Document G5Vo7jxvYdy64a39MQoNrknG7

c- _ MANUFACTURING CHEMISTS ASSOCIATION 182b CONNECTICUT AVENUE, N.W. WASHINGTON, D C. 20000 (202) 483-6126 WV / SUBJECT: Reports and Articles of Interest Gentlemen: Enclosed are copies of the following: DECEIVED '976 " - CUM^rr 1. Report on "Congenital Central Nervous System Malfor mations, Kanawha County, West Virginia", from the Center for Disease Control, Public Health Service-CDC-Atlanta, EPI-7660-2, July 26, 1976. 2. Title pages of papers supplied by Dr. Torkelson: (a) "Toxicology of Vinyl-Chloride Monomer", by J. G. Budlovsky, M.D., presented at C.I.C. Conference, London, Ontario, June 1, 1976. (b) "Gefahrdung von Konsument und PVC-Arbeitern durch Vinylchlorid", by Ch. Schlatter, Toxikologie 106, 647-650 (1976). (c) "Untersuchungen uber die Reaktivitat von Stoffwechsel-produkten des Vinylchlorid", by H. M. Bolt et al., presented at a symposium in Bonn 1976. (d) "untersuchungen zum Stoffwechsel von Vinyl chlorid unter dem Blickpunkt der chemischen Karzinogenese", by H.M. Bolt et al., Institut fur Toxikologie der Universitat Tubingen und Institut und Poliklinik fur Arbeits-und Sozial- medizin der Universitat Koln. BOR 010379 (e) "Vinyl Chloride-Associated Liver Disease", reprinted from Annals of Internal Medicine, Vol. 84, No. 6, June 1976. h*/ 6 yXc . -2 3. Items supplied by Dr. Mayo Smith are: (a) "Genetic Risks of Vinyl Chloride", Lancet, page 1079, May 1976. (b) "Working Group for Vinyl Chloride Code of Practice", including papers by A. J. Fox and P. F. Collier. (c) "Summary of Presentation by Dr. W. Freiesleben on the Vinyl Chloride Issue". 4. Notice of intent by NIOSH to review certain Criteria Documents including VC. Federal Register, Vol. 41, No. 147, Thursday, July 29, 1976, pages 31585 and 31586. 5. Key pages from Midwest Research Institute report, "Evaluation of the Environmental Toxicants, Vinyl Chloride and Vinylidene Chloride (VDC), by Cheng-Chun Lee et al.. Progress Report No. 9, January 1 through March 31, 1976. (VC) 6. Availability of new photocopy facilities at MCA. 7. Copy of January 1976 financial statement, inadver tently omitted from the minutes of the last meeting. Sincerelv. MF: ec Enclosures Milton Freifeld Project Manager Vinyl Chloride Research BOR 010380 ITEM 1 * COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE 'O TECHNICAL PANEL, AUGUST 27, 1976, MR. M. FREIFELD ;/ Vs''' FOR ADMINISTRATIVE USE LIMITED DISTRIBUTION NOT FOR PUBLICATION PUBLIC HEALTH SERVICE-CDC-Atlanta EPI-76-60-2 July 26, 1976 fjore'! TO : Director, Center for Disease Control FROM : Cancer and Birrh Defects Division Bureau of Epidemiology SUBJECT: Congenital Central Nervous System Malformations, Kanawha County, West Virginia SUMMARY Data available through the Birth Defects Monitoring Program (BDMP) revealed that from 1970 through 1974, Kanawha County, West Virginia-- where 1 of the 40 polyvinyl chloride production plants in the United States is located--had rates of congenital central nervous system defects that v;ere significantly higher than national EDMP rates for those years. In February 1976 an investigation was undertaken because of the possibility that these higher than expected rates may have been related to parents' occupational or residential exposure to vinyl chloride. The study confirmed that an increase in CNS defect rates had occurred in Kanawha County, and cases clustered primarily in the area east of the plant; however, no relationship between infants with malformations and parents' exposure to vinyl chloride could be estabjisbed, INTRODUCTION Because of continuing concern regarding the possibility that birth defects of the central nervous system (CNS) may be caused by parents' occupational or residential exposure to vinyl chloride, CDC's Birth Defects Branch, Cancer and Birth Defects Division, Bureau of Epidemiology, reviewed 1970-1974 data available through the Birth Defects Monitoring T>rcp,rar'. (BDMP), a hospital-based system for monitoring the inci dence of birth defects end other newborn conditions noted in infants discharged from approximately 1,200 Uniter5 States hospitals (1). Of the 40 polyvinyl chloride (PVC) pro duction plants in the United States (2), 17 are located in counties which have at least ] hospital that was participating in the BDMP in 1974 and thus could be included in the review. In 10 of the 17 counties, BDMP data arc reported on less than 50% of the total reported births: therefore. even though higher than normal CNS rates were noted in 2 of these count os, they were not included in this study because of the low percentage of total birth.' they represented. In the 7 counties where the majority of births are reported to the BptIP, 2 had rates of CNS defects in infants born from 1970 through 1974 that were significantly higher than national BDMP rates for these years: Lake County, Ohio (Painosville), the sice of a previous investigation (3), sod Kane...ha County, West Vi"giniv. Hie Kanawha County findings (Table 1) were discussed with William L. Cooke, M.D., West Virginia State Epidemic1 rgls% and Peter Infante, D.D.S., Dr.P.H., National Institute BOR 010381 for Occupational Safety and Health (NIOSH), who agreed with the need for further Investigation. On February 10, Larry Edmonds, M.S.P.H., and Carol E. Anderson, M.D., met with Or. Cooke in Charleston, West Virginia, and began an investigation. Others who participated in the investigation and in the preparation of this report included Joseph Carney, Director, and Lucas Neas, Statistician, West Virginia State Department of Health, Division of Vital Statistics; Paul Seekford, M.D., Director, and Edna Smith, R.N., Charleston-Kanawha County Health Department; and Carl Beard, II, Director, West Virginia Air Pollution Control Commission. BACKGROUND The principal centers of population in Kanawha County (1970 population 229,113) are Charleston, South Charleston, Dunbar, St. Albans, and Nitro. All are located along the Kanawha River, which flows from southeast to northwest through the valley's hilly terrain. In 1970 the chemical industry employed 12Z of the county's work force. There are 7 major chemical plants and several smaller ones in the Kanawha River Valley within 10 miles of Charleston. Only 1 of these plants produces PVC. This Diant, which beean production in 1935, uses the solvent, emission, and modified emulsion processes. Vinyl chloride monomer (VCM) is released into the atmosphere as part of the production process. METHODS Two data sources were used in this investigation: 1) BDMP listing of infants born with CNS defects from January 1, 1970, through December 31, 1974, and 2) West Virginia Department of Vital Statistics records (birth and fetal death certificates) on infants born with CNS defects from January 1, 1.968, through December 31, 1974. Data obtained from these 2 sources were not entirely comparable (4), since BDMP data represented 95X of all hospital births in Kanawha County without regard to parents' residence, and vital statistics records represented only those infants born to county residents. The data were examined separately for trends, and then both sets were combined to deter mine all CNS defects incidence for 1970 through 1977*. A case was defined as a hospitalconfirmed CNS defect in an infant born between January 1, 1970, and December 31, 1974, to parents who were residents of Kanawha County at the time of the infant's birth. We reviewed hospital records to confirm diagnoses, rule out miscoding, and check each mother's place of residence. For each confirmed case, we selected 2 controls from vital statistics records. These controls, all with parents "who resided in Kanawha County, were the first liveborn infants without malformations born immediately before and after an infant with a CNS defect and were matched according to the following criteria: 1) month of birth, 2) race, 3) paternal education (number of years: 0-8, 9-12, and 13 and over), and 4) maternal age within 2 years. With the permission of the attending physicians, we interviewed by telephone the families of affected infants and 1 randomly chosen control. The following information was obtained: 1) history of previous pregnancies, including information about miscarriages, stillbirths, and children with malformations in their family, 2) 5-year residential history before and including the year of birth of the child in question, and 3) 5-year occupational history for both parents, including location of work and exposure to chemicals. Case and control families could not be interviewed blindly, since the families often remarked about either the malformation or the normal development of their child. The Kanawha County Health Department and the NIOSH staff assisted in locating families who had changed residences and/or jobs and those who did not have telephones. 2 BOR 010382 RESULTS Except for 1974, Kanawha County rates shown in the BDMP for total CNS, as well as the particular defects anencephaly and hydrocephaly, were higher than U.S. rates (Table 1). A decline In total CNS defect rates In Kanawha County was noted In both data sets (Tables 1 and 2). In both data sources, the total rates In 1974 were distinctly lower than those in previous years, although the decline was also evident in the 1973 vital records data. Earlier data were available only for 1968 and 1969 from vital records. In both years, there were fewer cases than there were in 1970. The highest BDMP rates for all defects occurred in 1971. Preliminary BDMP data obtained for 1975, the year following the study period, showed that total CNS rates were similar to U.S. rates. Table 1 Reported Incidence* of CNS Malformations in Kanawha County, West Virginia, and the United States Birth Defects Monitoring Program, 1970-1975 Anencephaly Kanawha Co. U.S. 1970 1971 1972 1973 1974 Cases Rate Cases Rate Cases Rate Cases Rate Cases Rate 3 9.0 6 16.3 6 16.6 2 5.2 4 9.6 5.6 5.4 4.9 4.9 4.4 Spina bifida Kanawha Co. U.S. 4 12.0 8 21.8 1 7.2 7.9 2.8 4 10.5 2 7.4 6.4 4.8 6.0 Hydrocephalus ** Kanawha Co. U.S. 2 6.0 4 10.9 2 4.8 4.9 5.5 4 10.5 0 4.9 4.5 0.0 3.8 Other CNS Kanawha Co. U.S. 3 9.0 1 2.7 2 5.5 1 2.6 0 0.0 4.2 3.9 4.4 4.1 4.2 Total CNS Kanawha Co. 12 35.9 19 51.7 11 30.5 11 28.9 6 14.4 U.S. 21.8 22.1 21.6 19.9 18.4 *Rates per 10,000 total births **Excludes cases with spina bifida Table 2 Incidence* of CNS Malformations Reported through Vital Records**, Kanawha County, West Virginia, Realdenta, 1968-1974 1968 1969 1970 1971 1972 1973 1976 Cases Rate Cases Rate Cases Rate Cases Rate Cases Rate Caaes Rate Cases Rate Anencephaly 5 13.6 3 7.6 9 24.1 5 13.2 6 17.5 3 9.0 - 0.0 Spina bifida 6 16.3 3 7.6 5 13.4 4 13.2 2 5.8 - 0.0 1 3.0 Hydrocephalus 2 5.4 2 5.1 2 5.3 3 7.9 S 14.6 2 6.0 - 0.0 Other CNS - 0.0 - 0.0 - 0.0 1 2.7 - 0.0 - 0.0 - 0.0 Total CNS 13 35.4 8 20.3 16 42.8 13 34.4 13 37.9 5 15.0 . 1 3.0 *Rates per 10,000 total births **Blrth and fetal death certlflcatea. West Virginia State Department of Health 3 BOR 010383 Confined rates for Kanawha County for the hospital and vital statistics data are given in Table 3. The rates were high from 1970 through 1972, with a decline in 1973 and only 1 case reported in 1974, giving a 1974 rate well below expected. Forty-seven confirmed CNS defect cases were in infants born to residents of Kanawha County at time of the child's birth. Families of 46 of these infants and of their matched controls were located and interviewed. Five infants' parents were not residents of Kanawha County at the time of conception and were excluded from further analysis. All mal formed Infants were white, and females predominated (25:16), as usual in anencephaly and spina bifida cases. No seasonal variation was noted in the rates. Of the spe cific defects, anencephaly had the highest rate. Table 3 Confirmed Cases and Rates* of CNS Malformations, Kanawha County Residents, 1970-1974 Malformation Anencephaly 1970-1974 1970 1971 1972 1973 1974 Cases Rate Cases Rate Cases Rate Cases Rate Cases Rate Cases Rate 23 13.0 9 24.1 5 13.2 6 17.5 3 9.0 - 0.0 Spina bifida 15 8,5 4 10.7 6 15.9 3 8.7 1 3.0 1 3.0 Hydrocephalus 7 4.0 - 0.0 3 8.7 3 8.7 1 3.0 - 0.0 Other CNS 2 1.1 1 2.7 1 2.7 - 0.0 - 0.0 - 0.0 Total CNS 47 26.7 14 37.5 15 39.7 12 34.9 5 15.0 1 3.0 Per 10,000 total births Age, Education, and Socioeconomic Index - Close case-control matching was achieved for paternal education, maternal age, and Hollingshead Index, an indicator of socioeconomic status (Table 4). Case and control groups were also comparable regarding maternal edu cation (12.4 and 12.0 years, respectively). Paternal age was slightly older in the case group (27.3 years) than in the control group (25.8 years), but the difference was not statistically significant. Table 4 Age, Education, and Socioeconomic Index, CNS Defect Cases and Controls, By Malformation Matching Variables Paternal education* Maternal age* Total CNS Anencephaly Spina Bifida Other CNS Cases Controls Cases Controls Cases Controls Cases Controls 12.6 12.8 12.6 12.2 13.7 14.1 10.9 12.0 24.3 23.9 24.8 24.4 25.8 25.1 24.3 20.3 Non-matching variables Paternal age* 27.3 25.8 26.8 26.4 29.2 26.5 25.4 22.7 Maternal education* 12.1 12.0 11.9 11.9 12.7 12.5 12.1 11.9 Hollingshead Index Mean score Class *Mean number of years 47.5 IV 45.5 IV 49.3 IV 48.5 IV 4 ` 38.9 38.6 III III 58.3 IV 49.4 IV BOR 010384 Generally, cases and controls were similar In the specific defect categories. Among the specific defect categories, parents in the spina bifida group (both case and control) had the highest education and were the oldest; in the "Other CNS" category (mainly hydrocephalus), parents had the least education and were the youngest. Reproductive History - The total number of previous pregnancies of mothers in the case group (49) was almost the same as that observed for mothers In the control group (48). Other similarities included live births (cases 78%, controls 77%), fetal deaths (cases 22Z, controls 23%), and other children with congenital anomalies (1 in each group). The fetal death rates among cases and controls were higher than the rate of 16.1% reported by Warburton and Fraser (5). A family history of birth defects was reported by 11 of 41 families in the case group but by only 4 of 41 in the control group. Five "case" parents and no "control" par ents reported a family history of CNS defects. A possible explanation for the differ ence is that parental recall is affected by the birth of a child with a congenital malformation (6). Occupation - Two "case" fathers and 2 "control" fathers were employed in the PVC plant at the time their affected infants were conceived. Fathers of 3 additional controls had worked in the plant on a contract basis for a short time and therefore also had had possible exposures. None of the mothers in either group had ever worked at the PVC plant. One other occupational category is worth noting. In the case group, 2 mothers were employed in dental laboratories when they became pregnant, and 2 fathers had worked in dental laboratories before their infants were conceived. Parents in the case and control groups were asked about the location of their place of work at the time of their infant's conception. Only parents with a permanent work location were counted, thus excluding workers such as truck drivers and salesmen. The homes of housewives and unemployed parents were considered to be their place of employment. On this basis, distance from work place to the PVC plant was calculated. No difference was observed between case and control groups for either parent regard ing distance of work place from the PVC plant. Residence - Parents' place of residence at time of their infant's conception was plotted on county maps, and we then calculated distances from the PVC plant. Table 5 presents the mileage from the plant by 1-mile Increments up to 15 miles. Using a chi-square test at 1-mile intervals, we found no significant difference between the 2 groups. Matched pairs of cases and controls were also tested by using the matched pair t-test of significance; no differences were noted. Table 5 Residential Distance from PVC Plant, Cases and Controls, By Malformation Distance from Plant (Miles) Total CNS Cases Controls Anencephaly Cases Controls Spina Bifida Cases Controls Other CNS Cases Controls <1 3200 3200 <2 440034 10 <3 9 10 1 5 5 4 3 1 < 4 14 14 4 6 6 5 4 3 <5 17 15 6 7 7 5 4 3 < 6 21 16 9 8 8 5 4 3 < 7 23 17 9 8 10 6 4 3 <8 24 22 10 10 10 9 4 3 < 9 27 24 12 11 11 9 4 4 < 10 30 30 15 13 11 11 4 6 < 15 35 34 19 16 12 12 4 0 TOTAL 41 41 21 21 13 13 7 7 5 BOR 010385 Although no differences were observed In measured distance within concentric circles, within the 3-mile zone of the PVC plant, there were more case family residences In the area northeast of the river and more control family residences in the area south of the river (Figure 1). Fig. I CONGENITAL CNS DEFECTS CASES AND CONTROLS, CHARLESTON-SOUTH CHARLESTON, WEST VIRGINIA, AREA Using the PVC plant as the origin, we determined x and y coordinates for parents' residence at time of each infant's conception (case and control groups). Four cumulative groups were defined for both cases and controls based on distance of residence from the PVC plant: <3 miles, <5 miles, <10 miles, and the total group. Case and control groups were then compared for statistically significant differences in their respective centers of gravity (average position), using multivariate extensions of the Wilcoxon matched-pairs signed-ranks test and the Kruskal-Wallis test (2). The matched-pairs test was used to test the total group (all case-control pairs). Since in the distance-defined groups case-control pairs were split, these 3 groups were analyzed by the (unpaired) Kruskal-Wallis analysis of variance. The only significant difference was for infants in the case and control groups whose famili s resided within 3 miles of the plant (p <.02) 'Table 6). 6 BOR 010386 Table 6 Significance Testing of Differences in Centers of Gravity, CNS Defect Cases and Controls Distance from Plant X2 (2 Degrees of Freedom) Probability <3 miles 5 miles 10 miles All distances 8.72 3.06 1.09 0.91 <.02 >.20 >.30 >.50 The case and control parents who resided within 3 miles of the PVC plant at their child's conception had a higher socioeconomic status than those who resided more than 3 miles from the plant, as reflected by a class III Hollingshead Index; the remaining group had a class IV. The distribution of this group by date of birth was similar to the remaining group. There were 9 infants in the case group: 5 with spina bifida, 2 witli congenital hydrocephalus, 1 with microcephaly, and 1 with enencephaly, Tn at least 3 cases there was evidence of a familial component to the defect occurrence. One mother gave birth to 2 of the infants: 1 with spina bifida and another with anenc.ephaly. Another case mother reported that her sister had spina bifida, and a third mother had a cousin with a heart defect. Although familial components do not exclude an environmental cause, they do suggest the possibility of genetic causation. There was no difference in previous stillbirths or abortions between case and control parents who lived within 3 miles of the PVC plant or between these parents and those who lived more than 3 miles from the plant. No difference was noted between the mean years of residence of case parents (1.9) and control parents (2.0) who lived within 3 miles of the PVC plant. Environmental Studies - Atmospheric and environmental data related to VCM and other emissions in Kanawha County are limited. Data on VCM emissions provided by the South Charleston plant at the request of the West Virginia Air Pollution Commission are provided in Table 7. The data included the average amount (pounds per hour) of each year's emissions from 1967 through 1975 and the number of abnormally heavy emissions. On October 1, 1974, after the largest known single emission in the years 1967-1975, measurements were made by plant personnel in the community. The wind was blowing from the southwest, and the highest atmospheric VCM levels (grab samples) were to the northeast (.1 - .2 ppmv). The wind patterns in Kanawha Valley are variable according to the season of the year, time of day, and place of measurement. Monthly wind measurements also made at the plant indicated that the wind was blowing out of the south and west 42% of the time, and north and east 33% of the time during the months the infants with CNS defects were conceived. 7 BOR 010387 Table 7 Annual Average Vinyl Chloride Monomer Emissions, South Charleston Plant, West Virginia Year Emissions (lbs/hr) Estimated Number of Abnormally H< 1967 1968 1969 1970 1971 1972 1973 1974 1975 240 260 250 260 270 235 265 180 76 28 18 12 5 2 0 *Amounts ranged from 1,000-8,000 pounds, with an estimated average of 2,000 Source: Polyvinyl chloride plant, at the request of the West Virginia Air Pollution Commission Should the release of emission coincide with the southwest winds, then one might expect that more emissions could be blown from the plant to the northeast. The West Virginia Air Pollution Control Commission measured suspended and settleable particulate matter, another indicator of wind direction, at various points within the community (Table 8). The reported levels were greater in the southwest, suggesting a prevailing wind from the northeast. Table 8 Mean Annual Levels of Suspended and Settleable Particulate Matter, 1965-1975 Year Geometric Mean Suspended Particulate Matter (microgram/cubic meter) 12 Arithmetic Mean Settleable Particulate Mat (tons/square mile/month) 13 1965 1967 1968 1969 1970 1971 1972 1973 1974 1975 1970-1973 1967-1973 205 171 150 136 102 105 123.2 160 113 131 107 107 93 94 114.5 92.2 133.2 82.3 68.6 47.6 30.0 24.0 18.0 57.7 62.0 68.9 63.6 35.4 35.9 24.0 24.0 15.0 18.5 13.3 38.1 'South Charleston High School (southwest) *Federal Building, Quarrier Street (northeast) *North Charleston Fire Department (northeast) Source: West Virginia Air Pollution Control Commission 8 BOR 010388 DISCUSSION The investigation in Kanawha County confirmed that an increase had occurred in total congenital CNS malformation rates in 1970-1974. Rates were highest in 1970-1972 and dropped in l`)73 to hcluw national rates and in 1974 to only 1 confirmed case. Such a decline was not unique to Kanawha County. A similar, though less marked, trend was also present in BDMP data for other parts of the country. Furthermore, preliminary 1975 BDMT data on CNS defects for the county were higher chan 1974 data, suggesting that the apparent low incidence for that year may reflect the variability of small numbers. As in the Faincsvflle sLudy (3), there were no differences between case and control groups regarding parents' prv-sihle occupational exposure to VCM or to other environmental agents at time of their child's conception or for 5 years before conception. On this basis, there was no evidence that the high CNS defect rate for Kanawha County was related to parental occupation in industries producing PVC or other chemicals. A difference be twees, the .locations of residences of the case and control groups within a 3-mile radius of the plant was noted. Although approximately the same number from each group resided within the 3-mile area, those in the case group tended to live east of the plant, and those in the control group lived across the river and south of the* plant. Such a pattern might be chance distribution, or it could be related in some way to an environmental exposure limited to the part of the city lying oust of the plant. Aside from a slightly higher socioeconomic status, there was nothing to distinguish the families of cases and controls from other families who lived within the 3-mile area. Furthermore, there was no difference in the attribution of the types of defects or the years of birth (or concept ion}. Since the investigation was undertaken because of a possible association between the high CNS defect, rates observed in Kanawha County and the presence of a PVC plant, we gave partii.ular attention to the possibility that the cluster may have been caused bv increased VCM emissions. To explain the case cJustii on the basis of a teratogenic effect of atmospheric VCM exposure, one woul'* also expect an approximate correlation between a decrease in atmospheric ''M levels and a fall in CNS defect rates. The decrease in CNS rales which occurred in 1973 preceded the decline in measured VCM emissions and lagged considerably behind the overall decrease in particulates noted in the late 1960s. This investigation did not reveal an association between the case clustering within 3 miles of the plant and exposure to VCM or other chemicals. Available data suggest that atmospheric, and mctcorologic conditions along the Kanawha River are variable. To propose that some wind-born teratogen had settled in a particular location in the community, one would have to postulate also the timing of plant emissions with the appropriate wind direction and other atmospheric conditions. No data are available to reconstruct such circumstances. Furthermore, it must be noted that over 100 compounds other than VCM have been associated with emissions from the plants in the Kanawha Valley area. One study estimated rh.u. 5.1,457 tons of organic compounds, including VCM, were emitted each yea- by Charleston ehcr-.iral plants (8). Some of these coronounds have been identified as toxic to animals and humans; their individual and combined teratogenic potentials are not known. 9 BOR 010389 Although there was a cluster of CNS defect cases to the east of the PVC plant In Kanawha County, the role of VCM or other compounds in explaining this cluster is conjectural at present. REFERENCES 1. Center for Disease Control: Congenital Malformations Surveillance, Annual Summary 1974. Atlanta, CDC, 1975 2. Environmental Protection Agency: Scientific and Technical Assessment Report on Vinyl Chloride and Polyvinyl Chloride. Issued June 1975 3. Edmonds LD, Falk H, Nissira JE: Congenital malformations and vinyl chloride. Lancet, 1098, Nov 1975 4. Hay S: Variables in underreporting of clefts on birth certificates. Public Health Rep 82:985, 1967 5. Warburton D, Fraser C: Spontaneous abortion risks in man: Data from reproductive histories collected in a medical genetics unit. Am J Human Genet 16:1, 1964 6. Fraser FC, Warburton D: No association of emotional stress or vitamin supplement during pregnancy to cleft lip or palate in man. Plastic and Recon structive Surgery 33:395-399, 1964 7. Puri ML, Sen PK: Nonparametric Methods in Multivariate Analysis. New York, John Wiley, 1971, pp 184-193 8. Department of Health, Education, and Welfare: Kanawha Valley Air Pollution Study. Washington Government Printing Office, 1970 Larry D. Edmonds, M.S.P.H. Birth Defects Branch Cancer and Birth Defects Division Bureau of Epidemiology Lcvuxf (2* Carol E. Anderson, M.D. Birth Defects Branch Cancer and Birth Defects Division Bureau of Epidemiology J. William FlyntJ, Jr.,\$.D. Chief, Birth Defects Branch Cancer and Birth Defects Division Bureau of Epidemiology Clark W. Heath, Jr., M.D., Director Cancer and Birth Defects Division Bureau of Epidemiology DISTRIBUTION Mailing keys 53-1,2,3 William L. Cooke, M.D., State Epidemiologist, State Department of Health, State House, Building 3, 1800 Washington Street E., Charleston, West Virginia 25305 Joseph Carney, Director, Department of Vital Statistics, State Department of Health, Building 3, 1800 Washington Street E., Charleston, West Virginia 25305 Page H. Seekford, M.D., Director, Kanawha County-Charleston Health Department, 1426 Kanawha Boulevard E., Charleston, West Virginia 25301 Carl G. Beard, II, Director, West Virginia Air Pollution Control Commission, 1558 Washington Street E., Charleston, West Virginia 25311 Ralph Rhodes, Director, Toxic Substances, Environmental Protection Agency, Region III, Sixth and Walnut Streets, Philadelphia, Pennsylvania 19106 John Finklea, M.D., Director, National Institute for Occupational Safety and Health, 12420 Parklawn Drive, Rockville, Maryland 20852 Bobby F. Craft, Ph.D., Deputy Associate Director for Cincinnati Operations, National Institute for Occupational Safety and Health, U.S. Post Office Building, Room 543, 1014 Broadway, Cincinnati, Ohio 45202 Peter Infante, D.D.S., Dr.P.H., Biometry Branch, Division of Field Studies and Chemical Investigations, National Institute for Occupational Safety and Health, U.S. Post Office Building, Cincinnati, Ohio 45202 10 BOR 010390 Robert W. Miller, M.D., Chief, Epidemiology Branch, National Cancer Institute, National Institutes of Health, A-521 Landow Building, Bethesda, Maryland 20014 Lawrence A. Plumlee, M.D., Medical Science Advisor, Environmental Protection Agency, 401 "M" Street, S.W., Room 905, West Tower (RD 678), Washington, D.C. 20460 Arnold H. Spellman, Manager, Project Development Croup, Information Services, Commission on Professional and Hospital Activities, 1968 Green Road, Ann Arbor, Michigan 48105 Gabriel Stickle, Vice-President for Program, National Foundation-March of Dimes, 1275 Mamaroneck Avenue, White Plains, New York 10605 Daniel C. Seigel, S.D., Chief, Biostatistics Section, Epidemiology and Biometry Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 31, Room 2A10, Bethesda, Maryland 20014 11 BOR 010391 ITEM 2 (a) Jlii i,.) COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANEL, AUGUST 27, 1976, MR. M. FREIFELD TOXICOLOGY (V VUJYL-CHLOiU DL MONCv'iir, ^ je>7c' ^ This paper was presented at the occupational health session of the C.I.C. Conference, London, Ontario, June 1, 1976. The speaker from Occupational Health Protection Branch, Toronto, was responsible for setting the VCM level in Ontario at 10 ppm in the atmosphere. He stated that the 1 ppm level, commonly accepted by some regulatory agencies, is unrealisticly low. J. 0. Butllovshy, M.D. MEDICAL COYSCLTANT occi!P.vno\-\:# health xlot cal sicc-icr. occi'i'ATk>;;al health protectu'1.: BOR 010392 VK.'Y! -t\!l ' K1 !,P. ''iiivl eh 1 i r i iio < tli 1 > j i 11 y 1 ) is a chlori noted hydrocarbon It i r. a color!"..-. heavier than ;.-ir, i l :> density be i lift 2.10. It, is flat ii.-ab11 ami 1 nr J ve S 1.1 HE boiliny point - vapour pivsf.n'*o 700 utn lift (13.80) II is r.l iftlif.lv f.i'iu'il e in voter, soluble :i n ethanol, very soluble in ethyl of her. It. in a colorless fay with a v ark sweetish odor resembling c.hlc.roform. Its YLV is 10 p.p.u. or 20 ing/m^ with a C-.level of 25 p.p.m. for 15 minutes. Itr. sweet odor can lit: detected only in high concentrations. All chlorinat.ed aliphatic hydrocarbons have common Lor.ic effects, lliey ore si.iur. 1) neurotoxic -------------- depressant of the CMS 2) local irritant --------------- respiratory tract, eyes, skin 3) systemic toxic --..... ....... liver, kidneys. Wit h all chlorinated hydrocarbons, acute and chronic intoxication can ho expected. Tie acute intoxications very often have a hi phasic course. In tin', first phase, usually anesthesia prevails, win:teas in the second phase, the cyst eiuie. effects like liver damage develop. Thi'S'1 can 1 1 oi'<e eliroai: consequences of acuLe Intoxications. BOR 010393 Schweiz, med. Wschf. 106. Nr. 19 (1976) JLiLM 2 (b) : *V6 647 31 O'Brien J. R.: Aspirin, haemostasis and thrombosis. Brit. J. Haemat. 29, 523(1975). 32 Patzold U.. Engelhard! P.: Cerebrate Gcnissver'ehlUssc in jungen Lcbcnsjahren. Ein Benrag zur Frage der dtiologischen Bedeutung oraler Ovulationshcinnter. Nervcnarzt 45. 602 (1974). 33 Phillips L. L-.Turksoy R. N..Southam A. L.: Influence of ovarian function on the fibrinolytic enzyme system. II. Influence of exogenous steroids. Amcr. J. Obstet. Gynee. 57. 1216 (1961). 34 Quick A. J.: Salicylates and bleeding The aspirin tolerance test. Amer. J. med. Sci. 252. 265 (1966). 35 Reed D. L.. Coon W, W.: Thrombocmbolies in patients receiving progestational drugs. New Engl. J. Med. 769. 622 (1963). 36 Vessey M. P.. Koll K.: Investigation of relation between use of oral contraceptives and thromboembolic disease. Brit. med. J. /965/11. 199. 37 Weiss H. J., Aledort L. M.. Kochw-a S.1 The effects of salicylates on the hemostatic properties of platelets in man. J. clin. Invest. 47, 2169(1968). 38 Wcnig Ch.: Cerebrate Ischitmic und Ovulationshemmer. Dtsch. med. Wschr. 99. 1521 (1974). 39 Wijuja I... bnijdcr J A.. Nieweg H. O.: Acclylsalicylic acid as a cause of pancytopenia from hone marrow damage. Lancet 10661 It. 768. 40 Wilbert L.. Hillmer T., Hunstetn W, et al.: F.inDuss oraler Ovulationshemmer auf klimsch-cheinische Normalwerte. Dtsch. med. Wschr. 94. 844 (1969). 41 Wohlfeil R., Schifter R., Schliack H.: Schlaganfalle junger Frauen bei Einnahmc von Ovulationshemmern. Fortschr. Neu rol. Psychiat. 41. 166(1973). 42 Wright I. S.: FDA report on Enovtd: ad hoc advisory committee for evaluation of a possible etiulogic relation with thrombo embolic condilions. J. Amcr. med. Ass. 185, 776 (1963). 43 Zucker M. B,, Peterson 1.. Inhibition and adenosine diphosphatc-induced secondary aggregation and oiher platelet func tions by acclylsalicylic acid ingestion. Proc. Soc. exp. Biol. (N.V.) 127, 547 (1968). COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANEL, AUGUST 27, 1976, MR. M. FREIFELD Toxikologie 0 Schweiz, med. H'schr. 106, 647-650(1976) Institut fbr Toxikologie dcr Eidgenbssischen Technischen Hochschule Zurich.und der Universitat Zurich Gefahrdung von Konsument und PVC-Arbeitern durch Vinyichlorid Also, the risk of liver hemangiosarcomas should not be higher under present working conditions than in the general population. Worldwide, 42 cases of VC sarco mas have been described among the 20000 to 40000 workers exposed since 1930. The consumer uptake of VC from PVC-packaged food is almost a million times lower than the carcinogenic threshold dose, and this rules out any danger arising from that source. Ch. Schlatter Zusammenfassung. In den vergnngenen zwei Jahren wurde die Vinylchlorid-Exposition der Arbciter in PVC-Polymerisationsbetrieben massiv gesenkt, so dass weitere Falle der vorwiegend das Bindegewebssystem betreffenden, seit 10 Jahren bekannten VinylchloridKrankheit nicht mehr auftreten diirften. Ebenso diirftc die Wahrscheinlichkeit der Entstehung von Hamangiosarkomen der Leber unter den gegenwartigen Expositionsbedingungen nicht mehr hoher als bci der Allgemeinbcvolkcrung sein. Bislter sind auf der ganzen Welt unter den scit 1930 expontcricn 20000-40000 PVC-Polymcrisations-Arbcttcrn 42 Sarkomfallc bckannt geworden. Die Bclastung des Konsumcnien mit Vinyichlorid in Lebensmitteln aus PVC-Vcrpackungsmaterial ist mehr als 10'mal geringer als die karzinogene Dosis, so dass cine Gefahrdung durch dicse Quelle nicht bestcht. Summary. Over the past two years the level of exposure of workers in PVC polymerization factories to vinylchloride has been greatly lowered. Titus there should be no further cases of so-called vinylchloride disease, which mainly affects the connective tissues. Korrciponden;: Prof. Or. Ch. Schluln-r. Inrntut fur ToMkologir. Sehorensiratie 16, CH-860J Sihwcrzenhuch twi Zurich Vinyichlorid- Krankheit In den vergangenen zehn Jahren traten in verschiedenen PVC-Produktionsbetrieben bet 10-20% der Arbeiter, die jahrelang Vinylchlorid-Konzentration von 100-500 und mehr ppm ausgesctzt waren, Erkrankungen auf (Zusammenfassung der bis Mai 1974 bekann ten Bcfunde bei Selikoff und Hammond [5]). Insgesamt wurden auf der ganzen Welt zwischcn 1000 und 5000 Arbciter betroffen. Die Hauptveranderungen bestanden im Abfall der Thrombozytenzahl und in Bindegcwcbswucherungcn, vor allem entlang dcr Blutgefasse. Dies fuhrte z.u Zirkulationsstorungen in den Handcn (erhohte Kaltccmplindlichkcil, schmerzhafte Gefasskrampfe [Raynaud-Syndrom| und Abbau des lctztcn Knochengliedes [Akroosteolysc]), in der Haul (Bindegewebsinfiltrationcn wie bei Sklcrodcrmic). in den Lungen (Restriktion des funktionstiichtigen Gewebes; Partialinsulfizicnz) und in der Leber (periportalc Fibrosen mit portalcr Hypertonic, leichte Funktionscinbussen (Erhohung der Transaminascn und er hohte Bromsulphthalein-Rctentionl). Die Erkrankungen. die relativ Jeictil diagnostiziert und im Anlangsstadium, solangc nur ein Ablall der Thrombozytenzahl vorliegt, wahrschcinlich auch vOllig geheilt werden konnen, traten bei niederen Konzcntraiioncn nicht auf. Wegen dcr heute allcrorts eingeleiteten Schutz- M^ BOR 010394 JUi 1 S '.976 .. us deo Institut fUr Toxikologic der Gniversltat TUbingen und den. Institut und PolAklinik flir Arbeitc- und Sozialmedizin der Waiversitlit Koln COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE- TECHNICAL . . PANEL, AUGUST 27> 1976,' MR. M. FREIFELD ' ... Wntorsuchungen iiber die Reaktivitat von Stoffwechsel- produkten des Vinylchlorid .. HM* Bolt, H. Kappus, A. Buchter und W. Bolt %# . Einleitung , ,, Ht * Die vorliegenden Konzcptionon zum molekularen Kochanismus der 'chcainchen Kanzerogenese gehen davon aus, dafi ein cheraischcc Nonzero- # gen - entveder selbst Oder in der Form eines in Organisraus gebildeton reaktiven Metaboliten -- nit makromolekularcn Zellbectandteilen in Y/echselwirkung tritt (eieho z.B. die Uberslchten von Miller, 1970; Stier,1973? Grelm,1974)* Hierbei konzentriert sich das Intercsse auf die Mbgllchkcit, daB durch irreversible (kovalente) Bindung von reaktiven Substanzen an zellulare DNS die genetische Information der Zolle verandert v/erden kann. .Daraus sich ergebondo mutagene V/irkungen v/eraen in bakteriellen Testsystcncn untorsucht (Groim, 1970* Andorerscits konnen solche Effckte durch somatische Mutationen zur 4 Kanzerogcnocc flihren* Aus dieson Grundcn konzentrierten sich unsere in Folgondcn zusannengofaBten Arbciten Uber Vinylchlorid (VC) auf die Frago der nogliehen Interaction von reaktiven Vinylchloridnetabo- litcn nit MakrcnolckUlon in Sinnc oiner kovalcntcn Bindung an Protcinc Und HukleinsUurcn. Ur.sere Untcrsuchungen v/urden caratlich an Ratten BOR 010395 V VJ u Ko6<j ,-mc ITEM 2 (d) COPIED AUGUST BY MCA FOR DISTRIBUTION TO 27, 1976, MR. M. FREIFELD THE VINYL CHLORIDE TECHNICAL PANEL, Untcrcuchungen zun Stoffv/cchscl von Vinylchlorid untor dcm Blickpunkt der c-henicchen KarzinogcneGe E.M. Dolt, E. ICappuG, A* Buchter und \'U Bolt InGtltut liir Toxikologic dor Univcrsitat Tubingen und Institut und Po3.1klinik filr Arbelto- und Sozialmedizln der Universitat Koln .Eouectc Untcrcuchungen haben gczcigt, daft Vinylchlorid (VC) in vivo oincc GOhnellen Stof fv-T.-chcel untorllegt (l - 6). Ale primarcr Metabolit t v/ird dabcl wahrschcinllch das nehr roaJttionsfahige Epoxld (Chlorathylcroxid) gcbildct (3, 6 9), Renktionen von Kotaboliten dcG Vinylchlorid Bit makre-olckularcn Zellbectandteilen sind von groftea Intercsse, da dicce in Zusac'-mennang mit der Wirkung dec Vinylchlorid ale chcmicchcs Knnzorogcn gesehen werden. In baktoriollen Toctcystcncn v/urde fectgeetollt (8, 10, 11), daft nikrosonale Enzyme der Leber aus Vinylchlorid ! lite bilden, die nutegenc 'iVirkungen bccitzcn. V/ir konnten friiher zeige (12), daft bei Inkubationen in vitro mit Lebcrmikroconcn und NADFH ebenfalls Metabolite entotchon,. die irrcvorsibcl (kovalont) an SKGruppen cnthaltcnd;. pro trine und an Kukleinsauren (RNS) binden* Auch nach Vinyl c.h? ori(k.T'>;pocition von Ration in vivo clnd in der Leber BOR 010396 j. i __ Reprinted Ironi ANNAI S OF INI fltMAI MEDICINE Vul. B4; No. G Juiiu, 1970 HrmU'l in U.S.A, JUL 1 !)V]/I) COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANEL, AUGUST 27, 1976, MR. M. FREIFELD Vinyl Chloride-Associated Liver Disease Moderator: PAUL D. BERK, M.D., F.A.C.P. Discussants: JAMES F. MARTIN, M.D.; ROBERT S. YOUNG, M.D., F.A.C.P,; JOHN CREECH. M.O.; IRVING J. SELIKOFF, M.D.; HENRY FALK, M.D.; PHILIP WATANABE, Ph.D.; HANS POPPER, M.D., F.A.C.P.; and LOUIS THOMAS, M.D.; Gethesda, Maryland Although polyvinyl chloride has been produced from vinyl chloride monomer for more than 40 years, recognition of toxicity among vinyl chloride polymerization workers is more recent. In the mid 1960s, workers involved in cleaning polymerization tanks were found to have aero-osteolysis. In 1974, the same populat'on of workers was found to he at risk for an unusual type of hepatic fibrosis and angiosarcoma of the liver. We describe two cases of vinyl chloride-associated liver injury, one of hepatic fibrosis and one of angiosarcoma. Histologic features of these lesions are simi'ar to the hepatic fibrosis and angiosarcomas resulting from chronic exposure to inorganic arsenicals. Preliminary studies suggest that the toxicity of vinyl chloride may result from formation, during high-dose exposure, of active metabolites by mired function oxidases of the liver. Epidemiologic studies indicate an increased incidence not only of liver disease, but also of cancers of the brain, lung, and possibly other organs. Dr. Paul D Berk*: Polyvinyl chloride, the most widely used synthetic plastic, has been manufactured for more than 40 years by polymerization of vinyl chloride monomer gas at a number of plants in the United States and in many Other countries. Worldwide production of polyvinyl chlo ride in 1972 totaled more than 18 billion pounds, of which about 25% was made in the United Slates, and items manufactured from po'yvnyl chloride arc virtually ubiq uitous. They include building materials such as pipes and cables, home furnishings, toys, records and other recrea tional items, clothing, packaging material, and a host of other products. Although for many years vinyl chloride monomer and polyvinyl chloride were Ihmiglil to he en tirely inert, in the mid-1960s Wilson anil associates (I) in Louisville and investigators in Europe (2-4) reported that the development of acro-ostcolysis, a skin disorder characterized by Raynaud's phenomenon, scleroderma Chief, Section on Diseases of the Liver, Digestive Dfve.iv branch, National Institute of Arthritis, Metabolism, and Digestive Diseases. An edited transcription of a Combined Clinical Staff Conference at the Clinical Center, Ilcthcsda, Maryland, 14 November 1974. by the National Institute of Arthritis, Metabolism, and Digestive Discuses, N.inoiul Institutes of lical h, U $, Department of Health, Education, and Welfare. Annals of Internal Medicine 84:717 731, 1976 like dermal induration, and bone lesions, was an occu pational hazard to workers involved in the polymerization of vinyl chloride monomer. At greatest risk were those who manually cleaned the tanks in which the polymerization reaction occurs. At the same time, other reports described nonspecific alterations of hepatic structure and function in vinyl chlo ride monomer polymerization workers (5), and a poorly characterized condition called "chronic epithelial hepatitis" was reported in roughly 15% of such workers examined in Russia (6). These reports of hepatic abnormalities in the vinyl chloride industry, published for the most part in the industrial hygiene literature of eastern Europe, at tracted little attention until very recently. Then the situation was dramatically altered by the almost simultaneous reports of hepatic fibrosis, splenomegaly, and portal hypertension among vinyl chloride workers in Germany (7), and the discovery of three cases of angiosarcoma of the liver, an otherwise rare tumor, in workers involved in the production of polyvinyl chloride from vinyl chloride monomer at a plant in this country (8, 9). The subsequent introduction into this plant of a systematic surveillance system has thus far resulted in the detection of several more cases of angio sarcoma, as well as many instances in which abnormal findings in liver function tests, or scintigraphic evidence of splenomegaly, or both, were detected in otherwise asymp tomatic workers. Similar screening efforts at polyvinyl chloride production plants in several countries quickly brought the number of workers with documented angiosar coma to 19 (10) t- Not all of these cases have been pub lished. Results of animal experiments strongly support the pre sumed relation between exposure to vinyl chloride gas and hepatic angiosarcoma. Italian investigators (11) had re ported several years ago that rats subjected to prolonged inhalation of high concentrations of vinyl chloride devel oped carcinomas of the zymhal gland and other organs. More recently, Maltoni and LcFcminc (12) presented data t As of 10 February 1975. the Center for Disease Control Knew of 27 cases of hepatic angiosarcoma >n vinyl chloride workers: 15 in the United States, 6 in Canada, 2 in the United Kingdom, 3 in Germany, and 1 in France. 717 'I BOR 010397 . -.4 i! '------J1 . Lji III i 44 ^a, ismt?--.** 111 i ifrsl*. i Va*!1 ITEM 3 COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANEL, AUGUST 27, 1976, MR. M. FREIFELD flin 4N(.F.T, MAY U, 1976 (a) 1 he subject being spontaneous abortion, the use of a ques tionnaire, and the ensuing low response-rales, can be viewed sympathetically, but musi detract from the accuracy ol the study. Ihc data are presented only after an age adiustiiHtu procedure which behaves very misleadingly. A crude percent age of 10-1 for a sample whose average age is 26-4 is adjusted violently downwards io 6 -1, while a figure of 16-5 for a sample of average age 30-2 is only reduced marginally io 15 x, Pre sumably the adjustment is heing done within the study and the small sample st/c is the cause of this anomaly. It would have been better to'havc adiustcd all the figures in accordance wuh national figures, but perhaps, in such a delicate area, such stat istics arc not available or are unreliable. It is to be hoped that the complete study will be published without delay, with the above omissions rectified, so that n svill be possible to put this, at present isolated, question in context. Central Medical Group. Imperial Chemical Industrie*. Wrfmttow, Chethire SK9 1QH G. M. 1'ADDLt SOCIAL STIGMA AND TUBERCULOSIS Sir,--You have stated1 that "Within the U.K. tuberculosis Fix. 2--E-mcttlng nil, in 1J mollof-b*hy pair,. is no longer feared. It is widely known io be curable with little inconvenience to the patient and it carries little, if any, social r<0001, paired I test). For the F-rosetting cells the mean for the mothers vm 68-3(o (s.d. 2-')%) and for the babies 61-9 (J.D. 3-7','e). I bis diffrrence ten is significant (p<0 001) and the correlation coefficient is also significant (r. 0-74, p<0-005) (fig- 2). The E rnieties in the mothers tanged from 63% to 72%. We had no counts of less than 50',r and cannot calculate in the same way as llnlbrccht and Knmlos, but our counts for the babies ranged from 58" to 65'r which is higher than their figures and nearer the mean of 53% reported by Campbell et al.* and Steel ct al.1 1 here is considerable variation in Ii-rosette counts due to technique. We used the method described by Sticmswiird et al.' In testing each mother anil baby's cells together, however, variation due to technique should not greatly affect ihc ratios. rhe normal range of T cells in newborns is probably wide. However, our findings suggest that there is a direct relation* ship between the number of F-iosetiing ceils in some mothers and their babies. Since these cells are the maior subpopulation of pcnpheral-hlood lymphocytes, it is likely that the correla tion between the total blood-lymphocyte counts is largely due to the correlation between the H-roscttmg cells (T cells). This raises the possibility that these cell populations in the fetus arc vgulatcd by maternal factors. stigma". Personal experience in Belfast showed that fear still existed in some patients before their disease was explained to them. Because of this we have tried to find out if social stigma still exists. We asked 32 patients with pulmonary tuberculosis and 31 controls with other chest diseases of similar age, sex, and social background, about their attitudes towards their disease. In the tuberculosis group only 2 of the 13 with a family history of tuberculosis and 7 of the 19 without such a history knew that it was still possible to develop the disease in Belfast. In fact, there are at present about 100 new cases notified each year in a population of 600 000. Only 17 of the 32 patients with tuberculosis knew that their disease was infectious. 2 university students were among the group who did not know. A similar proportion thought the dis ease was in some way related to an inherited weakness of ihc chest. Both the tuberculosis group and the contrul group were asked if they had any sense of shame or similar emotional feel ings because of their illness. 5 of the 31 control patients expressed feelings of inferiority, shame, embarrassment, and a sense of social isolation. These were all related in specific physical disabilities such as cough, sputum, or dyspnrra 12 of the 32 tuberculosis patterns described feelings of shame, in feriority, and a fear of social ostracism. None of these altitudes IbriMh ll.itl ('hiMfin'i Hospital, 'L.fHhr.irr M9 2AA D. I, K, Ev*NS were related to specific physical complaints. 1 he interview with another patient was cancelled due lo obvious embarrass ment and shame about discussing the disease. An additional 4 1... ""sutaji < hmn and Unit KfklMM'l IlMllltllr, tWkw MTU VtlX N.Vyramfroumthuthe group of tuberculosis patients although not sulfcring from a direct social stigma about the disease expressed a sense M. Palmer ofguilt and shame at the reflection of their hie style I he.se pa tients were males who had been heavy drinkers with tamihcs, although none were alcoholics. GENETIC RISKS OF VINYL CHLORIDE Improved social conditions here in (he pusi helped to reduce the incidence of pulmonary tuberculosis. However, in nuns !5r,-- ilic insertion in ihc paper by Or Infante and his col large cities there is increasing alcoholism, overcrowding, squat leagues (April 3, p. 7341 that *`a significant excess of fetal loss ting, and drug taking, as well as an increase in the numbers w;n observed among wives following exposure to v.c.M*'* is of old people. Such features may arrest the downward trend mh.Ii as in have justified much more complete presentation. in notifications of the disease. Jf ihc lack of knowledge about Anv assertion o|\m.h intportance should at least be supported tuberculosis and the continued social stigma mol lust in elderlv h\ a specification ot the methods ol datu collection, and a tabu lation ol the raw data before analysis. patients) exist in other areas of the U.K. then perhaps now is the time to increase public education ahoui a prv-'nt.ib1.- .-nd curable disease. 1 I Jtmilsll t I . \\.ill.1.1` , Wot.l, |,, Avmlrv tirrrn, A , Vu, V I'/in . If. Imtmt" 19 74. |K, 41.4 -V Sicvl. t- M , l-.v.n,, Smith, M. A. I.umeet, 1971,,, 914 1. Suconwilnl, J., JunJiil. M , Vinky, F., Wig/cll, H-, i*ly, R. iM. 1*73, i, IJJ1. Fiw.itrtirdfi IImpilal, Ucilut Ills Hills I. Lmutti, J97J, U, JJ. John Cumviiis l:RHn SUSHIRI) BOR 010398 ffCStAKCl I A 01', BOR 010399 Abstracts of papern submitted fot publication on the Mortality ..ludy of Workers xp ned to Vinyl Chloride Monomer. (A) the MO.m.LTPY of wchk;-:bs r.xpo.i) to vinyl j.hlohidk MUKOMod. IN THE .MANUrC7U:<r; Or HOL'/VINYl, ONLO.IIDL IN OrtsAT M.< IfA IN Hy A.J.FOX find P.F,COLLIER . <zs to *-- <x. cc X t s 0) Identification particular:; were obtnind for over 7,000 men who were at fiome time between 19^0 and 197* exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride. Approximately 99% of these have been traced and their mortality experience studied. The overall standardised mortality ratio, V5**4, shows a .significant reduction compared with the national rates. Four cases of liver cancer are found. Two of these have been confirmed by a panel of liver pathologists as angiosarcoma and two as not angiosarcoma. There is no evidence supporting the hypothesis that cancers other than those of the liver are associated with exposure to vinyl chloride monomer. The two cases of angio ;arcoma were found in men who has been exposed to high concentrations although the second man died only eight years after exposure. The industry in Great Britain has expanded considerably since the Second World War with over 50 per cent of men having entered within the last decade. Conclusions drown aboutjtbe influence of vinyl chloride monomer on the mortality experience of men in this indust ry must consequent ly be tempered bv the reservation that, the fu IL impact may not yet be in evidence. (Submitted to the British Journal of Industrial Medicine) (B) LOW MOHTALITY RATES IN INDUSTRIAL COHORT STUDIES PITS TO SELECTION TOR WORK AND SURVIVAL IN THE INDUSTRY By A.J.FOX and P.K.COLLIER Occupational groups are often described as relatively healthy because their mortality rates are lower than the national average. Although correct this confuses the issue for those interested in assessing the effects of exposure to a particular chemical. By a further analysis of data collected in a study of oil men ever `'xpo.ed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain, three factors h*ve been shown to contribute to the low mortality rates that were observed. The three factors, the selection of a healthy population for employment; the.survival in the industry of the healthier men; and the length of time that this population has been pursued, have all been quantified. The mortality experience within five years of entering this industry was shown to be as low as 27 per cent of that expected; for circulatory disease and respiratory disease as low as 21 per cent. There was a progressive increase in standardised mortality ratio with the length of time since entry such thut the effect had almost disappeared 15 years alter entry. To avoid confounding the selection effect with the survival effect the latter was measured by separating men who survived 15 years after entering the industry according to whether or not they were still in the industry after this period, Thoso who hnd left experienced an overall standardised mortality ratio some 50 per cent higher than those still in the industry. This effect although consistent in the age groups between 25 and '/l\ und all cause groups studied was greatest in those aged between 25 and and for lung cancer and respiratory disease. (Submitted to tint British Journal of Preventive and Social Medicine) COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANEL, AUGUST 27, 1976, MR. M. FREIFELD /WOIOSAHCOHA STUDY This study of oil car.es of angiosarcoma of the liver in Great Britain from 197** onwards is continuing. The Panel of Pathologists is reviewing the histology of cases certified by cause of death, between 1965-73 and a report should be ready this year. The follow-up of recent cases to investigate occupational exposure to vinyl chloride should also start soon : the Employment Nursing Advisers who will be interviewing the next of kin have undergone preliminary training at St. Thomas's Hospital and testing of the questionnaire they will be using is now taking place. I ' ANOIOSAHCOMA OK THE LIVEN IN PVC FABRICATORS (PROPORTIONAL MORTALITY CTUDY) The results of a study of death certificates (1970-72) bearing the occupation co ?* "plastics worker" was published in the Lancet, January 3''Qt 1976. About r*- v: 605*5 of these may have been engaged in working with PVC. The only statistically significant excesses for the causes of death were stomach cancer and diseases %. of the urogenitary system. The number of deaths due to all cancers was wr\ m slightly higher than expected but' there was a deficit of lung cancer and only one death from liver cancer ( certified as primary carcinoma). There were three deaths from liver disease with 3*6 expected. This study does not say there is no excess risk from these causes of death - any excess mortality which may be present in PVC fabricators may not be large enough to be detected amongst plastics workers as a group. i- WG VCU(?6) P3 BOR 010400 JLifrl'l -> summary or Tin: i>m:r.i-:i!Ti\T'iow by dk. w. iwi:T}-:r.u-:itis$E4&.*: G/v --- ------------------------ -------------------------------------------------- -------------- -------- on the vtnyj. cm.crime issue AUG? 1976 - : .a : , ^V, The medical world is \.'eli informed now of the effects of . 1* Vinyl Chloride (VCM). The orders of magnitude are as t ..follows : among 50.000 exposed people, about 500 cases of -.diagnosed lesions are known, of which 50 have so far developed angiosarcoma. We have to be aware that more cases of angio- t #^ . .safeoma will occur due to the very-long latency period iron first exposure, but we trust that under today's working conditions no new cases will be induced. The metabolism of VCil has been extensively investigated and the biochemical reaction which is dangerous for health has *,**''* ffV . i...* *bee nr,i'de ntified, apart f,rom the identification of other rea c- " tions that detoxicate VCM physiologically. . . ' ** , . ** . , / . j In the area of VCM production, polymerisation of VCM to PVC and PVC processing, the industry can comply with the concen- tration limits indicated by governments. Most plants have i-about 5?ppm or less VCM in the working atmosphere, although the way.;p measurement of such levels varies in different * countrreJS, giving some non-comparable results. It is likely, ->r ;V- ~/r howeyer^vthat a maximum allowable concentration of '5 ppm will be complied with. % The problem of VCM emissions/iir.mis'sicns has not been solved yet. Legal concentration limits are still being studied. The 13.5. have set a 3.0 ppm limit to any source of VCM, with - an overall maximum emission of 400 grammes VCM per metric ton of PVC produced. . Proposed regulations arc being discussed presently in the Federal Republic of Germany. COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE.TECHNICAL PANEL, AUGUST 27, 1976, MR. M.' FREIFELD BOR 010401 Concerning legal limits of VCM migration in food contact applications, most governments are waiting for the results of ClVO1s and MM/fOMl's experiments, but appear prepared .to set a Unit of 50 parts per billion (0.05 ppm), though ;* # ` *J *. * * .i * ; / it is a political and scientifically arbitrary figure. * ..`In this area, the VCM problem is part of the general food ` .packaging issue, looked after by Mr. Rodeyns. .". ..... . - Apart from the food packaging c}uestion, the problems related to VCM that still have to be solved are' : . *. ... .standardization of analytical. methods, v;here the CEFIC '>j.'.yCM .Working Group will publish another v/hite boo};. '7 Production 'technology in some areas, e.g.` copolymers, for ; obtaining eqmilly low residual VCM content in all corancr- ,,;Cial PVC types. `. ; `. * 1 : * ~ ?*. '*" .* These technical problems are expected to be solved in due ** t.\. course* "--* * /rv --v,v % * * m. t4U . .. . . ..\ .... - The main problem "" _ -" is a politi-c---a---l one. . , In- the U.S. .the industry *7- has reacted inconsistently towards proposals of the Occupatio nal Safety and Health Administration limits, which has harmed the credibility and political statute of the industry vis-S-vis the government and the public. In^ Europe, the industry should realize its political position and APME should be the political centre to articulate and present the industry's position to. the authorities and the public. Most important would be to bridge the information gap between the public and chemical industry since a wide range of fears and suspicions - from cancer to the atomic bomb ~ coagulates to locating the origin of all misery into the generally unknown regions of chemical industry. BOR 010402 V). FrcioaJobon o o o 7th May 19 >>v t 1 :t::y & 2. Date of PROS ENT REPORT ED LIVER AN01 OHAROOMA CASES IN EUROPE 3.' 4. First VC/ Cats of PVC S^pcsure Diagnosis 5. 6. 7. 8. Years from Years Age at First of Date of Diagnosis Exposure to Expo- Death Dii'.cnosis sure 9. Occupation ir* * 10. Histological Ef,, Confirr.'ation ice 01 .ce 02 15.C-j.1S24 CO.Ol.1946 C0.C0.1911 CO.CO.1959 CC.C0.1S6? 43 00.00.1975 63 21 19 19.02.1967 - 16 12 24.01.1975 Polymerisation {10-vcars)_ Yes Yes 03 Ce.Cl.1920 C0.C0.1S46 15.01.1975 55 A/ 27.01.1927 CC.CO.1949 15.01.1976 48 i y ci 15.05.1934 00.00.1965 19.04.1971 N. 36 29 26 06 29 29.03.1975 prcduoticnY Sj6_years) Compounding (3 years) 26 04.01.1976 1949-1957 product ion v.crkcr, frcra 1957 autoclave cleaner * 03 16.04.1971 Production of PVC sacks Yes Yes Yes11 t y 02 y 03 13.11.1929 CO.OO.1957 14.03.1220 CO.01.1953 13.12.1972 00.07.1975 4 V t 43 55 15 05. 00.12.1972 Polymerisation Yes 22 21 10.07.1975 Polymerisaticn Yes hit Autoclave Cleaner (8 years) Polymerisation Autoclave Operator (12 years) ` ay a:'. 01 NU on 02 21 23.12.1915 23.05.1927 27.11.1911 00.03.1950 14.C3.1951 00.01.1945 en 03 * 20.12.1971 56 20 20.10.1570 43 19 C0.C3.1972 61 27 t1 details not yet available 20 04.01.1972 PVC worker ; 18 20.10.1970 Polymerisation 27 16.03.1972 VC monomer pro duction Yes Yes Yes BOR 010403 : *L_ l * t l r.*v* Cl *IA 26.07.1531 14.10.1957 i ** , ;# ny :iy C2 03 CT UA 04.05.1930 16.07.1930 01.10.1356 09.05.1952 * r 1 * ;--y C4 ti{* t 1 1 04.C9.1930. 16.04.1957 4. | fry 05 I5-r 01.01.1932 00.00.1962 t r j.r.y Co :K 02.05.1936 02.04.1960 I . jr.y 07 rl i 4ji i* jny 03 1' 04.03.1230 CO.CO.1957 29.C3.1926 00.00.1954 CO. 00.1971 00.10.1963 00.03.1973 . 00.C0.1974 CO.CO.1975 00.12.1973 26.11.1974 12.11.1975 * i ~1 40 33 43 44 '' 43 33 . 44 ' 49 a * \ t u. '14 . 12 ' ' 11 t 17 i 13 13 .17 ; 21 VC? V i 3JV:^ 20.04.1901 00.00.1946 V ^50.12.1972 0 02.OS. 1937 00.02.1966 CO.12.1974 .. 71 37 , .26 I 09 /. W. . 10. 12 12 21 17 12 05 17 * 21 4 20 14.12.1971 Pol\merisaticn 25.01.1969 Tolyrcrisation. 10.10.1973/''Filling pesticides : . cans v/ith vc j - 25.11.1974 t jc cJL ion (11 years) Separators (6 years) t , 10.01.1975 Polymerisation '* 16.12.1974 Polymerisation ' Yes -- 25.11.1974 Polymerisation temprorarv autoclave cleaning Yes 13.11.1975 Folymerisat icn temprorary auto- . clave cleaning' (12 years) technique appli cation (foreman) (8 years) Yes 00.12.1972 Polymerisation mainly autoclave ' cleaning 03 1/2 24.12.1974Autocalve cleaner . full time Yes Qll- 0& (fa** t ; . -- i , .* ;srccra involving liver, lung and pericardium (histology). This case is not homogeneous with the other ones lis :e of the shorter time of latency and length of exposure, and because the primary site of the angicsarcora, alt re It to be defined, seems to be pericardium. ; BOR 010404 ITEM 4 NOTICES 31585 Moitpr, auoust 23 ..... :lsm. ..... i f'v 3:43 am. i t* i* 10:16a.m..____ J1' 10:30 am. ? \ 10:46 am. ' 1 V * V' 1 }\ [ / tlam___ I '1 i ,, 11:48 a.m. i L 12:16 pm.______ - 1:30 p.m. ..f ' f' *' .* * 2:15 pm. 2:46 p.m.______ 3:15 p.m.--------3:30 p.m. . 4:30 p.m.--------- Call to order and an nouncement*. Approval of minutes. PN^roa re port on CZM program. Issues and concern* of the Alaska coastal program. A panel (IlHcimnliMt. K:o* notnlc (tc|Miii(lrnce on ttio rofi*t. Ntilive Inter- oalft and concerns. l>lu'Ui.,shm of rImivo Ui|iIi :t. lli luf rcccas. Continuation of panel. Resource niniingciiicnl/ fish and game. Alaska CZM Program--A review of IP* protftuHtt to date and It* response to Issues and concerns raised above. above toplrs. Oral BtuteiiU'nts (If any) by Interested persons. Lunch, A panel discussion. OCS policy development. community Impacts study methods. Indus. trial problems and work - lng arrangements with State. above topics. Continuation of panel. Federal planning for lease sales, baseline studies. The impact of Yskutat. Brief recess. tlons. Adjourn. Tuesday, August 24 * 11:10 a.m..--------- Leave Juneau via Alaska 10:50 a.m. airlines flight 63. j, J 1:30 a.m. s.--. Onsite Inspection of City *J * of Yakutat. Meetings with local officials re- r, 6p.m____ gardlng OCS Impacts. l: , 7:25 p.m. Alaska airlines 66. 1 9:06 p.m. -------- Arrive Juneau, Please contact executive secretary to receive add!'ft tlonftl information on on- site visit: Dr. Richard V Keating, 202/634-4245. - Wednesday, August 25 9 a nt__ 0:16 a.m. ..... Legislative issues related ** to Alaska coastal man- Qffcmcnt, A panel dis cussion. The Tanker Dill. State.local relationships. CZM legislative inltiAUvcs. J 10 a.m____ 10:30 a.m. ubove topic*. 10:46 a.m. 11:16a.m. Forest practices. IwgUatlvo needs from the udministration's view. 12 n............ above topics. 1:30 p.m. for coastal management. ty, Webmesdat, Auoust 25--continued 2 pjn__________ 2:30 p.m... .. 3 p in _____ ____ 3:15 p in_____ _ 4:30 p.m______ committee's discussion of above topic. Rc/airt on Interstate co ordination /or VCS Issurj (I'oi'lllo). Brief Committee's recommenda tions. Adjourn. TiiuasDsr. August 20 (Ism.____ .. l>. 15 a.in______ 10 .in__________ 10:15 n.in---------10:46 a m______ l!:30a.m_______ 1 p.m__________ 2:30 p.m_____ _ 3 p.m__________ 3.15pm______ 4 p.m__________ 4:30 p.m............ 7:45 pm______ 7:10 p m______ Cult to order, t/iiminltlrr's recommenda tion* of substantive potteirs for evaluation of CZM. Brief recess, CiiiilUiunllon of above topic. Ducii.vsion o/ GAO final re port. Lunch. Jtrvleta of national legisla tion amending the CZM Act. A panel discussion. OCZM report on SBC imple mentation at the na tional tevet. Brief recess. committee's recommenda tions. Discussion of agenda, time and place of next meet ing. Adjourn. Leave Juneau via Alaska airlines 07. Arrive Anchorage. FaniA v. August 27 7:45 a.m---------8:15 a m_______ A.M-------------------P.M--__________ 6 p.m----------------6:30 p.m---------- Leave Anchorage via Alaska aeronautical flight 109. Arrive Kenal. Inspections. Meetings with local officials. Kachemak Bay--A case study or State decision making and public atti tude -- Prank Tupper, Kachemak Bay Defense Fund. Beaufort Sea Lease Sale-- A case study No. 2 of State decision making-- Pat Dobey. Department of Natural Resources. Leave Kenal via Alaska aeronautical 134. Arrive Anchorage. Please contact Executive Secretary to receive additional information regarding onsite visit: Dr. Richard Keating. 202634-4245. Dated: July 22. 1976. T. P. Gleiter, Assistant Administrator for Administration. National Oce anic and Atmospheric Admin istration. I PR Doc.70-21973 Filed 7-28-76:8:45 ami DEPARTMENT OF HEALTH, EDUCATION, ANO WELFARE Alcohol, Drug Abuse, and Mental Health Administration NATIONAL ADVISORY MENTAL HEALTH COUNCIL Meeting In accordance with .V.-.iinn 30(a)(2) of the Federal Advisor., unittee Act (5 U.S.C. Appendix I). announcement Is made of the following National Advisory body scheduled to assemble during the month of September 1976: Nations!. Anvisoar Mental Health Council tjoploinber B 10; 0:30 a.m. Conference Unom 14 105, Parklawn Building, llockvlllc, Maryland Open: September B Closed: Otherwise Contact: Mrs. /ella Dlgga, Room 11-101. Park lawn liulldtiiK. 5IKI0 Ftshoro Lane, Rockville.Maryland 2005`J, 301 -443-4333 Purpose: The National Advisory Men tal Health Council advises the Secretary, Department of Health. Education, and welfare, the Administrator, Alcohol, Drug Abuse, and Mental Health Admin istration, and the Director, National In stitute of Mental Health, regarding the policies and programs of the Department in the'fleld of mental health. The council reviews applications for grants-in-aid relating to research, training, and serv ices in the held of mental health and makes recommendations to the Secretary with respect to approval of applications for, and the amount of, these grants. Agenda: On September 8, the meeting will be open for discussion of NIMH pol icy issues. These will include current administrative, legislative and program developments. Otherwise, the Council will conduct a final review of grant ap plications for Federal assistance and this session will not be open to the pub lic, in accordance with the determina tion by the Administrator, Alcohol, Drug Abuse, and Mental Health Admin istration, pursuant to the provisions set forth in Section 552(b)(5) and 552(b) (6), Title 5. U.S. Code, and Section 10(d) of Public Law 92-463 (5 U.S.C. Appendix I). Substantive Information may be ob tained from the contact person listed above. The NIMH information Officer who will furnish summaries of the meeting and rosters of the committee members is Mr. Edwin Long, Deputy Director, Di vision of Scientific and Public Informa tion, NIMH, Room 15-105, Parklawn Building. 5600 Fishers Lane, Rockville, Maryland 20852,301-443-3600. Dated: July 23,1976. Carolyn T. Evans, Committee Management Officer, Alcohol, Drug Abuse, and Mental Health Administra tion. (FR Doc.76-21967 Filed 7-28-76:8:46 am| Center for Disease Control OCCUPATIONAL SAFETY AND HEALTH Request for Information on Certain Chemical/Physical Agents Section 20(a)(3) of the Occupational Safety and Health Act of 1970 l (29 U.S.C. 669(a) (3) 1 provides that the Secretary of Health, Education, and Welfare, on the basis of information available to him, shall develop criteria dealing with toxio materials which will describe exposure levels that arc safe for various periods of ,* BOR 010405 FEDERAL REGISTER, VOl. 41, NO. 147--THURSDAY, JULY 29, 1976 COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL i 315.SC NOTICES \ employment, Sort Ion 22ie) of the Art. 5. Methods in- hiding instruments, for evidence of effectiveness. No person tins authorizes the National Tnslltuie fur air sampling oi. I "itplc analysis of the submitted any data In support of the pos Occupational Safety and Health chemical ngeni ',.i methods of mca- sibly effective Indications, and those In (NIOSH 1 to develop recommended oc- suiing levels of e ' "suic to the physical dications arc now reclassified ns lacking r.upatloiml safety and health standards agent . Milr.tanl lnl evidence of elfectlveness. Tills (criteria document.':> nnd to perfnrm nil (i The need fm ni.'dtral evaminatIons nollcc tillers an opixirlnnlfy for a hear fimctlon.s of tlic Secctary of Health, for workers exposed to sueh agcnl:;. the ing roiiccrnhig those Indications nml sets Education, and Welfare, under seellons frequency of sueh examinations, and the forth the conditions for marketing the 20 and 21 of the Act. Since 1972. NIOSII specific diagnostic tests which should be drug products for the indication for has developed and forwarded to the used and the rationale of their selection. which they continue to be rcgaided as Assistant Secretary for I^nbor criteria 7. Woik practices or procedures winch effective. Persons who wish to request a documents on more than 30 subjects. may be instituted for centrol of the work hearing may do so on or before August 30, Published and unpublished Information place environment in normal operations 1976. relating to Tnany of the criteria docu and those which may be instituted when The notice that follows does not per ments which were published during 197!!- occupational cnvuonmonlal levels are tain to the indications staled in the 1974 has increased at such a rate that temporarily exceeded or where peak con March 9, 1971 notice to lack substantial NIOSH must now consider an update, centrations of chemical agents in man evidence of effectiveness. No person re of the following 13 criteria documents: are reached. quested a hearing concerning them, and Criteria Documents: CTO Number 8. The types of records concerning oc they arc no longer allowable in labeling. i Hot Environments,___. I7:t3-oomo cupational exposure to such agents that Any such product labeled for those Indi Caron Monoxide mi-noooo employers should be required to main cations is subject to regulatory action. Noise __________________ Uptravlolct Radiation. Inorganic Lead Coke Ovens................. .. Toluene Inorganic Mercury_____ Vinyl Chloride...'.____ s i i ... ~~" Sulfuric Acid Ammonia Cotton Dust Silica............................... .. 17113 -00007 17113-00013 1733-00013 1733-00015 1733-00010 1733-00032 (Not available from GT'O) 1733-00034 1733-00030 1733-00044 (Not available from GPO) tain. 9. Warning devices and labels which should be required for the prevention of occupational diseases and hazards caused by such agents. All information received concerning tiic.se substances, except that informa tion which is trade secret and protected by Section 15 of the Act. will be avail able for public inspection at the fore going address. 1. NDA 9-295: Vlbazlne Hytlroehloi tdc Tablets containing bucllzlne hydrooliloildc; previously marketed by Pfizer Laboratories. Division of Pfizer, Inc., 236 E. 42d St.. New York, NY 10017 2. NDA 10-911:' Ducladlil-S Tablets con taining bueii7.ine hydrochloride: Stuart Pliarmaceut teals, Division oi I. C. I.. United States, Inc.. P.O. Box 751. 3411 Sllverslde Rd.. Wil mington. DE 19897. 3. NDA 11-378; Softran Tablets containing bucllzlne hydrochloride: previously marketed by Stuart Pharmaceuticals. i f; i 4t > I I u, v * ii Each criteria document includes among Dated: July 20. 1976. In a notice published in the Federal other items an evaluation of available Edward J. Baier, Register of February 2. 1973 (38 FR Information relative to the areas listed Acting Director, National Insti 3208). the approval of NDA 11-378 for below. tute tor Occupational Safety Softran Tablets was withdrawn on the Any person having new information and Health. ground of failure to submit required re or data in any of the areas listed below, or in other areas considered relevant to |FR Doe.7G-21906 Filed 7-28-76:8:45 am] ports under section 505<j> of the Federal Food, Drug, and Cosmetic Act (21 U S C. the establishment of a safe and health 355(J)). At the time that notice was pub ful occupational environment involving Food and Drug Administration lished. no final conclusions concerning its these agents is requested to submit such information, with accompanying docu lDocket No. 7GN-0249; DESI 9295) possibly effective indications had been reached. Those conclusions have now mentation to the Director, Division of BUCLIZINE HYDROCHLORIDE FOR been reached, and the purpose of includ Criteria Documentation and Standards ORAL ADMINISTRATION ing Softran (buclizine hydrochloride) Development. (Federal Reotster Notice No. 6). NIOSH. 5C00 Fishers Lane. Park Building. Room 3-18, Rockville, MD Drugs for Human Use; Drug Efficacy Study Implementation; Followup Notice and Opportunity for Hearing Tablets (NDA 11-378) In this notice is to inform all Interested persons of sucli conclusions and offer from the opportu 20852, within 30 days. 1. Establishment of safe occupational environmental levels for such agents in cluding levels for acute and chronic exposure to airborne concentrations of the chemical agents as well as safe prac tices concerning direct contact with such agents. In a notice (DESI 9295; Docket No. FDC-D-302 (now Docket No. 7GN-0249)) published in the Federal Register of March 9, 1971 <36 FR 4558), as amended by a notice published in the Federal Register of March 13. 1975 <40 FR 11794). the Food and Drug Administra nity to request a hearing concerning all issues relating to its legal status. Such drugs are regarded as new drugs (21 U.S.C. 321(p>). Supplemental new drug applications are required to revise the labeling in and to update previously approved applications providing for sucli drugs. An approved new drug application 2, Establishment of biologic stand ards, l.e., the levels of such agents, me tion announced its conclusions that the drug products described below are <1) is a requirement for marketing sucli drug products. tabolites, or other effects of exposure eircctive for the management of nausea, In addition to thcholdcr(s) of the new which mny be present within man with vomiting, and dizziness associated with drug nppllcnl.lon(s) specifically named out his suffering 111 ctTccts Liking Jnto inoLInu sickness: (2) lucking substantial shove, tills notice applies to all persons consideration (a) the correlation of air evidence of effectiveness for the follow who manufacture or distribute a drug borne concentrations of. and extent of ing claims* "Conditions In which emo product, not the subject of an approved exposure to, such substances with ef tional stress Is a complicating or causa new drug applii allon. that is identical, fects on specific biologic .xvs toms of mini tive factor such as essential hyperten related, or similar to a. ding product such as the circulatory, respiratory, uri sion, stciliity, hyperkinesia, palpiLiition, named above, as dolined in 21 CTTt 310.6. nary. and nervous system, and (b> the cramps, hypcrliiUrosis. tremor, headache, It Is the responsibility of every drug man > . \ 'analytical methods for determining the amount of the substance which may be and insomnia"; "Additional anliliistamiiiic, nntlnauseant, antlmolioii sick ufacturer or distributor to review this notice to determine whether it covers any present within man, ness. and hypotensive properties make it drug product he manufactures or distrib 3. Engineering controls, including ven a unique compound in the field of non- utes. Any person may request an opm- tilation, environmental temperature, hu plicnoUiiazine tranquilizers"; and for the lon of the applicability of Uns notice midity, and housekeeping nnd sanitation relief of bronchial asthma; nnd (3) pos to a specific drug product he manufac procedures, with attention to the tech sibly etTcrlhe for its oilier labeled Indi tures or distributes that may lie identi nological feasibility of such controls, cation:;. including vertigo. The March 9. cal. related, or similar to a drug product 4. Specifications for the conditions 1971 notice also olfered an opportunity named In tills notice by writing to Uie under which personal protective devices for a hearing concerning the Indications Food and Drug Administration. Bureau should bo required. concluded at that lime to lack substantial of Drugs, Division of Drug Labeling Coin- FEDERAL REGISTER. VOL. 41, NO. 147--THURSDAY, JULY 19, 1976 >* ! *^ BOR 010406 irds ITEM 5 COPIED BY MCA FOR DISTRIBUTION TO THE VINYL CHLORIDE TECHNICAL PANE?TL AUGUST 27, 1976, MR. M. FREIFELD EVALUATION OF THE ENVIRONMENTAL TOXICANTS VINYL CHLORIDE (VC) AND VINYLIDENE CHLORIDE (VDC) by Cheng-Chun Lee Joseph M. Winston Paul J. Peters Jagdish C. Bhandari John R. Hodgson Jack H. Hagensen Thomas W. Reddig Ellen R. Ellis PROGRESS REPORT NO. 9 1 January through 31 March 1976 Contract No. NO1-ES-2-2084 (Continuation of NIH-NIEHS-72-2-2084) MRI Project No. 3612-B V For National Institute of Environmental Health Sciences P.0. Box 12233 Research Triangle Park, NC 27709 Attn: James S. Woods BOR 0X0407 016 661.()?(): EVALUATION OF THE ENVIRONMENTAL TOXICANTS VINYL CHLORIDE (VC) AND VINYLIDENE CHLORIDE (VDC) (Progress Report No. 9) ABSTRACT We have continued to study the inhalation toxicity of various levels of vinyl chloride (VC) and one level of vinylidene chloride (VDC) in rats and mice. At the end of 6 months, rats of both sexes exposed to 50, 250, or 1,000 ppm of VC or 55 ppm of VDC, 6 hours a day, 5 days a week, did not show any significant adverse effects on various clinical laboratory data or cause any apparent gross or microscopic lesions. The weight gains of rats exposed to VDC were less than those of the controls. Exposure to 50, 250, or 1,000 ppm of VC caused a number of deaths or early terminations in mice during the 21st to 26th week. The clinical signs in these mice included rough hair coat, lethargy, anorexia, and sudden weight loss. The high level caused changes in the peripheral blood elements including decreased hematocrit, hemoglobin concentration and/or erythrocyte count, and neutrophilia with a corresponding lymphopenia. The macrophage count in the lung washings was also elevated. All three levels caused acinar proliferation and/or bronchiolar adenoma; the middle and high level also caused angiosarcoma in the liver and/or mammary gland, ductular adenocarci noma, and squamous cell and anaplastic carcinoma in the mammary gland. The squamous cell and anaplastic carcinomas metastasized to the lung. The in cidence and severity of these tumors were in direct proportion to the levels of VC. In addition, malignant lymphoma occurred in the heart, lung, liver, spleen and kidney of one mouse exposed to the low level, and infiltrated the cervical tissue surrounding the trachea, blood vessels and esophagus of one mouse exposed to the high level. There was also a hemangioma in the connec tive tissue attached to the salivary gland of one mouse exposed to the high level. The tumors were responsible for deaths or early terminations of some mice. At 250 or 1,000 ppm of VC, nearly all mice that died or were terminated during the 21st to 26th weeks had tumors in one or more tissues. Exposure to the high level of VC also caused other lesions in the liver of some mice which were probably associated with angiosarcoma; these included infiltration of nucleated erythrocytes, focal degeneration with necrosis, and infiltration of inflammatory cells in the sinusoids and parenchyma. Exposure to 55 ppm of VDC for up to 6 months in mice did not cause any adverse signs, including changes in laboratory data or macrophage counts in the lung washings. At the end of 6 months, one male of the eight mice which were terminated had a mild bronchiolar adenoma and two other males had mild acinar proliferation in the lung. BOR 010408 iv IV. DISCUSSION AND CONCLUSIONS A. Rats Exposure of rats of both sexes at 6 hours/day and 5 days/week for up to 6 months to 50, 250, or 1,000 ppm of VC or 55 ppm of VDC did not cause any serious adverse effects. The weight gains of the female rats exposed to 55 ppm of VDC were less than those of the controls during the 6th month. The laboratory results, including hematology, clinical blood chemistry, serum immunoglobins, serum proteins, and macrophage counts in lung washings were not apparently affected. The cytogenetic effects as measured by chromosomal chan ges in bone marrow cultures are under evaluation. Collagen content in the liver and lung of these rats was not apparently altered. Exposure to VC or VDC did not cause any apparent changes in organ weights nor cause any lesions. B. Mice 1. Vinyl Chloride Exposure to various levels of VC caused a number of deaths in mice between the 21st and 26th weeks. There were two deaths in the group^ exposed to 50 ppm, three early terminations in the group exposed to 250 ppm, and four deaths in the group exposed to 1,000 ppm. Clinical signs in these mice in cluded rough hair coat, lethargy, anorexia, and sudden weight loss. One fe male exposed to the middle level and three females exposed to the high level had tumors in the mammary gland which were from white to gray to dark red in color. Exposure to the high level of VC caused some changes in the peri pheral blood elements. There were decreases in hematocrit, hemoglobin con centration and/or erythrocyte count. Neutrophilia with a corresponding lympho penia occurred. These changes were not seen in the control mice or in mice exposed to 1,000 ppm of VC for 1, 2, or 3 months ..2/ The macrophage count in the lung washings of mice of both sexes exposed to the high level was elevated Since macrophage counts were not performed in mice exposed to the low or mid dle level, the possibility of a dose response relationship cannot be assessed. Exposure to various levels of VC did not cause any other apparent changes in peripheral blood elements or clinical blood chemistry tests. As for rats, the cytogenetic effects as measured by chromosmal changes in the bone marrow cultures are under evaluation. Gross and microscopic examinations revealed that 50, 250, or 1,000 ppm of VC caused acinar proliferation and/or bronchiolar adenoma in the lung. The middle and high level also caused angiosarcoma in the liver and various tumors in the mammary gland. The angiosarcoma was also found in the mammary 9 BOR 010409 gland of two females and hemangioma in the connective tissue adjacent to the salivary gland of one male exposed to the high level. The pathogenesis or sequence of changes for the various tumors in the mammary gland is complex. Whether the- tumors started at first as ductular adenocarcinoma and then un derwent a metaplastic change to squamous cell and anaplastic carcinomas, or all tumors started simultaneously is questionable. However, the squamous cell and anaplastic carcinomas did metastasize to the lung, suggesting a strong malignancy of the neoplasms. In addition, a marked, diffuse malignant lym phoma was found in the heart, lung, liver, spleen and kidney of one mouse exposed to the low level of VC and a malignant lymphoma infiltrated the cervical tissue surrounding the trachea, blood vessels and esophagus of one mouse exposed to the high level. Between the 5th and 6th months the var ious tumors occurred in five of 10 mice necropsied at 50 ppm, 10 of 11 mice necropsied at 250 ppm, and ail 12 mice necropsied at 1,000 ppm. The severity of these tumors in the lung, liver, and mammary gland was also in direct proportion to the exposure level of VC. These tumors were responsible for the various deaths and early terminations of some mice. Exposure to the high level of VC also caused other lesions, probably associated with angiosarcoma, in the liver of some mice. These lesions were infiltration of nucleated erythrocytes, focal degeneration and necrosis, and infiltration of inflammatory cells in the sinusoids and parenchyma. Intra nuclear inclusions increased in the hepatic cells of two mice exposed to the high level of VC. The significance of this increase as related to the treat ment is questionable. 2. Vinylidene Chloride Mice exposed to 55 ppm of VDC for up to 6 months did not show any adverse signs, any changes in laboratory data or macrophage counts in the lung washings. Cytogenetic effects are under evaluation. One male of eight mice terminated at the end of 6 months had a mild bronchiolar adenoma. Two other males had mild acinar proliferation in the lung. These three and another male also had increased intranuclear inclusions in the hepatic cells. The clinical significance of this increase is not understood. 10 BOR 010410 MANUFACTURING CHEMISTS ASSOCIATION 1B2& CONNECTICUT AVENUE, N.W. WASHINGTON, D C. 20009 (202) 483-6126 July 7, 1976 NOTICE MCA has recently acquired a Dex 580 telecopier which is compatible with most other telecopiers on the market today. The telephone number for this unit is 202/265-9351. The caller should notify the MCA operator of the type of sending machine before starting the message. BOR 010411 Eoidemioloov Studv (a) Health Study of VC Workers (6/13/73) lb) Adjustment/- Travel (8/16/73) (c) Adjustment/- Extension (3/12/74) Id) Retabulation of Data (7/13/74) te) Study of Workers/ 4 plants (11/5/74) If) Extended Epidem iology Study (4/22/75) Sub-Total InvoIced (Committed) $ 91,940 S 52,597 $144,537 Received $ 91,940 S 52,597 $144,537 VINYL CHLO! RESEARCH PROGRAM Financial Statement - April 1. 1976 Research Contracts Time Travel DISBURSEMENTS Misc. Research Contracts $ 71,345 $ 3,950 S 5,250 $ 1,000 f 10,350 $ 3 2,000 $123,695 $ 2,933 $ 2,933 -0-0- ? 34 -0$ 34 $ 91,895 S 28,764 $120,659 Total Balance on Contract $123,626 $ 3.236 $ 3,236 \ Balance on Hand $ 20.911 Chronic Inhalation Studies Industrial BIO-TEST Labs (a) Origina1-Protocol (2/1/73) (b) Additional Animals- 100 rats (5/22/73) (Restart-Agreement) (8/31/73) (c) Z B-T L Contract Adjustments Id) Holding 4 Chambers for 14 weeks (*) Sub-Total $190, 281 $ 50,000 $240,281 $190, 281 $2,665/1 $2 79/2 $149,000 $130,375 $ 50,000 $ 15,000 $ 3,785 $240,281 $164,000 $ 3,785 $2,665 $279 $ 10,000 $ 7,840 $ 20,000 $168, 215 $18,625/3 $ 5,000/3 $174,944 $23,625 3. Dow Studies (a) Metabolic 'b) Teratology (c) Extension of Studies Sub-Total S101, 250 S149.990 5251,240 $101, 250 S 149, 990 $251,240 S 50,000 $ 20,000 S154.090 $224,090 $ 3, 528 $ 3,528 -O-0- 5 50,000 S 20,000 -0- $154,090 _________ -0- $224,090 $227,618 GRAND TOTAL $636,050 $636,058 $511,985 Note; 1. Gasque, Kociba & Torkelson to Italy 2. Cylinders for Vinyl Chloride 3. Due I B-T L - Receipt of Final Report BOR 010412 $10,246 $2,665 $313 $512,964 $526,188 $26,661 $ 23,622 S109,9:0