Document rBOQ0JypvONoa9MOBQZZQnamv

I'fei-;iO vil ' ; v-,; ; 197-1 ' cion. `a of thin a 1976'. ' JRure 92-lWc tacts: ^astii f I., anti ang], j tudy of and it* >nes, J doride oogenic lioride bioafjI Fact hJoride among 23-628 n. S., lisease Ann. t, and orkers Acad. eumodust. G. B., ia, B. udy of m, rat "ide in 1975). i berg, romoiride. ce on danu- -r, R. -et, i: Environmental Health Pernpectot.-' Vol. il. pp. 211-220, 19S1 Review of Experimental Carcinogenesis by Compounds Related to Vinyl Chloride by Kenneth C. Chu* and Harry A. Milmant The experimental carcinogenesis results on six compounds related to vinyl chloride are reported. Vinylidene chloride, given by inhalation, was carcinogenic in male CD-I mice, male CD rats, Sprague-Dawley rats and male Swiss mice. Trichloroethylene, given by gavage and inhalation, was carcinogenic in the B6C3F1 mice. When given by gavage, perchloroethylene was carcinogenic in the B6C3F1 mice, and dichloroethane was carcinogenic in Osborne-Mendel rats and B6C3F1 mice. Dibromoethane, given by gavage and inhalation, was carcinogenic in B6C3F1 mice, F344 rats and Osborne-Mendel rats. Finally, epichlorohydrin was carcinogenic in male Sprague-Dawley rats and B6C3F1 mice. Introduction Since the carcinogenicity of vinyl chloride (VC) was demonstrated in experimental (1) and epid emiologic studies (2), data on the potential carcino genicity of vinyl chloride structural analogs and related compounds have been increasing. This paper will attempt to review the experimental carcinoge nicity data on a number of these compounds, while another paper (5) will discuss the epidemiologic results. HH Vinyl chloride VC H ,CI C = Cs H Cl Vinylidene chloride VDC Cl ,CI Nc=c /s H Cl Trichloroethylene TCE Cl Cl II H-C-C-H I I. HH 1,2 -Dichloroethane DCE Br Br II H-C-C-H II , .H H 1,2 "Dibromoethane DBE `National Cancer Institute, Bethesda, Md. 20205. * Environmental Protection Agency, Washington D.C. 20460. October 1981 Cl / C \ Cl Tetrachloroethylene PCE H HH I II H-C-C-C-CI \/ I OH Epichlorohydrin EPC 211 040578 SL Results Vinylidene Chloride (VDO A summary of some of the ca:vkvgen bioassays of vinylidene chloride is giver, ir. Table 1. The strongest evidence of a carcinogenic effect was in a bioassay involving Swiss mice performed by Maltoni et al. (4, 5). In this study, 24T50 dosed male mice had kidney tumors as compared to 0 190 in the controls. In the study by Lee e: rJ. (6\ 7), dosed 1 CD-I mice and CD rats had two or three liver angiosarcomas. Since this type of tumor was in duced by vinyl chloride in human? and rodents and the study was terminated after ordy one year, the . results are viewed as biologically significant. In an inhalation study in Sprague-Dawley rats by Maltoni et al. (4, 5), increases in mammary gland tumors in the dosed animals were reported. However, these incidences did not follow a dos^response relation-^ ship. In contrast to these positive sttidtes, a number of nonpositive two-year carcinogen r .oassay studies have been reported (6-9). Most no;role is this initial report that preliminary evaluauors of vinylidene chloride in a two-year National Toxicology Pro gram (NTP)/NCI bioassay of Fischer 344 rats, given at 2-10 mg/kg of body weight and :f B6C3F1 mice, given at 1-5 mg/kg of body weight, did not indicate any significant increased incidences of tumors in the dosed animals as compared to controls. Trichloroethylene (TCE) A summary of some of the carcinogen bioassays of trichloroethylene is reported in Table 2. In B6C3F1 mice, this compound, given by gavage, was found to be carcinogenic, inducing hepatocellular tumors (10). In confirmation of this finding, an inhalation study in B6C3F1 mice, performed by Biotest Labo ratories, gave similar results (11). Bioassays of TCE were nonpositive in two strains of rats, the Sprague-Dawley and Osborne-Mendel (10-12). Additional NTP/NCI carcinogen bioassays are under way in five strains of rat and the B6C3F1 mice to examine species and strain differences. Tetrachloroethylene (Perchloroethylene) PCE The carcinogen bioassay results of testing PCE are given in Table 3. In B6C3F1 mice, this com pound, given by gavage, was carcinogenic inducing hepatocellular tumors. Studies in two strains of rats, Osborne-Mendel and Sprague-Dawley, produced no carcinogenic ef fects (13-U). Additional carcinogen bioassays in four strains of rats and the female B6C3F1 mice are currently underway at NTP/NCI. 1,2-Dichloroethane (DCE) The experimental carcinogenicity results of test ing DCE are given in Table 4. In B6C3F1 mice, the Species/Str* Mouse, CD-I Rat, CD Rat, Spr-Daw 212 Route (vehicle)b Inhal Inhal Inhal T-nhle 1. Bioassays of vinylidene choride (VDC). Dose ppm or mg/kg' Dosing period Group Target site (tumor (duration), wk size incidences)11 Reference M 55 0 T- 55 0 N 55 0 -- 55 0 / 150 100 50 25 1 10 0 5T 150 100 50 25 10 0 52D(52) 52D(52tt ) 52D(52) 52D(52) 52D(life) * "" - 52D(tifel "" *** "* *" 36 Liver, hemangiosarcoma 36 (2/35 0/26) 36 Liver, hemangiosarcoma 36 (1/35 0/36) 36 Hemangiosarcoma 36 (2/36 0/35) 36 NSC 36 60 NSC 30 30 30 30 100 60 Mammary gland 30 (nondose response) 30 30 30 100 {6.7) {6.7) U.5) Environmental Health Perspectives SL 040579 4ii_. dwi&fcj V -in. i J'JIV `Kj|. UUM. J. tins jpr .j ie) CE -in;iit! .el elhi -IV St:'ir -- ----- joedcs'Str1 Table 1 (cont.) Route Dose Dosing period Group Target site (tumor (vehicle)11 Sex ppm (duration), wk si2e incidences)11 or mg kg' Vnase. Swiss Inhal M F 25 52D(life) 150 Kidney 10 30 (24 150 0 190) 0 " " 190 25 52D(life) 150 NSC 10 " " 30 0 " " 190 Rat. Spr-Daw Gav (Olive oil) M 20 52D(life) 50 NSC 10 " " 50 5 50 0 " '' 50 Hamster, Chin Inhal F M 20 52D(life) 50 NSC 10 3 "M n 50 50 0 50 25 52D(life) 30 NSC 0 " " 30 Mouse B6C3F1 (NCI) Rats, F344 (NCI) Rat, Spr-Daw Gav (Corn oil) Gav (Corn oil) Inhal F M F M F M 25 52D(life) 30 NSC 0 " " 30 10 (103) 50 NSC* 2 50 " 50 10 (103) 50 NSC* 2 " 50 0 " 50 5 (103) 50 NSC* i " 50 0 50 5 (103) 50 NSC* i " 50 0 " 50 75 7SD(104) 86 NSC 25 " 85 0 " 86 Rat, Spr-Daw Water F M 75 78D(104) 86 NSC 25 84 0 " 88 200 (104) 47 NSC 100 " 48 60 48 0 " 80 Rat, Wistar Rat, Spr-Daw --- Inhal Inhal F 200 (104) 47 NSC 100 48 60 " 48 0 " 80 M 200-100 52D(104) 51 NSC 0 " 30 F 200-100 52D(104) 23 NSC 0 " 30 M 100 52D(104) 30 NSC (O 16 0 " " 30 F 100 52D(104) 30 NSC 75 " " 21 0 " " 30 'Chin = Chinese hamster; F344 = Fischer 344 rat; Spr-Daw = Sprague-Dawley rat. Gav = gavage; Inhal = inhalation. 'Units; ppm for inhalation; mg'kg for other routes. NSC = Not shown to be carcinogenic. 'Preliminary results. October 1981 SL 040580 Reference (4, 5) (4, 5) (4,5) (8) (8) (9) (9) 213 -1 S compound, given by gavage, was carcinogenic, in ducing lung tumors in both sexes and mammary gland and uterus tumors in dosed female animals (15). The chemical was also carcinogenic in Osborne-Mendel rats, giving forestomach tumors and extrahepatic hemangiosarcomas in both sexes, sub cutaneous fibromas in the males and mammary gland tumors in the females (15). In contrast, a preliminary report by Maltoni (12) indicated that DCE was not shown to be carcino genic in an inhalation study with Swiss mice and Sprague-Dawley rats. Since there were strain and Species/Str3 Mouse B6C3Fld Mouse B6C3Fld Rat, Osb-Mdld Rat, Spr-Daw Rat, Charles Rivet4 Rat, Marshall (NCI) Rat, ACI (NCI) Rat, F344 (NCI) 214 Route (vehicle)*1 Gav (Com oil) Inhal Gav (Com oil) Gav (Olive oil) Inhal Gav (Com oil) Gav (Com oil) Gav (Com oil) Table 2. Bioassays of trichloroethylene (TCE). Dose, Dosing period Group Target site (tumor Sex mg/kg (duration), wk size incidences)' Reference M 2339 1169 0 78D(90) *" tf * 50 Liver, hepatocellular 50 (31/48 26/50 1/20) 20 U0) F 1739 869 78rD(9it 0) 50 Liver, hepatocellular 50 11/47 4/50 0/20) 0 HH 20 M 600 ppm (104) 300 ppm " 100 Liver, hepatocellular 100 (43/97 31/100 28/95 18/99) (21) 100 ppm 0 " 100 100 F 600 ppm (104) 100 Liver, hepatocellular 300 ppm " 100 (13/99 9/94 4/100 6/99) 100 ppm " 100 0 100 M 1097 549 78D (1H10) 50 NSC 50 (10) 0 * * 20 F 1097 549 78D(110) "" 50 NSC 50 0 UH 20 M 250 50 0 52D(140) hn "n 30 NSC 30 30 m F 250 52D(140) 30 NSC 50 UH 30 0 " " 30 M 600 ppm (104) 100 NSC (11) 300 ppm 100 ppm 0 " " 100 100 100 F 600 ppm (104) 100 NSC 300 ppm 100 100 ppm 0 " 100 100 M 1000 500 (110) " 50 Assay still in progress 50 St. 2/79 0 50 F 1000 (110) 50 Assay still in progress 500 50 0 50 M 1000 500 (110) " 50 Assay still in progress 50 St. 2/79 0 50 F 1000 500 0 (110) " " 50 Assay still in progress 50 50 M 1000 500 0 (110) " " 50 Assay still in progress 50 St. 6/78 50 F 1000 (110) 50 Assay still in progress 500 50 0 50 Environmental Health Perspectives SL 0AO581 .... ' ' - -o  I'-TtHrMlirirr trifrrH -- Tabic 2 (cont.) lj inn. and fit Osb-Mdl and [VCD pat, August iNCI) 'IHV B*t. B6C3F1 (NCI) Route (vehicle)11 Sex Dose, mg/kg Dosing period Group Target site (tumor (duration), \vk size incidences)c Gav M 1000 (Com oil) 500 0 F 1000 500 0 Gav M 1000 (Com oil) 500 0 F 1000 500 0 Gav M 1000 (Com oil) 0 F 1000 0 (110) " (110) " (110) " (110) " (11II 0) (110) 50 Assay still in progress 50 St. 12/79 50 50 Assay still in progress 50 50 50 Assay still in progress 50 St. 10/79 50 50 Assay still in progress 50 50 50 Assav still in progress 50 St. 6/78 50 Assay still in progress 50 Reference F344 = Fischer 344 rat: Osb-Mdl = Osborne-Mendel rat; Spr-Daw = Sprague-Dawley rat. ''Gav = gavage, Inhal = inhalation. fNSC = Not shown to be carcinogenic. "With 0.09% epichlorohydrin. dose differences as well as route of administration differences between the NTP/NCI and Maltoni stud ies, the causes of the differences in the experimen tal results are not readily apparent. 1,2-Dibromoethane (DBE) The results of some carcinogen bioassays on DBE are given in Table 5. In bioassays on B6C3F1 mice and Osborne-Mendel rats, DBE given by gavage was carcinogenic, inducing multiple tumors in each species and sex. There were not only chemically induced tumors at the site of application (forestomach tumors) but also tumors distant from the site of application (lung tumors in mice and extrahepatic hemangiosarcomas in male rats and hepatocellular tumors in female rats) (16). In addition, a preliminary analysis of an inhala tion study of DBE performed by NTP/NCI indi cates that nasal cavity tumors were found in dosed rats and dosed female mice. Furthermore, elevated incidences of lung tumors were found in the dosed mice as well as elevated incidences of mammary gland tumors in dosed females of each test species. Meso theliomas were also induced by DBE in male rats. Epichlorohydrin (EPC) The bioassay results on epichlorohydrin are given in Table 6. Recently, this compound, given by inhalation, was found to be carcinogenic inducing nasal cavity tumors in male rats (17). In addition, experiments by Van Duuren (18-19) indicated that EPC was an initiator in a two-stage study and induced local sarcomas by subcutaneous injection, addition more comprehensive epidemiological stud ies involving the manufacture, production and use of these compounds should be undertaken. A summary of some of the bioassay results for each compound by speeies/strain is given in Table 7. Discussion The data on these compounds can generate some interesting points for discussions, such as the prob able mechanism of some of these compounds, the controversy over TCE results and suggestions for future action. In the first case, studying the summary table indicates that the compounds (DBE, DCE, and EPC) which are proposed to alkylate directly, gave forestomach tumors when given by gavage or nasal cavity tumors when given by inhalation while the compounds which are proposed to require meta bolic activation did not produce these types of tu mors. One can envision that these compounds, due to their alkylating ability and their ability to induce site of application tumors, are direct-acting carcin ogens. Two of these former compounds, DBE and s October 1981 215 SL 040582 Table 3. Bioassays of perchloroethylene (PCE). Species/Str Route (vehicle)11 Sex Dose, mg kg Dosing period Group Target site (tumor duration i. wk size incidences)' Mouse B6C3F1 Rat, Osb-Mdl Rat, Spr-Daw Rat, Sherman (NCI) Rat, Wistar (NCI) Rat, Long-Evans (NCI) Rat. F344 (NCI) Rat, B6C3F1 (NCI) Gav M 1072 7SDi90> 50 Liver, hepatocellular (Com oil) 536 50 (27/48 32/49 2,20) 0 20 F 772 TSDiOOj 50 Liver, hepatocellular 3*6 50 (19/48 19/48 0'20j 0 * " 20 Gav M 941 TlDillO) 50 NSC (Com oil) 471 0 , 50 20 F 949 474 0 71DU10) "" * 50 NSC 50 20 Inhal (Com oil) M 600 ppm 300 ppm 52D1135) "* 96 NSC 96 0 96 F 600 ppm 52D< 135) 96 NSC 300 ppm 0 ** " 96 96 Gav M 750 (103) 50 Assay still in progress (Com oil) 375 50 St. 2/78 0 50 F 750 375 0 (103) * " 50 Assay still in progress 50 50 Gav M 7-50 (103) 50 Assay still in progress (Com oil) 375 50 St. 11/78 0 " 50 F 750 (103) 50 Assay still in progress 375 50 0 * 50 Gav (Com oil) M 750 375 (103) " 50 Assay still in progress 50 St. 7/78 0 50 F 750 375 (103) " 50 Assay still in progress 50 0 50 Gav M 750 (103) 50 Assay still in progress (Com oil) 375 50 St. 9/78 0 50 F 750 (103) 50 Assay still in progress 375 50 0 50 Gav F 200 (103' 100 Assay still in progress (Com oil) 100 100 50 100 25 100 0 100 *F344 = Fischer 344 rat; Osb-Mdl = Osbome-Mer.del rat; Spr-Daw = Sprague-Dawley rat. bGav = gavage; Inhal = inhalation. CNSC = Not shown to be carcinogenic. Reference (id) (id) (14) DCE, also induced tumors distant from the site of application. This fact may be an important point in the controversy over TCE. This controversy stems from the fact that the results on TCE indicated that the mice studies were positive while the rat studies showed the chemical did not produce a carcinogenic effect. There have been several explanations. It has been postu lated that epichlorohydrin, used as a stabilizer in the TCE tested, is responsible for the positive effect, not TCE (21). The NCI Technical report on TCE (10) indicated that there was 0.09% EPC in 216 Env ironmental Health Perspectives SL 040583 -W Table 4. Bioassays of 1,2-dichloroethane (DCE). ----------- Route (vehicles Sex Dose, mgikg Dosing period Group Target site (tumor (duration), wk size incidences)' Referenee B6C3F1 F.t, Osb-Mdl Mouse, Swiss PjI, Spr-Daw Gav (Com oil Gav (Com oil.1 Inhal Inhal M 195 78D(91) 97 " " 0 F 299 78D(91) 149 " " 0 -M 95 69D(110) 47 " " 0 F 95 69D(93) 47 (110) 0 M 250-150 ppm (life) 50 ppm 10 ppm 5 ppm ll 0" F 250-150 ppm 50 ppm 10 ppm 5 ppm (life) ** " " 0 M 250-150 ppm (life) 50 ppm 10 ppm 5 ppm 0 F 250-150 ppm (life) 50 ppm 10 ppm " 5 ppm 0 50 Lung 50 (15/48 1/47 0/19) 20 50 Lung (15/48 7/50 1/20) 50 Mammary gland (7/48 9/50 0/20) 20 Uterus (5/47 5/49 0/20) 50 Forestomach (9/50 3/50 0/10) 50 Hemangiosarcoma (7/50 9/50 0/20) 20 SQ Fibroma (6/50 5/50 0/20) 50 Mammary gland 50 (18/50 1/50 0/20) 20 90 NSCd 90 90 90 180 90 NSCd 90 90 90 180 90 NSCd 90 90 90 90/180 90 NSCd 90 90 90 90/180 (15) (15) (12) (12) *Osb-Mdl = Osbome-Mendel rat: Spr-Daw = Sprague-Dawley rat. bGav = gavage; Inhal = inhalation. fNSC = Not shown to be carcinogenic. bPreliminary results. the TCE. The doses of TCE were about 2000-1000 five strains of rat. If EPC is the active compound, mg/kg of body weight, corresponding to less than 2 the mice study should not show a carcinogenic mg/kg of body weight of epichlorohydrin. If epich- effect. However, if TCE is the active agent then lorohydrin is the active agent, one might expect the B6C3F1 mouse study should be positive. The forestomach tumors from a gavage study because of results in the rats will also give insight into whether its alkylating ability. However, the target site in there is a species or a species/strain difference for the mice is the liver. In addition, if epichlorohydrin TCE. Similar types of studies are also underway is the carcinogen, then why are the results negative with PCE. In addition, Maltoni has indicated that in the rat? Direct-acting carcinogens, like epich he has started bioassays on TCE with B6C3F1 mice lorohydrin, are less likely to show such a species and Swiss mice. difference than compounds which would require With the possible resolution of the TCE issue, 1*C metabolic activation, such as TCE itself. Thus, an there still remains the differences in experimental u- alternative explanation is that there is a species results involving vinylidwe chloride (VDC). The in difference reflecting some type of metabolic or tar results in VDC may indicate that there are impor /e get site sensitivity difference between the species. tant species and strain differences. As a conse >n The answer may be forthcoming. NTP/NCI is quence, this compound may be an ideal candidate in testing TCE without EPC in the B6C3F1 mice and for studying species/strain differences systematical- October 1981 217 SL 040584 1 Table 5. Bioassays of 1,2-dibromethane (DBE). Species/Str* Mouse B6C3F1 Route (vehicle)1* Gav (Com oil) Sex M F Rat, Osb-Mdl Gav (Com oil) M F Mouse B6C3F1 (NCI) Inhal M F Rat, F344 (NCI) Inhal M F Dose, mg/kg 107 62 0 107 62 0 41 38 0 39 37 0 40 ppm 10 ppm 0 40 ppm 10 ppm 0 40 ppm 10 ppm 0 40 ppm 10 ppm 0 Dosing period (duration), wk 53D(7S) " 53D(90) "" (60) 34D(49) 47D" (63) 44D(61) 57D" (63) (103) * " (103) * (103) " " (10H 3) 1* Group size 50 50 20 50 50 20 50 50 20 50 50 20 50 50 50 50 50 50 50 50 50 50 50 50 Target site (tumor incidences) Forestomach (29/4945/500/20) Lung (10/47 4/45 0/20) Forestomach (28/50 46/49 0/20) Lung (6/46 11/43 0/20) Forestomach (33/50 45/50 0/20) Hemangiosarcoma (4/50 11/50 0/20) Forestomach (29/5040/50 0/20) Liver, hepatocellular (5/48 1/47 0/20) Lung (19/46 3/48 0/41)' Reference (IS) (16) Nasal cavity (6/50 0/50 0/50)' Mammary gland (8/50 14/50 2/50)' Lung (37/50 5/49 1/49)' Nasal cavity (28/5020/500/50)' Mesothelioma (25/50 7/50 1/50)' Nasal cavity (29/50 20/50 0/50)' Mammary gland (24/50 29/50 4/50)' *F344 *= Fischer 344 rat; Osb-Mdl = Osbome-Mendel rat. bGav = gavage; Inhal = inhalation. `Preliminary results. Table 6. Bioassays of epichlorohydrin (EPC). Species/Str* Route (vehicle)6 Sex Dose Dosing period Group Target site (tumor (duration), wk size incidences)' Reference Rat, Spr-Daw Mouse, ICR/Ha Swiss Mouse, ICR/Ha Swiss Mouse Mouse, C3H Mouse, ICR/Ha Mouse, ICR/Ha Inhal SC SC Skin Skin Skin IP M 100 ppm 30 ppm 0 6D(life) (life) F 1 mg in 0,1 ml (life) tricaprylin wklv F 1 mg in 0.05 ml tricaprylin (life) wklv 1 mg in 0.1 ml 1 dose acetone then 2.5 g phorbol 55D mvristate' -- 1 Br (life) F 2 mg in 0.1 ml 57D(57) acetone 3'wk F 1 mg in 0.05 ml (64) tricaprylin wkly 140 Nasal cavity 100 (15/140 2/100 0/100 0/50) 100 50 50 Local sarcomas (2/50 0/50) 50 Local sarcomas (7/50 1/50) 30 Initiator (10/30 3*30) 40 NSC 50 NSC 30 NSC *Spr-Daw = Sprague-Dawley rat, bIP = intraperitoneal injection; SC = subcutaneous injection; Skin = skin painting. 'NSC = Not shown to be carcinogenic. __ (17) (19) (18) (18) W) (18) (18) 218 Environmental Health Perspectives Si <o S8S V' .`J., frf*??JWtt>-iii`iri^irT`iiKTtfTMrr' Table 7. Summary of bioassay results on vinyl chloride analogs and related compounds for some tumor sites. -- --------- VC VDC TCE net Hemingio- SD Rat-G m-CD-1 Mouse-I Mouse-I* m-CD Rat-I Rat-I* PCE DCE m-OM Rat-G DBE m-OM Rat-G ECH Ijmp tumors Mouse-I" Rat-I* B6C3P1-G B6C3F1-G B6C3F1-Gb Mammary (fend tumors 'females1 Kidney ;umors Mouse-I* SD Rat-I m-Sw Mouse-I OM Rat-G B6C3F1-G F344 Rat-Ib B6C3F-Ib Hepatocellular tumors Korcstomach tumors B6C3F1-G B6C3F1-I B6C3F1-G f-OM Rat-G m-OM Rat-G OM Rat-G B6C3F1-G KiJ cavity tumors Local sarcoma F344 Rat-Ib f-B6C3Fl-Ib m-SD Rat-I f-ICR/Ha Sw Mouse-SP NSC F344 Rat-Gb OM Rat-G OM Rat-G SD Rat-I B6C3F1-Gb SD Rat-G SD Rat-G Sw Mouse-I Wis Rat-I CR Rat-I Ch Ham-I SD Rat-W SD Rat-I SD Rat-G Effect seen in at least two strains. Preliminary results on NTP/NCI studies. ly. In addition, the differences in the NCI and Maltoni studies on DCE could be the source for additional research. From an examination of Table 7, the compounds with positive results in multiple species yielding multiple tumor sites are the direct acting carcino gens, DBE and DCE. (EPC has not been tested extensively yet.) This strong evidence in experi mental carcinogenesis should, at least, trigger mea sures to decrease exposure to these compounds. In addition more comprehensive epidemiological stud ies involving the manufacture, production and use of these compounds should be undertaken. REFERENCES 1. Viola, P. L., Bigott, A., and Caputo, A. Oncogenic response of rat skin, lungs, and bones to vinyl chloride, Cancer Res. 31: 516-522 (1971). 2. Infante, P. Multiple site risk analysis of vinyl chloride related cancer in workers-review. Environ. Health Perspect. 41: 000 (1981). 3. Apfeldorf, R. and Infante, P. Review of epidemiological study results of vinyl chloride related compounds. Environ. Health Perspect. 41: 000 (1981). 4. Maltoni, C., Cotti, G., Morisi, L., and Chieco, P. Carcinoge nicity bioassays of vinylidene chloride: Research plan and early results. Med. Lav. 68: 241-262 (1977). 5. Maltoni, C. Recent findings on the carcinogenicity of chlori nated olefins. Environ. Health Perspect. 21: 1-6 (1977). 6. Lee, c. C., Bhandrai, J. C., Winston, J. M., House, W. B., Dixon, R, L., and Woods, J. S. Carcinogenicity of vinyl October 1981 chloride and vinylidene chloride. J. Toxicol. Environ. Health 4: 15-30 (1978). 7. Lee, C. C., Bhardari, J. C., Winston, J. M., House, W. B., Peters, P. J., Dixon, R. L. and Woods. J. S. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ. Health Perspect. 21: 25-32 (1977). 8. Rampy, L. W., Quast, J, F., Humiston, C. G., Balmer, M. F., and Schwetz, B. A. Interim results of two-year toxico logical studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ. Health Perspect. 21: 33-43 (1977). 9. Viola, P. L., and Caputo, A. Carcinogenicity studies on vinvlidene chloride. Environ. Health Perspect. 21: 45-47 (1977). 10. National Cancer Institute (NCI). Carcinogenesis bioassay of trichloroethylene. NCI-CG-TR-1 DHEW,Pub/NIH-76-802, 1976. 11. Bell, Z. G., Olson, K. J. and Benya. T. J. Final report of 219 SL 040586 . audit findings of Manufacturing Chemists Association (MCA) administered trichloroethylene chronic inhalation study at Industrial Bio-Test Laboratories, Nov. 1978. 12. Maltoni, C. Carcinogenicity bioassays of vinyl chloride monomer: A model of risk assessment on experimental basis. Environ. Health Perspect. 41: 000 (1981). 13. NCI. Bioassay of tetrachloroethylene for possible carcino genicity, NCI-CG-TR-13 DHEW/Pub/NIH-77-813 (1977). 14. Rampy, L. W., Quast, J. F., Leong, B, K. J. and Gehring, P. J. Results of long term inhalation toxicity studies on rats of 1,1,1-trichloroethane and perehloroethylene formulations. Paper presented at International Congress on Toxicology, Toronto, Canada; Abstracts, p. 27 (1977). 15. NCI. Bioassay of 1,2-dichloroethane for possible carcinoge nicity, NCI-CG-TR-44 DHEW/Pub/NIH-78-1361, 1978). 16. NCI. Bioassay of 1,2-dibromoethane for possible carcinoge nicity, NCI-CG-TR-86 DHEW/Pub/NIH-78-1336, 1978. 17. Laskin, S., Sellakumor, A. R., Kuschner, M., Nelson, N., La Mendola, S., Rusch, G. M., Katz, G. V., Dulak, N. C. and Albert, R. E. Inhalation carcinogenicity of epichlorohydrin. In press. 18. Van Duuren, B. L., Goldschmidt, B. M., Katz, C., Seidmann, I., and Paul, J. S. Carcinogenic activity of alkylating agents. J. Natl. Cancer Inst. 53: 695 (1974). 19. Van Duuren, B. L., Katz, C., Goldschmidt, B. M.. Frenkel, K., and Sivak, A. Carcinogenicity of halo-ethers. II. Structure-activity relationships of analogs of bis(chloromethyl) ether. J. Natl. Cancer Inst. 48: 1431-1439 (1972j. 20. Weil, C. S., Condra, N., Haun, C., and Striegel, J. A. Experimental carcinogenicity and acute toxicity of repre sentative epoxides. Am. Ind. Hyg. Assoc. J. 24: 305-325 (1963). 21. Hensehler, D., Eder, E., Neudecker, T., and Metzler, M. Carcinogenicity of trichbroethvlene: fact or artifact? Arch. Toxicol. 37: 233-236 (1977). 220 Environmental Health Perspectives SL 040587