Panel discussion on submammalian systems

A test of X-ray-induced recessive lethal mutations in mouse spermatogonia (500 rad) was carried out. The test was based on familial analysis, which allowed division on the P pairs into those with lethal heterozygous members and in others assumed to be lethal-free. The F1 males from the latter group, in back-crosses to their daughters, gave an excessive rate of intra-uterine death in comparison with lethal-free males. The excessive death is assumed to reflect the rate of new (induced + spontaneous) recessive lethals or rather lethal equivalents.Three ways of estimating the rate of new recessive lethal mutations gave a mean of 5.5% per genome. From previous tests we can assume that 1% are spontaneous mutations. Thus the data indicate that the mutation rate per rad per gamete is 9 × 10^?5. This value is identical with a previous estimate.The results are discussed in relation to population tests performed in the early 60'2. It is concluded that the lack of observable deterioration in the populations after several consecutive generations of exposure is in accord with the estimates in the present analysis which are more than an order of magnitude lower than assumed at the start of the population tests.It is also stressed that species with different DNA contents show similarities in point estimates of doubling dosages.     

Model-derived dose rates per unit concentration of radon in air in a generic plant geometry

A model for the derivation of dose rates per unit radon concentration in plants was developed in line with the activities of a Task Group of the International Commission on Radiological Protection (ICRP), aimed at developing more realistic dosimetry for non-human biota. The model considers interception of the unattached and attached fractions of the airborne radon daughters by plant stomata, diffusion of radon gas through stomata, permeation through the plant’s epidermis and translocation of deposited activity to plant interior. The endpoint of the model is the derivation of dose conversion coefficients relative to radon gas concentration at ground level. The model predicts that the main contributor to dose is deposition of ²¹⁴Po α-activity on the plant surface and that diffusion of radon daughters through the stomata is of relatively minor importance; hence, daily variations have a small effect on total dose.     

Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.

This study is a comprehensive analysis of the latest follow-up of the Colorado uranium miners cohort using the two-stage clonal expansion model with particular emphasis on effects related to age and exposure. The model provides a framework in which the hazard function for lung cancer mortality incorporates detailed information on exposure to radon and radon progeny from hard rock and uranium mining together with information on cigarette smoking. Even though the effect of smoking on lung cancer risk is explicitly modeled, a significant birth cohort effect is found which shows a linear increase in the baseline lung cancer risk with birth year of the miners in the cohort. The analysis based on the two-stage clonal expansion model suggests that exposure to radon affects both the rate of initiation of intermediate cells in the pathway to cancer and the rate of proliferation of intermediate cells. However, in contrast to the promotional effect of radon, which is highly significant, the effect of radon on the rate of initiation is found to be not significant. The model is also used to study the inverse dose-rate effect. This effect is evident for radon exposures typical for mines but is predicted to be attenuated, and for longer exposures even reversed, for the more protracted and lower radon exposures in homes. The model also predicts the drop in risk with time after exposure ceases. For residential exposures, lung cancer risks are compared with the estimates from the BEIR VI report. While the risk estimates are in agreement with those derived from residential studies, they are about two- to fourfold lower than those reported in the BEIR VI report.     

Do U.S. county data disprove linear no‐threshold predictions of lung cancer risk for residential radon?‐A preliminary assessment of biological plausibility

Lung‐cancer mortality (LCM) is elevated in underground miners who chronically inhaled the mutagenic, cytotoxic α‐decay products of radon gas. Epidemiologie studies of LCM rates vs. residential‐radon concentration levels are generally considered inconclusive. However, Cohen (Health Physics 68, 157–174, 1995) has hypothesized that data on LCM vs. residential radon concentrations at the U.S. county level are clearly inconsistent with a linear no‐threshold (LN) dose‐response model, and rather are consistent with threshold or hormesis model. Cohen's hypothesis has been criticized as “ecological fallacy,”; particularly because LN (but not threshold or hormesis) models are generally considered biologically plausible for agents like α radiation that damage DNA in linear proportion to dose. To assess the biological plausibility of Cohen's hypothesis, a preliminary study was made of whether a biologically realistic, cytodynamic 2‐stage (CD2) cancer model can provide a good, joint fit to Cohen's set of U.S. county data as well as to underground‐miner data. The CD2 model used adapts a widely applied, mechanistic, 2‐stage stochastic model of carcinogenesis to realistically account for interrelated cell killing and mutation (both assumed to have a LN dose‐response), cell turnover, and incomplete exposure of stem cells. A CD2 fit was obtained to combined summary data on LCM vs. radon‐exposure in white males in 1, 601 U.S. counties (from Cohen) and in white male Colorado Plateau (CP) uranium miners (from the National Research Council's “BEIRIV”; report). The CD2 fit is shown to: (i) be consistent with the combined data; (ii) have parameter values all consistent with biological data; and (iii) predict inverse dose‐rate‐effects data for CP and other radon‐exposed miners, despite the fact that optimization had not involved any of these dose‐rate data. The latter data were not predicted by a simplified CD2 model in which all stem cells were presumed to be exposed. It is concluded that this study provides preliminary evidence that Cohen's hypothesis is biologically plausible.     

Models for the analysis of radon-exposed populations

Radon-222 is a radioactive decay product of radium-226 and uranium-238, which are found throughout the crust of the earth. Studies of underground miners clearly show that exposure to radon and its decay products increases the risk of developing lung cancer. Data on standardized mortality ratios from eight cohort studies indicate that the radon-lung cancer relationship is statistically homogeneous, even though cohorts are from different types of mines and from different countries. Regression methods for cohort data based on a Poisson probability model permit a thorough consideration of risk patterns. In this report, we review these methods, wherein the disease rate in each cell of a multi-way table is modeled as a function of the cross-classifying variables. The National Academy of Sciences' Committee on the Biological Effects of Ionizing Radiation uses the Poisson regression approach to develop a model for age-specific lung cancer risk which depends on cumulative exposure, age at risk, and time since exposure. This model is reviewed and its implications discussed. The most important determinant of lung cancer is cigarette smoking. This paper discusses relative risk models for analysis of joint exposure to radon and tobacco products. The review of available studies suggests that the joint relationship of radon and smoking with lung cancer is consistent with a multiplicative model, but a submultiplicative relationship is most likely. An additive model is rejected.     

Radon in dwellings: The importance of ventilation

Summary People who live in industrial countries receive a radioactive dose of 2.4 mSv/y: the most important contribution to this dose is given by radon decay products. Radon is a noble gas generated from the disintegration of radium, which is found in soils and building materials. Owing to a bad air circulation, radon and its daughters may accumulate in a house. By using a mathematical model it may be shown that radon concentration is inversely proportional to the ventilation rate. Measurements of radon concentration through the method of activated carbon canisters, show that in a room with a double-pane window, kept continuously closed, the mean radon concentration can exceed the concentration of a similar room with a single-pane window of 190%. However, the radon concentration inside the energy-saving room may be decreased up to values slightly higher than those measured in the conventional window room, by simply opening the double-pane window a few minutes a day. A set of measurements carried out in a group of house in Reggio Emilia validates the effectiveness of that practice: radon concentrations in rooms with double-pane window closely approximated to those of rooms with ordinary window.     

Quantitative health impact of indoor radon in France

Radon is the second leading cause of lung cancer after smoking. Since the previous quantitative risk assessment of indoor radon conducted in France, input data have changed such as, estimates of indoor radon concentrations, lung cancer rates and the prevalence of tobacco consumption. The aim of this work was to update the risk assessment of lung cancer mortality attributable to indoor radon in France using recent risk models and data, improving the consideration of smoking, and providing results at a fine geographical scale. The data used were population data (2012), vital statistics on death from lung cancer (2008–2012), domestic radon exposure from a recent database that combines measurement results of indoor radon concentration and the geogenic radon potential map for France (2015), and smoking prevalence (2010). The risk model used was derived from a European epidemiological study, considering that lung cancer risk increased by 16% per 100 becquerels per cubic meter (Bq/m³) indoor radon concentration. The estimated number of lung cancer deaths attributable to indoor radon exposure is about 3000 (1000; 5000), which corresponds to about 10% of all lung cancer deaths each year in France. About 33% of lung cancer deaths attributable to radon are due to exposure levels above 100 Bq/m³. Considering the combined effect of tobacco and radon, the study shows that 75% of estimated radon-attributable lung cancer deaths occur among current smokers, 20% among ex-smokers and 5% among never-smokers. It is concluded that the results of this study, which are based on precise estimates of indoor radon concentrations at finest geographical scale, can serve as a basis for defining French policy against radon risk.     

The effect of a change in mutation rate on the incidence of dominant and X-linked recessive disorders in man

In order to assess the impact on man of a sustained change in mutation rate that might be caused by ionizing radiation or a chemical mutagen in the environment, it is important to determine the current incidence of genetic disease, the rate at which deleterious mutations arise and the number of generations that mutations persist before eliminated by selection. From these data it should be possibel to estimate both the increase in genetic disease in the first generation following the increase in mutation rate, and the rate at which a new equilibrium between mutation and selection would occur. In this paper the results of a survey to determine birth frequency, mutation rate and reproductive fitness for each of the important dominant and X-linked recessive disorders are described. It is estimated that these disorders affect about 0.6% of live-born individuals, including 0.1% of live-borns who carry a newly-arising mutation. These figures are approx. 50% lower than those used by the various committees that have assessed the genetic risk to man form ionizing radiation. If the mutation rate were to permanently double, the frequency of these disorders would be expected in increase in the first generation by 15%, to 0.7% of live-births. The increase in the first 2 generations would be 24% and a 50% increase would occur by the 9th generation. a calculation of the possible increase in dominant and X-linked recessive disorders due to exposure of a population to ionizing radiation indicates that the estimate made in 1977 by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) may be too high by a factor of 2–6 fold.     

A retrospective mortality study of workers exposed to radon in a Brazilian underground coal mine

Recently a high radon concentration was detected in the underground coal mine of Figueira, located in the south of Brazil. This coal mine has been operating since 1942 without taking cognizance of the high radon environment. In order to assess possible radon-related health effects on the workers, a retrospective (1979-2002) mortality study of 2,856 Brazilian coal miners was conducted, with 2,024 underground workers potentially exposed to radon daughters. Standard mortality ratio (SMR) analysis hints at lower mortality from all causes for both underground (SMR = 88, 95% CI = 78-98) and surface workers (SMR = 96, 95% CI = 80-114). A high statistically significant SMR for lung cancer mortality was observed only in the underground miners (SMR = 173, 95% CI = 102-292), with a statistically significant trend reflecting the duration of underground work. High statistically significant SMRs were observed for pneumonia as a cause of death between both surface (SMR = 304, 95% CI = 126-730) and underground miners (SMR = 253, 95% CI = 140-457). Because mortality from smoking-related cancers other than lung cancer was not found elevated in underground workers and because diesel equipments were not used in this mine, it can be concluded that the enhanced lung cancer mortality observed for underground miners is associated with exposure to radon and radon daughters, rather than other confounding risk factors.     

Calculation of the 1995 lung cancer incidence in the Netherlands and Sweden caused by smoking and radon: risk implications for radon

A two-mutation carcinogenesis model was used to calculate the expected lung cancer incidence caused by both smoking and exposure to radon in two populations, i.e. those of the Netherlands and Sweden. The model parameters were taken from a previous analysis of lung cancer in smokers and uranium miners and the model was applied to the two populations taking into account the smoking habits and exposure to radon. For both countries, the smoking histories and indoor radon exposure data for the period 1910-1995 were reconstructed and used in the calculations. Compared with the number of lung cancer cases observed in 1995 among both males and females in the two countries, the calculations show that between 72% and 94% of the registered lung cancer cases may be attributable to the combined effects of radon and smoking. In the Netherlands, a portion of about 4% and in Sweden, a portion of about 20% of the lung cancer cases (at ages 0-80 years) may be attributable to radon exposure, the numbers for males being slightly lower than for females. In the Netherlands, the proportions of lung cancers attributable to smoking are 91% for males and 71% for females; in Sweden, the figures are 70% and 56%, respectively. The risk from radon exposure is dependent on gender and cigarette smoking: the excess absolute risk for continuous exposure to 100 Bq m-3 ranges between 0.003 and 0.006 and compares well with current estimates, e.g. 0.0043 of the International Commission on Radiological Protection (ICRP). The excess relative risk for continuous exposure to 100 Bq m-3 shows a larger variation, ranging generally between 0.1 for smokers and 1.0 for non-smokers. The results support the assumption that exposure to (indoor) radon, even at a level as low as background radiation, causes lung cancer proportional to the dose and is consistent with risk factors derived from the miners data.     

Risk estimation based on germ-cell mutations in animals

The set of mouse germ cell mutation rate results following spermatogonial exposure to high dose rate irradiation have been presented as the most relevant experimental results upon which to extrapolate the expected genetic risk of offspring of the survivors of the Hiroshima and Nagasaki atomic bombings. Results include mutation rates to recessive specific-locus, dominant cataract, protein-charge, and enzyme-activity alleles. The mutability as determined by the various genetic end points differed: the mutation rates to recessive specific-locus alleles and enzyme-activity alleles were similar and greater than the mutation rates to dominant cataract and protein-charge alleles. It is argued that the type of mutation event scored by a particular test will determine the mutability of the genetic end point screened. When the loss of functional gene product can be scored in a particular mutation test, as in the recessive specific-locus and enzyme-activity tests, a wide spectrum of DNA alterations may result in a loss of and a higher mutation rate is observed. When an altered gene product is scored, as in the dominant cataract and protein-charge tests, a narrower spectrum of DNA alterations is screened and a lower mutation rate is observed. The radiation doubling dose, defined as the dose that induces as many mutations as occur spontaneously per generation, was shown to be four times higher in the dominant cataract test than the specific-locus test. These results indicate that to extrapolate to genetic risks in humans using the doubling-dose method, the extrapolation must be based on experimental mutation rate results for the same genetic end point.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biologically Based Prediction of Empirical Nonlinearity in Lung Cancer Risk vs. Residential/ Occupational Radon Exposure

Ecologic U.S. county data suggest negative associations between residential radon exposure and lung cancer mortality (LCM) that are inconsistent with clearly positive ones revealed by individual data on underground miners. If this inconsistency is due to competing effects of induced cell killing vs. mutations in alpha-radiation exposed bronchial epithelium, then linear extrapolation from miner data may overestimate typical residential radon risks. To investigate the plausibility of this hypothesis, a biologically based “cytodynamic 2-stage” (CD2) cancer-risk model was fit to combined 1950 to 1954 age-specific person-year data on white females of age 40+ y in 2821 U.S. counties (～90% never-smokers), and on five cohorts of underground miners who never smoked, conditional on a realistic rate of alpha-radiation-induced killing of human lung cells, and on linear-no-threshold dose-response relations for both processes assumed to affect cancer risk (alpha-induced mutations and cell killing). As summarized previously (Bogen, K.T., Hum. Exper. Toxicol. 17:691-6, 1998), a good CD2 fit was obtained that involved biologically plausible parameter values and (without further optimization) also predicted inverse dose-rate effects observed in the nonsmoking miners. The present paper reports mathematical details of the CD2 model used, as well as additional modeling results involving the same combined data set. The results obtained are consistent with the hypotheses that low-level radon exposure is nonlinearly related to LCM risk, and that current linear no-threshold extrapolation models overestimate LCM risk associated with relatively low residential radon concentrations (<～200?Bq m^?3). Testing this hypothesis would require more extensive individual-level epidemiological data relating residential radon exposures to LCM than are currently available.     

Lung cancer and indoor radon exposure in the north of Portugal--an ecological study

BackgroundIndoor radon exposure is a well documented environmental factor as a leading cause of lung cancer. Objectives: The aim of this study was to assess the risk of lung cancer and estimate the number of deaths due to indoor radon exposure in the north of Portugal, between 1995 and 2004. Methods: The sixth Biological Effects of Ionizing Radiation Committee (BEIR VI) preferred models were applied to estimate the risk of developing lung cancer induced by indoor radon exposure, by age and level of exposure, and calculated the number of lung cancer deaths attributable to this exposure. Lung cancer mortality data were granted by the North Regional Health Administration and indoor radon concentrations resulted from a national survey conducted by the Portuguese Environmental Agency. The smoking habit was accounted with two methods. A submultiplicative interaction between smoking and indoor radon exposure was considered. Results: Depending on the model applied and the method used to account for the smoking habit, the estimated number of lung cancer deaths attributed to indoor radon exposure, in northern Portugal, ranges from 1565 to 2406, for the period between 1995 and 2004. This indicates that of the 8514 lung cancer deaths observed, from 18 to 28% could be associated with indoor radon exposure.ConclusionsThis was the first study realized in Portugal on the impact of indoor radon exposure in lung cancer mortality. The application of the BEIR VI models led to a high number of lung cancer deaths due to indoor radon exposure.     

Dominant cataract and recessive specific locus mutations in offspring of X-irradiated male mice

Male mice were X-irradiated with 3.0 + 3.0 Gy or 5.1 + 5.1 Gy (fractionation interval 24 h). The offspring were screened for dominant cataract and recessive specific locus mutations. In the 3.0 + 3.0-Gy spermatogonial treatment group, 3 dominant cataract mutations were confirmed in 15 551 offspring examined and 29 specific locus mutations were recovered in 18 139 offspring. In the post-spermatogonial treatment group, 1 dominant cataract mutation was obtained in 1120 offspring and 1 recessive specific locus mutation was recovered in 1127 offspring. The induced mutation rate per locus, per gamete, per Gy calculated for recessive specific locus mutations is 2.0 X 10(-5) in post-spermatogonial stages and 3.7 X 10(-5) in spermatogonia. For dominant cataract mutations, assuming 30 loci, the induced mutation rate is 5.0 X 10(-6) in the post-spermatogonial stages and 1.1 X 10(-6) in spermatogonia. In the 5.1 + 5.1-Gy spermatogonial treatment group, 3 dominant cataract mutations were obtained in 11 205 offspring, whereas in 13 201 offspring 27 recessive specific locus mutations were detected in the spermatogonial group. In the post-spermatogonial treatment group no dominant cataract mutation was observed in 425 offspring and 2 recessive specific locus mutations were detected in 445 offspring. The induced mutation rate per locus, gamete and Gy in spermatogonia for recessive specific locus mutations is 2.8 X 10(-5) and for dominant cataract mutations 0.9 X 10(-6). In post-spermatogonial stages, the mutation rate for recessive specific locus alleles is 6.2 X 10(-5). In the concurrent untreated control group, in 11 036 offspring no dominant cataract mutation and in 23 518 offspring no recessive specific locus mutation was observed. Litter size and the number of carriers at weaning have been determined in the confirmation crosses of the obtained dominant cataract mutants as indicators of viability and penetrance effects. Two mutants had a statistically significantly reduced litter size and one mutant had a statistically significantly reduced penetrance.     

Radon, smoking and lung cancer risk: results of a joint analysis of three European case-control studies among uranium miners

A combined analysis of three case-control studies nested in three European uranium miner cohorts was performed to study the joint effects of radon exposure and smoking on lung cancer death risk. Occupational history and exposure data were available from the cohorts. Smoking information was reconstructed using self-administered questionnaires and occupational medical archives. Linear excess relative risk models adjusted for smoking were used to estimate the lung cancer risk associated with radon exposure. The study includes 1046 lung cancer cases and 2492 controls with detailed radon exposure data and smoking status. The ERR/WLM adjusted for smoking is equal to 0.008 (95% CI: 0.004-0.014). Time since exposure is shown to be a major modifier of the relationship between radon exposure and lung cancer risk. Fitting geometric mixture models yielded arguments in favor of a sub-multiplicative interaction between radon and smoking. This combined study is the largest case-control study to investigate the joint effects of radon and smoking on lung cancer risk among miners. The results confirm that the lung carcinogenic effect of radon persists even when smoking is adjusted for, with arguments in favor of a sub-multiplicative interaction between radon and smoking.     

The bystander effect in C3H 10T cells and radon-induced lung cancer.

Little, M. P. and Wakeford, R. The Bystander Effect in C3H 10T(1/2) Cells and Radon-Induced Lung Cancer. Radiat. Res. 156, 695-699 (2001).Bystander effects, whereby cells that are not directly exposed to radiation exhibit adverse biological effects, have been observed in a number of experimental systems, including C3H 10T(1/2) cells exposed to alpha-particle radiation. The bystander effect implies that risks from exposure to low doses of radiation obtained by linear extrapolation from data for high-dose exposures might be substantial underestimates. The best estimate of the ratio of the lung cancer risk among persons exposed to low (residential) doses of radon daughters to that among persons (underground miners) exposed to high doses of radon daughters is in the range of 2.4-4.0, with an upper 95% confidence limit of about 14. Assuming that the bystander effect observed in the in vitro C3H 10T(1/2) cell system applies to human lung cells in vivo, these epidemiological data imply that the central estimate of the number of neighboring cells that can contribute to the bystander effect is between 0 and 1, with an upper 95% confidence limit of about 7. As a consequence, the bystander effect observed in the experimental C3H 10T(1/2) cell system probably does not play a large part in the process of radon-induced lung carcinogenesis in humans.     

Lung cancer in French and Czech uranium miners: Radon-associated risk at low exposure rates and modifying effects of time since exposure and age at exposure

Radon is recognized as a public health concern for indoor exposure. Precise quantification derived from occupational exposure in miners is still needed for estimating the risk and the factors that modify the dependence on cumulated exposure. The present paper reports on relationship between radon exposure and lung cancer risk in French and Czech cohorts of uranium miners (n = 10,100). Miners from these two cohorts are characterized by low levels of exposure (average cumulated exposure of less than 60 WLM) protracted over a long period (mean duration of exposure of 10 years) and by a good quality of individual exposure estimates (95% of annual exposures based on radon measurements). The modifying effect of the quality of exposure on the risk is analyzed. A total of 574 lung cancer deaths were observed, which is 187% higher than expected from the national statistics. This significantly elevated risk is strongly associated with cumulated radon exposure. The estimated overall excess relative risk per WLM is 0.027 (95% CI: 0.017-0.043, related to measured exposures). For age at exposure of 30 and 20 years since exposure, the ERR/WLM is 0.042, and this value decreases by approximately 50% for each 10-year increase in age at exposure and time since exposure. The present study emphasizes that the quality of exposure estimates is an important factor that may substantially influence results. Time since exposure and simultaneously age at exposure were the most important effect modifiers. No inverse exposure-rate effect below 4 WL was observed. The results are consistent with estimates of the BEIR VI report using the concentration model at an exposure rate below 0.5 WL.