CHEMICAL IN RUBBER.pdf

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1. Exposure Data

In the context o this Monograph, the rubberindustry is restricted to the rubber-manu ac-turing industry, including the production otyres and general rubber goods and the processo re-treading. Te production o synthetic poly-mers in chemical plants is not discussed.

1.1 Manufacturing processRubber manu acturing generally comprises

the ollowing operations: raw materials handling,weighing and mixing; milling; extruding andcalendering; component assembly and building;curing or vulcanizing; inspection and nishing;storage and dispatch. A detailed description othese steps in the production process can be

ound in IARC (1982).Although the stages described below are

applicable to the majority o rubber goodsmanu actured rom solid polymer, a substantialproportion o rubber production involves the useo liquid latex. Tis applies to the manu acture odipped rubber goods (such as rubber gloves andsome ootwear), oam-latex products (such asmattresses, cushions, etc.), and extruded thread

products (such as elasticated abrics and surgicalhose).

1.1.1 Raw materials handling, weighing andmixing

All the materials required or the manu-acture o the nished product are assembled.

Te raw polymer, either natural or synthetic is

brought together at this stage with a variety ocompounding chemical additives be ore beingintroduced into a mixer. Te extensive range ochemicals required and the volume o raw mate-rial handled can give rise to substantial quanti-ties o airborne dust.

1.1.2 Milling

From the mixer, the uncured rubbercompound usually passes to one or more millingmachines, where it is thoroughly blended to ensurean even dispersion o its chemical constituents.At this stage, considerable heat is generated, and,although many technical improvements havebeen introduced in recent years, the job o milloperator still involves a considerable degree ophysical exertion and exposure to umes arising

rom the heated compound.

OCCUPATIONAL EXPOSURES IN THERUBBER MANUFACTURING INDUSTRY

Occupational exposures in the rubber-manufacturing industry were considered by previousIARC Working Groups in 1981 and 1987 ( IARC, 1982, 1987 ). Since that time new data havebecome available, which have been incorporated in this Monograph, and taken into consid-eration in the present evaluation.


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IARC MONOGRAPHS 100F

1.1.3 Extruding and calendering

Te extruders orce the rubber compoundthrough a die into various orms, which are thencut to appropriate lengths. Strips o sofenedrubber compound are ed into multiple-rollmilling machines (calenders) to orm rubbersheeting, or to apply the rubber directly ontowoven textile abric, which can then be woundoff onto a roll. During such manu acturing oper-ations, umes are ofen generated.

1.1.4 Component assembly and building

At this stage, solvents are requently used,with the possibility o inhalation o solvent vapours or o direct effects o the solvent on theskin o the operator.

1.1.5 Curing or vulcanizing

Heat is applied to the product, usually by useo steam, in a curing mould, press, or autoclave.Operators working in the area are exposed bothto heat rom the presses and to umes rom theheated rubber products. Chemical reactions takeplace throughout the manu acturing process,and may give rise to new, more volatile chemicals.

1.1.6 Inspection and nishing

Tis involves the handling o cured rubberproducts, ofen while still hot. It usually involvesdirect and extensive skin-contact with thesur ace o the nished article (during inspection)and may also involve exposure to vulcanizing

umes. Grinding, trimming, repair, painting andcleaning may also entail exposure to rubber dust,

umes and solvents.

1.1.7 Storage and dispatch

Large quantities o stored rubber goods mayrelease considerable amounts o toxic substances,either as vapours or as constituents o the bloomon the sur ace o nished goods.

1.2 Chemicals used in the rubber-production process

A wide variety o natural or synthetic elas-tomers, llers (e.g. carbon black, precipitatedsilica or silicates) and additives are used incompounding to create the necessary propertieso the nal rubber product. Te actual chemi-cals used in this process have changed over timeand vary extensively depending on the manu ac-turing sector (e.g. tyres, general rubber goods,re-treading), and on the specic plant.

Compounding ingredients are classiedas vulcanising agents (e.g. elemental sul ur,sul ur donors such as organic disulphides and

higher sulphides, peroxides, urethane cross-linking agents); vulcanization accelerators (e.g.sulphenamides, thiazoles, guanidines, thiurams,dithiocarbamates, dithiophosphates, andmiscellaneous accelerators such as zinc isopropylxanthate and ethylene thiourea); vulcanizationactivators (e.g. zinc oxide, magnesium oxide,lead oxide); retarders and inhibitors o vulcani-zation (e.g. benzoic acid, salicylic acid, phthalicanhydride, N -nitrosodiphenylamine (NDPA),N -(cyclohexylthio)phthalimide); antidegradants;

antioxidants (e.g. phenolics, phosphites,thioesters, amines, bound antioxidants such asquinone-diimines, miscellaneous antioxidantssuch as zinc and nickel salts o dithiocarbamates);antiozonants (e.g. para-phenylenediamines, tria-zine derivatives, waxes); anti-reversion agents (e.g.zinc carboxylates, thiophosphoryl derivatives,silane coupling agents, sulphenimide acceler-ator, hexamethylene-1,6-bis thiosulphate diso-dium dehydrate, and 1,3-bis(citranimidomethyl)benzene); plasticisers and sofeners (e.g. petro-

leum products such as petroleum waxes andmineral oils, coal-tar products such as coumaroneresin, pine products, synthetic sofeners, andother products such as vegetable oils and ats);and miscellaneous ingredients (such as peptisingagents, blowing agents, bonding agents, andpigments) ( Datta & Ingham, 2001).

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Rubber-manufacturing industry

1.3 Human exposureWorkers in the rubber-manu acturing

industry are exposed to dusts and umes romthe rubber-making and vulcanization processes.

Potential exposures include N -nitrosamines,polycyclic aromatic hydrocarbons, solvents,and phthalates. Inhalation is the main route oexposure, although workers may have dermalexposure as well (e.g. to cyclohexane-solublecompounds). Details on historical occupationalexposures in the rubber-manu acturing industrycan be ound in the previous IARC Monograph (IARC, 1982).

Data rom studies published since theprevious evaluation ( IARC, 1982) are summa-

rized below. Tese are mainly rom Europe andNorth America. Hardly any current exposuredata rom Asia, where production o rubbergoods has increased considerably during thelast two decades, was available to the WorkingGroup.

Several industry-wide surveys have beencarried out in the United Kingdom ( Dost et al., 2000) and in the Netherlands ( Kromhout et al., 1994; Vermeulen et al., 2000). In these studies,inhalable dust concentrations, curing- ume

concentrations and solvents were measured.A recent European Concerted Action createda large exposure database or the rubber-manu acturing industry in ve countries (theUnited Kingdom, Germany, the Netherlands,Poland, and Sweden). Te Improved ExposureAssessment or Prospective Cohort Studies andExposure Control in the Rubber-Manu acturingIndustry (EXASRUB) database contains resultso 59609 measurements collected rom 523surveys in 333 actories between 1956 and 2003.

Te database consists primarily o measure-ments o N -nitrosamines ( n = 21202), rubber dust(n = 13655), solvents (n = 8615) and rubber umes(n = 5932) (de Vocht et al., 2005). Te long time-span and the presence o longitudinal data romseveral countries provide insight into long-termtemporal trends in exposure concentrations inthe rubber-manu acturing industry.

1.3.1 Dust from rubber processing

An industry-wide survey in the Netherlandsin 1998 showed geometric mean concentrationso inhalable dust that varied rom 0.8 to 1.9 mg/m3

and rom 0.2 to 2.0 mg/m 3 when analysed by plantand by department, respectively. Actual inhalabledust concentrations depended to a large extenton specic conditions within the departments othe 10 plants involved in the study ( Kromhoutet al., 1994). Comparison o the exposure levelsnine years later revealed a reduction rate o 5.7%per annum or exposure to inhalable particu-late matter. On average, median inhalable dustconcentrations went down rom 1.00 mg/m 3 to0.59 mg/m 3 between 1988 and 1997. Te steepestdecline was observed in companies and depart-ments with the highest exposure levels in 1988and in workers with long employment. However,the highest concentrations were still seen inthe compounding and mixing departments(Vermeulen et al., 2000).

Dost et al. (2000) reported on exposuredata collected in an industry-wide inventoryin the United Kingdom during 199597 rom29 re-treading plants, 52 producers o general

rubber goods, and seven producers o new tyres.Te results show similar patterns at somewhatelevated levels.

Tese ndings were conrmed in an analysiso dust-exposure data (13380 inhalable and 816respirable dust measurements collected between1969 and 2003) in the EXASRUB database.Geometric mean inhalable dust concentrationschanged by 4% (range 5.8 to +2.9%) per year.Signicant reductions were ound in all veparticipating countries or handling o crudematerials and mixing and milling (7% to 4%per year) and or miscellaneous workers (11% to5% per year). Average geometric mean personalexposure levels ranged rom 0.72 mg/m 3 in theNetherlands to 1.97 mg/m 3 in Germany. Up to45- old differences were observed betweenthe countries in the early eighties, but these

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differences diminished considerably in the twodecades aferwards. In most countries, personalmeasurements appeared to be on average 24times higher than stationary measurements(de Vocht et al., 2008).

1.3.2 Fumes from rubber curing

Heating and curing o rubber compoundsgenerates a visible ume. Tis ume has a complexchemical composition, which makes detailedanalysis rather difficult. Te cyclohexane-soluble

raction (CSF) o total particulate matter has beenused as an indicator o ume contamination inthe areas in which the samples were taken. Such

monitoring studies are reviewed below.In the 1988 Dutch industry-wide survey,Kromhout et al. (1994) reported a geometric meanCSF concentration o 0.39 mg/m 3 (n = 163) in thecuring departments o 10 actories. Considerable variation was seen between the companies, witha range o geometric mean concentrations o0.211.16 mg/m 3.

Median exposures reported or the UnitedKingdom industry-wide study were highest in thegeneral rubber goods companies at 0.40 mg/m 3,

intermediate or re-treading plants at 0.32 mg/m 3 and lowest or manu acturers o new tyres at0.22 mg/m 3. Process-specic CSF concentrationsin rubber goods production were as ollows:0.40 mg/m 3 in moulding, 0.33 mg/m 3 in extru-sion, 0.18 mg/m 3 in milling. For re-treading,levels were 0.32 mg/m3 or pressing, 0.19 mg/m3

or extruding and 0.10 mg/m 3 or autoclaving(Dost et al., 2000).

Analysis o 5657 CSF measurements in theEXASRUB database collected between 1977 and2003 showed an annual decrease in concentra-tion o 3% (range 8.6% to 0%). Steepest declineswere seen in curing (8.6% per year) and mainte-nance and engineering departments (5.4% peryear) (de Vocht et al., 2008).

1.3.3 N-nitrosamines

Nitrosamines in the rubber-manu acturingindustry are ormed in the vulcanising process,with its extensive use o chemicals such as tetram-ethyl thiuram disulde, zinc-diethyldithiocar-bamate and morpholinomercaptobenzothiazole.

Exposures to volatile nitrosamines weremeasured at 24 French rubber-manu acturingplants rom 1992 to 1995. A total o 709 exposuremeasurements (109 in the personal breathingzone, and 600 area samples) were collected.Te ollowing ve different nitrosamineswere identied: N -nitrosodimethylamine(NDMA), N -nitrosodiethylamine (NDEA),N -nitrosodibutylamine, N -nitrosopiperidine,and N -nitrosomorpholine (NMor). Eightysamples, in which the concentrations were eitherzero or not quantiable were excluded. NDMAwas the most requently encountered nitro-samine (detected in 98% o the remaining 629samples) and represented the most important

raction o the total nitrosamine concentration.For all nitrosamines present, 141 o the concen-trations measured exceeded 2.5 g/m 3. Te salt-bath curing process generated particularly high

nitrosamine levels, with 90% o the 96 meas-urements showing concentrations higher than2.5 g/m3, many values even exceeding 20 g/m 3 (Oury et al., 1997).

ime trends o personal exposure to NDMAand to NMor over two decades (19802000) inthe German rubber-manu acturing industrywere analysed and compared with exposuresobserved in the Netherlands, Poland, Sweden,and the United Kingdom over the same timeperiod. A total o 2319 NDMA and 2316 NMormeasurements contained in the EXASRUBdatabase were analysed. Results rom Germanyaccounted or 88% and 85% o the data or thesetwo amines, respectively. For both NDMA andNMor, the average geometric mean concentra-tion in Germany was 0.13 g/m 3. Geometricmean concentrations o NDMA ranged rom

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0.05 g/m3 in the Netherlands to 0.34 g/m 3 in Sweden, while those o NMor ranged rom0.03 g/m3 in the United Kingdom to 0.17 g/m 3 in Poland and Sweden. Exposure to NDMAand NMor decreased on average 25- old in theGerman rubber-manu acturing industry overthis time period, mainly due to the introductiono modern curing systems. Comparable levelswere observed in the other European countries(de Vocht et al., 2007).

In a study rom Italy, personal expo-sures to nine airborne N -nitrosamines(NDMA, NDEA, N -nitrosodi- n-propylamine,N -nitrosodiisopropylamine, N -nitrosodi-n-butylamine, N-nitrosopiperidine, N-nitroso-

pyrrolidine, and NMor) were measured in 34workers rom our Italian actories that manu ac-tured rubber drive belts or automobile engines.Airborne levels were very low and, in mostcases, below the limit o detection o 0.06 g/m3(Iavicoli & Carelli, 2006)

Personal exposures to six nitrosamines(NDMA, NDEA, N -nitrosodi- n-butylamine,N -nitrosomorpholine, N -nitrosopiperidine,and N -nitrosopyrrolidine) were measured inthe rubber-manu acturing industry in Sweden(Jnsson et al., 2009). Te exposures ranged

rom less than the limit o detection to 36 g/m3,and differed with the vulcanization methodused. Workers involved in salt-bath vulcanizina-tion had the highest level o exposure (median,4.2 g/m3).

Although average levels o N -nitrosaminesare nowadays well below the current exposurelimits, exposure to these chemicals has not beeneliminated and incidental high exposures do still

occur.1.3.4 PAHs

In a 1997 cross-sectional study o 116 Dutchmale workers in the rubber-manu acturingindustry, Peters et al. (2008) collected urinesamples on weekdays and on Sundays, and deter-mined the concentration o 1-hydroxypyrene.

Te concentrations were signicantly higherin workweek samples compared with thosecollected on Sunday. However, this increasewas not uni orm across tasks and only reachedstatistical signicance or the curing department(P = 0.003).

1.3.5 Solvents

Kromhout et al. (1994) measured exposuresto solvents in 10 rubber-manu acturing plantsin the Netherlands in the late 1980s. Te extento use o individual solvents varied widely andtotal solvent concentrations were reported. Tequantitative assessment o exposure to solventswas restricted to paraffins (hexane, heptaneand octane); aromatic compounds (toluene,xylene, trimethylbenzene, naphthalene andisopropylbenzene); chlorinated hydrocarbons(trichloroethylene and 1,1,1-trichloroethane);ketones, alcohols and esters (methylisobutyl-ketone, 2-ethoxyethanol and isobutylacetate).Tese were chosen on the basis o in ormation onsolvents, cements, and release and bonding agentsused in the 10 plants. Te geometric mean concen-tration by plant varied rom 0.546.9 mg/m 3 and

ranged rom 0.434.6 mg/m3

by department,with the highest exposures reported in the pre-treating departments.

1.3.6 Phthalates

wo studies reported on exposure to phtha-lates, which are used as plasticizers in therubber-manu acturing industry. A total o 386spot-urine samples were collected rom 101 Dutchworkers employed in nine different actories, andanalysed or the presence o phthalic acid and2-thiothiazolidine-4-carboxylic acid. Sampleswere collected on Sunday and during the work-week on uesday, Wednesday, and Tursday.Geometric mean concentrations o phthalicacid showed a signicant 2- old increase (pairedt -test; P < 0.05) during the workweek comparedwith the concentrations measured on Sunday

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(GM, 83 g/l), with absolute increases o approx-imately 70 g/l. Te concentrations did not differmarkedly between uesday, Wednesday andTursday (GM, 148 g/l, 152 g/l and 164 g/l,respectively). Increases seemed to be restrictedto specic actories and/or departments (e.g.moulding and curing) ( Vermeulen et al., 2005).

In a pilot biomonitoring study in severalindustries, Hines et al. (2009) reported thatworkers rom a rubber boot manu acturing planthad 3- old higher geometric mean concentra-tions o diethylhexyl-phthalate metabolites inpost-shif urine than the concentrations meas-ured in the general population.

1.3.7 Dermal exposureKromhout et al. (1994) and Vermeulen et

al. (2000) reported on dermal exposures tocyclohexane soluble compounds in the rubber-manu acturing industry in the Netherlands.Dermal CSF levels decreased in a similar patternas inhalation exposures over a 9-year period(19881997).

2. Cancer in Humans

Te literature reviewed in previous IARC Monographs (IARC, 1982, 1987) provided suffi-cient evidence o a causal association betweenexposures in the rubber-manu acturing industryand cancer. Te recent Working Group decidedto review evidence rom individual studies thatappeared afer the earlier evaluation ( IARC, 1982)making use o a systematic review by Kogevinas et al. (1998). Evidence rom meta-analyses

published by Stewart et al. (1999), Borak et al. (2005) and Alder et al. (2006) was not consid-ered since these studies combined a varietyo exposure circumstances that would tend todilute any observed effect. Te Working Grouprealized that the complexity o occupationalexposure in the rubber-manu acturing industryhad so ar precluded a clear conclusion about an

association between increased cancer mortalityand incidence and exposure to particular chemi-cals (except historically well known associationsbetween 2-naphthylamine and bladder cancer,and benzene and leukaemia). Future studies in therubber-manu acturing industry may overcomethis problem by making use more systematicallyo the wealth o exposure data available in theindustry ( de Vocht et al., 2005, 2009).

2.1 Cancer of the bladder

In the previous IARC Monograph (IARC, 1982) it was concluded that there was sufficientevidence o an excess occurrence o urinary

bladder cancer in workers in the rubber-manu-acturing industry. Te rst evidence appearedwhen a substantial excess o bladder cancer wasnoted among workers in this industry in theUnited Kingdom ( Case et al., 1954).

2.1.1 Cohort studies

Among workers in the British rubber-manu-acturing industry, the death rate rom bladder

cancer during 19361951 was almost twice thato the general population (Case & Hosker, 1954).Studies in other countries also showed an excesso bladder cancer in workers in this industry, butthese studies were based on small numbers.

Kogevinas et al. (1998) conducted asystematic review o epidemiological studies oncancer in the rubber-manu acturing industry.Tis review included cohort and casecontrolstudies published afer the previous evaluation(IARC, 1982), which were conducted in acilitiesthat manu actured and repaired tyres, manu ac-

tured cables and other rubber goods. Te authorsound that moderately increased risks or bladdercancer were reported in 6 o 8 cohort studies oworkers employed in the rubber-manu acturingindustry in different regions o the world. In

our studies that reported results by calendarperiod, the risk was highest among workersemployed be ore 1950 (Delzell & Monson, 1984a,

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b, 1985a, b; Gustavsson et al., 1986; Negri et al., 1989; Szeszenia-Dabrowska et al., 1991). One othese studies reported potential co-exposure to2-naphthylamine ( Szeszenia-Dabrowska et al., 1991).

wo cohort studies o Polish workers publishedbe ore 1998 were updated and an excess mortalityrisk or bladder cancer was reported (see able 2.1,available at http://monographs.iarc. r/ENG/Monographs/vol100F/100F-31- able2.1.pd ). Inthe most recent ollow-up o a cohort o Polishworkers involved in the manu acture o rubber

ootwear, non-statistically signicant increasedrisks or bladder cancer were ound among menand women ( Szymczak et al., 2003). In a cohort

study among workers in rubber-tyre manu-acture in Poland (Wilczyska et al., 2001), no

increased risk or bladder cancer was observedamong all workers, but analysis o a subcohorto men involved in mixing and weighing o rawmaterials, milling, extruding and calendaring,showed a non-signicantly increased risk. A job-exposure matrix (JEM) or occupational expo-sure to aromatic amines was used in the analysiso this cohort (de Vocht et al., 2009). Tis JEMwas set-up with data rom EXASRUB, whichprovided estimates o geometric mean concentra-tions or airborne chemicals in each departmentin the actory during the study period. Internalanalyses showed an increased risk in the highesttwo quartiles o exposure to aromatic amines.

2.1.2 Synthesis

Studies in the rubber-manu acturing industrywith documented exposure to 2-naphthyl-amine clearly show an increased risk o cancero the urinary bladder. More recent studiesthat included workers with no recorded expo-sure to 2-naphthylamine identied moderatelyincreased risks or bladder cancer. [Te WorkingGroup could not rule out that the increased risksin recent studies were attributable to exposure to

2-naphthylamine, or whether other exposures inthis industry contributed to this risk.]

2.2 LeukaemiaIt was concluded in the previous IARC

Monograph (IARC, 1982) that there was sufficientevidence o an excess occurrence o leukaemia inworkers in the rubber-manu acturing industry.

2.2.1 Cohort studiesKogevinas et al. (1998) noted our cohort

studies that ound moderately increased risksor leukaemia among workers in the rubber-

manu acturing industry in the USA ( Norsethet al., 1983; Delzell & Monson, 1984a, b, in twodepartments o a rubber plant in Akron, Ohio), inItaly (Bernardinelli et al., 1987), and in Germany(Weiland et al., 1996), while our studies did notreport an excess risk ( Gustavsson et al., 1986;Negri et al., 1989; Sorahan et al., 1989; Carloet al., 1993). Te magnitude o the risk variedbetween studies, with the highest risks oundin studies conducted in North America. Teresults supported the conclusion that the excess

risk or leukaemia was attributable to exposureto solvents, particularly benzene. Te authorsindicated that a variety o solvent mixtures, withor without benzene, had been used in rubbercements, glues, binding agents, and releaseagents.

Cohort studies on leukaemia that werepublished since the review paper mentionedabove (Kogevinas et al. (1998) are summarizedin able 2.2 (available at http://monographs.iarc. r/ENG/Monographs/vol100F/100F-31-

able2.2.pd ). Strai et al. (1998) reported anexcess risk or leukaemia in a cohort o maleworkers employed in one o ve large plants inGermany that produced tyres or general rubbergoods (SMR, 1.5; 95%CI: 1.02.1). An increasedrisk was observed in work area I (Preparationo Materials) where solutions were made up,

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and in work area II ( echnical Rubber Goods).Non-signicant excesses were also seen in otherareas. Longer duration o employment was asso-ciated with increased incidence o leukaemia inwork area I, particularly among those workerswith 10 or more years o employment (SMR, 3.0;95%CI: 1.55.6).

Li & Yu (2002a) conducted a nested casecontrol study (7 cases o leukaemia, 28 controls)in a rubber-manu acturing acility, and reportedan excess risk or leukaemia in workers o theinner-tube department, but not in other depart-ments o the plant. Te odds ratio or leukaemiawas 7.81 (95%CI: 0.878.8) or one or more yearso work in the inner-tube department.

2.2.2 Casecontrol study

McLean et al. (2009) conducted a population-based casecontrol study in New Zealand, with225 cases o leukaemia and 471 controls. Fulloccupational histories were obtained by inter- view. Among those reporting working as rubber/plastics machine-operators (9 cases, 4 controls),the age-, sex- and smoking-adjusted risk estimatewas 3.8 (95%CI: 1.113.1). Te strongest ndings,

nonetheless, were or plastics rather than or therubber-manu acturing industry.

2.2.3 Synthesis

Te Working Group concluded that therewas an increased risk or leukaemia amongworkers in the rubber-manu acturing industry.Te excess risks may be associated with exposureto solvents, in particular benzene.

2.3 Malignant lymphoma includingmultiple myeloma and otherlymphopoietic cancers

It was concluded in the previous review(IARC, 1982) that there was limited evidence o an excess occurrence o lymphoma among

rubber-manu acturing workers. Excess occur-rence o lymphoma had been noted in workersexposed to solvents in departments like ootwearproduction and tyre manu acture ( Veys, 1982).


Kogevinas et al. (1998) reported excess risksor malignant lymphoma, including multiple

myeloma, ranging rom 1.7 to 3.6 in threecohort studies in the USA ( Norseth et al., 1983;Delzell & Monson, 1984a, b, in a rubber plantin Akron, Ohio) and Italy ( Bernardinelli et al., 1987), while there was no excess risk in two othercohort studies, in Italy and the United Kingdom

(Negri et al., 1989; Sorahan et al., 1989). Delzell & Monson (1984b , 1985b) reported excess risksor multiple myeloma in certain departments o

a rubber plant in Akron, Ohio, as did Gustavsson et al. (1986) in Sweden.

Cohort studies published since 1998 areincluded in able 2.2, on-line. In Germany,Mundt et al. (1999) observed an increased risk

or lymphatic system cancers among womenemployed in one o ve large plants that producedtyres or general rubber goods. All cases were

seen among women hired afer 1950. In theUnited Kingdom, an increased mortality risk ormultiple myeloma was ound among men andwomen in 41 British rubber actories that manu-

actured tyres and general rubber goods ( Dost et al., 2007). Women also had increased multiple-myeloma incidence (SRR, 8.1; 95%CI: 1.723.7).Excess mortality was observed among workers inthe general rubber sector (seven deaths observed,one expected).

Wilczyska et al. (2001). did not nd anoverall increase in mortality risk or cancerso lymphatic and haematopoietic tissues in arubber-tyre plant in Poland.

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2.3.2 Synthesis

Te Working Group concluded that there issufficient evidence o excess malignant lymphomaamong workers in the rubber-manu acturingindustry.

2.4 Cancer of the lung

In the previous IARC Monograph (IARC, 1982) it was concluded that there was suggestiveevidence o an excess incidence o lung canceramong rubber-manu acturing workers, but thatthe evidence or a causal association with occu-pational exposures was limited .


Kogevinas et al. (1998) noted that the morerecently reviewed studies tended to conrm amoderate excess risk or lung cancer. Positivendings were reported in ve cohort studies(Delzell & Monson, 1985a, in the curing depart-ment; Gustavsson et al., 1986; Zhang et al., 1989;Szeszenia-Dabrowska et al., 1991; Solionova & Smulevich, 1993). Tese risks were ound among

workers in tyre-curing departments, mixingand milling, in vulcanization workers, and ina study on jobs with high exposure to umes orsolvents. In three studies excess risks up to 1.5were reported ( Delzell & Monson, 1984b, in theaerospace-product department; Sorahan et al., 1989; Weiland et al., 1996), while in ve cohortstudies excess risks were not ound (Norseth et al., 1983; Delzell & Monson, 1984a, 1985b, inindustrial-products and reclaim departments;Bernardinelli et al., 1987; Negri et al., 1989; Carlo et al., 1993).

Cohort studies on lung cancer publishedafer the above-mentioned review ( Kogevinas et al., 1998) are listed in able 2.3 (available athttp://monographs.iarc. r/ENG/Monographs/ vol100F/100F-31- able2.3.pd ). In most studiesmoderate but consistent increases in risk or

lung cancer were ound; two studies reported noincrease in risk ( Dost et al., 2007; deVocht et al.,2009).

From a study o a cohort o German womenemployed in rubber-manu acturing plants,Mundt et al. (1999) reported an increased risk

or lung cancer mortality. Stronger associationswere observed or certain periods o employ-ment. Among a cohort o German men, a signi-cantly increased risk or lung cancer mortalitywas observed (Strai et al., 2000a). Using internalcomparisons, the authors showed increased risksamong those employed during one year or morein work areas that involved preparation o mate-rials, technical rubber goods and tyre produc-

tion (Strai et al., 1999). Trough retrospective,semiquantitative estimates o exposures tonitrosamines, asbestos and talc, an increasedrisk or lung cancer in association with highexposure levels or asbestos was observed. Anexposure characterization in which categorieso medium and high exposure levels o talc werecombined with medium exposure to asbestosrevealed an exposure-response relationship withlung-cancer incidence ( Strai et al., 2000a).

Szymczak et al. (2003) reported excesslung-cancer mortality among men and womenemployed in a rubber- ootwear plant in Poland.Tere were increased risks by duration o employ-ment, but no trend was observed. A population-based cohort study o non-smoking women inChina also showed an increased risk or lungcancer, afer controlling or exposure to second-hand smoke, education level and amily historyo lung cancer (Pronk et al., 2009).

2.4.2 Casecontrol studiesTe ndings o population-based case

control studies are listed in able 2.4 (availableat http://monographs.iarc. r/ENG/Monographs/ vol100F/100F-31- able2.4.pd ). Most notably, intwo large multicentre studies o non-smokers,increased risks or lung cancer were ound among

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women who reported having been employed inthe rubber-manu acturing industry ( Pohlabeln et al., 2000; Zeka et al., 2006).

2.4.3 SynthesisOverall, the cohort studies suggest an

increased lung-cancer risk among workers inthe rubber-mau acturing industry. Tis conclu-sion is supported by the ndings o population-based casecontrol studies. Te Working Groupconcluded that there is evidence o excess lungcancer among workers in the rubber-manu ac-turing industry.

2.5 Cancer of the larynxIn a previous IARC Monograph (IARC, 1987)

it was indicated that cancer o the larynx hadbeen reported as occurring in excess in workersin the rubber-manu acturing industry, but thisexcess was not consistent.


In his review, Kogevinas et al. (1998) reported

a small but consistent excess risk or laryngealcancer in seven cohorts, but indicated that theavailable evidence did not permit an evaluationto be made o the specic agents that may beassociated with the increased risk or this cancer.

Strai et al. (2000a) ound increased mortalityrom laryngeal cancer among workers in the

German rubber-manu acturing industry (seeable 2.3, on-line). Te authors indicated that the

excess risk may be associated with employmentin weighing and mixing and with exposure toasbestos, talc or carbon black. Dost et al. (2007)did not nd an increased risk or laryngealcancer mortality and incidence among workersin the British rubber-manu acturing industry.De Vocht et al. (2009) did not nd increasedmortality rom laryngeal cancer in a plant thatmanu actured rubber tyres. Tey also did not

nd an association with exposure to aromaticamines or inhalable aerosol.

2.5.2 Synthesis

Te Working Group concluded that there wasinconsistent evidence o excess laryngeal canceramong workers in the rubber-manu acturingindustry. [ obacco smoking is a risk actor orlaryngeal cancer, yet in many studies no adjust-ment or smoking status was made.]

2.6 Cancer of the stomach

In the previous IARC Monograph (IARC, 1982) it was concluded that there was sufficientevidence o an excess o stomach cancer amongworkers in the rubber-manu acturing industry,and limited evidence o a causal association withoccupational exposures.


Te conclusions o the previous WorkingGroup ( IARC, 1982) were supported by cohortstudies o male workers in specic rubber acto-ries. A study in a rubber plant in Akron, Ohio(USA) showed an excess o stomach cancerprimarily among workers involved in jobs earlyin the production line, where exposures aremainly to particulate matter, but also to some

ume rom uncured rubber (Delzell & Monson, 1982). A casecontrol analysis o stomach canceramong male workers in the same plant showeda positive association with work early in theproduction line and with jobs in curing andmaintenance ( McMichael et al., 1976). Further

analysis, according to estimated exposure tospecic agents, showed a positive associationwith exposure to talc ( Blum et al., 1979). Inone study in the United Kingdom, mortality

rom stomach cancer was increased among allworkers, but particularly among men in jobsearly in the production process ( Parkes et al., 1982). In a second study in the United Kingdom,

550


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excess mortality rom stomach cancer was alsoobserved among all workers, but not amongparticular occupations ( Baxter & Werner, 1980 ).

Kogevinas et al. (1998) reported low excessrisks or stomach cancer in seven cohort studies.Te risk was elevated mainly in mixing andmilling departments in two studies ( Wang et al., 1984; Gustavsson et al., 1986) and in jobs withhigh exposure to dust in a third study ( Sorahan et al., 1989). Kogevinas et al. (1998) indicatedthat cohort studies published afer 1982 eitherdid not conrm the presence o an excess risk orsuggested the presence o only a slightly elevatedrisk.

Cohort studies on stomach cancer published

since the above-mentioned review are listedin able 2.5 (available at http://monographs.iarc. r/ENG/Monographs/vol100F/100F-31-

able2.5.pd ). In casecohort study in Chinao workers in a rubber-manu acturing plant,Li & Yu (2002b) reported an increased risk

or stomach cancer. Increased risks were alsoreported by duration o work in inner tyre-tubemanu acturing and milling departments. Mundt et al. (1999) ound excess risks or stomach canceramong German women employed in the rubber-manu acturing industry, which was strongeramong workers hired afer 1960.

Strai et al. (2000a) reported a moderatelyincreased risk or stomach cancer among maleworkers in the German rubber-manu acturingindustry. An exposure-effect association withtalc was observed, but no association with nitros-amines. Data appeared to indicate an associationwith carbon black, but afer adjustment or talc-and asbestos-containing dusts, the risk estimate

was lower and no longer signicant.On the basis o internal comparisons, Neves et al. (2006) ound an increasing risk or stomachcancer among workers in the rubber-manu ac-turing industry employed in small companiesin comparison with workers at large companies,with 10-year lagging and control or con ounding(RR, 3.47; 95%CI: 2.574.67). Company size was

used as a surrogate o probability o exposure tocarcinogenic substances. De Vocht et al. (2009)

ound a moderate excess risk or stomach cancer,particularly among workers in the maintenancedepartment o a tyre-manu acturing plant, whileDost et al. (2007) showed a modest excess ostomach-cancer incidence among male workersin a study o British rubber plants.

2.6.2 Synthesis

Te Working Group concluded that there wasevidence o an excess o stomach cancer amongrubber-manu acturing workers.

2.7 Cancer of the oesophagusTe previous IARC Monograph (IARC, 1982)

determined that there was inadequate evidenceor excess occurrence o cancer o the oesophagu

among workers in the rubber-manu acturingindustry.


Kogevinas et al. (1998) reported an increased

risk or oesophageal cancer in our cohorts(Delzell & Monson, 1985b, in reclaim-depart-ment workers; Sorahan et al., 1989; Szeszenia-Dabrowska et al., 1991, Weiland et al., 1996).Other cohorts studies showed no effect.

Strai et al. (2000b) reported a signi-cantly increasing trend or oesophageal cancerwith increasing exposure to nitrosamines (see

able 2.5, on-line). ests or trend and associa-tions were also signicant or cancers o the lipand oral cavity. In Poland, Szymczaket al. (2003)reported a signicant excess risk among rubber-

ootwear workers.

2.7.2 Synthesis

Te Working Group concluded that therewas some evidence or an excess risk or cancero the oesophagus among workers in the

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rubber-manu acturing industry. [Te WorkingGroup noted that in none o the studies adjust-ments were made or tobacco or alcohol use.]

2.8 Cancer of the prostateTe previous IARC Monograph (IARC, 1982)

concluded that the evidence o excess risk orprostate cancer was limited and that the evidence

or a causal association with occupational expo-sures was inadequate.


Kogevinas et al. (1998) reported excess risksor prostate cancer in ve studies ( Norseth et al.,

1983; Delzell & Monson 1984a, in the indus-trial-products department; Bernardinelli et al., 1987; Solionova & Smulevich, 1993; Weiland et al., 1996). Other studies did not report anyexcess (Delzell & Monson, 1984b, 1985b; in theaerospace-products and re-claim departments;Gustavsson et al., 1986; Sorahan et al., 1989;Szeszenia-Dabrowska et al., 1991).

Since then, only one casecohort study thatinvestigated the association between prostatecancer and work in the rubber-manu acturingindustry has been published ( Zeegers et al., 2004). In this study a non-statistically signicantincreased risk or prostate cancer was ound.

2.8.2 Synthesis

Te Working Group concluded that there isweak evidence o excess risk or prostate canceramong workers in the rubber-manu acturingindustry.

2.9 Other cancersTe previous IARC Monograph (IARC, 1982)

determined that or cancers o the brain, thyroidand pancreas, the evidence was inadequate or anexcess in occurrence o these cancers and or acausal association with occupational exposures.


Kogevinas et al. (1998) reported that nd-ings or other cancer sites were not consistentbetween studies, or were derived rom too ew

studies. Since this review, studies on workers inthe rubber-manu acturing industry with excesscancers o the brain, pancreas, gallbladder,cervix and liver have been reported (see able 2.6available at http://monographs.iarc. r/ENG/Monographs/vol100F/100F-31- able2.6.pd ).

2.9.2 Synthesis

Te Working Group concluded that there islittle evidence o excess risks or cancers at sitesother than those mentioned above, being asso-ciated with work in the rubber-manu acturingindustry. [Excess risks ound in single studiesmay be related to specic exposure circumstancesoccurring in particular rubber-manu acturingplants. One problem in evaluating ndings orother cancer sites is that reporting may have beenincomplete in cohort and casecontrol studies,with possibly pre erential reporting o positivendings.]

3. Cancer in Experimental Animals

No data were available to the Working Group.

4. Other Relevant Data

Te rubber-manu acturing industry hasused and still uses a wide variety o substancesthat belong to many different chemical catego-ries, e.g. carbon black, aromatic amines, PAH,N -nitrosamines, mineral oils, other volatileorganic compounds rom curing umes, traceamounts o monomers rom synthetic rubber like1,3-butadiene, acetonitrile, styrene, vinyl chlo-ride, ethylene oxide, etc. (See Section 1). For thisreason, it has been difficult to relate the observed

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553

T a b l e 4

. 1 B i o m o n

i t o r i n g s t u

d i e s a n

d c y

t o g e n e

t i c a s s a y s a m o n g w o r k e r s

i n t h e r u

b b e r - m a n u

f a c t u r i n g

i n d u s t r y

R e f e r e n c e

D e s c r

i p t i o n o f e x p o s e

d a n

d

c o n t r o l s

E x p o s u r e

l e v e

l s

C y t o g e n e t

i c / g e n o t o x

i c

e n d

- p o i n t

R e s p o n s e

i n

e x p o s e d

R e s p o n s e

i n

c o n t r o l s

C o m m

e n t s

D e g r a s s i e t a l .

( 1 9 8 4 )

I t a l y

E x p o s e d :

V u l c a n i z e r s ( n = 3 4 ) i n a

r u b b e r p

l a n t

C o n t r o l s :

W o r

k e r s ( n = 1 6 ) i n t h e s a m e

p l a n t a n d

l i v i n g i n t h e s a m e

g e o g r a p h i c a r e a

A i r b o r n e p a r t i c u

l a t e

m a t t e r r a n g e

d r o m

0 . 5 t o 3 . 4 , w i t h a n

a v e r a g e ( S D ) o

1 . 1 ( 1 . 1 ) m g / m

3 .

E x p o s u r e

d u r a t i o n

( S E ) w a s 8 . 2 0 . 8

y r

C h r o m o s o m a l

a b e r r a t i o n s

( p e r 1 0 0

c e l l s )

1 . 9 1 . 4 ( e x c

l . g a p s )

2 . 1 1 . 5 ( e x c

l

g a p s )

N S

S C E ( p e r c e

l l )

5 . 2 1 . 3

5 . 2 0 . 7

C i g a r e t t e s m o k i n g

w a s a s s o c i a t e d w i t h

i n c r e a s e

d S C E i n

e x p o s e d a n

d c o n t r o

l s .


a b e r r a t i o n s w e r e n o t

c o r r e l a t e d

H e m a P r a s a

d

e t a l . (

1 9 8 6 )

I n d i a

E x p o s e d :

W o r

k e r s ( n = 3 5 ) e m p l o y e d

o r 3 1 2 y r i n a r u b

b e r

a c t o r y .

T e r e w e r e 2 0 u n e x p o s e

d

c o n t r o l s

( n o t s p e c i e d

)

N R



( p e r 1 0 0

c e l l s )

R a n g e d

r o m 1 . 5 7 t o

2 . 7 5 , i n c r e a s e d w i t h

l o n g e r t i m e a t w o r

k

0 . 6 p e r 1 0 0 c e

l l s P < 0 . 0 5

N o i n o r m a t i o n i s

g i v e n a b o u t s m o k i n g .

S a s i a

d e k ( 1 9 9 2 )

P o l a n d

E x p o s e d :

V u l c a n i z e r s ( 1 4 w o m e n , 7

m e n ; 1 4 w e r e s m o k e r s ) i n a

r u b b e r p

l a n t . C o n t r o l s :

N o n - e x p o s e d w o m e n

( n = 7 )

a n d m e n

( n = 7 ) , o

w h o m 5

w e r e s m o

k e r s

E x p o s u r e

d u r a t i o n

w a s 1 4 . 2 9 . 7 y r

( r a n g e 2 3 5 y r )



( p e r 1 0 0

c e l l s )

2 . 2 1 . 0 6 ( i n c l .

g a p s )

0 . 9 1 . 0 ( i n c l .

g a p s )

P < 0 . 0 1

S C E ( p e r c e

l l )

1 6 . 1

3 . 5

1 0 . 0

1 . 5

P < 0 . 0 0 1

S a s i a

d e k ( 1 9 9 3 )

P o l a n d

E x p o s e d :

V u l c a n i z e r s ( 1 9 w o m e n , 7

m e n ; 1 0 w e r e s m o k e r s ) i n a

r u b b e r p

l a n t . C o n t r o l s :

N o n - e x p o s e d w o m e n

( n = 1 5 )

a n d m e n

( n = 1 0 ) , o w

h o m 1 0

w e r e s m o

k e r s

E x p o s u r e

d u r a t i o n

w a s 0 . 5 3 0 y r

( m e a n

1 5 . 6

9 . 5 y r

) .

S C E ( p e r c e

l l )

1 3 . 2

2 . 9

( r a n g e

9 2 0 )

9 . 8 1 . 8 ( r a n g e

7 1 4 )

P < 0 . 0 0 1


14/22


554

R e f e r e n c e

D e s c r


d a n

d

c o n t r o l s

E x p o s u r e

l e v e

l s

C y t o g e n e t

i c / g e n o t o x

i c

e n d

- p o i n t

R e s p o n s e

i n

e x p o s e d

R e s p o n s e

i n

c o n t r o l s

C o m m

e n t s

W a r

d e t a l .

( 1 9 9 6 )

U S A

W o r

k e r s i n a b u t a d i e n e -

p r o d u c t i o n p l a n t ( 1 0 h i g h -

e x p o s e d , 1 0 l o w - e x p o s e

d ) i n

e x a s , U S A . N o n - e x p o s e d

c o n t r o l s

r o m e l s e w

h e r e

( n = 9 ) . A l l 2 9 w e r e n o n -

s m o k e r s .

S e c o n d s t u d y : o l

l o w - u p

a f e r 8 m o . O n g o i n g s t u d y

a m o n g w o r

k e r s i n a s t y r e n e -

b u t a d i e n e r u b

b e r p

l a n t i n t h e

s a m e a r e a . D a t a a r e p r e s e n t e d

o n 1 6 h i g h - e x p o s e

d ( 5

s m o k e r s ) a n

d 9 l o w - e x p o s e

d

( 3 s m o k e r s

) s u b j e c t s

E x p o s u r e s u r v e y

b y

t h e c o m p a n y : m e a n

l e v e l 3 . 5 7 . 2 5 p p m

F r o m 8 - h p e r s o n a l

b r e a t h i n g z o n e a i r

s a m p l e s : 0 . 3

0 0 . 5

9 ,

0 . 2 1 0 . 2 1 , a n d

0 . 1 2 0 . 2 7 p p m

o r

h i g h - , i n t e r m e d i a t e -

a n d l o w - e x p o s u r e

a r e a s

P a s s i v e d o s i m e t e r s

w o r n

d u r i n g t h e 8 - h

s h i f : o

4 0 s a m p

l e s ,

2 0 w e r e > 0 . 2 5 p p m ,

1 1 w e r e > 1 p p m

a ) H P R T m u t a n t s ,

l y m p h o c y t e s

b ) b u t a d i e n e

m e t a b o l i t e i n u r i n e

( s e e c o m m e n t s )

3 . 9 9 2 . 8 1

( h i g h )

a n d 1 . 2 0 0 . 5 1 ( l o w )

H P R T m u t a n t s / 1 0 6

c e l l s

1 . 0 3 0 . 1 2

H P R T m u t a n t s

p e r 1 0 6 c e l

l s

P < 0 . 0 2

5 . 3 3 3 . 7 6

*

( h i g h ) 2

. 2 7 0 . 9 9

( m e d i u m ) ,

2 . 1 4 0 . 9

7 ( l o w )

m u t a n t s / 1 0 6 c e l

l s

* P < 0 . 0 2

N o n - s m o k e r s :

7 . 4 7 5 . 6 9 ( h i g h ) * *

1 . 6 8 0 . 8

5 ( l o w )

S m o k e r s :

6 . 2 4 4 . 3

7 ( h i g h ) * *

3 . 4 2 1 . 5

7 ( l o w )

* * P < 0 . 0 1

C o m m e n t :

d i h y d r o x y b u t a n e

m e r c a p t u r a t e ,

1 , 2 - d i h y d r o x y - 4 ( N -

a c e t y l - c y s t e i n y l

)

b u t a n e , w a s m e a s u r e

d

i n u r i n e b y G C / M S .

T e h i g h - e x p o s u r e

g r o u p s (

b u t a d i e n e -

m o n o m

e r p l a n t o n l y )

h a d s i g n i

c a n t l y

h i g h e r

l e v e l s .

M o r e t t i e t a l .

( 1 9 9 6 )

I t a l y

W o r

k e r s a t 4 r u

b b e r p l a n t s

( n = 1 9 ; 9 s m o k e r s ) a n

d 2 0

a g e - m a t c

h e d ( 5 y r

) b l o o d

d o n o r s a s c o n t r o l s ( 8 o

w h o m w e r e s m o k e r s )

N R

a ) m u t a g e n i c i t y i n

u r i n e

b ) u r i n a r y e x c r e t i o n o

t h i o e t

h e r s

a ) , b

) : n o d i ff e r e n c e s

b e t w e e n e x p o s e

d

a n d c o n t r o l s

c ) D N A d a m a g e i n

l y m p h o c y t e s

m e d i a n m i g r a t i o n

d i s t a n c e i n C o m e t

a s s a y : 3 7 . 9

9 m

m e d i a n

m i g r a t i o n

d i s t a n c e : 3 3 . 8 1

m

P > 0 . 0 5

d ) S C E

5 . 5 1 0 . 8

2 /

m e t a p h a s e

6 . 0 6 1 . 1 5

P > 0 . 0 5

e ) M N o r m a t i o n

2 2 . 8

4 1 5 . 8

2 M N

p e r 1 0 0 0 b i n u c l e a t e d

c e l l s

1 3 . 7 4

4 . 4 2

P < 0 . 0 5

T a b l e 4

. 1 ( c o n

t i n u e d

)


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555

T a b l e 4

. 1 ( c o n

t i n u e d

)

R e f e r e n c e

D e s c r


d a n

d

c o n t r o l s

E x p o s u r e

l e v e

l s

C y t o g e n e t

i c / g e n o t o x

i c

e n d

- p o i n t

R e s p o n s e

i n

e x p o s e d

R e s p o n s e

i n

c o n t r o l s

C o m m

e n t s

M a j o r e t a l .

( 1 9 9 9 )

H u n g a r y

S u b j e c t s

( n = 2 9 , a m o n g

w h o m 2 4 w e r e s m o k e r s ; 2 3

m e n , 6 w o m e n

) w i t h m i x e d

i n d u s t r i a

l e x p o s u r e d u r i n g

3 2 0 y r i n t h e r u b

b e r -

m a n u a c t u r i n g i n d u s t r y .

C o n t r o l s w e r e

l i v i n g a n

d /

o r w o r k i n g i n t h e v i c i n i t y

o c h e m i c a

l p l a n t s ,

b u t h a d

n o o c c u p a t i o n a

l e x p o s u r e

t o c h e m i c a

l s ( i n d u s t r i a

l

c o n t r o l s )

E x p o s u r e s i n c

l u d e d

a r o m a t i c s o

l v e n t s ,

d u s t , t a r , l u b r i c a t i n g

o i l . N o q u a n t i t a t i v e

d a t a g i v e n

E x p o s e d

I n d u s t r i a l

c o n t r o

l s

a ) c h r o m o s o m a l

a b e r r a t i o n s p e r 2 9 0 0

m e t a p

h a s e s s c o r e

d

3 . 3 8 0 . 2

6

1 . 6 0 0 . 6 2

P < 0 . 0 1

b ) P C D :

- m i t o s e s w i t h 3

c h r o m o s o m e s

1 1 . 4

5 1 . 4

3

1 . 5 7 0 . 4 4

P < 0 . 0 1

- m i t o s e s w i t h > 3

c h r o m o s o m e s

6 . 0 0 1 . 1 8

0 . 3 2 0 . 1 0

P < 0 . 0 1

c ) a n e u p l o i

d y

5 . 6 4 0 . 4

4

6 . 2 0 0 . 4 3

N S

S o m o r o v s k e t

a l . (

1 9 9 9 )

S l o v a k

R e p u b l i c

W o r

k e r s ( 2 7 m e n , 2 w o m e n ;

1 8 s m o k e r s , 1

1 n o n - s m o k e r s )

i n a r u b b e r t y r e

a c t o r y .

T e

i n d u s t r i a

l c o n t r o l s c o m p r i s e d

2 2 c l e r k s

( 8 m e n , 1

4 w o m e n ;

1 4 s m o k e r s , 8 n o n - s m o k e r s )

r o m t h e s a m e a c t o r y .

A s e c o n d c o n t r o

l g r o u p

c o m p r i s e d 1 7 m e n a n

d 5

w o m e n ( 7 s m o k e r s , 1 5 n o n -

s m o k e r s ) w

h o w o r k e d i n a

l a b o r a t o r y i n B r a t i s l a v a

A i r s a m p l i n g w a s

o l l o w e

d b y a n a l y s i s

o s t y r e n e , t o l u e n e ,

b u t a d i e n e , P A H s ,

a l k a n e s , a n

d a l k e n e s

a ) D N A b r e a

k a g e

( C o m e t a s s a y )

b ) c h r o m o s o m a l


c ) M N a s s a y

S a m p l e 1

( 1 9 9 6 ) :

3 3 % D N A i n t a i l

S a m p l e 2

( 1 9 9 7 ) :

4 5 % D N A i n t a i l

F a c t o r y c o n t r o l s :

1 3 % D N A i n t a i l

L a b o r a t o r y

c o n t r o

l s :

2 2 % D N A i n t a i l

P < 0 . 0 0 0 0 1

1 a b e r r a t i o n / 1 0 0

c e l l s


0 . 4 a b e r r . / 1 0 0

c e l l s

L a b o r a t o r y

c o n t r o

l s :

0 . 2 a b e r r . / 1 0 0

c e l l s

P < 0 . 0 0 0 0 1

6 . 5 M N / 2 0 0 0 c e

l l s


2 . 1 M N / 2 0 0 0

c e l l s

L a b o r a t o r y

c o n t r o

l s :

1 . 5 M N / 2 0 0 0

c e l l s

P < 0 . 0 0 0 0 1


16/22


556

R e f e r e n c e

D e s c r


d a n

d

c o n t r o l s

E x p o s u r e

l e v e

l s

C y t o g e n e t

i c / g e n o t o x

i c

e n d

- p o i n t

R e s p o n s e

i n

e x p o s e d

R e s p o n s e

i n

c o n t r o l s

C o m m

e n t s

Z h u e t a l .

( 2 0 0 0 )

G u a n g z h o u ,

C h i n a

W o r

k e r s [ 1 9 7 m e n

( 1 3 0

s m o k e r s ) a n

d 1 7 4 w o m e n

( 6 s m o k e r s

) ] a t a a c t o r y

t h a t p r o d u c e d t y r e s ,

p a d s a n d o t

h e r p r o

d u c t s .

A m o n g t

h e s e , 2

8 1 w e r e i n

r u b b e r - p r o c e s s i n g j o b s

,

a n d 9 0 c o n t r o l s w e r e i n

m a n a g e m e n t . T e r e w e r e 3 1 8

d r i n k e r s a n

d 5 3 n o n -

d r i n k e r s

E n v i r o n m e n t a l

m o n i t o r i n g o d u s t ,

t o l u e n e , x y

l e n e ,

g a s o

l i n e , H

2 S , S O 2

D N A b r e a

k a g e

( C o m e t

a s s a y ; r e s u

l t s g i v e n a s

t a i l m o m e n t )

A l l r u b b e r w o r k e r s :

1 . 7 7 ( 1 . 6 4 1 . 9 0 ) * m

F i n i s h i n g :

1 . 8 1 ( 1 . 4 8 2 . 2 1 ) m

C a l e n d e r i n g :

1 . 7 7 ( 1 . 5 4 2 . 0 3 ) m

V u l c a n i z i n g :

1 . 6 4 ( 1 . 4 6 1 . 8 3 ) m

M i x i n g :

2 . 5 4 ( 1 . 9 5 3 . 3 1 ) * *

m

M a n a g e r i a l

w o r k e r s :

1 . 5 2 ( 1

. 3 6 1 . 7 1 )

m

* P = 0 . 0

4

C o m m e n t : N o n -

d r i n k i n g , n o n -

s m o k i n g m i x e r s

a l s o h a d

h i g h e r

t a i l m o m e n t t h a n

c o m p a r a

b l e m a n a g e r s :

2 . 2 5 ( 1 . 6

6 3 . 0 3 ) v s

1 . 3 9 ( 1 . 1 8 1 . 6

3 ) m

( P = 0 . 0

4 9 )

* * P = 0 . 0 0 2

M a e t a l .

( 2 0 0 0 )

e x a s , U S A

M a l e n o n - s m o k i n g w o r k e r s

a t a s t y r e n e - b u t a d i e n e

p o l y m e r p l a n t . C o n t r o

l s w e r e

e m p l o y e e s a t t h e U n i v e r s i t y

o e x a s M e d i c a l B r a n c h

B r e a t h i n g - z o n e

a i r s a m p l i n g w i t

h

p e r s o n a l m o n i t o r s

A n a

l y s i s o H P R T

v a r i a n t s a n d m u t a n t s ,

a n d o e x o n

d e l e t i o n s

i n t h e H P R T g e n e i n

l y m p h o c y t e s , w

i t h a

m u l t i p l e x P C R a s s a y

H P R T v a r i a n t s p e r

1 0 6

c e l l s : 6 . 8 6 3 . 2 5

( n = 1 2 )

2 . 3 6 1 . 0 4

( n = 8 )

P < 0 . 0 5

H P R T m u t a n t s

p e r 1 0 6

c e l l s :

1 7 . 6

3 5 . 0

5 ( n = 1 0 )

8 . 4 7 2 . 8 8

( n = 1 1 )

P < 0 . 0 5

W a r

d e t a l .

( 2 0 0 1 )

e x a s , U S A

( s t u d y

c o n d u c t e d i n

1 9 9 8 )

W o r

k e r s i n a B D r u

b b e r

p l a n t : 2 2 i n a h i g h -

e x p o s u r e a n

d 1 5 i n a

l o w - e x p o s u r e g r o u p , w i t h

l e v e l s o 1 . 7 1 0 . 5 4 ( S E )

a n d 0 . 0 7 0 . 0 3 ( S E ) p p m

b u t a d i e n e , r e s p e c t i v e l y

E x p o s u r e t o 1 , 3 - B D

w a s m o n i t o r e

d w i t h

o r g a n i c v a p o u r

m o n i t o r s a n

d v a r i e

d

r o m 4 . 0 4 3 . 4 5

p p m

( t a n k

a r m )

t o 0 . 2 9 0 . 3 3

( l a b o r a t o r y

) .

L o w a r e a s *

h a d

0 . 0 5 0 . 0 6 p p m

* p a c

k a g i n g , b a l i n g ,

w a r e

h o u s e , s h i p p i n g

H P R T m u t a n t a n a

l y s i s

i n l y m p h o c y t e s

H i g h - e x p o s u r e

g r o u p :

A l l ( n = 2 2 )

1 0 . 6

7 1 . 5 1 ( S E )

N o n - s m o k e r s

( n = 1 2 ) 8 . 6

4 1 . 6 0

S m o k e r s

( n = 1 0 )

1 3 . 1 0

2 . 5

7

L o w - e x p o s u r e

g r o u p :

A l l ( n = 1 5 )

3 . 5 4 0 . 6 1


( n = 1 4 )

3 . 4 6 0 . 6 5

S m o k e r s 4 . 6 1

P = 0 . 0 0 1

P = 0 . 0 1 1

C o m m e n t : i n c r e a s e s

i n H P R T v a r i a n t

r e q u e n c y o

a b o u t

t h r e e o l

d a r e s e e n a t

a v e r a g e B D e x p o s u r e

l e v e l s o 1 3 p p m

T a b l e 4

. 1 ( c o n

t i n u e d

)


17/22


557

T a b l e 4

. 1 ( c o n

t i n u e d

)

R e f e r e n c e

D e s c r


d a n

d

c o n t r o l s

E x p o s u r e

l e v e

l s

C y t o g e n e t

i c / g e n o t o x

i c

e n d

- p o i n t

R e s p o n s e

i n

e x p o s e d

R e s p o n s e

i n

c o n t r o l s

C o m m

e n t s

A m m e n

h e u s e r

e t a l . (

2 0 0 1 )

e x a s , U S A

W o r

k e r s ( n = 2 4 ) i n t h e

r e a c t o r , r e c o v e r y , t a n k

a r m

a n d l a b o r a t o r y a r e a o a B D

r u b b e r p

l a n t r e p r e s e n t e d

a h i g h - e x p o s u r e g r o u p .

W o r

k e r s ( n = 2 5 ) i n

b l e n

d i n g ,

c o a g u l a t i o n ,

b a l i n g , s h i p p i n g ,

t h e c o n t r o l r o o m a n

d u t i l i t y

a r e a s w e r e a l o w - e x p o s u r e

g r o u p

W o r

k e r s w e r e

a s k e d t o w e a r a n

o r g a n i c v a p o u r

m o n i t o r d u r i n g o n e

8 - h w o r k - s

h i f , t o

m e a s u r e e x p o s u r e t o

b u t a d i e n e / s t y r e n e .

L o w e r d e t e c t i o n

l i m i t : 0 . 2 5 p p m B D


l y s i s


H i g h - e x p o s u r e

g r o u p :


( n = 1 9 )

6 . 8 1 . 2 *

( S E )

S m o k e r s

( n = 5 )

6 . 1 2 . 0

L o w - e x p o s u r e

g r o u p :


( n = 2 0 )

1 . 8 0 . 2

S m o k e r s

( n = 5 ) 3 . 3

0 . 5

* P < 0 . 0

0 0 5

V e r m e u

l e n e t

a l . (

2 0 0 2 )

t h e

N e t

h e r l a n d s

W o r

k e r s i n t h e r u b

b e r -

m a n u a c t u r i n g i n d u s t r y

( n = 5 2 ; a l l n o n - s m o k e r s )

M u t a g e n i c i t y o n

l i k e l y s k i n - c o n t a c t

s u r a c e s

( h i g h , 2 5

r e v e r t a n t s / c m

2 ; l o w ,

< 2 5 r e v / c m

2 ) a n

d i n

a m b i e n t a i r ( h i g h

,

2 1 0 r e v / m

3 l o w ,

< 2 1 0 r e v / m

3 ) t e s t e d

i n Y G 1 0 4 1 o S .

t y p h i m u r i u m

D N A - a d

d u c t a n a l y s i s

i n e x

o l i a t e d b l a d

d e r

c e l l s c o

l l e c t e d

r o m

2 4 - h u r i n e ,

b y

3 2 P - p o s t

l a b e l l i n g .

S a m p l e s

r o m 3 2 s l o w

a n d 2 0 a s t a c e t y l a t o r s

( b a s e d o n N A T 2

a n a l y s i s )

O 5 2 u r i n e s a m p l e s ,

4 6 g a v e r e

l i a b l e d a t a

o r t

h e p r e s e n c e o

t h r e e m a i n a d

d u c t s :

1 i n 4 1 s a m p l e s , 2

i n

1 3 s a m p

l e s , 3 i n 2 9

s a m p l e s

N R

T e s l o w N A T 2

s u b j e c t s h a d l o w e r

l e v e l s o a d

d u c t s

1 3 t h a n t h e a s t

a c e t y l a t o r s . (

P < 0 . 0 4 ;

P = 0 . 3 2 ; P = 0 . 1 5 ,

r e s p )

N o i n o r m a t i o n i s

g i v e n o n t h e i

d e n t i t y

o t h e a d

d u c t s

L a ff o n e t a l .

( 2 0 0 6 )

P o r t u g a l

E x p o s e d m a l e w o r

k e r s

( n = 3 2 ) a n d n o n - e x p o s e

d

m a l e c o n t r o l s ( n = 3 2 ) i n

a r u b

b e r t y r e

a c t o r y i n

O p o r t o , o w h o m 3 9 % w e r e

s m o k e r s

N R

a ) t h i o - e t h e r s i n p o s t -

s h i f u r i n e

0 . 4 1 0 . 0

5 m M

0 . 2 4 0 . 0 2 m M

P < 0 . 0 1

b ) m i c r o n c

l e u s t e s t

( M N p e r 1 0 0 0 c e

l l s )

2 . 3 4 0 . 3

3

1 . 8 4 0 . 2 9

N S

c ) S C E / c e

l l

4 . 3 5 0 . 2

0

4 . 3 8 0 . 1 7

N S

d ) D N A - b r e a

k a g e

( C o m e t a s s a y )

( t a i l

l e n g t

h , m

)

4 4 . 7

2 0 . 6 6

4 8 . 2

5 0 . 7 1

P < 0 . 0 1


18/22


558

R e f e r e n c e

D e s c r


d a n

d

c o n t r o l s

E x p o s u r e

l e v e

l s

C y t o g e n e t

i c / g e n o t o x

i c

e n d

- p o i n t

R e s p o n s e

i n

e x p o s e d

R e s p o n s e

i n

c o n t r o l s

C o m m

e n t s

P e t e r s e t a l .

( 2 0 0 8 )

t h e

N e t

h e r l a n d s

W o r

k e r s ( n = 1 1 6 ; 4 5 s m o k e r s ,

7 1 n o n - s m o k e r s ) i n t h e

D u t c h r u

b b e r - m a n u a c t u r i n g

i n d u s t r y , s e l e c t e d o n t h e

b a s i s o t

h e i r u n c t i o n i n t h e

p r o d u c t i o n p r o c e s s . U r i n e

a n d b l o o d w e r e c o

l l e c t e d

N R

W e e

k d a y s a m p l e s :

S u n d a y s a m p l e s :

a ) H y d r o x y p y r e n e i n

u r i n e ( r e s u

l t o r n o n -

s m o k e r s )

0 . 1 5 0 . 1 9 m o l / m o l

c r e a t i n i n e

0 . 1 2 m o l / m o l

c r e a t i n i n e

P < 0 . 0 0 0 1

b ) M u t a g e n i c a c t i v i t y

i n u r i n e ( r e v e r t a n t s / g

c r e a t i n i n e ) o w o r k e r s

i n c o m p o u n

d i n g a n

d

m i x i n g

1 0 5 1 1

6 5 2 2

P < 0 . 0 5

c ) D N A a d

d u c t s i n

u r o t

h e l i a l c e l

l s a n

d

i n p e r i p

h e r a

l b l o o d

m o n o c y t e s

I n c r e a s e

d c o m p a r e

d

w i t h c o n t r o l

M u s a k e t a l .

( 2 0 0 8 )

C z e c

h

R e p u b l i c

W o r

k e r s i n a t y r e p

l a n t

( n = 1 7 7 ; 6 9 s m o k e r s ) a n

d 1 7 2

c o n t r o l s

( 4 9 s m o k e r s )

P e r s o n a l s a m p l e r s

w o r n i n b r e a t h i n g

z o n e . A v e r a g e B D

l e v e l i n t h e m i x i n g

d e p a r t m e n t w a s

2 . 6 0 . 2 m g / m 3



( p e r 1 0 0 m e t a p

h a s e s )

2 . 5 1 . 8

1 . 7 1 . 2

P = 0 . 0 5 5

W i c k l i ff e e t a l .

( 2 0 0 9 )

e x a s , U S A

W o r

k e r s i n a B D r u

b b e r p l a n t

( s e e W a r

d e t a l . ,

2 0 0 1 a b o v e )

C u r r e n t e x p o s u r e s :

m e a n 9 3 . 5

p p b ,

m e d i a n 2 . 5 p p b


l y s i s


C u r r e n t , l o w , e x p o s u r e s t o b u t a d i e n e

i n t h i s p l a n t

d o n o t s e e m t o i n c r e a s e

t h e H P R T m u t a n t r e q u e n c y . H o w e v e r ,

o l d e r w o r k e r s s

h o w e

d i n c r e a s e

d H P R T

m u t a n t

r e q u e n c i e s ,

l i k e l y d u e t o

p r e v i o u s c

h r o n i c e x p o s u r e t o h i g h e r

l e v e

l s o b u t a d i e n e .

B D , s

t y r e n e - b u t a d i e n e ; h , h o u r o r h o u r s ; H P R T , h y p o x a n t

h i n e - g u a n i n e p h o s p

h o r i b o s y l t r a n s e r a s e ; m o , m o n t h o r m o n t h s ; M N , m

i c r o n u c l e u s ; N R , n o t r e p o r t e d ; N S , n o t s i g n i

c a n t ;

P C D , p r e m a t u r e c

h r o m o s o m e c o n d e n s a t i o n ; S C E : S i s t e r - c

h r o m a t i d e x c h a n g e ; S D s t a n

d a r d

d e v i a t i o n ; S E s t a n

d a r d e r r o r ; v s , v e r s u s ; y r , y e a r o r y e a r s

T a b l e 4

. 1 ( c o n

t i n u e d

)


19/22


cancer hazards in the rubber-manu acturingindustry to exposure to specic chemicals.

able 4.1 presents a list o bio-monitoringstudies and cytogenetic assays among workersin the rubber-manu acturing industry in variouscountries and at different times. Tese studieshave ocused on analysis o chromosomal aberra-tions, sister-chromatid exchange, micronucleus

ormation, premature chromosome condensa-tion, DNA breakage, DNA-adduct ormation,mutagenicity in urine, and mutation in the HPR gene. For each o these endpoints, in most studiesa positive response has been observed in exposedworkers compared with non-exposed controls. Itis noted that the studies listed in able 4.1 span a

period o approximately 25 years.Te multiple genetic and cytogenetic effects

observed among workers employed in the rubber-manu acturing industry provide strong evidenceto support genotoxicity as one mechanism orthe observed increase in cancer risk. However,due to the complexity and changing nature othe exposure mixture and the potential interac-tions between exposures in this industry, othermechanisms are also likely to play a role.

While it is clear that exposures to some agentsin the rubber-manu acturing industry have beenreduced over time, the outcome o recent cytoge-netic studies continues to raise concerns aboutcancer risks.

5. Evaluation

Tere is sufficient evidence in humans or thecarcinogenicity o occupational exposures in therubber-manu acturing industry. Occupational

exposures in the rubber-manu acturing industrycause leukaemia, lymphoma, and cancers o theurinary bladder, lung, and stomach.

lso, a positive association has been observedbetween occupational exposures in the rubber-manu acturing industry and cancers o the pros-tate, oesophagus, and larynx.

No data in experimental animals with rele- vance to the rubber-manu acturing industrywere available to the Working Group.

Te multiple genetic and cytogenetic effectsobserved among workers employed in the rubber-manu acturing industry provide strong evidenceto support genotoxicity as one mechanism orthe observed increase in cancer risks. However,due to the complexity and changing nature o theexposure mixture and the potential interactionsbetween exposures in the rubber-manu acturingindustry, other mechanisms are also likely toplay a role. While it is clear that exposure to someagents in the rubber-manu acturing industryhas been reduced over time, the results o recent

cytogenetic studies continue to raise concernsabout cancer risks.

Occupational exposures in the rubber-manu-acturing industry are carcinogenic to humans

(Group 1).

References

Alder N, Fenty J, Warren F et al. (2006). Meta-analysis omortality and cancer incidence among workers in thesynthetic rubber-producing industry. Am J Epidemiol ,164: 405420. doi:10.1093/aje/kwj252 PMID:16873420

Ammenheuser MM, Bechtold WE, Abdel-Rahman SZet al. (2001). Assessment o 1,3-butadiene exposure inpolymer production workers using HPR mutations inlymph

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