Document K6R8OzeBJz7VapQbqOvk5Zprx

R&S 108059 BIO-MEDICAL RESEARCH .DOCUMENT DESCRIPTION FORM Duplicate in all cards:-- 0000166 63 68 69 _ 76 /V,v 0S5T5Q year as-1961- File number [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space > Ay 20 21 n i, j "Vi' .n- 40 , * ' > Y 41 11 /l* V Y, Z & / / 'i ,, I 77 78 Sub-Index Code 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 61 62 21 */> ysy/-''y y s'('s /- i- t! if-? v /r^O 7 S/py? <f 22 ,Iwj * p) /I <' -'M, , ^^r. .. ^ ' 'fl-I A (f y t'c /> fWl- tv'//7S l/'fyfy /*/'p'fp Otr--- - , /-/o ,/ Syty ~y----y -y /' ,y yo 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 /;<r/; /} /-/?}/ Sf?s) 61 62 31 32 Brief Summary 61 62 61 62 63 64 b1 C Mutation Research, 'll (197C) 131--1-12 KUuviur/Norlh-Hftlland Biomedical Press 131 y -- 0000166 -easotOT R&S 108060 CARCINOGENIC, MUTAGENIC AND TERATOGENIC RISKS ASSOCIATED WITH VINYL CHLORIDE PETER F. INFANTE, JOSEPH K. WAGONER and RICHARD J. WAXWEILER Division of Surveillance, Ilueard Evaluations and Field Studies. National Institute for Occupational Safety and Health, Main Post Office Building, Cincinnati, Ohio 45202 (U.S.A.) (Received May 13th, 1976) Summary The data presented demonstrate clearly that vinyl chloride (VC) is related to a significant excess of mortality from cancer of the liver, lung and brain among workers occupationally exposed to VC. The risk of dying from cancer of the lymphatic and hematopoietic system also appears to increase with an increase in latency. These cancer sites conic have been predicted by the animal bioassay conducted by Maltoni. With regard to the liver, even the histopathologic type of cancer (angiosarcoma) was observed first in experimental animais. A study of cancer mortality among populations residing proximate to VC polymeri/.alion facilities also demonstrated an increased risk of dying from CNS and lymphatic cancer. These latter findings raise cause for concern about out-plant emissions of VC, but without further study these cancers obviously cannot be interpreted as being related to out-plant exposure to VC. Various test systems now have elicited a positive mutagenic response to VC. Thus, our observations of a significant, excess of fetal mortality among the wives of males, who were occupationally exposed to VC, raise public health concern that VC may be mutagenic in humas. With regard to the teratogenicity of VC, observations of a significant excess of children born with birth defects were reported among populations residing proximate to VC polymerization facilities. Additional epidemiologic study is needed to determine whether a repeated pattern of cxecssive numbers of children born with birth defoets c;ui be observed in other communities with VC polymerization facilities. Introduction In 1920, the first adverse health effects of vinyl chloride (VC) were reported (22|. Since then, numerous investigators have reported the toxic effects of VC on the central nervous system, the liver, the bones of the fingers and the lungs V* 132 [2,5,9--12,18,20,28], More recently, the study of VC toxicity has broadened to assess the spectrum of carcinogenesis [2,15,10,21,20,29,20], mutagenesis [1,3,4,0,13,14,22,2d]. and leralogenosis [8], These efforts were stimulated by the work of Viola et al. [29] who, in 1971, reported the induction of tumors of the skin, lungs and hones in rats exposed by inhalation lo 30,000 ppm of VC over a period of twelve months. Widespread concern for the carcinogenic activity of VC, however, did not occur until early 1974, when Creech and Johnson [2] reported four deaths from angiosarcoma of the liver among workers employed in the manufacture of polyvinyl chloride (PVC) resins. It was later learned that Malfoni had previously demonstrated VC-induced hepatic angiosarcomas, lung adenomas, brain neuroblastomas, lymphomas and various other tumors in mice, rats and hamstc-rs [15,16]. With regaid to mutagenicity, several investigators have induced mutations via microbial test systems [1,14,24], Also, VC metabolites have induced mutations in mammalian cells [6], In addition, reports from several countries have demonstrated significant excesses of chromosomal aberrations among workers exposed to VC as contrasted with those not exposed [3,1,13,23], Because of these observations and of the widespread exposure to VC among both workers and the general population, the National Institute for Occupational Safety and Health (NIOSH) in the U.S.A. undertook an epidemiologic program to evaluate the magnitude and spectrum of VC toxicity lo humans. This program was 4-fold in nature and sought to evaluate: (1) The site-specific risk of cancer among workers exposed to VC [30). (2) The risk of some cancers among populations residing proximate to VC polymerisation facilities [8]. (3) 7 he site specific risk of congenital anomalies among populations residing proximate to VC polymerization facilities [S]. (4) The risk of fetal wastage among the wives of workers occupationally exposed to VC [7]. Cancer risk among workers exposed to VC To assess the neoplastic risk of workers exposed to VC, a population con sisting of employes from four VC polymerizing facilitates was selected for cohort mortality study |30]. Since occupationally induced cancers often take many years to become manifest, the study cohort was restricted to workers who had achieved five or more years of employment and for whom at least 10 years had lapsed since initial employment. Thus, the exposure period was five or more years and the latency period was 10 or more years. Follow-up for study cohort members was greater than 95". Table 1 shows the total mortality experience among the study cohort. The expected numbers nr.e based on United States mortality daUi applied lo NIOSll's modified life-fable method. For all malignant neoplasms, there were 35 ohseived vs 23.5 expected, the SM II was 149. This excess was significant at the P< 0.05 level of confidence. For total mortality, 136 deaths were observed vs 126.3 expe-ted. Selecting a cohort with at least five years work experience and 10 years latency eliminated the "healthy worker effect" [19| and so there were more total deal In. than expected and this was mostly at the expense of cancer mortality. Table 11 shows cancer mortality experience by greater than 10 and 15 year latency periods. At the greater than 10 year latency period, only biliary and R&S 108061 133 TAnn: I MOftTAMTV KXPKfUIiNCJi AMONG COJIOHT WQUKKHS LXPOSKD TO VINYL CIILOKIDE Cause of death ICD code * Observed Expected SMR b All malignant neoplasms Heart Non-malignuru respiratory diseases Cirrhosis All other cauv.-x <1 40--205) (400--4 43) <470-527) (581 > 35 57 G 2 36 23.5 54.7 3.4 4.0 40.7 149 e 104 17G 50 88 * JCD, International Clarification of Diseases, 7th revision, k SMfl, standardized mortality ratio, c Significant at f* < 0.05, liver cancer deaths were significantly in excess; however, when the sub-cohort with 15 years of latency since initial employment was used, deaths from three categories of cancer were significantly in excess. The excess in mortality from cancer of the lymphatic and hematopoietic systems was not significant; however, the SMR increased from 159 to 176 with an increase in latency. These comparisons show the importance of latency when looking for occupationally-induced cancers. TABLE II CANCER MORTALITY BY INTERVAL SINCE INITIAL EXPOSURE AMONG WORKERS EXPOSED TO VINYL CHLORIDE Site of malignancy 10+ years 15+ years All malignant neoplasms Drain and CNS cancer Hespiratory svsiem cancer Diliary and li\cr cancer Lymphatic and hematopoietic system cancer * All other malignant neoplasms Ob$., nbver^etl. Obs. * Exp, b SMR c Obs. Exp. SMR Obs. Exp. SM It Obs. Exp, SMR Obs. Exp. SMH Obs, K\p. SMR 35 23.5 149 3 0.9 329 12 7.7 156 7 0.6 1155 c 4 2.5 159 9 11,7 77 31 16.9 < 184 c 3 o .a < 498 d 11 5.7 < 194 7 0.4 < 1606 c 3 1.7 < 176 7 8.4 83 ** SMU, slatiU.iuli/i-il moil.iUlv r.iiiu. ^ Significant .it /' U,tK. r Significant at /* *' 0.0', 108062 37 & W 134 In laboratory studios, Mnltoni has induced hepatic angiosarcomas, lung adenomas, brain neuroblastomas and lymphomas [1C]. Therefore, the predictive value of animal bioassay studies can be demonstrated, not only by the observation of a significant excess of angiosarcoma of the liver among VC workers, but also by significant excesses of lung and brain tumors. Cancer risks in populations residing near VC polymerization facilities The risk of some cancers among adult populations residing in the only three Ohio communities with VC polymerization facilities was assessed [8]. All three communities had at least one facility in operation by 1954 and Paincsville had a second plant in operation by 19G7. The community population sizes varied from 12.000--24,000. Between 19G0--70 the population had remained stable in Paincsville and Ashtabula, but had increased by 00% in Avon Lake. As reported previously, for the three communities taken as a whole, there were no apparent differences in racial origin or family income as compared to the aver age for the State [ 8], As a result of previous findings [26], cancers of the central nervous system, lymphatic and hematopoietic systems, wore selected for study. Because of possible error in death certificate data in terms of metastases from other primary' sites, data for lung and liver cancers were not analyzed. Table III shows data for observed versus expected CNS cancer deaths in the white population by sex for the period 195S--73. North Ridgoville is the only community shown which does not have a PVC polymerization facility. It was included in the analyses of the cancer data because it is located contiguous to Avon Lake and because it had a high incidence of children born with birth defects [8]. If North Ridgevillc had not been included in the analyses of cancer mortality, little difference in the results would have been observed. Expected values arc based on the occurrence in the balance of the counties over the same period of time. As shown in Table III, there was a significant excess of CNS cancer deaths in males. The excess was greatest in Paincsville and North Ridgevillc. With all communities combined, there wore 27 CNS cancer deaths observed in males versus 14.1 expected; the SMR was 191. The difference was significant at. P < 0.01. In females, with all groups combined, there was only a slight excess. With sex groups combined, the excess was significant at P < 0.01. It may be note worthy that one father-daughter combination for CNS tumor deaths occurred in Paincsville, The daughter dic'd of a papillary ependymoma in 1963 at the age of 16. The father died two years later of a glioblastoma'multiforme at tire age of 58. It would be difficult to determine whether this observation is the result of genetic or environmental factors. Table ill also shows deaths from lymphomas. Although the differences between observed and I'xpeeted deaths in males were not significant, there was a consistent excess in each community. In females, there were excess lymphoma deaths in two of the four communities. With sex groups combined, a significant excess of lymphoma deaths was observed in Ashtabula. With sex groups and communities combined, the number of observed deaths was 61 versus 48.7 expecLcd. The SMR was 125. This was signiticanl at R&S 108063 R&S 108064 135 TAIiLE III run 45ohsekveii anij expected df.aths three types of cancer for residents years and older in TIIF. OHIO communities with vinyl chloride polymerization FACILITIES. 1958-73 Expected numbers of cancer deaths based on occurrence over the same period of time in the balance of the counties in which the communities are located. Ashtabula Paincsvillc Avon Lake N FlidfU'viIIi* Cummunttti's Combined Males Obs./Kxp. SMR CNS cancer (191 -- 192)* 7/ 6.1 12/ 3.8 2/ 2.3 6/ 1.9 115 31C d 87 31C b 27/14.1 191 c Females Obs./Kxp. G/ 3,8 2/ 2,8 1/1.8 2/ 1.5 11/ 9.9 SMU 158 71 56 133 111 Sexes combined Obs./Lxp. SM R 13/ 9.9 14/ G.G 3/ 4.1 8/ 3.4 38/24.0 131 212 b 73 235 b 158 c 1 too AshUbuL Paincsvillr Avun Lake N. HidccvilU* Con) rminitifs Com brnod Leukemia and aleukemia (204 13/14.7 8/ 7.1 1/ 3.6 2/ 3.2 88 i in 28 63 11/ B.G 7/ 6.8 5/ 2.2 01 1.9 2 1/28.6 84 23/19.5 128 103 227 0 118 24/23.3 15/13.9 6/ 5.8 2/ 5.1 47/48.1 103 108 103 39 98 Ashtabula Paincsv illc Avon Lake N. Kidp-villf Communilus Combined Lvmphumu (200-203)* 18/12.6 '2/10.4 4/ 3.3 3/ 2.8 143 115 121 107 37/29.1 127 14/ 5.8 4/ 8.3 5/ 2.9 1/ 2.G 24/19.6 241 c 48 172 38 122 32/18.4 1G/1H.7 9/ 6.2 At 5.4 Gl/46.7 174 c 80 145 74 125 * International Classification of Diseases, fith revision codes. b /' A 0.05. c / < 0.01, d / < O.tlO2. 0.05 < P< 0.10. Data' were then analyzed for leukemia and aleukemia mortali ty. As shown in Table III, the observed versus expected mortality was virtually identical. Birth defeets among populations resitting near VC polymerization facilities The oeeurrenee of birth defeets was studied [S] for the same three Ohio communities with VC polymerization facilities. Birth data for residents of North Kidgerille were not combined with data for the three index communities in the initial analyses (Table IV) because the high incidence of birth defects in North Uidgeville, which lies contiguous to Avon Bake, was identified in subsequent analyses [S|. Data for North Kidgeville, however, were included in subsequent analyses (Table V) for specific birth malformations. The observa tions among community residents were compared to both the occurrence in R&S 108065 136 TAISLK IV RESIDENT BIRTHS. M A LP'Olt.M ATI ON RATE PER 1000 LIVE BIRTHS IN OHIO AND IN THU EK SELECTED COMMUNITIES AND OBSERVED VERSUS EXPECTED MUMUEHS OK MALFORMA TIONS IN EACH CITY. YEARS COMBINED. 1070 -7.1 Malformations arc based on codes 740--759 of llic International Classification of Diseases, 8th revision, 1908. Are Entire state of Ohio Ashtabula city Painosvillc city Avon Lake cii> All three communities combined Birlbs 719, 287 1900 1381 738 1019 Malformations Rate/lO'1 Number observed 10.1 17..1 18.1 20.3 18.2 7293 33 23 13 73 Number expected a _ 19.3 14,0 7.3 40.8 x3 -- 9.78 b 10.29 b 7.50 b 27.13 r * Expected numbers arc based on state rate per 1000 live births. b P < 0.01. c P < 0.001. the balance of the counties in which the communities are located and to the occurrence in the Slate for the period 1970--73. Between 1970--73, the rate for birth defects changed from 9.3 to 11.3 per 1000 live births for the balance of the counties, from 9.G to 10.S for the entire state, whereas, the rate for the three index cities combined changed from 17.0 to 22.5. Thus, the incidence of birth defects lor children born in the index cities was almost twice as great as the incidence in the balance of the counties or in the entire State, and the differences appear to be increasing with time. Table IV shows data for malformation rates in each index community versus the rale for the entire State. These differences were all highly significant. Tin* rates ranged from 17.47 in Ashtabula to 20.33 in Avon Lake,'as compared to 10.14 for the entire State. When the community experience was compared to the occurrence in the balance of the counties in which the communities were tabu: v OBSERVED. EXPECTED AND RELATIVE RISE FOR SPECIFIC CONGENITAL ANOMALIES IN INDEX AREAS INCLUDING N. RIDGEVU.LE. 1970--71 Defect catey.oi y Number of defects RR b Observed Expected All di-fi-i ls (740 750. 718. 75!l) 0 Central nervous system (7-10 7-19) Cleft palate and lip (7-19) Genital (ii|Mti< 732) Clubfoot (7 3 |) All other defeets ion 17 10 10 23 43 5G.0 5.0 0.5 8.4 8.2 27.2 ].y& 3.02 1.53 1.90 2.79 1.38 ** KxcUuhw skin. hair .uni u.uN (737), ^ K It. relatnc risk (o1*mt\el/u\pei-ted). c International Classifnalion of Disease codes, 8th revision, are shown in parentheses. R&S 108066 137 located, the differences remained significant. Therefore, whether yon compare the occurrence in the communities to the expected, based on the average for the State, or for the balance of the counties, the excess of children with congenital anomalies in the communities appears to he significant. Table V shows observed versus expected numbers and the relative risk for total and selected malformations. Although an increase in most organ systems was observed, Lire greatest excess of severe defects included malformations of the CNS, cleft lip and palate, club foot and genital organs. These observations have been reported previously in more detail IS]. Fetal mortality among wives of workers exposed to VC Since VC had elicited a positive mutagenic response via microbial test systems [1,6,14,2d] and also had been associated with significant excesses of chromosomal aberrations in tiic lymphocytes of workers occupationally exposed to VC [3,4,13,23], concern was expressed that VC may induce germinal mutations. Thus, a questionnaire-interview survey was conducted to ascertain the incidence of fetal loss (defined as any product of conception not born alive) among wives of workers exposed to VC [7a], All current VC polymerization and polyvinyl chloride (PVC) fabrication workers were included for study together with a similar number of current rubber workers selected from work areas relatively free from known toxic materials and matched as a group to the VC workers by age. No interviews were conducted with workers' wives and no data were obtained concerning maternal age, except indirectly through paternal age. Group participation rates ranged from 62--77 percent. Data ior the wives of VC polymerization workers (study group) were contrasted with data for the wives of PVC fabrication ami rubber workers ("controls"), who wore known to have had very low- or no VC exposure, respectively. The data in Table VI show the paternal age distribution for fetal deaths according to the husband's exposure. Prior to husband's exposure, the crude fetal death rales for the control and study group were 6.9 and 10.17;, respectively. Subsequent to husband's exposure, the crude rates were S.S and 16.5C;, respectively. As can be seen in Tabic VI, the excess in fetal mortality subsequent to husband's exposure, was associated wiLh younger-aged husbands. For husbands 30 years of age and older, the rates for the control group 17/112 (12.07;.) and primary VC exposure group 9/69 (137;) were about the same; whereas, for husbands less than 30 years of age, the rates for the control group 7/131 (5.37c) and primary VC exposure group 14/70 (20.07g) were significantly different, /' < 0.001, x7 ~ 10.52, with one degree of freedom (df). Tire excess of fetal mortality among wives of younger-aged husbands may he a reflection of a practice of placing newly lured personnel because of little or no seniority, in jobs where i ccupatioual exposures to VC may have been worse. This hypo thesis, however, needs lurllier assessment in oilier working populations. Since parental age was positively correlated with fetal mortality in this population and in a previous study |25|, fetal mortality rates for the study group were adjusted to the .ige-dislril>tilion of the control group. 138 TAUJ.K VI PATC.ltNAI. ACK JilSTltlllUTION COK KKTAL DKATIIS ACCOltDINCi To IIUSDAND'S VC KXl'O- simc Paternal ace group (years) *'ContmtM Primary VC VIxposure i t 'i nancies Petal deaths Pregnancies Petal deaths <N) (N) r> (N> (N) (G.) <20 20--2-1 25-20 30-3-1 2^35 A1J ages crude rate Mcaa paternal age a conception (year) Ace-adjusted 1 rate Prior to husband 's exposure 31 2 6.5 80 4 5.0 38 4 J 0.5 6 1 16.7 4 0 0.0 11 6.9 (6.9) 7 44 56 27 14 148 26.4 0 0.0 2 4.5 7 12. 5 5 18,5 1 7.1 15 10.1 (6.1) >20 20--2-1 25-20 30--31 >35 AH ar.es crude rate Mean paternal ape at conception (year) Ap.c* adjusted * rate Subsequent to husband*? exposure 2 43 87 87 55 273 30.4 0 4 3 7'iwji 10 -2, 0.0 9.3 3.4 8.0 18.2 8.8 (8.8) 0 22 48 36 33 139 30.2 0 0.0 3 13.6 1 1 22.9 3 8.3 U 18.2 23 1G.5 (16.8) * Kclrtl mortality rnt.-s for primary VC exposure croup ary direct *i: r-.idius:cd to tlio pati-nul diiu-dixlriliulion of thy pryitoancios in the control itroup (shown m pwrriiilu-M a). R&S 108067 TAULK " ME ACC ` GE-ADJUSTKO ECTAC DEATH KATES "Controls" J Prnn.irv VC i-xiJiiyun; ^ .Number of families Mean patcrn.il age at conception (years) Number uf fetal deaths among wives Number of ptegnaneies Age-adjusted fetal di.ithx/100 preg. c Number of families Mcjm paternal age at concept ton (years) Number of fetal deaths among w tees Number of pici'iiamics Ago-adjusted fetal dealhx/\00 pu-g, c Prior tn husband's exposure 95 . 23.0 11 159 6.9 70 2G.4 15 148 6.1 Subsequent to husband'`s exposure 113 30.4 24 G2 30,2 23 : :.i 8.8 139 15.8 d a Kubbci ami P\ (_* f.iliric.iiiiin n,t'iki't'>. ^ N't' polytm'ri.'aum wurld'iN. ** HiUcs nip'`.i(l|\iNti`(l 14* `Vimiiol" ymup paternal age distiibutiim. NllllMMIllt'lll (ii IItltli.llltK* i'Npfi'.lJli1, tin* fli'ljWi'tieV trl ft'l.lj .IHtiMU,' VllVt"; T.iS r.t'f.ili'l' iu tin* W expusmc rump .is nimii.io'il to the "cunt lols" (/' < 0.0b) m` f*i the Irequenr \ in tin* xtiulv >jou| pf'or (it lm*liari<J\ exposure (/* v. ti.02) 1 *\ arc-adjusted Iii->(|n.ir* testing. 139 The data in Tabic VII show fetal death rates per 100 pregnancies for the wives of male workers in the control and study groups. Prior to their husband's exposures, the rates were 6.9% and 6.1% for the control and study ('roups, respectively. Subsequent to husband's exposure, however, the rates were 8,8% for the control group versus 15.8% for the study group. This difference was significant at the /> <0.05 level by Mantel-Haenszel Chi-square testing [17] (xJ~ 4.84, df - 1). Further, the before and after exposure comparisons indicated changes in rates from 6.9 to 8.8% for the control group as compared to a change from 6.1 to 15.8% for the study group. The rates for before and after husband's exposure in the study group were significantly different (P < 0.025, x2 = 5.78, df = 1). For the study group, it may be noted that before exposure age-adjustment reduced the crude rate from 10.1 to 6.1%; whereas, after exposure the crude rate was reduced from 16.5 to 15.8%. The greater reduction in rates for the before exposure age-adjustment resulted from a difference in the age distribution of the husbands in the two groups. As can be seen in Table VII, prior to husband's exposure, the mean paternal age in the study group was 26.4 years as compared to only 23.0 years for the control group, whereas, subsequent to husband's exposure, the mean ages of the two groups were virtually the same, i.e., 30.4 years versus 30.2 years. In both situations mean age was a good measure of central tendency. To determine whether women who had chronically experienced abortions might have weighted (lie results in favor of a higher fetal mortality rate in the primary VC exposure group, data for the pregnancies of women who had two, three or four or more spontaneous abortions were eliminated. The data were then recalculated to determine whether or not the trend of a greater mis carriage rale could be maintained. As shown in Tabic VIII, the trend was maintained for each analysis. table vin NUMBER or PREGNANCIES AND AGR-ADJUSTEU FETAL DfcATU HATES ACCOItniNG to nosBAND'S VC EXPOSURE EXCLUDING PREGNANCIES IN WOMl'N WITH >2. 3 OR 4 FETAL DEATHS Rates for the primary VC exposure r.roup arc aRO-adjustcd to the Control group Controls Primary VC exposure Number of pregnancies Fetal death rate Number of pruenaucics Fetal death /ate Before husband'* t:\posuri' After Ihi^UjihI's exposure 't.l Fetal deaths excluded 1S5 2SS 5.BS, 4,1% 12G 111 1.7 To G.2^ Before husband's exposure After hu-ib.ind'* exposure ^3 Fetal (lc.itIts excluded ] VJ r..yr0 2Gb G,RC. Ml 120 3. IT. 1 0.8'n Before Ituxb.ind*$ After expoxtt c jvl Fetal deaths excluded Kit) 2Gb 142 127 &.R% I l.K'-a R&S 108068 R& s 108069 140 As reported previously [7a], additional analyses suggested that the significant excess in fetal mortality after the husband's exposure would not seem to be the result of bias from interviewers nor from respondents. Because of the highly volatile nature of vinyl chloride [27], carry-home exposure to the wife would seem unlikely. Therefore, the leading possibility for the mechanism involved would seem to bo germ-cell damage in the male through direct VC exposure. References 1 Dartsch, H,, C. Mnlnviclle and li. MonlcsAno, Human, tat <md mouse liver-mediated mutagenicitv of vinyl chloride in lyphimurium strains. Int. J, Cancer, 15 (1975) *129--4 37. 2 Creech, J.L.. Jr. and M.N. Johnson. Anriosarcoma of liver in the manufacture nf polyvinvl chloride, J. Occup, Med., 16 (107*1) 1 GO-1 Til, 3 Dueatnun. A.. K. Uirschhorn and I.J. Sclikoff, Vinyl chloride exposure and human chromosome aberrations, Mutation Kes.* 31 (1975) lt>3--168, 4 Kunes-Cravioto. K., 11. Lambert and J. Lindstcn, Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1 (1975) 459. 5 Gedrip.k. P,, It. Muller and II, Dechtclslu'imcr, Morphnlbpy of liver damage amonc polyvinvl chloride workers, Ann. NY Acad. Sci. 246 (1 975) 27fi--285. 6 Uuherman. E.. 11. Dartsch and L. .Sachs. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chluroothylenu oxide and 2-chIoroacetaJdchy de, Int. J, Cancer, 16 (19 jT>) G39--G44. 7a Infante, P.K., J.K. Wagoner and A.J. McMiehacl, Genetic risks of vinvl chloride. Lancet, 1 (1976) 734-735. 7b Infante, P,K.,J. K, Wagoner, A.J. McMiehacl, R.J. Wawteiler and H. Falk, Genetic risks of \ in> 1 chlnndr, Lanevt. 1 (107G) 1239 -- 1 290, 8 Infante, P.K., Oncoitcn.c arid niuta(v*nic risks n communities with polvvinvl chloride production facilities, Ann. NY Arad 5ic.i , 271 (1976) 49--57. 9 Kroner, C.G. and J.K. Mutchler. The correlation of clinical and environmental measurements for vinkers exposed to vn> 1 chloride, J, Aimr. Ind. IIvr. Assoc.. 33 (19 72) 19 -30. 10 I.an^e, C.K., S. Julie, G. Stem ami G. Wltnian. Further lesulls in polwin) I chloride production workers, Ann. NY Arad. 8ci., 246 (1975) 18-21. 11 Lester, LX. L.A. 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Wash ington, D.C., February 1974. 1G Maltoni, C. ami t. Lvfendii*1, Catcinogenu-ilv bioassavs i>f vinyl rhlmide, Cvment results, Ann. N'\ Ac.ul. SeL, 246 (1975) 195-218. 17 Mantel, N. nnd W. Huciis/el, Si.ilislieal aspects of the analysis of data from retrospective studies- of disease, .1. Natl. Cancer. Inst.. 22 (195!)) 71'.) -7-1H. 18 Marsleller, H.J.. W'.K, Lelh.ich, It. Muller ami 1*. GeJn;k, Unusual splenomey.ilir liver disease as evi* dcnccd by peritoneoscopy and funded liver biopsv anionr. polyvinyl chloride production workers, Aon. NY Acad. Sci.. 2 If. (197 5) 95 18 1. 19 MeMichael, A.J,. S,Ci. Ilavtu > and II.A. Tv roler. Observations on the evaluation of oecupatinn.d morl.ilitv data. J. Oecup. Med.. 17 (1 975) 128-131. 20 Miller, A., A.5. Triislem, M. fhii.iMg, I.J. Nchkoff and II, Wursliaw. ClMiir.es in pnlmon.irv function in vvorkeis expo.ed to vinvl t blonde and |iul\ viinl ehltnule, Ann. 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