Problems in epidemiological studies in connection with the

determination of radon-caused lung cancer are discussed. Biasing and confounding effects have led to very divergent results in epidemiological studies and there is still doubt on the carcinogenic effect of radon progenies in the concentration range of usual indoor air (say below several hundred Bq/m3). Nevertheless, epidemiological

investigations seem to be the key tool to decide this question. Main advantages and disadvantages of case-control and ecologic studies are discussed and an overall

uncertainty estimation is given for both types of investigations

Friedmann, H.

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IL NUOVO CIMENTO Maggio-Agosto 1999VOL. 22 C, N. 3-4Radon and lung cancer: case-control vs. ecologic studies (*)H. FRIEDMANNInstitut für Radiumforschung und Kernphysik, University of ViennaBoltzmanngasse 3, A-1090 Vienna, Austria(ricevuto il 9 Giugno 1998; revisionato il 9 Dicembre 1998; approvato il 18 Dicembre 1998)Summary. — Problems in epidemiological studies in connection with thedetermination of radon-caused lung cancer are discussed. Biasing and confoundingeffects have led to very divergent results in epidemiological studies and there is stilldoubt on the carcinogenic effect of radon progenies in the concentration range ofusual indoor air (say below several hundred Bq/m3 ). Nevertheless, epidemiologicalinvestigations seem to be the key tool to decide this question. Main advantages anddisadvantages of case-control and ecologic studies are discussed and an overalluncertainty estimation is given for both types of investigations.PACS 87.50 – Effects of radiation and external fields on biomolecules, cells andhigher organisms.PACS 87.50.Gi – Ionizing radiations (ultraviolet, X-rays, ions, g-rays, electrons,positrons, neutrons, and mesons, etc.).PACS 89.60 – Environmental studies.PACS 87.90 – Other topics in biological and medical physics (restricted to newtopics).PACS 01.30.Cc – Conference proceedings.1. – IntroductionEpidemiological investigations on miners (cohort studies) clearly showed anenhanced lung cancer risk for people working in an atmosphere with high radonprogeny concentration (a summary can be found in [1] and [2]). From theseinvestigations a risk coefficient was deduced and according to the usual philosophy inradiation protection the observed risk in the miner studies was linearly extrapolated tothe radon (progeny) concentration people are commonly exposed to in their homes.Such an extrapolation leads to a radon-related contribution of 5 to 15% (depending onthe mean radon concentration in a country) to the total lung cancer mortality. With anormalised total lung cancer death rate of approximately 50 per 100000 inhabitants in ayear, radon is responsible for the lung cancer death of approximately 50 people per(*) Paper presented at the “Fourth International Conference on Rare Gas Geochemistry”,Rome, October 8-10, 1997.G Società Italiana di Fisica 335H. FRIEDMANN336year in a population of 1 million. The question is whether the linear extrapolation of thelung cancer risk from the miners’ studies to the average population is justified.Primarily, it is important to know if an additional lung cancer risk at lower radonconcentrations, below several hundred Bq/m3, say, exists at all. If this can be provedthen the question arises whether the risk is as large as it appears from a linearextrapolation or rather lower. Supposing the latter is true, mitigation measures shouldstart in houses with high radon exposure of the inhabitants while in case of a lineardose-effect relation a general reduction of indoor radon concentrations seems to benecessary.In radiation protection the dose concept is generally accepted. That means that anyradiation exposure (in case of radon measured in Bq Qh/m3, WLM, mJ Qh/m3 , R) isconverted into a dose by a dose conversion factor (DCF). The dose multiplied by adetriment factor finally gives the health risk. Within this concept the problem is to findthe correct conversion factors and their possible exposure dependencies. Three waysare thinkable to solve these questions:– The theoretical approach: The interaction of radon progenies with cells can beestimated by mathematical models and DCFs can be deduced [3]. Unfortunately thereis a discrepancy between the DCF deduced from miners data and from modelling. Thelatter gives substantially higher DCFs.– Animal experiments: It is rather easy to expose animals to a certain radonprogeny dose and to observe the lung cancer risk. However, only with rather highradon exposures a statistically significant effect can be observed. This is, of course, alsoa consequence of the limited number of animals in such experiments. Another mainquestion is whether results from animal experiments can be transferred to humans.This is not only due to anatomic differences, but also to the length of exposure, age atexposure and possible dose-rate effects (see, e.g., [4]).– Epidemiological investigations.2. – Problems in epidemiological investigations on the lung cancer risk of radonThe essential problem in epidemiological studies on the lung cancer risk of radon isto detect a very small effect above a large background. This means that it is necessaryto have a large data base to reduce statistical uncertainties and to have a very goodknowledge of the background (lung cancer caused by other factors) as well as a goodunderstanding of the reasons causing the investigated effect (lung cancer).Deficiencies in one of these groups can totally destroy any correlation. This is probablythe reason for the very controversial results of epidemiological investigations on radonand lung cancer [2, 5].Generally, there are two epidemiological approaches: the case-control study and theecologic study. The case-control study tries to estimate the radon exposure of peoplewith lung cancer and compares it with the exposure of people from a control groupwithout lung cancer. The control group has to fit in most of the relevant parameters(age, gender, smoking etc.) with the investigated lung-cancer group. The ecologicstudy compares the lung cancer rate in certain areas as a function of the mean radonconcentrations in these areas. Both types of investigations suffer from differentshortcomings, some concerning both types of investigations and others specifically one type.RADON AND LUNG CANCER: CASE-CONTROL vs. ECOLOGIC STUDIES 3372.1. Common problems. – The main problems are the insufficient control of otherlung-cancer–causing factors (confounders) and unrealistic uncertainty estimation.Both problems may have several reasons. There are a number of avoidable errorsources which sometimes were not taken into consideration as seriously as necessary.These are mainly:– standardisation to different reference groups (age distribution, gender,urbanisation, social distribution etc.);– usage of surrogates (g-dose rates, geological information etc.) instead of realradon data;– incorrect measurement results and wrong annual mean estimates;– too small database.Apart from this, there are a lot of problems which directly influence the outcome ofepidemiological studies but are not yet solved or the used assumptions are not reallyproved. So many parameters and/or the way they influence the lung cancer risk areunknown, e.g.:– Does radon act as an absolute (independent of the background lung cancerrisk) or as a relative risk (increasing with background lung cancer risk)?– Is there a dose-rate dependence of the radon risk?– Is there an age dependence of the radon risk?– What is the importance of the age at exposure?– How can the aerosol-size distribution influence the radon risk and how canaerosol-size distribution be determined for the past?– How to determine the annual mean ratio of unattached to attached progeniesfor all investigated groups/persons, especially for the past?– If radon gas is measured: what is/was the relevant equilibrium factor?– What is/was the breathing volume of the investigated groups?– Do we have enough information about time-dependent changes in confoundinginfluences (e.g., change in smoking behaviour)?These problems may have similar or different influence on case-control and ecologicstudies but generally concern both types of investigations. But there are a lot ofproblems which mainly concern only one type of epidemiological studies.2.2. Main problems in case-control studies. – One group of main problems incase-control studies arise from the fact that individual data are necessary and noaveraging is possible. Uncertainties are often introduced when the data from the lungcancer group have to be retrieved from relatives and friends. Further problems resultfrom fitting or at least normalising the control group to the lung cancer group. Finally,several assumptions are necessary during the analysis of the data, to model theinfluence of radon and other factors on the lung cancer risk (model dependence).Essential questions are:– What is the uncertainty in the determination of the radon (progeny) exposurefor a whole life (or at least for the last 20 years)? Is it possible to determine the radonH. FRIEDMANN338progeny exposure in former homes, at work etc., and all the relevant parameters ina way that gives sufficient information for a risk estimate?– How to weight the exposure in the past? According to the miners data it isassumed that the exposure from more than 15 years ago is half as important as theexposure incurred between 5 and 15 years before risk evaluation [4]. But this remains amodel assumption for the common population and the uncertainty in this assumption israther difficult to estimate.– What personal lung cancer risks are known and to what extent may theyinfluence the radon lung cancer risk? How did these additional risks (smoking,asbestos, dust etc.) change in time and how are former exposures to such confoundingfactors to be weighted?– Is it possible to identify all special events which may have influenced the lungcancer risk for members of the investigated groups, e.g., diseases?– The control group must fit the lung cancer group in gender, age distribution,smoking behaviour, social behaviour etc. This is usually not possible. Therefore,modelling of the influence of all the relevant parameters is necessary to normalise bothgroups to the same parameter set. Is it possible to estimate the uncertainty introducedby this normalisation correctly?– How can the risk of confounding factors be measured? E.g., is pack-years anadequate measure for smoking? It does not take into account tar concentration,life-time variation of smoking behaviour, way of smoking (inhaling) etc.Several of the above questions can be answered only by using the informationavailable from an average of people. Therefore, even in case-control studies some of thesevere problems of ecologic studies are present.A severe non-scientific problem with case-control studies is their costs which aregenerally higher than for ecologic studies.2.3. Main problems in ecologic studies. – In ecologic studies individual parametersare substituted by mean values of a group. This can reduce uncertainties for severalvariables, however, a lot of new problems will be introduced.Ecologic studies can be divided into 2 classes: comparison studies and regressionstudies. In a comparison study the lung cancer rate in two or more areas are comparedwith the mean radon exposure in these areas. In a regression study the populationof an area is divided into groups with different radon exposure and the total lungcancer risk is then calculated as the sum of the risks in these groups:P4a 01a 1 S(R1 )1a 2 S(R2 )1a 3 S(R3 )1R1a n S(Rn )with P the total lung cancer risk, S(Ri ) the size of the group with a mean radon(progeny) concentration Ri and a i the lung cancer risk related to the mean radonconcentration Ri . The a i can be computed by least-squares fit or bymaximum-likelihood methods or some other methods from the data of more than nregions. Usually, the frequency distribution of the indoor radon concentration followsa log-normal distribution. Therefore, S(Ri ) can be calculated from a determination ofthe radon concentration in a statistically correctly selected sample. The problem isprimarily bound to a 0 (background) which can be expected to be different in differentareas and must be adjusted for all other known lung cancer risks. If synergy effectsRADON AND LUNG CANCER: CASE-CONTROL vs. ECOLOGIC STUDIES 339between the radon risk and other risks exist, the a i are dependent on a 0 , which makesany regression analysis even more complicated.There are a lot of problems in ecologic studies:– The uncertainty in the determination of the (annual, life-time) exposure isdependent on the applied measurement method (long-term measurement, repeatedmeasurements) but should not be as critical as in case-control studies.– Uncertainties in the frequency distribution of the indoor radon concentration(usually log-normal distribution) can lead to wrong risk estimates. If the lung-cancerrisk is not linearly dependent on the radon exposure, equal mean radon values mayresult in significant different lung cancer risks because of different geometric standarddeviation. This problem cannot easily be solved in a comparison study.– It must always be proved that the sample selection from an area is random.– How are other lung cancer risks and effect modifiers (non-additive risk effects)to be treated? Mean values may not be representative for the risk (‘non-linearity’ —e.g., many people smoking only few cigarettes and few people smoking many cigarettesgive similar means). Profound investigation on the social distribution of confoundingeffects (e.g., in Austria smoking is strongly correlated with urbanisation and severalother parameters) and its change in time (increase in women lung cancer rate becauseof increased smoking) is necessary.– Wrong or insufficient cancer statistics: Tests of reliability of the cancer dataare necessary. Large errors can be introduced in any statistics if the lung cancerstatistics are incorrect even in a few areas only. Special attention must be paid topersons who died in hospital counting them to their domicile.– Migration: There is always a migration between areas of different mean radonconcentration. In principle it should be possible to correct for this effect on the basis ofcensus data and data of the registration office. (In Europe the migration effect is of theorder of equal or less than 5% per year and is not as important as in the U.S.A.) Inaddition, the time dependence of the radon risk (age at risk) could play an importantrole in case of migration.– A model is necessary to correct for confounding effects. The errors introducedby wrong modelling of the lung cancer risk of other noxes depend on the size of theirrisk. Synergy effects can lead to substantial errors because the mean of the product oftwo effects is different from the product of the means (aXYbc aXbaYb). This problemcan partly be overcome by a careful selection of areas with very similar influence ofconfounding factors.– A correct estimate of the uncertainties (which is sometimes rather difficult)and sufficient statistical power are always necessary. This problem is of course similarfor case-control studies.3. – DiscussionToday case-control studies are favoured because it is assumed that biasing can bemore easily controlled. Several case-control studies are already launched [6-10] andpooling of these data is planned for the future [11]. There are publications, e.g. [12],which tried to show the on-principle inability of ecologic studies to estimate theradon-caused lung cancer risk. Most of these papers do not take uncertainties intoH. FRIEDMANN340account. However, the essential point in any epidemiological study is the correctestimate of uncertainties in the investigation. This means that the size of a possibleradon-caused lung cancer risk which can be detected within an epidemiological studycan only be estimated by a strict analysis of the uncertainties of all possible inputparameters, an analysis of the influence of all necessary assumptions and normalisationprocedures, and a correct statistical treatment of all data.For a typical case-control study with 2 groups of approximately 1000 people each,perfect cancer diagnosis and a very well-matched control group, the total uncertainty(1 standard deviation) for the relative change in lung cancer risk can be estimated to beof the order of 70% (contributions ordered by importance: model-dependent correctionfor other risks, uncertainty in exposure, synergy effects, matching). This means that areally significant result can only be expected for groups when the ratio of their radonconcentrations exceeds a factor of two.For a comparison study with 10000 inhabitants in each region, a 10 years’ perfectcancer statistics and a lung cancer rate of the order of 5 per year for the investigatedareas, the total uncertainty is again in the 70% range (contributions ordered byimportance: model-dependent correction for other risks, migration, synergy effects).In this case a significant result can only be expected in regions with radonconcentrations leading to an odds ratio of more than 2.There are some advantages in case-control studies, however, a correct ecologicstudy will give comparable results. Therefore, statements denying the importance ofecologic studies seem to be rather questionable.R E F E R E N C E S[1] LUBIN J. H., BOICE J. D., EDLING C. H., HORNUNG R., HOWE G., KUNZ E., KUSIAK A.,MORRISON H. I., RADFORD E. P., SAMET J. M., TIRMARCHE M., WOODWARD A., XIANG Y. S. andPIERCE D. A., US National Institutes of Health, NIH publication, 94 (1994) 3644.[2] NRC, NATIONAL RESEARCH COUNCIL, BEIR VI: The Health Effects of Exposure to IndoorRadon (National Academic Press, Washington, D.C.) 1998.[3] ICRP, Annals of the ICRP, 24, no. 14 (1994), ICRP Publ. 66.[4] NATIONAL ACADEMY OF SCIENCE, BEIR IV: Radon and Other Internally Deposited AlphaEmitters (National Academic Press, Washington, D.C.) 1988.[5] LUBIN J. H. and BOICE J. D., J. Nat. Cancer Inst., 89 (1997) 49-57.[6] AUVINEN A., MA¨KELA¨INEN I., HAKAMA M., CASRE´N O., PUKKALA E., REISBAKA H., RYTO¨MAAT., J. Nat. Cancer Inst., 86 (1994) 1829-1837; 88 (1996) 966-972.[7] LE´TOURNEAU E. G., KREWSKI D., CHOI N. W., GODDARD M. J., MCGREGOR R. G., ZIELINSKI J.M. and DU J., Am. J. Epidemiol., 140 (1994) 310-322.[8] PERSHAGEN G., ÅKERBLOM G., AXELSON O., CLAVENSJO¨ B., DAMBER L., DESAI G., ENFLO A.,LAGARDE F., MELLANDER H., SVARTENGREN M. and SWEDJEMARK G. A.: New England J.Med., 330 (1994) 159-164.[9] RUOSTEENOJA E., MA¨KELA¨INEN I., RYTO¨MAA T., HAKULINEN T. and HAKAMA M., HealthPhysics, 71 (1996) 185-189.[10] ALAVANJA M. C. R., BROWNSON R. C., LUBIN J. H., BERGER E., CHANG J., BOICE J. D. jr., J.Nat. Cancer Inst., 86 (1994) 1829-1837.[11] SAMET J. M., J. Nat. Cancer Inst., 89 (1997) 4-6.[12] GREENLAND S. and MORGENSTERN H., Int. J. Epidemiol., 18 (1989) 269-274.

Radon and lung cancer: case-control studies versus ecologic studies

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Radon and lung cancer: case-control studies versus ecologic studies

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