Document MMq91L8p4eY7vEBVG201O143k

Occupational Hazards of Vinyl Chloride and Stvrena Trends in Cancar Mortality Among Workers in the Synthetic-Polymer* Industry William J. Nicholson, Paul K. Henneberger aad Diane Tarr Occupational Hazards in the VC-PVC Industry William J. Nicholson, Paul E. Benneberger end Berbert Seldman Occupational Haaards in Production of Processing of Styrene Polymers - Epidemiologic Findings William J, Nicholson end Diene Tarr Lectures presented at a course on occupational haxards of plasties end synthetic elastomers. Institute of Occupational Health, Helsinki, Finland, November 22*27, 1982 Published in: Industrial Hasards of Plastics and Synthetic Elastomers Eds. J. Jarviaelo, P. Pfaffll, E. Valnld (1984) Progress in Clinical sad Biological Hesearch: Volume 141 Alan E. Lisa, Inc., Nev Tork, pp. 65*78, 155*176,263*278. ENVIRONMENTAL SCIENCES LABORATORY MOUNT SNA< SCNOOb O* MtO'ClNf O* T*C C'TV W*l V C*<* ON 0* r. $ ic* * TRENDS IN CANCER MORTALITY AMONG WORKERS IN THE SYNTHETIC POLYMERS INDUSTRY William J. Nicholson, Paul X. Henaeberger and Diane Tarr Environmental Sciences laboratory, Mount Sine! School of Medicine of City University of New York New York, New York 10029, U.5.A. INTRODUCTION i * ,, The reactive double -bonded structure of ethylene-like molecules allows a vide' 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, . 197$). These epoxides or their reaetive metabolites can bind to cellular macromolecules and may be responsible for * the carcinogenicity of the parent moleeule. Epoxide forma tion has been suggested es an intermediate in the cagciaogenic action of vinyl chloride (Van Duuren, 1975) and vinyl idene chloride (Meltonl, 1977), and in tht mutagenic ection of styrene (Milvy and Cargo, 1976). The epoxides of tthyl- ene, styrene end vinyl chloride have been shown to be carci nogenic, as well as dirtetly mutagenic in bscterlel test systems without the need for ectivation. The potential for conversion of ethylene-like molecules to the epoxides is greeter for uasymmetri'cal structures such as vinyl chloride end vinylidcae <chloride than for symmetrical structures, such es ethylene, 1,2-dichloroethylene or tctrachloroethylent. It is beyond the ;fcope of this review to discuss the ~ i structure-activity relationships of tbs monomers used in the plastics industry. Nevertheless, eveileble 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 la understood, e coherent picture of the dose and time dependence of cancer should emerge. ' URL 05369 # V . At th.it time, dttt are available on both experimental tad human carcinogenesis from exposure to vinyl ehloridt (VC) tad on its metabolism that provide Information importtot for the understsnding of observed dose-response rela tionships. This paper will consider these dttt on VC la detail tt they provide estiattef of the treads la future disetse potential from past exposures tad infatuation on the efficacy of current occupational standards. As human and animal data accumulate oa the effects of exposure to other monomers, the approach suggested by VC can be applied to their evaluation. DOSE-RESPONSE RELATIONSHIPS'l, VC is one of the best studied chemicals in animal systems. The magnificent research by Maltoni aod associates (1981) on nearly 7,000 animals over a tea year period is virtually unmatched in experimental eareinogenesis. A principal featura of their results is summarized in figure 1 which shows the dose-response relationship for tha percent age of animals thst developed hemenglosarcoms (ESA) of the liver from 4 hr/day, 5 day/wk, 52 wk exposures to different concentrations of VC. As:can be seen, the relationship a non-linear one with evidence of saturation at high con- 'f -t .. *'' 1' administered concentration of vinyl chloride (ppm) Figure 1. The percentage of rata developing liver hemangiosarcoma from 52 wk exposures to VC for 4 hr/day, 5 day/wk. *' U R L 05370 centratioas. However, t concentrations of VC lass than 500 ppm, a reasonably linear, dose-response relationship obtains. Gehring tt al (1978) have explained the non-linearity in terns of Michaelis-Meaten kinetics* in which the transfomation of VC to a reactive intermediate follows the equation, V * VaS/ (Xa +- S) (1) V and VB are the rate and maximum rate, respectively, for ' the biotransfozmation of VC, S is the concentration of VC in inspired air, and K , the Michaelis constant. X 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 ESA and the quantity of VC metabolised 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 baen 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 tht dose-response relationship is % 8SA -0.066 v 0.0039 V (2' SO O 3D k? 25 20 O<O-SJJ\ 10 u.tf 9 si 2 wu x** \ 0.9 "-S 0.2 Figure 2. Linear and probit dose-response relationships for the quantity of VC mctaholiaed/6 hr exposure (5 day/wk,S2 vk). :\.. .< . Gehring et *1 (1976) fitted the early data of Malto&i and Lefesine (1975) to a log-probit nodel. Figure 2B ahova the log-probit plot using all available data fron the stud ies from Halto&i et al (1981). The unweighted least squares regression line is Problt * 0.24 4 1.01 log V (3) cal rationale for the use of a log-probit relationship - in carcinogenesis and its use as a Beans 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 netabolized is biologically plausible and fits all available data. Its use is strongly suggested. TIME COURSE OF CANCER Much of taman eancer hat been found to follow a power law relationship with age (Arnitage and Doll, 1963; Cook et el, 1969), (4) where R it the incidence rate of eencer at a specific site, t is ege, end b end k ere constants specific to site. In general, k is between 4 and 6 for most epithelial nalignaneiea. While data for exposures to specific carcinogens are United, bronchogenic earcinosa fron cigarette smoking and mesothelioma free asbestos exposure also follow a power law of tine fron onset of exposure with an exponent between 3 end 5 (Doll end Peto, 1978; Newhouse and Berry, 1976; Peto-. et al, 1982). These findings have been interpreted in terns of e multistage nodel of carcinogenesis, the implications of which have been discussed by Peto (1977), Whlttemore and Keller (1978), and Day and Brown (1980), aaoog others. Deviations fron the above tine course occur with exposures to carcinogens that interact synergistieally, such as asbes tos end cigarette saoking in the production of lung cancer. This interaction can be incorporated in the nultistage no del, but e more complicated relationship obtains. However, URL 05312 i URL 0537? - i. . for a rare tumor, such as HSA, interactive effects say sot be important and a power, lav relationship should adequately describe the time course of risk folioviag exposure. Some data arc available from the use of Thorotrast in Japan and Denmark that indicate the incidence rate of ESA 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 ESA given by Eq. 4. Figure 3 shows the number of cases of USA aecording.to various maasures of time that have been identified i'a the United States, Western Europe and the world (KIOSH, 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: ih t*.i FjCMort) (5a) VCi fh t*.i Tj(Mort) (5b) :j-i * `j-i I_ C FjCMort) (5c) where i represents ' the ^quinquenium of exposure and j, the quinqueaium of observation, i runs from 1 to 8, represent ing the years 1935-1974 and j from 1 to 9, extending the observations- through 1979* The F.(Mort) are the appropriate age and calendar . year adjustments to the population in ----W ; ` V*. V ' * . w (... 1 > It a l M U H u Veer f flret CiHwrt Yteo el [ipeiuft * ^ 0 700 Mm n n m CeieMer Veer ef Deetit e n - r ^ =-- 1--^ * io it le ** m u ee Veen SMtct Ontet ef .Eteeeun ta Oeeth Figure 3. The number ef eases of hemanglosareoma of the liver in the U.S., Western Europe end the world according to seve ral time criteria. qulnqueniua 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 metabdliied VC is linear in the range of most worker exposures, the'risk of BSA is propor tional to the total population exposure; one need not know the number of workers exposed and' their vinyl chloride exposure separately. Relative values for the C.'s can he determined from two sets of dsts. The first is tfee incidence of HSA according to calendar period of first exposure (1.). Here the C.'s ere directly proportions! to the incidence1in a given calendar period and available data are sufficient to establish res* sonable values of C. for the time period 1935-1955. Addi tional data on C. can -be developed from published data on. the production ofvC monomer. Figure 4 displays the avail able information on production in the United States (S.P.I., 1975-1978; U.S. Tariff Commission, 1948-1966) 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 s metric ton of VC in different time periods .c As it would be expected that more workers were employed per tonne of VC produced during ear lier years, an adjustment is required to aeeount for produc tivity. Initial estimates of this factor ara also indicated in Figure 4. The relative population exposure, taken to be the product of production, the workforce productivity ad justment, end the exposure adjustment is shown by the solid too too too to to 10 t I Figure 4. The production of VC in the U.S. and Western Europe elong with estimates of the population exposures to VC poly merization workers in different calendar periods. "(LATtVC fOTUiATION tXPOWJftt s *:' -' .:yi 3 ` TabU 1 . , , Maapurpd pad utlaittd ticwinru to vinyl chlorli* cp pplympriiaglen erkiri la variout tlat ptrlodt 'r * Approxlaata Calendar Vlayl chlorlda >6wi (ppb) ralatlyp Prlo4 krMt (1*76) Oct pc *1 (1975). Suelu t al (1*75) axpcaurt kfftt* 1950 1950*51 1955*59 1900*0* 1905-09 1970-7* 1000 1000 *00 .- 500 500 - *00 500 - *00 150 - 500 100 - *00 100 - *00 20 - 60 -,200 - 900 20 - 90 *0 - 50 .40 - 60 3 3 3 2 1.5 1 lines across each quiaquenium. The dashed lines aeross each quiaquenium during earlier years are those determined by fitting the observed BSA ineideaee to Eq. 5a and matched to the value estinsted from production data in the quiaquenium 1955*1559. As can he seen, the comparison of the two sets of data suggested that the population exposure prior to 1960 vas slightly less in some quiaquenla than that estimated by the use of the adjustment factors, indicated in Figure 4. r; `f.' The procedure of estimating the relative values for C.r particularly in ttie years after 1960, is clearly an approxi mate one. To consider how sensitive eny projections of future mortality ara to the choices of C 'a, alternate choices ara shown by tho light : solid lines *in Figure 4a. Any realistic estimates of the C *s must lie between the two lines. 1; Relative values of 1., and I. , were calculated using the relative values of shown in Figure 4, values of k between 2 end 4, and absolute values determined by matching to the incidence data of BSA found in Figure 3. In this calculation, the age distribution used for time of first exposure vss: 15-19, 6.5%; 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 typieal patterns of employment for long-term workers in the chemical industry (Nicholson et al, 1982; Wong, 1982). Separate calculations were made for the 'v C 2 S cn United States and Vcstera Europe. The results of this procedure, combioinf the, data for the United States and Western Europe, are shows in Figure 5. As can be seen I, the incidence according to years from onset of exposure Is best fit by a value of It * 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 *# for Westers 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 some European plants or that more workers were exposed per tonne of VC produced. c U S0- YEAR OP FIRST EXPOSURE YEARS OF EXPOSURE 49*49 15*49 TS-T5 YEAR OF DEATH YEARS SINCE ONSET OF EXPOSURE . ^ -. rl .ff. ' -is ; Figure 5. A comparison of the calculated incidence of hemangioaarcoma of the liver with that observed in the U.S. and Western Europe according' to several time criteria and models for calculation. ? . vV-r S1* 's'. URL 05378 * On* ut of dm that differs*, significantly from that calculated is the distribution ef 'eaaes according to years of VC exposure. As Motioned previously* ve assumed the distribution of employment tines in*the VC industry would be a decreasing exponential.with a naan employment tine of 12 years. The significant deficit .of caaea with enploynent tines less than 10 years suggests that the available informatlon on duration of VC exposure nay hot be correct, that our assuned employment distribution nay. be in error, that there nay be an uaderascertainnent of cases with shorter exposures, or that there nay he proportionately less risk for shorter exposures than would be predicted on .a linear dose-response relationship. It should bo mentioned that duration of em ployment is not an important variable in assessment of popu lation risk. Shorter employmenttimes 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. 3a. These date ere 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 end projections assum ing that the risk of ESA will Increase ^uadratically with age of exposure. This age dependence wss suggested by expe rimental results of Groth et si (1981). -We also considered a time course for HSA that increased as t3 for only 45 years and remained constant thereafter. As can be seen, the pro- Xatla 2 ProltctloM of uottalltv la the Caitad States sod tfostera lurooo to the voiT_Z0A0_froo posuri to vinyl chloride Prior to iS73 focal ho1teu4 ItortaUg MpdalCalf* States* ra torn.. f AS pears free onset of axposure Spar exposure curve, Fig. a lower exposure curve. Fit. * age* ' . 1 190 360 630 310 2A0 *90 260 540 1190 2760 1120 26 deaths have occurred through 1979 39 deaths have oeeurrad through 1979 it4 4 jected numbers of HSA for the United States range from 200 to 600 and, for Western Europe, from 350 to 2,600. (The greater range for Europe is the result of the sore recent usage of pattern.) The most probable projection for future disease is felt to be that represented by s 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 say 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 abort term workers may have been missed. The projections also depend on the choices of the C. end the k. Ve have projected mortality based on reasonable choices for these parameters. However, other choices cannot be absolutely excluded. While these uncertainties exist, te data indicate that, within a factor of 2 or 3, future HSA^getelity from exposures prior to 1975 will be about 350 deaths in the United^ States and 1,200 in Western Europe.^ FurOter, 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 baavily exposed . group,,USA 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 *5 . Nicholson et al (1983) have shown that liver HSA accounts for at least 50% of all. VC-induced malignancies. Thus, it would appear that avenge exposures of 200-500 ppm in pre vious years will lead to 1,000-4,000"excess cancer "deaths in all workers exposed to*1 VC in Western Europe and tha United 8tstes prior*"* *I97$71If a staadar<TVf~r ppm is mat, the average exposuxe^of all the workers would be between 0.2-0.3 ppm, 1,000 times less than that which existed previously. One would expect the VC-induced malignant rlak to be reduced by a corresponding amount. This Implies tbet, if the VC industry complies with a 1 onm standard, cancer from tmpley- URL 05379 'fM : i '.t j.;. ment therein would be virtually eliminated. However, there will still remain a risk of developing KSA of the order of 1(> per individual for a working lifetime, based os a United States or European workforceof about 10,000 workers. SUMHARY A hi*h risk of death from liver KSA has bees documented from past exposures to VC. Similar to ether carcinogens, the risk of VC-induced liver HSA appears to increase as the second or third power of time from osset 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 550-2,600 is Western Europe from liver HSA. These projeetle&s also suggest that a 1 ppm standard is the VC industry will go far to protecting workers from future malignant disease. REFERENCES Armitage P, Soil R (1961). Stochastic models for carcinoge nesis. In: Proceedings of the Fourth Berkeley Symposium on hethemetical Statistics and Probability. (Ed. Heyman J) Univ Calif Press, Berkeley pp. 19-36. Barnes AW (1976). Vinyl chloride and the production of PVC. Proc Roy Soe Had 69:277-260. Bonsa 6, Kanaehlar D (1976). Chemieal reactivity, biotrans formation and toxicity of polyehlorlanted aliphatic com pounds. CRC Crit Rev Toxieol 5:395. Cook FJ, Doll R, Fallinghsm SA (1969). A mathematical model for the ege distribution of eaneer in man. Int J Cancer 4:93-112. Day RE, Brown CC (1960). Hultistage models and primary prevention of eaneer. J Hatl Cancer Inst 64:977-989. Doll R, Peto R (1976). Cigsrette smoking and bronehial carcinoma: dose end time relationships smong regular smokers and lifelong non-smokers. J Epldcm Comm Health 32:303-313. Faber H (1976). Halignaneies in Danish Thorotrast patients. Health Physics 35:153-158. Gehring PJ, Blau GE (1977). Haehaniams of carcinogenesis: dose response. J Environ Path Toxicol 1:163-179. URL 05380 M*f t Gehring PJ, Vatanabe PC, Park CN (1976). Resolution of dose-rasponse toxicity data for ehe&ieale requiring meta- bolic activation: exaaple - vinyl chloride. J Toxicol Appl Pharmacol 44:581*591. Groth DH, Coate WB, Ullaad BIJ, Hornung, RV (1981). Effects of aging on the induction of angiosarcoma. Environ Health Persp 41:53-57. Boel DC, Kaplan KL, 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 HT Acad Sci 246: 195-224. Haltoni, C (1977). Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Persp 21:1-5. Haltoni C, Lefeaine G, Ciliberti A, Cotti G, Carretti 0 (1981). Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis. Environ Health Persp 41:3-29. Milvy P., Garre AJ (1976). Mutagenic activity of styrene oxide (1,2-epoxycthylbenzene), a presumed styrene metabo lite. Mutat Res 40:15-18. Mori T, Kato T, Shiaaaine T, Watanabe S (1979a). Statisti cal analysis of Japanese Thorotzast-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. Rational Institute of Occupational Safety and Health (U.S.) (October,1982). Reported cases of angiosarcoma of the liver among vinyl chloride polymerisation workers. Hevhouse ML, Berry G (1976). Prediction of mortality from mesothelial tumors in ssbastos factory workers. Brit J Indus Med 33:147-151. Hicholson 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. Hicholson VJ, Hannaberger P, Seidaao H. Occupational ha zards in tba VC-FVC industry.. This volume. Organization for Economic Cooperation and Development, Chemieal Industry (1971). Quoted in: Levinson C. Work ha zard: vinyl chloride. ICF Geneva. Ott MG, Langner RR, Holder BB (1975). Vinyl chloride expo- aure in a controlled induatrial environment. Arch Environ Health 30:333-339. % T s-- i: Ofr- U' v r&r*-; Peto ft (1977). Epidemiology, multistage models and shorttorn mutagenicity tost*. Ia: Origins of Human Cancer (Eds. Hiatt HH, Watson JT>, Winston JA). Cold Spring Harbor laboratory pp. 1403*1430. The Society of the Plastics Industry, Inc (1975-1982). Faets and Figures of the U.S. Plasties Industry, Hew York. Sueiu 1, Prodsn SI, Faduraru A, Pascu L (1975). Clinical manifestations in vinyl chloride poisoning. Ann FT Acad Sei 246:53-69. U.S. Tariff Coamisslon (1948-1968). Polyvinyl chloride and eopolymer production data. Van Duuren B (1975). On the possible mechanism of carcino genic action of vinyl chloride. Ann NY Acad Sei 246:258-267. Vhittemore AS, Keller JB (1978). Quantitative theories of eareinogenesis. Society for Industrial and Applied Mathe matics Review 20:1-30. Wong 0 (1981). An epldemoilogic study of workers potenti ally exposed to brominated chemicals: with a discussion of multifactor adjustment. In: Quantification of Occupa tional Caneer (Eds. Peto R, Sehaeidexman M). Banbury Report 9 Cold Spring Harbor Laboratory pp. 359-378. C XJ oon u> 0rs0> Ip