Document QMYOBKeaZqxYenQn840KK3ko
734 THE LANCET, At'Ktt. 3, 1 `776
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 ofEpidemiology, Centerfor Disease Centre ` ind School of Public Health, University of North
Carolina
Sumi ry 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'iv'ndents, nor from women who had experienced r' onic 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.-4 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.1-1 However, Purchase et al.5 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, Sclikoff 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 rang-4 Tom 62 to 77%. Data for the wives of v.c.m. polymerisation workers (primary v.c.m. group) * ;.-e . -itrasicd with data for the wives of P.v.c. fabri,,;tion and rubber workers ("controls"), who were kno-' i to have had very low or no v.c.m. exposure, respccti. :y. A total of 95
v.c.M. polymerisation and US rubber and P.v.c. fabri cation workers were interviewed, "uternal 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 numbe 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 ageTTHrlelardeaTK-raterior the primary v.c.m) exposure group were age-adjusted to the control group, fable i shows the age-adjusted feta) death-rates for wives of the primary v.c.m. exposure group
versus the control group, both prior to and subsequent to eacn 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 Alamel-Haenszel Chi-square testing.11 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at C<0-05 (y5=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 27/142 (12-0%), respectively; whereas, for
TAHLt 1-- Ml AN fATlKNAL Al>t, M'MgtK (O PKl CMNCll ANI Ml Al dvatm*ratls ArctiHotst; u> hl'ahanu'n \ x. Utl'UM'KI
-
f'tUtr (.* hmt'jnJ'i
Vunifvr of { jftttlici Mean paternal jp-'
at conception tyr.> Number oi fei*J
Jt jihi 3iiu*n^ <*i\ei dumber of pregnanctci
fetal dCJtht/UW preg.J Svbi.yueur to AmAunJ'i ripufvrr; Number of familiei Mean paternal a^e at Conception lyr.j Number of fetal IVathi amoiifc* rho Number of pretfoanetei Acv-jJimteO fetal
prc ;
"tmotroU"'
Primary t .< ei[>nwre*
23 0 M m nv 113 JIM
3*
S-K
70
'n-4 1? 14X ft t>2 JO. 2
3i
1)4 1 '*;
'Rubber p.v.c. fabrication worker*.
|v polymeruaiiun murker*
jKatCl aRc-aJiuiteO to `\ontrol" j;roUp paternal ape Jutrihutmii
^Nubiequent to huibanJS ecfviutc. the frequency l tet*l Jeath* anting
v.cwat lipniftetnily greater in tbr primary ,m, eiptnorc tffoup ihan m the "tun
troll" [r<,0-0J or m the tiudy proup prior io huibanJ'* eijxnyre ir*,U 02, b> jge-aJfOHrJ thi-iquare leiimg
THE LANCET, APRIL 3, 1976
R&s 002377
TABLE n--Mf.o: MTIR.sAL AUt, N'L'MHER Of Pftt'CNANCflS, AND FfMI
CHATN'ftATLS aCCOROINU to HI'SUAND'S V.C. fXPOSI RL JACt cmso
mCNASCtFS OF
W(TII * 3 Ft'TAL WATlft
-
I'n.tr h UmtuiJ'i i-tpom*?
AWjn pJtvJ'hJl ft
j( c'ffKVptum i*r '
N'umhcr of iVtjf
atuotii: wiho
NtimfcvJ' *f
prCf.TWfWu'i
A^d'UaJiuSfeJ fc'ljf
JdJthNMOU
I
rnmary '*t >nir*J"* V.t M. <HP4**UfC
230 `H
159 6-9
26-3 v
HI 31
pJh'fhjJ
4f vVttxVpe
Number of
Jv'jlhs j.
Ntmtlvr `t
prrt.'n.nKV*
VV'jJfUMCct fc'Wl
Jejthv'lOU prcjl,;
30-2 IR 265
30`B 14 120 10-H
Kubtvf jnJ pa -i. ribru.'a(i<jn wor!iffi, *v i , pt'UmcrtsjlnEn vtuf^r*
;Kjtc\ jyv-jJiuMwl u* ''contfc'l" 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.)
.-'..-.hermore, intragroup comparisons indicated an incre- , in age-adjusted rates for the primary v.c.M. exp .,,.-e group from 6-19c before exposure to 15-897 subsequent to the husband's exposure. This difference
also was significant, f<0-02 (y/=5-51, df=l).u Similar comparison for rates in the control group, 6-9f,c versus 8-8%, indicated no significant difference.
To determine whether women who h3d 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 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 3-1% (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-foid 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 Tviewer. The results demonstrated a general trend for e -ch interviewer to report a higher ascertainment a.~- g v.c.M. polymerisation workers than among the c- ..i ol group.
Further, the possibility was entertained that the interv:- between the date of interview and the date of fetal los: night have influenced the results through dif
ferences in recall. The interval, however, was esunwteu to have been about two years less for C'-.nrols, 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 everc 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 worker' themselves did not always know into which of our employment categories they were being allocated. For example, jcvenri r.v.c. fabrication workers who were included in the control group thought that they had a prime';' 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 arc 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,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 tor reprims should be addressed to I'.b'.L, hi.1.0.S.It,, I'osi Office building, Room 515, Cincinnati, Ohio 45202, U..N.A.
REFERENCES
L Banach, II., M.L. olL, C. Momeaano, K. /nr./. C-JO?5. IS, 4 2*. 2. la'priemi. N-, Uarale, K , Varoncctl*. S,, e. al. .Sfnn/Non Het. tin ihe prea, . 5. Rannug, LI., Johni-in. A., Ramrl, C., Wachmeuicr, C. A- r4n,/.in. IvN, J.
194.
4. Huberman, E,, Banach, It.. Sacha, I., /nr./. Cancer, 1475, 14, 4,14. 5. ITueaiman, A,, Hirsehhom, K,, SelilolT. I. J. Mvtation Uci. 1V75, 51, 14.1 4. l-'unes-Craa-ioto. If. lumbers, 11, Lindaicn, J., Lhrenberg, t... N'aiaraun,
A. T,, Oalenuart-Golkar, S. /.nnrrf. 1475.1, 454. 7. Purehaac, L !'. H , Richardaon, C. K., AnJcraon, I>. thij. 1475, a Mi 5. llillrtlad, t... ITiiii-Liciiaen. P,, Vnpuhl,ahe%i 4. SeliVolf. L J , N LL.H-S, Conference on Pnhln. I lealth Impllaaiiona , ..ill
pencils of dailies Martufaeiurr. Pinch oral. North Carolina, July, 14 74 10, Infante. P, E. Ann. ,V. 1" AcjJ, Set ,in Ihe pr -a,). 11, Shapiro, S , Jonca, li. V',, Denaen. P, M, .sfi/rjnf 1442.40.7
12, Manlel, N , Hacnarcl, W,/. N'om C--neer/nw. 1454,27, ?|v.
15 United Siaiei Lmironmenial 1'rotcaiiun Ajcncy, aamplmg jnd analvoa ol aeleei loaie tobataneca, uat in nml chluriJe, Contract no ohlllThan Jan, 20,1=74