R. William Field

Residential radon and risk of lung cancer : A combined analysis of 7 north american case-control studies

Background: Underground miners exposed to high levels of radon have an excess risk of lung cancer. Residential exposure to radon is at much lower levels, and the risk of lung cancer with residential exposure is less clear. We conducted a systematic analysis of pooled data from all North American residential radon studies. Methods: The pooling project included original data from 7 North American case–control studies, all of which used long-term α-track detectors to assess residential radon concentrations. A total of 3662 cases and 4966 controls were retained for the analysis. We used conditional likelihood regression to estimate the excess risk of lung cancer. Results: Odds ratios (ORs) for lung cancer increased with residential radon concentration. The estimated OR after exposure to radon at a concentration of 100 Bq/m3 in the exposure time window 5 to 30 years before the index date was 1.11 (95% confidence interval = 1.00–1.28). This estimate is compatible with the estimate of 1.12 (1.02–1.25) predicted by downward extrapolation of the miner data. There was no evidence of heterogeneity of radon effects across studies. There was no apparent heterogeneity in the association by sex, educational level, type of respondent (proxy or self), or cigarette smoking, although there was some evidence of a decreasing radon-associated lung cancer risk with age. Analyses restricted to subsets of the data with presumed more accurate radon dosimetry resulted in increased estimates of risk. Conclusions: These results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted using miner data and consistent with results from animal and in vitro studies.

A Combined Analysis of North American Case-Control Studies of Residential Radon and Lung Cancer

Cohort studies have consistently shown underground miners exposed to high levels of radon to be at excess risk of lung cancer, and extrapolations based on those results indicate that residential radon may be responsible for nearly 10–15% of all lung cancer deaths per year in the United States. However, case-control studies of residential radon and lung cancer have provided ambiguous evidence of radon lung cancer risks. Regardless, alpha-particle emissions from the short-lived radioactive radon decay products can damage cellular DNA. The possibility that a demonstrated lung carcinogen may be present in large numbers of homes raises a serious public health concern. Thus, a systematic analysis of pooled data from all North American residential radon studies was undertaken to provide a more direct characterization of the public health risk posed by prolonged radon exposure. To evaluate the risk associated with prolonged residential radon exposure, a combined analysis of the primary data from seven large scale case-control studies of residential radon and lung cancer risk was conducted. The combined data set included a total of 4081 cases and 5281 controls, representing the largest aggregation of data on residential radon and lung cancer conducted to date. Residential radon concentrations were determined primarily by α-track detectors placed in the living areas of homes of the study subjects in order to obtain an integrated 1-yr average radon concentration in indoor air. Conditional likelihood regression was used to estimate the excess risk of lung cancer due to residential radon exposure, with adjustment for attained age, sex, study, smoking factors, residential mobility, and completeness of radon measurements. Although the main analyses were based on the combined data set as a whole, we also considered subsets of the data considered to have more accurate radon dosimetry. This included a subset of the data involving 3662 cases and 4966 controls with α-track radon measurements within the exposure time window (ETW) 5–30 yr prior to the index date considered previously by Krewski et al. (2005). Additional restrictions focused on subjects for which a greater proportion of the ETW was covered by measured rather than imputed radon concentrations, and on subjects who occupied at most two residences. The estimated odds ratio (OR) of lung cancer generally increased with radon concentration. The OR trend was consistent with linearity (p = .10), and the excess OR (EOR) was 0.10 per Bq/m3 with 95% confidence limits (−0.01, 0.26). For the subset of the data considered previously by Krewski et al. (2005), the EOR was 0.11 (0.00, 0.28). Further limiting subjects based on our criteria (residential stability and completeness of radon monitoring) expected to improve radon dosimetry led to increased estimates of the EOR. For example, for subjects who had resided in only one or two houses in the 5–30 ETW and who had α-track radon measurements for at least 20 yr of this 25-yr period, the EOR was 0.18 (0.02, 0.43) per 100 Bq/m3. Both estimates are compatible with the EOR of 0.12 (0.02, 0.25) per 100 Bq/m3 predicted by downward extrapolation of the miner data. Collectively, these results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted by extrapolation of results from occupational studies of radon-exposed underground miners. E. G. Létourneau and J. B. Schoenberg have retired; J. A. Stolwijk holds an emeritus position. We acknowledge the helpful input of the following individuals who served on the International Steering Committee for the North American combined analysis: Ken Chadwick (CEC Radiation Protection Program), Susan Conrath (U.S. Environmental Protection Agency), Sarah Darby (Oxford University), Evan Douple (U.S. National Academy of Sciences), Colin Muirhead (UK National Radiation Protection Board), and Susan Rose (U.S. Department of Energy). Salary support for Drs. Field, Lynch, and Steck was provided in part by grant numbers R01 ES05653 and P30 ES05605 from the National Institute of Environmental Health Sciences, NIH and grant number R01 CA85942 from the National Cancer Institute, NIH. This research was supported by grants from the Canadian Institutes of Health Research (formerly the Medical Research Council of Canada) and the Natural Sciences and Engineering Research Council of Canada to D. Krewski, who currently holds the NSERC/SSHRC/McLaughlin Chair in Population Health Risk Assessment at the University of Ottawa. Financial support for the meetings of the Analysis Team and the Steering Committee was also provided by Health Canada and the U.S. Department of Energy. We are grateful to Dr. Huixia Jiang for assistance with the combined analysis, and to Jackie Monaghan for technical assistance in preparing this report.

Chronic lymphocytic leukaemia: an overview of aetiology in light of recent developments in classification and pathogenesis

This overview of the epidemiology of chronic lymphocytic leukaemia (CLL) summarizes the evolution of classification and coding systems and describes the intersection of pathogenesis and aetiology. The role of the putative precursor to CLL, monoclonal B‐cell lymphocytosis (MBL), is considered, and ideas for future investigations of the MBL‐CLL relationship are outlined. We discuss the epidemiology of CLL, focusing on descriptive patterns and methodological considerations. Postulated risk factors are reviewed including the role of ionizing and non‐ionizing radiation, occupational and environmental chemical exposures, medical conditions and treatments, and lifestyle and genetic factors. We conclude by raising key questions that need to be addressed to advance our understanding of CLL aetiology. Recommendations for future epidemiological studies are given, including the standardization of reporting of CLL across cancer registries, the clarification of the natural history of MBL, and the circumvention of the methodological shortcomings of prior epidemiological investigations in relation to radiation, chemical exposures and infectious agents.

Lung cancer risk and red meat consumption among Iowa women

OBJECTIVE Some epidemiologic studies suggest that diets high in total fat, saturated fat, or cholesterol are associated with increased risk of lung cancer. Others suggest that diets high in red meat consumption, particularly well-done red meat, are a lung cancer risk factor. In Iowa, we had the opportunity to investigate concurrently the role of meat intake and macronutrients in lung cancer etiology. METHODS A population-based case-control study of both non-smoking and smoking women was conducted in Iowa. A 70-item food frequency questionnaire (FFQ) was completed by 360 cases and 574 frequency-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Multivariate models included age, education, pack-years of smoking, yellow-green vegetable intake, fruit/fruit juice intake, nutrient density calories, previous non-malignant lung disease, alcohol consumption and body mass index (BMI). RESULTS When comparing the fifth (highest) to the first (lowest) quintile of consumption of total fat, saturated fat and cholesterol, we obtained odds ratios of 2.0 (1.3-3.1), 3.0 (1.9-4.7), and 2.0 (1.3-3.0) respectively. However, when red meat was entered into the model along with total fat, saturated fat or cholesterol, the excess risk for the macronutrients disappeared while an odds ratio of 3.3 (1.7-7.6) was obtained for red meat. The odds ratios for red meat consumption were similar among adenocarcinoma cases, OR=3.0 (1.1-7.9) and non-adenocarcinoma cases, OR=3.2 (1.3-8.3) and among life-time nonsmokers and ex-smokers OR=2.8 (1.4-5.4), and current smokers, OR=4.9 (1.1-22.3). Yellow-green vegetables were protective with an odds ratio of 0.4 (0.2-0.7). CONCLUSIONS Consumption of red meat, was associated with an increased risk of lung cancer even after controlling for total fat, saturated fat, cholesterol, fruit, yellow-green vegetable consumption and smoking history, while yellow-green vegetables are associated with a decreased risk of lung cancer.

Occupational and environmental causes of lung cancer.

Because tobacco smoking is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. The goal of this review is to describe the occurrence and recent findings of the 27 agents currently listed by the International Agency for Research on Cancer (IARC) as lung carcinogens. The IARCs updated assessments of lung carcinogens provide a long-overdue resource for consensus opinions on the carcinogenic potential of various agents. Supplementary new information, with a focus on analytic epidemiologic studies that has become available since IARCs most recent evaluation, are also discussed.

An Overview of the North American Residential Radon and Lung Cancer Case-Control Studies

Lung cancer has held the distinction as the most common cancer type worldwide since 1985 (Parkin et al., 1993). Recent estimates suggest that lung cancer accounted for 1.2 million deaths worldwide in 2002, which represents 17.6% of the global cancer deaths (Parkin et al., 2005). During 2002, the highest lung cancer rates for men worldwide reportedly occurred in North America and Eastern Europe, whereas the highest rates in females occurred in North America and Northern Europe (Parkin et al., 2005). While tobacco smoking is the leading risk factor for lung cancer, because of the magnitude of lung cancer mortality, even secondary causes of lung cancer present a major public health concern (Field, 2001). Extrapolations from epidemiologic studies of radon-exposed miners project that approximately 18,600 lung cancer deaths per year (range 3000 to 41,000) in the United States alone are attributable to residential radon progeny exposure (National Research Council, 1999). Because of differences between the mines and the home environment, as well as differences (such as breathing rates) between miners and the general public, there was a need to directly evaluate effects of radon in homes. Seven major residential case-control radon studies have been conducted in North America to directly examine the association between prolonged radon progeny (radon) exposure and lung cancer. Six of the studies were performed in the United States including studies in New Jersey, Missouri (two studies), Iowa, and the combined states study (Connecticut, Utah, and southern Idaho). The seventh study was performed in Winnipeg, Manitoba, Canada. The residential case-control studies performed in the United States were previously reviewed elsewhere (Field, 2001). The goal of this review is to provide additional details regarding the methodologies and findings for the individual studies. Radon concentration units presented in this review adhere to the types (pCi/L or Bq/m3) presented in the individual studies. One picocurie per liter is equivalent to 37 Bq/m3. Because the Iowa study calculated actual measures of exposure (concentration × time), its exposures estimates are presented in the form WLM5–19 (Field et al., 2000a). WLM5–19 represents the working level months for exposures that occurred 5–19 yr prior to diagnosis for cases or time of interview for control. Eleven WLM5–19 is approximately equivalent to an average residential radon exposure of 4 pCi/L for 15 yr, assuming a 70% home occupancy. Ernest G. Létourneau and Janet B. Schoenberg are retired; Jan A. Stolwijk has emeritus status. Salary support for Drs. Steck and Field was provided in part by grant numbers R01 ES05653 and P30 ES05605 from the National Institute of Environmental Health Sciences, NIH and grant number R01 CA85942 from the National Cancer Institute, NIH.

A Review of Residential Radon Case-Control Epidemiologic Studies Performed in the United States

Lung cancer is the leading cause of cancer death in the United States for both men and women. Although most lung cancer deaths are attributable to tobacco usage, even secondary causes of lung cancer are important because of the magnitude of lung cancer incidence and its poor survival rate. This review summarizes the basic features and major findings from the published U.S. large-scale residential radon case-control studies performed in New Jersey, Iowa, and Missouri (two studies). The methodology from an unpublished study covering Connecticut, Utah, and Southern Idaho is also presented. Overall, the higher categorical risk estimates for these published studies produced a positive association between prolonged radon exposure and lung cancer. Two studies (Missouri-II and Iowa) that incorporated enhanced dose estimates produced the most compelling evidence suggesting an association between prolonged residential radon exposure and lung cancer. The prevailing evidence suggests that the statistically significant findings may be related to improved retrospective radon exposure estimates. The general findings from the U.S. studies, along with extrapolations from radon-exposed underground miners, support the conclusion that after cigarette smoking, prolonged residential radon exposure is the second leading cause of lung cancer in the general population.

Residential radon exposure and lung cancer: Variation in risk estimates using alternative exposure scenarios

The most direct way to derive risk estimates for residential radon progeny exposure is through epidemiologic studies that examine the association between residential radon exposure and lung cancer. However, the National Research Council concluded that the inconsistency among prior residential radon case-control studies was largely a consequence of errors in radon dosimetry. This paper examines the impact of applying various epidemiologic dosimetry models for radon exposure assessment using a common data set from the Iowa Radon Lung Cancer Study (IRLCS). The IRLCS uniquely combined enhanced dosimetric techniques, individual mobility assessment, and expert histologic review to examine the relationship between cumulative radon exposure, smoking, and lung cancer. The a priori defined IRLCS radon-exposure model produced higher odds ratios than those methodologies that did not link the subjects retrospective mobility with multiple, spatially diverse radon concentrations. In addition, the smallest measurement errors were noted for the IRLCS exposure model. Risk estimates based solely on basement radon measurements generally exhibited the lowest risk estimates and the greatest measurement error. The findings indicate that the power of an epidemiologic study to detect an excess risk from residential radon exposure is enhanced by linking spatially disparate radon concentrations with the subjects retrospective mobility.

Radon, secondhand smoke, glutathione-S-transferase M1 and lung cancer among women

Tobacco smoke and ionizing radiation induce oxidative stress by transmitting or generating reactive oxygen species (ROS). We hypothesized that glutathione‐S‐transferase M1 (GSTM1) null homozygotes would have decreased ability to neutralize ROS that might increase their susceptibility to lung cancer. A case‐only design was used with lung cancer cases pooled from 3 previously completed case‐control studies using archival tissue samples from 270 lung cancer cases to genotype GSTM1. Radon concentrations were measured with long‐term α‐track radon detectors. Secondhand smoke (SHS) was measured with questionnaires and interviews. Unconditional logistic regression was used to calculate the interaction odds ratios (OR) and 95% confidence intervals (95% CI). Radon concentrations >121 Bq m−3 were associated with a >3‐fold interaction OR (OR = 3.41; 95% CI = 1.10, 10.61) for GSTM1 null homozygotes compared to GSTM1 carriers; the linear trend was significant (p trend = 0.03). The SHS and GSTM1 interaction OR was also elevated (OR = 2.28; 95% CI = 1.15–4.51) among never‐smokers. This may be the first study to provide evidence of a GSTM1 and radon interaction in risk of lung cancer. Additionally, these findings support the hypothesis that radon and SHS promote neoplasia through shared elements of a common pathway.

Variation in yearly residential radon concentrations in the upper midwest.

It is well known that inhalation of 222Rn and 222Rn decay products increases the risk of lung cancer. While the occurrences of high radon areas in the United States are generally known, studies examining the temporal yearly radon variation in homes across different regions are lacking. This information is essential to assess the ability of a year-long radon measurement to predict the future radon concentration in a home or reconstruct the retrospective residential radon concentration. The purpose of this study is to help fill this gap by examining the temporal variation of residential radon concentrations in homes over several years as well as to explore factors that affect the yearly temporal variability of residential radon concentrations. The coefficient of variation was used as a measure of relative variation between multiple measurements performed across homes over several years. Generalized linear model analyses were applied to investigate factors affecting the coefficient of variation. The median coefficient of variation between the first and second test period was 12%, while a median coefficient of variation of 19% was found between the first and third test period. Factors impacting the coefficients of variation were found to vary for different types of homes and by floors of a home. This study provides important insights into the uncertainty of residential radon gas concentrations that can be incorporated into the sensitivity analyses for the risk estimates of both the North American and global pooling of residential radon studies to improve risk estimates.