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ot Vinyl Chloride Cytogenetics Dante J. Ptcciano, Ph.D.; Ray E. Flake, M.D.; Peter C. Cay, 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 hoen reported to be carcinogenic in animals' ` and human beings' and mutagenic in bacterial test systems * ' * There have been reports of increased frequencies of chromosomal aberrations in workers exposed to vinyl chloride at polyvinyl chloride (PVC) facilities ' * ' Similar increases were not found upon cytogenetic evaluation of German PVC workers'" nor in our own preliminary investigation of a group of American VC workers " One study hased on interviews with male employees has indicated an increased rate of fetal wastage among wives of VC-exposed workmen involved in polymerization operations 11 We have rerently completed lytngenetic evaluation of all currently-employed workers exposed to vinyl chloride at tile Dow (Freeport) Texas Division Both vinyl chloride and vtnylidene chloride are produced in this plant Vinylidenc chloride has also been reported as mutagenic in bac terial 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 F fom Oi cup4t*onal Hp.\lih and Moduli Rn<,r,iffh, Dow USA (Dr* Pw- Ciitno ,\nd Kftan> and Dcpairmenl of Industrial Mrdtcmp Dow Chemical U.5 A , Divivfon IDta FlaVe and Cay' Frrf[V>M TX 7754T Material from this report was presented at the Sth International Congress of Homan Gennttcs Mpxko City October 10*15, 1976 Journal of Occupational Medicine/Vot 19, No. 8/August 1977 Vinyl chloride monomer has been produced at the Texas Divi sion nl Dow Chemical USA 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 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 (05HA) 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 |ob 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 lor periods ranging between one and 3)2 months (average. 48.3 months) at the lime 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.'*' Stan dard procedures, as previously described," 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- 527 SL 071244 Table 2. -- Cytogetic Study of 209 Wofkpri Exposed to Vinyl Chloride, Ho ol cultures No ol crlls Chromatid breads Chromosome breaks Rings, dicentrics, and eichtnges Abnormal cells Worker* 203 10 433 2 4% l 0*i on 3 7% Controls 295 14 761 3 6% 1 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-5 ppm The estimated exposure levels were based on calculations for spec ifk job classifications to which members of the1 vinvl chloride study group were assigned Three categories of aberration were c hosrn for this analysis- chromatid breaks, chromosome breaks, and the proportion of abnormal cells. As shown in Tahle 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 tlx* proportion of abnormal celts (Table 5). In all three cases, most of both groups were found to have 2ero-to-five percent aberrations, and the vinyl chloride* workers with the* highest level of estimated exposure showed aberration rates not significantly different (Km those of tlx* con trol group Findings for both groups, workers and controls are considered to he within the range of normal variation as seen in this laboratory. ing agents The records srlrc tod for in( fusion 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 c ould not be completely eliminated the avrrago age of the vinvl r hloride workers was 39.5 years (range. 18 to f>7 years), and the average age of the pre employment control group was 25.1 years (range 18 to 50 years). Discussion The* reports that have appeared, to date, concerning chromosome aberrations in vinyl chloride workers have no! been in agreement This < onfhet may he due either to the small number of workers studied or to differences in exposure levels, or both. Tlx* Swedish group studied by Funes-Cravioto et al,H was com posed of seven PVC workers who hid 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 Results As shown in Table 2 data from both groups -- vinyl < hlnnrle workers and preomployment controls -- were stored and com pared on the hasis of chromatid breaks; chromosome breaks: rings, dicentrics, and esc bange figure's, and tlx* proportion of ab normal cells The proportion of abnormal c elk was calculated to show tin* overall frequency of aberrant tells, that is, the ratio of cells with at least one aberration to M>e total number of cells examined. Results, expressed in terms of the mean percentage for these categories of aberration showed no major difference* be tween the two groups for any of the c lassifications Using Chi-square analysis it was dec ided to see if differences in various aberration rates c ould be detec ted within the two groups. Accordingly, both groups were divided into those showing zeroto-five percent aberrations and those showing greater-than-five 528 Titbit 3 -- Distribution of Chromatid Aberrations Related to Vinyl Chloride (VO Exposure Eiposurf lo VC * 1 ppm 1-5 ppm >5 nm Controls No in Group 709 70 98 41 295 % of Group with 05% Aberration* % of Group with > 5% Aberration* 90% 10% 77 23 80 20 75 25 2C Nj| - 7 75 IP-0 06) ttposwe levels estimates hased on calculations lor specify iob classifications prior non sure iff individuals may Save been higher or lower, exposure levels Iff individuals are known Ip vary within pih classifications Vinyl Chloride Cytogenetics/Picciano et at SL 071245 TM* 4. -- Distribution of Chromosome Aborratfons Related to Vinyl Chloride (VC) Exposure. Exposure to VC < 1 ppm 1-5 oixn >5 ppii Controls No. In Group Z09 70 n 41 295 % Of Grouo wth 0* 5% AtarltiftrtS % ! Group *irti > Aborretiont 96% 4* 94 6 ' 95 5 94 6 JC '01 0355 IP 5 0 95) v * t. Tbl 5, -- Distribution of Abnormal Colli RtloM to ' I Vinyl Cblorido (VC) Exposure. exposure io VC 1 ppm 1-5 ppm > 5 ppm Control* No, In Grouo 209 to 93 41 295 H ol Group with 05% AfeTTtions % of Group with > %% Aborritiont r 84% 16% n . 79 ( 73 ( . V , 1 ' 27 . 70 30 X'ffl - 597 (P-0,12) ; .3 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 Thiess" 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 af11 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" 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 shown" 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 tlx' 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." A-bomb survivors,1' radium dial paint ers, n persons exposed to Thorotrast." and workers exposed to lead,'* 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:" radium dial painters were found to be at increased risk of osteogenic sarcoma;TM and Journal of Occupational Medicine/Vol. 19. No. 8/August 1977 thorium dioxide-exposed persons have an increased rate of liver tumors." This relationship between chromosomal breakage and neoplasia strongly suggests that cytogenetic analyses may be a useful tool for delecting 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 arc also being monitored as part of the continuing medical surveillance program. The auttow* acknowledge wtih appreciation the technical assurance ot Mr* A tmscofnbe and Mr* D Mensik. the suggestions of Mrs. M. Benge, the editrtg of Ms, T, B. lloyd and the advice of Dr C. B Jacobson. References I Viola PL, Bigotti A, and Caputo A' Oncogenic response* of rat skin, lungs, and bows to vinyl < Hondo, Cancer Res 31 516-519, 1971. 2. Mahoni C and lefemine G' Carcinogenicity to bioassays of vinyl chloride I Research pl.m and early results, Environ Rrs 7 387*405. 1974 1, Creech |l and Johnson MN: Angiosarcoma of the liver in the manufac ture of jlyvmyl chloride /OM 16 ISO-151. 1974 4 R.tnnug U. Johansson A, Ramel C. and Warhtmeister CA` The mutagenicity of vinyl chlonde after metabolic activation. Amtoo 3:194-197, 1974 5 MaJjveiUe C Bartsch H, Barton A et al' Mutagenicity of vinyl chloride, chloroethylene oxide, chloroacetaldehyde and chloroethanol. Biochem ftophys Res Common 63:363-370. 1975, 6, Bartsch H. Malavnlle C. and Montesano R` Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in 5, typhimvrtvm strains. Ini / Cancer 15 429-437. 1975 7, Funcs-Cravioto F, Lambert B. 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Montes,wo R. and Tomatis L: Tissuemediated mutagenicity of vinylidene chloride and 2-chIorobutadiene in Salmonella typhimunum, Nature 255 641-643. 1975 14 Occupational Safety and Health Administration: Exposure to vinyl chloride, Federal Register 39(194): 35809-35B98, October 4, 1974 15 Rowe VK Experience in industrial exposure control. Ann NY Acad 5ci 246:306-310. 1975, 16. Moorhead PS, Nowell PC. Mellman W|, Batlips DM. and Hungerford 529 SL 071246 DA Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Off Res 20 611-616, I960. 17. Kifan D| and PiccUno D: Cytogenetic surveillance of industrial popu lations. In Chemical Mufaflens: Principles and Methods fry 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 0. 20. Fteift & Thiess, Reference 10. 21. Purchase et al. Reference 9. 22. Kilian et al. Reference 11. 23. Court Brown WM Homan population cytogenetics In Frontiers of 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 2.676-6B2, 1962, 2$. Bloom AD, Nakagome Y. Awa AA. and Neriishi S' Chromosome aberrations and malignant disease among A-bomb survivors. Amer f Pub H/lh 60 641-644, 1970. 26. Vaughan |: Bone disease induced by radiation. Int Rev Exp Path 1:243-396, 1962. 27. Fischer P, Gnlob E. Kunze-MUhl E. Haim AB et al: Chromosome aberrations in peripheral blood colls in man following chronic irradiation from internal tleposits of Thorotrast. Radiat Res 29 505-515, 1966 28. Garza Chapa R. lenh CH. Alvarez M, and Sanchez F| Chromosome analysis m males occupationally exposed to lead (Abstract 325). In Ab stracts V* International Congress of Humor) Grnvtict. S Armendares and R Lisker, eds Excerpt* Medic*. Amsterdam, 1976 29. Sampson R), Key CR. Buncher CR. and lijima A: Thyroid carcinoma m Hiroshima and Nagasaki, I Prevalence erf thyroid carcinoma at autopsy. Hiroshima 1957-68, Nagasaki 1951-67 ABCC Technical Rrpori 23-68, 1968. 30 Muller I, David A. Rejskova M. and Brezikova D: Chronic occupation al exposure to. strontium-90 and radium-225, Loncrl 2 129*131. 1961, 31 Fischer P. Golob E, Kunzc-Muhl E, and Mullncr T: Chromosomal aberrations in thorium dioxide patients. Ann NY Acad Sci 145:769-766, 1967. 530 Vinyl Chloride Cytogenetics/Picciano et al SL 071247