Criteria for a Recommended Standard - Occupational Exposure to

Background photo on cover by James Lockey, M.D.: Photomicrograph of a rat lung in inhalation studies with airborne fibers.

Inset photo on cover, courtesy of Kevin H. Dunn: NIOSH industrial hygienist performing air sampling to evaluate engineering controls in simulated work ac-tivities using RCF materials.

Criteria for a Recommended Standard

Occupational Exposure to Refractory Ceramic Fibers

DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health

ii Refractory Ceramic Fibers

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DHHS (NIOSH) Publication No. 2006–123

May2006

Safe • Healthier • PeopleTM

Refractory Ceramic Fibers iii

Foreword

WhentheU.S.CongresspassedtheOccupationalSafetyandHealthActof1970(PublicLaw91–596),itestablishedtheNationalInstituteforOccupationalSafetyandHealth(NIOSH).ThroughtheAct,CongresschargedNIOSHwithrecommendingoccupationalsafetyandhealthstandardsanddescribingexposurelimitsthataresafeforvariousperiodsofemployment.Theselimitsin-cludebutarenotlimitedtotheexposuresatwhichnoworkerwillsufferdiminishedhealth,func-tionalcapacity,orlifeexpectancyasaresultofhisorherworkexperience.Bymeansofcriteriadocuments,NIOSHcommunicatestheserecommendedstandardstoregulatoryagencies(includ-ingtheOccupationalSafetyandHealthAdministration[OSHA]),healthprofessionalsinacademicinstitutions,industry,organizedlabor,publicinterestgroups,andothersintheoccupationalsafetyandhealthcommunity.Criteriadocumentscontainacriticalreviewofthescientificandtechni-calinformationabouttheprevalenceofhazards,theexistenceofsafetyandhealthrisks,andtheadequacyofcontrolmethods.

Thiscriteriadocumentisderivedfromreviewsof informationfromhumanandanimalstudiesofthetoxicityofrefractoryceramicfibers(RCFs)andisintendedtodescribethepotentialhealtheffectsofoccupationalexposuretoairbornefibersofthismaterial.RCFsareamorphoussyntheticfibersproducedbythemeltingandblowingorspinningofcalcinedkaolinclayoracombinationofalumina,silica,andotheroxides.RCFsbelongtotheclassofsyntheticvitreousfibers(SVFs)—ma-terialsthatalsoincludefibersofglasswool,rockwool,slagwool,andspecialtyglass.RCFsareusedincommercialapplicationsrequiringlightweight,high-heatinsulation(e.g.,furnaceandkilninsu-lation).CommercialproductionofRCFsbeganinthe1950sintheUnitedStates,andproductionincreaseddramaticallyinthe1970s.DomesticproductionofRCFsin1997totaledapproximately107.7millionlb.Currently,totalU.S.productionhasbeenestimatedat80millionlbperyear,whichconstitutes1%to2%ofSVFsproducedworldwide.IntheUnitedStates,approximately31,500workershavethepotentialforoccupationalexposuretoRCFsduringdistribution,handling,installation,andremoval.Morethan800oftheseworkersareemployeddirectlyinthemanufactur-ingofRCFsandRCFproducts.WithincreasingproductionofRCFs,concernsaboutexposurestoairbornefiberspromptedanimalinhalationstudiesthathaveindicatedanincreasedincidenceofmesotheliomasinhamstersandlungcancerinratsfollowingexposuretoRCFs.StudiesofworkerswhomanufactureRCFshaveshownapositiveassociationbetweenincreasedexposuretoRCFsandthedevelopmentofpleuralplaques,skinandeyeirritation,andrespiratorysymptomsandcon-ditions(includingdyspnea,wheezing,andchroniccough).Inaddition,currentandformerRCFproductionworkershaveshowndecrementsinpulmonaryfunction.

Afterevaluatingthisevidence,NIOSHproposesarecommendedexposurelimit(REL)forRCFsof0.5fiberpercubiccentimeter (f/cm3)ofairasa time-weightedaverage(TWA)concentra-tionforuptoa10-hrworkshiftduringa40-hrworkweek.LimitingairborneRCFexposurestothisconcentrationwillminimizetheriskfor lungcancerandirritationoftheeyesandupper

iv Refractory Ceramic Fibers

respiratorysystemandisachievablebasedonareviewofexposuremonitoringdatacollectedfromRCFmanufacturersandusers.However,becausearesidualriskofcancer(lungcancerandpleuralmesothelioma)maystillexistattheREL,continuedeffortsshouldbemadetowardreducingexpo-surestolessthan0.2f/cm3.Engineeringcontrols,appropriaterespiratoryprotectionprograms,andotherpreventivemeasuresshouldbeimplementedtominimizeworkerexposurestoRCFs.NIOSHurgesemployerstodisseminatethisinformationtoworkersandcustomers.NIOSHalsorequeststhatprofessionalandtradeassociationsandlabororganizationsinformtheirmembersaboutthehazardsofexposuretoRCFs.

JohnHoward,M.D.Director,NationalInstituteforOccupationalSafetyandHealthCentersforDiseaseControlandPrevention

Foreword

Refractory Ceramic Fibers v

Executive Summary

lungcancer.However,studiesofworkerpopu-lationswithoccupationalexposuretoairborneRCFshaveshownanassociationbetweenex-posure and the formation of pleural plaques,increasedprevalenceofrespiratorysymptomsand conditions (dyspnea, wheezing, chroniccough),decreasesinpulmonaryfunction,andskin,eye,andupperrespiratorytractirritation[Lemastersetal.1994,1998;Lockeyetal.1996].Increased decrements in pulmonary functionamongworkersexposedtoRCFswhoarecur-rent or former cigarette smokers indicate anapparent synergistic effect between smokingandRCFexposure[Lemastersetal.1998].Thisfindingisconsistentwithstudiesofotherdust-exposed populations. The implementation ofimprovedengineeringcontrolsandworkprac-ticesinRCFmanufacturingprocessesandenduseshaveledtodramaticdeclinesinairbornefiberexposureconcentrations[Riceetal.1996,1997;Maximetal.2000a],whichinturnhavelowered the risk of symptoms and health ef-fectsforexposedworkers.

In2002,theRefractoryCeramicFibersCoali-tion(RCFC)establishedtheProductSteward-ship Program (PSP), which was endorsed bythe Occupational Safety and Health Admin-istration(OSHA).ContainedinthePSPwererecommendationsforanRCFexposureguide-lineof0.5fiberpercubiccentimeter(f/cm3)ofairasatime-weightedaverage(TWA)basedonthecontentionthatexposuresat thisconcen-tration could be achieved in most industriesthatmanufacturedorusedRCFs.Atthistime,the available health data do not provide suf-ficientevidence forderivingaprecisehealth-based occupational exposure limit to protect

TheNationalInstituteforOccupationalSafetyandHealth(NIOSH)hasrevieweddatachar-acterizing occupational exposure to airbornerefractoryceramicfibers(RCFs)andinforma-tion about potential health effects obtainedfromexperimentalandepidemiologicstudies.Fromthisreview,NIOSHdeterminedthatoc-cupationalexposuretoRCFsisassociatedwithadverserespiratoryeffectsaswellas skinandeyeirritationandmayposeacarcinogenicriskbasedontheresultsofchronicanimalinhala-tionstudies.

In chronic animal inhalation studies, expo-suretoRCFsproducedanincreasedincidenceofmesotheliomas inhamsters [McConnell etal. 1995] and lung cancer in rats [Mast et al.1995a,b].Thepotentialroleofnonfibrouspar-ticulatesgeneratedduringinhalationexposuresintheanimalstudiescomplicatestheissueofdeterminingtheexactmechanismsanddosesassociatedwiththetoxicityofRCFsinproduc-ingcarcinogeniceffects[Mastetal.2000].Theinductionofmesotheliomasand sarcomas inrats and hamsters following intrapleural andintraperitoneal implantation of RCFs pro-videdadditionalevidenceforthecarcinogenicpotential of RCFs [Wagner et al. 1973; Davisetal.1984;Smithetal.1987;Pottetal.1987].Lung tumors have also been observed in ratsexposed to RCFs by intratracheal instillation[ManvilleCorporation1991].

IncontrasttothecarcinogeniceffectsofRCFsobservedinexperimentalanimalstudies,epide-miologicstudieshavefoundnoassociationbe-tweenoccupationalexposuretoairborneRCFsandanexcessrateofpulmonaryfibrosisor

Executive Summary

vi Refractory Ceramic Fibers

against lung cancer. However, given what isknown from the animal and epidemiologicaldata, NIOSH supports the intent of the PSPand concurs that a recommended exposurelimit(REL)of0.5f/cm3asaTWAforuptoa10-hrworkshiftduringa40-hrworkweekwilllowertheriskfordevelopinglungcancer.Keeping exposures below the REL should re-duce the risk of lung cancer to estimates be-tween0.073/1,000and1.2/1,000(basedonex-trapolationsof riskmodels fromMoolgavkaretal.[1999]andYuandOberdörster[2000]).KeepingworkerexposuresbelowtheRELwillalsoreducetheriskofirritationoftheeyesandupperrespiratorysystem.

The risk for mesothelioma at 0.5 f/cm3 is notknown but cannot be discounted. Evidencefromepidemiologicstudiesshowedthathigherexposuresinthepastresultedinpleuralplaquesinworkers,indicatingthatRCFsdoreachpleu-raltissue.BothimplantationstudiesinratsandinhalationstudiesinhamstersshowthatRCFscancausemesothelioma.Becauseoflimitationsin thehamsterdata, the riskofmesotheliomacannotbequantified.However,thefactthatnomesotheliomahasbeen found inworkers andthatpleuralplaquesappear tobe less likely inworkerswithlowerexposuressuggestsa lowerriskformesotheliomaattheREL.

Because residual risks of cancer (lung cancerandpleuralmesothelioma)andirritationmaystill exist at the REL, NIOSH further recom-mends that all reasonable efforts be made toworktowardreducingexposurestolessthan0.2f/cm3.Atthisconcentration,therisksoflung

cancerareestimatedtobebetween0.03/1,000and0.47/1,000(basedonextrapolationsofriskmodelsfromMoolgavkaretal.[1999]andYuandOberdörster[2000]).

MaintainingairborneRCFconcentrationsbe-low the REL requires a comprehensive safetyand health program that includes provisionsforthemonitoringofworkerexposures,instal-lationandroutinemaintenanceofengineeringcontrols,andthetrainingofworkers ingoodworkpractices.Industry-ledeffortshavelike-wise promoted these actions by establishingthePSP.NIOSHbelievesthatmaintainingex-posures below the REL is achievable at mostmanufacturingoperationsandmanyuserap-plications, and that the incorporation of anactionlevel(AL)of0.25f/cm3intheexposuremonitoringstrategywillhelpemployersdeter-minewhenworkplaceexposureconcentrationsareapproachingtheREL.TheALconcepthasbeenanintegralelementofoccupationalstan-dardsrecommendedinNIOSHcriteriadocu-ments and in comprehensive standards pro-mulgatedbyOSHAand theMineSafetyandHealthAdministration(MSHA).

NIOSHalsorecommendsthatemployersim-plementadditionalmeasuresunderacompre-hensive safety and health program, includinghazardcommunication,respiratoryprotectionprograms, smoking cessation, and medicalmonitoring. These elements, in combinationwitheffortstomaintainairborneRCFconcen-trationsbelowtheREL,willfurtherprotectthehealthofworkers.

Refractory Ceramic Fibers vii

Contents

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiExecutiveSummary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vAbbreviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiGlossary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xivAcknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

1 Recommendations for a Refractory Ceramic Fiber (RCF) Standard . . . 11.1RecommendedExposureLimit(REL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2DefinitionsandCharacteristics.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.2.1NaturallyOccurringMineralFibers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2.2RCFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2.3SVFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.3SamplingandAnalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.4ExposureMonitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.4.1SamplingSurveys. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.4.2ActionLevel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.5HazardCommunication.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.6Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.7ProductFormulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41.8EngineeringControlsandWorkPractices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

1.8.1EngineeringControls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.8.2WorkPractices.................................................. 5

1.9RespiratoryProtection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.9.1RespiratoryProctectionProgram. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61.9.2RespiratorSelection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.10SanitationandHygiene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.11MedicalMonitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1.11.1OversightoftheProgram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91.11.2ElementsoftheMedicalMonitoringProgram . . . . . . . . . . . . . . . . . . . . . . 9

1.12LabelingandPosting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111.13SmokingCessation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2 Background and Description of RCFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.1Scope............................................................... 13

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Contents

2.2Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.3ChemicalandPhysicalPropertiesofRCFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2.3.1FiberDimensions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.3.2FiberDurability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

3 RCF Production and Potential for Worker Exposure . . . . . . . . . . . . . . . . . 183.1Production. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183.2PotentialforWorkerExposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183.3RCFManufacturingProcess. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183.4RCFProductsandUses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

3.4.1ExamplesofProducts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203.4.2ExamplesofApplications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

4 Assessing Occupational Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224.1AirSamplingandAnalyticalMethods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224.2SamplingforAirborneFibers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

4.2.1NIOSHFiber-CountingRules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224.2.2EuropeanFiber-CountingRules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

4.3SamplingforTotalorRespirableParticulates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234.4SamplingforAirborneSilica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244.5IndustrialHygieneSurveysandExposureAssessments. . . . . . . . . . . . . . . . . . . . . . 24

4.5.1UniversityofPittsburghSurveyofExposuresDuringRCFManufacturing 254.5.2UniversityofCincinnatiStudyofExposuresDuringRCFManufacturing. 254.5.3RCFC/EPAConsentAgreementMonitoringData . . . . . . . . . . . . . . . . . . . . 264.5.4ExposuresDuringInstallationandRemovalofRCFFurnaceInsulation. . 314.5.5International(Canadian,Swedish,andAustralian)SurveysofRCFExposure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334.5.6JohnsHopkinsUniversityIndustrialHygieneSurveys. . . . . . . . . . . . . . . . . 344.5.7NIOSHHHEsandAdditionalSourcesofRCFExposureData. . . . . . . . . . 344.5.8Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

5 Effects of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385.1HealthEffectsinAnimals(InVivoStudies). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

5.1.1Intrapleural,Intraperitoneal,andIntratrachealStudies. . . . . . . . . . . . . . . . 385.1.2ChronicInhalationStudies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425.1.3DiscussionofRCFStudiesinAnimals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535.1.4LungOverloadArgumentRegardingInhalationStudiesinAnimals . . . . . 56

5.2CellularandMolecularEffectsofRCFs(InVitroStudies). . . . . . . . . . . . . . . . . . . 585.3HealthEffectsinHumans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

5.3.1MorbidityandMortalityStudies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605.3.2RadiographicAnalyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

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Contents

5.3.3RespiratoryConditionsandSymptomAnalyses. . . . . . . . . . . . . . . . . . . . . . 765.3.4PulmonaryFunctionTesting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775.3.5MortalityStudies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785.3.6NIOSHHHEs.................................................. 805.3.7Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

5.4CarcinogenicityRiskAssessmentAnalyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

5.4.1DECOS[1995] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835.4.2Fayerweatheretal.[1997].. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855.4.3Moolgavkaretal.[1999] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855.4.4Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

6 Discussion and Summary of Fiber Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . 896.1SignificanceofStudieswithRCFs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896.2FactorsAffectingFiberToxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6.2.1FiberDose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916.2.2FiberDimensions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916.2.3FiberDurability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

6.3SummaryofRCFToxicityandExposureData. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

7 Existing Standards and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . 96

8 Basis for the Recommended Standard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998.1Background. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998.2RationalefortheREL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

8.2.1CarcinogenesisinAnimalStudies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018.2.2HealthEffectsStudiesofWorkersExposedtoRCFs. . . . . . . . . . . . . . . . . . . 1068.2.3CarcinogenicRiskinHumans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078.2.4ControllingRCFExposuresintheWorkplace. . . . . . . . . . . . . . . . . . . . . . . . 109

8.3Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

9 Guidelines for Protecting Worker Health . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139.1InformingWorkersaboutHazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

9.1.1SafetyandHealthTrainingProgram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139.1.2LabelingandPosting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

9.2HazardPreventionandControl. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

9.2.1EngineeringControls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149.2.2ProductReformulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179.2.3WorkPracticesandHygiene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179.2.4PersonalProtectiveEquipment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1189.2.5RespiratoryProtection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

9.3ExposureMonitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

x Refractory Ceramic Fibers

Contents

9.3.1WorkplaceExposureMonitoringProgram . . . . . . . . . . . . . . . . . . . . . . . . . . 1199.3.2ActionLevel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219.3.3SamplingStrategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

9.4MedicalMonitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

9.4.1ObjectivesofMedicalMonitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229.4.2CriteriaforMedicalScreening. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229.4.3WorkerParticipation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239.4.4MedicalMonitoringProgramDirector . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239.4.5RecommendedProgramElements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 9.4.6WrittenReportstotheWorker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1269.4.7WrittenReportstotheEmployer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279.4.8EmployerActions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

9.5SurveillanceofHealthOutcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279.6SmokingCessation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

10 Research Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

AppendicesA.AirSamplingMethods.................................................. 147B.FunctionalJobCategoriesforRCFWorkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179C.CellularandMolecularEffectsofRCFs(InVitroStudies) . . . . . . . . . . . . . . . . . . . . 183

Refractory Ceramic Fibers xi

Abbreviations

ACGIH AmericanConferenceofGovernmentalIndustrialHygienistsACS AmericanCancerSocietyAl aluminumAL actionlevelA1

2O

3alumina

Al2Si

2O

5[OH]

4siliceouskaolin

AM arithmeticmeanAPF assignedprotectionfactorATSDR AgencyforToxicSubstancesDiseaseRegistryB

2O

3boronoxide

BAL bronchoalveolarlavage°C degree(s)CelsiusCaO calciumoxideCFR CodeofFederalRegulationsCI confidenceintervalDECOS DutchExpertCommitteeonOccupationalStandardsdG 2-deoxyguanosineDNA deoxyribonucelicacidEDXA energydispersiveX-rayanalyzere.g. forexampleEID EducationandInformationDivisionEPA U.S.EnvironmentalProtectionAgency°F degree(s)Fahrenheitf/cm3 fiberspercubiccentimeterofairFe ironFEF

25–75 forcedexpiratoryflow(liter/second)between25%and75%ofthe

forcedvitalcapacityFe

2O

3 ferricoxide

FEV1 forcedexpiratoryvolumeinonesecond

FEV1/FVC ratioofforcedexpiratoryvolumeinonesecondtoforcedvital

capacityFJC functionaljobcategoryFVC forcedvitalcapacityg/cm3 gramspercubicmeterofairGM geometricmean

xii Refractory Ceramic Fibers

Abbreviations

GMD geometricmeandiameter

GML

geometricmeanlengthGSD geometricstandarddeviationGSH glutathioneγ-GT γ-glutamyltransferaseHEPA high-efficiencyparticulateairHHE HealthHazardEvaluationhr hour(s)HTE hamstertrachealepithelialIARC InternationalAgencyforResearchonCanceri.e. thatisIgG immunoglobulinIJT industryjobtitleILO InternationalLaborOfficeILs interleukinsK

2O potassiumoxide

lb pound(s)LDH lactosedehydrogenaseLOAEL lowestobservableadverseeffectlevelLOD limitofdetectionMAC maximumachievableconcentrationMAN ManvilleRCFmg/m3 milligramspercubicmeterMgO magnesiumoxidemin minute(s)ml milliliter(s)MLE maximumlikelihoodestimatemm millimeter(s)MMC metalmatrixcompositesMMMF man-mademineralfiberMMVF man-madevitreousfiberMSDS materialsafetydatasheetMSHA MineSafetyandHealthAdministrationMTD maximumtolerateddoseMVK Moolgavkar-Venzon-Knudsonn numberNa

2O sodiumoxide

ng nanogram(s)NIEHS NationalInstituteofEnvironmentalHealthSciencesNIOSH NationalInstituteforOccupationalSafetyandHealth

Refractory Ceramic Fibers xiii

Abbreviations

nl nanoliter(s)NOAEL noobservableadverseeffectlevelNTP NationalToxicologyProgramODC ornithinedecarboxylaseOM OsborneMendelOR oddsratioOSHA OccupationalSafetyandHealthAdministrationP probabilityPA posteroanteriorPCM phasecontrastopticalmicroscopyPEL permissibleexposurelimitPFT pulmonaryfunctiontestPG prostaglandinPPE personalprotectiveequipmentPSP ProductStewardshipProgramRCF refractoryceramicfiberRCFC RefractoryCeramicFibersCoalitionREL recommendedexposurelimitROM reactiveoxygenmetaboliteROS reactiveoxygenspeciesRPM rodentpleuralmesothelialSAED selectedareaelectrondiffractionSD standarddeviationSEM scanningelectronmicroscopySi siliconSiO

2silicondioxide

SMR standardizedmortalityratioSVF syntheticvitreousfiberTEM transmissionelectronmicroscopyTIMA ThermalInsulationManufacturersAssociationTiO

2titaniumdioxide

TLV thresholdlimitvalueTNF tumornecrosisfactorTWA time-weightedaverageUCL upperconfidencelimitUICC UnionInternationaleContreleCancerUJT uniformjobtitlesWHO WorldHealthOrganizationZrO

2 zirconiumdioxide

µm micrometer

xiv Refractory Ceramic Fibers

Glossary

Action level (AL):Astatisticallyderivedconceptusedtopermitanemployertohaveconfidence(e.g.,95%)thatifameasuredexposureconcentrationisbelowtheAL,thenonlyasmallprobabilityexiststhattheactualconcentrationisabovetheexposurelimit. Oftenestablishedashalfoftheexposurelimit,theALshouldbedesignatedfordeterminingwhenadditionalcontrolsareneededoradminis-trativeactionsshouldbetakentoreduceexposures.Thepurposeofusingthisreferenceistoindicatewhenworkerexposurestohazardoussubstancesmaybeapproachingtheexposurelimit.

After-service refractory ceramic fiber (RCF):RCFthathasbeensubjectedtogreaterthan1,800oF(~1,000oC)andhaspartiallyconvertedtothesilicapolymorphcristobalite.Inexperimentalstud-ies,thisfiberisalsocalledRCF4.

Aspect ratio:Thelengthtowidthratioofafiber.

Costophrenic angle:Locationonachestradiographwheretheribsandthediaphragmappeartomeet.

Dyspnea grade 1:Shortnessofbreathonexertion,classifiedaslessseverethangrade2.

Dyspnea grade 2:Shortnessofbreathonexertion,excludingshortnessofbreathassociatedwithhurryingonthelevelorwalkingupaslighthill,andclassifiedasmoreseverethandys-pneagrade1.

FEF25–75

:Forcedexpiratoryflow(liter/second) that isbetween25%and75%of the forcedvitalcapacity.

FEV1:Forcedexpiratoryvolumeinonesecond,orthemaximumvolumeofairthatcanbeforcibly

expiredduringthefirstsecondofexpirationfollowingamaximalinspiration.

Fiber counting rules:Criteriaforidentifyingandcountingfibersduringairsamplingandexposureassessment.Thethreemainconventions forfibercountingaredescribedbelow(and inSection4.2.1andAppendixA).

■ NIOSH “A” rules—anyparticle>5µmlongwithanaspectratio(lengthtowidth)greaterthan3:1isconsideredafiber.

■ NIOSH “B” rules—anyparticle>5µmlongwithanaspectratioequaltoorgreaterthan5:1andadiameter<3µmisconsideredafiber.

■ World Health Organization (WHO) reference method for man-made mineral fiber—anyparticle>5µmlongwithanaspectratioequaltoorgreaterthan3:1andadiameter<3µmisconsideredafiber.

Refractory Ceramic Fibers xv

Glossary

FVC:Forcedvitalcapacityorthemaximumvolumeofair(inliters)thatcanbeforciblyexpiredfromthelungsfollowingamaximalinspiration.

High-efficiency particulate air (HEPA) filter:Adry-typefilterusedtoremoveairborneparticleswithanefficiencyequaltoorgreaterthan99.97%for0.3-µmparticles.Thelowestfilteringeffi-ciencyof99.97%isassociatedwith0.3-µmparticles,whichisapproximatelythemostpenetratingparticlesizeforparticulatefilters.

Inspirable dust:Thefractionofairborneparticlesthatwouldbeinspiredthroughthemouthandnoseofaworker.

MAN:ArefractoryceramicfiberproducedbytheJohnsManvilleCompany.

Occupational medical monitoring (incorporating medical screening, surveillance):Theperiodicmedicalevaluationofworkerstoidentifypotentialhealtheffectsandsymptomsrelatedtooccupa-tionalexposuresorenvironmentalconditionsintheworkplace.Anoccupationalmedicalmonitor-ingprogramisasecondarypreventionmethodbasedontwoprocesses,screeningandsurveillance.Occupationalmedicalscreeningfocusesonearlydetectionofhealthoutcomesforindividualwork-ers.Screeningmayinvolveanoccupationalhistoryassessment,medicalexamination,andmedicalteststodetectthepresenceoftoxicantsorearlypathologicchangesbeforetheworkerwouldnor-mallyseekclinicalcareforsymptomaticdisease.Occupationalmedical surveillanceinvolvestheongoingevaluationofthehealthstatusofagroupofworkersthroughthecollectionandanalysisofhealthdataforthepurposeofdiseasepreventionandforevaluatingtheeffectivenessofinterven-tionprograms.

Pleural plaques:Discreteareasofthickeningthataregenerallyontheparietalpleuraandaremostcommonly locatedat themidcostalandposteriorcostalareas, thedomeof thediaphragm,andthemediastinalpleura.Presenceofplaquesisanindicationofexposuretoafibroussilicate,mostfrequentlyasbestos.

Radiographic opacity:AshadowonachestX-rayfilmgenerallyassociatedwithafibrogenicre-sponsetodustretainedinthelungs[Morgan1995].Opacitiesareclassifiedbysize,shape,location,andprofusionaccordingtoguidelinesestablishedbytheInternationalLaborOffice[ILO2000]www.ilo.org/public/english/support/publ/books.htm).

Refractory ceramic fiber (RCF):Anamorphous,syntheticfiber(ChemicalAbstractsServicesNo.142844–00–6)producedbymeltingandblowingorspinningcalcinedkaolinclayoracombina-tionofalumina(Al

2O

3)andsilicondioxide(SiO

2).Oxidesmaybeaddedsuchaszirconia,ferric

oxide,titaniumoxide,magnesiumoxide,calciumoxide,andalkalies.Thepercentage(byweight)ofcomponentsisasfollows:alumina,20%to80%;silicondioxide,20%to80%;andotheroxidesinsmalleramounts.

Respirable-sized fiber:Particles>5µmlongwithanaspectratio>3:1anddiameter≤1.3µm.

Shot:NonfibrousparticulatethatisgeneratedduringtheproductionofRCFsfromtheoriginalmeltbatch.

xvi Refractory Ceramic Fibers

Glossary

Standardized mortality ratio (SMR):Theratiooftheobservednumberofdeaths(fromaspecifiedcause)totheexpectednumberofdeaths(fromthatsamecause)thathasbeenadjustedtoaccountfordemographicdifferences(e.g.,age, sex, race)betweenthestudypopulationandthereferentpopulation.

Synthetic vitreous fiber (SVF):Anyofanumberofmanufacturedfibersproducedbythemeltingandsubsequentfiberizationofkaolinclay,sand,rock,slag,etc.Fibrousglass,mineralwool,ceramicfibers,andalkalineearthsilicatewoolsarethemajortypesofSVF,alsocalledman-mademineralfiber(MMMF)orman-madevitreousfiber(MMVF).

Thoracic-sized fiber:Particles>5µmlongwithaspectratio>3:1andadiameter<3to3.5µm.Thoracicreferstoparticlespenetratingtothethorax(50%cutat10-µmaerodynamicdiameter).Mineralandvitreousfiberswithdiameters3to3.5µmhaveanaerodynamicdiameterofapproxi-mately10µm.

Refractory Ceramic Fibers xvii

Acknowledgments

ThisdocumentwaspreparedbytheEducationandInformationDivision(EID),PaulSchulte,Ph.D.,Director.ThomasLentz,Ph.D.;KathleenMacMahon,D.V.M.;RalphZumwalde;andClaytonDoakweretheprincipleauthorsofthisdocument.OthermembersoftheDocumentDevelopmentBranch,inparticularMarieHaringSweeney,Ph.D.,wereextremelyhelpfulinprovidingtechnicalreviewsandcomments.

Forcontributionstothetechnicalcontentandreviewofthisdocument,theauthorsgratefullyac-knowledgethefollowingNIOSHpersonnel:

Education and Information Division

HeinzAhlers,J.D.JohnBailer,Ph.D.JeffBryantDavidDankovic,Ph.D.JeromeFleschCharlesGeraci,Ph.D.StephenGilbertG.KentHatfield,Ph.D.EileenKuempel,Ph.D.BonitaMalit,M.D.RichardNiemeier,Ph.D.RonaldSchulerJohnSheehy,Ph.D.RandallSmithLeslieStayner,Ph.D.DavidVotawJoannWessJohnWhalen

Division of Applied Research and Technology

PaulBaron,Ph.D.KevinH.DunnJosephFernbackLaurenceReedLloydStettler,Ph.D.MarkToraason,Ph.D.

Division of Surveillance, Hazard Evaluations, and Field Studies

MitchellSingal,M.D.

Division of Respiratory Disease Studies

DonaldCampbellRobertCastellan,M.D.DanielHewettPaulHewett,Ph.D.MarkHoover,Ph.D.PaulMiddendorf,Ph.D.ErnestMoyer,Ph.D.JohnParker,M.D.LeePetsonk,M.D.

Health Effects Laboratory Division

VincentCastranova,Ph.D.DanLewisKennethWeber,Ph.D.

Pittsburgh Research Laboratory

AndrewCecala

Office of the Director

FrankHearl,P.E.AnitaSchill,Ph.D.RosemarySokas,M.D.

xviii Refractory Ceramic Fibers

Acknowledgments

TheauthorswishtothankSusanAfanuh,VanessaBecks,GinoFazio,AnneHamilton,andJaneWeber for theireditorial supportandcontributions to thedesignand layoutof thisdocument.Clerical support in preparing this document was provided by Judith Curless, Pamela Graydon,RosmarieHagedorn,NormaLouHelton,andKristinaWasmund.

Finally,specialappreciationisexpressedtothefollowingindividualsandorganizationsforservingasindependentexternalreviewersandprovidingcommentsthatcontributedtothedevelopmentofthisdocument:

ChrisBurleyEuropeanCeramicFibresIndustryAssociationParis,France

JohnCherrie,Ph.D.LibertySafeWorkResearchCentreAberdeen,UnitedKingdom

JohnDement,Ph.D.DukeUniversityMedicalCenterDurham,NC

WilliamKojolaAFL-CIO,SafetyandHealthDepartmentWashington,DC

DavidLai,Ph.D.OfficeofPollutionPreventionandToxicsU.S.EnvironmentalProtectionAgencyWashington,DC

GraceLeMasters,Ph.D.UniversityofCincinnati,CollegeofMedicineCincinnati,OH

MortonLippmann,Ph.D.NewYorkUniversity,SchoolofMedicineTuxedo,NY

JamesLockey,M.D.UniversityofCincinnati,CollegeofMedicineCincinnati,OH

PeterMcClure,Ph.D.SyracuseResearchCorporationNorthSyracuse,NY

EugeneMcConnell,D.V.M.ToxPathRaleigh,NC

NationalInsulationAssociationAlexandria,VA

DennisO’Brien,Ph.D.UnitedAutomobile,AerospaceandAgriculturalImplementWorkersofAmericaDetroit,MI

RefractoryCeramicFibersCoalitionWashington,DC

CarolRice,Ph.D.UniversityofCincinnati,CollegeofMedicineCincinnati,OH

JolandaRijnkels,Ph.D.HealthCounciloftheNetherlandsDenHaag,TheNetherlands

ScottSchneiderLaborers’HealthandSafetyFundofNorthAmericaWashington,DC

JayTurim,Ph.D.SciencesInternational,Inc.Alexandria,VA

CindyFraleighWheelerOfficeofPollutionPreventionandToxicsU.S.EnvironmentalProtectionAgencyWashington,DC

Refractory Ceramic Fibers 1

1 Recommendations for a Refractory Ceramic Fiber (RCF) Standard

mesothelioma, and other adverse respiratoryhealth effects (including irritation and com-promisedpulmonaryfunction)associatedwithexcessiveRCFexposureintheworkplace.Lim-itingexposureswillalsoprotectworkers’eyesandskinfromthemechanicalirritationasso-ciatedwithexposuretoRCFs.Inmostmanu-facturingoperations,itiscurrentlypossibletolimitairborneRCFconcentrationsto0.5f/cm3orless.ExceptionsmayoccurduringRCFfin-ishing operations and during the installationandremovalofRCFproducts,whenthenatureof jobactivitiespresentsachallengetomeet-ing the REL. For these operations, additionalprotective measures are recommended. Engi-neeringandadministrativecontrols,respiratoruse,andotherpreventivemeasuresshouldbeimplementedtominimizeexposuresforwork-ers in RCF industry sectors where airborneRCF concentrations exceed the REL. NIOSHurgesemployers todisseminate this informa-tiontoworkersandcustomers,andRCFman-ufacturers should convey this information todownstream users. NIOSH also requests thatprofessional and trade associations and labororganizationsinformtheirmembersaboutthehazardsofexposuretoRCFs.

1.2 Definitions and Characteristics

1.2.1 Naturally Occurring Mineral Fibers

Manytypesofmineralfibersoccurnaturally.Asbestos is the most prominent of these fi-bersbecauseofitsindustrialapplication.The

TheNationalInstituteforOccupationalSafetyand Health (NIOSH) recommends that expo-suretoairbornerefractoryceramicfibers(RCFs)becontrolledintheworkplacebyimplementingthe recommendations presented in this docu-ment.Theserecommendationsaredesignedtoprotectthesafetyandhealthofworkersforuptoa10-hrworkshiftduringa40-hrworkweekovera40-yearworkinglifetime.Observanceoftheserecommendationsshouldpreventorgreatlyre-ducetherisksofeyeandskinirritationandad-verserespiratoryhealtheffects(includinglungcancer) in workers with exposure to airborneRCFs. Preventive efforts are primarily focusedon controlling and minimizing airborne fiberconcentrations to which workers are exposed.Exposuremonitoring,hazardcommunication,training, respiratoryprotectionprograms, andmedical monitoring are also important ele-mentsofacomprehensiveprogramtoprotectthehealthofworkers exposed toRCFs.Theseelements are described briefly in this chapterandingreaterdetailinChapter9.

1.1 Recommended Exposure Limit (REL)

NIOSHrecommendsthatoccupationalexpo-surestoairborneRCFsbelimitedto0.5fiberpercubiccentimeter(f/cm3)ofairasa time-weightedaverage(TWA)concentrationforuptoa10-hrworkshiftduringa40-hrworkweek,measured according to NIOSH Method 7400(Brules)[NIOSH1998].

This recommended exposure limit (REL) isintended to reduce the risk of lung cancer,

2 Refractory Ceramic Fibers

1 ■Recommendations for a Refractory Ceramic Fiber Standard

asbestosmineralsincludeboththeserpentineasbestos(chrysotile)andtheamphibolemin-eral fibers, including actinolite, amosite, an-thophyllite, crocidolite, and tremolite [Petersand Peters 1980]. Since ancient times, min-eralfibershavebeenminedandprocessedforuseasinsulationbecauseoftheirhightensilestrength, resistance to heat, durability in ac-idsandotherchemicals,andlightweight.Thepredominant forms of asbestos mined andused today are chrysotile (~95%), crocidolite(<5%),andamosite(<1%).

For thepurposesof thisdocument,naturallyoccurring mineral fibers are distinguishablefromsyntheticvitreousfibers(SVFs)basedonthecrystallinestructureofthemineralfibers.Thispropertycausesthemineralfiberstofrac-turelongitudinallywhensubjectedtomechan-ical stresses, thereby producing more fibersofdecreasingdiameter.By contrast, SVFsareamorphousandfracturetransversely,resultingin more fibers of decreasing length until thesegmentsarenolongerofsufficientlengthtobeconsideredfibers.Naturallyoccurringmin-eralfibersaregenerallymoredurableandlesssoluble than SVFs, a property that accountsfor thebiopersistenceandtoxicityofmineralfibersinvivo.

1.2.2 RCFs

RCFsarea typeofSVF; theyareamorphoussynthetic fibers produced from the meltingand blowing or spinning of calcined kaolinclayoracombinationofalumina(Al

2O

3)and

silicondioxide(SiO2).Oxidessuchaszirconia,

ferric oxide, titanium oxide, magnesium ox-ide,calciumoxide,andalkaliesmaybeadded.Thepercentageofcomponents(byweight) isasfollows:alumina,20%to80%;silicondiox-ide,20%to80%;andotheroxides insmalleramounts. Like the naturally occurring min-eral fibers, RCFs possess the desired qualities

of heat resistance, tensile strength, durability,and light weight. On a continuum, however,RCFsarelessdurable(i.e.,moresoluble)thantheleastdurableasbestosfiber(chrysotile)butmoredurablethanmostfibrousglassandoth-ertypesofSVFs.

1.2.3 SVFs

SVFsincludeanumberofmanmade(notnatu-rallyoccurring)fibersthatareproducedbythemeltingandsubsequentfiberizationofkaolinclay,sand,rock,slag,andothermaterials.ThemajortypesofSVFsarefibrousglass,mineralwool(slagwool,rockwool),andceramicfibers(includingRCFs).SVFsarealsofrequentlyre-ferredtoasmanmademineralfibers(MMMFs)ormanmadevitreousfibers(MMVFs).

1.3 Sampling and Analysis

Employers shall perform air sampling andanalysistodetermineairborneconcentrationsofRCFsaccordingtoNIOSHMethod7400(Brules)[NIOSH1998],providedinAppendixAofthisdocument.

1.4 Exposure Monitoring

Employersshallperformexposuremonitoringasfollows:

■ Establishaworkplaceexposuremonitor-ing program for worksites where RCFsorRCFproductsaremanufactured,han-dled,used,installed,orremoved.

■ Includeinthisprogramroutineareaandpersonal monitoring of airborne fiberconcentrations.

■ Designamonitoringstrategythatcanbeusedto



—evaluateaworker’sexposuretoRCFs,

—assesstheeffectivenessofengineeringcontrols, work practices, and otherfactors in controlling airborne fiberconcentrations,and

—identify work areas or job tasks inwhichworkerexposuresareroutinelyhigh and thus require additional ef-fortstoreducethem.

1.4.1 Sampling Surveys

Employersshallconductexposuremonitoringsurveystoensurethatworkerexposures(mea-suredbyfull-shiftsamples)donotexceedtheREL.BecauseadverserespiratoryhealtheffectsmayoccurattheREL,itisdesirabletoachievelowerconcentrationswheneverpossible.Whenworkers are potentially exposed to airborneRCFs,employersshallconductexposuremon-itoringsurveysasfollows:

■ Collect representative personal samplesovertheentireworkshift[NIOSH1997a].

■ Perform periodic sampling at least an-nually and whenever any major processchangetakesplaceorwheneveranotherreason exists to suspect that exposureconcentrationsmayhavechanged.

■ Collect all routine personal samples inthebreathingzonesoftheworkers.

■ Ifworkersareexposedtoconcentrationsabove the REL, perform more frequentexposure monitoring as engineeringchanges are implemented and until atleast two consecutive samples indicatethatexposuresnolongerexceedtheREL[NIOSH1977a].

■ Notifyallworkersofmonitoringresultsandofanyactionstakentoreducetheirexposures.

■ Whendevelopinganexposuresamplingstrategy,considervariationsinworkandproduction schedules as well as the in-herentvariabilityinmostareasampling[NIOSH1995a].

1.4.1.1 Focused sampling

WhensamplingtodeterminewhetherworkerRCF exposures are below the REL, a focusedsamplingstrategymaybemorepracticalthanarandomsamplingapproach.Afocusedsam-pling strategy targetsworkersperceived tobeexposedtothehighestconcentrationsofahaz-ardoussubstance[LeidelandBusch1994].Thisstrategyismostefficientforidentifyingexpo-sures above the REL if maximum-risk work-ersandtimeperiodsareaccuratelyidentified.Short tasks involving high concentrations ofairbornefibers could result in elevatedexpo-sureoverfullworkshifts.

SamplingstrategiessuchasthoseusedbyCornandEsmen[1979],Riceetal.[1997],andMax-imetal.[1997]havebeendevelopedandusedspecificallyinRCFmanufacturingfacilitiestomonitorairbornefiberconcentration.Inthesestrategies, representative workers are selectedfor sampling and are grouped according todust zones, uniform job titles, or functionaljobcategories.Theseapproachesareintendedtoreducethenumberofrequiredsamplesandincreasetheconfidenceofidentifyingworkersatsimilarrisk.

1.4.1.2 Area sampling

Areasamplingmaybeusefulinexposuremon-itoringtodeterminesourcesofairborneRCFsand to assess the effectiveness of engineeringcontrols.

1.4.2 Action Level

Anactionlevel(AL)athalftheREL(0.25f/cm3)shall be used to determine when additional



controls are needed or when administrativeactionsshouldbetakentoreduceexposuretoRCFs.ThepurposeofanAListoindicatewhenworkerexposurestohazardoussubstancesmaybe approaching the REL. When air samplescontainconcentrationsatorabovetheAL,theprobability is high that worker exposures tothehazardoussubstanceexceedtheREL.

TheALisastatisticallyderivedconceptpermit-tingtheemployertohaveconfidence(e.g.,95%)thatifresultsfrompersonalairsamplesarebe-lowtheAL,theprobabilityissmallthatworkerexposuresareabovetheREL.NIOSHhascon-cluded that theuseof anALpermits the em-ployer to monitor hazardous workplace expo-sureswithoutdaily sampling.TheALconcepthasservedasthebasisfordefiningtheelementsof an occupational standard in NIOSH crite-ria documents and comprehensive standardspromulgated by the Occupational Safety andHealthAdministration (OSHA) and the MineSafetyandHealthAdministration(MSHA).

1.5 Hazard CommunicationEmployersshalltakethefollowingmeasurestoinformworkersaboutRCFhazards:

■ Establish a safety and health trainingprogram for all workers who manufac-ture,use,handle,install,orremoveRCFproductsorperformotheractivitiesthatbringthemintocontactwithRCFs.

■ Inform employees and contract work-ers about hazardous substances in theirworkareas.

■ Instructworkersabouthowtogetinfor-mation frommaterial safetydata sheets(MSDSs)forRCFsandotherchemicals.

■ Provide MSDSs onsite and make themeasilyaccessible.

■ Inform workers about adverse respira-tory health effects associated with RCFexposures.

■ Inworkinvolvingtheremovalofrefrac-tory insulation materials, make workersaware of the potential for exposure torespirablecrystallinesilica,thehealthef-fectsrelatedtothisexposure,andmeth-odsforreducingexposures.

■ Make workers who smoke cigarettesor use other tobacco products aware oftheir increased risk of developing RCF-inducedrespiratorysymptomsandcon-ditions(seeSections1.12and9.6forrec-ommendationsaboutsmokingcessationprograms).

1.6 TrainingEmployersshallprovidethefollowingtrainingforworkersexposedtoRCFs:

■ Trainworkerstodetecthazardoussitua-tions.

■ Inform workers about practices or op-erations that may generate high air-bornefiberconcentrations(e.g.,cuttingandsandingRCFboardsandotherRCFproducts).

■ Trainworkershowtoprotectthemselvesby using proper work practices, engi-neeringcontrols,andpersonalprotectiveequipment(PPE).

1.7 Product FormulationOne factor recognized as contributing to thetoxicity of an inhaled fiber is its durabilityand resistance to degradation in the respira-torytract.ChemicalcharacteristicsplaceRCFsamongthemostdurableSVFs.Asaresult,an



inhaledRCFthatisdepositedinthealveolarre-gionofthelungwillpersistlongerinthelungsthan a less durable fiber. Therefore, NIOSHrecommends substituting a less durable fiberfor RCFs or reformulating the chemistry ofRCFstowardthisendtoreducethehazardforexposedworkers.Aspartofproductsteward-shipefforts,severalRCFproducerswithintheRefractory Ceramic Fibers Coalition (RCFC)havedevelopednewand lessbiopersistentfi-berstermedalkalineearthsilicatewools[Max-imetal.1999b].Newlydevelopedfibersshouldundergo industry-sponsored testing beforetheirselectionandcommercialusetoexcludepossibleadversehealtheffectsfromexposure.

1.8 Engineering Controls and Work Practices

1.8.1 Engineering Controls

Employersshalluseandmaintainappropriateengineeringcontrolstokeepairborneconcen-trationsofRCFsat orbelow the RELduringthe manufacture, use, handling, installation,and removal of RCF products. EngineeringcontrolsforcontrollingRCFsincludethefol-lowing:

■ Localexhaustventilationordustcollec-tion systems at or near dust-generatingsystems

—BandsawsusedinRCFmanufactur-ing and finishing operations havebeen fitted with such engineeringcontrols to capture fibers and dustduring cutting operations, therebyreducingexposuresforthebandsawoperator[Venturin1998].

—Discsandersfittedwithsimilar localexhaustventilationsystemseffectivelyreduce airborne RCF concentrations

duringthesandingofvacuum-formedRCFproducts[Dunnetal.2004].

■ Enclosed processes used during manu-facturing to keep airborne fibers con-tainedandseparatedfromworkers

■ Water knives, which are high-pressurewaterjetsthateffectivelycutandtrimtheedgesofRCFblanketwhile suppressingdust and limiting thegenerationof air-bornefibers

1.8.2 Work Practices

Employers shall implementappropriateworkpracticestohelpkeepworkerexposuresatorbelowtheRELforRCFs.The followingworkpractices are recommended to help reduceconcentrationsofairbornefibers:

■ Limittheuseofpowertoolsunlesstheyareequippedwith localexhaustordustcollectionsystems.

—Beawarethatmanuallypoweredhandtoolsgeneratelessdustandfewerair-borne fibers, but they often requireadditional physical effort and timeandmayincreasetheriskofmuscu-loskeletaldisorders.

—Theadditionalphysicaleffortrequiredby hand tools may also increase therateanddepthofbreathingandcon-sequently affect the inhalation rateanddepositionoffibersinthelungs.

■ Use ergonomically correct tools andproperworkstationdesigntoreducetheriskofmusculoskeletaldisorders.

■ Usehigh-efficiencyparticulateair-filtered(HEPA-filtered)vacuums.



■ Use wet sweeping to suppress airbornefiber and dust concentrations duringcleanup.

■ Whenremovingafter-serviceRCFprod-ucts,dampeninsulationwithalightwa-terspraytopreventfibersanddustfrombecoming airborne. (However, use cau-tion when dampening refractory linings during installation,sincewatercandam-age refractory-lined equipment, causingthegenerationofsteamandpossibleex-plosionduringheating.)

■ CleanworkareasregularlyusingaHEPA-filteredvacuumorwetsweepingtomini-mizeaccumulationofdebris.

■ Ensure that workers wear long-sleevedclothing,gloves,andeyeprotectionwhenperforming potentially dusty activitiesinvolving RCFs or RCF products. Forsome activities, disposable clothing orcoverallsmaybepreferred.

1.9 Respiratory ProtectionRespirators shall be used while performingany task for which the exposure concentra-tion is unknown or has been documented tobehigherthantheNIOSHRELof0.5f/cm3asaTWA.However,respiratorsshallnotbeusedastheprimarymeansofcontrollingworkerex-posures.

When possible, use other methods for mini-mizingworkerexposurestoRCFs:

■ Productsubstitution

■ Engineeringcontrols

■ Changesinworkpractices

Use respirators when available engineeringcontrolsandworkpracticesdonotadequately

control worker exposures below the REL forRCFs.NIOSHrecognizes that controllingex-posurestoRCFsisaparticularchallengeduringthefinishingstagesofRCFproductmanufac-turingandduringtheinstallationandremovalofrefractorymaterials

1.9.1 Respiratory Protection Program

When respiratory protection is needed, em-ployers shall establishacomprehensiverespi-ratoryprotectionprogramasdescribedintheOSHA respiratory protection standard [29CFR*1910.134].Elementsofarespiratorypro-tection program must be established and de-scribedinawrittenplanthatisspecifictotheworkplace.Theplanmustincludethefollow-ingelements:

■ Proceduresforselectingrespirators

■ Medicalevaluationsofworkersrequiredtowearrespirators

■ Fit-testingprocedures

■ Routine-use procedures and emergencyrespirator-useprocedures

■ Procedures and schedules for cleaning,disinfecting,storing,inspecting,repairing,discarding,andmaintainingrespirators

■ Procedures for ensuring adequate airqualityforsupplied-airrespirators

■ Traininginrespiratoryhazards

■ Training in the proper use and mainte-nanceofrespirators

■ Programevaluationprocedures

■ Proceduresforensuringthatworkerswhovoluntarily wear respirators (excludingfilteringfacepiecesknownasdustmasks)

*Code of Federal Regulations.SeeCFRinreferences.



complywiththemedicalevaluationandcleaning, storing, and maintenance re-quirementsofthestandard

■ Adesignatedprogramadministratorwhoisqualifiedtoadministertherespiratoryprotectionprogram

Employersshallupdatethewrittenprogramasnecessarytoaccountforchangesinthework-place that affect respirator use. In addition,employers are required to provide at no costtoworkersallequipment,training,andmedi-calevaluationsrequiredundertherespiratoryprotectionprogram.

1.9.2 Respirator Selection

WhenconditionsofexposuretoairborneRCFsexceedtheREL,properrespiratoryprotectionshallbeselectedasfollows:

■ Select, at a minimum, a half-mask, air-purifyingrespiratorequippedwitha100series particulate filter. This respiratorhasanassignedprotectionfactor(APF)of10.

■ Provideahigherlevelofprotectionandprevent facial or eye irritation fromRCF exposure by using a full-facepiece,air-purifying respirator equipped witha 100-series filter; or use any powered,air-purifyingrespiratorequippedwithatight-fittingfacepiece(full-facepiece).

■ Consider providing a supplied-air res-piratorwitha full facepiece forworkerswhoremoveafter-serviceRCFinsulation(e.g., furnace insulation) and are there-fore exposed to high and unpredictableconcentrations of RCFs. These respira-torsprovideagreaterlevelofrespiratoryprotection.Usethemwhenevertheworktaskinvolvespotentiallyhighconcentra-tionsofairbornefibers.

■ Always perform a comprehensive as-sessmentofworkplaceexposures tode-termine the presence of other possiblecontaminants(suchassilica)andtoen-surethatproperrespiratoryprotectionisused.

■ UseonlyrespiratorsapprovedbyNIOSHandMSHA.

Forinformationandassistanceinestablishingarespiratoryprotectionprogramandselectingappropriaterespirators,seetheOSHARespira-tory Protection AdvisorontheOSHAWebsiteat www.osha.gov. Additional information isalso available from theNIOSH Respirator Se-lection Logic[NIOSH2004],theNIOSH Guide to Industrial Respiratory Protection [NIOSH1987b],andtheNIOSH Guide to the Selection and Use of Particulate Respirators Certified un-der 42 CFR 84[NIOSH1996].

1.10 Sanitation and Hygiene

EmployersshalltakethefollowingmeasurestoprotectworkerspotentiallyexposedtoRCFs:

■ Donotpermitsmoking,eating,ordrink-inginareaswhereworkersmaycontactRCFs.

■ Provide showering and changing areasfree fromcontaminationwhereworkerscan store work clothes and change intostreet clothes before leaving the worksite.

■ Provide services for laundering workclothessothatworkersdonottakecon-taminatedclotheshome.

■ Protect laundry workers handling RCF-contaminatedclothesfromairbornecon-centrationsthatareabovetheREL.



Workers shall take the following protectivemeasures:

■ Donotsmoke,eat,ordrinkinareaspo-tentiallycontaminatedwithRCFs.

■ Iffibersgetontheskin,washwithwarmwaterandmildsoap.

■ Applyskin-moisturizingcreamorlotionas needed to avoid irritation caused byfrequentwashing.

■ Wear long-sleeved clothing, gloves, andeyeprotectionwhenperformingpoten-tiallydustyactivitiesinvolvingRCFs.

■ VacuumthisclothingwithaHEPA-filteredvacuumbeforeleavingtheworkarea.

■ Do not use compressed air to clean theworkareaorclothinganddonotshakeclothingtoremovedust.Theseprocesseswill create a greater respiratory hazardwithairbornedustandfibers.

■ Donot wearwork clothes orprotectiveequipment home. Change into cleanclothesbeforeleavingtheworksite.

1.11 Medical Monitoring

Medical monitoring (in combination withresulting intervention strategies) representssecondarypreventionand shouldnot replaceprimarypreventioneffortstocontrolairbornefiber concentrations and worker exposuresto RCFs. However, compliance with the RELfor RCFs (0.5 f/cm3) does not guarantee thatallworkerswillbefreefromtheriskofRCF-induced respiratory irritation or respiratoryhealth effects. Therefore, medical monitoringis especially important, and employers shallestablishamedicalmonitoringprogramasfol-lows:

■ Collect baseline data for all employeesbeforetheybeginworkwithRCFs.

■ Continue periodic medical screeningthroughouttheirlifetime.

■ Usemedicalsurveillance,whichinvolvesthe aggregate collection and analysis ofmedical screening data, to identify oc-cupations,activities,andworkprocessesinneedofadditionalprimarypreventionefforts.

■ Include all workers potentially exposedto RCFs (in both manufacturing andend-use industries) in an occupationalmedicalmonitoringprogram.

■ Provideworkerswithinformationaboutthepurposesofmedicalmonitoring,thehealth benefits of the program, and theproceduresinvolved.

■ Include the following workers (whocould receive the greatest benefits frommedicalscreening)inthemedicalmoni-toringprogram:

—Workers exposed to elevated fiberconcentrations (e.g., all workers ex-posed to airborne fiber concentra-tionsabove theALof0.25F/cm3,asdescribedinSection9.3)

—Workers in areas or in specific jobsandactivities(regardlessofairbornefiberconcentration)inwhichoneormoreworkershavesymptomsorre-spiratory changes apparently relatedtoRCFexposure

—Workers who may have been previ-ously exposed to asbestos or otherrecognized occupational respiratoryhazards that place them at an in-creasedriskofrespiratorydisease



1.11.1 Oversight of the Program

Assign oversight of the medical monitor-ingprogramtoaqualifiedphysicianorotherqualifiedhealthcareprovider (asdeterminedbyappropriateStatelawsandregulations)whoisinformedandknowledgeableaboutthefol-lowing:

■ Administering and managing a medicalmonitoring program for occupationalhazards

■ Establishing a respiratory protectionprogram based on an understanding ofrequirements of the OSHA respiratoryprotection standard and types of respi-ratoryprotectiondevicesavailableattheworkplace

■ Identifying and managing work-relatedrespiratoryeffectsorillnesses

■ Identifying and managing work-relatedskindiseases

1.11.2 Elements of the Medical Monitoring Program

Include the following elements in a medicalmonitoring program for workers exposed toRCFs:(1)aninitialmedicalexamination,(2)pe-riodicmedicalexaminationsatregularlysched-uled intervals, (3) more frequent and detailedmedicalexaminationsasneededonthebasisofthefindingsfromtheseexaminations,(4)work-ertraining,(5)writtenreportsofmedicalfind-ings,(6)qualityassurance,and(7)evaluation.These elements are described in the followingsubsections.

1.11.2.1 Initial (baseline) examination

Performaninitial(baseline)examinationasnearaspossibletothedateofbeginningemployment(within3months)andincludethefollowing:

■ A physical examination of all systemswithanemphasisontherespiratorysys-temandtheskin

■ Aspirometric test (note thatanyonead-ministeringspirometrictestingaspartofthemedicalmonitoringprogramshouldhavecompletedaNIOSH-approvedtrain-ingcourseinspirometryorotherequiva-lenttraining)

■ AchestX-ray(allchestX-rayfilmsshouldbe interpreted by a certified NIOSH BReader using the standard International Classification of Radiographs of Pneumo-conioses [ILO 2000, or the most recentequivalent])

■ Othermedicaltestsasdeemedappropri-atebytheresponsiblehealthcareprofes-sional

■ Astandardizedrespiratorysymptomques-tionnaire,suchastheAmericanThoracicSociety respiratory questionnaire [Ferris1978,orthemostrecentequivalent]

■ Astandardizedoccupationalhistoryques-tionnaire thatgathers informationaboutallpastjobswith(1)specialemphasisonthosewithpotentialexposuretodustandmineralfibers,(2)adescriptionofalldu-tiesandpotentialexposuresforeachjob,and (3) a description of all protectiveequipmenttheworkerhasused

1.11.2.2 Periodic examinations

Administer periodic examinations (includ-ing a physical examination of the respiratorysystemandtheskin,spirometrictesting,are-spiratorysymptomupdatequestionnaire,andanoccupationalhistoryupdatequestionnaire)atregularintervalsdeterminedbythemedicalmonitoring program director. Determine the



frequency of the periodic medical examina-tionsaccordingtothefollowingguidelines:

■ Forworkerswithfewerthan10yearssincefirst exposure toRCFs, conductperiodicexaminationsatleastonceevery5years.

■ Forworkerswith10ormoreyearssincefirstexposuretoRCFs,conductperiodicexaminationsatleastonceevery2years.

AchestX-rayandspirometrictestingareim-portant on initial examination and may alsobeappropriatemedicalscreeningtestsduringperiodic examinations for detecting respira-tory system changes, especially in workerswithmorethan10yearssincefirstexposuretoRCFs.Aqualifiedhealthcareprovidershouldconsultwiththeworkertodeterminewhetherthe benefits of periodic chest X-rays warranttheadditionalexposuretoradiation.

1.11.2.3 More frequent evaluations

Workersmayneedtoundergomorefrequentanddetailedmedicalevaluationsiftheattend-ingphysiciandeterminesthatheorshehasanyofthefollowingindications:

■ Neworworseningrespiratorysymptomsorfindings(e.g.,chroniccough,difficultbreathing,wheezing,reducedlungfunc-tion,orradiographicindicationsofpleu-ralplaquesorfibrosis)

■ Historyofexposuretootherrespiratoryhazards(e.g.,asbestos)

■ Recurrentorchronicdermatitis

■ Othermedicallysignificantreason(s)formoredetailedassessment

1.11.2.4 Worker training

Provide workers with sufficient training torecognize symptoms associated with RCF

exposures(e.g.,chroniccough,difficultbreath-ing,wheezing,skinirritation).Instructwork-erstoreportthesesymptomstothedesignatedmedicalmonitoringprogramdirectororotherqualifiedhealthcareprovider forappropriatediagnosisandtreatment.

1.11.2.5 Written reports of medical findings

Followinginitialandperiodicmedicalexami-nations,thephysicianorotherqualifiedhealthcareprovidershallgiveeachworkerawrittenreportcontaining

—resultsofanymedicaltestsperformedontheworker,

—a medical opinion in plain languageabout any medical condition thatwould increase the worker=s risk ofimpairment from exposure to air-borneRCFs,

—recommendations for limiting theworker=s exposure to RCFs (whichmay include the use of appropriatePPE,aswarranted),and

—recommendations for further evalu-ation and treatment of any medicalconditionsdetected.

Followinginitialandperiodicmedicalexami-nations,thephysicianorotherqualifiedhealthcareprovidershallalsogiveawrittenreporttotheemployercontaining

—occupationally pertinent results ofthemedicalevaluation,

—a medical opinion about any medi-calconditionthatwouldincreasetheworker=sriskofimpairmentfromex-posuretoairborneRCFs,

—recommendations for limiting theworker=s exposure to RCFs or other



agents in the workplace (which mayincludetheuseofappropriatePPEorreassignmenttoanotherjob),and

—astatementtoindicatethatthework-er has been informed about the re-sultsofthemedicalexaminationandabout any medical condition(s) thatshould have further evaluation ortreatment.

Findings,testresults,ordiagnosesthathavenobearing on the worker=s ability to work withRCFsshallnotbeincludedinthereporttotheemployer.Safeguardstoprotecttheconfiden-tiality of the worker=s medical records shallbe enforced inaccordancewithall applicableregulationsandguidelines.

1.11.2.6 Quality assurance

Employersshalldothefollowingtoensuretheeffective implementation of a medical moni-toringprogram:

■ Ensurethatworkersfollowthequalifiedhealthcareprovider’srecommendedex-posure restrictions for RCFs and otherworkplacehazards.

■ EnsurethatworkersuseappropriatePPEif they are exposed to RCF concentra-tionsabovetheREL.

■ Encourageworkers toparticipate in themedicalmonitoringprogramandtore-portanysymptomspromptlytothepro-gramdirector.

■ Provideanymedicalevaluationsthatarepartofthemedicalmonitoringprogramatnocosttotheworkers.

■ When implementing job reassignmentsrecommended by the medical programdirector,ensurethatworkersdonotlosewages,benefits,orseniority.

■ Ensurethatthemedicalmonitoringpro-gram director communicates regularlywith the employer’s safety and healthpersonnel (e.g., industrialhygienists) toidentifyworkareasthatmayrequirecon-trol measures to minimize exposures toworkplacehazards.

1.11.2.7 Evaluation

Employers shallevaluate theirmedicalmoni-toringprogramsasfollows:

■ Periodically have standardized medicalscreeningdataaggregatedandevaluatedby an epidemiologist or other knowl-edgeable person to identify patterns ofworkerhealththatmaybelinkedtoworkactivities and practices requiring addi-tionalprimarypreventiveefforts.

■ Combine routine aggregate assessmentsof medical screening data with evalu-ations of exposure monitoring data toidentifyneededchangesinworkareasorexposureconditions.

1.12 Labeling and Posting

Employersshallpostwarninglabelsandsignsasfollows:

■ PostwarninglabelsandsignsdescribingthehealthrisksassociatedwithRCFsatentrancestoworkareasandinsideworkareas where airborne concentrations ofRCFsmayexceedtheREL.

■ Depending on work practices and theairborne concentrations of RCFs, stateonthesignstheneedtowearprotectiveclothingandtheappropriaterespiratoryprotectionforRCFexposuresabovetheREL.



■ Ifrespiratoryprotectionisrequired,postthefollowingstatement:

Employersshallencouragesmokingcessation

amongRCF-exposedworkersasfollows:

■ Establishsmokingcessationprogramsto

informworkersabouttheincreasedhaz-

ards of cigarette smoking and exposure

toRCFs.

■ Provide assistance and encouragement

forworkerswhowanttoquitsmoking.

■ Prohibitsmokingintheworkplace.

■ Disseminate information about health

promotion and the harmful effects of

smoking.

■ Offer smoking cessation programs to

workersatnocosttoparticipants.

■ Encourageactivitiesthatpromotephysi-

cal fitness and other healthy lifestyle

practices affecting respiratory and car-

diovascularhealth(e.g.,throughtraining

programs,employeeassistanceprograms,

andhealtheducationcampaigns).

NIOSH recommends that all workers who

smoke and are potentially exposed to RCFs

participateinsmokingcessationprograms.

RESPIRATORY PROTECTION REQUIRED IN THIS AREA

■ PrintalllabelsandwarningsignsinbothEnglish and the predominant languageofworkerswhodonotreadEnglish.

■ Verbally informworkers about thehaz-ardsandinstructionsprintedonthe la-belsandsignsiftheyareunabletoreadthem.

1.13 Smoking CessationNIOSHrecognizesasynergisticeffectbetweenexposuretoRCFsandcigarettesmoking.Thiseffectincreasestheriskofadverserespiratoryhealth effects induced by RCFs. In studies ofworkersexposedtovariousairbornecontami-nants, combined exposures to smoking andairbornedusthavebeenshowntocontributeto the increased risk of occupational respira-tory diseases, including chronic bronchitis,emphysema, and lung cancer [Morgan 1994;Barnhart1994].


2 Background and Description of RCFs

2.1 ScopeInformationaboutRCFswascollectedandre-viewedforthisdocumenttoassessthehealthhazardsassociatedwithoccupationalexposuretothisairbornefiber.Chapter2describesthebackground for studying thehealtheffectsofworkplace exposures to RCFs. Informationis presented about the physical and chemicalproperties of RCFs, including the morphol-ogy,dimensions, anddurabilityoffibers thatmake up RCF-containing products. Chapter3 discusses the production and uses of RCFsasahigh-temperatureinsulationmaterial;thechapteralsodescribesthenumberofworkerswithpotentialforexposuretoRCFs.Chapter4presentsareviewoftheliteratureonpotentialworkplaceexposurestoairborneRCFsduringmanufacturingandendusesofRCFproducts.Chapter5describestheeffectsofexposuretoRCFs—firstwithreviewsofanimalstudiesandthenwithadescriptionofepidemiologicstud-ies of RCFs, focusing on U.S. and Europeanworkers in the RCF manufacturing industry.Recent quantitative risk assessments of RCFsare also summarized in this chapter. Chapter6containsadiscussionoffibercharacteristicsandtheparameters(dose,dimensions,anddu-rability)thatdeterminefibertoxicity.Chapter7summarizesexistingstandardsandguidelinesfor occupational exposure to RCFs. Chapter 8providesthebasisandrationalefortheNIOSHREL. Chapters 1 and 9 provide recommenda-tionsandguidelinesforminimizingexposuresto airborne fibers of RCFs in the workplace.Finally, Chapter 10 discusses futureareas for

researchrelatingtofibertoxicityandoccupa-tionalexposures.

2.2 Background

In 1977, NIOSH reviewed health effects dataonoccupationalexposuretofibrousglassanddeterminedtheprincipaladversehealtheffectstobeskin,eye,andupperrespiratorytractir-ritationaswellasthepotentialfornonmalig-nantrespiratorydisease.AtthattimeNIOSHrecommendedthefollowing:

Occupationalexposuretofibrousglassshallbecontrolledsothatnoworkerisexposedatanairborneconcentrationgreaterthan3,000,000fiberspercubicmeterofair(3fiberspercubiccentimeterofair);...airborneconcentrationsdeterminedastotalfibrousglassshallbelim-itedtoaTWAof5milligramspercubicmeterofair[NIOSH1977].

NIOSH also stated that until more informa-tion became available, this recommendationshouldbeappliedtootherMMMFs,alsocalledSVFs.Sincethen,additionaldatahavebecomeavailablefromstudiesinanimalsandhumansexposedtoRCFs.ThepurposeofthisreportistoreviewandevaluatethesestudiesandotherinformationaboutRCFs.

2.3 Chemical and Physical Properties of RCFs

RCFs(ChemicalAbstractsServiceNo.142844–00–6)areamorphousfibersthatbelongtothe


2 ■Background and Description of RCFs

largerclassofSVFs,whichalsoincludesfibersof glass wool, mineral wool, slag wool, andspecialtyglass.SVFsvaryaccordingtochemi-cal and physical properties, making themsuitable for different uses. Like the naturallyoccurring mineral fibers defined in Section1.2,RCFspossessdesiredqualitiesofheatre-sistance, tensile strength, durability, and lightweight. The maximum end-use temperatureforRCFsranges fromapproximately1,050to1,425oC(1,920to2,600oF),dependingontheexact chemistry of the fiber. Unlike naturallyoccurring mineral fibers, however, SVFs suchasRCFsandfibrousglassarenoncrystallineinstructure and fracture transversely, retainingthesamediameterbutcreatingshorterfibers.Incontrast,thecrystallinestructureofmineralfiberssuchasasbestoscausesthefiberstofrac-ture along the longitudinal plane under me-chanicalstresses,resultinginmorefiberswiththesame lengthbut smallerdiameters.Thesedifferences in morphology and cleavage pat-ternssuggestthatworkwithSVFsislesslikelytogeneratehighconcentrationsofairbornefi-bers thanworkwith asbestos for comparableoperations, since large-diameter fibers settleout in the air faster than small-diameter fi-bers[AssuncaoandCorn1975;Cherrieetal.1986;Lippmann1990].During themanufac-turingofRCFs,approximately50%ofproduct(byweight)isgeneratedasfiber,and50%isabyproductmadeupofnonfibrousparticulatematerial called shot. Selectedphysical charac-teristicsofRCFsarepresentedinTable2–1.

RCFsareproducedbytheblowingorspinningoffurnace-meltedsiliceouskaolin(Al

2Si

2O

5[OH]

4)

clayorblendsofkaolin,silica,andzircon.RCFsarealsoreferredtoasalumina-basedorkaolin-basedceramicfibersbecausetheyareproducedfrom a 50:50 mixture of alumina and silica[IARC 1988]. Other oxides (including thoseofboron,titanium,andzirconium)areaddedasstabilizerstoalterthephysicalpropertiesof

RCFs [RCFC 1996]. The addition of stabiliz-ersandbindersalters thepropertiesofdura-bilityandheatresistanceforRCFs.Generally,three typesofRCFsaremanufactured, andafourth after-service fiber (often recognized intheliterature)isdistinguishedaccordingtoitsuniquechemistryandmorphology.Table2–2presentsthechemistriesofthefourfibertypes,numberedRCF1throughRCF4.RCF1isaka-olin fiber; RCF2 is an alumina/silica/zirconiafiber; RCF3 is a high-purity (alumina/silica)fiber;andRCF4isanafter-servicefiber,charac-terizedbydevitrification(i.e.,formationofthesilica polymorph cristobalite), which occursduring product use over an extended periodof time at temperatures exceeding 1,050 to1,100oC(>1,900oF).AnotherfibersubcategoryisRCF1a,preparedfromcommercialRCFsus-ingalessaggressivemethodthanthatusedtoprepare RCF1 for animal inhalation studies[Brown et al. 2000]. RCF1a is distinguishedfromRCF1usedinchronicanimalinhalationstudies,theformerhavingagreaterconcentra-tionoflongerfibersandfewernonfibrouspar-ticles.Thelowerratioofrespirablenonfibrousparticles to fibers in RCF1a compared withRCF1 has been shown to affect lung deposi-tionandclearanceinanimalinhalationstudies[Brownetal.2000;Bellmanetal.2001].Chap-ter5presentsadditionaldiscussionofanimalstudiesandtestfibercharacteristics.

2.3.1 Fiber Dimensions

Fibersofbiologicalimportancearethosethatbecomeairborneandhavedimensionswithininhalable,thoracic,andrespirablesizeranges.Thoracic-sizedfibers (<3 to3.5μmindiam-eter) and respirable-sized fibers (<1.3 μm indiameter) with lengths up to 200 μm [Tim-brell 1982; Lippmann 1990; Baron 1996] arecapable of reaching the portion of the respi-ratory system below the larynx. Respirable-sized fibers are of biological concern because



theyarecapableofreachingthelowerairwaysandgasexchangeregionsofthelungswhenin-haled.Longerorthickerairbornefibersgener-allysettleoutofsuspensionor,ifinhaled,aregenerally filtered out in the nasal passage ordepositedintheupperairways.Thoracic-sizedfibersthatareinhaledanddepositedintheup-perrespiratorytractaregenerallyclearedmorereadilyfromthelung,buttheyhavethepoten-tialtocauseirritationandproducerespiratory

symptoms.Fiberdimensionsarea significantfactor indetermining theirdepositionwithinthelung,biopersistence,andtoxicity.

RCFsandotherSVFsaremanufacturedtomeetspecifiednominaldiametersaccordingtothefi-bertypeandintendeduse.RCFsareproducedwithnominaldiametersof1.2to3μm[Esmenetal.1979;Vu1988;TIMA1993].Typicaldi-ametersforanindividualRCF(asmeasuredin

Table 2–1 . Selected physical characteristics of RCFs

Characteristic Description

Softeningpoint 1,700to1,800˚C

Refractiveindex 1.55to1.57

Specificgravity(density) 2.6to2.7g/cm3

Shotcontent(nonfibrousparticulate) 20%to50%byweight

Nominaldiameter(bulk) 1.2to3μm

Length(bulk) 2to254μm

Dissolutionrate(atpH=7.4) 1to10ng/cm2/hr

Sources:RCFC[1996],TIMA[1993],andIARC[1988].

Table 2–2 . The chemistry of stock RCFs (% oxide)

Oxide component RCF1 RCF2 RCF3 RCF4

Silicondioxide(SiO2) 47.7 50 50.8 47.7

Alumina(Al2O

3) 48 35 48.5 48

Ferricoxide(Fe2O

3) 0.97 <0.05 0.16 0.97

Titaniumdioxide(TiO2) 2.05 0.04 0.02 2.05

Zirconiumdioxide(ZrO2) 0.11 15 0.23 0.11

Calciumoxide(CaO) 0.07 0.05 0.04 0.07

Magnesiumoxide(MgO) 0.98 0.01 <0.01 0.08

Sodiumoxide(Na2O) 0.54 <0.3 0.19 0.54

Potassiumoxide(K2O) 0.16 <0.01 <0.01 0.16

AdaptedfromMastetal.[1995a].



RCF-containing products) range from 0.1 to20μm,with lengthsrangingfrom5to200μm[IARC1988].InbulksamplestakenfromthreeRCF blanket insulation products, more than80% of the fibers counted by phase contrastopticalmicroscopy(PCM)were<3μmindi-ameter[Brown1992].Thisresultisconsistentwith those from another study of bulk sam-ples of RCF insulation materials [Christensenetal.1993],whichfoundthefiberstohavegeo-metric mean diameters (GM

D) ranging from

1.5 to 2.8 μm (arithmetic mean [AM] diam-eter range=2.3 to 3.9 μm; median diameterrange=1.6to3.3μm).

Studies of airborne fiber size distributions inRCF manufacturing operations indicate thatthesefibersmeetthecriteriaforthoracic-andrespirable-sizedfibers.OneearlystudyofthreedomesticRCFproductionfacilitiesfoundthatapproximately 90% of airborne fibers were<3μmindiameter,and95%ofairbornefiberswere <4 μm in diameter and <50 μm long[Esmen et al. 1979]. The study showed thatdiameterandlengthdistributionsofairbornefibers in the facilities were consistent, with aGM

Dof0.7μmandageometricmeanlength

(GML) of 13 μm.Another study [Lentz et al.

1999] used these data in combination withmonitoring data from two additional studies[MacKinnon et al. 2001; Maxim et al. 1997]at RCF manufacturing plants to review char-acteristicsoffiberssizedfrom118airsamplescovering20years(1976–1996).Fiberswithdi-ameters <1 μm (n=3,711) were measured bytransmission electron microscopy (TEM). Ofthese, 52%haddiameters<0.4μm,75%haddiameters<0.6 μm, and 89% had diameters<0.8μm.Fiberlengthsrangedfrom<0.6to>20μm,with68%offibersmeasuring2.4to20μmlongand19%of thefibers>20μmlong.OnthebasisoftheresultsofTEManalysisof3,357RCFsobservedon98airsamplescollectedinRCFmanufacturingsites,Allshouse[1995]re-

portedthat99.7%ofthefibershaddiameters<3μmand64%hadlengths>10μm.Measure-mentsofairbornefibersintheEuropeanRCFmanufacturingindustryarecomparable:Rood[1988] reported that all fibers observed wereinthethoracicandrespirablesizerange(i.e.,di-ameter<3to3.5μm),with median diametersrangingfrom0.5to1.0μmandmedianlengthsfrom8to23μm.

Cheng et al. [1992] analyzed an air sampleforfibersduringremovalofafter-serviceRCFblanketinsulationfromarefineryfurnace.Fi-berdiametersrangedfrom0.5to6μm,withamediandiameterof1.6μm.Thelengthoffi-bers ranged from 5 to 220 μm. Of 100 fibersrandomly selected and analyzed from the airsample,87%werewithinthethoracicandre-spirablesizerange.Anotherstudyofexposuresto airborne fibers in industrial furnaces dur-inginstallationandremovalofRCFmaterialsfoundGM

Dvaluesof0.38and0.57μm,respec-

tively[Perraultetal.1992].

2.3.2 Fiber Durability

Fiberdurabilitycanaffectthebiologicactivityoffibersinhaledanddepositedintherespira-torysystem.Durablefibersaremorebiopersis-tent,therebyincreasingthepotentialforcaus-ingabiologicaleffect.Durabilityofafiber ismeasured by the amount of time it takes forthefibertofragmentmechanicallyintoshort-erfibersordissolve inbiologicalfluids.RCFstested in vitro with a solution of neutral pH(modified Gamble’s solution) had a dissolu-tionrateof1to10ng/cm2perhr[Leineweber1984].Thistestisbiologicallyrelevantbecauseofthesimilarityofthesolutiontothecondi-tions of the pulmonary interstitial fluid. Bycomparison,otherSVFs(glassandslagwools)aremoresoluble,withdissolutionratesinthe100s of ng/cm2 per hr [Scholze and Conradt1987].Along a continuum of fiber durability



determinedintestsusingsimulatedlungflu-idsatpH7.4,theasbestosfibercrocidolitehasadissolutionrateof<1ng/cm2perhr,RCF1andMMVF32(Eglass)havedissolutionratesof1to10ng/cm2perhr,MMVF21hasadis-solutionrateof15to25ng/cm2perhr,otherfibrousglassandslagwoolshavedissolutionratesintherangeof50to400ng/cm2perhr,andthealkalineearthsilicatewoolshavedis-solution rates ranging from approximately60to1,000ng/cm2perhr[Christensenetal.1994;Maximetal.1999b;Mooreetal.2001].

Chrysotile,whichisconsideredthemostsol-ubleformofasbestos,hasadissolutionrateof<1to2ng/cm2perhr.

RCFsdissolvemorerapidlythanchrysotile,eventhoughRCFshaveathickerdiameter(byanor-derofmagnitude)thanchrysotile.Therateofdissolutionisanimportantfibercharacteristicthat affects the clearance time and biopersis-tenceofthefiberinthelung.Thesignificanceoffiberdimension,clearance,anddissolution(i.e.,breakage,solubility)isdiscussedinChapter6.


3 RCF Production and Potential for Worker Exposure

3.1 Production

RCF production in the United States beganin 1942 on an experimental basis, but RCFswere not commercially available until 1953.SalesofRCFsweremodestinitially,buttheybegantoexpandwhenthematerialgainedac-ceptanceasaneconomicalalternativeinsula-tionforhigh-temperaturekilnsandfurnaces.CommercialproductionofRCFsfirstreachedsignificantlevelsinthe1970sasoilshortagesnecessitated reductions in energy consump-tion.ThegrowingdemandforRCFshasalsobeenstrongly influencedbytherecognitionofhealtheffectsassociatedwithexposuretoasbestos-containingmaterialsandtheincreas-inglystringentregulationoftheseproductsintheUnitedStatesandmanyothercountries.

AnnualdomesticproductionofRCFswasanestimated85.7millionlbin1990;in1997,pro-duction of RCFs in the United States totaled107.7million lbannually [RCFC1998].Cur-rently,totalU.S.productionisestimatedtobe80millionlbperyear,representingabout1%to 2% of the worldwide production of SVFs[RCFC2004].RCFsarealsoproducedinMex-ico, Canada, Brazil, Venezuela, South Africa,Australia, Japan, China, Korea, Malaysia, Tai-wan, and several countries in Europe [RCFC1996]. In the United States and Puerto Rico,the primary producers of RCFs include A.P.Green Industries (Pryor, OK), Unifrax Cor-poration (NiagaraFalls,NY, formerlyCarbo-rundum), Thermal Ceramics (Augusta, GA),

and Vesuvius (King of Prussia, PA, formerlyPremierRefractoriesandChemicals).Thelat-ter three producers account for an estimated90%ofdomesticproductionandaremembersoftheRCFC,whichhasbeenactiveinmoni-toringexposures,developingproductsteward-shipprograms,andfundingresearchtostudyRCFhazardsandsafeworkpracticesforRCFmanufacturinganduse.

3.2 Potential for Worker Exposure

Approximately 31,500 workers in the UnitedStatesarepotentiallyexposedtoRCFsduringmanufacturing,processing,orenduse.Asimi-larnumberofworkersarepotentiallyexposedtoRCFsinEurope.Oftheseworkers,about800(3%)areemployedintheactualmanufactur-ingofRCFsandRCFproducts[Maximetal.1997;RCFC2004].

3.3 RCF Manufacturing Process

ThemanufactureofRCFs(Figure3–1)beginsbyblendingrawmaterials,whichmayincludekaolin clay, alumina, silica, and zirconia ina batch house. The batch mix is then trans-ferred either manually or automatically to afurnacetobemeltedattemperaturesexceed-ing1,600oC.Onreachingaspecifiedtemper-atureandviscosityinthefurnace,themolten


3 ■RCF Production and Potential for Worker Exposure

Fibers are producedby blowing or spinningmolten materials drainedfrom furnace.

Bulk fiber is packaged.

Felt or blanket is curedin tempering oven.

Product is shipped,stored, or fabricatedinto specialty product.

Figure 3–1. Process flow chart for RCF production.

Batch is melted in furnace at >1600˚C.

Lubricants are addedand fibers are processedby needle-felting machine.

Fibers settle intocollection chamber.

Blanket is cut tospecificationsand packaged.

Raw materials (AI2O3,SiO2, TiO2, MgO, CaO,Na2O, K2O, etc.) areadded to batch mix.



batchmixturedrainsfromthefurnaceandisfiberized,eitherthroughexposuretopressur-izedairorbyflowingthroughaseriesofspin-ningwheels[Hill1983].Fansareusedtocreateapartialvacuumthatpullsthefibersintoacol-lectionorsettlingchamber.RCFsmaythenbeconveyedpneumatically toabaggingarea forpackagingasbulkfiber.Somebulkfibermaybeuseddirectlyinthisform,oritmaybepro-cessed to formtextiles, felts,boards,cements,and other specialty items. Other RCFs areformedintoblanketsasbulkfiberinthecollec-tionchambersettlesontoaconveyorbelt.Theblanket passes through a needle felting ma-chinethatinterlocksthefibersandcompressestheblankettoaspecifiedthickness.Fromtheneedler, the blanket is conveyed to a temper-ingoventoremove lubricants thatwereadd-edinthesettlingchamber.Thelubricantsareburnedoff,andtheblanketiscuttodesiredsizeandpackaged.Aswiththebulkfiber,theRCFblanketmayundergoadditionalfabricationtocreate other specialty products. Many of theprocessesareautomatedandaremonitoredbymachine operators. Postproduction processessuchascutting,sanding,packaging,handling,andshippingaremorelaborintensive,butthepotentialexistsforexposuretoairbornefibersthroughoutproduction.

3.4 RCF Products and UsesRCFsmaybeusedinbulkfiberformorasoneof theRCF specialtyproducts in the formofmats, paper, textiles, felts, and boards [RCFC1996].Becauseofitsabilitytowithstandtem-peratures exceeding 1,000 °C, RCFs are usedpredominantly in industrial applications, in-cluding insulation, reinforcement, and ther-mal protection for furnaces and kilns. RCFscan also be found in automobile catalyticconverters, in consumer products that oper-ateathightemperatures(e.g.,toasters,ovens,

woodstoves), and in space shuttle tiles. RCFshavebeenformedintonoise-controlblankets[Thorntonetal.1984]andusedasareplace-ment for refractory bricks in industrial kilnsand furnaces[RCFC1996].RCFshave foundincreasing application as reinforcements inspecialized metal matrix composites (MMC),especially in the automotive and aerospaceindustries [Stacey 1988].A summary of RCFproductsandapplicationsareprovidedhere.

3.4.1 Examples of Products

■ Blankets—high-temperature insulationproducedfromspunRCFsintheformofamatorblanket

■ Boards—high-temperatureinsulationpro-ducedfrombulkfibersintheformofacompressed rigid board (boards havea higher density than blankets and areusedascorematerialorinsandwichas-semblies)

■ Bulk RCFs—fiberswithqualitiesofhigh-temperatureresistancetobeusedasfeed-stockinmanufacturingprocessesorotherapplicationsforwhichproductconsisten-cyiscritical—typicallyinthemanufactureofotherceramic-fiber-basedproducts

■ Ropes and braids—high-temperature in-sulation produced by textile operationsand used for packing, seals, and wickingapplications

■ Woven textiles—high-temperature in-sulationproducedbytextileprocessesintheformofcloth,tape,orsleeves

■ Papers and felts—flexiblehigh-temper-atureinsulationproducedbypapermak-ingprocessesandusedforseals,gaskets,andotherautomotiveandaerospaceap-plications



■ Vacuum cast shapes—high-temperatureinsulationproducedbyformingspecial-izedshapesonprefabricatedmoldswithwetfibersandthendryingthembyvacu-umandheat,therebytransformingbulkfiberintorigid,shapedproducts

■ Specialties—forms(i.e.,mixes,cements,and caulking compounds) that containwet, inorganic binder and are used asprotective coating putties as well as ad-hesivesandheatandfirebarriersinhigh-temperatureapplications

■ Modules—packagedfunctionalassemblyof blanket insulation with hardware forattachingtothesurfacesof furnacesandkilns

3.4.2 Examples of Applications

■ Insulationliningsofhigh-temperaturein-dustrialfurnacesandrelatedequipment

■ Hot spot repair of industrial furnacelinings

■ Industrial furnacecurtains,gaskets,andseals

■ Insulationofpipes,ducts,andcablesas-sociated with high-temperature indus-trialfurnaces

■ Fire protection for industrial processequipment

■ Aircraftandaerospaceheatshields

■ Commercialandconsumerappliancescon-sistingofprefabricatedchimneys,pizzaov-ens,self-cleaningovens,andwood-burningstoves

■ Automobile applications consisting ofbrakepads,clutchfacings,catalyticcon-verters, air bags, shoulder belt controls,andpassengercompartmentheatshields


4 Assessing Occupational Exposure

4.1 Air Sampling and Analytical Methods

The conventional method used to assess thecharacteristics and concentrations of expo-sures to airborne fibers is to collect personalandenvironmental(area)airsamplesforlabo-ratoryanalysis.

Personalsamplesarethepreferredmethodforestimating the exposure characteristics of aworkerperformingspecifictasks.Forpersonalsampling, a worker is equipped with the airsampling equipment, and the collection me-diumispositionedwithintheworker’sbreath-ingzone.Areasamplingisperformedtoevalu-ateexposurecharacteristicsassociatedwithanareaorprocess.Samplingequipmentforareasamplingisstationary,incontrasttopersonalsampling,whichallowsformobilitybyaccom-panying theworker throughout the samplingperiod.

4.2 Sampling for Airborne Fibers

ThetwoNIOSHmethodsforthesamplingandanalysisofairbornefibersofasbestosandoth-erfibrousmaterialsareasfollows:

■ Method7400describesairsamplingandanalysisbyPCM

■ Method7402describesairsamplingandanalysisbyTEM

Both methods (listed in the NIOSH Manual of Analytical Methods[NIOSH1998]andpro-videdinAppendixA)involveusinganairsam-plingpumpconnected toacassette.Thecas-sette consists of a conductive cowl equippedwitha25-mmcelluloseestermembranefilter(0.45-to1.2-µmporesize).Thepumpisusedtodrawairthroughthesamplingcassetteataconstantflowratebetween0.5and16L/min.Airborne fibers and other particulates aretrappedonthefilterforanalysisusingmicro-scopicmethods.Methods7400and7402canbe used to count the number of fibers (andthereforecalculateconcentrationbasedonthevolumeofairsampled)andmeasurethefiberdimensions.Fiberconcentrationisreportedasthe number of fibers per cubic centimeter ofair(f/cm3).Althoughthetwomethodsdifferinpreparationofthesamplingmediaforanaly-sis,themajordistinctionbetweenthemistheresolvingcapabilitiesofthemicroscope.WithPCM,0.25µmisapproximately thediameterofthethinnestfibersthatcanbeobserved[De-mentandWallingford1990].TEMhasalowerresolutionlimitwellbelowthediameterofthesmallestRCF(~0.02 to0.05µm) [Middleton1982]. TEM also allows for qualitative analy-sis of fibers using an energy-dispersive X-rayanalyzer(EDXA)todetermineelementalcom-positionandselectedareaelectrondiffraction(SAED) for comparing diffraction patternswithreferencepatternsforidentification.

4.2.1 NIOSH Fiber-Counting Rules

TheappendixtoNIOSHMethod7400speci-fies two setsoffiber-counting rules thatvary


4 ■Assessing Occupational Exposure

accordingtotheparametersusedtodefineafi-ber.UndertheArules,anyparticle>5µmlongwithanaspectratio(lengthtowidth)>3:1isconsidered a fiber. No upper limit exists onthefiberdiameter intheAcountingrules.IntheB rules,afiber isdefinedasbeing>5µmlongwithanaspectratio≥5:1andadiameter<3µm.Theupper-diameterlimitintheBrulesrestrictsthemeasurementtothoracicandre-spirablefibers.Itisimportanttonotewhichsetoffiber-countingcriteriaisusedwhenreport-inganalyticalresults.NIOSHrecommendsus-ing Method 7400 with the B rules for evalu-ating exposures to airborne RCFs. NIOSHMethod7402specifiesuseoftheA rules,withalower-diameterlimitof0.25µmtoallowcom-parison with results obtained from NIOSHMethod7400.Method7402canalsobeusedtocompare fiber counts obtained from Method7400(Brules).TEMpermitstheidentificationandcountingoffibers<0.25µmindiameter;0.25µmistheapproximateresolutionlimitforPCM.

4.2.2 European Fiber-Counting Rules

In Europe, a slightly different fiber-countingconventionisused.TheWorldHealthOrgani-zation(WHO)referencemethodforMMMFs[WHO/EUROTechnicalCommitteeforMon-itoringandEvaluatingAirborneMMMF1985]recognizesafiberas>5µmlongwithadiameter<3µmandanaspectratio≥3:1.Severalstudiescomparing fiber counts determined with dif-ferentcountingconventionshavefoundgoodagreementinairsamplingforRCFexposures.Buchtaetal.[1998]comparedfibercountsofairsamplesforRCFexposuresasanalyzedus-ing theNIOSHA andB rules;bothmethodsproduced similar results, with no statisticallysignificantdifferenceinfiberdensitymeasure-ments on sample filters. Maxim et al. [1997]found that fiber counts made using NIOSHMethod7400Brulesareequaltoapproximately

95%ofthecountsdeterminedusingtheWHOreferencemethod.InstudieswithotherSVFs,Lees et al. [1993] also found that fiber expo-sure estimates were slightly higher using theA rulesbutwerecomparabletothevaluesob-tainedusingB rules.Breysse et al. [1999] re-portedasimilarfindingwhencomparingRCFfibercountsdeterminedbybothAandBrules:theratioofAtoBcountswas1.33.Thesere-sultssuggestthatforairborneRCFexposures,mostfiberswitha>3:1aspectratioalsomeetthe≥5:1aspectratiocriterionandare<3µmindiameter.

4.3 Sampling for Total or Respirable Airborne Particulates

Airborne exposures generated during workwithRCFsmayalsobeestimatedbysamplingforgeneraldustconcentrations.Samplingforparticulates not otherwise regulated is de-scribedinNIOSHMethod0500fortotaldustconcentrations and in NIOSH Method 0600fortherespirablefraction[NIOSH1998].Bothmethods(alsoincludedinAppendixA)useasamplingpumptopullairthroughafilterthattrapssuspendedparticulates.NIOSHMethod0600 uses a size-selective sampling apparatus(cyclone)toseparatetherespirablefractionofairbornematerialfromthenonrespirablefrac-tion.Themassofairborneparticulatesonthefilter is measured using gravimetric analysis,and airborne concentration is determined astheratiooftheparticulatemasstothevolumeofairsampled,reportedasmg/m3(orµg/m3).Thismethoddoesnotdistinguishfibersfromnonfibrousairborneparticles.NoNIOSHRELexistsforeithertotalorrespirableparticulatesnot otherwise regulated. The OSHA permis-sibleexposurelimit(PEL)forparticulatesnototherwiseregulatedis15mg/m3fortotalpar-ticulatesand5mg/m3forrespirableparticulates



as 8-hr TWA concentrations. The AmericanConference of Governmental Industrial Hy-gienists(ACGIH)thresholdlimitvalue(TLV)forparticles(insolubleorpoorlysoluble)nototherwise specified is10mg/m3 for inhalableparticlesand3mg/m3 for respirableparticlesas8-hrTWAconcentrations[ACGIH2005].

4.4 Sampling for Airborne Silica

BecausesilicaisamajorconstituentofRCFs,thepotentialexistsforexposuretosilicadur-ingworkwithRCFs(e.g.,inmanufacturingorduring removal of after-service RCF furnaceinsulation). As with sampling for respirableparticulates, sampling for respirable silica in-volves using a pump to draw air through acyclone before collecting respirable airborneparticlesonafilter.Qualitativeandquantita-tive analysis of the sample for silica contentcanbeperformedusingthefollowinganalyti-calmethods:

■ X-raypowderdiffraction(NIOSHMeth-od7500)

■ Visible absorption spectrophotometry(NIOSHMethod7601)

■ Infrared absorption spectrophotometry(NIOSHMethod7602)

TheNIOSHRELforrespirablecrystallinesili-cais0.05mg/m3asaTWAforupto10hr/dayduringa40-hrworkweek[NIOSH1974].TheACGIHTLVforcrystallinesilicais0.05mg/m3asan8-hrTWA[ACGIH2005].

4.5 Industrial Hygiene Surveys and Exposure Assessments

Assessments of occupational exposures, in-cludingquantitativemeasurementofairborne

fiberconcentrationsassociatedwithmanufac-turing, handling, and using RCFs, have beenperformed using industrial hygiene surveysandairsamplingtechniquesatmultiplework-sites.Sourcesofmonitoringdatathatcharac-terizeoccupationalexposurestoRCFsincludethefollowing:

■ UniversityofPittsburghstudiesofexpo-suresatRCFmanufacturingsites in the1970s[CornandEsmen1979;Esmenetal.1979]

■ An ongoing University of Cincinnatiepidemiologic study with exposure as-sessmentsthatusehistoricalmonitoringdata and current monitoring strategies[Riceetal.1994,1996,1997]

■ A5-yearconsentagreementbetweentheRCFCand theU.S.EnvironmentalPro-tectionAgency(EPA)tomonitorworkerexposures inRCFmanufacturingplantsandinsecondaryusersofRCFsandRCFproducts [RCFC 1993; Everest 1998;Maximetal.1994,1997,2000a]

■ Studies of exposure to airborne fibersduring the installation and removal ofRCF insulation in industrial furnaces[Gantner 1986; Cheng et al. 1992; vandenBergenetal.1994;SweeneyandGil-grist1998;Maximetal.1999b]

■ International (Canadian, Swedish, Aus-tralian)industrialhygienesurveysofoc-cupational exposures to RCFs [Perraultetal.1992;Krantzetal.1994;Rogersetal.1997]

■ Astudyofend-userexposurestoRCFin-sulationproductsbyresearchersatJohnsHopkinsUniversity[Cornetal.1992]

■ NIOSHHealthHazardEvaluations(HHEs)ofoccupationalexposurestoRCFs



4.5.1 University of Pittsburgh Survey of Exposures During RCF Manufacturing

Inthemid1970s,researchersfromtheUniver-sity of Pittsburgh conducted environmentalmonitoringtoassessworkerexposurestoair-borne fibers at domestic RCF manufacturingfacilities. This research effort was one of thepioneeringstudiesintheuseofworkplaceex-posuregroupingsordust zonesforestablishinga sampling strategy [Corn and Esmen 1979].Inaseriesofindustrialhygienesurveys,Esmenetal.[1979]collected215full-shiftairsamplesatthreeRCFmanufacturingplants.Table4–1summarizes the sampling data for the threefacilities (A, B, and C) by fiber concentra-tion of total airborne dust. Although a widerangeofvaluesforindividualsamplesexisted(<0.01to16f/cm3),average(AM)concentra-tionsrangedfrom0.05to2.6f/cm3.Thehigh-estexposureconcentrationsweremeasuredinmanufacturing and finishing operations dur-ingwhichsanding,cutting,sawing,anddrill-ingoperationswereperformedandventilationwas lacking. A large number of these opera-tionswerenotedinplantA,whichisreflectedby theelevatedfiberanddust concentrationsfor this plant.When data were compared forsimilar operations and dust zones, exposureconcentrations were consistent across plants.Analysesofairsamplesalsoincludedmeasure-mentoffiberdimensions.Approximately95%

oftheairbornefibersmeasuredwere<4.0µmindiameterand<50µmlongwithaGM

Dof

0.7µmandaGMLof13µm.

4.5.2 University of Cincinnati Study of Exposures During RCF Manufacturing

In1987,researchersfromtheUniversityofCin-cinnati initiated an industry-wide epidemio-logicstudyofworkerswhomanufactureRCFs.OneaimofthestudywastocharacterizecurrentandformerexposurestoRCFsandsilicainU.S.RCFmanufacturingfacilities.Datafrominitialsurveys conducted at five RCF manufacturingplants indicated airborne RCFs with a GM

D

rangingfrom0.25to0.6µmandaGMLranging

from3.8 to11.0µm[Lockeyetal.1990].Theairborne TWA fiber concentrations for thesefiveplantsrangedfrom<0.01to1.57f/cm3.Af-terthefirsttworoundsofquarterlysampling,Riceetal.[1994]hadcollecteddatafrom484fibercountsamples(382sampleswithvaluesgreater than the analytic limit of detection[LOD], 39overloaded samples, 36 sampleswith values below the LOD, and 27 samplesvoidedbecauseoftamperingorpumpfailure).They also collected 35 samples from personsworkingwithrawmaterialsthatwereanalyzedquantitatively and qualitatively for respirablemassandforsilicapolymorphs(quartz,tridy-mite,andcristobalite).Asamplingstrategywasdeveloped by identifying more than 100job

Table 4–1 . Industrial hygiene survey data for three RCF* manufacturing plants†

AM total airborne dust AM fiber concentration

Plant No . samples mg/m3 Range f/cm3 Range

A 76 6.05 0.37–100.00 2.6 0.02–16.0

B 67 1.6 0.19–9.73 0.63 0.04–6.7

C 72 0.85 0.05–2.34 0.05 <0.01–0.29

Source:Esmenetal.[1997].*Abbreviations:AM=arithmeticmean;RCF=refractoryceramicfiber.†Fibersweredefinedashavinganaspectratio>3:1.Transmissionelectronmicroscopywasusedtomeasurefibers≤1 µmindiameter.



functions across 5 facilities. These job func-tionswereconsolidatedintoindustryjobtitlesbasedonsimilaritiesoffunction,proximitytocertainprocesses,andexposurecharacteristicswithindesignateddustzones.Table4–2pres-entsmedianTWAexposurestoairbornecon-centrationsofRCFsbyjobtitleatplantssam-pledin1987.TWAfiberconcentrationsrangedfrombelowtheanalyticalLODto1.04f/cm3forworkersin20differentindustryjobtitles.Fiberconcentrationsobtainedbyrinsingthewallsofthesamplingcowl,whereasignificantnumberof fibers accumulated during sampling [Cor-nettetal.1989;Breysseetal.1990],rangedfrombelowtheanalyticalLODto1.54f/cm3.Ofthe35samplesanalyzedforthesilicapolymorphs,quantifiablesilicawasfoundin5samples:4ofthe samples contained cristobalite in concen-trationsrangingfrom20to78µg/m3,and1ofthe samples contained 70 µg/m3 quartz. Themeasurable silica exposures occurred amongworkersemployedasrawmaterialhandlersandfurnaceoperators.

As the studyprogressed,approximately1,820work history interviews were conducted andevaluated to refine uniform job titles and toidentify dust zones according to the meth-odofCornandEsmen[1979].Fouryearsofsamplingdata(1987–1991)weremergedwithhistoric sampling data to construct exposureestimatesfor81jobtitlesin7facilitiesforspec-ified time periods [Rice et al. 1997]. Overallexposuresdecreased.Themaximumexposureestimatedwas10f/cm3inthe1950sforcardingin a textile operation; subsequent changes inengineering, process, and ventilation reducedexposureestimatesforall20jobtitlestonearorbelow1f/cm3[Riceetal.1996,1997].Thestudyreportedthatatmorerecentoperations(1987–1991),exposureestimatesrangedfrombelowtheanalyticLODto0.66f/cm3.

Subsequently,Riceetal.[2005]publishedtheresultsfromananalysisofexposureestimates

for10yearsoffollow-upsampling(1991−2001)at5of7facilities(2facilitieshadclosedbefore1991).Theresearchersfoundthefollowinges-timatesfor122jobtitlesstillactivein2001:

Number and % Exposure estimate of job titles (f/cm3)

97(79%) . . . . . . . . . . ≤0.2517(14%) . . . . . . . . . . >0.25to0.58(7%)........... >0.5

Thestudyshowsthatexposuresdecreasedfor25% of job titles, remained stable for 53%,and increased for22%.Of the job titleswithincreasedexposureestimates,9estimateswere>0.1f/cm3(range=0.1to0.21f/cm3),and19estimates were <0.1 f/cm3. The exposure es-timates for this study do not include adjust-mentsforrespiratoruse.

4.5.3 RCFC/EPA Consent Agreement Monitoring Data

In1993,theRCFCandtheEPAenteredintoane-gotiated5-yearconsentagreementtodeterminethemagnitudeofRCFexposuresintheprimaryRCF manufacturing industry and in secondaryRCF-use industries [RCFC 1993; Maxim et al.1994, 1997; Everest 1998]. Another purpose ofthisconsentagreementwastodocumentchangesinRCFexposuresduringthe5yearsoftheagree-ment(1993–1998).TheQualityAssuranceProj-ectPlan in theconsentagreementcontains theanalytical protocols, statistical design, descrip-tionoftheprogramobjectives,andtimetablesformeetingtheobjectives[RCFC1993].

During each year of the consent agreement, aminimum of 720 personal air samples (mea-sured as 8-hr TWAs) were collected accordingtoa stratifiedrandomsamplingplan.Of these,320 samples were collected in RCF manufac-turing and processing (primary) facilities. Theremaining 400 samples were collected in RCF



Tabl

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customer facilities referred to as end-use (sec-ondary)facilities.Theresearcherscollectedato-talof4,576samples.Anumberofend-usefacili-tieswererandomlyselectedfromalistofknownpurchasersofRCFproducts.Theremaindercon-sistedoffacilitiesthatvolunteeredforsamplingoncetheylearnedoftheconsentagreement.Thestratafromwhichthe720sampleswerecollectedconsistofeightfunctionaljobcategoriesderivedsothatresultscouldbeaggregatedforcompari-son across industries, facilities, and similar jobfunctions[RCFC1993].Thiscategorizationwasbased on the approach instituted by Corn andEsmen[1979].AppendixBlistsdefinitionsandmajor work tasks for each functional job cat-egory.TWAandtask-lengthaverageairsamplingdataweregatheredaccordingtoNIOSHMeth-od7400(Brules)andanalyzedusingPCMandTEM.Dataonrespiratoruse(bytype)werealsocollected[Maximetal.1998].

As background for the consent agreementmonitoringplan,baseline(nowreferredtoashistorical) information about airborne fiberconcentrationswasobtainedthroughpersonalsampling of workers at RCF manufacturingfacilitiesfromJanuary1989toMay1993.Ex-posuremonitoringstrategiesusedduring thebaseline period (1989–1993) provided theframeworkfor theconsentagreement(1993–1998) monitoring protocol. Table 4–3 pres-entsAM and geometric mean (GM) concen-trations of RCF exposures determined fromhistoricaldata(1989–1993)by functional jobcategory. Table 4–4 contains these summarystatisticsforall5yearsofRCFconsentagree-mentmonitoringdata.Table4–5summarizesdata from samples collected during the 5thyearoftheconsentagreementonly(June1997toMay1998).Table4–6presents theaverageairbornefiberconcentrations for thebaseline(1989–1993)andconsentagreementmonitor-ing(1993–1998)periodsbymanufacturingandend-usesectors.

Acomparisonofvalues fromTables4–4,4–5,and4–6withthoseinTable4–3indicatesthataverageairborneconcentrationsfor1993–1998were lower than those for theprecedingbase-line sampling period (1989–1993). However,acomparisonofvalues inTables4–5and4–6showsthataverageconcentrationsfortheentire5-year consent agreement monitoring period(1993–1998) are equal to those of year 5 (i.e.,nochange).

Afterthefirst3years(1993–1996)ofthecon-sentagreementmonitoringperiod,Maximetal.[1997]performedinterimanalysesofthesedatacombinedwithhistoricaldatafromthebaselinemonitoringperiod(1989–1993).Thefollowingconclusions about RCF exposures were basedon these analyses of data from 1,600 baselinesamplesand3,200consentagreementsamples:

■ Airborne concentrations of RCFs aregenerallydecreasingintheworkplace.

■ Ninety percent of airborne concentra-tionsofRCFsintheworkplacearebelow1f/cm3.

■ RCF concentrations have an approxi-matelylog-normaldistribution.

■ Significantdifferencesexistinworkplaceconcentrationsbyfacility.

■ Workplaceconcentrationsvarywithfunc-tionaljobcategory.

■ Respiratorusagevarieswiththeworker’sfunctional job category and the associ-atedaveragefiberconcentration.

■ Workplacesampleshavealowerratioofrespirable nonfibrous particles to fibersthansamplesusedininitialanimalinha-lation studies [Mast et al. 1995a,b; Mc-Connelletal.1995].

Functionaljobcategorieswiththehighestaver-ageTWAfiberconcentrationsincluderemoval(AM=1.2f/cm3),finishing(AM=0.8f/cm3),and



Table 4–3 . TWA* concentrations of airborne RCFs in personal samples collected during the baseline sampling period (1989–1993),† by functional job category

Functional job category

Manufacturing (primary production) End use (secondary processing)

No . samples

AM GM No . samples

AM GM

f/cm3 SD f/cm3 GSD f/cm3 SD f/cm3 SD

Assembly 120 0.5 0.92 0.22 3.94 130 0.29 0.36 0.13 4.08

Auxiliary 119 0.15 0.18 0.07 4.01 26 1.1 2.26 0.2 6.33

Fiber 438 0.52 0.79 0.22 4.17 — — — — —

Finishing 127 0.76 0.63 0.49 3.11 84 1.57 5.72 0.47 4.18

Installation — — — — — 201 0.69 1.09 0.3 4.31

Mixingforming 89 0.27 0.34 0.15 3.23 47 0.41 0.55 0.17 4.71

Other 129 0.33 0.86 0.09 4.25 57 0.38 0.69 0.14 4.88

Removal — — — — — 49 1.36 2.97 0.28 6.48

Total 1,022 0.46 0.74 0.19 4.37 594 0.75 2.49 0.23 4.85

*Abbreviations:AM=arithmeticmean;GM=geometricmean;GSD=geometricstandarddeviation;RCF=refractoryceramicfibers;SD=standarddeviation;TWA=time-weightedaverage.†DatacollectedfromAugust1989toMay1993[RCFC1993].

Table 4–4 . TWA* concentrations of airborne RCFs in personal samples collected during the 5-year consent agreement monitoring period, 1993–1998,† by functional job category



No . samples

AM GMNo .

samples

AM GM

f/cm3 SD f/cm3 GSD f/cm3 SD f/cm3 GSD

Assembly 362 0.28 0.27 0.18 2.76 369 0.31 0.4 0.14 4.1

Auxiliary 237 0.12 0.19 0.05 3.87 311 0.19 0.37 0.07 4.68

Fiber 421 0.26 0.47 0.14 3.27 — — — — —

Finishing 359 0.65 0.56 0.47 2.44 622 0.99 2.09 0.35 4.5

Installation — — — — — 456 0.42 0.51 0.2 3.83

Mixingforming 379 0.28 0.27 0.17 2.96 332 0.31 0.47 0.17 3.07

Other 167 0.14 0.21 0.07 3.22 385 0.17 0.46 0.04 4.66

Removal — — — — — 176 1.92 2.85 0.82 4.22

Total 1,925 0.31 0.42 0.16 3.65 2,651 0.56 1.39 0.16 5.22

Source:Maximetal.[1999a].*Abbreviations:AM=arithmeticmean;GM=geometricmean;GSD=geometricstandarddeviation;RCF=refractoryceramicfibers;

SD=standarddeviation;TWA=time-weightedaverage.†DatacollectedfromJune1993toMay1998.



installation(AM=0.4f/cm3).TheremainderofthefunctionaljobcategorieshadaverageTWAconcentrations near or below 0.3 f/cm3. Al-thoughdifferentjobsandactivitiesareassoci-atedwiththethreehigherexposurefunctionaljobcategories,similaritiesexistthatcontributetoexposureconcentrations.First,removalandinstallationactivitiesareperformedatremotejobsiteswhereimplementingfixedengineeringcontrolsmaybedifficultorimpracticalforre-ducingairbornefiberconcentrations.Removalrequires more mechanical energy and mayinvolve fracturing the structure of the RCFproduct, resulting in fiber release and higherconcentrations of airborne fibers. Finish-ingactivitiesareperformedatfixed locationswhereitispossibletoimplementengineeringcontrols,buttheyalsoinvolvemechanicalen-ergytoshapeRCFproductsbydrilling,sand-ing,andsawing.Theseprocessesalsoresultinthedispersalofairbornefibers.

Regardingparticle-to-fiberratio,Maximetal.[1997] found average workplace values to bemuch lower(0.53;n=10;rangenotreported)thantheaverageratio(9.1;n=7)inthesamplesused in a series of animal inhalation toxicitystudieswithRCFs [Mast et al. 1995a,b,2000;McConnelletal.1995].

Monitoringperformedduringthebaselinepe-riod(August1989–May1993)andthe5-yearconsent agreement period (June 1993–May1998)provideddatafromnearly6,200airsam-ples in thedomesticRCF industry.Table4–6presents the summary statistics of workplaceRCFexposureconcentrationsforthebaseline(historical) and consent agreement monitor-ingdata.Thedatasuggestthat(1)theAMsandGMs of RCF concentrations were higher forworkersduringthebaselineperiodthandur-ingthemorerecent(consentmonitoringdata)period,and(2)AMandGMexposureconcen-trationswerelowerforworkersinmanufactur-ingfacilitiesthanatend-usesites.

Table 4–5 . TWA* concentrations of airborne RCFs in personal samples collected during year 5 of the consent agreement monitoring period, June 1997 to May 1998



No . samples

AM GM No . samples

AM GM


Assembly 78 0.28 0.25 0.19 2.48 92 0.28 0.39 0.1 5.32

Auxiliary 44 0.16 0.21 0.08 4.05 89 0.18 0.36 0.06 4.98

Fiber 85 0.29 0.29 0.18 2.85 — — — — —

Finishing 77 0.6 0.57 0.44 2.11 126 0.93 1.49 0.37 4.43

Installation — — — — — 81 0.34 0.49 0.17 3.54

Mixingforming 75 0.23 0.24 0.14 2.78 69 0.28 0.31 0.18 2.65

Other 39 0.22 0.34 0.12 3 70 0.05 0.12 0.02 3.07

Removal — — — — — 39 2.3 3.9 0.58 6.15

Total 398 0.31 0.37 0.18 3.12 566 0.54 0.14 0.13 5.83

Source:Maximetal.[1999a].*Abbreviations:AM=arithmeticmean;GM=geometricmean;GSD=geometricstandarddeviation;RCF=refractoryceramic

fibers;SD=standarddeviation;TWA=time-weightedaverage.



4.5.4 Exposures During Installation and Removal of RCF Furnace Insulation

To evaluate exposures to airborne dust as-sociated with removing RCF furnace insula-tion,Gantner[1986]conductedsurveyswithair sampling at five sites. The surveys wereperformed at sites where workers removedmodules or blanket-type insulation manu-allyusingknivesor trowels.Duringremovalactivities,workersworedisposable,single-userespirators,disposableprotectiveclothingortheir own personal clothing, and (in somecases) goggles or other protective eyewear.Personal sampling was performed for totaldustconcentrationaswellas respirabledustconcentration using a cyclone.Area sampleswere collected in the center of work zones(industrial furnaces) at 9 ft above the floor,whichwasat thebreathingzone levelof theworkers,whowereonscaffolding.Atotalof24 air samples were collected, including 14personal samples (9 for respirable dust and5 for total dust concentrations) and 10 area

samples (3 for respirable dust and 7 for to-tal dust concentrations). Bulk samples of theinsulation materials were analyzed for cristo-balitecontent,whichrangedbetween0%and21%. In area air samples, cristobalite contentranged from 4% to 15%. Personal respirabledust concentrations averaged 4.99 mg/m3(range=0.12to16.9mg/m3),andpersonaltotaldustsamplesaveraged13.95mg/m3(range=0.31to35.8mg/m3).Concentrationsinareasampleswere lower,averaging1.61mg/m3(range=0.1to3.4mg/m3)forrespirabledustand8.98mg/m3(range=0.96to36.2mg/m3)fortotaldust.Asexpected, the highest cristobalite concentra-tions inbulksampleswere foundonthe faceof insulation materials closest to high tem-peratures in furnaces (threshold temperaturenear1,700oF).Resultsofthesurveysindicatedthat concentrations of respirable cristobaliteexceeded theACGIH TLV (then [10mg/m3]/[%SiO

2 + 2]/2) in 75% of the samples, al-

thoughallsamplingtimeswereshortbecausetheremovaltasklastsonly26to183min.TheTLVforcristobalitehassincebeenloweredto0.05mg/m3asan8-hrTWA[ACGIH2005].

Table 4–6 . TWA* concentrations RCFs in personal samples collected at manufacturing facilities and end-use site during the baseline (1989–1993) monitoring periods

Type of site No .

samples

Baseline data (1989–1993)†

No . samples

Consent monitoring data (1993–1998)‡

AM GM AM GM


Manufacturing(primaryproduction)

1,022 0.46 0.74 0.19 4.37 1,527 0.31 0.42 0.16 3.65

End-use(secondaryprocessing)

594 0.75 2.49 0.23 4.85 2,085 0.56 1.39 0.16 5.22

Total 1,616 0.56 1.63 0.2 4.56 4,576 0.46 1.1 0.16 4.53

Sources:RCFC[1993]andMaximetal.[1999a].*Abbreviations:AM=arithmeticmean;GM=geometricmean;GSD=geometricstandarddeviation;RCFs=refractoryceramic

fibers;SD=standarddeviation;TWA=time-weightedaverage.†DatacollectedfromAugust1989toMay1993[RCFC1993].§DatacollectedfromJune1993toMay1998[Maximetal.1999a].



Chengetal.[1992]studiedexposurestoRCFsduring the installation and removal of RCFinsulation in13 furnacesat6refineriesand2chemical plants. Air samples were collectedand analyzed according to NIOSH Method7400 (A rules); sampling times ranged from15 to 300 min. Samples collected during mi-normaintenanceand inspectiontasks(n=27)showedGMconcentrationsof0.08to0.39f/cm3(range=0.02to17f/cm3).Samplingperformedduring installation of RCF insulation (n=59)revealed GM concentrations of 0.14 to 0.62f/cm3 (range=0.02 to 2.6 f/cm3). The highestexposures were observed in samples collect-ed during removal of RCF insulation (n=32),withGMconcentrationsof0.02 to1.3 f/cm3(range=<0.01 to 17f/cm3). Workers work-ingoutsideofenclosedspaces(furnaces)wererarely exposed to more than 0.2 f/cm3. Onesample of after-service RCF insulation wasanalyzedforfiberdiameterandlength:mediandiameterwasreportedas1.6µm(range=0.5to6µm),and length ranged from5 to220µm.Of100fibersrandomlyselectedandanalyzedfromtheairsample,87%werewithinthere-spirablesizerange.Fourpersonalsampleswerecollectedduringremovalofafter-serviceRCFmodulesandfirebricksandwereanalyzedforrespirablecrystallinesilica(cristobalite).Sam-ples revealed concentrations ranging from0.03mg/m3to0.2mg/m3(GM=0.06mg/m3).

AtaDutchoil refinery,vandenBergenetal.[1994]performedpersonalairmonitoringforairbornefiberstoassessworkerexposuresdur-ingtheremovalofRCFinsulationfromexpan-sionseamsinaheat-treatingfurnace.The8-hrTWAexposuresfor5workerssampledrangedfrom 9to 50 f/cm3 (GM=16 f/cm3). SweeneyandGilgrist[1998]alsomonitoredworkerex-posurestoairborneRCFsandrespirablesilicaduring the removal of RCF materials fromfurnaces. Personal samples from two work-ers taken during the removal of after-service

RCFinsulationrevealedexposuresof0.15and0.16f/cm3.Exposurestototalparticulate(18.3and22.4mg/m3as8-hrTWAs)wereabovetheOSHAPELof15mg/m3.Exposureconcentra-tionsforrespirabledustcontainingcrystallinesilica (2.4% and 4.3%) were also above theOSHA PEL. The elevated concentrations ofrespirableandtotaldustwereassociatedwithremovalof conventional refractory liningus-ing jackhammers, crowbars, and hammers.AworkerperformingroutingtoinstallnewRCFinsulation was exposed at 1.29 f/cm3 (8-hrTWA).PersonalsamplesfromanotherworkerusingabandsawtocutnewRCFinsulationre-vealedconcentrationsof1.02f/cm3asan8-hrTWA.

In theRCF industry,workerexposures to re-spirable crystalline silica (including quartz,cristobalite,andtridymite)mayoccurduringtheuseofsilicainmanufacturing,removalofafter-service insulation, and waste disposal.Focusing on exposures of workers who in-stall,use,orremoveRCFinsulation,Maximetal.[1999a]collected158personalairsamplesanalyzedforrespirablequartz,cristobalite,andtridymite over the RCFC/EPA 5-year consentagreementmonitoringperiod(1993–1998).Atotalof42removalprojectsweresampled.Forsmall jobs, all workers engaged in insulationremoval were sampled; for larger jobs, work-erswereselectedatrandomforsampling.Airsamplingandanalysiswereperformedaccord-ingtoNIOSHMethod7500forcrystallinesili-cabyX-raydiffraction;samplingtimesrangedfrom37 to588min (AM=260min, standarddeviation[SD]=129min).Shortsamplingtimesreflected theshortdurationofRCF insulationremovaltasks(abenefitovertime-intensivere-moval of conventional refractories). RemovalofRCFblanketsandmodulesisperformedbyusingknives,pitchforks,rakes,andwaterlanc-es, or by hand-peeling. The study noted thatmost (>90%) workers wear respirators (with



protectionfactorsfrom10to50ormore)whenremoving insulation.Analysisof158 samplesfoundthefollowing:

■ Fourteen samples had task-time respi-rablequartzconcentrationsrangingfrom0.01to0.44mg/m3(equivalent8-hrTWArange=0.004to0.148mg/m3);theremain-derofsampleswerebelowtheLOD.

■ Threesampleshaddetectableconcentra-tionsofcristobalite thatwerebelowtheNIOSHRELof0.05mg/m3.

■ Onesamplecontainedtridymite(0.2mg/m3)ataconcentrationexceedingtheNIOSHRELof0.05mg/m3.

4.5.5 International (Canadian, Swedish, and Australian) Surveys of RCF Exposure

Perrault et al. [1992] reported on the charac-teristicsoffiberexposuresthatoccurredduringtheuseofsyntheticfiberinsulationmaterialsonconstructionsitesinCanada.Fiberdimensionsweremeasuredfrombulksamplesofinsulationmaterialsusedatfiveconstructionsites.Areaairsampleswerealsocollectedduringtheinstalla-tionof compositeRCFandglasswool insula-tion,glasswoolalone, rockwool (bothblownandsprayedon),andRCFsalone.

Respirable fiber concentrations were highestduringremovalandinstallationofRCFs(0.39to 3.51 f/cm3) compared with concentrationsmeasured during installation of rock wool(0.15to0.32f/cm3),compositeRCFandglasswool(0.04f/cm3),andglasswoolalone(0.01f/cm3).Diametersoffibersinbulksamplesdif-feredsignificantlyfromdiametersinairbornefibers.RCFshadthesmallestGM

Doffibersin

bulksamples(0.38to0.55µm)comparedwithglasswool(0.93µm)androckwool(1.1to3.9

µm). For airborne fibers, rock wool (sprayedon)hadaGM

Dof2.0µm, followedbyRCFs

(1.1µm),compositeRCFsandglasswool(0.71µm),glasswool(0.5µm)andblownrockwool(0.5µm).Elementalanalysisandcomparisonof bulk samples with air samples revealed agreaterconcentrationoffiberswithoxidesofsiliconandaluminuminairsamples.Forsiteswitheitherglasswoolorrockwoolinsulation,airborne samples contained fewer fibers withsiliconoxideasthesoleconstituentthanbulksamples.Theauthorsconcludedthatairbornefiberconcentrationswereaffectedbythetypeof fiber material used and the confinementofworksites.Theauthorsalsoconcludedthatcharacterizationoffibersinbulksamplesisnotagoodrepresentationofphysicalandchemicalparametersoftheairbornefibers.

A report by the Swedish National Institutefor Occupational Health [Krantz et al. 1994]describes exposure to RCFs in smelters andfoundriesbasedonindustrialhygienesurveysand sampling at 4 facilities: a specialty steelfoundry (2,500 workers), a metal smeltingplant (1,500workers), an aluminum foundry(450workers),andanironfoundry(450work-ers).RCFproductswereusedintheseplantsinladles, tapping spouts, holding furnaces, heattreatmentfurnaces,andspillprotectionmats.Workersandcontractorswereplacedintothreeexposure categories, depending on their po-tentialforexposure(asdeterminedbydistancefromafibersource).Thehighestexposurestoairborneceramicfibers(category1)hadmedi-anconcentrationsof0.26to1.2f/cm3andin-volvedabout3%(n=160)oftheworkersattheplantssurveyed.Secondaryexposures(catego-ries2and3)involvedanother33%(n=1,650)oftheworkersandhadmedianconcentrationsof0.03to0.24f/cm3.Duringcertainopera-tionssuchasremovalordemolitionofRCFmaterials in enclosed spaces, concentrationsofupto210f/cm3weremeasured.Totaldust



concentrations increased with fiber concen-trationandwereashighas600mg/m3duringdemolitionand60mg/m3duringreinsulation.Medianfiberdiametersfrombulksamplesan-alyzedbyelectronmicroscopyrangedfrom0.6to1.5µm,whichwascomparabletothediametersofairbornefibers.Onthebasisofairsamplingdata,fiber dose(assumingaworkinglifetimeof40years[fiberconcentration×exposuretimeperyear×40years])wasestimatedfor8oc-cupationswithcategory1exposures.Dosees-timatesrangedfrom0.05fiber-years/cm3foracleanerto85fiber-years/cm3forabricklayerorcontractor.Doseestimatesforthe6otheroc-cupations ranged from 0.6 fiber-years/cm3 to3.1fiber-years/cm3.

Researchersat theAustralianNationalOccupa-tionalHealthandSafetyCommissionestablishedatechnicalworkinggrouptoinvestigatetypi-calexposuresinSVFmanufacturinganduserindustries[Rogersetal.1997].TheRCFman-ufacturing industry isrelativelysmall inAus-tralia:2plantsemployingroughly40workershavebeenmanufacturingRCFssince1976and1977. Since the plants began manufacturingRCFs,152personshavebeeninvolvedwithpro-duction.Airbornefiberconcentrationsinbothplantsdecreasedovertimeasaresultof(1)theintroductionof anational exposure standardof0.5f/cm3forsyntheticfibersandasecond-arystandardof2mg/m3forinspirabledust,(2)theuseofvariouscontrolsandhandlingtech-nologies,and(3) increasedawarenessofdustsuppressionbytheworkforce.GMconcentra-tions of airborne fibers before implementa-tion of the synthetic fiber exposure standard(1983–1990) measured 0.52f/cm3 (geometricstandarddeviation[GSD]=3.9)and0.29f/cm3(GSD=2.5) for plants1and 2, respectively.GMconcentrationsforthesubsequentperiod(1991–1996)droppedto0.11f/cm3(GSD=4.1)atplant1and0.27f/cm3(GSD=3.3)atplant2.

4.5.6 Johns Hopkins University Industrial Hygiene Surveys

AreportofRCFend-userexposuredatapre-pared for the Thermal Insulation Manufac-turers Association (TIMA) showed that us-ing blanket, bulk, and vacuum-formed RCFsduring certain operations resulted in high fi-berconcentrations[Cornetal.1992].Forex-ample,25personalairsamplescollectedfromworkers installing RCF blanket modules hadanAM,8-hrTWAconcentrationof1.36f/cm3(SD=1.15).Thefiberswerecollectedandana-lyzed using NIOSH Method 7400 (B rules).Seventeen vacuum formers had AM expo-sure concentrations of 0.71 f/cm3 (SD=0.83)whileusingbulkRCFproducts.Twenty-eightworkerswiththejobtitlevacuum-formed RCF cast finisher had AM exposures of 1.55f/cm3(SD=1.51). Table 4–7 summarizes exposuredatacollectedforthe17occupationssampledduring the study. Scanning electron micros-copy(SEM)wasusedtomeasuredimensionsofapproximately3,500fibersfromselectedairsamplesofthe17occupations.GMfiberdiam-etersrangedfrom0.9to1.5µm,andGMfiberlengthsrangedfrom20.4to36.1µm.Fiberas-pectratiosbasedonthesedatarangedbetween16:1and30:1.

4.5.7 NIOSH HHEs and Additional Sources of RCF Exposure Data

NIOSHhasconductedHHEsinvolvingpoten-tial exposures to RCFs at the following workplaces:anRCFmanufacturingfacility[Lyman1992], a steel foundry [O'Brien et al. 1990],a power plant [Cantor and Gorman 1987], afoundry [Gorman 1987], and a railroad carwheel and axle production facility [Hewett1996].Table4–8summarizesdataonairbornefiber concentrations and dimensions fromthesestudies.



Table 4–7 . Summary of 8-hr TWA* RCF exposures for workers using RCF insulation products

PCM (f/cm3) SEM (f/cm3)Gravimetric

(mg/m3)

RCF product Occupation n AM SD n AM SD n AM SD

RCFblanket Modulefabricator 5 0.44 0.4 7 0.54 0.8 4 6.26 6.5

Moduleinstaller 25 1.36 1.15 23 1.19 0.8 11 14.2 18.7

Blanketinstaller 8 0.37 0.29 9 0.33 0.24 4 1.42 1.2

Investmentcaster 20 0.73 0.88 18 0.65 0.57 6 3.59 3.75

Generalfabricator 20 0.55 0.55 19 0.46 0.55 7 0.86 0.49

Fabricationmaintenance — — — — — — — — —

RCFbulk Vacuumformer 17 0.71 0.83 13 0.6 0.57 7 1.1 0.7

Vacuummaintenance — — — — — — — — —

Vacuumwarehouse — — — — — — — — —

Sprayer 1 1.53 — 1 1.15 — — — —

Sprayfeeder 1 0.24 — 1 0.21 — — — —

Vacuum-formedRCFs Generalfabricator 2 0.52 0.58 2 0.2 0.05 2 0.57 0.35

Paperfabricator — — — — — — — — —

Paperfinisher — — — — — — — — —

Castfinisher 28 1.55 1.51 32 1.17 1.17 8 4.05 5.42

Finishingmaintenance 1 0.12 — 2 0.07 0.01 1 0.75 —

Boardinstaller 9 0.78 0.84 9 0.66 0.67 1 6.09 —

Source:Cornetal.[1992].*Abbreviations:AM=arithmeticmean;PCM=phasecontrastmicroscopy;RCF-refractoryceramicfiber;SD=standarddeviation;SEM=scanningelectronmicroscopy;TWA=time-weightedaverage.



Table 4–8 . NIOSH Health Hazard Evaluations involving investigation of exposures to RCFs*

Reference Worksite

Samples Concentration

Fiber dimensionNo . Type f/cm3 SD

Lyman[1992] RCFmanufacturing 286 Breathingzone 0.69 — —

4 Breathingzone 4.02 1.82 —

126 Breathingzone 0.81 — AMD=0.6µm

— — AML=13.8µm

24 Breathingzone 1.65 — —

O’Brienetal.[1990] Steelfoundry 48 Fibersinaninsu-latingblanket

— — D=<1.5µm(81%offibers)

— — L=4-64µm(77%offibers)

54 Fibersinsettleddust

— — D=<0.5µm(73%offibers)

— — L=4-64µm(62%offibers)

CantorandGorman[1987]

Powerplant 4 Breathingzone 0.26 0.08 D=0.5-2.0µm(73%offibers)

2 Area 0.08 0.01 L=>20µm(60%offibers)

Gorman[1987] Foundry 7 Breathingzone 0.1 0.06 D=<2µm(96%offibers)

5 Area 0.4 0.26 L=<20µm(80%offibers)

Hewett[1996] Railroadcarwheelandaxlemanufac-turer

6 Breathingzonenearheattreatmentplant

0.024 0.012

—

14 BreathingzoneduringRCFremoval

1.44 0.84—

1 Breathingzone 3.04† — —

1.7‡ — MeanD=0.71(SD=0.44)

— — MeanL=11.9(SD=11.3)

*Abbreviations:AMD=arithmeticmeandiameter;AML=arithmeticmeanlength;D=diameter;L=length;RCFs=refractoryceramicfibers;SD=standarddeviation.†Measuredbyphrasecontrolopticalmicroscopy(PCM).‡Measuredbytransmissionelectronmicroscopy(TEM).



4.5.8 Discussion

Recentandhistoricalenvironmentalmonitor-ingdata[Esmenetal.1979;CantorandGor-man1987;Gorman1987;O=Brienetal.1990;Chengetal.1992;Brown1992;Cornetal.1992;Lyman1992;Allshouse1995;Hewett1996]in-dicate that airborne concentrations of RCFsinclude fibers in the thoracic and respirablesizerange(<3.5µmindiameterand<200µmlong [Timbrell 1982; Lippmann 1990; Baron1996]).Workersareexposedtotheseconcen-trations during primary RCF manufacturing,secondary manufacturing or processing, andend-use activities such as RCF installationand removal. Sampling data from studies ofdomestic primary RCF manufacturing sitesindicatethataverageairbornefiberconcentra-tionshavesteadilydeclinedbynearly2ordersofmagnitudeoverthepast2decades.Riceetal. [1997] reportanestimatedmaximumair-borne concentration of 10 f/cm3 associatedwith an RCF manufacturing process in the1950s.Esmenetal.[1979]recognizedaverageexposureconcentrationsrangingfrom0.05to2.6 f/cm3 in RCF manufacturing facilities inthemid-tolate-1970s.Duringthelate1980s,Riceetal. [1994,1996,1997]calculatedaver-ageairborneconcentrationsinmanufacturingfacilitiesthatrangedfrom<LODto0.66f/cm3.Maxim et al. [1994, 1997, 2000a] report thatfromthelate1980sthrough1997,concentra-tionsrangedfromanAMof<0.3to0.6f/cm3(GM0.2f/cm3).

For many RCF manufacturing processes, re-ductions in exposure concentrations havebeen realized through improved ventilation,engineering or process changes, and prod-uct stewardship programs [Rice et al. 1996;Maxim et al. 1999b]. Several functional jobcategories continue to be associated with fi-ber concentrations that exceed the average;these include finishing operations during

manufacturing, removal operations, and in-stallation performed by end users.Activitiesin these three categories require additionalmechanical energy in handling RCF prod-ucts(e.g., sawing,drilling,cutting,sanding),which increases the generation of airbornefibers.Removalandinstallationactivitiesareperformedatremotesiteswhereconventionalengineering strategies and fixed controls aremoredifficulttoimplement.Forcertainoper-ationsinwhichairbornefiberconcentrationsaregreater(suchasremovalofRCFproductsfromfurnaces),jobsareperformedforshortperiodsandalmostuniversallywiththeuseofrespiratoryprotection[Maximetal.1998].

One additional consideration during workinvolving RCF exposure is the potential forexposure to respirable silica in the forms ofquartz, tridymite, and cristobalite. Althoughthe potential for such exposure exists in pri-marymanufacturing(becausesilicaisamajorcomponentofRCFs),monitoringdataindicatethattheseexposuresaregenerallylow[Riceetal. 1994]. Maxim et al. [1999a] reported thatmany airborne silica samples collected to as-sessexposuresduringinstallationandremovalofRCFproductscontainconcentrationsbelowtheLOD,withaverageconcentrationsofrespi-rable silica ranging from 0.01 to 0.44 mg/m3(equivalent 8-hr TWA range=0.004 to 0.148mg/m3).Otherstudiesindicateagreaterpoten-tialforexposuretorespirablesilica(especiallyintheformofcristobalite)duringremovalofafter-service RCF materials [Gantner 1986;Chengetal.1992;Perraultetal.1992;vandenBergenetal.1994;SweeneyandGilgrist1998].Processesassociatedwithhighconcentrationsofairbornefibersgenerallygeneratehighcon-centrationsoftotalandrespirabledustaswell[Esmenetal.1979;Krantzetal.1994].


5 Effects of Exposure

Animalstudiesreporttheconcentration(s)towhichtheanimalswereexposed.Thedistinc-tion between administered exposure concen-tration and received dose is important whenanalyzingthesestudies.Thedoseaffectingthetargettissuesisknownonlywhentheamountof fiber present in the lung is measured andreported.Toanalyze the resultsofRCFstud-ies,thenumberoffibersperexposure,theirdi-mensions,durabilities,andthedelivereddoseshouldbeconsideredformakingcomparisonsandconclusionsregardingpotentialandrela-tivetoxicity.

5.1.1 Intrapleural, Intraperitoneal, and Intratracheal Studies

Instillation and implantation studies deliverfibersdirectlytothetrachea,pleuralcavity,orperitonealcavity,bypassingsomeofthedefenseandclearancemechanismsthatactoninhaledfibers. Implantation of fibers into either thepleuralorabdominalcavitiesdeliversfibersdi-rectlytothepleuralorabdominalmesothelium,bypassingsomeorallofthenormaldefenseandclearancemechanismsoftherespiratorytract.Intratrachealinstillationdeliversfibersdirectlytothetrachea,bypassingtheupperrespiratorytract. These exposure methods do not mimicanoccupationalinhalationexposureofseveralhours per day for several days per week overan extended period. However, one advantageof these studies is that they allow the admin-istrationofaprecisedoseoffibersthatcanbereplicated between animals. They also permittheadministrationofhigherdosesthanmaybeobtainablebyinhalationexposure.

5.1 Health Effects in Animals (In Vivo Studies)

ThehealtheffectsofRCFexposureshavebeenevaluated inanimal studiesusing intrapleural,intraperitoneal, intratracheal, and inhalationroutesofexposure.Alloftheserouteshavedem-onstrated the carcinogenic potential of RCFs.Chronicinhalationstudiesprovideinformationthatismostrelevanttotheoccupationalrouteofexposureandhumanriskassessment.Mech-anisticinformationaboutfibertoxicitymayalsobederivedfromothertypesofstudies.StudiesinvestigatingthecellulareffectsofRCFsinvitroarereviewedinSection5.2andAppendixC.

Whencomparingtheeffectsofafiberdose inanimalstudies, it ispossible tocomparefibersonagravimetricbasis (effectperunitweight)or a fiber basis (effect per number of fibers).The same gravimetric dose of different fibertypesmaycontainvastlydifferentnumbersoffibers because of differences in their dimen-sions.RCF1isarelativelythickfibercomparedwithmanytypesofasbestos,suchaschrysotile,afibercommonlyusedasapositivecontrolinpulmonarycarcinogenesisexperiments inani-mals (see Table 2–2 for descriptions of RCF1,RCF2,RCF3,andRCF4).AgravimetricdoseofRCF1usuallycontainsfarfewerfibersthanthesamegravimetricdoseofchrysotileasbestosfi-bers,makingadirectcomparisonoftheireffectsdifficult when the number of fibers per unitweight isnot reported.Comparisononaper-fiberbasis rather thanaweightbasisprovidesinformation most applicable to occupationalriskassessment.


5 ■Effects of Exposure

Although the results of implantation and in-stillationstudiesmaynotbedirectlyapplicableto occupational exposure and human healtheffects, they provide important informationabout the potential toxicity of RCFs. Experi-mentsthatcontrolfiberdimensionsandothervariablesprovideinformationaboutthephysi-ological characteristics relevant to fiber tox-icity. They provide a less expensive, quickermeanstoscreenthepotentialtoxicityofafiberthaninhalationstudies.

Manyoftheimplantationandinstillationstud-iesreviewedherereporttheadministeredfiberdoseonagravimetricbasisratherthanonaper-fiber basis. Some studies assess the toxicity ofboth RCFs and asbestos independently, whichallows for thecomparisonof thesefibersonagravimetricbasisbutnotonaper-fiberbasis.

5.1.1.1 IntraperitonealImplantationStudies

Inintraperitonealstudies,fibersareimplanteddirectly into the abdominal cavity, bypassingthe respiratory system defense and clearancemechanisms that act on inhaled fibers. Al-thoughtheimplantedfibersactonsomeofthesametargetcelltypesasthefibersofaninhala-tionexposure(suchas themesothelium), theeffectselicitedintheabdominalmesotheliumcannot be assumed to be identical to the re-sponseofthepleuralmesothelium.Table5–1summarizestheresultsofthreeRCFintraperi-tonealimplantationstudies[Davisetal.1984;Smithetal.1987;Pottetal. 1987].Abriefde-scriptionofthesestudiesfollows.

Davisetal.[1987]dosedWistarratswith25mgceramic aluminum silicate dust by intraperi-tonealinjection.Tumorswereinducedin3of32rats:2fibrosarcomasand1mesothelioma.Smith et al. [1987] dosed Osborne Mendel(OM) rats and Syrian hamsters with 25 mgRCFs by intraperitoneal injection. Abdomi-nal mesothelioma induction rates were 83%

(19/23)inOMratsand13%(2/15)and24%(5/21) in two groups of male hamsters. Cro-cidoliteasbestosat25mginducedabdominalmesotheliomasin80%(20/25)ofOMratsand32%(8/25)ofhamsters.Thedifferenceintu-morincidencereportedbyDavisetal.[1984]andSmithetal.[1987]maybeexplainedinpartbydifferencesinfiberlength.Eighty-threeper-centofRCFfibersusedbySmithetal.[1987]had a length >10 µm; 86% had a diameter<2.0µm.Ninetypercentoftheceramicalumi-numsilicatematerialusedbyDavisetal.[1984]hadalength<3µmandadiameter<0.3µm.

Pottetal.[1987]dosedfemaleWistarratsbyintraperitonealinjectionwith9or15mg/weekfor 5weeks with 2ceramic (aluminum sili-cate)woolfibers,Fibrefrax(RCFs),andMAN(ManvilleRCFs);totaldosesof45and75mgwere administered, respectively. Fifty percentofFibrefraxfibershada length<8.3µmanddiameter<0.91µm.Exposure toFibrefraxfi-bers induced abdominal tumors (sarcomas,mesotheliomas,orcarcinomas)in68%oftherats.FiftypercentofMANfibershadalength<6.9µmanddiameter<1.1µm.Thenumberoffibersindifferentlengthcategorieswasnotreported.ExposuretoMANfibersinducedab-dominaltumorsin22%oftherats.Chrysotile(UICC/B)injectedintraperitoneallyatasingledoseof0.05,0.25,or1.00mginducedabdomi-nal tumors in 19%, 62%, or 86% of rats, re-spectively.Fiftypercentofchrysotilefibershadalength<0.9µmanddiameter<0.11µm.Thenumberoffibersperdosewasnotreportedfortheceramicfibersandasbestos.Salineinducedtumorsin2%ofrats.

5.1.1.2 Intrapleural Implantation Studies

Intrapleural implantation studies permit theinvestigation of the effect of RCFs directlyonthepleuralmesotheliumwhilecontrollingvariablessuchasinhalationkineticsandtrans-location.



Tabl

e 5–

1 . I

ntr

aper

iton

eal i

mp

lan

tati

on s

tud

ies

of R

CFs

* in a

nim

als

Ref

eren

ce

Spec

ies

Nu

mb

er a

nd

sex

p

er g

rou

p

Fib

er d

ose

Fib

er d

imen

sion

s (µ

m)

Tu

mor

inci

den

ce

Dav

ise

tal

.

[198

4]W

ista

rra

ts

32,s

exu

nsp

ecifi

ed25

mg

cera

mic

fibe

rs

(a

lum

inu

ms

ilica

teg

lass

)

L=90

%<

3

D=

90%

<0.

31

mes

oth

elio

ma

2fi

bros

arco

mas

Firs

ttu

mor

occ

urr

ed8

50d

ays

p

osti

nje

ctio

n.

Pott

et

al.

[1

987]

Wis

tar

rats

47

,fem

ale

54

,fem

ale

36

,fem

ale

102,

fem

ale

9m

g(×

5)=

45m

gR

CFs

(Fib

refr

ax)

15m

g(×

5)=

75m

gM

anvi

lle

R

CFs

(M

AN

)

1m

gU

ICC

/Bc

hry

soti

le

2

mls

alin

e(×

5)=

10m

l

L=

50%

<8.

3

D=

50%

<0.

91

L=50

%<

6.9

D

=50

%<

1.1

L=

50%

<0.

9

D=

50%

<0.

11

N

A

32m

esot

hel

iom

as,s

arco

mas

,or

ad

enom

aso

fth

eab

dom

inal

ca

vity

12m

esot

hel

iom

as,s

arco

mas

,or

ad

enom

aso

fth

eab

dom

inal

ca

vity

31m

esot

hel

iom

as,s

arco

mas

,or

ad

enom

aso

fth

eab

dom

inal

cav

ity

2m

esot

hel

iom

as,s

arco

mas

,or

aden

omas

of

the

abdo

min

al

cavi

ty

Smit

he

tal

.

[1

987]

Osb

orn

e

Men

delr

ats

23

,fem

ale

25m

gR

CFs

(Fi

bref

rax)

G

ML=

25.0

L=83

%>

10

G

MD=

0.9

D

=80

%<

2

20a

bdom

inal

mes

oth

elio

mas

See

foot

not

esa

ten

dof

tab

le.

(Con

tin

ued

)



Tabl

e 5–

1 (C

onti

nu

ed) .

In

trap

erit

onea

l im

pla

nta

tion

stu

die

s of

RC

Fs*

in a

nim

als

Ref

eren

ceSp

ecie

sN

um

ber

an

d s

ex

per

gro

up

Fib

er d

ose

Fi

ber

dim

ensi

ons

(µ

m)

Tum

or in

cid

ence

Smit

he

tal

.[

1987

](

con

tin

ued

)

25,f

emal

e25

,fem

ale

125,

fem

ale

25m

gU

ICC

cro

cido

lite

0.5

mlp

hysi

olog

ical

sal

ine

Cag

eco

ntr

ols

Mea

nL

=3.

1(S

D,1

0.2)

L=95

%≤

5N

A N

A

20a

bdom

inal

mes

oth

elio

mas

0

abdo

min

alm

esot

hel

iom

as 0

abdo

min

alm

esot

hel

iom

as

Syri

an

go

lden

ham

ster

s

15,m

ale

25m

gR

CF

(Fib

refr

ax)

L=83

%>

10G

ML=

25.0

D=

80%

<2

GM

D=

0.9

2ab

dom

inal

mes

oth

elio

mas

21,m

ale

25m

gR

CFs

GM

L=25

.0L=

83%

>10

GM

D=

0.9

D=

80%

<2

5ab

dom

inal

mes

oth

elio

mas

25,m

ale

25m

gU

ICC

cro

cido

lite

Mea

nL

=3.

1(S

D,1

0.2)

L=

95%

≤5

8ab

dom

inal

mes

oth

elio

mas

25,m

ale

112,

mal

e

0.5

mlp

hysi

olog

ical

sal

ine

Cag

eco

ntr

ols

NA

NA

0ab

dom

inal

mes

oth

elio

mas

0ab

dom

inal

mes

oth

elio

mas

* Abb

revi

atio

ns:

D=

diam

eter

;GM

D=

geom

etri

cm

ean

dia

met

er;G

ML=

geom

etri

cm

ean

len

gth

;L=

len

gth

;NA

=n

ota

pplic

able

;RC

Fs=

refr

acto

ryc

eram

icf

iber

s;

SD

=st

anda

rdd

evia

tion

;UIC

C=

Un

ion

In

tern

atio

nal

eC

ontr

ele

Can

cer;

UIC

C/B

=U

nio

nI

nte

rnat

ion

ale

Con

tre

leC

ance

r/Ty

pe

B.



Table 5–2 summarizes the results of the in-trapleural study of Wagner et al. [1973]. In-trapleuralinjectionof20mgofceramicfiber(unspecified type) or 20 mg for each of twosamplesofchrysotileproducedmesotheliomasin10%(3/31),64%(23/36),and66%(21/32)ofWistarrats,respectively.Themeanceramicfiberdiameterwas0.5to1.0µm.Thelengthsofthechrysotilefibersweremostly<6µm.Thechrysotilefiberdiameter,RCFfiberlength,andnumberoffibersperdosewerenotreported,making a direct comparison of the samplesdifficult.

5.1.1.3 Intratracheal Instillation Studies

Thetechniqueofintratrachealinstillationhastheadvantageofaffectingthesametargettis-sues (other than the upper respiratory tract)as an inhalation exposure. Other advantages,compared with inhalation exposure, includeasimplertechnique,lowercost,accuratedos-ing, and theability todelivermaterials (suchas long fibers) that may not be respirable torodents[Driscolletal.2000].The fasterdoserateandbolusdeliveryoftrachealinstillationmay affect the response of the lung defensemechanisms, resulting indifferences inclear-anceandbiopersistence relative toan inhala-tion exposure. Intratracheal instillation mayalsoproduceaclumpingoffiberswitharesult-ing effect on fiber distribution and clearance[Davisetal.1996;Driscolletal.2000].Intra-tracheal instillationresults inaheavier,morecentralizeddistributionpattern;inhalationex-posureresultsinamoreevenlyandwidelydis-tributedpattern[Brainetal.1976].Table5–3summarizes the results of two RCF intratra-cheal instillation studies [Smith et al. 1987;Manville 1991]. A brief description of thesestudiesfollows.

In the study by Smith et al. [1987], SyriangoldenhamstersandOMratsweredosedwith2mgofRCFssuspendedinsaline(Fibrefrax)

by intratracheal instillation once a week for5weeks(10mgtotal).Theanimalsweremain-tainedfortherestoftheirlives.Approximately50%oftheRCFswere<20µmlongwithameanfiberdiameterof1.8µm.Noprimarylungtu-morsdevelopedinRCF-exposedanimals.Theseanimalsdidnothaveanincreasedincidenceofpulmonaryfibrosisortumorproductioncom-paredwithcontrols;however,theratshadasta-tisticallysignificantincreaseinbronchoalveolarmetaplasia. The median lifespan was 479 daysfor hamsters and 736 days for rats. Hamsters(median lifespan 657 days) and rats (medianlifespan663days)exposedtothesamedosingschedule with 2 mg crocidolite asbestos had astatisticallysignificantincreaseinbronchoalve-olarlungtumorsin20of27(74%)and2of25(8%) animals, respectively. The fiber numbersperdosewerenotreported.

Manville[1991]reportedastatisticallysignifi-cantincreaseinlungtumorsinFischerratsex-posedintratracheallyto2mgofRCF1,RCF2,RCF3,andRCF4insaline[Manville1991].An-imals were terminally sacrificed at 128 weekswithinterimsacrificesat13,26,52,78,and104weeks.RCF1,RCF2,RCF3,andRCF4exposureresulted in adenomas or adenocarcinomasin6of109(5.5%),4of107(3.7%),4of109(3.7%),and7of108(6.5%)rats,respectively.Onemesotheliomawasidentifiedinaratex-posedtoRCF2.Exposureto0.66mgchrysotileasbestosresultedin8primarylungtumorsin8of55rats(14.5%).Thefiberdimensionsandnumbersperdosewerenotreported.

5.1.2 ChronicInhalationStudies

In animal bioassays, administering RCFs bychronic inhalation most closely mimics theoccupational route of exposure. Exposure toRCFsoveratimeperiodthatapproximatesthelifespanoftheanimalprovidesthemostaccu-ratepredictionof thepotentialpathogenicityandcarcinogenicityofthesefibersinanimals.



Table 5–2 . Intrapleural study of RCFs* in animals

Reference SpeciesNumber

per group† Fiber doseFiber dimensions

(µm) Tumor incidence

Wagneretal. [1973]

Wistarrats 31

35

35

35

36

32

20mgceramicfibers (aluminumsilicate)

20mgaluminumoxide20mgfiberglass20mgglasspowder20mgCanadianchrysotile20mgCanadianchrysotile

D=0.5–1.0 AreaD=<10 L=60%>20 D=55%2.5–7 AreaD=<8 L=92%<6 L=92%<6

3mesotheliomas1mesothelioma0mesotheliomas1mesothelioma23mesotheliomas21mesotheliomas

*Abbreviations:D=diameter;L=length;RCFs=refractoryceramicfibers.†Thesexratioforallgroupswasapproximately2maleratsto1femalerat.



Tabl

e 5–

3 . I

ntr

atra

chea

l stu

die

s of

RC

Fs* in

an

imal

s

Ref

eren

ce

Spec

ies

Nu

mb

er a

nd

se

x p

er g

rou

pFi

ber

dos

eFi

ber

dim

ensi

ons

(µm

)Tu

mor

inci

den

ce

Man

ville

[

1991

]Fi

sch

er3

44r

ats

109,

mal

e

107,

mal

e

109,

mal

e

108,

mal

e

55,

mal

e

118,

mal

e

2m

gR

CF1

(0.2

mlo

fa

10-m

g/m

lsu

spen

sion

) 2

mg

RC

F2

(0

.2m

lof

a10

-mg/

mls

usp

ensi

on)

2m

gR

CF3

(0.2

mlo

fa

10-m

g/m

lsu

spen

sion

) 2

mg

RC

F4

(0

.2m

lof

a10

-mg/

mls

usp

ensi

on)

0.66

mg

Can

adia

nc

hry

soti

le

(0

.2m

lof

a3.

3-g/

mls

usp

ensi

on)

0.2

ml

(v

ehic

len

ots

pec

ified

)

NR

NR

NR

NR

NR

NR

6lu

ng

aden

omas

4lu

ng

tum

ors:

3ad

enom

as

1

carc

inom

a

1m

esot

hel

iom

a

4

lun

gtu

mor

s:

2

aden

omas

2ca

rcin

omas

7lu

ng

aden

omas

8lu

ng

tum

ors:

4ad

enom

as

4

carc

inom

as

0

lun

gtu

mor

s

See

foot

not

esa

ten

dof

tab

le.

(Con

tin

ued

)



Tabl

e 5–

3 (C

onti

nu

ed) .

In

trat

rach

eal s

tud

ies

of R

CFs

* in a

nim

als

Ref

eren

ce

Spec

ies

Nu

mb

er a

nd

sex

per

gro

up

Fi

ber

dos

eFi

ber

dim

ensi

ons

(µm

)

Tum

or in

cid

ence

Smit

he

tal

.

[198

7]O

sbor

ne

Men

delr

ats

22

,fem

ale

25

,fem

ale

25

,fem

ale

12

5,fe

mal

e

10m

gR

CFs

(Fi

bref

rax)

(2m

g/w

eek

×5

=10

mg)

10m

gU

ICC

* cro

cido

lite

(2

mg/

wee

k×

5=

10m

g) Sa

line

con

trol

s C

age

con

trol

s

GM

L=25

.0

GM

D=

0.9

L=3%

>10

D

=80

%<

2 L=

95%

≤5

mea

nL

=3.

1(S

D,1

0.2)

NA

NA

0lu

ng

tum

ors

2br

onch

oalv

eola

rtu

mor

s 0

lun

gtu

mor

s 0

lun

gtu

mor

s

Syri

ang

olde

nh

amst

ers

25

,mal

e

27,m

ale

24

,mal

e

112,

mal

e

10m

gR

CFs

(Fi

bref

rax)

(2m

g/w

eek

×5

=10

mg)

10m

gU

ICC

cro

cido

lite

(2m

g/w

eek

×5

=10

mg)

Salin

eco

ntr

ols

Cag

eco

ntr

ols

GM

L=25

.0

GM

D=

0.9

L=

83%

>10

D

=80

%<

2

mea

nL

=3.

1(S

D,1

0.2)

L=

95%

≤5

N

A N

A

0lu

ng

tum

ors

20b

ron

choa

lveo

lar

tum

ors

0lu

ng

tum

ors

0lu

ng

tum

ors

* Abb

revi

atio

ns:

D=

diam

eter

;GM

D=

geom

etri

cm

ean

dia

met

er;G

ML=

geom

etri

cm

ean

len

gth

;L=

len

gth

;NA

=n

ota

pplic

able

;NR

=n

otr

epor

ted;

RC

Fs=

refr

acto

ry

c

eram

icfi

bers

;SD

=st

anda

rdd

evia

tion

;UIC

C=

Un

ion

In

tern

atio

nal

eC

ontr

ele

Can

cer.



The effects seen in animals may be used topredict the effects of these fibers in humans,although interspecies differences exist in re-spiratoryanatomy,physiology,andtissuesen-sitivity.Chronicinhalationstudiesprovidethebestmeanstopredictthecriticaldiseaseend-pointsofcancerinductionandnonmalignantrespiratorydiseasethatmayoccurinhumansbecause of fiber exposure [McConnell 1995;Vuetal.1996].

FivechronicRCFinhalationstudieshavebeenconducted on rats or hamsters [Davis et al.1984;Smithetal.1987;Mastetal.1995a,b;Mc-Connelletal.1995].Thesestudiesaresumma-rizedinTables5–4and5–5andaredescribedbelow.

Davis et al. [1984] exposed Wistar rats bywhole-bodyinhalationto10mg/m3(95f/cm3)ceramic (aluminum silicate glass) dust for7 hr/day, 5 days/week for 12 months. Ninetypercentoftheexposurefiberswereshort(<3µm)andthin(<0.3µm).Theparticleratioofnonfibrousparticulatetofiberswas4:1.Eightof 48 exposed rats (17%) developed pulmo-naryneoplasms:1adenoma,3bronchialcarci-nomas,and4histiocytomas.Interstitialfibro-siswasobserved.Nopulmonarytumorswereobservedincontrolanimals.

Smithetal.[1987]exposedOMratsandSyr-ian golden hamsters by nose-only inhala-tion to 10.8±3.4 mg/m3 (200 f/cm3) ceramicfiber(Fibrefrax)for6hr/day,5days/weekfor24months.Theratioofnonfibrousparticulateto fibers was 33:1. Exposure to RCFs did notinduce pulmonary tumors in rats. One RCF-exposedratandonechambercontrol ratde-velopedprimarylungtumors.RatsexposedtoRCFshadmoreseverepulmonarylesionsthanhamsters,andagreaterpercentageofratshadfibrosisthanhamsters(22%versus1%,respec-tively).Undersimilarconditions,exposure to7 mg/cm3 (3,000 f/cm3) crocidolite asbestosproduced pulmonary tumors in 3 of 57 rats,

including 1 mesothelioma and 2 bronchoal-veolar tumors. No pulmonary tumors wereobservedincrocidolite-exposedhamsters.Ex-posure to slag wool at 10 mg/m3 (200f/cm3)andseveralfibrousglassesatsimilargravimet-ricconcentrationsdidnotresultinpulmonaryneoplasms(notshowninTable5–4).

Mast et al. [1995a] exposed Fischer 344 ratsbynose-onlyinhalationto30mg/m3(187±53WHOf/cm3RCF1,220±52WHOf/cm3RCF2,182±66 WHO f/cm3 RCF3, 153±49 WHOf/cm3RCF4)ofoneoffourtypesofRCFsfor6hr/day,5days/weekfor24monthsandhelduntilsacrificeat30months.Groupsof3to6animals were sacrificed at 3, 6, 9, 12, 15, 18,and24monthstoexaminelesionsanddeter-minefiber lungburdens.Otheranimalswereremoved from exposure at the same timepoints and held until sacrifice at 24 months.Positivecontrolratswereexposedto10mg/m3(1.06±1.14×104WHOf/cm3)chrysotileundersimilarexposureconditions.RCFfiberswithameandiameterof1µmandmeanlengthof20to30µmwereselected.Aparticleratioofnon-fibrousparticulatetofiberof1.02–1.88:1wasreported.Interstitialfibrosiswasfirstobservedat6monthswithRCF1,RCF2,andRCF3andat 12 months with RCF4 exposure. Pleuralfibrosis was first observed at 9 months withRCF1,RCF2,andRCF3andat12monthswithRCF4exposure.Aprogression in the severityofpleuralfibrosiswasseeninanimalsexposedto30mg/m3for24monthsandexaminedat6monthspostexposure.Theincidenceoftotallung tumors was significantly increased fromcontrols after exposure to RCF1, RCF2, andRCF3butnotRCF4.Neoplasticdisease,includ-ingadenomasandcarcinomas,wasobservedinalltreatmentgroups:withRCF1,in16of123rats(13%);RCF2,9of121(7.4%);RCF3,19of121(15.7%);RCF4,4of118(3.4%);andchrys-otile, 13 of 69 (18.5%). Mesotheliomas wereinducedinsomeratsinalltreatmentgroups:2withRCF1;3withRCF2;2withRCF3;1with



Tabl

e 5–

4 . C

hro

nic

inh

alat

ion

stu

die

s of

RC

Fs* in

an

imal

s

Ref

eren

ce

Spec

ies

Nu

mb

er a

nd

sex

p

er g

rou

pFi

ber

dos

eFi

ber

dim

ensi

ons

(µm

)Tu

mor

inci

den

ce

Dav

ise

tal

.

[198

4]W

ista

rra

ts48

,sex

un

spec

ified

10m

g/m

3 cer

amic

fibe

rs

(a

lum

inu

ms

ilica

teg

lass

)95

fibe

rs/c

m3

L~90

%<

3D

~90

%<

0.3

8pu

lmon

ary

tum

ors:

1

aden

oma

3

bron

choa

lveo

lar

ca

rcin

omas

4h

isti

ocyt

omas

16n

onpu

lmon

ary

tum

ors:

8

ben

ign

8

mal

ign

ant

1

per

iton

eal

m

esot

hel

iom

a40

,sex

un

spec

ified

Con

trol

NA

No

pulm

onar

ytu

mor

s

Non

pulm

onar

ytu

mor

s:

11b

enig

n

9m

alig

nan

t

Mas

tet

al.

[1

995a

]Fi

sch

er3

44r

ats

123,

mal

e29

.1(

SD,5

.2)

mg/

m3 R

CF1

234

(SD

,35)

tota

lf/c

m3

187

(SD

,53)

WH

O† f/

cm3

mea

nL

=22

.3(

SD,1

7.0)

mea

nD

=0.

98(

SD,0

.61)

16lu

ng

tum

ors:

8

aden

omas

8

carc

inom

as

2

pleu

ralm

esot

hel

iom

as12

1,m

ale

28.9

(SD

,4.5

)m

g/m

3 RC

F226

8(

SD,4

5)to

talf

/cm

3

220

(SD

,52)

WH

Of/

cm3

mea

nL

=18

.7(

SD,1

5.5)

mea

nD

=1.

07(

SD,0

.69)

9lu

ng

tum

ors:

4ad

enom

as

5

carc

inom

as

3

pleu

ralm

esot

hel

iom

as

See

foot

not

esa

ten

dof

tab

le.

(Con

tin

ued

)



Tabl

e 5–

4 (C

onti

nu

ed) .

Ch

ron

ic in

hal

atio

n s

tud

ies

of R

CFs

* in

an

imal

s

Ref

eren

ce

Spec

ies

Nu

mb

er a

nd

sex

p

er g

rou

p

Fib

er d

ose

Fi

ber

dim

ensi

ons

(µm

)

Tum

or in

cid

ence

121,

mal

e29

.2(

SD,7

.0)

mg/

m3 R

CF3

213

(SD

,44)

tota

lf/

cm3

182

(SD

,66)

WH

Of/

cm3

mea

nL

=24

.2(

SD,1

7.9)

mea

nD

=1.

05(

SD,0

.7)

19lu

ng

tum

ors:

10

ade

nom

as

9

carc

inom

as

2

pleu

ralm

esot

hel

iom

as

118,

mal

e30

.1(

SD,7

.8)

mg/

m3 R

CF4

206

(SD

,48)

tota

lf/c

m3

153

(SD

,49)

WH

Of/

cm3

mea

nL

=12

.7(

SD,9

.9)

mea

nD

=1.

38(

SD,0

.7)

4lu

ng

tum

ors:

2ad

enom

as

2ca

rcin

omas

1pl

eura

lmes

oth

elio

ma

13

0, m

ale

Air

on

lyN

A2

lun

gad

enom

as

Mas

tet

al.

[19

95b]

Fisc

her

344

rat

s13

1, m

ale

3.0

(SD

,0.4

)m

g/m

3 RC

F136

(SD

,17)

f/cm

3

26(

SD,1

2)W

HO

f/cm

3

mea

nL

=19

.88

(SD

,17

.93)

mea

nD

=1.

03(

SD,0

.73)

2lu

ng

aden

omas

134,

mal

e8.

8(S

D,0

.7)

mg/

m3

91(

SD,3

4)f/

cm3

75(

SD,3

5)W

HO

f/cm

3

mea

nL

=20

.54

(SD

,17.

08)

mea

nD

=1.

04(

SD,0

.72)

5lu

ng

tum

ors:

4ad

enom

a

1ca

rcin

oma

1

mes

oth

elio

ma

132,

mal

e16

.5(

SD,1

.1)

mg/

m3 R

CF

162

(SD

,37)

f/cm

3

120

(SD

,35)

WH

Of/

cm3†

mea

nL

=20

.11

(SD

,16.

87)

mea

nD

=1.

06(

SD,0

.72)

2lu

ng

tum

ors:

1ad

enom

a

1ca

rcin

oma

132,

mal

eA

iro

nly

NA

1lu

ng

aden

oma

See

foot

not

esa

ten

dof

tab

le.

(Con

tin

ued

)



Tabl

e 5–

4 (C

onti

nu

ed) .

Ch

ron

ic in

hal

atio

n s

tud

ies

of R

CFs

* in a

nim

als

Ref

eren

ce

Spec

ies

Nu

mb

er a

nd

sex

p

er g

rou

pFi

ber

dos

eF

iber

dim

ensi

ons

(µm

)

Tum

or in

cid

ence

McC

onn

elle

tal

.

[199

5]Sy

rian

gol

den

h

amst

ers

102,

mal

e30

mg/

m3 R

CF1

256

(SD

,58)

f/cm

3

215

(SD

,56)

WH

Of/

cm3

mea

nL

=22

.12

(SD

,6.7

)m

ean

D=

0.94

(SD

,0.6

3)42

ple

ura

lmes

oth

elio

mas

49, m

ale

10m

g/m

3 ch

ryso

tile

,Can

adia

n8.

4(S

D,9

.0)×

104 f/

cm3

3.0

(SD

,1.4

)×10

3 WH

Of/

cm3

mea

nL

=1.

68(

SD,2

.71)

mea

nD

=0.

09(

SD,0

.06)

Non

e

106,

mal

eN

egat

ive

con

trol

sN

AN

one

Smit

he

tal

.

[1

987]

Osb

orn

e-M

ende

l

ra

ts

55

, fem

ale

10.8

mg/

m3R

CFs

(Fi

bref

rax)

,

200

f/cm

3

GM

L=

25G

MD=

0.9

Non

e

57, f

emal

e7

mg/

m3 U

ICC

cro

cido

lite,

3,

000

f/cm

3

L=95

%≤

51

mes

oth

elio

ma

2br

onch

oalv

eola

rtu

mor

s

59, f

emal

eC

ham

ber

con

trol

sN

AN

one

125,

fem

ale

Roo

mc

ontr

ols

NA

Non

e

Syri

ang

olde

n

ham

ster

s70

,mal

e10

.8m

g/m

3 RC

Fs(

Fibr

efra

x),

20

0f/

cm3

GM

L=25

GM

D=

0.9

1m

esot

hel

iom

a

58,m

ale

7m

g/m

3 UIC

Cc

roci

dolit

e,

3,00

0f/

cm3

L=91

%≤5

Non

e

58,m

ale

Ch

ambe

rco

ntr

ols

NA

1br

onch

oalv

eola

rtu

mor

112,

mal

eR

oom

con

trol

sN

AN

one

* Abb

revi

atio

ns:

D=

diam

eter

;GM

D=

geom

etri

cm

ean

dia

met

er;

GM

L=ge

omet

ric

mea

nle

ngt

h;L

=le

ngt

h;N

A=

not

app

licab

le,R

CFs

=re

frac

tory

cer

amic

fibe

rs;

U

ICC

=U

nio

nI

nte

rnat

ion

ale

Con

tre

leC

ance

r;W

HO

=W

orld

Hea

lth

Org

aniz

atio

n.

† W

HO

fibe

rsh

ave

diam

eter

s<

3µm

,len

gth

s>

5µm

,an

das

pec

tra

tios

>3:

1[W

HO

198

5].



Tabl

e 5–

5 . N

ontu

mor

lun

g ef

fect

s in

an

imal

s ex

pos

ed to

RC

Fs* b

y in

hal

atio

n

Ref

eren

ceSp

ecie

s

Fib

rosi

s

Lun

g ch

ange

s

Lu

ng

fib

er b

urd

en

Dav

ise

tal

.

[198

4]W

ista

rra

ts

Min

imal

per

ibro

nch

iola

r

fibr

osis

Inte

rsti

tial

fibr

osis

at

fin

al

sacr

ifice

Mea

n%

of

lun

gar

ea

(n=

6ra

ts)=

5.0%

Ran

ge=

0.2%

–14.

5%

Larg

ear

eas

ofa

lveo

lar

pr

otei

nos

is

Foam

yan

dag

greg

ated

m

acro

phag

es

Mea

n=

4,13

0µg

n=

4ra

ts

R

ange

=2,

800–

6,80

0µg

Mas

tet

al.

[1

995a

]Fi

sch

er3

44r

ats

Inte

rsti

tial

fibr

osis

see

na

t

3m

onth

s(R

CFs

)

6m

onth

s(R

CF2

,RC

F3)

12

mon

ths

(RC

F4)

Ple

ura

lfibr

osis

see

na

t

9m

onth

s(R

CF1

,RC

F2,R

CF3

)

12m

onth

s(R

CF4

)

Alv

eola

rbr

onch

ioliz

atio

n,

mic

rogr

anu

lom

as,c

olla

gen

depo

siti

on,a

nd

alve

olar

m

acro

phag

ede

posi

tion

w

ere

seen

at

6

mon

ths

(RC

F1)

9

mon

ths

(RC

F2,R

CF3

)

12m

onth

s(

RC

F4)

3.70

×10

5 RC

F1fi

bers

/mg

dry

lun

g9.

58×

105 R

CF2

fibe

rs/m

gdr

ylu

ng

2.57

×10

5 RC

F3fi

bers

/mg

dry

lun

g5.

95×

105 R

CF4

fibe

rs/m

gdr

ylu

ng

See

foot

not

eat

en

dof

tab

le.

(C

onti

nu

ed)



Tabl

e 5–

5 (C

onti

nu

ed) .

Non

tum

or lu

ng

effe

cts

in a

nim

als

exp

osed

to R

CFs

* by

inh

alat

ion

R

efer

ence

Spec

ies

Fibr

osis

Lu

ng

chan

ges

Lun

g fi

ber

bu

rden

Mas

tet

al.

[199

5b]

Fisc

her

344

rat

sR

ever

sibl

ein

ters

titi

al

fi

bros

iss

een

at

12m

onth

s

in

16-

mg/

m3 g

rou

p

Ple

ura

lfibr

osis

was

min

imal

Inte

rsti

tial

fibr

osis

pro

gres

sed

in1

6-m

g/m

3 gro

up

such

that

itw

asir

reve

rsib

le

Ple

ura

lan

din

ters

titi

al

fibr

osis

wer

eir

reve

rsib

lea

t

fin

als

acri

fice

.

Mic

rogr

anu

lom

asin

16-m

g/m

3 dos

egr

oup

at

3m

onth

s

Sim

ilar

but

less

sev

ere

in

ot

her

dos

egr

oups

Pro

gres

sion

ina

ll3

grou

ps

at

6m

onth

s

Alv

eola

rbr

onch

ioliz

atio

nin

16-m

g/m

3 gro

up

Dos

e-a

nd

tim

e-de

pen

den

t

in

crea

ses

occu

rred

inlu

ng

and

lu

ng/

body

wei

ghts

.

RC

Fsw

ere

clea

red

quic

kly

from

lun

gso

fan

imal

sw

ith

lon

g

re

cove

ryp

erio

ds.

McC

onn

elle

tal

.

[199

5]Sy

rian

gol

den

ham

ster

sP

leu

ralfi

bros

isp

late

aued

af

ter

12m

onth

sas

dif

-

fu

sed

thic

ken

ing

tor

aise

d

nod

ule

s.

Fibr

osis

see

nb

etw

een

12a

nd

18m

onth

ssh

owed

incr

ease

dse

veri

ty.

Alv

eola

rbr

onch

ioliz

atio

n,

m

icro

gran

ulo

mas

,an

d

colla

gen

dep

osit

ion

;

alve

olar

mac

roph

age

aggr

egat

ion

RC

Fbu

rden

sle

vele

dof

fbe

twee

n

9an

d12

mon

ths.

Rec

over

yan

imal

ssh

owed

dec

reas

ed

R

CF

burd

ens

wit

hd

ecre

asin

g

le

ngt

hs

and

wid

ths.

Smit

he

tal

.

[1

987]

Osb

orn

e-M

ende

l

rat

s12

/55=

22%

Bro

nch

oalv

eola

rm

etap

lasi

a,

1/5

5=2%

2.18

±0.

99×

104 fi

bers

Syri

ang

olde

n

h

amst

ers

1/70

=1%

Bro

nch

oalv

eola

rm

etap

lasi

a,

2/6

9=3%

0.86

±0.

45×

104 fi

bers

* Abb

revi

atio

n: R

CFs

=re

frac

tory

cer

amic

fibe

rs.



RCF4;and1inthechrysotileexposuregroup.Allmesotheliomasweredetectedatorafter24monthsofexposure.MostRCFfibersrecoveredinthelungwere5to10µmlongregardlessofexposuretimeandrecoverytime.An80%re-ductioninfiber lungburdenwasseeninratsallowedtorecover for21monthsfollowing3monthsofRCFexposure.

Mastetal.[1995b]exposedFischer344ratsbynose-onlyinhalationto0(air),3,9,or16mg/m3(0,26±12,75±35,or120±35WHOf/cm3)RCF1for 6 hr/day, 5 days/week for 24 months andheldthemuntilsacrificeat30months.FiberswereselectedbysizeasinMastetal.[1995a].Aparticleratioofnonfibrousparticulatetofi-bersof0.9–1.5:1wasreported.Groupsof3to6animalsweresacrificedat3,6,9,12,18,and24months toexamine lesionsanddeterminefi-berlungburdens.Otheranimalswereremovedfromexposureatthesametimepointsandhelduntilsacrificeat24months.Interstitialfibrosiswasobservedafter12monthsofexposureinthe9-and16-mg/m3exposuregroups.Pulmonaryfibrosiswasfirstobservedafter12monthswith16mg/m3exposureandafter18monthswith9mg/m3exposure.ThemeanWagnergradesofpulmonarycellularchangeandfibrosisinratsexposedto0,3,9,16,and30mg/m3ofRCFsfor24monthswere1.0,3.2,4.0,4.2,and4.0,respectively.Ratsexposedatthesamerangeofdosesfor24monthsandallowedtorecoverfor6monthshadmeanWagnergradesof1.0,2.9,3.8,4.0,and4.3.Theseverityofinterstitialandpleuralfibrosiswassimilarbetweenthoseani-malssacrificedat24monthsandthoseallowed6monthsofrecoveryfollowingthe24monthsofexposure.Theincidenceofpulmonaryneo-plasmswasnotstatisticallydifferentfromthecontrols in all exposure groups. One pleuralmesothelioma was observed in the 9-mg/m3exposure group. A dose-related increase oc-curredinfiberlungburden.Fiberlengthsof5to10µmweremostprevalentinthelungfibersrecoveredafter3monthsofexposurefollowed

by21monthsofrecovery,after12monthsofexposure,andafter24monthsofexposuretoalldosesofRCFs.Animalsexposedfor3or6monthsandthenallowedtorecoveruntilsac-rificeat24monthshadlungburdensreducedby96%to97%comparedwithanimalsnotal-lowedrecoverytime.

McConnelletal.[1995]exposedSyriangoldenhamstersbynose-onlyinhalationto30mg/m3RCF1 (256±58 WHO f/cm3) for 6 hr/day, 5days/weekfor18monthsandheldthemuntilsacrificeat20months.Positivecontrolanimalswereexposedto10mg/m3(8.4±9.0×104WHOf/cm3) chrysotile asbestos. Groups of 3 to 6animals were sacrificed at 3, 6, 9, 12, 15, and18months to examine lesions and determinefiber lung burdens. Other animals were re-movedfromexposureatthesametimepointsandhelduntilsacrificeat20months.Intersti-tialandpleuralfibrosiswerefirstobservedafter6 months of exposure in RCF-exposed ham-sters. No pulmonary neoplasms developed.Forty-two of 102 (41.2%) RCF-exposed ani-mals developed pleural mesotheliomas. Mostmesotheliomas developed after 18 months ofexposure. Animals exposed to chrysotile de-velopedamoresevere interstitialfibrosisandpleural fibrosis than those exposed to RCFs.No neoplasms were observed in the lungs orpleuraofthechrysotile-exposedoraircontrolanimals. The greatest percentage of retainedfibershad lengthsof5 to10µmanddiam-eters<5µminthelungsafter6monthsofex-posurefollowedby12monthsofrecovery.

McConnelletal.[1999]conductedamultidosechronicstudyoftheeffectsofamositeinhala-tion in hamsters. The data can be comparedwiththeeffectsofRCF1.Syriangoldenham-sterswereexposedto0.8(36±23WHOf/cm3),3.7(165±61WHOf/cm3),or7mg/m3(263±90WHOf/cm3)amositeasbestos.Pleuralmeso-theliomaincidencesof3.6%,25.9%,and19.5%,respectively,werereported.Theaerosolmean



diameteroftheamositeasbestoswas0.60µm±0.25; its aerosol mean length was 13.4 µm±16.7. The dimensions of this asbestos fiberweremoresimilartothoseoftheRCFsusedinthechronicinhalationstudiesofMcConnelletal.[1995]thanthechrysotileasbestosusedasthepositivecontrolinthatsamestudy.

NIOSH[Dankovic2001]analyzedthehamsterdatafromtheRCF[McConnelletal.1995]andamositestudies[McConnelletal.1999].Adose-responsemodelwasdevelopedforamositeandwasusedtopredicttheamositeresponseattheoneandonlydoseatwhichRCFsweretestedinhamsters.Themodeledamositeresponsewascompared with the observed RCF response.TheseresultsarepresentedinFigures5–1and5–2. Log-probit, log-logistic, multistage, andunrestricted Weibull models were analyzed.The transformation for the log-probit andlog-logistic models was log (fibers/cm3 +1).ThedosemetricofthemultistageandWeibullmodelswasfibers/cm3,astheydidnotrequirealog-transformation.Resultsofthelog-probitmodel analysis of these data indicated RCF/amositerelativepotencyestimatesof1.85and1.19,usingWHOfibersandfibers>20µmasthe dose metric, respectively. The model fitswerepoorwhentheamositehigh-dosegroupand20µm-fiberdosewereincluded.Sensitivityanalysesinwhichthehigh-doseamositegroupwasdroppedsuggestthattherelativepotencyof RCFs to amosite could be as low as 0.66based on the log-probit model. Results usingthelog-logistic,multistage,andWeibullmod-els were similar to those using the log-probitmodel,withanoverall rangeofRCF/amositerelative potency estimates from these modelsusingall fouramositedosegroupsof1.03 to1.89.Althoughnocleartoxicologicbasisexistsfor disregarding the high-dose amosite data,sensitivity analyses based on excluding thesedatasuggestthatthepotencyofRCFsrelativetoamositecouldbeaslowas0.47,basedonthemultistagemodel.Thesemodels indicatethat

the plausible carcinogenic potency estimatesforRCFsrelativetoamosite,basedonhamstermesotheliomas,rangefromabouthalftonear-lytwicethecarcinogenicityofamosite.

5.1.3 DiscussionofRCFStudiesinAnimals

Theintrapleural,intraperitoneal,andintratra-chealRCFstudieshavedemonstratedthecar-cinogenicityofRCFs.Becauseofthenonphysi-ologicdeliveryoffibersbythesemethods,itisdifficult to compare their results with thoseof an inhalation exposure. Although trachealinstillation may result in different distribu-tionpatternsthananinhalationexposure,thisrouteofexposure isusefulasascreeningtestforrelativetoxicityandtocomparethetoxicityof new materials with the toxicity of materi-alsforwhichdataalreadyexist[Driscolletal.2000].Trachealinstillationalsoisusefulwhentestingfibersrespirablebyhumansbutnotro-dents.Chronic inhalationstudiesprovide thedatamostrelevanttooccupationalexposuretoRCFs.

The RCF chronic animal inhalation studiesdescribed above allow for the comparison ofhealtheffectsofexposuretodifferentdosesofRCF1,different typesofRCFs,and the inter-speciessusceptibilityoftheratandhamstertoRCFexposure.

Results of the multidose chronic inhalationtestingofRCF1 inrats indicate thepathogen-icpotentialofRCFsathighdoses[Mastetal.1995a,b]. The incidence of total lung tumorswas significantly increased from controls afterexposureto30mg/m3RCF1,RCF2,andRCF3butnotRCF4.Adose-responserelationshipwasdemonstrated for nonneoplastic pulmonarychangesinratsexposedto3,9,and16mg/m3

RCFs.Theseverityofinterstitialandpleuralfi-brosiswassimilarbetweenthoseanimalssacri-ficedat24monthsandthoseallowed6months



Exposure concentration (f/cm3)

Exposure concentration (f/cm3)

Figure 5–1 .ProportionofhamsterswithmesotheliomasfollowingexposuretoamositeorRCFs.Con-centrationsarebasedonfibers>20µmlong.The95%confidencelimitsarebasedonassumingabi-nomialdistribution.Dashedlinesrepresentthelog-probitmodelfittedtotheamositedata[Dankovic2001].(Source:McConnelletal.[1995,1999].)

Figure 5–2 .ProportionofhamsterswithmesotheliomasfollowingexposuretoamositeorRCFs.Con-centrationsarebasedonWHOfiberdimensioncriteria.The95%confidencelimitsarebasedonas-sumingabinomialdistribution.Dashedlinesrepresentthelog-probitmodelfittedtotheamositedata[Dankovic2001].(Source:McConnelletal.[1995,1999].)



ofrecoveryfollowingthe24-monthexposure.Spontaneousprimarypulmonarymesothelio-masarerareinrats[AnalyticalSciencesIncor-porated1999].Therefore,thepresenceofanymesotheliomaintreatedanimalsisbiologicallysignificantandwarrantscaution.

Comparing the chronic effects of RCF1 withitspositivecontrol,chrysotileasbestos, inthehamster isdifficultbecauseof thedifferencesindose,dimensions,anddurabilityofthetwofiberstested[McConnelletal.1995].Morere-cent dose-response data on amosite asbestosprovide a comparison because these amositefiberdimensionsmorecloselyresemblethoseof RCF1 [McConnell et al. 1999]. The meanlengths of the RCFs and amosite asbestos fi-bers were 22.1 (±16.7) and 13.4(±16.7) µm,respectively. Forty-three percent of RCF fi-bers and ~26% of amosite asbestos fiberswerelongerthan20µm.Themeandiametersof theRCFsandamositeasbestosfiberswere0.94(±0.63)and0.60(±0.25)µm,respectively.Interstitialandpleuralfibrosiswereseenmuchearlier with amosite exposure than with RCFexposure. RCF exposure at 215 (±56) WHOf/cm3resulted inmesotheliomas in42of102(41%)hamsters.Amositeasbestosexposureat263(±90)WHOf/cm3resultedinmesothelio-mas in 17 of 87 (19.5%) hamsters. Modelingof these data indicates that the plausible car-cinogenicpotencyestimates forRCFsrelativetoamosite,basedonhamstermesotheliomas,rangefromabouthalftonearlytwicethecar-cinogenicityofamosite[Dankovic2001].Dif-ferences in the physical characteristics andbiopersistence of RCF1 and amosite asbestosmustbeconsideredbeforeextrapolatingtheseanimaldatatohumanrisk.

Hamsters showed a greater susceptibility tomesotheliomainductionafterRCF1exposurethan did rats under similar exposure condi-tions[Mastetal.1995a;McConnelletal.1995].Chronicinhalationstudiesofamositeasbestosinhamstersshowednopulmonaryneoplasms,

buthighincidencesofmesotheliomaoccurredatdosesof125and250f/cm3[McConnelletal.1999].Manyofthemesotheliomasinthemorerecenthamsterstudieswereidentifiedonlyonmicroscopic examination [Mast et al. 1995a;McConnelletal.1995,1999].Previousstudiesreportingmesotheliomasonlybymacroscopicidentification may have underestimated themesothelioma incidence. Recent, short-terminhalation studies indicate that hamster me-sothelial cells may have a more pronouncedinflammatory and proliferative response toRCF1exposurethanthoseofrats[Everitt1997;Gelzleichteretal.1996a,b,1999].ThereasonsforthisspeciesdifferenceinresponsetoRCFshavenotbeenexplained.Theresultsof theseanimalstudiesindicatetheneedfortheinclu-sionofthehamsterasasensitivetestspeciesinthosestudiesinwhichpleuralmesotheliomaisanendpointofconcern.

Results fromMastetal.[1995a] indicatethatunder the conditions studied, exposure toRCF4 may have a less pronounced effect onpulmonarypathologythanexposuretoRCF1,RCF2, and RCF3. Rats exposed to RCF4 didnothaveasignificantincreaseintotallungtu-mors compared with controls; those exposedto RCF1, RCF2, and RCF3 did. Exposure toRCF4producedalessseverefibrosisthanwasseenintheotherRCFexposuregroups.Differ-encesinthedimensionsorphysicalpropertiesof RCF4 may explain its different respiratoryeffects from RCF1, RCF2, and RCF3. RCF4was produced by heating RCF1 in a furnaceat2,400ºFfor24hr.ThisAafter-service@fibercontained approximately 27% free crystal-line silica. Silicotic nodules were observed inthe RCF4-exposed animals. RCF4 fibers wereshorter (~34% between 5 and 10 µm ) andthicker(~35%<0.5µm)thanthoseofRCF1,RCF2,andRCF3.

Theparticlecontentof theRCF testmaterialmayhavebeenresponsibleforsomeofthere-spiratorypathologyobservedinthesestudies.



However,ananalysisoftheratioofnonfibroustofibrousparticulatesinthereviewedstudiesdoes not indicate a correlation between theparticulatecontentandobservedeffects.Smithetal.[1987]performedtestingwiththehigh-est particulate to fiber ratio at 33:1 and didnot report a high tumor incidence. Compar-ing studies based on the ratio of nonfibrousparticulatestofibersiscomplicatedbydiffer-encesamongthestudies infiberpreparation,doses tested, fiber dimensions, and methodsof fiber analysis. The techniques used to de-tectandmeasurenonfibrousparticulateshaveimprovedovertimesothatthecomparisonofrecentandolder studiesmayreflect these in-consistencies.

ThesechronicRCFinhalationstudiesindicatetheabilityofRCFstoinducecancerintwolab-oratory species—mesotheliomas in hamstersandpulmonarytumorsinrats.ThelateonsetoftumorsindicatestheimportanceofchronicstudiesontheeffectsofRCFexposure.Short-termintraperitoneal,intrapleural,intratrache-al, and inhalation studies provide importantinformationabouttheactionoffibers,thefi-bercharacteristicsassociatedwithtoxicity,andpotentialtoxicity.CurrentlyitisonlythroughlifespantoxicologictestingofanimalsthattherespiratoryandotherchronichealtheffectsofRCFscanbeaccuratelyassessed.

5.1.4LungOverloadArgumentRegardingInhalationStudiesinAnimals

Mastetal.[2000]publishedareviewinterpret-ingtheresultsofchronicinhalationstudiesofRCF1inratsandhamsters[Mastetal.1995a,b;McConnelletal.1995].Inthereview,theau-thorssuggestthepossibilitythatthemaximumtolerateddose(MTD)mayhavebeenexceededandthatlungoverloadmayhavecompromisedthe pulmonary clearance mechanisms of test

animals.Buildingontheconceptoflungover-load (first advanced by Bolton et al. [1983]),Mastetal.[2000]consideredparticulatecoex-posure(i.e.,nonfibrousparticulateorshot)tobeaconfounding factor thatmayhavehadamajor effecton theobservedchronic adverseeffects.TheauthorsproposethattheMTDwasexceededatthehighestexposureconcentrationof30mg/m3forRCF1intheratbioassay.

The concept of pulmonary overload in theFischer344ratsisbasedontherecognitionthatexcessive particulate exposures (>1,500 µg/rat,according to Bolton et al. [1983]) eventuallyreducetheclearanceeffectivenessofthelungs,causingthenormallinearclearancekineticstofollowanonlinearpattern.Onacellular level,the overload conditions may result in alveolarmacrophages becoming engorged with par-ticulate, pulmonary and alveolar inflamma-tion,increasedtranslocationofparticlestotheinterstitiumandlymph,granulomaformation,pulmonaryfibrosis,andlungtumors,depend-ing on the time and severity of the overload[Mastetal.2000].Ambiguityaboutthedefini-tionofMTDforchronicinhalationstudieswithanimalswasalsoaconcernexpressedbytheau-thors.Onereference[Morrow1986]recognizesthe MTD as that which causes “a significantfunctionalimpairmentoflungclearance.”AtaNationalToxicologyProgram(NTP)workshoponestablishingexposureconcentrationsforin-halation studies in animals, it was concludedthatthehighestexposureconcentrationshouldproduceonlyminimalchangesinlungdefensemechanisms as measured by clearance [Lewisetal.1989].AtasimilarworkshopconvenedbytheEPA,itwasproposedthattheMTDforfi-berinhalationstudiesisequivalenttothelungdoseproducedatthemaximumachievablecon-centration (MAC) [Vu et al. 1996]. The MACiscalculatedasthehighestfiberconcentrationbasedona90-daystudythatresultsinsignifi-cant changes in alveolar macrophage clear-ancerates,lungburdennormalizedtoexposure



concentration,cellproliferation,inflammation,lungweight,andothermeasures.

ThemethodologydescribedfortheRCFchron-icinhalationstudiesinvolvedprocedures(i.e.,wetcycloneseparationtechnology)forremov-ing the nonfibrous particulate fraction fromthecommercialfiber(RCF1)usedforthe in-halationexposures[Mastetal.1995a,b2000;McConnell etal.1995].Thisprocess resultedinanaerosolwitha9.1:1particle-to-fiberratio[Maximetal.1997;Mastetal.2000],comparedwithastudybySmithetal.[1987],whichre-ported 33 nonfibrous particles per fiber inairborneexposures.ResultsfromEsmenetal.[1979]indicatethatdespiteapoorcorrelationbetweenmassoftotalairbornedustandfiberconcentrationinRCFsmeasuredinmanufac-turing,fibersgenerallyconstituteonlyasmallportionofthetotaldust.Thisfindingiscon-sistentwithotherreportedmeasuresofoccu-pational exposures to airborne RCFs [Krantzet al. 1994; Trethowan et al. 1995]. However,Maxim et al. [1997] reported an averageparticle-to-fiber ratio of 0.53:1 (n=10, rangenotreported),orroughly1particleto2fibersinRCFmanufacturingfacilities.

MuhleandBellmann[1996]conducteda5-dayinhalationstudywithFischer344ratstomea-surethebiopersistenceofRCF1(withthe9:1particulate-to-fiber ratio) and RCF1a (RCF1that is further processed to reduce particu-latemass).Thestudyshoweda1.5-foldlongertime-weightedhalf-lifeforRCF1(t

1/2=78days)

compared with RCF1a (t1/2

=54 days). Thatstudyalsoinvolveda3-weekinhalationexperi-mentwithFischer344rats,inwhichtheclear-anceofRCF1(t

1/2=103days)wasalmosttwice

aslongasthatofRCF1a(t1/2

=54days).

In a follow-up study by Brown et al. [2000],femaleWistarratswereexposedtoRCF1andRCF1abyinhalationfor3weeksandfollowedfor12monthstoevaluatealveolarmacrophageclearance and inflammation. The exposure

concentrationswere130fibers/ml>20µmforRCF1 and 125 fibers/ml >20 µm for RCF1a.ThenonfibrouscontentofRCF1wasapproxi-mately 25%, whereas the nonfibrous contentofRCF1awas2%.Themeandiameterofthenonfibrousparticleswas2to3µm.Theaero-solexposuretoRCF1containedtwiceasmanyshortfibers(<20µm)asRCF1aandtwicetheamountofdust(fibersandnonfibrousdust/mg·m3)asRCF1a(51versus25.8mg/m3).Attheendoftheinhalationperiod,animalsexposedtoRCF1ahadahigherpulmonaryconcentra-tionoflongfibersbutlowerconcentrationsofshortfibersandnonfibrousparticles.Thedif-ferenceinparticlecontentwasenhancedinthelungs—15timesmoreparticleswerefoundinthe lungs of the RCF1-exposed animals thaninthoseexposedtoRCF1a.Intheaerosolex-posure,onlyaneightfolddifferencewasfoundinthenumberofparticlesbetweenRCF1andRCF1a. The RCF1a-exposed animals had ahalf-timealveolarclearanceof80days(71–91)compared with 60 days (49–77) for the con-trols; clearance half-time for exposed RCF1animals was 1,200 days (573-infinity) com-pared with 66 (58–88) for the correspondingcontrols. To evaluate respiratory inflamma-tion, bronchoalveolar lavage (BAL) measure-ments(lactosedehyrdogenase[LDH],γ-gluta-myltransferase[γ–GT],totalprotein,reducedglutathione [GSH]) were taken at the end ofthe3-weekstudyperiodandatsubsequentin-tervalsoverthenext12months.Immediatelyfollowingthe3-weekinhalationstudy,allBALmeasurements were statistically elevated inbothRCF1andRCF1aanimals.However,after91daysofrecovery,theBALmeasurementsforRCF1aanimalsreturnedtonormal.Indicationsof inflammation continued for RCF1 throughtheentireobservationperiod.ThegreaterandmorepersistentinflammationseenwithRCF1wasattributedtothegreatermassofmaterialortoincreasedactivityofthenonfibrouspar-ticles,althoughthehighconcentrationofshortfibers in RCF1 (twice that of RCF1a) could



have contributed to the observed impedanceinalveolarmacrophageclearanceandinflam-mation.

Tranetal. [1997]examinedhowoverloadingthealveolarmacrophagedefensesystemaffectstheclearanceoffibersversusthatofnonfibrousparticles. Modeling was performed based ondataforratsexposedbyinhalationtotitaniumdioxide (TiO

2) at 1, 10, and 50 mg/m3 or to

glasswool(MMVF10)at3,16,and30mg/m3.Lung burdens and clearance kinetics duringexposure(0to100weeks)werecomparedwiththoseat3,10,and38dayspost-exposure.Themodelsshowedthatoverloadingofthelungbyfibersornonfibrousparticlesaresimilarwhenfibers are short (<15µm). This observationisplausible,asnonfibrousparticlesandshortfiberssmallerthanthediameterof thealveo-larmacrophagearemostreadilyengulfedandcleared via the macrophages. When this de-fense isoverwhelmed(lungburden≥10mg),these particles are cleared less effectively. Forfiberslongerthan15µm,phagocytosisbyalve-olarmacrophageisreduced.Asfiberlengthin-creases,fiberstendtobeclearedbydissolutionand disintegration of long fibers into shorterfibers or fragments. Therefore, clearance oflongfibersisnotaffectedbytheoverloadingofmacrophage-mediated defenses with shorterfibersornonfibrousparticles.

The exposure concentrations for the RCFchronic inhalation bioassays were measuredandreportedasmassinmg/m3.Monitoringofexposuresasperformedbygravimetricanaly-sisdoesnotdistinguishfibersfromnonfibrousparticulate, although fiber concentration anddimensionswerealsocheckedbyphasecontrastandelectronmicroscopy[Mastetal.1995a,b].Consequently,theparticulatefractionwasin-cluded in the dose measurements. This factdoescomplicateeffortstocomparetherelativetoxicity of fibers, nonfibrous particulate, andtotal combined particulate, especially regard-ingthelungoverloadhypothesis.Duringpro-

ductionofRCFsandRCFproducts,however,the nonfibrous particulate fraction is associ-atedwiththefiber,asshowninTable2–1(i.e.,20%to50%ofRCFsbyweightisnonfibrousparticulate). This suggests that occupationalexposurestoairborneRCFsnecessarilyinvolvecoexposures to a fraction of nonfibrous par-ticulate,asuggestionthathasbeensupportedby exposure assessment studies [Esmen et al.1979;Krantzetal.1994;vandenBergenetal.1994;Trethowanetal.1995;Maximetal.1997;Mastetal.2000].

5.2CellularandMolecularEffectsofRCFs(In VitroStudies)

ThecellularandmoleculareffectsofRCFex-posureshavebeen studiedwith twodifferentobjectives.Onepurposeoftheseinvitrostud-iesistoprovideaquicker,lessexpensive,andmorecontrolledalternativetoanimaltoxicitytesting.Theseexperimentsarebest interpret-edbycomparingtheirresultswiththoseofinvivo experiments. The second objective of invitrostudies is toprovidedata thatmayhelpto explain the pathogenesis and mechanismsofactionofRCFsatthecellularandmolecu-lar levels.Thesecytotoxicityandgenotoxicitystudiesarebest interpretedbycomparingtheeffectsofRCFswiththoseofotherSVFsandasbestosfibers.Invitrostudiesserveasscreen-ingtoolsandprovideinsightsintothemolecu-larmechanismsoffibers.Theyareanimpor-tantcomplementtoanimalstudies.CurrentlyitisnotpossibletousethesedatatoderivetheNIOSHRELforRCFs.For thisreason,adis-cussionofinvitrostudiesisincludedhere,butthemorecomprehensivesummariesofstudiesareincludedinAppendixC.

The toxicity of fibers has been attributed totheirdose,dimensions,anddurability.Anytest



systemthatisdesignedtoassessthepotentialtoxicity of fibers must address these factors.Durability is difficult to assess using in vitrostudies because of their acute time course.However,invitrostudiesprovideanopportu-nity tostudy theeffectsofvaryingdosesanddimensions of fibers in a quicker, more effi-cientmethodthananimaltesting.Theydonotcurrentlyprovidedatathatcanbeextrapolatedtooccupationalriskassessment.

Theassociationbetweenfiberdimensionandtoxicity has been documented and reviewed[Stanton et al. 1977, 1981; Pott et al. 1987;Warheit1994].RCFsmayhavedifferenttoxici-ties,dependingon thefiber lengthrelative tomacrophagesize.Longerfibersaremoretoxic.Fiberlengthhasbeencorrelatedwiththecyto-toxicityofglassfibers[Blakeetal.1998].Man-ville code 100 (JM–100) fiber samples withaveragelengthsof3,4,7,17,and33µmwereassessedfortheireffectsonLDHactivityandratalveolarmacrophagefunction.Thegreatestcytotoxicitywasreportedinthe17-and33-µmsamples, indicating that length is an impor-tantfactorinthetoxicityofthisfiber.Multiplemacrophages were observed attached alongthelengthoflongfibers.Relativelyshortfibers(<20 µm) were usually phagocytized by onerat alveolar macrophage [Luoto et al. 1994].Longer fibers were phagocytized by two ormore macrophages. Incomplete or frustratedphagocytosismayplayarole inthe increasedtoxicity of longer fibers. Long fibers (17 µmaveragelength)wereamorepotentinduceroftumor necrosis factor (TNF) production andtranscription factor activation than shorterfibers (7 µm average length) [Ye et al. 1999].Thesestudiesdemonstratetheimportantroleoflengthinfibertoxicityandsuggestthatthecapacityformacrophagephagocytosismaybeacriticalfactorindeterminingfibertoxicity.

Several of the in vitro RCF studies (summa-rizedinAppendixC)reportedadirectassocia-tionbetweenalongerfiberlengthandgreater

cytotoxicity. Hart et al. [1992] reported theshortestfiberstobetheleastcytotoxic.Brownet al. [1986] reportedanassociationbetweenlength,butnotdiameter,andcytotoxicactivity.Wrightetal.[1986]reportedthatcytotoxicitywascorrelatedwithfibers>8µmlong.Yeglesetal.[1995]reportedthatthelongestandthickestfiberswerethemostcytotoxic.ThefourmostcytotoxicfibershadGMlengths≥13µmandGMdiameters>0.5µm.Theproductionofab-normal anaphases and telophases was associ-atedwithStantonfiberswitha length>8µmanddiameter<0.25µm.Hartetal.[1994]re-portedthatcytotoxicityincreasedwithincreas-ing average fiber lengths from 1.4 to 22 µm,butdidnotincreasewithaveragelengthsfrom22to31µm.

Additional studies assessing the cytotoxicityofspecificRCFfiberlengthsareneeded.Suchstudieswillhelptodescribetheassociationbe-tween fiber length and toxicity for RCFs andmayallowdeterminationofathresholdlengthabove which toxicity increases significantly.Inaddition toprovidingdataon thecorrela-tionbetweenfiberlengthandtoxicity,invitrostudieshaveprovideddataontherelativetox-icity of RCFs compared with other fibers, al-thoughsomeuncertaintiesremainintheinter-pretationofthesestudiesbecauseofdifferencesin fiber doses, dimensions, and durabilities.RCFs have direct and indirect effects on cellsandalter gene function in similarways.Theyarecapableofinducingenzymereleaseandcellhemolysis.Theymaydecreasecellviabilityandinhibit proliferation. RCFs affect the produc-tionofTNFandreactiveoxygenspecies(ROS)andaffectcellviabilityandproliferation.Theyinducenecrosisinratpleuralmesothelialcells.They may also induce free radicals, micronu-clei, polynuclei, chromosomal breakage, andhyperdiploidcellsinvitro.

Invitrostudiesprovideanexcellentopportu-nityforinvestigatingthepathogenesisofRCFs.However, comparisons are difficult to make



between in vitro studies based on differencesin fiber doses, dimensions, preparations, andcompositions. Important information suchas fiber length distribution is not always de-termined. Even when comparable fibers arestudied,thecelllineorconditionsunderwhichtheyaretestedmayvary.Muchoftheresearchtodatehasbeendoneinrodentcelllinesandincellsthatarenotrelatedtotheprimarytar-get organ. In vitro studies using human pul-monarycelllinesshouldprovidepathogenesisdatamostrelevanttohumanhealthriskassess-ment.

Short-term in vitro studies cannot take intoaccounttheinfluenceoffiberdissolutionandfiber compositional changes that may occurover time. In an in vivo exposure, fibers arecontinually modified physically, chemically,andstructurallybycomponentsofthelungen-vironment. This complex set of conditions isdifficulttorecreateinvitro.Justasitisunlikelythatonlyonefactorisanaccuratepredictoroffibertoxicity,itisunlikelythatanyoneinvitrotestisabletopredictfibertoxicity.

5.3 Health Effects in Humans5.3.1 Morbidity and Mortality Studies

Twomajorresearcheffortsevaluatedthemor-bidityofRCF-exposedworkers—oneconduct-edinU.S.plantsandoneinEuropeanplants.Table 5–6 describes the populations analyzedforbothstudies.Theobjectiveoftheseresearcheffortswastoevaluatetherelationshipbetweenoccupational exposure to RCFsandpotentialadverse health effects. These studies includedstandardizedrespiratoryandoccupationalhis-tory questionnaires, chest radiographs, andpulmonary function tests (PFTs) of workers,aswellasairsamplingtoestimateworkerex-posures.ThestudiesofEuropeanplantsbeganin1986.Studysubjects includedonlycurrentworkers at seven RCF manufacturing plants

[Rossiter et al. 1994; Trethowan et al. 1995;Burgeetal.1995].Afollowupcross-sectionalstudy conducted in 1996 evaluated the samemedicalendpointsinworkersfromsixoftheseseven European manufacturing plants (oneplanthadceasedoperation)[Cowieetal.1999,2001]. Current and former workers were in-cludedasstudysubjectsinthefollowupstudy.The studiesofU.S.plantsbegan in1987andinvolvedevaluationsofcurrentworkersatfiveRCFmanufacturingplantsandformerwork-ersattwoRCFmanufacturingplants[Lemas-tersetal.1994,1998;Lockeyetal.1993,1996,1998,2002].

In the United States, the earliest commercialproductionofRCFsandRCFproductsbeganin1953;inEurope,RCFproductionbeganin1968. The demographics of the U.S. and Eu-ropean populations were similar at the timethey were studied, although the average ageof U.S. workers was slightly higher than thatof the workforce in the 1986 European stud-iesbecauseof theearlierdevelopmentof thisindustry in the United States. The mean agefortheEuropeanRCFworkerswas37.7inthe1986 study [Trethowan et al. 1995] and 42.0for males and 39.4 for female workers in the1996 study [Cowie et al. 1999]. In the U.S.RCFmanufacturing industry, theaverageageis 40for current workers and 45 for formerworkers[Lemastersetal.1994].Themeandu-rationofemploymentintheEuropeancohortwas10.2years(range7.2to13.8years)in1986[Trethowanetal.1995]and13.0yearsin1996[Cowieetal.1999].TheU.S.studyreportsthemeandurationofemploymentfor23workerswithpleuralplaquesas13.6years (±9.8); themedian is 11.2 years (range 1.4 to 32.7) [Le-mastersetal.1994].

The following text and Table 5–7 summarizefindingsfromtheU.S.andEuropeanresearchefforts, organized according to results fromradiographicexaminations,respiratorysymp-toms, and PFTs. Discussion of two related



Table 5–6 . Cited studies of populations with occupational exposures to RCFs*

Population analyzed Outcome measures

Study DesignEmployment

status Number% male workers

% female workers Radiography PFT Symptoms

European:

Burgeetal.1995‡ Cross-sectional Current§ 532 100 0 N Y Y

Rossiteretal.1994‡ Cohortmorbidity Current** 543 100 0 Y N N

Trethowanetal.1995‡ Cross-sectional Current 628 91 9 Y Y Y

Cowieetal.1999†† Cross-sectional Current 695 90 10 Y Y Y

Former 79 85 15

United States:‡‡

Lemastersetal.1994 Cross-sectional Current 627 83 17 Y N N

Lemastersetal.1994 Cross-sectional Former§§ 220 91 9

Lockeyetal.1993: Cohortmortality Currentandformer

684(including46deceasedand5losttofollowup)***

100 0 N N N(Causeofdeath)

Cohortmorbidity Currentandformer

801(par-ticipants;99%providedrespiratoryhistory,94%providedPFTs,and90%providedchestX-rays[radi-ography])

85 15 Y Y Y

Lockeyetal.1996 Cohortmorbidity Current 370 NA NA Y N N

Former 282††† NA NA NA NA NA

Nestedcase-control

Both(17caseswith3controlseachmatchedoncurrentversusformerstatus)

NA NA Y Y N N

Lockeyetal.1998 Cross-sectionalandlongitudinal

Current 361‡‡‡ 100 0 N Y N

Seefootnotesonnextpage.



*Abbreviations:N=number;NA=notavailablefrompublishedcitation;PFT=pulmonaryfunctiontest;RCFs=refractoryceramicfibers;Y=yes.

†Currentversusformer(andleaver)workerstatusatanRCFmanufacturingplantasdeterminedattimeofsurvey.‡StudyincludedcurrentworkersatsevenceramicfibermanufacturingplantsinthreeEuropeancountries.

§Fromapossible708currentworkers,628eligibleparticipantswereidentifiedand596hadchestX-rayexaminations;51femaleworkersand13unexplainedotherswereexcludedfromanalysis.

**Fromapossible708currentworkers,628eligibleparticipantswereidentifiedand596hadchestX-rayexaminations;2unreadablefilmsandthoseof51femaleworkerswereexcludedfromtheanalysis.

††StudyincludedcurrentworkersatsixceramicfibermanufacturingplantsinthreeEuropeancountriesaswellasleaversfromthefirstthreeEuropeanstudies[Burgeetal.1995;Rossiteretal.1994;Trethowanetal.1995](oneofthesevenplantsin-cludedearlierhadceasedoperation).

‡‡StudiesincludedcurrentandformerworkersatfiveRCFmanufacturingplantsintheUnitedStates.§§Fromapossible1,030eligiblecurrentandformerworkers,183wereeitherdeceased,notlocated,ordidnotagreetochestX-

rayexaminations.***Fromapossible729eligiblecurrentandformerworkersat2plantsitesforwhomindividualworkhistorieswereavailable,45wereexcludedonthebasisofinsufficientexposurestofibersorinsufficientdataregardingfiberexposures.

†††Fromapossible868eligiblecurrentandformerworkersat2plantsites,148wereeliminatedforlackofexposurecharacterizationdataandlosstofollowup.Oftheremaining720workers,68didnotagreetochestX-rayexaminations.‡‡‡Fromapossible963eligiblecurrentworkersatfiveplantsites,209femaleworkerswereexcludedaswellas393maleworkers

withfewerthan5PFTsessions.

mortality studies is also presented in Sec-tion 5.3.5 [Lockey et al. 1993; Lemasters etal.2003].TwoHHEsofworkplacesinvolvingworkersexposedtoRCFsarealsodescribedinSection5.3.6[Kominsky1978;Lyman1992].

5.3.2 Radiographic Analyses

In both the European and U.S. studies citedin Table 5–6, the study populations includ-edworkers atmultipleplants involved in themanufactureofRCFsorRCFproducts.Aspartoftheinvestigationofpotentialeffectsofexpo-suretoairborneRCFs,chestradiographywasperformed. In all studies, chest radiographswere read independentlyby three readersus-ingtheInternationalLabourOffice(ILO)1980 International Classification of the Radiographs of Pneumoconioses [ILO 1980]. Identifiers onfilmsweremaskedtoensureablindreviewbyreaders,andqualitycontrolmeasuresandtestsof agreement were used to check consistencyamongthereaders.Foreachtypeofabnormal-ityanalyzed,themedianofthethreereadingsforeachfilmwasused.

5.3.2.1 Pleural abnormalities

Inthe1986studyofEuropeanRCFworkers,re-sultsofthechestradiographyindicatedapreva-lenceof2.8%(15/543) forpleuralabnormali-tiesamongmaleworkers[Rossiteretal.1994].Of the 15 cases with pleural abnormalities, 4hadbilateraldiffusethickening(1withcalcifi-cation),1showedbilateralpleuralcalcificationonly,7presentedwithunilateraldiffuse thick-ening,and3showedcostophrenicangleblunt-ingonly.Thepossibilityforconfoundingeffectswas recognized because of other exposures:52% of workers reported previous employ-ment industy jobs, including4.5%withpriorasbestosexposuresand7%withpriorMMMFexposures.Whenfemaleworkerswereincludedinthesamepopulation,Trethowanetal.[1995]reported a prevalence of 2.7% (16/592) forpleuralabnormalities.Twocaseswereknowntohavepreviousexposuretoasbestos,andthepos-sibilityforexposuretootherrespiratoryhazardswasacknowledgedforotherpersonswithpleuralabnormalities.Cowieetal.[1999,2001]reportedpleural abnormalities in 10% (78/774) and



Tabl

e 5–

7 . U

.S .

and

Eu

rop

ean

mor

bid

ity

stu

die

s w

ith

RC

Fs*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Lem

aste

rs

et

al.1

994

(U.S

.stu

dy)

Cro

ss-s

ecti

onal

stu

dy:

1,03

0cu

rren

tan

dfo

rmer

wor

kers

at

five

U

.S.R

CF

prod

uct

ion

fa

cilit

ies

empl

oyed

10

/87–

8/89

.Mal

ew

orke

rs:a

tle

ast

1ye

ar

ofe

mpl

oym

ent

in

fibe

rdi

visi

on.F

emal

ew

orke

rs:a

tle

ast

1ye

ar

ofe

mpl

oym

ent

in

fibe

rdi

visi

ona

nd

≥4h

rp

erw

eek

in

prod

uct

ion

.

Post

eroa

nter

iorc

hest

X-r

aye

xam

ina-

tions

wer

epe

rfor

med

for8

47w

ork-

ers.

Occ

upat

iona

land

resp

irat

ory

heal

thh

istor

ies

wer

eob

tain

edu

sing

stan

dard

ized

que

stio

nnai

re.S

tand

ard-

ized

mea

sure

sofp

ulm

onar

yfu

nctio

n

(FEV

1,FV

C,a

ndF

EF25

–75)w

ere

used

.

Rad

iogr

aph

ic a

nal

yses

: P

leu

ral c

han

ges

Pleu

ralc

hang

esw

ere

seen

in3

.4%

ofp

rodu

ctio

n

wor

kers

(23/

686)

and

in0

%o

fnon

prod

uctio

nw

orke

rs

(0/1

61);

91.

3%o

fple

ural

cha

nges

wer

ecl

assi

fied

as

pleu

ralp

laqu

es.N

oir

regu

laro

paci

tiesw

ere

obse

rved

.

Mu

ltip

lelo

gist

icr

egre

s-si

onfo

un

da

stat

is-

tica

llys

ign

ifica

nt

asso

ciat

ion

bet

wee

n

pleu

ralp

laqu

esa

nd

tim

esi

nce

firs

tR

CF

prod

uct

ion

job

(>20

ye

ars)

aft

era

dju

st-

men

tfo

rkn

own

as

best

ose

xpos

ure

an

da

stat

isti

cally

si

gnifi

can

tas

soci

a-ti

onb

etw

een

ple

ura

lpl

aqu

esa

nd

dura

tion

(>

20y

ears

)of

RC

Fex

pos

ure

. (Con

tin

ued

)

Ple

ura

l ch

ange

s

P

reve

lan

ce

Ite

m

(%)

OR

95

% C

I

Year

sof

late

ncy

:†

>0–

10

1.3

1.0

—>

10–2

03.

62.

9‡,§

0.8,

9.7

>20

11

.4

7.7‡,

§ 2.

0,2

9.1

Year

sof

RC

F

ex

posu

re:

>0–

10

1.9

1.0

—>

10–2

04.

32.

5**,†

† 0.

9,7

.0>

20

20.7

8.

8**,†

† 2.

6,3

0.1

* Abb

revi

atio

ns:

CI=

con

fide

nce

inte

rval

;FE

F 25–7

5=fo

rced

exp

irat

ory

flow

bet

wee

n2

5%a

nd

75%

of

the

FVC

;FE

V1=

forc

ede

xpir

ator

yvo

lum

ein

1s

econ

d;F

VC

=fo

rced

vit

al

c

apac

ity;

OR

=od

dsr

atio

;RC

Fs=

refr

acto

ryc

eram

icfi

bers

. † La

ten

cy:t

ime

sin

cefi

rst

RC

Fex

posu

re.

‡ Com

pare

dw

ith

>0–

10y

ears

of

late

ncy

.§ A

dju

sted

for

year

sof

late

ncy

an

dye

ars

ofa

sbes

tos

exp

osu

re.

**C

ompa

red

wit

h>

0–10

yea

rso

fR

CF

expo

sure

.††

Adj

ust

ed(

con

fou

ndi

ng

vari

able

sn

otd

escr

ibed

).



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n m

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Lem

aste

rs

et

al.1

998

(U.S

.stu

dy)

Cro

ss-s

ecti

onal

stu

dy:

742

of7

53a

ctiv

ew

orke

rs(

597

mal

e;

145

fem

ale)

at

five

R

CF

man

ufa

ctu

rin

gsi

tes

wh

op

arti

ci-

pate

din

occ

upa

tion

al

his

tory

inte

rvie

ws

be

twee

n1

987

and

1989

.

Med

ical

Eva

luat

ion

:

Mod

ified

Am

eric

anT

hor

acic

So

ciet

y(A

TS)

qu

esti

onn

aire

.Sp

irom

etri

cev

alu

atio

n(

pul-

mon

ary

fun

ctio

n)

att

ime

ofA

TS

inte

rvie

w.M

easu

res

incl

ude

dFE

V1,F

VC

,an

dFE

F 25%

–75%

.

Exp

osu

re a

sses

smen

t:

Occ

upa

tion

alh

isto

ryin

ter-

view

Pro

du

ctio

n w

ork:

Defi

ned

as

spen

din

g≥4

hr/

wee

k(1

0%o

fw

ork

tim

e)in

pr

odu

ctio

na

reas

.

Sym

pto

m a

nal

ysis

P

reva

len

ce (

%)

N

onp

ro-

Pro

du

c-

du

ctio

n

ti

on

S

ymp

tom

w

orke

rs

wor

kers

O

R†

95%

CI

Mal

ew

orke

rs

n=

80

n

=51

7—

—

Dys

pnea

1

2.5

15.7

7.3‡

1.7,

30.

5D

yspn

ea2

0.

04.

8

—

P

=0.

03‡

Wh

eezi

ng

3.8

10.3

2.

50.

8,8

.5A

sth

ma

2.5

2.3

1.0

0.2,

4.7

Ch

ron

icc

ough

5.

07.

41.

00.

3,3

.0C

hro

nic

ph

legm

3.

85.

81.

20.

4,4

.6P

leu

riti

cpa

in

0.0

1.6

—

P=

0.31

On

eor

mor

e

sym

ptom

s11

.3

29.6

2.

9‡ 1.

4,6

.2

Fem

ale

wor

kers

n

=59

n=

86

—

—

Dys

pnea

1

18.6

25

.6

1.3

0.6,

3.2

Dys

pnea

2

0.0

10.5

—

P=

0.00

1‡

Wh

eezi

ng

1.7

7.0

3.9

0.4,

38.

8A

sth

ma

0.0

3.5

—

P=

0.21

Ch

ron

icc

ough

1.

79.

35.

40.

6,4

6.9

Ch

ron

icp

hle

gm

1.7

9.3

3.8

0.4,

33.

5P

leu

riti

cpa

in

0.0

3.5

—

P=

0.21

On

eor

mor

e

sym

ptom

s20

.3

40.7

2.

4‡ 1.

1,5

.3

Pre

vale

nce

of

resp

ira-

tory

sym

ptom

s(e

xcep

tfor

as

thm

a)w

asa

ppro

xim

atel

y2-

to5

-fol

dhi

gher

in

prod

ucti

onw

orke

rsth

anin

n

onpr

oduc

tion

wor

kers

.

(Con

tinu

ed)

*Abb

revi

atio

ns:

AT

S=

Am

eric

anT

hor

acic

Soc

iety

;CI

=c

onfi

den

cein

terv

al;F

EF 25

%−

75%

=F

orce

dex

pira

tory

flow

bet

wee

n2

5%a

nd

75%

of

the

FVC

;FE

V1=

forc

ede

xpir

ator

y

volu

me

in1

sec

ond;

FV

C=

forc

edv

ital

cap

acit

y;n

=n

um

ber;

OR

=o

dds

rati

o; P

=p

roba

bilit

y;R

CFs

=r

efra

ctor

yce

ram

icfi

bers

.† A

dju

sted

for

age,

sm

okin

g(c

ateg

ory

and

pack

yea

rs),

an

dye

ars

ofp

ossi

ble

asbe

stos

exp

osu

rein

alo

gist

icr

egre

ssio

nm

odel

.‡ St

atis

tica

llys

ign

ific

ant

(P<

0.05

).



Ta

ble

5–7

(C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n m

orb

idit

y st

ud

ies

wit

h R

CF

s*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Lem

aste

rs

et

al.1

998,

c

onti

nu

ed

(U.S

.stu

dy)

Mu

ltip

le

regr

essi

on

anal

ysis

† of

chan

gein

vo

lum

e(m

l)

ofh

eigh

t-ad

just

ed

spir

omet

ric

mea

sure

s(9

5%C

I)

asso

ciat

ed

wit

hR

CF

emp

loym

ent

dura

tion

.C

ontr

olle

d

for

smok

ing

stat

us.

Pulm

unar

y fu

ncti

on

Δ v

olum

e in

(ml)

Item

C

urre

nt sm

oker

s Pa

st sm

oker

s N

ever

smok

ers

Mal

ew

orke

rs

n=

245

n=

174

n=

173

[FV

C]

year

sof

RC

F

emp

loym

ent

–165

.4‡ (

–279

.8,–

51.0

)–1

55.5

‡ (–30

1.9,

–9.

1)

–40.

6(–

175.

1,19

3.8)

[FE

V1]

year

sof

RC

F

emp

loym

ent

–134

.9‡ (

–231

.3,–

38.5

)–7

2.5

(–19

5.9,

50.

9)

–20.

4(–

133.

7,9

2.9)

Fem

ale

wor

kers

n

=56

n

=20

n

=68

[FV

C]

year

sof

RC

F

emp

loym

ent

–110

.8(

–411

.5,1

90.0

)–3

30.5

(–8

72.1

,211

.1)

–350

.3‡ (

–692

.0,8

.7)

[FE

V1]

year

sof

RC

F

emp

loym

ent

13.9

(–2

18.7

,246

.5)

–321

.4(

–740

.2,9

7.4)

–2

23.5

(–4

87.7

,40.

7)

Year

sof

RC

F

prod

uct

ion

em

plo

ymen

tw

ere

sign

ifi-

can

tly

rela

ted

to

volu

me

decl

ine

in(

1)F

VC

for

mal

ecu

rren

tan

d

pas

tsm

oker

s,

(2)

FEV

1inm

ale

curr

ent

smok

-er

s,a

nd

(3)

FV

C

for

fem

ale

nev

er

smok

ers.

* Abb

revi

atio

ns:

CI=

con

fide

nce

inte

rval

;FE

V1=

forc

ede

xpir

ator

yvo

lum

ein

1s

econ

d;F

VC

=fo

rced

vit

alc

apac

ity;

n=

nu

mbe

r;O

=od

dsr

atio

;RC

Fs=

refr

acto

ryc

eram

icfi

bers

.† V

aria

bles

incl

ude

din

mod

el:s

mok

ing

cate

gory

,in

tera

ctio

nte

rmfo

rdu

rati

ono

fR

CF

prod

uct

ion

an

dsm

okin

gca

tego

ry,i

nte

ract

ion

term

for

pack

-yea

rsa

nd

s

mok

ing

cate

gory

,wei

ght,

and

plan

tlo

cati

on.

‡ Stat

isti

cally

sig

nif

ican

t(P

≤0.0

5).

(Con

tin

ued

)



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n m

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ceSt

udy

des

ign

and

pop

ula

tion

Eval

uat

ion

met

hod

sR

esu

lts

Com

men

ts

Lock

ey

et

al.1

996

(U.S

.stu

dy)

Coh

ort s

tudy

:6

52w

orke

rs(

a)w

how

ere

em-

plo

yed

betw

een

10/8

7

and

12/

91o

rw

ho

had

≥1

year

ofe

m-

plo

ymen

tin

the

RC

F

div

isio

nat

one

oft

wo

p

lant

site

s,

and

(b)

who

com

plet

eda

n

o

ccup

atio

nalh

isto

ry

a

ndp

rovi

ded

post

erio

r-

an

teri

ora

ndtw

o

obl

ique

che

stX

-ray

s.

Nes

ted

case

-con

trol

st

udy:

17

case

sof

ple

ural

pla

que

mat

ched

to

3c

ontr

ols

bys

exa

nd

em

ploy

men

tsta

tus

(

curr

ento

rfo

rmer

w

orke

r;p

rodu

ctio

nor

n

onpr

oduc

tion

)

Hea

lth

: O

ccup

atio

nal

his

tory

inte

rvie

w,

i

nfo

rmat

ion

abo

utw

ork/

hom

e

asb

esto

sex

posu

re;c

hest

X-r

ays.

Exp

osu

re:

Est

imat

edc

once

ntr

atio

ns

of

fibe

rex

posu

refo

rea

chjo

bus

ing

h

isto

rica

lpla

ntp

roce

ss,d

esig

n

an

den

gin

eeri

ng

con

trol

s,a

nd

s

ampl

ing

data

plu

sw

orke

r

in

terv

iew

s[R

ice

eta

l.19

94,1

996]

.

Exp

osu

re:

Con

trol

san

dca

ses

rein

terv

iew

ed

wit

had

diti

onal

que

stio

ns

rega

rd-

in

gas

best

ose

xpos

ure

(app

lica-

t

ion

,man

ipul

atio

n,a

nd

dist

ance

f

rom

exp

osur

e).A

sbes

tos

expo

-s

ure

cate

gori

zed

(rat

ing

inde

x=

h

igh,

med

ium

,low

)fr

omin

ter-

v

iew

dat

a.

Rad

iogr

aph

ic a

nal

yses

Int

he

coh

ort

stu

dy,

20c

ases

of

pleu

ral

plaq

ue

wer

eid

enti

fied

int

he

coh

ort:

18

prod

uc-

tion

wor

kers

an

d2

non

prod

uct

ion

w

orke

rs.

Int

hre

elo

gist

ic

regr

essi

onm

odel

s,

pleu

ralp

laqu

es

wer

eas

soci

ated

(P

<0.

001)

wit

h

year

ssi

nce

firs

t

RC

Fpr

odu

ctio

n

job,

du

rati

ono

fR

CF

prod

uct

ion

jo

bs,a

nd

cum

ula

-ti

vefi

ber-

mon

ths/

cm3 .

18o

f20

cas

esw

ere

rein

terv

iew

ed;1

7w

ere

incl

ude

din

th

eca

se-c

ontr

ol

stu

dy.O

ne

was

de

ceas

ed,o

ne

refu

sed

inte

rvie

w,

and

one

wit

h

asbe

stos

exp

osu

re

was

exc

lude

d.

Pla

que

pre

vale

nce

Ite

m

(%)

OR

† 95

% C

I

Year

ssi

nce

firs

tR

CF

pr

odu

ctio

njo

b:0‡

0.9

1.0

—

>0–

10

1.7

1.4

0.

2,1

0.3

>

10–2

02.

82.

20.

4,1

1.2

>

20

12.5

9.

51.

9,4

8.2

Year

sof

RC

F

empl

oym

ent:

0

0.9

1.0

—

>0–

10

1.4

1.1

0.2,

6.1

>

10–2

07.

46.

11.

2,2

9.7

>

20

26.3

22

.3

3.6,

137

.0C

um

ula

tive

fi

ber-

mon

ths/

cm3 :

>

0–15

0.

31.

0—

>

15–4

55.

315

.4

1.9,

125

.4

>45

-135

6.

421

.3

2.6,

176

.2

>13

57.

824

.2

2.6,

224

.9C

ase-

con

trol

s:

Year

ssi

nce

firs

tRC

F

pro

duct

ion

job

—

1.2

1.0,

1.5

Cum

ulat

ive

RC

F

fi

ber-

mon

ths/

cm3 (

log)

:

Adj

uste

dfo

rye

ars

sin

cefi

rsta

sbes

tos

exp

osur

e—

2.

81.

3,5

.8

Adj

uste

dfo

ras

best

os

r

atin

gin

dex

—

3.8

1.5,

9.9

* Abb

revi

atio

ns:

CI=

con

fide

nce

inte

rval

;P=

prob

abili

ty;O

R=

odds

rat

io;R

FCs=

refr

acto

ryc

eram

icfi

bers

.† A

llbu

tla

ste

ntr

yar

ead

just

edfo

rye

ars

sin

cefi

rst

asbe

stos

exp

osu

re.L

ast

entr

yis

adj

ust

edfo

ras

best

osr

atin

gin

dex,

as

indi

cate

d.‡ N

onpr

odu

ctio

nw

orke

rs.

(Con

tin

ued

)



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n m

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Lock

ey

et

al.1

998

(U.S

.stu

dy)

Cro

ss-s

ecti

onal

an

d

l

ongi

tud

inal

stu

dy:

Of

apo

ssib

le7

54m

ale

wor

kers

,th

e

stu

dyin

clu

ded

361

w

ho

(1)

wer

eh

ired

b

efor

e6/

30/9

0,

(

2)w

ere

empl

oyed

≥1

mon

tha

ton

eof

five

U.S

.RC

F

man

ufa

ctu

rin

g,

fac

iliti

es,a

nd

(3)

par

tici

pate

din

at

l

east

five

(of

ap

os-

sib

les

even

)P

FTs

es-

sio

ns

betw

een

6/8

7

an

d6/

94.

Med

ical

eva

luat

ion

:Ye

arly

spi

rom

etri

c

ev

alu

atio

n(

pulm

onar

y

fun

ctio

n)

betw

een

19

87a

nd

1994

.M

easu

res

incl

ude

dFV

C

and

FEV

1.

Exp

osu

re a

sses

smen

t:Pe

riod

an

djo

b-gr

oup-

spec

ific

ex-

posu

rec

once

ntr

atio

ns;

est

imat

ed

for

each

of

five

RC

Fm

anu

fact

ur-

ing

faci

litie

san

das

sign

edto

eac

h

wor

ker

base

don

job

his

tory

.

Cum

ulat

ive

RC

Fex

posu

re(

fibe

r-

mon

ths/

cm3 )

esti

mat

edfr

om

date

of

firs

tP

FT(

1987

)th

rou

gh

fin

alP

FTd

ate.

Pre

-198

7da

tao

nfi

ber

con

cen

trat

ion

sfr

omtw

opl

ants

pe

rmit

ted

calc

ulat

ion

of

cum

ula-

tive

fibe

rco

nce

ntr

atio

ns

from

fi

rstd

ate

ofR

CF

expo

sure

for

wor

kers

att

hese

pla

nts

on

ly.

Pu

lmon

ary

fun

ctio

n: c

ross

-sec

tion

al a

nal

ysis

of

i

nit

ial p

ulm

onar

y fu

nct

ion

test

for

522

wor

kers

Reg

ress

ion

coe

ffici

ent

RC

F p

rod

uct

ion

ye

ars

FV

C†,

‡ F

EV

1†,‡

≤7§

–65.

6(0

.44)

–8

0.6

(0.2

5)

>7§

–219

.4(

<0.

01)

–205

.2(

<0.

01)

193

mal

ew

orke

rs

wer

eex

clu

ded

from

th

ean

alys

isb

ecau

se

they

did

not

par

tici

-pa

tein

at

leas

tfi

ve

PFT

ses

sion

s.O

n

aver

age,

non

par-

tici

pan

tsw

ere

olde

r,sm

oked

an

dw

eigh

ed

mor

e,a

nd

had

low

er

hei

ght-

adju

sted

an

dp

erce

nta

ges

ofp

re-

dict

edlu

ng

fun

ctio

n

valu

es.

(Con

tin

ued

)

* Abb

revi

atio

ns:

FE

V1=

forc

ede

xpir

ator

yvo

lum

ein

1s

econ

d;F

VC

=fo

rced

vit

alc

apac

ity;

PFT

=pu

lmon

ary

fun

ctio

nte

st;R

CFs

=re

frac

tory

cer

amic

fibe

rs.

† Inm

illili

ters

.‡ H

eigh

t-ad

just

ed;v

aria

bles

incl

ude

din

th

ean

alys

isw

ere

age,

cat

egor

ical

RC

Fpr

odu

ctio

ny

ears

(0,

≤7

year

s,>

7ye

ars

[fir

stte

st])

,sm

okin

gca

tego

ry,

pac

kye

ars,

wei

ght,

and

plan

tlo

cati

on.

§ Com

pare

dw

ith

non

prod

uct

ion

wor

kers

.



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n m

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ce

Stu

dy d

esig

n

and

pop

ula

tion

Eval

uat

ion

met

hod

sR

esu

lts

Com

men

ts

Lock

eye

tal

.199

8(

Con

tinue

d)

(U.S

.stu

dy)

Pu

lmon

ary

fun

ctio

n: l

ongi

tud

inal

an

alys

is

(Con

tin

ued

)

R

egre

ssio

n c

oeffi

cien

t

Item

F

VC

†,‡

FEV

1 †,‡

Cu

mu

lati

ve e

xpos

ure

:In

itia

lRC

Fpr

odu

ctio

nc

ateg

ory,

≤7

year

s‡,§..

....

....

....

....

....

....

..–5

5.2

–38.

9

Init

ialR

CF

prod

uct

ion

cat

egor

y,

>

7ye

ars‡,

§..

....

....

....

....

....

....

.–1

68.3

**

–99.

6

Follo

wu

pcu

mu

lati

veR

CF

expo

sure

(fi

ber-

mon

ths/

cm3 )‡,

§..

....

....

....

0.7

+0.

5

Pro

du

ctio

n e

mp

loym

ent d

ura

tion

:In

itia

lRC

Fpr

odu

ctio

ny

ears

,≤7

year

s‡,§..

...

–66.

3–3

7.6

Init

ialR

CF

prod

uct

ion

yea

rs,>

7ye

ars‡,

§..

..–1

71.0

**

–100

.3

Follo

wu

pR

CF

prod

uct

ion

yea

rs§ ,

††.

....

....

.+

5.3

+0.

2

Cu

mu

lati

ve fi

ber

exp

osu

re:

Init

ialc

um

ula

tive

RC

Fex

posu

re,

>15

–60

fibe

r-m

onth

s/cm

3 ,‡‡

...

....

....

..–3

6.2

–100

.2

Init

ialc

um

ula

tive

RC

Fex

posu

re,

>60

fibe

r-m

onth

s/cm

3 ,‡‡

....

....

....

....

–156

.0

–104

.7

Fo

llow

up

cum

ula

tive

RC

Fex

posu

re,

fi

ber-

mon

ths/

cm3 ,

‡‡..

....

....

....

....

..+

0.8**

+

0.2

* Abb

revi

atio

ns:

FE

V1=

forc

ede

xpir

ator

yvo

lum

ein

1s

econ

d;F

VC

=fo

rced

vit

alc

apac

ity;

P=

prob

abili

ty;R

CFs

=re

frac

tory

cer

amic

fibe

rs.

† In

mill

ilite

rsfo

rm

ale

wor

kers

test

edfi

veto

sev

ent

imes

.‡ H

eigh

t-ad

just

ed;v

aria

bles

incl

ude

din

th

ean

alys

isw

ere

age,

cat

egor

ical

RC

Fpr

odu

ctio

ny

ears

toin

itia

ltes

t,fo

llow

up

cum

ula

tive

RC

Fex

posu

re,p

ack

year

sat

init

ialt

est,

d

ich

otom

ized

sm

okin

gat

eac

hte

st,w

eigh

tat

init

ialt

est,

wei

ght

chan

gea

nd

plan

tlo

cati

on.

§ Com

pare

dw

ith

non

prod

uct

ion

wor

kers

.**

P<

0.05

.††

Hei

ght-

adju

sted

;var

iabl

esin

clu

ded

int

he

anal

ysis

wer

eag

e,c

ateg

oric

alR

CF

prod

uct

ion

yea

rsto

init

ialt

est,

follo

wu

pR

CF

prod

uct

ion

yea

rs,p

ack

year

sat

in

itia

ltes

t,di

chot

omiz

eds

mok

ing

att

he

tim

eof

eac

hte

st,w

eigh

tat

init

ialt

est,

wei

ght

chan

ge,p

lan

tlo

cati

on.

‡‡H

eigh

t-ad

just

ed;v

aria

bles

incl

ude

din

th

ean

alys

isw

ere

age,

cat

egor

ical

cu

mu

lati

veR

CF

exp

osu

reto

init

ialt

est,

follo

wu

pcu

mu

lati

veR

CF

expo

sure

,pac

k

yea

rsa

tin

itia

ltes

t,di

chot

omiz

eds

mok

ing

ate

ach

test

,wei

ght

atin

itia

ltes

t,w

eigh

tch

ange

,pla

nt

loca

tion

.



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n m

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Bu

rge

eta

l.19

95

(Eu

rop

ean

stu

dy)

Cro

ss-s

ecti

onal

stu

dy:

From

ap

ossi

ble

708

cur -

ren

tw

orke

rs,6

28e

ligib

le

part

icip

ants

wer

eid

enti

fied

,an

d59

6of

th

ese

had

ch

est

X-r

aye

xam

inat

ion

s.A

fter

ex -

clu

sion

of

51fe

mal

ew

orke

rs

and

13u

nex

plai

ned

oth

ers,

da

taw

ere

avai

labl

efr

om

pulm

onar

yfu

nct

ion

test

sfo

r53

2m

ale

wor

kers

ins

even

E

uro

pea

nR

CF

prim

ary

prod

uct

ion

pla

nts

.

Hea

lth

: W

orke

rsw

ere

eval

uate

dby

as

elf-

adm

inis

tere

dex

pan

ded

resp

ira -

tory

que

stio

nn

aire

that

incl

uded

qu

esti

ons

rega

rdin

gsp

ecifi

csy

mpt

oms.

Pul

mon

ary

fun

ctio

n

test

ing

was

als

ope

rfor

med

.

Exp

osu

re:

Who

le-s

hift

per

son

ala

irs

ampl

es

wer

eco

llect

edfr

omr

ando

mly

se

lect

edw

orke

rsfr

omr

epre

sen

-ta

tive

job

cate

gori

esin

eac

hof

se

ven

RC

Fpr

oduc

tion

pla

nts

.Sa

mpl

esw

ere

colle

cted

an

dan

alyz

eda

ccor

din

gto

aW

HO

/E

UR

O[

1985

]re

fere

nce

met

hod

for

MM

MFs

too

btai

nd

ata

on

insp

irab

lea

nd

tota

lmas

san

dre

spir

able

fibe

rco

nce

ntr

atio

n.

Stat

isti

cal a

nal

ysis

:O

dds

rati

os(

wit

h95

%C

I)

adju

sted

for

plan

t,se

x,s

mok

-in

g,a

nd

age

wer

eca

lcul

ated

fo

rsy

mpt

oms

(i.e

.,dr

yco

ugh,

ch

ron

icb

ron

chit

is,w

heez

e,d

yp-

snea

≥2,s

tuff

yn

ose,

eye

an

dsk

in

irri

tati

on)

and

curr

ente

xpos

ure

cate

gori

esu

sin

gm

ulti

ple

logi

stic

re

gres

sion

.M

ulti

ple

linea

rre

gres

sion

coe

ffici

ents

for

lun

gfu

nct

ion

rel

ated

toc

umul

ativ

eex

posu

res

con

trol

led

for

the

effe

cts

ofr

espi

rabl

efi

ber

and

insp

irab

lem

ass

sepa

rate

lya

nd

toge

ther

.

Sym

pto

m a

nal

yses

E

xpos

ure

E

ffec

t

Cu

rren

t con

cen

trat

ion

s of

insp

irab

le m

ass:

† <

2.5

mg/

m3

Bas

elin

e2.

5to

<3

mg/

m3

Eye

irri

tati

on

[2.2

5(1

.43,

2.2

3)]‡

3m

g/m

3 D

ryc

ough

[3.4

2(1

.41,

8.3

3)]

D

yspn

ea ≥

2

[5

.84

(2.2

5,1

5.26

)]

Stu

ffy

nos

e

[2

.01

(1.1

3,3

.57)

]

Eye

irri

tati

on

[4

.78

(2.6

6,8

.6)]

Sk

inir

rita

tion

[3.3

(1.

8,6

.05)

]C

urr

ent c

once

ntr

atio

ns

of r

esp

irab

le fi

ber

s:†

<0.

2f/

cm3

Bas

elin

e0.

2to

<0.

6f/

cm3

Dry

cou

gh

[2

.53

(1.2

5,5

.11)

]

Stu

ffy

nos

e

[2

.06

(1.2

5,3

.39)

]

Eye

irri

tati

on

[2

.16

(1.3

2,3

.54)

]

Skin

irri

tati

on

[1

.25

(0.7

4,2

.11)

]≥0

.6f/

cm3

Dry

cou

gh

[2

.01

(1.0

5,3

.84)

]

Dys

pnea

2

[2

.66

(1.3

1,5

.42)

]

Eye

irri

tati

on

[2

.63

(1.7

,4.0

8)]

Sk

inir

rita

tion

[3.1

8(2

.01,

5.0

3)]

Cu

rren

tex

posu

res

tob

oth

insp

irab

led

ust

an

dre

spir

able

fi

bers

wer

ere

late

dto

dry

co

ugh

,stu

ffy

nos

e,e

yea

nd

skin

irri

tati

on,a

nd

brea

thle

ss-

nes

s.N

oan

alys

iso

fcu

mu

la-

tive

exp

osu

res

was

per

form

ed

wit

hr

esp

ect

tos

ympt

oms.

Ch

ange

sin

lun

gfu

nct

ion

wer

em

ore

stro

ngl

yre

late

dto

cu

mu

lati

vee

xpos

ure

tofi

bers

th

anto

cu

mu

lati

vee

xpos

ure

to

insp

irab

lem

ass.

Dec

re-

men

tsin

lun

gfu

nct

ion

wer

elim

ited

toc

urr

ent

smok

ers

and

form

ers

mok

ers,

su

gges

t -in

gth

ate

xpos

ure

tofi

bers

pr

omot

esr

espi

rato

rye

ffec

tso

fsm

okin

g.

(Con

tin

ued

)

* Abb

revi

atio

ns:

CI=

con

fide

nce

inte

rval

;MM

MFs

=m

an-m

ade

min

eral

fibe

rs;R

CFs

=re

frac

tory

cer

amic

fibe

rs.

† Sepa

rate

logi

stic

reg

ress

ion

mod

els

(adj

ust

edfo

rag

e,s

ex,s

mok

ing,

an

dpl

ant)

.‡ Fi

gure

sin

bra

cket

s=[O

R(

95%

CI)

].



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n M

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ceSt

udy

des

ign

and

pop

ula

tion

Eval

uat

ion

met

hod

sR

esu

lts

Com

men

ts

Bu

rge

eta

l.19

95,

con

tin

ued

(Eu

rop

ean

stu

dy)

Sym

pto

m a

nal

yses

, con

tin

ued

E

xpos

ure

E

ffec

t

Cur

ren

t con

cen

trat

ion

s

of in

spir

able

mas

s:§

2.5

to<

3m

g/m

3Ey

eir

rita

tion

[1.

90(

1.15

,3.1

5)]**

≥3m

g/m

3 D

yspn

ea≥

2[4

.74

(1.5

6,1

4.4)

]

Eye

irri

tati

on[

3.31

(1.

62,6

.77)

]C

urre

nt c

once

ntr

atio

ns

of r

espi

rabl

e fi

bers

:§

0.2

to<

0.6

f/cm

3 N

one

stat

isti

cally

sig

nific

ant

≥0.

6f/

cm3

Skin

irri

tati

on[

2.67

(1.

52,4

.70)

]

Pul

mon

ary

fun

ctio

n‡‡

Cum

ulat

ive

insp

irab

le

mas

s ex

posu

re:‡‡

Form

ers

mok

ers

FVC

–8

.7m

l/m

g@ m

3pe

rye

ar

FEV

1–6

.4m

l/m

g@ m

3pe

rye

arC

umul

ativ

e re

spir

able

fi

ber

expo

sure

:‡‡

Cur

rent

sm

oker

sFE

V1

–32

ml/

f @cm

3pe

rye

ar

FEF 25

–75–

63m

l/s

per

f @cm

3pe

rye

ar

Form

ers

mok

ers

FEV

1–3

7m

l/f @c

m3pe

rye

ar

Cum

ulat

ive

resp

irab

le

fibe

r ex

posu

re:§§

Cur

rent

sm

oker

sFE

V1

–36

ml/

f @cm

3pe

rye

ar

Exp

osur

e

Mea

n c

urre

nt i

nsp

irab

le m

ass:

Prim

ary

prod

ucti

on

1.7

to3

.4m

g/m

3

Seco

ndar

ypr

oduc

tion

1.

8to

11.

2m

g/m

3

Mea

n c

urre

nt r

espi

rabl

e

fibe

r co

nce

ntr

atio

n:

Prim

ary

prod

ucti

on

0.2

to0

.88

f/cm

3

Seco

ndar

ypr

oduc

tion

0.

49to

1.3

6f/

cm3

Mea

n c

umul

ativ

e ex

posu

re:

Insp

irab

lem

ass

28.2

4m

g/m

3Ay

ear

Res

pira

ble

fiber

s3.

84f/

cm3Ay

ear

(Con

tin

ued

)

§M

ult

iple

logi

stic

reg

ress

ion

(ad

just

edfo

rag

e,s

ex,s

mok

ing,

an

dpl

ant)

of

sym

ptom

pre

vale

nce

by

curr

ent

resp

irab

lefi

bers

an

dcu

rren

tin

spir

able

mas

sas

inde

pen

den

tva

riab

les

afte

rad

just

men

tfo

rth

eot

her

.*

* Figu

res

inb

rack

ets=

[OR

(95

%C

I)].

†† O

nly

sta

tist

ical

lys

ign

ific

ant

asso

ciat

ion

s(P

<0.

05)

are

show

n.

‡‡ Li

nea

rre

gres

sion

mod

elin

gof

cu

mu

lati

vee

xpos

ure

sto

insp

irab

lem

ass

and

resp

irab

lefi

bers

sep

arat

ely

(adj

ust

edfo

rag

e,h

eigh

t,an

dsm

okin

g).

§§ Li

nea

rre

gres

sion

mod

elin

gw

ith

bot

hc

um

ula

tive

exp

osu

rev

aria

bles

int

he

sam

em

odel

(ad

just

edfo

rag

e,h

eigh

t,an

dsm

okin

g).



Ta

ble

5–7

(Con

tin

ued

) . U

.S . a

nd

Eu

rop

ean

mor

bid

ity

stu

die

s w

ith

RC

Fs*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Ros

site

ret

al.

1994

(Eu

rop

ean

stu

dy)

Coh

ort m

orb

idit

y

stu

dy:

628

cu

rren

tly

wor

k-in

gem

ploy

ees

in

seve

nE

uro

pea

n

RC

Fpr

odu

ctio

n

plan

ts.5

43m

ale

wor

kers

wh

oh

ad

read

able

ch

est

radi

ogra

phs

wer

ein

clu

ded

int

he

anal

ysis

(59

6of

62

8w

orke

rs[

95%

]h

adc

hes

tra

dio-

grap

hs;

51

wom

en

and

2u

nre

adab

le

film

sw

ere

ex-

clu

ded)

.

Hea

lth:

Che

str

adio

grap

hsa

nd

ques

tion

nair

ew

ere

adm

inis

tere

d.D

ata

for

14d

escr

iptiv

ev

ari-

able

sw

ere

colle

cted

fo

rea

chw

orke

ras

fo

llow

s:p

rodu

ctio

n

plan

t;ag

e;y

ears

sin

ce

first

em

ploy

men

tat

plan

t;ye

ars

sinc

efir

st

expo

sed

toR

CFs

;yea

rs

ofe

mpl

oym

enti

nth

e

plan

t;cu

rren

tres

pi-

rabl

efib

ere

xpos

ure;

cu

rren

tnon

resp

irab

le

fiber

exp

osur

e;c

ur-

rent

insp

irab

lem

ass

expo

sure

;cum

ula-

tive

resp

irab

lefi

ber

expo

sure

;cum

ulat

ive

nonr

espi

rabl

efib

er

expo

sure

;cum

ulat

ive

insp

irab

lem

ass

exp

o-su

re;n

umbe

rof

jobs

at

the

plan

twit

has

best

os

expo

sure

;pri

ora

sbes

-to

sex

posu

re.

Rad

iogr

aph

ic a

nal

ysis

Eff

ect

Pre

vale

nce

Ple

ura

lch

ange

s2.

8%(

15/5

43)

Larg

eop

acit

ies

0Sm

allo

paci

ties

7.

0%(

38/5

43)

Irre

gula

r5.

5%R

oun

ded

3.5%

Mix

ed

5.2%

Stat

isti

cal a

nal

ysis

:

Prev

alen

ce o

f ple

ural

cha

nges

(n=

15)

as-

soci

ated

with

age

(χ2 =

18.8

5, P

=0.

0008

).

Prev

alen

ce o

f cas

es o

f sm

all o

paci

ty p

rofu

-si

on (

n=38

) re

late

d to

prod

ucti

onp

lant

(χ2 =

22.

10,P

<0.

0001

);

smok

ing

year

ssi

nce

first

em

ploy

men

t,ye

ars

ofe

mpl

oym

ent,

prio

ras

best

ose

xpos

ure,

cu

rren

tnon

resp

irab

lefi

ber

expo

sure

(no

χ2

repo

rted

, P≤0

.05)

.

Prev

alen

ce o

f cas

es w

ith m

ostly

rou

nded

op

acit

ies (

n=23

) re

late

d to

heav

ysm

okin

g(χ

2 =2.

18,P

=0.

14);

asb

esto

sex

posu

rew

ithi

nth

eR

CF

plan

ts

(χ2 =

3.08

wit

hco

ntin

uity

cor

rect

ion,

P=

0.08

);b

utn

ota

ge(

χ2 =1.

25,P

=0.

87)

or

prod

ucti

onp

lant

(χ2 =

5.1

3,P

=0.

53).

Prev

alen

ce o

f cas

es w

ith m

ostly

irre

gula

r op

acit

ies (

n=15

) re

late

d to

age

(χ2 =

38.

9,P

<0.

0001

);c

urre

ntn

on-

resp

irab

lefi

ber

leve

ls(

χ2 =5.

2,P

=0.

07);

ye

ars

sinc

efir

stR

CF

empl

oym

ent(

χ2 =8.

16,

P=0.

09);

yea

rso

fR

CF

empl

oym

ent

(χ2 =

8.70

,P=

0.07

);b

utn

otp

lant

(P=

0.23

).

Ple

ural

cha

nge

s(n

=15

)in

clud

ed

four

cas

esw

ith

bila

tera

ldif

fuse

thic

ken

ing

(on

ew

ith

calc

ifica

-ti

on);

on

ew

ith

bila

tera

lple

u-

ralc

alci

fica

tion

on

ly;s

even

wit

h

unila

tera

ldif

fuse

thic

ken

ing;

th

ree

wit

hco

stop

hren

ica

ngl

ebl

unti

ng

only

.Pre

vale

nce

of

pleu

ralc

han

ges

was

ass

ocia

ted

wit

hag

e.

Irre

gula

rop

acit

ies

wer

ere

late

dto

ag

e,c

urre

ntn

onre

spir

able

fibe

rco

nce

ntr

atio

ns,

an

ddu

rati

on

and

late

ncy

of

RC

Fe

mpl

oy-

men

t.O

vera

ll,a

slig

hta

ssoc

ia-

tion

was

not

edfo

rpr

eval

ence

of

smal

lopa

citi

esa

nd

wor

kin

gin

ce

ram

icfi

ber

prod

ucti

on(

i.e.,

RC

Fem

ploy

men

tlat

ency

an

ddu

rati

on).

The

res

earc

hers

con

-cl

uded

itw

asu

nlik

ely

that

fibe

rex

posu

rew

asth

em

ain

cau

seo

fra

diog

raph

ica

bnor

mal

itie

s.

The

pos

sibi

lity

for

con

foun

din

gef

fect

sdu

eto

oth

ere

xpos

ures

is

rec

ogn

ized

:52%

of

wor

kers

re

port

edp

revi

ous

empl

oym

ent

inin

dust

ries

wit

hpo

ten

tial

ex

posu

reto

dus

ts,i

ncl

udin

gas

best

os(

5%),

sto

ne

quar

ryin

g(2

%),

iron

/ste

elfo

undr

ies

(6%

),

refr

acto

ryb

rick

wor

k(1

0%),

an

dm

an-m

ade

min

eral

fibe

rs(

8%).

(Con

tinu

ed)

* Abb

revi

atio

ns.

N=

nu

mbe

r;P

=pr

obab

ility

;RC

Fs=

refr

acto

ryc

eram

icfi

bers

.



Tabl

e 5–

7 (C

onti

nu

ed) .

U .S

. an

d E

uro

pea

n M

orb

idit

y st

ud

ies

wit

h R

CFs

*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Tret

how

an

eta

l.19

95

(Eu

rop

ean

stu

dy)

Cro

ss-s

ecti

onal

resp

ira-

tory

mor

bidi

ty st

udy:

628

curr

ent

wor

kers

in

sev

enE

uro

pea

n

RC

Fm

anu

fact

uri

ng

plan

ts.

Mea

na

ge=

37.

7ye

ars.

Mea

nd

ura

tion

of

empl

oym

ent

=1

0.2

year

s.

91%

wer

em

ale

wor

kers

an

d9%

w

ere

fem

ale

wor

kers

.

44%

wer

ecu

rren

tsm

oker

s.

Hea

lth

:A

sel

f-ad

min

iste

red

que

stio

nn

aire

w

asu

sed

too

btai

nin

form

atio

n

abou

tres

pira

tory

,nas

al,e

ye,a

nd

skin

sym

ptom

s,p

lus

deta

ilso

fsu

b -je

cts=

occ

upat

ion

alh

isto

ry.P

FTw

as

also

per

form

ed,a

nd

ches

tX-r

ays

wer

eob

tain

edfr

om5

92s

ubje

cts.

Exp

osu

re a

sses

smen

t:14

0jo

bsw

ere

iden

tifi

eda

nd

clas

si-

fied

into

sev

enm

ain

gro

ups.

Full-

shif

tp

erso

nal

air

sam

ples

wer

eco

llect

edfo

rra

ndo

mly

sel

ecte

dw

orke

rsin

eac

ho

fth

ese

ven

mai

n

grou

ps.

Insp

irab

led

ust

mon

itor

ing

was

p

erfo

rmed

acc

ordi

ng

toa

nA

CG

IH

met

hod

.

Res

pira

ble

fibe

rco

nce

ntr

atio

nw

as

mea

sure

dac

cord

ing

toa

WH

O/

EU

RO

[19

85]

refe

ren

cem

eth

odfo

rM

MM

Fs.

(Res

pira

ble

fibe

ris

de -

fin

eda

s<

5µm

lon

gw

ith

an

asp

ect

rati

o>

3:1

and

adi

amet

er ≤

3µm

.)

Stat

isti

cal a

nal

ysis

:P

ulm

onar

yfu

nct

ion

indi

ces

wer

eco

mpa

red

for

cum

ula

tive

exp

osu

re

grou

ps.S

ympt

oms

wer

ein

vest

i -ga

ted

bylo

gist

icr

egre

ssio

n,a

nd

pulm

onar

yfu

nct

ion

by

linea

rre

gres

sion

.Mod

els

wer

eco

ntr

olle

dfo

ref

fect

sof

age

,sex

,sm

okin

gh

abit

s,a

nd

prev

iou

sex

pos

ure

to

resp

irat

ory

haz

ards

.

Rad

iogr

aph

ic a

nal

ysis

E

ffec

t P

reva

len

ce

Ple

ura

lch

ange

s2.

7%(

16/5

92)

Larg

eop

acit

ies

0Sm

allo

paci

ties

13

%Ir

regu

lar

5.1%

Rou

nde

d3.

2%M

ixed

4.

7%

Sym

pto

m a

nal

yses

Cu

rren

t re

spir

able

f/cm

3 E

ffec

t [O

R† (

95%

CI)

]

<0.

2B

asel

ine

0.2

to<

0.6

Dry

cou

gh

[2.5

3(1

.25,

5.1

1)]

St

uff

yn

ose

[2.0

6(1

.25,

3.3

9)]

E

yeir

rita

tion

[2

.16

(1.3

2,3

.54)

]≥0

.6

Dry

cou

gh

[2.0

1(1

.05,

3.8

4)]

D

yspn

ea ≥

2[2

.66

(1.3

1,5

.42)

]

Eye

irri

tati

on

[2.6

3(1

.7,4

.08)

]

Skin

irri

tati

on[

3.18

(2.

01,5

.03)

]

Pre

vale

nce

of

smal

lopa

citi

esin

crea

sed

wit

ha

ge,s

mok

-in

g,a

nd

prev

iou

sex

posu

reto

as

best

os,b

ut

not

wit

hc

um

ula

-ti

vee

xpos

ure

sto

cer

amic

fi

bers

.No

desc

ript

ion

of

this

an

alys

isis

pro

vide

d.Sy

mpt

oms

pres

ent

int

he

stu

dyp

opu

lati

onw

ere

rela

ted

toe

xpos

ure

tor

espi

rabl

efi

bers

.St

atis

tica

llys

ign

ifica

nt

incr

eas -

esw

ere

not

edin

th

epr

eval

ence

of

dys

pnea

(bo

thg

rade

s)w

ith

in

crea

sin

gcu

mu

lati

vefi

ber

expo

sure

gro

ups

.Lu

ng

fun

ctio

nte

sts

show

eda

sign

ifica

nt

rela

tion

bet

wee

nin

-cr

easi

ng

cum

ula

tive

exp

osu

re

tor

espi

rabl

efi

bers

an

dde

cre -

men

tsin

FE

V1a

nd

FEF 25

-75in

cu

rren

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atio

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ican

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* Abb

revi

atio

ns:

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eram

icfi

bers

;FE

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pleuralplaquesin5%(40/774)ofstudypartic-ipants.IntheU.S.study,23caseswithpleuralabnormalities (all production workers) wereidentified from847maleand femaleworkers(686production,161nonproduction)[Lemas-tersetal.1994].Theprevalenceofpleuralab-normalities amongallworkerswas2.7%andforproductionworkersonly,3.4%.Ofthecas-es,21wereclassifiedashavingpleuralplaquesand 2 as having diffuse pleural thickening.Oneworkerreportedhavingpreviouslydiag-nosedkaolinosisfromprioremploymentinakaolinmine.Lockeyetal.[1996]conductedafollowupreportbasedonreviewof652chestfilmsfromcurrentandformerworkersattwooftheU.S.plants.Theyreportedaprevalenceofpleuralchangesof3.1%(n=20), including19pleuralplaquecasesand1withdiffusepleu-ralthickening.Pleuralplaqueswerepresentin18 (4.1%) production workers and 2 (0.9%)nonproductionworkers.Thetwononproduc-tionworkerswithpleuralplaqueshadworkedwith RCFs as laboratory technicians. Fromstatistical analyses of pleural abnormalities,Rossiter et al. [1994] reported an associationwith age [χ2=18.85, P=0.0008]. However, noattemptwasmade toassesswhetheranasso-ciation existed between pleural abnormalitiesandRCFexposure.Trethowanetal.[1995]alsonoted that pleural abnormalities were relatedtoagebutnotindependentlytoceramicfiberexposures.Cowieetal. [1999,2001]reportedpleural abnormalities to be associated withage, exposure to asbestos, and body mass in-dex(weightdividedbyheightsquared).Whenthedatawereunadjusted for age, an associa-tionexistedbetweenpleuralchangesandyearsworked at the plant. Lemasters et al. [1994]foundthatpleuralabnormalitieswereassoci-atedwithtimesincefirstRCFexposure(RCFlatency)afteradjustingfordurationofasbes-tosexposureandtimesincefirstasbestosexpo-sure(oddsratio [OR]=2.9[95%CI=0.8–9.7]for >10 to 20 years of RCF latency, and 7.7[95% CI=2.0–29.1] for >20 years of RCF

latency,whencomparedwithworkershaving<10yearsofRCFlatency).Pleuralabnormali-tiesremainedstatisticallysignificant(P<0.001)withtimesincefirstRCFexposure(latency)af-teradjustmentfortheeffectsofsmoking,bodyweight, and latency and duration of asbestosexposure.Thepositiveassociationpersistedaf-ter exclusion of workers exposed to asbestos.Inmultiplelogisticregressionanalyses,anas-sociation between duration of RCF exposureandpleuralabnormalitiesremainedsignificant(χ2=7.75, P=0.005)afteradjustmentforasbes-toslatency,asbestosduration,andage[Lemas-ters et al. 1994]. In subsequent analyses withadjustmentforage,researchersfoundthatas-sociations persisted between pleural plaquesand latency and duration of RCF exposure[Lockeyetal.1996].Inthreeseparateanalyses,Lockey etal. [1996] found that prevalence ofpleuralplaquesrelatedtothefollowing:

■ >20yearsofRCFlatency(OR=9.5[95%CI=1.9–48.2])

■ >20yearsRCFexposuredurationinpro-duction jobs (OR=22.3 [95% CI=3.6–137.0])

■ CumulativeRCFexposureinthehighestexposure category (>135 fiber-months/cm3)(OR=24.2[95%CI=2.6–224.9])

Results of a nested case-control study of the20 workers with pleural plaques (matched to3controlsbasedonsex,RCFemploymentsta-tus,andproduction/nonproductioncategory)support the associations of pleural changeswith RCF latency, RCF exposure duration,and cumulative RCF exposure [Lockey et al.1996].Alatencyvalidityreviewwasalsocon-ducted, involving analysis of 205 historicalchest radiographs available for workers withpleural changes. The purpose of the reviewwas to confirm that for persons with pleuralplaques,abiologicallyplausiblelatencyperiod(≥5 years) existed between initial RCF expo-sureandappearanceofapleuralplaque.Of18pleuralplaquecasesforwhichhistoricalchest



radiographswereavailable,only1hadalatencyperiodof<5yearsfrominitialRCFproductiontorecognitionofapleuralplaque.

AsubsequentanalysisbyLockeyetal.[2002]included chest radiographs for 625 currentworkersobtainedevery3yearsat5RCFman-ufacturing sites and 383 former workers at2 of the 5 sites. Pleural changes were seen in27workers(2.7%),ofwhich19werebilateralplaques (70%) and 3 were unilateral plaques(11%).CumulativeRCFexposure(>135fiber-months/cm3)wassignificantlyassociatedwithpleuralchanges(OR=6.0,95%CI=1.4,31.0).Theresearchersnotedanincreasingbutnon-significanttrendinvolvinginterstitialchangesand RCF exposure duration in a productionjobandcumulativeRCFexposure.

5.3.2.2 Parenchymal Opacities

In the 1987 European study, Rossiter et al.[1994]foundthat7%(38/543)ofthecurrentmale workers had small parenchymal opaci-tieswithmedianprofusionof1/0ormore.Nolarge parenchymal opacities were observed.Bothpredominantlyrounded(n=23,or4.2%)andpredominantlyirregular(n=15,or2.8%)small parenchymal opacities were identified.Prevalence of rounded, small opacities wasnot associated with age (P=0.87) or produc-tionplant(P=0.53).However,withprevalenceofopacities,strongerassociationsexistedwithasbestos exposure in RCF production plants(P=0.08)andheavysmoking(P=0.14)[Rossit-eretal.1994].Predominantlyirregular,smallopacitieswereassociatedwithage(P<0.0001)but not with production plant (P=0.23). Af-terallowingforage,associationswithcurrentnonrespirablefiberconcentrations,yearssincefirst RCF employment, and duration of RCFemployment approached statistical signifi-cance(P=0.07to0.09).Inasubsequentanaly-sisofsmallopacitiesforbothmaleandfemaleworkers,Trethowanetal.[1995]notedthatthe

prevalence of small opacities increased withage,smoking,andpreviousexposuretoasbes-tosbutnotwithcumulativeRCFexposure.Nodescriptionoftheanalysiswasprovided.Cow-ieetal.[1999]reportedthat10of51(19.6%)menwithRCFexposurebefore1971hadsmallopacities of category 1/0 or greater. Eight ofthese10hadbeenexposedtoasbestos,and9wereeithercurrentorex-smokers.IntheU.S.study,noanalyseswereperformedtoassesstherelationshipbetweensmallopacitiesandRCFexposurebecauseofthesmallnumberofcas-es (n=4) identified by Lemasters et al. [1994,1996].

5.3.3 Respiratory Conditions and Symptom Analyses

Using respiratory health questionnaires, theU.S.andEuropeanstudiessoughttoidentifyre-spiratoryconditionsandsymptomsthatcouldbe associated with exposure to RCFs. Lockeyet al. [1993] administered to 717 subjects astandardized respiratory symptomsquestion-naire that included questions about the fol-lowing symptoms and conditions: chroniccough, chronic phlegm, dyspnea grades 1and2(describedintheDefinitionssectionofthis document), wheezing, asthma, pleurisy,and pleuritic chest pain. Logistic regressionanalyses were adjusted for age, sex, smoking(pack years), duration of asbestos exposure,durationofproductionemployment,durationof other hazardous occupational respiratoryexposure, and time since last RCF employ-ment.Withtheexceptionofasthma,forwhichself-selectionoutofproductionjobsmayhaveoccurred,adjustedORsforrespiratorysymp-tomsweresignificantlyelevatedinproductionworkerscomparedwithnonproductionwork-ers.Resultsofasubsequentanalysiswith742RCFworkersbyLemasters et al. [1998] indi-catedthattheprevalenceofrespiratorysymp-tomsandconditions(except forasthma)wasapproximately twofold to fivefold higher in



production than in nonproduction workers.The most frequently reported symptom formaleproductionworkerswasdyspneagrade1(15.7%,comparedwith2.5%fornonproduc-tion),followedbywheezing(10.3%,comparedwith3.8% fornonproduction).Prevalenceofone or more respiratory symptoms and con-ditionsamongfemaleproductionworkerswas40.7%,comparedwith20.3%fornonproduc-tionworkers.

Trethowanetal.[1995]examinedtherelation-shipofdrycough,chronicbronchitis,dyspnea(twogrades),wheeze,stuffynose,eyeirritation,andskin irritationtocurrentandcumulativeRCF exposure estimates among 628 workers.Current exposures were based on air sam-plingmeasurementstakeninassociationwiththerespiratoryhealth survey.Theresearchersnotedeyeandskinirritationwerefrequentinall plants and increased significantly, as diddyspnea and wheeze, with increasing currentexposure concentrations (i.e., 0.2 to 0.6 and≥0.6 f/cm3)aftercontrolling forage, sex,andsmoking habits. The most frequent symp-tom, nasal stuffiness (in 55% of the group),showed no clear association with increasingcurrent exposure. Chronic bronchitis, with aprevalenceof12%amongallworkers,alsoap-pearedunaffectedbyincreasingcurrentexpo-sureconcentration.Drycough,eye irritation,and skin irritation all seemed to be associat-ed with increasing exposure, especially at thehighest exposure concentration (≥0.6 f/cm3).Analysesofcumulativeexposuretorespirablefibers showed statistically significant associa-tions with dyspnea but no apparent associa-tionwithchronicbronchitisandwheeze.Inaseparateanalysisofthesamecohort,Burgeetal.[1995]investigatedtherelativeimportanceof respirable RCF exposure versus inspirabledustexposureinpredictingrespiratorysymp-tomsandconditions.Thestudy foundwork-ers=currentexposurestobothinspirabledustandrespirablefiberswererelated(P<0.05)to

drycough,stuffynose,eyeandskinirritation,andbreathlessness(dyspnea)afteradjustmentfortheeffectsofsmoking,sex,age,andplant.Only skin irritation was significantly associ-ated with current RCF exposure after con-trollingforexposuretoinspirabledust.Burgeetal. [1995] did not analyze the relationshipbetween symptoms and cumulative exposureindices.Cowieetal.[1999,2001]reportedthatrecurrentchestillnesswasassociatedwithesti-matedcumulativeexposuretorespirablefibersbutwasnotsignificantlyassociatedwithrecentexposure.

5.3.4 Pulmonary Function Testing

Trethowan et al. [1995] analyzed spirometrytest results from 600 of 628 current workerswhoparticipatedat7EuropeanRCFproduc-tionplants.Inseparatemultiplelinearregres-sionanalysesformaleworkersineachsmokingcategory(current,former,never),theauthorscontrolledforage,height,andpastexposurestovariousrespiratoryhazards(includingprevi-ousemploymentinotherceramicfiberplants).Results associated cumulative RCFs with sta-tistically significant (P<0.05) decrements inFEV

1inbothcurrentandformersmokersand

withdecreases inFEF25-75

incurrent smokers.Inneversmokers(n=154),allregressioncoef-ficientsofcumulativeRCFexposureinrelationtolungfunctionweresmall,positive,andnotstatisticallysignificant.

Aswiththesymptomsdata,Burgeetal.[1995]further analyzed the spirometry data fromthe European study to discern whether theobserved effects were more highly associatedwith current respirable RCF exposure thanwithconcurrentinspirabledustexposure.Inamultiplelinearregressionmodelthatexcludedcumulative inspirable dust exposure, statisti-cally significant (P<0.05) decreases in FEV

1

andFEF25-75

amongcurrentsmokersandFEV1

among former smokers were associated with



cumulative exposure to respirable RCFs. In amultiplelinearregressionmodelthatincludedvariables for cumulative dust and cumulativerespirable RCFs, the only statistically signifi-cant (P<0.05) association for these variableswas for the decrease in FEV

1 among current

smokersassociatedwithcumulativerespirableRCFexposure.Nocumulativedust-associatedcoefficients remained statistically significantafteradjustingfortheeffectofcumulativeRCFexposure.Thus,theinvestigatorsattributedtheadversepulmonaryfunctioneffectobservedinsmokers to the fiber component of occupa-tional dust exposures at RCF manufacturingplants.

Cowieetal. [1999,2001]observedthatRCF-exposed male workers (n=692) showed adecrease in FEV

1 and FVC only for current

smokers, the strongestassociationbeingwithestimated cumulative exposure to respirablefibers.TheaverageestimateddecreaseinFEV

1

andFVCwasmild,approximately100ml.Fe-maleRCF-exposedworkers(n=82)hadade-creased FEV

1 with increasing cumulative ex-

posuretorespirablefibersandrespirableandtotaldust.Amongthefemaleworkers,cumu-lativeexposuretototaldustwasmoststronglyassociatedwithdecreasedpulmonaryfunctionmeasurements.

Lemastersetal.[1998]anaylzedPFTdatafor736 male and female current workers at fiveU.S. RCF plants. They reported decreases inthe percentage of predicted FVC and FEV

1

withevery10yearsofRCFproductionwork.Although the decreases were greatest amongcurrentmalesmokersandformermalesmok-ers,theyweregreaterthandecreasesassociatedwith smoking alone. No significant changeswerenotedinpulmonaryfunctionofRCFpro-ductionworkerswhoneversmoked.AseparatestudybyLockeyetal.[1998]involvedlongitu-dinalanalysisofdatafromacohortof361cur-rent male RCF workers hired before June 30,1990,whohadparticipatedinatleastfivePFT

sessionsbetween1987and1994.Bycompari-son,nonparticipantswhowereexcludedfromthe analysis according to the criteria abovewereonaverageolder,smoked,weighedmore,and had lower height-adjusted and percent-predictedlungfunctionvalues.Cross-sectionalanalysisoftheinitialpulmonaryfunctionses-sion in a regression model included coeffi-cients for age, ≤7 versus >7 RCF productionyears,smokingstatus(packyears,currentver-susformersmoker),weight,andplantlocation(categorical).Theanalysis founddecreases inFVCandFEV

1forworkersemployed>7years

inproductioncomparedwithnonproductionworkers. In longitudinal analysesof followupproductionyears(i.e.,frominitialPFTtofinalPFT)andfollowupcumulativeexposure(i.e.,frominitialPFTtofinalPFT),neitherofthesevariableshadaneffectonFVCorFEV

1.These

results led theauthors toconclude thatmorerecent exposure concentrations during 1980–1994 had no adverse effect on the longitudi-nal trend of pulmonary function [Lockey etal.1998].DecrementsinFVCandFEV

1noted

in initial cross-sectionalanalysesofPFTdatawerebelievedtoberelatedtoearlierhigherex-posureconcentrations.

5.3.5 Mortality Studies

Table5–8presentsfindingsfromacohortmor-talitystudyoftwoU.S.RCFproductionplantsreportedbyLockeyetal.[1993].Thestudyisbasedonacohortof684maleworkersattwoRCF production plants who were employedforatleast1yearbetweenJanuary1,1950,andJune1,1988.Fiveworkerswerelosttofollow-upand46weredeceased.Becausethisisarela-tivelynew industry (40years at the timeofthestudy)thathasexperiencedrecentgrowthoftheworkforceattheplantsstudied,person-years at risk were limited at higher latencies(for example, only 126.37 person-years with>30yearssincefirstRCFjob).Usingstandard-izedmortalityratios(SMRs),theauthorsfound



Tabl

e 5–

8 . M

orta

lity

stu

dy w

ith

RC

Fs*

Ref

eren

ceSt

udy

des

ign

an

d p

opu

lati

onEv

alu

atio

n m

eth

ods

Res

ult

sC

omm

ents

Lock

eye

tal

.199

3

(U.S

.stu

dy)

Coh

ort m

orta

lity

stud

y:

Cu

rren

tan

dfo

rmer

m

ale

wor

kers

at

two

plan

tsi

tes

empl

oyed

at

leas

tly

ear

int

he

man

-fa

ctu

reo

fR

CFs

bet

wee

n

10/1

/50

and

6/1/

88.O

fth

e68

4w

orke

rsw

ho

met

th

ecr

iter

ia,6

33

(92.

5%)

wer

eal

ive,

46

(6.7

%)

wer

ede

ceas

ed,

and

5(0

.7%

)w

ere

lost

to

follo

wu

p.

Cau

se-s

pec

ific

SMR

s

w

ere

calc

ula

ted

usi

ng

the

tota

lU.S

.mal

e

po

pula

tion

as

the

refe

ren

cep

opu

la-

ti

on.P

erso

n-y

ears

wer

est

rati

fied

by

age,

race

,cal

enda

rti

me,

late

ncy

,an

dcu

mu

la-

ti

ved

ura

tion

.

Dem

ogra

phic

s:

62

4C

auca

sion

s

60n

on-C

auca

sion

s

Wor

ker

dis

trib

uti

on

Yea

rss

ince

firs

tP

erso

n-y

ears

RC

Fjo

b

atr

isk

Stat

istic

ally

sign

ifica

ntin

crea

se

ind

eath

sfro

mth

efo

llow

-in

g:(

1)p

neum

ocon

iose

san

dot

herr

espi

rato

ryd

isea

se

fort

hec

ateg

ory

ofC

auca

-si

anm

ale

wor

kers

with

>

30y

ears

ofR

CF

late

ncy

(n=

2,S

MR

=2,

614

[95%

C

I=24

6–7,

490]

);(2

)can

cers

of

the

dige

stiv

eor

gans

an

dpe

rito

neum

forn

on-

Cau

casi

anm

ale

wor

kers

(n

=2,

SM

R=

913

[95%

C

I=11

0–3,

295]

);(3

)can

cers

of

the

urin

ary

orga

nsfo

rm

ale

wor

kers

with

>15

–20

year

sofR

CF

late

ncy

(n=

2,

SMR

=3,

306

[95%

CI=

311–

9,47

1]).

The

pow

erto

det

ecta

sign

ifi-

cant

incr

ease

inm

orta

lity

for

any

spec

ific

caus

ew

aslo

w

beca

use

ofth

esm

alln

umbe

rof

dea

thsi

nth

eco

hort

.

1to

5

3,39

0>

5to

10

3,15

5>

10to

15

2,51

2>

15to

20

1,19

7>

20to

25

518

>25

to3

027

7>

30

126

Tota

l11

,175

C

ause

of

deat

h

SMR

(95

%C

I)

All

cau

ses:

40C

auca

sion

s97

(69

–132

)

6n

on-C

auca

sion

s12

6(4

6–27

4)

All

can

cers

:

11C

auca

sion

s12

1(6

0–21

6)

2

non

-Cau

casi

ons

263

(32–

950)

4lu

ng

can

cers

† 11

4(3

1–29

1)

2ca

nce

rso

fth

eu

rin

ary

or

gan

s† 46

7(5

7–1,

687)

6

can

cers

of

the

dige

stiv

e

or

gan

s† 25

9(9

4–56

3)

2pn

eum

ocon

iose

san

dot

her

resp

irat

ory

dise

ase†

205

(25–

740)

* Abb

revi

atio

ns:

CI=

con

fide

nce

inte

rval

;RC

Fs=

refr

acto

ryc

eram

icfi

bers

;SM

R=

stan

dard

ized

mor

talit

yra

tio.

† Com

bin

edr

ace

coh

ort.



the combined-race cohort to have no signifi-cant elevations associated with specific causesofdeath,includingcancersofthelung,digestiveorgans and peritoneum, urinary organs, andpneumoconiosesandotherrespiratorydisease.The authors noted that the power to detect asignificantincreaseinmortalityforanyspecificcausewaslowbecauseofthesmallnumberofdeathsinthecohortandgenerallyshortlaten-cies.However,astatisticallysignificantincreaseindeaths frompneumoconiosesandotherre-spiratory disease occurred in Caucasian maleswith>30yearsRCF latency (n=2,SMR=2,614[95%CI=246–7,490]).Astatisticallysignificantelevation in deaths from cancers of the diges-tive organs and peritoneum also occurred fornon-Caucasian males (n=2, SMR=913 [95%CI=110–3,295]).Inaddition,astatisticallysig-nificant elevation occurred in the number ofdeaths from cancers of the urinary organs formaleworkerswith>15to20yearsofRCF la-tency(n=2,SMR=3,306[95%CI=311–9,471]).

Lemastersetal.[2003]publishedasubsequentanalysisofcurrentandformermaleworkersemployedbetween1952and2000atthetwoRCF manufacturing facilities (942 subjects)investigating a possible excess in mortality.Themortalityanalyticmethodsincluded(1)standardizedmortalityratioscomparingthiscohortwiththegeneralandStatepopulationsand(2)aproportionalhazardsmodelthatre-latesriskofdeathtothe lifetimecumulativefiber-months/cm3 exposure among the RCFcohort,adjustedforageathireandforrace.Theanalysisfoundnoexcessmortalityrelat-ed to all deaths, all cancers, or malignanciesordiseasesoftherespiratorysystem(includ-ing mesothelioma) but found a statisticallysignificant association with cancers of theurinaryorgans[SMR=344.8(95%confidencelimits of 111.6, 805.4)]. Based on the smallsize of the cohort, the young average age(51 years), and a mean latency of 21 years,the researchers concluded that the findings

warrantcontinuedsurveillanceofthecohortmortalityregistry.

Walker et al. [2002] used the same cohort ofmaleRCFproductionworkersdescribedbyLe-mastersetal.[2003].Walkeretal.performedariskanalysiscomparingthelungcancerandme-sotheliomainthecohort’saccumulatedmortal-ity experience to that which would have beenexpected if RCFs had a carcinogenic potencyapproximating various forms of asbestos. TheauthorsreportedthatdeathsfromlungcancerintheRCFcohortwerestatisticallysignificantlybelow that which would be expected if RCFshadthepotencyofeithercrocidoliteoramosite.Themortalitywasalsolowerthanwouldbeex-pected if RCFs had the potency of chrysotile,butthedifferenceisnotstatisticallysignificant.For mesothelioma, the authors concluded theanticipated numbers of deaths under hypoth-esesofasbestos-likepotencyaretoosmalltoberejectedby thezerocases seen in theRCFco-horts [Walkeretal.2002].NIOSHresearchersnotedthatthisanalysisbyWalkeretal.wasnotbasedon themostcurrentupdateof theRCFcohort.Inaddition,theasbestosriskassessmentmodelsusedbyWalkeretal.[2002]werefittedto studies with longer followup periods thanthecohortofRCFworkers.Becausethesemod-elsdonot specify lengthof followup, it isnotpossibletoadjust forthesedifferences.Conse-quently,itislikelythattheRCFcohorthasnotbeenfollowedforasufficientlengthoftimetodemonstratetherisksthatwereobservedintheasbestos cohorts. NIOSH believes the mortal-itystudybyLemastersetal.[2003]andtheriskanalysisbyWalkeretal.[2002]haveinsufficientpower fordetecting lungcancer riskbasedonwhatwouldbepredictedforasbestos.

5.3.6 NIOSH HHEs

Aspartofitsmissionasapublichealthagen-cy, NIOSH performs HHEs at the request ofworkers,employers,or labororganizations toinvestigate occupational hazards associated



withaworkplaceorwork-relatedactivity.Onesuch HHE involved evaluating worker expo-surestoceramicfibersatacompanymanufac-turingsteel forgings[Kominsky1978].Atthefacility, furnaces for heat-treating steel ingotswerelinedwithRCFfeltandbatting,andthislining required regular maintenance and re-placement. Among the workers interviewedweresixbricklayersinvolvedinfurnaceliningmaintenance.Fourofthebricklayersreportedhavingexperienced irritationofexposedskinareas and of the throat during the handlingandinstallationoftheRCF-containinginsula-tion. On the basis of the reported symptomsand their consistency with known effects ofRCFs,thesymptomsofirritationwereattrib-utedtoRCFexposure.Noattemptwasmadetomeasureairbornefiberconcentrations.Anoth-erNIOSHHHE[Lyman1992] resulted fromanOSHAinspectionthatidentified18casesofoccupationallungdiseaserecordedin1yearataplantmanufacturingfirebricks,ceramicfiberproducts, and other thermal insulation com-ponentsfromkaolin.About600workerswerepotentiallyexposedtorespiratoryhazardsthatincluded not only RCFs but also kaolin dust,crystalline silica dust, and (for maintenanceworkers) asbestos. A total of 38workers hadbeen referred to a pulmonary physician forevaluation based on 2 rounds of chest X-rayscreeningoftheworkforce in1980and1986.Diagnoses were related to pleural thickening(n=10),pleuralplaques(n=3),diffusepulmo-naryfibrosis(n=21),mesothelioma(n=1),andothermiscellaneousconditions.Atleast20ofthese cases were classified as work-related bythe pulmonologist who evaluated the cases.The nonoccupational classification of someoftheremaining18caseswasquestionedbyaNIOSHphysicianwhoperformedaretrospec-tive record review. The 38 cases were reclas-sified on the basis of job histories into thosewhowerelikelytohavebeenexposedtoRCFs(n=19,including4withpleuralabnormalitiesand8withdiffusefibrosis)andthoseunlikely

tohavebeenexposedtoRCFs(n=19,including9withpleuralabnormalities,13withfibrosis,and 1 with mesothelioma). However, no at-temptwasmadetoanalyzefurtherforanas-sociationof thecaseswithexposuretoRCFs.Thereportimpliedthatoccupationalexposuretokaolindustandtoasbestoscausedmanyorallofthejob-relatedconditions.

5.3.7 Discussion

TheradiographicanalysesoftheU.S.and1996Europeanworkergroups suggest anassocia-tionbetweenpleuralabnormalities,includingpleural plaques, and RCF exposure [Lemas-ters et al. 1994;Lockey et al. 1996;Cowie etal.1999].FromRossiteretal.[1994]itislessapparentwhethersuchanassociationwasin-vestigated.Trethowanetal.[1995]reportthatpleuralabnormalitieswerenotindependentlyrelatedtoRCFexposure.Differencesbetweenthefindingsof theU.S. studiesand thoseoftheinitialEuropeanstudiesmayberelatedtothelonglatencybeforepleuralabnormalitiesare detectable, in particular, pleural plaquesfollowingRCFexposure.Workersexposedtoasbestos developed asbestos-associated pleu-ralplaquesafteralatencyperiodofmorethan15yearsafterinitialexposure[Hillerdal1994]andinsomecases,after30to57years[Beginetal.1996].TheEuropeanRCFindustryde-velopedmorethanadecadeaftertheU.S.in-dustry.Asaresult,workersintheU.S.groupare slightly older with a longer average em-ploymentdurationinRCFmanufacturingandtime since first exposure to RCFs. Historicalairsamplingdataalso indicatethatairbornefiber concentrations were much higher inearlyU.S.RCFmanufacturing.These factorsmight explain thefindingofRCF-associatedpleuralabnormalitiesintheU.S.workersbutnot intheEuropeanworkers.Afurtherpos-sible explanation may involve differences intheradiographicsurveillancemethodologies.BoththeU.S.andtheEuropeanstudiesused



the1980ILOclassificationsystemsforpneu-monoconiosestoreviewposteroanteriorviewchestradiographsforstudysubjects.However,Lockeyetal.[2002]begantosupplementtheseviewswithleftandright45oobliqueviewfilmsasastandardpracticeforradiographicsurveil-lance.Thismethodology,knownasafilmtri-ad,wasevaluatedagainsttheposteroanterior-only view to determine reliability, sensitivity,andspecificityofeachmethod[Lawsonetal.2001]. The evaluation, involving 652 subjectsin the RCF study, showed the film triad hadconsiderably higher interreader reliabil-ity (κ=0.59) than the posteroanterior-onlymethod(κ=0.44).Theauthorsconcludedthatthe film triad method provides an optimumapproach.

The U.S. and 1986 European studies yieldedlittleevidenceofanassociationbetweenradio-graphicparenchymalopacitiesandRCFexpo-sure.IntheU.S.study,smallopacitieswererare[Lockeyetal.1996].Smallopacitiesofprofu-sioncategory1/0orgreaterweremorefrequentinthe1986Europeanstudy[Trethowanetal.1995],butexposurestosilicaandotherdustswere believed to account for many of thesecases. The results of statistical analyses didnotimplicateRCFexposure[Trethowanetal.1995]oryieldedresultsonlyslightlysuggestiveofanRCFexposureeffect[Rossiteretal.1994].Inthe1996evaluationoftheEuropeancohort,smallopacitiesofcategory1/0orgreaterwerepositivelyassociatedwithRCFexposuresthatoccurredbefore1971[Cowieetal.1999].Tenofthe51(19.6%)maleworkersexposedbefore1971developedcategory1/0orgreateropaci-tiesC8hadalsobeenexposedtoasbestosand9wereeithercurrentorex-smokers.

BoththeU.S.[Lockeyetal.1993;Lemastersetal.1998]andtheEuropean[Trethowanetal.1995;Burgeetal.1995;Cowieetal.1999]studies found that occupational exposuretoRCFsisassociatedwithvariousreportedrespiratorysymptomsandconditions,after

adjustingfortheeffectsofage,sex,andsmok-ing. Exposure to RCF concentrations in therange of 0.2 to 0.6 f/cm3 was associated withstatistically significant increases in eye irrita-tion(OR=2.16,95%CI=1.32–3.54),stuffynose(OR=2.06,95%CI=1.25–3.39),anddrycough(OR=2.53,95%CI=1.25–5.11)comparedwithexposureconcentrations lowerthan0.2f/cm3[Trethowanetal.1995]. IncreasingORsweredemonstrated for RCF exposure concentra-tionsgreaterthan0.6f/cm3comparedwithex-posure concentrations <0.2 f/cm3 for wheeze(P<0.0001), dyspnea (P<0.05), eye irritation(P<0.0001),skinirritation(P<0.0001),anddrycough(P<0.05)butnotstuffynoseorchronicbronchitis [Trethowan et al. 1995]. Lockey etal.[1993]foundthatdyspneawassignificantlyassociatedwithexposureto>15fiber-months/cm3(that is,>1.25fiber-years/cm3)relativetoexposure to ≤15 fiber months/cm3 (dyspneagrade 1COR=2.1, 95% CI=1.3–3.3; dyspneagrade2—OR=3.8,95%CI=1.6–9.4).Lockeyetal.[1993]alsofoundstatisticallysignificantas-sociations between cumulative RCF exposureandchroniccough(OR=2.0,95%CI=1.0–4.0)andpleurisy(OR=5.4,95%CI=1.4–20.2).Le-masters et al. [1998] also noted associations(P<0.05) between employment in an RCFproduction job and increased prevalence ofdyspnea and the presence of at least one re-spiratory symptom or condition. RecurrentchestillnessintheEuropeancohortwasasso-ciatedwithcumulativeexposuretorespirablefibers and was most strongly associated withcumulativeexposuretorespirabledust[Cowieetal.1999].

In cross-sectional analyses involving spiro-metric testing, both the U.S. [Lockey et al.1998;Lemastersetal.1998]and1986Europe-an[Trethowanetal.1995;Burgeetal.1995]studiesfoundthatcumulativeRCFexposurewasassociatedwithpulmonaryfunctiondec-rements among current and former smok-ers. The 1996European study demonstrated



decrementsincurrentsmokersonly[Cowieetal.1999].Theobserveddecreasedpulmonaryfunction in the European workers remainedsignificantly associated with cumulative RCFexposure, even after controlling for cumula-tive exposure to inspirable dust [Burge et al.1995]. A longitudinal analysis of data frommultiplePFTsbyLockeyetal. [1998] led theresearcherstoconcludethatexposurestoRCFsbetween 1987 and 1994 were not associatedwithdecreasedpulmonaryfunction.Thefind-ingsfromtheU.S.andEuropeanstudiessug-gest that decrements in pulmonary functionobservedincurrentandformersmokersresultfrom an interactive effect between smokingandRCFexposure.

5.4 Carcinogenicity Risk Assessment Analyses

Theliteraturecontainsthreesignificant inde-pendent risk analyses of occupational expo-sure to RCFs and potential health effects. Ineachof theseanalyses,healtheffectsdatade-rived from multidose and MTD studies withratswereusedwithmodelstoextrapolaterisksto human populations. The modeling of ef-fectsobservedinexperimentalanimalstudieswasnecessitatedby the lackofadequatedataonadversehealtheffects inhumanswithoc-cupationalexposurestoRCFs.Thethreestud-ies,describedindetailbelowandinTable5–9,include the following studies: Dutch ExpertCommittee on Occupational Standards (DE-COS) [1995], Fayerweather et al. [1997], andMoolgavkaretal.[1999].

5.4.1 DECOS [1995]

In1995,DECOS(aworkgroupof theHealthCounciloftheNetherlands)publishedareportevaluating the health effects of occupationalexposure to SVFs. The purpose of the reportwas to establish health-based recommended

occupationalexposurelimitsforspecifictypesof SVFs.As one of the criteria for determin-ingtheairborneexposurelimitsforsixdistincttypesofSVFs,riskassessmentswereperformedfor each fiber type, including RCFs. The riskanalysisforRCFswasbasedontheassumptionthatRCFsareapotentialhumancarcinogenasindicatedbythepositiveresultsofcarcinoge-nicitytestingwithanimals.Ahealth-basedrec-ommended occupational exposure limit wasdeterminedusingthefollowingrationale:

1.If the carcinogenic potential of RCFs iscaused by a nongenotoxic mechanism,an occupational exposure limit of 1 re-spirablef/cm3asan8-hrTWAshouldberecommended based on an NOAEL of25f/cm3andasafetyfactorof25.

2.If the carcinogenic potential of RCFs islinkedtoagenotoxicmechanism,amod-elassumingalinearrelationshipbetweendoseandtheresponse(cancer)shouldbeusedtoestablishtheoccupationalexpo-surelimit.

Themodelindicatedthatanexcesscancerriskof4×10-3 isassociatedwithaTWAexposureto5.6respirablef/cm3basedon40yearsofoc-cupationalexposure.Acancerriskof4×10-5isassociated with exposure to 0.056 f/cm3, anda linear extrapolation indicated that occupa-tionalexposureto1respirablef/cm3asan8-hrTWA for 40 years is associated with a cancerriskof7×10-4.

TheDECOSanalysisreliedonthedatafromalong-term multidose study with rats exposedtokaolinceramicfibers[Bunnetal.1993;Mastet al. 1995b]. These data showed that expo-sure by inhalation to 25 f/cm3 (3 mg/m3) for24 months produced a negligible amount offibrosis (mean Wagner score of 3.2). Conse-quently,theDutchcommitteeviewed25f/cm3as the NOAEL for fibrosis. The report alsonotesthatat thetimeofpublication,nodata



Tabl

e 5–

9 . R

isk

asso

ciat

ed w

ith

exp

osu

re to

RC

Fs* a

t 1 f/

cm3 (

TW

A)

as d

eter

min

ed b

y th

ree

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existedfromretrospectivecohortmortalityormorbidityandcase-controlstudiesofpersonswithoccupationalexposurestoRCFs.Thelin-earmodelingapproach in thisanalysisof theexposure-responserelationshipusingtheani-maldatadoesnottakeintoconsiderationpos-sibledifferencesindosimetryandlungburdenbetweenratsandhumans.

5.4.2 Fayerweather et al. [1997]

Fayerweather et al. [1997] conducted a studyprimarily focusing on the risk assessment ofoccupational exposures for glass fiber insula-tion installers. They performed risk analyseswith several other types of SVFs, includingRCFs.OnlytheanalysiswithRCFsispresent-ed here. This analysis applied an EPA linear-ized multistage model (representing a linearnonthresholddose-response)todatafromratmultidoseandMTDchronicinhalationbioas-says[Mastetal.1995a,b] todetermineexpo-suresatwhichAnosignificantrisk@occurs;i.e.,nomore thanoneadditional cancer caseper100,000 exposed persons. Nonlinear modelswere also used for comparison: the Weibull1.5-hitnonthresholdmodel(representingthenonlinear,nonthresholddose-responsecurve)andWeibull2-hitthresholdmodel(represent-ing the nonlinear, threshold dose-responsecurve). Fiber inhalation by rats was equatedto humans by determining the fibers/day·kgof body weight for the animals and using anexposurescenarioof4hr/day(consistentwithinsulationinstallationworkers=schedules),for5days/weekand50weeks/yearover40work-ingyearsofa70-yearlifespan.RCFCinterpret-edtheresultsoftheanalysiswiththelinearizedmultistagemodeltorepresentariskof3.8×10-5for developing lung cancer over the work-ing lifetime at an exposure concentration of1 f/cm3 [RCFC 1998]. Using the nonlinearmodels, estimates of nonsignificant expo-sures(i.e.,aworkinglifetimeexposureassoci-ated with no more than 1 additional cancer

case/100,000 exposed persons) were 2 and 3orders of magnitude higher. Conversely, therisk estimates for exposure to 1f/cm3 for aworkinglifetimewerelowerusingtheWeibull1.5-hitnonthresholdandWeibull2-hitthresh-oldmodels.

5.4.3 Moolgavkar et al. [1999]

Thisreportdescribesaquantitativeassessmentof theriskof lungcancerassociatedwithoc-cupational exposure to RCFs [Moolgavkar etal.1999].Amajorpremiseunderlyingtheriskassessmentisthathumansareequallysuscep-tibletoRCFsasrats,atthetissuelevel.Theriskanalysis was performed using data from twochronic inhalationbioassaysofRCFs inmaleFischer344rats[Mastetal.1995a,b].Dosim-etryintheriskassessmentwasbasedonafiberdepositionandclearancemodeldevelopedbyYuetal.[1996]thatwasusedtoestimatethelung burdens of fibers in humans. The dose-response model used for the risk assessmentwasthetwo-mutationclonalexpansionmodel,commonlyreferredtoastheMoolgavkar-Ven-zon-Knudson(MVK)model.TheMVKmodelwasfittedtotheratbioassaydatatoestimatetheproportionalincreaseintheratlungtumorinitiationrateinRCF-exposedrats,relativetothebackgroundinitiationrateinnonexposedrats.An MVK model for human lung cancerwas then created by fitting the model to theage-specificlungcancerincidenceforeitheroftwo human cohorts. Finally, the human lungcancer rate for a given tissue dose was esti-matedby increasingthetumorinitiationrateinthehumanmodelbythesameproportionalamountthatanidenticaltissuedosewouldin-creasetheinitiationrateintheMVKmodelforrats. The assumption was made that, for anygiventissuedose,theproportionalincreaseinthe lung tumor initiationrate(relative to thebackgroundrate)isthesameinhumansasinrats.Thetwohumancohortsusedforthehu-manmodelingwereanonsmokingAmerican



CancerSociety(ACS)cohort[Petoetal.1992]andacohortofworkersfromthesteelindustry(notexposedtocokeovenemissions)believedtoberepresentativeofindustrialworkers.Be-cause of the difference in the baseline lungcancer risk, risk estimates based on the SteelIndustry cohort were approximately 4 timeshigher than those based on the ACS cohort.Both central estimates (maximum likelihoodestimates[MLEs])and95%upperconfidencelimits (UCLs) were developed. Three equa-tions were tested to describe the relationshipbetween initiation rate for lung cancer andlungburden:

I=Aexp(Bd) (exponential)I=A+Bd2 (quadratic)I=A+Bd (linear)

whered=lungburdeninfiberspermilligramoflung(whichcanvarywithtime)andAandB are constants (different for each model).With each equation, calculations were madetodeterminetheexcessriskforaworkeraged20 to 50 to develop lung cancer by age 70whenexposedtoRCFsataconcentrationof1.0fiber/cm3for8hr/day,5days/week.

Usingtheexponentialmodel,theexcessriskoflungcancerassociatedwith1.0f/cm3wasesti-matedtobe3.7×10-5(MLE)and4.9×10-5(95%UCL),basedontheACScohort.Forthesameconditionstheriskoflungcancerwas1.5×10-4(MLE)and1.8×10-4(95%UCL)basedontheSteelIndustrycohort.Usingaquadraticequa-tion,theresearchersreportedslightlyloweres-timates of excess risk of 4.1×10-6 (MLE) and1.2×10-5(95%UCL)fortheACScohort,and1.4×10-5 (MLE) and 4.3×10-5 (95% UCL) forthe Steel Industry cohort. The highest esti-matesofexcessriskresultedwithalinearequa-tion:2.7×10-4(MLE)and1.5×10-3(95%UCL)for theACScohort,and1.1×10-3(MLE),and5.8×10-3(95%UCL)fortheSteelIndustryco-hort.Additionalriskestimateswerecalculatedaccording to the conditions described above

(i.e.,ACScohortversusSteelIndustrycohort;MLEand95%UCLforexponential,quadratic,andlinearmodels)butwithdifferentexposureconcentrations.Theexcessriskwasalsocalcu-latedforexposureconcentrationsof0.75f/cm3,0.5f/cm3,and0.25f/cm3.TheseriskestimatesarepresentedinTable5–10.

AsshowninTable5–10,thehighestriskesti-mates at each of the three exposure concen-trationsare associatedwith the linearmodel,followedbytheexponentialmodel.Thelowestriskestimatesareassociatedwiththequadraticmodel.Ateachexposureconcentration,moreconservativeriskestimatesareobtainedfortheACScohortthantheSteelIndustrycohort.

Attherecommendedexposureguidelineestab-lishedbytheRCFC(0.5f/cm3),thehighestriskestimate(linearmodel,SteelIndustrycohort)is the MLE of 5.3×10-4 or 5.3/10,000 (95%UCL=2.9×10-3).At0.5f/cm3,theriskestimatesforthesteelindustrycohortareroughly1orderofmagnitude(factorof10)lowerwiththeex-ponentialmodel (MLE=7.3×10-5, 95%UCL=9.1×10-5), and 2 orders of magnitude lowerusing the quadratic model (MLE=3.5×10-6,95% UCL=1.1×10-5). At the lowest exposureconcentration (0.25 f/cm3), the highest riskestimate(SteelIndustrycohort,linearmodel)wastheMLEof2.7×10-4(95%UCL=1.4×10-3).Again,onaverage,theriskestimatesfromthe3modelsusingthesteelindustrycohortare3to4timeshigherthanforcorrespondingmodelvalueswiththeACScohort.

The authors concluded that the risk estimatesbasedonthetwocohorts“representboundsonriskslikelytobeseeninoccupationalcohorts.”However,anoccupationalcohortisunlikelytosharethenonsmokingstatusoftheACScohort.Therefore,ofthetwohumanpopulationsusedformodelfittingintheMoolgavkaretal.[1999]risk assessment, the steel industry cohort maybe the preferable cohort to use for estimatingtherisksfromoccupationalexposurestoRCFs.



TheMoolgavkaretal.[1999]reportalsoindi-cates airborne fiber concentrations estimatedtoresultinexcesslifetimeriskforcancerof10-4(1in10,000)basedontheapproachesusedbyDECOS[1995]andFayerweatheretal.[1997]and using the MVK model for both theACScohort and the steel industry cohort. Withthe DECOS [1995] linearized, nonthresholdmodelapproach,anexcesslifetimecancerriskof 10-4 was calculated to result from a fiberconcentrationof0.14f/cm3.Usingthelinear-ized,multistagemodelapproachdescribedinFayerweather et al. [1997], a fiber concentra-tionof2.6f/cm3wasestimatedtocorrespondtotheexcesslifetimecancerriskof10-4.WiththeMVKexponentialmodel,anexcesslifetimecancer risk of 10-4 was determined for fiberconcentrations of 0.7 f/cm3 for the Steel In-dustrycohortand2.7f/cm3fortheACScohort[Moolgavkaretal.1999].

5.4.4 Discussion

Theestimatedlungfiberburdenfordosimetryin theanalysisbyMoolgavkaret al. [1999] is

a methodological improvement over the riskassessment for RCFs by Fayerweather et al.[1997],whichwasbasedsolelyontheinhaledfiberconcentration.Modelinglungburdendo-simetryshould,intheory,compensatefortheknown differences between rats and humansinfiberdepositionandclearance.Similarly,us-inganMVKmodelfordose-responseestima-tion could compensate for differences in cellmutation and proliferation rates in rats andhumans. However, some key parameter val-ues in the MVK and lung dosimetry modelsarepoorlyknown.Forexample,thedosimetrymodel for humans has been validated withonly three human tissue samples taken fromworkers whose exposures to RCFs were notmeasured[Yuetal.1997].

A review and comparison of risk modelingapproaches for RCFs by Maxim et al. [2003]describesthethreemodelshereaswellasad-ditionalmoresophisticatedvariationsofquan-titativeriskanalysesforRCFs.Usingapproach-essuchasbenchmarkdosemodeling,Maximetal.[2003]producedRCFunitpotencyvaluesrangingfrom1.4×10-4to7.2×10-4.

Table 5–10 . Estimates (MLE* and 95% UCL) of excess risk of lung cancer at three exposure concentrations using exponential, quadratic, and linear models for an ACS cohort and a steel industry cohort

Exposure

ACS cohort Steel industry cohort

Exponential Quadratic Linear Exponential Quadratic Linear

0.75 f/cm3:MLE

2.8×10-5

2.3×10-6

2.0×10-4

1.1×10-4

7.9×10-6

8.0×10-4

95%UCL 3.7×10-5 6.8×10-6 1.1×10-3 1.4×10-4 2.4×10-5 4.3×10-3

0.5f/cm3:MLE

1.8×10-5

1.0×10-6

1.3×10-4

7.3×10-5

3.5×10-6

5.3×10-4

95%UCL 2.5×10-5 3.0×10-6 7.3×10-4 9.1×10-5 1.1×10-5 2.9×10-3

0.25 f/cm3:MLE

9.2×10-6

2.5×10-7

6.7×10-5

3.6×10-5

8.8×10-7

2.7×10-4

95%UCL 1.2×10-5 7.5×10-7 3.6×10-5 4.6×10-5 2.7×10-6 1.4×10-3

AdaptedfromMoolgavkaretal.[1999].*Abbreviations:ACS=AmericanCancerSociety;MLE=maximumlikelihoodestimate;UCL=95%upperconfidencelimit.



A common weakness among all three of therisk analyses stems from uncertainty aboutpossibledifferencesinthesensitivityofhumanlungstofibers,ascomparedwithratlungs.ThepossibilityofsuchadifferenceisacknowledgedinthereportbyMoolgavkaretal.[1999],buttheeffectof thisuncertaintyon theriskesti-matesisnotexploredquantitatively.Asanex-ample,Pottetal.[1994]estimatedthatinthecase of asbestos fibers, humans are approxi-mately 200-fold more sensitive than rats, onthebasisoffiberconcentrationinair.Pottetal.[1994]furthernotedthatacrocidoliteinhala-tionstudythatwasnegativeintheratresultedinaratlungfiberconcentrationthatwasmorethan1,000-foldgreaterthanthefiberconcen-trationsinthelungsofasbestosworkerswithmesotheliomas.Insupportofthisanalysis,re-sultsofastudybyRödelspergerandWoitowitz[1995]ledtheauthorstoconcludethathumansareatleast6,000timesmoresensitivethanratstoagiventissueconcentrationofamphibolefi-bers.Althoughamphiboleasbestosfibershavephysicochemical characteristics which differfromthoseofRCFs,thesefindingsraiseques-tionsaboutusingexperimentalanimaldataforpredicting human health effects and assum-ingthattargettissues inhumansandratsareequallysensitivetoRCFtoxicity.

ThelungcancerriskestimatesforRCFsderivedbyMoolgavkaretal.[1999]mayalsobeunder-estimatedforoccupationallyexposedworkersbecause of several basic assumptions madein the lung tissue dosimetry. Tissue dosim-etrymodelingintheMoolgavkaretal.[1999]

risk assessment is based on the assumptionthataworkerisexposedtoRCFsfor8hr/day,5days/week,52weeks/year,fromage20to50[Moolgavkaretal.1999].Analternativeanaly-sis, inwhichtheassumptionwaschangedto8hr/day,5days/week,50weeks/yearfromage20to60,wasalsodescribedbutnotpresentedindetail. Inbothcases, thebreathingrateforlightworkwasassumedtobe13.5liters/min-ute. Additional information might be gainedfromassuminganexposureperiodof8hr/day,5days/week,50weeks/year,fromage20to65,with a breathing rate matching the Interna-tionalCommissiononRadiologicalProtection“Reference Man” value for light work, whichis 20 liters/minute [ICRP 1994]. In addition,thecumulativeexcessriskof lungcancerwascalculatedonlythroughage70[Moolgavkaretal.1999].Thispracticemayunderestimatethelifetimeriskoflungcancerintheexposedco-hort,sinceasubstantialfractionofthecohort maybeexpectedtosurvivebeyondage70.Theexcessriskmightalsobecalculatedinacom-peting-risks frameworkusingactuarialmeth-odsuntilmostorallofthecohortispresumedtohavediedbecauseofcompetingrisks(gener-ally85years).Finally,riskestimatesderivedbyMoolgavkaretal.[1999]werebasedsolelyondatafromstudies withrats,ignoringdatafromstudies of hamsters [McConnell et al. 1995].Because42%ofthehamsters inthesestudiesdevelopedmesotheliomas,usingthisdatabasefortheriskassessmentwouldproducehigherestimatesofriskthantheanalysisbasedontheratdata.


6 Discussion and Summary of Fiber Toxicity

comparativemeasuresoftoxicityfordifferentagents. RCFs implanted into the pleural andabdominal cavities of various strains of ratsand hamsters have produced mesotheliomas,sarcomas,andcarcinomasatthesitesoffiberimplantation[Wagneretal.1973;Davisetal.1984; Pott et al. 1987]. Similar tumorigenicresponseshavebeenobservedfollowingintra-tracheal instillation of RCFs [Manville Cor-poration1991].ThesedataprovideadditionalevidenceofthecarcinogeniceffectsofRCFsinexposedlaboratoryanimals.

Epidemiological data have not associated oc-cupationalexposuretoRCFsundercurrentex-posureconditionswithincreasedincidenceofpleuralmesotheliomaor lungcancer[Lockeyet al. 1993; Lemasters et al. 1998]. However,in epidemiologic studies of workers in RCFmanufacturingfacilities[Lemastersetal.1994;Lockey et al. 1993, 1996; Rossiter et al. 1994;Trethowanetal.1995;Burgeetal.1995;Cowieetal.1999],increasedexposurestoairbornefi-bershavebeenlinkedtopleuralplaques,smallradiographicparenchymalopacities,decreasedpulmonary function, respiratory symptomsandconditions(pleurisy,dyspnea,cough),andskinandeyeirritation.

Manyoftherespiratoryeffectsshowedastatis-tically significantassociationwithRCFexpo-sureaftercontrollingoradjustingforpotentialconfounders,includingcigarettesmokingandexposure tononfibrousdust.Yet inPFTs, theinteractive effect between smoking and RCFexposure was especially pronounced, basedon the finding that RCF-associated decreases

6.1 Significance of Studies with RCFs

Three major sources of data contributing tothe literature on RCFs are (1) experimentalstudieswithanimalsandinvitrobioassays,(2)epidemiologicstudiesofpopulationswithoc-cupational exposure to RCFs (primarily dur-ingmanufacturing), and (3) exposureassess-ment studies that provide quantitative andqualitativemeasurementsofexposuresaswellasthephysicalandchemicalcharacteristicsofairborneRCFs.Eachofthesesourcesofinfor-mation is considered integral to this criteriadocument for providing a more comprehen-sive evaluation of occupational exposure toRCFsandtheirpotentialhealthconsequences.

Datafrominhalationstudieswithanimalsex-posedtoRCFshavedemonstratedstatisticallysignificant increases in the induction of lungtumorsinratsandmesotheliomasinhamsters[Mast et al. 1995a,b; McConnell et al. 1995].Other inhalation studies with RCFs haveshownpathobiologic inflammatoryresponsesin lungandpleural tissues[Gelzleichteretal.1996a,b].Implantationandinstillationmeth-ods have also been used in animal studieswith RCFs to determine the potential effectsofthesefibersontargettissues.Thesestudieshaverecognizedlimitationsforinterpretingre-sults because the exposure techniques bypassthenaturaldefenseandclearancemechanismsassociatedwiththenormalrouteofexposure(i.e., inhalation).However,theyareusefulfordemonstrating mechanisms of toxicity and


6 ■Discussion and Summary of Fiber Toxicity

in pulmonary function were limited to cur-rentand former smokers [Lockeyetal.1998;Lemasters et al. 1998; Trethowan et al. 1995;Burge et al. 1995]. The interactive effect be-tween exposure to airborne fibers and ciga-rette smokehasbeenpreviouslydocumented(e.g., Selikoff et al. [1968] ). However, unlikemaleworkers,nonsmokingfemaleworkersdidshowstatistically significantdecreases inPFTresultsassociatedwithRCFexposure[Lemas-tersetal.1998].AnalysesofdatafrommultiplePFTsessions[Lockeyetal.1998]haveledre-searcherstoconcludethatdecreasesinpulmo-nary function were more strongly influencedbythehigherexposurestoairborneRCFsthatoccurred in the past. This conclusion seemsplausible,sincehistoricalair-samplingdatain-dicatethatairbornefiberconcentrationsweremuchhigherinthefirstdecadesofRCFmanu-facturingandthatformerworkershadpoten-tiallyhigherexposures.

Multiplestudieshavebeenperformedtochar-acterizetheconcentrationsandcharacteristicsof airborne exposures to RCFs in the work-place. Current and historical environmentalmonitoring data [Esmen etal. 1979; CantorandGorman1987;Gorman1987;O’Brienetal.1990;Chengetal.1992;Brown1992;Cornetal.1992;Lyman1992;Allshouse1995;Hewett1996]indicatethatairborneexposurestoRCFsincludefibersintherespirablesizerange(<3.5μmindiameterand<200μmlong[Timbrell1965; Lippmann 1990; Baron 1996]). TheseexposuresoccurinprimaryRCFmanufactur-ingaswellas insecondary industries suchasRCF installation and removal. Sampling datafromstudiesofdomestic,primaryRCFmanu-facturing sites indicate that average airbornefiberconcentrationshavesteadilydeclinedbynearly 2 orders of magnitude over the past 2decades.Forexample,Riceetal.[1997]reportamaximumexposureestimateof10f/cm3as-sociatedwithanRCFmanufacturingprocessinthe1950s,andEsmenetal.[1979]measured

averageexposureconcentrationsrangingfrom0.05to2.6f/cm3inRCFfacilitiesinthemiddletolate1970s.Riceetal.[1994,1996,1997]sug-gestaverageconcentrationsinmanufacturingranging from<LODto0.66 f/cm3 in the late1980s, and Maxim et al. [1994, 1997, 2000a]reportthatconcentrationsfromthelate1980sthrough1997ranged fromanAMof<0.3 to0.6f/cm3(GM0.2f/cm3).Formanymanufac-turingprocesses,evengreaterreductionsinex-posureshavebeenrealizedthroughimprovedventilation, engineering or process changes,andproductstewardshipprograms[Riceetal.1996;Maximetal.1999b].

Althoughthepotentialexistsforexposuretore-spirablecrystallinesilicaintheformsofquartz,tridymite, and cristobalite during work withRCFs, exposure monitoring data indicate thatthese exposures are generally low [Rice et al.1994].Maximet al. [1999b] report thatmanyairborne samples of crystalline silica collectedduring the installation and removal of RCFproducts contain concentrations below theLOD,withaverageconcentrationsofrespirablecrystalline silica per measurable task rangingfrom0.01to0.44mg/m3(equivalent8-hrTWArange=0.004 to 0.148mg/m3). Other studieshaveshowngreaterpotentialforexposuretore-spirablecrystallinesilica(especiallyintheformof cristobalite) during the removal of after-serviceRCFmaterials[Gantner1986;Chengetal.1992;Perraultetal.1992;vandenBergenetal.1994;SweeneyandGilgrist1998].Forpro-cessesassociatedwithhigherconcentrationsofairbornerespirablefibers,therearealsogeneral-lygreaterconcentrationsoftotalandrespirabledusts[Esmenetal.1979;Krantzetal.1994].

6.2 Factors Affecting Fiber Toxicity

To accurately interpret the results of experi-mentalandepidemiologicstudieswithRCFs,



it is important toconsiderrecognized factorsthatcontribute tofiber toxicity forRCFsandother SVFs in general. The major determi-nantsoffiber toxicityhavebeen identifiedasfiberdose(oritssurrogate,airbornefiberex-posure),fiberdimensions(lengthanddiame-ter),andfiberdurability(especiallyasitaffectsfiber biopersistence in the lungs) [Bignon etal.1994;Bunnetal.1992;BenderandHadley1994;Christensenetal.1994;LockeyandWi-ese1992;Mooreetal.2001].

6.2.1 Fiber Dose

Themeasurementofairbornefiberconcentra-tions is frequentlyusedasa surrogate foras-sessingdoseandhealthrisktoworkers.Analy-sesofhistoricalandcurrentairsamplingdataindicate that occupational exposure concen-trationsofairborneRCFshavedecreaseddra-maticallyinthemanufacturingsector[Maximetal.1997;Riceetal.1997].Inchronicinhala-tionstudiesofRCFs[Mastetal.1995a,b;Mc-Connell et al. 1995], both rats and hamsterswereexposedtoarangeofsize-separatedRCFconcentrationsinanose-onlyinhalationpro-tocol.WhenairborneRCFsaregenerated,halformoreof theaerosol is composedof respi-rableparticlesofunfiberizedmaterialthatwasformerlyacomponentofthefiber[Mastetal.1995a,b].Becauseofthenatureofthismixedexposure, it isdifficult todetermine the rela-tive contributions of the airborne fibers andnonfibrous particulates to the adverse effectsobservedinhumansandanimals.Ithasbeenpostulatedthatthenonfibrousparticulatesmayhave contributed to an overload effect in theMastetal.[1995a,b]animalstudieswithRCFs[Yuetal.1994;Mastetal.1995a,b;Maximetal.1997;Brownetal.2000].Burgeetal.[1995]have suggested that the health effects seen inRCF-exposed workers are a consequence ofcombinedparticulateandfiberexposure,butthe decrements in lung function are more re-latedtofiberexposurecombinedwithsmoking.

Other studies have shown that for processesassociated with higher concentrations of air-borne respirablefibers, there is alsoagreaterconcentrationoftotalandrespirabledust[Es-menetal.1979;Krantzetal.1994].

6.2.2 Fiber Dimensions

Throughout the literature, studies supportthe theory that fiber toxicity is related to fi-ber dimensions [Timbrell 1982, 1989; HarrisandTimbrell1977;Stantonetal.1977,1981;Lippmann 1988]. Initially, fiber dimensions(lengthanddiameter)playasignificantroleindeterminingthedepositionsiteofafiberinthelungs.Longerandthicker(>3.5µmindiam-eter)fibersarepreferentiallydeposited in theupper airways by the mechanisms of impac-tion[Yuetal.1986]orinterception.Timbrell[1965]suggestedthatdirectinterceptionplaysan importantrole in thedepositionoffibers,asthefibercomesintocontactwiththeairwaywallandisdeposited.Fibersbeingdepositedinthelargerciliatedairwaysaregenerallyclearedvia the mucociliary escalator. Thinner fiberstendtomaneuverpastairwaybifurcationsintosmallerandsmallerairwaysuntiltheirdimen-sions dictate deposition either by sedimenta-tionordiffusion[AsgharianandYu1989].An-otherfactorthatmayenhancedepositionistheelectrostaticchargeafibercanaccumulatedur-ingdust-generatingprocessesinoccupationalsettings[Vincent1985].Thefiberchargemayaffectitsattractiontothelungsurface,causingthefiber tobedepositedbyelectrostaticpre-cipitation.

Althoughthedimensionalcharacteristicsandgeometry of a fiber influence its depositionintherespiratorytract,thefiber’slengthandchemicalpropertiesdictate its clearanceandretention once it has been deposited withinthealveolarregion.Forthefiberthattraversestherespiratoryairwaysandisdepositedinthegas exchange region, possible fates include



dissolution,clearanceviaphagocyticcells(al-veolar macrophages) in the alveoli, or trans-location through membranes into interstitialtissues. Both test animals and workers havebeenexposedtoRCFsofsimilarlengthanddi-ameter[Allshouse1995],andtheseexposuresinclude fibers of respirable dimensions [Es-menetal.1979;Lockeyetal.1990;Chengetal.1992].Sinceratsandotherrodentsareobligatenasalbreathers,fibersgreaterthanabout1µmindiameteraretoolargefordepositionintheiralveoli [Jones1993].Bycomparison,humanscaninhaleanddepositfibersupto3.5µmindiameterinthethoracicandgasexchangere-gionsofthelung.Thisphysiologicaldifferencepreventstheevaluationoffiberswithdiametersofabout1 to3.5µm(whichwouldhavehu-manrelevance)inrodentinhalationstudies.

Theroleoffibersizeininducingbiologicalef-fects iswelldocumentedandreviewed in theliterature[Stantonetal.1977,1981;Pottetal.1987;Warheit1994].Stantonetal.[1977]hy-pothesized thatglassfibers longer than8µmwithdiametersthinnerthan0.25µmhadhighcarcinogenicpotential.Inareviewofthesig-nificanceoffibersizetomesotheliomaetiol-ogy,Timbrell[1989]concludedthatthethin-ner fibers with an upper diameter limit of0.1µmaremorepotentforproducingdiseasesoftheparietalpleura(e.g.,mesotheliomaandpleuralplaques)thanthickerfibers.ThatvalueforfiberdiameteriscitedbyLippmann[1988]inhisasbestosexposure indices formesothe-lioma. Oberdörster [1994] studied the effectsofbothlong(>10–16μm)andshort(<10μm)fibersonalveolarmacrophagefunctions,con-cludingthatbothwillleadtoinflammatoryre-actions—although a distinct difference existsinthelong-termeffectsbecauseofdifferentialclearance of fibers of different sizes. Alveolarmacrophagesconstitutethefirstlineofdefenseagainstparticlesdepositedinthealveoli; theymigratetositeswherefibersaredepositedandphagocytizethem.Theengulfedfibersarethen

movedbythemacrophagestowardthemuco-ciliaryescalatorandremoved fromthe respi-ratory tract. The ability of the macrophagesto clear fibers is size-dependent. Short fibers(<15 µm long) can usually be phagocytizedby one rat alveolar macrophage [Luoto et al.1994; Morgan et al. 1982; Oberdörster et al.1988,Oberdörster1994],whereaslongerfibersmaybeengulfedbytwoormoremacrophages.Blakeetal.[1998]havesuggestedthatincom-pleteorfrustratedphagocytosismayplayaroleintheincreasedtoxicityoflongerfibers.Fiberlengthhasbeencorrelatedwiththecytotoxicityofglassfibers[Blakeetal.1998],withgreatestcytotoxicityforfibers17and33µmlongcom-pared with shorter fiber samples. Long fibers(17μmaveragelength)tendtobeamorepo-tentinducerofTNFproductionandtranscrip-tion factoractivationthanshortfibers(7μmaveragelength)[Yeetal.1999].

Whencomparingthedimensionsofairbornefiberswiththosefoundinthe lungs, it is im-portant to consider the preferential clearanceof shorterfibersaswellas theeffectsoffiberdissolutionandbreakage.Yuetal.[1996]eval-uated these factors in a study that led to thedevelopmentofaclearancemodelforRCFsinratlungs.Resultsofthatstudyconfirmedthatfibers10to20µmlongareclearedmoreslowlythanthose<10µmlongbecauseoftheincom-plete phagocytosis of long fibers by macro-phages.Thepreferentialclearanceofshorterfi-bershasalsobeendocumentedinstudieswithchrysotileasbestosandothermineralfibers,inwhichtheaveragelengthofretainedfibersin-creasedduringadiscreteperiodfollowingde-position[Coinetal.1992;Churg1994].Thisincrease might also be explained by the lon-gitudinal cleavage pattern of asbestos fibers,which results in longer fibers of decreasingdiameters[Coinetal.1992].Bycontrast,anybreakageofRCFswouldoccurperpendicularto the longitudinalplane,resulting inshorterfibersofthesamediameter.Fortheclearance



model developed by Yu et al. [1996], the ef-fect of fiber breakage was also assessed fromexperimental data and incorporated into themodel.Theauthorsconcludedthatthesimul-taneouseffectoffiberbreakageanddifferentialclearanceleadsonlytoasmallchangeinfibersize distribution in the lung. This result sug-geststhatthedimensionsoffibersinthelungarecloselyrelatedtothedimensionsoffibersmeasured in the airborne samples (adjustedfordeposition);thus,mostshortfibersinthelungsoriginatedasshortfibersinairborneex-posures.

The dimensions of airborne fibers have alsobeen characterized for workers with occupa-tionalexposuretoRCFs.Onestudyofdomes-ticRCFmanufacturingfacilitiesfoundthatap-proximately90%ofairbornefiberswere<3μmindiameter,and95%ofairbornefiberswere<4μmindiameterand<50μmlong[Esmenet al. 1979]. The study showed that diameterand lengthdistributionsof airbornefibers inthefacilitieswereconsistentwithaGM

Dof0.7

μmandaGMLof13μm.Anotherairsampling

studyofdomesticRCFmanufacturingsitesre-portedthat99.7%ofthefibershaddiametersof<3μmand64%hadlengths>10μm[Alls-house1995].MeasurementsofairbornefibersintheEuropeanRCFmanufacturingindustryarecomparable:Rood[1988]reportedthatallfibersobservedwereinthethoracicandrespi-rable size range (i.e., diameter <3μm), withmedian diameters ranging 0.5 to 1.0 μm andmedian lengths from 8 to 23 μm. During re-moval of RCF products, Cheng et al. [1992]foundthat87%ofairbornefiberswerewithintherespirablesizerange,withfiberdiametersranging from 0.5 to 6 μm (median diame-ter=1.6μm)andfiberlengthsrangingfrom5to220μm.Anotherstudy[Perraultetal.1992]of airborne fiber dimensions measured dur-inginstallationandremovalofRCFmaterialsinindustrialfurnacesreportedGM

Dvaluesof

0.38and0.57μm,respectively.

6.2.3 Fiber Durability

Biopersistence (and specifically the retentiontime of the fiber in the lungs) is consideredtobeanimportantpredictoroffibertoxicity.Fiber solubility affects the biopersistence offibers deposited within the lung and is a keydeterminantoffibertoxicity.BenderandHad-ley[1994]suggestthatsomeoftheimportantconsiderations of fiber durability include thefollowing:

■ Fiber size—particularly length as it re-lates to the dimensions of the alveolarmacrophages

■ Fiberdissolutionrate

■ Mechanical properties of the fibers, in-cludingpartiallydissolvedand/ordigest-edfibers

■ Overloading of the normal clearancemechanismsofthelung

Bignonetal.[1994]arguethatfibersthatarebiopersistentinvivoandinvitroaremorebio-logicallyactivethanlessdurablefibers.

ThedurabilityofRCFs[Hammadetal.1988;Luotoetal.1995]providesabasisforsuggest-ingthatthesefibersmightpersistlongenoughtoinducebiologicaleffectssimilartothoseofasbestos. In vitro durability tests have shownRCFstobehighlyresistanttodissolutioninbi-ologically relevantmixtures suchasGamble’ssolution[ScholzeandConradt1987].Theper-sistenceofRCFsinboththeperitonealcavity[Bellmanetal.1987]andthelung[Hammadetal.1988]hasbeenrecognizedinexperimen-tal studies. Hammad et al. [1988] sacrificedrats exposed to either slag wool or ceramicfibers via inhalation at 5, 30, 90, 180, or 270daysafterexposure.Thelungsoftheanimalswere ashed in a low-temperature asher, andthefibercontentofthelungswasevaluatedbyPCM.Theresearchers foundthat24%of the



deposited RCFs persisted in the lungs of ratssacrificed270daysfollowingexposure.Inthesame study, the lungs of rats exposed to slagwoolcontainedonly6%oftheslagwoolfibers270daysafterexposurecomparedwith thosesacrificed 5 days following inhalation. Fromthese results, itwasconcluded thatRCFs fol-low a clearance pattern of relatively durablefibersthatpersist,translocate,orareremovedby some mechanism other than dissolution.Similar results were obtained in the study byMast et al. [1995b], which shows that RCFsarepersistent in the lungsof rats exposedbyinhalation.Specifically,comparedwiththefi-berburdeninthelungsofanimalssacrificed3monthsafterexposure(recovery),thelungsofanimalssacrificedafter21monthsofrecoverycontainedapproximately20%ofthedepositedfibers. Of the retained fibers (measured withbothSEMandTEMtechniques)54%to75%had diameters <0.5 µm, and more than 90%were5to20µmlong.

Researchershavesuggestedthatfibersdepos-ited in the gas exchange region with lengthsless thanthediameterofanalveolarmacro-phage are phagocytized and cleared via themucociliary system or the lymph channels.DissolutionoffiberswithintheAlMoccursifthefibersarenotresistanttotheacidicintra-cellularconditionsorapH~5[Nybergetal.1989].Fibersthatarenotengulfedbyalveo-larmacrophagesaresubjectedtoapHof7.4intheextracellularfluidofthelung.AstudyofSVFdurabilityinratalveolarmacrophagesreportsthatRCFsaremuchlesssolublethanglasswoolandrockwoolfibersbasedontheamounts of silicon (Si) and iron (Fe) dis-solved from the fibers in vitro [Luoto et al.1995].RCFs in ratalveolarmacrophagecul-turedissolved less than10mgSi/m2offibersurfaceareaandlessthan1mgFe/m2offibersurfacearea.Glasswooldissolvedmorethan50mgSi/m2,androckwooldissolvednearly2mgFe/m2whenmeasuredovercomparable

timeperiods.However,degradationanddis-solution of deposited RCFs may still occur,based on the findings of higher dissolutionofaluminum(Al)fromRCFs(0.8to2.4mgAl/m2) in alveolar macrophages than fromtheotherSVFs[Luotoetal.1995].Inanotherstudy,SEManalysisoffibersrecovered fromthelungsofrats6monthsafterinhalationofRCFsrevealedanerodedappearance,causingthe researchers to conclude that dissolutionof Si in the fibers is a plausible mechanismfor long-term fiber clearance [Yamato et al.1994].

SVFsingeneralarelessdurablethanasbestosfibers.RCFsaremoredurablethanmanyotherSVFs,withadissolutionratesomewhathigherthanchrysotileasbestos.Undertheextracellu-larconditionsinthelung,chrysotile—themostsolubleformofasbestos—hasadissolutionrateof<1to2ng/cm2/hr.RCFshaveasimilardis-solutionrateofabout1to10ng/cm2/hrunderconditionsexperiencedinpulmonaryintersti-tialfluid.OthermoresolubleSVFscanbe10to1,000timeslessdurable[ScholzeandCon-radt 1987; Christensen et al. 1994; Maxim etal.1999b;Mooreetal.2001].Atthemeasuredsolubilityrate,anRCFwitha1-µmdiameterwould take more than 1,000 days to dissolvecompletely[Leineweber1984].

6.3 Summary of RCF Toxicity and Exposure Data

In addition to the main determinants of fi-bertoxicity(dose,dimension,anddurability),other factors such as elemental composition,surface area, andcompositioncanalso influ-encethetoxicityofthefiber.Thus,itisdifficulttopredictafiber’spotentialforhumantoxicitybasedsolelyoninvitroorinvivotests.Basedon consideration of these factors, the majorfindings from the RCF animal and humanstudiesareasfollows:



■ Toxicologicevidence fromexperimentalinhalation studies indicates that RCFsare capable of producing lung tumorsinlaboratoryratsandmesotheliomasinhamsters [Mast et al. 1995a,b; McCon-nell et al. 1995]. However, interpretingthesestudieswithregardtoRCFpotencyanditsimplicationforoccupationallyex-posedhumanpopulationsiscomplicatedbythe issueofcoexposuretofibersandnonfibrousrespirableparticulate.

■ ThedurabilityofRCFscontributestothebiopersistenceofthesefibersbothinvivoandinvitro[Bellmannetal.1987;Schol-zeandConradt1987;LockeyandWiese1992].

■ Cytotoxicityandgenotoxicitystudiesin-dicatethatRCFs

—are capable of inducing enzyme re-leaseandcellhemolysis[Wrightetal.1986;Fujinoetal.1995;Leikaufetal.1995;Luotoetal.1997],

—affectmediatorrelease[Morimotoetal.1993;Ljungmanetal.1994;Fujinoetal.1995;Leikaufetal.1995;Hilletal.1996;Cullenetal.1997;Gilmouretal.1997;Luotoetal.1997;Wangetal.1999],

—may decrease cell viability and in-hibitproliferation[Yeglesetal.1995;Okayasuetal.1999;Hartetal.1992],

—affect cell viability and proliferation[Hartetal.1992],and

—may induce free radicals, micronu-clei,polynuclei,chromosomalbreak-age,andhyperdiploidcells[Brownetal.1998;Doppetal.1997;Hartetal.1992].

■ Exposure monitoring results indicatethatairbornefibersmeasuredinboththemanufacturing and end-use sectors ofthe RCF industry have dimensions thatfall within the thoracic and respirablesizeranges[Esmenetal.1979;Lockeyetal.1990;Chengetal.1992].

■ Epidemiologicstudiesofworkers intheRCF manufacturing industry report anassociationbetweenincreasedexposuresto airborne fibers and the occurrenceof pleural plaques, other radiographicabnormalities, respiratory symptoms,decreased pulmonary function, and eyeandskinirritation[Lemastersetal.1994,1998;Lockeyetal.1996;Trethowanetal.1995;Burgeetal.1995].Currentoccupa-tionalexposures toRCFshavenotbeenlinked to decreases in pulmonary func-tionofworkers[Lockeyetal.1998].

■ WorkerexposuretoairbornefiberintheRCF industry over the past 20 years ormore have decreased substantially, re-portedlyastheresultofincreasedhazardawarenessandthedesignandimplemen-tationofengineeringcontrols[Riceetal.1997;Maximetal.1997].

These observations warrant concern for thecontinued control and reduction of occupa-tionalexposurestoairborneRCFs.


7 Existing Standards and Recommendations

lengths≥10µmforup to10hr/dayduringa40-hr workweek. NIOSH also recommendedthatairborneconcentrationsdeterminedasto-talfibrousglassbelimitedtoa5mg/m3ofairasaTWA.Atthattime,NIOSHconcludedthatexposure to glass fibers caused eye, skin, andrespiratory irritation.NIOSHalso stated thatuntilmoreinformationbecameavailable,thisrecommendation should be applied to otherSVFs.

TheAgencyforToxicSubstancesandDiseaseRegistry (ATSDR) calculated an inhalationminimal risk concentration of 0.03 f/cm3 forhumans based on extrapolation from animalstudies[ATSDR2002].TheAgencyusedmac-rophageaggregation,themostsensitiveindica-torofinflammationfromRCFs,asthebasisforthisvalue.Calculationofthisvalueisbasedonexposureassumptionsforgeneralpublichealththatdifferfromthoseusedinmodelsfordeter-miningoccupationalexposurelimits.

ACGIHproposedaTLVof0.1f/cm3asan8-hrTWA for RCFs under its notice of intendedchangestothe1998TLVs[ACGIH1998].Onfurtherreview,thisconcentrationwasrevisedto0.2f/cm3[ACGIH2000].ACGIHalsoclas-sifies RCFs as a suspected human carcinogen(A2designations)[ACGIH2005].Ontheba-sis of a weight-of-evidence carcinogenic riskassessment,theEPA[1993]classifiedRCFsasaGroupB2carcinogen(probablehumancar-cinogenbasedonsufficientanimaldata).

ACGIH and EPA designations are consistentwith thatof the InternationalAgency forRe-search on Cancer (IARC), which classified

Standardsandguidelinesforcontrollingwork-erexposurestoRCFsvaryintheUnitedStates.Othergovernmentsandinternationalagencieshavealsodevelopedrecommendationsandoc-cupationalexposurelimitsthatapplytoRCFs.Table7–1presentsasummaryofoccupationalexposure limit standards and guidelines forRCFs.

Within the United States, the RCFC formallyestablished a recommended exposure guide-lineof0.5 f/cm3asanelementof itsproductstewardship program known as PSP 2002,whichwasendorsedbyOSHAasa5-yearvol-untaryprogram[OSHA2002].Aspartofthatprogram,theRCFCrecommendsthatworkerswearrespiratorswhenevertheworkplacefiberconcentration is unknown or when airborneconcentrationsexceed0.5f/cm3.ThisexposureguidelinewasestablishedbytheRCFConOc-tober 31, 1997, and replaces the previous ex-posureguidelineof1f/cm3setbytheRCFCin1991.

Beforethisagreement,theOSHAGeneralIn-dustryStandardwasmostapplicabletoRCFs,requiringthataworker’sexposuretoairbornedust containing <1% quartz and no asbestosbelimitedtoan8-hrPELof5mg/m3forrespi-rabledustand15mg/m3fortotaldust[29CFR1910.1000].

NIOSH has not previously commented onoccupational exposure to RCFs. However, inaddressing health hazards for another SVF(fibrousglass),NIOSH[1977] recommendedanexposurelimit(REL)of3f/cm3asaTWAfor glass fibers with diameters ≤3.5 µm and


7 ■Exisiting Standards and Recommendations

Table 7–1 . Occupational exposure limits and guidelines pertaining to RCFs*, by country

Country Regulated substance Exposure limit†

Australia Syntheticmineralfibers 0.5f/cm3

Inspirabledust 2mg/m3

Austria Totaldust(listssuperfinefibersassuspectedcarcinogen) 10mg/m3

Canada RCFs 0.5f/cm3

Denmark Manmademineralfibers 1f/cm3

Totaldust(nonstationaryworksite) 5mg/m3

Finland Glasswoolandmineralwool 10mg/m3

France Generaldust,mineralwool 10mg/m3

Germany Syntheticvitreousfibers 0.5f/cm3

Netherlands RCFs 1f/cm3

NewZealand Syntheticmineralfibers 1f/cm3

Norway Syntheticmineralfibers 1f/cm3

Poland Glasswool 2f/cm3

Totaldust 4mg/m3

Sweden Syntheticinorganicfibers 1f/cm3

UnitedKingdom[HSE2004] Machine-mademineralfibers(exceptRCFsandspecial-

purposefibers)

2f/cm3

RCFs 1f/cm3

Totaldust(gravimetriclimit) 5mg/m3

UnitedStates:ACGIH RCFs 0.2f/cm3

ATSDR[2002]‡ RCFs 0.03f/cm3

NIOSH§ RCFs 0.5f/cm3

Glassfibers,otherSVFs[NIOSH1977] 3f/cm3

Totalfibrousglass 5mg/m3

OSHA[2002] RCFs 0.5f/cm3

Respirabledust(<1%quartz,noasbestos) 5mg/m3

Totaldust(<1%quartz,noasbestos) 15mg/m3

Source:AdaptedandupdatedfromU.S.Navy[DOD1997].*Abbreviations:ACGIH=AmericanConferenceofGovernmentalIndustrialHygienists;ATSDR=AgencyforToxicSubstancesDisease

Registry;NIOSH=NationalInstituteforOccupationalSafetyandHealth;OSHA=OccupationalSafetyandHealthAdministration;

RCFs=refractoryceramicfibers;REL=recommendedexposurelimit;TWA=time-weightedaverage.†8-hrTWAunlessotherwisespecified.‡Inhalationminimalrisklevelbasedongeneralpublichealthassumptions,notoccupationalexposure.

§TheNIOSHRELisestablishedasaTWAforuptoa10-hrworkshiftina40-hrworkweek.


7 ■Exisiting Standards and Recommendations

ceramicfibers,includingRCF,as“possiblycar-cinogenictohumans(Group2B)”[IARC1988,2002]. The IARC characterization was basedon“sufficientevidenceforthecarcinogenicityofceramicfibersinexperimentalanimals”andalackofdataonthecarcinogenicityofceramicfiberstohumans[IARC1988,2002].DECOS[1995]determinedthat“RCFsmayposeacar-cinogenic risk forhumans,” and set ahealth-based recommended occupational exposurelimitof1f/cm3.

TheGermanCommissionfortheInvestigationofHealthHazardsofChemicalCompoundsinthe Work Area published a review of fibrous

dusts[Pott1997]classifyingRCFsascategoryIIIA2,citing“positiveresults(forcarcinogenic-ity) from inhalation studies (often supportedbytheresultsofotherstudieswithintraperito-neal,intrapleural,orintratrachealadministra-tion).”

IntheUnitedKingdom,theHealthandSafetyCommissionof theHealthandSafetyExecu-tivehasestablishedamaximumexposurelimitforRCFsof1.0f/mlofair,withtheadditionaladvisory toreduceexposures to the lowestasreasonably practicable concentration basedonthecategory2carcinogenclassificationforRCFs[HSE2004].


8 Basis for the Recommended Standard

ditions(includingdyspnea,wheezing,coughing,andpleurisy)observed inRCFworkers tobeadversehealtheffectsassociatedwithexposuretoairborneRCFs[Lemastersetal.1998;Lock-eyetal.1993;Trethowanetal.1995;Burgeetal.1995;Cowieetal.1999].

AnassociationbetweeninhalingRCFsandfi-brotic or carcinogenic effects has been docu-mented in animals, but no evidence of sucheffectshasbeenfoundinworkers intheRCFmanufacturing industry. The lack of such anassociation could be influenced by the smallpopulationofworkersinthisindustry,thelonglatency period between initial exposure anddevelopmentofmeasurableeffects,thelimitednumber of persons with extended exposureto elevated concentrations of airborne fibers,anddecliningoccupational exposureconcen-trations. However, the evidence from animalstudies suggests that RCFs should be consid-eredapotentialoccupationalcarcinogen.ThisclassificationisconsistentwiththeconclusionsofACGIH,EPA,DECOS,andIARC.(Seedis-cussioninChapter7.)

Given these considerations, the NIOSH ob-jective in developing an REL for RCFs is toreduce the possible risk of lung cancer andmesothelioma. In addition, maintaining ex-posuresbelowtheRELwillalsohelptopre-ventotheradverseeffects,includingirritationoftheskin,eyes,andrespiratorytract inex-posedworkers.ToestablishanRELforRCFs,NIOSHtookintoaccountnotonlytheanimaland human health data but also exposure

8.1 BackgroundIntheOccupationalSafetyandHealthActof1970(PublicLaw91–96),CongressmandatedthatNIOSHdevelopandrecommendcriteriaforidentifyingandcontrollingworkplacehaz-ardsthatmayresultinoccupationalillnessorinjury. In fulfillingthismission,NIOSHcon-tinues to investigate the potential health ef-fects of exposure to naturally occurring andsynthetic airborne fibers. This interest stemsfrom the results of research studies confirm-ingasbestosfibersashumancarcinogens.Sig-nificant increases in the production of RCFsduringthe1970sandconcernsaboutpotentialhealth effects led to experimental and epide-miologicalstudiesaswellasworkerexposuremonitoring. Chronic animal inhalation stud-iesdemonstratedthecarcinogenicpotentialofRCFs,withastatisticallysignificantincreaseintheincidenceoflungcancerormesotheliomain two laboratory species—ratsandhamsters[Bunnetal.1993;Mastetal.1995a;McConnellet al. 1995]. Evidence of pleural plaques ob-servedinpersonswithoccupationalexposuresto airborne RCFs is clinically similar to thatobservedinasbestos-exposedpersonsaftertheinitial years of their occupational exposuresto asbestos [Hourihane et al. 1966; Becklakeetal.1970;Dementetal.1986].NIOSHcon-sidersthediscoveryofpleuralplaquesinU.S.studies of RCF manufacturing workers to beasignificantfindingbecausetheplaqueswerecorrelatedwithRCFexposure[Lemastersetal.1994;Lockeyetal.1996].Inaddition,NIOSHconsiders therespiratorysymptomsandcon-


8 ■Basis for the Recommended Standard

information describing the extent to whichRCF exposures can be controlled at differ-ent workplaces. On the basis of this evalua-tion, NIOSH considers an REL of 0.5 f/cm3(asaTWAforupto10hr/dayduringa40-hrworkweek) to be achievable for most work-placeswhereRCFsorRCFproductsareman-ufactured,used,orhandled.Maintainingex-posuresattheRELwillminimizetheriskforlungcancerandreduce theriskof irritationoftheeyesandupperrespiratorysystem.Theresidual risks of lung cancer at the REL areestimated tobe0.073 to1.2per1,000basedonextrapolationsofriskmodelsfromMool-gavkaretal. [1999]andYuandOberdörster[2000].

The risk for mesothelioma at the REL of0.5 f/cm3 is not known but cannot be dis-counted.Evidencefromepidemiologicstudiesshowed that higher exposures in the past re-sultedinpleuralplaquesinworkers,indicatingthatRCFsdoreachpleuraltissue.Bothimplan-tationstudiesinratsandinhalationstudiesinhamstershaveshownthatRCFfiberscancausemesothelioma. Because of limitations in thehamsterdata,theriskofmesotheliomacannotbequantified.However,thefactthatnomeso-theliomahasbeenfoundinworkersandthatpleuralplaquesappear tobe less likely tooc-curinworkerswithlowerexposuressuggestsalowerriskformesotheliomaattheREL.

Because residual risks of cancer (lung can-cer and pleural mesothelioma) and irrita-tion may exist at the REL, NIOSH furtherrecommends that all reasonable efforts bemadetoworktowardreducingexposurestolessthan0.2f/cm3.Atthisconcentration,therisksoflungcancerareestimatedtobe0.03to 0.47 per 1,000 based on extrapolationsof risk models from Sciences International[1998],Moolgavkaretal.[1999],andYuandOberdörster[2000].

MaintainingairborneRCFconcentrationsatorbelowtheRELrequirestheimplementationofacomprehensivesafetyandhealthprogramthatin-cludesroutinemonitoringofworkerexposures,installationandroutinemaintenanceofengi-neeringcontrols,andworkertrainingingoodwork practices. To ensure that worker expo-suresareroutinelymaintainedbelowtheREL,NIOSHrecommendsthatanALof0.25f/cm3bepartoftheworkplaceexposuremonitoringstrategytoensurethatallexposurecontrolef-forts(e.g.,engineeringcontrolsandworkprac-tices) are inplaceandworkingproperly.ThepurposeoftheAListoindicatewhenworkerexposures to RCFs may be approaching theREL.ExposuremeasurementsatorabovetheALindicateahighdegreeofcertaintythatcon-centrations of RCFs exceed the REL. TheALisastatisticallyderivedconceptpermittingtheemployer to have confidence (e.g., 95%) thatif exposure measurements are below the AL,only a small probability exists that the expo-sureconcentrationsareabovetheREL.Whenexposures exceed the AL, employers shouldtake immediate action (e.g., determine thesourceofexposure,identifymeasuresforcon-trollingexposure)toensurethatexposuresaremaintainedbelowtheexposurelimit.NIOSHhasconcludedthatanALallowsfortheperi-odic monitoring of worker exposures in theworkplacesothatresourcesdonotneedtobedevoted to conducting daily exposure mea-surements.TheALconcepthasbeenaninte-gral element of recommended occupationalstandards in NIOSH criteria documents andin comprehensive standards promulgated byOSHAandMSHA.

8.2RationalefortheRELTherecommendationtolimitoccupation-alexposurestoairborneRCFstoaTWAof0.5f/cm3isbasedondatafromanimalandhuman studies, risk assessments, and the



availabilityofmethodstocontrolRCFex-posures at the REL in many workplaces.EstablishingtheRELforRCFsisconsistentwith the mission of NIOSH mandated intheOccupationalSafetyandHealthActof1970. This Act states that NIOSH is obli-gatedto“developcriteriadealingwithtoxicmaterialsandharmfulphysicalagentsandsubstances which will describe exposurelevels that are safe for various periods ofemployment, includingbutnot limited tothe exposure levels at which no employeewill suffer impaired health or functionalcapacitiesordiminishedlifeexpectancyasaresultofhisworkexperience.”Thecarci-nogenicityfindingsfromthechronicnose-onlyinhalationassaysofRCF1inratsandhamsters [Mast et al. 1995a,b; McConnellet al. 1995] warrant concern about pos-sible health effects in workers exposed toRCFs. Although no increase in lung can-cer or mesothelioma mortality has beenobserved in worker populations exposedtoRCFs,radiographicanalysesindicateanassociation between pleural changes (in-cluding pleural plaques) and RCF expo-sure [Lemasters et al. 1994; Lockey et al.1996; Cowie et al. 1999, 2001]. Both theU.S. [Lockey et al. 1993; Lemasters et al.1998]and theEuropean[Trethowanetal.1995;Burgeetal.1995;Cowieetal.1999,2001] studies have found RCF-associatedrespiratory symptoms, pulmonary func-tionreductions,andpleuralabnormalitiesamongRCFproductionworkers.

Severalindependentevaluationshavequantita-tivelyestimatedtheriskoflungcancerforwork-ersexposedtoRCFsatvariousconcentrations[DECOS1995;Fayerweatheretal.1997;Mool-gavkaretal.1999].NIOSHevaluatedthesestud-iestodeterminewhetheranappropriatequali-tativeorquantitativeassessmentoflungcancerrisk could be achieved. In addition, exposureinformation was collected during the 5-year

monitoringperiodcoveredundertheconsentagreementbetweenRCFCandEPA[Maximetal. 1994,1997,1998].NIOSHused the expo-sure informationtoevaluate the feasibilityofcontrolling workplace exposures at manufac-turingandend-use facilitieswhereRCFsandRCFproductsarehandled.

8.2.1 Carcinogenesis in Animal Studies

ChronicinhalationstudieswithRCFsdemon-stratesignificantincreasesintheincidenceofmesotheliomainhamstersandlungcancerinrats.Tables8–1through8–4presentasynop-sisofthemajorfindingsofthesestudies[Mastetal.1995a,b;McConnelletal.1995].Resultsfrom chronic animal inhalation studies withchrysotileandamositearealsopresented(i.e.,results for the positive control groups); thesedataprovideareferencepointfordeterminingtherelativetoxicityofRCFs[Mastetal.1995a;McConnelletal.1999].

Chronic inhalation exposure to RCF1 at30 mg/m3 (187 WHO f/cm3) induced a13%(16/123)incidenceoflungtumorsinF344rats[Mastetal.1995a].Theincidenceoflungcancerat lowerdosesdidnotshowastatisti-callysignificantdifferencefromtheunexposedcontrolgroup.Lungfiberburdensinthemulti-dosechronicratstudyrevealedadose-responserelationship [Mast et al. 1995b]. In the rat,16 mg/m3 (120 WHO f/cm3) appeared tobe the NOAEL for lung cancer and 3 mg/m3

(26WHO f/cm3) appeared to be the NOAELfor fibrosis. Although it has been suggestedthatfibrosisinanimalsisaprecursortocarci-nogenesis,adefinitelinkhasnotbeenshownforRCFsorotherfibers.NolungcancerswerefoundinhamstersexposedtoRCF1[McCon-nelletal.1995].



Table 8–1 . Doses and dimensions of RCFs* in chronic inhalation studies with F344 rats

Dose

(mg/m3)

WHO Total % Fibers >20 µm

long

Mean fiber diameter†

Mean fiber length†

Reference Fiber type

f/cm3 SD

f/cm3 SD

µm SD µm SD

Mastetal.

1995a

RCF1

30

187 53

234 35

43

0.98 0.61

22.3 17.0

Mastetal.

1995b

RCF1 6

9

3

0

120 35

75 35

26 12

0 —

162 37

91 34

36 17

0 —

43

—

—

—

0.98 0.61

——

——

——

22.3 17.0

——

——

——

Mastetal.

1995a

Chrysotile

asbestos

10 1.06+1.14×10

4 1×10

5 NR 0.10 0.15 2.2 3.0

*Abbreviations:NR=notreported;RCFs=refractoryceramicfibers;SD=standarddeviation;WHO=WorldHealthOrganization.†Arithmeticmean.

Table 8–2 . Results of RCF* chronic inhalation studies with F344 rats

Dose

(mg/m3)

Time of first

occurrence (months) Lung

neoplasms

Pleural

mesotheliomasWHO Interstitial

fibrosis

Pleural

fibrosisReference Fiber type f/cm3 SD Number % Number %

Mastetal.

1995a

RCF1

30

187 53

6

9

16/123 13

2/123 1.6

Mastetal.

1995b

RCF1 16

9

3

0

120 35

75 35

26 12

0 —

12

12

None

None

12

18

None

None

2/124 1.6

5/127 3.9

2/123 1.6

1/129 0.8

0—

1/127 0.8

0 —

0 —

Mastetal.

1995a

Chrysotile

asbestos

10 1.06+1.14×104 3 9 13/69 18.8 1/69 1.4

*Abbreviations:RCF=refractoryceramicfiber;SD=standarddeviation;WHO=WorldHealthOrganization.



Table 8–3 . Doses and dimensions of RCF* in chronic inhalation studies with Syrian golden hamsters

Dose

(mg/m3)

WHO Total% Fibers

>20 µm longMean fiber diameter†

Mean fiber length†

Reference Fiber type f/cm3 SD f/cm3 SD % f/cm3 SD µm SD µm SD

McConnell etal.1995

RCF1

30

215 56

256 58

43 — —

0.940.63

22.1 16.7

McConnell etal.1995

Chrysotile asbestos

10 3.0×103 1.4×10

3 8.4×1049.0×10

4 NR — — 0.090.06 1.68 2.71

McConnell etal.1999

Amosite asbestos

7.1

3.7

0.8

263 90

165 61

36 23

NR —

— —

— —

~26 69 24

~233814

~28106

0.600.25

——

——

13.4 16.7

——

——

*Abbreviations:NR=notreported;RCFs=refractoryceramicfibers;SD=standarddeviation;WHO=WorldHealthOrganization.†Arithmeticmean.

Table 8–4 . Results of RCF* chronic inhalation studies with Syrian golden hamsters

Time of first occurrence

Dose

(mg/m3)

WHO Interstitial

fibrosis

Pleural

fibrosis

Hamsters with pleural mesotheliomas†

Reference Fiber type f/cm3 SD Number %

McConnell etal.1995

RCF1

30

215 56

6months

6months

42/123 41.6

McConnell etal.1995

Chrysotile asbestos

10

3.0×10

3 1.4×10

3

3months

6months

0 —

McConnell

Amosite

7.1

263 90

13weeks

13weeks

17/87 19.5 etal.1995 asbestos 3.7 165 61 13weeks 13weeks 22/85 25.9

0.8 36 23 13weeks 13weeks 3/83 3.6

*Abbreviations:RCF=refractoryceramicfiber;SD=standarddeviation;WHO=WorldHealthOrganization.†Nolungneoplasmsweredetected.



Chronic inhalation exposure to RCF1 at30 mg/m3 induced a 41% (42/102) incidenceof mesotheliomas in Syrian golden ham-sters [McConnell et al. 1995]. Determininga dose-response relationship for inducingmesotheliomaisnotpossiblebasedoncurrent-lyavailabledatabecauseofthesingleexposuredosetestedinthehamsterandbecauseofthelow, sporadic occurrence of mesothelioma intheexposedrats[Mastetal.1995a].Yettheoc-currenceofmesotheliomasintheratandthehighincidenceinthehamsterarebiologicallysignificantbecausethespontaneousincidenceofmesotheliomasinratsandhamstershashis-toricallybeenverylow[AnalyticalSciencesIn-corporated1999].

Toassessthesignificanceofthemesotheliomaincidence observed in RCF-exposed ham-sters, these results were compared with thoseobtainedfromhamstersthatwereexposedtochrysotile asbestos and were used as positivecontrolsforthestudy[McConnelletal.1995](seeTables8–3and8–4).However,thechrysotile-exposedhamstersfailedtodevelopanytumorsand therefore could not be considered truepositivecontrols.Basedontheseresults,apo-tencyrankingcouldnotbeassignedforRCFsrelativetochrysotile,sincethecarcinogenicre-sponserateforthelatterwaszerointhisstudy.Thetwofiberstestedalsodifferedwithregardtotheirdoseandfiberdimension.

TheMcConnelletal.[1999]studyofhamstersexposed to amosite asbestos provides dose-responsedata for comparisonwith theRCF1dataofMcConnelletal.[1995](SeeTables8–3and8–4.).TheseseparatestudiesexaminedtheeffectsofRCF1oramositeasbestosinhamstersusing relatively similar exposure conditions,experimentalconditions,andfiberdimensions[McConnell et al. 1995, 1999]. Exposure to263 WHO f/cm3 and 165 WHO f/cm3 ofamosite asbestos induced pleural mesothe-liomas in 20% and 26% of the hamsters,

respectively[McConnelletal.1999].Aconcen-trationof215RCF1WHOf/cm3inducedme-sotheliomasin41%ofhamsters[McConnelletal.1995].Interstitialandpleuralfibrosiswerefirst observed at 13 weeks following amositeasbestos exposure and at 6 months followingRCF1exposure.Althoughaveragefiberdimen-sionsfortheRCF1andamositeasbestossam-plesweresimilar,theRCF1samplecontainedahigherpercentageoffiberslongerthan20μm[McConnell et al. 1995, 1999]. Longer fibershavebeenassociatedwithincreasedtoxicityinexperimentalanimalstudies[Davisetal.1986;Pottetal.1987;DavisandJones1988;Warheit1994;Blakeetal.1998].

Resultsfromadose-responseanalysisusingthemesotheliomadatafromtheRCFandamositeasbestoshamsterstudies[McConnelletal.1995,1999] indicated that the carcinogenic potencyestimates for RCFs ranged from about half totwotimesthecarcinogenicpotencyestimatesforamositeasbestos[Dankovic2001](seeSection5.1.2).Thisanalysismaynotpredictthemeso-theliomariskinhumans,sinceRCF1containedagreaterpercentageoffiberslongerthan20µmand because of differences in fiber durability.Amositeasbestosisamoredurablefiberwithalongerinvivohalf-lifethanRCF1[Maximetal.1999b;Hesterbergetal.1993](seeTable8–5).YetRCFsaremoredurableandlesssolublethanmanyothertypesofSVFsthathavenotdemon-stratedcarcinogenicityinexperimentalstudies.Thischaracteristicissignificant,asthedurabil-ityofasbestosandSVFs(includingRCFs)maybelinkedtotheriskoflungcancerinanimalschronicallyexposedtothesefibers[Bignonetal.1994;BenderandHadley1994;Hammadetal.1988;Luotoetal.1995].Becauseofthelongla-tencyperiodforthedevelopmentofmesothelio-masinhumans,Berry[1999]hypothesizedthatfibersofsufficientdurabilityareneededtocausethisdiseaseinhumans.ExtrapolationoftheRCFdose-responsedata for lungcancerandmeso-thelioma inexposedrodents should take into



Table 8–5 . Dissolution constant (Kdis

) and weighted in vivo half-life (t0 .5

) of amosite asbestos and RCF1

Fiber type Kdis

(ng/cm2 per hr) t0 .5

(days)

RCF1

7.6

89.6

Amositeasbestos 1.3 418.0

Source:AdaptedfromMaximetal.[1999].*Abbreviation:RCF=refractoryceramicfiber.

account the durability of RCFs in humans.Someevidenceindicatesthatratsarelesssen-sitivethanhumanstothedevelopmentoflungcancerandmesotheliomafromexposuretoas-bestosandmaythereforerepresentaninappro-priatemodelforhumanriskassessment.Pottetal.[1994]hypothesizedthatinchronicinhala-tionstudies,ratsmayhavealowersensitivitytoinorganicfibertoxicitythanhumans.Thelungcancerriskfrominhalingasbestosmaybetwoordersofmagnitudelowerinratsthaninhu-mans,andthemesotheliomariskfrominhalingasbestosmaybethreeordersofmagnitudelow-erforrats.RödelspergerandWoitowitz[1995]measured amphibole fiber concentration inthelungtissuesofhumanswithmesotheliomaand compared the results with fiber burdensreported inrats.Asignificantly increasedOR(OR=4.8, 95%; CI=1.05–21.7) for mesothe-lioma was seen in humans with amphiboleconcentrations between 0.1 and 0.2 fiber/μgof dried lung tissue. The lowest tissue con-centration reported to produce a significantcarcinogenic response in rat inhalation stud-iesofamphiboles(specificallycrocidolite)was1,250fibers/μgofdriedlungtissue.Bycompar-ingtheseresults,RödelspergerandWoitowitz[1995]estimatedthathumansareatleast6,000timesmoresensitivethanratstoagiventissueconcentrationofamphibolefibers.

This work is refuted by other scientists whofavortheratasanappropriatemodelforeval-uating the risk evaluation of lung cancer inhumans[MaximandMcConnell2001].Limi-tations of the Rödelsperger and Woitowitz[1995]andPott[1994]analyses(discussedear-lier)includethelackofadose-responseanaly-sis, analysis of only one epidemiologic study,inadequatecomparisonsofexposureduration,lackofaccountingforthepotentiallymultipli-cativeeffectofsmokingandasbestosexposure,lackofconsiderationoflatencyandclearance,anddifferentfibermeasurementtechniques.

In summary, multiple factors affecting thecomparabilityofdifferentfibertypesandani-malmodelsreportedintheliteraturemakeitdifficulttodeterminewhetherthecarcinogen-icpotencyofRCFsinanimalsissimilartothatin humans. Extrapolation of the animal datatohumansisfurthercomplicatedbyalimitedunderstandingofthemechanismsoffibertox-icity. Consequently, any extrapolation of thecancerriskfoundinanimalsexposedtoRCFsmustaccountfordifferencesbetweenhumansand rodents with regard to fiber depositionandclearancepatterns,uncertaintyabout theroleofRCFdurabilityforpotentiatinganad-verseeffect,andpossiblespeciesdifferencesinsensitivitytofibers.



8.2.2 Health Effects Studies of Workers Exposed to RCFs

Two major research efforts evaluated themorbidityofworkersexposedtoairbornefi-bersintheRCFmanufacturingindustry.OnestudywasconductedintheUnitedStatesandtheotherinEurope.Theobjectiveofeachwastoevaluatetherelationshipbetweenoccupa-tional exposure to RCFs and potential ad-verse health effects. These studies containedmultiplecomponentsincludingstandardizedrespiratory and occupational history ques-tionnaires, chest radiographs, pulmonaryfunctiontestsofworkers,andairsamplingtoestimate worker exposures. The first studiesof European plants were conducted in 1986and included current workers at seven RCFmanufacturing plants [Rossiter et al. 1994;Trethowan et al. 1995; Burge et al. 1995]. Afollowup cross-sectional study conducted in1996 evaluated the same medical endpointsinworkersfromsixofthesesevenEuropeanmanufacturing plants (one plant had ceasedoperation) [Cowie et al. 1999, 2001]. Cur-rentaswellasformerworkerswereincludedas study subjects in the followup study. ThestudiesofU.S.plantsbegan in1987and in-volvedevaluationsofcurrentworkersatfiveRCFmanufacturingplantsandformerwork-ersattwooftheplants[Lemastersetal.1994,1998, 2003; Lockey et al. 1993, 1996, 1998,2002].IntheUnitedStates,theearliestcom-mercial production of RCFs and RCF prod-uctsbeganin1953. InEurope,RCFproduc-tionbeganin1968.ThedemographicsoftheU.S. and European populations were similarat the time they were studied, but the aver-ageageanddurationofemploymentfortheU.S.workerswereslightlyhigherthanfortheworkforce in the 1986 European studies be-cause of the earlier development of this in-dustryintheUnitedStates.

8.2.2.1 Pleural changes in humans

TheradiographicanalysesoftheU.S.and1996European populations in RCF manufactur-ing detected an association between pleuralchanges and RCF exposure [Lemasters et al.1994; Lockey et al. 1996; Cowie et al. 1999,2001]. In the initial European studies, Tre-thowanetal.[1995]foundpleuralabnormali-ties in a small number of RCF workers whohad other confounding exposures that didnot include asbestos. Differences observed inpleural abnormalities between the U.S. andEuropeanworkerpopulationsmaybe relatedto the latency of exposure required to causespecificpleuralchanges[Hillerdal1994;Beginetal.1996],especially the formationofpleu-ralplaques,whichwerefirstobservedinstud-ies of the U.S. RCF manufacturing industry,with its longer latency period. Historical airsamplingdataalsoindicatethatairbornefiberconcentrationsweremuchhigherinearlyU.S.RCF manufacturing. Therefore, in additionto their longeroverall latency,RCFmanufac-turing workers in the United States probablyhad generally higher exposures in the earlyyearsoftheindustrythandidtheirEuropeancounterparts.ThesefactorsmightexplaintheappearanceofRCF-associatedpleuralplaquesin the U.S. studies before their detection intheEuropean studies.TheU.S. and1986Eu-ropeanstudiesyieldedlittleevidenceofanas-sociation between radiographic parenchymalopacitiesandRCFexposure.IntheU.S.study,smallopacitieswererare,withonlythreecasesnoted in one report [Lockey et al. 1996] andonly one case (with small rounded opacitiesofprofusioncategory3/2attributabletopriorkaolinminework)notedintheother[Lemas-ters et al. 1994]. Small opacities of profusioncategory1/0orgreaterweremorefrequentintheEuropeanstudybyTrethowanetal.[1995],but confounding exposures were believedto account for many of these cases. The re-sultsofstatisticalanalysesindicatedeitherno



associationwithRCFexposure[Trethowanetal. 1995] or an association slightly suggestiveofanRCFexposureeffect[Rossiteretal.1994].InamorecomprehensiveevaluationoftheEu-ropean study population, small opacities ofcategory1/0orgreaterwerepositivelyassoci-atedwithRCFexposuresthatoccurredbefore1971[Cowieetal.1999].

8.2.2.2 Respiratory symptoms, irritation, and other conditions in humans

InboththeU.S.[Lockeyetal.1993;Lemastersetal.1998]andtheEuropean[Trethowanetal.1995;Burgeetal.1995;Cowieetal.1999,2001]stud-ies,occupationalexposuretoRCFswasassociatedwith various reported respiratory conditions orirritationsymptomsafteradjustingfortheeffectsofsmoking.WorkerexposuretoRCFsatconcen-trations of 0.2 to 0.6 f/cm3 was associated withstatistically significant increases in eye irritation(OR=2.16, 95% CI=1.32–3.54), stuffy nose(OR=2.06, 95% CI=1.25–3.39), and dry cough(OR=2.53, 95% CI=1.25–5.11) compared withexposuretoconcentrationslowerthan0.2f/cm3[Trethowanet al. 1995].Between the0.2 to0.6 f/cm3and>0.6f/cm3RCFexposuregroups,a statistically significant increase occurred inORs for wheezing (P<0.0001), grade 2 dyspnea(P<0.05),eye irritation(P<0.0001),andskinir-ritation(P<0.0001)—butnotforstuffynose[Tre-thowanetal.1995].Lockeyetal.[1993]foundthatdyspneawassignificantlyassociatedwithcumula-tiveexposureto>15fiber-months/cm3(i.e.,>1.25fiber-year/cm3)relativetocumulativeexposureto≤15fiber-months/cm3(dyspneagrade1–OR=2.1,95%CI1.3–3.3;dyspneagrade2–OR=3.8,95%CI1.6–9.4)afteradjustingforsmokingandotherpotential confounders. Lockey et al. [1993] alsofound a statistically significant association be-tween cumulative RCF exposure and pleurisy(OR=5.4,95%CI=1.4–20.2),andanelevatedbutnonsignificant association between cumulativeRCF exposure and chronic cough (OR=2.0,95%CI=1.0–4.0).Lemastersetal.[1998]also

noted associations (P<0.05) between employ-mentinanRCFproductionjobandincreasedprevalence of dyspnea and the presence of atleast one respiratory symptom after adjustingthedataforconfounders.Recurrentchestillnessin the European study population was associ-atedwiththeestimatedcumulativeexposuretothoracic-sizedfibersbutwasmorestronglyas-sociatedwithestimatedcumulativeexposuretothoracic-sizeddust[Cowieetal.1999,2001].

Incross-sectionalanalyses,boththeU.S.[Lock-ey et al. 1998; Lemasters et al. 1998] and the1986European[Trethowanetal.1995;Burgeetal.1995]studiesfoundthatcumulativeRCFexposure is associated with pulmonary func-tion decrements among current and formersmokers. Lemasters et al. [1998] also foundstatistically significant deficits in pulmonaryfunction measures for nonsmoking femaleworkers. The decreased pulmonary functionin the European study population remainedsignificantly associated with cumulative RCFexposure,evenaftercontrollingforcumulativedust exposure [Burge et al. 1995]. The 1996European study found pulmonary functiondecrements only in current smokers [Cowieet al. 1999, 2001]. In a longitudinal analysisofdatafrommultipleserialpulmonaryfunc-tiontests,Lockeyetal.[1998]concludedthatthemorerecentRCFconcentrationsoccurringafter1987werenotassociatedwithdecreasedpulmonaryfunction;rather,decreases inpul-monaryfunctionweremorecloselyrelatedtotypically higher concentrations that occurredbeforethistimeperiod.TheU.S.andEuropeanstudiessuggestthatdecrementsinpulmonaryfunction observed primarily in current andformersmokersareevidenceofaninteractiveeffectbetweensmokingandRCFexposure.

8.2.3 Carcinogenic Risk in Humans

Moolgavkaretal.[1999]derivedriskestimatesforlungcancerinhumansonthebasisofthe



resultsfromthetwochronicbioassaysofRCFsinmaleFischer344rats[Mastetal.1995a,b].Several models (linear, quadratic, exponen-tial)wereusedtoestimateandcomparerisksusing reference populations comprised of ei-theranonsmokingACScohortoracohortofsteelworkersnotexposedtocokeovenemis-sions (seeTable5–10 for riskestimates).Theexponentialmodelprovidedthebeststatisticalfitofthedata.Thelinearmodelprovidedthehighestestimatesofhuman lungcancer risksfrom exposure to RCFs when used with thereferent steel workers cohort (considered tobemostrepresentativeofworkersexposedtoRCFs because it includes blue collar workerswhosmoke).Lungcancerriskestimateswerecalculatedusingeachmodelatexposurecon-centrationsof0.25f/cm3,0.5f/cm3,0.75f/cm3,and1.0f/cm3.TheRCF-relatedlungcancerriskdeterminedfromthelinearmodelforthelow-estconcentration(0.25 f/cm3)was0.27/1,000forthecohortofsteelworkerscomparedwith0.036/1,000using theexponentialmodel and0.00088/1,000 for the quadratic model whenusingthesamereferentpopulation.

The risk estimates incorporated multiple as-sumptions, includingahumanbreathingrateof 13.5L/min (considered light work) andmultiple criteria for defining the length oftimeaworkercouldbeexposedtoRCFsoveraworkinglifetime.Higherriskestimatescouldbe expected if the assumptions more closelyrepresentedthoseusedbyNIOSHandOSHA:(1) a human breathing rate of 20 L/min and(2) a worker exposure duration of 8 hr/day,5days/wk, 50 wk/yr, from age 20 to 65 withtheriskcalculatedbeyondage70(e.g.,toage85).Furthermore,thecalculatedriskestimatescouldbeanunderestimationofthelungcancerrisk to humans because the models assumedthatthetissuesensitivitytoRCFsintheratisequal to that in humans. Although the lungcancerriskestimatesderivedfromtheratdataare reason for concern, estimates of human

riskformesotheliomafromthehighincidence(41%)ofmesotheliomainhamsterscannotbeappropriatelymodeledsinceonlyasingleex-posurewasadministeredinthestudy.Primar-ily on the basis of chronic animal inhalationstudies [Mastetal.1995a,b;McConnell etal.1995],NIOSHconcludesthatRCFsareapo-tentialoccupationalcarcinogen.Furthermore,theevidenceofpleuralplaques [Lemastersetal.1994;Lockeyetal.1996]observed inper-sonswithoccupationalexposurestoairborneRCFsisclinicallysimilartothatobservedinas-bestos-exposedpersonsaftertheinitialyearsoftheiroccupationalasbestosexposures[Houri-haneetal.1966;Becklakeetal.1970;Dementetal.1986].NIOSHconsidersthediscoveryofpleuralplaquesinU.S.studiesofRCFmanu-facturing workers to be a significant findingbecausetheplaqueswerecorrelatedwithRCFexposure [Lemasters etal. 1994; Lockey et al.1996]. In addition, NIOSH considers the re-spiratorysymptomsandconditions(includingdyspnea,wheeze,cough,andpleurisy)[Lemas-tersetal.1998;Lockeyetal.1993;Trethowanetal.1995;Burgeetal.1995;Cowieetal.1999]inRCFworkerstobeadversehealtheffectsthathavebeenassociatedwithexposuretoairbornefibersofRCFs.

Insufficient evidence exists to document anassociation between fibrotic or carcinogeniceffectsandtheinhalationofRCFsbyworkersin the RCF manufacturing industry thoughthese effects have been demonstrated in ani-mal studies.The lackofanobservedassocia-tion between RCF exposure and these effectsamong workers could be affected by one ormorefactors, includingseveralrelatingtothestudy population: the relatively small cohort,the proportion of workers with short tenurerelativetowhatmightbeexpected(ontheba-sisofanasbestosanalogy)intermsofdiseaselatency, and workers with limited cumulativeexposurestoRCFs.



8.2.4 Controlling RCF Exposures in the Workplace

Table 8–6 summarizes exposure monitoringdata collected by the RCFC under a consentagreementwiththeEPA[Everest1998;Maximetal.1997].Thesedataindicatethatexposuresto RCFs during 1993–1998 had an AM fiberconcentration of about 0.3 f/cm3 for manu-facturing and nearly 0.6 f/cm3 for end users.Maximetal.[1997,1999a]reportedresultsforboth manufacturing and end-use sectors inwhich airborne fiber concentrations through1997werereducedtoanAM<0.3–0.6f/cm3.

Theexposuremonitoringdatacollectedaspartof theRCFC/EPAconsentagreementprovideassurance that when appropriate engineeringcontrolsandworkpracticesareused,airborneexposuretoRCFscanbemaintainedformostfunctionaljobcategories(FJCs)attheRELof0.5f/cm3.Formanymanufacturingprocesses,reductionsinexposureshaveresultedfromtheimproved ventilation, engineering or processchanges, and product stewardship programs[Rice et al. 1996; Maxim et al. 1999b]. ThesedataprovidethebasisfortheNIOSHdetermi-nationthataRELof0.5f/cm3asaTWAcanbeachieved.

AlthoughmanyRCFmanufacturingandend-userjobtaskshaveexposurestoRCFsatcon-centrations below 0.5 f/cm3, exposure moni-toringdataalsoindicatethatnotallFJCsmaybe able to achieve these RCF concentrationsconsistently. FJCs that currently experienceairborneAM fiber concentrations >0.5 f/cm3includefinishing(manufacturingandenduse)andremoval(enduse).Typicalprocessingdur-ingfinishingoperations(e.g.,sawing,drilling,cutting, sanding) often requires high-energysourcesthattendtogeneratelargerquantitiesofairbornedustandfibers.ForRCFinsulationremoval, activities are performed at remotesiteswhereconventionalengineeringcontrolsandfixedventilationsystemsaremoredifficult

to implement. For some operations, such asremovalofRCFinsulationtilesfromfurnaces,the release of high airborne fiber concentra-tionscanoccur.However,removalofRCFin-sulationtilesisnotroutineandisgenerallyac-complishedinashortperiodoftime.Workersalmost universally wear PPE and respiratoryprotectionduringthesejobtasks[Maximetal.1997,1998].

NIOSHacknowledgesthatthefrequentuseofPPE, including respirators, may be requiredforsomeworkershandlingRCFsorRCFprod-ucts.ThefrequentuseofPPEmayberequiredduring job tasks forwhich(1)routinelyhighairborne concentrations of RCF (e.g., finish-ing,insulationremoval)exist,(2)theairborneconcentration of RCF is unknown or unpre-dictable,and(3)jobtasksareassociatedwithhighly variable airborne concentrations be-causeofenvironmentalconditionsortheman-ner inwhichthe jobtask isperformed.InallworkenvironmentswhereRCFsorRCFprod-uctsarehandled,controlofexposurethroughtheengineeringcontrolsshouldbethehighestpriority.

8.3SummaryThe following summarize the relevant infor-mationusedasthebasisfortheNIOSHassess-mentofoccupationalexposurestoRCFs:

■ Airborne concentrations of RCFs havebeen characterized as containing fibersofdimensionsinthethoracicandrespi-rable size ranges. RCFs are among themost durable types of SVFs. In tests ofsolubility,RCFsarenearlyasdurableaschrysotile asbestos but significantly lessdurable than amphibole asbestos fiberssuchasamosite.

■ Chronic, nose-only inhalation studieswithRCFsinanimalsshowastatistically



Table 8–6 . Airborne fiber concentrations in the RCF* industry during 1993–1998, by functional job category and production status† (f/cm3 as TWA)


and production status

Minimum

value

First

quartile Median

Geometric

mean

Arithmetic

mean

Third

quartile

Maximum

value

Total:

Manufacturing

Enduse

0.001

0.002

0.070

0.052

0.186

0.173

0.16

0.16

0.313

0.560

0.407

0.524

7.700

30.000

Assembly:

Manufacturing

Enduse

0.001

0.002

0.110

0.050

0.208

0.159

0.18

0.14

0.281

0.316

0.366

0.402

2.154

2.837

Auxiliary:

Manufacturing

Enduse

0.001

0.002

0.019

0.021

0.038

0.066

0.05

0.07

0.112

0.198

0.132

0.198

1.347

2.678

Fiber:

Manufacturing

Enduse

0.004

—

0.063

—

0.145

—

0.14

—

0.257

—

0.299

—

7.700

—

Finishing:

Manufacturing

Enduse

0.004

0.006

0.316

0.124

0.488

0.383

0.47

0.35

0.663

0.991

0.803

0.986

4.044

30.000

Installation:

Manufacturing

Enduse

—

0.003

—

0.084

—

0.236

—

0.20

—

0.434

—

0.559

—

3.371

Mixing/forming:

Manufacturing

Enduse

0.004

0.010

0.090

0.074

0.184

0.159

0.17

0.17

0.292

0.319

0.364

0.369

1.445

4.109

Other:

Manufacturing

Enduse

0.007

0.003

0.027

0.013

0.070

0.030

0.07

0.04

0.112

0.194

0.177

0.102

1.900

6.400

Removal:

Manufacturing

Enduse

—

0.010

—

0.373

—

1.914

—

0.82

—

1.816

—

2.340

—

16.000

Source:AdaptedfromEverest[1998].*Abbreviations:RCF=refractoryceramicfiber;TWA=time-weightedaverage.†Fiberconcentrationsweredeterminedduringmonitoringperformedovera5-yearperiod(1993–1998)undertheRefractoryCeramicFibersCoalition/EnvironmentalProtectionAgency(RCFC/EPA)consentagreement.ConcentrationsweredeterminedbyNIOSHmethod7400“B”countingrules.



significant increased incidence of lungtumors in rats and pleural mesothelio-masinhamsters.ThesedatasupporttheNIOSH determination that RCFs are apotentialoccupationalcarcinogen.

■ Epidemiologicstudiesofworkers intheRCF manufacturing industry show anincreased incidence of pleural plaques,respiratory symptoms (dyspnea andcough), skin and eye irritation, and de-creased pulmonary function related toincreasing exposures to airborne fibers.Some of these conditions are docu-mentedforexposureconcentrationsinarangeaslowas0.2to0.6f/cm3.StudiesofworkersexposedtoairborneRCFsshownoevidenceofexcessriskforlungcancerormesothelioma.However,theinabilitytodetectsuchanassociationcouldbebe-causeof(1)thelowstatisticalpowerfordetectinganeffect,(2)theshortlatencyperiod for most workers occupationallyexposed,and(3)thehistoricallylowanddecreasingfiberexposuresthathaveoc-curredinthisindustry.

■ Riskassessmentanalysesusingdatafromchronic inhalation studies in rats indi-cate that the excess risk of developinglungcancerwhenexposed toRCFsataTWAof0.5f/cm3foraworkinglifetimeis 0.073 to 1.2/1,000. However, on thebasisoftheassumptionsusedintheriskanalyses,NIOSHconcludesthatthisriskestimateismorelikelytounderestimatethan to overestimate the risk to RCF-exposedworkers.Reductionof theRCFTWA concentration to 0.2 f/cm3 wouldreducetheriskforlungcancerto0.03to0.47/1,000. OSHA attempts to set PELsforcarcinogensthatreflectanestimatedriskof1/1,000butislimitedbyconsider-ationsoftechnologicandeconomicfea-sibility.

■ RCFexposuredatagatheredunderacon-sent agreement between RCFC and EPA,whichincludeda5-yearcomprehensiveairmonitoring program (1993–1998), indi-catethatairborneexposureconcentrationstoRCFshavebeendecreasing.Monitoringresults showthat75%to>95%ofTWAexposureconcentrationmeasurementsinallFJCs(withoneexception)werebelow1.0f/cm3.InallbuttwooftheeightFJCs,>70%ofTWAmeasurementswerebelowtheRCFCrecommendedexposureguide-line of 0.5 f/cm3. On the basis of the re-viewofthesedata,NIOSHhasconcludedthattheRELof0.5f/cm3canbeachievedinmostworkplaceswhereRCFsorRCFproductsaremanufacturedorused.

■ The combined effect of mixed exposurestofibersandnonfibrousparticulatesmaycontributetoincreasedirritationofthere-spiratorytract,skin,andeyes.Engineeringcontrols and appropriate work practicesusedtokeepairborneRCFconcentrationsbelowtheRELshouldhelptominimizeair-borneexposurestononfibrousparticulatesaswell.Becausetheratiooffiberstonon-fibrous particulate in airborne exposuresmayvaryamongjobtasks,exposuremoni-toringshouldincludeeffortstocharacterizeparticulatecompositionandtocontrolandminimize airborne fibers and nonfibrousparticulateaccordingly.

From the assessment described above andthroughoutthisdocument,NIOSHconcludesthat on a continuum of fiber toxicity, RCFsrelatemorecloselytoasbestosthantofibrousglassandotherSVFsandshouldbehandledac-cordingly.NIOSHconsidersallasbestostypesto be carcinogens and has established a RELof0.1 f/cm3 forairborneasbestosfibers.Thisvaluewasdeterminedonthebasisofextensivehumanandanimalhealtheffectsdataandtherecognizedlimitsofanalyticalmethods.



RecognizingthatRCFsarecarcinogensinani-malstudiesandgiventhelimitationsinderiv-inganexposurevaluethatreflectsnoexcessriskof lung cancer or mesothelioma for humans,NIOSHrecommendsthateveryeffortbemadetokeepexposuresbelowtheRELof0.5f/cm3asaTWAforupto10hr/dayina40-hrwork-week.Theseeffortswillfurtherreducetheriskfor malignant respiratory disease and protectworkers from conditions and symptoms de-rivingfromirritationof therespiratorytract,skin,andeyes.

From the analysis of historical exposure data(seeChapter4)andtheexposuredatacollect-edaspartoftheRCFC/EPAconsentagreementmonitoringprogram(Table8–6),NIOSHhasdeterminedthatcompliancewiththeRELforRCFsisachievableinmostmanufacturingandend-use job categories. Although routine at-tainment of TWA exposures below the RELmaynotcurrentlyoccuratalljobtasks,itdoesrepresent a reasonable objective that can beachievedthroughmodificationofthejobtaskortheintroductionorimprovementofventi-lationcontrols.


9 Guidelines for Protecting Worker Health

■ Establish procedures for reporting haz-ards and giving feedback about actionstakentocorrectthem.

■ Instruct workers about using safe workpracticesandappropriatePPE.

■ Informworkersaboutpracticesoroper-ationsthatmaygeneratehighconcentra-tionsofairbornefibers(suchascuttingand sanding of RCF boards and otherRCFproducts).

■ Makeworkerswhoremoverefractoryin-sulationmaterialsawareofthefollowing:

—Theirpotentialforexposuretorespi-rablecrystallinesilica

—Healtheffectsrelatedtothisexposure

—Methodsforreducingtheirexposure

—Types of PPE that may be required(includingrespirators)

9.1.2 Labeling and Posting

Althoughworkersshouldhavereceivedtrain-ingaboutRCFexposurehazardsandmethodsforprotectingthemselves,labelsandsignsserveasimportantremindersandprovidewarningstoworkerswhomaynotordinarilyworkinthearea.Employersshoulddothefollowing:

■ PostwarninglabelsandsignsaboutRCF-associated health risks at entrances andinsideworkareaswhereairborneconcen-trationsofRCFsmayexceedtheREL.

Thefollowingguidelinesforprotectingworkerhealth and minimizing worker exposures toRCFs are considered minimum precautionsthatshouldbeadoptedasapartofasite-specificsafetyandhealthplantobedevelopedandover-seenbyappropriateandqualifiedpersonnel.

9.1 Informing Workers about Hazards

9.1.1 Safety and Health Training Program

Employersshouldestablishasafetyandhealthtraining program for all workers who manu-facture, use, handle, install, or remove RCFproductsorperformotheractivitiesthatbringthem into contact with RCFs.As part of thistraining program, employers should do thefollowing:

■ Informallpotentiallyexposedworkers(in-cluding contract workers) about RCF-associated health risks such as skin, eye,andrespiratoryirritationandlungcancer.

■ ProvideMSDSsonsite:

—Make MSDSs readily available toworkers.

—Instructworkershowtointerpretin-formationfromMSDSs.

■ Teach workers to recognize and reportadverserespiratoryeffectsassociatedwithRCFs.

■ Trainworkerstodetecthazardoussitua-tions.


9 ■Guidelines for Protecting Worker Health

■ Statetheneedtowearappropriaterespi-ratoryprotectionandprotectiveclothinginareaswhereairborneRCFsmayexceedtheREL.

■ Ifrespiratoryprotectionisrequired,postthefollowingstatement:

9.2.1 Engineering Controls

Engineering controls should be the principalmethod for minimizing exposure to RCFs intheworkplace.

9.2.1.1 Ventilation

Achieving reduced concentrations of air-borneRCFsdependsonadequateengineeringcontrolssuchaslocalexhaustventilationsys-temsthatareproperlyconstructedandmain-tained.Localexhaustventilationsystemsthatemployhoodsandductworktoremovefibersfrom the workplace atmosphere have beenusedbyRCFmanufacturers.Oneexampleisa slotted-hooddustcollectionsystemplacedoveramixingtanksothatairbornefibersarecaptured and collected in a bag house withHEPAfilters[RCFC1996].Othertypesoflo-calexhaustventilationordustcollectionsys-temsmaybeusedatorneardust-generatingsystemstocaptureairbornefibers.BandsawsusedinRCFmanufacturingandfinishingop-erationshavebeenfittedwithsuchengineer-ingcontrolstocapturefibersanddustduringcuttingoperationsandtherebyreduceexpo-sures for the band saw operator [Venturin1998]. Disc sanders fitted with similar localexhaust ventilation systems are effective inreducing airborne RCF concentrations dur-ingsandingofvacuum-formedRCFproducts[Dunnetal.2004].Forqualitycontrollabora-toriesorlaboratorieswhereproductionsam-plesarepreparedforanalyses,exhaustventi-lationsystemsshouldbedesignedtocaptureandcontaindust.Forguidance indesigninglocal exhaust ventilation systems, see Indus-trial Ventilation—A Manual of Recommended Practice, 25th edition [ACGIH 2005], Rec-ommended Industrial Ventilation Guidelines[HagopianandBastress1976],andtheOSHAventilationstandard[29CFR1910.94].

RESPIRATORS REQUIRED IN THIS AREA.

■ PrintalllabelsandwarningsignsinbothEnglish and the predominant languageofworkerswhodonotreadEnglish.

■ If workers are unable to read the labelsand signs, inform them verbally aboutthehazardsandinstructionsprintedonthelabelsandsigns.

9.2 Hazard Prevention and Control

Proper use and maintenance of engineeringcontrols,workpractices,andPPEareessentialfor controlling concentrations of airborne fi-bersduringthemanufacturing,use,andhan-dling of RCF products. Minimizing exposuretoRCFsmaybeaccomplishedthroughacom-bination of the following work practices andcontrols:

■ Engineeringcontrolsandventilation

■ Productreformulation

■ Workerisolation

■ PPE (such as protective clothing andequipmentandrespirators)

■ Proper decontamination and waste dis-posal



Additional engineering controls have beenevaluated by the Bureau of Mines for mini-mizingairbornedustinundergroundminingoperationsandatindustrialsandplants.Thesecontrols may also have applications for RCFfinishing,installation,andremovaloperations.Theuseofairshowers(alsoknownasacanopyaircurtainoranoverheadairsupplyisland)in-volvespositioninganairsupplyovertheheadofaworkertoprovideaflowofclean,filteredair to the worker’s breathing zone [Volkweinet al. 1982, 1988]. Proper design and evalua-tion are critical for ensuring that filtration isadequate to remove airborne fibers from theairsupply.Also,selectionoftheairsupplyflowrateisimportanttomakesurethatthevelocitydeliveredtotheworker’sbreathingzoneissuf-ficienttoovercomecrossdraftsandmaintainacleanairflow.

9.2.1.2 Tool selection and modification

TheRCFChasreportedthatusinghandtoolsinstead of powered tools can significantly re-duce airborne concentrations of dust. How-ever,handtoolsoftenrequireadditionalphysi-caleffortandtime,andtheymayincreasetherisk of musculoskeletal disorders. Employersshould therefore use ergonomically correcttoolsandproperworkstationdesign toavoidergonomichazards.

The additional physical effort required tousehandtoolsmayalsoincreasetherateanddepthofbreathingandmayconsequentlyaf-fect the inhalation and deposition of fibers.Foroperationssuchascutting,sawing,grind-ing,drilling,andsanding,thehighlevelofme-chanicalenergyappliedtoRCFproductswithpowertoolsincreasesthepotentialforelevatedconcentrations of airborne fiber. Examples[Carborundum 1992] of how airborne fiberconcentrationsareaffectedby theequipmentusedtoprocessRCFproductsincludethefol-lowing:

■ A testofhand sawingversus theuseofapoweredjigsawshowedan81%reduc-tion in concentrations of airborne dustgenerated.

■ A comparison of hand sanding versuspowersandingshoweda90%reductionin concentrationsof airbornedustgen-erated.

■ Whenalightwatermistisappliedtothesurface of a vacuum-formed board be-fore sanding, airborne dust concentra-tionisreducedby89%forhandsandingand88%forpoweredsanding.

■ Theuseofacorkbore(coredrill)versusanelectricdrillwithatwistbitforcuttingholes in RCF product forms reduces air-bornedustconcentrationsbyabout85%.

9.2.1.3 Engineering controls for RCF finishing operations

ResearchersatNIOSHhavebeenworkingwithindustrial hygienists at RCFC member facili-ties to study the effectiveness of engineeringcontrolsdesignedandappliedtoRCFfinishingoperations.Becausehandtoolsarenotalwaysapracticalsolutiontomanufacturingandend-use facilities requirements, engineering con-trolsarebeingdesignedandevaluatedforusewithpoweredtools.

AjointprojectbetweenNIOSHandRCFCwasinitiatedin1998andinvolvedinvestigatingen-gineeringcontrolsforusewithapedestalbelt/disc sander [Dunn et al. 2000, 2004]. Theseunits are frequently used by the manufactur-ersaswellasthecustomerfacilitiestoproducevacuum-formed boards sized to the requireddimensions.Acontinuousmistingnozzleandsimple local exhaust ventilation system wereintegratedforuseonthepedestalsandingunit.Themisterconsistedofastandardatomizationnozzlethatwassetforalow-waterflowrateto



minimizepartdegradation.Thelocalexhaustventilation system used two hoods or pickuppointswithatotalairflowof700ft3/min.

Duringproductionofvacuum-formedboards,these two controls reduced fiber concentra-tionsinthebreathingzoneasfollows:

% decrease in airborne fibers:

Discsandingusingwatermist . . . . . . . 88

Discsandingusinglocalexhaustventilation . . . . . . . . . . . . . . . . . 99

Beltsandingusingwatermist . . . . . . .50

Beltsandingusinglocalexhaustventilation . . . . . . . . . . . . . . . . . 99

Thesestudieshighlight thepotential forsig-nificantreductionsinworkerexposureusingwell designed and maintained engineeringcontrols, but their effectiveness needs to bevalidatedinthefield.

9.2.1.4 Wet methods for dust suppression

Fibercountsare lower inmorehumidatmo-spheres. Examples of using water to suppressdustconcentrationsaredescribedasfollows:

■ At one RCF textile facility, misters havebeenaddedabovebroadloomsandtapeloomstodecreasefiberconcentrations.

■ Waterknivesarehigh-pressurewaterjetsthatareusedtocutandtrimedgesofRCFblanketwhilesuppressingdustandlimit-ingthegenerationofairbornefibers.

■ DuringtheinstallationofRCFmodulesin a furnace, a procedure called tamp-ingistypicallyperformed.Aftermodulesareputinplaceonthefurnacewall,themodules are compressed by placing a

1-ft length of 2- by 4-ft lumber againstthe modules and tapping it lightly withahammer.TheprocesshelpsensurethattheRCFmodulesareinstalledtightlyinplace.Whenalightwatersprayisappliedto the surface of the modules beforetamping,airbornefiberconcentrationisreduced by about 75% [Carborundum1993]. The water is applied with a gar-den-type sprayer that is setonmistus-ingabout1galofwater/100ft2ofsurfacearea.However,cautionisadvisedregard-ing thedampeningof refractory-liningsduring installation. The introductionof water can damage refractory-linedequipmentduringheatingwithexplosivespallingfromthegenerationofsteam.

■ After-service RCF insulation removedfrom furnaces may be wetted to reducethereleaseoffibers.

9.2.1.5 Isolation

Some manufacturing processes may be en-closed to keep airborne fibers contained andseparatedfromworkers.

■ Whenpossible, isolateworkersfromdi-rect contact with RCFs by using auto-matedequipmentoperatedfromaclosedcontrolboothorroom.

■ Maintainthecontrolroomatgreaterairpressurethanthatsurroundingthepro-cessequipmentsothatairflowsoutrath-erthanin.

■ Make sure workers take special precau-tions (such as using PPE) when theymustenterthegeneralworkareatoper-formprocesschecks,adjustments,main-tenance,assembly-linetasks,andrelatedoperations.



9.2.2 Product Reformulation

One factor that contributes to the toxicity ofan inhaled fiber is the durability of the fiberanditsresistancetodegradationintherespira-torytract.ThechemicalcharacteristicsofRCFsmake themoneof themostdurable typesofSVFs.Asaresult,aninhaledRCFofspecificdi-mensionswillpersistlongerinthelungs.Mod-ifying the physical characteristics of RCFs orreformulatingtheirchemistrytoproduce lessdurable fibers are recommended options forreducingthehazardforexposedworkers.SuchanapproachhasbeentakenbyoneRCFmanu-facturerindevelopingtwomoresolubletypesofSVF[Maximetal.1999b].However,cautionisadvisedfordevelopinganddistributingsuchmodifiedfibers.Possibleadversehealtheffectsofnewlydevelopedfibersshouldbeevaluatedbefore introducing them intocommerce.Ap-propriatetestingofthesefibersshouldbeper-formedtoprovideinformationaboutthefibertoxicologyandpotentialadversehealtheffectsassociatedwithexposuretothesefibers.

9.2.3 Work Practices and Hygiene

Usegoodworkpracticestohelpreduceexpo-suretoairbornefibers.Thesepracticesincludethefollowing:

■ Limittheuseofpowertoolsunlesstheyareequippedwith localexhaustordustcollection systems. When possible, usehandtools,whichgeneratelessdustandfewerairborneparticles.

■ UseHEPA-filteredvacuums,wetsweeping,oraproperlyenclosedwetvacuumsystemforcleaningupdustcontainingRCFs.

■ DuringremovalofRCFproducts,damp-eninsulationwithalightwaterspraytokeepfibersanddustfrombecomingair-borne.

■ Clean work areas regularly with HEPA-filtered vacuums or with wet sweepingmethods to minimize the accumulationofdebris.

■ LimitaccesstoareaswhereworkersmaybeexposedtoairborneRCFs:permitonlyworkerswhoareessentialtotheprocessoroperation.

Use good hygiene and sanitation to protectworkers as well as people outside the work-place who might be contaminated with take-homedustandfibers:

■ Do not allow workers to smoke, eat, ordrink in work areas where they contactRCFs.

■ IfRCFsgetontheskin,washwithwarmwaterandmildsoap.

■ Applyskinmoisturizingcreamasneededto avoid dryness or irritation from re-peatedwashing.

■ Vacuum contaminated clothes with aHEPA-filteredvacuumbeforeleavingtheworkarea.

—Do not use compressed air to cleantheworkareaorclothing.

—Donotshakeclothestoremovedust.

■ Donotwear contaminatedclothesout-sidetheworkarea.Instead,takethefol-lowingmeasures toprevent takingcon-taminantshome:

—Changeintostreetclothesbeforego-inghome.

—Leave contaminated clothes at theworkplacetobelaunderedbytheem-ployer.



—Store street clothes in separate areasof the workplace to keep from con-taminatingthem.

■ Provideworkerswith showersandhavethemshowerbeforeleavingwork.

■ Prohibitremovalofcontaminatedclothesorotheritemsfromtheworkplace[NIOSH1995b].

9.2.4 Personal Protective Equipment

Wear long sleeves, gloves, and eye protectionwhen performing dusty activities involvingRCFs.

9.2.5 Respiratory Protection

NIOSHrecommendsusingarespiratorforanytaskinvolvingRCFexposuresthatareunknownorhavebeendocumentedtobehigherthantheNIOSHRELof0.5 f/cm3(TWA).Respiratorsshould not be used as the primary means ofcontrollingworkerexposures.Instead,NIOSHrecommends using other exposure-reductionmethods, such as product substitution, engi-neering controls, and changes in work prac-tices. However, respirators may be necessarywhenavailableengineeringcontrolsandworkpracticesdonotadequatelycontrolworkerex-posuresbelowtheRELforRCFs.NIOSHrec-ognizesthiscontroltobeaparticularchallengeinthefinishingstagesofRCFproductmanu-facturingaswellasduringtheinstallationandremovalofRCFinsulationmaterials.

If respiratory protection is needed, the em-ployer should establish a comprehensive re-spiratory protection program as described inthe OSHA respiratory protection standard[29CFR1910.134].Elementsofarespiratoryprotectionprogramshouldbeestablishedanddescribed in a written plan that is specific tothe workplace. This respirator program mustincludethefollowing:

■ Proceduresforselectingrespirators

■ Medicalevaluationsofworkersrequiredtowearrespirators

■ Fittestingprocedures

■ Routine use procedures and emergencyrespiratoruseprocedures

■ Procedures and schedules for cleaning,disinfecting, storing, inspecting, repair-ing,discarding, andmaintaining respi-rators

■ Procedures for ensuring adequate airqualityforsupplied-airrespirators

■ Traininginrespiratoryhazards

■ Training in the proper use and mainte-nanceofrespirators

■ Programevaluationprocedures

■ Procedures for ensuring that workerswhovoluntarilywearrespirators(exclud-ingfilteringfacepiecerespiratorsknownas dust masks) comply with the medi-calevaluationandcleaning,storing,andmaintenance requirements contained inAppendix D of the OSHA respiratoryprotectionstandard

■ Adesignatedprogramadministratorwhoisqualifiedtoadministertherespiratoryprotectionprogram

The written respiratory protection programshouldbeupdatedasnecessarytoaccountforchangesintheworkplacethataffectrespiratoruse.Allequipment,training,andmedicaleval-uationsrequiredundertherespiratoryprotec-tionprogramshouldbeprovidedatnocosttoworkers.Workers should use only respiratorsthathavebeencertifiedbyNIOSH[2002].



WhenairborneRCFconcentrationsexceedtheREL,NIOSHrecommendsthefollowingrespi-ratoryprotection:

■ At a minimum, use a half-mask, air-purifying respirator equipped with a100 series particulate filter (this res-piratorhasanassignedprotectionfactor(APF)of10.

■ For a higher level of protection and forprevention of facial or eye irritation, usea full-facepiece, air-purifying respirator(equippedwitha100 seriesfilter)or anypowered,air-purifyingrespiratorequippedwithatight-fittingfullfacepiece.

■ For greater respiratory protection whenthe work involves potentially high air-borne fiber concentrations (such as re-moval of after-service RCF insulationsuch as furnace insulation), use a sup-plied-airrespiratorequippedwitha fullfacepiece, since airborne exposure toRCFscanbehighandunpredictable.

Acomprehensiveassessmentofworkplaceex-posuresshouldalwaysbeperformedtodeter-minethepresenceofotherpossiblecontami-nants (such as silica) and to ensure that theproperrespiratoryprotectionisused.Table9–1providesadditionalguidanceforselectingap-propriaterespiratoryprotectionwithregardtoairbornefiberconcentrationsandtheNIOSHRELforRCFs.

Workersmayvoluntarilychoosetouserespi-ratory protection even when airborne fiberconcentrations are below the NIOSH RELor other applicable Federal or State stan-dards.Whenrespiratorsareusedvoluntarilybyworkers,employersneedtoestablishonlythose respiratory protection program ele-mentsnecessarytoassurethattherespiratoritselfisnotahazard[29CFR1910.134].The

exceptionisthatfiltering-facepiecerespirators(forexample,any95or100seriesfilter)canbeusedwithoutarespiratorprotectionprogramwhentheyareusedvoluntarily.

Forinformationandassistanceinestablishingarespiratoryprotectionprogramandselectingappropriate respirators, see the OSHA Respi-ratoryProtectionAdvisoron theOSHAWebsite at http://www.osha.gov.Additional infor-mation is available from the NIOSH Respira-tor Selection Logic[NIOSH2004]documentathttp://www.cdc.gov/niosh/docs/2005–100 andthe NIOSH Guide to the Selection and Use of Particulate Respirators Certified under 42 CFR 84[NIOSH1996].

9.3 Exposure Monitoring9.3.1 Workplace Exposure Monitoring

Program

The workplace exposure monitoring programforworksiteswhereRCFsorRCFproductsaremanufactured,handled,orusedshouldincluderoutine environmental and personal monitor-ingofairbornefiberconcentrations.Themoni-toring strategy should be designed to assesstheeffectivenessofengineeringcontrols,workpractices, PPE, training, and other factors incontrolling airborne fiber concentrations. Themonitoring program should also be used toidentifyareasor tasks that areassociatedwithhigherexposurestoRCFsandthatthereforere-quireadditionaleffortstoreducethem.

The goal of an RCF exposure monitoringprogramistoensureamorehealthfulworkenvironment where worker exposure (mea-suredbyfull-shiftsamples)doesnotexceedtheREL.BecauseadverserespiratoryhealtheffectscanoccurattheRELforRCFs,achiev-ing lowerconcentrations isdesirablewhen-ever possible. For work involving potential



Table 9–1 . Respiratory protection for exposure to RCFs*

Airborne concentration of RCFs or conditions of use Minimum respiratory protection options

5.0f/cm3(10×REL) Anyair-purifying,elastomerichalf-maskrespiratorequippedwitha100series(NH,R,orP)filterI

Anynegativepressure(demand),suppled-airrespiratorequippedwithahalfmask

12.5f/cm3(25×REL) Anypowered,air-purifyingrespiratorequippedwithahoodorhel-metandahigh-efficiencyparticulateairfilter(HEPAfilter)

Anycontinuous-flow,supplied-airrespiratorequippedwithahoodorhelmet

25f/cm3(50×REL) Anyair-purifying,full-facepiecerespiratorequippedwitha100series(NH,R,orP)filterI

Anypowered,air-purifyingrespiratorequippedwithatight-fittingfacepiece(halforfullfacepiece)andaHEPAfilter

Anynegativepressure(demand),supplied-airrespiratorequippedwithafullfacepiece

Anycontinuousflow,supplied-airrespiratorequippedwithatight-fittingfacepiece(halforfullfacepiece)

Anynegativepressure(demand),self-containedrespiratorequippedwithafullfacepiece

500f/cm3(1,000×REL) Anypressuredemand,supplied-airrespiratorequippedwithahalf-mask

*Abbreviations:APFs=assignedprotectionfactors;HEPA=high-efficiencyparticulateair;NIOSH=NationalInstitueforOccupationalSafetyandHealth;RCFs=refractoryceramicfibers.

HN-100seriesparticulatefiltersshouldnotbeusedinenvironmentswherethereispotentialforexposuretooilmists.IAssignedprotectionfactors(APFs)forotherhalf-maskandfull-facepieceparticulaterespiratorscertifiedunder42CFRPart84are

beingstudiedbyNIOSH.RecommendedAPFsfortheserespiratorswillberevisedaccordingly.



exposuretoairborneRCFs,performtheexpo-suresamplingsurveyasfollows:

■ Collect representative personal samplesfor the entire work shift using NIOSHMethod 7400 (B rules) [NIOSH 1977a,1998].

■ Perform periodic sampling at least an-nually and whenever any major processchangetakesplaceoranotherreasonex-ists to suspect that exposure concentra-tionsmayhavechanged.

■ Collect all routine personal samples inthebreathingzonesoftheworkers.

■ For workers exposed to concentrationsabove the REL, perform more frequentexposure monitoring until at least twoconsecutive samples indicate that theworker’sexposuresnolongerexceedtheREL.

■ Notifyallworkersaboutmonitoringre-sults and any actions taken to reducetheirexposures.

■ Make sure that any sampling strategyconsiders variations in work and pro-ductionschedulesaswellastheinherentexposurevariability inmost workplaces[NIOSH1995a].

9.3.2 Action Level

NIOSH has recommended an action level(AL) of 0.25 f/cm3for determining when ad-ditional controls areneededorwhenadmin-istrative actions should be taken to reduceRCF exposures. The purpose of the AL is toindicatewhenworkerexposurestoRCFsmaybeapproachingtheREL.Measurementofex-posureconcentrationsatorabove theAL in-dicate that there is ahighdegreeof certaintythatRCFconcentrationsexceedtheREL.TheALisastatisticallyderivedconceptpermitting

theemployertohaveconfidence(forexample,95%)thatifthemeasuredexposureconcentra-tionisbelowtheAL,onlyasmallprobabilityexiststhattheexposureconcentrationisabovethe REL. NIOSH has concluded that the useof anAL permits employers to monitor RCFexposures in the workplace without devot-ingunnecessaryresourcestoconductingdailyexposure measurements. TheAL concept hasservedasthebasisfordefiningtheelementsofan occupational standard in NIOSH criteriadocuments and in comprehensive standardspromulgated by OSHA and MSHA. Employ-ersshoulddeterminewhethertheuseofanALof0.25f/cm3providesadequateassurancethatworkerexposuresarebeingmaintainedbelowtheREL.Insomeworkenvironments,thehighdegree of exposure variability for certain jobtasksmayrequirealowerALtoassurethatex-posuresarebeingmaintainedbelowtheREL.Similar exposure monitoring strategies havebeenespousedbytheAmericanIndustrialHy-gieneAssociation, which recommends that ifmeasuredexposuresare less than10%of thedesignated exposure limit (for example, RELorPEL),thereisahighdegreeofcertaintythattheexposurelimitwillnotbeexceeded.

9.3.3 Sampling Strategies

Whensamplingtodeterminewhetherwork-er exposures are below the REL, a focusedsampling strategy may be more practicalthanrandomsampling.Afocusedsamplingstrategy targets workers perceived to havethehighestexposureconcentrations[LeidelandBusch1994].AfocusedstrategyismostefficientforidentifyingexposuresabovetheRELifmaximum-riskworkersandtimepe-riodsareaccuratelyidentified.Focusedsam-plingmayhelpidentifyshort-durationtasksinvolvinghighairbornefiberconcentrationsthatcouldresultinelevatedexposuresoverafullworkshift.



Sampling strategies such as those used byCorn and Esmen [1979], Rice et al. [1997],andMaximetal.[1997]havebeenderivedandusedinRCFmanufacturingfacilitiestomoni-torairbornefiberconcentrationsby selectingrepresentativeworkersforsampling.Therep-resentative workers are grouped according todustzones,uniformjobtitles,orfunctionaljobcategories. These approaches are intended toreducethenumberofrequiredsampleswhileincreasingtheconfidenceofidentifyingwork-ersatsimilarrisk.

Areasamplingmayalsobeusefulinexposuremonitoring for determining sources of air-borneRCFexposuresandassessingtheeffec-tivenessofengineeringcontrols.

9.4 Medical MonitoringNIOSHrecommendsperiodicmedicalevalu-ation,ormedicalmonitoring,ofRCF-exposedworkerstoidentifypotentialhealtheffectsandsymptomsthatmayberelatedtocontactwithairbornefibers.ThefollowingsectionsdescribetheobjectivesofmedicalmonitoringandtheelementsofamedicalmonitoringprogramforworkersexposedtoRCFs.

The primary goals of a workplace medicalmonitoring program are (1) early identifi-cation of adverse health effects that may berelatedtoexposuresatworkand(2)possiblehealthtrendswithingroupsofexposedwork-ers.Thesegoalsarebasedonthepremisethatearly detection, subsequent treatment, andworkplace interventions will ensure the con-tinuedhealthoftheaffectedworkforce.

9.4.1 Objectives of Medical Monitoring

Medical monitoring and resulting interven-tions represent secondary prevention andshouldnotreplaceprimarypreventioneffortstominimizeworkerexposurestoRCFs.Inthe

caseofRCFs,medicalmonitoringisespeciallyimportantbecauseachievingcompliancewiththe REL of 0.5 f/cm3 does not assure that allworkerswillbefreefromtheriskofrespiratoryirritationorchronicrespiratorydiseasecausedbyoccupationalexposure.Earlyidentificationof respiratory system changes and symptomsassociated with RCF exposures (such as de-creased pulmonary function, irritation, dys-pnea, chronic cough, wheezing, and pleuralplaques)maysignaltheneedformoreinten-sivemedicalmonitoringandtheassessmentofexistingcontrolstominimizetheriskoflong-termadversehealtheffects.Anongoingmedi-calmonitoringprogramalsoservestoinformworkersofpotentialhealthrisksandpromotesanunderstandingoftheneedforandsupportofexposurecontrolactivities.

Amedicalmonitoringprogramservesasanef-fective secondary prevention method on twolevels—screening and surveillance. Medicalscreeningintheworkplacefocusesontheearlydetection of health outcomes for individualworkersandmayinvolveanoccupationalhis-tory,medicalexamination,andapplicationofspecificmedicalteststodetectthepresenceoftoxicants or early pathologic changes beforethe worker would normally seek clinical careforsymptomaticdisease.Bycontrast,medicalsurveillance(describedinSection9.5)involvestheongoingevaluationofthehealthstatusofagroupofworkersthroughthecollectionandaggregate analysis of health data for the pur-poseofpreventingdiseaseandevaluatingtheeffectivenessofinterventionprograms.

9.4.2 Criteria for Medical Screening

Todeterminewhether testsorprocedures formedicalscreeningareappropriateandrelevanttoagivenhazard(inthiscase,exposuretoair-borneRCFs), the following factors shouldbeconsidered:



■ Prevalence of an associated disease orsymptomsinthepopulation

■ Riskof toxicity associatedwith theex-posure

■ Consequencesoffalsepositivetestresults

■ Sensitivity,specificity,andpredictiveval-ueofthescreeningtest(s)tobeused

■ Reliability and validity of the screeningtest(s)

■ Abilityofthescreeningtest(s)toidentifydisease early so that effective treatmentor intervention may be used to impedediseaseprogression

■ Availability,accessibility,andacceptabil-ity of followup, further diagnostic tests,andeffectivemanagementofthedisease

■ Benefitsof thescreeningprogramcom-paredwiththecosts[Wagner1996].

On the basis of these criteria, NIOSH rec-ommends a medical screening program forRCF-exposedworkers that require initial andperiodicmedical examinations.Theelementsof theprogramshould includeaphysical ex-amination, occupational history, respiratorysymptom questionnaire, spirometric test-ing,andchestradiographwhenwarranted.Ifa particular medical screening test indicatesthe presence of exposure-related disease orthe increasedprobability thatdiseasewillde-velop, further evaluation and diagnostic test-ingmaybeneeded.Recommendedguidelinesandschedulesforspecificmedicaltestsarede-scribed in Section 9.4.5 (Recommended Pro-gramElements).

9.4.3 Worker Participation

All workers potentially exposed to RCFs, inboth manufacturing and end-use industries,

may benefit by being included in an occupa-tional medical monitoring program.Workersshould be provided with information aboutthepurposesofmedicalmonitoring,thehealthbenefits of the program, and the proceduresinvolved. The following hierarchy describesworkerswhoshouldbeincludedinamedicalmonitoring program and who could receivethegreatestbenefitfrommedicalscreening:

■ Workers exposed to elevated fiber con-centrations(forexample,allworkersex-posedtoairborneRCFsatconcentrationsabovetheALof0.25f/cm3[describedinSection9.3])

■ Workers in areas or in jobs and activi-tiesinwhich,regardlessofairbornefiberconcentration,oneormoreworkershaverecentlydevelopedsymptomsorrespira-tory changes apparently related to RCFexposure

■ Workerswhomayhavebeenpreviouslyexposedtoasbestosorotherrespiratoryhazards thatplace thematan increasedriskofrespiratorydisease

■ Workers with potential exposure to air-borneRCFswhoalsosmokecigarettesorothertobaccoproducts(seeSection9.6,SmokingCessation).

9.4.4 Medical Monitoring Program Director

Oversight of the medical monitoring pro-gramshouldbeassignedbytheemployer toaqualifiedphysicianorotherqualifiedhealthcare provider (as determined by appropriateState laws and regulations) who is informedandknowledgeableaboutthefollowing:

■ Theadministrationandmanagementofamedicalmonitoringprogramforoccu-pationalhazards



■ Theestablishmentofarespiratoryprotec-tionprogrambasedonanunderstandingoftherequirementsoftheOSHArespi-ratoryprotection standardand typesofrespiratory protection devices availableattheworkplace

■ The identification and management ofwork-relatedrespiratoryeffectsorillnesses

■ The identification and management ofwork-relatedskindiseases

9.4.5 Recommended Program Elements

Recommended elements of a medical moni-toringprogram forworkers exposed toRCFsinclude provisions for an initial medical ex-aminationandperiodicmedicalexaminationsatregularlyscheduledintervals.Dependingonthe findings from these examinations, morefrequent and detailed medical examinationsmay be necessary. Worker education shouldalsobeincludedasacomponentofthemedi-calmonitoringprogram.SpecificelementsoftheexaminationsandschedulingaredescribedbelowandillustratedintheflowchartdiagraminFigure9–1.

9.4.5.1 Initial medical examination

An initial (baseline) examination should beperformedasnearaspossibletothedateofbe-ginningemployment(within3months).Theinitialmedicalexaminationshouldincludethefollowing:

■ A physical examination of all systems,withemphasisontherespiratorysystemandtheskin

■ Aspirometrictest(Anyoneadministeringspirometric testingaspartof themedi-cal monitoring program should havecompleted a NIOSH-approved training

courseinspirometryorotherequivalenttraining.)

■ AchestX-ray(AllchestX-rayfilmsshouldbe interpreted by a NIOSH-certified Breader using the standard InternationalClassification of Radiographs of Pneu-moconioses[ILO2000orthemostrecentequivalent].)

■ Othermedicaltestsasdeemedappropri-ate by the attending health care profes-sional

■ Astandardizedrespiratorysymptomques-tionnairesuchastheAmericanThoracicSocietyRespiratoryQuestionnaire[Ferris1978orthemostrecentequivalent]withadditionalquestionstoaddresssymptomsofpleuriticchestpainandpleurisy

■ Astandardizedoccupationalhistoryques-tionnaire that gathers (1) informationaboutallpastjobs(withspecialemphasisonthosewithpotentialexposuretodust),(2)adescriptionofalldutiesandpoten-tialexposuresforeachjob,and(3)ade-scriptionofallprotectiveequipment theworkerhasused

9.4.5.2 Periodic medical examinations

Periodic examinations (including a physicalexaminationoftherespiratorysystemandtheskin,spirometrictesting,arespiratorysymptomupdate questionnaire, and an occupationalhistory update questionnaire) should be ad-ministeredat regular intervalsdeterminedbythemedicalmonitoringprogramdirector.Thefrequency of the periodic medical examina-tions should be determined according to thefollowingguidelines:

■ For workers with fewer than 10 yearssincefirstexposuretoRCFs,periodicex-aminationsshouldbeconductedatleastonceevery5years.



I. Worker participation?

WorkinvolvespotentialforexposuretoRCFs,especial-lyforworkerswhoare

■ exposedtoelevatedfiberconcentrations(forexample,aboveadesignatedAL),

■ inworkareaswhereoneormoreworkershaverecentlydevelopedrespiratorysymptomsorchanges,

■ previouslyexposedtoasbestosorotherrespira-toryhazards

YES

II. Initial medical examination

(within3monthsofbeginningemployment)

■ Examinationofrespiratorysystemandskin

■ Spirometrictest

■ ChestX-ray

■ Standardizedrespiratorysymptomquestion-naire

■ Standardizedoccupationalhistoryquestion-naire

III. Adverse symptoms/health outcomes?

■ Respiratorysymptoms(forexample,chroniccough,difficultybreathing,shortnessofbreath,wheezing)


■ Medicallysignificantreasonforadditionalas-sessment

YES

IV. More frequent or detailed medical examination and treatment

(asdeterminedbyprogramdirector)

NO Maynotrequiremedicalmonitoring

NO

V. Periodic medical examination

■ Examinationofrespiratorysystemandskin

■ Spirometrictest

■ Standardizedrespiratorysymptomupdatequestionnaire

■ Standardizedoccupationalhistoryupdatequestionnaire

YESVI. Adverse symptoms/health outcomes?

(describedinIII.)

VII. Continue with guidance and schedule in V.

Figure 9–1 .FlowchartofmedicalmonitoringguidelinesforworkersexposedtoRCFs.Thisflowchartisintendedasasimplifiedrepresentationoftheminimumrequirementsoftherecommendedmedicalmonitoringprogramguide-lines.Administrationandmanagementoftheprogramshouldultimatelyrelyonthejudgmentofthemedicalmoni-toringprogramdirector.Frequencyofperiodicmedicalexaminationsareasfollows:

■ IftimesincefirstRCFexposureis<10years,examinationsshouldbeconductedatleastevery5years.

■ IftimesincefirstRCFexposureis≥10years,thenexaminationsshouldbeconductedatleastevery2years.



■ Forworkerswith10ormoreyearssincefirstexposuretoRCFs,periodicexamina-tions shouldbeconductedat leastonceevery2years.

AchestX-rayandspirometrictestingareim-portantuponinitialexaminationandmayalsobeappropriatemedicalscreeningtestsduringperiodic examinations for detecting respira-tory system changes—especially in workerswith more than 10 years since first exposureto RCFs. The value of periodic chest X-raysin a medical monitoring program should beevaluatedbyaqualifiedhealthcareproviderinconsultationwiththeworkertoassesswhetherthe benefits of testing warrant the additionalexposure to radiation. As with the frequencyof periodic examinations, the utility of thechestX-rayasamedical testbecomesgreaterforworkerswithmorethan10yearssincefirstexposuretoRCFs(basedonthelatencyperiodbetweenfirstexposureandappearanceofno-ticeable respiratory system changes). Becausepersons with advanced fiber-related pleuralchanges experience difficulty in breathing asthe parietal and visceral surfaces become ad-herentandloseflexibility,itmayprovebenefi-cialtodetectfibroticchangesintheearlystagessostepsmaybetakentopreventfurtherlungdamage.Similar recommendationshavebeenmadeforasbestos-exposedworkersdiagnosedwithpleuralfibrosisorpleuralplaquestopre-ventmoreserioustypesofrespiratorydisease[Balmes1990].

9.4.5.3 More frequent medical examinations

Anyworkershouldundergomorefrequentanddetailedmedicalevaluationifheorshehasanyofthefollowingindications:

■ Neworworseningrespiratorysymptomsorfindings(forexample,chroniccough,difficulty breathing, wheezing, reduced

lung function,or radiographicevidenceofpleuralplaquesorfibrosis)

■ Historyofexposuretootherrespiratoryhazards(forexample,asbestos)


■ Othermedicallysignificantreason(s)formoredetailedassessment

9.4.5.4 Worker education

Workers should be provided with sufficienttraining to recognize symptoms associatedwith RCF exposures (such as chronic cough,difficulty breathing, wheezing, and skin irri-tation).Workers should also be instructed toreport these symptoms to designated safetyandhealthpersonnelandaphysicianorotherqualifiedhealthcareprovider forappropriatediagnosisandtreatment.

9.4.6 Written Reports to the Worker

Followinginitialandperiodicmedicalexami-nations,thephysicianorotherqualifiedhealthcareprovidershouldprovideeachworkerwithawrittenreportcontainingthefollowing:

■ Results of any medical tests performedontheworker

■ Medicalopinioninplainlanguageaboutany medical condition that would in-crease the worker=s risk of impairmentfromexposuretoairborneRCFs

■ Recommendations for limiting theworker=s exposure to RCFs, which mayinclude the use of appropriate PPE, aswarranted

■ Recommendationsforfurtherevaluationandtreatmentofmedicalconditionsde-tected



9.4.7 Written Reports to the Employer

Followinginitialandperiodicmedicalexami-nations,thephysicianorotherqualifiedhealthcareprovidershouldprovideawrittenreporttotheemployercontainingthefollowing:

■ Occupationally pertinent results of themedicalevaluation

■ A medical opinion about any medi-cal condition that would increase theworker=sriskofimpairmentfromexpo-suretoairborneRCFs

■ Recommendations for limiting theworker=s exposure to RCFs (or otheragentsintheworkplace),whichmayin-cludetheuseofappropriatePPEorreas-signmenttoanotherjob,aswarranted

■ Astatement to indicate that theworkerhas been informed about results of themedicalexaminationandaboutthemed-icalcondition(s)thatshouldhavefurtherevaluationortreatment

Findings,testresults,ordiagnosesthathavenobearing on the worker=s ability to work withRCFsshouldnotbeincludedinthereporttothe employer. Safeguards to protect the con-fidentiality of the worker=s medical recordsshouldbeenforcedinaccordancewithallap-plicableregulationsandguidelines.

9.4.8 Employer Actions

Theemployershouldassurethatthequalifiedhealth care provider=s recommended restric-tionsofaworker=sexposuretoRCFsortooth-erworkplacehazardsarefollowedandthattheRELforRCFsisnotexceededwithoutrequir-ingtheuseofPPE.Effortstoencourageworkerparticipation in the medical monitoringpro-gramandtoreportsymptomspromptlytotheprogramdirectorareessentialfortheprogram=ssuccess.Medicalevaluationsperformedaspart

of the medical monitoring program shouldbeprovidedbytheemployeratnocosttotheparticipatingworkers.Iftherecommendedre-strictionsdeterminedbythemedicalprogramdirector include job reassignment, such reas-signmentshouldbeimplementedwiththeas-suranceofeconomicprotectionfortheworker.Whenmedicalremovalorjobreassignmentisindicated,theaffectedworkershouldnotsuf-ferlossofwages,benefits,orseniority.

Theemployershouldensurethatthemedicalmonitoring program director communicatesregularlywiththeemployer=ssafetyandhealthpersonnel(suchas industrialhygienists),em-ployee representatives, and safety and healthcommitteestoidentifyworkareasthatmayre-quireevaluationandimplementationofcon-trolmeasurestominimizetheriskfromexpo-suretohazards.

9.5 Surveillance of Health Outcomes

Standardized medical screening data shouldbeperiodicallyaggregatedandevaluatedbyanepidemiologistorotherknowledgeablepersontoidentifypatternsofworkerhealththatmaybelinkedtoworkactivitiesandpracticesthatrequireadditionalprimarypreventionefforts.Routine aggregate assessments of medicalscreeningdatashouldbeusedincombinationwithevaluationsofexposuremonitoringdatatoidentifychangesneededinworkareasorex-posureconditions.

Oneexampleof surveillanceusinganalysesofmedical screening data is the ongoing epide-miologicstudyofRCFworkersdescribedintheRCFCproduct stewardshipplanreferred toasPSP2000[RCFC2001].Elementsof thisplanmaybeadaptedandmodifiedbyotheremploy-erstodevelopmedicalsurveillanceprogramsforworkerswhoarepotentiallyexposedtoRCFs.



9.6 Smoking Cessation

NIOSHrecognizesasynergisticeffectbetweenexposure toRCFsandcigarette smoking thatincreasestheriskofadverserespiratoryhealtheffects.Thecombinedeffectsofsmokinganddust exposures have been recognized as con-tributing to the increased risk of respiratorydiseases,includingchronicbronchitis,emphy-sema,andlungcancer.NIOSHurgesemploy-ers to establish smoking cessation programsthat (1) inform workers about the increasedhazardsofcigarettesmokingandexposuretoRCFs and (2) provide assistance and encour-agementforworkerswhowanttoquitsmok-ing. NIOSH recommends that all workerswhoarepotentially exposed toairborneRCFfibersandwhoalsosmokeshouldparticipateinasmokingcessationprogram.Withregard

tosmoking intheworkplace,NIOSHrecom-mendsthatemployersdothefollowing:

■ Prohibit workers from smoking in theworkplace.

■ Disseminate information about healthpromotion and the harmful effects ofsmoking.

■ Offersmokingcessationprogramstowork-ersatnocosttoparticipants.

■ Collectdetailedsmokinghistoriesaspartofthemedicalmonitoringprogram.

■ Use training, employee assistance pro-grams,orhealtheducationcampaignstoencourage activities promoting physicalfitness and other healthy lifestyle prac-tices that affect respiratory and cardio-vascularhealth.


10 Research Needs

NIOSH[1993]hasdevelopedafiberresearchstrategythatproposesthefollowing:

■ Research into the mechanisms for hu-manfiberdisease

■ Epidemiologic studies of fiber-exposedworkers for whom limited or no healthdataexist

■ Toxicologic experiments with fibers forwhichhealtheffectshavenotbeenestab-lished

Theresearchstrategyalsoconsiderstheuseful-nessofintegratingfiberdatafromvarioussci-entific disciplines (toxicology, epidemiology,industrialhygiene,occupationalmedicine) toelucidatethecharacteristicsoffibers.

Inaddition,NIOSHrecommendsthatthefollow-ingstepsbetakenwithregardtoRCFresearch:

1. Conductbasicscientificinvestigations,including in vitro and in vivo animalstudies,todelineatethemechanismofactionforRCFtoxicity.

2. Conduct comparable studies for oth-erSVFsandnaturalfibers so that themechanisticdatacanbecompared.Forinstance,Coffinetal.[1992]examinedthe ability of different synthetic andnaturalfiberstoinducemesotheliomas.Theysuggestedthatinadditiontofiberlengthandwidth,currentlyundefinedintrinsic surface characteristics of thefibersaredirectlyrelatedtotheirmeso-theliomainductionpotency.

3. Conductaseriesofinvitroandinvivoanimalstudiestoensurethatfibertox-icity studies share a consistent, stan-dardized approach. Such studies willensure comparability of results in avarietyofexperimentsthatallusewell-characterized, known concentrationsof synthetic or natural fibers.A seriesofcontrolled,systematicinvitrostud-iesofthefactorsbelievedtobeinvolvedin RCF pathogenicity should producevaluable data on their mechanism ofaction. Invitrostudiesprovideanex-cellentopportunitytoinvestigatefibertoxicity factors such as dose, dimen-sion, surface area, and physicochemi-cal composition. This information isanimportantsupplementtodatafromchronicinhalationstudies.

4. Assure thatan independentagencyortestinglaboratoryassemblesandkeepsasetofreferencesamplesofRCFs(sim-ilartotheUnionInternationaleContrele Cancer [UICC] asbestos samples).Well-characterizedRCFmaterialrepre-sentativeofthatfoundinoccupationalexposurescouldserveasanimportantcomponent of future animal toxicol-ogy research into the mechanisms offiber-induced disease. Additional SVFsuchasfibrousglass,mineralwool,andotherceramicfibersshouldalsoberep-resentedinthisrepository.

5. Initiate and continue occupationalhealth surveillance for industries that


10 ■Research Needs

manufacture,process,install,orremovenew fibrous materials. Understandingofthisemergingindustryisimperativeso that exposures to synthetic fibrousmaterialscanbeavoidedandindustry-specificcontrolscanbedeveloped.

6. ContinueandexpandsurveillanceofRCF exposure in U.S. manufactur-ing facilities. Continue monitoringofairbornefiberandtotalparticulate

concentrations and analyze them to-getherwith thehealthdatausingepi-demiologic research methods. Extendsurveillance efforts to include assess-mentsofworkerexposureinsecondaryfacilities.

7. Assesstheeffectsofvariableworksched-ules(suchasshiftslongerthan8hr)onRCFexposureconcentrationsandhealtheffects.


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APPENDIX A

Air Sampling Methods*

*ReprintedfromNIOSHManual of Analytical Methods (NMAM),FourthEdition,8/15/94.


Appendix A ■Air Sampling Methods






























































Appendix BFunctional Job Categories

for RCF Workers

Table B–1 . Functional job categories for RCF workers

Functional category Definition General examples Additional comments

Fibermanufac-turing

Theproductionormanu-factureofRCFbulkorblanket,exceptinasupervisorycapacity.Includesalljobfunc-tionsontheproductionline,frommixingtherawingredientstopackagingthefinishedproduct(bulkorblanket)attheendoftheline.

Rawmaterials,furnaceman,furnaceoperator,orassistantfurnaceoperator

Productionworkerorrelief

Blanketline

Workingleader

Needler

Slit/cut/pack

Lineutility

Utilityoperator

Chopperoperator

Endofline,baggingofbulkRCF

Endoflinetrimming,rolling,andpackagingofRCFblanket

Nonetodate

Finishing CuttingormachiningRCFmaterialsafterfibermanufacture.Handorpowertoolsmaybeusedinfinishingoperations.

OperatingdiestamponRCFblanketorpaperexceptforautomotiveapplications

Sawing,slotting,trimming,orfilingcastingtipsorrisersleeves

Cuttingblanketforductwrap

WorkinginanareawherefinishingistakingplacebutnotpersonallyworkingwithRCFsunlessinasupervisorycapacityorinotherauxiliary operations.

(Continued)

AdaptedfromMaximetal.1997.


Appendix B ■Functional Job Categories for RCF Workers

Table B–1 (Continued) . Functional job categories for RCF workers


Finishing(Continued)

CuttingortrimmingRCFboardorothervacuum-formedRCFmaterialcapacity

SandingRCFboardorothervacuum-formedRCFmaterial

Loadingsander

Off-linecuttingandtandemrerollingand/orrepackagingofRCFblanket

CuttingortrimmingRCFmod-ulesforuseinappliances

MillingorroutingRCFboardorothervacuum-formedRCFmaterial

Off-sitecuttingofbattenstripsfromRCFblanket

EXAMPLE:Unloadingdryformsfromthedryingovenandtakingthemtothefinishingareaforfinalshaping,orpackagingshapesimmediatelyafterfinishingwouldbeconsideredfinish-ing.However,unloadingdryformsfromanovenandtak-ingthemtobepackaged,orpackagingshapesthatcomedirectlyfromthedryingovenwouldbeconsideredauxiliary operations.

Installation Buildingormanufactur-ingindustrialfurnacesorboilers,refineryorpetro-chemicalplantequip-ment,kilns,foundries,electricpowergenerators,andindustrialincinera-torsatenduserlocations.Includesfurnacemainte-nance.Doesnotincludefactorymanufactureofindustrialfurnacecompo-nents.

Installinghardwareormodules

On-sitecutting(trimming)modulestofit

Caulkingandfillinggaps

WrappingmoldswithRCF

SprayingorpumpingRCFcast-ablematerialinsidefurnace

Cuttingandinstallinglaid-inblanket

Workinginsidefurnacedur-ingtheinstallationofRCFmaterials,eventhoughnotworkingdirectlywiththatmaterial(e.g.,aplumberorelectricianworkinginsideafurnaceduringaninstalla-tion)

Removal Removalofafter-serviceRCFmaterialfromanin-dustrialfurnace,etc.,thathascompleteditseco-nomiclife.IncludestheremovalofRCFmaterialduringfurnacemainte-nance.

Unwrappingandknockingoutmolds

Furnacedisassembly

Furnacemaintenance

Cleanupanddisposalofre-movedmaterial

Workinginsidefurnacedur-ingtheremovalofRCFmaterials,eventhoughnotworkingdirectlywiththatmaterial(e.g.,aplumberorelectricianworkinginsideafurnaceduringaremoval)

Assemblyoperations

CombiningorassemblingRCFmaterialwithothermaterial(RCForother),exceptautomotiveappli-cations.Includesfactoryassemblyofindustrialfurnacecomponents.

Laminating

Cuttingmaterialformodules

EncapsulatingRCFblanket

Unpackingblanketandloadingintomodulefolder

(Continued)





Assemblyoperations(Continued)

Installingbandsaroundmodules

Packagingmodulesatendofline

Trimmingmodulesandinstall-inghardware

Assemblingappliances

Off-siteassemblyofindustrialfurnacecomponents(originalequipmentmanufacture)

ChangingRCFgaskets,etc.inappliances

Cuttingandassemblingmaterialforsound-proofingexhaustducts

SewingRCFmaterial

StaplingRCFmaterial

BallmillingorgrindingRCFmaterial

MixingRCFputties,compounds,orcastables

Mixing/form-ing

Wetendproductionofvacuum-castshapes,board,andfelt

FormingRCFboardorshapes

Weighing,batching,ormixingmaterialstobeformed

Placingwetpartsonconveyor

Operatingmixingmachine

Felting

Premixingdrymaterialsbeforeaddingtomixtank

Auxiliaryop-erations

JobsinwhichworkersarepassivelyexposedtoRCFswhileperformingtheirnormaldutiesandwhoseexposures are not likely to parallel those of workers working directly with RCF materials.IncludescertainjobsinwhichRCFsmaybehandledbutwithsmallprobabilityofsignificantexposures(e.g.,ware-houseworkerorpersonunloadingcompletedpartsforpackaging).

MovingRCF-wrappedmoldsintoandoutoffurnace

Warehouseduties,includingdockwork,loadingtrucks,movingmaterials

Supervising

Drivingforklift

MakingcartonstopackageRCFsatendofline

Qualitycontrolinspection

Packagingdryparts

Maintainingorrepairingequip-mentexceptfurnaces

(Continued)





Auxiliaryoperations(Continued)

CleaningfurnacesorplantareaswhereRCFsareused

Removingvacuum-formedpartsfromovenand/orpackagingthem(nofinishing)

Other(notelsewhereclassisfied)

AlldutiesperformedintheproductionofRCFpaper,textiles,andautomotivecomponentsorotherin-dustrysectorsnotcoveredinanyoftheforegoingcategories.Also,expo-suresthatcannotreason-ablybeincludedinthecategorieslistedabove(i.e.,notelsewhereclassi-fied).Industrialhygienistpersonnelshouldexplaintasksandindustrysectorsasfullyaspossibleforob-servationsinthiscategory.

Diecuttingpartsforautomotiveairbagfilters,gaskets,mufflers,orcatalyticconverters

Wrappingsubstrateforcatalyticconverter

Operatingformertomakerov-ing

Operatingtapeloom

Operatingcardingmachine

Papermaking

WrappingRCFblanketaroundahotweldsotheweldmaycoolwithoutstressbetweenthehotseamorjointandthecoolersurroundingmetal(notelsewhereclassified)


Appendix C

Cellular and Molecular Effects of RCFs (In Vitro Studies)

human pulmonary cells. The human alveolarmacrophagehasavolumeseveral timesgreaterthanthatoftheratalveolarmacrophage[Krom-backetal.1997].Macrophagesizeandvolumemayaffect(1)thesizerangeoffibersthatcanbe phagocytized, dissolved, and cleared by thelungsand(2)theresultingpathogenicityofthefiber.Eventheuseofahumanlungcelllinedoesnotguaranteethatinvitroresultswillbedirectlyapplicable to the intact human response. Theinvivointegrationofstimulifromthenervous,hormonal,andcardiovascularsystemscannotbereproducedinvitro.

Anotherpointtoconsiderwhenreviewingthesedataisthenumberanddefinitionsofvariablesusedindifferentstudies.Variablesincludedif-ferences infibertype,fiber length,fiberdose,celltype,andlengthofexposuretested,amongothers.Disparateresultsbetweenstudiesmakestrongconclusionsfrominvitrostudiesdiffi-cult.Atthesametime,thesestudiesmaypro-videimportantdataregardingthemechanismofactionofRCFsthatwouldnotbeobtainableinothertestingvenues.

RCFsmayexerttheireffectsonpulmonarytar-getcellsviadirectorindirectmechanisms.Di-rectmechanismsaretheresultanteffectswhenfiberscomeindirectphysicalcontactwithcells.DirectcytotoxiceffectsofRCFsinclude effectsoncellviability,responses,andproliferation.

The cellular and molecular effects of RCF ex-posures have been studied with two differentobjectives.Onepurposeoftheseinvitrostud-ies is to provide a quicker, less expensive, andmore controlled alternative to animal toxic-ity testing. These experiments, which strive toact as screening tests or alternatives to animalstudies,arebestinterpretedbycomparingtheirresultswith thoseof invivoexperiments.ThesecondobjectiveofinvitrostudiesistoprovidedatathatmayhelptoexplainthepathogenesisandmechanismsofactionofRCFsat thecel-lular and molecular levels. These cytotoxicityand genotoxicity studies are best interpretedbycomparingtheeffectsofRCFswiththoseofotherSVFsandasbestosfibers.Invitrostudiesserve as an important complement to animalstudiesandprovideimportanttoolsforstudy-ingthemolecularmechanismsoffibers.ItisnotyetpossibletousethesedatainthederivationofanREL.

Drawingstrongconclusions relevant tohumanhealthbasedontheseinvitrostudiesisimpossi-ble.Onepointtoconsiderwhenreviewingthesedata is the relevance of the cell types studied.ManystudiestodatehaveexaminedtheeffectsofRCFsonrodentcelllines.ThecytotoxiceffectsofRCFsmayvarywithcellsize,volume,andlineage.Effects observed in the cells from organs otherthanthelungoreffectsinspeciesotherthanthehumanmaynotbesimilartothoseelicitedwith


Appendix C ■Cellular and Molecular Effects of RCFs (In Vitro Studies)

IndirectcellulareffectsofRCFsinvolvethein-teractionoffiberswithinflammatorycellsthatmay be activated to produce inflammatorymediators. These mediators may affect targetcellsdirectlyormayattractothercellsthatactontargetcells.AninflammatorycelltypeoftenusedinRCFinvitrostudiesisthepulmonarymacrophage.Pulmonarymacrophagesarethefirst line of defense against inhaled materialthatdeposits in thealveoli, andamong func-tions,theyattempttophagocytizeparticlesde-positedinthelung.EffectsofRCFexposureonmacrophagesandotherinflammatorycellsareassessedbythemeasurementofinflammatorymediatorreleaseinvitro.

Threeimportantgroupsofinflammatoryme-diators are cytokines, ROS, and lipid media-tors (prostaglandins and leukotrienes). Someof thecytokines thathavebeen implicated intheinflammatoryprocessincludeTNFandin-terleukins(ILs).TNFandmanyILsstimulatethedepositionoffibroblastcollagen,aninitialstep infibrosis, andprostaglandins (PG)s in-hibittheseeffects.ROSincludehydroxylradi-cals,hydrogenperoxide,andsuperoxideanionradicals.OxidativestressoccurswhentheROSlevelinacellexceedsitsantioxidantlevel.Oxi-dativestressmayresultindamagetodeoxyribonucelicacid(DNA),lipids,andproteins.

Either direct or indirect effects of RCFs mayresultingenotoxiceffectsonpulmonarytargetcells.Changes in thegeneticmaterialmaybeimportant in tumor development [Solomonetal.1991].Genotoxiceffectsmaybeassessedthrough theanalysisofchromosomechangesoralterationsingeneexpressionfollowingex-posuretoRCFs.

ThefollowingsummaryofRCFinvitrostud-iesexaminestheirdirecteffectsoncellprolif-eration and viability and indirect effects viareleaseofTNF,ROS,andotherinflammatorymediators. The genotoxic effects of RCFs are

alsoexaminedandsummarized.TableC–1de-scribesRCFcytotoxicitystudiesinvolvingtheirdirecteffectsoncells.TableC–2describesRCFcytotoxicity studies involving the release ofmediators.TableC–3summarizesRCFgeno-toxicstudies.

C.1 Direct Cytotoxic Effects of RCFs

RCFsmayhaveadirectcytotoxiceffectontar-getcells.Measurementsofcellviabilityandcellproliferationarebothindicationsofcytotoxiceffects. Cell viability can be assessed throughthe detection of enzymes released by cells ordyestakenupbycellsthatindicatealteredcellmembraneintegrityorpermeability.Measure-mentofcytoplasmicLDHandtrypanblueex-clusionaretwomethodsusedtoassesscellvia-bility.LDHisacytoplasmicenzyme;itsreleaseindicates plasma membrane damage. Trypanblueisadyethatcanonlypenetratedamagedcellmembranes.β-glucuronidaseisalysosom-al enzyme, it assesses lysosomal permeabilityandmembraneviability.Itmayalsobereleasedwhen alveolar macrophages are activated byfrustrated phagocytosis. The cytotoxic effectsofRCFsonratpleuralmesothelialcells,por-cine aortic endothelial cells, human-hamsterhybrid(A

L)cells,humanmacrophages,macro-

phage-like P388D1 cells, and human alveolarepithelial cells are summarized in Table C–1andC–2andinthetextbelow.

Luoto et al. [1997] evaluated the effects ofRCFs, quartz, and several MMVFs on LDHlevels inratalveolarmacrophagesandhemo-lysisinsheeperythrocytes.RCF1,RCF2,RCF3,andRCF4at1.0mg/mlinducedalowerreleaseof LDH (less than 20% of control) from ratalveolar macrophages compared with quartz(approximately 40% of control) [Luoto et al.1997].RCF1stimulatedthelowestamountof



LDHrelease(lessthan10%ofcontrol),lowereven than TiO

2 (approximately 15% of con-

trol). RCF1, RCF2, RCF3, RCF4, MMVF10,MMVF11, MMVF21, and MMVF22 at 0.5,2.5, and 5.0 mg/ml induced a dose-depen-dent increase in sheeperythrocytehemolysis.RCF1andRCF3inducedslightlymorehemo-lysisthanotherMMVFs.Thehemolyticactiv-ityofMMVFswassimilartothatofTiO

2,and

muchlessthanthatofquartz.

At doses of 100, 300, and 1,000 µg/ml RCFs(unspecifiedtype),anincreasedreleaseofLDHwas induced from rat macrophages [Leikaufetal.1995].Atequivalentgravimetricdosesof1,000µg/ml,theeffectsofRCFsweremuchlessthanthoseofsilica.Ceramicfibers(unspecifiedtype)at50µg/mlinducednodifferenceinLDHlevelscomparedwithnegativecontrolsinratal-veolarmacrophages[Fujinoetal.1995].Chrys-otile,crocidolite,amosite,andanthophylliteas-bestosallinducedsignificantincreasesinLDHandβ-glucuronidaselevels.Ceramicfibersalsoinduced a significant increase in β-glucuroni-dasebutmuchlessthanthatinducedbyeachoftheasbestosfibertypes.

In the permanent macrophage-like cell lineP388D1,anelutriatedceramicfiber(unspeci-fiedtype)at10or50µg/mlafter24or48hrhad no significant effect on cell viability asmeasuredbythetrypanblueassay[Wrightetal.1986].Theelutriationprocessusedforthisexperimentprovidedmainlyrespirablefibers.All other fibers examined, excluding short-fiberamosite, reducedviability.Although thespecificdataontheeffectofexposuretofiberson enzyme release was not presented, an as-sociationbetweendecreasingcellviabilityandincreasinglossofintracellularglucosaminidaseandLDHwasreportedundermostconditionsinvestigated. Cytotoxicity was correlated withfiberlengthsgreaterthan8µmwhenallfibertypeswerecombined.

Theeffectof severalfiberson theviabilityofrat pleural mesothelial cells was investigated[Yegles et al. 1995]. On a per weight basis,the rank order of cytotoxicity was NationalInstitute for Environmental Health Sciences(NIEHS) chrysotile, RCF3, MMVF10 andRCF1,Calidriachrysotile,RCF4,andallothers.Basedonthetotalnumberoffibers,therankorder of cytotoxicity was RCF3, MMVF10,RCF1, RCF4, MMVF11, NIEHS chrysotile,amosite, and all others. Cytotoxicity was de-pendent on fiber dimensions as the longest(RCF3,MMVF10,RCF1,MMVF11)orthick-est(RCF4,RCF1,MMVF11,RCF3)fiberswerethemostcytotoxic.

RCF1,RCF2,RCF3,andRCF4werefoundtoinhibit theproliferationandcolony-formingefficiency of Chinese hamster ovary cells invitro [Hart et al. 1992]. The inhibition wasconcentration-dependent. RCF4 was leastcytotoxic,RCF2wasintermediate,andRCF1andRCF3werethemostcytotoxic.Acorrela-tionexistedbetweenaveragefiberlengthandtoxicity, with the shortest fibers being leastcytotoxic.LC

50s for theRCFranged from10

to30µg/cm2.Ineachassay,theRCFswerelesscytotoxic than those of the positive controlsofcrocidolite(LC

50=5µg/cm2)andchrysotile

(LC50

=1µg/cm2)asbestos.

At0to80µg/cm2RCF1,tremolite,anderion-ite were significantly less cytotoxic to human-hamster hybrid A

L cells than chrysotile as de-

terminedby the surviving fractionofcoloniesafterfiberexposure[Okayasuetal.1999].RCF1,crocidoliteasbestos,andMMVF10at25µg/cm2induced focalnecrosis in ratpleuralmesothe-lialcellsafter24hrthatbecameamoreobviousnecrosisby72hr[Janssenetal.1994].At72hr,thequalitativeeffectsof25µg/cm2RCF1werecomparabletothoseof5µg/cm2crocidoliteas-bestos. In contrast,minimalnecrosiswas seenat 25 µg/cm2 crocidolite asbestos, RCF2, and



MMVF10fibersinhamstertrachealepithelialcellsat24hr;nonecrosiswaspresentat72hr.

RCF1, RCF2, RCF3, and RCF4 as well as as-bestosandotherfibershadadose-dependenteffectoncytotoxicity,asmeasuredbycellde-tachment,inthehumanalveolarepithelialcelllineA549[Cullenetal.1997].Celldetachmentisassociatedwithepithelialdamage,animpor-tant step in the inflammatory process. Thesecells are a primary target of inhaled fibers.Whenequivalentdoses(10,25,50,and100µg/ml) were tested with various fibers, all RCFshadalesssignificanteffectthanbothcrocido-liteandamositeasbestos.Whenthedosedatawereadjustedforthenumberoffibers,RCF1,RCF2, and RCF3 were more cytotoxic thanRCF4andcrocidolite.

Inanassaydeterminingtheabilityoffiberstoinducean increase inthediameterofhumanA549cells,anelutriatedceramicfiber(unspec-ified type) had a midrange of activity whencompared with 12 other fibers [Brown et al.1986].Itwasmoreactivethanmostvarietiesofamositetested(butnotUICCamosite)butlessactivethanthechrysotilefibers.Anassociationwasfoundbetweenincreasinglengthandassayactivity.When these same fiber samples weretestedforcolony inhibition inV79/4Chinesehamsterlungfibroblasts,theceramicfiberhadevenlesseffectthantheTiO

2control.Analysis

ofallfibersupheldtheassociationbetweenin-creasinglengthandincreasedactivity.Inbothassays,fiberdiameterwasnotrelatedtoactiv-ityinmostcases.

Chrysotileasbestosat10µg/cm2andcrocido-lite asbestos at 5 µg/cm2 altered porcine aor-ticendothelialcellmorphologyandincreasedneutrophil adherence [Treadwell et al. 1996].RCF1fibersat10µg/cm2didnotchangecellmorphologyorincreaseneutrophilbinding.

ThesestudiessuggestthatRCFsmayhavesomesimilardirectcytotoxiceffectstoasbestos.Theyarecapableofinducingenzymereleaseandcellhemolysis.Theymaydecreasecellviabilityandinhibit proliferation. In most studies, the ef-fectsofRCFsaremuchlesspronouncedthanthe effects of asbestos at similar gravimetricconcentrations.Fiberlengthwasdemonstratedtobean important factor indetermining thecellresponsesinmanystudies.

C.2 Indirect Effects of RCFs: Effects on Inflammatory Cells

In addition to direct effects on target cells,RCFsmayhaveindirectmechanismsofactionbyactingoninflammatorycells.Inflammatorycells,suchaspulmonarymacrophages,mayre-spondtofiberexposurebyreleasinginflamma-torymediatorsthatinitiatetheprocessofpul-monaryinflammationandfibrosis.CytokinesandROSareamongtheinflammatorymedia-torsreleased.Manystudies,summarizedbelowand in Table C–2, have investigated this linkbetween fiber exposure and mediator releasetotrytoelucidatethemechanismofactionofRCFs.Cytokinesareaclassofproteinsthatareinvolvedinregulatingprocessessuchascellse-cretion,proliferation,anddifferentiation.Oneof thecytokinesmost commonlyanalyzed inRCFcytotoxicitystudiesisTNF.TNFhasbeenimplicatedinsilica-andasbestos-inducedpul-monary fibrosis [Piguet et al. 1990; LemaireandOuellet1996].TNFandmanyILsareas-sociated with collagen deposition (an initialstageoffibrosis),andPGsinhibittheseeffects.ExperimentsontheeffectsofRCFexposureonTNFproductioninvariouscelltypeshavehaddifferingresults.

TNFsecretionhasbeenassociatedwithex-posuretoasbestosbothinvitroandinvivo



[Perkins etal. 1993]. In vitro incubation ofhuman alveolar macrophages from normalvolunteers with 25µg/ml chrysotile asbestosresulted in increased levels of TNF secretion.Alveolarmacrophagesfrom6humansubjectsoccupationally exposed to asbestos for morethan 10 years secreted increased amounts ofthe cytokines TNF, IL–6, PGE

2, and IL–1ß in

vitro.Fivehumansubjectsoccupationallyex-posedfor lessthan10yearsdidnotshowin-creases in these cytokines. The two exposuregroupswerematchedforage,smokinghistory,and diagnosis. The increased TNF secretioninbothinvitroandchronicinvivoasbestos-exposedconditionssuggestsitsimportanceintheresponseofthelungtofiberexposure,al-thoughthesmallexposuregroupsizeswarrantcautionindrawingstrongconclusions.

When equal numbers (8.2 106) of variousfibertypes,includingRCF1,RCF2,RCF3,andRCF4, were incubated separately with rat al-veolar macrophages, silicon carbide whiskers,amosite, and crocidolite asbestos stimulatedthe highest TNF release [Cullen et al. 1997].RCF1,RCF2,RCF3,andRCF4showednosig-nificantincreaseinTNFreleasecomparedwithcontrol.

Incontrast,ceramicfibers(unspecifiedtype)at50 µg/ml (1.72 105 f) significantly increasedTNFreleasecomparedwithcontrolsinratal-veolar macrophages [Fujino et al. 1995]. Po-tassium octatitanate whisker, chrysotile, andcrocidoliteasbestos inducedthegreatestTNFrelease. Alveolar macrophages exposed to ei-ther300or1,000µg/mlRCFsor1,000µg/mlasbestosshowedasignificantincreaseinTNFproduction[Leikaufetal.1995].At300µg/mlRCFs,a significantelevationoccurred in leu-kotriene B

4.At 1,000 µg/ml RCFs, significant

elevationsoccurredinleukotrieneB4andpros-

taglandin E2. Levels induced at lower doses

werenotdifferentfromcontrols.Atequivalent

doses,theeffectonthelevelsofallmediatorsmeasured was greater after asbestos exposurethanafterRCFexposure.

ChrysotileA,chrysotileB,crocidolite,MMVF21,RCF1,andsiliconcarbideat100µg/mlcausedasignificantlyincreasedsynthesisofTNFmRNAafter90minutesof incubationwithratalveo-larmacrophages[Ljungmanetal.1994].After4hrofincubation,chrysotileAstillhadasignifi-cantly increased TNF mRNA production, andallotherfiberswereatbaselineconcentrations.None of the fibers studied increased TNF re-leaseat90minutes.However,anincreasedTNFbioactivity occurred after 4 hr of incubationwith chrysotile A, chrysotile B, crocidolite, orMMVF21.RCF1at100µg/mldidnotincreaseTNFproductionundertheseconditions.

Chrysotile asbestos and alumina silicate ce-ramicfibersincreasedinvitroalveolarmacro-phageTNFproductioninratsexposedtociga-rette smoke invivoand in ratsunexposed tosmoke[Morimotoetal.1993].Asbestosat50and100µg/mlinducedasignificantlygreaterTNFreleaseinratsexposedtocigarettesmokeversus unexposed rats. No significant differ-enceswerefoundbetweengroupsatalldosesof RCF fibers tested (25, 50 and 100 µg/ml).RCF exposure, in contrast to chrysotile, didnot have a significant synergistic effect withcigarettesmokeexposure.

InadditiontothecytokinessuchasTNF,an-other group of inflammatory mediators thathas been studied in vitro are the ROS. Thesemediators, also referred to as reactive oxygenmetabolites (ROMs) are normally producedduringtheprocessofcellularaerobicmetabo-lismandinphagocyticcellsinresponsetopar-ticleexposure.Onemoleculareffectofasbestosexposurehasbeendemonstratedtobethein-ductionofROS[Kampetal.1992].OxidativestressoccurswhentheROSlevel inacellex-ceedstheantioxidantlevel.ROSmayresultin



damagetoDNA,lipidsandproteinsandhavebeenimplicatedinhavingaroleincarcinogen-esis[Klaunigetal.1998;Vallyathanetal.1998].Thisresearchhassuggestedthatfreeradicalac-tivitymaybe involved in thepathogenesisoffiber-inducedlungdisease.

TheabilityofRCFstoinducethereleaseoffreeradicals has been studied in rodent alveolarmacrophages.RF1andRF2(Japaneseceramicfibers)at200µg/mlinducedasignificantpro-ductionofsuperoxideanionandasignificantincreaseinintracellularfreecalciuminguineapig alveolar macrophages [Wang et al. 1999].Both superoxide anion and increased intra-cellular calcium are associated with oxidativestress.Superoxideanionsmaygeneratehydro-gen peroxide and hydroxyl radical, classifiedasROSorfreeradicals.RF2exposureresultedinasignificantdepletionofglutathione.Glu-tathioneisacellularantioxidantthatprotectscellsagainstoxidativestress;depletionofglu-tathioneisassociatedwithoxidativestress.TheRFsdidnotaffecthydrogenperoxideproduc-tion.Ineachtest,theeffectsofchrysotileweresignificantlygreaterthanthoseoftheRFs.

RCF1,MMVF10,andamositeasbestosat8.24×106f/mlinducedasignificantdepletionofintra-cellularglutathioneinratalveolarmacrophages[Gilmouretal.1997].RCF1hadsimilareffectstoamositeasbestos,whereasMMVF10causedthegreatestdepletionofglutathione.

RCF1, RCF2, and RCF3 induced a greaterproductionofROMsinhumanpolymorpho-nuclearcellculturesthanRCF4andchrysotile[Luotoetal.1997].Adose-dependentproduc-tionofROMswasseeninallRCFsandotherMMVFstestedfrom25to500µg/ml.QuartzhadagreatereffectonROMproductionthanallfiberstested.

RCF1hadahighbindingcapacityforratim-munoglobulin (IgG), a normal component

oflungliningfluid[Hilletal.1996].Atdoses>100µgRCF1,fiberscoatedwithIgGinduceda significantly increased superoxideanionre-lease.Thissupportsthepremisethatlunglin-ing fluid and other substances that fibers areexposed to invivomay significantly alter theeffectoffibersoncells. IgG-coated longfiberamosite asbestos, in spite of a poor bindingaffinityforIgG,inducedacomparablesuper-oxideanionreleaseresponsetothatofcoatedRCF1.

Brown et al. [1999] investigated the abil-ityofRCF1,amositeasbestos,siliconcarbide,MMVF10,Cole100/475glassfiber,andRCF4tocausetranslocationofthetranscriptionfac-torNF-κBtothenucleusinA549lungepithe-lial cells. RCF1, amosite asbestos, and siliconcarbideproducedasignificantdose-dependenttranslocationofNF-κBtothenucleus;theoth-er fibers tested did not. Equal fiber numbersweretested.

These cytotoxicity studies indicate that RCFsmaysharesomeaspectsoftheirmechanismofactionwithasbestos.Theybothaffectthepro-ductionofTNFandROSaswellascellviabil-ityandproliferation.TheeffectsofRCFshaveusuallybeenlesspronouncedthanthoseofas-bestos.Resultsofinvitrostudiesaredifficulttocompare,evenwithinstudiesofdifferentfibertypes, because of different study designs, dif-ferentfiberconcentrationsandcharacteristics,anddifferentendpoints.

C.3 Genotoxic Effects of RCFs

Inaddition to researchassessing thecytotox-icity of RCFs, studies have also assessed thegenotoxicityofRCFs.Mostgenotoxicityassaysassesschanges inordamage togeneticmate-rial.Methodsthathavebeenusedtoinvestigatethegenotoxicityoffibersincludecell-freeorin



vitro cell systems investigating DNA damage,studiesofaneuploidyorpolyploidy,studiesofchromosome damage or mutation, gene mu-tationassays,andinvestigationsofcellgrowthregulation[Jaurand1997].Severalstudies,de-scribed below and in Table C–3, have exam-inedtheabilityofRCFstoproducegenotoxicchangesincomparisonwithasbestos.

Severalfibers,includingRCF1andRCF4,wereassayedforfreeradicalgeneratingactivityus-ingaDNAassayandasalicylateassay[Brownet al.1998]. The DNA plasmid assay showedonlyamositeasbestostohavefreeradicalactiv-ity.ThesalicylateassayshowedamositeaswellasRCF1 tohave free radical activity.Coatingthefiberswithlungsurfactantdecreasedtheirhydroxyl radical generation. Differences inRCF1resultsinthetwoassayswereproposedto be a result of increased iron release fromRCF1 in the salicylateassay.An ironchelatorinhibited theRCFhydroxylationof salicylate.RCF4showednofreeradicalactivity.

When equal fiber numbers were compared,RCF1, RCF2, RCF3, and RCF4 had minimalfree- radical-generating activity on plasmidDNA compared with crocidolite and amositeasbestos [Gilmour et al. 1995]. RCFs andotherMMVFproduceda smallbut insignifi-cant amount of DNA damage. This damagewas mediated by hydroxyl radicals. No cor-relationwas foundbetween ironcontentandfreeradicalgeneration.At9.3×105fibersperassay,amositeproducedsubstantial freeradi-cal damage to plasmid DNA [Gilmour et al.1997]. Amosite significantly upregulated thetranscription factors AP–1 and NFkB; RCF1hadamuchsmallereffectonAP–1upregula-tiononly.

SVFs, including ceramic fibers (unspecified),werereportedtoformhydroxylradicalsbasedon the formation of the DNA adduct 8-hy-droxydeoxyguanosine(8-OH-dG)from2-de-

oxyguanosine (dG) in calf thymus DNA andsolution [Leanderson et al. 1989; LeandersonandTagesson1989].Ceramicandglasswoolfi-bershadpoorhydroxylatingcapabilitiesrelativetorockwoolandslagwoolfibers[Leandersonetal.1989].Hydroxylradicalscavengers,suchas dimethyl sulfoxide, decreased the hydrox-ylation. Compounds that increase hydroxylradicalformation,suchashydrogenperoxide,increasedhydroxylation.Rockwool incombi-nationwithcigarettesmokecondensatecausedasynergistic increasein8-OH-dGformation;ceramicandglasswoolfibersdidnothavesyn-ergisticeffectswithcigarettesmoke[Leander-sonandTagesson1989].

RCF1,RCF2,RCF3,andRCF4inducednucle-ar abnormalities, including micronuclei andpolynuclei, in Chinese hamster ovary cells[Hartetal.1992].Micronucleimayformwhenchromosomes or fragments of chromosomesare separated during mitosis. Polynuclei mayarisewhencytokinesis fails aftermitosis.Theincidenceofmicronucleiandpolynucleiafterexposureto20µg/cm2RCFwasfrom22%to33%. At 5 µg/cm2, chrysotile and crocidoliteinduced nuclear abnormalities of 49% and28%,respectively.

Amosite, chrysotile, and crocidolite asbestos,andceramicfiberscausedasignificantincreaseinmicronuclei inhumanamnioticfluid cells[Dopp et al. 1997]. The response was dose-dependent with asbestos fiber exposure butnot with ceramic fiber exposure. Significantincreases in chromosomal breakage and hy-perdiploidcellswerenotedafterasbestosandceramicfiberexposure.

RCF1, RCF3, and RCF4 did not induce ana-phase aberrations in rat pleural mesothelialcells [Yegles et al. 1995]. Of all fibers tested,UICCchrysotilewasthemostgenotoxiconthebasisofweight,numberoffiberswithalength>4 µm and number of fibers corresponding



toStanton=sandPott=scriteria[Stantonetal. 1981;Pott etal. 1987].

TheeffectoffibersonthemRNAlevelsofc-fosandc-junproto-oncogenesandornithinedecarboxylase(ODC)inhamstertrachealepi-thelial (HTE) cells and rodent pleural meso-thelial(RPM)cellswereexamined[Janssenetal.1994].ODCisarate-limitingenzymeinthesynthesisofcompoundsinvolvedincellprolif-erationandtumorpromotion,thepolyamines.InHTEcells,crocidoliteinducedasignificantdose-dependentincreaseinlevelsofc-junandODC mRNA but not c-fos mRNA. RCF1 in-ducedonlysmallnondose-dependentincreasesinODCmRNAlevels.InRPMcells,crocidolitefibersat2.5µg/cm2significantlyelevated lev-elsofc-fosandc-junmRNA.RCF1increasedproto-oncogeneexpressionat cytotoxic levelsof25µg/cm2;nosignificanteffectwasseenatconcentrations≤5µg/cm2.

RCF1 fibers were nonmutagenic in the hu-man-hamsterhybridcelllineA

L[Okayasuetal.

1999].Chrysotilewasasignificant inducerofmutationsinthesamesystem.

These studies demonstrate that RCFs maysharesomesimilargenotoxicmechanismswithasbestos including induction of free radicals,micronuclei,polynuclei, chromosomalbreak-age,andhyperdiploidcells.Otherstudieshavedemonstratedthat,usingcertainmethodsanddoses,RCFsdidnot induceanaphaseaberra-tionsandinducedproto-oncogeneexpressiononly at cytotoxic concentrations. RCFs werenonmutagenicinhuman-hamsterhybridcells.

C.4 Discussion of In Vitro Studies

Thetoxicityoffibershasbeenattributabletotheirdose,dimensions,anddurability.Anytestsystemthatisdesignedtoassessthepotential

toxicity of fibers must address these factors.Durability is difficult to assess using in vitrostudies because of their acute time course.However,invitrostudiesprovideanopportu-nity tostudy theeffectsofvaryingdosesanddimensionsoffibersinaquicker,moreefficientmethod than animal testing. Although theyprovideimportantinformationaboutmecha-nismofaction,theydonotcurrentlyprovidedatathatcanbeextrapolatedtooccupationalriskassessment.

Theassociationbetweenfiberdimensionandtoxicity has been documented and reviewed[Stantonetal.1977,1981;Pottetal.1987;War-heit 1994]. Fiber length has been correlatedwiththecytotoxicityofglassfibers[Blakeetal.1998].Manvillecode100(JM–100)fibersam-plesofaveragelengthsof3,4,7,17,and33µmwere assessed for their effects on LDH activ-ityandratalveolarmacrophagefunction.Thegreatestcytotoxicitywasreportedinthe17µmand 33 µm samples, indicating that length isanimportantfactorinthetoxicityofthisfiber.Multiplemacrophageswereobservedattachedalongthelengthoflongfibers.Relativelyshortfibers, <20µm long, were usually phagocy-tized by one rat alveolar macrophage [Luotoet al. 1994]. Longer fibers were phagocytizedby twoormoremacrophages. Incomplete,orfrustrated,phagocytosismayplayaroleintheincreasedtoxicityoflongerfibers.Longfibers(17 µm average length) were a more potentinducer of TNF production and transcrip-tionfactoractivationthanshorterfibers(7µmaveragelength)[Yeetal.1999].Thesestudiesdemonstrate the important role of length infibertoxicityandsuggestthatthecapacityformacrophagephagocytosismaybeacriticalfac-tor in determining fiber toxicity. The toxicityof individualfibersofthesametypeofRCFsmaydifferaccordingtotheirsizeinrelationtoalveolarmacrophages.



Several RCF in vitro studies reported a di-rectassociationbetweena longerfiber lengthandgreatercytotoxicity.Hartetal.[1992]re-portedtheshortestfiberstobetheleastcyto-toxic.Brownetal.[1986]reportedanassocia-tionbetweenlengthandcytotoxicactivitybutnot between diameter and activity.Wright etal. [1986] reported that cytotoxicity was cor-relatedwithfibers>8µmlength.Yeglesetal.[1995] reported that the longest and thickestfiberswerethemostcytotoxic.ThefourmostcytotoxicfibershadGMlengths≥13µmandGMdiameters>0.5µm.Theproductionofab-normalanaphasesandtelophaseswasassociat-edwithStantonfiberswithalength>8µmanddiameter≤0.25µm.Hartetal.[1994]reportedthatcytotoxicityincreasedwithfiberlengthupto20µm.Allofthesestudiesdemonstratetheimportanceoffiberdimensionsoncytotoxicity.Otherstudieshavenotreportedthelengthdis-tributionoffibersamplesused.WhenstudiesaredonewithRCFsforwhichspecificlengthsareassessedforcytotoxicity(suchashasbeendonewithglassfibers)[Blakeetal.1998],itwillbepossibletodeterminethestrengthoftheas-sociationbetweenRCFfiberlengthandtoxic-ityanddeterminewhetherathresholdlengthexistsabovewhichtoxicityincreasessteeply.

Inadditiontoprovidingdataonthecorrelationbetweenfiberlengthandtoxicity,invitrostud-ieshaveprovideddataontherelativetoxicityofRCFscomparedwithasbestos.Uncertaintiesex-istintheinterpretationofthesestudiesbecauseof differences in fiber doses, dimensions, anddurabilities.RCFsdoappeartosharesomesim-ilar mechanisms of action with asbestos. (SeereferencesinTablesC–1,C–2,andC–3.)Theyhavesimilardirectandindirecteffectsoncellsand alter gene function in similar ways. Theyare capable of inducing enzyme release andcellhemolysis.Theymaydecreasecellviabilityand inhibit proliferation. They both affect theproductionoftumornecrosisfactorandROS,andaffectcellviabilityandproliferation.They

inducenecrosisinratpleuralmesothelialcells.Theyalsomayinducefreeradicals,micronuclei,polynuclei,chromosomalbreakage,andhyper-diploidcellsinvitro.

Invitrostudiesalsoprovideanexcellentoppor-tunityforinvestigatingthepathogenesisofRCF.However,comparisonsaredifficulttomakebe-tweeninvitrostudiesbecauseofdifferencesinfiberdoses,dimensions,preparations,andcom-positions.Importantinformation,suchasfiberlength distribution, is not always determined.Even when comparable fibers are studied, thecelllineorconditionsunderwhichtheyaretest-edmayvary.Muchoftheresearchtodatehasbeendoneinrodentcelllinesandincellsthatarenotrelatedtotheprimarytargetorgan.Invitrostudiesusinghumanpulmonarycelllinesshouldprovidepathogenesisdatamostrelevanttohumanhealthriskassessment.

Short-term in vitro studies cannot take intoaccounttheinfluenceoffiberdissolutionandfiber compositional changes that may occurover time. In an in vivo exposure, fibers arecontinually modified physically, chemically,andstructurallybycomponentsofthelungen-vironment. This complex set of conditions isdifficulttorecreateinvitro.Justasitisunlikelythatonlyonefactorwillbeanaccuratepredic-toroffiber toxicity, it ismuchmoreunlikelythatanyoneinvitrotestwillbeabletopredictfibertoxicity.Bestresultsareobtainedbytox-icityassessmentinseveralinvitrotestsandincomparisonwithinvivoresults.Invitrostud-iesprovideanexcellentopportunitytoinves-tigate factors important tofiber toxicity suchasdose,dimension,surfacearea,andphysico-chemicalcomposition.Theyprovidetheabil-itytoobtaininformationthatisanimportantsupplement to thedataof chronic inhalationstudies.Theydonot currentlyprovide infor-mationthatcanbedirectlyappliedtohumanhealthriskassessmentandthedevelopmentofoccupationalexposurelimits.


Appendix C ■ Cellular and Molecular Effects of RCFs (In Vitro Studies)

Tabl

e C

–1 .

In v

itro

cyt

otox

icit

y of

RC

Fs:* d

irec

t eff

ects

on

cel

ls

Ref

eren

ceC

ell l

ine

and

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Bro

wn

et

al.

[198

6]A

549

cells

Cel

ldia

met

er

V79

/4C

hin

ese

ham

ster

lun

gfi

brob

last

s C

olon

yin

hib

itio

n

Elu

tria

ted

(E)

cera

mic

(u

nsp

ecifi

ed)

Tit

aniu

md

ioxi

de

Qu

artz

Sh

ort

fibe

ram

osit

eU

ICC

cro

cido

lite

Efa

ctor

yam

osit

eE

UIC

Cc

roci

dolit

eE

bru

cite

U

ICC

am

osit

eSu

per

fin

ech

ryso

tile

E

UIC

Ca

nth

ophy

llite

U

ICC

ch

ryso

tile

A

Et

rem

olit

eE

lon

gfi

ber

amos

ite

EU

ICC

ch

ryso

tile

A

Not

rep

orte

dN

otr

epor

ted

A54

9ce

lls:

25o

r50

µg/

ml

V79

/4c

ells

:0,

5,1

0,2

5,7

5,

or1

00µ

g/m

l

A54

9as

say:

C

hry

soti

lee

ffec

t>

cera

mic

eff

ect>

m

ost

amos

ites

(n

otU

ICC

am

osit

e).

V79

/4a

ssay

:C

eram

icfi

ber

had

no

effe

ct.

Cer

amic

fibe

rh

add

iffe

ren

tre

sult

sin

th

etw

oas

says

.

Ass

ocia

tion

fou

nd

betw

een

incr

eas-

ing

fibe

rle

ngt

h(

allt

ypes

)an

dac

tivi

tyin

bot

ha

ssay

s.

Cu

llen

et

al.

[1

997]

Hu

man

alv

eola

r

epit

hel

ialc

ells

C

elld

etac

hm

ent

RC

F1

RC

F2

RC

F3

RC

F4

Lon

gam

osit

eC

roci

dolit

eC

100/

475

glas

s10

4Eg

lass

Si

licon

car

bide

1

Silic

onc

arbi

de2

M

MV

F10

MM

VF1

1M

MV

F21

MM

VF2

2

Geo

met

ric

mea

n:

10

.42

±2

.66

12

.43

±2

.66

14

.99

±2

.64

6

.82

±2

.00

3

.03

±2

.86

4

.96

±2

.57

2

.88

±2

.62

3

.50

±2

.17

8

.73

±2

.25

N

otd

one

23

.91

±2

.39

14

.21

±2

.64

15

.66

±2

.76

13

.67

±2

.34

Geo

met

ric

mea

n:

0.

79±

2.0

7

0.84

±2

.01

0.

71±

2.1

2

0.94

±1

.71

0.26

±1

.75

0.

15±

1.5

3

0.22

±1.

85

0.

25±

1.6

0.47

±1

.39

N

otd

one

1.

13±

1.9

0

0.57

±2

.01

0.

81±

1.7

6

0.89

±1

.78

10,2

5,5

0,o

r

100

µg/m

lA

teq

uiv

alen

tdo

ses,

all

RC

Fsh

adle

ss

effe

ctt

han

cro

cido

lite

and

amos

ite

asbe

stos

.

Wh

ena

dju

sted

for

equ

ival

ent

fibe

rn

um

bers

,cro

cido

lite,

RC

F4,

MV

F11,

an

dam

osit

ew

ere

leas

tcy

toto

xic;

RC

F1,R

CF2

,an

dR

CF3

w

ere

mor

ecy

toto

xic

than

cro

cido

-lit

ean

dam

osit

e.

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–1 (

Con

tin

ued

) . I

n v

itro

cyt

otox

icit

y of

RC

Fs:* d

irec

t eff

ects

on

cel

ls

Ref

eren

ceC

ell l

ine

and

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Fujin

oet

al.

[199

5]R

ata

lveo

lar

mac

roph

ages

LD

H

β

-glu

curo

nid

ase

Cer

amic

Gla

ssPo

tass

ium

oct

atit

anat

eM

agn

esiu

ms

ulf

ate

(lon

g)M

agn

esiu

ms

ulf

ate

(sh

ort)

Ch

ryso

tile

asb

esto

sC

roci

dolit

eas

best

osA

mos

ite

An

thop

hylli

teE

rion

ite

Geo

met

ric

mea

n:

29

.5±

3.1

12

.8±

3.0

2

.8±

2.0

12

.0±

2.3

4

.9±

2.1

0

.7±

1.9

1

.3±

2.3

2

.7±

2.5

2

.5±

3.5

1

.4±

2.0

Geo

met

ric

mea

n:

1.

92±

2.9

0.

54±

2.2

0.

41±

1.5

0.

44±

1.6

0.

31±

1.5

0.0

85±

1.4

0.

20±

1.5

0.

32±

1.8

0.

36±

2.3

0.

21±

1.6

50µ

g/m

lLD

H:

Cer

amic

fibe

r,m

agn

esiu

ms

ulf

ate

wh

iske

rs,a

nd

erio

nit

ew

ere

not

di

ffer

ent

from

con

trol

;all

oth

ers

sign

ifica

ntl

yin

crea

sed

leve

ls.

β-gl

ucu

ron

idas

e:A

llfi

bers

cau

sed

asi

gnifi

can

tin

crea

sec

ompa

red

wit

hc

ontr

ol;

chry

soti

lec

ause

dth

eh

igh

est

rele

ase.

Har

tet

al.

[1

992]

Ch

ines

eh

amst

er

ovar

yce

lls

Cel

lpro

lifer

atio

n

Col

ony

form

atio

n

RC

F1R

CF2

RC

F3R

CF4

UIC

CC

roci

dolit

eU

ICC

Ch

ryso

tile

Geo

met

ric

mea

n:

21

.5±

16.

12

16.7

±1

5.03

24

.3±

18.

82

9.2

±7

.08

1

.8±

1.9

4

1.65

±1

.83

Geo

met

ric

mea

n:

1.

03±

0.7

3

1.11

±0

.82

1.

22±

0.9

8

1.43

±0

.79

0.

21±

0.1

2

0.12

±0

.07

RC

F1–4

:0,

5,1

0,o

r

20µ

g/m

l

Cro

cido

lite:

0

or5

µg/

ml

Ch

ryso

tile

:0,

1,2

,or

5

µg/m

l

RC

Fsin

duce

da

con

cen

trat

ion

-de

pen

den

tde

crea

sein

col

ony

form

atio

na

nd

cell

prol

ifer

atio

n.

LC50

:R

CFs

10–3

0µg

/cm

2

Cro

cido

lite

5µg

/cm

2

Ch

ryso

tile

1

µg/c

m2

RC

Fcy

toto

xici

ty:R

CF1

an

dR

CF3

are

mos

tcy

toto

xic;

RC

F2

isin

term

edia

te;R

CF4

isle

ast

cyto

toxi

c.

Leik

auf

eta

l.

[199

5]R

ata

lveo

lar

mac

roph

ages

LD

H

RC

FC

roci

dolit

eas

best

osSi

lica

Tit

aniu

md

ioxi

de

Med

ian

:

4.9

2.

5

Not

ava

ilabl

e

Not

ava

ilabl

e

Med

ian

:

0.59

0.

28

0.88

0.

18

100,

300

,1,

000

µg/m

l

RC

Fsin

duce

dm

oder

ate

incr

ease

sin

LD

Hle

vels

.%o

fco

ntr

ol:

RC

Fs

100

µg/

ml—

158%

R

CFs

3

00µ

g/m

l—17

4%

RC

Fs1

,000

µg/

ml—

295%

Si

lica

1,0

00µ

g/m

l—89

6%

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–1 (

Con

tin

ued

) . I

n v

itro

cyt

otox

icit

y of

RC

Fs:* d

irec

t eff

ects

on

cel

ls

Ref

eren

ceC

ell l

ine

and

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Luot

oet

al.

[199

7] Sh

eep

eryt

hro

cyte

s

H

emol

ysis

Rat

alv

eola

r

m

acro

phag

es

LD

H

RC

F1

RC

F2

RC

F3

RC

F4

MM

VF1

0M

MV

F11

MM

VF2

1M

MV

F22

Mea

n:

21.2

9±

17.

42

20.1

8±

19.

63

25.6

6±

25.

74

10.3

4±

11.

59

23.2

1±

15.

57

15.6

5±

13.

31

26.0

2±

23.

10

20.7

5±

20.

52

Mea

n:

1.30

±0

.72

1.39

±0

.98

1.37

±0

.87

1.33

±1

.02

1.42

±0

.78

1.12

±0

.88

1.18

±0

.64

0.88

±0

.45

Hem

olys

is:

0.5,

2.5

,or

5.

0m

g/m

l

LDH

:1.

0m

g/m

l

Hem

olys

is:

Dos

e-de

pen

den

tin

crea

sein

he-

mol

ysis

indu

ced

bya

llfi

bers

an

ddu

sts.

RC

F1a

nd

RC

F3w

ere

slig

htl

ym

ore

hem

olyt

ict

han

all

oth

erfi

bers

bu

tm

uch

less

th

anq

uar

tz.

LDH

:R

CF1

indu

ced

the

leas

tLD

H

rele

ase;

MM

VF

22h

adt

he

grea

test

fi

ber-

indu

ced

LDH

rel

ease

;qu

artz

in

duce

dth

egr

eate

stL

DH

rel

ease

ov

eral

l.

Oka

yasu

et

al.

[1

999]

Hu

man

-ham

ster

hy

brid

ALc

ells

Su

rviv

ing

co

lon

ies

UIC

Cc

hry

soti

le

Trem

olit

eE

rion

ite

RC

F1

Geo

met

ric

mea

n:

1.78

±2

.3

1.41

±2

.7

1.31

±2

.9

13.5

±2

.7

Geo

met

ric

mea

n:

0.12

±0

.08

0.13

±3

.43

0.23

±2

.74

0.95

±2

.6

0–40

0µg

/ml

0–80

µg/

cm2

Ch

ryso

tile

was

mor

ecy

toto

xic

th

ano

ther

fibe

rs.

Mea

nle

thal

dos

es:

Ch

ryso

tile

~

4µg

/cm

2 R

CF1

35µ

g/cm

2 Tr

emol

ite

4

0µg

/cm

2 E

rion

ite

42

µg/c

m2

Wri

ght

eta

l.

[198

6] P

388D

1

Tr

ypan

blu

eas

say

L

DH

co

nce

ntr

atio

ns

G

luco

sam

inid

ase

co

nce

ntr

atio

ns

UIC

Cc

roci

dolit

eU

ICC

am

osit

eU

ICC

ch

ryso

tile

A

EU

ICC

cro

cido

lite

EU

ICC

am

osit

eE

UIC

Cc

hry

soti

leA

E

UIC

Ca

nth

ophy

llite

E

cer

amic

fibe

rE

lon

gfi

ber

amos

ite

Shor

tfi

ber

amos

ite

Et

rem

olit

e

Cu

mu

lati

vefi

ber

len

gth

dis

trib

u-

tion

sre

port

ed

Alm

ost

allfi

bers

m

easu

red

had

di

amet

ers

less

th

an3

µm

;de

tails

not

re

port

ed

Fibe

rn

um

ber

in

10

-10 g

±S

D:

112

±1

0

76±

6

185

±1

8

1

09±

10

112

±1

4

1

44±

20

169

±1

5

15±

0.4

19±

1

Tryp

anb

lue

assa

y:

Cer

amic

fibe

rsa

tbot

hdo

ses

had

the

low

estd

egre

eof

cyt

otox

icit

y;a

llot

her

fiber

s,ex

clud

ing

shor

t-fib

er

amos

ite,r

educ

edv

iabi

lity.

Fibe

rs>

8µm

wer

eus

ually

mos

tef-

fect

ive

ind

ecre

asin

gvi

abili

tya

nd

incr

easi

ngL

DH

and

glu

cosa

min

i-da

sec

once

ntra

tion

s;in

divi

dual

fibe

ref

fect

sw

ere

notr

epor

ted.

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–1 (

Con

tin

ued

) . I

n v

itro

cyt

otox

icit

y of

RC

Fs:* d

irec

t eff

ects

on

cel

ls

Ref

eren

ceC

ell l

ine

and

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Wri

ght

eta

l.

[1

986]

(Con

tin

ued

)

Eb

ruci

te

SFA

ch

ryso

tile

T

itan

ium

dio

xide

Q

uar

tz

44±

2.7

22

±1

.6

152

±1

47.

4±

0.5

Fibe

rdo

se:

10o

r50

µg/

ml

80µ

g/m

l20

µg/

ml

Yegl

ese

tal

.

[199

5]R

atp

leu

ral

m

esot

hel

ialc

ells

C

ellv

iabi

lity:

Mit

och

ondr

ial

in

tegr

ity

RC

F1

RC

F3

RC

F4

MM

VF1

0M

MV

F11

Ch

ryso

tile

(ch

rys)

,UIC

C

Ch

rys

445

(Can

adia

n)

Ch

rys

443

(C

anad

ian

)C

hry

s,s

hor

tC

anad

ian

C

hry

s,s

up

erfi

ne

Can

adia

n

Ch

rys,

ph

osph

oryl

ated

Can

adia

n

Ch

rys,

ph

osph

oryl

ated

,

mill

edC

anad

ian

U

ICC

ch

rys,

leac

hed

wit

h

ox

alic

aci

d

Ch

rys,

Cal

idri

aC

hry

s,N

IEH

SA

mos

ite

Cro

cido

lite

Att

apu

lgit

e

Mea

n:

19

.2±

15.

0

31.8

±3

6.0

8

.9±

7.2

21.5

±1

6.8

16

.7±

12.

9

1.7

±2

.2

2

.3±

2.3

1.9

±1

.9

1

.6±

1.4

2.4

±3

.1

4

.7±

5.2

4.7

±5

.9

2

.3±

1.8

2.8

±3

.0

4

.2±

1.2

2.4

±1

.8

2

.1±

3.6

0.8

±0

.5

Mea

n:

1.

30±

0.8

0

0.74

±0

.50

1.

30±

0.6

0

0.55

±0

.50

1.

10±

0.9

0

0.05

±0

.04

0.

04±

0.0

3

0.04

±0

.04

0.

06±

0.0

8

0.04

±0

.03

0.

04±

0.0

3

0.07

±0

.09

0.

17±

0.1

1

0.05

±0

.04

0.

05±

0.0

5

0.31

±0

.20

0.

19±

0.1

2

0.04

±0

.03

12.5

,25,

50,

75,

or

100

µg/

cm2

Cyt

otox

icit

yp

erw

eigh

tba

sis:

Ch

rys

NIE

HS

>R

CF3

>

MM

VF1

0=R

CF1

>C

hry

s,c

alid

ria

>R

CF4

>a

llot

her

s

Cyt

otox

icit

yp

erto

taln

um

ber

of

fi

bers

:

RC

F3>

MM

VF1

0>

RC

F1>

RC

F4>

MM

VF1

1>

Ch

rys,

N

IEH

S>am

osit

e>

allo

ther

s

Fibe

rle

ngt

ha

nd

diam

eter

cor

rela

ted

w

ith

cyt

otox

icit

y:lo

nge

sta

nd

thic

kest

fibe

rsw

ere

mos

tcy

toto

xic.

*Abb

revi

atio

ns:

E=

elu

tria

ted;

LD

H=

lact

ate

dehy

drog

enas

e;M

MV

F=m

an-m

ade

vitr

eou

sfi

ber;

NIE

HS=

Nat

ion

alI

nst

itu

teo

fE

nvir

onm

enta

lHea

lth

Sci

ence

s;R

CFs

=re

frac

tory

ce

ram

icfi

bers

;SD

=st

anda

rdd

evia

tion

;UIC

C=

Un

ion

In

tern

atio

nal

eC

ontr

ele

Can

cer.



Tabl

e C

–2 .

In v

itro

cyt

otox

icit

y of

RC

Fs:* e

ffec

ts o

n m

edia

tor

rele

ase

Ref

eren

ceC

ell l

ine

and

en

dp

oin

ts

F

iber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Cu

llen

et

al.

[1

997]

Hu

man

alv

eola

r

ep

ith

elia

lcel

ls

T

NF

RC

F1

RC

F2

RC

F3

RC

F4

Lon

gam

osit

eC

roci

dolit

eC

100/

475

glas

s10

4Eg

lass

Si

C1

SiC

2M

MV

F10

MM

VF1

1M

MV

F21

MM

VF2

2

Geo

met

ric

mea

n:

10

.42

±2

.66

12

.43

±2

.66

14

.99

±2

.64

6

.82

±2

.00

3

.03

±2

.86

4

.96

±2

.57

2

.88

±2

.62

3

.50

±2

.17

8

.73

±2

.25

Not

don

e

23.9

1±

2.3

9

14.2

1±

2.6

4

15.6

6±

2.7

6

13.6

7±

2.3

4

Geo

met

ric

mea

n:

0.

79±

2.0

7

0.84

±2

.01

0.

71±

2.1

2

0.94

±1

.71

0.26

±1

.75

0.

15±

1.5

3

0.22

±1.

85

0.

25±

1.6

0.47

±1

.39

N

otd

one

1.

13±

1.9

0

0.57

±2

.01

0.

81±

1.7

6

0.89

±1

.78

8.2×

106 fi

bers

(>

5µm

lon

g)Si

C1,

SiC

2,c

roci

dolit

e,a

nd

lon

gam

osit

est

imu

late

dth

eh

igh

est

TN

Fpr

odu

ctio

n.

RC

F1–R

CF4

did

not

sh

ow

mor

eT

NF

acti

vity

th

anin

co

ntr

olc

ult

ure

s.

Fujin

oet

al.

[199

5]

Rat

alv

eola

r

mac

roph

ages

T

NF

Cer

amic

G

lass

Po

tass

ium

oct

atit

anat

eM

agn

esiu

ms

ulf

ate

(lon

g)

Mag

nes

ium

su

lfat

e(s

hor

t)

Ch

ryso

tile

asb

esto

sC

roci

dolit

eas

best

os

Am

osit

eA

nth

ophy

lite

Eri

onit

e

Geo

met

ric

mea

n:

29

.5±

3.1

12.8

±3

.0

2

.8±

2.0

12.0

±2

.3

4

.9±

2.1

0.7

±1

.9

1

.3±

2.3

2.7

±2

.5

2

.5±

3.5

1.4

±2

.0

Geo

met

ric

mea

n:

1.

92±

2.9

0.54

±2

.2

0.

41±

1.5

0.44

±1

.6

0.

31±

1.5

0

.085

±1

.4

0.

20±

1.5

0.32

±1

.8

0.

36±

2.3

0.21

±1

.6

50µ

g/m

lA

llfi

bers

sig

nifi

can

tly

in-

crea

sed

TN

Fpr

odu

ctio

n

abov

en

o-fi

ber

con

trol

s;p

o-ta

ssiu

mo

ctat

itan

ate

cau

sed

the

hig

hes

tT

NF

prod

uct

ion

.

See

foot

not

eat

en

dof

tab

le(C

onti

nu

ed)



Tabl

e C

–2 (

Con

tin

ued

) .

In v

itro

cyt

otox

icit

y of

RC

Fs:*

eff

ects

on

med

iato

r re

leas

e

R

efer

ence

Cel

l lin

e an

d

end

poi

nts

Fib

er t

ype

Len

gth

(µ

m)

Dia

met

er (

µm

)

D

ose

Res

ult

s

Gilm

our

eta

l.

[1

997]

Rat

alv

eola

rm

acro

phag

es

G

luta

thio

ne

RC

F1

Am

osit

eas

best

os

MM

VF1

0

Not

rep

orte

dN

otr

epor

ted

8.24

×10

6 /ml

All

fibe

rss

ign

ifica

ntl

ylo

wer

ed

intr

acel

lula

rgl

uta

thio

ne.

MM

VF1

0ca

use

dth

egr

eate

st

decr

ease

.

RC

F1a

nd

amos

ite

had

sim

ilar

ef

fect

s.

Hill

et

al.

[1

996]

Rat

alv

eola

r

mac

roph

ages

Sup

erox

ide

anio

n

rele

ase

afte

rco

atin

gw

ith

rat

im

mu

nog

lobu

lin

(IgG

),a

nor

mal

co

mpo

nen

tof

lu

ng

linin

gfl

uid

.

MM

VF2

1R

CF1

L

FAa

sbes

tos

SiC

Jo

hn

sM

anvi

lleC

ode

10

0/47

5(g

lass

)

WH

Of/

µg

5,4

62

9,0

15

16

4,70

5

70,

550

2

1,74

2

Perc

enta

gele

ngt

h

di

stri

buti

ona

lso

repo

rted

.

Not

rep

orte

dR

CF1

,M

MV

F21:

125

µg–

20

mg/

ml

Cod

e10

0/47

5,

Si

C:1

25µ

g–

1

mg/

ml

LFA

asb

esto

s:

15

.6µ

g–

5

mg/

ml

IgG

-coa

ted

RC

F1fi

bers

and

Ig

G-c

oate

dLF

Aa

sbes

tosfi

bers

in

duce

da

sign

ifica

ntly

incr

ease

dsu

pero

xide

ani

onre

leas

e.

Coa

ting

ofR

CF1

fibe

rsa

tdos

es

>10

0µg

gre

atly

incr

ease

dth

eir

su

pero

xide

pro

duct

ion.

RC

F1fi

bers

had

ah

igh

bind

ing

affin

ityfo

rIgG

;LFA

asb

esto

sdid

no

t.

Leik

auf

eta

l.

[1

995]

Rat

mac

roph

ages

T

NF

LT

B4

P

GE

2

RC

F(u

nsp

ecifi

ed)

Cro

cido

lite

asbe

stos

Si

lica

TiO

2

Med

ian

:4.

92.

5N

A

NA

Med

ian

:0.

59

0.28

0.

88

0.18

100,

300

,1,

000

µg/m

lT

NF

prod

ucti

onw

asin

crea

sed

afte

rex

posu

reto

300

an

d1,

000

µg/m

lRC

Fs.

LTB

4leve

lsw

ere

elev

ated

aft

er

expo

sure

to3

00o

r1,

000

µg/m

lR

CFs

;PG

E 2con

cent

ratio

ns

wer

eel

evat

eda

fter

exp

osur

eto

1,0

00µ

g/m

lRC

Fs;e

ffect

sat

low

erd

oses

wer

eno

tsig

nific

ant.

Ate

quiv

alen

tdos

es,a

sbes

tos

in-

duce

da

grea

ter

resp

onse

than

R

CFs

inT

NF,

LT

B4,o

rP

GE

2co

nce

ntr

atio

ns.

See

foot

not

eat

en

dof

tab

le(C

onti

nu

ed)



Tabl

e C

–2 (

Con

tin

ued

) . I

n v

itro

cyt

otox

icit

y of

RC

Fs:* e

ffec

ts o

n m

edia

tor

rele

ase

Ref

eren

ceC

ell l

ine

and

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Lju

ngm

ane

tal

.

[1

994]

Rat

alv

eola

r

m

acro

phag

es

T

NF

Cro

cido

lite

Ch

ryso

tile

A

Ch

ryso

tile

B

MM

VF2

1

MM

VF2

2R

CF1

Si

Cw

h

Mea

n:

9

.9±

7.8

Not

rep

orte

d

Not

rep

orte

d

24.6

±1

9.9

21

.4±

17.

6

22.4

±1

9.0

N

otr

epor

ted

Mea

n:

0.

3±

0.2

Not

rep

orte

d

Not

rep

orte

d

1.3

±0

.8

1.

2±

0.7

1.1

±0

.8

N

otr

epor

ted

100

µg/m

lC

hry

soti

leA

,ch

ryso

tile

B,

croc

idol

ite,

MM

VF2

1,

RC

F1,a

nd

SiC

wh

incr

ease

dT

NF

mR

NA

con

cen

trat

ion

saf

ter

90m

inu

tes;

con

cen

-tr

atio

ns

had

ret

urn

edto

ba

selin

eaf

ter

4h

ours

ina

llbu

tch

ryso

tile

A.

Ch

ryso

tile

A,c

hry

soti

leB

,cr

ocid

olit

e,a

nd

MM

VF2

1in

duce

dan

incr

ease

inT

NF

bioa

ctiv

ity

afte

r4

hou

rs

ofin

cuba

tion

;RC

F1d

id

not

indu

cea

sig

nifi

can

tin

crea

se.

Luot

oet

al.

[199

7]R

ata

lveo

lar

mac

roph

ages

RO

M

RC

F1

RC

F2

RC

F3

RC

F4

MM

VF1

0M

MV

F11

MM

VF2

1M

MV

F22

Mea

n:

21

.29

±1

7.42

20.1

8±

19.

63

25

.66

±2

5.74

10.3

4±

11.

59

23

.21

±1

5.57

15.6

5±

13.

31

26

.02

±2

3.10

20.7

5±

20.

52

Mea

n:

1.

30±

0.7

2

1.39

±0

.98

1.

37±

0.8

7

1.33

±1

.02

1.

42±

0.7

8

1.12

±0

.88

1.

18±

0.6

4

0.88

±0

.45

25,5

0,1

00,

200,

400

,or

500

µg/m

l

All

fibe

rss

how

eda

dos

e-

dep

ende

nt

resp

onse

to

RO

Mp

rodu

ctio

n.

RC

F1,R

CF2

,or

RC

F3e

x-p

osu

rer

esu

lted

inh

igh

er

RO

Mp

rodu

ctio

nt

han

R

CF4

or

chry

soti

lee

xpo-

sure

.

Qu

artz

had

th

egr

eate

ste

ffec

ton

RO

Mp

rodu

ctio

n.

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–2 (

Con

tin

ued

) . I

n v

itro

cyt

otox

icit

y of

RC

Fs:* e

ffec

ts o

n m

edia

tor

rele

ase

Ref

eren

ceC

ell l

ine

and

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Mor

imot

oet

al.

[199

3]

Rat

alv

eola

r

m

acro

phag

es

T

NF

Can

adia

nc

hry

soti

le

Alu

min

asi

licat

ece

ram

ic

(J

apan

)

Not

rep

orte

dM

ass

med

ian

ae

rody

nam

icd

i-am

eter

=3

.1µ

m

25,5

0,o

r

100

µg/m

lB

oth

fiber

sstim

ulat

eda

dos

e-de

pend

entT

NF

prod

uctio

nby

al

veol

arm

acro

phag

es.

Chr

ysot

ilest

imul

ated

gre

ater

T

NF

prod

uctio

nth

anc

eram

ic

fiber

sin

cells

from

rat

sex

pose

dto

cig

aret

tesm

oke

and

cells

fr

omr

atsn

ote

xpos

edto

smok

e.

Chr

ysot

ilein

duce

dhi

gher

TN

Fpr

oduc

tion

insm

oke-

expo

sed

rats

than

inc

ontr

ols;

cera

mic

fib

ere

xpos

ure

resu

lted

inn

osi

gnifi

cant

diff

eren

ceb

etw

een

T

NF

prod

uctio

nin

smok

e-

expo

sed

rats

and

con

trol

s.

Wan

get

al.

[199

9]G

uin

eap

iga

lveo

lar

mac

roph

ages

Sup

erox

ide

anio

n

Hyd

roge

np

erox

ide

GSH

Intr

acel

lula

rfr

ee

calc

ium

Japa

nfi

brou

sm

ater

ial:

G

W1

=g

lass

woo

lR

W1

=r

ock

woo

lM

G1

=m

icro

gla

ss

RF1

=r

efra

ctor

yce

ram

ic

RF2

=r

efra

ctor

yce

ram

ic

RF3

=r

efra

ctor

ym

ulli

te

PT

1=

pot

assi

um

tit

anat

eSC

1=

sili

con

car

bide

T

O1

=t

itan

ium

oxi

de

WO

1=

wol

last

onit

eC

hry

soti

le

20.2

±2

.58

16.5

±2

.51

3.0

±2

.22

12.0

±2

.36

11.0

±1

.96

11.0

±1

.75

6.

0±

2.0

46

.4±

2.4

52

.1±

2.0

010

.5±

2.0

3N

otr

epor

ted

0.88

±3

.10

1.80

±2

.32

0.24

±2

.35

0.77

±2

.53

1.10

±2

.00

2.40

±1

.37

0.35

±1

.51

0.30

±1

.58

0.14

±1

.53

1.00

±1

.72

Not

rep

orte

d

20

0µg

/ml

Chr

ysot

ilea

nda

llfib

erso

ther

th

anW

O1

sign

ifica

ntly

in

crea

sed

supe

roxi

dea

nion

pr

oduc

tion.

Chr

ysot

ilesi

gnifi

cant

lyin

crea

sed

hydr

ogen

per

oxid

epr

oduc

tion;

R

Fdi

dno

t.

Chr

ysot

ile,R

F2,P

T1,

TO

1,S

C1,

W

O1,

and

MG

1si

gnifi

cant

ly

decr

ease

dG

SHc

once

ntra

tion.

Chr

ysot

ile,R

F1,R

F2,S

C1,

TO

1,

PT1,

MG

1,a

ndR

W1

sign

ifi-

cant

lyin

crea

sed

intr

acel

lula

rfr

eec

alci

um.

Ina

llte

sts,

chry

sotil

eha

dgr

eate

ref

fect

stha

nth

ose

ofth

eR

CFs

.

* Abb

revi

atio

ns:

GSH

=gl

uta

thio

ne;

GW

1=gl

ass

woo

l;Ig

G=

imm

un

oglo

bulin

;LFA

=lo

ng

fibe

ram

osit

e;L

TB

4=le

uko

trie

ne

B4;

MG

1=m

icro

gla

ss;M

MV

F=m

an-m

ade

vitr

eou

sfi

ber;

P

GE

2=pr

osta

glan

din

E2;P

T1=

pota

ssiu

mt

itan

ate;

RC

Fs=

refr

acto

ryc

eram

icfi

bers

;RF1

=re

frac

tory

cer

amic

;RF2

=re

frac

tory

cer

amic

;RF3

=re

frac

tory

mu

llite

;RO

M=

reac

tive

ox

ygen

met

abol

ites

;RW

1=ro

ckw

ool;

SC1=

silic

onc

arbi

dein

Wan

get

al.

[199

9];S

iC=

silic

onc

arbi

de;T

NF=

tum

orn

ecro

sis

fact

or;T

iO2=

tita

niu

md

ioxi

de;T

O1=

tita

niu

mo

xide

in

Wan

get

al.

[199

9];w

h=

wh

iske

rs;W

O1=

wol

last

onit

e.



Tabl

e C

–3 .

In v

itro

gen

otox

ic e

ffec

ts o

f R

CFs

*

Ref

eren

ceTe

st s

yste

m a

nd

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Bro

wn

et

al.

[199

8]P

lasm

ido

X17

4RF1

D

NA

D

NA

sci

ssio

n

Salic

ylat

eas

say

H

ydro

xylr

adic

al

gen

erat

ion

Lon

gfi

ber

amos

ite

asbe

stos

Si

C

RC

F1

RC

F4

MM

VF1

0C

ode

100/

475

glas

s

Siz

edi

stri

buti

on

>10

>

20

64

.75

35.

25

60

.86

27.

6

77.3

64

5.27

59.3

51

7.96

85.2

46

7.17

50.0

01

9.32

Not

rep

orte

dP

lasm

ida

ssay

:9.

249×

105 f/

20µ

l

Salic

ylat

eas

say:

8.

24×

107 f/

ml

Pla

smid

ass

ay:

On

lya

mos

ite

had

free

rad

ical

ac

tivi

ty.

Salic

ylat

eas

say:

A

mos

ite

and

RC

F1h

adfr

ee

radi

cala

ctiv

ity.

Coa

tin

gth

efi

bers

wit

hlu

ng

surf

acta

nt

decr

ease

dhy

drox

yl

radi

cala

ctiv

ity.

An

iron

ch

elat

orin

hib

ited

hy-

drox

ylat

ion

by

RC

F1.

Dop

pet

al.

[199

7]H

um

ana

mn

ioti

c

fl

uid

cel

ls

M

icro

nu

clei

H

yper

dipl

oidy

Ch

rom

osom

al

brea

kage

Am

osit

eas

best

os

Cro

cido

lite

asbe

stos

-R

hod

esia

nc

hry

soti

le

as

best

os

Cer

amic

(u

nsp

ecifi

ed)

Gyp

sum

Ave

rage

:2.

05

1.71

2.

24

12.0

3

Ave

rage

:0.

24

0.25

0.

10

0.90

0.5,

1.0

,5.0

,or

10.0

µg/

cm2

All

fibe

rsc

ause

da

sign

ifica

nt

incr

ease

inm

icro

nu

clei

.

Dos

e-de

pen

den

tre

spon

sew

as

seen

wit

ha

sbes

tos

but

not

wit

h

cera

mic

fibe

rex

pos

ure

.

Asb

esto

san

dce

ram

icfi

bers

in-

duce

dch

rom

osom

alb

reak

age

and

hyp

erdi

ploi

dce

lls.

Gilm

our

eta

l.

[1

995]

Pla

smid

oX

174R

F1

DN

A

D

eple

tion

of

su

perc

oile

dD

NA

Shor

tfi

ber

amos

ite

Lon

gfi

ber

amos

ite

Cro

cido

lite

asbe

stos

RC

F1R

CF2

RC

F3R

CF4

MM

VF1

0M

MV

F11

MM

VF2

1M

MV

F22

Not

rep

orte

dN

otr

epor

ted

Test

eda

teq

ual

fi

ber

nu

mbe

rs:

6.16

6×10

5 or

9.24

9×10

5 or

1.23

32×

106

RC

F1,R

CF2

,RC

F3,a

nd

RC

F4

had

am

inim

alfr

eer

adic

al

effe

ctc

ompa

red

wit

ha

sbes

tos

fibe

rs.

RC

FD

NA

dam

age

was

med

i-at

edb

yhy

drox

ylr

adic

als

but

was

not

ass

ocia

ted

wit

hir

on

con

ten

t.

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–3 (

Con

tin

ued

) . I

n v

itro

gen

otox

ic e

ffec

ts o

f R

CFs

*

Ref

eren

ceTe

st s

yste

m a

nd

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Gilm

our

eta

l.

[199

7]

Pla

smid

oX

174R

F1

DN

A

D

eple

tion

of

s

up

erco

iled

DN

A

R

ata

lveo

lar

mac

roph

ages

A

ctiv

atio

no

ftr

an-

s

crip

tion

fact

ors

Am

osit

eas

best

os

MM

VF1

0R

CF1

Not

rep

orte

dN

otr

epor

ted

Equ

alfi

ber

nu

mbe

rsp

er

assa

y.

DN

Aa

ssay

:9.

3×10

5

Iron

ass

ay:

8.24

×10

7 /ml

RC

F1a

nd

MM

VF1

0in

duce

dsi

g-n

ifica

ntl

yle

ssD

NA

free

rad

ical

da

mag

eth

ana

mos

ite

asbe

stos

.

Am

osit

esi

gnifi

can

tly

upr

egu

-la

ted

tran

scri

ptio

nfa

ctor

sA

P–1

an

dN

FkB

;RC

F1h

ada

mu

ch

smal

ler

effe

cto

nA

P–1

on

ly.

Har

tet

al.

[199

2]C

hin

ese

ham

ster

ov

ary

cells

M

icro

nu

clei

in

duct

ion

Po

lyn

ucl

ei

indu

ctio

n

RC

F1

RC

F2

RC

F3

RC

F4

UIC

CC

roci

dolit

eU

ICC

Ch

ryso

tile

Mea

n:

21.5

±1

6.12

16

.7±

15.

03

24.3

±1

8.82

9

.2±

7.0

81

.8±

1.9

41.

65±

1.8

3

Mea

n:

1.03

±0

.73

1.11

±0

.82

1.22

±0

.98

1.43

±0

.79

0.21

±0

.12

0.12

±0

.07

RC

Fs1

–4:

0,5

,10,

or

20

µg/

ml

Cro

cido

lite:

0

or5

µg/

ml

Ch

ryso

tile

:0,

1,2

,or

5

µg/m

l

Nu

clea

rab

nor

mal

ity

inci

den

ce:

At2

0µg

/cm

2 ,RC

Fw

as2

0%to

33%

.

At5

µg/

cm2 ,c

roci

dolit

ew

as2

8%.

At5

µg/

cm2 ,c

hrys

otile

was

49%

.

Jan

ssen

et

al.

[199

4]H

amst

ert

rach

eal

e

pith

elia

l(H

TE

)

cel

ls

mR

NA

con

cen

tra-

tion

so

fc-

fos,

c-

jun

,an

dO

DC

RP

Mc

ells

mR

NA

con

cen

tra-

tion

sof

c-f

os,

c-ju

n,a

nd

OD

C

Cro

cido

lite

Ch

ryso

tile

M

MV

F10

RC

F1

Poly

styr

ene

bead

sR

iebe

ckit

eE

rion

ite

Mea

n:

11.4

1

.1

19.8

24

.0

—

—

6.0

Mea

n:

0.27

0.

08

1.36

1.

07

1.05

0.

80.

8

Asb

esto

s:

≤5µ

g/cm

2

All

oth

erfi

bers

:1.

25–2

5µg

/cm

2

HT

Ec

ells

:C

roci

dolit

ein

duce

dsi

gnifi

cant

do

se-d

epen

dent

con

cent

rati

ons

ofc

-jun

and

OD

Cm

RN

A.

RC

F1in

duce

dsm

alln

on-d

ose-

depe

nden

tinc

reas

esin

OD

C

mR

NA

con

cent

rati

ons

only

.

RP

Mc

ells

:C

roci

dolit

eat

2.5

µg/

cm2 in

duce

del

evat

edc

-fos

and

c-j

unm

RN

A

conc

entr

atio

ns.

RC

F1a

t25

µg/c

m2 in

crea

sed

c-

fos

and

c-ju

nm

RN

A

conc

entr

atio

ns.

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–3 (

Con

tin

ued

) . I

n v

itro

gen

otox

ic e

ffec

ts o

f R

CFs

*

Ref

eren

ceTe

st s

yste

m a

nd

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Lean

ders

one

t

al

.[19

89]

Cal

fth

ymu

sD

NA

Hyd

roxy

lati

on

of

2-dG

to

8–O

H–d

G

dGs

olu

tion

Hyd

roxy

lati

ono

f

dG

to8

–OH

–dG

Eu

rop

ean

sou

rce:

Fi

ber

1=

cer

amic

Fi

ber

2=

gla

ssw

ool

Fibe

r3

=c

eram

ic

Fibe

r4

=r

ock

woo

lFi

ber

5=

roc

kw

ool

Fibe

r6

=r

ock

woo

lFi

ber

7=

roc

kw

ool

Fibe

r8

=r

ock

woo

lFi

ber

9=

roc

kw

ool

Fibe

r10

=r

ock

woo

lFi

ber

11=

roc

kw

ool

Fibe

r12

=s

lag

woo

l Fi

ber

13=

roc

kw

ool

Fibe

r14

=r

ock

woo

lFi

ber

15=

sla

gw

ool

Fibe

r16

=r

ock

woo

l

Surf

ace

area

(m

2 /g):

0.

95

0.91

1.

10

1.30

0.

36

0.60

0.

73

1.01

1.

28

1.16

1.

18

1.14

1.

30

1.06

0.

90

0.62

Not

rep

orte

d10

mg

fibe

ran

d1.

0m

lPB

Sw

ith

0.5

mg

DN

Ao

r

0.5

mM

dG

All

fibe

rsc

ause

dsi

gnifi

can

thy

drox

ylat

ion

of

dG.

Gla

ssw

oola

nd

cera

mic

fibe

rs

had

poo

rhy

drox

ylat

ing

capa

c-it

yre

lati

veto

roc

kw

ools

an

dsl

agw

ools

.

Lean

ders

one

t

al

.[19

89]

Cal

fth

ymu

sD

NA

Hyd

roxy

lati

ono

f

dG

to8

–OH

–dG

Eu

rop

ean

sou

rce:

R

ock

woo

lG

lass

woo

lC

eram

ic

Not

rep

orte

dN

otr

epor

ted

10m

gfi

ber

and/

or3

00µ

lsm

oke-

PB

Sor

10

0µM

H2O

2in

1.0

mlP

BS

wit

h0

.5m

gD

NA

Cer

amic

an

dgl

ass

woo

lfibe

rs

cau

sed

less

DN

Ah

ydro

xyla

tion

th

anr

ock

woo

l.

Roc

kw

oola

nd

ciga

rett

esm

oke

con

den

sate

had

as

yner

gist

ic

effe

cto

nh

ydro

xyla

tion

.

Cer

amic

or

glas

sw

oolfi

bers

an

dci

gare

tte

smok

eco

nde

nsa

ted

id

not

hav

ea

syn

ergi

stic

eff

ecto

n

hydr

oxyl

atio

n.

Oka

yasu

et

al.

[1

999]

Hu

man

-ham

ster

h

ybri

dA

Lcel

ls

M

uta

tion

ass

ay

UIC

Cc

hry

soti

le

Trem

olit

eE

rion

ite

RC

F1

Geo

met

ric

mea

n:

1.78

±2

.3

1.41

±2

.7

1.31

±2

.9

13.5

±2

.7

Geo

met

ric

mea

n:

0.12

±0

.08

0.13

±3

.43

0.23

±2

.74

0.95

±2

.6

0–80

µg/

cm2

RC

F1w

asd

eter

min

edto

be

non

mu

tage

nic

.

Ch

ryso

tile

was

th

em

ost

mu

ta-

gen

ico

ffi

bers

exa

min

edb

ased

on

fibe

rco

nce

ntr

atio

n.

See

foot

not

eat

en

dof

tab

le.

(Con

tin

ued

)



Tabl

e C

–3 (

Con

tin

ued

) . I

n v

itro

gen

otox

ic e

ffec

ts o

f R

CFs

*

Ref

eren

ceTe

st s

yste

m a

nd

en

dp

oin

tsFi

ber

typ

eLe

ngt

h (

µm

)D

iam

eter

(µ

m)

Dos

eR

esu

lts

Yegl

ese

tal

.

[1

995]

Rat

ple

ura

lmes

o-th

elia

lcel

ls

An

aph

ase/

telo

phas

eab

erra

tion

s

RC

F1

RC

F3

RC

F4

MM

VF1

0M

MV

F11

UIC

Cc

hry

soti

le

Ch

rys

445

(Can

adia

n)

Ch

rys

443

(Can

adia

n)

Ch

rys,

sh

ort

Can

adia

n

Ch

rys,

su

per

fin

e

C

anad

ian

C

hry

s,p

hos

phor

ylat

ed

C

anad

ian

C

hry

s,ph

osph

oryl

ated

mill

edC

anad

ian

UIC

Cc

hry

s,le

ach

ed

w

ith

oxa

lica

cid

C

hry

s,C

alid

ria

Ch

rys,

NIE

HS

Am

osit

eC

roci

dolit

eA

ttap

ulg

ite

19.2

±1

5.0

31.8

±3

6.0

8.9

±7

.2

21.5

±1

6.8

16.7

±1

2.9

1.7

±2

.2

2.3

±2

.3

1.9

±1

.9

1.6

±1

.4

2.4

±3

.1

4.7

±5

.2

4.7

±5

.9

2.3

±1

.8

2.8

±3

.0

4.2

±1

.2

2.4

±1

.8

2.1

±3

.6

0.8

±0

.5

1.30

±0

.80

0.74

±0

.50

1.30

±0

.60

0.55

±0

.50

1.10

±0

.90

0.05

±0

.04

0.04

±0

.03

0.04

±0

.04

0.06

±0

.08

0.04

±0

.03

0.04

±0

.03

0.07

±0

.09

0.17

±0

.11

0.05

±0

.04

0.05

±0

.05

0.31

±0

.20

0.19

±0

.12

0.04

±0

.03

12.5

,25,

50,

75,

or

100

µg/

cm2

UIC

Cc

hry

soti

lew

ast

he

mos

tge

not

oxic

on

th

eba

sis

of

wei

ght,

nu

mbe

rof

fibe

rs>

4µm

lon

g,a

nd

nu

mbe

rof

fibe

rs

corr

esp

ondi

ng

toS

tan

ton’

san

dPo

tt’s

cri

teri

a.

Cer

amic

an

dgl

ass

fibe

rsd

idn

ot

indu

cea

nap

has

eab

erra

tion

s.

*Abb

revi

atio

ns:d

G=

deox

ygua

nosi

ne;f

=fib

ers;

HT

E=

ham

ster

trac

heal

epi

thel

ial;

OH

–dG

=hy

drox

ydeo

xy-g

uano

sine

;mR

NA

=m

esse

nger

RN

A;M

MV

F=m

an-m

ade

vitr

eous

fibe

r;

NIE

HS=

Nat

iona

lIns

titu

tefo

rE

nvir

onm

enta

lHea

lthS

cien

ces;

OD

C=

orni

thin

ede

carb

oxyl

ase;

PB

S=ph

osph

ate-

buff

ered

sal

ine;

RC

Fs=

refr

acto

ryc

eram

icfi

bers

;RP

M=

ratp

leur

alm

eso -

thel

ial;

UIC

C=

Uni

onIn

tern

atio

nale

Con

tre

leC

ance

r.

Documents

Criteria for a Recommended Standard - Occupational Exposure to