Radon; international recommendations.
Although WHO recommends indoor radon concentrations of <100 Bq/m3 (3), just a few countries around the world have enforced reference levels. In Europe, with more than 30% of areas with concentrations above 100 Bq/m3(3), the European Directive for the protection against dangers coming from ionizing radiation (2013/59/Euratom) established a reference level of 300 Bq/m3 in EU homes and workplaces. Nowadays, radon regulation policies vary in each country (5-7). In the USA (5), the EPA recommends testing indoor radon concentration and fix homes if it is higher than 4pCi/L (148Bq/m3). The US EPA level of 4 pCi/L is called an action level, but it is not mandatory from a federal perspective. In the rest of the world, the International Atomic Energy Agency has recommended
a reference level of 1000 Bq/m3 for workplaces aiming at 300 Bq/m3 (8,9).
Radon and carcinogenesis
Alpha radiation coming from radon decay, releases a large amount of energy in a very short linear track alpha (high-energy transfer capacity, HET). The alpha radiation from the radon progeny directly damages the respiratory epithelium that is especially sensitive to radiation and produce multiple cytotoxic and genotoxic effects that favours carcinogenesis (4, 10, 11). These genomic alterations include multiple double-strand breaks on the DNA, single mutations as point deletions or substitutions that alter nucleotide sequence, and chromosomal abnormalities as rearrangements, mainly studied in blood cells.The consequence of this genomic instability is the modification of the cell cycle, dysregulation of apoptosis, cell
growth and carcinogenesis (10).Although some studies describe radon-induced mutations in concrete genes, to date no molecular profile has been associated to radon.
Interestingly, tobacco and radon share a carcinogenic process, and it is known that they act in a synergic way, rising almost 25 times the risk of death by lung cancer in smokers (4). Both carcinogens induce the generation of free radicals and oxidative stress and DNA breaks, a common early phase of both carcinogenesis processes (13). Unfortunately, little is known about the clinical impact of both cocarcinogens combined.
Epidemiological evidence
Nowadays, radon is responsible for 3-14% of lung cancer case. The EPA estimates that about 21,000 people die in USA each year from radon-related lung cancer (5) and in Europe, around 21000 deaths are related to radon exposure, that represent the 2% of all deaths from cancer (14).
The relationship between radon and lung cancer was first demonstrated in the uranium miners, who developed many lung diseases including lung cancer (15-20). Years later, this association was also demonstrated in general population, with residential radon, in several studies then combined in the European, American, and Chinese pooling studies (16). Overall, it is estimated a linear increase of 16% of lung cancer risk per 100 Bq/m3 of indoor radon. All histological subtypes of lung cancer have been associated with radon, including adenocarcinoma histology (20-21), particularly in non-smokers, but
no specific lung cancer profile has been associated with radon yet.
Molecular epidemiology and radon in lung cancer
Approximately 15-25% of lung cancer cases occur in never smokers. Recent
research suggests that lung cancer in this subgroup could be a different disease, with higher survival rates, a different age of onset, a greater proportion of adenocarcinoma histology and a different biological pathway than lung cancer in smokers (22). Especially in non-squamous histology, there exist different genomic alterations, the majority mutations (such as in EGFR, BRAF, HER2 genes) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), that lead to activation of cancer molecular pathways that promote carcinogenesis and proliferation.The discovery of these alterations has had a great clinical impact, because targeted therapies improved patient’s outcomes compared to conventional treatments, such as chemotherapy (23).
Taking together radon as first cause of lung cancer in non-smokers, and that this population often present withdriver molecular alterations, we hypothesised that radon may play a role in the carcinogenesis of these subtype of lung cancer. So far, three studies have evaluated this hypothesis, measuring indoor radon in dwellings of patients with EGFR/BRAF mutations and ALK fusions, showing higher radon levels (>100Bq/m3), but with small number of patients to draw solid conclusions.
In the Radon France ecological study, we found a correlation between the prevalence of somatic driver molecular alterations and radon risk area based on the official French map, in a cohort of 116.424 patients with lung cancer (24).Later, in the BioRadon France ecological study, we studiedthe radon estimation in the patient’s childhood home of 3.994 patients with tumoursharbouring these molecular alterations. We observed that patients with lung cancer in France lived during childhood in areas with radon estimation above the median/mean of France for general population. In addition, we observed more lung cancer in non-smoker in high radon areas, in line with previous evidence, raising the idea that cumulative radon exposure, including childhood, should be considered in radon studies.
Despite the mentioned evidence, there is still a lack of research to identify the patient’s and tumor profile related to radon gas, or other carcinogens, such as airpollution, asbestos, etc.) and how they can impact, to improve thepatients’ care and to promote cancer prevention strategies (25).
Toincrease knowledge in this field, The Consortium RADONORM (Managing risk from radon and natural occurring radiative material [26] ) was designed to initiate and perform research and technical development to implement the European radiation protection Basic Safety Standards, active since September 2020. This will strengthen the scientific and technical basis at different levels, including combining biomedical, and ecological research with mitigation development and social science research(27). In this, we are currently participatingwith 3 different projects with the objective to define for the first time the lung cancer profile associated with radon in rats, miners, and patients with lung cancer, and secondly to design for the first time a radon-associated signature in lung cancer. In this task, several European partners are involving, such as IDIBAPS, Spain, Gustave Roussy, the Radioprotection and Nuclear Safety Institute (IRSN), France; and the European Organization for Research and Treatment of Cancer (EORTC), among others, carrying out the following projects:
a) Preclinical cohort: The Radon-rats study, a retrospective molecular characterization of radon-induced lung cancer induced in rats from the lifespan French Atomic Energy Commission (CEA) experiments in rats exposed to alpha radioactivity,
b) Occupational cohort. The Radon-miners study, a retrospective molecular characterization of lung cancer in Uranium miners exposed to radon from the Wismut Miners cohort, and
c) Residential cohort: The BioRadon, a large prospective study that will perform a comprehensive clinical, pathological and molecular profiling of 993 patients with lung cancer exposed or not to indoor radon in Europe.
Finally, an unresolved matter is the evaluation of the impact of radon in combination with other relevant carcinogens such as tobacco (25), asbestos or even the genetic factors (e.g., sex, ancestry, etc.). More specific studies studying both carcinogens together and even with others (e.g., environmental pollution, asbestos, etc.) should be carried out to provide a basis of the synergism mechanisms of radon-other factors interaction, for improving our understanding of lung cancer.In line with this, we are currently working on the exposome applied to lung cancer in our patients, a concept that gathers all the environmental carcinogens that the human being is exposed from birth onwards.
Present and future perspectives: Legislation and cancer prevention
As indicated, the current legislation is very different depending on the country. Nevertheless, we recognise the efforts to pass new bills that aim to introduce radon reference levels in each country. Although the pool of reference, action and recommended radon levels may seem contradictory, we must point out that they depend mainly on two factors.
First, the legislation must be achievable and consider the so-called ALARA principle (“as low as reasonably achievable”). Thus, the EU decided to introduce a reference level of 300Bq/m3 in the EU member states. It is essential to point out that it is a reference level and not a limit. Therefore, EU member states can implement lower levels in their territories.
On the other hand, the WHO recommends a level of 100Bq/m3. It comes from the epidemiological evidence regarding the increase in the relative risk of lung cancer due to radon exposure.
Future legislation and bills in the world must reduce the legal radon reference levels as much as possible based on the ALARA principle. There is no threshold below the risk of lung cancer due to radon exposure is zero.
In order to reduce the disease burden associated with radon, it is crucial to generate knowledge about radon and to raise awareness among population and national authorities. Once we are aware of the consequences of radon exposure, we need to detect population at risk, and regulate radon maximum levels. Since the scientific evidence has described a linear increase of lung cancer risk of 16% for every increase of 100 Bq/m3 in radon concentration (14),in the future health authorities should consider these values when limiting indoor radonlevels.
If high indoor radon concentration is found, then authorities should promote methods and tools to prevent radon exposure (ventilation, barrier methods, etc). It is also indispensable to identify exposed population to high indoor radon concentration at risk of developing lung cancer that could benefit from lung cancer screening programmes. The National Comprehensive Cancer Network (NCCN) Expert Panel for Lung Cancer Screening (27) feels that radon is a risk factor if there is a documented sustained and substantially elevated radon exposure and recommends lung cancer screening with low-dose CT. Recently, the United States Preventive Services Task Force (USPSTF) has expanded the inclusion criteria for lung cancer screening with low-radiation-dose chest CT (subjects between 50 and 80 years, pack-year index greater than 20) (28). It would be interesting to know whether those smoking subjects with an additional risk factor (such as radon exposure) benefit from less stringent criteria. Furthermore, it should be investigated whether non-smokers with a sustained and significant exposure to environmental radon could undergo a lung cancer screening program with low-radiation dose chest CT.
Final remarks
During the last decades substantial progress has been done in the radon field and its undeniable relationship with lung cancer, but there is still much work to do andquestions to resolve.It is time to expand knowledge about radon. We hope that the ongoing studies, focused on the comprehensive characterization of lung cancer induced by radon, will strengthen scientific knowledge on radon, enriching the previous evidence, integrating clinicaland molecular oncology data on a radon-associated signature, also defining the impact of radon exposure on the cancer responseand patient's outcomes. These studies will also raise the awareness of this preventable but silent risk factor, promoting radon plans and strategies on cancer prevention.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
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