Modifiers of Exposure-Response Estimates for Lung Cancer among Miners Exposed to Radon Progeny Richard W. Hornung, James Deddens, and Robert Roscoe National Institute for Occupational Safety and Health, Cincinnati, Ohio The association between lung cancer and exposure to radon decay products has been well established. Despite agreement on this point, there is still some degree of uncertainty regarding characteristics of the exposure-response relationship. The use of studies of underground miners to esti- mate lung cancer risks due to residential radon exposure depends upon a better understanding of factors potentially modifying the exposure-response relationship. Given the diversity in study populations regarding smoking status, mining conditions, risk analysis methodology, and referent populations, the risk estimates across studies are quite similar. However, several factors partially contributing to differences in risk esti- mates are modified by attained age, time since last exposure, exposure rate, and cigarette smoking patterns. There is growing agreement across studies that relative risk decreases with attained age and time since last exposure. Several studies have also found an inverse exposure-rate effect, i.e., low exposure rates for protracted duration of exposure are more hazardous than equivalent cumulative exposures received at higher rates for shorter periods of time. Additionally, the interaction between radon exposure and cigarette smoking appears to be intermediate between additive and multiplicative in a growing number of studies. Quantitative estimates of these modifying factors are given using a new analysis of data from the latest update of the Colorado Plateau uranium miners cohort. - Environ Health Perspect 1 03(Suppl 2):49-53 (1995) Key words: radon, lung cancer, miners, risk, modifiers Introduction The association between lung cancer and radon gas ( 222Rn) and its decay products (radon progeny) has been well document- ed (1-4). Despite the abundance of evi- dence that exposure to radon decay prod- ucts causes lung cancer, there is still uncer- tainty concerning the characteristics of the exposure-response relationship. Among the issues still being debated are the appro- priateness of using epidemiologic studies of miners for indoor radon risk estimates, the existence and nature of an exposure- rate effect, the form of the radon/smoking interaction, and modification of relative risk by a number of temporal factors. These issues must be addressed to provide a better understanding of lung cancer risks to both miners and the general public. Next to cigarette smoking, radon expo- sure poses the greatest risk of lung cancer, with an estimated 6600 to 24,000 lung cancer deaths per year in the United States attributable to indoor radon and its decay This article was presented at the Fifth International Conference of the International Society for Environmental Epidemiology held 15-18 August 1993 in Stockholm, Sweden. Address correspondence to Dr. Richard W. Hornung, National Institute for Occupational Safety and Health, 4676 Columbia Parkway, Mailstop R-44, Cincinnati, OH 45226. Telephone (513) 841.4400. Fax (513) 841-4470. products (5). Even though extrapolation from miner populations to indoor environ- ments is problematic, the miner-based risk models remain essential to our understand- ing of the radon/lung cancer relationship. A number of case-control studies of indoor radon have been initiated in recent years; but these studies often have serious methodologic problems, especially in accu- rately assessing historical indoor exposure levels. Because of the lack of accurate expo- sure data to characterize retrospective indoor radon levels, it is necessary to exam- ine important determinants of the radon/lung cancer risk relationship in underground miners. The purpose of this presentation is to provide an overview of current occupa- tional epidemiologic studies of radon decay products, with particular attention to the nature of the exposure-response models and factors that may modify this relationship. The latest results of many international miners studies will be pre- sented, with quantitative examples from a new update and analysis of uranium min- ers from the Colorado Plateau of the west- ern United States. Since this presentation is directed at a broader view of exposure-response modifiers across several different studies, details of the new analy- sis of the Colorado Plateau study will not be provided. An article reporting an in- depth description of the latest analysis is in preparation. Form of the Exposure- Response Model Most attempts to quantify the dose- response relationships in radon research have centered on the linear relative risk model (4,6). There are persuasive argu- ments for a linear relationship made by radiobiologists using the one-hit theory and other mechanistic models. Another advantage of the linear model is that its simplicity facilitates comparisons across various study populations. This review of risk models across differ- ent epidemiologic studies of miners will focus on the linear model. In most studies relative risk models are the method of choice since they provide an adequate fit to most data and they are generally simpler in form than attributable risk models. The general form of the linear relative risk model is: (tZ) = XO(t)( + fiz) where X(tz) is the lung cancer mortality rate at age t, with exposure z, X0(t) is back- ground or unexposed lung cancer mortality rate at age t, and /3 is the linear risk coeffi- cient to be estimated. Table 1 summarizes the linear relative risk relationships in seven of the major studies of underground miners. With the exception of the Colorado Plateau data, the estimates range from 0.6 to 3.6% excess Environmental Health Perspectives 49 HORNUNG ETAL. Table 1. Exposure-response relationship in seven miners studies. Study Excessive relative risk/WLM Reference Chinese tin miners 0.6% Xuan et al. (12) Czech uranium miners 1.5% Sevc et al. (9) Beaverlodge (Canada) uranium miners 3.3% Howe et al. (10) Ontario (Canada) uranium miners 1.3% Muller et al. (24) Newfoundland fluorspar miners 0.9% Morrison et al. (7) Swedish iron miners 3.6% Radford and Renard ( 1 1) Colorado Plateau (US) uranium miners 0.2-1.6%a Hornung et al. (25) 'Reported as a range due to modification of relative risk by temporal factors, exposure rate, and cigarette smoking. Lowest risk is for older miners, longer time since last exposure, and higher exposure rates. relative risk per unit exposure (working- level month [WLM]). A working-level month is defined as any combination of exposure time and exposure level equiva- lent to 170 hr at one working level (WL). One WL is the concentration of short-lived radon decay products per liter of air giving rise to 1.3 x I05 MeV of a-radiation. Given the wide difference in populations in these studies, smoking habits, type of mining conditions, and risk analysis methodology, these estimates are fairly homogeneous. However, there are several factors that may further explain much of the difference in these risk estimates. Because of the existence of a number of such effect modifiers (interactions) in the Colorado Plateau data, Table 1 reports a range of relative risk coefficients rather than a single, possibly misleading, overall estimate of excess relative risk. Modifiers of Relative Risk Estimates Atained Ag The background risk of lung cancer rises rapidly after age 40, reaching a peak in the late 60s or early 70s. For linear relative risk estimates to be meaningful, they must remain stable over all age ranges. In many recent analyses of mining cohorts, there has been a discovery of a decrease in relative risk per WLM with increasing age at risk (3,4,7-9). One explanation for this phe- nomenon may be that the high relative risks estimated for large exposures would be dif- ficult to maintain as background lung can- cer risks rise in older age groups. This implies that the proportional hazards assumption for relative risk models, i.e., that excess risk is proportional to back- ground at all ages, does not hold. If this is a general pattern in all radon-exposed cohorts, then it is misleading to cite an overall risk coefficient. Only age-specific risk coefficients would be meaningful. Comparison of results among several stud- ies would require estimation of excess rela- tive risk for each of several age intervals. Since most of the miners cohorts listed in Table 1 have quite different age distribu- tions and each generally reports overall rela- tive risk, this may partially account for dif- ferences in risk coefficients. In our recent analysis of the Colorado Plateau uranium miners cohort, we quanti- tatively modeled the relative risk of lung cancer as a function of cumulative radon exposure for three different intervals of attained age: < 60, 60-70, and > 70. We chose a linear relative risk model versus the power function model used in an earlier analysis (3) because the linear model now produces slightly lower deviance in the updated follow-up through 1990 and is simpler to interpret. Plots of the three linear relationships are given in Figure 1. Table 2 contains relative risk estimates for several combinations of cumulative exposure and attained age. 40 30 20 10 0 Time since Last Exposure Most of the miners in Table 1 worked for relatively short periods in underground mining compared to typical duration of employment in other occupational studies. The average duration of exposure ranged from approximately 2 years for the Beaverlodge study (10) to 18 years for the Swedish study (11). The mean duration of underground exposure among the Colorado Plateau miners was approximately 4 years. For this reason, much of the time of follow- up in these studies includes inactive person- years, i.e., person-years when no additional exposure to occupational radon progeny is occurring. It is of interest, therefore, to determine if relative risk estimates change with increasing time since last exposure. Several studies have found that there is a statistically significant decline in relative risk with increasing time since last underground mining (3,4,9,12). Although time since last exposure is certainly correlated with age, these effects seem to be independent, at least in the Colorado Plateau study and the BEIR IV combined analysis of four cohorts. If this effect is applicable to other cohorts (some of which made no mention of having tested for it), we have a second temporal factor that could account for observed differences in risk coefficients across miners studies. Our analysis of the Colorado Plateau data models the effect of time since last exposure as an exponential decay in relative risk. The half-life of age-specific relative ,, Age< 60 11 , "I 11 ,l .-I .11 "I 11 "I .11 .11 11 11 1-1 .11 .11 I - - - - - - - Age 60-70 ,-, -_-_- _---- Age>70 ,"I_ _ 0 1000 2000 3000 4000 5000 Exposure, WLM Figure 1. Age-specific linear relative risks. Environmental Health Perspectives .a) 1G I - - 50 MODIFIERS OF LUNG CANCER RISK ESTIMATES DUE TO RADON Table 2. Relative risk among Colorado Plateau miners, by exposure and age categories using the linear relative risk model for exposure and adjusting for smoking and time since last exposure. Age Exposure < 60 60-70 > 70 50 WLM 1.33 [1.07,1.58] 1.06 [1.01,1.10] 1.03 [.99,1.05] 100 WLM 1.66 [1.13,2.18] 1.11 [1.03,1.20] 1.05 [.99,1.11] 500 WLM 4.28 [1.67,6.88] 1.56 [1.14,1.99] 1.27 [.99,1.55] 1000 WLM 7.56 [2.34,12.77] 2.13 [1.28,2.981 1.53 [.98,2.09] 5000 WLM 33.79 [7.73,59.84] 6.64 [2.41,10.87] 3.67 [.89,6.45] risk is approximately 15 years after the end of effective exposure (retirement from min- ing plus 5-year lag). This means that the relative risk for a given cumulative expo- sure is reduced by 50%, 15 years after effective exposure, compared to current miners and those within 5 years of last exposure. Figure 2 represents a plot of the proportional decline in relative risk as a function of years since last exposure. Exposure Rate Most studies of the relationship between exposure to radon progeny and lung cancer utilize cumulative exposure as the primary causative agent. The use of cumulative exposure carries with it the implicit assumption that exposures to high levels for short periods are etiologically equiva- lent to long-term exposures to low levels of radon progeny. Animal and in vitro studies (13-15) have shown that the exposure rate or intensity is an important factor in addi- tion to cumulative exposure. Specifically, these studies indicated that protracted 10 exposures at low levels of exposure were more carcinogenic than shorter term expo- sures to high levels of a-radiation. A simi- lar effect was observed for epidemiologic studies in earlier analyses of the Colorado Plateau uranium miners (3,16). Since then, an inverse dose-rate effect has also been observed in several other studies of miners (9,17,18). Although similar effects have not been observed for low Linear Energy Transfer (LET) radia- tion, i.e., y-radiation, X-rays, etc., there have been at least two explanations offered for the presence of an inverse effect in a- radiation studies. Brenner and Hall (19) suggest that one would expect an inverse dose-rate effect at higher dose rates due to the wasted dose from multiple traversals of individual lung epithelial cell nuclei when one traversal is sufficient to cause genetic alterations. Elkind (15) hypothesizes that cells are more sensitive to transformation during certain time windows near mitosis. This would make protracted exposures more hazardous since more cells would 20 30 Time since last exposure, years Figure 2. Decline in relative risk as a function of time since last exposure; 95% confidence intervals denoted by broken lines. progress into the sensitive windows over a long period without a high probability of being killed. We reestimated the dose-rate effect in our most recent analysis of the Colorado Plateau uranium miners study. We consid- ered exposure rate both as an independent multiplicative effect on the linear cumula- tive exposure model and as an effect modi- fier by introducing an interaction term between cumulative exposure and exposure rate. The latter model was simplified by examining the interaction of exposure rate with a dichotomous variable for cumula- tive exposure indicating cumulative expo- sure above or below the mean for the cohort. When exposure rate was introduced as an independent effect in the risk model, the regression parameter was negative (f3=-0.18, SE=0.06), indicating a higher risk for protracted exposures. The magni- tude of the estimate was larger than previ- ously estimated using vital status follow-up through 1982 (3). Our current analysis indicated that a 10-fold reduction in dose rate will increase the relative risk by 51%. Figure 3 illustrates the protraction effect as a function of exposure rates. When the interaction of exposure rate and cumulative exposure was introduced into the model, the result was not statistically significant (p= 0.06), but suggestive of a stronger inverse effect at higher levels of exposure. Radon/Smoking Interaction One of the most important issues regarding the lung cancer risk associated with radon exposure is the effect of cigarette smoking on this relationship. Conclusions as to the nature of this interaction have varied across different studies. Radford and Renard (11) reported that the interaction among Swedish iron miners was additive, i.e., the relative risk for a miner who smoked was roughly the sum of the relative risks for radon progeny exposure and cigarette smok- ing. A similar finding was reported by Sevc et al. (8) for the Czech uranium miners. An analysis by Samet. (20) of a cohort of New Mexico uranium miners (largely distinct from the Colorado Plateau cohort) indicat- ed that the interaction was essentially multi- plicative. This would imply that the joint effect of exposure to radon decay products and cigarette smoking can be estimated as the product of their individual relative risks. The combined analysis of four cohorts (Colorado, Swedish, Ontario, and Beaverlodge) by the BEIR IV Committee (4) found an interaction intermediate between additive and multiplicative. A similar intermediate effect was reported in Volume 103, Supplement 2, March 1995 1.0 0.8 0.6 0.4 r- =.I a) * _ > OTo .'E2 ,o 0.2 0.0 I 0o 51 HORNUNG ETAL. 5 10 Exposure rate reduction factor 15 20 Figure 3. Increase in relative risk as a function of an x-fold reduction in exposure rate; 95% confidence limits denoted by broken lines. the most recent analysis of the Chinese tin miners cohort (12). The analyses of the Colorado Plateau data benefited from the fact that it is the only miners cohort with smoking informa- tion on each member of the study. An ear- lier analysis of these data with vital status follow-up through 1977 indicated a multi- plicative radon/smoking interaction (21,22). With an additional 5 years of fol- low-up (vital status through 1982), the relationship appeared to be intermediate between additive and multiplicative (3). Since those analyses, NIOSH has con- ducted a smoking status survey of surviving miners and next of kin of deceased miners. Table 3. Results of NIOSH smoking survey. Respondents Nonrespondents Total number 2205 1142 Alive 1330 304 Deceased 867 832 Unknown 8 6 Lung cancers 224 153 Median exposure 420 449 Prior smoking category,' percent Never 20 13 Current 69 79 Former 11 8 New smoking category percent Never 17 Current 32 Former 51 'Smoking status distribution based upon data collected prior to 1969. These data were used in all previous analyses of Colorado Plateau data. bSmoking status distribution reported by respondents to questionnaire mailed in 1986. Results from this questionnaire were used to update smoking data when appropriate. Table 3 illustrates the reported changes in smoking status since the previous survey with smoking data through 1969 (23). We used these new smoking data to more closely examine whether the radon/smoking interaction was continuing to move away from multiplicative toward additive. Results indicated that the inter- action was still intermediate between addi- tive and multiplicative and had not changed substantially since the 1982 fol- low-up, even though there were 8 addi- tional years of mortality data. There is, however, a suggestion that the interaction is decreasing from multiplicative as follow- up lengthens and the cohort ages, although this trend is not statistically sig- nificant. Table 4 shows the nature of the radon/smoking interaction by length of follow-up for several miners cohorts. Discussion There is no doubt as to the causative rela- tionship between exposure to radon progeny and lung cancer. All of the studies of miners have demonstrated a strong exposure- response relationship. What remains as a matter for additional study is the accurate estimation of the excess risk per unit of exposure and the identification and nature of factors that alter this relationship. Table 1 indicates that the differences in risk coeffi- cients are not great given substantial differ- ences in study populations, referent popula- tions, and statistical methods of analysis. However, several factors have been identi- fied in a number of studies which could fur- ther account for observed differences in excess relative risk. These factors include age, time since last exposure, exposure rate, and cigarette smoking. Since all studies of miners differ to some degree with respect to the distribution of these factors, it is impor- tant to consider their effects when compar- ing risk coefficients across studies. Investigation of the effect of these mod- ifying factors is especially important when considering the risk to the general popula- tion from indoor radon. The use of results from studies of underground miners to estimate risks from radon in the home environment is widely debated. However, the limitations in case-control studies of indoor radon, such as the lack of data on historical exposures and generally low sta- tistical power, make the results from stud- ies of miners our best source for current indoor risk estimates. The effects of these modifying factors have important implications with regard to understanding the indoor radon problem. For example, if the interaction of cigarette smoking and radon exposure is multiplicative then there is enormous benefit to smoking cessation programs in high radon areas. However, if the effect is submultiplicative, the risk to nonsmokers may be substantial on a relative-risk scale. Similarly, if the inverse exposure-rate effect holds at the lower levels experienced in homes, then extrapolation from the higher exposed mining populations could actually underestimate risk to the public. A decrease in relative risk with the temporal effects of attained age and time since last exposure would emphasize the potential benefit of radon mitigation programs, especially for younger residents. We believe that further examination of these modifying factors is the key to a responsi- ble public health response to the radon problem. Table 4. Nature of radon/smoking interaction by length of follow-up. Study Length of follow-up Joint effect Reference Colorado Plateau 30 years Submultiplicative Hornung et al. (25) Swedish iron miners 44 years Additive to submultiplicative Radford and Renard (11) Czech uranium miners 25-30 years Additive to submultiplicative Sevc et al. (9) New Mexico uranium miners 18 years Multiplicative Samet (20) Environmental Health Perspectives 3.0 2.5 1 2.0 1.5 1.0 C. *e - o c R . 0.5 0.0 0 I I I ------------------------------------------ 52 MODIFIERS OF LUNG CANCER RISK ESTIMATES DUE TO RADON REFERENCES 1. Lundin FD Jr, Wagoner JK, Archer VE. Radon Daughter Exposure and Respiratory Cancer, Quantitative and Temporal Aspects. National Institute for Occupational Safety and Health and National Institute of Environmental Health Sciences Joint Monograph No 1. Washington:National Institute for Occupational Safety and Health, 1971. 2. NIOSH. Radon progeny in underground mines. DHHS Publ No 88-101. 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