Document b5jj2bDJzx6dnn7pL11M0oRBg

January 28, 1976 i-hlf fcjfflrtgj,. 1 ts G J976 GENETIC RISKS OF VINYL CHLORIDE By k Peter F. Infante * Joseph K. Wagoner Anthony J. McMichael+ * Richard J. Waxweiler Henry Falk0 Division of Surveillance, Hazard Evaluations and Field Studies National Institute for Occupational Safety and Health, 0Bureau of Epidemiology, Center for D^isease Control, and +School of Public Health, University of N. Carolina Mailing Address: NIOSH, Post Office Building, Room 515 Cincinnati, Ohio 45202 USA GENC 006579 In the past year, several reports have indicated that vinyl chloride monomer (VCM) is mutagenic in microbial test systems. 1 -3 VCM metabolites 4 also have induced mutations in mammalian cells. Likewise, reports from four countries have shown an excess of chromosomal aberrations in lympho cytes of workers exposed to VCM as compared to controls.5" However, Purchase et al., 7 have stated recently, though no animal data were presented, that the mutagenic effects of VCM expressed as chromosomal aberrations in lymphocytes in humans do not occur in germ cells in mice; they concluded that the potential for mutagenfc effects on the fetus via sperm seemed unlikely. In a study without controls, Selikoff observed fetal death rates q among wives of VCM workers that ranged from7-14 per 100 pregnancies. These rates appear to have been higher than expected.^ To develop further data on this question, a study of pregnancy out come was made among the wives of workers exposed to VCM. All current VCM polymerization and polyvinyl chloride (PVC) fabrication workers were in cluded for study together with a similar number of current rubber workers (8% of all such workers) selected from workareas relatively free from known toxic materials and matched as a group to thd VCM workers by age. Group participation rates ranged from 62-77 percent. Data for the wives of VCM polymerization workers (primary VCM exposure group) were contrasted with data for the wives of PVC fabrication and rubber workers ("controls"), who were known to have had very low or no VCM exposure, respectively. A total of 95 VCM polymerization and 158 rubber and PVC fabrication workers were interviewed. Paternal age, pregnancy outcome and estimates for the time GENC 006530 2- - of conception of all pregnancies were ascertained by interview in October, 1974, from males employed at a rubber manufacturing, PVC fabricating and VCM polymerizing facility. 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. 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 VCM exposure group were age-adjusted to the control group. Table I shows the crude and age-adjusted fetal death rates for the wives of the primary VCM exposure group versus the control group, both prior to and subsequent to each group's respective exposures. Among pregnancies occurring prior to exposure, fetal death rates were 6.9% for the controls versus 6.1% (age-adjusted) for the primary VCM exposure group.* These rates were not significantly different by Mantel-Haenszel Chi-square testing. 12 Among pregnancies occurring subsequent to the hus- . band's exposure, the difference in frequency ovf fetal deaths between groups was significant at P<0.05(x2 =4.00,df=l). 1? Although the underlying distri butions differed, mean paternal ages were virtually the same, 30.4 versus 30.2 years. The significant difference between the groups subsequent to exposure was a reflection of a relatively greater fetal mortality rate associa ted with younger-aged husbands in the primary VCM exposure group. Among preg nancies occurring subsequent to exposure, the fetal mortality rates associated with husbands 30 years of age and older for the primary VCM exposure and control groups were 9/69 (13.0%) and 17/142 (12.0%), respectively; whereas. GENC 004531 3- - for husbands less than 30 years of age, fetal mortality was 14/70 (20.0%) for the primary VCM exposure group as compared to 7/131 (5.3%) for the con trol group. (These data are not shown in Tables). Furthermore, intragroup comparisons indicated an increase in ageadjusted rates for the primary VCM exposure group from 6.1% before exposure to 15.8% subsequent to the husband's exposure. This difference also was significant, P<0.02(x2=5.51,df=1). 12 Similar comparison for rates in the . control group, 6.9% versus 8.8%, indicated no significant difference. To determine if women who had chronically experienced abortions may have weighted the results in favor of a higher fetal-death rate-^in the pri mary VCM group subsequent to husband's exposure, pregnancies of women who S' had more than two abortions were eliminated from the analyses and the data were recalculated to determine whether or not the trend was maintained. 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 II show that the trend was maintained. Prior to exposure, the fetal death rates in the control and primary VCM exposure groups were 6.9% and 3.1% (age-adjusted), respectively, whereas, after exposure, the rates were 6.8% and 10.8%, re spectively. Subsequently, data were eliminated for pregnancies of women v 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 VCM group subsequent to exposure. To determine whether differences in fetal loss may have been the result of one or two interviewers weighting the results, the data were analyzed by individual interviewer. The results demonstrated a general trend for each GENC 006582 -4_ f interviewer to report a higher ascertainment among VCM polymerization workers as compared to the control group. Further, the possibility was entertained that the time interval between the date of interview and the date of fetal loss might have influenced the results through differences in recall. The time interval, however, was es timated to have been about two years less for controls, suggesting that if a bias did exist, it would have been toward 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 analyzed to determine the dis tribution 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 minimal. Finally, the workers may have been subject to bias resulting from prior knowledge of known hazards of vinyl chloride. However, the workers them selves did not always know into which of our employment categories they were being allocated. For example, several PVC fabrication workers who were in cluded in the control group thought that they had a primary VCM exposure as a fabrication worker. In addition, the questions regarding pregnancy out come were contained in a much larger interview^questionnaire, the results of V which demonstrated very few significant differences with no consistent bias for the parameters ascertained between the workers with a primary VCM exposure as compared to 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 VCM. The excess did not appear to be the result of bias from interviewers, respondents, nor from women who experienced GEHC 006583 5- - 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 VCM exposure from the father might be considered, although these mechanisms seem highly unlikely .. 1T in view of the highly volatile characteristic of VCM. 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 sig nificant excesses of chromosomal aberrations among workers exposed to VCM, the leading possibility is germ cell damage in the father through direct VCM exposure. The increased occurrence of fetal mortality among wives of workers subsequent to VCM exposure now raises serious scientific and public health concern for the possible genetic risks of vinyl chloride to humans. 6ENC 006584 6- - REFERENCES 1. Bartsch, H., Malavielle, C. and Montesano,. R. Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in S. Typhimurium strains, Int. J. Cancer, 1975, 15, 429. 2. Loprieno, N., Barale, R., Varoncelli, S., et al. Evaluation of the genetic effects by vinyl chloride monomer (VCM) under the influence of liver microsomes. Mutation Res, In press. - 3. Rannug, U., Johansson, A.,'Ramel, C. and Wachtmeister, C. A. The mutagenicity of vinyl chloride after metabolic activation, Ambio 1974, 3, 194. 4. Huberman, E., Bartsch, H. and Sachs, L. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde. Int. J. Cancer, 1975, 16, 639. 5. Ducatman, A., Hirschhorn, K. and Selikoff, I. J. Vinyl chloride exposure and human chromosome aberrations^ Mutation Res, 1975, 31, 163. 6. Funes-Cravioto, F., Lambert, B., Lindsten, J. et al. Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1975, i, 459. GENC 006585 7- - 7. Purchase, I.F.H., Richardson, C.R. and Anderson, D. Chromosomal and dominant lethal effects of vinyl chloride, Lancet 1975, ii, 410. 8. Hillestad, L. and Thiis-Evensen, E. Preliminary report on the medical examination of 288 employees at the PVC plant, Norsk Hydro a. s., Porsgrunn Fabrikker. Unpublished manuscript. 9. NIEHS Conference on Public Health Implications of Components of Plastics Manufacture, Pinehurst, North Carolina, July, 1974. Selikoff, I.J. Statement during discussion. ~^ 10. Infante, P.F. Oncogenic and mutagenic risks in communities with poly vinyl chloride production facilities, Ann. N.Y. Acad. Sci, In press. 11. Shapiro, S., Jones, E.W. and Densen, P.M. A life table of pregnancy terminations and correlates of fetal loss, Millbank Quarterly, 1962, 40, 7. 12. Mantel, N. and Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of diseas^, J. Natl. Cancer Inst, 22: 719-748, 1959. 13. United States Environmental Protection Agency, Sampling and analysis of select toxic substances. Task III, Vinyl Chloride. Contract No. 68-01-2646, January 20, 1976. GENC 006586 TABLE I MEAN PATERNAL AGE, NUMBER OF PREGNANCIES AND FETAL DEATH RATES ACCORDING TO HUSBAND'S VC EXPOSURE "CONTROLS"* PRIMARY VCM EXPOSURE111 PRIOR TO HUSBAND'S EXPOSURE NUMBER OF FAMILIES MEAN PATERNAL AGE AT CONCEPTION (YEARS) NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 - 95 23.0 11 159 - 6.9 70 26.4 15 148 ^ 6.1 SUBSEQUENT TO HUSBAND'S EXPOSURE NUMBER OF FAMILIES MEAN PATERNAL AGE AT CONCEPTION (YEARS) NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 113 30.4 24 273 8.8 V 62 30.2 23 139 15.8* -+ RUBBER AND PVC FABRICATION WORKERS. 1 VC POLYMERIZATION WORKERS. 6 RATES AGE-ADJUSTED TO "CONTROL" GROUP PATERNAL AGE DISTRIBUTION. * SUBSEQUENT TO HUSBAND'S EXPOSURE, THE FREQUENCY OF FETAL DEATHS AMONG WIVES WAS SIGNIFICANTLY GREATER IN THE PRIMARY VCM EXPOSURE GROUP AS COMPARED TO THE "CON TROLS" (P<0.05) OR TO THE FREQUENCY IN THE STUDY GROUP PRIOR TO HUSBAND'S EXPOSURE (P<0.02) BY AGE-ADJUSTED CHI-SQUARE TESTING.12 GENC 006587 TABLE II MEAN PATERNAL AGE, NUMBER OF PREGNANCIES AND FETAL DEATH RATES ACCORDING TO HUSBAND'S VC EXPOSURE EXCLUDING PREGNANCIES OF WOMEN WITH > 3 FETAL DEATHS "CONTROLS" PRIMARY VCM EXPOSURE1 PRIOR TO HUSBAND'S EXPOSURE* * MEAN PATERNAL AGE AT CONCEPTION (YEARS) NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/I00 PREG.0 23.0 - 11 159 6.9 26.3 ' 9 141 3.1 SUBSEQUENT TO HUSBAND'S EXPOSURE MEAN PATERNAL AGE AT CONCEPTION (YEARS) NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 30.2 18 265 6.8 30.8 14 120 10.8 + RUBBER AND PVC FABRICATION WORKERS. * VC POLYMERIZATION WORKERS. 0 RATES AGE-ADJUSTED TO "CONTROL" PATERNAL AGE DISTRIBUTION. 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