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FILE NAME Talc TALC DATE 2002 DOC TALC176 DOCUMENT DESCRIPTION Journal Article - A Cohort Mortality and Nested 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 control study of French and Austrian talc workers P Wild K Leodolter M R^'fr^'gieHr Schmidt Zidek G Haidinger See end of article for authors affiliations Correspondence to Dr P Wild Avenue de Bourgogne BP n 27 54501 Vandoeuvre Cedex France Accepted 8 August 2001 Occup Environ Med 2002,59 98 105 Objectives To study whether the mortality from 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 subjects who had been working continuously 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 control studies focusing on malignant and malignant respiratory diseases were set up to estimate possible response relations with cumulative exposure to talc dust based on an industry specific job 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 CI 0 76 to 189 189 Austria SMR 1 06 seven observed 95 CI 0.43 to 2.19 A significant excess mortality was found for all nonmalignant respiratory diseases in the French cohort due to a significant excess for pneumoconiosis SMR 5.56 three observed 95 CI 1.12 to 16 2 The control study of malignant respiratory disease showed an increased mortality in the highest exposure groups odds ratio OR 25 25 for a cumulative exposure 80y0.mg/mwith a significant trend 100 y mg 108 108 with cumulative exposure to talc On the contrary no increasing trend could be found in the control study of lung cancer This result must be interpreted considering the small cohort size Adjustment on smoking and exposure to quartz did not influence these results to any extent Conclusions The mortality from malignant respiratory disease was found to be related to high cumulative exposure to talc dust The small excess in lung cancer does not seem to be attributable to talc is mined in many countries and processed in Tnumerous manufacturing industries for use in paints ceramics rubber products roofing materials papei in- secticides cosmetics and pharmaceuticals Talc MgSi 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 particles 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 milled some cleavage fragments less than % within the talc powder meet the World Health Organisation WHO definition 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 residues so that the mined and milled ore hardly ever consists of pure talc Exposure to talc must therefore be considered bearing in mind the coexposures which quartz is the most important to each site It 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 performed among workers from the talc industry reported inconclusive results concerning an increased risk of neoplasms of the respiratory system Although the risk of 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 inineral or other features of the cohorts In this paper we report the results of two ustorical cohort mortality studies conducted in the Austrian and the French talc industries and of two nested control studies focused on malignant and malignant respiratory diseases METHODS Industrial sites and exposure assessment The French site site A is in the French Pyrenees The ore 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 nearby talc mill Quartz contamination is low from detectable to less than % The Austrian sites comprise three mines sites B C and D with their respective mills in the Styrian Alps and a head office in the city of Graz site E The ore mined in ite B consists of a chlorite mixture with dead rock inclusions of about 25 mainly gneiss The dead 1ock is dumped in the mine so that the milled product is chlorite and contains from 0 % to % quartz In site C the material mined was a dolomite aggregation with a medium talc content of 25 The percent- age of quartz in the end products was below % singular parts Abbreviations SMR standardised mortality ratio IC international classification of diseases JEM job exposure matrix www.occenvmed www.occenvmed com Downloaded from oem bmjjournals.com on 12 April 2006 Cohort mortality and nested control study of French and Austrian talc workers 99 in the mine ich in dolomite could contain -3 quartz In site D a light greyish quartz chlorite mica schist leucophylite 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 JEM 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 JEM 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 measurements carried out in 1986-7 in the French site A on less systematic measurements in 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 were 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 al The assignment of the workplaces to the four semiquantitative levels was done as follows @ No exposure to talc was coded for office workers A mean dust concentration of 02 02 mg based on 168 measurements was obtained in 1986 in 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 exposure lower than 5 mg 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 confinement or local exhaust ventilation Eight jobs were in this category in the French site in 1986 mean exposures ranged from 05 to 26 mg the range of the 100 exposure measurements carried out that year was 0 11-17 mg 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 In site C 33 measurements in 1991-2 ranged from 0.02 to 4 1 mg An exposure higher than 30 mg 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 in 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 Such measurements were described as quite common in the job periods attributed to the highest category Three measurements of the exposure in such situations were identified in Austria from the workers wearing individual protective equipment to be 73 82 and 159 mg A medium exposure between 5 and 30 mg was coded for all jobs which did not enter the preceding categories This included the more recent French production workers in the dustier areas such as bagging or milling the onsite maintenance workers or in the early days some workers in jobs near very dusty areas such as the oven workers 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 French site A with measured mean exposures from 3.6 to 256 256 mg range of the 193 exposure measurements vas 021 to The 134 mg In Austria 17 measurements were made in site B and eight in site C ranging between 6 5 and 19 6 m The main other exposure that was assessed was quartz which occurred mostly in underground mining tunnelling and barrage building but also while milling minerals that contained quartz as in site D. More precisely st bjects were said to be exposed to quartz if they were employed in mining or milling of leucophylite Austrian site D 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 in sites with known exposure to quartz or tunnelling or barrage building in the Pyrenees 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 year between 1 January 1945 and 31 December 1994 It comprised all staff of the milling site including administrative workers and executives Most of the subjects employed at the quarry were excluded because due to the high altitude he quarry runs only during summer A few workers were employed in the winter also and were thus included in the cohort The data were abstracted from 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 1 January 1945 and 31 December 1996 The vital status of all subjects was assessed by contacting the registry offices of the respective birth places and by searching a computerised data base of all people who hac died in France since 1978. An individual tracing procedure was set up for all foreign born subjects The cause of death was determined 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 ICD until 1978 and ICD the eafter For all subjects who died before 1968 we relied on the causes of ' death obtained from an earlier mortality study The Austrian cohort The Austrian cohort consisted of all male workers employed continuously for at least 1 year between 1 January 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 are only available in a computerised form since that year We used two sources of information for the subjec s private and employment data the company's registries and the catalogues of the regional social insurance fund VADOeB Complete work histories within the company were ava lable The vital status of all subjects and if no longer alive the dates and causes of death within the study period were assessed by matching the subjects names and their dates of birth with the national mortality data set from Statistics Austria coded with ICD until 1979 and ICD thereafter The control study Following Breslow and Day we considered the nested control study as a Cox model with time variable age in which the controls are sampled from the risk set With this approach the risk set of a given case consisted of all subjects www.occenvmed www.occenvmed com Downloaded from oem bmjjournals com on 12 April 2006 100 Wild Leodolter Refr^'gieret al Table 1 Observed Obs and expected Exp numbers of deaths standardised mortality ratios SMRs 95 CI of the | main causes of death by cohort . French cohort Austrian cohort | Cause of deatht All causes Cardiovascular system malignant respiratory diseases Pneumoconiosis Digestive tract All cancers Stomach cancer Mesothelioma Lung cancer Violent death Obs Exp SMR 95 Cl Obs Exp SMR 95 Cl 294 3175 0.93 0 82 1 04 52-007 89 4 075 58 95 106 1137 0.93 0.76 to 13 52-007 329 061 0 37 to 94 I 26 24 106 0.69 to 1.55 52-07 3 05 556 556 1,12 to 16 2 52-007 14 171 0.82 0 45 to 1 38 52-007 37 027 001 to 52 | 01 - - , 87 104 48 to 197 183022 784 102 081 to 127 127 17 23 073 42 17 183022 43 118 0.38 to 2 75 - 25 0 40 001 to 25 183022 03 - = ON 01 - - 183022 170 123 076 07to61 89 ON 66 106 43 to 19 \ 183022 261 261 84 0 53 to 1.28 15 131 14 0 64 to 1 88 | In the 1968-96 period by comparison with local rates coded according to the ICD and ICD ; 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 control studies were thus set up @ The lung cancer 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 malignant respiratory diseases included all deaths with ICD codes 10.9 silicotuberculosis or 460 0 to 519.9 or ICD codes 460 0 to 519.9 for their main or asso- ciated causes of death In Austria the work histories could be abstracted from company records 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 control status on the basis of existing documents or when the information was missing by contacting former colleagues 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 For the French cohort the local d^'partementde l'Ari^gel'Ari^geand 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 at risk for each member of the respective cohort starting with the first anniversary after entering employment or | 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 % 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 of death Standardised mortality ratios SMRs were 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 control studies The work histories were combined with the job exposure matrix to obtain individual estimates of cumulative cumulative exposures Assigning concentrations of 2.5 mg for jobs with low exposure 10 mg for medium exposure and 40 mg for high exposure the cumulative exposure was obtained by summing all job periods the product of the duration of exposure by the assigned concentrations This was done unti death for the cases and for the controls until the age at which the corresponding case died To account for the latency period of lung cancer a second lagged estimate of the cumulative exposure was obtained by summing the exposure until 10 years before the age at death of the case The statistical analysis was done by concitional logistic regression which takes into account the matching structure This was especially important because for two cases less than three controls were available in the risk set so that an unequal number of controls were sampled by case Moreover missing confounder information especially smoking also gave unequal numbers of controls per case when adjusting for them As the main 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 exposure to tak dust was transformed into units of 100 years mg One unit is for instance obtained as 40 years at 25 mg low exposure as 10 years of medium exposure or as 25 years in a highly exposed job Other indices characterising the exposure to talc such as the maximal talc exposure exposure or the duration of exposure and employment were also fitted Smoking exposure to quartz or a history or underground work were fitted as binary exposed versus exposed variables to adjust for these variables when stimating the effect of exposure to talc The goodness of fit of the successive models was assessed by the likelihood ratio test No attempt was made to adapt the shape of the exposure 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 to the cohort before 1968 101 deaths 24 lost to follow up 24 missing causes of death 9596 person and 945 subjects contributed person to the cohort from 1968 on 294 deaths six lost to follow up five missing causes of death 19 253 person From the 294 deaths 268 91 were matched with the file of death certificates 21 were obtained from the doctor and five remained missing In the Austrian cohort a total of 542 men was included among them 457 still alive and 67 dead at the end of the study period resulting in 9469 person www.occenvmed www.occenvmed com Downloaded from oem.bmjjournals com on 12 April 2006 Cohort mortality and nested control study of French and Austrian talc workers 101 [ | Table 2 Data n % description of the malignant respiratory diseases control study France Austria Cases Controls Cases Administrative information Started employment 1930 1930-1949 1950 15 38 16 41 81211 81211 29 25 46 40 41 35 - | 100 - Controls - 2167 2167 1 33 Smoking information Missing information 38 22 19 1 100 3100 3100 Data source Previous documents 23 64 53 55 - Colleagues 13 36 43 45 - * Classification smoker Light smoker Heavy smoker Smokert 16 44 40 43 1 | 6 17 16 17 1 | 14 39 24 26 1 | | - 14 15 1 | Occupational exposure Missing job history 43 1 I Data source Employed as Talc exposure Previous documents Colleagues Manual worker Office worker Manager None Light Medium Heavy 37 95 25 37 95 25 1 6115 6115 - 6115 6115 27 69 99 85 13 11 100 89 87 44 26 22 12 10 22 19 56 48 1 100 - 1 100 1 1 1 1 1 100 3 100 ~ 2'66 2'66 13 133 13 133 13 133 13 133 Other exposures Quartzt 13 Underground work 38 22 76 1 100 1 100 1 33 13 133 Total 39 116 1 3 Percentage among subjects with known smoking habits tas defined in the text #smoker without further information inFrance 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 B 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 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 main 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 malignant respiratory disease in the French cohort can be caused by a significant excess for pneumoconiosis based on three cases Mortality from malignant respiratory respiratory 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 significant excess in both cohorts Nested control study for malignant respiratory diseases Among the subjects who died of malignant respiratory disease there were 10 cases of pneumoconiosis including silicotuberculosis and 10 chronic obstructive pulmonary diseases restricted to chronic bronchitis and chronic obstruction The 20 other causes included cases of pneumonia or bronchopneumonia five cases and other diseases six cases For nine out of the 40 subjects the cause was associated secondary with the main cause It is to be noted that 39 out of 40 Table 3 Cumulative exposure y.mg/mto talc in the malignant respiratory diseases control study exposed 100 100-400 400-800 800 Controls 23 Cases 6 | OR i Cumulative exposure to talc i ' All cases " Pneumoconiosis COPD 19 32 1 8 022 1.00 100 y mg 40 cases and OR 108 17 102 19 q 197 115 controls 95 Cl 02 to 099 to 0 86 to 1.16 1 38 1 20 22 16 2 53 www.occenvmed www.occenvmed com Downloaded from oem bmjjournals com on 12 April 2006 102 Wild Leodolter Refr^'gier al Table 4 Data n % description of the lung cancer control study France Austria : Administrative information Year of hire 1940 1940-1959 1960 Cases Controls Cases Controls | 5 22 21 31 - - ! 12 52 30 45 2 29 8 14 61261 61261 16 24 5 71 13:62 13:62 Information on smoking Missing information 11 48 17 25 j - Data source | Previous documents 9 75 33 66 5 71 8 38 Colleagues 3 25 17 34 2129 2129 13 62 | Classification smoker Light smoker Heavy smoker Smokert 18 22 44 ~ 12 57 2 17 5 10 2 29 3 14 | 8 67 16 32 4 57 15 18 7 14 1 14 5 24 Occupational exposure information Missing job history - 1 - - | Data source Employed as Exposure to talc Previous documents Colleagues Manual worker Office worker Manager None Light Medium Heavy 21 91 62 94 7 100 21/100 21/100 2191 2191 46 - - ' } 22 96 53 80 6186 6186 1781 1781 ; 14 11 17 14 4 19 | - 23 - - | 6 26 20 30 3 43 3 14 ; 3 13 9 14 - 2 10 4 17 8 12 2 29 8 38 10 43 29 44 2 29 8 38 : Other exposures Quartzt Other carcinogens Underground work 3 13 - 29 58 1 7 11 4 57 1 14 5 71 6 29 - 4 19 Total 23 67 7 21 | Percentage among subjects with known smoking habits as defined in the text smoker without further information inFrance subjects with a history of underground mining in other mines two cases and four controls or tunnelling three controls in Austria all underground mining two cases 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 controls met the matching criteria giving a total of 119 controls Table 2 describes the general characteristics of the 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 respectively 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 exposejodb 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/mThe statistical modelling of this trend as a continuous linear independent factor without any covariate adjustment gives a significant regression coefficient Restricted to the cases from pneumoconiosis and their controls this trend was clearly higher with an estimated slope equal to 1.17 v 1.08 for all malignant respiratory diseases On the other hand this trend was barely noticeable s ope 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 24 24 the OR for smoking was 0.71 No 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 interaction was not significant Increasing trends in mortality were also found although less clearly when considering duration of exposure latency and maximal level of exposure data not shown Nested control study for lung cancer Table 4 describes the general characteristics of the lung cancer control data by country For one case only one control met the matching criteria This gave 88 controls Unfortunately given the old age of the cohort for nearly 50 of the French cases no smoking information could be ascertained whereas such information could be retrieved for all cases and controls in the Austrian study The classifica 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 employei before 1940 in the French study compared with none in the Austrian study Out of 30 cases 28 were blue collar workers compared with 70 out of 87 controls Fourteen controls came from site B two from site C foui from site D and one from site E compared with three cases from site B one from site C two from site D and one from site E. The analysis by cumulative exposure to talc table 5 did not show any increasing trend 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 not change this absence of trend neither did the lagging of exposure estimate These analyses showed the expected large OR OR 213 213 95 CI 2 07 to 219 with smoking and an increased although not significantly so OR for exposure to quartz OR 2 19 95 CI 0 74 to www.occenvmed www.occenvmed com Downloaded from oem bmjjournals.com on 12 April 2006 Cohort mortality and nested control study of French and Austrian talc workers 103 Table 5 Cumulative exposure y.mg/mto talc in the lung cancer control study exposed 100 100-400 400-800 800 Controls 23 18 15 21 10 Cases 9 6 7 5 3 OR | 086 086 1.07 060 060 073 Cumulative exposure to talc ( 30 cases and 87 controls 100 y mg 95 CI 098 0 88 to 1 10 6.45 When adjusting both for smoking and quartz quartz became significant No interaction with smoking could be fitted given that only one smoking case was included The results from analysis of the French cohort alone did not dif- fer from the present results to any extent DISCUSSION Few mortality studies among talc workers have been published Although the mortality from 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 al 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 study came to the conclusion that due to lack of information on smoking or on cumulative exposure in individual workers and due to the fact that the authors used national lung cancer rates for comparison a firm interpretation of an increased risk of lung cancer cannot be made from this study There were four successive studies conducted among miners and millers in the Gou- verneur talc district of upper New York State who mined and milled a natural mixture of minerals consisting of 45 tremolite 25 serpentine 25 talc and % 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 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 A study investigating 392 miners and millers in Vermont talc mines -90 talc -9 chlorite and -18 magnesite reported an increased risk of lung cancer for miners but not for millers although millers were thought to have higher exposure concentrations The investigators mentioned several potential factors which no further information was available having an impact on risk exposure to iadon smoking previous work in another talc mine The American Thoracic Society concluded that the results of this study did not show any risk of lung cancer related to exposure Another study of a large cohort among Italian talc -86 talc -40 chlorite dolomite and magnesite miners found no evidence for an excess risk of cancer The authors attributed the increased risk of pneumoconiosis to exposure to silica A previous study of a cohort of workers from the French site A included in our cohort showed a sig- nificant increase in mortality for malignant respiratory diseases but no significant excess in cancer mortality A study by Wergeland et al did not report any excess risk for lung cancer in a cohort of 389 talc 55 talc 11 chlonte 29 magnesite miners and millers Furthermore a risk lower than unity was found for malignant respiratory diseases In summary none of the studies already mentioned was able to prove an increased risk of lung cancer among miners and millers reliably attributable to exposure to talc whereas the risk for malignant respiratory diseases was in excess in most of the study sites There are also reports of studies of talc exposure other than in the mining industry In 1987 a study on talc exposure in the manufacture of ceramic plumbing fixtures was published The authors found a significantly increased risk for lung cancer that showed a rend with duration of employment in fibrous talc jobs There was no increased risk for lung cancer either among non workers nor among fibrous talc workers A recent study among workers in the rubber industrysuggested that the increased mortality found from lung and stomach cancer cancer 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 response relations and few gave any quantitative level of exposure Our study is a first attempt to measure the usk associated with exposures to different concentrations of talc dust while adjusting for possible confounders This would increase the relatively small statistical power in detecting a response relation which is an essential part of a discussion of causality The strength of the conclusions to be drawn from such a study depends however apart from the statistical power on the validity of the information collected The different aspects to be discussed are cohort selection causes of death exposure assessment and confounder information In our study we included by design only hose employees who had worked for the company for at least 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 Spain north Africa who did not live in France during the winter season and whose mortality would have been comparable neither with the local population nor the population of millers Secondly the mortality of this population 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 interpret as the nonoccupational characteristics including personal lifestyle are usually different from long term workers and can confound a response relation An already mentioned example is the study by Gamble who showed that the risk of lung cancer was increased only in short term workers wh ch he attributed to smoking and other influencing factors rather than to exposure to talc The causes of death were mostly based on death certificates which are probably more reliable in Austria given the high rate of postmortem examinations in this country Misclassification occurred certainly within the group of nonmalignant respiratory disease and some deaths from nonmalignant respiratory disease and even lung cancer may have been misclassified Moreover no cause of deat 1 could be found for 24 deaths in the early French cohort This may have biased the SMR although the same misclassification occurred in the population rates However it is unlikely that diagnosed lung cancers or malignant respiratory disease were in fact other causes Therefore if some cases were not diagnosed the risk set sampling paradigm ensures that this results in a loss of statistical power but not in bias This conclusion conclusion relies on the assumption that the diagnosed cases had similar exposure to the diagnosed cases The validity of the exposure assessment as ve implemented it depends on the one hand on the preciseness of the job histories and on the other hand on the industry specific JEM Although the job histories from the Austrian data can reason- ably be relied on as individual job histories were kept in the www.occenvmed www.occenvmed com Downloaded from oem bmjjournals com on 12 April 2006 104 Wild Leodolter R^'fr^'gieret al company files the French data are more questionable as they relied mostly on data from former studies in the early *" 1980s The individual work histories recorded in 1980 relied even at that time on rather ancient memories The French work histories 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 workers by the JEM 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 exposed The likelihood of misclassifica- tion between these broad categories is therefore low The JEM 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 for light exposure and 10 mg 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 concentration is however the 40 mg assigned to the high exposure category which only relied on some measurements made in high exposure circumstances which still happened occasionally in the 1980s However given that such circumstances were the rule rather than the exception in earlier times the mean exposure in these highly exposed jobs was certainly above 30 mg On the other hand it probably did not exceed 60 mg 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/mas 40 years of the present standard of high exposure of 10 years of extreme exposure A retrospective validation of the exposure assessment is that it enabled the detection of a response 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 in this study and is dis- cussed with its effect on the results of the control studies As already stated the clearest result of this study was the significant response relation between cumulative exposure to talc and mortality from malignant respiratory diseases This response relation is due to the large odds ratios in the categories above 400 years.mg/mHowever 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 response relation is high for the study of pneumoconioSis but virtually undetectable in the analysis restricted to chronic obstructive pulmonary disease This may indicate that high exposure to talc dust is fibrogenic but does not cause obstructive syndromes This agrees also with findings in Wild et al in which a restrictive syndrome rather than an obstructive 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 particle overload states that the pulmonary clearance by the alveolar macrophages is inhibited by high exposure to highly insoluble but cytotoxic particles Oberdorster concluded from an experimental 2 year inhalation study that talc particles behave like other 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 smoking was OR The risk from smoking was also found in the lung cancer study It is therefore unlikely that the low smoking OR is due to a major misclassification in the data collection for smoking The analyses of the control studies on lung cancer did not find any response relation be it by maximal dose latency duration of exposure or cumulative exposure This fact as well as the lower risk in exposed thar in 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 exposure exposure misclassification as already discussed However this negative finding must be interpreted in the context of the relatively low power of this study A formal evaluation of the power is not feasible as our analysis relied mostly on an internal estimation of a response relation However despite all the uncertainties 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 years.mg/mis unlikely It must be further stressed that this result is obtained in a cohort followed up over 50 years with considerable exposure and with a ean duration of employment exceeding 20 years in which a not too obvious trend for malignant 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 major confounder Moreover restricting the analysis to the subfile of sites A and B for which the exposure was qualitatively close did not change the results In the subfile with known smoking habits habits the adjusted and 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 without the smoking information The missing smoking information in nearly a third of the cases remains the main weakness of this study on lung cancer CONCLUSIONS For highly exposed subjects the mortality from nonmalignant respiratory diseases seems to increase with cumu- lative exposure to talc This contrasts with the absence of any response relation for lung cancer ACKNOWLEDGEMENTS We thank Dr Daniela Kar~-m~-afon r critically reviewing the manuscript and Drs Annette Leclerc and Sylvaine ( oidier for helpful discussions Authors affiliations P Wild Institut National de Recherche et de Securite NRS Departement Epid^'miologieVandoeuvre France K Leodolter Austrian Workers Compensation Board AUVA Graz Austria M R^'fr^'gieOrccupational Medicine Talc de Luzenac Luzenac France H Schmidt Occupational medicine Luzenac Naintsch Graz Austria T Zidek G Haidinger Division of Epidemiology Institute 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 1976,2 255-84 2 International Agency for Research on Cancer IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans Silica and some Silicates Lyon France IARC 1987 IARC Mor ographs Volume 42 3 Wild P Refregier M Auburtin G et al Survey of the respiratory health of the workers of a talc producing factory Occup Environ Med 1995 52 470-7 www.occenvmed www.occenvmed com 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The talc inhalation study a critical appraisal focused on lung partcle overload Regul Toxicol Pharmacol 1995 27 223-41 BA Bary aS igi 8 Click on the Top 10 button on the homepage to see which are the best read articles each month www.occenvmed.com www.occenvmed www.occenvmed com