To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1983
Energy Deposition leads to Increase, lung cancer
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Direct deposition of ionizing energy leading to lung cancer||non-adjacent||Moderate||Moderate||Brendan Ferreri-Hanberry (send email)||Under development: Not open for comment. Do not cite||EAGMST Under Review|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
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 Supporting this KER
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).
Uncertainties and Inconsistencies
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.
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.
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 modulating factors
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).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The domain of applicability for this KER is multicellular organisms that possess lungs.
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.
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.
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.
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.
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.126.96.36.199.
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.
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.
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.
Hei, T.K et al. (1994), "Malignant transformatin of human bronchial epithelial cells by radon-simulated α-particles.", Carcinogenesis 15(3):431-437, doi: 10.1093/carcin/15.3.431.
Hofmann, W. et al. (2002), "Energy deposition, cellular radiation effects and lung cancer risk by radon progeny alpha particles.", Radiat Prot Dosimetry, 99(1–4):453–456. doi:10.1093/oxfordjournals.rpd.a006830.
Jorge, S.-G. et al. (2012), "Evidence of DNA double strand breaks formation in Escherichia coli bacteria exposed to alpha particles of different LET assessed by the SOS response.", Appl. Radiat. Isot. 71(SUPPL.):66–70. doi:10.1016/j.apradiso.2012.05.007.
Jostes, R.F. (1996), "Genetic, cytogenetic, and carcinogenic effects of radon: a review.", Mutat. Res. / Rev. in Genet. Toxicol. 340(2-3):125–139. doi: 10.1016/s0165-1110(96)90044-5.
Kendall, G.M. & T.J. Smith (2002), "Doses to organs and tissues from radon and its decay.", Journal of Radiological Protection. 22(4):389-406.doi:10.1088/0952-4746/22/4/304.
Kennedy, A.R. et al. (1978), "Enhancement of X-ray Transformation by 12-O-Tetradecanoyl-phorbol-13- acetate in a Cloned Line of C3H Mouse Embryo Cells1.", Cancer Res. 38(2):439-43.
Krewski, D. et al. (2005), "Residential Radon and Risk of Lung Cancer.", Epidemiology. 16(2):137–145. doi:10.1097/01.ede.0000152522.80261.e3.
Krewski, D. et al. (2006), "A combined analysis of north American case-control studies of residential radon and lung cancer.", J. Toxicol. Environ. Heal. - Part A. 69(7–8):533–597. doi:10.1080/15287390500260945.
Larsen, J.E. & J. Minna (2011), "Molecular Biology of Lung Cancer: Clinical Implications.", Clin. Chest Med., 32(4):703–740. doi:10.1016/j.ccm.2011.08.003.
Lomax, M.E., L.K. Folkes & P.O. Neill (2013). "Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy", Statement of Search Strategies Used and Sources of Information Why Radiation Damage is More Effective than Endogenous Damage at Killing Cells Ionising Radiation-induced Do. 25:578–585. doi:10.1016/j.clon.2013.06.007.
Lubin, J.H. et al. (1995), "Lung Cancer in Radon-Exposed Miners and Estimation of Risk From Indoor Exposure.", JNCI Journal of the National Cancer Institute. 87(11):817-27. doi:10.1093/jnci/87.11.817.
Luebeck, E.G. et al. (1999), "Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.", Radiat., Res., 152(4):339-51, doi: 10.2307/3580219.
Massion, P.P. & D.P. Carbone (2003), "The molecular basis of lung cancer: molecular abnormalities and therapeutic implications.", Respiratory Research, 4(1):12, doi: 10.1186/1465-9921-4-12.
Miller, R.C. et al. (1995), "The Biological Effectiveness of Radon-Progeny Alpha Particles.", Radiat. Res. 142(1):61–69. doi:10.2307/3578967.
Miller, R.C. et al. (1996), "The Biological Effectiveness of Radon-Progeny Alpha Particles V . Comparison of Oncogenic Transformation by Accelerator-Produced Monoenergetic Alpha Particles and by Polyenergetic Alpha Particles from Radon Progeny.", Radiat Res., 146(1):75-80. doi: 10.2307/3579398.
Monchaux, G. et al. (1994), "Carcinogenic and Cocarcinogenic Effects of Radon and Radon Daughters in Rats.", Environmental Health Perspectives, 102(1):64-73, doi: 10.1289/ehp.9410264
Müller, W.U. et al. (2016), "Current knowledge on, radon risk: implications for practical radiation protection?", radon workshop, 1/2 December 2015, Bonn, BMUB (Bundesministerium für Umwelt, Naturschutz, Bau und Reaktorsicherheit; Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety). Radiat Environ Biophys. 55(3):267–280. doi:10.1007/s00411-016-0657-2.
Nenoi, M., B. Wang & G. Vares (2015), "In vivo radioadaptive response: A review of studies relevant to radiation-induced cancer risk.", Hum Exp Toxicol. 34(3):272–283. doi:10.1177/0960327114537537.
Nikjoo, H. et al. (1997), "Computational modelling of low-energy electron-induced DNA damage by early physical and chemical events.", Int. J. Radiat. Biol. 71(5):467–483. doi:10.1080/095530097143798.
Beir V. 1990. Health Effects of Exposure to Low Leveles of Ionizing Radiation. National Academies Press.
Beir V. 1999. Health Effects of Exposure to Low Leveles of Ionizing Radiation. National Academies Press.
Okayasu, R. (2012), "Repair of DNA damage induced by accelerated heavy ions-A mini review.", Int. J. Cancer. 130(5):991–1000. doi:10.1002/ijc.26445.
Panov, S.Z. (2005), "Molecular biology of the lung cancer.", Radiology and Oncology 39(3):197–210.
Pitot, H. (1993), "The molecular biology of carcinogenesis.", Cancer, 72(S3):962–970, doi: 10.1002/1097-0142(19930801)72:3+3.0.CO;2-H.
Ramkissoon, A. et al. (2018), "Histopathologic Analysis of Lung Cancer Incidence Associated with Radon Exposure among Ontario Uranium Miners.", International Journal of Environmental Research and Public Health 15(11):2413. doi:10.3390/ijerph15112413.
Robertson, A. et al. (2013), "The cellular and molecular carcinogenic effects of radon exposure.", International Journal of Molecular Sciences. 14(7):14024-63. doi:10.3390/ijms140714024.
Rodríguez-Martínez, Á. et al. (2018), "Residential radon and small cell lung cancer.", Cancer Lett. 426:57–62. doi:10.1016/j.canlet.2018.04.003.
Rothkamm, K. et al. (2015), "Review DNA Damage Foci: Meaning and Significance.", Environ. Mol. Mutagen. 56(6):491-504, doi:10.1002/em.
Rühm, W., M. Eidemüller M & J.C. Kaiser (2017), "Biologically-based mechanistic models of radiation-related carcinogenesis applied to epidemiological data.", Int. J. Radiat., Biol. 93(10):1093-1117. doi: 10.1080/09553002.2017.1310405.
Sanders, H.R. & M. Albitar (2010), "Somatic mutations of signaling genes in non-small-cell lung cancer.", Cancer Genet Cytogenet. 203(1):7–15. doi:10.1016/j.cancergencyto.2010.07.134.
da Cunha Santos, G., F.A. Shepherd & M.S. Tsao (2010), "EGFR Mutations and Lung Cancer.", Annu Rev. Pathol., doi:10.1146/annurev-pathol-011110-130206.
Shah, D.J., R.K. Sachs & D.J. Wilson (2012), "Radiation-induced cancer: A modern view." Br. J. Radiol. 85(1020):1166–1173. doi:10.1259/bjr/25026140.
Sheen, S. et al. (2016), "An updated review of case-control studies of lung cancer and indoor radon-Is indoor radon the risk factor for lung cancer?", Ann. Occup. Environ. Med., 28(1), doi:10.1186/s40557-016-0094-3.
Sher, T., G. Dy & A.A. Adjei (2008), "Small cell lung cancer.", J. Thorac. Oncol. 2(8):S269–S271. doi:10.1097/01.jto.0000283046.50283.51.
Smith, J. et al. (2003), "Impact of DNA ligase IV on the delity of end joining in human cells.", Nucleic Acids Research. 31(8):2157-2167.doi:10.1093/nar/gkg317
Smith, L.E. et al. (2003), "Radiation-induced genomic instability: Radiation quality and dose response.", Health Phys. 85(1):23–29. doi:10.1097/00004032-200307000-00006.
Sutherland, B.M. et al. (2000), "Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation.", J. of Rad. Res. 43 Suppl(S):S149-52. doi: 10.1269/jrr.43.S149
Torres-Durán M. et al. (2014), "Residential radon and lung cancer in never smokers. A systematic review.", Cancer Lett. 345(1):21–26. doi:10.1016/j.canlet.2013.12.010.
Vogelstein, B. & K.W. Kinzler (2004), "Cancer genes and the pathways they control.", Nat. Med, 10(8):789–799. doi:10.1038/nm1087.
World Health Organization R guid. (2009), "Indoor Radon a Public Health Perspective.", Int J Environ Stud. 67(1):108. doi:10.1080/00207230903556771.
Wu, L.-J. et al. (1999), "Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells.", Proc Natl Acad Sci. 96(9):4959–4964. doi:10.1073/pnas.96.9.4959.
Zabarovsky, E.R., M.I. Lerman & J.D. Minna (2002), "Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers.", Oncogene, 21(45):6915-6935, doi:10.1038/sj.onc.1205835.
Zarnke, A.M. et al. (2019), "BEIR VI radon: The rest of the story.", Chem Biol Interact. 301(February):81–87. doi:10.1016/j.cbi.2018.11.012.