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Origins of Human Cancer BOOK A Incidence of Cancer in Humans edited by H. H. Hiatt Harvard School of Public Health J. D. Watson Cold Spring Harbor Laboratory J. A. Winsten Harvard School of Public Health COLD SPRING HARBOR CONFERENCES ON CELL PROLIFERATION VOLUME 4 CSHi Cold Spring Harbor Laboratory 1977 Origins of Human Cancer 1977 by Cold Spring Harbor Laboratory All rights reserved International Standard Book Number 0*87969*119-0 Library of Congress Catalog Card Number 76-57915 Printed in the United States of America Cover and book design by Emily Harste This publication was supported in part by grants from the Rita Allen Foundation and the Charles E. Merrill Trust. . '-**.*.*1 0^18081 Vinyl Chloride Cytogenetics Dante 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. Vmyl chloride (VC' has been reported to he carcinogenic in animals' 2 and human heings1 and mutagenic in bacterial test systems.'1 ' h There have been reports of increased frequencies of chromosomal aberrations in workers exposed to vinyl chloride at polyvinyl chloride (PVO facilities7 " ' Similar increases were not found upon cytogenetic evaluation of German PVC workers10 nor in our own preliminary investigation of a Rroup 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 w We have recently completed cytogenetic evaluation of all currently-employed workers exposed to vinvl chloride at the Dow 'Freeport' Texas Division Both vinvl chloride and vinvlidene chloride are produced in this plant Vinvlidene 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 Frnm Occupational Health and Medical Research Dow Chemical USA lOrs Pit * nano and Kilan> and Department of lnduAtn.il wdn me Dow Chemical U S A To*<ja Division IDta Flake and Cav1 Freeport TX '7S41 Material from thiA report was presented at the ^th International CongreAA of Human CenencA Metito City October 10-1S 197b 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 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 |ob classifications, based on records of both personnel and area monitoring (Tahle 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 16 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- 527 SL 4I809 Table 1. -- Estimated Expotur* ta Vinyl Chloric!* (VC) lor Vinyl Chtoricte-ftelated Job Clarification*. Job Classification Supervisor RAO Engineer Production Engineer Technical Specialist Development Lab (lab Supv) Quality Control Lab instrument Man Electrician Covered (Insulators) Painter Pipefitter Machinist Welder (Boilermaker) Maintenance (Utility Man) Material Handler Production Foreman Shift foreman Control A Op (V2 A Chloride) Control A Op (E A Cl) Control A Op (Vinyl) Control A Op (Chlorination) Control B Op (Oxy A Chloride) Control C Op (Chloride A Vinyl) Control C Op (Chlorination) Class 1 Op Class t Op (Parts) Class 3 Qo Production Clerk Unit Manager Estimated Exposure in Parts per Wilton, at Tm-Weiftitat-Amat* 1973 1974 1960 1972 Before 1960 17 44 82 1 7 44 82 17 44 82 05 05 05 1 2 39 7 7 87 1)4 15 2 1 3 40 78 1 3 40 78 03 03 03 07 07 07 09 09 09 24 5 1 89 06 06 06 1 3 40 78 05 05 05 13 40 78 44 1 109 $2 79 U 7 09 09 09 28 55 93 23 50 80 07 07 07 46 73 11 l 2 6 53 9 I 53 80 118 05 05 06 26 53 9.1 07 0 7 07 07 07 07 Tibi* 2. -- Cytogenetic Study ol 209 Woritete Expoiod to Vinyl Chlorido. No of cultures No of celts Chromatid breaks Chromosome breaks flings dicentrics, and exchanges Abnormal cells Workers 209 10.483 2 4"* 1 0* 0 4* 3 7* Controls 295 14.761 3 6* 1 I* 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 tor specific job classitications to which members of the vinvl chloride study group were assigned Three categories ol aberration were c hosen tor this analysis chromatid breaks, chromosome breaks, anti the proportion of abnormal cells. As shown in Table 1, 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 vinvl chloride workers with the highest level of estimated exposure showed aberration rates not significantly different than those ot the c nntrol group Findings for both groups, workers and controls arcconsidered to be within the range of normal variation as seen in this laboratory ing .lgentx Tho records selor ted for inr lunon in the control group were matched to those ol the sfudv group, insofar as possible, for sex number of tells analyzed, and time period during which the culture was initiated Age variation between the two groups t ould not be completely eliminated the average age ot the vinyl t hloride workers was 19 5 years (range 18 to 87 vearsl and the average age of the preemplovment control group was 25 1 years (range 18 to 50 years) Discussion The reports that have appeared, to date, concerning chromosome aberrations in vinvl chloride workers have not heen in agreement This conflict mav be due either to the small number ot workers studied or to differences in exposure levels, or both The Swedish group studied hv Funes-Cravioto et al1" was com posed ol seven PVC workers who had been exposed for nine to 29 vears and who were found to have an me reased trequenc v of chromosome breakage The level of exposure for this group was Results As shown in Table 2, data from both groups -- vinvl r hloride workers and preemployment tontrols -- were -r orerl and com pared on the basis of chromatid breaks chromosome' breaks, rings dicentrics and exc hange figures and the proportion of ab normal cells The proportion of abnormal tells was calculated to -how the overall frequency of aberrant cells that is the ratio of cells with at least one aherration to the total number of cells examined Results, expressed in terms ol the mean percentage for these categories of aberration showed no maior differences be tween the two groups for any of the r lassific ations Using Chi-square analysis, it was decided to see if difterenc es in various aberration rates could be deter tod within the two groups Accordingly, both groups were divided into those showing /eroto-hve percent aberrations and those showing greater-than-five 528 Table 3. -- Distribution of Chromatid Aberrations Related to Vinyl Chloride (VC) Exposure. Exposure to VC' <! ppm \ 5 ppm >5 pom Controls No in Group 209 70 98 41 295 * of Group with 05% Aberrations * Of Group with > 5* Aberrations 90* 10* 77 23 80 20 75 25 JC'OI.- 7 75 (P-006) Exposure levels are estimates based on emulations tor soerilir 10b classifications pno' moo sure for individuals may have Open higher or lower exposure levels tor individuals are known Iq vary within |ob classifications Vinyl Chloride Cytogenetics/Picciano et al * Table 4. -- Distribution of Chromosome Aberrations Rotated Table 5. -- Distribution of Abnormal Celts Related to to Vinyl Chloride (VC) Exposure. Vinyl Chlortdo (VC) Exposure Exposure to VC *1 ppm 1-5 ppm >5 pom Controls He. In Group 209 70 98 41 295 % of Group with 05% Aberrations % of Group vith >9* Abomttonl 9S% 4* 94 6 95 5 94 6 JC'O) - 0.355 (pa 0 95) Exposure to VC X 1 opfll 1-5 ppm > 5 ppm Controls No. bi Group 209 70 98 41 295 % of Group with 055 Aberrations k of Group with > Jk Abumtium 84H 71 - 73 , 70 16% 29 27 30 JC1- 5.97 (P5012) 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 al1" 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 ThiessTM 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 bv Purchase el a/21 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 vinvl 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.24 A-bomb survivors,2' radium dial paint ers,2'' persons exposed to Thorotrast,2' and workers exposed to lead.28 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.;q radium dial painters were found to be at increased risk of osteogenic sarcoma;'0 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 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 Thr author* acknowledge with appreciation the technical assistance of Mrs A Linscomhe and Mrs 0 Mensik, the suggestions ol Mrs M Benge, the editing of Ms T B Lloyd, and the advice of Or C B Jacobson 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 Lefemme G Carcinogenicity to bioassays of vtnyl chloride, I Research plan and early results Environ Res 7 387-405, 1974 3 Creech |L and Johnson MN- Angiosarcoma of the liver in the manufac ture of polyvinyl chloride !OM 16 150-151, 1974 4 Rannug U lobansson A, Ramel C, and Wachtmeister CA, The mutagenicity of vinyl chloride after metabolic activation Ambto 3:194-197. 1974 5 Malaveille C Bartsch H. Barbin A et al: Mutagenicity of vinyl chloride, chloroethvlene oxide, chloroacetaldehyde and chloroethanol, Biorhem fiiophvs 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 tvphimunum strains fntI Canter 15 429-437, 1975 7, Funes-Cravioto F. Lambert B Lindsten | et al Chromosome aberrations in workers exposed to vinvl chloride. Lancvt 1459, 1975 8 Ducatman A, Hirschhorn K. and Selikoff I), Vinyl chloride exposure and human chromosome aberrations Mutat 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 I and fhiess AM- Chromosome analysis after vinyl chloride ex posure Artx'tt\mod Sostalmcd Praeventimed 9-280*283, 1974 11 Kilian D|, Picuano D|, and Jacobson CB. Industrial monitoring- A cytogenetic approach Ann NY Acad Set 269:4-11, 1975 12 Infante PF. Wagoner |K, McMichael AJ, Waxweiler RJ, and Falk HGenetic risks of vinyl chloride Lancef 1 734-735, 1976, 13 Bartsch H, Malaveille C. Montesano R, and Tomatis l* Tissuemediated mutagenicity of vinvlidene chloride and 2-chlorobutadiene in Salmonella (ypbimunum Nature 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 m industrial exposure control Ann NY Acad Set 246 306-310, 1975, 16 Moorhead PS. Nowell PC, Mellman W|. Battips DM, and Hungerford 529 SI* DA Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res 20 613-616. 1960. 17, Kilian D| and Pitciano D' Cytogenetic surveillance of industrial popu lations, In Chemical Mutagens Principles and Method* lor 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 WM1 Human 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 2:676-682. 1962. 25. Bloom AD, Nakagome Y, Awa AA, and Nemshi 5' Chromosome aberrations and malignant disease among A-bomb survivors. Amer / Pub Hllh 60-641-644, 1970 26. Vaughan | Bone disease induced by radiation, Int Rev Exp Path 1:243-396. 1962 27 Fischer P, Colob E, Kunze-MUhl E, 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 3251', In Ab stracts V International Congress of Human Cenetics, S Armendares and R Lisker, eds Excerpta Medica. Amsterdam, 1976 29, Sampson R|, Key CR. Buncher CR. and lipma 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 MuHer I, David A, Rejskova M, and Brezikova D: Chrome occupation al exposure to strontium-90 and radium-225 Lancet 2,129-131, 1961 31, Fischer P, Golob E. Kunze-Muhl E, and Mullner T. Chromosomal aberrations in thorium dioxide patients, Ann NY Acad Set 145 769-766, 1967 530 SL 041812 Vinyl Chloride Cytogenetics/Piccianct et al