildhood cancer cases: 99777.7 1 Bq/m3, 90th: 139.9 Bq/m3All leukemias
AHR: 0.90; 95% CI: 0.56–1.43
Acute lymphoblastic leukemia
AHR: 0.90; 95% CI: 0.56- 1.43		Hauri D et al.
(2013) [54]
a: 1 Average cumulative exposure; 2 lifetime Rn exposure. WLM: Working Level Month; O/E: observed/expected cases; 95% CI: 95% confidence interval; RR: Relative Risk; CLL: chronic lymphocytic leukemia; ALL = acute lymphatic leukemia; AML: acute myeloid leukemia; n.s.: not significant. b: 1 Arithmetic mean of time-weighted radon concentrations; 2 ALL: acute lymphatic leukemia; RR: Relative Risk; 95% CI: 95% confidence interval; OR: odds ratio; r: correlation coefficient; AHR: Adjusted Hazard Ratio.
Table
Table 3. Skin cancer: General Population.
Table 3. Skin cancer: General Population.
Study
Design		Sample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Ecological study28,9891 40 Bq/m3
1 ≥230 Bq/m3		Non-melanoma skin cancers, showed a significant increase in incidence in the high-radon postcode sectors (≥100 Bq/m3) compared with the low-radon sectors (<60 Bq/m3) and this effect was observed for both sexes.Etherington et al.
(1996) [78]
Prospective study811,961mean ± sd: 53.5 ± 38.0 Bq/m3 range: 6.3–265.7 Bq/m3HR = 0.98; 95% CI: 0.97–1.00, per each 100 Bq/m3
no significant association		Turner et al.
(2012) [46]
Ecological study 18,350 mean ± sd: 98.1 ± 73.1 Bq/m3Malignant melanoma
Rn concentration ≥ 230 Bq/m3
RR: 0.85; 95% CI: 0.65–1.11
Basal cell carcinoma
Rn concentration ≥ 230 Bq/m3
RR: 0.81; 95% CI: 0.66–1.00
Squamous cell carcinoma
Rn concentration ≥ 230 Bq/m3
RR: 1.76; 95% CI: 1.46–2.11		Wheeler et al.
(2012) [79]
Ecological study206,454range:
0–≥100 Bq/m3		0.182 registrations
per 100,000 population per year
95% CI: 0.04–0.32 p-value = 0.011		Wheeler et al.
(2013) [80]
Prospectic cohort57,053median: 38.3 Bq/m3BCC
Adjusted IRR: 1.14;
95% CI: 1.03–1.27
SCC
Adjusted IRR: 0.90; 95% CI: 0.70- 1.37
MM
Adjusted IRR: 1.08; 95% CI: 0.77–1.50		Bräuner et al.
(2015) [81]
Ecological study2294Cutpoint set:
50 Bq/m3		Risk of non-pulmonary cancer
HR: 1.2; 95% CI: 0.9–1.6
Connective tissue and others of the skin
HR: 1.5; 95% CI: 0.6–3.8
(except melanoma)		Barbosa-Lorenzo
et al.
(2016) [82]
Mortality cohortsTot: 5,249,462 skin cancer deaths: 2989mean ± sd: 91.8 ± 47.8 Bq/m3MM
HR3: 1.41; 95% CI: 1.09–1.80 at 30 years
HR3: 1.05; 0.94–1.18 at 75 years
Adjusted HR: 1.16; 95% CI: 1.04–1.29 at 60 years 		Vienneau et al.
(2017) [83]
1 Average radon levels for postcode sectors; 2 adjusted coefficient per 1 Bq/m3 increase; 3 per 100 Bq/m3; 95% CI: 95% confidence interval; sd: standard deviation; IRR: incidence rate-ratios; HR: Hazard Ratio. BCC: basal cell carcinoma; SCC: squamous cell carcinoma; MM: malignant melanoma.
Table
Table 4. Stomach cancer: Workers and General Population.
Table 4. Stomach cancer: Workers and General Population.
Study
Design		Sample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Cohort study64,209155 WLMO/E: 1.33; 95% CI: 1.169–1.52
Mortality: no significant association		Darby et al.
(1995) [40]
Cohort study141589 WLMO/E: 1.45; 95% CI: 1.04–1.98
Mortality: no significant association		Darby et al.
(1995) [41]
Cohort study28,54621 WLMIncidence: Overall excess 1
RR: −0.12; 95% CI: −0.59–0.35
Mortality: overall excess 1
RR: −0.082; 95% CI: −0.61–0.45
No significant association		Navaranjan et al. (2016) [86]
Ecological study5218Groundwater: 100 Bq/L Indoor air: 100 Bq/m3Groundwater Rn exposure and
stomach cancer
OR: 1.24; 95% CI 1.03–1.49		Messier et al.
(2017) [87]
Ecological study56,385IQ range: 53–184 Bq/m3Statistical association in women
RR: 1.17; 95% CI 1.02–1.32		López-Abente et al.
(2018) [49]
Cohort study16,43453 WLMSMR: 1.27; 95% CI: 1.02–1.51
SIR: 1.37; 95% CI: 1.11–1.63		Kelly-Reif et al.
(2019) [64]
1 Per 100 WLM; WML: Working Level Month; 95% CI: 95% confidence interval; O/E: observed/expected cases; SMR: Standardized Mortality Ratio; SIR: Standardized Incidence Ratio; RR: relative risk; IQ: interquartile range; OR: Odd ratio.
Table
Table 5. Kidney cancer: Workers.
Table 5. Kidney cancer: Workers.
Study
Design		Sample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Cohort study508636.6 WLMA significant excess of kidney cancer deaths was observed (n = 20; SMR = 2.0; 95% CI: 1.22–3.09), which was not associated with cumulative Rn exposureVacquier et al.
(2008) [42]
Cohort study 28,546 21 WLMNo association for kidney cancer with increasing cumulative Rn exposure Navaranjan et al. (2016) [86]
Cohort studyFrench cohort: 3377; German cohort: 58,986 median:
4.7 WLM range:
0–128.4 WLM
median: 18.4 WLM range:
0–3224.5 WLM 		French cohort
SMR: 1.49; 95% CI: 0.73–2.67
German cohort
SMR = 0.91; 95% CI: 0.77–1.06
No significant association		Drubay et al.
(2014) [90]
WML: average cumulative exposures; 95% CI: 95% confidence interval; SMR: Standardized Mortality Ratio.
Table
Table 6. Breast cancer: Workers and general population.
Table 6. Breast cancer: Workers and general population.
Study
Design		Sample Size
(n)		Radon
Conc.		ResultsReference
(Year)
Cohort studySchool employees: 520 Classrooms:
<2 pCi/L Utility tunnels:
29–33 pCi/L		SMR: 5; 95% CI: 1.03–14.6Neuberger et al. (1997) [92]
Observational cohort study74,8061 water: 1.3–9 Bq/LHR: 1.59; 95%CI: 1.10–2.31Kristbjornsdottir et al.
(2012) [93]
Prospective cohort study 811,961 mean ± sd: 53.5 ± 38.0 Bq/m3 range:
6.3–265.7 Bq/m3		HR: 0.91; 95% CI: 0.82–1.01Turner et al.
(2012) [46]
Prospective cohort study112,639 female2 P20: <27.0 Bq/m32
P40: ≥27.0–37.7 Bq/m3
2 P60: ≥37.7–50.1 Bq/m3
2 P80: ≥50.1–74.9 Bq/m3
2 P100: ≥74.9 Bq/m3		For women in the highest quintile of exposure (≥74.9 Bq/m3)
HR = 1.38; 95% CI: 0.97–1.96 (ER-/PR-)
No association was observed for ER+/PR+ breast cancer		VoPham et al.
(2017) [94]
1 Geothermal hot water from drilled wells; 2 P20: 1st quintile, P40: 2nd quintile, P60: 3rd quintile, P80: 4th quintile, and P100: 5th quintile; 95% CI: 95% confidence interval; SMR: Standardized Mortality Ratio; HR: Hazard Ratio; ER-/PR-: Estrogen Receptor negative/Progesterone receptor negative; ER+/PR+: Estrogen Receptor negative/Progesterone receptor negative.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mozzoni, P.; Pinelli, S.; Corradi, M.; Ranzieri, S.; Cavallo, D.; Poli, D. Environmental/Occupational Exposure to Radon and Non-Pulmonary Neoplasm Risk: A Review of Epidemiologic Evidence. Int. J. Environ. Res. Public Health 2021, 18, 10466. https://doi.org/10.3390/ijerph181910466

AMA Style

Mozzoni P, Pinelli S, Corradi M, Ranzieri S, Cavallo D, Poli D. Environmental/Occupational Exposure to Radon and Non-Pulmonary Neoplasm Risk: A Review of Epidemiologic Evidence. International Journal of Environmental Research and Public Health. 2021; 18(19):10466. https://doi.org/10.3390/ijerph181910466

Chicago/Turabian Style

Mozzoni, Paola, Silvana Pinelli, Massimo Corradi, Silvia Ranzieri, Delia Cavallo, and Diana Poli. 2021. "Environmental/Occupational Exposure to Radon and Non-Pulmonary Neoplasm Risk: A Review of Epidemiologic Evidence" International Journal of Environmental Research and Public Health 18, no. 19: 10466. https://doi.org/10.3390/ijerph181910466

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop