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Poli, D. Radon and Non-Pulmonary Neoplasm Risk. Encyclopedia. Available online: https://encyclopedia.pub/entry/15234 (accessed on 07 December 2023).
Poli D. Radon and Non-Pulmonary Neoplasm Risk. Encyclopedia. Available at: https://encyclopedia.pub/entry/15234. Accessed December 07, 2023.
Poli, Diana. "Radon and Non-Pulmonary Neoplasm Risk" Encyclopedia, https://encyclopedia.pub/entry/15234 (accessed December 07, 2023).
Poli, D.(2021, October 21). Radon and Non-Pulmonary Neoplasm Risk. In Encyclopedia. https://encyclopedia.pub/entry/15234
Poli, Diana. "Radon and Non-Pulmonary Neoplasm Risk." Encyclopedia. Web. 21 October, 2021.
Radon and Non-Pulmonary Neoplasm Risk
Edit

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.  

radon epidemiological studies cancer risk environmental exposure

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].
Figure 1. Decay series of Uranium, Thorium, and Actinium. Pa = Protactin, Ac = Actinium, Ra = Radium, Tl = Tallium.
The concentration of Rn outdoors is typically low and, in any case, does not exceed a few tens of Bq/m3. 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.

2. Brain and Central Nervous System (CNS) Cancer

Results are summarized in Table 1a–c.
Table 1. Brain and Central Nervous System (CNS) cancer.
a: Workers
Study Design Sample Size
(n)
Radon
Conc.
Results Reference
(Year)
Cohort mortality study 1785 70.4 WLM 1 SMR: 1.89; 95% CI: 0.78–3.89
Expected number of deaths 3: p-value = 0.03
Tirmarche et al. (1993) [34]
Cohort mortality study 64,209 155 WLM 1 O/E deaths 4: 1.01; 95% CI: 0.95–1.07
No significant association
Darby et al.
(1995) [35]
Cohort mortality study 1294 89 WLM 1 O/E deaths 4:1.21; 95% CI 1.03–1.41
No significant association
Darby et al.
(1995) [36]
Cohort study 5086 (4140 exposed to radon) 36.6 WLM 1 No significant association Vacquier et al.
(2008) [37]
Cohort study 49,268 Ex-E
7931 NE
279.4 WLM 2 O/E 4: 1.02; 95% CI: 0.98–1.05 Kreuzer et al.
(2008) [38]
Cohort study 4137 794–808 WLM No significant association Schubauer-Berigan
et al.
(2009) [39]
Cohort study 3377 17.8 WLM 1 SMR: 2.00; 95% CI: 1.09–3.35 Vacquier et al.
(2011) [40]
b: General Population
Study Design Sample Size
(n)
Radon
Conc.
Results Reference
(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) [41]
Cohort study 57,053 40.5 Bq/m3 IRR: 1.96; 95% CI: 1.07–3.58 Bräuner et al.
(2013) [42]
Ecological study 251 GM: 100–200 Bq/m3 Spearman’s Rho:
0.286 (males; p-value: <0.001;)
0.509 (females; p-value: <0.001)
Ruano-Ravina et al.
(2017) [43]
Ecological study 13 153.9 Bq/m3 RR: 1.28
Statistical association
López-Abente et al.
(2018) [44]
Ecological study New Jersey: 14,662;
Iowa: 8429;
Wisconsin: 8023;
Pennsylvania: 22,940; Minnesota: 5338
4.6–8.6 pCi/L Negative association: p-value <0.0001 Monastero et al.
(2020) [45]
c: Pediatric Population
Study design Sample Size
(n)
Radon
Conc.
Results Reference
(Year)
Ecological study Total death: 2706
Brain and CNS disease: 454
0–10,692 pCi/l 1 Medium 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) [46]
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) [47]
Case-control study Cases: 2400 Controls: 6697 mean: 48 Bq/m3
range: 4–254 Bq/m3
No significant association Raaschou-Nielsen et al. (2008) [48]
Cohort study Childhood cancer cases: 997 median: 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) [49]
Case-control study Cases: 27,447 Controls: 36,793 mean: 22 Bq/m3 ERR: 3%; 95% CI: 4–11;
p-value: 0.35
Kendall et al.
(2013) [50]
Cohorts Total: 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) [51]
Ecological study 5471 cases of CNST 1 41.0 Bq/m3 IRR: 1.07; CI: 0,95–1.20 per 100 Bq/m3
No significant association
Berlivet J et al.
(2020) [52]

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.

2.1. 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) [34]. 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 [35]. 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 [36]. 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 [37]. 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) [40].
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 [38][53]. 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 [39].

2.2. 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 [54]. 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 [42]. 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 [43]. 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 [44].
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 [45], as well as the Turner’s study performed in the American Cancer Society cohort [41].

2.3. 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 [46]. 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) [47].
In contrast with these results, in a Danish children cohort, the cumulative Rn exposure was not associated with risk for CNS tumor [48], 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 [49]. 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 [50]. 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 [51]. 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) [52]. 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 [55].

3. Leukemia

The main results are described in Table 2a (Workers) and Table 2b (General and Pediatric Population).
Table 2. Radon exposure and leukemia.
a: Workers
Study
Design
Sample Size
(n)
Radon
Conc.
Results Reference
(Year)
Cohort mortality study 4320 196.8 WLM 1 O/E deaths: 1.11; 95% CI: 0.98–1.24
No significant association
Tomàsek et al.
(1993) [56]
Cohort study 64,209 155 WLM 1 O/E: 1.93; 95% CI: 1.19–2.95
No significant association
Darby et al.
(1995) [35]
Retrospective case–cohort study 23,043 mean ± 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) [57]
Cohort study 58,987 279.4 WLM No significant association
O/E: 0.89; 95% CI: 0.74–1.06
Kreuzer et al.
(2008) [38]
Cohort study 17,660 100.2 WLM All 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) [58]
Cohort study 16,434 53 WLM All 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) [59]
b: General and Pediatric Population
Study
Design
Sample Size
(n)
Radon
Conc.
Results Reference
(Year)
Ecological study 45 <120 Bq/m3 Lymphocytic 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) [60]
Ecological study Area ≥ 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) [61]
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) [62]
Case-control study Cases: 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) [63]
Case-control study Cases: 82
Controls: 209
Median:
27 Bq/m3
Range:
10–584 Bq/m3
OR: 1.30; 95% CI: 0.32–5.33 Kaletsch et al.
(1999) [47]
Case-control study Cases: 3838 cases (1461 ALL)
Controls 7629
1 24.0 Bq/m3 OR: 0.80; 95% CI: 0.64–0.99 UKCCS [64]
(2002)
Ecological study Data not provided UK: 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) [65]
Ecological study Leukemias and lymphomas: 4851 median: 21 Bq/m3, RR: 1.06; 95% CI: 0.99–1.12 Gilman et al.
(1998) [66]
Ecological correlation study 53,146 High 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) [67]
Cohort study Childhood cancer cases: 997 77.7 1 Bq/m3, 90th: 139.9 Bq/m3 All 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) [49]

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.

3.1. 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 [56]. 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 [35]. 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) [57].
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) [38].
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 [58].
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) [59].

3.2. 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 [68]. Subsequently, significant correlations between Rn concentration and several leukemia subtypes in England and Wales have been observed [69]. 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 [60]. 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 [65].

3.3. 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 [61]. 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 [62]. 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 [63].
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)] [47].
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 [64].
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 [65]. In the same way, for data from throughout Britain, a significant correlation for childhood leukemia with Rn concentration by county was observed [70]. 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 [66].

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