Int. J. Cancer: 122, 183–189 (2008) ' 2007 Wiley-Liss, Inc.
Risk of lung cancer following exposure to carbon black, titanium dioxide and talc: Results from two case–control studies in Montreal Agnihotram V. Ramanakumar1,3, Marie-Elise Parent1,2, Benoit Latreille2 and Jack Siemiatycki1,3* 1 Centre de recherche du CHUM, Universit e de Montr eal, Montr eal, Queb ec, Canada 2 INRS-Institut Armand-Frappier, Universit e du Queb ec, Laval, Queb ec, Canada 3 D epartement de m edecine sociale et pr eventive, Universit e de Montr eal, Montr eal, Queb ec, Canada The International Agency for Research on Cancer (IARC) recently evaluated the carcinogenicity of three poorly soluble weakly-toxic substances: carbon black, titanium dioxide and talc. Though there is evidence of carcinogenity in experimental animals for these substances, the evidence in humans is sparse and equivocal. In the context of two large population based case–control studies of lung cancer carried out in Montreal, we were able to study the possible relationships between the exposure to each of these substances and subsequent risk of lung cancer. We were able to distinguish talc used for industrial purposes from that used for cosmetic purposes. Interviews for Study I were conducted in 1979–1986 (857 cases, 533 population controls, 1,349 cancer controls) and interviews for Study II were conducted in 1996–2001 (1,236 cases and 1,512 controls). Detailed lifetime job histories were elicited, and a team of hygienists and chemists evaluated the evidence of exposure to a host of occupational substances. Lung cancer risk was analysed in relation to each exposure, adjusting for several potential confounders, including smoking. Subjects with occupational exposure to carbon black, titanium dioxide, industrial talc and cosmetic talc did not experience any detectable excess risk of lung cancer. The results are consistent with the recent evaluations of the IARC Monographs. ' 2007 Wiley-Liss, Inc. Key words: lung cancer; carbon black; talc; titanium dioxide; case– control studies; Canada; occupational risks; chemical hazards
Lung cancer remains the leading cause of cancer deaths in Canada and other industrialised countries.1 Prevention of cancer requires identification of modifiable risk factors. Apart from smoking, one of the most fruitful areas for identification of lung cancer risk factors has been the occupational environment. The Monograph Programme of the International Agency for Research on Cancer (IARC) conducts evaluations of carcinogenic risks of different agents, and thereby provides the information base for cancer prevention throughout the world.2 Recently, an IARC Working Group evaluated the carcinogenicity of three poorly soluble low-toxicity particulate materials: carbon black, titanium dioxide and talc.3 IARC considered these agents together because they appear to cause tumours in the respiratory tract of rats through similar mechanisms, and because they may share some toxico-kinetic similarities. Carbon blacks are strong black pigments and they have been used extensively in the rubber, paint and printing industries. Carbon blacks do not occur as natural compounds, but are produced by thermal decomposition of hydrocarbons.4,5 Carbon black dust is mainly composed of elemental carbon. Titanium dioxide is a white pigment, produced from ilmenite ore or from titanium slag. It is primarily used as a whitening and mollifying agent in paints, varnishes, lacquers, paper, plastics, ceramics, rubber and printing ink.5,6 Mineral talc (Mg, Si, Fe, O) is a member of the silicate family; it can occur in platy form or, exceptionally, in asbestiform fibres, which should not be confused with asbestos. The products marketed as talc are mixtures of talc and other minerals, depending on the deposit and its geological origin. The purer forms (90% talc) are used for cosmetic and hygiene products; less pure mixtures (35–75% talc) are used in many industries, including agriculture, ceramics, paint, paper, roofing and rubber.5,7 For each agent, IARC evaluated the animal evidence and the epidemiologic evidence, and derived an overall evaluation. For Publication of the International Union Against Cancer
carbon black and titanium dioxide it was considered that there was sufficient evidence of carcinogenicity in animal experiments, whereas the experimental evidence was considered limited for talc. For all three substances, it was considered that the available epidemiologic evidence was inadequate to judge human carcinogenicity, either because of the small number of informative studies or because of conflicting findings within studies or between studies. A small exception was the unique case of perineal (vaginal) use of talc for hygiene purposes, where there was limited evidence of excess risk of ovarian cancer. In the face of these uncertain experimental and epidemiologic evaluations, the overall evaluations were equivocal: carbon black, titanium dioxide and perineal use of body powders were considered possibly carcinogenic to humans (Group 2B); inhaled talc not containing asbestos or asbestiform fibres was considered not classifiable as to its carcinogenicity to humans (Group 3). The existing epidemiologic evidence on lung cancer is mainly drawn from industry-based cohort/mortality studies. Although some of these studies were quite large and had quite good exposure data, most of them suffer from the limitation of having little or no data on potential confounding factors, most notably smoking. We have a unique opportunity to provide additional evidence on all three agents from two large population based case–control studies conducted in Montreal. The primary objective of these 2 studies was to evaluate the possible role of occupational exposures in cancer etiology. For Study I the subjects were interviewed from 1979 to 1986 and for Study II the subjects were interviewed from 1996 to 2001. Study I included 14 major sites of cancer, including lung cancer, while Study II included only lung cancer. Both studies collected detailed information on a large set of agents and mixtures, including titanium dioxide, carbon black and talc. Further, talc exposure was classified separately according to 2 major classes: industrial-grade talc and cosmetic talc. In addition to detailed occupational histories, the questionnaires included several socio-demographic and lifestyle items, notably lifetime smoking history. The present report describes the possible associations between lung cancer and each of the following: carbon black, titanium dioxide, industrial talc and cosmetic talc. While some results from Study I have been previously published regarding titanium dioxide and carbon black,4,6 the present analysis represents a new statistical approach and it allows us to juxtapose and combine results of the two studies.
Material and methods The study area, metropolitan Montreal, consisted of 2.7 and 3.1 million population in 1979 and 1996, respectively. Study I included only men aged 35–70 years and Study II included both Grant sponsor: Institut de recherche en sante et securite´ du travail du Quebec, National Health Research and Development Program, National Cancer Institute of Canada, Medical Research Council of Canada. *Correspondence to: CRCHUM, Room No. 312, 3875 Rue St. Urbain, Montreal, Quebec, Canada H2W 1V1. Fax: 11-514-412-7106. E-mail:
[email protected] Received 10 November 2006; Accepted after revision 26 June 2007 DOI 10.1002/ijc.23021 Published online 23 August 2007 in Wiley InterScience (www.interscience. wiley.com).
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men and women aged 35–75. In both studies, the cases and controls were restricted to Canadian citizens. Details of subject ascertainment and data collection have been presented previously.8–10 In both studies, cases were ascertained in the 18 largest hospitals located in the metropolitan area. In Study I, there were 857 successfully interviewed lung cancer cases, representing 79% of eligible subjects. In Study II, a total of 1,236 cases (471 females; 765 males) were interviewed, representing an overall response rate of 86%. In both studies, population controls were randomly sampled from population based electoral lists, stratified by sex and age to the distribution of cases. In Study I, 533 were successfully interviewed (response rate 70%). In Study II, 1,512 population controls (613 females; 899 males) were interviewed (response rate 70%). In Study I, an additional control group for the lung cancer series was constituted by sampling among other cancer patients; we refer to this series of 1,349 subjects as ‘cancer controlsÕ. These cancer controls included 14 major sites of cancer, none of which comprised more than 20% of the total. Exposure assessment The methodology of exposure assessment has been presented previously.9,10 After obtaining informed consent, interviews were conducted using structured questionnaires to obtain detailed information on socio-demographic and lifestyle factors. A semistructured questionnaire was used to obtain details of each job the subject had held during his working lifetime. For each job, the subject was asked about the company, its products, the nature of the worksite, main and subsidiary tasks, use of protective devices and equipment maintenance. For some occupations, supplementary questionnaires were developed to assist the interviewers with detailed technical probing. A team of chemists and hygienists examined each subject’s description of his jobs and translated each job into potential exposures from a list of 294 substances, without knowledge of the case or control status.10 For each substance that the chemists identified as being present in a job, duration of exposure was estimated as the duration of the job. The experts also coded the exposure according to three dimensions: (i) their confidence that the exposure actually occurred (possible, probable and definite); (ii) frequency of exposure during a normal work-week (30% of the time) and; (iii) relative concentration of the substance (low, medium or high). Concentration levels were established with reference to certain occupations in which the substance is found. The exposure assessment was based not only on the worker’s occupation and industry, but also on individual characteristics of the workplace and tasks as reported by the subject; an illustrative example is in the Appendix of Parent et al.11 Four of the agents on the checklist of exposures evaluated by the experts were carbon black, titanium dioxide, industrial talc and cosmetic talc. The latter two are distinguished by the relative purity of the commercial talc mixture, and the experts relied on the nature of the reported usage to classify the substance in one or other of these categories. Exposure to carbon black and titanium dioxide occurs in industries that produce these substances and where they are used as raw materials in a production process (e.g., paint, rubber manufacture). The products thereby produced contain carbon black or titanium dioxide, but in a matrix. Users of these products (e.g., painters, printers) may well be exposed to dusts containing these agents. In fact, on a population level, there are likely many more workers exposed to these end products containing carbon black and titanium dioxide than there are to the pure agents. For this reason, and because there was no clear indication of the form of these agents that might be carcinogenic, if any, we included in our exposure assessment of these agents both the pure agents and the dusts of end products containing these agents. Statistical analysis For each of the four agents under consideration, a time– weighted average of frequency and concentration was calculated over all jobs held by a subject. This index was then split into
categories of exposure as follows: unexposed, exposed at nonsubstantial level, exposed at substantial level. Exposures occurring 20 years
Titanium dioxide
Industrial talc
Cosmetic talc
N
%
n
%
n
%
N
%
5,487 268
100.0 4.9
5,487 206
100.0 3.8
5,487 267
100.0 4.9
5,487 194
100.0 3.5
24 96 148
0.4 1.7 2.7
9 85 112
0.2 1.6 2.0
70 95 102
1.3 1.7 1.9
38 66 90
0.7 1.2 1.6
62 87 119
1.1 1.6 2.2
32 91 83
0.6 1.7 1.5
34 190 43
0.8 3.4 0.7
49 140 5
0.9 2.5 0.1
224 36 8
4.1 0.6 0.2
172 31 3
3.1 0.6 0.1
213 54 0
3.9 1.0 0
136 58 0
2.5 1.0 0
148 56 64
2.7 1.0 1.2
90 50 62
1.6 0.9 1.3
110 58 99
2.0 1.1 1.8
90 44 60
1.6 0.8 1.1
black at concentrations of 2.5 mg/m3, whereas the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value is 3 mg/m3.16 Also, exposure of rats to talc produced lung tumours at 6 mg/m3 whereas the ACGIH threshold is 2 mg/ m3.17 Such findings provoked concern about risks to workers. But they also provoked some debate about the relevance of the rat findings for humans. Based on various lines of evidence it has been argued that the rat is an unsuitable model regarding the tumourigenic effects of poorly-soluble particles.18 First, the same concentrations of exposure to carbon black, titanium dioxide and talc that have produced lung tumours in rats have not been shown to produce lung tumours in hamsters or mice.16,19 Second, lung response to chronic exposure to particles has been shown to differ between rats and monkeys.20 Finally, there are significant structural differences between rat and human lungs in the regions associated with responses to poorly soluble particles.21 Nor has epidemiologic data clearly resolved the issue for any of the three agents. Epidemiologic evidence concerning carbon black mainly comes from the carbon black production industry, where carbon black was the prime industrial exposure. Large-scale cohort studies of carbon black production workers have been conducted in the United Kingdom,22 in the United States3,23 and in Germany.24 In the European studies, there were slight excess overall lung cancer standardised mortality ratios, but no indication of dose-response. In the US study, there was no overall excess and no dose-response.23 Additional evidence is provided by studies on workers who were exposed to carbon black in some other industries. Italian dockyard workers who manipulated bags of carbon black were not found at excess risk of lung cancer, nor were workers in a range of US industries where there was some carbon black exposure.25,26 A study of workers in the rubber industry in Germany who were exposed to carbon black showed no significant excess risk of lung cancer after adjustment for potential confounding by asbestos and talc.27 There have been three large cohort studies among production workers in the titanium dioxide industry.28–30 The largest, conducted in six European countries, found a slightly increased risk for lung cancer compared to the general population. However, there was no evidence of an exposure–response relationship within the cohort. The other cohort studies, both of which were conducted in the USA, did not report any increased risk for lung cancer. There is some inconclusive evidence that use of cosmetic talc for feminine hygiene purposes may be associated with an increased risk of ovarian cancer through translocation of talc fibres from the perineum or the vagina to the ovaries.31–33 Our estimate of risk related to both cosmetic and industrial talc is not relevant to the perineal route of exposure. The carcinogenic effect of expo-
sure to inhaled talc not contaminated by asbestiform fibres has been investigated in five relatively small cohort studies of talc miners and millers in the USA, Norway, Italy, France and Austria.34–37 Some of these workers were likely also exposed to radon and quartz. Most of these studies reported no excess risk of lung cancer. Nor has there been evidence of excess risk of lung cancer in a few small cohorts in some other industries that may use industrial talc, such as ceramic,38 rubber,27,39 glass fibre production,40 printing41 and pulp and paper.42 It is important to mention some methodological issues that may influence the validity of our findings. All cancer cases were incident and histologically-confirmed. Response rates were quite high, over 80% for case groups and over 70% for population control groups. We had extensive information on potential confounders, covering socio-demographic and lifestyle factors, including smoking history, as well as other occupational exposures such as asbestos. The availability of good quality smoking histories is particularly important for studies of lung cancer. Even the cohort study which had some smoking data would not have had the complete lifetime smoking history, which we were able to obtain. The parameterisation of the smoking history used an approach recommended by Leffondre et al.13 The study was carried out in a population that is unique in North America for its rather narrow ethnic diversity. Two-thirds of the study population was of French Canadian origin. This considerably diminishes the risk of confounding by genetic and environmental factors related to ethnicity. Finally, by contrast with most cohort studies, we had information on the worker’s complete lifetime work history, not just the history with one of his employers. Occupational exposures were attributed to the subjects on the basis of their detailed lifetime job history reported at interview, with consideration for the specific tasks carried out, the raw materials and the use of protective gear. We have demonstrated that the self-report of occupational history was valid.43 Our team of chemists and industrial hygienists attributed exposure to the subjects using a method for which reasonable reliability44,45 and validity46,47 have been demonstrated. Still, our exposure assessment protocol was based on expert opinion rather than direct measurement or biomarkers and it inevitably entailed some degree of measurement error. Since this work was done blindly with respect to the disease status, we can assume that any misclassification would have occurred at random with respect to the outcome and thus would lead to an attenuation of estimates of association. Our assessment of exposure frequency and concentration was semiquantitative, based on the descriptions provided by the subjects and established by our expert chemists and industrial hygienists. One of the characteristics of our study that may be seen as both an
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1 Odds ratio adjusted for age, family income, ethnicity, respondent status, years of schooling, tobacco smoking (three variables) and exposure to at least one of the other occupational hazards (asbestos, silica, cadmium compounds). Non-exposure was defined as not exposed to any of 4 substances (titanium dioxide, carbon black, cosmetic talc, and industrial talc).– 2For this analysis we pooled all the cases and we pooled all the controls (in Study I this means we included both population and cancer controls). The statistical model included a variable for study population (I or II) and sex.
0.9 (0.5–1.3) 1.0 (0.7–1.5) 0.7 (0.3–1.8) 53/98 47/74 6/24 0.8 (0.4–1.5) 1.0 (0.4–1.7) 0.4 (0.1–2.1) 30/48 28/41 2/7 0.7 (0.3–1.7) 0.9 (0.4–2.3) – 8/17 8/12 0/5 15/25 11/18 4/7 15/8 11/3 4/5
1.3 (0.5–3.1) 2.1 (0.5–11.4) 0.3 (0.1–2.0)
0.8 (0.4–1.6) 1.2 (0.4–2.2) 0.4 (0.3–3.6)
1.0 (0.6–1.5) 1.0 (0.7–1.4) 0.9 (0.6–1.8) 67/127 49/92 18/35 – – – 0/1 0/1 0/0 1.1 (0.7–2.0) 1.1 (0.6–2.2) 1.4 (0.4–3.1) 32/37 21/25 11/12 35/60 28/43 7/17 35/29 28/23 7/6
0.9 (0.5–1.7) 0.9 (0.6–1.8) 0.6 (0.2–2.7)
1.1 (0.6–2.0) 1.1 (0.6–1.8) 0.7 (0.3–1.7)
1.0 (0.8 –1.5) 1.0 (0.6–1.7) 1.2 (0.4–3.6) 76/120 68/110 8/10 0.5 (0.1–3.4) 0.5 (0.1–3.4) – 2/5 2/5 0/0 1.0 (0.7–2.1) 1.1 (0.7–2.0) 0.8 (0.2–4.7) 36/38 33/34 3/4 38/55 33/53 5/2 38/22 33/18 5/4
1.1 (0.7–2.0) 1.1 (0.6–2.1) 1.2 (0.3–4.7)
1.2 (0.8–1.9) 1.0 (0.6–1.6) 6.1 (0.9–35.2)
1.1 (0.9–1.5) 1.1 (0.9–1.7) 0.8 (0.4–1.5) 98/145 92/135 6/10 1.3 (0.6–2.9) 0.9 (0.5–2.5) – 15/16 13/16 2/0 0.9 (0.5–1.6) 1.0 (0.5–1.7) 0.7 (0.1–4.9) 31/40 29/36 2/4 52/58 50/53 2/5 52/31 50/30 2/1
1.2 (0.7–2.0) 1.2 (0.8–2.2) 1.3 (0.1–35.9)
1.5 (0.9–2.2) 1.5 (1.0–2.3) 0.5 (0.1–2.9)
1.0 1,829/2,969 1.0 417/527 1.0 676/789 1.0 736/1,191 1.0
No exposure Carbon black Any exposure Non-substantial exposure Substantial exposure Titanium dioxide Any exposure Non-substantial exposure Substantial exposure Industrial talc Any exposure Non-substantial exposure Substantial exposure Cosmetic talc Any exposure Non-substantial exposure Substantial exposure
736/462
Ca/Co Ca/Co
OR (95% CI)
OR (95% CI)
Ca/Co
OR(95% CI)
Ca/Co
OR (95% CI)
Ca/Co
Pooled2 Females Study II: 1979–1986 Males Cancer controls Study I: 1979–1986 Population controls Exposure level
TABLE IV – ODDS RATIO1 OF LUNG CANCER FOR EXPOSURE TO CARBON BLACK, TITANIUM DIOXIDE AND TALC FROM TWO CASE-CONTROL STUDIES IN MONTREAL
OR (95% CI)
RISK OF LUNG CANCER
advantage and a disadvantage is the fact that exposure to these agents was predominantly in user industries rather than in the industries that produce these agents. For the most part, these workers were exposed to complex mixtures of substances, of which some of the four substances of interest may have been minor components. The advantage is that it provides a more realistic assessment of risks for the vast majority of workers exposed to these agents than do the cohort studies of extremely highly exposed workers. The disadvantage is that it might represent levels of exposure below those that produce detectable risks. Further, exposure to carbon black and to titanium dioxide was attributed to workers who worked with products, such as paints and rubbers, which contain these substances in matrices. It is possible that this affects the carcinogenicity of these substances, one way or the other. But given the fact that many more workers are exposed to these substances in such end-use forms than in their pure form, we thought it was important to evaluate carcinogenicity in this form. The quality of interview response may differ between selfrespondents and surrogate respondents.48 In our studies, about 35% of cases’ and 10% of controls’ information came from a surrogate respondent, usually the spouse. In a recent study of the comparability of responses from proxy and self-respondents, it was found that, for many variables, including height, weight, physical activity and consumption of alcohol and cigarettes, there were small differences between proxies and self-respondents.49 Our impression was that proxies report quite confidently about jobs held, though reporting of details of job tasks may be more doubtful. When we restricted the analyses to self-respondents only, the results were almost identical. The choice of control group is problematic in any case–control study.50 In Study II, we had only a population control group, but in Study I, we had 2 options and we exercised both. Although a population control group appears to be more representative of the base population, cancer controls are less susceptible to response bias and information bias.9,27 There are pros and cons to both options and we cannot affirm that one is necessarily more valid than the other. We believe that it is advantageous to compare results from using 2 different control groups, as it is to compare the results of two different studies. There were no indications in any of the analyses that any of the four substances was associated with lung cancer. Since there were few exposed women in the studies, we are less confident of those negative findings among women. Nonetheless, for cosmetic talc, where there were a fair number of women exposed, there was no indication of excess risk. In conclusion, the results of our two community-based studies indicate that workers in our study base with occupational exposure to carbon black, titanium dioxide, industrial talc and cosmetic talc did not experience any excess risk of lung cancer. These findings are consistent with the evaluations of the IARC working group that reviewed these substances.3
Acknowledgements The collection of original data was supported by grants from the Institut de recherche en sante et securite du travail du Quebec, the National Health Research and Development Program, the National Cancer Institute of Canada and the Medical Research Council of Canada (Principal Investigator: Dr. Jack Siemiatycki). Dr. Jack Siemiatycki holds a Canada Research Chair in Environmental Epidemiology and Population Health at the Universite de Montreal, Montreal, Canada. Dr. Agnihotram V. Ramanakumar is supported by a postdoctoral fellowship grant from the National Cancer Institute of Canada, under the PREECAN (Programme of Research in Environmental Etiology of Cancer). Mr. Benoit Latreille is a chemist and Dr. Marie-Elise Parent is an Associate Professor at the Institut Armand-Frappier of the Institut national de la recherche scientifique (INRS) of the Universite du Quebec, Laval, Canada.
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APPENDIX TABLE AI – THE PREVALENCE OF EXPOSURE TO CARBON BLACK, TITANIUM DIOXIDE AND TALC, AND DISTRIBUTION BY DIMENSION OF EXPOSURE AMONG STUDY SUBJECTS Subjects of Study I Exposure dimensions
Carbon black Ca
con
Titanium dioxide Ca
Con
Subjects of Study II
Industrial talc
Cosmetic talc
Carbon black
Ca
Ca
Ca
Con
Con
Con
Titanium dioxide Ca
Con
Industrial talc
Cosmetic talc
Ca
Ca
Con
Con
Total study subjects 857 1,882 857 1,882 857 1,882 857 1,882 1,236 1,512 1,236 1,512 1,236 1,512 1,236 1,512 No. exposed to substance 54 93 41 79 62 112 17 47 51 70 41 45 43 50 48 82 Confidence level Possible 2 3 2 2 26 22 1 14 5 14 3 2 11 11 9 14 Probable 16 23 10 20 12 30 10 28 24 33 23 32 22 31 14 14 Definite 36 67 29 57 24 60 6 5 22 23 15 11 10 8 25 54 Frequency 30% of work-week 31 20 19 32 7 12 0 0 30 38 16 16 11 13 1 4 Concentration Low 40 77 33 72 53 84 14 30 46 61 31 36 41 35 39 53 Medium 9 13 5 7 9 28 3 17 5 9 10 9 2 15 9 29 High 5 3 3 0 0 0 0 0 0 0 0 0 0 0 0 0 Duration 1–10 years 21 49 14 28 25 41 3 6 32 46 23 29 22 21 32 49 11–20 years 12 24 9 26 22 24 5 13 6 14 9 6 5 9 5 21 >20 years 21 20 18 25 15 47 9 28 13 10 9 10 16 20 11 12
