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V<L- li-a/u TERATOLOGY 27: 359-370 <1983) Evaluation of the Association Between Birth Defects and Exposure to Ambient Vinvl Chloride GILLES THfiRIAULT, HILDA ITURRA and SUZANNE GINGRAS Deportment ofSocial and Preventive Medicine* Faculty of Medicine* Lovoi Univemty; Ste-Foyt Quebec, Canada G1K 7P4 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 polymerisation plant in 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 in birth defects involved most organ systems, and variation in birth-defect rates among school districts could not be accounted for by estimates of VCM in the atmosphere. 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 carcino genic in animals (Viola et aL, '71; Maltoni and Lefemine, '74,75) and man (Creech and Johnson, 74; Thomas and Popper, 75; Makk et al., 76; Delorme and ThOriault, 78; Monson et al., 74; Waxweiler et aL, 76). It is mutagenic in man: Chromosome breaks have been observed in lymphocytes of workers ex posed to VCM (Funes-Cravioto et ah, 75; Ducatman et aL, 75; Fleig and Thieas, 78; Ltonard et al., 77; Hansteen et al., 78; Kucerova et ah, 79), in microbial tests, in Dro sophila, in yeast, and in mammalian cells (Drevon and Kuroki, 79; Bartsch and Montesano, 75; Loprieno et aL, 76; Magnusson and Ramel, 76). VCM generates mutations primarily through one of its metabolites, chloroethylene oxide, and with the involve ment of Uver microsomal enzymes (Bartsch and Montesano, 75; Vainio, 78; Rannug et ai, 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 re mains 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 amniotic 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 teratogen icity 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 - 13*C. It is processed Rm*4 April S. 1982; accepted December 11982. AOnrn reprint rwiunli u Ciltai P. Theriault, Inititutu of Occupational Health and Safety. McGill UniTornty, 1130 Pina AvanuaWaat. Montreal. Quebec HJA1A3. 1983 ALAN R. LISS, INC. 360 C. THfiRlAULT, 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 Shawinigan (population 27,000), a vinyl chloride polymerization plant has been in op eration since 1943. The plant, which employs about 250 workers, currently 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, Shawinigan 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 Shawinigan 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 in 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 during 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 study was to a shorter period (January 1,1973, to December 31, 1979) because it 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 ofa birth defect A birth defect was defined as a gross phys ical anomaly present at birth or detected at the hospital during the first days after deliv ery (within the first 4-6 days). A list of birth defects to be included in the study was drawn beforehand and only those that fit this list were retained. Two major difficulties were encountered. In birth defects of the cardiovascular system, it soon became apparent that in several hos pitals, no diagnoses other than murmurs of the heart were reported, whereas in other hospitals (e.g., Shawinigan), thorough inves tigations were conducted, leading to precise diagnoses. Consequently only heart mur murs 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, calcaneum varus and valgus, metatar sus adductus, and abnormal positioning of fingers or toes were not included in the study, foot anomalies which required either a cast or surgery for correction in the year follow ing birth, were considered defects. Comparison communities To assess the importance of the excess of birth defects in Shawinigan, three compari son communities were chosen, based on their similarity to Shawinigan in population size and structure, socioeconomic level, and med ical-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 -s physcted at r delivof birth ; drawn his list ntered. system, al hosnurs of 1 other i invesprecise : murided in Severs were subse- itarsus 2tatar ing of study, a cast follow- ess of nparii their n size 1 med> take >ental plant leauher a nondmtrol comurate Die. vided lirths were 1 from listry >itals lities The 1 the 1 BIRTH DEFECTS AND VINYL CHLORIDE 361 school district boundaries. Birth-defect chil dren and controls were identified and data were collected from several medical files in' 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 Rimouski) 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 ofcases 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 in 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 ofcontrols Each control was a live-bora infant without congenital malformation whose parents re sided in Shawinigan 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 (within the city limits of Shawinigan). Estimates ofVCM air concentrations Two studies were conducted to assess the VCM concentration in ambient air in Sha winigan (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- 362 G. THERIAULT, H. ITURRA, AND S. GINGRAS tion in various locations in Shawinigan was estimated by a consultant firm using a dis persion model. This model used the PasquillGifford 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, humidity, and tempera ture), and topographic variables (including buildings), as well as such variables as pro duction, emissions, and plume height Statistical analysis Chi-squared analyses were used to test dif ferences between groups. Degree of signifi cance was based on Bailar and Ederer's ('64) "Ratio of Poisson Variable to its Expecta tion." RESULTS Birth defects in Shawinigan From January 1966 through December 1979, there were 4,534 live births and 33 stillbirths in Shawinigan. Of the live infants, 150 had birth defects, and of the stillbirths, nine bad 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. 1116 ages of tire 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 rates observed in each compari son community or in all three comparison communities together. The excess occurred OCO0(,:"OO'IH C*- CM C f- O -- T* -- o N Z 2 CM C-i -- 111 *4' f-s 1s |E 2 s :|!* 1 I41 E ill !i BIRTH DEFECTS AND VINYL CHLORIDE 363 nf n ^> 4c .C2Q2(-i a a fa C h |i u3i| e? te u* ^ ^ me r- ci \Crtdrt6n loo c--b r2i r2i 0f)iQ!D*3nr>Ssp!o* |1 rs*> -o e > a o'? ill aisofA(lbjTd6iao^ct^^iMvrtotpOinatAnt oc3* uJ t s== J" Srto^*^-Oto?^^ C9 Eg iOoi | Miillsl*l1s 82 H* i- in 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 Shawinigan and Drummondville, where they were significantly higher (Table 5). The pro portion of malformed children among the stillborn was higher in Shawinigan (27.3%) than in the comparison communities (total, 12.4%; Drummondville, 15.3%; Baie-Comeau-Hauterive, 10.0%; Rimouski, 10.2%; chi-square with Yates correction * 4.07, P = 0.04). This is consistent with previous find ings of an excess of birth defects in Shawini gan. Mothers who gave birth to malformed chil dren were significantly younger in Shawini gan than in 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 in mean gestational age at birth. Seasonal variation in birth-defect rates Figure 1 compares the monthly birthdefect rates in Shawinigan with those for Drummondville and Rimouski The Shawin igan curve is V-shaped, with the lowest rates in the summer, whereas the curve for the comparison communities is flatter. Seasonal variation in birth-defect rates was 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 Shawini gan, with the highest rates in March and the lowest in September no such variation was observed in the comparison communities. Geographical distribution ofbirth-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 L 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 I II 364 G. THERIAULT, H. ITURRA. AND S. GINGRAS TABLE 4. Yearly distribution nf malformed children 0966-1979) Year 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 Shawinigan 16 13 8 6 15 6 6 18 8 15 13 14 11 10 Rate1 3.54 3.52 2.30 1.68 4 70 2.08 2.19 6.84 2.97 4.40 3.98 4.56 3.33 3.11 Comparison communities 31 33 24 27 24 30 34 44 43 51 36 50 52 47 Rate 1.82 1.96 1.51 1.78 1.66 2 05 2.43 3.17 2.81 3.10 2.20 2.76 2.88 2.69 SH/Companson communities 1.95* 1.80 1.52 0.94 2.83* 1.01 0.90 2.16* 1.06 1.42 1.81 1.65 1.16 1.16 Total 159 3.48 'Number of malformed children per 100 births. `P < 0.05. 526 2.35 1.48* 95*# Confidence interval 11.08. 3.52) (0.96. 3.39) (0.69. 3.34) (0.41.2.18) (1.55.5.17) (0.53, 1.94) (0.36. 2.20) (1.28.3 65) (0,48, 2.331 (0.81.2.49) (0.93.3.51) (0.93. 2.93) (0.61. 2.20) 10.60, 2.26) (1.24. 1.75) * i >t c L ; - < Lc c c c c L TABLE 5, Numberi ofstillbirths, with and without birth defects, and number* expected in Shawinigan based on rate* m the comparison communities ____________ Condition Number of stillbirths With birth detects Without birth defects Total Total number of births Obaerved in Shawinigan Observed in Dnimmondville Expected baaed on Dnnnmondville Observed in Baie-Comeau- Hauterive Expected baaed on Baie-Comeau-Hauterive Obaerved in Rimouaki Expected baaed on Rimouaki Expected baaed on all comparison communities P < 0.06. "P < O.0L 9 15 7.98 7 4.24 5 3.65* 5.51 24 83 44.16** 63 38.18* 44 32.12 38.78 33 98 52.14** 70 42.42 49 35.77 44 29 4567 85_84 7535 62_57 -- 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. Cat+control study Far 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 bora 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 TABLE 6 Births with t Births witho Births with ( Births witho Total birth* '! " 0.80; P: Si 010;A: fect Two reported ha their pregn. There wa tween case previous ab previous sti ers and nor one previot two groups ence betwei er's age. h exposed to of pregnane nancy; eip> BIRTH DEFECTS AND VINYL CHLORIDE 365 TABLE 6. Comparison oftotal birth defects1 and CNS birth defects1 between school districts with high and lout atmospheric vinyl chlqrtde concentration Births with defects Births without defsets Births with CNS defects Births without CNS defects School districts with high VCM levels 87 2.289 16 2,356 School district* with tow VCM levels 70 2,125 13 2.182 Total 157 4,410 29 4,538 Total births 0.80; P > 0.35. - 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 repotted. 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 1. 366 G. THERIAULT, H. ITURRA. AND S. GINGRAS TABLE 7. Distribution ofcasts and controls by diseases of the mothers during pregnancy1 Disense Cases None Bleeding at the beginning oT the pregnancy Hypertension Rubella Lithiasis of the gall bladder Renal calculua Psychosif Premature labor Phlebitia Hydramnioe Obesity Placenta pratvia Epilepsy Nonpsychotie mental diaordera Wound Infectioua or paraaitic disease Other diseases of ths mothsr 44 6 3 1 1 1 1 2 1 2 0 0 1 2 0 4 3 Tbtal for diseases 2d Unknown 0 Total 'Partitioning dniMM v no diMM. xl - 0.34; P > 0.45. 68 Controls 48 3 6 0 1 0 0 1 0 0 3 l 0 0 1 6 2 20 0 68 TABLE B. Distribution ofcases and controls by mother's occupation1 Mother** occupation Cases Before pregnancy During pregnancy Control Before pregnancy During pregnancy Work outside home without exposure to chemicals 41 22 42 20 Work in VCM industry 0 0 0 0 Work outside home with expoeure to chemicals 2 1 2 1 Stay at homa 25 45 24 47 Total 68 68 68 68 'Pnrtitioninf May at ham* va. work ouUkW how kalian stagnancy; xf - 0.03; P > 0.85; pnitwing My at bama va. work setaida homo during pmgnancy; xf - 0.13; P > 0.71. TABLE 9. Distribution ofcasts and controls by father's occupation1 Father's occupation Casas Ever worked in vinyl chloride industry Ever worked in industries with exposure to chemicals Never worked in industries with Unknown Tbtal 0 20 43 5 68 `xf - 0.73; P > 0-3. Controls 0 25 39 4 68 was mease the city; tl between th VCM plant Excess o: the vicinit; plants and these birti chloride m first descr (Infante, tween 197 birth to mi the index of the thr mostly the per alime clubfoot. In anal} Center for birth defec et al. (75) for one ci plant, but aly and t Painesvill study, nor fected inft the two *, Painesvill had; none within tw more, asif trol mothf of the PV( Another sized feu women * plants. Al were grea were occu among ecu methodolc In a rep " tries, Mac evidence ; generates heavily e be regard and tera available Downs ei methods concludec catedasac Controls 48 3 6 0 1 0 0 1 0 0 3 1 0 0 1 6 2 20 0 68 iring mancy 20 0 1 47 58 i f r ! BIRTH DEFECTS AND VINYL 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 between 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 in 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 in either group lived within two miles of either plant. Further more, a significantly larger proportion ofcon trol mothers worked within a 10-mile radius of the PVC plant Another stvdy (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 ("77) 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 (1) VCM exposure and lymphocyte aberrations in workers and (2) 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 have 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 ah association could not be substantiated. Birthdefect rates in Shawinigan were high for tire 15-year period, and women who gave birth to malformed children were, on average, younger in 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 ofbirth defects in Shawinigan was not correlated with esti- 363 G. THERIAULT. H. ITURRA. AND S. GINGRAS mates of VCM concentrations in the commu nity. Malformation rates were not relatively high either near the plant or in the area where VCM concentrations were estimated to be highest, and the school district with the highest birth-defect rate was far from the plant. There was no difference in occupational or residential history between the parents who gave birth to malformed infants and the con trols. Both groups 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 in Shawinigan. 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 in excess in Shawinigan. Possible explanations of the results as artifactual are not convincing. It is unlikely that Shawinigan's physicians were more in clined to diagnose birth defects than were physicians in the comparison communities since they did not know about such an asso ciation when the diagnoses were made (ex cept in 1979, where no difference was seen from previous years). Birth defects were in cluded in this study on the basis of their obviousness, and the birth-defect rates were the same in the three comparison communi ties. Furthermore, for severe birth defects like those of the CNS, which cannot be mis diagnosed, rates were higher in Shawinigan 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 in 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 risk 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 after the first third of pregnancy, and four more cases were untraceable. Thus, as many as 11% ofthe 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 Shawinigan 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 (Ungvary et al., '78; John et ah, '77). How ever, stillbirth rates were no higher in Shaw inigan than in the comparison communities, and in the case-control study, abortion rates reported were not higher for case than for control mothers. Several industries in Shawinigan 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 who worked at the aluminum plant, and the comparison community with an alumi num electrolysis plant (Baie-Comeau-Hauterive) had lower birth-defect rates than did Shawinigan. Thus, the aluminum industry probably was not responsible for the excess of birth defects in Shawinigan. 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 in 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 poesible etiologie 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 expoeed community. In view of the high numbers of angiosarcoma of the liver ob served among production workers and the possible large emissions ofVCM, 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 deft tricts twice a ones was 80* been 99% ha< high. This resear of contract N of Social an University, u Environment tent has beet report pub] it Printing OfTi The author Kempf, Drs and Jeff Bea tection Agee and assistant Bailar, J.C.. and the ratio of a metric*. 30:63 BarUch. H., an carcinogenic < 32.-93-113. Creech. J-L-. Jrof liver in thi Occup. Med., i Delorme. F., am sarcoma of tht Med.. 20.-338- Downa. T.D.. RLabarthe <19? wattage: A cr Plaetice Indus Drevon, C-, and chloride, viny Chinese bama Ducatman, A., Vinyl chloridi trrations- Mtr - Edmond*. 1~D.. ital malforma Edmonda, L.D., James (1978) formstion* Sr community tt. Fleig. I- nd A chloride. J. Oc Funes-Crsviotc berg, A.l. Ns Chramoeome chloride. Lane Green, T-, *nd I chloride with act.. 22.211-2 Hansteen, L-L, Heldaae (1978 genetic follow Infanta. P-F-, J. weiler. and H ride. Lancet,. Infante, P-F- (1 I the ure re loss ects owa\vies, ites for pol1 of po; in uch the ope lse- be>arnd tii- 1U- iid try ss salu- th >re he ed ed re ve rts !W as Id rs of BIRTH DEFECTS AND VINYL CHLORIDE 369 of birth defects in the highly exposed dis tricts twice as high as in the poorly exposed ones was 80%. This probability would have been 99% 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 the U.S. Environmental Protection Agency. Its con tent has been made the object of a complete report published by the U.S. Government Printing Office: 1981-757-012/7327. 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 Bailar. J.C., and F. Ederer (1964) Significant* factor* for th* ratio of a Poiaaon variable to ita expectation. Bio metrics. 20-639-643. BartSch, H., and R, Montesano (1975) Mutagenic and carcinogenic effects of vinyl chloride. Mutation Re*., 32.-93-113. Creech, Ji., Jr., and M.N. Johnson (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med., 16.-150-15L Delorme, F., and G. Thfriault (1978) Ten cases of angio sarcoma of th* liver in Shawinigan, Quebec. J. Occup. Med.. 20:338-340. Downs. T.D., R.A. Stallones, R-F. Frankowaki, and DJL Laberth* (1977) Vinyl chloride, birth defects, and fetal wastage: A critical review. Prepared for the Society of Plastic* Industrie*. Inc., Sept. 16. Drevon, C,, and T. Kuroki (1979) Mutagenicity of vinyl chloride, vinyliden* chloride and chloropren* in V79 Chines* hamster cells. Mutation Re*., 67.-73-182. Questman. A., K. Hinchhorn. and LJ. Selikoff (1975) Vinyl chloride exposure and human chromosome eherration* Mutation Res., 31.-163-168. Edmonds, L.D., H. Falk, and J.E. Niaaim (1975) Congen ital malformations and vinyl chloride. Lancet, 2.-1098. Edmonds, L.D., C.E. Anderson, J.W. Flynt, Jr., and L.M. Jamas (1978) Congenital central nervous system mal formation* and vinyl chlorida monomer expoeure: A community study. Teratology, 17:137-142. Fleig, L, and AM. This** (1978) Mutagematy of vinyl chlorida. J. Occup. Mad., 20557-561. Funea-Cravioco, P, B. Lambert, J. Lindate, L. Ebrenberg, AJ. Natsrjan. and & Oatarman-Gilkar (1975) Chrnmceom* aberrations in warkarm exposed to vinyl chloride. Lancet, 1.-459. Green. T, and DJI. Hathway (1978) Interactions ofvinyl chloride with rat livw DNA in vivo. Cbotn. BioL Intar. act.. 22211-224. Hanataen, L-L-, L. Hillestad. E. Thiis-Evanaen, and S3. Haldaas (1978) Effect* of vinyl chloride in man, a cyto genetic follow-up study. Mutation Re*., 51:271-278. Infanta. PS., J.K. Wagoner. A.J. McMichaeL R.J. Waxweiler, and H. Falk (1976) Genetic risks of vinyl chlo ride. Lancet, 1:734-735. Infante, P.F. (19761 Oncogenic and mutagenic risks in. communities with polyvinyl chloride production facili ties. Ann. N.Y. Acad. Sci., 271:49-57. John. J.A., Fj\. Smith. B.K.J. Leong. and B.A. Schweti (1977) The effects of maternally inhaled vinyl chloride on embryonal and fatal development in mice. rata, and rabbits. Toxicol. Appl. Pharmacol., 39:497-513. Kucerova, M,, Z. Polivkova, and J. Batora (1979) Com parative evaluation of the frequency of chromosomal aberrations and the SCE numbers in peripheral lym phocytes of worker* occupationally exposed to vinyl chloride monomer. Mutation Res.. 67.-97-100. Lack, 1. (1977) The etiology of human malformation*. Insights from epidemiology. Teratology, 5:303-314. Leonard. A., G. Dccat, E.D. Leonard. M.J. Lefevre, L.J. Decuypcr, and C. Nicaisc (1977) Cytogenetic investi gations on lymphocytes from workers exposed to vinyl chloride. J. Toxicol. Environ. Hlth., 2-1135-114L Loprieno, N., R. Barale. S. Baroncelli, C. Bauer, G. Bron- latti, A. Cemmellini, G. Cerdignani, C. Corsi, G. Gervasi. C. Leporini, R- Nieri, A.M. Roaai, G. Stretti, and G. Turchi (1976) Evaluation of the genetic effects in duced by vinyl chloride monomer (VCM) under mam malian metabolic activation: Studies in vitro and in vivo. Mutation Rea., 40:85-96. MacMahon, B. (1977) Vinyl Chloride and Human Repro duction. Manuscript prepared for th* Society of Plattics Industrie*. Inc.. Aug. 11. Magnuaaon. J.. and C. Ramel 119761 Mutagenic effects of vinyl chloride in Drosophila melanogaater. Mutation Rea., 36:115 (abstract). Makk. L.. F. Delorme. J.L. Creech. L.L. Ogden, E.H. Fadelt. C.L. Songster, J. Clanton, M.N. Johnson, and W.M. Chrinopheraon (1976) Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer, 37:149-163. Maltoni. C,, and G. Lefemine (1975) Carcinogenicity bioassays of vinyl chloride: Current results. Ann. N.Y. Acad. Sci., 246:195-218. Maltoni, C,, and G. Lefemine (1974) Carcinogenicity bioassays of vinyl chloride: Research plans and aarly result*. Environ. Rat., 7:387-405. Monaon. R_R_. J.M. Peters, and M.N. Johnson (1974) Pro portional mortality among vinyl chloride worker*. Lancet. 2:397-398. Myrianthopouloa, N.C. and CS Chung (1974) Congeni tal malformation* in xinglttona: Epidemiologic aun ey. Birth Defect*. lOmi-58. Rannug, U., A. Johansson, C. Ramel, and C.A. Waiht- meistar (1974) The mutagenicity ofvinyl chloride a ter metabolic activation. Ambio, 3:194-197. Smithell*. RW. (1976) Environmental teratogen* of man. Br. Med. Bull., 32.-27-33. Tbdriault, G_P^ H- Iturra, and S. Gingraa (1981) Associ ation between birth defects and exposure to ambient vinyl chloride. US. Environ. Protect Agency Report No 600-1-81-0S7, Research Triangle Park, North Caro lina 2771L Thomas. LS,, and H. Popper (1975) Pathology of angio sarcoma of th* liver among vinyl chloride-polyvinyl chloride woskaia. Ann. N.Y. Acad. Sci- 246:268-277. Ungvery. G., A. Hudak. E. Tatrai, M. Lorinet, and G. Folly (1978) Effect* of vinyl chloride exposure alo:i* and in combination with trypan blue applied system atically during all thirds of pregnancy on the fetus** of CFY rata. Toxicology, 17.-45-54. Vainio, H. (1978) Vinyl chlorida and vinyl benxane (Styrtoe)--metabolism, mutagenicity and carcinogenicity. Chem BioL Internet. 22.-117-124. Viola, Pi., A. Bigotti, and A. Caputo (1971) Oncogenic response ofrat akin, lungs, and bona* to vinyl chloride. Cancer R**, 31.516-522. ucc 040784 370 C. THERIAULT. H. ITURRA. AND S. CINGRAS W.lLer, S.C., and J.M. Elwood (1975) A t*t for Mon.lity of events with a variable population at riak. Br. J. Prevent. Soc. Med., 29:18-21. Waxweiler, R.J., W. Stringer, J.K. Wagoner, J. Jones. H. TMk. and C. Can*- (1976) Neopltttic ritk among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci. 271.-4(M8. Normal ar Fetus Stu Examinati ABSTR aminati fetus; p obtaine hydrocl The introdu carnivore, into togenesis as ar commonly use morphs, is an the several adv. 77) in using tl under laboratc can be accurst Ferrets, like seasonal breec ^ the breeding t March to Aug side the breed, mals to artific processes invo in the feiret t Methods ofobt are described b , Our method adult male anc condition in a; of artificial lig they are requi they are transt (14 hours ofar weeks they gt by the conditic A few male a that a situatic are available i is not a compr the reader she Gulamhusein teratogeniewt Estrut is chi ing of the vuh ter mating an the beginning 1983 ALAN R