Document 2jEX1kwvQ70mov9BJ0qkJB3E7

--** copied by MCA for distribution to the Vinyi Chloride Technical panel . and Research Coordinators, April 17, 1978, Mr, J. T. Seawell ' -Angiosarcoma of tha Liven An Epidemiol gic Survey '2 Judith Brady, B.S., * Rorinda Liberators,3 Philip Harper, B.S.,3 Peter Greenwaid, M.D., 4 William Burnett, M.O.,4 J. N. P. Davies, M.D., * Monica Bishop, M.D.. * Adele Polan, M.A., * and Nicholas Vienna, M.D. *1 ABSTRACT--Diagnosed Irom 1970 through 1975, the annual Incldnneo rata far angiosarcoma ol tha IIvor among resident* ot Net* York State (excluding Near York City) was 0.23 par million. A case-control study Indicated that direct exposure to arsenic, vinyl chloride (VQ, and thorium dioxide was a significantly Impor tant factor In tha etiology of this disorder (P<0.02). Direct ex posure to thaaa chemicals could not b* demonstrated for 19 (73%) ol the 25 study patlonts. The tact that 5 ot theso patients lived nearer to VC fabrication or polymerization plants than did their matched controls lent soma support to tho hypothesis that Indirect modes ot exposure, not specifically related to occupa tion, might bo Important In the etiology ol this disorder.--J Natl Cancer Inst 59: 1353-1383,1977. ASL. a rare vascular tumor (7), has been associated with exposure to ThO, (2, 3), As [used both in pesticides (4, S) and as a drug (Fowler'i solution--potassium aneoite) (5-4)]. and most recently, VC (9-13). Since most studies have centered around specific occupational groups, little is known about the actual incidence of ASL and the propor tion of cases that can be attributed to exposure to the above chemicals. This report evaluates each of these issues in a geographic-based population. METHODS Incidence study.--AH residents of. New York State (ex cluding New York City),1 who had ASL diagnosed from 1970 through 1975 and reported to the Tumor Registry of the Cancer Control Bureau, New York State Department of Health, were used in the incidence study. This 6-year period was selected because during this time the Registry estab lished a mechanism to improve reporting of cases through periodic examinations of the percent of cases accessioned in to the State Cancer Registry by death certificate only from specific regions and by an ongoing survey of hospital records. In addition, as a check on ascertainment, a list of all reported cases was compared with a list of patients who developed ASL in the same study area and time period and were derived from: 1) an ongoing survey of all pathologists, epidemiologists, cancer-referral centers, and tumor regis tries in the United States conducted by the Center for Disease Control, Atlanta. Georgia, and 2) case records on VC disease obtained from the Bureau of Industrial Hygiene, New York State Department of Labor, Albany. An overall annual incidence rate for the 6-year period was calculated with the use of the 1970 census population. Maleifemale ratios for ail patients were obtained and analyzed. Cost-control study.--All eases of ASL reported to the Tumor Registry among New York State residents IS yean of age or older and diagnosed from 1958 through 1975 were studied. For each patient, 1 matched control with an inter nal malignant tumor other than primary liver cancer was selected from the same registry by means of the following VOL. 59. NO. 5. NOVEMBER 1977 criteria: same 5-year age group at diagnosis, race. sex. coun ty of residence (when possible, the control was selected from the same minor civil division, as defined by the L'.S. Bureau of the Census. Washington, D.C. or the one of most similar population density and size within the county), and alive or dead status. When more than 1 individual matched the above criteria, a table of random numbers was used to select a control. Using a prepared questionnaire, field in vestigators obtained information concerning various ex posures (by occupations or hobbies) to hepatotoxic chemicals including VC. As. and ThO, for study patients and their matched controls. In addition, medical, familial, residential, and occupational histories of both groups were studied. Residential histories of all patients and controls up to the time of diagnosis were plotted on maps, indicating the geographic locations of all industrial complexes using Vc and/or As. Inquiries were also made with the New York State Department of Environmental Conservation, Albany, concerning the ambient emissions of these chemicals associated with all pertinent companies. Additional docu mentation of exposure was obtained from medical records, industrial reports, and on-site visits to residences of patients and controls and the industrial complexes with which they were associated. For statistical purposes, each subject and his/her matched control were dichotomized according to direct exposure (worked with or ingested VC.-arsenicals. or ThO,). The fre quencies of the two cells that show dissimilar exposure histories were tested with the use of the binomial (PmQ,m M) (14) in which Q. equals probability of failures. All instances in which d'rec? exposure to at least one of the above agents could not be documented for either a patient or control were excluded from statistical analyses. The histology slides for all patients included in the in cidence and case-control studies were reassessed and AiauvtATtOM isuc ASL-angiosarcoma of the liver; ThOj-thorium dioxide; As- sneak; VC - vinyi chloride. 1 Received February 15.1977; accepted June IS. 1977. * Supported in part by Public Health Service (rant CA12707 from the National Cancer Institute. 1 Bureau of Occupational Health and Chronic Disrate Retearch. New York State Department of Health, Empire State Plata. Tower Building. Albany. N.Y. 1SSS7. * Cancer Control Bureau. New York State Department of Health, Em pire State Plan. Tower Building. 1 Department of Pathology. Albany Medical College. Albany, N.Y. 12308. 1 Department of Pathology, Veteran Administration Hospital. Albany, N.Y.12208. 1 Address reprint requests to Dr. Nicholas Vianna. 1 New York City was ealuded from the incidence ttudy because reporting from this area was not required until 1973. y' f h` iT r 1 \'f*PB 1 VR*T" ucc 002790 1384 BRADY ET AL. diagnosed a* ASL by our panel of pathologists (Dr, J. N. P. Davies, Dr. M. Bishop) or by Dr. L. Thomas (National Cancer Institute. National Institutes of Health. Bethesda. Md.) and by Dr. H. Popper. (Mount Sinai Hospital. New York, N.Y.). Autopsy material on 12 patients in the in cidence study and on 19 in the case-control study was also examined. RESULTS Incidanca Study All 16 study patients with histologically confirmed ASL included in the incidence study were found in the Tumor Registry of the Cancer Control Bureau, when they were compared with lists of patients from the other two sources. The annual incidence rate for these patients (8 males and 8 females), whose ASL was diagnosed from 1970 through 1975, was 0.25 per million. The median age of all patients was 51 years (males, 61.5 yr; females. 38 yr), with a range from 4 months to 77 years; the maleTcmale ratio was l'-l. All the males were over 40 years of age. whereas half the females were under 40 years of age. Of the study patients, 14 were Caucasian; 1 was Oriental; and 1, Negro. Caso-Control Study In the study area from 1958 to 1975. 27 patients v-ich corfirmed ASL were identified in the Tumor Registry, Or. - p- tient. a 65-ycar-old male Caucasian with a doeurr.c-. history of chronic exposure to As pesticides, was c::ck'd'-d because histologic reassessment suggested a diagnosis r" pericytoma of the liver. Table 1 summarizes the demo graphic data and occupational and possible reiidcrd''1 ex posure histories of the 2G patients in this study. Seven pa tients (fll-7) had documented exposure to VC. As, or YhH_. for 16-60 years prior to diagnosis. There were 6 pairs o11,-.tients who were exposed and controls who were re: ex posed: however, no patients or controls had reverse o;;r 1 \ (r<0.02). Statistical analysis was limited to patients wit1, dr---. mented direct exposure; however, for C-G2 years >" diagnosis of their di*ease, 5 patients (dC-12) lived industrialised areas no mere than <'.,09 few. fabrication or polymerisation facte.-ics (table l). C ", * importance is the fact that the ambient emission. " r`. monomer for the factory located approximately l.Td from the recidc-icc of patient t`).0 were as hif i rs fT.r i ,, Table 1.--Dumagmphis data and expatunt histatyt of 28 Naui.Yorh.Stats rssidsnts wit''. S\SL: I95r ' thrsuz!s 3?Z -- Patient - Uo. 1 G4 C 2 32 C 3 54 C - ----------- - 4 - - -CO ... c . 3 40 c 0 47 7 52 c c ,^r0^, du^nosii 9 1973 cr 1953 <7 1968 <7 . 1970 <7 1931 cr 1973 cr 1938 oxposuro As As VC VC VC ThO, ThO, "Duration of = exposuva 1 before diagnosis, yr =60 =30 18 --30- IS 28 29 F.rf esura hi'tosy Direct: Dairy rarmor--frequently vorket with arjenwr' pastieides Commorchl cardonor--used arsenical pestici 'w Choinhrlopsrator^-VCraonoiT'^a sndpolyr'* u .. proseduras - Chemical cpsratot--supervisor of VC monomo-1 ' polymerization procedures . Chemical operate-/--polymerization preccdo-,(eHoncd ro-.etor tan'/) Given injer-'iona cf ThO,--ventrirulop-nnh'Givcnin-aefiennoi 1 hOg- ortr.iographr 8 43 c 9 1970 9 31 c 9 1974 10 62 c 9 1973 11 31 0 9 1972 12 <0 c 9 1935 13 47 N 1973 14 c cr 1974 15 J2 c cr I960 1G 17 O 63 c o 1959 c <7 1075 10 S3 c 9 1971 19 G7 c 9 1967 29 21 22 7710 45 c cr 1972 c 9 1974 c cr 1970 23 24 60 G3 c <7 1971 c or 1973 25 10 N 9 1970 28 60 c V 1939 Pooribl* locCimated distance from residence to VC i nVC^faetoryfc 22 4.599 feet 27 509 feet 62 1,709 foot 8 1,00 feat 15 d.fOO.ce: 4' i *C=*Cuejian: N "Negro; 0"Ori*nt*L " PVC"polyvinyl chloride. J NATL CASCO. INST VOL St. NO. 5. NOVEMBER 197' UCC 002791 ANGIOSARCOMA OF THE LIVER 1385 -' parts per million in 1975.* No pertinent exposure or residen tial history was obtained for 14 patients (#13-26, table 1) with ASL, despite interviews with all available relatives and employers. Although each patient and control lived within the same minor civil division, all controls resided more than l mile from all relevant plants. The distributions were similar for subjects and controls with regard to religion, marital status, years of education, occupation of spouse, travel history, prior liver disease, social history, exposure to drugs (including birth control pills), and familial history of cancer or liver disease. One patient (#14) and his matched control were alive and both were interviewed. In the other 25 instances, both the patient and control were deceased. In 18 instances, the spouses of both the subject and matched control were interviewed, whereas in the other 7 pairs, another first degree relative (sib, parent, or offspring) was contacted. Thus we made every effort to achieve com parable quality of information for patients and controls. Twenty-two (84.6%) of the 26 study patients lived in nine urban counties containing 52% of the State's population. Six of the 8 patients exposed to VC (#3, 4. 5, 8. 9. and 10) resided in two urban counties, whereas both documented exposures to As occurred in rural areas. direct support to the hypothesis that exposure outside the in dustrial setting is an important factor, but the few patients involved and the lack of information concerning the air levels of monomer around their residences severely limii in terpretation. Accordingly, this issue must be considered unresolved at present. Future studies should also evaluate the possibility that residents close to certain smelter-related industries and farms have an increased risk of developing ASL due to arsenical contamination of the air and soil. In a study of 10 patients with ASL in Wisconsin (17). 1 patient lived near a chemical company that made plastics and resin, and 7 pa tients lived on farms during their lifetimes. The marked male preponderance observed in this (17) and previous in vestigations (1, 11) has suggested the potential importance of occupational exposure. In out incidence study we ob served a sex ratio of unity, largely due to the high frequency of ASL in young adult females. This observation, if verified, can be interpreted as being consistent with the hypothesis that the hazards associated with certain occupations extend beyond the industrial plant. REFERENCES DISCUSSION Our results suggest that the rate for ASL in New York State, excluding New York City, might be greater than the expected annual incidence of 0.14 per million in the United States (13). Of greater importance is the observation that 19 of the 26 patients studied (73%) had no documented direct exposure to any of the three chemicals implicated in the etiology of this disorder. This finding raises the possibility that other toxic substances are involved and/or more in direct modes of exposure, not specifically related to occupa tion, play a major role. If one considers the first alternative, it might be important to evaluate other chemicals that cause fibrosis involving the liver and other organs and are hepatotoxic, features shared by As (6, 7), Thorotrast (J), and VC (1). Certain chlorinated hydrocarbons such as chloropropene, which are structurally similar to VC and are hepatotoxic. should also be examined. Interestingly, this and a previous study (13) suggest that alcoholism and prior liver disease do not predispose one to ASL. Although no proved cases of ASL have been found among workers not exposed to gaseous VC (16), Block (12) sug gested that this disorder results from chronic, low-level ex posure to this chemical. One way of evaluating this possibili ty is to determine whether subjects with ASL with no perti nent occupational history lived nearer to VC factories prior to the diagnosis of the disease than did their matched con trols. Although this finding is particularly true for polymerization plana, varying amounts of trapped gaseous VC are released upon heating* in the fabrication process. In this study, 5 people with ASL lived nearer to polymerization (patient #10) and fabrication plants (patients #8. 9. 11. 12) than did their matched controls. In addition, all 5 patients resided in these locations for long periods (8-62 yr) prior to ASL being diagnosed. These observations lend some in- * Information obtained from the New Vorlt State Department of En vironmental Conservation. (1) AlrEnga D: Primary angiosarcomas of th* liver. Ini Surg 60:198205, 1975 (2) McMahon HE. Murphy A5. Bates M; Endothelialcell sarcoma `of liver following ihoromst injections. Am J Pathol 25:585-595, 1947 (3) Da Silva Hosta J: Law lesions in man caused by colloidal thorium dioxide (Thorotrast); A new caae of sarcoma of the liver twenty-*wo yean after the injection. Arch Pathol 62:405-418,1956 (4) Roth F: Chrome arsenic poisoning in vineyard workers of the Moteile with ipecial reference to arsenic cancer. Z Krebsforch 61:287-519. 1956 (5) FiechTner JJ. Reyzs CN J: Angiosarcoma of the liver in a rural population: Four cates diagnosed in a 29 month period. JAMA 256:1704-1706,1976 (6) Landik JJ, Stanuy RJ, Sumner HW. et al: Angiosarcoma of liver associated with Fowler's solution (potassium anenite). Gastroen terology 66:1582-1586. 1975 (7) Regsuon W. Kim U. OjPIna J. et aL- Hemangioendothelial sarcoma of the liver from chronic arsenic intoxication by Fowler's solution. Cancer 21:514-522. 1966 (8) DalDERup LM, Freni SC, Bka* C, et al: Angiosarcoma of the liver. Lancet 1:246. 1976 (F) Catxot JL Jx. Johnson MN: Angiosarcoma of liver in the manufacture of polyvinyl chloride. J OccupMed 16:150-151.1974 (10) Lzi FI. Massy DS: Angiosarcoma of the liver in a vinyl chloride worker. Lancet 1:1516-1516.1974 (JI) Falk H, WaxwEILER R: Epidemiological studies of vinyl chloride health effects in the United States, Proc R Soc Med 69:505-505. 1976 (12) BLOCK JB: Angiosarcoma of the liver following vinyl chloride ex posure. JAMA 229:55-54. 1974 (13) Heath CW, Falk H, CxUCH JL Jr: Characteristics of cases of angiosarcoma of the liver among rinvl chloride workers in the United States. Ann NY Acad Sci 246:251-256, 1975 (14) SitciL S: The case of two rotated samples. In Non Parametric Statistics for Behavioral Sciences (Harlow H. ed). New York. Toronto. London: McGraw-Hill, 1956, pp 65-67 (15) Falk H. CRUOt JL Jr. HkaTH CW, et al: Hepatic disease smong worsen al a vinyl cmorale polymerisation plant. JAMA 250:59-65. 1974 (74) Mark L, Dilmoai F. Caiich JL Jr. ct al: Clinical and morpho logic features of hepatic angsoaarcoma in viny) chloride workers. Cancer 57:149-165. 1976 (77) FikCHTHtR J. Rrni C. RenTMEOTO K. et al: Epidemiologic notes and repons: Angiosarcoma of the Liver.-Wnconstn. Morbidity and Mortality Weekly Report, rol 25. Atlanta. Center for Disease Control. 1976. pp 57-56 VOL. 59. NO. S. NOVEMBER 1977 J NATL CANCER INST UCC 002792