Document NE32Lxj4BYb1BX27pRxoZEEJp

R&S 002540 DOW CHEMICAL U.S.A. 1803 Building 1 March 1985 MIDLAND, MICHIGAN 48640 Dr. Hasmukh Shah Chemical Manufacturers Association 2501 M Street, NW Washington, D.C. 20037 Dr. M. N. Johnson B. F. Goodrich Company 500 S. Main Street Akron, OH 44318 Mr. R. N. Wheeler Union Carbide Corporation P.0. Box 8004 South Charleston, WV 25303 The enclosed series of papers on vinyl chloride and styrene came to my attention through Brian Bennett of ICI. They obviously will have to be included in the review by Sir Richard Doll and probably should be sent to Environmental Health Associates. Sincerely yours. Theodore R. Torkelson, Sc.D. Health & Environmental Sciences 517/636-5197 Encs. T 25 Ilk L AN OPERATING UNIT OF THE DOW CHEMICAL COMPANY Occupational Hazards of Vinyl Chloride and Styrene J3 Co CO O o CtoJ1 vy William J. Nicholson, Ph.D. R&S 002542 Occupational Hazards of Vinvl Chloride and Stvrene Trends in Cancer Mortality Among Workers in the Svnthetic Polymers Industry William J. Nicholson, Paul K. Henneberger and Diane Tarr Occupational Hazards in the VC-PVC Industry William J. Nicholson, Paul K. Henneberger and Herbert Seidman Occupational Hazards in Production of Processing of Stvrene Polvmers - Eoidemioloeic Findings William J. Nicholson and Diane Tarr Lectures presented at a course on occupational hazards of plastics and synthetic elastomers, Institute of Occupational Health, Helsinki, Finland, November 22-27, 1982 Published in: Industrial Hazards of Plastics and Synthetic Elastomers Eds. J. Jarvisalo, P. Pfaffli, H. Vainio (1984) Progress in Clinical and Siological Research: Volume 141 Alan R. Liss, Inc., New York, pp. 65-78, 155-176,263-278. ENVIRONMENTAL SCIENCES LABORATORY MOUNT S' N A I SCHOOL OF MCDlClNC OF Tm C ! T V UNlV(H5lTV OF NEW V O R * TRENDS IN CANCER MORTALITY AMONG WORKERS IN THE SYNTHETIC POLYMERS INDUSTRY William J. Nicholson, Paul X. Henneberger and Diane Tarr Environmental Sciences Laboratory, Mount Sinai School of Medicine of City University of New York New York, New York 10029, U.S.A. INTRODUCTION The reactive double bonded structure of ethylene-like molecules allows a wide variety of chemicals to undergo polymerization. Unfortunately, this same structure has been found capable of transformation to an epoxide by the mammal ian mixed function oxidase system (Bonse and Eenschler, 1976). These epoxides or their reactive metabolites can bind to cellular macromolecules and may be responsible for the carcinogenicity of the parent molecule. Epoxide forma tion has been suggested as an intermediate in the carcino genic action of vinyl chloride (Van Duuren, 1975) and vinylidene chloride (Maltoni, 1977), and in the mutagenic action of styrene (Milvy and Garro, 1976). The epoxides of ethyl ene, styrene and vinyl chloride have been shown to be carci nogenic, as well as directly mutagenic in bacterial test systems without the need for activation. The potential for conversion of ethylene-like molecules to the epoxides is greater for unsymmetrieal structures such as vinyl chloride and vinylidene chloride than for symmetrical structures, such as ethylene, 1,2-dichloroethylene or tetrachloroethylene. It is beyond the scope of this review to discuss the structure-activity relationships of the monomers used in the plastics industry. Nevertheless, available data suggest that carcinogenicity depends on the metabolism of these monomers to reactive intermediates and that these reactions may be non-linear. However, when the metabolism of a com pound is understood, a coherent picture of the dose and time dependence of cancer should emerge. R&S 002543 R&S 002544 At this time, data are available on both experimental and human carcinogenesis from exposure to vinyl chloride (VC) and on its metabolism that provide information import ant for the understanding of observed dose-response rela tionships. This paper will consider these data on VC in detail as they provide estimates of the trends in future disease potential from past exposures and information on the efficacy of current occupational standards. As human and animal data accumulate on the effects of exposure to other monomers, the approach suggested by VC can be applied to their evaluation. DOSE-RESPONSE RELATIONSHIPS VC is one of the best studied chemicals in animal systems. The magnificent research by Maltoni and associates (1981) on nearly 7,000 animals over a ten year period is virtually unmatched in experimental carcinogenesis. A principal feature of their results is summarized in Figure 1 which shows the dose-response relationship for the percent age of animals that developed hemangiosarcoma (HSA) of the liver from A hr/day, 5 day/wk, 52 wk exposures to different concentrations of VC. As can be seen, the relationship is a non-linear one with evidence of saturation at high con- *2 u-- * * ADMINISTERED CONCENTRATION OF VINYL CHLORIDE (ppm) Figure 1. The percentage of rats developing liver hemangiosarcoma from 52 wk exposures to VC for A hr/day, 5 day/wk. centrations. However, at. concentrations of VC less than 500 ppm, a reasonably linear dose-response relationship obtains. Gehring et al (1978) have explained the non-linearity in terms of Michaelis-Menten kinetics, in which the trans formation of VC to a reactive intermediate follows the equation, V = yins/ocis + S) (1) V and V are the rate and maximum rate, respectively, for the biotransformation of VC, S is the concentration of VC in inspired air, and K , the Michaelis constant. K was deter mined experimentally to be 860 pg/1 and V to be 5,706 |jg/4 hr. Figure 2A displays the dose-response relationship between the percentage of animals with liver HSA and the quantity of VC metabolized according to Eq. 1. As can be seen, a direct liner relationship exists with no evidence of a threshold or altered slope at low doses. The possibility of a non-linear dose-response relationship from detoxifica tion kinetic steps has been postulated (Gehring and Blau, 1977); and discussed in detail (Hoel et al, 1983), but no evidence exists for such non-linearity in the data yet available. The unweighted least squares regression equation for the dose-response relationship is % HSA = -0.066 + 0.0039 V < *8 2*2<ft o< 2 --oO s* Ei (2' 30 < (ft 5 2 5; 5 10 oz It < 2 S1 I = 0.9 "5 0.2 V log V V (^g of vinyl chloride metabolized / 4 hr! Figure 2. Linear and probit dose-response relationships for the quantity of VC metabolized/4 hr exposure (5 day/wk,52 wk). DO </) o cIsn? cn Gehring et al (1978) fitted the early data of Maltoni and Lefemine (1975) to a log-probit model. Figure 2B shows the log-probit plot using all available data from the stud ies from Maltoai et al (1981). The unweighted least squares regression line is Probit s 0.24 + 1.01 log V (3) 2 While such a plot fits the observable data (r - 0.68), the linear d^se-response relationship fits the data somewhat better (r - 0.77). Further, there is very limited biologi cal rationale for the use of a log-probit relationship in carcinogenesis and its use as a means of extrapolation to predict effects at very low exposures would appear to be more an act of faith than of science. On the other hand, a linear dose-response relationship between the incidence of HSA and the quantity of VC metabolized is biologically plausible and fits all available data. Its use is strongly suggested. R&S 002546 TIME COURSE OF CANCER Much of human cancer has been found to follow a power law relationship with age (Armitage and Doll, 1961; Cook et 1, 1969), R = btk (4) where R is the incidence rate of cancer at a specific site, t is age, and b and k are constants specific to site. In general, k is between 4 and 6 for most epithelial malignan cies. While data for exposures to specific carcinogens are limited, bronchogenic carcinoma from cigarette smoking and mesothelioma from asbestos exposure also follow a power lav of time from onset of exposure with an exponent between 3 and 5 (Doll and Peto, 1978; Nevhouse and Berry, 1976; Peto et al, 1982). These findings have been interpreted in terms of a multistage model of carcinogenesis, the implications of which have been discussed by Peto (1977), Whittemore and Keller (1978), and Day and Brown (1980), among others. Deviations from the above time course occur with exposures to carcinogens that interact synergistically, such as asbes tos and cigarette smoking in the production of lung cancer. This interaction can be incorporated in the multistage mo del, but a more complicated relationship obtains. However, for a rare tumor, such as HSA, interactive effects may not be important and a power law relationship should adequately describe the time course of risk following exposure. Some data are available from the use of Thorotrast in Japan and Denmark that indicate the incidence rate of HSA does follow Eq. 4 (Mori et al, 1979a; Mori et al, 1979b; Faber, 1978). The material was used in these countries over a limited period of time, so the incidence per calendar year and estimates of the population at risk can be used to estimate incidence rates by time from onset of exposure. While the data are very limited, they are consistent with a power law dependence of risk and suggest an exponent of ap proximately 3. Three is also compatible with the incidence of liver HSA in the mortality study of polymerization work ers described elsewhere in this volume (Nicholson et al, 1983). However, only nine cases are available for analysis. PROJECTIONS OF FUTURE MORTALITY FROM PAST VC EXPOSURE Sufficient data have accumulated on the pattern of mortality from past VC exposures to allow an estimate future mortality from these exposures of using a linear dose-re sponse relationship and a time course for risk of death from liver HSA given by Eq. 4. Figure 3 shows the number of cases of HSA according to various measures of time that have been identified in the United States, Western Europe and the world (NIOSH, 1982). The distributions shown in Figure 3 are the result of the exposure to VC of various groups of individuals in different periods of time since 1935. Equa tion 4 indicates that the incidences (not incidence rates) according to calendar year, year of exposure, and year from onset of exposure, respectively, are: (5a) (5b) (5c) where i represents the quinquenium of exposure and j, the quinquenium of observation. i runs from 1 to 8, represent ing the years 1935-1974 and j from 1 tc 9, extending the observations throuRh 1979. The F.(Mort) are the appropriate R&S 002547 -Yor of Firtt Expoturt Yoon of Eipeiurt * M U TO n to Calendar Yoor of Dooth -Jin-flu. Fs VMlTfD STATES i[\ r"^ i-''] i---- > rH 0 II to It 90 St *0 Ytort Sine* Onto! of Eipoturt to Ototn Figure 3. The number of eases of hemangiosarcoma of the liver in the U.S., Western Europe and the world according to seve ral time criteria. quinquenium j from normal mortality. The C.'s are propor tional to the total population exposure, i.e., the average number of workers exposed in a given time period times the average VC concentration. Since the dose-response relation ship for both inspired and metabolized VC is linear in the range of most worker exposures, the risk of HSA is propor tional to the total population exposure; one need not know the number of workers exposed and their vinyl chloride exposure separately. R&S 002548 Relative values for the C.'s can be determined from two sets of data. The first is tfee incidence of HSA according to calendar period of first exposure (I.)- Here the C_.'s are directly proportional to the incidence1 in a given calendar period and available data are sufficient to establish rea sonable values of C. for the time period 1935-1955. Addi tional data on C. can be developed from published data on the production of1VC monomer. Figure 4 displays the avail able information on production in the United States (S.F.X., 1975-1978; U.S. Tariff Commission, 1948-1968) and Western Europe (O.E.C.D., 1971). A first approximation to the population exposure in different years would be to consider the C^'s to be proportional to VC production. However, average VC concentrations changed over the years of concern (Table 1) and an adjustment for the different relative exposures in different times must be made. This adjustment is indicated in Table 1 and on Figure 4. Further, an ad justment must be made to take into account the different number of workers required to produce a metric ton of VC in different time periods. As it would be expected that more workers were employed per tonne of VC produced during ear lier years, an adjustment is required to account for produc tivity. Initial estimates of this factor are also indicated in Figure 4. The relative population exposure, taken to be the product of production, the workforce productivity ad justment, and the exposure adjustment is shown by the solid 30 CO o oN> <J1 P* (O lUIISOJXl NOIlVirUOd jA llT D U Figure 4. The production of VC in the U.S. and Western Europe along with estimates of the population exposures to VC poly merization workers in different calendar periods. R&S 002550 Table 1 Measured and eetlrated exooeures to vlnvl chloride co polvaernatior. workers ir. verioue tiae periods Approximate Calendar Vinyl chloride exposures (apg) relative Period Berne* (1976) Ott tc el (1975) Suclu et el (1975) expoeurt Before 1950 1950-54 1955-59 1960-64 1965-69 1970-74 1000 1000 400 - 500 300 - 400 300 - 400 150 - 300 100 - 400 100 - 400 20 - 80 20 - 80 200 - 900 40 - 50 40 - 60 5 5 3 2 1.5 1 lines across each quinqueaium. The dashed lines across each quinquenium during earlier years are those determined by fitting the observed KSA incidence to Eq. 5a and matched to the value estimated from production data in the quinquenium 1955-1959. As can be seen, the comparison of the two sets of data suggested that the population exposure prior to 1960 was slightly less in some quinquenia than that estimated by the use of the adjustment factors indicated in Figure 4. The procedure of estimating the relative values for C., particularly in the years after I960, is clearly an approxi mate one. To consider how sensitive any projections of future mortality are to the choices of C.'s, alternate choices are shown by the light solid lines ^n Figure 4a. Any realistic estimates of the C.'s must lie between the two lines. 1 Relative values of I., and I._. were calculated using the relative values of C.1 shown in1 Figure 4, values of k between 2 and 4, and absolute values determined by matching to the incidence data of RSA found in Figure 3. In this calculation, the age distribution used for time of first exposure was: 15-19, 8.5%; 20-24, 26%; 25-29, 26%; 30-34, 15%; 35-39, 11%; 40-44, 7%; 45-49, 4%; 50-54, 2.5%. This distribution was that of 740 VC workers examined by Mount Sinai School of Medicine personnel during 1974. The pattern of duration of employment was assumed to be a decreasing exponential with an average employment time of 12 years. This corresponds to typical patterns of employment for long-term workers in the chemical industry (Nicholson et al, 1982; Wong, 1982). Separate calculations were made for the United States and Western Europe. The results of this procedure, combining the data for the United States and Western Europe, are shown in Figure 5. As can be seen I._., the incidence according to years from onset of exposur^ is best fit by a value of k = 1. A value of 3 is compatible with the data, but values greater than A can be ruled out. I. is relatively insensitive to the choice of k, but a value oi A fits the data best. An interesting feature of this calculation is that the separate determination of the C.'s for Western Europe and the United States indicates that he population exposures per tonne of VC produced were approximately four times greater in Western Europe than the United States. This would sug gest that more intense exposures occurred in some European plants or that more workers were exposed per tonne of VC produced R&S 002551 YEAR OF DEATH YEARS SINCE ONSET OF EXPOSURE Figure 5. A comparison of the calculated incidence of hemangiosarcoma of the liver with that observed in the U.S. and Western Europe according to several time criteria and models for calculation. One set of data that differs significantly from that calculated is the distribution of cases according to years of VC exposure. As mentioned previously, we assumed the distribution of employment times in the VC industry would be a decreasing exponential with a mean employment time of 12 years. The significant deficit of cases with employment times less than 10 years suggests that the available informa tion on duration of VC exposure may not be correct, that our assumed employment distribution may be in error, that there may be an underascertainment of cases with shorter exposures, or that there may be proportionately less risk for shorter exposures than would be predicted on a linear dose-response relationship. It should be mentioned that duration of em ployment is not an important variable in assessment of popu lation risk. Shorter employment times would have required more men to be exposed, but their average exposure would be proportionately lower. Using the values of C.'s determined by the preceding analysis and values of k from 2 to 4, the mortality from liver HSA is calculated to the year 2040, using Eq. 5a. These data are listed in Table 2, separately for Western Europe and the United States. Also shown in the data for the United States are projections using values of C.'s indi cated by the solid curves of Figure 4 and projections assum ing that the risk of HSA will increase quadratically with age of exposure. This age dependence was suggested by expe rimental results of Groth et al (1981). .We also considered a time course for HSA that increased as tJ for only 45 years and remained constant thereafter. As can be seen, the pro- R&S 002552 Table 2 Projection* of mortality Is the United Sut and Uc*ra Europe to the year 2Q4Q from exposure* to vinyl chloride prior to 1973 Total Projected Mortality ModelUnited State** Western Europe*1 ta t3 t" t3. to 43 years froo onset of ftxposurt t*. upper exposure curve, Pig. L c3. lower exposure curve, Tig. 4 e3, + Age* 190 3&0 630 310 240 4 SO 260 540 1190 2760 1120 26 deaths have occurred through 1979 39 death* have oeeurred through 1979 jected numbers of HSA for the United States range from 200 to 600 and, for Western Europe, from 550 to 2,800. (The greater range for Europe is the result of the more recent usage of pattern.) The most probable projection for future disease is felt to be that represented by a power of 3, a choice suggested by Thoratrast data and the very limited mortality data on HSA in the study by Nicholson et al (1983). Lower values are also reasonable, but the fit to the data would suggest that the use of a power of 4 may be inappro priate. Obviously, many caveats exist in the consideration of these projections. The estimates strongly depend upon a reasonable ascertainment of cases through 1979. The concerns for VC-induced HSA in recent years would suggest that ascer tainment was fairly good, at least for long term employees and pensioners. However, some cases in short term workers may have been missed. The projections also depend on the choices of the C. and the k. We have projected mortality based on reasonable choices for these parameters. However, other choices cannot be absolutely excluded. While these uncertainties exist, the data indicate that, within a factor of 2 or 3, future HSA mortality from exposures prior to 1975 will be about 350 deaths in the United States aod 1,200 in Western Europe. Further, these deaths will occur in a relatively small population. In the United States, the group at highest risk would be comprised of fewer than 5,000 individuals. Among this heavily exposed group, HSA may account for 10% of all deaths (Nicholson et al, 1983). Clearly, any intervention techniques that might be developed to reduce this projected risk could be efficiently applied. OCCUPATIONAL STANDARDS FOR VC Nicholson et al (1983) have shown that liver HSA accounts for at least 50% of all VC-induced malignancies. Thus > it would appear that average exposures of 200-500 ppm in pre vious years will lead to 1,000-4,000 excess cancer deaths in 11 workers exposed to VC in Western Europe and the United States prior to 1975. If a standard of 1 ppm is met, the average exposure of all the workers would be between 0.2-0.5 ppm, 1,000 times less than that which existed previously. One would expect the VC-induced malignant risk to be reduced by a corresponding amount. This implies that, if the VC industry complies with a 1 pom standard, cancer from employ- R&S 002553 ment therein would be virtually eliminated. However, there wil^ still remain a risk of developing HSA of the order of 10 per individual for a working lifetime, based on a United States or European workforce of about 10,000 workers. SUMMARY A high risk of death from liver HSA has been documented from past exposures to VC. .Similar to other carcinogens, the risk of VC-induced liver HSA appears to increase as the second or third power of time from onset of exposure. It is possible to project future mortality using this power rela tionship, estimates of VC exposure, and observed mortality to 1980. These projections suggest that 200-600 deaths may occur in the United States and 550-2,800 in Western Europe from liver HSA. These projections also suggest that a 1 ppm standard in the VC industry will go far to protecting workers from future malignant disease. REFERENCES Armitage P, Doll R (1961). Stochastic models for carcinoge nesis. In: Proceedings of the Fourth Berkeley Symposium on Mathematical Statistics and Probability. (Ed. Neyman J) Univ Calif Press, Berkeley pp. 19-38. Barnes AW (1976). Vinyl chloride and the production of PVC. Proc Roy Soc Med 69:277-280. Bouse G, Henschler D (1976). Chemical reactivity, biotransformation and toxicity of polychlorianted aliphatic com pounds. CRC Crit Rev Toxicol 5:395. Cook PJ, Doll R, Fellingham SA (1969). A mathematical model for the age distribution of cancer in man. Int J Cancer 4:93-112. Day NE, Brown CC (1980). Multistage models and primary prevention of cancer. J Natl Cancer Inst 64:977-989. Doll R, Peto R (1978). Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidem Comm Health 32:303-313. Faber M (1978). Malignancies in Danish Thorotrast patients. Health Physics 35:153-158. Gehring PJ, Blau GE (1977). Mechanisms of carcinogenesis: dose response. J Environ Path Toxicol 1:163-179. R&S 002554 R&S 002555 Gehring PJ, Vatanabe PG, Park CN (1978). Resolution of dose-response toxicity data for chemicals requiring meta bolic activation: example - vinyl chloride. J Toxicol Appl Pharmacol 44:581-591. Groth DH, Coate WB, Ulland BM, Hornung, RW (1981). Effects of aging on the induction of angiosarcoma. Environ Health Persp 41:53-57. Hoel DG, Kaplan NX, Anderson MV (1983). Implication of non linear kinetics on risk estimation in carcinogenesis. Sci 219:1032-1037. Maltoni C, Lefemine G (1975). Carcinogenicity assays of vinyl chloride: current results. Ann NY Acad Sci 246: 195-224. Maltoni, C (1977). Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Persp 21:1-5. Maltoni C, Lefemine G, Ciliberti A, Cotti G, Carretti D (1981). Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environ Health Persp 41:3-29. Milvy P., Garro AJ (1976). Mutagenic activity of styrene oxide (1,2-epoxyethylbenzene), a presumed styrene metabo lite. Mutat Res 40:15-18. Mori T, Kato Y, Shimamine T, Watanabe S (1979a). Statisti cal analysis of Japanese Thorotrast-administered autopsy cases. Environ Res 18:231-244. Mori T, Maruyame T, Kato Y, Tahahashi S (1979a). Epidemio logical follov-up study of Japanese Thorotrast cases. Environ Res 18:44-54. National Institute of Occupational Safety and Health (U.S.) (October,1982). Reported cases of angiosarcoma of the liver among vinyl chloride polymerization workers. Newhouse ML, Berry G (1976). Prediction of mortality from mesothelial tumors in asbestos factory workers. Brit J Indus Med 33:147-151. Nicholson VJ, Perkel G, Selikoff IJ (1982). Occupational exposure to asbestos: population at risk and projected mortality - 1980-2030. Am J Indust Med 3:259-311. Nicholson WJ, Henneberger P, Seidman H. Occupational ha zards in tbe VC-PVC industry.. This volume. Organization for Economic Cooperation and Development, Chemical Industry (1971). Quoted in: Levinson C. Work ha zard: vinyl chloride. ICY Geneva. Ott MG, Langner RR, Holder BB (1975). Vinyl chloride expo sure in a controlled industrial environment. Arch Environ Health 30:333-339. R&S 002556 Feto R (1977). Epidemiology, multistage models and short term mutagenicity tests. In: Origins of Human Cancer (Eds. Hiatt HH, Watson JD, Wins ten JA). Cold Spring Harbor Laboratory pp. 1403-1430. The Society of the Plastics Industry, Inc (1975-1982). Facts and Figures of the U.S. Plastics Industry, Hew York. Suciu I, Prodan El, Paduraru A, Pascu L (1975). Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sci 246:53-69. U.S. Tariff Commission (1948-1968). Polyvinyl chloride and copolymer production data. Van Duuren B (1975). On the possible mechanism of carcino genic action of vinyl chloride. Ann NT Acad Sci 246:258-267. Whittemore AS, Keller JB (1978). Quantitative theories of carcinogenesis. Society for Industrial and Applied Mathe matics Review 20:1-30. Wong 0 (1981). An epidemoilogic study of workers potenti ally exposed to brominated chemicals: with a discussion of a multifactor adjustment. In: Quantification of Occupa tional Cancer (Eds. Peto R, Schneiderman M). Banbury Report 9 Cold Spring Harbor Laboratory pp. 359-378. R&S 002557 OCCUPATIONAL HAZARDS IN THE VC-PVC INDUSTRY William J. Nicholson, Paul K. Henneberger and Herbert Seidman. Environmental Sciences Laboratory, Mount Sinai School of Medicine of CUNY, New York, New York 10029 (WJN, PH) and American Cancer Society, 4 W. 35th Street, New York, New York 10001 (HS). INTRODUCTION On January 24, 1974, The Wall Street Journal publish ed an article describing the occurrence of three deaths from hemangiosarcoma of the liver among polyvinyl chloride (PVC) production workers at the B.F. Goodrich Tire and Rubber Company plant in Louisville, Kentucky. This announ cement shattered the relatively complacent view toward health effects associated with plastic production in general and PVC production in particular. At the time, U.S. and Western European production of vinyl chloride (VC) exceeded 6 x 10 metric tons. Numerous mortality and clinical studies were undertaken in the major producing countries in an attempt to establish the extent of the carcinogenic risk and to identify clinical parameters useful for surveillance of exposed groups. Because of the immediate concern in 1974, most of these studies were com pleted between 1974 and 1977. Several reviews and sympoilia on human health effects from VC exposure have been published recently. A superb one is by Lelbacb and Marnteller (1981). The exposures were high that led to the disease observed in these various studies. Typical concentrations in the industry were estimated to be about 1,000 ppm prior to 1955, from 300-500 during 1955-1970, and from 100-200 during 1970-1974 (Barnes, 1976). However, variations from such exposures would have occurred in specific plants (Rowe, 1975). While historical average exposures were generally less than 1,000 ppm, peak exposures often ex ceeded 5-10,000 ppm (where workers lost consciousness) and, on occasion, 40,000 ppm (where plants exploded). During 1974, exposures were reduced to about 10-20 ppm in the U.S. industry (Jones, 1981) and even further, follow ing the promulgation of a 1 ppm standard by the Occupa tional Safety and Health Administration in 1974. MORTALITY STUDIES OF VC-EXPOSED WORKERS Table 1 shows the populations observed and the follow up characteristics of twelve cohort studies of vinyl chlo ride exposed workers. The studies were independent with the exception that the portions of the population reported in thp Equitable Environmental Health Study (1978) were included in some other U.S. studies. The proportionate mortality study of Monson et al (1974) is not included as the VC-exposed individuals studied therein were included in the cohort mortality study of Waxweiler et al (1976). The size of the cohorts varied greatly, from 255 in the study of Nicholson et al (1975) to 9,677 in the Equitable Environmental Health study. A notable feature of all of the studies is that the populations followed were rela tively young or recently employed, even though many plants in the studies started production in the 1940s. Most workers were hired after 1950, when U.S. and Western European production increased sixfold in ten years (Nicholson and Henneberger, 1983). Thus, few deaths occurred among most of the groups observed and data on effects 25 or more years from onset of exposure are li mited. The total mortality exceeded 10% of the observa tion cohort in only three studies. Further, the inclusion of recently employed individuals or those with short employment diluted the effects from VC exposure. Only five studies limited consideration to individuals with more than one year of exposure. In all cases, however, some individuals with more than 20 years from onset of employment were available for observation. The follow-up terminated in the mid-1970s for all studies. Table 2 compares the results for cancer of all sites and chronic liver disease in all 12 studies. Cancer is elevated in most of the studies, although it does not achieve a 0.05 level of significance except in the studies by Waxweiler et al (1976) and Nicholson et al (1975). In the study by Ott et al (1975), a highly exposed subgroup with 15 years latency had 8 cancer deaths compared to 3.2 R&S 002558 Table 1 PnnultIon and foilou-np characterlatIca ol twelve tudlai of vlnyl_ chloride erpantd workers Study Analyela cohort Country alte Bertazzl et al. 1979 fluffier ct al. 1979 Byren et al. 1976 Duck et al. 1975 Equitable Env. Health, 1978 Fo and Collier 1976, 1977 llaauda 1979 Nicholson- et al. 1975 Ott et al. 1975 Helnl et al. 1979 Theriault and Allard, 1981 tieawe Iter et al. 1976 ITAL USA sue UK USA UK JAP I1SA USA CER CAN USA 477/ 464 750 2113 9677 7409 304 255 522 6544 451 1787 Percent add Itlonal untraced 13.8 11.0 low 0.3 4.9 1.1 0.1 0.8 0.0 7.3 2.8 0s 3 Headier of deotha analyzed 62 28 58 116 707 393 26 24 79 414 59 136 Percent of total 1.1 6.0 7.7 6.4 7. 1 5.1 8.6 9.4 15.1 6.1 11.1 10.6 lllnlanna caposure (years) 0. 5 0.2 >0 >0 I >0 1 5 >0 >0 5 5 Hlnlaam Earlleet latency possible (years) exposure 0.5 1952 0.2* 1948 >0* 1945 >0* 1948 l* (1915) >0* 1940 1 1969 10* 1947 >0 1942 >0 HA 5* 1941 10* 1940 Haalnun l.ASt follow-up year of (years) fol low-up 22 1977 27 1975 28 1974 20 1975 2St 1972 35 1974 20 1975 25 1974 31 1971 HA 1974 30 1977 22 1973 * Longer lntenclcu considered for aou causes of death. 6SS?00 R&S 002560 Table 2 Observed and expected daaths aaonr vinvl chloride exposed vorkeri la twelve studies Cancer of all sltaa Deaths Studv Obsar. Exoce. SMR Bertazzl at al 30 30.9 97 Bufflar at al 3 yr. latency Byron at al 8 6 - 5.19 4.34 - 154 138 - Duck at al 35 36.44 96 Equitable 139 141.39 104* Fox 4 Collier 115 126.77 91 Maauda 8 5.8 138 Nicholson 9 3.9 230 Ott at al 13 yr. latency 13 9 16.0 9.2 81 98 Relnl at al 94 90.6 112* Theriault 4 Allard 20 16.37 122 Vaxvailer at al 15 yr. latency 35 31 23.5 16.9 149+ 184++ Chronic liver disease. Deaths Obsar. 3 0 Exoec. - - SMR - 0---- 14 26.45 56++ 1 2.68 37 5 1.00 500* 1 (0.6) 167 3 2.7 111 14 18.4 - 2 4.0 82 m 50 a Adjusted for ualmovn- causes of death ( ) Estlsated as a parcantaga of U.5. rates + p < 0.05 ++ p < 0.01 a SHE of control population squally high expected (p < 0.05). The absence of significant findings in other studies may be attributed to their low power. The study of Bertaz2i et al (1979) may be biased because of low follow-up in the group. Fourteen percent of the population were untraced and person-years at risk were calculated for these individuals as if they were alive. The low SMR of 44 for all causes of death suggests that proportionately more deaths occurred in untraced groups than in the traced. The studies by Buffler et al (1979), Byren et al (1976), Masuda (1979), and Theriault and Allard (1981) had very few deaths available for analysis. That of Ott et al (1975) also was limited by the number of deaths and further by virtue of a study group with rela tively lower exposure (through better industrial hygiene control). While having more deaths available for analysis (136), the study by Duck et al (1975) was significantly R&S 002561 diluted by the inclusion of many individuals with very short and recent periods of exposure. Turning to chronic liver disease, one remarkable finding is the absence of significantly elevated mortality from this cause in most of the populations under observa tion. The only study with a significant elevation is that of Masuda (1979) in which five deaths from chronic liver disease occurred where only one was expected. However, this must be considered in the light of an equally high mortality from liver disease (6 observed vs. 1.4 expected) in a comparison population followed for control purposes. Five of 62 deaths from chronic liver disease seen in the study by Bertazzi et al (1979) are unusual, but the limi tations of this study and lack of details make evaluation difficult. The generally benign results in other studies contrast sharply with the severe liver disease from VC exposure documented in clinical studies (Marsteller et al, 1975). Hepatomegaly, hepatic fibrosis, portal hyper tension, and bleeding esophageal varices have commonly been found in individuals heavily exposed to VC, even without concomitant exposure to alcohol. Table 3 lists the mortality data for primary cancer of the liver and biliary passages and for cancer of the lung, trachea and bronchus. In the case of liver cancer, the overall data are consistent and dramatic. Hemangiosarcomas of the liver were found in eight of the twelve studies. In each of the eight, a very large and highly significant SMR for liver cancer was seen. Methodological limitations can account for negative data in the other four studies. The large SMR's observed, however, are largely the result of low values for the expected number of cases rather than a high incidence of observed cases. Only 29 separate liver hemangiosarcomas were identified in all twelve studies. As the overall excess number of deaths from liver and biliary cancer in all studies was 47, some hemangiosarcomas may not have been identified. The low numbers must also be considered in light of the limited follow-up times in most studies. The evidence for lung cancer is less clear. There is an elevation in some studies, but at a level that does not achieve statistical significance, except in the 15 year latency population of Waxweiler et al (1976). This, in part, may be the result of the low power of many of the Table 3 Obaerved and expected deacha fron aalactad cauaaa mom vinvl chlorldo-axpoaad worker* Cancer of th* liver and biliary paaaatea Oba.* Ext). BaaangioSMB aarcoaaa Cancor of the lung. traehaa and bronchus Oba. Em. S3 Bertaztl 8 (1.0)b (BOO)" 3d 7 (7.7>c (91) Buffler 3 yr. latency 0 (0.17) 0 3 1.73 289* 4 1.49 268 30 Syren 10 yr. latency 4 4 0.97 * 0.(8 413 * 389 " 2 2 3 . 1.78 168 > 0) Duck OP* 0 16 13.53 103 19 yr. latency 14 10.69 131 o o Cquitable 10 (4.5) (224)* 5 45 44.29 107* IO cn 13 yr. latency 41 37.0 111 o> to fox and Collier 13 yt. latency 4 0.71 363 " 46 31.23 28 26.0 90 108 Haauda i 0.( 167 0 1 (0.8) (123) Nicholson 3 (0.12) (2300)w 3 0 (1.1) -- Otc laini 0 (0.3) -- 12 0.9 1323 0 4(3?) 5.2 77(96?) 4 22 24.6 93f Theriault 13 yr. latency 8 (0.3) (1600) *** 8 2 5.78 2 4.23 35 47 Waxveiler 13 yr. latency 7 7 0.6 1133 6 0.4 1606 ** 6 12 7.7 11 3.7 156 1947 Total of nonduplicated henanglotarcoBaa 29 - < o.os < 0.01 < 0.001 a All verified liver cancer deache, Including thoa* astabliahad by review of all avallabla information. b ( ) txpactad daatha aatinetad on the baaia of 1930-19(9 U.S. adjuated ratoa. ICD 153/1CD 140-203. e ( ) Expected doatba eatlaatad on tha baaia of national aga adjuetad tataa, ICO 162-163/1CD 140-203. d Qna heaangloaarcoaa oecurrad In a PVC fabricator, a Includaa cancan of tha pancraaa. f Adjusted for unknovn eauaaa of death. studies. Only two have an 80% power to detect an overall risk of 1.5 (Beaumont and Breslow, 1981). Of signifi cance, however, are the very low SMR's in the groups studied by Theriault and Allard (1981), Reinl, et al (1979), and Nicholson et al (1975), cohorts that would be expected to manifest a high risk on the basis of the many bemangiosarcomas that were found. The four largest stu dies, although in some cases limited by inclusion of short-term and recently employed workers, also are note worthy for the SMR's close to 100. Where available, data on subcohorts with longer latency (> 15 yr) suggest some increased risk. Waxweiler et al (1981) undertook a detailed analysis of the exposure of those with lung cancer in their previ ously published study (Waxweiler et al, 1976) in an at tempt to identify particular etiological agents. The analysis used a serially additive expected dose model (Smith et al, 1980) in which a dose measure during each year of exposure was accumulated for each study individual for a variety of potentially carcinogenic agents. The cumulative doses for those with lung cancer were compared with those of other individuals in the plant under study. The results showed that the greatest correlation of lung cancer was with exposure to PVC dust. Secondarily, expo sure to vinylidene chloride appeared to be important, but only for large cell and adenocarcinoma. The serially additive dose for VC monomer differed little in those with lung cancer compared to others in the plant, except, possibly, for large cell cancers. Thus, evidence to date does not establish that VC monomer is an important lung carcinogen in exposed worker populations, although it is recognized that limited long term observation has so far been available. In all stu dies considered here, a slight deficit of cases was seen compared to the number expected. In the subcohorts with more than 15 years from onset of exposure, an overall excess of 10% was observed. If, in addition, one consi ders a "healthy worker effect," any excess lung cancer would still be considerably less than the excess of liver cancer. A qualification to this conclusion is that no study specifically considered cigarette usage. If cigar ette smoking was much less common among VC workers than the general population, higher SMR's would have been seen if smoking specific data were available. However, this R&S 002563 possibility is unlikely, considering the many different populations studied. The uncertainty in human data is also reflected in animal studies. Increased lung cancers have been seen in mice but not in rats or hamsters (Maltoni et al, 1981). Table 4 shows the results for brain and central nervous system cancers and for cancers of the lymphatic and hematopoietic systems. Cancers of the brain and central nervous system were significantly elevated in a number of studies, although the results differed consider ably across studies. Again, negative data may be simply the result of limited long-term follow-up or the low power of the study. In such cases the information is only sufficient to set an upper limit on relative risk of brain cancer. In contrast to lung cancer, however, the largest study group has a significantly elevated risk of brain and central nervous system malignancy. As with lung cancer, the data on brain and CNS cancer in animals are equivocal. Neuroblastomas and brain malignancies are observed in rats exposed to VC, but not among mice or hamsters (Maltoni et al, 1981). The human data are also mitigated by the recent finding of brain and central nervous system tumors in a variety of chemical plant exposure circumstances (Alexander et al, 1980; Selikoff et al, 1982). Excess brain malignancies, but not. the etiological agents, have been identified in several Texas and Louisiana chemical/ petrochemical plants. VC exposure was documented for some cases, but it could not explain the overall findings. As individuals in many of the VC studies considered here were exposed to other chemicals and petrochemicals, the pos sible role of these agents cannot be excluded. Further, it has been suggested that some working groups, with employer-paid medical plans, may have better case ascer tainment than is generally available (Greenwald et al, 1981) and, thus, more brain malignancies identified. In any case, the number of excess malignancies of the brain and central nervous system (approximately 10) in all studies is considerably less than the number of hemangiosarcomas identified in the same populations. Similar results are obtained for malignancies of the lymphatic and hematopoietic system. Here again, the analysis is limited by the few deaths and disparate re sults which occurred in different studies. Overall, there would appear to be an elevated risk, but the influence of R&S 002564 Table 4 Observed tad expected deaths from selected causes among vinyl chloride exposed workers Cinctr of the brain 4 Cancer of the lymphatic central nervous system end hematopoietic svatem Obeer. ExnCt SMR Obser. txpecc. SMR Bertaxzl 1 (0.8)* 125 Bufflar Syren 0 (0.1) - 2 0.33 612f buck Equitable aa - 12 5.90 203+ Tex & Collier 2 3.66 55 4 (3.0)" (133) 0 (0.5) - 0-- - m 20 17.01 124 9 9.01 100 Mzzuda Nicholson Ott Re ini 0 (0.15) - 1 (0.1) (1000) 1 0.4 (250) 2 1.3 162 0 (0.3) - 2 (0.4) (500) 1 (1.6) (63) 15 7.7 214+* Theriault 0 0.6 - 1 1.67 60 Wexweiler 3 15 yr. latency 3 0.9 329. 0.6 498' 4 2.5 159 t < 0.05 t* < 0.01 * ( ) " Expected estimated from the ratio of aga itandardiiad O.S. rataa IC3 193/ICS 140-105. ( ) Expected estimated from the ratio of 1950-1969 O.S. rataa ICS 200-205/ICB 140-250. confounding exposures precludes definitive statements. The overall excess of such malignancies (about 10) is also much less than those from primary hemangiosarcomas of the liver. EFFECT OF REDUCTION OF EXPOSURE TO VC As mentioned previously, most mortality studies followed populations only to the 1972*1975 period. No data exist on the risk to previously exposed populations after cessation of exposure in 1974, although bemangiosarcomas have been noted among retirees. We have recently coaipleted a follow-up through 1981 of the population reported in 1975 (Nicholson et al, 1975) to determine whether a high risk of liver cancer continues, following significant reduction in exposure. The original group R&S 002565 R&S 002566 employed at a VC polymerization plant in Niagara Falls, New York, has been expanded by 40 additional workers, all exposed for five years, who achieved ten years from onset of exposure subsequent to April 1974. Additionally, 195 individuals employed at a VC polymerization plant in South Charleston, Vest Virginia, with five years of exposure and ten years from onset in December, 1966, were identified and traced through 1980. Table 5 lists the observed and expected deaths by cause for both groups with the deaths occurring after 1974 separately identified. (These are preliminary data; full Tibia 3 Observed aad expected deaths aaocg vinyl chlorlda polymerisation workers Mlatara Falla. NT (H 296) (January 1, 1956 - Deeanbcr 31, 1981) Cauaa of daath Observed 56-73 74-81 All causal 24 All cancer 8 luat Colon/reetm 0 1 Inin 1 Liver 3 Lynphoaa 2 reserves 1 Cirrhosis of liver 1 Cardiovascular disease 13 20 8 2 2 0 3 1 0 1 8 Total 44 16 2 3 1 6 3 1 2 21 Expected 40.87 9.01 3.25 1.39 0.33 0.19 0.55 0.50 1.41 19.88 SMR 108 177 62 216 303 3158* 545* 200 142 106 South Charleston, WV (N - 195) (Deeaeber 1, ;L966 Deeaeber Jl. 1980) Cauaa of daath Observed 66-73 74-80 Total Expected All causes 14 All cancer 2 ! Colon/rectua 1 0 rain 0 Liver 0 Lymphoma 0 Yancreaa 0 Cirrhosis of liver 0 Cardiovascular dlsaaae 10 22 36 10 12 12 00 00 44 00 1- 1 11 10 20 44,74 10.65 4.07 1.89 0.43 0.23 0.59 0.67 1.81 27.24 SMR 80 113 49 -- 1739" -- 150 55 73 a p 0.05 b p 0.001 e p * 0.0001 R&S 002567 pathological review of all available specimens has not been completed.) Among the 44 deaths that occurred in the Niagara Falls cohort, 6 were from primary cancer of the liver, including 5 hemangiosarcomas. Three of the hemangiosarcomas occurred in the period prior to 1974 and 2 subsequently. Similar findings occurred among the smaller group in West Virginia. Here, of 36 deaths, 4 were from hemangiosarcoma, all of which occurred subsequent to 1974. Thus, the risk of neoplastic VC disease continues undimi nished, even though exposures to the monomer have been significantly reduced. The combined data from both groups are shown in Table 6 and demonstrate an excess risk of cancer, which is totally accounted for by the enormously increased risk of liver malignancy observed in each time from onset of exposure category. The excess lymphomas which achieved significance at the p < 0.05 level in the Niagara Falls group lose significance when combined with the data from South Charleston. A deficit of lung cancer was observed in both study groups and brain malignancies were about equal to the number expected. It is not certain whether the results of these two plants will be reflected in the results of other plants in future years. The South Charleston plant was the first facility to commercially produce VC. The New York plant opened immediately following the cessation of World War II. Thus, we are observing effects in populations that include many individuals with long times from onset of exposure. There is no information on whether the expo sures in these two plants were significantly different from those of the majority of other VC polymerization facilities. It is known that pre-1974 exposures in the Mew York plant were sufficiently high to cause loss of consciousness to some individuals (4.5% of those examined in the clinical survey of 1974) (Lilis et al, 1975). MORBIDITY AND CLINICAL FINDINGS AMONG VC-EXPOSED WORKERS Clinical abnormalities from VC exposure predated by 25 years the documentation of its carcinogenicity. Vari ous VC-related abnormalities were reported in Eastern European literature, including hepatomegaly (Tribukh et al, 1949), angioneurosis (Filatova and Gronsberg, 1957), osteolytic lesions of distal phalanges (Smirnova, 1961), Raynaud's phenomenon and sclerodermalike skin lesions (Suciu et al, 1963). However, VC disease was not seri- Table 6 R&S 002568 Observed and expected deaths acong yIby! chloride exposed workers In two polymerization facilities by tine from onset of exposure Tear* alnca onsat of exposure Cause of death 10 - 19 20 - 29 30+ Total Obs. Jih All causes 24 19.13 All canesr 7 3.72 Lung 1 1.26 Liver 2* 0.08 lrals 1 Lymphoma 2 0.27 ClrThosis of liver 0 0.76 Cardiovascular 14 8.74 disease Parson years 2924 Obs. Ex?. 30 34.83 9 7.98 1 2.96 3* 0.18 0 1 0.46 3 1.24 15 17.58 Obs. - 26 31.64 12 8.03 2 3.08 5b 0.17 0 0 0.41 0 0.87 12 16.40 2734 1404 Obs. 80 85.61 28 19.66 4 7.31 10 0.42 1 0.76 3 1.14 3 2.85 41 42.73 SMR 93 142 55 2381 132 263 105 96 a. hemaagiosarcoma b. A heaanglosarcouss and 1 hepatoma ously considered in the Vest until the published descrip tion of Raynaud's syndrome, acroosteolysis, and pseudoscleroderma in two Belgium VC reactor cleaners (Cordier et al, 1966). Additional cases were soon noted (Wilson et al, 1967) and a comprehensive epidemiological study of 5,011 U.S. workers employed in production and polymeriza tion was undertaken. It showed that 11.9% had possible X-ray signs of acroosteolysis, compared with 3.2% in a Michigan general population control group, with 2% defi nitely having Raynaud's phenomenon or X-ray evidence of acroosteolysis (Dinman et al, 1971). The conditions were clearly associated with the cleaning of reactors, in which a heavy exposure to VC occurred. Only one case of Ray naud's phenomenon occurred among 557 workers employed in PVC fabrication. During the early 1970's, VC liver disease was de scribed in detail by Marsteller et al (1973, 1975). Observations on selected workers showed hepato- and sple nomegaly to be common. Peritoneoscopy and guided liver biopsy identified severe portal hypertension in some, generally without cirrhotic fibrosis, although perisinusoidal and focal or diffuse capsular fibrosis were common ly seen. The portal hypertension could lead to bleeding esophageal varices, with possible fatal consequences. In heavily exposed individuals', the portal hypertension and hepatic fibrosis often progressed after cessation of exposure (Martin et al, 197A). The histology of malignant and nonmalignant liver disease has been veil described by Fopper and Thomas (1975; Thomas et al, 1975), who suggest ed the possibility of an interrelationship between hemangiosarcoma and the proliferation of sinusoidal lining cells and hepatocytes seen in VC fibrosis. Lelbach and Marsteller (1981) have also noted that the vast majority of hemangiosarcoma cases have appeared on a background of some degree of hepatic fibrosis. The implications of these suggestions for a hemangiosarcoma dose-response relation are uncertain. During 1974, extensive studies were undertaken by the Environmental Sciences Laboratory of the total workforces of three polymerization plants in the states of Hew York, Michigan and West Virginia. The results from the New York plant (Lilis et al, 1975) indicated the presence of acroosteolysis in heavily exposed individuals. Hepato- and splenomegaly or hepatic tenderness was commonly observed and associated with duration of exposure and elevated alkaline phosphatase levels. Sixty-four of 354 had an enlarged or tender liver or spleen and of these, 41% had elevated alkaline phosphatase. Liver function tests were not particularly revealing, except for a correlation of elevated alkaline phosphatase levels with duration of exposure. Additionally, carcinogenic embryonic antigen titers were slightly higher among vinyl chloride exposed groups than in a smoking matched control population (Anderson et al, 1978). Tamburro and Greenberg (1981) have evaluated the effectiveness of federally mandated screening tests for vinyl chloride exposed workers. Figure 1 shows the re sults on specificity and sensitivity for 78 individuals with hepatic status determined by biopsy. ICG clearance had the highest combined sensitivity and specificity, with SGPT the second most useful test. Elevated alkaline phosphatase had the greatest specificity of all tests, particularly for chemically-induced liver injury, but was lacking in sensitivity. SGOT and GGPT were of limited use because of their low specificity for chronic liver disease. They recommended the use of ICG clearance for screening, to be followed with alkaline phosphatase determinations for those with altered clearance. R&S 002569 (&A3 ^ SENS III SPEC 3 > 5n Q < <J i CAQ CO "0.5 TESTS Figure 1: Sensitivity end specificity of various biochemical screening tests and their sensitivity and specificity sum values (S & S) based on 78 with biopsy documentation of their hepatic status. Three of the seven individuals who died after 1974 with hemangiosarcoma in the previously described mortality followup were examined in 1974. One, who died 22 months after examination, had no noteworthy abnormalities on examination (alkaline phosphatase was 88, slightly high). A second, who died three years after examination, had a slightly enlarged, palpable liver (11 x 6 cm) with normal blood counts and chemistry. Only one of the above drank alcohol at all and be only drank 2-3 beers/month. The third, who died 22 months after examination, had a slight ly enlarged liver (11 x 8 cm) and spleen (13 x 8 cm), and slightly elevated alkaline phosphatase (93), SGOT (52) and CEA (4.7). Thrombocytopenia was also present (75,000). Mo data are available on later clinical parameters, but the above results are clearly not sufficiently specific for identification of a special risk. Pulmonary abnormalities also have been associated with VC/PVC exposure. Small opacities, predominantly irregular, of profusion 1/0 or greater were found in 20 of 1,216 workers employed at PVC production in an Italian plant (Mastrangelo et al, 1981). .All had been exposed to high levels of PVC dust (>10 mg/ni ). Lilis et al (1976) R&S 002570 reported that approximately 20% of VC/PVC workers with high exposures to PVC dust had abnormal X-rays, which correlated with duration of exposure and, also, vith cigarette smoking. In contrast, only 4.7% of individuals in a PVC plant with low dust levels had abnormal X-rays. In addition to "typical pneumoconiosis," a granuletomous reaction to PVC dust has been reported (Arnaud et al, 1978). Hiller et al (1975) have observed pulmonary func tion abnormalities (a reduction in the ratios FEV^/FVC and MKF/predicted HMF) in both smokers and non-smokers heavily exposed to PVC dust (and also to VC monomer). Haltoni and Lodi (1981), observed greater percentage of abnormal spu tum cytological results among VC exposed workers compared to several other groups of manufacturing workers or miners Only workers in the chromium industry demonstrated a greater proportion of abnormal cells. Ducatman et al (1975) have observed an increased frequency of chromosome abnormalities in the lymphocyte cultures of VC workers. Host of the abnormalities were "unstable" changes, such as fragments, dicentrics, and rings. This was confirmed by Purchase et al (1978), among others. Some of the group studied by Purchase were resam pled 18 and 42 months later (Anderson et al, 1980). In those studied during January 1976, the frequency of abnor malities was increased in those who continued VC/PVC employment, but decreased in those who left the industry. In January 1978, no increased frequency was found in any worker. The authors attributed the decrease to the reduc tion in VC exposure. HEALTH HAZARDS IN THE PVC PROCESSING INDUSTRY Prior to identification of hemangiosarcoma in VC polymerization workers, little effort was made to control cither the concentration of residual monomer in PVC dust or exposures to dust and VC that occurred in the various forming operations of the PVC fabricating industry. VC concentrations in excess of 10 ppm occurred frequently. While these concentrations were significantly lower than those of the polymerization industry, the much greater employment in the processing industry (hundreds of thou sands vs. tens of thousands in the polymerization work) raised concern for population health effects, particularly for malignant disease for which no threshold was known. However, only two hemangiosarcomas have been documented in R&S 002571 Ft&S 002572 the PVC processing industry, one in an accountant in a plant making PVC fabric and one in an Italian plant making PVC sacks. A third case may have occurred in an electri cal wire insulator, but' the pathological diagnosis is uncertain (Lloyd, 1975).' This is in contrast to 85 cases known to have occurred among polymerization workers (NIOSH, 1982). This is somewhat comforting and indicates a signi ficantly lower total VC-related neoplastic risk among fabrication workers. However, it should be noted that case finding is likely to be poorer in this group than in polymerization workers. A proportionate mortality study has been conducted of 4,341 deaths of former employees of 17 PVC fabricators (Chiazze Jr., et al, 1977). The direct PMR's suggested an excess in total cancer mortality among both white men and white women with the major excesses concentrated in can cers of the digestive organs. An excess of breast cancer was also seen in women, but not confirmed in a case-con trol study (which was of very low power and could only detect a threefold increased risk) (Chiazze, Jr. et al, 1980). The results of the proportionate mortality study must be considered cautiously. In such studies, elevated cancer risks and are typically seen because of a "healthy worker effect," which leads to a reduction in cardiovascu lar deaths relative to those of cancer. If PCMR's (pro portionate cancer mortality ratios) had been calculated, rather than PMR's, digestive cancer would still be elevat ed but not at an 0.05 level of significance. Interest ingly, an excess of stomach cancer was seen in the propor tional mortality study of Baxter and Pox (1976). SUMMARY Overall, the results of the analysis of 12 studies of VC production and polymerization workers demonstrate an enorsMusly elevated risk of liver malignancies, the possi bility of a twofold increased risk of brain and central nervous system tumors and perhaps, also, of malignancies of the lymphatic and hematopoietic system. However, the role of other agents cannot be excluded in the etiology of nonhepatic malignancies. Bronchogenic carcinoma does not appear to be increased from exposures to VC monomer, although a relationship to PVC dust was suggested in one study. These conclusions must be considered in light of limited data on workers followed more than 25 years from R&S 002573 onset of exposure. Considering the numbers of observed end expected deaths in all studies, it would appear that the excess of malignancies at nonhepatic sites is less than the excess of liver tumors. Data presented elsewhere in this volume (Nicholson and Henneberger, 1983) suggest that exposure reductions in 1974 may have virtually eliminated the VC-associated risk of liver cancer if the current U.S. standard is met. To the extent that VC exposure is associated with other cancers, a similar risk reduction would be expected. Raynaud's phenomenon, acroosteolysis, sclerodermalike skin lesions, hepato- and splenomegaly with noncirrhotic hepatic fibrosis, and severe portal hypertension have been associated with past heavy exposures to VC. Evidence exists that the liver disease and portal hypertension may progress following cessation of exposure. However, all of the above syndromes were found largely in heavily exposed individuals. Their occurrence would be much less likely in workers exposed only to concentrations currently allow ed. Pulmonary deficits, X-ray abnormalities, and, per haps, lung cancer have been associated with VC/FVC expo sure. Because of the possible contribution of PVC dust to these findings, engineering controls during polymer dry ing, bagging and usage are warranted. REFERENCES Anderson HA, Snyder MS, Lewinson T, Woo C, Lilis R, Selikoff 1J (1978). levels of CEA among vinyl chloride and poly vinyl chloride exposed workers. Cancer 42:1560-1567. 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Long-term mortality study of vinyl chloride and polyvinyl chloride workers in a Japanese plant. Arh hig rada toksikol 30:403-409 (suppl). Hiller A, Teirstein AS, Chuang H, Selikoff 1J, Warshaw R (1975). Changes in pulmonary function in workers expos ed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 246:42-52. Honson RR, Peters JM, Johnson MN (1974). Proportional mortality among vinyl chloride workers. Lancet 11:397-398. National Institute for Occupational Safety and Health (U.S.)(October, 1982). Reported cases of angiosarcoma of the liver among vinyl chloride polymerization workers. (Unpublished). Nicholson WJ, Hammond EC, Seidman H, Selikoff IJ (1975). Mortality experience of a cohort of vinyl chloridepolyvinyl chloride workers. Ann NY Acad Sci 246:225-230. Nicholson WJ, Henneberger F (1983). Trends in cancer mor tality among workers in the synthetic polymers industry. This volume. Ott HG, Langner RR, Holder BB (1975). Vinyl chloride exposure in a controlled industrial environment. Arch Environ Health 30:333-339. Popper H, Thomas LB (1975). Alterations of liver and spleen among workers exposed to vinyl chloride. Ann NY Acad Sci 246:172-194. Purchase IFH, Richardson CR, Anderson D, Paddle GM, Adams WGF (1978). Chromosomal analysis in vinvyl chloride exposed workers. Mutation Res 57:325-334. Reinl W, Weber H, Greiser E (1979). The mortality of German vinyl chloride (VC) and polyvinyl chloride (PVC) workers. Arh hig rada toksikol 30:399-402 (suppl). Rowe VX (1975). Experience in industrial exposure con trol. Ann NY Acad Sci 246:306-310. Selikoff IJ, Hamond EC, Eds. (1982). Brain tumors in the chemical industry. Ann NY Acad Sci 381:1-364. Smiranova NA (1961). On the question of bone lesions due to chronic intoxication by olefins and vinyl chloride. Vestn Renigenol Radiol 36:63-66 (Russian text). Smith AH, Waxweiler RJ, Tryler HA (1980). Epidemiologic investigation of occupational carcinogenesis using a serially additive expected dose model. Am J Epidem 112:787-797. Sucui I, Drejman I, Valaskai M (1963). Contribution to the study of vinyl chloride disease. Med Interna 15:967978. Tamburro CH, Greenberg R (1981). Effectiveness of Fede rally required medical laboratory screening in the de tection of chemical liver injury. Environ Health Fersp 41:117-122. Theriault G, Allard P (1981). Cancer mortality of a group of Canadian workers exposed to vinyl chloride monomer. J Occ Med 23:671-676. Thomas LB, Popper H, Berk PD, Selikoff IJ, Falk H (1975). Vinyl-chloride-induced liver disease. From idiopathic portal hypertension (Banti's syndrome) to angiosarcomas. N Engl J Med 292:17-22. Tribukh SR, Tikhomirova NP, Levina SV, Koslov LA (1949). Working conditions and measures for their sanitation in the production and utilization of vinyl chloride plas tics. Gigiena Sanit 10:38-44. Waxveiler RJ, Stringer W, Wagoner JK, Jones J (1976). Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271:40-48. Waxweiler FJ, Smith AH, Falk H, Tryoler HA (1981). Excess lung cancer risk in a synthetic chemicals plant. Environ Health Persp 41:159-165. Wilson RH, McCormick WE, Tatum CF, Creech JL (1967). Occupational acroosteolysis. J Am Med Assoc 201:577-581. R&S 002577 J R&S 002578 OCCUPATIONAL HAZARDS IN PRODUCTION AND PROCESSING OF STYRENE POLYMERS - EPIDEMIOLOGIC FINDINGS William J. Nicholson nd Diane Terr Environmental Sciences Laboratory, Mount Sinai School of Medicine of CUNY, New York 10029 INTRODUCTION Of the major plastic monomers, styrene is exceeded only by ethylene, propylene and vinyl chlorid^ in terms of produc tion. In 1977, approximately 3 x 10^ metric tons were produced in the United States and 7 x 10 metric tons world wide (IARC, 1979). Approximately 60% of the monomer pro duced was used in homopolymers, largely for the packaging industry. Other important uses of styrene are in the pro duction of copolymers with acrylonitrile (SAN) and acryloni trile and butadiene (ABS). Styrene also finds widespread use as a copolymer with butadiene in the production of the synthetic elastomer, styrene-butadiene rubber (SBR), which forms the basis of approximately 80% of U.S. rubber products. Finally, it is extensively used as a solvent and cross-link ing agent for polyester resins in the fiber reinforced plastic (FRP) industry. Estimates of the number of workers employed in the various industries using styrene-based polymers are given in Table 1 along with typical exposure levels (Tossavainen, 1978). In addition to occupational exposure, low-level environmental contamination can occur from combustion of styrene-based products, as the thermal decomposition of polystyrene leads to evolution of the monomer, in contrast to other polymer materials. MORTALITY STUDIES OF STYRENE-EXPOSED WORKERS Studies on the mortality of populations exposed to styrene are fraught with difficulty because of confound- T*bl* 1 Occupation*! axpoaura* to ftyrasa Froeoi* Foreoat of Hiuktr of cproBo worker* production Involved Honnor production Folpaor production (rs.ass.m) talaioread plastic* production (Til) Tolpaor procojalsj 100 60 - 70 10,000 30,000 20 - 30 200,000 5-10 1,.000,000 (7S.A1S.SBR) Typical xpoauro (ppa) 1-20 1-20 20 - 300 0.01 - 1 Frou Toar*alaaa, 1978 R&S 002579 ing exposures to other knows carcinogenic materials. Benzene exposures can occur in the production of styrene monomer, as the principal production process utilizes benzene to produce ethylbenzene, which, is turn, is dehydrogenated to form styrene. Copolymerization invol ves exposures to acrylonitrile and/or butadiene, which are carcinogenic in animals (Huff, 1983). Finally, some of the additives used in styrene products may be carcino genic, as well as other chemicals used in facilities producing styrene or polystyrene. Only three studies provide data on possible human carcinogenicity of styrene, each having some of the confounding exposures mentioned above. All were of groups of individuals employed in monomer production, polymerization or polymer fabrication, where exposures were relatively limited. Ho data exist on the mortality of individuals employed in the FRF industry, where sty rene concentrations were (and are) commonly ten times higher. Table 2 lists the cohorts observed and some of the characteristics of the three studies. As can be seen from Table 2, the large number of indivi duals lost to follow-up in the study by Frentzel-Beyme et al (1978) severely limits its usefulness. Of those exposed, 7% of the German workers and 71% of foreign "guest workers" were untraced. Of those traced, 74 had died, 12 from cancer. Only 37 deaths occurred in those with five or more years of exposure. The overall result did not demonstrate excess mortality for any cause of death. However, the limitations of the study are clear. Table 2 Population nd follow-up character!*tica of three atudla! of atyrcne expoaed worker* Studv Analyil* cohort Countrv aixa Hunter of Percent Percent deathe f traced anal-zed total Ott at al. 1980 Xlcoolaen at al. 1978 Trantzel-Bayae at al. 1978 0SA 05A cut 2901 J60 1960 97.1 100.0 93.0Ger 29.Oror 303 S3 73 10.1 11.8 3.7 Minima Minisun ixpoiurt latascy Teara (vaart) (-ear*) fellov-un Ixpoeurc! Ott at al. 1980 Sleholaon at al. 1978 Freatzal-Beyac at al. 1978 1 S 1 as. 1 1910-1975 10 1960-1975 1 DO . 1956-1976 <10 ppn (3)* < 20 ppa (5) < 1 ppab * ( 3 *cleared average exposure Current aeasureaent alter lnatallatlon of controls R&S 002580 The study of Nicholson et *1 (1978) successfully traced all of 563 men employed in styrene production, polymerization and polymer processing who had 5 years of employment on May 1, 1960 and were 10 years from onset of work in a large U.S. production facility. The basic mortality data are shown in Table 3 and demonstrate no excess mortality from any cause of death. Analyses according to years from onset of exposure and calendar years of observation did not reveal any pattern of excess mortality. However, because of the limited number of desths, the data can be used only to establish upper ltaits of risk. For example, the data are only suffici ent to indicate that the SMR for lymphoma or leukemia is less than 280 at the 0.05 level of significance and that of lung cancer, less than 220. While no excess mortality was identified in the cohort observed, the above publica tion mentioned the existence of 7 deaths from leukemia and 5 of malignancy of the lymphatic system among 444 deaths known to have occurred in the plant workforce. While the ages of death were not available for exact proportionate mortality calculations, the number of lymphomas is in line with expectations, while leukemia appears to be in excess by as much as a factor of two. However, the possibility of high exposures to benzene in the facility during earlier years weskens the likelihood R&S 002581 tibia 3 Ixpactad tad obaanrad aortallty axparlanca* of 560 Individual* anpioyad la ttyraa* production and polymerisation prior to 1 May 1955. followed tan years after oeaet of exposure (1 May 1960 -- 31 Deeenber 1975) Cauaa of Daach Ixpactad Obaarvad SMK All cuu* Caacar Caacar of tha lung lauhxala Lyspho*** Othar caacar Kmart aad circulatory dla. Kaiplratory dlaaaaas Othar cauaaa of daath 106.41 21.01 6.99 0.79 1.25 11.99 56.35 6.64 22.41 93 17 6 1 4 9 52 1 13 79 91 117 126 90 75 92 5 58 From Nicholson at al. 1979 of association of any possible excess of leukemia with styrene exposure. The final study of styrene mortality is that of Ott et al (1980) who described the experience of 2,904 individuals with potential exposure to styrene prior to January .1, 1976. Three hundred three deaths occurred, 292 among production and nonprofessional research employees. The mortality experience for this latter group is shown in Table 4 and is compared to the expected deaths calculated from U.S. white male rates and rates from observations on other company eaiployees. As can be seen, the mortality of styrene-exposed individuals compares favorably with each group; the only excess of note being six leukemias compared to 2.9 expected using U.S. rates and 1.6 from company rates. Lymphomas were also elevated, but not at an 0.05 level of significance. The excess leukemia was further investigated in an analyis of cancer incidence in the styrene-exposed population com pared to that expected from rates of the Third National Cancer Survey. In this analysis, it was found that a signi ficant number of lymphatic leukemias (5 observed vs. 0.26 expected) occurred in individuals who were exposed to sty rene (< 5 ppm), ethylbenzene (< 5 ppm), polystyrene extru sion fumes, and colorants. Indeed, four of the five cases worked in the same general area during the period of time, 1947-1948, although their dates of death and other exposures varied widely. Interestingly, there were no deaths of lymphocytic leukemia among 442 individuals exposed to higher R&S 002582 Table Observed and expected deaths by cause for total production and non-professional research employee* (2310 M), 1940-1976 Observed Causaa deaths All causes 282 Malignant neoplasms 35 Respiratory system 14 Digestive system 16 Lymphatic sod hematopoietic 6 system except leukemia leukemia 6 Other sites 13 Cardiovascular disease 143 Mommallgnant respiratory die. 1Z All other causes 72 fxpeeted deaths OS white males 337 .8 64.2 20.8 18.0 4.5 2.9 18.0 172.4 14.3 106.9 SMR 79 87 67 89 133 207 72 S3 84 67 7roa Oct ct al. I960 Expected deaths, Compter eomnarlsen 287.6 65.0 23.9 21.2 1.6 SMR 98 85 39 67 230 1.6 15.7 141.5 10.0 71.1 373 83 101 120 101 concentrations of styrene (5-9 ppm). Because of a lack of a definitive exposure-response-relationship and the presence of possible confounding exposures, the authors refrained from drawing any conclusions on an etiological relationship. In 1976, nine cases of various types of leukemia were identified in two SBR plants and reported to the U.S. National Institute for Occupational Safety and Health (Meinhardt et *1, 1976). All occurred after 1971 in a population of 5,600 workers. No data were presented on the expected numbers of deaths from leukemia in the group. Concern generated by the findings in the two plants led to reports on the leukemias present in two large ongoing studies of rubber workers. HcMichael et al (1976) reported a relative risk of 6.2 for lymphatic and hematopoietic malignancies among employees producing elastomers, including SBR. However, this was based upon only 6 cases, 3 leukemias and 3 lymphomas. In a subsequent case control study of the same plant, a relative risk of 2.A was found for the same exposure group (Spirtas et al, 1976). The difference in the two values reflect the uncertainties associated with small numbers of cases. A similar investigation by Honson et al (1978) showed an excess of leukemia to be present in calendering, extrusion, tire building and rubberized fabrics. However, the excess was associated with exposure to solvents and not to styrene. R&S 002583 Since 1976, considerable interest has existed in poten tial carcinogenicity of styrene. This has been heightened by the data on mutagenicity and possible carcinogenicity of styrene and styrene oxide (Huff, 1983). Some suggestive human data are available from studies of polymerization workers and SBR production facilities. The irony of the situation is that no studies have been conducted of groups exposed to the enormously higher concentrations found in the FRP industry. The data available on styrene carcinogenicity are such that they can provide no assurance of safety at these higher exposures. CARCINOGENIC RISK FROM COMONOMERS USED WITH STYRENE The two principal comonomers used in- styrene-based copolymers have each been shown to be carcinogenic in ani mals. Of these, acrylonitrile has also been associated with lung cancer in humans. In a group of 1,345 male employees, with potential exposure to acrylonitrile and followed from 1956 through 1976, 8 cases of lung cancer occurred compared with 4.4 expected from company rates (O'Berg, 1980). Fur ther, there was a correlation of increased risk with inten sity and duration of exposure. Among production workers employed between 1950 and 1952, 6 lung cancer deaths were observed.vs. 1.5 expected (p < 0.01). A second study of 327 employees of a rubber chemicals plant with potential expo sure to acrylonitrile identified 9 deaths of lung cancer compared to 5.9 expected, based on mortality rates for U.S. white males (4.7 based on mortality rates for other rubber workers from the same city) (Delzell and Monson, 1982). The excess was greatest among those who had worked for more than 5 years in the facility. These data, while limited by the saiall numbers, strongly suggest that acrylonitrile is carci nogenic for humans. While butadiene has been demonstrably carcinogenic in animals (Huff, 1983), no data are available from human exposures. CLINICAL FINDINGS AMONG STYRENE-EXPOSED WORKERS A variety of symptoms have been reported from styrene exposure, dating from the rapid increase in production during World War II. Eye, nose and throat irritation, various respiratory symptoms, and gastrointestinal dis turbances, such as nausea, vomiting and loss of appetite, are commonly reported by styrene-exposed workers. Other abnormalities reported include headaches, tiredness and sleep disturbance. After a period of exposure, adaptation may occur and there can be a decrease in the various symp toms. Nevertheless, significant alterations still exist among currently employed workers. Several systematic studies of the various clinical ef fects from styrene exposure have been conducted in recent years. Many of these focused on possible neurological alterations and clearly demonstrated adverse findings at moderate styrene exposures (less than most national stand ards). The most extensive of these is that by investigators from the Institute of Occupational Health of Finland (Seppalainen and Harkonen, 1976; Lindstrom et al, 1976; Harkonen, 1977; Harkonen et al, 1978). They examined 98 workers employed at 24 plants manufacturing FRF products. Air concentrations were sampled and ranged from 5 to 300 ppm. The means of five post-workday urine mandalic acid (MA) concentrations ranged from 7 to 4,700 mg/1 with a lin ear relationship existing between the log of the MA concen tration and the log of the styrene concentration. The mean value of MA in the population was 808 mg/1 and corresponded to an exposure of about 40 ppm of styrene. Abnormal EEG's were found in 30% of those with MA in excess of 700 mg/1, compared to about 10% for those with lower MA values and normal controls (Seppalainen and Harkonen, 1976). Lindstrom et al (1976) noted increased visuomotor inaccuracy (syimnetry drawing and Bourdon -Wiersma tests) and lowered psychomotor performance (Mira test) for various MA concentrations rang ing from 800-2,000 mg/1 (See also: Harkonen et al, 1978). Fatigue, irritation, difficulty in concentration, nausea, dizziness, and lightheadedness were more frequently reported by the styrene-exposed workers than by unexposed controls (Harkonen, 1977). A deteriorating EEG among styrene workers has also been described by Klimkova-Deutschova et al (1973). Alterations of nerve conduction have been documented by Rosen et al (1978) who observed an increased duration and decreased amplitude of sensory action potentials. Lilts et al (1978) suggested the possibility of a decrease in peroneal nerve conduction velocity. The decrease, however, was only asso ciated with length of employment and not intensity of expo- R&S 002584 sure. Subjective symptoms of physical and mental tiredness after styrene ex jure have been reported by Klimkova-Deutschova et al (1' 3) and Cherry et al (1980), among others. The reported neurological findings among atyrene-exposed workers are less serious than those reported in some other groups occupationally exposed to solvents, such as as paint ers (Lindstrom, 1980; Hane et al, 1977). Howev&r, the continued exposure to concentrations causing the observed abnormalities may lead to more serious central nervous system impairment. In addition to neurological disturbances, alterations of pulmonary function have been noted among styrene-exposed workers. Lorimer et al (1977), in an examination of 494 polymerization workers, found a reduction in FEV^ to be associated with intensity of exposure and with urine MA concentration. Further, the workers in the higher exposed group reported a greater percentage of acute and recurrent lower respiratory symptoms. Harkonen (1977) reported an increase in incidence of chronic bronchitis which correlated with intensity of exposure. On the other hand, Axelson et al (1978) did not find any abnormalities of pulmonary func tion asiong 27 FRP boat manufacturing workers. Laboratory test results have been rather unremarkable. Lorimer et al (1977) suggested the possibility of increased lymphocytosis among polymerization workers and Checkoway (1982) found a correlation between decreased red blood cell count and increased basophil count with styrene/ butadiene exposure. Increased blood enzyme concentrations, charac teristic of abnormal liver function, occasionally have been reported. Lorimer et al (1977) found a significant increase in concentrations of GGTP (gamma glutamyl transpeptidase) and Hotz (1980), noted increased concentrations of OCT (orinthine carbamoyl transferase) and ALAT (alanine amino transferase) among polymerization workers. SUMMARY OF HUMAN MORTALITY AND MORBIDITY The lisdted epidemiological studies of mortality asso ciated with styrene exposure do not demonstrate any excess cancer risk that can be attributed to styrene, although elevated risks for leukemia have been noted in exposed groups. However, these excesses may be related to exposures R&S 002585 R&S 002586 LU to other chemicals, such as benzene. The studies are se verely limited because of the relatively low styrene expo sure of the groups studied. They provide no guidance on carcinogenic risk in populations much more heavily exposed as in the FRF industry. The significant clinical findings among styrene-exposed workers are largely limited to abnor malities of the central nervous system, where a variety of objective and subjective symptoms have been reported in the FRF industry. Concern for long-term degnerative neurologi cal disease exists for continued long-term exposure in this industry. 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