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American Journal of Epidemiology Advance Access originally published online on August 9, 2007
American Journal of Epidemiology 2007 166(9):1005-1014; doi:10.1093/aje/kwm183
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Occupational Exposure to Lead Compounds and Risk of Cancer among Men: A Population-based Case-Control Study

M.-C. Rousseau1, M.-E. Parent1, L. Nadon1, B. Latreille1 and J. Siemiatycki2

1 INRS–Institut Armand-Frappier, University of Quebec, Laval, Quebec, Canada
2 Department of Social and Preventive Medicine, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

Correspondence to Dr. Marie-Claude Rousseau, INRS–Institut Armand-Frappier, 531 Boulevard des Prairies, Laval, Quebec, Canada H7V 1B7 (e-mail: marie-claude.rousseau{at}iaf.inrs.ca).

Received for publication November 8, 2006. Accepted for publication May 17, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The International Agency for Research on Cancer recently classified inorganic lead as a probable carcinogen, while organic lead remained unclassifiable. Uncertainty persists because of limited epidemiologic evidence. The authors addressed the relation between occupational exposure to lead and the risk of 11 types of cancer among men in a case-control study conducted in Montreal, Quebec, Canada, in the 1980s. Incident cases (n = 3,730) and general population controls (n = 533) were interviewed to elicit information on job history and potential confounders. Expert chemists translated each job into a list of substances to which the subject had potentially been exposed. Exposure to lead was classified into three categories: organic lead (3% of subjects ever exposed), inorganic lead (17%), and lead in gasoline emissions (39%). Odds ratios and 95% confidence intervals were estimated by logistic regression using two control groups: general population controls and cancer controls. Stomach cancer was associated with organic lead when the authors used population controls (odds ratio (OR) = 3.0, 95% confidence interval (CI): 1.2, 7.3) and cancer controls (OR = 2.0, 95% CI: 1.1, 3.8) and with substantial exposure to lead in gasoline emissions when they used cancer controls (OR = 2.9, 95% CI: 1.4, 5.9). There was no association with inorganic lead and little evidence for associations with other cancer types.

case-control studies; inorganic chemicals; lead; male; neoplasms; occupational exposure; organic chemicals

Abbreviations: IARC, International Agency for Research on Cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Lead is one of the most ubiquitous metals in our environment, with exposures deriving from both natural and manmade sources (1). In 2006, lead metal consumption worldwide was evaluated at 8 million tons, mainly for production of lead-acid batteries (71 percent), pigments (12 percent), rolled extrusions (7 percent), munitions (6 percent), and cable sheathing (3 percent) (2, 3). The International Agency for Research on Cancer (IARC) has conducted several evaluations of the carcinogenic potential of lead compounds (4–8). An IARC Working Group met in 2004 to update previous evaluations for organic lead—molecules containing carbon-hydrogen bonds—and inorganic lead. The IARC Working Group reclassified inorganic lead from "possibly carcinogenic" to humans (group 2B) in the previous evaluation to "probably carcinogenic" (group 2A), based on limited evidence in humans and sufficient evidence in animals. Organic lead remained unclassifiable, with inadequate evidence on carcinogenicity among both humans and animals (1). More recently, increased risks of brain tumors were observed among persons occupationally exposed to lead (9, 10). Epidemiologic studies so far suggest weak associations with inorganic lead exposure, mostly for lung cancer, stomach cancer, and, to a lesser extent, kidney and brain cancers (1, 11).

In view of the scant and equivocal epidemiologic evidence on the carcinogenicity of lead compounds, we aimed to gather additional evidence concerning cancer risks incurred as a consequence of occupational exposure to different forms of lead. We performed the analysis using data collected in a population-based case-control study in Montreal, Quebec, Canada, in which several types of cancer were studied and detailed information on occupational and lifestyle characteristics was gathered.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population and design
The methods of this population-based case-control study have been described elsewhere (12, 13). Briefly, Canadian men aged 35–70 years who were residents of Montreal and surrounding suburbs were eligible to participate. Over 20 types of cancer were included in the study. Cancer cases diagnosed between 1979 and 1985 were ascertained from the major hospitals in Montreal, providing almost complete coverage (97 percent) of all cancer cases. Ethics committees at all participating institutions approved the study protocol.

Among the 4,576 eligible patients with histologically confirmed primary incident cancer, 3,730 (82 percent) were interviewed. Results are presented here for 11 cancer types with 90 or more cases interviewed: esophagus, stomach, colon, rectum, pancreas, lung, prostate, bladder, kidney, melanoma, and non-Hodgkin's lymphoma. Seventy patients were diagnosed with primary tumors at two different sites and were included in each of the relevant case series.

Two control series—population controls and cancer controls—were available, and both were used for the present analyses. Population controls were sampled from electoral lists, which in Canada are based on active population enumerations carried out before each election. The sample was frequency-matched to cases by 5-year age group. Among the 740 potential population controls sampled and contacted, 533 (72 percent) agreed to be interviewed. A cancer control series was also constituted for each cancer case series; controls were selected from subjects diagnosed with other cancers. Lung cancer cases were excluded from all cancer control series. In addition, subjects with cancer diagnosed at an anatomically contiguous site were excluded from the pool of potential controls (e.g., stomach cancer cases could not serve as cancer controls for the esophageal cancer series, and vice versa). Finally, subsampling was carried out to ensure that no single cancer type could comprise more than 20 percent of any cancer control series.

Data collection
Trained interviewers conducted an in-person interview with each participating subject. If subjects were unavailable for interview (deceased, too ill, or other), the interview was carried out with a close family member. Proxy respondents answered for 825 cancer patients (22 percent) and 67 population controls (13 percent). The interview consisted of two parts: 1) a structured section in which information was collected on sociodemographic characteristics, lifestyle factors such as frequency of consumption of certain foods, tobacco and alcohol use, and medical history; and 2) a semistructured section in which the subject was asked to provide a description of each job held in his lifetime, along with details relating to specific tasks.

A team of chemists and hygienists examined each subject's job descriptions and translated each job into potential exposures from a list of 294 substances, without knowledge of the subject's case/control status (14). For each substance identified as being present in a job, duration of exposure was estimated as the duration of time spent working in the job. The chemists also coded the exposure according to three dimensions: 1) their confidence that the exposure actually occurred (possible, probable, or definite); 2) frequency of exposure during a normal workweek (<5 percent, 5–30 percent, or >30 percent of the time); and 3) relative concentration of the substance (low, medium, or high). 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 given in the appendix of the paper by Parent et al. (15).

The exposure checklist included 10 lead-related substance groups. One of them was an umbrella category labeled "lead compounds" which included all others but was not used for the present analysis. We regrouped the remaining nine categories into three: inorganic lead, organic lead, and lead in gasoline emissions. The inorganic lead category included six substances: lead fumes, lead dusts, lead chromates, lead carbonates, lead oxides, and lead in lubricating oils and greases. The latter substance was included with inorganic lead because of the presence of an additive called lead naphthenate, which, although organic, reverts gradually to elemental lead during use of the lubricant (16). Organic lead included exposure to noncombusted leaded motor vehicle gasoline and aviation gasoline specifically due to tetraethyl and tetramethyl lead used as additives, and for which the phasing out in Canada occurred from the mid-1970s to the early 1990s (17–19). In fact, approximately 90 percent of exposure to this category of organic lead was from exposure to lead in motor vehicle gasoline. The lead compounds in engine emissions differ from those of the liquid fuel. Upon combustion, over 90 percent of the organic lead additives in gasoline are transformed into inorganic form, so that lead in engine exhaust is primarily inorganic rather than organic (20). Logically, we might have included lead in gasoline emissions with inorganic lead. However, the exposure circumstance is so different between this substance and the other inorganic lead substances and the prevalence of exposure is so high that it would dominate the category. We thus decided to maintain lead in gasoline emissions as a separate category.

For lead-containing mixtures such as gasoline and gasoline emissions, the concentration of exposure was originally attributed by the experts for the entire mixture. In order to assign a concentration to the lead component of the mixture, we adopted the convention of decreasing the concentration level. For example, if a subject was exposed to gasoline emissions at the highest concentration level, we assigned lead in gasoline emissions at the medium level. Subjects assigned to gasoline emissions at the low level were considered unexposed to lead in gasoline emissions. Because of this convention, there were no subjects exposed at high concentration for two of our exposure variables, organic lead and lead in gasoline emissions.

Exposure index
For each of the three exposure groupings 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 a nonsubstantial level, or exposed at a substantial level. Exposures occurring 5 or fewer years before diagnosis or interview and exposures coded with the lowest confidence level were excluded. Subjects were classified as having been exposed at the substantial level if they had been exposed at a concentration and frequency of medium or high for more than 5 years (excluding the 5 years before diagnosis or interview). All other exposed subjects were then classified at the nonsubstantial level. Subjects were considered unexposed if they had not been occupationally exposed to any form of lead.

Statistical analyses
Adjusted odds ratios and 95 percent confidence intervals were estimated by unconditional logistic regression, with a separate model for each of the cancer types. The three types of lead exposure were modeled separately, and results were mutually adjusted for one another if excess risks were observed with more than one type of lead.

Selection of potential confounders was based on a priori knowledge and prior empirical evidence from this study. All models were adjusted for age, family income, cultural origin (French Canadian; English Canadian; Italian, Jewish, or other European; or other) or birthplace (North America, Europe, or other), and respondent status (self or proxy). All models except those for melanoma and non-Hodgkin's lymphoma were adjusted for smoking. Smoking was modeled with three variables: ever smoking versus never smoking, number of years since quitting if an ex-smoker, and the natural log of "cigarette-years," defined as the number of cigarettes smoked per day times the number of years of smoking (21). Models for lung cancer were further adjusted for ever exposure to asbestos, silica, arsenic, cadmium, and chromium (VI).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Selected characteristics of the study groups are presented in table 1. Population controls had a slightly higher yearly income and a lower proportion of ever smokers than most of the cancer case groups. Proportions of ever smokers were highest among lung, esophageal, and bladder cancer cases.


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  		TABLE 1. Selected characteristics of cancer cases and population controls in a study of occupational exposure to lead compounds, Montreal, Quebec, Canada, 1979–1985

 
Lifetime prevalence of occupational exposure to any lead compounds in the entire study population was 47 percent. Using the chemists' original checklist designations, the proportions of subjects ever exposed to specific forms of lead or lead-containing substances were: lead in gasoline emissions, 39 percent; lead fumes, 4 percent; lead from lubricating oils and greases, 4 percent; lead from motor vehicle gasoline, 3 percent; lead chromates, 3 percent; lead oxides, 2 percent; basic lead carbonate, 2 percent; lead from aviation gasoline, 0.5 percent; and lead dusts, 0.5 percent. The lifetime prevalences of exposure to the three lead groupings under consideration here are presented in table 2. In the entire study population, the numbers exposed were: lead in gasoline emissions, 1,645 subjects (39 percent); other inorganic lead, 726 subjects (17 percent); and organic lead, 126 subjects (3 percent). Spearman's rank correlation coefficients (rs) for correlations between lifetime exposure indices for the three types of lead were 0.17 between organic lead and lead in gasoline emissions, 0.12 between organic and inorganic lead, and 0.06 between lead in gasoline emissions and inorganic lead. When considering all 294 substances evaluated in our study, the strongest correlations involving lead compounds were between the following: organic lead and xylene (rs = 0.46), organic lead and toluene (rs = 0.40), lead in gasoline emissions and carbon monoxide (rs = 0.72), lead in gasoline emissions and polyaromatic hydrocarbons (rs = 0.53), inorganic lead and tin compounds (rs = 0.57), inorganic lead and soldering fumes (rs = 0.48), and inorganic lead and zinc compounds (rs = 0.45).


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  		TABLE 2. Lifetime prevalence of occupational exposure to different forms of lead and distribution of participants by dimension of exposure among all 4,263 study participants, Montreal, Quebec, Canada, 1979–1985

 
Exposure was coded by the chemists/industrial hygienists on the basis of not only job title and industry but also the description provided by each subject of each job held during his life. The main occupations to which exposure to lead was attributed and the most typical exposure codings per occupation are shown in table 3. Almost half of the subjects exposed to organic lead were mechanics. Those exposed to inorganic lead were mainly painters, electrical or electronics workers, mechanics or repairmen, and plumbers. Over half of the subjects exposed to lead in gasoline emissions were either motor transport workers or driver-salesmen. The hygienists' level of confidence in the exposure's having taken place was high for all categories of lead and within most occupations entailing lead exposure. Frequency of exposure was generally intermediate or high, and concentration of exposure was relatively low for most subjects exposed.


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  		TABLE 3. Main occupations to which exposure to lead was attributed and most frequent exposure codings attributed by the expert chemist-hygienists, Montreal, Quebec, Canada, 1979–1985

 
Odds ratios for the associations between ever exposure to lead and cancer are presented in table 4. Results are presented for both population controls and cancer controls. For organic lead, there were significantly elevated odds ratios for stomach cancer with both control groups. There was also some indication of excess risk of rectal cancer, but this was not consistent between the two control groups. For other sites, there were no significantly elevated odds ratios, though a few were suggestively elevated with population controls. Ever exposure to inorganic lead and to lead in gasoline emissions was not associated with any of the 11 cancer types analyzed, irrespective of control group.


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  		TABLE 4. Odds ratios for associations between occupational exposure to lead and specific cancers, obtained using population controls and cancer controls, Montreal, Quebec, Canada, 1979–1985

 
Further refinement was based on subdividing the exposed subjects by lifetime level of exposure into nonsubstantial and substantial exposure subgroups. This was not possible for organic lead, since all subjects were exposed at relatively low concentrations, and thus all were considered exposed at nonsubstantial levels. Table 5 shows the resulting associations between lifetime exposure to inorganic lead and lead in gasoline emissions and three types of cancer included in our study and for which there has previously been suggestive evidence of an association with lead: stomach, lung, and kidney cancers. The mainly null findings for inorganic lead and for lead in gasoline emissions in relation to these three cancers, as seen in table 4, were also observed in the more detailed analyses of table 5. However, there was a hint of increased risk of lung cancer with inorganic lead exposure, as well as a suggestion of increased risk of stomach cancer in relation to substantial exposure to lead in gasoline emissions.


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  		TABLE 5. Odds ratios for associations of occupational exposure to inorganic lead and exposure to lead in gasoline emissions with stomach, lung, and kidney cancers, according to lifetime level of exposure, Montreal, Quebec, Canada, 1979–1985

 
In view of the excess risks of stomach cancer seen with both lead in gasoline emissions and organic lead, and given the considerable overlap in the occupations exposed to these two forms of lead compounds, we analyzed them in the same model to examine their joint and separate effects on stomach cancer risk. As is shown in table 6, the increased risk of stomach cancer occurred with organic lead rather than lead from engine emissions, though this finding was based on small numbers.


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  		TABLE 6. Odds ratios for the separate and joint effects of occupational exposure to organic lead and lead in gasoline emissions in relation to stomach cancer, Montreal, Quebec, Canada, 1979–1985

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Experimental evidence suggests that inorganic lead is weakly mutagenic but only at high, toxic doses (22). However, it has indirect genotoxic effects when administered in combination with other DNA-damaging agents, suggesting a possible co-carcinogenic effect (23). This probably occurs when lead ions interact with enzymes implicated in DNA processing and repair (24–26). Experimental studies suggest increased incidences of kidney cancer, and to a lesser extent lung, brain, and hematopoietic cancers, among rodents exposed to inorganic lead (7, 8, 27). Less is known about the carcinogenicity of organic lead. In one study, subcutaneous injection of tetraethyl lead significantly increased the development of lymphoma among female mice but not male mice (28). Organic lead is absorbed through the respiratory tract and skin more efficiently than is inorganic lead. It is partly metabolized into ionic lead, which is expected to harbor the carcinogenic properties of inorganic lead (29).

Several studies have focused on cancer risk among workers exposed to lead in industries such as battery manufacturing, smelting, and pigment production, where exposures to mainly inorganic lead compounds occur at high levels. Results from such studies and meta-analyses have suggested that there may be excess risks for lung (30–39) and stomach (11, 31, 36, 40, 41) cancers among these workers. Most studies suggestive of a link between lead exposure and stomach cancer have focused on inorganic lead (12, 32, 40–42). Evidence on organic lead is scarce; one case-control study suggested a twofold risk of digestive cancers among workers with the highest cumulative exposure to tetraethyl lead in a manufacturing plant (43). Findings on other types of cancer have been null or inconsistent.

It has been suggested that some of the previously reported associations with lead compounds might have resulted from confounding due to smoking and/or other occupational exposures. Moreover, the presence of exposures highly correlated with lead, such as arsenic, chromium, and cadmium, makes it difficult to disentangle their independent effects (33, 35, 36, 40, 44, 45).

As with many other metals, it is difficult to evaluate the human carcinogenicity of lead because the element is found in so many different forms. There is little or no epidemiologic evidence available for individual forms, and it is only by grouping them that sufficient evidence can be assembled. Our strategy was inspired by that used by IARC—namely, to try to distinguish the classes of organic and inorganic lead compounds. We further separated out lead in gasoline emissions from the general class of inorganic lead compounds because of its unique characteristics. Emissions from gasoline engines are complex and variable mixtures in which lead is one of many constituents. The results we show for gasoline emissions cannot be said with confidence to represent the lead fraction. While null findings would provide evidence against the carcinogenicity of lead in gasoline emissions, positive findings might result from the lead fraction or other components of engine emissions. In addition, while the "organic lead" category comprised both lead in motor vehicle gasoline (precombustion) and lead in aviation gasoline, the findings were largely driven by exposure to lead in motor vehicle gasoline (89 percent). Such exposure to lead from liquid fuels occurs through inhalation of vapors and dermal contact (46, 47). Finally, the category labeled "inorganic lead" comprised a grouping of six different compounds or forms of lead exposure, resulting in a heterogeneous group.

Some other methodological aspects of our study should be noted. All cancer cases were incident and histologically confirmed. In contrast with investigators in some of the previous studies on lead exposure and cancer risk, we had extensive information on potential confounders, covering sociodemographic and lifestyle factors, including smoking history, as well as other occupational exposures. Occupational exposures were attributed to subjects on the basis of their detailed lifetime job history as reported at interview. We have demonstrated that such self-reporting of occupational history is valid (48). Our team of chemists and industrial hygienists attributed exposure to subjects using a method (14) for which reasonable reliability (49, 50) and validity (51, 52) have been demonstrated. While our exposure assessment protocol was detailed and painstaking, it was based on expert opinion rather than industrial measurements or biomarkers, and it inevitably entailed some degree of measurement error. Since this work was done blindly with respect to disease status, we can assume that any misclassification would have occurred at random with respect to the outcome and thus would have led to an attenuation of estimates of association. Our assessment of exposure frequency and concentration was semiquantitative, based on descriptions provided by the subjects, and established by our expert chemists and industrial hygienists. In our study, exposure to lead occurred predominantly in industries and occupations where large numbers of workers have been exposed, but at low levels. This represents an advantage by providing a more realistic assessment of risks for the vast majority of lead-exposed workers than is found in most cohort studies of very highly exposed workers. However, such low levels of exposure may be below those which produce detectable risks.

There are pros and cons to both types of controls (13, 15, 53); we cannot say with certainty which type provides a better representation of the source population. We have chosen to present the results obtained with each control series separately. If the results provided by the control groups are similar, as they were for most results in this paper, confidence in the inferences is increased. If they appear to differ, as they did for a handful of associations, we are confronted with the same challenge as when interpreting two studies that have generated seemingly different results.

In this report, we studied the risk of 11 different types of cancer among men from Montreal, Quebec, Canada, who were exposed to various forms of lead through occupations such as mechanic, construction worker, transport worker, and driver-salesman. Most workers were exposed at either intermediate (5–30 percent of the workweek) or high (>30 percent of the workweek) frequencies but at relatively low concentrations. The most consistent positive finding was an association between exposure to organic lead and risk of stomach cancer. An excess risk of stomach cancer was also found among subjects exposed to lead in gasoline emissions at substantial levels. In an analysis of joint exposure to organic lead (i.e., lead-containing liquid fuels) and lead in gasoline emissions, it appeared that the excess risk of stomach cancer was primarily attributable to lead-containing liquid fuels. Among the 14 cases with stomach cancer who had been exposed to organic lead, nine were exposed while working as mechanics, a line of work entailing exposure to numerous other chemicals. In addition to lead, mechanics are commonly exposed to monoaromatic and polyaromatic hydrocarbons, alkanes, solvents (notably xylene and toluene), and carbon monoxide, to name only a few substances. These agents may have confounded or interacted with organic lead. On the one hand, none of these substances is known to be a risk factor for stomach cancer, and on the other hand, we had insufficient statistical power to assess possible interactions or to fully control for possible confounding by these co-exposures.

Apart from these various indications of excess risk of stomach cancer, there were no persuasive associations between the three forms of lead and cancer at any site, except for a suggestion of an association between organic lead and rectal cancer. Inorganic lead was not associated with any of the cancer sites. We previously reported an excess risk of stomach cancer among men exposed at a substantial level to lead dust, one of the six constituents of our inorganic lead grouping (54). This excess, based on few exposed cases, was diluted out in the entire category of inorganic lead.

In conclusion, our study supports the hypothesis that stomach cancer may be associated with lead exposure, incriminating particularly organic lead and possibly lead in gasoline emissions. We observed little evidence for associations with other types of cancer, including lung and kidney cancers.


   ACKNOWLEDGMENTS
 
This study was supported by research and personnel support grants from Health Canada, the National Cancer Institute of Canada, the Institut de recherche en santé et sécurité au travail du Québec, and the Fonds de la recherche en santé du Québec. The fieldwork was supervised by Lesley Richardson, and the chemical coding was carried out by Dr. Michel Gérin, Dr. Louise Nadon, Denis Bégin, and Ramzan Lakhani. Marie Désy provided support for the statistical analyses.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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