Document 2J8MMqmJ5Jj6b5nB38zamxxEN

of Laboratory Animal sks for Man, 179-189. Mtors). Carcinogenic 283 P49ft$, IARC , International Agency tistics When Examining Carcinogenicity. J. :ime Feeding. Study In 'alldity as a Bloassay <icol.t 3$3-67. iafflottt; U. (1976). Small Rodents. NCI Washington, Trend In Life Table ive Val ue of Rodent ion of Human TJIsks. rrent Concepts ^and Jsis. Supramol. Willin J. Nicholson, Paul K. Henneberger and Diana Tarr : Environmental Sciences Laboratory, Mount Sinai dlchool of Medicine., tfP City University of New York New York,'New York 10029, U.S.A. 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 Henschler, 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 interaiediate 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 unsymmetrical 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 monoaiers 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. OLI 3837 IS 5 N / N>cfto4on, HaimsOargsr, Mid Tmt At this tine, 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 RELAT1ONSH1PS 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 4 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- AOMINISTERED CONCENTRATION OF VINYL CHLORIDE (ppm) Figure 1. The percentage of rats developing liver hemangio sarcoma from 52 wk exposures to VC for 4 hr/day, 5 day/wk. OLI 3838 >n both experimental to vinyl-chloride information-importdo>e-respohe~ ifela- ^ hese_. dAfcs on VC. in . i le trendif-fxn future--5 d infotflijPt(op^on.the >rds. As. htuu^ond * f expooypnStn^fffchef can* b~applied to * :hemicals- in animal Itoni eodFaeseeiates ten year- period is carcinogenesis. A notarized-in Figure 1 tip for the percent? arcowr(HSA) of the aosures to different te relationship is a at ion at hi^h con* m* Canear Mortality / $7 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 terns of Michaelis-Menten kinetics, in which the trans formation of VC to a reactive intermediate follows the equation, V = VmS/(Kn + S) a) 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 pg/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-respouse relationship is % HSA = -0.066 + 0.0039 V (2) 90 ting liver hemangio4 hr/day, 5 day/wk. 02 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), OLI 3839 (t / NteUoMon, HMMbMjw, <d Tmt Gehriog et al (1978) fitted the early data of Haltoni and Lefemine (1975) to a log-probit Model. Figure 2B shows the log-probit plot using all available data from the stud ies fron Maltoni et al (1981). The unweighted least squares regression line is Probit = 0.24 1.01 log V (3) 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 listited biologi cal rationale for the use of a log-probit relationship in carcinogenesis and its use as a neans of extrapolation to predict effects at very low exposures would appear to be ore 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. TIME COURSE OF CANCER Much of hunan cancer has been found to follow a power law relationship with age (Armitage and Doll, 1961; Cook et al, 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 law of time from onset of exposure with an exponent between 3 and 5 (Doll and Peto, 1978; Newhouse 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, OLI 3840 ly data- f Maltoni 1. Figure 2B shows data from the stud* ghted leave squares -fjS ' (3) ta 0.68}, the the data somewhat ry limited bidlogi-' it relationship in >f extrapolation to fould appear to be i the other hand, a n the Incidence of ;d is biologically Jts use is strongly to follow a power toll, 1961; Cook et (4) it a specific site, cific to site. In ithelial malignaaic carcinogens are arette smoking and follow a power law exponent between 3 Berry, 1976; Peto iterpreted in terms he implications of '), Whittemore and 0), among others, cur with exposures ly, such as asbeson of lung cancer, the multistage moobtains. However, f! i i Cancar Mortality / M 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 dsta sre available from the use of Thorotrast in Japan and Denmark that indicate the incidence rate of HSA doea 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 sre 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 193S. 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: F.(Mort) j-i J th . F.(Mort) J-* J (5a) (5b) I C. F.(Mort) iJ (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 to 9, extending the observationa through 1979. The F.(Mort) sre the appropriate age and calendar year adjustments to the population in OLI 384X TO / Mtehotatti, Hwntboyr, and Tavr .A I ,,r^ woaio WTn,Pi_ WCUCfItTOfPftt* ____ & a USWTIATCTDtt - n nn >6 M 41 M l M Y#r of Firtt Eupftairi f WcuCaWofftcN .--jlilAn, Ps____ . mumtretoi M TO T5 M CaWnSor V*r of Doom to I* to I* MUM Yoon Sinca Ontot of Eipoturo to Dooth Figure 3. The number of cases of hemsngiosarcoma of the liver in the U.S., Western Europe end the world according to seve ral time criteria. quinqueniua 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. OLI 3842 * N H If el Eipetof* Ontet el Etpewrt M DpbIN osarcoma of the liver I according to seve- le C^s are propor, i.e., the average ne period times the -response relation?C is linear in the : of HSA is propor- one need not know eir vinyl chloride Cancar MonaMty / 71 Relative values for the C.'s can be determined from two sets of data. The first is tie incidence of HSA according to calendar period of first exposure (I ). Here the C.'s are directly proportional to the incidence1in 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 of1 VC monomer. Figure 4 displays the avail able information on production in the United States (S.P.I., 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 Cj'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 500 RELATIVE POPULATION EXPOSURE CALENDAR TEAR calendar tear 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. OLI 3843 I Uw|o||i|o|dn|lounui nvnnv0v^pH| ino Vwmara Table 1 Measured and estimated muwrti to vinyl chloride to polymer1tatIon worker* In various tin* period! Approximate Calendar Vinyl chloride exposures (ppm) ralatlva Period Serna* (1976) Ott cc al (1975) Suclu et a1 (1975) exposure Before 1950 1950-56 1955-59 1960-64 1965-69 1970-74 1000 1000 400 - 500 300 - 600 300 - 400 150 - 300 100 - 400 100 - 400 20 - 80 20 - 80 200 - 900 40 - 50 40 - 60 lines across each quinquenium. The dashed lines across each quinquenium during earlier years are those determined by fitting the observed HSA incidence to Eq. 5a and matched to the value estimated from production data in the quinqueniun 1955~1959. As can be seen, the comparison of the two sets of data suggested that the population exposure prior to I960 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 1960, 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 Lin 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 HSA 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 OLI 3844 tnyl chloride :lae purloda ^ ' Approxiaat* pn) " '". ralativa ;t 1 <44JSj xpoxur lines across each Jse determined by 5a and matched to n the quinquenium of the two sets sure ptior to 1960 that estimated by ited in Figure 4, Lve values for C., .early an approxiiy projections of C.'s, alternate lesjta^ Figure 4a. .e n^raeen the two calculated using e 4, values of k mined by matching Lgure 3. In this or time of first 5-29, 26V, 30-34, 0-54, 2.5V This examined by Mount 974. The pattern be a decreasing ime of 12 years, f employment for (Nicholson et al, were made for the Canoar MortaMy / 71 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 1, , the incidence according to years from onset of exposure is best fit by a value of k = 2. A value of 3 is compatible with the data, but values greater than 4 can be ruled out. I is relatively insensitive to the choice of k, but a value of 4 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 the 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 sosm European plants or that more workers were exposed per tonne of VC produced. 45*49 55*99 S9-S9 7S-T9 YEAR OF DEATH YEARS SINCE ONSET OF EXPOSURE Figure 5. A comparison of the calculated incidence of heman gi os a rcoraa of the liver with that observed in the U.S. and Western. Europe according to several time criteria and models for calculation. OLI 3845 74 / yUchotaon, HMMbifgvr( snd Tht 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 assuned 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 suggest 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 say 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. 4a. 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 t for only 45 years and remained constaut thereafter. As can be seen, the pro- Tabla 2 Projections of mortality In the United States end Western Europe to the year 2040 from exposures to vinyl chloride prior to 197S Total Projected Mortality ModelUnited States* Western Europeb t1 t3 tH t3, to 45 years from onset of exposure t3, upper exposure curve. Fig. 4 t3, lower exposure curve. Fig. 4 t3. + Age1 190 340 630 310 240 450 260 540 1190 2780 1120 * 26 deaths have occurred through 1979 39 deaths have occurred through 1979 OLI 3846 ficantly from that according to years y, we assumed the industry would be loyment time of 12 s with employment available informa- correct, that our error, that there shorter exposures, t risk for shorter near dose-response it duration of em eses sment of popujuld have required exposure would be |by the preceding Khe mortality from (0, using Eq. 4a. ately for Western n in the data for lues of C.'s indiprojections1 assumquadratically with suggested by expeWe also considered for only 45 years be seen, the pro- d State* 3 froa to 1975 1ctd Mortality 4 Utrn Europeb 540 1190 2780 1120 \ i Canoar Motmsty / 78 jected numbers of HSA for the United States rsnge 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 thst 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 and 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 all 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 ppm standard, cancer from employ- OLX 3847 n i NldtolioWj Mid Tmt eot 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 ..f REFERENCES Armitage F, Doll R (1961)- Stochastic models for carcinoge nesis. In: Proceedings oi 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. Bonse G, Henschler D (1976). Chemical reactivity, biotrans formation 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 ME, 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 nou-smokers. J Epidem Comm Health 32:303-313. Faber M (1978). Malignancies in Danish Tborotrast patients. Health Physics 35:153-158. Gehring PJ, Blau GE (1977). Mechanisms of carcinogenesis: dose response. J Environ Path Toxicol 1:163-179. OLI 3848 ted. However, there HSA of the order of fetime, based on e >out 10,000 workers. >een documented from sr carcinogens, the to increase as the of exposure. It is .ng this power rela- observed mortality . 200-600 deaths may 3 in Western Europe `Uggest that a 1 ppm o protecting workers dels for carcinogeBerkeley Symposium ility. (Ed. Neyman production of PVC. activity, biotrans>ted aliphatic corn- mathematical model man. Int J Cancer nodels and primary r Inst 64:977-989. ting and bronchial ips among regular Epidem Comm Health lorotrast patients. of carcinogenesis: 1:163-179. Canear Mortaflty / 77 Gehring PJ, Watanabe PG, Park CH (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 NL, Anderson MW (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, Carrettl 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 follow-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 angiosarcoaia 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 WJ, 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 the VC-PVC industry. This volume. Organization for Economic Cooperation and Development, Chemical Industry (1971). Quoted in: Levinson C. Work ha zard: vinyl chloride. ICF Geneva. Ott MG, Langner RR, Holder BB (1975). Vinyl chloride expo sure in a controlled industrial environment. Arch Environ Health 30:333-339. OLI 3849 7 / Htchomon,Hawnaha>p>r,andTMT Peto 8 (1977). Epidemiology, multiatage models sad short term mutagenicity teste. 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, New York. Suciu 1, Prodan El, Paduraru A, Pascu L (1975). Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sci 246:53-69. U.S. Tariff Cosmlasion (1948-1968). Polyvinyl chloride and copolymer production data. Van Ouuren B (1975). On the possible mechanism of carcino genic action of vinyl chloride. Ann NY 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 epidemiologic 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. ;1 OLI 3850 REPt Intr last beca ized plas knowi pets> publ: emplt are < ethei in pJ incli offsg Publi effec f requ on sp husba pater vinyl the ei