Acrylonitrile and cancer: A review of the epidemiology

Regulatory Toxicology and Pharmacology 52 (2008) 342–351

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Regulatory Toxicology and Pharmacology

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Acrylonitrile and cancer: A review of the epidemiology

Philip Cole a, Jack S. Mandel b,*, James J. Collins c

a Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, USAb Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, Room 430, Atlanta, GA 30322, USAc Dow Chemical Company, Midland, MI, USA

a r t i c l e i n f o

Article history:Received 10 July 2008Available online 1 October 2008

Keywords:AcrylonitrileCancerEpidemiologyCohort studies

0273-2300/$ - see front matter � 2008 Elsevier Inc. Adoi:10.1016/j.yrtph.2008.09.004

* Corresponding author. Fax: +1 4047278737.E-mail address: [email protected] (J.S. Man

a b s t r a c t

Several retrospective cohort epidemiology studies evaluated a number of health outcomes in workersexposed to acrylonitrile (AN). The epidemiology studies included in this review have been publishedsince 1970 and were identified through Ovid and MEDLINE retrieval services using search words ‘‘acry-lonitrile and cancer”. We identified 26 studies which examined mortality and/or incidence rates amongpersons with AN exposure. Where cohorts have been updated the most recent data were relied upon butdescriptions of the earlier publications are provided for background and rationale. Results are providedfor all causes of death and all cancers. Detailed results and discussions are provided for the cancers whichhave received the most attention and for which some positive results have been reported. These includelung, bladder, prostate, and central nervous system cancers. In this review the four most informativecohort studies are evaluated and it is apparent that the results do not support a causal relationshipbetween AN and all cancers or any specific type of cancer. IARC actually downgraded acrylonitrile from‘‘probably carcinogenic” to ‘‘possibly carcinogenic to humans” finding that ‘‘the earlier indications of anincreased risk among workers exposed to acrylonitrile were not confirmed by the recent, more informa-tive studies”. This was one of few downgrades of classification by IARC. Our review of the epidemiologydata is consistent with the conclusions of the earlier IARC review which found no consistent findings ofincreased cancer risk across studies.

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1. Introduction

Acrylonitrile (CAS No. 107-13-11), a chemical intermediary usedin the manufacture of acrylic fibers, resins, plastics, rubbers, andother products such as acrylamide, has been in commercial produc-tion since 1940. In 1978, it was estimated there were 125,000 work-ers potentially exposed in the United States (OSHA, 1978).Acrylonitrile (AN) is acutely toxic to humans at relatively low levels.Exposure in excess of 500 ppm for several minutes is consideredlethal for humans; and headache, nausea, and dizziness have beenreported at exposures between 20 and 150 ppm for short periods(Schwanecke, 1966; Sakurai, 2000; Wilson, 1944). Long-term bioas-says of rats exposed through inhalation or drinking water producedcancer at several sites with tumors of the central nervous system(CNS) being the predominant type. The CNS tumor excess in rats oc-curred at exposures as low as 20 ppm in an inhalation study (Collinsand Strother, 1999). Daily average AN exposures in excess of 20 ppmhave been reported in workers.(workers (Re-evaluation of some or-ganic chemicals et al., (IARC, 1999). Recently, a cancer bioassay wasconducted in mice exposed to AN via gavage (Ghanayem et al., 2002).Although no brain tumors were observed, several tumor types wereidentified as being potentially related to AN exposure.

ll rights reserved.

del).

Several retrospective cohort epidemiology studies evaluated anumber of health outcomes in workers exposed to AN. Most work-place exposure to AN was from inhalation, but dermal exposure alsooccurred. Average inhalation exposure was generally highest duringacrylic fiber production, especially in the polymerization and spin-ning processes where unreacted AN was present (Stewart, 1998;Swaen et al., 2004; Benn and Osborne, 1998). The levels in these fiberoperations were estimated to average from 7 to 20 ppm in the 1950sand 1960s, falling to 3–9 ppm in the 1970s (Re-evaluation of someorganic chemicals et al., (IARC, 1999). Other significant exposuresmay have occurred in monomer production and in the manufactureof AN-based resins, nitrile rubbers, carbon fibers, acrylamide, adipo-nitrile, and acrylic acid (Stewart, 1998; Swaen et al., 2004; Benn andOsborne, 1998). Exposures in these processes were estimated to bein the 1–4 ppm range with some operations having levels up to15 ppm (IARC, 1999). Since the early 1980’s, exposure levels in theseoperations have been below 2 ppm for acrylic fiber production andgenerally below 1 ppm for all other AN operations (Stewart, 1998).

2. Methods

The epidemiology studies included in this review have beenpublished since 1970 and were identified through Ovid andMEDLINE retrieval services using search words ‘‘acrylonitrile and

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P. Cole et al. / Regulatory Toxicology and Pharmacology 52 (2008) 342–351 343

cancer”. We identified 26 studies which examined mortality and/orincidence rates among persons with AN exposure (Swaen et al.,2004; Benn and Osborne, 1998; Kieselbach et al., 1979; Thiesset al., 1980; Werner and Carter, 1981; Waxweiler et al., 1981; Delz-ell and Monson, 1982; O’Berg, 1980; O’Berg et al., 1985; Chen et al.,1987, 1988a,b; Thomas et al., 1987; Collins et al., 1989; Swaenet al., 1992, 1998; Mastrangelo et al., 1993; Blair et al., 1998; Marshet al., 1999, 2001; Scelo et al., 2004; Czeizel et al., 2004; Starr et al.,2004; Wood et al., 1998; Kauppinen et al., 1995; Symons et al.,2008). We excluded studies not written in English (Kieselbachet al., 1979; Thiess et al., 1980), studies included in larger studies(O’Berg, 1980; O’Berg et al., 1985; Chen et al., 1987, 1988a,b; Col-lins et al., 1989; Marsh et al., 1999), or studies that were updated insubsequent studies (Werner and Carter, 1981; Swaen et al., 1992,1998; Wood et al., 1998). We relied primarily on data from four co-hort studies we considered to be the most informative based onsize, duration of follow-up, and potential for high exposure. Thesestudies are referred to below as the National Cancer Institute, Du-Pont, United Kingdom, and Dutch studies (Blair et al., 1998 includ-ing reanalyses by Marsh et al. (2001), and Starr et al. (2004),Symons et al. (2008), Benn and Osborne (1998)), and Swaen et al.(2004). Studies by Mastrangelo et al. (1993), Delzell and Monson(1982), and Waxweiler et al. (1981) are briefly discussed althoughfor reasons given below did not receive as much consideration.Similarly, three population-based case-control studies includingthose of Scelo et al. (2004), Kauppinen et al. (1995), and Thomaset al. (1987) are presented briefly. Where cohorts have been up-dated the most recent data were relied upon but descriptions ofthe earlier publications are provided for background and rationale.Results are provided for all causes of death and all cancers. Detailedresults and discussions are provided for the cancers which have re-ceived the most attention and for which some positive results havebeen reported. These include lung, bladder, prostate, and centralnervous system cancers. Results are presented with the standard-ized mortality ratio (SMR) or relative risk (RR) followed by 95%confidence interval (CI) in parentheses. Most of the numbers wererounded for ease of presentation.

3. The cohort studies

The cohort studies that primarily included workers with highAN exposures are the focus of this review. Two of these studies,Czeizel et al. (2004) and Waxweiler et al. (1981) are small andCzeizel et al. is a prevalence survey. Therefore, these studies arediscussed only briefly. Czeizel et al. administered questionnairesabout cancer to 783 workers employed in June, 2000 at a plantwhere AN was used since 1973. Exposed workers reported a some-what lower frequency of cancer than unexposed workers but be-cause of the small number of cancers and the lack of validationof the diagnoses, this study has limited value for describing orassessing cancer risk. The study of Waxweiler et al., is a nestedcase-control study at a plant with a lung cancer excess (Waxweileret al., 1981). The study examined lung cancer rates and severalexposures at the plant including AN. The study found no significantassociation of AN exposure with lung cancer risk. Neither of thesestudies reported an increased risk for cancer. The six remaining co-hort studies are described in more detail.

3.1. The National Cancer Institute study

The largest AN study is the National Cancer Institute’s (NCI) USindustry-wide study of 25,460 workers (545,368 person-years offollow-up) employed at one of eight facilities from the 1950sthrough 1983 (Blair et al., 1998). This study included the popula-tion of Collins et al. (1989) and Marsh et al. (1999). Vital statuswas determined through 1989 for 96% of the workers, and 94% of

the death certificates were obtained for the 2038 workers assumedto be deceased.

Some of the facilities had various AN producing or using opera-tions which included four monomer production, three acrylic fiber,two resin operations, and two acrylamide operations. AN expo-sures first occurred in the 1950s for six of the facilities and inthe 1960s for two. Other chemicals present in these plants in-cluded hydrogen cyanide, ammonia, acetic acid, dyes, phosphoricacid, sulfuric acid, acrylamide, methyl methacrylate, butadiene,ammonia hydroxide, and vinyl bromide.

Extensive personal and area AN sampling conducted by the par-ticipating companies and by the NCI from 1960 onward provideddata that was used to estimate daily, average, and peak (15 minabove 20 ppm) exposures for job and department combinationsfor each worker (see Table 1). The use of respirators, the potentialfor dermal exposure, and the amount of physical activity also wereevaluated when estimating exposure (Stewart, 1998). To assessaccuracy and precision, the exposure estimates were comparedto the monitoring data for those job and department combinationswhere they were available.

A 10 percent sample (2655) of the study population was se-lected for a nested case-cohort study to evaluate the effect ofsmoking on lung cancer rates. A total of 71% of the selected work-ers (1890) completed the interview and 66% of them had eversmoked cigarettes. The RR for lung cancer among ever cigarettesmokers compared to never smokers was 4 (95% CI: 2–8). Thislow RR for smokers could have occurred by chance or from mis-classification by smoking status. The proportion of cigarette smok-ers was higher among workers with AN exposure than amongother workers, and there was an increasing prevalence of smokingwith increasing AN exposure. This substudy suggests that the SMRsfor smoking-related diseases in the cohort findings may be con-founded by smoking.

SMRs were calculated using the United States general popula-tion data to derive expected numbers. In addition, mortality ratesfor exposed persons by exposure level, and time since first expo-sure were compared to unexposed workers using Poisson regres-sion. It is unclear how ‘‘time since first exposure” was calculatedfor unexposed workers. The exposure metrics included cumulativeexposure, duration, frequency of peaks, average, and intensity (i.e.,highest job exposure held). The exposure categories for severalexposure metrics were formed by grouping person-years intoquintiles and deciles. Results were presented for several causesof death although the emphasis was on lung cancer.

The study has several strengths including the largest number ofworkers and person-years of exposure among the AN studies. As out-lined in Table 2, The exposure assessment, based on extensive per-sonal and area AN exposure monitoring, appears to be well done.The study included several sources of high AN exposures includingmanufacturing acrylic fibers, the monomer, resins, acrylamide, andadiponitrile. The study attempted to take into account potential con-founding exposures including potential workplace carcinogens andcigarette smoking. The analyses used internal and external compar-ison groups, examined various exposure lags, and considered expo-sure response using multiple exposure metrics for several causes ofdeath. There were some limitations of this study, however. Theworkers were relatively young and further follow-up may be neededto assess mortality risk more fully. In addition, it was likely that theeffect of smoking on lung cancer findings is underestimated since therisk ratio (4) is only about one-third of that generally found.

The all causes of deaths combined SMR for exposed workerswas 70 (60–70) and for unexposed workers was 70 (70–80). Forall cancers combined the SMR for exposed workers was 80 (70–90) and for unexposed workers the SMR was 90 (80–100). Thisstudy, because of its size and strengths, does not provide supportfor the notion that AN is carcinogenic to highly exposed workers.

Table 1Exposure assessment and analyses for six of the cohort studies

Study Exposure categories Exposure assessment Analyses

The NCI Study(Blair et al., 1998)

5 Categories in ppm-years <0.13, >0.13–57, <0.57–1.5, <1.5–8.0, 8.0+

Based on extensive industrial hygienemonitoring when available, processdescriptions and changes, and expertjudgment when no or little monitoring dataavailable

Primary analyses uses cumulative exposure toAN with the 5 categories. Other cumulativeexposure category cutpoints used, metrics(such as number of peaks), and other exposurefactors such as respirator use and level ofphysical activity considered

The United Kingdom Study(Benn and Osborne, 1998)

3 Categories based on level and exposurepotential: ‘‘high exposure”, ‘‘exposure”and ‘‘possible exposure”

Based on expert judgment and work history Analyses based on highest exposure levels.There are no cumulative exposure estimates

The Dutch Study(Swaen et al., 2004)

3 Exposure categories in ppm-years:<1, 1–10, 10+

Based on industrial hygiene monitoringwhen available, process changes over time,and expert judgment

Primary analyses uses cumulative exposure toAN for the 3 categories. Peak exposure(<10 ppm, 10–20 ppm, and >20 ppm) andrespiratory use also considered

The DuPont Study(Symons et al., 2008)

Cumulative exposures in proportionalhazards model

Based on industrial hygiene monitoring,process descriptions, use of protectiveequipment, and expert judgment

Other than use of the proportional hazardsmodel, intensity of exposure (<10 ppm and10+ ppm) for workers with cumulativeexposure greater than 10 ppm-years

The Nitrile Rubber Study(Delzell and Monson, 1982)

3 Categories for years of employment: <5,5–14, and >15

Duration of exposure based on workrecords. There is no mention of exposuremonitoring data use

Duration of exposure is used in analysis.Analysis also presented by year startedworking: <1950, and 1950+

The Italian Study(Mastrangelo et al., 1993)

3 Categories of exposure: ‘‘high” (stockingAN and polymerization), ‘‘low” (fibermanufacture), and ‘‘episodic high”(maintenance)

Based on work records and expertjudgment. There is no mention of exposuremonitoring data use

The analyses was based on the 3 categories ofexposure. Duration of exposure also presentedfor: 1–4, 5–9, 10–14, 15–19, and 20+ years

344 P. Cole et al. / Regulatory Toxicology and Pharmacology 52 (2008) 342–351

3.2. The DuPont studies

O’Berg evaluated cancer incidence and mortality between 1956and 1976 among workers potentially exposed to AN at a DuPonttextile fibers plant in Camden, South Carolina where AN had beenused since 1950 (O’Berg, 1980). A qualitative exposure assessmentdesignating workers as having low, moderate, and high exposurewas developed by a committee. Deaths were ascertained fromthe DuPont Mortality File and through the Social Security Admin-istration. Incident cancer cases were identified from the DuPontCancer Registry and included cancer information on the 95% of ac-tive employees enrolled in the company’s insurance program.There were 89 total deaths (77.4 expected), 20 cancer deaths(17.4 expected), and 25 cancer cases observed (20.5 expected).There was no information on potential confounders, such assmoking.

The author considered the mortality follow-up too short to pro-vide sufficient latency. Therefore, the incidence data were reliedupon even though they were limited to cancers diagnosed whileworkers were actively employed with DuPont.

In an update to this study, cancer incidence was evaluatedthrough 1983 and mortality through 1981 (O’Berg et al., 1985).The results from this study shifted the emphasis from lung cancerin the previous study to prostate cancer. This occurred becausethere were fewer than expected lung cancers during the 7-year fol-low-up period but there was a significant excess of prostate cancer.Further follow-up of the cohort was recommended.

Chen et al. evaluated cancer incidence and mortality at a differ-ent DuPont facility, located in Waynesboro, Virginia where AN wasused as a main ingredient in Orlon production (Chen et al., 1987).

Table 2Description of four follow-up studies of mortality among persons exposed to acrylonitrile

Study Non-exposed

Subjects Person-years

1. DuPont 49,213 1,490,7052. United Kingdom 490 —3. The Netherlands 3961 134,3224. National Cancer Institute — 196,727

Exposure was assessed qualitatively as low, moderate or highbased on a review of work history information by a committee ofseven workers. There were 92 deaths from all causes (177.2 and124.0 expected based on US and DuPont mortality rates) and 21from cancer (36.4 and 30.0 expected). Based on the DuPont CancerRegistry from 1956 to 1983, 37 incident cancer cases were identi-fied among workers in the AN cohort (36.5 expected).

As a follow-up to the original O’Berg study, Chen et al. con-ducted a retrospective cohort study of workers exposed to dimeth-ylformamide (DMF) and AN to determine whether exposure toDMF and AN separately or in combination was associated withcancer incidence (Chen et al., 1988a,b). Since only 16 employeeswere exposed exclusively to AN the study could not contributesubstantially to the findings on AN alone.

Wood et al. combined the cohorts from all the previous studiesof DuPont workers and evaluated mortality and cancer incidenceamong workers with potential exposure to AN (Starr et al., 2004).Two DuPont facilities that manufactured Orlon acrylic fiber inWaynesboro, Virginia and Camden, South Carolina were includedin this update. The Waynesboro facility operated from 1947 to1990 and the Camden facility which consisted of two plants oper-ated from 1950 to 1985 and from 1952 to 1991.

Since industrial hygiene monitoring was implemented at thefacilities in 1975, these data along with information on the plantsand operations, and the work history information, enabled thedevelopment of a quantitative exposure assessment. More specifi-cally, exposure estimates for AN involved a review of the generalhistory of the plants and descriptions of the processes includingoperating changes, a matrix of work area names and job titles forproduction workers, documentation of the use of personal protec-

Exposed Follow-up

Subjects Person-years Begins Ends

2548 95,657 1947 2002864 — 1950 19912842 79,205 1956 2000— 348,642 1953 1983


tive equipment, air sampling for personal and area concentrations,plant production records, and information from several employeepanels that described working conditions and work practices. Anestimate of AN exposure was derived in terms of the averageppm for a 40 h work week for each job-title-work area combina-tion by time period. Exposure estimates were ranked into fourgroups—low, moderate, high, and very high based on the distribu-tion of jobs at the plants. Four measures of AN exposure were eval-uated (latency, duration of exposure, highest exposure level everattained and cumulative exposure in ppm-years).

There were over 2500 employees with at least six months ofemployment representing 71,763 and 49,577 person-years forthe mortality and morbidity analyses, respectively. Deaths wereascertained through the DuPont Mortality Registry, Social SecurityAdministration, and the National Death Index and incident cancercases through the DuPont Cancer Registry. Unlike the prior studies,an effort was made to validate the completeness of the cohort. Vi-tal status was ascertained for about 99% of the cohort.

Using US mortality data to derive expected values, the SMR forall causes of death and all malignant neoplasms were 69 (62–75)and 78 (64–93), respectively. They were 91 and 86 when the Du-Pont mortality rates were used as the comparison group. The stan-dardized incidence ratio (SIR) for all cancers was 97 (79–118)based on the DuPont Cancer Registry data.

The authors pointed out that the DuPont cohort had someadvantages over the NCI study in that it included workers exposedto AN for at least six months, had a very high completeness of fol-low-up (about 99%), a relatively high proportion of workers ex-posed prior to 1956 (39%), a standardized approach to estimatecumulative exposure for all workers and the ability to evaluateboth incidence and mortality. Further, the authors considered thatthe use of the DuPont mortality rates provided an opportunity tocontrol for the healthy worker effect.

Symons et al. updated the Wood et al. retrospective cohortstudy by adding 11 additional years of follow-up (Symons et al.,2008). The cohort, consisting of 2548 male workers with at leastsix months of AN exposure at either plant from 1947 to 1991,was followed for mortality through December 31, 2002.

AN exposure estimates were derived as in the prior study byWood et al. Mean intensity values were assigned based on esti-mated exposure intensity categories that ranged from less than0.2 ppm to greater than 20 ppm. As summarized in Table 1, Cumu-lative exposure was estimated in ppm-years starting with firstexposure date until the last date of work-related AN exposure.Cumulative exposure was calculated by summing the products ofeach worker’s mean intensity multiplied by the duration of timefor all job and work area concentrations.

Mortality was determined by matching the cohort to the Du-Pont Mortality Registry which existed since 1957 and the NationalDeath Index to update vital status on all employees. Expecteddeaths were derived using US mortality data for Whites and mor-tality data for a regional DuPont employee population (Region 7)which was considered to be more comparable to the cohort mem-bers, 93% of whom were white.

Relative risks of mortality were estimated with hazard ratios(HR) for all-cause and cause-specific outcomes assuming a lin-ear exposure–response relationship. Measures of AN exposurewere included in a Cox proportional hazards regression modelthat included total summary estimates as well as 5-year laggedintervals for cumulative exposure and an indicator for greaterthan 10 ppm for mean intensity exposure. The model outcomewas a time variable measuring age at death or end of follow-up date from age at first exposure. The potential confounderstaken into account in the models were decades of birth from1900 to 1960 and employment in South Carolina from 1950through 1952.

There were 95,657 person-years of observation for the total co-hort including 23,368 for the AN exposed group. Over 67% of thecohort had mean intensity estimates greater than 2 ppm. The839 deaths from all causes resulted in SMRs of 92 (86–98) and69 (64–74) based on DuPont death rates and the US populationdeath rates, respectively. There were 240 cancer deaths with SMRsof 92 (81–104) and 73 (64–82), respectively. The SMRs were sim-ilar when the analysis was restricted to workers with >10 ppm-years of cumulative exposure.

The study had a number of strengths as discussed by theauthors. The exposed cohort was relatively large, follow-up wascomplete for over 99%, the quantitative risk assessment was con-ducted independently of the mortality assessment and the workershad some of the highest occupational AN exposures ever reported.There were also some limitations including having race data ononly 58% of the cohort, the lack of smoking data, and cancer inci-dence data only for active workers. However, these limitationswere unlikely to alter the conclusion of the study that there wasno evidence for increased cancer mortality due to AN among highlyexposed acrylic fiber production workers.

3.3. The Dutch study

This long-term retrospective cohort study of workers exposed toAN in The Netherlands was first published in 1992 (Swaen et al.,1992). Updates appeared in 1998 (Swaen et al., 1998) and 2004 (Swa-en et al., 2004). The study included 2842 workers with exposure to ANand an unexposed group of 3961 men who worked at a nitrogen fix-ation (fertilizer) plant. This description is based on information in allthree published reports while the results are from the 2004 paper.Findings in the first two papers are similar but are less precise.

The study was restricted to men since there were too few ex-posed women to provide information. The study also was limitedto Dutch citizens as it was infeasible to follow-up non-citizens,most of whom were Belgian. The 2842 exposed men worked atone of eight plants where AN monomer or polymer was made.The processes where AN was employed varied greatly amongplants. The potential exposures included manufacture of monomer,acrylic fibers, acrylic paints, nitrile rubbers, resins, and acrylamide.The highest observed short-term exposure limits (STEL) rangedfrom 10 to 30 ppm and the average exposure ranged from about0.5 ppm at the lowest exposure plant to 1–5 ppm at the highest.Exposure estimates were developed cumulative AN exposure andpeak exposures based on AN monitoring data, process changesover time and expert judgment (Table 1).

Exposure began in 1959 at one of the plants and at various yearsthrough 1973 at the others. The fertilizer plant was older than anyof the AN plants and the unexposed cohort was older than the ex-posed cohort. The end of follow-up was December 31, 2000. About1.2% of the workers in each cohort were lost to follow-up. Expectednumbers of deaths were derived from the age-, sex-, and time-spe-cific mortality rates of the population of the Netherlands. The ex-posed cohort experienced 79,205 person-years at risk of deathand the average duration of follow-up was 28 years. Among the ex-posed subjects 432 (15%) were deceased. The non-exposed cohortexperienced 134,322 person-years at risk and the average durationof follow-up was 34 years. Among the non-exposed workers, 1343(34%) were deceased.

The SMR for all-cause mortality was 92 (84–102) for exposedworkers and 87 (82–92) for the non-exposed workers. For the cat-egory ‘‘all cancer” the SMR was 89 (75–104) among the exposedand 86 (78–94) among the non-exposed.

The major positive features of the Dutch study are its generalhigh quality, long duration of follow-up and the fact that manyof the workers had moderate to high exposure to AN. It is of valuethat three types of comparisons could be made: The exposed group


could be evaluated for dose–response, the exposed cohort could becompared with the non-exposed as the major comparison and theexposed cohort could be compared with the general population ofthe Netherlands. Finally, the analyses were thorough and detailed,particularly with respect to lung cancer and brain cancer.

The study also has limitations. Even at the most recent follow-up, December 2000, the number of exposed decedents was rela-tively small. In particular, there were only 153 deaths, including51 due to cancer, among persons with >10 ppm-years of exposure.Among the malignancies only lung cancer provided data (67deaths) sufficient for detailed internal analyses. Colon cancer wassecond with 12 deaths observed.

Despite its limitations, the Dutch study provides considerablesupport for the view that AN is not carcinogenic for human beingsand is not associated with an increase in mortality from any majorcause of death.

3.4. The United Kingdom study

This long-term retrospective follow-up study of workers ex-posed to AN in the United Kingdom was first published in1981(Werner and Carter, 1981)and updated in 1998 (Benn and Os-borne, 1998). The original report included 1111 men who wereemployed at one of six plants in the UK from 1950 to 1978. Theseworkers polymerized AN for various products or were involved inthe manufacture of acrylic fibers. Follow-up extended throughDecember 1978 and comparisons were made with expected num-bers of deaths derived from national mortality rates. This report in-cluded a total of 68 deaths (72 expected) among men exposed for 1year or longer. There were 21 cancer deaths with 19 expected. Thesmall size of this study and several significant limitations (de-scribed below) make this report difficult to interpret and theremainder of this presentation relates to the update.

The update included the original cohort and additional workersbringing the total to 2763 men. In conducting the update severalproblems came to light relating to the assembly of the original co-hort. For one, 785 subjects at one of the plants (Factory 5) initiallyhad been overlooked. No explanation was found for this and thesemen were added to the cohort. In addition, the majority (no num-ber provided) of workers originally coded as ‘‘spinners”, with pre-sumed high exposure to AN, were considered misclassified. Thesemen were recategorized into groups with minimal or no exposure.

Of the 3013 men potentially available for the updated study,165 (5.5%) were excluded because they were employed for lessthan 1 year. Of the remaining 2848, 85 (3.0%) were lost to fol-low-up and were excluded from the mortality analyses.

Jobs at the six factories were categorized as involving ‘‘high”,‘‘possible”, or ‘‘no or little” exposure to AN. The numbers of sub-jects who held a job in each of these categories were approxi-mately 1130, 1072, and 1857, respectively. These numbers add tomore than 2,763 because a worker was counted in each categorywhere he ever was employed.

Because of limitations in the available records it was not possi-ble, for about 50% of the cohort, to estimate the actual duration ofemployment at each exposure level. Several indirect approacheswere used to estimate these durations.

(Most of the confidence intervals in this presentation weredeveloped by the present authors.) There were 409 decedents fromall causes of death with 486 expected, giving an SMR of 84 (77–92).There were 121 cancer deaths giving an SMR of 88 (73–106). Dataare presented for six forms (or groups) of cancer and for none ofthese was there a significantly elevated SMR.

Because Factory 5 had unique issues relating to cohort assemblyand to the categorization of exposure for many subjects, some find-ings are presented separately for it. Factory 5 contributed 2208(73%) of the 3013 subjects potentially available for inclusion in

the study, but only 283 (25%) of the 1130 men who ever workedin a high exposure job.

The overall significant deficit in all-cause mortality (SMR = 84)was due to findings for Factory 5 for which the SMR was 77 (68–87). At the other factories the all-cause SMR was 98 (83–115).The overall deficit of cancer deaths (SMR = 88) also was due tofindings at Factory 5, where the SMR was 76 (60–97). Elsewhere,the SMR was 112.

Findings for Factory 5 can be compared with those for the otherfactories among men who were employed in ‘‘high exposure” jobsfor 1 year or longer. Six causes of death were evaluated and in eachinstance the SMR was lower, usually much lower, for the workersat Factory 5.

There were 791 (our estimate) workers (all factories) who were‘‘ever exposed to high levels of AN”. For this group the SMR for all-cause mortality was 94 (80–110), for all cancer it was 116 (89–151).

The study provides findings on men ‘‘exposed to high levels” ofAN according to age at death, year of first exposure, time since firstexposure and duration of such exposure. No pattern suggestive ofan occupational cause was seen in these data. Unfortunately, thesedata were not presented separately for Factory 5 and for the otherplants.

If this report is interpreted as one study, with all factories com-bined, it is straightforward: there is no pattern of positive resultsand findings are generally consistent with the lowered mortalityrates usually attributed to a healthy worker effect (HWE).

If the report is seen as representing one study of Factory 5 andanother study of the other factories, slightly different pictures ap-pear: at Factory 5, mortality rates are consistently and strikinglylow with most SMRs below 80. This may reflect an HWE but alsomay have resulted in part from some of the implementation issuesat that Factory. In the ‘‘other” study, SMRs are typically in the vicin-ity of 100, though there is also some evidence of a HWE.

In sum, the interpretation of the UK study of AN workers isproblematic. The results appear questionable but, as presented,do not support the presence of a carcinogen at the plantsstudied.

4. Other cohort studies reviewed but considered not asinformative

4.1. The nitrile rubber study

Delzell and Monson examined 327 men employed in a nitrilerubber operation and who worked at a rubber plant for 2 or moreyears between January, 1940 and July, 1971 (Delzell and Monson,1982). The nitrile rubber workers also may have worked in otherdepartments in the rubber plant. Nitrile rubber is a mixture ofbutadiene and AN. Vital status follow-up was done from January,1940 to July, 1978.

The 327 workers in this operation had overall death rates belowexpected levels with an SMR = 80 (70–100) but the SMR of 120(80–190) for all cancers combined, was slightly greater than ex-pected but not statistically significant. The rubber plant wherethese nitrile rubber workers were employed had previously re-ported high rates of bladder cancer and leukemia (Delzell andMonson, 1981).

The study by Delzell and Monson is relatively small and therewas no attempt to characterize the exposure levels to AN in this ni-trile rubber process as shown in Table 1. Confounding exposuresmust also be considered since the nitrile rubber workers may haveworked at other jobs in the rubber plant where high rates of blad-der cancer and leukemia previously had been reported. This studyis not persuasive of an increased cancer risk of any form of cancerdue to AN exposure.


4.2. The Italian study

The study of Mastrangelo et al. examined death rates of 671male workers who had at least 12 months of AN exposure in an ac-rylic fiber manufacturing facility between 1959 and 1988 (Mastr-angelo et al., 1993). Vital status was ascertained from 1959 to1990 and no one was lost to follow-up. SMRs were calculated com-paring workers to a regional population in Italy.

The exposures involved the polymerization of AN and the dis-solving of the polymer using dimethylacetamide (DMAC) tomake the fiber. As shown in Table 1, Workers were classifiedas having high exposure if they worked in polymerization, lowexposure if they worked in fiber manufacture, and episodic highexposure if they were in maintenance. The workers were strati-fied by these potential exposures for analysis. The study alsoconsidered DMAC exposure. Smoking was considered by dividingstudy subjects into two groups, non-smokers and smokers whichincluded ever smoked. It is not mentioned in the study if allworkers or a portion of the workers were classified as to smok-ing status.

Overall death rates (SMR = 102, 95% CI: 70–145) were at ex-pected levels and overall cancer rates were greater than expectedbut not statistically significant (SMR = 137, 95% CI: 71–240).

A strength of this study is the lack of potentially confoundingworkplace exposures since this is an acrylic fibers plant with expo-sure to AN and DMAC but little else. This study also had relativelycomplete follow-up and attempted to take into account smokingstatus. This study was, however, small and the exposures recent.There was no discussion in this study about how deaths certificateswere obtained or how deaths were coded.

5. Cancers

5.1. Lung cancer

The studies reviewed used differing labels and ICD codes to des-ignate lung cancer. The most inclusive label was ‘‘cancer of therespiratory tract” and the least inclusive was ‘‘cancer of the lungand bronchus”. The data presented are for the most inclusive cate-gory presented in each study, always referred to as ‘‘lung cancer”.

In 1980 O’Berg published the first epidemiologic study of thecancer experience of persons with occupational exposure to AN(O’Berg, 1980). Overall, there were eight cases of lung cancer ob-served with 4.1 expected giving an SMR of 195 (84–384). The ex-cess cases occurred primarily among wage workers with morethan ‘‘low level” exposure and who were first exposed during1950–1952, the startup period for AN-related processes. SMRsdid not increase with increasing duration of exposure, but datafor evaluating this were quite limited. Confounding by cigarettesmoking could not be assessed but seven of the eight cases weresmokers. There was no excess of deaths due to lung cancer with8 observed and expected numbers ranging from 7.1 (DuPontemployees) to 10.3 (general population in contiguous counties).

In a 1985 update of the same cohort, O’Berg et al. extended thefollow-up period by 5 years from 1976 to 1981 (O’Berg et al.,1985). This increased the total number of cancer cases by 79% from24 to 43. However, the number of lung cancer cases increased only25%. There was only a slight excess of lung cancer cases with 10 ob-served and 6.0 expected among wage workers. There was no excessof lung cancer in the 5-year incremental follow-up period.

Chen et al. did not find any increase in lung cancer (5 observed,6.9 expected) among workers exposed to AN in the DuPont facilityin Waynesboro nor in workers exposed to both dimethylformam-ide and AN at a DuPont facility (14 observed, 13.2 expected) (Chenet al., 1987). Wood et al. combined the cohorts from the previous

studies and evaluated mortality and cancer incidence among work-ers with potential exposure to acrylonitrile (Wood et al., 1998). Forlung cancer the SMR was 74 (55–99). There was no significant rela-tionship between any of the exposure measures and lung cancerincidence.

The most recent update of the mortality experience of DuPontemployees with exposure to AN relates to the long-term follow-up of 2548 workers included in the previous studies (Symonset al., 2008). The cohort experienced 88 lung cancer deaths with96 expected, giving an SMR of 92 (75–114). The most heavily ex-posed workers had a similar SMR of 95. The highest SMR (actuallya hazard ratio) for lung cancer, 109 (67–177), was based on 55deaths occurring among workers with a mean intensity of expo-sure of 10+ ppm and a cumulative exposure of 10+ ppm-years. Thiswas the most heavily exposed subgroup of the study cohort.

The original study by O’Berg raised the issue of an AN–lung can-cer relationship in human beings. In retrospect, it appears likelythat the positive finding was due to chance and/or confoundingby cigarette smoking. None of the subsequent reports of AN ex-posed persons at DuPont facilities were positive for lung cancer.

The final, ‘‘analysis population” of the United Kingdom studyconsisted of 2763 men who were employed for at least 1 year.For this entire group, the SMR for lung cancer was 103 (77–135)based on 53 deaths observed. However, at one of the plants, factory5, the SMR was 89 (61–127) based on 30 deaths whereas at theother five factories it was 129 (81–194) based on 23 deaths. Thehighest SMR reported for lung cancer among the most exposedmen also is seen at these other five factories where it was 147(93–221), again based on 23 deaths. The highest SMR for lung can-cer reported in the paper is 610 (198–1421) based on five lung can-cer deaths at all six factories combined. This SMR occurred amongmen who were under age 45 at death, the youngest group forwhich data are provided. Elevated SMRs also are seen for men firstexposed in 1969 and later (SMR = 270, seven deaths) and who hadmore than 15 years of AN exposure (SMR = 204, four deaths). It islikely that all three of these elevated SMRs are based on the samedecedents, men who represent one of the first birth cohorts tosmoke in large numbers. However, the study included no informa-tion on the smoking habits of the men and so confounding bysmoking can not be evaluated.

The National Cancer Institute study with a total of 134 lung can-cer deaths among exposed workers is important because of itslarge size, generally high quality, and detailed analyses. The SMRfor lung cancer among all exposed workers is 95 (reported as0.9) with a 95% confidence interval of 85–115. The most highly ex-posed workers had more than 8 ppm-years of exposure to AN.These persons experienced 26 lung cancer deaths giving an SMRof 155 (95–245). Detailed results were presented, including nearly250 SMRs and RRs for lung cancer alone. The highest in the reportis 245 (100–585) but it relates to ‘‘ever salaried” workers, many ofwhom may not have been exposed to AN. The highest value given,265 (125–575), is a RR based on 13 lung cancer deaths. But this oc-curred among workers with relatively low exposure (0.13–0.57 ppm-years) and during an intermediate latency period (11–19 years). There is a ‘‘slight” dose–response effect but no excessof lung cancer among men with exposures of less than 8 ppm-years. There is no latency effect. Limited data were available tocontrol findings for smoking. There appears to be a modest reduc-tion (10–20%) in RRs when this was done, primarily among work-ers with 20+ years of follow-up, or latency. However, it is likelythat the control of confounding by smoking was only partial at bestand full control would have resulted in a 40–50% reduction inSMRs.

The NCI study engendered publications by other groups. Marshet al. reported an update relating to workers at one of the eightplants included in the NCI study (Marsh et al., 1999). It is not pos-

Table 3Observed and expected numbers of lung cancer deaths and SMRs for exposed subjectsin four major follow-up studies

Study Obs. Exp. SMR Smoking controlled

DuPont 88 95.6 92 NoUK 53 51.5 103 NoNCI 134 141.0 95 PartialDutch 67 62.5 107 No

Total 342 350.6 98 —95% CI — — 88–109 —


sible to make a direct comparison of these findings with those ofthe NCI study itself. However, the AN exposure levels at the plantstudied by Marsh were higher than those of the entire NCI cohortwith a mean of 27.3 ppm-years. In fact, nearly 70% of the person-years at this plant were contributed by persons who accumulated8.0+ ppm-years of AN exposure, the level used to designate thehighest quintile of cumulative exposure in the NCI study. AlthoughAN exposures of the workers in this study were higher than thosein the overall NCI study, lung cancer SMRs were lower and nonewas greater than 122. Marsh also conducted internal analysesusing the non-exposed cohort members as the referent group. Inthese analyses there was a suggestion of trends of increasing RRswith increasing exposure to AN, using several indices of such expo-sure. However, none of these trends was statistically significant orcontrolled for cigarette smoking.

In another paper, Marsh et al. reanalyzed the original NCI dataset (Marsh et al., 2001). They found that workers not exposed toAN had quite a low SMR of 68 (55–95) for lung cancer. All catego-ries of exposed workers had SMRs below 100, including the mostexposed group which had an SMR of 92 (65–145). In an unusualapproach Marsh conducted a number of ‘‘internal” analyses twice.One was conventional and developed RR estimates using the non-exposed as the referent group. The second analysis, however, wasbased entirely on SMRs. A comparison of these two sets of analysesindicated that the SMRs were virtually always lower than the cor-responding RRs. Marsh et al. suggested that the analyses based onSMRs, which showed no dose–response relationships are morereliable.

Overall, The NCI study does not support a relationship betweenexposure to AN and lung cancer. The authors of the 1998 reportsuggested that they may have found, ‘‘...carcinogenic activity atthe highest levels of exposure, but analyses of exposure–responsedo not provide strong or consistent evidence for a causal associa-tion”. Marsh’s extension and reanalyses of the NCI data supportthe interpretation that the NCI study is negative for an AN–lungcancer relationship.

The Dutch study of 2842 AN workers included 67 deaths fromlung cancer with 63 expected, giving an SMR of 107 (83–136).The group with the highest AN exposure level, >10 ppm-years,experienced an SMR of 115 (73–171) based on 24 deaths observed.Part of this highest exposure group, men with 10–20 years of la-tency, experienced the highest lung cancer SMR reported in thestudy. This SMR was 143 (74–249), based on 12 deaths. Therewas no control of the lung cancer findings for cigarette smokingbut the generally negative findings for lung cancer and for othersmoking-related diseases suggest that the study subjects smokedabout as much as did the general population with which they werecompared.

The few positive results that are seen in this study are not partof any consistent dose–response or temporal relationships. Thisstudy generally is well done and, despite a few, non-significant, po-sitive findings for lung cancer, is persuasively negative for thatdisease.

5.1.1. Lung cancer overviewFindings on the possible relationship between occupational

exposure to AN and lung cancer are summarized in Table 3. Theoverall SMR is a statistically non-significant 98 and is based on atotal of 342 deaths observed. None of the individual studies ismeaningfully positive. No study produced a consistent exposure–response relationship or other internal findings supportive of acausal relationship. Three of the studies had no control for ciga-rette smoking and in the fourth, the NCI study, control was partialat best.

There are two additional cohort studies that are small but pre-sented data on lung cancer and warrant mention for the sake of

completeness. In 1982 Delzell and Monson reported 9 deaths and5.9 expected from lung cancer (SMR = 153 (75–295)) among work-ers with potential exposure to AN at a rubber chemicals plant(Delzell and Monson, 1981). In 1993 Mastrangelo et al. reported2 deaths observed and 2.6 expected (no observed death amongpolymerization or fiber manufacture workers) among workers atan acrylic fiber factory (Mastrangelo et al., 1993).

5.2. Bladder cancer

A recent meta-analysis indicated that bladder cancer rates werehigher than expected among AN exposed workers (Collins andAcquavella, 1998). The high bladder cancer rates in this reviewwere limited to three studies, Kieselbach et al., Thiess et al., andDelzell and Monson where exposure to aromatic amines was men-tioned as a potential confounding exposure (Kieselbach et al.,1979; Thiess et al., 1980; Delzell and Monson, 1982). Examiningthe four largest studies, only the NCI study and the Dutch study re-port risk estimates for bladder cancer mortality (Swaen et al.,1998; Blair et al., 1998). The NCI study reports an SMR of 100(40–280) for unexposed workers and an SMR of 80 (40–180) forAN exposed workers. This study also presented relative risk esti-mates compared to unexposed workers of 0.0, 1.0, 1.1, 0.4, and0.6 for cumulative exposure categories of <0.13, >0.13–0.57,>0.57–1.5, >1.5–8.0, and >8.0 ppm-years. Relative risk estimatesof 0.0, 0.3 and 0.7 for time since hired were also presented for<10 years, 10–20 years, and >20 years. The Dutch study reportedan SMR of 92 (53–150) for unexposed workers and an SMR of109 (35–252) for exposed workers. No trend or latency analyseswere presented in this study.

While the United Kingdom study and the DuPont study did notreport the results of bladder cancer separately, they both examinecategories containing this cause of death (Benn and Osborne,1998). The UK study examines the category ‘‘genitourinary organs”(ICD 9 179–189) and report an SMR of 81 (42–141) among exposedworkers. No trend or latency analyses were presented. The DuPontstudy examined the category of ‘‘urinary organs” (ICD 9 188–189)and reported an SMR of 100 (57–162) compared to the US popula-tion, and an SMR of 129 (74–209) compared to other DuPont work-ers in the same region of the country as the two plants in the study.This study also examined exposure–response for this categoryusing a Cox regression adjusted for several factors. The hazard ratiofor the category of urinary organs was 98 (38–278). Two otherstudies examined bladder cancer risk. Mastrangelo et al. reportedno bladder cancer deaths among 671 fiber workers, but no ex-pected number were reported (Mastrangelo et al., 1993). Delzelland Monson observed two cases of bladder cancer versus 0.5 ex-pected (SMR = 400, 95% CI: 48–1445).

5.2.1. Bladder cancer overviewThe SMRs for the studies which examined bladder cancer are

presented in Table 4. The overall SMR was 99 (71–137) indicatingno overall increased risk for bladder cancer. Further, additionalanalyses in one of these studies did not find increasing rates withincreasing exposure or increasing time since first exposure.

Table 4Observed and expected numbers of bladder cancer deaths and SMRs for exposedsubjects in four major follow-up studies

Study Obs. Exp. SMR

DuPont* 16 12.4 129UK** 12 14.8 81NCI 6 7.5 80Dutch 5 4.6 109

Total 39 39.3 9995% CI — — 71–137

* Includes all urinary organs.** Includes genitourinary organs.


5.3. Central nervous system cancers

Cancers of the CNS are difficult to study in occupational groupsbecause the cancer is relatively uncommon. There are four studieswhich examined CNS cancers among AN exposed workers. In theearliest study, Mastrangelo et al. reported one death from CNS can-cer (SMR = 263, 95% CI: 67–1466). This death occurred in one of thehigher duration of exposure categories, but not the highest dura-tion category but occurred in the longest time since first exposurecategory of 20+ years (Mastrangelo et al., 1993). Three of the fourlargest studies provided data for CNS cancers. The NCI study ob-served 12 deaths from CNS cancers among exposed workers(SMR = 70, 95% CI: 40–130). The SMR for unexposed workers was130 (70–230) (Blair et al., 1998). The relative risk estimates wereall well below 1.0 for all cumulative exposure and time since firstexposure categories. The Dutch study found six CNS cancers amongexposed workers (SMR = 125, 95% CI: 45–271), and an SMR of 89(41–169) for unexposed workers (Swaen et al., 2004). The SMRsdecreased for increasing cumulative exposure levels. Similarly,there was also no relationship between SMRs and peak exposurecategories or time since last exposure. The DuPont study reportedSMRs for exposed workers of 71 (26–154) compared to the US pop-ulation. Workers with greater than 10 ppm-years of cumulativeexposure had similar SMRs (SMR = 71, 95% CI: 23–166). The SMRswere similar when DuPont workers in the same region were usedas a comparison. When exposure–response for CNS cancers using aCox regression adjusted for several factors was employed, the haz-ard ratio was 1 (0–3). When 5, 10, and 15-year exposure laggingwas used in the Cox regression, the hazard ratios were 1 (0–5), 2(0–6), and 2 (0–8). The British study did not report risk estimatesfor CNS cancers (Benn and Osborne, 1998).

5.3.1. Central nervous system cancers overviewOf the three cohort studies which reported relative risk esti-

mates for CNS cancers shown in Table 5, two reported risk esti-mates less than one and one reported a risk estimates greaterthan one; none was statistically significant. The three most recentstudies, NCI, Dutch and DuPont, are also the largest studies to

Table 5Observed and expected numbers of brain and central nervous system cancer deathsand SMRs for exposed subjects in four major follow-up studies

Study Obs. Exp SMR+

DuPont 6 8.1 74UK NR* NR NRNCI 12 17.1 70+

Dutch 6 4.8 125

Total 24 30.0 8095% CI — — 51–119

* Not reported.+ Or hazard ratio (HR).

examine CNS cancer risks among AN workers as shown by the nar-row confidence limits relative to the earlier studies. However, eventhe three largest studies have very few deaths from CNS cancer.None of these studies showed any increase in CNS cancer risk withincreasing exposure. The DuPont study did report some increasedrisk with cumulative exposure when exposures were lagged. How-ever, comparable analyses by the NCI and Dutch studies did notshow similar increased risks. The larger studies also have been ableto evaluate exposure–response and these analyses showed littleevidence of increasing risk with increasing exposure.

5.4. Prostate cancer

Of the 25 incident cancer cases (20.5 expected using DuPontrates and 25.5 expected using the Third National Cancer Surveyrates) identified in the original O’Berg study, three were prostatecancers (0.9 expected) O’Berg, 1980. Little attention was paid tothis finding until the follow-up study 5 years later where theemphasis was shifted from lung cancer to prostate cancer whichwas the predominant finding in the first study (O’Berg et al.,1985). In this second O’Berg study, there were a total of 43 cancercases (36.7 expected), and six were prostate cancers (1.8 expected,p < .05 using DuPont data and 2.0 expected, p < .05 using NCI data)which was the only significant finding. All six prostate cancer casesoccurred among hourly workers who worked at least 20 years afterfirst exposure and four of the cases occurred in the highest expo-sure category. The author considered a number of explanationsfor the prostate cancer finding including detection bias, confound-ing and chance but was not able to suggest a causal relationship.

An analyses of the mortality data showed that the standardizedmortality ratio was 115 for all causes of death based on 155 deaths,114 for all malignant neoplasms, and 100 for prostate cancer basedon one observed death. It was assumed that there was insufficientfollow-up time to evaluate in prostate cancer mortality and thatfurther follow-up was warranted.

Chen et al. found one prostate cancer death and 0.9 expected(Chen et al., 1987). There were five incident prostate cancer casesand 1.9 expected and 3 of the 5 cases had jobs in the highest expo-sure category. Two had more than 10 years of exposure. Four of thefive cases occurred among the hourly employees (1.3 expected). Allfour prostate cancer cases occurred during the 1975–1983 period(0.9 expected, p < .05) and three of the four cases had more than20 years of latency (0.6 expected).

Wood et al. found SMRs of 129 (64–230) and 106 (53–189) forprostate cancer mortality when using the United States mortalitydata and the DuPont Mortality Registry, respectively, to derive ex-pected values (Wood et al., 1998). There was an inverse relation-ship between prostate cancer mortality and exposure; the SMRwas lower for the higher exposed group (54) compared to the low-er exposed group (280). The SMR for the highest exposure meanvalue (30 ppm) was 56.

The SIR for the 12 incident cases of prostate cancer was 158(82–276). The SIRs for the highest cumulative exposed group andthe lowest cumulative exposed group were about the same andneither was statistically significant. The highest mean exposure le-vel, which was 30 ppm, had an SIR of 192 (52–492). Despite theearlier findings from O’Berg and Chen, results from this largerstudy with improved exposure information, did not show a signif-icant relationship between prostate cancer incidence or mortalityand any of the exposure measures.

In the most recent update of this cohort, Symons et al. reportedan SMR for prostate cancer of 91 (59–135) using the US populationto derive expected values and 102 (66–151) using the DuPont Mor-tality Registry to derive expected values (Symons et al., 2008). Forworkers with over 10 ppm-years of cumulative exposure, the SMRswere 89 (56–135) and 99 (62–150) for the two comparison groups,


respectively. The adjusted hazard ratio estimates for 100 ppm-years was 0.8 (0.5–1.3) which was not significant. Models withcumulative exposure measures lagged by 5-year intervals showedlittle change in relative cancer mortality risks within the cohort.For 5, 10 and 15-years lagged exposures the hazard ratios were0.9, 1.0 and 1.0. Analyses limited to workers with cumulative expo-sures greater than 10 ppm-years showed no significant increase forprostate cancer mortality. Overall the DuPont studies provided nosupport for a causal association between AN exposure and prostatecancer.

In the NCI study, the SMR for prostate cancer for all exposedworkers was 0.9 (0.6–1.5) based on 16 deaths, all of which oc-curred among white men (Blair et al., 1998). The RRs for time sincefirst exposure were 1.0, 0.4, 0.9, and 1.2 for all workers, <10 years,10–20 years, and >20 years, respectively. There was no increasedrisk with increased exposure (relative risks were 1.9, 0.3, 0.7, 1.5,and 0.4 for increasing cumulative exposure categories from <0.13to >8.0 ppm-years).

The Dutch study found two prostate cancer deaths among theexposed cohort (SMR = 164, (18–592) (Swaen et al., 1992). Thesetwo deaths occurred in the highest exposed group and amongthose with the longest latency (0.5 expected). In a follow-up studythe SMR for prostate cancer in the exposed group was 83 based onfour deaths (Swaen et al., 1998). In a follow-up study, the SMR forprostate cancer in the exposed group was 92 based on eight deaths(Swaen et al., 2004).

5.4.1. Prostate cancer overviewOverall, the results for prostate cancer do not support a causal

relationship with AN. The interest in AN and prostate cancer orig-inated with an unexpected finding in the early O’Berg study whichfound an excess based on very few cases. The subsequent DuPontstudies based on large cohorts and larger numbers of prostate can-cers found no significant excess and no dose–response relation-ships. The NCI and Dutch also did not find a significant excess ofprostate cancer. As shown in Table 6, among the four major cohortstudies there were 61 observed deaths from prostate cancer and65.9 expected giving a combined SMR of 93 (72–120). Based onthese results, it is unlikely that there is a causal relationship be-tween AN and prostate cancer.

6. The case-control studies

There are two population-based case-control studies that exam-ined lung cancer and brain cancer. There are two major advantagesof AN population-based case-control studies compared to cohortstudies of highly exposed AN workers. First is the ability to evalu-ate a relatively large number of uncommon cancers such as braincancer as was done by Thomas et al. (1987). Second is the abilityto address potential confounding factors such as cigarette smokingwhile examining lung cancer risk as in the study of Scelo et al.(2004). However, major weakness of the population-based case-

Table 6Observed and expected numbers of prostate cancer deaths and SMRs for exposedsubjects in four major follow-up studies

Study Obs. Exp SMR+

DuPont 25 24.5 102UK* 12 14.9 81NCI 16 17.8 90+

Dutch 8 8.7 92

Total 61 65.9 9395% CI — — 72–120

* All genitourinary cancers.+ Or HR.

control study are the fact that there were few exposed subjects,only 59 workers, and valid exposure information was difficult toobtain because of having to rely on recall often from surrogateinformants lacking firsthand knowledge of the workplace or workpractices. Thus, misclassification of exposure was more likely incase-control studies. Scelo et al. report 39 case of lung cancer withacrylonitrile exposure versus 20 controls (RR = 2.2, (1.1–4.4)). 22%of the AN exposed jobs in their case-control study occurred in themanufacture of footwear supposedly from nitrile rubbers (Sceloet al., 2004). The exposures referred to in this study presumablywould be to nitrile rubbers made up of butadiene and AN whichhave been used in specialty footwear for construction and farming.There would be low potential for exposure because the AN in thisapplication was polymerized and made up only a small portion ofthe nitrile rubber. While the study of Thomas et al. found no asso-ciation of AN with CNS cancer (RR = 0.9, (0.5–1.6)), the study ofScelo et al. did find such an association with exposure and lungcancer, but the RR was small. Given the low potential for highAN exposure, we will not consider the population-based case-con-trol studies further.

7. Comments

Acrylonitrile is a relatively potent carcinogen in rats and miceproducing cancers at multiple sites at exposure levels that mightoccur in the workplace. In some of the early epidemiology studies,such as the first DuPont AN study, a high rate of lung cancer amonga small group of highly exposed workers suggested that AN mightalso be a human carcinogen (O’Berg, 1980). This finding led to theundertaking of four large epidemiology studies of many plants inthree countries. These studies included many workers with highexposure to AN. Three of these studies used extensive AN monitor-ing over time to examine exposure–response.

In the present review the four most informative cohort stud-ies are evaluated and it is apparent that the results do not sup-port a causal relationship between AN and all cancers or anyspecific type of cancer. The same conclusion was reached by Col-lins and Acquavella in (1998) in their meta-analyses of 22 stud-ies of AN workers (Collins and Acquavella, 1998). They reportednon-significant meta-RRs of 0.9 for lung cancer, 1.2 for braincancer, 1.0 for prostate cancer, and a significant meta-RR of 1.8for bladder cancer. However, this RR of 1.8 was considered unli-kely to be related to AN since there was no dose–response rela-tionship and the excess was limited to plants where aromaticamines, known to cause bladder cancer, had been present. Cog-gon and Cole published a review that focused on the more infor-mative studies (NCI, Dutch, and DuPont) and concluded that theweight of evidence indicated that AN was not a human carcino-gen (Coggon and Cole, 1998). They endorsed further studies ofmore highly exposed workers in an effort to resolve the possibil-ity of a small risk at high exposure levels. In 1999, IARC reacheda similar conclusion (IARC, 1999). In fact, IARC actually down-graded acrylonitrile from ‘‘probably carcinogenic” to ‘‘possiblycarcinogenic to humans” finding that ‘‘the earlier indications ofan increased risk among workers exposed to acrylonitrile werenot confirmed by the recent, more informative studies”. Thiswas one of few downgrades of classification by IARC. Our reviewof the epidemiology data is consistent with the conclusions ofthe earlier IARC review which found no consistent findings of in-creased cancer risk across studies.

8. Conflict of interest statement

Drs. Cole and Mandel performed the work under a contract withthe AN (acrylonitrile) Group.


References

Benn, T., Osborne, K., 1998. Mortality of United Kingdom acrylonitrile workers—anextended and updated study. Scand. J. Work Environ. Health 24 (Suppl. 2), 17–24.

Blair, A., Stewart, P.A., Zaebst, D.D., et al., 1998. Mortality of industrial workersexposed to acrylonitrile. Scand. J. Work Environ. Health 24 (Suppl. 2), 25–41.

Chen, J.L., Walrath, J., O’Berg, M.T., Burke, C.A., Pell, S., 1987. Cancer incidence andmortality among workers exposed to acrylonitrile. Am. J. Ind. Med. 11, 157–163.

Chen, J.L., Fayerweather, W.E., Pell, S., 1988a. Cancer incidence of workers exposedto dimethylformamide and/or acrylonitrile. J. Occup. Med. 30 (10), 813–818.

Chen, J.L., Fayerweather, W.E., Pell, S., 1988b. Mortality study of workers exposed todimethylformamide and/or acrylonitrile. J. Occup. Med. 30 (10), 819–821.

Coggon, D., Cole, P., 1998. Acrynonitrile and human cancer—an overview. Scand. J.Work Environ. Health 24 (Suppl. 2), 81–82.

Collins, J.J., Acquavella, J.F., 1998. Review and meta-analysis of studies ofacrylonitrile workers. Scand. J. Work Environ. Health 24 (Suppl. 2), 71–80.

Collins, J.J., Strother, D.E., 1999. CNS tumors and exposure to acrylonitrile:inconsistency between experimental and epidemiology studies.Neurooncology 1, 221–230.

Collins, J.J., Page, L.C., Caporossi, J.C., Utidjian, H.M., Lucas, L.J., 1989. Mortalitypatterns among employees exposed to acrylonitrile. J. Occup. Med. 31 (4), 368–371.

Czeizel, A.E., Szilvasi, R., Timar, L., Puho, E., 2004. Occupational epidemiologicalstudy of workers in an acrylonitrile using factory with particular attention tocancers and birth defects. Mutat. Res. 22, 79–89.

Delzell, E., Monson, R.R., 1981. Mortality among rubber workers III: cause-specificmortality, 1940–1978. J. Occup. Med. 23 (10), 677–684.

Delzell, E., Monson, R.R., 1982. Mortality among rubber workers: VI. Men withpotential exposure to acrylonitrile. J. Occup. Med. 24 (10), 767–769.

Ghanayem, B.I., Nyska, A., Haseman, J.K., Bucher, J.R., 2002. Acyrlonitrile is amultisite carcinogen in male and female B6C3F1 mice. Toxicol. Sci. 68 (1), 59–68.

Kauppinen, T., Partanen, T., DeGerth, R., Ojajarvi, A., 1995. Pancreatic cancer andoccupational exposure. Epidemiology 6 (5), 498–502.

Kieselbach, N., Korallus, U., Lange, H.J., Neiss, A., Zwingers, T., 1979. Acrylonitrile—epidemiology study—Bayer 1977. Zentralbl. Arbeitsmed. Arbeitsschutz.Prophyl. 10, 256–257.

Marsh, G.M., Gula, M.J., Youk, A.O., Schall, L.C., 1999. Mortality among chemicalplant workers exposed to acrylonitrile and other substances. Am. J. Ind. Med. 36,423–436.

Marsh, G.M., Youk, A.O., Collins, J.J., 2001. Reevaluation of lung cancer risk in theacrylonitrile cohort study of the National Cancer Institute and the NationalInstitute for Occupational Safety and Health. Scand. J. Work Environ. Health 27(1), 5–13.

Mastrangelo, G., Serena, R., Marzia, V., 1993. Mortality from tumours in workers inan acrylic fibre factory. Occup. Med. 43, 155–158.

O’Berg, M.T., 1980. Epidemiologic study of workers exposed to acrylonitrile. J.Occup. Med. 22 (4), 245–252.

O’Berg, M.T., Chen, J.L., Burke, C.A., Walrath, J., Pell, S., 1985. Epidemiologic study ofworkers exposed to acrylonitrile: an update. J. Occup. Med. 27 (11), 835–840.

OSHA, 1978. Notice issuing final standard for acrylonitrile October 3, 43, 45762.IARC, 1999. Re-evaluation of some organic chemicals, hydrazine and hydrogen

peroxide/IARC Working Group of the Evaluation of Carcinogenic Risks toHumans, vol. 71. Lyon, France.

Sakurai, H., 2000. Carcinogenicity and other health effects of acrylonitrile withreference to occupational exposure limit. Ind. Health 38, 165–180.

Scelo, G., Constantinescu, V., Csiki, I., Zaridze, D., et al., 2004. Occupational exposureto vinyl chloride, acrylonitrile and styrene and lung cancer risk (Europe). CancerCauses Control 15, 445–452.

Schwanecke, R., 1966. Safety hazards in the handling of acrylonitrile andmethacrylonitrile. Zentralbl. Arbeitsmed. Arbeitsschutz. 16 (1), 1–3.

Starr, T.B., Gause, C., Youk, A., Stone, R., Marsh, G., Collins, J., 2004. A risk assessmentfor occupation acrylonitrile exposure using epidemiology data. Risk Anal. 24 (3),587–601.

Stewart, P., 1998. Exposure assessment for a study of workers exposed toacrylonitrile. Scand. J. Work Environ. Health 24 (Suppl. 2), 42–53.

Swaen, G.M.H., Bloemen, L.J., Twisk, J., Scheffers, T., Slangen, J.J.M., Sturmans, F.,1992. Mortality of workers exposed to acrylonitrile. J. Occup. Med. 34 (8), 801–809.

Swaen, G.M.H., Bloemen, L.J., Twisk, J., et al., 1998. Mortality update of workersexposed to acrylonitrile in The Netherlands. Scand. J. Work Environ. Health 24(Suppl. 2), 10–16.

Swaen, G., Bloemen, L., Twisk, J., et al., 2004. Mortality update of workers exposed toacrylonitrile in The Netherlands. J. Occup. Environ. Med. 46 (7), 691–698.

Symons, J.M., Kreckmann, K.H., Sakr, C.J., Kaplan, A.M., Leonard, R.C., 2008. Mortalityamong workers exposed to acrylonitrile in fiber production: an update. J. Occup.Environ. Med. 50 (5), 550–560.

Thiess, A.M., Frentzel-Beyme, R., Link, R., Wild, H., 1980. Mortality study in chemicalindustry employees of different production operation with exposure—amongother substances—to Acrylonitrile. Zentralbl. Arbeitsmed. Arbeitsschutz.Prophyl. Ergon. 30 (7), 259–267.

Thomas, T.L., Stewart, P.A., Stemhagen, A., et al., 1987. Risk of astrocytic braintumors associated with occupational chemical exposures—a case referentstudy. Scand. J. Work Environ. Health 13, 417–423.

Waxweiler, R.J., Smith, A.H., Falk, H., Tryoler, H.A., 1981. Excess lung cancer risk in asynthetic chemicals plant. Environ. Health Perspect. 42, 159–165.

Werner, J.B., Carter, J.T., 1981. Mortality of United Kingdom acrylonitrilepolymerisation workers. Br. J. Ind. Med. 38, 247–253.

Wilson, R.H., 1944. Health hazards encountered in the manufacture of syntheticrubber. J. Am. Med. Assoc. 124, 701–703.

Wood, S.M., Buffler, P.A., Burau, K., Krivanek, N., 1998. Mortality and morbidity ofworkers exposed to acrylonitrile in fiber production. Scand. J. Work Environ.Health 24 (Suppl. 2), 54–62.

Documents

Acrylonitrile and cancer: A review of the epidemiology