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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 Cold Spring Harbor Laboratory 1977 Origin* of Human Canear 1977 by Cold Spring Harbor Laboratory All rights reserved International Standard Book Number 0-87969-119-0 Library of Congress Catalog Card Number 76-J7913 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. r Vinyl Chloride Cytogenetics Dante ). Picciano, 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 been reported to be carcinogenic in animals' 1 and human beings' and mutagenic in bacterial test systems * 5 6 There have been reports of increased frequencies of chromosomal aberrations in workers exposed to vinyl chloride at polyvinyl chloride (PVC) facilities.7 * 6 Similar increases were not found upon cytogenetic evaluation of German PVC workers,fl 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 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 0< cupatiorMl Health and Medical Rp^e.irt h Dow Chemical U S A (Dr< Pitt utno and Kiliam and Department of Industrial Medicine Dow Chemical USA Texas Division iDrs Flake and Cav* Freeport TX 77S41 Material from this report was presented .it the Sth International Congress of Human Genetic* Mexico City October 10-1 ^ 1976 Journal of Occupational Medicme/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 " Although the threshold limit values for vinyl chloride had been 500 parts per million fppm) 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 joh 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 m 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,'6 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- 527 SL 102046 au Tlbl* 1. -- Extimitod Expoiurn to Vinyl Chloride (VC) for Vinyl Chlorid**R*ltKf Job Classifications. Jab ClwKteotlM Supervisor RJrO Engineer Production Engineer Technical Specialist Development Lab flap $ypv) 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 & Chloride) Control A Op (E 4 Cl) Control A Op (Vinyl) Control A Op (Chlorination) Control B Op (Oxy 4 Chloride) Control C Op (Chloride 4 Vinyl) Control C Op (Chlorination) Class l Op Class 1 Op (Parts) Class 3 Op Production Ctoh Unit Manager Estimated Exposure in Parts pr Million, m Tfne-Wiightid-Avernf 1M0-1972 Mere i960 11 44 82 1 7 44 82 1 7 44 82 05 05 05 1 2 39 77 87 114 152 1 3 40 78 1 3 40 78 03 03 03 0 7 07 07 09 09 09 24 5 I 89 06 06 06 1 3 40 78 05 05 05 1 3 40 78 4 4 7 1 109 52 79 11 7 09 09 09 28 55 93 23 50 80 07 07 07 46 73 11 I 26 53 9 1 5 3 80 118 05 05 05 26 53 9 i 07 07 07 07 07 07 Tibi* 2 -- Cytopnotic Study of 209 Wortiorx Eibond to Vinyl Chloridn. No ol cultures No of cells Chromatid breaks Chromosome breaks Pings dicentrics, and exchanges Abnormal ceils Workers 209 10,483 2 4% 1 0% 0 4% 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 I-to-8 ppm, and greater-than-S ppm The estimated exposure levels were based on calculations tor spec itic job classifications to which members of the vmvl c hloride studv group were assigned Three categories ot aberration were' c hosen tor this analysis chromatid breaks, chromosome breaks and the1 proportion of abnormal cells As shown in Tahle 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 S parts per million are almost identical to those of tho control group Similar conclusions were reached upon evaluation of the data for chromosome breaks (Table 4) and the proportion of abnormal cells (Table S) 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 .igents Tho rp< ords seloctod for inclusion m thu control group worn matched to those ot tho sjudv group, insofar a< possihle. for se\ number of cells analyzed, and time period during which the culture was initiated Age variation hetween the two groups r ould not be completely eliminated the average age ot the vinyl chloride workers was 19 1 years 'range, 18 to 87 vearsl and the average age of the pre employment control group was 2S 1 years (range 18 to SO years) Discussion The reports that have appeared, to date concerning chromosome aberrations in vinyl chloride workers base not been 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 bv Funes-Cravioto et at'" 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 hreakage The level of exposure for this group was Results As shown in Tahle 2, data from both groups -- vinyl i hlonde workers and preemployment controls -- were stored and com pared on the basis of chromatid hreaks' chromosome breaks: rings dicentrics, and exchange figures' and the proportion ot ab normal cells The proportion of abnormal c ells was i ale ulated to show the overall frequrnc y of aberrant i ells that is the ratio of tells with at least one aberration to die total number of cells examined Results, expressed m terms ot the mean percentage for these categories of aberration, showed no ma|or differences be tween the two groups for anv of the c lasxilic ations Using Chi-square analysis it was decided to see if ditterences in various aberration rates could 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 Toblo 3. -- Distribution of Chromotid Aborrationi Itoiltod to Vinyl Chloridn (VC) Exposure. Exposure to VC* < 1 pprrt 1 5 opm 5 ppm Controls No. In Group 209 70 98 41 295 % of Group with 05% Aberration % of Group with * 5% AbomtioM 90% 10% 77 23 80 20 75 75 X 431 . 7 75 IP 0 06) Exposure levels vt estimates based on calculations to soeok >ob classifications put* expo sure to individuals may have been higher or lower exposure levels lor individuals are known to va'v wthm 10b classifications vinyl Chloride Cytogenetics/Picctano et al SL 102047 Teble 4. -- Distribution of Chromosome Absmtions Related to Vinyl Chloride (VC) Eipoture. Exposure lo VC <1 ppm 1-5 ppm >5 ppm Controls No. In Group 209 70 98 41 295 H of Group with 09% Abomtkirt* % of Group with > 5* Abwrittom 96* 4* 94 6 95 5 94 6 XW - 0 355 (PSO951 Table 5. -- Distribution of Abnormal Colls Rotatod to Vinyl Chlortdo (VC) Exposu . Exposure to VC < l pom 1 5 ppm > 5 ppm Controls No, In Group 209 ;o 98 41 295 * at Sroup with 09% Abomtfem * of Creep wtth > 5% Abomttont 846 Vi 71 73 , 70 16* 29 27 30 X1- 597 (P*012) 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 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 e( 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 laboratory22 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 |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 shown21 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,22 A-bomb survivors,2' radium dial paint ers,2,1 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,2'' radium dial painters were found to be at increased risk of osteogenic sarcoma:10 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. The authors arlsnowledge with appreciation the technical assistance of Mrs A. LmH Otnbe and Mrs D Mens*, the suggestions o( Mrs, M Benge, the editing of Ms T 8. Lloyd, and the advice ol Or C B lacobson. References I 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 G: Carcinogenicity to broassays of vinyl chloride I Research plan and early results. Environ Res 7 387-405, 1974 3 Creech It and lohnson MN Angiosarcoma of the liver in the manufac ture of polyvinyl chloride. /OM 16:150-151, 1974 4 Rannug U lohansson A. Ramel C, and Wachtmetster CA The mutagenicity of vinyl chloride after metabolic activation. Ambro 3-194-197, 1974 5 Malaveille C, Bartsch H, Barbin A et ah Mutagenicity of vinyl chloride, chioroethvlene oxide, chloroacetaldehyde and chloroethanol. Biocftem Biophvr Res Commun 63 363-370, 1975 6 Bartsch H. Malaveille C. and Montesano R: Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in 5. typhrmurlum strains. Int I Cancer 15 429-437. 1975 7, Funes-Cravioto F, Lambert B Lindsten | et al: Chromosome aberrations m workers exposed to vinyl chloride, Lancvt 1-459. 1975, 8 Ducatman A. Hirschhorn K, and Selikoff l|: Vinyl chloride exposure and human chromosome aberrations Mu,el Res 31163-16B, 1975. 9 Purchase IFH, Richardson CR, and Anderson D: Chromosomal and dominant lethal effects of vinyl chloride. Lancet 2 410-411. 1975 in Fleig I and Thiess AM Chromosome analysis after vinyl chloride ex posure Arherttmcd Sozialmed Praeventrmed 9-280-283, 1974 II Kilian Dl Picciano D|. and lacobson C8: Industrial monitoring: A cytogenetic approach Ann NY Acad Sci 269:4-11, 1975. 12 Infante PF. Wagoner |K, McMichael A|, Waxweiler R|, and Falk H: Genetic risks of vinyl chloride Lancet 1 734-735. 1976 13 Bartsch H, Malaveille C, Montesano R, and Tomatis l: Tissuemediated mutagenicity of vinvlidene chloride and 2-chlorobutadiene in Salmonella lyphimurium Nature 255:641-643, 1975. 14 Occupational Safety and Health Administration- Exposure to vinyl chloride Federal Register 39(1941: 35889-35898, October 4, 1974 15 Rowe VK Experience in industrial exposure control. Ann Ny Acad 5cr 246-306-310, 1975 16. Moorhead PS, Nowell PC, Mellman Wl, Battips DM. and Hungerford 529 SL 102048 DA Chromosome preparations of leukocytes cultured from human peripheral hlood Fxp Cod Res 20:613-616, 1960 17 Kil'an Dl and Ptcciano D: Cytogenetic surveillance of industrial popu* lations In Chemical Mutagens Principle* and Methods 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 WM 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. Jacobs 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 Nenishi 5 Chromosome aberrations and malignant disease among A-bomb survivors, Amer I Pub Hlth 60 641-644 1970 26 Vaughan I Bone disease induced by rjdiation Int Rev Exp Path 1 243-396 1962 27 Fischer P Golob E, Kunze-MUhl E, Haim AB et al1 Chromosome aberrations m peripheral blood cells in man following chrome irradiation from interna! deposits of Thorotrast Radial Res 29 505-515, 1966 28 Garza Chapa R, Leah CH. Alvarez M, and Sanchez FI Chromosome analysis in males occupationally exposed to lead (Abstract 325'' In Ab stracts V fnternadonaf Congress of Human Cenof/cs. S Armendares and R lisker, eds fxcerpta Medica Amsterdam, 1976 29 Sampson RJ Key CR. Buncher CR and li|ima A Thyroid carcinoma in Hiroshima and Nagasaki l Prevalence of thyroid carcinoma at autopsy Hiroshima 1957^68. Nagasaki 1951-67 ABCC Technical Rrport 25-68 1968 30 Muller J, David A, Re|skova M, and Brezikova D Chronic occupation al exposure to strontiunv90 and radium-225 Lancet 2 129*131 1961 31 Fischer P, Golob E, Kunze-Muhl E, and Mullner T* Chromosomal aberrations m thorium dioxide patients. Ann NY Acad Sci 145 769-766, 1967 &Z 530 49 s/Picciano et al