Asbestos-related Pleural Plaques and Lung Cancer

• review -----I~III.t--------------=::=:::::::: -:::=.

Asbestos-related Pleural Plaques and Lung Cancer*

William Weiss, M. D. The English-language literature was reviewed to evaluate a possible relationship between asbestos-related pleural plaques and lung cancer in the absence of parenchymal asbestosis. There were six cohort studies in which the comparison group was limited to unexposed persons or the general population, four lung cancer case-control studies, and three autopsy studies. or the 13 investigations, only 3 supported the hypothesis that lung cancer risk is elevated among persons with pleural plaques over the risk in unexposed people: 2 cohort studies from the same city in

England with much the same data and 1 case-control study. These three studies had the most defects in design. The other ten studies failed to con6rm the hypothesis. Thus, the weight of the evidence favors the conclusion that persons with asbestos-related pleural plaques do not have an increased risk of lung cancer in the absence of parenchymal asbestosis. (Chest 1993; 103:1854-59)

EpidemiolOgiC studies over the past three decades have established that workers exposed to asbestos in most circumstances are at increased risk of developing lung cancer. Recent literature':" reveals disagreement about the concept that the increased risk is limited to those workers who first develop asbestosis. Several animal experiments support this concept, but controversy and uncertainty about the idea continue. Another approach in considering the validity of this concept is to examine the relationship between asbestos-related pleural plaques and the risk of lung cancer in the absence of asbestosis. Pleural plaques among workers exposed to asbestos may be used as a marker of the exposure. If the risk of lung cancer is not elevated in such persons compared with the risk in unexposed persons or the general population, then this observation would provide additional evidence for the concept that asbestosis is a necessary precursor for asbestos-related lung cancer. In this article, the term "asbestosis" is defined as diffuse parenchymal fibrosis caused by asbestos. I will review the relevant literature and weigh the evidence after assessing the methodologic aspects of each study.

tionship between pleural plaques unaccompanied by asbestosis (parenchymal disease) and lung cancer. The exclusion of asbestosis was determined by whatever method was used to detect the pleural disease (eg, radiographic or autopsy evidence). The types of investigations were limited to epidemiologic studies with cohort or case-control design and to prevalence studies in autopsy populations. If more than one report was published on the same study, the latest publication was used. The report of each cohort investigation was examined for information on the location of research, type of work or exposure to asbestos, type of asbestos, number of and source of cohort members with pleural plaques and of control subjects, degree of completeness and period of follow-up, sources of possible bias, control for confounders, consideration of latency, and statistical method. When the source of cohort members was a population survey, the degree of compliance was noted if given. The outcome measure was the relative risk for lung cancer, with the probability value or 95 percent confidence limit (CL) provided by the authors. In most studies the relative risk was measured by the standardized mortality/morbidity ratio (SMR). If the measure was morbidity, data were obtained from a cancer registry. When a probability value or CL was not provided by the investigators, I calculated these by standard methods. U,13 Comparisons between persons with plaques and control subjects were restricted in this analysis to those in which the controls were not exposed to asbestos or were members of the general population. Reports of case-control studies were examined for information of similar nature plus information on the method for reading the chest x-ray films for pleural plaques, including the number of readers and whether readings of case and control films were concurrent and blind to case-control status. The outcome measure was the odds ratio with the probability value, usually determined from a X2 test. Similar information was obtained from the autopsy studies. The outcome measure was the "relative risk" with 95 percent CL as provided by the authors in one study or the odds ratio I calculated from the data given, with a probability value based on a Xl test either given by the authors or calculated from the data.

MATERIAL AND METHODS

The literature published in English on asbestos-related disease and on the etiology and epidemiology of lung cancer was obtained through an ongoing search of Index Medicus and MEDLARS II covering the period from 1965 to mid-l992. References cited in the published articles were also examined if relevant. An article published in a foreign language was included if there was an English abstract with sufficient information in it. Studies accepted for analysis were those dealing with the rela-

CL = con6denee limits; SMR = standardized mortality/or morbidity ratio

RESULTS

*From the Department of Medicine, Hahnemann University, Philadelphia. Reprint requests: Dr. \\ms, 3912 Netherfield Road, Philadelphia 19129

1854

The studies in this review are examined in order of decreasing design value: cohort, case-control, and autopsy reports. A proportional mortality ratio study Asbestos-related Pleural Plaques and Lung Cancer (WIlliam ~/ss)

Table l-Daigra ofCohort Stutlia o/Pleural PltJquea and Lung Cancer in lWIona &posed to Atbatoa Persons With Plaques Type of

Study/yrlLocation,

Type of

Exposure

No.

Source

408 429 700

Review of fUm collections "Known to author" X-ray survey

Asbestos"

Fletcher18/1972/Barrovv, UK Edge18/1979/Barrow, UK Kiviluoto et al 18/1979/Finland

Shipyard Shipyard Near mines

Hughes and Weill7fI991/ New Orleans Sanden et alJO/I99~Sweden Partanen et alI1/1992/Finland

Asbestos cement plants Shipyard Near mine and plant

Ch, Am, Cr Ch, Am, Cr Mainly An

Controls

62t 837 604

No.

Local population

700

X-ray survey in 1969 Employee survey Community survey

Source

604

UK mortality rates X-ray survey in area with no exposure Louisiana mortality rates

Local population rates Community survey

·Ch = chrysotile; Am = amosite; Cr = crocidolite; An = anthophyllite. tOf 62 patients, 56% had plaques with or without diffuse pleural thickening, and 44% had only diffuse pleural thickening.

Table 2-Fol1ow-up, Confounders, and UJtency in Cohort Studies of Pleural PltJquea and Lung Cancer in lWIona &posed to Atbatoa Follow-up

ConfoundenConnolled

Study/yrlLocation

%

Period

Smoking

Age and Sex

Other

Latency Considered

Fletcher18/1972/Barrovv, UK Edge18/1979/Barrovv, UK Kiviluoto et al 19/1979/Finland Hughes and Weill 7/1991/ New Orleans

100 98-99

1960-70 1964-77 1962-77 1969-83

No No No Similar to US blue-collar workers, 1970 Similar to general population No

Yes Yes No Yes

No Date of first x-ray study No No

No No No 20+ years

Yes Yes

Period Community

20+ years No

Sandenetal·/1~weden

99.9 99

1978-87 1972-89

Partanen et alll/1999JFinland

Table 3-SttJtiBtictJl Method and Relative Bilk in Cohort Studies ofPleural Plaquea and Lung Cancer in lWIona &posed to Atbatoa Relative Risk· Study/yrlLocation

Statistical Method

o

E

OlE

6.74

2.37

8.5

1.88 0.93

<0.02 >0.10

2

1.5

1.33

>0.10

8 28

9.9 25

0.81 1.07

>0.10 0.62-1.83

Fletcher18/1972/Barrovv, UK

SMR

16

UK Kiviluoto et al18/19791 Finland Hughes and Weill 7/1991/ New Orleans Sanden et al·/l~weden Partanen et alI1/1992/Finland

SMR for 407 with plaques Cumulative incidence

16 13

Edge18/1979/B~

*E

SMR SMR Proportional hazards model

14

P or 95% CL 0.0047

Comments Potential selection bias; best evidence for subjects 8 of 16 case patients died in first 2 yr Calcified plaques studied; data from cancer registry

Data from cancer registry Survey compliance 40%

= expected number; 0 = observed number.

by Navratil et al l 4 was excluded because this type of investigation does not include data on populations at risk. A cohort study by Loomis et allS was also excluded because it was based on a vague definition of pleural abnormality in a survey of a sample of the US population and because there was no relationship between pleural abnormality and asbestos exposure elicited through a nonspecific occupational history

Cohort Studies Six studies are summarized in Tables 1 through 3. They date from 1972 to 1992, beginning with two from the city of Barrow in the United Kingdom, a shipbuilding site. The earliest investigation was done by

Fletcher, 16 who generated the hypothesis that persons with pleural plaques have an increased risk of developing lung cancer. The study by Fletcher" is seriously flawed. He "felt that an epidemiological study should be carried out but permission could not be obtained for a prospective study . . . so retrospective examinations of existing collections of routine administrative and mass survey films were used." This search revealed 408 men with pleural plaques. He then chose a group of 404 men with normal chest films matched by age as controls. Both groups were followed up for 10 years (1960 through 1970), and their mortality experience was compared with that of the Barrow general population CHEST I 103 I 6 I JUNE, 1993

1855

using the SMR (the observed-to-expected ratio). Only age and sex were controlled in these comparisons. Unfortunately, Fletcher used "best evidence" for the causes of death in the men with plaques (ie, information from medical records as well as death certificates), but he used only death certificate diagnoses to calculate the expected numbers of deaths from rates in the Barrow population. He did not state whether "best evidence" was pursued in the control group. The SMR for the men with plaques was 2.37 (p<0.005), while that for the control group was 1.25 (p = 0.52). A few years later a second study from Barrow was reported by Edge'? with similar results, but methodologic details were not provided. In a later article on the same investigation, Edge" stated that "it did not prove possible to select a cohort. As an alternative, all men with radiologic evidence of pleural plaques known to the author . . . were compared with a control group from the neighboring city of Carlisle, where there is no known industrial asbestos exposure [italics added]." Controls were matched by age, sex, and date of first radiograph, and none had plaques. Follow-up covered 6 or more years. Edge found 19 deaths from lung cancer in 429 Barrow men with plaques and only 4 in 429 Carlisle controls. He recognized that 198 men with plaques were found in hospital or clinic sources and that this may have biased the results. Indeed, 13 of the 19 had evidence suggestive of lung cancer at the time of the first x-ray films; these 13 should have been excluded. However, he compared 231 of the men with plaques discovered on "routine films" with the 429 men in Carlisle, all found by examination of "routine films." The lung cancer death frequency was 2.6 percent in the study group, compared with 0.9 percent in the control group. This difference is not statistically significant at the 0.05 level by X2 with Yates'correction. Edge then reduced the number of men with plaques from 429 to 407 by excluding 3 lost to follow-up and 19 who died within the first year offollow-up, including 3 with lung cancer. Calculating observed and expected (based on national rates) numbers of lung cancer deaths, he found the following ratios by period of follow-up: 0 to 2 years, 8:1.8; 2 to 4 years, 0:1.9; 4 to 6 years, 2:2.0; 6 + years, 6:2.8. Thus, 8 of the 16 patients with lung cancer died within the first 2 years, indicating serious selection bias. The ratio for the period 2 or more years after the start of observation was 8:6.7= 1.19, with 95 percent CLs I calculated to be 0.51 to 2.35. While his Table 8 shows the ratio rising from 0:1.9 during the period 2-4 years to 6:2.8 6 or more years after the start of observation, the last ratio is not statistically significant at the 0.05 level. Furthermore, given the figures cited above for the number of subjects with evidence of lung cancer at the start of observation (n = 13), several of the 8 patients who died 1856

more than 2 years after the start of observation must have had evidence of lung cancer at the start of observation and should have been excluded. The studies by Fletcher" and by Edge17,18 were done in the same city, with considerable overlap of the time periods (1960 through 1970 and 1964 through 1971, respectively) in which chest films were reviewed; therefore, it is likely that many subjects with plaques were common to both studies. Both were subject to selection bias. Essentially the two studies taken together represent the initial cohort research that generated the hypothesis that workers with pleural plaques are at increased risk of lung cancer. The other four cohort studies may be considered as a group to test the validity of this hypothesis. There are some differences in design (Table 1). TW019.21 had cohorts derived from community x-ray surveys in Finland, one2D dealt with shipyard employees in Sweden, and one? included employees of two asbestos cement plants in New Orleans. The types of asbestos to which these cohorts were exposed were specified in three studies: mixtures of chrysotile, amosite, and crocidolite in tw07,20 and mainly anthophyllite in one.21 The numbers of persons with pleural plaques varied. In the study by Hughes and Weill,7 56 percent of the 62 subjects had plaques with or without diffuse pleural thickening, and the rest had only diffuse pleural thickening, each subgroup contributing 1 of the 2 lung cancer cases G. M. Hughes, personal communication, 1992). Table 2 shows that the completeness of follow-up was given in only two of the four studies,7,20 both close to 100 percent. The periods offollow-up varied a little. Only two of the studies had a limited attempt to control for smoking habits. 7,20 In three studies,7,20,21 the investigators controlled for age and sex. There is doubt about adjustment for differences in age and sex between the plaque group and the controls only in the study by Kiviluoto et al. 19 Two of the four studies controlled for latency by limiting the results for the plaque groups to observation at 20 or more years after beginning of exposure to asbestos. 7,20 Table 3 shows the statistical methods and results in the cohort studies. Kiviluoto et al I9 used cumulative incidence of lung cancer from a cancer registry for the plaque group and the control group, while the other investigators used SMRs or a proportional hazards model to obtain the relative risks. None of the relative risks in these 4 studies is statistically significantly different from 1.00. They vary from 0.81 to 1.33, the latter being based on only 2 observed cases," If one sums the observed and expected numbers of lung cancers for these 4 studies, they total 51 and 50.4, respectively, giving a summary ratio of 1.01, which is a reasonable measure of overall relative risk weighted by the expected numbers." The 95 percent AsbesIoe-r8Iate Pleural Plaquesend LungCancer (WIllIam KWss)

4) was a hospital or clinic in three studies,19.25.26 and was population-based in the other. 24 In the latter study by Hillerdal," the source of the cases and the controls was the entire population of a county with a participation rate of 64 percent in chest x-ray screening. 9:1 The only confounders controlled for were age in three studies I9.m.26 and sex in two I9.25 (Table 5). There was no control for smoking habits in any of the four studies. The report by Hillerdal'" made no mention of control even for age. The method for reading chest films to determine the presence of pleural plaques in the case and control groups was not given in detail except partially in one study 25 Only Thiringer et alm specified the use of more than one reader. Concurrent readings of films in the two groups was mentioned in three reports. 19.m.J6 Blind readings were not mentioned in two reports I9.25 and were not done in the other two studies. 24 •26 From available information, Hillerdals study24 was the weakest methodologically since multiple independent readers were not used, the readings were not blind to case-control status, and the readings for cases and controls were not concurrent. Table 6 shows that Hillerdals study24 was also the weakest in terms of data for results. He provided no numbers for the persons with plaques among the lung cancer cases and the controls; the odds ratio had to be estimated from a bar graph; and although he provided a probability value, he did not indicate the statistical method used. It is only his study that showed a statistically significant elevation of the odds ratio. In view of all the problems in method, his result carries little weight. The results in the other three reports are consistently negative; therefore, the case-control studies fail to support the hypothesis.

Table 4-Daign oICae-Control Stadia o/Pleural Plaqua and Lung Cancer Cancer Cases Study/yrlLocation

No.

Controls No.

Source

Kiviluoto et alle/ 1979/Finland HillerdalIC/ 19801Sweden

69 Turlcu City Hospital 209 Uppsala Coun~ 1971-1976

Thiringer et allIS/ 19801Sweden Mare and Szamosi-/ 19801Sweden

132 Chest clinic in Gothenberg 159 Consecutive

cases

admitted to hospital

Source

69 Chest x-ray file 33,010 1976 survey of general population, 64'11 compliance 187 Chest x-ray file 159 Patients with claudication or pacemaker

CLs for this ratio based on the Poisson distribution are 0.75 and 1.33.

Case-Control Studies Four reports of case-eontrol studies are summarized in Tables 4 through 6. All appeared in 1979 or 1980. An article by Harber et ali3 has been excluded because both case patients and control subjects were exposed to asbestos and most of the workers included were referred after filing a claim for compensation for asbestos-related lung disease. Since both case patients and control subjects were exposed, Harber et al addressed the question whether pleural disease in workers exposed to asbestos is a marker for increased risk of lung cancer compared with absence of pleural disease in exposed workers. This is not the question considered in this review In addition, this study is potentially biased by the source of referral. Table 4 shows that one study'" was done in Finland while the other three were done in Sweden.24-i6 The article by Mare and Szamosf" was published in Swedish, but an English abstract was available and additional information was obtained (K. Mare, personal communication, 1992). All four studies specifically collected data on the frequency of pleural plaques, excluding other forms of pleural disease, among case patients and controls. The source of lung cancer cases and controls (Table

Autopsy Studies There are three investigations in which an association between pleural plaques and lung cancer was sought at autopsy28-30 (Table 7). The percentage of deaths in which autopsy was done was provided in only one report;29it was only 25 percent. Age was the only factor controlled for, and no study controlled for smoking habits. The estimated relative risk was slightly elevated in all three studies, but none was statistically significant. Thus, these investigations provide no support for the hypothesis.

Table 5-Control ofConfounden and Methodfor Beading Chat Filma in Cae-Control Studie. ofPleural Plaques and Lang Cancer ComoundenConbolled

Method for Reading Plaques

Study/yrlLocation

Age

Sex

Smoking

No.ofReaden

Concurrent Readings

Blind Readings

Kiviluoto et al·81l9791Finland

Yes No Yes Restricted to ages 60 to 70 yr

Yes No Yes No

No No No No

Not given Not given 3 1

Yes

Not given

Yes Yes

Not given No

HillerdalICI19801Sweden Thiringer et al151l98OlSwed en Mare and Szamosi-/19801 Sweden

No

No

CHEST I 103 I 8 I JUNE, 1993

1857

Table 6-StatiBtical Method and Relative BiBle &tirnate8 in Case-Control Studiea o/Pleural Plaqua and Lung Cancer Estimated Relative Risk No. With Plaques

Statistical Method

Study/yr/Location Kiviluoto et alI8/1979/ Finland HillerdallW/19801Sweden

Xs*

Controls

P

Odds Ratio

Value

Comments

0.75

>0.05

Odds ratio and p value calculated from data Numbers not given, odds ratio estimated from graph, p value from author 23% of patients and 12% of controls were aged 70 + yr Data from English abstract, XS calculated from data

7

9

Not given

Not given

Xi

22

32

0.97

>0.05

Xs*

22

20

1.12

>0.05

Not given

Thiringer et allP.'5 1980/ Sweden Mare and Szamosi- 19801 Sweden

Cases

.....4

<0.01

*With Yates' correction. DISCUSSION

The weight of evidence in this review is against the hypothesis that persons with asbestos-related pleural plaques are at increased risk of lung cancer compared with unexposed persons or the general population. Ten of the 13 studies examined were negative. Furthermore, the three positive studies were all most seriously deficient in terms of design and potential for bias and confounding. Cohort studies entail a design that permits assessment of pleural plaques as a precursor to lung cancer risk; therefore, this type of investigation is most suitable for this purpose. Case-control studies herein, and autopsy studies always, provide information only on the prevalence of both pleural plaques and lung cancer at one point in time, when cancer is already present; therefore, they examine only for an association without giving any information on the temporal relationship between the two entities. In addition, low autopsy rates allow for significant bias, which may account for the small elevations, statistically insigni6cant, of the odds ratios in the three reports described herein. The cohort design is more desirable than the case-

control design because it provides a direct estimate of incidence rates, and therefore of relative risk, while the case-control design yields only an approximation of the relative risk provided certain assumptions are met, namely, the cases must be representative of all cases of lung cancer and the controls must be representative of the population that gave rise to the cases. These assumptions are not met in many case-control studies. U nfortunately, there are defects of one sort or another in all the studies of these types included in this review However, the defects in the ten negative studies are less important than those in the three positive studies. The failure to adjust comparisons for differences in smoking habits is one of the sources for confounding when searching for small differences in risk." Only two of the cohort studies1•JO made an attempt to establish comparability of smoking habits; both showed no substantial difference between the persons with pleural plaques and the comparison group, and there was no increased risk of lung cancer among the persons with plaques in either study. These two studies were also the only ones taking latency (interval between onset of asbestos exposure and

Table 7-Autopay Studia ofPleural Plaques and Lung Cancer Characteristics and Results

Meurman, I96&"

Location of study Percent of deaths autopsied Factors controlled Control for smoking Statistical method

Finland Not given Mean age similar, both sexes included No Xi, Yates'correction

No. with plaques No. with lung cancer (%) No. without plaques No. with lung cancer (%) Degree of association P value or 95% CL Comment

103

1858

3 (2.91) 152 4 (2.63) Odds ratio = 1.11 >0.70 Odds ratio calculated from data

Mollo, 1984Turin, Italy 25 age, men only No Age-adjusted relative, risk, 95% CL

199

14 (7.0) 566 26 (4.6) Relative risk = 1.51 0.75-3.09 Relative risk calculated by authors

Wain et al, 198430

Durham NC Not given Mean age similar, men only No XS 25 4 (16) 409 55 (13.6) Odds ratio = 1.23 >0.70 Odds ratio calculated from data

Asbesto8-r8Iated Pleural Plaques and Lung

cancer (William MWss)

diagnosis of lung cancer) into account. None of the four case-control studies controlled for smoking habits, despite the fact that this information could have been easily obtained. A significant problem in evaluating evidence in the published literature arises from publication bias.3i•33 This results from the tendency of authors, and to a lesser degree editors, to shrink from reporting negative results. Therefore, the literature commonly begins with a positive report or two on a particular issue, followed by a series of negative reports when other investigators attempt to repeat the initial results. This phenomenon is exemplified by the literature reviewed here with the exception that one negative autopsy study, that by Meurman'" in 1966, antedated the positive cohort studies of Fletcher" and Edge. 17 •18 Meurman's data were limited to small parts of a very long article on asbestos bodies and pleural plaques in Finnish autopsies. The likelihood of publication bias in the literature reviewed here lends undue prominence to the three positive studies included. While it is difficult to prove a negative proposition, pragmatism requires that we make decisions based on available evidence. The weight of the evidence considered in this review indicates that lung cancer risk is not elevated among persons with asbestos-related pleural plaques in the absence of asbestosis. Toconfirm this conclusion, a large unbiased study of an asbestosexposed cohort with pleural plaques, defined by strict criteria, and an unexposed cohort with good control of confounders is desirable. REFERENCES 1 Weiss w: Judging causality in environmental cancer. Pa Med 1985; 88:27-32 2 Browne K. Is asbestos or asbestosis the cause of the increased risk of lung cancer in asbestos workers? [editorial]. Br J Ind Med 1986; 43:145-49 3 Churg A. Neoplastic asbestos-induced disease. In: Churg A, Green FHY. Pathology of occupational lung disease. New York: Igaku-Shoin MedicalPublishers, 1988; 285-87 4 Sluis-Cremer GK, Bezuidenhout BN. Relation between asbestosis and bronchial cancer in amphibole asbestos miners. Br J Ind Med 1989; 46:537-40 5 Roggli VL. Human disease consequences of fiber exposures: a review of human lung pathology and fiber burden data. Environ Health Perspect 1990; 88:295-303 6 Edelman DA. Does asbestosis increase the risk of lung cancer? Int Arch Environ Health 1990; 62:345-49 7 Hughes JM, Weill H. Asbestosis as a precursor of asbestos related lung cancer: results of a prospective mortality study. Br J Ind Med 1991; 48:229-33 8 Bignon J, Brochard I! Inconsistencies and limitations. In: Liddell D, Miller K. Mineral fibers and health. Boca Raton, FIa: CRC Pres~ 1991; 198-99 9 Sluis-Cremer GK. Asbestos disease at low exposures after long residence times. Ann NY Acad Sci 1991; 643:182-93 10 Wagner JC, Berry G, Skidmore M Tlmbrell ~ The effects of the inhalation of asbestos in rats. Br J Cancer 1974; 29:252-69 11 Davis JMG, Cowie HA. The relationship between fibrosis and

12

13

14

15

16 17 18 19 20

21

22 23 24 25

cancer in experimental animals exposed to asbestos and other fibers. Environ Health Perspect 1990; 88:305-09 Gardiner MJ, Altman DC. Statistics with confidence: confidence intervals and statistical guidelines. Belfast, Northern Ireland: Universities Press, 1989; 50-63 Haenszel ~ Loveland DB, Sirken MG. Lung cancer mortality as related to residence and smoking histories: I. white males. J Nat! Cancer Inst 1962; 28:947-1001 Navratil M, Moravkova K, Gafronova M, Hruska F. The fate of people with pleural hyalinosis (plaques): relationship to direct and indirect asbestos exposure. Czech Med 1988; 11:146-56 Loomis D~ Collman G~ Rogan WJ. Relationship of mortali~ occupation, and pulmonary diffusing capacity to pleural thickening in the First National Health and Nutrition Examination Survey Am J Ind Med 1989; 16:477-84 Fletcher DE. A mortality study of shipyard workers with pleural plaques. Br J Ind Med 1972; 29:142-45 Edge JR. Asbestos related disease in Barrow-in-Furness. Environ Res 1976; 11:244-47 Edge JR. Incidence of bronchial carcinoma in shipyard workers with pleural plaques. Ann NYAcad Sci 1979; 330:289-94 Kiviluoto R, Meurman LO, Ha1cama M. Pleural plaques and neoplasia in Finland. Ann NYAcad Sci 1979; 330:31-3 Sanden A, Jarvholm B, Larsson S, Thiringer G. The risk of lung cancer and mesothelioma after cessation of asbestos exposure: a prospective cohort study of shipyard workers. Eur Respir J 1992; 5:281-85 Partanen 1: Nurminen M, Zitting A, Koskinen H, Wilkeri M, Ahlman K. Localized pleural plaques and lung cancer. Am J Ind Med 1992; 22:185-92 Morgan ~ Foliart DE, Wong O. Asbestos and gastrointestinal cancer. West J Med 1985; 143:60-5 Harber ~ Mohsenifar Z, Oren A, Lew M. Pleural plaques and asbestos-associated malignancy. J Occup Med 1987; 29:641-44 Hillerdal G. Pleural plaques and risk for cancer in the County ofUppsaia. Eur J Respir Dis 1980; 61(suppl 107):111-17 Thiringer G, Blomqvist N, Brolin I, Mattson SB. Pleural plaques in chest x-rays of lung cancer patients and matched controls (preliminary results). Eur J Respir Dis 1980; 61(suppl 107):119-

22

26 Mare K, Szamosi A. Is pleural plaque a warning signal of increased lung cancer risk? Lakartidningen 1980; 77:3216-17 [English abstract in International Cancer Research Data Bank Cancergram: lung cancer-e-diagnosis, treatment (series CT08 No. 81103). Bethesda: National Cancer Institute, March 1981 27 Hillerdal G, Hillerdal 0, Nou E. Radiologically visible pleural plaques in a one-year material from a health survey in 1976: a cross-sectional study. Eur J Respir Dis 1980; 61(suppl 107):8998 28 Meurman L. Asbestos bodies and pleural plaques in a Finnish series of autopsy cases. Acta Pathol Microbiol Scand 1966; suppl 181:7-107 29 Mollo F, Andrion A, Colombo A, Segnan N, Pira E. Pleural plaques and risk of cancer in Turin, northwestern Italy. Cancer 1984; 54:1418-22 30 Wain SL, Roggli VL, Foster WL Jr. Parietal pleural plaques, asbestos bodies, and neoplasia: a clinical, pathologic, and roentgenographic correlation of 25 consecutive cases. Chest 1984; 86:707-13 31 Axelson o. Confounding from smoking in occupational epidemiology [editorial]. Br J Ind Med 1989; 46:505-07 32 Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991; 337:867-72 33 Dickersin Ie, Min Y,Meinert CL. Factors inHuencing publication of research results: follow-up of applications submitted to two institutional review boards. JAMA 1992; 267:374-78

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