Overview of Preventable Industrial Causes ofOccupational CancerElizabeth WardNational Institute for Occupational Safety and Health, Centers for Disease Control and Prevention,Department of Health and Human Services, Cincinnati, Ohio

This paper summarizes what is known about preventable causes of occupational cancer, including single agents, complex mixtures, and broadoccupational associations. Epidemiologic methods have been very successful in documenting cancer risks associated with single agents.Epidemiologic data are most conclusive when an exposure-response relationship can be demonstrated. Examples of agents for which epidemiologicstudies provide evidence of an exposure-response relationship include benzene and (concurrent exposure to) ortho-toluidine and aniline. Vinyl chlorideand bischloromethyl ether are examples of associations between single agents and rare histologic types of cancer. It is more difficult to conductepidemiologic studies to identify cancer risks associated with complex mixtures. Studies of diesel exhaust and lung cancer and metal machining oilsare cited as having employed advanced industrial hygiene and epidemiologic methods for studies of complex mixtures. Elevated cancer risks havealso been identified in broad occupational groups, including painters and dry cleaners. Epidemiologic case-control studies are often used to detectsuch associations but are limited in their abilities to detect the causal agents. Major gaps exist in knowledge of occupational cancer risks .amongwomen workers and workers of color. Because epidemiologic research measures illness and mortality that have already occurred, a positive studycan be interpreted to represent a failure in prevention. The challenge we face in the next decade is to identify interventions earlier in the causalpathway (toxicologic testing, biomarkers of exposure or precancerous changes, institution of engineering and good industrial hygiene practices toreduce occupational exposure levels) so that occupational cancer can be prevented. - Environ Health Perspect 103(Suppl 8):197-203 (1995)

Key words: carcinogen, standards, occupational health, epidemiology

IntroductionIt is estimated that about 4% of all cancers

are due to occupation (1), concentratedamong lung and bladder cancer. A total of10 to 20% of lung cancers (2) and 21 to

27% of bladder cancers (3,4) are estimatedto be related to occupational exposure.

This paper will summarize what is knownabout preventable causes of occupationalcancer and highlight some critical gaps inknowledge. Knowledge of occupationalcancer risks will be discussed in relation to

This paper was presented at the President'sCancer Panel Conference on Avoidable Causes ofCancer held 7-8 April 1994 in Bethesda, Maryland.Manuscript received 9 March 1995; manuscriptaccepted 24 March 1995.

Address correspondence to Elizabeth Ward,National Institute for Occupational Safety and Health,Centers for Disease Control and Prevention, MailStop R-13, 4676 Columbia Parkway, Cincinnati,OH 45226. Telephone: (513) 841-4203. Fax: (513)841-4486.

Abbreviations: BCME, bischloromethyl ether; Cl,confidence interval; U.S. EPA, U.S. EnvironmentalProtection Agency; IARC, International Agency forResearch on Cancer; NCI, National Cancer Institute;NCHS, National Center for Health Statistics; NTP,National Toxicology Program; NIOSH, NationalInstitute for Occupational Safety and Health; OSHA,Occupational Safety and Health Administration; PCE,perchloroethylene; ppm, parts per million; PEL, per-missible exposure limit; REL, recommended expo-sure limit; RR, relative risk; SIR, standardizedincidence ratio; SMR, standardized mortality ratio;pg/M3, micrograms per cubic meter.

single agents, complex mixtures, and broadoccupational categories.

Sources of Data onOccupational CarcinogensThe most comprehensive source of infor-mation about both occupational and non-occupational carcinogens is a series ofmonographs published by the InternationalAgency for Research on Cancer (IARC)(5). These monographs are prepared withthe help of international working groups ofexperts. IARC has published reviews onover 1000 substances. Each review containsa brief description of the chemical andphysical properties of the agent, methodsand volume of production, use patternsand occurrence, summaries of experimentalcarcinogenicity tests, a brief description ofother relevant biological data (toxicity andgenetic and related effects), summaries ofcase reports and epidemiologic studies ofcancer in humans, and an evaluation of itscarcinogenicity. IARC classifies agents (orexposure circumstances) according to theircarcinogenicity, which ranges from car-cinogenic to humans (Group 1) to proba-bly not carcinogenic (Group 4). Amongthe 100 definite and probable carcinogens,approximately 40% involve primarilyoccupational exposures (6).

Within the United States, the NationalToxicology Program (NTP) publishes an

annual report on carcinogens each year. Thislegislatively mandated document [Section301(b) (4) of the Public Health ServiceAct] contains "a list of all substances whichare known to be carcinogens or may reason-ably be anticipated to be carcinogens and towhich a significant number of personsresiding in the United States are exposed."It also contains information on the extentand nature of exposure and each standardestablished by a Federal agency with respectto the substance. The Seventh AnnualReport on Carcinogens listed 24 substancesknown to be carcinogenic and approxi-mately 140 substances that are reasonablyanticipated to be carcinogens (7).

In the United States, the agencies man-dated to ensure the health and safety of theworking population are the OccupationalSafety and Health Administration (OSHA)within the Department of Labor, and theNational Institute for Occupational Safetyand Health (NIOSH) within the Centersfor Disease Control and Prevention.OSHA, the agency charged with promul-gating and enforcing occupational healthstandards, has standards for 24 carcinogens(Table 1). These standards specify not onlythe permissible exposure limit (PEL) forthe concentration of the substance in airbut also other requirements for labeling,personal protective equipment, and med-ical screening. OSHA standards require

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Table 1. Potential occupational carcinogens recognized by NIOSH.Acetaldehyde2-Acetylaminogluorene (O)aAcrylamideAcrylamideAcrylonitrile (0)Aldrin4-Aminodiphenyl (0)AmitroleAniline and homologso-Anisidinep-AnisidineArsenic, inorganic (0)ArsineAsbestos (0)Asphalt fumesBenzene (0)Benzidine (0)Benzidine-based dyesBerylliumButadienetert-Butyl chromate; class, chromium,Cadmium dust and fume (0)CaptafolCaptanCarbon tetrachlorideChlordaneChlorinated campheneChlorodiphenyl (42% chlorine); class,polychlorinated biphenyls

Chlorodiphenyl (54% chlorine); class,polychlorinated biphenyls

ChloroformChloromethyl methyl ether (0)bis(Chloromethyl) ether (0)P-ChloropreneChromium, hexavalent [Cr(VI)]Chromyl chloride; class, chromium, hexavalentChryseneCoal tar pitch volatiles; class, coal tar productsCoke oven emissions (0)DDT (dichlorodiphenyltrichloroethane)Di-2-ethylhexyl phthalate (DEHP)2,4-DiaminoanisoleoO-Dianisidine-based dyes1,2-Dibromo-3-chloropropane (0)Dichloroacetylene (DBCP)p- Dichlorobenzene3,3' -Dichlorobenzidine (0)Dichloroethyl ether1 ,3-DichloropropeneDieldrinDiesel exhaustDiglycidyl ether (DGE); class, glycidyl ethers4-Dimethylaminoazobenzene (0)Dimethyl carbamoyl chloride1,1-Dimethylhydrazine; class, hydrazinesDimethyl sulfateDinitrotolueneDioxaneEnvironmental tobacco smokeEpichlorohydrinEthyl acrylateEthylene dibromideEthylene dichlorideEthylene oxide (0)Ethyleneimine (0)Ethylene thioureaFormaldehyde (0)Gallium arsenide8O, Occupational Safety and Health Administration.

GasolineHeptachlorHexachlorobutadieneHexachloroethaneHexamethyl phosphoric triamide (HMPA)HydrazineKeponeMethoxychlorMethyl bromide; class, monohalomethanesMethyl chlorideMethylhydrazineMethyl iodide; class, monohalomethanesMethyl hydrazine; class, hydrazines4,4'-Methylenebis(2-chloroaniline) (MBOCA)Methylene chloride4,4'-Methylenedianiline (MDA) (0)a-Naphthylamine (0)3-Naphthylamine (0)Nickel, metal, soluble, insoluble, and inorganic; class,nickel, inorganic

Nickel carbonylNickel sulfide roasting4-Nitrobiphenyl (0)p-Nitrochlorobenzene2-Nitronaphthalene2-NitropropaneN-Nitrosodimethylamine (0)Pentachloroethane; class, chloroethanesN-Phenyl-o-naphthylamine; class, 0-naphthylaminePhenyl glycidyl ether; class, glycidyl ethersPhenylhydrazine; class, hydrazinesPropane sultone3-Propiolactone (0)

Propylene dichloridePropylene iminePropylene oxideRadonRosin core solder, pyrolysis products(i.e., formaldehyde, acetaldehyde, malonaldehyde)

Silica, crystalline cristobaliteSilica, crystalline quartzSilica, crystalline tripoliSilica, crystalline tridymiteSilica, fusedSoapstone, total dust silicatesTremolite silicates2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (dioxin)1,1 ,2,2-TetrachloroethaneTetrachloroethyleneTitanium dioxideo-Tolidine-based dyeso-TolidineToluene diisocyanate (TDI)Toluenediamine (TDA)o-Toluidinep-Toluidine1,1,2-Trichloroethane; class, chloroethanesTrichloroethylene1 ,2,3-TrichloropropaneUranium soluble compoundsVinyl bromide; class, vinyl halidesVinyl chloride (0)Vinyl cyclohexene dioxideVinylidene chloride (1,1-dichloroethylene);class, vinyl halides

Welding fumes, total particulatesWood dustZinc chromate; class, chromium

companies to reduce exposures to specifiedlevels. In addition to the comprehensivestandards for the 24 carcinogens, OSHAmay have PELs limiting occupationalexposure to potential carcinogens based onother health effects.

NIOSH, the agency charged with con-ducting occupational health research andissuing recommendations, has identified131 substances as potential occupationalcarcinogens (Table 1). Many of thesesubstances were identified by NIOSH aspotential occupational carcinogens basedon animal data alone. NIOSH recom-mends that exposure to these substances bereduced to the lowest feasible concentra-tion (8). While NIOSH-recommendedexposure limits (RELs) are not legallyenforceable, they serve as technology-forcing goals in reducing exposure.

Occupational cancer epidemiology inthe United States is conducted by a num-ber of Federal agencies, including NIOSH,the National Cancer Institute (NCI), andthe National Institute for EnvironmentalHealth Sciences (NIEHS), as well as aca-demic institutions. Many of these agenciesalso have toxicology programs that evaluatechemicals for carcinogenicity. Althoughanimal studies are critically important inthe identification of potential occupationalcarcinogens and the interpretation of epi-demiologic study results, this paper willfocus on data from epidemiologic studies.

Single Agents asPreventable Causes ofOccupational CancerIdentification of single agents as pre-ventable causes of occupational cancer ismost frequently done by retrospectivecohort studies. These studies require theidentification of sizable populationsexposed historically to the agent of interestin the absence of other potential carcino-gens. The populations are followed for can-cer mortality and/or incidence, allowing a20- to 40-year latency period for cancersto develop.

The confirmation of an agent as anoccupational carcinogen is most persuasivewhen an exposure-response relationship isdemonstrated. Exposure-response may beevaluated in the overall cohort, or in anested case-control study when it is moreefficient to characterize exposure in only aportion of the cohort. Data can be used inrisk assessments to estimate the reduction inrisk associated with a decrease in exposure.

An example of a study demonstratingan exposure-response relationship is a

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study of rubber hydrochloride workerspotentially exposed to benzene at twoplants (9,10). A total of 1165 white menwith at least 1 ppm-day exposure tobenzene between January 1, 1940, andDecember 31, 1965, were included in thestudy. Air monitoring data for benzenewere available from the two plants as earlyas 1946. Based on these data, a matrix wasdeveloped linking each job title with anestimate of the time-weighted average ben-zene exposure. Linking this matrix with theindividual job histories allowed calculationof the cumulative lifetime exposure (ppm-years) for each individual. Table 2 summa-rizes the results of the standardizedmortality ratio (SMR) analysis, in which apattern of higher risk with higher cumula-tive exposure was observed. This data setwas used by OSHA in 1987 to demon-strate that the 1 ppm PEL for benzenewould prevent a significant risk of materialhealth impairment (11).

In studies in which historical industrialhygiene data are unavailable, duration ofexposure is sometimes used as a surrogatefor dose. In a study of bladder cancer inci-dence among workers exposed concurrentlyto the aromatic amines ortho-toluidine andaniline in a rubber chemicals manufactur-ing plant, no historical industrial hygienedata were available (12). Investigators usedduration of employment as a surrogate fordose, and found a striking relationship(Table 3).

Strong associations also have been estab-lished for certain chemicals that cause raretypes of cancer. For example, workersexposed to vinyl chloride have died fromliver cancer at a rate seven times thatexpected; most of the deaths were due toangiosarcoma of the liver (13), a histologictype that accounts for under 1% of liver neo-plasms diagnosed in the United States (14).The carcinogenicity of bischloromethylether (BCME) was first recognized by theoccurrence of three cases of small cell lungcancer among 45 workers from the same

Table 2. Standardized mortality ratios (SMRs) forleukemia among workers exposed to benzene in arubber hydrochloride plant.

Benzeneexposure,ppm/year0.001-40

40-200200-400

>400Total

Observeddeaths

22239

Expecteddeaths

1.830.620.170.042.66

SMR

1.093.22

11.8666.373.37

Table 3. Standardized incidence ratios (SIRs) for bladdercancer among workers exposed to ortho-toluidine andaniline in a rubber chemicals manufacturing plant.

Years in Number of Observed Expecteddepartment persons cases cases SIR

< 5 584 0 0.75 -5-9.99 51 1 0.11 8.8> 10 73 6 0.22 27.2

Total 708 7 1.08 6.5

Adapted from Ward et al. (12).

facility in a Philadelphia chemical plant(15). Summarizing the data to date,Steenland et al. (2) found that in a total of3332 workers exposed to BCME studiedworldwide, 98 lung cancer cases wereobserved and 24.1 were expected (SMR =4.1). Studies have typically exhibited amarked dose response and a histologicspecificity for small cell tumors (2).

Because it is possible to develop evi-dence for a causal relationship between thespecific agent and the cancer excess, single-agent carcinogens can be effectively con-trolled. Twenty-three of the 24 carcinogensregulated by OSHA, including benzene,asbestos, BCME, and vinyl chloride, aresingle-agent exposures.

Complex Mixtures asPreventable Causes ofOccupational CancerMany occupational exposures involvecomplex mixtures rather than chemicallyspecific substances. Diesel exhaust is anexample of a complex mixture that is car-cinogenic in animals (16) and is consid-ered a probable human carcinogen byIARC and NIOSH. Levels of occupationalexposure are difficult to quantify becauseuntil recently there was no air samplingmethod specific to diesel exhaust (17). In1988, a review of the carcinogenicity ofdiesel exhaust concluded that the epidemi-ologic evidence was limited by the diffi-culty in defining and quantifying exposure,the relatively short time between initialexposures and analysis of risk in some stud-ies, and the need to control for cigarettesmoking (18).

Recent epidemiologic studies haveimproved on earlier research. Smoking datahave been collected and an attempt hasbeen made to measure diesel exposure cur-rently and then extrapolate back to histori-cal levels. For example, Steenland et al.(19) conducted a nested case-control studyof lung cancer deaths within the TeamstersUnion. Interviews with next of kin wereconducted to determine smoking history;

both Teamster Union records and next-of-kin interviews were used to determinework history. Odds ratios for jobs withdiesel exposure were compared with thosewithout. Long-term (>35 years) truck dri-vers of primarily diesel trucks had an oddsratio of 1.89 (95% confidence interval[CI] = 1.04-3.42); individuals whose mainjob was truck mechanic had an odds ratioof 1.69 (95% CI=0.92-3.09), which wasnot related to length of exposure. Anindustrial hygiene survey (17,20) used ele-mental carbon as a marker of dieselexhaust. This survey estimated that air con-centrations of elemental carbon in thework area of mechanics averaged 26.6Pg/m3, while air concentrations in the cabsof long-haul trucks averaged 5.1 pg/m3.Background levels in residential areasaverage 1.1 pg/m3.

There are approximately 1.5 millionU.S. workers exposed to diesel exhaust,principally in the trucking and constructionindustry. Steenland et al. (2) estimated thatapproximately 800 of the 100,000 lungcancer cases diagnosed among U.S. maleseach year are attributable to occupationaldiesel exposure. Diesel exposures amonglong-haul truck drivers, the largest occupa-tional group exposed to diesel emissions,are being reduced by U.S. EnvironmentalProtection Agency (U.S. EPA) regulationsfor allowable truck emissions. However,truck mechanics and railroad workers maycontinue to have substantial exposures.

Another example of complex mixturesthat have been recognized as potentiallycarcinogenic are cutting and lubricatingoils. These products are thought to beresponsible for the excesses of cancer of thescrotum, bladder, and digestive tract thathave been observed among workers in themachining and metalworking occupations.In a recent example, a case-control studyof occupational causes of bladder cancerfound an elevated risk among drill pressoperatives (Table 4) that was related tolength of exposure (3). In 1981, NIOSHestimated that there were 6 million workersin nonagricultural industries exposed to

Table 4. Number cases and controls and relative risks(RR), according to duration of employment in the occu-pation of drill press operator, white males.

Duration, Trendyear Cases Controls RR test, p

< 5 22 33 1.0 0.0085-9 14 14 1.810+ 12 9 2.4

From Silverman et al. (3).

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Adapted from Rinsky et al. (10).

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mineral oils, 2 million to lubricating oils, 1million to cutting oils, and 1 million tomotor oils. The complexity and diversity ofcutting oils, however, make it difficult todetermine the actual carcinogenic exposure.A major epidemiologic study was con-

ducted to examine the risks associated withthe three major classes of machining fluids:straight oils (cutting oils), which are naph-thenic or paraffinic mineral oils; solubleoils, which contain emulsifying agents tosuspend the oil drops in water; and syn-thetic oils, in which synthetic chemicals aresubstituted for oils (21). This cohort mor-tality study included more than 45,000workers from three plants, almost 1 millionperson-years of follow-up, and over 10,000deaths. An analysis of three subcohorts everexposed to straight oils (n= 13,967), solu-ble oils (n=23,488) and synthetic fluids(n=8446) suggested associations of expo-sure to straight oil with rectal, laryngeal,and prostatic cancers. For each of thesecancers, the SMR for those ever exposed tostraight oils was elevated, there was someindication in the poisson modeling of atrend in risk with increasing duration ofexposure, and the association was consis-tent across plants (Table 5) (22). No can-cer excesses were associated with soluble oilexposure. There was some evidence of anassociation between pancreatic cancer andexposure to synthetic fluids. In a separateset of analyses, investigators examined riskof several cancers in relation to quantitativeestimates of cumulative exposure to specifictypes of machining fluids; some analyseswere limited to grinding occupations.These analyses demonstrated an exposure-response relationship for exposure tostraight oils and laryngeal cancer, for grind-ing operations and esophageal cancer, and

for exposure to straight oils and rectalcancer. The rate ratio for rectal cancerincreased in a monotonic fashion up to 2.9(95% CI=1.3-5.0) in the highest exposurecategory.

This study was unique both in terms ofits massive size and extensive exposure char-acterization. The exposure characterizationrequired that type of machining fluid usedbe assigned to each job-department-plant-calendar-year combination after review ofplant purchasing and industrial hygienerecords and interviews with plant personnel.Estimates of total machining fluid aerosolwere based on current measurements oftotal aerosol collected by the investigatorsin assembly, machining, and grinding oper-ations in the three study plants and histori-cal air sampling data collected by thecompany as well as on extensive interviewswith plant personnel (23). One of the rea-sons it was possible to conduct such adetailed exposure assessment was that thestudy was jointly sponsored by the GeneralMotors Corporation and the UnitedAutoworkers Union and therefore investi-gators had full access to company records,facilities, and knowledgeable personnel.

In summary, studies of complex mix-tures may require more refined methods ofexposure assessment than studies of singleagents. In the diesel studies, a method ofmonitoring for a component of dieselexhaust not present in cigarette smoke,manufacturing emissions, or wood smokewas developed. In the machining fluidsstudy, a detailed historical reconstructionwas used to characterize exposure todifferent types of machining fluids.Development of better exposure assess-ment techniques is at the cutting edge ofoccupational epidemiology.

Table 5. Relationship between duration of exposure to straight-oil and risk of rectal, laryngeal, and prostatic cancer.

Exposure to Number of deathsCause of death straight-oil, years due to cause of death Rate ratio 95% Cl

Rectal cancer 16 1.0>0-0.99 5 0.93 0.34-2.56

1.00-2.49 6 1.20 0.47-3.082.50-7.49 9 1.64 0.72-3.76> 7.50 21 3.17 1.62-6.24

Laryngeal cancer 13 1.0> 0-0.99 6 1.26 0.48-3.321.00-7.49 8 1.02 0.41-2.49>7.50 11 2.02 0.86-4.75

Prostatic cancer - 64 1.0>0-0.99 16 0.83 0.48-1.43

1.00-2.49 21 1.27 0.77-2.092.50-7.49 24 1.26 0.78-2.03> 7.50 40 1.52 1.01-2.29

Cl, confidence interval. Adapted from Tolbert et al. (22).

In addition to their utility in mixed-exposure situations, sophisticated exposureassessment techniques are needed to deter-mine a quantitative exposure-responserelationship for single-agent studies. Forexample, Greife et al. (24) used 2350 air-sampling data points collected at 21 com-panies, to develop and validate a statisticalmodel to estimate ethylene oxide exposurefor a retrospective cohort mortality studyin the medical supplies industry. Stewart etal. (unpublished data) developed a complexexposure assessment strategy for a cohortmortality study of workers exposed toacrylonitrile. The study included eightplants that had started production between1952 and 1965, but seven of the eightstarted taking air samples only in the late1970s, and even after that time there wereno air sampling data available for most ofthe jobs. A variety of techniques were used,including a ratio method, which estimatedexposure for unmonitored jobs by assumingthat the ratios of similar jobs at differentplants would be similar, and a homoge-neous exposure group method based oncombining jobs with similar exposures.

Occupational Groups atHigh Risk for CancerIn addition to identification of carcinogenicagents, associations between employmentin particular occupations/industries andcancer have been identified by mortalitysurveillance projects and by case-controlinterview studies. A large mortality surveil-lance database has been created byNIOSH, NCI, and the National Centerfor Health Statistics (NCHS) by fundingstate health departments to code industryand occupation on death certificates. Atotal of 28 states are included for 2 years ormore from 1979 to 1990, yielding a totalof over 5,000,000 records (25). This data-base is available on public use tapes, notonly to Federal agencies, but also to non-government researchers. In recent years,NIOSH researchers have utilized this data-base to examine cancer mortality amongwomen (25) and occupational risk factorsfor breast cancer (26), and NCI researchershave used it to examine cancer mortalityamong farmers (27).

In case-control studies, the occupa-tional histories of persons with cancer arecompared with the occupational historiesof persons without cancer. Usually theinformation on occupations and exposuresis gathered by interview with the patient(or control) or the next of kin. The disad-vantages of these types of studies are that

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the information on occupational exposuresis usually less specific than in cohort stud-ies, and if the cases and controls are derivedfrom the general population, it will be dif-ficult to detect associations with rare expo-sures or occupations. The advantages ofcase-control studies are that nonoccupa-tional risk factors such as smoking can betaken into account and entire lifetimeoccupational histories can be considered.Often the results of case-control studiesare used to suggest cohort studies to per-form. Much of our knowledge about risksassociated with particular occupations isderived from surveillance efforts andcase-control interview studies.

Painters have been shown to haveincreased risks of lung cancer and cancersof the esophagus, stomach, and bladder inmany studies, while excesses of leukemiaand cancers of the buccal cavity and larynxwere observed less consistently (28). In1989, IARC concluded that there is suffi-cient evidence for the carcinogenicity ofoccupational exposure as a painters.Thousands of chemical compounds areused in paint products as pigments, exten-ders, binders, solvents, and additives, someof which are recognized to be potentialhuman carcinogens(28). Painters areemployed in numerous industries, includ-ing heavy machine manufacturing, con-struction, automobile refinishing, and finearts (28). In some of these applications,worker exposure may be controlled bystandards related to specific components ofthe paint or solvents used (for example,chromium compounds, lead, toluene).Because there is little epidemiologic data toassociate the elevated cancer risks inpainters to specific exposures, it is notknown whether standards put in place inthe last 10 to 20 years will protect paintersfrom the elevated cancer risks experiencedby earlier cohorts. It is estimated that500,000 individuals are employed aspainters in the United States.

Workers in the dry-cleaning industryare also known to have elevated cancerrisks. Unlike many broad occupationalassociations, the risks of dry cleaning havebeen documented primarily by cohortstudies. Studies have reported elevated ratesfor urinary tract (29-31), bladder (32,33),esophageal (29,33), pancreatic (32,34),colon (33), and lymphatic (29) cancersamong dry-cleaning workers. In most ofthese studies, it could not be determined towhich specific solvent or solvents eachworker was exposed. Historically, solventsused in dry cleaning include carbon

tetrachloride, petroleum solvents (Stoddardsolvent), trichloroethylene, and per-chloroethylene (tetrachloroethylene, PCE).

Approximately 500,000 people work inthe dry-cleaning industry in the UnitedStates. Perchloroethylene is used by over90% of all dry-cleaning plants (35). IARChas concluded that there is sufficient evi-dence for the carcinogenicity of per-chloroethylene in animals (5) based onpositive bioassay results in two species ofanimals. Stoddard solvent, a petroleum-based mixture of alkane and aromatichydrocarbons, is used by about 10% of alldry-cleaning plants. The OSHA PEL forboth solvents is 100 ppm as an 8-hr time-weighted average exposure. NIOSH con-siders perchloroethylene a potentialoccupational carcinogen and recommendsthat exposure be reduced to the lowest fea-sible levels. The NIOSH-recommendedexposure level (REL) for Stoddard solventis 67 ppm.

NIOSH investigators have identifiedan excess of esophageal cancer among asmall cohort (n=625) of dry-cleaningworkers exposed only to perchloroethylene(33). The SMR for esophageal canceramong workers with > 5 years of exposureand >20 years of latency was 7.17(95% CI = 1.92-19.8). NIOSH and NCIresearchers recently have conducted anationwide search for epidemiologic studycohorts exposed only to perchloroethyleneor Stoddard solvent.

To summarize, occupational groups athigh risk for cancer are readily identified bysurveillance and case-control studies andmay in addition be documented by cohortstudies, particularly of unions representingoccupational groups. It has been difficultto take preventive action because thespecific causal agents are not known.

Summary andRecommendationsAlthough the cancer policies ofOSHA andNIOSH do not require adequate epidemi-ologic evidence to regulate an occupationalcarcinogen, in the past human studies havebeen the most potent drivers for regulatoryaction. Increasingly, NIOSH and OSHA,as well as the U.S. EPA and other regulatoryagencies, have emphasized the importanceof animal studies in making regulatorydecisions. Techniques of risk assessmenthave developed substantially over the pastdecade, and OSHA has used risk assess-ments based on animal data in developingseveral recent regulatory actions (butadi-ene, methylene chloride) (36,37). Some

may question the use of animal studies inidentifying potential human carcinogens(38), but a recent review article demon-strated that 25 to 30% of agents, sub-stances, or chemicals that have beencausally or strongly associated with cancerin humans were first identified as beingcarcinogenic in experimental animals (39).Moreover, it is hoped that increased under-standing of the molecular mechanisms ofcancer induction will allow the design ofeven more predictive animal models in thefuture (39).A related area of research that may

reduce the gap between experimental mod-els and identification of cancer risks inhuman populations is molecular cancerepidemiology. This has been defined toinclude the estimation of internal dosethrough biological monitoring of the con-centration of chemicals or their metabolitesin blood, urine, or other tissue; the estima-tion of biologically effective dose throughmeasurement of the amount of carcinogenthat has interacted with cellular macromole-cules including DNA and protein adducts;the detection of early biologic effects suchas sister chromatid exchange, DNA hyper-ploidy, or oncogene activation; and theidentification of genetic factors in suscepti-bility (40). Such measures of exposure, sus-ceptibility, and cellular damage may behelpful in correlating carcinogenic effectsbetween species, investigating chemical-specific exposures and effects in mixed-exposure situations, and identifyingbiological changes in populations whoseaverage or maximum latency is too shortfor cancer to be manifest. Eventually stud-ies may be designed to demonstrate a directrelationship between specific indicators ofcellular damage and increased cancer risk,thus increasing the value of the indicator indetecting potential human carcinogens.

Nonetheless, traditional epidemiologicstudies will continue to be important inidentifying and confirming occupationalcancer risks. Traditional techniques ofoccupational epidemiology (retrospectivecohort study with retrospective exposureassessment) are very effective in dealingwith single-agent exposures. Creative epi-demiologic and industrial hygiene tech-niques have been utilized to investigateoccupational risks associated with complexmixtures and to determine quantitativeestimates of exposure-response. Theseefforts tend to be very costly because theyrequire large populations and extensiveexposure assessment activities. In contrast,although much is known about associations

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between particular occupations and cancerrisk, there has been less progress in identi-fying the specific causal agents. Newmethods are currently being developed toallow the identification of causal agents viacase-control interview studies. Identifi-cation of the causal agents would facilitateprevention by allowing intervention to betargeted at the exposures of concern. Thecancer risks associated with broad occupa-tional categories are important becausethey affect a large number of people.

In addition to epidemiologic andindustrial hygiene research to identify thecausal agents responsible for elevated can-cer risks in certain occupations or associ-ated with exposure to complex mixtures,there is a great need for information aboutoccupational cancer risks among womenand minority workers (41,42). Studies ofoccupational cancer risks among femaleworkers are particularly needed to examinerisks of hormonally related cancer. Fewstudies of breast cancer, the most commonincident cancer among U.S. women, have

addressed occupational and environmentalchemical exposures, and many cancerstudies of industrial cohorts have excludedwomen (43). Although there is no reasonto believe that minority and nonminorityworkers might have a differential responsesto occupational carcinogens, there is sub-stantial evidence for differential assignmentof minority and nonminority persons tohigher exposure jobs within the sameindustry which results ultimately in differ-ential mortality patterns. For example, anobservation of higher lung cancer riskamong black steelworkers was one ofthe factors leading to the identification ofcoke oven emissions as potent humancarcinogens (44).

In addition to the importance of occu-pational cancer research to the preventionof cancer associated with occupation,occupational studies are important in theidentification of carcinogens that mayincrease cancer in the general population.Many chemicals for which the cancer risksare best studied in the occupational

environment are of concern because oftheir presence in consumer products or inthe environment. Examples include for-maldehyde, which is present in woodproducts, benzene, which is present ingasoline, methylene chloride, which is usedin wood stains, paint thinners, and a vari-ety of other consumer products, and anumber of pesticides to which the generalpopulation may be exposed residentiallyand through food residue (7).

In conclusion, because epidemiologicresearch measures illness and mortality,situations that have already occurred, apositive study can be interpreted as a fail-ure in prevention. The challenge of thenext decade will be to identify potentialinterventions earlier in the causal pathway(toxicologic testing, biomarkers of exposureor precancerous changes, institution ofengineering and good industrial hygienepractices to reduce occupational exposurelevels) so that occupational cancers canbe prevented.

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