Document 2Jp0GK61NmkDVLrEkd96bY1Gg

i ``fitly sensitive f>r opinion. ;s Mulalinn Jlrscareh. 11 (1976) I.'l 1--112 Elxrvicr/Norlh-tlolland Biomcilicnl Press i:u ') Mrs. J. Novot- fmwhirtlon III. Urf. VnJ. JJ. Plenum chanct* tlurtnc aUrrrMliontt n. Humancrn*lik. ft i Imuran i/ysiKhm* *. 0*lrrmai>*C*hvr. i with A/athinpnnr. Ihr preparation nt 53.1 -an#. tn* Uritmrnt wUh inr nf lhr fwiurn* uH iral acrnU, rh\tinn. t, T'*wng O'JTfiJ 2Tt 2?*. `vuntJ a>H*rrjtton< r Kea., .14 (|f>TR) v Hlimdi* \vrk*ra* . 3/2 < t yT.ij *<;- >n. ffi-alih \rrh. 28 il in niiM Inf th** , S|>nnsrf*\Vrl4i. i the nffuiiutiMiul I cvtotiin-inriMfrrt CARCINOC.ENIC, MUTAGENIC AND TERATOGENIC RISKS ASSOCIATED WITH VINYL CHLORIDE PETER F. INFANTE, JOSEPH K. WAGONER and RICHARD J. WAXVEILER Dii tsi'tn ttf Surveillance. Hazard Kvaluation* and Field SIudIt's. Xa.'iunal Institute fur Occupational Safety and Health. Main Post Office Guilding. Cincinnati. Ohio 45202 (U.S.A.) (Received May 13lh. 1976) Summary Tiie 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 o[ 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 dyine from CNR and lymphatic cancer. These latter findings raise cause Tor 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 lest 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 he mutagenic in humas. With regard to the teratogenicity of VC, observations of a significant excess of children bom 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 lDDO, the first adverse health effects of vinyl chloride (VC) were reported |22|. Since then, numerous investigators have reported the toxic ericeLs uf VC on the central nervous system, the liver, the Ixmes of the fingers and the lungs L c*> p* fT - 12,5.9--12.18.20,28|. More recently, the study of VC toxicity has broadened to assess the spectrum of carcinogenesis | 2,15,16,21,26,29,30], mutagenesis [1,3,*1,6,13,14,23,24]. and teralogenosis |8J. These efforts were stimulated by the work of Viola et aJ. [291 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 early 1974. when Creech and Johnson [2] reported four deaths from angiosarcoma of the liver among workers employed in the manufacture of polyvinyl chloride (l*VC) resins. It was later learned that Maltoni had previously demonstrated VC-induced 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 [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 [3,4.13,23], Because of these observations and of the widespread exposure to VC among botli 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-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 polymerization facilities [3], (3) The site specific risk of congenital anomalies among populations residing proximate to VC polymerization facilities [81. (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%. Tabic 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 the 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 II shows cancer mortality experience by greater than 10 and 15 year latency periods. At the greater than 10 year latency period, only biliary and TAIII.I Mimt Cause All m-. Heart N*nm Al! *th 3 1CD. * SMlt c Sian; liver with catc\ canc how The* occu TAtll. CANt TO V Site r* All n* Drain Resin Hiliur | Lvm- AH N5 or * ot * K x o ** SV o ll Su oa Sa o i;l broadened mutagenesis ro stimulated induction of ion 30,000 '.corn for the ' 1974, when ia of the liver toride fPVC) (rated VC-inlymphomas mutations via ed mutations 'untries have long workers I. Because of both workers il Safety and n to evaluate program was sk of cancer ncers among (3) The site iroximate to >ng the wives ul n conselected for mcers often estricted to for whom at isure period ... Follow-up cohort. The applied to , there were icnificant at re observed ; experience md so there expense of md 15 year biliary and V TARI.K i MOHTAI.ITY K.X1M1UIKNCK AMONG COHORT WOltKI* KS 1I.XmSKI) TO VlKVI. nit.miiDK Cause of death ICO co<l. ' Oh vrvril Cx|M-rttl SM It '* Alt malignant neoplasms llrsrt NVnmahgnant respiratory diseases Cirrhosis All other cause* (140-205) (400--445) (470--527) (581) 35 57 6 2 36 23.3 54.7 3.4 4.0 40.7 143 c 104 17(1 50 8a 4 ICO. International Classification of Dixi'-wi, 7U revision. ** SMft. slaMil.ircti/ctl mortality ratio. c Significant at /' < 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 occupationallv-induced cancers. TABLE II CAN'CKK MORTALITY BY INTERVAL SINCE INITIAL EXPOSURE AMONG WORKERS EXFOSEU TO VINYL CHLORIDE Site of malignancy 10* years i IS* vests All malignant neoplasms Drain and CMS cancer Respiratory svstem cancer Biliary and liver cancer Lymphatic and hematopoietic system cancer All other malignant neoplasms Ob*. * Exo. 6 SMIt e Ob*. Ksu. SMR Obs. Exp. SMR Obs. E.*P. SMR Ohs. Exp. SM It Obs. K*r*. SMIt 35 23.5 149 d 3 O.D 329 72 7.7 756 7 0.8 1153 * 4 2.5 159 9 11.7 77 31 16.9 < 181 r 3 0.6 < 498 11 5.T < 194 rt 7 0.4 < ItiOB * 3 1.7 < 176 7 8.4 < S3 9 Ob*., obwncd. h K.*t.. rsprctrtl. c SMH.'Uiwlartli/ctl mortality ratio. ^ Siniiifiranl at I* < 0.05. c Significant at /' < 0.01. eoosoosz 6GC 002047 BFG37228 1 i \: fir ?; A 1 131 t-r _ t" - In laboratory studies. Maltoni has induced hepatic angiosarcomas, lung adenomas, brain neuroblastomas and lymphomas |1G|. 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--2-1,000. Between 1960--70 the population had remained stable in Painesville and Ashtabula, but had 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 to the aver age for the Slate [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 metastasos 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 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 bom 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 Painesville and North Ridgcville. With all communities combined, there were 27 CNS cancer deaths observed in males verrus 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 III also shows deaths from lymphomas. Although the differences between oliserved and expected deaths in males were not significant, there was a consistent excess in each community. In females, then! were excess lymphoma deaths in two of the four communities. With sox 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 expected. The SMR was 125. This was significant at I i . TAItl.KIII OltSKIlVKU AN1> K ykaks asij oim.i kaciutiks. 10&S-7 Expected numlicn nl ihc counite* tit which \ l A*Uubul | P.unetv ill** ! Avon I.Jke j S. M illCe' ill*' | Communities j Combined C l n 1 Ashlabutt pjtinesvdl** Avon lakr N. Rkiceville Ciunniuiiilu't Combined ) AshUbul.i I Painesville Avon Lahr | N. Hitlervilk | CmnmuniUe* \ Continued * International CU b r < 0.05. /' < (MU. J d r < 0.002. | o,05<p<o.r l ty. As shown i ; identical. Birth defects a: The occurrv communities ' North Ridgevil in the initial a rth Kidgevi )set|iu*ul @ns amonfl v U3 'is. lung n\ the only by mong VC ly three Ml three villc had s varied I stable akc. As were no the aver- system, ausc of > other s in the he only . It was 'ous to h birth yscs of 'served, unties if: it no. .e 7 CNS s 191. - With notocurred he age he age result renres re was xccss lined, h sex ls 61 t at V*3 taiii.k in OII.SKUVKII ANI> KXI'KCTKL) HKATIIS HJ TIIIIKK TYPl S OK CANCKK Km KKXIOKNTS Hr> YKAKS AM) IIUIKII IN T1IE OHIO COMMUNITIES WITH VINVI. Cl IU) III UK TOL YMKHIZATIDN KACILITIKS. If)all--73 Ex pccutl number* */ <ranrer drutht based on occurrence over the same period of time in the balance of the counties in which the communities arc located. Males Kemalf* Sexes combined AshtaDulj Piimcst tfU* Avon lukr N. UitJcc'HW* Cummumtirs Combined Obs./Kxs. s;MR CNS cancer <191 -192)* 7/ B.l 12/ 3.3 It 2.3 m i.9 27/14.1 11s 31 S d 8T 316 6 191 e Obs./Exp. 6/ .7.8 2/ 2.8 it i.8 It 1.5 lit 0.0 SMR in a 71 5#; 13.7 111 Obs./Exp. SMR 13/ 9.9 14/ 6.6 3/ 4.1 8/ 3.4 38/24.0 131 212 b 73 233 b 15* ' AsftUbuU Painrvillc Avon N. H iilgrvttli* Corn bmrd Leukemia and aleukemia (204--207)a 13/1-1.7 8/ 7.1 u 3.s 21 3.2 S3 113 28 S3 11/ 8.6 11 C.8 5/ 2.2 0/ 1.0 24/23.6 84 23/19.5 128 103 227 0 lift 24/23.3 13/13.9 6/ 5.8 2/ 3.1 47/48.1 103 108 103 39 98 Ashtabula Painrsvtllc Avon Lakr N. Itidccviltr Cmrmmili<*s Combined Lvmnh'imaj (200--203>J 13/12 6 12/10.4 4/ 3.3 3/ 2.3 37/29.1 143 ns 121 107 127 14/ 5.8 4/ 8.3 5/ 2.9 1/ 2.6 24/19.6 International Classification Of Diseases. 8th revision code*. * r < 0.05. 2 11 c 4ft 172 38 122 32/18.4 16/18.7 91 6.2 .4/ 3.4 61/48.7 174 r 8 It 145 74 123 1 p < 0.002. 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 defects among populations residing near VC polymerization facilities The occurrence of birth defects was studied |8| for the same three Ohio communities with VC polymerization facilities. Birth data for residents of North Ridgeville 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 Itidgeville, which lies contiguous to Avon I.ake, 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 ft, ft O G V*- " C WM **c Jr- ZJ-c*CbiZ BFG37230 GC 002043 I 136 vtr TABLE tV RESIDENT BIRTHS. MALFORMATION RATE PER 1000 LIVE BIRTHS IN OHIO AND IN THREE SELECTED COMMUNITIES AND OBSERVED VERSUS EXPECTED NUMBERS OF MALFORMA TIONS IN EACH CtTY. YEARS COMBINED. 1970--73 Malformations ire based on eodts 740--759 of the Intcrnaunnal Classification of Diseases. 8th revision. 1968. Area Entire state of Ohio Ashtabula ettv Painrsville city Avon Lake eitv All three communities combined Births 719.287 1900 1381 738 4019 Malformations Rate/1 0"1 Number observed 10.1 17.4 18.1 20.3 18.2 7293 33 25 15 73 Number expected * -- 19.3 1-1.0 7.5 40.8 2 X -- 9.78 b 10.29 '* 7.56 >' 27.13 c * Espectert numbers are based on state rate per 1000 live births. b/*'<0.0t. * P < 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 bom 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 STECIFIC CONGENITAL ANOMALIES IN INDEX AREAS INCLUDING N. KIDCEVILI.E. 1970-73 Defect catecory Number of defects Observed Expected RR b AU defects (740-758. 758. 759) e Central nervous svstrm (740--749) Cleft palate and li (749) Genital organ* (732) Clubfoot (754) AU other defects 109 17 to 16 23 43 56.0 5.6 6.3 8.4 8.2 27.2 1.95 3.02 1.53 1.90 2.79 1.58 * KsHudrs skin, hair ami nails (757). ** Rtt, rrlaliw? risk (obirrvHl/Mpcetrcl). * International Classification of Disease codes, 8th revision. <*rr shown in parentheses. located, the occi the Slat congenit Tabic total an was obs the CNJ have be< Fetal m Sinci system: chrome exposet germ in: asccrta: born a polyme include selects mateiu with w indirec perern contra: ("coni rcspcc- Tire accord fetal < respn16.5r; As husba 30 yc prima husba (5.3rv differ of fet of a i Jsi in J* thesis <Q paren O and i Cl) adjus m-XM GGC 002050 y BFG37231 V ..NO IN THREE MALFOH.MA- **< revision. '.78 b '1.23 *> MS b 13 c <i and to the 73, the rate " the balance rate for the incidence of e as great as ate, and the inity versus iific*>nt. The o. red to is compared unities were NOMA LIES IN l> V:. V'rr' 1.17 I located, the differences remained significant. Therefore, whether you 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 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 i was observed, the greatest excess of severe defects included malformations of I the CNS, cleft lip and palate, club foot and gemtai organs. These observations i have been reported previously in more detail (Sj. Fetal mortality among wives of workers exposed to VC ; Since VC had elicited a positive mutagenic response via microbial test ! systems 11,6,1-1,24 ] 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 [7aJ. All current VC polymerization and polyvinyl chloride (PVC) fabrication workers were i 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 the 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 gToup wore 6.9 and 10.1%, respectively. Subsequent to husband's exposure, Uie 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 j 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 j (5.3%) and primary VC exposure group 14/70 (20.0%) were significantly different, P < 0.001, XJ " 10.52, with one degree of freedom (df). The excess of fetal mortality among wives of youngcr-agctl husbands may be a reflection 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* I thesis, however, needs further 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 Cor the study group wen* ! adjusted to the age-distribution of the control group. BFG37232 tri- TAI1LK VI PATERNAL AGE GlSTitlllUTION KOIt FETAL DEATHS ACCORDING TO IIILSUAND'S VC SURE Paternal age gruup (yean) "Controls" Primary VC 1Exposure <20 20-24 25--29 30-34 >35 All ages crude rate Mean paternal ace at conception (year) Age-adjusted * rale Pregnancies Fetal deaths (N) (N) r-> Prior to husband's exposure 31 90 38 6 4 159 23.0 2 6.5 4 5.0 4 10.5 l 16.7 0 0.0 1 2 6.9 (6.9) Pn-enancirs <N> 7 44 56 27 u 148 26.4 Fetal <li atbs (N> (~-> 0 00 2 45 7 12.5 5 1 8.5 l 7.1 1 5 10.1 (6.11 >20 20--24 25--29 30-34 ^35 All ages crude rate Mean paternal age at conception (year) Age* adjusted 1 rate Subsequent to husband's exposure 1 43 87 87 55 273 30.4 0 0.0 4 9.3 3 3.4 7 8.0 10 IS.2 24 8.8 (R.8) 0 22 4H 36 33 139 30.2 0 0.0 3 I3.fi 11 22.9 3 8.3 6 18.2 23 16.5 (1 5.8) Fetal mortality rates for primary VC exposure group are direct acc-adiuxtctt to the paternal agi<di*tribu* lion ol the prepiancm m the control group (show n in pamuhrscs). TABLE VII MEAN PATERNAL. NUMBER OK PREGNANCIES AND ACE*ADJUSTED FKTAI. DEATH RATES ACCORDING TO HUSBAND'S VC EXPOSURE `Controls" * Primarv VC exposure ** Number of families Mean paternal age at conception (yean) Number of fetal deaths among wive* Number of pregnancies Agc*adjusted fetal deaths/100 preg. 6 Nunrtier of families Mean paternal age at conception (yean) Number of fetal deaths among wives Number of pregnancies Accadiustnl fetal deaths/100 preg. c Prior tn husband's exposure 9ft 23.0 11 159 6.9 70 2G.4 1ft US 6.1 Subsequent to husband's exposure 113 30.4 62 30.2 24 23 273 9.8 139 15.8` Rubber ami PVC fabrication workers. ^ VC polvmeri/alion workers. e Italics age`adjusted l **c*mtrol** grnup paternal age dixlritmimu. d .Siilmeitueol to Imdumis* exposure, the frcipirncv of fetal deaths *%tvex wax signiln antl% in the prtoiarv VC rxtmxurc group as compared to the coolmlx** ff*. 0.1)5) or t* le fretpworv in the study grnup prior to husband's exposure (/* < 0.02) lie agrurtiosted testing. The data wives of mat exposures, t respectively. 8.8^ for thwas sicniftc; f17| ir= \ itidicated ci' to a changeafter hushr. (P< 0.025. before exp< whereas, a: greater redt a differenei be seen in study groit: group, who groups wer situations n To deter micht have primary V( three or fi then recait carriage rn maintained TAUt.K Vttt N'UMUKK U) BANOS VC DKATUS Rates tor the t Oeforc husiaAfter <0 Before busi- 01 A flt*r hushan Q O . (..r.- Ilu-J... f\ Allrr lluUi-m ! C9 BFG37233 5 1 .> 51 VC KXI't). ire 1 rU <N> O 0.0 2 4.3 7 12.3 S J9.3 1 7.1 1 3 10.1 (S.l) t| o.o .1 13.5 l 22.9 .1 S.JI '* 15.2 lti.5 U3.5) 'sHiitribu* r * - 0 The data in Table V11 show Mat death rates per 100 pregnancies for thiwives of male workers in the control and study croups, l'rior to their hushnnd's exposures, the rates were 6.9% and 6.1% for the control and study (Troup*, respectively. Subsequent to husband's exposure, however, the rates were 8.S% for the control group versus 15.8% for the study group. This difference was significant at the P<0.05 level by Mantel-1 laenszcl Chi-square testing [If] <x:= 4.8 1,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, xz = 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 age 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. :es (Hure ^ cr*att*r nrr in the TABLE VIII NUMBER OK PREGNANCIES AND AGE-ADJUSTKD FETAL DEATH RATES ACCORDING TO HUSBANDS VC EXPOSURE EXCLUDING PREGNANCIES IN WOMEN WITU >2. 3 OR A FETAL DEATHS Ratci fr the primary VC exposure (roup are ge-liutcd to the Control group Controls Primary VC exposure ' Number of Fetal Number of Fetal prstiuncit* death pretttianeics death rat* rate Qvfore husband** espoiun A (U r husband's exposure Fetal deaths excluded 155 255 s.sr -1.7't 120 in 6.2** Before husband's exposure Alter husband'* exposure jl3 Fetal deaths rsdwlnl I5B 285 S.Wr 6.S'> 141 129 3.1". to.r* U*frt* huduiidl exposure AHi-r iiutbaiHTsexiMiture >4 Fetal death* excluded 155 265 .** A-*''* 142 137 ll.S'i I -`tT--- i.>% I f i .?$5 I 1 r & V 140 As reported previously |7a), additional analyses suggested that the significant excess in fetal mortality, after the husband's exposure would not seem to he 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 Rausch. II.. C. MaUvirllc and II. Mnti*sano. Human, fat and mutc liwr*mvrlialvd muiuct-niriiv of vitivl elUtindc m iv/fhinntrium strains. Int. .1. Cancer. 1 ft (1975) 129--4.17. 2 Crcvcb. J.L.. Jr. and M.N. Johnson. Ancpwurroma of livvr in the manufacture f p*l>vinv| rhlorirlt*. J. Occup. Med.. 16 (1974) 150-- 151. 3 Dueuliitan, A.. K. Ilirschhorn snd I.J. Selikoff. Vinyl chloride exposure and human chromosome aberrations, Mutation Res.. 3t (107ft) 4 Funcs-Cravintn. F.. D. Lambert and J. Lindsten, Chromosome aberrations in workers exposed to \inyl chloride. Lancet 1 (1975)459. ft Gcdriek. P.. H. Muller snd II. Beehtrtsheimer, Morphology of liver damage among polyvinvl chloride workers. Ann. NY Acad. Sci., 24*5 (1975) 27H-2H5. 6 Hubetman. K,, H. Bartsch snd L. Sachs. Mutation induction in Chinese hamster V79 cells by two vinvl chloride metabolites, ehloroethylene oxide and 2chlomacruldrhydc. fnt. 4. Cancer. 16 (1975) 639-844. 7a Infantr. P.F.. J.K. Wagoner and A.J. McMichael. Genetic risks of vinyl rhlnridn. Lancet. I (t97i?) 7.74 -7.75. 7b Infante. P.K..J, K. Wagoner. A.J. McMichael. RJ. Waxwi-ilcr ami II. Falk. Genetic risk* of vinvl rhU<i<)-. Lanrvt. I (1976) I2f*9--1290. 8 Infante. P.F.. Onrosenic and mutaitenie risks in eummunitirs with pulwinvl chloride production facilitirs. Ann. NY Acad. Sci.. 271 (197(1) 49--57. 9 Kramer. C.G. and J.K. Mutchler. The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. J. Amer. Ind. Ilyg. Anne.. 33 (1972) 19--30.* 10 Lunev, C.E.. 5. Juhc. G. Stein and G. Vellman. Further result* in fmlvvinv) chloride production workers. Ann. NY Acad. Sci.. 248 (1975) 18--21. 11 Lester, D., L.A. Greenberg and W.R. Adams. Effects of single ami repeated exposures of human* ami ruts to vinvl chloride. J. Amer. Ind. llvg. Assoc.. 24 1198.7) 285--275. 12 Ltlis. R.. II. Andrrson. \VJ. Nicholson. S. Daunt. AJS. Fiachhvin and IJ. Sciikbff. Prvvitirnrr of disease among -invi chloride and polyvinyl chloride workers. Ann. NY A^ad. Sci . 216 (1975) 2*2--41. 13 token. E. and K. Thiis*Evrnsen. Preliminary report on the medical examination of 288 employees at the PVC plant. Norsk Hydro a.s,. Porsgmnn Fabrikker. Porscnmn. N* orwav. unpublished. 14 Loprieno. N.. R. Barafe and S. Baroncelli. evaluation of the genetic effects induced bv vinvl chloride monomer (VCM) under mammalian metabolic activation: studies in vitro and in vivo. Mutation Res.. 40(1976)85-95. 15 M*lt**ns. C.. Preliminary report on the carcinogenicity bioassays of vinyl chloride. U3. Dept. Labor Informal Fact-Finding Hearing on Possible Hazards of Vinvl Chloride Manufacture and Use. Wash* iogutn. D.C.. February 1974. 16 Mullon*. C, and G. Lefcmine. Carcinogenicity binatsays of vinvl chloride. Current results. Ann. N*Y Acad. Sci. 24ti (1975) 195--218. 17 Muntri N. and W. Haens/el. Statistical aspects of the analysis of data from retrospective studies of disease. J. NaU. Cancer. Inst., 22 (1959) 719--748. 18 Marstetler. il.J.. W.K. Lclbaeh. R. Mujler and P. Gedigk, Unusual spleiiomegaiic liver disease as cv* denred by pentnnenscopy and guided liver bfopsv amns polyvinyl rhl<>ril production worker*. Aim. NY Arad. Sci.. 246 <1975)95--134. 19 McMSrharl. A.J.. S.G. Haynes and If.A. Tyrokr. Observation* on the evaluation of oreupationa) mnrtalitv data. J. Occup. Med.. 17 (1975) 128--131. 29 Miller, A,, A.S. Teintcin. M. Chuang. I.J. Selikoff and R. IVarstetw. Changes in jmlmmiarv function in Nirhohms. W.J.. K.C. Hammond. II. Sctrtman and I.J. Selikoff. Mortality experience *f a elort of vinvl rMorMle-pnlyvinvl chloride workers, Ann. NY Aeail. Sri.. 2 til (I!I75> 2*25 *230. |*attv. F.A.. VV.P. Yant and C.P. Waite. Acute response of rnint-.t pigs U of some com* mereial orgjnir compounds. Public HealUi Report*. 45 (1930) 191*3 -- 1971. Putrhnr. I.F.H.. C.ll. Rirhardaon and f>. Anderson. Chromosomal anil tlmnininl tetlial effects of vinvl rhlorwh*. F^mcrt. II 11975) 410 4 11. 24 ttannug. U.. mrtaboiic set 25 Shapiro. S.. h !'. MilHian) 26 Tibmhaw, I and its polvn 27 Umt.il Stab* Task III. vin* 28 Vrilman. C vinvl rhlorut 29 Viola. P.L.. ride. Cancer 30 VVs.\ttvrlef. workers exp ?,5003010 BFG37235 i ic significant cm to In* the nf '* highly if . would iism involved i-xposurc. muU*i-nuiiv of * xmyI chloride. J. art chromosome rxftoud tn vinyl 'lyvny| (hluridr `'TO ceil* bv two inctr, 16 (1975) -meet. 1 (1976) ride production 'iwrmcnu for nde production i of hurnm md *f. Jrtico of * (U.u) 22-41. 'Hi employers at ><v vinvt ehlnridr *. Mutation flea.. .S. Dept. (.abor - and Use. Wash* "'suits. Ann..NY ctiv* studies of t disease as evi* * vnrkrn, Ann. *( occupational i.ifv function in (1975) 12-52. tif a cohort of 'nnte new com* 'thal effects of 111 21 llanniiS. U,, A. J<44iisvmi. C. :md C.A. Wjrhlnti'iib'r. The mt>(;nrni*iiv of vtiivi rhlnridr after mrUimiie activation. Ambio. -1 (|974) 194--197. 25 Shapiro. S.. K.'V. Jones and P.M. Dense*. A life table of pregnane* terminations ami correlates of fetal loss. MiUlwiiK Uuarierlv. 40 (1962) 7--45. 26 7'aiKTsha**. Ml. and W.R. Guitry. Mortality study of workers in the manufacture of vinyl chloride and iisP^lvmers. J. Occup. Med. 16 (1971) 509--516. 27 Umuil SUtes Kn%ronmenlal Protection Agency. Sampling and analysis of select twxir substances. Task HI. vuivl chloride.Contract No. 68--01--2646. Jan 20. 1976. 28 Wlunan. C... C.E. Lance. S. Juhe, G. Sirin and U. Qactawr, Clinical manifestations and course of vm> | rhlorine disease. Ann. NY Acad. Sei.. 246 (1975) 6--17. 29 Vi.iia. PL.. A. Hicotti and A. Capuln. Oncogenic response of rat skin, tunes and bonus to vinyl chin* tide. Cancer lies. 3* (1971) 516-519. 30 WaxvvtMicr. R.J.. W. Stringer. J.K. Wagoner. J. Jones, H. KaJk and C. Carter, Neoplastic risk among worker* npOKii to nnyl chloride. Ann. NY Acad. Sei-. 2T J (1976) ,79--48. BFG37236 (train*. Mutation Rc*., 19 1373) roKfMitr of xrtodvima pitmanay. 23S <1972) 80-S3. -lamentation croup in xeroderma complementation data retardine (Mutation Research, 37 (1976) 313-316 1 Etscvier/N'orth-Holland Biomedical Pres* *1r Short communication i HIGH RATE OF CHROMOSOMAL ABERRATION IN PVC WORKERS I. SZE.NTESI, HORNYAK. G. UNO VARY, A. CZEIZEL, Z. BOGNAR'and M.TLVAR Laboratory ofHuman Genetics, National Institute of Hygiene; Department of Experimental Pathology, State Institute of Occupational Health, H-1966 Budapest, Gyali ut 2--6 (Hungary) (Received March 26th, 1976) (Revision received June 15th, 1976) (Accepted June 23rd, 1976) 11 Occupational diseases, such as acro-osteolysis, Raynaud's phenomenon and .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 (the liver [2,5,8,11--13,16]. The mutagenic properties of cancerogenic com- i pounds are of great interest, since mutagenicity can be proved earlier and by .simpler methods. Besides investigations on experimental mutagenesis [1,9,10], |the results of four studies of chromosome aberrations in 7,11,13 and 56 wor- ikers 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 tin the other two [7,14]. The occurrence of chromosomal aberrations was in- tvariably higher in the exposed groups than in the controls. This paper reports on the chromosome examination of 45 PVC workers ex- iposed 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) land 49 normal controls (no occupational exposure to chemicals) were exam ined. Hie chromosome analyses were performed in parallel and simultaneously tin 48-h cultures of peripheral blood, 'fhe chromosome aberrations. (Table I) o? .were blind scored by one microscopist. Table I also indicates the distribution of iage and sex. ( The following conclusions were drawn. The rate of numerical chromosome Cx5 o aberrations did not differ significantly between PVC workers and controls. 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