You are here

  • Home
  • Archive
  • Volume 68, Issue 10
  • Occupational exposure to arsenic, cadmium, chromium, lead and nickel, and renal cell carcinoma: a case–control study from Central and Eastern Europe

Article Text

Article menu

Download PDFPDF

Workplace
Original article
Occupational exposure to arsenic, cadmium, chromium, lead and nickel, and renal cell carcinoma: a case–control study from Central and Eastern Europe
  1. Paolo Boffetta1,2,
  2. Luc Fontana3,
  3. Patricia Stewart4,5,
  4. David Zaridze6,
  5. Neonilia Szeszenia-Dabrowska7,
  6. Vladimir Janout8,
  7. Vladimir Bencko9,
  8. Lenka Foretova10,
  9. Viorel Jinga11,
  10. Vsevolod Matveev12,
  11. Helena Kollarova8,
  12. Gilles Ferro13,
  13. Wong-Ho Chow4,
  14. Nathaniel Rothman4,
  15. Dana van Bemmel4,
  16. Sara Karami4,
  17. Paul Brennan13,
  18. Lee E Moore4
  1. 1International Prevention Research Institute, Lyon, France
  2. 2The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, USA
  3. 3Department of Occupational Health, University Hospital, Saint-Etienne, France
  4. 4Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
  5. 5Stewart Exposure Assessments, LLC, Arlington, Virginia, USA
  6. 6Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia
  7. 7Department of Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland
  8. 8Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic
  9. 9Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
  10. 10Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  11. 11Department of Urology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
  12. 12Department of Urology, Russian Cancer Research Centre, Moscow, Russia
  13. 13International Agency for Research on Cancer, Lyon, France
  1. Correspondence to Dr Paolo Boffetta, International Prevention Research Institute, 95 cours Lafayette, Lyon 69006, France; paolo.boffetta{at}i-pri.org

Abstract

Objectives To investigate the risk of renal cell carcinoma (RCC) in Central and Eastern Europe in relation to exposure to known and suspected carcinogenic metals.

Methods During 1999–2003, the authors conducted a hospital-based study in Czech Republic, Poland, Romania and Russia, including 1097 cases of RCC and 1476 controls. Occupational exposure to arsenic, cadmium, chromium(III), chromium(VI), lead and nickel was assessed by teams of local industrial hygiene experts, based on detailed occupational questionnaires.

Results The ORs for RCC were 1.55 (95% CI 1.09 to 2.21) for exposure to lead and 1.40 (95% CI 0.69 to 2.85) for exposure to cadmium. No clear monotonic exposure–response relation was apparent for either duration of exposure or cumulative exposure to either metal, although the OR for the highest category of cumulative exposure to lead was 2.25 (95% CI 1.21 to 4.19). Exposure to other metals did not entail an increased risk of RCC.

Conclusions For cadmium, the lack of statistical significance of most results, potential confounding and the absence of clear dose–response relations suggest that an association with RCC is unlikely to be causal. In the case of lead, however, the elevated risk in the category of highest cumulative exposure is noteworthy and justifies further investigation.

  • Arsenic
  • cadmium
  • chromium
  • kidney cancer
  • lead
  • nickel
  • occupation
  • renal cell carcinoma
  • epidemiology
  • cancer
  • metals

https://doi.org/10.1136/oem.2010.056341

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    What this paper adds

    • Heavy metals have been suspected to increase the risk of renal cell carcinoma.

    • The lack of statistical significance, potential confounding and absence of clear dose–response relations suggest that an association between cadmium exposure and RCC is unlikely to be causal.

    • The elevated risk in the category of highest cumulative exposure to lead justifies further investigation.

    Renal cell carcinoma (RCC) is the most common form of kidney cancer and accounts for about 3% of all adult tumours worldwide.1 The incidence of RCC has been increasing in most affluent countries over the last few decades.

    The highest national incidence rate of kidney cancer worldwide in 2002 was reported in the Czech Republic (23.3/100 000 in men and 10.4/100 000 in women); rates were also high in other countries of Central and Eastern Europe (range in men 12–19/100 000, vs an average of 10.3/100 000 in Europe as a whole).2 Established risk factors for RCC include cigarette smoking, hypertension and high body mass.1 However, these factors account for a relatively small fraction of cases and do not explain the high incidence in Central and Eastern Europe.

    RCC is generally not considered an occupation-related cancer, but some occupational exposures or employment in certain jobs or industries have been associated with an increased risk of this neoplasm. Occupational epidemiological research to date has focused on potential roles of asbestos, gasoline and organic solvents, in particular trichloroethylene.1 In addition, exposure to heavy metals and employment in metal-related industries have been associated with kidney cancer risk. Arsenic, beryllium and cadmium and their compounds, as well as nickel compounds and chromium(VI) compounds are classified by the International Agency for Research on Cancer (IARC) as established human carcinogens. Inorganic lead compounds are classified as probable carcinogens (http://monographs.iarc.fr). However, for none of these agents was the classification based on evidence of increased risk of RCC in humans. A carcinogenic effect of heavy metals on the kidney is plausible, since urinary elimination is their main route of excretion, and the proximal tubules are especially sensitive due to their high reabsorption activity. Furthermore, occupational exposure to arsenic, cadmium and lead may induce chronic renal disease,3 and exposure to arsenic in drinking-water has been associated with an increased risk of kidney cancer mortality in ecological studies.4

    The countries in Central and Eastern Europe are of particular interest for the study of occupational carcinogens, since the frequency and intensity of exposure have been in many instances higher and more varied than those found recently in other industrialised countries.5 To date, no study has been conducted of occupational risk factors for RCC in this region. We report here the results of a hospital-based case–control study of RCC, carried out in four Central and Eastern European countries, which included a detailed assessment of exposure to occupational agents.

    Materials and methods

    A hospital-based case–control study was conducted in Brno, Ceske Budejovic, Olomouc and Prague (Czech Republic), Lodz (Poland), Bucharest (Romania) and Moscow (Russia). All centres used the same study design, including strategy for recruitment, inclusion and exclusion criteria, and questionnaire. All newly diagnosed and histologically confirmed cases of kidney cancer (ICD-O26 code C.64) were identified at participating hospitals (one in each area) between 1999 and 2003. Cases had to reside in the study area for at least 1 year prior to diagnosis. Histological slides of cases were reviewed by an expert pathologist for standardised confirmation and classification. Only confirmed cases of RCC were retained in this analysis.

    Controls had the same residency restriction, came from the same hospitals as the cases during the same time frame and had conditions unrelated to smoking. They were frequency-matched to cases on sex and age. Patients with cancer or genitourinary disorders, except for benign prostatic hyperplasia, were also excluded from the controls. Some of the controls were recruited for parallel studies of lung cancer7 and head and neck cancer.8 No single disease made up more than 20% of the diseases of controls in each centre. Diagnoses of controls included digestive diseases (20.3%), central nervous system diseases (14.3%) diseases of the eye and ear (16.9%), and muscoloskeletal and connective tissue diseases (12.1%). The study protocol was approved by relevant ethics committees, and all study subjects provided informed consent.

    Interviewers were trained at each centre to perform face-to-face interviews using standard questionnaires. Proxy interviews were not performed. Cases and controls were asked about their lifestyle habits, in particular tobacco consumption, anthropometric measures 1 year before diagnosis, and their personal and familial medical history. A general questionnaire was administered for each job held at least for 1 year and included a description of the tasks performed, machines used, working environment and time spent on each task. To improve the precision of the assessment, specialised occupational questionnaires were also used in cases of employment in specific jobs or industries likely to entail exposure to known or suspected occupational carcinogens. Details on the questionnaires have been reported previously.9

    For each job in the subject's work history, a team of chemists, industrial hygienists and occupational physicians from each centre evaluated the frequency and intensity of exposure to 70 agents and groups of agents, based on the general occupational questionnaire, the specialised questionnaires, and their own experience in industrial hygiene and knowledge about historical working conditions in the study areas.9 The agents assessed included arsenic and arsenic compounds, cadmium and cadmium compounds, chromium(III) and chromium(III) compounds, chromium(VI) compounds, nickel and nickel compounds, and lead and lead compounds. For each of these agents except for lead (because it was assessed after the other exposures had been evaluated), separate assessments were made for dust and fumes or mist. Frequency of exposure was assessed as less than 5%, 5% to 30% and greater than 30% of total working time. Intensity of exposure was assessed as low, medium and high, based on agent-specific categories; to standardise the application of the intensity index, benchmarks were set, consisting of jobs that would typically fall in each category. Although exposures are expressed on a quantitative scale (eg, as μg/m3-years for cumulative exposure), few measurements were available, and exposure levels are to be interpreted on a relative rather than absolute scale. This applies in particular to analyses based on cumulative exposure. Examples of jobs entailing exposure to cadmium and lead are listed in appendix 1. For each agent considered to be present, the industrial hygienists also noted the degree of their confidence that the job would entail exposure to the agent, categorised as possible, probable, or definite. Exposure assessment was carried out blindly in regard to the subject's disease status.

    Two indices were developed to model exposure: (1) duration of exposure, expressed as the total years the subject worked in a job in which exposure occurred, and (2) cumulative exposure, calculated as the product of duration of employment in each exposed job multiplied by the midpoint of the frequency category and by the intensity weight of the job, summed across all of the subject's jobs. The intensity weight was the midpoint of each agent-specific intensity category (table 1).

    View this table:
    Table 1

    Weights for categories of intensity of exposure and jobs with highest proportion of subjects exposed to metals included in the study

    Unconditional logistic regression modelling was initially used to quantify the association between exposure to metals and risk of RCC, estimating ORs and their 95% CIs. ORs for exposure to each agent were calculated in reference to subjects unexposed to that agent. Separate analyses were conducted for exposure to dust, fumes and either form of metal. The analyses were additionally modelled to account for a 20-year lag, in which jobs held in the last 20 years before diagnosis (cases) or interview (controls) were excluded. Given the toxic effect of lead exposure on the central nervous system, we repeated the analysis of this metal after exclusion of controls admitted to the hospital for this group of diseases.

    For exposures for which a positive association with RCC was suggested by the primary analysis, exposure–response relations were examined by applying tests for trend to ORs for increasing levels of exposure. All regression models were adjusted for gender, age (5-year categories), study centre, and known or suspected risk factors of RCC: place of residence (rural/urban), tobacco smoking (non-smokers, ex-smokers, and current smokers of 1–19, 20–39 and 40 or more pack-years), body mass index (calculated as weight/height2 and classified in five categories: less than 25, 25–27.4, 27.5–29.9, 30–34.9 and 35 or more kg/m2) and self-reported history of hypertension. Additional modelling was performed, adjusting for multiple occupational metal exposure (ever/never exposure).

    All analyses were performed using the packages SAS, version 9.0 and STATA (Release 9).

    Results

    A total of 1097 RCC cases and 1476 controls were identified between 1999 and 2003. The country-specific participation rate ranged from 90% to 99% among cases and from 90% to 96% among controls. The distribution of cases and controls by sex, age, study centre, residence, tobacco smoking, body mass index and history of hypertension is shown in table 2. The proportion of women was higher among cases than among controls. The age distribution of cases and controls was similar. High body mass index and hypertension, but not tobacco smoking, were associated with risk of RCC in this population. The mean number of jobs held by cases (3.8) was similar to that of controls (4.0).

    View this table:
    Table 2

    Selected characteristics of the study population

    The proportion of controls ever exposed to metals (dust and fumes combined) was 1.4% for arsenic, 1.8% for cadmium, 5.6% for chromium(VI), 5.9% for chromium(III), 4.8% for lead and 3.4% for nickel. In table 1, jobs with the highest proportion of subjects exposed to each metal are listed. Subjects exposed to chromium(III) were often also exposed to chromium(VI) (r2=0.83, p<0.001 for ever exposure to dust and fumes); moderate correlations were found between exposure to arsenic and cadmium (r2=0.46), cadmium and chromium(III) (r2=0.43), chromium(III) and nickel (r2=0.56), and chromium(VI) and nickel (r2=0.47). Exposure to lead, on the other hand, was only weakly correlated with exposure to the other metals under study (ranging from an r2=0.13 (arsenic) to r2=0.21 (cadmium)).

    The ORs for ever exposed to the metals under study are reported in table 3. An increased OR were observed for exposure to cadmium and lead, while no increased risk of RCC was observed for exposure to arsenic, chromium(III), chromium(VI) or nickel (the OR for exposure to the last agent was significantly decreased). For none of the metals for which exposure was assessed separately for dusts and fumes was there any evidence of a different effect on RCC risk (not shown in detail).

    View this table:
    Table 3

    ORs (adjusted for sex, age, centre, residence, tobacco smoking, body mass index and hypertension) of renal cell carcinoma for ever exposure to selected heavy metals

    The results of analyses restricted to exposures with a high level of confidence were similar to those including all assessments. The OR for ever exposure to lead dusts or fumes was 1.54 (95% CI 0.99 to 2.39, based on 46 exposed cases and 41 exposed controls), while that for ever exposure to cadmium was 1.61 (95% CI 0.68 to 3.81, based on 11 exposed cases and 11 exposed controls).

    Exclusion of jobs with exposure to metals assessed with low confidence resulted in minor changes in the risk estimates (table 3). Exclusion of controls admitted to hospital for diseases of the central nervous system resulted in OR for ever exposure to lead of 1.54 (95% CI 1.06 to 2.22, based on 80 exposed cases and 63 exposed controls).

    In further detailed analyses of exposure to cadmium and lead, there was no evidence of intercountry heterogeneity in the OR for exposure to either lead (p value of test for heterogeneity 0.12) or cadmium (p value 0.55). No exposure–response relationship was apparent for either duration of exposure to either metal or cumulative exposure to cadmium (table 4). The analysis by cumulative exposure to lead did not reveal a clear trend, but the OR in the category at highest exposure was significantly elevated (table 4). The results were not different for subjects who either were exposed at the time of the study or quit within 5 years, and those who had quit exposure for 5 years of more (OR for current exposure or short-term quit 1.69 (95% CI 0.56 to 5.13) for cadmium, 1.46 (95% CI 0.97 to 2.20) for lead). The inclusion of a 20-year lag in the exposure did not modify the results (not shown in detail). The risk estimate for exposure to lead was not confounded by exposure to other metals; in particular, the OR for ever exposure to lead was 1.51 (95% CI 1.06 to 2.14) after adjustment for cadmium exposure. Exposure to lead, however, appeared to exert some confounding effect on risk estimates for cadmium exposure: after adjustment for lead exposure, the OR for ever cadmium exposure was 1.27 (95% CI 0.71 to 2.29). Exclusion of job with low-confidence exposure did not result in any important changes in the risk estimates (not shown in detail).

    View this table:
    Table 4

    ORs (adjusted for sex, age, centre, residence, tobacco smoking, body mass index, hypertension and other metals) of renal cell carcinoma for duration of exposure and cumulative exposure to cadmium and lead (dust and fumes combined)

    We conducted additional analyses on subjects ever exposed to more than one metal. The OR for exposure to cadmium and lead was 2.77 (95% CI 1.00 to 7.68, based on 13 exposed cases and eight exposed controls). Results for other combinations of exposure were unremarkable.

    Discussion

    Of the six heavy metals examined in our study, we found a suggestion of an excess risk associated with occupational exposure to cadmium and lead. However, the absence of a clear dose–response relation limits the degree to which one can make causal inferences about the association.

    IARC recently evaluated the evidence for carcinogenicity of inorganic lead compounds and concluded that the evidence was sufficient in animals and limited in humans, leading to a classification as a probable human carcinogen.11 The evaluation of human evidence was mainly based on an excess risk of stomach cancer among workers exposed to lead, while the data on kidney cancer were considered to be inadequate. This conclusion regarding kidney cancer is consistent with the results of a meta-analysis of the epidemiological literature through 2000, which reported a combined RR for kidney cancer of 1.01 (95% CI 0.72 to 1.42).12 On the other hand, it has been shown that the kidney, specifically the tubular epithelium of the renal cortex, is a major target organ for the carcinogenicity of inorganic lead salts in experimental animals; renal cortical adenomas and carcinomas have been produced in rats and mice of both sexes following exposure via several routes of administration to high doses of various soluble salts of lead such as lead acetate, lead subacetate and lead phosphate.11 However, lead oxide and lead fumes, the main forms of human exposure, have not been shown to be carcinogenic in experimental systems.11

    Cadmium is a recognised human carcinogen, based on an increased risk of lung cancer in humans.13 The possibility that cadmium is involved in kidney cancer development cannot be excluded, given the long residence time of the metal in the renal cortex and the nephrotoxic effects following occupational and environmental exposure.14 15 Subsequent to the IARC evaluation, an association between cadmium exposure and kidney cancer has been reported in four community-based case–control studies.16–19 However, in two of these studies, information on exposure to cadmium was self-reported by the study subjects,16 18 which increases the likelihood of recall bias, and in a third study a strong association was detected between RCC and exposure to many agents,19 which might result from selection or information bias. In addition, the evidence from industry-based studies does not support the existence of an association, and clinical studies have detected lower levels of cadmium in the kidney of RCC patients as compared with controls.20 Our study provides only weak evidence of a carcinogenic role of cadmium, because of the lack of a dose–risk relation and the likelihood of a confounding effect of lead exposure. Although interesting, the results for combined exposure to lead and cadmium are limited by their lack of precision.

    Chromium(VI) compounds are classified as human carcinogens because of the evidence of a causal association with cancers of the lung and the nose and sinuses.21 The evidence linking chromium(VI) compounds to RCC risk is weak,22 and our results are compatible with the lack of an association. We did not observe an association between RCC risk and chromium(III) compounds, including metal chromium. Similarly, we did not observe an increased risk of RCC among those occupationally exposed to nickel, and the significantly reduced OR is likely the play of chance. Although some nickel compounds have been shown to induce renal cancer in rats and malignant transformation of human kidney cells,23–25 the evidence from occupational epidemiological studies is not consistent.26 27

    We failed to detect an association between occupational exposure to arsenic and risk of RCC. An increased risk of kidney cancer mortality has been reported consistently in ecological studies of people exposed to arsenic via drinking-water contamination, and overall the evidence is weaker than for other types of cancer such as lung and bladder.4 Orally ingested arsenic is a shared risk factor for transitional cell cancer throughout the urinary tract.1 28 In workers exposed by inhalation, the predominant neoplastic effect is an increased risk of lung cancer, whereas when exposure occurs orally, skin, lung and bladder cancer are observed.29 The evidence of a specific association between occupational exposure to arsenic and risk of RCC is not persuasive.18 30

    Our study has several methodological strengths. The use of panels of local experts and the collection of additional detailed information through the use of specialised questionnaires is considered a superior approach in retrospective assessment of occupational exposures in community-based studies.31 We aimed at validity and consistency in exposure assessment across countries by stressing the joint training of the experts, and a validation exercise (which, however, did not include lead) indicated good reliability in the assessments of a range of occupational agents.7 The large sample size, and the high response rates are additional strengths of our study.

    A potential limitation of the study is the use of hospital-based controls, whose exposure distribution might not represent that of the underlying population.32 We attempted to address this by recruiting controls with a wide range of diagnoses. Apart from neurological conditions, the diseases of the controls are not known to be associated with heavy metal exposure. The results for tobacco smoking, showing no association with RCC, are compatible with a small excess risk, but can also suggest bias from the selection of controls. On the other hand, tobacco smoking is a relatively weak risk factor of RCC, and several other studies did not detect an association.33 Potential residual confounding by uncontrolled occupational and environmental metal exposure from general air pollution is an additional limitation. The lack of environmental measurements is an important additional limitation of our study, which had to rely on retrospective recall by study subjects of their occupational history and other risk factors. However, since controls were also hospital patients, any bias in recall is likely to be non-differential with respect to exposure, which would tend to attenuate risk estimates. Exposure misclassification is difficult to exclude in studies based on retrospective assessment; this would result in effect underestimation if it is non-differential between cases and controls. The limited number of subjects exposed to the metals under study is an additional limitation to take into consideration.

    A major problem in studies of health effects of occupational exposure to metals is the difficulty in isolating the effects of a specific metal, because of coexisting exposures in most occupational settings. In addition, metal-induced carcinogenesis depends not only on the level and duration of exposure, but also on speciation of the metals, as physicochemical characteristics of metals and their compounds can influence their toxicokinetics and toxicodynamics and therefore their biological effects.34 In addition, genetic susceptibility likely modifies the effect of metal exposure on RCC risk. A recent study evaluated the interaction effect of glutathione S-transferase (GST) M1 and T1 null polymorphisms on the association between occupational metal exposure and RCC risk.35 Compared with GSTM1 null subjects, those with the active allele showed a higher risk of RCC associated with exposure to metals. Although suggestive, this finding requires confirmation.

    Nephrotoxicity of these metals is explained by the fact that urinary elimination is a main route of excretion from body and by the high reabsorptive activity of proximal tubules, leading to metal accumulation in the kidneys, largely in the proximal tubule cells. Thus, the proximal tubule seems to be the major site of metal-induced nephrotoxicity. The mechanisms of nephrotoxicity at the cellular level of various toxic metals are still known only in fragments.36 Recent studies using in vivo and in vitro models of nephrotoxicity have indicated an oxidative stress with associated lipid peroxidation, apoptosis and necrosis as common phenomena in the course of nephrotoxicity of these metals induced by toxic metals.36 However, a number of other phenomena, such as the selective inhibition and/or loss of various membrane transporters, enhancement of ion conductances, increased cytoplasmic concentration of calcium, deranged cytoskeleton and cell polarity, impaired endocytosis, swelling and fragmentation of mitochondria, increased expression of metallothionein, heat-shock and multidrug resistance proteins, loss of cell membrane integrity, as well as the damage of mitochondrial and genomic DNAs have been fragmentarily demonstrated for the action of some toxic metals, but their importance for the course of nephrotoxicity and the sequence of events in relation to oxidative stress, apoptosis and necrosis have not been clearly established.36 Finally, the few isolated studies of combined metal exposures indicate that the pathological effects may be altered due to unknown interactions of these metals within the kidney. Biological factors within the cell such as metal-binding proteins and inclusion bodies may also influence metal–metal interactions37 Metals can therefore cause cellular and molecular lesions that would be relevant to oncogenesis in various cellular model systems. Several diverse mechanisms of metal-induced carcinogenesis may be involved, and they are believed to be involved in all stages of cancer development. Since carcinogenesis induced by metals involves a variety of facets, it is difficult to identify one common mechanism. It is very likely that each metal has its own unique molecular mechanisms which contribute to the cancer development. However, several common pathways, including those initiated by oxidative stress, may be shared by several of these carcinogenic metals. Moreover, they can also enhance carcinogenic effects with other factors in an additive or synergistic manner.37

    In conclusion, the results of our study do not support an increased risk of RCC following occupational exposure to chromium, nickel or arsenic. For cadmium, the lack of statistical significance of most results, the possibility of confounding and the absence of clear dose–response relations argue against the conclusion that RCC is induced by occupational exposure to cadmium. In the case of lead, the elevated risk in the category of highest cumulative exposure is noteworthy and justifies further investigations.

    Acknowledgments

    The authors thank K Straif, IARC, for his comments on the final draft of the manuscript.

    Appendix 1

    Examples of jobs entailing cadmium and lead exposure

    Cadmium

    Fumes

    • High: zinc smelting, foundries, welding or soldering on cadmium plated material (eg, aircraft industry, electronics), cadmium plating, manufacture of cadmium-tin welding rods.

    • Medium: welding or soldering with cadmium-tin welding rods (mainly magnesium welding), foundries using a lot of scrap metals, manufacture of silver welding rods.

    • Low: welding or hard brazing with silver rods; plastic pyrolysis products (from cadmium pigments or stabilisers) with a low confidence.

    Dust

    • High: foundries (casting areas), manufacture of silver or cadmium-tin welding rods, manufacture of cadmium pigments or other cadmium compounds.

    • Medium: mechanical loading or mixing of cadmium compounds (eg, plastic industry, paint manufacture), polishing or mechanical work on cadmium plated parts.

    • Low: hand work on or buffing cadmium plated parts.

    Lead (fumes and dusts not broken out)

    • High (>150 μg/m3): ore processing lead or alloy or brass foundries; secondary smelting; torch cutting of scrap metal or lead painted parts; welding of galvanised parts; hot tinning; ammunition manufacture; indoor firing with unjacketed bullets; manufacture of lead salts or alkyds; kiln workers in pottery, ceramic, or glass factories; spraying of high lead paints or pottery glazes; indoor (dry) hand scraping of lead paints; grinding or blasting of lead painted parts; manual typography; dry cleaning of lead contaminated areas; sand blasting; lead acid battery manufacture.

    • Medium (50–150 μg/m3): tin, copper, ferrous, or scrap metal foundries; masonry for furnaces or tanks; mechanical typography; battery assembly or conditioning; sorting, loading, or delivering of batteries; indoor (wet) hand scraping of lead paints; brazing; hot galvanising; small quantities of manual lead melting; outdoor firing with unjacketed bullets; radiator soldering; radiator manufacture.

    • Low (<50 μg/m3): wave soldering; compounding or processing of polyvinyl chloride; gasoline and exhaust; lead arsenate use; incinerator fumes; outdoor hand scraping of lead paints; brazing; soldering.

    References

    1. ↵
      1. Schottenfeld D,
      2. Fraumeni JF
      1. McLaughlin JC,
      2. Lipworth L,
      3. Tarone RE,
      4. et al
      . Renal cancer. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. New York: Oxford University Press, 2006:1087–100.
    2. ↵
      1. Ferlay J,
      2. Shin HR,
      3. Bray F,
      4. et al
      . GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC CancerBase No 10 [Internet]. Lyon, France: International Agency for Research on Cancer, 2010. http://globocan.iarc.fr.
    3. ↵
      1. Stellman JM
      1. Hemstreet GP
      . Renal-urinary systems. In: Stellman JM, ed. The ILO Encyclopaedia of Occupational Health and Safety. 4th edn. Geneva: ILO, 1998;8:2–10.
      OpenUrl
    4. ↵
      1. IARC Working Group
      International Agency for Research on Cancer. Arsenic in drinking-water. IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 84. In: IARC Working Group, ed. Some Drinking-Water Disinfectants and Contaminants, Including Arsenic. Lyon: IARC, 2004:39–267.
      OpenUrl
    5. ↵
      1. Fabianova E,
      2. Szeszenia-Dabrowska N,
      3. Kjaerheim K,
      4. et al
      . Occupational cancer in Central European countries. Environ Health Perspect 1999;107(Suppl 2):279–82.
      OpenUrlPubMedWeb of Science
    6. ↵
      1. Percy C,
      2. van Holten V,
      3. Muir C
      . International Classification of Diseases for Oncology. 2nd edn. Geneva: WHO, 1990.
    7. ↵
      1. Scelo G,
      2. Constantinecu V,
      3. Csika I,
      4. et al
      . Occupational exposure to vinyl chloride, acrylonitrile and styrene and lung cancer risk (Europe). Cancer Causes Control 2004;15:445–52.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Hashibe M,
      2. Boffetta P,
      3. Zaridze D,
      4. et al
      . Contribution of tobacco and alcohol to the high rates of squamous cell carcinoma of the supraglottis and glottis in Central Europe. Am J Epidemiol 2007;165:814–20.
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Mannetje A,
      2. Fevotte J,
      3. Fletcher T,
      4. et al
      . Assessing exposure misclassification by expert assessment in multicenter occupational studies. Epidemiology 2003;14:585–92.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      International Labour Office. International Standard Classification of Occupations. Revised Edition 1968. Geneva: ILO, 1968.
    11. ↵
      1. IARC Working Group
      International Agency for Research on Cancer. IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 87. In: IARC Working Group, ed. Inorganic and Organic Lead Compounds. Lyon: IARC, 2006:39–468.
      OpenUrlFREE Full Text
    12. ↵
      1. Steenland K,
      2. Boffetta P
      . Lead and cancer in humans: where are we now? Am J Ind Med 2000;38:295–9.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. IARC Working Group
      International Agency for Research on Cancer. Cadmium and cadmium compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 58. In: IARC Working Group, ed. Beryllium, Cadmium, Mercury, and Exposures in the Glass Manufacturing Industry. Lyon: IARC, 1993:119–237.
      OpenUrl
    14. ↵
      1. Satarug S,
      2. Moore MR
      . Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect 2004;112:1099–103.
      OpenUrlPubMedWeb of Science
    15. ↵
      1. Bernard A
      . Renal dysfunction induced by cadmium: biomarkers of critical effects. Biometals 2004;17:519–23.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Mandel JS,
      2. McLaughin JK,
      3. Schlehofer B,
      4. et al
      . International renal-cell cancer study. IV. Occupation. Int J Cancer 1995;61:601–5.
      OpenUrl
    17. ↵
      1. Pesch B,
      2. Haerting J,
      3. Ranft U,
      4. et al
      . Occupational risk factors for renal cell carcinoma: agent-specific results from a case–control study in Germany. MURC Study Group. Multicenter Urothelial and Renal Cancer. Int J Epidemiol 2000;29:1014–24.
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Hu J,
      2. Mao Y,
      3. White K
      . Renal cell carcinoma and occupational exposure to chemicals in Canada. Occup Med 2002;52:157–64.
      OpenUrlAbstract
    19. ↵
      1. Brüning T,
      2. Pesch B,
      3. Wiesenhütter B,
      4. et al
      . Renal cell cancer risk and occupational exposure to trichloroethylene: results of a consecutive case–control study in Arnsberg, Germany. Am J Ind Med 2003;43:274–85.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Il'yasova D,
      2. Schwartz GG
      . Cadmium and renal cancer. Toxicol Appl Pharmacol 2005;207:179–86.
      OpenUrlPubMedWeb of Science
    21. ↵
      1. IARC Working Group
      International Agency for Research on Cancer. Chromium and chromium compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 49. In: IARC Working Group, ed. Chromium, Nickel and Welding. Lyon: IARC, 1990:49–256.
      OpenUrlPubMed
    22. ↵
      1. Cole P,
      2. Rodu B
      . Epidemiologic studies of chrome and cancer mortality: a series of meta-analyses. Regul Toxicol Pharmacol 2005;43:225–31.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Sunderman FW,
      2. Maenza RM,
      3. Hopfer SM,
      4. et al
      . Induction of renal cancers in rats by intrarenal injection of nickel subsulfide. J Environ Pathol Toxicol 1979;2:1511–27.
      OpenUrlPubMed
    24. ↵
      1. Kasprzak KS,
      2. Diwan BA,
      3. Konishi N,
      4. et al
      . Initiation by nickel acetate and promotion by sodium barbital of renal cortical epithelial tumors in male F344 rats. Carcinogenesis 1990;11:647–52.
      OpenUrlAbstract/FREE Full Text
    25. ↵
      1. Haugen A,
      2. Machle L,
      3. Mollerup S,
      4. et al
      . Nickel-induced alterations in human renal epithelial cells. Environ Health Perspect 1994;102(Suppl 3):117–18.
      OpenUrl
    26. ↵
      1. IARC Working Group
      International Agency for Research on Cancer. Nickel and nickel compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 49. In: IARC Working Group, ed. Chromium, Nickel and Welding. Lyon: IARC, 1990: 257–445.
      OpenUrlPubMed
    27. ↵
      1. et al
      1. Arena VC,
      2. Sussman NB,
      3. Redmond CK
      et al. Using alternative comparison to assess occupation-related mortality risk. Results for the high nickel alloys workers cohort. J Occup Environ Med 1998;40:907–16.
      OpenUrlCrossRefPubMedWeb of Science
    28. ↵
      1. Schottenfeld D,
      2. Fraumeni JF
      1. Silverman DT,
      2. Devesa SS,
      3. Moore LE,
      4. et al
      . Bladder cancer. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. 3rd edn. Oxford University Press, New York. 2006:1101–27.
    29. ↵
      1. Tchounwou PB,
      2. Patlolla AK,
      3. Centano JA
      . Carcinogenic and systemic health effects associated with arsenic exposure—a critical review. Toxicol Pathol 2003;31:575–88.
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Enterline PE,
      2. Day R,
      3. Marsh GM
      . Cancers related to exposure to arsenic at a copper smelter. Occup Environ Med 1995;52:28–32.
      OpenUrlAbstract/FREE Full Text
    31. ↵
      1. Siemiatycki J
      . Exposure assessment in community-based studies of occupational cancer. Occup Hyg 1996;3:41–58.
      OpenUrl
    32. ↵
      1. Wacholder S,
      2. Silverman DT,
      3. McLaughlin JK,
      4. et al
      . Selection of controls in case–control studies. II. Types of controls. Am J Epidemiol 1992;135:1029–41.
      OpenUrlAbstract/FREE Full Text
    33. ↵
      International Agency for Research on Cancer. Tobacco Smoke and Involuntary Smoking. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Vol. 83. Lyon: International Agency for Research on Cancer, 2004.
    34. ↵
      1. Yokel RA,
      2. Lasley SM,
      3. Dorman DC
      . The speciation of metals in mammals influences their toxicokinetics and toxicodynamics and therefore human health risk assessment. J Toxicol Environ Health B Crit Rev 2006;9:63–85.
      OpenUrlCrossRefPubMed
    35. ↵
      1. Buzio L,
      2. De Palma G,
      3. Mozzoni P,
      4. et al
      . Glutathione S-transferases M1-1 and T1-1 as risk modifiers for renal cell cancer associated with occupational exposure to chemicals. Occup Environ Med 2003;60:789–93.
      OpenUrlAbstract/FREE Full Text
    36. ↵
      1. Sabolić I
      . Common mechanisms in nephropathy induced by toxic metals. Nephron Physiol 2006;104:107–14.
      OpenUrlCrossRef
    37. ↵
      1. Leonard SS,
      2. Bower JJ,
      3. Shi X
      . Metal-induced toxicity, carcinogenesis, mechanisms and cellular responses. Mol Cell Biochem 2004;255:3–10.
      OpenUrlCrossRefPubMed
    View Abstract

    Footnotes

    • Funding This study was supported by a grant from the European Commission's INCO-COPERNICUS Program (contract IC15-CT98-0332) and by the Intramural Research Program of the US National Cancer Institute.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Ethics approval was provided by the IARC and national collaborating centres.

    • Provenance and peer review Not commissioned; externally peer reviewed.