P 1 Summary P 2 3 Part 1 General Information P 4 7 Part 2 Exposure among healthcare workers P 8 11 Part 3 Health Effects

Transcription

1 TOXICOLOGY PROFILE METHOTREXATE IN THE HEALTH CARE INDUSTRY P1Summary P23Part1GeneralInformation P47Part2Exposureamonghealthcareworkers P811Part3HealthEffects P8PulmonaryEffects P8EffectsonBone P8Hepatotoxicity P910Carcinogenicity P10CytogeneticToxicity P11Teratogenicity,ReproductiveandDevelopmentalEffects P12Part4Regulations P1316Part5ControlMeasures P1723References

2 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH This report focuses on methotrexate (MTX) in the healthcare industry, including basic properties, use in healthcare settings, exposure routes, health effects, regulations and control measures. Methotrexate is a widely used anti-neoplastic, anti-inflammatory and immunosuppressive drug, administered via oral or injection. Healthcare workers may be exposed to methotrexate through dermal contact, inhalation and unintentional swallowing or injection during drug preparation, drug administration, waste handling and spills. Methotrexate has negative effects on pulmonary system, bone, and liver. It is not classifiable as carcinogen by IARC, and there are contradictory conclusions concerning its carcinogenicity in animal and human studies. However, MTX showed carcinogenicity in one epidemiology study and co-carcinogenicity in two animal studies. MTX has shown to be cytotoxic as it can induce chromosome aberrations. MTX has negative reproductive effects and was evaluated as a human teratogen by IARC. Currently, there is no occupational exposure limit established for methotrexate in Canada or any other international bodies. Methotrexate exposure can be reduced or eliminated by substitution or using pharmacy isolators, or vertical laminar ventilation hood. One study showed a significant reduction of MTX in the urine after the use of a laminar ventilation hood in one pharmacy unit. PPE such as gloves, respiratory protection, gowns and eye protection should be used as a last resort. 1

3 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY Part 1 General Information I) Name Methotrexate II) Formula OHSAH C 20 H 22 N 8 O 5 III) CAS Number IV) Synonyms and trade names 4Amino10methylfolicacid 4AminoN10methylpteroylglutamicacid Antifolan CL14377 N[p[(2,4Diamino6pteridinyl)methyl]methylamino]benzoylL(+)glutamicacid N(4[[(2,4Diamino6pteridinyl)methyl]methylamino]benzoyl)Lglutamicacid N[p[(2,4Diaminopteridin6ylmethyl)methylamino]benzoyl]Lglutamicacid L(+)N(p[[(2,4Diamino6pteridinyl)methyl]methylamino]benzoyl)glutamicacid Ledertrexate amethopterin AMethopterin Methotrexatespecia Methotrexatum Methylaminopterin MEXATE MTX MethotrexateSodium V) Properties and Use Thechemicalstructureofmethotrexateissimilartofolicacid.Methotrexateinhibitstheenzymedihydrofolate reductase,whichdecreasesdnaandrnasynthesis[1].consequently,growthofcancercellsisstopped.therefore,itis usedintreatingcancerssuchaschoriocarcinoma,leukemiainthespinalfluid,osteosarcoma,breastcancer,lungcancer, nonhodgkinlymphoma,andheadandneckcancers[7].inaddition,methotrexateisanimmunosuppressiveandanti inflammatorymedicine,whichcanreducetheactivityoftheimmunesystemandbodymetabolism[8].inrheumatoid arthritis,thisactionhelpstoreduceinflammationinthejointsandthusreducepainandswelling;italsolimitsdamage tothejointsandhelpstopreventdisabilityinthelongterm[8].morerecently,methotrexatehasbeenusedinwomen ofreproductiveagefortreatmentofectopicpregnancy[67]. 2

4 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY Methotrexatehasbeenwidelyusedinoncochemotherapyathighdoses(1000mg5000mgaday)[1,2]andinthe treatmentofothernonneoplasticdiseasesatmuchlowerdosesandlongerdurations[34],suchaspsoriasis[3], rheumatoidarthritis[4],andsteroiddependentasthma[5].methotrexatemaybetakenbymouthasatabletorgiven byinjectioneitherintothemuscleorundertheskin.injectionsmaybeusedinsteadoftabletsifthemedicineisnot beingabsorbedwell,orifthepatientmayfeelsick(nausea)orvomitwhentakingthetablets[1]. VI) Side-effects Themostfrequentlyreportedadversereactionsincludeulcerativestomatitis,leukopenia,nausea,andabdominal distress[6].otherfrequentlyreportedadverseeffectsaremalaise,unduefatigue,chillsandfever,dizzinessand decreasedresistancetoinfection[6]. VII) Analytical Methods HPLC ReversePhaseHPLCwithUVdetectorhasbeenusedasananalyticalmethodinmostenvironmentalandbiological monitoringstudies.limitofdetectioncanbeaslowas0.07g/m 3 forairsamples[28],18ng/gloveforglovesamples [31],0.001ng/cm 2 forsurfacewipesamples[33],and2nmol/lforurinesamples. Radioimmunoassay Fluorescencepolarizationimmunoassayandotheranalyticalmethodsareusedtoquantifymethotrexateconcentration. However,thisapproachissusceptibletoseveralinterferingsubstances,suchasmethotrexatemetabolite7 hydroxymethotrexatel[29]. OHSAH 3

5 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY Part 2Exposure among healthcare workers I) Healthcare workers at risk Bothclinicalandnonclinicalworkersmaybeexposedtoantineoplasticdrugsnotonlywhentheyprepareand administratedrugs,butalsowhentheycleanupspills,touchcontaminatedsurfacesduringthepreparation,ordispose ofhazardousdrugsandmedicalwaste[9,10].jobtaskswithpotentialexposuretomethotrexatecanbecategorizedinto threegroups: drugpreparation, drugadministration and wasteandspillshandlinganddisposal [11]: DRUGPREPARATION Withdrawalofneedlesfromdrugvials[11]. Breakingopenofampoules[11]. Reconstitutingpowderedorlyophilizeddrugsandfurtherdilutingeitherthereconstitutedpowderor concentratedliquidformsofhazardousdrugs[12]. Expellingairfromsyringesfilledwithhazardousdrugs[11]. Countingoutindividual,uncoatedoraldosesandtabletsfrommultidosebottlesorunitdosinguncoated tabletsinaunitdosemachine. Crushingtabletstomakeoralliquiddoses[1315]. Compoundingpotentpowdersintocustomdosagecapsules. Contactingmeasureableconcentrationsofdrugspresentondrugvialexteriors,worksurfaces,floors,and finaldrugproducts,suchasbottles,bags,cassettes,andsyringes[1619]. DRUGADMINISTRATION Administeringhazardousdrugsbyintramuscular,subcutaneous,orintravenous(IV)routes. Generatingaerosolsduringtheadministrationofdrugs,eitherbydirectIVpushorbyIVinfusion. Clearingofairfromthesyringe[11]. PrimingtheIVsetwithadrugcontainingsolutionatthepatientbedside. Leakageatthetubing,syringeorstopcock[11]. Performingcertainspecializedproceduresintheoperatingroom,suchasintraoperativeintraperitoneal chemotherapy[20,21]. OHSAH 4

6 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY II) Monitoring Data Therearebothenvironmentalandbiological(urine)monitoringstudiesofmethotrexateamonghealthcareworkers.Air andwipesampleswerecollectedtoassessmtxlevelsintheworkingenvironment,andurinesampleswerecollectedas biologicalindicatorsofexposure.resultsoftheenvironmentalandbiologicalmonitoringstudiesaresummarizedin table1andtable2respectively. Air Glove Surface WASTE&SPILLSHANDLINGANDDISPOSAL Handlingwastesofpatientswhoreceiveantineoplasticdrugs,suchasurine,fecesandsweat[11]. Handlingbodyfluidsorbodyfluidcontaminatedclothing,dressings,linens,andothermaterials[22,23]. Handlingcontaminatedwastesgeneratedatanystepofthepreparationoradministrationprocess. Handlingunusedhazardousdrugsorhazardousdrugcontaminatedwaste. Decontaminatingandcleaningdrugpreparationorclinicalareas. Transportinginfectious,chemical,orhazardouswastecontainers. Removinganddisposingofpersonalprotectiveequipment(PPE)afterhandlinghazardousdrugsorwaste. Table1.Environmentalmonitoringofmethotrexateinhealthcaresettings OHSAH Sampling Analysis Area ExposureLevel Reference Size Method Drugpreparationarea 17 AllsamplesbelowLOD. HPLC a [17] Drugpreparationarea Pharmaceuticalplant 4 8 MTXwasdetectedinonlyonesampleduringdrug preparation(0.3g/m 3 ) Mean:10g/m 3 Range:0.8~182g/m 3 Clinicalpharmacydepartment 2 BothsamplesunderLOD Clinicalpharmacydepartment, outpatientdepartment (preparation) Drugpreparationarea Oncologydepartment Drugpreparationarea Drugpreparationarea Amongthe10pairsofgloves,4pairswere contaminated,rangingfrombelowlodto49g/glove MTXwasdetectedinonly2samples,withthelevelof 220and1900g/pair. MTXweredetectedon9pairsofgloves,rangingfrom 18to49.3ng/glove. Contaminationofthelaminarairflowhoodrangedfrom 2~633ng/cm 2,whilecontaminationoffloorwasnot found. Only3samplesdetectableinsidetheisolator(ranged from1.81to8.61ng/cm 2 ) HPLC FPIA b, LOD c 0.07g/m 3 HPLC/UV, LOD:0.3g/m 3 HPLC/UV, LOD: 6g/glove HPLC Enzymelinked immunoassay, LOD 18ng/glove HPLC HPLC/UV Clinicalpharmacydepartment, N/A ContaminationoffloorandhoodswithMTXwasfound HPLC/UV, [30] [26] [28] [30] [30] [17] [31] [26] [27] 5

7 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY outpatientdepartment (preparationandadministration), andoncologydepartment Oncologydepartment Drugpreparationarea Drugpreparationarea intheoutpatientdepartment(administration)and oncologydepartment,rangingfrom5.5to5.9ng/cm 2 ContaminationwithMTXwasdetectedamongall samplingspots(mean:14.8ng/sample,range11~19 ng/sample). MTXwasdetectedonthehood,floors,doorhandles andtaps,rangingfrombelowlodto251ng/cm 2. Contaminationofsurfacesofhood,telephone,handles, tableboardandshelveswasfound,withrangefrom belowlodupto64.5g/m 2. a.highperformanceliquidchromatography b.fluorescencepolarizationimmunoassay c.limitofdetection d.highperformanceliquidchromatography/electrosprayionizationtandemmassspectrometry Table2.Biologicalmonitoring(urine)ofmethotrexateamonghealthcareworkers JobCategory Pharmaceutical plantworker Sampling Size 11 LOD:0.4~1 ng/cm 2 MTXLevel AnalysisMethod Ref. Mean a :13.4g Range:6.124g FPIA Enzymelinked immunoassay HPLC/EITMS e, LOD:1.1g/L HPLC/UV, LOD: 0.001ng/cm 2 Oncologyward Enzymelinked 20 AllsamplesbelowLOD [31] staff immunoassay,lod:2nmol/l a.mtxequivalent,whichwasadjustedforbackgroundfluorescentlevels.totalurinewascollectedinportionsduringtheperiodofabout7296hstartingfrom thebeginningoftheworkingday III) Route of Occupational Exposure and Elimination Primaryroutesforexposureamonghealthcareworkersareinhalationanddermalabsorption[9,11].Inadvertent ingestionfromhandtomouthcontactandunintentionalinjectionthroughneedlesticksorsharpsarepossiblebutless commonroutesofexposure[24,25]. Inhalation Inhalationofantineoplasticdrugsmayoccurduringaerosolizationofpowderorliquidduringreconstitutionorfrom inhalationofvaporsfromaccidentalspillage,whichmayoccurduringdrugpreparationoradministrationtothepatients. Dermal Administeringthedrugstothepatients,andhandlingthepatientsdirectlymayexposehealthcareworkersto antineoplasticdrugsthroughdermalcontact.forexample,nursesmaycomeintocontactwithbodilyexcretionssuchas urine,feces,sweatandsalivaincaringforthepatientswhoreceiveantineoplasticdrugs. Oneenvironmentalcontaminationstudysuggestedthatmethotrexatemightpermeatethroughcottonorlatexgloves, butthepermeationrateismuchslowercomparedwithcyclophosphamideand5fluorouracil[17].onepossiblereason [28] [31] [32] [33] OHSAH 6

8 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY forthedifferencemightbethatmethotrexatehasahighermolecularweightandpolaritythantheothertwo substances,bothofwhichwillpreventquickpermeationofgloves. Biologicalhalflife Methotrexatecanbeeliminatedthroughsweatandurine[88].Usingpharmacokineticanalysis,theeliminationhalflife wascalculatedbeto11.1hours[88]. OHSAH 7

9 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH Part 3Health Effects I) Pulmonary Effects Methotrexatecanbeassociatedwithavarietyofacutetoxicreactionswhengiveninarelativelylargedoseoverashort periodoftime[38].inonestudy,aftergivinganextremelylargedoseofmethotrexate(15mg/m 2 /i.v./day 5days), childrenwithlymphocyticleukemiadevelopedacutedrugreactionsconsistingofinflammationofthevaginal,pleural, pulmonary,andbladderepithelium,aswellasskinandconjunctivesurface,andsevereulcerationofthegastrointestinal tract[38].pulmonaryreactionswerethesiteofthemostseriousreactions[38],includingepisodesofpneumonia reportedtooccurapproximately12daysafterthefirstdoseofintravenousmethotrexate. II) Effects on Bone Clinicalresearchhasverifiedthedetrimentaleffectsofmethotrexatechemotherapyonbonethroughincreasedfracture incidence[3840].quantitativestudiesusingsinglephotoabsorptiometrydemonstratedareductioninbonemineral contentbetween6and9monthsaftermethotrexatetreatment[41].inaddition,itiswelldocumentedthatonecourse ofmethotrexatewillinduceosteopeniaanddepressboneformation14daysfollowingtreatment[42].oneanimalstudy withspraguedawleyratsfocusedonwhetherthealternationinbonewasreversibleornot,andtheyfoundthat methotrexatealtersbothcorticalandcancellousbone,andrecoveryfromosteoblastandosteoclastwasnotobserved [43].AnotheranimalstudywithfemaleSpragueDawleyratsfoundthatprolongedadministrationoflowdose methotrexateinratscausedsignificantosteopeniaandincreasedboneresorptions[37]. III) Hepatotoxicity Methotrexateismetabolizedintoapolyglutamatedform,thenthemetaboliteisretainedwithinthelivercelllongterm, whichmaybethemajorcauseofhepatotoxicity[48,49].thereareseveralcasereportsofhepaticfibrosisatautopsyin leukemiapatientswhoreceivedantimetabolitetherapy,includingmethotrexate[44,45].forpatientsreceivinglow dosemethotrexatetherapy,advancedhepaticfibrosisismuchlessfrequent[50].abnormalliverfunctiontestshave beennotedinwomenreceivingmethotrexateforchoriocarcinoma[46],andincreasedmortalityfromhepaticdisease wasfoundamongpsoriaticsreceivingmethotrexate[60].onestudyfocusingonhepatotoxiceffectsamong22patients receivingintensivemethotrexatetherapyfoundthatvaluesforsgot,sgpt,ldhandbspweresignificantlyhigherin casesthanthecontrolgroup;inaddition,liverbiopsiesrevealedinflammationofchronicportalappearingin7cases[47]. Aretrospectiveanalysisof104psoriasisandpsoriaticarthritispatientstreatedwithmethotrexatefounddifferent outcomes:inmostcases,adversedrugreactions(adr)weremild,andliverchangesandserumenzymelevelincreases werenotamajorprobleminthepatients[51]. 8

10 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH IV) Carcinogenicity Animalstudies Animalstudiesconcerningthecarcinogenicity,mutagenicity,cytotoxicityandclastogenicityofmethotrexateare summarizedintable3below.fromtheresultswecanseethattherewasnoincreasedtumorrateamongmethotrexate treatedrats,miceandhamsters. Table3.Animalstudiesconcerningthecarcinogenicityofmethotrexate Study group Dose Conclusion Ref. SpragueDawleyrats SwissmiceandSyrian goldenhamsters Miceandrats 0.1,0.2and0.4mg/kgMTXasdietary admixturesona5dayson,9daysofffor 23mo. Themicewereadministered10,8,5,or3 ppmofmtxinthedietonalternate weeksforlife,whilethedoseofthe hamsterswas20,10,or5ppm. 0.15~1.0mg/kg/dose,3timesweeklyfor6 mo. Noevidenceofeitherearlyonsetorincreasedincidenceofany tumortypewasfoundinthemtxtreatedgroup.inaddition,no significantincreaseinchromosomalaberrationswasseeninany dosegrouprelativetothecontrolgroup.thusitisconcluded thatmtxhasnooncogenicpotentialinrats. Theincidenceoftumorswasnotincreasedineitherspecies. Theincidenceoftumorswasnotincreasedineitherspecies. Humanstudies Therearehumanstudiesconcerningthecarcinogenicriskofmethotrexatetreatment,includingoneepidemiological studyandseveralcasereportsofpatientswhodevelopmalignanciesduringorfollowingmethotrexatetreatment,and theresultsaresummarizedintable4.5outof6studiesdidnotrevealelevatedincidenceofcanceramong methotrexatetreatedpatients,andtheremainingonestudyfounda2foldrelativeriskafteradjustingforpossible confounders. Table4.Humanstudiesconcerningthecarcinogenicityofmethotrexate Studypopulation/case Conclusion Notes Ref. 1380patientswithsevere psoriasistreatedwithmtx andpuva. 224patientsreceivedMTX therapyduring1960to patientswithsevere psoriasis Highlevelexposuretomethotrexateisasignificant independentriskfactorfordevelopingsquamouscell carcinoma(scc),withrelativeriskof2.1(95%ci1.4~2.8). Noincreasedincidenceoftotalinternalmalignancy was found,nordidanyonetypeofneoplasmappear predominant. Casecontrolanalysisshowednoincreaseoftheriskof noncutaneousorcutaneousmalignancy.relativerisk was0.96and1.2fornoncutaneousandcutaneous malignanciesrespectively. Thisstudyadjustedforconfounding factorssuchasage,sex,geographic residenceandlevelofexposuretopuva radiation,whichiscommonlyusedin combinationofmtxtotreatpsoriasis. Noadjustmentofconfoundingfactors, includingothertherapiesreceivedbythe patients. Apsoriasispatienttaking Thepatientdevelopedtransitionalcellcarcinomaofthe Definitivecauseandeffectjudgment [58] [34] [55] [56] [57] [60] [61] 9

11 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY MTX. nasopharynxwithmetastasistothecervicalnodes. cannotbemadeonthebasisofisolated Patientswithchronic reports obstructivepulmonary Therearethreecasesofmalignancies:malignant disease(copd),asthmaand neoplasm,pneumonitisandpancytopenia. rheumatoidarthritisreceiving lowdosemtx patientswith rheumatoidarthritis ThestudydidnotshowanincreasedSIRoflymphomain patientsreceivingmtxcomparedwiththosewhowere neverexposedtomtx.theyalsodidnotfindacausal relationshipbetweenrheumatoidarthritisandthe developmentoflymphoma. Epidemiologystudywithlargest investigationscaleever. Inaddition,methotrexatehasbeenadministeredincombinationwithknowncarcinogenstotestforitscocarcinogenic potential,whicharesummarizedintableasbelow.3outof5studiesshowednegativeeffects,andtheremaining2 showedpositiveeffects,whichindicatedthatmethotrexatemayactasapromoter.studiesconcerningtheco carcinogenicityofmethotrexatearesummarizedintable5. Table5.Studiesconcerningcocarcinogenicityofmethotrexate Species MTX regimen Carcinogen regimen Conclusion Ref. Syrian hamsters WhiteSwiss mice Syrian hamsters Syrian golden hamsters C3Hf/HeN mice 0.06mg,3timesperweek, 8to12weeksintotal 0.2mg/kgindiet 0.15mgsubcutaneous,1 timeperweek,18~26 weeksintotal 0.1mgTOP3timesper weektobuccalpouchfor 6~12weeks 2mg/kgintraperitoneal,3 timesperweek,23weeksin total 0.5%DMBATOPtobuccalpouch,3 timesperweek,8to12weeksintatal 0.5%methylcholanthrene(MC)TOP for11weekstoshaveddermis 0.5DMBATOPtotongue3times weeklyfor18~26weeks 0.5%DMBATOP3timesperweekto buccalpouch ComparedwiththegroupreceivingDMBA alone,mtxtogetherwithdmbaaccelerated tumorgrowth,andthetumorsoccurredearlier andweremoreanaplastic. ComparedwiththegroupreceivingMCalone, MTXtogetherwithMCresultedinincreased tumorrateanddecreasedtumorlatency. Nococarcinogeniceffects Nococarcinogeniceffects OHSAH UVlight,3timesperweek Nococarcinogeniceffects [54] V) Cytogenetic Toxicity Methotrexatewasreportedasaweakclastogenanditinducedchromosomalaberrationsinbonemarrowofmiceafter multipletreatments[62].methotrexatecouldinducechromosomalaberrationsinmicebonemarrow,anditwasfound highlyclastogenicinmicebonemarrowevenafteralowdosesingletreatment[75].otherstudiesshowedits clastogenicityinhumanbonemarrowofmethotrexatetreatedpatients[63,64],butitwasnonclastogenicinhuman lymphocytesinvivo[64].inaddition,aprogressiveaccumulationofstrandbreaksinpostreplicationdnaarisingoutof spontaneousandnormallyrepaireddnalesionsthathadnotbeenrepairedduetoshortageofdttpandpurine nucleotidesaftermethotrexatetreatmenthasbeenreported[76]. [59] [76] [35] [36] [52] [53] 10

12 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH VI) Teratogenicity, Reproductive and Developmental Effects Methotrexateachievesitsantineoplasticandantiinflammatoryeffectsthroughinhibitionofdihydrofolatereductases; thisactioninterruptsthesynthesisofthymidylate,purinenucleotides,andtheaminoacidsserineandmethionine, therebyinterferingwiththeformationofdna,rnaandproteins[68].thusmethotrexatehaspotentialreproductive effectsduringpregnancy[67]. Mostofthereportedcasesofpregnantwomenexposedtomethotrexatehavedocumentednormalpregnancy outcomes[70,71].however,ofthe48reportedcasesofmethotrexateexposure,threehavedocumentedfatal deformities[7274].allthreeexposureswereinthefirsttrimester,whentheriskforanomaliesresultingfromexposure tofolateantagonistsisassumedtobehighest.methotrexateexertscytotoxicitytotrophoblastsandhasthepotentialof inducingearlyabortion[66].anecdotalreportsofpatientstreatedwithmethotrexateforarthritishaveimplicated methotrexateaseitherateratogenoranabortifacient[69]. Consequently,basedonthosecasereports,methotrexateisahumanteratogenaccordingtoIARCevaluation[65].US FoodandDrugAdministration(FDA)hasplacedmethotrexateinriskcategoryD(thereispositiveevidenceofhuman fetalrisk,butthebenefitsfromuseinpregnantwomenmaybeacceptabledespitetherisk)basedonthefactthatitmay causeneuraldefectswhenusedinthefirsttrimester[67]. 11

13 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY Part 4Regulations I) Exposure Limit Currently,thereisnooccupationalexposurelimitestablishedformethotrexateinCanadaoranyotherinternational bodies. II) Hazard Classification Hazardclassificationofmethotrexatewassummarizedintable6below. Table6.Hazardclassificationofmethotrexate System/Jurisdiction Classification/Note Ref. NDSL(NondomesticSubstancesList).TheNDSLisaninventoryofsubstancesthatarenot HealthCanadaDomestic onthedslbutareacceptedasbeinginuseinternationally.substancesthatarenotonthe SubstancesList(DSL) DSLbutarelistedontheNDSLaresubjecttotheNewSubstancesNotificationsRegulations [77] (ChemicalsandPolymers)oftheCanadianEnvironmentalProtectionAct,1999. IARC Methotrexateisnotclassifiableastoitscarcinogenicitytohumans(Group3) [65] IARC Methotrexateisahumanteratogen [65] USFDA RiskcategoryD(thereispositiveevidenceofhumanfetalrisk,butthebenefitsfromusein pregnantwomenmaybeacceptabledespitetherisk) [67] USNIOSH RegistryofToxicEffects(RTECS)IdentificationNumber:MA [78] OHSAH 12

14 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY Part 5 Control Measures Sincenogovernmentalregulatoryagencieshaveestablishedanexposurelimitformethotrexate,controlmethods shouldeliminateorreducepotentialexposureasmuchaspossible. I) Substitution Substitutioninvolvesusingalesshazardoussubstanceorasubstanceinalesshazardousform.AustralianWorkSafe Vctoria[49]recommendsthatsubstitutioncanbeachievedfromthefollowingaspects: Purchase single-dose preparations Purchase cytotoxic drugs in liquid form rather than in powder form Use a more dilute form of cytotoxic drug where possible Incorporate handling techniques that minimize aerosol generation Purchase drugs in vials, not ampoules Purchase drugs in plastic vials, or vials reinforced with plastic casings. II) Engineering Controls Handlingtechniquesandequipment Equipmentusedforpreparingdrugsshouldreducethepotentialofgeneratinghighpressureorreleaseofcytotoxic drugs[79].engineeringcontrolmethodsforhandlingcytotoxicdrugsinclude[79]: Use of Luer-lock syringes and fittings to keep connections together Use of Luer-slip syringes (only if Luer-lock connections are incompatible) such as intrathecal needles Use of syringe-to-syringe connectors when transferring solutions from one syringe to another Use of wide bore needles to reconstitute and draw-up cytotoxic drugs Use of filter needles only when the cytotoxic drug has been removed from a glass ampoule, or if particulate matter is visible, for example if coring of a vial rubber has occurred Use of air-venting devices to equalize pressures and to prevent the passage of powder, aerosols and liquids PharmaceuticalIsolators Isolationisonewaytoreducetheriskofexposure,asitinvolvesseparatingpeoplefromthesubstancebybarriersto preventorreducecontact[49].theuseofapharmaceuticalisolatorwasdevelopedoutofthreemainconsiderations [80]:(i)Ithastoprovideaphysicalbarrierandapermanentlyclosedworkingenvironment,whichpreventdirectskin OHSAH 13

15 14 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH contactbetweenhandlersandtoxicproducts.(ii)theairisreleasedthroughanairexhaustsystemoutsidethe preparationroomdirectlyintotheatmosphere,whichavoidsinhalationrisksofthecytotoxicdrugs.(iii)ithastoprotect thepharmaceuticalproductfrommicrobiologicalcontaminationduringdrugreconstitution. Bothpositiveandnegativepressureisolatorscanbeusedtoachievetheabovefunction.Theisolatorsareenclosed systemsthatrelyonasteadyflowoffilteredairduringuse.aslightpressuredifferentialisplacedontheisolator(either positiveornegative),andairenteringandleavingtheisolatorunderbothpressureconditions,willgothroughthehigh efficiencyparticulateair(hepa)filters[81].however,incaseofaleakintheisolator,thepositivepressuresystemwill allowairthatmaybecontaminatedwithcytotoxicdrugtoentertheworkplace;whileanegativepressuresystemwilllet airwhichcontainsbacterialentertheisolatorandcontaminatethepreparation.onestudybyukhsefocusedon comparingtheeffectivenessofpositiveandnegativepressureisolatorsintwopharmacyunits;nosignificantdifference wasfoundintheoperators exposurelevels[82].inaddition,theexposurelevelandmeasuredabsorptionwere significantlylowerthanpreviousstudiesdoneinhealthcareworkenvironments,withoutisolationsystems,which suggestthatacorrectlydesignedisolatorcanreducetherisktotheoperator;regardlessifthepressuredifferenceis positiveornegative. Verticallaminarflowhood Horizontallaminarflowworkbenches,whicharecommonlyusedinordinarypharmaceuticaldepartment,arenot recommendedforpreparingcytotoxicdrugs.thereasonisthatwhilethistypeofunitprovidesproductprotection,it mayexposetheoperatorandtheotherroomoccupantstoaerosolsgeneratedduringdrugpreparationprocedures[83]. Therefore,averticallaminarflowbiologicalsafetycabinetthatprovidesbothproductandoperatorprotectionisneeded forthepreparationofcytotoxicdrugs.thisisaccomplishedbyfiltrationoftheincomingandexhaustairthroughahepa filter.itshouldbenotedthatthefiltersarenoteffectiveforvolatilematerialsbecausetheydonotcapturevaporsand gases.onestudyfoundthattheurineburdeninoncologicnursesdecreasedafteracentralpharmacyunitwithlaminar airflowswithoutsideairexhaustwasinstalled[88]. Personnelshouldbefamiliarwiththecapabilities,limitationsandproperutilizationofthebiologicalsafetycabinet selected[83]. III) Administrative controls Training Employersshouldensurethatonlyemployeeswhohavereceivedappropriatetraining,andhaveobtainedtherequired levelofproficiencyareperformingtasksinvolvingtheuseofmethotrexate.trainingshouldoccuronanongoingbasis, witharevieweverytwoyearsorwhennewequipmentisintroducedorprocedureschange[79].

16 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH Thetrainingshouldincludethefollowingelements: Occupational hazards of exposure to cytotoxic drugs and waste Legislative requirements for health and safety Legislative requirements for waste management The risk management process Control measures and work practices to be adopted when handling cytotoxic drugs and waste Maintenance of equipment Correct selection, use, cleaning and disposal of personal protective equipment Procedures to be adopted in the event of an accident, injury or spill Access to first aid resources Storage, transport, treatment and disposal of cytotoxic waste Spillmanagement Onestudyindicatesthatcommonlyusedcleaningagents,suchasCaviCide,Phenokil,chlorohexidineandbleach, cannotcompletelyeliminatecytotoxicdrugcontaminatedsurfaces,evencombinedwithorganicsolventsordeionized water[84].thus,extraprecautionstopreventspillsofcytotoxicdrugsareneeded. Ifspillsofcytotoxicdrugsandrelatedwastesoccur,theymustbedealtwithimmediatelyastheypresentahighriskof exposure.peopleintheimmediatevicinityofaspillshouldbealertedimmediatelyandtoldtostayclear[85].ancillary workersshouldassistonlyinthecontainmentofaspill,whilealertingtrainedpersonnel[85]. OtherAdministrativeControls Otheradministrativecontrolmeasuresinclude: Allocate responsibilities for health and safety Reduce the number of employees who work with cytotoxic drugs Keep containers of cytotoxic drugs secure and tightly lidded when not in use Prohibit eating, drinking and smoking in work areas Develop and implement standard operating procedures for all work activities Provide appropriate information, education and training to employees Use cytotoxic signs and labels to clearly identify all cytotoxic drugs from other waste Develop emergency procedures to deal with spills 15

17 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY IV) Personal Protective Equipment SpecificinformationonPPEtoprotectworkersfromcytotoxicdrugexposureisavailableunderSection6ofWorkSafeBC OHSRegulation.Accordingtosection6.55,apersonalprotectiveequipmentprogramshouldincludethefollowing elements[86]: Medicalglovesthataremanufacturedanddesignedforusewhenhandlingcytotoxicdrugs Amoistureresistant,longsleevedgownwithcuffs Ifthereisariskofcontactwithaerosols,anapprovedrespirator Ifthereisariskofeyecontact,eyeandfaceprotection Usedgownsandglovesmustnotbewornoutsidethepreparation,administrationorstorageareaand umustbehandledashazardouswasteorcontaminatedlinen. WCBSaskatchewanhasthefollowingrequirementsconcerningtheuseofrespirators,gloves,protectivegownandeye protection[87]: Approved respiratory protective devices include a reusable facemask with filter cartridges, or a disposable filter mask. The filter cartridges or the filter mask must provide HEPA filtration and carry NIOSH label with either N100, P100, or R100 rating. These respirators are available from most safety equipment suppliers. Surgical masks are neither suitable nor adequate to protect the worker. Thicker gloves provide better protection, as cytotoxic drugs can permeate most glove materials including latex. Non-powdered gloves are preferred because powders adsorb the drugs. Powdered latex gloves also adsorb latex proteins. Workers who use powdered latex gloves are exposed to more of the latex proteins that cause latex allergy in some persons. Workers who have developed an allergy to latex proteins must be provided with vinyl or nitrile gloves or glove liners. A gown made of low permeability fabric with a closed front, long sleeves, and closed cuffs is recommended. Eye protection, such as splash goggles, should be made available for use in any situation where there is a risk of splashes into the eyes. Eye protection should also be used when cleaning up spills. OHSAH 16

18 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY References [1]SessinkPJM,FriemelNSS,AnzionRBM,BosRP(1994).Biologicalandenvironmentalmonitoringofoccupational exposureofpharmaceuticalplantworkerstomethotrexate.intarchoccupenvironhealth65: [2]BlackDJ,LivingstonRB(1990).Antineoplasticdrugsin1990.Areview(partI)Drugs39: [3] ChenML,ChiouWL(1981).Sensitiveandrapidhighperformanceliquidchromatographicmethodforthe simultaneousdeterminationofmethotrexateanditsmetabolitesinplasma,salivaandurine.jchromatogr 226: [4]FurstDE,KremerJM(1988)Methotrexateinrheumatoidarthritis.ArthritisRheum31: [5]MullarkeyMF,BlumensteinBA,AndradeWP,BaileyGA,OlasonI,WetzelCE(1988).Methotrexateinthetreatment ofcorticosteroiddependentasthma:adoubleblindcrossoverstudy.nengljmed318: [6]Druginformationonline(2009).MethotrexateSideEffects.Retrievedfrom th,2009 [7]AmericanCancerSociety.Methotrexate.Retrievedfrom th,2009. [8]AustralianRheumatologyAssociation(2008).PatientInformationonMethotrexate.Retrievedfrom th,2009. [9]NIOSH(2004).ALERT:PreventingOccupationalExposurestoAntineoplasticandOtherHazardousDrugsinHealth CareSettings.Retrievedfromhttp:// th,2009. [10]BeauchampH(1997).HealthEffectsofOccupationalExposuretoAntineoplasticDrugs:AnIntegrativeResearch Review.Retrievedfromhttp:// th,2009. [11]ShobabL,WardH,TeschkeK,RatnerPA,ChungJ,ChowY(2005).Aretrospectivecohortstudyofcancerrisks amongnursesinbritishcolumbia:potentialexposuretoantineoplasticdrugs.reporttotheresearchsecretariatofthe Worker scompensationboardofbritishcolumbia. [12]FransmanW,VermeulenR,KromhoutH(2004).OccupationaldermalexposuretocyclophosphamideinDutch hospitals:apilotstudy.annoccuphyg48(3): [13]DorrRT(1983).Practicaltechniquesforpreparationandadministrationofcytotoxicagents.PresentedatPractical ApproachestoSafeHandlingofAnticancerProducts,Mayaguez,PuertoRico,Nov.25. OHSAH 17

19 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH [14]ShahsavaraniS,GodefroidRJ,HarrisonBR(1993).Evaluationofoccupationalexposuretotablettriturationdust [Abstract].Presentedatthe28thAnnualASHPMidyearClinicalMeeting,Atlanta,GA,December28. [15]HarrisonBR,SchultzCD(2000).Determinationoftablettriturationdustinworkzoneair.JOncolPharmPract 6(1):23. [16]McDevittJJ,LeesPSJ,McDiarmidMA[1993].Exposureofhospitalpharmacistsandnursestoantineoplasticagents.J OccupMed35(1):5760. [17]SessinkPJM,VanderKerkhofMCA,AnzionRBM,NoordhoekJ,BosRP(1994).Environmentalcontaminationand assessmentofexposuretoantineoplasticagentsbydeterminationofcyclophosphamideinurineofexposedpharmacy technicians:isskinabsorptionanimportantexposureroute?archenvironhealth49(3): [18]ConnorTH,AndersonRW,SessinkPJ,SpiveySM(2002).Effectivenessofaclosedsystemdeviceincontaining surfacecontaminationwithcyclophosphamideandifosfamideinani.v.admixturearea.amjhealthsystpharm 59:6872. [19]SchmausG,SchierlR,FunckS(2002).Monitoringsurfacecontaminationbyantineoplasticdrugsusinggas chromatography/massspectrometryandvoltammetry.amjhealthsystpharm59: [20]WhiteSK,StephensAD,DowjatB,SugarbakerPH(1996).Safetyconstiderationsintheuseofintraoperative intraperitonealchemotherapy.cancertreatres82: [21]StuartOA,StephensAD,WelchL,SugerbakerPH(2002).Safetymonitoringofthecoliseumtechniqueforheated intraoperativeintraperitonealchemotherapywithmitomycinc.annsurgoncol9(2): [22]CassY,MusgraveCF(1992).Guidelinesforthesafehandlingofexcretacontaminatedbycytotoxicagents.AmJ HospPharm49(8): [23]KromhoutH,HoekF,UitterhoeveR,HuijbersR,OvermarsRF,AnzionR,VermeulenR(2000).Postulatingadermal pathwayforexposuretoantineoplasticdrugsamonghospitalworkers.applyingaconceptualmodeltotheresultsof threeworkplacesurveys.annoccuphyg44(7): [24]DuvallE,BaumannB(1980).Anunusualaccidentduringtheadministrationofchemotherapy.CancerNurs 3(4): [25]SchreiberC,RadonK,PethranA,SchierlR,HauffK,GrimmCH,BoosKS,NowakD.(2003).Uptakeofantineoplastic agentsinpharmacypersonnel.part2:studyofworkrelatedriskfactors.intarchoccupenvironhealth76:1116. [26]SessinkPJM,AnzionRB,VandenBroekPHH,BosRP(1992).Detectionofcontaminationwithantineoplasticagents inahospitalpharmacydepartment.pharmaceutischweekbladscientificedition14(1):1622. [27]CrausteMancietS,SessinkPJM,FerrariS,JomierJY,BrossardD(2005)Environmentalcontaminationwithcytotoxic drugsinhealthcareusingpositiveairpressureisolators.annoccphyg49(7):

20 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH [28]SessinkPJM,FriemelNSS,AnzionRBM,BosRP(1994).Biologicalandenvironmentalmonitoringofoccupational exposureofpharmaceuticalplantworkerstomethotrexate.intarchoccupenvironhealth65: [29]MaderRM,RizovskiB,StegerGG,WachterA,KotzR,RainerH(1996).Exposureofoncologicnursestomethotrexate inthetreatmentofosteosarcoma.archenvironhealth51(4): [30]SessinkPJM,BoerKA,ScheefhalsAPH,AnzionRNM,BosRP(1992).Occupationalexposuretoantineoplasticagents atseveraldepartmentinahospital.environmentalcontaminationandexcretionofcyclophosphamideandifosfamidein urineofexposedworkers.intarchoccupenvironhealth64: [31]ZieglerE,MasonHJ,Baxter(2002).OccupationalexposuretocytotoxicdrugsintwoUKoncologywards.Occup EnvironMed59: [32]SabatiniL,BarbieriA,TosiM,ViolanteFS(2005).Anewhighperformanceliquidchromatographic/Electrospray ionizationtandemmassspectrometricmethodforthesimultaneousdeterminationofcyclophosphamide,methotrexate and5fluorouracilasmarkersofsurfacecontaminationforoccupationalexposuremonitoring.jmassspectrum 40: [33]FloridiaL,PietropaoloAM,TavazzaniM,RubinoFM,ColombiA(1999).Highperformanceliquidchromatographyof methotrexateforenvironmentalmonitoringofsurfacecontaminationinhospitaldepartmentandassessmentof occupationalexposure.jchromatb726: [34]HallC,ThamP,ManandharM,ChengM,NobleJF,IatropoulosM(1988).Methotrexate:Assessmentofinvivo clastogenicityandcarcinogenicity.toxicolpathol16(1):1021. [35]ShklarG,CataldoE,FitzgeraldL(1966).Theeffectofmethotrexateonchemicalcarcinogenesisofhamsterbuccal pouch.cancerresearch26: [36]BarichLL,SchwartzJ,BarichD(1962).Oralmethotrexateinmice:Acocarcinogenicaswellasanantitumoragentto methylcholanthreneinducedcutaneoustumors.jinvestdermatol39: [37]KimberlyMD,WestSG,McdermottMT,HufferWE(1994).Theeffectoflowdosemethotrexateonbone metabolismandhistomorphometryinrats.arthritis&rheumatism37(2): [38]NesbitM,KrivitW,HeynR,SharpH(1976).AcuteandchroniceffectsofMethotrexateonhepatic,pulmonary,and skeletalsystems.cancer37: [39]AtkinsonSA,FraherL,GundbergCM,AndrewM,PaiM,BarrRD(1989).Mineralhomeostatisandbonemassin childrentreatedforacutelymphoblasticleukemia.jpediatr114: [40]StanisavljevicS,BabcockAL(1977).Fracturesinchildrentreatedwithmethotrexateforleukemia.ClinOrthop 125:

21 20 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH [41]GnudiS,ButturiniL,RipamontiC,AvellaM,BacciG(1988).Theeffectsofmethotrexateonbone.Adenstometric studyconductedon59patientswithmethotrexateadministeredatdifferentdoses.italjorthoptraumatol 14: [42]FriedlaenderGE,TrossRB,DoganisAC,KirkwoodJM,BaronR(1984).Effectsofchemotherapeuticagentsonbone. JBJS66A: [43]WheelerDL,GriendRAV,WronskiTJ,MillerGJ,KeithEE,GravesJE(1995).Theshortandlongtermeffectsof methotrexateontheratskeleton.bone16(2): [44]O RourkeRA,EckertGE(1964).Methotrexateinducedhepaticinjuryinanadult.ArchInternMed113: [45]PopperHP,RubinE,GardiolD,SchaffnerF,ParonettoF(1965).Druginducedliverdisease.ArchInternMed 115: [46]BerlinNI,RallD,MeadJAR,FreireichEJ,VanScottE,HertzR,LipsettMB(1963).Folicacidantagonists Effectson thecellandthepatient.anninternmed59: [47]HershEM,WongVG,HendersonES,FreireichEJ(1965).Hepatotoxiceffectsofmethotrexate.Cancer19(4): [48]NairMG,BaughCM(1973).Synthesisandbiologicalevaluationofpolygammaglutamylderivativesof methotrexate.biochemistry12: [49]KremerJM,GalivanJ,StreckfussA(1986).Methotrexatemetabolismanalysisinbloodandliverofrheumatoid arthritispatients.associationwithhepaticfolatedeficiencyandformationofpolyglutamates.arthritisrheum29: [50]AithalGP,HaugkB,DasS,CardT,BurtAD,RecordCO(2004).Monitoringmethotrexateinducedhepaticfibrosisin patientswithpsoriansis:areserialliverbiopsiesjustified?alimentpharmacolther19: [51]WollinaU,StanderK,BertaU(2001).Toxicityofmethotrexatetreatmentinpsoriasisandpsoriaticarthritisshort andlongtermtoxicityin104patients.clinrheumatol20: [52]MarefatP,SchmidW(1976).Theeffectsofmethotrexateonchemicalcarcinogenesisofhamstertongue.JDentRes 58:1748. [53]LevijIS,RwomushanaJW,PolliakA(1970).Effectoftopicalcyclophosphamide,methotrexate,andvinblastineon 9,10dimethyl1,2benzanthracene(DMBA)carcinogenesisinthehamstercheekpouch.EurJCancer6: [54]DaynesRA,HarrisCC,ConnorRJ,andElchwaldEJ(1979).Skincancerdevelopmentinmiceexposedchronicallyto immunosuppressiveagents.jnatlcancerinst62: [55]RustiaM,ShubikP(1973).Lifespancarcinogenicitytestswith4aminoN 10 methypteroylglutamicacid (methotrexate)inswissmiceandsyriangoldenhamsters.toxicolapplpharmacol26:

22 21 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH [56]WeisburgerEK(1977).Bioassayprogramforcarcinogenichazardsofcancerchemotherapeuticagents.Cancer 40: [57]SternRS,LairdN(1994).Thecarcinogenicriskoftreatmentsforseverepsoriasis.Cancer73: [58]CraigSR,RosenberEW(1971).Methotrexateinducedcarcinoma?ArchDerm103: [59]TrenkwalderP,EisenlohrH,PrechtelK(1992).Threecasesofmalignantneoplasm,pneumonitisandpancytopenia duringtreatmentwithlowdosemethotrexate.clininvest70: [60]BailinPL,TindallJP,RoenigkHH(1975).Ismethotrexatetherapyforpsoriasiscarcinogenic?Amodified retrospectiveprospectiveanalysis.jama232: [61]SternRS,ZierlerS,ParrishJA(1982).Methotrexateusedforpsoriasisandtheriskofnoncutaneousorcutaneous malignancy.cancer50: [62] KasaharaY,NakaiY,MiuraD,YagiK,HirabayshiK,MakitaT(1992).Mechanismofinductionofmicronucleiand chromosomeaberrationsinmousebonemarrowbymultipletreatmentsofmethotrexate.mutatres280: [63] KroghJM(1967).Chromosomestudiesinpatientstreatedwithazathioprineandamethopterin.ActaMedScand 182: [64]KroghJM,NyforsA(1979).Cytogeneticeffectofmethotrexateonhumancellsinvivo.Comparisonbetweenresults obtainedbychromosomestudiesonbonemarrowcellsandbloodlymphocytesandbythemicronucleustest.mutatres 64: [65]InternationalAgencyforResearchonCancer(1981).IARCmonographsontheevaluationofthecarcinogenicriskto humans,vol26.someantineoplasticandimmunosuppressiveagents.lyon,france. [66]WiebeER(1996)Abortioninducedwithmethotrexateandmisoprostol:Acomparisonofvariousprotocols. Contraception.55: [67]NguyenC,DuhlAJ,EscallonCS,BlakemoreKJ(2002).Multipleanomaliesinafetusexposedtolowdose methotrexateinthefirsttrimester.obstetgynecol99: [68]KatzungBG(1995).Basicandclinicalpharmacology.AppletonandLangepp [69]KozlowskiRD,SteinbrunnerJV,MacKenzieAH,CloughJD,WilkeWS,SegalAM(1990).Outcomeoffirsttrimester exposuretolowdosemethotrexateineightpatientswithrheumaticdisease.amjmed88: [70]WarkanyJ,BeaudryP,HorseinS(1959).Attemptedabortionwithaminopterin.AmJDisChild97:

23 ICA [71]DaraP,SlaterL,ArmentroutS(1981).Successfulpregnancyduringchemotherapyforacuteleukemia.Cancer 47: [72]MilunskyA,GraefJW,GaynorMF(1968).Methotrexateinducedcongenitalmalformations.JPediatr72: [73]PowellHR,EkertH(1971).Methotrexateinducedcongenitalmalformations.MedJAust2: [74]DinizEM,CorradiniHB,RamasJL,BrockR(1978).Effectonthefetusofmethotrexateadministeredtothemother: Presentationofacase.RevHospClinFacSaoPaulo33: [75]ChoudhuryRC,GhoshSK,PaloAK(2000).Cytogenetictoxicityofmethotrexateinmousebonemarrow.Environ Toxicol&Pharmacol8: [76]LiJ,KaminskasE(1984).AccumulationofDNAstandbreaksandmethotrexatecytotoxicity.ProcNatlAcadSciUSA 81: [77]HealthCanada(2009).InCommerceListofFoodandDrugsActSubstances.Retrievedfrom nd,2009. [78]USNIOSH(2009).RegistryofToxicEffects(RTECS)Identification.Retrievedfrom nd,2009. [79]AustralianWorkSafeVictoria(2003)Handlingcytotoxicdrugsintheworkplace.Retrievedfrom [80]MancietSC,SessinkPJM,FerrariS,JomierJY,BrossardD(2005)Environmentalcontaminationwithcytotoxicdrugs inhealthcareusingpositiveairpressureisolators.b.occhygsoc7: [81]U.K.HSE.HandlingcytotoxicdrugsinisolatorsinNHSpharmacies.Retrievedfrom ponjuly8 th,2009. [82]MasonHCytotoxicdrugexposureintwopharmaciesusingpositiveornegativepressurizedenclosuresforthe formulationofcytotoxicdrugsreportno.hef/01/01,hslsheffield [83]U.S.OfficeofResearchServices,DivisionofOccupationalHealthandSafety.Recommendationsforthesafeuseof handlingofcytotoxicdrugs.retrievedfrom th, [84]WorkSafeBC(2008).ReducingCytotoxicDrugExposureinHealthcare:DeterminantsInfluencingCleaning Effectiveness(reportno.RS2006DG03).Retrievedfrom th,2009. TOXICOLOG LPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY OHSAH 22

24 TOXICOLOGICALPROFILEOFMETHOTREXATEINTHEHEALTHCAREINDUSTRY [85]AustralianWorkCoverNewSouthWales(2008)Cytotoxicdrugsandrelatedwasteriskmanagement.Retrievedfrom July9 th,2009. [86]WorkSafeBC.OHSRegulation.Part6Substancespecificrequirement.Retrievedfrom th,2009. [87]WCBSaskatchewan(1999)Cytotoxicdrugs.Retrievedfrom th,2009. [88]MaderRM,RizovskiB,StegerG,WachterA,KotzR,RainerH(1996).Exposureofoncologicnursestomethotrexate inthetreatmentofosteosarcoma.archenvironhealth51(4): OHSAH 23