Document 2J0rQx8gVzqpxEdLDxO7NpBR6

VINYL CHLORIDE (Teratogenicity) Supplement to Feb. 3, 1982 Package References EPA Project Summary - "Association Between Birth Defects and Exposure to Ambient Vinyl Chloride" Sept. 1981; pp. 1-6 Infante, P. F.; et al; Lancet, Vol. 1, April 3, 1976; pp. 734-735 Infante, P. F.; et al; Lancet, Vol. 1, June 12, 1976; pp. 1289-1290 Infante, P. F.; Ann. NY Acad. Sci., Vol. 271, 1976; PP. 49-57 ucc 06^05 v>EPA United States Environmental Protection Agency Research and Development Health Effects Research Laboratory Research Triangle Park NC 27711 EPA-600/S1-81-057 Sept. 1981 Project Summary Association Between Birth Defects and Exposure to Ambient Vinyl Chloride Gilles P. Theriault, Hilda Iturra, and Suzanne Gingras To better define the association between exposure to vinyl chloride monomer (VCM) and the occurrence of birth defects, this epidemiological study was made in Shawinigan, Quebec. Canada, where a vinyl chloride polymerization plant has operated since 1943. Birth-defect rates in Shawinigan during the last 16 years were compared with rates in three other communities, and seasonal and spatial variations in Shawinigan's birth-defect rate were correlated with estimated VCM concentrations in the environment Shawinigan had an excess of birth defects which fluctuated seasonally in a way that could correspond 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 stillbirths in Shawinigan, the excess in birth defects involved most 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. This Project Summary was devalopedby EPA's Health Effects Research Laboratory, Research Triangle Park, NC, to announce key findings of the research report that is fully docu mented In a separate report of the same title (see Project Report ordering information at back). Introduction Vinyl chloride monomer (VCM) is carcinogenic in man and other animals and mutagenic in microbial assays, Drosophila, yeast, mammalian cells, and man. VCM generates mutations primarily through one of its metabolites, chloroethylene oxide, and with the involvement of liver microsomal enzymes. Although miscarriages and fetal losses among the wives of workers exposed to VCM have been studied, such effects remain undocumented. VCM was found in the fetal and maternal blood and the amniotic fluid of pregnant rats after exposure to air containing VCM; two studies of VCM teratogenicity in animals failed to demonstrate fetal malformations, but showed increased fetal death rates. At normal temperature and pressure, VCM is a gas: it liquifies at -13 C. It is processed into polyvinyl chloride (PVC; a plastic) through polymerization reac tions in autoclaves. The gas is released into the environment during unloading, processing, and autoclave-cleaning operations. The concentration of VCM ucc 06A106 to which people in the community are exposed depends on production rate, wind direction, wind velocity, and distance from the plant. In Shawinigan (population 27,000), a vinyl chloride polymerization plant (owned by B.F. Goodrich Co., Ltd.) has operated since 1943 and currently produces 25,000 tons/yr of PVC. Ten cases of angiosarcoma of the liver have been reported among workers at this plant. In addition to the PVC plant, Shawinigan has two chemical plants, one aluminum electrolysis plant, one carbide plant, and one pulp and paper mill. A great number of pollutants are discharged into its environment. Fur thermore, prevailing winds tend to blow from the pollution sources towards the town's residential areas. In 1975, a high birth-defect incidence (mostly central nervous system abnor malities) was found in three Ohio towns with PVC plants. However, two sub sequent studies failed to find any association between birth defects and either work at or proximity of residence to these plants. Inal 977 study, a higher birth-defect rate was found in Shawinigan than in Drummondville (a town without a PVC plant); the highest rates in Shawinigan were in the vicinity of the plant. The present study was an attempt to associate this high frequency of birth defects with exposure to VCM. One objective of this study was to establish birth-defect and stillbirth rates in Shawinigan and to compare these rates with those for other communities, in an attempt to confirm the high birthdefect rates previously observed. An other objective was to try to correlate seasonal and spatial variations in the birth-defect rate with variations in VCM concentration in the environment. The final objective was to compare a group of parents who gave birth to malformed infants with a control group of parents of normal children with respect to residential and occupational history and several birth-defect risk factors. In determining birth-defect rates in Shawinigan, the study included all stillbirths and malformed children born of mothers who resided within the city limits of Shawinigan at the time of delivery and who delivered between January 1, 1966, and December 31, 1979. The case-control study was limited to a shorter period (January 1973 to December 31,1979), because it required information based on the mothers' recollection of events during their pregnancies. A birth defect was 2 defined as a gross physical or anatomic developmental anomaly present at birth or detected at the hospital during the first days after delivery. To assess the importance of the excess of birth defects in Shawinigan, three comparison communities were chosen, based on their similarity to Shawinigan in population size and structure, socioeconomic level, and medical-care facilities. To take into account the influence of environmental pollution, one town with an aluminum plant but no VCM-emitting plant (BaieComeau--Hauterive) and two towns with neither a VCM nor an aluminum plant (Drummondville and Rimouski) were chosen as control communities. 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 three preceding years. Birth-defect children and controls were identified and data were collected from several medical files and hospital rosters (delivery-room daybooks, birth-detact rosters, discharge lists, mothers' and children's medical files, and birth rosters). Shawinigan's 14 school districts were used as the unit of spatial distribution of birth defects. For the case-control study, the mothers of affected infants and matched controls were interviewed at home. Cases and controls were matched by maternal age within two years, sex of the infant, and place of residence of the mother. Two studies were conducted to assess vinyl chloride concentration in the air in Shawinigan. The first was a study of the feasibility of measuring VCM in the air at several locations in Shawinigan using air sampling and analysis techniques (summarized in an appendix to the report of the present study). Its conclusion was that environ mental VCM concentrations could be assessed by ambient air sampling at various sites in Shawinigan; depending on location, sampling detected levels up to 45 ppb. During winter, VCM tended to accumulate in the snow in the vicinity of the plant, and VCM concentrations differed between indoor and outdoor samples. The report recommended a continuous one-year sampling program with special attention to meteorologic, topographic, and demographic data to establish the true VCM concentrations to which the Shawinigan population is exposed. Considering the high cost of such a sampling program, it was decided that for the present study, ambient vinyl chloride concentrations in Shawinigan would be estimated using a dispersion model based on production records and the results of previous air-monitoring activities. This study was conducted by a subcontractor. The dispersion model used the PasquiII-Gifford equation, and its variables included wind direction and velocity, rainfall, humidity, tempera ture. topography, and estimated VCM production and emissions. The model allowed construction of isopleths of estimated vinyl chloride concentration over Shawinigan. Results From January 1966 through Decem ber 1979, there were 4534 live births and 33 stillbirths in Shawinigan. Of the live infants, 150 had birth defects, and of the stillbirths. 9 had birth defects. The birth defects reported most frequently were those of the musculoskeletal system, followed by the cardiovascular, central nervous, and urogenital sys tems. The ages of the mothers did not differ significantly among the various types of birth defect. Defects of the central nervous system (CNS) were particularly frequent among malformed infants with short gestation periods. The yearly numbers of malformed children per 100 births varied from 1.68 (in 1969) to 6.84 (in 1973), with an overall rate of 3.48. Detailed analysis of the monthly distribution of birth defects and the distribution by affected system for the year 1973 showed no single large increase that could account for the high rate in that year. Nor did the yearly distribution by system show any par ticular feature that could account for the annual variation in the overall rates. Furthermore, birth-defect rates did not consistently increase or decrease with time. The observed number of malformed children in Shawinigan was higher than would be expected based on the rate for each comparison community or for all three comparison communities together (see Table 1). The excess birth defects in Shawinigan occurred in the central nervous, cardiovascular, urogenital, and musculoskeletal systems, the eye and ear, and the chest. As the types of defects found in excess in Shawinigan were also the most common types of defects overall, it can be concluded that birth defects in general were in excess in Shawinigan. The proportion of mal formed infants was greater in Shawinigan than in the comparison communities in ucc 061107 Table 1. Number of Malformed Children Observed in Shawinigan Compared with Expected Numbers Based on Rates for the Comparison Communities (1966-1979f Affected System Observed in Shawinigan Expected Based on Drummondville Expected Based on Baie-Comeau-- Hauterive Expected Based on Rimouski Expected Based on All Comparison Communities Central nervous 30 19.69* 18.18* 15.33** 17.96* Cardiovascular 37 19.69** 13.94** 43.06 24.29* Gastrointestinal 11 9.04 9.70 10.95 9.80 Urogenital 30 19.15* 13.94** 13.14** 15.72** Musculoskeletal 49 36.71 27.88** 40.14 34.70* Mouth and upper airways Eye and ear 17 6 6.92** 1.06** 13.33 1.82* 13.14 -- 10.82 1.02** Chest 3 0.53* -- 0.73 0.41* Syndromes and other defects 6 6.92 9.70 10.95 8.98 Total 159 102.68** 98.80** 124.08** 107.36** *Ratio of Poisson variable to its expectation (36); * indicates p < 0.05; " indicates p <0.01. all years except 1969 and 1972 (see Table 2). The number of stillbirths differed only between Shawinigan and Drummondville, where the number of stillbirths was significantly higher. The proportion of malformed children among the still born was higher in Shawinigan than in the comparison communities. This is consistent with previous findings of an excess of birth defects in Shawinigan. Mothers who gave birth to malformed children were significantly younger in Shawinigan 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 communities in mean gestational age at birth, except in the case of chest malformation, for which the sample size was very small. Figure 1 compares the monthly birth- defect rates for Shawinigan with those for Drummondville and Rimouski. The Shawinigan curve is V-shaped, with the lowest rates in the summer, whereas the curve for the comparison communi ties is flatter. The seasonal variation in birth-defect rates was statistically significant for Shawinigan, but not for the comparison communities. The spatial distribution of birth defects in Shawinigan with respect to the PVC plant was analyzed; in no Table 2. Distribution of Malformed Children for Each Year (1966-1979) Comparison Tear_______ Shawinigan__________ Rata*_________ Communities 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 Total 16 13 8 6 15 6 6 18 8 15 13 14 11 10 159 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 3.48 31 33 24 27 24 30 34 44 43 51 36 50 52 47 526 ''Number of malformed children per 100 births. * indicates p< 0.05. Rates 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 2.35 SH/Comparison 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 1.48* 95% Confidence Interval (1.08. 3.52) (0.6, 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. 2.33) (0.81. 2.49) (0.93. 3.51) (0.93, 2.93) (0.61. 2.20) (0.60. 2.26) (1.24, 1.75) 3 ucc 061108 previous abortions. There was one ptevious stillbirth among the control mothers and none for the case mothers; there was one previous malformed child in each of the two groups. There was no significant difference between cases and controls in the father'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 pregnancy; exposure during the third trimester did not differ significantly between case and control mothers. Table 4 summarizes the mothers' occupations before and during their pregnancies. None of the women were ever exposed to VCM at work before or during pregnancy. The working experi ences of the case and control mothers before and during pregnancy did not differ, nor did their smoking habits or alcohol consumption. Two mothers of Month oi Birth defective infants reported having used the drug LSD before their pregnancies. Figure 1. Monthly distribution of birth-defect rates. There was no significant difference between cases and controls in the father s occupational exposure to school district did the ratio of observed not differ significantly, nor was there a chemicals, and no fathers were ever to expected number of birth defects significant difference between case and exposed to vinyl chloride (see Table 5). differ significantly from 1. The four control mothers in number of previous The distance between each mother's districts with the highest rates are pregnancies. place of residence and the VCM plant located on the north-south axis passing Mothers of malformed infants reported was measured to 100 m, using a map through the vinyl chloride plant; the no excess of diseases during pregnancy; of the city; there was no significant district in which the plant is located had however, the following diseases sus difference between the two groups in abcut the expected number of birth pected to bear a high risk of birth defect distance from the VCM plant. defects. The yearly average concentra tion of vinyl chloride was estimated for were reported more frequently by case than by control mothers; rubella, Discussion each school district, based on data from hydramnios, epilepsy, nonpsychotic Some observations of this study a study entitled "Dispersion Patterns of mental disorders, and psychosis. There support the existence of an association Vinyl Chloride Emitted by B.F. Goodrich was no significant difference between between VCM in the air and birth Co., Ltd., Shawinigan, Que." (which is case and control mothers in number of defects in the exposed community. appended to the report of the present study). Birth-defect rates did not differ between school districts with high and low VCM exposure, either for all birth Table 3. Comparison of Total Birth Defects* and CNS Birth Defects* Between School Districts with High and Low Atmospheric Vinyl Chloride Concentration defects or for CNS defects (see Table 3). Likewise, school districts adjacent to the plant did not differ from the other school districts in numbers of birth defects (total or CNS), nor did districts Births with defects School Districts With High VCM Levels': School Districts With Low VCM Levels Total 87 70 157 differ within and beyond a one-mile radius of the vinyl chloride plant- For the period January 1973 to Births without defects 2285 2125 4410 December 1979, 68 cases of birth Births with CNS defects were identified in Shawinigan defects . 16 13 29 and matched with controls (42 male and 26 female pairs). Five of the cases were stillborn; all of the controls were born Births without CNS defects 2356 2182 4538 alive. There was no significant difference Total births 2372 2195 4567 between cases and controls in number of weeks' gestation at delivery. The `X1, - 0.80; p> 0.35. frequencies of previous birth defects in "Xs, =0.10; p> 0.70. the families of cases and controls did cSchool districts nos. 1, 3. 5, 6, 7. and 8. ucc 061109 Table 4. Distribution of Cases and Controls by Mother's Occupation* Mother's Occupation Cases Before During Pregnancy Pregnancy Control Before During Pregnancy Pregnancy 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 chemicals 2 1 21 Stay at home 25 45 24 47 Total 68 68 68 68 Partitioning stay at home vs. work outside home before pregnancy: X, - 0.03; p>0.85. Partitioning stay at home vs. work outside home duringpregnancy: X, = 0.13; p> 0.71. while others tend to contradict such an association. High birth-defect rates in Shawinigan were confirmed for a 15year period, and women who gave birth to malformed'children were, on average, younger in Shawinigan than in the comparison communities. These results are consistent with previous findings for three Ohio towns with PVC plants. The present study revealed seasonal variation in birth-defect rates that could correspond to variation in atmospheric VC.M concentrations. VCM could not be measured in air samples during Decem ber, January, and February. It is believed that during these months, VCM tends to accumulate near the plant as a liquid, because the outdoor temperature is below its liquefaction point; this VCM would be released into the air in the spring. Birth-defect rates were lowest in September, which is eight months after midwinter, corresponding to the time between the first third of pregnancy and delivery. This observation would tend to support an association between VCM concentration in the air and birth defects in the community. One con sultant believed that below its liquefac tion point, VCM would remain in the air in droplets, at a concentration similar to that found at higher temperatures. However, because people spend more time indoors during the winter than the rest of the year, winter exposure would tend to be low in any case. On the other hand, several observa tions of the present study tend to argue against any association between VCM concentration in the air and birth defects in the community. The spatial distribution of birth defects in Shawinigan cannot be explained on the basis of estimates of VCM concentrations in the community. Malformation rates were not relatively high either near the plant or in the area whereVCM concentrations were estimated to be highest, and the school district with the highest birthdefect rate was far from the plant. However, VCM concentrations were not measured directly, but estimated by a theoretical dispersion model based on approximate production and emission values, because the B.F. Goodrich Co. would not release the actual values. Table 5. Distribution of Cases and Controls by Father's Occupation* Father's Occupation Cases Controls Ever worked in vinyl chloride industry 00 Ever worked in industries with exposure to chemicals 20 25 Never worked in industries with exposure to chemicals Unknown Total `X1, = 0.73; p> 0.39. 43 5 68 39 4 68 There was no difference in occupa tional or residential history between the parents who gave birth to malformed infants and the control parents. Both groups resided at similar distances from the plant, and none of the parents had worked at the plant. Furthermore, all types of birth defects were in excess in Shawinigan, rather than those of any particular system. 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 artifactua! are not convincing. It is unlikely that Shawinigan's physicians were'more inclined to diagnose birth defects than were physicians in the comparison communities. Birth defects were included in this study on the basis of their obviousness, and the birthdefect rates were the same in the three comparison communities. Furthermore, for severe birth defects like those of the CNS, which cannot be misdiagnosed, rates were much higher in Shawinigan than in any of the comparison com munities. The method by which the data were collected made it 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 of Shawinigan who were at risk of having a malformed child migrated to the city for delivery, thereby increasing 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 % of the birth-defect cases observed in Shawinigan might actually have come from elsewhere, reducing the number of observed cases to 142. However, birth-defect rates would still be sig nificantly 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 results more often in high rates of fetal loss and miscarriage than in birth defects. However, stillbirth rates were no higher in Shawinigan than in the comparison communities, and in the 5 ucc 061110 case-control study, abortion rates were not higher for case than for control mothers. Several industries in Shawinigan emit pollutants into the atmosphere, and several of the pollutants may interact to generate potent mutagenic or teratogenic chemicals in the com munity. The analysis of such an envi ronment and its association with the excess of birth defects was beyond the scope of the present study. However, in the case-control study, there was no difference between the numbers of case and control parents who worked at the aluminum plant, and the comparison community with an aluminum elec trolysis plant (8aie-Comeau--Hauterive) had lower birth-defect rates than did Shawinigan. Thus, the aluminum in dustry probably was not solely respon sible for the excess of birth defects in Shawinigan. Among risk factors (other than occu pational or environmental exposure to a pollutant) 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 fre quently by mothers of malformed children than by control mothers. Drugs prescribed to control epilepsy have been reported to be associated with birth defects and could account for a few birth defects observed in Shawinigan, as could LSD. No other risk factor was reported more frequently by the case than by the control mothers. An association between VCM in the air and birth defects in the exposed community cannot be substantiated at the present time. If the association exists, it cannot be measured by the methods used in this and in previous studies or in populations of the sizes studied so far. Conclusions The conclusions of this study can be summarized as follows: 1. For the years 1966 through 1979, there was an excess of birth defects in the population of Shawinigan, Quebec. This result is similar to the findings for several U.S. cities where vinyl polymerization plants operate. 2. Birth-defect rates underwent a seasonal variation that could cor respond to variation in the con centration of VCM in ambient air. 3. Mothers from Shawinigan who gave birth to malformed infants 6 were younger than mothers from the comparison communities who also gave birth to malformed infants. 4. The excess malformations involved not only the central nervous system, but almost all body sys tems. 5. No correlation was found between the spatial distribution of birth defects in the town and estimates of VCM concentrations in the air. (These estimates were based on approximate data, since informa tion on PVC production and VCM emissions was not available.) 6. Occupational exposure as a causal agent was ruled out, because none of the parents in the study had ever worked at the VCM plant. 7. Cases and controls did not differ in distance of residence from the plant. 8. No excess of stillbirths was ob served in Shawinigan, and abortion rates were no higher for mothers of malformed infants than for mothers of normal infants. Some observations of this study support an association between VCM in the air and birth defects in the exposed community, while others tend to indi cate that no such association exists. As the present results are inconclusive, the possibility that VCM generates birth defects in human communities requires further consideration. This would best be accomplished through a program during the next five to ten years to monitor VCM concentration in the air and birth defects in the exposed communities. Gilles P. Theriault. Hilda Iturra. andSuzanne Gingras are with the Department of Social and Preventive Medicine. Faculty of Medicine. Laval University, Ste-Foy. Quebec, Canada G1K 7P4. Jeff Beaubier and Gregg Wilkinson are the EPA Project Officers (see belowJ. The complete report, entitled "Association Between Birth Defects andExposure to Ambient Vinyl Chloride." (Order No. PB 81 -238 883; Cost: $71.00, subject to change) will be available only from: National Technical Information Service 5285 Port Royal Road Springfield, VA 22161 Telephone: 703-487-4650 The EPA Project Officers can be contacted at: Health Effects Research Laboratory U.S. Environmental Protection Agency Research Triangle Park. NC 27711 PUS GOVERNMENT PRINTING OFFICE. IM1 - 757 012 7327 ucc 061111 Not.cc: Thir, r'FrtpriNl may bp pr1 734 bv roov'iiii'f inii,';1- \7 ij b Occasional Survey GENETIC RISKS OF VINYL CHLORIDE Pete* F. Infante Joseph K. Wagoner Anthony J. McMichael Richard J. Waxweilek Henry Falk Division ofSurveillance, Hatard Evaluations and Fitld Studios, National Institutefor Occupational Safety 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 V.CJ4., 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 ofa 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 find'ngs, 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.cm., raise scientific and public-health concern for the possible genetic risks of v.cm. to man. In the past year, several reports have indicated that vinyl-chloride monomer (v.c.m.) is mutagenic in micro bial test, systems.1-' v.c.m. metabolites also have in duced mutations in mammalian cells.4 Likewise, reports from four countries have shown an excess of chromoso mal aberrations in lymphocytes of workers exposed to v.c.m. compared with controls.'-* However, Purchase et al.T have stated (though no animal data were presented), that the mutagenic effects of v.c.M. expressed as chro mosomal aberrations in lymphocytes in humans do not occur in germ cells in mice; they concluded that the potential danger of mutagenic effects on the fetus via sperm seemed unlikely to exist. In a study without con trols, Selikoff observed fetal death-rates among wives of v.cjh. workers that ranged from 7 to 14 per 100 preg nancies.* These rates appear to have been higher than expected.10 To develop further data on this question, pregnancy outcome has been studied among the wives of workers exposed to v.c.m. All current v.c.m. polymerisation and polyvinyl-chloride (p.v.c.) fabrication workers were in cluded for study together with a similar number of cur rent rubber workers (8% of all such workers) selected from work areas relatively free from known toxic materials and matched as a group to the v.c.m. workers by age. Group-participation rates 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 p.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 TH!i LANCET, APRIL 3,1976 v.c.m. polymerisation and 158 rubber and P.v.c. fabri cation workers were interviewed. Paternal age, preg nancy outcome, and estimates for the time of conception of all pregnancies were ascertained by interview in Oct ober, 1974, from males employed at a rubber manufac turing, p.v.c. fabricating; and v.c.m. polymerising facil ity. As part of a larger survey of worker health, date of first employment in the job categories was determined from company records. Mean paternal age, total number of conceptions, total number of fetal deaths (defined as any product of conception not born alive), and fetal deaths per 100 conceptions were then computed for each group prior to and subsequent to the worker's date of employment. No interviews were conducted with workers' wives and no data were obtained concerning maternal age, except indirectly through paternal age. Since fetal loss is known to increase with ascending parental age, the fetal death-rates for the primary v.c.m. exposure group were age-adjusted to the control group. Table i shows the age-adjusted fetal death-rates for wives of the primary v.cj*. exposure group versus the control group, both prior to and subsequent to each group's respective exposures. Among pregnan cies occurring prior to exposure, fetal death-rates were 6-9% for the controls versus 6-1% (age-adjusted) for the primary v.cjh. exposure group. These rates were not significantly different by Mantel-Haenszel Chi-square testing.11 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at p<0-05 (^*=4 00, df=l).1J Although the underlying dis tributions differed, mean paternal ages were virtually the same--30-4 versus 30-2 years. The significant dif ference between the groups subsequent to exposure was a reflection of a relatively greater fetal mortality-rate as sociated with younger-aged husbands in the primary v.cja. exposure group. Among pregnancies occurring subsequent to exposure, the fetal mortality-rates associ ated with husbands 30 years of age and older for the pri mary v.cja. exposure and control groups were 9/69 (13-0%) and 17/142 (12 0%), respectively; whereas, for ti ?! <! t*i ! I TASU I--MEAN PATERNAL ACE, NVM3EX OP PREGNANCIES, AND PETAL DEATH-RATES ACCORDING TO HDSIAND's V.C. EXPOSURE -- Prior ta kutband's tspcutr*: Number of families Mean paternal age at conception (yr.) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 preg.$ Subsequent to kkfbamd'i tspoturtr Number of families Mean paternal age at conception (yr) Number of fetal ]>raihs among wives Number of pregnancies Agc-adruttal fetal deathi/100 preg t Primary "Omtrola"* v.c-m. orposuref 95 230 11 139 6-9 113 30-4 24 273 8-8 70 26-4 13 MS 61 62 30-2 23 139 13-8 `Rubber tad f.v e, fabrication worker*, fv c- polymerisation workers(Raiet age-adsusied to "control'* group paternal age tjiainbutton. ^Subsequent to husband's exposure, the frequency of fetal deaths among r*es was significantly greater m the primary v c.m. exposure group than in the "con-* troU" (f<0-05) or m the study group prior to husband's exposure r-0 02 by age-adjusted chi-square testing." THE r.Ai oi \U N'u Sui F Me i \u. r A* KuM *NKTju. hus 14/ coir (the f inct exp sub alsc con 8-8 T exp fav- ucc 061112 7HET~ANCKT,*AJ>*It. 3, 1976 735 TA1LC II--MEAN FATtlMAL AGE* fAtGNAHCUS, AVD >ETAL MATH`MTf ACCOHDIMO TOHlSlAND'i V,C EXPOSURE EXCLUDING PREGNANCIES OF *OM!N WJTH * J PETAL DEATH* - Awr to katbunft Mpggnwe: .Mean paternal afg at conception (jr.) Number of fetal deaths among wmt Number of pregnaaci-- Age-adjusted f<ul deatta/100 prcg4 Subityoonr to ktubomfs rtywarg; Mean paternal aft at conception (yr.) Number of fetal Iniht imimg aim Numbcof pregnaacm Age-adjusted fetal dcatWIOO preg4 Primary Coniruli"* v.c.m. cxpoiuret 33-0 11 159 69 )01 it 265 6$ 26 3 9 141 31 30-1 14 120 10* `Rubber and f.* (abncatia* norton* tx. jdtfomvmim wetfcai *Rof ay >djiKd >^wwireT* paternal ip distribution. husband* ten than 30 years of age, fetal mortality was 14/70 (20-0%) fix' the primary v.c.m. exposure group compared with 7/131 (5-3%) for the control group (these data are not shown in tables.) Furthermore, intragroup comparisons indicated an increase 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 also was significant, r<002 (y_a=S-51 df=l).,J Similar comparison for rates in the control group, 6-9% versus 8-8%, indicated no significant difference. To determine whether women who had chronically experienced abortions might have weighted the results in favour of a higher fetal death-rate in the primary v.c.m. group subsequent to husband's exposure, pregnancies of women who had more than two abortions were elim inated from the analyses and the data were recalcu lated to determine whether or not the trend was main tained. The decision to exclude all pregnancies among families associated with more than two abortions was made without prior knowledge of how these families were distributed among the exposure categories. The data in table n show that the trend was maintained. Prior to exposure, the fetal death-rates in the control and primary v.cj*. exposure groups were 6-9% and 3-1% (age-adjusted), respectively, whereas, after expo sure, the rates were 6-8% and 10-8%, respectively. Sub sequently, data were eliminated for pregnancies of women who had experienced, firstly, more than one abortion, and, secondly, more than three abortions, and each time the trend wet maintained. No changes in rates for controls were observed, whereas a 2-3-fold increase was observed in the primary v.c.m. group subsequent to exposure. To determine whether differences in fetal loss might have been the result of one or two interviewers weight ing the results, the data were analysed by individual in terviewer. The results demonstrated a general trend for each interviewer to report a higher ascertainment among v.c.M. polymerisation workers than among the control group. Further, the potability was entertained that the inter val between the date of interview and the date of fetal loss might have influenced the results through dif 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 woriters who were included in the control group thought that they had a primary v.c.m. exposure as a fabrication worker. In addition, the questions regarding pregnancy outcome were contained in a much larger interview questionnaire, the results of which demonstrated very few significant differences with no consistent bias for the parameters ascertained between the workers wish a primary V.C.M. exposure, and the other groups. This observation at 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 access did not appear to be the result of bias from interviewers or respondents, nor from women who experienced chronic abortions weighting the results. Several mechanions by which such fetal loss may arise are suggested. Either fetal or maternal toxicity or germcell mutagenesis in the mother through indirect v.c.m. exposure from the father might be considered, although these mechanisms seem highly unlikely in view of the highly volatile nature of v.c.m.11 When the findings of the present study are taken in conjunction with the prior demonstration of a mutagenic response via microbial test systems and observations of significant excesses of chromosomal aberrations among workers exposed to v.c.m., the leading possibility is germ-cell damage in the father through direct v.c.m. exposure. The increased fetal mortality among wives of workers subsequent to v.c.m. exposure now raises serious scientific and publichealth concern for the possible genetic risks of vinyl chloride to man. Rtquans for reprint, ibaild br iddraKd to P.F.I., N.I.O.S.H., Poit Oflltt Buildinj, Room J1J, Cindnniti, Ohio 45202, U.S.A. RirsazNCts 1 Remcfc. H., Malavidk, C, Montesaoo, R. Int.J Cancer. 1975,15* 42i*. 2 Lopneno, N.p Barak, Yarotwxlli, sL, et a). Mutaocn Re*, (m the `res*. J. Rajonuf, U,t Johan--nt, A-+ Ramct, C, Wtocmer, C A. Ambto. 1974, J, 194. 4. Huberotn, E., Barlach, 1L, Sachs, L. Int.J, Cantor, 1975, 16,639. 5. Due*Until, Htracbbn* K,, Sditoff, I. J, Afutarie* Ret. 1975* 31* 163. 6. FuocfrCrivtOMt F,, Laeabeft, B., Linditeu, J., Ehrenberg, L,, Nataraiaii, A. f., Quintian Oofear, S. Lancet, 1973, i, 459. * Purchase, 1. F. H., Hiiiwdiun, C. R., Andenon, 0. tbid. 1975, * 4 to, i. Hiltatad, L., Thiit-Evaaca, E. Unpublished. 9. SeUkoif, j. j., NJ.E.H.S. Conference on Public Health Impticauons of Com ponents of Pltrtice Manufacture, Pmehunt, North Carolina, July, 1974. 10 Infame, P. f.Ann.N.Y.AcaA. bci. tin the pro**). 11. Shapiro, $., Jonca, . W,, Denser*, P. M. Mttbnmk Q, 1962,40,7. 12. Mantel, N,, Haeniit., Or.J, Sam. Cancer Inn. 1959,22, 719. 13. United Statea Envtrearontal Protection Agency, sampling and nalym of select toxic iUbtum, iaak m vinyl chloride. Contract no. 61^31-1646. Jan. 20,197*. 1 *~ IJ. 19: t*! lancet, jwe 12,1976 1289 "Ne 01K,, 'non * disca^ Bnuie been it HI i ph, =*l thtr N* I-dltr V 1 pn> uniuiiu? lighesi- Stew, m I'rfiioc. mv puivf urrmu.^ 0 mititf*, i ndivaJua, >*ft **' c iiO\crw :hoJ that C* ihi.T-4 jroup P ehlIJrrc vjuinf the i:* ulJrcn m tendmett mixpri-; ny pjptf my x nt- rts ot 1 mJK'jtt ly Jiwp to iM ho \% *hk ne s *trar.p idiMuat* k t* t**1 ,o lor.pCT *i li \% iberw V Ihen: do ** iuid r* id2UJ aulJ r-J noi lltCTCJ* td|U' * I I*'1 ' 1, * 6*' ^.iixd after 1963. In particular, the incidence of convulitt recorded for 19(5 wai more than double the 1963 figure. I Sod difficulty in grasping bow such evidence indicates an as- ., between removal of adjuvant and disappearance of jjwn reactions. Even Dr Tint, whom he cates, seems far from art. - ,,r-- of Bwnnalof)r tnd Virology, **"* ` _,, a/ Uaw twifpf. 'aL MIS rT f Noel W. Peeston ( 5u,--The merit* of whooping-cough vaccination will never W settled by a series of letters in Tkt Lancer, but 1 fed never- i that 1 must correct two of the statements made by Dr ' Ba-uli and Professor Stewart in their tetter of May 15 ip. 1574). In the first place, Sako did publish dinical observations vaccinated and control subjects, taking careful note of ; cqwure: 30 cases in 159 exposed vaccinated . 137 cases , imb 13 deaths) in 149 exposed unvaednated infants or young j cfcldrcn. This is detailed in the reference cited, and farther miis can be found in a later paper.1 But others did far more artfully designed studies than Sako, and obtained similar uni the work of Silverthorne, Milter, Kendrick, SingerIreob, Coppolioo, Bdl, and otheri is liberally cited in the Innture aid I will not take op space by detailed references Snt. One cannot, however, overlook the masterful studies by . pc British Medical Research Cooncd,' and the fact is that, ( mb three exceptions, every properly controlled study on , hoopieg-cougb vaccine haa shown it to be moderately to j ngbljr elective. It it, of course, possible to prepare a poor vac- ore sod, conceivably, a good vaccine that is irrelevant because | rf differences in serotype. But these problems have been cor* sumf in the U.K-, and Dr Fraser's analysis (May 1, p. 969) iaqgesu that, with a little more attention to the younger in to*, whoopinfeough vaccine in Glasgow might prove satislaaory to alL My second point concemi alum. In the first place its use has m "loog been discontinued" as a component of vaccines; st ban four U.S. manufacturers still use it ami it is included in e of the most widely used forms of diphlhcria-tetanus-perams vstxine*. However, its use is diminishing since it is hwigbt to be less effective as an adjuvant than the other salts d Aluminium. Yet this very fact renders Sako's results more, Kber than less, impressive. ;; JSMalcKoid, iNtn Geoefsev Eoeall GENETIC RISKS OF VINYL CHLORIDE ^ ?StE,--Dr Paddle (May 15, p. 1079) asks us to specify the : *ribod of data collection used in our study (April 13, p. 734) * w*to show a ubulation of the data before age adjustment. | A mentioned several times, the data were obtained by imer1 ** with the workers. The range foe response-rates, which -taw umilar for the study and control groups, were also in- '*d. As we stated, the question* about pregnancy outcome t 'Bt contained in a much larger interview questionnaire which the initial item of a cross sectional health survey that in- Hw*d a physical examination, X-rays, and laboratory tens. ^ at results of the survey demonstrated very few significant dif- and no consistent bias toward a higher prevalence for . "dices measured in either the study or control group. The ""view protocols were administered by six interviewers (two ' j***1* teams of three interviewers) front the Center for T"**** Control, each with experience in field health surveys, ) ~***L'ntervicw took 15-30 min, and was carried out in a ' v,n interview booth. The interviewers had participated formal review of the questionnaire before the study. In physician member of the survey team reviewed ^~vretponses immediately after the interview and, where 2J"pnate, sought further elaboration from the interviewee. W.yp.Au. 1947,14,29. W Rocrtb Council r. mtd.J. 155V, i, 9*4 FATISNAL AOI DISTSISVTIOH FOa FETAL PIATHI ACCOADINO TO HUSSaNO'S V.C. IXFOSl'AI Pllttfwl *s*(yr) "Control*" Primary exposure Pregnane** Fetal death* Pregnancies Feial death* Bt/otf ttpotun: <20 20-34 2*-39 30-34 >3J AU iftsa crude nu Menu patcrael *f* lit conceptioa Age-djimcd rate* 31 SO 3! 6 4 159 23-0 jr* 2 i-m) * (10 %^) 1 0 u .. 70 44 2 (4-S^ 56 7 (J2'Sfr/ 37 J 14 \ 148 ts (ia-Kj 26-4yr. (t-ltl A/itr txpOtttT*: <20 30-24 23-39 30-34 >33 All ifM, crude rau Pli hi inHnnl [> ateooctpifa* A(Hdjwud rew* 1 43 7 17 S3 273 AM jr* 0 * v-m 3 fj-ny 7 (t-try 16 (11-1*) /*-<%) .. (i *v 0 22 J ru-6<y 41 11 (21.9%) 36 j rs-nj 33 (u-rtj 239 13 302yt. -- * Fciol nAlabtyvom for pomoiy vx. rxpowre froup on direct Ip odnuted to the poicmol Of* dbuibutioa otthe yrvftuocic, m the control group. The table shows data for Age-specific fetal mortality-rates before age adjustment, for both time periods (i.c, before and after the husband's exposure). Before the husband's exposure, the crude fetal mortalityrates are 10-1% for the study group and 6-9% for the control group. However, after direct age adjustment the study-group rate became 6-1%. This is the result of a younger paternal age for pregnancies in the control group. For example, pregnancies to wives of men less than 30 years of age made up 93-7% (149/159) of the control-group pregnancies as compared to 72-3% (107/184) of the study-group pregnancies. Our paper indicated this difference in age between the groups for before exposure comparisons. Table I in that paper showed that the mean paternal ages were 23-0 years for the control group and 26-4 yean for the study group. Aa shown here in the table, subsequent to husband's expo sure, the crude fetal mortality-rates were 8-8% and 16-5% for the control and study groups, respectively. With direct age adjustment the 16-5% was reduced to 15-8%. Age adjustment for the subsequent to exposure comparisons resulted in little change in the rates because the sge distributions for pregnan cies in both the study and control groups after exposure were similar. For example, pregnancies to wives of men younger than 30 year* of age made up 48-0% (131/273) of the controlgroup pregnancies and 50-4% (70/139) of the study-group pregnancies. We hope this explanation of the age-adjustment procedure is now clear. It is the fact that the two standard age distribu tions derive from the control group's populations of pregnan cies, rather than of persons (whether fathers or not) that prob ably accounts for the numerical behaviour that Dr Paddle finds "misleading". In the subsequent to husband's exposure comparisons, the significant difference in fetal mortality-rates was a result of pregnancy outcome associated with husbands younger than 30 years of age. This difference was significant at r<0-001 (ykslO-52, O.F.=>l). If vinyl chloride (v.c.) is indeed related to this observed difference, the excessive fetal mortality at these ages could, in theory, be a reflection of placing newlyhired personnel, with little or no seniority, in exposure cate gories that had relatively worse environmental exposures. In our paper of April 3 we cited eight references which have demonstrated that v.c. had elicited a positive response in mi crobial test systems and had been associated with significant excesses of chromosomal aberrations in lymphocytes of workers occupationally exposed to it. Three additional studies which alto have demonstrated a positive mutagenic response to L tr T :* 1 v T~*1. cy < ucc 061114 i \ I I \i i 1290 the lancet, juni 12,1574 v.c., have been drawn to our attention recently; in two of then studies, the microbial ttst system war used,11 while in the third, Tndtieantia waa used.1 Therefore, we do not agree with Dr Paddle's statement that this is an "isolated" question. Divimoa ol Surveillance, Hutrd Evaluation* nod Field Studte*, National Imtiiuu for Occupational Safety and HttMti QndMMi) Ohio 45226s U-SA. and Burra* of Ep*dem*okfY, Center for Dtaeaw Control and School of Fublic Health, Univcnny ofNorth Carolina Peter Fa Infante Josira K. Wagoner Amthowt J. McMichael RjcKawJ. Waxwe her Hum* Falk PLASMA-GLUCAGON AFTER PANCREATECTOMY Sir,--Dr Barnes aod Dr Bloom (Jan. 31, p. 129 reported no circulating immunoreactive glucagon (i-Rjg.) in both the basal state end after arginine stimulation in five pancreatectomiacd patients. Dr Gerich and his codeagues (April 17, p. 815) have made similar observations in another patient. We have evaluated i.r.g. dynamics in a totally pancreatectomised patient, with results quite different from thorn died above. Because of the heterogeneity of i.ra>. qirfiei measured by anti serum 30JC, we assay before and after acestme extraction. The post-extraction assay measures prrdnminaaety lx.g. of <9000 daltons (s-i.a.o.), and subtracting s-tJUC- from total plaamws-wa. (unextrseted) allows quantification of the larger molecular weight i.r.g. species (L-t.xdt.), A 30-year-old male, member of a multiple endocrine aden oma type i family, underwent a total pancreatectomy, hemigastrectomy, and duodenectomy in 1967 for removal of an in sulinoma. He has remained free of disease subsequently. Further evidence of total pancreatectomy was afforded by essentially unmeasurable basal levels of C peptide with failure to rise during an arginine infusion (by A. Rubetmein, Univer sity of Chicago). His basal, fasting concentrations of s-i.r.g. and l-i.r.0., before an arginine infiiawn, 24 h after receiving bis standard insulin dose (21 units lente and 10 units semilente) were 35 pg/ml and 104 pg/tnl, respectively. These values sre within normal limits for our laboratory. The accompany ing table depicts the plasma levels of small and large molecular weight i.r.o., glucose, and C peptide during the administration of arginine (500 mg/kg/30 min). The arginine infusion pro duced a small but definite rise in s-t.n-C. with no change in L-1.R.G. In addition, a 50 mgfdl increase in plaima glucose con centration occurred concurrently with the increase in s-l.R-G. Several factors may be involved in the difference betw een our observations and those of Dr Banes and IV Bloom. Unger et al., using antiserum 30K, failed to demonstrate i.r.g. in the plasms of pdncteatectomised dogs;14 s*2u*3b*s*eq9uently several itv.estigators'-* have observed circulating I.R.O. (30K) in pancreatectomised dogs (and other species) when they are deprived of insulin for several days, demonstrating the sensitivity of extrapancreatic alpha cells to inhibition by insulin. Because of ethi cal considerations achieving this degree of insulin deficiency may not be appropriate in man, but our patient may have been more insulin deficient than those previously reported. Although alpha ceils indistinguishable from pancreatic alpha cells have been repotted in the stomach of man,4 earlier u ork by Muller et al.14 failed to demonstrate a rise in i.r.g. (30K) with arginine infusion in two pancreatectomised patients. However, these patients did have significant piasma-t.R.c. 1. Gsrro, A J , Guttcnplsn. J. R.t Milvy, P. Muution Pwz. 1976.3> S l 2. Andrew,, A. W-, Zswistnwski, E. S., ViLeniinr, C. R. tied. ;ut the pro, 3. Npsfrow, A Peoonil cpmmunielllon. 4. Up|er, R. H , Ohnedo, A , A|uilsr.psrsda, E., Eiwmnw* A. y elin I'-en 1949,59,110, 5- Vrintc, M, Ptk. S., Kawsmori, R.0a6c#t, 1974,23.901. 4 MutuyuM.T., Fos, P. Nc. Sm. up. Biat. Mad. 1924.1*7. 7.Mathilcr, R., Hardin,. P., Chou, M., Mwtiilcr.G, Slaa. j- Diamond. D., Meld. J. Endoceenetogy, 1975,94,47t. 4- Dot*TM, rt., Sakurai, H., Faloofis, G., Valvefde, 1., fiaetenf. D, Orel, L, Unger. R. Scene*. 1975,117,544. 9. Unger, R. Uteei, 1975,1.1034. 10 Muller, W, Brennan. M., Tan, M,, Aoki, T. DiaAaw. 197a. * 12. if OLOCOSt, ICG . 4>D C PEPTIDE CONCINTUkTIOKS OUUSO ASCUUnt IxrcilOH Glu;t>e tag 41 ii-IUO. (pt/al) (Pl/m1) Control 10 20 25 30 35 45 60 90 22* 33 104 0*7 233 57 103 2*2 74 101 253 91 265 77 O'T 99 0.7 0*7 9| 2^3 61 274 51 92 99 levels in the basal state. Plasma contains several different mol ecular weight species that are measured as 5.R.G. (30K).11 >* Therefore, it is possible that the antiserum used by Dr Barnes and Dr Bloom does oot react with all the i.ilg. plasma com ponents measured in assays using antiserum 30K. In addition, the partial gastrectomy and duodenectomy that is usually done in conjunction with a total pancreatectomy in man may result in at least partial removal of the source of extrapancreatic glu cagon and may vary in different patients depending upon the extent of the surgery. While our patient is potentially unique in being a member of a family with multiple endocrine neoplasia, we fed that on the basis of his results we can only conclude that: (1) in this pancrestectomised man, i.r.g. (30K) of both Urge and small molecular weight(s) circulates in the basal state, and that at least the small-molecular-weigbt fraction shows a rise with arginine; (2) the increase in plasma-glucose that accompanied the s-i.r.g. rise suggest that this s-i.r.g. is biologically active; and (3) the existence of an extrapancreatic source of biolog ically active glucagon id man haa not been excluded- Department of Medicine, Diabetei Center, University of Washington* Seattle, Waihinfion 98144, L .S.A. Jerry P. Palmer Phillip L. Werner James W. Benson John w. Ensincr Sir,--We read with interest the article by Dr Bloom and Dr Barnes (Jan. 31, p. 219) on the absence of pancreatic gluca gon-like immunoreactivity (i.r.g.) in the plasma of pancreatec tomised man. The data generated diametrically opposed dev on the diabetogenic role of pancreatic glucagon by Dr Gench and his colleagues on the one hand (April 17, p. 855) and Dr Donowiiz and Dr Felig on the other (April 17, p. 855). We wish to add information which may help to resolve these con tradictory views. In contrast to the findings of Bloom and Barnes, we13 found high levels of "pancreatic" i.r.g. in the plasma of a pancteatectomised pauent, as did Muller et at.14 in two other patients. Although 509 of * he pancreatic I.R.G. could be accounted for by factors in plasma which interfere with the assay11 the rest appeared immunometrically as pancreatic i.r.g. and presum ably derived from an extrapancreatic source. In contrast to i.r.g. in porcine duodenal extracts,14 which closely resembles true pancreatic i.r.g., the i.r.g. in pancreatectomised human plasma is dissimilar in physicochemical properties (gel electro phoresis), is not stimulated by arginine, insulin hypoglycstmia, or tolbutamide, or suppressed by glucose, and has no apparent role in blood-glucose regulation.11 We have previously" referred to the various forms of gastrointestinal pancreatic i.r.g. found 1 1 VfiUcrJt, I, Dobbv, K , Lnjer, R Mataholufn, 1975,24* 102). t2, Vilverdt, l, \ ilUnueht* M., Lozano, |., Marco, J, J. </, Endoct. 1974, J9, 1090 13. Botha, J, I,., Vtmk. 4.1.. Child, F,, Jackie*, W. P l , U'npuWihhed. 14. Muller* W. A , Brennan, M F , Tan, M. H., Aoki, T. T. Diabtt**, 1974, 2J* 512, 15 Weir, C C, Turner R C. Martin, D. B. Norm m*t. Ft*. 1973* 5* 241. 16. Saak), H., Ruba!ci\a. 0., Bicteiu, D., Bta*quez, ., Srikaitt, C- B , Otvi. L.f Unger. R, H c>:t, Invtti. 1975, $6, 135. 17. Vimk.A L, J*;kwn, W. P, l' L*nctt 1975, i, 694. ucc 061115 if `wiences cot relation of clinical and cnId tin;l tMondc. Amcr. Ind. 1 U. Baiiinir. 1975. Clinical iscnic. Ann. N.Y. Acad. Sci. 1975. Further results in polyAcad Sci 246; 18-21. SUM, A. S. FlSCIItlUN 4 1. J. vinyl chloride .md polyvinyl 2 41. sense among polyvinyl work- 1975. Morphology of liver n. N.Y. Acad. Sci. 24ft: 278- 4 P, Gimme. 1975. Unusual itoncoscopy and guided liver irkers. Ann, N.Y. Acad. Sci. likoff 4 R. Warshaw. 197J. .posed to vinyl chloride and 42-52. ncogenic response of rat skin, 31: 516-519. sarcoma of liver in the manu6: 150-151. carcinogenicity bio-assays of aCi-Finding Hearing on PosUsc. y bioassays of vinyl chloride: 218. : J. C. Calandra. 1975. Inmicc to vinyl chloride. Ann. Mioblastoma multiforme. In F.d. Vol. 2: 2028. MeGraw- Morphological, Epidcmioloaiversitics Press. Oslo, Nor- 974. Frequency of different Jinlion exposure. Cancer 34: at. 1971. Histological types .7; 515-523. 1974. A study of the his* cring from asbestosis in the ity study of workers in the . Occup. Med. 1ft: 509-518. Blejer. This annal. . 1975. Observation on the jp. Med. 17: 128-131. I. 1, Scliroff. 1975. Morpolyvinyl chloride workers. Ann. NY Acad. Sci. Nt^Kre'T^/iristprint mnyfin nrrtprtori by copyright lakv (Title 17 U.S. Code). ONCOGENIC AND MUTAGENIC RISKS IN COMMUNITIES WITH POLYVINYL CHLORIDE PRODUCTION FACILITIES* - Pctcr'F, Infante Ohio Department oj Health Columbus. Ohio 43216 Much attention has been focused on the relation between vinyl chloride exposure and angiosarcoma of the liver.1"' Studies also have indicated that vinyl chloride produces cancers of multiple sites in laboratory animals ' and perhaps in humans.'1 Little information, however, is available regarding the relation between vinyl chloride exposure and the developmental status of prod ucts of conception among women associated with such exposure. In a study of stillbirths and miscarriages among wives of vinyl chloride workers in two plants, Sclikoff ** observed rates of 140/1,000 pregnancies in one population and 72/ 1,000 in a second population. Although there has been no explanation of these findings, a comparison of these data with those for the state of Georgia, which records all products of conception, results in rates that are two to four times greater than the rate in Georgia.1 Miscarriages and stillbirths from the latter source/ however, might still be underreported, especially in the first trimester of pregnancy. Because data on a national basis for miscarriages of all products of conception are lacking, it is difficult to determine whether the rates in the wives of these workers were actually higher than expected or whether they were the result of differences in case ascertainment. Ducatman and coworkers' also have observed a significantly greater number of chromosomal breaks in lymphocytes among workers exposed to vinyl chloride as compared to controls; these findings have been duplicated in Sweden.1* The relation of chromosomal breaks in plant employees to mutagenesis and birth defects in their children, however, has not yet been studied. In view of these observations, an epidemiologic study of the distribution of congenital anomalies in Ohio residents living in the three communities that have polyvinyl chloride production facilities was undertaken. Since the study by Tabershaw and Gaffey11 had shown an excess number of deaths from cancer of the ccniral nervous system, leukemia, and lymphomas among vinyl chloride workers, data from state vital statistics records for these neoplasms were also analyzed. The three Ohio communities that have polyvinyl chloride production facilities lie in the northeastern part of the state. Two cities, Painesville and Ashtabula, are situated about five miles from the coast of Lake Erie; the third, Avon Lake, * This study was initiated at the request of the Industrial Union Department of the AFL-CIO. Reprint requests should be addressed to Dr. P. F. Infante, Division of Field Studies and Clinical Investigations, Biometry Branch, P. O. Building, 5th and Walnut Streets, Room 515, Cincinnati, Ohio 45202. % \. v & k s>l s' '/ ' = ml# 4-' :M 'ii?< .' =/- V. ttiiJ ris%? 7fA`^ *U**V ,, IV,..- Ef*5 ^>a `^fiVsd - H*- tfc.* '7>J 8ft . '4$** " ' ^ 1jSftT; * . * ~ <i-'' - dtME 50 Annuls NV.v York Ae.ulcmy of Sciences is located on the lake. I'aincsville is about thirty nnlcs to the west of Ashtabula and Avon l.akc lies about fifty miles west of Painesvillc. The population of the three communities ranges from 24,000 in Ashtabula to 12,000 in Avon Lake, The polyvinyl chloride production facility in Ashtabula began operations in 1954; the one in Avon l.ake hegan in 1946. Two plants arc located in Painesvillc; one began operation in 1946 and the other began in 1967. Between the two census years I960 and 1970. the population of Avon Lake increased by thirty percent, whereas the populations in the other two communities have re mained about the same. The median family income in Painesvillc is equal to that of the state as a whole, the median income in Ashtabula is below the state median, and the income in Avon Lake is above it. Since 1968, information for specific congenital malformations in Ohio residents has been recorded on birth certificates.'" Since 1970, this information has been coded according to the International Classification of Diseases, 8th Revision, as adapted for the United States (Codes 740-759)." Any information recorded under the congenital anomalies section of the. certificate that did not fit into these codes was omitted from the analyses. Thus, data for conditions such as prematurity and hyaline membrane disease, and so on, were eliminated. Data for deaths resulting from cancer of the central nervous system, leukemia, and lymphomas in the adult population aged 45 years and older were also analyzed. For lymphomas, data for mycosis fungoidcs from 1958 to 67 were not included in the analyses. Results For the four-year period 1970-73, the numbers of children with congenital malformations and rates per 1,000 resident live births were computed separately for each of the three cities as well as for the entire state.'These data are shown in Table 1. For the entire state, the rate of malformations per 1,000 live births was 10.14. The rates in the three index cities ranged from 17.37 in Ashtabula to 20.33 in Avon Lake. If malformations had occurred in the three cities at the expected rate based on the state average (10.14/1,000 live births), the total expected number of children with malformations in each of the three cities would have ranged from 19.27 in Ashtabula to 7.48 in Avon Lake. As shown in Table 1, the differences between the observed and expected numbers of mal formations in each city were significant at the p < 0.01 level by the x~ lest. With data for all three of the cities combined, the occurrence of malformations was much greater than expected (*= = 27.13, p < 0.001). Malformations at birth in these three cities were then compared to congenital malformations for residents living in the balance of the three counties in which the cities were located. As shown in Table 2, the differences in the frequency of malformations were significantly greater in two cities versus the remainder of the counties. With data for alt three cities combined and data for all three counties combined, the difference in the number of malformations per 1,000 live births between the cities and the balance of the counties was highly signifi cant (p < 0.001), To maximize sample size, data for the three index cities were combined and the rates of malformations were computed for each year and compared to the rates for the balance of the counties and for the entire state. As shown in Figure 1, the rates for the balance of the counties and for the entire state appear to be about the same, whereas the rate in the three index Ohio Ashl pain Avo: AH i Disc t t 5 citii deg per wit ind ave Nt li ^ \ ' 'vv-FSv' ucc 061117 Scu nets Ui :1k- wt'l of Avht.ihula, lit. Hit population of the to 12.(100 in Avon Lake, ibulii began operations in onl-i arc located in Paines;an in 1067. Between the Avon f akc increased.by two communities have re in p.niiesvillc is equal to slitahnla is below the state alfoniiations in Ohio resi de 1970, this information .ification of Diseases, 8th -759)." Any information be certificate that did not Thus, Jala for conditions id so on, were eliminated, nervous system, leukemia, tars and older were also cs from 1958 to 67 were ' children with congenital were computed separately te. These data are shown ions per 1,000 live births from 17.37 in Ashtabula red in the three cities at 000 live hirths), the total h of the three cities would on I.ake. As shown in ipectcd numbers of mal- .01 level by the x testirrence of malformations ) n compared to congenital : three counties in which crcnces in the frequency ics versus the remainder d and data for all three nalformations per 1,000 unties was highly signifi- r the three index cities computed for each year nties and for the entire of the counties and for c rate in the three index Infante: Communities with PVC Production facilities 51 Iami t. 1 Rimdini Births, Maiiormation Rail Pib 1,000 Livj. llmnis in Ohio and in Thrie Si.irnLD Commlniiiis and Oislrvmi vs. Exwcti.d Nimiilrs of Malformations in Each City: Years Combust d, 1970-73 Area Ohio Ashtabula Paincsville Avon Lake All three communities Births 719,287 1,900 1,381 73* 4,019 Rate 10.14 17.37 18.10 20.33 18.16 Malformations Number Number Ob- Ex- served peeled t 7,295 33 25 15 73 -- 19.27 14.00 7.48 40.75 X1 __, 9.78 J 10.29 t 7.56 i 27.13 Malformations arc based on codes 740-759 of the International Classification of Diseases, Eighth Revision, 1968. f Expected numbers arc based on state rale/1.000 live births, t p <0,01. 5 p <0.001. cities is about twice as great and appeals to be increasing to a slightly greater degree with time. With regard to race, ten percent of the births during the period under study were among black women and ten percent of the children with birth defects indicated were also black. In addition, mothers in the three index communities who gave birth to children with malformations were, on the average, one year younger than mothers in the balance of the counties who Table 2 Number of Births and Malformations and Rates for Tiirff. Si u ctld Cities in Comparison to Occurrence in the Balance of tiie Counties in which the Index Cities are Located: Years Combined, 1970-73 Ashtabula Balance of Ashtabula County P.iinesville Balance of Lake County Avon Lake Balance of Lorain County All three cities Balance of all three Counties Births 1,900 4,821 1,381 11,842 738 18,544 4,019 35,207 Malformations Rates/1,000 N Live Births 33 17.37 68 14 10 25 18.10 84 7.09 15 20,33 222 11.97 73 18.16 374 [0.62 X* 0.96 18,27 * 4.03 t 18.21 t. s r* # *V J .. -..--.c.-tia . v.; :, ' ;.c. I: '** - >4. . 1 -T_~, x,',-7 ut' a,,C_-iir..,` '--*.J'2/' \ <. t\y< *'''' : . -V + X-S"* V` 52 Annals New York Academy of Sciences delivered children with eongcnil.il .'mum.dies. lino, r.iec and milcrii.il ,1^. djj not appear lo be related to llic olocivcil differences. In ilie llircc index ciiics the malformation rales at ihc ho'.pn.i] where most of the area children were born were consistently greater for the city children than for children from the balance of the counties born at these same hospitals. Therefore, differences in reporting attributable to specific hospitals did not appear to be a factor. On the basis of population size, three other county-city combinations were then matched to each of the study area county-city combinations and malforrnalion rates were computed for each city and balance of the county, as done previously for the study areas. The differences in the frequency of malforma tions between the balance of the counties and the cities were not significant. a t * 22 I i" iiH , l.s TVs# ln0#H Cltist . time t CfeMtn Efttits Sutg----- - M FOR 11 *Nt> l-"R Count) Ashtabul Lake Lorain * Cot Cil) v::` v *S.- l * /^Ssf'--.'vc '. -if **- A* ^ ^ ; "'7 ^ Zc f: '. ;"r $0% ''p'r U.) -t". V -GW*-** V -- *!<*.**F&- Figure I. Congenital malformations in Ohio residents in rates per 1,000 live births in the three index cities combined, in the balance of the counties in which these cities are located, and in the entire state, 1970-73. (ICD, 8th Revision Codes 740-759). Malformation rates were then computed for nine cities in the vicinity of the index communities that were most similar in size lo the index communities. In the surrounding cities, two of nine had significantly greater numbers of mal formations than expected. One community, Geneva, which is twelve miles from Ashtabula, and a second community, North Ridgeville, eight miles from Avon Lake, had rates of 25 and 27 malformations/1,000 live births, respectively. These data are shown in Table 3. Since North Ridgeville was proximate to Avon Lake, data for the former were combined with those from the three primary cities being studied, and the occurrence of specific malformations was compared to the expected, which was based on the state average over the period 1970-73, Table 4 shows data for observed versus expected defects and relative risks for specific malformations. Significant excesses were observed for defects Central Eye (7* Ear, fai Heart ( Other c Respirr Cleft p Otheri Other ' Gcnir Urina Clubf Other Other Skin, Other Multi *R -`'Af-irf-' V\ "V SSsasigsr-:-. a . ` ^ I ` -'a wIT-1J*&7. vmL T -Vs i ucc 061119 --tv -4-^" -r Sciences ace and maternal age did In the three index cities, f the area children were i,in for children from the Therefore, differences in 'ar to be a factor, y-city combinations were ibinations and malforma- of the county, as done frequency of malformawere not significant. in rales per 1,000 live ]f the counties in which ICD, 8th Revision Codes cs in the vicinity of the index communities. In eater numbers of maleh is twelve miles from eight miles from Avon ve births, respectively, nlle was proximate to those from the three ific malformations was verage over the period cd defects and relative e observed for defects Infante: Communities with 1*VC Production Facilities 53 Tame 3 County and Ciiy Population ano Number of Births, Malformations and Malformation Rate ff.r 1,000 lave Births tor the Three Ohio Cities where Polyvinyl CmoRine is Manufactured and for 10 Cutes Surrounding the Index .Cities: Years Combined, 1970-73 County Ashtabula Lake Lorain County Population * City 98,237 197,200 256,843 1. Ccmncaut 2. Geneva Ashl;ibuU t 3. Mentor 4. Willoughby 5. Eastlake 6. Wickliffe 7. Willowick Painesville t 8. North Ridgcvitle 9. Lorain City 10. Elyria Avon Lake t Popu lation * 14,522 6,449 24,313 36,912 18,634 19,690 21.354 21,231 16,536 13,152 78.185 53,427 12,261 Malfor mations IndiBirths cated Rule/ 1,000 996 433 1,900 2,767 1,459 1,618 1,077 841 1381 1,174 6.345 4.811 738 12 12,05 II 25.40 33 17.37 20 7.23 3 2.06 10 . 6.18 7 6.50 4 4.76 25 18.10 32 27.26 71 11.19 46 9.56 15 20.33 * County and city population figures are based on estimates of 1972 population. * City with polyvinyl chloride manufacturing facility. Table 4 Observed vs. Expected and Relative Risk for Specific Congenital Anomalies in Index Areas: 1970-73 Defeci Category Central nervous system (470-749) Eye(744) Ear, face, neck (745) Heart (746) Other circulation (747) Respiratory system (748) Cleft palate and lip (749) Other upper alimentary tract (750) Other digestive system (751) Genital organs (752) Urinary system (753) Clubfoot (754) Other limbs (755) Other musculoskeletal (756) Skin, hair, and nails (757) Other unspecified (758) Multiple systems (759) Number of Cases Observed Expected 17 5.62 0 0.58 2 I3J 3 2.32 1 0.48 2 0.57 10 6.54 12 2.33 4 1.90 16 8.40 0 0.56 23 8.23 13 11.10 1 1.88 5 2.78 2 0.54 3 3.63 RR * 3.02 0.00 1.48 1.29 2.08 3.51 1.53 5., 5 2.11 1.90 O.CO 2.79 1.17 0.53 1.80 3.70 0.83 - -* 4 T-*"1 ' -Jr- 1 '* ,v .i 1?V' 's H ` 13 ;5 * *| t ` *> \. ' '.~.;-*iqfe i- ---- ' tfi; -. . . Zii..' ._ '-V : rjv ;- -A-'';1 -Vi'- Fv ., - *r, V*V; ft'V 1 *\ r vV-V;,/' * -JJ1 ~ -S-->.*EJ 54 Annuls New York Academy of Sciences of the central nervous system, upper alimentary tract, genital organs, and clubfoot. Because of the severity of the defects involved, the greatest cause f0f concern appears to be defects of the central nervous system. These were anen ccphaly, spina bifida, and hydrocephalus. Since slate records indicated that two-thirds of the children with anenccphaly are found among stillhirths, observed versus expected anomalies of the central nervous system were computed f0r stillbirths and live births of residents in the three communities with polyvinyl chloride production facilities, plus North Ridgeville, which was located proxi mate to Avon Lake. With all communities combined, the data in Tabi.e 5 show that there were significantly greater numbers of central nervous system defects than expected, both among stillbirths and live births. Among stillbirths and live births combined, there were 25 CNS defects observed versus 8.42 expected More than half the cases occurred in Paincsvillc and six each occurred in North Ridgeville and Ashtabula, whereas none were observed in Avon Lake. There were 8 CNS anomalies versus 2.8 expected among stillbirths and 17 versus 5.6 expected among live births. Of the eight stillbirths, four had anencephaly, three had spina bifida with hydrocephalus, and one had hydrocephalus only. All four of the stillbirths with anenccphaly occurred in Paincsville. Since the report by Tabershaw and Gaffey" has shown an excess of deaths from CNS tumors, leukemia, and lymphomas among workers exposed to vinyl chloride, observed deaths from these cancers were compared to the expected number for the white population ages 45 years and older for the period 1958-73. Since there were no deaths reported in blacks for any of these cancers, data are shown only for whites. The risk of death from these cancers in the community is expressed as a Standardized Mortality Ratio (SMR),15 which is the ratio of the number of observed to expected deaths based on a standard population times 100. The Ohio white population over the same period was used as the standard population. With the data for all four communities combined, Table 6 shows there were 38 deaths from CNS tumors versus 24 expected, significant at p < 0.01 by x5-testing. The greatest contribution to the excess CNS tumors Table 5 CNSObserved and Expected Anomalies of the and Relative Risk among Live and Stillbirths in the Index Area Communities: 1970-73 Ashtabula Paincsville Avon Lak N. Ridgeville Communities Combined Among Stillbirths Observed/ Expected RR* 2/1.03 5/0.75 0/0.40 1/0.63 1.95 6.70 0.00 1.58 8/2.81 2.85 * RR = relative risk, t p <0.001. Among Live Births Observed/ Expected RR 4/2.05 8/1.49 0/0.80 5/1.27 1.95 5.36 0.00 3.94 17/5.61 3.03 Live and Stillbirths Combined Observed/ Expected RR 6/3.08 13/2.24 0/1.20 6/1.90 1.95 5.80 0.00 3.16 2J/8.42 2.97 t Observed for Resin Coitinu Ashtabula Paines'ill' Avon I.ak N. Ridge' Ooiiiniutii bined Ashtabul. painesvif Avon La' N. Ridge Commur bined Ashtabu painesvt Avon Ls N. Ridg< Commit bined * ICC P< deaths the an: have t excess 420. obser amon D lympi same tumo data . cantly white s-fp# <Wvv'' UCC 4 061121 t .[ tel. jvnilal urg.ins, .mil club Ivcd, lilt gic.itcst finite for in system. T hese were linenst,ilo records indicated that id among stillbirths, observed . system were computed for communities with polyvinyl !c. which was located proxid, the data In Table 5 show mral nervous system defects ribs. Among stillbirths and served versus 8.42 expected. i six each occurred in North ,-rved in Avon Lake. There stillbirths and 17 versus 5.6 ths, four had ancnccphaJy, ic bad hydrocephalus only, in Paincsville. . shown an excess of deaths ig workers exposed to vinyl compared to the expected Ider for the period 1958-73. y of these cancers, data are : cancers in the community R)," which is the ratio of on a standard population nc period was used as the utumitics combined. Table sus 24 expected, significant to the excess CNS tumors !S ano Relative Risk Communities: 1970-73 Live and Stillbirths Combined Observed/ * Expected RR ?5 6/3.08 1.95 16 13/3.24 5.80 >0 0/1.20 000 >4 6/1 90 3.16 t3 25/8.47. 2.97 t Infante: Communities witlrYV'C Pioduction Facilities 55 Tami l 6 OllSI HVIII AND 1 ` M't t till CaNCLM DiaTIIS ANO SrANI)AMI)l/I I) MoitlAIMV Kaiios i ok R/siiiinis 45 Vi aks and Oii>lh IN Iniii x Com muni t n x iiv Six: 1958- 73 * Communities Ashubula Paincsville Avon Lake N. Ridgeville Communities com bined Ashtabula Paincsville Avon Lake N* RidgeviUc Communities com bined Ashtabula Paincsville Avon Lake N. Ridgcville Communities com bined Males Obv/F.xp. $M* Females , Obs./Exp. SMR 7/6.90 12/4.26 2/1.68 6/1.43 CNS (191-192) 10! 6/4.74 282 2/3.14 119 1/1.05 420 2/0.87 127 64 95 230 Leukemia ;md Aleukemia (204-207) 13/12.63 8/7.47 1/2.70 2/2.47 103 107 37 81 11/9.38 7/6.34 5/1.84 0/1.68 117 110 272 0 18/14.77 12/8.88 4/3.50 3/3.07 Lymphomas (200-203) 122 14/12.29 13 J 4/8.25 114 5/2.53 98 1/2.25 114 48 198 44 Sexes Combined Obs./Exp. SMR 13/11.64 14/7.40 3/2.71 X/2.30 38/24.07 112 189 110 348 158 t 24/22.01 15/13.81 6/4.54 2/4.15 47/44.51 109 109 132 48 106 32/27.06 16/17.13 9/6,03 4/5.32 61/55.54 118 ' 93 149 75 110 * 1CD 8th Revision Codes, f P <0.01. deaths was from mate residents of Paincsville. If these were eliminated from the analyses, the differences between expected and observed deaths would not have been significant. Although the numbers are small, the data also show an excess of CNS tumor deaths in North Ridgcville males, who had an SMR of 420. If these findings arc compared to the data in Table 5, it may also be observed that the same communities had the greatest excess of CNS anomalies among stillbirths and live births, especially Paincsville. Deaths attributed to leukemia and aleukemia (Codes 204-207) and to lymphomas (Codes 200-203) in the communities appeared to be about the same as the expected. For the balance of the counties, mortality from CNS tumors and leukemia was not significantly different from the expected, t hese data are shown in Table 7. Deaths from lymphomas, however, were signifi cantly lower among white males in the balance of I.orain County and among white females in the balance of Ashtabula County. . -vv. H.: ill t^ : l .? f* ''. i A Z, >' s5 T* yx f ) * /` I;; -- . ; . , v -yfct ^!.. tot* imwi J_ *" -M P^. --T- FA, Wlr KMKT. - -W'rzr* L ' vrx '?*' > , z?- z***+* - L-* -y- ; 1 uiaU qri 177 ^ :: * Discussion and Summary The results of the findings suggest that mothers living in communities with PVC-production facilities gave birth to an excess number of children with congenital malformations as compared to the expected based on the state average or based on the experience in the balance of the counties in which these cities arc located. Other county-city combinations matched by population size showed no significant differences in incidence of congenital malformations. Maternal age, race, and possible differences in hospital reporting were not considered factors accountable for the observed differences. With regard to specific mal- ,IlcC CJ1C the bcivsccr and sill Ia of the' Table 7 OnsravED ano Expected Cancer Deaths and Standardized Mom achy Ratios ior Residents 43 Years and Older in Balance of Counties, by Sex; 1958-73 Balance of County Ashtabula Lake Lorain Ashtabula Lake Lorain Ashtabula Lake Lorain * p <0.05. t p <0.01. CNS (191-192) Males Obi-/Exp- SMR Females Obs./Exp. SMR 19/21.42 89 11/13.26 83 32/34.78 92 19/21.41 89 30/S0.89 98 39/31.95 122 Leukemia and Aleukemia (204-207) 44/38.15 49/50.55 91/83.37 115 97 109 24/26.30 39/35.56 53/59.54 91 no 89 39/45.05 78/64.76 78/101.60 Lymphomas (200-203) 87 120 77 * 16/34.32 50/48.37 74/78.76 47 t 103 94 Sexes Combined Obs./Exp. SMR 30/34.68 51/56.19 89/82.84 87 91 107 68/64.45 88/86.11 144/142.91 106 102 101 55/79.37 128/113.13 152/180.36 69 t 113 84 * 1. C 2. fI 1. C 4. N 5. < ( 6| 7. 8. 9. 1 to. 11. formations, anomalies of the central nervous system appear to be of the greatest concern. An excess number of central nervous system defects was observed among stillbirths and live births from the index cities, with the exception of Avon Lake. Most of the excess, however, was attributable primarily to Painesville and secondarily to a community located proximate to Avon Lake, North Ridgeville. Deaths from central nervous system tumors in adult male residents of Painesvillc and North Ridgeville were also significantly greater than expected. On a community basis, excess deaths from the other cancers were not apparent. Since many underlying factors could be responsible for the mutagenic and/or teratogenic and carcinogenic mechanisms involved, these preliminary findings obviously do not link polyvinyl chloride production with the increased occur* * '.iy uf S, knees VIMARY niters Ihing in communities with -xccss number of children with ipci ted hnsed on the Male average he counties in which these cities niched by population size showed jcnital malformations. Maternal 1 reporting were not considered cs. With regard to specific mal- Infante: Communities with PVC Production Futilities 57 icnee of congenital malformations .utd cuilr.il netvous system tumors, hut indi cate the need for further study of possihlc contributing factors. Possible relations between central nervous system tumors in adults and ( NS defects among live and stillbirths in other populations might also be given consideration. Acknowledgments I appreciate the assistance of Mary Smith, Nancy Stafford, and Karl Wise of the Vital Statistics Department, Ohio Department of Health. References StANDARDtzr.D Mortality Ratios L Ol- Counties, BY Sex: 1958-73 nates sp. SMR 6 83 1 89 S 122 cmia Sexes Combined Ohs./Exp. SMR 30/34^68 51/56.19 89/82.84 87~ 91 107 i 1. Creech, J. L. Jr. 4 M. N. Johnson. 1969. Angiosarcoma of liver in the manu facture of polyvinyl chloride. J. Occ. Med. 14: 150-151. 2. Center for Disease Control, 1974. Angiosarcoma of the liver among poly vinyl chloride workers--Kentucky. Morbidity and Mortality Weekly 23: 4950. 3. Center for Disease Control. 1974. Angiosarcoma of the liver--Connecti cut, Morbidity and Mortality Weekly 23: 210, 216. 4. MaRSTF.ller, H. J. & W, K. Lelbach. 1974. Unusual splenomegalic liver dis ease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. In Program of New York Academy of Sciences Working Group on Toxicity of Vinyl Chloride--Polyvinyl Chloride. New York, N.Y. May 10-11. 5. MaLToni, C. 4 G. Lefemine. 1974. Carcinogenicity bioassays of vinyl chlo ride. I. Research plan and early results. Env. Res. 7: 387-405. 0 91 6 110 4 89 68/64.45 88/86.11 144/142.91 106 102 101 6. TaBershaW, I. R. i XV. R. GaffeY. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occ. Med. 16: 509-518. 7. Georgia Dept, of Human Resources. 1971. Vital and Morbidity Statistics, Atlanta: 22. 8. Ducatman, A., K. Hirschorn 4 I. J. Selikoff. 1975. Vinyl chloride exposure and human chromosome aberrations. Mutation Res. 31: 163-168. 2 47 t 7 103 6 94 55/79.37 128/113.13 152/180.36 69 t 113 84* 9. Funes-Cravioto, F., B. Lambert, J. Lindsten, L. Ehrenberg, A. T. Natarajan & S. Osterman-Golkar. 1975. Chromosome aberrations in workers exposed to vinyl chloride. Lancet i: 459. 10. Naylor, A., A. P. Eaton, E. R. Aplin 4 B. Eska. 1974. Birth certificate revi sion and reporting of congenital malformations. Am. J. Pub. Health 64: 786791. 11. U. S. National Center for Health Statistics. 1968. International Classifica tion of Diseases, Adapted for use in U.S. 8th edit. : 338-361. U S. Public tern appear to be of the greatest is system defects was observed Health Service. Washington, D.C. 12. Liuenfeld, A. M., E. Pedersen 4 J. E. Dowd. 1967, Cancer Epidemiology: Methods of Study : 106, Johns Hopkins Press. Baltimore, Md. 13. Selikoff, I. J. Personal communication. :\ cities, with the exception of ittrihutablc primarily to Paines- roximate to Avon Lake, North tumors in adult male residents nificantly greater than expected, thcr cancers were not apparent, nsiblc for the mutagenic and/or ved, these preliminary findings :tion with the increased occur*