Document RJrw1q1jyqmKOwN2grZ66kXea

R&S 136418 Vinyl Chloride Cytogenetics Dante ). Picciano, Ph.D.; Ray E. Flake, M.D.; Peter C. Gay, M.D.; and D. lack Killan, 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. Vmvl chloride (VO has been reported to be carcinogenic in animals' ; and human beings' and mutagenic in bacterial test svstems4 ' " There have been reports of increased frequencies of chromosomal aberrations in workers exposed to vmvl chloride at polvvinvl chloride (PVC) facilities.' " ' Similar increases were not found upon cytogenetic evaluation of German PVC workers"1 nor in our own preliminary investigation of a group of American VC workers." One studv based on interviews with male emplovees has indicated an increased rate of tetal wastage among wives of VC-exposed workmen involved in polymerization operations.'*' We have recently completed cytogenetic evaluation of all currentlv-emploved workers exposed to vinvl chloride at the Dow (Freeport) Texas Division. Both vinvl chloride and vinvlidene 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 vinvlidene chloride is far less than the exposure to vinvl chloride. From Of.ruoatronal Hoalth and Medical Rete.nvh Dow Chemical USA 'Drs Pict ujno and Kilam and Department ot industrial Medic me Dow Chemical USA Texas Division Dr- Flake and Gav Freeport TX 77i-n Material from this report wa-t presented at the Sth International Congress of Human Genetics Mexico Citv October 10-1S 1976 Vinvl chloride monomer has been produced at the Texas Divi sion of Dow Chemical U.S A since 1948. There are no vinvl 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 vinvl 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 vinvl chloride f.or 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 vears prior to 1968 are less reliable. For the purposes of this study, estimates of exposure were calculated for specitic job classifications, based on records of both personnel and area monitoring (Table 1). However, actual exposure mav varv 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 16 Stan dard procedures, as previously described,1' 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 preemplovment examination and who, at that time, had no known exposure to chromosome-break- Raprintad from Journal of Occupational Madictna August. 1977. Volume 19. No. B pp. 527-530 R&S 136419 Table 1. -- Estimated Exposure to Vinyl Chloride (VC) for Vinyl Chloride-Related Job Classifications. Job Classification Supervisor RAO Engineer Production Engineer Technical Specialist Development Lat) Hat) Suov) Quality Control lab instrument Man Electrician Coverers (Insulators) Painter Pipefitter Machinist Welder (Boilermaker) Maintenance (Utility Man! Material Handier production Foreman Shift Foreman Control A Qp (V2 A Chloride) Control A Op (E A Ctl Control A Qo (Vmvl) Control A Qp (Chlorination! Control 6 Qp (Qxv A Chloride) Control C OP (Chloride A Vmvl) Control C Op (Chlorination) Class l Oo Class 1 Oo (Parts) Class 3 Op Production Clerk Unit Manager Estimated Exposure in Parts per Million. n Tvne-Wi;hted-Average 1973-1974 1960-1972 Before 1960 I 7 44 82 1 7 44 82 1 7 44 32 05 05 os 12 39 7 7 87 114 152 l 3 40 78 1 3 40 78 03 0,3 03 0 7 07 07 09 09 09 24 5 I 39 06 06 06 1 3 40 73 05 05 05 1 3 40 78 4 4 7 1 109 S3 79 II 7 09 09 09 23 55 93 23 50 80 0 7 07 0 7 46 73 11 l 26 53 9 1 53 30 . 113 05 05 05 26 53 9 l 07 07 07 07 07 07 Table 2. -- Cytogenetic Study of 209 Workers Exposed to Vinyl Chloride. Mo ot cultures Mo o( ceils Chromatid Breaks Chromosome Breaks Rings dicentrics, and eicttanges Abnormal cells Workers 209 10J33 2 4% 1 0% 0 4'- 3 7% Controls 29= 14 7i; 3 5^ 1 1 =5 G 2% 4 5*5 aercent aberrations and the vinvl chloride workers were separated into those w-ith estimated TWA exposure levels ot lessthan-1 ppm. trom 1-to-5 ppm, and greater-than-8 ppm The estimated exposure levels were based on calculations for specific |ob classifications to svhich members or the vinvl chloride studv group were assigned Three categories ot aberration were chosen tor this analysis- chromatid breaks chromosome break' and the proportion ot abnormal cells. As shown in Table 1 no significant differences were round when these groupings were compared on the basis ot chromatid aberrations. Results trom those workers with estimated exposures ot greater than 5 parts per million are almost identical to those ot the control group. Similar conclusions were reached upon evaluation ot the data for chromosome breaks (Table 4i and the proportion ot abnormal cells (Table Si. In all three cases, most oi both groups were tound to have zero-to-rive percent aberrations, and the vinvl chloride workers with the highest level ot estimated exposure showed aberration rates not signiticantlv ditterent than those of the con trol group. Findings tor both groups, workers and controls are considered to be within the range ot normal variation as seen in this laboratory. ing agents The records selected tor inclusion in the control group were matched to those of the studv group, insotar as possible, for sex number ot cells analyzed, and time period during which the culture was initiated Age variation between the two groups could not be completely elimmated: the average age of the vmvl chloride workers was 19 8 vears Tange 18 to 87 vearsi, and the average age of the preemplovment control group was 28 1 vears range 18 to 80 vearsi Discussion The reports that have appeared to date concerning chromosome aberrations in vinvl chloride workers have not been in agreement. This conflict mav be due either to the small number ot workers studied or to dirrerences in exposure levels, or both. The Swedish group studied bv Funes-Cravioto et a!'" was com posed ot seven PVC workers who had heen exposed tor nine to 29 vears and who were tound to have an increased trequencv of chromosome hreakage The level ot exposure tor this group was Results As shown in Table 2 data from both groups -- vmvl chloride workers and preomplovmont controls -- were scored and com pared on the basis of chromatid breaks- chromosome hreaks, rings, dicentrics and exchange figures- and the proportion of ab normal cells The proportion ot ahnormal cells was calculated to show the overall trequencv ot aberrant cells that is the ratio of cells with at least one aberration to the total numher of cells examined. Results expressed in terms ot the mean percentage tor these categories ot aberration showed no ma|or differences be tween the two groups lor anv ot the classifications Using Chi-square analysis it was decided to set' it differences in various aberration rates could be detected within the two groups Accordingly, both groups were divided into those showirg zeroto-tive percent aberrations and those shosving greater-than-tive Table 3 -- Distribution of Chromatid Aberrations Related to Vinyl Chloride (VC) ExpoMire, Erposure (0 VC < \ ppm 1 5 ppm > 5 ppm Controls No, in Group 299 70 93 41 295 % of Group with 05% Aberrations % of Group with > 5% Aberrations 90% 10% 77 23 aa 20 75 25 X 'at - 7 75 (P - 0 06) EtMSu's levels are climates naseS on ralculatiwis for swok I0O r.lassifisainr'x Orror *roc Sure individuals may have t>een higher y low**r etpgsur? levels for individuals are knrjwn to vary wunm too classifications t' Table 4. -- Distribution of Chromosome Aberrations Related to Vinyl Chloride (VC) Exposure. Exposure to VC x 1 pom 15 oom >5 ppm Controls No. in Group 209 70 98 41 295 S af Group with 0* $% Aberrations \ Of Group with > i% Aberrations 4% 94 6 95 5 94 6 X!<3> - 0.3SS (P = Q95) Table 5. -- Distribution of Abnormal Cells Related to Vinyl Chloride (VC) Exposure. Exposure ip VC < l ppm 1 5 oom > 5 pom Controls No. in Group 209 70 98 41 295 % of Group with 0' 5\ Aberrations % of Group with > 5* Aberrations 16\ 71 29 73 27 70 30 K ;!3I - 5 97 (P-0 12) reported to have continuously decreased over a period of vears until immediately prior to the studv 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 alw 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 bv Fleig and Thiess:n worked with either VC or PVC or both for periods ranging between six and 34 vears 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 bv Purchase et a/.-'1 concluded that the frequencv of cvtogenetic 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 vinvl 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 vounger than those already settled into |obs. 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 bv 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. Cvtogenetic dose-response curves, similar to that suggested here, have been reported for x-irradiated ankylosing spondylitics.2' 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:-"' radium dial painters were found to be at increased risk of osteogenic sarcoma:10 and thorium dioxide-exposed persons have an increased rate ot liver tumors M This relationship between chromosomal breakage and neoplasia strongly suggests that cvtogenetic analyses mav be a useful tool for detecting environmental situations which mav be associated with increased cancer risks to the workers The present studv is one or several involving Texas plant em ployees to investigate the possibility that increased rates of fetal loss or birth defects in offspring are experienced bv wives of vinvl chloride workmen and to determine the morbiditv-mortalitv 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 studv 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 acknowledqe with appreciation the technical assistance or Mrs A Lin* scombe and Mrs D Mensik the sumestiom or Mrs m Sense, the editing or Ms T 8 llovd and the advice or Dr C 8 Ucobson References 1. Viola PL, Bigotti A. and Caputo A' Oncogenic response or rat *kin lungs, and bones to vinvl chloride Cancer Res 31`516-519, 1971 2 Maltom C and Lefemme C Carcmogemcitv to btoassavs ot vinvl chloride 1 Research plan and earlv results Environ Re< 7 387-405 1974 3, Creech IL and lohnson MN, Angiosarcoma of the liver m the manufac ture or polvvinvl chloride lO\1 16 150-151 1974 4 Rannug U lohanMon A Ramel C. and Wachtmeister C-A The mutagemcitv of vinvl chloride arter metabolic activation Ambm 3 194-197. 1974,' 5 Malaveille C Bartsch H Barbm A et al. Mutagemcitv or vmvl chloride, chloroethvlene oxide, chioroacetaldehvde and chloroethanol Biochem Biophvs Res Commun 63,363-370 1975 6. Bartsch H Malaveille C. and Montesano R` Human, rat and mouse liver-mediated mutagemcitv or vmvl chloride in $ tvphimunum strains Ini I Cancer IS 429-437 1975 7, Funes-Cravioto F. Lambert B lindsten J et ai` Chromosome aberrations in workers exposed to vinvl chloride Lancvt 1459 1975 8 Ducatman A. Hirschhorn K, and Selikoff l|. Vinvl chloride exposure and human chromosome aberrations. N-fu ar Res 31 `163-168, 1975 9 Purchase IFH Richardson CR. and Anderson D` Chromosomal and dominant lethal effects or vinvl chloride Lancet 2.410-411 1975 10 Fleig I and Thiess AM, Chromosome analysis after vmvl chloride ex posure. Arbeitsmed Sozialmed Pracventimed 9`28Q*283 1974, 11 Kilian D| Picciano Dl. and Jacobson CB` Industrial monitoring, A cvtogenetic approach Ann \Y Acad So 269:4-11, 1975 12, Infante PF Wagoner IK, McMichael Al. Waxwe'ler Rl and Falk H Cenetic risks of vmvl chloride Lancet 1 734-735 1976 13 Bartsch H Malaveille C Montesano R. and Tomans L Tissuemediated mutagemcitv or vmvhdene chloride and 2-chlorobutadiene m Salmonella tvphimunum vatt/re 255 641-643, 1975 14 Occupational Sat'etv and Health Administration- Exposure to vmvl chloride federal Register 39f194i 35889-35898. October 4. 19'4 15. Rowe VK' Experience in industrial exposure control Ann \'Y Acad So 246 306-310 1975 16, Moorhead PS. Nowell PC. Mellman W|. Battips DM, and Hungerrord R&S 136420 4\ DA: Chromosome preparations or leukocytes cultured rrom human peripheral blood Exp Ceil'Re* 20:613-616 1960 17 Kilian D| and Picciano D: Cvtogenetic surveillance or industrial popu lations, In Chemical Mutagen*' Principle* and \1ethod< tor Their Detection Vol 4 New York1 A Holiaender 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 W\V Human population cvtogenetics In Frontier< or S/o/ogv 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 studv or chromosome damage persisting after x-rav therapv for ankvlosing spondvhtis Lancet 2:676-682 1962. 25 Bloom AD. Nakagome Y. Awa AA. and Nernshr S' Chromosome aberrations and malignant disease among A-bomb survivors Amer / Pub H/rh 60 641-644 19*0 26 Vaughan |, Bone disease induced bv radiation int Re\ fxn parn 1 243-396 1962 27 Fischer P Colon E Kunze-Muhl Haim AB et al Cnrnmn^nme aberrations in peripheral blood cells m man following chronic irradiation from internal deposits or Thorotrast Radiat Re* 29 305-515 iu^h 28 Garza Chapa R Leah CH AKarez M and Sanchez FI Chromosome analysis in males occupationally exposed to lead Abstract 323 In 4n"fracfs V /nrernjuona' Congress or Human Conefc* S Armendare-' and R Lisker, eds, Excerpta Medica Amsterdam 19"6 29 Sampson R| Kev CR Buncher CR and liiima A Thvroid carcinoma m Hiroshima and Nagasaki I Prevalence of thvroid carcinoma at autopsv, Hiroshima 1957-68 Nagasaki 1951-67 AflCC Techno, ai Renort 23-68 19^8 30, Muller |. David A Reiskova M and Brezikova D Chronic occuoational exposure to stromium-90 and radium-223 Lancer 2 129-131 1961 31 Fischer P Colob E, Kunze-Muhl E and Mullner T Chromosomal aberrations m thorium dioxide patients Ann \> Acjc/ So 145,*69-"66 1967 R&S CO o> tO