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RECEIVED AC3 1 0 1983 TERATOLOGY 2T 359-370 <1983 Evaluation of the Association Between Birth Defects and Exposure to Ambient Vinyl Chloride ABSTRACT Birth defects incidence for infants born to residents of Shawinigan, Canada in 1966-1979 were significantly higher than in three compar ison communities. Since there has been a vinyl chloride polymerization plant m this town since 1943 from which ten cases of angiosarcoma of the liver have been identified, this study explores the possible association between exposure to vinyl chloride monomer (VCM) in ambient air and the occurrence of birth defects in the community. The excess of birth defects fluctuated seasonally in a way that corresponded to changes in VCM concentration in the environment. Mothers who gave birth to malformed children were younger on average in Shawinigan than in the comparison communities. However, there was no excess of still-births in Shawinigan, The excess m birth defects involved most organ systems, and variation m birth-defect rates among school districts could not be accounted for by estimates of VCM m the atmij^phere. The occupational and residential histories of parents who gave birth to malformed infants were compared with those of parents of normal infants. The two groups did not differ in occupational exposure or closeness of residence to the vinyl chloride polymerization plant. Some descriptive data from this study raised the hypoth esis of an association between VCM in the air and birth defects in the exposed community, but as a whole, within the sample size available, such an associa tion could not be substantiated. Vinyl chloride monomer (VCM) is carcinogenic in animals (Viola et al,, '71; Maltoni and Lefemme, '74,'75) and man (Creech and Johnson, '74; Thomas and Popper, '75; Makk et al., '76; Delorme and Theriault, '78; Monson et al., '74; Waxweiler et al., '76). It is mutagenic in man: Chromosome breaks have been observed in lymphocytes of workers exposed to VCM (Funes-Cravioto et al., '75; Ducatman et al., '75; Fleig and Thiess, '78; Leonard et al., '77; Hansteen et al., '78; Kucerova et al., '79), in microbial tests, in Dro- sophila, in yeast, and in mammalian cells (Drevon and Kura&fL "79; Bartsch and Montesano, '75; LofoiHRiet al., '76; Magnusson and Ramel, "7t vlyfrf generates mutations primarily through'ae of its metabolites, chloroethylene oxide, and with the involve ment of liver microsomal enzymes (Bartsch and Montesano, '75; Vainio, '78; Kannug et al., '74; Green and Hathway, '78). Although miscarriages and fetal losses among the wives of exposed workers have been sus- pected (Infante et al., '76), such an effect remains undocumented (MacMahon, '77; Downs et al,, '77). VCM teratogenicity has yet to be documented. VCM was present in the fetal and maternal blood and the ammotic fluid of pregnant rats after exposure to contaminated air (Ungvary et al., '78). Two studies of VCM teratogenicity in animals (Ungvary et al., '78; John et al, '77) failed to demonstrate fetal malformations but showed increased fetal mortality rates, . VCM mutagenicity and possible teratogenicity in man raised the question of the origin of birth defects in communities near VCMemitting plants. At normal temperature and pressure, VCM is a gas; it liquifies at -13C. It is processed --------------- Received April 8. 1982; accepted December 1. 1982 Address reprint requests to Gilles P Theriault, Institute of Occupational Health and Safety, McGill University, 1130 Pine Avenue-West, Montreal, Quebec H3A 1A3. 1983 ALAN R. LISS. INC * 360 G THERIAL'LT H ITURRA, AND S GINGRAS into polyvinyl chloride (PCV, a plastic) through polymerization reactions in auto claves. The gas is released into the environ ment during unloading, processing, and autoclave-cleaning operations The concen tration of VCM to which people in the com munity are exposed depends on production rate, wind direction, wind velocity, and dis tance from the plant. In Shawmigan (population 27,000), a vmvl chloride polymerization plant has been m op eration since 1943. The plant, which employs about 250 workers, current1,:, produces 25,000 tons/year of PCV Ten cases of angiosarcoma of the liver have been reported among work ers at this plant. In addition, Shawmigan has two other chemical plants, one aluminum electrolysis plant, one carbide plant, and one pulp and paper mill. Several pollutants are discharged into the environment. This study pursues four objectives. First, to compare the birth-defect and stillbirth rates in Shawmigan with other communities in an attempt to document the high birth-defect rates previously observed in this town; sec ond, to correlate monthly and seasonal vari ations of birth defects with concentration of VCM in the environment; third, to correlate geographic variation in birth-defect rates with estimates of VCM in the air m the sev eral residential areas; and finally, to com pare a group of parents who gave birth to malformed infants with a control group with respect to residential and occupational his tory, as well as exposure to other risk factors known to generate birth defects, METHODS Study population and observation periods For the assessment of birth-defect rates, the population comprised all women who de livered dunng the study period and whose residence was within the city limits of the study or the comparison communities at the time of delivery. It extended from January 1, 1966, to December 31,1979. The starting year 1966 was selected because, due to hospital reorganizations, the information was unob tainable in a suitable form prior to that date. The case-control ttaif was limited to a shorter period (Jawafty 1,1973, to December 31, 1979) because ft required information based on the mothers' recollection of events during their pregnancies. It included only Shawinigan mothers who gave birth to a malformed child and their controls. Definition of a birth defect A birth defect was defined as a gross phys ical anomaly present at birth or detected at the hosDital dunng the first days after deliv ery iwithtn the first 4-6 days), A list of birth defects to be included in tne study was drawn beforenand and only those that fit tms list were retained Two major difficulties were encountered. In birth defects of the cardiovascular system, it soon became apparent that m several hos pitals. no diagnoses other than murmurs of the heart were reported, whereas in other hospitals ie.g., Shawir.iganj, thorough inves tigations were conducted, leading to precise diagnoses. Consequently only heart murmurs judged severe enough were included in the study, under a separate category Sever ity and significance of heart murmurs were assessed by consulting the children's subse quent medical records. Although such minor defects as metatarsus varus, caicaneum varus and valgus, metatar sus adductus, and abnormal positioning of fingers or toes were not included m the study, foot anomalies which required either a cast or surgery for correction in the year following birth, were considered defects Comparison communities To assess the importance of the excess of birth defects ;n Shawinigan, three compari son communities were chosen, basec on their similarity to Shawinigan m population size and structure, socioeconomic level, and medical-care facilities (Table 1), In order to take into account the influence of environmental pollution, one town with an aluminum plant but no VCM-emitting plant (Baie-ComeauHauterive) and two towns with neither a VCM nor an aluminum plant (Drummondville and Rimouski) were chosen as control communities. The recourse to referent com munities was necessary because no accurate national or provincial data were available. Data sources - The Quebec Population Registry provided the annual numbers of births and stillbirths in the communities; as the 1979 data were not available, numbers were estimated from the 3 preceding years. The Quebec Ministry of Social Affairs provided a list of hospitals where women residing in these communities gave birth during the study period. The School Board of Shawinigan furnished the ^physcted at r delivif birth drawn ms iist ntered vstem, al hosuirs of . other tnvesorecise : murided m Sever5 were subse- tarsus etatar ing of study, a cast follow- n size ! med: take lental plant aeauher a nondintrol comurate bie. vided nrths were from ustry litals titles The i the BIRTH DEFECTS AND VIV; ,, CHLORIDE school district boundaries. Birth-defect chil dren and controls were identified and data were collected from several medical files m the hospitals (delivery-room daybooks, birthdefect rosters, discharge lists, mothers' and children's medical files, and birth rosters). For two referent communities (Baie-Comeau-Hauterive and Rimouskii our physi cian reviewed the files not only of known malformation cases, but of all newborns, to ensure that all cases had been reported Identification of cases Malformed infants born to mothers who resided in the study communities were iden tified from the birth-defect rosters and the departure lists of the delivery hospitals, A physician reviewed the medical files and de cided whether or not each infant met the definition of a birth-defect child. When m doubt, he referred to consultation reports or specialists' advice. In the case-control study, mothers of all affected infants and matched controls were interviewed at home by two medical students. * Selection, of controls Each control was a live-born infant without congenital malformation whose parents re sided in Shawnnigan and whose birth imme diately followed that of the malformed child. Cases and controls were matched by mater nal age within 2 years, sex of the infant, and place of residence of the mother iwithin the city limits of Shawnnigan). ,, 'z c * J e*> > Is Estimates ofVCM air concentrations Two studies were conducted to assess the VCM concentration in ambient air m Shawumgan (Theriault et al., '81). The first con sisted in actual measurements of VCM on air samples in several locations in town Field sampling was done with Bendix BDX 44 Super Sampler pumps, VCM was absorbed on activated charcoal, and samples were ana lyzed with a Perkin-Elmer model F-42 headspace analyzer gas chromatograph. The desorbent was N,N-dimethylacetamide in water. This first pilot study reached the fol lowing conclusions: VCM air concentration varied from nothing to 45 ppb; during winter, VCM accumulated in the snow in the vicin ity of the plant; VCM concentration differed between indoor and outdoor samples. Considering the high cost of a comprehen sive air-monitoring program and the results of the first study, ambient VCM concentra- CMA 100081 362 G THERIAULT. H ITURRA AND S GINGRaS tion in various locations in Shawinigan was estimated by a consultant firm using a dis persion mode! This model used the PasquiliGifTord equations and allowed the develop ment of isopleths of vinyl chloride concentra tion over Shawinigan. It employed meteoro logical variables (such as wind direction and velocity, rainfall, humiditv, and tempera ture), and topographic variables (including buildings), as well as sucn variables as pro duction, emissions, and plume height. Statistical analysts Chi-squared analyses were used to test dif ferences between groups Degree of signifi cance was based on Bailar and Ederer's C64) "Ratio of Poisson Variable to its Expecta tion." RESULTS Birth defects tn Shawinigan From January 1966 through December 1979. there were 4,534 live births and 33 stillbirths m Shawinigan Of the live infants, 150 had birth defects, and of the stillbirths, nine had birth defects As shown in Table 2, the birth defects reported most frequently were those of the musculoskeletal system, followed by the cardiovascular, central nerv ous, and urogenital systems. The ages of the mothers at delivery did not differ signifi cantly among the various types of birth de fect. The gestation periods were shorter for infants with defects of the central nervous system. The yearly numbers of malformed children per 100 births varied from 1.68 (in 1969) to 6.84 (in 1973), with an overall ratio of 3.48. Detailed analysis of the monthly distribution of birth defects and the distribution by af fected system for the year 1973 showed no single large increase that could account for the high ratio observed that year. Nor did the yearly distribution by system show any particular feature that could account for the annual variation in the overall ratios. Fur thermore, birth-defect ratios did not increase or decrease with time. Shawinigan and the comparison communities As can be seen in Table 3, the observed numbers of malformed children in Shawini gan were higher than would be expected based on the races observed in each compari son community or in all three comparison communities together. The excess occurred  3. N um ber o f m a tfo rm e d c h ttd te n o b se rve d tn S h a w in ig a n c o m p a re d w ith expected n u m b e rs fo r the c o m p a n io n corn m a n t i t r \ i ^ 7 {J) BIRTH EFFECTS AND \ !N'i L CHLORIDE 363 -He -a 5c V-- 1 * * * * ** * 3 5 y C| *NO;r'r'CO,?" |-g 3.11 C' = i/; r: 3 <r: i c*; x^" "4. C > * C +^w ^C * - * C-. * C <'I %c_ Zit sS !ri, -- cr, --* e-; tp -- < w s 8, ill e 2 i l j; _ a*.8a =; uooiSEwumiS" m the central nervous, cardiovascular, 'uro genital, and musculoskeletal systems, and in the eye and ear, and the chest The malformation rates were greater in all years except 1969 and 1972 (Table 4) The number of stillbirths differed only between Snaw'impar. and Drummondville, where they were significantly higher Table 5) The pro portion of malformed children among the stillborn was higher m Shaw-imgan (27,3%) than in the comparison communities (total, 12 47-; Drummondville, 15,3%; Baie-Comeau-Hautenve, 10.07c, Rimouski, 10 27c, chi-square with Yates correction = 4 07, P = 0.04). This is consistent with previous find ings of an excess of birth defects in Shawinigan. Mothers who gave birth to malformed chil dren were significantly younger in Shawinigan than m the comparison communities for all malformations combined and for defects of the CNS, mouth and upper airways, and eye and ear Children in Shawinigan did not differ from those in the comparison commu nities m mean gestational age at birth. Seasonal variation in birth-defect rates Figure'! compares the monthly birthdefect rates m Shawinigan with those for Drummondville and Rimouski. The Shawin igan curve is V-shaped, with the lowest rates m the summer, whereas the curve for the comparison communities is flatter. Seasonal variation in birth-defect rates w'as compared between Shawinigan and the other three communities using Edward's method for testing seasonality of events, as modified by Walter (Walter and Elwood, '75). There was a significant seasonal variation in Shawmigan, with the highest rates in March and the lowest in September; no such variation was observed in the comparison communities. Geographical distribution of birth-defect rates The geographical distribution of birth de fects in Shawinigan with respect to the dis tance from the VC plant was analyzed using school districts as the units; in no school dis trict did the ratio of observed to expected number of birth defects differ significantly from 1. The district in which the plant was located had approximately the expected number of birth defects. Birth-defect rates did not differ between school districts with high and low VCM ex posure, either for all birth defects or for CNS CMA 100083 364 G THERIAULT, H ITURRA. AND S GINGRaS Year 1966 1*467 1965 1969 1970 1971 1972 1973 1974 1975 1976 1977 197S 1979 TABLE 4 Ycarl\ distribution -V malformed children <196$-1979} 5na'*,inigan Rate1 Compandor communities Rate SH-ComDAr-ison communities 16 3 54 13 3 52 S 2 30 6 1 6S 15 4 :n 6 2 06 6 2 19 18 6 r>4 S 2 97 15 4 40 13 3 98 14 4 56 11 3,33 10 3 11 31 I S2 33 1 96 24 I 51 77 1 75 24 ; 66 30 2 05 34 2 -13 44 3 17 4.3 2 SI 5 1 3 10 36 2 20 50 2 76 52 2 88 47 2 69 I 95* 1 80 1 52 0 94 2 S3* 1 01 0 90 2 16" ; 06 1 42 1 61 1 65 1 16 1 16 Total 159 3 48 'Number of malformed children per 100 births 'Pc 0 05 526 2,35 1 48* 95^ Confidence interval U Or 3 52 i 10 96 3 jy. i0 69 3 341 ' i > H 2 16' '155 5 17 i '0 53 1 94' <0 36 2 20* 1 2b 1 65) i0 \b 2 33`U 61 2 49' -04) 2 5 1 i (0 93 2,93) 10 61.2 20) >0 60. 2 26) 11,24 1 75i TABLE 5 lumbers of stillbirths, with and without th defects and num bers expected in Shaunnigan based on rates in tne comparison communities Condition Witn birtn defects Number of stillbirths Without , birth defects Total Total number of binns Observed m Shawinigan Observed in Drummondville Expected based on Drummond ville Observed m Baie-Comeau- Hauienve Expected based on Baie^Comeau-Hautenve Observed m Rimouski Expected oased on Rimouski Expected, based on all comparison communities 9 15 7 98 7 4 24 5 3 65* 5.51 24 S3 44.16** 63 38.18* 44 32 12 38 78 33 98 52 14* * 70 42 42 49 35 77 44.29 456 t 8584 -- 7535 -- 6257 -- *P < 0.05 **P <001 defects (Table 6). Likewise, school districts adjacent to the plant did not differ from the other school districts in numbers of birth de fects (total or CNS), nor did districts differ within and beyond a 1-mile radius of the VCM plant. Case-control study For the period January 1973 to December 1979, sixty-eight cases of birth defects were identified in Shawinigan and matched with controls (42 male and 26 female pairs). Five of the cases were stillborn; all of the controls were born alive. There was no significant difference between cases and controls in number of weeks' gestation at delivery. The frequencies of previous birth defects in the families of cases and controls did not differ significantly, nor was there a significant dif ference between case and control mothers in number of previous pregnancies. Mothers of malformed infants reported no excess of diseases during pregnancy; how ever, the following diseases suspected to bear a high risk of birth defect were reported by cases only: rubella, hydramnios, epilepsy, nonpsychotic mental disorders, and psy chosis (Table 7). Among the mothers of mal formed infants, five reported previous occurrences of epilepsy, mental disorders, or both. Their children showed the following birth defects: two cases of hypospadias, one of congenital cataract, one of Down's syn drome, and one interventricular septal de 1 ! i j 1 : " c * - c c 1 c w c c L < TABLES Birtns vvan > Births vvitno Births with ' Births wuho Total births 0 80, P , 0 10 P : fect. Two reported hi their pregn There w. tween case previous ai previous st ers and nor one previoi two groups ence betwe er's age. 1 exposed to of pregnan exposed di nancy; exp BIRTH DEFECTS AND VINYL, CHLORIDE 365 ,, TABLE 6 Comparison of total birth defects and CVS earth defects- bctmeeti school districts, u ith high and hue atmospheric 'vnv/ cnlnndc concentration School districts w ith high VCM levels School district* with lo^ VCM levels Total Birthf mm defects Births ^ ithout defects Births w'ltft CNS defects Births runout CNS defects 87 2.285 16 2.356 "0 2.125 13 2 1S2 157 4,410 29 4.538 Total births = 0 80 P > 0 35 :it - 0 10 P ? 0 70 2.372 2.195 4,567 feet. Two mothers of defective infants reported having used the drug LSD before their pregnancies. There was no significant difference be tween case and control mothers in number of previous abortions reported. There was-one previous stillbirth among the control moth ers and none for the case mothers, there was one previous malformed child in each of the two groups. There was no significant differ ence between cases and controls in the fath er's age. No mother (case or control) was exposed to x-rays during the first trimester of pregnancy, and only one case mother was exposed during the second third of preg nancy, exposure during the third trimester did not differ significantly between case and control mothers. Table 8 summarizes the mothers' occupa tions before and during their pregnancies. None of the women was ever exposed to VCM at work before or during pregnancy. The working experiences of the case and control mothers before and during pregnancy did not differ, nor did their smoking habits or alcohol consumption. There was no significant differ ence between cases and controls in the fath er's occupational exposure to chemicals, and no fathers were ever exposed to vinyl chlo ride (Table 9). The distance between each mother's place of residence during the first trimester of pregnancy and the VCM plant CMA 100085 366 G THERIAULT, H ITURRa, AND S GINGRaS TABLE 7 Distribution of casts and controls bv diseases of the mothers during pregnancy^ Disease None Bleeding at the beginning of the pregnanc> Hypertension Rubella Luhiasis of the gall bladder Renal calculus Psvchosis Premature labor Phlebitis Hvdrammos Obesity Placenta praevia Epilepsy Nonpsvchotic mental disorders Wound Infectious or parasitic disease Other diseases of the mother Cases 44 6 3 1 1 1 2 1 2 0 0 1 2 0 4 3 Total for diseases 24 Unknown 0 Total 'Partitioning diseases vs no disease, 0,54, P > 0 45 68 * Controls 48 3 1 0 0 I 0 3 1 1 6 2 20 0 68 Mother's occupation TABLE s Distribution of cosct ond controls by mother's occupation Before pregnancy Cases During pregnancy Control Before pregnancy During pregnanc> Work outside home without exposure to chemicals 41 22 42 20 Work in VCM industry 0 0 0 0 Work outside home with exposure to chemicaJs 2 1 2 1 Stav at home 26 45 24 47 Total 68 68 68 68 'Partitioning siav at home vs work outside home before pregnancy r? * 0 03. P > 0 85, pinioning stay at home vs work outside home during pregnancy, if * 0 13; F > 0,71 TABLE 9. Distribution of cases and controls by father's occupation1 Father's occupation Ever worked m vinyl chloride industry Ever worked in infantries with exposure to chemical* Never worked in with exposure to chiWlfctli Unknown Total Cases 0 20 43 5 68 lx\ 0 73; P > 0.39 Controls 0 25 39 4 68 was measi the city, tj between tr VCM pian Excess c the vicinit plants am these birt chloride rr first descr (Infante, tween 19' birth to m the index of the th: mostly the per alimt clubfoot In anal Center fo birth deft et al. ('75 for one c plant, bu' aly and Painesvil study, no fected mi the two Pamesf.nl had, nont within tv more, a s trol moth of the PV Anothe sized fet women plants. A were gre. were occ among cr methodo In a re1 tries, Ma evidence generate heavily . be regar and ter availabl Downs t methods conclude cated as BiHTh DEFECTS AND ^ INYL CHLORIDE 367 was measured to * 100 m. using a map of 'the city; there was no significant difference between the two groups in distance from the VCM plant. DISCUSSION Previous studies Excess of birth defects in communities in the vicinity of vinyl chloride polymerization plants and the possible association between these birth defects and emissions of vinyl chloride monomer into the atmosphere were first described for three Ohio communities (Infante. '76). The excess was constant be tween 1970 and 1973. Mothers who gave birth to malformed children were younger in the index communities than in the balance of the three counties. The excess involved mostly the central nervous system (CNS), up per alimentary tract, genital organs, and clubfoot. In analyzing data collected through the Center for Disease Control's hospital-based birth defects monitoring program, Edmonds et al. ('75) found no increase m CNS defects for one city in Pennsylvania with a PVC plant, but confirmed the excess of anencephaly and spina bifida previously noted in Painesville, Ohio. However, in a case-control study, none of the interviewed parents of af fected infants had ever worked at either of the two PVC polymerization plants in Painesville, whereas two fathers of controls had. none of the parents m either group lived within two miles of either plant. Further more, a significantly larger proportion of con trol mothers worked within a 10-mile radius of the PVC plant. Another study (Infante et al., '76) empha sized fetal losses and miscarriages among women whose husbands worked at PVC plants. Although it concluded that fetal losses were greater among women whose husbands were occupationally exposed to VCM than among controls, this study was criticized for methodological weaknesses. In a report to the Society of Plastics Indus tries, MacMahon C77) concluded that the only evidence so far was to the effect that VCM generates chromosome breakages in workers heavily exposed to it, but that VCM should be regarded as a potential human mutagen and teratogen until better evidence was available. In another report to the Society, Downs et al. ('77) criticized the statistical methods used in vinyl chloride studies and concluded that the existing evidence indi cated associations between (I) VCM exposure and lymphocyte aberrations in workers and (21 VCM exposure of workers and fetal was tage among the workers' wives. Those au thors found no evidence for an association between VCM exposure and birth defects, but cautioned that such associations may not nave been detectable by methods available at the time and that monitoring should con tinue. A high incidence of CNS birth defects was found in Kanawha County, West Virginia, from 1970 to 1974 (Edmonds et al , '78). As there is a polyvinyl chloride plant in Kana wha County, a possible relationship between CNS defects and parental exposure to VCM was investigated In a case-control study, no relationship was found between birth defects and parental occupation. Although the pat tern of case-family residences tended to differ from that of controls, it did not correlate with local wind direction and air pollution. The present study Some descriptive data from this study raised the hypothesis of an association be tween VCM in the air and birth defects in the exposed community, but as a whole, within the sample size available, such an association could not be substantiated Birthdefect rates in Shawinigan were high for the 15-year period, and women who gave birth to malformed children were, on average, younger m Shawinigan than in the compari son communities. These results are consist ent with previous findings for three Ohio towns with PVC plants (Infante. '76). The seasonal variation in birth-defect rates corresponded to variation in atmospheric VCM concentration. No VCM was found in air samples during December, January, and February, It is believed that during these months, VCM tends to accumulate near the plant as a liquid, because the outdoor tem perature is below its liquefaction point. This VCM would be released into the air in the spring. Birth-defect rates were lowest in Sep tember, which is 8 months after midwinter, corresponding to the time between the first third of pregnancy and delivery. These obser vations favor an association between VCM concentration in the air and birth defects in the community. On the other hand, several observations of the present study tend to argue against any association between VCM concentration in the air and birth defects in the community. The geographical distribution of birth defects in Shawinigan was not correlated with esti- 36S G THERIAULT. H ITL'RRA. AND S GINCRaS mates of VCM concentrations in the commu nity Malformation rates were not relatively high either near the plant or in the area v. here VCM concentrations were estimated to be highest, and the school district with the highest oirth-aefect rate was far from the plant. There was no difference m occupational or residential History between the parents who gave birth to malformed infants and the con trols. Both gToups resided at similar dis tances from the plant, and none of the parents had worked at the plant. Further more. all types of birth defects were in excess m Shawmigan These results agree with those for the three Ohio cities; however, agents known to be teratogenic in humans and experimental animals have very' specific effects, and it seems unlikely that any agent would produce the variety of malformations found m excess m Shawmigan. Possible explanations of the results as artifactual are not convincing It is unlikely that Shawimgan's physicians were more in clined to diagnose birth defects than were physicians m the comparison communities since they did not know about such an asso ciation when the diagnoses were made (ex cept m 1979, where no difference was seen from previous years). Birth defects were in cluded m this study on the basis of their obviousness, and the birth-defect rates were the same m the three comparison communi ties, Furthermore, for severe birth defects like those of the CNS, which cannot be mis diagnosed, rates were higher in Shawmigan than in any of the comparison communities. The method by which the data were collected was the same everywhere. It is very unlikely that a bias m the quality of the information from the archives of the regional hospitals could have influenced the results The possibility remains that pregnant mothers residing outside Shawinigan, who were at nsk of having a malformed child, migrated to the city for delivery, thereby in creasing the birth-defect rate for that town. In the case-control study, six mothers (6.7%) were rejected because they had moved to the city of Shawinigan attar the first third of pregnancy, and four more cases were untraceable. Thus, as many as 11% of the birthdefect cases observed in Shawinigan might actually have come from elsewhere, reducing the number of observed cases to 142. How ever, birth-defect rates would still be signifi cantly higher than in the comparison communities, leading us to believe that the excess noted in Shawmigan was real Animal studies have shown that exposure to high levels of VCM during pregnancy re sulted more often in high rates of fetal loss and miscarriage than in birth defects (Ungvarv et al . '7S, John et a!., '77) How ever, stillbirth rates were no higher in Shaw inigan than m the comparison communities, and in the case-control study, abortion rates reported were not higher for case than for control mothers. Several industries m Shawmigan emit pol lutants into the atmosphere and several of the pollutants may interact to generate po tent mutagenic or teratogenic chemicals in the community. A thorough analysis of such an environment and its association with the excess of birth defects was beyond the scope of the present study. However, in the casecontrol study, there was no difference be tween the numbers of case and control par ents w-ho worked at the aluminum plant, and the comparison community with an alumi num electrolysis plant (Baie-Comeau-Hautenve' had lower bneth-defect rates than did Shawmigan. Tfius, the aluminum industry probably was not responsible for the excess of birth defects in Shawmigan. Among risk factors (other than occupa tional or environmental exposure to a pollu tant) known to be associated with birth defects, epilepsy and mental disorders before and during pregnancy and the use of the drug LSD before pregnancy were reported more frequently by mothers of malformed children than by control mothers Drugs pre scribed to control epilepsy have been re ported to be associated with birth defects (Smithells, '76) and could account for a few birth defects observed m Shawinigan, as could LSD. These differences, however, could be due to a recall bias whereby the mothers of malformed infants were more aware of exposure to possible etiologic agents during their pregnancy than the mothers of normal children. In the present study, we were unable to substantiate the presence of an association between VCM in the air and birth defects in the exposed community. In view of the high numbers of angiosarcoma of the liver ob served among production workers and the possible large emissions of VCM, it can mean that such an association does not exist. It can also be the result of a small number of obser vations. The probability of finding an excess of birth def trices twice ; ones was 80 been 99^r ha nign This resea of contract L of Social ar University, En\ n onmen tent has bee report ptub 1; Printing Off The autho Kempf. Drs and -Jeff Be; tection Age and assisiar Bailar. J C . an the ratio of a metrics, 20 6. Bartsch. H a carcinogenic 32 93-113, Creech. J L , Jr of liver in t: Occup Med Delorme. F , a: sarcoma of tr Med . 20 338 Downs T.D . R Laoanhe (19 wastage A c Plastics Inau Drevon, C . an chloride, vin Chinese ham Ducatman, A. Vinyl chiorit erratipns, M1 - Edmonas, L.D ital malfoim Edmonds. L.D James (1976 formations a community ; Fleig. I., and chloride J C F unes-Craviot berg, A.I N Chromosomi chloride. Lai Green, T., and chloride wit! act.. 22:211- Hansteen. I -L Heldaas (19' genetic folio Infante, P.f, weiler, and nde. Lancet Infante, ?J. i tire re* OSS .'CtS OW T.W'ses, :es for JOjof po rn jch :ne ipe .sebe;arnd ni- 1U- jid iry rSS ia- ne ed ed re_e::s w as id rs of al 10 m in :h b\e ;n m Tss 3IRTH DEFECTS AND vinyl CHLORIDE 369 of birth defects in the highly exposed dis tricts twice as high as in the poorly exposed ones was 807c. This probability would have been 997^ had the excess been three times as high ACKNOWLEDGMENTS This research was conducted in fulfillment of contract No 68-02-2780 by the Department of Social and Preventive Medicine, Laval University, under the sponsorship of tne U S, Environmental Protection Agency its con tent lias been made the obiect of a complete report published by the U.S, Government Printing Office: 1981-757-0127327, The authors are most grateful to M James Kempf. Drs David Mage. Gregg Wilkinson and Jeff Beaubier, U.S Environmental Pro tection Agency for their valuable guidance and assistance. LITERATURE CITED Baiiar, J C , and F Ederer 11964> Significance factors for tne ratio of a Poisson variable to its expectation Bio metrics 20639-643 Barxseh H, and R, Mont^sano (1975) Mutagenic and carcinogenic effects of vm\l chloride Mutation Res, 32-93-113 Creech J.L. Jr . and M N Johnson >19741 Angiosarcoma of liver in the manufacture of polyvinyl chloride J Occup Med , 16 150-151 Delorme, F , and Q Theriault (1976) Ten cases of angio sarcoma of tne liver in Shawmigan, Quebec J Occup Med 20338-340, Downs, T D , R A Stallones. R F Frankowski, and D R Labarthe .19771 Vinyl chloride, birth defects, and fetal wastage A critical review Prepared for the Society of Plastics Industries, Inc , Sept 16 Drevon, C, and T Kutoki (1979) Mutagenicity of vinyl chloride, vmylidene chloride and chloroprene in V79 Chinese hamster cells, Mutation Res , 67 73-182 Ducatman, A , K Hirschhom, and I.J Sehkoff (1975) Vinyl chloride exposure and human chromosome ab errations, Mutation Res., 31 163-168 Edmonds LD.H Falk, and J.E. Nisstm (1975) Congen ital malformations and vinyl chlonde Lancet, 2 1098 Edmonds, L,D,, C,E Anderson, J W, Flytit, Jr . and L.M. James (1978) Congenital central nervous system mal formations and vinyl chlonde monomer exposure, A community study, Teratology, 17:137-142, Fleig, L. and A.M. Thiess (1978) Mutagenicity of vinyl chloride J Occup. Med., 20 557-561. Funes-Cravioto, F. B. Lambert. J, Lindate, L Ehrenberg, A.I. Natai^am and S. Ostercnan-Gilkar (1975) Chromosome aberrations in workers exposed to vinyl chlonde. Lancet, J 459 Green, T., and D-E. Hathway (1978) Interactions of vinyl chlonde with rat liver DNA in vivo. Chem. Biol. Inter act., 22:211-294. Hansteen, I.-L., L Hillestad, E. Thiis-Evensen, and S.S Heldaas (1978) Effects of vinyl chloride in man, a cyto genetic follow-up study. Mutation Res., 51:271-278 Infante, PF. J.K Wagoner, A.J, McMichael, R.J. Waxweiler, and H Falk (1976) Genetic naks of vinyl chlo ride. Lancet, 1 734-735. Infante, PF (1976) Oncogenic and mutagenic risks in. communities with polwmvl chloride production facili ties Ann NY Acad Sci.2"My-57 Jonn J A,, F A Smith, B K J Leone and B A Scftwetz (1977' The effects of maiernaliv mnaiec vmvl chloride on embryonai and feu! development m mice rats, and rabbis Toxicol Apo! Pharmacol . 39 497-513 Kucc'-ova. M Z Po.iNKova and J Batora 1979j Com paranve evaluation of the frequent" of enromo^ornn1 aberration^ and the SCE number* ;n peripheral !vm phoevtes of corners occupational!:* exposed to '..nv cmoridc monomer Mutation Res 67 97-100 Leek, 1 (197^t The etiology of human malformations !nicnts from ppioemioloin, Terainloir* 5 303-3)4 Leonard. A G Decal ED Leonard M J Lolevrc LJ Decuvper and C Nicaisc '1977' Cytogenetic im^-ti gallons on Jvmphncvte^ from worker? exposed to turn! chloride J Tomcoi Environ Hlth , 2 1135-1141 Loprieno, N R Barale.S Baruncolli.C Bauer. G Bron zetti. A Cammellini. G Cerdignani, C Corsi, G Ger vasi. C Leponm. R Nien.AM Rossi. G Streiti and G Turchi 11976' Evaluation of the genetic effects mduced by vmv! chlonde monomer (V'CM1 under mam maiian metabolic activation Studies in vitro and in vivo Mutation Res . 40 85-95 MacManon, B (1977) Vin> i Chloride and Human Repro duction Manuscript prepared for the Society of Plas tics Industries. Inc., Aug II Maqnu^son. J , and C Runic: i 1976> Mutagenic effects of \ inx 1 chlonde in Drosophila meianocaster Mutauon Res 38 115 'abstract1 Makk, L, F Deiorme. JL Creech, L,L Ocacn. EH Fade'' C L Songster J Clanton, M N Jonnson and \\ MChristopnerson 11976'Clinical and morpnotopie featuies of heoatic angiosarcoma m vm\, cnlonde workers Cancer 37 149-163 Maltom, C . and G Lefemine (1975^ Carcinogenicity bioassays of vinvi chionde Current results Ann. N Y Acad So , 246 195-218 Maltom, C., and G Lefemine (1974) Carcinoeemcitv bioassays of vmvl chlonde Researcn plans and ear.} results Environ Res., 7.387-405 Monson R R. J M, Peters, and M N, Johnson 11974 j Pro portional mortality among vinyl chlonde workers Lancet. 2 397-398 Mynanthopoulos. N.C and C S Chung (1974) Congeni tal malformations \n singletons Epidemiologic survev Birth Defects, KXmi-58 Rannug, U . A, Johansson, 0 Ramel, and C A Wachtmeister (1974) The mutagemcitv of vinyl chlonde after metabolic activation Ambio, 3 194-197 Smithells, RW (1976) Environmental teratogens of man Br, Med Bull.. 32-27-33 Thenault, GP, H. hurra, and S. Gtngras (1981) Associ ation between btnh defects and exposure to ambient vinyl chloride U.S. Environ Protect Agency Report No 600-1-81-057, Research Triangle Park, North Caro lina 27711. Thomas. L,B,, and H Popper (1975) Pathology of angio sarcoma of the liver among vinyl chloride-polyvinyl chlonde workers, Ann. N.Y. Acadi Sci., 246.26S-277 Ungvary, G,, A. Hudak. E, Tatrai, M Lorincz, and G Folly (1978) Effects of vinyl chlonde exposure alone and in combination with trypan blue applied system atically dunng all thirds of pregnancy on the fetuses ofCTY rats. Toxicology. 11 '45-54 Varnio. H. (1978) Vinyl chlonde and vinyl benzene (Sty rene)--metabolism, mutagenicity and carcinogenicity Chem Biol. Interact., 22111-124. Viola, F.L., A Bigotti, and A, Caputo (1971) Oncogenic response of rat skin, lungs, and bones to vinyl chlonde. Cancer Res., 31:516-522. CMA 100089 I 370 G THERIAULT, H ITURRA. AND S GINGRAS Waiter, S C , and J M Elwood (1975j A test for seasonal (tv of events with a variable population at nsa, Br J Prevent Soc Mod 29 18-21 Wajweuer, RJ, W Stronger, J,K Wagoner, J Jones. H Falk, and C Carter 11976' Neoplastic risk among ^orsers exposed to vinyl chloride Ann NY Acad So 271,40-48 Normal ar Fetus Stu Examinati ABSTr aminat fetus: p obtains hyaroc The introdu carnivore, inti togenesis as acommonly use morphs, is an the several adt '77! in using t under laborati can be accura Ferrets, ilk seasonal bree the breeding March to Aug side the breec mals to artifi processes mvc in the ferret Methods of obt are described 1 Our methoc adult male an. condition in a of artificial lig they are reaui they are trans; (14 hours of ar weeks they g' by the conditu A few male ; that a situati are available is not a comp: the reader sh Gulamhusein teratogenic w Estrus is ch ing of the vul ter mating ar the beginnin; $ 1983 ALAN i CMA 100090