Document N2ygon5LYEYr6qJkj0qzB6knV

JOSE?H . jisoxe h.sickxa>- CHASirs H. "IEHA.S WILLIAM H. BORGHESANI. JR. ROBERT RTIERXAN watt." Z v. 3U.CZ david l. kite. martin w. bercovici JOHN S. ZLDRED JOSEPH E. EMBLEZ. JR. CARO EE C. HARRIS MICHAEL Z. MORROKE IaSST s. SOLOMON JOSS B. OCBZCS CHRISTINE A. MEAGHER SHIRLEZ S. RCJLMOTO LAWRENCE ?. HAIPRIK DEBORAH SHOR TRTNEER C.BOCGLAS JARRETT EBWaRB L, KORWEE uw oeeices Kellsa^d Hscemjlv OSO IT'' STREET. N. w. SEITZ lOOO WASHING TOM. 0.C.20036 May 9, 1980 TELEPHONE 202 457-UOO CABLE aBDRESS"EZLMaN" writer's direct DIAL XUESIK (202) 457-1116 Docket Officer Docket E-034 Room S6212 U.S. Department of Labor 200 Constitution Avenue, N. W. Washington, D. C. 20210 Re: Docket E-034, Occupational Safety and Health Administration Request for Infor mation on Vinyl Chloride and Polyvinyl Chloride - 44 Fed. Reg. 74928, December 18, 1979; 45 Fed. Reg. 668, January 29, 1980. Dear Sir: Pursuant to Section 4 of the Administrative Procedure Act, as amended, 5 U.S.C. Section 553(c), and the above-refer enced U.S. Department of Labor - Occupational Safety and Health Administration (OSHA) Request for Information on Vinyl Chloride and polyvinyl Chloride and the subsequent Notice extending the time during which interested persons are invited to submit written data, views, and comments with regard to the issues described in the original Notice, The Society of the Plastics Industry, Inc. (hereinafter referred to as "SPI" and/or "The Society"), by its attorneys, hereby submits in quadruplicate certain information which is intended to be responsive to the Agency's Request. OCC 6370 T INTRODUCTION AND SUMMARY OF INFORMATION PRESENTED SPI is a corporation organized under the Not-forProfit Corporation law of the State of New York. Its 1500 member companies and individuals and 67 operating divisions include those who supply raw materials; process or manufac ture plastics or plastics products; engineer or construct molds or similar accessory equipment for the plastics indus try; and engage in the manufacture of machinery used to make plastics products and materials of all types. SPI is the major national trade association of the plastics industry. The majority of its members are the processors and converters of the plastics resins and end products which represent 75% of the dollar volume of sales of plastics in this country; SPI's membership also represents 95% of all plastics materials and machinery manufactured in the U.S.A. The Society's concern with vinyl chloride and poly vinyl chloride begins with the manufacture of the ethylene dicnloriae (used to manufacture the monomer) and the manufac ture of vinyl chloride monomer (VCM), carries forth through its polymerization into polyvinyl chloride (PVC), continues with the various processes which convert the PVC resin into its multitude of end uses, and includes, ultimately, the re cycling or disposal of PVC products. In the United States there are 17 ethylene dichloride plants, 13 plants which produce vinyl chloride monomer and 42 polymerization plants. OCC 6371 Twenty-two companies representing over 951 of the domestic VCM and PVC capacity are active members of SPI's PVC Safety Group* SPI's PVC Safety Group has prepared the information, data and views contained in what follows, and it is presented in a form which corresponds in large part to the explicit re quests for information contained in the Agency's Notice. In summary/ The Society's responses to the questions asked are as follows: 1. OSHA is aware of the studies on vinyl chloride sponsored by Imperial Chemicals Industries/ Limited; Montedison; Rhone-Poulenc Industries; and Solvay et Cie. in Dr. Maltoni's laboratory in Bologna, Italy. These most recent data of Maltoni indicate pos sible effects in rats exposed to 10 ppm of vinyl chloride but no increase in tumors was found in experimental rats exposed below 10 ppm. It is clearly evident that rodents are more suscepti ble than humans and that human experience should be given higher importance than animal studies. Animal data have predicted an angiosarcoma in cidence rate over 500 times higher than that observed in man. 2. It has been reported in the literature that VCM can exert a carcinogenic effect transplacentally 3 occ however, this phenomenon has only been demon strated in pregnant rats exposed to very high concentrations. Additional work in this area needs to be done using lower, more realistic doses since available data indicate that the rates of metabolism in the rat shift as exposure concentrations of vinyl chloride change. Vinyl chloride did not cause significant embryonal or fetal toxicity and was noc teratogenic in stud ies in rats, mice or rabbits. We know of no valid scientific paper associating vinyl chlor ide with human birth defects at any level of exposure. While no carcinogenic effect of inhaled PVC has been demonstrated in animals or man, recent data indicate that like most nuisance dusts slight effects may occur in the lungs following exposure to high concentrations of the dust. Although there are no new epidemiological data on health effects associated with vinyl chloride exposure which would appear to change the conclu sions from those considered in the current stan dard, The Society has contracted for a complete, independent analysis of all available, relevant epidemiologic data. This is particularly im portant since it is not always made clear in subsequent papers reviewing them chat many of OCC 6373 the studies which neve been reported represent repealed investigations of the same population or subsets thereof. Considering the magnitude of this project, it will not be finished by the May 9, 1980 deadline associated with the Request but these materials will be submitted to the Agency when they have been completed. 5. The Society is not aware of any new, unpublished case reports on cancer associated with vinyl chloride or polyvinyl chloride but is submitting to the Agency the most recent, world-wide com pilation of all liver angiosarcoma cases asso ciated with VCM. 6. It has been demonstrated that if mutagenic ef fects occur as monitored by chromosomal analysis of circulating lymphocytes, they were the re sults of high exposures; the changes have not been permanent since they have been reversible. The changes did not occur at lower levels of exposure. The clinical significance of the re versible changes is not known. 7. 3eing a poorly soluble gas, vinyl chloride does not accumulate from chronic exposure, but, rather, is rapidly exhaled after exposure ceases, Hence, there can be no body burden in the usual meaninc of the term. d - OCC 6374 3 and 9. An overview of ?VC manufacturing operations, types of resin, residual monomer levels, and PVC dust experience is presented with infor mation on monitoring results, control technology and personal protective devices. Variability in resin type and the resin type relationship to differing residual monomer content in the resin, varying VCM exposure potential from both resin and dust, and the type of PVC dust and other conditions which might be expected in both the polymerization and fabricating indus tries are explained. 10. SPI is unaware of any change in the types of occupations, jobs and industries which present a potential for exposure to VCM or PVC. The Society has no data on the numbers or break down by sex of employees exposed. 11. The VCM/PVC industry is engaging in the use of appropriate engineering controls, work prac tices and personal protective equipment and is trying to stay in compliance with the existing standard; the industry knows of no additional, feasible measures to reduce exposure below the present level. PVC dust is adequately regulated by OSHA's nuisance dust permissible exposure level (29 C.F.R. 51910.1000) and has not been shown to be hazardous at that level of exposure. OCC 6375 6 II. SPECIFIC INDUSTRY RESPONSES TO INFORMATION REQUESTED (1) Experimental Test Results for Carcin ogenicity of Vinyl Chloride At Atmos pheric Exposures Less Than 50 oom The current studies on vinyl chloride are those con ducted in Dr. Maltoni's laboratory in Bologna, Italy. As OSHA is aware, these investigations are sponsored by Imperial Chemicals Industries, Limited; Montedison; Rhone-Poulenc In dustries; and Solvay et Cie. These most recent data of Maltoni indicate probable effects in rats exposed to 10 ppm of vinyl chloride but no increase in tumors was found in experimental rats exposed be low 10 ppm. As to the mammary tumors Maltoni noted at lower levels, the data are not convincing because the experimental animals used are known to have a high incidence of spontane ous mammary tumors. As will be discussed below rodents are more susceptible than humans and human experience should be given higher importance than animal studies. Dr. Maltoni's data were reported in detail at a re cent OSHA/NIOSH/NIEHS sponsored Symposium, March 20 and 21, 1980 in Bethesda, Maryland. An unedited stenographic tran script of the entire Symposium and photographic copies of most of the slides are attached as Appendix A. In Maltoni's studies, rats, mice and/or hamsters were exposed to concentrations ranging from 30,000 ppm to OCC 6376 / 1 ppm. The attached summary statement by the European spon sors quotes Dr. Maltoni and indicates that extensive statis tical evaulations of Dr. Maltoni's data have been completed. Appendix B. In that summary, Dr. Maltoni summarized his animal studies as follows: ...the following tumours should be given proper attention viz, extra-hepatic angiosarcomas, hepa tomas, Zymbal gland carcinomas, liver angiosar comas, neuroblastomas, nephroblastomas, fore stomach papillomas and mammary carcinomas. In oncological terms, the meaning of the results at the lowest doses may be better evaluated by considering, not separately, but together, the tumours found to be VCM dependent. Thus the fol lowing results should be considered: - at 25 ppm - In 120 animals, 5 liver angiosarcomas, 4 Zymbal gland carcinomas and 1 nepnro-. blastoma. at 10 ppm - In 120 animals, 1 liver angiosarcoma, 2 extra-hepatic angiosarcomas and 2 Zymbal gland carcinomas. at lma/ka - In 150 animals, 3 liver angiosarcomas, 1 extra-hepatic angiosarcoma, 1 hepatoma and 5 Zymbal gland carcinomas.... These data add to that previously published by Dr. Maltoni since tumors occurred in rats exposed to 25 or 10 ppm of vinyl chloride gas. Maltoni's European sponsors state, In addition, it is worthwhile emphasising that none of the previously cited tumours have been observed at 5 ppm by inhalation and 0.03 mg/kg by ingestion. These data will be published as part of the proceed ings cf Club de Cancerocenese Chemicue held at the Curie OCC 6377 3 Foundation in Paris, France, November 10, 1979. These pro ceedings, which will be supplied to OSHA as soon as available, will contain an even more complete report of Maltoni's stud ies than was presented in 3ethesda on March 20, 1980. In regard to the response of laboratory animals to vinyl chloride gas, the attached paper by Gearing, Watanabe and Park is extremely pertinent. Appendix C. This paper indicates the necessity of considering the rate of metabolism and body size of different species when comparing the response of different species to vinyl chloride. Many factors, such as those considered by Gehring, Watanabe and Park, no doubt are involved in the wide differ ence between the high incidence of angiosarcoma in small ro dents and the much lower incidence in man. It is clearly evident that rodents are more suscepti ble than humans and that human experience should be given higher importance than animal studies. Dr. David Rail, Direc tor of NIEHS, has commented on the wide difference between the susceptibility of man and rodents. Appendicies D and E. He stated that in regard to angiosarcoma the available data ...project a cancer incidence rate 500 times higher than has so far been reported in man by epidemiological studies for vinyl chloride. (Rail, 1977, Appendix D, p. 2.) OCC 6378 9 (2) Studies of Transplacental Carcinogenic and Teratogenic Effects in Humans or Animals at Anv Level of Exposure to Vinvl Chloride It has been reported that VCM can exert a carcinogenic effect transplacentally--1/--2/ ; nowever, tne pnenomenon has only been demonstrated in pregnant rats exposed to very high (10,000 or 6,000 ppm) concentrations of the material. Additional work needs to be done using lower, realistic doses since available data indicate that rates of metabolism in rats shift as exposure concentrations of vinyl chloride chang and that some mechanisms of metabolism are saturable.--3/ Vinyl chloride did not cause significant embryonal or fetal toxicity and was not teratogenic in studies in rats, mice or rabbits--^ even at levels which resulted in maternal toxi city. We know of no valid scientific paper associating vinyl 1/ Maltoni, C., Vinyl Chloride Carcinogenecity: An Experi mental Model for Carcinogenesis Studies. In "Origins of Human Cancer. Book A: Incidence of Cancer in Humans. H.H, Hiatt, J.D. Watson and J.A. Winsten, Cold Spring Harbor, Cold Spring University, 1977. 2/ Maltoni, C., Carcinogenicity Bioassays of Vinyl Chloride Monomer: A Model of Risk Assessment on Experimental Basis. Symposium Paper No. 1 (1980). 3/ Watanabe, P.G. and Gehring, P.J., Dose Dependent Fate of Vinyl Chloride and Its Possible Relationship to Ocogenicity In Rats. Environmental Health Perspectives 17:145-152 (1976). 4/ John, J.A., Smith, F.A., Leong, B.K.J., and Schwetz, B.A. The Effects of Maternally Inhaled Vinyl Chloride on Em bryonal and Fetal Development in Mice, Rats, and Rabbits. Toxicol, and Appl. Pharmacol. 3_9:497-513 (1977). occ chloride with human birth defects at any level of exposure. 1. TRANSPLACENTAL CARCINOGENESIS Maltoni has reported that exposure of female rats to 10,000 and 6,000 ppm of vinyl chloride has resulted in transplacental effects in their offspring. No data have been found in which pregnant animals have been exposed to lower concentrations. Rice--5 / , although not having actually studied vinyl chloride in his laboratory, reviewed the sub ject of transplacental carcinogenesis. In discussing the above-mentioned work of Maltoni, Rice refers to the important role of biotransformation of VC to the probable carcinogenic metabolite. This metabolic transformation in the pregnant female, the possibility of a similar transformation in the fetus, the kinetics of placental transfer (which processes can be bidirectional), and the metabolic degradation in both the gravid female and the fetus all illustrate the complexity of transplacental carcinogenesis. Rice also rightly points out that in the case of VCM the probable carcinogenic metabolite has a relatively short half-life. This would limit the times for transfer across the placenta to the fetus and for distribution to the fetus. Although the data of Maltoni indicate that the metabolite either crosses the placental barrier or is formed in the fe tus in sufficient concentration to elicit a carcinogenic 5/ Rice, J., Transplacental Carcinogenic Effects. Sympo sium Paper No. 27 (1980). OCC 6380 response, the short half-life suggests that the effect would be minimized at lower levels of maternal exposure. Unfortu nately, sufficient data are lacking on much of the foregoing, and, therefore, definitive conclusions cannot be reached. Another complicating factor, even over and above those usually recognized in extrapolating from Maltoni1s transplacental carcinogenic data to rats to a possible hu man situation, is the knowledge that rats are far more sen sitive to VCM than humans. (See response to Request no. 1.) In addition, there are marked differences in placental struc ture between humans and rodents. The following discussion of the possible effects of these differences in placentation with regard to teratogenesis is equally germane to the consideration of transplacental car cinogenesis : ...Both man and the test animals commonly used pos sess chorioallantoic placentae, but that of man is the hemochorial one consisting essentially of fetal villi hanging in a pool of maternal blood. The chorioallantoic placenta of rodents and lagomorphs (rabbits) is the complex hemoendothelial type which consists of closely juxtaposed and highly modified fetal and maternal cells, permeated by a labyrinth of blood sinuses. An even more significant differ ence between the two types is that man has only the chorioallantoic placenta, whereas the rodents and the lagomorphs have a yolk-sac placenta as well. In man, once the chorioallantoic placenta has formed, most if not all, drugs reach the fetus by this route. In the rodents, often used as test animals, the pre sence of two types of placentae in the same animal means that the drugs might reach the embryo in two different ways, and it seems probable that in the earliest mosz vulnerable stage, the drugs that enter OCC 6381 the embryo do so predominantly via the yolk-sac placentae/.... The marked difference in the structure of the pla centa between rats and humans, the alteration in metabolism at lower dosages, and the recognized higher susceptibility of the rat to angiosarcoma must all be taken into account in interpreting Maltoni's results at extremely high concen trations. The highly idealized scheme (Figure 1) may serve to highlight some of the complexities of these factors. 2. TERATOGENIC EFFECTS The landmark study of the teratogenic potential of VCM remains the industry-supported study of three species by John et al., first reported in part at the 14th Annual Meeting of the Society of Toxicology in 1975. John and her co-workers subsequently published a detailed report of the work--1^, and again reiterated the findings at this most recent Symposium. The authors' published summary of this important study is as follows: ...Groups of pregnant CF-1 mice, Sprague-Dawley rats and New Zealand white rabbits were exposed to 500 ppm of vinyl chloride 7 hr. daily during the period of major organogenesis. Subsequently, other groups of mice were similarly exposed to 50 ppm of vinyl 6/ "The Testing of Chemicals for Carcinogenicity, Mutageni city and Teratogenicity," Minister of Health and Welfare, Canada, 1973. 7/ John, J.A., Smith, F.A., Leong, 3.K.J. and Schwetz, 3.A., The Effects of Maternally Inhaled Vinyl Chloride on Em bryonal and Fetal Development in Mice, Rats, and Rabbits. Toxicol, and Appl. Pharmacol. 3_9;497-513 (1977). OCC 6382 13 EXOGENOUS CHEMICAL \ PREGNANT FEMALE V LEGEND -------- CHEMICAL -------- TOXIC (CARCINOGENIC) METABOLITE ...........NON-TOXIC (NON-CARCINOGENIC) META30LITE FIGURE 1. HIGHLY CONCEPTUALIZED SCHEME OF THE PATHWAYS FROM MATERNAEXPOSURE TO A CHEMICAL TO THE EXPOSURE OF FETAL TARGET ORGANS. THE INFLUENCE OF THE PHYSICOCHEMICAL PROPERTIES OF THE SPECIFIC CHEMICAL. AS WELL AS MANY BIOLOGICAL CAPABILITIES OF THE ORGANISM, ON THESE PATHWAYS ARE NOT CONSIDERED IN THE DRAWING. OCC 6383 14 chloride and rats and rabbits were exposed to 2500 pom of vinyl chloride. While maternal toxicity was observed, vinvl choride alone did not cause signi ficant embrvonal or fetal toxicity and was not tera togenic in anv of the species at the concentrations tested. Maternal toxicity was more prominent among mice than among rats and rabbits. Simultaneous ex posure of some of the pregnant animals to vinyl chloride by inhalation plus 15 percent ethanol in the drinking water resulted in toxic effects greater than those associated with exposure to vinyl chloride alone in the three species. The maternal toxicity ' was enhanced to an extent greater than the embryotoxicity. (Emphasis added.) It should be noted that, to our knowledge, the con clusions reached by John ejt al. with regard to the terato genic potential of VCM have not been seriously questioned and, in fact, have been confirmed. Dr. John, in her presentation at the Symposium, dis cussed briefly the results of two additional studies of the teratogenic potential of VCM which have appeared in the re cent literature. The first was a report of work carried out in Hungary,--7 the findings of which were consistent with those reported by John et al. The second report, origina ting with the Institute of Hygiene and Occupational Health in Bulgaria, is still available only in abstract form. Al though sufficient detail is not presented in the abstract to permit a critical evaluation of the study, the report al leges a teratogenic response at much lower levels of VCM exposure than those shown to have no effect by either Ungvary 3/ Ungvary, G., The Teratogenic Effect of Vinyl Chloride. MUNKAVZDELEM (Work Safety) 25:29-33 (1979). occ" or John et a_l. A complete assessment of this Bulgarian study is essential before it can be given any credence. Dr. John also mentioned the Symposium presentation of Hehir--9 '/ . As far as can be determined from the transcrip tion of Dr. Hehir's talk, as well as what can be gleaned from a prepublication copy of the CRSC report--^, the study did not address teratogenesis. All Fq animals were exposed before mating but progeny were not. Thus, although effects on reproductive capacity or genetic changes in the germ cells (e.g., dominant lethal effects) could possibly be manifest, true teratogenic events dependent upon exposure of the fetus could not be revealed. It should be noted, however, that the Fq exposure did not result in any alterations in the various parameters monitored in the F^, F^, and genera tions . In summary, the most completely documented study of the teratogenic potential of VCM, viz., the study of John et al., reveals that under the high exposure conditions of that study inhalation of VCM by pregnant rats, mice or rab bits was neither embryo nor fetotoxic, nor was it teratogenic 9/ Hehir, R. , Cancer Induction Following Single and Multiple Exposures to a Constant Amount of Vinyl Chloride Monomer. Symposium Paper No. 5 (1980). 10/ Hehir, R.M., 3ierbower, G., Willigan, D.A., Kolaja, G., Marrs, G.E., Hinton, D.E., Dimmick, R.L. and Wiles, J.S., Toxicology, Carcinogeniity and Reproductive Effects of Single and Multiple Exposures to Vinyl Chloride in Rats and Mice. CPSC Preoublication Release, April 1, 1979 . OCC 6385 --O even at concentrations sufficient to cause maternal toxicity. While an additional published report basically confirms the latter conclusions, results available only in abstract form from the Bulgarian literature purport to reveal a teratogenic effect for VCM at lower levels. Although this latter infor mation is contradictory of the study by John and her coworkers, as well as that of the Hungarian study, its full significance must await evaluation of the complete report when it becomes available. Further, it should be noted that the maximum dose levels tested in the study of John et: al. , 2500 ppm in rats and rabbits and 500 ppm in mice, provide ample margin for safety extrapolation from these test species to the human situation. Finally, to our knowledge, there are no reports which clearly relate birth defects in humans to maternal, or for that matter, paternal exposure to VCM. Two relevant studies which have been published--indicate no relationship be tween population exposure to VCM in the area surrounding PVC formulation plants and birth defects. Infante et al.,--13/ 11/ Edmonds, L.D., Anderson, C.D., Flynt, J.W. Jr., and Heath, C.W. Jr., Congenital Cental Nervous System Mal formations, Kanawan County, West Virginia. U.S. Public Health Service, CDC, Atlanta, EPA-76-60-2 (1976). 12/ Edmonds, L.D., Falk, H. and Nissim, J.E., Congenital Malformations and Vinyl Chloride. Lancet iJ^lOSB (1975). 13/ Infante, P., Wagoner, J.K., McMichael, A.J., Waxweiler, R.J. and Falk, H., Genetic Risks of Vinyl Chloride. Lancet 11:734-35 (1976). OCC 6386 17 have suggested a causal relationship between paternal expo sure to VCM in the industrial setting and pregnancy outcome. The adequacy of the data supplied by Infante et al. was al- most immediately questioned--14/ . More recently, Haas and Schottenf elc--^ have leveled severe criticisms at the Infante study, and the following is extracted from their paper: ...Analysis of questionnaire responses suggested that the number of fetal deaths per 100 conceptions was higher in the VCM-exposed group than in the comparison group. This difference was reported only for the period following vinyl chloride exposure. Adjustments removing women who were chronic aborters eliminated statistically significant differences. While the authors felt that these observations were likely to reflect a real difference in pregnancy outcome not attributable to either interviewer or patient recall bias, the conclusions were based on indirect sources of information and could not take into account the multiplicity of maternal factors known to affect oreonancv outcome. The study design precluded documenting in even the crudest manner the validity of pregnancy histories. Without such adjustments and validation, the inferences made can not be sustained and little light is shed on the possible association of abnormal oreonancv outcome with paternal occupational exposure to VCM. (Em phasis added.) Likewise, others have raised serious doubts regarding the validity of the conclusions drawn by the authors of the Infante et al. study. For example, Downs et al.--'^ so com- 14/ Paddle, G.M., Genetic Risks of Vinyl Chloride Lancet 1:1079 (1976), Appendix F. 15/ Haas, J.F. and Scnottenfeld, D., Risks to the Offspring from Parental Occupational Exposures. J. Occup. Med. 21:607-13 (1979). Appendix G. 16/ Downs, T.D., Stallones, R.A. , Frankowski, P..F. and Labarthe, D.R., Vinyl Chloride, 3irth Defects, and Fe tal Wastage: A Critical Review. Private Communica tion. Appendix H. OCC 6387 13 _ pletely discredited the study that their ultimate conclusion was as follows: ...It does not seem possible to salvage anything from this study.... Among the more specific criticisms are the following: The authors cave no information on the distribution of workers' reported recall of time intervals since oreonancies. Such information would be useful in assessing the validity of this study, since it is well known that the reliability of recall of oast events decreases with time elapsed since the events. The authors' analytical methods are invalid since the ...test requires that the two rates being com pared be independent, and this is not the case.... ...The methods used bv the authors to test signifi cance are inappropriate since pregnancies are clus tered. ... ...The misleading conclusions drawn bv the authors were brought about through the selection and use of their control group. ...The purpose of adjusting rates is to make them comparable. Adjusting a rate r to a population A and another rate to a population B, and then com paring the adjusted rates r and s is contrary to the purpose of adjusting rates, and the resulting comparison does not make any sense. But this is precisely what the authors do when they adjust the prior exposed rate to the prior control group, then adjust the subsequent exposed rate to the subsequent control group, and then compare the adjusted rates. When adjusted rates are to be compared the rates should be adjusted to the same population. ...The comparisons of rates made bv the authors are irrelevant to the hypotheses tested by them and to rheir corresponding conclusions. (Emphasis added.) OCC 6388 IS - Similarly, McMahon--^ opens his review of the Infante paper with the following comment: ...It is disappointing to see an article of such poor quality as this published in the Lancet. The data are subject to serious criticism on several counts. and, after detailed point-by-point analysis of the study, presents the following conclusory statement: In short, this paper deserves ...no consideration whatsoever in weighing the question of whether there is or is not a genetic risk associated with exposure to VCM. (Emphasis added.) The foregoing reviews, two of which were available in 1977, completely rebut the scientific validity of the paper by Infante et al. in this matter. Absent a scienti fically sound defense of this paper by the authors or their scientific peers, continued citation of this paper is in appropriate . 17/ MacMahon, B. (Professor of Epidemiology, Harvard School of Public Health) Vinyl Chloride and Human Reproduction. Private Communication, 1977. Appendix I. OCC 6389 20 (3) Experimental Studies of Carcinogenicity and Other Toxic Manifestations For Any Level of Polyvinyl Chloride Exposure. These Effects Should Include, But Are Not Limited to, Mutagenicity, Teratogeni city, Embryo Toxicity, and Other Trans placental Effects As Well As Cytotoxic and Cvtogenic Effects on Sperm Cells. To the Greatest Extent Possible, Complete Information Concerning the Industrial Source of the Polyvinyl Chloride, the Size and Characteristics of the Particles, and Exposure Levels or Concentrations of PVC and Residual VC Should Be Included for Each Studv ___ While no carcinogenic or other toxic effect of inhaled PVC has been demonstrated in animals or man, recent data in dicate that, like most nuisance dusts, slight effects may occur in the lungs following high exposures to PVC dust.--18/ Two reports on PVC dust were presented during the 18/ The American Conference of Governmental Industrial Hy gienists in the preface to the 1979 List of Threshold Limit Values for Chemical Substances in the Work Air makes the following statement concerning nuisance par ticles : Nuisance particulates. In contrast to fibrogenic dusts which cause scar tissue to be formed in lungs when inhaled in excessive amounts, so-called "nuisance" dusts have a long history of little adverse effect on lungs and do not produce significant organ ic disease or toxic effect when exposures are kept under reasonable control. The nui sance dusts have been called (biologically) "inert" dusts, but the latter term is inappro priate to the extent that there is no dust which does not evoke some cellular response in the lung when inhaled in sufficient amount. However, the lung-tissue reaction caused by inhalation of nuisance dusts has the following characteristics: (1) The architecture of the air spaces remains intact. (2) Collagen (scar tissue) is not formed to a significant extent. (3) The tissue reaction is potentially reversi ble . OCC 6390 course of the Symposium, that is, the papers by Groth and Wacner. The paper fcv Frongia, et. al. , cited as reference no. 3 in the December 18, 1979 Notice, is one of many pub lications which deal with experimental exposure of test animals to vinyl chloride. In addition, SPI is aware of feeding studies conducted either with polyvinyl chloride resin, polyvinyl chloride copolymer resins, or low molecular weight fractions extracted from commercial PVC resins and/or copolymers. Two of these reports, one done at Harvard and one by Smith et al., are attached as Appendices J and K. Other reports are in the files of the Food and Drug Adminisration (FDA) and efforts are being made to obtain copies. As soon as they have been released to us, copies will be sent to the Docket Officer. With regard to the papers presented by both Groth and Wagner, the specific nature and particle sizes of the samples used are not completely clear. It is essential that when written versions of their papers become available for study, these deficiencies be eliminated. For the present, we can only assume that fine particles (dispersion resins) were used. As noted by Wagner, these may contain surfactants or other suspending agents. Hence, their use may result in effects which were misattributed. As stated by Dr. Wagner, he has not been able to reproduce the positive results of his early work despite repeated attempts. Nevertheless, taking the reports at face value, both studies appear to be consistent in demonstrating that exposure OCC 6391 zz - of experimental animals to respirable PVC dust results only in a low level of toxic response and in the retention of dust particles in the lungs with the development of macro phage aggregates, a normal clearance mechanism used by the lung. It is significant to note that these experimental exposures (at least in the work of Groth with monkeys) did not result in impairment of pulmonary function. Although both authors considered that the dust induced a low-level pneumoconiosis--in the exposed animals, their reports did not indicate the presence of fibrotic tissue which is ob served in acute pneumoconiosis resulting from exposure to other substances such as silica. The observations of Groth and Wagner appear to be quite consistent with the experimental work and observations reported by Frongia and his co-workers. Thus, it appears that in the experimental animals studied, exposure to re spirable PVC dust particles results in retention of such dust particles for long periods of time, perhaps for the entire lifetime, and the development of macrophagic responses to these particles. A major deficiency in all these studies is the ab- 19/ Pneumoconiosis, which literally means dust in the lung, can range from benign effects such as mere storage of particles in the lung to very severe effects such as fibrotic changes and death. It must be emphasized that as used in this response and by the speakers at the March 20-21 Symposium only lung storage and very minimal tis sue response were seen. Fibrotic changes were not ob served . occ 6392 sence of a control using another inert "nuisance" dust. Thus, the observations made as a result of exposure to PVC dust may be a characteristic response of many dusts rather than a phenomenon unique to PVC. As to the ingestion studies undertaken for the pur pose of assuring the safety of PVC packaging materials, feed ing either the whole resin or the low molecular weight (ex tractable) fractions showed no observed chronic effects up to the maximum quantities used, i_.e. in the range of 5%-10% of the animals' diets. In this connection, one other study should be mentioned, i-e., that conducted by CIVO/TNO in Holland, a copy of which is attached as Appendix L. It is mentioned here only because a porous PVC powder was incor porated into the animals' diets as the vehicle to carry vinyl chloride monomer in a feeding study intended to measure the carcinogenic response of rats to vinyl chloride monomer. In that study, while it was not one directed at PVC, there was no observed effect attributed to exposure to PVC. Summarizing, except for the feeding studies utili zing PVC and its copolymers, studies which showed no toxic effect attributable to PVC, and those studies discussed above, SPI is not aware of other experimental studies dealing with the toxicity of PVC. Perhaps comment should be made on the speculative remarks made at the 3ethesaa Symposium concerning the impact of PVC dust on occupational exposure to vinyl chloride. OCC 6393 The hypothesis is that the dust is carried into the lung and thereby distributed throughout the body . Even were the hypothesis correct, and we think it is not, the quantity of monomer currently contained in PVC is so small that it would make this speculative exposure of no practical significance. OCC 6394 (4) Epidemiologic Studies of Either Vinyl Chloride or of Polyvinyl Chloride (i.e., cohort, cross-sectional, or case-control) Because of the importance of this area of informa tion, The Society postponed preparing responsive commentary until the recent Conference to Reevaluate the Toxicity of Vinyl Chloride, Polyvinyl Chloride and Structural Analogs had been held. Prior to this Symposium it had been specu lated that, perhaps, some new epidemiologic data or infor mation might be presented concurrently with the industrysponsored presentation of Dr. W. Clark Cooper. This, of course, did not happen. In fact, it is The Society's view that nothing new in this area was presented at all. However, because of the Agency's interest in the subject area, SPI concluded that a detailed review of the existing epidemiology would be in order and appropriate for filing with this OSHA Docket in response to the request for this information. Accordingly, The Society has contracted for a complete, independent analysis of all the relevant epidemiologic data. Considering the magnitude of this pro ject, it is obvious that it will not be finished by the May 9, 1980 deadline associated with the Request; hence these materials will be submitted when completed. It should be pointed out that, as is apparent from papers presented at the Bethesda Symposium, a factor complicating the preparation of this analysis involves the fact that it is not always OCC 6395 made clear in subsequent papers reviewing them that many of the studies which have been reported represent repeated investigations of the same population or subsets thereof. OCC 6396 (5) Case Reports and Case Series of Brain, Lympho-hematopoietic, Lung, and Liver Cancers By Facility and Relevant Demo graphic Variables, Such As Age, Sex, Race, Date of Diagnosis, Date of Death, Date of First Exposure, and Length of Exposure For Either Vinyl Chloride or Polvvinvl Chloride At present, The Society is unaware of any informa tion responsive to request #5 which is not already contained in the published literature. However, since the papers prepared by Dr. John Staf ford of Imperial Chemical Industries, Ltd. were not consid ered appropriate for presentation at the above-referenced Symposium, it has occurred to SPI that the Agency might care now to have a copy of the most recent compilation of data on the world-wide incidence of angiosarcoma of the liver. Dr. Stafford's tables, copies of which have already been supplied (and, indeed, have been supplied on an ongoing ba sis) to the Director of the National Institute for Occupa tional Safety and Health, are a complete compilation of all liver angiosarcoma deaths due to exposure to vinyl chloride monomer through January, 1980. Appendix M. As can be seen from a review of these data, there have been only 42 cases of liver angiosarcoma reported in the last five years and a total of 84 cases reported to date. For background information on how Dr. Stafford came ro be interested in keeping a register of the liver angio sarcoma cases refer to the attached correspondence between Dr. Stafford and Dr. Robbins of NIOSH. Appendix. N. OCC 6397 23 (6) Mutagenicity Study Results of Vinyl Chloride or Polyvinyl Chloride As Measured By Analysis of Human Body Fluids, e.g., Direct Mutagenic Testing With Peripheral Blood Lymphocytes, NonDisjunction In Humans With YFF Sperm Test And In Vivo Cytogenetics It has been demonstrated that if mutagenic effects occur, as measured by circulating lymphocytes, they were the results of high exposures; the measured effects have not been permanent changes since they were reversible. The effects did not occur at lower levels of exposure. The clini cal significance is not known. The attached report by Hansteen, Hillestad, ThiisEvensen and Keldaas is extremely important. Appendix 0. The mean chromosome-breakage frequency, which was signifi cantly higher than controls when analyzed in 39 workers in 1974, was found on subsequent reexamination 2-2.5 years later to be no higher than the controls. Hence, whatever "effects" may have been measured or whether they were related to high exposure to vinyl chloride or not, the "effects" reverted to normal when exposures to vinyl chloride (and possibly other materials) were reduced. It is our understanding that similar results on a similar study are being prepared for publication by ICI in England and that they will supply a copy of the manuscript when it is available. Picciano et al. found no effect in a study of men producing vinyl chloride monomer and those workers probably had lower levels of exposure than those above. Appendix ?. 29 OCC 6398 hey summarized their data as follows: This report presents cytogenetic findings from a group of 209 workers employed for up to 28 years in the manufacture of vinyl chloride monomer at the Texas Division of Dow Chemical U.S.A. Cytogenetic evaluation results from this group were compared to results found in examination of individuals being considered for employment. Statistical analyses were performed on a group basis for chromatid aber rations, chromosome aberrations and proportion of abnormal cells; no statistical difference of significance was found between the two groups. Comparison of these results with reported studies suggests that the level of cytogenetic aberrations in vinyl chloride workers is pro bably related to the length and level of expo sure, and that risk of adverse genetic effect can be avoided in controlled, minimal-exposure environments. Fabricant attempted to summarize the mutagenic stud ies on vinyl chloride at the Symposium, This report merely reviewed the collected, previously-published information; nothing new was presented. The Fabricant report pointed out that in the U.S. genetic anomalies resulting in infant mortality increased from 5% in 1915 to 15% in 1965. She alleged that 33% of pediatric hospital admissions are due to genetic defects and that 80% of all clinical mental retardation in the U.S. arises from genetic causes. She speculates that these ob servations are cue to "an environmental component" creating birth defects. No mention is made of higher incidence as a result of the use of improved diagnostic tools or longer survivership of affected infants. This author also relied on the discredited paper OCC 6399 30 by infante e_t al. This publication (reference 12 in the December 18 Notice in the Federal Register) alleging repro ductive effects in wives as a result of mutagenic changes in husbands who were exposed to vinyl chloride has been dis credited because of faulty methodology. See Appendicies G, H, and I. The faulty nature of this study has been re peatedly called to OSHA's attention and, therefore, absent a sound scientific defense of this study by the authors or their scientific peers, Fabricant should not have cited it. 31 OCC 6400 (7) 3ody Burden Measurments of Vinyl Chloride In Humans The meaning of this specific request for information is not clear. Being a poorly soluble gas, vinyl chloride does not accumulate from chronic exposure but, rather, is rapidly exhaled after exposure ceases. Hence, there can be no body burden of vinyl chloride as the term is usually applied to the accumulation of heavy metals, large organic compounds or radio nuclides. Baretta, Stewart and Mutchler studied this subject and reported on "Monitoring Exposures to Vinyl Chloride Va por: Breath Analysis and Continuous Air Sampling." American Industrial Hygiene Association Journal, Vol. 30, NovemberDecember 1969. The data in this study clearly shows a rapid decay in the expired air in industrially exposed employees and laboratory subjects when exposure to VCM ceases. Published metabolic studies on laboratory animals--20'/ and human subjects also indicate rapid excretion of vinyl chloride in expired air. This, again, is consistent with the high volatility and low solubility of vinyl chloride gas. 20/ Watanabe, P.G., McGowan, G.R. and Gehrina, P.G,, Toxicol, ana Appii. Pharmacol. 36:339-352 (1976). OCC 6401 32 (8) For Operations Involving Polyvinyl Chloride, the Types of Resin in Use, the Concentration of Vinyl Chloride Trapped in the Resin, and the Concentration of VC and PVC Dust in the Atmosphere Where Indi viduals Are Working. This Information Should Include Estimates of the Particles Sizes and Concentrations of Particles That Fall Within the Resuirable Range and (9) In PVC Bagging and Milling Operations, Atmospheric Levels of PVC and VC, Moni toring Devices Used to Detect VC, and the Type of Respirator Protection Program for Individuals Working in These Operations. This Should Include the Sensitivity and Validity of the Analytic Techniques in Use Information supplied to answer the inquiries cited above is likely to create confusion if used out of context. Past regulatory effort on the part of OSHA has resulted in the promulgation of regulations that covered resins contain ing any amount of contained vinyl chloride and materials that contained little or no vinyl chloride monomer; therefore it appears necessary to call OSHA's attention to all aspects of the industry. Operations involving polyvinyl chloride are broken down into the following sections; 1. Manufacture of PVC 2. Distribution 3. Compounding 4. Fabrication into semi-finished materials 5. Conversion of semi-finished materials to finished products OCC 6402 33 The manufacture of synthetic resins (PVC) from vinyl chloride and other monomers involves reacting these monomers in agitated pressure vessels in the presence of catalyses in such a way that these liquids and/or gases are converted to solid resins. A considerable amount of heat is generated by the reaction. This is removed by cooling the vessel. As the monomer is converted to polymer during the reaction, the rate of reaction slows down. The unconverted monomers are removed from the reacting mass by heat and vacuum, and the resin (PVC) is recovered as a dried powder or as a latex or solution. The polymerization reaction may take place in pure monomer, in a solution, in a water-monomer emulsion or in a water-suspension of monomer. The nature of the poly merization process determines the nature of the subsequent recovery process and the nature of the resin particles pro duced. Currently there are four basic vinyl chloride poly merization techniques; 1. Suspension 2. Emulsion/Dispersion 3. Bulk 4. Solution Suspension polymerization is the major process used for the manufacture of PVC resins and is used for about 82- 85% of U.S. production. (Figure 1). It involves the char ging of one or two parts water and one part vinyl chloride OCC 6403 VC MONOMER Vf AT fill SUSPENDING AID INITIATOR l uui I WATER SUSPENSION POLYMERIZATION PROCESS PI CURE 1 OCC 6404 monomer or co-monomer mixture to an agitated reactor along with initiator and suspending agents. The mass is reacted at 50 to 65C until about 85-90% of the monomer is converted zo resin. The resin-water mixture is then heated, sometimes under vacuum, until the unconverted monomer is substantially removed. The resin is then removed from the water and dried in rotary, flash or fluid bed dryers by exposure to heated air. The dried resin is transferred to storage silos prior to shipment in bulk containers or in paper bags. If only vinyl chloride monomer is reacted, the product is homopoly mer PVC. If a monomer such as vinyl acetate is mixed with the vinyl chloride, then a co-polymer PVC is produced. Resin products of the suspension resin process are many and varied in terms of molecular weight, composition, particle size, monomer retention, heat stability and ultimate use. A general description of the various grades of resins follows: (a) General purpose homopolymer for flexible mate rials such as shower curtains and wire insula tion are porous, large particle (~100 microns or more diameter) size, high molecular weight resins with good heat stability and low monomer retention characteristics. These resins contain essentially no particles less than 10 microns in diameter and the residual monomer content is in the range of non-aetectable (N.D.) to 25 ppmw.21/ Particle porosity is a critical property. 21/ Particles 10 microns or larger in diameter are considered non-respirable. _ "3 O - OCC 6405 (b) Homopolymer resins for pipe manufacture are dense, large particle size ("100 microns in diameter), high molecular weight resins with good heat stability. Monomer retention char acteristics are medium to low. , These resins contain essentially no particles less than 10 microns in diameter and residual monomer content is in the range of N.D. to 30 ppmw. Generally the lower the molecular weight the higher the monomer retention. Particle density is a cri tical property. (c) Homopolymer resins for rigid extruder shapes and calendered rigid sheeting are dense, medium particle size (~80 microns in diameter), medium molecular weight resins with reasonable heat stability and medium monomer retention charac teristics, These resins contain essentially no particles less than 10 microns in diameter and the residual monomer content ranges from N.D. to 50 ppmw. Particle density is desirable and porous particles are difficult to produce. (d) General purpose copolymer resins for rigid sheet ing, molding and flooring are medium particle size ("80 microns in diameter), glassy to low porosity, low to medium molecular weight, and high in monomer retention with poor heat sta bility. Comonomer content ranges up to 20%. The monomers most often used are vinyl acetate and vinylidene chloride. These resins contain essentially no particles less than 10 microns in diameter and residual monomer in the range of 100 to 300 ppmw. The poor heat stability coupled with the glassy particles make vinyl chloride monomer removal difficult. Copolymer resins offer ease of fabrication and have the ability to take up high loadings of fillers and pigments. (e) Copolymer resins for coating applications are low molecular weight, medium particle size ("75 microns in diameter), glassy non-porous par ticles, poor in heat stability and high in monomer retention. Co-monomer content ranges up to 40%. These resins contain few particles less than 10 microns and residual vinyl chloride monomer contents of 25 to 100 ppmw. OCC 6406 37 (f) Plastisol additive resins for dispersion resin fabrication are medium molecular weight, small particle size (~25 microns in diameter), low in particle porosity, and medium in heat sta bility materials. The addition of these re sins to a dispersion resin plastisol reduces the plastisol viscosity and reduces the pro duct cost. The ability to perform uniformly in a plastisol is critical. These resins con tain appreciable quantities of particles smaller than 10 microns in diameter and contain N.D. to 25 ppmw of residual vinyl chloride monomer. Suspension process plants are generally meeting the permissible personal exposure limit of 1 o" o* mv TWAO_ im.Dosed by the OSHA Standard but are having difficulty meeting the 5 ppmv ceiling value without the use of respirators. Cer tain tasks, such as maintenance, cleaning and correcting process upsets, involve personnel exposure to brief periods of high vinyl chloride concentrations. These personnel are protected by continuus air-supplied respirators. Elimination of all use of respirators cannot be considered a realistic requirement. Suspension PVC, except for plastisol additive resins, presents no hazard from exposure to respirable dusts since these resins contain essentially no particles less than 10 microns in diameter. Indeed, except for the plastisol ad ditive resins, the use of cyclone collectors on resin dryers and resin transfer systems obviates the presence of such particles in suspension resins, i_.. , such particles are lost in the dryer exhaust. OCC 6407 38 Emulsion /dispersion oolvmer ization is the second most widely used process for zhe manufacture of PVC resins and amounts to 10-12% of total U.S. production. One of the important things to understand about emulsion polymerization is that it is not a single process but a family of processes, each producing specialized products that are defined or speci fied in terms of performance in a particular application. In the interest of brevity only the two major process families, the water soluble initiator system and the oil-soluble ini tiator system, will be discussed. (Figure 2). In the water soluble initiator system one to two parts water, one part monomer, 0.01 to 0.03 parts surfactant and water-soluble initiator (a redox system or a persulfate salt) are charged or fed to an agitated reactor and reacted at 30 to 60C to form a latex emulsion. The reactor agita tion must be sufficiently vigorous to emulsify the monomerwater mixture but not so vigorous that the latex is desta bilized. When 80 to 95% of the monomer is converted to poly mer the latex may be gently stripped of the unconverted mono mer with heat and vaccum or it may be subjected to a second initiator treatment and reacted to essentially 100% monomer conversion. The product of this polymerization may be simply filtered and shipped to consumers as a latex for use in the manufacture of coatings, mastics, laminations, and the like, or the polymer may be recovered as a dry resin. Recovery techniques vary. The most commonly used is to spray-dry "4I -1L Ku) EMULSION POLYMERIZATION PROCESS I IGURE t') OCC 64U the latex, though some resins are recovered by coagulating the latex and dewatering with subsequent drying of the coagulum (resin). In the oil soluble initiator svstem one part monomer containing an organic peroxide is emulsified in one to two parts water containing 0.01 to 0.03 parts surfactant. The . resulting emulsion is reacted at 30 to 60C to form a latex. From this point onward the oil soluble initiator system is similar to the water soluble initiator system. The choice of process depends to a great extent on the ultimate use of the resin. If resin particle size is critical the oil soluble initiator system is preferred. The resin particles formed during emulsion polymerization range in size from 0.05 to 2 microns. In the course of re covery and drying these may be agglomerated to particles as large as 30 microns. For some uses the agglomerates may be ground to a median particle size of about two microns. The small particle size results in rapid loss of residual vinyl chloride so that the resin contains only about 1 ppm free monomer. Because of handling problems nearly all the resin is bagged. In this process, the small amount of mono mer retained easily escapes before the resin arrives at a fabricating plant. Some proprietary dispersion resins, how ever, have material handling properties comparable to larger particle size suspension resins. These can be shipped, stored, conveyed and processed in bulk instead of in bags. 43 Resin products of the emulsion process are more difficult to list because most products are sold on a performance ba sis as opposed to suspension products which are sold largely on specification and price. A rough classification is as (a) Plastisol resins are the major emulsion pro cess products. These are very small particle size (2 to 3 micron diameter), non-porous, very high molecular weight, 100% vinyl chloride re sins with good heat stability and low monomer retention characteristics. These resins consist of particles less than 10 microns in diameter, contain significant amounts of surfactants and about 1 ppmw of residual vinyl chloride mono mer. When stirred into approximately 60 parts of plasticizer per hundred parts resin, these resins yield a viscous liquid plastisol which, when baked, fuses to a flexible vinyl plastic. (b) Foam resins are substantially the same as the plastisol resins except that they are medium molecular weight instead of high. The lower molecular weight yields a plastisol which fuses near the temperature at which a blowing agent yields up its gas. This is how a stable plastic foam is formed. (c) Organosol resins are a special variety of plasti sol resin primarily used for metal coating. If a high molecular weight PVC homopolymer dis persion resin is very finely ground and the remaining agglomerates are loosely bound together, it can be blended further with ketone, naphtha, pigments, stabilizers and adhesion promoters to yield a liquid coating material. This or ganosol is coated on metal and baked to provide a tough, abrasion resistant coating. (a) Specialty resins are an assortment of materials that make use of the flexibility of the emulsion process for their manufacture. These are made from vinyl chloride in combination with other monomers. The resins are recovered from the latex by coagulation and subsequent drying. Uses of these materials range from film for food packaging to modifiers for other resin fabrication. Further characterization of these OCC 6413 4-4 materials is not possible, and they are men tioned here only to call attention to the fact that these important resins are impacted by vinyl chloride and polyvinyl chloride regula tions . (e) Latexes, too, are an assortment of materials generated by the flexibiltv of the emulsion process. These are liquid materials containing 40 to 50% resin solids emulsified in water. Latexes containing resin solids high in vinyl chloride content are usually formulated with plasticizers and solvents and applied to a sub strate. The substrate is heated or baked to yield a resin film. Latexes containing resin solids low in vinyl chloride content will yield a resin film when the latex coating is simply air dried. These latexes find major use in latex paints, impregnants, mastics and adhe sives. Since both types of latexes are used as liquids, there is obviously no possibility of PVC dusts. Depending on the latex produced, most PVC latexes contain less than 10 ppmw of residual vinyl chloride monomer. This monomer is released slowly, and employee exposures in subsequent formulating and use is rarely over 0.5 ppmv. As is the case with suspension PVC process plants, emulsion process PVC plants are generally meeting the OSHA permissible exposure limit of 1 ppmv TWAg for employees. However, these plants, too, are experiencing difficulty meeting the ceiling limit without reasonable use of respira tors. The manufacture of dispersion PVC resins represents a source of respirable PVC dusts, and dust respirator use is usually required in dusty locations such as bagging. Certain proprietary dispersion resins do, however, have low dusting properties which greatly simplify control of the workplace dust normally associated with handling dispersion resins. occ 46 47 OCC 6416 Bulk polymerization is the third major process in terms of volume for the manufacture of ?VC resins but ac counts for only about 5% of CJ.S. production. (Figure 3). The process involves the charging of vinyl chloride mono mer and initiator to a first stage polymerizer where about 10% of the monomer is converted to polymer. This batch is ' then transferred to a second stage polymerizer where addi tional monomer and sometimes initiator are added. The poly merization is continued until about 80-85% of the monomer is converted to polymer. The unreacted vinyl chloride is removed by heat and vacuum and the finished resin product transferred to storage bins for later shipment to fabricating plants. The absence of water in the polymerization stage eliminates the need for the drying step. The advantages of the bulk process are its simpli city, the uniformity of the resin particle size, the high porosity of the resin particles, the purity of the polymer (no soaps or suspending aids) and the granular, low dustiness of the product. The disadvantages are less flexibility in product mix (homopolymers only) than the suspension process and poorer removal of residual monomer. These bulk process resins are competitive with suspension process PVC homopoly mers. Bulk process PVC resins are used in applications where clarity of the finished plastic, uniform resin particle size and high resin particle porosity are desired. A sim ple classificarion of zheir uses is as follows: 48 OCC 6417 o c c 6418 BULK POLYMERIZATION PROCESS FIGURE 3 (a) Rigid and flexible plastic materials produced by extrusion and calendering requires resins with large porous parcicles (100 microns in diameter), good heat stability and low monomer retention. These medium molecular weight homo polymer resins contain essentially no particles less than 10 microns and the residual VC mono mer concent is less than 50 ppmw. (b) Rigid plastic moldings, plastisol additive re sins and powder coatings are made from low mole cular weight homopolymers with a particle size of 75 microns. Particle porosity is good and monomer retention is low. There are few par ticles less than 10 microns in diameter and residual vinyl chloride content is less than 5 0 ppmw. Bulk process plants have the same general types of personnel exposures to vinyl chloride noted for suspension process plants. Solution polymerization is a process unique to one company and accounts for about two percent of the total resin produced. (Figure 4). Vinyl chloride monomer, co-monomer, solvent and initiator are fed to a continuous reactor system. The polymer formed is soluble in the reacting mass so that the reactor product is a viscous resin solution. This solu tion is distilled to remove the unconverted monomers and the resin is recovered by treating the resin solution with water and drying the product. The resin particle is very porous, is always a copolymer, is free of soaps and suspend ing agents, has a median particle size of 75 microns and contains less than 0.2 ppm residual vinyl chloride. Solution process PVC resins are very often confused with suspension process resins for solution application. Molecular weight OCC 6419 50 F K111U R A SOLVENT VINYL RESIN PROCESS WATER VENT i Ul OCC 6420 WASTE WATER of these resins ranges from low to very low to achieve solu bility in solvents. Essentially all these materials are used for coatings in combination with other resinous mate rials . The solution ?VC resin process, because of its na ture, exposes personnel to vinyl chloride concentrations below 0.5 ?pm. The resin contains essentially no particles less than 10 microns in diameter. In addition to the resins produced by the four basic processes there are resins which are chemically modified in a second operation after the resin has been produced. The major product in this area is chlorinated PVC. In the coatings area copolymer resins are often modified through reactive sites in the co-monomer. These materials are men tioned only to note their existence and to point out that the very nature of chemical modification and subsequent pro cessing removes all possibility of their release of vinyl chloride in subsequent applications. Distribution of PVC resins poses some potential for personnel exposure to vinyl chloride monomer and to polyvinyl chloride. The structure and the economics of the distribu tion system have acted to cause such exposures to be minimal except for certain special situations. Suspension and bulk process PVC resins, except for plastisol addition powder coating, solution coating and ex OCC 6421 52 - port sales move from the producing plant to the user via bulk carriers such as rail cars (containing approximately 150.000 pounds) or hopper trucks (containing approximately 35.000 pounds). These carriers are loaded via gravity from overhead bins or by pneumatic conveyor. The carrier is sealed during transit. On arrival at the delivery site, the carrier is unloaded by pneumatic conveyor to a storage silo. There is some vinyl chloride monomer emitted during the loading and unloading process, but personnel exposure is well below the OSHA Standard "action level". Monitoring of this operation when the resin contained 800 ppmw of resi dual vinyl chloride monomer showed personnel VCM exposures of approximately 1 ppmv TWAg. Although there is no recent data, with current residual VCM levels of approximately 50 ppm, one would expect personnel exposures to be down around 0.1 ppm TWAg. There is some resin dusting and spillage in the loading and unloading process, but the relatively large particle sizes and remote contact by personnel obviate any potential hazard. The bagging of the 5 to 10% of suspension and bulk process resins that are handled in this fashion is highly automated and messy, but personnel exposure to dusts or VCM are negligible. Resin is delivered to the packaging machine via gravity or pneumatic conveyor. The packaging machine operator inserts the filling tube into a filling valve-type kraft paper bag and actuates the machine to fill the bag. The filled bag drops off the filling tube to a conveyor and 53 the operator repeats the operation with another hag. Filled bags are automatically or manually stacked on pallets which may be shored in a warehouse awaiting shipment or may be loaded on a truck or railcar immediately. When the filled bag drops off the packing machine a small puff of resin and air is emitted from the bag valve as it closes. Subsequent handling of the bag causes some shifting of resin out of the valve. There are also faulty bags which may break on filling. Thus, the resin bagging area is usually messy. However, monitoring conducted in these areas indicates personnel vinyl chloride exposures are less than the OSHA Standard "action level," Dust measure ments for suspension and bulk resin bagging show less than 3 1 mg/m respirable dust. Bagging and storage of suspension and bulk process resins causes a significant reduction in the residual vinyl chloride content of the resin. Tests of moderately porous medium molecular weight resins show a reduction of over 50% in free monomer after one week. Handling and transport of suspension and bulk PVC resin in bags via truck or rail car appears to present no unusual hazards if normal work space ventilation standards are met in storage, loading and un loading resins. Except for some special situations where bulk trans port or fiber drums are used, essentially all emulsion pro cess PVC resins are packaged in kraft paper multi-wall bags. The bagging operation is essentially the same as that ce- - 54 - OCC 6423 scribed for suspension and bulk process resins. Vinyl chlor ide exposure is less than zhe OSKA Standard "action level." The NIOSH study by Mr. J.H. Jones in 1974 indicated that exposure is not likely unless it comes from emissions in adjacent operations.--22/ Dust exposure is potentially a problem due to the resin's small particle size but local ventilation can control this readily. Current dust monitor3 ing shows respirable dust less than 5 mg/m . The storage and truck shipment of emulsion PVC resins offer minimal vinyl chloride exposure opportunities for per sonnel. Warehouse and closed truck vinyl chloride monitoring show levels well below 0.5 ppmv vinyl chloride in the air. Solution process PVC resins are also packaged pri marily in kraft paper multi-wall bags. Bagging is essen tially the same as described for suspension resins. The NIOSH study in 1974 indicated vinyl chloride exposure to baggers of N.D. to 0.7 ppmv and total dust of less than 2 mg/m3. Vinyl chloride exposure currently is about 0.1 ppmv with no change in total dust exposure. is about 0.1 mg/m^. Respirable dust Monitoring o JC. storage and truck shipment of solution process PVC resins usually shows undetectable amounts of 22/ Jones, J.H., Worker Exposure to Vinyl Chloride During Production and Fabrication of Vinyl Chloride and Poly vinyl Chloride. Study conducted with the Benaix Cor poration under NIOSH Contract CDC-99-74-50. Draft of rhis Report is at Appendix Q. See p. 36. vinyl chloride monomer. Polyvinyl chloride latexes are most often handled and shipped in tank cars or trucks and in fifty-five gallon drums. There is some emission of vinyl chloride during loading and unloading operations but, if the latex contains 10 ppmw residual vinyl chloride or less, the personnel ex posures are less than 0.5 ppmv. Dust is not a problem with latex shipments. Compounding a PVC resin or latex means the mixing of that material with pigments, stabilizers, plasticizers, fillers and other additives to yield an intermediate material for subsequent conversion into finished or semi-finished products. In major plastics operations this is simply a single process step in a large integrated factory, but in the specialty resin area, as well as with small plant opera tions, a compound is produced by one plant and is subsequent ly shipped in a container to the user. Thus, in terms of regulation, these materials are classified as polyvinyl chlor ide. Often, however, the properties of the material are completely dissimilar to the PVC resin raw material, i_.e. , the vinyl chloride monomer content is diluted or reduced by heating and dustiness is reduced sharply or eliminated completely. Some examples are pelletized PVC compounds, powder blends, organosols, plastisols, lacquers, dry blends, and latex paints. The purpose of compounding is to combine the resin anc additives into a homogeneous state suitable for further OCC 6425 3D processing. The level of compounding ingredients employed for PVC is substantially higher than for mosz plastics. Resin content of a compound may vary from 99% for rigid sheet ing to 15% for floor tile. Some compounding ingredients introduced in PVC fabrication are as follows: (a) Plasticizers are high boiling temperature esters of phtnalic acid, adipic acid, azelaic acid, phosphoric acid and so on. Epoxidized oils, epoxy resins, and polyester resins are also used. (b) Heat stabilizers are compounds of lead, barium, cadmium, tin and zinc. Epoxies and phosphites are also used. (c) Fillers consist of clay, talc, mica, asbestos, calcium carbonate, titanium dioxide, diatomaceous earth and barytes. (d) Pigments may be inorganic compounds, such as titanium dioxide, chromium oxide, ultramarine blue or molybdate orange, or they may be organic compounds, such as phthalocyanine, quinacridone and benzidine salts. (e) Modifying resins improve processing character istics and impact resistance. These are acry late, ABS, and chlorinated polyethylene resins. (f) Lubricants make subsequent processing easier. Some of these are waxes, stearic acid and metal stearates. (g) Light stabilizers provide ultra-violet light resistance. Examples are benzotriazoles or benzophenones. (h) Fungicides give resistance to fungal attack. Materials commonly used are amines, arsenates and organotins. (i) Flame retardants, such as antimony oxide and the boranes, are used where plasticizer con tent is high. 57 (j) Anti-static agents reduce dust and dust pickup. These are often amine compounds. (k) 3righteners yield a whiter, clearer film. (l) Anti-oxicants, such as bispnenol A, are some times used. Additionally, particularly in the coatings area, there are specialized additives such as surfactants, pig ment wetting aids, solvents, and diluents. These compounding ingredients and additives are men tioned in some detail to show the difficulty of isolating causative agents if an employee health problem is believed to exist in the PVC fabricating area. It is certainly a mistake to attribute dust problems solely to PVC dust and toxic vapor problems solely to vinyl chloride monomer. Compounding PVC resins for subsequent fabricating via calendering, extrusion or molding involves two basic steps; dry or powder blending followed by melt compounding. The choice of equipment is important because variations in the homogeneity of the resin compound may cause serious de ficiencies in processing and in the finished product. The calendering, extrusion and molding operations involve large scale operations with suspension and bulk process PVC resins which are almost always handled in bulk. Resin is charged from a bulk silo to a weigh hopper and dumped into the mixer. Plasticizers are metered into the charge. Other additives are charged by similar techniques though small volume addi tives may be first mixed into a portion of the plasticizer. occ 6427 53 also appear as part of the total dust measurement, (See attached Tables 30 and 32 from the KIOSK report along with flow sheets for calendering, pipe extrusion and flexible film extrusion). Plastisol techniques for compounding and fabricating PVC involve the use of dispersion process ?VC resins along with plastisol additive resins from the suspension and bulk PVC processes. The principal advantages to this fabrication technique are low investment in fabricating equipment and flexibility in changing from one product to another. A basic plastisol might consist of 100 parts dispersion process PVC resin, 55 parts dioctyl phthalate plasticizer, 5 parts epoxy plasticizer and 3 parts barium, cadium, or zinc liquid sta bilizer. Heating the plastisol to 350-375? fuses it into a flexible homogeneous plastic. In practice, however, the only time this simple formulation is used is to test resins. Additive resins are used to reduce cost, to alter the plasti sol viscosity and to increase the hardness. Reactive resins, such as epoxies and acrylates, are added for hardness. Pig ments are added for color and opacity. Anti-foamers reduce foaming during deaeration and fusion. Plastisol preparation is carried out in a slow speed, unheated mixing vessel. Plasticizer is weighed or metered into the vat and followed by the requisite number of bags of various resins, fillers and so forth. When the mixture is homogeneous, it is either transferred to a deaerator or occ 6428 51 -rrr'-v' ZZzLzzr~C.t Zr^SZ Kfj- llsnoar n n * it ? K&ir yjLrar If 5e.ir r -- e.-.eg.- M -- '-' 7 .12 v.0! 5.7; 11.67 iD.O 6.06 11.67 6.23 OCC 6429 62 The mixer is closed and heat is applied externally or gener ated by the shear action of the mixer itself. The charge is subjected to mixing and heat (approximately 2QQ-250F) for some predetermined time or until the mass is a dry pow der. Gases from the charge are vented outside the work area. On completion of the dry or powder blending, the mix may be cooled and stored for subsequent use or charged directly to a high intensity mixer or to an extruder. The mixers and/or the extruder melt the dry or powder compound blend to secure a hot plastic mass. For calendering, the mixer or extruder charge is transferred to the calender where it is formed into flexible film or into rigid sheets as semi-finished products. For extruded products, the ex truder may simply be fitted with a die, as in the manufacture of pipe, to form the finished product. The industrial hygiene survey carried out by NIOSH in 1974 and 1975 indicated that vinyl chloride monomer exposures for this type of operation in the range of N.D. to 0.6 ppm. (See attached Table 33 from the NIOSH report). With the current low levels of re sidual vinyl chloride monomer in suspension and bulk process PVC resins, vinyl chloride monomer exposure is negligible. Dust is a problem in calendering, molding and extrusion processing but as Mr. Jones points out in his NIOSH report the dust is probably not all PVC since fillers and other additives are used. Mr. Jones does not mention, how ever, that plasticizer aerosols formed during processing 59 l* oo' 1 Chic ride Sanolirg La zz. zy jo: -4li Tabrk.nation Plants Sa--pled Calender Perscmrel ?_r?_ qt^ o pft^s _T_ 2S 7B Irrrusi" ?trsrr:tl 58 Lab Parsc-r-rie'1, IS Maintenance Personnel . 10 Molding Personnel 16 Plastisci Lirpirg Personnel AO Miscellaneous Personnel 20 Total of Personal Sara: las 268 Composite of All Area Sarnies 32 *** X C?p=) 0.57 0.11 0.09 0.08 0.01 _ <0.01 0.01 <0.01 0.14 0.04 (?^> 0.24 0.05 0.04 0.05 <0.01 <0.01 <0.01 <0.01 0.03 0.05 Tange (??=) KC-2.44 KD-0.69 10-0.7 6 ND--0, 68 KO--0.02 Xt>-0.03 K>-0.O6 10-0.01 NT-2.44 --0.6S * x - TVA - 60 - OCC 6431 ** -- --* 1! i! 11 0 \ Z^z le 1Z T" V S Header Are^s v~ "'' Arta Isnb-irr Zz-xzz Are* Calender Art* Tliszisci Hzzzzzig ?r>m r_j gr 7lAz line >os: "irlr1-" 6.67 1.67 6.67 ..13.33 6.67 7-9 7.37 - 63 - OCC 6432 Vcfil to Dm! Collector Mdilcar a\ a*. FIGURE IV-11 TYPICAL CALENDERING OPERATION OCC 6433 Dirocl VenJ FIGUltli IV-fl FI.EXIHLE PVC FILM EXTRUSION WITH IN-PLANT COMPOUNDING OCC 6434 t CTl t FIGURE IV-9 TYPICAL PVC PIPE EXTRUSION OPERATION OCC 6435 Viiiii o> FIGURE IV-12 SOLVENT CAST PVC FILM PRODUCTION o c c 6436 the mixing vessel may be closed and a vacuum applied to remove entrained air carried in by the solid components. After deaeration the plastisol is ready for fabrication. It may be coated on a release paper, on a metal substrate or on a fabric. These items pass into an oven where the plastisol is fused to yield a plastic film which may be stripped from the release paper or a coated metal sheet or fabric. The plastisol may be poured into metal molds which are subsequently heated. This fuses the plastic for later removal from the mold. To produce foamed plastic, the plas tisol may be mechanically frothed or a blowing agent such as an aside can be added. The blowing agent releases gas during the fusion step and the result is a sponge-like plas tic . Plastisol fabrication is likely to be less sophis ticated, involve smaller plants and be more labor intensive than conventional PVC fabrication. In such operations, the potential for exposure to PVC dust and vinyl chloride monomer is usually greater. Dispersion PVC and PVC plastisol addi tive resins are low in residual monomer content when manufac tured and are usually shipped and used in paper bags after a considerable time lag for analysis and warehousing. Ac cordingly, vinyl chloride monomer exposure in this type of operation is minimal. The attached table from the NIOSH survey in 1974-1975 could be said to be representative of the VCM exposures in plastisol operations. -os -- OCC 6437 Exposure to dust may be considerable in these opera tions due to the small particle size of dispersion and ad ditive ?VC resins as well as the small particle size of the fillers and pigments. During the fusion step plastisols also give off plasticizer aerosols which appear as a part of total dust. Because dust control is largely an individual matter for each installation to resolve based on plant con figuration and the like, no generalized statement can be made for the industry except to point out that the dust is not wholly PVC. Organosols are a specialized version of a plastisol. Ketones, esters and hydrocarbons are added to the plastisol to yield a low viscosity liquid composition which is sprayed, roller-coated or brushed onto a substrate. The resulting coated substrate is baked to drive off the diluents and fuse the coating. Solution coating is a small, specialized area of PVC resin fabrication. PVC resins dissolved in organic sol vents and applied to a suitably prepared substrate yield coatings with excellent resistance to water, alkalis, acids and weather. The resins used are copolymers produced by solution polymerization or by special suspension resin pro cesses. These resins must be exceptionally free of electro lytes and insoluble materials. The resin typically is dis solved in a mixture of toluene, methyl ethyl ketone and methyl isobutyl ketone. Pigments and stabilizer are added - oyQ _ OCC 6438 <------cf "Ir-l C;_lcri.de 5.?--p' * -; Oc: Job L-S.S ? e.rsg--icl Plis^iLsol .lipp --g ?arscx3tl ?D~al s: Paxsanal Samples Crrr^site o; All Araa Sa=ples 4r* AC Lu U OA O *-* dh c?--) XD 0.01 KD (??=) XD 0.01 <0.01 XD (=--> KD KI--0.06 ID-C. 06 ID * x " 7VA OCC 6439 70 and the mixture "ground" in a colloid mill or similar device. The resulting coating is sprayed on the substrate and either oven or air-dried. Each coating is formulated for perfor mance in certain areas and coating formulations are closely guarded by individual formulators. Formulation of coatings is a small scale operation . generally dealing with resins in paper bags and solvents in bulk. There is little or no exposure to residual vinyl chloride monomer from most solution resins since VCM is vir tually non-detectable in the resin. Dust exposure from re sin and pigments is low because only small volumes are handled. Most formulators have fume control systems for control of solvent vapors and these also remove dusts from the work area. Monitoring for vinyl chloride monomer at coating for mulators generally shows non-detectable to 0.05 ppmv. Solvent cast PVC film is a small fabrication opera tion which is based on solution coating with solvent recovery. Higher molecular weight resins are often used to achieve higher film strength. A high solids vinyl resin solution is cast on a stainless steel belt. Heat drives off the solvent until a very thin transparent film can be stripped off and dried further on heated rolls. The solvent is col lected and reused. More expensive solvents, such as tetrahyarofuran, are often used to reduce solution viscosity. Exposures to dust and vinyl chloride monomer are similar to that of a coating formulator. PVC and PVC copolymer dispersions are produced for - /11 _ 0CC 6440 use in latex form for coating, binder and saturant appli cations. These latexes fall into two categories. One is a PVC homopolymer or copolymer, high in vinyl chloride con tent, for industrial use. The second is a copolymer latex containing less than 50% vinyl chloride in the polymer. This type of process forms films drying the latex at ambient temperature. Latexes are formulated with the additives listed earlier for vinyl resins plus thickeners, surface active agents, colloids, solvents and anti-foamers. Open or semi open vessels equipped with low speed, low shear agitators are used for formulation. Oils such as plasticizers are often emulsified with water prior to addition to the mix. Depending on the latex the finished compound may be applied to a substrate by dipping, roller coating or spraying and the coated substrate baked to fuse the resin and drive off the water or it may simply be applied and air dried as a latex paint. When pigments and fillers are used, dust is a poten tial problem during the charging of the formula mix. There is, of course, no PVC dust. Residual vinyl chloride monomer in the latex is controlled by the latex producer. Latexes containing 10 ppmw or less RVCM do not emit enough vinyl chloride monomer during formulation or application to cause employee exposures in excess of the OSHA standard "action level". Latexes containing more than 10 ppmw RVCM are usuar processed under controlled conditions where employee exposur - I j. - OCC 6441 is within the prescribed limits. The PVC resin industry is very large, and the ver satility of the products is such that all uses and modes of application cannot be covered in this brief overview. Others include powder coating, blending resin for polyethyl ene wire compounds, and rug fiber flame proofing. Health hazards in these applications are negligible. Conversion of semi-finished PVC plastics to finished products involves drilling, cutting, welding, and heating of the material. Considerable concern has been expressed by many persons that heated PVC will breakdown to its monomer or that enough residual VCM is contained in the product to be emitted during heating or welding. There are a number of studies by NIOSH, SPA and others that conclusively show that this is not the case although there can be evolution of plasticizer fumes, acetic acid, hydrogen chloride and, ultimately, oxides of carbon when PVC is heated. Trace amounts of vinyl chloride have been detected in some cases but only after considerable production of irritating gases which would preclude employee inhalation. As regards vinyl chloride monitoring devices where there is potential massive exposure to vinyl chloride via leaks, vessel rupture or emergency discharge, the most ef fective monitors are those automatic systems based on organic vapor detection, chromatographic analysis, and infrared ab sorption spectroscopy. These give prompt warning of such VCM emissions and permit prompt protective action by the 73 emplovee. Portable units such as the HNu unit or the Century Systems Cor?, OVA-98 are extremely useful for leak control and on the spot monitoring. Respirators in use for vinyl chloride protection are those prescribed by NIOSH, Most vinyl chloride and poly vinyl chloride producers rely heavily on self-contained breathing air units or hose-fed breathing air masks. (10 ) Types of Occupations, Job Classi fications, and Industries Where Where Exposure to Either VC or PVC At Any Level May Occur, and The Num bers of Employees Involved in Each Vinyl Chloride and Polyvinyl Chloride Exposure Situation, Separated By Sex and Race ____________________________________ As to the types of occupations, jobs and industries presenting a potential for exposure to either vinyl chloride or polyvinyl chloride, SPI is unaware of any change in these * areas whatsoever since the time of the initial OSHA rule making on vinyl chloride. As the industry trade association, SPI neither has nor collects data on the numbers of employees involved in each exposure situation, separated by sex and race. / D - OCC 6443 (11) Appropriate Engineering Controls, Work Practices, and Personal Pro tective Equipment Available to Re duce Levels of Exposure to VC or PVC Below the Current Standards Or To the Lowest Levels Feasible The Society is informed that the individual company members of the PVC Safety Group are presently engaging in the use of appropriate engineering controls, work practices and personal protective equipment to reduce levels of expo sure to vinyl chloride and polyvinyl chloride to the current ly permitted levels. As to vinyl chloride, the current standard for controlling occupational exposure to VCM is sufficiently strin gent that great difficulty has been encountered by industry in coming into compliance with the standard that is currently in effect. Because of its stringency, not all work places are at all times in compliance with the current standard. In short, there are no feasible, additional engineering con trols, work practices and/or personal protective equipment available to reduce levels of vinyl chloride scientifically below the present exposure level. Therefore, it would seem that the current standard is the lowest level attainable and that techniques to reduce the current exposure levels are not known. Furthermore, S?I submits that the present permitted exposure level is adequate to safeguard employee health. No new evidence has been presented to refute this conclusion. 76 As to PVC generally, we know of no reason to control exposure to the polymer because polyvinyl chloride in any form is not a health hazard. In fact, PVC is so stable and inert that it finds use in such demanding applications as surgical implants, medical tubing and high voltage electrical wir e. As to respirable dust which may be associated with certain operations involving PVC production, these dusts are currently governed by OSHA's nuisance dust regulations. 29 C.F.R. 1910.1000. Controls are utilized to comply with these regulations and to protect workers from any hazard which would be associated with exposure to the dust. Con sequently, extensive investigation into appropriate engi neering controls, work practices and personal protective equipment available to reduce the levels of exposure to PVC dust further are not areas known to us to have been investi gated in any great detail. As a final comment it should be noted that inasmuch as PVC dust has not been shown to be a health hazard at levels below those to which it is currently controlled (or at any other level, for that matter), we know of no purpose which would be served by speculating on methods to reduce levels of exposure. - // - OCC 6445 III. CONCLUSION As to VCM, OSHA is aware of Maltoni's experiments which indicate possible effects in animals exposed to 10 ppm VCM. The Agency must also be aware that no increase of neoplasms was found in animals exposed to less than 10 ppm. Based on these and previous experiments, it is clearly evident that rodents are more susceptible to VCM than are humans. Accordingly, that cancer can be induced in animals at levels lower than previously reported seems to be of scientific interest only. The fact is that human experience should be given higher importance than animal studies, the animal data having predicted a cancer incidence rate over 500 times greater than that observed in man. The Agency also appears to be interested in another report from Maltoni to the effect that VCM can exert a car cinogenic effect transplacentally. This phenomenon, however, has only been demonstrated in pregnant rats exposed to very high concentrations of vinyl chloride. Additional work in this area needs to be conducted using lower, more realistic doses since available data indicate that the rates of meta bolism in the rat shift as exposure concentrations of vinyl chloride change. Of further interest to OSHA should be the fact that vinyl chloride did not cause significant embryonal or fetal OCC 6446 73 toxicity and was no: teratogenic in studies in rats, mice or rabbits. In tact, SPI knows of no valid scientific paper associating vinyl chloride with human birth defects at any level of exposure. Regarding effects in humans caused by exposure to vinyl chloride, there is no new epidemiologic data on vinyl chloride exposed populations. The Society has, however, contracted for a complete, independent analysis of all avail able, relevant epidemiologic data. This is particularly important since it is not always made clear in subsequent papers reviewing them that many of the studies which have been reported represent investigations of the same population or subsets thereof. The next epidemiologic data on VCM ex posure is expected to be the five year update on the original Tabershaw and Gaffey study. The Society is informed that this study will soon begin under the direction of the Chemical Manufacturers Association and will be a straight forward epidemiology update with special emphasis on neoplasms of the brain. In the meantime, SPI is submitting to the Agency with these Comments the most recent compilation of all liver angiosarcoma cases associated with VCM. If mutagenic effects occur as monitored by chromo somal analysis of circulating lympocytes, it has been demon strated that they were the results of high exposures; the changes have not been permanent since they have been rever sible. The changes did not occur at lower levels of exposure. 79 OCC 6447 The clinical significance of the reversible changes observed " is not known. Being' a poorly soluble gas, vinyl chloride does not accumulate from chronic exposure but, rather, is rapidly exhaled`after exposure ceases. Hence, there can be no body burden in the usual meaning of the term. ' Responsive to the Agency's questions about person nel exposure eo VCM and appropriate engineering controls, work practices and personal protective equipment available to reduce levels of'exposure to'VCM below the currentstan dards or to the lowest levels feasible, the VCM/PVC industry is presently using appropriate engineering controls, work practiced and personal protective equipment" aimed at achieving compliance with the existing standard. It'must be recog nized by OSHA, however, that the Vinyl Chloride Standard - is'very*stringent and industry is still encountering signi ficant difficulties''relative to achieving full time compli- " ance with it. Although* the industry has made tremendous strides in controlling' VCM "exposure, the variability in resvn type and the resin type relationship to differing VCM expo sure potential has the industry in a position where the use of work practices'and respiratory protective equipment to achieve day-to-day " compliance with the standard is still- wide-spread. Because of process variability no additional^- feasible measures'* to reduce exposure levels significantly- - below the oresent level are known by the industry to exist. It would appear that they are all in use and that the present occ 80 permitted exposure level is adequate to safeguard employee a_ . health. .. ___ __ As to PVC, experimental studies show no carcinogenic or other toxic manifestations related to polyvinyl chloride, exposure. Solid PVC has long been known to be inert and . the effects resulting from experimental exppsure Xo PVC dust, appear to be characteristic of nuisance dusts in,,general. The effects appear to be similar in man, that is, they are limited to deposition of dust in the lungs in a manner ,,which can cause slight effects to occur.but no carcinogenic or other toxic effects have been observed, . Regarding epidemiology or case reports of cancer, ^associated with exposure to PVC, the. only new information that S?I knows to be available is that presented by Dr. Seaton at the Bethesda Symposium. As to that study and the,,, others referenced in the Request for Information,, it= is, The, Society's position that PVC dust is adequately regulated . by OSHA's general dust control standards and has not been r-shown to present any hazard at .these low levels.. As to the hypothesis ..that PVC dust carried into, the lung can result in its being distributed throughout the, body, SPI believes that, even were this hypothes is co' rrect -- and it is-not thought to be correct, the minute quantity of mono- merlin ,PVC dust particles, is so small that it would make . this-speculative exposure of no practical significance. In PVC manufacturing operations, both the quantity -and size of dust particles vary depending on the resin SI OCC 6449 being handled. The same variability is inherent in the resi dual vinyl chloride in dust particles and other conditions which might be expected in manufacturing and fabricating different resins. In light of these conditions, appropriate control technology, work practices and personal protective equipment are employed as required. In addition to the information anc views presented above, the Agency should be advised as noted in the body of this document that SPI has additional comments and infor mation to submit for the Record. These materials will be assembled and supplied to the Docket Officer when they are available. The foregoing considered, SPI's PVC Safety Group most strongly asserts that, based on the information being considered by the Agency in its reassessment of VCM, no data are available to suggest any new or greater hazard associated with occupational exposure to vinyl chloride. The Society is also steadfastly of the opinion that PVC dust is merely a nuisance dust and that no adverse health hazard information has been presented to change this position. Accordingly, SPI suggests that the available data indicate that both vinyl chloride and polyvinyl chloride are adequately regulated to protect worker health. Respectfully submitted. .INDUSTRY, INC. OCC 6450 82 Jse T.: , [f m F~/ D>^a a Journal of Occupational Medicine August 1974 Vol. 16 No. 8 Mortality Study of Workers in the Manufacture of Vinyl Chloride and its Polymers* Irving R. Tabershaw, M.D. and William R. Gaffey, Ph.D. Animal studies have shown that inhalation of vinyl chloride produces in rats angiosarcoma of the liver as well as cancers of the lung, kidney, skin and other sites. Although workers in occupations involving exposure to vinyl chloride have been found to have an increased risk of hemangiosarcoma, no excess of other cancers has so far been reported. This historical prospective mortality study of 8384 men who had at least one year of occupational ex posure to vinyl chloride before December 31, 1972, demonstrated that cancers of the digestive system (primarily angiosarcoma), respiratory system, brain, and cancers of unknown site, as well as lym-. phomas, occurred more often than expected in those members of the study population with the greatest estimated exposure. The mortality from other cancers was lower than that of the general male population, with the exception of cancers of the buccal cavity and pharynx. There was an excess of these cancers, which however was inversely related to estimated exposure. The explanation for the latter finding is not apparent. The other major findings of the study are: (1) The overall mortality of the study population was ap proximately 75% of what would be expected in a comparable population of U.S. males: (2) No cause of death showed a statistically significant excess over what would be expected in a comparable U.S. male population; and, (3) No deaths identified as angiosarcoma of the liver were found other than those previously identified. This is the first epidemiological study which suggests that in humans vinyl chloride may also be associated with cancer of multiple sites. Drv. Tabershaw and Gaffey are from Tabenhaw-Cooper Associates, Inc., Suite 308, 6000 Executive fUvd., RockviHe, MO 20652. "Die rrsearch on which tNs report is based was supported by a group of companies engaged in the syn thesis and/or the polymerization of vinyl chloride, and administered in their behalf by the Manufacturing Chemists Association. ^o( Occupational Mtdicinc/Vol. 16, No. 8August 1974 OCC 6451 509 V-inyl chloride in its manufacture and particularly those producing the to have had the greatest exposure monomer, thjs determination could be those with low scores will have ha- polymerization has been identified as a narcotizing agent,' as a liver toxin,7 3 and as a vasospastic agent producing -a made on the basis of job titles. Usually, however, exposure was a function of both job title and the location of the job least, even though the true exfx*^ each group may vary considerate person to person. specific occupational disease, acroosteolysis,4 Recently, vinyl chloride has been incriminated as a carcinogen producing in a group of workers engaged in the -manufacture of polyvinyl chloride a rare fatal liver tumor, hemangiosarcomaT Large doses of the in the plant, so that the assessment of ex posure had to be made on a case-by case basis by plant officials. Data were collected for as far back in time as complete records were kept. In most cases this covered the entire history of the plant. In others, records were kept Jy The estimated exposure history ^ worker was summarized by calcoj an txposure Index Hi). this wa*-T ' >y multiplying the number of mon-. reach job by the exposure score. \tti these overall exposed jobs, and 7". tmube. total Jnum5erjirmon1hs w _ chemical in rats reportedly produced for a fixed period such as a decade. In a posure.. cancer of the skin, lung and other few, records - were kept for different * organs.4 Unpublished but public in periods, depending on whether the Follow-up of Study Population formation7 indicates that inhalation ex worker had died on the job or had left 'A follow-up procedure was instrj. periments with rats in doses easily employment. for those who had left employmnr * reached in manufacturing operations In most planK it was impossible to whose vital status could not be-tv-- produces in addition to angiosarcoma of 1 ) quantify exposure. However, industrial^ mined at the local plant, usint> V _ the liver, skin, kidney and other hygiene and safety personneTHn each\\ mail foUow-uo_and retail cretin K-. malignant lesions. ' pTgnt were able to identify certain job^p ' investigations. Table 1 shows It* , ^ The present study, however, was not restricted to the conditions and sites and locations as involving the highesP status of the population as of Deo--exposures in the plant, and to classify 31, 1972. Follow-up is 85% com;-- suggested by the above investigations, other exposures as medium or low but concerned itself with the entire spec relative to the "high" represented by the trum of causes of death, to the extent jobs with the greatest exposure. Con permitted by the size of the study group. sequently, each exposed job in a The objectives of the study were: (If To worker's history was scored 1, 2, or 3 to compare the mortality of individual^ indicate low, medium or high estimated who have worked in vinvl rhlnridp ]_exosyre. Jjlants with tha^ nf the--general This gross classification has two major Those who were not found were t.r(and began their exposure) about *years before the group on which fii. up was complete, and had about s. the duration of employment in ex|*-jobs with a slightly higher HI. Alitv-,there appears to be nothing very unv>-- about this group in terms of work h population: (2) To compare mortality failings, as a result of the subjective and exposure, it is nevertheless true'*- patterns within the population of vinyl nature of the estimates. The first is that their exposures took place further t- - chloride workers, based upon estimated the scores represent estimated relative in time than that of the group ^occupational exposure; and (3) To compare mortality among vinyl chloride exposure within a given planL It is therefore possible that, in objective cessfully traced. It is therefore po'-'- 1 -< that their mortality, after a substa--- workers with the mortality of other oc terms, a "high" score in one plant latent period, might show a somr-`- cupational groups. corresponds to a "medium" or even different pattern from that of the '* * The study population consisted of in "low" score in another. The second is group. dividuals from 33 plants who had that the scores usually do not take into All of the subsequent analysis h worked for at least one year in a job in account changes in exposure over time. cerned with the 7128 workers on****" volving exposure to vinyl chloride before A worker with long service may follow-up was complete. Table 2 **" December 31,1972, and included retired therefore have had jobs in the remote their distribution by duration of exp*" and terminated as well as active past which involved "low" exposure employment and the year in wbth workers^ For each such worker the date relative to other jobs at that time, but employment began. Although a1--* of birth and an employment history were which might be "high" in comparison half the study group first entered * obtained, and the vital status of the with current exposures in the same job. posed employment in 1960 or u'r worker as of December 31, 1972, was This subjective classification is therefore there are nevertheless 854 workers * * ascertained. For those found to have of questionable validity in characterizing 20 years or more exposure, and Vw< died, those death certificates that were the exposure of a given worker. For with 15 years or more. Table 3 sho'*r* available were obtained and the cause epidemiological purposes, however, relationship between duration d of death determined. The observed mor tality was compared with that of the those who have high scores can reasonably be expected, on the average. posure and El. There does not apt*-' t be a close relationship between T* United States male population. Data Collection Jn each plant, data were collected for each worker stated by the plant management to have been employed for at least one year in a job involving ex posure to vinyl chloride. In some plants. 510 t Muntar PvCHtf Trblt L -- Fellew-p Stihu ul t3U Vinyl CWorii* HotUn. Wn Dwrf tut 1774 IS} tooJO *0J i2 list 1SJ Ml U te't . M KL 371 HJ * II Mortality Study of Workers in Manufacture ot Vinyl Chloride ut is* --M o CxpOSUrr mil_ viH Kjvp fy*. , ^HferahJ. re history <y ,_ * by cjit.y, . This vm ^ ^ ber of moors _ re score. ./*.^ :>b$, and d.. ... )f months < .. Population * jre was in*:.`j- i employmi-n' * 4 rid not be f,._ ant, using c. -~ tail credit h-T, shows thr . j n as of Deo-- .s 85% com; found were osure) about on which ((/' d had about *. yment in exp--- i gher El. AIiM.j .hing very un---- . j of work hi'" <- | Mess true i re further I-' | : the group 'J j therefore po"i her a substi"how a somew- that of the im - at analysis is r T workers on " h *" . ie. Table 2 shs j sration of e*p'^ j rear in which r- | Although 'j i first entered " ( tn I960 or b" B54 workers * " posure, and ,`J Table 3 sho"4-1 duration o: " foes not appe-f | p between the J ^ duration of exposure, that is ' vvith a-higher El do not differ '^nlll,,y in duration of exposure " those with a lower El. One im- s*jn is that in assessing the relalionbetween mortality and exposure, , jgration and level of exposure can w ojmined separately, as well as in ^-CjfUliotV calculation of Risk of Death ;v risk of death is expressed as a ^dardiied Mortality Ratio (SMR), ,nch is the ratio of the number of ^jr\ed deaths in the study population .. v number of deaths to be expected .. j comparable population of U.5. SMR's were calculated for overall -/.jlity and for 33 major cause groups, Tjble A shows observed and expected -uhs. and the SMR, for each of these jo-^s for the total study group. In *rulating the SMR's for specific causes, *r 24 deaths for which no certificates .ne found were assumed to have thej-ne cause distribution as those for >-wch certificates were available. In the standard population, each SMR `>uld be equal to TOO. Therefore, the utistical significance of the deviation of ?jfh SMR in the study population from v- expected value of TOO was tested.* A *-*le dagger indicates those SMR's *h*ch differed significantly from TOO at *v 5% level, that is, which had a .'ifaability of .05 or less of occurring by Mnce. A double dagger indicates those -Vh were significant at the T% level. 'Mg'* based on fewer than five ob-'ned cases were not tested for ' cnificance. fable 5 shows the same SMR's for -xkers with an Exposure Index below ' 5 versus those at T.5 or above. The -iding point of T.5 represents a level 'j;Nvay between "low" and "medium." fable 6 shows similar results for *'kers with less than five years ex- Tibl 2. -- Oirtribation tji Months in Eipmed Employment by Yr*r in Which fiposur* Befit, fet 7171 Vtnyi Chloride Workers with Completed Followup. T*af Lx*< 5br1f4 1330 35 1940-49 19SG-S9 : 196069 1970-71 Tetii Totit 3S 10X9 336t 71S 7171 <(0 2 13S 393 1714 715 2SSS (0119 4 93 257 H42 IZ0-I71 l 119 313 195 Vanthi o< [lyawn I*fr2JS 7*0-295 3tKV35 4 t 13 151 277 237 631 32 im Ul 7K 545 230 Uitkftovf 5 34 2 , ; \ 3 posure versus those with five years or more. In order to examine the possible in teraction between duration and level of exposure, the study population was divided into four groups on the basis of both El (low vs high) and duration of ex posure (short vs long) using the same dichotomization as Tables 5 and 6. Table 7 shows the results for short ver sus long exposure in the low El group, and Table 8 shows the same comparison in the high El group. In each of the above tables, deaths for which certificates had not been received were assumed to be distributed as a uniform percentage of all causes. The cause specific SMR's were therefore ad justed upward by a percentage which varied in each subgroup. Results of Analysis The overall mortality of the study population is statistically significantly lower than that of the U.S. male population. There were 352 observed deaths compared with 467 expected, for an SMR of 75. Table 4 shows that no specific cause of death was statistically significantly greater than expected. Several, par ticularly heart disease, accidents and "other diseases" not detailed in the tables, were significantly below their expected values. When the study population is divided according to intensity and duration of exposure (Tables 5 and 6) and com binations of these measurements (Tables 7. and 8) three major patterns emerge. For malignant neoplasms as a whole, the SMR increases with increasing ex posure, whether measured by level, duration, or both. In the high exposure group with 5 years or more exposure (Table 8) there are 36 observed cases and 26.11 expected. For cardiovascular-- renal diseases as a group, there are also increases in the SMR with increasing exposure, but the numbers of observed cases remain less than expected, the differences being statistically significant in all groups ex cept the high exposure, long duration group in Table 8. For all other causes, there are no con sistent relationships with exposure. Within the malignant neoplasms, the largest (although not statistically) significant SMR is in cancers of the buc cal cavity and pharynx, with five ob served, Z84 expected, and an SMR of 189. However, Tables 5 to 8 show that all these cases have Exposure Jndexes below 1.5 and four out of the five have less than five years exposure. Table 10 is a listing of these deaths with age at death, duration of exposure, and cause as stated on the death certificate. Cancer of the digestive system shows tlpturt W<t Table 3. -- Ifc. inf t ri 7121 VTnyf Chloride Wwltn b] Months of Exposed Employment ind tposurc Index. IviUa M Eipoaero wa la S < W-1M 120179 ' 1(0-123 240299 30&3S1 3WM11 Hi % la % la t la S Nil \ 4l \ Unkftwa bott CwlHicil* 1.01.4 1-3+ 4032 (100) 3057 (100) 1715 (43) 1240 (41) 1125 (3) (71 (3) 402 (10) 295 (10) 4oe (io) 3*0 (12) 247 (7) 291 (10) 92 (2) 159 (5) It (0) 21 (1) 23 J* 32J 11 ' l*1 39 773 (100) 2955 (41) 17H (25) 07 (10) 7 (11) StS (I) 231 (4) (1) 39- 39 (1) J de/Tabersha*.^ Jil,nil of Occupational Medicine/Vol. 16, No. 8/August 1974 OCC 6453 51 Table 4,~-- Observed Deathsipectrd Deaths and Standardized Mortality Ratios in Vinyl Chloride Worker!. Cm ol Dull) wrth LC.D. Romta1 AV aum 352/4S7J1 Tubeicutovt (001-019) Tuber euho ^ respiratory tystem (001-004) Maliynant neoplesms (140 70$) MalipnaM neoplasms. buccal canty and phryni (140-148) Malignant neoplasms, dipsti* organs and peritoneum (150-159) Milipnant neoplasms, respiratory system (1WM64) . Militant neoplasms. tenital otjini (170179) Malifnant neoplasms, urinary grpnj (ISO-121) V.jlijqant neoplasms. other and unspecified sHn (190-199) leuieima and aleukemia (204) Lymphomas (700-703. 705) ,, Diabetes BwHHui (260) Major cardiovascular and lenal diseases (330 334 , 4CKWB. W2-594) Vascular lesions ifiediftf CHS (330334) . -^ Rheumatic lev* l chronic rheumatic heart dis. (400402, 410-416) . Arteriosctaotk heart disease (420) ^ \ J\ - . . sr*__ * Nonrhevmilic endocarditis (421, 422) ^r"t - v Hypedensive heart disease (440443) ' * ? . - `jV'^ r- Other hypcrlASfve disease (444447) - - '-f- - -7 Chrtmic & unspedtied nephritis 4 renal sclerosis (592 594) ' * " 1," ,. . - t` Influenza and pneumonia (480493) ' . . "V. . Wee* e4 slomadi and duodenum (540. 541) - . .. >>* 79/77.16 hn.u 19/21.67 29/23.93 3/3.S5 10.60 17/11.75 30.77 6)6,06 7^31 155/207.46. 13/2A.S* - . ...-- . S/Ei? r.-r 121/13733 , i/6^j .; '.^s_ 3/9.33 . c ' - 3/2.60'- \ ' ' 0/472 . ';- t 5j9.96 - . - / ,, ZO.D ` Appendiotb (550-553) Hsnia and intetmal obstruction (560, 561. 570) GtrHh, duodenitn. enteritis and adrtu (543, 571, 572) Cirrhosis 0* Itver (Wl) ` .- : Hypspluia of prostate (6J0) ]* ... '"-t:-'- Symotoms. senility and ifl-defined cmdibons (780-795)-"- ^ AO othei diseases (residual) " ` -" * ~ r*7" * ^ - m" - 't * '' * *- 0/0.66 - 1/lil 1/U1 3A5.60 a^)39 - ^ 1/73* ; 71/45.71 Motor vehicle aoidents (81Q-23S) -> - 17/3230 . other aebdeuts (800-802, 840-962) ' \ `^ - -v s Suibde (963. 970-973) * ` * . Homiode (964, 980 985)i- !-- -.^ ` ^ Me. 4 erkm ^^ s'.-; ^ ` -r " .'r-r*-, -- f~=^T , ' y, 1 1600.64 -" ' 16/16.63 1/11/96 , / :/-"-771U. t \ j,," ^T" In y n? j, j( lis jqj J20 i 1 ! i i i jt i 1 \ 1 1 .i( . H is ii _JS )j| ( y '" U c 71 17 21 0 li 4) .56 1 O* 107 9 * 3 *( j t j 1 i i L*4 4 0* jltfiU WlllfMI lympfa p ail YntvUt irlfMtL Nonrta Oita Chitac 3L"jjr of l^ndibi hernia aa CjTlittii. (-thdVS hfTfiptn J-I atta vet Kt (! ittdc ~K rf. "SMR'i adjutfed fa deaths with cause untawi. tSignifkant at 5% k*d. 45ifni&cvTt si ]* no excess in the study population as a Malignant neoplasms of other and un organs, and leukemia, have fewer >" whole. However, in those workers with specified sites show an excess in the than expected. The number of ca**' ` an El of 1.5 or higher, there are 12 ob total group, and an increase with both too small to examine any trends. served cases where 9.1-4 are expected level and duration of exposure (Tables 5 Discussion (Table 5). In the subgroup of the above and 6). The relationship with exposure is The favorable overall mortality c* workers with five years or more ex more pronounced, since those with ex study population is a phenomenon f'" posure, there are 11 observed cases and posures of less than five years have monly observed in working popu'*','T^ 7.47 expected. fewer cases- than expected. Standardized Mortality Ratios in if*" Respiratory cancer shows a slight ex The lymphomas, although occurring at 80's and below have been fouM cess in the total group, and a similar pat about the expected rate when the whole Even in occupations with well tern for different exposure categories, group is considered, are concentrated hazards which cause an increa with 13 observed versus 10.28 expected almost entirely in the high exposure, from a specific cause, the overal' when the Exposure Index is 1,5 or "long duration group. In that category tality may still be favorable bcca1^ ^ higher, and 12 observed versus 8.50 ex pected when, in addition, the duration there are four cases observed and 1.84 expected. the iow risk from other major cam'' death, frequently in the cardio'*^'* of exposure is five years or more. Cancers of the genital and urinary -- renal category.'11 occ 6454512 Mortality Study of Workers in Manufacture of Vinyl ChloritWTabersha*. U?. ' l adf `V kid 4*^-iua4 sifw " s Cher t ' '"'-ntic " 'rally 1 - the " * drat and * "X n i n j 1ac *- A M.ng V, hei e c. ^ cfO --------- * LA * IU n 1 1SJ n IK 111 *3 * 57 * n % 11 . m i 54 ' ' w 71 j V 71 4 IS , L u* 102 9* j -- - j *-" . 5l -- Observed Oeslhi^ip+rted Deaths and Stindirdired Mortal ty Ratios in Vinyl Chloride Wo'kerv by Esti mated lev*t uf Espouirt- itb LC.CL *u Dili -- Otn.1*, ir Obi/tap SHt* -- 1U/270J3 70 1SJ/19S.U 1001-013) M respiratory system (001-006) ' 0/3J4 oa.n 0 0/2.33 0 0/2.18 0 0 ncopljsTM* (HO 205) **(1X111 iwptiWU. bocul ontj nd plurpii (140-1**) J vi'^nAMt neoplasms, dtpstive orpns ind peritoneum (150-159) (-*"1 wxilnmi. itjpintsrr lytfuii (160-164) neoplasms, pnttil vfins (170*179) ^ neoplasms, urinary <#t*nl (180-161) neoplasms* other and unspecified sites (190-199) IfvVrmn and aleukemia (204) Ifnphoma* (200-203. 205) j mtHihrt (260) ^ tirdtuvncvlir and renal disuses (330-334. 4QO-4&S, 592 594) i Yucutir Itjionj afledinj CN5 (330-334) somatic fever 6 chronic rheumatic hart dts. (400-402, 410416) i/rermscferdk hart disease (420) ftttiheomitic endocarditis (421. 422) Hjjjtrttnlnt Suit dnuH (440443) OtVi hypertensive disease (444 447) Chronic 6 unspecified nephritis 4 renal sclerosis (592-594) r, ' 37/4421 Mi2 7/12-SO 11/13J6 W.X 1/2.07 9^J7 1/2.11 1/3 48 S/3 65 *4/120.11 7/14.42 ia 68/7834 ` 0/4^0 1/5.4* . 1/132 . _ - 0/2.50 ' 90 130 60 7 66 93 51 146 49 31 146 75 52 SO 92 0 19 70 0 41/32.67 0/131 I2A.I4 13/1028 1/1.43 0A.52 8M_S2 2A37 5/2.54 2/2.65 69/86.99 6/10.06 2/2.85 51/58.05 1/7.89 2/3*6 2/1.07 0/1.77 134 0 141 135 75 0 190 136 212 ; 81 85 7 64 75 95 36 56 201 0 w4enji and pneumonia (480493) vie* d stomach and duodenum (540. S41) t^ndiotis (550-553) 53.80 1/221 - 08139 92 46 0' 0M.13 1/1.60 0/D27 0 (6 0 **aii and intestinal obstruct**) (S60. 561, 570) 0/0*8 0 JA)3 171 . j CctMtis, duodenitis enteritis and coMti (543, 571. 577) 043.76 0 196 * (wrhii of liver <541) -- ---------------------------------------------------------------------- L - hyperplasia of prostate (610) ^ Symptoms, senility sad 31-dtfmed condiioru (78D-795) 41 other diseases (residual) 2/8.90 0/432 14/21.90 23 0 0 68 7 1/6.64 041.14 1/3.09 6/15.89 16 -0 34 -41 * j i j j * J - ,v?tor vehicle acodents (S10-635) Kim Ktidtntt <800*02, 840962) (963, 970979) KoTMadt (964. 980 985) >t U wirVtn PnVmvyejr* *-- . 'L - &/19.08 45 * 9/13.46 72 11A733 66 + 6/12.67 50 - 93.73 96 7/7.02 107 0,38 - 0 1/4.94 21 *" `T ,` -4 X ' ' * JJ8T. __ . 4032 . 45354 --------- m--1 *_ 3057 ------- . ,____ , _ m- . , 32101---- *W1 etxiyy cases * is. ry of on to" uUiit*^ the I*** xind ' {jfltr-'I ased ,,a rail nx* cause '* '^*1 adjusted far deaths with cause wflbtQtfi 'S^iScjflt >f 51 fewL at It feM. r x 'n-view of these facts, SMR-s which *> higher than expected may be worthy * 'attention even if they are not 'J'ntically significant. This is especially r<*- <n the present study since the numi of deaths from many causes is quite Jrv*,l. and even a relatively high 5MR not reach statistical significance. * in addition, a particular cause '1,,s a consistent pattern of increase ' *h exposure or estimated exposure, findings are particularly interesting. ** *hese criteria, mortality from -?ntive cancer, respiratory cancer, can cer of other and unspecified sites, and lymphomas, appear to be related to ex posure as defined in this study. In view of the association between vinyl chloride exposure and angiosar coma of the liver, the digestive cancers were examined further to see what con tribution angiosarcoma made to the ob served mortality pattern. Of the 19 digestive cancers, seven were liver cancers, of which two were angiosarcomas according to the death certificate. However, among angiosar coma deaths in vinyl chloride workers identified by other investigators, there were six which occurred in the present study population during the study period. They were all found in the course of the study. Table 'll shows these cases with the cause of death as given on the death certificate. Note that one case was certified as cirrhosis, and was so considered throughout this study, since the validity of comparisons with population data required that cause of death be 'determined only from in formation on the death certificate. The other five were correctly classified as ,J*ml of Occupational Medicine/Vol. 16, No. 8/August 1974 OCC 6455 513 Table , --- Observed Deaths/Expected Deaths and Standardized Mortality Ratios in Vinyl Chloride Workers bj Duration tri Exposed Employment ] Caju el Doth wrtk LCJL Xi All uuifl lubetcvlosa (001-019) Tuberculosis of respiratory system (001-008) Kahynant nepotism* (140 70S) Malifntnt neoplasms. bocca! cavity and pharynx (140 )48) Malignant neoplasms, diyesitvt fns and peritoneum (150*759) Malignant neoplasms, respiratory system (160-164) Malignant neoplasm!. itnitj] orpins (170-17$) Malignant neoplasms, urinary organs (180-18)) Malignant neoplasms, other and unspecified sites (190-199) Leukemia and aleukemia (204) .. , lymphMiB (200-203, 205) Diabetes melfahn (260) Major ordrovneutar and renal diseases (330-334, 4(XU68. 592 594) Vascular lesions iflrriing CN$ (330-334) Rheumatic lever 6 chronic rheumatic heart dr*. (400-402. 410-416) Aricricscferatic heart disease (420) Nonrheumatfc endocarditis (421, 422) Hypertensive heart disuse (440-443) Other hypertensive disuse (444447) Chronic unspecified nephritis I renal sclerosis (592*594) Influenza and pneumonia (480493) (Rat of stomach and duodenum (540. 541) Appendicitis (550 SS3) Hernia and intestinal obstructioa (560. 561. 570) Gastritis, duodenitis. enteritis and tvlrtis (543. 571. 572) Cirrhosis of fiver (581) Hyperplasia d prolate (610) Symptoms, senility and ill-defined condition! (780-795) All other diseases (residual) Motor vehicle accidents (810835) 0ll.tr kIu (80M02 MO-90) Suiudt (993, 970 979) Hmcife (964. 980 975) 1*4. af Wortarv PuxanfOfi * -1 - * * ` ' * " < 60 months ObsXxp iur 94/14031 67 * 0/223 0/2.07 00 13/19.96 <*.70 2526 3/5.0 0,99 0/023 2/340 1/125 1/2.01 78 688 46 65 0 '0 71 96 60 2/1.80 134 2R251.45 2/5.97 2/229 21/3224 0/1.79 1/2.42 `0/0.79 0/1.55 65 * 81 101 7$ * D 49 0 0 3/2.93 123 1/1.07 112 0)024 0*.42 ' 0 0 1*40 301 1/4.49 26 0.0.07 0 1/228 53 4/11.97 *0 10,116.14 7/12.94 75 5 * 6/634 114 1/5.80 70 - -* 4 - , 2955 3*201 ; L U months ObsExp 251/329J0 0/3.55 0/3.33 85/57.61 1/2.16 17/1636 71/18.51 3/2.76 1/2.79 15/8.23 20.53 5/4.07 5/4.54 125/15729 9/18.71 3/433 98/105.33 1335 2/7.01 3/1.82 0/2.76 7/7.09 1/2.78 0/0.43 1/1.10 0/0.92 2/11.18 0/033 OA.09 16/7634 7/16 65 10/1712 10/1018 0*20 4134 *32*0 SKI- 1 | j| ( 1l % ( i 116 .7 10b --U* in 31 187 i : l ; i 1 ! \ 11 - 1 m :* <3* i 68 96 20 j 30 i 170 . t' -* 3? : 7 0 u; 1 i* . 6! D: 6) ' ,1- i ; 1W ! fi * SMfTs adjusted for deaths with cantt mLnurv. ` 'tjijnifioii d 51 ImL ^Significant it 11 fovd. t*a* U Ci Kbim let Vilift Uit Hal Hi. Ujl Hal Hi Ui ir Ukn Apper, Hffw, CtSln Cuibr Hpr Sywip A v Held Other I Smoc 'l^o - OCC 6456 514 Mortality Study of Workers in Manufacture of Vinyl Chloride/Tabersha** ^Rll t - ojnift th "* i im- Tibia 7. -- Observed De)thixpcded Deaths and Standardised Mortality Ratios In Virift Chloride Workers with Cipasure indices Below L5. by Duration ol Ejposed Employment. "* ' '* J Death with LCD. h*. < 60 Months tipesura JL 60 Months Dpavrl A - 1> 1 1 in <r IS III 11? 37 111 1! lit ill *1* 41* U X 30 IW o 25 jr u M I.Vicuten (001-019) TctiefOilosn td respiratory system (001-003) i ' ' ' neoplasms (140-705) Mjhfnant neoplasms, buccal crrity and pha/yttt (140-143) Mjlifnant neoplasms* ditestivc crpns and peritoneum (150-159) Uiliyaast neoplasms, respiratory system (160-164) UilipiAt neiplasrai, genital orpos (170-179) Ujlifnifit itaplasm. urinary orpns (180-131) Malignant neoplasms, ethm and unspecified sites (190-199) Lrotarii and aleukemia (704) lymphomas (200-703. 205) -- ' '! - j (hibetm mellit&s (260) . Utjer cardtwescohi and ithiI diseases (330-334. 400-468. 592 594) , v, - * Yjjcubr lesions affecting CHS (330-334) . ^ "... - . Kheumitic lever 3 chronic rheumatic heart dis. (400402, 410416) -- i Arteriosclerotic heart disease (420) '- Namheumitic endocarditis (421.422) Hypertensive heart disease (44044 3) ^ v ' ll ' Other hyptfloum disease (444447) ` j Chronic 3 orrspeofied nephffttf 3 icnal sctaa&ii (592 594) t"tj;nra and pneumonia (480493) 'Jut ef stomach and duodenum (540. 541) ifOMltita (5553) ha md intestinal obstruction (560, 561. 570) ' CntrHti, duodenitis, enteritis and colitis (543, 571, 572) c 1): 4J* u` IOC 1 I' ! 1 -. 'Cvihovi of fiver (531) Hjptrplasia et prostate (6)0) Symptoms, senility and ill-defined conditions (780-795) ij] ether diseases (residual) Ustr Rhidt Koint] (110^35) ttutfjctidtflh I10M02, *4(7962) i-s^t (963. 570-97$) ... I ! . (964. 910-915) QH/U9 s*/n_n 0/L41 0A.31 8/12J6 4A3.45' _ 1/3.43 2/153 ` 0A6S OA7^5 ` 1/D.S7 Ofl.73 * - - 0/126 ; - 2/U5 . . 2\ni3t~ . 2/3.53 2/130 ; 16/21.14 .v - ' 0/U! 1/131 , C/4LS0 >- ' 0/0.97 3/1J6 . 0/0.68 0/0.15 0AI.Z7 0/026 mm . 0/0.05 0/1.43 4/7,45 3/9.87 3/7.9! 3/4 JJS 0/3_ES SM8* ObvEip 43* 132/11171 - o 0 Q/1.97 0AJ5 73 1036 . , 34 65 0 0 V` 120 0 0. 29/31.46 1/1.17 6/9.0! 9/10.00 2/1.62 1/1.53 1/4.43 1/1.40 1/223 203 " 73 * ' 99 . 1S5 ; a.. 0 74 0 -- ' 0 3/230 63/96. S2 . S/lOil. 1/2.49 52/97.S7 0/3.02 0/3.90 1/13)2 ` 0/1.53' `'' 183 2/3J5 0 1/1.53 0 0/024 0 0/0.61 0 0/0.51 42 1/6.09 0 0A1.20 0 0/2.79 63 ion 2.92 35 5/922 44 1/9.15 36 6/5.66 0 0/3.43 SMI* 731 ` 0 0 95 11 ' a 93 . . 127 67 117 . ' .73 : 46 124 75 * 49 + T_. ` 41 ' ? 93 ; 0 .0 ` ' 101 0 53 67 0 0 0 16 0 0 79 56 13 109 0 **- M Morten | *nn-ytan 1715 7141! 2317 23920 ^ * adjusted fo deaths ith came unknown, 'Vr^tunt it j* ferd. 'V'kjfll * II Inri. ibersha*. b=uul of Occupational Medidne/Vol. 16. No. 8August 1974 OCC 6457 * sis Table L -- Observed Deaths/fcipected Deaths and Standardized Mortality Ratios in Vinyl Chloride Workers with Exposure indices of 1.5 or Greater, by Duration of Exposed Employment txu <( 'ootb Hh LLD. >. M Cjoja lubttculmii (001-019) Tuberculosis of resoinlcry 'System (001-008) Maltjoint neoplasms (HO 70S). - Malignant neoplasms.' buccal cavity and pharynx (HD-148) Malignant neoplasms, digestive organs and peritoneum (150-153) Malignant neoplasms, respiratory system rtl6D164) ~ Malignant neoplasms, genital organs (170-173) , i Malignant neoplasms. urinary organs (180-181) ' - i Malignant neoplasms, other and unspetiW sites (190-193) leukemia and aleukemia (204) ** ' lymphomas (200-203, 205)- * ` Diabetes mellrtus (260) Major cardimscular and renal diseases (330-334. 4 00-468, 5S2 594) Vascular lesions afleding CN$ (330-334) - - ' Rheumatic Wf X chronic rheumatic heart do. (4DQ-40Z, 410416) . , Arteriosde/otk heart disease (420) Nonrheomatic endocarditis (421, 422) * Hypertensive heart disease (440443) ', V-; * i Other hypertensive disease (444447),,, . - V? Chronic X onspeerfed nephritis X renal sclerosis (452-694) Influenza and pneumonia (480493) Utter of stomach and duodenum (540, 541) Appendicitis (550-553) -. Hernia and intestinal obstruction (560. 561, $70) * Gastritis, duodenitis, enteritis and colitis (541. 571. 572) Cinhosii td liver (581) Hyperplasia of prostate (610) Symptoms, senility and iU-debned conditions (780 795) An other diseases (residual) Mota vehide acadrrrts (810-835) Other rcodents (800 TO. 840962] 5uib<le (963. 970 979) Homicide (964 . 980 985) Hu. *f Kwhvt Pim-ThI < 60 Months Exposure ObiAia 5UR* 34/4733 79 0X1,76 070.71 0 0 5/S37 07023 ' 1/1.67 171.79 0X123 07026 1/1.18 170.44 141.71 96 0 76 71 0 0 107 288 171 0X1.61 7/16.54 27127 0X122 s/10.41 0X137 0X1.76 07027 0X134 ` 0 54 * 135 0 1 * 0 .-0 0 0 0X139 0 1X1.35 362 0*1.08 0 010.14 D 1/0.14 904 07136 0 0X1.01 0 170JO 158 074.02 0 73.05 146 4/4.73 107 377.40 158 17218 58 1240 1783 L 60 Months Etpourt Obsip sni* 119/147.11 yr- 07137 0/1,48 36726.11 041.99 - 11/7.47 127830 171.41 0/126 77331 171.13 4 71,84 27234 4: j" ; 34~i "; 8 151 1-144 ! i 73 0 204 90 222 ; t 100' 62/70.46 478.19 2/2.04 46/47351/722 2/3.10 2X1J1 0/123 w 50 100 i i 66 253 ! 01 0/3.13 0/125 0/0.19 1/0.49 o; o .* 0i 201 j 0X1.41 13.08 0X1.13 0 20 ! ! 0/220 6/11.88 2/7.43 0 51' 2t 2/736 4/4.62 0/2.76 26 u 8 1817 19JOS - *SMR's adjusted b deaths with cuv unknowv. tSigni&cxnt it 5% Inrti, iSitnttcMl * 11 fe**L OCC 6458 516 Mortality Study of Workers in Manufacture of Vinyl Chloride/Taber$ha, b Export! sm- 11 ' 141 " . - . lit 1*4 73 t 7w 90 m 100 90 100St 44 U ; " - > W--r~ 0 0 am - 70 - SI1 2t 71 ---------------------- - " fl* . * 1 117 UOS * i. } Stadj TjM 1. -- Other Ualigrundtt (190-195, LC.D.) io YDM Epidemiology Study Population. Age st Drtk Km. LpaW Cause as C'n*u ,_ Aatofny vu 3* 3700 TOSS !. 3946 - . `t 4433 , 4400 ' 7773 - 7300 7371 - 7306 tt `- ' 5769 5746 , * 2150 1C- . 4S 7 . 43 54 - SI. .. .. 57.. " 44 5S S3 ; 52 . 7 54 4771 ; 54 *T 47K 61 5743 7301 n 55 its 50 9 4 si 51 -* 771 211 749 71S -239 701 193 300 318 lGfi 133 Widtspiad metastatic melanoma (1 yr.) Malignant melanoma <4 taci ' i Malignant melanoma with vidtspreal mrtastascs no T Brain tumor (carcinoma) (S mn.) * Meningitis and pneumonitis (5 via.) Ependymoma, fourth ventricle-brain (2 mos. postop craniotomy) no Astrocytoma, malignant-ldt cerebral hemisphere (1 yr.) / Cardnoma of the brain__ _ Arteriosclerosis Pneumonia due to static congestbn * ^ .. 1\ no -1i ' . Brain tumor, glioblastoma multifarme (It moi) Brain tumor, malignant (2 mov) *, * . 5 Brain tumor, malignant ^ no Thyroid carcinoma with metistases CardBomaltnh Cardnoma vertebral body no i yes -. t liposarcoma with metastasis (3 mos.) Cardnomatosii, primary region not An ova (Past history, rheumatoid arthritis. myoordiat infarction) Cardiac arrest (1 hr.) Respiratory arrest and cerebral hypoxia (2 days) Widespread metastatic tardnom* (2 mos.) y no -. - `i A :3 -."-s -i Generalized metastasis vndrflertntiited (7 mos.) Squamous Cdl carcinoma, primary site undetermined J Metastatic cardnoma of abdomen Critical site undetermined (Pulmonary emphysema) i Cardnomatosis (4 mos.) Primary sHt undetermined no j - - ,, . ' 3 'zbershaw, Gj"r ^nil of Occupational Medicine/Vol. 16, No. 8/August 1974 OCC 6459 si liver ^ancer, but only two were specified as angiosarcoma. If th.re had been no angiosarcomas, Table 10. -- Witifnmt Neoplasms ol Buccal Carily and Pharynx (140-141, 1 C.D.) in VCM Epidemiology Study Population. the number of deaths classified as cirrhosis in this study would have Study ft*. Aye tt Death Vol Lt(wd Cause as Gird decreased by one, and the number classified as digestive cancer would have 3003 31 49 Carcinoma ol Up ith metastasis te lung and neck (5 yri) m decreased by five. The pattern of duration and intensity of exposure in these five cases was such that if they had not been present there would have been no relationship between exposure and digestive cancer. The mortality pattern in Jhis cause group is therefore attributable to angiosarcomas of the liver. The other cause group worth further investigation is cancer of other and un 3431 3001 7365 56 57 54 30 Pulmonary edema (SO ma.) Pulmonary metastases (taicinoma. tpidermoid, longue and mandibk) 71 Metastatic squamous cell tx primary Ituon palate 40 Atelectasis due to metastasis to mediastinum (4 mot) Multiple malignant metastasis to brain. In*r 4 mediastinum (1 jt,) Adeno-carnnorm mf nasal pharynx * i m Poh t yts : -af 1 Not specified sites, both because it is a <2 rO heterogeneous category and because it seems, unlike the other cancers, to be more related to duration than to level of exposures. Table 9 shows a list of the specific causes included in this category, which is essentially brain cancer and generalized cancer with primary site unknown. About 40% of the observed deaths were due to brain cancer. In the general male population, about 22% of this category is due to brain cancer, so that not only is the mortality from cancer of other and unspecified sites excessive, but brain cancer is overrepresented within the category. The possibility exists based on the lack o'rspecmcTtyol some of the'listed causes Vial SOme Ql tfe brain ranrers were, nni unidentified site such as the lung. The cancers of the buccal cavity and pharynx are difficult to explain because of their occurrence in the low exposure, short exposure group. It is possible that this is a chance occurrence, that ex posures to other substances were in volved, or that the mouth and pharynx may be peculiarly susceptible because of the gaseous nature of the chemical. Possible Biases in the Calculation of Risk There are two major potential sources of bias in the study. The first is that the follow-up rate is lower than is desirable. The second is that observations of workers with long exposures followed by a long latent period are not adequately represented, so that the power of the study to delect causes of death associated with long exposure and long latency is impaired. Populations with such characteristics exist and 3354 t 3 25 Missive hemorrhage into tracheo-tree Status post UrynfO-pKarynfetiQRTy, kft radial neck diuedtofi WeH-differentiated heritmihng squamous cril carcinoma d kt pyriform sinus (met) ro i t----- ---------- Table 11* -- Angiosarcoma Deaths in VCM Epidemiology Stud; Population. Study No. Aft it Dutt Wei- L*pcSd Cause is Gift* Autwrty 4250 54 203 Cirrhosis of liver (set. weeks) ye 42SS 57E5 60 45 281 Bleeding horn hepatoma (3 days) (Ltttmecs cirrhosis) 167 Angiosarcoma ft. lobe d D*er (10 mos.) 7 7? 7303 3S 174 liter bilure (1 mo.) Cancer of Titer, primary (1$ mos.) 7376 52 238 Cardiac tampanade and massive left hemothorax (mins.) Widely metastatic angiosarcoma of (rrcf (4 mos.) 7335 43 214 Hepahc failure Primary carcinoma fiver T ___ , should be investigated. References 1. Lester D. Greenberg LA. Adams WR: Ef fects of single and repeated exposures of humans and rats to vinyl chloride. Am Ind Hyg Assoc I 24:265-75, 1963. 2. Marsteller H|, Lelbach WK. Muller R, et al: |Chronic toxic liver lesions in the PVC (polyvinyl chloride) -- producing workers.] Dtsch Med Wtschenschr 98:2311-14, 1973. 3. Kramer CG. Muichler IE: The Correlation of clinical and environmental measurements (or workers exposed to vinyl chloride. Am Ind Hyg Assoc / 33:19-30, 1971 4. Dodson VN, Dinman BD. Whilehouse WM, et al: Occupational acroosieolysis III. A - clinical study. Arch Environ Hhh 22.83-91. 1971. 5. Creech |L. lohnsoo MN; Angiosarcoma of liver in the manulaclure of polyvinyl chloride. I Occup Med 16:150-51. 1974. 6. Viola PL, Bigotti A, Cupuio * ceogenic response of rat skin, fu"** * bones to vinyl chloride. Cancer Ret 3' '* 1971. 7. Occupational Safety and ministration: Occupational Safely and '** Standards. Emergency Temporary 5u'vV' Exposure 10 Vinyl Chloride. ft-cVral k"*- 39 (67) 12342-44. April 5, 1974. 8. Chiang CL: Standard error of I*T *^ adjusted death, rale. Vila) 5ratitw' Reports, 47 (1961) pp 27S-285. 9. Lloyd IW. Ciocco A: Long-lert" Study of steelworkers; I. Methodo)'*1 1 cup Med 11:229-310. 1969. ^ 10. Tabershaw/Cooper AssoCUtrt. ^ published. 11. Redmond CK. Ciocco A, Uovd HW: Long-term mortality 'l"' steelworkers: tV. Mortality frofn , neoplasms among coke overt wnrkr" cup Med 14-621-629. 1972 sorman n.lliam . \ Palcht Expr f =- -duels i "!!). al ti - -n or ** ; tfVsib' -r 1 in i - T -m: a t* ! * nn u < urrie i * ^ more f * ~ lunj i ** 'it h*fi i -! * v f i! M*c t Hxirt c '*>' fa- *- - l.-d *A - - lilt * Vjrtv - --"I. a Its *' vi'iT *i OCC 6460 s518 Mortality Study of Workers in Manufacture ol Vinyl Chloride/Tat*11^** E-J> TOXICOLOGY AND APPLIED PHARMACOLOGY 49, 15--21 (1979) Risk of Angiosarcoma in Workers Exposed to Vinyl Chloride as Predicted from Studies in Rats P. J. Gehring, P. G. Watanabe, and C. N. Park Toxicology Research Laboratory, Health and Environmental Research, and Computations Research Laboratory, Dow Chemical U.S.A., Midland, Michigan 48640 Received June 1, 1978; accepted December 2, 1978 Risk of Angiosarcoma in Workers Exposed to Vinyl Chloride as Predicted from Studies in Rats, Gehring, P. J., Watanabe, P. G., and Park, C. N. (1979). Toxicol. Appl. Phar macol. 49, 15-21, Dose-response data for the induction of angiosarcoma in rats exposed to various levels of vinyl chloride (VC) together with attendant biotransformation data were used to estimate the risk of developing angiosarcoma in persons exposed to VC, Since a biotransformation product of VC, not VC per se, is responsible for the induction of angiosarcoma, the body surface area of people relative to rats was used to estimate the dose of the carcinogen biotransformed from VC by the former. Four models were used to extrapolate the data. Using a probit model, 10 hepatic angiosarcomas were pre dicted to occur in a recently reported epidemiological cohort of 9677 workers whereas five have occurred. Linear models and that based on the equation. Risk = 1 --e~f*, where x = dose, do not appear as reliable. For an 8-hr day, 5 days/week, 35-year time-weightedaverage exposure of 1 ppm, the predicted incidence of hepatic angiosarcoma using the probit model is 1.5 x 10~`. Exposure of rats (Maitoni and Lefemine, 1975) and humans (Creech and Johnson, 1974; Tabershaw and Gaffey, 1974; Makk el a}., 1976; Fox and Collier, 1977) to vinyl chloride (VC) has been associated with the development of hepatic angiosarcoma. Nu merous studies in rats indicate that it is not VC per se which is responsible for production of angiosarcoma but rather a reactive meta bolite formed from it in tbe body (Bartsch etal., 1975;Barbin etal., 1975;Kappus et al., 1976; Malavielle et al., 1975; Bolt et al., 1975; Watanabe et al., 1972). Biotransfor mation of VC in rats is a nonlinear process occurring in accordance with MichaelisMenten kinetics: a - VmSI(Km + S) (1) and maximum velocity, respectively, for the biotransformation of VC expressed as micro gram equivalents VC metabolized daily. S and Km are the concentration of VC being inhaled and the Michaelis constant expressed as micrograms of VC per liter of air, res pectively. Utilizing the foregoing information, Gehring et al. (1978) revealed a good corre lation between the probit percentage inci dence of angiosarcoma in rats exposed to varying concentrations of VC, 4 hr daily, and the amount of vinyl chloride biotransformed, v, microgram equivalents VC metabolized per day. The probit equation is: Probit percentage incidence = -1.625+1.543 Logo. (2) (Watanabe et al., 1976a,b,c; Bolt et al., Hypothesizing that the biotransformation 1976) . In this equation, v and Vm are velocity of VC is related directly to body surface area, 15 0041-008X179/070015-07102.0010 Copyright 1979 by Academic Press, Inc, All righu Of reproduction in any form reserved. Printed in Great Britain o c c 6461 16 GEHRING, WATANABE, AND PARK Gehring et al. (1978) determined that the being experienced by workers exposed to amount of VC transformed to a reactive vinyl chloride. form by man on a mass equivalent basis to rat is: METHODS V jrg/8 hr = 1675 pg/hr- 5 pg/liter 860 /rg/liter + S /rg/liter Utilizing this relationship together with the foregoing probit equation, it was deter mined that incidence of hepatic angiosarcoma Four mathematical models were selected to analyze their reliability for calculating the incidence of hepatic angiosarcoma in rats as function of micro gram equivalents of VC metabolized daily by rats exposed 4 hr/day, 5 days/week for 1 year. These models were as follows: (A) Probit % in workers exposed to 200 ppm should be Probit % = a + b(Logc) approximately 1 %. This incidence is 50-fold = -1.625+ 1.543(Logu). higher than that experienced (Fox and Collier, 1977). Various plausible explana tions were put forth to explain this difference including greater sensitivity of rats and in creasing latency for development as v (B) Linear % = a+m = -1.48 + 0.389 x lO-^c). (C) Linear forced through origin decreases. %~bv One plausible explanation not mentioned = 0.3565 x 10-3(t.-). was that in worker populations studied to- (D) One-hit model (Cancer Assessment Group, date, many were exposed for only fractions National Cancer Institute) of their working life. Furthermore, for some, the duration since initial exposure was likely insufficient for development of clinically detectable disease. Recently available is a comprehensive epidemiological study1 entitled, "Epidemio logical Study of Vinyl Chloride Workers, Final Report." In this study, reasonably detailed information on 10,173 workers has been obtained for duration of exposure and lapsed time since first exposure. Thus, much better information is available % = \-e-fTM = [I--exp( --0.38x 10-xu)]l00. The constants given for the preceding models were determined by linear regression analysis and rep resent the best fit of the data for the incidence of hepatic angiosarcoma versus the amount of VC metabolized daily in rats exposed to different con centrations of VC (Gehring et at., 1978). The data used to derive the constants are given in Table 1. Using the equations derived for the models, the predicted incidence of angiosarcoma for the groups of rats exposed to different concentrations of VC were calculated. These results are shown also in now to assess the reliability of the model proposed by Gehring el al. (1978) for pre dicting the incidence of hepatic angiosarcoma in humans utilizing data collected 'in rats. Table 1. All four models overpredict the incidence of hepatic angiosarcoma in rats exposed to 10,000 ppm VC. This is as expected because this exposure resulted in excessive mortality unrelated to development of This assessment is reported here. In ad dition, three other models for estimating the incidence have been used for comparison of their reliability for predicting the incidence 1 Prepared for Manufacturing Chemists Associa tion, 1825 Connecticut Avenue, N.W., Washington, D.C. 20009; prepared by Equitable Environmental Health, Inc., 6000 Executive Blvd, Suite 308, Rock ville, Md. 20852, January, 1978. angiosarcoma. With respect to the predicted versus experimental incidence of hepatic angiosarcoma experienced by groups of rats exposed to the remaining concentra tions of VC, none of the four models is unequivocally more reliable than any other. Thus, any one of the four models represents adequately the experimental data. Since no clear preference is discernible, all four models will be used to predict the incidence of hepatic angiosarcoma experienced or to be experienced by workers exposed to VC. OCC 6462 VINYL CHLORIDE--RISK. ASSESSMENT 17 TABLE 1 Predicted Incidence of Angiosarcoma in Rats Exposed to Vinyl Chloride Using Various Models Versus Dose (d, VC Metabolized per day) Compared to Experimental Results Exposure' (ppm) Dose` (u, /rg/day) Experimental* (%) Predicted percentage (Models)* A B CD 10,000 6,000 2,500 500 250 50 5521 5403 5030 3413 2435 739 14.8 (9/61) 21.7 (13/60) 22.0 (13/59) 11.9(7/59) 6.8 (4/59) 1-7 (1/59) 19.8 20.0 19.7 18.9 19.3 20.5 19.3 18.6 17.9 18.1 17.9 17.4 12.1 11.8 12.2 12.2 8.1 8.0 8.7 8.8 1.4 ' 1.4 2.6 2.8 * From Maltoni and Lefcmine (1975). `Calculated from v = (5706 0/g VC/4 hr)-J0rg/liter)l/[86O (/ig/Iiler) + 5(/rg/liter)l, where 5 = 2.56 Org/ppm/Iiter) x exposure (ppm) (Gehring er a/., 1978). * Model A. Probit %= -1.625 + 1.543 Log (dose); Model B. '/. = -- 1.48+0.389x 10`2 (dose); Model C, % = 0.3565 x lO"2 (dose); Model D. % = [1 '] 100, where 0 = 0.38 xlO-*. RESULTS AND DISCUSSION The incidence of hepatic angiosarcoma in subgroups of 9677 workmen with respect to their duration of exposure are given in Table 2. These workers include 95.1 % of the 10,173 in the cohort study; the remainder could not be traced. The atmospheric concentrations of vinyl chloride to which these workers had been exposed were Dot quantitated, except sub jectively into high, medium, and low cate gories. Since the time-weighted-average (TWA) exposure recommended by the Ameri can Conference of Governmental Industrial Hygienists (ACGIH) prior to 1972 was 500 ppm and subsequently 200 ppm until adop tion of the Occupational Safety and Health Act standard of less than 1 ppm in 1974, it is assumed that even those exposures sub jectively deemed low were high. Indeed, it is reasonable to expect the TWA exposures of 200 ppm and greater for 8 hr were common rather than the exceptions. Table 3 depicts the average theoretical rat equivalent daily doses of biotransformati'on products of VC received by workers exposed to 200 or 500 ppm for 8 hr daily. 5 days/week adjusted for the fraction of their working life during which exposure occurred. The doses, v, arc expressed as micrograms per 8 hr and were calculated from Eq. 3 (given under Introduction) multiplied by the fraction of an assumed 35-year working life during which exposure occurred. Having estimated the rat equivalent daily doses of biotransformation products of VC received by the various subgroups of 9677 workmen exposed to a TWA of 200 or 500 ppm VC, the predicted incidence of hepatic angiosarcoma for each subgroup was calculated (Table 4). Examination of the data in this table indicates that Models C and D overestimate the incidence of hepatic angiosarcoma experienced by these workers while Model B underestimates the incidences. Models C and D may overpredict because they do not address either the enzymatic biotransformation of VC or repair of the lesion leading to development of angio sarcoma, both of which are likely to be dis tributed normally in human or animal populations. It may be argued that Models C and D overpredict because the recommended TWA exposure values of 200 or 500 ppm VC are OCC 6463 18 GEHRING, WATANABE, AND PARK TABLE 2 Incidence of Angiosarcoma in 9677 Workmen Exposed to Vinyl Chloride* Population Duration of exposure (years) Mean exposure duration (years)* Fraction of working life' Observed angiosarcomas 4384 (0.31)' <4 2 0.06 1 (18 years)' 2339 (0.27) 5-9 7 0.20 0 946 (0.58) 10-14 12 0.34 2 (15 and 23 years) 1007 (1.0) 15-19 17 0.49 2 (18 and 19 years) 677 (1.0) 20-24 22 0.63 0 324 (1.0 25 + 27 0.77 0 Total 9677 * From "Epidemiological Study of Vinyl Chloride Workers", Final Report January 1978, prepared by Equitable Environmental Health, Inc., Rockville, Md., for Manufacturing Chemists' Association, Washington, D.C, * Assumed mean duration of exposure. ' Mean duration of exposure divided by 35 years. ' Fraction of population incurring first exposure 15 or more years prior to study. ' Duration between first exposure aDd diagnosis. higher than those actually incurred by workers included in the epidemiological study. Undoubtedly, some were exposed to smaller levels. Many were reported exposed to much higher levels; in some cases at or above the odor threshold of approximately3500 ppm. Unfortunately, in the absence of TABLE 3 Average Theoretical Rat Equivalent Daily Doses or Biotransformation Products Received by a 70-kg Human Exposed to 200 or 500 ppm Vinyl Chloride for Various Fractions of an Assumed 35-year Working Life Mean exposure duration (years) Fraction c, micrograms per 8 hr of averaged over 35 hr* working . life 500* . 200 2 0.06 60 7 0.20 200 12 0.34 341. 17 0.49 491 22 0.63 631 27 0.77 771 38 125 213 306 394 481 ' v = [1675 ftgJS hr-5 pg/liter]/[860 pgfliicr + S fig/ liter] x (fraction of working life). * Parts per million. ' analytically determined exposure levels, ap proximations of the actual TWA values must be used. For a TWA exposure of 100 ppm VC, the predicted number of workers de veloping angiosarcoma in this epidemiological cohort are 4, 0, 30, and 32 for mathematical Models A, B, C, and D, respectively. For a 50-ppm TWA, the corresponding numbers are I, 0, 17, and 18. Thus, utilizing values for TWA exposures which are thought to underestimate the actual exposures appear to overpredict still the number of workers developing angiosarcoma of the liver when mathematical Models C and D are used, albeit Model A apparently underpredicts when a TWA exposure of 50 ppm is used. When a TWA of 200 ppm is utilized to represent the atmospheric concentration to which these workers were exposed, the pre dicted incidence of angiosarcoma of 10 cases using Model A compares favorably with that experienced, five cases. For a significant number of workers, the time elapsed since initial exposure has yet to reach 15 years, the shortest time needed for development of angiosarcoma in 1 of 5 of the afflicted workers (Table 2). Thus, it may be OCC 6464 VINYL CHLORIDE--RISK ASSESSMENT 19 TABLE 4 Predicted Number of Angiosarcomas in Workers Exposed to 500 or 200 ppm Vinyl Chloride 8 hr/day, 5 days/week for Various Fractions Oe a 35-year Working Lite Versus the Numbers Observed Using Biotransformation and Angiosarcoma Incidence Data from Rats and Four models for Extrapolation* Angiosarcomas predicted (Models)* Angiosarcomas Population observed A 500* 200 B 500 200 C 500 200 .D 500 200 4384 2339 946 1007 677 324 Total 9677 1 0.2 0.0 0 0 9.4 5.9 10.0 6.3 0 2.4 0.8 0 0 16.7 10.4 17.7 11.1 2 3.0 u 0 0 11.5 7.2 12.1 7.6 2 6.8 2.7 4.0 0 17.6 11.0 18.6 11.7 0 7.3 3.0 6.6 0.3 15.2 9.5 16.0 10.1 0 4.9 2.1 4.9 1.3 8.9 5.6 9.4 5.9 5 25 10 16 2 79 50 84 53 * Observed number of angiosarcomas from "Epidemiological Study of Vinyl Chloride Workers," Final Report January 1978, prepared by Equitable Environmental Health Inc., Rockville, Md., for Manufacturing Chemists Association, Washington, D.C. * Model A, Probit % = -1.625+1.543 Log (dose); Model B, % = -].48 + 0.389x 10"3 (dose); Model C, % = 0.3565 x 10-3 (dose); Model D, % = [1 -- ioo where /! -- 0.38 x 10"*. The constants in these models were obtained using the biotransformation and angiosarcoma incidence data for rats exposed to vinyl chloride (Gehring er o/., 1978). * Parts per million. anticipated that a few additional cases of hepatic angiosarcoma will occur in this population. It is comforting that an epidemic of cases, as has been envisioned by some, is not to be anticipated. As indicated in the beginning of the paper, the previous attempt to extrapolate data from experiments in rats to predict the occurrence of hepatic angiosarcoma in vinyl chloride workers appeared to overpredict the ob served incidence even when differences in the biotransformation of VC to active products by humans and rats were incorporated in the extrapolation. The foregoing analysis using a probit percentage incidence model (Model A) has revealed that data collected in experiments on rats may be used to predict the incidence of hepatic angiosarcoma in humans with reason able accuracy. Further verification of this model will be assisted greatly by determina tion of the rate of biotransformation of VC by humans exposed to sufficient concentra tions of VC to allow such measurement. Currently, this must be estimated, by the rate of biotransformation in rats and its assumed relationship to body surface area (Gehring et al., 1978). Nonetheless, the correlation between predicted and observed incidence of hepatic angiosarcoma in vinyl chloride workers seems to justify both the assumptions and the model (Model A, Probit %) used to make the predictions. Since the predicted incidence of hepatic angiosarcoma in humans using results from studies in rats appears justifiable, it is of interest to use the same procedures to esti mate the incidence in workers exposed to 1 ppm 8 hr/day for a 35-year working life, the upper limit of the current Occupational Safety and Health Act standard. These predictions are shown in Table 5 for all four models. Models C and D predict an incidence OCC 6465 20 GEHRING, WATANABE, AND PARK TABLE 5 Predicted Incidence of Angiosarcoma in Workers Exposed to 1 ppm Vinyl Chloride 8 hr/day, 5 days/week for 35 years Using Biotransformation and Angiosarcoma Incidence Data from Studies in Rats* estimate, reliably, the risk of developing angiosarcoma in persons exposed to VC. There is every reason to believe that similar data can and should be used in the assess ment of risk of exposure to specified levels of other substances. (A) Probii % or logarithm probability J.5x or 1.5/100,000,000 (B) Linear not forced through origin None predicted below exposures of 98.7 ppm. (C) Linear forced through origin 1.7 x 10-3% or 1.7/10,000 or 377/1,000,000 (D) One-hit model (CAG) 1.89x 10~3% or 1.9/10,000 or 189/1,000,000* V * Rat equivalent daily dose of biotransformatioo products received by workmen exposed for 8 hr to 1 ppm vinyl chloride is: V -- [3675 /ig/hr-2.S6 ,ug/Hter]/[S60 pgfliter + 2.56 pg/litcr] = 4.97 ug/8 lir. comparable to that experienced by workers exposed to much higher levels, again revealing their inadequacy because of overprediction. Model B, although a linear model, predicts zero response at 98.7 ppm VC. Thus, ex posures to levels below this are not predicted to induce hepatic angiosarcoma. Using what appears to be the most reliable model (Model A, Probit %), the predicted inci dence of hepatic angiosarcoma is 1.5 x 10'6% or 1.5 cases in 100,000,000 workers. It is emphasized that use of Models A, C, and D to predict the incidence of hepatic angiosarcoma in workers exposed to 1 ppm VC assumes no threshold or even an in flection point in the dose-response curve (even though a threshold might occur). In summary, the use of animal data for the assessment of risk in humans exposed to a chemical is not as mystical as frequently assumed. Dose-response data for the in duction of angiosarcoma in rats exposed to various levels of VC together with attendant biotransformation data have been used to REFERENCES Barbin, A., Bresil, H., Croisy, A., Jacquignon, P., Malavielle, C., Montesano, R., and Bartsch, H. (1975), Liver-microsome-mediated formation of alkylating agents from vinyl bromide and vinyl chloride. Biochem. Biophys. Res. Comm. 67, 596603. Bartsch, H., Malavielle, C., and Montesano, R. (1975). Human, rat, and mouse liver mediated mutagenicity of vinyl chloride in Salmonella typhimurium strains. Jnr. J. Cancer 15, 429-437. Bolt, H. M., Kappus, H., Kaufmann, R,., Appel, K. E., Buchter, A., and Bolt, W. (1975). Meta bolism of '*C-vinyl chloride in vitro and in vivo. Inserm 52, 151-164. Bolt, H. M., Kappus, H., Buchter, A., and Bolt, W. (1976). Disposition of (l,2-`*C)vinyI chloride in the rats. Arch. Toxicol. 35, 153-362. Creech, J. L,, and Johnson, M. N. (1974), Angio sarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16, 350-151. Fox, A. L., and Collier, P. F. (1977). Mortality ex perience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Brit. J. Jnd. Med. 34, 1-10. Gehring, P. J., Watanabe, P. G., and Park, C. N. (1978). Resolution of dose-response toxicity data for chemicals requiring metabolic activation: Example--vinyl chloride. Toxicol. Appl. Pharmacol. 44, 581-591. Kappus, H., Bolt, H. M., Buchter, A., and Bolt, W. (1976). Liver microsomal uptake of ["C]vinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol, Appl. Pharmacol. 37, 461-471. Mark, L., Delmore, F., Creech, J. L., Ogden, L. L., Fadell, E. H,, Songster, C. L., Clanton, J., Johnson, M. N., and Christopherson, W. H. (1976). Clinical and morphologic effects of hepatic angiosarcoma in vinyl chloride workers. Cancer 37, 149-163. Malavielle, C., Bartsch, H., Barbin, A., Camus, A. M., and Montesano, R. (1975). Mutagenicity of vinyl chloride chloroethyleneoxide, chloroacetaldchyde, and chlorocthanol. Biochem. Bio phys. Res. Commun. 63, 363-370, OCC 6466 >ping VC. milar 5sessels of ON, P., RTSCH, tion of 1 vinyl 7, 596- ,NO, R. ediated monella 437. Appel, . Metain vivo. d Bolt, oridc in VINYL CHLORIDE--RISK. ASSESSMENT 21 Maltoni, C.. and Lefemine, G. (1975). Carcino genicity assays of vinyl chloride: Current results. Ann. N.Y. Acad. Sci. 246. 195-224. Tabershaw, I. R,, and Gaffey, W. R. (1974). Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16, 509-518. Watanabe, P. G., McGowan, G. R., Madrid, E. O., and Gehring, P. J. (1976a), Fate of [14C]vinyl chloride following inhalation exposure in rats. Toxicol. Appl. Pharmacol. 37, 49-59. Watanabe, P. G., McGowan, G. R., and Gehring, P. J, (1976b). Fate of [1,`C]vinyl chloride after single oral administration in rats. Toxicol. Appl. Pharmacol. 36, 339-352. Watanabe, P. G., Hefner, R. E., Jr., and Gehring, P. J. (1976c). Vinyl chloride induced depression of hepatic nonprotein sulfhydryl content and effects On bromosulphthalein (BSP) clearance in rats. Toxicology 6, 1-8. Watanabe, P. G,, Zempel, J, H,, Pegg, D. G., and Gehring, P. J. (1978). Hepatic macromolecular binding following exposure to vinyl chloride, ToxT col. Appl. Pharmacol. 44, 571-579. ality ex chloride chloride 0. c, C. N. ity data .ivation: armacol. d Bolt, `C]vinyl kylating acol. 37, Ogden, LANTON, j, W. H. f hepatic . Cancer . Camus, agcnicity chloro*m. Bio-" ' i i ! i ; ; ; j I i l OCC 6467 vc.VJWiriV?'' j 'n-M `V'A i i A o i ; : ,, v A : Cancer Mortality in U.S. and Related industries by Thomas i. Mason* Counties in the United States have been identified with chemical establishments whose primary manufacturing processes use vinyl chloride. Site-specific cancer mortality comparisons have revealed an excess of multiple myeloma in males associated with two of the manufacturing categories, synthetic rubber and synthetic fibers. A causal rela tionship between these manufacturing categories and multiple myeloma couid not be established. An industry-based assessment of the occupational contribution to this excess is needed to evaluate the etiologic importance of this relationship. Introduction Anviosarcoma-of the liver-baa.bffp_p-r4eatified among workers who are heaffily exposed to wipvl chloHde~TT!g)TThere lshe possibility Juiat individuals residing in areas with manu facturing plants using vinyl chloride may be exposed to this chemical. The present investiga tion of site-specific cancer mortality by county evaluates the risk of malignancy among resi dents of counties in the United States with possible environmental exposure to vinyl chloride. Methods The 1963 Census of Manufacturers (S) was used to identify counties with chemical estab lishments identified by Standard Industrial Classification (SIC) codes 2821-2824. These establishments are engaged primarily in manu facturing plastics materials and synthetic resins (SIC 2821), synthetic rubber (SIC 2822), cellulosic man-made fibers (SIC 2823), or synthetic organic fibers (SIC 2824). Vinyl chloride is not used in manufacturing cellulosic fibers. The category was included, however, to complete SIC Groups No. 282 which was selected to represent plastics and related in- ' Epidemiology Branch, NCI, Landow Building, Bethesda, Maryland 20014. dustries. The number of people employed in each of the four manufacturing categories was then obtained for individual counties in the United States. As such this is a conservative estimate because classification is a function of the main items manufactured. Counties in each of the four manufacturing categories were ranked on the proportion of the total county population employed. Those counties in the upper quartile of the distribution of nonzero proportions-for each manufacturing category were retained as study counties. As a compari son group, two counties were chosen for each study group county, matched by state and the per cent of the population living in urban areas (4). Site-specific cancer mortality rates were calculated for the white population in study and control counties as well as the total United States for the period 1950 to 1969 and its four 5-yr component intervals. Mortality data by age, race, sex, cause of death, and county of usual residence were provided by the National Center for Health Statistics. Population esti mates were obtained from published census statistics of 1950, 1960, and 1970, and intercensal estimates were derived by linear inter polation. All rates were age-ad] usted by the direct method with the total U.S. population 1960 as the standard, and are expressed per 100,000. Rates were calculated for 29 individual sites and 6 combined sites (5). The variance June 1975 OCC 646879 FIGURE 1. Study counties with chemical establishments primarily engaged in manufacturing plastics materials and synthetic resins with associated controls. Upper 25% of counties ranked on proportion of their total 1963 population employed in manufacturing category SIC 2821 and controls. for each mortality rate was-calculated by fol lowing the methodology of Chiang (6). Com parisons for males were made to the total United States as well as to control counties, utilizing a standardized normal test of signifi cance at p = 0.05 (7). Comparisons for females were made for only those sites for which a significant male excess had been detected. Results Figures 1^4 identify study counties (upper 25 Jo of the distribution of proportions of in dividual county populations employed in each manufacturing category) and their respective controls. The geographic patterns are distinct for each category, since no county satisfied the selection criterion for more than one type of manufacturing. Demographic characteristics for individual counties (Table 1) were taken from the 1960 Census (-4). There are marked differences for urbanization between the cate gories, i.e., synthetic rubber manufacturing takes place in highly urbanized areas, whereas fibers are made in rural places. Age-adjusted cancer mortality rates for each manufacturing category were compared initially to total U.S. rates, and then to control counties. Table 2 presents only those rates for sites in white males which were significantly (p < 0.05) greater than the total U.S. and control counties. No anatomic site of cancer was found excessive in more than one manufacturing category for the 20-year period 1950-69. Also, no significant excesses were found for counties manufacturing cellulosic fibers. Due to disease classification changes in 1958, rates for primary liver cancer [ICD 155.0, Seventh Revision ICD ()], were calculated for the interval 1958-1967. This includes angiosarcoma deaths which were not separable from other forms of liver cancer in our mor tality data. Of the counties considered, only those with synthetic rubber manufacture had 80 Environmental Health Perspectives OCC 6469 ,U*H - ,T-' $Z**v, IK & -s & M 3$a? Figure 2. Study counties with chemical establishments primarily engaged in manufacturing synthetic rubber with associated controls. Upper 25% of counties ranked on proportion of their total 1963 population employed in manufacturing category SIC 2822 and controls. consistently greater rates lor livff,r_re-nr.gr in ft>not significantly greater than that of 2U3<for general than thoj-ntai TT s ratp nf 1.34 for tBeurrohI7(Ji~couittiea. . White 'male's7~Ho\vever, the rate of 2.71 for V'ft r-LCohipansons ot daTl for females by manu- counties manufacturing synthetic rubber -was facturing category were restricted to those ^-----------=------------------------ 1 ^ anatomic sites for -which a male excess had been Table 1. Characteristics of counties for manufacturing categories and controls. detected. The only ^ite with a significant excess in comparison to both total U.S. and controls Plastics (SIC 2S21) Syn thetic rubber (SIC 2822) Cellu- losic fibers (SIC 2823) Syn thetic fibers (SIC 2824) was lung cancer in counties with synthetic rubber manufacture. The rates were 7.74 (study group), 6.72 (control), and 6.29 (total U.S.). Time Trends Associated -with Manufacturing Number of counties Total popula tion, 1960 Range employed in the specific category, % Urban, % Manufac turing Control 21 4 979,417 514,649 0,5-3.7 0.6-2.4 50.2 47.0 80.2 90.4 5 130,105 4.3-10.1 33.9 48.2 5 220,798 2.4-1.4 43.1 4177 Categories Time trends were investigated by subdividing the interval of study (1950-1969) into'four 5-yr intervals and comparing mortality rates for all sites of cancer which were included in the 20-yr comparisons. Significant differences for males were detected for two sites (cancer of the rectum and multiple myeloma) which were Weighted averages of individual county estimates. not at excess for the total time period, and June 1975 OCC 6470 81 Figure 3. Study counties with chemical establishments primarily engaged in manufacturing cellulosic man made fibers with associated controls. Upper 25% of counties ranked on proportion of their total 1963 population employed in manufacturing category SIC 2823 and controls. Table 2. Age-adjusted mortality rates per 100,000 white males by manufacturing category for cancer sites which were significantly (p <0.05) greater than the total U.S. and control counties 11950-1969). Mortality rates per 100,000 Manu facturing Total Control counties U.S. counties Plastics (SIC 2S21) Testis (ICD 178)* Other endocrine (ICD 195) Synthetic Rubber (SIC 2S22) Nasal sinuses, etc. (ICD 160) Lung (ICD 162,163) Bladder (ICD 181) Synthetic Fibers (SIC 2824) Multiple myeloma (ICD 203) 0.91 0.39 0.73 48.69 7.84 2.24 0.83 0.31 0.43 37.98 6.78 1.76 0.71 0.24 0.37 45.08 6.35 1.79 * All ICD numbers refer to the International Classifica tion of Diseases, Sixth Revision (9). b Includes suprarenal, parathyroid, thymus, pituitary, and pineal glands. these were excessive only in the interval 196&1969. For counties manufacturing plastici materials and synthetic resins, cancer of thf rectum in males remained constant in con trast to a decline in the control counties anc the total U.S. The rates were 7.30 per 100,00( per year for manufacturing, compared to 5.2< in control counties and 6.62 in the total Unitec States. For females, mortality rates for recta cancer declined over time in both manufactur ing and control counties. Mortality rates foi multiple myeloma among males m-cminU?s~^itt yntht rubher manufacture did notdBiei from controls and.total United atafes'througl For T9B5--19fiRr_hoxuever._the rates wen 46 fsfairiu^e-rrmn) , (control)- There was'~no comparable difierenci monf Decreasing Trends Mortality rates decreased in time for cancel 82 Environmental Health Perspective: OCC 6471 3 $ E3 -t**: -j*i-* :cjmus Z3 I 1 .rji.iitL II S FIGURE 4. Study counties with chemical establishments primarily engaged in manufacturing synthetic organic fibers with associated controls. Upper 25% of counties ranked on proportion of their total 1963 popula tion employed in manufacturing category 2824 and controls. of the testis in counties with plastics and syn thetic resin manufacture, and for cancer of the nasal cavity and accessory sinuses among- males in counties with synthetic rubber manufacture. Thg rate of decline..for testis was .greater for manufacturing counties than control counties afTd total Unfed States. For nasal cavity and, acCE5S0ry"silTuses7 mortality rates declined at a greater rate for control counties than the total U.S. and counties with synthetic rubber manu facture. Increasing Trends Lung cancer among males increased at a greater rate in control counties than in counties with synthetic rubber manufacture. The In crease in these manufacturing counties was greater than for the total U.S. For all other sites given in Table 2 (other endocrine, bladder, and multiple myeloma) the rate of increase was greater in the manufacturing counties than the controls, and also greater for both county categories than the United States rate for change. Discussion This .-investigation of the possible__ixealth hazard to residents df~UumiUffs in UieUnited ^iates with chemicaTehlabtishiiigtitslising vlnvl m din it variables on^theresults cou be completely controlled for. The selection cfjfjrtsrT'or control "couhtiei takes into am-" siteration the effect of urbanization and also regional ditferencesjn diagnosis. However/flie effect of cigarette smoking which is associated \^ith cancers of the lung and bladder (TO1 could not be controlled for. The finding of excess mortality tor lung cancer among men~~and womeirTfTcounties with synthetic rubber manu facture could be due to differences in ~smo5ing habits, and not be directly related to the rrjnfiu- June 1975 83 OCC 6472 featuring process. Thece is^_also a dilutiqna) en^cnvhicVi may urevent~TKe~~idenfiTjcafioii of excesses among small snheets of the population with relei^nt exposure. The reported excess of angiosarcomapf thp-liver among vinyTchlonde workers~Wvs~not detected in this investigation. ThisJs duetothe grouping of diagnoses in disease classfficaHon as lyeTl^fts the small number of casesT'No^refinement oithe^data to'smaller j'poprnfetTon units than counties, however, was possible. Mortality rates for cancers of the nasal cavity and accessory sinuses and bladder among males were excessive only in counties with synthetic rubber manufacture. This find ing may be unrelated to the manufacturing of synthetic rubber, but is consistent with previous findings suggesting that chemicals may be carcinogenic at the sites of absorption and excretion {11). Occupational studies have reported excess mortality due to cancers of the digestive system, liver and biliary tract,' lung, brain, and lymphatic and hematopoietic tissues among vinyl chloride workers {1,2). The only sitespecific comparison which detected increases for males in more than one of these manufactur / ing categories was for multiple myeloma. Mortality rates for this site were greater for counties with synthetic rubber and synthetic fiber manufacture than their corresponding controls and the total United States. An excess tiplo Jiyalnmn in fii-mari; has'TTePn re- Ifpfl P9) i Tlng_rnay relate to the male excess <o in the rural couhties(l[^%~1irrban) witTPs'yn- theHcfitfer maiiufacfureTTlowever, it does not explain the finding of an excess for males in counties with synthetic rubber manufacture (80.27c urban). Multiple myeloma is included in the broad classification for cancers of lymphatic and hematopoietic tissues. An evalua tion of the contribution of mortality from this site to the excess for the broader classification among vinyl chloride workers is needed. Acknowledgements The critical review of this manuscript by Robert W. Miller, M.D., Joseph F. Fraumeni, Jr., M.D., and Robert Hoover, M.D. is gratefully acknowledged, as well as the technical assist ance of Frank W. McKay in the computerized preparation of the figures. REFERENCES 1. Monson, R. R., Peters J. M., and Johnson, M. N. Proportional mortality among vinyl chloride work ers. Lancet 2: 397 (1974). 2. Tabershaw, I. R., and Gaffey, W. R. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup, Med. 16: 509 (1974). 3. U.S. Bureau of the Census. Census of Manufac turers, 1963, Vols. 1, II. U.S. Government Printing Office, Washington, D.C., 1966. 4. U.S, Bureau of the Census. U.S. Census of Popula tion: 1960, Vol. I, Characteristics of the Population. Parts 2-52. U.S. Government Printing Office, Wash ington, D.C., 1963. 5. Mason, T. J, and McKay, F. W. U.S. Cancer Mortality by County: 1950-1969, U.S. Government Printing Office, Washington, D.C., 1973. 6. Chiang, C. L. Standard Error of the Age-Adjusted Death Rate (Vital Statistics Selected Reports, 47, 9). U.S. Government Printing Office, "Washing ton, D.C., 1961. 7. Dixon, W. J., and Massey, F. J. Introduction to Statistical Analysis. McGraw-Hill, New York, 1969. 8. World Health Organisation. Manual of the Inter national Statistical Classification of Diseases, In juries, and Causes of Death, 7th Revision, Adopted 1955. Vol. 1. World Health Organization, Geneva, Switzerland, 1955. 9. World Health Organization. Manual of the Inter national Statistical Classification of Diseases, In juries, and Causes of Death, 6th Revision, Adopted 1948. Vol. 1. World Health Organization, Geneva, Switzerland, 1948. 10. Hammond, E. C, Smoking in relation to death rates of 1 million men and women. In: Epidemiological Study of Cancer and Other Chronic Diseases, Natl. Cancer Inst. Monograph No. 19, U.S. Government Printing Office, Washington, D.C., 1966. 11. Cole, P., Hoover, R., and Friedell, G. H. Occupation and cancer of the lower urinarv tract. Cancer 29: 1250 (1972). 12. Milham, S. Jr. Leukemia and multiple myeloma in farmers. Amer. J. Epidem. 94: 307 (1971). 84 Environmental Health Perspectives OCC 6473 FACT SHEET VINYL CHLORIDE AND HEALTH When any questions of employee or community health arise, such as occurred during the Burlington Township Planning Board hearings on Tenneco's plant modernization program, everyone involved with the facility is naturally concerned. Tenneco management firmly and sincerely believes that neither our Burlington employees nor the the community have any cause for concern. Our confidence is based on two factors: 1) Comparison and evaluation of all the scientific data compiled by independent sources on this subject. 2) The actual experience of vinyl chloride plants during the 40 years the industry has been oper ating in this country. The issues and the facts can be summarized as follows: DOES EXPOSURE TO VINYL CHLORIDE MONOMER (VCM), THE RAW MATERIAL USED BY TENNECO'S BURLINGTON PLANT, INCREASE THE RATE OF BIRTH DEFECTS IN CHILDREN? Facts: 1) The principal research cited at the Planning Board hearings to indicate increased risk was a 1974 study of communities in Ohio with vinyl plants which showed a higher-than-normal rate of birth defects. The researcher attributed these to exposure to vinyl chloride. OCC 6474 -- z. -- Following publication of this study, the Center for Disease Control (CDC) of the U.S. Public Health Service conducted two investigations of its own. The first, which reviewed the original work in Ohio, concluded that the evidence available "did not establish any association between (birth defect) cases and vinyl chloride exposure." Specifically, it found that non,e of the parents of the affected children had ever worked in a vinyl plant. The CDC's second investigation studied Charleston, West Virginia, site of a vinyl chloride plant since 1948. The CDC concluded that "no relationship between infants with malformations and parents' exposure to vinyl chloride could be established." 2) Many other studies with mice and rats in the U.S. and England, and conducted at exposure levels ranging from 50 parts per million to 50,000 parts per million, have produced no evidence that vinyl chloride causes birth defects. For example, a study for the Consumer Product Safety Commission (CPSC) on these animals failed to detect any evidence of birth defects caused by vinyl chloride monomer. CAN EXPOSURE TO VCM CAUSE CANCER AMONG EMPLOYEES OR PERSONS LIVING IN THE COMMUNITY? 1) When the question of possible risk was first raised, the federal Environmental Protection Agency (EPA) calculated (more) that, based on national mortality rates, for the 10 years between 1964-74 there should be only 6 cases of angiosar coma among 5 million people if vinyl chloride posed no risks. The EPA then studied the 5 million people living within a five-mile radius of vinyl plants in the U.S. and found not 6 angiosarcoma cases during that period but only 3. In other words, there were actually fewer cases than would have been expected if no vinyl chloride plants existed in these communities. It should also be noted that during the period covered by these studies, vinyl chloride emissions were not controlled. Since then, permissible emission levels have been drastically reduced by the Occupational Safety and Health Administration (OSHA). 2) Tenneco's health records include no cases of angiosar- -4 coma (liver cancer - the type of cancer.thought to be associated with exposure to vinyl chloride monomer) in any plant employee and Tenneco has been operating vinyl plants for more than 20 years. 3) In the previously-mentioned CPSC research, in which t rats and mice were tested at VCM exposures up to 50,000 parts per million, no angiosarcoma cases were found. 4) Vinyl chloride used to be used as a propellent in hair sprays, which brought relatively high concentrations into close proximity with a woman's face. There are no indica tions that this exposure produced angiosarcoma among women. (more) OCC 6476 CAN DUST OF POLYVINYL CHLORIDE (PVC), THE PLASTIC RESIN PRODUCED BY THE BURLINGTON PLANT, CAUSE CANCER? Facts: 1) Scientific studies indicate PVC dust poses no health hazard to people, animals or plants. 2) During more than 40 years of PVC production, extensive research has consistently shown that employees in vinyl plants are as healthy as workers in other industries, and healthier than the general population. 3) National Cancer Institute statistics show that Burlington County's cancer mortality rate is 9% below the New Jersey State average. OCC 64T7