Document Xzv3DLLrb7QQp4mX0583xNnn4

4*S'S 'aw turn trrqrr>ru xrmvm Mill ip C*ororr f'V>*r*(Ci77!l ' is* tr_- Potential Atmospheric Carcinogens mrcda ,oj Phase 1 Identification and Classification i lt .i i' i U u l i MQNS 022068 RESEARCH REPORTING SERIES Research 'eports I the Office ct Research and Development, u S Environmenial Protection Agency have been grrupe-t '"to nme series Tnese n ne broad cate gories were established 10 fac-.t tat* devc'c*r.o application ot en vironmental technotogy Elimination fad'tionai grouping was consciously plannee to 'os'er technology transfer ar\t a ma/inum interface -n related fields The nine series are 1 Environmental Health Efiects 3i ^-y. " 2 Environmental Protection Tec' 3 Ecological Research .gy 4 Environmental Monitoring 5 Socioeconomic Environmoora.'ll- r _$ 6 Scientific and Tecnnicai Ass,'ts .s' Aa 7 Interagency Energy-Env 'or - " t-.-vi ; - j- : ?*..* ; - 8 Scec-at Repo"S 9 Miscellaneous Reports This report has been assigned to the ENvtRONMf **TAk "'OTECTiQN tECn NOtOGV senes Ths senes oesc'-bes research rt'`o'i~ii u de\e oo ano comonatrate instrumentalien, equipment, and methodon, 1 'pai' o' prevent r" vironmentat degradation from point jnq r-" &>". so.. vs.. I pot-uK- * Trns*o' provides me new or improved technom, -c-. vo conin'- a~o treatment <tf pollution sources to meet environrr--ji g ,a tv star tards This documenfis to N pLoiic though the National Technical informa* norVSerfce.Sgrmfligttf ViSV1^ <5 MONS 022069 MOWSAUTO RESEARCH CORPORATION DAYTON LABORATORY Dayton. Ohio 45407 Contract Mo.: Agency: Report Seguence: Period Covered: Title: Authors: Contract Manager: Issue Date: Report No.: Disposition: REPORT DISTRIBUTION 68-02-2773 Job No.: 106.1020 U.S. Environmental Protection Agency Interin Report September 1977 - October 1978 Potential Atmospheric Carcinogens ; Phase I. Identification and Classification C. R. McMillin, L. B. Mote and D. C. DeAngelis C. R. McMillin 12 February 1980 KRC-DA-870 (EPA-600/2-60-015) Retain or destroy; do not return report. copy 1 2 3 4 5-6 7 B 9 10 11 12 13 14 15 16 17 IB 19 20 21 22 23 24 25 Addressees C. J. Eby L. B. Stevens/Central Files H. L. i11iams/R. C. Binning T. Z. Linxveiler F. J. Winslov/O. B. Nelson Central Files Technical Reports Library, R2C P. F. Cunningham, F3EA G. L. Jessee, A2SD T. R. Hetrger. CS4C D. E. wade. CS4B C. N. Dougald R. L. Haute A. D. Snyder D. C. DeAngelis C. R. McHillin W. H. Baynes .J. J. Brooks , D. J. Daha D. S. West J. V. Pustmger R. A. Lidgett P. Graham, B2SL B. G. Ward, A2SG P. Beret Location Washington Dayton Dayton Dayton Dayton st. Louis St. Louis St. Louis St. Louis St. Louis Dayton Dayton Dayton Dayton Dayton Dayton Dayton Dayton Dayton Dayton Louvain-La-Neuve St. Louis St. Louis HERL/EPA/CIM codtiinued) BKSl/EfJ HONS 022070 contracts Ho. t 68-02-2773 Job Ho.t 106.1020 Report Ho.i KRC-DA-870 (EPA-600/2-8Q-015) Issue Date: 12 February I960 Distribution List Only* J. s. Harris, G5ED R. K. Flitcraft R. E. Opferkuch G. L. Ball E. C. Eimutis J. R. Gibson W. H. Hedley T. W. Hughes G. C. Rawlings St. Louis Dayton Dayton Dayton Dayton Dayton Dayton Dayton Dayton Hay (oBMst ;Sicopy Iron the Deytoo Central File Office. BKSlSftA MONS 022071 PA-iqD/2-80-015 January 1980 POTENTIAL ATMOSPHERIC CAXCIKOGINS Phase 1. Idem1flcat1 on and Classification by C. B. McMillin, L. B. Mote, and D. G. DeAngelis Monsanto Research Corporation Dayton, Ohio 45407 Contract N'o. 68-02-2773 Project Officer Janes Mulik Atnoavr.or ic Chen istry and Physics Division Enviroriental Sciences Research Laboratory Research Triangle Park. North Carolina 27711 ENVIRONMENTAL SCIENCES RESEARCH LABORATORY OFFICE OP RESEARCH AND DEVELOPMENT . ` L`. S. % ENVMOMMEflAL [PROTECTION AGENCYJ RESEARCH'TRXJVIGw VwXj) NORTH CAROLINA 127711 MQNS 022072 DISCLAIMER This report ha* been reviewed by the Environmental Services Research Laboratory, RTP, v.S. kr.-ircnmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views ir-J i,,l ivies of the U.S. Environmental Protection Agency, nor : r.rr. t: on of trade names or commercial products const it.: to enov: sencr.t r r recommendation for use. ii MONS 022073 ABSTRACT On tha basis of a comprehensive literature search, 20 significant atmospheric carcinogens were identified from more than 12S highvolume chemicals having the potential of becoming airborn pollutants. The pollutants were divided into probable carcinogens (substantial data indicating carcinogenicity, generally including positive animal studies), possible carcinogens (positive mutageni city results troai at least one fairly well-established test or from several less established tests), and probable noncarcinogens (negative results on the bulk of the tests which had been con ducted). These evaluations are presented along with all of the references used to make the deterrinations. Additional data were col .-icted for the possible and probable Carcinogens including th.ir nr.uii production, emissions, atmo spheric persistence, and relative mutagenic and carcinogenic potencies. The pollutants were then ranked based on a benzo(a)vyrene equivalent (potencyi annually on:tt*-d remaining after 24 hours in the environment. From the top port io-.v, of these 2 lists. 20 significant carcmooens were choscr. ft- future analysis, avoiding closely similar chemical types. A r.ta'o-of-the-art review of the effect of cofactors on the camn.rjcnicity of chemicals was also completed in the first ph.rve of this research. To locate optimum sampling sites m cities of interest, a series of carcinogen isopleths >< generated. The locations of station ary sourcas of carcinogenic pollutants wore first determined. Using information such as me corral'.zed wind direction and spaed, and the height, terperature. and rate of flow of the sources, the probable locations of maximum cirrinogenic pollution concentration were computed. This report was submittsd in partial fulfillment of Contract No. SI-02-2773 by Monsanto Research Corpcratior ur.Ur the sponsorship of the U.S., Envlronsmntal Protection Pgency. The report covers the period 29 Septsbber 1*'7 to 11 October 1*79. and work was completed as of Pscsmbar 1971. Ill MONS 022074 CONTENTS Abstract....................................................................................................................ill Figures.....................................................................................................................vi Tables........................................................................................................................... vi 1. Introduction ............................................................................................ 1 2. Conclusions............................................................................................ 3 3. Recommendation*................................................................................... S 4. Selection of 20 Significant AtmosphericCarcinogens. . 6 Careinoiens selection of candidate chemical... . . 6 Evaluationof carcinoqemcity.......................................... 11 Summary on the review of the carcinoqens literature.............................................................................. 13 Production ' . and probable carcinogens . 14 Emission of in.d probable carcinogens . . 14 Atmosfhe:it i-Tsistor.ce of possible and probable car cine .......................................................................................... 14 Potcncv f o.'-rio.'' v *. rcfablecarcinogens. . . 24 Relative -im :cr..: incr.cy................................................. 27 Relat: .--' care lr.ooer, :c potency........................................ 27 Prior111zat ion of possible and probable carcinogens .................................................................................... 27 5. State-of-the-Art Rev. . i fircinogenic Cofactors. . . 32 6. Carcinogen Iscpleth ' : .ration................................................. 33 References................................................................................................................ *7 Appendices A. Review of tne rare ir.o; .n literature of 125 chemicals . 82 B. Review of thr c ire-n refactor literature............... 217 v MQNS 022075 nanus Number 1 Ethylene Dichiora.de O'.icontrations in Houston, ' /.s .it 500 .) kn/cm) 2 Ir.:. u1 Data 3 Output Data 4 H..~stc:. .'arcinoij'Ti T:;opleth 5 Locat:tr.s of Maximum Concentration of Pollutants in Houston TABLES 1 ?z- 1: -..i: / . ;: of Candidate Carcinogens 2 So-.: 't i\ leer, ion rf Candidate Chemicals 3 A. .i 1 r 'duct ior. Kicares 4 .'r . . - Probable Carcinogens 5; :vv- ru"! Possible Carcinogens . >i :..t-Rjr <cd Probable Carcinogens 7 bn ns - H i-.ked Possible Carginogens S ;.n. ; ;n.;, T-. rsistent-Sar.kcd Probable Carcinogens 5 Z~. -.cns 'Pvrs t ster.ce-Ranked Possible Carcinogens 10 ?.e! >'> M,,:agc:c Potency 11 ?r. iry Mutagenic Potency Data 13 3th.<.r A-tagen Data to Consider 1J P.ol.v ,vc Mutagenic/Carcinogenic Potency c: : robab'.o Carcinogens 14 Mut i.-.lt : Cir : mogeme Potency of ; :;.e jreir.ogor.s .3 ?ur . . . r.'oablc Carcinogens by Equivalent E. 5ta)P After 24 Hours 16 Ran-.-r.g cf Ppssiolc Carcinogens by Equivalent Emissions'of B'a'P After 24 Hours 17 Cher.cals m Tcf M Probable Carcinogens on MRC Data Base That Are Found in Four Cities 18 Average Concentrations at Points of.Maximum Pollution in Houston Pag* 31 32 36 40 41 3 7 10 13 13 15 16 l7 18 30 31 31 23 24 25 26 29 40 VE MONS 022076 SECTION 1 INTRODUCTION The growing recognition that exposure to certain substance* in the environment may pose health hazards has prompted a critical exam ination of the available screening procedures and analytical methodology fur reliable monitoring. Although the U. S. Environ mental Protection Agency iEPA) is generally concerned with a wide range of pollutants, the pollutants or hazardous materials that are also carcinogenic have been assigned a high priority owing to their adverse effects on public health. The objective cthis research was to develop samplina and ana lytical techniques vd instrumentation for 15 of the most signifi cant; atmospheric carcinogens and field validate the technology which is devo'.-pod. the first phase of this research several tas'<s were c -cleted, including (1) the identification of 20 significant strosphor.o carcinogens from which the EPA was to select i5 pollutants fer study; (2) the collection of information pertaining to the effects of cofactors, inhibitors, promoters, stc., r car. si) and the generation of carcinogen iso- phe t'n iec-dt" tntim-iff sampling sites in the cities to be used for : c'.i validation of the developed technology. In crier tc select these 20 significant atmospheric carcinogens, .Monsanto Research Corporation (MRC) first selected a number of candidate chc.-icali having the potential of becoming atmospheric pollutants wh.ch are produced in fairly high volume and have been cited ih the literature as being carcinogens or portential car cinogens. The primary (original) literature was consulted to see wrsothcr it indicated that the chemicals were carcinogenic. The r.-.ex.icals were then classed as either probable carcinogens, possible carcinogens, or probable noncarcinogens. Production figures, er.ission figures, environmental persistence data, and potency data were then'*assembled In order to prioritize the chemicals. Twenty pollutants representing a variety of chemical types were then selected from the most significant possible and probable carcinogens. C'-.c .-implication to tha carcinogenic effect of materials considered in this project is the possible synergistic effects of other materials on the chosen carcinogens. It is well established that other material? can act c&facs>rs and either enhance or inhibit t MQNS 022077 erqiatic effects or which materials have this property. A comprehensive literature search on the state of the art of car cinogenic cofactors therefore was conducted. This search and the resulting review concentrated on the effects of various industrial chemicals or. the carcinogenic potential of other industrial chem icals. it also lightly covered other cofactor effects such as physiological (e.g., hormonal), genetic, medical (e.g., disease states), environmental {e.g., light), dietary, and other factors that affect the initiation or growth of cancers. A portion of the effort in the first phase of this research was devoted to determining the location of optimum sampling sites in four cities where field validation of the sampling and analysis equipment i-.d techniques is to occur (Houston, Los Angeles, Birm ingham, 3nd Newark). Tr. crdcr tc accomplish this task, the MRC Source Assessment Data Base wu iwi -o obtain most of the necessary input for the EPA Cl inavw'.c tic'! Dispersion Model (CDM) . The chemicals included in the s\_). - : > from the list of probable chemical carcinogens cer.wr-.'vi irlier in the project. The carcinogenic isopleths we--' it-d for Houston for inclusion in this report. ;r t :-lining two years cf this contract, sampling and .i-.uly* 'finiques and instrumentation will be developed for at :.* . . S e: the atmospheric carcinocens selected and a field vi); of this methodology will be conducted. 2 MONS 022078 SECTION 2 CONCLUSIONS An extensive review of the primary carcinogen and mutagen litera ture of more than 125 chemicals having the potential of becoming atmospheric pollutants was conducted. It was determined that for 38 of these chemicals there is a substantial amount of informa tion confirming either that they are carcinogenic or that they have been regulated as a carcinogen. These chemicals usually had both positive animal studies and mutagenicity tests. Another 23 chemicals were determined to be possible carcinogens. For uhese chemicals, one or more significant mutagen tests were reported to be positive but carcinogen results were ambiguous if they had beer, conducted. The remaining chemicals had been labeled poten tial carcinogens in this literature at some point. However, a careful review of the presently available literature indicates that they are probably non-carcinogenic. Inf. rmation was gathered on the 66 possible and probable careinToensi sc that a prior itization model could be used to determine the most significant atmospheric pollutants. Production volumes, '.mission factors, atmospheric half-life values, mutagenic potency, and carcinogenic potency were considered in determining the significance of the pollutants. A final ranking was made for both the possible and probable carcinogens based upon the equiva lent kilograms of benzo(a)pyrene emitted per year remaining after 24 hours in the atmosphere. From these two ranked lists, 20 pollutants were selected which represented a variety of chemical types and were high in the cr-.critned ranking. These chemicals are as follows: bcnzo(a)y mn-, tetrachloroethylene, ethylene dichloride, benzene, carbon tcrachloride, ethylene dibromide, toluene-2,4-diamine, dioxane, nrrylonitrile, chrysene, benzyl chloride, benzidine, pentachlorophenol, dichloropVopene, styrene, hcxachlorobutadiene. di2-ethylhexyl) phthelite, vinyl acetate, ethylene oxide, and acrolein. A roviev of more than 2,300 literature citations of the carcmo:ens cofactor literature was coeipleted. This review includes sections on dietary cofactors, physical agents and body materials, therapeutic agents, anditreatments.jenvironmental^cofactors. Industrial fcfiemicali a&t dolltitants. and esoteric materials and 3 022O'?9 other substances. The development of cancer in laboratory animals and humans is a complicated process which may be enhanced or inhibited by a wide variety of conditions. Probably the most significant cofactor is smoking. Smoking exposes individuals not only to carcinogenic substances but also has been demonstrated to Increase the risk of personnel exposed to agents such as asbestos and radiation. A scries of isopleths were generated for Houston which illustrate that there are three locations in that city with approximately the same total average carcinogenic pollution burden. The burden at the first location is almost totally due to benzene with a ^inor component of ethylene dichloride. The burden at the other tvo locations ntiarily comprise ethylene dichloride with signi ficant amounts of carbon tetrachloride and chloroform and lesser amounts of trichloroethylene and vinyl chloride. A model of the isopleths illustrates the importance of properly selecting the sampling sites. I HONS 022080 SECTION 3 RBCOWHENDATIONS It is recommended that 15 chemicals be selected by EPA for use in this research Iren among the 20 chemicals listed in the Con clusions section. These chemicals will be the target pollutants for tne research on sampler development and analytical technique develc'r-ent. With the prioritization model devised for this research, the relative significance of any other chemicals or pollutants of interest can easily be determined. A large r-.rcer of varied influences affect the development of cancer m hu.nar.s and animals. With the exception of smoking, which is c'.egrly an important carcinogenic cofactor, the signi ficance "!f - my of these cofactors has yet to be demonstrated. From the carcinogen isopleths generated for Houston, it is readily apparent that the sarpltn location selected greatly influences the quantity and c'-oositicn of the pollutants being monitored. Since a area ter variety cf pollutants can be found at the second and thiri ri tne three locations examined, it is recommended that one of there 1 mrs he used for the field validation of the sampler for -h.u ct.tract and for contract 68-02-2774, using the portable carcinogen sampler. 0 MQNS 022081 SECTION 4 sr:.-:c~: ):; OF 20 *!C:;iFICANT ATMOSPHERIC carcinogens The firs*. ta^V re r..red :n this contract was to identify 20 signifies;-.? a:: cs: rr-ric, . i rcunogenic, pollutant chemicals. In order tc sol -r * these 20 -.i:-ificant atmospheric carcinogenic*, Monsanto Rcs<a rch Ccrpcrat: r (MRC) first selected a nunber of candidate -si; a.- produced in fairly high volume and have bee :t : is : a carcinogen or potential carcinogen by sone pie of 111 -* t ivjf. The primary (original) literatui was consultu : t indicated that the cher.icals -.ere c3rcir.oc<-.- . 1 Ts were then classed as either probable ca re incaer.?-. ssi;.:- v,i: .r.ogens, or probable noncarcinogons. Producticr . . . .s f i jures, environmental persistence da* a, a:.-: . : th*; issenbled in order to prioritize the rr.fr . . > . - ;: . : cc resent ing a variety of cher- icoi *. . or the post significant possible arc! ; : r. SELECT :tc. .he first : : :.i: j. . i:e rr.- r; ..i 1 s was obtained by dcterrinir.c which cher.c.i. :. * he . .re "ssessment Data Base lli ar. also fo-r..! ' . h : . 'js;- rted Carcinogen List 121. II] lingtis, ' criteria \ Tectlmc i! , anc .1. I. . uilw f^ourea Assestrerit: Non- I-isstcr.j. rPA-6OO/2-77-10 (National :orration Service N:o. p* -1977. (2) SuSOCvt:.: ...lrciroge ns - A Subfile of Ith ataaevs L: it, 1970 Fditior., H. L; Ch&B Melon-:ic . NICSK); 75-188, lAS. (cpf Education, ir.d Viel'fare, National. Ins (ard 'Health.' ' 1.1 1 1 cuoauorvil G HONS 022082 _ ____ c<Jpoundfra9raS*RC 'emi'siionr <J4t *lso on the 1976 HIOSH SbapecVed Carcinogen List oW warn cited in the "Registry of ToxicjXffacts of Chemical Sub stances* [1} as a mutagen, teratogen^ or neoplastic agent. Of these-M, 47 compounds had references:',indicating positive sattt genic, carcinogenic, teratogenic, or^beoplastic test results, the remaining 36 are on the suspected carcinogen list only be cause of current interest, with citations such as "currently undergoing tests," "candidate for additional oncological infor mation," or "TPA selected for priority attention as point source water effluent discharge toxic pollutant." These two lists of chemicals are shown in Table 1. Or. Sawicki's list of atr.-.-sp.-.t.-ric vapors and gases (4) was checked against the mosh list, and materials common to both compilations were found to be present cn our l:st. The 1972-1973 "Survey of Compounds which Have Boor. Tested for Carcinogenic Activity" [5) for which positive result- were obtained was checked against the source assess--r.t data base. It was found that our prelim.nary list include. i.l "rt.ound3 c'Ton to both tabulations. A report it.ed Tre) ; Scoring of Organic Air Pollutants" lists 637 m-.ic chf.-. -i'. , along with their production, volatil ity, and toxicity data > .. of these chemicals, 108 are cited as hem: cif r --jtj^cn:; -r mrinocenic, or as producing r.ooplasrs. .';bt r ict: men...- already -inder consideration and `he him pr.ly loi-rud *.' .-r to 74 materials, r 1; r: :;.it: ng cher.cals : -n.ch pr : iguros were not availiblv or were less than 4 56,000 kilrir.v '. million pounds) per year produced * list cf .3 _\hec*i:\ln * .rther evaluated. There am listed Pelow wit. tv . r ar.r j.i l ra-:.. t:yr. , 1- r-.-ai.stry '! "r: \ ,r iffoctr. .'hcmical i'ubstances, " i-.irws I md I ` . f. '. Fairchild, - d. 3HEW lublicatior. d-T-vIl) "3-12 1 Dopam.-er.t o: Health, Fdueation. ana '.- -Ifare, I. it to-j'. ':*;titutc tar -rupational Safety and H-alrh, .-'opt umbo: l *7 7. .4. Sawick:, . . Chemical Cr~: osition and Potential " er.otoxic" Aipects of "cllut<td Atro-.uhercs. In: Air Pollution and Cancer -.n'.Man, ''./*oh-, ' . Fchmahl, and L. Teratis, eds. Intcrr.atioril Atency fer Research on Cancer Scientific Pub lication .16, 1977. p.p. 127-157. 15] Survey cf Compounds Vlhich Have Been Tested for Carcinogenic Activity', Volume* 1`through 7. ' D8EH Publication ho. (NIH) 75, Public Health Service Publication Ho. 149, C.S. Depart ment of Health, Education, and Keiface, National Ir.stitutoa qfjlefcich* HONS 022083 J3 11 fimUTl PRELIMINARY LIST^OP BRNDIDATB CAJRClNCXTEHf Caxcinooenic/neoplaatic/ teratoqenlc/mutaaenlc coapound* Ealeeiona. metric NO. of tona/vr typ 1 Trlcfcloroe thy1e ne 2 Vinyl chloride 3 lmtM 4 roraaldehyde 5 Maleic anhydride 6 Cartoon tetrachloride 7 Chloroprene 8 Hethyl ethyl ketone 9 Ethylene oxide 10 Propylene oxide 11 Phenol 12 1, 1-Dichloroet hano 13 Chlorofora 14 Naphthoquinone 15 Ethylene dibroaud* 16 D.chlorobutene 17 Ber.ro la) pyrene 18 Methyl methacrylate 19 Acrylonitri !; 20 fotchlorohydr m 2: i v ircq jinonc 22 1 .pnenyl 23 >phtha. it.c 24 ( r-iparoi 25 1 inthion 26 CMrracetlc a. .! ; 7 DichIcrcphcnc. 28 xetnylenedia.-.i 1 me 23 Benzyl chloride 10 DDT U Poiychlorina-.e.l biphenyl* 22 Naphthyl *thyicarbanate 73 Quinone 3* Hydrazine 35 Cndcsulfin 14 Dlchloror.apr.thc| rone 3' T r1chioropheno1 If xethyietyrene 34 Dicniofovlny1 d^Tu-thyl phoephate 40 Trichlorfon 41 Anthracene 42 lea*(a)anthracene 4) El%fcUocofthyi; ether 44 C4^4f 45 Olazlnen 46 Si troaodiMthylamne 47- pywnr . 158,070 142,290 102,348 40,695 18,764 12,672 7,459 5,324 4,540 4.386 4,383 2.559 1.069 1,051 886 866 8 30 727 S38 224 101 92 90 5 42 37 37 26 24 19 18 12 6 3 2 0.9 0.5 0.5 0.2 0.1 0.1 <0.1 <9-1 <0.1 <0.1 <0.1 <V.l 5 6 15 16 3 11 2 2 8 2 13 2 4 1 2 1 58 1 4 2 1 1 1 2 1 3 3 1 1 1 1 1 1 1 1 1 1 l 1 1 1 1 1 l 1 1 Li (con* fined) 8 MONS 022084 TABLE 1 (continued) Candidates with no references cited Emissions metric No. of industry tone/yr __ tflgj emitting 1 Toluene 331,473 2 Trichlorocchane . 180,128 3 Tetracnloroethylene 77,418 4 Ethvlenc dichloride 67,079 5 Acetone 29,057 6 Hethyler.e chloride 27,130 7 Carbon di sul I icle 25,768 8 Methyl chloride 22,944 9 Ethanol 11,548 10 Aero loin 6,495 11 .Styrene 5,625 12 Vinylidene chloride 1,328 13 Dichlorodii1uorooethane 425 14 Allyl chloride 421 IS Dichlorosthylene 419 16 Trichlorofluoruthane 85 17 Anil me 8 18 Nitrobenzene 45 19 Ml trophcnols 11 20 Heptschlor 11 21 Malathion 10 22 Tetrachloroet.-.anc 9 2 J Diphenyl oxide 7 24 Methyl bromide 6 2S ti-Dichlorobemro*.- 3 26 --Dichlorobenzene 3 27 fclthane 2 2t Er.dr in 2 29 Dim trotoluene 0.4 30 Ni trochlc robe mere 0.3 31 Dichloroprocionlc acid 0.2 32 Dursban 0.1 33 Ethyl benjenc 0.1 34 riooranvhene <0.1 3S Guthior. M Toxaphene <0.1 <0.1 11 1 4 10 11 5 7 7 12 4 4 4 1 2 1 1 1 3 1 1 1 1 2 1 2 2 1 1 1 1 1 1 1 1 1 1 * MONS 022085 Chemical_______ '_________ Productions kg/yr Acetaldehyde Aldrin Benzidine Chlorobe.-.zi late Cumene hydroperoxide Di- (2-ethy Ihex'y 1)phthalate Dimethylhyarazinc Oisodiuir rothanearsonatc Eptam Ethylene uly.-ci Ethy lenim: r.c Hexaroethy ler.et etrami r.e 4,4 ' -Methy ler.e his (2-chloroar:line) Morpholine Maphtha Pentachicrcthrr. .1 n-Pentan<? Sorbic acid Tetraethyl lead Toluene-. . .rso 680 11 5 1 900 180 0.5 16 2 1,700 2 46 3.5 10 3,800 20 220 18 160 29 1 f tr.; 90 cor: ' r-.:- r -t, "Research Troqran on hazard Priorif * " r. Jher 1 c 11 s " (7), 33 had already been c .. .or*.-.;. ly:.ud::.; -lids such as polyurethane, high-boilir.q 1 : .. ds sue:. a? : 1 fluids, and low-volume chcncals such . : v.ir t. . dye * !6 chcr:cals to be con sidered for in.. .: Thr* v ' < uerch loroethylenc, vir.yItoluenc, : 2-~orci: tv..~:a/ . . rr>: tentatively identified as being nonca:.: .-.gens. A :e:r*-., : !*'2-rhloruethyl) ether, is produced or released m 'xtrer.. 1. :. 1 quantities, if at all. The remaining 12 are is fallows: Hcxachlorobenrene Hexachiorobutadme Tetrabr :roethine Uichlorop roper.c Sulfolane ,y 2-MethoryethaneJ 4,4-Mothylene bis .2-chlrrcam 1 :..e) Dimethy 1 amine Oioxane Ethyinn mine Benzidine Dichlorofcensidine |7] BrotAV S| IX , et al. Besdairch Program on KazardlPrlorlty Ranking of .Vanufacturcq Chemicals. National Technical diforiattonl Sertici 'No, P$ 62r 161', 197?. to HONS 022086 jluMtotfofattwar^^irorunfrltjl 1 ?ate$$$Selected Chemicals!^ lvaXnBceS'74?Wujipected carcinogen* for their environmental per sistence. More chan 20 of.theae chemicals were alreadyaonder consideration. Many of the rest of the chemicals are either produced in low quantities (<455 Jtg/yr) or are essentially non volatile. The remaining chemicals and their production volumes ar* listed below: Di-tert-butyi peroxide Hydroqen peroxide 1 -Naphthy lam.i ne Benzoyl chloride 1.4 x 10* 0.9 x 10* 3.2 x 10* 5.8 x in* lioTa! metabolite ,\; r 1 '2 life 10 min A series of reports on 11 compounds prepared by the Office of Air Quality Plannina and Standards Department of FPA consists cf carcinogenic and muiiyenic information for the air pollution assessment of these cor.pcur. is. Those vh:cu. were not yet being considered were added *" our list. MRC's Environments. ..-./tical Science' -.er (EASC) personnel suegested that a - tier hich-volum.- - c :uals should be con sidered :n this prc ect if they report".: to be carcinogens rr mutagens, lr.clud.r. v n l ortpropar.: _cthy'. no . A summary of the s .n this project is sr. \f : r. T ;! into m.-.u r. -nls for i nvest: cat: on 2. EVALUATION OF CARCINCOEN!CITY Ar. attempt was made to nntair. ;r;r.iry l:*- riturv references for each of the chemicals -t.ier cons . lerat. .r,. A computer informa tion retrieval search as aiso -ce for oacr of the chemicals using both the CA-SCIBLlNu nr.u ?0X:.:N1. ditn bases. The primary litet iture shows or. what basis a o.-.e.-.: :ui wu added to the N10SH Suspected Carcinogen ,(iisi while ::c CANCf. :.1NE and TOXLISE bases list recent tests run on the compounds and current thoughts on each compound in. the puolishcd '.iterator". Based on these source* of data, coupled wit.-, information from Reference 5, a qualitative determination was made as to which chemicals are probaole carcinogens, possible carcinogens, or probable noncarcinoqess for. purposes of this project* Ma4y dfk thead fchafcii&ts krel durrerf ly undergoing Icarcinogenirfrity tests J iTtverqfbraL ItliisaHipss Represent only wnlindJfcaeion t>f which chemical a iall. orofeablvl be labeled a s* carcinogens 4a iter t HONS 022087 fiCSER?2. -- - ttambar of potential Candida ti SOURCES FOR SELECTION OF CANDIDATE CHEMICALS -- . -- . Number of candidates selected Source >300 83 NBC Source Assessrv.-nt hata Base (1) and NIOSH Suspected ".irclnoqena List (J) 6J7 JO Preliminary "nrir. : of Organic Air ~ollutarsts. ''A ar.J indicated as a tiru: r.oceri ->r *utaqcn 90 12 i-t-searcf. Pro-.'r c. or. Hazard Priority r.ir.Ajnq of Manufactured Chemicals |7| ar.J -..-.d icat id a- ^ nutagen or :j: i, r. 74 rr-' i.-w of -r.vi: rr.T.til rate of i '.tet'i .calr. 'Hi and production o: VCt* <.i vr '^4 >1,106 * 1J7 ' . * t Comprehensive testing cc plcte. 7h..-.elusion of chemicals with so little data is r.oeoss.iry :-,r thi. project since only a few chemicals have Leer, ipec.fieally designated as known human carcinogens. In the evaluation of car.'ir.cyer..:ty, two cf the major problems encountered were lack of data and conflicting data. Maleic anhydride exemplifies tr.c ferner probit-'. it is on the NIOSH list because of a 1961 tt-sc. wr.vre two enr of three male rats of an unspecified strafifn devoid:-.; locai omas after repeated injections of maleic anhydride. A chev-. f the current litera ture did not uncover any ether s igr.: f io :n t tests which have been conducted on maleic anhydride. Conflicting data exist for formaldehyde. Many reports show for maldehyde as a mutagen and/or a carcinogen in many types of short-term test systems. There are also comments to the effect 1311 S. 6., ct al(. Rfvifevi of the Environmental! Fate fof ad Chemicals I EPA-S6O/i-77-0Q3 (National Technical # lont SeV^icI :,fe> P l2f 1*1) J May 197*7. 12 MQNS 022088 MAf *C Another problem is' that some of the suspected carcinogens have been administered with, bemsene as the solvent. The solution was to disregard such data'll there were sufficient other data avail able on the compound. If other data were not available, we had to consider whether benzene was carcinogenic by the route of administration, and as a last resort, how potent benzene was by that route of administration. In addition to the available primary references, general sources of information on the carcinogenicity o: -hericals were consulted, such as International Agency for Research cn Cancer Monographs and results from National Cancer Institute broassays. In the search for information on 127 fairly high-volume chemicals suggested by some type of literature as be me carcinogenic, sub stantiating carcinogenic data wore f"'.:- :i m the literature for 38. These were labeled probable earem:c-_>r.r,. Information such as mutagenicity data indicated that another 26 chemicals may possibly be carcinogenic, although jj'j or. them are incomplete. These 28 were labeled oossiblo carcinogens. This project has as its ultimate product or-, ambient air sampler coupled with an analytical protocol capjbl : sampling a broad range of chemicals. As such, the ova lu.it i * o: what is a possi ble carcinogen has been fairly broad ,'.g., ore positive estab lished mutagenic test:, and chemicals or. the tesulting list should not be construed or. reputing regulation, but only as chemicals in which there are positive muta.er.lc indicators. In general, however, more data are needed. SUMMARY REPORT ON THE REVIEW OF THE C.\?.C IhOOEN MTERATURE A summary report has been generated which rovw.s the available carcinogen literature on more than 125 chemicals. Based on abstracts of the primary literature, ar.-i the actual papers where possible, a determination was made m each case as to how the chemical would be classified for :1 s rep:t t. f Chemicals for which the overwhelming preponderance of information indicated carcinogenicity or for which regulations had already been enacted to treat the chemical as a carcinogen (e.g., benzene) were clashed as probable carcinogens. This' generally included positive animal studies coupled with positive mutagenicity tests. Chemicals on which one or mpr& signi:icant mutagenicity jtests were positive (a positive rfiimt in at Jleast ;one well,-estagl.shed mutagen test) with ambijgfloullcpxcipogfn results werd aabeldd It3 MONS 022089 bod*lbl TUStrtK&qkn*. It it believed that ifeHOdgftflfW)*#! species and routes of administration were tested, these 'ehenicala would most likely be labeled carcinogenic. The remaining chemicals have been labeled potential carcinogens at some point ir. the literature- However, a careful review of the presently available literature indicates that they are probable noncarcincgens. For the 66 probable and possible carcinogens, mere data were obtained pertaining to quantity emitted, quantity produced, some r_irket forecasts, persistence m the air (primarily as related to photo-oxidation and reaction with !i0 and > radicals), and measures of volatility (boiling point and vapor pressure). A cumulative listing of the summaries of the 125 chemicals eval uated containing the above information along with all of the references to where the information was obtained is included as Appendix A. PRODUCTION OF POSSIBLE AND PPOBABLF CARCI .OCT.'S In addition to the production figures : . a Appendix A, "A Review of the Carcinogen literature o: - r. cals , * production information was gleaned : i or Crvm. oa`. i .oo ! *. ji"` wring News, Chemical Marketing Reporter, and from <1 . -'.4 : .frit research service to which we subscribe. A sumr'iry .i";.a additional production volumes is shown ir. Table i. Using data from the above sources, the : 'bn! . md possible carcinogens were ranked accordim to reduction volume, as shown in Tables 4 and 5. The most recent pro ii.ction data were consid ered most significant. EMISSION OF POSSIBLE AND PROBABLE CARCINMr NS Although the ranking o: the chemicals in C idles A and 5 indicates which materials should be considered "high-volume" chemicals, a more realistic approach to ambient air sar.pl mq should depend on the amount of the chemical being released to the atmosphere. Thus the emissions will\se the basis for all future ranking of these chemicals. The production figures obtained were utilized to calculate the quantity emitted in cases where literature values fog emissions were not available. The starting point for each of the cher: -tis was its quantity emitted. Where this information was r.o: available, a simplified assumption waslmade ;along,,the line* .of Fuller, ot aid [6, PB 264 442J ,joal klfiaqtidn|(e|g.I fof' production J.s jlost to the atfosptferl^ (c|dqtei7n{ncft^h^fqu9qt|^r emitted .per year*. L4 HONS 022090 TABLi W?gWOITlOftAL rtOO^CtltyflCrGOlLE^ Chemical Froducxioa* Production, ______ *1_______ Tear _____ Tear Acrolein Acrylonitrile Aldrln Allyl chloride5 Beneene Bcnsyl chloride iipheny1 Captan Carbon tetrachlorIda Oilordar.e Ch lorolora Chloropr*nec Dichlorcbutene" 0iohloropropane* S-.chlorovinyl dimethyl phosphate 3: - i 2-ethylhexvl1 phthalata rmitrotoluene' Eoichlorohydrm Ethylene dibroaide Ethylene dichlorida Ethylene oxide Porau Idehyde Hepteehlor Kcxachlorobonzene reapteber. rothiatola Methyl chloride Me thylenediaaine5 Horphotinc l-Niphthy lasiine S i troth lorobcns ana*1 Pentachlorophcnol Propylene oxide Styrene Tetraehloroathylea* Tetraethyl lead Tetraethyl lead and tetraaethyl lead Toluene-2,4-dlaaliji TrlchloroethyUoW Trichloropheool , .i X 10* . X 10 . X 10* 3.0 X 10* 2.1 X 10 6.4 X 10* . X 13* 4.1 X 10* 4 . 1 X 10T 2.2 X 10" 4 . > X 10* 1.5 X 10* 4, X 10 4.7 X 10* 9.4 X 10* 1.5 X 10* 1.4 X 10* 1.4 X 10* 2 .5 X IV 1.2 X 10* 1.) X \19 l.C X i V *.: X .0' 1.5 X 10* 5.5 X 10* 4 . 5 X i 7* 4.7 X 0 2.: \ i.? X !: 2.9 X i 2.5 X ; 2.9 X 10* 9.1 X 10 4.5 X IT * 2.1 X i: 1.x X 1 . t X ;o 1.1 X l Jr_fv**lT.Q 4.2 X 4.7 X :o 1.1 X :v 2.2 >1 IV 7.7 X if 7.3 X 10* J.C X 10 2.1 X 10 2.7 X :o 3.1 X it> 1. ) X 1C* 1.6 X jl 1.) X 10 1.0 X ilO* 1.6 > pa* 1974 1676 1974 1*74 1975 1*76 1971 1976 1974 1975 1975 19" 1975 1974 1974 1976 1976 1976 1976 5.5 X 10 4. ) X 10 5.0 X 10* 3.2 X io- 3.7 X 10 4.1 X 10 4.9 X 10* 1.3 X 13 1975 1973 1974 1975 197"' 1975 1973 1975 19 7f. 1974 1976 19*3 .971 1977 17 74 '.97 1 1975 1974 1976 l?'t 1773 1974 1974 l?'4 '.7'6 17 5.5 X 10* 3.5 X 10* 1. 7 X n 1.9 X IV 2.6 X ia 7 ~ X 10 1.4 X 10* 1. 1 X U" 1974 1974 1975 1971 1977 1974 1975 1971 1976 1973 1975 1973 19 7n 1975 1977 1975 1973 19* 1974 1973 1916 li 4.9 X 10T 2.3 X 19 6. d X :o ? f 0 X 10* 2 . X 10 2.7 X 10* 3.2 X 10* 3.2 X 10* 1974 1974 1975 1974 1976 1974 1975 197J 3.1 X 10* iojr 1975 fl 97 4 (tentfoupti) 15 HONS 022091 TABLE 3 (continued) _ Chemical vinyl ecetete Vinyl bromide! Vinyl chloride Vmylldene chloride Chrysene* Production, tq Tear 4.6 a 10* 1.0 a 10* 1.9 x 10* 7.6 x 10* 2.5 x 10* 7.0 x 10' 1 . ? X 10* L9 75 1974 1975 1976 1974 i 197? bo ' W 6.4 x 10* 1074 6.9 x 10 1971 1 .9 x 10* 1975 2.4 x 10* 1971 `production flqures cited sre dinnd from the following sources, with no nore than two years of ftqures par reference! Chemical and tnqlneerlno Kan, June. 1 *7S; Chemical Marketlnq Reporter, various issues> and a multiciient research service subscription (complete Information ie not available to the general public). b capacity. ''The 1976 production of polyr: lorrprvr.e was . .4 x 11* kq. Assume 1.4 * 10* kq at chloroprene was produced ft: this use. ^Butadiene is converted to either 7.)-dichlcrobutene-l for rhloroprene Manufacture of 1,4-1:_-hiorobutene-f for adiponitnle nunuficture. In 1976, 1.4 q polychlcroprem .as produced. Assume 1.4 x 10* dlchlorooi'.-. r.e r-av have been used. *7he bow capacity for diehiotep: : -10 w.is 14 -illior. klioqrums ir. !9?4 while the Shell e.ipK.ty :'nr a JioM .roprof cne/ J ichloropropane mature was si: 1; > iiloorias. Assume half tnc Shell mature was dichirr rpr yor.a and the rapacity equals the production to qive 2.5 * 17* Vq for both facilities. trinitrotoluene ie an interca-i.ate in the sut-jfecturc cf toluene diamne. A qroee assumption wruld be to equate the production o! theie chenlcele. 10* kq formaldehyde was sed to make .-ethylenedlaniline, with 0.41 kq formaldehyde usee. :>r each kq c'. re thy lenedianillne produced. This yields a production of 1.6 x kq sethylensdiantltne. "in 1976, 7.4 a 10' kq of HNO were used to make nitrochiorobenrene where 0.47 kq mo, la used to make 1.0 kq nitrochlorobenzene. Therefore, the 1974 production of nitrochlorobenzene was about 6.2 a 10* kq. uae of 2,4,5-T herbicide ! is teen restricted hy the government i t' 'To produce Sire modacrylic, rrcisicc i cr.-J. Assure 25* of the 1.14 a 10* kq xwdscrylic capacity was Sir end it was operatlnq at 614 capacity tc c.ve a vinyl brosiie consumption of 1.9 a 10*. kq. ' `Assume ISO mg chrysene per grasi organic ato-ospheric particulate natter. HRC Source Assesement Data Base. -'_iy 1977 , cites 1.1) a 10* kf of benzene soluble orqanic particulate natter emitted Hiis frajjucqs tfr (U7fx, lO^kg J* MONS 022092 CMKmc^aciinpc^oir^ixAHicTOr proMHWiaucwoGWs* 111 ^Cbamlcsl 1 Ethylene diohloride 2 Vinyl chloride 3 Acrylonitrile 4 Sen sene J Carboo tetrachloride 4 Tetrachloroethylane 7 Chloroform Trichloroethylene * Olchlorobutene 10 Epichiorohydrin 11 Ethylene dibroalde ' 13 Toluenediasdne 13 Dinltrotoluene 14 Vinylldene chloride IS Benyl chloride It DDT 17 Hydretlne It Chlordane It Oloxane 20 Bensidene 21 Captan 22 Methylene bin(chloroaniline) 23 Ethylenlmine 24 Dichlorobentldlne 2S Heptachlor 2t Chlorobentllate 27 Benso(a)pyrene 21 Dimethylhydratine 29 Chrysene 30 Dlaminaniaole 31 Bens(a)anthracene 32 Tetrachloroethane 33 Bis(chloromethyl) ether 34 Nit rosodiamthy1amine 35 Ethyl carbamate (urethane) 3t Trichlorofon 37 Polychlorinated biphenyls (1.8 x 10*3 31 Aldrin (3.0 x 10*1 Production, S.5 x 10* 2.t x 10* (.1 x 10* 6.4 x 10* 3.0 x 10* 3.2 x 10* 1.5 x 10 1.4 x 10* 1.4 * 10* 1.4 x 10 1.2 x 10 1.0 x 10* 1.0 x 10 7.0 x 10' 4.1 x 10' 2.0 x 10' 1.7 x 10' 9.6 x 10 7.4 x 10* 4.7 x 10* 4.5 x 10* 3.5 x 10 2.2 x 10* 2.1 x 10* 9.1 x 10* 9.0 x 10* 9.3 x 13' <5.0 x 10* ;. 7 x 10* 1.4 x 10* l .0 x 10* 9.1 x 10 * <4.5 x 10* <4.5 x 101 <4.5 x 10* 1.0 x 10* -0-0- rear 1977 1974 1976 1974 1977 1976 1976 1976 1776 1973* 1975 1976 1976* 1976 1976 1971 1974 1974 1973 1976c 19 75 197' 1974 1976c 1974 19'6C 197 7'- 0 1973 1977* 1970C .* 19 7 7C * 197?C.3 1974 1977c 9"4C 197,'C .4 19 7 4 J 19*4' ``Average of eeveral^dlfferent n-.-nber*. &Intermediate In toluene diamine manufacture. Assumed equal production. CDocument published in cited year which contains production rt figure. Assume emitted quantity equals produced quantity. *Ouaneity imported. ^Assume emission is It of production ,from stationary sources ^ijjd ignore non*tationary sources. ^llrrspt produetioh ,'assumed to be ^ro; but litefratvrO .values also cited'. 17 MGNS 022093 fKm 9, WtOOOCTlOW-RANKED POSSIBLE CARCI NOGESS Rank 1 2 3 4 S 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Chemical Styrene Formaldehyde Ethylene oxide Ctttwno hydroperoxide Propylene oxide Vinyl acetate Allyl chloride Di-(2-ethylhexyl) phthalate Methyl chloride Tetraethyl lead Chloroprene Nitrochlorobenzenc Pentachlorophenol Dichloropropene Acrolein Methylenediani1ine Morpholine Hexachlorobutadier.r Dichlorovinyl dimethyl phosphate 1-Naphthylamine Mercaptoben2othiazc 1,1-Dichloroethane Di-tert-buty 1 perox. Hexachlorobenzene Vinyl bromide Dichloronaphthoauir.cnc Trichlorophenol Biphenyl (2.2 x 10T Production, V.M J.O X ) o * 2.1 X 10* 2.0 X 10* 1.4 X 10* 7 7 X 104.3 X i0 2 . i 10" 1 .8 V 17" 1 .7 X I 0 1 .6 X 1 0 1 .6 X } n 4.9 X * i"' 7 2 . 1 X io^ 2 .B X 10' i.4 x i ,> 7 l.: 17' l X ;07 (> . - 1 6 > . .* 106 7 * 10 *i j 1C'* 2 . t 1 0` . 4 .% 10 s 4.5 /. 10" 1.9 X 10" 9.0 !C 10* 5.0 X ; r> 2 " '- Year 1977 1975 1975 1974 1976 1975 1975 1974 1976 1973 1974 1974 19 7 5 a 1976 1974a 72, 76a 1974 1975^ 1976 1974 1974 1977b . c 1977b 1974 1975, 1977? *c 1977b,c 197 5 dAverage of production f i. ^Datc of publication of ref -rer.ee. cAssume evasions afe equ.il tc production. d Rough estimate. . Current production is assumed tc bo zero since the pro duction of polychlorinated bipheniyls (PCB's) has stopped. Literature value is given for comparison. on. wjs naeced, the nature of i fclfractidn suchfaslO. pf sesitasl intermediates!for; sive mariners while the! $isn^d fchafciall oflth&la HONS 022094 iaderiberdtaXy pleased to tM YA^Qnrcnstlti (1a ntf 03 was used; it'represents lOOt of production plus afXMfugftive emission from production sources.) Much mors weight JijKr.been placed on figurea from the literature which hava bean norej&xtenalvcly evaluated than on those numbers where an emission rlctor had been used to calculate ?-: ssions. Where no other values ware available, emissions wore injured to bo a fraction of production as related above. ?h.- >-i ssions-ranked probable and possible carcinogens are shown in Tmles 6 ar-.d 7, Where more than one significant emission figure was available, the log average was used, with the MRC Source '.nuessment Data ease emissions given twice the weight ow ntr r ir.fornation. ATMOSPHERIC PERSISTENCE OF POSSIBLE AND PRCB\?.:.E CARCINOGENS In this project, atmospheric carcinogens ire of interest as opposed to occupational carcinogens. l-'or * ret nogens to be pre sent in the atmosphere, they need to h.v v homo stability. A iw of the carcinogens are rapidly dcgrad'.-l 'ey : h*. , moisture, or other factors as opposed to a few othvr that, ire known to have a very long environmental persistence. '. t see-? reasonable that carcinogenic chemicals that degrade t.oror.ts in. the atmosphere should be considered less significant. that are very persistent in the environment. Several time frames were considered rc> err; how "no. ro-ii- nental persistence should be regarded .is i actor in the concentration of carcinogens in the atm. '-i.r.otv. A long tim-' franc (e.g., 30 days) would allow for he ;i: s ipp'-arunce oi those materials that degrade as they move iv :y from, the source, how ever, many of the sources of emission..- arc !--n11od near cities in which the population would be exposed a - - of a few hours. Twenty-four hours was chosen as a rc.i-, .;: i,- * *e. The literature references used for this ' ' . ilation are shown in Appendix I in the summaries of each of t.v chemicals. The half life used was that quoted for photodeorodet :~n, HO radical, and radical reactions with the test cher ica'? . Tables 8 and 9 show the annual'quantit^s of probable and :.oss:ble carcinogens emitted that would be in the atmosphere 14 hears after emission. If no data were available on degradation, it was assumed that the quantity; emitted remained after 24-hours. - :e::eral, th.s per sistence correction factor was only sion:f leant fcr'thd 'few chemicals indicated in the literature t' hive atmospheric half lives .of,, jainutes to hours. 19 HONS 022095 TABUS 6. SMlSaiOHS-RMOCECr PROBABLE CARCIhOCENS* Rank tliona. -kjZltr 1 Trichloroethylene 2 Tetrachloroethylen* 3 vinyl chlorld* 4 Ethylene dichlorld* 3 Benzene 4 ChIordan* 7 Dioxana* 1.7 sr 10* 1.2 X 10* 1.2 X 10 8.8 X 10T 7.4 X 10' 9.6 X 10* :. 4 X 10* t Ethylene dibroedd* 4.3 X n* 9 Chloroform 2. * X 10* 10 Carbon t*trachlorld* 1.6 X 10' 11 Chlorobenxilata 9.0 X 10' 12 Olchlorobaton* 8 . 7 X 10 13 Senzo(el pyrene 14 Toluene-2,4-dla*in* 8. ) X 10' 4 . 4 X 10* 13 vinylidcn* chlorid* 16 Benzyl chlorid*c 4 . 1 X 10' 4.: X 10' 17 Acrylonitril* 3. * X 1 ?' 1 Epichlorohydrin 2. i X 10' 1* Benzidine 7 n X 10* 20 Methylene bi* (chloroan 11 . nt: 21 Ethyleninln* 22 DOT 2) Chrysene 24 Heptachlor 4 . 0 X 1C* 7 _ 7 X 10 " :. X 1 2' [ *- X !'* 1.: X :- 23 Tetrachloro*thane 26 Cinethylhydrazinec 0.4 X :cj < f . Z X 10' 27 Dichlorobenzidine 28 Hydrazine 4 . $ X 101 1, 3 X 10' 28 Dinitrotoluen* 4. ; X 10' 30 Diaainoaniaolec 1.4 X 10' 31 Trichlorfon 1.0 X 10' 32 Benz In anthracene^ ! . 3 ;< 10' 11 Bis(chloronethy1) ether <. .0 X 10' 34 Captan < ( . ' X 10' 33 Nitrosodlaethylamine 36 Ethyl carbamate (urethane > * ;.; X 1C' 4. 37 Aldrin (3.0 * 10). 38 Polychlorinated biphenyl 11. x 10|C.e -- ..... *when nor* than on* aiqnificarst er.izsior. fii-jr-- 1* available, th* 19 average jscd. v.ih the MRC data baa* figure given twice th* woi-.-.t of th* other .valuo* ^Atauaed emission factor of 1.00 of production. cAssumed caiaslon factor of 0.01 of production. "s^u.masaEtss.'"' """ i an MONS 022096 TABLE 7. ENISSI0NS-RANXEDP0S9IBLE CARCINOGENS* Rank l 2 3 4 5 6 7 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Chemical Formaldehyde Dichloropropene^ Pentachlorophenol** Cumene hydroperoxide Methyl chloride Ethylene oxide Hexachlorobutadine Chloroprene Tetraethyl lead Acrolein Styrene Morpholine Propylene oxide 1,1-Dichloroethane Di- (2-ethylhexyl) phthalate Allyl chloride Vinyl acetate Hexachlorobenzene 1-S'aphthylaminec Mercaptobenzothiazole Methylenedianiline Di-tert-butyl peroxidec Vinyl bromide Dichloronaphthoquinone Trichlorophenol Nitrochlorobenzene Dichlorovinyl dimethyl phosphate . Biphenyl (9.2 x 10*) Emissions, kg/yr 4.8 X 10' 2.8 X 107 2.1 X 107 2.1 X 107 1.6 X 107 9.7 X 10* 7.3 X 10 6.9 X 10* 6.6 X 10* 6.5 X 10 5.6 X 10 5.5 X 10 4.4 X 1C* 2.6 x 10* 2.4 X 10 7.1 X 10 6.8 X 10 2.3 >: n* 3.2 X 19* 2.7 X 10" 2.6 X 10" 1.4 X 10" 4.0 X 10 9.0 X 19 * 5.0 X 10* 3.0 X 10* 2.0 X 10* 0 4When more than one significant emission figure is available, the log average is used, with the MRC data base figure given twice the weight of the other values. ^Assumed a release factor of 1.00 of production. cAssumed a release factor of 0101 of production. ^Current production of PCB's is zero, so assumed biphenyl, emissionsi also tzpro. Literature value s also givfeQ.t 2% HONS 022097 TABLE 8. EM ISSIORSf/PERSISTENT-RAWKED PROBABLE CARCINOCKNS Rank Chemical 1 Ethylene dichloride 2 letrachloroethylene } Benzene 4 Vinyl chloride 5 Trichloroethylene 6 Cerbon Tetrachloride 7 Ch lordsne 8 Ethylene dibroadde 9 Dioxane . 10 Dichlorobutene 11 Benzo (a) pyrene 12 Chlorobenzilate 13 Chloroform 14 Toluene-2,4-dimaine 15 Benzyl chloride It Acrylonitrile 17 vinylidene chloride 11 Benzidine 19 DOT 20 Ethylenimine :i Chrysene 22 Methylene bis(chloroani1ine) 23 Heptachlor 24 Tetrachloroethane 25 Dichlorobenzidine 2 Epichlorohydrin 27 Dinitrotoluene 28 Diaainoaniaole 29 Trichlorofon 30 Captan 31 Benz(a(anthracene 32 Ethyl carbamate (urethane) 13 Dimethylhydrasine 34 Hydrazine 35 Nitrosodiaethylemine 36 Bis(chloromethyl) ether 37 Aldrin (3,9 x 10)b 38 Polychlorinated biphenyls (1.7 x 10)c A tso spheric half-life Emitziona, kp/yr, remaining after 24 hours 234 h 2.0 d 7.0 d 12 h 0.3 d 10 vk N.A.* 20 h 9.6 h N.A. N.A. N.A. 13 h N.A. N.A. N.A. 24 h 1d N.A. 1.5 d 12 h N.A. N.A. 1d 3h N.A. N.A. N.A. N.A. N.A. N.A. 2.1 h 1h 1h 25 min N.A. 9.1 X 10' 8.5 X 10' 5.9 X 10' 3.0 X 10' 1.7 X 10' 1.6 X 10* 9.6 X 10* 2. 1 X 10* . 1.3 X 10* 8.' X 10* 8.3 X :o 9.0 X 10' 7.2 X 10' 4.4 X 10' 4. 1 X '.O' 3.7 X 10 7 .; X 10' 3.5 X lo 1.9 X ll* 1.7 X 10- 1 . 7 X 10* \ X 10" i t l X 10i . * X 10 7. 3 X 10' 8.6 X 10' 4.0 X 10' 1.4 X 13' :.o X 10* <1.0 X 1C' <1 .0 X 10' 4.5 2.0 >1.0 >1.0 >1.0 0 N.A. 0 'rtriilttnc* oiu cduid not be found. Aasurted that the chem ical does not degrade appreciably in 24 hours. ^Current production assumed to be zero, but literature value alsq cited. cP4iaarV|sobJzcsBamviedyi amissions Vastproduction o( polyfc^^iraefjgip|jm^K|^ic|Jgas^been|atoppqd! Average fez MONS 022098 TABLE 9. EMISSIONS/PERSISTENCE-RANKED POSSIBLE CARCINOGENS Rank Chemical 1 Dichloropropene 2 Pentachlorophenol 3 Methyl chloride 4 Styrene 5 Morpholine 6 Tetraethyl lead 7 Hexachlorobutadiene 8 1 ,l-Dichloroethane 9 Chlocoprene 10 Di-(2-ethylhexyl) phthalate 11 Vinyl acetate 12 Hexachlorobenzene 13 Allyl chloride 14 Cumene hydroperoxide 15 Ethylene oxide 16 Methylenedianiline 17 Propylene oxide 18 Acrolein 19 Di-tert-Butyl peroxide 20 1-Naphthylamine 21 Mercaptobenzothiazole 22 Vinyl bromide 23 Dichloronaphthoquinone 24 Trichlorophenol 25 Nitrochlorobenzene 26 Dichlorovinyl dimethyl phosphate 27 Formaldehyde . 28 Biphenyl (9.2 x 10*)D Atmospheric half-life Bnissions, kg/yr, remaininu after 21 hours 3d N.A. a 1 yr N.A. N.A. 2d <1 d N.A. <10 h 1d N.A. 2d 9h 3h 3h N.A. 3h 2.6 h 79 h 12 h 9.6 h N.A. N.A. N.A. N.A. 2.2 X 107 2.1 X 1G7 1.6 y 10" 5.6 X 10 5.5 X 10* 4.7 X 10* 3.4 X i 2.6 V 1. ) V ; 7* l.: V * * ' 6.8 :< 105 1.6 y 10s 1 .1 V 107 8.2 X !03.8 X 102.6 :< \ f) - 1. 7 X n1.1 X 10- 1 . 1 n8.0 X 10* 4.8 X 10' 4.0 X 10 9.0 X 10J 5.0 X 10J 3.0 X 10 J N.A. 1.2 h N.A. 2.0 X 10* 45.8 0 aN.A. - Persistence data could not be found. Assumed thit the chemical does not degrade appreciably in 24 hours.. ^Primary source of biphenyl emissions was production of poly chlorinated biphenyls, which has been stopped. Average literature value given in. parentheses. 23 MONS 022099 insaTqrnps^EvmmoBABQs' cakio&* vE^wss decided that tha'potency of tha possible and probable ^carcinogens would ba determined, where possible, by the average o4 the mutagenic potency relative to benzo(a)pyrene using two different mutagenic tests and the carcinogenic potency relative to benzo(a)pyrene using two different species or routes of administration. Data required for potency calculations based on any specific test system was unavailable for many compounds. This is particularly true for carcinogenic data; such information is often conflicting when it can be found. It is important, however, to tnfco into account the fact that some chemicals are more potent carcinogens than others. Absolute potency data, however, should not :.e required in order to determine the relative significance of a number of chemicals. Thus, a system to determine relative poten cies was devised. Several decisions were made concerni\: w the data would be treated: (1) Both mutagenic and carcinogenic potencies would ):- used, with the final result being an average of the two r.urhors. (2) Missing data would be handled by using an aver<rv ; :.cy determined from the rest of the compounds within i.-h :rruo.ossrbic vs. probable). (3) Bcr.ao (a)pyrene was selected as the basis for corp .r .- : because rf the large number of test systems in wh.uh . : n i.; beer, evaluated. ' (4) The relative carcinogenic potencies would be determi:by comparing only data from the same species and rrutc of adr.-.mstration. For example, if chiordane had been evalu.it oi n. hamsters by addition of the chemical to their food. benzo (a! pyrene data generated by the oral route on a. .-'.ms would be used to determine the relative potency ~. thv m - :r. compounds.5 (5) When several sets ',t>f test data wore available, th . iv -r v:- of the relative carcinogenic (or mutagenic) poter.; ; .ru: d be used to assure that results from any one test .1 r.c: overshadow other results which were orders of mag-.it- . different. (6) Average mutagenic potencies would be assigned to uc-.- C4 MONS 022100 ...er ................. I sumos that unless othsr ;efiecii< firthfaverag* potency. For^the viral enhances**! ig&Spotency of 4.1 x 10"* ug/ml was assigned|^a^chenicals rtvlch there were no data.. The average ofthese,two ire gives a relative mutagenic potent/ of 5.3"x'10-9 for any chemicals that have no mutagenic data cited in the literature. Likewise, the average relative carcinogenic potency was found to be 1.4 x 10~2. (7) In test systems where no benzo(a)pyrene data were available, secondary standards would be used to back calculate a potenc relative to benzo (a)pyrene. RELATIVE MUTAGENIC POTENCY Efforts were made to assemble mutagenic potency data. In addi tion to the data cited in Appendix A, some riita are displayed in Tables 10, 11, and 12. ' TABLE 10. RELATIVE MUTAGENIC POTENCY I Compared to benzo (a)pyrene 1 Chemical Allyl chloride 191 DOT (101 Diaminoar.'.sole 111) Dlchlorovmyl dimethyl phosphate |12| Hydrazine (13) Methyl chloride (14) Tetrachloroethar.e (IS) Toluene-2,4-diamine (16) Potency rev/nnole i 0.01 S.66 1. IS 0.043 0.12 0.008 0.43 PclAtlVC potency S .0 X 10-' 8.S X 10- 4.7 X io- 1.1 X lo-i 3.6 X 10-* 9.9 X 10** 6.4 X lo- 3.6 X 10-> (91 Mutation Research,.57:11-15, 1978. iJ (10) Journal of Aoricultural and Food Chemistry, 24:560, 1976. (Ill Biochemical Pharmacology. 26(81:729-734, 1977. 112J Mutation Research, 31:268-269 , 1975. 113) Mutation Research, 40(21:73-83, 1976. (14) Mutation Research, 40 (3):273-275, 1976 . liSl (&ft<*&4Jfesearch, 34*2576. 1574. !t* ft;8(fdings) of thelMatipnAL Acaddmy qf 3cl <irf;d^ I fcSe iKStS Jatci, 72 (6 s 2?2>?242l: 1975T . 2S MONS 022101 OMaicol terylMlulIt Hal UI.ntkr.owM iMtidiM 8amo(a)pyrene Hmyl dilorlte CpUA ClllOrdAM Chry*en# D i ch l -ro6#n t1 d 1 a# oiehiorofcutana 0ln.thylhjdr.Hn, Ethylan# dibromid# Ethylan# dichlorid# EthyItniAine HAptAChlOT Mydratln# 1.4-H#thyl#n# bl*(2- chloroanllin#) Nitroaodimmthylamln# Vtnyl chloride .nylid#n# chlorld# Chloropren# f .>r*a Idehyd# 1 -tiaphthy laaun# r#ntAcMoroph#nol Propyl#n# oxid# 7*tr##thyl lr*4 Vinyl ACtAt# Vinyl bromid# data Ifftiariia, nv/toU M 10-* 0.0 X 19-* 1.2 X io- 1 1.7 X 19-* 2.1 X 10-' 3.1 X 10-' 2.4 X 10" J $.0 X 10-* 1.7 io- 2.2 X 10 " l. X 10-* 2.9 X 10"* 7.3 X io-* 2.S X 10 3.5 X 10-* 1.3 X 10- Viral MkOCOMI. Vt/Ml 1.0 io- 1.0 io- 1.1 x 10-* 1 1.4 X ID'* *.4 > 10-* J.J i io- l. 10-* 1.4 x 10-* 1.0 x 10-* 1.0 * 10"* 3.2 * 10-* Mqativ POflt IN'# 4.4* 1.3 * i.o * 9.0* 3.; * 6.4 x 1.3 x IO'* 10- ' io-* 10'* io- - to 10- TABI.K 12. OTHER MUTAGEN DATA TO CONSIDER .Vo*.'fAiIa "*Ly: iatttr 117) m t ro*od umt thy 1 mi ln# OiMUiylhydratint JOT CthylrM dlbrcmid# Vinyl chlorld# Awnfircr;^# vvnvi<uzs |H| OfcMoroviflyl dla#tbyi phoi(.fut PxntAcnlorcphAnol Cthyltn# dibecmd# Capua r#c##xiv* lt.Ml mitAtion* *t 6.8 moli rcAivc lethal nutAtiona At 2.0 nmol* r#c#t#lv# mutAtior.* At 0.14 nmol# r#c#**Lv# lethal nutation* At 0.3 nmol ciumi r#c#*iv lethal mutations IB molt for 6 h ^i##s 11.7 ad#* And 19 trp1 mutant* 0,19 mol# for 6 h otv#* 6.6 ada* end 4.3 trp' mitant* 0.17 mol# foi 27 h Btv*A 10.8 Ad#-* And 8.8 trp* mutant 0.17 mol# for 27 h <jitaa 12.5 Ada* And 17.7 trp* mutant* (1,7 talernXtiqnal Agency foa Research pa Cancex^ Scienoif ic Pub- lildtlAlBo. 1^; 11976 ^.11^112?, and 633. 18 DreSdtf4:ilna 1 Aaencjt fo'xmBe'BAarA]* Ctf CAncSt*' Stfiferttl f it Pub ' UXafclcfckJip. ilff rU97A t>d.kUdii8l 24 MQNS 022102 problem.encountered 'I* that dlffaring? rniH^y~,nraa<Tpi p. eratlon nay cause the' potency relative tobenzcftaypyrenal to vary as -10*. For'example, benzene on;6ttsejskin has* a toxics dose lov(TDLo) of 1,200 g/kg (over a 49-week period), while benzo (a)pyrene haa a TDLo of 2 ugAg for a relative potency of 2 x 10"*. Subcutaneously, 1 mg/kg benzene has been suggested to cause cancer (no controls) versus 0.004 mg benzo(a)pyrene for a relative potency of 4 x 10-3 and a difference in potency of six orders of magnitude. In spite of the problems associated with this type of calculation, an average mutagenic potency and an average carcinogenic potency was calculated for each chemical, as s..own in Tables 13 and 14. The log average of these two numbers was then determined as also shown in Tables 13 and 14. PRIORITIZATION OF POSSIBLE AND PROBABLE CARCINOGENS Since this project is directed at atmospheric carcinogens, sore consideration should be given to whether a specific chemical Lj much more likely to be found in the air, in water, or in the soil or other solids. Many different parameters could be used to put more emphasis on chemicals which are atmospheric pollutants such as whether the chemicals at ambient temperature are solids, liquid, or a gas. The solid-liquid-gas classification would not distinguish between highly volatile liquids such as chloroform and benzene and liquids with very low vapor pressures such as the polychlorinated biphenyls. Since boiling point data are readily available and correlate well with vapor pressure, it was thought that boiling point might be a valid parameter to consider. On the other hand, solids might be in the atnosphere as particulate matter or carried on other particulates. Thus it was decided not to include these data in the priorit:zation model. Many data on various properties of the selected possible and probable carcino gens, however, are listed in Appendix A for each chemical. The prioritization model that was used to determine which sig nificant carcinogens in the atmosphere should be sampled for this project results in an equivalent kilograms of benzo(a)pyrene emitted per voar after 24 hours in the atmosphere. This number Is generated by multiplying: (aT the kilograms emitted per year, times (b) the* fraction present after 24 hours, tires (c) the potency relative to benzo(a)pyrene. From the top chemicals in these prioritizations, -20 chemifcals were selected which represent a variety of chemical types. Of these 20 chemicals, 15 will be selected by EPA for use in the srtions of this contract and contract -l-2j[74i ipofct^licifcogerf testae) iisf )(eV 'chemicalsj rn :|aixl I 'Bielcf areffootnoted qn}Tablets 1" if1 pfobamefehd possible tfarcinogfens b >ik<btiiz> fci4vT4nei4f.tdr|244 hq[urs. *1 MONS 022103 TABLE 13. RELATIVE MUTAGENXCXCARCXNOGENIC POTENCY OF PROBABLE CARCINOGENS (Compared to bcnzn(a)pyrene) Cheaical 1 benaola Ipyrane 2 DOT 1 neptachlor 4 Nitrosodiaethy1aalne 5 Aldrln 4 bent(a 1 anthracene ? Polychlorinated biphenyla 4 Bi tchioroMihyl) ether 4 tthy lemaine ;o ChloroJora i; Dianinoenitole 12 Trichlorfon 1) Carbon tetrachloride !4 31 ch lo robe nr .11 :.o ;s frVyler.e dibromde \i Dimtrbtoluer.e n Tetrachloroethylene 1 8 Captar. Toiuene-2.4-Jienine 23 Vinylidene chloride 21 Bcorene 22 Z: -hlorobjrcne i i Aer y ion 11 r i iv 24 T r ch loroe thy 1 ene 2S Mvthyler.e hi (chloroani line) Ethylene dlchlcrrde 27 Chlordane 21 Ethyl carbaaatc (urethane) 24 Chrysene 10 Vinyl chloride J1 Tctrachloroethane )2 Diosane )] Chicrobenailate 14 tpichlorohydrm n Disethylhydratlne M A/draaine w teas id in* M m(l cblor ide Mutagenic)ty compared to 0(a)P 1 .0 -IS.I K IQ-Jja.k 1.1 X 10- 1.3 X 10 -- <S.B X 10-) j.a X io- is.a X 10'*) is.a X io-*ie 1.3 X io- (5.a X io-) 1.4 X 10 -- is.a X 10--> -IS.S X 10*) i.i X 10" 2.1 X 10-* (S.O X 10 -) is.a X 10-*) 5.`. X 10-* 1. 2 X IC-* 1.7 X 10-* is.a X 10-*) 7.4 X 10-* 4 . ; X 10 -- 6.3 X io-- 2.7 X 13-* 1.2 n 19-* > X 10-* -is.a X io-> 3. X 10 -- 2.5 X io- 3.1 X 10 -- is. a X io-i (S.l X 10*I is.a X 10 -- 1 S.2 X 10 -- 1.7 X 10 -- 1.4 X 10 -- a.3 X 10 -- Caretnoqenlclty coapared to 0U1P Average autagealc. carcinogenic ----- E2S*SS___ 1.0 3.7 1.1 11.0 S.O X 10 -- 3.0 X 10-* a.o X !0- 7.0 X 10-* 4.6 X 10- S.O X 10-* 11.4 X 10- *) 2.a X 10- 2.5 X io-- a. i X 10 -- 0.31 *(1.4 X 10-*) 11.4 X io-i 7.a X 10 -- 2.9 X io- a.4 X io-*i 4.0 X io- 2.3 X io- s.o X io- * 1.1 X io- 7.0 X 10 -- (1. 4 X 10-3 1.7 X 10 -- l.B X 10-* 2.S X 10 -- 3.0 X 10** * f 1. 4 X JO-*) 6.2 X 10 -- 6.0 X 10 -- 4.0 X 10-* 6.6 X 10-- 1.2 X io -- 4.5 X 10 -- 1.3 X 10 -- 1.0 l.S 10* 1.2 io- .* 10S.4 n3.4 10- 2.2 10- 2.0 102.0 101.7 101.4 io- 1.3 101.2 10 9.4 10- 9.3 10 4.0 10 9.0 10 6.6 10 4.0 10- 4.4 10 4.1 10- 4.a 104.7 10 4.3 10- 4.3 io- 4.1 10- 3.2 10 3.2 1C1.0 102.7 10 2.1 10 1.4 10 1.4 10- l.S 10l.S 10- 1.4 10- 4.5 io3.3 10- 'Parentheses indicata that no statistical data vert available, ao an average potency aa(uad. '* ainua indicates that the cheaical wai not a autagen by the teat reported. CA plua Indicates that the cheaical vat positive on the teat, but no nuaerial data >er reported. & MONS 022104 TABLE 14. HI I.ATIVI. TACENIC/CARCIMOGENlC POTENCY OP P! bl.r. CARCINOGENS [Com|>.irod to bcnro (a ) pyrene ) Chemical_____________ * Hexachlorobeniene l Formaldehyde * Tetraethyl lea^l 4 Dichlorohaphthoquinone S Allyl chloride Chloroprcnc 7 Mcrcaptobcnzothiazole 8 Hexachlorobutadicne 9 Oichlorovinyl dimethyl phosphate 0 Pentachlorophenol 1 Nit rochIor oben zone 2 Styrene 3 Acrolein 4 Ethylene oxide 5 1,1-Dichloroethane Dichloropropcne 7 Oi-(2-othyihoxy1) phthalete Vinyl acetate > Hethylenediani1ine 0 Vinyl bromide 1 Morpholine Methyl chloride 3 01-tert-butyl peroxide 1-Naphthylamine * Propylene oxide Trichlorophenol 18 Cumene hydroproxide tr Biphenyl Mutagenicity compa rad to B(a)P (5.1 X 10'*)* 3.3 X 10* X7.3 10- X(5.8 10-) X4.5 io- X1.3 10-> X(5.8 10~a J X(5.8 10'*) X1.1 10-* 2.6 X io- (5.8 X 10-M 15.8 X io-)c (5.8 X io-> (5.8 X 10*> 15.8 X io-i (5.8 X 10*) (5.8 X 10-*l 3.3 X 10-* (5.8 X io-*> 2.3 X io-> 15.8 X io-i 2.0 X 10- (3.8 X 10-) 1.7 X 10-* 1.8 X io- (5.8 X io-*) -(5.8 X 10-> (5.8 X io-> Average mutagenic/ Carcinogenicity carcinogenic compared to B(a)l'put-incy 5.9 X 10- ' 5.9 X 10"* 1.7 X io- 1.7 X 10-* -11.9 X i0->)b 6.4 X 10- * 5.2 X 10-* 3.9 X 10-' X5.8 10- 1.4 X io1 . 1 X io9.9 X io- 9.3 X io9.1 X 10* 5.5 X io4.8 X io- -11.9 X 10-*) 7.6 X io- -(1.9 X 10*) -(1.9 X io-i -(1.9 X 10-*) 11.8 X io-) -(1.9 X 10->) -(1.9 X io-> 1.3 X 10-* -(1.9 X 10 - * 3 1.1 X 10-* -(1.9 X 10->) 7.3 X io--0.9 X io-t 6.0 X 10-* 1.7 X 10-* 1.4 X 10-6.1 X io- 3.5 X 10- 7.6 X 10- 4.6 X 104.0 X 10). 1 X 103. 3 X io- 3.3 X 103.3 X 103.3 X 10- 3. 3 X 10- 2.1 X 102.5 X 102.5 X 10- 2. 1 X 10- 2.1 X 10- 2.0 X 101.9 X 10* 1.7 X 104.7 X 10- 5.9 X 104.5 X 10* 2.1 X io- Mftentheses indicate that no atatlatical data were available, ao an average potency HjnruiedT ` AppUnuSaindicatea that the chemical was not a mutagam by the teat reported. fjXfclua indicates that the chemical was positive on the teat, but no numeriai data rOere reported. HONS 022105 Ct--lcfcl benzo (a) pyAae Tetrachloroathylena Ethylene dichlortd* Benzene Carbon tetrechlorid* Vinyl chloride Trichloroethylene Chlorilar.e Ethylene dlbroaide Chloroform Dichlorobutene Toluene-2,4~diuune DPT Dioxane Acrylonitrile `hlorobonsilate iuj\jehior vmylidene chloride :thyleninina !v-r.*yi .-Monde `.'hrysone Methylene bitfchloroanilinel 3*'nzi2;ne ; ;. hi irohfnrtdire Tt:a;h1oroethane r'-yu 'a) anthracene I laair.?ar.isole 'picnlvrohydnn 7rirhlcrfon Captar. : 11 rosod laethy 1 amine B. s icr.lcrcmethyl) ether r carbamate (urethane) '.rethylrydrazine Mv 1 rax me ;J: .r. (3.0 z 10*)C iiiychlormated biphenyl* ;i.f i io)c v<> nuUdnj jfter 24 Iwtft 8.3 X 10** 9.5 X 1079 9.1 X io'a 5.9 X 10'a 1.6 X 10'a J.O X JO' 1.7 X 10' 9.6 X 10* 2.1 X 10*b 7.2 X 10s fl . 7 X 1C5 4.4 X lC'a 1.9 X 10* 1.3 X lr.e* 3.7 X 10,a 9.9 X J * I 4 X ! * 4 X17 1 X r* 4.1 X , v* 1.7 X I0"a 1.1 X 10" 3.5 X 10*a :. i X n3 9.4 X ;r. 4." X 10J <1 ' X i-:* *. .4 X ~>J 9.0 X i1 1.0 X l \* <1 . 7 X 10 >1 .0 <1.0 4.5 2.0 >1.0 0 ca*eiao9ale i.o 9.0 a 10-' 4.1 X 10- 4 9 X 10'* 1.2 X ;o-J 2.7 X lO"' 4. 1 X 1C-3 3.: X t , - ^ 9. > X ! O'3 1.7 X 13'1 4.8 X 19 J f*. X 1 - - J 1 . j X IP"' 1.9 X 10-7 A. X 1 i. X r-> 1. 2 X 1 - 1 :. . X 10-J X nJ 1 X i --* X 9 *-3 4. X , - 3 X IV* X * 9-1 2 . . X ic- X --J j . ; X - 2 . . <9 X \ , * 1. * X . -3 X J 6. *> X 10"3 9.e X 10a 1 X 10-' 3.2 X 10*7 1.5 X 1 c~3 l \ X ;c.-7 '.A X * -* - 2 *9 9 X 1 2" J * *8 iq a'fter 24 hour* 8.3 X 13* 7.7 K 10* 3.7 X 1C 2.8 a 10* 1 .* K 10* 8,2 X 7. 1 X D* 3.1 X i* 2 .; X 0** ! . 2 X A** 4.2 X O'1 2.6 X 10* ;-.8 X 1C 7 2 . f X 107 i. 3 X I."5 ~ X 'J 1. X r. J X X X ' `X l3 J J 7 A. > X o' . i X >0' y 10' ` . v .> <K.. 0" >9.b X 10-7 >2.0 X 10" 3 1.5 X c - a i.; X 10-7 *; . A < O'5 a.;r,e of 20 significant f'arctnoqer.s which wro selected fer ari-; ical type and hiah ranklna in prioritization. of chem- bA of 22JMbiiacT lTi KK has re. mirnded that tetraethyl lead and orncr.e hydroperwldi baidroppnd fits the Ust ot 70 and replaced by ethylene dibreatdf^: 9lCtUort>propn. CNow out of production. MONS 022106 TX&tu (V sagEnssw*N6 'BY BQQXVfi&Sflf Emissions, kg/yri average mutagenic/ Average x kg remaining remaining carcinogenic after Chemical________________after 24 hour*______ potency ______ 24 hours pentachlorophenol Dichloropropene Tetraethyl lead Methyl chloride Styrene Hexachlorobutadiene Chloroprene Morpholine Hexachlorobenzere 1,1-Dichloroethane Di-(2-ethylhexyl) phthalate Vinyl acetate Ally! ch;oride Ethylene oxide Methylenedianilme Cuacr.e hydroproxide Acrolein Mcrcaptobenxothiaxole Di-tert-butyl peroxide -Jlapnthy lanir.e D:chioronaphthoquinone Vir.yl bromide Propylene oxide Dichlorovinyl dimethyl phosphate Kitrochlorobenxene Formaldehyde Tnchlorophenol Biphenyl (9.2 x 10*) 2.1 X 107* 2.2 X l<>7b 4.7 X 10**.b 1.6 X 107 5.6 X io* 3.4 X io* 1.3 X 10* S.5 X 10* 1.6 X 10* 2.6 X 10* 1.2 X 10** 6.8 X 10** 1.1 X 10* 3.8 X J0** 2.6 X 10* 8.2 X 10***" 1.1 X 10** 4.8 X 10* 1.1 X 10* 8.0 X 10* 9.0 X 10* 4.0 X 10* 1.7 X 10* 2.0 X 10* 3.0 X 10* 45.8 5.0 X 10* 0 4.0 X 10-* 3.3 X 10'* 1 . A X 10'* * 0 X 10'* 3.3 X 10'* 4.8 X 10'* 9.1 X 10'* 2.! X 10'* 5.8 >. ! 0~* 3.3 X 10'* 2.7 X 10'* .. . b X 10'* 9.3 X 1 * O 3.3 X ;. * 2.5 X r - 3 4. 5 X 3. 3 X s. $ X 1 .? X ic--" j - -3 1-3 1 -3 rrr X 3 9.9 X i.-* " 1 X i 3 4.7 X 1 " 4.6 X i:-* 3.3 X 1C " 3 1. *5 X 10'* 5.9 X 1 -n -- <e 2.1 X 10'* 8.x X 10* 7.3 X 10* 5.2 X 10* 3.1 X 10* 1.9 X 10* i .6 X 10* 1.0 X 10* 1.1 X 10* 9.4 X 108.6 X 10* 3.9 X 10* 1.7 X 10* l."- X 10* 1 . 3 X 10* 0.( X 10' y~. ` X 10' 3. ( X 101 2.6 X 10' 1 ' X 10' i.4 X 10' 8.9 8.4 9.0 9.2 X 10' 6.6 X 10'1 6.4 X 10'1 3.0 X 10*' ** acr.e of 20 significant carcinogens which were select* i f.r var:i e t y o chenical type and high ranking in prioritization. bA* of 22 February 1979, Mtft ha* recommended that to tract.-.-.-; lead and cumene hydroperoxide be dropped'froa the list of 20 ar.d rcy'.acei fcy cthv'.cr.c dibromide and dichloropropene. 31 HONS 022107 SECTION >5 STATE-OP-THE-ARTTREVIEW'OP CARCTNOCEN 1C COFACTORS Because a portion of this contract!'was to be devoted to the determination of ,the effects of' eaircinogepic cofactors, a litera ture search was conducted that resulted in a review of the state of the art of carcinogenic cofactors. This review concentrated on the effects of various industrial chemical.* on the carcino genic potential of other industrial chemicals. It also lightly reviewed other cofactor effects such is physiological (e.g., hormonal), genetic, medical (e.g., disease states), or.-ir.jnmental (e.g., light), dietary, and other factors that affect the initia tion or growth of cancers. Some of the key words or word stems utilirc.l in this comuter search wore: cocarcinogen... or co-carcino-ion.. . syncarcinogen... Other words or word stems which were used in <-c:i eircir.o.jen.. . included: modifier... promoter... inhibitor... - enhances... synergy or synergism t i'-.n - . th /ror. : tno National Library of Medicine data b i.*-s , ".I T!.inf., tox- CASCERLINE, and CANCERPROJ were search. - .DC system, CHEMCCS (chemical abstracts) was searched. T.-.e ictal number of literature citations printed off line was 2,31'the p< rcer.tages free, the various data files were: MF.IM.INE, 10: TOXLINE, 40%; CANCLRLINE, 45*. CANCERPROJ, 2%} and CHEMCOS. . . These abstract s were rev.owed alone with several book.- and othe- refi r-'ic-' papers. % summary of the 'state of the art" oi careinoe-T. roi.icf.-rr. is included in Appendix B, "A Review of the Carcir..- : r. c factor Literature." HONS 022106 SECTION 6 CARCINOGEN ISOPLETH GENERATION A portion of the effort in the first phase of this contract was to be devoted to determining the location of optimise sampling sites in four cities where field validation of the sampling and analysis equipment and techniques is to occur (Houston, Los Angeles, Birmingham, and Newark). In order to accomplish this task, the MRC Source Assessment Data Base was used to obtain most of the necessary input for the E'PA Climatological Dispersion Model (COM). Meterological data from the National Climatic Center (STAR com puter program) were reviewed for Houston, Los Angeles, Newark, and Birmingham. These data consisted of joint frequencies of occurrence of wind direction, wind speed, and atmospheric stability (Pasquill stability classes). It was decided that only one set of isopleths would be generated for each of the target cities and that it would include the tr.:ajl_ mass of those carcinogenic chemicals included on the V.RC -e Assessment Data Base that are emitted in these cit e:;. This decision reflects the purpose of these particilar isopleths: to aid in the selection of sampling sites to be us<-d in evalua ting the portable and high-volume sampler systems, for this purpose, the important factor is the mass of emissions, not t.ne potency of the carcinogens. The chemicals included in the study are from the 1. of probable chemical carcinogens generated earlier in the project. The prob able carcinogens are generally chemicals for which, minal studies have been positive, with supporting mutagenic datJ. er for vnich government regulations have been promulgated that require the chemical to be handled as a carcinogen regardless of the animal data. The chemicals were selected from the list of probable carc:no:cns ordered according to annual mass of emissions released to the environment corrected for atmospheric degradation after 24 hours. From rthe top 30 chemicals, 19 were on the source assessment data base.* Many of the other 11 chemicals are pesticides that are 13 MONS 022109 currently bWing phased'19'chemicals elected for evaluation ara shown*along with thq. target cities in which they are found iff Table 17. TABLE 17. CHEMICALS IM TOP ?<? PROBABLE CARCINOGENS ON MRC DATA BASE THAT ARE FOUND IN FOUR CITIES* Compound Ethylene dichloride Ethylene dibromide Vinyl chloride Chloroform Carfccn tetrachloride Vinylidene chloride Benzene Aery lor. i t r i 1 c Dichlorobutcne Trichloroethylene Tetrach loroethane Epich Lorohydr ir. Ben zv 1 chloride Fciyiny 1 idcr.e DDT Houston X X X X X X X X x X X Newark X X V X V V s* X V Los Angeles X X X x X X x X Birmingham JFrcc annual emissions in the United States that remain after 2i ".cirs. .'ll s'urcos c: emission were located <_r. naps :n Universal Trans verse Mercator (UTV.) coordinates for four cities. The input dan *ore .lathered ar.d keypunched. The convert icr. fror. street addresses to U7M coordinates were Tore i.rticult ird tir.e con suming than originally estimated. The Houston area was selected for the first simulated dispersion modeling'. Annual r.eterolccical data (from the STAB. .tot,puter program (19) for Houston -ore initially used with a c;urs grid of about 50 * 50 km un about 2-km intervals) . th approximately 625 rocopr.cr points. The average stack heights used were as listed in the mf.C Source Assessment Data Base (SADB) (1). Annual pro duction rates and emission factors ve.r also from the SADB. (19] Seasonal J. Annual (Day/Might) K:r.d Distribution by f-asquil Stability Claasep (6^, STAB program. U.S. Department of Commerce, National 6ceanic*and Atmospheric Administration, Environmental Data Service, National Climatic Center, Asheville, North*Carolina, .JDulv 15,. 1977. MQNS 022110 ____ ____ *^*9$'*: P*P*<ribiftflol tppflh| f20i. e i9C'AftTlttar*H0iateir'fe*p*rature of 21.11*C Ja from the Sta- leal Abstract of^thaiOnited states f21?; Jh'ttack diameter ff?30 ' was'estimated by MRC personnel. .Exit velocities^for given, stack, diameters, andU flow rates were found.,for a typical' process *{22,^231. *AYga* exit temperature of 38*C 'was assumed. Environmental persistence was assumed to be a 1-veek half-life (essentially nondegrading for this model). The appropriate maximum was located; then the area around the maximum was "fine tuned* and rerun for the final isopleth to be plotted. A three dimensional concentration isopleth was made. Along with the other sources of pollution, there were eight point sources for ethylene dichloride and five for vinyl chloride in the Houston area. All were located in Deer Park and Pasadena, southwest of Houston. The companies from which the emissions occur are primarily Shell Chemical Company, Ethyl Corporation, and Diamond Shamrock Company. A preliminary computer run was conducted using only the ethylene dichloride and vinyl chloride data for Houston. The EPA CDM [24) was used for the computerized analysis. Initial results with a relatively coarse grid show the maximum total pollution about 1 km north of the Shell plant. A ma? of this area with a qroundlevel isopleth of 500 yg/m3 for ethylene bichloride is shown in Figure 1. Listings of the CDM input parameters and computer out put are shown in Figures 2 and 3. In the parameters on the first sheet of Figure 2, sigma Z is the standard deviation of the vertical wire profile. The joint fre quency function indicates the wind direction and stability class [20) Holzworth, G. C. Estimates of Mean Maximum Mixing Depths in the Contiguous United States. M.onthly Weather Keview, 92 15):2 35-242, 1964. [21) Statistical Abstract of the United States, 97th Edition. U.S. Bureau of the Census, Kashir.uccn, D.C., 1976. p. 161. [22) Khan, 2. S., and T. W. Hughes. Source Assessment: Poly vinyl Chloride. EPA-600/2-78-004i, U.S. Environmental Protection Agency, Cincinnati, Ohio, May 1978. 105 pp. |231 Scientific and Technical Assessment Report on Vinyl Chloride and Polyvinyl Chloride. EPA-600 6-75-004, U.S. Environmen tal Protection Atjency, Washington, D.C., December 1975. 130 pp. * [24] Busse, A. D., and.J. R. Zimmerman. User's Guide for the flbutologicali)ij[p<r>ion Model. EPA-R4-73r024, U.S. fnvSllronoental*Projection Agency, Research Triangle Park, Nozjth Carolina, December 1973. 144 pp. 35 MQNS 0221U Figure 1. Ethylene dichloride concentration# in Houston, Texas at 500 ua/m3 (3 kro/cra). MONS 022112 cc* ftlM !m' C Utftl wlIO t'UOl O' !C III (MO MUO limiUhll ClftltCft (gil M?MI|a#| I .1*1*114 *tI INC lifOMHMK or !h( vcatich imo MO'UC Ir IUoium Cun ig<11 l.imtM'M I.IIIIIKMI UtHIK.ll i*t uurin . HtpA t H Ait* ioocii 1.1 MiTAOKirf ciaii iIjih . IH< <1 IMAtOlHlCAl HAM *0<tuftAt AMO A* 1(0*004 MtlU* Kl|Mt 9.kTIM|tll MimtOI) |M( 011 AMO XUmT o.toeooCoi .CUM riffOAt iUmii: o. iOMoc*n fMC #!*. AMO-.I.MIN 0 1-C A(A (MIUIOM iMvCHtO'f *A10 I.HUIUtll .ttt!'tcf! 1,1 1,1 rMf *tctm or a |Atic (* loiter I0VAIC IIM th( or ui*uc:o" ccmiodco !* ji. e. Aiooi #(M 0.54JI0K #l l*( INMUL ftAOIM. l*Ol*l*r 10(L*H 0,I|94(*01 TmC *OJ*L inCcHMt r AC 10* I UA(n I I !H( AA?|0 Of (*|9ft10* 1*10 TO *4' MtO liAfll ucto*. AMO AM aula a i0fM or a iuoi(C'd ioih . rx(f a i .. * * TH Mio COtWMIO* riCTO* K*ll THC AIA tCMCHlVOC <<0AH Xj nJ TnC MCAT AAU hAL* L I'C fOI M **0 M <fOM lf*C ftlOMA l CQCrMCliM UU flu 9.*mic-i i.aismUWi t.un*oin o.nmii.ji uimKoi l.lltMKMt o.lf|IOC*l l.tllJ'tlMI l.ltIMHOI l.tiDlKtM MIIUKtll 0,AMKM I.UIIK*tt i.mviNiM I.MIHKaII MIIIMCaM (continued) Figure 2. Input data. MONS 022113 ICC to* l 3.*10050(0) 1 ) o. laooiat01 % o.oieooot 03 1 o.metof oj * 5 1 ,UM9K*I1 to 0,MttH(-t) It t.ootm'ii 13 9,(49900(0) u t, mom *o to l.tTIMK'lt t O.tlMIIM) it t MMm 03 t t.thillcll 1 t.miitc 01 0 I.JITQIOCO? MfllQKOt 4 7 9,214449(02 o.mooiroj * Mmm oi It II II D t.nttotr 03 1% 11 9,1*494*10) 14 4,919949(05 1.749(491*9) 9.9I9949C9I 4.145449c *91 9,911944c *4) 4.197#44C *41 9,115049( -11 914 19941 <; ,*+(O > l.it'09( * 40449391-4) 40*9909(0) 1) 4,999499(0) 4.599494C-9) I.J400?0(-9) 14 ,50040(0) co VCUJ oh r*n%. at* % v> u) V* U) u* Int vrtUt MCQvlHCT rude 7104 '0 Hi4!(!" CL 'll 1 0.2 50991(*0) t.9 0.0 0.4 90 4.270090(0) 0.0 0.0 90 t.C 0,310000(0) 6.0 0.9 40 o 0,ITII00(*0 3 0.9 9.0 40 90 9.7)9904(0) 9.9 0.0 90 40 090099(0) 9.9 0.4 90 40 .554949(0) 0.0 9.9 90 to i.lTOiooc-ei 9.9 4.9 40 40 0,114940(02 9.1 9.0 9.9 40 0. >190*0(05 9.9 0.9 90 90 4.4*940(O) .0 9,0 90 40 6.910000(03 9.9 9.9 9.9 40 1,531000(0) 9.9 9,9 40 90 g.Moooocoo 9,9 90 40 O 6,1*000010) 9,9 9.4 9.4 40 9.310000(0) 9,9 9,9 90 40 lH( jomf Mctucucf fuMcnoft '04 IT44UIM CLOU .17*949(03 0.173499(0? e.uMoocoj O./OOOOOCOJ 0.101000(03 o.moooiot UlllllfOI 4.241499C0| 0.3)3000(03 ,155990(03 0.14)009(03 0.109009(03 0,141909(0! ,*09909(03 9,7)9999( 0) 0.1)7009(03 9.91090(03 9. 740090(0) 0.501000(0) 9, l l|99t(OI 0.340094(03 4,1JI494C Ol 1.171414(01 0.1)4400(0) 0.390000(03 0.9*0400(0) ft )( Ol 0.115044(01 0.40440010) 1,399499(05 4.379040(0) 4.994199(09 4.0 9.4 4.9 4.9 4.4 4,1 9,9 4.9 9.9 4,0 4,4 9.4 4.4 1,4 4.4 40 I 40 40 40 40 40 90 O O 4.1 9.4 9.1 4.9 IO 40 9.4 4.1 . e 40 t.C 40 90 40 to 90 40 40 40 4,4 9.1 40 4.9 90 <m( v<lf >tunci rtwctiM ro* intuit? ull l 4.111444(03 9.111444(01 <014494(0! 6,17*444(01 045944(03 1.17)449(03 4,194999C *43 0*1444(01 9,ll*044(*93 .01499(03 <.34194(0) 6.12*944(03 0**944(0! 0*4304(0) 1.479446C *9) 1,01949(0! 4 041944(03 4.314449C-92 4019994(03 9017999(01 0.33444(03 9,47)144(02 9.449000(01 4.454094(03 4,01299(01 900949(03 034999( 01 4,199049(03 4.977999(03 4.199999(0! 0 49999( 0! 9079999(01 1079999(01 t,MMI(*) 9.179009(0) O.IMIOOf *91 0.519044(0) 9 099409(0) 9,4*9494(01 00*7449(0) 9.151999(02 .**9999( 05 4.2)4944(0* 9 099999( 05 1,179444( 05 4.149499(0) 4049419(0) .>54449(0) 9,249949(0* .994994(0* 9*4 9*4 9*9 9.4 4.9 44 10*9449(0) 4,194994(0* 4.4 1*9 4.9 9 144944(0* 4.4 4.9 4.9 9.9 4.1 9.4 9,9 9.1 9.4 9,9 4.1 1.4 9.4 4.9 9.9 9.4 49 (continued) Figure 2 (continued) MONS 02211* SCC 10* cl o, 'ftjpooros 0,))}(CCf 0) J , i oo ot - c > 0 , *9000<>0 1 0 . 1 050001-0/ 0 , 7 09.709C -0 7 0.))0009(>05 0,9)0000t-0 o.*4ooo4t-o> 0 , >40099t*9> 0,1 OP 80 010 > e,ntotO(>) 0.2*00001-0) 0.220090t*9> 9, jTttOOt-O) o, 2 5 ooooi*02 0 , 1 > 0C Of - C2 0 ,2*2 009( -7 0,1970941-07 0 , JTOfOOl-02 o , i Wgcoc o* 0,2/04Cvl-0.` 0,>040tut-02 9,141404147 O.lOlOCOfO 2 9,440000(*41 0,144000(*9) 0.9)00001 * 91 9.)90OO9(-C! o,200001>o s O.tCOOOOl.Ol 0,26)4901-9> 0.27|099(*91 9 . l4*|00t * 91 9.194)901-0) 9.1 )*949C- 0) 9,l*7f0(-91 9,27)4191*91 9.1*12991*91 0 ,*)f 4991 *01 9.1944091-01 0.9700001*92 0.4920901-02 C.90)0001-01 0, *720001-01 0,I*#99C~9* Xi 9,1014001*01 CO* v(|)0 TM . vi g> J* .5 u* tc joint V. f 7 0*l ! ION * Of 1 1)|wt 1 UM4 t C.>fc690(*3? o. imyot o/ 0./sooout91 o,2*)909t`02 4.)|490Q(-92 0 . 2ft*Q3C-2 e.;;oooi-oa 0,7*19001-02 9.SS'OOSC-Of 0.1*10091- 02 O.OOOOOOC-O) 0,9440091*41 C. W*99C*9I 0.4000001-15 o.itooooc-o) 0,U9Q04f-02 o.noorot-oj 0 .*)!0( 0l .'*> 9,91*1.0Of >01 0,k2i SOflC -H 0.92*090(-?l O,*9*9vOL .99 4.))v.tf( 9,7440441-92 ,1T199C>1 O.UOOOOC-91 0,t99l)9(*0> 9,7409991.81 0,1010091.97 0 . ># ton .of f*jo;or 0. I42C0C; - J/ 0 . Mf 9001 -11 9,727UC(*7 9,li000(-0 7 0.99M'00(*01 C .9UC00C >pf 0 . *9*99 It * 67 9 . 1*9Q9C * O l j , )*900(*01 C . t HOOCC *91 9. TkOIOOf.0$ 9. W9690C-4* 9.1T )900(*91 9 . *9 9001-47 9.470CC91-4) 0 . >900991*11 .T99909C* 9.2M4901-9) 9 . )|409CC*4) O.*t:*>0C*9> O.UJJJOl.41 0,4M040t*4l 9. 10*0001-01 0. 1090891*41 9,1490901.91 9.14949 01.40 f,l9*1*49 4.1194091.41 9,1910491*41 g,M909C*l< rnt JOINT F9C4ul*C7 fUNC'ION f OR UlllLl'T :utt 4 0.27*0001-92 3.72*0001.172 9. JJf0091 -0? 0,19)0001*02 3,*740031 -07 0,7790441-02 c.2v)oop(*ai 0. 1*41001 * ui 3,*J90lf-0l 9,92 0 04 0( OS J.*ftO0O9(-O) 9, * *00JCf91 0.*000001-01 r.**;3oc(-o5 9, **09041 -OS 0.12*0001*02 o.tolv-yf-C7 t.)'63C'97 4,94c:.'{ Of 0 . ))9Vtf4t .01 0,424640*;< 0,7*90-81. ' 0.71406 Of.31 9,10410*1.' 1 O.llTvOPf *02 0,4*4000l..> 9, *49101 C - * * O.UOOt-HO' 9,)000*Cf-M 9,1* 7449*. 9 I 9,1496901.02 c. J4ic9;t ;,lt'7 9Qt.3 4 . 10*0641-0 7 ;.i**:oaio.siiito< -t / 0, JiOC Jf'C *07 9.796f .7 0.)76 2l't-9l 0.*1099*1-0* 0.2l2`.*60(*4.t J, )J*6V{ -3 > :.42*ocoi.c> O.TtfCOOf.01 9. i ' * c s 11 -1: 9.*970001*02 tmc join* Mtoci`**.i runctjo* *o iuiiiH* fc*ii 0, 12*4001-0) 0.4**0091*91 4,71 99091-02 0,**70091 -02 9,6 200091*92 9,42 1000(92 0,112)991-01 0.1)21901*01 9,1491091ll 9.14*9001-92 0,2140991*92 9,2* 70991*92 0.2790991*02 0.2940991*02 9.2)99091*92 9,*9)0091-02 0.)|}v09(-02 0.11)3001*02 0. 4)09SCI . > 0,lOOOOOf-9> 0,5)69001-0) 0.1*40<91*02 o.i4)c:cf.92 |,)*4oet -92 9>4491OC-42 9,4206901*9) 4.4999691-9) 9,21999JC- 61 4.44000O1-C) 9.)10J40C-0> 9,1119991*92 4.1440991-42 0.9 9. C 6.C 2.3 o.; c.c 0.J 9.0 9.9 0.9 9,9 0.0 o.o 0.9 9.9 9.0 9.10 > f 06(* 0 7 t.ii*: j -oi .*9yO0f-0* *1.1109901*91 ,,\L6v4V**0> 4 , 1V 0-9TI*04 0.11604*1*91 O,2100*0t*91 J, *494031*9* i) 1904901-94 3,? 4,foOOOOC-O* 3,1000001*9* 0,1*91901-91 9 , 1 08641- 9* 0.1120091*42 4 o.o 0,0 9.0 0.0 o.o 9.0 o.o 0.4 0.4 9,9 0.0 9.9 6.0 O.O 9,9 0*4 9.l9k 41*91 9.9 .4 4.4 9.1949 94104 0.4 9,1410491*94 99444941.94 9.4419901*94 0.9 4.4 4,4 4.1119441.94 t.lMM9(.4 0,1440911.> 0*9499991*94 9.*484991.0* 9.1 0,1940991*9* 4.4 0,7419941 .JR 9.418 08*1 * 94 9.1444111.9* 9.7499941.9* 9,1099 111*9* 9.9 4.1 9,9 0,0 0.1199931*91 9,1144941-91 9,Until.9> 9.9 0,9 9,1 A9,9A 0.9 R * S* 9 .1a 0,1 9.9 1o 1.0 0.9 4*4 (continued) Figure 2 (continued) HONS 022U5 $V*CI IHW* TTtft09*( *t #|M9*C< II lvar *1 M fhMm 1 Mmmi I.HHVl l ftmiK II |tO)U aa ti t.U99M l |.I|IMCI |,9lMIIll jiMIMf *! tfwiMoo lilMllt *M (.999110** l.llllHtM t.miutii >. * t.i . i.a 9C ft.* .'.t fa .C a. 9.9 I.C D iiauo* ?%im< au* ^1 llll(ftl 1/ftlftfftl u iao*i timqOoi t%*99094 iftiao*> 1*999001 iaO9C*09 w 0 aioaai .ft) a 9ft ftftiaot! 9 a 9fftt 09 0 riaaeoa* 9 ft499r.0% uoogf.os in a }M6(*ai a mo(oi a 9 roQt*ai f0t *MftC**J a 0 }t}aftai)oCa(o*'fi c 0 W]/}?o<(oaJ! a uioooo* o t.UO'(Ql .iaaaa{*ai i,uttt(u V.19*99091 t.iaaaooai a.*99*9009 > 0,1aK0 aM.v'MaaKuM* a.naaar.a 99?***t9 o a*U ouCM. n -"I'1 *9*.a(ti. a* Figure 2 (continued) MONS 022116 CO" *1 I* Mil . AMI A t*S Kl Ut|C A<!(Ol "Out TO I AC (OMiTC coo*om*c$ O 1 0 1 O l O p 1 1 a f l l,l IT.M 0. 0. too. It. ill. w. HI. It. IMS 11.10 0. 0. til. 0. 111. i. HI. 0. Ml IMS . 0. m. 11. 004. if. 004, If. 01,00 I'.H 0, *. s r o 11. no. . no. tl* 0.0# 11,10 . 0. m. ii. H4. n. IT. 11. 0,90 |,00 9, . 10. It. i*. "14. tl. 10,00 Ol.OO 0. 0. Ml. IT. Ml. w. tl. tl. 0.00 1".0l 0. 1, "01. 11. "01, t. *01. IT. 1,00 Ot.OO . , no. 11. 10M >>. 001, to. 1,00 00.00 0. 0. no. n. 111. OH. 1". 1.00 to.00 0. 1, 014* 11. m. It. 104. tl. 01.00 10.00 0, 0. ot. 19. 01. n. It. 99. 1,00 11,00 0. 0, Ill, II. 104, . 4, II. 1,00 1},1Q 0, 0, m. to. |T4, h. 14. H. 1,00 1),I0 0, 0, T|, 11, TO". n. Tl". tl. 01,00 11.00 0, , no* 0M 410. . 410. OM 1.00 11,00 0, 0, 111* to. 111. ti. HI* 99. 9,f| 11,10 1, 0, m. 10. I1T, H, IT. It. 40,00 09,00 o. 1, 001. 11. HI. 11. 11. ft,00 ||,00 o. 0, ItT. IT* 04T. It. Ut. IT, IMI if.il I, o. Yl a II, T4, >. T4* 11* 01,00 o. 0, 1>l. IT. Til. IT. Til. T. 0,01 it.oi 0, 0, 1111. 10. IIT4. tl. im. II. 10,00 Vl.ll 0, 0, 11. Ill, 1*. hi* U. 10,00 fj.OI . 1. ton* 0T. lT|, t. ti'ti IT. 10,00 1i0l t. 1, no. II. HI. It. too. 90. 10 00 11,M 0. o. 4*1, II. 4"?. I*. 44?, 0 00 10,to 1' 1, 11, ai. IT* 1 u?. Ha 11,00 11,00 t, 1, >1. 11. III* 1*. HI. II. It, 00 11 00 It 00 10*01 01.00 io 00 o, , 0, nr. t. lie. 1, 401. IT, on. tl. HO. 01. 49$. IT. IT, U. HO. t>. ill. IT. 10. 91. 11.00 11.00 it*00 it * 00 o. 0, OM , 1' 11, 1". 1"l. to. H. I. t. II. 401. It. tl. 11,00 it oo A11, ,01 11,00 A1*A,A0A0 11,00 *! ii*oo I*,1.*ft. 1e *11 k0,7 AOl0 ,It I' t, 1# * A ' t, 101* t, "41. 1. )* o. Ml. ! 014. I, "IT* , in. 04, III. 41. 41. IT, 0". 1", fit. II* 074* 91 HT. 11. *11. It. Ut. U. 41. IT. 0*. I. 1. it. 14, II. IT* 1. 11. 94, II. IT. 90. 11. 11. 9,00 19.00 1|.00 1,00 1*00 1,00 11,00 11,00 0,00 10.01 1)* 01 1|, 11*00 1i*M 10.10 I4*M ? 10.00 AV 11 A * 1A 0* A0 * 0A * 0. 1, III, 11 411. 1, T|1. Aw * Ill. 1 a 1911 AV , lt 111. Ao 11 0. HI. 11* 111. 11* 411. 01. 101. 04. oil. 10, 111* II, **. 11. HI, II* II* 0. 111* t*. lit. M. HI. I. 101. >. HI, It, 111. t*. m, 11. IT|. I*. II. 1*. H, 91. 91. It. 4. 01. 11. II. H* H. \ (continued) Figure 3. Output i.ata. HONS 022117 CtfQM ISA 91.9* 91.00 *>,90 9 1 . #0 ). 00 91,06 91,00 91.04 9% . 00 94.00 9 , 00 94,00 99,90 94.00 94,00 94.09 94,99 94.90 94,00 94,00 99,00 99.00 99,00 99,90 99.00 99,90 99,90 99,00 99.99 99.00 99,00 99.00 99.00 44,Cft 94,00 9, 03 90,90 99,00 90.90 90.90 90,00 9O.90 90.00 90,00 90,00 97.00 99,90 91,00 99,00 99,00 l# 14.30 90,00 9 l , 10 9>.00 4j ,00 9* . 00 49.00 9a . H 49 .00 14.00 It. 00 00.00 09,00 40.00 4) . 00 47.00 4J.C0 94.00 99,00 9 ,00 IT.00 01.oc 04.00 09.90 90.00 4o, ;o 40.40 Il .00 4} .00 4?. 00 4 3.00 9k . 00 44.00 0 7,30 00.00 09.OC 09.90 9C . 00 90*00 90,90 91.00 4) .40 9}00 9ft,40 9s.OO 7.00 00.30 04.00 40,0C 9ft00 *r 1 . 0. 0, . , . . . . . . . . . 0. 0. 0. 0. 0, 4. 0. 0. 1, 0. . 3. 9. . . 0. 0. 0. . 0. . 0. 0. 0. 0, 0, 0, c. 0, 0. 0. o. 0. 0, 0. tC* trMfft* 7*11'. JS i*KOOO*OM 14 CullC (T|Oi tot it *r p1 *1 0 3. 09). 1 . 051 0 . 1911. 14. 1570 9. uii. 0. 1041. 1101 fto! 1051 0 . 14 | , 14. 741 0, 449. 3ft. 559 0. *44 . 29 . 0, *45. 0. 15* e. *01. 0. 0 . 4 ftO, 11. 7*. 54* 30. *43 29, 417 n. 919 0. 1010. 0. lot. 0 . 0900, 0, 1930. 0. 1011, 0. t|4. 14 . 1010 1. 197 7 7. 3900 1531 *! 1015 4*. 739 0, 940. 0, 4*4, 10. 940 11. n 0, 115. 0. *41. 0. 901. 19, 114 l*. *4) 7. 997 0. 400. 1. 400 0. 409, 3 . 1134. 9 , 01 > 0, 457. 0. 0. 5 M . 11. 909 11. 1139 11 071 11 417 12 . 1*9 15. 47 | 0. 54ft. 0. 14*. 0. *44. 0. 914. 0 . 149. 14, 50) If* 7 0* 11 *45 IS. 55* 0. 15 9 0. 574. 0. 307. 0. 300. 0. 5*1. i. 1 * * . 9. 904. 0. ITT. 0, 9W. 0. *19. 0. Ill, 0, 14ft. 0, m. 3, 1 TO, 0. 9|. 0, III. 1. 5 15 7 i 317 11. 100 II. 541 to. 144 11, 904 10, |7T to. 913 1ft, 419 11, 101 7, 191 4. 1 > 1 4, 179 11 * 9, 1f*t4ft1ft i l 1 Ci*U**4ttOM 1l l I i ix MW**C| :I * I \ 0 il 9 0 9I 99 99 9 ft 9 ft 9 f&t 9 ft :i A i il. * t. * > i (continued) Figure 3 (continued) MONS 022118 ooo mt *'{ * I Pi lM<l Ml <w*l<IMNi CUK 'BUI B*t I p* pI pI (HiniH; *1 * t XKMU pi r lI ,1 *1 Figure 3 (continued) HONS 022119 as a fractloY'bf'the average total for a year. The compass la divided into 16 seeto^q beginning with 1 for nort;;-; by northeast around to 16 for north.' The source inpu* X and V coordinate parameters are taken fro* topographic mans and are i:. kilometers. SI and S2 are point source emission rat.-.; for thyl.T..- ?; chlo ride and vinyl chloride, respectively. l ss t.u.<. -.eight in meters, D is stack diameter in meters, is exit icci.r, of the effluent, and T is average ambient temp-.-rature >- : -irees centi grade. The output data show the ground-level concentrations of ethylene dichloride and vinyl chloride respectively, as PI and P2. The X and f coordinates correspond to those in the input. Any number of receptor locations (points where a computed concentration is requested) may be used. The output coordinates hav been used to plot the isopleth in Figure 1 for ethyl. :.o dich'orvdo . Two variables unknown at the time if i muleth r.-;rat : . - : -,r those sources were the temperature o: the uo-.cs lev.'.;-.: the stacks and the exit velocity of these qasp'i. A o; a i . h vn of isopleths generated at 38 *C and 300 C showed the ccation of maximum concentration at the same point, but Mio `iOO- : ' ' iso- uloth shifted outward by about half a '< i 1 arc *. e r h.ih.T temperature. Discussions with plant oc.-rf..*nr.vl :t h. : u.i-uton uea indicated that scrubbers .ire used in ..' ; lar.* , which wo.. 1 d suggest' that the lower ter: :i r- -.-.stir. :;i I res nt exit velocities wore used to or- :v : hi* * ho inode 1 is not sensitive to this input. At th;s point, a tape of the recently : over! '.'b.M t. : pro gram was received; it was utilized in t;.-i rest this study. "ho rrs: cf the input data for Houston we re m".' -red :'-vr oil of the probable carcinogens indicated, and -.he .-or :.-:tor; .ied was run. The results were plotted and a three-d :.\*ial model was .isser.i led. The results are shown in figure 4. Three i i: i.-rc'.-, locat :c-r.s were found to have similar, h;.;h concentrations carcinogens. These aress were located or. a map of t:< .is shown in Figure 5. At the three points dflPfc'ximum carcinogen concert ra. : or.. he composition and eoncaptSLtion of each ccmnoncnt carcir.t >.c chemical was.detintiMdlf Results are displayed Table These! 6ra^ 'be'sampled in the third phase of this contracts and KfiVbiract 68-02-2774 (portable carcinogen tester). Similar data| irejbelrfetgengrjsteid for the other cities of interest. HONS 022120 44 Figure 4. Houston carcinogen *. soo! t(; TABLE 18. AVERAGE CONCENTRATIONS AT 'TINTS r MAXIMUM POLLUTION IN HOLST. I (Micrograns per cubic meter; Compound Acrylonitrile Benzene Carbon tetrachloride Chloroform Dichlorobuten? Ethylene dic/aoride Tetrachloroethane Epichlorohydrin Trichloroethylene Vinyl chloride Vinilydene chloride Ethylene dibromide 82,88 1.0 1,366.0 6.0 2.0 1.0 26.0 0.009 0.15 5.0 7.0 0.004 0.14 90,9-' 0.1 6.0 190. J 92.0 0.02 977.0 3.022 1.0 12.0 15.0 0.165 0.01 -5,90 1.1 5.0 : ;:.o ::i.o 0.02 '7.0 0.018 i.O ;o.o 2.0 7.220 0.10 MGNS 022121 Figure 5. Location! pt irAiif.un nn^-r'.rauoM of pollutants? *n fciustoru + HONS 022122 REFERENCES 1. Eimutis, E. C., and R. P. Quill. Source Assessment: Non criteria Pollutant Emissions. EFA-600/2-77-107e (National Technical Information Service Ho. ?B 270 550), 1977. 2. Suspected Carcinogens - A Subfile of the NIOSH Toxic Sub stances List, 1976 Edition, H. E. Christensen, ed. Publica tion No. (NIOSH) 7S-188, U.S. Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health. 3. Registry of Toxic Effects of Chemical Substances, Volumes I and II, E. J. Fairchild, ed. DHEW Publication No. (NIOSH) 78-104-A, U.S. Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health, September 1977. 4. Sawicki, E. Chemical Composition and Potential "Genotoxic" Aspects of Polluted Atmospheres. In: Air Pollution and Cancer in Man, U. Mohr, D. Schmahl, and L. Tomatis, eds. International Agency for Research or. Cancer Scientific Pub lication No..16, 1977. pp. 127-157. 5. Survey of Compounds Which Have Been Tested far Carcinogenic Activity, Volumes 1 through 7. DHEW Publication No. (NIH) 75, Public Health Service Publication No. 149, U.S. Depart ment of Health, Education, and Welfare, National Institutes of Health. 6. Fuller, B., et al. Preliminary Scoring of Selected Organic AirvPollutants. National Technical Information Service Nos. PB 264 442 through PB 264 446, 1976. 7. Brown, S. L., et al. Research Program or. I'.ar.ard Priority Ranking of Manufactured Chemicals. National Technical In formation Service No. PB 263 161, 1975. 8. Radding, S. B., et al. Review of the Environmental Fate of Selected Chemicals. EPA-560/5-77-003 (National Technical Information Service Nq. PB 267 121), May 1977. 9. Mut'ation Research, 1978 . 1*0. 0oidroaiL of Agricultural*and iFood Chemistry, 24^56.0i 1976. 4 7. HONS 022123 11. Biochemical'-Pharmacology, 2618)1729-'>94,? 1977. 12. Mutation Research, 31:260-269, 1975. 13. Mutation Research, 40(2):73-$3, 1976. 14. Mutation Research, 40<3):273-275, 19 76. 15. Cancer Research, 34:25", "97J. 1`. Proceedings of the National Academy of Sciences of the United States, 72(6):2423-2427. 1975. 17. International Agency for Research on Cancer Scientific Pub lication Mo. 12, 1976. pp. 61, 125, ar.u 623. 18. International Agency tor Research on Cancer Scientific Pub lication No. 10, 1974. pp. H-l-lSI . 19. Seasonal <, Annual (Day/Night' Wind Distribution by Pasquill Stability Classes (6), STAR Pro-iran. U.S. Department of Commerce, National Oceanic and Atmospheric Administration, Environmental Data Service, Nation.ii Climatic Center, Ashe ville, North Carolina, July i", 1977. . 20. Molzworth, C. C. Esti.r.v.os ,f in the Contiguous United 02(5) : 2 35-1*42 . 1964. y.ixlr.ir ";xing Depths hi v W- u'hcr Review, 21. Statistical Abstract of the United Stares, 7*.h Edition. U.S. Bureau of the Census, Washington, D.O., 1976. p. 191. 22. Nha.n, Z. S. , and T. K. Hughes. Source Asses.'.'.ent: Poly vinyl Chloride. EPA-600/2-73-904i. C.S. Environmental Protection Agency, Cincinnati, Ohio, May 1978. 105 pp. 23. Scientific and Technical Assessment Report on Vinyl Chloride and Polyvinyl Chloride. EPA-600/6-75-004, U.S. Environmen tal Protection Agency, Washington, D.C., December 1975. 130 pp.. 24. Busse, A. D. , and J. R. Zimmerman. ''s-rr's dc.c.c for t.n.e Climatological Dispersion Model. rPA-F.4-73-724, U.S. F.nvi- ror.ir.ontal Protection Agency, Research Triangle Park, North Carolina, December 1973. ;p. 25. Davies, J. C. Co-Carcinogenesis with Respect to the Con tents o: Cigarette Tobacco. R. Soo;. JHealth J. 93(6):296- 301, 1973. '` *3 MONS 022124 26. Hartwell, J. L.~ Survey of Compounds Which Have Been Tested for Carcinogenic Activity, Second Edition. National Tech nical Information Service No. PB 216 478, 1951. 27. Shabed, L. M., t7al^Th* Feasibility of Preventing the Effects of Carcinogens on Man. Kazan Med. Zh, (5):92-93, 1973. 29. Terrell. J. I!., and I. Schmoltz. Cigarettes: Chemical Effect of Sodium. Nitrate Content. Science, 160:1456, 1966. 29. Izard, C. Mutagenic Effects of Acrolein and its Two Epox ides, Glycidol, and Glycidal, in Saccharomycaa Ce.-e; . C. R. Acad. Sci., Ser. D., 276(231:3037-3040, 1973. 30. Epstein, S. S., et al. Detection of Chemical Mutagens hy the Dominant Lethal Assay in the Mouse. Toxicol. Appi. Pharmacol., 23:288-325, 1972. 31. Bignami, M., et al. Relationship Between Chemical Str\; and Mutagenic Activity in Some Pesticides: The t':sc r;f 7 .: uriun and ar<ni ' lu8 Sidulana. Mutat. Res., 46(3):243-244, 1977. ' ' 32. Allport, J., et al. A Study of Industrial Data c r. id i`.. Chemicals for Testing. National Technical Inforr.it: :;r. . r- vicc No. PB 274 264, 1977. 33. Verschucren, K. Handbook of Environmental Data on ~r-.:.:r'.ic Chemicals. Van Nostrand Reinhold Co., New York, I'.'/'. 34. Milvcy, and M. Wolff. Mutagenic Studies with Acryloni trile. Xutat. Res., 48 (3-4):271-278, 1977. 33. Venitt, S., et al. Mutagenicity of Acrylonitrile (Cyar.o- o thy lone) in >. A.-jv fi.7 Mutat. Res., 45:283-29^. 36. Acrvlonitrile Linked to Cancer in Workers. Chem. Liu;. News, 55:6, 1977. 37. Finklea, J. F. Acrylonitrile. Am. Ind. Hyg. Asscc. J., 38:417-422, 1977. 38. Song, J., and W. E. Ka$ville. Carcinogenicity of Altlrin and Dieldrin on Mouse and Rat Liver. Fed.-Proc., 23:336, 1964. 39. Diechmann, W. B., et al. : Tunorigenicity of Aldrin, Diel drin, and Endi*ih in'the Albino Rat. Ind. Med. Sure., 39 CD : 426-4 34 /: 19.50. 49 HONS 022125 40. Wurstcr, C. F. Aldrin and Dieldrin. '`Environment, 13(8)t 33-45, 1971. 41. Epstei:., S. S. Prevention - Environmental F.xposuro: An Overview, Including `he Rolf- of Pesticides. Third Inter national Symposium or. Detection and Prevention of Cancer, 1976. p. 5. 42. Epstein, S. S. Case Study 5: Aldrin and Dieldrin Suspen sion Based on Experimental Evidence and Evaluation and Societal Needs. Ann. N.Y. Acad. Sci., 271:187-195, 1976. 43. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5, 1974. pp. 25-38. 44. Brown, S. L., et al. Research Program on Hazard Priority Ranking of Manufactured Chemicals. National Technical In formation Service No. PB 263 164, 1975. 45. iap.c Monographs: F.valuation of the Carcinogenic Risk of Chemicals to Man, Volume 4, 1974. pp. 27-36. 46. Flue.-:, E. R. , et al . Evaluation of a DNA Polymerase- ficiont Mutant of for the Rapid Detection of Carcinogens. Chem. Biol. Interact., 15:219-231, 1976. . 47. Schna1 1, D. Prufung von Naphthalin und Anthracen auf Carcerogenc wirking an Ratten. Zeitschrift fur Krebsforschung, 60:697-710, 1955. 48. Stanton, M. F., et al. J. Natl. Cancer Institute, 49(3): 867-877, 1972. <9. Pienta, R. J., et al. Morophological Transformation of Early Passage Golden Syrian Hamster Embryo Cells Derived from Cryopreservea Primary Cultures as a Reliable in Viiyj Sioassav for Identifying Diverse Carcinogens. Int. J. Cancer,'19:642-655. 1977. 50. DiPaolo, J. A.* et al. Oualtitation of Chemically Induced Neoplastic Transformation of BALB/3T3 Cloned Cell Lines. Cancer Research,.32:2686-2695, 1972. 51. Purchase, I. F. H., et al. Evaluation of Six Short-Term 7ests for Detecting Organic Chemical Carcinogens and Recom mendations for Their Use. Nature, 264:624-627, 1976. 52. McCann, J., et al. Detection of CardLin^ea^ai Mutagens |in the Sc 1-rcnaZ Zcr/Microsome Test, Assay fcf30| Chemicals J Proc. Natl.* Acad. Sci!. i (USA)l, 72l51B3-513^1 ft9l5f. 50 MONS 022126 53. IARC Monograph*: Evaluation of the Carcinogenic Risk o Chemicals to Man, Volume 3, 1973. pp. 45-68. 54. TLVs-' Threshold Limit Value* for Chemical Substances and Physical Agents in the Workroon Environment with Intended Changes for 1 977. American Conference o: Cuvv-'rr.Tental Industrial Hygienists, 1977. 55. IAAC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Kan, Volume 7, 1974. pp. 203-222. 56. Brown, s. L., et al. Research Program on Hazard Priority Ranking of Manufactured Chemicals. National Technical In formation Service No. PB 263 162, 1975. 57. Walker, P. Air Pollution Assessment of Benzene. National Technical Information Service No. PB 256 734, 1976. 58. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 1, 1972. pp. 80-86. 59. Vesselinovitch, S. D., et al. Factors Modulating Benzidine Carcinogenicity Bioassay. Cancer Res., 35(10):2814-2819, 1975. 60. 3rown, S. L., et al. Research Program on Hazard Priority Ranking of Manufactured Chemicals. National Technical In formation Service No. PB 263 163, 1975. 61. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 3, 1973. pp. 91-136. 62. Takizawa, N. On the Carcinogenic Action of Certain Quinones. Proc. Imperial Acad. (Tokyo), 16:309-312, 1940. 63. Tiedmann, H. Ztschr. Naturforsch., 8b:49-50, 1953. 64. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man; Volume 15, 1977. pp. 255-264. G5. Vogel, E. Differential Sensitivity of Immature and Mature Oocytes of drosophila Velanogasicv to the Induction of Dominant Lethals Following Treatment of Mono- and Polyfunc tional Aziridine Analogues. Mutat. Res., 14:250-253, 1972. 66. Lueers, H., and G. Obe. Possible Mutagenic Activity of a^Benzoquinone. Mutat. Res., 15:77-80, 1972. 67 IARC M&no'grapfis: i EJriluatibn, bf thej Carcinogenic Risk of cSemicals ta Man* Voiume<lh.J 1976k I5JLMONS 022127 McCann. J., et al. Detection of Carcinogens as Mutagens: Bacterial Tester Strains v-th R fact:/,: Plasmids. proc. Nat, Acad. Sci (USA;, 72:979-983, 1075. 69. Evaluation of Carcinogenic, Teratogenic, and Mutegenle Activities of Selected Pesticides and Industrial Chemicals, Volume X. National Technical Information Service No. PB 223 159, 1963. 'j. IAS'.' Monographs: evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 4, 1974. pp. 231-238. Smith, A. H., and L. Ellis. Styrene Butadiene Rubber Syn thetic Plants and Leukemia (Letter to Editor). J. Occup. od., 19(7):441, 1977. ... DiV:to, G.. and G. L. Sommi. The Incidence of Infectious s-Mtes, Hemcpathies, and Neoplasms in Workers Expcned to c r. Disulfide. Folia Med. (Napoli), 46 ( 11) : 972-979, 1963. 1. :a?.C Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 1, 1972. pp. 53-60. Air Pollution Assessment of Carbon Tetrachloride, v i :nal Technical Information Service No. PB 256 732, 1976. . "ishbe in, L. Industrial Mutagens and Potential Mutagens, I. iialogcnated Aliphatic Derivatives. Mutat. Res., 32:267-308, 19 7, Furman, F. A., et al. Arch. Inst. Pharmacodym., 102:113 11', i 9 5 3. `'7. Inr.es, J. R. M., et al. J. Nat. Cancer Inst., 42:1101-1114, '959. 79. Li.-.,ore, J. D., ct al. Vinyl Chloride Mutagenicity via the M.vrabolites Chlorooxirane and Chloracetaldehyde Monomer Hydrate. Biochem. Biophys. Acta, 442:409-419, 1976. Ta;.: it, u., et al. The Mutagenicity of Chlorcethylene Oxide, Chloroacetaldehyde, 2-Chloroethanol and Chloroacetic Acid, Conceivable Metabolites of Vinyl Chloride* cijem. Biol. Interact., 12 (3-4):251-263, 1976. dartsch, U., et al. Human, Rat and Mouse-Liver Mediated Mtotaoenicity of Vinvl Chloride*in 5.; rvrA.i.'frfcvMP iSjt&ins. Sftt.fjJCancer, 15(3) :429-437J 1975 3L. ille,jC.f et.al. , Mutagenicitv of .Vinyl idI ethyleneoxide, Chloi*oacetalceity&e an<#5njprdefnap<il.. ' (Biophys. Res. Comm; J 63 (-2) :`363-37rf,|l5. 52 HONS 022128 82. Bfoadsar of Chlordaaa'for Possible Carcinogenicity (CAS Mo. 57-74-9). National Technical Information Service No. P3 271 977. 83'. Bakke, O. M., and T. Midtvedfc. Influence of Gene-Free Status on the Excretion of Simple Phenols of Possible Significance in Tumor Promotion. Experimentla, 26(51:319, 1370. 64. Bock, T. G., et 1, Composition Studies on Tobacco. XLIV. Tumor-Promoting Activity of Subfractions of the Weak Acid Fraction of Cigarette Sacking Condensate. J. Nat. Cancer Inst., 47(2):429-436. 1971. 85. Shustova, M. N.. and L. N. Samiolovieh. Blastomogenic!ty of Neutralised Soots from the Sulfate Shop of a Coke Plant. Gig. Sanit., 36(71:103-104, 1971. 86. Bone, E. S., et al. The Production of Urinary Phenols by Human Gut Bacteria, (Meeting Abstract). J. Med. Microbiol., 9(2):vi, 1976. 87. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5, 1974. pp. 08. Jurek, A. Carcinogenicity of Pesticides. Rocrn. Panstw. Zakl. Hig., 25(5) :56 3-S76, 1974. 89. IARC Monographs: Evaluation of th- ..'jrcinogenic Risk of Chemicals to Man, Volume 1, 1972. 61--65. 90. Powers, M. B., and R. W. Yoelker. Evaluation of the Onco genic Potential of Chloroform by Long-Term Oral Administra tion in Rodents (Meeting Abstract). Toxicol. Appl. Pharmacol., 37:179, 1976. 91. Renne, H. A., ct al. Pathology of Lor.-:-Tern Oral Adminis tration of Chloroform in Rodents .Mcotirn Abstract). Toxocol. Appl. Pharmacol., 37:179-180, IJ'C. 92. Chloroform Tagged as Carcinoaer. ir. Mice. Chem. Eng. News, 54:6, 1976. 93. Khachatryan, E. A. The Pole of Chloroprene in the Process of Skin Neoplasm Formation. Gig. Tr. Prof. Zaboi., 16:54- *5, 1972. ` 94.. Khachatryan, E. A. The Occurrence of Lung Cancer Among People Workinq with Chloroorene. Problems in Oncoloqv, J8:*5$ 1972. 95. Ahacnatrvan, -E. ' A fLuilg* Cancer Irscidende* Among-Chloroprene <2&<iifcngf (talkers. Ifopjpx fr#co}.> : 3<972i. B3 HONS 022129 96. C3to, B. C., et al. Assay of Industrial Chemical? in Syrian Hamster Cells for Enhancement of Viral Transfonwtio Proc. Am. Assoc. Cancer Pcs., 18:155, 1977. 97. Bartach, >i., et al. The i'redlctive Value'of Tisauas-Hedlated Mutagenicity Assays to Assess the Carcinogenic Bisk of Chem icals. IARC Sci. Pub. No. 12, 1976. pp. <67-491. 93. Zilfynn, v. N., et al. Experimental Study of Chloroprene for Carcinogenicity. Ycpr. Onkol., 23:61-65, 1977. 99. Zilfyan, V. N., et al. Results of a Study of Chloroprene for Carcinogenicity. Zh. Eksp. Klin. Med., 15:54-57, 1975. 100. Lloyd, J. W. Cancer Risks Among Workers Exposed to Chloro prene. Ann. N.Y. Acad. Sci., 271:91-93, 1976. 101. 1ARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, volume 3, 1973. pp. 159-177. 102. Epstein, S. S., and H. Shafner. Chemical Mutagens in the Human Environment. Nature, 219:385-387, 1968. 103. Radiation Research, Supplement 3:193, 1963 (as cited in Reference 2) . 104. J. Nat. Cancer Inst., 37:825, 1966 (as cited in Reference 2). 105. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5, 1974. pp. 83-124. 106. Vocel, E. The Relation Between Mutational Pattern and Concentration by Chemical Mutagens in ?roaovhi. .. . IARC Sci. Pub. Ho. 12, 1976. pp. 117-137. ' 107. Kotin, P., and H. L. Falk. Radiation Research Supplement 3: 193-211 , 1963 (as cited in Reference 5}: 108. Saffioti, U., and P. Shubik. Nat. Cancer Inst. Monog., 10:489-507, 1963,T(as cited in Reference 5). 109. Hoshing, H., et al. Gann 61(2):121-124, 1970 (as cited in Reference 5) . 110. Van Duuren, B. L., et al. J. Nat. Cancer Inst., 39:1217 1228, 1967 (as cited in Reference 5). 111. Documentation of the. Threshold Limit Valjigs for| ^ub^tahoes in .Workroom!Air. American Conference of Governments!! *i{- diistVial^Hygienists,' 1976. pp. 96-97. 54 HONS 022130 U3N ?.ShublK", at al.' Survey of Compounds*Which Have Boon Tested for Carcinogenic Activity, Supplement I. National Technical Information Service No. PB 216 248. 1957. 112. Singh, A. R., et al. Mutagenic and Antifertility Senaitivitie* of Mice to Di-2-ethylhexyl Phthalata (OEHP) and Dlmethoxyethy1 Phthalate fDMEP). Toxicol. Appl. Pharmacol., 29(1):35-46, 1974. 12 4. 115. Mathur, S. P. Reap; ror.c tr tc Evidence of the Utilization of Dioctyl and Di-2-cthylhexvi Phthalate Plasticizers. J. Environ. Qual., 3(3):207-209, 1974. Peakall, D. B. Phthalate Esters: occurrence and Biological Effects. Residue Reviews, 54:1-41, 1975 (177 references). 116. 2^7 ' Recent Progress in Safety Evaluation Studies on Plasticizers and Plastics and Their Controlled Use in Japan. Environ. Health Perspec., 17:203-209, 1976. Singh, A. R., et al. Mutagenic and Antifertility Sensitivities of Mice to Phthal ic-Acid Esters. J. Anim. Sci., 38 (1) : 216, 1974. ..g ' Taylor, B. F., and E. F. Corcoran. Biodegradation of Phthalic Acids and Esters. Contract ES-00994-02, National Institute of Environmental Health Sciences, 1975. 1-0* Autain, J. Toxicity and Health Threats of Phthalate Esters, Review of the Literature. Environ. Health Perspec., 4:3-26, 1973. Yagi, Y., et al. Teratogenicity and Mutagenicity of a Phthalate Ester. Teratology, 14:259-260, 1976. 121. Dillingham, E. O., and J. Autain. Teratogenicity, Mutagenicity and Cellular Toxicity of Phthalate Esters. Environ. Health Perspec. 3:81-89, 1973. 122. Landon, J. C. Carcinogenesis Bioassay of Di(2-ethylhexyl) Phthalate. National Cancer Institute contract with Tracer Jitco, Inc., 10/76-9/77, 1977. 123. Saeger, V. W., and E. S. Tucker. Biodegradation of Phthalic Acid Esters in River Water and Activated Sludges. Appl. Environ. Microbiol., 31(1): 29-34, 1976. D24* Palmar, Ki A., et al. The.Mutagenic{Assay oftSome Hair Dye Components Usingfthe Thymidine Kinang ,ocus fof L51178Y Mouse |ypprf?4 teljls ((Meeting .'Abstract) * \ Toxicol} Appl. -Pharmacol. 3 7*{ 1)[: 10 8 j 1976.' HONS 022131 125. 125. Kinkel, H. J., and S. Kolzmann. Study of Long-Term Percuta neous Toxicity and Carcinogenicity of Hair Dye* (Oxidising Dyes) ir. flats. Food Cosmet. Toxicol., 11 (4) j641-648, 1973. Outnett. C., et al. !.ong-Tor?i Toxicity Studies on- Oxida tion Hair Dyes. FoodCosmet. Tori col., 13(3):353-357, 1975. Burnett, C. , et a). Dominant Lethal Mutagenicity 'Study on Hair Dyes. U. T-:<icoJ. Environ. Health, 2 (3) 1657-662, 1977. 128. Dybing, ., and s. S. Thorgeirsson. Metabolic Activation of 2,3-Diaminoanisole, a Hair-Dye Component. Biochem. Pharmacol., 26(8):729-734, 1977. 129. Dybing, E., and T. Aune. Hexachlorobenzene Induction of 2,4-Diaminanisole Mutagenicity vitro. Acta Pharmacol. Toxicol., 40(S):575-583, 1977 (24 references). 130. Ames. B. N., et al. Hair Dyes are Mutagenic; Identifica tion of a Variety of Mutagenic Ingredients. Proc. Natl. Acad. Sci. (USA) 72(61:2423-2427, 1975. 131. Blijleven, W. G. Mutagenicity of Four Hair Dyes in >;; r" Mutat. P.os. , 48 '2) ; 181-185, 1977. 132. Health Hazards; 2 , i-Diamir.oan i solo. Occupational Safety & Health Reporter, 7(351:1331, 1978. 133. 2,4-Diaminoanisole (4-Methoxy-----phenylenediamine) in Hair and Fur Dves. Current Intelligence Bulletin 19, January 13, 1978. ` ' 134. Kimbrough, R. D., and T. B. Gaines. Effect of Organic Phos phorous Compounds and Alkylating Agents on the Rat Fetus. Arch. Environ. Health, 16:805-808, 1968. 135. 136. Trinh-Var.-Bao, et al. Chromosome Aberrations in Patients Suffering Acute Organic Phosphate Insecticide Intoxication. Humangenetik, 24:33-57, 1974. r Tzoneva-Maneva, M. T., et al. Influence of Diazinon and Lindane on the Mitotic Activity and the Caryotype of Human Lymphocytes, Cultivated ir. Viira. Bibl. Haematol, (Base 1), 33(11:344-347, 1971. 137. Marshall, T. C., et al. Screening of Pesticides for Muta genic Potential Using .c >.'!> 1 i : ?: ; i -turium eMptapts;. J4 Jlgric.: Food Chen.; 24 :560-563, 1976 13.8. MQhn, Sj. . 5-Methyltryptophan Resistance MUtaCibn^irf faohffr H/iU fe'Mutat*. 'Res. 20(1) :7-<15f il97fef 56 MOWS 022132 Ashwood-Smith', } 'fet al. MutagcrfiCiby Nature, 240:<19-417, 1972. 140 IARC Monographs: Evaluation of the Carcinogenic Ri*K of Chemicals to Han, Volume 7, 1974. r . 211-244. 141. Guerin, M., et al. Inhibitory Action of Chemical Carcino- qena on Mitosis of Rat Lung Cell Cultures; 2. Comparative Study of Carcinogenic and Moncarcinogenic Substances. C. R. Soc. Biol., 165: 2255-2258, 1971. 142. Prasad, I. Mutagenic Effects of the Herbicide 3',4*-Oichloro-propionanilide and Its Degradation Products. Can. J. Microbiol., 16r369-372, 1970. 143. Prasad, I., and D. Pramer. Mutagenic Activity of Some Chloroanilines and Chlorobenzenes. Genetics, 60:212-213, lO^. 144. IAKC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 4 , 1974 . pp. 49-55. 145. Stula, E. F., at al. Experimental Neoplasia in Rats from Oral Administration of 3,3-Dichlorobenzidine, 4,4'-Methyler.ebi s {2-chloroanii ine), and 4,4 1-Methy lenebis (2-methylanilino). Toxicol. Appl. Pharmacol., 31(1):159-176, 1975. 146. Rartsch, H., et al. Alkylating and Mutagenic Metabolites oi Halogenated Olefins Produced by Human and Animal Tissues Pro.-. Am. Assoc. Cancer Res., 17:17 , 1976. 147. Van Duuren, B. L., et al. Carcinogenic Activity of Di- and Tn- functional o-Chloro Ethers and of 1,4-Dichlorobutene-2 ;CR/HA Swiss Mice. Cancer Res., 35:2553-2557, 1975. 148. Andrews, A. w., et al. The Identification of Endogeneous and Exooencous Mutagenic Compounds. 4th Carcinogenesis Bioassay Program, Orlando, Florida, February 1976. 149. Stevens, S., et al. Phenotypic and Genetic Effects in .VYProduced by Selected Gases and Gases Mixed wit'll Oxvgen. Develoo. * Ind. Microbiol., 12: 346-353 , 1971. ` 150. Schwetz, B. A.J et al. Embryo- and Fetotoxicity of Inhaled Carbon Tetrachloride, 1,1-Dichloroethane, and Methyl Ethyl Ketone in Rats. Toxicol. Appl. Pharmacol., 28:452-464, 1974. ` 152;. National Cancel: Institute Draft Summaries ;of Bioassay: Re ports, \ , 1-Dichlaaroethane. Chera. Reg. (Rep.1, lit 4 Sr) ? i S^7- 1593,11978. 57 MONS 022133 152. Ar.derscfi, k. V., et ai. Evaluation of Herbicides forPossi- blo Mutagenic Propcrt;*?. J. Agr. Food Chen., 20:649-656, 1972. 153. Boutwell, R.,.l(.r and D. . Bosch. The Tumor-Pronoting Action of Phenol and Related Compounds for Mouse Skin. Cancer Rea., 19:41'--(24, 1959. 174. Torkclson, T. P., and. Oycn. The Toxicity of 1,3-Dichlo- : opropene ss Poccrr-.imd by Repeated Exposure of Laboratory Animals. Am. Indust. Hyc. Assoc. J.. 38(5):217, 1977. 155. DeLorenzo, P., at al. Mutagenicity of Pesticides Contain ing 1,3-Dichloropror>er:e. Cancer Res.. 37 (6/: 1915-1917, 1977. 156. Neudecher, T., et al. . . Mutagenicity of the Soil Nematicide 1,3-Dich 1 nr propone. Expcrientia, 33 (8): 1084-- 1085, 1977. 157. Shirasu, H., et a 1 . v.j tacion ; o l tv Screening of Pesticides m the Microbial Ryster . l\jt it:. Res . , 40: 19-30, 1976. 15 5. 3xoassay of Diehl .rvo- f r : ssibie Carcinogenicity, CAS No. 62-73-7. National . :ul Info: mation Service No. ?3 270 937, 1977. 159. Rieger, M. M. Cos: vt. .'c:* r. Cosmet. Perfum. , r,l 4 ,: .' j - j , 19 7 6 I.i terature Survey. 6. 160. liadidian, Z., et a 1 . 1968. . lancer Ins:. , 41 (41:985-1036, 161 . Dushutin, K. K., and E. D. Sopach. The Role of the Reaction of Dimethylamine with N itrncon Tetroxidc and Ozone in Atmospheric Pollution. i-i>:. Sa:. ih ., 7:14-18, 1976. 162. 16 3 . IARC Monographs: ival.. j: . r the Carcinogenic Risk of Chemicals to Man, V n 4, :974. pp. 137-143. Wilson, R.. R. 5pn-' : V tr.r. Rvsnonse to Dimethyl hydrazine. Toxido1. A: : 1 . pr.arcaccl . , 33 ( 3) : 647-650, 1976. 164. National ^n&er Instit-t.o. Oratt Summaries of Bioassay Reporgr,|a^4-sDinitrotoluene. Chen. Reg. Rep., 1 (45): 1598, 1978. 165. Kociba,. R.. J, gt al. i, 4-D: n>:ar.o: Correlation of the Results! Iffe cilroiiit Ir.gestior. and Inhalation Studies jv/ith i 1DgAfiparailfnx Fatg in P-atist Aerbsp.' Med.f Res. iuabi (Tdch*fcJ* ) &MRl3-TR-125, 1973. f ofc. 345-3541 =fe MONS 022134 Alternative? in.'Dxoxane 9(4):237-243, 1973. 167. IARC Monograph: Kvnluation o the Carcinogenic Risk of Chemicals to Man, Volume 11, 1976. pp. 247-256. 168. Torkelson, T. R. , et ai. 1,4-nioxan*-. II. 2-Year Inhala tion Study In Rates. Toxicol. Appl. Pharmacol., 30(2): 287-298, 1974. 169. Simmon, V. F., et al. Mutagenic Studies of Twenty Pesticides. Toxicol. Appl. Pharmacol., 37(1)j109, 1976. 170. National Cancer Institute Draft Cumaries of Bioassay Reports. Chem. Reg. Rep., 1(43;: 1608-1609, 1978, 171. Grant, W. F. Cytological Effects of Environmental MutaaersPesticides. Mutat. Res., 2.1 (4) : 22J-222, 1973. 172. Van Dijck, P., and M. Van do Voorde. Mutagenicity Versus Carcinogenicity of Organochloride Insecticides. Meded. Fac. Landbouwwet. , Rijksuniv. Gent, 11(2, part 2) : 14 91 -- 1498, 1976. 173% IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 3, 1574. pp. 157-171. 174 IARQ Monographs: Evaluation of the Carcinogenic Risk of ' Chemicals to Man, Volume 11, 2576. pp. 131-139. 175 ' Kurinnyi, A. I. Mutagenic Activity of Some Pesticides Derivatives of Urea, Carbamc, and Thioc*rbamic Acids. Tsitol. Genet., 11(4):337-359, M77. 17r ` Hakeek, H., and A. Shehai.. and Cotoran on Viri'. ":t:. 311, 1974. Cytological Effects of Eptam Egvv:. J. Bot., 16 ( 1-3) : 3 0 3 - ' Rydberg, U., and S. Skerfuing. The Toxicity of Ethanol: 177` A Tentative Risk Evaluation. Adv. Exp. Med. Biol., 85B: 403-449, 1977 (57 references). 178> Braun, RIand Schoeneick. influences of Ethanol and Carbpn .Ttrachlcirida on the Mutagenic, Effec^vity of Cyclo- pktospnaiuRleffffr the*Rost-Mediated Assay wiztp9dlhon*lla Typhimurium MUtat. Res., 31 (3) :191-194, 1975. A79.. Charbey ,1 R.J C.Aletj al. Evaluation of. theiEffect^of^Ethanol on-the Frequency iof jMicronuclei inf the1Bone; Marrow of Swiss lieef.f Mu tall Ri^.i t43(3) 1441-444.U9177. 59 MONS 022135 ISO? Opdyke< D. L. Monographs onPragrtridV taw''Materia Is Ethyl benzene. Food Cosmet. Toxicol., 13(Suppl,)>803-804, 1973. 181. XARC Monographs: Evaluation of th* Carcinogenic Risk of Chemicals to Man, Volume IS, 1977. p'. 195-209. 182. Johna, R. Air Pollution Assessment of Ethylene Dibromide. National Technical Information Service No. PB 256 716, 1976. 183. New Findings on Two Carcinogens Reported to Subcommittee by NIOSH. occur;.', t: ona 1 Safety & Health Reporter, 7(35) :1331, 1978. 184. Johns, R. A:r Pollution Assessment of Ethylene Dichloride. National Technical information Service No. PB 256 733, 1976. 185. iiomburger, F. Carc:not;:nLcity of Several Compounds. National Technical Informal ; n Service No. PB 183 027 , 1968. 26 pp. 186. Mason, ,M. M. 1' i oology .::. -u Carcinogenesis of Various Chemicals Used, in the Ptopar.n n.-r, of Vaccines. National Technical Information r / i ;v Nc:. PB 195 185, 1969. 55 pp. 187. Dorse, P. H. rti'.u c! Newborn Mice with Seven Chemical Adjuvants tc dele !>'t-. r:-: :: Tre :: Safety. National Tech nical Infers :.t ion. Scr".V-. PH 155 153, 1969. 1 35 pp. 188. Coon, R. , et al . A;i Lr..;.inhalation Studies on Amnor.ia, :i thy ler.e Glycol, Cortr.a i i euydo, Dimethy lamine, and F.thanol. Toxicol.' Appl. Pharmacol 16 (3) :645-646, 1970. ISO. IARC Monograms: Eva! - *. :o:i of me Carcinogenic Risk of Chemicals to Man, Vol ir -- ii, ?p. 157-167. 190. :ARC Monographs: Evnluc vlc of the Carcinogenic Risk of Chemicals to Mon, Vo .076. pp. 37-46. 191. .A: cos, J. C., and .'!. F. Arcus. Chemical Induction of Cancer, Volume 11A. Academic !'r ;s, New York, 1974. pp. 26, 237. 192. Hoffman, D., et al. J. Natl. Cancer Inst., 49:1165-1175, 1972. 193. Rao, T. K., ct al. Envi remr.ental Mutagenesis of EnergyRelated Effluents. Gene tics, 83.S60, 1976. 19.4; Watanabe, F., et all Gann. 45:451-462, 1954 (as cited ,in Reference 5). 19.5, Investigation of, S^egted Potential Environmental Contami-r nants: * Forma laehytfe. National Tecmlcar itifoVmation ServicejNol PQ?256fl39, 1976. 60 MONS 022136 11a i*t mew 'j.Genet. Cytol., 10(4) : 66S-6711976. 197'. Jorgenson, T. A., et al. /V fTeo Mutgnei* investiga tions of Ten Commercial Pesticides- Toxicol. Appl. Pharmacol.. 37(1):109, 1976. 198. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5, 1974. pp. 173-191. 199. Bioaasay of Heptachior for Possible Carcinogenicity, CAS No. 76-55-8. Motional Tecnnical Information Service No. PB 271 967. 200. Khera, K. S. Hexachlorobenzer.e: Teratogenicity and Domi nant Lethal Studies in Rats. Toxicol. Appl. Pharmacol., 29(11:109, 1974. 201. Poyland, E., et al. Kidney Tumors in Hats Following Treat ment with 2-Acetylaminofluorene, Tryptophan, ar.d 14-Sacchnrolactone and the Failure of Substances Which Cause Porphyrinuria to Induce Tumors. In: British Empire Cancer Campaign 1963 - Part 2: Scientific Report, 1963. pp. 58-59. 202. Guerzoni, M. E., et al. Mutagenic Activity of Pesticides. Riv. Sci. Tecnol. Alincr. ti Nutr. Urn. ' I ta l.) , 6 (3) : 161-165 , 1976. 203 . Cabral, J. R. P., et al. Carcinogen.-.- Activity of Hexachlorobenzene in Hamsters. Nature, 269 i 5*.:28) : 510-51 1, 1977. 204. Test for Carcinogenicity of Organic Contaminants of United States Drinking Waters by Pulmonary Tumor Response in a Strain of Mice. Cancer Res., 37(81:2717-2720, 1977. 205. Results of a Two-year Cnror.ic Toxicity Study with Hexachlorobutadiene in Rats (Meeting Abstract). Toxicol. Appl. Pharmacol., 41 (1) :204. 1977. 206. Kociba, R. J., et al. Results of a Two-Year Chronic Toxi city Study'With Hcxachlorobutndiene in Rats. Am. Ind. Hyd. Assoc. J.38(11):589-602, 1977. 207. Reproduction Study in Japanese Quail Fed HexachlorobutadieneJfor 90 days. Toxicol. Appl.Pharmacol., 30(2):255-- 265, 1974. 208. Della Porta, G., et al. Mon-Carcinogenicity of Hexamethyl enetetramine in Mice! and (Rats.; iFood Cosnet. Toxicol., ;6i`:70.777i5,; 1968. 61 MONS 022137 20*; IMC*Monographs: Evaluation of the circinoganic ftt)f Of ` Chanical* to Man, Volume 1974. 127-136. 210. Rot,'P.TXJWfv-, and M. H. Salaman. Further Studios on' ln- coaplsts Carcinogenesis. British J. of Cancer, 9177-203, 1955. 211. Boyland, E., et al. Materials into Cancer, 18: 57 S - -: , Farther Exper cuts on Implantation of .ry Bladder uf Mice. British J. of 212. Van Duuren, B. I.., an;i a. M. il^ldschridt. Cocarcinogenic and Tumor-Promot tm Age-.ts : n Tobacco. J. Natl. Cancer Inst., 56 : 12 37- 1 2-12, 197*.. 213. Hecht, S. S., e: al. Study of Tubacco Carcinogenesis; XIII: Tumor-Promot i r.q Subfractions of the Weakly Acidic Fraction. J. Natl. Cancer I.-.-jt., ',5'6) : 1329-1 336, 1975. .1-1. Interaction Be twee:. Hyd: o : j : .none .r : Cigarette Smoke Con densate in Short-Term S ; r. Ten;.- :: : Carcinogenicity. 70X1,INK . ' 2 15 . National Cancer 1 r> . .. . : <f .. . : of Bioassay Reports. Cher.. '<>::. he .. .-:*i0 3, 1978. 216. F. i 1 ir.skas, K. a; .: A. >. Against Mamma; / : ..: - . . o: 7,12-[)i~. : .'.! . . Natl. Cancer ins* . . ' * v. : I ion by DDT Prolonged Fced- to Female Rats. J. , '.'5. 2;7. Pickens , F., and ... . N. ..'nees. : . i * t: r-r Studies on the Carcinogenic and ..rc-wtl.-inr.il. *ory ivitv of Lactones and Related Substance?. 9r t. 7. , 17: 100-109, 1963. 21S. Evaluation of Care . :v. .get-.: ;, 7ogc-n ic , and Mutagenic Activities of Selected cv.L- am! Industrial Chemicals, Volume III. National Tec!...: to '. Information Service No. V3 223 161, 1968. 219. Evaluation of,?arc.noge: tc, Ter.it ci-r.;v, and Mutagenic Activities of Selected Pesticides and industrial Chemicals, Volume II- National Technical Information Service No. PB 223 160, 1963. 220. Ehrenberg, L., et al. t:. the Reaction Kinetics and Muta genic Activity of Methyiatir.u and Beta-Halogenoeth^lating , da30iir.e Additives. Radii?. Lot., i 4 ; 7) : 185-194 , L974. 22J Embryo Toxicity, and-Feto Toxicity cf Inhaled Carboy Tetra chloride*. 1*, l-n'ichlerolthano, 'and Methyl Ethyl Ketone in Rata.I ibxijcol.t At>pJ.- fharrtecol.t *29(11 !l232 lOT^. * 32 HONS 022138 212 X.jMori. Proc. !*? ac.ic. . japag as cited * n Reference' " 223. fJakah^raW. , and K. Mori. G.'.rn, 34:;4j-ns, 3940](h* cited cir Reference 5). 224. Horton, A. K., at al. Cancer Pcs-'irci., 25:1759-1763, 1965 (as. cited in Reference 5). 225. Singh, A. R., et al. Embryonic-Feta; Toxicity and Tera togenic Effects cf a Group of Methacrylate Esters in Rats. J. Dental Research, 51: 1632-! 638, 1972. 226. 1ARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 4, 1974. op. 65-71. 227. OSHA Compliance Guide, 29 CFR Part 1910, 1978. 228. Methylene Chloride Passes Earlv Toj-f;. Chen. F.ng. News, 55 (19) :6. 1977. ' 229 . Mutation Research, Volume 53, Jar.oory 1978. 2 30 . 1ARC Monographs: Evaluation of tJ- C.: m noi-er.ic Risk of Chemicals to Man, Volume 4, 1Q74. 79-65. 231. Schoental, R. Carcinogen.: ar. ! Chronic :frocts of 4,4'- Diaminodiphenylmethane, an Enoxvrr-K in Hai ii nor. Nature, 219:1162-1163, 1968. '` 232 . Steinhoff, D. , and E. Crundw.r.. Cat.cercgunen Wirkung von 4,4*-Diaminodiphenylmethan urJ 2,4'-Diaminodiphenyl- r.ethan. Naturioissenschafter., 57:247-248, 1970. 233. Cigiena l Sanitariya, 34: 40, l?f>9. (Translated in Hygiene and Sanitation.) 234. Toxic Substances: Proposed Occupational Safety and Health Standards for Alkyl Benzenes, Cyclohexane, Ketones, and Ozone, fed. Regist. 40 (1961:47 262-47 31.1, 1975. 235. Effect of Alpha-Methylstvreni and Tert-Dodocyi Mercaptan on the Skin of Animals. Vop. Gig. l'r. Profzabol., Mater. ,Nauch. Konf.? 1972, pp. 247-249. 236. Reversible Damage to the Skin of Experimental Animals Sub jected to the Inhalation of Butadiene and Alpha-Methyl styrene. Mater. Nauch. Sess., Posoyashck. 50-Letiyu Obrazov. SSSR, Omsk. Gas. Med. Inst.; 1972. pp. All-873. 237. Effect of Isopropylbenzene and Alpha-Methylstyrene on Leu , copoiesis. Farmakol. Toksikol., 35(4):491-492, 1972. 63 MONS 022139 ,239. Effect of the W L.arvae. . ' Mamtier. 50-Letiyu SSSft; 5.i9. Grc-cnb! Jtt, M., or. al. IA34, .''<1 (as cited ir. c..r 1-ver.ee ,if:i pn liduRjlfly ic.'i, TcsJ^Jasfichj I n: t. , 46:5):1029- 240. Sander, J., and G." Bunfclc'. Z. Kr-'l -.forseh, 7Hlf:54-6t, 1969. 241. Fomenko, V. N, , and E. E. S' rekal'v.v.. Mutagenic Action c>f Sene Industrial Poisons us ?. Fv.n.cr: .if Concentration and Exposure Time. Toksikcl. Gov. ?r . >hin. veshehestv., 13:51-57, 1973 (CA 79:147728.. 242. Kigukina, N. V. Evaluatio:. of '`arioer of Morpholine During Chronic Action. Toks . :..v. Pi Khim. Veshe hestv., 1 3 : 92- 100, 1973 (CA 79:14 1345) 243. IARC Monographs: Evaluation of the . ;:crnogenic Risk of Chemicals to Man, Volume 4, 1974. : . sv-gg. 244. OS1IA Connl ianco Guido, 5 9 CKH Part .A'', l-VU, 1978. pp. 298-300. 24 5 . Arcos, J. C. , and M. F. /.: .is. Ch- " cer, Volume IIA. Academic ro:,s, ` 237, and 278. 1 Induction of Can -A r-., 1974. op. 194, ' 246. Kraomcr, M. , ct al. `.nu . ' to Detect Chemical .Mutagens, Naunvn-S ?.: led- ; nr. Arch. Pharma ho 1. , 284:46K, 1974, ` 247 . Eabezhinskiy, M. A. Inv-.-su jatior.:- n. Fesi:-.ic Carcino genic Effects of Beta-Scvin. Vcui . g.-iko'. ., 16 ( 11) : 106-107, 1970. ' 248. Dorigqn, J., and J. Hushon. A:r Pollution Assessment of Nitrobenzene. National Technical Information Service No. PB 257 776, May 1976. 249. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 1, 1-972. ?p. 95-106. 250. 251. Bretschneider, K., and J. Katz. Occurrence and Analysis of Nitrosamines in Air. IARC Sci. Pub. No. 14, 1976. pp. 395 399. Fine, D. H., et al. N-Nitroso Compounds in Air>nd Water. IARC Sci. Pub. No., 14,. 1976. pfc- 401-408. 64 MQN5 022140 I52f YfadiffR. 'C. i et. al. halogcnated Crpahic^ In Tap'Hater: A|Toxicological Evaluation, 'in: The Envlrojutenial Impact of Water Chlorination, J.'atior..-!l Technical Information BervicetNo. CONF 751096. 1976. rs. 213-22S. 2531 Vogel, E., and J. L. R. Chandler. Cyclamate and Some Pesticides :r. Bxperientia, 30(61:621-623, 1974. Mutagenicity Testing of r.::: Mtlanctjaittr. ' 2541 Buselmaier, W., et al. Cornea: .it sve Investigations on the Mutagenicity of Pesticides in v.ar.r.jl lan Test Systems. Mutat. Res., 21(1):25-26, 197?. 255. Daugherty, R. C., and K. Piotr.uwska. Screening by Negative Chemical Ionization Mass Speerrometry for Environmental Contamination with Toxic Residues: Application to Human Urines. Proc. Natl. Acad. Sci., 73(6):1777-1781, 1976. 256. Salaman, M. H., and O. M. Glenicnning. Brit. J. Cancer, 11:434-444, 1957. 257. Hossak, D. J., and J. C. Richardson. Examination of the Potential Mutagenicity o: H.ii: Dye Constituents Using the Micronucleus Test. Expi.rientia, 33( 3 1 : 377-378 , 1977 . 258. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 7, 1974. pp. 361-289. 259. Lloyd, J. W., et al. Pclvchiormated Biphenyls. J. Occup. Med., 18 (2) : 109-113, 1976'. ' 260. Andrews, E. J., ct al. PCS Dirt. Science, 1 90 (4083): 255 257, 1973. 261. Ito, N., et al. Histopathological Studies on Liver Turnongenesis in Rats Treated with Polychlorinated Biphenyls. Gann, 65(61:545-549, 1974. 262. Laurence, C. PCB? and Melanoma (letter to the editor). ' N. Engl. J. Med., 296(2):106-109, 1977. 263. Gibel, W., et al. Experimental Study on Cancerogenic Activity of Propanol-1, 2-Methylpropanol-l, and 3-Methylbutanol. Arch. Geschwulstforsch, 45(11:19-24, 1975. 264. Gibel, W., et al. Studies on the Toxicity and Mutagenicity of Single Fusel Oil Components on K. Coli. Acta Biol. Med. iGer.,:23s843-852, 1969. 265. IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 15, 1977. pp. 223-243. 65 MONS 022141 266. IARC Mot^og^apttaj: evaluation, of the. ferginoggiUtv Chemical* to lah, Volumo ll,J 1;>:6. Ip. ir-l-ing^ 267. Rowe, L. K., et. iL. 7 C.V : C *. ty . : ; re; . Oxide Determined cr. Experiments'. A.-..' : r.d ..-*.: . HU!:., 13: 228-236. 1936.' 268. 26 9. 270. 27 1 . 272. 27 3. 2 7 1. 2 7 9. Arcos, J. C.,'and v. f. Ar-Ms. 11 induction of Cancer, Volume IIA, Acadc-; V -rk. '.974. pp. 210, 237. Dickens, r., et 1. ; r . t. J . . r': 1 34- 144 . 1966. Dickens, F., and :. 2 . ' ..yfor- . 46:108, 196a. r.'p. Cane. Camp., Dickers, F., et ... i* r ; \ . r. r, : 762-768, 1968. Grant, 1. F., et a! . l.c-Terr. of Sarbic Acid in the Rat. Food Crr.r^i . 7ICO 1 . . .j.'.'*: 31-49. 1975. Hondy, R. J., et al. !.ong-Tr.rr~ 7cx i >-i tv Studies of Sorbic Acid in Mice. Ford V c-sr.-t. T: . , i4(5) : 381-386, 1976. "asc:., P. L. , et al. :/* r-.ijj -To?' >i Parasorbic Acid in Rats. Food Cos:--: . 7'".': ;o 1. , 14 3i : *, `-394, 1976. Facia , T. Mu tact*:-, i >:; -.. *. t;..! 0 r. -. i Screening of Food Additives by Li:'. are?.' '.t-Ass.jv P<:v., r sion Procedures. 1 ARC Sci. Pub. Ho. 12, '.''" . : : . ' . 2~- . De.Mc-cstcr, C., ct al. V .* i A' sv *.y cf Styrene and .-tvrene Oxide. Arch. Ir.t. Physioi. . .--tin., 85(2):398- 399, 1977. 277. Vair.io, H., et al. A Study or. the Mutagenic Activity of Styrene and Styrene Oxide. Scar.d. J. Work Environ. Health, 2(3):147-151, 1976. 278. Stolz, D. R'/ Mutagenicity Testing of St-rene and Styrene EDOxidr in Sa.'-tv. ' ~ r. Bull. Environ. Contain. Toxicol., 17 (6):7 39-742, 1977. 279. Loprieno, N., et al. Mutagenicity of Industrial Compounds: Styrene and Its Possible Metabolite Styrene Oxide. Mutat. Res., 40(4):317-324, 1976. 280. Yeung, C. K. X., and C. R. Phillips. Estimation of Physiblogical Smog Sympton Potential from Chemical React!vitx,oj/ Hydrocarbons. Atm. Environ., 7, 1973. 281. Gray, A. W. A, Arch. Ind. Hyg., 2:407-419*1950. 66 mons 0221A2 28?. Brea, H., et a'l. The Mutagenicity and DNA-Modifying Effect o! naloalkanes.; career Ris.; ;34^2516*2579/ l?i. 283. Rosenktfanz, H/ S. Mutauomcity and*DNA-Modifying Activitf:' A Comparison of Tv *-* 1 Assays. Mu tat. Res.. 41(1) 61-70, 1976. ' 284. Kraybill, H. T Origin, Classiffcation, and Distribution of Chemicals in Drink i.-.u Water with an Assessment of their Carcinogenic Potential. In: The Environmental impact of Water Chlorination, National Technical Information Service No. CONF 751096, 1976. p. 229. 285. Chemical Regulati;-.:. rnr-orte: , 1 (511:1861, 1978. 286. Fuller, B. B. Air tvllyticn Assessment of Tetrachloroethylene. National TN.'.-lini col Information Service No. PB 256 731, 1976. '> ; 287. Bioassay of TetraohIoroethylene for Possible Carcinogenicity, CAS No. 127-18-4. National Technical Information Service No. PB 272 940, 19'7. 288. F.pstein, S. S., and N. "antel. Carcinogenicity of Tetra ethyl Lead. Exper i : r.t ia. .74 (61:580-581, 1968. 289. IARC Monographs: '.valuation of the Carcinogenic Risk of Chemicals to Man, Vciunc 2, 1973. pp. 150-100. 290. Kennedy, G. L., et il. Teratogenic Evaluation of Lead Comoounds in Mice ar.-i Rats. Food Cosmet. Toxicol., 3(61:629632, 1975. 291. Robinson, T. R. Health, How Can It Be Measured. In: HEW Publ. (NIOSH) 76-134, 1976. pp. 114-130. 292. 293. Walker, P. Air Pollution Assessment of Toluene. National Technical Information Service No. PB 256 735, 1976. Giles, A. L. , et al. Poniidl Carcinogenicity Study by Mouse-Skin Paintinn with 2,4-Toluenediaminc Alone or in Representative Hair Dvc Formulations. J. Toxicol. Environ. Health, 1 (3):433-440.' 1976. . 294. Bridges, B. A., and M. H. Green. Carcinogenicity of Hair Dyes by Skin Painting in Mice (letter to editor). J. Toxicol. Environ. Health, 2(1)s251-252, 1976. 295. Shah, M. J., et al. Comparative Studies of Bacterial Muta tion and Hamster Cell Transformation Induced by 2,4-Toluenedianine (Meeting Abstract). Proc. Am. Assoc. Cancer Res., 18:22, 1977. 67 HONS 022143 296, Cancer Research, 29: 1137, 1969. 79l\ Plants, R, J., et al. Correlation o{Tfcacterial Mutagenicity and Hanstsr Cell Transformations with Tumoriganicity Induced by 2,4-Tclunedtawir:e. Cancer Lett. (Amsterdam), 3(1/2): 45-52, 1977. 298. Biod.-ssay of 1,1,1-Trichioroethane for Possible Carcinogen ic;!.". Carcinog. Tech. Rep. Serv. - Nat'l. Cancer Inst. (('.S'. I; ISS NCI-CC-TR-.i, 1975. 70 pp. 299. Carcinogenesis Bioassay of Trichloroethylene. CAS No. 79 01-'.. National Cancc: Institute Carcinogenesis Technical Report Services, Nunb-r 2, February 1976 (NC1-CG-TR-2). 300. Full r, B. B. Air Pollution Assessment of Trichloroethyl ene. National 1 tchr i ,.i 1 Information Service No. PB 256 731, 1316. 301. .r-i..., F., c*t al. Synergistic Toxicity and Carcino genicity of "ircons" anri Piperonyl Butoxido. Nature, 214: 52(- '.29, i 9r,7 . 302 . ' , :.. , .. cil. a-.': ' i.; ' - 3 * - 4'1', 1977. t.ibolic Activation of Haloalkanas Mu tagen ici ty. Xonobiot ica, 7(7): ' . !03. l.v: Pri I ini nary dat >. '. 97 . tr ichlorof luoromethane, Nov. 27, 304 . Cytological Effects Prrhi aides on Pesticides. V. Effects of Some . . .'yi ole-: i a , 39 ( 4 ) : G6 3-64 3 , 1974. 305. I ARC Monograph:?: . iiuat.cn of tr.c- Carcinogenic Risk of Chemicals to Man, V. lume 7, 1974. pp. 111-140. 306. Garibyan, D. K. , ar.d S. A. Papoyan. Study of the Blastor-* ionic Activity of Certain Chemical Substances Using a i!: ch-Spswd Test Method. Clig. Sanit. , 8:74-76, 1977. 307. Garibyan, p. K., and S. A. Papoyan. Use of Sebaceous Gland ReactionaAa.a Teat for. Rapid Determination of Carcinogenic Activityf^Chcroicals. Nokot. Itogi Izuch. Zagryazneniya Vr.esh.' Srady Xanstscrcgen. Veschostoami; 112-115, 1972. 308. Bjrbin, A., et al. Liver-Microsone-Mediated Formation of Al^ylitiiq Agents :rc- vir.yl Bromide and Vinyl' Chloride. Biach4n. |B(LOQhy4 Res. Conn., *67 (2) : 506-603, i l'97S. 309. lA^lioi ChamiqaJ Evaluation ojf Jthfe ,Cp^|cipogfnic Risk ofi Volume 7, 19,74. pp|. 291-305. 68 MONS 022144 310. IARC Information Bulletin on the Survey of Chemicals Being Tested for Carcinogenicity. International Agency for Research on Cancer, Lyon, Bulletin Ho. 5, July 1975. 311. Greim, H. G., et al. Mutagenicity in vitro and Potential Carcinogenicity of Chlorinated Ethylenes as a function of Metabolic o-xirane Formation. Biochea. Pharmacol., 241)0132017, 1975. 312. Food Additives, Packaging Material for Use During Irradia tion of Pre-Packaged Foods. Fed. Register, 33:4569, 1968. 313. Caputo, a., et al. Oncogenicity of vinyl Chloride at i-ow Concentrations in Rats and Rabbits. IRCS, 2:1582, 1911. 314. Hushon, J., and M. Kornreich. Air Pollution Assessment of Vinylidenc- Chloride, National Technical Information Service No. PB 256 738, 1976. 315. 316. Pound, A. W. '...duced Cell Proliferation and the Initiation of Skin Tumor Formation in Mice by Ultraviolet Light, Pathology. 2U):Pro-275, 1970. M. A., et al. Ultrastructural Alterations in . Hamster Chock Pouch epithelium in Response to a Carcmugen. Arch. Oral tiiol . , 8 ( 7.) : 1 45- 165 , 1963. 317. iiockor, K. Definitions and Terminology in Carcinogenesis Analyses ind Proposals (Meeting Abstract). Third Inter national Symposium on Detection and Prevention of Cantu-r, 1976. p. 67. 318. Vuspa, S. )!., et al. Cutaneous Chemical Carcinogenesis: Past, Present, and Future. J. Invest. Dermatol., 6711) : ! ^9-203, 1975. 319. Rogers, A. . Reduction of n-Nitrosodiethylamine Carcino genesis in Rats by Lipotrope or Amino Acid Supplementation of a Marginally Deficient Diet. Cancer Res., 37(1):19l- 199, 1977. . ' 320. Syrotuck, J. A., and 3. S. Worthington. Nutritional pffects on Syngeneic Tumor Immunity- and Carcinogenesis in Mice* I.* Selected Essential Amino Acids (Meeting Abstract). Feq. Proc., 36(3):1163, 1977. 321. Leuchtenbergerk C., and R. Leuchtenberger. ,Protect:on of Hamster!Lung Cultures by L-Cysteinel Against Carcinogenic Ef feet's-ofi Fresh Smoke from Toba'cco or Marihauana ettes |(f^ee{:ing |Abgtract) < J.) Cell 4 Biol.,- 70 (2/Part I): 44alj19 7 6. 69 MONS 022145 322. Takanuua, K. et al. Effect of Phenobarbital and DL-Ethionine on 4-(DimothylaitinoJaxobensene-Motabolixing Enzymes and Carcinogenesis. Gann, 64 (4) i363-372, 1973. 323. .'to, h\, et al. Tne Development of Carcinoma in Liver of Rata .rested with n-Toluylenediaine and the Synergistic and Antagonistic effects with Other Chemicals. Cancer Res., 2915) :>n->-114S, 1969. , 324 . ivadonsk:, J. L., et al. Cocarcinogenic Interaction Between 7,L-Tryptophan and 4-Aminobiphenyl or 2-Naphthylamine in bugs, Natl. Cancer Inst., 58 (6) : 1831-1834, 1977. 325. Ito, N., et al. Effect of Various Carcinogenic and Non:arc: oogenic Substances on Development of Bladder Tumors :r. Ra:s Induced by n-Butyl-M- (4-hydroxybutyl) ru trosoamine . 'mu, . 2) : i;-i-l30, 1974. 326. '..i:. ..ah i, M. Tl." I'..-!.: cf the Promoter L-Tryptopha.-. on 'I .'r.cs i s ; n the Urinary Bladder. 2. Urinary Bladder :.n r i: r ;<T.ic i ty of Fanft (Initiating Factor) and L-Tryptophan ; : !'icror ::: V.jcc. Jpn. J. Urol., 68 ( 9 ) : 7 3 1 -7 3 6 , 337. .7. 1., and 5. M. Newberne. Dietary Effects on 'nr . .i I Cai-c ir.o r.v ; a in Animal Models for Color, and : 7;.: ,is. Can.-.;-; ? , 35(ll/Part 2) :3427-1411, 1975. 3 28. ; k , i.. Dietary Vitamin A and Human Lung Cancer. 1: . .' . Cancer, l5(4i:5bi-565, 1975. 3 29. , L. Inhibit* or. of Tumor igenes i s by Topical .'cap 1 i . a ;::n of Low Peso? of Vitamin A Acid an.: r luorouraci l. Expo;Mentia, 31(41:49.1, 1975. 3 30. Suqim.ura, T. Carcinogens in Foods and Food Products. Proceedings of the Eleventh Canadian Cancer Research Conference, Natl. Cancer Inst. Canada, Toronto, Ontario, 6-8 May 1'976, 19f4f. 331. Schoental, R, The Role of Nicotinamide and of Certain Other Modifying Factors in Diethylnitrosamir.e Carcinogenesis: Fusaria* Mycotoxins rar.fl "Spontaneous" Tumors ir. Animals and Man. Cancer (Suppl.); 40(4):1835-1840, 1977. 331. WattenbL-rg, ,L. W. , et al^ Dietary Constituents Altering the Response to Chnial Oircinoqens. Fed. Prcc. , 35:1327-1331. 1976. 70 MONS 022146 333. Wattenberg, L. W. Inhibition of Chemical Carcinogenesis by Antioxidants and Some Additional Compound*. In: Fundamental* in Cancer Prevention, Proceedings of the 5th International Symposium of The Princess Takamatsu Cancer Research Fund (Tokyo, 19 7 5) , The Princess Takamatsu Cancer Research Fund, Tokyo, Japan, 1976. pp. 153-166. 334. Chovanlec, J., t al. Histology of Tumour Formation in the Bladder of Rata Recalving Dietary Saccharin and a Single Dote of n-Methyl n-Nitro*ourea (Meeting Abstract). B. j. Cancer, 29(11:93, 1974. 335. Hicks, R. M., and J. Chowaniec. The Importance of Synergy Between Weak Carcinogens in the Induction of Bladder Cancer in Experimental Animals and Humans. Cancer Res., 37(8, Part 2):2943-2949, 1977. 336. Roe, J., et al. Feeding Studies on Sodium Cyclamate, Sacc:.urin and Sucrose for Carcinogenic and Tumour-Promoting Activity. Food Cosmet. Toxicol., 8 (2) : 135-145, 1970. 337. N'or.jr.i, T. Inhibitory Effect of Caffeine on Chemical Carr.r.'.'ionesin in Mice (Meeting Abstract). Proc. Am. Assoc. Cancer Res., 19:244, 1977. 338. Chaliis, U. C. , .m:) C. D. Bartlett. Possible Cocarcinogenic Effects of Co f ` r-. c inst i tutonts . Nature (Lond.!, 254 (5500): 532-' - i. 19"0. 3 39 . Wo t.in.ibe, K., >_ t o '. . Effect of Bile Acids and Neutral Stercis or. Bence ( i: : yrene-Induced Tumorigenesis in Skin of Mice: Brief Communication. J. Natl. Cancer Inst., 60(6): 1501-:503, 1978. 340. Altman, R. F., et il. Phospholipids Retard and Cholesterol Promotes the Fermat:on of Tumours Induced by Carcinogenic Hydrocarbons. . Narurforsch. (B), 23 (9): 1277-1279, 1968. 341. Bingham, E., pT al. Multiple Factors in Carcinogenesis. Ann. \.V. Acofd. ,'Ci., 271:1 4-21, 1976. 342. Blunck, J. M., and c. E. Crowther. Enhancement of Azo Dye ffarcinogenesia by Dietary Sodium Sulphate. Eur. J. Cancer, 11(1):2J-3i, 1975. * 343. Honburger, F., and E. Boger. The Carcinogenicity of Essential Oils, Flavors, and Spices:, A Review. Cancer Res*, ?#(11): 2372-2374, 1968). J4*i. Saiamana Ml H, ,, agd F..J. Roe. cocarcmogenesis. Br'. Mod. Bull.'.! 20 <5)139-1*44'1964. 71 HONS 022147 M5. schrM, R., n0 . Gib^fl^tenapo^Ale sad Cocareiaofwile Pl*nt Product*f 'II. rTitfiMijipl^ tlltjermss Synthoiffd by Ptcridophyta (Filicinae)t;judi#pin>aiophyta (Cyadinaaa; ' :>icotyledoneae, MorocotyladonaaaF^^Arch. Geschwulstforsch., 33(2): 189-188, 1969. 346. Zschiesche, H., and G. Bruns. Carcinogenesia of 7-- <ot.-.cholesterol. Oncology, 18 (4) : 289-299, 1964. 347. itr/sc:-., and F. Sischoff. Triolein as a Cocarcinogen, vi. --or., 2 3(2, rt. 1): 106, 1964. 348. r>zagnv.:::e, i.. (., and P. M. Krasniyanskaya. A Study of Possible Carcinogenic and Cocarcinogenic Properties of 'verheated Oils. Soohshch. Akad. Nauk. Gruz. SSR, 67(1}: . - .7 <i , 1Q72 . 4 ?-~n, ... 1 . K:fo;t of Uigh-Olcic and II i'th-Linoleic . f !'wcr -;Lr. *;i: M a rotary Tumors Induced '.n Rats by 7,12- r.y 1 bo.. 7 . a Ipho ) ar.t hr joene . J Nutr., 107(83 : 1 353-1360, rr::; 1f* ? 7 . v . .; , p. * al . V.i-tabolism and Cocarcinogenicity . s. rcuoii State Higher Kduc. :'ys., School of i'ood i*nce and Technology, Corvallis, Oregon. ; .. t a 1. Vticrgisn Between Cyclopropenoid Fatty :vr;:rui Cirrinocens in Rainbow Trout (Salmo . Ctnc-r P a., 28 (1 1) : 2 31 2-2 31 8 r 1968. .... .. . '. '.i. , Nutrition, and Cancer. Adv. Exp. ; . , .1 : . -. ;077. . ' >. . ;: . , ' it . t.'.d - :. . ?. !'Civr ; of Carcinogens or Suspected on V:r ii .aokenogenesis in C57BL/10, SJb/.l Mice Hvbr :."coti r.g Abstract). Proc. Am. Assoc. t . , ':!! '>, . '~8 . 3 .. ... . V.. Fur (fllr-i i r exogenous Precursor of Certain ":.rans ar.c Possible Toxicologic Agent in liumans. ... C-.18 (1 Z : 1550-1551, 1972. 355. . ::>.ovsKii, B. S', et al. Carcinogenic And Cocarcinogenic re. r. of Cried Fruit Extract. Vopr. Onkol. , 20(4):58-61, .374. 35-. . .thtnar., K. J. The Effect of AlfcofiolIdpnsuir.ption on Risk : Cancer af th-i Head and Neck] \ (Head fend Neck Cander, .'-ato-of-tho-Ar*-.* Conference} St J Louis,. Mq.', February, 16-18, 1576.}. Carvngqspqpef 88 fl, |P/itS 21 8)*:51-o5.f 197b.* 72 HONS 022148 357. Broas, I. 0., and J. Coomb*. Early Onset of Oral Cancer Among Women Who Smoke and Drink. Proc. Am. Assoc. Cancer Res., 17:1, 1976. )H Gibel, w., and c. wittlg. On the Experimental Induction of Carcinoma of the Bsopbagu*. Dtsch. Gesundheitsv., 19(14): 635-637, 1964. 359. Radike, M. J., at al. Effect of Ethanol and Vinyl Chloride on the Induction of Liver Tumors: Preliminary Report. Environ. Health Perspect., 21:153-155, 1977. 360. Jayant, K. Statistical Appraisal of the Association of Smoking and Chewing Habits to Oral and Pharyngeal Cancers. Indian J. Cancer, 14(41:293-299. 1977. 361. Ranadive, K. J., et al. Experimental Studies on Betel Nut and Tobacco Carcinogenicity. Int. J. Cancer, 17 (4): 469-47 6, 15 April 1976. 362. Hecht, S. S., et al. Chemical Studies on Tobacco Smoking Determination of Hydroxybenryl Alcohols and Hydroxypheny1 Ethanols in Tobacco and Tobacco Smoke. J. Anal. Toxicol., 2 (2): 5 6-59, 1978. 363. DiPaolo, J. A., ar.d r. J. Donovan. /n Vizro Morphologic Transformation of Syrian Hamster Cells by U.V.-Irradiation is Enhanced by X-Irradiation and Unaffected by Chemical Carcinogens. Int. J. Radiat. Biol., 30 (1):41 -- 53, July 1976. 364. Palotay, .1. L., et al. Carcinogen-Induced Cutaneous Neoplasms in Monhuman Primates. J. Natl. Cancer Inst., 57(6) : 1269-1274 , 1976 . 365. Lohsoor.thorn, P. The Epidemiologic Study of Subsite Large Bowel Cancer. Diss. Abstr. Int. (B), 36(9):4399-B, 1976. 366. Werner, B,, et al. Cholecystectomy and Carcinoma of the Colon, An .Experimental Study, 2. Krebsforsch., 88(3):223- 230, 1977!' ' 367. Williamson, R. C., e.t al. The Effect of Pancreatobiliary , Diversion on Testica^ Carcinogenesis (Meeting Abstract). Br. J. Surg., 64(11)j837, 1977. 363. Reddy, B. s. Role of Bile Metabolites in Colon Carcino genesis. Car.ceri (Suppl.), 36:2401-2406, 1975. 369. : Reddy*j, }B. ^.S.' 'etjall i Promoting Effect of Bile Acids on Colon Carcinoaenesis d.n .Germf ree and ConventionaliRats (Mfeet&ng Abstract)}.! Troc. Iaw. `Assoc. 'Cancer Res* , 18:119, 19,77 13 MONS 022149 370. 371. Wyndcr, E. L. Metabolic Epidemiology of Colon Cancer. Aaer. Health Foundation, Inc., Hew fork. Hew'York. * - * Curtis, G. L., tit j1. Enhancement of 7,12-Diaethylbenianthracene Skit; Carcinogenesis by Adenosine, 3',5'Cyclic Monophosphate. Cancer Res., 34 (9) : 2192-2195, 1974. 372. Freund, H., et al. Breast Cancer Arising in Thoracotomy Scars (Letter to Hoi tor). Lancet, 1(79501:97, 1976. 373. Glaser, A. Pathologic and Clinica'. Aspects of Bone Tumors. Zentraibl. Chir., 101(6):321-329, 1976. 374. Lung Cancer and Chronic Bronchitis. Med. M. Aust., 51(24): 926-927, 1964. 375. Stenbac);, F., ur.c! 0. Curtis. Mechanism of Action of Poly cyclic Hydrocarbon C.ircinoger.s: Immunological Aspects Otcctir.-: Abstract). Sound. J. Immunol., 6(11):1196, 1977. 376. Fukushima, S., et ol . Effects of Foreign Bodies on Gastric Carcinogenesis in Fats Treated with n-Methyl-n'-nitro-nr.itrosocuanidm- V.NN'o.i . (Proc. Jpn. Cancer Assoc., 33rd Annual Coo t: r. ;, Oot'ti-r 1974.) Gann, 67 , 1975. 377 . Kogan, A. .K. H., un:) v. I. Kulitskaia. The Effect of a Stationary Magnetic Field on Induced Carcinogenesis. Patol. Fizinl. Exsp. Ter., (21:63-68, 1977. 378. Suzuki, f. Errcct o: Hotary Motion on Carcinogenesis. J. Cagey.i City Un;v. Mod. Assoc., 19(41: 1517-1558, 1969. 379 . Harris, c. c. Tr.i_- Carcinogenicity of Anticancer Drugs: A Hazard ir. Car.. C,37 (2) : 1014-1023 , 1976. 380. Arscneau. J. C-, . t al. Synergistic Carcinogenic Effect of i'rocarbazir.c and z.r.c Radiation in CDF Mice. Proc. Am. .Assoc. Cancer Res 16:120, 197 5. 381. Kosir, A. Contribution of Carcinogenesis. Acta Med. Xugosl., 16(2): 172-180," 1962. * 382. Medina, D. Enhancement of Mammary Tumor Formation in Mice by a'Cytostatic Dr:.-;, Melphalan. Cancer Res., 37(1) : 3 17 -- 319, 1977. 383. t. V., and s. Hayashicfe. Enhancement 5-})|tro- 2<f|iayl)-2-thia2lyl) fcrmamide (FANFT), Carcirfcgailciiy fcor R*t* urinary Bladder hv Al'lopurrnol .* f^rbc.?Aiipf7i!B|oc|lc7>ncer P4i7til43f,fl976.. ' ` 14 HONS 022150 314. Maize, J. C. Skin Cancer in Insunoeuppressed Patients. JAMA, 237<17),1857-1858, 1J77. 385. 1AAC Monographs: Evaluation of tha Carcinogenic Risk of Chemical* to Man, Volume 10, 1878. pp. 153-181. 3882 VassalInovitch. S. D., and V. Mihailovich. The Inhibitory Effect of Criseofulvin on the "Promotion* of Skin Carcinogenesis. Cancer Res., 28 (12):2463-2465, 1968. 387. Langbein, w. Contribution to the Cocancerogenic Effect of Clgnolin in Animals. Radiobiol. Radiother. (Berl.), 13(2):233-240, 1972. 388. Weisburger, J. H., et al. Modification of Diethylnitros- aroine Liver Carcinogenesis with Phenobarbital but Not with Irrwjnosuppress ion . J. Natl. Cancer inst., 54 (5) ; 1185-1188, 197 5. 389. Kitagawa, T. , ,md H. Sugano. Enhancement of Azo-Dye Hepatocarcinog-nesis with Dietary Phenobarbital in Rats. Gann, 68 12):255-256, 1977. 390. Van Duuren, P. L. Tumor-Promotlng and Cocarcinogenic Agents m Chemical Carcinogenesis. In: Chemical Carcinogens, Searle, C. K., cd., American Chemical Society Monograph 1973, American Chemical Society, Washington, D.C., 1976. pp. 24-51. 391. Slaga, 7. J., et al. Mechanism of Action of Steroidal Anti-Inflammatory Agents that Inhibit Skin Carcinogenesis. Proc. Am. Assoc. Cancer Res., 16:37, 1975. 392. Kawaguchi, r. Studies on Experimental Induction of Endometrial carcinoma in Rabbits, Especially Related to Their Carcinogenesis (Meeting Abstract). Acta Obstet. Gynaecol. Jpn., 21 (1):68, 1976. ,v 393. ; Muhlbock, 0., a^d I,. M. Boot. The Mode of Action of Ovarian ' Hormones in the Induction of Mammary Cancer in Mice. BioIhsm.l Pharmacol., 18 (4):S27-630, 1987. 394 . Warren, S., ar.d o. Gates. Radiation Carcinogenesis, Progress Report IV, 15 March 1976 -,15 May 1977. /Available through National Technical Information Service, Springfield, tfA,(as C00-3017-31 ,iEYr76r&-02-30L7. .1977. 15 do. Fraction ofi Estrogen and Rat; Mammary Amors (18511) . PS MONS 022151 396. For*berg, J. G., and L. S. Brelatein. a Synergistic Effect r;f Oestradlol and Prolactin Influencing the Incidence of j-Mcthyichcianthrcn* induced Cervical Carcinoma* in Nice. Acta Pathol. Hi"rob:oi. Scand (A). 84(51:384-390, 1976. 397. Vorherr, u. Contraception Poetabortion and Postpartim, Advantages and Disadvantage* of Ronaonal Contraceptive- with Particular Reference to the Relationship Between PeHla Sex Hormor.es and Thrcmbeembolism and Carcinoma of the Breast ar.d Genitals. Gynaecol. Rundach. , 15(l):48-73, 1975. 398. Lemon, li. M. Kstriol and Prevention of Mammary Carcinoma. Cancer Dctec. Prevent., 1 (2):263-281 , 1976. 399. Welsch. C. W. Effects of a Norefhynodrel-Mestranol Combination (E.NOVIL on Development and Growth of '.i rr; n-Induced Mimmary Tumors in Female Rats. Cancer, . j j: .-60', 1969. 400. Chevrel, B. Role ' ' Steroid Hormones :n the Development of Mali': r.am Turners Letter to Editor) . Nouv. Presse. Med 5(17! :11 45, 19 ;**. 401. Gurkjio, B. r- . , us d M, A. Zabczhinsky. Modification of '.'hcrica 1 Cam r.ogenvsi s with Adrenergic Compounds. Vestn. Yu ad. y.v d. Nuuk Sf.S!4, ! 2): 38-4 2, 1973. 402. ..ctir o 1 . , i . , a! .. Formation and Do termination of .r.es tr. Ci :.,r-'tto Smoko. Anal . Chem., 48(4):645- r 0. 403 . Ai;us, M. F., and j. c. Arcos. MydrocarLon-Nitrosamine Synergism as a Possible Amp lying Factor in Lung Tumoriccnesis bv Trbacco 'moke. J. Theor. Biol., 56 (21 :491-498, 1976. 404 . 40b. L'CCrt. i . G. Cocarr;no genic Activity of nicotine. Proc. An. Assoc .' 'ar.cer ?r>ffs., 17:2, 1 9 7 6 - Etiolouv of Nasoph,,:vngeal Carcinoma. Lancet, 2(80001 :1393, 19764 4 06. -*>' l4lS, C. . ; rives'. ; .or. : .! in the Colder, iium.s 1976. al. Pathologic and 11 trastructural iiA- 1 react'd Trur.solantable Melanoma . Bull Career (Paris), 6 3 <11:73-86, 407* . <?. , et al. DNA`Reparation,and-Chrojnosoma <rmidin .Human Cells Infected wi th?LPfc X>nCorfiaviIus * If. / ft6?::71*2-71*6, 0.91V. 76 MONS 022152 409. Bryan, w. R. current Concepts of viral Neoplasia. South. Med. J., 57(11}t1263-1267, 1964. 409. Kazzucco, K. The Effect of Various Solvents (Benzene, Toluene, Acetone) Used with Carcinogens on the Collagen Content of the Mouse Dorsal Skin. Osterr. Z. Onkol., 2(2-3):49-51, 1975. 410. Bingham, E., and H. L. Falk. Environmental Carcinogens. The Modifying Effect of Cocarcinogens on the Threshold Response. Arch. Environ. Health, 19(6):779-7S3, 1949. 411. Bingham, E., and P. J. Nord. Cocarcinogenic Effects of n-Alkanes and Ultraviolet Light on Mice. J. Natl. Cancer Inst., 58(4):1099-1101, 1977. 412. Tanaka, T. Influence of n-Dodecane on Rats Exposed Transplacentially to Benzo(a)pyrene and Nitrosomethylurethan During Pregnancy (Meeting Abstract). Third Internationa! Symposium on Detection and Prevention of Cancer, 1976. pp. 296-287. 413. Horton, A. W. Cellular Mechanisms of Chemical Carcino genesis. National Technical Information Service No. PB 225 631, 1973. 91 pp. 414. Mori, H., et al. Effect of Carbon Tetrachloride on Carcinogenicity of Petasites Japonicus, and Transplantability of Induced Tumors. Gann, 68(6):841-845, 1977. 415. Mirme, H. Modifying Effect of Water-Soluble Shale Pheno'. on Carcinogenesis. Vopr, Profil. Zagryaz. Okruzhayushchi . Chel-. Sredy Kantserogennymi Veshchestvami; 16-18, 1972. 416. Hccxer, E. Aspects of Cocarcinogenesis. In: Scientifi Foundations of Oncology, T. Symington and R. L. Carter, eds., William Heinemann Medical Books, Ltd., Chicago, 1976. jpp. 310-318. 417. Falk', K D.| PossJrfzle Mechanisms of Combination Effects .. Chemical, Carcinogenesis. Oncology, 33(2):77-85, 1976. 418. Pershagen,. <?., et al. Mortality in a Region Surrounding .. Arsenic Emitting Plant. Environ. Health Porspect., 19:1: 137. 1977. 419. iGargusi Ji l.,ietial.i Utilization of Newborn Micejin:the BiqaBswi^Ichfraicdl' Carcinogens.? Toxicol..' App$.': Pharmacol;. (15 138 t*2-B59.11961. 7.7 MONS 022153 <20. 421. Sakharov, I. I., fc-al# Th Cocarcinoqenic Activity of Sulfonol HP-1. Glg.7 Tr. Prof. Zabol., (9):56-58, 1973. ' . r ` V Pyleva, Z. A., et al. Data or. the Biological Properties of Olefin Sulfate. Vopr. Onkol., 24(1)s >5 -- 60 * 1978. 422. Lccver.gurt, G., and B. L. van Oouri.-n. Evaluation of Chemical flame Retardants for Carcinogenic Potential. J. Toxicol. Environ. Health, 2(3):539-546, 1977. 42). Arrhenius, E., et al. Disturbance of Microsomal Detoxica tion Mechanisms in Liver by Chlorophenol Pesticides. Ch**. Biol. Interact.,. 18(1)*35-46, 1977. 424. Arkhipov, G. N., and I. N. Kozlovu. Study of the Carcino qenic Properties of the Herbicide, Amine Salt of 2,4Oichciorphenoxyacetic Acid. Vopr. Pitan., (5)*83--84, 1974. 4.5, Uchiyama, M., et al. Cocarcinogenic Effect of DDT and PCB Feed mu on Methylcholanthrene-Induced Chemical Carcinoger.esis. Bull. Environ. Contam. Toxicol., 12(61 :687-693, 1974. 4; u . ra'--: . :!. , et al. Analysis of Various Factors on Liver Care j nr :-'r.esis in Mice Induced by Benzene llexachlor ide (BHC) and iecnnical Polychlorinated Dinher.yls (PCBs) . J. Sara. Med. Assoc., 25(61:635-648, 1974' (Reed. 1975). 427. Capeeo, A. V. Ammonia: A Modulator of 3T3 Cell Growth. Disc. A. str. Inst. (B), 38(91:4085, .1978. 428. T<ub:n, Z. , and I. S. Levij. Chemical Carcinogenesis m the Hamster Cheek Pouch: Influence oi Inhibitors and Inducers of Alkaline Phosphatase. Pathol. Microbiol. (Basel), 43(11:26-30, 1975. 42m. Lane, B. P., and M. J. Mass. Carcinogenicity and Cocarcino genicity of Chrqpium Carbonyl in Heterotopic Tracheal Grafts. Cancer Res., 37(51:1476-1479, 1977. 430. Hayatfsu, H., at al'. Potential Cocarcinogenicity of Sodium BMPCOhlcrita. i NattecdMfiond.) #. 233(5320) :^95,(1971>. 431. Magnta, C., et al. Effect cf Hydrogen Peroxide, Fenton's Reagent, and Iron Ions on the Carcinogenicity of 3,4Benzopyrene. Gann.-6.4 (3) : 277-285. 1973 32. Delihfcinn, w B. addl J .1 L 4 Radomski. Synergysm|Amor\g< Oral Cati ifcbyens and Tumorigfiis,' Report of Preliminary Exjieri- s| f Tdxiicfl. (A$()lf njiann&col. 6(3) :3l^-34>V, fly64.. 78 MONS 022154 <33. Braedin, ?. B., *ndD. H. Buss. Ferruginous (Asbestos) Bodies in thtfftangs of Rural Dwellers. Urban Dwellers, and Patients with Pulionary Neoplasms. South.. Med. J.. 69(4):401-404, 1976. 4!4. Eirxbrcdt, H. J. Combined Effort of .Fine Duat on the Lung. Staub Reinhaltung Luft, 36(31:122-126, 1976. 435. Rom, W. K., Aid'A. M. Langer. Carcinogenicity of Fibrous Glass (Letter to Editor). Heat. J. Med., 124(5)t413, 1977. 4J6. Nordenson, I., at al. Occupational and Environmental Risks xn and Around a Smelter in Norther Sweden, XI. Chromosomal Aberrations in Workers Exposed to Arsenic. Uereditas, 80(1);4 7-50, 1978. 437. Ishinishi. N., et al. Preliminary Experimental Study on Carcinogenicity of Arsenic Trioxide in Rat Lung. Environ. Health Perspect.. 19:191-196. 1977. 438. Uzawa, T. Hiatopathologica 1 Studies on Pulmonary Reaction by Beryllium Oxide in Rat (Experimental Tumorous Action of BEO Combined with Carcinogenic Hydrocarbons). Bull. Tokyo Med. Den:. Univ., 9 (3):440, 1963. 439. Notteshein, p., et al. Carcinogenic and Cocarcinogcmc Effects of inhaled Synthetic Smog and Ferric Oxide Par ticles. J. Natl. Cancer Inst., 55(11:159-169, 1975. 440. 441. Sellakumar, A., et al. Effects of Different Dusts on Respiratory Carcinogenesis in Hamsters Induced by Benzo(n)pyrcr.e and Diethylnitrosamine. Eur. J. Cancer, 12(4): 313-319, 1976. Bock, F. G., et al. Cocarcinogenic Activity of Peroxy Compounds. J. Natl. Cancer Inst., 55(6):1359-1361, 1975. 442. Kripke, H. L.:, and T. Borsos. Accelerated Development of Benzo*t)pyrene-induced Skin Tumors xn Mice Treated with Pyran Copolymer. J. Natl. Cancer. Inst., 53(51:1409-1410, 1 9 74 . 443. Shapiro, R. genetic Effects of Bisulfite (Sulfur Dioxide). Mutat. Res., 39(2):149-176, 1977. 444. Calop, J.,.etial: A Study of the Influence of Trace Elements itlcx Hddrg2<yl3.tion ofBer.zof(a)pyrend- Eur. J- Toxicol! Eavifwiilivq.L (9.(5) : 271-286. 1976. 89 HONS 022155 44S. Shinkin, M. B., et al* Lung Tumor Response in Hie* to Metals and Metal 8alta. Adv. Exp. Med. Biol., 91:85-91, 1977. 44fc. K::. jv ishj, N., and T. Okamoto. Effects of Lead Oxide on th* : .".d act ion of Lung Tumors in Syrian Hamsters. J. Natl. 'la.'iCt i Inst.., 52(5)il605-1610, 1974. 417. c.irdesa. A., et al. The Syncarcinogenic Effect of Methylrhol anthr'ene and DiaethyInitrosamine in Swiss Mice Krebsforsch., 79(2):98-107, 197J. 448. Uu:>z, M., et al. Prevention of 2-AcetylaminofluorencInduced Extrahepatic Short-Term Effects by 3-Methyl.:ho>.nthrene. Exp. Pathol. (Jena), 1 3 (4-5) : 262-267, 1977. 440. i' A. , et al. Effects of Intraperitoneal Injections : :.-:.nc*thyl- and Diethy Ini trosamme, Alone or S unu 1 taneously on S* ss Mice. Z. Krebsforsch., 82 (3) : 233-238 , 1974 . 4.0. Toupinn, o. C., et al. The Interaction of Benzo(a)pyrene ar..J !>`.o (o) pyrene in Respiratory Tract Carcinogenesis i.: : Abstract). Proc. An. Assoc. Cancer Res., 19:43, 4., __S., ct al. Synca rc i r.occns i s in Cultured C3H/10T1/2 'Meeting Abstract). Proc. Am. Assoc. Cancer Res., .6:8. :077. 4 2. :11 i tv r , x. S., et al. Effect of Ozone on Benzpyrene iiv.i: -I'/lasc Activity in the Syrian Golden Hamster. Cancer I!-,;;.. -1(6) : 7 3 0 - 7 3 3 , 197 1. 4''. Si ; i :V. .mar, A. R., et al . Influence of Croton Oil m )ir:-srv.r Lur.g Carcinogenesis. Proc. Am. Assoc. Cancer Res., i:50, 1975. 4;>4. iio.'V.i r, E. Cocaccinogonic Agents Derived from ;.jphcrbiaceae. planta. Med., 1968:24-25, 1968. 4 -5. Hevki-r, E. New Toxic, Irritant, and Cocarcinogenic Dierpenei Esters feoa Euphorbiacea^ and*from Thymelaeaceae. Pure Applt chjm.,*5919)s1423-1431, J977I 4-6. 7 Huusen, H. Z., et al . Persisting Oncogenic Herpesvirus Indeced byIthfe Tumour Promoter TPANature (Lond,), 27feh651)?373ii75ll978l 4,5Z, Kcpoitowskii Df,^ eL aT.' ^Epidermal Intercellular Relationships OurxngstfafcinqgeA^rei^ and* Ccfcax^clnogenfeJis* as* rfevealecf by ScpijniD</El'eccrbn Microscopy. Virchow's \ Arch.1 (Cell Pathol.), 80 HONS 022156 458. Janoff, A., at al. Local Vascular Change* Induced by the Cocarcinogsrf Phorbol Myristate Acetate. Cancer Res., 30(10):2567-2571, 1970. 459. Soper, C. J., and F. J. Evans. Investigations into the Mode of Action of the Cocarcinogen 12-O-Tetradecanoyli..horbol-13-acstate Using Auxotrophic Bacteria. Cancer Res.. 37(8, Part 11:2487-2491, 1977. 460. rsud*, H., at al. Synergistic Effect of Urinary Bladder carcinogenesis in Rats Treated With n-Butyl-N-(4-hydroxyi'.utyl) nitrosaadne, n-14- (5-Nitro-2-furyl) -2-thiazolyl) formamide, n-2-Pluorenylacetamide, and 3,3*-Dichlorobenzidine. Oann, 68 (2):183-192, 1977. 461. Kallistratos, G. Prevention of 3,4-Benzpyrenc Carcino genesis by Naturally Occurring and Synthetic Compounds. Muench. Med. Wochenschr., 117 (10): 391-394, 462. .ruhaut, R., et al. Inhibitor Effect of Ellipticine :0imethyl-5, II-(6H) Pyrido (4,3-B Carbazole) on Rat Liver Carcinogenesis Induced by BT6 (n,n-Dimethyl-p-benzothiazolylazo) Aniline): Incidences on Cytochrome P450 and Arqinase Activity (Meeting Abstract). Fourth Meeting of the European Association for Cancer Research (held at tniversite de Lyon, September 13-15, 1977), European Association for Cancer Research, Lyon, France, 1977. p. 86. 8?3 HONS 022157 APPENDIX A * REVIEW OF THE CARCINOGEN LITERATURE OP 125 CHEMICALS INTRODUCTION The first task of EPA Contract 68-02-2773 is to identify 20 sigr.fleant atmospheric carcinogens. Sampling and analytical method ology based on porous polymer sorbents and gas chromatography/mass >:jcc trove try will then be developed for 15 of these chemicals. :orJcr to identify significant carcinogens, the literature has :eon reviewed for about 125 chemicals to determine whether they should be considered carcinogens for this project. The results for each chemical are given in this appendix. An index to the chemicals precedes the results. . .f-.-oT.t criteria must be used to define what test results indi. i v i rc: r.oyenici ty depending on the use for which the resulting ; c. .mended. For this program, some chemicals have been .cl .a. or. the possible carcinogen list based on a limited ,ni;v ,'f short-term mutagenicity data. If these lists should a.-,, d for other purposes, it would be expedient to review the . . :ji ,;re cited and draw the appropriate conclusions based on : r ;iu : .U* lines . r i..:s project, a probable carcinogen generally has at least s._:e positive animal data coupled with positive mutagenicity data from at least one well-established mutagenicity test or several utaoenicity testa which have not been as extensively validated, r.j mutagenicity teffts which were considered fairly well estab lished include the Ames la Zjp'ninurium test and the enhancement of viral transformation tests (e.g., B. C. Casto), with the y. roZifc (jol A) differential toxicity and the DrosrvhiIs .cuts c.iso considered important. '. :'.:i l carcinogenicity tests were considered less significant i: were conducted more than 5 to 10 years ago, tested by the subcutaneous rouie tof .administration demonstrating, only local tdmors, I utilized! only fal few animals,! or reported no concurrent fcdntrotl laftiima'i^ S4 ^slJjWBttiLibs, pihc'.Northbrook*, j Illinois, has been a consulTanLi-ir (Monsanto I Research Corporation !on!tnis EPA contract. 82 MONS 022158 INDEX Chemical Acetaldehyde Acetone Acetonitrile Acrolein . Acrylonitrile Aidrin Ally1 Chloride Aniline Anthracene don: a) anthracene Iter, zer.e Benzidine Benzo (a) pyrene Denzoqu:none (Ouinone) ::oy 1 Peroxide .!onzvi Chloride h:;honyl ?: s .'chloronethy l) Ether l.'.it ad icno r. `arbor. bisulfide Carbon Tctracnloride Ch)e:acetic A :id .'hiordane Crossls _`h i orobonzi la to Chiric form Ch 1 oroprone C1'. i 'jro:>:`or)^nfr '*;;rvseru' Cor one iivjrcr.-croxide YV~ . hi-tort-butyl Peroxide Di (2-ethy1hexy1) Pht^alate i.4-Diaminoanisole :. .1 virion -Dichlorobenzene -Dichlorobenzene Dichlordbenzldfne Dichlorobutene Dichlorodifluoromethane 1, i-Dichloroethane D ich loronaphthoqui'none Dichlorophenol Dichloropropene Qichlorqprqpiortic tACidJ Dichlorovinyl Dimethyl! Phosphatel lDi$hl$iivo3)` Dime thy Xacetair.ide 03 16 17 11 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 115 116 11' 113 119 120 122 124 125 126 127 128 129 130 V1 b3 135 1X6 MONS 022159 IfKicic - Continued Cher.icaJ Dimethyl amine Dimethylhydrazlne Dinitrotoluene 1 ic>xar,e Dioneny1 Cr ide i sod i ar: M:thonearsonate .Oars bar. rr.iosul f jp r.'pichlor ohydr i n ! r. t an r _ h.) no L be." 0`"C ' r r.'. 1 e:i* :: br ~r.: do ichlor ide vlco' 'yco 1 p.v 1 or.- '.Os! .10 !.yl .. r i re -.nora :.c :e prra loo ' -..ocfcer . o'nt<iw_. . I .-.l :: i.l icnc ;cwa; i;.-. Lot rnni r.e vdi oi:u. r.jr.L* .'..i r. . atp :cr. Anhydride v ;:: >i -j tobc n zot a:a zo1 e ethyl Bromide .thyl `Mocidc ethyl Ketone r:-.yl Methacrylate ' MMeethylene Bis(2-chloroaniline) I?**-Matnyleae^ C Vorhyleneoi v'o:hyistyrei^e Morpholine J.^uhtna l-tNaphtlyl artiM it(m tt/T catbajn^tfe 84 !!S! 137 n* 139 140 141 142 143 144 14 5 146 147 143 149 150 10 i 152 153 154 155 156 157 158 159 HO 162 HI 164 h: 166 1 <> 7 168 169 no 171 L72 173 174 175 176 177 ITS 179 180 181 1*82 183 84 HONS 022160 Index - Continued Chemical Nitrosodimethy1amine sitrochlorobonzene Parathion Pentane Pentachlorophenol Phenol Polychlorinated Biphenyls Propanol Propylene Oxide Pyrene Sorbic Acid Styrene Sulfolane let rabrorr.oeth.ine Tetrachloroethane Tetrachloroethyiene Tetraethyl Lead Toluene Toluene Diisocyanate Tol uenedi amir.e Toxaphenc Tr ichlorfon Trichioroethane Trichloroethylene Tr:chloro flueromethane Trxchlorophenol Vr ethane Vinvl Acetate Vinyl Drox.ide Vinyl Chlorine vir.ylijeno c.-,:->ride Xylene 185 186 187 188 189 190 191 192 193 194 195 196 197 199 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 213 216 85 HONS 022161 Acetaldehyde Acetaldehyde is possibly a carcinogen promoter (25), but no refer ences to it as a carcinogen or mutagen were found in TOXLINE or CANCERLINE. Two references by Nakahara and Mori in 1939 and 1940, as reported by Hartwell (26), demonstrated no tumors in rats fed acetaldehyde in their food for more than 300 days. It is probably rot a carcinogen. 12.51 Davies, J. C.f Co larcinogenesis with respect to the Contents 'of Cigarette Ibacdof. | rV.Soc. Health J., ( 93 (6) : 296301,1^97}. I2*k*4rty|lii foij Carcir.ogeni nical Ilnforraati V 86 MQNS 022162 Acetone Acetone (2-propanone, dimethyl ketone, Chemical Abstract Service (CAS) No. 67-54-lJ has been extensively tested for carcinogenic activity both by itself and as a negative solvent control for other chemicals (5). No significant positive results could be found on CANCSRLINE or TOXLINE for acetone. It is also negative on most in v''.:> tests and is used as a negative solvent control for ranv chericaIs in these tests. 87 HONS 022163 Acetonitrile The only data suggesting that acetonitrile is a carcinogen are equivocal res..Its from a 2-year rat study (6J. It is considered a noncaroinogen for this project. 98 HONS 022164 Acrolein Acrolein appears to be toxic and reduces ciliary action of~the branchial epithelium i27, 28J, but it is not mutagenic in S'. c<-rjuigia* (29) or dominant lethal mice tests 130). Acrolein has been found to be a mutagen to the TA1538 and TA98 strains '> -c- "jrhimtriui 131). It will be considered to be a possible carcinogen for this project. ?reduction and Persistence 1t is estimated that 6.5 x 10"' kg is emitted per year, primarily associated with acrylic acid manufacture (1). Other estimates ire 4.2 x 10s kg/yr released from 2.8 x 10' kg produced [6] and a production of 2.8 x 107 kg produced in 1974 with a 6.7% growth forecast through 1979 132). It has an atmospheric half-life estimated at 2.6 hours [3]. Its boiling point is -88C and it has a vn:,or pressure ox 220 mm at 20C [33]. Nhabad, b. M., ct al. The Feasibility of Preventing the :ffects of Carcinogens on Man. Kazan Med. Zh, !5):92-93, i 97 2. ;23) Terrell, J. ii., and I. Schmeltz. Cigarettes: Chemical Iffect of Sodium Nitrate Content. Science, 160:1456, 1968. 29; Izard, C. Mutagenic Effects of Acrolein and its Two Epox ides, Glyeidol, and Glycidal, in v ir.e! i i ie . C. 2. Acad. Sci., Ser. D., 276 (23): 3037-3040, 1973. [30! (31| Epstein,. S . S., /rt al. Detection of Chemical Mutagens by the Dominant Lethal Assay in the Mouse. Toxicol. Appl. Pharmacol., 23:288-325, 1972. ` ucture . .i ; r;* r.c i jr; emu Res., 46(3):243-244, 1977. Mutat. (32) A11pop5, J., et al. A Study of Industrial .Data $*4capdldStd cnenupaisjfor Resting. National Technical 'inform^tfqiv Servipl NQ.j PB 274 264, 0.977. [33] VeVschiferfnp f (Handbook of`Environmental fDa^ grl 0*g$4i Chimicils. Van Nostrand Reinhold Co.,! New York, 1J971. HONS 022165 Acrylonitrile Positive Ames tests (34), . coli mutation tests (35), and viral transformation enhancement tests (personal communication with B. C fas'to on 9 February 1978) have been reported along with negative recessive lethal l rcaphi la nalanagasUr and negative Victa faba chromosome a'o< . ration tests [32], Human epidemiological evidence points toward acrylonitrile being a carcinogen (38). Additionally, a 1-year Interim report from the Manufacturing Chemists Associa tion of ongoing ingestion and inhalation studies of acrylonitrile in laboratory rats reports the rats developing a variety of tumors including carcinomas (37). Based on these findings, acrylonitrile is being placed on the probable carcinogen list for this project. Production and Persistence It is estimated that 3.7 x 10* kg is emitted per year (11 . 'Another estimate is 9.6 x 10* kg per year 16].) Acrylonitrile has a boiling ooint of 77C and a vapor pressure of 100 mm at 23 C (33|. ` (34) MiIvey, P., and M. Wolff. Mutagenic Studies with Acryloni trile. Mutat. Res., 48{ 3-4): 271-278 , 1977. ;35i Ven.itt, S.. et al. Mutagenicity of Acrylonitrile iCy.mo- h.9t7' 13*1 MjyjRjnltrite Linked to Cancer" ini Workdrs. Chem. Eno*. iNews, B5^6T:i57/. Lit if.} `Acryldnierllf*.? (Am.' )Ind. iHyq? Assoc.' Ji, 2; *1977. 30 MQNS 022166 Aldrin Aldrin has been found to cause neoplasia in two strains of alee [33} and tumors in weanling rats (39). Aldrin is converted into dieldrin in the environment (40], and dieldrin is a carcinogen at O.i ppm in dietary exposure to nice (411. Thus the sale and pro duction of aldrin was suspended (42}. Many other animal studies have been conducted with questionable results (43), and sosm ir, vitro tests have been negative (18). Since there are enough data to suspend production of aldrin, it will be considered a probable carcinogen for this project. Production and Persistence It is estimated that 4.5 x 10* kg aldrin were produced in 1971 (43). Another production estimate is 1.1 x 10T kg/year (1976) [61. (38) Song, J., and W. E. Harville. Carcinogenicity of Aldrin and Dieldrin on Mouse and Rat Liver. Fed. Proc., 23:336, 1964. [39} 140] Diechmann, K. 3., et al. Tumorigenicity of Aldrin, Diel drin, and Endrin in the Albino Rat. Ind. Med Surg., 39(10): 426-434, 1950. Wurster, C. r. Aidrin and Dieldrin. Environment, 13(8) 33-45, 1971 HI) Epstein, S. s. - Pretvent tion . - Environmental Exposure: An Overview, Including the Role of Pesticides. Third Inter national Symposium on Detection and Prevention of Cancer, 1976. p. 5. (.42) -Epstein, S; S. Case Study 5: Aldrin and Dieldrin ibuspensionfBasedjon Experimental Evidence and,Evaluation .and fqcaetal Needs.* tAnn. Nild. Acad. Sci., 271: 187-195,* 1976. (0gj |AR*Mo$ogtaVhi: EJralfiattidn of the Carcinogenic* Ri'sk tof Cnemfcals to Man, Vplujne f5i 1974. pp. 25-38. 91 MONS 022167 Aliya'Cfiioyida Allyl chloride (3-chloropropn,' CAS No. 107-05-1) la7on7th6 MOf-it Safety Alert hist. No references have been found on to.xlise, CAMCERLJNB, or inth* Stanford Research Institute ftudy on hazard priority ranking. (7], to indicate that allyl chloride is a carcincvcr. or mutagen. A recent reference, however, reports that allyl iori de is a mutagen in 5. tjpr: ^uriun, s, esrtvitiat, .lid . i test system* 19 J . It is therefore classified as a possible c ire ; r.o jit. for this project. Prodtion ai! ! -r j i stence It is estimated t:..f 4.2 x 10* kg is emitted per year from ->tat -.or. try so:,;-..s !1|. Another estimate is 2 x 10* kg released from a produc \ ir. ;f 1.) x 10* kg per year '441, ar-d a production ir.ito cf l.i x kg in 1972 (61. !t t s reported to take -mares for 50' >f the allyl chloride in a l-ppr solution to wat' rite at 2'"'' (ill. It has a ha 1 f -1 i f e with iio radical of .'I h .trs and vi *, radicals of 9 hours, md it hydrolyzes with ; n, i rf ' tvs |441. It has a : 1 : r. : of 45C, a ... : V. rr. .it 'OVT, nd a solubility of 3. 1 g/1 ! 331 . brown, h. b.. et al. Research rrograr. c:. Hazard Priority Ranking of Manufactured Chemicals. National Technical Inforia tlor.l Servici hoi PS *63} 164} 1975. 92 MONS 022168 Aniline The IARC monograph on aniline (45] reports that aniline is'probably not a carcinogen and that what early researches believed was cancer from aniline was most likely due to impurities such as benzidine. It has tested negative on a differential growth . ccli test (pol A) (46) and on S. typhinuriu^ strains TA1535, 1537, 100, and 90 with and without roicrosomes [321. It has also been reported negative in reversion to prototrophy in Aepcrgillua . (methj-) and several other tests [32). It was classi fied r.egat ive/inadequate in one of the latest reviews [32] and w. 11 bo considered a probable noncarcinogen for this project. [45] IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 4, 1974. pp. 27-36. [46) Fluck, E. R., tt al. Evaluation of a ENA PolymeraseDeficient Mutant of I. Coli for the Rapid Detection of C&c&ogens.v ;Chera. Biol. Interact., 15:219-231, 1976. 03 MOWS 022169 >nfhracfne Anthracene ie on the NIOSH Suspected Carcinogen List because of two 1955 references. In the first one (47), anthracene was found to be noncarcinogenic orally and interpertioneally. But when injected in 550 doses over a 2- to 3-year period (6 tines/ week - total dose 4.5 g/rat), 5 out of 9 rats developed local fibrosarcomas. It is now known that multiple injections can sometimes cause fibrosarcomas. Recent studies (48) have shown anthracene to be a noncarcinogen and it is presently being used as a noncarcinogenic standard on studies to develop short-term assays for carcinogens (49-52). 71 -v.-hr.all, D. i'rufu.ng von Wiphthalin ar.d ;.:.thrac.en auf Ca:-crcacr.c Kirkmo an Ratter.. Zeitschrift fur Krubsforschur. . oO: (-97-710, 195 3. !-:ji 5tar.ion. r., et al. J. Natl. Cancer institute, 49(3): ;n~-S'7, 1972. .vr.t.i, . J., et a!, y.oropho logical Transformation of .ar'.y nssacc .'olden Syrian Hamster Embryo Cells Derived frar. Cryopreserved Primary Cultures as a Reliable ' Nsoassav for Identifying Diverse Carcinogens. I.nt. J. .'.incur.* 19:642-655, 1977 . ! -30) PiPaoio. J. A., et al. Quantitation of Chemically Induced Neoplastic Transformation of BALB/3T3 Cloned Cell Lines. Cancer Research, 32:2686-2695, 1972. [511 Purchase, X. F. H., et al. Evaluation of Six Short-Term Tests for Setgating Organic -Chemical Carcinogens and Recom mendations Tor Their Use. Nature, 264:624-627, 1976. McCann, J., ct al Detection of Carcinogens as Mutagens the i.'-'i: }m/Microsomnee Test,. Assay ;.Ooff;;_ 300 j:CChepmmiica'ls~*' ?rog. IJafcll 'j5ci}-I\ (USA)|72: 5135-5139?, {1975 - 914 HONS 022170 Bern(a)anthracene Benz (a)anthracene (1,2-benzanthracene, CAS No. 56-55-3) is well known as a carcinogen. It is carcinogenic orally, subcutaneously and topically for mice (53J. It is one of the standard carcino gens used to evaluate the validity of short-term testa and will be considered a probable carcinogen for this project. Production and Persistence It is estimated that less than 100 kg/year is emitted from carbon black furnaces, the only stationary source cited for this chemi cal |1|. It is emitted in the exhaust from gasoline engines (61.7 mg/kg exhaust tar) and diesel engines (2.3-15 i,g/mJ exhaust) |53], It has been detected in the air, soil, food, and cigarette smoke condensate lS31. It has a boiling point of 400C |53). ! 331 IAHC .Monographs: Evaluation of the Carcinogenic Risk of Chenicals to Man, Volume 3, 1973. pp. 45-68. 95 MONS 022171 BenaettaK Benson** YCXfr^fro^ 91-43-2) is onetfjTftlk^lhdustriai substances sus pected of carcinogenic potential to nan as listed by the American Conference of Governmental Industrfal'jfrgisniats 154], and it will oon be controlled as a carcinoge'rffJtm International Agency for Research on Cancer 155] reports animal "data which *.do not permit the conclusion that carcinogenic activity has been demonstrated.* In human data they support a relationship between exposure to benzene or benzene mixtures and the development of leukemia. Along with some positive studies {561, many references occur in the 1iteratuare where benzene is a negative solvent control in animal studies {5). In spite of these references, it is believed that benzene induces chromosomal damage in animals and man (32] and is a known carcinogen. An asressment of the air pollution aspects of benzene has been conducted 157]. Since benzene is being controlled as a carcinogen, it will be considered a probable carcinogen for this project. Production and P--rsistfinro It is cst ir.ato-i that 1 >: ; * : b-T..v-e is I : r ' i. v. t.\ y 1 vi-:.t -vas.-cr from ic.'n .isin.: operations : \t r:hut:: : ovi-r *' of t::e total ! . . Another estimate is >i x t per year : lea s-'i fro- .`-r.ror *: a L ..vs jf benzene [Of'. 1* reacts rjpidly .th (. - ' iays tut wly with ROj and , .1:. : has .1 12.0 1 : 1 ."it;.-. - f f : ".A ! . Its boiling : nsr.t . HO . i '0 ar..! . h.i-> i : vss.ro 1 ' ~~ at 20*C -III. .i-,] Th' *hr.-.:.iolrt I.ir.i: V.il-.e.s for Chemical r' :: stances and Pi"., sica 1 A icnts in the workroom Environment -with Intended Chances for 1977. American Conference of c.overn.ment Indus trial hyqionists, 1977. !77| IA?C Mor.ogr*fhs: Evaluation of the Carcinogenic Risk of Chemicals tb Kan, Volume 7, 1974. pp. 203-222. 156 J. Brown ,.S. L...et al. Research, Proaram on ^Hazard Priority ' Milking of Manufactured Chemicals'.* National Technical Information Sorvico No. PS 263 162/ 1975. i D7 ] Walksr, ?.. Air Pollution Assessment of Benzene. National TlcbiifcaJl Hf4n*ation Service fro.i KB |56|i34i l?7t6. 26 HONS 022172 Benzidine Benzidine 19 reported to be carcinogenic in the mouse, rat, hamster, and possibly in the dog [58|. Given orally, it has pro duced bladder carcinoma in the dog after a long latent period and liver tumors in the rat and hamster. Benzidine was a carcinogen to mice when given either by stomach intubation or in food l59|. These references, along with many others in TOXLINE and CANCERLINE show that benzidine should be considered a probable carcinogen. Production and Persistence It is estimated that 4.7 x 10* kg is produced per year (6). A release factor of 0.915 is assumed which would give 7 x 10" kg released per year. This is probably too high since benzidine is well known as a carcinogen. Perhaps 7 x 10J kg would be closer to reality. It reacts with OH and Oj with a ti, of 1 day (601. It has a boiling point of 402*C (331 and can be sublimed ISP). (58) IARC Monographs: Evaluation of the Carcir.oce.n:c Risk of Chemicals to Man, ytflume 1, 1972. pp. 80-86. (59) Vesselinovitch, S. 0., et al. Factors Modulating Benzidine Carcinogenicity Bioassay. Cancer Res., 3S(10):2814-2819, 1975. (60) Brown, S. L., et al. Research Program on Hazard Priority Ranking of Manufactured Chemicals. National Technical 'Information Service No. PB 263 163, 1975. 97 HONS 022l73 Bento(a)pyrene Ben*bta)pyrne (3,4-benzpyrene, CAS No. 50-32-9) is veilestablished carcinogen following wany different.administrations including oral, akin, subcutaneous and intratracheal routes (61). Positive results have been reported with mice, rats, guinea pigs, monkeys, newts, hamsters, and ducks {611. It will be considered a probable carcinogen for this project. Production and Persistence Although not ranufactured in quantity, it is a byproduct of com bustion. It is estimated that 8.3 x 10* kg per year is released from stationary sources, with 96% of this coming from: (1) coal refuse piles, outcrops and abandoned mines, (2) residential ex ternal combust:on of bituminous coal, ()) coke manufacture, and M) resident:!', "xternal combustion of anthracite cual |l|. It his a ho:'.:: : : t '-f 311C at 10 na and 4 75C at 7 6 0 mrv [<>'. ). {1 ] JARC Monographs: Evaljiatiion of tha Carpinp<}enic Risk of iheiiucki.1 to Man, Voiurefe, Il973. pp. 91-J36 9'8 HONS 022174 Benzoquinone (Quinone) Japanese references from 1940 r62J and 1941 (as reportedrIn Reference 5) state that 3/8? mice painted with benzoquinone (in benzene) developed skin cancer with 9/87 papillomas'" after'200 da/s compared to 0/46 skin cancers and 1/46 papillomas for the benzene control. Skin painting with a benzene solution in 1953 was said to cause 16/80 ear duct carcinomas [63J. In 1954 an 1956, inha lation experiments with a total of 50 treated mice were conducted with negative results (64]. By subcutaneous injection, 24 rats were tested with negative results in 1957 [64]. More recent references show that benzoquinone does not decrease hatchability of the ~ros ;r>hi l a nelanogaatcr (65], is not mutagenic toward :r:- or cultured human leukocytes 165], produces no increase '.n recessive sex-lined lethan mutations in Dr^aophi'. ., and did not significantly alter the rate of chromated transloca tions or breaks in leukocytes (66]. No other significant data were found in TOXLISE, CANCERLINE, or Reference S. Benzoquinone is therefore to be considered a probable noncarcinogen for this project. .62] T.i< i r iw.i, . >- the Carcinogenic Action of Certain Qui .ocr-.s . Tree. I-:.':-ui Acad. (Tokyo), 16:309-31 2, 1940. 63] Tiedmann, H. Jtschr. Naturforsch., 8b:49-50, 1953. :o<] .'ARC Monograph^:f Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 15, 1977. pp. 255-264. 165] Vogel, E. Differential Sensitivity of Immature and Mature Oocytes of :rca:phila Vtlanogaater to the Induction $ Dominant Lethals Following Treatment of Mono- ana polyfunc tional Aziridine Analogues. Mutat. Res., 14:250-253,,1972. '66] Lueers, H., and G. Obe. Possible Mutagenic Activity!Qf. p-Benzc (uinone. Mutat. ;Res., 15:77-80,) 19.72. 99 HONS 022175 Benzoyl Peroxide Benzoyl peroxide (CAS No. 94-36-0) was extensively tested in nice and rats between 1962 and 1967 by 6 authors on more than 1,100 animals [5J.T Benzoyl peroxide is on the NIOSH Suspected Carcinogen List because in one of these studies, 1/30 mice devel oped a squamous papilloma after application of benzoyl peroxide in benier.e to the skin. No recent mutagen or carcinogen refer ences could be found on TOXLINE or CANCERLINE. It has been found negative in a dominant lethal mouse test, on an ;. ccli (pol A) mutagen test, and a Micrococcus p;/orct.:a test [32]. There is very little doubt that benzoyl peroxide should be considered a noncarcinogen. WO MONS 022176 msrnm or.zyI chlcnde ( i-cl.orotoluc-nc, CAS'No. 100-44-7) lias be^i^. ound positive on a differential growth F. calif (poV AT mutigOT cst f 4 6 ' . It is also positive on a subcutaneous rat test att .1 c/kg (51 weeks) in 3/14 rats ar.d at 3..9I4A9 irt 6/8 rati ^67 J . t i? weakly mutagenic in *. tests at 2 ra/rlate IfR', TJ :p considered careinooor. ic m rats by the IARC !e 7 ' . It is or,3icored a probable camr.ooen fer this project. rod;. :i;t. and "ern: ."V'r.o? i.-l 10' kg vas produced s hv ru ;f.icfjre o ` w...... ic pr iucts ! 67) ro ! 197 et i.. Ceterricn : Carrir.cyens as Mutagens '$er trams vitr. 3 rector Plastds.. Prcu. I:s^. Vi9?9-<*$s . T. 9 TSt 101 HONS 022177 mmi ii one ret^^ncfVhich 'shovs luocut.ineous . 92-52-4) jq induce an cxccs s of tur.ors tin; referMM^lccuid be ft on ! in CANCER!. yl is ther e?7rtplaced or. hr." ossil.le c.i phenyl (dipheavl, ruce '69] , NO cr 7o;< i,-ine . Prod - t .tir.<: Persistence ; t is . r.: : r* i -.hat 9.2 19* : row r. .. i ore cf : ol y.*h 1 : his ' hor.y 1 -r . ;s. :s it- : . the: " . ' . . : : <:: 1 !: * : Crc:nc;;:.:r, Tra-.:.: . iv.t.os of IfCted Pesticides clure li :ia. .J ' ostr::i. Service ii>2 icals, ; *>* HONS 022178 Bl(chloromethyl) Ether Bis(chloromethyl) ethar (BCME, dichloromethyl ether; CAS No. 542-88-1) is carcinogenic to mice following inhalation, skin application and subcutaneous administration (70). It is also carcinogenic to rats by inhalation and subcutaneous administra tion (701. Epidemiological data suggest it is also a human carcinogen (70). It is being regulated as a carcinogen and will be considered a probable carcinogen for this project. Production and Persistence It is estimated that less than 100 kg BCME is emitted per year (11. A primary source of emissions is the production of polymethyler.e polypheny.' isocyanate (11. Its production in 1974 was estimated to be less than 450 kg (8). In water the half-life of BCME is 38 seconds and in the air (50'* relative humidity) its half-life is 25 minutes (81. ft has a boiling point of 1 2 4 C (81 (70) IARC Monographs:* Evaluation of the Carcinogenic Risk of Chemicals to Min? .vpl vine 4 , 1974. pp.. 231-238. io i MOMS 022179 Butadiene 1,3-Butadiene (CAS No. 106-99-0) has not been extensively tested for mutagenicity or carcinogenicity. No references could be found on TOXLINE, CANCERLINE, or in the seven collected volumes of Reference 5 on tests conducted, although there is interest in a possible relationship between styrene-butadiene rubber plants and neoplasms nf the lymphatic ar.d hematopoietic tissue 171]. Butadiene will bo considered a probable noncarcinogen for this project. 1711 Smith, A. i'.( and L. Lilts. Styrer.e Butadiene Rubber Syr. Dietic Plants ar.d Leukemia (Letter to Editor). J. Occup. Hed.. 19(7):441, 1977. 104 HONS 022180 Captan Captan has bten found to be a potent mutagen, in both prokaryote and eukaryote test systems too numerous to list. It has also been found to produce hepatomas in mice 169J. ' Because of the many positive mutagenicity tests along with a marginally positive mouse carcinogenicity test, captan has been placed on the probable carcinogen list. Production and Persistence It is estimated that less than 100 V.g per year of captan is emitted (1). (Another estimate is production of 8.1 x 10* kg per year with 0.01 released, or 8 x 10* kg per year emitted (61.) 105 MONS 022161 Carbon Disulfide There is nothing in TOXLINE or CANCERLINE to indicate that carbon disulfide is a carcinogen or a mutagen. One industrial epideaio~ logical study showed carbon disulfide to have no correlation with incidence of cancer [72). 172! DiVito, and. G, L. Somni. The Incidencetof< Infectious Diseases, Ho-opathicd,` and Neoplasms in Workers Exposed to tarbon* Disulfide. Folia'-Med. (Napoli),' 4<T( 11)^972-9791 1967 106 HONS 022182 Carbon Tetrachloride Carbon tetVachToride ftetrachloromethane, CAS No. 56-23-3T has been reported to produce liver tumors in the mouse, hamster, and rat following administration by inhalation and oral ingestion 173). It was not a mutagen as tested by several microbial sys tems (32). Carbon tetrachloride is considered a probable carci nogen for this project. Production and Persistence It is estimated that 1,2 x 107 kg of carbon tetrachloride is emitted per year (1). Another estimate is a production of 4 . > x 10' kg with 2.7 x 107 kg released [71. A document is avail able on the air pollution assessment of carbon tetrachloride (74). Estimates of carbon tetrachloride production include 4.5 x 10' kg i 197oi [73), 4.8 x 10'' ku [6), 7.3 x 10* kg ( 1974) [8] and 5.3, 4.1, and .3.8 x 10* kg for 1974, 1975, and 1976 C.2]. It is fore cast that the 1975-1 976 ih.-cline will continue. The half-life of c irber. tetrachloride in the water is about 70,000 years |7), and i.\ the troposphere it is about 10 years (8!. It is estimated to have j half-l;fc of 10-V- weeks toward atmospheric phot odour.a Ja- |74). The boiling point of carbon tetrachloride i9 76.7"C, am! it has a vapor pressure o: 90 mm at 20C 1331. Tor a review 'f its production, uses and biological activity, see the Fishbeir. article 1751. i')! IARC Monographs: evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 1, 1972. pp. 53-60. [74) Johns, R. Air Pollution Assessment of Carbon Tetrachloride. National Technical Information Service No. PB 256 732, 1976. : '5i Fishbein, L. Industrial Mutagens and Potential Mutagens, I. ilalpgenaded Aliohatic Derivatives ; Mutat. Rest, (32$267-308, 1976. lb7 mqns Q22183 Chloracetic Acid Chloracetic acid (monochloroacetic acid, CAS No. 79-11-8) har baan raported at being carcinogenic in mice whan injected sub- cutaneouily at 100 mg/kg (2J. The primary reference, however, does not report a statistical difference in tumors; data reported for the test Tice are not much different from those for the control mice ,'69|. In other tests, chloracetic acid was negative when given to h rats as 0.005-0.13 of their diet for 208 days 17 6 J and negative when given at 46.4 n-i/V.g in the water of 72 mien for days 7-2i followed by 149 n in their diet for another 17 rr.nr.ths It has also tvo.i f nor.mutagemc by ?. aubtilia 178] and - '-. ,- '"4-9'.; testa '*.- . All of these d c n o n t r c t. ' -h.it chi 'r.iC'.*t ic ic: : i not .1 rjto.jcn nor a ''`t 1: ..t ':. I... r . .:* dr.l t . .-.ichvm. : .1.il : v. *n ~>-r I 1: 409-4 1 9, 1976. '79! Sanr.u:. ' n 1. Th.*- i c'h 1 oruot hy! on*1 xide, .IK. ruacera*. iehyde. . - - r. mol and Chloroacotic Acid, Cehcr ; vat jrY.it ahe I . . < ' I .*h Ion tie. Chon. Biol. Interact., 12 i J-4) : 2 51 -,o j. .j-t. (80) Bartsch, H., et al. .Human, Sat ar.d Youse-Liver Mediated Mutagenicity of Vinyl Chloride to. K'-r.rtum Strains. Int. J. Cancer. 15(31:429-437, 1975. ' [611 Malavoi lie, C., et al. city of Vinyl Chloride, CHloroet -.ylcneoxido, [Chloroacotaidehyde and Chloroetbaniol. Bloc hem. hiophvs. Sea. Comm., 63(2) : 363--370, -1915 108 MONS 022184 Chlordane Chlordane has been found to be a carcinogen to mice in a study conducted by the National Cancer Institute (82). It is also a mutagen in tests like the enhancement of viral transformation (personal communication with B. C. Casto on 9 February 1978). It is considered a probable carcinogen for thi3 project. Production and Persistence It is estimated that 1.1 x 107 kg per year of chlordane is produced (6). 132] Bioassay of Chlordane for Possible Carcinogenicity (CAS No. 57j-74r$. iNalifcnal TechnicaliInformation ServicesNo. fPB| *71 9774 109 MONS 022185 Cresols Cresols (primarily a-crcsol) have been shown to be promoters of carcinogenicity when given with initiators such as 3,4-benzpyrene (Kaiser), diraethylbenzanthracene 183) or in complex mixtures (84, 85). On the other hand, normal adults excrete about 30 mg of volatile phenols per day of which 90% is :-cresol [86). Thus, cresols are probably not carcinogens bet could be promoters. -' : . an.; luo.tce of Aern-Free Status \.tv: . tr. c: F: ' Is Possible Significance r Fronot ier.. Kxpor ic.cn 11 a , J G ; 5 : o 1 9, 1970. .''oc'., V. . , i-t a 1 . Cor.ros: t :or. Studios or. Tobacco. XLIV. : ,,:r.or-.:'ror.otir,(C Activity of i-ubfract ions of the Weak Acid Fraction of Oigarc*. to .-'r.ttir.-: Ccr.d<.r.sate. J. Nat. Cancer Inst., 4 7(23:4 29-436, 1971. '.SSI Shustova, >*.. N., and L,. S'. Samioiovich. Blastomogenicity of Neutralized Soots from the Sulfate Shoo of a Coke Plant. Sig. Sanit., 36 (7;:103-104, 1971. ' ,i86i ror.e, t. S., et al. The Production of Urinary Phenols by Human Gut 3acteria, (Meeting Abstract). J.Med. Mic[rol}io( .d 9(2): vi^ 1976. 110 HONS 022186 Chlorobenzilata Chlorobenzilate (CAS No. S10-15-6) hat been found to produce hepa tomas in mice when administered orally (69,77,87) and is listed by the U.S. Commission on Pesticides and Their Relationship to Environmental Health as a group B chemical (positive results in one or more animal species at 0.01 significance level (88)). Several short-term tests have been negative for chlorobenzilate (18). For this project, it is considered a probable carcinogen. Production and Persistence A 1976 reference (6) cites a production of 9 x 10s kg per year, and it is said (87) that the 1971 production was 1 x 10* kg. 187) I ARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5, 1974. pp. 75-31. (881 Jueek, f\. Carcinogenicity of Pesticides. Roczn. Panstw. ZMI* ltfg.,, 25.(5)* 563-576, 19.74.: 111 MONS 022187 CHforefom; Soma of the current literature 189-92) indicates that chloroform is a carcinogen. Even though more data are required before a final determination is made, the positive data on mice and rats suggest that chloroform be placed on the probable carcinogen list for this project. Production and Persistence It is estimated that 1 x 10* Kg chloroform is emitted per year ill. Another estimate is 1.7 x 101 Kg per year (60) emitted. Production estimates are 1.3 x 10* Kg per year (8), 1.1 x 10* [61, and 1.1 x 10* Ku per year (89 1. About 96'' of production is con verted tc rhlcrodifluoromethane. In the troposphere chloroform degrades slowly with a 10-year half-life (8). It reacts with HO radical with a v of 1} hours i81 and hydrolyzes with a t- of 3,000 years [-,'01 . Trie log partition coefficient is 1.9"? for chiorcterm [rZ'. It has a vapor pressure of 160 mm at 2QC and a bo 11 me po::.- -'2'C [331. It tabes only '.3-23 minutes to .i por.it i V.i : : to chloroform from a pm sol it.on it 2S*C 6-[ I ARC r.. :raphs: Evaluation o: thi fir;11 no-sen ic Risk of Cher:ca1s to.^ar.. Volume 1, 1972. ;p. 61-65. Powers, V.. 3*., and R. W. Ycelker. Evaluation of the Or.co- .cr. ic Potential of Chloroform try :..r..:-Torn Oral Administra tion in Rodents (Meeting Abstract . Toxicol, Aopl. Pharmacol., 37:179, 1976. ` 91) Renne, R. A., et al. Pathology of hona-Terra Oral Adminis tration of Chloroform in Rodents (Meeting Abstract). Toxo- col. Apol. Pharmacol.M 37: 179-1 80, 1976. i?4) Chloroform Tagged as carcinogen in Mice. Chem. Engl News, S4:6, 1976. 112 MONS 022188 Chloroprene Chloroprene (2-chloro-1,3-butadiene, CAS No. 126-99-8) although known to b toxic wee not considered'to ba a suspected carcino gen until three Russian papers linked occupational exposure of chloroprene to skin and lung cancers [93-95). Since that tine, a short-term viral enhancement [961 test at 125 t.g/ml (personal communication with B. C. Casto on 9 February 1978) and S. typhiruriun (Amos) tests [97J have been positive, while long-term rat and mouse studies have been negative [9C991. A review of health records and death certificates for DuPont Corporation employees exposed to chloroprene convinced investigators that no excess of any disease similar to that seen for vinyl chloride had been observed (100). However, some increase in lung cancer has been seen this population [100). Chloroprene has also been found to accelerate the growth of transplanted Crocker murine sarcoma in the rat [44]. Thus, it lies on the border between a possible and a probable carcinogen. It will be classified as a possible carcinogen for this project. Production and Persistence It is estimated that 7.5 x 10* kg chloroprene is emitted per year [1). Another estinate is 2.7 x 10* kg/year released |44i. Sore estimates of production arc about 1.8 x 10* kg/year !f,44j, i.6 x 10* kg/year [8), and 1.3 x 10* kg and 1.6 x 10* kn m 1974 and 1975, with 4i annual growth predicted through 19H1 ;j2I. T'ccauso of its low solubility and high volatility, it will soon migrate to the atmosphere [8|. In the atmosphere it is said to nave an atmospheric half-life of less than 10 hours because rf 'I! radical reaction [31, Its boilinu point is 59.4V v.d it has a vapor pressure of 200 rr. at 20*C ill). ! r< 3! Khachatryan, E. A. The Sole of Chloroprene m the Process of Skin Neoplasm Formation. Gig. 7r. Pro:, .t.iio'. Ik :9455, 1972. ! 94) Khachatryan, E. A. The Occurrence of Lung Cancer Amor..People Working with Chloroprene. Problems m oncolo.iy. 18:85, 1972. / i95) Khachatryan, E. A. Lung Cancer Incidence Among Chloroprene Handling Workers. Yopr. Or.kol., 18:85-86, 1972 . (96) CastB?V.'0.JTe<falj Assay of Industrial Chemicals in Syrian Hamate^ Celle ifor Enhancement of Viral Transformation. Proc, Am. .Assoc. Cancer Res., 18:155. 1977. (97) Bartfccll jHl, etiel. The Predictive. Value of Tissues-Mediated Mutaheificfty`Assayi to Assess the Carcinogenic Risk of ChtmcAs IA&C Bci.iPub.' 197$.j pp. (467-491J.. 113 HONS 022189 Chloroprene References - Continued I9I| Zilfyan, . 0., *t al. Expermental Study or Chloropreye for Carcinogenicity. Yopr. Cnkol., 23:51-65. 1977. 1991 2:lfy*n, y. H., at al. Results of a study of Chloroprene for Carcinogenicity. Zt. EKsp. Kim. K'.ed., i5:3*-37r 1973. {100] clovd, Jt W. .cancer Risks Arong Workers Exposed; to qhlOr;oi p'rene. Ann. N.V.Acad. Sci., `271 :91-93, 1976.114. MONS 022190 Chloropropane No reference to carcinogenic or mutagenic action of chloropropane could be found in TOXLINE, CANCERLINE, or any of the other refer ences consulted. It is probably a noncarcinogen and will be con sidered as such for this project. #5 MQNS 022191 Chrysene Chrysene (benio(a)phananthrena, CAS No. 218-01-9] is (airly well established as a weak carcinogen. It has produced skin twaors in nice following repeated painting, and 2-20 mg injected subcutane ously in mice produced tumors after a long induction period (101] It is also a mutagen causing 167 revertants per microgram [52], It is considered a probable carcinogen for this project. Production and Persistence a11 he. h chrysene is not u manufactured chemical, it is a product of cor jstton found widely dispersed in the environment. In one tost . automobile exhaust, 12 ..g was ound after 1 minute of rrri'.T. or. ;; Oil. In the atmosphere, . ; 0-490 chrysene has o urvd :.er gram organic par t icu l.i:- matte: (101). It has a Vo i l :rt hi 488*C (31!. fion IARC .Monograph*: Evaluation of the Carcinogenic Risk df: Chemical's, t^ Man/ Volume 3, 1973 . do. 159-177. li6 MQNS 022192 Cumene Hydroperoxide Cumm hydroperoxide (diaethylbensyl hydroperoxide) is cited es being a carcinogen but at 34 and 90 mg/kg did not induce satistically significant doeinant lethal effects in nice {30, 102). Cumene hydroperoxide is said to cause neoplasms in mice both by Inhalation at 304 mg/kg 1103) and subcutaneously at 10 g/kg 11041. On the basis of the two animal studies, it is considered a possi ble carcinogen for this project. Production and Persistence It is estimated f81 that the 1974 production was 1.4 x 10* kg. Another estimate of production (6! i3 9.1 x 10* kg per year with a production loss factor of 0.015, or 1.3 x 107 kg/ycar. It has a vapor pressure of 1 mn at 70*C (6). Because of its low volatil ity and moderate solubility in water, it is not likely to remain in the atmosphere |9|. Photochemical and HO radical reactions arc likely pathways for transformation of peroxides in the atmos phere with a half-life of less than a few hours (81. 1102) Epstein, ~~5. S., and H. Shafr.dr. Chemical Mutagens in the .rHuman Environment. Neture, 219:385-387, 1968. 11Op) Radiation Research* Supplement 3:193, 1963 las cited in ' 'Refertile* 2). .(194) UUNht.i Cancer'Instf., 07:82 5, il966 (as citedfirtReferer.ee 2). Ill HONS 022193 DDT DDT [ 1,1,1-trichloro-2,2-di-(4-chlorophenyl) ethan*, CAS Ho. 50*29-3) has both positive and negative in vivo and in vitro data. It wis negative in feeding studies of dogs and aonkeys 1105! and in a differential growth E. coli (pol A) mutagen test . Glv n irailv, it produced liver cell tumors in several strains Oi nice, and some of its metabolites produced lung tumors :i ;r, i eu ! 4 ^ i . It is positive in a rtcessive lethal Vrotophila st. i0^!. All things considered, it is probably a carcinogen .! - : 11 ! -lass if ied as one for this project. r ' '.l .'122T- 111: Insistence : 1 0" 1 , 2 :< II'T : was the cst irtated production (105). In 1971 . t w fo :: : : the air in concent rat ions of 0.1 nq/mJ to 1.56 . T1 ha 1 f-1: fe is estimated to 15 years 1105). ia r r isuri' -if 1 . rt x 1-V rn at 20 C and a molting 105! IARC Mor.ccraphs: Evaluation of the Carcinogenic Bi.sk .of Chemicals to Man, Volume 5, 1974, pp. 13-1)4, ; 1C-i: `.'oael . II. The Relation Dctvegn Mutational fjatteri fend Condor.;racic n bv Chemical, Mutagens in .' r.-jfcaniiti.l SA8C ici, I :b. Nc. 12, 1976. pp.' 117-137. 113 HONS 022194 Dl-tert-butyl Peroxide Di-tert-butyl peroxide (bis(1,l-dinethylethyl) peroxide, CAS Mo 110-05-41 has been found to induce malignant lymphoma in 7/35 mice which inhaled 100 pg/mJ of this chemical 1107). (Tert-butyl hydroperoxide has also been found negative by akin application tests on mice (109, 110).) Di-tert-butyl peroxide is on a list of 'suspected carcinogens" studied for environmental fate (8). Sxr.ce the positive mice test results were by the inhalation route, which has fewer false positives than does injection, ditert-butyl peroxide will be considered a possible carcinogen for this project. Considering the type and date (1961) of the posi tive tests, however, negative short-term in :i`.r mutagenicity data would probably change its classification to a probable noncarcir.oaen by the criteria used for this project. rrodjt.oa and Persistence I'ri . is estimated to be 3 million pounds per year |8|. It : r. nly ; ! ; :htly volatile but moderately soluble in water. Thus ... d;-tert-butyl peroxide will remain in the water sys tem. '. r. the water the presence of >1 ppm feJ+ and MnJ+ leads to 11 ion to acids and alcohols with t> >-10 hours (8). Ir. : : i nr-os: here p hotochenica 1 and HO radical decomposition leads a *. . of 79 hears (8) . ;:0~' Xot in, P., and H. L. Kalk. Radiation Rcsearc!: Supplement 3:193-211,1963 (as cited in Reference 5). (108) Saffioti, U.,jpu$P. Shubik. Nat. Cancer Inst. Monog,, 10:489-507, 19(3 (as cited ih Reference 5). (109) Hoshing, ll., at al. Gann 61(2):121-124, 1970 (as cited in 1110) van Duuren,; B.; L.!,; et al'. } J. Nat. Cancer Inst., 39:1217": 1228?, 1967 i(asi Cited (in -Reference 5). lift MOWS 022195 D1(2-ethylhexylP Phthdlata 0\(2-ot(.ylM;xyl) phthalate (OEHP, dioctyl-phthalate, OOP: CAS Ho. U7-8I-7) s a high-voluma plasticiser yhich had in the paat been con si:.'-.*rod virtually nontoxic as judged by various acute and ri rc: -.tits [1111. Although early animal test9 (dog, guinea rj. .ere negative (112), at least one source [6) now cites "Ov.; effects in rats orally given 43.2 g/kg (96 weeks) ::y . :.exy 1) phthalate. Although this dose is rather high, `.so several references which show this chemical to :.e L . r .vjenic and teratogenic (113-121). It is therefore classed a. a possible carcinogen for this project, at least until a care;.: vr. bioassay being conducted under NCI contract (122J is rcr.-i .id. . .:-,d reported. : rod nd_Pors : stereo ' ' - ''. i: ih.it 2.(> 10' kg DEMP is emitted per year from ;rci's ;![. ither estimates are 2.0 x !0 <q pro . ...:- d <,()! ,ir.d 1 . H :< 10* kg produced in 1974 |6|. t trade r.i: idly in water and si idee (123). : .. ` :.!' with the HO radical with a half-life of 1 . : .-.a-: . : oil ; rs r -.t of 385C and a vapor pressure . .i o : i i j . . vr.Mti.on of the Threshold Limit Values for Substances .. rkre-om A:r. American Conference of Covernnenta 1 Ir.- hygienists, 197'. . pp. 96-97. . ... : r . . , ot al. Surof Compounds Which Have Been r Carcinogenic Activity, Supplement 1. National 1 r.: v rr.j t : on Service !.'o. PB 216 24R, l'.*a7. J A. R.. et al. Mutagenic and Antifertility Sensitiv- .: s of to Di-2-othylhexyl Phthalate (Df.'HP) and A ir.ethoxvefhy 1 Phthalate (DMEP) . Toxicol. Appl. Pharmacol., 1974. .x.ithur, i. P. Respiremotric Evidence of the Utilization of Dioctvl and*Di'r2-ethyihcxyl Phthalate Plasticizers. J. Environ. Qual., 3(31:207-209, 1974. :'M till 3. -3. Phthalate Esters: Occurrence ar.d Biological 1:feets Residue Reviev.s, 54:lr4.1# 1975; (177 references) . ilif.) Rodent Progress in [Safety EvaluAtfion Sti/dies <fni Plasticizers and Plastics and Their Contrdlledf u4^ lrf Japan. Environ. Health fctfipec,, 11:2Q3-2Q9,1976l K20 HONS 022196 Oi (2-ethylhexyl) Phthalate References - Continued ;: : 7 | *:n;h. A. 9., ct al. Mutagenic and Ant 1 fcrti11ty Sor.si- -..us Mice to Phthalic-Acid Esters. J. Anim. He;., }& : 1974. [ 18 I Taylor, 3. y. , and F.. F. Ccrcora: . iiiodo-jradat ion of Phtra: Acids and F.sters. Contract !?-009`M-02, National of i.r.viror.nenta 1 Health. Sciences, 1777. '1191 A .air., . `vxicity and Health Threats o: Phthalate Esters, review n: :.he literature. ~r.v i r~r.. Health rerspec., 4:3-26, 1973. '1201 Vagi, Y., et al. Teratogenicity and Mutagenicity of a Phthalate Ester^ Teratology, 14:259-260, 1976. [1211 Dillingham, E. fO., and J. Autain. Teratogenicity, Mutage nicity and Cellular Toxicity of Phthalate Esters. Environ. Health Perspec. 3:81-89, 1973. (1221 Landon, J. c. Carcinogenesis Bioassay-of Di(2-ethylhexyl) . Phthalate. National Cancer Institute contract with Tracor Jitco, Inc., 10/76-9/.77. 1977. 11231 Saeger, V. W., and E. S-' Tucker. Biodegradation of Phthalic Acid testers in River Vater ;and Activated Sludges. Appl. Erfviron. Microbiol.) *31 fl) i29-34, 1976. 121 MONS 022197 2t4-Dfaglnoarilgt>Itt , 4-Dinrunoar.isole M-methoxy-^phehylenediamine) was nonamta'n:c .r. the LM178Y mouse lyaphoaa'cell test (124) and negative : rat sXi'. ' i * Si (in combination with other chemicals) and mouse '..r. i'.J'fij the suljfate form) carcinogen tests. It did not pro:-.tha l mutations in rats (127). -'.i :.-:vr sh-.-w to be mutagenic in J. |128-1 30|, *' - ' Jet!vat ion. It also induced sex-linked reccs- '''i. it :or. 5 in i jnoj.icicr (1311 (sulfate ' ' I-. i.*t . vity in the active germ cells (spermatids : '.t : . Preliminary results from an NCI study indi- ! !'.J. -ice red this chemical (0.12% to 0.24%) had ' i - - :ci f ic (thyroid and skin) malignant tumors : : :der.ioloqic studies suggest excess cancer ' M32). Diaminounisolc is on the Si.Tftl ' : its carcinogenic potential 1133! and will .: .-.i ro i n for this project. iny ".:rri-r.t .lcr.t--.it ic product; on but reports : .inds per year are imported (133!, :1. Trie "ur a lent c Assay of So no ' sir.: the Th/in-Jino Kir.ane l.ocus of ' 1 : ilf "';in : Abstract . Toxicol . 1 : 03 , 1 i~c . iii:: il'i: A; : l . .in ! . ll.i 1 .T.ir.i:. St i.ly of 1-'r.-i-'V-Tr. JVrru- ' a: d '.'a r cr. j->'r.: -: y -l.i : : by. s ui i os. Kcod Cosr.ot . Toxicol., 1 4 ) : i:4 !-64 8 . . il. 1 c r. r luxicity Studios on .Mi.!.; .. i sr..-.-t. Toxicol., 1 3 i 3 i : 3 a 3 - 3 , ' - if al. Dominant '..ethal l-'.utaion: r i ty Study r :.a;r -s. J. Toxicol, l.nviron. Health, 2 ( 3) : 657-t>b2 , !i' D-.binc, F., artd^s/S. Thor g oil ^ss$n.* *Me$abottc Activation 2, j-D: a.-unoan isole, a Hair-Dye Component. Blochem. : .lurrjce'.., 25 (I) 1729-734, 1977. : 0-. 1 orblicnier.e (Induction of J Acjta iPharaacol irMerlhP^) HONS 022198 2,4-Oiaminonr.isole Peferenccs - Continued !U0! Arcs. 3. ct al. Hair Dyes are Mutagenic; Identifica tion c: a Variety of Mutagenic Ingredients. ?rcc. Natl. Acj.1. ci. .f-JSAl 72 (6) :2423-2427, 1975. il311 Bl:; lever.. W. G. Mutagenicity of Four Hair Uyes ir. tl.: .tfv.'aic.rearer. Mutat. Res., 48 (2) : 181-185, 1977. - |132) Uealth Hazards; 2,4-Diaminoanisole. Occupational Safety i. Health Reporter, 7(351:1331, 1978. j|H3j pii-Diarr.i.r.oanisole (4-Methoxy-r-phenylenediamine) in Hai: and Fur'byes. {Current Intelligence Bulletin 19, January 13, 1*784 123 HONS 022199 PUSIhor s>ron has been reported to be; slightly teratogenic in rate ,'n given on the ilth day<otffre*tation (134). An increase in or-atid breeds hae been feoted in the lymphocytes of humans after i's - vcri of phosphate Insecticides including diazinon (135) and -"a : t i vated human lymphocytes (1361. c.'h'r hand, diazinon has been found to be nonmutagenic m ' natation tests [137). :: a: . the v-' ` :3 . t a.>l cause mutations T>. - to prototrophy -. ' 8 i . r-r a -!e r:: in the 5-MT V. test : test [1391, two other mitotic qene conversion ' " rformat ion indicates that diazinon if pro: - a . i: . . .. . . , jr.i T. J. '.air.os. : of "r in rs- . . a.ns A lr. 1 a; i no A: :if ,r. - h- :-.i: fetus . . . -. . aith, 16 : 805-303. 106-. , *. ui. Chrcrosorv A: v- r: a t : v ha t: or.:-a . ' : :ar..c i'r.osr hai :: sooticido tr.toxic.v. :-. r . 5-57, l r4. : : i, r., et al. inf luor.oo o: Diazinon arc: inr.o on the yftotic Activity and rh-.- daryotype of iinra:. . h .yp's, '..icivatcd ` liaer.atol. (hast* i!, >3 1. : 5 4 4 ^ ' 4 ~ , 1*71. ?! .Marshall, 7. C., et al i icare^ning o: iestieides for Muta- er.ic Potential Using AiMubo?" : - -r: . - Mutants. \sr.e. rood Chea., 24:560-563, 1976. ; ''-'.otnvltryptopijam Resistance Mutations in -'s et c ] r K-i2.' Siftai.tiei: 20(1) :7-15, 1973.. ) Aphwcoc-Snith, *t- <J4 ill Mutagenicity of Senior,vps. . '.atari;. ?40; 4.15-419,11#72.' 134 MONS 022200 Dichlorotenzen* A negative animal study of o-dichlorobenzene (CAS No. 95-50-1) has been conducted (5), but it was a short-term (<6 months) study which would not be expected to show carcinogenicity. A few positive case studies have been reported, but with insuffi cient supporting evidence to show cause and effect (HO). A few > ::rc tests have been conducted (141-1431. In Aep*rgillut >i.i, 200 mg/ml for 60 minutes causes an increase in rever sion to methionine prototrophy from 3 x 10* to 5 x 10* reversions [12). It was negative in a S. t-^chimurijn spot test at 1-5 -1 i" cigth strains(32). Because of the limited positive test data on systems which have not been extensively evaluated, _-d ichiorocer.ze.no will to considered a probable noncarcinogen (with some significant positive data) for this project. , UOi IARC Mcr.c r.ir: a : Evaluation of the Ca re ; notion l c Ri.Vi of Chemicals tc vn, Volume 7, 1974. pp. 2 3 1 -- 24 4. [14 1] Guerin* M., e: a 1. Inhibitory Action of Chemical Carcino gens on' ,'1i tos: s,'of Rat Lung Cell Cultures: 2. Comparative Study of Carcinogenic and Noncarcinogenic Substances. C. R. Soc. Biol.165:2255-225S, 1971. :142| Prasad, I. Mutagenic Effects of the Herbicide 3`,4'-Dichloro-propionar.ilide and Its Degradation Products. Can. 0,iHlcrobiol., 16:369-372, 1970. (143) 9rtfsad, I., and D. Pramer. Mutagenic Activity of Some Ch^olrcSanilines!and Chlorobenzenes Genetics, 60:212-213;, *L9?8. '125 HONS 022201 p-Dichlorober.zene ary negative aniaa studies of ?-dichlorobon*ene (CAS No. 06-46-7) have been conducted [5], but all of them have been hort-term (<9 aonths) studies which would not be expected to l-.iv .arcinogcnicity. A few positive case studies have been > 'r d but w;th insufficient supporting evidence to show cause ,-:'fect (140). A few in tests have been conducted (141 ; . it is reported that : -dichlorobenxene is a m.utaqer. to . plants and causes chromosomal breaks {561. in '' :*. , TOO r.q/ml for 60 minutes causes an increase :r. reversion o prototrophy from ) x 10* to 11 x 10 reversions ; . :>-'C.iv.se of the limited positive test data or. systems which ... .......... t been extensively evaluated, :-dichloroben/ene w. II re 1. red a rrobable nor.carc; roier. with some significant positive .r this t roject. a 26 MONS 022202 Olchlorobenildlne 3,3*-Dichlorobeniidlne (CAS No. 91-94-1) has been found to b carcinogenic in the rat following oral and subcutaneous adminis tration and in the hamster after oral administration (144, 145). Many other positive responses are noted in TOXLINE and CANCERLINE, and it is considered a probable carcinogen for this project. Production and Persistence It is estimated that 2.1 x 10* kg is produced per year with 1.5 x 1C5 k-.: per year released (AO). Other estimates of produc tion are l.t 10* kg in 1971 (1441 and 2.L x 10* kv per year (61. Dichlorcieczid i.-.c is somewhat reactive towards R02 'v. - 40 days) and very reactive towards HO and Oj (f.. = 1 c:ay> (60! - Its meltl r.-.* ijoi nt i s 1 1 3 *0 [ 1 44 ) . [i44( . |l4$i< IARC Monographs: Evaluation of the Care ir.oee:. :c Risk of Chemicals to Man, Volume 4, 1974 , pp. 49-55. Stula a. i\, et al. Experimental Neoplasia in Rats fYom Oral Adituniitra^ion ,of, 3.3-tDichl9roben:idi:'.e, 4,4 ' -fiethylene Jbisfa-chloroanifint), and 4,4''-Methylene bi`s\2-metJiylani<ihq)> fTcxicoll Appl. Pharmacol:, 31(1):159-176, !?75. H27 MONS 022203 Dichiorobutene 1,4-nichlorobuten*-2 is a mutagen of 5. typhimurium with microsones enhancing the effect (146). 3,4-Dichlorobutene-l is also a mutagen in that system with or without nicotinamide adenine d in'jc 1 eotide phosphate (NADP), giving 490 reverts/umole with NADP ana 3 4 1 reverts,' .mole without NADP {14 6] . Tr jio-1, 4-dichlorolets'-.7 his been : und to be a weak carcinogen to ICR/HA Swiss nee when liven by subcutaneous injection or by intraperitonea 1 i r. ior. but not by skin application (147] . It was found not to z<: turor initiator in a two-stage test (147], Because of the c i re i".o ten: c and mutagenic data, it has been placed on the probable -lrcinogcn list for this project. r. i s tore*' ,.-v of .o'. - 3 ; : o:.- <<: is on it ted per year in the r.ir.ji , 4-111 oh lorobutcnc has i boil: rit; i *6i Lartscn'. lw*et al. Alkylating and Mutagenic Metabolites bf l!*iogenAedl01efFins Produced-by Human! and] Animal Tissues, (rcfef A; Msoftj t4nc4r ftes. 17:?.7i i$76. fiff Hifuutdnlter Ij.l et al| C4rc*ni>g ,,. ,- ard ,,4-Dlcnlorobutene-2 CanceiJ R^s;., 35 32551-2$5>, l97;5? f 28 MOSS 22204 Dlchlorodlfluororoethane Dichlorodifluoromethane (Freon-12) has been shown to be nonmutagonic in 5. :phimur' um tests (148) but may cause some (mutagenic?) chanacs in conidia formation in "mroapora craaea [149]. More information is needed on the mutagenic and carcinogenic potential of Freons. "-o other information could tc found on CANCERLINE or T1st. At t)n' present time, it appears as if Freor.s are nonw'3rci".03i?ris. U48| Andrews, A. W., et al. The Identification of Er.dogeneous and Exo^eneous Mutagenic Compounds. 4th Carcinogenesis Bioassay Program^ Orlando. Florida, February 11976. (1491 SCevens, s et hi i Phenotypic and Genetic! Effectfe in flfxed with Oi'x,cyg1eaPp 'VoDdeuvceeldo.pb. y.InSde.leMcteicdroGbaisoels., and Gases. 12:346-353 1*71 129 MQNS 022205 1'. l-Dichloroathan The primary reference (150) cited for 1,l-dlchloroethane (CAS No. '5-34-3) in the NIOSH Suspected Carcinogen list shows very minor teratogenic effects eveh at the highest concentration used (6,000 ppn) . Although there are many references to 1,2-dichlorcethane, TOXLISE and CANCERLINE provided no significant references ,.n the mutagenicity or carcinogenicity of 1,1-dichloroethane. A recent report from the National Cancer Institute {151) disclosed findings indicative of a possible carcinogenic potential for this compound but could supply no conclusive evidence. Investigators found dose-related marginal increases in mammary adenocarcinomas md in hemar.giosarconas among female rats and a statistically significant increase in the incidence of endometrial stromal ; >lyps amc; ; cosed female nice. For this project i,1-diohlor - thane will be classified as a possible care motion. cc t:on and Per s l s tor.ee : t is estimate! that 2.6 x 10* Kg of dichloroethar.c is emitted er ar fro:-, nationary sources til. Half of the 1,1-dichlcr :m ce 11! viporate from a 1-ppn water sol-at ion at 25"C in . 2 .-mutes !3: . It has a boiling point of r>7.3c'C and a va;*<v r--ss..r' cf mn at 20*C [33). - : 1501 Schwctz, B. A., et^al. Embryo- and Fototoxicity of Inhaled xlton Tetrachloride,; 1 lwD^chloroetha,n^, andf Methyl; Ethyl c|dne in|Rats. Tpxvcoj. Apjpl.j Pharmacol.-4 20^452-464, Sonllj Cancer' Institute' Drtifd S unmarigs bf P ioassay ReIs,1l-lDichlorpecnane;. . fchero. Reg.; RepJ ' 3 (4 5) :'1597- B-3C HONS 022206 Dlchloronaphthogulnone wicnioronauhthoquinone (Dichlone) did not cause point mutation in j .: : rot * al test system 1152). It has, however, been found to cftjse reticulum cell sarcomas (Type A) In 9/64 mice when injected jix'utaneously in B6C3F1 or B6AKF1 strains of mice compared to : coll sarcomas for the subcutaneous controls (69) 7;.;'; -is significant at a 0.01 confidence level. Because of the v 1 ;r-bor of mice involved, and the lack of other references or. CASCL.-ii-INi and TOXLINE, dichloronaphthoquinono will be consid ered a possib)* carcinogen for this project. Prod -j cti or > nd_ Persistence 1v is ost;-.itc(! `.hat 900 kg/year are omitted from stationary siirces 3ichloronaphthc.iuinone bus a molting point o. 19J'C i-J i 7.34 vipor density (3 3i . {.:2; AnrieEscd.f K J J 4, j eti al;. f Evaluation ofj Kqrbi^idasj fotjflpBaifr. tie Mutagpni Properties. , J. Aarl Food Chcm., 20: g4j)-<|5, 19721 1J1 MONS 022207 Nothing was found in CANCERLINE to indicate that dichlorophenol :s a carcinogen or a mutagen. A 1959 reference [1531 cited in the riIOSH Suspected Carcinogen list shows that 2,4-dichlorophenol may to a promoter or cocarcinogen when applied to the skin of .r. combination with benzene and dimethylbe.nzanthracene. -r `"iar. this reference, d i ch lorcphenol is not listed in Refer ee..:'- v. hoe;, use of the lack of data, dichlorophenol has been riac'd ~n t:..- rcbablo noncarcinogen list as a possible promoter. 1153* BMtvfi:, K., and D. K. Bostlt. Thfe -Tumor-Promoting ` /Hica of PhqnoL and! Relate^ compounds ,for Mouse Skin, icirfcei U9*4134l24?, U959. 132* MONS 022208 Dlchloropropene i.3-DichJoropropene at 1 ppm for 6 month* ha* been shown to have no adverse effects [1541. Both da and trnnn isomers are muta genic to TA1535 and TA100 C. tuphimurium strain* without activa tion {31, 155, 156). It will be considered a possible carcinogen for this project. ?_reduction ar.d rcrsistence It is estimated trsat 6 x 101 pounds of a dichloropropane/ dich1oropropene mixture is manufactured a year (56). Assuming 504 dichlorcj. ropene, 3 x 107 pounds is released a year. It is said to react with OH and 0, with a ti, =* 3 days, and to have a ti. - 7 Jays : r. water ! 561 . It has a boiling point of 104C and 50' of a 1 --p; ~ water solution will evaporate in 31 r.inv* es (33). (154) Torkelson, T, R., and F. Oyen. The Toxicity of 1,3-Dichloroproper.e as Determined by Repeated Exposure of Laboratory Animals. Ar.. Indust. Hyg. Assoc. J., 38 (5) :217, 1977. (155) DeLorerro, F., ct al. Mutagenicity of Pesticide^ Containr ing 1,3-Oichloroprooene. Cancer Res., 37 (6) :19lS-l9L7. 29- ` 10&, ,1977. '' ' '' if- 13 3 MQNS 022209 Dichloroproplonlc Acid Dichloropropionic acid (Dalapon) is a herbicide which has been found no.-mutagenic in a o. t y-h -u, r- i ii test (152). No other significant data have been found, so it has been placed on the probable nor.curci nogen list. X34 mons 022210 Dichlorovlnyl Olasthyl Phosphate (Oichlorvos) Oichloroviny1 iimethyl phosphate (OOP) has been shown to be mutagenic m many different short-tern tests (18], including J. 'iun tests (157J, but has been shown to be noncarcinogenic by oral and inhalation studies in rats and mice 1158), Because o: the r-^tjqcn studies, OOP is to be listed on the possible car om. :er. : ;sc for this project. P - :,-.Tsistence it .s estimated that 200 kg/year is emitted from stationary sources !lj. ffOP has a boiling point of 120*C at 14 mm |3J). 11:7; rasa, Y., et al. Mutagenicity [Screening of Pesticides ; fc -'.icrobiai 'System. Mutat& i(ep., 40^:19-30, 1976. f 15 5z . oas'sav of bichlorVos for fpfcsAbfe CaSrci^.bgcnicjiey, CA ' >:-~3-7. National Technical* Znforpiaeipn Service; No. ?B. 2'C337 19774 135 HONS 022211 PlKathylacetamido Direthylacetamide was negative in a mitotic index test for epi dermal hyperplasia [159]. It is cited in the NIOSH Registry of Toxic Cffectn of Chemical Substances as being teratogenic to rats after intranetitoneal (I.P.) injection. One reference was found in trv: jjrv-. - of Chemical Substances Which Have Been Tested for r.i m r. :c ` ;tivity (1968-19C9) in which rats were given the ; r.ior jastr ically at 0.1 to 30 mg/d for 260 doses [1601. The r imer.: f.j.nd do not appear to be related to dose. No other reference;"' Id be found in CANCKRLINF. or TOXLINE which would .'i ::< m thi-. c inethyiacetamidc is a r.ut.,.:o;i or a carcinogen, so i t wi. : : cl iss .: ted as a probable noncarcinonor. for this proiect . !159) Hinder,' M. *M. CosRiethc science: 1 975 Literature Survey. (Josacti feqfu.tj., 91 (V i2Sr36,, .1976. [ 16-y ] tfajjdiirj. 196|.: 'eta&< J. Naf. Cancer Inst. t .41 (4) f985-10 36, 136 MOMS 022212 Diasthylaaine Direethylanine (methanamine, N^Mthyl) has been reported to com bine with nitrates or nitrites both in vicr-5 and in etvo (by saliva or intestine flora) to font the carcinogen called dimethylrut rosaminc or mtronodimethylsnine (more than 20 references in TO .'(LINE. Dioethylnnine may also combine with ozone and nitrogen t-trcxidr :r * he n*rosphere (161). In TOXLINE and CANCERLINE there are ~! i ar.j 16 references, respectively, which deal with mutagen:c or ;ar:ir.^gcnic aspects of dimethylamine. These refer ences, dlor.c wrth those in Chemical Abstracts, appear to indicate that althe ugh dimethylamine is a potert cocarcinogen, it is not by itself carcinogenic. For this project, it will be considered a r.or.carcir.ogon but will be considered when cofactors are C-vj 1 :a to i . ,i61j Dushutin, !y K., apd of Dimethylamine with pheric .Pollution.. 'Gi_ . MONS 022213 Dl--thy lhydf line 1, 1 --'imcthy lhydrazine (CAS Ko. 57-14-7) has been found to be carcinogenic in mice after oral administration 1162) . It also causes tumors of the colon in rata (but not swine, dogs, or "Jincj pigs - perhaps because of toxicity) fed 30 mg/kg dimethyl- yira? ir.e Many other positive references are found in ar..i .'.'PCERLINE, and it is considered a probable careino- o -*,*. : .-r this : -oject. Productior. ana Persistence Production is estimated at <5 x 105 kg :r. 197 1 (6, 9, 1621, with .i C.'.i fraction of dispersion Since it is polar, nonvolatile. a;.u soluble :r. water, chore would not be a significant Cr.ir.?ccr to the atr. sp' -to ! 8} . It reacts with oxidizing na_>ria'. s : r. the and has an expected half-life of 2.1 hoar.-i : ri - : t : :. with :.c !:0 radical | 3 | . f> i not hy 1 hy! ra z i ne has a io;'. :n ; oi:v. if >. ' and a vapor pressure of 157 m at 25C |t I . i}62j IA1JC Monographs: Evaluation of. the Carcinogenic ;iisk of Chemicals .to Man, Volume 4, 1974. pp .. 1 37-i 4 3. [J5.3] Wilsoii, R. B.' Species Variation in Response to DinethyL^ygra?ine. Toxiool. Appl. Pharmacol.. 33.(3) :647-650. 1976. 198 MONS 022214 Pinltrotoluene 2,4-wir.it.rotoluene Nat been found by the National Cancer Institute to be noncarcinogenic to mice but carcinogenic to rata (164). It ha* been placed on the probable carcinogen list for this project. !r;diction and Persistence It :s ostirated that 400 kg dinitrotoluene is emitted per year stationary sources [1]. It has a boiling point of 300*C : 33.. ! 1641 .National dancer institute Dr^ft Summaries of Biodss&'f Resorts*. 2*.4-binitrololuene* Chem. Recj. Refc.J 114!>) -1918. 139 HONS 022215 Oioxane i , ;-ri-.o '.'.'i io. 123-91-1) has been shown to be carcinogenic to re*-. ifcCI and guinea pigs 1167] by oral administration, it pf'..dii :< i ,-v,; ,-nant tumors of the nasal cavity and liver in rats ir.;i t ::o:s of the liver and gall bladder in guinea pigs. It was a: s \.:i L'.-v >s a promoter in a two-stage s/.ir. carcinogenesis cc-. :,.t produced no carcinogenic effect in one inhala- stn'.y in rats [168!. For this project, it is considered a ; :et;m . ire.-.c.*en. ?' ``o !..c*. i : n arfc rjs i stence 7h-. 16'! f.r. has been estimate-.: to : .1 x 10* kg |6, 44, ; ro.iuctior. to ho '.-5 : !!67], with most : !"aso(! to the onv: rtr'.ro:'. t 44! . 1:. the' atnos- -a . thi ;:o raltc.i'. v;'h .i nalf-l ife of 9.6 he- :: :; ; 1 ; r.c :cmt of '.'I * an.: i 'Mpor pressure rr. A t 2 5 ": - , ! i .' ' ! . .. et al. 1 , I-Pxa: : rel at ion o: the ; e s - 11 r. :: .'hrer. :c Ir.cestior. an.: inhalation Studies with .is .:oso-:'vj'or.dent Fate in. Rats. Aorosp. Med. Res. Lao. Tern. A.MRL-71^125, 1973. pp. 345-354. 1 , : :.s, ... i*. al. Dose-Response u.nJ Jltrastructural Alternatives in Dio*an Carcinogenesis. Eur. J. Cancer, J67j ` * ' y-::.r o.-'is; F.ulauat ior. o: tin- Care mogjDnic Risk cf * n '-Ian, Vqlurse 11, 19" 6. ::p. 247-256. 1 !'.tfkels.-r.. 7l F', eif hj. 1,4-?i rxane. :i. 2-Year| In.h.a la- t'ior. Stud in P.atjs. Toxicol. A.pn 1 . Fhar-acol;, 3012): iv74 140 MGNS 022216 Diphenyl Oxide No positive or negative data could be found for diphanyl oxida {phenyl athar, CAS No. 101-94-8) on TOXLINE, CANCERLINE, or in the Survey of Conpounds Which Hava Bean Tested for Carcinogenic Activity (Volunes 1-7). It is, therefore, listed as a probable noncarcinoqen for this project. 141 HONS 022217 Dlsodium Hethanearsonate Disodiuir methanearsonate has been oited as being carcinogenic, but no further data are given in this reference 16). It hae bee.-, found to be nonnutagenic when tested with five strains of f. jY 'i-uriu-., mitotic recombination of S. aereviaiae, and rela tive toxicity assays in E. coli and ?. ju:til'd (169). in ail tests except tho 3. oubi'-ia, the chemical was tested using the S-9 victosome activation. Methanearsonates have also been tested for :v ;;.ioor,esis by other authors (152, 157J. The lack of confirmi:.r dsta from TOXLINE or CANCERLINE and all indications other than th' fir.Tt reference demonstrate that this chemical is probably a r,or..: \: -; r.ooer.. (ifif?! slmnM. f4 pesticides. ifr.i'.ttifc MutagfenifcfSttdifes o t frfdhH Appl., Pharmacol;. , 31(1): 109, X9lh 14? HONS 022218 Dursban Dursban has bean shown to be more toxic to the repair deficient strains of fl. -ubtilit and V. ~oli than in repair proficient strains of these organisms. It was not, however, found to be a sutagen on 5. :jphinuriun assays or on the mitotic recombination of F. (169). It is considered a noncarcinogen for this project. 143 MONS 022219 tndoiiul'fin Rndoaulfan has been found to marginally lncreieel (f * 9.05) the tote) number of tumors and the pulmonary edenbeMie in mice given the compound orally 169). Endosulfan has been found to be r.onmutagenlc in three different E. ?ol mutagen tests 1181. In a National Cancer Institute study 1170], endosulfan was found to he r.oncarcinogenic to both mice and rats. Because of the tod amount of positive .arcinogenic data and the many negative studios, endosulfan nas beer, placed on the probable noncarcinouen oaf say 144 HONS 022220 BldrTrf Kndrin (CAS No. 72-20-9) has been reported to cause chromosome breakage In cells (171). Endrin was nonautagenic by a s. typhimurium test using mouse liver microtomes 1X72] and has tested negative on several . tali tests (18). Rat feeding studies (up to 100 pp?i) showed ro increase in tumor incidence (173J. Endrin will b-* ror-.sidcrcd x probable noncarcinogen for this project. U71) jCran:., w. r. Cvtological Effects of Environmental Mutagens1 Pesticides. Mutat. Rea.*, 21U)*1* 221-222, 1973. i 1 - j; var. . and Carcir.cgonirity of 'Fafc. Lar.dbouwet., :1493.i 1976. H. Van de Voorde. Mutagenicity Versus Organochloride Insecticides. Meded. Rijhaunivt Gent, <41(2. oart 23 11491 -- QX7 ponographs: ' Evaluation*of* the-Carcinogenic* 'Risk of dlsAixIlsftc.lMani Vdliim54 19711 i t tip. 1157-J171.. 145 HONS 022221 Eplchlorohydcin Eplchlorohydrin (chlororoethyltdxirane/ l-clvloto-^, 3-*poxy-propane; CAS Mo. 106-89-8) has been rsported to be carcinogenic in nice by subcutaneous injection and active as an initiator in a two-stage shin carcinogensis study in mice (174). Epichlorohydrin is also a mutagen causing chromosome aberrations, mutating 5. typhimuriui in a host mediated assay and inducing reversions to prototrophy in 2. :<:'>! -(T, <??' i, and Saurospor* aratta (32). It will be considered a probable carcinogen for *"his project. Production and Persistence It is estimated that 2.2 x 10* kg is emitted per year 11). Pro duction in 1973 vis estimated (8, 32, 174! to be 1.6 x 10* kg, 1.5 x I9* kg a:\vl 8.2 x 19T kg with a more reccr.t estimate 16] of j.2 x 13" kn. :r.c ;.:oduction is expected to grow 4-5! a year ',32). In the itmospnere epoxides have a half-life of 3 to .1 hours; 14! . i.Lichlcrohycrin has a boiling point of lH'c and a vapor :ressure 12 mm at 20"C !33|. (1741 1ARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Mai\, iVoliuae ilia 197.6. pa.ilS.7h3V. 14fc HONS 0Z2222 gptam Eptam (ethyl dl-n-ptopylthiocarbamate, CAS No. 759-94-4) was negative In a bone marrow chromosomal aberration test when fed to rats at 1/5 (LDS0 - 1,630 mg/kg) |175], Eptam may have had an effect on v<da fabc (176). It is cited as belonging to the C4 classification of pesticides (88) (negative, but in only one species of animal) but also referenced as being a neoplastic agent [). Neither of these primary references could be found on CANCERLINw. TOXLINE, MEDLINE, or in the entire collection of Reference 5. For this project it will be classified as a noncar cinogen . (175) Xurinnyi-, A. 1. Mutagenic Activity of Some Pesticides Derivatives of 6rea, Carbamic, and Thiocarbamic Acids. Tsitol. Genet., 11 (4):357-359, 1977. (176) Halted, H.', snd Vi ihehab. Cytological Effects of Eptam and COtoran on Vioii Faba. Egypt. J. SOt., 16(1-3):303311, 19'4. 147 HONS 022223 Etnahdl uch has been written about the Mutagenicity and carcinogenicity f nthanol '(177] (87 references liTtOXUNE) for both positive 17n J and negative" (178) result'sTf'lt has been tested extensively r animal ay tans 151. In general it is considered a noncarcin- j-.d nonr.Jtagen and has been renoved from the lastest NIOSH . :m.ed C i rc i nogens List. It wffll be considered a probable ncarcinogen for this project. :-v.;:vr.:, and Skorfuine. The Tnxie \ r.tjtivc Sisk .` valuation. Adv. : 0 J-a 19. 1977 57 references). V-. : l )..i: t. i : ; o 1 . , ? 5.- : 17 3! Draun. R., and ,'S. Schoeneick. Influences of Ethanol and \irbcn tetrachloride on the Mutagenic Effecttvity of Cyclo phosphar.ide in the Host-Mediated Assay with ' . rjyhifturium. Mutat. Res., .31 (?) s 19,1-194 , 1975. '79) Charbey, R. C., et al. Evaluation of the Effect of Ethanol on the '-`requency of Micronuclei in the Bone Marrow of Swiss Mice . Muta c. Res... 43 ( J>.j 44!rA44i*L9V7. 148 MONS 022224 Ethylbenzene No data have been found to inJicate that ethylbenzene is a muta gen or a carcinogen. 'A review of its use as a fragrance is noted !130}. Ethylbenzene has been found noncarcinogenic to rats, guinea pigs, rabits and monkeys by inhalation and to rats or.111y [ 71 . It is negative on the viral enhancement of hamster cell transformation (personal communication from B. C. Casto on 9 February 1978). It is therefore classified as a noncarcinogen for this project. ,'180) Opdyke, D. L. Monographs on Fragrance Raw Materials Ethyl benzene^ ?ogd Cosmet. Toxicol., 11(Suppl.):803-804, 1975. 149 HONS 022225 Ethylene' No data were found to indicate that ethylene is a;mutagen or a. carcinogen. It is also a normal metabolite of the human body. I*- is therefore classified as a probable noncarcinogcn for this -ro '.<? . t . 150 MQNS 022226 Ethylene Dlbrontde Ethylene dibromide (1,2-dibro&oethane, ethylene bromide; CAS No. 106-93-4) has been found to produce squamous-cell carcinomas of he forestomach in mice and rats after its oral administration 1181). It has also been reported to be mutagenic in S. typhiE. soli, Ifauroepora oratta, S. asrtviiiat, Tradaaeantia, . - rr:-.:o rarettaani, and Droaophila relanogaatar test systems ; 3:, 7 5, 182). Ethylene dibromide will be considered a probable carcinogen for this project. Production and Persistence : t is estimated that 8.9 x 10* kg of ethylene dibromide is omitted per year from stationary sources |i). Another reference cites a production of 1.43 x 10* kg- with 1.38 x 10* kg released ;7;. Other references cite production of 1.5 x 10* kg (1974) iS, 181), 1.4 x 10* kg 16), and 1.5 x 10* kg, 1.2 x 10* kg for 1374 anc 1975 I 32). The use of ethylene dibromide in gasoline predicted to drop by 101 a year through 1980, while its use .i5 a fumigant may be terminated by EPA action in light of the ::cv<- animal studies !32). Its air pollution potential has been ise.sse.: ; 132|. Atmospheric oxidation of alkyl halides is re- t'j have a half-life of less than 20 hours, while the half- 1 : f i* r ' !:0 radical attack is 234 days (8). Ethylene dibromide ' .is i ling point of 131.6*C and a vapor pressure of 11 mm at -'I. : 191) 1AHC Monographs: Evaluation of the Carcinogenic Risk of Chemical^ to Man, Volume 15, 1977. pp. 195-209. 11821 Johns, R. Air Pollution Assessment of Ethylene Dibromide. National Technical^Information Service No. PB 256 736, 1976. 151 MQNS 022227 Ethylene Plchloride Ethylene dichloj:id}(l,2,-dichloroethane, ethylene, chloride; CAS 107*06-2) ha* been found in preliminary results to be carci nogenic when fed'to male and female rats bythe National Cancer Institute [183]. Rats fed ethylene dichloride had a significant vXwss of site-specific malignant and nonmalignant tumors. In -;ther studies it has been negative by inhalation in rats, guinea ri.rs and nor.lteys but mutagenic to fruit flies (1841 . Because of ; :: t; .*e animal studies, it is included on the probable car- : i-r. list for this project. Productjc- and Persistence ; . -:-atcd that 6.7 x 10" k ; ethylene dichloride is ! year fro-- stationary sources (1). Other references . . : .... . : . on of 3.9 x 10V : produced with 2.1 x 10" kg ", 4.2 x 1 O' kg ;!9"i j 6 ] produced, and production : ;. k.q, 3.6 x 10' k>;, ar.d 3.6 x 10* kg in 1974, 1975, . . . An air pollution assessment of ethylene dichlo- :. : r made 1341- 'thy 1 dichloricle reacts slowly s vi th a h a 1 f -! : : i 1,000 days and is resistant ;. : rui dee radar :c r. ; ited !:< , 4 i The HO reaction half-life s ;*>;. !t has a iao i 1 : oir.t : , vat cr j.r< .:s at 20~C 133! i, i 3 ;; '.ew bindings on Two Carcinogens Reported to Subconar.ittoe by :.r*Sii. Occupational Safety * Health Reporter, 7 (35): 1 331 , 1978. * (184i Johns, R. Air Pollution Assessment of Ethylene Dichloride. '..tional.lactankcal Information Service!No.iPB*256 1733, 19,76. 152 HONS 022228 Ethylene Glycol Although ethylene glycol (1,2-ethanediol) has been reported to give neoplastic effects at 4 g/kg on mouse skin [6], no other confirming reports of carcinogenicity or mutagenicity have`been round. Many reports indicate that ethylene glycol is noncerclnenenic in different species by various routes of administration. These include 18 tests reported in 8 articles before 1950 on rats, mice, and rabbits in food, drinking water, intravenously, c-".rcutaneously, intermuscularly, and via inhalation - all with relative results (26). More recently, tests have been negative for ethylene glycol (1851 luding subcutaneous rat te9ts (186), subcutaneous newborn mice rests (187), and inhalation tests using rat, guinea pig, rabbit, and monkey { 1 3 ) . :t is also negative in the : -on/? I l -i : mutagens .'.2, 52). All in all, ethylene glycol will be i .icred a r.oneai c: nuger. for this project. . , iiom.bur.ier . : . i: emo scnicity of Several Compounds. National " .-chr.: e j i in'orratton Service ho. Pfl 183 027 , .363. > rp. s*<) v3SOni vt v. Tcxicr.'.ocy and Careinoqenosis of Various Chemicals 'Csed m the Preparation of Vaccines. National Technical Information Service No. ?B 1^5 135, 1969. 55 pp. 137) Derse, P. H. Injection of Newborn Mice with Seven Chemical Adjuvants to Help Determine Their Safety. National Tech nical Information Service No. PB 195 153, 1969. 135 pp. (.38) Coon, R., et al. Animal Inhalation Studies on Ammonia, Ethylene Glycol, Formaldehyde. Dimethylanine, and Ethanol. Toxicol. Appl. Pharmacol., 16 (J):64 5-646, 1970. 153 HONS 022229 Ethylene Oxide Ethylene oxld#' (oxirana. 1,2-epoxyethane; CAS No. 75-21-8) hat *vin found negative on skin-painted nice and subcutaneously in- oii rats (189). Short-tern inhalation tests (6 months) on i ; ;s, mice, rats, rabbits, guinea pigs, and monkeys were nega .39]. An excess of tumors was found in mice exposed to oxide-treated ground-corncob bedding as an experiment ned to test for carcinogenicity of ethylene oxide (1891. . oxide is a mutagen in 5. typhinuriu-, "c:<roor.''ra ?raa^^ . -rs.-vr tests [ 32, 189). It will be considi : . .1 possible carcinogen for this project based on the - iiaccnicity data. . : or. ana Persistence ::na*.od that 1.5 x 10 kc ethylene oxide is emitted per 1 . .n stationary sources (l). Other estimates of production . ; 1.3 x 10 * produced with 4.5 x 10"' kg released |44), . ' ku produced (6!, i.8 x 10* kg produced in 1974 (8), * k i produced in 1975 !!B9), and 1.8 x 10 kg and . * k : produced in 1974 and 1975 (32). Its primary use . -.tii r.-.-J la tc is <cted to grow at 4. 7-5.2'* per year > : 5:;. : >: s m the atmosphere, ''pcxidcs would Ly Hr* r id :.?al> witr. a 3- to 11-hour half-life |8|. t 1 with :: radical:- has also boor, estimated to 'live - >: i. 0 day a :44; mi 23 hours |3|. It has a boil in-: urc of 1,09 5 . 20-C ( >3| . 15'**, IARC Monographs: Evaluation of the Carcinogenic Risk of Chainicals^o Man.iVolume.11, 1976. pp.. 157-16.7. 154 MQNS 022230 Ethylenlmine Ethyleniraine (Aziridine, CAS No. 151-56-4) is well documented as ceing a potent mutagen, and it is used as a mutagen in many plant studies (533 references on TOXLINE to its use as a mutagen or carcinogen). It has also been found to be carcinogenic in at least two strains of mice following oral administration, produc ing ' iver-coll and pulmonary tumors (1901. Subcutaneous injection of ' dotes in suckling mice produced increased incidence of lung tumors in males. Subcutaneous injection in oil produced local tumors in rats (190). It is considered a probable carcin ogen for this project. Production and Persistence It is estimated that 2.7 x 10" kg is released to the environment per year (44). Estimates of production are 2.3 x 10 kg, 1.4 >: 10 kg, 2.2 x 10* kg (1974), and 2.3 x 10 kg per year (6, c, 32, !4'. Ethylenimine is infinitely soluble in water (6), basic, and polar, and could therefore be expected to be very siov to escape from water to the atmosphere |8|. Its reaction w 11 ;;o :n the atmosphere has been found to have a half-life of 1 . 5 lays (44), 47 hours (8), and 56 hours |8J. It has a boiling ;c-i; of and a vapor pressure of 160 mm at 20CC (1901 . (190) IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals ,to Man, Volume 9, 1976. pp. 37-46. 155 MQNS 022231 Pluorantheno Fluoranthene (CAS No. 206-44-0) was tested for carcinogenicity In 1935 and 1938 on mice by skin (0.31 in benzene for 501 days) and oral (10 mg for 18 months) routes of administration with negative results (51. Arcos and Argus reported in 1974 that in '.96 3 or 1964 others had found fluoranthene negative by subcuta neous tests in XVII nc/Z strain of mice (191); fluoranthene is :enernl)y considered noncarcinogenic (191). Recent tests of ousc skin application, alone or followed by croton oil, were jgative after 15 months and 20 weeks, respectively (192). It i.as bc`.'n tested on TA98, 100 ar.d 1537 strains of 5. rr,'hi-,riufor rutagenic i ty (193). It is considered a probable noncarcir.ouor, (or this pro]ect. 'I Arcos, J. c.. <jnd f. Chemical Induction o: Cancer, Volume' 11A. Academic i'rcss. New York, 1974 FP- 26, 237. MCI Hoffman, D., et al. j. N.nl. Cancer Inst., 49:1165-1175, 197 J. (193, Rao, T. K., et al. Environmental Mutagenesis of Energyl)alat*d .Effluents. Genetics, 83;S60, 1976. 1 56 HONS 022232 Formaldehyde formaldehyde (methanal,-formalin, methyl aldehyde; CAS No. 50-00-0) has been tested for carcinogenicity with n nny animal species in short-term (usually less than a year) tests (5). However, 1,300 mq/kq (05 weeks) caused neoplastic effects in rats ' [6), and 1 ml of 0.4% formaldehyde solution caused spindle cell sarcomas and fibrosarcomas at the injection site of 4/10 rats evaluated at least 649 days (194}. Formaldehyde has been shown r.o be a mutagen in Drotophi'.a -e.'j^ogaater, S. aoli, barley, Yicia iba, yeast, and viral transformation enhancement tests (4, 44, and personal communication with B. C. Casto on 9 February 1978), hut negative on the mouse dominant Lethal test (30]. For this rojcct formaldehyde will bo considered a possible carcinogen. ..eduction and Persistence : . is eutimated that 4.1 x 10'' kg formaldehyde is emtt-'i per year from stationary sources with 82* cf this being from charcoal :;'.i f jc . uro and catalytic cracking in petroleum refining |1). '.her estimates of production include 2.6 x 10* kg produced and 2.; x kg released (C-J, 2.6 x 10* kg produced and 6.4 x 10T kg r-.'lease.i [44), 2.6 x 10* kg produced (197 4) (8], and 2.9 x 10* kg and 2.6 x 10* kg produced in 1973 and 1976 [32]. The production formaldehyde is projected to grow by 4-53 per year m the next r- /'urs ! 121 . In solution it is essentially nonvolatile, but in ;r it '.ill rejet with HO radical with a half-life of 2.6 hours a) or ..2 hours 144). As a gas it has a boiling point of -21C tnd a v i: or pressure of 1,946 mr. at 25C [4>) . Its environmental fate an: biological and environmental effects have beer, studied it! . 1194) Watanabe, F., et al. Gann, 45:451-452, 1954 (as cited in Reference 5). 1195) Investigation of Selected Potential Environmental Contami nants: Formaldehyde. National Technical Information Service No. PB 256 839, 1976. 157 HONS 022^33 Cuthion Guthioityhas been found to be mutagenic in that it induced chromo some breaks in diploid (WI-38 (female embryonic lung)] and hetero- ploid ]S8p-i (male neoplastic larynx)] cells (196]. Guthion also increased mitotic recombination in S. cara-jiaiaa (169} . However, it did not prove to be a mutagen in 5- typhimuriun assays (1691 or in . or S. aubtilie systems (169) and did not induce dominant lethal effects in nice 1197}. For this project it is considered a noncarcinogen. -------------------------------------rf 196J Alam, M. 7., 'and S. 5. Kasatiya. Cytological Organic Phosphate Pesticide on Hunan Cells . snet. Cytol., 18(4);665-671, 1976. Effects C 1197] Jorgenson, T. A., et al. -r Mutagenesis Investiga tions of Ten Commercial pesticides. Toxicol. Appl. Hleriacol,., t37(ljtl09. 1976. 158 HONS 022234 Heptachlor The IARC monograph on heptachlor (heptachloro-tetrahydronethanoindene, CAS No. 76-44-8) shows this compound to have both poaitivo and negative data, with more negative tnan positive (198). It is a mutagen as tested by the enhancement of viral transformation (personal communication with B. C. Casto on 9 February 1978). Recent NCI testa (199) with rats and mice demonstrated that heptachlor is a carcinogen for the liver in rice under the conditions of their bioassay. It is considered a probable carcinogen for this project. Production and Persistence It is estimated that 1.1 ; 10" kg heptachlor is emitted per year from stationary sources (1). Estimates of production include 2.7 x 10* kg (1971) and 2.7 x 10* kg produced t r f. it has a .-v l ting ooint of 95C ar..i a vapor pressure o: ) 10 " m ,u 2" >; (193). ' 1198) IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5, 1974. ?P- 173-191. (199) Bioassay of Heptachlor for Possible Carcinogenicity, CAS No. 76-55-8. National Technical Information Service No. PB 27U 967. 159 HONS 022235 Hexachlorobenzene Hexachlorobenzene (benzene hexachlorida, CAS No. 118-74-1) induces microsomal enzymes (129), is only slightly teratogenic [200|, and teats positivsr/negative f 301 and negative (200) on the dominant lethal teat in rata. When fed to rats it was noncarcinogenic (201), and by S. tv;hirurium tests (using mouse liver microsomea) it was negative (1721. Hexachlorobenzene was, however, mutagenic when tested with 5. ceraviiiae at 100 ppm 1202) , and when fed to 6-week-old Syrian golden hamsters at concentrations up to 200 ppm it induced hepatomas, hemangiomas and thyroid adenomas in a dose response manner 1201). It is therefore considered a possible carcinogen for thin project. Production and Persistence It has t>, 2 days in the air, reacting with OH to form pontachiorophcnol. Its production is estimated to be 6 x 10' kq per year, and 1.3 x 10' V.is used in a dispersive manner as a fungi cide for a total of 2.2 >: 10' : released I "! . It has a boiling :oint of 312-326C 1311. ! 2 0 0 | Xhora, K. S. :h-:<aeh Loro! onzotie: Tcratocenielty ant! Domi nant Lethal St utiles in i*..its. Toxicol . Arpl . Pnarmacol . , .'''(11: 109, 1974 . |2011 3cyland, ?.., et al. Kidney Tumors in Rats Following Ireat,-ent with 2-,\cetylon;:io: luorene. Tryptophan, and 14-Sacchar- olactone and the Failure of Substances Which Cause Porphyrinuria to lgduce Tumors. In: British Empire Cancer Campaign 1963 - PaVt 2: Scientific Report, 1963. pp. 58-59. (202) Guerzoni, M. E., et al. Mutagenic Activity of Pesticides. Riv. Sci. Tecnol. Alimenti Nutr. lira. (Ital.), 6 (3) : 161-165, 1976. 1203J Cabral, J. R. P., et al. Carcinogenic Activity of Hexachlorobenzena m Hamsters. Nature* 264(5628):510-511, 1977. 16C MONS 022236 Hexachlorobutadiene Hexachlorobutadiene injected I.P. in mice apparently caused no lung adenomas [204]. A study with rats on diets containing hexa- ch lorobutadiene showed no effects at 0.2 mg/kg/day or less, but renal tubular adenomas and adenocarcinomas at 2 and 20 mg/kg/day 1205, 206). A reproduction study also showed no effects at 0.2 but effects at 20 mg/kg/day. At the high doses some toxicity was also evident. A 90-day feeding study (0.3-30 ppm) on Japanese ;uail showed little effect of this chemical [207]. NIOSH has a safety alert out on the basis of the above tests, and hexachlorouutadiene is considered a possible carcinogen for this study. production and Persistence It is estimated that 3.6 x 10 kg is produced in the United States . th 3.3 x 10* kg being released per year |7|. It reacts with ;! aru i), with a t'^ of less than 1 day and has a luw water solu bility 17). The boiling point of hcxachlorobutadlene is 210*C > . th a vapor pressure of 22 r~ at 100*C (33). J0 :! Test for Care ir.ogenicl ty of Oruamc Contain rants ot '.'rsitcd States Drinking Waters by Pulmonary Tumor Response in a Strain of Mice. Cancer Res., 37 (8): 2717-2720, 1977. ; T-p: Results of a Two-year Chronic Toxicity study with Hcxachlorobutadier.e in Rats (Meeting Abstract). Toxicol. A?pl. Pharmacol., 4^1): 204, 1977. ; 1C61 Xociba, R. J.', et al. Results of a Two-Year Chronic Toxi city Study with Hexachlorobutadiene in Rats fxTH Ind. Cyd. Assoc. J., 38(11)1589-602, 1977. 1207] Reproduction Study in Japanese Quail Ted Hexachlorcbutadiene for 90 days. Toxicol. Appl. Pharmacol., 30(21:255265. 1974 161 HONS 022237 Hexamethylenetetramine Hexamethylenetetramine (CAS No. 100-97-0) has been extensively tested in both rats and mice (51. Almost all of these tests show that this chemical is noncarcinogenic when given either orally !up to St of drinking water) or subcutaneously (25 g/kg) [208J. It has been tested on r. joli differential growth (pol A) test with positive results which was considered a false positive (46). ! t has also been reported to be nonmutagenic to posi tive in oral mouse dominant lethal test, negative in an intra- pcritoneal mouse dominant lethal test, and positive on a chromo somal abberation test in cultured lymphocytes [32], Hexamethy- 1 or etramine will be considered a noncarcinogen (with some : os: t.ive data1 for this project because of the extensive negative ir.jl data. 12081 Della Porta, G., et al. Non-Carcinogenicity of Hexamethylenetetrarine in Mice and Rats. Food Cosmet. Toxicol., 162 MONS 022238 Hydrazine Hydrazine-(diamine, CAS No. 302-01-2) haa been ahovn to be car cinogenic in nice after oral and intraperltoneal adniniatratlon and in rata following oral adniniatratlon (209). It was negative in hamatera after oral adniniatratlon (2091. Hydrazine ia con sidered a probable carcinogen for this project. Production ard Persistence It is estimated that 3.5 x 10* kg hydrazine is emitted per year (1). In 1966, production of hydrzine was 7 x 10* kg per year with more than 70t of this going toward rocket fuels {2091. Pro duction waa estimated at 1.4 x 10* kg in 1971 and at 1.7 x 10' kg sn 1974 {8, 32). The demand for hydrazine is expected to increase 13-17* a year until 1985 [32|. Hydrzine is polar, nonvolatile and water soluble, suggesting that it will not transfer to the atmosphere at significant rates 181. Oxidation by HO radirals m the gas phase is reported to be rapid with a half-life of less ran 1 hour [81. It has a boiling point of 113#C and a vapor ; ressure of 16 rm at 20*C (331. (2091 IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 5,. 1974. pp. 127-U6. 163 MQNS 022239 Hydroqulnone Hydroquinone is listed on the N10SK Suspected Carcinogen List, but it is apparently there by mistake. The 1955 reference cited [210] shows 20 mg of hydroquinone applied to the skin of mice (in benzene) developed only 1 tumor out of 22 surviving mice as compared with 1 tumor out of 22 surviving mice for the croton oil control. A more recent reference cites hydroquinone as a bladder carcinogen when implanted in cholesterol pellets, producing 323 tumors vs 121 for the cholesterol control (211]. Hydroquinone is said to be an inhibitor of 3,4-benzopyrene carcinogenesis (2121, inactive as a promoter [2131, and slightly active as a promoter (214J of carcinogenesis. Hydroquinone has been reported as more toxic to repair deficient : (pol A*) indicating that it may induce DNA damage (321, but negative in inducing antibiotic resistance in -r: pyrogens |32|. Chromosome aberrations have boon noted in severil plant systems after treatment with hydroquinonc 1321. These muta genic references almost place hydroquinone on the possible carcin ogen list, but they involve test systems which have not been extensively evaluated. Hydroquinone will he considered a : roi ncr.carci nogen (with some significant positive data) for this project. [2101 Roc, T. J. C., and M. H. Sal ana:-.. further Studies on Inoo.-clete Carcinogenesis. Dritish .1. of Cancer, 9: 1 77-20 ), 1935. [211) Boy land, E., ot al. Further experiments on Implantation >: Materials into the Urinary Bladder of Mice. British J. >: Cancer. 18:575-581, 1964. (2121 Van Duuren, B. L., and B. M. ColJschmidt. Cocarcinogenio and Tumor-Bjromoting Agents ir. Tebacco. J. Natl. Cancer Inst., 56 >'1237-1242, 1976. 1213] Heeht, S. S., et al. Study of Tobacco Carcinogenesis; XIII: Tumor-Promoting Subfractions of the Weakly Acidic Fraction. J, Natl. Cancer Inst., 55(6):1329--1336, 1975. [214] Interaction Between Hydroquinone and Cigarette Smoke Con densate in Short-Term Skin Tests fer Carcinogenicity. ffOXLINEw 164 MQNS 022240 Kelthane Kelthane ha been'found nonmutagenic to E. eoli bacteria in the WP2 TYR to prototrophy test [1391. It is considered a probable noncarcinogen for this project. 165 MONS 022241 Malathion Malathion has been demonstrated not to be a teratogen {1341, and Ames et al. consider it not to bo a mutagen 152). It has been found to be nonautagenic in four test systems [18), and a study by the National Cancer Institute found it to be noncarcinogenic to rats and noncarcinogenic to mice [215]. Malathion was found norvmutagenic by a dominant lethal test in mice (197) but was a slight promoter in rats when given with dimethylbenz(a)anthra cene (216). Tor this project Malathion is classed as a probable noncarcinogen. -----------------------------------rr--i4 1215) National Cancer Institute Draft Fumr-aries of Bioass.v. Reportsi Chen. Reg. Rop., 1145>: 1602-1603, 1978. 12161 Silnskas, K. 'C., and A. B. 0!ey. Protection by DDT Against Mansury Tumors and Leukemia During Prolonged Feed ing of 7,12-Dinethylbenz(a)anthracene to Female Rats. J. NatL.eanaee.Jnst., 55(31:653-658, 1975. 166 HONS 022242 Maleic Anhydride Only one 1963 reference cites maleic anhydride as a carcinogen (217}. In this paper three rats of an unspecified species were injected SSO times with maleic anhydride. Two of the three rats developed fibrosarcomas at the injection site. No other indica tions could be found in the literature suggesting that maleic anhydride may be a mutagen or a carcinogen in any test systems. In the atmosphere maleic anhydride could be expected to be con verted rather rapidly to maleic acid 'or which r.o evidence has been found to suggest it has any carcinogenic or mutagenic potential. Since naleic anhydride has some degree of toxicity and is a lacrimator, animal studies will probably show it to be a r.or.carci nogen. (217} Dickens, F., and H. E. H. Jones. Further Studies on the Carcinogenic and Growth-Inhibitory Activity of Lactones and Related.Substances^ Brit4 J>* Cancer, 17:100-108, 1963. 67 HONS 022243 Morcaptobenzothiazole Mercaptobcnzothiazole (2-benzothiazolcthiol, Captax; CAS No. 149-30-4) was one of the 80 chemicals evaluated as having the greatest potential for environmental effects (7]f This report cited a negative mice feeding study (77) in which two groups of 36 mice of slightly different strains were given 464 mg/kg raercaptobenzothlazole in gelatin orally on days 7-28 and then 1,492 ppm in their diet for 17 months with no increase in tumors found. Seventeen months is a little on the short side for carcinogen evaluation by present standards. In another study (69) mercaptobcnzothiazole was given orally and subcutaneously at 100 and 215 mg/kg, respectively, to two mouse strains (36 mice per strain). It was found to cause a statis- tistically significant (0.01 level)'increase in type A reticulum cell sarcomas when given subcutaneously. It may have been tested for mutagenicity (218) and teratouenic activity, but tne results are unclear (219). Dccause of the limited tests thus far con ducted, more ` or ' d ita ni it; change its classifi cation but it will be considered a possible carcinogen for this ; ro : no t . ' ' rodin;i and J vr s i stcr.ce The production of rorcattobenzeth ..i:r le is estimated at 2.7 x l"* i : > r year with the release of .'.7 >; lO* V. ; per year (7). : v .s relative towards R'l (t - 8 iay-; , (in 1 day), and m, it. - 9 . ( h r ) ('; . 4 The : . - . . r.utaccnicity test h.is recently been con iueted on r.orcaptobonzothiazole with r.eut/.v results (personal commoni- c.ition with Paul firaham, Monsanto > rnany, on 26 January 197 )) . This information would most likely hav" changed the classifica tion given to mercaptobenzoth i ar.o lto probable noncarc i nogt :i uy the criteria used in this rcg>ort. i218] Evaluation of Carcinogenic, T.-i atogemc, and Mutagenic Activities of Selected Pesticides jnd Industrial Chemicals, Volume III. National Technical Information Service No. PB 223 161, 1968. (219) Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and Industrial Chemicals, Volume II. National Technical Information Service so. PB 1223 160. 1968. 168 MONS 022244 Methyl Bromide Methyl bromide has been tested on barley and is said to be a methylating compound [220]. No other references were found on the mutagenic or carcinogenic potential of methyl bromide, so it has been placed on the probable noncarcinogen list. [220) Ehrenberg, L., et el. On the Reaction Kinetics and Muta genic Activity of Methylating and fleta-llalogenoethylating Gasoline Additives., Radiat. Bot., 14(3):185-194, 1974 . 169 MONS 022245 Methyl Chloride No data have been found indicating that nethyl chloride (chlorotoe thane, CAS No. 74-87-3) is a carcinogen (e.g., TOXLINE, CANCER LINE, and Reference S). However, it does appear to be a mutagen to S. typhimuriui 114} . Because of the close correlation between mutagens and carcinogens, methyl chloride has been placed on the possible carcinogen list. Production and Persistence It is estimated that 2.3 x 10T kg methyl chloride is emitted per year from stationary sources [II. Another estimate (4 4 J is 7.6 x 10* kg/year released from a production of 2.1 x 10* kg. Other production estimates are 2.1 x 10* kg, and 2.2 x 10* kg, 1.6 x 10* kg and 1.7 x 10* kg produced in 1974, 1975, and 1976, with a projected growth of S' per year [6, 12]. Reaction in tho atmosphere with the IIO radical is slow, with a half-life : about 1 vear [44). It takes 27 minutes for 50' of a L-ppn water solu tion to evaporate at 25C I'll. Methyl chlori.V has a boiling point of -24C and a vapor pressure of 1,900 rj- ' a*.ml at 20'C mri 2,150 mm (2.93 atm' at 25V 31]. 170 0 ZZ^b Methyl Ethyl Ketone Methyl ethyl} ketone (MEK, 2-butanone) is included on the NIOSH Suspected Carcinogen List because of a teratogenic reference and as a priority pollutant. MEK does appear to be embryotoxic, f*to- toxic, and perhaps teratogenic when tested at high concentrations (1,000-3,000 ppm) [ISO, 221). Rat feeding studies conducted in 1939 and 1940 were negative (222, 223). Mouse skin application tests in 1965 of mixtures containing MEK were generally negative it. the absence of benzo(a)pyrene [224J. MEK has also been tested on TA 1535, 1536, 1537, and 1538 strains of -H i - bacte ria (Ames Test) and on WP2-try mutagen tests with both being negative (157). No other references cculd be found on TOX- l.INE or CANCERLINE indicating that MEK is a mutagen or a carcino gen. It is considered a probable noncaremooen for r h: s project. .'.11. i.rt-ryc Toxicity and T . : c i t . o: (:.h 11 chloride, I,I-Dichloroothano, and Methyl Ethyl Hats. Toxicol, /yppi. Phjrracol . , 29il.:U5, 1*'4. J.'J, Nakahara, W. , and K. Mori. ?rcc. Imp. Acad., da; a: , 15:278-281, 1939 (as cited in Reference 5). i 223] Nakahara, W.,and K. Mon. Cann, 34:143-145, 1940 (as cited in Reference 5). ' (224) Norton, A. W., et al. Cancer Research, 25:1759-1763, 1965 (as cited ia itfierna ) . 1)71 MONS 022247 Methyl Methacrylate Methyl methacrylate is on the NIOSH Suspected Carcinogen List because of a paper which shows that C.25 mg/kg of the compound (1/5 LDo) caused 8% of the rat fetuses to have gross abnormal ities (hemangiomas) but no skeletal malformation (225). A search of the literature could find no other references irdicating methyl methacrylate to be a mutagen or a carcinogen. rt is therefore listed as a probable noncarcinogen for this project. (225] Singh, A. R., et al. Erabryonic-Fetal Toxicity and Tera togenic Effects of a Group of Methacrylate Esters in Rats, j. Dental Research, 51:1632-1638, 1972. 17,2 MONS 022248 4^4*-Methylene Big(2-chloroanillne) 4,4'-Methylene bis(2-chloroaniline) or MOCA (CAS No. 101-14-4) has been found to be^a carcinooen In mica and rat* after oral administration and produces distant tumors in the rat after sub cutaneous administration (226). It is an OSHA regulated carcino gen [227). Many other positive references are found in TOXLINE and CANCERLINE and it is considered a probable carcinogen for this project. Production and Persistence It is estimated that 4.5 x 10" kg is emitted per year from a 3 x 10* kg production (56). Other estimates of production arc 1.5-2.5 x 10* kg in 1970 [226) and 3.5 x 10* kg in 1972 16, 8, 226] . The reaction with the HO radical in the atmosphere is estimated to yield a half-life of 12 hours [8] or 1 day |56|, while the o3 half-life is 1 day [56] and the ROa half-life is 39 days [56]. It is said to have a melting point of 1,.0'C i 2 26) and a negligible vapor pressure (6). (226) IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 4, 1974. pp. 65-71. (227) OSHA Compliance Guide, 29 CFR Part 1910, 1978. 173 MONS 022249 Methylene-Chloride There ere no positive date on methylene chloride (dichloromethane) in TOYLINE or CANCERLINE. Interim results of carcinogenic tests in a 2-year inhalation study involving nearly 2,000 animals ex posed to concentrations of methylene chloride as high as 3,S00 ppm were negative (228). One recent paper cites methylene chloride as being positive in the Ames test 12291. Methylene chloride is still considered a noncarcinogen for this project until further testing is completed because of the negative NCI animal data. (228) Methylene Chloride Passes Early Tests, chem. Eng. News. 55 (19):6, 1977. 1229) Mutation Research, Volume 53, January 1978. *174 HONS 022250 Methylenedlaniline The IARgjjabnooreph (230) on reethylenedianiline |4,4-diaminodiphenyl methane* bis (n-aminophenyl(methane; CAS No. 101-77-9) indicates both'positive and negative data have been obtained ' from animal testing of the compound. Given orally to rats, it was found to be noncarcinogenic. Kethylenedianiline is on the niosh safety alert list because of some significant positive results (231, 232) and it can at least be considered a possible carcinogen for this project. Production and Persistence It : s estimated that 2.6 x 10" kg is emitted per year from sta tionary sources II). The production has been estimated to be 5 10* kg, 7 x 10' . .., and 1 >: 10 in 19*5, 1966, and 1972 It has a -e'.tim: m.mt 'f 91"C am! i boiling point of : t it n m ; u;. ' ' ;: . :, IARC Monographs: Kvalua: im tr. C.ircir.uoer.iO Pi<'i Chemicals to Mar.. Vc. ...t.o 4, .974. pp. 79-H5. Schoental, R. Cafirfc:r.oger:c and Chronic Effects cf 4,4`Diaainodipher.ylmethano, ar. Eooxvrosir, Hardener. Nature, 219:1162-1163. 196S. (232) SteinhOff, D., and E. Grundmann. Zur Cancerogenen Wirkung von 4,4'-Diamnodiphenylnethar. und 2,4*-Diaminodiphenyletban. . Naturwisser.schaften, 57:247-248, 1970. 175 MOWS 022251 Methylstyrene One reference cited in the NIOSH Suspected Carcinogen List shows methylstyrene to be a teratogen [233). Permissible exposure: limits have been determined for methylstyrene [234). Application of methylstyrene to rabbit [235| inhalation or rat skin (235, 236] demonstrated only a reversible [236) irritating response to the chemical. Other toxic responses have been noted in rats, rabbits [237], and housefly larvae [238], but no indication of carcinogen or mutagenic responses were found on TOXLINE or CANCERLINE. ' .a : l:ar. ::a a;-. i t-i t ic: . ') >'<. i:. (:y;iene >::c .-utstancos: Pro:. 'ecu pa t: or.a ! .vifoty and health t.mdards for Alkyi LVr.zones, Cyclohexane, Ketones, and tone . Mod. Reaist. 4 2 . : : 4 7jr ;-47 l 3 , 10?;. : foci o f Ah ha-Me*. :v . \ tore .r.i! TVrt-Codery1 Mercaptan on :.e <-.ir. ,'f Ar.im.ils. W: . 7`r. Pro:;.i:'o; . , Mater. r.:ch. r-rt.: 1972. 247-24-. ! =-'vors :t le Damage to tr.e Sk i n of experimental Animals Suboete.l to the Inhalation of 3utadienc and Alpha-M.ethy 1styre.-.e. Mater, liauch. .-css., Pnsoyashck. 50-Letiyu Obrazov. 55SR, Oqfsk. Gas. Med. Inst.; 19 72. pp. 87 1 -873. .237; l.ffecc of Isopropylbenzene and Alpha-Methylstyrene on Leucopoiesis. Parmakol. Toksikol., 35(41:491-492, 1972 . [238] Effect of the Wastes from Phenol Production on Housefly' Larvas. Mater. Konf. Molodvkh. I'ch. Stud., Posvyashch. 50-Letiyu SSSR; 1973. pp. 375-377. 176 HONS 022252 Morpholine Morpholine (diethyleneinide oxide, tetrahydro-1,4-isoxazine; CAS No. 110-91^8) *'i cited in one reference as causing neoplastic effects in the mouse after oral administration of 6.33 g/kg over 28 weeks (6). This refers to a study (with no control animals) in which 40 Swiss mice (20M, 20F) were given neutralized morpho line in their food 1239]. After 40 weeks, 5 malignant lymphomas and 5 lung adenomas were found in the surviving 38 animals. (When given in combination with sodium nitrite, many more tumors were found.) Tn another study, 100 g/kg morpholine as 0.53 of the diet for rats produced no tumors, but 0.5' sodium nitrite added gave 7 tumors (."'40| . Many other studies hive been conducted with sodium r.i trite added to produce nitrosomor; ho 1ino ' ar.ri . ` i'issinn studies, morpholine in i i r in 0.003-0.07 r.;M urm- ontrations for 4 months caused rutiu-rnc chromosomal ab- rrattons :\ tone marrow cells in rats (341) and guinea pigs [ 24 2]. Th_ 'iture classification of morpholine requires more data, but for hi? project it will be considered a lossiblo carcinogen. :: duct i or. and Persistence fi- mated that 1 >: IT . it. - td ;or year 16'. and >: 10' : : is J ' ' ] Clreenblatt, V., ot .ll. . '.at I. dancer Inst., 4 6 ( t>) : 1 ` 9 -- Icii, 1971 (as cited in Reference 5'-. .'1 ! dander, J., and C. ilunklo. 2. : obs forsch, 7 3:1 ) 1 54-66, 1969. .4;| Tomenko, V. N., and E. i-, strekalova. Mutagenic Action of Some Industrial Poisons as a Function of Concentration and exposure Time. Toicsiko!. Nov. Prom. Khin. Veshehestv., 13:51-57, 1973 (CA 79:143228). 1242] Migukina,' N. V. Evaluation of the Danger of Morpholine During Chronic Action. Toksikol. Kov. Prom. Khim. Veshe hestv., 13:92-100, 1973 (CA 79:143345). vi HONS 022253 Naohtha Naphtha {coal tar naphtha) is cited in Reference 6 as a recognized carcinogen. Actually, naphthas vary in coaposition depending on their source, with coal tar naphtha being mainly benzene and its honologs. From other sources naphtha could be principally paraf fins, methanol and acetone, or gasoline. Even as a mixture naphtha is not found in Reference 5. Of the primary ingredients of naphtha, only benzene is a recognized carcinogen, and since benzene is covered separately, naphtha will be dropped from consideration. 178 HONS 022254 l-W&phthylamine l-Naphthylamine (alpha-naphthylamine, CAS No. 134-32-7) no car cinogenic effect when given orally to hams tors, and both oral and subcutaneous tests with mice gave inconclusive results (243). In dogs, it was demonstrated that 1-naphthylami.no, if carcino genic at all. was less so than the 2-isomer ( 24 3|. r.rhor tests cn legs (26). hamsters, mice, rats, and rabbits ,'1121 show that ; -:\ '.phthyl amine may be carcinogenic and that it is generally nr.o.t anmaced with the 2-isomer, which is a potent carcinogen , 4 ' , 244). It is an OSH.N reg-.i 1t ed carcinogen Code o: Federal Re 7.. 1 at ions 29 CFR 1910.1 004) whether or rot it is truly a car cinogen '244 1. It is j 1 so pcs it.1, c on the . - 4 - tut ''2 and or. at enhancement o: v : r a 1 t mans format ion test (nets -tj 1 .re-: if.cat lor. with !>. C. Cast- or. ubruary 1* 7 g i . v r these It is considered a : s .. : . i rc : r. ' :nr h : s tr 'ntt. . t; or. it : her s : ster.ee i. : ; ".as been ;: : - i* : V : :: 1 9 74 : - : . : tnos: here [0) ir. ! : i?ts 34 IARC "cr.ograpr.s: Kva 1 .m: of * 'Carc c Fise : Chomcals to Man, Volume 4 , 1 9 74 . pc. 8'-96. .'4; msi-A liar.ee Ju:;ie, 29 .; ' I'art i?10, 1004, 19.8. : u. 298-300. 179 MONS 0Z2&5 Naphthalene Naphthalene (CAS No. 91-20-3) has generally been negative when given to rats and aic* by various routes of administration (including 10 g total oral* dose ovir''33 months') Wifh only a few tumors reported by other authors in experiments without control animals (51. rt is generally considered to be a noncarcinogen by various authors (2451 . It has been tested in G46 S. typhC-ur^u- and K-12 T. : strains (246). Another reference reports nega tive results for r .phiruriu-. strains TA 98, 100, 1535 and 1537 f52|. Naphthalene is considered a probable noncarcinogen for this project. Arcos, 'and >!. K. Ar:.:s. Chemical Induct ior. >:' C.r..- eor, v.':-.:r.e 11A. Academe Tress. New York, 1 974. . 1 '4 ;j7. a:-..! 278. ( 2461 Kracocr, M.. et al. and r. n:- to Detect Chemical Mutagens. Naunyn-Schmodebergs Arch. Phar.nakol .. 284 ; 4-. ;, 1974. 180 HONS 022256 Naphthoquinone Naphthoquinone is on the NIOSH Suspected Carcinogen List because of a 1940 Japanese reference (621. In this paper a-naphthoquinone (in benzene) painted daily on the backs of mice caused*3/77 skin cancers and 11/77 papillomas compared to 0/46 skin cancers and i/46 papillomas for benzene alone on mice surviving 200 days. .-Naphthoquinone produced no cancers or papillomas out of 25 mice surviving 200 days. A survey of recent literature from TOXLINE. CANCERLINE, and Refer ence 5 found no pertinent references. Since the only positive reference is outdated and reports the use of benzene as the sol vent, naphthoquinone is being placed on the probable noncarcincen \\3t for this project. 181 MGNS 022257 1-Naphthyl*)fethylgafrl?afaitfg The primary reference to this compound's carcinogenic potential from a Russian journal has not been obtained. Another Russian reference from the same year (247J declares that 2-naphthyl methyIcarbamate is carcinogenic while 1-naphthyl methylcarbamate is noncarcinogenic. 1-Naphthyl methyIcarbamate tested on male and female mice of two strains was found to be noncarcinogenic (69!. No other references were found in CANCERLINE to indicate that this chemical is a carcinogen. There are negative mice feeding studies (18 months) and rat intergastric studies reported [5|. It is probably a noncarcinogen based on the available literature. |247] Zabezhinskiy, M. A. Investigations on Possible Carcino genic Effects of Beta-Sevin. Vopr. Onkol., 16 (11):106-107, 1970. 1S2 MONS 022258 Nitrobenzene Although on structural basis nitrobenzene (CAS No. 98-95-3) has been predicted to be'a carcinogen, there was no positive indica tion from actual teats of the chemical cited in "Air Pollution Assessment of Nitrobenzene* [ 248) or or. CANCERLINE or TOXLINE. It has been reported to induce sex-linked recessive lethal muta tions in ?roothila mtla<-.o^aa ter when administered as a vapor for 8-10 Jays 132). With only one i*: \>itrr' positive test reported, nitrobenzene will be considered a noncarcinoqen (with some posi tive data) for this project. Corigan, J.f and J. Hushon. Air Pollution Assessment of :;itrobenzene. National Technical information Service No. P3 257 776, May 1976. 183 MQNS 022259 Nltrophenol So data on the carcinogenicity of nitrophenols could be found on CANCERLINE or TOXLINE, but p-nitrophenol hae been found to be mutagenic by one teat system and nonmutagenic by five other test systurns (18). When comparing 5. tapin'nurzurf teat results with other systems, Ames classified nitrophenol as a nonmutagen (52). Fcr this project, nitrophenols will be classed as probable non- ca r* r.O'Jens . *84 HONS 022260 Nltrosodlmethylamlna Tht;e axe many data showing nitrosodimethylamine (dimethylnitroso amine) to be a potent carcinogen (249). It has, therefore, been placed'on the probable carcinogen list for this project. In the final selection of carcinogens, however, it may not be advantage ous to select this compound. This is because nitrosodimethylamine rapidly decomposes in sunlight (250), under normal conditions is of no significance as an air pollutant (250), and has generally been found only in the air near certain manufacturing plants which had mow repaired) leaks in their systems (251). production and Persistence Nitrosodimethylamine is emitted in loss than 100-kg year guantitios from. the dimethylhydrazine stationary sources (1). One estimate.: of production is less than 450 kg/year (8). Photolysis of nirosndirethylamine is reported to be rapid with a half-life of less than hour (8). It has a boiling point of 152"C [331. in] :a>C Mn-.ngraphs: Evaluation of the Carcinogenic ms* of Chemicals to. Man, Volume 1 , 1972. pp. 95-106. ,25C; Brotschr.eider, K.. and J. Matz. Occurrence and Analysis of ::itrosaminea in Air. IARC Sci. Pub. No. 14, 1976. pp. 395 399. 251! fine, D. H., et al. N-Nitroso Compounds in'Air and Water. IARC Sci. Pub. No. 14, 1976. pp. 401-408. 185 MQNS 022261 Nltrochlordbenzenai Nitxochlorobenzene icftlorpnitrobenzene) has been found to mutate S' typhir.uriu* (252`T,tJM i*indicated as a carcinogen causing neoplasms i rr anotherTrfetnee' s summary * (Sect a while listed as not tested in an appendix to the same reference |6J. For this project it will be considered a possible carcinogen. Production ar.d Persistence It is st mated that 3 x 10* kg nitrochl.robv.nzene is omitted p.-r year zro- stationary sources [1J. An estimate of production is O.i 10' kg or each of the isomers produced in 1967 If.;. sitr - .rr.lti -oenzene reacts with oxidizino materials in the itmosphcrc i 6 i . In the soil, microflora decomposes this chemical in f>4 J.i . s ! 1) - and o-isomers have boiling points c. 2 1". 24.'. ana 4 "> V with a vapor pressure of 10 nm at 25 c 111) . 12521 Tardifi, R. G,, at al. Kalogena.ted Organics ir Tap Water: A Toxicological Jhfa&dation. ' Irt: The Environmental impact of Water Chlorination, National Technical Information Service \o. CQNF< 7SJ.Q96, 1976. pc. 213-228 . 1^6 HONS 02^^62 Parathion Nothing was found in CANCERLINE to indicate that parathion is a mutagen or carcinogen. The NIOSH Suspected Carcinogen List refer ence cites parathion as beltfg?' slight teratogen onlfr when given in sufficient nuantitiy as to cause toxic poiaioning to be appar ent in the daxs (134]. It has been found to be nonmutagenic by several different jitro tests {18], but does cause an anti mitotic action in cells [171]. It is therefore classified as a probable r.or.rir'inoqen for this project. 187 HONS 022263 Pentane Although n-pentane if cited as a carcinogen in one reterence (6J, no primarytreferenced could be found to substantiate this allega tion -.n 70XLT ><F, CANCERLINE, or Reference 5. It is said that aliphatic hydrocarbons may be cocarcinogens |4J. For this project pentane w.Il be considered a noncarcinogen. 188 MQNS 022264 Pentachlorophonol Pentachlorophenol (CAS Ho. 87-86-5) has been found negative in soae relatival/ short studies on rabbit skin and orally in rats and cats (26). Hore recently it has been found negative in two strains of mice both orally and subcutaneously [69]. Pentachlorophenol is also negative in 2>;,i.-;;Jsi 2a. tests (253J, in a host-mediated assay mediated assay in nice 1254], and in other ncrcbial systems 1152]. Some authors consider pentachlorophenol a <novn mutagen |2SS], and there are other positive as well as negative short-term tests tv i (18 j . It is also positive at the 100-,g level in the h r::t .r embryo adenovirus enchancement assay 'personal conununica : -r. *; th B. c. Casto on 17 February 1979). For these reasons, i-Morophenol will be considered a possible carcinogen for : irijec: for the first round rf evaluations. r rr:j- ion and Persistence n. :.-.ato cf predict : r. r. : s 2.1 1'' : 1969 capacity anti a c: .s . t ior. of 2.3 x 1 7 ' :: 1 ', . In the soil it doc ratios !y in -7 2 days 133'. It has a fcotlmo point of llO'C ar.d i . . or : : i.-ss iri.' of 1.1 ,291' .294; Vogel, and J. 1. K. Chandiv:. Mutagenicity Tost n: : of Cyclarute and Some Pesticides m ' : " . xper ier.t la, JO (6 >: 621-62 3, 1974 . ' "I* Buselmaier, W., etf al. Comparative investigations on the Mutagenicity of Pesticides ir. Mamalian Test Systems. Mutat. Res., 21(1)125-26, 1973. !25i| Daugherty, R. C., and K. Piotrowska. Screening by Negative Chemical Ionization Mass Spectrometry for Environmental Contamination with Toxic Residues: Application to Human. Crines. Proc. Natl. Acad. Sci., 73(6): 1777-1781, 1976. 189 HONS 022265 fffggbl phenol (hydroxybenzene, CAS No. 108-95-2) has been reported to 9ive rise to papillomas after administration on mouse skin (153, 256). Phenol has also been reported negative by injection and negative on the skin of mice[5J. It has recently been given in combination with other chemicals (5). In mutagenicity tests, phenol has been found to be mutagenic to Irceophila, revert . coli to streptomycin independence, and induce chromosome breakage in the root tip of Allium aipa while being inactive in reverting SeuroMpora cratsa to adenine prototrophy (32). Phenol is also said to cause second chromosome breaks in rrzsophi/.j and to cause chromosome breaks in Vida and Ailiu* and it is terato genic in chickens (44). One must also remember, however, that normal adults excrete approximately 30 mg of volatile phenols per cay in their urine (mainly p-cresol and phenol) produced by gut bacterial metabolism of tyrosine (861. Phenol has tested nega tive in a nicronucleus test 1257], The only positive animal tests were conducted in the fifties with later negati"' results. The positive tests are with systems which have not hco:i extensively evaluated. Although it is a borderline chemical, phenol will be considered a probable noncarcinogen (with some !>ositive data) for this project. '2561 Salaman, M. H., and O. M. Clendenning. hrit. J. Cancer, 11:4 34-444, ^57. [257] Kossak, D. J., and J. C. Richardson. Examination of the Potential Mutagenicity of Hair Dye Constituents Using the Micronucleus Test. Experientia, 33(31:377-378, 1977. 190 HONS 022266 Polychlorinated Biphenyla Polychlorinated biphenyls (PCB, chlorinated diphenyls, Aroclors, Kanechlors) have been cited extensively in the literature as carcinogens ,(258, 259). On close.inspection, many of the carci nogenicity studies on PCB's have been questionable (5, 260) or negative (261], and the increase in cancer among PCB worker* has been questioned (262). The latest NCI study of PCB's was negative, but they concluded chat from the open literature PCB's jre probably promoters of carcinogenesis. The PCB's fall on the corder between possible and probable carcinogens using the crite ria for this project. Because of the positive animal studies (2, 25B), they will be classed as a probable carcinogen for this project. Production and Persistence It is estimated th it 1. 9 y. 10" kg is emitted per year (1). Other stiMtes of production are 1.4 x lO' kg, 2.S x 10* kg, and 1.8 x 10T kg (1904' i 6, 8, *>*!.' Production of PCB's has been phased out within the last year, so emissions should have dropped t zero. PCB's are essentially nonvolatile, but evaporation to he atmosphere is thou :> . to !o important (8). Reaction with HO radical predicts a half-lif.- o: 26 days |V.]. PCB's have a boil- point of 36 ; ir : a viper pressure loss than l mm at '33.. 1 ARC Monographs: evaluation of the carcinogenic Risk of Chemicals to Man, Volume 7, 1974. pp. 261-289. - 91 Lloyd, J. a., et al. Polychlorinated Biphenyls. J. Gccup. Med., 18(21:109-113, 1976. .i60| Andrews, T. 257, 1973. et al. PCB Diet. Science, 180(40831:255- ,261) ito, N.. et ai. iffstopathological Studios on Liver Turnongenesis in Rats Treated with Polychlorinated Biphenyls. Gann, 65(61:545-549, 1974. 1262) Lawrence, C. PCB? and Melanoma (letter to the editor). N. Engl. J. Med., 296(21:108-109, 1977. . 191 HONS 022267 propanol Iri* 1939 and 1940, propanol (propyl alcohol, CAS No. 71-23-8)'; was found noncarcinogenic in rat feeding studies (222, 223). Tha only currant references which could be found were Gibel et al. who refer .ito tumor formation after oral (50 g/kg) and subcutane ous (6 g/kg) administration of propanol to rats (263) and an 'oli test (264). The studies which have been conducted on iso propanol have been negative (265). Propanol will be considered a probable noncarcinogen (with some significant positive data) for this project. -`63) Gibel, W., et al. experimental Study o:i C.incorouemc Activity of Propa.nol-1, 2-V.echylpropano 1 -1, and 3-Methylbutanol. Arch. Geschwulstforsch, 45(1):19-24, 1973. -'14) Gibel, W., et al. Studies on the Toxicity and Mutagenicity of Single Fusel Oil1*Components on . Acta Biol. Med. Ger., 23:843-852, \969. (265) IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 15, 1977. pp. 223-243. 192 HONS 022268 Propylene oxide (methyloxirane, 1,2-epoxypropane; CAS No. 75-56-9) has been reported to cause local sarcomas in a limited number of rats liter subcutaneous injection (266). It was negative in relatively short-term (>200 days) studios in rats, guinea pigs, rabbits and annkeys given propylene oxide by inhalation (266, .'6'!. by in vitro teats, transfonset ion of hamster cells (961 v.:rroJ at 250 ng/ml (persons! communication with B. C. Casto -.i > February 1978). It is also reported to cause reversion to .10''".: no, prototrophy in V a roar era r/t9j, and recessive lethal ?...* i' . : r. :n i1 i - ' ; n - , ju t (32). For this project it vi. . .- nsidered a possible carcinogen. :'_i !.'. *i and Persistence ' . : . f : i >. '.mated that 4.4 x 10* kg propylene oxid*' is .mi t ted per . other ur.iJuction estimates include '. "> x 10* 1 i per , 4.0 X 10* kg (1374) (3), 3.0 x 10* kg (1975) (266), and . ' ki i'. '75i (12) with L'.S. consumption predicted to grow . .a year from 19 7 S to 1980 ( 32). If dispersed in the epoxides wo-;:.! be oxidized by HO radio lls with a .: i-ll r.jirs H J . The rate constant half- .- : i i '. react i t. ;redi;t a 23-ho-jr ho 1: -- ! i r - f< r aliphatic . . J; . ; r ; y>r.r xi ! has a fcoilir.: : <: Ji.'l'i.' in.! :*:;i:- : rr i * .">'C i *> 1 . V.er-.ecraphSf Evalcat ion of the Care mooen i c Hiss oi '.meals to .v!n, Volume 1 1. 1 976. pp. 191-199. Sowe, L. K.. et al. Toxicity of Propylene Oxide Determined rr*. Experimental Animals. Arch-. Industr. tilth.. 1 3:228-236, .956. 19 3 MONS 022269 Pyrene Pyrene (CAS No. 129-00-0) has generally been tested on mouse skin with negative results {SI. It has also been reported negative on mouse t<in followed by croton oil or preceded by benro(a)pyrene (51. It? Is usually considered to be noncarcinogenic 152. 261) and has been reported as nonmutagenic to strains 7k 99, 100, 15J5 ard 1517 1521. It :s considered a noncareinogen for this project. - > \rccs. J. C., and X. 1. Argus. Chemical Induction of .'inccr, volume HA. Ac.uier.ic Press, l.'cw York. 1974. ;p. H, 237. 194 HONS 022270 Sbrtfia Aaw Sorbic acid (2,4-hexadienoic acid, CAS No'. 110-44-1) is a widely used food preservative. In 1966 and 1968, Dickens ct al. re ported several rat studies with sorbic-acid. In these test (uaing 6-12 rats) sorbic acid injected subcutaneously at 2 mq/injection in oil or water sonetlaea caused local fibrosarcoaas at the injec tion site (269-271). Given in the drinking water at 0.1 g/1, no effects were seen (271). It is now known that the pH of the injected solution may cause local fibrosarcomas in some strains cf rats. In more recent dose response studies, rats (?72| and mice (27)! (groups of '100 animals) were given 0%, 1.5%, or 10% cf their diet as sorbic acid with no carcinogenic response. Also sorbic acid with 1.000 ppai parasorbic acid gave no carcinogenic response (274). Several > tests (e.g.. have been negative for sorbic acid but positive for reaction products of sorbic acid and sodium nitrite 12"*5!. Bettor subcutaneous tests should be conducted on sorbic ic;d, bit the negative results on the recent large-scale foedir.: tests and negative re sults sj;uost that sorbic acid mould be considered a noncargmo- gen at tN present tire. ,'t9: .. al. ir.t. . " i.-.cv r. - ' : : J4-U4. : *. . ;~o: 271) r.. and H. 9. Wayfcrth . Brit . !:r.p. Car..-. ' : * . . 196. 3.c.e.-.s. r.. et al. Srit. J. C ancer. 1 > :762-T*.9. 1 *. ^ . `ran:. I . r.. vt al. lor.g-Terr. Texici e* l* jr r'crt'ic A.* id :n *. r.t- ? .it. roc ` Co.ssct. Toxicol. . 1J(I : ) :-gs. :97i. Her.dy, S . et al. Lang-Term Toxiei y Studies of Sorbic Acid in Mice. Food Cosaet. Toxicol., \ 4 (S):381-386 , 1976. 2'i! Mason, ?. Ll, et al/1" long-term Toxicity of Parasorbic Acid Rats. rood Cosset. Toxicol., 14 l S) : 387-394. 1976. 12751 Kada, 7. Mutagenicity and Carcinogenicity Screening of Food Additive* by the Rac-Assay and Reversion Procedures. IARC Sci. Pud. NO. 12, 1976. pp. 105-115. 195 HONS 022271 Styrene Styrene (vinyl benrene, CAS No. 100-- 4 2-5) has been found to be both poiitive 1276. 277) and negative 1278) on the ryphir.urium mutagen test after activation with s-9 microsones. without S-9 activation it has been found negative by this test [276, 270[. In other systems, styrene was found positive on a host-mediated forward mutation, gene-conversion yeast system but negative in this system with microsooes only (not host-mediated). It was negative on a Chinese hamster cell tost 1279), in : : j *!.*.: it and r - . nutation tests (32), and in enhancement of viral transformation tests :personal communication with B. c. casto on 9 February 1978). it would thus appear that a metabolic product of styrene is a weak r.uta-ien and styrene should probably to consi J.-:-`d a possible rare me :or.. Producticr ar.-i Pers . . ter.ee it is estimated tr.j '..t x li* . : . t r o -. .>:r i : : <.; i; from stat: r.ary sour.'v.-i 'll. tr-t-r cur.** L*st itj.-j v , ; i i ' > ; : ; ce.: i n :r. it ,spn. -ct.-.: in.- : i ... s i : i . .. i. . . i a. . -l.'.U : V. ri-r.v * 1 >l. is'-. ..It . r. Teaicol., 17. t*:~J9.27": Lopner.o, S., e; al. v.t.i ,c.-..c: :y of Industrial - ; aur. Js : Styrene and 1 ts,'rossiblv vetitclito Styrene CxiJe. utat. Res.. 40 14) 1 317-324, 1976. [280] Yeung, C. It.. K., and C. R. i nil lips. Estimation of Physio logical Snog Sympton Potential fren Chemical Reactivity of Hydrocarbons. Atm. Environ., '. 1973. 196 MQNS 022272 Sulfolane Sulfolane (tetrahydrothiophene-1,1-dioxide, CAS No. 126*33-0) was 1 of the 80 chealeala selected as having the greatest potential environaental effects [7]. Carcinogenicity and nutagenicity were not cited as reasons for its selection. No data could be found m any of the references searched pertainmq to nutagenicity or carcinogenicity of this chcr.ical. It is considered a probable nor.carcir.cgtn for this project. 197 HONS 022273 Tetrabromoethana Tetrabromoethana (CAS Ho. 79-27-6) waa 1 of 00 chemicals having potential for environmental effects (56). It has tested negative in some short-term (92 day), limited-exposure (15 min/day) tests on rats, slice, rabbits and'guinea pigs (281i. It has tested posi tive in an ; :; (pol A*, pol ,\~) differential growth mutagen test rut negative in 5. tj r r - strains TA 1530 and TA 1535 1262, 233). With only one r positive test (which has not been extensively validated) tetrflbronrethane will be considered a prooable nor.carcinogen for this project. , 91 , .r . A . * \. A* .r Rrlrjvfvt' ^ . . Ub.'i bfiO.'n.. el 4*. the Y-*-J of rtjlcjlu.'.i-j. Cunct-r Sv a? j r%A-y.ou:: y. ~j i ". i *i, 1*3. 4. 1283i Roser.krans, it. S. Mutagen;.*:*.; and DSA-Modif yir.g Activ.ty: A Cor irison of Two MicreMal tssays.- Mutat. K*s.. 4 1 : 1976. 193 HONS 022274 Tetrschloroethane 1,1,2,2-Tetrachloroethane (CAS No. 79-- 34 -- 5 j has been four-1 to be mutagenic in the j. typhir-uriu* system for TA 1530 and TA 1535 trains [2B2J. It has been cited as a carcinogen based on a National Cancer Institute bioassay !284| where it was foond to be a carcinogen for mice but not for rats |2B5|. It is therefore considered i probable carcinogen for this project. Predict i ~>n and Persistence It is estimated that 3.4 x 1C1 Vg is emitted per year frem sta tion ry snur.-ri in maV ; r. r t r ich lorrvt nvl no from e thy 1 '. P.va: orat:: ' trim a l-cpm acljtior. ' f water at ?r.'y i-cc.r . .. 31'. .'t has a /in'. or 14'.-1 ' i- : a vj; r :: > s : ' r~ it JC s : . t. i* : dr I j r -. r. r : 'AJter 't 28 >! Z U* j ^ r : \*tton . s* :h, ; 9:*. or.^I Tec a. ::s. lattor. Kcpcr:er, 1. : T. .*. & b . t " -. r r-* : 3 j 1 : r.: o r r -i 1 ?* 1 , 1 *?a n? HONS 022275 tteOrachloroethyrena' Reference 286 cites extensive toxicological data but reports no evidence of carcinogenicity, mutagonici ty or teratogenicity *.or tstrach.oroethylone (perchloroethylone, CAS ?io. 127-18-4) in humana. Also no difference in the incidence of tumors was uo- erved between control and expcrincntal rats exposed to 300 or 600 ppm of tetrachioroethyiene. A recent report by NCI, however, has shown `.etrachloroethy Lene to be a liver carcinogen in B6C ??' i of both sexes [287], Tetrachloroethylcne has, therefore, beer. ass iqned to the probable carcinogen list. Production and P eisistence It is est mated that 7.8 x 10" Vg te tr achlo root hy lone is j.cr year from s-- .itiDnary sources vj*. h solver*. ..'Vi; or l ion ` r .!*.)rv isxr. t: rs accc. * * ` - J ' ^ ^ better t'M.n >9* f that i*y 'll. ' . .`-.i-r v ; *. ;t4*.cs 0: ; r' . .' -.son i r !. ' :< 0' - ;1 ;:. i. i X 1'J* : .r.C 2.'. 1 ' " : r 1 ci se ! . 7 ! , .i:: r-rcduct i o \ 1 *. 1. 1.: : < 't;. i- i i.O x IT* t : : 1 974 . :' , .ir i : '. : 1::. A 9~- : :. .1 r O ' *e . :* j yir irowtn , f '-I : t . r. 1 : :rt it ir i: ar2* f . r . .* 1* :c t1 . r. : 1 ior t : r s . ;- ^ x: * 1. * * v . . r r *. : xc s ^ : ' . : t .* * * *T i ' t T ' ' i ` *.*.* t ;.t . :/, : tv ,-r i . .: r 1 i : ` l`X' iT'.Vu . : 1 :. t . : * .j * . * j 1 ! - . . . ' ` " I *n . *' ! v t \ { 'T .* * . , : :r - : - :* f : .: > : i : v.i: t ri . : r * . . : ! . * . * .i 1 ; ,; -; 9 **. . *. ' S 5 " . ! : . ' ! 1 . *. . . 1 * ; ` : . . ; * i *. * .1 12861 fuller, b. Air i .iluiicr. ethylene, .at'iona 1 Tech:., ji 1 PB 256 731. 1976. 99 pp. -f Totracr1.: r-at: >r. -*erv: * r-. 1287 J Bioassay of Tetrachloroethylcne for Possible Carcir.ou nicitv, cas h'o. 127-18-4, Nst tonal Technical lnfornu Ssrvico So. m 272 940, 1977. or. 200 HONS 022276 Tetraethyl Titad pCi^uiKhyl lead (tetraethyl plumbant* CAS Ho. 78-00-2) has been Induce lymphomas when injected aubcutaneouely into neo natal aice (288) although the significance of this test has been qaastlonad (289). Oral doses ware not found to be teratogenic (290)^ and an epidemiological study found no health hasard from occupational exposure (291). Tetraethyl lead has been found to cause DNA fragmentation and to enhance viral transformation in hamator embryo at the 12.5-ug level (personal cooesunicstion with > C. Casto on 17 February 1978>. Tetraethyl lead is considered a possible carcinogen for this project. Production and Persistence One estimate of release to the environment is 1.1 x 10* kg per year {44} from a production of 1.4 x 10* kg. The release figure notes that most of this is through use in gasoline where it is converted to lead halides and sono lead phosphates (44,'. Another set of figures rites a release of t,, *> x 10* from a ;r >.!:? ion of 1,4 x 10* v.; in 197J |4J. The 1*H production has beer, est; - mated to be 2.4 x 10* kg 1)891. Tr.o production of tetraethyl lead is expected to decrease rapidly from these fijur*s because of regulations re-fuiring less lead in rasotme (27J. In the air it has a half-life of 2-1 days Iron reactions with no .mj , radicals >. It has a boiling imt of IT'1 'de.-^nposes and a vapor press-re of 0,15 ar at , JJ!. 1288) Epstein. 5. S., and N. Mantel. ,'arf.nogcr.i r: ty f :.tr.iethyl lead. Cxparientia, 24(f> i 580-581, l***. 1289) XAJC .Monographs: Evaluation of the Carcinogenic Pis< o: Chemicals tb ran. Volume 2, l"l. pp. 150-140. tilt) VlnnsilT C. L.. at al. Teratogenic Evaluation of Lead CeoUmif ts Micetand *at*> food Cosmeti flpsicoi., Jf4):42W. 1975. (291) Robinson. T. r. Health, How t'.in ft Be Measured. Pnbl. (NIOSH) 74-134, 1974. pp. 114-130.. t*rw *01 HONS 022277 t&smi An1 earchjOf CAMC2RLINE and.TOXMNE along, with, the iffis dorUht "Air Pollution Aaaassaient' or Toltine"*f!29ZJ%na the ? SUiter4 Research Institute hazard priority ranking* Illtfailed to tlBd data which would Indicate'that1 toluene tia'rfdaiipinogen. It tested negative [461 in a differential growth mutagen test ' using r. (pol A) and will be considered a noncarcinogcn for this project. I29i) I'alXcr. P. Air Pollution Assessment of Toluene. National Technical Information Service Xc. PB 25S 735, 1974. 102 HONS 022278 raWEl^UWOgyanata Thar* arl po data on TOXLINE or CANCERLINE to indicate that toluene''diisocyanate is a autagen or a carcinogen. 20(3 HONS 022279 ,TMndUagy Toluenedi&aine (toluenc-2,*-diamine, CAS No. 95-80-7)f genoxaUAf^ used as a hair dye, has been.found by;several studies to be non^ carcinogenic wheruapplied to the skiniof mice [126, 2931 and rats 11251, although the same'data can b Interpreted to show increased lung tumors and total tumors in the te9t groups [294]. Tolucno- diaminc has been reported to produce hepatomas in rats when fed .it 0.1> of diet, for It weeks (2951 or 11 g/kg for 16 weeks 12961. In rats, 280 mg/kg (35 weeks) subcutaneously is reported to cause neoplasms (6). It has also been found to cause morphological transformation in primary Syrian hamster embryo cells. It also mutates 5. lyphtnuriu-. strains TA 1538 and TA 98 at 0.5 ,.g/ml when activated with the 39 microsomes [295, 2971. With positive ^ :m ntu.' and >. vitro tests, toluenediamine will be considered a ' probable carcinogen for this project. Production and Persis^tence One estimate of production is 2.9 x 107 kg per year with 0.015 as a fraction of production loss (61. It has a boiling point of 292 C and a vapor pressure of 1 mm at 106.5C (6). 12531 Giles, A. L., ot a'.. Dermal Carcinogenicity Study by Mouse-Skin Painting with 2,4-Toluencdiaminc Alone or in Representative Hair Dve Formulations. J. Toxicol, environ. Health, 1 (3): 4 33-4 40,`1976. (2941 Bridges, B. A., and M. li. Green. Carcinogenicity of liair Dyes by Skin Painting in Mice (letter to editor). .1. Toxicol. Environ. Health, 2 (1): 251-252, 1976 . 129:1 Shah, M. J., ct al. Comparative Studies of Bacterial Muta tion and Hamster Cell Transformation Induced by 2,4-Toluono- diamine (Meeting Abstract). Proc. Am. Assoc. Cancer Res., 18:22, 1977. 12961 Cancer Research, 29^fl37, 1969. '.29 7 ) pienta, R. J., et al. Correlation of Bacterial Mutagenicity and Hamster Cell Transformations with Tumorigenicity Induced by' 2,4-Tolucnediamine. Cancer Lett-. (Amsterdam) ,> 3 (1/2) : 45-52, 1977. 204 MQNS 022280 Toxapnana Ho significant data were found to indicate that toxaphene ia a mutagenfbr ;a$carcinogon. It tests negative on the dominant lethal test for mice (301. It has been placed on the probable '-.cncarcinogen list for this project. 205 MQNS 022281 TtIcWIortpre Tricbjorfon^has been; found to Mf carcinogenic to nice, rats, and cats''cjiven orally', subcutaneously, *cotaheously. or intensuscularly (3, 5). It has also been found to be mutagenic by at least five different test systems [3, ^]. It is, therefore, to be considered i probable carcinogen. Product ion and Persistence It is estimated that 100 kg/year of trichlorfon is emitted from stationary sources {1). 206 MONS 022282 Trichloroethane A'Natibn*lv<p&Acer Institute bioassay^of 1,1,1-trichlocoetftan* found rio*corrolation between this cheslcal and any cancers which developed in the control versus the test rat3 and mice (298)'.'' It was negative on an enhancement of viral transformation teat (personal communication with B. C. Casto on 9 February 1978) . It has been placed on tne noncarcinogen list for this project. [298) Bioassay of 1,1, i-Trichloroethane for Possible Carcinogen icity. Carcinog. Tech. Reo. Serv. - N'atl. Cancer Inst. (U.S.); ISS NCI-CC-TR-3, 1975. 70 pp. 207 MONS 022283 Trichloroetbyl^ne^trjchloroethene, TCE:'CASfHo. 79-01-6) has b*4n|^oun4 to ,induci-ml'qh fncldcncc of ..hepatocellular carclnpma infB6C3-l mlc^of'goK-sexe-sTii^! t299f. ItThas also been found to be weakly mutagenic in F. ccli and to the TA 100 strain of tjphinurium (0.8-2.01 vapor dose response when exposed 1 hour) in the presence of activated nierosomes (32). A review of the production, uses and environmental effects has been compiled by f'ishboin |7S). TCE is considered a probable carcinogen for this project. Production and Persistence It is estimated that 1.6 x 10* kg of TCE is emitted per year with 95* of that coming from solvent evaporation in degreasing opera tions (1). Another estimate is a production of 1.93 >: 10" kg with 1.95 x 10* kg released [71. Other production estimates (6, 81 include 1.8 x 10 kg ( 1974) and 1.3 10" kg/year, with about 60" of the production released to the environment (309'. Produc tion has also been reported to be 1.8 x 10 kg (1974), 1.3 x 1C" ( 1 97 5) and 1.4 x 10 kg (1976) with a 1`- decline predicted for future years (32). Since that prediction, ">SHA has lower'"! th*'- standard for occupational exposure and SOI found that- TCF n.sctumors in mice which will mean a much creator decline in the ex pected production (32). TCE has a high atmospheric photodeurad.. tion rate with a half-life of 0.3 day at sea level MOD], ,'|th< sources predict atnospheric reaction with the !(<"' radical w. th : half-life of 36 hours (81 or less than 50 h-mrs (71. dun : : high volatility and low water soluhility it is expected f i;: rapidly migrate into the atmosphere. lr. fact ->0' of i 1 solution will evaporate from water at 2 5'c m 19-24 minuter '3* . Its boiling loint'is 86.7C and it has a vapor pressure o: -9 -v at 20C 133]. (2991 Carcinogenesis B^eassay of Trichloroethylene, CAS So. '>Oi-6. National Cancer Institute Carcinogenesis Techn,.a i Report Services, Number 2, February 1976 (NCI-CG-TR-?. (300) Fuller, B. B. Ain Pollution Assessment of Trichloroethyl ene. National Technical Information Service No. PB 256 730, 1976. 2(7.8 MQNS 022284 T*ichlorogHidroam than* .Jrr'ljilceS trichlorof luoromethane *'(Freon-ll, V-ll) in' combination wi'tSr thjr'insectieidal synergist pfperonyr butoxide Increased the incidence of malignant hepatomas while Freon-11 by itself was found to be noncarcinogenic [301). No other carcinogenic data were found on Freon-11, and it has been found to be nonniutagenic in S. tuphinurium tests with and without microsomal activation (302). Preliminary results frcm an NCI bioassay show no differ ence between control and treated male or female rats (303). It is probably not a carcinogen. [301) Epstein, S. S., et al. Synergistic Toxicity am: Carcino genicity of "rreons" and Piuerorwl 3utox icie. Nature, 214: 526-528, 1967. '' [302) L'ehleke, H-, et al. Metabolic Activation of Haloalkares and Tests in '.'itnu for Mutagenicity. Xencbiotica, 7(7): 393-400, 1977. [303) NCI Preliminary data on trichlorof luororr,ethane, Nov. 27, 1976. 209 MONS 022285 Wfflhlorophano l Tglqflltfirpphanol > (2)4,$-trichlorophenol, Dowlcid* 2S CAS Mo*. 88- 06-3Mf^nSrben'found toi b a /carcinogen in micetwhan given^orally but 7iot> 'subcutaneously 169, 77]. Scven/seventy-tw hepatomas, 6/72 pulmonary adenomas, and 7/72 reticulum cell sarcomas were found. (2,4,5-Trichlorophenol was only evaluated by the subcu taneous route [69) and was found negative by this route of admin istration, as was 2,4,6-trichlorophenol.> Trichiorophenol may cause abnormal pollen in broad bean plants [304]. No other pertinent literature references were found on TOXLINE or CANCER LINE to substantiate or refute the carcinogenic potential of trichlorophenol. It has been placed on the possible carcinogen list for this project. Production and Persistence It is estimated that 5 x 102 Kg tnchlorophc-r.ol :s emitted from stationary sources per year (II. Since this is used as a pesti cide, nonstationary sources (or total production) should be con sidered. It completely disappears ir. soil suspensions in 5 days (33). Tr ichlorophenol (2,4,6) has a toil i no poir.t of 244.SC and a solubility of 800 mo/1 at 23'C ' I . [304] Cytolr :ical Effects of Pesticides. V. Effects of Some^ Herbicides on Yici-i r :i a. Cytologia, 39(4 1:663-64 3, 1 0'-*- 210 HONS 022286 Urethane Urethane (ethyl carbamate. CAS Not 51-79-6) has be^n,shown: to*,be carcinogenic in mice, rats and hamsters folloving'adainiatratlon by tho oral, inhalation, subcutaneous or intraperitonoal routes (305). It generally causes lung tumors, lymphomas, hepatomas, melanomas, and vascular tumors. With all of these positive data, urethane is considered a probable carcinogen for this project. Production and Persistence The only production data which could be found cited from one L'.S producing company with no data given and production below 454 from a second company (3051. It has a toiling point of 18JC, sublimes at 102C and 54 mm l i, -and is volatile at room tempera ture [305J. aThe name urethane.is sometimes applied to high molecular weight polyurethanes used as loans, elastomers and coatings. Such products are not made from the chemical urethane and do not generate it cn decomposition. (303) IARC Monographs: Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 7, 1974. pp. 111-140. 211 HONS 022287 vinyl* Acitfte VinylTa (CAS No. 108-05-4) has;been found to be noncarcin- oageannilci^l lMjaitla at 2,:500 ppm for* 4 br/day- for 12 months by C. ' Haltoni *75). It hag also been found negative on mouse skin (306), mouse sebaceous glands (307), and 0. typhivuriui tests (52, 97, 146). Both commercial vinyl acetate (96) and repeated tests of purified vinyl acetate (personal communication with B. C. Casto on 9 February 1978) have been found to be mutagenic at a level of 150 ug/ml in viral transformation of Syrian hamster cells. Because of this enhanced transformation, vinyl acetate will be considered a possible carcinogen for this project for the first round of evaluations. Production and Persistence it is estimated that 6.8 x 10r' ku is emitted per year from sta tionary sources [1). Another estimate is a release c- 7.8 x r6 kg from a production of 5.5 x 10 kg (6). (t. reacts with oxuiuinir r.atcrials in the atmosphere [6J, and has a boiling point of 7 30 C and a vapor pressure of 33 mm at 20r (jj|. 1306) Garibyan, D. K., and S. A. Papoyan. Study of the Blasto mogenic Activity of Certain Chemical Substances Using a High-Speed Test .Method. Gig. Sanit., 8:74-76 , 1977. ( 307) Gari.bvan, D. K., and S. A. Papoyan. Use of Sebaceous Gland Reactions as a Test for Rapid Determination of Carcinogenic Activity of Chemicals. Neicot. Itogi Izuch. Zagryazneniya Vnesh. Sredy Kanstserogen. Veschestoani; 112-115, 1972. 212 MONS 022288 Vinyl BfQKlde Vinyl beoaitf* (b*OM*thylene. CASNol J$93-60-2) ha&00t OMn tested very much. It was not found in'Reference 5* uand from CANCERLINE and TOXLINE only one author has conducted in citn tests on it. In this test, S. typhinuriu* strain TA ICO was found to give a dose-response mutation frequency of 26 and 9 revertarts per micromole per hour with and without the S9 liver mcrosome fraction [146]. It was also found that liver fractions from human biopsies converted vinyl bromide to more mutagenic compounds. Another study by the same authors demonstrated that vinyl bromide is activated by the liver homogenates in the same manner as is vinyl chloride [308], Although there is not much information on which to base any decision, vinyl bromide will be considered a possible carcinogen for the first phase of this project. Production and Persistence It is estimated that 4 x 103 kg/year of vinyl bromide is emitted from stationary sources (i). [308] Harbin, A., et al. I.iver-Microsome-.Vediated Formation of Alkylating Agents from Vinyl Bromide and Vinyl C.nloiido. Biochem. Biophys. Bos. Comm., 67 (2):596-603, i 975. $13 HONS 022289 Vinyl* ChWfBg Chilo^CIjCAS NO.; .75-01-4) has b*ifj found to causa lung tumors? mamMiryfcarcindfBas and'angiosarcomas'nice following exposure by inhalation (309]. Similar exposure for rats product's angiosarcomas of the liver and other organs, zymbal gland care. - nomas, and nephroblastomas (309]. In view of the extreme rarity of angiosarcoma of the liver in the general population, in cjsos in vinyl chloride workers is evidence of a causal relationship. It has also been found to be a mutagen of S. typhii-ir 'Ames test (97| and in enhancement of viral transformation (personal communication with B. C. Casto on 9 February 1978). Production and Persistence It is estimated that 1.4 x 10* kg is emitted per [li. T1 1973 production of vinyl chloride was 2.4 x 10' n in the United :'ahcs, of which 97% was used for production of polyvinyl chloriJi i309|. A 1974 EPA estimate was 9 x L07 kg released to the a rmospl.v c [3091 . Other estimates of production are 2.5 x 109 k: : 1 974 18] and 2.5 x 10" kg, 1.9 x 10* kg and 2.6 x 10' ki ic I '-i, . '75, and 1 976 [32|. The demand for PVC is expected to inoi -.-a -. .it .ir, annual rate of 8-10t. through 1981 [321. Tn the at.ro. hi:' : r reacts with, the HO radical with a 12-hour half-lit- :i a bo11 j n<: ueint of -14C and a vapor nressure of - c ' 133). ' i [3091 IARC .V nographs: Evaluation of the Carcinogenic Pish of Chemicals to Man, Volume 7 , 1974. pp 291-703. 2U MONS 022290 Vinylidene Chloride vinylidene chloride (1,1-ai'chloroethyleifeT'CAS MGiF75-35-4) `hair been found to be mutagenic in the F. iyph<^urium' test (97, 14r> 310] and in a metaboliiing ir osystem with E. coli K12 [311], It has also been reported to be carcinogenic in rets and rabbits (312], and in preliminary studies 200 ppm wore carcinogenic to rats and mice by inhalation [313]. On reference concludes that airborne emissions of vinylidene chloride are not likely to pose a significant risk to the general population (314). vinylideno chloride has been placed on the probable carcinogen list for this project. Production and Persistence It is estimated that 2.1 x 10' kg are emitted a year from sta tionary sources, with 70* of this coning from the oxychloriranon of ethylene dichlonde [1]. Other estimates of product .nr: and release are production of 2.7 >: 10T kc with 4.1 x i0'` '<; released ! 7) , production of 1.2 x 10' kg with 1.4-1.8 x 10* ku omitted ar.ci , a 5-103 growth rate r rodicted * 3141, 1.2 '.0 ha :,r .uo.o with 1.1 x 10 kreleasv-i *".], 7.7 x 10" vi traduced fro- 1 ' 1975 wth a 7 growth predicted . I 12:, and 7.7 x 10' : rr luc- : in 1972 [8], The Oj and HO reactions are si mated : i - !..ss> than a 1-day half-life (61, while another referer.c- ' half-life of 26 hours (B ] . Lvaporation of r>0; frem tion at 25C will occur in 22 minutes [31]. It ha.; > . i: - sure of617 mr. at 25'Car.d a boil me point of 37'c < !. (310| IARC Information Bulletin on the .`-'urvey of Cher.:cal;; !. Tested for Carcinogenicity. International ,V:ercy : r Research on Cancer, Lyon, Bulletin Ho. 5, July (311) c.reim, i-I. G., et al. Mutagenicity ' ' ar. : 'to ntial Carcinogenicity of Chlorinated rchylenes as a : met i n o'. Metabolic Oxirar.e Formation. riechcn. Pharma.-. .I - 2017, 1975. (312) Food Additives, Packaging Material for Use During Irradia tion of Pre-Packaged Foods. Fed. Register, 33:4569, 1968. (313] Caputo* A,, et al. Oncogenicity of Vinyl Chloride at Low Concentrations in Rats and Rabbits. IRCS, 2:1582,'1974. (314] Hushon, J., and M. Kornreich. Air Pollution Assessment of Vinylidene Chloride. National Technical Information Service No. PB' 256 738, 1976. 215 0222^1 HONS WleiW .u<rScisa filtera ture ugfcfiftf that xylenes are noncarcinogenic irri tant* [315, 316] Other literature''indicates that all ot tho ' xylenes cause neoplasias on nice after dermal application [61. This may refer to the same study where an increased number of unspecified tumors were observed in the mouse upoi; dv.nal appli cation of mixed xylene after the use of croton oil or methane (7 J . The results of this study are considered equivocal (7) and would at most 3uggest that xylenes are promoters. The old xylene carcinogen literature is negative after skin painting mice and xylene is considered a noncarcinogen for this project. |313| Pound, A. V*. induced Cell Proliferation a::.: t!v :iat.ion of Skin Tumor Formation in Mice bv '.'1 travio'.-.t '. :oht. Pathology. 2 14):269-275, 1970. ' [316) Listgarten, M. A., et al. L'Ltrastr.uctural Alterations in Hamster Cheek Pouch Epithelium in Response to a Caro;r.ugcr.. Arch. Oral Biol,.. 8 : 14 5-165. 1963. 216 HONS 022292 APPENDIX B A REVIEW OF THE CARCINOGEN COFACTOR LITERATURE INTRODUCTION This appendix presents the state-of-the-art review of the carcino gen cofactor literature that was performed as part of the first year's effort on this contract. Primary emphasis is given to industrial chemicals and the effects of cofactors on the carcino genic potential of those chemicals. The information presented is derived from more than 2,300 litera ture citations (most included abstracts) accessed from CANCERH'.f , TOXLINE, MEDLINE, CANCERPROJ, AND CHEMCON searched through the National Library of Medicine and Systems Development Corporatic. Some of the keywords or word stems* utilized in the comouter search were carcinogen, . . , cocarcinogen..., and syncarcinope:'.. . . . Other words used in cor. unction with carcinogen.. . include.".: modifier(s), promoter(n), inhibitor(s), enhancer(s), syren:-.-, . synergism. This review attempts to summarize some of the si ficant find inns reporter: in the multitude of literature f> this subject. BACKGROUND Chemically induced .arc i:-., jenesis in man is rapidly becoiii:-.: i of the greatest concerns of society. Statistical data on the incidence of cancer in .humans and laboratory testing on animals have indicated that a wide variety of chemical compounds are responsible at least in part for many of the various forms of human cancer. Those substances traverse a number of interfoce anJ enter or contact the human body through media such as .si:, rood, water, physical contact, and mcdicaticn. In-addition tr..substances can undergo various changes at each interface, v:-r.:the media of transport, or within the human receptor. Nor.earc conic substances when metabolized by the body have leer, found tv produce carcinogenic byproducts. - The word stems and all terms beginning with them (indicated by ..t) were searched. I2J.7 HONS 022293 ch>'a(or* qfiwrilly^oc^%^llfUuit of a biphasic xesponao> initiation and protaoUon. )prxotion implies a latent period after inltfatlonfot a target recapt&r. -This also implies that th* system or eachaniscL can be inactivated or inhibited, tn cony.ir.etion wi-h tills<theory many'carcinogenic and noncarci nogeni.o compounds or their metabolites have been found to interact with other chemicals or agents to enhance or inhibit carcinogenic activity. This modification can take place by preliminary, simultaneous, or subsequent contact of each substance with the target receptor. Obviously a complete characterization of the interne:, ion of ;- cal substances in human carcinogenesis is a monumental task because chemicals that are carcinogenic or are ccfactors of potential carcinogens exist simultaneously in the vuriou-. spheres of our environment and may act to inhibit or enhar. other- .-..rein- oqenic activity in varying degrees. This review presents t:.-- findings of various researchers in the -iron of car -1 - l ; . factors: it identifies each substance, its method ; nt-. r.ic* : . the human organs it affects, and its sphere of tin:-.;-port and entry into the human body. Apparently the terminology in the area of ca rc i!-.o:;'\.ic coin ms not boon standardized or widely accepted, nr.'-; toi s ' .oc.ir ri:K'-:cn, sync.irc: nocn, promoter, nr.d .-nhar. e *. a:......... used interchangeably. According ft> iit-ckor j `\~\ thi ' :.`;o of terminology m carcinogenesis has ibai a : con fusion in t.ror f>t ielo ;y. Pecker it tto nt.ir.dar :; ?.>. those toms as follows: fol i vary rare 1 nogens : first order eti rc i :.t < : i risk The ~ost simple toxicologic process ft r iiiif'f. :ir.: their carcinogenic effect is uni factor. a! rxv - .rc target tissue. : ny.--.carc i oogenesis : generation of neoplasii onus*..! i -.licitfactorial exposure to the target tissue. K:-... osurv to a submani fcstational dose of a solitary carcmoq.v-. ::.o., bpnzo (a)pyrene| nay induce a distinct inclination to cancer, while a subsequent exposure to either a solitary carcinogen or to a cocarcinogen may augment the irreversible effects caused by the initial exposure. When exposure >5 to more than one solitary carcinogen, it is sometimes railed pluricarcinogenesis. 1317 J liecker, E. Definitions and Terminology in Carcinogenesis Ana lyses ;and Proposals .,(Meeting Abstract), Third Inter national Symposium on Detection and Prevention of Cancer, 1976, p, 67. - 218 MONS 022294 Coetrel nogenrtie t expoHr tX h dose 7ofth* solitarycarc i nogen f&rlowed *tiffl$cpe*fr? ter c cocarci nogen which alone; doe* nob* produce ttaeora 09 cancel ocher tonna frequently employee! arei Promoterst agents that interact with membranes, stimulate and alter genetic expression, and increase coll proliferation rate. Promotion, unlike initiation, is reversible, and t*.-' promoting agents must be applied repeatedly before tumors arc formed (318). Enhancement: this term is often used to describe synergistic elTects of chemical agents. Usually when the chenical agent tested increases the incidence of cancer cells or decreases the response time of cancer manifestation over chat of theknown carcinogen, it is said to enhance carcinogenic act: cy. aoe.nts that block or retard the carcinogenic of a known carcinogen. Also called anticarcinonci.r.. Discussion of carcinogenic cofactors is presented by the tjsu- means of human exposure, that is, dietary cofactors, physical agents and body materials, therapeutic agents and tr-M'.-i.'iits, environmental cofactors, and industrial chemicals nr.! . .`one carcinogenic ccfactors exist in several spheres no: '.ur. introduced to the body in various forms. In addi-t. mr., rtair. cofactors have demonstrated both synergistic and inhiL'i1 -:y activity. These overlaps and contradictions arc add rt >. : .-.he review. D: i.TAFtV COFACTORS Dietary cofactors are those agents which are taken ; n 11 part of routine dietary intake, or in some form supr.ii":; diet, which if present or absent affect careinogen it. .ivivity. Included in this category are dietary related agents such as cooking aerosols. laboratory studies on rats (319) fed diets deficient in i inntropes (choline, methionine, folic acid), amino acids, and r;.ic:r.. (318) Yuspa, S. H., et al. Cutaneous Chemical Carcinogenesis: Past, Present, and Future. J. Invest. Dermatol., 67(1): 199-208, 1976. (319| Rogers, A. E. Reduction of n-Nitrosodiethylamine Carcino genesis in Rats, by Lipotrope or Amina Acid Supplementation of a Marginally Deficient Diet. Cancer Res., 37(1):194199, 1977. 219 HONS 022295 I'*** Mjj _J *<& anotasr, study tlSn'of *aae<Juate*biet dfy not *" ____n__l_n_d__u_ _o_t_l_b_n__._*__M__a^t-b^U^-^^^^ontainadjanr bathuctho aino r 1,1potrope 'supplement, Wejiff^osjulated to haver fbnlbitory tfrtLhss also bean cjflPf&ta&lbf foundJinctbrstudies* ipsl carcinogen useB^in ifchlS? study wais'H-rutrSsttaietnyl* amino. The protoin amino acid L-cystolnc has been found t > also inhibit cigarette smoko induced;qjfcncer,(321>), while other amino scids such as Dl-ethionine have bseiT'daionstrated to accel^ratt chemically induced carcinogenesi* in animal teste [122, 32;'. DL-tryptophan, another common diotary component, has boon ost'.-i in several studies, all of which demonstrated promotion of chemically induced carcinogenesis in animals (324-22')!. ATth.: study of dietary components was performed 1327 ) which shoved tn.it (320) Syrotuck, J. A., and II. S. Worthington. Nutritional on Syngeneic Tumor Immunity and Carcinogenesis n V.j Selected Essential Amino Acids (Meeting Abstract). Proc.. 36(3!:1163, 1977. F' oi. [321] I.ouchtenborger, C. , and R. Leuchtenborgvr. Protect i <;n ' : Hamster I.ung Cultures by L-Cysteino Against Co: tims. n Effects of Fresh snikc from Tobacco or Murih.i ;.mn ir- ettes (Moctinu Abstract). .1. Col!. Bio!., 70 7 ; . 44a, 19 7 6. 1322) Takor.iua, E. , .-t a:. Effect of T'honobnrbi ta.e Db-Ethiomr.c on 4-iDimcthy lamino) a/obcnzer.o-'' .nzymes ar.d C ircinc-tonosis. C,ann , 64 ( 41 :36 3- ' .., . ' ; . ! 32 j; : to, N., ot a). The Development of Cnrcirer.. :' Rats Treated with "-Toluylcnediaminc and t!i. : and Antagonistic effects with Other I'horuca! r. 'v 29(S> si 137-1145, 1969. i r 1224) Radomsk i , J. 1.., ct al. Coca r e t nogen i c l.-.r* . D, L-Tryptophon and 4-Aminobiphenyl or 2-Naph? hy : Doqs. J. Natl. Cancer Inst., 58(6):1831-1R34, i (325 ) Ito, N. , et al. Effect of Various Carcinogr: i .r..': -;or.carcinogcnic FubsUtnces on Development of I r 7 . rs in Rats Induced by n-Butvl-N- (4-hydroxvbuty!) n iros- imi Gann, 65(2>:l23-130, 1974. 1326 ] Matsushima, M. The Role of the Promoter L-Try . :.:i.i . Tumoricenesis in the Urinary Bladder. 2. V. . ::..rv Carcinogenic! ty of FANFT (Initiating Factor) and ; v ; !. {Promotingpfactor) in Mice. Jpn. J. Urol., *>R ! 8) : 7 ?: - " 3f , 1977. (3271 Rogers, A. E., and P. M. Newberne. Dietary Kttectr. n Bpltasical Carcinogenesis in Animal 'Models lor Colon and Uver Tumors. Cancer Res., 35(ll/Part 2):3427-3431, 1975. 220 HONS 022296 colon tui>or^lMaca^aitol>T 'dlitery fa take or dietary deFxpiency 6f vitSuilrTf/u' who enhancing of wat augnented*-byvdipotrope deficieacy Ajparvey of .8,278 Norwegian.Ben^reaUljtad in findings which: ejiggest that vitamin > active compound inhibit pulmonary cafcioQoenesia in man.[328 Vitamin A in conjunction with Fluorouracil haa been shewn to inhibit 7,12-dieethylbenzanthracene (DMBA) induced skin tumor* in rabbits [329). Vitamin B2 deficiency and hepatic injury resulting from inadequate food intake have been postulated to promote liver cancer [330). However, nicotinamide, a 3 vitamin, haa been shorn in animal tests to promote the development of kidney neoplasms and increase the. incidence of pancreatic tumors. It was also suggested that it may offer some protection against the acute effects of liver cancer but not against tumor induction [3311. Studies have shown that synthetic inducers of increase:! micro somal mixed function oxidase activity may inhibit the r.eeoiastic effect of chemical carcinogens ! 3 3 2) . An increasing .number of these substances are beir.n found in natural products. Cruciferous vegetables including brusscls sprouts, cabbage, and cauliflower have been fount! tc contain : r.clo le-3-ace ton i tr i lc, indrle-3-carbinol, and :, 3'-dl:ndolyme thane which have been identified as inducers of oxidase activity-, or potential carcinogenic inhibitors. Another category of dietary inhibitors comprises the an: i '>::.! mts. Several of these compounds have beer, found to inhibit the rareirroenic effects of a variety of chemical carcinogens in i.-.ir.i! tests. Considerable wort, has beer, done with butylatod hyuroxyi.ntsoiv tBilA) and butylatod hydroxytoluenc (OUT), phenol: (J.'ol :i u > 1 r. e, d. Dietary Vitarm A and Human Lung Cancer. Ir.t. J. Cancer, l a ( 4 ) : 56 1 - uf, a, 1975. ! 3 2 `J) Pratkin, L. Inhibition, of Tumor igenesis by Topical Application of Low hoses of Vitamin A Acid and Fluorouracil. Kxper icr.t ia, 31(4> 1975. [ 3 30J Sun imuru, T. Carcinogens in Foods and Food Prodicts. Proceedings of the Eleventh Canadian Cancer Research Conference, Natl. Cancer Inst. Canada, Toronto, Ontario, 6-8 May 1976, 1976. i3311 Schoental, R. The Role of Nicotinamide and of Certain Other Modifyinq'fcactors in Diethylr.itrosamine Carcinogenes is : Fusaria Mycotoxins and "Spontaneous" Tumors in Animals and Man. Cancer (Suppl.), 40{4):1835-1840, 1977. [332] Wattenberg, L. W. et al. Dietary Constituents Altering the Ressonse to Chemical Carcinogens. Fed. Proc., 35:1327-1331, 1976. 221 MQNS 022297 ^T-lBHAjMd BUT wre addadSttfttht diet of mic vltH ft&T^py^ri# i8'(a)P] it was foona,tnat,e 1 ther anti oxidant inhibitadPcareinogenesi*. Other antloddants having carcinogenic inhibiting capabilities include diaeibylhydrazine, tetraethyl-, thiureif disulfide, ethoxyquin, disu\firaa, dimethylditij4o)&fWti 6-ethoxy-1, 2-dihydro-2,2,4-trimothylquinolino ( coiweriCalrSnliftl. food additive) i cysteamine, benzyl isothiocyannte and benzyl ' thiocyanate (naturally occurring antioxidants), sodium selenide, and o-tocophenol (330, 332, 333J. barge quantities of salt may enhance the action of gastrocarclnogens such as M-mcthyl-N'-nitroN-nitrosoguanidine (MNNG) (330], The artificial sweeteners saccharin and cyclamatcs have been shown to act as cocarcinogens with subcarcinogonic doses of N-methyl N-nitrosourea, a stronq bladder carcinogen, when tested on rats (334, 335). Another study on mice, however, concluded that these artificial sweeteners had no carcinogenic or coc.ircinogemc activity under the experimental conditions ! 3 3*"; . Coffee has been shown to contain constituents of which some have been shown to promote and others to inhibit carcinogenesis. Caf feine has been tested on mice as a post treatment t<> exposure to l-ni troquinol inc- 1-oxido (4 MOO), a known carcir:ou.:., an.; showed inhibitory properties [337|. In contrast chloro-;enio acid (15* of the soluble constituent of coffee) has been shrwr. v :>.* a very powerful catalyst for N-:.itrosounine formation : the di-jestivo i 1 3 3: V.'a ttcr.bcrg , L. K. Inhibition of Chcmic'i rc :;y Antioxidant.-, an i Some Additional Coin . . Fundamentals in Cancer Prevention, Pruo . International Syr;::>'s ium c-f The Princess , Research Fund, Tokyo, Japan, 1976. nogenes t s In: '! the 6th ~mc..-r (J34) Chowaniec, J., et a). Histology of Turin-:r in. ^.n m the Bladder of Rats Receiving Dietary Saccharin mu a Single Dose of n-Methyl n-Nitrosourea (Meeting Abstract). B. J. Cancer, 29(1):93. 1974. 133 5] dicks, R. M. , and J. Chowaniec. The Import a:. . of Synergy Between Weak Carcinogens in the Induction o; Bladder Cane-r in experimental Animals and Humans. Cancer Res., 37(3, Part 2):2943-2949, 1977. 1 336) Roe, F. J., et al. Feeding Studies on Scdi..:. .. .larate, Saccharin and, Sucrose for Carcinogenic ami Tun.>ur-Promoting Activity, food Cosmet. Toxicol., 0(2):13b- 143, 1970. (337] Nomura, T. Inhibitory Effect of Caffeine on Chemical Carcinogenesis in Mice (Meeting Abstract). 1'roc. Am. Assoc. Cancer Res., 18:244, 1977. 222 HONS 022298 tractf,'T338B3i:?Teata icreyUgfaMonTa1c<f indicate ,,tlu) 12 neutral .*ee- rola' (cholesterol, capfos tSnorr'and* caprostanone) are eodeiratel/ inhibitory.jon B(a)P cayMiogeneiia (339). However, other researchers have foundfcholeaterol to promote carcinogenesm vhictk.was previously inhibited by phospholipids (340|. Nitrosoamines, known to have carcinogenic: activity, have been shown to act synergiatlcally with B(a)P, resulting in a higher incidence of lung and stomach tumors in animals than if each agent were administered separately (341). Nitrosoamines may not enter the human body as such but can be formed through metabolic processes and altered by other agents. For instance, nitrites can react with secondary amines to yield mtrosoamir.es, and substances such as gallic acid and 4-methylcatechol (in coffee) enhance formation of nitrosoamines, whereas ascorbic acid depresses formation of nitrosoamines I 3 30 J. Dietary sodium sulfate has been shown to enhance azo dye carcinoqenosis [142]. Many major constituents of essentia] oils, flavors, and snicos are also considered tumor promoting and carcinogenic. The major constituent of orange oil, D-limonenc, is a skin t-.jr.or promoting agent in mice, while turpentine oiL and eucalyptus oil contain the cocarcinogcns !.-pinene and phel landrene. Other essential oils with lower terpenc levels have less tumor promo tine [338) Challis, d. C. , and C. D. Hurt ic: : . Possible- Cc car e : i.c-ier. ic Effects of Coffee Constitutcnts. Nature (bond.), 234(5300): 532-533, 1975. (239) Watanabe, K., ct al. Effect of Pile Acids ami Neutral sterols on Ucnzo(a)pyrone-Induced Tumoriccnesis in Skin of Mice: ttrief Communication. .1. Natl. Cancer Inst., <5 0 {ft) ; 1501-1303, 1978. 1340) Altman, !. F., et al. Phospholipids Retard and Cholesterol Promotes the Formation of Tumours Induced by Carcinogenic Hydrocarbons. Z. Naturforsch. (D), 23 (9) : i 277-1279 , 1968. (341) Bir.gham, E., et al. Multiple Factors in Carcinogenesis. Ann. N.Y. Acad. Sci., 271:14-21, 1976. (342) Blunck, J. M.,and C. E* Crowther. Enhancement of Azo Dye Carcinogenesis by dietary Sodium Sulohate. Eur. J. Cancer, 11(1):23-51, 1975. ` 223 MOMS 022299 ferity' ft43r:^iawmb** aoc*rcinognic (344L4<51. Studies Indicating that certain cooking on* possess cocarcino-- genic activity have been reported since 1964* Triolein/, a major, constituent of cottonseed oil and sesame oil* was .tested oh mice and was found to be cocarcinogenic (546, 347J. Tests with butter oil and sunflower oil hove d:-c ns t rated tnat, when overheated, these oils possess carcinogenic and cocarcino genic properties (3481. Studies using a mutant safflower oil rich in oleic acid indicate that polyunsaturated fats act as cocarcinogens (3491. Cyclopropenoid fatty acids (CPFA) (e.g., sterculic acid and malvalic acid) occur in certain foodstuffs such as cottonseed oil, kapok oil, and flour and have been demonstrated to act as powerful tumor promoters or cocarcinoger.:- for aflatoxin [ 34 3 ! iior.bursev , F., and C. 3c>ror. I'urcinouenic! t,y Essential Oils, Flavors, and Voices: A -'ovk-*'. <.\ir..vr Eos. , 28 ( 1 1) : 2372-2374 , 1 <K-8 . ' i 3441 saianan, M. II. , and F. J. null. , 20(2) : 1 39- 144, 19-.t . Coe.arc : rogo- < '345J Schramr., R. , and W. C.i re : i c m:! ......... Plant Products, II. Care mo seme Pubs' Ptor idephyta (Filicinac! nr.: Pri-rr.a toprv t' . : r . , Dicotvledonoae, Monocotvledor.o ie) . Arc:.. .;<-i:wa 1 ,.i forr.cn . , 33(21:169-188, 1969. * [ 346) Zschicschc, K. , and G. Rru.-.s. i.'.iri inogor.es . cholesterol. Oncology, IS (4;:269-299 , 1964. 7-Xeto- [347] ilryson, G., and F. Uischof:'. Triolein a ; ; .''.-ru i . v Fed. Proc., 23(2, Pt. 1):106, 1964. ;r:i . (348| Dzagnidzc, L. I., and P. N. Krasriyanskava. A vu-d-.. o: Possible Carcinogenic and Gcearcmogoni I'rnp'i"-:' - Overheated Oils. Soobshch. Akad. Nauk. Grur. SSH, 229-231, ,4$72. 1 349) Dayton, S., et al. Effect of High-Oleic and High-Linoloic Safflower Oils on Mammary Tumors Induced in Rates by 7,12-- Dimethylbenz (alpha*) anthracene. J. Nutr., 107 (3) : 13 S3-1360, August 1977. ' 224 HONS 022300 n4txted ItVtttCanceriftf trout [350-352). BcaaMkVitMta? be?\ tttjlMthe high^ incidence .of colon cancer ii\ man is doe to lack ot?3lcary fiber, studies ve'ie conducted on''rata usiogr wheat bran^Miectin, alfalfa, and carragecnin. Fifteen percent dietary carrageen!n promoted colon tumors, and the modifying effect of dietary fibers depended on the type of fiber used 13S31. A study of furfural on the respiratory tract of hamsters suggests it is a cocarclnogenie agent with B(a)P (354J. Furfural can be found in cigarette smoke but also in foodstuffs including bread, coffee, processed fruits and juices, and alcoholic beveragos. This may be supported by a study which showed that extracts from dried plums showed cocarcinogenic activity (3551. Although alcohol is not part of what is considered a normal diet, alcoholic beverages are consumed by many people. It i3 estimated that alcohol plays an etiological role in greater than 50*. .if the oropharyngeal cancers in the i ni ted States 1355). 350) S inr.huber, R . , vO. , e t 3 1 . Me Label ! sr. and Cocarcinccienic : t\ of Cy-clopropen r F> . Oregon Ft a te H i fiber F.d uc. Sys., School Agriculture, F r;o<! S c icnc i rid Tech no 1ogy, Co rvallis, Oregon 3 31; Pee, D. J., et a Syror : l sr. HetW i.cr. Cyc lop ropenoid Fatty Acids and Cher. :ca 1 Care: on on S m ?a i r.t.ow Trout (Sa.r.e Cairdneri). C ar.co r Ros. , 2 8 ( 111:2 31 2-231 8 , 1968. 3321 3531 Petering, ii. 2 ^ ) ;et, Mu t r ; t ton, ant: Can eer . Med. Biol., 91 : 207 -228, 1 977 . Adv. Raikow, R. 3. V * f OTwS 'J i Car c lr.og n o r Sus pected Carcinogens on Viral l.uekor.cgcr.osis in. C"B!./10, SJL/J Mice and Their FI Hybrid (Mcotir..: Abstract . i'ror. Am. Assoc. Cancer Res., 19:23, 1975. i 3 5 -i ] Rick, E. W. Furfural: Exoacr.cus Precursor of Certain Urinary Furans ar.d Possible Toxicolonic Agent in Humans. Clin. Che.T.. , 18 ( 12) : 1550- 1351, 1972. (355) Ruchkovskii, B. S,, et al. Carcinogenic and Cocarcinogenic Action of Dried ^ruit Extract. Vopr. Cr.koi., 20 (41:58-61, 1974. (3561 Rothman, K. J. The Effect of Alcohol Consumption on Risk of Cancer of fthe Head and Heck. (Head and Neck'Cancer, State-of-the-Art Conference, St. Louis, MO., February 16-18, 1976.) Laryngoscope, 88(1, Part 2, Suppl. 8) 151-35, 1978. 225 HONS 022301 i\n investigation of the incidence of oral cancer in'JKfcwrs whfl smoke and drink indicates that alcohol is a cocarcind^en '*itn cigarette smoke f3S71. Thia is also suggested in another study brother study performed on rats suggests a synergism between inhaled vinyl chloride and ingested alcohol in *. umor igenesis (359]'. ' ' Investigations of the effect of masticatory substances such as chewing tobacco and betel ruts have indicated that in conjunction with tobacco smoke these substances .--av be cocarcinogens (360. ? 61! . ' PHYSICAL AGENTS AND BODY MATERIALS Physical agents which act as carcinogenic cofactors are generally those which act upon or contact the human body buc usually are .not chemical in nature, such as forces or forms of energy (x-rays). Body materials are those which relate to body chemistry or body f line l ions. The tissues in the human oral cavity are generally exposed to repeated low doses of x-rays from diagnostic medical and dental radiology. Studies have been performer! on hamster cells and hamster check pour.ch where repeated low doses of x-rays have x h 11. . t cd carcinogenic or tumor ;.. ror.ct inn activity with rei eated low di scs ''I a known carcinogen (ir'.B.M 'r whore x-rav treatment . ; 3 37 j Brass, I. D., and J. Coombs. Marly Onset of Oral Cancer Among Women Who Smoke and Drink. Proc. Am. Assoc. Cancer Res.^ 17:1, 1976. (3591 Gibel, W., and G. Wittig. On the Experimental Induction o: Carcinoma of the Esophagus. Dtsch. Cosundheitsw., 19(19): 333-637, 1964. '359] Sadskc, >1. J., et al. Effect of Ethanol and. Vir.yl Chloride on the Induction of Liver Tumors: Preliminary Keptrf. Environ. Health i'erspent. , .11: 1"1 ^3, ln7~. . 6 0) ..'ayjr.t, K. Stasis:seal Aprr.iiral of thv Association of Smoking and Chewing iiabi*s to "'r1 and rh.iryr..teal Cancers. Indian 3. Car.ccr , 14 ( 4 ) ; 1 3 3-2 99 , 1)7'. 1361! Ranadive, K. J., et al. Experimental Studies on Betel'Ndt and Tob. cco Carcinogenicity. Int. .3. Cancer, i7 (4) : 469-476, 13 Acrii 1976. 226 HONS 022302 E^VtJUDlIM1$trat:ion of the ciljjlftpgemc agent [367, 363). fhtf'TOCRtH^flnect of ultravioletrfw)flight is not quite as vel&*d0&tae^-A>study of the effect of UV light exposure to hamster heellB^followed by B(a)P or N-acetoxyfluorenyl-acetamide resulted, in neither an additive nor.synergistic enhancement observedT witHTeither chemical agent'alone [36 3 ) . However, another study showed significant enhancement by UV light on DMBA initiatod skin carcinogenesis (1201. '.'he explanation appears to bo in the sequence of exposure. An additional study on nonhuman primates demonstrated that DMBA was oncogenic when applied to the skin in combination w*th UV light (364). Removal of the gall bladder (cholecystectomy) has been suggested in several studies to have a cocarcinogonic effect in cancer of the colon. A detailed investigation of 760 cases of large bowel cancer revealed a strong associate between cholecystectomy and ascending colon cancer [365]. An experimental study on nioi was initiated when another greup of researchers showed clinical findings that 10k of patients with carcinoma of the large bowel had previous cholecystectomies. This cocarcinogenic effect was verified in the animal tests with the carcinogen 1,2-d imechylhydraz ine (L>MII). The cocarcinogenic effect of cholecystectomy was assumed to be due to an increased produc tion of secondary bile salts by the colonic bacteria and the lack of reserptive function of the gall bladder for some carcinogenic material (3661. Bile salts in the colon introduced by surgical means have been demonstrated in other animal studies to enhance 1362) iiecht, S. S., et ai. Chemical Studies on Tobacco SmokmDetermination of Hydroxybenzyl Alcohols and llydroxyphcnyl Ethanols m Tobacco and Tobacco Smoke. J. Anal. Toxicol., 2 (2) : 56-59, 1978. (363) DiPaolo, J. A., and P. J. Donovan. Morphologic Transformation of Syrian Hamster Cells by l.'.VIrradiation is Enhanced by ."-Irradiation and Unaffected by Chemical Carcinogens. Int. J. Radiat. Biol., 30(1): 41-- 53 , July 1976. (3641 Palotay, J. L., et al. Carcinogen-Induced Cutaneous Neoplasms in Nonhuman i'rinates. J. Natl. Cancer Inst., 57(61: 1269-1274, lj|76. |365] Lohsoonthron, P. 'The Epidemiologic Study of Subsite Largo Bowel Cancer. Diss. Abstr. Int. (B), 36(91:4399-6, 1976. ( 3661 Werner,. 3. , et al. Cholecystectomy and Carcinoma of the Colon, An Experimental Study. 2. Xrebsrorsch., 83(31:221- 230, 1977. ' * ?27 MQNS 022303 tfci ckf&YfB^frilc effect'' of 368).^^Other^iubatances present in Ui large; bowel^i been tested^ in animal models for their cofactor acttVIf^*',Wle acids suchs cholic acid, chenodroxycholic acid, aad'Slithocholic acid were tested on rats with the carcinogen MNHG and indicated that prUnary-bile acids modified to,secondary bile acids by intestinal bacteria exert a strong promoting efeet*In*colon cancer (369) . These same bile acids along with neutral sterols acted as inhibitory agents to B(a)P induced skin tumors on mice (339J Fecal samples of patients with colon cancer have shown large amounts of bile acids, cholesterol metabolites, high fecal bacterial 7-alpha-dehydroxylase and cholesterol dehydrogenase activity (370). The chemical fluid, adenosine 3',5'-cyclic monophosphate, is found in all living cells and is essential for muscular action. This substance has been found to enhance skin carcinogenesis by 7 ,12-d ir.cthy lbenzanthracenc (371). Previous findings that trauma is a potential cocarcinogen was supported by two cases of women who developed breast cancer in. old thoractomy scars. 1 r. each, case the comb i r.a 11 on of pear tissue and surgical trauma sec-nod significant in. the development of cancer [372], ft has also been reported that chronic inflamma tion can be a cocarclno>:- nic factor in the formation of bone cancer [ 3 7 3 J . (367) V.'i 11 ians::t, ? . C., "t a'. Th.-- h:': p-r of F.mcrea t`'h : 1 i ary Diversion or. 7-st:,u! '.'are i r.ogen-.-s : s ;'' ' mg Abstract) . Or. J. Surg., 64C li ssi37. 1977. ( 368) Reddy, !3. S. Role of 0;lo "t tnboliH's in colon Carcino genesis. Career < Ee::p 1 . ! , ',6:2401-2 4 06, i 97 5. [369] Reddy, D. S., et a 1. Colon Careino, rones is (Meetino Abstract'. 1977. ' Promoting Effect of 3ilc Acids on in Gcrmfree and Conventional Rats I'rce. Am. Assoc. Cancer Res., 18:119, 1370] Wyndor, E. 1.. Melaholie Epidemiology of Colon Cancer. Amer. Health Foundation, Inc., New York, Now York. (371) Curtis, J. L., et al. Enhancement of 7,12-Dimcthy1benzanthraccne Skin Carcinogenesis by Adenosine, 3',6`Cyclip Monophosphate. Cancer Res., 34 (9) : 2192-2195, 19/4. (3721 Freund, li. , o't al. Breast Cancer Arismo in Thoracotomy Scars (Letter to Editor). Lancet, 1(7950):97, 1976. (373) Glaser, A. Pathologic and Clinical Aspects of Bone Tumors. Zentr nlbl. Chir., 101 (6): 321-329, 1976. 228 HONS 022304 In a-survey of lung cancer patients who saoked, chronic bron chitis was shown to be cocarcir.ogenic with cigarotte smoke (374J. In a study of the mechanism of action of polycyclic aromatic hydrocarbon carcinogens it was suggested that antibodies to the carcinogen may enhance the tur.origenicity of the carcinogen [375). The effects of chronic mechanical irritation of the gastric mucous membrane on stomach carcinogenesis was investigated. It was concluded that foreign bodies had promotive effects in glan dular stomach carcinogenesis by MNNG, possibly by prolonging retention of the carcinogen and in turn the exposure to the gas tric mucous membrane 1376). Tests conducted in Russia on the effect of magnetic fields on rats concluded that magnetic fields enhanced tumor growth initi ated by B (a)P or polyvinyl chloride (PVC) 1 377). It has also been reported that rotary motion causes stress which stimulates the functioning of the pituitary glad or adrenal cortex, thus promoting tumor development (378). THERAPEUTIC AGENTS AND TRE\7".rNT5 Tests have shown that sr"' m'. therapeutic agents exhibit carcino genic cofactor activity. : . is most ironic that certain cancer therapy drugs have been i to bo carcinogenic as well as therapeutic in experiment a. systems. An example of this is actinomycin D which can ,i> a cancer therapy drug, anticarcino gen, and carcinogen ,'373;. '. -c:- -,1;',ccr therapy drugs also act as cccarc inegens a:..: nut: men tv- tumor igen ic i tv of chemical carcinogens. Clinic tl .studies succesting an increase'! incidence of malignant r.nco'. as- s :: : itients with id'dcV. i n ` s disease treated [374] Lung Cancer and Chrv : ; .'trench.: t i s. Med. 926-927, 1964. Aust., 3! (24): (375) Stonback, F., and c. Curtis. Mechanism of Action of Poly cyclic Hydrocarbon Carcinogens: Imnunologica 1 Aspects (Meeting Abstract). Scant!. J. Immunol., <7(11) : : 1^*5, 1977. ( 376 ) Fukushima, S. , et al. Efforts of Foreign Bodies on Gastric Carcinogenesis in Rats Treated with n-Methyl-n1-nitro-r.nitrosoguaniaine (MNNG). (Free. Jpn. Cancer Assoc., 33rd Annual Meeting, October 1974.' Gann, 67, 1975. (377) Kogan, A. K.rH. , and V. I. Kulitskaia. The Effect of a Stationary Magnetic Field on Induced Carcinogenesis. Patol. Ffciziol.. iElspp. Ter., (2):63-6S, 1977., (378) buzuki, S. Effect of Rotary Motion on Carcinogenesis. Nagoya City Univ. Med. Assoc., 19(4):1517-1553, 1969. [379] Harris, C. C. The Carcinocren tertv cf Anticanccr Drugs: A .Hazard 'in Man. (Cancer, 37 ( 2):1014-1023. 1976. 229 MQNS 022305 intensively with radiation and chemotherapy, prompted testing on. aniaala. Teat, results'indicated that procarbazine and ionising radiation hav.a a'Synergistic cflroinoqeniciaction (380). other tests with urethan, an antileukemic drug, demonstrated its behuvie as both a carcinogenic and cocarcinogenic agent (344, 381). Melphalan (L-phenylalanine mustard), a cytostatic drug used in the treatment of breast car.cer, markedly enhanced mammary tumor formation in aicqj (382).' Results of'tests on aliopurinol, used in the treatment of gout and human neoplasia, demonstrate its enhancement potential of bladder cancer in rats induced by N[4(5-nitro-2-furyl)-2-thiasolyl)formamide (PANFT) (383). Data from several cancer centers'indicate that immunosuppressive drugs (in transplant recipients) may also act as cocarcinogens with UV light in the induction of skin cancer 1384). Criseofulvin, an antifungal antibiotic, acted as a cocarcinogen with skin applications of 3-methyIcholanthrene in mice but not with B(a)P |385). In a similar study griseofulvin was found to inhibit skin tumors promoted by croton oil and induced by P'a)P out lacked promoting activity bv itself [386]. dignol i r., used in the treatment of psoriasis, was tested on mouse r-km lira: iMted with a carcinogenic .went {DM DA or tar;. The ! 3 no; s.--. .1. C. , ct al. Synergistic Carcinogenic -if feet of ; r-v.-irb.-i;: i nc and Ionizing Radiation in CDF Vice. Proc. Am. Assoc. Cancer Res., 1 s 1120, 19 7 j. [ 3B11 Posir, A. Contribution of Carcinogenesis. Acta Ved. : r,l . , 16 (2) : 172-180, 1962. ;.lr>2] Mcui.-.a, D. Enhancement of Mammary Tumor Formation in Mice :y a Cytostatic Drug, Melphalan. Cancer Res., 9l ' ' 7 o _ :317- i.;.-,' C. Y., and S. Mayashide. Enchancement c f ! 4- ( 5-n : t re 2-furyi'-2-thiazolyl) formar.idc ("ANFT Carcinogen;city for Pat Urinary Bladder bv Aliopurinol. Proc. Am. Assoc. Cancer Acs., 17:149, 1976. ` 1384] Mai.'.c, J. C. Skin Cancer in I.mmunosuporessed Fatients. JAMA, 237(17):1857-1858, 1977. [385] I ARC Monographs,yaluatinof.the Carcinogenic Risk of Chemicals* to Man,] Volume 10, 1976. p?. .153-161. . 3 o 6 , A. sue 1 i:\ov itch, S. D. , and . Mihailovich. The inhibitor-/ 1-::; ect of. Griseofulvin on the "Promotion" of Skin Carcinogenesis. }Cancer SRe^.t, 28 ( 12) : 2463-2465, 1968. 2 3Q HONS 022306 application of cignolin promoted the formation of skin tumors in More than one-third of the animals tested (387]. /Vninal 9tJdies cmployinq the sedative phenobarb1tai have demon strated that it can act as a carcinogenic inhibitor or enhancing agent. Phenobarbttal given together with diethylnitrosoamine (DENA) reduced the severity of liver carcinogenesis but when administered after DENA it enhanced carcinogenesis (388). Phenobarbital also enhanced azo-dye induced liver carcinogenesis in rats (389' while inhibiting 4-(dimethylamino)azobenzene induced carcinogenesis (322J. Steroidal anti-inflammatory agents have been tested on mouse skin and have been found to inhibit skin carcinogenesis. Dexamethasone and fluocinolone were the most effective inhibitors while estra diol, estrone, estriol, testosterone and progesterone were found to act as inhibitors but to a lesser degress (390, 391). Steroidal compounds have also been tested for their cofactor activity in other human applications. Estradiol dipropionate, an estrogenic compounds, was tested on rabbits with the care inoc.cn me thyicholanthrone, unci the results suggest that estrogen may promote uterine cancer 1392'. Similar studies with estrogenic compounds and prolactin suggest a (387) Lar.gbein, W. Contribution to the Coca nee rogue it Effect rf Cignolin in Animals. Radiobto 1. Radiothor. (Perl.), 1 3 ( 2 ) : 2 3 3 - 2 4 C, 1972. (388) Wcisburger, 0. I!., et al. Modification of DiethyInltroso- arnine Liver Carci negenes i s with Fher.obarbi tal but Mot with Immunosuppression. J. M.itl. Cancer Inst., 54 (51 : 11 S3--1188, 1973. ` (389) Kitagawa, 7., and !!. Sugar,o. Enhancement of Azo-Dye Hcuatocarcinogenesis with Dietary Phenobarbita1 in Rats. Gann, 68 ( 2): 255-256, 1977. (390) Van Duuron, B. L. Tumor-Promoting and Cocarciroqcnic Agents in Chemical Carcinogenesis. In: Chemical Carcinogens, Scarlo, C. E., ed., American Chemical Society Monograph 1973, American ^hcmical hociotv, Washington, D.C., 'o?.',. pp. 24-51. / ' (391) Slaga, T. J., et al. Mechanism of Action of Steroidal Anti-Inflammatory Agents that Inhibit Skin Carcinogenesis. Proc. Am. Assoc. Cancer Res., 16:37, 1975. ;352) Kawaguchi, K. Studies on Experimental Induction or Endometrial Carcinoma in Rabbits, Especially Relate:: to Their Carcinogenesis (Meeting Abstract). Acta Cbr.tet. Gynaecol. Jpn., 21(1):68, 1976. 231 HONS 022307 synergistic effect on format ion of rat mammary tumors {393-3951 and a synergistic ^effect on cervical carcinoma* induced by 3Mthylcholanthrene %(HCA) {396). However, other researchers, 'although recognizing that estroneand estradiol -are linked to carcinogenicity and cocarcinoqenicity, feel that estrogen levels in ora' contraceptives are too low to affect genital carcinoma and do not elevate the risk of breast cancer (397). Another study performed on rats gives evidence to support the concept that sustained elevation of estrinl ir, body fluids inhibits breast carcinogenesis (3931. Enovid, a mammary growth promoting agent, is made up of 98.51 norethynodrel and list mestranol. Tests conducted with this substance on rats sugget that it may inhibit the carcinogenic induction of mammary tumors but may enhance the growth of tumors already present (399). 3ased on medical histories of two women it was suggested that liver cancer may be caused by a synergistic effect of estrogen and progesterone (400). ( 39 3 ) Muhlbock, 0., and L. M. Hoot. The .Mode of Action of Ovarian Hormones in the Induction of Mammary Cancer ir. Mice. Biochcm. Pharmacol., I 6(41 : f 27-630< 1967. 13 9 4] Warren, S., and O. Cates. P.adiation Carcinogenesis, Progress Report IV, 15 March 1976 - 15 May 1977. Available through National Technical reformation Service, Springfield, VA, as COO-301 7-31, FY-76-s-02-3017, 1977 . 15 pp`. |39r'l hee, C. , et al. Interaction of Estrogen and Prolactin on Hormone-Dependent Rat Mammary Tumors. Proc. 3oc. Exp, Biol. Med., 143(11:224-226, 1975. (3961 Forsbero, J. G., c.r.ci I.. S. Droisteir.. A Synergistic Effect of Oestradiol and Prolactin Influencing the Incidence of 3-Methylcholanthrcno Induced Cervical Carcinomas in Mice. Acta Pathol. Microbiol. Scar.d (A), 84 (5) : 384-3fin , 1976. (3971 Vorherr, H. Contraception Postabortion and Postpartum, Advantages and Disadvantages of Hormonal Contraceptive with Particular Reference to the Relationship 3etween Female Sex Hormones and Thromboembolism, and Carcinoma of the Breast and Genitals. Gynaekol. Rundsch., 15(11:48-73, 1975. (398) Lemon, II. M. Estriol and Prevention of Mammary Carcinoma. Cancer Detec. Prevent., 1 (2) : 263-281, 1976. (399) Welsch, C.W. Effects of a Norethynodrel-Mestranol Combination (ENOVID) on Development and Growth of carcino gen-induced Mammary Tumors in Female Rats.. Cancer, 23(3)Y60*>6<f7?**69. ` 14001 Chevrei, 3. Role of i'toroi.: Hormones in the Development cf Malignant Tumors (Letter to Editor). Nouv. Presse. Med., 5(17) :1145, H976,'. 232 HONS 022308 Several adrenergic agents have been tested on aniaals for their cofactor effect. Noradrenaline and atropin were found to enhance liverVcancer while isoprenalin inhibited it [401]/ ENVIRONMENTAL COFACTORS Cigarette amok# it an important environmental constituent contain ing Many components which exhibit carcinogenic cofactor activity. A sariea of 21 tobacco smoke components and related compounds were tested for cocarcinogenic activity on mouse skin with B(a)P as the active carcinogen. The results of the tests are summarized in Table B-l. ' TABLE B- 1. COCARCINOGENESIS EXPERIMENTS: SUMMARY Cocarcinogenic activity Weak or Potent moderate Catechol Benzo ( v:) pery lene Pyrogallol I.auryl alcohol Decane Tet radecane Undecane Pyrene 3[eJ P Fluoranthene Inhibitory activitv Partial Complete Phenol Esculin FhlU'T'' 1 Oucrcetin Rosorcmc 1 Siua lene iii'X jdocani- Oleic acid Hydro.:u mono Limoni'no Six of the 21 compounds were also tested is tumor promoters in two-stage, carcinogenesis. No direct correlation was found between tumor promoting activity and cocarcinoqenic activity. The cocarcinoger.s pyrogallol and catechol did not. show tumor promoting activity, while oecanc, totradoc.ir.e, anthralin, and phorbol myristate acetate showed both types of activity [2!2|. In addition, tumor promoting or cocarcinogenic activity has beer. (401) Gurkalo, 3. , and M. A. Zabezh i n a'-'.y . Modification of Chemical Carcinogenesis with Adrenergic Ccr.oounds. Vestn. Akad. Med. Nauk SSSR, (21:33-4.?, 1373. 233 HONS 022309 attributed to other cfcwpounds isolated6from cigarette stroke including alkyl naphthalenes and nitrosoanines [402, 403?. These findings are lm|f>ortant because many of the above substances are alsr contacted by non through either industrial pollution or natural sources (food, etc.). Another study was undertaken to examine the effect of nicotine on the carcinogenic activity of cigarette smoke condensate on mouse akin. Early in the experiment the largest administered dose of nicotine appeared to inhibit tumor formation. However, at 37 weeks the results demonstrated that low to moderate concentra tions of nicctine act as important cocarcinogenic stimuli [4041. Another important potential environmental factor is human viruses. A study of nasopharyngeal carcinoma in Southeast Asia has suggested an undefined cocarcinogenic role for Epstein-Barr virus 1405). Cocarcinogenic activity of viruses was also suggested in a stuuv of h.inster tumors. Primary tumors grafted to new animals showed malignant characteristics not present in the ori tinal tumors. The malignant potential of the cells could be correlated .;ith the- presence of viral particles acting as cocarcinogens (406). further readies have been conducted to specifically investiuate the cocarcinogenic activity of viruses. <>n one test human embryo lung cells were infected with oncornavirus I.PV and then treated with the carcinogen MNNG. It was concluded that a synergistic effect existed between MNNG and the oncogenic virus 1407). Anotht r s i ir.t: icant finding ir. the area of cocarcinogenic viruses |402] Sehr.ci to, !., et al. forma*. :<::: and Determinat i of Naphthalenes ir. C ienro r to Smoke. Aral. Chcm. , 48(4):645- 6 5 0 , 1 7 7 ii. i4Cji Argus, f., and J. C. A:cos. hydrocarbon-.'.': t r -snanine Syr.er.: ism as a Possible Amp lying factor ir. l.ur.e '.'urmori- genesi s bv Tobacco Smoke. J. Theor. Biol., 56 ( 2) : 49 1-4<>3, 197.;.. ' ;404J Dock, f. 0. Cocarc tr.o.n :i! c Activity of Nicotine. Assoc, dancer Res., 17:2, An. [405] Etiology of Nasopharyngeal Carcinoma. Lancet, . (homo) :1 n1, 1976 [406] DeMicco-Pagis, C., et al. Pathologic and Ultrastructurul Investigation of a DMBA-Induecd Transplantable Melanoma th ponder} Hamster. Bull .Cancer . (Paris), 63 [11:73-86, 1976. D:.A Reparation and Chromosome ,/A fc, l . .<.4V>I7 4 n ~ * a Infected with LPV Oncornavirus. ilocr. V irusol(6) : 712-716 , 1977. 234 MONS 022310 was observed when nice, after successive infections withfthree muse-adopted strains of influenza and exposure to ozonised gasoline aerosol/ developed lung cancer (408). INDUSTRIAL CHEMICALS AND POLLUTANTS There is not a clear distinction between industrial' chesdAls and industrial pollutants because in most cases the cheajcale produced and used by industry may also be discharged to environment. Testa on rats have suggested a synergistic effect between inhaled vinyl chloride (the monomer used in producing polyvinyl chloride) and ingested alcohol in tumorigenesis (359). There hat been some concern over the solvents employed in testing carcinogens as to their potential cofactor effect. Many of these solvents are also industrial chemicals, and the findings of test programs may also relate to industrial exposure. Benzene, toluene, and acetone were tested in this regard and it was con cluded that benzene and toluene have cocarcinogenic potency while acetone had no effect 1409). Acetone has been reported by others as cocarcinogenic (4). Other solvents which have been tested include docalin, n-dodecane, and 1-dodecanol. In these tests n-dodecane, decalin and 1-dodccanol were found to be cocarcinogenic solvents depending on the concentration of the carcinogenic materials used |B(a)P and benzan thracene) (410). It has also been reported that the use of ndodecane as a solvent for 3(a)P can result in a 1,000-fold enhancement of the effective concentration of B(a)P for skin tumor induction (341). Other studies confirm the cocarcinogenic properties of these materials, including n-decane and tetradecane with B(a)P and UV light [411, 412). (408) Bryan, W. R. Current Concents of Viral Neoplasia. South. Med. J., 57 (11) : 1263-1267, 1964. (409) "azzucco, K. The effect of Toluene, Acetone) Used with Content of the Mouse Dorsal 2(2-3):49-5l, 1975. Various Solvents (Benzene, Carcinogens on the Collagen Skin. Osterr. Z. Onkol., |410] (411) Bingham, E., and H. L. Falk. Environmental Carcinogens, The Modify inn Effect of Cocarcinogens on the Threshold Response.. Arch. Qitviron. Health, 19 (f>) : 779-783, 1969. f Bingham, E., and P. J. Nord. Cocarcinogenic Effects of n-Alkanes and Ultraviolet Light on lice. J. Natl. Cancer insti,' 5ff(4K:1099-1101, 1977. ; 4:2 j Tsr.akj, T. Influence of r.-Dodocar.v an Rats Exposed Transrlaccr.tially to Be.nzo(a) pyrene and ::i trosomethvluiethan During Pregnancy (Meeting Abstract). Third International Svmnosium an Detection and Prevention of Cancer, 197.6. pp.' 286-267. 2 35 MQNS 022311 A mi'h*c||CL, oil (Orakeol 6VR) was analysed and consisted of three major"components, one containing promoters (e.g., hexadecane), anothai*'.1ntainlng ma inly 4fnhiM tore, and the third containing both promoters and inhibitors Mil]. Carbon tetrachloride, a widely ised solvent (e.g., cleaning, fire extinguishers), has been tested on rats and is suspected of a-.*ting as a cocarcinoqen in formation of liver tumors (414). Total phanols from wasta waters ofa shale processing plant applied to mouse akin after a subcareinogenic dose of B{a)f resultad;in development of malignant neoplasms (415). Others have also reported the cocarcinogenic activity of phenols and anthralin (1,8,9-anthracenetriol) used in the textile industry 1344, 416, 4171. Investigation into the frequency of cancers in an aldehyde factory suggest, that there may be a syncarcinogenic effect between some aliphatic aldehydes (which are ulso present in automobile exhaust and cigarette smoke) and some air pollutants 1418]. Because dodecylbenzene has been reported to be a cocarcinogen and tumor promoter (341, 4191 a group of Russian scientists have tested Sulfor.ol N'P-1, a surfactant made from dodecylbcnzene r-jl fonr. te , for its potential cocarc i nooen ic i ty. Sulfonol NP-1, a mixture of sodium salts of alkylbcnzene sulfonic icids, sodium sulfate, and nonsu1fonated organic compounds, acted as a (413) Horton, A. w. Cellular .Mechanisms ol Chemical Carcino genesis. National Technical Information Service No. PB 225 631, 1973. 91 pp. (4141 Mori, et al. Effect of Carbon Tctrachloride on Carcinogenicity of Petasitcs Japonicus, and Transplant- ability of Induced Tumors. Gann, 68(61:841-845, 1977. [415] Mirme, H. Modifying Effect of Water-Soluble Shale Phenols on Careinogenesis. Vopr. Profil. Zagryaz. Okruzhayushchei. Chel. Study Xantserogennyni Vcshchestvami: 16-18, 1972. (4161 Becker, E. Aspects of Cccarcinoqencsis. In: Scientific Foundations of Oncology, T. Symington and R. L. Carter, eds., William Heinemann Medical Books, Ltd., Chicago, 1976. pp. 310-318. (4171 Falk, li. L. ;i*Possible Mechanisms of Combination Effects in Chemical Cafcinogenesis. Oncology, 33(2):77-85, 1976. (4181. Pershagen, G., et al. Mortality in a Region Surrounding an ' AAenic Emitting PlRntl | Environ. Health Perspect. , 19:133 137, 1977. [419] Cargos, J. L., ot al. Utilization of Newborn Mice m the Bioassav of Chemical Carcinogens. Toxicol. Aool. Pharmacol. 15(2 :552-559, 1969. " 236 MQNS 022312 cocarcinogen but did not exhibit carcinogenic properties'T4201. Another surfacc-actLve agent, olefine sulphate, has been tested and demonstrated to enhance B(a)P induced akin cancer [OIK The flame retardants tec rak i s (hydroxymethy 1) phosphonium chloride (Tll?C) and Pyrcset 7>'.P (nixed acetate/phosphr.te of same phos phonium base) have been tested on mouse skin and found to be active as tumor pre.-oters with DMBA initiation (422). THPC and Pyroset TKP have been widely used in cotton fabrics, particularly children's sleepvaro. Other chlorinated compounda found to exhibit cocarcinogenic properties include polychlorinated biphenyla (PCBs) and certain pesticides and herbicides. Chlorophenol pesticides and the herbicide 2,4-D (amine salt of 2,4-dichlorophenoxyacetic acid) were tested on mice and rats and are suggested as potential cocarcinogens [423, 4241. Similar results were obtained from tests on PCB and HOT (425, 426]. As with all agricultural products, pesticides and herbicides, besides being industrial chemicals and pollutants, also result in human exposure during'us.vuo and through the food chair.. Ammonia, found in many chemical products including fertilizers, has beer, tested on mouse cells as r:;or:un salts and a number of primary (420] Sakharov, I. I., ct al. The Cocarcinogenic Activity of Sulfonol l.'P-i. Gm. 7r. Prof. Zabol., (9) : 56--58, 1973. (421] Pyleva, Z. A., ct al. Data on the Biological Properties of Olefin Sulfate. Vopr. Onkol., 24(11:55-60, 1978. (422] Loevengart, G., and 3. L. Van Duuren. Evaluation of Chemical Flame Retardants fer Carcinogenic Potential. J. Toxicol. Environ. Health, 2 ( 3) : 539-546, 1977 . (423] Arrhenius, E., ot. al. Disturbance of Microsomal Detoxica' tior. Mechanisms in Liver by Chlorophenol Pesticides. Chon. Biol. Interact., 1 Sv 11 : 35-46, 1977. (424] (425] Arkhipov, G. 1.'., and I. N. Kozlova. Study of the Carcino genic Properties o: the Herbicide, Amine Salt of 2,4Dicholorphenoxyacer ic Acid. Vopr. Pitar.., (5) :C3--84, 1974. Uchiyama, "if et al. Cocarcinogenic Effect of DDT and PCB Feeding on Methyicholanthrene-Induced Chemical Carcino- {enesis. Bull. Environ. Contam. Toxicol., 12(6):687-693, 974. (`.-I; Nagasaki , _t . Analysis of Various Factors on Liv.r Carcinogenesis i r. .'-'ice Induced by Benzene iiexachlcride (BiiC) ar.d Technical Polvchlorinated Biphen.vls (PCBs). jJ. llara. Mcc. As see., 25(61:635-640, (P.ecd. 1975). 237 HONS 022313 emlnea. The evidence implied that ammonia may he carcinogenic or cocarcinogenie (427!. Orthophosphate and 1-phenylalanmo were tested on hamster cheek pouches and found to promote tumor growth. Phenylphosphate, on the oth*r hand, inhibited? careInogenesii (428). Chromium car bonyl, when tested on rata, was demonstrated to be a carcinogen and acted synergistically' with B(a)P [4281. Results of tests with sodium hypochlorite show that it Is cocarcinogenic; however, it was concluded that this chemical is not a practical carcino genic hazard (430). Repeated application of hydrogen peroxide after application of B(a)P to nouse skin markedly inhibited the carcinogenicity of B(a)P (4311. Other industrial chemicals have been tested and found to be carcinogenic cofactors. Four chemical substances, N-nitrosopiper- iJino, N-nitrosomorpholine, diethyinitrosoamine, and U-2- fIuorenylacetamide) were fed to mice for 4 weeks. Each substance inhibited the induction or urir.ary bladder cancer by n-butyl-N- :i-hydroxybuty1)nitrosoamine {3 J5J. In tests on oral carcinogens :: was found that 2-aninOfiaphthalcne and 4-nitrobiphe.nyl were ry srais t ic ir. the development of bladder cancer m doqs iS.]. Whcr. two chemicals of 'ha- same organotropy (affect mo . .a.. an. organs) , such as the :v.r carcinogens :::! hv in i troso- a:u; 4-dime thy laninoa / t! .zone , were applied *o mice, the f sy la.T'i i s t: r . ."yr.car:: nogener, i s was nc t bserved, htwcV- r , w':.': chemical cat -::.c- -of differin'? oreanet ropy were -.st- t mr-ous !*. i -i 1'7 J Capuco, .3. V. Amonia: A Modulator of 373 C< 1 1 Growth, hiss. Abstr. Ir.st. (8), 3 3 (91 : 48063 . 1379. '.428! Hub in, D., and I. S. >';. Chemical Carcinogenesis in the hamstor Cheek ?ouch: Influence of Inhibitors and Inducers of Alkaline Phosphatase. Pathol. Microbiol. (Basel', 13:1, :26- 30, 1975. 42o; : jj..d y. j. v....-,*, Carcinogen ic: . y and Cocurcino- : o: o : t v or Chromium Carhor.v! m hi terotop i r Tracheal Crafts. Cancer Res., 37 ( 5)s 1476- 1 479, 197'. ' i 4 3 01 hayatsu, H., et.al. Potential Cocarcip.oqer.ic i ty ot' Sodium hypochlorite, /Nature (Lend.), 233(53201:495, 1971. (431; N'agata, C., et al. Effect of Hydrogen Peroxide, Fenton's Reagent, and Iron Jons on the Carcinogenicity of 3,4Benzopvrene. cann, 64 ( 3> : 27:7--285, 1973. (432) Deichmann, W. 3., and J. L. Radomski. Synergism Among Oral Carcinogens arid Tumoi^igens, Jteoprt of Preliminary Experi ments. T^JCCOli. *ppl . E|hrS*CCft , p{3) |343-344, 1964. 233 MONS 022314 Other chemical substance! of potential industrial exposure have been investigated through- medical histories of people employed in manufacturing operations or exposed to the chemical substance. The lung:; of IOC consecutive patients at autopsy and 24 patients with pulmonary r."c;,!.isr,s were analyzed. Morn than 904 of the patients frcr- :.vr. ,-roups hod ferruginous (asbestos) bodies m their lungs with :,o apparent difference in the incidence or quantity between the randomly selected group and'')those with pulmonary neoplasms. This supports the view that asbestos acts as a cocarcincgon in causing pulmonary neoplasms. These find ings also indicate that asbestos dust contamination is widespread throughout rural and urban environments |433|. ' In a review of toxic challenges to the lung, mention is made of the synergism b.-twoen quartz and environmental irradiation. How ever, about tinf- id fewer workers with occupationally heavv dust exposure dice: '-f bronchial carcinoma than men of equivalent ago in the general perflation (434). fibrous glass, whose cancer- causing potential has been cstur 1 :shed in animal studies, s postulated to is a cocarciii./iL-:'. with cigarette smoke and other care: inhaled An invest; : : v.-u-.r..- . r 11 i i: .or.g anti U-r c.r.nloy <js exposed to ar.se:.:.- showed a r. . : ic.mt !y increased frequency : employees vers.::; control s. f. - wr : . a coc.ircinogcnic action of arsenic with i :.ir--t to sr.ok ias proposed to be responsible for the poor co::'t ! v between ncy of aberrations and arsenic exposure |4'v). 7r.<- results nf irai *.i.sting with arsenic trioxido. r.( t.. i or-:, and ref.nary flue dust indicated that solid arsenical substances acted coca: c : nocemea 1 ly with Bia)P 1-13?). Experimental results from oxpe : .v: rats to beryllium oxide and carbon black with a kr.cwr. care. :-.c :er. showed both to be tumor 1 4 33 ] Breed:::, ?. !i., and D. Ii. is-nss. Ferruginous (Asbestos) Bodies :the bungs of Sural Dwellers, Urban Dwellers, and: Patter.-. : ..:ih dtilnonarv he--: '.asms. South. Med. J., 69(4' : c-i. i9~6. ' 1434) Einbrcd:. !!. J. Combined Effort of Fine Dust on the burnt. Staub Rcmhaitunq buft, 10(3): 122- 126, 1976. 1435] Rom, and fr. M. banger. Carcinogenicity of Fibrous Glass '!.otter to Editor). West. J. Med., 126 (51 :413, 1977. [436] Norde.nson, I., et al. Occupational and Environmental Risks Jn and Around a Smelter in Northern Sweden, lit Chomosomal Aberrations in Workers Exposed to Arsenic. Hereditas, 88(1) : 4 7-50 , 1978. 1 4 37 ) Ishir., o-. al. Prcl nmary Experimental Study or. Carcir.. tciiv of Arsenic Trioxide in Pat Lung.' Environ. Health Frsuect.. 19:196-196, 1977. MQNS 022315 promoters with bar/lUus being the more potent promoter 1438). Several studies conducted on hamnters have demonstrated that Iron oxide (FeiOs) dust enhances chemically induced carcinogeni city (439, 4401 ' Peracet c acid, |erb*pzoic_acld, and ^chloroperbensoic acid were found to be active tiaor prctoters in akin carcinogenesis when tasted on rats 14411t Pyran copolymer has been tested on mice and found to promote B(a)P induced skin tumors [442). One of the more important categories of environmental pollution is the area of combustion products. Because combustion operations are widely scattered throughout the population, human exposure cannot be avoided. Sulfur dioxide (SOj), which is emitted from conbustion sources firing sulfur laden fuel (coal, oil), showed significant cocareinogenic effects with B(a)P, another combustion pracuct, in animal experiments (4431 . Studies on trace elements, emitted from most fossil fuel combus tion systems, especially coal-fired units, hive produc'd somewhat t r idictery results. vf:.- tests or. a series of trace ''.ime.ts indurated that some trace elements have have a cocarcino- .'i tic effect m IKaJT induced runc-T (44!;. Another study or-, concluded that there was r.o evidence rf trace element (4 181 Czawa, 7. Iiistoiiatholoeic.il Studies on Pulmonary Reaction by beryllium Oxide in Rat x: er irer.t a 1 Tumorous Action of iuc Combined with Carcinr tru: Hydrocarbons). Pull. Tokyo Med. Dent. Univ., 9(3): 440, 190. ,4i9i Netiothcm, P., et al. Ca: .. ii'.nger.ic .r.d Cocareinogenic F.ffects of Inhaled Synthetic S,-;oq and Ferric Oxide Par ticles. J. Natl. Cancer Inst. , 9 3 (: 1 39-169 , 1975. ; -i 101 Sollakur.ir, A., et al. Effects of Different Dusts on Tespiralory Carcinogenesis in Mam.sters Induced !y Ber.zo(ajovnuie and Diethylnitrosoanine. Fiir. J. Cancer, 12(4!: 31'.-319, 1976. .4411 ?. ck , 0., et al. Coca 1 nouen ic Activity of iVroxy Compounds. J. Natl. Cancer Inst., 35 ( 6) : l 3 59-1 36 ! , 1975. il42] Kripfcc, M. L., and T. Borsos. Accelerated Development of 3en zo (a) pyre.fus- Induced Skin Tumors i r. Mice Treated wit): Pvran CocolyMer. J. Natl. Cancer Inst., 53(5):1409-1410, 1974. ` [443] Shapiro, R Sciatic effects of Bisulfite (Sulfur Dioxide). MutBt. Bear, lf(2)I14V-176, 1977. . i Calop, J., et al. A Study >f the Influence of Trace Elements on the Hydroxylat ion of Pence (a) pyrer.e . Fur. j. Toxicol. Erivirctn. I!yg. , 9 ( 5) : 271-286, 1976. 40 HONS 022316 cocarcinogenesia with 3-methylcholanthrcne [445]. Lead oxide, an emission from automobiles burin? leaded gasoline, was tested on hamsters with B(a)P as the carcinogenic substance. Results suggested that lead oxide is a cocarcinogenic material (446). Lead oxide is also found in and around lead smelters and battery plants. Polycyclic hydrocarbon* (PCH) are also emitted from most combus tion systems. They are products of incomplste combustion and are emitted in greater quantities from the less efficient combustion equipment. A number of compounds in this class of material are considered carcinogenic; this has stimulated studies on the possible cocarcinogenic effect of PCH. 3-Methylcholanthrene (MCA) and'dimethylnitrosoamine (DMN) were tested on mice and found to act synergistically, resulting in enhancement of lung cancer and kidney tumors [4471. However, MCA has also been reported to inhibit or prevent tumorigenesis induced by carcinogenic aromatic amines or azo dyes [448]. Nitrosoamines such as diethylnitrosoamine (DEN) and DMN can be formed from nitrous compounds emitted to the atmosphere. These compounds have been tested on mice by others and found to be cocarcinogenic in the lung 14 491. Usually considered to be a noncarcinogcnic PCH, benzo(e)pyrene (B(c)P| has been reported to act as a cocarcinogen when applied to mouse skin with B(a)P. However, when tested in a respiratory tract tumor model, B(c)P did not act as a cocarcinogen and may have inhibited B(a)P carcinogenicity [450J. Three other PCH [4451 Shimkin, M. G., et al. Lung Tumor Response in Mice to Metals ana Metal Salts. Adv. Exp. Med. Biol., 91:85-91, 1977. (4461 Kobayas'.ii, N., and T. Okamoto. Effects of Lead Oxide on the Induction of Lung Tumors in Syrian Hamsters, j. Natl. `Cancer Inst., 52(5):1605-1610, 1974. (447) Cardesa, A., et al. The Syncarcinogenic Effect of .'tethylcholanthrene and Dimethylnitrosoamine in Swiss Mice. Z. Krebsforsch., 79 (2):98-107, 1973. [44C1 Danz, M., et al* Prevention of 2-AcetylaminofluoreneInduced Extrah^patic Short-Term Effects by 3-Methyl cholanthrene. Exp. Pathol. [Jena), 13(4-5):262-267, 1977. (449] Cardesa, A., et si. Effects of Infraperitoneal Injections of Dimethyl- sndf Diethylnitrosoamine, Alone or Simultaneously on Swiss Mice. Z. Krebsforsch., 82{3):233-238, 1974. [450j Topping, D. C., et al. The Interaction of Benzo(a)pyrene and Benrro(e)pyrene in Respiratory Tract Carcinogenesis (Meeting Abstract). Proc. Am. Assoc. Cancer Res., 19:43, 1978. 241 HONS 022317 carcinogenic*compounds (MCA, B(a)P, and DMBA) were tested in subeffectijy* concentrations to determine the synergistic action of any ,twC|ipispounds. All combinations of any two of those compounds eiHibited a synergistic action (451). Ozone, - secondary pollutant, results from the photo-oxidation of primary combustion pollutants such as nitrogen oxides and hydro carbons. Tests on hamsters ox:?osed to ozone followed by B(a)P resulted ltr B(a)P induced lung cancer with ozone acting as a cocarcinogen f4521. The eofactor effects of industrial chemicals and pollutants are suiunarized in Table B-2. ESOTERIC MATERIALS AND OTHER SUBSTANCES Several substances have been found that act as carcinogenic co factors, but they have little or no potential for human exposure and are employed mainly as research substances. A prime example is croton oil which has been found to be a strong promoter and can be relied upon to exhibit promoting properties when studying cancer mechanisms or substances suspected of initiating carcino genesis. Croton oil, a plant extract (Euphorbiaceae), has been reported to act mainiy as a promoter (344, 453] but has also been reported as a cocarci.nogen [343]. Possibly the difference is actually caused by a r.isuse ir terminology. Several other studies have reported substances related to the Euphorbiaceae plant family that also acted as promoters or cocarcinogens. Latex samples from a plant in this family showed toxic and oocarcincgcnic activity traceable to a palmitic acid ester cf a colvfunctional ditcrpcnc [434]. A followup study ccr.: need the cocarcrnogenic activity of ditcrper.e esters of Euphorbiaceae (4551. TPA (12-0-tetradecanoylphorbol-13-acetate), sometimes referred to as PMA (phorbol nyristate acetate), is also a substance from the Euphorbiaceae family which has been reported ,451) Mondal, S., et al. Syncarcinogenes is in Culture C3M/10TS Cells (Meeting Abstract). Proc. Am. Assoc. Cancer Res., 18:8, 1977. ; 4 5 21 Palmer, M. S., et al. Effect of Ozone on Benzpyrene ' Hydroxylase Activity in the Syrian Colden Hamster. Cancer Res., 31 (6) :730-733`, 1971. j453] Sellakumar, A. R., et al. Influence of Croton Oil in Hamster Lung Carcinogenesis. Proc. Am. Assoc. Cancer Res., 16:57, 1975. ' [4541 Uepkex. E. Gocarcinogenic Agents Derived from Euphorbiaceae. wed.* m 124-25, 1968. ; 4 35 ] Keeker, E. Now Toxic, Irritant, and Coenrcinogenic Diterpene Esters from Euphorbiaceae and from Thymelaeceae. Pure ApdI. Chem. , 59,(9) .-'1423-1431 , 1977. 242 HONS 022318 e vc TABLE B-2 . INDUSTRIAL CARCINOGENIC COFACTORS AND THEIR EFFECTS WITH SOLITARY CARCINOGENS fufAcior __ Aibtiloi Fibrou* ^Un hi in l c brtyl)iu* uitJ< CfbA bltk |foa oail NlKUC aci4 firbMioic ac id t*nioic aciJ luUtir Aioitdt Otoft* t|*c *lrntt t4t Olid* )*NathychoUMhrnc i*Mtih)rl(K')iolaiuhi iif B*Aiot#>i-yc*n# bbMO()|7lAA FiqalMh X X X X X CofAcior Cocacclnoqrh __ XyftcArc ___ X X X I I X X X X X X Inhibitor soiitAiv crciwqn or miLUBE. Cnviron^rnlAt CACCtnot*** Envwon*cntl Inadiatton Cn}Artt uuk* (`Kitrlti ADk( bn|ol)p>rriiv IllJlH iv'-Nri f.y IcnoUnt ht n .v'-Heih/ U'hu) jnt hr ftr BUIF, dathylnitrobOMiAi HUwvn CAfcinojtn) (h*j*n cAicinoifan) {Xnown care irw>qri> B<A)F U)P IfAlP ihaip PtMtbylMiroAOaiA X Kut dy*, KOMUC tflAll I(a>F (thin) 1 lUlf UopUAtdry tr*ct) - HONS 022319 Vilt/l cMui iu Mru'wic Toiuvf-t' Acatui.i D*<) Mi /)*0AJrv A/* 1UckIce ik> i n-tfc`canv n-Talf a<)i`*n MiAtf1 oil (Ora**;! uVK) Cafbuit ttwachlot i Ji khanoia AntluJ 1 tn M lj he1 iw* allied) Jo UwitcyibBnii'At lUlfOftoi NP*1 Oiafina iuIUu TABLE B-2 (continued). -. _ - fcftcur i/m~ hnotr Cocaiciooqan >yncicimjn 1' >J X X X X X X X X X X X X I X X X X Vt U# circiiwn Q KUll' Ii))i ktrd il< ulk't (Known care t i<**7ni On-iwr. er`iniMtnj I'oJ jvyclIr ih.iut w hydrocarbons IHJ'-]'. l<fuxj;>ihrt<. **na Hlnll , , W UjM Wnsi.tl.rvwnw UV 1ijht UV a*ht (Known tali'trojan) rUlU )i|vnuu| u>r (Known carctnoqan) All ;oUuti.')t . iJutovn v.w . i.i ,< n> i-** hy I ctn> 1 ani hr ana k(a)r (conelnuod) HONS 022320 s*z tabu: B-2 (continued) Cof ai-tof _ Tali 4k t a thydihy 1) * phoi|<)iun|tf cMui i>l( *yrot-TKP tolychlorinotaJ biphci.yia Chloroptonol 7,4-0 harbiciJv PUT |M.*lllCidw AMOiuua co*i4un<l Ol lSLilihOl>llAl v l-Wurnylalauinv Phany tpitoaptutu I'hfUBiu* caiLuityl Sodiuo hyvMoiitf Hydroqan i^roitdv H-niiro*opiparidin N~nilioaoMorpho) Ina 0iinylniUo*O4Av ll-W luorny)ctt*Aldtf J`Aainon4|>hUuliM 4 Dum ihy I ino tPbtru mr Proa*tr Ci'ftctur CtH'airutugtJn ^vncareiftOOin Inhibitor Solitary crdMW UUUu^ a i X X X X X X X 7,|2>ojaihylbani(alanthracana >. i UI*atftcM *wmm huciaU*,' 4UyitolMkrM (<MM*4rcinof>) (Known carcinoma*) Machylcholanihrana (Known carcinoqan) %. 10-Dioathy l-1 * 9, 10~Diaathyl~l, J-banuAthrxcana X t, 10-Di**thy1*11'baaiaiuhrKaiM X X(a)P 4-NitroquinoJin*l'Oal4a X ftlalP X n* uty 1 N 14 >liydroinrkut|rl) nl tratOMi im X n-iutyl-K- (4-hyilraykutyl)>ttra*OMiA X ft-lutyl-N- K-hydreiybutyUatUMMaiM X n-otyl-ll-(4-kydraxykutyl)llroaoaa4M X 4-Nltrobtpfeanyl X HiUyUltmMalM HONS 022321 to bo cocarcinogenic 1456-458) Phorbol is the parent dleterpene of TPA and is not cocarcinogenic (459). Other reported promoters and cocarcinogens of unknown signifcance, as far as potential human exposure, include 4-ethylsulfonylnapbthaleoe-i-sulfonaide (promoter) p44), andn-butyl-H-MhydroxybutyHknitrosoaaine, N-(4-(3-nitro-2-furyl)-2-thlaiolyl! focmamide, and 3,3'-dichlorobensidlne $cocareinogens) (460). Inhibitors of unknown origin and unknown human significant include alpha-naphthylisothiocyanate, p-hydroxypropiophenone (323), .ris-aconetic acid, putrescine (461), and elipticine (462). M56| .-or ilausrr., H. Z., et al. Persisting Oncogenic Herpesvirus induced tiy r.iis Tumour Promoter TPA. Nature (Lond.), .'.'7 2 (5651) : 373-375, 1978. '457] Koritowski, D., et al. Epidermal Intercellular Relationships During Carcinogenesis and Cocarcinogencsis as Revealed by Scanning Electron Microscopy. Virchows Arch. (Cell Pathol.), 24 (4): 317- 333 , 1977. (456) Janoff, A., ct al. local Vascular Changes Induced by the Cocarcinogen, Phorbol Myristate Acetate. Cancer Res., 30(13):2567-2571, 1970. (459] Sc:;cr, C. J., and F. J. Evans. Investigations into the Mode of Action of the Cocarcinogen 12-O-Tetradecanoylphorbol-13-acctate Using Auxotrophic Bacteria. Cancer Res., 37(8, Part 1) :2487-2491 , 1977. 1460] rsuda, H., et al. Synergistic Effect of Urinary Bladder Carcinogenesis in Rats Treated With n-Butyl-N-(4-hydroxy- butyl )nitroaoamine, n-(4--(5-Nitro-2-furyl)-2-thiazolyl]formamide, n-2-Fluorenylacetamide, and 3,31-Dichlorobenzidine. Gann, 68(2U183-192, 1977. (461] K.i 11 istrnto:;, G. Prevention of 3,4-Benzpyrene Carcino genesis by Naturally Occurring and Synthetic Compounds. Mcunch. .Miid. V.'ochenschr. , 117 (10) : 391--394 , 1975. (462) Truhart, R., et al. Inhibitor Effect of Ellipticine |Dinethyl-5, II-(6H) Pyrido (4,3-B Carbazoie) on Rat Liver Carcinogenesis Induced,by BT6 (n.n-Dimethyl-p-benzotih Jazply-jl^zc) Aniline]: Incidences on Cytochrome P450 and .Yrgitusej Activity? (Meeting ^Abs'tract). Fourth Meeting of taie raropean4Association for:Cancer Research (held at lfo|v4it de Lyon, (September |13-1, .1977), European ffsso<Jlat{Lor. for]Cancer (Research, Lyon, France, 19771, d. 86. 246 MONS 022322 ,, TICMN1CAL RIfOAT OATA (Kwm<jkMWIMWKmii trfe* > | *0* >J EPA-600/2-80-015 .......... POTENTIAL ATMOSPHERIC CARCINOGENS Rhase 1. Identification and Classification 1 MdniiiriMtlUiOWDO A M#Jt OAT( lanutry 1980 _f #<">00**ING OftG*"{Ar<0* COOt Carl It. NcMIltii, Lai and 8. Note. and Daryl 6. DeAngellsf nNRwCt-MM-W870wommijo &' ho (0M.Hi 00*Hir*1`OV HH> 4NO OMMM' Monsanto Research Corporation layton laboratory '. 1515 Nicholas Rood, P.0. Box 0, Station 5 Cayton. Ohio 45407 . s- .<: *5is;. mmi \s doiU ; Environmental Sciences Research Laboratory ~ RTP, NC | Office of Research and Oevelopment | 'J. S. Environmental Protection Agency I Pesearch Triangle Park, North Carolina 27711 ia 2SiS^iTVrt\lVo *" 60-02*2777 ii *m o* mc*v hi> ><*>oe covi *ia Interim 9/77 - 10/73 i* jON*e*iG osc* tos' " " " EPA/600/09 A comprehensive literature search Identified more than 125 high-volume chemicals having | the potential of becoming airborne carcinogenic pollutants. Based on carcinogenicity ! and mutagenicity data, the pollutants were divided into three categories: probable carcinogens, possible carcinogens, and probable noncarcinogens. Additional data were collected for the possible and probable carcinogens Including their annual production, emissions, atmospheric persistence, and relative mutagenic and carcinogenic potencies. The pollutants were then ranked on the basis of a calculated equivalent weight of : bemo(a) pyrene emitted per year after 24 hours in the atmosphere. From the top i portions of these two lists. 20 compounds, representing various chemical classes, ere chosen for future analysis. A state-of-the-art review of the effect of cofactors on the carcinogenicity of chemicals was also completed. To locate optimum sampling sites in cities of interest, aiserles of carcinogen isopleths was generated. Using information such as the lbcationsiof stationary sources of carcJnogepic pollutants, normalized wind direction* amf IpVed. and the height, temperaturerand rate of flow of the sources, lly #cobaM.eil4BBtJons of maximum carcinogenic pollution concentration were computed, 1 . '* A *Hr ?oUytioft *C*rClnqen| `Review* * IdetH firing DlSCl*TOS M WBOJ aNOOCCWlM asa,ss b 'OCNT'Fif ns 0*1 S 1 SOlO TfiAVS . COi'. 1 J I.l"., 139 06E 050 > . iiv ker'p'W>ttlftfcT REllEBSE M 1 SIC-<T Class , rfiai Mimas*. UMlas'sIFIED J 30 CLA*S - UNCLASSIFIED fci . . .MGNS .. 022323