Factors Modifying the Radon-Related Lung Cancer Risk at Low Exposures and Exposure Rates among German Uranium Miners

Abstract

It is still not fully understood whether and how factors such as time, age and smoking modify the relationship between lung cancer and radon at low exposures and exposure rates. Improved knowledge is necessary for the dose conversion of radon in working level month (WLM) into effective dose, as currently discussed by the International Commission on Radiological Protection (ICRP). An update of the German uranium miner cohort study (n = 58,974 men) with a 10-year extension of mortality follow-up (1946-2013) was used to further examine this issue. Internal Poisson regression was applied to estimate the excess relative risk (ERR) for lung cancer mortality per unit of cumulative radon exposure in WLM with exponential time-related effect modifiers. In the full cohort restricted to <100 WLM the estimated overall ERR/WLM was 0.006 [95% confidence interval (CI): 0.003; 0.010] based on 1,254 lung cancer deaths and 1,620,190 person-years at risk. Both age at and time since exposure turned out to be important modifiers of the ERR/WLM and were included in the final model. Here, the ERR/WLM centered on age at exposure of 30 years, and 20 years since exposure was 0.016 (95% CI: 0.008; 0.028). This value decreased statistically significantly by approximately 40% and 60% for each 10-year increase in age at exposure and time since exposure, respectively. The joint effect of smoking and radon exposure was investigated in the sub-cohort of miners hired in 1960 or later, which includes data on smoking status. The centered ERR/WLM was slightly higher for non/light smokers compared to moderate/heavy smokers (0.022 versus 0.013). The current findings provide evidence for an increased lung cancer risk at low radon exposures or exposure rates that is modified by age and time. The observed risk is lower, but statistically compatible to those of other miner studies at low exposures or exposure rates. These findings reject an additive- and support a sub- to (supra-) multiplicative interaction between smoking and radon.

Combined effect of alpha particles and cigarette smoke on human lung epithelial cells in vitro

“…Cigarette smoke and radiation affect the cells in vitro in an additive way (Narayanan and Rao 1988;Piao and Hei 1993;Zhou et al 1999). The synergistic action, whether sub-, supramultiplicative or multiplicative, of cigarette smoking and radiation exposure was observed in epidemiological studies (Moolgavkar et al 1993;Leuraud et al 2011;Tomasek 2011;Gilbert et al 2013;Hunter et al 2015;Kreuzer et al 2018). Mauderly et al (2010) explained in their animal study the supra-additivity of cigarette smoke to alpha particle exposure in causing malignant lung cancer via delayed clearance of the alpha-emitting PuO 2 from the lungs due to particulate smoke.…”

“…Previous studies described the following three possible ways of interaction between radiation exposure (alpha particles in epidemiological studies) and cigarette smoking: additive (Narayanan and Rao 1988;Piao and Hei 1993;Zhou et al 1999;Pierce et al 2003;Tomasek 2013), multiplicative (Pershagen et al 1994;Kreisheimer et al 2003;Jacob et al 2005;Hunter et al 2015;Kreuzer et al 2018), and supra-additive (or sub-multiplicative) (Moolgavkar et al 1993;Zhang et al 2006;Mauderly et al 2010;Leuraud et al 2011;Tomasek 2011;Meenakshi and Mohankumar 2013;Gilbert et al 2013;Hunter et al 2015;Kreuzer et al 2018). In recent years, the possibility of a supramultiplicative model has been further claimed (Kreuzer et al 2018). The influence of smoking on radio-sensitivity was also debated to vary with specific conditions, including smoking rate (Monchaux et al 1994;Liddell and Armstrong 2002;Furukawa et al 2010;Egawa et al 2012).…”

“…The combined effect was supra-additive (sub-multiplicative) or multiplicative rather than additive according to multiple epidemiological studies (Moolgavkar et al 1993;Leuraud et al 2011;Tomasek 2011;Meenakshi and Mohankumar 2013;Gilbert et al 2013;Kreuzer et al 2018). However, those epidemiological studies gave no explanation regarding the mechanisms behind the supra-additivity.…”

Radon Biomonitoring and microRNA in Lung Cancer

“…Kreuzer et al demonstrated a clearly increased excess risk of lung cancer at low cumulative radon exposures [45]. Moreover, it was shown that excess relative risk (ERR) for lung cancer mortality per unit of cumulative radon exposure in WLM was 0.006 (95% confidence interval (CI): 0.003; 0.010) based on 1254 lung cancer deaths [45]. According to Yarmoshenko et al the relative risk (RR) of radon-induced lung cancer mortality was 0.026 (90% CI: (0.11-0.17)) and 0.83 (90% CI: (0.52-1.12)) per radon concentration 100 Bq/m 3 for males and females, respectively [46].…”

“…It has been proven experimentally that an increase in the concentration of radon in living quarters for every 100 Bq/m 3 leads to an increase the risk of lung cancer to 7% annually [44]. Kreuzer et al demonstrated a clearly increased excess risk of lung cancer at low cumulative radon exposures [45]. Moreover, it was shown that excess relative risk (ERR) for lung cancer mortality per unit of cumulative radon exposure in WLM was 0.006 (95% confidence interval (CI): 0.003; 0.010) based on 1254 lung cancer deaths [45].…”