Document gaeLwvpXdok80YELRBD0pjmaJ

'ru THE LANCET, APRIL 3, 1976 Occasional Survey GENETIC RISKS OF VINYL CHLORIDE Peter F, Infante Joseph K.. Wagoner Anthony J. McMichael Richard J. Waxweiler Henry Falk Division ofSurveillance, Hatard Evaluations andField 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 1 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"' 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.5-* 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.10 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. 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 rates ranged from 62 to 11%. 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 SL 041575 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 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 (thfined as any product of conception not born alive), md fetal deaths per 100 conceptions were then computet for each group prior to and subsequent to the workers date of employment. No interviews were conduced with workers' wives and no data were obtained onceming maternal age, except indirectly through patenal age. Since fetal loss is known to increase wit) ascending parental age, the fetal death-rates for the primary v.c.m. exposure group were age-adjusted to the cotrol group. Table i shows the age-adjusted fetal death-rates for wives of the primary v.c.m. expsure group versus the control group, both prior to ari subsequent to each group's respective exposures. Anng pregnan cies occurring prior to exposure, fetal deth-rates were 6-9% for the controls versus 6-1% (age-aisled) for the primary v.c.m. exposure group. These ates were not significantly different by Mantel-Haenil Chi-square testing.13 Among pregnancies occurrin/ subsequent to the husband's exposure, the difference n frequency of fetal deaths between groups was significant at pcO-05 (x3=4-00, df=l).13 Although tb underlying dis tributions differed, mean paternal ag* were virtually the same--30-4 versus 30-2 yean. Ik significant dif ference between the groups subseques to exposure was a reflection of a relatively greater fetslmortality-rate as sociated with younger-aged husband in the primary v.c.m. exposure group. Among pnyiancies occurring subsequent to exposure, the fetal mrtality-rates associ ated with husbands 30 years of age ad older for the pri- (13-0%) and 17/142 (12-0%), respectively; whereas, for TABLE 1--MEAN PATERNAL AGE, NUMBER ^PREGNANCIES, AND FETAL death-rates according to husbsd's v.c, EXPOSURE -- Prior 10 husband's exposure: Number offamilies Mean paternal age at conception (yr.) Numbef offetal deaths among wives Number ofpregnancies Age-adjusted fetal dcaiha/100 preg4 Subsequent to husband's exposure: Number of families Mean paternal age at conception (yr.) Number of fetal Deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 preg4 ,' Tonirol,'# 95 230 it H9 6-9 in 30-4 24 273 8-8 Primary exposure! 70 26S 15 US 6-1 62 30-2 23 139 15-8$ -Rubbcr md p.v.c. fabrication owSfli fv.c. polymerisation workers. {Rates age-adjusted to "control" age OMnbuuon. ^Subsequent to husband's xxpoxatt, fe frequency of fetal deaths among wives was significantly greater in ibepdnmyvjdM- exposure group than in the "con trols" (r<0-05) or in the study prior W husband s exposure (p<0-02) by age-adjusted chi-square testing. Y- ' *k tK hi U CO ;u in. cx su ah co 8- ex fa- W( in, Jat tai fai mi we da Pr an 3*; su; sec wo ab< eat for wa ex[ ha' ing ter eac am coi vaJ los * Tjfi; LANCIT, APRIL 3, 1976 J TABLE II--MEAN PATERNAL AGE* NUMBER OF PREGNANCIES, AND FETAL DEATH-RATES ACCORDING TO HUSBAND'S V.C. EXPOSURE EXCLUDING PREGNANCIES OF WOMEN WITH * 3 FETAL DEATHS -- Prtor 10 husband's exposure; Mean paternal age at conception {yr.) Number of feta) deaths among wives Number of pregnancies Age^adjusied fetal deathV'lOO preg.f Subsequent to husband's exposure; Mean paternal age at conception (yr,) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal dcaths/100 preg4 Primary "Controls"* V.CJH. cxposuref 230 ,, 159 6-9 30-2 18 265 6-8 24 J 9 141 3<1 30 8 14 120 10-8 Rubber and p.vx. fabncauoo workers, fv.c, polymerisation workers. tKaies age-adjusted to "control" paternal age distribution. husbands less than 30 years of age, fetal mortality was 14/70 (20-0%) for the primary v.c.M. 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.c.M. exposure group from 61% before exposure to 15 8% subsequent to the husband's exposure. This difference also was significant, p<002 (yJ=5-51, df=l).1J 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.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 table n 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 loss might have influenced the results through dif 735 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.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 germ 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.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 public- health concern for the possible genetic risks of vinyl chloride to man. Requeui for rrprinu should be addressed to P.F.I., N.I.O.S.K., Post Office Building, Room 515* Cincinnati, Ohio 45202, U.S.A. REFERENCES 1. Baruch, H,, Malavielk, C., Montesano, R. Int.J. Cancer. 1975, 15, 429 2 IsOpncno, N., Barale, R., Varoncelli, S-, at. Mutation Res. (in the press). 3. Rannug, U., Johanaaoo, A., Ramd, C, Wachmeister, C. A. Ambio. 1974, 3, 194. 4. Hubcrman, E., Barlach, H,, Sachs, U /./ Cancer, 1975, 14,639. 5. Ducatman, A., Hirschhom, K-, Sehkoff, I. J. Muuturti Res. 1975, 31, 163. 6. Funes-Cravioto, F., Lambert, B., Lindsten, J., Ehrenbcrg, L., Natarejan, A. T., Ostcrman-Golkar, S. Lancet, 1975, i, 459. 7. Purchase, I. F. H., Richardson, C. R., Anderson, D. tbid. 1975, u, 410. 8. HiUettad, L,, ThUs-Evcmen, E. Unpublished. 9. SellkoIf, 1. j., N.I.E.H.S. Conference on Public Health Implications of Com ponents of Plastics Manufacture, Pinehurst, North Caialma, July, 1974. 10. Infante, P. F. Ann. N.Y. Acad. Set. (in the press). 11. Shapiro, S., Jones, E. W., Denicn, P- M. Milbank Q. 1962,40, 7. 12. Marne), N., Hacnszel, W.J. Nam. Cancer Inst. 1959,22,719. 13. United States Environmental Protection Agency, sampling and analysis of select toxic substances, task tu vinyl chloride. Contract no. 68-01-2646. Jan. 20,1976. SL 041576