Document YGb7Q0vOOBj2QLgVxRdaD2avO

*A: CSf'flZ Ew'iroHmenta( Health Per*i>et't>\e?i Vol. pp. wr-llJ, 19*1 y / '* -* R&S 116797 ^ /rm * f ** Epidemiology of Hepatic Angiosarcoma in the United States: 1964-1974 * W* ' - . by Henry Falk,*f John Herbert,* Steven Crowley,* Kamal G. Ishak,* Louis B. Thomas,** Hans Popper and Glyn G. Caldwell* A nationwide survey of hepatic angiosarcoma (HAS) in the United States during the years 1964 through 1974 identified 168 cases. Of these, 42 cases (25%) were associated with known etiologic factors, such as vinyl chloride monomer exposure during preparation of poly(vinyl chloride), use of Thorotrast in angiography, exposure to inorganic arsenic, and treatment with androgenic* anabolic steroids; 126 cases (75%) are of uncertain etiology. HAS most often affects males (ratio of approximately 3:1), peaks in the sixth and seventh decades of life (somewhat earlier than other sarcomas of the liver) and appears to occur more often in the industrialized Northeast and Midwest (although reporting artifact may be a factor). There is an extraordinary relative risk for poly(vinyl chloride) polymerization workers; there may also be other chemical-industrial associations that require further investigation. Prospective epidemiologic studies of HAS should be considered as a means of identifying other causative factors (e.g,, chemicals or drugs) related to HAS. Introduction This report is an overview of the nationwide hepatic angiosarcoma (HAS) case-finding study for the years 1964-1974 conducted by the Centers for Disease Control (CDC). At the start of this study, three causative factors had been identified for HAS: vinyl chloride mono mer (VCM) (1, 1), Thorotrast 73), and inorganic arsenic* U). The recently discovered association between VCM and HAS has served as a stimulus for this investigation, and multiple epidemiologic studies of polyvinyl chloride (PVC) polymerization -Chronic Diseases Division, Center for Environmental Health, Centers for Disease Control. Public Health Service, U.S. Dept, of Health and Human Services, Atlanta, Georgia 30333. -Author to whom reprint requests should be addressed. ^Department of Hepatic Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20012. --Laboratory of Pathology, National Cancer Institute, Na tional Institutes of Health. Bethesda, Maryland 20014. SStratton Laboratory for Liver Disease. Mount Sinai School of Medicine of the Citv University of New York, New York 10029. workers exposed to VCM have since demonstrated very high relative risks for the development of HAS (5, 6). Thorotrast is a colloidal suspension of thorium dioxide, a radioactive alpha-emitter with markedly prolonged radiologic and biologic halflives, which was used for carotid angiography and liver-spleen scans in the period 1930-1955. The thorium dioxide is sequestered by the reticuloendo thelial system, primarily in the Kupffer cells of the liver: radiation injury to adjacent cells is the presumed carcinogenic mechanism. Epidemiologic studies of Thorotrast recipients have shown very high relative risks for the development of HAS as well as hepatocellular tumors (7, 8). The association between arsenic and HAS is based on data from several small autopsy series in German vintners in the 1940s and 1950s U. 9), which demonstrated an increased incidence of liver disease, including HAS. These workers were exposed to inorganic arsenical pesticides during application of the pesticide and also by drinking beverages prepared from the skins of the sprayed grapes. Subsequently, HAS cases were reported following long-term ingestion of Fowler's solution (potassium arsenite) (10. ID and October 1981 107 t DO flo /) o> -si <oo0 arsenic-contaminated well water (12). Individual cases suggesting associations between HAS and hemochromatosis (IS) and copper exposure (U) have also been reported. Earlier reports from this study reviewed cases associated with single causative factors (15-18), including androgenic-anabolic steroids which we feel are implicated as a fourth cause of HAS (19). In this paper, we present an overview of the case finding effort, placing the known causative factors and cases of idiopathic origin in perspective. Methods Information relating to cases of HAS occurring in the United States during the years 1964 through 1974 was solicited by CDC in a variety of ways: (1) announcements were placed in seven medical journals; (2) a mailing was sent to all pathologists in the country; (3) separate mailings were sent to all state epidemiologists, major tumor referral centers, and statewide tumor registries; (4) a death certificate review for International Classification of Diseases (ICD), Eighth Revision, Code 197.8 (liver tumors, unspecified primary or secondary) for the period 1966-1973 was conducted with the assistance of the National Center for Health Statistics (NCHS) and the 50 state health departments (Code 155.0, primary liver tumors, was not reviewed because it would have been impractical to obtain the much larger number of certificates in this category and because it was felt that the majority of cases of HAS listed as such on the death certificate would have been coded as 197.8); (5) arrangements were made with the Armed Forces Institute of Pathol ogy (AFIF) to include cases in their files (1943-1975) in the review; (6) a number of cases were identified from industrial surveys of PVC polymerization workers and others potentially exposed to VCM; and (7) permission was requested to include the previously published cases of HAS occurring in 1964-1974. The evaluation procedure for each identified case was as follows: Initially, permission was requested to review the appropriate pathologic specimens (all submitted non-AFIP case material was reviewed at the National Cancer Institute's Laboratory of Pa thology by H. P. and L. B. T.). Following confirmation of the diagnosis, the local physician was notified, and, with his permission, the nearest of kin was identified and contacted. Consent was obtained to review medical records, and a questionnaire was administered by telephone to obtain detailed occu pational, residential, and chemical exposure histo ries. In selected instances, friends, employers, previous physicians or others were also interviewed. 108 0 In all, approximately 350 submitted cases were reviewed by the pathology review group, som^^ outside our requested time period of 1964-1974^^ Pathologic specimens were obtained for review in approximately 95% of cases, many of which were considered by our pathology panel not to be HAS. Since survival after diagnosis is very brief and many cases were only diagnosed at autopsy, we have included all 168 confirmed cases with death during 1964-1974 in the study group. The above effort is essentially a case review. Subsequently, the 22,432 death certificates obtained from the review of Code 197.8 were used to carry out a case-control study of occupation as recorded on the death certificate in the following manner. Death certificates were sought for all 168 confirmed HAS cases; 166 were available. Controls were sought from among the 22,432 death certificates in ICD Eighth Revision Code 197.8 (liver tumor, unspecified primary or secondary) that had been obtained in the HAS case-finding effort (see above); certificates of confirmed HAS cases were excluded from the control selection process. Although deaths in Code 197.8 might not represent the ideal control group, the rationale was that these deaths resulted from a broad variety of tumors of multiple sites metastatic to the liver or represented cases which were diagnostically uncertain; it was therefore unlikely that any single diagnostic category would predominate or that the occupational listings woul be heavily biased by any single group of cases. Up to four controls (as many as were available) were matched to each case s* 30 years of age on the basis of the following criteria: age (6 years), sex, race, county of residence, and year of death (3 years). One hundred thirty-five cases were success fully matched (79 of these had 4 matched controls; the overall ratio of controls to cases was approxi mately 3:1). Individuals who could not be matched were primarily young females and residents of sparsely populated counties. A combined occupation and industry coding scheme was developed to accommodate all listings recorded on the certificates and to group listings on the basis of potential hazardous exposures. The data were analyzed by Rothman's method for matched groups with multiple controls per case (20). Results Our study identified 168 deaths from confirmed HAS during the years 1964 through 1974. For this rare tumor, the best sources of case identification were the pathologists, with the largest number of cases identified through the single mailing to all pathologists and the second largest number of cases Environmental Health Perspectives identified through pathology referral centers (par certificate survey (these latter cases were not ticularly the AFIP). confirmed by pathologic review). HAS has a strik Table 1 summarizes the results of the death ing male preponderance of approximately 3:1; this certificate review portion of the case-finding effort is not true for other hepatic sarcomas. HAS also and points up some of the inadequacies of using this appears to occur more often in younger age groups. method in epidemiologic studies of uncommon tu The higher proportion of males than females with mors. Only 42% of the cases initially identified on HAS first appears in the 40- to 49-year-old group the death certificate as HAS were confirmed as (Fig. 2) and is associated with a younger peak age such on pathologic review; 50% of the cases were for males than females, although the mean age for confirmed not to be HAS. Furthermore, only 23% female HAS cases (50.1 years) is lower than that for of all the total cases in our study during the years males (57.9 years). These findings are not solely 1966-1973 would have been identified by the death related to the VCM-induced cases among polymer certificate search alone. It can be seen that an ization workers. The male preponderance is also epidemiologic study based only on a death certificate present in the Thorotrast, arsenic, and androgenic- search ofC<xie 197.8 would have been quite inadequate. anabolic steroid associated cases, as well as in the Figure 1 compares age, race and sex data for the idiopathic cases (Table 2). Cases with known etiolo confirmed HAS cases in our study with 131 cases of gy, however, have a younger age distribution than non-angio hepatic sarcoma identified in the death idiopathic cases (Table 3), with a mean age of 51.0 years compared to 57.6 years for the idiopathic Table 1. HAS cases, CDC survey: death certificate review-- code 197.8 (8th revision ICO), 1966-1973 cases. Table 4 presents the 168 cases of HAS by year of death and etiologie status. The VCM-, Thorotrast- Length of review 7.5 years (1966-1971, 1973, 1/2 of 1972) t Total number of death certificates reviewed 22,432 and androgenic-anabolic steroid-associated cases were more common during the latter part of the study Sarcomas of the liver, death certificate diagnoses: Angiosarcoma (HAS) Leiomyosarcoma Fibrosarcoma 74 (36.1%) 24 (11.7%) 14 ( 6.8%) Table 2. HAS case*, CDC survey, 1964-1974: sex ratios, etiologie categories. Sarcoma (type unspecified) Sarcoma (other types) 64 (31.2%) _29 (14.1%) Male Female Ratio Total Final pathologic diagnoses of 74 cases identified on death certificate as HAS Confirmed HAS Confirmed not HAS No pathology available 205 31 (42%) 37 (50%) 6 ( 8%) Vinyl chloride Thorotrast Arsenic Androgenic-anabolic steroids Subtotal Idiopathic 12 15 4 3 34 93 0 (12 : 0) 5 ( 3 : 1) 2 ( 2 : 1) _1_ ( 3 : 1) 8 ( 4.3: 1) 33 ( 2.8: 1) R&S 116799 Figure 1. Hepatic angiosarcoma (HAS) cases compared with non-angio hepatic sarcoma cases, by age group: U.S., 1964-1974. October 1981 AGE GROUP(TEARS) Figure 2. Hepatic angiosarcoma cases, by age group and sex: U.S., 1964-1974 109 R&S 116800 Table 3. HAS eases, CDC survey, 1964-1974: age distribution for cases of known cause and for idiopathic cases. Age, yr Known etiology No. % Idiopathic No. % 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 *80 Total 1 ( 2) 0 ( -) 0 ( -) 4 (10) 8 (19) 22 (52) 4 (10) 3 ( 7) 0 ( -) 42 2 ( 2) 4 ( 3) 1 ( 1) 8 ( 6) 19 (15) 24 (19) 39 (31) 21 (17) 8 ( 6) 126 period. For the VCM- and androgenic-anabolic steroid-associated cases, this is due to the rela tively recent introduction of these causative agents. For the Thorotrast-induced cases, however, this pattern was an unexpected finding. Based on the originally calculated latent period of approximately 20 years (21), the general impression was that such cases would be diminishing by 1975. However, the number of cases appeared to still be increasing as of 1974, apparently due to an increase in cases having relatively low-dose angiographic procedures and prolonged latent periods (16). The arsenic-associated cases (including five adults with a history of pn^^ longed use of Fowler's solution and one child witfl^P environmental exposure) occurred primarily during the earlier years of the study and may represent the tail end of a larger problem in previous years. The number of idiopathic cases was low during the first few years of the study (perhaps related to poor recall by pathologists, and to the fact that the death certificate- search started with 1966). Case num bers, however, remained steady for most of the study period except for a.spurt in 1974. The latter occurred right after the original report and the attendant publicity of the first cases of VCM- induced HAS (January 1974) and may be related to improved diagnostic evaluation. Review of the idiopathic cases occurring in 1974 demonstrated a large number of elderly cases with no evidence of clustering in a particular exposure setting. The HAS mortality rate for the entire United States during the study period was 0.75 cases per 107 population per year. Crude mortality rates by region, based on county of residence at time of diagnosis (Table 5), suggest a somewhat higher incidence in the Northeast and in the industrial portions ofthe Midwest. There was also an increase in the mountain region, although this is based on a very small number of cases. The rates were low in farming states and in the South; however, since Table 4. HAS cases, CDC survey, 1964-1974; distribution by causative factors and year of death. 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 Idiopathic 4 10 9 13 12 13 11 12 13 11 18 Vinyl chloride 1 - - - 3 2 1 1- 3 1 Arsenic 1- 1 2 1- - - - 1-- Thorotrast --- 1 22324 1 5 Androgenic-anabolic steroids - - - 1- - - 1- 1 1 Total 6 10 10 17 18 17 15 16 17 17 25 Total 126 12 6 20 4 168 Region 1. New England 2. Mid-Alantic 3. E.N. Central 4. W.N. Central 5. S. Atlantic 6. E.S. Central 7. W.S. Central 8. Mountain 9. Pacific Total 110 Table 5. HAS cases, CDC survey, 1964-1974: distribution by region. States Pop. 1970 No. of cases (HAS/10V-) ME, NH. VT, MA, RI, CT NY, NJ, PA OH, IN, IL, MI, WI MN, LA, MO, ND. SD, NB, KS DE, MD, DC, VA. WV, NC, SC, GA, FL KY, TN, AL, MS AR, LA, OK, TX MT, ID, WY, CO, NM, AZ, UT, NV WA, OR, CA, AK, HI 11,847,186 37,152,813 40,252,678 16,324,389 30,671,337 12,804,552 19,322,458 8,283,585 26,525,744 203,184,742 12 (0.92) 38 (0.93) 35 (0.79) 10 (0.56) 23 (0.68) 7 (0.50) 12 (0.56) 10 (1.10) 21 (0.72) 168 (0.75) No. of idiopathic cases (idiopathic HAS/107/yr.) 9 (0.69) 28 (0.69) 30 (0.68) 9 (0.50) 15 (0.44) 1 (0.07) 10 (0.47) 7 (0.77) 17 (0.58) 126 (0.56) Environmental Health Perspectives  many cases are diagnosed only after referral to major hospital and tumor centers, it is possible that low rural rates could be artifactual. To summarize this portion of the study, it is apparent that HAS has a strong male preponder ance, that it appears to occur more often in younger age groups than other sarcomas of the liver, and that there may be geographic differences which are unrelated simply to the distribution of VCM associ ated cases (the largest number of which were in Kentucky and West Virginia). As part of the follow-up effort we looked at occupation in the death certificate case-control study. Table 6 shows that the case-control ratios were elevated only for the last two occupational categories. The first of these (#7) shows a highly significant difference for chemical workers that is entirely related to expo sure to VCM; all 10 cases were PVC polymerization workers. The last category (#8) combined a large number of laboring groups with potential exposure to a variety of chemicals; included are laborers, machinists, maintenance workers and others. The association of this heterogeneous grouping of occu pations with HAS is not statistically significant, nor in reviewing the individual occupational data from the interviews with family members were we able to identify a specific chemical, plant, or process as a causative factor. Nevertheless, taken together with the earlier findings, this association suggests that some chemical exposure or industrial factors may be related to a portion of the idiopathic cases. Such an association would not be unreasonable; machin ists, e.g., are potentially exposed to trichloroethyl ene (an experimental hepatocardnogen that is struc turally related to vinyl chloride), inorganic arsenic and nitrosamines (which have been identified in cutting fluids and are a known cause of HAS in animals) (22, 23). Discussion A particularly intriguing feature of HAS is that there are now four probable causes of this tumor, and yet about 75% of the cases are of uncertain etiology. Given that the HAS cases associated with the four quite distinct etiologic factors (VCM, Thorotrast, arsenic, and androgenic-anabolic ste roids) share a common morphologic progression to HAS which is indistinguishable from that of idio pathic cases (4), it is likely that additional causal factors are (or will be) associated with HAS. In this study, the male preponderance, the younger age distribution, the possible geographic relationship with industrial portions of the country, and the suggestion from the death certificate case-control October 1981 Study that groups with chemical exposure may be at higher risk, raise the possibility that some of the idiopathic cases may be related to presently unidentified environmental or occupational expo sures. This study and that of Baxter et al. (25) confirm the limited diagnostic reliability of death certificate diagnosis of HAS and the need to assess a variety of Table 6. Occupation aa recorded on death certificate, casecontrol study, CDC HAS survey, 1964-1974. Occupation Cases (N - 135) Control (N = 421) Professional, technical, engineers Managers, administrators Sales, wholesale/retail trade Clerical Communications Finance, insurance, real estate Business, store owners, proprietors Service workers Housewife, homemaker Military, government Unlisted, retired, disabled 16 5 3 9 1 2 5 8 18 2 5 40 23 29 13 5 4 11 36 58 3 12 74 (55%) 234 (56%) Agricultural (farming, stock, feed, fisherman) 4 (3%) 23 (5%) Mining Transport 1 (1%) 4 (3%) 8 (2%) 21 (5%) Carpenters, craftsmen 2 (1%) 9 (2%) Manufacturing (unspecified. untitled, other) 2 13 Lumber, logging, wood products 03 Metal, steel 05 Food, beverages, tobacco. packing 26 Textiles 39 Paper, printing 15 Rubber/plastics 12 Automobile - 0 1 --3 9 (7%) 46 (11%) Chemical Machinist-metal cutter 10 (7%) 1 (0%). P = 4.29 x 10-^ 7 14 Machine operators 0 8 Forgers, molders, casters 1 3 Painters 14 Sanitation, water works, power 3 2 Maintenance, custodians 5 9 Laborers 8 20 Construction 12 Heavy equipment operators 2 6 Repair services 15 Mechanics ""2 6 31 (23%) 79 (19%) p = 0.11* Statistical analysis for case-control study with multiple matches (20). Ill R&S 116801 R&S 116802 sources of data in order to identify cases for studies of rare tumors such as HAS. The Thorotrast data are instructive because the initial estimate of the latency period has lengthened with time; recent cases have been in individuals who had relatively low-dose procedures but pro longed latent periods (16), This accentuates the need to continue evaluation of VCM exposed groups for the possible appearance of a similar pattern. The time frame covered by our study is perhaps too early to detect a sizable number of cases with relatively low VCM exposure either in occupational or environmental settings. In addition, Thorotrastinduced HAS was noted approximately 10 years before Thorotrast-induced hepatocellular tumors were recognized; given the identical morphologic appearance after VCM exposure, involving mixed hyperplasia of sinusoidal cells and hepatocytes, and the occurrence of hepatocellular tumors in experi mental animals exposed to VCM (26), we need to continue to follow-up VCM-exposed cohorts for the possible appearance of hepatocellular tumors. Cases of HAS associated with various factors have previously been reported (U, 27, 28); individ ual cases associated with hemochromatosis, prior radiotherapy, chloroprene exposure and chemother apy with urethane were also noted in this study, but we have not discussed them in detail here. Itwould appear valuable to continue epidemiologic studies of this rare tumor. This might enable early detection of additional etiologic factors for this disease, such as the various structural analogs of vinyl chloride (e.g., vinyl bromide and vinylidene chloride) which have had industrial use. However, because of the difficulty and time involved in establishing adequate surveillance for rare tumors such as HAS or mesothelioma, it would be best to establish a single framework for studying a number of rare tumors or marker illnesses at once. One would then be able, e.g., to survey pathologists or other groups at a single time to obtain information on a variety of such conditions. HAS is a rare tumor with at least four probable causes and undoubtedly others that have not yet been identified. Ascertainment of the range of causative agents for HAS, as well as for more common tumors, presents a challenge to epidemiol ogists. We acknowledge the support of Clark W. Heath, Jr., Matthew Zack, Joyce Cannon, Robert Albin, Alice Little and Caroiyn Forrester of the Centers for Disease Control; Paul Leaverton of the National Center for Health Statistics; Irving J. Selikoff of the Mount Sinai School of Medicine; Norman C. Telles of the Bureau of Radiologic Health; and Donald M. Austin of the California Tumor Registry. We particularly appreciate the 112 %support of the many physicians, pathologists, and tumor regi trars who provided information and participated in the study| REFERENCES 1. Creech, J. L., Jr., and Johnson, M. N. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J. Occup. Med. 16: 150-151 (1974). 2. Falk, H., Creech, J. L., Jr., Heath, C. W., Jr., Johnson, M. N., and Key, M. M. Hepatic disease among workers at a vinyl choloride polymerization plant. J. Am. Med. Assoc. 230: 59-63 (1974). 3. MacMahon, H. E., Murphy, A. S., and Bates. M. I. Endothelial-cell sarcoma of liver following Thorotrast injec tions. Am. J. Pathol. 23: 586-561 (1947). 4. Roth F. Arsen Lebertumoren (Hemangioendotheliom). Z. Krebsforsch. 61: 468-503. 1957. 5. Waxweiler, R. J., Stringer, W,, Wagoner, J. K., Jones, J., Falk, H., and Carter, C. Neoplastic risk among workers exposed to vinyl chloride. Ann. N.Y, Acad. Sci. 271: 40-48 (1976). 6. Spirtas, R., and Kaminski, R. Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers--1977 update of the NIOSH register. J. Occup. Med. 10: 427-429 (1978). 7. Da Silva Horta, J., Da Motta, L. C., and Tavares, M. H. Thorium dioxide effects in man--epidemiological, clinical and pathological studies (experience in Portugal). Environ. Res. 8: 131-159 (1974). 8. Faber, M. Twenty-eight years of continuous follow-up of patientB injected with thorotrast for cerebral angiography. Environ. Res. 18: 37-43 (1979). 9. Roth, F. Delayed sequelae of chronic arsenism in vintners on the Moselle. Deut. Med. Wochenschr. 82:211-217 (1957). 10. Lander, J. J., Stanley, R. J., Sumner, H. W., Boswell, C., and Asch, R, D. Angiosarcoma of the liver associates with Fowler's solution (potassium arsenite). Gastroenterol ogy 68: 1582-1586 (1975). 11. Regelson, W., Kim, U., Ospina, J., and Holland, J. F. Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer 21:514-522 (1968). 12. Rennke, H., Prat, G. A., Etcheverry, R. B., Katz, R. U., and Donoso, S. Hemangioendothelioma maligno del higado y arsenirismo cronico. Rev. Med. Chile 99: 664-698 (1971). 13. Sussman, E. B,, Nydick, I., and Gray, G. F. Hemangio endothelial sarcoma of the liver and hemochromatosis. Arch. Pathol. 97: 39-42 (1974). 14. Pimentel, J. C., and Menezes, A. P. Liver disease in vinyard sprayers. Gastroenterology 72: 275-283 (1977). 15. Berk, P. D., Martin, J. F., Young, R. S., Creech, J., Selikoff, I. J., Falk, H., Watanabe, P., Popper, H., and Thomas, L. Vinyl-chloride-associated liver disease. Ann. Intern, Med. 84: 717-731 (1976). 16. Falk, H., Telles, N. C., Ishak, K. G., Thomas, L. B., and Popper, H. Epidemiology of Thorotrast-induced hepatic angiosarcoma in the United States. Environ. Res. 18: 65-73 (1979). 17. Falk, H,, Herbert, J. T., Edmonds, L., Heath, C. W., Jr., Thomas, L. B., and Popper H. Review of 4 cases of childhood hepatic angiosarcoma-elevated environmental ar senic exposure in one case. Cancer 47: 382-391 (1981). 18. Falk, H., Caldwell, G. G., Ishak, K. G., Thomas, L. B. and Popper H. Arsenic-related hepatic angiosarcoma. Am. J. Ind. Med. (in press). 19. Falk, H., Thomas, L. B,, Popper, H. Ishak, K. G. Hepatic angiosarcoma associated with androgenic-anabolic steroids. Lancet 2: 1120-1123 (1979). Environmental Health Perspectives 20. Rothman, K. J. Computer analysis for case-control studies with individual matching. Int. J. Biomed. Comput. 5: 241-247 (1974). 21. Baserga, R., Yokoo, H., and Henegar, G. C. Thorotrastinduced cancer in man. Cancer 13: 1021-1031 (1960). 22. LARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 20: Some Halogenated Hydrocarbons. Trichloroethylene. IARC, Lyon, 1979, pp. 545-72. 23. Rappe, C., and Zingmark, P. A. Formation of Nnitrosamaines in cutting fluids. In: Environmental As pects of fif-Nitroso Compounds. E. A. Walker, et al., Eds., IARC Scientific Publication 19, Lyon, 1978. 24. Popper, H., Thomas, L. B., Telles, N. C,, Falk, H., and Selikoff, I. J. Development of hepatic angiosarcoma in man induced by vinyl chloride, Thorotrast, and arsenic-- comparison with cases of unknown etiology. Am. J, Pathol. 92: 349-376 (1978). 25. Baxter, P. J., Anthony, P. R,, MacSween, R. N. M., and Scheuer, P. J. Angiosarcoma of the liven Annual occurrence and aetiology in Great Britain. Brit. J. Ind. Med. 37:213-221 (1980). 26. Maltoni, C. Predictive value of carcinogenesis bioassays. Ann. N.Y. Acad. Sci. 271: 431-47 (1976). 27. Locker, G. Y., Doroshow, J. H., Zwelling, L. A., and Chabner, B. A. The clinical features of hepatic angiosarcoma: A report of four cases and a review of the English literature. Medicine 58: 48-64 (1979). 28. Daneshmend, T. K., Scott, G. L., and Bradfield; J. W. B. Angiosarcoma of liver associated with Phenelzine. Brit. Med. J. 10: 1679 (1979). R&S 116803 October 1981 113 DOW CHEMICAL U.S.A. 1803 Building December 6, 1982 MIDLAND. TO: J. M. Lanham, M.D. cc: R. R. Cook B. B. Holder J* E. LeBeau J. R. Venable SUBJECT: ALBERTA AMBIENT AIR STANDARDS FOR VINYL CHLORIDE I have reviewed the two articles you provided that form the basis for Alberta's assessment of ambient air standards for vinyl chloride |^Falk^t^il^l98^0^and Kuz^uack and Mc^aughy (1975)]. The Falk et al. article appears to be a well-balanced account of the epidemiology of hepatic angiosarcoma (HAS) in the United States. What is lacking is an assessment of VCM exposure intensities associated with VCM induced cases of HAS. Further more, there Is no indication of whether or not HAS cases were associated with proximity to VCM emission sources. Apparently this was not the case, since it would have been pertinent to report such an association. A cautionary note was sounded in that for thorotrast-induced HAS cases, lower exposure was asso ciated with longer latency. However unlike VCM, thorotrast is persistent in the body. 1 have enclosed a similar article on the epidemiology of HAS in Great Britain (Baxter et al.). That study did not include controls when assessing risk factors, used occupation AN OPERATING UNIT OP THE DOW CHEMICAL COMPANY as shown on the death certificates rather than as obtained through interview and therefore is a much less reliable assessment of BAS epidemiology. Even so, there is only the possibility of one case linked to geographic proximity to a FVC facility (no risk ratio provided) and several possible cases linked to low level VCM exposure at work. The following are areas of difficulty I see with the Kuzamack paper: (1) assessment of the consistency of the animal risk assessment models with human epidemiologic data across the dose-response curve, (2) the problem of discrimination between the alternative mathematical models (e.g., linear versus problt) based on existing data, (3) consistency of the mathematical models with biologic knowledge (e.g., knowledge about the metabolic activa tion requirements of VCM), (4) the assertion that HAS accounts for only one half the VCM induced cancers and, R&S 1 (3) applicability of the United States risk assessment to a situation in which the potential target population is o> oo o much smaller R&S 116806 -3- The validity of the extrapolation of rat data to humans (Kuzamack and MeCaughy) is based on crude estimates' of HAS risk from existing positive human occupational studies of highly** exposed VCM employees. Clearly, there is a correspondence in that both man and rodents evidence increased HAS risk with expo sure. The validation, however, is performed at only one point on the dose-response curve, and therefore, does not validate the correspondence at lower exposures (see Gehring et al. article for an. alternative approach to the extrapolation issue). There are now much more extensive human data than were available either to Kuzamack and MeCaughy or Gehring et al. Internationally, the number of VCM-related cases now exceeds 100. What has been remarkable is that most of the cases worked as autoclave cleaners at one time or another and that cases tended to cluster in certain plants. This would suggest that higher TWA exposures were experienced by the cases than the 350 ppm TWA assumed by Kuzamack and MeCaughy. It may also be that there is' a steep slope in the doseresponse curve. The issue facing the Alberta government is that of the nature of the dose-response curve at very low exposure intensities. Currently, there is no evidence in man that exposures below 1 ppm lead to HAS cases. Gehring et al. have shown that the number of predicted cases based on extrapolation to low level R&S 116807 4- exposure depends greatly on the model assumed (e.g., linear versus probit). Unfortunately, It Is difficult to distinguish between alternative models based on experimental data because sample sizes at low doses may be inadequate. The only test of a model model can come from a comparison of predictions with actual human experience at lower exposure intensities. This has not been formally done to my knowledge. 1 have included articles by Tamburro, Watanabe et al., and Guengerlch and Watanabe concerning the mechanism of action of VCM. It is evident that metabolic activation plays a role and that alternative metabolic pathways are available. The mathematical models proposed by Kuzamack and McCaughy simply do not consider these biologic issues. Recent articles by Theriault do not support the contention HAS accounts for only one half of the cancers induced by VCM. An important component of risk assessment is knowing the size of the population possibly at risk. In the United States, this was estimated to be in excess of 4 million people within a 5 mile radius of VCM or FVC plants. The number of people possibly at risk in Alberta must be much smaller than 4 million. This should be considered in the risk assessment. In summary, to my knowledge, epidemiologic evidence that people exposed to less than 1 ppm VCM are at increased risk of -5- developing HAS is lacking. Yet because of the signal tumor nature of HAS, such evidence would be relatively eas&y to develop. The regulatory actions are being contemplated based on extrapola tion of an-fTnal data via mathematical models to low level exposures rather than based on direct human evidence. While the objective is clearly to prevent any cases of VCM-induced HAS from occurring, it is unclear whether or not a more stringent ambient air standard will impact on the likelihood of such cases. *\ (^r 0} M* G* Ott Epidemiology, H&ES 1803 Building Midland, Michigan MGO/aag R&S 116808