Document kReoZgZ1wOwEyMqd0RrvakdO

WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC MONOGRAPHS ON THE EVALUATION OF THE CARCINOGENIC RISK OF CHEMICALS TO HUMANS Chemicals, Industrial Processes and Industries Associated with Cancer in Humans IARC Monographs, Volumes 1 to 29 SUPPLEMENT 4 Report of in IARC ad hoc Working Oroup which met in Lyon, S-12 February 1982 to ndviee the Director, IARC, on chemicale, industrial procestee and industries that are carcinogenic for humans October 1982 INTERNATIONAL AGENCY FOR RESEARCH ON CANCER HONS 027570 METHODS Th* data on each chemical war* reviewed In detail Mon th* meeting by Mtocttf member* ot th* group: th* animal atudiaa and ahort-tarm teal raautta wan avaluiiaa by experiment*Kata and tha human itudn by an apidamiotoglat. taring lha meeting ot me Working Oroup that* aaaaaamamt wan debated and adoptad. and ovaral avakwtioni o) cardnogaWclty tor humana wara mad* on tha baala ot tha oombinad avtdanoa tram human* and experimental ayatama [Tabt* 1). Bttaf daaortptton* ot th* data on wtxdt th* aaaaaamanu and avaluatlon* wara baaad ar* gtvan In lha aaetlon on Raautt*. togathar with ralaranoa* to th* Monograph! volume* In which thay war* avaluatad prtvloutty and. whan apptcabl*. to papara pubtlahad aubaequantly. Aaaaaamant ot avldanca tor eartlnoganklty Pom atudiaa In Humana Evidence ot eardnogenldty Pom human atudiaa ooma* from (hr** main aouroaa: 1. Caa* raport* ot mdiyldual cancar pattanta who wat* expoaed to th* chamicai or prooaaa. 2. Daaoriptlv* epW*mlologlc*l atudla* In which th* Inddeno* ot oanoar In human population* wa* found to vary In apao* or bm* with axpoaur* to th* agant*. 3. Analytical *p*d*mlologtc*l (caaeoontroi and oohort) atudiaa in wNch individual axpoaur* to th* chamicai or group ot chamicai* wa* found to b* aaaodated with an tncraaaad Halt ot oanoar. Thro* criteria mutt bt mat batora a cauaal aaaodatlon can ba Intarrad batwaan axpoaur* and oanoar h humana: t. Than l| no idantlflad blaa which oould explain lha taaooiatlon. 2. Th* poaatbdty ot oontoundlng hat baan conaldarad and njlad cut a* explaining m* aaaodatlon. 3. tha aaaoeiatlon It undtaty to ba dua to chanoa. in ganaral. although a alngit atudy may b* Mfoatva ot t oauta-ahact raiattorwhip, oontldanc* In Interring a oauaal aaaodatlon la tncraaaad whan aavaral ardapandant atudMa ar* ooncordant In ahowlng lha aaaodatlon. whan tw aaaodatlon It Itrong, whan thar* It a doaeraaportae ralatlonanip. or whan a reduction In axpoaur* la fodowad by a raductlon In thalnddancaot oanoar. Th* degree* of avtdanoa for oardnoganldty Pom ttudtot In Manana wart catagortnd L Sufficient avtdanoa ot oardnoganidty. which mdfoawa that thar* it a oauaal ralattonehlp between th* agent and human oanoar. I Untied avtdanoa ot eardnogenlolty. which indfoaw* that a oauaal Interpretation la entdfol*, but that attemativ* axplanadcna, auch at chanoa, Mat or ooMoundng, could wrt ttfffpftWy frf tKPftftftfl. I. awdaguafo avtdanoa, which Indcaw mat on* ot tore* condition* pravadad: (a) twra wart law parpnant data; (b| lha avalablt atudfoa, wNfo ahowlng tvldanea of aaaodatlon, dto not exclude ohano*. Mu or oordoundtog; (c) ttudfo* war* avaaaMt whloh do not ehow avldanoa ot carcinogenicity. HONS 027571 12 IARC MONOGRAPHS SUPPLEMENT 4 Atttttmtnt of tvhtnct hr eere/nogsrUeffy from studies In mptrlmtnhl tnlmtli These assessments iri classified Into lour groups: I. Sutn&tnt tvxhnot ol carcinogenicity, which Indlcales that there * an Sweated Incidenoe of malignant tumours: () to multiple species or strains: or (b) m muttlpH experiments (prslerably with dlfforont routes Ol administration or Utlng different Oom levels); or (c| to n unusual dogro* with regard to meldonoo. tit* or typo of tumour, or go t onset. Addltlonil evidence mty M providod by data on dose-rnponn oflocta. wo* at Information from short-term ttata or on chemical structure. M. Umlhd evidence of carcinogenicity, which means that the data suggest s carcinoge nic effect but are limited because: (a) the studies Involve s single species, atrsm, or experiment; or (b) the experiments are restricted by Inadequate dosage levels, Inadequate duration ot exposure to the agent. Inadequate period of follow-up. poor survival, too few animals, or Inadequate reporting; or (c) the neoplasms produced often occur sponta. neously and. m the past, have been difficult to classify as malignant by histological criteria atone (e.g., lung and aver tumours in mloa). i. Inadequate evidence, which indicates that because of ma|or qualitative or quantita tive limitations, the studies cannot be Interpreted as showing either the presenos or absenoe ol a carcinogenic sheet; or that within the limits of the tests used, the chemical Is not carcinogenic. The number of negative studies is small, sinoe. In general, studies that show no effect are less likely to be published than those suggesting eardnogenidty. tv. No data indicates that data were not available to the Working group. The categories tufUchnt evidence and Ported evfdenoe refer only to the strength of the experimental evtdenoe that these chemicals are carcinogenic end not to the extent of their carcinogenic activity nor to the mechanism Involved. The dasslftcetlon of any ohemlcai may change as new information beoomes available. assessment of data Prom short-term Nats Because of the large number and wide variety of short-term teats that may be relevant for the protection of potential carcinogens, the data relative to each oonyound have been summarized in the form of tables. These Indicate both the type of teat used and the btotogtoal complexity of the tost system. DNA gtmtgtr Includes evtdenoe for covalent binding to DNA, induction of DNA breakage or repair, Induction of prophage In bacteria, and a positive response In testa of comparative survival In DNA repalr-proftolenl and DNA repeir-detlcfent bacteria. 'Uuhgtnlell/ refers to Induction of mutations In cultured oela or in organieme (eg, heritable alterations in phenotype. Including forward or reverse point mutatlonai rooomblnatlon. gene oonvaretohi and spocfflo-locus mutation). 'CTvvfflotomaf tnomtttf refers to the Induction of chromosomal aberratlone. toduding breaks, gape, rearrangements and mtorenudei, slater chromatid exchange and aneupiotdy. Other' refers so various additional endpoints, including oea transformation (T), i.e., morphologi cal transformation and colony formation In agar: dominant lethal (DL) teats; morphologL oal abnormeWee In sperm (SA); and mltoohendrial mutation (Mt). The biological systems Include: 'Prokaryote*', i.e.. bacteria, In me presence or absenoe of an exogenous metaboac activation system, and oalutar systems; 'Fungi and preen plant*: 'insects', usuaSy DtotophOt miltnoguhr, 'kfammasan ee*s (In vttroy;,either rodent or human somatic oels or cat inee In outturn; `Mammals (In vivo)', atudtoe In which the test oompound wee edmMatsred to Intaet experimental anlmeli; and 'Humana (to vivoy, etudtoe of cabs horn groups ot IndMduats drawn from a population exposed to the aubetanoe to question. MQNS 027572 methods u In thesa tabes, * WWlti that the result was judgsd by tht Working Group to b* dgnMoontly positlvt In ono or mor imyi; v Indicates that II u judgio to pt negative from on ovtluotton of ono or moro assays; and f Irvkcatts mot oonirodictory results won obtained In assays from dtftoronl laborolonoo or In dlfftrtnt bfotogtool aytiamo or tool (ho rotult woo ludged (o bo equivocal. Tho Individual tables tor ooch oonioundsr# eummerlsed, for purpoooo of oomporfton. In Appendix 3. Tho overall ovidonoo summarised In tho table wot ad|udgod to fal Into ono of Woo categories luMdtni, smrred and inadequate. l. Svflfoienf avtoanoa, whan there won at least throe positive results in at least two of throe teat systems measuring DNA damage, mutagenicity or chromosomal effects. When two ot the positive results were tor the same genetic effect, they had to be domed bom systems of different biological complexity. H. Urn/fed evfdenos, when there wars at least two positive results, either tor different endpoints or In systems representing two levels of biological complexity. HI. fnadeguafe evidence, when there were generally negative or only one positive lest results. Up to two positive test results were considered Inadequate If they were eocompenied by two ot mors negetive test results. The Working Group was unable to define criteria for'negative' evidence In establishing these categories the Working Group gave greeter weight to the three primary endpoints DNA damage, mutagenicity and chromosomal effects and Judge ments were made on the quality as well as on the quantity ot the evidence In a minority of Maes, strict Interpretation of these criteria was tempered by oonsiderstton of a variety ot other lectors (such as the purity ot the lest oompound. problems of metabolic activation, appropriateness ot the test system) which, in the judgement of the Working Group, would plaoe e oompound In e category above or below that Indtoaled by the summary table. grtlutUen of eerefnegento ritk to humtnt At present, no objective oritaria exist to Interpret data from studae In experimental animals or from short-term testa directly In terms of human risk. Thus, In the ebeenoe of sufWent evidence from human studies, evaluation of the carcinogenic risk to humana was based on consideration of both the epidemiological and experimental evidence. The breadth of the categories of evidence defined above allows substantial variation within each. The decisions reached by the Group regarding overas risk Incorporated these differences, even though they ooutd not always be redacted adequately In the placement of an exposure Into e petPculer category, et Bated In Table t. The chemicals, groups of ohemicelt. Induetrial prooetsee or oocupabonai axpoeures wore thus put Info one of three groups: Group 1 The oriemtoer. group of onemfoa*. hOuttritl process or oooupettonef exposure is etn/noondo Id humtnt. This category w*s used only when there wee suflWenf evfdenoe from epidemiological studtos to support a Musa) association betwean the sxposura and oanger. HONS 027573 14 (ARC MONOGRAPHS SUPPLEMENT 4 Group? Th* ohomicol. group of Chomicolt. Muttritl proof or oecuptHoml txpoun It protMty cordnogomc to tumor*. Thrt category Pduda* mpoHni lot which, at on* xtrama, th* avidano* ol human carcinogenicity K timott tuttlaonr, * wan iipcwH lor which, (I th* olh*r axtram*. It I* Inadequate. To f*1l*ct th* ring*, th* category Ml dhridad Into higher (droop 4) *n<J lowtr (droop 0) dagraa* ol *vld*no*. U*u*lty, e*l*gory 2A wa* raaarvad lor ixpown tor whlcn th*r* wit at l*in tmitoa rrUonot ol c*ranog*mcrty to humant. Th* flat* from itudia* p *xp*nm*ntal arwnal* pltyM in Important rot* P aitlgning Hud** to category 2. and particularly tho* p Qroup 0; thut. th* oomppatlon ol uMatnt trOtoot P anlm*li and Inadequate data P human* utuiny r*tun*d P a cmiifeauon ol 2B. In tom* caui the WorXPg Group oon*ld*r*d that th* Known eh*mie*l propart** ol compound and th* mult* from shorl-t*rm t**tt alowad It* tr*n*l*r from Group 3 to 20 or from Group 20 to 2A. droop J Th* ctwnlctl, group of ommtoolt. InOuttml proof or occupMonol onpoturt eonnot Oo cuutnta tt to Itt ctrcmogoolctty to humont. RESULTS AND CONCLUSIONS Th* aaaaaamanta ol daaraaa ol *vid*no* tor carcPoganicity to human* and P xp*nm*nui animal* and tor activity P ahotMarm t**ta, aa wa* at tha tummary valuation* ol earePoganlc rf*k to human* art glv*n p Tabl* 1. Group T: Th* WorKIng Group oondudad that th* toaowpg 7 Pduatrial proc***** and occupational *xpo*um and 23 Champa* and group* ol ch*mtc*>> art cauaaty aaaodatad with eanoar P human* . Pduatrtal prooaai*i and oocupattonal *po*ur**: Auramp* manulactur* Boot and ahoa manulacturi and repair (oartaP occupation*) Furniture manulactur* toopropyl atoohol manulactur* (*tronp*cid procaaa) pvokp wiiiy Rubb*r POuatry (oartaP occupation*) Underground haamatlt* mPPg (with axpoaura to radon) Bine* ? twvt not yvt smpi sowstm in im Atonoyipfts pnpwrrm. MONS 027574 RESULTS AND CONCLUSIONS Ch*mlel *nd group* ot ch*mic*i: *-AmlnoOlph*nyl Analgttic mixture* oonUilnlng phantMUn* Arnlc tnd trtonlc oompoundt* AlbMtO* Authlopnn* B*nt*n BirttiiSni N.MMN2'ChkMlhyl).2-naphthyl*ngn* (Chlomtphulnf) Bll(chlorom*thyf)*th*r *nd t*ehnlc*Ugr*d* ohlorom*thy< mtthyl *th*r 1,4-But*n*dlol dlm*thn**ulphon*t (Mytoun) C*rt*ln oomblrwd ch#molh*r*py tor lymphoma' (Including MOPP*) wmorvnouoM Chromium *nd o*rt*ln chromium compound*' Conjugttod ontrogtnc CyMopho*ph*mld* Dt*thytttboitrol MOphMn M*lhox(l*n with uttrt-vlolat A thtrtpy (PUVA) Muturdpu 2-N*phthylmin* Soot*, tor* tnd o*tu Trootulphtn Vinyl ohlortd* IS Croup fc Th* Mlowlne St ch*mle*i, group* ot chemical* or Muttrtil prooMM* *r* proddpy o*romog*mc to human* OrwptA AoryiomtrM AlUtodn* B*ruro(l)>yran* BorytononddoryRum compound** ComMnodoraloontraoopdv**' Otothyl Mphtt* Dlm*thy<*ulph*t* Manufeohn ol maganta* MoM and oartaln nicitpi oompotmd* Nttrogan mustard Oxymathoton* PhantMdn ProcarOajin* ortop-TeUdto* 'TXM*irpoin*|r)i*rpon**lilBr*ur*rnBpmie*toBihlMr*m*nnct>*to*u>**. * fMVMMi Mftfin RuM MnsWM IM ptvMffN * MMM Mi My ivy m oortpooMon, ptrttouferty in mMmi Ni uniw of MMM90V poijfoycic vomvc HONS 027575 ie IARC MONOGRAPHS SUPPLEMENT 4 Group IB AcdnomydnD Adrtamydn AmHrole Auremlne (technical grade) Benzotrtchloride Bleehloroethyl Ntroeourea (BCNU) Cadmium and cadmium compound* Carbon tetrachloride CMorampnameor 1 K2-Chloroatt\/lKLcyelohyt-1 -nttroeouree (CCNU) Chloroform CNorophendt (occupational exposure tor Oaptatm Dacarbazina DOT 3,3'-Olchlorobenzldlne Dtenoettrol 3.3-Dlmethoxybenxk)lne (ortho-Dlanitldlns) Olmethyleaibamoyl chloride 1.4-Dloxane Diracl Black 3* (technical grade) Direct Blue E (technical grade) Direct Brown K (technical grade) bptora-o--r-o* nyano EWnytceetredioi cinyitni oion)nvo9 Ethylene oxide Ethylene thlouree Fomeldehyde (gee) Hydrazine Meatrenol Metronidazole Horetfiieterone OeatredtoMTg Oeetrone Phenazopyrttne Phenytoln Phenctcyeoettc add herUddee (occupeticnal expoeure tor --^ P*ybhlortnaled Mpherryle Progeeterone PropyDNouraci Sequanbel oral oontracepttvee* TetracWorodfcenzo^erpdMxIn (TCDO) 8.4.4-Trtohlotpphenol TrtafazMdkiyl^penpbenzoquInone (Trtaziquone) Trle(1-exlrtdlny1)phoeph(ne autphtde (TNoiape) Uraoimuatard Group * The remaining $4 chemicale. groupe of chemicele. Induetrial proceeaee and oocupetlenal expoeuree ootid not be deaalfled aa to Ihelr carcinogenicity to humane. * TTw MpountD Mpnvlii kr 9m 9MU1 wttvoMC iNM h krara nwM M hmM- MONS 027576 RESULTS AND CONCLUSIONS 17 Tabla 1. Summary avaluatjont of eardnoganlc rtak to humana from chamfcala, mduatrial procaaaaa and Muatrtaa' baaad on avldanca lor cardnoganldty to humana and to ammala and lor aetMty m ahort-tarm taatat Chamlcal, prooaaa orlnduatry Ma--ty-*-v---m-nrl-i Actmomycmo Adrtamyctn Aflatoxmt AWrtn 4-Amlnoblphanyl AmUrda Anaaathatlea, voiatHa Analgaalc mtaturaa oontammo phMMath Pnanaoatm AnNnt Araanlc and eartaffl araanic oompoundt AabNtoa Aorvnm# (tachmcal grada) Manufactura of auramma Aiatdoprma Bamana SanMna Banxtdna-Oaaad dyaa Oaaot Hack 31 naohmoai (Tada) onctatuatnaehnioai gndal ond Brown M nadmioal drada) 0aryflum and darylum OOfflPOUnd) NALM(2-ohk>roathyq3- n---a--p-Mn.--o--w---i-a---m--n--t (CtaomaohaOna) BlacHoroathyl nwoaouraa H|(CNU)|l hi 11 ^ t Evldanoa tor cardnoganldty at humana Imltad madaquata madaquata mttad madaquata auffldant inadaquata Inadaquata auffldant Imltad Inadaquata auffldant auffldant Imltad auffldant auffldant auffldant auffldant Evldanpd lor cardnopartdty mamma* tuftoont Imltad auffldant auffldant Hrrutad auffldant auffldant madaquata Imltad auffldant Imltad madaquata auffldant Mtad kmnoo kmftao auffldant Evldanoa for activity m ahort-tarm taata auffldant auffldant auffldant auffldant madaquata auffldant madaquata madaquata no data Hrrittt) Inadaquata Imltad Inadaquata auffldant a auffldant Imltad auffldant Summa^ valuation of eardno* panic rtak to human* 2A 2B 28 2A 3 1 28 3 1 2A 3 1 1 28 1 1 t 1 inftdiQutti Mdnuati madaquata WIVIM auffldant aufftciant Mmhod WfnQUnt madaquata no data no data Inadaquata 28 2B 28 2A Mtaitnt Inadaquata mnao auffldant mtad auffldant 1 20 auffldant auffldant Imltad 1 ' in WICilariamaMI'a. term* data* humana wart avattak t itamauiaainaiaiaiuaiwarmhunanaaminogmaaaaaatmamaamaM.aamo*anoawnei amnr^w, am m imra nor ml aam wnaioiriB n nt mnc Uprerovu MONS 027577 II IARC MONOGRAPHS SUPPLEMENT 4 Chemical, prOOCaa ormquaty Bleomydna 1,44utanedtol dlmethaneaulphonate (Mytaran) Cadmium and cadmium compound* Carbon tatracNorida Cartam comblnad chemotherapy tor lymphomaa (Including MOPP) CNorambud Chloramphanlool Chtordana/HaptacNor l-tP-ChtoroathylU-cydohtaytt-nltroaouraa (CCNU) Chlorinated toluanee (production of): Beniyl cNortde Benzol chtortde Bantaiohtoilda MruotnOrSOnOt CNorotorm Chtorophenda (occupational eapcaurato) Chtofopnnt Chromium and curtain chromium oompounda Claplatln Ctohbrato dOfMptwrw ayVjOudaTiniamAMv Cyckphoaphamlda 2,44 and aatara (Sm (too PtwnoxyttvDc aom harblddaa, occupational expoeura to) Daearbadna Dapaona DOT ortbpOtoNorobaniana and parpOtohlorobaniana Evldanoa tor carol- noganictty Inhuman* Evidence tor card- noqtnWty in animals Evldenoe tor activity In hort-tarm teeta Summary valuation of oarelno- pamcnalt to humana Inadaquata Inadaquata autltdant 3 autltdant MmHad Imdiquitt llmltad ufAotont autltdant autltdant Inadaquata inadaquata 1 28 28 ufAotont authctont Hmrtsd Inadaquata Inadaquata ulttdem Inadaquata Imitad autltdant Inadaquata ultldant inadaquata Inadaquata autltdant 1 1 20 3 28 Inadaquata Inadaquata inadaquata Inadaquata Inadaquata Imftad Inadaquata autltdant Inadaquata Inadaquata ftooiqua* Inadaquata autltdant Imttod Inadaquata mltad autltdant autltdant Inadaquata autltdant VmTnillNrl Hmnad inMiqutn mltad suffleisnt UfflCitftt Inadaquata mltad mltad Inadaquata tufAdtoi tufflotent (Or VI) Inadaquata (Cr III) auMdant Inadaquata no data inadaquata autltdant 3 3 3 28 2B 28 3 1 28 3 3 3 1 Inadaquata inadacpiat* inadaquata Inadaquata inadaquata inadaquata lufltottnt mftad aufAoisnt tnodtquito Inadaquata mltad Inadaquata inadaquata imdaquata 3 28 3 28 3 MONS 027578 RESULTS AND CONCLUSIONS It Ctiamical. procaaa orlnduatiy 3,3'-Olohlorobaniid(nf Wcfdoromathana OMdrtn Diathyl aulphata S.t'-DKiMIhoxybtnzidlrw (ortho- UtnUkUnt) Dlmattiylcarbamoyt cMonda Dlmythyl aulphata 1,4-Otonan* eptcNocohydfWi Etfiylony dlbromlda Ethylyny oxlda Ethytyna thlouraa S-Fluorouradl FormaWahyda (gaa) H*ueMorocydoh*n* Hydralulrw Hydrizir* MuiMh Bom and aboa manufactory and repair (oartam oooupattom) Carpantry and joinary (oartaln xpCMUMt) Furniture manufacture Loatftar gooda manufacture laafiar tanning Lumbar and aawmi Induatry Pulg and papar manufacture (oartaln axpoaurea) Rufafctr Indurtry (otrtain ooeupAtiont) Iron fextran oornpitx monmnc ton nyorizxN load and load compound# Manolaetura of laopropyl alcohol (itovo^old pidovh) Itoprapyf oil Manutaoture of magenta Maganta (taoMcaf grada) Milphiltn Marcaptopurtna Evtdanea forcarot- noganlcfty In human Evidence for caretnoganidty In animal# Evldanoa lor activity In anofl-tarm taata Summary evaluation of eareinogenlertelc tohumana Inadaquata inadaquata Inadequate Mmnd Inadaquata Inadaquata inadaquata Inadaquata Inadaquata inadaquata Inadaquata Inadaquata Inadaquata Inadaquata Inadaquata Inadaquata Inadaquata aufflciant Inadaquata mltad aufflciant aufflciant auffloiant uflWant aufflciant aufflciant aufflciant ftmtted aufflciant Inadaquata aufflciant Rmfted limited aufflciant aufflciant rmtad Inadaquata aufflciant umtad aufflciant auffloiant Inadaquata ftufftetont aufflciant aufflciant imitad InMid auffloiant Inadaquata aufflciant aufAcient 2B 3 3 2A 2B 2B 2A 2B 28 ZB 2B ZB 3 2B 3 3 2B aufflciant tnadaquata euffbent bMdaouatt Inadaquata Inadaquata Inadaquata aufflciant madiQuiit inadaquata btadiquM ufllotnt inadaquata mm#* Inadaquata aufMant inadequate . . . a . aufflciant Untried aufflciant (tor aoma aalta) Inadaquata Inadaquata aufflciant Inadaquata . . . . . . . Inadaquata imiM Inadaquata no data - Inadaquata aufflciant uMoont 1 3 1 3 3 3 3 1 3 3 3 1 3 2A 3 1 3 MONS 027579 20 IARC MONOGRAPHS SUPPLEMENT 4 Chamicaf, procaaa or industry Mtthotraxata Mathoxaatan with uttraviolat A tturapy (PUVA) MatronldazoU Mustard gas 1-Naphthyiamina 2-NapnthyUmlna Nk*p uflnlng Nlc*l na oartain nlckal compound* Nitrogen muatard (So* alto Crum eombinad efumothrapy tor lymphoma*) Oaatrogant and progattlns Combinad oral oontracapthrta Saquantlal oral oonlraoapttvat Othr oattrogan-proga*tin eomomationa Conjugated oaatrogana Evtdanoa for oard* noQanldty m humans madaquata auflldant madaquata auffldant madaquata auffldant auffldant Imitad Evtdanoa tor cardnoganidty m animals madaquata luftoaant auffldant Imitad madaquata auffldant suffldsnt Evtdanoa for activity m short-ttrm taata auffldant auffldant Imitad auffldant auffldant auffldant a madaquata Sunma/y valuation of oardnsganlc rtak tohumam 3 1 28 1 3 1 1 2A madaquata amitad Hmitad Inadaquata auffldant auffldant . madaquata auffldant madaquata . Inadaquau 2A 2A 2B 3 1 Oaatrogana DUnoattroi Diathytattboaatrd EtNnykuatradlol Maatranoi OoatrdioM7p Oaatront Imitad auffldant madaquata Inadaquau madaquata madaquata madaquata auffldant auflldant auffldant auffldant auffldant madaquata Inadaquau Inadaquau Inadaquau Inadaquau madoquat* 28 1 28 28 28 2B Progaatmc Chtormadmona acatata OtmatHaurona Ethynodtol OUoataU 17-Hydroxyprogasuron# eapraau Lynoaatranol Madnwysrogaatarona aoauu Magaatrol aoauta NaxortmIa-t*a-r--o*n--a* Nortthynodral Norgattrai ProgMiarona * aufMoant (of (w tdmomM- madaquata inadaquata Inadaquau Inadaquata Inadaquau inadaquau Inadaquau Imitad Inadaquau Imitad madaquata Inadaquau mad Imitad Inadaquau inadaquau madaquata no data inadaquata madaquata Inadaquata 3 3 3 3 3 3 3 inadaquata inadaquau Inadaquau Inadaquata auffldant Imitad inadaquau auffldant Inadaquau Inadaquau nodau Inadaquau 28 3 3 20 MONS 027580 RESULTS AND CONCLUSIONS 21 Chamlenl. prooaaa ormduatiy Oxymathdona Pantaohlorophand (Saa alao Chtorophanola, oooupatlonal axpoaurato) Phanaaopyridna pnananma PhanePartiital manoxyaoatic add nartiddaa (oooupatlonal axpoauro to) Ptny*ut*ioni NManyL2-naphthylamma pitanytom PotaMtttotMd Mptenyti NdnUonKBMMoCirtain oomblnad cMmotharapy lor hrmthomas) ProearMUna (Boo alao Cactam oornpmad chamotharapy (or lymphomaa) PropyflNouradl Saeeliarm Soota, tara and oM antofa^yrana ftplronoUetw* Styrtnt Styw*oxtt Mtahnnla SJtamathoxawta 2,44-T and oatara (Soa ado Phanoxyaoadc add axpoauro to) TatradOorodtiantopafa-dtoxln (TCOO) ortto-TeMdma Trooautphan 2,4.3-TitcNorophanol (Soa alao CHorophanda, occupational axpoauro to) j,4,*.TrtdOorophanoi (Saa alao Cworophtnotoa ooouprtonM axpoauro to) Evtdanca toreweL noganldty Inhumana ttniM Erldanea terewoL noQtnicity manfmala nodau Evtdanca tor iCtMty in horMdrm ttttt nodatt Summary avaluaBon olcardnogame flak lo humant 2A mtdtquat* madaquata madaquata inwMQuitv HuwwQ madaquata madaquata ImlM madaquata InadtQuata auflldant Imtttd Hnthad no data InadtQuttt Imhad auflldant madaquata no data madaquata madaquata madaquata inadaQuata madaquata inadaquata 3 2B 3 3 2B 3 3 at kwdiquM hadtquat* inadaquata 3 madaquata toAdtqitftd madaquata initfM|uMi auCManl madaquata madaquata inidipuM intdtqu* madaquata auffldvnt auModnt MM MM auflldant auflldant ftnHpd MM MM (nadtQuita MM auflldant no data Inadaquata Inadaquata auflldant no data auffldant auffMant madaquata madaquata 2A 2B 3 3 1 2A 3 3 3 3 3 madaquata madaquata madaquata madaquata auflldant Inadaquata madaquata auMdant InMad auMdant no data MM Inadaquata madaquata madaquata auffldant madaquata madaquata 3 2ft 3 2A 1 3 madaquata madaquata no data 3 madaquata auflldant no data 20 MONS 027581 22 (ARC MONOGRAPHS SUPPLEMENT 4 I o Chamlcal. procdaa orlnduatiy Trla<ulfldinyl>tfra-ddnioquona fTrtaouonal TiH(mulri<*nyflpho*phln utphlda (TNotapa) Undawound naamawt mining Haamatlta Uracil muataid VlnttMtin* Vlnortitlna (Sm *te> Cartaln eombmad ehamotharapy tor lymphomaa) Vinyl eWorld* Vlnyddana ohlortda Evfdanoa torevcL nogaNdty mtmmana Evtdanca torearoinoganlcfty toartmala Evtdanca toraetMty In ahoH-tarm taata Summary avaluatlon of carano. gantcrtaK to Humana miMQUIll totdtquat* umotm Inadaquata inadaquata Inadaquata imn*d $umcm Inadaquata auftoant Inadaquata umctom ufflotont madaquaia auffldant Inadaquata 29 28 1 3 28 3 Inadaquata auttoar* Inadaquata hadtquat* Mffldant iflVttd nftdtquat* ufMant auffldant 3 1 3 HONS 021582 Fourth Annual Report on Carcinogens Summary 1985 NTP 85-002 US DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service HONS 027583 Contents Executive Summary Page t Introduction 5 Substance* or group* ol substances, and technological or manufacturing procaaaaa that arc known to b* carclnoganlc: 4-Aminobiphenyl Analgesic mixtures containing phenacetm' Arsenic and certain arsenic compounds Asbestos Azathioprine Benzene Benzidine N.N-bis(2-chloroethyl)-2-naphthylamine (chlornaphazine) Bis(chloromethyl)ether and lechnicat grade chloromethyl methyl ether 1,4-Butenediol dimethylsuHonate (myleran) Certain combined chemotherapy lor lymphomas Chlorambucil Chromium and certain chromium compounds Coke oven emissions Conjugated estrogens Cyclophosphamide Diethytslilbestrol Hematite underground mining Isopropyl alcohol manufacturing (strong-acid process) Manufacture ol auramine Melphalan Uethoxsalen with ultra-motet A therapy (PUVA) Mustard gas 2-Naphthylamine Nickel refining (lubber industry (certain occupations) Soots, tars, and mineral oils Thorium dioxide Vinyl chloride 20 24 26 29 31 34 31 44 46 47 52 54 58 60 61 64 85 201 202 203 125 126 136 137 138 204 205 169 199 'Agents in italics are new to this Report. Ill HONS 027589 lufefttftOM Of poupt ! miDMiaoh that m*y rtwwwblyb* nttotprted te ba earotnoeena: 2-Aosiylaminoltuorene AorytonKrtta Mrltmyotn Aflatoxln* 2-Amlnoenthraqulnont l'AmlnO'2'mathytanthraquinone AmHrole o-Artbdine and ranitidine hydrochloride Artmfta* Benzanthracene Benzo(b)Kuoran(hene Benzo(e)pyiene Banzotdohtonde BeryMum end oertein beryllium oompounde BMtlomthyt nHneourt Cadmium and ertein oedmkim oompound# Carbon letreohlorlde l-fi-ChtOtoethy^S-cyolohOKyi-l-niltosoofe* (CCNU) Chloroform 4 -Chtoro-rphenyfaneaVamine p-CraakHna Cupterron Cycasm Oaoerbezme DDT 2,4-Diamlnoanleola autfeie 2.4-Diammototuene Dlbent(e.h)eoridine DlbenKe.paortdine Dibetv(a,h)anthrao#ne 7H-Dfbenzo(o.g)o*rt>*zoie Dfoenzo(e,h)pyrene dbeno(a,l)pyrene - 1,2-Oibromr3-chloropropane 1,2-Dlbromoethana (EDB) 3,3'-Dlohlorobenzidina 1,2-Dbhtoroethene Dlapoxybutana Dl(2-9lhy1hexyl)phthalaie Drefhyf suffer* 3.3'-Drme1hoxybenzldine lv 15 15 1? 16 19 21 23 24 26 33 38 39 40 42 45 48 GO 55 58 5? 82 63 64 89 66 89 69 71 ri 72 74 74 75 76 77 79 61 82 83 88 87 4 Dimethylaminoaiobenzene 3.3'-Dimethy1bertfidine Oimathytearbamoyl chloride I. 1-Nn>efhy/hydrew>e Dimethyl sulfate MDioxane Direct Black 38 Direct Blue 8 Eptchlorohydnn Estrogens fnof con/upafetf| I. Estrsdiot 17$ Ettropens (not coryupeted): 2. Estrone Eftrogtnt (not conjogttod) 3 EtNnyteslredtoi Esfropen* (not con/ugtted): 4. Mesfrtnol Ethylene oxide Ethylene thiourea formaldehyde (Gas) Hexachtorobenzene Hextmoihyiphosph<x*mkfo Hydrazine and hydrazine eutlete Hydrazoberuene Iron dextran complex Kepone* (Chtofdecone) Lead aoetale and lead phoephale lindane and other hexecNorocydohexane ieomera 2-Mefhyfa/Wcfcne (propykrnelmine) 4,4'-Me(hyfnebis(2-chkxoanmrie) (MBOCA) 4.4'-Methylenebis(N.Ndimethy0beraertamfne 4,4'-MethybnodmnMn* and It* dVi/drochtoride Methyl iodide Metrontduote MtoMer'e ketone Mirex Nickel and certain nickel compound* NkrHotrlacetic acid S-NKro-o-arwdine Nkrofen Nffropen mustard 2-AMrcpropane NNitroeodinbutytemine NNitroeodieihanotamine NNtooaodiethylemine N-Nitro*odimeihyc*mine v Pap* 99 90 9! 92 93 95 96 99 99 100 102 t03 105 100 109 ttO 113 114 115 II? 119 119 120 121 123 12? 129 130 131 132 133 134 135 139 140 142 143 144 145 149 149 149 151 MONS 027585 p.NHiModWwny'**'* NWtowdWopylirnln# NNlKW-N-MiytufM NN'0Nmmy(lir** N-Nnnom*n<vln)iirrtni N-NWomo<ptr NNKiownontoolM N-ttttMMUpM*"* NNIUMopyiniMUo NWMouiMdw NortMMnm OxymMSOloo* Pheneoetto Phenaiopyrldine hydroohtoride Phenytom and eodium salt of phanytom Poiybromineled biphenyls Polyobtorlnaled biphenyls Prooarbadna and prooerbetine hydrochloride frooMferone M-Propene aufione S-PwpWaotone FrqpyfthtourecH fteeerptoa Saccharin afrofe Salenkim aullida StreptMofocto SuHeHato t.S.fJ-TatraoNorooKbantdp-dtoxIn (TCO0) Thiourea 7dwen* dtoocyanale b-foMdtoa and bloiuidtoe hydrochtoride Toxaphene 2,4,6-Triohtofophenol TtM1iilrtdtoy1)phoepNtto lutMe Ttts&S-dtbtoritopropylJphoiphato Urathane Acronyma and Abbreviation# Unite at Meeeuremenl Synonym end Trade Name Index V) Pape 162 154 155 155 158 1ST 158 159 160 169 162 164 165 168 16? 169 170 172 173 174 176 176 177 179 180 182 163 184 185 188 187 190 191 193 194 196 196 198 208 209 210 EXECUTIVE SUMMARY The Fourth Annual Papon on Carcinopans, prepared by th National Toxicology Program (NTP), U S. Public Health Service, ii issued by lb# Secretary erf the Department erf Health and Human Services (DHHS), pursuant to Public Law 95-622 ot November 9, 1978.* This taw requires the Secretary to publish an annual report which con tains "a ttot ot aH substances (i) which either are known to ba carcinogens or wbioh may reasonably be anticipated to be oercinogens end (fl) to which a significant number ot persons residing in the United States are exposed;..." Annual reports should also provide available information on the nature ot exposures, the estimated number of persons potentially exposed, and the extant to which the implementation of Federal regulations decreases the nek to public health liom exposure to these substances For the purpose of this Report, "known oercinogens" ere defined as those substances tor which the evidence from human stutkes indicates that there is a causal reiattonehip between exposureto the substance and human cancar. Subatanoaa "which may reasonably be antoptied to be carcinogens" are defined as those tor which there Is a limited evidence of carcinogenicity in humane or sufficient evidence of car cinogenicity in experimental animals Substances in the above categories, tor which potential exposure ot persons residing w the United States has been demonstrated, are included in the * Sacuyi Jtl Par*ppH (> Report. Also included era soma eubetancea which have been banned, or the use of wh<h has been restricted, because people previously axpoaed are potentially at risk or because tome of these eubstences et* remain w the en vironment. The Fourth Annual Report does not contain all known or reasonably anticipated carcmogens Additional substances with identified carcinogenic properties es Helmed above wiK be included m the sub sequent Annual Reports. Several problems ere encountered m developing the information required lor the Annual Reports on Carcinogens Estimating n minder ot people poten tially exposed to a subatanoa and tden lifying the nature, route, end rmensrty ot this potential exposure are drfAoA tasks It li often impossibf# to obtain aoourafa production volumes and uea patterns tor most chemicals. Theinformation that is being collected by (he US En vironmental Protection Agency under the Toxic .Substances Control Act. at toast that part which is public record, may eaaiit in obtaining more aocurete potential txpoeur# estimates to the future, to eddkton, toe upoomtog Na konst Occupational ExpoeureSurvey* * will provide new information on tot ax tent and ctograe of potential exposures tor different subeianoes and manufec luring prooeesae Perhaps the hardest leak to preparing tha Report to to evaluate toe effectivaneaa ot Pedetsl regulations in decreasing toe rtoktopufckchearth. One * AnupdessnsnmntOotuomormhu*o Survey omOuCMd torn >#n u i|74 by t* Cm** *w Owmm CcrewMiscNt w*M# k OoeupwionU SsMv me Hmto ICOOUK*^ HONS 027986 raaaon i that virtually a* Federal lawi oonoernadwtth reducing rM haw been enacted wbtin balan 18 year*. Thus, gfwn *w rrtatfwly Jong period between axpOiuraloaoarctnooenandtheoneet of dlaaaM, lha extent to which iha regulation* Implemented during these IS years hava reduced tha risk remains unknmvn, Anothar raaaon ia that ratiabia information on paat exposures which ooutd ba uaad a a baseline for eetimating future risk raduoiion ii ganaralty not available. Nonathataaa, decreasing txpoaur# rtroukf ba oonaidarad a raduolng oaroinoganlc rl*k awn if tha reduction cannot ba quamibed ai present. Iha Fourth Annuai Report lists tab apart! inoiudad ara tha entries from lha Third Annual Report and 31 additional ubrtanoe* or groupa of lubsianoei Tha naw entries wara choeen from thoaa daalgnaiad by lha Agenda* par ticipating in tha praparatton of lha Report,* from thoaa tartad within tha National Toxiootogy Program and tha National Canotr Intillula Carclnoganwn BM>*aaay Program,' or (rom thoaa avifualad by tha international Aganoy for Research on Oanoer flARC), a oomponant of tha World Haarth Or- * Cartw* lor Omm* CortroiftMeftal InMtuW to Ooouprtorrt trtrty and HMh(CPCMioaH), Comumv Freducl $a>sty Cvrmtton (0PS9, u a CiMranmmie Fiflwaen *o*rwy (EM), Food MDrug AawMrtfontFOA), Niton* In Mh/lt* ol H*rtlWN#Hon*f Ctnoar m*tiM* (MHMC9. Nihon* (nvM*t V HttfrVNorWIn Mutt Ol Bnnionmtnlal HtMlh ScHkii prirtWtHj). Ntfonsi KWMta rtHManwahonai iPivy or Martomo (NifVNiM). tnd u 8 Dapan rrw* of labJOocupa*orw 8*Mv and **>to tnmliMion tOOUOSHA) "NMptld NNWCH! genization (WHO), localad In Lyon. Franca. Of tha 148 antriaa, 24 aubrtancaa or group! of aubatancai and 5 occupa tiona) axpoaura* (etioiogc agant(a) unknown) associated with a technolog ical procew aio listad as "known carcinogen*" ubatanoaa 4-Aminobiphenyl Analgaalc mixture* containing phanacatin Araanic and cartain arsenic compounds Aabartoa AzatMoprina Benzene Benzidine N,N-Bla(2chlofoeri>yl)2napf>lliy1a- mtne (chtomaphazina) Bi*(chloromethy1)ethff and Ieohnice! grade ohforomafhyt methyl ether 1.4-Butenedioi dimathylaultonata (mylaran) Certain oombinad chamolharapy tor lymphomaa Chtorambud Chromium and oertain chromium compounds Coke own amissions Conjugaled artrogans Cyclophoaphamide DMhylrtllbartrol Mafphalan Methoxaaien with irtra-vioirt A therapy (puva) Mustard Qas 2-NapNhy1amin Nickel refining Thorium dioxide Vinyl chloride Occupational Exposure* Hematite underground mining Isopropyl alcohol manufacture (strong-acid process) Momtattwa of aucemme Rubber manulaclura (certain occupations) Soots, tars, and mineral oils One hundred nineteen substances or groups of substance* are included because they "may reasonably be an ticipated to be carcinogens.'' Nickai ap pears In both lists because occupational exposure associated with nickel refining Is known to be carcinogenic although specif substances which may be responsible tor tha carcinogenesis in humans have not yet been identified; end elemental nickel and certain nickel compound* may reasonably be antioi paled to be carcinogens. For each substance or group of substance! or occupational exposure associated w*h a teohnotogtoat prooesa. there is a summary description In cluding a synopsis of the evidence that explains inclusion mthi* Report. This Is followed by a collation of regulatory in formation received from tha partici pating Agencies. Among (he 146 entries, two are natural substances which are not used or pro duced commercially: aflaioxina and cyeasin Two ara food or coemetic ad ditives. saccharin and aafrofe. Safrofs has been banned for most uses. The use ol saccharin hasbeen continued by Congressional mandate. Thirteen pesticides are listed: emitrote; Aramile*; arsenical pesticides; 1,2-dibromo 3 ehforopropane; haxachlorobentene. Kepone*. Hndane and other hexachiprocycloheane isomers, mxax. nilrofen; aulfaltaie, toxaphane, 2.4.6-MicHoioohenot.andOOT Mortol these substances have been banned or limited in use Thera are 3t therepeutc substances Twelve of (he*e are enlicencer agents adriamycm, bischloroethyf ntiroaourea. 1,4 buianedwi dimethylsuHonale (mylereh). certain combined chemotherapy for lymphoma*, chtorambuc*. l(2-cNo roelhyl)-9 cyclohexyl t-ntiroaourea (CCNU). cyc*ophoephnida. dacarba tine. metphafan. nitrogan mustard. pro carbazine, and tna(t azdtnyt)phos phine aullide. Six are hormonal con jugated estrogens, drath/nibeenoi. estrogen* (not conjugatad-astradioM7p, astrona, athinylailradioi. mestranoO, norathirterone. oxymethoione. and progastarone. Tha remain ing 13 ere uaad in other therapeutic ap plication*: analgesic mixtures contain ing phenacetin, atathioprin*, N.N-bn (2-chforoathyt)-2-r>apNhyfamina, non dextran complex, mathoxaalen wuh uftra-vtolet A therapy (PUVA), matron idazoie, phanaoattn, phanazopyitdma hydrochloride, phenyton, propykhrourec!, reeerpine. aatenium suiSds, end strepiorotoewv Two or theee other therapeutics are no longer produced o* ueed in the United 8tiiee: N,N-bfe{2-chlproethy1)2-ftaphBtytamlna and straptozotodn Frw ofthe anticanoar agemi also are no longer produced but ire imported into the U.8. edhemycift, oNorambuc*. cydophoaphamide, deoerbame, and me phalan. Six of (ha antioanoer agents are imported and produoad W hm4*d quanWiaa by one US manufacture bs chtoroathyt nkroaouraa. 1.4butanedioi dimethyt autfonaia, t-(2-chiororthy0 3 HONS 027587 ydOhSxyM-Mroaoufsa. nUroQtn mu* tsrd, gfooeft>ikns, and ws (1 ****/) phosphine MW*. The famaining 96 substances may be tMM m various Wustrisl chamteds tf byproducts (33); dyes. <* Warm* dillet, and pigmenls (20); oombutUon ptOdvOU (14); advents (7). metal* end mstal ooropoundi ooourring in mining, extraction. and fining prooetaes (8); andyttoat ard teseetoh ohemtoais (6); And chemloalA uaed ior misceKaneou* purpoeae (9). The (Ivc occupstlonsl exposures (tlologlOAl agents(i) unknown) AMOOWAd with a teohnofogtoel pTOOe* known to bs oaroinopenic ere theee AAiooiAlAd with hemelHs underground mining, ieoptopyl atochot manutaotute (strong-add prooess), manufacture erf Aurvnlrw, rubber manufacture (oertein oooupattons), and soot*. tars and minaral oils. BoitrMo knowfadga and (udgmantpiay Important roles in grading the available etrfdanoe of otrofnopenKtiy at sufficient, Untied, or Inadequate. StmWy. in a* but ona oatagory ot substenoee, regu latory aotion It an intarpratation by the tagulaiori ol thek Congtesilonai mandata*. Tha oniy mandatad exospuon n lha daUbarata addition ol additives and odors lo foods Tha Dalanay Ciauaa in t* Food Additivs# Amendment of 1950 to tha Fadaral Food, Orug, and Cosmaiic Act raqukaa that''no addrfna ba daamad to ba aala il it it found lo induct cancer whan ingested by man or animal, or if n it found, altar lent which ara appropriata lor lha evaluation of tha aaiaty ol food additives. to mduoe canoar in man or animala;.,," * Corrections ot suggestions, as wek at any additional information that tha reader may hava thouid ba aant lo tha Dkactor, National Toxiootogy Program, P.0, Box 12233. ftaaaarch Triangla Park. North Carolina 27709. Summartaa of Mi Report may ba obtainad from tha Pubko information Office, National Toxioctogy Program. B2-04, P.O. Box 12233, Research Triangla Park. North Carolina 27709. Copiat of tha oompiata Raport ara available lor a taa Irom tha National Taohnical Information Sarvioa, 6265 Port Royal Road. 8prtngfiafd. Vir ginia 22101. Request number PB 65-134633 thouki ba Indicatad. lo Mr arty tubturem he* ton bsnrwd on SW Asse *1 fw Pstinay Osmss FMdefHln iter or* eHwwwvm rate Aeoordnetos* FOA. tern luMtnoM wsr* u**<f to mtfa tfwtivat lo tood pooksdng maMU INIHUDUUIJON Cancer it lha aacond moat common cause rides* in the United States. One in every four Americana will aufler horn cancer aometime during thair lifetime; ona in every live will die from cencer. In 1963. more then 440,000 Americana eked ot cancer1 Ineckfcfcontothephyticel end emotional fullering caused by cencer, thlt dttette may cost tht Na tion at much at $39 tuition tach yaar In (oat production and income, medical expenses, end research resource* For these reasons, the American public it conoerned about cancer end canoer hazards, especially about ways to pre vent the occurrence or decreaae the in cidence ot cancers. Contrary to popular bshsl, oancsr Is not ona but many diseases which may hava different causes. Most sdentlils now consider that abort one-third to twothirds of an cancers are eeeociated wfth the environment in which we live and work. In this context, the environment Is understood as "anything that Interacts with humans, including substances eaten, drunk, and smoked, natural and medical radiation, workplace ex posures. drugs, aspects of sexual behavior, end substances In air. water, and so*-"* Some cultural and behavioral patterns, span from deftned hsbk# of smoking end aloohot consumption, may igniticently influence the development of tumors in the gastrointestinal tract, breast, uterus, and prostata. Theee aspects of social environment, personal behavior, and habits ate aomatlmaa ceded "lifestyle-" Although we rarely know tha environmental (actors and conditions which ara responsible tor the development ol epeotfic cancers, in soma cases we are beginning to heve eome underYkng Most covers that are associated wsh a* environment should ba avoidable, toast potarasny Development of cancer also depends on "host lectors" Host lectori ara at tributes of human organisms ssacciwsd with individual differences in lha risk of developing a specified oancat. A host factor may ba associated with reduced risk of a canoer, not only with mereesed risk.* Examples ot boat (actors art snmunolopical and endocrina functions, nrtritionaf status, genetic oonsutukon. age. end sex.4 As Americans have become more end more oonoetned abort the enwronment end oanoer. they have repealedfy ashed the Federal Government lo clarify what is known About oenoer-ceuemg tub stances The puttie wants to know and should know which substances are regirded as cancer hacerde in the work piece and in the general environment and how was wa ere protected from expoeure lo theee substances. Section 262 of Puttie Law 96622 of November 9. 1V704 reflects the re quests for mis information, Paregrepn (4) of Ma section stipulates that the "Secretary shal publish an annuel report which oortelne- "(A) a *st of ell subrtenoee (I) wmoti either are known to be eeroinogens or may reasonably be entioipeied to be cardnogene and (V) lo which a significant numbsr of parsons residing in ths United Ststss are sxposed; * CommunXy Momtl H*Mh Csmsn Aci Asrwndmsrti 6 HONS 027588 "(B) (nlwmtUon concerning the n*Wf of auch exposure and the Mtlmatad number of person* ex posed to euoh substance*; "(C) MMement IdenlltyinQ (0 each aubatanoa contained in the UK under aubpwayaph (*) iw whth no eluent, ambient, or axpoaura standard has been established by a Federal gsney; and (U) tor each effluent, wrv btant, or axpoaura standard aatabiiihad by a Federal agency wfth raapaot to a aubatanoa oonuinad In tha HM undar subparagraph (A), t axianl to wNoh, on the basis oI avaliaWa medtoal. aoianUfo. or othar dart*. suoh atandard. and implamantallon of suoti standard by aganoy, daoraaaai the risk to pub lic health from axpoaura to the aubatanoa____" In this effort ara. Conttr* lor Disease Controt/Natkxial Inatiiute for Oooupetionai Safety and Health (CDCfNIOSH) Consumer Product Safety CommitHon (CPSC) US. Environmental Protection Agency (EPA) Food and Drug Administration (FDA) National Institutes of Heaith/Nationai Canoer InsHute (NIHfNCl) National Institutet ol HarttVNattonal InitHut# of Environmental Health Sctonoee (NIH/NIEHS) National Inuxmet of HeelttVNational Ubrary of Medicine (NIH/NLM) U.8. Dapartmant of Ubor/Oooop*. onal Safety and Harth Admira tion (DOUOSHA) Annual Reports on Carcfnopene are leaued in response to these requiremanta. Thaaa Raporta diaouaa indMduaf ubatanoaa, mixture* of ohwnlcafs or exposures associated with teohnotogtoal prooaaaaa which are known to be oaromogena or wNoh may raaaonabty be annolpued to be oarolnogana; may oonlaln Information reoefved from Padaral aganolat participating in tha preparation of tha Report*. PertWpante Within tha Department of Worth and Human 8arvtoaa. tha reaponaibllity for praparino thaaa Annual Report* ha* been given to tha Nation* Toxlooiogy Program.* Othar agendas partUpebn Four of thaaa agenciei-CPSC, EPA. FDA. and OSHA-ere response* lor ragutrtng hazardous aubatanoa* and Hmlbnp the axpoaura to and uaa of auoh aubatanoa* Mantffytng Carotnogana For many year* Government research *Oano!ei, Industries, universities, and othar reeearoh organiiatlona have rtrdad vahoui aubatanoH toaaoartam S>oea which mlghi cause canoer. other Fadaral agendas have baan develop ing Information on possible axpoaura and potarviflf hazards and mawng rule* *nd regulation* to oontrol aubatanoa* whloh have been identified a* carcinogen#, ' OHHI aotneiM penttpeorg * NT? m NirUNCt. NIWNlfHS, WWNontf Can* tor ToiiooiofXMi kmaroh (?OA/Ncrm. *r* nrwMjlAAU ' The largest single national testing efion, fte National Canoer InsMute's Cardnogenesi* Taeting Program, has now become a part of NTP/NlEHS. The NCI Clearinghouse on Environmental Car cinogen*. ooni*ting of a panel of ex perts from governmental and non governmental Institution*, we* reviewing the NCI tatting reauXa, and an analyse of reauRa of NCI catdnoQanasti b<o assays of 190 chemcat* was pub lished* The Technical Report* Review Subcommittee of the NTP Board of Scientific Counselor*, augmented by an ad hoc penal of expert* in charmed carcmoganeii*. ha* replaced the NCI Clearinghouse as tha body oI non government experts conducting peer review* of the NTP cardnoganasia bioassay results. Many of tha substance*, mixtures of chemical*, and oooupetionai axpoaura* associated with soma technologic* prp oaaaat lined In the Fourth Annual Report on Ctr&nogont have baan chosen from the "IARC Monograph* on tha Evaluation ol the Carcinogenic Risk ol Chemical* to Humana" published by the international Agency for Rasaarch on Cancer (IARQ In Lyon, Franoe.4 Each monograph la the produot of an individual working group of experts In chemical cardnooeneafs and ratalad fields Tha experts evaluate Via dal* for each aubatanoa included In a mono graph. Tha evaluation is based on the published information available at tha time the working group was convened A Join! IARC/WHO ad hoc working group mat In October 1977 to review and revise tha criteria for judging the adequacy of available data. The terms ` 1h* IARC *** ISO.OQunAJbenThomM. aasrz lygnOfftox Z, frame WHCMAAC pvtsce Sons mey be ottened bom WHO Putfcetorw Centre USA. *9 Shwiden Av***. Albany. New York }?10 'sufficient evidence' and Mmied evidence' ol carcinogenicity mad m these criteria rater only to the *noury and adequacy of the available twdanca and nof lo the potency ol carcmoganc alfact or tha mechanisms involved An updated vsraton of thaaa criteria v eluded in each IARC Monograph Volume The (ARC Monograph Supple ment 4 contains reevafuatrons by an ad hoc working group ot all chamcelt, kv dustrial proceeee* and oocupationai ex posure* lor whioh eome data on car cinogenicity m humane are avertable either in the lire! 20 volume* or monographs or in ofhsr subsequent publications * For tha most part human data ara discussed only for those m ihn Report that have baan devaluated m (ARC Monograph Supplement 4 A direct oompariaon of the IARC evaluator** *yj p* *vaiu*tion ol NClfNTP bioassay result** cannot b* mads because different criteria ware used to assess ie evidence; but thaaa criteria can be related.' Al such evHuelion* involve a component of personal Judgment. In soma cases lha avertable vidence may be assessed diltarenily depending on the criteria used and lha composition of tie group of experts Thus eocordtnQ to an OTA oorratatrv* interpretation to than IARC eqmvNenti daaaaa 1 and2inNClcJ*afcat<on may be regarded as euftoen ewdance animal caromogana'-* Ctause (i) in subparagraph (A)(4) of Sscbon 2ft2 requiree "e M of art eubeUroee which are ailhar known lo be carpnogana or may reasonably be antopaisd to be carcinogens" For tha purpose of this Report, tha two categories m tha iaw-thoaa substance* known to b* HONS 027539 koipeled to bo oeromopene-releie to tf** (ARC OfHOrto lor the degree ol OvWonoo* Mtoftowi: 1, Known lo bo carcinogens: There to "sufHotent evidence ol car cinogenicity" ifom studies in humans "which indicates causal relationship between the sgeni and human oenoer." 2. Reasonably aniicipetsd to bo oerolnogens: A, Tber# 0 ''limited evidence of cardnogenWty" from studies in human*, "whloh indicates that oouool Intorprolotfon it credit*, but that eflsrnetive explanations, auoh at ehanoo. bias or oonfounding, ooukf not adequately bo exduded," or B There is "outttotoni evidence ot oardnogontolty" from studies m oxporimontal animals "which in dicates that thoro it an incroaood incidence ol malignant tumora: (a) in muttipia spades or atraino. or (b) m multiplo experiments (proforably w*h differert route* of odmlnlatration or using different doeo levels), or (c) to an unuouai degree with rooard to Inoidonoa. oHo or typo ot tumor, or ago at onset. Additional evidence may bo provktod by data oonoornmg dooa roaponoo effeots, as wol m intormatton on mutagenicity or ohomloal structure" Moot of tha oubdanooa oontainod in ro Annual Report oan bo idontillod ohomioalty, Some oaroinogans ooour naturally, oomo ara produood when matarlalo ara burnod. and othoro ora praoam In raw matarlalo. or in in- 'vnutfuiMiv enu unai prooucto ol industries. in oomo coooo only the ox poouro aooocioiod with specific tech nological or manufacturing procooo. oc cupation or industry, or a therapeutic treatment can bo rotated to an in croaood inddonoo ol canoar in human*, bd the iuboianoe(s) spodlicaily rooporv ibta cannot ba identified. Some x amplat ol ouch technological prooooaei ora tho undorgiound rdntng ol hamafts end the elrong-acid procou lor the manufacture ol ioopropyl olcohd. The reader It reminded that the fourth Annuo/ Report on Cerctnopent (and al previous editor*) ii a condensation d large amounts oI dots and oonduoion* mode by bodies which poor review th data submitted at evident* about cancer and rto relation to apedlic expooureo. A* ouch, the Fourth Annual Report on Cet&noger* mutt ba lea* detailed about the actual teoti and thou drawbacks. The original monograph* on eeoh kiting ore grven m the lootnotod roforonooi and the reader is adviood to turn to Ihooa for specific argument*, both pro end oon, which wont into iho lining deration humans tprdomiotogicsi investigations give the best information on canoarcausing agonti, but such studios of groups of indrviduafa do hove shortcom ings. They may require oboorvotiono over o long time because the latent period between initial exposure end cancer occurrence may bo up to 20-30 year*. Intentional, long term exposures ol human groups ara, of course, unac ceptable. As an alternative, qualified scientists moke educated predictions about the effects in humans, based on the effects observed in studies with ex perimental animals. Although lost animals may respond dif ferently from humans, experience has shown that most known human car cinogens also causa cancer In ex periments! animals if adequately letted * This finding is understandable ttnoe cancer begins In Individual oslls end ail mammalian oaks are com parable in structure end function. The basic premise ol experimental cardnogenesn research Itthat subsumes which produoe oenoet in rodents end other experimental animals effect human cede ki a similar way. Human and Animal Btudles Sort* undemanding ot the human end animal studies used for identifying oardnogano H noooooary to olarffy what Is meant by the word* "known" and "rae oonabty anildpeted." The otrongatt evidonoo for o relationship botwoon ex posure to o suspected oubofance and canoar In humane comes from opt domldogioal studies. Although we have adequate optdemioiogiea! evidence only for a few carcinogen*, we think the patterns seen mthen ttudles show how other onimO ooroinogons might affect Relatively large dotes of chemiceft are used in animal studies to oompeneete tor the smeH number ot experiments! animals exposed as compared lo the size of human populations and also fo optimiza the potential raaponee. Animal tatts ara coatfy, lake years to complete, * Th*4e*fiMtp>owcrnoewVc*yin*ipWlmrv Id *r*nttd etMrtocetrvourdiihouUrewbe n0wM m mead, and se eWkno* tor bmasne m prMAt MWM More note* MU would ineM bonrono Metort Mdone* arena oarnegan(aaabannna.p M). Boh*hew eon* pound* ere known euttdenl eedanoe human oerdnopan* and art often dritcuk to imerprst in terms ot human cancer risk. They ere. nevertheless, tie best testing tool we hove for detecting potential hazards1 Arxmsf tests do not prove beyond dou that a eubstence w* or w* not cause cenoer in humans. Even "sufloem evidonoo" of carcinogenicity in expenmeniar emmals mey prove not lo be definitive. But if we are to prevent cenoer. we cannot wait 20 to 30 years to obtain definitive evidence of harm to human health. Therefore, eubstence* which show "sufficient evidence" of cancer ceueetion to experimental ani mals are considered for practical put poee* a* reasonably articipeladhuman carcinogens. Incluefon ef Bufeetanoee The Fourth Annual Report content eubstanoee. groups of substances and exposures associated with ffchnofogical processes which were Mad m tie Third Aiwusl Report. Where necessary, the informalion has been updated The Fourth Annual Report prepares Mormadon on 31 additional substenoss Etch has been chosen either from substances tested by the NCI Car dnogeneeie Testing Program or tie Na tional Toxicology Program (NTPy from dnigotfions of t* parvcjpMr^ agen cies, or from substenoes evaluated by the IARC working groups Other subsianoee horn ttie same sources w be added to subsequent Annual Reports. The Summery of the Fourth Annuel Report Ms al tie substarwes end lecn nofoqtott prnnissss hoarded. The se e divided Mo two oubMi. One oontsm tubetanoee. groups of subsianoes. or leohnologioaf procssssi known to be MONS 027590 ovctnogene (2ft entriaa), The other bat ol 119 entries MuOm substance* ot groups of suMlenoM vtftoh may raa- ooofebfy bo antopded to bo oardnogarto. Nlokd appears in both eubMs beoeuse Iho r**S refining prooess is known to bo oorotnooonlo, Mwreas elementd ntokot and owltin nickel com pounds may raowwibty bo anwetpeted to bo oarotnoQOni. A oubotanoo not Mod In thli Annual Report may itlilbs a known caroinopan ot a roaoonabty anuoipatad caromogan. Moro oubotanooi than thooo inofudod may potoniiafly prooom a caroinopenic risk to parsons kving in mo Vfnusd 8taloo. Thooo substances will bo Incor porated Into eubeequenl Annual Re port* oo taooutooi permit. 8omo ohemloafs wll be tnotudedese rest* ofiedino portormad by Industry m rooponoo lo EPA'o requests undot tho Toxic Sob- lUnoot Control Act. Tho Notional To*lootogy Program Ml alio provide now information lor thooo roporti ao further taot roauHo booomo avaHabio. lonidng radiation, uhravioM radiation (tnokidlno sunlight), toboooo, dooholio beverages, and aomo viruses art known or impeded to bo oerttnogen* They hove not boon inoluded (n thli Report (wrtees aotog m oohjuncton wNh o ohemlod) booauoo lonliino radtodon ( dbouoood thoroughly tn a Oenord Aooountlng OMoo report* and a reoent Surgeon Oenerd's report* reviewe the ovorwhotmlng telaMoneMp between toboooo and oanoer. Several publica tion* Issued by tha National Canoor lmtkuio, explain the rolallonehip ol alooholio beverages. ultravioioi radia tion. and viruses to oanoer. Certain manufacturing proooeooe hove aloo boon conpderod by Iho Interna tional Agency lor Research on Canoor PARC) end hive bean classified by this Agency ai eourceo ol oxpoouro Much are aaoociaiod with incroaeod Incidoncei ol cancer in workoro m (hose Mings. Among thooo are Boot and Shoo Manufacture and Repair, and Fur niture Manufacture. The IARC report! dealing with these processes are given In the reference! el the end of Ihie In troduction," end the intereated reader it referred to theoe document! tor detaila. Theoe prooeesea wore believed by IARC to oonetitute exposure* which coueed cancer in eome humans and in aome settings" The National Tomlodogy Program dooe not dnegree with theoe Judgment!. However, theee proceeiee are not Med oeparately in this Report, einoe neither the ipedfio coueee ol me oencwi nor me specific etept in the prooeeoee have been Identified. Fur ther, IARC haa recognited that theee two manufacturing procoaoei vary eionlficantiy from one country to another, and mat the likelihood it great of variation In expoeuret to whatever ceutoe #>e oenoere that are aeon. Theoe menutecturtng prooeteet have alio changed eipnikcantly In eovoral courv thee over the !a low yeere, porticularty with regard to the mix of ohemtode. etc. (uted in the veriout Mope of the prq oeee) which could be tho putstive ooroinogone" Eatlmetfng Bxpoouro Aooording to Ctouso (U) of subporograph (4XA). thli Report t* required to inotude thoee eubitonoei''to whiche oignlficant number of people residing in the Linked Stetee are exposed" Subetenoee to which only e lew people are exposed ere not Included for the moot pari. Yet eome eubetencei which have been 10 banned or restricted in use ere con tained in the Report (e g . eatrole. areenical pesticides, mirex) either because people who were previously exposed remain potentially at risk, or because these substances ere stiN present in the environment Subparagraph (4)(B) requires that tha Annual Reports provide "information concerning the nature Of auch exposure end the estimaied number of persons exposed to ouch substances " The determination ot the number of people potentially exposed and the route, inten sity, and duration of auch exposure for each substance remains a formidable task, This Report attempts to respond to these questions, and wherever ade quate answers could be obtained, they are included in Sections (lift end MIC. Exposure to carcinogens can occur anywhere. Some carcinogens have always been present in the environ ment, and their amount varies, depend ing on geographical location and other environmental conditions. Every year human activities may add more car cinogens to the ambient err, water, food. eoS, end occupational environment. Although scientists attempt to estimate the amount ot carcinogens present in and added lo the environment, there H no rekebfe way to predict who is ex poeed lo whet ceroinogen end when ex posure oocure. Also, since human populations are always exposed to many chemicals at tha same lima, this may modify tha effects of a specific expoaura aither by multiplying (synergism) or reducing Ms action {antagonism). If exposure is linked to a specific habit such as smoking, a specific use such as medical diagnosis or treatment, or a restricted environment such asthe work place, our ability to estimate exposure improves, end in eome cease the are of population segments involved can be estimaied Production and usa data may also help eobmale posable ex posure. but this information may not be pubkefy avertable for many substances, and where x it. M may be outdated or even contradictory. The National Occupational Husk) $ur vey (NOHS), conducted by CDCf NlOSH from 197? to 1074. gave mfor motion on the number of worken poten tisNy expoeed end on eome broader aspects of potential oocupeiionai expo sure. The forthcoming National Occupa lional Exposure Survey (a repeal of NOHS) should yield valuable mlormadon with respect lo more recent pose ble exposures Subsequent Annual Re ports on Carcinogens w* explore this and other available data bases, and their strength* and bmitationi. Regulatory Status Subparagraph (4X0 of Section 262 ifso require* "a Adamant idenlrfyvtg (i) each substance contained m the M under subparagraph (A) for which no effluent, ambient, or exposure standard has been eeiabMhed bya Faderd agency. The Fourth Annuel Report responds lo this requirement by appending to the description of each substance a sum mery of Federal regulation# at submit ted by the pertioipeiing egsnoio* Some of these standards Md regulator* htv* been enacted lor reasons otter men (hs carcinogenicity of the outdance, lor m tones, to prevent other adverse health offsets or to improve the QueMy of the environment or food. Sold or liquid wades or wades discharged mo trie wr mayoorSdncarcmogana. yet twee may MONS 027591 b IMUWid M tONtC MlMinOM Of hatar&uipoMertiendnolepecifical- fy as oarttnoger*. But tf theea raguiatXXW reduoe Mpoaura lo oeroinogen*. Ihon tf* oanoar risk poaed by ouch tubetenoe* wW olio decrease. lottmotH* Risk Reduction Olouoo (li) In subparagraph (4XC) requtroo o statement identifying "for oooh effluent, ambient, or OKpoouro standard established by Federal agency wtth reepeot to a oubninoo contained in the Dot undo* subparagraph (A), the extern to whloh. on t* b*iii of ovaliobto medtoal. edentite, or othor dolo. ouoh standard, ond tho Impiomontolion of auoh standard by tho ogoncy, doormm the risk to publlo health from exposure to tho oubMonooi". TNo require* quan tified Informoiion on Iho emounl of proioohon from oonoor tho public receive* from established Podoroi standards. Estimating tho ornoum of hoofm proteclion lo perhaps tho moot diffioufl took In proporlng tho Annual Reports. Ono reason is (hot moot Fodoraf lowo oonoornod with reduoing oonoor risk have boon onootod within tho loot 16 yoori. Given tho long porlod between tho InHUf oxpoouro lo a oftrofnogon ond tho onool ot dioooM, It lo ofW too ooity to evaluate how much Fodoraf otondordo ond othor roQuiatlono have docrooood tho human oonoor rtok. Anothor roooon lo thot mformolion on pool oxpoouro iovolo. t^tlohoouldoorvoooobooollno lot animating Mute riskreduction, often lo not available or ooouroto. Tho rtok " tho probability ol developfng oonoor - depend! on tho Wens!y, rouio, ond duration of oxpoouro to o wroinogon. Individuals may roopond differently to eimlar oxpoouro*. depend log on hoot loctoro ouch to ago, mk, nutritional ototuo, overall health, ond inhorltod choroctoriatico. Only in a tow Instances, whore otudioo of long-term human oxpoouroo ond cancer tnordonoo In roainciod enwowneoti *r* available. con tlok bo osbmatod with oonfidenoo. The regulation ot oabooloa In tho work pieoe provide* o good exempli, In 1069, under tho Wetsh-Heaiey Act, which then regulated only the frrmo with Government contract*, tho atandard for permissible axpoouro waa t2 fibora of aobaatoo par oubic cantimofar (om*) of air. Under tha Occupational Salety and Haafth Act. thi* standard waa reduoed lo 6 fib*ra'om in 1972 and lo 2 hberafem' In 1976. On April 17, I960, a Joint NI08H-0$HA Working Group racommonded tha arimmation of aa noneeeentlal uooa of aobaaloa end lh# im plementation of a pubic haafth program to reduoe human oxpoouraa. On Aprl 10.1964, OSHApropooed a rule lower ing the pemniidble oxpoouro lo 0.2 or 0.6 ftbereforo* (6 micromotoro In length) and requiring othar provisions lor employe# protection. Tha high risk m workers exposed prior to 1969 la well known. The actual data on exposure level* in the *40e. '60t. and '60a ara fragmentary, although axpoouro levelo wore undoubtedly unacceptably high by today's standard*. Mesothelioma (primarily an aobootoo-induoed cancer) and lung and other oanoere. tha Incldeno* of which la increased by ex posure to asbestos, oenerefy taka 20-40 yoore or more to devaiop and beoome apparent. For these reason*, w* wR not know until oarty in the next century to whet extent tho series of ex posure reduction* in lha 70* and '60* have reduced tho canoer ask in persons exposed to asbestos. One possible way lo provide quan titative estimates ol nik reducton might be to assume that the cancer risk is directly proportional to exposure This approach also supposes that data on post and present exposure levels ore available, or that conditions in ell work pieces are in compliance with regula tions. However, information supporting these assumptions is only rorety ob tainable. Nevertheless, it is reasonable and prudent to aooept that Iho reduc tion of exposure, for any roooon, par ticularly to substances shown to be carcinogenic in experimental animals. wiH decrease the incidence of cancer. This is the basis of current regulatory poke>* which aim to lower human ex posure to cancer-causing substances and thereby improve public health. For a more detailed discussion of the issues involved, see the previously cited report to Congress on the asMsemeni of technologies lor determining cancer risks from the environment.* References f. Notional Cantor tor Health Statistics communication. 2 Office of Technology Assessment, Congress of the United States. Asses* merit of Technologies lor Determining Cancer Risk* from Ihe Environment. U S. Government Printing Office. Washington. D.C.. 1061. pp. 9.66-109. 211 214. 3 Cote, P. Epidemiological Ckros to Host Factors in Human Carcinogen#**. In: H. Banach and B Armstrong, eds. Host Factors m Human Caroinogena*s. (ARC Scientific Publication*. No 3 Lyon, Franco: Internotion*! Agency t Research on Cancer. 1962, p 3 4. Bortsch, H,, end 6. Armstrong, to Host Factors in Human Coronogenes IAAC Scientific Publications, No 3 Lyon. France: (niornalionof Agency f> Rtiearch on Cancer. 1962. p u 5 Griesemer. R.A. ond C. Coot Toward a Classification Schama t Degree* of Experiment*! Evidence i Iho Carcinogenicity of Chemical* I. Animals, in: R. Montessno. H. 6artac< and L. Tomoiis. ads. Molecular *r CetMer Aspects of Carcinogen Scree ing Tests. IAAC Scientific PubHcehon No. 27 Lyon. France Inlernaiion Agency lor Research on Cancer. IM< pp 259 61. 6. International Agency tor Researc on Canoer (IAAC) Chemioafa. Induem Processes and Industrie Aseodtt* with Cancer in Humana. IARC Mon graph! on the Evaluation olth* C* ctnogenic Aak of ChomcalttoHuman Supplement 4. Lyon. France IARC 1982, 292 pp 7. International Agency for ReMarc on Cancer (IAAC). Long-Term an Short-Term Screening Assays for Ca cinogena: A Critical Appraisal. IAA> Monographs on the Evafuakon of m Carcinogenic Auk of Chemicals t Humans. Supplement 2. Lyon. Franct IAAC. I960. 6 Comptroller Goner*). U S Gener, Accounting Offioo. Probisms of Aaoeo! ing Canoer Risk of Low Level lononRadiation Exposure. Report to the Cor grass of the United Stales EMO-fl1 t Washington, DC, 1961, 9. Ofliof of Smoking and Health, irw Health Consequence* of Smok>ng Cancer, a Report of the Surgeo' General. Rooky**. Maryland u S MONS 027592 OeptoVnenl of Health end Human ServtoM, PuWto Health Sefvtee. 1962 10. See, lor example, Shlmkln, M.B. Science and Cenoer. NiH Putdcattone No. 10-SOe, Third Bullion. National Cenoer IndHule, National Indilutee oi HaaHh. Betheeda, Maryland: U.8. Department ot Health and Human 8er- vtoee. 1M0. II. IntarnadonalAgancyforfiaeiarch on Career (IARC) Wood, Loath* and Soma Associated Industries. iarc MonoQrapha on tha Evaluation ot th Carcinogenic Risk ot Chamkali to Humana. Volume 25. 412 pp. Lyon. France: IARC. 1061. pp. 99190, 240-277. 2-ACETYLAMINOFLUORENE CAHOINOOENICITY Incorporation ol (hit compound into the teed earned irecreated incidences ot malignant lumora in a variety ot organa In the rat.' Long-term atudlea m whloh mloe were given 2-aoetyt aminoMuorene (AAF) in the diet showed increased in cidence* ot liver and urinary bladder cenoere.' PROPERTIES AAF occur* in the form ot crydalkne needle*, ft l* insoluble in water USE AAF ie used as a positive control by toxicoiogiati to study the carcinogenicity and mutagenicity of aromatic amines. AAF was Interred lor use as a pesticide, but was never marketed because it was carcinogenic in expertmental animats. PRODUCTION AAF la Imported from Europe and distributed by several spacially chemloal companies A typical distributor docks about 10 pounds ot AAF and usually sent X In 1-, ot 2^gram quantises. Total eoSmaied US. usage la leas than 20 pounds par year *W1ooa.RH ,f MP.MAJ Coe TheTeitelly end CorcMtopontc Acllvtiy ol 8-AMl/mM)anrnt Cenew Ret V UWt. pp aeaeoe 'stofta. JA. end M.A MaNman. adi Wove Sent in Cane* RWk AMmnwrt jto Study} FrecMOnotoreSympoeium. J EnWo" Pdhel. and ?o*ca( vo< 3. ISM. pp MU Tha 1079 T9CA Inventory report* one producer but no production volume ' EXPOSURE Human exposure lo AAF msy occur through inha)siion and dun absorption People who fees the graded risk to AAF exposure are chemists, oharmcai dockroom workers, and homed**' researchers. Although nsdwr NIOSH nor OSHA sstimded the number ot U S workers expoead to this animal car omogan, ttmey be lavmr than 1.000 m 200 laboratories that era poa*bi> exposed. R6QULATION8 EPA regutalea AAF under the Reeourct Conservation and Reoovery Act am (ha Comprehensive Environment* Response Compensation and IwMft) Act. Because AAF la carcinogen* ir animate. OSHAprarmigMad a dMdarr tor theohemtodon February it, t9M dedgnedng protective dothing. hypent prooedure* lor workari, and specie engineering requirements lor tht manufacture or processing or AAF ACRYLONITRILE CARCINOGENICITY There ia eufHctert evidence lor the cer emooeniefty ot acrylorwir<le in ex pertmentd anlmda.4 AcrytonXN* wet carcinogenic In rate when admmrdereo 'leito Subatanpaa Cort'M Act, Cnameai SutMMno* kwarawy, ISIS puds VatrnMond Agano? lor Raaaann on Cwvw IARC MonogmpNon the IwfcMOondewCw dragortpRMdCNnwdoloHunww h(N mar* 4 ttf pp Lyen. Frwwa IARC IS*}. pp rfie MONS 027593 PRODUCTION Accordingto MO, the U S, produciion ol dioabromoblphanyt reported to Ih* U.S. Intamalional Trade Commission wai graaiar than 10,000 pound* for i960. The 1070 TSCA Invenlory identlhet otw oomptny ptoduclng tn unstated amount of hexebromobiphany!4* Eeriltf. EPA alto reported one U S producer of PBBt.**ProduoWon of tome PBBt oetted In the tale 1970't. CPSC reported that the oolo U.S. manufacturer of hexebromobiphenyt oeated production to 1974 tnd holdth remaining nook oftho product until tho supply wet eiheuded In April, 197#, Prom 1970 to 1974. about 11 mVUon pound* of htxebromobiphenvi war# manufaolurod by a tingle U S oompany and marketed undar the irado namesPiramaitar BP-6 and Firematfer FF-1. Commercial production ol PBBt bagan to 1970. tor* and 051 to S81 ppm in thaw adipoaa tissue. REGULATIONS lha cataoory of PBBs, potentially con teining uplo 200-300 individual chemi cait. It aubjtct to a tpaolal TSCA 6(a) reporting rule. EPA hat proposed hendkng andreport/reoordkeeping requiremantt lor PBBt undar tha Resource Conaarvatton and Recovery Act. Undar aaction 406 of tha Food. Drug, and Cosmetic Act, PDA ragutatat PBBoom pound* at unavoidable arwironmaniai oomammamt. In ooopereten with the Contort for Ditaata Control and tho PubHo Htalth Oapanmant of lha State Of Mlohlgan, FDA monitors tho long (arm human haalth affocti from acute axpotura to PBBt POLYCHLORINATED IXP08URS BIPHENYLS PDA atalad that potantlal human expoaut* to P8B> i through ingetfion of food* ooniaMne P0Btaaiduaa. Preeeni aouroat of PBBt aaam to bt residue* lematotog In and around plant* that formerly manulaoturad, prooaaaad, or produoad ptoduoti using PBBt In 1974, Via Nabonri Occupation* Hazard Survey enimaled that 4.900 worker* wartpottltty exposedtoPSBt. For exampla, worker* in ona oompany that manulaoturad PDBi were poaalbfy exooaad diraotly to PBBi by akin oontact. nhatatlon, and unintentional ingestion; nvestigatorsdetected M to 1,729 ppb X haxabromobiphanyi In lha workara' `"tvmp SvOtltnoti Control Act, Chernw* hlMIVM tfty*on W*. putfe itowfl CARCINOGENICITY Tha avtdanoa for carcinogenicity of ptiyohtortoaledbiphonytt (PCBt) in ex perimental anlmtto It tutkcfant.441 Car- tain mixturat of PCBi (o g, KanaoMor #00. Aroolof 1254 and t260) war* eartinogento In mtoa and rati after admmutrabon In lha dial, produolng liver tumort.***44* PCS (1260) wa* car- ^WiwtorWAaoreytpTfWtrahmCoriCOr, iaro Monoo^rw onrwEvoXiMon ertwC. anepencMtoetChaMottotoHument Sup*# mmwziiOsMpp.Lyon. Prone#: IARC. IMS.pp "VtenwWMl Aptneytor RotttrchonConoor. IARC Manowtpht on th* tvWwWWfl or Of Cw oancxprtofttoWChtrnioMtoHumeni vu it 140 pp Lyon,frtneo: IARC, 1*74. 4)103 170 1 tinogenic in the tamale rat. alto produc ing liver tumort 40 The evidence lor the carcinogenicity of PCBt in humant it madeouelt 441 A slight mcrette in the incidence ol cencer. particularly metanoma ot tha tkin, has been reported m a amen group of men exposed occupationally to Aroctor 1254. a mixture ol PCBt.44' PROPERTIES PCBt vary in appearance from mobile, oily liquids to whit* crystalline aoiidt to herd, noncryttalline reant. At lormt are inookibla in water. USE Since 1974, all utet of PCBt in the United Sielet have been confined to closed tyatema. Before 1972. PCBt were uttd In tranilormer cooling liQuidi. heal lransltr and hydraulic fluids, vacuum pump fluidi. lubricants, plasticizers, filler* in invedment casting waxes, surface coating* and sealants, pesticide extenders, and copy paper. PRODUCTION The 1979 TSCA Inventory idenlifiet one company producing 36.556.600 pounds ol PCBt 444 PCBs are no longer produced in the United States, except lor KmXed research and develop ment applications; Import and export of the compound* hat not been permitted Since July. 1979. Prior to 1977, annual "Hrtwntbontl Agency tor Rtttarch on Ctnoor IARC MonoQrtpht on lha EvUuMwn ol lha CorCayooxncfkiXolChtrnuHtoMtn 326 pp Lyon. Plane* IARC. <074. pp Ml COO "'Tone Subttancai Connol Acl. Chemti Svbuinca Invamory, 1070 pvt*c taeortf domeetc production of PCBt wat about 35 mAon pound! Oomathc production reached a peak volume ol 66 mdson pounds In 1970and decreased lo eboui 41 nvtUon pounds by 1974 PCBt hrti were produced m the United Stttoi n. 1929 EXPOSURE The release of PCBt from prior mduatna utet and the pertinence ol the com poundi to the environment he> teMed in widespread oontammewm o water end aok. with ouboequom potto fiat exposure of the general population Routes of axpotura include tkm ebeorp lion and ingMion, a maior eource ol e> poture it through the caet A Hh report indrcaied thet tth. cheese, eggs end contaminaied animal teed were it> motor U.S commodrtieo m which PC8 were lound. The percentage of looampiat oontaminated with PCB decretted between 1973 and 197! Residues of PCBt have been detects in human milk and (at tampiee coded* Irom the genertl U 8 populetron EP< report! that about 12 m4kon perton w4hm t2mlieeof three erotknoandnn protected commerdsf incmereton me potttbty be expoeed to reteatet i PCBt REGULATIONS In 1970. EPA banned PCBt as e pen tide Ingredfcnl and cancaiad regnin lion of produoti oontaming PCBe P. promuigaied toxic potutem affluer etandarde in 1977 and modified th marking and tfttpoed rule m I97i which wat effective in identifying an ekminating tome PCB sources In I97t EPA issued ben on manuteciunm MONS 02 7594 ptcotttinB, and diWrtbding PCB* in oommrce; mod monutaoturtog ceased voluniarty fcotora these Mm were PROCARBAZINE AND PROCARBAZINE issued. EPA proposed a wiier quality Otiterta dooument that wtfl proiect HYDROCHLORIDE fraehwaltr. eehwater. *rxJ equeirC organism*, well ei human heelih, PCB* are reguWsd M hukrdoui CARCINOGENICITY There t euHtcied evidence lor car wihm under the Resource Conserve- cinogenicity in human* ot intensive lion and Recovery Ad and the Com' chemotherapeutic regimen* that m- prehewh* Environmental Reeponee ctuda alkylating agent*, vinca alkaloid*, OcmpanMtion and liability Ad. EPA procarbazine hydrochtorida, andpred recently aeaeaaed dr pdMfon eouroee /Waona. Thare i* inadequate evidence otPCB* andle ooneidartng ha need lor (or oaroihOQenloity ol procaibazme reputation o( errtMtoft* Irom hemere' hydrochloride alone in human* lore, the only aouroa lor aftloh oonlrde Thare I* eutlident evidence lor the may be manual, under the 8eie Drink- carcinogenicity ol procarbazine in ex iftO Water Ad, EPA le preparing a report to Congress on he nature and extent ofPCBoontamlniilon. a* we* a*reoom- penmemal animals.44*44* taboraiory axpoaura of animali to procarbazine wee dudied by Wraperioneel injection. mandatton* tor toflhar regulatory action, Itnaoaeeary, In rate, lymph eyetem cancer* andcanoart of the mammary gland and olfac In 1979, PDAedaWthed tolerance* tory nerve were induced in etetieHceky tor PCB*in Mveial toodt and in teed* eigmheant number*, Inmice, cancer* ol (or tood'produdftp admail, in 1979, the lymph eyetem or leukemia, cancer* tour ol thoeetotaranooe ware reduced. ol the oilectory nerve, pulmonary The toterenoet now are 1.6 ppm (tat naopiaem*. and oanoar* o> the uteru* been} In mUfc and menulaotuted dairy produdi, 3 ppm (lal bad*) In pouHry, 03 ppm In egge, 0 2 ppm In finished were Induced In etaliilically efgndicant number*.444 Evidenoe olcarcinogenicity we* also animalt*ad, 2 ppmInanimat teed oom found in mtoe and rate following ad- ponant* ot ahhial odpln, B ppm in ttah minliMMton bypavaga; in rale totoMng and theMnh (adrbie ponton), and 0.2 ppm inMart andJunior foods. FDA ha* towered the PCB arandard in fiah and *h*t)i)*h from t ppm lo 2 ppm and ha* ettabllihed aotton I*veil ol 9 ppm pel ba*m7)rin""r*avdmn|*oeaitaannod 1io0ppppmm iinn ppaappeerr tood->pPeMokltaging matlaerial, 08HA ReMWCTl on Cex*r WRC Menoeraph* Eveuaton at n*. Jl^^fWkerOrwmteWitoHwmen* va** PPLyon.Plane* lAAC.te*! PP ji?\2 Tww tmtgt) la PCB, OMortn,. wo 5 25 tof,SPB,oortiWn0Mp#rcw **piki m tun. lo, toxic Moon Mtw mn om r".1* W<**M Cwomoomoty Teemed 5HS18!2?No- -0HMswaB^i!lrSS 7Mt* 124 pp bttmot. Utt^tno. W# IARC "on0'ipnor>ih*a*E*a*M*aoonnorCiharnrc?err JX"*"" C>w- , i*e*5p 172 intravenou* edminidmion and in one Instance followinQ iraneplacenial ax poaura. Two etudiM in two apactoe ol nonhuman primaiM euggeet that pro carbazine hydrochloride may also pro duce leukemia vhen administered bv multiple route* lo (ha *ame animal. PROPERTIES Procarbazine i* a white lo pale yellow crystalline powder that i soluble but unctable in water and aqueous Solution*. USE Procarbazine hydrochloride re used mainly ei an aniineoplaatto agent to treat Hodgkin'* deeasa and oat-oal caroinoma ol the lung FDA approved He use in 1969. indicating that the drug should be used as sn adjunct to stan dard therapy. PRODUCTION The 1979 T6CA Inventory reports no production data tor procarbazine and *s hydrochloride.4*1 EXPOSURE Possible exposure to procarbazine and its hydrochloride occur* during manufacture ol he drug; direct ax poaura oocur* during adminMration o( prooarbazina hydrochloride to pedant* In 1960. the National Prescription Audit reportad 15 mUltor* prescription* dispensed for the drug Some ol ha metabolites ot procarbazine are both carclnostatto and carcinogenic. *mTomc SubtiarcM CcmwU Act. Chwwed Subetnc* inveniory. isrs pwtsc leowd REGULATIONS There 4 no indication Iwtprocerbazmi and procarbabna hydrocNodda poaa a waste or pollution problem and therefore. EPA hu Wile intereel m tm reguiaixm Procarbazine hydrochloride >* subtect to FDA prescription druQ labeling requMmem* PROGESTERONE CARCINOOENICiTY There i* *uiclent evidence hat pro gedarona 4 oarchoganc m supermen tal animal*441 Progaelarona wa Mat by subcutaneous and intramuscular m jection in mice, rat*, rabbits, and dog' and by euboutaneou* imptantakon n mica and rat*. In mica and dog*, pro gaatarona was tested atone; M rat* am rabbet, a wm given In oombmeaon ms other chemtcalt. When given atom progesterone Incraaaad ha toodanc ot ovarian, utahna, and mammar tumor* in mica. In tamale mica, ires mant ol newborn animat* with pr< geetaroneanhanoad ha ooourranoa pracanoarou* and caroarou* wwons < ha genial trad and Incraaatd man mary tumorjgeoss4.** Dog* traau with progaWtron# lor tour yea davatopad a doae-ralaiad mcidanca mammary gland naoplaam*.44*^ Admin4tratton ol propMtarona oombtnaion wth known eardnogen* mtoe, rati-and rabbiiaWeded ha. t*Wsws*ndAfw>lR*ini<iiCwv (ARC Uenegsda cn m (rhaaon d C dnegsrwNdidCtamiediisHurmm 9m mod 4. |M pp Lvory, Piano* MAC, >M2. i 202 209 ^Naarretoml Mney lor Rnawch i Can IARC Menogr**M on m Cvduden d d* C onoQ*noNSdOismc4dHuiwn vd |U pp Lyn.S'ir* IARC. ISrS.p* Ml * 173 MONS 027595