occupational risk factors for lung cancer in the french electricity

American Journal of EpidemiologyCopyright © 2000 by The Johns Hopkins University School of Hygiene and Public HealthAll rights reserved

Vol. 151, No. 9Printed in U.S.A.

Occupational Risk Factors for Lung Cancer in the French Electricity and GasIndustry

A Case-Control Survey Nested in a Cohort of Active Employees

J.-C. Martin,1 E. Imbernon,2 M. Goldberg,1"3 A. Chevalier,3 and S. Bonenfant2

The main aim of this study was the analysis of occupational lung cancer risk factors in the French nationalelectricity and gas company (Electricite de France-Gaz de France (EDF-GDF)). A case-control survey nestedin a cohort of male employees was undertaken. The study population consisted of all male staff who were activeat EDF-GDF between January 1, 1978, and December 31, 1989. During this period, 310 cases of lung cancerwere identified in the cancer register set up by the medical department of the company. For each case, four age-matched controls who were free of cancer at the time of occurrence of the case's lung cancer were randomlyselected. Occupational exposures to 21 chemical agents were assessed for each subject using a job exposurematrix. The associations between lung cancer and the different agents were estimated using conditional logisticregression analysis. After adjustment for various occupational confounding factors, the analysis showedincreased lung cancer risks linked to exposure to crystalline silica (highest exposure class: odds ratio = 2.27;95% confidence interval: 1.10, 4.68) and creosotes (highest exposure level: odds ratio = 2.14; 95% confidenceinterval: 1.06, 4.31), with significant dose-response relationships for both exposures. Am J Ep/dem/o/2000;151:902-12.

creosote; electricity; lung neoplasms; occupational exposure; silicon dioxide

Lung cancer is the most common cancer amongmales in France, with an incidence rate of 64.2 per100,000, and it represents the primary cause of cancerdeath among men there (61.6 deaths per 100,000males) (1). While tobacco use is the main nonoccupa-tional risk factor (2), many occupational procedures oragents are recognized to cause or suspected of causinglung cancer. According to Doll et al. (3), 15 percent ofmale lung cancer cases that occur in industrializedcountries are linked to occupation, which implies thatlung cancer is the most frequent occupational cancer.Many occupational pulmonary carcinogens havealready been identified. The main carcinogens areasbestos, arsenic and its compounds, tars, soot, coal

Received for publication December 11, 1998, and accepted forpublication May 12, 1999.

Abbreviations: Cl, confidence interval; EDF-GDF, Electricite deFrance-Gaz de France; OR, odds ratio.

11nstitut National de la Sante et de la Recherche Medicale(INSERM), Unite 88, Saint-Maurice, France.

2 Division Epidemiologie, Service General de Medecine duTravail, Electricite de France-Gaz de France, Paris, France.

3 Cellule Epidemiologie, Service General de Medecine deControle, Electricite de France-Gaz de France, Paris, France.

Reprint requests to Dr. Jean-Christophe Martin, INSERM, Unite88, Hopital National de Saint Maurice, 14 rue du Val d'Osne, 94415Saint-Maurice Cedex, Paris, France.

tar, beryllium and its compounds, cadmium and itscompounds, hexavalent chromium and its compounds,nickel and its compounds, radon and radon com-pounds, ionizing rays, and crystalline silica; hazardousoccupations include coal gasification, iron mining orsmelting, painting, and aluminum and coal production.Other agents are now under suspicion: nonrefined ormoderately refined mineral oils, benzene, creosotes,manmade mineral fibers, and nonarsenic insect repel-lents (4, 5).

The long latency period (15-20 years) betweenoccupational exposure and clinical occurrence, plusthe multifactoral features of exposure, do not facilitatethe identification and quantification of occupationalexposure or the epidemiologie study of risk factors.Nevertheless, investigation of these factors is easier inlarge companies with stable staffs who are exposed toa limited number of agents. Electricite de France-Gazde France (EDF-GDF), the French national electricityand gas company, possesses these features, and manystudies of its employees have already been undertaken(6-9). Moreover, a job exposure matrix allowing theretrospective evaluation of occupational exposures hasbeen developed by the company (10). The job expo-sure matrix is specific to the company and was devel-oped by an expert group (MATEX) comprising mainlyepidemiologists and occupational physicians. Thirty

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Occupational Risk Factors for Lung Cancer 903

different potential cancer agents which are (or were)used (in the past) are included in the job exposurematrix. This reflects the wide variety of trades andmaterials used within the company for electricity andgas production from various sources (coal, oil, nuclearfuel, and hydroelectric), as well as transmission anddistribution. In this company, lung cancer representsthe second most common male cancer after cancer ofthe upper respiratory tract, with a mean annual inci-dence rate among active workers of 24.9 per 100,000for the period 1978-1992 (11).

The main aim of the survey was research on andstudy of occupational risk factors for lung cancer atEDF-GDF, to identify whether the specific conditionsin this industry were associated with a higher risk oflung cancer for established lung carcinogens. The sizeof the population and the number of chemical agentsstudied also allowed assessment of the potential role ofmore or less well established carcinogenic agents thatare suspected to have an effect on the occurrence oflung cancer.

MATERIALS AND METHODS

Study design

A case-control study nested in a cohort was under-taken. The study population comprised a cohort ofmale workers who were active in the companybetween January 1,1978, and December 31,1989, rep-resenting approximately 1,400,000 person-years (6, 7).One individual contributed to the total number ofperson-years from January 1, 1978, or from the date ofemployment with the company if this was after thatdate, to the date of one of the following events: cancerdiagnosis, death, retirement, or the end of the studyperiod.

Case definition

All subjects diagnosed with lung cancer {Inter-national Classification of Diseases, Ninth Revision(12), code 162) between January 1, 1978, andDecember 31, 1989, were included. They were identi-fied through the cancer register set up by the generalmedical department of EDF-GDF, which manages thesocial security fund specific to the company. SinceEDF-GDF is a state-owned utility, workers who areaffected by disease and are unable to work due to dis-ability stay on the company rolls (medical benefits arepaid by the company). Because of this feature, no can-cer case that occurred during employment activitywas excluded from registration (11). A total of 310lung cancer cases were identified over the studyperiod.

Selection of controls

Controls were randomly selected, using the inci-dence density sampling method (13), from workerswho were active in the company on the date of thecase's diagnosis and were free of cancer on that date.They were matched to the cases by year of birth. Foreach lung cancer case, four controls were selected.Fifteen controls were excluded because of missingdata in their career history. A total of 1,225 controlswere included in the study.

Inclusion criteria

Subjects with less than 1 year's activity in the com-pany were excluded. In the case of multiple cancers inthe same individual, only the first reported cancer wasrecorded.

Evaluation of occupational exposures: the MATEXjob exposure matrix

A job exposure matrix is a correspondence tablebetween occupations and potential exposures to sev-eral cancer agents. It allows attribution of an exposureto an individual using solely knowledge of his occupa-tional history (14). It comprises columns correspond-ing to various cancer agents and lines corresponding todifferent occupations. The cells at the intersection givethe exposure indices.

The cancer agents included in the MATEX job expo-sure matrix were those included in InternationalAgency for Research on Cancer groups I, HA, and IIB(15). Other cancer agents or exposures of particularconcern that existed or had existed in the companywere added. Among these agents, six belonged togroup I and are known lung carcinogens: asbestos,coal tar, crystalline silica, cadmium compounds,chromium compounds, and coal gasification. Nineother agents belonged to groups I, DA, and IIB and aresuspected lung carcinogens: manmade mineral fibers(i.e., ceramic and glass fibers), mechanical oils, cuttingfluids (classified in our study under nonrefined ormoderately refined oils), herbicides/pesticides (mainlyused in the company to clean the soil in substationsand around pipes and power lines), benzene,hydrazine, creosotes, chlorinated solvents, and poly-ester resins. Six of these agents have no suspected lungcancer relation to date: polychlorinated biphenyls,polyurethane resins, epoxy resins, aromatic solvents(with the exception of benzene), petroleum solvents,and toluylene diisocyanate.

The lines of the job exposure matrix corresponded tooccupational groups created in the most discriminatingway possible according to identical tasks or the same

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904 Martin et al.

occupational tasks. The evolution over time of thetasks undertaken in the different occupations andexposures related to these tasks was also taken intoaccount. The entry lines to the job exposure matrixwere thus constituted of approximately 2,000 "occupa-tion periods."

For each cancer agent, the cells contained two expo-sure indices. The first index was a quantitative level ofexposure, expressed in number of fibers per milliliterfor asbestos or in parts per million for benzene andtoluylene diisocyanate. A semiquantitative measureexpressed as proportion of time worked under expo-sure to the considered agent (hours per week) wasrecorded for the majority of the other cancer agents.For three agents (manmade mineral fibers, crystallinesilica, and herbicides/pesticides) only qualitative infor-mation (exposed/nonexposed) was available. The sec-ond index was an exposure probability correspondingto the proportion of workers in each occupation per-forming the tasks considered to be exposed. The EDF-GDF MATEX job exposure matrix has been describedin detail elsewhere (8-10).

The occupational history of each subject wasextracted from the staff file of the company and linkedwith the data from the matrix. Each occupation wasclassified in the lines of the job exposure matrix. Inthis way, a level and a probability of exposure wereattributed for each episode of occupational history ofthe subject and each potential cancer agent. A cumula-tive career exposure level was calculated for each indi-vidual included in the study, taking into account thelevel of exposure in each episode together with theprobability of exposure. The cumulative doses wereexpressed in fibers per milliliter per year, parts per mil-lion per year, or hours per year according to the con-sidered agent. The career exposure length was calcu-lated for the three agents with qualitative exposurelevels. For each agent, the subjects were distributedinto five exposure classes: one class with no exposureand four classes determined according to the distribu-tion of cumulative exposures among all exposed sub-jects (cases and controls) or according to total expo-sure lengths (<25th percentile, 25th-50th percentiles,50th-75th percentiles, and >75th percentile). Lowdoses of ionizing radiation are suspected to be car-cinogenic, especially in the nuclear industry (16), butthis agent was not analyzed, since only four cases hadbeen exposed.

Statistical analysis

In the absence of individual data on tobacco con-sumption, the socioeconomic status of the subjects wasused to control for this factor. The cases and controlswere classified according to their socioeconomic sta-

tus upon entry into the company. The French nationalsocio-occupational status classification was used (17)to identify five socio-occupational categories: seniorexecutives, middle executives (including technicians),clerks, skilled workers, and unskilled workers.

Conditional logistic regression models taking thematching into consideration, adjusted for socioeco-nomic status, were used to assess the associationsbetween the cancer agents included in the job exposurematrix. All of the agents were systematically explored,except asbestos, for which the association with lungcancer risk has already been described for this cohort(8). Because a significant association between asbestosexposure and lung cancer has been established in thispopulation, an adjustment for asbestos was undertakenin all analyses. Two types of analysis were developedfor each agent. The first type used a model with a qual-itative binary exposure variable (ever/never). The sec-ond type analyzed cumulative exposure and trends inrisk, which were assessed by fitting into the logisticregression model a numerical variable equal to themean exposure in the exposure group of the subject.

These preliminary analyses identified the agentswhich should be taken into account in the overall mod-els to assess their individual role. A logistic regressionmodel was constructed for each of them in whichexposure to the identified agent was included in termsof exposure categories and the other agents wereincluded as dichotomous variables; other known car-cinogenic agents for which no association with lungcancer was observed in our sample were neverthelessincluded in these full models as dichotomous vari-ables. Trend odds ratios were also calculated. The oddsratios and their 95 percent confidence intervals werecalculated using EGRET software (18).

RESULTS

Lung cancer and socio-occupational variables

The mean age of the 310 cases at the time of diag-nosis was 49.9 years (standard deviation 5.24; range,23-60 years), which was identical to that of the con-trols (mean age = 49.9 years; standard deviation 5.26).A total of 153 cases (49.4 percent) were aged 50-54years, 88 (28.4 percent) were aged 4 5 ^ 9 years, 28 (9percent) were aged 40—44 years, 26 (8.4 percent) wereaged >55 years, and 15 (4.8 percent) were aged <40years. No significant differences between cases andcontrols were observed for age.

Table 1 presents the distribution of cases and controlsaccording to socioeconomic status and duration ofemployment. The skilled and unskilled workers repre-sented 65 percent of the sample. The senior and middleexecutives represented 6.1 percent of the cases as com-


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TABLE 1. Odds ratios for lung cancer, by socioeconomic status at first employment and duration ofemployment, in a cohort of workers in the French national electricity and gas company (EDF-GDF*),1978-1989

No. ofcases

(n = 310)

No. ofcontrols

(n= 1,225)

Oddsratio

Socioeconomic status when first employedSenior executiveMiddle executive (includes technicians)ClerkSkilled employeeNonskilled employeeNot specified

Duration of employment (years)1-1011-2021-30>30

* EDF-GDF, Electricite de France-Gaz de France,t Reference category.

95%confidence

interval

91073

12098

0

848

17678

79107257480299

3

36162756271

1.00f0.872.542.263.08

i.oot1.361.051.36

0.33, 2.241.21,5.331.09,4.671.47,6.48

0.48, 3.870.36, 3.050.45,4.15

pared with 15 percent of the controls. The well-knownassociation between lung cancer and socioeconomic sta-tus was found: Odds ratios were 3.08 (95 percent confi-dence interval (CI): 1.47,6.48) for unskilled workers and2.26 (95 percent CI: 1.09, 4.67) for skilled workers, ascompared with senior executives (8). Therefore, all logis-tic regression analyses were adjusted for this variable. Nosignificant association was found between the number ofyears worked and the occurrence of lung cancer.

Lung cancer and occupational exposures

Table 2 presents the results of the dichotomousanalysis. Among the known lung carcinogens, all of theunadjusted odds ratios were higher than 1.0, and threewere significant: coal tar, cadmium, and crystalline sil-ica. The unadjusted odds ratios were also elevated andclose to significance for chromium compounds andcoal gasification (odds ratio (OR) = 1.62 (95 percent

TABLE 2. Associations between lung cancer and occupational exposures (ever/never) in a cohort ofworkers in the French national electricity and gas company (EDF-GDF*), 1978-1989

Exposure

Coal tarCadmiumChromiumCoal gas productionCrystalline silicaManmade mineral fibersMechanical oilsCutting fluidsHerbicides/pesticidesBenzeneCreosotesHydrazinePolyester resinsChlorinated solventsPCBs*Epoxy resinsPolyurethane resinsAromatic solventsPetroleum solventsToluylene diisocyanate

No. ofcases

183245

4926

12833

13061

4073521144428

4253231149752

40283

No. ofcontrols

64841912558

4129

1241075096

14481372920

12322

OR*

1.521.481.621.891.910.961.282.041.361.311.850.810.851.640.991.351.211.551.371.06

95% CI*

1.10,2.091.12, 1.970.93, 2.820.93, 3.861.34,2.710.43,2.160.88, 1.871.27,3.301.05, 1.781.00, 1.711.30,2.650.38, 1.690.35, 2.051.27,2.120.74, 1.320.90, 2.020.78, 1.870.91,2.641.05, 1.780.65,1.73

O R /

1.241.201.311.641.590.731.151.861.111.021.560.670.791.370.911.141.071.101.080.94

95% CI*

0.88,1.750.88, 1.630.74, 2.330.80, 3.401.08,2.350.32,1.700.77, 1.701.14,3.060.82,0.75,1.08, I0.31,0.32,1.02,0.66,0.75,0.68,0.62,0.79,0.57,

1.501.402.271.461.921.851.261.741.681.941.471.56

* EDF-GDF, Electricite de France-Gaz de France; OR, odds ratio; CI, confidence interval; ORs, odds ratioadjusted for socioeconomic status and asbestos exposure; PCBs, polychlorinated biphenyls.


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906 Martin et al.

CI: 0.93, 2.82) and OR = 1.89 (95 percent CI: 0.93,3.86), respectively). After adjustment for socio-economic status and asbestos exposure, the odds ratiofor crystalline silica remained significantly higher than1.0 (OR = 1.59; 95 percent CI: 1.08, 2.35); for theother four agents, the odds ratios remained higher than1.2 but were not significant. Among the suspected lungcarcinogens, the unadjusted odds ratios were signifi-cantly higher than 1.0 for cutting fluids (OR = 2.04; 95percent CI: 1.27, 3.30), herbicides/pesticides (OR =1.36; 95 percent CI: 1.05, 1.78), creosotes (OR =1.85;95 percent CI: 1.30, 2.65), and chlorinated solvents(OR = 1.64; 95 percent CI: 1.27, 2.12); after adjust-ment for socioeconomic status and asbestos, cuttingfluids (OR = 1.86; 95 percent CI: 1.14,3.06), creosotes(OR = 1.56; 95 percent CI: 1.08,2.27), and chlorinatedsolvents (OR = 1.37; 95 percent CI: 1.02, 1.85)remained significantly associated with lung cancer risk.The six agents not considered to be lung carcinogenswere not associated with the disease after adjustmentfor socioeconomic status and asbestos.

Table 3 presents the results of the analysis under-taken according to levels of exposure to the agents.Exposures for which there were less than 10 exposedcases were not analyzed by level of exposure; theseexposures were manmade mineral fibers, hydrazine,and polyester resins. For coal tar (OR = 2.07; 95 per-cent CI: 1.19, 3.61), cadmium (OR = 2.28; 95 percentCI: 1.41, 3.69), coal gasification (OR = 4.60; 95 per-cent CI: 1.40, 15.1), and crystalline silica (OR = 2.90;95 percent CI: 1.58, 5.33), all four well-known lungcarcinogens, the unadjusted odds ratios were higherthan 2.0 and significant in the highest exposure cate-gory. After adjustment for socioeconomic status andasbestos, the odds ratios still showed an associationwith lung cancer risk for exposure to the highest levelof coal gasification (OR = 3.87; 95 percent CI: 1.15,12.9), as well as for the highest exposure levels of cad-mium (OR = 1.69; 95 percent CI: 1.00,2.88) and crys-talline silica (OR = 2.37; 95 percent CI: 1.25, 4.49).Concerning the highest exposure to coal tar, the oddsratio was equal to 1.53 but was no longer significantlydifferent from 1.0; nevertheless, a cumulative expo-sure level gradient seemed to exist. Exposure to sus-pected carcinogens showed significantly high unad-justed odds ratios in the higher exposure categories formechanical oils (OR = 1.96; 95 percent CI: 1.02,3.78), herbicides/pesticides (OR = 1.55; 95 percentCI: 1.00, 2.39), benzene (OR = 1.62; 95 percent CI:1.03,2.53), creosotes (OR = 2.33; 95 percent CI: 1.22,4.44), and chlorinated solvents (OR = 2.29; 95 percentCI: 1.54, 3.40). After adjustment for socioeconomicstatus and asbestos exposure, the odds ratios for thelatter two agents remained higher than 1.0 (OR = 2.32

(95 percent CI: 1.20,4.51) and OR = 1.88 (95 percentCI: 1.20, 2.96), respectively). Although the adjustedodds ratios for cutting fluids and mechanical oils werenot significant, they increased with level of exposure.No nonsuspected agents showed any association afteradjustment for socioeconomic status and asbestos; allodds ratios were nonsignificant or nearly so, or lowerthan 1.0, in all exposure categories.

Trend odds ratios were calculated for eight agents:coal tar, cadmium compounds, coal gasification, crys-talline silica, mechanical oils, cutting fluids, creosotes,and chlorinated solvents (table 3). These odds ratioswere higher than 1.0 for five of the eight agents stud-ied: coal gasification, crystalline silica, cutting fluids,creosotes, and chlorinated solvents. For the other threeagents (coal tar, cadmium compounds, and mechanicaloils), the lower bounds of the 95 percent confidenceintervals were very close to 1.0 (0.98 and 0.99). Theseeight agents were therefore kept in the analysis for fur-ther assessment.

Finally, eight full models were constructed (one foreach of the eight agents). For each model, the oddsratios were adjusted for socioeconomic status, for theseven other agents, and for exposure to asbestos andchromium, which are known lung carcinogens. Anodds ratio of 2.27 (95 percent CI: 1.10, 4.68) wasobserved in the highest exposure category for crys-talline silica, with a significant exposure-responserelationship, although the increase in odds ratios withlevel of exposure was not regular. Although the oddsratios were not significant, they were elevated in thehigher exposure categories for cadmium and coal gasi-fication (OR = 1.79 and OR = 2.14, respectively); thetrend odds ratios were not significantly different from1.0. A statistically significant increased lung cancerrisk for exposure to creosotes (OR = 2.14; 95 percentCI: 1.06, 4.31) and a significant exposure-responserelationship were observed. Concerning cutting fluids,a strong association was observed: The odds ratios cor-responding to each exposure category were higher than2.0, as were the trend odds ratios, although none werestatistically significant; the trend odds ratio was high(OR = 2.4), but the values were practically equal foreach exposure category. Exposure to mechanical oilsor chlorinated solvents was not significantly associ-ated with lung cancer risk after the other factors weretaken into account, although the trend odds ratio andthe odds ratio for the highest level of exposure to chlo-rinated solvents were close to significance.

DISCUSSION

A previous study undertaken in the same populationevidenced a clear association between exposure toasbestos and lung cancer (8). In our study, the system-


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TABLE 3. Associations between lung cancer and occupational exposures (cumulative exposure) in a cohort of workers in theFrench national electricity and gas company (EDF-GOF*), 1978-1989

Cumulativeexposure categoryt

Coal tar01234

Cadmium01234

Chromium01234

Coal gas production01234

Crystalline silica01234

Mechanical oils01234

Cutting fluids01234

Herbicides/pesticides01234

No. ofcases

1,04246474842

98063666254

1,176177

1015

1,1997775

1,09727363530

1,09534363129

1,16415151714

81811087

106104

No. ofcontrols

24615131620

22620201628

2914663

2982316

25513121119

2696

111014

2818777

18634262935

OR*

1.00§1.411.181.472.07

1.00§1.381.291.142.28

1.00§0.983.492.470.83

1.00§1.171.780.624.60

1.00§2.141.471.392.90

1.00§0.731.221.341.96

1.00§2.282.041.732.18

1.00§1.401.321.221.55

95% Cl*

0.78, 2.570.63, 2.220.82, 2.671.19,3.61

0.82, 2.310.77, 2.160.65, 2.001.41,3.69

10.32, 3.01 (1.17,10.40.89, 6.810.24, 2.93 (

10.24, 5.610.44, 7.260.08, 5.14 (1.40, 15.1

11.08,4.220.76, 2.860.69, 2.791.58,5.33 !

10.31,1.75 (0.61,2.450.63, 2.831.02,3.78

DR.*

.00§1.261.031.191.53

.00§1.201.09D.951.69

.00§D.822.82>.O2D.64

.00§1.021.593.553.87

.00§1.791.23.18

>.37

.00§).74.00.24.67

1.00§0.92, 5.650.82,5.110.70, 4.310.86,5.51 !

.81

.73

.772.20

1.00§0.91, 2.140.83,2.10 10.78, 1.89 11.00,2.39 1

.19

.12

.01

.13

95% Cl*

0.68, 2.320.55, 1.960.65, 2.190.85, 2.76

0.71,2.030.65, 1.840.53, 1.691.00,2.88

0.27, 2.550.94, 8.510.72, 5.650.18,2.29

0.21,4.940.39, 6.490.07, 4.571.15, 12.9

0.89, 3.600.61,2.460.58, 2.421.25, 4.49

0.31, 1.790.49, 2.050.58, 2.660.85, 3.28

0.72, 4.560.68, 4.380.70, 4.470.86, 5.63

0.76,1.860.69,1.820.63, 1.600.71, 1.82

Meant

17.867.1

147.4380.8

2.38.7

20.7101.8

066.7

151.3260.7475.7

02.05.7

10.921.7

016.559.5

146.7425.7

03.69.6

18.142.3

ORa*

1.04

1.20

NO*

1.10

1.04

1.05

2.41

95% Cl*

0.98, 1.11

0.99, 1.46

1.01,1.21

1.01, 1.07

0.99, 1.12

1.07,5.40

Table continues

atic analysis of all occupational cancer agents includedin the EDF-GDF MATEX job exposure matrix (exceptfor asbestos) showed, after adjustment for differentoccupational confounding factors, a high risk of lungcancer linked to exposure to crystalline silica, which isa known lung carcinogen (OR = 2.27 for the highestexposure category), and a significant exposure-response relationship. The highest level of exposure to

creosotes was associated with lung cancer risk (OR =2.14), and there was a statistically significant exposure-response relationship. Elevated odds ratios were alsoobserved in the highest exposure categories for cad-mium, cutting fluids, and chlorinated solvents,although associations did not reach statistical signifi-cance. None of the unsuspected lung cancer agentsshowed an association with the disease at any step of


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908 Martin et al.

TABLE 3. Continued

Cumulativeexposure categoryt

No. ofcases

No. ofcontrols OR* 95% Cl* OR/ 95% Cl* Mean* 0R o 95% Cl*

Benzene01234

Creosotes01234

Chlorinated solvents01234

PCBs*01234

Epoxy resins01234

Polyurethane resins01234

Aromatic solvents01234

Petroleum solvents01234

TDI*01234

87389879284

1,11126322927

80010510711796

90278837785

1,11127262833

1,12824212626

1,17313101613

82396

10310994

1,14224172418

20325312031

260168

1115

16638362545

22923182119

273111574

2819

1064

2905735

18731292439

2887555

1.00§1.211.540.931.62

1.00§2.541.091.592.33

1.00§1.721.671.032.29

1.00§1.180.851.050.88

1.00§1.702.321.000.49

1.00§1.511.910.930.62

1.00§1.522.870.741.64

1.00§1.451.270.971.90

1.00§1.161.180.811.11

0.76, 1.940.99, 2.370.57, 1.551.03,2.53

1.35, 4.770.50, 2.370.78, 3.231.22, 4.44

1.14, 2.591.09,2.540.65, 1.651.54, 3.40

0.71, 1.940.50, 1.470.63, 1.740.53, 1.47

0.81,3.601.21,4.450.43, 2.330.17, 1.42

0.68, 3.330.88, 4.130.38, 2.270.21, 1.78

0.53, 4.351.06,7.790.21,2.590.57, 4.70

0.94, 2.260.82, 1.970.61, 1.561.25,2.89

0.50, 2.730.43, 3.250.30,2.190.41,3.00

1.00§1.031.240.711.13

1.00§1.930.861.322.32

1.00§1.451.450.871.88

1.00§1.090.810.940.80

1.00§1.411.900.870.43

1.00§1.331.630.830.57

1.00§1.062.100.501.18

1.00§1.241.050.741.42

1.00§1.041.080.720.97

0.64,1.680.79,1.960.42, 1.220.67,1.90

1.00, 3.730.39, 1.900.64, 2.721.20,4.51

0.95, 2.230.93, 2.270.53,1.431.20,2.96

0.65, 1.820.46, 1.420.56, 1.590.46, 1.38

0.66, 3.040.98, 3.700.37, 2.070.15, 1.24

0.60, 2.980.75, 3.570.33, 2.040.20, 1.66

0.36, 3.120.76, 5.850.14, 1.790.40, 3.47

0.79, 1.960.66, 1.670.45, 1.230.88, 2.29

0.44, 2.480.39, 2.980.26, 1.960.36, 2.63

04.9

20.453.0

165.7

04.8

17.144

159

NC*

1.22 1.05,1.43

1.13 1.02,1.27

NC

NC

NC

NC

NC

NC

* EDF-GDF, Electricite de France-Gaz de France; OR, odds ratio; Cl, confidence interval; OR,, odds ratio adjusted for socioeconomic sta-tus and asbestos exposure; ORa, trend odds ratio adjusted for socioeconomic status and asbestos exposure; NC, not calculated; PCBs,polychlorinated biphenyls; TDI, toluylene diisocyanate.

t 0, not exposed; 1, <25th percentile; 2, 25th-50th percentiles; 3, 50th-75th percentiles; 4, >75th percentile.t Expressed in years for crystalline silica, in ppm-years for benzene and toluylene diisocyanate, and in hours/week-years for the other

occupational exposures.§ Reference category.


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the analysis, which indicates good specificity of theMATEX job exposure matrix for evaluation of occu-pational exposures.

Methodological aspects

The cancer register set up by the company's healthinsurance fund allowed for a comprehensive census ofcases, when the disease occurred during the course ofthe subject's activity in the company (11). Never-theless, this register does not record cases that mani-fest after retirement. The subjects included in our studywere mostly under 50 years of age, whereas in theFrench male population, lung cancer incidence ratesprogress strongly with age up to the age of 70 years(1). Retirement age for EDF-GDF workers whose jobsinvolve heavy physical strain is 55 years; these skilledor unskilled workers represent the occupationalcategory most exposed to chemical agents. Becausechemical-induced lung cancers generally occur 10-20years after the beginning of occupational exposure, thelack of recorded data on retired subjects entails a lossof power for the study. Moreover, the possible bias cre-ated by the truncation of data collection could havedecreased the lung cancer-exposure associations if thelatency period is very long, but it cannot explain thepositive associations which were observed.

The job exposure matrix method presents numerouspractical advantages for the evaluation of exposuresthrough retrospective epidemiologic studies. Neverthe-less, there are two methodological limitations. First, theevaluations of individual exposure levels were imprecise(even when they were quantified in the matrix), since thejob exposure matrix gives average levels per occupation.Second, misclassification at an individual level isinevitably generated, since the subjects are attributed theexposure of the occupational groups to which theybelong; this entails misclassification because of the vari-ability of exposure inside the same group (14). However,misclassification is nondifferential, since it was equallydistributed among cases and controls. When the expo-sure variables are dichotomous (exposed/nonexposed),misclassification tends to bias the odds ratio toward 1.0and therefore underestimate the possible associationexisting between disease and exposure (19); misclassifi-cation between levels of exposure tends to reduce theexposure-response relationship (20) and may explainwhy the increase in odds ratios with the level of expo-sure was not regular for some exposures. Therefore, ifthe absence of a significant association between an agentand disease may be explained by the existence of non-differential misclassification, the misclassification can-not explain the significant associations observedbetween various exposures and the occurrence of dis-

ease. The job exposure matrix used in our study is spe-cific to the industrial sector, which comprises a limitednumber of well-known occupations, and this is not thecase in the general population; therefore, it usually gen-erates less misclassification (19).

Data on tobacco consumption were not available.Smoking has often been discussed as a confoundingfactor in studies of the relation between lung cancerand occupational factors. Most investigators believethat within an occupational cohort, the confoundingeffect is weak or absent (21-23). Individual behaviorsregarding smoking are strongly linked to socio-economic status. Various studies undertaken at EDF-GDF (8, 24) have found that skilled or unskilledworkers and clerks smoked more than the middle orsenior executives, particularly among the youngerworkers. In 1994, an analysis of the associationbetween current tobacco use and occupational expo-sures assessed through the MATEX job exposurematrix was undertaken using a sample of current EDF-GDF workers (24). This analysis, which adjusted forage, sex, and socioeconomic status, did not show anysignificant association between smoking status andany of the occupational exposures included in the jobexposure matrix. Although only current tobacco con-sumption was studied, it is probable that the absenceof association also existed in the past. Moreover, anestimate of the potential confounding effect of expo-sure to these agents, smoking, and lung cancer occur-rence showed that it varied from 1 percent for cre-osotes to a maximum of 9 percent for herbicides/pesticides. These analyses showed that adjustment forage, sex, and socioeconomic status is sufficient tocontrol for the confounding effect of smoking in epi-demiologic surveys of lung cancer and chemical occu-pational risks in this population. Socioeconomic sta-tus at first employment was used in the analysis as anadjustment variable, because behavior linked to socialenvironment is most strongly expressed at the start ofadult life.

It is possible that systematic adjustment for socio-economic status in the models introduced a certainlevel of overadjustment, because socioeconomic statusis associated with occupational exposure factors.Nevertheless, because the socioeconomic status cate-gory used here was socioeconomic status at firstemployment, and because there has been considerablesocial mobility in recent decades, associations betweenlow socioeconomic status categories and occupationalexposures are likely to be less strong than one couldexpect (25). In any case, overadjustment tends todecrease the association between exposure and lungcancer risk, and it cannot explain the high odds ratiosobserved for some cancer agents.


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910 Martin et al.

Despite the small number of subjects exposed tosome agents, the analyses overall had adequate statis-tical power. The upper bounds of the 95 percent confi-dence intervals for the odds ratios in the final modelsshowed that the analyses had the power to exclude rel-ative risks higher than relatively small values (alwayslower than 2.0, except for cutting fluids). All the same,it is possible that the reason most trend odds ratios,except those for crystalline silica and creosotes, werenot significant in the final models (although they wereclose to significance) was lack of power, especially ifwe consider intercategory misclassification, whichoften flattens out the exposure-response curve (20).

Lag time from tumor diagnosis was studied by con-ducting similar analyses excluding the exposures thatoccurred during the last 10 years before diagnosis;these analyses yielded the same results. This could beexplained by the fact that, generally and for all of theagents, the major portion of cumulative exposurecomes from the most remote working years.

Known lung carcinogens

At EDF-GDF, tasks which involved exposure to crys-talline silica were sanding and grinding, which werelinked to various activities (repairing metallic equip-ment or constructing a tunnel, for instance). It is likelythat exposures at EDF-GDF were lower than those inother industries where an elevated risk of lung cancerwas evidenced. However, the highest crystalline silicaexposure category showed, after adjustment for con-founding factors, a highly significant odds ratio (OR =2.27) and a significant exposure-response relationship.The role of crystalline silica in the occurrence of lungcancer is recognized by the International Agency forResearch on Cancer, which has classified this agent ingroup I since late 1996 (26). Before this date, manystudies had evidenced significant statistical linksbetween this agent and lung cancer (27, 28). However,the possible interference of smoking behavior or expo-sure to other carcinogens was not always assessed. It isreasonable to think that in our study these confoundingfactors were correctly taken into account in the fullmodel, allowing for a true appreciation of the role ofcrystalline silica. Nevertheless, this agent was one ofthe three agents that the job exposure matrix does notrecord in a quantitative way. The levels shown by theexposure categories were career-length exposures anddo not represent an evaluation of the dose received.

At EDF-GDF, exposure to cadmium and chromiumresulted mainly from welding. This activity was per-formed by a wide range of workers in the company—e.g., maintenance workers, pipe fitters, and mechanics.The welding of stainless steel elements used achromium component stick which issued chromium

vapors during fusion of the stick and the steel.Occupations dealing with activities concerningchromium pigmentation paints have been classified inthe job exposure matrix as exposure to chromium.None of these occasional exposure circumstancesexpose workers to high cumulative doses. The studiesthat have shown an association between chromiumexposure and lung cancer have concerned subjectswho worked in the production of chromium salt ormetal electrolysis chroming, meaning that exposure tochromium was continuous and much higher than thatof the EDF-GDF workers (29, 30). This could explainthe absence of an association between chromium andlung cancer in this study.

Exposure to cadmium among EDF-GDF workersalso occurs during the occasional use of welding stickswhich issue vapors of this metal. The weekly amountsof cadmium exposure were small. This probablyexplains why the observed association, althoughremaining high in the highest exposure category, wasno longer significant in the overall multivariate model.Indeed, the association between cadmium and lungcancer has been described among casting workers ornickel-cadmium workers, who are highly exposed tocontinuous cadmium vapors (31, 32).

The tasks which exposed the EDF-GDF workers tocoal tar were more varied. They comprised coating ofunderground pipes, electrical cables, or gas pipes andthe related maintenance work, but also gas factorychimney sweeping. This latter exposure is responsiblefor skin cancers through direct contact and lung cancerthrough inhalation (33). Annual exposure trendsshowed a decrease starting at the end of the 1960s, dueto the closing of the EDF-GDF gas factories (gas madeby coal gasification was no longer produced after thatdate) and to the general use of plastic compounds forpipe coating. However, levels of exposure were weakeven before that time. The mean annual exposure lev-els were at their highest from 1955 to 1965. The num-ber of subjects exposed in our sample, which was max-imal during this period, nevertheless remained small(around 30). However, the highest exposure categorypresented a high socioeconomic status-adjusted oddsratio (OR = 3.87; 95 percent CI: 1.15, 12.9) and a sig-nificant odds ratio trend (OR = 1.10; 95 percent CI:1.00, 1.21). The odds ratio for this category remainedhigh after adjustment for other confounding factors(OR = 2.14) but was no longer significant, and theexposure-response relationship did not remain.

Suspected lung carcinogens

Creosotes constitute a family comprising variouscompounds. They are used for the protection of


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wooden poles, which are extensively used for distribu-tion power lines. Creosotes are produced by the distil-lation of coal tars, which are themselves producedfrom coal distillation. Their toxicity is generally sub-sumed under that of tars and coal tars (34). Never-theless, they are not reported as known lung or skincarcinogens, which classifies them in the InternationalAgency for Research on Cancer's IIA group (15).Their normal use needs no heating, the main exposureroute being skin contact. However, inhalation of theproduct during wooden post painting cannot beexcluded. The odds ratio for the highest exposure cat-egory was greater than 2.0 in our study, with a signifi-cant exposure-response relationship. Creosotes, coaltars, and coal gasification involve exposure to polynu-clear aromatic hydrocarbons, a family of substancessuspected of causing skin and lung cancers (5).

In our study, cutting fluids and mechanical oilswere classified under nonrefined or moderatelyrefined mineral oils, since they are an ingredient inthose two products (34). They are extensively used atEDF-GDF in workshops, especially in the powerplants, where a wide range of mechanical activitiestake place. The nonrefined or moderately refinedmineral oils contain variable proportions of polynu-clear aromatic hydrocarbons. The use of cutting fluidsproduces oil mists which can be inhaled, whereastasks exposing workers to mechanical oils mainlycause skin disease by direct contact. In our study,exposure to cutting fluids was always associated witha higher lung cancer risk, but not exposure tomechanical oils.

Conclusion

This study has demonstrated the lung-carcinogeniceffects of crystalline silica. It also reinforces the plau-sibility of a lung-carcinogenic effect for exposure toseveral other agents for which the effect is not yetestablished, such as creosotes and cutting fluids.Although the observed associations were not signifi-cant, this can be partly explained by the relatively lowlevels of exposure and by different statistical influ-ences which tend to decrease observed associations(nondifferential misclassification and potential over-adjustment for socioeconomic status). The study alsoshowed the usefulness of an industry-specific jobexposure matrix for the study and surveillance of occu-pational cancers. At the time the study was undertaken,French legislation did not allow access to the nationalcause-of-death database on an individual basis. Arecent change in legislation now makes it possible, andwe are currently planning a mortality study designed toinclude postretirement follow-up of all EDF-GDFworkers.

ACKNOWLEDGMENTS

The authors express their thanks to the occupationalphysicians of EDF-GDF, particularly the members of theMATEX expert group for their participation in developmentof the job exposure matrix; to R. Vatre for database devel-opment; and to the physicians of the social security depart-ment of EDF-GDF, who compiled the cancer cases.

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