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t. Vinyl Chloride Cytogenetics Dante J. Picciano, Ph.D.; Ray E. Flake, M.D.; Peter C. Gay, M.D.; and D. Jack Klllan, M.D. This report prerents 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.5.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 animals' 1 and human beings' and mutagenic in bacterial test systems.4 ' * There have been reports of increased frequencies of chromosomal aberrations in workers exposed to vinyl chloride at polyvinyl chloride (PVC) facilities.7 * 4 Similar increases were not found upon cytogenetic evaluation of Cerman PVC workers'0 nor in our own preliminary investigation of a group of American VC workers." 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." 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." 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 Occutunonxl Multh and Meeical <t*wwch. Dm Chemical US A. 'On. fVciaoo and Kiltani and Department ol Industrial Medicine. Oow Chemical US A . Teas Division IDtv flak* and Cayl. Freeport, TX 77S41 Material Irons Ihn report was presented at the Sah International Congress of Human Cenetcs. Mexico Citv. October 10-1V 1V7& 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.'4 Although the threshold limit values for vinyl chloride had been 500 parts per million (ppm) until 1974. Dow had established a goal of 50 ppm or below in 1959." 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,'7 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- Journal of Occupational Medicine/Vol. 19. No. 8/August 1977 GGC 003516 527 's,r r. Table 1. -- Estimated Exposure to Vinyl Chloride (VC) for Vinyl Chlorido-Rolatod Job Classifications. Job Classification Supervisor DSD Engineer Production Engineer Technical Sp-Mlnt Ocwforont 1*0 (1*6 Sum) Quality Control Lad instrument Min Etetncwi Cmcfttt (Insulators) Fainter Pipefitter Madnmst Welder tBsi>ermatttr) Ml*U~4ncv (Utility Man) Materia* Handler Production Foreman Shit! Forman Control A 09 (V2 A Chloride) Control a 0s (E t Cl) Cow?! A Op (Vinyl)' Comrp) A Op (Chlorination) Control B 09 (0*y A Chloride) Control C Op (Chloride A Vinyl) Control C Qo (CWonnatwl Class 1 09 Cass f Oo (Parrs) Class 3 Oo Production Clerk Unit Manager Estimated Exposure in Parts par Million, a* Trie-Weighted-Average 1973-1974 1960-1972 Betore I960 17 44 82 17 44 82 17 44 67 OS 05 05 12 39 77 (7 114 152 13 40 78 13 40 78 03 03 03 07 0.7 0.7 0.3 09 09 24 51 89 06 06 06 13 40 78 OS 05 05 13 40 78 4.4 7.1 109 57 7.9 117 03 09 09 26 55 93 23 SO 80 07 07 07 46 73 11.1 76 S3 91 53 80 118 05 05 0.5 76 53 91 07 0,7 07 0.7 0.7 0.7 Table 2. -- Cytogeftetic Study of 209 Workers Eiposed to Vinyl Chloride. No. ol cultures No ol cells Chromatid breaks Chromosome breaks Rings. dcenUKS. and exchanges Abnamal tails Worton 209 10483 24% 10% 04% 3.7% Contrail 295 14 761 36% 11% 0 2S 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-5 ppm. The estimated exposure levels were based on calculations for specific job classifications to which members of the 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 5 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 5). In all three cases, most of both groups were found to have zero-to-five percent aberrations, and the vinyl chloride workers with the highest level of estimated exposure showed aberration rates not significantly different than those of the con trol group. Findings for both groups, workers and controls, are considered to be 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 between the two groups could not be completely eliminated: the average age of the vinyl chloride workers was 39.5 years (range. 18 to 67 years), and the average age of the preemployment control group was 25.1 years (range 18 to 50 years). * Results As shown in Table 2, data from both groups -- vinyl chloride workers and proemplovment controls -- were scored and com pared on the basis of chromatid breaks; chromosome breaks; rings dicentrics, and exchange figures; and the proportion of ab normal t ells. The proportion of abnormal cells was calculated to show the overall frequency of aberrant cells, that is. the ratio of cells mth at least one aberration to the total number of cells examirvvl Ri-mjIis expressed in terms of the mean percentage for those i aovori.'s of aberration, showed no major differences betxsrvn is- two groups for any of the classifications. L'sing l h.-MUure analysis, it was decided to see if differences in jriixis .iln-rr Hum rau>s could be detected within the two groups. Acvirid'ngh truth groups were divided into those showing zeroto-tive ivrrent ahivraimns and those showing greater-than-five 528 Discussion The reports that have appeared, to date, concerning chromosome aberrations in vinyl chloride workers have not been 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 by Funes-Cravioto et al" was com posed of seven PVC workers who had been exposed for nine to 29 years and who were found to have an increased frequency of chromosome breakage. The level of exposure for this group was Table 3. --- Distribution ol Chromatid Aberration Related to Vinyl Chloride (VC) Espoiure. Exposure to VC* <1 nan 1-5 com >5 wm Controls No. in Group 209 70 98 41 295 % of Group with 0* $% Aberrations % el GrOUO eitk s 5% Abviatiens 90% tos 77 23 80 20 75 25 JC-U).- 775 19=0061 Eigosae MS arc estimates baste on tatcuiatoistct seecihc lab ctassUixatais en erne sue tv intMhieis mat hint ben mglnr or kmr. neoun Wets let mdendiaM n anon to van wiimi too ttasuhatim Vinyl Chloride Cytogenetics/Picdano et al GGC 00351 Table 4. -- Distribution at Chromosome Aberration* Related to Vinyl Chloride (VC) Exposure. Exposure to VC r 1 pem 1-5 ppm 5 ppm Controls * * ** No. In Group 209 70 58 41 295 H of Group with 05% Aberrations % of Group with >5% Aberrations %% 4% 94 t 95 5. : 94 - 6 JC'tn - 0355 17=095) S" - ^ .V- -" '* - - 1 1 ' I--W M Table 5. - Distribution of Abnormal Calls Related to Vinyl Chloride (VC) Esposure. ' Exposure to VC si ppm 1-5 ppm >5 ppm Controls s--* - '' 1 V- He. In Group 209 70 98 4t 295 K ol Group with 0* 5% Aberrations S ol Grouo with > 5* Abtreethun its 16% 71 29 7] 27 70 30 KkJI- 5.97 <P=0.I2> : e* -- ^ # a */- iJ 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. Yhe 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 Cerman workers investigated by Fleig and Thiess20 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 et al.1' 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 laboratory*2 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 shown22 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.2* A-bomb survivors.2' radium dial paint ers,2* persons exposed to Thorotrast,22 and workers exposed to lead.21 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;2* radium dial painters were found to be at increased risk of osteogenic sarcoma:20 and Journal of Occupational Medicine/Vol. 19, No. 8/August 1977 thorium dioxide-exposed persons have an increased rate of liver tumors.21 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. Mens*, the suggestions oI Mrs. M. Benge, the editing oI Ms. T. B. Lloyd, and the advice of Or. C 8. lacobson. 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. Maltoni C and Lefemine C: Carcinogenicity to bioassavs of vinyl chloride. I. Research plan and early results. Environ Res 7:387-405. 1974. 3. Creech IL and Johnson MN: Angiosarcoma of the liver in the manufac ture of polyvinyl chloride. /OM 16:150-151. 1974. 4. Rannug U, Johansson A. Ramel C. and Wachtmeister CA: The mutagenicity of vinyl chloride after metabolic activation. Ambio 3:194-197. 1974. 5. Malaveille C. Bartsch H. Barbin A et al; Mutagenicity of vinyl chloride, chloroethylene oxide, chlorciacetaldehyde and chloroethanol. Blochem Biophys Res Common 63:363-370, 1975. 6. Bartsch H. Malaveille C. and Montesano R: Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in S. typhimurium strains. Int I Cancer 15:429-437. 1975. 7. Funes-Cravioto F. Lambert B. Lindsten J et al; Chromosome aberrations in workers exposed to vinyl chloride. Lancvt 1:459. 1975. 8. Ducatman A, Hirschhorn K, and Selikotf l|: Vinvl chloride exposure and human chromosome aberrations. Mu,at Res 31:163-168. 1975. 9. Purchase IFH. Richardson CR. and Anderson O: Chromosomal and dominant lethal effects of vinyl chloride. Lancer 2:410-411. 1975 10. Fleig I and Thiess AM: Chromosome analysis after vinvl chloride ex posure. Arbeitsmed Soiialmed Praeventimed 9280-28J. 1974 11. Kilian Dl. Picciano Dl, and Jacobson CB- Industrial monitoring- A cytogenetic approach. Ann NY Acad Set 269:4-11. 1975 12. Infante PF. Wagoner |K. McMichael Al. Waxweihrr Rl. and Falk. H: Cenetic risks of vinyl chloride. Lancet 1:734-735. 1976 13. Bartsch H. Malaveille C. Montesano R. and Tomans l Tissuemediated mutagenicity of vinvlidene chloride and 2-< hlixnhuiadnme m Salmonella typhimurium. .Nature 255:641*641. 1975 14. Occupational Safety and Health Administration- txpusive to V.nvl chloride, federal Register 39(1941: 35889-15898. OitiRvf 4 1974 15. Rowe VK: Experience in industrial exposure control Ann NY *<ad Vi 246:306-310. 1975. 16. Moorhead PS. Nowell PC. Mellman WJ. Baltips DM and HursgeKred 529 GGC 00351S DA: Chromosome preparations of leukoc cultured from human 'peripheral blood, ftp Cell Set 20:611-616, Vs6Q. ** 17. Kilian Dl and Picciano D: Cytogenetic surveillance of industrial popu lations. In Chemical Mutagens; Principles and Methods for Their Detection, Vol 4, New York: A Hollaender. ed. Plenum Press, 1976. pp 321-339. 18. Funes-Cravioto et al. Reference 7, 19. Ducatman et al. Reference 8. 20. Fleig & Thiess. Reference 10. 21. Purchase et al. Reference 9. 22. Kilian et al. Reference 11. 23. Court Brown WM: Human population cytogenetics. In Frontiers of Biology. Vol V. A Neuberger and EL Tatum, eds. North Holland Publishing, 1967. pp 1-31. 24. Suckton ICE. 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 5: Chromosome aberrations and malignant disease among A-bomb survivors. Amer I Pub Hllh 60:641-644, 1970. 26. Vaughan J: Bone disease induced by radiation. Int Rev p Path 1:243-396, 1962. 27. Fischer P, Colob E. Kunze-Mlihl E, Haim AS 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 of Human Genetics. S Armendares and R Lisker, eds. Excerpta Medica. Amsterdam, 1976. 29. Sampson Rl, Key CR. Buncher CR. and lijima A: Thyroid carcinoma in Hiroshima and Nagasaki. I. Prevalence of thyroid carcinoma at autopsy. Hiroshima 1957-68. Nagasaki 1951-67, A8CC Technical Report 25-68.1968. 30. Muller |, David A. Rejskova M, and Srezikova O: Chronic occupation al exposure to strontium-90 and radium-225. Lancet 2:129-131, 1961. 31. Fischer P. Colob E, ICunze-Muhl . and Milliner T: Chromosomal aberrations in thorium dioxide patients. Ann NY Acad Set 145:769-766, 1967. 530 Vinyl Chloride Cytogenetics/Picciano et al GGC 003519