a Medical Institute for Environmental Hygiene at the Heinrich Heine University of Düsseldorf, Germany.
b Institute of Medical Epidemiology, Biometry and Medical Informatics at the Martin Luther University, Halle, Germany.
c Institute for Kidney and Hypertension Research, Berlin, Germany.
d Bremen Institute for Prevention Research and Social Medicine, Bremen, Germany.
e Collaborators of the Multicenter Urothelial and Renal Cancer Study (MURC Study Group): Wolfgang Barth, Uta Brettschneider, Elisabeth Bronder, Katrin Farker, Johannes Faßbinder, Rainer Frentzel-Beyme, Eberhard Greiser, Karin Greiser, Lothar Heinemann, Annemarie Hoffmann, Wolfgang Hoffmann, Werner Hofmann, Christine Lautenschläger, Ullrich Matz, Martin Molzahn, Wolfgang Pommer, Manfred Steinkohl.
Reprint requests: Beate Pesch, Unit of Environmental Epidemiology, Medical Institute for Environmental Hygiene, Auf'm Hennekamp 50, 40225 Düsseldorf, Germany.
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Abstract |
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Methods In a population-based multicentre study, 935 incident RCC cases and 4298 controls matched for region, sex, and age were interviewed between 1991 and 1995 for their occupational history and lifestyle habits. Agent-specific exposure was expert-rated with two job-exposure matrices and a job task-exposure matrix. Conditional logistic regression was used to calculate smoking adjusted odds ratios (OR).
Results Very long exposures in the chemical, rubber, and printing industries were associated with risk for RCC. Males considered as substantially exposed to organic solvents showed a significant excess risk (OR = 1.6, 95% CI : 1.12.3). In females substantial exposure to solvents was also a significant risk factor (OR = 2.1, 95% CI : 1.04.4). Excess risks were shown for high exposure to cadmium (OR = 1.4, 95% CI : 1.11.8, in men, OR = 2.5, 95% CI : 1.25.3 in women), for substantial exposure to lead (OR = 1.5, 95% CI : 1.02.3, in men, OR = 2.6, 95% CI : 1.25.5, in women) and to solder fumes (OR = 1.5, 95% CI : 1.02.4, in men). In females, an excess risk for the task soldering, welding, milling was found (OR = 3.0, 95% CI : 1.17.8). Exposure to paints, mineral oils, cutting fluids, benzene, polycyclic aromatic hydrocarbons, and asbestos showed an association with RCC development.
Conclusions Our results indicate that substantial exposure to metals and solvents may be nephrocarcinogenic. There is evidence for a gender-specific susceptibility of the kidneys.
Keywords Cadmium, cadmium compounds, case-control study, gender differences, job-exposure matrix, occupation, renal cell carcinoma, trichloroethylene
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Introduction |
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In historical cohort studies, insulators4 and asbestos products workers5 showed significantly elevated mortality rates for kidney cancer. Thus far, the International Agency for Research on Cancer (IARC) considered only iron and steel founding an occupational setting which may exert a cancer risk for the kidneys.6 This was mainly based on a 1972 report of excess risk among coke-oven workers,7 but this was no longer seen after 30 years of follow-up.8
Limited epidemiological evidence of risk has been found for solvents and petrochemicals.914 Chlorinated solvents in particular have attracted attention as an occupational hazard.1517 Recently, IARC concluded that tetrachloroethylene (PCE) and trichloroethylene (TCE) are probably carcinogenic to humans.18 There is evidence, based on animal experiments and limited epidemiological data, for both nephrotoxicity and nephrocarcinogenicity.
The historical finding of an impact of cadmium exposure on RCC development19 was investigated in subsequent studies on heavy metal exposure with conflicting results.12,2022 Cadmium can be stored in the renal cortex at much higher levels than in other tissues.23 Cadmium was evaluated as a human carcinogen, but the kidneys were not implicated as a target organ.24
For cadmium and TCE exposure, gender differences in susceptibility are known.25 Higher risks in solvent-exposed women found in a recent study support earlier findings.26 Our study included two East German regions with a high employment rate for women.
Our multicentre population-based case-control study was conducted from 1991 to 1995 and aimed to estimate the RCC risk for occupation-related agents besides other risk factors. A structured questionnaire was used by centrally trained interviewers to obtain detailed exposure information. Expert-rating approaches were adapted or developed to assess lifetime exposure to the agents under study. The present paper reports the possible impact of occupation-related agents on RCC development. The excretory portion of the kidney was analysed among urothelial carcinomas. Further results are reported elsewhere.27,28
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Material and Methods |
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Cancer cases and controls
From 1991 to 1995, this population-based case-control study was conducted in five German regions (West Berlin, Bremen, Leverkusen, Halle, Jena). Eligible were German nationals without age limit for both cases and controls. Two case series were enrolled simultaneously, with a total of 1035 urothelial cancer cases and 935 RCC cases. For 95% of RCC cases, diagnosis was confirmed histologically in the 6 months before recruitment, and for 5% of RCC cases diagnosis was confirmed by sonography only. In all 88.5% of RCC cases were interviewed in the first 2 months after diagnosis. Participation of the large hospitals in the study areas assured a population-based enrolment of cases but this was ascertained by a preceding cancer incidence study.27
The controls were frequency-matched to cases by region, sex (Table 1), and age (5-year age groups). The matching procedure aimed for a 1 : 2 matching for urothelial cancer and a 1 : 4 matching for RCC cases to controls. During the recruitment, an increase in the incidence rates of RCC was observed. Therefore, the recruitment period of RCC cases was expanded to clarify possible causes. Finally a group of 4298 randomly selected population controls from local residency registries was enrolled. This control group was used in the statistical analysis of both cancer sites.
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For quantifying the exposure to specified agents, we adapted two job-exposure matrices (JEM) (the so-called British JEM30 and the so-called German JEM31). Experts within our study group developed a corresponding job task-exposure matrix (JTEM). For every job title and job task, respectively, the exposure matrix provided an expert rating in terms of the probability and the intensity of exposure to a specified agent. To obtain an agent-specific measure of a subject's lifetime exposure, the products of duration, probability, and intensity were summarized over all jobs held or job tasks operated, respectively. We referred to these exposure variables as exposure indices.
Statistical analysis
Conditional logistic regression models32 were applied for risk estimation using the SAS procedure PHREG,33 separately for males and females. The risk estimation was conditional on 45 strata resulting from nine age groups (<40, 4049, 5054,..., 7579, 80+) and five study regions.
Considering possible highly non-linear associations between risk estimates and exposure measures, four exposure categories were defined for each exposure variable using the 30th, 60th and 90th percentiles of the distribution of the exposure variable among the exposed controls. Concerning exposure duration, we referred to these categories as short, medium, long and very long duration of exposure, and with respect to exposure indices, as low, medium, high and substantial exposure. The reference groups comprised the unexposed subjects and the subjects with short duration or low exposure.
Smoking was implemented as a confounder, because it is considered as a risk factor34,35 and had a higher prevalence among German blue-collar workers.36 It was measured as log (packyears + 1). Additionally, the quitting of smoking and the exclusive smoking of other tobacco products were included. Socioeconomic status (SES) was not used since it can represent occupational risk to a high degree. Table 3 shows the risk estimates for tobacco smoking and SES. We ignored mutual confounding by other agents or occupations because of the low prevalence of people in high-risk jobs and the difficulty of disentangling the joint effect of mixtures, a ubiquitous circumstance in the workplace.
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Results |
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Table 5 presents the logistic regression results for job groups and job tasks, selected for metal, solvent, or polycyclic aromatic hydrocarbon (PAH) exposure, based on duration of exposure. Male chemical workers, rubber workers, and printers with a very long employment duration showed significantly elevated risks for RCC. Among the job tasks selected for risk estimation, there was a significant excess risk for females exposed in soldering, welding, milling and a non-significantly elevated risk among males for galvanization. For metal degreasing, the OR were slightly, but insignificantly elevated for the majority of exposure categories in males and females.
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Occupation-related exposure to aromatic amines based on both the JEM and JTEM approach was not associated with significant excess risk. Significant elevated OR were found with no clear pattern for the use of paints and pigments, of film developers and also cutting fluids. These products can produce exposure to aromatic amines, but also to other agents like solvents and metals.
Exposure variables for mineral oils and petrochemicals were occasionally associated with RCC development based on different expert ratings, but the lack of specificity of the exposure variables has to be taken into account. In the British JEM, mineral oil exposure was rated together with tar and pitch exposure. Among other agents with excess risks were PAH and asbestos.
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Discussion |
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The lower response rate of controls, 71%, compared to 88% of cases may be explained by the different mode of recruitment (cases were contacted in hospitals and controls at home) and cannot rule out a selection bias. However, the similar distribution of SES among male cases and controls does not indicate a strong selection bias. It further supports that SES-associated factors, especially tobacco smoking and occupation-related agents, did not contribute to RCC development, unlike urothelial cancer in men.27,28 Smoking is not considered a strong risk factor for RCC.34,35,37 Some studies have reported an even higher prevalence of selected white-collar occupations among cases,11,38 but due to the large number of job titles variation by chance has to be taken into account.
The SES figures for females were different, with higher risks in lower social classes. A Danish study has also reported a more pronounced social class effect in females.39 Smoking in women is not a strong risk factor which would explain this SES effect. A possible gender difference of susceptibility will be discussed.
Self-assessed exposure to chemical agents has been considered of low reliability.40 An expert-rating of exposure to selected agents can only be based on job titles or job tasks, resulting in crude categories for exposure probability and intensity.41 The British JEM, developed for cancer studies in England and Wales, did not consider temporal changes in exposure after 1950. The German JEM was originally developed for Parkinson's disease, focusing on solvent exposure in East and West Germany. Exposures to solvents were more sensitively rated than in the British JEM. In all, 67% of the occupations classified unexposed to organic solvents using the British JEM were considered exposed with the German JEM. On the other hand, only 7% of the job titles considered unexposed using the German JEM were rated as exposed with the British JEM. The rating of experts was not significantly different with respect to unexposed occupations, but did differ in probability and intensity of exposure.
Exposure indices derived from an expert rating of job tasks can have a higher agent-specificity than indices derived from job titles. On the other hand, a loss of sensitivity has to be taken into account for job tasks where a knowledge of the technology or materials is necessary to gain exposure information. Limitations of exposure matrices also hold for the JTEM-based exposure indices.
Dose-response relations
One of the postulates for epidemiological evidence is the demonstration of a dose-response relation. For many occupation-related risk factors, only a small fraction of the general population is substantially exposed which results in a limited power to detect dose-response relations in population-based case-control studies.2
Exposure misclassification tends to smooth dose-response relations towards the null value. For exposure variables based on duration of exposure only, which do not suffer from a strong recall bias or misclassification, excess risks were mainly found for the highest exposure category. For agent-specific exposure indices, which additionally implement the experts' ratings, excess risks were not predominantly found in the highest exposure category.
A possible misspecification of the exposure index has to be discussed as another methodological shortcoming which can smooth effects. For this study, cumulative exposure indices were developed according to the 1986 US EPA guidelines for carcinogenic risk assessment.42 The underlying assumption of toxicological equivalence of exposure time and concentration may not be appropriate for solvents and metals. The 1996 revised guidelines of the US EPA refer to the growing evidence that defence mechanisms can detoxify low or even medium doses of xenobiotics,43 e.g. cadmium via metallothionein binding and TCE via cytochrome P450-mediated oxidation.44
Occupations and job tasks
Historical cohort studies have shown excess risks for insulators,4 asbestos product workers,5 and coke-oven workers.7 The IARC considered only coke production and iron and steel founding as occupational circumstances which may also be associated with kidney cancer.6 The more recent International Renal Cell Cancer Study also found significant excess risks for these industries.12 A high kidney cancer mortality was found in the East German centre of iron and steel founding (Eisenhüttenstadt) in both males and females.3 In our study regions, coke production as well as iron and steel founding were not among the main industries. For metal production, females showed an excess risk, but based on three cases only. With the data of our study, occupations in the processing and assembling of metal products showed elevated OR for both males and females. Furthermore, men working in galvanization and women in welding, soldering, and milling were associated with elevated risks but based on few cases. An excess risk was also found in a Finnish study for metal manufacturing workers.11
The risk of RCC among oil refinery workers has been repeatedly investigated with conflicting results.4547 A high kidney cancer mortality in both genders was found in the East German centre of mineral oil refining (Grimmen).3 From an updated mortality study, an excess risk was reported for US petroleum refining workers,48 but the mortality of US refinery workers is still discussed with respect to methodological shortcomings.49 Related exposures to petroleum products, especially gasoline, have been suggested as risk factors after the induction of RCC in male rats following gasoline exposure. Several case-control studies investigated the kidney cancer risk for exposure to petrochemicals.10,12 Our agent-specific results indicate a possible risk of mineral oils and petrochemicals.
Among other occupations reported in the literature with elevated risks were painters,50 printers,11,51 chemical workers,11 and textile workers.38 We can support an RCC risk for chemical and rubber workers, as well as for printers and painters with a very long duration of exposure.
Heavy metal exposure and RCC risk
Damage to the kidneys is one of the primary actions of heavy metals at high doses. Cadmium, which can be stored in the renal cortex at much higher levels than in other tissues,52 and inorganic lead, which was found to induce RCC in animal experiments,6 have been investigated for nephrocarcinogeniticy in humans with conflicting results.12,1922 With the data of our study, cadmium exposure was shown to have a significant excess risk. Furthermore, we found significant effects for lead and solder fumes. In an updated cohort of lead smelter workers, an excess risk for kidney cancer was found.21 Fu and Bofetta reviewed epidemiological studies of the carcinogenic effects of inorganic lead.53 There is limited support for an elevated risk for kidney cancer but the epidemiological evidence is still inadequate.
Attributing effects to specific metals is difficult because of their common occurrence in ores or alloys, and in many occupational settings with solvents. Furthermore, different metals can compete for proteins like methyltransferases and metallothionein.54 Cadmium compounds can also increase synergistically the effects of other chemicals.24
The detoxification of metals by metallothionein-binding is a limiting factor in nephrotoxicity and supports the finding that it is mainly high levels of free metals which induce nephrotoxic effects.55 A long-lasting exposure to low doses cannot be considered as toxic as very high concentrations with shorter duration of exposure.
Solvent exposure and RCC risk
Long-term carcinogenicity studies in animals suggest that some chlorinated hydrocarbons may be carcinogenic in humans.18 Chlorinated solvents are widely used bulk chemicals. Tetrachloroethylene is a standard solvent for dry cleaning. There have been several studies of a RCC risk for dry cleaning solvents.12,26,56,57 Trichloroethylene is an important vapour degreaser for the cold cleaning of metal parts and it is a general solvent for fats, rubber, paints, printing inks, and other products. Positive findings in German workers with TCE exposure have been reviewed,58,59 and the epidemiological evidence is still considered limited.60
Our results could not demonstrate convincingly that chlorinated solvents are risk factors for RCC, but due to the many increased risks found among the multiple comparisons they merit further attention as potential renal carcinogens. The increase in relative risk was low, and a dose-response relation could not be shown, which we attribute to a possible misspecification of the exposure index. The health effects of TCE were reviewed by Kaneko et al.,15 with evidence for the development of kidney disorders at high exposure levels. Trichloroethylene is detoxified in a cytochrome P450-mediated pathway. Under high TCE concentrations, a pathway with glutathione conjugation can be induced which is considered to produce the ultimate carcinogen.44 Therefore, equitoxicity of low doses of TCE with long duration of exposures and high doses with shorter duration cannot be assumed.
Other occupation-related agents
Among the main hazards of coke-oven workers are PAH and aromatic amines. For high and substantial PAH exposure, assessed with the British JEM, we found a slightly increased risk among males. This effect corresponds to the risk estimates for asbestos. The role of asbestos in the aetiology of kidney cancer as causal agent was disputed by Smith et al.61 McLaughlin et al. considered the association of asbestos and RCC development as the most consistently observed occupational link.2 Confounding by heat in the workplace, for both asbestos and PAH exposure, has to be taken into account in the context of fluid balance and renal physiology.
Selected aromatic amines have been classified as carcinogens,6 but the kidneys were not considered a target organ. Abuse of phenacetin, chemically related to aromatic amines, can induce nephropathies,62 but the RCC risk is controversial.2 The risks estimated for aromatic amine exposure based on agent-specific expert ratings were not significantly elevated, but excess risks were found for chemical and rubber workers, dyers, and printers, who can have contact to aromatic amines among other agents. Excess risks were also found for workers using cutting fluids and film developers which supports further investigations on aromatic amines.
Gender differences
Nephrotoxicity is one of the primary health effects of many suspected risk factors of RCC, among them phenacetin abuse62 and cadmium exposure.52 For TCE, tubular damage was demonstrated in highly exposed RCC patients.63 Hypertension and diabetes can also induce nephropathic disorders. Benichou et al. attributed 12% of the RCC risk in men and 39% in women to hypertension.35 In our study, hypertension and diabetes could be shown as risk factors especially in women.27 Furthermore, gender effects may be important in heavy metal exposures. Females have been considered to be susceptible to cadmium toxicity.64 Cadmium can accumulate in the renal cortex to high levels in females.65
For exposure to TCE, the gender effects to be expected are less clear. Domeseci et al. discussed higher risks for females exposed to solvents.26 Due to the small numbers of occupationally exposed women, the results were of limited power. Gender differences in the biotransformation of TCE are likely, supported by higher levels of trichloroacetic acid in the urine of females.66 More general factors, especially a higher elimination rate of xenobiotics in men or the higher body fat of women, which can store solvents, are relevant.26
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References |
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