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734 r &S 004348 Occasional Survey GENETIC RISKS OF VINYL CHLORIDE Peter F. Infante Joseph K. Wagoner Anthony J. McMichael Richard J. Waxweiler 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 ofPublic 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. The significant excess did not seem to be the result of bias from interviewers, re spondents, nor from women who had experienced chronic abortions 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 risks of v.c.M. to man. In the past year, several reports have indicated that vinyl-chloride monomer (v.c.m.) is mutagenic in micro bial test systems.1-3 v.c.m. metabolites also have in duced mutations in mammalian cells.* 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.3-* However, Purchase et al.7 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, Selikoff observed fetal death-rates among wives of v.c.m. workers that ranged from 7 to 14 per 100 preg nancies.* 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 of workers exposed tO V.C-M. All current V.C.M. polym^ricniinn anil polyvinyl-chloride (v.v.r.l fabrication workers were jo`tjudeJ for study together with a similar_number of cur rent rubber workers (8% of all such workers) selected from "work areas relatively free from known toxic materials and matched as a group to the v.c.m. workers 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 v.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 ^______ __ canon wnrtTrTTvrrc interviewed. Paternal age, preg nancy outcome, and_estimates lor the lime ol conception pf itU pregnancies were_asccriaineiTby interview'In'OcF' ober, 197-L-from.malaccmploye'd aV'a' rubber manufao luring, t'.v.C. fabricating, and v.c.m. polymerising faclt-~ ity. As part of a larger survey of worker health, date of first employment jn 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 deaths per 100 conceptions were then computed for each group prior to and subsequent to the worker's djun-of. employment. No interviews were conducted wijh workers' wives and no data were obtained concerning 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 were age-adjusted to the control group. Table t shows the age-adjusted fetal death-rates 7for wives of the primary v.c.m. exposure group versus the control group, both prior to and subjcqii&at- to each group's respective exposures?'Amongpregnan- cies occurring prior to exposure, fetal death-rates were 6-9% lor the controls versus 6-1% (age-adjusted) for the primary v.c.m. exposure group. These rates were not significantly different by Mantel-Haensxel Chi-square testing.13 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at f<0-05 (y3=4-00, df=l).13 Although the underlying dis tributions differed, mean paternal ages were virtually the same--30-4 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 (12-0%), respectively; whereas, for TABLE I----MEAN rATERNAL ACE, NUMBE K OE RKECNAM'.IES, AND FETAL DEATH-RATES ACCORDING TO HUSBAND'S V.C. EXBOSURE -- "Control*"* Pnur to huibonJ't expoturt: Number of famiiict * * Mean paternal age ut conception (yr.) Number of fetal dcatht among wive* Number of pre^iuncict Age+iiiiiuktcJ feu) jMihi/ioo tnti Skbu'tjut/ii to JmibenU't txpcturft Number of famdio Mean paternal age ul conception (yr.) Number ol Ictal Dcdllik amontf wivea Number of pregnane**) A^c-aJjuticJ fetal Jcaiht/lOO pregt * `Q k 95 230 11 139 4-9 113 30C 24 273 ii Primary v.cj*. capoiurcf 70 26-4 13 141 4-1 62 30-2 23 139 ISIJ Rubber *uJ kv i. UbnCalien workcrv |vjj. ivlyiiKTikj(ioi) worker*. }K*irfc 4i; uJ>UkirJ lo "control" group egc Jitribotioa. (bobkcijucm lo hukbanJ'i capture, the frequency of fetal dcathi minunf wire* we* kimitbrfi>Jy greater in (he primary v.c.m. ci|*jiurc group (ban in (be "coft* tfolk" (* O-oSi or in the fciuJy group prior lo bukb*<U** capoturc (r^O-QJ) by uyC'wJlUktcd L'hr^UMfC ICfcWllg,11 4 R&S 004349 *riif t.AHf.FT, Armi. 3, 1976 735 TAM f ]} -*UFAW fATFANAI AttF, OF MtFf.NaM'lM, AWD FFTAL aci hiwino to m*MAwn ' v.c. niHiM'iF rict.imiNO [Mr.MANtlf *OF WOMFN W|TJ| * } FFTAL DF ATIl'3 -- Primary "Ilontml*"* v.c.M. *poaurt /Vi.r (.* 4sihW't etpn/rre: Mean paternal apr at enneeptinn ivr.) Numtvr of leial death* among wives Number of pregnancies Apradiusir.l leial deatM'100 prrg % Xubre^uent i* hmbmJ't reposare: Mean paternal age at conception (vr.) Number of fetal Jraths among wivri Number of pregnancies Ape-adiuocd fetal dciih*/|00 prep t 2J-0 11 159 * J0-2 It 265 A-Il JSJ 141 31 J0-I 14 220 10-1 Rubber inj r.vf. fabrication worken. fv c. fvh*mcf*>i'n worVrrv JKatc* apt-aJiuMcd to "'control" putmtl ifc distribution. husbands less than 30 years of age, fetal mortality was 14/70 (20-071 for the primary v.c.M. exposure group compared with 7/131 (5-371 for the control group (these data arc not shown in tables.! Furthermore, intragroup comparisons indicated an increase in ace-adjusted rates for the primary v.c.M. exposure group from 6-17 before exposure to 15-87 subsequent to the husband's exposure. This difference also was significant. t'<0-02 (y.J-5-51, df-- 11 Similar com^rison for rates in the control group, 6-97 versus 8-^^vtdicatcd no significant difference. I^Wetcrminc whether women who.had chronically experienced abortions might have weighted the results in favour of a higher fetal death-rate in the primary v.c.M. group subsequent to husband's exposure, pregnancies of women who-had more than two abortions were eliminated-'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. The data in table it show that the trend was maintained. Prior to exposure, the fetal death-rates in the control and primary v.c.M. exposure groups were 6-9% and 3-17 (age-adiusted), respectively, whereas, after expo sure, the rates were 6-87 and 10-87, 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 rotes for controls were observed, whereas a 2- 3-fold increase was observed in the primary v.c.M. group subsequent to 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 ama^g v.c.M. polymerisation workers than among the 1 group. Trthcr, 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- fercnccs in recall. The interval, however, wns estimated to hove been about two years less 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 eases 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 control 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 others 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.13 When the findings of the present study arc taken in conjunction with the prior demonstration of a mutagenic response via microbial test systems and observations of significant excesses of chromosomal aberrations among workers exposed to. v.c.M., the leading possibility is germ-cell damage in the father through direct v.c.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 chloride to man. Requesti for reprints should be addressed to P.F.I., N.I.O.S.H., Post O/Tice lluilding, Room 515. Cincinnati, Ohio 45202, U.S.A. REFERENCES J. jbrmh, It.* Multifile,<!,, Mnnimnfi, R, irf/.J, Cancer, 1973* IS, 429. 2. l/ipm-rio. N,t Humic. R.. Varnncclli* $* el Mutation Ret, (in (hr pros). 3. Rannug, l),, Johansson, A.* Rtroel, C,, Vt'achroemcr, C. A. Ambia. 1974* 3, 194. 4. tluherman, t`,, ftartvh,!{., Seht, //./. Cancer, 1973* U, 639. 3. Ducatman, A.* Hirschhorn, K,, .ScltknfT, 1. J. Fex. 1973, 31, 163. 6. FunrWJfjvwio, F,, lumber*, B,, ljndsten, J., Ehrenberg, L-, Natirajan, A, l` , Ostcrman-fiolkar, S. Lancet, 1975, t, 439. 7. Purchase. 1.1;. 11., Riehardvm, C- R-* Anderson, D. iW, 1973, ii, 410. 5. 1bii*-l:.vcfi*cn, E. Unpublished. 9. SelikolT, 1. J., N.I.fi.Hi. Conference on Public Health Implications of Con* ponenti of Plastic* Manufacture, Pinekuiui, North Carolina, July, 1974. 10. Infante, P- F. Ann, S.Y,Acad. Sci (in the press). 11. .Shapiro, S,, Jones, E. W. Densen, P. M.Afi/bflnk Q. 1962,40,9. 12- Mantel. N., Haensicl, V'. J. blatn. Cancer Inti. 1939,22, 719. 13. United States Environmental Protection Agency, sampling and analysis pC select toxic substances, task in vinyl chloride. Contract no. 6141*2646, Jan. 20, 1976.