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~w omppr k t tho nd to modjm rhr hlr to m thr 1S<!tVP h will ppon tan i id to ( omP .Kx in* i the Vinyl Chloride Cytogenetics yC '12- Dante ). Picciano, Ph.D.; Ray E. Flake, M.D.; Peter C. Cay, M.D.; and 0. lack Kilian, M.D. This report presents cytogenetic finding) from a group of j 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. chloride (VC) has been reported to be carcinogenic in animals' } and human beings' and mutaRenic 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.? * 'l Similar increases were not lound upon cytogenetic evaluation of German 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 11 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 geported 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. trims OctufHlirmal Health and Medical Research Dow Chemical USA (Drs theciano and Hikin' and DepinnserH of Industrial MiHrine Dow Chemical USA. Texas , Division (Drs Flake and Gayl, Freeport, TX 77SA1 Material from thw report was presented at the Sth International Cnnxtess of Human Oeneocs Mexen City October 1tl-1S 197ft Journal of Occupational Medicine/Vol. 19, No. 8/August 1977 Vinyl chlonde monomer has been produced at the Texas Divi sion of Dow Chemical USA since 1948. There are no vjiiyl 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 1959.1' 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 fLppm from 1968 to 1973; in 1974, TWA concentrations 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 (Tattle 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 tune of thts in vestigation. As part of the medical surveillance program for this group, peripheral hlood 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 rvtogettetic-data from a group of 295 "preemployment examinee4" who had chromosome evalua tion done as part of routine proempknyment examination and who, at that time, had no known exposure to chromosome-break - 527 SL 097307 TaMn 1. -- UU--m tipi--i to Vinyl Cktortdo (VC) ter Vltyl Job ClamHtUtoo Supervisor R&O Engine* Production Engineer refhncji Specialist Qfk)pm*ru LA (LA Supv) Quality Control LA instrument Man Electrician Coverers (Insulators) Painter P'Ootnter Machinist Welder (BoilwmiMr) Mainterance (Utility Nani Material HandOr Production Foramen Shift Foreman Control A Op (V2 4 Chloride) Control A Op (E 4 CD Control A Op (Vinyl) Control A Op (CMormation) Control B Op EOay 4 CWqnde) Control C Op (CNonde 4 Vinyl) Control C Op (Chlortruiton) Class 1 Op Class 1 Op (Pvts) Clast 3 Op Production Clerk Unit Manager EilPalM Eapowta Parte par MNMm, m TleeeWeiitoed-Average 71-1174 1940*1972 Mon 19M ir w 44 82 1 7 44 82 1 7 4 4 82 OS 05 05 1 7 39 7 7 8 7 114 15 2 1 3 40 78 1 3 40 78 03 03 03 07 0 7 07 09 09 09 2 4 5 l 89 06 06 06 1 3 40 78 05 05 05 1 3 40 7ft 1 4 7 ] 109 52 79 11 7 09 09 09 28 55 93 23 50 SO 07 Q 7 07 46 73 LL 1 26 5 3 9 1 53 80 118 05 05 0 5 26 53 9 1 07 0 7 07 07 07 07 TaMa I. -- Cytofaaaelc Study of 2M WoHui* Ei t Vinyl Cktoridu, No at cultures No at cells Chromatid breaks Chromosome ttrtAs Rings dicentrics, and etchengei Abmvmtt cate Wbrttan 209 10 483 2 4% 1 0% 0 4% 3 7% Caetnk 295 14,161 3 6% l 1% 02% 4 5% percent aberrations, and the vinyl chloride workers were separated into those with estimated TWA exposure levels cat k-sx- than-1 ppm. from l-to-S ppm, and greater-than-5 ppm The estimated exposure levels were based on calculations for specific |ob 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 propcartion 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 ot greater than 5 parts per million are almost Identical to those of the control group, --' - Similar conclusions were reached upon evaluation of'tlf?dM4 for chromosome hreaks (Table 4) and the proportion of abnormal cells (Table SI In all three cases, most of both groups were found to have zero-to-five |>ert ent aberrations, and the vinyl chloride workers with the? highest level ot estimated exposure showed aberration rates not significantly different than those of the con trol group. Findings for both groups, workers and controls, arc- considered to be within the range of normal variation as seen in this laboratory. ms .tgentx The retordx xolet ted tor inclusion in the control group wore matched to those ot the study group. insol.tr as possible tor sex number ot rolls 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 19 5 years Irange 18 to H7 yearsl. 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 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 a!'" was com posed of seven PVC workers who had been exposed for nine to 29 years and who were round 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 chloride workers and preemptoyment controls -- were scored and com pared on the basts of chromatid hre.tkv chromosome breaks, rings, cIkentries, and exchange figures: and the proportion ot ab normal cells The proportion of ahnormal cells was calculated to show the overall frequency of aberrant cells, that is, the ratio of cells with at least one aherration to the total numher ot cells examined. Results, expressed in terms of the mean percentage tear these categories of aberration, -Flowed no ma|or differences he- tween the two groups for anv ot the ctassitic at ions Using Chi-square analysis, it was derided to see il differences in various aberration rales could be detected within the two groups Accordingly, hoth groups were divided into those showing zero- to-Mve percent aberrations and those showing greater-than-tive 528 Tabla 3. -- Dtotrlbutton af ChrsuatM AhuntlM* Itototod to Vinyl Chtorid* (VC) Expmno. Eituwa to VC* < 1 txm 1-S m >6 man Control* Nom Group 209 70 94 41 295 % of Graa# Kith 05% ttarttftaM % *1 Onnd ndt >M temnlNaa 90N ION 77 75 2S in ............. ' Eunsure levels He esimates toed on calaiMtm to tceohc 140 rtaudunnni rr p sure In .ndisuluals nay last Men latlat a lower exoonn lewh tor rndtvetaeN *0 tram to vary ynthrn rob classtlicatmns Vinyl Chloride Cytogenetrcs/Ptcoano et ai IP o9738 sx^ --TiMb . mwMlNi if Chtmmw AtwiUi Rtit*4 w Wirt CWwMt (VC) tumm. i 1 txjXBurt to VC 11 mm 15 om t5 mm Controls m, III 6np 209 70 w 41 295 --3f^| wttfc 0- 5% Mmrttbm % *! Qm *Wi >5% AfearrvttoM 96% 94 95 94 4% 6 5 6 X 'i - o 3 O'* 0 95) TtMt 5. -- OWrfttUtt < UtawiMl Ctl RtfaM tg Vlityt ChltfMt (VC) EitMure. EfOosuix to VC < 1 ope> 1 5 mm * 5 mm Cutftttt ID M Brent 209 \ 79 X 91 41 ;95 % l iron *m o> 5% tovTfttm % *f Qraav *** 6% mini MS IB* na 13 V 10 30 XU) - 5.57 19*012) found m.Uid isurtw '>' ill reported to have continuously decreased over a period of years until immediately prior to the study when VC concentrations in :he polymerization department were estimated to be 20 to 30 npm 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 100 ppm at times. The group of ten German workers investigated by Fleig and Thiess!0 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 a/ 22 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 inireased aberrations in workers exposed to "higher" levels of vinvl ihloride, 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 hncause it has been shown" that the cytogenetic change most often associated with aging is chromosome loss, rather than chromosome breakage On the basis of oiif 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 he 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," radium dial paint ers," 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;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 " 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 im reased 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 wrves 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 alt past and present VC workers. Current workers are also being monitored as part of the continuing medical surveillance program. The juthtifs,icknowledge with appreciation the technical assistance of Mrs, A LmwombeandMn D Mem* the luggestiom of Mrs M Benge, the editing ot Ms T I. llovd and the advice of Or C B lacobson. References 1 Viola FT, Rigotti A. and Caputo A; Oncogenic response ol rat skin, lungs and hnnos to vinyl chloride Cincor Rri 31 516-519, 1971 2 Maitnm C and lefemme C Carcinogenicity to bioassavs of vinyl chloride I Research plan and early results fnviron Res 7 387-405, 1974 \ Cre h |L and Johnson MN Angiosarcoma of the liver m the manufac ture of polyvinyl chloride IOM 16.150-151, 1974 4 Rannng II lohansson A, Ramel C. and Wachtmeister CA The mutagemt ity of vinyl t Monde after metabolic activation Ambto 3 194-197, 1974. 5 Malaveille C 8artsch H, Barbin A et al Mutagenicity of vinyl chloride, chloroethylene oxide, chloroacetaldehyde and cHioroetHanoi. 8<ochem 8ophys 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 5 tvphtmunum strains. Inf / Oncer IS 429-437, 1975, 7 Funes-Cravioto F, Lambert B, Lmdsten ) et al Chromosome aberrations m workers exposed to vinyl chloride LantW 1 459, 1975, B Ducatman A. Hirschhorn K. and Selikoff l|* Vinyl chloride exposure and human chromosome aberrations Mutaf Res 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 l and Thiesx AM: Chromosome analysts after vinyl chloride ex posure Arbeinmed Soztalmed Praeventimed 9:280-283, 1974. 11 Kilian Dl. Picciano D|, and lacobson CB: Industrial monitoring: A cytogenetic approath Ann NY Arad Vi 269`4*11, 1975, 12 infante Pf, Wagoner IK, MrMichael A|, Waxweiler R|. and Falk H Genetic risks of vinyl chloride lancet 1 734*735. 1976, 13 Sartsch H, Malaveille C. Montesano R. and Tomato L: Tissuemediated mutagenicity of vtnylidene chloride and 2*chlorabutadlene in Sa/monef/a (vphtmurium Nature 235 641-643, 1975. 14 Occupational Safety and Health Acfrninistration: Exposwt to vinyl chloride federa/ Reorder 39(194): 35889-35898, October 4, 1974 15 RnweVK Experience in industrial exposure control. Ann NV Acad 5rf 246:306'310. 1975 16 Moorhead PS. Nowell PC, Meltman W|. Battips DM. and Hungedord 529 SL 097309 i DA: Chromosome preparations of leukocytes cultured tram human pertfiiefa* blood *p Cell Res 10.613-616, 1960 Hlih 60-641-644 1970 2b Vaughan | Bone disease induced by radiation fnt Rev up Pith 17. Kiiian D| and PkcunoD: Cytogenetic surveillance of industrial popu 1 243-396, 1962 lations. In Chemical frAxagen*; Principles And Methods tor fhotr Defection, Vd 4, New York: A Hoflaender ed. Plenum Press. 1976 fjp 121-339 27 Fischer P Colob , Kunze-MUhl Haim AB et al Chromosome aberrations in [peripheral bl<x>d cells in man following chrome irradiation 18 Funes-Cwwato t at. Reference 7 19 Ducatman et al. Reference 8. Uom internal deposits of Thorotrast Radial Res 29 505-S15 196b 28 Garza Chapa R leah CH Alvarez M and Sanchez F| Chromosome 20 Fleig & Threw, ReferenceRlO. analysis m males oci upabonallv exposed to lead (Abstract 325)' In Ah 21 Purchase et ai. Refewnqf9 sfrjif? V' international Congress of Human Onef/cs 5 Armendares and R 22 Kalian et al, Reference 11 Loker eds Exierpta Mi^lira, Amsterdam, 1976 23 Court Brown WM human population cytogenetics In frontiers of 29 Sampson RJ Key CR Buncher CR, and li|ima A Thyroid carcinoma in Biology, Vol V, A Neuberger and EL Tatum, eds North Holland Publishing 1967, pp 1-31 Hiroshima and Nagasaki I Prevalence of thyroid tarunoma at autopsy Hiroshima 195 7-68 Nagasaki 195 1 -67 ASCC Tv< hnn al We/Hirf 25-68 14b6 24 Buckton KE, lacob* PA, Court Brown WM and Ooll R A studv ot chromosome damage persisting alter x-ray therapy for ankylosing spon dylitis Lancet 2 676-662, 1962 30 Muller ), David A Repkova M, and Brezikova D Chronic occupamn al exposure to strontium-90 and radium-225 Lancet 2 129-1 11 1961 31 Fischer P Golob F Kunze-Muhl F, and Mullner T Chromosomal 25 Bloom AD, Nakagome Y, Awa AA and Nemshi S Chromosome aberrations in thorium dioxide patients Ann NY Acad Sci 145 769-261) aberrations and malignant disease among A-bomb survivors Amer ) Pub 1967 X 530 Vinyl Chloride Cytogenetics/Picoano eta SL 097310