Document xL3LLbjZnkjq6D6VmnK9mdzG

INDUSTRIES Subject: To: Dow Study on Vinyl Chloride Cytogenetics oy, M. D. M. Perez Roig, M. D. Dr. Z. G. Bell, Jr. R. E. Sourwine INTER OFFICE CORRESPONDENCE Date: August 18, 1977 From: Lee B. Grant, M. D. location: 14 West Attached is a recent article showing no increased frequency of chromosomal aberrations in 209 present and former VCM plant employees. Since there is a strong relationship between chromosome breakage and neoplasia, this report supports the general observation of lack of angiosarcoma generally observed in VCM manufacturing. Lee n. lirant, fl. JJ. Corporate Medical Director Attachment cc: Dr. C. H. Powell Dr. F. C. Dehn SL 028366 Vinyl Chloride Cytogenetics Dante J. Picciano, Ph.D.; Ray E. Flake, M.D.; Peter C. Gay, M.D.; and D. Jack Kilian, M.D. This report presents cytogenetic findings from a group of 209 workers employed for up to 28 years in the manufacture of vinyl chloride monomer at the Texas Division of Dow Chemical U.S.A. Cytogenetic evaluation results from this group were compared to results found in examination of individuals being considered for employment. Statistical analyses were per* formed on a group basis for chromatid aberrations, chromo some aberrations and proportion of abnormal cells; no Statistical difference of significance was found between the two groups. Comparison of these results with reported studies suggests that the level of cytogenetic aberrations in vinyl chloride workers is probably related to the length and level of exposure, and that risk of adverse genetic effect can be avoided in cohtrolled, minimal-exposure environments. Vinyl chloride (VC) has been reported to be carcinogenic in animals1 2 and human beings' and mutagenic in bacterial test systems.4 1 ^ There have been reports of increased frequencies of chromosomal aberrations in workers exposed to vinyl chloride at polyvinyl chloride (PVC) facilities 7 s , Similar increases were not found upon cytogenetic evaluation of German PVC workers10 nor in our own preliminary investigation of a group of American VC workers.11 One study based on interviews with male employees has indicated an increased rate of fetal wastage among wives of VC-exposed workmen involved in polymerization operations.12 We have recently completed cytogenetic evaluation of all currently-employed workers exposed to vinyl chloride at the Dow (Freeport) Texas Division Both vinyl chloride and vinylidene chloride are produced in this plant Vinylidene chloride has also been reported as mutagenic in bacterial test systems.11 However, while these Dow workers are involved with the production of both compounds, the degree of contact with vinylidene chloride is far less than the exposure to vinyl chloride. From Occupational Health and Medical Research, Dow Chemical USA (Drs, Pic ciano and Kilian) and Department of Industrial Medicine, Dow Chemical U.,A . Texas Division (Drs. flake and Cay), Freeport TX 77541 Material from this report was presented at the Sth International Congress of Human Genetics, Mexico City, October 10-15, 1976, Journal of Occupational Medicine/Vol. 19, No. 8/August 1977 Vinyl chloride monomer has been produced at the Texas Divi sion of Dow Chemical U.S.A. since 1948. There are no vinyl chloride polymerization operations. Average exposure levels, as is the case for almost all vinyl chloride monomer plants, have been generally lower than those reported for facilities involved in polymerization operations.14 Although the threshold limit values for vinyl chloride had been SIX) parts per million (ppm) until 1974, Dow had established a goal of 50 ppm or below in 1959.1'1 The current Occupational Health and Safety Administration (OSHA) standard for vinyl chloride is one ppm as a time-weighted-average over an eight-hour workday. We have found that the TWA con centration of vinyl chloride for all VC-related job classifications was approximately 5 ppm from 1968 to 1973; in 1974, TWA con centrations were 1 to 2 ppm. Since 1975, average levels of expo sure have been lowered to less than 1 ppm. Estimates of average exposure levels for the years prior to 1968 are less reliable. For the purposes of this study, estimates of exposure were calculated for specific job classifications, based on records of both personnel and area monitoring (Table 1). However, actual exposure may vary from individual to individual within the same job classification and accidental, short-term exposures of some workers to concentra tions in excess of the standard probably occur from time to time. Documentation of such incidents is difficult. Methods Our study group was composed of 209 workers who had worked in the vinyl chloride plant for periods ranging between one and 332 months (average, 48.3 months) at the time of this in vestigation. As part of the medical surveillance program for this group, peripheral blood samples were obtained, and evaluation of lymphocyte chromosomes was performed. Lymphocytes were cultured using a modification of the Moorhead technique.1'' Stan dard procedures, as previously described,17 were used for incuba tion, processing, and analysis Findings were compared to cytogenetic data from a group of 295 "preemployment examinees" who had chromosome evalua tion done as part of routine preemployment examination and who, at that time, had no known exposure to chromosome-break- SL 028367 527 Table 1. -- Estimated Exposure to Vinyl Chloride (VC) for Vinyl Chloride-Related Job Classifications- Job Classification Supervisor R&Q Engmeef Production Engineer Technical Specialist Development lab (Lab Supv.) Quality Control Lab Instrument Man Electrician Cowers (Insulators! Painter Pipefitter Machinist Welder (Boilermaker) Maintenance (Utility Man] Material Handler Production Foreman Shift foreman Control A Op mi Chloride) Control A Op (E t Cll Control A Op (Vinyl) Control A Op (Chlorination) Control B Op (Qxy & Chloride) Control C Op (Chloride & Vinyl) Control C Op (Chlorination) Class \ Op, Class 1 Op (Parts) Class 3 Op Production Clerk Unit Manager , Estimated Exposure In Parts per Million, as T ene-Weighted-Average 19731974 I960 1972 Before 1960 I 7 44 82 17 4.4 82 1 7 44 82 05 05 05 12 39 7,7 87 114 15.2 1 3 40 78 1 3 40 78 03 0,3 03 07 07 0.7 09 09 09 24 51 *9 06 06 06 I 3 40 7,8 05 05 05 1 3 4 0 78 44 71 109 52 7.9 11 7 09 09 09 28 55 93 2,3 50 80 07 07 07 4.6 73 11 1 26 53 9 1 53 8.0 118 0,5 05 0b 2,6 53 91 07 07 07 07 0.7 0.7 Table 2. --- Cytogenetic Study of 209 Workers Exposed to Vinyl Chloride. No ot cultures No ot cells Chromatid breaks Ctromosome breaks Rings, dicentrics and exchanges Abnormal cells Workers 209 10.483 2,4% 10% 04% 3,7% Controls 295 14,761 3 6% l 1% 0.2% 4 5% percent aberrations, and the vinyl chloride workers were separated into those with estimated TWA exposure levels of lessthan-1 ppm, from 1-to-5 ppm, and greater-than-S ppm The estimated exposure levels wore based on calculations (or specific job classifications to which members erf tire' vinyl chloride study group were assigned. Three categories of aberration were chosen for this analysis- chromatid breaks, chromosome breaks, and the proportion of abnormal cells. As shown in Table 3, no significant differences were found when these groupings were compared on the basis of chromatid aberrations. Results from those workers with estimated exposures of greater than S parts per million are almost identical to those of the control group Similar conclusions were reached upon evaluation of the- data for chromosome breaks (Table 4) and the proportion of abnormal cells (Table S). In all three cases, most of both groups were found to have zero-to-five percent aberrations, and the vinyl chloride workers with die highest level of estimated exposure' showed aberration rates not significantly different than those of the' con trol group. Findings for both groups, svorkers and controls, are considered to he within the range of normal variation as seen in this laboratory. ing agents. The records selected for inclusion in the control group were matched to those of the study group, insofar as possible, for sex, number of cells analyzed, and time period during which the culture was initiated. Age variation hetween the two groups could not be completely eliminated: the average age of the vinyl chloride workers was 19,S years (range, 18 to 67 years), and tire average age of the pre employment control group was 21.1 years (range 18 to TO years) Discussion The reports tbit hive appeared, to date, concerning chromosome aberrations in vinyl chloride workers have not hoen in agreement. This conflict may be due either to the small number of workers studied or to differences in exposure levels, or both. The Swedish group studied bv Funes-Cravioto et al1" was com posed of seven PVC workers who had been exposed for nine to 29 years and who were found to have an inc leased frequent y of chromosome breakage. The level of exposure for this group was Results As shown m Table 2, data from hoth groups -- vinyl chloride workers and preemployment controls -- were scored and com pared on the hasis of chromatid breaks; chromosome breaks, rings, dicentrics, and exchange figures; and the proportion of ab normal cells The proportion of abnormal Cells was calculated to show the overall frequency of aberrant i ells, that is, the ratio of cells with at least one aberration to the total number of cells examined. Results, expressed in terms of the mean percentage for those categories of aberration, showed no ma|or differences be tween the two groups for any of the classifications Using Chi-square analysis, it was decided to see if differences in various aberration rates could be detected within the two groups Accordingly, both groups were divided inter those showing zeroto-five percent aberrations and those showing greater-than-five Table 3. -- Distribution of Chromatid Aberrations Related to Vinyl Chloride (VC) Exposure. Exposure to VC* < \ ppm t-5 ppm 5 ppm Controls No in Group 209 70 98 4) 295 % of Group with 05% Aberrations % of Group with > 5% Aberrations 90% 10% 77 23 80 20 75 25 X '13) .= 7 75 (P-006) Exposure levels are estimates based on calculations tor specific |0b classifications, prior expo sure for rndwiduafs may have been higher or tower exposure levels foriridmduals are known to vary withm |ob r.lassdfcatons 528 Vinyl Chloride Cytogenetics/Picciano et al SL 028368 Table 4. -- Distribution of Chromosome Aborrations Related to Vinyl Chloride (VC) Exposure. Exposuce to VC < l Km l b ppm >5 ppm Controls No. In Group 209 70 98 41 295 % of Greyp with 05% Aberrations 14 of Group with >5% Aberrations 96% 4% 94 6 95 5 94 6 X'<3) - 0355 (PB095) Table 5. -- Distribution of Abnormal Cells Related to Vinyl Chloride (VC) Exposure. Exposure to VC <1 ppm 1-5 ppm 5 ppm Controls No, In Group 209 70 98 41 295 14 of Group with 05% Aberration* % of Group with > 514 Aberrations 84% 1614 71 29 73 27 70 30 X HI - 5,97 (P "0,12) reported to have continuously decreased over a period of years until immediately prior to the study when VC concentrations in the polymerization department were estimated to be 20 to 30 ppm. The U.S. group of 11 PVC workers surveyed by Ducatman et al" was also reported to show an increased rate of chromosome breakage following exposures estimated to have been in excess of 500 ppm at times. The group of ten German workers investigated by Fleig and Thtess20 worked with either VC or PVC or both for periods ranging between six and 34 years and with exposures esti mated to have decreased from greater than 500 ppm in 1945 to between 10 and 25 ppm in 1974. Evaluation of this group for in creased aberration rates was negative. The study of British PVC workers by Purchase e( a/.2' concluded that the frequency of cytogenetic aberrations was increased in 56 exposed workers as compared to 24 nonexposed individuals. Esti mates of the levels of exposure were not given in this report. The medical director of the surveyed group, however, has informed us that while further analyses of the data confirmed the findings of in creased aberrations in workers exposed to "higher" levels of vinyl chloride, no differences between worker and control groups were detected upon evaluation of the data for workers exposed to "lower" levels An earlier report from our laboratory22 concluded that there were no cytogenetic differences of statistical significance be tween a group of 121 workers exposed to vinyl chloride and a 75person control group. As in the work reported here, there was a discrepancy in the age composition of the two groups, because applicants seeking employment tend to be younger than those already settled into jobs. We do not believe, however, that this difference is a confounding factor in our comparison since the dif ference is not great and because it has been shown21 that the cytogenetic change most often associated with aging is chromosome loss, rather than chromosome breakage. On the basis of our negative findings and the conflicting find ings reported by others, we believe that the level of chromosome aberrations in workers exposed to vinyl chloride is probably re lated to the length and level of exposure and that the risk of ad verse cytogenetic effects can be avoided in controlled, minimalexposure environments. Cytogenetic dose-response curves, similar to that suggested here, have been reported for x-irradiated ankylosing spondylitics,21 A-bomb survivors,21 radium dial paint ers,26 persons exposed to Thorotrast,27 and workers exposed to lead.26 It has also been noted that the groups exposed to radiation later demonstrated significant increases in neoplastic incidence. A-bomb survivors, for example, have shown increased .rates of leukemia and thyroid carcinoma;29 radium dial painters were found to be at increased risk of osteogenic sarcoma;10 and Journal of Occupational Medicine/Vo!. 19, Nor 8/August 1977 thorium dioxide-exposed persons have an increased rate of liver tumors.11 This relationship between chromosomal breakage and neoplasia strongly suggests that cytogenetic analyses may be a useful tool for detecting environmental situations which may be associated with increased cancer risks to the workers. The present study is one of several involving Texas plant em ployees to investigate the possibility that increased rates of fetal loss or birth defects in offspring are experienced by wives of vinyl chloride workmen and to determine the morbidity-mortality ex perience of all past and present VC workers. A search has been made for cases of angiosarcoma of the liver; none have been found in our study group (533 individuals) which includes all past and present VC workers. Current workers are also being monitored as part of the continuing medical surveillance program. The authors acknowledge with appreciation the technical assistance of Mrs, A, linscombe and Mrs D Mensik, the suggestions of Mrs, M, Benge, the editing of Ms, T, B, Lloyd, and the advice of Dr C B }acobson References 1 Viola PL. Bigotti A, and Caputo A- Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-519, 1971. 2. Maltom C and Lefemine G1 Carcinogenicity to bioassays of vinyl chloride. I. Research plan and early results. Environ Res 7:387-405, 1974. I. Creech |L and lohnson MN: Angiosarcoma of the liver in the manufac ture of polyvinyl chloride. /OM 16:150-151. 1974, 4 Rannug U, lohansson A. Ramel C, and Wachtmeister CA: The mutagenicity of vinyl chloride after metabolic activation. Amhio 3:194-197, 1974. 5. Malaveille C, Bartsch H. Barbin A et al: Mutagenicity of vinyl chloride, chloroethylene oxide, chloroacetaldehyde and chloroethanol. Biochem Biophys Res Commun 63'363-370, 1975. 6. Bartsch H, Malaveille C. and Montesano R: Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in 5 lyphimurium strains. Int / Cancer 15:429-437, 1975. 7. Funes-Cravioto F. Lambert B, Lindsten | et al: Chromosome aberrations in workers exposed to vinyl chloride. Lancvl 1:459, 1975 8. Ducatman A, Hirschhorn K, and Selikoff II: Vinyl chloride exposure and human chromosome aberrations. Mutat Ra 31 '163-168, 1975 9. Purchase IFH. Richardson CR. and Anderson D: Chromosomal and dominant lethal effects of vinyl chloride. Lancet 2 410-411, 1975. 10 fleig I and Thiess AM: Chtcsmosome analysis after vinyl chloride ex posure Arhettsmoil 5o/ialmed Praevenumed 9 280-283, 1974. II, Kilian Dl, Picciano D|, and lacobson CB Industrial monitoring: A cytogenetic approach Ann NY Acad So 269:4-11, 1975 12. Infante PF. Wagoner |K,,McMichael Al. Waxweiler R|, and Falk H: Genetic risks of vinyl chloride, lancet 1.734-735. 1976 13. Bartsch H, Malaveille C, Montesano R. and Tomatis l' Tissuemediated mutagenicity of vinylidenc chloride and 2-chlorobuladiene in Sa/mone/fa typhtmurtimn Mature 255:641-643, 1975, 14 Occupational Safety and Health Administration: Exposure to vinyl chloride. Federal Register 39(194)- 35889-35898, October 4, 1974. 15. Rowe VK- Experience in industrial exposure control. Ann NY Acad Sci 246:306-310, 1975 16 Moorhead PS, Nowell PC, Mellman W], Battips DM, and Hungerford 529 SL 028369 DA: Chromosome preparations of leukocytes cultured from human peripheral blood, Exp Cell Res 20:613-616, 1960. 17, Kilian Dl and Picciano D: Cytogenetic surveillance of industrial popu lations In Chemical Mutagens: Principles and Methods lor Their Detection. Vol 4, New York- A Hollaender. ed. Plenum Press, 1976, pp 321-339 IB. Funes-Cravioto et at. Reference 7. 19. Ducatman et al. Reference 8. 20. Floig & Thiess, Reference 10. 21. Purchase et al. Reference 9. 22. Kilian et al, Reference 11. 23. Court Brown WM: Human population cytogenetics. In Frontiers ol Biology. Vol V, A Neuberger and EL Tatum, eds. North Holland Publishing, 1967, pp 1-31. 24. Buckton KE, lacobs PA, Court Brown WM, and Doll R: A study of chromosome damage persisting after x-ray therapy for ankylosing spon dylitis. Lancet 2:676-682, 1962. 25. Bloom AD, Nakagome Y, Awa AA, and Neriishi S: Chromosome aberrations and malignant disease among A-bomb survivors. Amer I Pub Hlth 60 641-644, 1970 26, Vaughan I Bone disease induced by radiation Int Rev Ftp Path 1:243-396. 1962. 27, Fischer P. Colob E. Kunze-Muhl F. Haim AB et al Chromosome aberrations in peripheral blood cells in man following chronic irradiation from internal deposits of Thorotrast Radial Res 29 505-515. 1966 28, Garza Chapa R, Leah CH. Alvarez M, and Sanchez F|: Chromosome analysis in males occupationally exposed to lead (Abstract 325>! In Ab stracts V International Congress ol Human Cenencs, S Armendares and R Lisker, eds, Excerpta Medica, Amsterdam. 1976. 29, Sampson Rl, Key CR, Buncher CR, and ligma A: Thyroid carcinoma in Hiroshima and Nagasaki. I. Prevalence of thyroid carcinoma at autopsy. Hiroshima 1957-68, Nagasaki 1951-67. ABCC Technical Report 25-68, 1968 30 Muller |, David A, Repkova M, and Brezikova D: Chronic occupation al exposure to strontium-90 and radium-225. Lancet 2 129-131, 1961 31. Fischer P, Colob E, Kunze-Muhl E, and Mutlner T: Chromosomal aberrations in thorium dioxide patients, Ann NY Acad Set 145:769-766, 1967. 530 Vinyl Chloride Cytogenetics/Picciano et al SL 028370