This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.
Relationship: 1983
Title
Energy Deposition leads to Increase, lung cancer
Upstream event
Downstream event
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 | EAGMST Approved |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
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).
| ID | Experimental Design | Species | Upstream Observation | Downstream Observation | Citation (first author, year) | Notes |
|---|
| Title | First Author | Biological Plausibility |
Dose Concordance |
Temporal Concordance |
Incidence Concordance |
|---|
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
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.
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)
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
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
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
Not identified.
The domain of applicability for this KER is multicellular organisms that possess lungs.