Document 3JgXaQOgw7LYxovgVJLK9D5Xa

FILE NAME: Talc (TALC) DATE: 2002 DOC#: TALC176 DOCUMENT DESCRIPTION: Journal Article - A Cohort Mortality and Nested Case-Contol Study of French and Austrian Talc Workers Downloaded from oem.bmjjournals com on 12 April 2006 98 ORIGINAL ARTICLE A cohort mortality and nested case-control study of French and Austrian talc workers , P Wild, K Leodolter, M Refregier, H Schmidt,T Zidek, G Haidinger O ccu p Environ M e d 2 0 0 2 ,5 9 9 8 - 105 See end of article for authors' affiliations Correspondence to Dr P W ild , Avenue de Bourgogne, BP n 27, 54501 Vandoeuvre Cedex, France, Accepted 8 August 2 0 0 1 Objectives: To study whether the mortality from non-malignant and malignant respiratory diseases of workers employed in French and Austrian talc mines and mills is related to their long term occupational exposure. Methods: Two historical cohorts were set up comprising all male sublets who had been working con tinuously for at least 1 year in a series of talc producing companies in France and Austria The French cohort consisted of those employed at a site in the French Pyrenees and working between 1 January 1945 and 31 December 1994 The Austrian cohort consisted of the workers employed between 1 January 1972 and 31 December 1995 in one of four industrial sites in the Austrian A ps The mortality within the cohorts was compared with local death rates. Two nested case-control studies focusing on non-malignant and malignant respiratory diseases were set up to estimate possible dose-response rela tions with cumulative exposure to talc dust based on an industry specific |ob exposure matrix Results: Mortality from lung cancer was in small excess in both cohorts (France, standardised mortality ratio (SMR) 1.23, 21 cases observed, 95% confidence interval (95% Cl) 0 7 6 to 1 89, Austria, SMR 1 06, seven observed, 95% Cl 0.43 to 2.19) A non-significant excess mortality was lound for all nonmalignant respiratory diseases in the French cohort due to a significant excess for pneumoconiosis (SMR 5.56, three observed, 95% Cl 1.12 to 16 2). The case-control study of non-malignant respiratory disease showed an increased mortality in the highest exposure groups (odds ratio (OR) 2 5 for a cumu lative exposure 5 8 0 0 y.m g/m 3) with a significant trend (O R /100 y m g/m 3 1 08) with cumulative exposure to talc On the contrary, no increasing trend could be found in the case-con'rol study of lung cancer This result must be interpreted considering the small cohort size Ad|ustment on smoking and exposure to quartz did not influence these results to any extent. Conclusions: The mortality from non-malignant respiratory disease was found to bo related to high cumulative exposure to talc dust. The small excess in lung cancer does not seem to be attributable to talc Talc is mined in many countries and processed m numerous manufacturing industries for use in paints, ceramics, rubber products, roofing materials, papei, in secticides, cosmetics, and pharmaceuticals. Talc12 (Mg,Si40,,,(OH),) is a member of the silicates group of miner als characterised by its structure in sheets which can be sepa rated by slight forces. This causes the plate shape of the talc pai tides and the smoothness in touch Other characteristics of talc as a mineral are softness, hydrophobic behaviour, and insolubility. Given this planar structure of the talc crystal, the term talc fibres is technically not correct. However, when nulled, some cleavage fragments (less than 1%) within the talc powder meet the World Health Organisation (WHO) defini tion of fibres, although in fact these fragments are elongated talc platelets As talc is formed by alteration or metamorphosis of rocks, it is associated with many types of minerals and may contain other minerals as lesidues, so that the mined and milled ore hardly ever consists of pure talc. Exposure to talc must there fore be considered bearing in mind the coexposures--among which quartz is the most important--specific to each site. It is noteworthy that, to our knowledge, no asbestos contamina tion has ever been clearly documented in the talc deposits, at least not in the European sites. Several mortality studies per formed among workers from the talc industry reported incon clusive results concerning an increased risk of neoplasms of the respiratory system Although the risk of non-malignant respiratory diseases was in excess in most of the study sites, the risk for cancer is different from study to study and may depend on the mineralogy of the exploited mineral oi othei features of the cohorts. In this paper we leport the lesults of two ustoiical cohoi t mortality studies conducted m the Austrian and the French talc industries and of two nested case-control studies focused on non-malignant and malignant lespnatory diseases METHODS Industrial sites and exposure assessment The French site (site A) is in the French Pyrenees The oie is a talc chlorite mixture which has been quarried since the end of the 19th century in an open cast pit at an alt tude of 1700 m The talc is sorted on the spot and dried and milled in a neaiby talc mill. Quartz contamination is low, from non-detectable to less than 3% The Austrian sites comprise three mines (sites B, C, and D| with their respective mills in the Styi lan Alps and a head office in the city of Graz (site E). The ore mined in Mte B consists ol a talc-chlorite mixture with dead rock inclusions of about 25% (mainly gneiss) The dead lock is dumped m ihe mine so that the milled product is talc-chlorite and contains from 0 5% to 4% quartz In site C, the material mined was a talc-dolomite aggregation with a medium talc content of 25% The percent age of quartz m the end products was below 1%, singular pai ts A b b re v ia tio n s : SMR, standardised mortality ratio, 1C), international classification of diseases, JEM, |ob exposure matrix w w w occenvmed com Downloaded from oem bmjjournals.com on 12 April 2006 Cohort mortality and nested case-control study of French and Austrian talc workers 99 in the mine, uch in dolomite, could contain 2%-3% quartz In sue D, a light greyish quartz chlorite mica schist (leucophyllte), an aggregation of more or less equal proportions of mica, chlorite, and quartz has been quarried and milled on site. The exposure to talc dust and quartz was coded through a site specific job exposure matrix (JEM ). The principles of the coding were agreed between the authors, and the codings of the JEM were harmonised before the statistical analysis. In Austria this JE M was developed by the occupational physician (HS) in collaboration with the managerial staff of the company on the basis of interviews of retired workers. In France, the JEM was developed by the occupational physician (MR) on the basis of the JE M developed for an earlier study,' which included a more detailed assessment but did not reach as far back in time as the present one. The talc exposure was coded in four semiquantitative categories which were based on systematic exposure measure ments carried out in 1986-7 m the French site A, on less sys tematic measurements m 1988-92 in the Austrian sites, and on descriptions of the workplaces obtained from management and long term workers The exposure measurements both in France and Austria weie obtained with the same type of per sonal dust sampler worn by the worker for at least half a shift. The results are gravimetric determinations of the respirable dust fraction (for details see Wild et aP) The assignment of the workplaces to the four semiquantitattve levels was done as follows No exposure to talc was coded for office workers. A mean dust concentration of 0 2 mg/m' based on 168 measurements was obtained in 1986 m site A for office workers. No exposure to talc occurred for those working in sites not exposed to talc. This was the case in the French mill, which included a separate power station and a carpentry, and in the mill in site D, in which no talc was milled before 1970, which does not mean that there was no exposure to dust, but that this dust did not contain any talc. An exposuie lower than 5 mg/m' was assessed for subjects with no direct contact to talc dust. This occurred for certain off site maintenance workers or garage mechanics, and for production workers in recent times with up to date dust con finement or local exhaust ventilation. Eight jobs were in this category m the French site in 1986, mean exposures ranged from 0 5 to 2 6 mg/m', the range of the 100 exposure measurements carried out that year was 0 11-17 mg/m'. In Austria most production workers had belonged to this category since 1980. The 173 exposure measurements in site B between 1988 and 1992 ranged from 0.02 to 4.61 mg/m' In site C, 33 measurements in 1991-2 ranged from 0.02 to 4 1 mg/m1. An exposure higher than 30 mg/m' was assessed for past production jobs, for which a high dust exposure was documented, for instance by low visibility due to the dustiness of the workplace. In the French mill, these jobs included the milling itself, the bagging, the storing, carrying, and cleaning of jute talc bags and the sawing of so called talc pencils The last time such an exposure was coded was for a cleaning job before 1985. In Austria this exposure level was coded for all workers in sites B and C before 1960 and for millers and onsite maintenance workers m site D between 1970 and 1980. At the end of the 1980s, no highly exposed workers remained, so that no direct exposure measurement could be obtained. However, in some extreme exposure situations which were rare in the 1980s, exposure was measured at concentrations above 50 mg/m'. Such measurements were described as quite common in the job periods attributed to the highest category. Three measuiements of the exposure in such situations were identi fied in Austria (from the workers wearing individual protective equipment) to be 73, 82, and 159 mg/m'. A medium exposure between 5 and 30 mg/m' was coded for all jobs which did not enter the preceding categories. This included the moie recent French production workers in the dustier areas such as bagging or milling, the onsite maintenance workers, or in the early days some vvoikeis m jobs near very dusty areas such as the oven workeis In Austria, this concentration was attributed to all workers in site B between 1960 and 1980 and for workers in site D from 1980 to 1990. Eleven workplaces in this category could be characterised by actual measurements in the Fiench sue A with measured mean exposuies from 3.6 to 15 6 mg/m' The range of the 193 exposure measurements v/as 0 21 to 134 mg/m'. In Austria 17 measurements weie made m site B and eight in site C ranging between 6 5 and 19 6 i ig/m' The main other exposure that was assessed was quai tz, which occurred mostly m underground mining, tunnelling, and barrage building but also while milling minerals that contained quartz as in site D. More precisely si bjects were said to be exposed to quartz if they were employed m mining oi milling of leucophylite (Austrian site Dj if they were underground miners in site B before the introduction in 1960 of modern drilling techniques, or if their earlier jobs involved underground mining m sites with known exposure to quaitz, or tunnelling or barrage building in the Pyienees Cohort definition and data collection The French cohort The French cohort consisted of all male workers in site A hav ing been employed continuously for at least 1 yeai between 1 January 1945 and 31 December 1994 It comprised all staff of the milling site (including administrative workers and execu tives). Most of the subjects employed at the quariy were excluded, because (due to the high altitude) he quanv urns only during summer. A few workers were employed in the winter also and were thus included in the c rhort The data were abstracted horn several administrative records and were checked for completeness with the annual pay sheets, which were available since 1945. This cohort was followed up for mortality between 1January 1945 and 31 December 1996 The vital status of all subjects was assessed by contacting the icglstry offices of the respective birth places and by seaiching a computerised data base of all people who hac died in France since 1978. An individual tracing procedure was set up foi all foreign born subjects. The cause of death was detei mined by matching the files of the deceased subjects w th the national files of causes of death, which exist since 1968 (coded using the eighth revision of the international classification of diseases (1CD-8)4 until 1978 and ICD-9' the eafter) Foi all subjects who died before 1968, we relied on the causes of death obtained from an earlier mortality studs 1 The Austrian cohort The Austrian cohort consisted of all male wo-kers employed continuously foi at least 1year between 1Januu y 1972 and 31 December 1995, in one of the four study site, located in the federal state of Styria (Austria). The reason 'or starting the Austrian cohort in 1972 is that the regional mortality data aie only available in a computerised form since that yeai We used two sources of information for the subjec s' pnvate and employment data, the company's legistries anti the catalogues of the regional social insurance fund (VADOeB) Complete work histones within the company weie ava lable The vital status of all subjects and, if no longer alive, the dates and causes of death within the study period wire assessed by matching the subjects' names and their dates of birth with the national mortality data set from Statistics Austna (coded with ICD-84until 1979 and ICD-9' thereafter). The case-control study Following Breslow and Day,7 we considered the nested case-control study as a Cox model with time variable age m which the controls are sampled horn the nsk set With this approach, the risk set of a given case consisted of all subjects wwv, occenvmed com Downloaded from oem bmjjournals com on 12 April 2006 100 W ild , Leodolter, Refrgier, et al Table 1 Observed (Obs) and expected (Exp) numbers of deaths, standardised mortality ratios (SMRs) (95% Cl) of the main causes of death by cohort Cause of deatbf Ail causes Cardiovascular system Non-mahgnant respiratory diseases Pneumoconiosis Digestive tract All cancers Stomach cancer Mesothelioma lung cancer Violent death ,,French cohort* Obs Exp 294 3175 106 113 7 26 24 6 3 05 14 17 1 80 78 4 5 4 3 0 03 21 170 22 26 1 SMR 0.93 0 93 1 06 5 56 0.82 1 02 1 18 1 23 0 84 95% Cl 0 82 to 1 04 0.76 to 113 0.69 to 1.55 1.12 to 162 0 45 to 1 38 0 81 to 1 27 0.38 to 2 75 _ 0 76 to 1 89 0 53 to 1.28 Austrian cohort Obs Exp 67 89 4 20 32 9 1 3 7 0 0 1 9 8 7 17 23 4 i 25 0 0 1 7 66 15 13 1 SMR 0 75 061 0 27 - 1 04 0 73 0 40 -- 1 06 1 14 95% Cl 0 5 8 t o 0 95 0 37 to 0 94 0 01 to 1 52 - 0 48 to 1 97 0 42 to 1 17 0 01 to 2 25 _ 0 43 to 2 19 0 64 to 1 88 *ln the 1968-96 period by comparison with local rates, fcoded according to the ICD-8 and ICD-9 at risk (alive and under observation) at the age at which the case has died. By this definition, another case is a potential control if he died at an older age. To account for the period effect only subjects who attained this age within the same 5 year period were considered eligible. We sampled three controls within each risk set thus achieving matched age and stratification on calendar periods.* We used the STATA software and the procedure "sttocc"' to implement these steps. TWo different case-control studies were thus set up. The lung cancer case-control study which included all cases with ICD codes 162.0 to 162.9 for their main or associate causes of death in either the 8th or the 9th revision. The study of non-mahgnant respiratory diseases included all deaths with ICD-8 codes 10.9 (silicotuberculosts) or 460 0 to 519.9 or ICD-9 codes 460 0 to 519.9 for their mam or asso ciated causes of death In Austria, the work histones could be abstracted from company tecords and were classified according to the exposure by one of us (HS) who worked as a occupational physician for the company. The smoking information was obtained from earlier unpublished studies on mortality and pneumoconiosis, from colleagues, and from records of the compensation claim insurance (AUVA). In France, the occupational histories and the smoking information were collected by an external interviewer blind to the case-control status on the basis of existing documents or when the information was missing, by contacting former col leagues. The existing documents consisted mostly of the paper files from the previous mortality study carried out in the beginning of the 1980s/' and the files of the occupational physician of the company. Analytical methods Cohort study We compared the mortality rate of the cohort with local death rates by standard life table methods.7 For the French cohort the local (dpartement de l'Artge) and the national mortality rates were used. The local mortality rates were only available since 1968 For the Austrian cohort we used the mortality rates of the federal state of Styria. We accumulated person-years at risk for each member of the respective cohort, starting with the first anniversary after entering employment, or 1 January 1945 (Austria- 1 January 1973). In France all subjects were followed up until 31 December 1996 or earlier in the case of death. Subjects lost to follow up (3%) were censored at the day they left the company. In Austria all sub jects were followed up until 31 December 1995 or earlier in the case o f d eath Stan d ard ise d m o rta lity ratios (S M R s ) WCr obtained by dividing the observed number of deaths by (age and period standardised) expected numbers. Furthermore 95% confidence intervals (95% CIs) were calculated with the Poisson assumption.7 Case-control studies The work histories were combined with the |ob exposme matrix to obtain individual estimates of cumul itive exposuies Assigning concentrations of 2.5 mg/m1for jobs with low expo sure, 10 mg/m' for medium exposure, and 40 mg/m1foi high exposure, the cumulative exposure was obtained bv summing all job periods, the product of the duration of exposure by the assigned concentrations. This was done unti death tor the cases, and for the controls until the age at which the corresponding case died. To account for the latency penod oi lung cancer a second lagged estimate of the cumulative expo sure was obtained by summing the exposuie until 10 years before the age at death of the case. The statistical analysis was done by concitional logistic regression1' which takes into account the matching sttuctuie This was especially important because for two ^ases, less than three controls were available in the i tsk set so that an unequal number of controls were sampled by case Moieover, missing confounder information (especially smoking) also gave unequal numbers of controls per case, when adjusting foi them. As the mam question was the cumulative effect of talc dust, this variable was fitted as a continuous var able To avoid unnecessary small odds ratios, the cumulative exposuie to talc dust was transformed into units of 100 years rrg/m' One unit is for instance obtained as 40 years at 2 5 mg/nv (low exposure), as 10 years of medium exposure, oi as 2 5 yeais m a highly exposed job Other indices char ictensmg the exposure to talc such as the maximal talc e>posure or the duration of exposure and employment were also fitted Smoking, exposure to quartz, or a history cr underground work were fitted as binary exposed versus non-exposed variables to adjust for these variables when (sttmating the effect of exposure to talc. The goodness of fit of the successive models v\as assessed by the likelihood ratio test." No attempt was made to adapt the shape of the exposure-response curve to obtain a better fit given the sparseness of the data. RESULTS Cohort study The French cohort comprised 1070 people, among which 712 subjects contributed person-years to the cohoit before 1968 (101 deaths, 24 lost to follow up, 24 missing causes of death, 9596 person-years) and 945 subjects contributed pet son-years to the cohort from 1968 on (294 deaths, six lost to follow up, five missing causes of death, 19 253 person-years) Fioni the 294 deaths, 268 (9l7o) weie matched with tht tile ol death certificates, 21 were obtained from the doctor, and five remained missing. In the Austrian cohort a totil of 542 men was included, among them 457 still alive and 67 dead at the end of the study period, resulting in 9469 person-yeais w w w occenvmed com Downloaded from oem.bmjjournals com on 12 April 2006 Cohort mortality and nested case-control study of French and Austrian talc workers 101 Table 2 Data (n (%)) description of the non-malignant respiratory diseases case-control study France Austria Administrative information Started employment <1930 1930-1949 35 1950 Cases 15 (38) 16 41) 8(21) Controls 29 (25) 46 (40) 41 (35) Cases 1 (100) - Smoking information Data source* Classification * f Missing information Previous documents Colleagues Non-smoker Light smoker Heavy smoker Smoker$ 3(8) 23 (64) 13 (36) 16(44) 6(17) 14 (39) 22 (19) 53 (55) 43 (45) 40 (43) 16(17) 24 (26) 14(15) 1 (100) _ - _ - - Occupational exposure Missing |ob history 4(3) - Controls - 2(67) 1 (33) 3 100) _ - __ - - Data source Previous documents Colleagues 37 (95) 2(5] 99 (85) 13(11) 1 (100) - 3 100) Employed as Talc exposure Manual worker Office worker Manager None Light Medium Heavy 37 (95) 2(5) 6(15| 6(15) 27 (69) 100 (89) 8(7) 4(4) 26 (22) 12 (10) 22 (19) 56 (48) -1 (100) - -- - 1 (100) 2 66) 1 33) - 1 33) 1 33) 1 33) Other exposures Quartzt Underground work 1 (3) 3(8) 2(2) 7(6) 1 (100) 1 (100) 1 (33) 1 33) Total 39 116 1 3 ` Percentage among subjects with known smoking habits, tas defined in the text, tsrnoker without further information, in France subjects with a history of underground mining in other mines (two cases and five controls], or tunnelling (one case and two controls], in Austria underground talc mining (the case and the control are from site 8] In the early French cohort (before 1968), the SMR from all causes was 0.78 with respect to the population of France, and four deaths from non-malignant respiratory disease were observed compared with 7.16 expected. For lung cancer, one death was observed versus 3 66 expected These figures must be interpreted with some caution as the French mortality rates exceed the local rates as both are available (by 30% for lung cancer) and 24% of the causes of death are missing Table 1 shows the mortality from the mam causes in the recent French cohort and the Austrian cohort. The lower than expected mortality in both cohorts for mortality from all causes and from cardiovascular diseases hints at a healthy worker effect The slight excess in the mortality from non-malignant lespiratory disease in the French cohort can be caused by a significant excess for pneumoconiosis based on three cases. Mortality from non-malignant re .piratory disease is, however, lower than expected in the Austrian cohort No pleural mesothelioma was found in either cohort but the expected number is small. Mortality from lung cancer showed a slight non-significant excess m both cohorts Nested case-control study for non-malignant respiratory diseases Among the subjects who died of non-inahgnam respuaron disease, there were 10 cases of pneumoconiosis (including silicotuberculosis) and 10 chronic obstructive pulmonaiy dis eases (restricted to chronic bronchitis and chronic obstiuction). The 20 other causes included cases cf pneumonia or bronchopneumonia (five cases) and other diseases (six cases) For nine out of the 40 subjects, the cause wa' associated (sec ondary) with the main cause It is to be noted that 39 out of 40 Table 3 Cumulative exposure (y.mg/m3) to talc in the non-malignant respiratory diseases case-control study Non-exposed <100 100-400 400-800 3800 Controls 23 19 32 19 Cases 6 1 8 9 OR 0 22 1 00 1 97 Cumulative exposure totale (O R /100 y mg/m3, 4 0 cases and 15 controls}1 OR 95% Cl All cases 1 08 1 02 to l . Pneumoconiosis 1 17 0 99 to 1 38 COPD 1 02 0 8 to 1 20 22 16 2 53 wvvw occenvmed com Downloaded from oem bmjjournals com on 12 April 2006 102 W ild, Leodolter, Refrgier el al Table 4 Data (n (%)) description of the lung cancer case-control study France Administrative information' Year of hire <1940 940-1959 31960 Cases 5(22) 12 (52) 6(26) Controls 21 (31) 30 (45) 16 (24) Information on smoking Missing information 11 (48) 17(25) Data source* Previous documents Colleagues 9(75) 3(25) 33 (66) 17(34) Classification*! Non-smoker ligh t smoker Heavy smoker Smoker! 1 (8) 2(17) 8(67) 1 (8) 22 (44) 5(10) 16 (32) 7(14) Austria Cases _ 2 (29) 5(71) 5(71) 2 (29) ,, 2 (29) 4(57) 1 (14) Controls _ 8(14) 13 162) - 8(38) 13 62) 12 57) 3(14) 1 (5) 5(24) Occupational exposure information Missing job history Data source Previous documents Colleagues Employed as Manual worker Office worker Manager Exposure to talc None Light Medium Heavy 21 (91) 2(9) 22 (96) 1(4) ~ 6(26) 3(13) 4(17) 10(43) 1 (U 62 (94) 4(6) 53 (80) 11 (17) 2(3) 20 (30) 9 (1 4 ) 8(12) 29 (44) - 7 (100) - 6 (86) 1 (H ) - 3 143) 2 (29) 2 29) - 21 il 00) - 17 181) 4(19) - 3(14) 2(10) 8 (38) 8 (38) Other exposures Q u a rtz! Other carcinogens Underground work 3(13) 2(9) 5(8) 1 (1) 7(11) 4(57) 1 (14) 5(71) 6(29) 4(19) Total 23 67 7 21 -Percentage among sublets with known smoking habits; fas defined in the text, f smoker without further information; in France subjects ro ll a history of underground mining in other mines (two cases and four controls), or tunnelling (three controls), in Austria all underground mining (two casus and four controls in site B, one case and no control in site C, two cases and no control in site D) subjects come from the French cohort. The single Austrian case (from site B, as were his three controls) had ICD code 504 (pneumopathy due to inhalation of other dust). For one case only two conti ols met the matching criteria giving a total of 119 controls. Table 2 describes the general characteristics of the case-control study The information about occupational exposure (list of successively held jobs) had to be obtained by interviewing colleagues for two cases and 13 controls These numbers are lespectively 13 and 43 when considering the smoking information It is noticeable that the smoking distri bution is very similar between cases and controls. The cases were employed earlier than controls, despite the matching on age, and the proportion of subjects ever exposed to a highly exposed job is higher among cases (69%) than among controls (50%). In table 3, the cumulative exposure groups showed an increasing trend, with an excess above 400 years.mg/m!. The statistical modelling of this trend as a continuous linear inde pendent factor without any covariate adjustment gives a significant regiession coefficient. Restricted to the cases from pneumoconiosis and their controls, this trend was clearly highei with ail estimated slope equal to 1.17 (v 1.08 for all non-malignant lespiratory diseases). On the other hand, this trend was barely noticeable (slope 1.02) in the subfile of chronic obstructive diseases. Adjustment on potential confounders did not change this trend to any extent. The OR for quartz (based on two exposed cases and three exposed controls) was equal to 2 4, the OR for smoking was 0.71. No non-smoking subjects exposed to quartz existed in the file so that the simultaneous effect of quartz and smoking could not be estimated. The trend with exposure was found to be slightly higher among smokers, but this inteiaction was not signifi cant. Increasing trends in mortality weie also found, allhough less clearly when considering duration of exposuie, latency, and maximal level of exposure (data not shown) Nested case-control study for lung cancer Table 4 describes the geneial characteristics o' the lung cancel case-control data by country For one case only one contiol met the matching criteria. This gave 88 controls Unfoitunately, given the old age of the cohort, for nearly 50% of the French cases no smoking information could be ascei tamed, whereas such information could be retrieved for all cases and controls in the Austrian study. The classffica ion by smoking is, however, as expected, with only one case out of 19 cases who did not smoke. Year of hire follows the cohort definitions with five cases and 21 controls first employe 1 befoie 1940 in the French study compaied with none in the Austnan studs Out of 30 cases 28 were blue collar workers compared with 70 out of 87 controls Fourteen controls came Irom site B, nvo from site C, foui from site D, and one from site E compared with three cases from site B, one from sue C, two fiom site D, and one fiom site E. The analysis by cumulative exposure to talc (table 5) did not show any increasing tiend The ORs were even lower than unity in the two highest exposure categories Adjusting for smoking, exposure to quartz, or underground work, or any two of these variables did noi change this absence of trend, neither did the lagging of exposuie estimate These analyses showed the expected large OR (OR 11 3, 95% Cl 2 07 to 219) with smoking and an increased, although not signifi cantly so, OR for exposure to quaitz (OR 2 1% 95% Cl 0 74 to w w w occenvmed com Downloaded from oem bmjjournals.com on 12 April 2006 Cohort mortality and nested case-control study of French and Austrian talc workers 103 Table 5 Cumulative exposure (y.mg/m3) to talc in the lung cancer case-control study Non-exposed o o V/ ICHMOO 400-800 >800 Controls 23 18 15 21 10 Cases 9 OR 6 0 86 7 1.07 5 0 60 3 0 73 Cumulative exposure to talc ( 30 cases and 87 controls} O R /100 y mg/m3 95% Cl 0 98 0 88 to 1 10 6.45). When adjusting both for smoking and quartz, quartz became significant No interaction with smoking could be fit ted given that only one non-smoking case was included. The results from analysis of the French cohort alone12did not dif fer from the present results to any extent DISCUSSION Few mortality studies among talc workers have been published. Although the mortality from non-malignant respi ratory disease was increased in most of the cohorts, the only cancer risks in the talc industry were reported in early Ameri can studies among miners and millers. In 1974 Kleinfeld et aln reported about a proportional mortality study that included 260 workers from New York State. Out of 108 deaths, 27% were due to pneumoconiosis, and there was one case of peritoneal mesothelioma. An excess in risk of lung cancer was noted the 13 cases of lung cancer constituted 12% of all deaths compared with an expected 3.7% based on 1955 United States rates. Risk did not show any association with duration of employment. Reviews of this study214 came to the conclusion that due to lack of infoimation on smoking or on cumulative exposure in individual workers, and due to the fact that the authors used national lung cancer rates for compari son, a firm interpretation of an increased risk of lung cancer cannot be made from this study.14There were four successive studies conducted among miners and millers in the Gouverneur talc district of upper New York State,15"'* who mined and milled a natural mixture of minerals consisting of 45% tremolite, 25% serpentine, 25% talc, and 5% anthophyllite." Although the three first follow up studies of this population found an excess mortality from lung cancer, the last study showed that this excess was found only among workers employed for less than 1 year. The authors concluded that the lack of an exposure-response gradient in their findings is not consistent with a causal relation and that the time of occurrence of lung cancer among the talc workers is more congruent with a smoking than a talc aetiology.1" A study investigating 392 miners and millers m Vermont talc mines2" (50%-90% talc, 7%-9% chlorite, and 2%-18% magnesite1*) reported an increased usk of lung cancer for miners but not for millers although millers were thought to have higher exposure concentrations. The investigators mentioned several potential factors--for which no further information was available--possibly having an impact on risk (exposure to ladon, smoking, previous work in another talc mine). The American Thoiacic Society concluded that the results of this study did not show any risk of lung cancer related to exposure.14Another study of a large cohort among Italian talc (47%-86% talc, 10%-40% chlorite, dolomite, and magnesite1' ) miners21 found no evidence for an excess risk of cancer. The authors attributed the increased risk of pneumoconiosis to e x p o su ie to silica. A previous, stu d y o f a co h o rt o f w ork ers from the French site A included in our cohort," showed a sig nificant increase in mortality for non-malignant respiratory diseases but no significant excess in cancer mortality. A study by Wergeland et aln did not report any excess risk for lung cancer in a cohort of 389 talc (55% talc, 11% chlonte, 29% magnesite1*) mineis and millers Fuitheimoie, a usk louci than unity was found for non-malignant respnatory diseases In summary, none of the studies already mentioned was able to prove an increased risk of lung cancer among nnneis and millers, reliably attributable to exposuie to talc, wheieax the risk for non-malignant respiratory diseases was in excess m most of the study sites. There are also leports of studies of talcexposure other than in the mining industry In 1987, a study on talc exposure m the manufacture of ceramic plumbing fix tures was published25 The authors found a significantly increased risk for lung cancer that showed a rend with duiation of employment in "non-fibrous talc" jobs There was no increased risk for lung cancer either among non-talc workeis nor among "fibrous talc" workers A lecent study among workeis m the rubber industry24suggested that the mcieased mortality found from lung and stomach cancc r was associated with exposure to asbestos and talc dust, which were raw materials used in this industry. None of the preceding studies attempted to investigate dose-response relations and few gave any quantitative level of exjrosure Our study is a first attempt to measuie the usk associated with exposures to different concentrations of talc dust, while adjusting for possible confounoers This would increase the relatively small statistical power m delecting a dose-response relation, which is an essential pan of a discus sion of causality. The strength of the conclusions to be drawn fiom such a study depends however, apart from the stat.stical powei, on the validity of the information collected The diffeient aspects to be discussed are cohort selection, causes of death, exposuie assessment, and confounder information In our study we included by design only hose employees who had worked for the company foi at leasi 1 year continu ously. This mainly had the effect of excluding the seasonal workers in the French cohort This population was excluded for several reasons Firstly, this population consists mostly of foreigners (Spam, north Africa) who did not live in France during the winter season and whose mortality would have been comparable neither with the local pojiulation nor the population of millers. Secondly, the mortalm of this popula tion would have been nearly impossible to trace and the causes of death would have been difficult to obtain Thirdly, from a more fundamental point of view, the mortality of short term workers is always difficult to interpret2 as the nonoccupational characteristics including personal lifestyle uie usually different from long term workers and can confound a dose-response relation. An already mentioned example is the study by Gamble1" who showed that the risk of lung cancel was increased only in short term workers, wh ch he attributed to smoking and other influencing factors ratkei than to expo sure to talc. The causes of death were mostly based on death certificates, which are probably more reliable in Austna given the high rate of postmortem examinations in this country2, Misclassification occurred certainly within the group of nonmalignant respiratory disease, and some deaths fiom nonmalignant respiratory disease and even lung i ancer may have been misclassified. Moreover, no cause of deat i could be found for 24 deaths in the early French cohort This may have biased the SMR although the same misclassification occurred m the population rates. However, it is unlikely that diagnosed lung cancers or non-malignant respiratoiy disease were in fact other causes. Therefore if some cases were net diagnosed, the risk set sampling paradigm ensures that this results in a loss of statistical power but not in bias This contusion relies on the assumption that the not-diagnosed cases had similai exposure to the diagnosed cases The validity o f the exposure assessment as ve implemented it, depends on the one hand on the preciseness of the job his tories and on the other hand on the industry specific JEM Although the job histories from the Austrian data can ieasonably be relied on as individual job histones weie kept in the ww n occenvmed com Downloaded from oem bmjjournals com on 12 April 2006 104 W ild, leodolter, Refregier, et al company files, the French data are more questionable as they relied mostly on data from former studies m the early 1980s ` The individual work histories recorded in 1980 relied even at that time on rather ancient memories. The French work histones only rarely recorded more than one job and when several jobs were mentioned, no time scale could be assessed. However, the possible misclassifications should not result in large quantitative misclassifications. The same (high) exposure level was attributed to nearly all earlier production woikers by the JE M , only some specific jobs such as maintenance workers were assigned medium exposures and some offsite jobs (cook or work at the power station) were considered to be non-exposed The likelihood of misclassification between these broad categories is therefore low. The JE M has been kept deliberately coarse with only four categories which span considerably different exposures. The concentra tions assigned are to a certain extent arbitrary as only the two lower exposure levels could be calibrated by actual exposure measurements. The concentrations chosen (2.5 mg/m' for light exposure and 10 mg/m' for medium exposure) were higher than the mean of the exposure measurements, but it was thought that even within these categories, the working conditions had already improved at the end of the 1980s when the measurements were taken The most arbitrary concentra tion is, however, the 40 mg/m' assigned to the high exposure category, which only relied on some measurements made in high exposure circumstances which still happened occasion ally in the 1980s. However, given that such circumstances were the rule rathei than the exception m earlier times, the mean exposure in these highly exposed jobs was certainly above 30 mg/m!. On the other hand, it probably did not exceed 60 mg/m' except in some very specific tasks such as cleaning jute bags of milled talc. It is none the less safer to interpret a value of 400 years.mg/m' as 40 years of the present standard of high exposure oi 10 years of extreme exposure. A retrospective validation of the exposure assessment is that it enabled the detection of a dose-resjionse relation for mortality from nonmalignant respiratory diseases despite a mortality that was only slightly above the expected The last possible validity issue refers to the confounder information which is mainly smoking m this study and is dis cussed with its effect on the results of the case-control studies. As already stated, the clearest result of this study was the significant dose-response relation between cumulative expo sure to talc and moitality from non-mahgnant respiratory diseases This dose-response relation is due to the large odds ratios in the categories above 400 years.mg/m'. However, given the uncertainty in the exposure assessment and the relative small data set, this value can hardly be interpreted as a threshold under which no risk exists. It is to be noted that this dose-response relation is high for the study of pneumoconio sis but virtually undetectable in the analysis restricted to chronic obstructive pulmonary disease. This may indicate that high exposure to talc dust is fibrogenic27 but does not cause obstructive syndromes This agrees also with findings in Wild el aP in which a restrictive syndrome rather than an obstiuctive syndrome was found. It is not clear however whether this effect is specific to talc. An alternative explanation has been forwarded a hypothesis coined as "par ticle overload",28 states that the pulmonary clearance by the alveolar macrophages is inhibited by high exposure to highly insoluble, but non-cytotoxic, particles. Oberdorster concluded from an experimental 2 year inhalation study2' that "talc par ticles behave like other low-toxicity particles such as TiO, or toner with respect to lung clearance and chronic pulmonary inflammation" A somewhat surprising result of the analysis is the low risk of smoking. It might be that subjects with chronic respiratory problems stop smoking earlier or do not take up smoking at all. This hypothesis is all the more plausible as information on smoking has often been obtained from relatives or colleagues and some former smokers might be misclassified as nonsmokers. However when restricting the analysis to chronic obstructive pulmonary disease, the expected risk from smok ing was O R = 2 .1. The risk from smoking was also found in the lung cancer study. It is therefore unlikely that the low smok ing OR is due to a major misclassification in the data collection for smoking The analyses of the case-control studies on lung cancel did not find any dose-response lelation, be it b/ maximal dose, latency, duration of exposure, oi cumulativ exposuie Tim fact, as well as the lower risk in exposed thar in non-exposed blue collar workers, indicates that the slight excess found in the cohort study is unlikely to be due to the exposure to talc It is also unlikely that this finding is due to e cposure misclas sification, as already discussed However, this negative finding must be interpreted in the context of the relatively low powei of this study. A formal evaluation of the power is not feasible as our analysis relied mostly on an inteinal estimation of a dose-response relation However, despite all the uncei tainties surrounding the trend estimate, the upper confidence level of this estimate indicates the approximate levels of risks excluded by our study. Thus a risk of lung cancer higher than 1.10/100 years.mg/m! is unlikely It must be fuithei stressed that this result is obtained m a cohort followed up over 50 years with considerable exposure and with a i lean duiation of employment exceeding 20 years, in which a not too obvious trend for non-mahgnant respiratory diseases could be shown There might be some residual confounding due to exposure to quartz especially in the Austrian site D as this exposure could not be measured Given that this site contributed only two cases, this should not be a majoi confounder Moieovei restricting the analysis to the subfile of sites A and B, foi which the exposure was qualitatively close, did not change the results. In the subfile with known smoking ha ins the adjusted and non-adjusted ORs were similar, which hints at an absence of confounding, but does of course not indicate whether the smoking distribution is similar among subjects with or with out the smoking information The missing smoking inhu mation in nearly a third of the cases remains the main weak ness of this study on lung cancer. CONCLUSIONS For highly exposed subjects, the mortality from nonmahgnant respiratory diseases seems to increase with cumu lative exjrosure to talc This contrasts with the absence of am dose-response relation for lung cancel ACKNOWLEDGEMENTS We thank Dr Daniela Karimian-Teherani lor critically reviewing the manuscript, and Drs Annette Leclerc and Sylvaine ( oidier for helpful discussions Authors' affiliations P W ild , Institut Nahonal de Recherche et de Scurit (NRS), Departement Epidmiologie, Vandoeuvre, France K Leo d o lte r, Austrian W orkers' Compensation Board AUVA), Graz, Austria M R frgier, Occupational M edicine, Talc de Luzenac, Luzenac, France H S chm idt, Occupational medicine, Luzenac Naintsch Graz, Austria T Z id e k , G H a id in g e r, Division of Epidemiology, Instrule of Cancer Research, University of Vienna, Vienna, Austria REFERENCES 1 Rohl AN, Langer AM, Selikoff IJ, et al Consumer talcums and powders mineral and chemical characterization J Toxicol Envi on Health 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The talc inhalation study a critical appraisal focused on lung partcle overload Regul Toxicol Pharmacol 1995 27 223-41 Click on the "Top 10" button on the homepage to see which are the best read articles each month www.occenvmed.com www occenvmed com