Document M4e2K0M4mLB4Gw8VVe0b8qdKz

1 (''(C(CAANNCER RESEARCH 40.1-1?. January 1980) \ \eoeooe-M72/80/owceooosoa.oo / An Evaluation of Chemicals and Industrial Processes Associated with Cancer in Kumari9 Based on Human and Animal Data: IARC Monographs Volumes 1 to 201 Report of an IARC Working Group*- a RECEIVED HtB 2 9 1980 .> Y. BARR ABSTRACT objectives of the Monograph* Program are to examine critically An International ad hoc Working Group of axperte In cancer research met at the International Agency for Research on Cancer {IARC) in JSnusy 1979 to evaluate the data on human and experimental animal carcinogenicity for 54 chemicals, groups of chemicals, and industrial processes. Monographs lor these chemicals were published in Vote. 1 to 20 of the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Bated on evidence from human studies, 16 of the 54 chemical* or industrial processes are human carcinogens. A furttwr 16 chemicals ere probably carcinogenic for humans, aHftough tha data were considered not adequate to establish a causal association. To reflect differing degrees of evidence of carcinogenicity within this group, the chemicals were further subdivided, with 6 chemicals exhibiting a high degree of evidence and 12 chemicals exhibiting a lower de gree. Data on the remaining 18 chemicals were considered insufficient to allow any evaluation of carcinogenicity. The report summarizes the background, purpose, and overall con clusions of the Working Group. The evidence supporting the evaluations Is given in the "Appendix." the data relating to carcinogenicity for chemicals lo which humans are known to be exposed; to evaluate these data with the help of experts in chemical carcinogenesis, epidemiology, and related fields; and to make this information available for the primary prevention of cancer. Selection of chemicals for evaluation is based on 2 criteria: (a) there are data related to carcinogenicity in humans or experimental animals; and (b) there is evidence of human exposure (4). In the first 16 volumes of the monographs, the assessments of carcinogenicity in humans and experimental animals were made separately. No attempt was made to estimate carcino genic risk to humans on the basis of data from experimental animals. However, most of the chemicals evaluated in the monographs had only data from animat studies. Specifically, of more than 350 chemicals evaluated in Vole, 1 to 16, only 46 (about 14%) had any human data. In cases where there was no information available from studies in humans, the IARC was asked repeatedly to consider making an assessment of the carcinogenic risk for humans which was based only on animal data. An ad hoc Working Group met in October 1977 to review the criteria for the assessment cf the carcinogenic risk of nrmoDucTioM chemicals to humans (3). The group drafted guidelines for In 1971, the Irfemstional Agency for Research on Cancer (IARC) began a program to prepare monographs on the eval uation at the csrtinogentc risk of chemicals to humans (1). The subsequent Working Groups which standardize the evaluations of carcinogenicity studies both In humans and in animals. Mora importantly, they recommended that in the absence of ade quate data in humans it is reasonable, for practical purposes, to regard chemicals for which there is sufficient evidence of * The program teesearwd In part by National Cxncw InMttut* Contract N01 CP4S608. Anaapanied varaicn of Ms report wtlibt pu&Nahad MtMCpIeinent lo tha Arc Monograph Series Rat. 6). * Tlda report was pnptrtd by Ralph AHhOUM. Janet Huff, LOTWttO TomatiS. and JuKnn Wilbourn, International Aotncy torRoccfcreh on Canoar. Requer* (or reprints should ba addiaaaad to Dr. L. Tomatic. Chief, Unff of Chemical caretmganoaia. IARC. ISO Cura Albert Thoms*, Gi372 Lyon Cadax 2, Frartcs. * Tills report mutts Vwn an atf ffoc Working Group wMeh mat In Lyon on January 16 lo 17,1STS. toadvtaa lhaOiractor tA (ARC on chemicals carcinogenic or liumrm*. WorMnp Group mambere: P. Armkavtr (UnKerafty of Oxford, Oxford. U. K.X B. K. Ammon?. Rapponai^ (Univ*ratty of Western Australia. Nsounds, Australia); A L. Brown, Cheawian (University of Wisoonain, Madison. WIs.); P. Booovdiu (tiutitut* of Experimental and Clinic*' Modieina, Tallin, UJB.B.R.k P. Cola (Harvard University, Cambridge, Maas.); N. E. Day (Mernstfonal Agency for Research on Cancer. Lyon. Franca): G. Delta Porta (tathute Naafonale per id Studio la Cuts dalTwnori. Milan, Italy); R. A. Gtteeemar, Rapporteur (National Cancer Institute, Dattirrrta. Md.>; T. Httohata (Kurume UnNoratty, Kurume. Ja* pan); W. ). Hunter (Conmission erf tha European Communities. Luxembourg): S. 0 Jeyakir (Leborstorio A Genetics B-ocMmie* ed Emluziontellea. Pavia. Kaly); L. Maud (Ecoie National* da la Same Pu&ttQue, Rennes. France): M. C. Pike (UniversityofScvllwroC aMcrwte Medical School. Loe Angetee. Calif.); R. Prevssvnann (liratltiri Iwt Tor*otegte end ChemcRherapie, Hanfgl&otg, Federal Republic of Germany); M. A 6ehnasMrmen (Nifwnsf Caneet tnatltutf. Betheada. Md.k L. Teppo (Finnish Cancer (togtetry, Helsinki. Plntond); D. 8. Thomas (Fred Kulcfc* toson cancer fiasaaich Center. Seattle. Wash.); J, K. Wagoner (Occupational Safety end HeehhAdnunafcebon.Wathfncfon, D. CJ;N. J. Wald, Vice-Chairman TUnivftisity of Oxford. Oxford, UX.L I. 6. Weinstein (Columbia Univorally, Now Yrak.N. Y). Reedrad June 6.1970:accepted &eptt>nix r IB, 1079. carcinogenicity ti e., a causal association) in animals (2) as if they presented s carcinogenic risk for humans. The use of the expressions "for praciicsi purposes" and "as if they presented a carcinogenic risk" indicates that at the present time a cor relation between carcinogenicity in animals and possible hu man risk eannot be made on a scientific basis, but rather only pragmatically, with the intent of helping regulatory agencies in making decisions related to the primary prevention of cancer. These guidelines were adopted starting with Vol. 17 of the Monographs. However, since these Criteria were not used for Vol8. I to 10, a further ad hoc Working Group was convened to reevaluate the data from animal studies for the chemicals evaluated in those volumes and to identify those for which there Is sufficient evidence of carcinogenicity (2). This Working Group did not consider chemicals or industrial processes for which epidemiologicsl data or case reports suggested an as sociation with the occurrence of cancer in humans (6). By the end of 1976, 20 volumes of foe Monographs had boon prepared. Of the 442 chemicals, groups of chemicals, and industrial processes evaluated therein, 143 (32%) have sufficient evidence cf carcinogenicity in experimental animals, whereas case reports or epidemiological studies have been JAtU JtY tw.y \ 1 \ AP00018438 P. Aithour-e et a/. published for only 60 of the 442 (14%). Because of flme limitations. 6 compounds with limited human evidence were not considered by the Working Group (o- and p-dichlorobenzene, dichlorobanzidine, phenylbutazone, 2,3,7,8-telrachiorodlbenzo-p-dioxin, o- and p-toluidine, vinylidene chloride). The group also did not consider sex hormone preparations (with the exception of diethyistilbeetrol), since they had repently been reevaluated for Vol. 21. There were thus 54 chemicals and industrial processes with data on carcinogenicity from human and animal studies reviewed by the Working Group. This report summarizes the deliberations and conclusions of this ad hoc Working Group. METHODS For each chemical, tha data were reviewed in detail before the meeting by 2 members of the group, the animal studies by an experimentalist and the human studies by an epidemiologist. Data that had become available since the publication of the relevant monograph were Included in this review. Separate assessments of the human and animal evidence of carcinogenicity were debated and adopted by the Working Group. An overall evaluation of carcinogenicity for humans was made based on the combined evidence. Brief descriptions of the data used to support the assessments end the evaluations appear in the "Appendix." We encourage the reader to consult these notes together with Table 1. For each chemical, tho "Appendix" gives references for the appropriate volume In the Monographs series and, where applicable, papers which have been published subsequently. Assessment of Evidence for Carcinogenicity from Expert* mental Animal Studies These assessments were classified In 1 of 5 groups. 4>Sufficient Evidence" of Carcinogenicity. There is an in* creased incidence of malignant tumors: (a) in multiple species or strains; (b) in multiple experiments (preferably with different routes of administration or using different dose levels); or (c) to an unusual degree with regard to incidence, site, or type of tumor, or age at onset. Additional evidence may be provided by data concerning dose-response effects as well as Informa tion on mutagenicity or chemical structure. "Limited Evidence" of Carcinogenicity. Data auggest a carcinogenic effect but are limited because; (a) the studies refer to a single species, strain, or experiment; (b) the experi ments are restricted due to inadequate dosage levels, inade quate duration of exposure to the agent, inadequate period of follow-up, poor survival, too few animals, or inadequate re porting; or (c) the neoplasms produced often occur spontane ously or are difficult to classify as malignant by histological criteria alone (e.g., lung and liver tumors in mice). "Inadequate 'Evidence.*1 Because of major qualitative or quantitative limitations, the studies cannot be Interpreted as showing either the presence or the absence of a carcinogenic effect. "Negative Evidence." Within the limits of the tests used, the chemical Is not carcinogenic. The number of negative studies is limited since, In general, studies showing no effect are less likely to be published than those suggesting carcinogenicity. "No Data.*' Data were not available to the Working Group. The categories "sufficient evidenca" end "limited ejtdaneo" refer only to the: strength of the experimental evidence that these Chemicals are (or are not) carcinogenic and not to the extent of their carcinogenic activity. The classification forany chemical may change as new information becomes avaiatrie. Assessment of Evidence for Carcinogenicity from Human Studies Evidence of carcinogenicity in humans came from 4 types of studies: (a) ease reports of individual cancer patients whowere exposed to the chemical orprocess; (b)epidemiological shales In which the incidence of cencer kv human populations was found to vary spatially or temporally with exposure to the agents; (c) epidemiological studies In which individuals wfth a cancer are compared with a control group free of that cencer to see whether the history of exposure to the presumed crannt agent la greater in the cancer patients g.e.. case-control stud ies); (d) epidemiological studies In which individuals with ex posure to the presumed causal agent are followed up to see if their cancer Incidence is higher than that of individuals wlffiout such exposure C/.e.. cohort or follow-up studies). Three criteria must be met to infer a causal assodttian between exposure end human cancer (3): (a) there is no identified bias which could explain the association; (b| Em possibility has been ruled out that the association is <fae to another uncontrolled variable (often called a confounding var iable) that is associated with both the cancer and the p(seined causal agent; (c) the association is unlikely to be due todance. In general, while a single study may be indicative of a nanreffect relationship, confidence in inferring a causal association is increased when several Independent studies all show the association, when the association is strong, when there is a dose-response relationship, or when reduction in exposure is followed by a reduction in the incidence of cancer. The degrees of evidence for carcinogenicity in human studies were categorized aa: (a) sufficient evidence ofcarcinopwiclty, a causal association between exposure and human cancerCM limited evidence of carcinogenicity, a possible carcinogenic effect in humans, but data not suffldenf to demonstrate causai association; (c) inadequate evidence of carcinogenic ity. data qualitatively or quantitatively insufficient to eUoweny conclusion regarding carcinogenicity for human*. Dividing lines were by no means firmly drawn between suf ficient evidence end limited evidence for animal studies and between inadequate evidence and limited evidence for both human and animal studies. When differences of opinion oc curred among the members of tits Working Group, the ddesification was made by majority vote. Evaluation of Uie Carcinogenic Risk to Humane Presently, no objective criteria exist to Interpret the afmal data directly In terms of human risk. Thus, in the absence of sufficient evidence from human studies, evaluation of the car cinogenic risk to humans was based on consideration the epidemiologies! and experimental evidence together. Fathermore, the breBdth of the above-defined categories for human and animal evidence allows substantial variation within each, and the decisions reached by the group regarding avail risk incorporated these differences, even though they could not CANCER RESEARCH VOL 40 AP00018439 I Chemicals and Human Cancer Ttbltl Ciw**H<atKnc4 tha gagra* ofevidence ol cerelnegenirffj' hr human of chamicalt or Industrial processes from MPC Monogrepn*. Vc/s. ) (o 20 Chemical or proceea Deoree of evidence* In human* In experimental animals Evaljai. 'rf` f ce'ci'4genle flak to humans 1. AcWONM* 2. AflatexJne 8. AUUntoebtohenyi Limited Limited Sufficient Sufficient Sufficient Sufficient 28 2A t 4. Antidote (amlnoMuole) S. Areenie end certain arsenic compounds e, Aabertoe 7. Jwremins* a. Manufacture of suramin* a. benzene 10. Senddbie Inadequate Sufficient Sufficient ' Limited Sufficient. 6uffleiant Suffleienl Sufficient Inadequate Sufficient Limited Not applicable* fnadequate Sufficient 28 1 1 28 1 1 1 11. Beryfltum and certain beryllium compounds* Limited Sufficient 28 i 12. Nft DM2 Chloro*lhy02naphthy(amlne (chlomtphazlne} Sufficient Limited 1 IS. SOME and technical grade CMME Sufficient Sufficient Sufficient Limited 1 14. Cadmium and certain cadmium compound** Limited Suffleienl 2A IS. Carbon tetrachloride Inadequate Sufficient 28 IS. CMorafnbue* 17. CtWeramptwnicol Limited Inadequate Sufficient No deta 2A 3 IB. CWordane and fceplaehtor Inadequate Limited 3 IB. Cffloroptftt 20. Cfvomkiei end certain chromium compound** > Inadequate . Inadequate Sufficient Sufficient 3 1 21. Cyetoptaastiamid* Limited Suffleienl 2A 22. PDT 23. Dtetdrto^ Inadequate Inadequate limited Limned 3 3 I 4* WVw|H8Mfifg( 38 Dtmathvtoarbambyfchlortde Sufficient Inadequate Sufficient Sufficient 1 28 26. oanathyl aulfete 27. EpieMcroftydrin Inadequate Inadequate Sufficient Limited SB 3 28. Ethylene oxide 29. Hematite* 30. Underground hematite mining Limited Inadequate Sufficient Inadequate Negative Net applicable 28 3 1 31. HCH Qeehnicel HCH and lindens) 32. iron dextran 33. teanlazkf Inadequate Inadequate inadequate Limited Sufficient limited 3 28 3 4. Isopropyl oils'1 * Inadequate fnadequate 3 38. Manufacture of Isopropyl alcohol (elrong acid process) Sufficient. Not applicable t. S6. Lead end oertain lead compounds* 87. Melphaten fnadequate Sufficient Sufficient <for some soluble seifs) Sufficient 3 1 38. Mustard gas 39. 2-Nephlhylemlne AO. Nletmand oertein nickel compound**** Sufficient Sufficient Limited Limited Sufficient Sufficient 1 t 2A 41. Nickel refining Sufficient Not applicable* 1 42. Oxymetioton* 43, PhanaceUn 44. Pbenobarttitone Limited Limited Limited No data Limited Limited 28 28 3 45. fFFiwnyf>2naptitriytaniine 4. Fhenytoin fnadequate Limited inadequate Limited 3 3 47. Potycltiorinaled biphenyl* Inadequate Sufficient 28 43. fteserpfne Inadequate Inadequate 3 42. Soots, teri, and mineral oils* 30. Styrene 81. Trichloroethylene 82. TriefeaMdiiiylVe-bantoquInone (trtazteuone) Sufficient Inadequate inadequate Inadequate Sufficient Limited Limited Limited 1 3 3 3 83. Trta(l-lfldinyt)pho*ptine sulfide (tntotepa) 34. Vinyl eWorld* -->...--. .-- .-tt:_____ --... Limited Suffleienl Sufficient Sufficient 2A 1 * For an explanation of the categories e< carcinogenic risk to humane, tee "Method*.1 * Pteaee refer to section on industrial ptocmm* end to the evaluation* In the `'Appendix." *Hf difficult to expoae experimental animals to the earn* condition* lo which worker* are exposed; therefore, no animal dataare available The apecMe compound* which may be reeponsfUe for a carcinogenic effect have not been Identified. alweyibo adequately reflected in the placement of a chemical into a particular category for Table 1. The evidence supporting these decisions is summai ized in the notes for each chemical in the "Appendix/* The chemicals, groups of chemicals, or industrial processes were placed into 1 of 3 gi oups. Group 1. The chemical, group of chemicals, or industrial process Is carcinogenic for humans. This category was used only when there wae sufficient evidence to support a causal association between the exposure and cancer. Group 2. The chemical or group of chemicals Is probably carcinogenic for humans. This category includes chemicals for which the evidence of human carcinogenfcfty is almost suffi cient as well as chemicals for which it Is only suggestive. To reflect this range, this category .has been divided info higher (Subgroup A} or lower (Subgroup BJ degrees of evidence. The JANUARY 1980 / t 3 AP00018440 R. Allhouse of a/. data from experimental animal studies ployed an important role The following 1ft chemicals and groups 1 eh*<nicafo could in assigning chemicals to Group 2, particularly to Subgroup B. not be classified ae to their carcinogenicity for tn--afl* Group 3. The chemical or group of chemicals cannol be (Group 3); classified as to its carcinogenicity for humans. RESULTS AND CONCLUSIONS Chloramphenicol Chlordane-heptachlor The separate evaluation# of animat and human evidence are' presented in Table 1. The Working Group concluded that the following 18 chemicals! groups of chemicals, and industrial processes are carcinogenic for humans (Group 1): Chloroprene DDT Dieidrlh Epiehlorohydrin Hematite 4-Amlnoblphenyl Arsenic and certain arsenic compounds Asbestos Manufacture of auramine4 Benzene Benzidine W,N-BJs(2-chloroethyl)-2-naphthylamine (chiomapha- zine) BCME5 and technical grade CMME Chromium and certain ehromium compounds4 Diethylstiibestroi HCH (technical grads HCH-tindano) (sonla2id leopropyt oils Lead and eertain lead compounds* Phenobarbitono N-Phenyl-2-naphthylamine Phenytoin Reserpine Styrene Trichloroethylene Tris(aziridinyf)-p-beiizoqidiwns (triszlquone) Underground hematite mining4 Manufacture of isopropyl alcohol by the strong add proc ess4 Melphalan Mustard gas 2-Naphthyiamine Nickel refining4 Soots, tars, and mineral oils4 Vinyl chloride The following 18 chemicals and groups of chemicals ere probably carcinogenic for humans (Group 2): Mining and Manufacturing Procaasea For some of the chemicals, part or an of the a--Janco indicating a carcinogenic effect for humans comos from an increased incidence of cancer in Individual* involved in the mining or manufacture of these chemicals. There is auOMent evidence that the manufacture of auramine, the underground mining of hematite, the manufacture of isopropyl alcohol by the strong-add process, and the refining of nickel are carcinogenic to humans, at least in the situations in which they have been Studied. Because these occupations include exposure toother factors in addition to the Indicated chemical, the respansfete carcinogens have not been identified; therefore, the laeutta Subgroup A (S Chemicals) Aflatoxins Cadmium and certain cadmium compounds4 cannot be generalized to all situations Involving the-- proc esses. Nonetheless, these processes should be aseuawd to carry a carcinogenic risk to humans unless proven other----. Chlorambucil Cyclophosphamide Nickel and certain nickel compounds4 REFERENCES Triad-azirldinyOphosphine sulfide (thiotepa) Subgroup B (12 Chemicals) Acrylonitrile Amitroie (amlnotrlazole) Auramine Beryllium and certain beryllium compounds4 Carbon tetrachloride Dlmethylearbamoyl chloride Dimethyl sulfate Ethylene oxide iron dextran Oxymetholone Phenacetin Polychlorinated biphenyls * The specific compound() which may be responsible for a carcinogenic effect in humans has not been identified. *T"-- abbreviations used sre: BCME, bisfcNofomethyf) ether; CMME. chioremtr-'.i methyl ether; DOT, dicMorodiphenyltrichloreethme; HCH. heiaehlaroeyelb.'-exane. 1. IARC Monoorap-- on tht EvatutBow pt th CwulnoowW. RVX f Owl n ill to Human#, V--. 1-20. Lyon. Franc*: Irfrrationii Ag#ocy lor n--it* on Csncsr, 1972-1870. Vol. 1.8am* Inoroanlo8ub--not*. CModnriad Hydrocarbon*.--iwW: Amin**, W4fitro*a Compound* and Naiuml Proauctspsmonapw--). 1S4pp^172. Vd. 2.8oin*tnorasnie --Org--ro--c Compound# <7 mow--peal. istw-. ierx Vol,3.C*rtolnPtorcycScArompBcHydrocrbqn#indltol--eg-- Cww pound* (17 monograph*), 271 pp.a IS73. Vol. 4. seme Anxnatts Amino*. Hydrazln* andn--tod Sub--icm, Nltroao Compound* and --*c*>*n*Qu* Alkylating Ag#--CMmono- ersotu).ssep0..is74. Vol. a 8om* OrsanotMMtna PoaMeldn (12 monograph#). 3** --- 197*. Vol. a. in Harmon** (IS monpgraphi). 24S pp-1274. Vot, 7. 8om* AntMhyrold snd Rslaitd Sub#tone**, IftdutPi and Industrial Clwnleaf* (22 monograph!), 324 pp> 1974. Vol. S. Soma Aromatic AzoCompound! (32 monograph#). 357pp. IS7A Vol. 9. 8--a AdddtoM. N-, 8- snd OdJuttard# and 8--i <24 monograph#). 26S pp., 197S. Vol. 10. 8-- Nttoraly Occurring flub--nc*i (32 war#--ItoL 3S3 pp.. 1076. Vot. 11. Cadmfam. Mek*!. 8o<na Epoakto*. MitcAtUnoeca lilai Chamieais and 6rwai Co--atfen* on VolatM An--* (24 monographs), 306pp., 1978. 4 CANCER RESEARCH VOL. 40 AP00018441 Chemtcafs and Human Cancer Vd. 12. Borne Gerbsmate*. TMocartwnn* and Cartaride* (24 mono* 3. 4*Aminob!phenyt (Group 1) gmfcal.262 W..19T6. Wof is. seme Mlaceuanaoua PharmactulicM SuMancas 07 mono- 9awM.2BSpp..197r. Ve>. 14. Aebedei (1 monograph), 100 pp.. 1977. 4-Aminobiphenyl is carcinogenic in mice, rats, rabbits, and dogs after p.o. administration, producing principally cancer of va. IS. Seme Fumlgenu, the Kertoicidet 2AD*ndlAW, CWorinsted Sfearendloitoa and MtaeeRanooua lilniblil Ckemicata (10 mono- VX*mi, 394 pp.. 1977. VoL is. Seme Aremetfc Aminet end Related Nitre Qamoeund*--Hair the urinary bladder (1). Epidemiological studies, which are confined to one series of workers occupationally exposed to commercial 4-eminobi- Sjm Colouring Agent* and Mtecelenoou* tedustlaf Chemical* 02 ptienyl, show a high incidence of bladder cancer (1,2). ocgnpha), 400 pp,, 1978. VBlIT.toire w-NItroao Compounded 7 monogtiX 80S pp., 1970. Not. IB. FotyeNortneied Biphenyf* end rotjtwnridnlerl SJptwnyls (2 METsphs). 140 pp., 1678. 1M. 19-Some Monomer*. Ptaetle* nd SyrtteaieBaatemer*. and Aer^ 1. IARC Menogr., 1:74-79,1072. 2. Melamed, M. R. Diagneatle cytology of urinary tract esretewma. Eur. J. Cancer. ft 297-292.1972. tate(17mon6graph*), 813 pp., 1979. Wei 20. Same Halog*rated HyWooaitoma (SB ewumle). In praaa, 4. Amitroie (Aminotfiazoie) (Group 2B) 1979. 9. SMaraetaiN Agency ter Reeeereh bn Cancer. Chemical* with Sufficient Amitrole Is carcinogenic In mice and rats, producing thyroid getJewL* s( Cvdnoganielty in Expsrtmamal Animat*. IARC Monograph*, Vtote. 1*17. IARC Internal Technical Report. No. 7B/003. Lyon, France: and Hver tumors following p.o. or s.c. administration (1,2). . hBemBonel Aoeney for Reaeareh on Cancer. 1978. Railroad workers who were exposed to emkroie and othar 9. krtenwHanai Agency for fteeearch ft-Canear. IARC Monograph* on the herbicides showed a slight (but statistically significant) excess OrnitEden of the Carcinogenic Kek of Chemicei* lo Humana, Vot. 19. pp. 19-23. Lyon. Franee: International Ageney ter fleimch en Cancer, 1979. of cancer when all sites were considered together. Because I 4. MameUonaf Agency for Rsaaarch on Cancer. Cnandcel Selection Crltaria workers were exposed to several different herbicides, however, . lor URC Monograph*. IARC Mental Technical Report Me. 79/003. Lyon. no conclusions could be made regarding the carcinogenicity Tmei: Mtmalional Aoancy ter Raaaarch eat Cancer. 1979. 9, MemHtenal Agency ter Heeearch on Canoar. Onaecal* and tedwtrtal of amltrolB alone (1). RmcMaaa Aaaocialed with Cancer In Humana. (ARCMonographs, Volt. 120. IARC Monographs Supplement 1. Lyon, Franco: tntemeticnel Agency . for RaaaarcR en Cancor, 1979. 8 ToomHb, L, Agtho, C., Serttch, H.. Huff, J,, Monteaeno, R,, Saracd, R.. Wnfcar.E_and Witbouni, J. Evaluation of the cardnogenidty si chemical*: 1. IARCMcnoor., 7:31-43,1974. 2. T*uda, H.lHan*nouetit,M.,T*tonial*u,M., Hires*.M., Hlrao, K.,TekahoaN, M.. and No, N. Tumorigenle ff*ct of S-emlr>o-l W-1,2,A-tri*iol* on rat thyroid. J. Natl. Cancer teat., 57: eei-S64v 1976. aaeeiawefth# MonographProgram oI tea InlemaHonatAgencytorResearch n Cmmar (1071 to 1977). Cancer Res.. 38- 877-805.1978. 5. Arsenic and Certain Arsenic Compounds (Group f) APPENDIX Descriptive Evaluations of tha Animal and Human Evidence of Carcinogenicity for Chemicals or industrial processes Evaluated in Vols. 1 to SO of the (ARC Monograph* 7. Acrylonitrile (Group 2B) Acrylonitrile is carcinogenic in rats after p.o. administration end inhalation, producing cancers of the brain, forestomeeh, end ZymbaJ's gland (1). The one available study suggests 4* to 6-foJd Increases In the rates of lung and colon cancer in men observed for 20 or mors years; hov.-ever, it is limited by the absence of information * on smoking and on exposure to other chemicals and by incom pleteness of follow-up (1). 1. MRCUonogr., 19:73-113.1670. 2. Atia&odrcs (Group 2A) Anatoxins are carcinogenic in mica, rata, fish, ducks, mar mosets. tree shrews, and monkeys by several routes ofadmin istration (including p.o.), producing mainly cancers of the fiver, colon.and kidney(l). Epidemiological shxfies have shown a positive correlation between the average dietary concentrations of aflatoxins in populations and the Incidence of primary liver cancer. These studies were undertaken to test this specific hypothesis. How ever. no studies tvavo been carried out which could link en increased risk of liver cancer to actual ailatoxin intake in individuals (1>. 1. lAF*CU<n>;-,, t,'i; SJ. 77. 1178. Information on the carcinogenicity of arsenic compounds in experimental animals was considered inadequate for evalua tion (2). Skin cancer In humans is causally associated with exposure to inorganic arsenic compounds in drugs, drinking water, and the occupational environment. The risk of luno cancer was increased 4 to 12 times in certain smelter workers who inhaled high tsveis of arsenic trioxide (2, 4, 7). However, In these studies, the influence of other constituents of the working atmosphere cannot be excluded. Case reports have suggested an association between exposure to arsenic compounds and blood dyscrasiaa and liver tumors (1, 3, 6, 6). 1. Brady, J., Ub*ratota, F., H*ip*r, P., Gfeenweld, P., Burnett, W., Davie*. J. N. P,, Bishop. M.. Poian. A., *nd Vlanna. N. Anotoaareoffl* orthe liver: an epidemiologic survey. J. NalL Cancer Inst. 59; 1383-1365.1977. 2. (ARC Menogr., 2:46-73.1973. 3. Kieldsberg, C. R., and Ward, H. P. Lnufcemta In araenle poteonlng. Ann. Intern. Med.. 77:935-937,1972. 4. Kurataune, M.. Tokudome, 8.. Shlrekuea, T., Yothkto, M,, TckumUau, V., Hayano.T., and Selta, M. Occupational lung cancer among copper anteliera. tel. J. Cancer, 13. 652-658.1974. 6. Kyi*. R. A., and Puu, 0. L. Hematologic sapnets' of arsenic Intoxication. N. Engl. J, Med.. 278:18-23.1065. 6. Lander, j. J,, Stanley. R. J., Sumner. H. W., Botwall. D. C., end Aech, R. D, Angtoeercoma el tee liver ateodaled with Fowler** solution (pete*iwm treenitc). OaatroeWerotofly, M 1662-1686,1975. 7. Tekodom*. 8.. end Kureicune, M. A cohort etudy on mortefily from oaneer end other canti among worker* at a metal rsftnery. tnt. J. Cancer. 17: 310-317.1876. S. Asbestos (Group 1) Ail types of commercial asbestos fibers which have been tested are carcinogenic in mice, rats, hamsters, and rabbits, producing mesotheliomas and lung cancers after inhalation and after Intrapleural, intratracheal, and i.p. administration (1). Occupational exposure to chrysotiie, amosile, anthophylllte, and mixtures containing r.'ocidcfito has resulted in a high JANUARY 1(!*'() $ IV t` . J, AP00018442 R.AIthouseetal. r incidence of lung cancer. A predominantly tremolitic material mixed with anthophyllite and small amounts of ehrysotile has also caused an increased incidence of lung cancer. Pleural and peritoneal mesotheliomas have been observed after oc cupational exposure to crocidolite, amosite. and ehrysotile asbestos. Gastrointestinal tract cancers were inoreased In groups exposed occupationally to amosite, ehrysotile, or mixed fibers containing crocidolite. An excess of cancer of the larynx was also observed in exposed workers. Mesotheliomas have occurred in individuals living In the neighborhood of asbestos factories and crocidolite mines and in persons living with as bestos workers. Both cigarette smoking and occupational ex posure to aebestos fibers independently increase lung cancer incidence. When present together, they act multiplicativaly (1). 1. tARCMonogr.. 14; t-106.1977................................ 7. Auramine (Group 2B) (L and The Manufacture of Auramine* (Group 1) Commercial auramine is carcinogenic in mice and rats after p.o. administration, producing liver tumors, and after s.c. injec tion in rets, producing local sarcomas (1). The manufacture of auramine (which involves exposure to other chemicals along with auramine) has been shown in one study to be causally associated with sn increase in bladder cancer. The actual carcinogenic compounds) has not been identified (D. 1.lARCMongr.. 7:69-73. 1972, 9. Benzene (Group 1) Benzene has shown no evidence of carcinogenicity when tested in mice by skin application. Other animal experiments were considered to be inadequate to evaluate the carcino genicity of benzene (3, S. 7). Several ease reports as well as an epidemiological case control study sugoest a relationship between benzene expo sure and leukemia (3). Two cohort studies (4, 6) showed an increased incidence of acute nonlymphocytic leukemia in work ers exposed to benzene. There has been an additional report of a large number of leukemia cases (most of which were acute nonlymphocytic) among a group of workers exposed to ben zene (1,2), 1, Aksoy, M., and Enfem. S. Followup study on ttio mortality and tha develop ment of leukemia in 44 pancytopenlc patients with chronic exposure to benzene. Stood. 62: 285-292.1870. 2. Afcsoy. M.. Erdam, S-. and DM1901, 6. Leukemia to shoa workers exposed chronically to benzene, Blood, 44: S37-S41,1974. S. IARC Moitegr., 7:203-221,1974. 4. Infante, P. F., Wagoner. J. K., Rinaky, R. A., and Young, R. 3. Leukaemia In benzena workars. Lanceu 2: 76-78.1977. 5. Maltonl, C., and Searnate. C. La prime prove aperimental <M1` aziene eancerooena del benzene. Oil Oeoedali dtlla Vita. 4:111 -113.1977. & Ott. M. 0., Townsend. J. C.. Fiehbeek. W. A., and Langner, R. A. Mortality among individuals ocosattonaily exposed to benzene. Arch. Environ. Heelth, 33: 3-10. 197S. 7. Ward. j. M.. Waisburger. J. H.. Yamamoto. R. 8., Beniamin, T,, Brown, C. A , and Wetsburger, E. K. Long-term effect of benzene In CS7BL/6N mice. Arch. Environ. Health. 30. 22-25.1975. Case reports and fcliow-up studies of workers provide suffi cient evidence that occupational exposure to benzidine ie causally associated with an increased risk of bladder cancer (2). This association is strengthened by data which suggest that the incidence of this cancer in workers decreased after a reduction in industrial exposure (1). 1. Ftrbsr. K. H.. HM. W. J., and Cobb, D. A. An iiiwmiwI of to* affect of Improved working condition* on bladder tumor Incidence in a benzidine manufacturing facility. Am. tod. Hyg. Assoc. 3. 87.- 91-68,1976. 2. lARCMenogr., r.*ao-as,ie72. 11. Berytliymand Certain Beryllium Compounds? (Group 2B) . .. Beryllium sulfate, beryl ore, and bertrendite produce lung tumors in rats following inhalation. BeryRium oxide and beryl lium sulfate produce lung tumors in monkeys following intrabronchial implantation or inhalation. Zinc beryllium silicate, beryllium metal, and beryllium phosphate afl produce bone tumors In rabbits following l.v. Injection (1). Five early epidemiological studies were considered inade quate to evaluate the caroinogenie effects of beryllium (1). Three recent epidemiological studies (2-4) concerned men occupationally exposed to beryllium, some of whom developed acute beryllium disease. The populations for these studies come from 2 beryllium refining and smelting plants, and both show a 1.5- to 2-fold increase in lung cancer mortality. The statistically significant excess of lung cancer mortality was limited to men employed for tess than 1 year and became apparent only after a follow-up of 15 years or more. There was r>o increase in risk with increased duration of employment. None of the studies adequately considerthe affects ofsmoking. The study that used data from the Beryllium Case Registry (2) shows that 6 of the 7 lung cancer deaths were in men whose exposure to beryllium was through refining and smelting; thus, none of the studies can rule out the effects of factors other than beryllium in the working environment 1. IARCMonogr, 1:17-26,1972. 2. Infants, P. F., Wsgonsr, J. K,, and Sprtoce. N. L. Mortality patterns from lung esneer and non-Atcptastfe respiratory dfessss among wMs male* in ths beiySumcass isgisby. Environ. Res., In press, 1979, 3. Mawcuso, T. F, OccupsUocsl lung cancerAmong bsrySiumweritsrs. Environ, Rea., In press, 1979. 4. Wagoner. J. K., Bsyllts, D. L., and Infante, P. F. Beryllium: an etfotogle agent In the Inductton of king cancer, non-neopleetic resptotiory disease end heart disease among industrially exposed workers. Environ. Res., in press, 1978. 12. N, N-Bis(2~chloroethy1)~2-naphthy1amrne (Chlomaphazine) (Group 1) N,N-Bis(2-chloroethyO-2-naphthylam1ne (chlornaphazine) produces lung tumors in mice following i.p. Injection and local sarcomas in rats after e.e. administration (1). The administration of chlornaphazine together with radioac tive phosphorus (sodium p'Pjphoephate) caused bladder can cer in 10 of 61 patients treated for polycythemia vera. Jn 46 patients treated with sodium ["PJphosphate alone, no cases of bladder cancer were found (1). 1. IARC Mongr,, 4:119-124,1974. 10. Benzidine (Group 1) 13. BCME and Technical Grade CMME (Group 1) Benzidine is carcinogenic in experimental animals after p.o. and s.c. administration, producing liver tumors in rats and hamsters and bladder cancers in dogs (2). BCME produce* tumors at the alte of application in mice after administration by inhalation, skin application, and s.c. injection and in rata after inhalation and s.c. administration. 6 CANCER RESEARCH VOL. 40 APObOt 8443 Chemicals anti Human Cancer Technical grade CMME (which Is almost always contaminated cirrhosis following exposure to carbon tetrachloride (1). with BCME) produces local sarcomas in mice after .c. admin I. (ARC Monogr.. 20. In preu. 1979. istration and is also an initiator of skin tumors (3). .Two studies of workers exposed to BCME and technical grade CMME showed an increased risk of king cancer, mainly oat celt cardnoma (3). Two subsequent studies have shown a positive association between atypical cells In bronchial excre tions (abnormal pulmonary eytology) and exposure to BCME (2. 4) which was not related to cigarette smoking. Several studies have demonstrated a significant excess of lung cancer among BCME- or CMME-expoaed workers (1,4-6) which was directly niatnrt to intensity and duration of exposure. Oat oell carcinoma was the predominant histotoQica] type ot lung can cer. The excess respiratory cancer mortality was most marked in workers under 55 years of age. The evaluation of CMME 76. Chlorambucil (Group 2A) Chlorambucil is carcinogenic in rats and mice following i.p. injection, producing lymphomas In rats and lymphosarcomas, ovarian tumors, and tung tumors in mice 0). Case reports have shown an association between chloram bucil treatment and development of leukemia (1). Women with ovarian cancer treated with a variety of alkylating agents, Including chlorambucil, subsequently had an increased Inci dence erf leukemia (3). Two cases of leukemia and one case of renal clear cell carcinoma have been reported in children treated for glomerulonephritis with chlorambucil (2). alone is complicated py the presence of 1 to 8% BCME as a contentment 1. Atoert, R-6-. Peatomecfc, B. 8 . Shore, R. E^Uppmarwy N, N.. mdfwrb. B. MorMty pattern* among workers exposed to drtownsttiyi ethers--a pirtriney reoort. Environ. HaaNh Perepeet. 11: SOS-214.1976. Z. Frost. J. K., Oupte. P. K., Eroxem. Y. F.. Cariar. D.. Ila*wider. O. H.. end LevkkU.L Pulmonary cytology alteration* In toxicenvlrownental Inhalation. Mum.PHhol. 4. 821-636.1673. . lABCMormar., 4:231-248.1674. 4. Leman, A A., Johnson, W. M,, Wagoner, J. K.. Archer, V. E., end Saocom- am. 0. Cytologic ofceervsHone and cencer toctoence feSowing txposure to BCME. Ann. N. Y.Aced. SO.. 271:71-BO. 1BT6. ft. PtoUnwc*. S. S, Shore. R. E,, wrd Albert,R. E. Occupational exposure to ctoan--aftqt ethers. J. Occup, Med.. 19.741-746.1977. . SSKsfto. K Lung cenoer due to exposure to tMCJNoromettyO other. tnd. Meant. if: IAS--148,1973. 1. IARC Monogr.. P: 126-134.1975. 2. Lenoir. O.. Queary, F., KteMmecht, C- Oagnadoux. M. F,, and Broyer. M. Complication* extre^onadloue* du chlorambucil chez I'enfant (* propo* do 300 obwivBiiofla da nSphropatniea gtontoruUlta* traitSea). Arch. Fr. P*'diatr., 34:798-807,1677. 3. Relmer. R. R.. Hoover. R.. Fraumenl. J. F,, Jr., and Youno. R. C. Acut* leukemia after aHt^atfne-agent tharapy of ovarian eaneor. N. Engl. j. Med., 297: 17T-1B1.1677. 17. Chloramphenicol (Group 3) No data were available on the carcinogenicity of chloram phenicol in experimental animals. Case reports have appeared describing patients with leuke mia who had previously had chloramphenicol-induced aplastic anemia. A follow-up study described 5 cases of leukemia In 14. Cadmium and Certain Cadmium Compounds (Group 2A) 126 patients who had bone marrow depression following treat ment with chloramphenicol (1). Cadmium chloride, oxide, sulfate, and sulfide are carcino genic in rata, causing local sarcomas after e.c. injection. Cad i. (ARC Monogr., 10: SS-96.1976. mium powder and cadmium sulfide produce local sarcomas in rate following l.m. administration. Cadmium chloride and cad mium eutfete produce testicular tumors in mice end rats foilow 18. Chlordane and HeplacWorfGroup 3) These compounds are eonsidered together, because they ing sx. administialion (1). are structurally similar and because they are often contami Early studies suggested that occupational exposure to cad nated one with the other. mium In some form (possibly the oxide) increases the risk of Chlordane and heptechlor (which contained about 20% proetate cancer In humans. In addition, one ol these studies chlordane) are carcinogenic in mice, producing liver tumors suggested an Increased risk of respiratory tract cancer (1). A following p.o. administration. The data for rats are inconclusive later study (2) showed a slight but not statistically significant (1>. increase in prostate cancer in battery plant workers (2 ob In one report 5 of 14 children with neuroblastoma had served versus 1.2 expected) and cadmium alloy workers (4 prenatal and/or postnatal exposure to chlordane. Possible observed versus 2.69 expected). A case-control study (3) of exposure in the remaining 9 children was not ascertained. renal cancer patients showed a 2.6-fold increased risk asso Three persons with acute leukemia were found to have been ciated with occupational cadmium exposure. Ibis relative risk exposed to chlordane (which contained 3 to 7% heptechlor) doubled when cigarette smoking was included. (ft 1. IARC Monogr., ffrSe-74,1976, 2. rqeBUiftui. T.. Frfbarg, l_, Ml Ratmslar. B. Mortaaty and wear morbidity rag cadmlunveMpaaod worker*: praifminvy raport. Environ. Health Peisped. 28;19S-204.1679, S. KotonaL L. N. Anoolatlon of cadmium wRh tonal cancer. Cancer <PW1a.L 37:1742-1789.1S7S. f 5, Carbon Tetrachloride (Group 2B) ' Carbon tetrachloride is carcinogenic in mice and rets, pro ducing Bver tumors after administration by various routes. it also produced liver tumors in trout and hamsters following p.o. administration Cl). Three case fepoits describe liver tumors associated with 1. 1AftCMonogr..20:lnpf#*,1979. 79. Chioroprene (Group 3) Tests for the carcinogenicity of chioroprene in animals were considered inadequate for evaluation (1 y. Epidemiological reports regarding cytogenie effects and re productive disturbances In workers exposed to chioroprene. and in their wives, are consistent with experimental evidence that chioroprene Is mutagenic. Several epidemiological studies regarding the carcinogenicity of chioroprene are inconclusive. There is one case report of angiosarcoma of the liver In a worker exposed to chioroprene (1). JANUARY ICito 7 i - -f AP00018444 R. Althousa at at. 1. IARC Monogr., 19:131-150,1979. 20. Chromium and Certain Chromium Compounds* (Group 1) Calcium chromate is carcinogenic in rats after administration by several routes, including Intrabronchial Implantation. Chro* mlum chromate, strontium chromate, and zinc chromate pro* duce local sarcomas In rats at the sites of application. The evidence for the carcinogenicity in mice and rats of barium chromate, lead chromate, chromic acetate, sodium dichromate, end chromium carbonyl is inadequate (2-4). There Is an increased Incidence of lung cancer among work* era In the chromate*produdng Industry (1, 2, 5, 6, 9) and possibly also among chromium platers (8, 10) and chrbmlum alloy workers (7). There is also a suggestion of increased incidence of cancers at other sites (7, 8); The chromium compound(s) responsible is not known. 1. Davit*. J, M. Lung-canevr mortality e< worfcara making chroma pigment*. Lancet, 1: 3S4,1978. 8.IARC Monogr., 2; 100-125,1973. 3. tvankovie, $.. and Prsuaamann. ft. AMsncs of tonic and etreinoQiniesffacti attai admintetration et Mgh do*** of chromic extd* ptfimant in eub-aeuM and long-term fatdfna xperiminti In rat*. Food Covntt. Toxicol., 13:347-* 351.1976. 4. Lan*. B, P., and Mat*. M. J. CtrckwgankSy and eocarelnoganieity of chromium earbonyl in h*(*rolopte trachaal graft*. Cancer ft**., 37,-14751*70.1977. 5. Lcngard, S., and Norsath, T. A cohort atudy of bronchial carcinomas In worxars producing eftromaie pigmanta. Sr. J. Ind, Med.. 32: 62-66, 1975. 6. Ohaaki, Y,, Aba, S.. Klmura. K,, Tauneta, V.. Mlkami, H., and Murae, M. Lung cancer in Japan*** chroma!* workers. Thorax, 33:372-374, 1976. 7. Pokrovskaya, L. V,, and Shabynina, N. K. Carcinoganoua hatard* in the production of chromium ferroalloy*. Qlg. Tr. Prof. Zabol., 10:23-25.1973. 8. Roy!*, H. Toxicity of chromic acid In the chromium plating Industry (1). Environ, ftta.. 10:39-53.1975. 8. Taylor, P. H. Tha relationship of mortality and duration ol employment aa reflected by a cohort of chromate workers. Am. J. Public Health. 56. 218S2S, idee. 10. Waimouse, J. A. H. Cancer among chromium plater*. Br. 3. Cancer. 32: 262.1976. 21. Cycfopfiospftaro/tfe (Group 2A) Cyclophosphamide is carcinogenic in mice and rats following l.p. injection, in rats following i.v. Injection, and In mice follow ing s.c. Injection. Oosages used were comparable to those used in clinical practice. It produced mainly lung and lymphoretlcular tumors, but also tumors of the liver and reproductive organs, sarcomas, squamous cell carcinomas of the skin (1), and bladder tumors (3). There are a number of case reports of bladder cancer and acute myeloid leukemia in persons treated with cyclophospha mide for a variety of medical conditions (1). A prospective epidemiological study of women with ovarian cancer showed an Increase of acute nonlymphocytic leukemia following treat ment with alkylating agents, including eydephosphamids (2). rats fed DOT (i;; 3). The epidomiokiolcal studies available were considered to be inadequate to allow an evaluation of the carcinogenicity of DDT (2). 1. Cabral. J. ft. P., Hall. R. 1C. and Shublk. P. Effect* of tong-term DOT Intake In rat*. Abstract presantad al 20th Congraaa of the European Society of Toxicology. Weat Berlin. Jim 25 to 26.167a 2. IABC Monogr..6: S3-124.1974. 3. Rasal, l_ Raver*. M.. RepottL O.. and Sand. L Long-term administration of 00Ttf pfxncbarbftat tta In WMar rats. InL J. Cvicer. 19:179-165,1977. 23. Diekjrin (Group 3) Dieldrin U carcinogenic In mice, causing a dose-related increase tn liver tumors following p.o. administration. Feeding studios In rats have shown no carcinogenic effect (1,2). A study of workers exposed to dieldrin involved too few subjects and Insufficient fofiow-up time to allow any conclusion <1). 1. IARC Monogr.. ft-12S-166,1974. 2. Stevenson, O. E., Thorpe, .. Hunt, P. F., and Walker, A. 1. T. The toxic effects of (Saldrln In rata: e nevafciaHon of data obtained In a two-year leading atudy. TexieoL ApgL Pharmacol, 36.- 247-254,1976. 24. Diethyistitbastrol (Group 1) ...................... QiethylstilbestFot is carcinogenic in mice, rals, hamsters, frogs (6), and squirrel monkeys, producing tumors principally in estrogen-responsive tissues (4,9). Olethylstilbeatrol causes dear cell carcinoma of the vagina in females exposed in utem (2, 4, 5). The evidence tor an association with other human cancers is either limited [endo metrium (1)] or inadequate [breast (1), ovary (3)]. 1. Bibbo. 14.. Heenuel. W. U., Wied, 0. L., Hubby, M.. and Httbcl. A. L A twenty-Jrv^y*ar foBow up study or women exposed to dlathylatilDastrol during pregnancy. N. Engl. J. Med.. 296; 763-767.1978. 3. Herbal, A. L, Cola, P.. Colton, T., ftobboy, 8. J., end Scully, R E. Agotnddenee end risk ol UiHhtUUboalrtil lalelad danroe( adenocardnotna of the vagina end cervix. Am. J. Oboist Gyneool., 126; 43-50.1977. 3. Hoevar. R.. Gray, L. A* end Fraumenl, J. F- Jr. Stflboatrol (cflethytaMbeMroi) end the risk el ovarian cancer, tenet. 2; 833-S34.1977. 4. IARC Monogr., ft 56-76.1974. 5. IARC Monogr., 91: In proa*. 1079. 6. Khudol*!. V. V. Carcinogenic ecSon ol dtothytiHbomul on frog*. Sun. Exp. BMl. Med., 61:996-900,1979. 25. Dimathytcarbamoy! Chlorida (Group 2B) Dimethylcarbamoyl chloride is carcinogenic In mice, produc ing local carcinomas after skin application and local sarcomas after a.c. or l.p. injection (1). A study of humans exposed to dimethylcarbamoyl chloride was considered Inadequate due to the small number of people observed (1). 1. [ARC Monogr., T2-- 77-S4. tSTft 1. lAftC Monogr., 9; 139*156,1975. '2. Rairrwr, ft R,, Hoovar, ft.. Fraumonl. J. F.. Jr, *nd Young, ft. C. Aeutt ltukRiia BtWf atkylatfng-ag*nt therapy of ovarian cancar. N. Engl. J M*d,, 297. 177-161,1977. 3. Schmaht, D,, and Habs. M. Carcinogenic action of low-dew cyclophospha mide given orally to Spraguo^awtoy rats In a fifalima axparlmenf. ini. J. Cancer. 23:706-712, 1979. 22. DDT (Group 3) DDT is carcinogenic in mice, causing liver tumors following p.o. administration (2). Nonmetastasizing liver tumors occur in 26. Dimethyl Sulfata (Group 2B) Dimethyl sulfate is carcinogenic in rats after Inhalation ors.c. injection, producing maJnfy local tumors, and after prenatal exposure, producing tumors of the nervous system (1). Four bronchia! carcinomas have been reported in men oc cupationally exposed to dimethyl sulfate (1). In an epidemiolog ical study, 6 cancer deaths were found against 2.4 expected, 3 of which were cancers of toe respiraloiytract(1.02 expected) (2). Neither of these differences was statistically significant. 8 CANCER RESEARCH VOL. 40 AP00018445 1. URCMoneer.,4; 271-278,1674. 2. Pen. s. mom( el workers axeotod to amaiftyi Mtlaie, 1932-1974. SiAmJttad to lha American Canteranea oi Governmental ana toduclriai i*re. 27. Bfichlorofrydrin (Group 3) Chemicals and Human Cancer pesticides (including HCH and lindane) showed an apparent excess of lung tumors and one case of leukemia; however. ih'S cannot be attributed to HCH or lindane exposure alone (1). 1. (ARC Monogr., 20; to prats, 1978. Ejriefflorohydrin produces local sarcomas in mice following s.c. Injection and was active at an initiator in a 2-slage carci nogenesis study in mice (2). Wen exposed to epiehlorohydrin for 15 years or more at 2 plants showed an increased number of deaths due to respira tory comer (8 observed, 4.7 expected) end leukemia <2 obecnred. 0.4 expected) (1). This excess was not statistically stgAKicant and furthermore cannot be attributed confidently to epichiorohydrin exposure alone, since these men were ex posed to ether chemicals, and cigarette smoking was not considered in toe analysis. 32. Iron Dextran (Group 2B) Iron dexlran is earelneganle in mice and rals after e.c. er i.m. injection, producing local tumors (2). There have been case reports of sarcomas associated with injections of iron dextran (1, 2). These appeared in the area which was probably the site of the injections, and the similarity of the local effect in humane and animals was noted. 1. Greenberg, O. Sarcoma after Intramuscular ton Injection. Br. Mod. j,. 2: 1508-1509, 1878. t. lAftC MonoQf., 2; 101-178,1873. 1. BMtt. P.C, imI Hcndmoi,V. L Updttid iMfimy towkmtxpoud to aefcMerrf*0rin. J. Occop. Med., in prat*, 1S79. *. WtCMorogr, tr.-181-1SS.1S7a 28. Ethylene Oxide (Group 2B) Solutions of ethylene oxide have been tested inadequately to mice by skin application and in rats by a.c. injection. No apartments towelving inhalation were available (3). Two studies of human populations exposed occupationally to ethylene oxide (1, 2) have shown increased rates of leuke mia. One of these studies also, showed increased rates of gastric cancer. This increase cannot be confidently attributed to ethylene oxide stone, however, since the workers were xpoeed to other chemicals as well. 1. Hogatedt, C.. Maiaqvtst. N.. and Wtdtnin. 8. Leukemia in worker* exposed to MfwtoM mode. J. Am. Med. Aaaae.. 241:1132-1133,1979. 2. Megatedt. C,, Rohidn. O.. Semdtoson, B. S.. Axatoon. O.. and Ehranbarg, L Kehortatudte sv dddtorsaJ.er tioe ensUHkto I toytonoxidfrAmsIiiltnlng. Ulk'. erttttfngeo. 7S- 3265-3287, 1978. 3. lAnCUenopr, It; 157-187, 1976. 20. Hematite* (Group 3) 90, end Underground Hematite Mining (Group 1) No carcinooenic effects were observed in mico, hamsters, or guinea pigs when ferric oxide was given intratrochoally (2).. Underground hematite miners have a high incidence of lung cancer, whereas surface hematite miners do not. It is not known whether this excess risk may be due to hematite, to radon (a known lung carcinogen), to inhalation of ferric oxide or aOIca, or to a combination of these or otberfactors (1). Some afutfiea of mats! workers exposed to ferric oxide dusts have shown an Increased incidence of king cancerwhile others have net (1,2). The influence of factors in the workplace other than ferric oxide cannot be eliminated. 33. Isoniazid (Group 3) Isoniazid produces lung tumors to mice after p.o., I.p., and s.c. administration. Studies in rats and hamsters were consid ered inadequate (1). Several early studies failed to show a significant excess of cancer among patients treated with isoniazid (1), A study of tuberculosis patients (3) followed for a mean of over 10 years showed a slight excess of respiratory cancers in patients treated with isoniazid (relative risk, 1.4; 95% confidence limits, 1.03 to 1.96 calculated by the Secretariat) and a deficit in patients not treated with isoniazid (relative risk, 0.3; 95% confidence Interval, 0.06 to 0.91 calculated by the Secretariat). Although the numbers are small, the effect was similar In both groups examined and was not seen for eaneert at sites other than respiratory. The excess is mainly for deaths within 4 years of the start of isoniazid therapy. No dose-response effect was seen either lor total consumption or for maximum daily dose. The striking differences in mortality between patients treated earlier in the study and those treated later and the uncertain relationship of tuberculosis to lung cancer in the absence of isoniazid therapy make these data difficult fo evaluate. A casecontrol study (2) of patients with bladder oancer reported that an excess of female cases but a deficit of male cases had previously taken isoniazid compared to controls without blad der cancer. However, the numbers were small, and the results were not statistically significant. 1. lARCMenogr.,4.-159-172, 1874. 2. Milter. C. T,, Neutel, c. I.. Nair, R , Merrett, L. D.. Laat. J. M,, and Colfim, W. E. Relative Importance of risk factors in bladder cardnooantsfs. J. Chronic Oit, 31: BI-SC, 1976. 3. Stott, H., Palo, J,, Stephana, R., and Pox. W. An atMtsmam of the cardDOflanletty of Isoniazid In patterns with pulmonary luberculoiif. Tubsrcte, 87:1-15,1878. 1. Axateon. 0,, ano sjotwro- A. Cancerincidence and axpoeure to iron oxide duet. J. Oeeup. Med., 21:419-422,1078. C. MRCMmwbTh 8:28-38.1872. 31. HCH (Technical HCH and Uadane) (Group $) Technical HCH, a- and jS-HCH, and lindane (y-HCH) are carcinogenic in mice when administered p.o., producing liver tumors. Stucfies in rats were considered inadequate (1). Approximately 30 cases of aplastic anemia and 3 cases of acute mynlnM leukemia following exposure to HCH or Undone lu'vo beer. imported. A study c1285 workers exposed fo ms :y 34. isopropyl Oils (Group 3) 35. and The Manufacture of Isopropyl A/co/to/ (Strong-Acid Process) (Group I) Isopropyl oils, formed during the manufacture of isopropyl alcohol by both the strong-acid and the weak-aeid processes, were tested Inadequately in mice by inhalation, skin applica tion, and s.c. administration. Isopropyl oils (strong-aeld proc ess) were also tested inadequately in dogs by Inhalation and by instillation into the einuGes (1). An increased Inridyiice of cancer of the paranasal sinuses JANUARY 1y00 9 AP00018446 ft. AHhouse et al. has been found in workers in factories manufacturing isopropyl alcohol by the strong-acid process in which isopropy! oils were formed as by-products (1). i. UflC Mor&gr., 15. 223-243,1877. 36. toad endCertain Lead Compounds4 (Group 3) Basic lead acetate la carcinogenic in rats and mice after p.o. administration, producing renal tumors. Lead acetate, lead aubaeetate, and laad phosphate are carcinogenic in rats, pro* duefng renal tumors after p.o., l.p., or s.c. administration (3). Other lead salts have been Inadequately tested (1, 4). No studies of organic lead compounds in animals were available. An early epidemiological study provided no evidence that exposure to lead or lead compounds caused cancer in humans <3X One prospective study of mortality In workers In lead Smelters and battery plants showed, respectively, 30 and 11 % Increased mortality from all malignant neoplasms (2). The find ings were statistically significant only In the smelter workers. An excess Of tumors was seen in the respiratory, urinary, and digestive systems, although none were significantly Increased when considered alone, A study of tetraethyl lead workers Is Inadequate because only workers who remained employed during the study period were included (5). {The Working Group noted that, while human exposure was mainly to metallic lead, the animal carcinogenicity data con cerned soluble lead salts. Thus, even with sufficient evidence in animals, laad and lead compounds were classified in Group 3.) 1. Coogan. P.. Stein. L.Mau. G , and Hast. Q. Th* tumorigenic action ol l*d St rate. Lab. Invest... 28; 473. 1972. 2. Coepar, W. C.. and Gaffy. W. R. Mortality of lead workers, j. Occup, Med., f?: 100-107,1975, 3. URCMOnofir.. 7:40-50, 1972. 4. No. N. Experimental studto* on tumors of fits urinary system of rats induced by cOsmical cvcinoosov Acta Pathol. Jpn., 23: 87-109.1973. $. Robinson, T. R.Thahsaltti of long ssrviea tatrastbyl laad workers. J.Occub. MM- IS. 31-40,1970. 37. Ueipftaian (Group 1) Melphaian la carcinogenic in mice and rate following Lp. Injection, producing lymphosarcomas, a dose-related Increase In lung tumors In mice, and peritoneal sarcomas in rats (1). Case reports of second primary cancers (mainly acute leu kemia) lr patients treated with melphaian have been published (2-5. 7). Epidemiological studies showed substantially in creased rates of leukemia in patients treated with melphaian lor multiple myeloma (8) and ovarian cancer (6, 9). Some of these patients were also treated with other alkylating agents and Ionizing radiation; however, sufficient numbers of patients were heated with melphaian alone to implicate It as the causal factor. Additionally, hie incidence of acute leukemia in patients with multiple myeloma has increased since the introduction of melphaian therapy (1). 1. Adamon, R, H,, and Sisber. S. M. AnlineoptMfic agents a* potential csrcfeoceni. In H. Hiatt. J- Walton, and J. Wlniten (ds.), Origins of Human Canosr. pp. 429-444. Cold Spring Harbor. N. Y.r Cold Spring Harbor Laboratory. 1977. 2. -6*J. R.. Sullivan. ** R-. Ron*. 0 J . and Hurley, T. H. Carcinoma of the breast Occurrencaatfar treatment with mlohaisn for multipte myeloma. J. Assoc OK Anal. Cham., 23G. 1609-1610, 1978. 3 Strron. 1. .. Abbot. C- ft.. Roberts. B. E . and Antonis. A. H. Acute liukemia I l after four years d melpbelan boatmen! for motemnQ. Hr. MeS. A* 1:2D. 1976. 4. Busksrd. N. A., Bey**. 0. A. and Grossman, 1_ I'Usma cel Mkeante foSowfng treatment with radiotherapy and meSpUallfi. Gan. Med. A*toe. i, 117:788-789.1977. 5. De Bock. R. F. K.. and Reeiermans. M. E. Leukemia after prolongs* ua* of fnsJpfteHn ter nofMnatlgnant disaasa. Lineal, t.-1208-1209.1977. 6. Etnhom,N.ActtslukemlafterGh*mQtheraQy(Mlolt8Uffl).CtnQW{Mi.t. 41: 444-447. 1978. 7. lARCMonogr.. 9:187-180.1975. ~ 8. Law. L P- and Btom. J. Second mUignfcod** w patient* with wteRpto myeloma. Oncology (Basel). 34:20-24.1977. 9. Reimer, R. R.. Hoover. R,, Fraumeni, J. F- Jr,, sad Young. R. C. Sorts leukemia slier atkytattng-egenl therapy ef orarian cancer. R. EnoL A Mad., 297:177-181,1977. 38. Mustard Gas (Group 1} Mustard gas is carcinogenic in mice, the only speciestasted, after inhalation or t.v. injection, producing lung tumors, and after s.o. Injection, producing local sarcomas (IX Several studies have shown an increased mortality Brom respiratory tract cancer among IndlvfdtiBla exposed to mustard gas. This mortality was greater In those with chronie ~r-ir?itional exposure than in those with sporadic exposure (1X 1. IARC Menoer-9:161-192.1976. .- 39. 2-Nephlhylamine (Group 1) 2-Naphthylamlne is carcinogenic, producing urinary bladder carcinomas in hamsters, dogs, and nonhuman primates and hepatomas in mice after p.o. administration (1). Epidemiological studies have shown that occupation* ex posure to 2-naphthylamine, either alone or when presentas an impurity in other compounds, is causally associated with Mad der cancer (1). 1, IARC Monegr.. 4:97-111.1974. 40. Nickel, Certain Nickel Compounds? (Group 2A) 41. and Nickel Refining (Group 7) Nickel subsutfide is carcinogenic in rats attar fnhaWfon, producing lung cancer. Nickel compounds (nickel powder, subsulfide, oxide, carbonate, and nickelocene) producedlecaf sarcomas in miee, rats, and hamsters when given i.m. Mdtel carbonyl produced a low incidence of king tumors Jo rats following inhalation (1). Epidemiological studies have demonstrated increased inci dences of cancer of the nasal cavity, king, and possibly teynx In workers in nickel refineries. It is not possible, however, to state with certainty which specific nickel compound(s) Is car cinogenic for humans (1). 1. tARCMoriogr., 71/76-112.1976. 42. Oxymethotone (Group 2B) No data from experimental animal studies were available to the Working Group (IX Ten eases of liver cell tumors have been reported in pWfents with blood disorders treated for long periods with erymethoione alone or in combination with other androgenic drugs; however, a causal relationship cannot be estabfahed. The increased risk of liver ceil tumors could be related to hepatic damage known to be caused by oxymetholone. Alter natively, patientswith congenital anemias may be al high* risk 12 10 CANCER RESEARCH VOL 40 AP00018447 Chemicals and Human Cancer of developing these tumors, and (his risk may become manifest naphthylamine was converted metabolically to 2-naphthyla- during theextended survival resulting from oxymetholone treat* mme in dogs (1). raentO). i. lASCMenogr.. ix wi-ias, i77. No excess of bladder tumors was found In men in a rubber processing factory with known exposure to N-phenyl-2-naphthylamine (which contained small amounts of 2-naphthyla- 43. Phenacetin (Group 2B) mine). However, a different study of rubber workers (who were not exposed to 2-naphthylamine) did show an increase of Rattled a diet containing phenacetin developed nasal and urinary tact tumors (2). W-Hydroxyphenacetln (a possible metabofiteofphenacetin}produced liver carcinomas In rats follow* Jng pLO- administration (1). Severs! studies indicate that die chronic abuse of analgesic mixture? ieassociated with papillary necrosis of the kidney and suggest relationship between papillary necrosis and the subsequent development of transitional cell carcinoma of the bladder tumors. In the letter study, the exposure was to several compounds, which probably included exposure to W-phanyI-2naphthylamlne. These findings do not permit an assessment of the carcinogenicity of A/-phenyl-2-naphthylamine. There is lim ited evidence from one study of 10 human volunteers that 0.03% of a single 10-mg dose of N-phenyt-2-naphthylamlne was converted to 2-naphthyiamine. a known bladder carcino gen (i). renal pelvis (1). These compounds contain phertacetin with 1. (ARC Monoflr.. IS: 325-MI, 1S78. other antSnflammatory drugs (often salicylates or antipyrine) and caffeine. 46. Phenytoln (Group 3) 1. uacuonogu 13:141-196.1977. a. tsaka. It. Ybahii. H.. Ota#. A.. Kolka. M.. Nagai. YM Keura. M., Suotyaau. 9L, me KanabayasIV. T. Tumors of Spraoua-Owl*y rat* induced by tone* --f*adtog ofahswscrtn. Osin. 7ft 29-38, 1979. Phenytoln is carcinogenic In mice after p.o. administration or by i.p. injection, producing lymphomas and leukemias (3). There are case reports end epidemiological studies of lym 44. PhanobarbitoneiGroup 3) phomas occurring in patients that received phenytoln (3); how Phenobartrtone sodium is carcinogenic, producing benign and malignant liver ceil tumors in mice and benign liver cell tumors in rats after p.o. administration (3). A possible relationship between anticonvulsant therapy in which pftenobarbitone was fncluded and the occurrence of cancerin humans has been investigated in one epidemiological study and reported in several case studies. In most instances, pheoobarbftone was given in conjunction with other drugs, in particular phenytoln (3). A further foik>w-up (1) of the patients from this study (wlio were hospitalized for long periods for the treatment of epilepsy) showed an excess of brain tumors, even more than 10 years after the diagnosis of epilepsy (12 ob served versus 4.3 expected), and an increase in liver tumors tl 1 observed versus 2.8 expected). Eight of the 1 1 liver tumor patients received Thorotrast, a known liver carcinogen, how ever, no excess of lymphomas was reported in a follow-up study of epilepsy patients, many of whom received phenytoln along with other antiepileptic drugs (2). Three recent papers (1,4, 6) report one case of malignant mesenchymoma and 2 cases of neuroblastoma in children with phenytoirt-Jnduced malformations. An epidemiological study (5) looked at the frequency of use of phenytoin and of phenobarbitone in moth ers of children with ehlldhood cancers compared with mothers of normal children. While more mothers of cancer patients reported a history of epilepsy, no differences were seen in the proportion of epileptic mothers taking either phenytoin or phen obarbitone. An excess of lymphomss (6 observed with 4 ex pected) was seen in children of epileptic mothers, but the occurrence of brain tumora waa not reported (see also "Phen obarbitone'*). ever. Furthermore, the origin of the brain tumors in these patients Is difficult to interpret, because the occurrence may be due to the underlying medics) condition rather than the drugs per ce. No excess of cancere-of any other sites were een. In another epidemiological study (2), significantly more mothers of children with brain tumors used "barbtturafes" (unspecified) when compared with the mother of children with other ceneers, but not when compared with the mothers of tionmal children. The reason these drugs were given was not specHtcaBy stated (see also "Phenytoin"). 1. Blattner, W. A., Henson. D. E,, Young, R, C-. and Fraumeni. J. F,, Jr. Malignant masstwhymoma and birth detects. Pranatal axposur* to phanytokv J. Am. Mad. Assoc.. 239:334-33$. 1077. 2. CtemiMaan, J.. and Hjalmgrfm-J*nsan, 6. la phenebsrbltal carcinogenic? A Mow-tip of B076ap*Dtic*.ecoi*icctenviron. Salary. 1:457-470,1978. 3. IARC Menogr., 13. 201-226, 1977. 4. Pender?****' T. W,, and Hanson. J. W. Fetal tiydantoin syndrom* and neuroblastoma. Lane*! 2:160.1974. s. Bandar*. B. M.. and Draper. Q. J. CMdheod cancer anddrug* in pregnancy. fir. Med. J,, 1:717-718,1B70, 8. Sherman. S.. and Rotzen. H. F*tei hydeniolnsyndrome and neuroblastoma. Lancet, 2; B17. lb7S- 1. OWMM.J., inj KjalgrimHtenMn, S. I* ptoncborbital etrefcvogecife? A 4eSoiioe4 8078p9*phcs.Eooto>lcW.En4ren. Safety, l:4S7-*70,19T8. 2. GdU, , Cordis, L., Tonatcia, J., and Szkio. M. hneassd risk of brain bmon In ehWrsn exposed lo barbiturates. J. NalL Cancer hist., 61:1031- losi.iere. a. SAACMonogr^ia-167-181.1977. 45. N-Phenyf-2-naphthytaminB (Group 3) A/-Phcnyt-2-n8phthy1amine was tested inadequately In mice by p.o. administration or by single a.c. injection. In a biolransfowtnllyn study, 0.0?% of a measured dose of W-phenyt-2- 47. Polychlorinated Biphenyls (Group 2B) Certain polychlorinated biphenyls are carcinogenic in mice and rata after p.o. administration, producing liver tumors (1). A slight increase in the incidence of cancer, particularly melanoma of the skin, has been reported in a email oroup of men exposed occupationally to Arochior 1254, a mixture of polychlorinated biphenyls (1). 1. IARC Mc-iogr.. 18:43-103,1978. \ jtAHUfcnr isso 11 AP00018448 R Althause et b>. 48. Resorpine (Group 3) Reserpine has been tested inadequately in mice and rats by p.o. administration (4). Thirteen case-control studies were available to the Working Group (1 -8), Most report a relative risk of between 1 and 2 for breast cancer associated with the use of reserpine. Patients taking reserpine tor more than 5 years had slightly higher relative risks. In 11 of the 13 studies, the relative risks were not statistically significant, although pooling of the studies gave a summary relative risk of 1.2 with 95% confidence Intervals of 1.1 to 1.4. The possibility of confounding due to several medical care variablea could not be excluded; hence, none of the studies, either singly or pooled, provide conclusive evi dence of a causal association. 1. Armstrong. 8., 8X999, D.. WhHt, fl,, end DoB. R, Ruwoffla tartvmttv* and Oroast cancortn hypoilsnitvo wornoft, Lancet 2; s-t 2,1876. 2. Aromas, A.. Haktma. M.. HftkuliMn, T,, Swan, E.. Tsppo, L, and fdfinpiKn* Htlkkil*, j. BrtMt caneor and dm of rauwoffls and other anttnypertensive scant* in hypertsnsh* pstisnts: * netionwids essooontrol study In Finland. Int. X Csneor. 78:727-738.1878. 3. Cnristoptw, L. X, Crooks. X, Osvidson, X F,, Erskino, Z. Q,, Gallon, 8. C., Mok, 0. C., and Wolr, R. D. A muttt-oantro study of rtuwoifi* darivatfoM and feraast canear. Eur. X CUn. Pharmacol., 11-400-417.1977. 4. IARC Monogr.. TO: 217-229.1976. 6. Kswltz, Jasdinaky. H,, etVdtor, P,, and Undtner. E. Rasarplno and breast cancer In woman in Germany. Eur. J. Clin. Phvmscol.. f 7:79-89.1077. 6. Kodim. O., and McCarthy, N. Rasarpina and brass* canear. Canear (Phil*.), 41; 761-768,1978. 7. Uienfeld, A. M., Chang. L., Thomas, D. B.. and Lavln, M. L. Rauwalftt dartvstivai and braaal canear. Johns Hopkins Mad. J.. 138:41-50^1875. 6. Williams, R., Feinlaib, M., Connor, R., and Stagens, N, Csss control study of sntihyeortsnsiva and diuretic usd by woman with malignant and benign breast lesions datactad in a mammography screening program. J. Natl. Canear insL, 81:327-335,1976. 49. Soots, Tars, and Mineral Oils!* (Group 1) Soots, coal tars, creosote oils, shale oils, and cutting oils are carcinogenic in experimental animals after skin painting or s.c. injection (4). Occupational exposure to coal soot, coat tar, and pitch, coal tar fumes, and. some impure mineral oils causes cancer of several sites, including skin, lung, bladder, and gastrointestinal tract (4). Recent epidemiological data have supported these conclusions (1 -3,5-7}. This effect may be due to the presence of polycyclic aromatic hydrocarbons in these materials. i j and Liuledijftf>r however, these deaths cannot be attributed styrene exposure alone (1). 1. lARCMenogr.. I9.-2SI-274.1B79. 2. Nallonal Canear tostHuta. Bloauay of atyrvna for poasiWa rirrfiMifartrni Tdi. Rep. Sar. No, 1 as. DHBW Publication No. g*H)7p-1741.TT 4Wj> 11. 0. C.t Unltad Stalaa Gowemmant PrinHng Offlea. 1979. 61. Trichloroethylene (Group 3) Trichloroethylene it carcinogenic in mice after p.o, adminis tration, producing hepatocellular carcinomas and king hmn (1). An epidemiological study of mortality bt man occupatiamly exposed to trichloroethylene showed no of cancer deaths (1). 1. iARCMcmo0r^2O:btpraaa,1979. 52. Tris(6zirkfinyl)-pJ>emoQuinone ( Tria2iquone) (Group 3} Trla(aziridlnyi-p-benroquinone (trlazlquone) is earctagentc in rats after i.v. or combined i.v. and f.p. injection, produting a variety of malignant tumors (1). The 4 available case reports were inadequate to evaJiMteVia carcinogenicity of trlazlquone (1). 1. (ARC Money, 9.-87-73,197S. 53. Tris(l-aziridinyQphosphine sulfida(Thlotapa) (Gnt>2AJ Tried-aziridinyOphosphina sulfide (Ihiolepa) is carcinogenic, in mice and rats after administration by various routes, produc ing a variety of malignant tumors (1,2). There are several reports and epidemiological etuefiaa sug gesting the development of acute nonlymphocytic leukemia in patients after ttfiotepa therapy for ovarian and other indignant tumors <1,3). 1. IARC Monogr., 9:65-9*. 1975. 2. NAltenM Cpoct hubhit*. Blowy f bitofpi tef p anlbli caed^gmtdtf- Teeh. Rap. 8*r. No. 88. DHEW Pubhcatfon No. (NfH) 73-1908. tea PPWashlrigtcn, D.C.: UnHad StatM Qovmmaw Printing Offco. 1978. 3. Raimar. R. R,, Hoovar, R.. Fmumonl. X F. Jr., and Young. R. C. *~rti Mukwnl* tar afkylaHng-o0Mt ewnpy nf ewiM egnev. N. bigLX tflad, 297:177-181,1977. 64. Vinyl Chloride (Group 1) 1. Andjslkovidi, C,, TpuibM. J~, Symons. M., and Williams, T, Mortality of rubber worker* with reference to work experience. J. Occup. Med., re: ae7-406, te77. 2. Decoufle, P. Further anatyala of cancer mortality among workers exposed to cutf.ng oil mist. X Natl. Canear Inal., 91:1036-1030,1970. 3. Hammond, E. C,, Setlkofl, I. X, Lawther, P. L., and Seidman, H. Inhalation el benxpyrena and cancer In man. Am, N. Y. Acad. 8d., 271: 116-124, 1976. 4. JARC Monegr., 3:22-42,1973. 8. McMtchaal, A. X, Splrtaa, R., Gamble, J. F., end Touaey, P. M. Mortality among rubber worker*: relationship to specific iota. X Occup. Med.. IB: 176-165.1976. 9. Redmond, C. K., Sirobino. B. R., end Cypress, R. H. Cancer experience amono eoke byproduct workers. Ann. N. Y. Acad. Sck, 271: 102-115, 1976. 7. Wigie, D. T. Bladder cancer: possible new high-risk occupation. Lancet 2: 83-84. 1977. 50. Styrene (Group 3) Styrene produces lung tumors in mice following p.o. admin istration, (1.2). Three deaths from leukemia and 2 deaths from lymphoma have been reported in workers exposed to styrene, benzene. Vinyl chloride is carcinogenic in mice, rate, and hamsters after administration p.o. and by inhalation, producing femora al 6everal sites including angiosarcomas of the liver (11 Vinyl chloride causes angiosarcomas of the iiver and amors of the brain, lung, and hemoiymphopoietlc system In tomans (1). 1. (ARC Monogr.. *9 377-437.1979. ACKNOWLEDGMENTS Secretariat tor the International Agency for Research on Cancer: R. Althouse; H. Bartach; N. Brestow; L A. Cooper; J, Est&ve; L. Griclule; J. E. Huff; O. Jensen; A. Unseli; R. Montesano; C. Muir; N. Muftos C. Partensky; V. Ponomartav; F. Repetto; R. Saracd; M. Stukonis; L. Tomatls; A. Tpyns; E. Ward; J. D. Wilboum. Bibliographical and secretarial assistance: R. Jotnaan; L. kitchen; D. Mietton; J. Mitchell; A. Peraonnaz. 12 CANCER RESEARCH VOL. 40 APOOOf8449