Document 82Xm7DmYBN2R8baXY5zg2wQR5

*,- riV,.`,vi.:".'",'**`,.1', . -'A RECEIVED KM. M t 734 JAN 2 3 1330 THE LANCET, AFRJL 3, ill , -jB the lancet, APRIL 3, Occasibnlil ^Survey GENETIC RISKS OF VINYL CHLORIDE Peter F. Infante Joseph K. Wagoner Anthony J. McMichael Richard J. Waxweiler Henry Falk Divijion ofSurveillance, Hazard Evaluations andFiald Studios, National Institutt for Occupational Softly 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 vxjh., 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.CJA. to man. In the past year, several reports have indicated that vinyl-chloride monomer (v.cm.) is mutagenic in micro bial test systems.1-1 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.cja. compared with controls.1-* However, Purchase et al7 have stated (though no *"'"*1 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.** To develop further data on this question, pregnancy outcome has been studied among the wives of workers exposed to v.c-m. All current vxjh. polymerisation and polyvinyl-chloride (r.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 77%. Data for the wives of v.c-M. polymerisation workers (primary v.c-m. group) were contrasted with data for the wives of r.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 v.cAt. polymerisation and 158 rubber and r.v.c. cation workers wee interviewed. Paternal age, nancy outcome; and estimates for the time of i tiiLI d ttlA> MTVKMA. DCJtt^UTtS ACCOftQINC rUCMAMCiM Ol of all pregnancies were ascertained by interview in' ober, 1974, from males employed at a rubber mi turing, r.vx. fabricating^ and v,cm, polymerising ity. As part of a larger survey of worker health, dat first employment in the job categories was deti from company records. Mean paternal age, total m Mr tm OutaWf 41pMurtr Urci ppuoqteenput^f**(fyr.) \iwateroffetal of conceptions, total number of fetal deaths (del any product of conception not born alive), and deaths per 100 conceptions were then computed for i group prior to and subsequent to the worker's employment. No interviews were conducted workers' wives and no data were obtained cone maternal age, except indirectly through paternal a{ --Since fetal loss is known to increase with parental age, the fetal death-rates for the primary ri exposure group were age-adjusted to the control plrpMOS fcttl JwtWlOO I Irfsrgirsl M KeWi tulu iiii age it CBdtfpuoo (yr.) of fcial Jratht mg wrm NwuOcrof rTrrniui in \orutuHi fetal JeaUu/100 pvvg4 Table I shows the age-adjusted fetal deal r v.c.&briwtoQ for wives of the primary v.c.M. exposure versus the control group, both prior to and sul ** <- uurioi. af^aJiimad u> -cootfol' to each group's respective exposures. Among husbands less than 3C des occurring prior to exposure, fetal death-rates it urtO (20-0%) for th 6-9% for the controls versus 6-1% (age-adjusted) fort twpired with 7/J3 primary v.cja. exposure group. These rates werej -these data are not sho significantly different by Maniel-Haenszel Chi- Furthermore, intra testing.11 Among pregnancies occurring subsequent! "crease in age-adjusi the husband's exposure, the difference in frequeocf! exposure group from fetal deaths between groups was significant?! absequeni to the hut p<0-05 (y*=4-00, df=l).11 Although the underlyingcj ^ was significant, p tributions differed, mean paternal ages were comparison for rates i the same--30-4 versus 30-2 years. The significant * *7. indicated no rigs ferencc between the groups subsequent to exposure!] , To determine whet a reflection of a relatively greater fetal mortality-TM* "penenced abortions i sodated with younger-aged husbands in the pra v.c-M. exposure group. Among pregnandes subsequent to exposure, the fetal mortality-rates ated with husbands 30 years of age and older for theg mary v.c.m. exposure and control groups were ! (13*0%) and 17/142 (12-0%), respectively; whe frvour of a higher feta tnup subsequent to hi who had mon "**ed from the anal' * determine whi The decision ti '*** assodated wit TAILS I--MIAS PATSANAL ACS, NUMBER Of fRSGKANCltS, ANU without prior k BeASa-RATSS ACCQRMNO TO NUSRAMD'S ISfOSOU ffoiributed imoc **> table u show Prior to knttooft iJifttmt: Nuoboroffooilioi M*9 pauml ft at cDoafbm (yr.) Nynba-dftad ihmha mmwj w>W Niimlw iifprunimM Af rtiwdfail dntWlOO png4 flam to kMikod*i Nvabcr offonflici filr--ftiirnil ip at ttocxpuoa (yr.) Number of(cut IT--ibi town riw Nuobff of AgHdjymdftuI dmWlOO pns4 "Comioli"* V4A ef 5 23-0 It 159 0*9 113 30.4 24 273 1 70 24-It1 Ml 4- 43 30-4 23 ij: is* *Rubbv r.vx. tsfcricsim rfccn. t*. pnlyitrimw wrtin. jJUtn if> to "Blwr group }Stitm|ucm to (mteafi opnm, iki ws agnifksady greowr * Uk pfwp irafe" {><0-05) or is tfc* ftody pouf prior a^adjuuod chftquorr taunt.1* exposure, the J* primary v.cj*. a (age-adjusted), r, `"f rates arete 6-f |U7> date were who had expe and, secondly "me the trend was nootrols were obser "*>*rvedwthepri Mire. K "b!len?i,,e whethl hten the result of **", the data TTseresuiut interviewer to , ' P01^ * group, fc'^PhUibih-: m "n`he date ol *h` have influ, UCC 005660 s?' Till Uncet, APRIL 3, 19, I V- * rubber and p.v.c. fa]* ..... u nf-- FATEAXAL AGE, HUMAEA Or FAEGNANC1ES, AND FETAL cwetL Paternal age, pn, 'otTm-AAt11 Accoanme to hoeaand's v.c. exaoeuae excluding *" rKEGNAHClES OF WOMEN WITH * 3 FETAL DEATH'S s for the time of concept - aaaFi-- gained by interview in ft; Primary .iployed at a rubber manufc "Conlroli"* vXaM, cspovnrtf *od vx.M. polymerising of worker health, datt( 4b categories was detenni* ^n paternal age, total numb m k&bwTi tspQtwrt: gunirppiwm(yr.) ftal lire unoof vivo 23 0 26-3 11 9 ^er of fetal deaths (defined, i not .bom alive), and fo . p^iwrirt rvere iben computed for c* r _^^W100 pref-t 159 69 141 3'1 ientio the worker's date -cws /were conducted *j 4a woe obtained concerns ytiy through paternal age. a to increase with ascends strata w the primary v.u .AmiUomIi* - ahowM * Itoabarffeil - M.4 a^XmM fad 30-2 11 265 6-1 301 14 120 lOS iljurted to the control groq ^-adpated fetal death** my vXJL exposure gtn p.vi Wirifitiw nicn, tartan {oih prior to and subseqne "exposures. Among pregu pbture,'fetal death-rates e ns61% (age-adjusted) ford youp/These rates were a ^Uatet-Haenszel Chi-squr aaes occurring subsequent i e difference in frequency i gpoups was significant i hmbands less than 30 years of age, fetal mortality was IV70 (20-0%) for the primary v.Cja. exposure group asnpared with 7/131 (J-3%) for the control group (thae data are not shown in tables.) Furthermore, intragroup comparisons indicated an iacreue in age-adjusted rates for the primary V.C.M. exposure group from 6*1% before exposure to 15*8% subsequent to the husband's exposure. This difference ^Although the underlying 6 rpstemal ages were vintul %2 years- The significant i 5IB sSUuDbSsequent to exposure a ^^ip't*aittaer fetal mortality-ratei Hu husi bands in the prior _ pregnancies occurri hieefcfereta,l mortality-rates am bo was significant, P<0-02 (y1=5-51, df=l).u Similar comparison for rates in the control group, 6-9% versus t`1%, indicated no significant difference. To determine whether women who had chronically experienced abortions might have weighted the results in fa*wr of a higher fetal death-rate in the primary v.cja. gmip 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 Mofige and older for the p 8 control groups were 9A ), rapeetively; whereat, i lated to determine whether or not the trend was main tained. The decision to exclude all pregnancies among bmilics associated with more than two abortions was OP fiaghancies, and ftti ade without prior knowledge of how these families pan's *x. sxposuaa tre distributed among the exposure categories. The ina~- Kt- Si PriMT VsCaM. tfpw* 70 M-4 4ua in table n show that the trend was maintained, rrier to exposure, the fetal death-rates in the control and primary vx-M. exposure groups were 6-9% and >1% (age-adjusted), respectively, whereas, after estpo- jnwthe rates were 6-8% and 10-8%, respectively. Subnq<*mtiy, data were rfiwii--tad for pregnancies of nT* 15 *bo had aperienced, firstly, more than one 141 "J!TM?0* and, secondly, more than three abortions, and asf. a- jp7. 4-1 tone the trend was maimad No changes in rates rmotrob were observed, whereas a 2-3-fold increase 62 *** observed in the primary VX.M. group subsequent to Ml To determine whether differences in fetal Iocs might Z> e lo the result of one or two interviewers weight- 11* the results, the dau rat analysed by individual in- JI tl-a : "ll,u,-w`- fhe results demonstrated a genoal trend for interviewer to report a higher ascertainment Y-c-M- polymerisation workers than among the .55"*8n>up. tW faui , Sr**TM' ^ possibility was entertained that the inter- >he date of interview and the date of fetal 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 vx.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 vx.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 germcell mutagenesis in the mother through indirect vx-M. exposure from the father might be considered, although these mrrhanisms seem highly unlikely in view of the highly volatile nature of v.cjr.1* 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 '/.cm., 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 ariemgic and publichealth concern for the poerible genetic risks of vinyl chloride to man. Xaqnan Cw nuAsn* AbooU be ^drwd to PJX, MX05Jl, Pott BnlLAMf, tit nwi.ml, DU. HIM, tt C A 1. aatra, m maIa-hd*. c, Hu....... a. iwlj. ow. ivtj. is. 2. LaoriABO. N. Bats*. IL. V,frdli. S, aL Mmimiim Mm. 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