Document em8BVYKvO5dqB91EL2XLbLoVM

734 THE lANClt, APRIL 3, 1976 Occasional Survey GENETIC RISKS OF VINYL CHLORIDE Peter F. Infante Joseph K. VUooner Anthony J. McMichael Rilhaho I Waxwiiler Henry Falk Division ofSurveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, and Bureau of Epidemiology, Center for Disease Control, and School of Public Health, University ofNorth Carolina Summary A study of pregnancy outcome among wives of workers exposed to vinyl-chlor ide monomer (v.c.m.) indicated, that, in comparison with controls, there was a significant excess fetal loss in the group whose husbands had a primary exposure to v.c.m., whereas no differences between the groups were observed before the husbands' exposures. The difference in fetal death-rates for the post-exposure comparisons was a reflection of a greater fetal loss associated with the wives younger-aged husbands. I he significant excess did not seem to be the result of bias from interviewers, re spondents, nor from women who had experienced chronic abortion* weighting the results These findings, in conjunction with the demonstration of a mutagenic response via microbial test systems and with observa tions of significant excesses of chromosomal aberrations among workers exposed to v.c.m., raise scientific and public-health concern for the possible genetic nsks of v.c.m. to man. In the past year, several reports have indicated that vinyl-chloride monomer i.v.c.m.) is mutagenic in micro bial test system*.'' v.c.m. metabolites also have in duced mutations in mammalian cells.4 Likewise, reports from four countries have shown an excess of chromoso mal aberrations in lymphocytes of workers exposed to v.c.m. compared with controls.' 1 However, Purchase et al.' have stated (though no animal data were presented), that the mutagenic effects of v.c.m. expressed as chro mosomal aberrations in lymphocytes in humans do not occur in germ cells in mice; they concluded that the potential danger of mutagenic effects on the fetus via sperm seemed unlikely to exist. In a study without con trols, SelikofT observed fetal death-rates among wives of v.c.m, workers that ranged trom 7 to 14 per 100 preg nancies.4 These rates appear to have been higher than expected.1* To develop further data on this question, pregnancy outcome has been studied among the wives ol workers exposed to v.c.m. All current v.c.m. polymerisation and polyvinyl-chloride (p.v.c.) fabrication workers were in cluded for study together with a similar numbt r ol cur rent rubber workers (8'f of all such wurkers selected from work areas relatively fret from kmiu toxic materials and matched as a group to the v.< .m worker* by age. Group-participation rates ranged from 62 to 77%. Data for the wives of v.c.m. polymerisation workers (primary v.c.m. group) were contrasted with data for the wives of p.v.c. fabrication and rubber workers ("controls"), who were known to have had very low or no v.c.m. exposure, respectively. A total of 95 v.c.m. polymerisation and 158 rubber and p.v.c. fabri cation workers were interviewed. Paternal age, preg nancy outcome, and estimates for the time of conception of all pregnancies were ascertained by interview in Oct ober, 1974, from males employed at a rubber manufac turing, p.v.c fabricating, and v.c.m. polymerising facil ity. As pan of a larger survey of worker health, date of first employment in the job categories was determined from company records. Mean paternal age, total number of conceptions, total number of fetal deaths .defined as any product of conception not born alive), and fetal death* per 100 conception* were then computed for each group prior to and subsequent to the worker's date of employment. No interviews were conducted with workers' wives and no data were obtained costcerning maternal age, except indirectly through paternal age. Since fetal loss is known to increase with ascending parental age, the fetal death-rates for the primary v.c.M. exposure group wert age-adjusted to the control group. Table i shows the age-adjusted fetal death-rates for wives of the primary v.c.m. exposure group versus the control group, both prior to and subsequent to each group's respective exposures. Among pregnan cies occurring prior io exposure, fetal death-rates were 6 9for the controls versus 6-1*> (age-adjusted) for the primary v.c.m. exposure group. These fates were not significantly different by Mantel-Haenszel Chi-square testing.11 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at p<0 05 ,y,-4-00,df f).11 Although the underlying dis tributions^ differed, mean paternal ages were virtually the same-^3(M versus 30-2 years. The significant dif ference between the groups subsequent to exposure was a reflection of a relatively greater fetal mortality-rate as sociated with younger-aged husbands in the primary v.c.m. exposure group. Among pregnancies occurring subsequent to exposure, the fetal mortality-rates associ ated with husbands 30 years of age and older for the pri mary v.c.m. exposure and control groups were 9/69 13 0';) and 17/142 (12 O'r), respectively; whereas, for M*lt I AMI fATSlCAl Mil, H1MIII Of PXCCXANCItS, AND PtTAl DI4TH`fcAT|\ CORDING jq HI ItlANO'f VT. EXPOSIRI /**' f.> 1 r(p`tt*rf Snmtot f timihfi Wt ir paternal agr 41 coricrpitun st \..tiiS r i't Inal Irath* jfTSimg uihC* Siifhlti >t \e-fetal vie rihi UM preg J Sh^iPJie, ft* 'Uithj'lJ i i-fprilrr NuniNr '(; tmilieN Mean paternal age at c`*tts'ep!Mtn vr S anther . if l, ia| 1 S' Ith . 4II>IMI< 4tVf4 \iunl> * iv| jn hitn- -i '* aJ.aMC : fetal It.. l-'lprtf t rnmnff t'.'nlrnh"* \ cm spoaurt *5 23 0 11 !'9 69 111 10 4 : ,l H 70 26 4 IS 141 61 62 30 2 :i 1w u it Rubber and p w fabrication workers < pol)Tnrrt i(KX) workers '* age-adiusted to "comruT1 group paternal Age distribution Subsequent to husband's exposure, tbr frequence of fetal death* among wives <*a4 Mgnihvantlv greater in (he primary vs m eipuiure group than to the "a&tmlt' r<0 0$ or in the nudv group poor to husbands cipsaurr ,e<0-02) by aft>a<JnivicJ hhi-square testing 14 BOR 013437 Ill) I 'SI I I , A (' H H IV 'f> 7iS rAni i i: mi ^r^iiiNu tm , m m'ii m i \. s*i > i , 11 IlM I M HA I f A 4< | HHIUH4# f < I H SlItKll S < 1 I fit a i li I I < I i IM M. CIH.MM 'I \ l.| Al'MI ^ .M III w 4 I I " \ I >1 i /*'|.if to * it'J'iJ i rtpo'u'e Me in p Mi rnil *n? il , '"LCpU.'-i \r . Number til lel j,teji jtv i) in:i Nu-riKr n| pmiji ,m^h 4 Arc j.lihVf,! K 'il Js 4 l\ 11*" pi eg k ubtt'^ni 'U i.i nit ^onJ i ftpt'iure Mein r *icru il i(fe 14 slom.epliA'n vf,. Number nl teidl lie Iihi i.vtv.k: *ive* N'umiIh r ..l pi'iK:,arli'e\ \(fe iJni't il teul Jcjlh' !1 pfrf : Mir, h ` | \ f ! :i H i 111 .J<V (S 9 . i{>'4urc| *#, 7 * ' 1 11 jo : JO s ?ri< i:o 10 * *Kubbef liilJ m v ( fabric itH'n **vker tv c prli rticrr illOl) niiirn JKitci igr iOuiMiO tn 1 <. < r\ie\ii' pjtrrng) igr luinbut'in. husbands less than 30 years of age, fetal mort 11ly was 14/70 (20-0'i) for the primary vc M exposure group compared with VI31 (5 3rP for the control group (these data are not shown m tables ! Furthermore, intragroup comparisons indicated an increase m age-adjusted rates for the prtmars v.c.m. exposure group from 6-1'7 before exposure to 15 8r7 subsequent to the husband's exposure. This difference also was significant, 0 02 5 51,dl 1; 11 Similar comparison for rates in the control group, 6 9'r sersus 8-8'J, indicated no significant difference. To determine whether women who had chromcaliv experienced abortions might have weighted the results in favour of a higher fetal death-rate in the primary \ ,< . w group subsequent to husband's exposure, pregnancies of women who had more than iwo abortions were elim inated from the analyses and the data were recalcu lated to determine whether or not the trend was main* tained. The decision to exclude all pregnancies among families associated with more than two abortions was made without prior knowledge of how these families were distributed among the exposure categories t"he dafa in table 11 show that the trend was maintained Prior 10 exposure, the fetal death rates in the control and primary \ t, M. exposure groups were b V'i and 3-IT, (age-adjusted), respectively, whereas, after expo sure, the rates were 6-8'7 and 10 8', , respectively. Sub sequently, data were eliminated for pregnancies of women who had experienced, firstly, more than one abortion, and, secondly, more than three abortions, and each time the trend was maintained No changes in rales for controls were observed, whereas a 2- 3-fold increase was observed in the primary v.c.w. group subsequent 10 exposure. To determine whether differences in fetal loss might have been the result of one or two interviewers weight ing the results, the data were analysed by individual in terviewer. The results demonstrated a general trend for each interviewer to report a higher ascertainment among v.c.M. polymerisation workers than among ihe control group. Further, the possibility was entertained that the inter val between the date of interview and the date of fetal loss might have influenced the results through dif- k'rciRri m ircall. | he interval, however, wa estimated to have been about two years lest for controls, suggest ing that, if a bias did exist, it would have been towards a greater ascertainment in the control group. In some cases, the worker failed to indicate the ages of his children and in other cases he was unable to recall the approximate time of his wife's abortion; therefore, the data were analysed to determine the distribution of fetal death-rates among the respondents in each occupational group who did not complete the interview properly. The difference in fetal death-rates between groups was very slight. Finally, the workers may have been subject to bias resulting from prior knowledge of known hazards of vinyl chloride. However, the workers themselves did not always know into which of our employment categories they were being allocated. For example, several p.v.c. fabrication workers who were included in the oontrol group thought that they had a primary v.c.m. exposure as a fabrication worker In addition, the questions regarding pregnancy outcome were contained in a much larger interview-questionnaire, the results of which demonstrated very few significant differences with no consistent bias for the parameters ascertained between the workers with a primary v.c.m. exposure, and the other groups. This observation as well as several othen presented above tend to support the validity of the study. In summary, a significant excess of fetal loss was observed among wives of workers following exposure to v.c.m. The excess did not appear to be the result of bias from interviewers or respondents, nor from women who experienced chronic abortions weighting the results. Several mechanisms by which such fetal loss may arise are suggested. Either fetal or maternal toxicity or germcell mutagenesis in the mother through indirect v.c.m. exposure from the father might be considered, although these mechanisms seem highly unlikely in view of the highly volatile nature of v.c.m." When the findings of (he present study are taken in conjunction with the prior demonstration of a mutagenic response via microbial lest systems and observations of significant excesses of chromosomal aberrations among workers exposed to ' < w , the leading possibility is germ-cell damage in the lather through direct v.i m. exposure. The increased fetal mortality among wives of workers subsequent to v.c.m. exposure now raises serious scientific and publichealth concern for the possible genetic risks of vinyl chlonde to man. Requests Tor reprints should be oddceased to P F I, N I O S H , Post Office Building, Room M5, Cincinnati, Ohio 45202, l' S A xifexcxcis t Martssh. It . Malasnlk. < . M.asienaiso, R /nr J Canter IV-', IS, 42V 1 I j.pneixi, V , Harale R VarwKTlti, S . ei al .Atara/ion Rei in the pern I Rannu^ C , Johansson, s , Ranrt. C,, WachJlseistee, C A Awhso 1V74, J, IV4 4 Huherrssan, 1; , Banach, H . Sacha, L /at J Cancer. 1V7S, la, SJV 5 rtu.aitnan. 4 . Hinchhcim, X . SatWolf. I J ifniar*on Res 1V7S, J|, 1SJ S 1 unes-craswsn, i l^nhen. B , Luxfcicn, J . Ehcenberg, L, Nataratan, 4 I . Siennan i nVkar. S /.aneat, tV7J, i, 45V runtime l 1 H , R.chanJaun. C. R , Anderson, O iNd ivn.ii, 410. II H.tleniad I rti,,. Femsats, F t ninibliihad V Seliki.lt. I | . s I F II s i laiteirnce on ISlWic Hea ih Insphcaisona nf Com- fonrnu .4 rtauics Matiulaalurv. ISnehsieni, Nucth t arulina, Julv, tV74 10 Intantc, r I- Van V V Yri .intbepsraa 11 Shapiro, S , Jonei, F X . Onsets, P M MdSaaSQ 1902,44,7 12 Mantel, N , Haanuei. X } Nan Confer/net 1959 2Z, 'IV U I n.ted Slates Emuoanutal Prwactasfl Agency, sampling and inalyiu at sclecl iokk tubtiancn, lask in rsnsl ,hlnesdc Contract no 6S-01-2S44 Jtn .'0. IV7 BOR 013438