Occupational and Environmental Medicine 1995;52:73-8 1 Cancer and occupational exposure to inorganic lead compounds: a meta-analysis of published data Hua Fu, Paolo Boffetta Abstract Objectives-To review and summarise the epidemiological evidence on the carcinogenicity of occupational exposure to inorganic lead. Methods-Case-control and cohort studies were reviewed and combined for meta-analysis. Fixed and random effect methods were used to estimate the summary effects. Results-The combined results show a significant excess risk of overall cancer, stomach cancer, lung cancer, and blad- der cancer, with relative risk ratios (RRs) and 95% confidence intervals (95% CIs) in the meta-analysis of 111 (105-117), 133 (118-149), 1-29 (1-10-1.50), and 1-41 (1'16-1-71) respectively. The RR (95% CI) for kidney cancer was also high, but did not reach significance (1.19 (0-96-148)). A separate analysis of studies of heavily exposed workers provided slightly increased RRs for cancers of the stomach (1.50) and lung (1.42). Conclusions-The findings from the workers with heavy exposure to lead pro- vided some evidence to support the hypothesis of an association between stomach and lung cancer and exposure to lead. The main limitation of the present analysis is that the excess risks do not take account of potential confounders, because little information was available for other occupational exposures, smok- ing, and dietary habits. To some extent, the risk of lung cancer might be explained by confounders such as tobacco smoking and exposure to other occupa- tional carcinogens. The excess risk of stomach cancer may also be explained, at least in part, by non-occupational fac- tors. For bladder and kidney cancers, the excess risks are only suggestive of a true effect because of possible publication bias. (Occup Environ Med 1995;52:73-81) Keywords: lead; neoplasms; meta-analysis Lead, one of the metals longest known to humans, is a major occupational toxin. Although poisoning due to occupational exposure to lead has been recognised for over 2000 years, the importance of lead in industry has led to its widespread production and use particularly for storage batteries. Whether lead is a carcinogen, however, is still not known. In 1980 and 1987, the International Agency for Research on Cancer (IARC) evalu- ated the evidence for carcinogenicity of lead and its compounds' 2 and classified lead and inorganic lead compounds as possible human carcinogens (IARC group 2B), on the basis of sufficient evidence for carcinogenicity in experimental animals but inadequate evidence for carcinogenicity in humans. Also, two epi- demiological studies have focused on expo- sure to organolead compounds. One found a prevalence of 5% (7/139) for skin cancer among workers exposed to tetraethyl lead, and among non-exposed workers of 2-9% (4/139).3 The other found excesses of res- piratory cancer (observed three, SMR 1-34, 90% CI 0 82-2 05) and brain cancer (observed three, SMR 1 86, 90% CI 0-51-4-82) in a cohort of 2510 workers who manufactured tetraethyl lead.4 Based on this inadequate evidence from human as well as animal studies, organolead compounds were placed in group 3 (not classifiable as carcino- genic to humans) by IARC.' 2 Insufficient statistical power is one potential reason for the inconsistent findings from epidemiological studies of occupational exposure to lead, as well as variability of type, level of exposure, and differences of study design. Although several reviews on carcino- genicity of occupational exposure to lead have appeared,5 none of these has provided a quantitative meta-analysis. The purpose of this review is to examine the complete scien- tific literature and carry out a quantitative assessment (meta-analysis) of the epidemio- logical results available on the carcinogenicity of exposure to lead and inorganic lead com- pounds (from now on referred to simply as lead). Description of previous epidemiological studies Exposure of workers to high concentrations of lead occurs in a variety of manufacturing processes. The principal types of primary industry with occupational exposure to lead are lead mining, smelting and refining, storage battery manufacture, welding and steel cut- ting, and printing.8 The highest exposure to lead occurs in the smelting and refining of the metal, where mean concentrations of lead in air can reach 4470 pg/M3n. Lead oxide dust seems to be the most common hazard in the manufacture of storage batteries, with recorded mean airborne concentrations of Unit of Analytical Epidemiology, International Agency for Research on Cancer, 150 Cours Albert-Thomas, F-69372 Lyon Cedex 08, France H Fu P Boffetta Department of Preventive Medicine, Shanghai Medical University, Shanghai 200032, People's Republic of China H Fu Correspondence to: Dr P Boffetta, Unit of Analytical Epedimiology IARC, 150 Cours Albert- Thomas, F-69372 Lyon Cedex 08, France. Accepted 15 September 1994 73 on May 26, 2021 by guest. Protected by copyright. http://oem.bmj.com/ Occup Environ Med: first published as 10.1136/oem.52.2.73 on 1 February 1995. Downloaded from
Transcript
Occupational and Environmental Medicine 1995;52:73-8 1
Cancer and occupational exposure to inorganiclead compounds: a meta-analysis of publisheddata
Hua Fu, Paolo Boffetta
AbstractObjectives-To review and summarisethe epidemiological evidence on thecarcinogenicity of occupational exposureto inorganic lead.Methods-Case-control and cohortstudies were reviewed and combined formeta-analysis. Fixed and random effectmethods were used to estimate thesummary effects.Results-The combined results show asignificant excess risk of overall cancer,stomach cancer, lung cancer, and blad-der cancer, with relative risk ratios (RRs)and 95% confidence intervals (95% CIs)in the meta-analysis of 111 (105-117),133 (118-149), 1-29 (1-10-1.50), and 1-41(1'16-1-71) respectively. The RR (95% CI)for kidney cancer was also high, but didnot reach significance (1.19 (0-96-148)).A separate analysis of studies of heavilyexposed workers provided slightlyincreased RRs for cancers of the stomach(1.50) and lung (1.42).Conclusions-The findings from theworkers with heavy exposure to lead pro-vided some evidence to support thehypothesis of an association betweenstomach and lung cancer and exposure tolead. The main limitation of the presentanalysis is that the excess risks do nottake account of potential confounders,because little information was availablefor other occupational exposures, smok-ing, and dietary habits. To some extent,the risk of lung cancer might beexplained by confounders such as tobaccosmoking and exposure to other occupa-tional carcinogens. The excess risk ofstomach cancer may also be explained, atleast in part, by non-occupational fac-tors. For bladder and kidney cancers, theexcess risks are only suggestive of a trueeffect because of possible publicationbias.
(Occup Environ Med 1995;52:73-81)
Keywords: lead; neoplasms; meta-analysis
Lead, one of the metals longest known tohumans, is a major occupational toxin.Although poisoning due to occupationalexposure to lead has been recognised for over2000 years, the importance of lead in industryhas led to its widespread production and useparticularly for storage batteries. Whether
lead is a carcinogen, however, is still notknown. In 1980 and 1987, the InternationalAgency for Research on Cancer (IARC) evalu-ated the evidence for carcinogenicity of leadand its compounds' 2 and classified lead andinorganic lead compounds as possible humancarcinogens (IARC group 2B), on the basis ofsufficient evidence for carcinogenicity inexperimental animals but inadequate evidencefor carcinogenicity in humans. Also, two epi-demiological studies have focused on expo-sure to organolead compounds. One found aprevalence of 5% (7/139) for skin canceramong workers exposed to tetraethyl lead,and among non-exposed workers of 2-9%(4/139).3 The other found excesses of res-piratory cancer (observed three, SMR 1-34,90% CI 0 82-2 05) and brain cancer(observed three, SMR 1 86, 90% CI0-51-4-82) in a cohort of 2510 workers whomanufactured tetraethyl lead.4 Based on thisinadequate evidence from human as well asanimal studies, organolead compounds wereplaced in group 3 (not classifiable as carcino-genic to humans) by IARC.'2
Insufficient statistical power is onepotential reason for the inconsistent findingsfrom epidemiological studies of occupationalexposure to lead, as well as variability of type,level of exposure, and differences of studydesign. Although several reviews on carcino-genicity of occupational exposure to lead haveappeared,5 none of these has provided aquantitative meta-analysis. The purpose ofthis review is to examine the complete scien-tific literature and carry out a quantitativeassessment (meta-analysis) of the epidemio-logical results available on the carcinogenicityof exposure to lead and inorganic lead com-pounds (from now on referred to simply aslead).
Description ofprevious epidemiologicalstudiesExposure of workers to high concentrations oflead occurs in a variety of manufacturingprocesses. The principal types of primaryindustry with occupational exposure to leadare lead mining, smelting and refining, storagebattery manufacture, welding and steel cut-ting, and printing.8 The highest exposure tolead occurs in the smelting and refining of themetal, where mean concentrations of lead inair can reach 4470 pg/M3n. Lead oxide dustseems to be the most common hazard in themanufacture of storage batteries, withrecorded mean airborne concentrations of
Unit ofAnalyticalEpidemiology,International Agencyfor Research onCancer, 150 CoursAlbert-Thomas,F-69372 LyonCedex 08, FranceH FuP BoffettaDepartment ofPreventive Medicine,Shanghai MedicalUniversity, Shanghai200032, People'sRepublic of ChinaH FuCorrespondence to:Dr P Boffetta, Unit ofAnalytical EpedimiologyIARC, 150 Cours Albert-Thomas, F-69372 LyonCedex 08, France.
Table 1 Case reports of renal tumor associated with heavy exposure to Pb
Age PbB(y) Employment (ugldl) Remarks Reference
48 Furnace 64 The tumour (renal cell carcinoma) Baker et al (1980)1tender at a contained 2-47 pg of lead/gsmelter for tissue, the renal contex contained22 y 1-07,ug/g, and renal medulla 0-78
pg/g (normal adult range: 0-27-1-27Pg/g)-
61 In a secondary 83 He had been repeatedly tested for PbB Lilis (1981)2lead smeltery and treated with morefor 34 y than five courses of chelation treatment
during the period ofemployment.
Pb = lead; PbB = blood lead.
lead from 50 to 5400 yg/m'.8 Exposure to leadfume occurs during high temperature (>500'C) operations such as welding or spray
coating of metals with molten lead. An aver-
age lead concentration in the breathing zone
of welders of structural steel has been foundto be 1200 ,ug/m'. According to the classifica-tion by Hernberg,9 among the high risk opera-tions are activities in which metallic lead or
lead coated materials are burned and leadfumes in high concentrations are generated;these include welding, cutting of lead and leadpainted constructions, spray painting, mixingof lead salt stabilisers used in the productionof polyvinyl chloride plastic, mixing of crystalglass mass, sanding or scrapping of lead paint,burning of lead in enamelling workshops, andrepairing of automobile radiators. Workers atmoderate risk include lead miners, solderers,plumbers, cable makers, automobile repairmechanics, ship repair workers, lead founders,lead glass blowers, and pottery glaze makers.We used Medline Express to search the sci-
entific medical literature; epidemiologicalstudies were found in only a few of thoseindustries mentioned above-that is, thosethat involve batteries, smelting, pigment,printing, and glass. In the industries withobviously mixed exposure such as pigment,glassworks, and printing, only those studiesthat separated lead exposure were selected.To reduce the extent of publication bias, an
Table 2 Characteristics of the cohort studies of expsoure to Pb
Study population Industry Follow up Exposure Reference
425 Male pensioners Battery 1926-60(1926-60, UK)
1898 Pensioners(1644 Men and 254women), 1925-76(including those above, UK)2352 Menand4680 Men(1946-70, USA)2300 Men and4519 Men,(same as above)1987 White men employed monthlyfor >1 y(1940-65, USA)1900 Workers(same as above)3831 Men firstemployed before 1967 for> 3 months, (Sweden)437 Workers employed> 3 y at worksites with highexposure to Pb (subcohort from above)57 Men with non-fatalclinical Pbpoisoning (1930-45, UK)1046 Menemployed past andpresent at any time,(1940-69, USA)700 Compositors and460 Pressmen (USA)1027 Compositors and778 Pressmen (USA)
700 Workers employed for > 5 y(before 1956, Italy)
1261 Male typesetters(employed in 1961, USA)468 Workers employedfor > 1 y,(1953-67, Italy)625 Male artglassworkers) 1 month ofemployment,(1964-1985, Sweden)1803 Men and 1946women, > 3 monthsof empoyment(Finland)
1925-76
Smelter
Battery
SmelterBatterySmelter
Smelter
Smelter
1946-70
1946-70
1946-801946-80
1940-77
1940-88
1950-81
158 Workers without exposure to Pb80 with light exposure,187 with PbU100-250,ug/l339 Workers without exposure to Pb626 with light exposure,933 with high exposure
Mean: PbU 173-2,ug/l,PbB 79 7,ug/dl;PbU 129 7,ug/l,PbB 62-7,ug/dlSame as above
Mean: airborne Pb 3-1 mg/mi,(standard at the time 0-2 mg/mi)PbB 56-3,ug/dlSame as above
Dingwall-Fordyce and Lane(1963)V3
Malcolm and Darnett (1982)'4
Cooper and Gaffey (1975)15
Cooper et al (1985)'6
Selevan et al (1985) l'
Steenland et al (1992) 8
Gerhardsson et al (1986)'9
Mean: PbB (1950) 58 2,ug/dlPbB (1974) 33 6,ug/dl
Pigment factory < 1981
Pb and Zn < 1979chromate pigment
Printing 1947-62
Printing 1958-69
Printing 1956-75
Printing 1961-84
Glassworks < 1985
None
Pb: Zn = 9:1no data onexposure to Pb available
Oil mist in air 5-21 mg/m3;No exposure to Pb availableGross ink mist 12-2 mg/mr;Respirable ink mist 1-4 mg/miNo exposure to Pb availableJob categories:compositors and stereotypes;photographers and photoengravers;pressmen;packers and forwarders;others12,ug Pb/m3, in 1942;< 10,ug Pb/m3 in 1970sProducing low qualityglass containers
Glassworks < 1964-85 0 001-0 110 mg Pb/m3
Glassworks 1953-86 Cohort was dividedinto oral glass blowers,automated glass blowers,and other glass workers
effort was also made to collect unpublishedpapers, and one report was obtained throughpersonal communication.'0
STUDIES BASED ON INDUSTRYCase reports of renal tumourThere are two case reports of renal tumourswith pathological evidence related to heavyexposure to lead." 12 Table 1 presents theirmajor characteristics.
Cohort studiesTable 2 presents the characteristics of cohortstudies of exposure to lead, and table 3 pre-
sents the results of these studies.Battery industry-The manufacture of elec-
tric storage batteries is a major source of occu-pational exposure to lead, especially leadoxide dust. In 1963, Dingwall-Fordyce andLane conducted a retrospective study of 425pensioners who had been exposed to lead inseveral companies in England."3 A non-signifi-cant increased risk for all malignant neo-
plasms was found. When the subjects were
divided into categories of exposure accordingto urinary lead concentrations, however, no
trend in risk was found with increased expo-sure.
In an extended cohort of 1898 pensionersfrom four lead acid battery companies inEngland based on the earlier study there was
no excess of deaths from all malignant neo-
plasms.'4 An excess of observed (136) over
expected (118-33) deaths from all cancer was,however, noted in men who died in service(proportionate mortality ratio (PMR) 1 15, P> 0 05). An increase in the PMR was seen
with exposure to lead, with a PMR for no
exposure of 1 02, for light exposure 1-06, andfor high exposure 1 30. A more detailedanalysis showed an excess of malignant neo-
plasms of the digestive tract among men inthe group with no exposure to lead who diedin service, with 21 observed against 12-56expected deaths (PMR 1-67, P = 0 009). Thisexcess mortality was almost entirely confinedto the period 1963 to 1966.
Battery plants and smelter workers-Cooperand Gaffey undertook a study of a cohort of7032 male workers in six lead productionfacilities (2352 men) and 10 battery plants(4680 men) in the United States.'5 High risksfor all malignant neoplasms were found sepa-rately among the smelter workers (significant)and the battery workers (NS). There were
excesses in deaths from digestive and respira-tory cancers among both smelter and batteryworkers. Only the SMR for respiratory cancer
among the battery workers was significant.Deficits of cancer of the urinary tract were
seen in these two subcohorts. Attempts torelate SMRs by cause to a classification intohigh, medium, low, and unknown exposure tolead produced no consistent results.
In 1985, Cooper et al'6 updated their previ-ous cohort study'5 to 1980. They expandedthe period of follow up from 24 to 34 years.They found a significant excess of deaths dueto all malignant neoplasms among the batteryworkers, which was largely explained by more
*High Pb/low other metals exposure; thigh exposure to Pb; tselected for meta-analysis; §95%CI was recalculated by present authors based on the observed deaths and the expected fromoriginal paper.
All exposure forevery 10 y ofemploymentExposure to Pb
/level-decade
Wingren and Axelson (1987)36
Siemniatycki (199 1)39
Ades and Kazantzis (1988)3"
Fanning (1988) 34
Wingren and Axelson (1987)36
Special for Pb Wingren and Axelson (1933)38
Siemiatycki (199 1)39
Test for trend:P > 0.05
Cooper (1989)'
Fanning (1988)84
For men,adjusted bycigarette smoking
P < 0.05
Risch et al (1988)"
Siemiatycki (1991)"
Siemiatycki (1991)"
Mallin et al (1989)40
* 0 1 level of significance; t selected for meta-analysis.
deaths than expected from malignancies ofthe stomach and lung. Among the smelterworkers, although there were excesses ofdeaths due to malignancies of all sites, thestomach, and lung, none reached significancebecause of small numbers. There were stilldeficits of deaths from malignancies of thekidney among both the battery and thesmelter workers.To attempt to evaluate the relative roles of
occupational and non-occupational factors fora significant excess of deaths from stomachcancer found in the subcohort of 4519 batteryworkers already mentioned,16 a nested case-
control study was carried out by Cooper etal.'0 Thirty cases and 120 controls were
involved in the study. No association was
detected between occupational exposure tolead and gastric cancer. Comparison of thecases and the controls based on quartiles foremployment and on months of employment10 and 20 years before death showed no trendof odds ratios (ORs) with the increasingemployment period. There were more foreignpeople among the cases, with an OR of 1 29(P > 0.05).Smelters-To examine patterns of death in
lead smelter workers, a retrospective analysisof mortality was conducted at a primary leadsmelter in the United States.'7 Exposures indepartments with high lead and those withhigh lead and low other metals were deter-mined from data obtained by an industrialhygiene survey. Overall mortality from cancer
was not raised. Non-significant excesses ofstandardised mortality ratios (SMRs) were
noted for respiratory cancer and kidney can-
cer. The SMR for kidney cancer in areas ofhigh lead and low other metal exposure
approached significance (SMR 3-01, 95% CI0-98-7 03). There was an increasing trend ofSMRs for lung cancer and kidney cancer withduration of exposure. The SMRs for lungcancer and for kidney cancer in the latentperiod of > 20 years were increased, althoughnone of these excesses was significant.
Steenland et al extended the follow up ofthis lead smelter cohort from 1977 up to1988.'1 There were still non-significantexcesses of deaths due to cancers of the stom-ach, lung, kidney, and bladder in the entirecohort. A significant SMR (95% CI) of 2-39(1 03-4-71) for kidney cancer, however, was
shown in the high exposure to lead group. A
Table S Meta-analysis for selected cancer sites of the studies of occupational exposure to Pb *
Overall Stomach Lung Lung Kidney BladderStatistics cancer cancer cancer(l) cancer(2)t cancer cancer
* All cohort and case-control studies reviewed were selected for meta-analysis except studies by Goldstein et al 22 and Pastemack and Ehrlich23 due to no RRavailable.t RRs (95% CI) were estimated with the random effect approach.42
* Only the studies that were conducted in battery or smelter industries were selected for meta-analysis.t RRs (95% CI) were estimated with the random effect approach.42
separate analysis of this high lead group,excluding those who had ever worked in twodepartments with high exposure to cadmium,continued to show an excess of kidney cancer.
Gerhardsson et al conducted a retrospectivecohort mortality study at a copper smelter innorthern Sweden, where lead was a major air-borne contaminant in the workplace.'9 In theentire cohort, the overall mortality and themortality from all malignant neoplasms weresignificantly increased. There were signifi-cantly high SMRs for stomach cancer andlung cancer. In the subcohort with high expo-sure to lead, non-significant deficits of overallmortality and of all malignant neoplasms werefound. A high SMR remained only for lungcancer, but was not significant. No consistentdose-response pattern was seen when the sub-cohort was subdivided according to mean orpeak blood lead values. The changes in SMRsfor all malignant neoplasms, lung cancer, andstomach cancer were marginal when a latentperiod of 15 years was used for analysis.
Pigment factories-In the manufacture oflead chromate pigment, lead exposure usuallyoccurs during the grinding or handling of thedried colours, along with exposure to chro-mates. Lead poisoning is often seen in work-ers from these factories. Davies analysed longterm mortality among workers who had leadpoisoning in three factories that made leadchromate pigments, which were generallybased on lead nitrate produced on site frommetallic lead and nitric acid.20 A total of 57men had non-fatal clinical lead poisoning, andamong 38 deaths, seven were from cancer:four from lung cancer and one each fromstomach cancer, colon cancer, and lymphaticleukaemia. The mortality from lung cancershowed a non-significant excess.
Sheffet et al conducted a cohort study in apigment factory in Newark, NJ, USA,which produced lead chromate pigment andzinc chromate pigment.21 Deficits of overallmortality and all malignant neoplasms werefound. There was, however, a significant ratioof 1 6 between observed and expected num-bers of deaths resulting from lung canceramong white men. The increase in deathsfrom lung cancer was also significant in whitemen for groups employed for >10 years(ratio 1:7) and for .2 years with at leastmoderate exposure (ratio 2:1). The ratios ofobserved to expected numbers of deaths fromstomach cancer was 2, pancreatic cancer1-7, and Hodgkin's disease 2-9, but thesewere not significant. Histories on smokingwere available for 14 of those who died of
lung cancer: 13 smoked, nine heavily. No spe-cific analysis for lead exposure was done.
Printing trades-Diseases related to leadhave long been one of the occupational haz-ards of the printing trades, although the use oflead has been almost entirely eliminated inrecent years with the introduction of photo-composition. Major occupational exposure tolead often occurred among compositors andstereotypers. There were many studies con-cerned with the mortality from cancer inprinting workers, but only four dealt specifi-cally with the occupations related to exposureto lead. Goldstein et al compared the 15 yearmortality of pressmen exposed to oil mist withthat of compositors in the printing industry,and found a slightly higher incidence of lungcancer in the compositors (six observed,incidence 1 170/1000) than in the pressmen(three observed, incidence 1.073/1000).22Another mortality study among pressmen andcompositors showed crude, non-specific deathrates/1000 of 12-8 for pressmen and 14-0 forcompositors and mortality from all malignantneoplasms of 2-40 for the pressmen and 2-94for the compositors.23 Bertazzi and Zocchettiinvestigated the mortality of newspaper print-ing workers in Milan; among compositors andstereotypers there was no excess of deaths forany cause except for neoplasms of the lym-phatic and haematopoietic tissue, for whichan SMR of 200 was based on only onedeath.24 Michaels et al conducted a cohortstudy of newspaper printers employed at aNew York Typographical Union on 1 January1961 who were likely to have been exposed toairborne lead concentrations below the cur-rent Occupational Safety and Health ActPermitted Exposure Limit of 50,g/m3.25Significant deficits in mortality were seen forall causes. The SMR for all malignant neo-plasms was 0-84, a deficit that approachedsignificance (95% CI upper limit of 1 00).There were non-significant excesses for can-cer of the bladder and for cancer of the pros-trate.
Glass manufacturing industry-The produc-tion of glass involves the use of many metals,especially lead. The production of heavy crys-tal glass (containing about 30% lead) andother art glasses with traditional non-mecha-nised techniques is an important source ofoccupational exposure to lead.26 TheInternational Agency for Research on Cancerhas reviewed and evaluated the risk of cancerfrom exposures in the glass manufacturingindustry and concluded that the manufactureof art glass, glass containers, and pressed ware
entails exposures that are probably carcino-genic to humans (group 2A).'6
Cordioli and his colleagues investigated anItalian cohort of 468 workers at a plant thatproduced low quality glass containers.27Significantly increased relative risk ratios(RRs) for overall cancer, lung cancer, andlaryngeal cancer were found. A Swedishcohort study of 625 male art glass workersshowed that mortalities from lung cancer,colon cancer, and pharyngeal cancer were inexcess.28 Sankila et al studied the incidence ofcancer in a cohort of 1803 men and 1946women in two Finnish plain glass manufac-turing factories.29 The risk of stomach cancerwas increased in glassblowers who used oraland automated methods. For lung cancer,there was an increased risk among glassblowerswho used automated methods, but not amongoral glassblowers. On the other hand, anexcess of skin cancer (melanomas and basalcell carcinomas excluded) among oral glass-blowers was found.
Studies ofproportionate mortality ratio (PMR)Of 241 male smelter workers diagnosed ashaving lead poisoning between 1928 and1959 in New South Wales, Australia, 140deaths were identified in a study of long termmortality of heavily exposed workers.30Comparison between workers poisoned bylead and other workers showed that the stan-dardised proportional mortality ratio (SPMR)for cancer was decreased (0-59). AnotherPMR study of workers exposed to lead wasconducted by Cantor et al among 7121 whitemen; members and retirees of the UnitedAssociation of Plumbers and Pipefitters inCalifornia who died in 1960-1979.3" As wellas lead fumes during the sealing of cast ironpipe joints, these workers were also exposedto asbestos, polycyclic aromatic hydrocarbons(PAHs), and other hazardous materials.There were significant increases in deathsfrom all malignant neoplasms, stomach can-cer, lung cancer, brain cancer, all lymphopoi-etic cancer, cancer of other lymphatic tissue,and benign neoplasms. A non-significantexcess of deaths from kidney cancer was seen.Among plumbers, the PMRs for kidney can-cer and lymphosarcoma or reticulosarcomawere significantly raised. Pipefitters had a sig-nificantly raised PMR for cancer, primarilydue to excess lung cancer. The PMRs forother cancer sites did not show significantexcesses. Deaths due to all lymphopoieticmalignancies and especially "other lymphaticcancer", approached- a significant excess.Finally, a proportionate cancer mortalitystudy was conducted among employees of theUnited States Government Printing Office.32An excess of deaths from multiple myelomawas confined to white workers in the compos-ing room, where lead was the major occupa-tional exposure.
Case-control studiesTable 4 shows the results of case-controlstudies based on industry.
Based on a cohort study of 4393 employees
in a non-ferrous smelter where exposures tocadmium, zinc, sulphur dioxide, arsenic, lead,and dust occurred, a nested case-controlstudy of lung cancer was conducted to iden-tify carcinogenic effects from specific depart-ments, processes, and contaminants." Amongvarious contaminants studied, cumulativeexposures to lead, as well as to arsenic, werecorrelated with an increased risk of lung can-cer.A study of death certificates dating back to
1926 was carried out for a total of 2073 menwho were employed in several manufacturingfacilities that included plastics, electricalequipment, and engineering factories as wellas those producing lead acid and other batter-ies. Among these men, 867 who were consid-ered to have had high or moderate levels ofexposure to lead (group 1) and 1206 menwith little or no exposure to lead (group 2)were chosen for a case-control study.'4 Foreach cause of death, deaths from other causeswere used as controls. There was no differ-ence found for all malignant neoplasmsbetween the two groups over the wholeperiod, with an OR of 0 95. There was, how-ever, a clearly diminishing gradient in the ORsfor cancer of the digestive tract from 1 58 inthe period 1926-1945 and 1 47 in 1946-1965to 0-97 in 1966-1985. No differencesbetween the two groups or any sign of a secu-lar trend were seen for other types of malig-nant neoplasm.
COMMUNITY BASED STUDIESA case-control study, which included 826 his-tologically verified cases of urinary bladdercancer and 792 randomly selected controlsfrom the general population, was conductedin Canada.'5 The ORs for occupational expo-sure to 18 classes of substances were calcu-lated. For men, a significantly increased riskwas seen only for exposure to tars, asphalt,and to lead compounds. Furthermore, a sig-nificant trend in risk with duration of expo-sure to lead compounds was also found (P =0-008).Wingren and Axelson conducted a case-
control study of risk of cancer for glassworkersin Sweden,'6 based on a preliminary study inthree parishes with glass industries.'7 The reg-isters of deaths and burials in a total of 11parishes in 1950-1982 were used as thesource of subjects. A moderate but significantincreased OR was found for glassworkers fortotal cancer (1-2; 90% CI (1-02-1-4)), stom-ach cancer (1-5; 1-1-2-0), colon cancer (1-6;1.04-2-5), and lung cancer (1-7; 1 1-2 5). Aseparate analysis for occupational titlesshowed that the highest risks for the threesites of cancer was among glassblowers. Forthe group of unspecified glassworkers, signifi-cantly increased risks were seen for colon can-cer and lung cancer. The authors laterattempted to identify certain exposures asdeterminants of the cancer risks.38 The risk ofstomach cancer in particular was associatedwith exposure to arsenic, copper, nickel, man-ganese, and to some extent lead andchromium. For colon cancer, an increasing
Cancer and occupational exposure to inorganic lead compounds: a meta-analysis ofpublished data
trend in risk was seen with increased use ofantimony and lead. For lung cancer, no obvi-ous trend with exposure to any metal wasfound.
Siemiatycki conducted a case-control studyof 3730 cases with histologically confirmedcancer and completed interviews in theMontreal metropolitan area in Canada.39From the assessment of occupational expo-sure to 293 substances, he found a positiveassociation at the 10% significance levelbetween exposure to lead compounds andcancer of the stomach, lung, bladder, and kid-ney after controlling for age, cigarette smok-ing, family income, ethnic origin, and blue orwhite collar occupation. A case-control studyof 12 916 men based on death certificates ofwhite and black men in Illinois, USA showed asignificantly high OR of 3T0 (eight cases) forbrain cancer among white manufacturers ofglass and glass products.40
Table 4 shows the results of the communitybased case-control studies.
Combination of epidemiological studiesTo obtain a quantitative picture of the risk ofcancer due to exposure to lead, a meta-analysiswas conducted by combining the results fromthe analytical epidemiological studiesreviewed. Attention was focused on overallcancer, stomach cancer, lung cancer, kidneycancer, and bladder cancer. Only the mostrecent updated studies were included if therewere several studies conducted in the samepopulation. Meta-analysis was done with thefixed effect approach described byGreenland.4' Briefly, the statistical componentof a study weight, w, is the inverse variancecomputed from the estimated standard error,SE, as 1/SE2. The weighted mean B of sum-mary effects from the study results is theweighted sum of the results, divided by thesum of the weights, (B = 2wb/Zw). The esti-mate s of the standard error of this mean is theinverse of the square root of the sum of theweights, s = 1/ 2w. The RR of the meta-analysis as the summary effects is given byexp(B) and 95% CI for the summary effectsby exp(B ± 1 96s). A rough test of whetherthe assumed common value is zero is given byZ = B/s, which has a standard normal distribu-tion if the assumed common value is zero. Astatistical test of the homogeneity assumptionis given by X'h = Zw(b - B)2. When hetero-geneity was indicated the random effectapproach was used to estimate the summaryeffects (B) and its standard error (SE).42No correction for confounders was made
because there were no data available in mostreports.
Table 5 summarises the results of the com-bination of the case-control and cohort stud-ies except for two mortality studies that lackedan estimation of cancer risk.22"2 After combi-nation, there are slight to moderate but signif-icant excess risks for all the cancer sites ofinterest. Bladder and stomach cancers havethe highest and second highest risks; RRsobtained through meta-analyses are 1 41(95% CI 1-16-1-71) and 1-33 (1-18-1-49),
respectively. As there was heterogeneity of theRR for lung cancer across the studies, the ran-dom effect approach was used to estimate thesummary effect; an RR of the meta-analysis(95% CI) for lung cancer of 1-29 (1-10-1-50)was obtained, compared with a fixed effectRR of the meta-analysis of 1-24 (1-16-1-33).The RR of the meta-analysis for kidney can-cer was raised, but not significantly.When meta-analysis was restricted to studies
that were conducted in battery or smelterindustries where exposure to lead was heavy,higher risks for cancers of the stomach, lung,and kidney were found compared with thosein the total studies. The risk for stomach can-cer increased from 1-33 to 1-50, lung cancer(random effect model) from 1-29 to 1 42, andkidney cancer from 1 19 to 1-22 (table 6). Asthere was only one study that showed anyresult for bladder cancer, no combined analysiswas made for that.
DiscussionAlthough the separate epidemiological studieshave yielded inconsistent results, our meta-analysis indicates that there is a significantexcess of deaths from stomach cancer, lungcancer, and bladder cancer among workersexposed to lead. Exposure to lead in differentindustries varied greatly. It was thought thatexposure levels in battery or smelter industriesare much higher than those in pigment, print-ing, or glassworks. The analysis for the studiesin the industries with heavy exposure to leadproduced risks for stomach cancer and lungcancer about 20% higher than those in studieswith a range of exposures. The findings fur-ther provide positive evidence to support thehypothesis that there might be higher risks forstomach cancer and lung cancer among theworkers exposed to lead.
Based on the findings from experiments,Goyer raised a hypothesis on mechanisms ofcarcinogenesis from lead including muta-genicity, a nuclear protein effect, tumour pro-motion, cellular proliferation, and cystichyperplasia induced by lead. Lead is a weakmutagen in mammalian cell systems throughindirect mechanisms that include distur-bances in enzyme functions that are importantin DNA synthesis or repair and in the controlof the DNA helical structure.43 Low concen-trations of lead acetate can activate partiallypurified protein kinase C from rat brain. Thisfinding indicates that lead may be acting as acocarcinogen or tumour promoter.44 Togetherwith activation of the enzyme protein kinaseC, formation of nuclear inclusion bodies com-posed of a non-histone acidic protein com-plexed with lead may influence regulation ofcellular growth and division.45 These eventscould constitute a basis for carcinogenesisinduced by lead.A limitation of most of the studies reviewed
is a lack of data on the level of cumulativeexposure to lead, as well as on potentialconfounders such as smoking and dietaryhabits, and exposure to other chemicals.Furthermore, no attempt was made in anystudy to identify the effects of different types
of lead compounds. Animal experiments haveindicated that some compounds (lead acetate,lead subacetate, and lead phosphate) causetumours, whereas the evidence of carcino-genicity for others such as metallic lead andlead oxide is still inadequate.' Another limita-tion of meta-analyses is publication bias, dueto the fact that positive results may be morelikely to be published, and the published stud-ies may fail to mention negative results. In 14studies with results for several sites of cancer(ignoring the case-control studies specific fora cancer site), 13 present results for lung can-cer, nine for stomach cancer, five for kidneycancer, and four for bladder cancer. Thiscould imply that the pooled results may havean overestimation of the risk of kidney andbladder cancers due to unpublished negativeresults; the pooled results on lung cancer, onthe other hand, are less likely to have beeninfluenced by such bias.
LUNG CANCERTobacco smoking is the most important causeof lung cancer, and most of the studiesreviewed did not provide any information onthis factor. According to an estimate bySiemiatycki et al,46 the confounding by ciga-rette smoking in most occupations amountedto no more than an OR of 1 2, which is close tothe present RR from the meta-analysis forlung cancer in the total studies (1 29) but lessthan to that from the studies with heavy expo-sure to lead (1 -42). Therefore, it is unlikelythat confounding from tobacco smoking com-pletely explains the excess risk of lung canceramong the workers with heavy exposure tolead. One study has found that after adjust-ment for smoking, ethnic, and socioeconomicfactors, there remained a high risk of lungcancer for exposure to lead compounds.39
In experimental studies, the risk oflung cancer due to exposure to lead mightalso be raised through exposure to othercarcinogens. Kobayashi and Okamoto foundthat lead oxide, given concurrently withbenzo[a]pyrene by intratracheal injection, hada cocarcinogenic effect in the production ofbronchoalveolar neoplasms in hamsters.47
Also, workers exposed to lead in the work-place may be simultaneously exposed to othersubstances such as arsenic, cadmium, andchromium, which have been confirmed to becarcinogenic.48 In a study of non-ferroussmelters, Ades and Kazantzis found that thepartial correlation between arsenic and leadwas particularly high.3' In glassworks, leadand arsenic have been used in the productionof most kinds of art glass and exposures tothem are strongly correlated.38 Gerhardssonand Nordberg determined the concentrationsof antimony, arsenic, cadmium, chromium,cobalt, lanthanum, lead, selenium, and zinc inlung tissue of 85 deceased smelter workersfrom the same Swedish smelting plant alreadymentioned and 25 rural and urban controls.49Workers who died from lung cancer hadhigher concentrations of antimony, arsenic,cadmium, lanthanum, and lead in the lungtissue than workers with other diseases or therural and urban controls. Differences of cad-
mium concentrations between these twogroups reached significance. In contrast, theconcentrations of selenium were significantlylower in the lung cancer group. These find-ings suggest that the cause of lung canceramong smelter workers may be multifactorial,with metals other than lead playing the majorpart. Compared with the other studiesreviewed here, however, the risk of lung can-cer in the Swedish cohort was the highest andthis produced significant heterogeneity whenit was included in the meta-analysis. In theprimary lead smelter where the cohort studywas conducted by Steenland et al, the concen-trations of airborne arsenic and cadmium inthe workplace were low.18 So the findingsfrom Gerhardsson and Nordberg's studycould not be representative of all situationswith a high risk for lung cancer in our meta-analysis.49
STOMACH CANCERIncidence of stomach cancer is inverselyrelated to socioeconomic status, with analmost threefold difference between the highestand lowest categories of social classic0 A largenumber of studies have confirmed the associa-tion of high risk of stomach cancer with exces-sive salt intake, deficient intake of fresh fruitsand raw vegetables, consumption of smokedor salted meat and fish, non-centralised watersupply, and infection with Helicobacterpylori.5' 52Some studies have shown that cigarette smok-ing increases the risk of transformation frommetaplasia to dysplasia in gastric carcinogene-SiS.5' 54 In the studies reviewed, none providedinformation on these risk factors. If the crite-rion of < 20% confounding by non-occupa-tional factors is applied,46 the RR of themeta-analysis of 1-33 for stomach cancer isunlikely to be entirely due to non-occupa-tional factors, in particular the RR from themeta-analysis of 1 50 for heavy exposure tolead. The case-control study of stomach can-cer among the battery workers did not detectany association of the high risk for stomachcancer with exposure to lead.'0 Other occupa-tional exposures that are suspected to be asso-ciated with risk of stomach cancer includeasbestos, wood dust, nickel, chromium, andprobably nitrosamines as well as some work-ing processes.55 No clear evidence, however,suggested that workers involved in the studiesreviewed had experienced exposure to suchsubstances possibly associated with stomachcancer, although the possibility could also notbe ruled out.
BLADDER CANCERIt is estimated that about 30%-40% ofbladder cancer in men is attributable to ciga-rette smoking, and 10%-50% is due to occu-pational exposures.55 The best knownoccupational association with bladder canceris exposure to aromatic amines. Bladdercancer is also associated with exposure toPAHs, dust, and heat risk factors.55 Duringmetal smelting, exposure to PAHs and heatalso occurs. Also, the raised RR in the meta-analysis for bladder cancer is more likely tobe affected by publication bias than that of
Cancer and occupational exposure to inorganic lead compounds: a meta-analysis ofpublished data
stomach cancer and lung cancer, because onlyfour studies presented the results of bladdercancer in 14 studies reviewed.
KIDNEY CANCERA non-significantly increased risk of kidneycancer was detected in the present meta-analysis. Animal experimental studies haveprovided convincing evidence for the induc-tion of renal adenoma and carcinoma afteroral doses of lead acetate or lead subacetateand parenteral doses of lead phosphate in ratsand mice.2 Calabrese and Baldwin proposedthat the enhanced susceptibility of renalepithelial cells to mitogenicity induced by leadmay contribute to the carcinogenic responseseen in this target organ.56 Combining thesefindings with an increased PMR for kidneycancer, of borderline significance, amongplumbers and pipefitters3' and two cases ofkidney cancer associated with heavy exposureto lead," 12 the evidence is still inadequate toeither confirm or rule out an associationbetween kidney cancer and exposure to lead.We are greatly indebted to Dr J Cheney (IARC) for hisvaluable review of this manuscript. This work was undertakenduring the tenure of a Research Training Fellowship awardedby IARC.
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