Document KG3Zdg7a7zmyLeRrqvD0bdMB2

tv' -.r^a-czu?. 734 THE I.ANCt I, At'Rtl. 3, 1976 Occasional Survey GENETIC RISKS OF VINYL CHLORIDE Peter F. Infante Joseph K. Wagoner Anthony J. McMichael Richard J. Waxweiler Henry Falk Dix-isi.rr. cf Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, and Bureau of Epidemiology, Center for Disease Centre ` 'r:d School ofPublic Health, University ofNorth Carolina Sum: ry A study of pregnancy outcome among wives of workers exposed to vinyl-chlor ide monomer (v.c.At.) 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 c' unic abortions weighting the results. These findings, .. 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"5 v.c.M. metabolites also have in duced mutations in mammalian cells.'1 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.5"* However, Purchase cl 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, Selikoff observed fetal death-rates among wives of v.c.M. workers that ranged from 7 to 14 per 100 preg nancies.' 'lliese 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 tc 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 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 rat.-s ranyd Tom 62 to 777o. Data for the wives of v.c.M. polymerisation workers (primary v.c.M. group) err . -iirasted with data for the wives of p.v.c. fabrication and rubber workers ("controls"), who were kno1' i to have had very low or no v.c.M. exposure, respecti1. :y. A total of 95 v.c.At. polymerisation and 15S rubber and p.v.c. fabri cation workers were interviewed. t'alernal age, preg nancy outcome, and estimates for the time of conception of 3ll pregnancies vvere ascertained by interview in Oct ober, 1974, from males employed at a rubber manufac turing, P.v.c. fr.bricating, and v.c.At. 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 numbe of fetal deaths ^defined as any product of conception not bor.i alive), and fetal deaths per 100 conceptions 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 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, "fable 1 shows the age-adjusted fetal death-rates for wives of the orimarv 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 to exposure, fetal death-rates were 6-9fc for the controls versus 6- lr( (age-adjusted) for the primary v.c.M. exposure group. These rates were not significantly different by Mantel-Haenszel Chi-square testing,15 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at p<0-05 (yJ=4-00, df= 1).1: 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.At, exposure group. Among pregnancies occurring subsequent to exposure, the fetal mortality-rates associ ated with husbands 30 years of age and older f or the pri mary v.c.At. exposure and control groups were 9/69 (13'0'c) and 17/142 (12-0'.,), res,...'lively; whereas, lor T.Ult.l I--MIAS I'ATIKSAL All!. St MHtK III I'm I,MSI 11 ASH IM AI miAm-HATis Ai'ctiHDtst. in m:!HANn\ i.e, i\ritM-ki _ /*ri,pr f,* t'fjStjurf; Number of (jsmJic* AU'Jn pjirnul jgc jt eoiteepdon t,> r.' Number of fetal Number of pre^fumie* fcwl ik'jihv/l()0 preg.j Sufru'>fU\`fU ft* ejpoiure; Number of fimifio Mcj/i pjiernjJ age j< conception ,\r.) Number of lei jI DgJih* jmong hitct Number of prc^njitiTC* A^e-jJiuiioJ few! tlcjiWlUO preg ; I'rtnurv "i \iiuroU"* *,',**. e\|>ure* VJ 23 0 II 6-V III JO -1 24 m :o 15 MS 61 a2 30-2 2J \y* Rubber anJ r.v,u, fjbfK'ation worker*, fv.c. fYilvoKfiiahurt worker*. J Koto to "eomrol" gruup p-tcoul age Jionhuiiom SSub*(Njucm 10 hu*b4nJ`* exp^nurc, (he frequency ttl feul Je,nbA jmmtf; vnn win iigmfievnily grtjicr m the prmury vg.m. exposure >;ruu; Oun m the `'con iroV' (i,<0-05) or in ihc iiudy groop prior iu husband'* c*|XJiur< 02, <jC'jJftjytgj t-hi-muirc telling w R&S 002372 I k/ - ,* ; V v. L' t * v' . ' THE LANCET, APRIL 3, 1976 R&S 002373 TABLE J!--MEAN PATERNAL AGt, NVMBtR OF PREGNANCIES, l\u PETAL DEATH-RATES ACCORDING TO lU'SHAND'S V.C. EXPOM.SE EXCLCDING ''PREGNANCIES OF WOMEN W(TH 'S 3 PETAL DEATHS - Primary "CowroN"" v.c.M, exposure? IVi,>r hujttinJ'i %'tpoiurt: Mean paternal age at conception \tr.' Number of fetal deaths aiming uttes Number of pregnjncie* .\i;e`jJfustfJ fetal deathv/UHI prcg.T ti* kutfrjnJ't erp,*ire' Mean paternal at concept* ' Number ol deaths a* .unc* Number of prt'Cn,ineu'\ Age-adiusted letal Jcath*/I00 preg.t 23*0 1) 159 69 30-2 1H 26? fr.S 26 y 9 141 3-1 30*8 14 120 10*8 Rubber auJ k.'.c. fabrication workers, c. polymerisation workers JRates aitc-aJiusted to "concur' paternal age distribution. husbands less than 30 years of age, feta! mortality was 14/70 (20-0f?) for the primary v.c.M. exposure group compared with 7/131 (5*3(r) for the control group (these data are not shown in tables.) .-'i-thermorc, intragroup comparisons indicated an incrr .. in age-adjusted rates for the primary v.c.M. exp --re group from 6-1^ before exposure to 15-8f/ subsequent to the husband's exposure. This difference also was significant, t'<0-02 (y3 = 5-51, df-- I).*J Similar comparison for rates in the control group, 6*9% versus 8-8fc, indicated no significant difference. To determine whether women who had chronically experienced abortions might have weigmed 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 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 tabic tl 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 int -rviewer. The results demonstrated a general trend for t *ch interviewer to report a higher ascertainment ar" ,g v.c.M. polymerisation workers than among the c ,.iol group. Further, the possibility was entertained that the intervs, between the date of interview and the date of fetal lose "night have influenced the results through dif ferences in recall. The interval, however, was estimated to have been about two years less for c'.,itro!s, suge.v.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 ot 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 bia* resulting from prior knowledge of known hazards of vinyl chloride. However, the worker*; themselves did not always know into which of our employment categories they were being allocated. For example, several I'.v.c. fabrication workers who were included in the control group thought that they had a prirr.r-y 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 weil 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 arc suggested Either fetal or maternal toxicity or gerntcell 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.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.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. Requests for reprints should be addressed to N.J.Q,S.]J,, Dost Office Huilding, Room 515+ Cincinnati, Ohio -*5202, L\N.A. REFERENCES \. lljrKh, It., Mataviellc, C, Montesano, K. int.J. Cu-uvr. I'D?. K. *:u, . (a.pnouN N\, Karate, K., Varoncclli. S-. aJ Afwjrio'i Hi*. m the press 3, Rannug, U., Johansson, A., Kamel, C.% U'aehmeistcr, C. A. 1*74, J. 194. 4. Hubcrman, E,, Baruch, H., Sachs, l,. Int.J, Cancer, 19TJ, 16, M*. y Dueatman, A,, Hirschhorn, K.f Selikotf, I. J. Alararton H<t. 19?}, 31, 163 A. |*'unes*Cravioto, l\, lumbers, K,, lanJsten, J., l-.hrenberj;, L., Nataraian, A, I'., Osterman^iolkar, S. Lancer, 197J,,4J9. 7.Purchase, 1.1'. |l,, KicharUwm, C. R., Anderson, D, iHJ, 19T5, ,t. a Id B, lliHextad, l.., 'I'htifUvcnscn, K. Unpublished. 9. Sclikoif. 1. J , NM-H.H.S. Conference on f'nhtic Health IcnplinaiHm* <* i *m ponents of ('Issues Manufacture, I'tnehum, North Carolina. July. I'*'* 10. Infante. I*. I"\ Wnn. *V.K. Wcud. Sei. \tn the pr . 11. Shapiro, S., Jones, K. Denscn, I'. M. Milt-jnk Q 1962. 40, . 12. .Mantel. N\, Maenml, Vt\_7Canctr Imt. 19J9, 22, 719. 13. United States linvironmentil Protection Ajencv, sampling anJ anaJvsis i.f select toxic substances, task Hi vjn>l chlundi. Contract no 6K4|J-264fi Jan. 20, 1976.