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Relationship: 1983

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Energy Deposition leads to Increase, lung cancer

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Energy Deposition

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, lung cancer

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Deposition of energy leading to lung cancer	non-adjacent	Moderate	Moderate	Brendan Ferreri-Hanberry (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	High	NCBI
mouse	Mus musculus	High	NCBI
rat	Rattus norvegicus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Ionizing energy can traverse matter to induce biological damage. Tissue regions and cell types that are within depths of the traversable energy particles then have a higher likely hood of becoming transformed into malignant tumours (NRC 1990; Axelson 1995; Jostes 1996; NRC 1999; Kendall and Smith 2002; Al-Zoughool and Krewski 2009; Robertson et al. 2013). This multistep process is initiated by ionizations within the cell (L.E. Smith et al. 2003; Christensen 2014). If these ionizations hit DNA molecules, DNA damage is incurred, possibly in the form of double-strand breaks (DSBs) (J. Smith et al. 2003; Okayasu 2012; Lomax et al. 2013; Rothkamm et al. 2015). Inadequately repaired DNA damage could further lead to mutations and chromosomal aberrations (CAs), which often accumulate in the cell and disrupt the cellular dynamic. If these aberrations affect critical genes involved in the control of cell-cycle checkpoints it can promote uncontrolled cellular proliferation. An abnormally high rate of proliferation in cells of the respiratory tract can lead to lung tumourigenesis (Bertram 2001; Vogelstein and Kinzler 2004; Panov 2005; Hanahan and Weinberg 2011). Radon gas exposure at high levels is especially linked to carcinogenesis of the lung (Axelson 1995; Miller et al. 1996; NRC 1999; Kendall and Smith 2002; Al-Zoughool and Krewski 2009; Robertson et al. 2013).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

There is strong biological plausibility for the association between the direct deposition of energy by ionizing radiation and lung cancer incidence. The majority of the evidence is drawn from studies using radon gas as the stressor. Radon, a radioactive noble gas, is considered to be the second leading cause of lung cancer, behind smoking (Robertson et al. 2013; Rodríguez-Martínez et al. 2018; Axelson 1995; Miller et al. 1996; NRC 1999; Kendall and Smith 2002; Al-Zoughool and Krewski 2009; Robertson et al. 2013). Deposited energy from radiation in the form of particles can enter the body most often through inhalation (NRC 1999; Kendall and Smith 2002). These particles can deposit onto lung tissue and decay, producing harmful radiation (Axelson 1995; NRC 1999; Kendall and Smith 2002; Al-Zoughool and Krewski 2009). The radiation can ionize molecules within the cell and initiate the process of lung cancer. There are numerous reviews available detailing the molecular biology involved in lung carcinogenesis (Zabarovsky et al. 2002; Danesi et al. 2003; Massion and Carbone 2003; Panov 2005; Sher et al. 2008; Brambilla and Gazdar 2009; Eymin and Gazzeri 2009; Sanders and Albitar 2010; Larsen and Minna 2011; Santos et al. 2011) and discussing potential therapeutic options for lung cancer patients (Danesi et al. 2003; Massion and Carbone 2003; Sher et al. 2008; Eymin and Gazzeri 2009; PhD and MD 2011; Santos et al. 2011). Briefly there are three cellular steps: initiation, promotion and progression (reviewed by Gilbert 2009). Initiation refers to the interaction between the cell and the cancer-inducing agent, in this case ionizing radiation. The end-result of this interaction is irreversible genetic change(s) (NRC 1990; Pitot 1993). This, in turn, may lead to malfunctions in various pathways and, as the cell continues cycling, increasing genomic instability (NRC 1990). The promotion phase occurs when a promotor is applied to the irradiated cells and reversibly alters gene expression in an epigenetic fashion (NRC 1990; Pitot 1993), often by binding to its respective receptor (Pitot 1993). The promotor is not carcinogenic if applied alone, but it is capable of enhancing the oncogenic effect of the radiation (NRC 1990). For example, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) is often used as a promotor and was shown to enhance the oncogenic effects of X-ray radiation when applied to C3H/10T½ cells in culture (Kennedy et al. 1978). In some cases, if the dose of the initiator is high enough, the promotion phase may be bypassed altogether (NRC 1990; Pitot 1993). The final irreversible stage of carcinogenesis is progression, which can be boosted by radiation exposure. This is defined as the point at which the benign tumour becomes malignant due to an accumulation of genetic abnormalities, including mutations and chromosomal aberrations. At this point, the tumour grows rapidly due to high rates of cell proliferation, and the levels of genomic instability continue to increase (NRC 1990; Pitot 1993).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

There is strong empirical evidence supporting the relationship between direct deposition of energy by ionizing radiation and the development of lung cancer. The evidence presented below is summarized in table 12, here (click link). Biologically based mechanistic models of carcinogenesis have been developed that describe the complex process of maliginancy (Ruhme et al. 2017; Luebeck et al. 1999; Zaballa 2016, Eidemuller 2012; Heidenreich 2012; Jacob 2007, Hazelton 2006; Brugmans 2004 and Heidenreich 2000). There is a vast number of reviews that provide evidence of this association (Axelson 1995; Jostes 1996; NRC 1999; Kendall and Smith 2002; Al-Zoughool and Krewski 2009; Robertson et al. 2013; Sheen et al. 2016; Chadwick, 2017; Clement et al. 2010; UNSCEAR 2019). Overall, there is strong empirical evidence available supporting dose and incidence concordance, strong epidemiological data, and strong support for temporal concordance.

Figure 1: Plot of studies (y-axis) against equivalent dose (Sv) used to determine the empircal link between direct deposition of energy and increased rates of lung cancer. The y-axis is ordered from low LET to high LET from top to bottom.

Figure 2: Plot of studies (y-axis) against time over which studies were conducted for a temporal response used to determine the empircal link between direct deposition of energy and increased rates of lung cancer. The y-axis is ordered from low LET to high LET from top to bottom.

Dose and Incidence Concordance

There are numerous studies available that provide evidence supporting a dose/incidence concordance between the direct deposition of energy by ionizing radiation and the incidence of lung cancer. Several in vitro studies showed that cells could be induced to obtain oncogenic characteristics through radiation exposure (Hei et al. 1994; Miller et al. 1995); these oncogenic transformations also increased in a dose-dependent manner in some cases (Miller et al. 1995). Likewise, irradiation of rats at levels comparable to those experienced by uranium miners (25 - 3000 WLM of radon and its progeny) resulted in a dose-dependent increase in lung carcinoma incidence (Monchaux et al. 1994). Furthermore, a simulation model was developed that predicted an increased probability of a lung tumour after exposure to radiation doses ranging from 0 - 800 WLM (Hofmann et al. 2002). Munley et al. ( 2011) exposed bi-transgenic CCSP-rtTA/Ki-ras mice 80–160 mGy and showed staistically significant increase in the frequency of lung cancer incidence with a higher number in females. Evidence also exists for a dose-dependent linear relationship between excess relative risk of lung cancer and exposure to other non-radon forms of ionizing radiation such as that from survivors of the atomic bombs at Hiroshima and Nagasaki (Cahoon et al., 2017).

Human Epidemiological Studies

Indoor Radon Exposure

Indoor radon levels and lung cancer risk has been studied to establish a relationship between indoor radon exposure and lung carcinogenesis. The World Health Organization (WHO) recommends residential radon levels to be 100 Bq/m³ or less. This is based on the results of the two most relevant, large-scale residential radon studies, encompassing populations across Europe (Darby et al. 2005) and North America (Krewski et al. 2005; Krewski et al. 2006). These studies found a positive association between indoor radon exposure and lung cancer risk (Darby et al. 2005; Krewski et al. 2005; Krewski et al. 2006). A systematic review of never-smokers exposed to residential radon encompassing 14 studies across the world suggested a possible increased risk of lung cancer. There were, however, inconsistencies in results across studies (Torres-Durán et al. 2014), predominately due to confounders and dosimetric calculations. In a review published by Sheen et al. (2016), analysis of results from 24 case-control studies examining residential radon exposure and lung cancer risk also found conflicting results. A portion of the studies did, however, show a significantly increased risk in subjects exposed to higher radon concentrations.

Outdoor Radon Exposure

In terms of outdoor radon exposure, most data is derived from studies of lung cancer in miners occupationally exposed to radon. Overall, there seems to be a positive association between radon exposure and lung cancer risk. This was evident in a cohort of uranium miners who worked in mines in Ontario, Canada between 1954 and 1996 (Ramkissoon et al. 2018); in tin miners from Yunnan, China followed from 1976 - 1988 (Hazelton et al. 2001); and in a pooled analysis of underground miners of various nationalities from 11 cohort studies (Lubin et al. 1995); in a recent cohort study of pooled uranium miners analysis, also known as PUMA (Rage et al., 2020). Furthermore, a section of a review paper that examined epidemiological studies of radon-exposed miners found a positive, statistically significant association between radon exposure and lung cancer risk in all studies examined (Al-Zoughool and Krewski 2009, UNSCEAR 2006). In one study looking at the histopathology of lung carcinoma in a cohort of German uranium miners, it was shown that the relative frequency of specifically SqCC was associatd with increased expousre to radon (Kreuzer et al., 2000). This was confirmed in a later study, which showed increased relative frequency of both SqCC and SCLC when compared to AC (Taeger et al., 2006).

Indoor and Outdoor Radon Exposure

The association between lung cancer risk, and radon exposure was further fortified by a large systematic review that synthesized results from 16 studies of both indoor and outdoor exposure. This systematic review analysed results from studies of miners, pooled population studies and case control studies. Overall, there was a positive association found between radon exposure and SCLC risk (Rodríguez-Martínez et al. 2018). Results from these epidemiological studies suggest that radon exposure is linked to lung carcinogenesis, whether people are exposed indoors or outdoors.

Temporal Concordance

There is empirical evidence supporting that the direct deposition of energy by ionizing radiation precedes the development of lung cancer. In cells that were oncogenically transformed by irradiation, the oncogenic characteristics were detected weeks after the irradiation (Hei et al. 1994; Miller et al. 1995). Similarly, tumours induced in nude mice by inoculation with oncogenic cells took months to grow (Hei et al. 1994), while lung cancer in rats exposed to radon were not detected for months to years (Monchaux et al. 1994). In humans, the risk of lung cancer was also found to increase with increasing time since exposure (Hazelton et al. 2001; Cahoon et al., 2017) and with longer periods of exposure (Lubin et al. 1995). In addition, the lung cancer simulation model developed by Hofmann (2002) was based on an average radiation exposure time of 4 years. One study using distributed lag non-linear models (DLNMs) showed that risk onset began at about 2 years following initial exposure to radon in uranium miners, with the mean lag period being 15 years (Aßenmacher et al., 2019).

Essentiality

Not identified.

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Uncertainties and inconsistencies in this KER are as follows:

Studies have shown that dose-rates (Brooks et al. 2016) and radiation quality (Nikjoo et al. 1997; Sutherland et al. 2000; Jorge et al. 2012) are factors that can influence the dose-response relationship.
Low-dose radiation has been observed to have beneficial effects and may even invoke protection against spontaneous genomic damage and induced mutations (Feinendegen 2005; Day et al. 2007; Feinendegen et al. 2007; Shah et al. 2012; Nenoi et al. 2015).
Deposition of ionizing energy is a stochastic event; as such, the nucleus is not the only region that may be affected by radiation exposure. In vitro evidence has shown that ionizing radiation may also cause genotoxic effects when deposited in the cytoplasm (Wu et al. 1999).
When analyzing the relationship between radiation exposure and lung cancer in miners, other confounding carcinogen exposures, including silica, diesel engine exhaust, arsenic and tobacco, should also be accounted for (Cocco et al. 1994; Hazelton et al. 2001; Cao et al. 2017).
There are inherent difficulties in measuring radon exposures in the general public. Residential radon levels are measured using alpha trackers, but people all have different lifestyles and spend differing amounts of time in their home. Furthermore, it is very common for people to move from home to home. These factors challenge the ability to accurately estimate an individual’s radon exposure and thus to extrapolate this to lung cancer risk (Axelson 1995; Robertson et al. 2013).
While some of the epidemiological studies summarized in a systemic review by Torres-Duran et al (2014) showed an association between residential radon exposure and lung cancer, others did not. This is a result of uncertainties in dosimetric considerations, radon exposure levels, confounders such as smoking
There has been controversy surrounding the ICRP-reported dose coefficients being used to estimate risk from radon exposure. These coefficients were different across several ICRP reports and thus gave different estimates of risk for an identical radon exposure scenario. A report by Muller (2016) highlighted these controversies and summarized the results of a radon workshop addressing the situation (Müller et al. 2016).
A paper by Zarnke (2019) critiques the conclusions drawn by the BEIR VI report regarding radon exposure and health effects. Based upon the authors’ analyses, radon exposure in the home is not linked to lung cancer, and may in fact be protective against smoking-induced lung cancer.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

There are several agents, summarized in the NRC 1990 report, that may affect radiation-mediated oncogenic transformations/carcinogenesis. Some agents can enhance the effects of radiation to increase the accumulation of oncogenic characteristics. These include hydroxyurea and 12-O-tetradecanoyl-phorbol-acetate (TPA) (NRC 1990). The effects of hydroxyurea were seen within 11 hours of treatment (Hahn et al. 1986), while the effects of TPA were evident both immediately following irradiation, and up to 96 hours post-irradiation (Kennedy et al. 1978). Other agents may reduce the effectiveness of radiation-induced malignant transformations. Suppressors of radiation-mediated oncogenic transformations include antipain (a protease inhibitor), selenium, and 5-aminobenzamide. Hormone levels may also have an effect on the radiation-carcinogenesis relationship. For example, high levels of thyroid hormone T3 worked synergistically with radiation to enhance oncogenic characteristics, while low T3 levels antagonized the effects of radiation (NRC 1990). Studies have also discussed sex as a modulating factor to radon induced lung cancer. Kim et al. 2016 reported that the proportion of lung cancer deaths induced by radon was slightly higher in females but after stratifying for smoking, the attributable risk of lung cancer death was similar between gender. A review analyzing sex differences of radiation response, generally found that the excess relative risk for lung cancer was higher in females than males when workers were exposed to plutonium at the Mayak nuclear facility (Narendran et al. 2019). Similarily, a higher excess relative risk for lung cancer was found in females after Japanese atomic bomb exposure (Cahoon et al. 2017; Ozasa et al. 2012)

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

There are many epidemiological studies available that provide quantitative data linking radiation exposure with lung cancer risk, incidence and/or death. Results from several of these studies are summarized in the table below.

Reference	Summary
UNSCEAR, 2000	Study of general population and its exposure to low LET radiation with a dose of 1 Sv. Study found a lifetime risk estimate for solid cancer mortality of 9% for men and 13% for women.
EPA, 2003	Study of the general population (USA) exposed to residential levels of radon found a lung cancer deaths linked at 14.3% (in 1995) at a risk per unit of radon exposure as 5.38x10^-4 per WLM. Two further studied sampled from strictly non- and smoking-populations for similar levels of residential radon exposure. From the smoking population the risk per unit radon exposure was higher, 9.68x10^-4 per WLM compared to the non-smoking population; 1.67x10^-4 per WLM.
Darby, 2005	Study covering 13 European cohorts who were exposed to residential levels of radon found that lung cancer risks increases by 8.4% per 100 Bq/m^3.
Krewski, 2006	7 North American cohorts were studied who were exposed to residential levels of radon. It was found that the odds ratio, OR(x) = 1 + 0.00096x. The odds ratio for subjects living in 1-2 residences with 20+ years of radon monitoring. OR(x) = 1 + 0.00176x.
Grundy et al., 2017	Study of the general population of Alberta (Canada) exposed to residential levels of radon in the range of 71.0 Bq/m3 (Alberta mean). Study found that overall, lung cancer deaths linked to radon were 16.6% (324 excess attributable cases). Ever smoker lung cancer deaths linked to radon: 15.6% (274 excess attributable cases). and never smoking lung cancer deaths linked to radon were: 24.8% (48 excess attributable cases).
Peterson et al., 2013	A study of the general population in Ontario exposed to residential levels of radon (Ontario mean: 43 Bq/m3) found the % of lung cancer deaths linked to radon as being 13.6% (847 cases). Ever smoker lung cancer deaths linked to radon: 15.6% (274 excess attributable cases). Never smoker lung cancer deaths linked to radon: 24.8% (48 excess attributable cases).
Lagarde et al., 2001	Study of the general population in Sweden exposed to residential levels of radon. Study found relative risk of lung cancer at different exposure levels: 50 Bq/m3: 1.08 with a confidence interval of 0.8-1.5. 80 Bq/m3: 1.18 with a confidence interval of 0.9 - 1.6. 140 Bq/m3: 1.44 with a confidence interval of 1.0 - 2.1. Overall excess relative risk: 10% per 100 Bq/m3.
Torres-Duran et al., 2014	Study of the general population (obtained through a systemic review of 14 studies) of residential radon exposure TABLE 2
Al-Zoughool and Krewski, 2009	TABLE 2

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Overall, studies suggest that there is a positive relationship between radiation exposure and lung cancer risk. A direct basis for the link has been provided by epidemiological studies in miners occupationally exposed to radon (UNSCEAR 2006, Lubin et al. 1995; Ramkissoon et al. 2018). In a study of tin miners exposed to radon, there was an increasing risk of lung cancer with increasing radon exposure (Hazelton et al. 2001). This positive relationship has likewise also been found in residential radon studies (Darby et al. 2005; Krewski et al. 2005; Krewski et al. 2006). A large systemic review encompassing miner cohort studies, pooled population studies, and case-control studies showed a strong association between residential radon concentration and lung cancer (Rodríguez-Martínez et al. 2018). Mechanistic in vitro (Miller et al. 1995) and in vivo (Monchaux et al. 1994) experimental models also provide data to support this relationship.

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

There is some quantitative data available regarding the time scale between radiation exposure and the development of lung cancer. In vitro oncogenic transformations were evident 6 weeks after cells were irradiated with X-rays or charged particles of varying LETs (Miller et al. 1995). Similarly, irradiated, tumourigenic bronchial epithelial cells were able to induce tumour growth within 13 weeks of injection into nude mice; tumours reached a size of 0.6 - 0.7 cm by 6 months post-inoculation. In comparison, unirradiated implanted cells did not induce tumour growth (Hei et al. 1994). Epidemiology studies also suggest that lung cancers are detected years after exposure to radiation (Lubin et al. 1995; Darby et al. 2005; Torres-Durán et al. 2014; Rodríguez-Martínez et al. 2018; Ramkissoon et al. 2018). Exposure to radon for longer periods of time predicts an increased relative risk of lung cancer; this risk increased with increasing duration of exposure over 5, 10 and 20 years (Lubin et al. 1995). In a study of tin miners, there were sharp increases in risk at approximately 40 years since first exposure and approximately 40 years since last exposure (Hazelton et al. 2001).

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not identified.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The domain of applicability for this KER is multicellular organisms that possess lungs.

References

List of the literature that was cited for this KER description. More help

Al-Zoughool, M. & D. Krewski (2009), "Health effects of radon: A review of the literature.", Int. J. Radiat. Biol., 85(1):57–69. doi:10.1080/09553000802635054.

Aßenmacher, M. et al., (2019), Exposure-lag-response associations between lung cancer mortality and radon exposure in German uranium miners. Radiat Environ Biophys., Aug;58(3):321-336. doi: 10.1007/s00411-019-00800-6. Epub 2019 Jun 19. PMID: 31218403.

Axelson, O. (1995), "Cancer risks from exposure to radon in homes.", Environ Health Perspect. 103(Suppl 2):37-43, doi: 10.1289/ehp.95103s237

Bertram, J.S. (2001), "The molecular biology of cancer.", Mol. Aspects. Med. 21:166–223. doi:10.1016/S0098-2997(00)00007-8.

Brambilla, E. & A. Gazdar (2009), "Pathogenesis of lung cancer, a roadmap for therapies.", Eur. Respir. J., 33(6):1485–1497. doi:10.1183/09031936.00014009.

Brooks, A.L., D.G. Hoel & R.J. Preston (2016), "The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.", Int. J. Radiat. Biol. 92(8):405–426. doi:10.1080/09553002.2016.1186301.

Brugmans, M. J. P. et al. (2004), "Radon-induced lung cancer in French and Czech miner cohorts described with a two-mutation cancer model", Radiation and Environmental Biophysics, 43(3). https://doi.org/10.1007/s00411-004-0247-6.](https://doi.org/10.1007/s00411-004-0247-6.

Cahoon, E.K. et al., (2017), Lung, Laryngeal and Other Respiratory Cancer Incidence among Japanese Atomic Bomb Survivors: An Updated Analysis from 1958 through 2009., Radiat Res., May;187(5):538-548. doi: 10.1667/RR14583.1. Epub

Cao, X. et al. (2017), "Radon-induced lung cancer deaths may be overestimated due to failure to account for confounding by exposure to diesel engine exhaust in BEIR VI miner studies.", PLoS One. 12(9):1–15. doi:10.1371/journal.pone.0184298.

Chadwick, K.H., (2017), Towards a new dose and dose-rate effectiveness factor (DDREF)? Some comments., J Radiol Prot., 37:422-433. doi: 10.1088/1361-6498/aa6722.

Christensen, D.M. (2014), "Management of Ionizing Radiation Injuries and Illnesses, Part 3: Radiobiology and Health Effects of Ionizing Radiation.", J. Am. Osteopath Assoc., 114(7):556–565. doi:10.7556/jaoa.2014.109.

Clement, C. H. et al. (2010), "Lung Cancer Risk from Radon and Progeny and Statement on Radon", Annals of the ICRP, 40(1). https://doi.org/10.1016/j.icrp.2011.08.011.](https://doi.org/10.1016/j.icrp.2011.08.011.

Cocco, P.L. et al. (1994), "Mortality of Sardinian lead and zinc miners: 1960-88.", Occup Environ Med., 51(10):674–682., doi:10.1136/oem.51.10.674.

Danesi, R. et al. (2003), "Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer." 55(1):57-103. doi:10.1124/pr.55.1.4.57.

Darby, S. et al. (2005), "Radon in homes and risk of lung cancer: Collaborative analysis of individual data from 13 European case-control studies.", Br Med J., 330(7485):223–226. doi:10.1136/bmj.38308.477650.63.

Day, T.K. et al. (2007), "Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate Induced by Low Doses of X Radiation Delivered after a High Dose.", Radiat Res. 167(6):682–692. doi:10.1667/rr0764.1.

Eidemüller, M. et al. (2012), "Lung Cancer Mortality (1950–1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models", (D.L. McCormick, Ed.)PLoS ONE, 8(7). https://doi.org/10.1371/journal.pone.0041431.](https://doi.org/10.1371/journal.pone.0041431

Eymin, B. & S. Gazzeri (2010), "Role of cell cycle regulators in lung carcinogenesis.", Cell Adh Migr. 4(1):114–123.

Feinendegen, L.E. (2005), "UKRC 2004 debate Evidence for beneficial low level radiation effects and radiation hormesis. Radiology.", 78:3–7. doi:10.1259/bjr/63353075.

Feinendegen, L.E., M. Pollycove & R.D. Neumann (2007), "Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology.", Exp. Hematol. 35(4 SUPPL.):37–46. doi:10.1016/j.exphem.2007.01.011.

Gilbert, E.S. (2009), "Ionizing Radiation and Cancer Risks: What Have We Learned.", Int. J. Radiat. Biol., 85(6):467–482, doi:10.1080/09553000902883836.

Hahn, P. et al. (1986), "Chromosomal Changes without DNA Overproduction in Hydroxyurea-treated Mammalian Cells: Implications for Gene Amplification.", Cancer Res. Cancer Research. 46(9):4607-12.

Hazelton, W. D. et al. (2006), "Biologically Based Analysis of Lung Cancer Incidence in a Large Canadian Occupational Cohort with Low-Dose Ionizing Radiation Exposure, and Comparison with Japanese Atomic Bomb Survivors", Journal of Toxicology and Environmental Health, 69(11).

Hanahan, D. & R.A. Weinberg (2011), "Review Hallmarks of Cancer: The Next Generation.", Cell. 144(5):646–674. doi:10.1016/j.cell.2011.02.013.

Hazelton, W.D. et al. (2001), "Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model.", Radiat Res. 156(1):78–94. doi:10.1667/0033-7587(2001)156[0078:aoahco]2.0.co;2.

Health Canada - Radon Guid. 2017. Guide for Radon Measurements in Residential Dwellings. :1–22.

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