Document NpBqdke2g82R6kr8ZK6yV4DE

f\ /c - V.n^C CrftGfcffct^ Reprinted from THE LANCET, April 3, 1976, />. 734 GENETIC RISKS OF VINYL CHLORIDE Peter F. Infante Joseph K. Wagoner Anthony J. McMichael Richard J. Waxweiler Henry Falx Division ofSurveillance, Haaard Evaluations and Field Studies, National Institutefor Occupational Safety and Health, and Bureau ofEpidemiology, Centerfor 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 dironic abortions weighting the results. These finding 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.1-1 v.cja. metabolites also have in duced mutations in mammalian cells.4 Likewise, reports from four countries have shown an of chromoso mal aberrations in lymphocytes of workers exposed to v.cM. compared with controls.*-* However, Purchase et aL7 have stated (though no animal data were presented), that the mutagenic effects of v.cja. expressed as chro mosomal aberrations in lymphocytes in humans do not occur in germ cells in mice; they concluded that the 2 i potential danger of mutagenic effects on the fetus via sperm seemed unlikely to exist. In a study without con trols, Sclikoff observed fetal death-rates among wives of V.CJU. workers that ranged from 7 to 14 per 100 preg nancies.* These rates appear to have been higher than expected.10 To develop further data on this question, pregnancy outcome has been studied among the wives of workers exposed to v.cj*. All current v.c-M. polymerisation and polyvinyl-chloride (p.v.c.) fabrication workers were in cluded 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.cm. workers by age. Group-participation rates ranged from 62 to 77%. Data for the wives of V.C.M. polymerisation workers (primary v.cja. 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.cjm.. 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.cm, polymerising facil ity. As part 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 deaths per 100 conceptions were then computed for each group prior to and subsequent to the worker's date of employment. So interviews were conducted with 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 for wives of the primary v.cm. exposure group versus the control group, both prior to and subsequent to each group's respective exposures. Among pregnan cies occurring prior to exposure, fetal death-rates were 6-9% for the controls versus 6-1% (age-adjusted) for the primary v.c.M. exposure group. These rates were not significantly different by Mantel-Haenszel Chi-square 3 testing.11 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at PCO-OJ (y^=s4-00, df=I}.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.cja, exposure group. Among pregnancies occurring subsequent to exposure, the fetal mortality-rates associ ated with husbands 30 yean of age and older for the pri mary V.cja. exposure and control groups were 9/69 (13*0%) and 17/142 (12-0%), respectively; whereas, for husbands less than 30 yean of age, fetal mortality was 14/70 (20-0%) for the primary v.cja. exposure group compared with 7/131 (5-3%) for the control group (these data are not shown in tables.) Furthermore, intragroup comparisons indicated an increase in age-adjusted rates for the primary v.cja. exposure group from 6-1% before exposure to 15*8% subsequent to the husband's exposure. This difference TAIt-E I--MEAN FATEENAL AOI, NUMSIE OF FEEOMANCSXS, AND FETAL MATH-tUTEl ACCOEDING TO HWAAKD'l T.C. EXFOSOKI Prior to kuikmd'r aponrt; Number offamfliee Mean paternal i(t at conception (ft.) Numberof Coal dcatba amongenvoi Number ofpregsancia Aft-vdiimed foul deatWlOO ptog4 Soiu^MBU to kuibiod'i trpoturt: Number offamiliee Mean paternal afe at CDMepcna (yr.) Number of feu! Deaibi amour trim Number of prrgnaaeim Aft? adjunct! feta] AaiWiOO prtgi Rubber tad r.tx. fabrication worker*, tec. polymeriaatioc workert. ERatee ageadjuitad to "amirol" ponppaternal at* daoibuikm. {Subsequent to huabood't opoeuto, the frequency of fetal death* emoot wivoa wai ligaificudy floater in die primary expoturt (roup than in the "ooo- uoli" (r<0-0!) or in die itudy (roup prior to huababd'i capocure (r<0.02) by aie-odjuatad ddoquato tearing.11 4 TABLE II--MEAN FATEINAt. ACE, HUMBLE Of FU6MANC1ES, AND FETAL DEATH-AATEJ ACCOKbMO TO HUSEAHD'S T.C. EXFOEUM EXCLUDINO FXECHANUXE OF WOMEN WITH A 3 FETAL DEATH'S -- Prior to Aujfafttf'i txpotvrt' Mon paternal age at conception (yr.) Number of fcul doth* among wina Number of pregnancies Ap*adjusted fetal <katb*/100 prcf4 Subs*qv*nt to Auttauf** tspen/rt; Mcun pwcrntl ** t uoimpUua (jr.) Number of fcul doth* among; wire* Number of pregnancies Age-adjusted fetal dtMWlOO pK(4 Prunury "Control,-- liX. oponiref 23-0 It 159 4-9 30-2 >1 245 4-t 24*3 9 141 3-1 30-1 14 120 1CL* 'Rubber *ad f,v.c. {tbricauos worker*, ff-c. polyrocriutiQu works*. JRms efc-odiuned in "control" petanel i|t dinribution. also was significant, p<0-02 (x*=5*51, df=l).`J Similar comparison for rates in the control group, 6*9% versus 8-8%, indicated no significant difference! To determine whether women who had chronically experienced abortions might have weighted the results in favour of a higher fetal death-rate in the primary v.cx. group subsequent to husband's exposure, pregnancies of women who bad more than two 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. The data in table u 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 3-1% (age-adjusted), respectively, whereas, after expo sure, the rates were 6-8% 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 rates 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 among v.c.M. polymerisation workers than among the control group. Further, the possibility was entertained that the inter val between the date of interview and the date of fetal toss might have influenced the results through dif ferences in recall. The interval, however, was estimated to have 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 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 control group thought that they had a primary v.cj*. 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.cja. 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. Hither fetal or maternal toxicity or germ- R&S 004403 6 cell 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.cum. 11 When the findings of the present study are 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.cja., the leading possibility is geno-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 public* health concern for the possible genetic risks of vinyl chloride to man. Requests for reprints should be addreacd to PJ'X, U-I.OSM-, Pott Office Building, Room 515, Cincinnati, Ohio 45203, U.S.A. amuxexs 1. Banach, R. Mslsricfle, C, Moousuo, R. /. /. Cnar. 1975,15,41*. 2. Loprieno, H, Bank, R* Vuwcdli, $, t at. Mutation Ra. (in the pros). J. Rarmufc U,, Johansson, A_ Kamel, C, Wsehmeiner, C. A. Ambio. 1974, J, 194. 4. Hubcneaa, E, Baruch, H, Sachs, L- Iu.J. Cancer, 1975,14, 619. 5. Dw-mnsn. A-, Kinchhwn. 1C, Sdikott, L J. Mutation Ra. 1975, II, 163. 4. Funes-Craviuo, F, Lambert, B, Uadms, J, Ehitsbog, L, Natanjaa, A. T, OHermanCielkar, S. Lantat, 1975, i, 459. 7. Purchase, L F. H, Ridurdsoa, C K, AmiowcfD. ibid. 1975, ai, 410. t. HiBcatad, L-, Thns-Eveasca, E. Unpublished. 9. SdiJuXT. L J, NJ.F.H.S. Geofacocc on Public Health Implications of Cesa- peeeau ef Flanks Manufacture, Piacham, North' Carolina, Juty, 1974. 10. lofsau, F. .Ann,N.Y.AcotLSci. (in the pros). It. Shapiro, S, Joaca. E. Demon, P. M.MOhatUt Q. 1961,40,7. 12. Mantel, N, Hatnsad, V?.}. Nom. Conor Itut, 2959,22.719. 1). United States Environmental Protection Aftncy, sasapliat tad analysis ef idea taaic substances, task m vinyl chloride. Contract m. 66-01*2446. Jam 20,1976. Primed in Great Britain 1976 The Lancet, 7, Adam Street, Adelphi, London, W.C.2. f: