Document 2jL3vXRy2gOKOeRBn3XK7K0d6

> * / i`nt)y sensitive /n futr opinion, ssi '> Mrs. J. Novot- >Kn prMtlu (,,,n. iij iir. Vol, .1. Pl.-mim tome charter tfurtnt: ahrmitinns. n. HuminKi-ni-tik. 6 t Imuran (Araihio* OsU*rmiio*r4Mih*`r, with A/athioprtm*, (hr prrparjtiiin of ' (ihfi.'i) .1,1.1-.i.is. nC (rr*(mrnt with nf of the frrquertd ical Jtrnis, rh firm. 1. TrtlinK <l!17fi) 271 27ft. tsmtitt) ahrrralion* *" Ur*.. .14 (IDTi;) ' khlnride workers. .1/2 (1117.1) Sli*rt, Wrh, 2S u m vitro for the " Spnnttrr-WrlaiE. * the oeruiMlioo.il * cvto^un-inHun-ft Mulalimi Itescarch. ! 1 (197G) 13l -- 1J 2 EUcvicr/Norlh-Holland Biotruuliral Press t1 CARCINOGENIC, MUTAGENIC AND TERATOGENIC RISKS ASSOCIATED WITH VINYL CHLORIDE PETER F. INFANTE, JOSEPH K. WAGONER and RICHARD J. WAXWEILER Division of Surveillance, Hazard 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 Tilt1 data presented demonstrate clearly that vinyl chloride (VC) is related to a significant excess of mortality from cancer of the liver, lung anti 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 could 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 animals. A study of cancer mortality among populations residing proximate to VC polymeriza tion facilities also demonstrated an increased risk of dying from CNR 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 excessive numbers of children born with birth defects can be observed in other communities with VC polymerization facilities. Introduction In 19-'I0, 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 132 ^ " (2,5.9--12,18,20,23|. More recently, the study of VC toxicity has broadened to assess the spectrum of carcinogenesis | 2,15,16,21,20,29,30], mutagenesis [1,3,1,6,13,14,23,24]. and teratogenesis [8]. These efforts were stiimilated by the work of Viola et al. [29] who, in 1971, reported the induction of tumors of the skin, lungs and bones in rats exposed by inhalation to 30,000 ppm of VC over a period of twelve months. Widespread concern for the carcinogenic activity of VC, however, did not occur until curly 1974. when Creech and Johnson [2] reported four deaths from angiosarcoma of the liver among workers employed in the manufacture of polyvinyl chloride (f*VC) resins. It was later learned that Maltoni had previously demonstrated VC-in duced hepatic angiosarcomas, lung adenomas, brain neuroblastomas, lymphomas and various other tumors in mice, rats and hamsters [15,16j. With regard to mutagenicity, several investigators have induced mutations via microbial test systems [1,14,24], Also, VC metabolites have induced mutations in mammalian cells [61. In addition, reports from several countries have demonstrated significant excesses of chromosomal aberrations among workers exposed to VC as contrasted with those not exposed [3,4.13,23]. 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 to humans. This program was 4-fo!d 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 polymerization facilities [8]. (3) The site specific risk of congenital anomalies among populations residing proximate to VC polymerization facilities [8], (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 99%, Table I shows the total mortality experience among the study cohort. The expected numbers are based on United States mortality data applied to NIOSH's modified life-table method. For all malignant neoplasms, there were 35 observed vs 23.5 expected, the SMR was 149. This excess was significant at tire P< 0.05 level of confidence. For total mortality, 136 deaths were observed vs 126.3 expected. 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 deaths 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 TAUU Miner Cause < AH mill llCJft Nonm Cirrh All oila 1C D b SMU c Sinn* liver with cate; canthow The? occt TABl. CANt TO V Site " All in Drain Kespi Bill*" Lvnr AH f. v SS * Ku S.i 'a* broadened mutagenesis stimulated rinH"r;tion of ion 30,000 icorn for the ' 1974, when ia of the liver iloride (PVC) (.rated VC-in% lymphomas mutations via ed mutations mntries have long workers I. Because of both workers al Safety and n to evaluate program was sk of cancer ncers among (3) The site roximate to mg the wives n conselected for ncers often restricted to for whom at sure period i. Follow-up cohort. The applied to , there were ignificant at re observed < experience and so there expense of md 15 year biliary and TAiii.i: i MO Id AI.ITY EXPERIENCE AMONG COIIOIIT WORKERS EXPOSED TO VIN\ I, CTII.OIIII>E Cause of death ICU codt ' Observed Expeetcd SMR *' AH malignant neoplasms Heart Non-malignant respiratory diseases Cirrhosis All other causes (140--205) (400--44.7) (470--ft27) (581) 3ft 57 6 2 36 23. ft 54.7 3.4 4.0 40.7 149 r 104 17fi 50 88 3 ICO. International Classification of Oisr.ises, 7th revision. ^ SMIt, standardized mortality ratio. C Significant at /* < 0.0ft. liver cancer deaths were significantly in excess; however, when the sub-cohort wi: , 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. tadlkm CANCER MOUTALITY 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 Respiratory svstem cancer Biliary and li\cr cancer Lymphatic and hematopoietic system cancer All other malignant neoplasms 3 Ohs,, nlwri*<!. ^ expected. c SM K, standardized mortality ratio. d Sir.mfirani at /* < 0.0ft. Significant at /* 0.01. Obs. 1 Exp. b SMR c Ob*. K*p, SMR Obs. Exp. SMR Obs. Exp. SMR Obs. Exp. SMR Obs. Exp. SMR 35 33.5 149 <* 3 0.0 320 12 7.7 T5G 7 O.fi liftj c 4 2.5 1 50 0 11.7 77 31 16,9 < 181 '' 3 0.6 < 498 11 11 5.7 < 194 *' 7 0.4 <* 1606 e 3 1.7 176 7 8.4 83 131 In laboratory studios, Maltoni has induced hepatic angiosarcomas, lung adenomas, brain neuroblastomas and lymphomas [16|. 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 Painesville had a second plant in operation by 1967. The community population sizes varied from 12,000--24,000. Between 1960--70 the population had remained stable in Painesville and Ashtabula, but bad increased by 30% 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 tu the aver age for the State [8], As a result of previous findings [26], cancers of the central nervous system, lymphatic and hematopoietic systems, were 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 wore not analyzed. Table. HI shows data for observed versus expected CNS cancer deaths in the white population by sex for the period 1958--73. North Ridgcville 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 [8J. If North Ridgeville 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 Painesville and North Ridgeville. With all communities combined, there were 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 Painesville. The daughter died of a papillary' ependymoma in 1963 at the age of 16. The father died two years later of a glioblastoma multiforme at the age of 58. It would be difficult to determine whether this observation is the result of genetic or environmental factors. Table 111 also shows deaths from lymphomas. Although the differences between observed and expected 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. Willi sex groups combined, a significant excess oT lymphoma deaths was observed in Ashlnluila. With sex groups and communities combined, the number of observed deaths was 61 versus 48.7 expected. The SMR was 125. 'I'liis was significant at taiii.k hi OIISI'.ItVKU AND K' YKAItS AM) OLDI-.H KACII.ITIKS, 1038 -7 Expected numbers oC the counties in which t ic I Ash tabula P,im*xv die Avon l-ikv \ N. H itlftevdU* ( Communities Coin binett l AshubuU Painesville Avon Lake N. Ridurvillr Communities Combined 1 AshtabuM Painesville Avon Lake M. K.iUu*viUe I Cbmrt'Utuliex { Combined International Claw* b / 0,05. c /' < 0,01, <1 p < 0.1)02. 0.05 < P< 0.1' ty. As shown i identical. Birth defects ai The occurrc communities t North Ridgevil in the initial a North Hidgcvi subsequent an: subsequent an lions among c nhs, lung the ^ only by "nong VC :>ly three All three villc had s varied d stable -ake. As were no ihc aver- system, ausc of n other is in the he only . It was nous to h birth yses of served, ^unties f: at TIC. .t* `7 CNS s 191. With noteeurred lie age ho age result renres re was Kccss lined, h sex as 61 it at intaiii.k Oll-SI-.lt Vi:i) AND l-.XPKCTI-.D HEATHS HJII THREE TYPi-S OK CAN Chit 11)11 RES I HUNTS -IT* YEARS AND OLDER IN THE OHIO COMMUNITIES WITH VINYI, CHLORIUE POLYMERIZATION FACILITIES. 1938--73 Expected numbers of ejneer deaths based on orcurrence ovr the same period of lime in the balance of the* counties in which the communities arc located. Males Females Sexes combined Ohs./Kxp. SMR Obs,/Exp. SMR Qos./Exp. SMR A'htJbulJ Puniest till' Avon N. UidiicMllt* Communities Combined CNS cancer <191-- I92)s 7/ (i.l 12/ 3,8 2/ 2.3 6/ i.o IIS 31G d 87 316 b 27/1-1.1 191 c 6/ 3.8 21 2.8 1/ 1.8 2/ 1.5 11/ 9.3 138 71 50 133 111 13/ 0.0 14/ 6.6 3/ 4.1 8/ 3.4 38/24.0 131 212 b 73 235 b 158 c Ashtubulu Painexvillc Avon Ukc N. Hkluevinr Communities Combined Leukemia and aleukemia (204 -- 207) a 13/14.7 8/ 7.1 1/ 3.li 2/ 3.2 88 113 28 63 11/ 8.8 7/ 6.8 5/ 2,2 0/ 1,0 24/28.6 84 23/13.3 138 103 227 0 118 24/23,3 15/13.9 e/ r>.8 2/ 5.1 47/48.1 103 ioa 103 39 08 Ashtabula Pjifiesville Avon Lake N, ItidtteviHr Communities Combined Lvmphumu (200--203)* 18/12.U 12/10.4 4/ 3.3 3/ 2.8 143 1 IS 121 107 37/20.1 127 14/ 3.8 4/ 8.3 5/ 2.0 1/ 2.8 24/19.G 211 c 48 172 38 122 32/18.4 16/18,7 9/ 6.2 4/ 5.4 61/48.7 174 r 86 145 74 125 Intrrnntioii.il Classification of Diseases. 8th revision codes. b / < n.<i.->, c r <0.01. d / < 0.002. 0.05 < P< 0.10. Data were then analyzed for leukemia and aleukemia mortali ty. As shown in Table til, the observed versus expected mortality was virtually identical. Birth defects among populations residing near VC polymerization facilities The occurrence of birth defects was studied |S| for the same three Ohio communities with VC polymerization facilities. Birth data for residents of North Uidgeville were not combined with data for the three index communities in the initial analyses (Table IV') because the high incidence of hirlh defects in North Itidgeville. which lies contiguous to Avon Lake, was identified in subsequent analyses [8|. Data for North Itidgeville, 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 VM* TABLE IV RESIDENT BIRTHS, MALFORMATION KATE PER 1000 LIVE BIRTHS IN OHIO AND IN THREE SELECTED COMMUNITIES AND OBSERVED VERSUS EXPECTED NUMBERS OF MALFORMA TIONS IN EACH CITY, YEARS COMBINED. 1970-73 Malformations are based on codes 740--759 of the International Classification of Diseases. 8lh revision. 1968. Area Entire stale of Ohio Ashtabula citv Painesvillc city Avon Lake citv AH three communities combined Births 719.287 1900 1331 738 4019 Malformations Rated O'" Number observed I O.l 17.4 18.1 20.3 18.2 7293 33 25 15 73 Nil mber expected * _ 19.3 14.0 7.5 40.8 xJ _ 9.78 b 10.29 11 7.56 h 27.13 c * Expected numbers are based on state rate per 1000 live births. b P < 0,01. CP< 0.001. the balance of the counties in which the communities are located and to the occurrence in the State 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 9.6 to 10.8 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 for 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 rate for the entire State. These differences were all highly significant. The 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 TABLE V OBSERVED. EXPECTED AND RELATIVE RISK FOR SPECIFIC CONGENITAL ANOMALIES IN INDEX AREAS INCLUDING N. RIDGEVILI.E, 1970-73 4 Defect category Number of defects un 11 Observed Expected All defect! (7*10--736, 758, 759) c Central m-fvous svsU'm (7 40--749) Cleft palate Jitd lip (749) Genital organs (752) Clubfoot (73-1) All other defects 109 17 10 lf> 2.7 43 Gti.O 5.6 6.5 8,4 8.2 27.2 1.95 3.02 1.53 1.90 2.79 1.58 * Exclude! !|t,n, li.or .uld nail* (757). b Kit, relative risk (ohscrvcd/expcclrd). c lntcrnatiun.il Classification of Disease codes, 8th revision, are Shown III parentheses. located, the occt the Stal congenit Table total an' was obs the CNf have be* Fetal m Sinct systems chrome exposet germ in; ascerta; born a polyme include, selects matchi with w indirec perern contra; ("coni respcc' The accord fetal t rcspec 16.57c As husba30 ye. prima; husba (5.3^ differ of fet of a i in jol thesis paren and i adjus *10 IN TIIUKE malpokma>** revision. :>.7S b '>-20 b T.iG b 7.13C <1 and to the 73, the rate r the balance rate for the incidence of e as great as itc, and the _unity versus fic*>nt. The red to >s compared unities were iNOMALIES IN I located, the differences remained significant. Therefore, whether you compare i the occurrence in the communities to the expected, based on the average fur the State, or for the balance of the counties, the excess of children with j congenital anomalies in the communities appears to be significant. ! Table V shows observed versus expected numbers and the relative risk for total .and selected malformations. Although an increase in most organ systems j was observed, the greatest excess of severe defects included malformations of j the CNS, cleft lipand palate, club foot and genital organs. These observations i have been reported previously in more detail [8], Fetal mortality among wives of workers exposed to VC : Since VC had elicited a positive mutagenic response via microbial test ! systems [ 1,6,Id,24 J and also had been associated with significant excesses of chromosomal aberrations in the 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 j included for study together with a similar number of current rubber workers I selected from work areas relatively free from known toxic materials and j 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 for tire wives of VC polymerization workers (study group) were contrasted with data for the wives of PVC fabrication and rubber workers ("controls"), who were 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 rates for the control and study group were 6.9 and 10.1%, respectively. Subsequent to husband's exposure, the crude rates were 8.8 and 16.5%, respectively. As can be seen in Tabic VI, the excess in fetal mortality subsequent to husband's exposure, was associated with younger-aged husbands. For husbands 30 years of age and older, the rates for the control group 17/142 (12.0%) and primary VC exposure group 9/69 (13%) were about the same: whereas, for husbands less than 30 years of age, the rates for the control group 7/131 (5.3%) and primary VC exposure group 14/70 (20.0%) were significantly different, P< 0.001, x% ~ 10.52, with one degree of freedom (df). The excess of fetal mortality among wives of younger-aged husbands may be a rcfleelion of a practice of placing newly hired personnel because of little or no seniority, in jobs where occupational exposures to VC may have been worse. This hypo thesis, however, needs further assessment in other working populations. Since parental age was positively correlated with fetal mortality in this population and in a previous study [25|, fetal mortality rales for the? study group were adjusted to the age-distribution of the control group. / 138 TAIIU-: VI PATERNAL A lit: DISTRIBUTION I'OK I'l-TAL DEATHS ACCORDING TO HUSBAND'S VC KXI'OSURE Paternal age group (years) "Controls'' Primary VC Exposure Pregnancies Kelt'il deaths Pregnancn s KiMjI <le,ubs <20 20-24 25--20 30-34 -135 All ages crude rate Mean paternal age at conception (year) Age-adjusted * raLe (N) <N) ra Prior to husband's exposure 21 80 38 6 4 1 50 23,0 2 u.n 4 5-0 4 10 5 1 16.7 0 0.0 11 6.9 (6.0) (N> 7 44 56 27 14 148 26,4 <N> r-> ' 0 00 2 45 7 12,5 5 18..') 1 7,1 1 5 10.1 (6.1) >20 20 *-24 25-20 30-34 _35 All ages crude rate Mean paternal age at conception (year) Age- adjusted a rate Subsequent to husband's exposure 1 43 87 87 55 273 30,4 0 0.0 4 03 3 3.4 7 8.0 10 18.2 24 8,8 (8.8) 0 22 48 36 33 139 30,2 0 00 3 J 3.6 11 22.0 3 8.3 6 18.2 23 16.5 (15.8) * Ketal mortality rates for primary VC exposure group are direct age-adjusted to the paternal age-distribution of the pregnancies in the control group (shoun in parentheses). TABLE VI! MEAN PATERNAL. NUMBER OK PRE<iNANCtES AND AGE-ADJUSTED PETAL DEATH KATES ACCORDING TO HUSBAND'S VC EXPOSURE Number of families Mean paternal age id conception (years) Number of fetal deaths among wives Number of pregnancies Agc-udjustcd fetal dcaths/100 preg. c Numlxr of families Mean pjtern.il .ge at conception (years) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 preg. c "Controls'* a Primary VC exposure Prior to husband's exposure 95 23.0 11 1 59 6,9 70 20.4 15 148 6.1 Subsequent to husband's exposure 113 30.4 24 27 3 8.8 62 30.2 23 139 15.8 11 * Rubber and PVC fabrication workers. ^ VC pnlvincri/ntion workers. ** Rates age-adiosted lo "contiol" group paternal age dedtiluilum. ^ Subsequent to husbands* ex puMire, tfie freipieno of fetal deal li> among u i\ es w as siem In an l|\ i n ,it in tin* primary VC exposure group js compared to tin "emit mis" (/* *. 0,05) or to ihe freqm nev in Ibr study group prior to busb.ind's exposure (/' < 0.02) bv age-.uliosted Chi-square testing. The data wives of mal exposures, t respectively. was signific: [17| (x:=-l . indicated eh | to a ehanye I after husbn ! (p< 0.025. : I before expi whereas, af1 greater redi a different be seen in ' study grouj group, wire groups wer situations n To deter nueht have primary V( three or f< then recah carriage ra maintained TAUi.r. viii NUMW'.U OV HAND'S VC DKATIIS Rates lot the I ---------------------- | Before husba: After husb.uu j\ ' Before hUSba A Iter huxb.in U<T.rr husba A Iter hushan t:i!> The (Jala in Table VII show fetal death rales per 100 pregnancies Tor Unwives 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 groups, respectively. Subsequent to husband's exposure, however, tire rates were 8.8% for the control group versus 15.8% for the study group. This difference was significant at the P<0.05 level by Mantel-Ilaens/cl Chi-square testing [17] (x:= -4.81.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, x: = 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 Tabic 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 ago was a good measure of central tendency. To determine whether women who had chronically experienced abortions might have weighted the 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 Table VIII, the trend was maintained for each analysis. TAUI.KVIII NUMUKH OK PREGNANCIES AND AGE-ADJUSTED KETAL DEATH RATES ACCORDING TO HUS BANDS VC EXPOSURE EXCLUDING PREGNANCIES IN WOMEN WITH >2, 3 OR 4 FETAL DEATHS Rati-j for the primary VC exposure Kroup are xge-adjusted to tlio Control croup Controls Primary VC exposure Number of pregnancies Fetal death rate Number of pregnancies Fetal death rate Before husband's exposure After husband's exposure ^2 Fetal deaths excluded 155 255 5.8% 4.7*7* 126 in 1.7*7 6.2% Before husband's exposure After husband's exposure Before husband's exposure After liuslund's exposure 2^3 Fetal deaths excluded 159 265 6.9% 6.6"#* >4 Fetal death** excluded 159 265 6.9'* 6,8*7. 141 120 142 127 3.1*c 10.8% 5.8% 11.8% As reported previously |7aJ, additional analyses suggested tliat thesignificant excess in fetal mortality after the husband's exposure would not seem to Ik- 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 be germ-cell damage in the male through direct VC exposure. References 1 Barl.sch, 11.. C. MaUvieDv and R. Monlesano, Human, ml and mouse liver-mediated inutagenieitv of vinvi chloride in .V. typlumtirium strains, Int. J. Cancer, 15 (1975) 129--*137. 2 Creech. J.L., Jr. anti M.N. Johnson, Angiosarcoma of liver in tin* manufacture of poly vinvi chloride, .1. Occup. Mcd,, lfi (1074) 1 50--1 51, 3 Ducjlnun, A.. K. Hirschhorn and l-J. Selikoff, Vinyl chloride exposure and human chromosome aberrations. Mutation Res.. 31 (1975) 163 -- 168. A I' 'V A-ravioto, F,. B. Lambert and J. Lindstcn, Chromosome aberrations in workers exposed to \in>l chloride. Lancrt 1 (1975) 459. 5 Gedrigk, P.. R. Muller and H. Bechtelsheimer. Morphology of liver damage amone poly vinvi chloride workers. Ann. NY Acad. $ri., 246 (1975) 278--285. 6 llulicrnun, E., H. Bartsch and L. Sachs. Mutation induction in Chinese hamster V79 evils hy two vinvi chlonde metabolites, chlorocthylenc oxide and 2-chIoroaceLaldehydc, Int. J. Cancer, 10 (1975) 639--044. 7a Infante. P.F., J.K. Wagoner and A.J. McMichjcl, Genetic risks of vinyl chloride. Lancet. 1 (1976) 734-735. 7b Infante, P.K.. J.K. Wagoner, A.J, McMichael, R.J, Waxvveilcrand II, Talk, Genetic risks of vinvi rhloude. Lancet. 1 (1976) 1289--1290. 8 Infante. P.F., Oncogenic and mula(tenir risks in communities with p<dyviuv! chloride production facilities, Ann. NY Acad, Sci., 271 (1970) 49--57. 9 Kramer, C.G. and J.K. Mutchler, The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. J. Amur. Ind. II vg, Assoc., 33 (1972) 19 --30. 10 Lance, C.E., S. Juhe. G. Stein and G. Vcltman, Further results in polwmvl chloride production workers, Ann, NY Acad. Sci.. 246 (1975) 1 8--21. 11 lister, D., L.A. Greenberg and W.R. Adams, Effects of sincle and repeated exposures of humans and tats to vinvi chloride, J. Amur. Ind, Hvg, Assoc., 24 (1963) 265--275, 12 Lilis, R.. H. Anderson, W.J, Nicholson, S. Daum. A.S, Fischhein and l.J. Selikoff. Prevalence of disease among einvl chloride and polyvinvl chloride workers. Ann. NY Acad, Sci , 246 (1975) 22--41. 13 Loken, E. and E, Thiis-Evensen, Preliminary report on the medical examination of 288 employees at the PVC plant. Norsk Hydro a.s.. Pnrsgrunn KabriKkcr, Porsgrunn. Norway, unpublished. 14 Loprieno. N., R. BaraJe and S. Baroncelli, Evaluation of the genetic effects induced bv vinvi chloride monomer (VCM) under mammalian metabolic activation: studies in vitro and in vivo, Mutation Res.. 40 (1976) 85-95. 15 Maltoni, C.. Preliminary report on the carcinogcmcitv bioassavs of vinyl chloride. U S. Dept. Labor Informal Fact-Finding Hearing On Possible Hazards of Vinvi Chloride Manufacture and Use. Wash ington. D.C., February 1974. 16 Maltum. C. and G. Lefcmine, Carcinogenicity bioassavs of vinvi chloride. Current results. Ann. NY Acad, Sci,. 246 (1975) 195-218. 17 Mantel. N. and W. Haens/el, Statistical aspects of the an.iHsis of d.itj from retrospective studies of disease. J. Natl. Cancer. Inst.. 22 (1959) 719-748. 18 Marsteller. II.J.. W.K. Lclbach, R. Mujlcr and I*. Geriigk. Unusual sptenomeg.dic liver disease as evi denced by peritoneoscopy and guided liver biopsv among poly vinyl chionrh production workers. Aon. NY Acad. Sci.. 246 (1975) 95--134. 19 McMicluel. A.J., 5.G, Haynes and II.A. Tyroler, Observations on the evaluation of occupational mortality data, J. Occup. Med.. 17 (1975) 128--131. 20 Miller, A., A.S. Tclrslein, M. Chining. l.J. Selikoff and R. Warshaw, Changes in puhtnmarv fuoeliun in workers exposed to vinvi chloride and polvvinvl chloride, Ann. NY Acad. Sci.. 246 (1975) I2--52. 21 Nicholson, \V J.,, F.C. Hammond. H. Seidman and !.<l. Selikoff, Morlalilv experieiire of ,i e/dwti of vinvi rhlonde-fiolyvinvl chloride workers, Ann, NY Acad. Sei., 2 16 (1975) 225 230. 22 Patlv. F.A.. W.P. Yant and C.P. Waite, Acute response of gmm-.i pigs to vapors of some new comni**rcij| organic compound*,. Public Health Report*;, 4 5 (I 930) I 963 -- 197 I . 23 Purchase, I.F.H., C.R. Kiehardson and t). Anderson, Chromosomal and dominant lethal effects of vinyl chloride. Lancet, I! (1975) 410 lit. 24 K.nuiug, U.. metabolic act ; 25 Shapiro, 5.. I , loss, Mitlhanl * } 26 Tubershaw, i j and its poivn 27 Unite.I ,stat. j Task III, vrni 28 Vcltman, G i vinvi chlnnrt ! 29 Viola. P.L.. { ride. Cancer | 30 Waxv\ viler. workers exp Ii1 III \ II I I I I icsi^n ifican l )-uni to be the of "'<? highly . would iism involved exposure. 1 muUnnitjlv of ' vinyl chlnrtdr, J. un (hromojomc exposed In vinyl nlvvinyJ chloride V79 cells by two mcer. 16 (1975) Lancet* 1 (1376) "( \inyl chloride, ride production masurements for `ride production "* of humans and . Jeiice of <!-.:> 22*41. 'H8 employees at ,er|. hv vinyl chloride *. Mutation Res.* Dept. Labor * and Use, Wash- H-sults. Ann. NY 'ctive studies of * f disease as evin workers* Ann. of occupational i.irv function tn (1975) 4 2-52. of a rohort of ''Onitf new com- `thaj effects of / I 21 It imohi: (J., A, Jnlbmwm, C. K.um,l and O.A, Wurhlmcixtrr, The iniHiir.emriLv of \iivl chloride .ifter metabolic uflivnlion, Ambit). 3 (1974) 194 197. 25 Shapiro, S.. K.W. Jont'i and P.M. tJenven, A life table ol pregnancy terminations and correlates of fetal Uivt. Mdllutik (Quarterly. 40 (1952) 7-- 15. 2ft Tahershuw, Lit* and W.R. Guffey, Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 1ft (1974) 500"5 1 ft. 27 United States Environmental Protection Agency. Samplim* and analysis of select toxic substances. Tusk III. vinvl chloride. Contract No. G8--01--264ft. Jan 20. 1976. 28 Vellmtin G., C*E. Lance. S. Juhc, G. Stem and U. Buchner, Clinical manifestations and rourse of vinyl chloride disease. Anti* NY Acad. Sci*. 246 (1975) 6--17. 29 Viola. 1\L.* A. Oicntti and A. Caputo. Oncogenic response of rat skm. lungs and bones to vinyl chlo ride* Cancer Res. 31 (1971) 516--519. 30 Waxwcder. R.J., W. Stringer, J.K. Wagoner. J. Jones, H. Kalk and C. Carter. Neoplastic risk among workers exposed to vinyl chloride* Ann. NY Acad. Sci., 271 (197ft) 39--48* (y^~ U''^-'',-^^ /' '>p) 313/ JtniiUt Mutation Res., "19 (1973) '* ragencity of xt+oderma pigmm- *..y.. A23,d8 (l1o9t72*,), 8on0_-_8S3.1 . dementation group in xeroderma complementation data regarding , 1 j Mutation Research, 37 (1976) 313--316 It Elsevier/North-Holland Biomedical Press Bj r ( Short communication i HIGH RATE OF CHROMOSOMAL ABERRATION IN PVC WORKERS i I. SZENTESI, E. HORNYAK, G. UNGVARY, A. CZEIZEL, Z. BOGNAR and M. TIMAR * i Laboratory of Human Genetics, National Institute of Hygiene; Department of i Experimental Pathology, State Institute of Occupational Health, H-l 966 Budapest, * Gyali ut 2--6 (Hungary) > (Received March 26th, 1976) f (Revision received June 15th, 1976) jji (Accepted June 23rd, 1976) v^yv-t*1 -, .v Occupational diseases, such as acro-osteolysis, Raynaud's phenomenon and 1 chronic liver lesion, were first diagnosed among PVC workers in the fifties [3, i 15,17]. Experimental studies and case reports published in the seventies dem onstrated a causal relationship between exposure to PVC and angiosarcoma of ithe liver [2,5,8,11--13,16]. The mutagenic properties of cancerogenic com pounds are of great interest, since mutagenicity can be proved earlier and by jisimplcr methods. Besides investigations on experimental mutagenesis [1,9,10], ;the results of four studies of chromosome aberrations in 7,11,13 and 56 wor kers exposed to VC were published in 1975 [4,6,7,14]. Exposure time was in * the range of 9--29 and 4--28 years in two reports [4,6] but was not known iin the other two [7,14]. The occurrence of chromosomal aberrations was in variably higher in the exposed groups than in the controls. This paper reports on the chromosome examination of 45 PVC workers ex posed to the compound VC for 0.5 to 12 years. i 45 PVC workers, 44 industrial controls (workers engaged in other chemical [plants, not exposed to PVC, and only indirectly exposed to other chemicals) fand 49 normal controls (no occupational exposure to chemicals) were exam ined. The chromosome analyses were performed in parallel and simultaneously iin 48-h cultures of peripheral blood. T*he chromosome aberrations. (Table I) were blind scored by one microscopist. Table I also indicates the distribution of jage and sex. f The following conclusions were drawn. The rate of numerical chromosome (aberrations did not differ significantly between PVC workers and controls. The {frequency of chromatid-type aberrations was higher in PVC workers than in the Itwo control groups (P < 0.001). Unstable chromosome-type aberrations were ?also significantly higher in PVC workers (P< 0.001). I The exposure-time of PVC workers is shown in Fig. 1. Values above the fconfidence limit of the norma] control group were regarded as "pathological" normal ' i> o cot ho logical 0 role Q female a a a a a o 1 a ao 2-3 a a o 4 -5 a a a a 6 -7 e-9 DO io-ii n D u u u u u LJ U3 HJ U II! i; Exposure time/yeors Fig. 1. Distribution of exposure-lime and number of "pathological" cases Jn PVC workers croup. Normal; () male, (o) female. Pathological: (} mole, () female. which means that 7 or 8 and more chromatid-type aberrations were found in 44--55 or 55--66 mitoses and 2 or more unstable chromosome-type aberrations in 15--101 mitoses. In contrast with earlier studies [6,7], our "pathological" PVC workers had been exposed to the compound for longer periods. These per sons, are being given a clinical check-up and thereafter it will be decided whether they can continue their present work. References 1 Bartsch, H,, C, Mnlavctllc, Ft. Montcsano and L. Tomalis, Tissue-mediated mutagenicity of vlnyllden* chloride and 2-chlorobutadlcne In SaJmortcJfa typhimurium, Nature. 255 <1975} 641--643, 2 Creech. J.L, and M.N. Johnson, Angiosarcoma of the liver in the manufactures of PVC, J. Occup. Med.. 16 (1974) ICO--161, 3 Dinman. B.D., W.A. Cook, W.II. Whitehouse. H.J. Magnusson and T. Dltchcch, Occupational aero- osteolysis, 1. An epidemiological study, Arch. Environ. Health, 22 (1971) 61--73, 4 Ducatmon, A., K, Hlrschhorn and J. SeUkoff, Vinyl chloride exposure and human chromosome aber rations, Mutation, lies., 31 (1975) 103--1G8. 5 Editorial, Anglosaicojna of the liver in vinyl chloride, polyvinyl chloride workers, J. Occup. Med., 16 (1974)309. 6 FuncS'Cravloto, F,, D, Lambert, J, LlndsteJn, L. Ehrenbcrg, A.T. Natarajan and S, Otlermnn-Golkar, Chromosome aberrations In workers exposed to vinyl chloride. Lancet, 22 (1976) 459, 7 Hanstech, I.L., L HillcsUd and E. ThUs-Evenson, Chromosome studies In workers exposed to vinyl chloride. Mutation Res., 38 (197G) 112 (abstract). 8 Lange, C.E., S. Jilhc und G. Vcllman, Liver angiosarcoma in two workers Ln a P VC*produclng factory. Dlsch. Med. Wochcnschr., 99 (1974) 1598--1699. 9 LoprJcno, N., A. Abbondondolo, A. Barale, S. Daroncelll, Mutagenicity of industrial compounds: vinyl chloride, stymie and their possible nivtuboHtcs, Mutation Kcs., 38 (I97G) 114--115 (abstract), IP Magnussen, J. and C. Kamel, Mutagenic effects of vinyl chloride In Drosophila mclanugustcr, Mutation Res., 38 (197G) 115 (abstract). 11 M&kk. L,, J.L, Creech, J.G, Whelan and M.N. Johnson, Liver damage and angiosarcoma in vinyl chlo ride workers, J. Amcr. Med. Ass., 230 (1974) G4--GS, 12 MaJtonl, C. and G. Lcfeminc. Carcinogenicity bloassays of vinyl chloride. 1. Research plan and early results. Environ, Res., 7 (1974) 387--*105. 13 Maltoni, C. and G. Lcfcnilnc, Carcinogenicity bloossays of vinyl chloride: current results, Ann. New Vori d, ScL, 246 (1975) 195-218, 14 Purch. ., I.F.H., C.R, Richardson and D, Anderson, Chromosomal and dominant lethal tv.ects of vl^^hloride, Lancet, 30 (1975) 410--411. 15 S.L.. N.P. Tikhomirova. S.U. Levina and L.A, Korlov, Working conditions and m s for