Crs Report For Congress Environmental Tobacco Smoke And Lung Cancer Risk

> BACK TO FORCESMAIN PAGE 212.07(1.07,4.01) _>21 2.55 (1.31,4.93)----- 31-191.27(0.85,1.89) 4 1-19 1.41 (1.03,1.94) _>201.10(0.77,1.61) _>20 1.93 (1.35,2.74)----- 51-100.82(0.42,1.61) 6 1-19 1.3 (0.7,2.3)* _>111.06(0.49,2.30) _>20 1.7 (0.9,3.2)*----- 71-191.12(0.7,1.8) 8 1-91.40(1.1,1.8) _>202.11(1.1,4.0) 10-191.97(1.4,2.7) _>20 2.76(1.9,4.1)----- 91-201.8 (0.6,5.6)*101-20 1.54(0.8,3.0) _>211.2 (0.3,5.2)*_>21 1.71(0.9,3.4)----- 11 1-201.76(1.0,3.2) 121-15 1.02(0.6,1.8) _>211.19(0.5,3.0) _> 16(1.0,9.5)----- 19 5-191.58 (0.4,5.7)* _>203.09 (1.0,11.8)*Table 4 - ETS Dose-Response Observations -- (Pack-Years)StudyExposureRR 95% CI Study Exposure RR95% CI----- 14 1-40 1.18 (0.44,3.20) 151-39.9 1.02(0.82,1.26) _>41 3.52 (1.45,8.59) _>40 1.43(1.07,1.91)----- 16 1-40 0.70 (0.52,1.18) 171-24 0.71(0.37,1.35) ->41 1.30 (1.0,1.7) 25-490.98(0.47,2.05) _>50 1.10(0.47,2.56)


Most of the studies report a small but positive effect which increases as exposure level increases.Three of the studies show effects of less than 10 percent excess risk at the highest exposure levels, andfour of the studies show no indication of a trend of increasing risk with increasing exposure. In addition,two studies which reported more than one measure of exposure, showed conflicting results. In one case atrend was indicated while using the other measure, it was not. Only 10 of the studies showed any resultswhich areVIEW THE CHARTSDOWNLOAD THE STUDY

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statistically significant at the 95 percent level, and for four of those studies, only the highest exposurelevels yielded statistically significant results. Three of the latter group reported its results in terms ofpack-years. One of that group, however, the study by Fontham did not show any statistically significantresults when exposure was expressed in terms of smoker years.42


Table 5 - ETS Dose-Response Observations -- (Smoker-Years)StudyExposure RR 95% CIStudy ExposureRR95% CI 18 1-21 1.6(0.8,3.2) 6 1-1921(1.0,4.3)* 22-391.4(0.7,2.9) 20-39 1.5 (0.8,2.7)* >_40 2.4(1.1,5.3) >_401.3 (0.7,2.5)*----- 8_40 1.88(0.82,4.33)----- 13 1-30 12 151-151.10(0.83,1.46) >_31 2.016-30 1.33(0.98,1.80) >_311.23(0.91,1.66)----- 20 20-291.1(0.7,1.8) 30-391.3(0.8,2.1) >_40 1.7(1.0,2.9)


Only eight of the studies which tested for trend found it to be statistically significant at the 95 percentlevel. Included in this group are two tier 4 studies;43 without these studies, and with the 95 percentstandard, only six would be significant. All of the trend analyses include zero exposure. If the trend waslinear down to zero exposure, then including that level in the trend analysis would yield the same resultsas when excluded. If there was a threshold effect, then a trend test which included the zero exposure levelmight show a trend even if an analysis which included only exposures above zero did not show such atrend. In other words a sharp rise at some exposure level above zero could incorrectly be interpreted as adose response trend over all exposure levels.

As mentioned above, EPA calculated an overall relative risk from the relative risk values at the highestexposure levels even though these studies did not all use the same measure of exposure level. For theseven U.S. studies giving such information, a combined relative risk of 1.38 with a 90 percent


42 It should be noted that when reporting relative risk for non-smoking females against smoker yearsof exposure, Fontham included all sources of exposure at home while the results measured againstpack-years included only spousal exposure.


43 In assessing the utility of the various epi studies for evaluating a linkage between ETS and lungcancer, EPA established a ranking system of four tiers, the lowest of which is tier 4. Studies falling in tier4 were excluded by EPA from its analysis of ETS and lung cancer.

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confidence interval of (1.13,1.70) was calculated.44 The EPA also performed a trend test for thecombined U.S. studies and found it to be statistically significant at the 99 percent level.

It is also worth examining the reported risk values at the lower exposure levels. Based on thedistribution of controls in these studies, a much higher fraction of the non-smoking population in theUnited States which is exposed to ETS, is exposed to the lower levels. Therefore, if there is a real effectat these lower levels, most of the risk would reside there. If there is a threshold exposure, however, it maybe that most of the exposed non-smoking population would be at no risk from ETS. The studies reportingtheir results as function of cigarettes per day and smoker years which show a trend, give no indication ofa threshold, i.e., a level below which the measured effect is negligible. For those studies presenting theirresults in terms of pack-years, however, all of them show negligible risks below some level, in the rangeof 40 pack-years. One study in this group showed no effect at any level.


Risk and Exposure Measurement

The results presented by these studies indicate that if there is any risk of developing lung cancer fromexposure to ETS, it increases as the exposure level increases. As mentioned, however, both the size ofthe effects measured and the lack of consistent, statistically significant data lead to considerableuncertainty.

An additional problem in trying to extract any conclusions from these 20 studies is the differentmeasures of exposure levels used, cigarettes per day, smoker years and pack-years. Pack-years -- anintegrated exposure of daily intensity summed over time -- is probably a better way to measure exposurelevels than cigarettes per day. This measure, however, is probably the least precise of the three measuresbecause it is most subject to recall error. Evidence from studies linking direct smoking with lung cancerindicates that the risk increases in proportion to the number of years smoked at a given level. One mightsuspect that any lung cancer risk from ETS would behave similarly.

Only if there is perfect correlation between cigarettes per day and number of years of smoking wouldthese measures serve as well as the pack-year measure. If that correlation is imperfect, the other dosemeasures are inferior to pack years, although the overall direction is likely to be the same.

At the same time, each of these measures require less recall. It is likely, however, that recall errorsare more serious for number of cigarettes per day than for number of years, especially if smoking occurredin the past. That is, it is probably easier to remember how many years someone smoked than how muchthey smoked. If so, years might be the best measure of exposure if recall bias is severe.


44 EPA Report, p. 144.

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One implication of the potential disparity between the different types of exposure measurements is thatcombining risk assessments of several studies at the highest exposure levels probably yields misleadingresults.

All of the twelve studies using cigarettes per day as a measure of exposure show elevated risk at thehighest exposure level although only about half are statistically significant -- not surprising given that moststudies are small. Not all show a consistent trend, however. All four of the pack-year studies also showelevated risk at high exposures, with three out of four statistically significant. (Again, the largest studiesshow a statistically significant risk.) Of the six studies using years, all involve positive results but only twoare identified as statistically significant.

The pack-year studies also offer evidence that non-smokers exposed to lower levels of ETS -- below40 pack-years -- have little or no relative risk of developing lung cancer from ETS. The two largestcase-control studies in terms of sample size -- Brownson and Fontham -- show this threshold behavior.Neither study, however, claims to be able to demonstrate a threshold effect because they lack thestatistical power to make such precise measurements at such small levels of relative risk.45 Indeed, aspointed out above, most epidemiologists state that it is virtually impossible to measure a relative risk below1.1 using currently available epidemiology techniques. When considering the confidence intervals for thevarious exposure levels for these two studies, several different curves could be drawn, including a straightline, to represent the variation of relative risk as a function of exposure. Nevertheless, the possibility cannotbe ruled out that a threshold level does exist if there is a real effect from ETS.


Critics of studies which assert that ETS is associated with an increased risk of lung cancer claim thatthese studies have not adequately accounted for potential confounders. They argue that the small values ofthe relative risk found in these studies (usually less than 2) makes the probability relatively high thatconfounders are the cause. Potential confounders are behavioral patterns or biological conditions whichmay be a risk factor for the disease under investigation. To be an actual confounder, however, these patternsand/or conditions must be associated with the exposure under study in that study. This pattern and/orcondition also must be present in sufficient strength to be a plausible source of the excess risk in thesituation under study. A third test of a candidate confounder can be made using dose-responseobservations.46 Any confounder that is to explain that risk likely would have to become stronger if and asthe integrated ETS exposure increases.


45 Dr. Michael Alavanja, personal communication, June 12, 1995.


46 Noel S. Weiss,,, American Journal of Epidemiology, Vol. 113, No. 5, May 1981, p.487-

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Critics argue that association of potential confounders with ETS exposure is likely to be met in ETSstudies because the health habits of non-smoking spouses of smokers are similar to their smokingspouses and are, therefore, inferior to non-smoking spouses of non-smokers. Several studies haveinvestigated this assertion. One group has examined the differences between exposed and unexposednon-smokers in terms of several dietary and related factors without attempting to measure relative risk,while the other group includes several studies which measured the relative risk of these factors inconjunction with that of ETS.

Two recent studies examined the dietary habits of a large populations of individuals who are exposedto ETS either at home or in the workplace.47 48 The two studies attempted to measure consumption ofdietary nutrients suspected of being associated with cancer risk, often as an inhibitor to developing cancer.Neither study attempted to measure the differences in dietary behavior as a function of level of ETSexposure. Both studies showed a difference in diets between non-smokers exposed to ETS and those notexposed for most of the nutrients tested.

In one of the studies, however, only a few of the differences for the nutrients were statisticallysignificant, and then only at the highest intake differences. The other study found that the differencesinvestigated were all statistically significant, but that the dietary differences between exposed andunexposed non-smokers was much less than the corresponding differences between smokers andnon-smokers. That study also concluded that the nutrient consumption by both exposed and unexposednon-smokers generally exceeded the recommended daily allowance. The authors speculated, however,that ETS and nutrients may interact in a way that would increase any nutrient requirements as a cancerinhibitor compared to when no ETS was present. The only disagreement between the two studies wasdietary fat where Emmons,, found that those exposed to ETS consumed a higher percentage ofcalories from fat than those unexposed, while Matanoski,, found no difference in intake of fatty acids between the two classes of exposure.

In another study which investigated both the effect of ETS exposure and diet on lung cancer risk, onlysmall differences were found between cases and controls for all foods included in the study except fruit.49The study found fruit intake generated a statistically significant relative risk for lung cancer of less thanone; i.e., it acted as an inhibitor. Controlling for each of these factors showed them to be independent ofone another in affecting lung cancer relative risk measurements.


47Matanoski,, American Journal of Epidemiology, Vol. 142, No.2


48Emmons, E.M.,,, European Journal of Clinical Nutrition, Vol. 49, 1995, p.336-345.


49Kalandidi, A.,, Cancer Causes and Controls, Vol. 1, 1990, p.15-21.

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A study focusing on beta carotene intake for non-smokers exposed to ETS compared to those notexposed found a statistically significantly lower amount in the former compared to the latter.50 The authorsestimated that such differences could act to reduce the measured relative risk -- total relative risk 'due toETS by about 10 percent. No relationship between beta carotene intake and duration of exposure to ETSwas found.

A 1991 study examined specific dietary habits of individuals exposed to ETS compared to those notexposed to ETS.51 The study was confined to factors for which there has been evidence of an associationwith an increased risk of lung cancer, diets low in beta carotene, and high in cholesterol and total fat.Results showed an inverse correlation between ETS exposure levels and consumption of beta carotene,cholesterol and total fat among non-smokers. Exposure levels were measured by cotinine levels and,therefore, only measured current exposure. On the basis of risk values relating a low beta carotene diet tothe risk of lung cancer, the researchers calculated corrections to the ETS risk values in order to determinethe adjustment that may be needed because of reduced beta carotene consumption. He found correctionsto the measured ETS risk values of about 11.5 to 12 percent. For cholesterol and total fat, however, sinceconsumption decreased with increasing ETS exposure, any confounding correction would tend to raise themeasured ETS risk value. No numerical corrections were presented in the paper.

Another study examined the possible contribution of a large number of food types as well as ETS tolung cancer risk among non-smoking women.52 The study measured the relative risk of developing lungcancer as a function of the food dosage consumed. The only dietary components to have statisticallysignificant relative risk factors were saturated fat, citrus fruits and juice, and beans and peas. The last foodreduced the risk as its consumption increased. No effect due to beta carotene was observed. Furthermore,the authors reported that no interaction between ETS and the various dietary components could bemeasured. The most important contributor to increased lung cancer relative risk was saturated fat. Womenwho consumed the highest amounts of saturated fat -- a mean value of 20 percent of their daily calories --had a lung cancer risk value of over 6. The paper reported that a biological link between saturated fatconsumption and lung cancer was still speculative although preliminary experimental evidence of such aconnection existed. The authors, however, were not able to offer any explanation for the connectionbetween citrus fruit consumption and lung cancer risk.

Analysis of other potential confounders is not as extensive as for dietary factors but some work hasbeen completed. One study explored the relationship


50 Sidney, S.,, American Journal of Epidemiology, Vol. 129, No.6, June 1989, p. 1305-1309.


51 Loic Le Marchand,, Cancer Causes and Control, Vol. 2, p.11-16.


52 Alavanja, M.C.R.,, Journal of the National Cancer Institute,Vol.85,No.23, Dec. l, 1993, p. 1906-1916.

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between pre-existing lung disease (asthma, pneumonia, emphysema, bronchitis and tuberculosis) andlung cancer risk.53 The authors measured a risk value of about 1.4 for never smoking women. From theseresults, the authors concluded that about 13 percent of all lung cancer deaths in never smoking womenwere due to a pre-existing lung disease. The research did not find any interaction between ETS exposureand pre-existing lung disease.

A 1983 study examined various factors including alcohol and marijuana consumption, and exposureto workplace hazards by a sample of the subscriber population at a Kaiser-Permanente Medical CareCenter.54 They found that these three factors were correlated with ETS exposure and, further, increasedas exposure to ETS, as measured in hours per week, increased. The percentage of those exposed to ETSwho also used alcohol and/or marijuana on a weekly basis was quite small, 7 percent or less, and includedboth males and females. The percentage exposed to workplace hazards ranged from 30 percent at no ETSexposure to 37 percent at the highest ETS exposure. The rate of increase in exposure to occupationalhazards with ETS exposure reported in the study was modest. The number of survey participants whoreported exposure to occupational hazards increased 7.5 percent as ETS exposure increased over 800percent on average. The connection, if any, between rate of increase in exposure to occupational hazardsand increased lung cancer risk was not given.

Finally, a study just published reviewed the lung cancer risk of a variety of potential confounders" Thispaper reviewed interactions between the various suspected contributors to lung cancer in non-smokingwomen. The authors determined that about 48 percent of all those lung cancers could be explained by theseven factors they covered. The largest contributor measured in the study was saturated fat (22 percent)followed by former smoking (17.5 percent), pre-existing non-malignant lung disease (10 percent), ETS(6 percent), occupation (5 percent), family history of lung cancer (4 percent) and domestic radon(1.5 percent). All but the ETS and radon measurements were statistically significant. When only lifetimenon-smokers were considered, however, the ETS contribution increased and became statisticallysignificant. Among this group of non-smokers, ETS was measured to have accounted for 7.5 percent of alllung cancer deaths. This contribution was still exceeded by previous lung disease and saturated fat. Inmaking these calculations, the authors controlled for all items except the particular factor being considered.No interactions between any of the items was found.

The evidence from these studies appears inconclusive about whether confounders may be responsiblefor the measured ETS risk values, particularly


53 Alavanja, M.C.R.,, American Journal of Epidemiology, Vol. 136. No.6, Sept. 15, 1992,p.623-632


54 Gary D. Friedman,, American Journal of Public Health, Vol. 73, No. 4, April 1983,p.401-405.


55 Alavanja, M.C.R.,, Cancer Causes and Control, Vol. 6, 1995, p.209.

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those at the most extensive ETS exposure levels. While it is fairly clear there are differences betweenexposed and unexposed non smokers for many of these potential confounders, it is uncertain whether thatdifference will be of consequence in developing lung cancer. There are several reasons for this. First, withfew exceptions the measured relative risks of these potential confounders are about the same as thosemeasured for ETS exposure and are at least as uncertain as the ETS values. As a result, in order toaccount for much or all of the measured risk value, a confounder or combination of confounders would haveto be present at levels intense enough to affect the etiology of lung cancer in many or all of the cases forwhich ETS induced lung cancer is suspected. Second, the potential confounder has to be either a likelycause or inhibitor of lung cancer. For example, alcohol consumption, which has been shown to be greaterin exposed than unexposed non-smokers, and which is a suspected cause of some cancers, has not beenshown to be connected by itself with lung cancer. There are indications, however, that excessive alcoholconsumption in conjunction with smoking can increase the lung cancer risk.

Furthermore, the uncertainties exhibited in the measurements of the risk of most of the potentialconfounders, as expressed by the absence of statistical significance or conflicting results, suggests thatnone of them can be considered a clear cause or inhibitor. For example, there is considerable uncertaintyabout the role of beta carotene -- long thought to be a cancer inhibitor -- in affecting the risk of lung cancer.Beta carotene is often mentioned as a confounder because non smokers exposed to ETS appear toconsume less than unexposed non-smokers. A recent study found that beta carotene not only did notinhibit the development of lung cancer, but may actually enhance the risk.56

A third reason is that there is disagreement, as reported above, about whether there are consumptiondifferences between exposed and unexposed nonsmokers for the potential confounder with the largestmeasured risk for lung cancer -- saturated fat. Fourth, studies which have attempted to control for thesepotential confounders -- in particular those by Fontham and Brownson 'do not find that they contribute anyconfounding to the measured ETS induced risk in those studies.

Fifth, evidence of potential confounders being correlated with increasing ETS exposure so as to offer apossible explanation for ETS dose response observations, is mixed. Examples of such confounder trackinghas been reported, but for many of these confounders there is a question about whether they are a lungcancer risk factor. The cholesterol and total fat observations may mean that some confounders could raisethe measured ETS risk values. Trend data showing the relationship between the levels of potentialconfounders and ETS exposure, are limited, however, so this possibility is speculative at this time.


56 The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, New England Journal ofMedicine, Vol.330, No.15, April 14, 1994, p.1029-1035.

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Misclassification Bias

Bias is generated from errors in the design, conduct, or analysis of an epidemiology study whichresult in a false measure of an association. There are several types of bias encountered in epi studies,including smoker misclassification, exposure misclassification and recall bias.Smoker misclassificationwould result from incorrectly assigning lifetime non smoker status to someone who actually smokes orwho was a former smoker. Exposure, or random, misclassification would be the result of assigningsomeone to the exposed category when they actually had not been exposed to ETS. Recall bias occurswhen someone reports an incorrect level of exposure to ETS because they are unable to recall the correctlevels. Included is the situation of not recalling that one's spouse actually smoked. Some of these errorsmay be systematic in that they are a result of events or behavior which could be predicted to push theerror in one direction. An example would be if some case group members provide incorrect informationabout their smoking or exposure status because of their disease status. Control group members, who donot have lung cancer, would have no reason to provide such incorrect information. Random errors cannotbe predicted by events or behavior. Such errors are just as likely to occur in the case as control groups.

In this analysis, the consequences of each of the three types of misclassification will be examinedusing a mathematical model developed by EPA to calculate the downward correction to the observedrelative risk values to account for smoker misclassification bias.57 The model has been expanded toexamine the effect of exposure misclassification and recall bias. In addition, modifications were made toallow for differential misclassification.

Smoker Misclassification

Smoker misclassification has drawn the most attention in the ETS studies to date. Surveys haveindicated that a fraction of self-reported nonsmokers are actually current or former smokers. Because therelative risk of developing lung cancer from direct smoking is so high compared to any of the measuredETS risk values, it is possible that only a small percentage of smokers would need to be misclassified asnonsmokers to account for a large part of the measured ETS risk. Furthermore, while suchmisrepresentation can occur for both exposed and unexposed non-smokers (both cases and controls),it may be more likely to occur to the former because smokers tend to be married to smokers. Thissituation would create a bias resulting in an overestimation of the risk value because it would increasedisproportionally the observations in the exposed cases.

The EPA model used to assess the consequences of smoker misclassification is dependent on anumber of parameters including the misclassification rates of current regular female smokers (althoughthey may have just recently quit), former female smokers, occasional female smokers, and the risk ofdeveloping


57 EPA Report, p.311-335.


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lung cancer from smoking for each group.58 In addition, the prevalence rate of never smokers for thegroup under study is required. There are several other parameters needed for the model which must bederived from experimental observations, but those listed above are the most critical.

Table 6 - Smoker Misclassification Consequences_________________________________________________________Misclassification ConditionRequired Rates and Adjusted RR Values Rate - % (RR=1.0)Rate-% (CI_

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